WO 2005/044812 PCT/US2004/035280
DIHYDROBENZOFURANYL ALKANAMINE DERIVATIVES AS 5HT2C AGONISTS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present invention claims priority benefit of U.S. Provisional Application Serial No. 60/514,454, filed October 24,2003, which is incorporated herein by reference in its entirety for all purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to novel 1 -(2,3-dihydro-l-benzofuran-2-yl)alkanamine derivatives that act as agonists and partial agonists of the 5-HT2C receptor, processes for their preparation, and their use in medicine.
BACKGROUND OF THE INVENTION
[0003] Schizophrenia affects approximately 5 million people. The most prevalent treatments for schizophrenia are currently the 'atypical' antipsychotics, which combine dopamine (D2) and serotonin (5-HT2A) receptor antagonism. Despite the reported improvements in efficacy and side-effect liability of atypical antipsychotics relative to typical antipsychotics, these compounds do not appear to adequately treat all the symptoms of schizophrenia and are accompanied by problematic side effects, such as weight gain (Allison, D. B., et. al., Am. J. Psychiatry, 156: 1686-1696,1999; Masand, P. S., Exp. Opin. Pharmacother. I: 377-389,2000; Whitaker, R., Spectrum Life Sciences. Decision Resources. 2:1-9, 2000).
[0004] Atypical antipsychotics also bind with high affinity to 5-HT2C receptors and function as 5-HT2C receptor antagonists or inverse agonists. Weight gain is a problematic side

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effect associated with atypical antipsychotics such as clozapine and olanzapine, and it has been
sug jested that 5-HT2C antagonism is responsible for the increased weight gain. Conversely, stimulation of the 5-HT2C receptor is known to result in decreased food intake and body weight (Walsh et. al., Psychopharmacology 124: 57-73, 1996; Cowen, P. J., et. al., Human Psychopharmacology 10: 385-391,1995; Rosenzweig-Lipson, S., et. al., ASPET abstract, 2000).
[0005] Several lines of evidence support a role for 5-HT2c receptor agonism or partial agonism as a treatment for schizophrenia. Studies suggest that 5-HT2C antagonists increase synaptic levels of dopamine and may be effective in animal models of Parkinson's disease (Di Matteo, V., et. al., Neuropharmacology 37: 265-272,1998; Fox, S. H., et. al., Experimental Neurology 15_1: 35-49,1998). Since the positive symptoms of schizophrenia are associated with increased levels of dopamine, compounds with actions opposite to those of 5-HT2C antagonists, such as 5-HT2C agonists and partial agonists, should reduce levels of synaptic dopamine. Recent studies have demonstrated that 5-HT2C agonists decrease levels of dopamine in the prefrontal cortex and nucleus accumbens (Millan, M. J., et. al., Neuropharmacology 37: 953-955,1998; Di Matteo, V., et. al., Neuropharmacology 38:1195-1205,1999; Di Giovanni, G., et. al., Synapse 35: 53-61, 2000), brain regions that are thought to mediate critical antipsychotic effects of drugs like clozapine. However, 5-HT2C agonists do not decrease dopamine levels in the striatum, the brain region most closely associated with extrapyramidal side effects. In addition, a recent study demonstrates that 5-HT2C agonists decrease firing in the ventral tegmental area (VTA), but not in the substantia nigra. The differential effects of 5-HT2C agonists in the mesolimbic pathway relative to the nigrostriatal pathway suggest that 5-HT2C agonists have limbic selectivity, and wi] be less likely to produce extrapyramidal side effects associated with typical antipsychotics.
SUMMARY OF THE INVENTION
[0006] The present invention relates to certain dihydrobenzofuranyl alkanamine derivatives and to their use in medicine. In one aspect, the invention relates to novel l-(2,3-dihydro-l-benzofuran-2-yl)alkanamine derivatives that act as agonists or partial agonists of the 5-HT2C receptor. The compounds can be used, for example, to treat schizophrenia and the concomitant mood disorders and cognitive impairments of schizophrenia. Compounds of the present invention are preferably less likely to produce the body weight increases associated with current atypical antipsychotics. The compounds of the present invention can also be used for the treatment of obesity and its comorbidities.
[0007] In certain embodiments, the invention relates to compounds of Formula 1:
-2-

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Formula 1
or pharmaceutically acceptable salts thereof; wherein:
R and R' are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring;
alternatively R and R' can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen;
R1 and R2 are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms;
R3a and R3b are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms;
R4, R5, R6, and R7 are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and n is 1, 2 or 3;
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wherein at least one of R0, R0, R° and R' is branched alkyl of 3 to 8 carbon atoms,
branched alkenyl of 3 to 8 carbon atoms, or -Y-R8, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, 0, and NH and R8 is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and
wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms.
[0008] In certain other embodiments, the invention relates to methods for treating a patient suffering from schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, L-DOPA-induced psychosis, psychosis associated with Alzheimer's dementia, psychosis associated with Parkinson's disease, psychosis associated with Lewy body disease, dementia, memory deficit, intellectual deficit associated with Alzheimer's disease, bipolar disorders, depressive disorders, mood episodes, anxiety disorders, adjustment disorders, eating disorders, epilepsy, sleep disorders, migraines, sexual dysfunction, substance abuse, addiction to alcohol and various other drugs, including cocaine and nicotine, gastrointestinal disorders, obesity, or a central nervous system deficiency associated with trauma, stroke, or spinal cord injury that includes administering to the patient a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof.
[0009] In still other embodiments, the invention relates to compositions comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The present invention relates to novel l-(2,3,-dihydro-l-benzofuran-2-yl)alkanamine derivatives that are agonists or partial agonists of the 2c subtype of brain serotonin receptors.
[0011] The term "alkyl," as used herein, refers to an aliphatic hydrocarbon chain having up to 8 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. The term "alkyl" includes, but is not limited to, straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. In some embodiments, the alkyl group is preferably branched having 3 to 8 carbon atoms. The term "lower alkyl" refers to an alkyl group having 1 to 3 carbon atoms.
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[0012] The term "alkenyl," as used herein refers to an aliphatic straight or branched
hydrocarbon chain having 2 to 8 carbon atoms that may contain 1 to 3 double bonds. Examples of alkenyl groups include vinyl, prop-1-enyl, allyl, methallyl, but-1-enyl, but-2-enyl, but-3-enyl, or 3,3-dimethylbut-l-enyl. In some embodiments, the alkenyl is preferably a branched alkenyl of 3 to 8 carbon atoms. The term "lower alkenyl" refers to an alkenyl group having 1 to 3 carbon atoms.
[0013] The term "cycloalkyl," as used herein, refers to asaturated or partially saturated, hydrocarbon ring containing 3 to 8 carbon atoms and more preferably 5 to 7 carbon atoms. Cycloalkyl groups may be monocyclic or bicyclic, and more preferably monocyclic. Bicyclic cycloalkyl groups are preferably bridged. "Bridged" refers to a cycloalkyl group that contains at least one carbon-carbon bond between two non-adjacent carbon atoms of the cycloalkyl ring. "Partially saturated" refers to a nonaromatic cycloalkyl group containing at least one double bond and preferably one double bond. Preferably, the cycloalkyl group is saturated. The cycloalkyl group may be unsubstiruted or substituted as described hereinafter. The term "alkylcycloalkyl," as used herein, refers to the group -R-cycloalkyl, where cycloalkyl is as defined above and R is an alkyl moiety having 1 to 6, preferably 1 to 4, and more preferably 1 to 3 carbon atoms.
[0014] The term "heterocycloalkyl," as used herein, refers to a 3 to 8 membered, and more preferably 5 to 7 membered cycloalkyl group in which one to three carbon atoms of the cycloalkyl group are replaced with a heteroatom independently selected from oxygen, nitrogen, or sulfur. The heterocycloalkyl group may be saturated or partially saturated, and may be monocyclic or bicyclic (such as bridged). Preferably, the heterocycloalkyl is monocyclic. The heterocycloalkyl group may be unsubstiruted or substituted as described hereinafter.
[0015] The term "aryl," as used herein refers to a 5 to 10 membered carbocyclic aromatic ring. The aryl may be monocyclic or bicyclic, and may be substituted or unsubstituted. Monocyclic aryl groups preferably have 5, 6, or 7 members and bicyclic aryl groups preferably have 8, 9 or 10 members. Exemplary aryl groups include phenyl and naphthyl.
[0016] The term "aryloxy," as used herein, refers to the group Ar-O-, where Ar is an aryl group of 5 to 10 carbon atoms as previously described.
[0017] The term "heteroaryl," as used herein, refers to a 5 to 10 membered monocyclic or bicyclic carbon containing aromatic ring having 1 to 3 of its ring members independently selected from nitrogen, sulfur or oxygen. Monocyclic rings preferably have 5 to 6 members and bicyclic rings preferably have 8 to 10 membered ring structures. The heteroaryl group may be unsubstituted or substituted as described hereinafter. Examples of heteroaryls include, but are
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not limited to", thienyl, fiiryl, pyrroly], imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyi,
isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, or quinazolinyl.
[0018] The term "perfluoroalkyl," as used herein, refers to a straight or branched aliphatic hydrocarbon chain of 1 to 6 carbon atoms and preferably 1 to 3 carbon atoms, in which all hydrogens are replaced with fluorine.
[0019] The term "alkanamido," as used herein, refers to the group R-C(=O)-NH- where R is an alkyl group of 1 to 5 carbon atoms.
[0020] The term "alkanoyl," as used herein, refers to the group R-C(=O)- where R is an alkyl group of 1 to 5 carbon atoms.
[0021] The term "alkanoyloxy," as used herein, refers to the group R-C(=O)-O- where R is an alkyl group of 1 to 5 carbon atoms.
[0022] The term "alkanesulfonamido," as used herein, refers to the group R-S(O)2-NH-where R is an alkyl group of 1 to 6 carbon atoms.
[0023] The term "alkoxy," as used herein, refers to the group R-O- where R is an alkyl group of 1 to 6 carbon atoms.
[0024] The term "perfluoroalkoxy," as used herein, refers to the group R-0 where R is a perfluoroalkyl group of 1 to 6 carbon atoms.
[0025] The terms "monoalkylamino" and "dialkylamino," as used herein, respectively refer to -NHR and ~NRRa, where R and Ra are independently selected from an alkyl group of 1 to 6 carbon atoms.
[0026] The term "carboxamido," as used herein, refers to the group NH2-C(=O)-. [0027] The term "carboalkoxy," as used herein, refers to the group R-O-C(=O)- where R is an alkyl group of 1 to 5 carbon atoms.
[0028] The term "carboxy," as used herein, refers to the group -COOH. [0029] The terms "halogen" or "halo," as used herein, refer to chlorine, bromine, fluorine or iodine.
[0030] The term "substituted," as used herein, refers to a moiety, such as an aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety having from 1 to about 5 substituents, and more preferably from 1 to about 3 substituents independently selected from a halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms. Preferred substituents are a halogen atom, a
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lower alkyl, a perfluoroalkyl of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms or a
perfluoroalkoxy of 1 to 3 carbon atoms.
[0031] The terms "effective amount" and "therapeutically effective amount," as used herein, refer to the amount of a compound of Formula 1 that, when administered to a patient, is effective to at least partially treat a condition from which the patient is suffering from. Such conditions include, but are not limited to, schizophrenia, schizoaffective disorder, schizophremform disorder, L-DOPA-induced psychosis, bipolar disorder, obesity, obsessive compulsive disorder, depression, panic disorder, sleep disorders, eating disorders, and epilepsy. [0032] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" refers to salts derived from treating a compound of Formula 1 with an organic or inorganic acid such as, for example, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, or similarly known acceptable acids.
[0033] The term "patient," as used herein, refers to a mammal. [0034] The terms "administer," "administering," or "administration," as used herein, refer to either directly administering a compound or composition to a patient, or administering a prodrug derivative or analog of the compound to the patient, which will form an equivalent amount of the active compound or substance within the patient's body.
[0035] The terms "treat" or "treating," as used herein, refers to partially or completely alleviating, inhibiting, preventing, ameliorating and/or relieving the condition.
[0036] The terms "suffer" or "suffering" as used herein refers to one or more conditions that a patient has been diagnosed with, or is suspected to have.

Formula 1
or pharmaceutically acceptable salts thereof;
-7-
[0037] In certain embodiments, the invention relates to compounds of Formula 1:

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wherein:
R and R' are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to 6 carbons in the cycloalkyl ring;
alternatively R and R' can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen;
R1 and R2 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or perfluoroalkyl of 1 to 6 carbon atoms;
R3a and R3b are, independently, hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms;
R4, R5, R6, and R7 are, independently, hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated; and nisi, 2 or 3;
wherein at least one of R4, R5, R6 and R7 is branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, or -Y-R8, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH and R8 is aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl; and
wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or perfluoroalkoxy of 1 to 6 carbon atoms.
[0038] As set forth above, R and R' are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or alkylcycloalkyl of 4 to 12 carbon atoms having 3 to
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6 carbons in the cycloalkyl ring. Alternatively R and R' can be taken together with the nitrogen to which they are attached to form a ring containing 2-5 carbon atoms, wherein one of the ring carbon atoms is optionally replaced by nitrogen, sulfur or oxygen. In some embodiments, R, R', R1, and R2 are each, independently, hydrogen or alkyl of 1 to 6 carbon atoms. In certain embodiments, R' is hydrogen, and R, R1, and R2 are each independently hydrogen or alkyl of 1 to 6 carbon atoms. In certain preferred embodiments, each of R, R', R1, and R2 is hydrogen.
[0039] As also set forth above, R3a and R3b may each be selected, independently, from hydrogen, halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms. In certain embodiments, R3a and R3b are each independently hydrogen or alkyl of 1 to 3 carbon atoms and more preferably hydrogen.
[0040] R4, R5, R6, and R7 may each be selected, independently, from hydrogen, halogen, cyano, hydroxyl, carboxyl, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, aryl of 5 to 10 carbon atoms, aryloxy of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, alkenyl of 2 to 8 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, carboalkoxy of 2 to 6 carbon atoms, carboxamido, alkanamido of 2 to 6 carbon atoms, alkanesulfonamido of 1 to 6 carbon atoms, amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms per alkyl moiety, cycloalkyl of 3 to 8 carbon atoms, and 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen or sulfur, wherein the cycloalkyl and heterocycloalkyl groups are saturated or partially saturated. Moreover, at least one of R4, R5, R6 and R7 is -Y-R8, wherein Y is selected from a direct bond, lower alkyl, lower ankenyl, O, and NH, and R8 is an aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, 3 to 8 membered heterocycloalkyl, branched alkyl of 3 to 8 carbon atoms, or branched alkenyl of 3 to 8 carbon atoms. Additionally, where any of R4, R5, R6, and R7 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, it may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms.
[0041] In certain preferred embodiments, Y is a direct bond. [0042] In certain embodiments, R4, R5, R6, and R7 are preferably selected from hydrogen, halogen, alkyl of 1 to 8 carbon atoms, perfluoroalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, alkenyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, 3 to 8
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membered heterocycloalkyl, aryl of 5 to 10 carbon atoms, or 5 to 10 membered heteroaryl,
provided that at least one of R4, R5, R6 and R7 is an aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, 3 to 8 membered heterocycloalkyl, branched alky] of 3 to 8 carbon atoms, or branched alkenyl of 3 to 8 carbon atoms, wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms. Preferably, at least one of R4, R5, R6 and R7 and more preferably at least one of R4, RS and R7 is an aryl of 5 to 10 carbon atoms, 5 to 10 membered heteroaryl, cycloalkyl of 3 to 8 carbon atoms, or 3 to 8 membered heterocycloalkyl.
[0043] In certain preferred embodiments of the invention, R4, R5, and R6 are, independently, hydrogen, halogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, perfluoroalkyl of 1 to 3 carbon atoms, or perfluoroalkoxy of 1 to 3 carbon atoms, and R7 is a branched alkyl of 3 to 8 carbon atoms, branched alkenyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, 3 to 8 membered heterocycloalkyl, aryl of 5 to 10 carbon atoms, or 5 to 10 membered heteroaryl, wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, cyano, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms. More preferably, R7 is a branched alkyl of 3 to 6 carbon atoms, branched alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl of 5 to 10 carbon atoms, or 5 to 10 membered heteroaryl, each of which may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms.
[0044] In other preferred embodiments of the invention, each of R4, R5 and R7 is, independently, aryl of 5 to 10 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, or 5 to 10 membered heteroaryl, and more preferably is phenyl or napthyl, or a 5 to 10 membered heteroaryl selected from thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, or quinazolinyl, each of which may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms.
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[0045J In certain other preferred embodiments of the invention, R7 is aryl of 5 to 10
carbon atoms, cycloalkyl of 5 to 7 carbon atoms, branched alkyl of 3 to 6 carbon atoms, branched alkenyl of 3 to 6 carbon atoms, or 5 to 10 membered heteroaryl, and more preferably is phenyl or napthyl, or a 5 to 10 membered heteroaryl selected from thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, quinolyl, isoquinolyl, quinoxalinyl, or quinazolinyl, each of which may optionally be substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to 6 carbon atoms. In preferred compounds of this embodiment, R, R', R1, and R2 are each, independently, hydrogen or alkyl of 1 to 6 carbon atoms.
[0046] In other preferred embodiments, R7 is aryl of 5 to 10 carbon atoms, cycloalkyl of
5 to 7 carbon atoms, or 5 to 10 membered heteroaryl, or more preferably phenyl, wherein said
aryl (including phenyl), cycloalkyl or heteroaryl may optionally be substituted with 1 to 5
substituents independently selected from halogen, hydroxyl, alkyl of 1 to 6 carbon atoms,
perfluoroalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and perfluoroalkoxy of 1 to
6 carbon atoms. In preferred compounds of this embodiment, at least one of R4 and R5 is
halogen, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 3 carbon atoms, or alkoxy of 1 to 6
carbon atoms. Even more preferred compounds are those in which at least one of R4 and R5 is
halogen, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 3 carbon atoms, or alkoxy of 1 to 6
carbon atoms, and R, R', R1, and R2 are each, independently, hydrogen or alkyl of 1 to 6 carbon
atoms. In other preferred embodiments, R7 is aryl of 5 to 10 carbon atoms, optionally substituted
with 1 to 3 substituents independently selected from a halogen atom, a lower alkyl, a
perfluoroalkyl of 1 to 3 carbon atoms, an alkoxy group of 1 to 3 carbon atoms or a
perfluoroalkoxy of 1 to 3 carbon atoms.
[0047] In certain embodiments, R7 is selected from from the group consisting of: 4-methoxy-2-methylphenyl, 2-chloro-4-(trifluorornethyl)phenyl, 2-chloro-4-methoxyphenyl, 2-chloro-4-(trifluoromethoxy)phenyl, ({7-[4-methoxy-2-(trifluoromethyl)phenyl, 4-ethoxy-2-methylphenyl, 4-ethoxy-2-(trifluoromethyl)phenylamine, 4-chloro-2-(trifluoromethyI)phenyl,
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4-fluro-2-(trifluromethyl)phenyl,
2-ethyl-4-methoxyphenyl,
2,4-dichlorophenyl,
2,4-dimethylphenyl,
4-isopropyl-2-methoxyphenyl,
4-isopropoxy-2-(trifluoromethyl)phenyl,
2-chloro-4-isopropoxyphenyl,
4-chloro-2-methyIphenyl,
2,6-difluorophenyl,
2-chloro-6-fluorophenyl,
2-fluoro-6-(trifluoromethyl)phenyl,
2,6-bis(trifluoromethyl)phenyl,
2,3-dichlorophenyl,
3 -chloro-2-fluorophenyl,
2-chloro-3-methylphenyl,
2,6-dichloro-4-methoxyphenyl, and
5-fluoro-2-methoxyphenyl.
[0048] In the compounds of the present invention, n is 1, 2 or 3, preferably 1 or 2, and
more preferably 1.
[0049] In still further preferred embodiments of the invention, the compounds of
Formula 1 are:
(±)-1 -(4-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine, (+)-1 -(4-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine, (-)-1 -(4-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine, (±)-l-[4-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (+)-l-[4-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (-)-1 -[4-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamme, (±)-(7-cyclopentyl-2,3-dihydro-l-benzofuran-2-yl)methylamine, (-)-(7-cyclopentyl-2,3-dihydro-l-benzofuran-2-yl)methylamine, (+)-(7-cyclopentyl-2,3-dihydro-1 -benzofuran-2-yl)methylamine, (±)-(5-ch]oro-7-cyclohexyl-2,3-dihydro-l-benzofuran-2-yl)methylamine, (±)-N-[(5-chloro-7-cyclohexyl-2,3-dihydro-l-benzofuran-2-yl)methyl]-N-methylamine, (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-l-benzofuran-2-yl)methylamine, (±)-(7-isopropyl-2,3-dihydro-l-benzofuran-2-yl)methylamine,
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(-)-(7-isopropyl-2-3-dihydro-l-benzofuran--yl)methylamine,
(+)-(7-isopropyl-2,3-dihydro-l-benzofuran-2-yl)methylamine,
(±)-l-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(-)-l-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(+)-l-(5-chIoro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(±)-l-(7-tert-butyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(-)-l-(7-tert-butyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(+)-l -(7-tert-butyl-2,3-dihydro-l -benzofuran-2-yl)methanamine,
(±)-l-(7-tert-butyl-5-chloro-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(-)-1 -(7-tert-butyl-5-chloro-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(+)-1 -(7-tert-butyl-5-chloro-2,3-dihydro-l -benzofuran-2-yl)methanamine,
(±)-(6-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(±)-l-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(±)-l-[7-(l-naphthyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 -[7-(3-chloro-4-fluorophenyl)-2,3-dihydro- l-benzofuran-2-yl]methanamine,
(±)-l-[7-(3,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 -(7-phenyl-2,3 -dihydro-1 -benzofuran-2-yl)methanamine,
(+)-(l-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine,
(-)-l-(7-phenyl-2,3-dihydro-l-benzofiiran-2-yl)methanamineJ
(±)-l-[7-(2-naphthyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l -(2',3'-dihydro-2,7'-bi-l -benzofuran-2'-yl)methanamine,
(±)-l-[7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-1 -[7-(3-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-l-(7-thien-3-yl-2,3-dihydro-l-benzoforan-2-yl)methanamine,
(+)-l-(7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(-)-1 -(7-thien-3-yl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(±)-l-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-1 -[7-(2-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(-)-1i -[7-(2-fluorophenyl)-2,3 -dihydro-1 -benzofliran-2-yl]methanamine,
(±)-l-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
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(-)'-l-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yJ}methanamine,
(+)-l-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(±)-l-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-1 -[7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-l-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[7-(2-isopropyIphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylamine,
(+)-[7-(2-isopropylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylamine,
(-)-[7-(2-isopropylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylamine,
(±)-l-[7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(3-methoxyphenyI)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(±)-1 -[7-(4-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-l-[7-(4-methylphenyl)-2,3-dihydro-l-ben2ofuran-2-yl]methanamine,
(-)-1 -[7-(4-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-l-[7-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]raethanamine,
(-)-l-[7-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(4-chlorophenyl)-213-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l - {7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-l -benzofuran-2-yl} methanamine,
(±)-1 - [7-(2,4-dichlorophenyI)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine,
(+)-1-(5-chloro-7-phenyl-2,3-dihydro-l-ben2ofuran-2-yl)methanamine,
(-)-l-(5-chloro-7-phenyl-2,3-dihydro-l-ben2ofuran-2-yl)methanamine,
(±)-l-[5-chloro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
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(±)-1-[5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine
(±)-l-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylamine, (-)-(5-chloro-7-thien-3-yl-2,3-dihydro-l-ben2ofuran-2-y])methylamine, (+)-(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylamine, (+)-N-[(5-ch]oro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]-N-methylamine, (-)-N-[(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]-N-methylamine, (±)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, (+)-l-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (-)-l-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (±)-l-(4-fluoro-7-phenyl-2,3-dihydro-l-benzofluran-2-yl)methanamine, (±)-l -[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofixran-2-yl]methanamine, (±)-l-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methanamine, (+)-1 -[7-(2-chlorophenyl)-5-fluoro-2,-3-dihydro-1 -benzofliran-2-yl]methanamine, (-)-1 -[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methanamine, (±)-l-(5-fluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methanamine, (±)-l-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanainine, (+)-l-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (-)-l -[5-fluoTo-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine, (±)-l-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (±)-l-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine, (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methylamine, (±)-1 -[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine, (±)-l-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methanamine, (±)-(5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylamine, (±)-(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-l-ben2ofuran-2-yl)methylamine, (-)_1 -(7-tert-butyl-5-methoxy-2,3 -dihydro-1 -benzofuran-2-yl)methanamine, (+)-l-(7-tert-butyl-5-methoxy-2,3-dihydro-l-benzofuran-2-yl)methanamine, (±).l-{7-[(lE-3,3-dimethylbut-l-enyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine, (±)-l-[7-(3,3-dimethylbutyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (±)-l-[4-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (±)-l-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine, (-)-1 - {4-[2-(trifluoromethyl)phenyl}-2,3-dihydro-1 -benzofuran-2-yl }methanamine, (+)-l-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
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(±)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[4-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (-)-l-[4-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (+)-l-[7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yI]methanamine, (-)-l-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (+)-l-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (+)-1 -[7-(3-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine, (-)-l-[7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (+)-l-[7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (-)-l-[7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (-)-l-{7-[3-(trifiuoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine, (+)-l - {7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l -benzofuran-2-yl}methanamine, (+)-l-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine, (-)-1 - {7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-l -benzofuran-2-yl} methanamine, (±)-l-[7-(2,6-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (±)-l-[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (-)-l-[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (+)-l-[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (±)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (-)-1 -[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine, (+)-l-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (±)-1 -[7-(2,4-difluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine, (+)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine, (-)-l-[7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (-)-l-[7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (+)-l-[7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (-)-l-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine, (+)-l-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanainine, (±)-1 -(7-benzyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine, (+)-1 -(7-benzyl-2,3-dihydro-1 -benzofliran-2-yl)methanamine, (-)-1 -(7-benzyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine, (±)-l-{7-[(E)-2-phenylvinyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine, or (±)-l-[7-(2-phenylethyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, or a pharmaceutically acceptable salt thereof.
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[0050]' In other preferred embodiments of the invention, the compounds of Formula 1
art
(±)-l-[7-(2,3-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-{[7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(-)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(-)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,4,6-trichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(5-chloro-2-methylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- [(7-pyridin-3 -yl-2,3 -dihydro-1 -benzofuran-2-yl)methyl] amine,
(+)-{[7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-N-[2-(aminomethyI)-2,3-dihydro-l-benzofuran-7-yl]-N-phenylamine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(4-methylphenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(4-chlorophenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(4-methoxyphenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-[4-(trifluoromethyl)phenyl]amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(4-fluorophenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(3,4-dichlorophenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(2,4-dimethylphenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(3,4-dimethylphenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(3-methylphenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(3-fluorophenyl)amine,
(±)-N-2-(aminomethyl)-N-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-7-amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-ben2ofuran-7-yl]-N-(4-methoxy-3-methylphenyl)amine,
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(±}-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(3-trifluoromethoxy)phenyl]amine,

(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(3-trifluoromethoxy)phenyl]amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(3-chloro-4-methylphenyl)amine,
(±)-N-[2-(aminomethyl)-2)3-dihydro-l-benzofuran-7-yl]-N-(3,5-dichlorophenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(3-chlorophenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(4-chloro-3-methylphenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(3,5-dimethyIphenyl)amine,
(±)-N-[2-(aminomethyl)-23-dihydro-l-benzofuran-7-yl]-N-(3-chloro-4-fluorophenyl)amine,
(±)-N-[2-(aminomethyl)-2,3-dihydro-l-benzofuran-7-yl]-N-(2-fluorophenyl)amine,
(±)- {[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[5-fluoro-7-(3-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methy]} amine,
(±)-{[5-fluoro-7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(±)- {[5-fluoro-7-(3-methylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[5-fluoro-7-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(±)- {[5-fluoro-7-(4-chlorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)- {[5-fluoro-7-(4-methylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)- {[5-fluoro-7-(4-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-[(5-fluoro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(±)-{[5-fluoro-7-(3-furyl)-2,3-dihydro-l-benzoifuran-2-yl]methyl}amine,
(±)-[(5-fluoro-7-pyridin-2-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(±)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(-)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(+)-{[5-fluoro-7-pyridin-3-yl-2,3-dihydro-l-ben2ofuran-2-yl]methyl} amine,
(±)-[(5-fluoro-7-pyridin-4-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(±)-[(5-fluoro-7-pyrimidin-5-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(±)-{[7-(2,3-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,4-difluorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(_).{[5.fluoro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[5-fluoro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,4-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
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(±)-{[7-(2,5-difluoropheriyl)-5-fluof6-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-fluoro-7-(5-methoxy-2-methylpheny])-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,6-difluorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzoforan-2-
yl]methyl} cyclopropanamine, (±)-l-cyclopropyl-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-
yl]methyl} methanamine, (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-
yl]methyl} cyclobutanamine,
(±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzoftiran-2-yl]methyl}ethanamine, (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}propan-l-
amine, (±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}propan-2-
amine,
(±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl} dimethylamine, (±)-l-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}piperidine (±)-1 - {[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl} morpholine (±)-l-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}pyrrolidine (±)-{[5-chloro-7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[5-chloro-7-(3-furyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (-)-{[5-chloro-7-(2,3-difluoropheny])-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (+)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}ainine, (±)- {[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
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(±)- {[5-chloro-7-(2,3-dimethoxyyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(-)- {[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(+)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-l -benzofuran-2- yl]methyl} amine,
(±)- {[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)- {[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yI]methyl} amine,
(±)-{[5-chloro-7-(2,6-dimethylphenyI)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzonaran-2-yl]methyl}amine,
(+)-{[5-chloro-7-(2,)5-dimethylphenyl)-2,3-dihydro-l-benzofiaran-2-yl]methyl}amine,
(±)- {[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(+)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(-)- {[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[(5-chloro-7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} cyclopropanamine, (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}(cyclopropylmethyl)amine, (±)-N- {[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl}cyclobutanamine,
(±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}ethanamine? (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}propan-2-
amine,
(±)- {[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} dimethylamine, (±)-l - {[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl}piperidine (±)-4-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}morpholine (±)-4-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}thiomorpholine (±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}propan-l-
amine, (±)-l-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methy]}piperazine
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(±)-1-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} pyrrolidine
(±)-{[(5-methyl-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(±)-{[7-(2-methylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2-chlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-({5-methyl-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl)amine,
(±)- {[7-(3-chlorophenyl)-5-methyl-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)- {[7-(3-methylphenyl)-5-methyl-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[7-(4-methylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(4-fluorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[ 7-(4-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl} amine,
(±)- {[7-(4-methoxyphenyl)-5-methy]-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzoifuran-2-yl]methyl}amine,
(-)- {[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,4-dichIorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(+)- {[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-ethyl-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-ethyl-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-isopropyl-7-(2-methylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[5-isopropyl-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-cyclopentyl-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-cyclopentyl-7-(2-chIorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[5-isocyano-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-isocyano-7-(2-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-(trifluoromethyl)-7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
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(±)- {[5-(trifluoromethyl)-7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,,
(±-}-{[5-(trifluoromethyl)-7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[5-(trifluoromethyl)-7-(2-(trifluoromethyl)phenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(3-methylphenyl)-2,3-dihydro-l-ben2ofuran-2-yl]methyl}amine, (±)-{[5-(trifluoromethyl)-7-(3-fluoropheny])-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[5-(trifluoromethyl)-7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[5-(trifluoromethyl)-7-(3-methoxyphenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}amine, (±)-{[5-(trifluoromethyl)-7-(3-(trifluoromethyl)phenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[5-(trifluoromethyl)-7-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}aniine, (±)-{[5-(trifluoromethyl)-7-(4-chIorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)- {[5-(trifluoromethyl)-7-(4-methoxyphenyl)-2,3-dihydro-l -benzofliran-2-yl]methyl} amine, (±)-{[5-(trifluoroniethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydro-l-ben2ofuran-2-
yl]methyl) amine,
(±)- {[7-(2,3-dimethylphenyl)-5-(trifluoromethyl)-2,3-dihydro-l -benzofuran-2-yljmethyl} amine, (±)-{[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine, (±)-{[7-(2,3-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)- {[7-(2,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine, (±)-{[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)-{[7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)- {[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine, (±)-{[7-(2,5-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[7-(2,6-dimethylphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[7-(4-butylphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-4-[2-(aminomethyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-7-yl]benzonitrile (±)-{[7-(3-furyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)- {[7-thien-3-yl-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
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WO 2005/044812 PCT/US2004/035280
(±)4[7-pyridin-3-yl-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]rnethyl}amine, (±)-[(5,7-diphenyl-2,3-dihydro-l-benzofuran-2-yI)methyl]amine, (±)-{(7-(2-chlorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-y]]methyI}amine, (±)-{[7-(3-chlorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[7-(4-chlorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}arnine, (±)- {[7-(2-fluorophenyl)-5-phenyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine, (±)-{[7-(3-f]uorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)- {[7-(4-fluorophenyl)-5-phenyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine, (±)-{[7-(2-methylphenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl} amine, (±)-{[7-(3-methylphenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyI}amine, (±)-{[7-(4-methylphenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[7-(2,4-difluorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}arnine, (±)-{[7-(2,5-dichlorophenyl)-5-phenyI-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[7-(2-chIorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)- {[7-(2-methyIphenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine, (±)-{[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[5-methoxy-7-(3-thienyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine, (±)- {[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-1 -benzoftiran-2-yl]methyl} amine, (±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)- {[7-(2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-1 -benzofliran-2-yl]methyl} amine, (±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[7-(2,4-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl} amine, (±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl} amine, (+)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (-)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofliran-2-yl]methyl}amine, (±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzoniran-2-yl]methyl}amine, (±)-{[7-(2,5-dimethoxylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yI]methyl} amine, (±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl} amine, (±)- {[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-ylJmethyl} amine, (±)- {[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l -benzofuran-2-yl]methyl} amine, (±)- {[7-fluoro-5-(2-methylphenyl)-2,3-dihydro-l -benzofliran-2-yl]methyl} amine, (±)-{[7-fluoro-5-(2-chlorophenyl)-2,3-dihydro-l-benzoniran-2-yl]methyl}amine,
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WO 2005/044812 PCT/US2004/035280
(±)-({7-fluoro-5-[2-(fluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl)amine,
(±)-({7-fluoro-5-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl)amine,
(±)-{[7-fluoro-5-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-fluoro-5-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-fluoro-5-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-fluoro-5-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-({7-fluoro-5-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl)amine,
(±)-{[7-fluoro-5-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-fluoro-5-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-fluoro-5-(4-chlorophenyl)-2,3-dihydxo-l -benzofuran-2-yl]methyl} amine,
(±)-{[7-fluoro-5-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-({7-fluoro-5-[4-(trifluorornethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl)amine,
(±)-{[7-fluoro-5-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}ethanamine,
(±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}cyclopropanamine,
(±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}cyclobutanamine,
(±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}propan-2-amine,
(±)- {[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(+)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)- {[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[{[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[6-chloro-7-(2-methylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)- {[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[6-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzoftiran-2-y]]methyl}methylamine,
(±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-[(N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-N-methyl-l-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yI]methanamine,
(+)-N-methyl-1 -[7-(2-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(-)-N-methyl-l -[7-(2-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
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(±)-[(N-methyl-l-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyI-l-[7-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyI-1-[7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,3-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methananiine,
(±)-[(N-methyl-l-[7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,5-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-N-methyl-l-(7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(±)-[(N-methyl-l-[7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-{[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-fluoro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} methylamine,
(.). {[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} methylamine,
(+)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
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(±}-{[7-(2,4-difluorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±}-{[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methy]amine,
(+)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyI}methylamine,
(-)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methyIamine,
(±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine, (±)- {[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-1 -benzofuran-2-
yl] methyl} methyl amine, (±)-{[7-(5-chloro-2-methoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-
yljmethyl} methylamine,
(±)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]methylamine, (±)-[(5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylarnine, (±)- {[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine, (±)-[(5-chloro-7-(2-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine, (±)-{[5-chIoro-7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} methylamine, (±)-{[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} methylamine,
(±)-{[5-chloro-7-(3.4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)- {[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-l -benzofuran-2-yl]methyl} methylamine, (±)-{[7-(2-chlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl} methylamine, (±)-{[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
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(±)-{[7-(3-methylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(3-chlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(4-methylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methy]amine,
(±)-{[7-(4-chlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(4-fluorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]rnethyl}methylamine,
(±)-{[7-(4-methoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,4-dichIorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yI]methyl} methylamine,
(±)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]raethyl}methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-ylJmethyl}methylamine,
(±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine?
(±)-{[7-(2,3-dimethylpheny])-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-l-ben2ofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-difluorophenyl)-5-methoxy-2)3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-y]]methyl}methylamine,
(±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methy]amine,
(±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl} methylamine, (±)-{[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl} methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[7-(2-chlorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[7-(3-chlorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[7-(4-chlorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[7-(2-fluorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[7-(3-fluorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-ylJmethyl}methylamine,
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(±)-{[7-(2-methylphenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methy]amine,
(±)-{[7-(2-methylphenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methy]amine,
(±)-{[7-(3-methylphenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(4-methylphenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methyIamine,
(±)-{[7-(2-methoxyphenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(3-methoxyphenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(4-methoxyphenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,4-difluorophenyl)-5-phenyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methy]amine,
(±)-{[N-methyl-l-[7-phenyl-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-N-methyl-l-[7-(3-methylphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
y]]methanamine, (±)-N-methy]-l-[7-(3-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methanamine, (±)-N-methyl-l-[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methanamine, (±)-N-methyl-1-[7-(3,4-difIuorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-
yl]methanamine, (±)-N-methyl-l-[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methanamine, (±)-N-methyl-l -[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-
yl]methanamine, (±)-{[7-(3-chIoro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} methylamine, (±)-N-methyl-1-[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-
y]]methanamine, (±)-{[7-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-fluoro-5-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[7-fluoro-5-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{[7-fluoro-5-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (±)-{7-fluoro-5-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-
yl} methyl)methylamine,
(±)-{7-fluoro-5-[2-methoxyphenyl]-2,3-dihydro-l-ben2ofuran-2-yl}methyl)methylamine, (±)-{7-fluoro-5-[3-methylpheny]]-2,3-dihydro-l-benzofuran-2-yl}methyl)methylamine,
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(±) - {[7-fluoro-5-(3-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine, (±) - {[7-fluoro-5-(3-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine, (±)-{7-fluoro-5-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-
yl} methyl)methylamine,
(±)-{7-fluoro-5-[3-methoxyphenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl)methylamine, (±)-{7-fluoro-5-[4-methylpheny]]-2,3-dihydro-l-ben2ofuran-2-yl}methyl)methylamine, (±)-{7-fluoro-5-[4-chlorophenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl)methylamine, (±)-{[7-f]uoro-5-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methy]amine, (±)-{7-fluoro-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-
yl} methyl)methyl amine,
(±)-{7-fluoro-5-[4-methoxyphenyl]-2,3-dihydro-l-benzofuran-2-yl}methyI)methylamine, (+){[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (-){[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (R)-[7-(2-chloro-phenyl)-(5-Fluoro-2,3-dihydro-benzofuran-2-yImethyl)methyl-amine, (R)-[7-(2,6-dichloro-phenyl)-5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl]ethylamine, (R)-[7-(2,6-dichloro-phenyl)-5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl]dimethylamine, {[(2R)-7-(5-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, {[(2R)-7-(4-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (-)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (+)-{[7-(2,6dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine, (±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]ethyl} amine, (±)-{2-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]ethyl}amine, (±)-{2-[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]ethyl}amine, (±)- {N-methyl-1 -[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine, (+)- {N-methyl-1 -[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine, (-)-{N-methyl-l-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine, (+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2)3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (-)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (-)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (+)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (+)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylarmine, (-)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methy]}methylamine, (-)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methy]}methylamine,
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WO 2005/044812 PCT/US2004/035280
(+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]rnethyl}methylamine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine, (-)- {[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine, or (+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine; or a pharmaceutically acceptable salt thereof.
[0051] The compounds of Formula 1 have affinity for and agonist or partial agonist activity at the 2c subtype of brain serotonin receptors and are thus of interest for the treatment of mental disorders, including psychotic disorders such as schizophrenia including paranoid type, disorganized type, catatonic type, and undifferentiated type, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, and psychotic disorder not otherwise specified; L-DOPA-induced psychosis; psychosis associated with Alzheimer's dementia; psychosis associated with Parkinson's disease; psychosis associated with Lewy body disease; bipolar disorders such as bipolar I disorder, bipolar II disorder, and cyclothymic disorder; depressive disorders such as major depressive disorder, dysthymic disorder, substance-induced mood disorder, and depressive disorder not otherwise specified; mood episodes such as major depressive episode, manic episode, mixed episode, and hypomanic episode; anxiety disorders such as panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, substance-induced anxiety disorder, and anxiety disorder not otherwise specified; adjustment disorders such as adjustment disorders with anxiety and/or depressed mood; intellectual deficit disorders such as dementia, Alzheimer's disease, and memory deficit; eating disorders (e.g., hyperphagia, bulimia or anorexia nervosa) and combinations of these mental disorders that may be present in a mammal. For example, mood disorders such as depressive disorders or bipolar disorders often accompany psychotic disorders such as schizophrenia. A more complete description of the aforementioned mental disorders can be found in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Washington, DC, American Psychiatric Association (1994), incorporated herein by reference in its entirety.
[0052] The compounds of formula 1 are also of interest for the treatment of epilepsy; migraines; sexual dysfunction; sleep disorders; substance abuse, including addiction to alcohol and various drugs, including cocaine and nicotine; gastrointestinal disorders, such as malfunction of gastrointestinal motility; and obesity, with its consequent comorbidities including Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers, some infertility, and early mortality.
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[0053] The compounds ot formula 1 can also be used to treat central nervous system
deficiencies associated, for example, with trauma, stroke, and spinal cord injuries. The compounds of Formula 1 can therefore be used to improve or inhibit further degradation of central nervous system activity during or following the malady or trauma in question. Included in these improvements are maintenance or improvement in motor and motility skills, control, coordination and strength.
[0054] In certain embodiments, the present invention therefore provides methods of treating, each of the conditions listed above in a patient, preferably in a human, the methods including administering a therapeutically effective amount of at least one compound of Formula 1 or a pharmaceutically acceptable salt thereof to a patient suffering from such a condition.
[0055] In other embodiments, the invention relates to compositions comprising at least one compound of Formula 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions include pharmaceutical compositions for treating or controlling disease states or conditions of the central nervous system. In certain embodiments, the compositions comprise mixtures of one or more compounds of Formula 1.
[0056] Certain of the compounds of Formula 1 contain stereogenic carbon atoms or other chiral elements (i.e. chirality axis) and thus give rise to stereoisomers, including enantiomers, diastereomers, and in the case of biphenyls, the formation of atropisomers. For definitions and an extensive discourse on atropisomers, see: Eliel, E.L. Stereochemistry of Organic Compounds (John Wiley & Sons, 1994, p 1142), which is incorporated herein by reference in its entirety. Although the stereochemistry is not shown in Formula 1, Formula 1 includes all of the stereoisomers of the l-(2,3-dihydro-l-benzofuran-2-yl)alkanamine derivatives, as well as mixtures of the stereoisomers. Throughout this application, the name of the product, where the absolute configuration of an asymmetric center is not indicated, is intended to embrace the individual stereoisomers as well as mixtures of stereoisomers. When it is necessary to distinguish the enantiomers from one another and from the racemate, the sign of the optical rotation [(+), (-) and (±)] is utilized. Furthermore, throughout this application, the designations R* and S* are used to indicate relative stereochemistry, employing the Chemical Abstracts convention which automatically assigns R* to the lowest numbered asymmetric center.
[0057] Where a stereoisomer is preferred, it may, in some embodiments, be provided substantially free of the corresponding stereoisomer. Thus, a stereoisomer substantially free of the corresponding stereoisomer refers to a compound that is isolated or separated via separation techniques or prepared free of the corresponding stereoisomer. "Substantially free," as used
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herein, means that the compound is made up of a significantly greater proportion of one
stereoisomer. In preferred embodiments, the compound is made up of at least about 90% by weight of a preferred stereoisomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred stereoisomer. Preferred stereoisomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred stereoisomers can be prepared by methods described herein. Methods for the preparation of preferred stereoisomers are described, for example, in Jacques, et al., Enantiomers. Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972), each of which is hereby incorporated by reference in its entirety.
[0058] This invention alsoprovides processes for preparing compounds of formula I which processes include one of the following:
a) reacting a compound of formula 7

wherein R1, R2, R3, R4, R5, R6,and R7 are as defined herein, with sodium azide and reducing the
product to give a compound of formula 1 wherein n is 1 and R and R' are both H;
or
b) reacting a compound of formula 7 as defined above with an amine of formula NHRR' where R and R' are as defined herein to give a corresponding compound of formula 1 wherein n is 1; or
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c) reacting a compound of formula 7 as defined above with sodium cyanide followed by
reduction to give a compound of formula I wherein n is 2 and R and R' are both H;
d) converting a compound of formula 1 as defined herein to a pharmaceutically acceptable
salt or vice versa;
or
e) isolating a specific enantiomer or diastereomer of a compound of formula 1 or a
pharmaceutically acceptable salt thereof as defined herein from a mixture thereof.
The l-(2,3-dihydro-l-benzofuran-2-yl)alkanamine derivatives of Formula 1 maybe prepared as illustrated in Scheme I.
Scheme I

Proc. A: ! a) NaN3, DMSO and b) reduction, or 2. NHRR'/DMSO Proc B: 1. a) NaCN/DMSO and b) H2/5% Rh on A12O3, NH4OH
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10059] Variables used are as defined for Formula 1, unless otherwise noted. The
appropriately substituted phenol (2) is alkylated with an appropriately substituted allyl bromide or alcohol (3) in the presence of a suitable base such as potassium carbonate in a solvent such as N,N-dimethylformamide. The phenols, allyl bromides, and allyl alcohols appropriate for the synthesis of the compounds of formula I are either commercially available or can readily be prepared by one skilled in the art. The resulting allyl ether (4) is treated in refluxing mesitylene or other suitable high boiling solvent to afford the desired Claisen rearrangement product. The 2-allyl phenol (5) intermediate is subjected to epoxidation of the double bond with 3-chloroperoxybenzoic acid in dichloromethane. The resulting epoxy phenol intermediate is treated with a suitable base such as potassium carbonate in a solvent such as methanol to induce cyclization to give the 2,3-dihydro-l-benzofuran-2-yl)methanol (6). Treatment of (6) with p-toluenesulfonyl chloride and a suitable base such as pyridine affords the tosylate (7). Conversion of (7) to the amine (1) can be accomplished, for example, by treatment with sodium azide in a solvent such as dimethylsulfoxide followed by reduction of the azide or direct treatment with an appropriately substituted amine to provide the compounds of Formula 1. Additionally, longer alkyl chains (i.e. 2-aminoethyl) may be prepared, for example, via treatment of (7) with sodium cyanide in a solvent such as dimethylsulfoxide followed by reduction of the nitrile.
[0060] The preparation of appropriately substituted phenols (2) in Scheme I, in particular the 7-aryl substituted phenols, is illustrated in Scheme Ia.

Scheme la
[0061] Utilization of a 2-halogenated methoxy benzene or a suitably protected 2-halogenated phenol (2a) permits the introduction of the aromatic substitutent through a palladium-catalyzed cross coupling reaction (i.e Suzuki reaction) with the desired boronic acid. Treatment of (2a) with a catalyst such as dichlorobis(tri-o-tolylphosphine)-palladium(II) in the presence of a suitable base such as potassium carbonate in a solvent such as dioxane provides the biaryl system. Subsequent removal of the protecting group, in this example demethylation of (2b) via reaction with borontribromide in dichloromethane affords the phenol (2).
[0062] Alternatively, the phenols (2) may be prepared by a reversal of the inherent reactivity associated with the partners in the cross-coupling reaction as shown in Scheme Ib.
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[0063] Installation of the biaryl system may also be accomplished via a palladium-catalyzed cross coupling reaction (i.e Suzuki reaction) of appropriate derivatives of 2,3-dihydro-1 -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (7) with the desired boronic acid (Scheme Ic). Treatment of (7) with a catalyst such as dichlorobis(tri-o-tolylphosphine)-palladium(II) in the presence of a suitable base such as potassium carbonate in a solvent such as dioxane provides the biaryl system.


¦35-
|0064] Alternatively, installation of the biaryl system may be accomplished via a palladium-catalyzed cross coupling reaction (i.e Suzuki reaction) of appropriate l-(2,3-dihydro-l-benzofuran-2-yl) derivatives (la) in either racemic or stereochemically pure form following separation of the enantiomers. For example, treatment of la and a boronic acid (Scheme Id) with a catalyst such as dichlorobis(tri-o-tolylphosphine)-palladium(II) in the presence of a suitable base such as potassium carbonate (as described previously) provides the desired biaryl system. Deprotection of the resultant product from the coupling procedure with, for example, iodotrimethylsilane in a solvent such as acetonitrile (foir X = NRCbz) then affords the title compounds of Formula 1.

WO 2005/044812 PCT/US2004/035280
[0065] The compounds of formula 1 can also be prepared in a stereoselective manner as illustrated in Scheme II.

[0066] Protection of the 2-allyl phenol (5) with a suitable protecting group such as benzyl by treatment with benzyl bromide in the presence of a suitable base such as potassium carbonate in a solvent such as N,N-dimethylforrnamide gives the benzyl ether (8). Treatment of (8) utilizing extant methodology known to one skilled in the art for the stereoselective oxidation of double bonds such as the Sharpless Asymmetric Dihydroxylation (A-D) provides the diol (9) in stereochemically enriched form. Many methods are available to one skilled in the art for the transfer of the stereochemical information present in (9) into the compounds of formula (1) with retention of stereochemical integrity. One such method involves deprotection of the benzyl ether with catalytic palladium on carbon under a hydrogen atmosphere (45 psi) in a solvent, such as methanol, to provide triol (10). Formation to the previously described 2,3-dihydro-l-benzofuran-2-yl)methanol (6) can be accomplished by treatment of (9) with hydrogen bromide in acetic acid to provide the intermediate vicinal acetoxy bromide followed by cyclization with a suitable base such as potassium carbonate in a solvent such as methanol.
[0067] Alternatively, the compounds of Formula 1 can be prepared via selective mono-protection of diol (9) with a suitable protecting group as illustrated in Scheme III.
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[0068] Treatment of (9) with tert-butyldimethylsilyl chloride in the presence of a suitable base such as imidazole in a solvent such as N,N-dimethylformamide followed by deprotection of the benzyl ether (as previously described) with catalytic palladium on carbon under a hydrogen atmosphere gives phenol (12). Cyclodehydration of (12) using standard Mitsunobu conditions, such as triphenylphosphine in the presence of diethylazodicarboxylate in a solvent such as toluene, provides the 2,3-dihydro-l-benzofuran-2-yl)methanol (13) protected as the silyl ether. Removal of the silyl ether in (13) using standard conditions such as tetrabutylamonnium fluoride in a solvent such as tetrahydrofuran then provides the alcohol (6) which can be converted to the compounds of the current invention as previously described (Scheme I).
[0069] In lieu of a protecting group, diol (9) can be converted to the mono-tosylated derivative (12a) by treatment with p-toluenesulfonyl chloride and a suitable base such as pyridine to give the desired product, as illustrated in Scheme IV.
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[0070] Deprotection of the benzyl ether with catalytic palladium on carbon gives phenol (12b) followed by cyclodehydration with triphenylphosphine in the presence of diethylazodicarboxylate (as previously described) provides the aforementioned 2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (7).
[0071] An additional route to the production of stereochemically enriched compounds of Formula 1 is illustrated in Scheme V.


WO 2005/044812 PCT/US2004/035280
[0072] Palladium or transition metal catalyzed transposition of the double bond present in the previously described 2-allyl benzyl ether (8) using an appropriate catalyst such as dichlorobis(acetonitrile)palladium(II) in dichloromethane provides styrene derivative (14). Treatment of (14) with selenium dioxide in dioxane provides the carbonyl derivative (15). Reduction of the carbonyl to the allylic alcohol (16) can be accomplished by treatment with an appropriate reducing agent such as tetrabutylammonium borohydride in a solvent such as dichloromethane. The allylic alcohol (16) provides a suitable intermediate for the stereoselective introduction of oxygenation that permits transfer of this stereochemical integrity into the compounds of formula (1). The Sharpless Asymmetric Epoxidation (A-E) reaction is a general method for the stereoselective epoxidation of allylic alcohols and treatment of (16) under the appropriate conditions provides epoxy alcohol (17) with a high degree of stereoselectivity. The alcohol present in (17) can then be tosylated with p-toluenesulfonyl chloride as previously described to give derivative (18). Deprotection of the benzyl ether with concomitant regioselective opening of the epoxide maintaining the stereochemical information introduced by the Sharpless A-E is accomplished under the appropriate conditions by treatment of (18) with palladium on carbon under a hydrogen atmosphere in a solvent such as ethanol. Cyclodehydration using Mitsunobu conditions as previously described then affords 2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (7).
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[0073] The preparation of Compounds of Formula 1 can also be accomplished in a
stereospecific manner utilizing an optically pure commercially available intermediate. This method is described in detail in a copending U.S. provisional patent application entitled "Process For Stereospecific Synthesis of Dihydrobenzofuran Derivatives," filed in the name of Dahui Zhou, et al. on the same date as the instant application. That application is incorporated herein by reference in its entirety for all purposes. As shown in Scheme VI, below, for example, reaction of benzyl (S)-(+)-glycidyl ether with the anion obtained by treatment of 2-bromoanisole with an alkyllithium such as n-butyllithium provides the resultant epoxy intermediate. Ring opening of the epoxide with a Lewis acid such as borontrifluoride diethyletherate provides diol (9a) with the primary alcohol protected as the benzyl ether. Deprotection of the methoxy group in 9a by treatment with 30% hydrogen bromide in acetic acid results in concomitant formation of intermediate vicinal acetoxy bromide (10a) followed by removal of the acetate with aqueous hydrogen chloride to provide diol (13a). Cyclodehydration with triphenylphosphine in the presence of diethylazodicarboxylate (as previously described) provides the desired 2-(bromornethyl)-2,3-dihydro-l-benzofuran (7b) that can be converted to the 7-bromo derivative (7c) by treatment with bromine in acetic acid.

[0074] A further method for the synthesis of stereochemically enriched compounds of Formula 1 is described in detail in copending U.S. provisional patent application entitled "Asymmetric Synthesis of 2-(methylamino)dihydrobenzorurans," filed in the name of Alexander Gontcharov, et al. on the same date as the instant application. That application is incorporated herein by reference in its entirety for all purposes. That method is illustrated in the preparation of the compound 2R-(-)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-2-aminomethylbenzofuran hydrochloride shown in Scheme VII.
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[0075] In certain embodiments, the invention relates to compositions comprising at least one compound of Formula 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such compositions are prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference in its entirety. Pharmaceutically acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable.
[0076] The compounds of Formula 1 can be administered orally or parenterally, neat, or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose,
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dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,
polyvinylpyrrolidine, low melting waxes and ion exchange resins.
[0077] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
[0078] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.
[0079] The compounds of Formula 1 can be administered rectally or vaginally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of Formula 1 can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of Formula 1 can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient can also be suitable. A variety of occlusive devices can be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or
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without a carrier, or a matrix containing the active ingredient. Other occlusive devices are
known in the literature.
[0080] Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
[0081] The amount of compound of formula 1 provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compounds of formula 1 are provided to a patient suffering from a condition in an amount sufficient to treat or at least partially treat the symptoms of the condition and its complications. An amount adequate to accomplish this is a "therapeutically effective amount" as described previously herein. The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age, and response pattern of the patient. The treatment of substance abuse follows the same method of subjective drug administration under the guidance of the attending physician. Generally, a starting dose is about 5 mg per day with gradual increase in the daily dose to about 150 mg per day, to provide the desired dosage level in the patient.
[0082] In certain embodiments, the present invention is directed to prodrugs of compounds of Formula 1. The term "prodrug," as used herein, means a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula 1. Various forms of prodrugs are known in the art such as those discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5,113-191 (1991), Bundgaard, et al., Journal of Drug Delivery Reviews, 8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is hereby incorporated by reference in its entirety.
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Intermediate1:1-allyl-2-(benzyloxy)-4-methoxybenze
[0083] To a solution of 2-allyl-5-methoxyphenol (20.30 g, 0.124 mol) in DMF (500 mL) was added potassium carbonate (68.35 g, 0.495 mol) followed by benzyl bromide (23.26 g, 0.136 mol) and tetrabutylammonium iodide (4.57 g, 0.012 mol). The reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (1000 mL) to dissolve any solids and extracted with diethyl ether (3 x 250 mL). The combined organic layers were washed with water (4 x 500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetaterhexanes 1:19) provided 28.44 g (90%) of l-allyl-2-(benzyloxy)-4-methoxybenzene as a colorless oil. Rf= 0.88 (silica, ethyl acetaterhexanes 1:9); Anal, calcd. for C17H18O2: C, 80.28; H, 7.13. Found: C, 82.43; H, 7.09.
Intermediate 2: (±)-3-[2-(benzyIoxy)-4-methoxyphenyl]propane-l,2-dioI
[0084] To a suspension of AD-mix-? (156.55 g) in water:tert-butyl alcohol (1:1, 800 mL) cooled to 0 °C was slowly added via an addition funnel a solution of l-allyl-2-(benzyloxy)-4-methoxybenzene (28.44 g, 0.112 mol) in water:tert-butyl alcohol (1:1,200 mL) and the reaction mixture was allowed to stir at 0 °C for 12 h. The reaction mixture was quenched by the addition of sodium sulfite. The reaction mixture was diluted with water (500 mL) and ethyl acetate (500 mL). The aqueous phase was separated and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:2) gave 30.50 g (95%, 27% ee) of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]propane-l,2-diol as a white crystalline solid, mp 82-86 °C; Anal, calcd. for C17H20O4: C, 70.81; H, 6.99. Found: C, 70.78; H, 7.16.
Intermediate 3: (±)-3-[2-(benzyloxy)-4-methoxypheny]]-2-hydroxypropyl 4-methylbenzenesulfonate
[0085] To a solution of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]propane-l,2-diol (30.50 g, 0.106 mol) in anhydrous pyridine (600 mL) cooled to 0 °C under a nitrogen atmosphere was added p-toluenesulfonyl chloride (22.18 g, 0.116 mol). The reaction mixture was allowed to stir at 0 °C for 12 h. The reaction mixture was quenched by the addition of water (10 mL). The reaction mixture was diluted with ethyl acetate (750 mL) and the organic layer was washed with aqueous hydrogen chloride (6 N, 4 x 400 mL), saturated aqueous sodium chloride (300 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification
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by flash column chromatography(silca, ethyl acetate:hexanes 2:8) gave 42.84 g (91%) of (±)-3-
[2-(benzyloxy)-4-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Rf= 0.28 (silica, ethyl acetate:hexanes 2:8); Anal, calcd. for C24H26O6S: C, 65.14; H, 5.92. Found: C, 64.59; H, 5.72.
Intermediate 4: (±)-2-hydroxy-3-(2-hydroxy-4-methoxyphenyl)propyI 4-methylbenzenesulfonate
[0086] To a solution of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate (42.84 g, 0.097 mol) in ethanol (600 mL) was added palladium on carbon (10 wt.%, 5.81 g) and the reaction mixture was shaken under an H2 atmosphere (50 psi) for 6 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide 32.27 g (95%) of (±)-2-hydroxy-3-(2-hydroxy-4-methoxyphenyl)propyl 4-methylbenzenesulfonate as a colorless oil. Rf= 0.34 (silica, ethyl acetate:hexanes 2:8); Anal.
calcd. for C17Hi8O5S: C, 61.06; H, 5.43. Found: C, 60.70; H, 5.37.
Intermediate 5: (±)-(6-methoxy-2,3-dihydro-l-benzofuran-2-yI)methyl 4-methylbenzenesulfonate
[0087] To a solution of (±)-2-hydroxy-3-(2-hydroxy-4-methoxyphenyl)propyl 4-methylbenzenesulfonate (32.27 g, 0.092 mol) in toluene (1000 mL) cooled to 0 °C was added triphenylphosphine (27.62 g, 0.105 mol) followed by dropwise addition of diethylazodicarboxylate (18.34 g, 0.105 mol) and the reaction mixture was allowed to stir at 0 °C for 15 min. The reaction mixture was quenched by the addition of water (10 mL). The solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:19) provided 22.53 g (74%) of (±)-(6-methoxy-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Rf= 0.67 (silica, ethyl
acetate:hexanes 1:9); Anal, caled. for C17H18O5S: C, 61.06; H, 5.43. Found: C, 60.70; H, 5.37.
Intermediate 6: (±)-(6-hydroxy-2,3-dibydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0088] To a solution of (±)-(5-methoxy-2,3-dihydro-lH-inden-2-yl)methyl 4-methylbenzenesulfonate (13.5 g, 40.5 mmol) in dichloromethane (250 mL) at -70 °C was added boron tribromide (27.0 mL, 1.0 N in dichloromethane) over 15 min. The reaction mixture was allowed to stir at -70 °C for an additional 15 minutes and allowed to warm to room temperature
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over on. The reaction mixture was quenched with ice water and the product extracted with ethyl
acetate (600 mL). The organic layer dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4- 1:1) afforded 10.15 g (79%) of (±)-(6-hydroxy-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow solid, mp 107-110 °C; Anal, calcd. for C16H16O5S: C, 59.99; H, 5.03. Found: C, 59.21; H, 5.05.
Intermediate 7: (±)-(6-phenyl-2,3-dihydro-l-benzofuran-2-yI)methyl 4-methylbenzenesulfonate
[0089] To a solution of (±)-(6-hydroxy-2,3-dihydro-l -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (8.67 g, 27.2 mmol) in anhydrous dichloromethane (300 mL) at 0 °C was added diisopropylethylamine (4.22 g, 32.6 mmol) followed by trifluoromethanesulfonic anhydride (8.45 g, 29.9 mmol) and the reaction mixture was allowed to stir at 0 °C for 1 h. The reaction mixture was quenched with water (300 mL) and diluted with dichloromethane (400 mL), The combined organic layers were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4- 2:3) afforded 10.3 g (84%) of (±)-(6-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl4-methylbenzenesulfonate as a tan solid. To a solution of (±)-(6-{[(rrifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-ben2ofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 4.43 mmol) in dioxane (50 mL) was added phenylboronic acid (1.08 g, 8.86 mmol),
tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.884 mmol), and lithium chloride (0.787 g, 17.43 mmol) and the reaction mixture was heated at 90 °C for 12 h. The reaction mixture was cooled to room temperature and diluted with water (500 mL) and ethyl acetate (500 mL). The organic layer was separated and washed with water (200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 0.170 g (10%) of (±)-(6-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as an oil. 1H NMR (DMSO d6) dH 7.75 (d, 2H); 7.56 (d, 2H); 7.42 (m, 4H); 7.28(t, 1H); 7.21 (d, 1H); 7.08 (d, 1H); 6.92 (s, 1H); 4.98 (m, 1H); 4.24 (dd, 1H); 4.18 (q, 1H); 3.29 (dd, 1H); 2.88 (dd, 1H); 2.46 (s, 3H).
Intermediate 8: 2-allyl-6-chloro-3-(trifluoromethyl)phenol
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[0090] To a solution of 2 chloro-5-trifluoromethyl-phenol (10.00 g, 0.05 mol) in N,N-
dirrxethylformamide (500 mL) was added potassium carbonate (28.12 g, 0.209 mol) followed by ally] bromide (7.38 g, 0.061 mol) and the reaction was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with water (4 x 500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 2-(allyIoxy)-l-chloro-4-(trifluoromethyl)benzene as a colorless oil. The oil was re-dissolved in mesitylene (35 mL) and heated at reflux for 12 h. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) provided 9.6 g (96%) of 2-allyl-6-chloro-3-(trifluoromethyl)phenol as a amber oil. Rf= 0.66 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) dH 9.84 (s, 1H); 7.43 (d, 2H); 7.16 (d, 1H); 5.84 (m, 1H); 4.95 (d, 1H); 4.89 (d, 1H); 3.46 (d, 2H).
Intermediate 9: (±)-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methanol [0091] To a solution of 6-chloro-3-(trifluoromethyl)-2-vinylphenol (9.67 g, 0.043 mol) in dichloromethane 225 mL) was added 3-chloroperoxybenzoic acid (77%, 21.15 g, 0.122 mol). The reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was washed with a 1:1 solution of 10% sodium sulfite:saturated sodium bicarbonate (2 x 200 mL). The solvent was removed in vacuo to give crude yellow oil. The oil was diluted with methanol (100 mL) and added to a solution of potassium carbonate (16.5 g, 0.119 mol) and methanol (825 mL) and the solution was allowed to stir at room temperature 2 h. The solvent was removed in vacuo. The residue was washed with water (1000 mL) and ethyl acetate (500 mL). The aqueous layer was acidified with 1 N aqueous hydrogen chloride and washed with ethyl acetate (500 mL). The combined organics were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate) and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4) provided 6.71 g (70%) of (±)-(7-bromo-4-fluoro-2,3-dihydro-l-benzofuran-2-yl)methanol as a yellow oil. Ry=
0.20 (silica, ethyl acetate:hexanes 1:4). Anal, calcd. for C10H8ClF3O2 C, 47.55; H, 3.19. Found C, 49.39; H, 3.57.
Intermediate 10: (±)-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyI 4-methylbenzenesulfonate
[0092] To a solution of (±)-(7-bromo-4-fluoro-2,3-dihydro-l-benzofuran-2-yl)methanol (8.5, g, 0.034 mol) in pyridine (150 mL) cooled to 0 °C was adde p-toluenesulfonyl chloride
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(7.06g , 0.037 mol) and the reaction mixture was allowed to stir at 0 °C for 12 h. The reaction
mixture was quenched by the addition of water (75 rnL), diluted with diethyl ether (600 mL), washed with aqueous hydrogen chloride (1.0 M, 750 mL), water (200 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) afforded 7.0g (51%) of (±)-[7-chloro-4-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid Ry= 0.60 (silica, ethyl acetaterhexanes 3:7); mp 89-92
°C; Anal, calcd. for C17H14CIF3O4S C, 50.19; H, 3.47. Found C, 50.30; H, 3.35.
Intermediate 11: (±)-(7-cyclapentyl-2,3-dihydro-l-benzofuran-2-yl)methanoI
[0093] Treatment of 2-allyl-6-cyclopentylphenol (6.97 g, 0.0344 mol) with 3-chloroperoxybenzoic acid (17.83 g, 0.1033 mol, 77%) and potassium carbonate (14.0 g, 0.1013 mol) generally according to the procedure described for Intermediate 9 afforded 4.1 g (54%) of (±)-(7-cyclopentyl-2,3-dihydro-l-benzofuran-2-yl)methanol as a yellow oil. Rf= 0.58 (silica,
ethyl acetate:hexanes 3:7); Anal, calcd. for C14H18O2 C, 77.03; H, 8.31. Found C, 76.5; H, 8.44.
Intermediate 12: (±)-benzyl (7-cycIopentyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate
[0094] To a suspension of (7-cyclopentyl-2,3-dihydro-l-benzofuran-2-yl)methylamine (2.4g, 9.46 mmol) in tetrahydrofuran (l00mL) cooled to 0 °C was added diisopropylethylamine (2.14 g, 16.58 mmol) followed by benzyl chloroformate (2.08g, 12.19 mmol) and the reaction mixture was allowed to stir for 15 min. The reaction mixture was quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (2 x 200 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 2.52 g (76%) of (±)-benzyl (7-cyclopentyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a yellow oil. Rf= 0.21 (silica, ethyl acetate:hexanes 2:8); Anal, calcd. for C22H25NO3 C, 75.19; H, 7.17; N, 3.99. Found C, 74.74; H, 7.02; N, 3.85.
Chiral HPLC separation of (±)-benzyl (7-cyclopentyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol.hexane 1:1) provided two fractions. Fraction 1 (Kt =
9.678 min, Chiralcel OJ, ethanol.hexane 1:1); Fraction 2 (Rt = 12.824 min, Chiralcel OJ, ethanol:hexane 1:1).
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Intermediate 13: (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-l-benzofuran-2-yl)methanol
[0095] To a solution of 4-chloro-2-cyclohexylphenol (23.00 g, 0.109 mol) in N,N-dimethylformamide (600 mL) was added sodium hydride (4.56 g, 0.114 mol, 60 wt.%) followed by allyl bromide (14.51 g, 0.120 mol) and the reaction mixture was allowed to stir at room temperature for 5 h. The solvent was removed in vacua and the residue diluted with water (500 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate), and the solvent removed in vacuo to give 29.0 g of l-(allyloxy)-4-chloro-2-cyclohexylbenzene as a brown oil. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 provided 18.0 g of 2-allyl-4-chloro-6-cyclohexylphenol. Treatment of the phenol (6.5 g, 0.026 mol) with 3-chloroperoxybenzoic acid (9.88 g, 0.045 mol, 77%) followed by potassium carbonate (10.00 g, 0.072 mol) generally according to the procedure described for Intermediate 9 afforded 4.6 g (67%) of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-l-benzofuran-2-yl)methanol as a white solid, mp 67-69 °C; Anal, calcd. for C15H19ClO2: C, 67.54; H, 7.18. Found: C, 67.81; H, 6.98.
Intermediate 14: (±)-methyI (5-chIoro-7-cycIohexyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate
[0096] Treatment of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-l-benzofuran-2-yl)methylamine (2.20 g, 7.28 mmol) with diisopropylethylamine (2.94 g, 22.7 mmol) and methyl chloroformate (1.08 g, 11.4 mmol) generally according to the procedure described for Intermediate 12 provided 2.30 g (93%) of (±)-methyl (5~chloro-7-cyclohexyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a white solid, mp 100-103 °C; Anal, calcd. for C17H22C1NO3: C, 63.06; H, 6.85; N, 4.33. Found: C, 63.16; H, 6.3; N, 4.25.
Intermediate 15: (±)-3-[3-benzyI-2-(benzyIoxy)phenyl]propane-l,2-diol
[0097] Treatment of 2-allyl-6-benzylphenol (12.11 g, 0.054 mol) with potassium carbonate (30.00 g, 0.217 mol), benzyl bromide (10.67 g, 0.062 mol), and tetrabutylammonium iodide (2.01 g, 0.005 mol) generally according to the procedure described for Intermediate 1 provided l-allyl-3-benzyl-2-(benzyloxy)benzene. Treatment of 1-allyl-3-benzyl-2-(benzyloxy)benzene (16.35 g, 0.052 mol) with AD-mix-a (76.02 g) generally according to the procedure described for Intermediate 2 gave 9.82 (54%, 25% ee) of (±)-3-[3-benzyl-2-
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(benzyloxy)pnenyl]propane-1,2-drol as a white crystalline solid, mp 55-58 °C; Anal, calcd. for C23H24O3: C, 79.28; H, 6.94. Found: C, 78.89; H, 6.96.
Intermediate 16: (±)-3-[3-benzyl-2-(benzyIoxy)phenyI]-2-hydroxypropyl 4-methylbenzenesulfonate
[0098] Treatment of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]propane-l,2-diol (9.76 g, 0.028 mol) with p-toluenesulfonyl chloride (5.87 g, 0.031 mol) in pyridine (250 mL) generally according to the procedure described for Intermediate 3 gave 9.88 g (70%) of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Anal, calcd. for C30H30O5S: C, 71.69; H, 6.02. Found: C, 70.41; H, 6.14.
Intermediate 17: (±)-3-(3-benzyl-2-hydroxypb.enyl)-2-hydroxypropyl 4-methylbenzenesulfonate
[0099] Treatment of (±)-3-[3-benzyl-2-(benzyloxy)phenyl]-2-hydroxypropyl 4-methylbenzenesulfonate (9.72 g, 0.019 mol) with palladium on carbon (0.97 g, 10 wt.%) generally according to the procedure described for Intermediate 4 provided 7.34 g (92%) of (±)-3-(3-benzyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Anal, calcd. for C23H24O5S: C, 66.97; H, 5.86. Found: C, 66.11; H, 5.95.
Intermediate 18: (±)-(7-benzyI-2,3-dihydro-l-benzofuran-2-yl)methyI 4-methylbenzenesulfonate
[0100] Treatment of (±)-3-(3-benzyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate (7.29 g, 0.018 mol) with triphenylphosphine (5.10 g, 0.019 mol) and diethylazodicarboxylate (3.39 g, 0.019 mol) generally according to the procedure described for Intermediate 5 afforded 6.57 g (94%) of (±)-(7-benzyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Anal, calcd. for C23H22O4S: C, 70.03; H, 5.62.
Found: C, 68.97; H, 5.42.
Intermediate 19: (±)-benzyl (7-benzyl-2,3-dihydro-l-benzofuran-2-yI)methyIcarbamate
[0101] Treatment of (±)-l-(7-benzyl-2,3-dihydro-l-benzofuran-2-yl)methanamine (2.0 g, 8.36 mmol) with diisopropylethylamine (1.62 g, 12.56 mmol) and benzyl chloroformate (1.64 g, 9.61 mmol) generally according to the procedure described for Intermediate 12 provided 2.96 g (95%) of (±)-benzyl (7-benzyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal, calcd. for C24H23NO3 C, 77.19; H, 6.21; N, 3.75. Found C, 75.58; H, 6.42; N, 3.55.
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Chiral HPLC eparanon of (±)-benzyl(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate
(Chiralcel OD, methanol) provided two fractions. Fraction 1 (Rt = 12.085 min, Chiralcel OD,
methanol); Fraction 2 (Rt = 17.945 min, Chiralcel OD, methanol).
Intermediate 20: (±)-(7-isopropyl-2,3-dihydro-l-benzofuran-2-yI)methyl 4-methylbenzenesulfonate
[0102] Treatment of 2-allyl-6-isopropylphenol (8.81 g, 0.05 mmol) with 3-chloroperoxybenzoic acid (22.43 g, 0.13 mol, 77%)) followed by potassium carbonate (13.82 g, 0.1 mol) generally according to the procedure described for Intermediate 9 provided (±)-(7-isopropyl-2,3-dihydro-l -benzofuran-2-yl)methanol. Treatment of (±)-(7-isopropyl-2,3-dihydro-l-benzofuran-2-yl)methanol (3.45 g, 0.018 mol) with p-toluenesulfonyl chloride (3.92 g, 0.021 mol) generally according to the procedure described for Intermediate 10 afforded 4.91 g (79%) (±)-(7-isopropyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Anal, calcd. for C19H22O4S C, 65.87; H, 6.4. Found C, 65.63; H, 6.32.
Intermediate 21: (±)-benzyl (7-isopropyl-23-dihydro-l-benzofuran-2-yl)methylcarbamate [0103] Treatment of (±)-(7-isopropyl-2,3-dihydro-l-benzoruran-2-yl)methylamine (2.2 g, 9.66 mmol) with diisopropylethylamine (3.12 g, 24.15 mmol) and benzyl chloroformate (1.81 g, 10.63 mmol) generally according to the procedure described for Intermediate 12 gave 1.2 g (59%) of (±)-benzyl (7-isopropyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal, calcd. for C20H23NO3 C, 73.82; H, 7.12; N, 4.3. Found C, 73.32; H, 7.33; N, 4.15.
Chiral HPLC separation of (±)-benzyl (7-isopropyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol) provided two fractions. Fraction 1 (Rt = 9.319 min, Chiralcel OJ, ethanol); Fraction 2 (Rt= 11.868 min, Chiralcel OJ, ethanol).
Intermediate 22: 2-allyl-4-chloro-6-isopropyI-3-methylphenol
[0104] Treatment of 4-chloro-2-isopropyl-5-methylphenol (10.00 g, 0.054 mol) with potassium carbonate (29.94 g, 0.217 mol) and allyl bromide (7.86 g, 0.065 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 8.92 g (73%) of 2-allyl-4-chloro-6-isopropyl-3-methylphenol as a colorless oil. Rf= 0.85 (silica, ethyl acetate:hexanes 1:9); Anal, calcd. for C13H17ClO: C, 69.48; H, 7.62. Found: C, 69.87; H, 7.43.
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Intermediated: (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methyl
4-methylbenzenesulfonate
[0105] Treatment of 2-allyI-4-chloro-6-isopropyl-3-methylphenol (8.88 g, 0.04 mmol) with 3-chloroperoxybenzoic acid (13.63 g, 0.079 mol, 77%)) followed by potassium carbonate (10.92 g, 0.079 mol) generally according to the procedure described for Intermediate 9 provided (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methanol. Treatment of (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methanol (5.95 g, 0.025 mol) with p-toluenesulfonyl chloride (5.66 g, 0.03 mol) generally according to the procedure described for Intermediate 10 afforded 6.71 g (69%) (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid, mp 103-105 °C; Anal, calcd. for C20H23ClO4S C, 60.83; H, 5.87. Found C, 60.67; H, 5.88.
Intermediate 24: (±)-benzyl (5-chIoro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate
[0106] Treatment of (±)-1 -(5 -chloro-7-isopropyl-4-methyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine (3.41 g, 12.3 mmol) with diisopropylethylamine (1.99 g, 14.2 mmol) and benzyl chloroformate (2.42 g, 14.2 mmol) generally according to the procedure described for Intermediate 12 gave 3.74 g (81%) of (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal, calcd. for C21H24ClNO3 C, 67.46; H,
6.47; N, 3.75. Found C, 67.01; H, 6.52; N, 3.56. Chiral HPLC separation of (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate (Chiralpak AD, ethanol) provided two fractions.
Intermediate 25: (-)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dibydro-l-benzofuran-2-yl)methylcarbamate
[0107] Fraction 1 obtained as a white solid from the separation of (±)-benzyl (5-chloro-7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate (Rt = 4.132 min,
Chiralpak AD, ethanol). [?]D25 = -38.52 (c 10.0 in methanol); mp 59-62 °C; Anal, calcd. for C21H24ClNO3 C, 67.46; H, 6.47; N, 3.75. Found C, 67.26; H, 6.41; N, 3.36.
Intermediate 26: (+)-benzyl (5-chloro-7-isopropyl-4-methyI-2,3-dihydro-l-benzofuran-2-yl)metbylcarbamate
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[0108] Fraction 2 obtained as a a white solid from the separation of (±)-benzyl (5-chloro-
7-isopropyl-4-methyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate (Rt = 5.393 min, Chiralpak AD, ethanol). [?]25D = +37.84 (c 10.0 in methanol); mp 59-62 °C; Anal, calcd. for C21H24ClNO3 C, 67.46; H, 6.47; N, 3.75. Found C, 67.2; H, 6.49; N, 3.58.
Intermediate 27: l-allyI-2-(benzyloxy)-3-tert-butyIbenzene
[0109] Treatment of 2-allyl-6-tert-butylphenol (12.5 g, 0.066 mol) with potassium carbonate (27.24 g, 0.197 mol), benzyl bromide (11.80 g, 0.069 mol), and tetrabutylammonium iodide (2.43 g, 6.57 mmol) generally according to the procedure described for Intermediate 1 provided 16.2 g (88%) of l-allyl-2-(benzyloxy)-3-tert-butylbenzene as a colorless oil. Anal, calcd. for C20H24O: C, 85.67; H, 8.63. Found: C, 86.27; H, 8.77.
Intermediate 28: (±)-3-[2-(benzyloxy)-3-tert-butylphenyI]propane-l,2-dioI
[0110] To a suspension of potassium ferricyanide (57.00g, 0.173 mol), potassium carbonate (24.00 g, 0.174 mol), hydroquinine anthraquinone-l,4-diyl diether (0.495 g, 0.578 mmol), and potassium osmate dihydrate (0.043 g, 0.117 mmol) in water tert-butyl alcohol (1:1, 600 mL) cooled to 0 °C was slowly added via an addition funnel a solution of l-allyl-2-(benzyloxy)-3-tert-butylbenzene (16.2 g, 0.058 mol) in tert-butyl alcohol (50 mL) and the reaction mixture was allowed to stir at 0 °C for 12 h. The reaction mixture was quenched by the addition of sodium sulfite. The reaction mixture was diluted with water (500 mL) and ethyl acetate (500 mL). The aqueous phase was separated and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetaterhexanes 3:2) gave 16.75 g (92%, 32% ee) of (±)-3-[2-(benzyloxy)-3-tert-butylphenyl]propane-l,2-diol as a white solid, mp 79-81 °C; Anal, calcd. for C20H26O3: C, 76.4; H, 8.33. Found: C, 76.39; H, 8.22.
Intermediate 29: (±)-3-(3-tert-buryl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate
[01111 Treatment of (±)-3-[2-(benzyloxy)-3-tert-butylphenyl]propane-l,2-diol (16.50 g, 0.053 mol) with p-toluenesulfonyl chloride (10.51 g, 0.055 mol) in pyridine (400 mL) generally according to the procedure described for Intermediate 3 gave 42.84 g (91%) of (±)-3-[2-(benzyloxy)-4-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the
tosylate with palladium on carbon (2.4 g, 10 wt.%) generally according to the procedure
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described for the intermediate 14.71 g(74%) of (±)-3-(3-tert-butyl-2-hydroxyphenyl)-2-
hydroxypropyl 4-methylbenzenesulfonate as a white solid, mp 98-101 °C; Anal, calcd. for C20H26O5S: C, 63.47; H, 6.92. Found: C, 63.24; H, 6.99.
Intermediate 30: (±)-(7-tert-butyl-2,3-dibydro-l-benzofuran-2-yl)methyI 4-methylbenzenesulfonate
[0112] Treatment of (±)-3-(3-tert-butyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate (14.66 g, 0.039 mol) with triphenylphosphine (11.18 g, 0.043 mol) and diethylazodicarboxylate (7.42 g, 0.043 mol) generally according to the procedure described for Intermediate 5 afforded 12.48 g (89%) of (±)-(7-tert-butyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Anal, calcd. for C20H24O4S: C, 66.64;
H, 6.71. Found: C, 66.28; H, 6.95.
Intermediate 31: (±)-benzyl (7-tert-butyI-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate
[0113] Treatment of (±)-l-(7-tert-butyl-2,3-dihydro-l-benzofuran-2-yl)methanamine (3.25 g, 13.4 mmol) with diisopropylethylamine (4.34 g, 33.6 mmol) and benzyl chloroformate (2.64 g, 15.5 mmol) generally according to the procedure described for Intermediate 12 gave 4.37 g (96%) of (±)-benzyl (7-tert-butyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a white solid, mp 73-76 °C; Anal. Calcd. for C21H25NO3 C, 74.31; H, 7.42; N, 4.13. Found C,
74.95; H, 7.51; N, 4.18. Chiral HPLC separation of (±)-benzyl (7-tert-butyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbarnate (Chiralcel OJ, ethanol) provided two fractions. Fraction 1 (Rt
= 9.100 min, Chiralcel OJ, ethanol); Fraction 2 (Rt = 14.428 min, Chiralcel OJ, ethanol).
Intermediate 32: (±)-(7-tert-butyl-5-chloro-2,3-dihydro-l-benzofuran-2-yI)methyl 4-methylbenzenesulfonate
[0114] Treatment of 2-tert-butyl-4-chlorophenol (12.73 g, 0.070 mol) with allyl bromide (10.01 g, 0.083 mol) and potassium carbonate (38.11 g, 0.276 mol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 gave 2-allyl-6-tert-butyl-4-chlorophenol. Treatment of the phenol with 3-chloroperoxybenzoic acid (35.90 g, 0.146 mol, 77%) followed by potassium carbonate (28.18 g, 0.204 mol) generally according to the procedure described for Intermediate 9 provided (±)-(7-tert-butyl-5-chloro-2,3-dihydro-l-benzofuran-2-yl)methanol. Treatment of the alcohol with with p-toluenesulfonyl chloride (10.27 g, 0.054 mol) generally according to the procedure described
for Intermediate 10 afforded 13.84 g (51%) (±)-(7-tert-butyl-5-chloro-2,3-dihydro-l-benzofuran-
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2-yl)methyl 4-methylbenzenesulfoate as a white solid, mp 74-77 °C; Anal, calcd. for
C20H23ClO4S C, 60.83; H, 5.87. Found C, 60.79; H, 5.80.
Intermediate 33: (±)-benzyl (7-tert-butyI-5-chloro-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate
[0115] Treatment of (±)-1 -(7-tert-butyl-5-chloro-2,3-dihydro-1 -benzofuran-2-yl)methanamine (1.80 g, 6.52 mmol) with diisopropylethylamine (2.11 g, 16.29 mmol) and benzyl chloroformate (1.28 g, 7.49 mmol) generally according to the procedure described for Intermediate 12 gave 2.33 g (95%) of (±)-benzyl (7-tert-butyl-5-chloro-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal, calcd. for C21H24ClNO3 C, 67.46; H,
6.47; N, 3.75. Found C, 67.27; H, 6.62; N, 3.66. Chiral HPLC separation of (±)-benzyl (7-tert-butyl-5-chIoro-2,3-dihydro-1 -benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt = 5.642 min, Chiralpak AD,
hexanerisopropanol 9:1); Fraction 2 (Rt = 6.494 min, Chiralpak AD, hexane:isopropanol 9:1).
Intermediate 34: (±)-benzyl (7-tert-butyl-5-methoxy-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate
[0116] Treatment of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-l-benzofuran-2-yl)methylamine (1.03 g, 3.8 mmol) with diisopropylethylamine (0.735 g, 5.7 mmol) and benzyl chloro formate (0.711 g, 4.2 mmol) generally according to the procedure described for Intermediate 12 gave 1.2 g (59%) of (±)-benzyl (7-tert-butyl-5-methoxy-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a colorless oil. Rr= 0.51 (silica, ethyl acetate:hexanes 2:8);
Anal, calcd. for C22H27NO4 C, 71.52; H, 7.37; N, 3.79. Found C, 71.2; H, 7.44; N, 3.77.
Intermediate 35: 2-(2-isopropyIphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboroIane
[0117] To a solution of dichloro[l,rbis(diphenylphosphino)ferrocene] palladium(II)dichloromethane adduct (0.92 g, 1.12 mmol) and l,l-bis(diphenylphosphino) ferrocene (0.62 g, 1.12 mmol) in dioxane (275 mL) was added 2-isopropylphenyl trifluoromethanesulfonate (10.0 g, 37.5 mmol), bis(pinacolato)diboron (10.48 g, 41.26 mmol) and potassium acetate (10.96 g, 55.83 mmol) and the reaction mixture was heated to 90 °C and allowed to stir for 36 h. The reaction mixture was cooled to room temperature and diluted with water (300 rnL) and extracted with diethyl ether (2 x 300 mL). The combined organic layers were washed with water (2 x 200 mL) and saturated aqueous sodium chloride (200 mL), were
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dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil.
Purification by flash column chromatography (silica, ethyl acetate:hexane 1:1) provided 3.9 g (43%) of 2-(2-isopropylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane as a pale yellow oil. 1H NMR (DMSO-d6 dH 7.57 (d, 1H); 7.38 (t, 1H); 7.30 (d, 1H); 7.13 (t, 1H); 3.57 (m, 1H); 1.27 (s, 12H);1.14(d,6H).
Intermediate 36: (±)-(4-bromo~2,3-dihydro-l-benzofuran-2-yI)rnethyl 4-methylbenzenesulfonate
[0118] Treatment of 2-allyl-5-bromophenol (27.25 g, 0.128 mmol), with 3-chloroperoxybenzoic acid (66.20 g, 0.384 mol, 77%) ) followed by potassium carbonate (44.18 g, 0.319 mol) generally according to the procedure described for Intermediate 9 provided (±)-(4-bromo-2,3-dihydro-l-benzofuran-2-yl)methanol as a yellow oil. Treatment of the oil with p-toluenesulfonyl chloride (15.65 g, 0.082 mol) generally according to the procedure described for Intermediate 10 afforded 24.7 g (78%) of (±)-(4-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid, mp 90-91 °C; Anal, calcd. for C16H15BrO4S: C,
50.14; H, 3.94. Found: C, 50.09; H, 3.82.
Intermediate 37: (±)-(4-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0119] To a solution of (±)-(4-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.05 g, 5.21 mmol) and phenylboronic acid (0.952 g, 7.81 mmol) in dioxane (50 mL) heated to 100 °C was added dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.205 g, 0.261 mmol) and potassium carbonate (1.80 g, 13.04 mmol) and the reaction mixture was allowed to stir at 100 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (250 mL), and filtered (celite). The organic layer was washed with water (2 x 100 mL) and saturated aqueous sodium chloride (100 mL), was dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 1.45 g (73%) of (±)-(4-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a clear oil. Rf= 0.34
(silica, ethyl acetate:hexanes 1:4); Anal, calcd. for C22H20O4S: C, 69.45; H, 5.30. Found: C, 69.17; H, 5.30.
Intermediate 38: (±)-benzyl (4-phenyl-2,3-dihydro-l-benzofuran-2-yI)rnethyIcarbamate
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[0120] Treatment of (±)-(4-phenyl-2,3-dihydro-l-benzofuran-2-yl)methanamine (0.622
g, 2.38 mmol) with diisopropylethylamine (0.447 g, 3.57 mmol) and benzyl chloroformate (0.462 g, 2.62 mmol) generally according to the procedure described for Intermediate 12 provided 0.601 g (70%) of (±)-benzyl (4-phenyl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a white solid, mp 132-134 °C; Anal, calcd. for C23H21NO3: C, 76.86 H,
5.89; N, 3.90. Found: C, 75.98 H, 5.80; N, 3.72. Chiral HPLC separation of (±)-benzyI (4-phenyl-2,3-dihydro-l-ben2ofuran-2-yl)methylcarbamate (Chiralcel OD, ethanol:water 15:85) provided two fractions. Fraction 1 (Rt = 6.651 min Chiralcel OD, ethanol water 1:3); Fraction 2
(Rt = 7.395 min, Chiralcel OD, ethanol:water 1:3).
Intermediate 39: (±)-[4-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyI 4-methylbenzenesulfonate
[0121] Treatment of (±)-(4-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 5.21 mmol), 2-methylphenyl boronic acid (1.06 g, 7.82 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.205 g, 0.261 mmol), and potassium carbonate (1.80 g, 13.04 mmol) generally according to the procedure described for Intermediate 37 provided 1.41 g (69%) of (±)-[4-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Rf= 0.42 (silica, ethyl acetate:hexanes 1:4); Anal, calcd.
for C23H22O4S: C, 70.03; H, 5.62. Found: C, 69.70; H, 5.45.
Intermediate 40: (±)-benzyI [4-(2-methyIphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0122] Treatment of (±)-l-[4-(2-memylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine (0.533 g, 1.94 mmol) with diisopropylethylamine (0.375 g, 2.90 mmol) and benzyl chloroformate (0.363 g, 2.13 mmol) generally according to the procedure described for Intermediate 12 provided 0.594 g (82%) of (±)-benzyl [4-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as colorless oil. Rf= 0.42 (silica, ethyl acetate:hexanesl :4);
Anal, calcd. for C24H23NO3: C, 77.19 H, 6.21; N, 3.75. Found: C, 76.0 H, 6.01; N, 3.55. Chiral
HPLC separation of (±)-benzyl [4-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate (Chiralcel OD, methanol) provided two fractions. Fraction 1,(Rt = 5.952
min Chiralcel OD, methanol); Fraction 2 (Rt = 7.345 min, Chiralcel OD, methanol).
Intermediate 41: 1 -ally l-2-(benzyloxy)-3-methoxy benzene
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[0123] Treatment of gualacol (25.00 g, 0.201 mol) with allyl bromide (29.24 g, 0.242
mo!) and potassium carbonate (83.50 g, 0.604 mol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 afforded 2-allyl-6-methoxyphenol as a brown oil. Treatment of the phenol with potassium carbonate (83.5 g, 0.604 mol), benzyl bromide (36.19 g, 0.212 mol), and tetrabutylammonium iodide (7.42 g, 0.020 mol) generally according to the procedure described for Intermediate 1 gave 23.61 g (45%) of 1-allyl-2-(benzyloxy)-3-methoxybenzene as a pale yellow oil. Rf= 0.71 (silica, ethyl
acetate:hexanes 1:9); Anal, calcd. for C17H18O2: C, 80.28; H, 7.13. Found: C, 79.09; H, 6.93.
Intermediate 42: (±)-3-[2-(benzyloxy)-3-methoxyphenyl]propane-l,2-diol
[0124] Treatment of (4-methoxy-l,3-benzodioxol-2-yl)methanol (23.61 g, 0.093 mol) with AD-mix-? (129.97 g) generally according to the procedure described for Intermediate 2 provided 26.49 g (99%, 34% ee) of (±)-3-[2-(benzyloxy)-3-methoxyphenyl]propane-l,2-diol as a colorless oil. Rf = 0.63 (silica, ethyl acetate:hexanes 3:2); Anal, calcd. for C17H20O4: C, 70.81;
H, 6.99. Found: C, 69.33; H, 7.12.
Intermediate 43: (±)-l-[2-(benzyloxy)-3-methoxyphenyl]-3-{[tert-butyl(dimethyl)silyl)oxy}propan-2-ol
[0125] To a solution of (±)-3-[2-(benzyloxy)-3-methoxyphenyl]propane-l,2-diol (50.23 g, 0.174 mol) in N,N-dimethylformamide (600 mL) was added tert-butyldimethylsilyl chloride (28.88 g, 0.192 mol) followed by triethylamine (22.03 g, 0.218 mol) and 4-(dimethylamino)pyridine (2.12 g, 0.017 mol) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction mixture was quenched by the addition of water (1000 mL) and was extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were washed with water (4 x 300 mL), aqueous hydrogen chloride (1.0 N, 400 mL), saturated aqueous sodium chloride (300 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 58.14 g (83%) of (±)-l-[2-(benzyloxy)-3-methoxyphenyl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol as a colorless oil. Rf= 0.48 (silica, ethyl acetate:hexanes
3:7); Anal, calcd. for C23H34O4Si: C, 68.62; H, 8.51. Found: C, 69.20; H, 8.91.
Intermediate 44: (±)-tert-butyI[(7-methoxy-2,3-dihydro-l-benzofuran-2-yl)methoxy]dimethylsilane
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[0126] Treatment of (±)-l-'[2-(benzyloxy)-3-methoxyphenyl]-3-{[tert-
butyl(dirnethyl)silyl]oxy}propan-2-ol (58.14 g, 0.144 mol) with palladium on carbon (5.81 g, 10 wt.%) generally according to the procedure described for Intermediate 4 provided (±)-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxypropyl)-6-methoxyphenol as a crude oil. Treatment of the phenol with triphenylphosphine (44.52 g, 0.170 mol) and diethylazodicarboxylate (29.56 g, 0.170 mol) generally according to the procedure described for Intermediate 5 gave 34.12 g (80%) of(±)-tert-butyl[(7-methoxy-2,3-dihydro-l-benzofuran-2-yl)methoxy]dimethylsilane as a colorless oil. Rf= 0.67 (silica, ethyl acetate:hexanes 1:9); Anal, calcd. for C16H26O3Si: C,
65.26; H, 8.90. Found: C, 64.26; H, 9.24.
Intermediate 45: (±)-(7-methoxy-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[01271 To a solution of (±)-tert-butyl[(7-methoxy-2,3-dihydro-l-benzofuran-2-yl)methoxy]dimethylsilane (34.12 g; 0.116 mol) in tetrahydrofuran (700 mL) cooled to 0 °C was added via an addition funnel tetrabutylammonium fluoride (140 mL, 1.0 M solution in tetrahydrofuran) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction was diluted with water (500mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give (±)-(7-methoxy-2,3-dihydro-l-benzofuran-2-yl)methanol, a crude oil. The alcohol was dissolved in dichloromethane (700 mL) and p-toluenesulfonyl chloride (33.14 g, 0.174 mol) was added followed by triethylamine (21.11 g, 0.209 mol) and then 4-(dimethylamino)pyridine (2.12 g, 0.017 mol). The reaction mixture was allowed to stir at 50 °C for 12 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 26.45 g (68%) of (±)-(7-methoxy-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white crystalline solid. Rf= 0.38 (silica, ethyl acetate:hexanes 3:7); mp 98-103 °C; Anal, calcd. for C17H18O5S:
C, 61.06; H, 5.43. Found: C, 60.80; H, 5.37.
Intermediate 46: (±)-(7-hydroxy-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0128] To (±)-(7-methoxy-2,3-dihydro-l-benzofuran-2-yl)methyl4-
methylbenzenesulfonate (10.00 g, 0.030 mol) was added hydrogen bromide (20 mL, 30 wt.% in acetic acid) and the resulting solution was heated to 40 °C. The reaction mixture was allowed to
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stir at 40 °C for 4h. The reaction mixture was cooled to room temperature and was diluted with
water (250 mL) and extracted with diethyl ether (3 x 200 mL). The combined organic extracts were washed with saturated sodium bicarbonate (3 x 300 mL), water (200 mL), and saturated aqueous sodium chloride (200 mL), were dried (magensium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:3) provided 7.34 g (77%) of (±)-(7-hydroxy-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as white solid. Rf= 0.31 (silica, ethyl acetate:hexanes 1:3);
mp 122-125 °C; Anal, calcd. for C16H16O5S: C, 59.99; H, 5.03. Found: C, 59.8; H, 4.73.
Intermediate 47: (±)-(7-{[(trifluoromethyl)sulfonyI]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0129] Treatment of (±)-(7-hydroxy-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.00 g, 3.12 mmol) with diisopropylethylamine (0.44 g, 3.43 mmol) and trifluoromethanesulfonic anhydride (0.92 g, 3.28 mmol) generally according to the procedure described for Intermediate 7 gave 1.05 g (74%) of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl4-methylbenzenesulfonate as a white solid. Rf= 0.45 (silica, ethyl acetate:hexanes 1:3); mp 60-63
°C; Anal, calcd. for C17H15F3O7S2: C, 45.13; H, 3.34. Found: C, 44.85; H, 3.04.
Intermediate 48: (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)mettaanol
[0130] Treatment of 2-allyl-6-bromophenol (61.4 g 0.288 mol) with 3-
chloroperoxybenzoic acid (77%, 149.18 g, 0.864 mol) ) followed by potassium carbonate (99.56 g, 0.72 mol) generally according to the procedure described for Intermediate 9 provided 49.00 g (78%) (86%) of (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methanol as an amber oil. Rf=
0.66 (silica, ethyl acetate:hexanes 1:9) 1H NMR (DMSO-d6) dH 7.23 (dd, 1H); 7.14 (dd, 1H); 6.71 (t, 1H); (5.01m, 1H); 4.85 (m, 1H); 4.99 (m, 2H); 3.36 (d, 2H).
Intermediate 49: (±)-(7-bromo-2,3-dinydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0131] Treatment of (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methanol (49.0 g, 0.214 mol) with p-toluenesulfonyl chloride (44.9 g, 0.235 mol) generally according to the procedure described for Intermediate 10 gave 66.00 g (80%) (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf= 0.44 (silica, ethyl
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acetate:hexanes 1:4); mp 120-122 °C; Anal, calcd. for CH15BrO4S: C, 50.14; H, 3.94. Found:
C, 48.47; H, 4.03.
Intermediate 50: (±)-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuraD-2-yl} methyl 4-methylbenzenesulfonate
[0132] To a solution of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.21 mmol) and 3,5-bis(trifluoromethyl)phenylboronic acid (0.86 g, 3.32 mmol) in dioxane (25 mL) heated to 90 °C was added tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol) and potassium phosphate (0.94 g, 4.42 mmol). The reaction mixture was allowed to stir at 90 °C for 12 h. The reaction mixture was allowed to cool and was diluted with diethyl ether (100 mL), filtered (celite), and the solvent was removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethylacetate:hexanes 1:9) afforded 0.75 g (66%) of (±)-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-l -benzofuran-2-yl} methyl 4-methylbenzenesulfonate as a white solid. Rf= 0.49 (silica, ethyl acetate:hexanes 1:3); mp 100-105 °C; Anal, calcd. for
C24H18F6O4S2: C, 55.82; H, 3..51 Found: C, 55.75; H, 3.35.
Intermediate 51: (±)-[7-(3-chIoro-4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate
[0133] Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3-chloro-4-fluorophenylboronic acid (0.87 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.68 g (48%) of (±)-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf= 0.43 (silica,
ethyl acetate:hexanes 1:3); mp 104-108 °C; Anal, calcd. for C22H18ClFO4S2: C, 61.04; H, 4.19. Found: C, 60.74; H, 4.13.
Intermediate 52: (±)-(7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0134] Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with phenylboronic acid (0.95 g, 4.97 mmol), tetrakis(triphenylphosphine)palladiurn(0) (0.38 g, 0.33 mmol), and
potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for
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Intermediate 50 provided 0.40 g (32%) of (±)-(7-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methyl
4-methylbenzenesulfonate as a white solid. Rf= 0.48 (silica, ethyl acetate:hexanes 1:3); Anal, calcd. for C22H20O4S.0.2H2O: C, 68.8; H, 5.35. Found: C, 68.78; H, 5.08.
Intermediate 53: (±)-benzyI (7-phenyI-2,3-dihydro-l-benzofuran-2-yI)methylcarbamate
[0135] Treatment of (±)-benzyl (7-phenyl-2,3-dihydro-l -benzofuran-2-yl)methanamine (1.5 g, 1.43 mmol) with diisopropylethylamine (0.277g, 2.14mmol) followed by benzyl chloroformate (0.268 g, 1.572 mmol) generally according to the procedure described for Intermediate 12 provided 1.64 (79%) of (±)-benzyl [7-phenyl-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as a clear oil. Rf= 0.68 (silica, ethyl acetate:hexanes 1:2); Anal, calcd. for
C23H21NO3: C, 76.86; H, 5.89; N, 3.90. Found: C, 75.10 H, 5.71; N, 3.90. Chiral HPLC
separation of (±)-benzyl [7-phenyl-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt = 10.746 min, Chiralpak AD,
ethanol:hexane 1:1); Fraction 2 (Rt = 13.433 min, Chiralpak AD ethanol:hexane 1:1).
Intermediate 54: (±)-[7-(2-naphthyl)-2,3-dihydro-l-benzofuran-2-yl]methyI 4-methylbenzenesulfonate
[0136] Treatment of (±)-(7- {[(trifluoromethyl)sulfonyl]oxy} -2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 2-naphthaleneboronic acid (0.86 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.513 g (36%) of (±)-[7-(2-naphthyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf= 0.42 (silica, ethyl
acetate:hexanes 1:3); Anal, calcd. for C26H22O4S: C, 72.54; H, 5.15. Found: C, 72.04; H, 5.04.
Intermediate 55: (±)-[7-(3,5-dichlorophenyI)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate
[0137] Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3,5-dichlorophenylboronic acid (0.95 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.22 g (15%) of (±)-[7-(3,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf= 0.48
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(silica;ethyl acetate:hexanesn1:3);nmpnl13-115 °C; Anal, calcd. for C22H18Cl2O4S: C, 58.8; H,
4.04. Found: C, 58.73; H, 3.77.
Intermediate 56: (±)-[7-(2-methylphenyI)-2,3-dihydro-l-benzofuran-2-yl]methyI 4-methylbenzenesulfonate
[0138] Treatment of (±)-(7-bromo-2,3-dihydro-1 -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 2-methylphenyl boronic acid (0.266 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 rnmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.358 g (70%) of (±)-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf= 0.43 (silica, ethyl acetate:hexanes 1:3); mp 98-100
°C; Anal, calcd. for C23H22O4S: C, 70.03; H, 5.62. Found: C, 69.83; H, 5.61.
Intermediate 57: (±)-benzyl |7-(2-methylphenyI)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0139] Treatment of (±)-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine (3.55 g, 12.9 mmol) with diisopropylethylamine (2.5 g, 19.4 mmol) and benzyl chloroformate (2.42 g, 14.2 mmol) generally according to the procedure described for Intermediate 12 provided 4.1 g (85%) of (±)-benzyl [7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as a clear oil Rf-= 0.64 (silica, ethyl acetate:hexanes 1:4);
Anal, calcd. for C24H23F4NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.95; H, 6.18; N, 3.53. Chiral HPLC separation of (±)-benzyl [7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate (Chiralcel OD, isopropanol:hexane 1:4) provided two fractions. Fraction 1 (Rt = 7.285 min, isopropanol:hexane 1:4); Fraction 2 (Rt = 9.361 min, Chiralcel OD,
isopropanol.hexane 1:4).
Intermediate 58: (±)-(7-thien-3-yI-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0140] Treatment of (±)-(7-bromo-2,3-dihydro-1 -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-thiophene boronic acid (0.334 g, 2.61 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.389 g (77%) of (±)-(7-thien-3-yl-2,3-dihydro-l-ben2ofuran-2-yl)methyl 4-
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methylbenzenesulfonate as a yellow solid.. mp 90-92 0C; Anal, calcd. for C20H18O4S2: C,
62.15; H, 4.69. Found: C, 62.2; H, 4.72.
Intermediate 59: (±)-benzyl (7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate
[0141] Treatment of (±)-l-(7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methanamine (0.56 g, 2.09 mmol) with diisopropylethylamine (0.406 g, 3.14 mmol) and benzyl chloroformate (0.393 g, 2.30 mmol) generally according to the procedure described for Intermediate 12 provided 0.54 g (71%) of (±)-benzyl (7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a colorless oil. Rf= 0.49 (silica, ethyl acetate:hexanes 2:8); Anal, calcd.
for C21H19NO3S.-0.3 H2O: C, 68.01; H, 5.33; N, 3.78. Found: C, 67.88; H, 5.18; N, 3.72. Chiral
HPLC separation of (±)-benzyl (7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate (Chiralcel AD, water:methanol 1:9) provided two fractions. Fraction 1 (Rf = 13.00 min,
(Chiralcel AD, water:methanol 1:9); Fraction 2 (Rt = 14.1 min, (Chiralcel AD, watenmethanol 1:9).
Intermediate 60: (±)-[7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate
[0142] Treatment of (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 2-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.422 g (81%) of (±)-[7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid, mp 99-101 °C; Anal, calcd. for C22H19FO4S: C, 66.32; H, 4.81. Found: C, 65.16; H, 4.86.
Intermediate 61: (±)-benzyl [7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0143] Treatment of (±)-1 -[7-(2-fiuorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine (1.5 g, 5.36 mmol) with diisopropylethylamine (1.04 g, 8.04 mmol) and benzyl chloroformate (1.01 g, 5.89 mmol) generally according to the procedure described for Intermediate 12 afforded 1.7 g (84%) of (±)-benzyl [7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as a colorless oil Rf= 0.68 (silica, ethyl acetate:hexanes 1:9);
Anal, calcd. for C22H18FNO3: C, 72.72; H, 4.99; N, 3.85. Found: C, 72.65 H, 5.41; N, 3.47.
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Chrial-HPEC-Separation of(±)benzyl [7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methylcarbamate (Chiralcel OJ, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rr = 13.628 min, Chiralcel OJ, hexane:isopropanol 9:1); Fraction 2 (Rt = 17.247 min, Chiralcel OJ, hexane:isopropanol 9:1).
Intermediate 62: (±)-{7-[2-(trifluoromethyl)phenylJ-2,3-dihydro-l-benzofuran-2-yl}methyl 4-methylbenzenesulfonate
[0144] Treatment of (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (10.00 g, 26.10 mmol) with 2-(trifluoromethy)phenylboronic acid (7.43 g, 39.14 mmol), dichlorobis(tri-o-tolylphosphine)palladiurn(II) (0.786 g, 1.3 mmol), and potassium carbonate (9.01 g, 65.19 mmol) generally according to the procedure described for Intermediate 37 afforded 8.46 g (72%) of (±)-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a tan solid, mp 116-118 °C; Anal, calcd. for C23H19F3O4S: C, 61.6; H, 4.27. Found: C, 61.91; H, 4.23.
Intermediate 63: (±)-benzyI {7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methylcarbamate
[0145] Treatment of (±)-l-{7-[2-(trif!uoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine (0.813 g, 2.46 mmol) with diisopropylethylamine (0.478 g, 3.69 mmol) and benzyl chloroformate (0.462 g, 2.71 mmol) generally according to the procedure described for Intermediate 12 gave 0.99 g (94%) of (±)-benzyl {7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}rnethylcarbarnate as a pale yellow oil Rf= 0.60 (silica, ethyl acetate:hexanes
2:8); Anal, calcd. for C24H20F3NO3: C, 67.44; H, 4.71; N, 3.15. Found: C, 67.43 H, 4.76; N,
3.15. Chiral HPLC separation of (±)-benzyl [7-(2-(trifiuoromethyl))-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, isopropanolxarbon dioxide 3:17) provided two fractions. Fraction 1 (Rt = 5.252 min, Chiralcel OJ, isopropanolxarbon dioxide 3:17); Fraction 2 (Rt =
6.280 min, Chiralcel OJ, isopropanolxarbon dioxide 3:17).
Intermediate 64: (±)-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate
[0146] Treatment of (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.00 g, 2.61 mmol) with 2,6-dimethylphenylboronic acid (0.783 g, 5.22 mmol), dichlorobis(rri-o-tolylphosphine)-palladium(II) (0.103 g, 0.135 mmol), and potassium
carbonate (0.90 g, 6.52 mmol) generally according to the procedure described for Intermediate
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37 provided 0.192 g(18%) of (±)[2,6-dimethylpnenyl)-2,3-dinydro-1 -benzoruran-Z-
yl]msthyl 4-methylbenzenesulfonate as a yellow oil. Anal, calcd. for C24H24O4S: C, 70.56; H, 5.92. Found: C, 68.01; H, 5.6.
Intermediate 65: (±)-benzyI [7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0147] Treatment of (±)-l-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine (0.947 g, 3.73 mmol) with diisopropylethylamine (0.725 g, 5.60 mmol) and benzyl chloroformate (0.7647 g, 4.48 mmol) generally according to the procedure described for Intermediate 12 gave 1.26 g (87%) of (±)-benzyl [7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as a colorless oil Rf= 0.56 (silica, ethyl acetate:hexanes 1:4);
Anal, calcd. for C25H25NO3: C, 77.49; H, 6.50; N, 3.61. Found: C, 77.42 H, 6.57; N, 3.62.
Chiral HPLC separation of (±)-benzyl [7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, methanol:carbon dioxide 4:6) provided two fractions. Fraction 1 (Rt = 2.89 min, Chiralcel OJ, methanokcarbon dioxide 4:6); Fraction 2 (Rt = 3.84
min, Chiralcel OJ, methanokcarbon dioxide 4:6).
Intermediate 66: (±)-[7-(2-methoxyphenyI)-2r3-dihydro-l-benzofuran-2-yI]methyl 4-methylbenzenesulfonate
[0148] Treatment of (±)-(7-bromo-2,3-dihydro-1 -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.31 mmol) with 2-methoxyphenylboronic acid (0.297 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)palladium(U) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 gave 0.399 g (74%) of (±)-[7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a tan solid, mp 100-103 °C; Anal, calcd. for C23H22O5S: C, 67.3; H,
5.4. Found: C, 66.95; H, 5.43.
Intermediate 67: (±)-benzyl [7-(2-methoxyphenyI)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0149] Treatment of (±)-l-[7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine (0.296 g, 1.01 mmol) with diisopropylethylamine (1.52 g, 1.5 mmol) and benzyl chloroformate (0.190 g, 1.11 mmol) generally according to the procedure described for Intermediate 12 afforded 0.33 g (84%) (±)-benzyl [7-(2-methoxyphenyl)-2,3-dihydro-l-
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benzofuran-2-yl]methylcarbarriate of a colorless oil Rf= 0.72 (silica, ethyl acetate:hexanes 2:8);
Anal, calcd. for C24H23NO4: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.68 H, 5.81; N, 3.43.
Intermediate 68: (±)-(7-(2-chIorophenyI)-2,3-dihydro-l-benzofuran-2-yl]methyI 4-methylbenzenesulfoaate
[0150] Treatment of (±)-(7-bromo-2,3-dihydro-l -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol)with 2-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.380 g (70%) of (±)-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a tan solid, mp 100-103 °C; Anal, calcd. for C22H19CIO4S: C,
63.69; H, 4.62. Found: C, 63.43; H, 4.69.
Intermediate 69: (±)-benzyl [7-(2-chIorophenyl)-2,3-dihydro-l-benzofuran-2-yl) methylcarbamate
[0151] Treatment of (±)-1 -[7-(2-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine (0.743 g 2.52 mmol) with diisopropylethylamine (0.488 g, 3.77 mmol) and benzyl chloroformate (0.472 g, 2.77 mmol) generally according to the procedure described for Intermediate 12 afforded 0.749 g (76%) (±)-benzyl [7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as a white solid, mp 155-157 °C; Anal, calcd. for C23H20ClNO3: C, 70.14; H, 5.12; N, 3.56. Found: C, 70.1; H, 5.15; N, 3.37. Chiral HPLC separation of (±)-benzyl [7-(2-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methylcarbarnate (Chiralcel OJ, hexane:ethanol 1:1) provided two fractions. Fraction 1 (Rt = 9.655 min, Chiralcel
OJ, hexane:ethanol 1:1); Fraction 2 (Rt = 16.300 min, Chiralcel OJ, hexane:ethanol 1:1).
Intermediate 70: (±)-benzyl [7-(2-isopropylpbenyl)-2,3-dihydro-l-benzofuran-2-yl] methylcarbamate
[0152] Treatment of (±)-[7-(2-isopropylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methylamine (1.69 g, 5.56 mmol) with diisopropylethylamine (1.08 g, 8.34 mmol) and benzyl chloroformate (1.04 g, 6.12 mmol) generally according to the procedure described for Intermediate 12 gave 1.92 (89%) of (±)-benzyl [7-(2-isopropylphenyl)-2,3-dihydro-l-benzoruran-2-yl]methylcarbamate as a yellow oil. Rf= 0.66 (silica, ethyl acetate:hexanes 1:4);
Anal, calcd. for C26H27NO3: C, 77.78; H, 6.78; N, 3.49. Found: C, 77.5; H, 6.7; N, 3.33. Chiral
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HPLC separation of (±)-7-(2-isopopylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methylcarbamate
(Chiralcel OD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rr = 8.131 min, Chiralcel OD, hexane:isopropanol 9:1); Fraction 2 (Rt = 11.048 min, Chiralcel OD, hexane:isopropanol 9:1).
Intermediate 71: (±)-[7-(3-methylphenyI)-2,3-dihydro-l-benzofuran-2-yl]methyI 4-methylbenzenesulfonate
[0153] Treatment of(±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 3-methylbenzeneboronic (0.68 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.899 g (69%) of (±)-[7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf= 0.44 (silica, ethyl
acetate:hexanes 1:3); mp 81-82 °C; Anal, calcd. for C23H22O4SO.2H2O: C, 69.39; H, 5.67. Found: C, 69.42; H, 5.49.
Intermediate 72: (±)-benzyl [7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl] methylcarbamate
[0154] Treatment of (±)-[7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine (1.76 g, 6.38 mmol) with diisopropylethylamine (2.47 g, 19.17mmol) followed by benzyl chloroformate (1.19 g, 7.02 mmol) generally according to the procedure described for Intermediate 12 provided 1.4 g (58%) of (±)-benzyl [7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as a clear oil. Rf= 0.68 (silica, ethyl acetate:hexanes 1:2); Anal, calcd. for C24H23NO3: C, 77.19; H, 6.20; N, 3.75. Found: C, 76.88 H, 6.25; N, 3.51.
Chiral HPLC separation of (±)-benzyl [7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt =
10.439 min, Chiralpak AD, ethanohhexane 1:1); Fraction 2 (Rt = 11.833 min, Chiralpak AD ethanohhexane 1:1).
Intermediate 73: (±)-[7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-metbylbenzenesulfonate
[0155] Treatment of (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-fluorophenylboronic acid (0.274 g, 1.96
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mmol), dichlorobis(tri-o-tolyphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium
carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.392 g (75%) of (±)-[7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid, mp 88-90 °C; Anal, calcd. for C22H19FO4S: C,
66.32; H, 4.81. Found: C, 65.63; H, 4.84.
Intermediate 74: (±)-benzyI [7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0156] Treatment of (±)-[7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine (0.798 g, 2.856 mmol) with diisopropylethylamine (0.554 g, 4.286 mmol) and benzyl chloroformate (0.536 g, 3.143 mmol) generally according to the procedure described for Intermediate 12 afforded 1.01 g(94%)of (±)-benzyl [7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]rnethylcarbamate as a white solid. Rr= 0.40 (silica, ethyl acetate:hexanes 1:4);
Anal. Calcd. for C23H20FNO3: C, 73.2; H, 5.34; N, 3.71. Found: C, 92.96; H, 5.38; N, 3.59.
Intermediate 75: (±)-[7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate
[0157] Treatment of (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.404 g (75%) of (±)-[7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid, mp 101-103 °C; Anal, calcd. for C22H19ClO4S:
C, 63.69; H, 4.62. Found: C, 63.59; H, 4.52.
Intermediate 76: (±)-benzyI [7-(3-chIorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0158] Treatment of (±)-1 -[7-(3-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine (1.6 g, 5.4 mmol) with diisopropylethylamine (1.197 g, 9.26 mmol) and benzyl chloroformate (1.02 g, 5.96 mmol) generally according to the procedure described for Intermediate 12 afforded 1.59 g (75%) of (±)-benzyl [7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]rnethylcarbarnate as a colorless oil. Rf= 0.56 (silica, ethyl acetate:hexanes 1:9);
Anal, calcd. for C23H20ClINO3: C, 70.14; H, 5.12; N, 3.56. Found: C, 69.11; H, 5.07; N, 3.37.
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Chiral HPLC separation of (±)-benzyl[7-(3-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt = 15.935 min Chiralcel OD, hexane:isopropanol 9:1); Fraction 2 (Rt = 18.546 min, Chiralcel OD, hexane:isopropanol 9:1).
Intermediate 77: (±)-[7-(3-methoxyphenyl)-2,3-dinydro-l-benzofuran-2-yl]metbyl 4-methylbenzenesulfonate
[0159] Treatment of (±)-(7-bromo-2,3-dihydro-l-ben2ofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 13.04 mmol) with 3-methoxyphenylboronic acid (2.97 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.512 g, 0.652 mmol) and potassium carbonate (4.51 g, 32.62 mmol) generally according to the reaction conditions described for Intermediate 37 gave 4.48 g (84%) of (±)-[7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid, mp 141-142 °C; Anal, calcd. for C23H22O5S: C, 67.3; H, 5.4. Found: C, 66.51; H, 5.41.
Intermediate 78: (±)-benzyl [7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0160] Treatment of (±)-l-[7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine (2.4 g, 9.4 mmol) with diisopropylethylamine (1.82 g, 14.10 mmol) and benzyl chloroformate (1.92 g, 11.28 mmol) generally according to the reaction conditions described for Intermediate 12 afforded 3.42 g (93%) of (±)-benzyl [7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf= 0.78 (silica, ethyl acetate:hexanes 1:4);
Anal, calcd. for C24H23NO4: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.52; H, 6.06; N, 3.28.
Intermediate 79: (±)-{7-[3-(trifluoromethyl)phenyI]-2,3-dihydro-l-benzofuran-2-yI}methyl 4-methylbenzenesulfonate
[0161] Treatment of (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-(trifiuoromethyl)phenylboronic acid (0.372 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.383 g(65%) of (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid, mp 90-93 °C; Anal, calcd. for C23H19F3O4S: C, 61.6; H, 4.27. Found: C, 61.52; H, 4.21.
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Intermediate:80 (±)-benzyl{3-trifluoromethylphenyl)-2,3-dihydro-l-benzofuran-2-
yl} methylcarbamate
[0162] Treatment of (±)-[7-(3-trifluoromethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine (1.67 g, 5.06 mmol) with diisopropylethylamine (0.98 g, 7.59 mmol) and benzyl chloroformate (1.04 g, 6.07 mmol) generally according to the procedure described for Intermediate 12 provided 2.1 g(97%)of(±)-benzyl {7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methylcarbamate as a colorless oil. Rf= 0.51; Anal, calcd. for
C24H20F3NO3: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.08; H, 5.05; N, 3.22.
Intermediate 81: (±)-[7-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate
[0163] Treatment of (±)-(7-bromo-2,3-dihydro-1 -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (11.2 g, 29.22 mmol) with 4-methylphenylboronic acid (5.96 g, 43.84 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(n) (1.148 g, 1.46 mmol), and potassium carbonate (10.10 g, 73.07 mmol) generally according to the procedure described for Intermediat< 37 afforded 9.8 g (85%) of (±)-[7-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate a white solid, mp 145-147 °C; Anal, calcd. for C23H22O4S: C, 70.03;
H, 5.62. Found: C, 69.91; H, 5.70.
Intermediate 82: (±)-benzyl [7-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0164] Treatment of (±)-[7-(4-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine (0.385 g, 1.396 mmol) with diisopropylethylamine (0.270 g, 2.09 mmol) and benzyl chloroformate (0.285 g, 1.675 mmol) generally according to the procedure described for Intermediate 12 provided 0.483 g (93%) of (±)-benzyl [7-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as colorless oil. Rf= 0.47 (silica, ethyl acetate:hexane 2:8);
mp 83-86 °C; Anal, calcd. for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.97; H,
5.99; N, 3.68. Chiral HPLC separation of (±)-benzyl [7-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate (Chiralpak OD, methanolxarbon dioxide 1:1) provided two fractions. Fraction 1 (Rt = 3.788 min Chiralpak OD, methanolxarbon dioxide 1:1); Fraction 2
(Rf = 4.398 min, Chiralpak OD, methanolxarbon dioxide 1:1).
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Intermediate 83: (±)-[7-(4methoxyphenyl)-2,3-dihydro-1-benzofuran2-yl)methyl 4-
methylbenzenesulfonate
[0165] Treatment of (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (3.0 g, 7.82 mmol) with 4-methoxyphenylboronic acid (1.78 g, 11.74 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.307 g, 0.391 mmol), and potassium carbonate (2.70 g, 19.57 mmol) generally according to the procedure described for Intermediate 37 provided 2.2 g (68%) of (±)-[7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid, mp 116-117 °C; Anal, calcd. for C23H22O5S: C, 67.30; H, 5.40. Found: C, 67.31; H, 5.35.
Intermediate 84: (±)-benzyl [7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0166] Treatment of 1 -[7-(4-methoxyphenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine (0.727 g, 2.49 mmol) with diisopropylethylamine (0.483 g, 3.73) and benzyl chloroformate (0.510 g, 2.99 mmol) generally according to the procedure described for Intermediate 12 provided 0.820 g of (±)-benzyl [7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf= 0.48 (silica, ethyl acetate:hexanes 1:5);
Anal, calcd. for C24H23NO4: C, 74.02; H, 5.95; N, 3.60. Found: C, 73.66 H, 6.13; N, 3.42.
Chiral HPLC separation of (±)-benzyl [7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate (Chiralcel AD, methanol) provided two fractions. Fraction 1 (Rt = 7.386
min, Chiralcel AD, methanol); Fraction 2 (Rt = 10.882 min, Chiralcel AD, methanol).
Intermediate 85: (±)-{7-[4-(trifluoromethyI)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl 4-methylbenzenesulfonate
[0167] Treatment of (±)-(7-bromo-2,3-dihydro-1 -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-(trifluoromethyl)phenylboronic acid (0.372 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.435 g (74%) of (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a light yellow solid, mp 116-118 °C; Anal, calcd. for C23H19F3O4S: C, 61.6; H, 4.27. Found: C, 61.37; H, 4.36.
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Intermediate 86: (±)-benzyl {7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-
yl}methylcarbamate
[0168] Treatment of (±)-l-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine (1.8 g, 6.14 mmol) with diisopropylethylamine (1.06 g, 8.20) and benzyl chloroformate (1.12 g, 6.56 mmol) generally according to the procedure described for Intermediate 12 afforded 2.38 g (91%) of (±)-benzyl {7-[4-(trifluorornethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methylcarbarnate as a white solid. Rf= 0.48 (silica, ethyl acetate:hexanes
1:4); mp 100-102 °C; Anal, calcd. for C24H20F3NO3: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.37; H, 4.69; N, 3.15.
Intermediate 87: (±)-[7-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate
[0169] Treatment of (±)-(7-bromo-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.408 g (78%) of (±)-[7-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid, mp 83-86 °C; Anal, calcd. for C22H19FO4S: C,
66.32; H, 4.81. Found: C, 66.11; H, 4.61.
Intermediate 88: (±)-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate
[0170] Treatment of (±)-(7-bromo-2,3 -dihydro-1 -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 4-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.367 g (68%) of (±)-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as an orange solid, mp 130-133 °C; Anal, calcd. for C22H19ClO4S: C,
63.69; H, 4.62. Found: C, 62.82; H, 4.56.
Intermediate 89: (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyI 4-methylbenzenesulfonate
[0171] Treatment of (±)-(7-bromo-2,3-dihydro-l -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2,4-dichlorophenylboronic acid (3.73 g, 19.57
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mmol), dichlorobis(tri-o-tolyphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium
carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.5 g (75%) of (±)-[7-(2)4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal, calcd. for C22H18Cl2O4S: C, 58.8; H, 4.04.
Found: C, 59.01; H, 4.09.
Intermediate 90: (±)-benzyl [7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl] methylcarbamate
[0172] Treatment of (±)-l-[7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine (1.9 g, 5.75 mmol) with diisopropylethylamine (1.11 g, 8.62) and benzyl chloroformate (1.18 g, 6.89 mmol) generally according to the procedure described for Intermediate 12 afforded 2.14 g (87%) of (±)-benzyl [7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as a white solid, mp 87-89 °C; Anal, calcd. for C23H19Cl2NO3: C, 64.5; H, 4.47; N, 3.27. Found: C, 64.65; H, 4.78; N, 3.08.
Intermediate 91: (±)-3-[2-(benzyIoxy)-5-chloro-3-methoxyphenyl]propane-l,2-diol
[0173] Treatment of 4-chloro-2-methoxyphenol (30.0 g, 0.19 mol) with sodium hydride (9.1 g, 0.23 mol, 60 wt.%) and allyl bromide (27.46 g, 0.23 mol) followed by treatment of the resultant allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 gave 2-allyl-4-chloro-6-methoxyphenol as a yellow oil. Treatment of 2-allyl-4-chloro-6-methoxyphenoi with sodium hydride (7.08 g, 0.177 mol, 60 wt.%) and benzyl bromide (30.27 g, 0.177 mol) generally according to the procedure described for Intermediate 13 provided l-allyl-2-(benzyloxy)-5-chloro-3-methoxybenzene as a pale yellow oil. Treatment of the olefin (35.5 g, 0.123 mol) of with AD-mix-a (132.0 g) generally according to the procedure described for Intermediate 2 gave 35 g (54%) of (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]propane-1,2-diol as a white solid, mp. 65-68 °C. Anal, calcd. for C17H19ClO4: C, 63.26; H, 5.93. Found:
C, 65.29; H, 6.23.
Intermediate 92: (±)-(5-chloro-7-methoxy-2,3-dihydro-l-benzofuran-2-yl)methyI 4-methylbenzenesulfonate
[0174] Treatment of (±)-3-[2-(benzyloxy)-5-chloro-3-memoxyphenyl]-l,2-propanediol (32 g, 0.1 mol) with p-toluenesulfonyl chloride (21 g, 0.11 mol) in pyridine generally according to the procedure described for intermediate 3 provided (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the tosylate with .
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palladium on carbon (2.32 g, 5wt.%) generally according to the procedure described for
Intermediate 4 afforded (±)-3-(5-chloro-2-hydroxy-3-methoxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the phenol with triphenylphosphine (23.6 g, 0.09 mol) and diisopropyl azodicarboxylate (18.2 g, 0.09 mol) generally according to the procedure described for Intermediate 5 afforded 28 g (76%) of (±)-(5-chloro-7-methoxy-2,3-dihydro-l-benzofuran-2-yl)rnethyl 4-methylbenzenesulfonate as a pale yellow solid, mp 99-102 °C; Anal, calcd. for C17H17ClO5S: C, 55.36; H, 4.65. Found: C, 55.35; H, 4.62.
Intermediate 93: (±)-(5-chIoro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0175] Treatment of (±)-(5-chloro-7-methoxy-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methyibenzenesulfonate (22.1 g, 0.06 mol) with hydrogen bromide (400 mL, 30 wt.% in acetic acid) generally according to the procedure described for Intermediate 46 gave 14.6 g of (±)-(5-chloro-7-hydroxy-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(5-chloro-7-hydroxy-2,3-dihydro-l-benzofuran-2-yl)rnethyl 4-methylbenzenesulfonate (4.5 g, 12.68 mmol) with trifiuoromethanesulfonic anhydride (2.34 mL, 13.9 mmol) and diisopropylethylamine (2.43 mL, 13.9 mmol) generally according to the procedure described for Intermediate 7 provided 6.27 g (99%) of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl4-methylbenzenesulfonate as a light yellow solid, mp 55-57 °C; Anal, calcd. for C17H14ClF3O7S2: C, 41.94; H, 2.90. Found: C, 42.10; H, 2.76.
Intermediate 94: (±)-(5-chloro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyI 4-methylbenzenesulfonate
[0176] Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with phenyl boronic acid (0.564 g, 4.60mmol), dichloro[l,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.252 g, 0.30 mmol), and potassium carbonate (0.829 g, 6.0 mmol) generally according to the procedure described for Intermediate 35 provided 0.94 g of a white paste. Re-cRfstallization from methanol afforded 0.6 g (47%) of (±)-(5-chloro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid, mp 127-130 °C; Anal, calcd. for C22H19ClO4S: C, 63.69; H, 4.62. Found: C, 62.51; H, 4.48.
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Intermediate 95: (±)-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl
4-methylbenzenesulfonate
[0177] Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with 3-chlorophenylboronic acid (0.72 g, 4.60 mmol), dichloro[l,l'-
bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.252 g, 0.30 mmol), and potassium carbonate (0.829 g, 6.0 mmol) generally according to the procedure described for Intermediate 35 gave 1.1 g (80%) of (±)-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yljmethyl 4-methylbenzenesulfonate as a white solid, mp 80-82 °C. Anal, calcd. for C22H18Cl2O4S: C, 58.8; H, 4.04. Found: C, 56.91; H, 3.82.
Intermediate 96: (±)-(5-chloro-7-thien-3-yI-2,3-dihydro-l-benzofuran-2-yI)methyI 4-methylbenzenesulfonate
[0178] Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1 -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with thiophene-3-boronic acid (0.62 g, 4.88 mmol), dichloro[l,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.265 g, 0.325 mmol), and potassium carbonate (0.898 g, 6.5 mmol) generally according to the procedure described for Intermediate 35 provided 0.22 g (17%) of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzomran-2-yl)methyl 4-methylbenzenesulfonate as a white solid, mp 115-117 °C; Anal, calcd. for C20H17ClO4S2: C, 57.07; H, 4.07. Found: C,
56.17; H, 3.85.
Intermediate 97: (±)-2-(azidomethyl)-5-chloro-7-(3-methylphenyl)-2,3-dihydro-l-benzofuran
[0179] Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with 3-methylphenylboronic acid (0.63 g, 4.60 mmol), dichloro[l,1-
bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.252 g, 0.30 mmol), and potassium carbonate (0.829 g, 6.0 mmol) generally according to the procedure described for Intermediate 35 gave (±)-[5-chloro-7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of the tosylate with sodium azide (0.31 g, 4.78 mmol) generally according to the procedure described for Intermediate 98 afforded 0.32 g (34%) of (±)-2-(azidomethyl)-5-chloro-7-(3-methylphenyl)-2,3-dihydro-l-benzofuran as a tan
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solid.mp 48-50°C; Anal.calcd. for C16H14ClN3O: C, 64.11; H,4.71; N, 14.02. Found: C,
62.95; H, 4.62; N, 13.72.
Intermediate 98: (±)-2-(azidomethyl)-5-chloro-7-thien-3-yI-2,3-dihydro-l-benzofuran
[0180] To a solution of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.5 g, 10.69 mmol) in dimethylsulfoxide (150 mL) was added sodium azide (3.6 g, 55.38 mmol) and the reaction mixture was heated to 70 °C and allowed to stir for 6 h. The reaction mixture was cooled to room temperature and diluted with water (300 mL) and diethyl ether (200 mL). The aqueous layer was separated and extracted with diethyl ether (200 mL). The combined organic layers were washed with water (3 x 200 mL), saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent removed in vacuo to afford 2.6 g (83%) of (±)-2-(azidomethyl)-5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran as a white solid, mp 50-52 °C; Anal, calcd. for C13H10ClN3OS: C, 53.52;
H, 3.45; N, 14.40. Found: C, 53.50; H, 3.33; N, 14.26.
Intermediate 99: (±)-benzyl (5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate
[0181] Treatment of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1 -benzofuran-2-yl)methylamine (2.45 g, 8.11 mmol) with benzyl chloroformate (2.07 g, 12.15 mmol) and diisopropylethylamine (3.43 g, 24.32 mmol) generally according to the procedure described for Intermediate 12 provided 2.6 g (81%) of (±)-benzyl (5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate as a white solid, mp 90-92 °C; Anal, calcd. for C21H18ClNO3S: C, 63.07; H, 4.54; N, 3.50. Found: C, 63.44; H, 4.51; N, 3.43. Chiral HPLC
separation of (±)-benzyl (5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:ethanol 1:1) provided two fractions. Fraction 1 (Rt = 11.538 min,
(Chiralpak AD, hexane:ethanol 1:1); Fraction 2 (Rt = 17.694 min, (Chiralpak AD, hexane:ethanol 1:1).
Intermediate 100: 2-(allyloxy)-l-bromo-4-fluorobenzene
[0182] Treatment of 2-bromo-5-fluorophenol (10.00 g, 0.052 mol) with potassium carbonate (29.30 g, 0.209 mol) and allyl bromide (7.60 g, 0.063 mol) generally according to the reaction procedure described for Intermediate 8 provided 12.1 g (99%) of 2-(allyloxy)-l-bromo-4-fluorobenzene as a colorless oil. Rr= 0.37 (silica, ethyl acetate:hexanes 1:9); !H NMR
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(DMSO-d6) dH 7.58 (dd, 1H);7.05 (dd, 1H); 6.75 (dt, 1H); 6.02 (m, 1H); 5.43 (d, 1H); 5.27 (d, lH);4.65(m,2H).
Intermediate 101: 2-allyl-6-bromo-3-fluorophenoI
[0183] Treatment of 2-(allyloxy)-l-bromo-4-fluorobenzene (12.00 g, 0.052 mol) in refluxing mesitylene generally according to the reaction procedure described for Intermediate 8 provided 11.5 g (95%) of 2-a]lyl-6-bromo-3-fluorophenol as a pale yellow oil. Rf= 0.48 (silica, ethyl acetate:hexanes 1:4); Anal, calcd. for C9H8BrFO: C, 46.78; H, 3.49. Found: C, 47.59; H, 3.47.
Intermediate 102: (±)-(7-bromo-4-fluoro-2,3-dihydro-l-benzofuran-2-yI)methanol
[0184] Treatment of 2-allyl-6-bromo-3-fluorophenol (9.01 g, 0.039 mol) with 3-chloroperoxybenzoic acid (77%, 13.46 g, 0.06 mol) followed by potassium carbonate (13.82 g, 0.10 mol) generally according to the reaction procedure described for Intermediate 9 gave 6.71 g (70%) of (±)-(7-bromo-4-fluoro-2,3-dihydro-l-benzofuran-2-yl)methanol as a white solid. Rf=
0.20 (silica, ethyl acetate:hexanes 1:4); mp 40-43 °C; Anal, calcd. for C9H8BrFO20.2 H2O: C, 43.13; H, 3.38. Found: C, 42.94; H, 3.15.
Intermediate 103: (±)-(7-brorno-4-fIuoro-2,3-dihydro-l-benzofuran-2-yl)methyI 4-methylbenzenesulfonate
[0185] Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-1 -benzofuran-2-yl)methanol (6.21 g, 0.025 mol) with p-toluenesulfonyl chloride (5.26 g, 0.028 mol) in pyridine (120 mL) generally according to the procedure described for Intermediate 10 afforded 8.85 g (88%) of (±)-(7-bromo-4-fluoro-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rr= 0.60 (silica, ethyl acetate:hexanes 1:1); mp 100-103 °C; Anal, calcd. for
C16H14BrFO4S:C, 47.89; 3.52. Found: 47.89;H,3.68.
Intermediate 104: (±)-(4-fluoro-7-pbenyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0186] Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 4.98 mmol) with phenyl boronic acid (0.91 g, 7.22 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.392 g, 0.498 mmol), and potassium carbonate (1.72 g, 12.46 mmol) acording to the procedure described for Intermediate 37 gave 1.07 g (54%)
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of (±)-(4-fIuoro-7-phenyl-2,3-dihydro-1-benzofuran-2-y])methyI 4-methylbenzenesultonate as a
white solid. Rf= 0.46 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) dH 7.70 (d, 2H);
7.53 (d, 2H); 7.40 (t, 2H); 7.32 (m, 4H); 6.77 (t, 1H); 5.15 (m; 1H); 4.31 (dd, 1H); 4.22 (dd, 1H); 3.30 (dd, 1H, obscured by H2O peak); 3.01 (dd, 1H).
Intermediate 105: (±)-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0187] Treatment of (±)-(7-bromo-4-fiuoro-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.05 g, 5.11 mmol) with 2-methylphenyl boronic acid (1.04 g, 7.66 mmol), dichlorobis(tri-otolylphosphine)-palladium(II) (0.201 g, 0.255 mmol), and potassium carbonate (1.77 g, 12.77 mmol) generally according to the procedure described for Intermediate 37 provided 1.38 g (65%) of (±)-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf= 0.34 (silica, ethyl acetate.-hexanes
1.5:8.5); Anal, calcd. for C23H21FO4S: C, 66.97; H, 5.13. Found: C, 66.95; H, 4.76.
Intermediate 106: 2-allyl-6-bromo-4-fluorophenoI
[0188] Treatment of l-(allyloxy)-2-bromo-4-fluorobenzene (23.90 g, 0.103 mol) in refluxing mesitylene (50 mL) generally according to the procedure described for Intermediate 8 provided 23.44 g (99%) 2-allyl-6-bromo-4-fluorophenol as a brown oil. Rf= 0.64 (silica, ethyl
acetate:hexanes 1:19); Anal, calcd. for C9H8BrFO: C, 46.78; H, 3.49. Found: C, 49.19; H, 3.59.
Intermediate 107: (±)-(7-bromo-5-fluoro-2,3-dihydro-l-benzofuran-2-yl)methanoI
[0189] Treatment of 2-allyl-6-bromo-4-fiuorophenol (25.1 g, 0.109 mol) with 3-chloroperoxybenzoic acid (77%, 56.24 g, 0.326 mol) followed by potassium carbonate (62.19 g, 0.45 mol) generally according to the procedure described for Intermediate 9 provided 20.98 g (78%) of (±)-(7-bromo-5-fluoro-2,3-dihydro-l-benzofuran-2-yl)methanol as a white solid. Rf=
0.54 (silica, ethyl acetate:hexanes 1:1); mp 53-57 °C; Anal, calcd. for C9H8BrFO20.l C4H8O2: C, 44.13; H, 3.47. Found: C, 44.17; H, 3.16.
Intermediate 108: (±)-(7-bromo-5-fluoro-2,3-dihydro-l-benzofuran-2-yI)methyl 4-methylbenzenesulfonate
[0190] Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-l -benzofuran-2-yl)methanol (11.5 g, 0.047 mol) with p-toluenesulfonyl chloride (9.76 g, 0.051 mol) generally according to
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the procedure described for intermediate 10 gave 12.50 g (66%) (±)-(7-bromo-5-fluoro-2,3-
dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf= 0.44 (silica, ethyl acetate:hexanes 1:4); mp 84-86 °C; Anal, calcd. for C16H14BrFC4S: C, 47.89; H, 3.52. Found: C, 47.65; H, 3.63.
Intermediate 109: (±)-(5-fIuoro-7-phenyI-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0191] Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-l -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with phenyl boronic acid (0.912 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 gave 1.62 g (82%) of (±)-(5-fluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. Rf= 0.54 (silica, ethyl acetate:hexanes 1:4); Anal, calcd.
for C22H19FO4S-0.2 C4H8O2: C, 65.82; H, 4.99. Found: C, 65.77; H, 4.99.
Intermediate 110: (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate
[0192] Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-methylphenyl boronic acid (1.017 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 provided 1.58 g (77%) of (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Rf= 0.47 (silica, ethyl acetate:hexanes
3:17); Anal, calcd. for C22H19FO4S-0.2 C4H8O2: C, 66.46; H, 5.30. Found: C, 66.25; H, 4.98.
Intermediate 111: (±)-[7-(2-chIorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyI 4-methylbenzenesulfonate
[0193] Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-l -benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-chlorophenyl boronic acid (1.17 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 afforded 1.44 g (67%) of (±)-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-
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yl]methyl4-methylbenzenesulfonate as a white solid. Rf= 0.26 (silica, ethyl acetate:hexanes
3:17): Anal, calcd. for C22H18ClFO4S: C, 61.04; H, 4.19. Found: C, 61.02; H, 3.95.
Intermediate 112: (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl 4-methylbenzenesulfonate
[0194] Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-fluorophenyl boronic acid (1.05 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 gave 1.94 g (94%) of (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-l-benzoruran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Rf= 0.38 (silica, ethyl acetate:hexanes 3:17); Anal.
calcd. for C22H18F2O4S: C, 63.45; H, 4.36. Found: C, 63.13; H, 4.19.
Intermediate 113: (±)-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl]methyl4-methylbenzenesulfonate
[0195] Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.01 g, 10.0 mmol) with 2-(trifluoromethyl)-phenyl boronic acid (2.85 g, 15.0 mmol), dichlorobis(tri-o-tolylphosphine)palladiurn(II) (0.786 g, 1.00 mmol), and potassium carbonate (3.46 g, 25.00 mmol) generally according to the procedure described for Intermediate 37 provided 4.34 g (93%) of (±)-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow oil. Rf= 0.54 (silica,
ethyl acetate.-hexanes 3:7); Anal, calcd. for C23H18F4O4S: C, 59.22; H, 3.89. Found: C, 60.19; H, 4.29.
Intermediate 114: (±)-benzyl {5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0196] Treatment of (±)-l-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine (3.11 g, 12.1 mmol) with diisopropylethylamine (2.34 g, 18.1 mmol) and benzyl chloroformate (2.27 g, 13.3 mmol) generally according to the procedure described for Intermediate 12 gave 4.35 (92%) of (±)-benzyl [5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf-= 0.83 (silica, ethyl acetate:hexanes 1:9);
Anal, calcd. for C24H22FO3.0.2 H2O: C, 72.97; H, 5.72; N, 3.55. Found: C, 72.8; H, 5.72; N, 3.48. Chiral HPLC separation of (±)-benzyl [5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-
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benzofuran-2-yI]methylcarbamate (Chralcel OD, hexane:sopropanol 8.2) provided two
fractions. Fraction 1 (Rt = 7.269 min, Chiralcel OD, hexane:isopropanol 8:2); Fraction 2 (Rt -8.449 min, Chiralcel OD, hexane:isopropanol 8:2).
Intermediate 115: (±)-beazyI [7-(2-chlorophenyI)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate
[0197] Treatment of (±)-l-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methanamine (2.92 g, 10.5 mmol) with diisopropylethylamine (1.70 g, 13.1 mmol) and benzyl chloroformate (1.97 g, 11.6 mmol) generally according to the procedure described for Intermediate 12 provided 3.02 (70%) of (±)-benzyl [7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methylcarbarnate as a colorless oil. Rf= 0.76 (silica, ethyl acetate:hexanes 1:9);
Anal, calcd. for C23H19ClFNO3O.5 H2O: C, 65.64; H, 4.79; N, 3.33. Found: C, 65.28; H, 4.73;
N, 3.18. Chiral HPLC separation of (±)-benzyl [7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:ethanol 1:1) provided two fractions. Fraction 1 (Rt = 9.322 min, Chiralcel OJ, hexane:ethanol 1:1); Fraction 2 (Rr = 13.646 min,
Chiralcel OJ, hexane:ethanol 1:1).
Intermediate 116: (±)-benzyI {5-fluoro-7-[2-(trifluoromethyI)phenyI]-2,3-dihydro-l-benzofuran-2-yI} methylcarbamate
[0198] Treatment of (±)-l-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine (1.87 g, 5.38 mmol) with diisopropylethylamine (1.74 g, 13.4 mmol) and benzyl chloroformate (1.01 g, 5.92 mmol) following the procedure described for Intermediate 12 provided 2.03 (85%) of (±)-benzyl {5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methylcarbamate as a white solid. Rf= 0.69 (silica, ethyl
acetate:hexanes 1:9); mp 76-80 °C; Anal, calcd. for C24H19F4NO3: C, 64.72; H, 4.3; N, 3.14. Found: C, 65.01; H, 4.3; N, 2.99.
Intermediate 117: (±)-(7-bromo-4,5-difluoro-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0199] Treatment of 2-allyl-6-bromo-3,4-difiuorophenol (5.0 g, 0.020 mol) with 3-chloroperoxybenzoic acid (77%, 8.1 g, 0.036 mol) followed by potassium carbonate (6.94 g, 0.050 mol) generally according to the procedure described for Intermediate 9 afforded (±)-(7-bromo-4,5-difluoro-2,3-dihydro-l-benzofuran-2-yl)methanol a brown oil. Treatment of the
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alcohol with ansopropylethylamine(2.57 g, 0.020 mol), p-toluenesulfonyl chloride (2.28 g,
0.012 mol), and 4-(dimethylamino)pyridine (0.29 g, 2.375 mmol) generally according to the procedure described for Intermediate 45 gave 2.9 g (35%) of (±)-(7-bromo-4,5-difluoro-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf= 0.46 (silica,
ethyl acetate:hexanes 1:3); 1H NMR (DMSO-d6) dH 7.73 (d, 2H); 7.50 (dd, 1H); 7.43 (d, 2H); 5.15 (m, 1H); 4.3 (dd, 1H); 4.22 (dd, 1H); 3.45 (dd, 1H); 3.08 (dd, 1H).
Intermediate 118: (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate
[0200] To a solution of (±)-(7-bromo-4,5-difluoro-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.59 mmol) in dioxane (30 mL) was added phenylboronic acid (0.656 g, 5.38 mmol), dichloro[l,l'-
bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.293 g, 0.359 mmol), and potassium carbonate (0.993 g, 7.18 mmol) and the reaction mixture was heated at reflux for 48 h. The reaction mixture was filtered (celite), rinsed (ethyl acetate), and the combined organic layers were washed with water (100 mL), aqueous sodium chloride (75 mL), dried (sodium sulfate) and the solvent was removed in vacuo to provide a crude solid. Purification by column chromatography (silica, ethyl acetaterhexane 1:9) afforded 1.19 g (80%) of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=
0.76 (silica, ethyl acetate:hexanes 1:9); 1H NMR (DMSO-d6) dH 7.69 (d, 2H); 7.50 (dd, 1H); 7.56 (d, 2H); 7.35 (m, 6H); 5.14 (m, 1H); 4.30 (dd, 1H); 4.20 (dd, 1H); 3.39 (dd, 1H); 3.05 (dd, 1H).
Intermediate 119: (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yI)methyl azide
[0201] To a solution of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.40 mmol) in N,N-dimethylformamide (25 mL) was added sodium azide (0.781 g, 12.02 mmol) and the reaction mixture was heated to 70 °C and allowed to stir for 3 h. The reaction mixture was allowed to cool and the solvent was removed in vacuo to provide a crude solid. The residue was suspended in ethyl acetate (100 mL) and washed with water (50 mL) and aqueous sodium chloride (50 mL), was dried (sodium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 0.68 g (99%) of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl azide as a white solid. Rf= 0.93 (silica, ethyl
acetate:hexanes 1:9); 1H NMR (DMSO-d6) dH 7.65 (d, 2H); 7.41 (m, 3H); 7.31 (t, 1H); 5.15 (m,
1H); 3.64 (m, 2H); 3.46 (dd, 1H); 3.10 (dd, 1H).
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Intermediate 120: (±)-[4,5-difluoro-7-(2-methyIpheny0-2,3-dihydro-l-benzofuran-2-yl)methyl4-methylbenzenesulfonate
[0202] Treatment of (±)-(7-bromo-4,5-dif!uoro-2,3-