DIAZEPINOQUINOLINES, SYNTHESIS THEREOF, AND INTERMEDIATES
THERETO
FIELD OF THE INVENTION
[0001] The present invention relates to methods for synthesizing compounds useful as
5HT2C agonists or partial agonists, derivatives thereof, and to intermediates thereto.
BACKGROUND OF THE INVENTION
[0002] 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).
[0003] 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
effect associated with atypical antipsychotics such as clozapine and olanzapine, and it has
been suggested 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).
[0004] 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 151.: 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
Page 1 of 36

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.5
Neuropharmacology 37: 953-955,1998; Pi 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 brajn 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 will be less likely to
produce extrapyramidal side effects associated with typical antipsychotics.
SUMMARY OF THE INVENTION

or a pharmaceutically acceptable salt thereof , wherein:
=== designates a single or double bond;
n is 0, 0,or 2;
Page 2 of 36
As described herein, the present invention provides methods for preparing compounds having
activity as 5HT2C agonists or partial agonists. These compounds are useful for treating
schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder,
substance-induced psychotic disorder, L-DQPA-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, gastrointestinal disorders, obesity, or a central nervous system deficiency
associated with trauma, stroke, or spinal cord injury. Such compounds include those of formula I:

R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -Ci„6 perfluoroalkyl, or -
OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group;
R3 and R4 are taken together to form a saturated or unsaturated 4-8 membered ring, wherein
said ring is optionally substituted with 1-3 groups independently selected from halogen, -
R, or OR;
R5andR6 are each independently -R; and
R7 is hydrogen or C1-6 alkyl.
[0005] The present invention also provides synthetic intermediates useful for preparing
such compounds.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0006] The methods and intermediates of the present invention are useful for preparing
compounds as described in, e.g. International Patent Application WO 03/091250, in the name
of Ramamoorthy, the entirety of which is incorporated herein by reference. In certain
embodiments, the present compounds are generally prepared according to Scheme I set forth
below:
Page 3 of 36


[0007] In Scheme I above, each of n, PG1, R1, R2, R7, and PG2 is as defined below and in
classes and subclasses as described herein.
[0008] In one aspect, the present invention provides methods for preparing chiral
quinoline compounds of formula J) according to the steps depicted in Scheme 1, above. At
step S-l, an aniline of formula G is reacted with formaldehyde, or an equivalent thereof , and
cyclopentadiene in the presence Qf a mineral acid. In certain embodiments, the Diels-Alder
reaction of N-benzylaniline and cyclopentadiene in the presence of concentrated HC1
provides the cyclopentenyltetrahydroquinoline F, wherein PG1 is benzyl. In other
embodiments, step S-l is performed in a manner substantially similar to that described by
Posson, et al, "Imino Diels-Alder Reaction: Application to the Synthesis of Diverse
Cyclopenta[c]Quinoline Derivatives" Synlett 2000, No. 2,209-212.
[0009] The PG1 group of formulae G and F is a suitable amino protecting group.
Suitable amino protecting groups are well known in the art and include those described in
detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd
edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
Suitable amino protecting groups, taken with the -NH- moiety to which it is attached, include,
but are not limited to, aralkylamines, carbamates, allyl amines, amides, and the like.
Examples of PG1 groups of formulae G and F include t-butyloxycarbonyl (BOC),
Page 4 of 36

ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc),
benzyloxocarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl,
chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the
like. In other embodiments, the PG1 group of formulae Q and F is benzyl.
[0010] At step S-2, the olefin of compound F is reduced and the amino group deprotected
by removal of PG1. One of ordinary skill in the art would recognize that, depending on the
choice of PG1, deprotection and olefin reduction may be performed in the same step. For
example, when the PG1 group of formula F is benzyl, reduction of the olefin would
simultaneously deprotect the amine group. Accordingly, in certain embodiments, the present
invention provides a method of forming a compound of formula E comprising the step of simultaneously reducing the olefin and deprotecting the amino group of formula F. Thus, in
certain embodiments, the PG1 group of formula F is an amino protecting group that is
removed by reduction, e.g. hydrogenation. For example, reduction of the double bond and
deprotection of a benzyl group is achieved in the same reaction by catalytic reduction with
Pd-C under a hydrogen atmosphere. In an alternate method, the removal of PG1 and olefin
reduction at step S-2 may be performed in a stepwise fashion using methods known to one of ordinary skill in the art.
[0011] At step S-3, the racemic compound E is treated with a chiral agent to form a
diastereomeric mixture thereof . In certain embodiments, the racemic compound E is treated
with a chiral acid to form a diastereomeric salt thereof . The resulting diastereomeric mixture
is then separated by suitable means to obtain a compound of formula D. Such suitable means
for separating diastereomeric mixtures are well known to one of ordinary skill in the art and
include, but are not limited to, those methods described herein. It will be appreciated that,
depending upon the chiral acid used, there may be one or more carboxylate moieties present.
In certain embodiments, the chiral acid has two carboxylate moieties as with, for example,
tartaric acid or a derivative thereof .
[0012] Accordingly, one of ordinary skill in the art would appreciate that a compound of formula E may form a hemi salt with said bi-functional chiral acid. As used herein, the term
"hemi salt" refers to an adduct having two molecules of a compound of formula E to each
molecule of chiral acid. Alternatively, the resulting salt may have a one-to-one mixture chiral
acid to a compound of formula E. In certain embodiments, the present invention provides a
compound of formula D wherein said compound of formula I) comprises equal molar
amounts of the chiral acid to an amine of formula E.
Page 5 of 36

[0013] In certain embodiments, each of the aforementioned synthetic steps may be
performed sequentially with isolation of each intermediate F, E, and D performed after each
step. Alternatively, each of steps S-l, S-2, and S-3, as depicted in Scheme I above, may be
performed in a manner whereby no isolation of intermediates F and E is performed.
[0014] When X is a chiral acid, the compound of formula J), at step S-4, is treated with a
suitable base to form the free base compound C. Free bases according to the invention are
also prepared, for example, by contacting a compound of formula D with a suitable base in
the presence of a solvent suitable for free base formation. Such suitable bases include strong
inorganic bases, i.e., those that completely dissociate in water under formation of hydroxide
anion. In certain embodiments, the base is added in an amount of at least about 1 mol. eq.
and, in other embodiments, in an amount of at least about 1 mol. eq. to about 10 mol. eq.
relative to the compound of formula D. Examples of such bases include alkaline metals,
alkaline earth metal hydroxides, and combinations thereof . In other embodiments, the
suitable base is sodium hydroxide.
[0015] Examples of solvents suitable for use during free base formation at step S-4
include polar solvents such as alkyl alcohols, such as Ci to C4 alcohols (e.g. ethanol,
methanol, 2-propanol), water, dioxane, or THF (tetrahydrof uran) or combinations thereof . In
certain embodiments, the suitable solvent is a Ci to C4 alcohol such as methanol, ethanol, 2-
propanol, water, or combination thereof . According to one aspect of the present invention,
aqueous sodium hydroxide is used at step S-4. According to another aspect of the present
invention, the free base formation at step S-4 is performed in a bi-phasic mixture of solvents
whereby the compound of formula C, as it is formed, is extracted into an organic layer.
Thus, a suitable bi-phasic mixture of solvents includes an aqueous solvent and a non-miscible
organic solvent. Such non-miscible organic solvents are well known to one of ordinary skill
in the art and include halogenated hydrocarbon solvents (e.g. methylene chloride and
chlorof orm), benzene and derivatives thereof (e.g. toluene), esters (e.g. ethyl acetate and
isopropyl acetate), and ethers (e.g. MTBE, THF and derivatives thereof , glyme, and diglyme)
and the like. In certain embodiments, the free base formation at step S-4 is performed in a bi-
phasic mixture comprising water and toluene. In other embodiments, the suitable base is
water soluble such that the reaction is performed in a mixture of toluene and a suitable
aqueous base, such as aqueous sodium hydroxide.
[0016] At step S-5, N-alkylation of the chiral compound C affords a compound of formula B. In certain embodiments, this N-alkylation is performed with 2-methyl-2-
Page 6 of 36

oxazoline in the presence of catalytic amount of acid to afford the N-acetyl-N-
ethylenediamine compound B, wherein n is 1 and PG2 is acetyl.
[0017] Removal of the PG2 protecting group of formula B, at step S-6, affords the
diamine compound of formula A. In certain embodiments, the PG2 group of formula B is
removed by acid hydrolysis. It will be appreciated that upon acid hydrolysis of the PG
group of formula B, a salt thereof is formed. For example, where the PG2 group of formula B
is removed by treatment with an acid such as trifiuoroacetic acid, then the resulting diamine
compound would be formed as its trifiuoroacetic acid salt. One of ordinary skill in the art
would recognize that a wide variety of acids are useful for removing amino protecting groups
that are acid-labile and therefore a wide variety of salt forms of a compound of formula A are
contemplated.
[0018] In other embodiments, the PG2 group of formula B is removed by base hydrolysis.
One of ordinary skill in the art would recognize that a wide variety of bases are useful for
removing amino protecting groups that are base-labile.
[0019] At step S-7, a compound of formula A is treated with formaldehyde, or an
equivalent thereof , to provide a compound of formula II. In certain embodiments, a
compound of formula A is treated with aqueous formaldehyde to provide a compound of
formula II. One or ordinary skill in the art would appreciate that substituted formaldehydes
may be used at step S-7 to afford a compound of formula Ha:

or a pharmaceutically acceptable salt thereof , wherein:
n is 0,1, or 2;
RandR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl, or -
OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-e alkyl group; and
R7 is hydrogen or a C1-6 alkyl group.
[0020] One of ordinary skill in the art will appreciate that a compound of formula II, as
prepared by the methods of the present invention, may be treated with a suitable acid to form
Page 7 of 36

a salt thereof . In certain embodiments, a compound of formula II is treated with HC1 to form
the hydrochloride salt thereof .
[0021] As used herein, the term "diastereomeric salt" refers to the adduct of a chiral
compound of formula E with a chiral acid.
[0022] As used herein, the term "enantiomeric salt" refers to the salt of the resolved
chiral compound of formula D, wherein said compound of formula D is enriched in one
enantiomer. As used herein, the term "enantiomerically enriched", as used herein signifies
that one enantiomer makes up at least 80% or 85% of the preparation. In certain
embodiments, the term enantiomerically enriched signifies that at least 90% of the
preparation is one of the enantiomers. In other embodiments, the term signifies that at least
95%» of the preparation is one of the enantiomers.
[0023] According to one aspect, the present invention provides a method for preparing a
compound of formula II:

or a pharmaceutically acceptable salt thereof , wherein:
nis 0,1, or 2;
1 9
R'andlT are each independently halogen, -CN, phenyl, -R, -OR, -Ci.$ perfluoroalkyl, or -
OC1-6 perfluoroalkyl;
each R is independently hydrogen or a Cj.6 alkyl group; and
R7 is hydrogen or Ci_6 alkyl.
[0024] As defined generally above, the n group of formula II is 0, 1, or 2. Accordingly,
the present invention provides a method for preparing a compound of any of formulae Ha,
nb,orIIc:

Page 8 of 36

wherein each of R1, R2, R7, and n is as defined above and herein.
[0025] According to another aspect, the present invention provides a method for
preparing a compound of formula II:

or a pharmaceutically acceptable salt thereof , wherein:
n is 0, 1,or 2;
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl, or -
OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
R7 is hydrogen or C1 alkyl,
comprising the steps of :
(a) providing a compound of formula A:

wherein:
nisO, l,or2;
R'andR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OCi_6 perfluoroalkyl; and
each R is independently hydrogen or a C1-6 alkyl group,
and
(b) reacting said compound of formula A with formaldehyde, or an equivalent thereof , to
form a compound of formula II.
[0026] According to one embodiment, step (b) above is performed using aqueous
formaldehyde. In certain embodiments, aqueous formaldehyde is added in an amount
sufficient to consume the compound of formula A. In certain embodiments, aqueous
Page 9 of 36

formaldehyde is added in amounts of at least about 0.90 mole equivalents, in amounts of about 0.90 mole equivalents to about 1.10 mole equivalents, or in amounts of from about 1.0
mole equivalents to about 1.05 mole equivalents relative to the compound of formula A.
[0027] According to another embodiment, step (b) is performed using a formaldehyde
equivalent. Such formaldehyde equivalents are well known to one of ordinary skill in the art.
In some embodiments, the formaldehyde equivalent is added in solid form to the reaction
solvent to form a reaction suspension or the solid formaldehyde equivalent may be suspended
in a reaction solvent and added to the reaction mixture. In other embodiments,
paraformaldehyde is used as the formaldehyde equivalent, and is added in amounts sufficient
to consume the compound of formula A. In some embodiments, paraformaldehyde is added
in amounts of at least about 0.90 mole equivalents, in amounts of about 0.90 mole equivalents
to about 1.10 mole equivalents, or in amounts of from about 1.0 mole equivalents to about
1.05 mole equivalents relative to the compound of formula A.
[0028] In certain embodiments, paraformaldehyde is in a solid form. Paraformaldehyde
suitable for the reaction is commercially available in prills (or other granulated forms) and
powders from a variety of suppliers such as Aldrich, Fluka, Celanese Chemicals, J.T. Baker,
Mallinckrodt Laboratory Chemicals, Miljac Inc., Sego Int. Corp., Spectrum Chemicals Mfg.,
Total Specialty Chemicals Inc., US Chemicals Inc., Riedel- de Haen, Acros Organics, Pfaltz
& Bauer Chemicals, Derivados, Lancaster Synthesis and EM Science. Certain suitable
powder forms have at least about 10% particles retained on a 200 mesh screen.
[0029] According to another embodiment, the present invention provides a method for
preparing a compound of formula A:

wherein:
nisO, l,or2;
R*andR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl; and
each R is independently hydrogen or a C1-6 alkyl group,
comprising the steps of :
Page 10 of 36


(a) providing a compound of formula C:
wherein:
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -Cj.6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl; and
each R is independently hydrogen or a C1-6 alkyl group,
and
(b) alkylating said compound of formula C to form a compound of formula B:

wherein:
nis 0, l,or2;
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
PG2 is a suitable amino protecting group,
and
(c) deprotecting said compound of formula B to form said compound of formula A.
[0030] In certain embodiments, the alkylation at step (b) above is achieved by reacting
said compound of formula C with a compound of formula wherein said
reaction is performed in a suitable medium and wherein:
nis 0, 1, or 2;
PG is a suitable amino protecting group; and
L1 is a suitable leaving group.
[0031] As defined above, L1 is a suitable leaving group. Suitable leaving groups are well
known in the art, e.g., see, "Advanced Organic Chemistry," Jerry March, 5th Ed., pp. 351-357,
Page 11 of 36

John Wiley and Sons, N.Y. Such leaving groups include, but are not limited to, halogen,
alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted
alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, and diazonium moieties.
Examples of suitable leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyl
(mesyl), tosyl, triflate, nitro-phenylsulfonyl (nosyl), and bromo-phenylsulfonyl (brosyl). In
certain embodiments, L1 is halogen. In other embodiment, L1 is an optionally substituted
alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, or optionally substituted
arylsulfonyloxy group.
[0032] According to an alternate embodiment, the suitable leaving group may be
generated in situ within the reaction medium. For example, the L1 moiety may be generated
in situ from a precursor of that compound of formula wherein said precursor
contains a group readily replaced by L1 in situ. Such an in situ generation of a suitable
leaving group is well known in the art, e.g., see, "Advanced Organic Chemistry," Jerry
March, pp. 430-431, 5th Ed., John Wiley and Sons, N. Y.
[0033] In certain embodiments, said alkylation reaction is optionally performed in the
presence of a suitable base. One of ordinary skill would recognize that the displacement of a
leaving group by an amino moiety is achieved either with or without the presence of a
suitable base. Such suitable bases are well known in the art and include organic and
inorganic bases.
[0034] A suitable medium is a solvent or a solvent mixture that, in combination with the
combined compounds, may facilitate the progress of the reaction therebetween. The suitable
solvent may solubilize one or more of the reaction components, or, alternatively, the suitable
solvent may facilitate the agitation of a suspension of one or more of the reaction
components. Examples of suitable solvents useful in the present invention are a protic
solvent, a halogenated hydrocarbon, an ether, an ester, an aromatic hydrocarbon, a polar or a
non-polar aprotic solvent, or any mixtures thereof . Such mixtures include, for example,
mixtures of protic and non-protic solvents such as benzene/methanol/water; benzene/water;
DME/water, and the like.
[0035] These and other such suitable solvents are well known in the art, e.g., see,
"Advanced Organic Chemistry", Jerry March, 5th edition, John Wiley and Sons, N.Y.
[0036] As defined generally above, the PC-2 group of formula B is a suitable amino
protecting group. Suitable amino protecting groups are well known in the art and include
Page 12 of 36

those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G.
M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein
by reference. Suitable amino protecting groups, taken with the -NH- moiety to which it is
attached, include, but are not limited to, aralkylamines, carbamates, allyl amines, amides, and
the like. Examples of PG2 groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl,
methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl
(CBZ), allyl, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl,
dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like. In other
embodiments, PG2 group is acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl,
or trifluoroacetyl. In still other embodiments, the amino protecting group is acetyl.
[0037] According to yet another embodiment, one or more reagents may perform as the
suitable solvent. For example, an organic base such as triethylamine or
diisopropylethylamine, if utilized in said reaction, may serve as the solvent in addition to its
role as a basifying reagent.
[0038] In other embodiments, the alkylation at step (b) above is achieved by reacting said
compound of formula C with in the presence of a suitable acid to form a compound
of formula B wherein n is 1 and PG2 is acetyl. Such suitable acids are well known in the art
and include inorganic acids, e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, nitric
acid, sulfuric acid or perchloric acid, or organic acids, e.g. acetic acid, oxalic acid, maleic
acid, tartaric acid, citric acid, succinic acid, malonic acid, lower alkyl sulfonic acids or aryl
sulfonic acids. In certain embodiments, the alkylation at step (b) above is achieved by
reacting said compound of formula C with in the presence of toluenesulfonic acid.
[0039] Yet another aspect of the present invention provides a method for preparing a
compound of formula D:

wherein:
I rR and R are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
Page 13 of 36

each R is independently hydrogen or a C1-e alkyl group; and
X is a chiral agent,
comprising the steps of :
(a) providing a compound of formula E:

wherein:
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl; and
each R is independently hydrogen or a C1-6 alkyl group,
and
(b) treating said compound of formula E with a chiral agent to form a compound of formula
D-l:

wherein:
RxandR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
X is a chiral agent,
and
(c) obtaining said compound of formula J) by suitable physical means.
[0040] The term "chiral agent" refers to an enantiomerically enriched group which may
be ionically or covalently bonded to the nitrogen of a compound of formula E. As used
herein, the term "enantiomerically enriched", as used herein signifies that one enantiomer
makes up at least 85% of the preparation. In certain embodiments, the term enantiomerically
enriched signifies that at least 90% of the preparation is one of the enantiomers. In other
embodiments, the term signifies that at least 95% of the preparation is one of the
enantiomers.
Page 14 of 36

[0041] Chiral agents which are ionically bonded to said nitrogen include chiral acids.
When the chiral agent is a chiral acid, the acid forms a diastereomeric salt with the nitrogen.
The resulting diastereomers are then separated by suitable physical means. Examples of chiral acids include, but are not limited to, tartaric acid and tartaric acid derivatives, mandelic
acid, malic acid, camphorsulfonic acid, and Mosher's acid, among others. In certain
embodiments, the chiral acid is ditoluoyl-D-tartaric acid. In other embodiments, the chiral
acid is ditoluoyl-L-tartaric acid. Chiral agents which may be covalently bonded to the
nitrogen are known in the art.
[0042] The term "separated by suitable physical means" refers to methods of separating
enantiomeric or diastereomeric mixtures. Such methods are well known in the art and
include preferential crystallization, distillation, and trituration, among others. Chiral agents
and separation methods are described in detail in Stereochemistry of Organic Compounds,
Eliel, E. L. and Wilen, S. H., 1994, published by John Wiley and Sons.
[0043] In certain embodiments, a chiral salt of formula D is obtained via preferential
crystallization of a diastereomeric salt formed at step (b) above. In other embodiments, the
crystallization is achieved from a protic solvent. In still other embodiments, the protic
solvent is an alcohol. It will be appreciated that the crystallization may be achieved using a
single protic solvent or a combination of one or more protic solvents. Such solvents and
solvent mixtures are well known to one of ordinary skill in the art and include one or more
straight or branched alkyl alcohols. In certain embodiments, the crystallization is achieved
from isopropyl alcohol.
[0044] In certain embodiments, the chiral salt of formula D comprises an equimolar
amount of chiral acid and amine. In other embodiments, the chiral salt of formula D
comprises a substoichiometric amount of chiral acid. As used herein, the term
"substoichiometric amount" denotes that the chiral acid is used in less than 1 mole equivalent
relative to the compound of formula E. In certain embodiments the chiral acid is employed
in less than 0.98 mole equivalents. In other embodiments the amine base is employed in less
than 0.95 mole equivalents.
[0045] It should be readily apparent to those skilled in the art that enantiomeric
enrichment of one enantiomer in the crystallized compound D causes an enantiomeric
enrichment in the mother liquor of the other enantiomeric form. Therefore, according to
another embodiment, the invention relates to a method of enhancing the %ee of a racemic or
enantiomerically enriched compound of formula P as compared with a compound of formula
Page 15 of 36

P-l. As used herein, the term "%ee" refers to the percent enantiomeric excess as would be
understood by one of ordinary skill in the art.
[0046] In another preferred embodiment, the crystallized compound D is optionally
subjected to an additional crystallization step to cause crystallization and further enrichment
of the depicted enantiomer.
[0047] According to another embodiment, the present invention provides a method of
obtaining an enantiomerically enriched compound of formula J):

wherein:
R'andR2 are each independently halogen, -CN, phenyl, -R, -OR, -Ci„6 perfluoroalkyl,
or -QC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
X is a chiral agent,
comprising the steps of :
(a) combining a compound of formula D-l:

wherein:
R*andR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
each R is independently hydrogen or a Ci alkyl group; and
X is a chiral agent,
with a suitable solvent and heating to form a solution thereof ; and
(b) allowing said solution to cool to cause crystallization of an enantiomerically enriched
compound of formula D.
[0048] In certain embodiments, the suitable solvent utilized in step (a) above is a protic
solvent. In still other embodiments, the protic solvent is an alcohol. It will be appreciated
that the crystallization may be achieved using a single protic solvent or a combination of one
Page 16 of 36

or more protic solvents. Such solvents and solvent mixtures are well known to one of
ordinary skill in the art and include one or more straight or branched alkyl alcohols. In
certain embodiments, the crystallization is achieved using a mixture of methanol and
isopropyl alcohol.
[0049] In certain embodiments, the present invention provides a compound of formula D-
1:

wherein:
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -Ci_6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
each R is independently hydrogen or a Ci_6 alkyl group; and
X is a chiral agent.
[0050] According to another embodiment, the present invention provides a compound of either of formulae D-l and D-2:

wherein each R1, R2 and X is as defined above and in classes and subclasses defined above
and herein.
[0051] According to one embodiment, the R1 and R2 groups of formulae D-l and D-2 are
each independently an R group. According to another embodiment, one of R1 and R2 is
hydrogen. According to yet another embodiment, both of R1 and R2 are hydrogen.
[0052] In certain embodiments, the X group of formulae D-l and D-2 is a chiral acid,
thus forming a chiral salt. In other embodiments, the X group of formulae D-l and D-2 is a
tartaric acid derivative. In still other embodiments, the X group of formulae D-l and D-2 is
ditoluoyl-D-tartaric acid.
[0053] Yet another embodiment provides a compound of formula D:
Page 17 of 36


wherein:
R'andR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -QC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
X is a chiral agent.
[0054] According to one embodiment, the R and R groups of formula D are each
independently an R group. According to another embodiment, one of R and R is hydrogen.
According to yet another embodiment, both of R andR are hydrogen.
[0055] In certain embodiments, the X group of formula D is a chiral acid, thus forming a
chiral salt. In other embodiments, the X group of formula D is a tartaric acid derivative. In
still other embodiments, the X group of formula D is ditoluoyl-D-tartaric acid.
[0056] According to another embodiment, the present invention provides a compound of formula D, wherein R1 and R2 are both hydrogen and said compound is of formula D-3:

[0057] In certain embodiments, a compound of formula D-3 is provided substantially free
of the corresponding enantiomer. "Substantially free," as used herein, means that the
compound is made up of a significantly greater proportion of one enantiomer. In other
embodiments, at least about 95% by weight of a desired enantiomer is present. In still other
embodiments of the invention, at least about 99% by weight of a desired enantiomer is
present. Such enantiomers may be isolated from racemic mixtures by any method known to
those skilled in the art, including high performance liquid chromatography (HPLC) and chiral
salt resolution, or prepared by methods described herein.
[0058] Yet another aspect of the present invention provides a method for preparing a
compound of formula D:
Page 18 of 36


wherein:
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C alkyl group; and
X is a chiral agent,
as described above and herein, wherein said method further comprises the step of treating
said compound of formula D with a suitable base to form the free-base compound of formula
C:

wherein:
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl; and
each R is independently hydrogen or a C1-6 alkyl group.
[0059] As used herein, the suitable base is an organic or inorganic base. Such suitable
bases include strong inorganic bases, i.e., those that completely dissociate in water under
formation of hydroxide anion. In certain embodiments, the base is added in an amount of at
least about 1 mol. eq. and, in other embodiments, in an amount of at least about 1 mol. eq. to
about 10 mol. eq. relative to the compound of formula D. Examples of such bases include
alkaline metals, alkaline earth metal hydroxides, and combinations thereof . In other
embodiments, the suitable base is sodium hydroxide.
[0060] According to one embodiment, the free base formation is performed in the
presence of a suitable solvent. Examples of solvents suitable for use during the free base
formation include polar solvents such as alkyl alcohols, such as Ci to C4 alcohols (e.g.
ethanol, methanol, 2-propanol), water, dioxane, or THF (tetrahydrof uran) or combinations
thereof . In certain embodiments, the suitable solvent is a Ci to C4 alcohol such as methanol,
Page 19 of 36

ethanol, 2-propanol, water, or combination thereof . According to one aspect of the present
invention, the suitable base is aqueous sodium hydroxide and, thus, the solvent is water.
[0061] According to another aspect of the present invention, the free base formation is
performed in a bi-phasic mixture of solvents whereby the compound of formula C, as it is
formed, is extracted into an organic layer. Thus, a suitable bi-phasic mixture of solvents
includes an aqueous solvent and a non-miscible organic solvent. Such non-miscible organic
solvents are well known to one of ordinary skill in the art and include halogenated
hydrocarbon solvents (e.g. methylene chloride and chlorof orm), benzene and derivatives
thereof (e.g. toluene), esters (e.g. ethyl acetate and isopropyl acetate), ethers (e.g. MTBE,
THF and derivatives thereof , glyme, and diglyme), and the like. In certain embodiments, the
free base formation is performed in a bi-phasic mixture comprising water and toluene. In
other embodiments, the suitable base is water soluble such that the reaction is performed in a
mixture of toluene and a suitable aqueous base, such as aqueous sodium hydroxide.
[0062] In certain embodiments, the present invention provides a compound of formula
III:

or a salt thereof , wherein:
nisO, 1, or 2;
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -Ci_6 perfluoroalkyl, or -
OCi„6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
R3 is NH2 or a suitably protected amino group.
[0063] In certain embodiments, the R1 and R2 groups of formula I are each R. In other
embodiments, one of R1 and R2 is hydrogen. In still other embodiments, both of R1 and R2
are hydrogen.
[0064] Suitable amino protecting groups are well known in the art and include those
described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by
reference. Suitably protected amino groups of R3 include, but are not limited to,
Page 20 of 36

aralkylamines, carbamates, allyl amines, amides, and the like. Examples of such groups
include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl,
trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, benzyl
(Bn), fluorenylmethylcarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl,
phenylacetyl, trifluoroacetyl, benzoyl, and the like. In other embodiments, the amino
protecting group is acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, or
trifluoroacetyl. In still other embodiments, the amino protecting group is acetyl.
[0065] In certain embodiments, the present invention provides a compound of formula
Ha or He, or a pharmaceutical acceptable salt thereof :

wherein each of R1, R2, and R7 is defined above and herein.
[0066] In certain embodiments, the present invention provides a compound of formula
Ila wherein R1, R2, and R7 are all hydrogen.
[0067] In other embodiments, the present invention provides a compound of formula lie
wherein R1, R2, and R7 are all hydrogen.
[0068] Pharmaceutically acceptable salts, including mono- and bi- salts, are those derived
from such organic and inorganic acids such as, but not limited to 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, and similarly known acceptable acids.
[0069] A used herein, the term halogen refers to chloride, fluorine, bromine or iodine.
The C1-e alkyl group may be a straight or branched chain alkyl. Suitable alkyl groups include
methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. The C1-6perfluoroalkyl group
may include a straight or branched chain alkyl. Suitable perfluoroalkyl groups include
trifluoromethyl and pentafluoroethyl.
EXAMPLES
[0070] As indicated herein, the %ee data was obtained via the following chiral HPLC
method:
Page 21 of 36

Column: Chiralcel OD 4.6 x 250
Mobile Phase: Hexane:IPA:MeOH:TEA 800:10:10:0.5
Flow rate: 1 mL/minute
Temperature: Ambient
Time: 12 minutes
Wavelength: 210 nm
[0071] As indicated herein, the % purity data was obtained via the following chiral HPLC
method:
Column: Chromolith Performance RP-18e (100 x 4.6 mm)
Mobile Phase: A = 95:5:0.1 water:CH3CN:H3P04
B = 95:5:0.1 CH3CN:water:H3P04
Gradient: 5% B to 95% B over 8 minutes
Flow rate: 1 mL/minute
Temperature: Ambient
Time: 10 minutes
Wavelength: 210 nm
Example 1 (Method A)
2,3>3a,4,5,9b-Hexahydro-lH-cyclopenta(c)quinoIine:

[0072] N-phenylbenzylamine hydrochloride (2.0 g) in 20 mL MeOH was cooled to ~5°C.
Freshly cracked cyclopentadiene (1.2 g, from atmospheric heating/distillation of dicyclopentadiene) was added to the solution followed by aqueous formaldehyde (37%, 1.04
g). The reaction temperature was maintained at 5-10 °C overnight (ca. 18 hrs). No starting
material was observed by TLC (10% ethyl acetate in hexanes). The reaction was then
allowed to warm to RT. The reaction was diluted with EtOAc and washed with 0.5N NaOH
solution, and then brine. Concentration of the organics gave 2.32 g of crude tricyclic product
as an oil. The crude oil from above in 20 mL 1:1 EtOH:EtOAc was treated with 0.175 mL IN
HC1 in EtOH and then 5% Pd-C (0.250 g, 50% wet). The mixture was shaken under 40-45
psi H2 overnight. The solids were removed by filtration through celite and the pad is rinsed
with EtOAc. The filtrate was concentrated to give a peach colored oil which crystallized
under vacuum to give 1.38 g (87%) debenzylated product.
Page 22 of 36


(-) 2,3,3a,4,5,9b-Hexahydro-lH-cyclopenta(c)quinoline di-p-toluoyl-D-tartaric acid (6):
[0073] A mixture of the racemic amine (16.0 g, 92.3 mmol), di-p-toluoyl-D-tartaric acid
(23.3 g, 60.3 mmol) in IPA (160 mL) was heated to 70 °C for 10-15 minutes. The solids
dissolved during this time. The solution was cooled to 0-5 °C over 3 hours. The resulting
solids were filtered, washed with cold IPA (60 mL), and dried at 40 °C to give 21.0 g (40%)
of the salt as an of f-white solid. Chiral HPLC: 85%ee; lH NMR (d6-DMSO) 8 7.91 (d, J=6
Hz, 4H), 7.40 (d, J=6 Hz, 4H), 6.97 (d, J=6 Hz, 1H), 6.84 (t, J=6 Hz, 1H), 6.4-6.6 (m, 2H),
5.83 (s, 2H), 2.9-3.1 (m, 2H), 2.8-3.1 (m, 1H), 2.8-2.9 (m, 1H), 2.5-2.7 (m, 1H), 2.5 (m, 1H),
2.3-2.5 (s, 6H), 2.0-2.2 (m, 3H), 1.8-2.0 (m, 1H), 1.2-1.7 (m, 4H); 13C NMR (d6-DMSO) 5
167.6, 165.0, 145.7, 144.9, 129.9, 129.8, 129.7, 126.2, 125.2, 116.4, 114.4, 71.7, 43.6, 40.7,
35.8,35.4,29.3,23.0,21.6.
Example 2 (Method B)
(-) 2,3,3a,4,5,9b-Hexahydro-lH-cyclopenta(c)quinoline di-p-toluoyl-D-tartaric acid (6:

[0074] In an alternative method, N-phenylbenzylamine (50 g) in 250 mL MeOH was
stirred mechanically until dissolved. 29 mL cone. HC1 was added in a single portion. The
mixture was allowed to cool to RT. The amine HC1 salt gradually came out of solution. The
Page 23 of 36

suspension was cooled in ice to about 15 °C and the freshly distilled cyclopentadiene [29.4 g,
cyclopentadiene is obtained by thermal cracking of dicyclopentadiene via atmospheric short
path distillation (pot temperature 165-170 °C, distillate ca. 60-70 °C). The cyclopentadiene
was collected into an ice-cooled receiver] was added in a single portion. The temperature
was allowed to drop back to 15 °C before proceeding, if necessary. Formaldehyde solution
(37% aqueous) in 150 mL MeOH was added dropwise so as to maintain an internal
temperature of 15-25 °C (15 mins addition time). A yellow solution resulted. Once the
addition was complete, the reaction was allowed to stir at RT overnight under nitrogen (12-
18h). The solution was clear, but greenish. The solution was transferred to a 2L Parr bottle
and treated with 1.5 g 10% Pd/C (50% wet) and shaken under 45 psi hydrogen until uptake
ceased. Once complete, the mixture was purged with nitrogen and treated with sodium
bicarbonate (58 g). The slurry was stirred until the solution was neutral to slightly basic by
damp pH paper. The mixture was then filtered through 1 cm celite and the pad rinsed with
MeOH (50 mL). The filtrate was concentrated in vacuo and 450 mL IPA added. The
mixture was stirred overnight and the resulting solids filtered and rinsed with 50 ml PA. To
the filtrate obtained above was added di-p-toluoyl-D-tartaric acid (63.3 g) in a single portion.
The slurry was heated to ca. 80°C to dissolve all solids. The mixture was then allowed to
gradually cool to RT and stir for 3 or more hours. The mixture was then cooled to 0-5°C in
ice and stirred at this temperature for 1-2 hours. The solids were filtered and washed with
100 mL of cold IPA. The faintly blue-green solids were dried in vacuo to afford the title
compound. Yield: 46.7 g (31%) Chiral purity (HPLC): 95:5%ee.
Example 3
(-) 2,3,3a,4,5,9b-Hexahydro-lH-cyclopenta(c)quinoline (7):

[0075] To a suspension of the ditoluoyl-D-tartrate salt (20.67 g, 37 mmol) in toluene (93
mL), aq. NaOH (12 mL of 30% NaOH diluted to 100 mL with water) was added over 5 min.
The two-phase mixture was stirred vigorously and the solids slowly dissolved. The two
layers were separated. The aqueous layer was extracted with toluene (46 mL). The
combined organic layers were concentrated to give 6.4 g (100% yield) of the free base as
Page 24 of 36

yellow oil. NMR (CDCI3) 5 7.09 (d, J=7.5 Hz, 1H), 6.9-7.0 (m, 1H), 6.6-6.7 (m, 1H), 6.4-
6.5 (m, 1H), 3.85 (bs, 1NH), 2.9-3.2 (m, 2H), 2.8-3.1 (m, 1H), 2.80 (t, J=10.3 Hz, 1H), 2.3-
2.4 (m, 1H), 2.0-2.2 (m, 1H), 1.8-2.1 (m, 1H), 1.3-1.8 (m, 4H).
Example 4
(-)[2-(l,2,353a,4,9b-Hexahydro-cyclopenta[c]quinolin-5-yl)-ethylaminetrifluoroacetic
acid salt (10):

[0076] A mixture of amine (6.4g, 36.9 mmol) and a catalytic amount of p-toluenesulfonic
acid (0.07g, 0.37 mmol) was heated to 165 °C. Added 2-methyl-2-oxazoline slowly over 2 h
to the reaction mixture at 165 °C. Cooled the reaction mixture to 60 °C and then added dil.
H2SO4 (6 ml of cone. H2S04 and 26 mL of water). Stirred for lh at 60 °C. Cooled to RT,
added toluene (40 mL) and 30% NaOH (30 mL). Filter of f the solids and wash it with toluene
(2x10 mL). Each wash was used to extract the aqueous layer. Washed the combined organic
extracts with water (25 mL). Concentrate the toluene layer to 20 mL volume and cooled to 10
°C. Added a solution of trifluoroacetic acid (2.4 mL, 31.2 mmol) in toluene (7.5 mL) over 15
min. Stirred for 2 h at 10 °C. It was filtered and washed with toluene (10 mL). Dried the TFA
salt at 55 °C in a vacuum oven. 7.7 g (yield 63%) HPLC 97.6% Chiral Purity 92.2 : 7.8.
Example 5
(-)-4,5,6,7,9,9a40A14242a-decahydrocyclopenta[c][l,4]diazepino[6,7,l-y]q«moluie
hydrochloride (12):

[0077] To a solution of N-ethylenediamine TFA salt (2.3 g, 7.0 mmol) in water 120 mL)
at 60 C was added aqueous formaldehyde (0.72 g, 37% wt in water, 8.8 mmol, 1.26 equivs)
Page 25 of 3 6

over a period of 2.0 h. After 19 h at 60 °C, it was cooled to ambient temperature. To the
reaction mixture sodium hydroxide (0.38 g) and isopropyl acetate (20 mL) was added. The
layers were separated and the aqueous layer was extracted with isopropyl acetate (10 mL).
The organic layers were combined and washed with water (10 mL). To the organic layer was
added conc.HCl (0.82 g) drop wise. The solids were filtered and washed with isopropyl
acetate (5 mL). The crude product (2.44 g) was heated to 70 °C in ethanol (14 ml, 200 proof ,
denatured with 4% ethyl acetate) and then water (1.0 ml) was added. The solution was cooled
to 5 °C over 3 hours. The product was filtered and washed with cold ethanol (2.4 mL). The
wet product (1.4 g) was dried in a vacuum oven for 20 hours at 40 °C to afford the title
compound (1.1 g, yield 60%) as a white solid. A second crop of 0.34 g (18%) was isolated
from the mother liquor. HPLC (area%): 96.5%; Chiral purity (HPLC): 99.87 : 0.13
Page 26 of 36

CLAIMS
We claim:
1. A method for preparing a compound of formula II:

or a pharmaceutically acceptable salt thereof , wherein:
nis 0,1, or 2;
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl, or -
OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
R7 is hydrogen or Ci_6 alkyl,
comprising the steps of :
(a) providing a compound of formula E


wherein:
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
Page 27 of 36
or -OC1-6 perfluoroalkyl; and
each R is independently hydrogen or a Ci_6 alkyl group,
(b) treating said compound of formula E with a chiral agent to form a compound of formula
D-l:


wherein:
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
X is a chiral agent,
(c) obtaining a compound of formula D by suitable physical means:

wherein:
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
X is a chiral agent,
(d) treating said compound of formula D with a suitable base to provide a compound of formula C:

wherein:
R'andRz are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
Page 28 of 36
or -OC1-6 perfluoroalkyl; and
each R is independently hydrogen or a C1-6 alkyl group,
(e) alkylating said compound of formula C to form a compound of formula B:


wherein:
nis 0, l,or2;
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -Ci_6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
PG2 is a suitable amino protecting group,
(f) deprotecting said compound of formula B to form a compound of formula A.

wherein:
nis 0,1, or 2;
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -Cj_6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl; and
each R is independently hydrogen or a Cj.6 alkyl group,
and
(g) reacting said compound of formula A with formaldehyde, or an equivalent thereof , to
form a compound of formula II.
2. The method according to claim 1, wherein each n is 1 and R and R are both
hydrogen.
3. The method according to claim 1 or 2, wherein said formaldehyde is aqueous
formaldehyde.
4. The method according to any one of claims 1,2, or 3, wherein the alkylation at
step (e) is achieved by reacting said compound of formula C with in the presence of
a suitable acid to form a compound of formula B:
Page 29 of 36

wherein n is 1 and PG2 is acetyl.
5. A method for preparing a compound of formula D:

wherein:
R1 andR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
X is a chiral agent,
comprising the steps of :
(a) providing a compound of formula E:

wherein:
R!andR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OC1-6 perfluoroalkyl; and
each R is independently hydrogen or a C1-6 alkyl group,
and
(b) treating said compound of formula E with a chiral agent to form a compound of formula
D-l:
Page 30 of 36


wherein:
R1 and R2 are each independently halogen, -CN, phenyl, -R, -OR, -Ci_6 perfluoroalky
or -OC1-s perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
X is a chiral agent,
and
(c) obtaining said compound of formula D by suitable physical means.
6. The method according to claim 5, wherein X is a chiral acid.
7. The method according to claim 6, wherein the chiral acid is ditoluoyl-D-
tartaric acid and the compound of formula D is obtained by crystallization from a protic
solvent.
8. The method according to claim 7, wherein the compound of formula D is
enantiomerically enriched.
9. The method according to claim 6, comprising obtaining an enantiomerically
enriched compound of formula D:

wherein:
R!andR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OCi„6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
X is a chiral agent,
comprising the steps of :
Page 31 of 36

(a) combining a compound of formula D-l:

wherein:
RWR2 are each independently halogen, -CN, phenyl, -R, -OR, -Ci.g perfluoroalkyl,
or -OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
X is a chiral agent,
with a suitable solvent and heating to form a solution thereof ; and
(b) allowing said solution to cool to cause crystallization of an enantiomerically enriched
compound of formula D.
10. The method according to claim 9, wherein X is ditoluoyl-D-tartaric acid and
said suitable solvent is a protic solvent.
11. The method according to claim 10, wherein said suitable solvent comprises a
mixture of methanol and isopropyl alcohol.
12. The method according to claim 9, further comprising the step of treating said
compound of formula D with a suitable base to form the free-base compound of formula C:

wherein:
R1and R2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl, or
-OC1-6 perfluoroalkyl; and
each R is independently hydrogen or a C1-6 alkyl group.
13. The method according to claim 12, wherein said method is performed in a bi-
phasic mixture of solvents.
Page 32 of 36

14. The method according to claim 13, wherein said method is performed in a
mixture of toluene and aqueous sodium hydroxide.
15. A compound of formula III:

or a salt thereof , wherein:
nisO, l,or2;
R1 and R2 are each independently halogen, -CISf, phenyl, -R, -OR, -Ci.6 perfluoroalkyl, or -
OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
R3 is NH2 or a suitably protected amino group.
16. The compound according to claim 15, wherein R3 is hydrogen or acetyl.
17. The compound according to claim 16, wherein R1 and R2 are each R.
18. The compound according to claim 17, wherein both of R1 and R2 are
hydrogen.
19. A compound of formula D-l:

wherein:
RJandR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl,
or -OCi_6 perfluoroalkyl;
Page 33 of 3 6

each R is independently hydrogen or a Ci_6 alkyl group; and
X is a chiral agent.
20. The compound according to claim 19, wherein X is a chiral acid and each of R1 and R2 is hydrogen.
21. The compound according to claim 20, wherein X is ditoluoyl-D-tartaric acid.
22. The compound according to claim 21, wherein said compound comprises an
equimolar amount of X.
24. The compound according to claim 19, wherein said compound is of formula
D:

23. The compound according to claim 22, wherein said compound is of either of formulae D-l or D-2:

25. The compound according to claim 24, wherein R1 and R2 are each
independently an R group and X is a chiral acid.
26. The compound according to claim 25, wherein both of R1 and R2 are hydrogen
and X is ditoluoyl-D-tartaric acid.
Page 34 of 36

27. The compound according to claim 19, wherein said compound is of formula
D-3:

28. The compound according to claim 27, wherein said compound is provided
substantially free of the corresponding enantiomer.
i
29. A compound of formula Ila or He:

or a pharmaceutically acceptable salt thereof , wherein:
nisO, l,or2;
R'andR2 are each independently halogen, -CN, phenyl, -R, -OR, -C1-6 perfluoroalkyl, or -
OC1-6 perfluoroalkyl;
each R is independently hydrogen or a C1-6 alkyl group; and
R7 is hydrogen or C1-6 alkyl.
Page 35 of 36

The present invention relates to methods for synthesizing compounds useful as 5HT2C
agonists or partial agonists, derivatives thereof, and to intermediates thereto.