This invention relates to process for preparing quinoline compounds and
products obtained therefrom
FIELD OF THE INVENTION
The present invention relates to methods for synthesizing
tetrahydroquinoline compounds, as well as intermediates and products associated
with such methods,
BACKGROUND OF THE INVENTION
International Patent Application WO 03/091250, in the name of
Ramamoorthy, discloses tetrahydroquinoline-containing compounds, methods for
their preparation, and methods for using them as, for example, psychotic and
antiobesity agents. Alternative synthetic methods for these and other
tetrahydroquinoline-containing compounds are desired.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides methods for preparing
tetrahydroquinoline-containing compounds by reacting benzodiazepines with
paraformaldehyde and suitable unsaturated moieties such as alkenes (including
dienes) or alkynes. In certain embodiments, the methods of the invention are
directed to preparing tetrahydroquinolines and involve reacting benzodiazepine with
a solid formaldehyde equivalent, such as paraformaldehyde and an alkene or alkyne
in the presence of a Lewis acid and a reaction solvent. Reaction solvents useful for
forming such tetrahydroquinoline-containing compounds include polar aprotic
solvents such as alkyl nitrites (e.g., acetonitrile, propionitrile and butyronitrile), esters
(e.g., ethyl acetate), chlorinated hydrocarbons (e.g., methylene chloride), N-alkyl
i..uniiu^ (e.g., dimethyl formamide), and mixtures [hereof.
Certain preferred methods include providing a compound of formula I:
(Figure Removed)
where:
R1 is alkyl, alkanoyl, aroyl, carboalkoxy, or carboalkoxyaryl;
R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen,
carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido,
alkanesulfonyl, alkanamido, amino, alkylamino, dialkylamino,
perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl;
R6 and R7 are, independently, hydrogen or alkyl;
n is 1 or 2; and
contacting the compound of formula I with at least one formaldehyde equivalent and
a reagent having either formula R4-CH=CH-R5 or formula R4-C5C-R5, in the presence
of a Lewis acid and a reaction solvent to form a compound of formula II:
(Figure Removed)
wherein each of R1, R2, R3, R6, R7, and n are as defined above;
the formaldehyde equivalent is in solid form at some time prior to the contacting;
R4 and R5 are, independently, hydrogen or alkyl of 1 to 6 carbon atoms, or
taken together with the carbons to which they are attached, form a cyclic
moiety that is cycloalkyl, cycloalkenyl, bridged bicyclic alkyl, bridged
bicyciic alkenyl, pyranyl or thiopyranyl in which the sulfur atom is
optionally oxidized to the sulfoxide or sulfone, and
the dotted line represents an optional double bond.
Preferred methods of the invention further comprise contacting a
compound of formula II with an acid having a pKa less than 1 and forming a bis salt
of formula III:
(Figure Removed)
wherein X is the counterion of the acid such as, for example, halogen,
hydrogensulfate, or an alkyl- or aryl- sulfonate.
The methods of the invention further include contacting the bis salt of
formula HI with base, thereby forming a free base having the formula IV:
(Figure Removed)
Preferred bases are alkaline metal hydroxides, alkaline earth metal
hydroxides, carbonates, phosphates, organic bases, and combinations thereof.
Sodium hydroxide in an aqueous solution is particularly preferred. Free bases
according to the invention can alternatively be formed by contacting a compound of
formula II with a base. Free bases according to the invention can also be prepared
by contacting a compound of formula I, where R1 is replaced by hydrogen, with a
formaldehyde equivalent and a reagent having either formula R4-CH=CH-R5 or
formula R4-CsC-R5 in the presence of a Lewis acid and a reaction solvent, where the
formaldehyde equivalent is in solid form at least prior to the contacting.
The free base of formula IV typically is formed as a racemic mixture.
Where a particular enantiomer is preferred it may be provided substantially free of
the corresponding enantiomer by isolation or separation methods known in the art
including, for example, high performance liquid chromatography and chiral salt
resolution, or by techniques described herein.
The racemic compound of formula IV is treated with a chiral agent to form
a diastereomeric mixture thereof. In certain embodiments, the racemic compound of
formula IV is treated with a chiral acid to form a diastereomeric salt thereof. As used
herein, the term "diastereomeric salt" refers to the adduct of a chiral compound of
formula IV with a chiral acid. The resulting diastereomeric mixture is then separated
by suitable means to obtain a the desired diastereomeric salt. 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 mo'rties as with, for example, tartaric acid or a derivative thereof.
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.
In preferred embodiments, the diastereomeric salts thus formed are
contacted with organic or inorganic acid having a pKa lower than the chiral resolving
acid to form the desired enantiomeric salt. As used herein, the term "enantiomeric
salt" refers to the salt of the resolved chiral compound of formula IV, wherein said
compound of formula IV is enriched in one enantiomer As used herein, the term
"enantiomerically enriched", as used ^srein 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. Acids for enantiomeric salt formation include hydrochloric acid,
sulfuric acid, phosphoric acid, hydrobromic and hydroiodic acid, malic acid, succinic
acid, trifluoro acetic acid, acetic acid, methane sulfonic acids, alkyl- and aryl sulfonic
acids, and combinations thereof.
Thus, representative enantiomeric salts are those having, for example,
formula Va or Vb
(Figure Removed)
wherein each of R2, R3, R4, R5, R6, R7, and n is as defined above and each Z is a
counter ion of the acids mentioned above. Examples of Z include, but are not limited
to, halogens such as Cl, Br and I, and ions including HSO<, H2PO4, MsO (where Ms is
mesylate), AcO (wherein Ac is acetyl), maleate, and succinate. Enantiomeric salts
once formed are preferably recrystallized to improve purity. Suitable recrystallization
solvents include aqueous alcohol such as alkyl alcohols like methanol, ethanol,
isopropanol, and butanol. In preferred embodiments, the enantiomeric salt is a
compound of formula G:
(Figure Removed)
in greater than about 90 area percent chiral purity, preferably greater than about 95
area percent chiral purity, more preferably greater than about 99 area percent chiral
purity (HPLC area percent of desired enantiomer relative to total HPLC area of
stereoisomers (enantiomers)). The free base name of compound G is (9aR, 12aS)-
4,5,6,7,9,ga.lO.H.i
The salt as shown in formula G has (-) optical rotation. One skilled in the art would
recognize that the optical rotation of G can change if converted to free base form.
The present invention also provides the compounds of formulae I, II, HI,
IV, G, Va, and Vb and other synthetic intermediates and products produced
according to the foregoing methods. Preferably, such compounds are provided in
greater than about 90 weight percent purity.
For example, the present invention provides compounds of formula V:
(Figure Removed)
where X is a counterion of an acid having a pKa less than 1.
The present invention also provides compositions comprising a
diastereomeric salt of a diaroyl-L-tartaric acid and a free base of formula Vlb:
(Figure Removed)
wherein each of R2, R3, R4, R5, R8, R7, and n is as defined above and neither of R4
and R5 is hydrogen.
!n other embodiments, compositions are provided that include at least
about 90 area percent HPLC of a compound of formula II:
(Figure Removed)
wherein each of R1, R2, R3, R4, R5, R6, R7, and n is as defined above and a
compound of formula VII:
(Figure Removed)
in less than an amount of about 10 area percent HPLC.
In yet other embodiments, compositions are provided that include a
compound of formula III:
(Figure Removed)
wherein each of R2, R3, R4, R5, R6, R7, n, and X is as defined above; and a compound
of formula X:
(Figure Removed)
wherein each of R2, R3, R4, R5, R6, R7, and n is as defined above, or a salt thereof, in
less than an amount of about 10 area percent HPLC.
!n yet other embodiments, compositions are provided that include a
diastereomeric salt of a diaroyl tartaric acid and a free base of formula IV:
(Figure Removed)
wherein each of R2, R3, R4, Rs, R6, R7, and n is as defined above, and a compound of
formula
(Figure Removed)
wherein each of R2, R3, R4, R5, R5, R7, and n is as defined above, or a salt thereof
(including diastereomeric salt) in an amount of less than about 10 area percent
HPLC.
In further embodiments, compositions are provided that include a
compound of formula G
(Figure Removed)
and one or more organic impurities in a total amount of about 2 area percent HPLC
or less, or one or more residual solvents in a total amount of 1.0 weight percent or
less.
Other embodiments provide compositions containing a compound of
formula G
and water in an amount of about 2.0 weight percent or less as measured by KF
titration. and/or where G has a hydrogen chloride content of from about 12.8 weight
percent to about 14.8 weight percent as measured by ion chromatography, based on
the total weight of the composition.
Even further embodiments provide a compound of formula G:
in the form of needle shaped crystals and/or having a median particle size of less
than about 25.
In yet further embodiments, a method is provided that includes providing a
compound of formula VIII:
(Figure Removed)
and contacting the compound of formula VIII with at least one formaldehyde
equivalent and a reagent having either formula R4-CH=CH-RS or formula R4-CsC-Rs,
in the presence of a Lewis acid and a reaction solvent to form a compound of formula
(Figure Removed)
where the formaldehyde equivalent is in solid form at least prior to the contacting;
R8 is a branched or straight chain alkyl group; a hetero-substituted alkyl group; an
aryl group or an arylalkyl group; and
R4 and R6 are, independently, hydrogen or alkyl of 1 to 6 carbon atoms, or taken
together with the carbons to which they are attached, form a cyclic moiety that
is cycloalkyl, cycloalkenyl, bridged bicyclic alkyl, bridged bicyclic alkenyl,
pyranyl or thiopyranyf in which the sulfur atom is optionally oxidized to the
sulfoxide or sulfone.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
In preferred embodiments, compounds according to the invention are
prepared according to the reaction scheme demonstrated below:
Scheme 1
(Figure Removed)
wherein:
R1 is alkyl, alkanoyl, aroyl, carboalkoxy, or carboalkoxyaryl;
R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen,
carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido,
alkanesulfonyl, alkanamido, amino, alkylamino, dialkylamino,
12.
perfluoroalkoxy, alkanoyloxy, alkanoyi, aroyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl;
R6 and R7 are, independently, hydrogen or alkyl; and
n is 1 or 2,
with a formaldehyde equivalent such as paraforrnaldehyde and an unsaturated
reagent that preferably has the formula R4-CH=CH-R5 or formula R4-CsC-R5in the
presence of a Lewis acid and a reaction solvent, and forming a compound of formula
II:
wherein:
R1 is alkyl, alkanoyi, aroyl, carboalkoxy, or carboalkoxyaryl;
R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen,
carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido,
alkanesulfony', alkanamido, amino, alkylamino, dialkylamino,
perfluoroalkoxy, alkanoyloxy, alkanoyi, «royl, ary!, arylalky!, hetercar/l, or
heteroarylalkyl;
R4 and R5 are, independently, hydrogen or alkyl or, taken together with the
carbons to which they are attached, form a cyclic moiety that is cycloalkyl,
cycloalkenyl, bridged bicyclic alkyl, bridged bicyclic alkenyl, pyranyl or
thiopyranyl in which the sulfur atom is optionally oxidized to the sulfoxide
or sulfone;
the dotted line represents an optional double bond.
R6 and R7 are, independently, hydrogen or alkyl; and
n is 1 or 2.
Representative compounds according to the invention are those in which
R1 is alkyl, alkanoyl, aroyl, carboalkoxy, or carboalkoxyary!. Preferred compounds
are those in which R1 is acetyl.
As defined generally above, R2 and R3 are each independently hydrogen,
hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano,
alkanesulfonamido, alkanesulfonyl, alkanamido, amino, alkylamino, dialkylamino,
perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl. In preferred embodiments, both R2 and R3 are hydrogen.
As defined generally above, R4 and R5 are each independently hydrogen
or alkyl of 1 to 6 carbon atoms, or, taken together with the carbons to which they are
attached, form a cyclic moiety that is cycloalkyl, cycloalkenyl, bridged bicyclic alkyl,
bridged bicyclic alkenyl, pyranyl or thiopyranyl in which the sulfur atom is optionally
oxidized to the sulfoxide or sulfone. The dotted line represents an optional double
bond. In preferred embodiments, the optional double bond is not present. In certain
embodiments, R4 and R5 are taken together with the carbons to which they are
attached to form a cycloalkyl ring. Cyclic groups formed by R4 and R5 are optionally
substituted with one to three substituents independently selected from halogen, alkyl
and alkoxy. Particularly preferred compounds are those in which R4 and R5, taken
together with the carbons to which they are attached, form a cyclopentyl moiety.
R6 and R7 can, independently, be hydrogen or alkyl, with both preferably
being hydrogen.
As defined generally above, n is 1 or 2, and in preferred embodiments is
1.
The compounds formed by the processes of this invention can contain
asymmetric carbon atoms and thus give rise to optical isomers and diastereoisomers.
While some formulas (such as , II, III, IV, etc.) herein are shown without respect to
stereochemistry, the present invention includes all such optical isomers and
diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and
S stereoisomers; as well as other mixtures of the R and S stereoisomers and
pharmaceutically acceptable salts thereof.
Where an enantiomer is preferred, it may, in some embodiments be
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 preferred embodiments, at least about 95% by
weight of a preferred enantiomer is present. In other embodiments of the invention,
at least about 99% by weight of a preferred enantiomer is present. Preferred
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.
The term "diastereomeric salt" as used herein, is the adduct of a chiral
amine such as:
(Figure Removed)
wherein each of R2, R3, R4, R5, R6, R7, and n is as defined above, with a chiral acid
such as L-tartaric acid, and in the case of resolving chiral acids with two carboxyl
groups includes both mono- and half-salts. The term "enantiomeric salt", as used
herein refers to the salt of the resolved chiral amine such as:
(Figure Removed)
wherein each of R2, R3, R4, R5, R6, R7, and n is as defined above.
"Organic impurities" as used herein, refers to any organic by-product or
residual material present in the desired product (such as those of formula IV or VI or
salts thereof), and do not include residual solvents or water. "Total organic
impurities" refer to the total amount of organic impurities present in the desired
quinoline product. Percent organic impurities such as total organic impurities and
single largest impurity, unless otherwise stated are expressed herein as HPLC area
percent relative to the total area of the HPLC chromatogram. The HPLC area
percent is reported at a wavelength where the desired product and maximum number
of organic impurities absorb.
The term "alkyl," as used herein, refers to a hydrocarbon group having 1
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 groups
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, npentyl,
isoperttyl, neo-pentyl, n-hexyl, and isohexyl. The term "lower alkyl" refers to
an alkyl group having 1 to 4 carbon atoms.
Arylalkoxy, as used herein, refers to the group -O(CH2)iAr, wherein r is 1-
6.
Alkanamido, as used herein, refers to the group -NHC(O)R where R is an
alkyl group.
Alkanoyl, as used herein, refers to the group -C(O)R where R is an alkyl
group.
Alkanoyloxy, as used herein, refers to the group -OC(O)R where R is an
alkyl group.
Alkanesulfonamido, as used herein, refers to the group -NHS(O)2R where
R is an alkyl group.
Alkanesulfonyl, as used herein, refers to the group -S(O)2R where R is an
alkyl group.
Alkoxy, as used herein, refers to the group -OR where R is an alkyi group.
The term "aryl" used alone or as part of a larger moiety as in "aralkyl",
"aralkoxy", or "aryioxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems
having a total of six to fourteen ring members, wherein at least one ring in the system
is aromatic and wherein each ring in the system contains 3 to 7 ring members. The
term "aryl" may be used interchangeably with the term "aryl ring".
The term "heteroaryl", used alone or as part of a larger moiety as in
"heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic ring systems having five to
six ring members and 1-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur. The term "heteroaryl" may be used interchangeably with the term
"heteroaryl ring" or the term "heteroaromatic". !n certain embodiments, such
heteroaryl ring systems include furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl,
oxadiazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, triazinyl, thiazolyl,
triazolyl, and tetrazolyl, to name but a few.
Groups containing aryl or heteroaryl moieties may optionally be
substituted with one to three substituents independently selected from halogen, alkyl,
and alkoxy groups.
Aroyl, as used herein, refers to the group -C(O)Ar where Ar is aryl as
defined above,
Arylalkyl, as used herein refers to the group --(CH2)rAr where Ar is aryl as
defined above and r is 1-6. Examples of arylalkyl groups include benzyl, phenethyi,
3-phenylpropyl, and 4-phenylbutyl.
Heteroarylalkyl, as used herein, refers to the group —(CH2)rHet, wherein
Net is a heteroaryl group as defined above and r is 1-6.
Carboxamido, as used herein, refers to the group -C(O)NH2.
Carboalkoxy, as used herein, refers to the group -C(O)OR where R is
alkyl.
Carboalkoxyaryl as used herein, refers to the group -C(O)O(CH2)iAr
where Ar is aryl as defined above, and r is 1-3. Preferably, Ar is phenyi and r is 1 to
form a benzyl moiety.
Halogen (or halo) as use J herein refers to chlorine, bromine, fluorine and
iodine.
Cycloalkyl and cycloalkenyl, as used herein, refer to saturated and
partially unsaturated, respectively, monocyclic hydrocarbon rings containing 3 to 8
carbon atoms, and preferably containing rings of 5, 6, or 7 carbon atoms. In the case
of cycloalkenyl, the hydrocarbon ring preferably contains one to two double bonds
and more preferably one double bond.
Bridged bicyclic cycloalkyl and bridged bicyclic cycloalkenyl, as used
herein, refer to saturated and partially unsaturated, respectively, bicyclic hydrocarbon
rings containing 8 to 10 carbon atoms. "Bridged", as used herein, refers to there
being at least one carbon-carbon bond between two non-adjacent carbon atoms of
the hydrocarbon ring. In the case of bridged bicyctic cycloalkenyl, the hydrocarbon
ring preferably contains one to two double bonds and more preferably one double
bond.
The yield of the compound of formula II is preferably greater than about
60%; more preferably greater than about 75%; more preferably greater than about
85%; and still more preferably greater than about 91%. Yield, as used herein and
unless indicated otherwise, refers to the yield from the immediate reaction rather than
the overall synthesis.
Preferred compounds according to the invention are those in which n is 1.
Particularly preferred compounds are those in which R1 is acetyl or hydrogen, R2, R3,
R6 and R7 are hydrogen, n is 1, and R4 and R5 are taken together with the carbons to
which they are attached to form a cyclopentyl moiety. Preferred cyclopentylcontaining
compounds are those having stereochemistry exemplified by the salt of
formula G:
(Figure Removed)
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 some preferred embodiments, paraformaldehyde is used as the
formaldehyde equivalent, and is added in amounts sufficient to consume a
compound of formula I. In some embodiments, paraformaldehyde is preferably
added in amounts of at least about 0.90 mole equivalents, more preferably in
amounts of about 0.90 mole equivalents to about 1.10 mole equivalents, and most
preferably in amounts of from about 1.0 mole equivalents to about 1.05 rnnie
equivalents relative to the starting compound of formula I.
Paraformaldehyde is preferably 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,
ethanol under reflux conditions for a time sufficient to form the bis salt of formula III.
Bis salts of formula III are preferably formed in yields of about 80% and more
preferably about 85%.
The bis salt of formula III can be contacted with base to form the
corresponding free base compound of formula IV. Preferably the bis salt and base
are combined in the presence of a suitable solvent in which the bis salt is at least
partially soluble in such as hot (about 60°C to 80 °C) water, polar solvents such as
alkyl alcohols, such as C\ to C4 alcohols (e.g. ethanol, methanol, 2-propanol),
dioxane, or THF (tetrahydrofuran) or combinations thereof to form the corresponding
free base. The base is preferably added in an amount of at least about 2 mol. eq.
and more preferably in an amount of at least about 2 moi. eq. to about 3 mol. eq.
relative to the bis salt of formula III. Preferred bases include alkaline metal
hydroxides or alkaline earth metal hydroxides, carbonates or phosphates, as well as
organic bases and combinations thereof. Sodium hydroxide is preferred. The free
base once formed may optionally be extracted using an extraction solvent. Preferred
extraction solvents include solvents which are immiscible with water and have at
least partial solubility with a compound of formula IV:
(Figure Removed)
wherein each of R2, R3, R4, R5, R6, R7, and n is as defined herein.
Examples of such solvents include alkyl ethers, alkyl acetates, or aromatic
hydrocarbons and combinations thereof such as ferf-butylmethylether (TBME),
diethyl ether, toluene, or ethyl acetate. The use of fe/t-butylmethylether is
particularly preferred. Preferred methods for the preparation of the free base include
adding sodium hydroxide solution (e.g., NaOH in water) to a hot suspension (70 °C -
100°C) of bis-HCI-salt in water to form the free base as an oil which can be separated
by extraction with TBME.
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. Preferred powder forms have at least about 10% particles retained
on a 200 mesh screen.
Lewis acids useful in the present invention are compounds that act as
electron pair acceptors. Lewis acids useful in the present invention include those of
the formula TiX4l ZrX4l AIX3, BX3, SiX4, SnX2, SnX2, RyAIX(3.y), R(y)SiX4-yi RyBX(3.y)i and
combinations thereof, wherein X is a halogen, or -OR; R is an alkyl or aryl; and y is 0-
3. BFa is particularly preferred. Preferably, the Lewis acid, such as BF3, is used in
amounts of about 2 mole equivalents to about 4 mole equivalents relative to the
compound of formula I.
The unsaturated reagent used in forming the compound of formula II is
preferably an alkene (including mono- and dienes) or alkyne. Preferred reagents
include those of formula R4-CH=CH-R5 or formula R4-CsC-R5. Cyclopentene is
particularly preferred. The unsaturated moiety, such as cyclopentene, is preferably
used in amounts of about 2 mole equivalents to about 8 mole equivalents relative to
the compound of formula I.
Reaction solvents useful in this invention for forming a compound of
formula II include polar aprotic solvents such as alkyl nitriles (e.g., acetonitrile,
propionitrile and butyronitrile), alkyl esters (e.g., ethyl acetate), N-alkyl formamides
(e.g., dimethyl formamide), and chlorina*sd hydrocarbons (e.gr,, methylene chloride).
In some embodiments, a reaction solvent is chosen that is capable of suspending the
solid formaldehyde equivalent. Acetonitrile-containing solvents are preferred.
Reaction solvents containing nearly all acetonitrile are particularly preferred.
Preferred solvents include those that contain at least about 90 weight percent
acetonitrile, preferably at least about 95 weight percent acetonitrile, and still more
preferably at least about 98 weight percent acetonitrile. The reaction solvent is
preferably added in an amount sufficient to dissolve the compound of formula I. In
some embodiments, solvent is added in concentrations of at least about 6 ml solvent
per gram of the compound of formula I.
Particularly preferred reaction conditions for forming compounds of
formula II include contacting a compound of formula I with about 2 mol. eq. to about (Figure Removed)

mol. eq. of cyclopentene and about 0.9 mol. eq. to about 1.2 mol. eq.
paraformaldehyde (preferably prills) in the presence of about 2.0 mol. eq. to about
4.0 mol. eq. BF3 and acetonitrile (using about 5 to about 20 ml per 1 g compound of
formula I). In this embodiment, reaction solvents that contain at least about 90
weight percent acetonitrile, and preferably nearly all acetonitrile, are particularly
preferred. The reaction temperature is preferably from about 20°C to about 50°C,
and more preferably from about 30°C to about 45°C.
In accordance with Scheme I, the compounds of formula II can be
converted, if desired, to free base compound of formula IV by contact with a base in
the presence of a suitable solvent, or alternatively, by contact with an acid in the
presence of a suitable solvent to form a bis-salt of formula 111, followed by contact of
the bis-salt with a base to form the free-base of formula IV.
Conversion of a compound of formula II to a bis salt of formula III
according to the invention preferably is effected by contacting the compound of
formula II with an acid having a pKa less than 1 in the presence of a solvent suitable
for forming a bis salt of formula III, and at a temperature and time sufficient to form
the bis salt. The acid is preferably added in an amount of at least about 2 mol. eq.
and more preferably in an amount of at least about 2 mol. eq. to about 4 mol. eq.
relative to the compound of formula II. Acids that may be used include, for example,
hydrochloric acid, alkyl- and/or aryl- sulfonic acids, sulfuric acid, phosphoric acid,
hydrobromic acid, hydroiodic acid, and combinations thereof. Preferred solvents
suitable for bis-sau formation include protic solvents such as alkanols and polar
aprotic solvents which are miscible with water, such as dioxan or glyme and
combinations thereof. Further examples of protic solvents include acetic acid or Cr
C4 alcohols. Preferred alcohols include ethanol, methanol, 2-propanol, or 1-butanol.
The use of hydrochloric acid and denatured ethanol is particularly preferred.
Conversion of a compound of formula II to a bis salt of formula III is
preferably carried out in about a 3:1 mixture of alcohol and concentrated aqueous
acid, more preferably in about a 2:1 mixture of alcohol and concentrated aqueous
acid, and still more preferably in about a 1:1 mixture of alcohol and concentrated
aqueous acid (by volume or weight). In the latter case, ethyl acetate typically is
added to increase recovery of the bis salt. In a preferred embodiment, the compound
of formula II is contacted with concentrated hydrochloric acid in the presence of
Free bases of formula IV are prepared, for example, by contacting a
compound of formula II with a suitable base, and preferably in the presence of a
solvent suitable for free base formation. Preferred bases for this conversion are
strong inorganic bases, i.e., those that completely dissociate in water under formation
of hydroxide anion. The base is preferably added in an amount of at least about 1
mol. eq. and more preferably in an amount of at least about 1 mol. eq. to about 10
mol. eq. relative to the compound of formula II. Examples of such bases include
alkaline metals, alkaline earth metal hydroxides, and combinations thereof.
Potassium hydroxide is preferred. Examples of solvents suitable for use during free
base formation include polar solvents such as alkyl alcohols, such as C1 to C4
alcohols (e.g. ethanol, methanol, 2-propanol), water, dioxane, orTHF
(tetrahydrofuran) or combinations thereof. Preferred solvents include Ct to 64
alcohols such as methanol, ethanol, 2-propanol, water and combinations thereof.
The use of both potassium hydroxide and methanol is preferred. In preferred
embodiments, the compound of formula II is refluxed in a mixture of methanol, water
and potassium hydroxide in proportions of about 2g methanol /1.5g water /0.7g
potassium hydroxide per 1g compound of formula II.
Alternatively, free bases of formula IV according to the invention can be
prepared directly by contacting a compound of formula I, in which R2, R3, R6 and R7
are defined as before and R1 is hydrogen, with a formaldehyde equivalent, such as
paraformaldehyde, and a reagent having either formula R4-CH=CH-R5 or formula
R4-C=C-R5in the presence of a Lewis acid and an alkyl nitrile containing solvent
wherein the formaldehyde equivalent, reagent, Lewis acid and reaction solvent are
as described above in connection with the formation of compounds of formula II.
Preferably, the reaction conditions, including proportions of formaldehyde equivalent,
unsaturated reagent, Lewis acid and reaction solvent relative to the compound of
formula I are as described previously herein. In a more preferred embodiment, about
1.1 mole equivalents of paraformaldehyde, about 8 mole equivalents of
cyclopentene, and about 3.5 mole equivalents of BF3 relative to the compound of
formula I are used to produce the free base compound of formula IV.
Generation of free base of formula IV from a bis salt of formula III typically
provides higher yields for the subsequent formation of the diastereomeric salt than
free base generated by direct hydrolysis with strong inorganic base. Additionally,
formation of free base from a bis salt may typically be done without using highly
caustic conditions.
Chiral free bases of formula IV, however formed, can be resolved by
isolation or separation methods known in the art including, for example, high
performance liquid chromatography and chiral salt resolution, or prepared by
methods described herein.
In preferred embodiments, separation of enantiomers is achieved through
contact of the free base of formula IV with a chiral resolving acid and a solvent for a
time and under conditions to form the corresponding diastereomeric salt. Examples
of useful chiral resolving acids include monofunctional carboxylic acid, difunctional
carboxylic acid, sulfonic acid, phosphonic acid, and combinations thereof, that are
relatively optically pure, i.e., at least about eight-five percent of a single enantiomer of
the acid is present. Difunctional carboxylic acids include tartaric acid esters, such as
diaroyl- ( e.g., ditoluoyl-, dibenzoyl-,) diacetyl, di tert butyl- tartaric acid, and
combinations thereof. Examples of such monofunctional carboxylic acids are
mandelic acid and its oxygen-substituted derivates, and combinations thereof.
Solvents preferred for use during resolution include polar protic and aprotic solvents
that are capable of dissolving a compound of formula IV and the chiral acid and in
which the desired diastereomeric salt has only limited solubility. Examples of such
solvents include C2-C4 alcohols such as ethanol, isopropanol, n-propanol, n-butanol;
ethyl acetate; isopropyl acetate; tetrahydrofuran; acetonitrile; and combinations
thereof. Diastereomeric salts thus former1 are preferably in yields of about 25%,
more preferably about 30%, and still more preferably about 35% out of the maximum
yield of 50%. (Maximum yield is 50% since only one enantiomer can be obtained.)
It is preferred that salt formation be accomplished using diaroyl tartaric
acids such as ditoluoyl tartaric acid (DTTA). Preferred diastereomeric salts are those
formed by contacting, in the presence of a solvent, ditoluoyl-L-tartaric acid with free
base E:
to form diastereomeric salts having the formula F:
wherein Tot is a toluoyl group. The use of ditoluoyl tartaric acid and a solvent that
contains isopropanol, ethyl acetate and combinations thereof is particularly preferred.
In one embodiment, the chiral resolving acid is preferably contacted with the free
base in an amount of about 0.2 mole equivalents to about 0.4 mole equivalents
relative to the free base. In another embodiment, the reaction preferably includes
using a solution having about 0.7 grams to about 1 .3 grams of chiral resolving acid
per about 10ml solvent (such as isopropanol and/or ethyl acetate) that is added to a
hot solution (temperature of about 70 °C to about 80 °C) having a concentration of -
about 4 ml to about 6 ml solvent (such as isopropanol) per gram of free base E.
The diastereomeric salt formed, such as diastereomeric salt F, is then
isolated by methods known in the art. For example, the solution of chiral resolving
acid and free base can be heated to near boiling, and then the resulting
diastereomeric salt slowly cooled over a period of time to ambient temperature or
cooler (if desired). After cooling, the solution is filtered to isolate the crystals. Such a
procedure as to diastereomeric salt F typically results in crystals that are easily
filterable. To increase purity, the resulting diastereomeric salt may optionally be
resuspended in a solvent such as isopropanol, refluxed for a sufficient time (such as
from about 1 hour to about 3 hours) and gradually cooled to recrystallize the salt.
J,iPreferred yields of diastereomeric salts F are greater than about 25%,
more preferably greater than about 30%, and still more preferably greater than about
35% (50% yield being maximum possible yield). The preferred chiral purity of the
diastereomeric salt is greater than about 80 area percent HPLC, more preferably
greater than about 85 area percent HPLC, and still more preferably greater than
about 90 area percent HPLC relative to the total HPLC area of diastereomeric salts.
The resulting diastereomeric salt containing the desired enantiomer can
be contacted, preferably in the presence of a solvent suitable for isolating the desired
enantiomer, with an organic or inorganic acid having a pKa lower than the chiral
resolving acid to form the desired resolved enantiomeric salt. Examples of such
acids include hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid,
hydroiodic acid, malic acid, succinic acid, trifluoro acetic acid, acetic acid, methane
sulfonic acids, alkyl- and aryl- sulfonic acids and combinations thereof. Suitable
solvents for forming the enantiomeric salt include polar solvents such as ethanol,
methanol, isopropyl acetate, ethyl acetate, isopropanol, n-propanol, n-butanol,
tetrahydrofuran, acetonitrile, and combinations thereof. Preferably, concentrated
aqueous hydrochloric acid and ethyl acetate are employed.
In a preferred procedure a suspension of diastereomeric salt F in ethyl
acetate and about 1 to about 1.5 molar equivalents hydrochloric acid (in concentrated
aqueous form) relative to the diastereomeric salt is heated to reflux for about four
hours to form the enantiomeric salt G:
(Figure Removed)
Tha resulting enantiomeric salt may be isolated by techniques known to
those skilled in the art such as by crystallization followed by separation of the
crystals. For example, in one preferred embodiment the resulting solution of
enantiomeric salt may be cooled gradually to form crystals of the enantiomeric salt,
followed by filtration to isolate the crystals. The isolated crystals may then optionally
,2.5
be recrystallized to increase purity. For example, in one preferred embodiment, the
isolated crude enantiomeric salt is mixed in a suitable solvent and heated to dissolve
the enantiomeric salt. The solution is then gradually cooled to effect crystallization.
Examples of preferred solvents from which the enantiomeric salts are recrystallized
include protic solvents such as Ci-C4 alcohols including ethanol, methanol,
isopropanol, n-propanol, n-butanol; water miscible polar aprotic solvents such as
tetrahydrofuran, dioxan, acetone, acetonitrile; water; and combinations thereof.
Preferably, the recrystallization solvent used is a Ci to C4 alcohol or mixtures of C, to
C4 alcohols with water.
In a preferred embodiment, crude enantiomeric salt G is dissolved in hot
denatured ethanol (about 60 °C to about 75 °C), and water is then added in a ratio of
1 ml water per about 10 ml to 15 ml ethanol. The resulting solution is then cooled to
about 5 °C over 3 hours. The resulting enantiomeric salt G is easily filterable and
has needle shaped crystal morphology. The crystals may then be optionally reduced
in particle size such as by milling and/or rnicronization. Preferably, the enantiomeric
salt G is reduced in particle size to convert the needles to short rods preferably
having an aspect ratio of less than about three. Such size reduction of the needle
shaped particles facilitates powder flow during subsequent processing. Preferably
after particle size reduction, the median (50%) particle size of enantiomeric salt G is
less than about 25 microns, and 90% of the particles are preferably less than about
70 microns as measured by laser diffraction (such as by a Malvern particle size
analyzer or equivalent).
A compound of formula G, however formed, is preferably present in at
least about 90 area percent HPLC chiral purity, more preferably at least about 95
area percent HPLC chiral purity, and even more preferably at least about 99 area
percent HPLC or 99.5 area percent HPLC chiral purity relative to the total HPLC area
of stereoisomers. The preferred yields of the product through the foregoing route are
about 60% more preferably about 70%, and still more preferably about 80%.
Although we do not wish to be bound by any particular theory, it is
believed that conversion of a compound of formula I to a compound of formula II
using a solid formaldehyde equivalent such as paraformaldehyde or trioxane that
may gradually dissolve and/or breakdown into formaldehyde in the reaction solvent
minimizes formation of the corresponding methylene dimer.
For example when solid formaldehyde equivalent such as
paraformaldehyde or trioxane in acetonitrile is used, a composition comprising a
compound of formula II and preferably no more than about 10 area percent HPLC
(determined by the UV absorption at 220 nm) more preferably no more than about 5
area percent HPLC of the corresponding methylene dimer of formula VII:
(Figure Removed)
is formed (based on total area of HPLC chromatogram). When dimethoxy methane
in acetonitrile is used about 50 area percent HPLC of the corresponding methylene
dimer is formed. When aqueous formaldehyde solution was used dimer was formed
to about 20 area percent HPLC and the starting compound of formula I was
degraded. Powdered paraformaldehyde is generally preferred, particularly when
used in high dilution (20ml acetonitrile per 1 g compound of formula I) Trioxane gave
similar results to the paraformaldehyde prills but typically with extended reaction
times. Using paraformaldehyde prills lead to about 4 area percent HPLC of
methylene dimer formation.
To the extent that the reaction product of this conversion is carried
forward in the synthetic scheme, the formation of dimeric forms of the corresponding
bis salts, free bases, diastereomeric salts, and enantiomeric salts is minimized, as
well. The present invention preferably provides the compounds of formula II and all
reaction products derived from them as compositions comprising the compounds of
formula II or derivative thereof and less than about 10 area percent HPLC, more
preferably less than about 7 area percent HPLC and even more preferably less than
about 5 area percent HPLC of the corresponding methylene dimer, (based on total
area of HPLC chromatogram). Thus, the invention provides compositions comprising
the compounds of formula II and less than about 10 area percent HPLC of their
corresponding methylene dinners, compositions comprising the bis salts of formula III
and less than about 10 area percent HPLC of their corresponding methylene dimers,
compositions comprising the free bases of formula IV and less than about 10 area
percent HPLC of their corresponding methylene dimers, compositions comprising the
diastereomeric salts of the invention and less than about 10 area percent HPLC of
their corresponding methylene dimers, and compositions comprising the
enantiomeric salts of the invention and less than about 10 area percent HPLC of their
corresponding methylene dimers, (based on total area of HPLC chromatogram).
In a preferred embodiment, the process of the present invention provides
a composition containing enantiomeric salt G. In some embodiments the
composition contains enantiomeric salt G in an amount of at least about 96.5 weight
percent and more preferably at least about 98 weight percent on an anhydrous basis,
based on the total weight of the composition.
In some other embodiments, the composition containing enantiomeric salt
G preferably contains from about 12.8 weight percent to about 14.8 weight percent,
and more preferably from about 13.5 weight percent to about 14.5 weight percent
HCI from G as measured by ion chromatography based on the total weight of the
composition.
In other embodiments, the composition containing enantiomeric salt G
preferably contains no more than about 2.0 area percent HPLC of total organic
impurities and more preferably no more than about 1.5 area percent HPLC total
organic impurities relative to the total area of the HPLC chromatogram. In otrier
embodiments, the composition containing enantiomeric salt G preferably contains no
more than about 0.6 area percent HPLC of any single impurity such as the
corresponding methylene dimer and more preferably no more than about 0.5 area
percent HPLC of any single impurity relative to the total area of the HPLC
chromatogram. According to another embodiment, the composition containing
enantiomeric salt G preferably contains no more than about 0.2 area percent HPLC
of any single impurity relative to the total area of the HPLC chromatogram.
According to yet another embodiment, the composition containing enantiomeric salt
G preferably contains no more than about 0.2 area percent HPLC of total impurities
relative to the total area of the HPLC chromatogram.
In yet other embodiments of the present invention, the composition
containing enantiomeric salt G preferably contains no more than about 2.0 weight
percent water and more preferably no more than about 0.30 weight percent water as
measured by Karl Fischer titration based on the total weight of the composition.
In other embodiments, the composition contains G at least one residual
solvent in an amount of about 0.5 weight percent or less. Other embodiments
provide compositions containing Compound G and at least one organic impurity or
residual solvent selected from at least one of ethanol, ethyl acetate, isopropanol,
methanol, or a dimer compound of formula H:
(Figure Removed)
or a salt thereof. In yet other embodiments of the invention, the composition
containing enantiomeric salt G preferably contains no more than about the following
residual solvents individually alone or in any combination: 0.5 weight percent
ethanol, 0.5 weight percent methanol, 0.5 weight percent ethyl acetate, 0.5 weight
percent isopropanol and/or 0.5 weight percent f-butyl methyl ether based on the total
weight of the composition.
One representative synthesis of compounds having formula G is shown in
the following synthetic scheme and discussed in greater detail in the experimental
examples that follow:
Scheme 2
(Figure Removed)
The preferred overall yield of syntheses of this type is greater than about
10%, more preferably greater than about 15%, and still more preferably greater than
about 20%,
The present invention also relates to compounds of formula IX and
methods for preparing them. Such compounds of formula IX are useful, for example,
for synthesis of psychotic and anti-obesity agents. In preferred embodiments,
compounds of formula IX are prepared by contacting compound of formula VIII:
(Figure Removed)
with an unsaturated reagent having formula R4-CH=CH-R5or R4-CsC-R5in the
presence of a Lewis acid, a formaldehyde equivalent and a reaction solvent, thereby
forming a compound of formula IX:
(Figure Removed)
where the formaldehyde equivalent is preferably in solid form at least prior to the
contacting.
Representative compounds according to the invention are those in which
R4 and R5 are. independently, hydrogen or alkyl of 1 to 6 carbon atoms or, taken
together with the carbons to which they are attached, form a cyclic moiety that is
cycloalkyl, cycloalkenyl, bridged bicyclic alkyl, bridged bicyclic alkenyl, pyranyl or
thiopyranyl in which the sulfur atom is optionally oxidized to the sulfoxide or sulfone.
Cyclic groups formed by R4 and Rs may optionally be substituted with one to three
substituents independently selected from halogen, alkyl, or alkoxy. Particularly
preferred compounds are those in which R4 and R5, taken together with the carbons
to which they are attached, form a cyclopentyl moiety.
R8 is a branched or straight chain alkyl group such as methyl, ethyl, npropyl,
isopropyl, butyl, or tertiary butyl; a hetero-substituted alkyl groun such as a
protected ethylamino or ethoxy group; an aryl; or an arylalkyl group. In preferred
embodiments, R8 is either methyl or benzyl.
Lewis acids useful for preparing compounds of formula IX include those
that are capable of depolymerizing formaldehyde equivalents and those that
facilitate the anilinium ion formation. Suitable acids include those previously
mentioned, for example, those of formula TiX4, ZrX4, AIX3, BX3, SiX4, SnX2, SnXz,
RyAIX(3.y), R(y)SiX4.yi RyBX^y), where X is a halogen or -OR; R is an alkyl or aryl; and y
is 0-3, and combinations thereof. Boron trifluoride is particularly preferred.
Formaldehyde equivalents suitable for forming compounds of formula IX
include those previously described such as paraformaldehyde (including prills and
powders), dimethoxymethane, formalin, trioxane, and poly and oligomeric forms of
formaldehyde in general as well as solutions of formaldehyde. Formaldehyde
equivalents that are provided to the reaction in solid form such as paraformaldehyde
and trioxane are particularly preferred. A preferred unsaturated reagent for use in
the present invention is cyclopentene.
Solvents useful in preparing compounds of formula IX include polar
aprotic solvents such as alkyl nitrites (e.g., acetonitrile, propionitrile and butyronitrile),
esters (e.g., ethyl acetate), N-alkyl formamides (e.g., dimethyl formamide),
chlorinated hydrocarbons (e.g., methylene chloride), and mixtures thereof. Alkyl
nitrile-containing solvents are preferred. Solvents containing nearly all acetonitrile
are particularly preferred. Preferred solvents include those that contain at least about
90 weight percent alkyl nitrile, preferably at least about 95 weight percent alkyl nitrile,
and still more preferably at least about 98 weight percent alkyl nitrile.
The solvent preferably is added in an amount sufficient to dissolve starting
material. In some embodiments, solvent is added in concentrations of at least about
6 ml solvent per gram starting compound of formula VIII. The combination of boron
trifluoride, paraformaldehyde and acetonitrile is particularly preferred. Reaction at
temperatures between about 1°C to about 30°C are preferred. Relative to the
compound of formula VIII, in a preferred embodiment, the reaction to form
compounds of formula IX, employs from about 2 to about 4 mole equivalents BF3,
from about 2 to about 9 mole equivalents cyclopentene, and from about 0.9 to about
1.1 equivalents paraformaldehyde (prills) in acetonitrile (using about 10 ml to about
20 ml per 1g starting material) are particularly proferred.
Compounds of formula IX preferably are formed in yields of at least about
55%. In preferred embodiments compounds of formula IX are formed in yields
greater than about 60%, more preferably yields greater than about 70%, even more
preferably yields greater than 80%, and still more preferably yields greater than about
90%.
The invention is further demonstrated in the following examples. The
examples are for purposes of illustration and are not intended to limit the scope of the
present invention.
EXAMPLES
Example 1
4-Acetyl-2,3,45-tetrahydro-IH-l,4-benzodiazepine (B)
To a 10 L jacketed reactor equipped with an overhead stirrer,
thermocouple, condenser, and positive nitrogen pressure, was charged 6.8 L
acetonitrile, 430.0 g (2.90 mol) compound A (1,4-benzodiazepine) and 441.0 g (3.19
me!, 1.1 eq) potassium carbonate. The stirred mixture was cooled to 0°C. Acetic
anhydride (311.4 g, 3.05 mol, 1.05 eq) was added dropwise to the reaction mixture
over a period of 30 minutes. The reaction was monitored by HPLC showing no more
than 2% of compound A after 30 minutes. The reaction was quenched by addition of
butylamine (21.2 g, 0.29 mol, 0.1 eq) and the inorganic solids were removed by
filtration.
The cake was washed with 1.1 L acetonitrile. The filtrate was concentrated
to a volume of 0.95 L by vacuum distillation (42 - 55 °C, 177-190 mmHg) and toluene
(2.1 L) was added to the concentrate. The mixture was again concentrated to a
volume of 1.20 L by vacuum distillation and toluene (0.52 L) was added. The reaction
mixture was cooled to 35°C and seeds (200 mg of compound B) were added. Heptane
(1.72 L) was added at 20°C and the mixture was cooled to 0°C for 1 h and to -5°C for
0.5 h.
The solid product compound B was collected by filtration and the cake was
washed twice with 0.55 L of heptane. The yellow solid was dried for 24 hours under
vacuum at 40°C to give 51SS g compound B, (93% of theoretical). 1H NMR (300MHz,
DMSO-d6):6 = 2.00(s, 1.2H), 2.1 (s, 1.8H), 3.02-3.13 (m, 2H), 3.58-3.62 (m, 2H), 4.40
(s, 0.4H), 4.56 (s, 0.6H), 5.59 (s, 0.4H), 5.65 (s, 0.6H) 6.67-6.82 (m, 2H), 7.00-7.16 (m,
2H) ppm.
Example 2
5-Acetyl-4,5,6,7,9,9a,10,l l.a-decahydrocyclopentatclll^Jdiazepino.linquinoline]
(C)
To a 1.0 L jacketed reactor equipped with an overhead stirrer,
thermocouple, condenser, addition funnel and positive nitrogen pressure was
charged acetylbenzodiazepine (40.0 g, 210 mmol, 1.0 eq.), paraformaldehyde prills
(6.30g, 210 mmol, 1.0 eq.), acetonitrile (480 ml) and cyclopentene (86.0 g, 1.26 mol,
6.0 eq.). To the reaction suspension at 12°C was added boron trifluoride etherate
(80.5 g, 567 mmol, 2.7 eq.) in 20 minutes. The reaction mixture was heated. The
reaction was monitored by HPLC. After the completion of the reaction, aqueous
sodium hydroxide solution (50.0 g NaOH in 250 ml of water) was added. The resulting
mixture was filtered, the top organic layer was washed with brine (50.0 rnl). The
organic layer was concentrated to 133 ml. Water (160 ml) was added to the hot
concentrated mixture. The reaction mixture was cooled to ambient temperature and
filtered. The cake was washed with a mixture of water and acetonitrile (5:1, 60 ml, 2
times). The wet product (82.0 g) was dried in a vacuum oven for 20 h at 45°C to
afford compound C (52.8 g, yield 93%) as an off-white solid. HPLC (area%): 94.5% C,
3.15% dimeric impurity compound methylene bis K±M,5,6,7,9,9a,10,11,12,12adecahydrocydopenta[
cK 1,4]diazepino[6,7,1-y]quinoline] 1 H NMR (300 MHz, DMSO-d6): 5
= 7.17-6.94 (m, 2H), 6.8S6.73 (m, 1H), 4.81 (d, j=13.7Hz, 0.4H), 4.56 (d, j=15.3Hz,
0.6H), 4.35 (d, j=15.3Hz, 0.6H), 4.16 (m, 0.6H), 3.98 (d, j=13.7Hz, 0.4H), 3.73 (m,
0.4H), 3.49 (m, 0.4H), 3.30-2.81 (m, 4.6H), 2.63 (m, 1H), 2.21 (m, 2H), 1.98 (m, 4H),
1.57 (m, 2H), 1.27 (m, 2H) ppm. (two conformers at 25 °C) dimeric impurity
compound methylene bis [(±)-4,5I6,7I9l9a,10I11,12(12a-decahydrocydopenta[c][
1,4]diazepinc{6l7,1-//lquinoline]: 6 = 7.08-6.77 (m, 4H), 4.95 (m, 0.6H), 4.39 (m, 4H),
4.05 (m, 0.4H), 3.29-267 (m, 3H), 2.33-1.93 (m, 15H), 1.76-1.20 (m, 6H) ppm. LC/MS:
(552 m/z)
Example 3
(-)-4,5,6>7,9,9a,10,11,12,12a-Decahydrocyclopentatc][1,4]diazepino[6,7,1-//]quinoline
(R,R)-di-p-toluoyltartaric acid salt (F) by alkaline hydrolysis
[00103] To a (2 L) jacketed reactor equipped with an overhead stirrer, thermocouple,
condenser, and positive nitrogen pressure was charged methanol (500 ml), water
(140 ml) and the mixture was cooled to 5 ± 5°C. Potassium hydroxide pellets (284.7 g,
2.263 mol) were added in 3-4 portions. The reaction mixture was warmed to 35 ± 5 °C
and compound C (Scheme 2,195.4 g, 0.650 mol) was added. The suspension was
refluxed for 18 hours. After cooling the reaction mixture to 0UC, water (385.0 g)
followed by concentrated hydrochloric acid (325.0 g, 3.25 mol. 5.0 eq) was added to
the reaction mixture. Ethyl acetate (600 ml) was added and the mixture was stirred
for 15 minutes and filtered. The cake was washed with ethyl acetate (1400 ml), the
washes were kept separate from mother liqueur. The filtrate layers were split and the
aqueous layer was extracted with washes from the filtrate. The combined organic
layers were concentrated to a volume of 450 ml. Ethyl acetate (850 ml) was added to
the mixture. The solution was concentrated to a volume of 300 ml. The concentrate
was distilled twice azeotropically with isopropanol (750 ml). Isopropanol (700 ml)
was charged to the residue and the mixture was heated to 70°C. The hazy solution
was clarified by filtration over celite (16 g), and washed with Isopropanol (100 ml).
The solution of E (racemic) was heated to 70°C and a solution of di-p-toluoyl-Ltartaric
acid (DTTA) (75.4 g, 0.165 mol, 0.30 eq) in isopropanol (600 ml) was added
maintaining the internal temperature above 70°C.
Seeds were added and the reaction mixture was allowed to cool to 20 ±
5°C over a period of 3 hours. The solid F formed was collected by filtration (filtration
time =15 mln, cake: height = 2.0 cm, diameter = 11.5 cm). The wet crude F (89.1 g)
(87% chiral purity) was suspended in isopropanol (630 ml) and heated to reflux for 2
hours. The mixture was allowed to cool to room temperature, the solid was collected by
filtration and washed with isopropanol (155 ml). After drying at 40°C for twelve hours,
F (65.8g, 24% yield, of the theoretical yield of 50%) was obtained with 92% chiral
purity.1 H NMR (300 MHz, DMSO-d6): 6 = 7.86 (d, j=8.0Hz, 4H), 7.32 (d, j=8.0Hz, 4H),
7.14 (d, j=6.6Hz, 2H), 6.81 (dd, j=6.3, 7.3Hz, 2H), 5.57 (s, 2H), 3.90 (dd, j=13,8,
36.2HZ, 4H), 3.15 (m, 2H), 3.02-2.87 (m, 10H), 2.59 (t, j=12.5Hz, 2H), 2.37 (s, 6H), 2.19-
2.15 (m, 4H), 1.99-1.96 (m, 2H), 1.62-1.58 (m, 4H), 1.35-1.21 (m, 4H) ppm. Chiral
HPLC: chirobiotic V 3.9 x 150 mm 5um, eluent 1L \,iethanol /0.9g NhUCFsCOa, flow: 1.5
ml, detect. 220 nm UV, Retention Time: E(S) = 4.71 min, E(R) = 4.38 min.
Example 4
(-)-4)5,6,7,9)9a,IO,11,12,12a-Decahydrocyclopenta[c][[1,4]diazepino[6,7,1-//Iquinoline
(R,R)-di-p-toluoyltartaric acid salt (F) by acidic hydrolysis
Compound C (0.30 kg, 1.1 mol) was added to a 5-10°C mixture of
concentrated HCI (2.5 eq, 0.274kg, 2.77 moles) and ethanol (0.30L, 0.23 kg). The
suspension was refluxed for 12-15 hours and reaction completion was monitored by
HPLC. After the reaction was complete, ethyl acetate was added (0.802 kg, 0.90 L)
over 40 minutes. The reaction mixture was cooled to ambient temperature, filtered
and washed with ethyl acetate (0.40 L, 0.356 kg) to afford the di-hydrochloride salt D
(0.291g, 87%). 1H NMR (300 MHz, DMSO-d6): 6 = 10.12 (m, 2H), 9.05 (m, 1H), 7.24
(d, j=7.23Hz, 1H), 7.18 (d, j=6.4Hz, 1H), 6.92 (dd, j=6.4,7.3Hz, 1H), 4.13 (m, 2H),3.44
(m, 1H), 3.09 (m, 4H), 2.93 (m, 1H), 2.67 (t, j=12.6Hz, 1H), 2.24 (m, 2H), 2.01 (m, 1H),
1.61 (m, 2H), 1.33 (m, 2H) ppm. Anal. Calculated for CwHaClaNz: C, 59.80; H, 7.36; Cl,
23.54; N, 9.30. Found: C, 59.82, H, 7.70; Cl, 23.42, N, 9.39.
D was heated to 75 ± 5°C in water (0.870 L, 0.874 kg) to give a solution.
The free base was generated in aqueous NaOH (0.249 kg 50/50 w/w sodium hydroxide
solution in 0.119 kg water) and was cooled to 35 ± 5°C in 1 hour before it was
extracted with TBME (0.450 L, 0.329 kg). After a solvent exchange to isopropanol
(0.92L, 0.710 kg), the organic layer was concentrated to (0.5 L, 0.459 kg). Isopropanol
(0.920L, 0.710 kg) was added to the concentrated mixture. Di-p-toluoyl-L-tartaric acid
(DTTA) (0.23 eq, 0.101 kg, 0.26 mols) in ethyl acetate (1.20 L, 1.02 kg) solution was
added dropwise to the free base solution in 1 hour at 75 ± 5° C. The solution was
cooled to ambient temperature in 6 hours. The product was filtered and washed with
ethyl acetate (0.400 L, 0.352 kg). Finally, the crude F was re-slurried in IPA (0.86 L,
0.667 kg) at reflux for 2 hours and then cooled to ambient temperature for 4 hours. The
product was filtered and washed with IPA (0.153 kg, 0.2 L). The wet product (223.7g)
was dried in a vacuum oven for 24 hours at 40 °C to afford F (150.7g, 32.3 % yield
from C). HPLC: 98.77%, Chiral Purity: 90%.
Example 5
(-)-4,5,6,7,9,9a,10,11,12,1£a-Decahydrocyclopenta[c][l,4]diazepino[6,7,l-
//Jquinoline hydrochloride (G)
To a suspension of F (72.0 g, 171 mmol) in ethyl acetate (860 ml) in a 2.0
L flask, was added concentrated HCI (20.0 g, 205 mmol, 1.2 eq.) at ambient
temperature. The suspension was refluxed for 3 hours and cooled to ambient
temperature. It was filtered and washed with ethyl acetate (115 ml) to afford the crude
hydrochloride salt (46.0 g, G). The latter was heated to 70°C in ethanol (276 ml, 200
proof, denatured with 4% ethyl acetate) and then water (22 ml) was added. The
solution was cooled to 5 °C over 3 hours. The product was filtered and washed with
ethanol (46 ml). The wet product (34.6 g) was dried in a vacuum oven for 20 hours at
40°C to afford G (32.0 g, yield 70%) as an off-white solid. HPLC (area %):
99.45%Chiral purity (HPLC): 99.9%
Analysis of separate batches of G prepared according to the procedures of
Examples 1, 2, 4, and 5 are described in the following table:
Tests
Purity (HPLC) (area %)
A) Total Organic
Impurities
B) Largest Single
Impurity
HC1 Content (weight %)
(Ion Chrom.)
Water Content (wt%, KF)
Chiral Purity (area%)
(HPLC)
Residual Solvents (wt%)
(GC)
Acetonitrile
Cyclopentene
Ethanol
Ethyl Acetate
Isopropanol
t-Butyl methyl ether
Batch 1
0.29%
0.11%a
14.1%
0.26%
Not
tested
ND,
DL=5
Not
tested
0.06%
0.001%
ND,
DL=0.00
Not
Batch 2
0.43%
0.21%a
14.0%
0.10%
Not tested
ND,
DL=8 ppm
Not tested
0.18%
ND,
DL=0.0010%
ND,
DL=0.0061%
Not Tested
Batch 3
1.48%
0.58%
[RRT=3.31]b
13.8%
0.11%
0.06%
Enantiomer
ND,
DL=7 ppm
ND,
DL=0.0005%
0.48%
0.01%
ND,
DL=0.0032%
Not Tested
Batch 4
0.51%
0.26%
[RRT=3.31]b
14.0%
0.12%
0.12%
Enantiomer
ND
DL=2 ppm
ND,
DL=0:0001%
0.21%
0.002%
ND,
DL=0.0010%
ND,
Tested
DL= 0.0003%
ND - None detected.
DL = Detection limit.
NMT = Not more than.
RRT = Relative retention time.
a: Purity was tested by a preliminary development method.
b: Actual RRT=3.22 (Variation due to HPLC gradient).
Example 6
(±)-4,5,6,7,9,9a,10,11,12,12a-Decahydrocyclopenta[c][ 1,4]diazepino[6,7,1 -/flquinoline
BF3.OEt2 (2.2 ml, 17.5 mmol) was dropped to a mixture of benzodia^epine
(0.74g, 5 mmol), cyclopentene (3.6 ml, 40.0 mmol), paraformaldehyde (165 mg, 5.5
mmol) in acetonitrile (20 ml) at room temperature. The mixture was heated at 45°C
(oil bath) for 5 h. It was concentrated in vacua. The residue was taken up with
EtOAc (150 ml) and washed first with a mixture of aqueous Na2CO3 and NaOH (200
ml), and then with brine (200 ml). The organic layer was dried and added HCI (1 N in
diethyl ether, 10 ml) and the resultant precipitates were collected by filtration. The
mixture was purified by flash chromatography on silica gel (5-15% MeOH in CH2Cl2)
to afford E (0.70 g, 53% yield.)
Example 7
5-Benzyl-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline
N-Phenyl-benzyl amine (4.58g, 25.00 mmol) was dissolved in 57 ml
acetonitrile under N2atmosphere. Cyclopentene (10.22g, 150.0 mmol) and
paraformaldehyde (788 mg, 26.25 mmol) were added in one portion. The mixture was
cooled to 1.5°C and BF3OEt2 (8.87g, 62.50 mmol) was added over a period of 2
minutes. The cooling bath was removed after addition was completed (reaction
temp=9°C). The reaction was completed after 2 hours (HPLC).
NaOH (10.5g in 20 ml water) was added and the mixture stirred overnight.
Layers were separated. An inorganic solid was separated by filtration and the
organic layer was extracted with ethyl acetate (3 times,10 ml). The combined organic
layers were washed with brine and dried over MgSO4. Evaporation of solvent and
flash-chromatography with heptane/ethyl acetate gave 5-Benzyl-2,3,3a,4,5,9bhexahydro-
1H-cyclopenta[c]quinoline (5.97g, 91% yield).
1H NMR (300 MHz, DMSO-d6): 6 = 7.51-7.19 (m, 5H), 7.05 (d, j=7.4Hz, IH),
6 88 (t, j=7.4Hz, IH), 6.57-6.52(m, 2H), 4.50 (dd, j=16.5, 24.2Hz, 2H), 3.09 (dd, j=5.0,
11.7Hz, 1H), 2.98-284 (m,2H), 2.33 (m, 1H), 2.1^ (m, 1H), 1.94(m, 1H), 1.63-1.40
(m, 4H) ppm.
LC-MS: (263m/z)
Example 8
5-Methyl-2,3,3a,4,5,9b-hexahydro-IH-cyclopenta[c]quinoline
N-methyl aniline (1.07g, IO.O mmol) was dissolved in 23 ml acetonitrile
under N2 atmosphere. Cyclopentene (4.08 g, 60.0 mmol) and paraformaldehyde
(300 mg, 10.0 mmol) were added in one portion. The mixture was cooled to 1.5°C
and BF3'OEt2 (3.55g, 25.0 mmol) was added over a period of 2 minutes. The cooling
bath was removed after addition was completed (reaction temp=9°C). The reaction
was completed after 2 hours (HPLC). NaOH (10.5g in 20 ml water) was added and
the mixture stirred overnight. Layers were separated. An inorganic solid was
separated by filtration and the organic layer was extracted with ethyl acetate 3x10 ml.
The combined organic layers were washed with brine and dried over MgSO4.
Evaporation of solvent and flash-chromatography with heptane/ethyl acetate gave 5-
Methyl-2,3,3a,4,5,9b-hexahydro-IH-cyclopenta[c]quinoline (1.08g, 57% yield).
1H NMR (300 MHz, DMSO-d6): 6 = 7.04-6.96 (m, 2H), 6.63-6.58 (m, 2H), 2.98-
2.78 (m,2H), 2.63 (t,j=9.93Hz, 1H), 2.33 (m, 1H), 2.13 (9m, 1H), 1.93 (rn, 1H),1.60-
1.34 (m, 4H)ppm.
LC-MS:(187m/z)

CLAIMS
We claim:
1. A method for preparing a compound of formula II:
(Figure Removed)
wherein
R1 is alky!, alkanoyl, aroyl, carboalkoxy, or carboalkoxyaryl;
R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alkanesulfonyl, aikanamido, amino, alkylamino, dialkylamino, petfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyi, heteroaryl, or heteroarylalkyl;
R6 and R7 are, independently, hydrogen or alkyl;
n is 1 or 2;
R and R5 are, independently, hydrogen or alkyl or, taken together with the carbons to which they are attached, form a cyclic moiety that is cycloalkyi, cycloalkenyl, bridged bicyclic alkyl, bridged bicyclic alkenyl, pyranyl or thiopyranyl in which the sulfur atom is optionally oxidized to the sulfoxide or sulfone; and
the dotted line represents an optional double bond, which comprises reacting a compound of formula I:
(Figure Removed)
wherein:
n, R1, R2, R3, R6 and R7 are as defined above,
with at least one formaldehyde equivalent and a reagent having either formula R4-CH=CH-R5or formula R4-CsC-R6, wherein R4 and R5 are as defined herein, in the presence of a Lewis acid and a reaction solvent to form a compound of formula II, providing that the formaldehyde equivalent is in solid form at least prior to the reaction.
2. The method of claim 1 wherein the formaldehyde equivalent comprises
paraformaldehyde.
3. The method of claim 1 or claim 2 wherein the reaction solvent comprises an
alkyl nitrile.
4. The method of any one of claims 1 to 3 wherein R1 is acetyl.
5. The method of any one of claims 1 to 4 wherein R4 and R5, taken together
with the carbons to which they are attached, form a cyclopentyl moiety.
6. The method of any one of claims 1 to 5 wherein R2, R3, R6 and R7 are
hydrogen.
7. The method of any one of claims 1 to 6 wherein n is 1.
8. The method of any one of claims 1 to 7 wherein the reaction solvent comprises at
least about 90 weight percent acetonitrile.
9. The method of any one of claims 1 to 8 wherein the yield of the compound of
formula II is greater than about 60%.
10. A product produced by the method of any one of claims 1 to 9.
11. The method of any one of claims 1 to 9 further comprising reacting the
compound of formula II with an acid having a pKa less than 1 to form a bis salt of
formula III:
(Figure Removed)
wherein X is a counterion to the acid having a pKa less than 1.
12. The method of claim 11 wherein X is a halogen, hydrogensulfate, or an alkyl-
or aryl sulfonate.
13. The method of 11 wherein the acid is hydrochloric acid.
14. A product produced by the method of any one of claims 11 to 13.
15. The method of any one of claims 11 to 13 further comprising reacting the bis
salt of formula HI with a base to form a free base of formula IV:
(Figure Removed)
16. The method of claim 15 wherein the base is aqueous sodium hydroxide.
17. The method of claim 15 or claim 16 wherein the free base of formula IV is
extracted with an extraction solvent that is immiscible with water.
18. The method of claim 1 further comprising reacting the compound of formula
with a base to form a free base of formula IV:
(Figure Removed)
19. The method of claim 18 wherein the base comprises a strong inorganic base.
20. The method of claim 18 or claim 19 wherein the base and compound of
formula II are contacted in the presence of a polar solvent.
21. The method of claim 20 wherein the base is potassium hydroxide and the
polar solvent comprises methanol.
22. A product produced by the method of any one of claims 15 to 21.
23. The method of any one of claims 15 to 21 further comprising reacting the free
base of formula IV with a chiral resolving acid to form a diastereomeric salt.
24 The method of claim 23 wherein the chiral resolving acid is a monofunctional carboxylic acid, difunctional carboxylic acid, sulfonic acid, phosphonic acid, or combinations thereof.
25. The method of claim 23 or claim 24 wherein the free base of formula IV and
chiral resolving acid are reacted in the presence of a polar solvent that is capable of
dissolving the compound of formula IV and is capable of crystallizing the
disstereomeric salt therefrom.
26. The method of claim 25 wherein the acid is ditoluoyl tartaric acid and the
polar solvent comprises isopropanol, ethyl acetate or combinations thereof.
27. The method of claim 25 wherein the diastereomeric salt produced is at least
oneof formula F:
(Figure Removed)
wherein Tol is a toluoyl group,
28. A product produced by ths method of any one of claims 23 to 27.
29. The method of any one of claims 23 to 27 further comprising contacting the
diastereomeric salt and an acid having a pKa lower than the chiral resolving acid to
form a corresponding enantiomeric salt.
30. The method of claim 29 wherein the diastereomeric salt and the acid are
contacted in the presence of a polar solvent capable of crystallizing the
corresponding enantiomeric salt therefrom.
31. The method of claim 30 wherein the acid is hydrochloric acid and the polar
solvent comprises ethyl acetate.
32. The method of any one of claims 29 to 31 further comprising crystallizing the
enantiomeric salt from a solution comprising aqueous alcohol.
33. A product produced by the method of any one of claims 29 to 32.
The method of claims 29 to 32 wherein the enantiomeric salt is at least one
compound of formula G: (Figure Removed)

35. A product produced by the method of claim 34. 36 A method for preparing a compound of formula !V
(Figure Removed)
wherein:
R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alkanesulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
R6 and R7 are, independently, hydrogen or alkyl;
n is 1 or 2;
R4 and R5 are, independently, hydrogen or alkyl or, taken together with the carbons to which they are attached, form a cyclic moiety that is cycloalkyl, cycloalkenyl, bridged bicyclic alkyl, bridged bicyclic alkenyl, pyranyl or thiopyranyl in which the sulfur atom is optionally oxidized to the sulfoxide or sulfone; and
the dotted line represents an optional double bond, which comprises reacting compound of formula I
(Figure Removed)
wherein n, R2, R3, Rs and R7 are, as defined above,
with at least one formaldehyde equivalent and a reagent having either formula R4-CH=CH-R5or formula R4-CsC-R5, in the presence of a Lewis acid and a reaction solvent to form a compound of formula IV,
providing the formaldehyde equivalent is in solid form at least prior to the reaction.
37 The method of claim 36 wherein the formaldehyde equivalent comprises paraformaldehyde,
38. The method of claim 36 or claim 37 wherein the reaction solvent comprises
an alkyl nitrile.
39. The method of any one of claims 36 to 38 wherein R4 and R5, taken together
with the carbons to which they are attached, form a cyclopentyl moiety.
40. The method of any one of claims 36 to 39 wherein R2, R3, R8 and R7 are
hydrogen.
41 The method of any one of claims 36 to 40 wherein n is 1.
42. The method of any one of claims 36 to 40 wherein the reaction solvent
comprises at least about 90 weight percent acetonitrile.
43. The method of any one of claims 36 to 42 further comprising contacting the
free base of formula IV with a chiral resolving acid tc form a diastereomeric salt.
44. The method of claim 43 wherein the chiral resolving acid is ditoluoyl tartaric
acid.
45. The method of claim 44 wherein the diastereomeric salt produced is at least
one of formula F:
(Figure Removed)
wherein To! is a toluoyl group.
46. A product produced by the method of any one of claims 436 to 45.
47. The method of any one of claims 43 to 45 further comprising contacting the
diastereomeric salt with an acid having a pKa lower than the chiral resolving add to
form a corresponding enantiomeric salt.
48. The method of claim 47 wherein the acid comprises hydrochloric acid, and
the diastereomeric salt and the acid are contacted in the presence of a polar solvent
that comprises ethyl acetate.
49. A product produced by the method of claim 47 or claim 48.
50. The method of claim 47 or claim 48 further comprising crystallizing the
enantiomeric salt from a solution comprising aqueous alcohol.
The method of claim 50 wherein the crystallized enantiomeric salt is at least
one compound of formula G: (Figure Removed)
52. A product produced by the method of claim 50 or claim 51.

53 A compound having formula:
(Figure Removed)
wherein X is a counterion of an acid having a pKa less than 1.
54. The compound of claim 53 wherein X is Cl.
55. A composition comprising a diastereomeric salt of a diaroyl-L-tartaric acid and
a free base of formula Vlb:

(Figure Removed)
wherein:
R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alkanesulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
R4 and R5 are, independently, hydrogen or aikyi or, idken together with the carbons to which they are attached, form a cyclic moiety selected that is cycloalkyl, cycloalkenyl, bridged bicyclic alkyl, bridged bicyclic alkenyl, pyranyl or thiopyranyl in which the sulfur atom is optionally oxidized to the sulfoxide or sulfone;
the dotted line represents an optional double bond; R6 and R7 are, independently, hydrogen or alkyl; and n is 1 or 2.
56. The diastereomeric salt of claim 55 wherein the diaroyi tartaric acid is
ditoluoyl-L-tartaric acid,
57. The diastereomeric salt of claim 55 having formula F:
(Figure Removed)
wherein Tol is a toiuoyl group.
58. A composition comprising:
a) at least about 90 area percent HPLC of a compound of formula If:
(Figure Removed)
wherein:
R1 is alkyl, alkanoyl, aroyl, carboalkoxy, or carboalkoxyaryl;
R2 and R* are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alkanesulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
R4 and R5 are, independently, hydrogen or alkyl or, taken together with the carbons to which they are attached, form a cyclic moiety selected that is cycloalkyl, cycloalkenyl, bridged bicyclic alkyl, bridged bicyclic alkenyl, pyranyl or thiopyranyl in which the sulfur atom is optionally oxidized to the sulfoxide or sulfone;
the dotted line represents an optional double bond;
R8 and R7 are, independently, hydrogen or alkyl; and
n is 1 or 2; and
b) a compound of formula VII:
(Figure Removed)
in less than an amount of about 10 area percent HPLC.
59. The composition of claim 58 wherein R1 is acetyl, R2, R3, R6 and R7 are hydrogen, n is 1, and R4 and R5, taken together with the carbons to which they are attached, form a cyclopentyl moiety.
60. A composition comprising: a) a compound of formula III: wherein:
R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alkanesulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
R4 and R5 are, independently, hydrogen or alkyl or, taken together with the carbons to which they are attached, form a cyclic moiety selected that is cycloalkyl, cycloalkenyl, bridged bicyclic alkyl, bridged bicyclic alkenyl, pyranyl or thiopyranyl in which the sulfur atom is optionally oxidized to the sulfoxide or sulfone;
the dotted line represents an optional double bond;
R8 and R7 are, independently, hydrogen or alkyl;
n is 1 or 2\ and
X is counterion to an acid having a pKa less than 1; and
(Figure Removed)
a compound of formula: R4

or a salt thereof, in less than an amount of about 10 area percent HPLC.
61. The composition of claim 60 wherein each of R2, R3, R6 and R7 is hydrogen, n is 1, X is Cl, and R4 and R5, taken together with the carbons to which they are attached, form a cyclopentyl moiety.
62. A composition comprising:
a) a diastereomeric salt of a diaroyi tartaric acid and a free base of formula IV:
(Figure Removed)

wherein:
R2 and R3 are, independently, hydrogen, hydroxy, alkyl, alkoxy, halogen, carboxamido, carboalkoxy, perfluoroalkyl, cyano, alkanesulfonamido, alkanesulfonyl, alkanamido, amino, alkylamino, dialkylamino, perfluoroalkoxy, alkanoyloxy, alkanoyl, aroyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
R" and R5 are, independently, hydrogen or alkyl or, taken together with the carbons to which they are attached, form a cyclic moiety selected that is cycloalkyl, cycloalkenyl, bridged bicyclic alkyl, bridged bicyclic alkenyl, pyranyl or thiopyranyl in which the sulfur atom is optionally oxidized to the sulfoxide or sulfone;
the dotted line represents an optional double bond;
R6 and R7 are, independently, hydrogen or alkyl; and
n is 1 or 2; and b) a compound of formula
or a salt thereof in an amount of less than about 10 area percent HPLC.
(Figure Removed)
63. The composition of claim 62 wherein the diaroyl tartaric acid is di-p-toluoyl-L-tartaric acid; each of R2, R3, R6 and R7 is hydrogen; n is 1; and R4 and R5, taken together with the carbons to which they are attached, form a cyclopentyl moiety.
64 A composition comprising: a) a compound of formula G:
(Figure Removed)
and
b) one or more organic impurities in a total amount of about 2 area percent HPLC or less, or one or more residual solvents in a total amount of 1.0 weight percent or less, or combinations thereof.
65. The composition of claim 64 wherein compound G is present in an amount of
at least about 96.5 weight percent on an anhydrous basis, based on the total weight
of the composition.
66. The composition of claim 64 wherein the organic impurities or residual
solvents comprise at least one of ethanol, ethyl acetate, isopropanol, methanol, or a
dimer compound of the formula:
(Figure Removed)

or a salt thereof.
67. The composition of claim 64 wherein the organic impurities or residual
solvents comprise at least one of the dimer compound, or a salt thereof, or ethanol.
68. The composition of claim 64 wherein the single largest organic impurity is
present in an amount of about 0.6 area percent HPLC or less.
69. The composition of claim 68 wherein the single largest impurity is a
compound of the formula:
(Figure Removed)

or a salt thereof.
70. The composition of claim 64 wherein the total residual solvents are present in
an amount of 0.5 weight percent or less.
71. The composition of claim 70 wherein the residual solvent comprises ethanol.
72. A composition comprising
a) a compound of formula G:
(Figure Removed)
and
b) water in an amount of about 2.0 weight percent or less, based on the total weight of the composition.
73 A compound of formula G:
(Figure Removed)

HN HCI G in the form of needle shaped crystals.
74. The compound of claim 73 wherein the needle shaped crystals are reduced to
have an aspect ratio of less than about 3.
75. A compound of formula G:
(Figure Removed)
HN-HCI G having a median particle size of less than about 25 microns.
fQ. The compound of claim 75 whesein 90% the particles have a particle size of less than about 70 microns.
77. A composition comprising a compound of formula G:
(Figure Removed)
wherein the hydrogen chloride content is from about 12.8 weight percent to about 14.8 weight percent as measured by ion chromatography, based on the total weight of the composition.
78. The composition of claim 77 wherein the compound of formula G has a chiral
purity of at least about 99.5 area percent HPLC in the composition.
A method for preparing a compound of formula IX (Figure Removed)

wherein:
R8 is a branched or straight chain alkyl group; a hetero-substituted alkyl group; an aryl group or an arylalkyl group; and
R4 and R5 are, independently, hydrogen or afkyl of 1 to 6 carbon atoms, or taken together with the carbons to which they are attached, form a cyclic moiety that is cycloalkyl, cycloalkenyl, bridged bicyclic alkyl, bridged bicyclic alkenyl, pyianyl or thiopyranyl in which the sulfur atom is optionally oxidized to the sulfoxide or sulfone, comprising reacting a compound of formula VHI:
(Figure Removed)
with a reagent having formula R4-CH=CH-RS or formula R4-CsC-R5in the presence of a Lewis acid, a formaldehyde equivalent, and a reaction solvent, to form a compound of formula IX providing the formaldehyde equivalent is in solid form at least prior to the reaction.
80. The method of claim 79 wherein the reagent is cyclopentene; the Lewis acid
is boron trifluoride; the formaldehyde equivalent is paraformaldehyde; the reaction
solvent is aceionitrile; R4 and R6 together form a cyclopentyl moiety; and R8 is methyl
or benzyl.
81. A product produced by the method of claim 79 or claim 80.
82. The Invention substantially such as herein be lore described