CHIRAL 3-CARBAMOYLMETHYL-5-METHYL HEXANOIC ACIDS, KEY INTERMEDIATES FOR THE SYNTHESIS OF (S)-PREGABALIN
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. provisional application
Serial Nos. 60/718,689, filed September 19, 2005; 60/754,392, filed December 27, 2005; 60/763,593, filed January 30,2006; 60/752,434, filed December 20,2005; 60/753,220, filed December 21,2005; 60/763,696, filed January 30, 2006; and 60/839,947, filed August 23, 2006, herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention encompasses the synthesis of (S)-(+)-3-(aminomethyl)-5-
methylhexanoic acid, (S)-Pregabalin, via the intermediate, (3R)-5-methyl-3-(2-oxo-2{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid.
BACKGROUND OF THE INVENTION
[0003] (S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound
having the chemical structure,
(Structure Removed)
is also known as 7-amino butyric acid or (S)-3-isobutyl GABA. (S)-Pregabalin, marketed under the trade name LYRICA , has been found to activate GAD (L-glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on-seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.
[0004] Several processes for the synthesis of (S)-Pregabalin are known. For example,
see DRUGS OF THE FUTURE, 24 (8), 862-870 (1999). One such process is illustrated in scheme 1.
Scheme 1

(Scheme Removed)
[0005] In Scheme 1, 3-isobutyl glutaric acid, compound 2, is converted into the
corresponding anhydride, compounds, by treatment with refluxing acetic anhydride. The reaction of the anhydride with NHUOH produces the glutaric acid mono-amide, compound 4, which is resolved with (R)-l-phenylethylamine, yielding the (R)-phenylethylamine salt of (R)-3-(carbamoyhnethyl)-5-methylhexanoic acid, compound 5. Combining the salt with an acid liberates the R enantiomer, compound 6. Finally, a Hoffmann degradation with Bra/NaOH provides (S)-Pregabalin. A disadvantage of this method is that it requires separating the two enantiomers, thereby resulting in the loss of half the product, such that the process cost is high.
[0006] Several stereoselective processes for the synthesis of (S)-Pregabalin have been
disclosed. For example, U.S. Patent No. 5,599,973 discloses the preparation of
(S)-Pregabalin using stoichionietric (+)-4-methyl-5-phenyl-2-oxazolidinone as a chiral
auxiliary that may be recycled. In general, however, that route is of limited use for scale-up,
principally due to the low temperature required for the reactions, the use of pyrophoric
reagent, such as, butyl lithium, to side reactions, and due to a low overall yield.
[0007] Another process is disclosed in U.S. Patent Application Publication No.
2003/0212290, which discloses asymmetric hydrogenation of a cyano-substituted olefin,
compound 7, to produce a cyano precursor of (S)-3-(aminomethyl)-5-methyl hexanoic acid, compound 8, as seen in scheme 2.
Scheme 2
(Scheme Removed)
[0008] . Subsequent reduction of the nitrile in compound 8 by catalytic hydrogenation
produces (S)-Pregabalin. The cyano hexenoate starting material, compound 7, is prepared
from 2-methyl propanal and acrylonitrile (Yamamoto et al, Bull. Chem, Soc. Jap., 58, 3397
(1985)). However, the disclosed method requires carbon monoxide under high pressure,
raising serious problems in adapting this scheme for production scale processes-:
[0009] A process published by G.M. Sammis, et al., /. Am. Chem. Soc., 125(15),
4442-43 (2003), takes advantage of the asymmetric catalysis of cyanide conjugate addition reactions. The method discloses the application of aluminum salen catalysts to the conjugate addition of hydrogen cyanide to a,|3-unsaturated imides as shown in scheme 3. Reportedly, TMSCN is a useful source of cyanide that can be used in the place of HCN. This process is not practicable for large scale production due to the use of highly poisonous reagents. Moreover, the last reductive step requires high pressure hydrogen, which only adds to the difficulties required for adapting this scheme for a production scale process. Scheme 3
(Scheme Removed)
[0010] In 1989, Silverman reported a convenient synthesis of 3-alkyl-4-amino acids
compounds in SYNTHESIS (1989, 955). Using 2-alkenoic esters as a substrate, a series of GABA analogs were produced by Michael addition of mtromethane to a,[}-unsaturated compounds, followed by hydrogenation at atmospheric pressure of the nitro compound to amine moiety as depicted in scheme 4.
Scheme 4(Scheme Removed)

[001 1] Further resolution of compound 14 may be employed to resolve Pregabalin.
This, of course, results in the loss of 50 percent of the product.
[0012] Recent studies have indicated that cinchona alkaloids are broadly effective in
chiral organic chemistry. A range of nitroalkenes were reportedly treated with dimethyl or diethyl malonate in tetrahydrofuran in the presence of cinchona alkaloids to provide high enantiomeric selectivity of compound 15,
and its analogues. For example, see H. Li, et al., J. Am. Chem. Soc,, 126(32), 9906-07 (2004). These catalysts are easily accessible from either quinine or quinidine, and are reportedly highly efficient for a synthetically C-C bond forming asymmetric conjugate addition as shown hi scheme 5.
Scheme 5(Scheme Removed)
[0013] Ra represents several alkyl and aryl grbups. The scope 01 the reaction nas
been extended to other nitroolefins and applied to prepare ABT-546 employing
bis(oxazoline)Mg(OTf)2. See, for example, D.M. Barnes, et al., J. Am. Chetn. Soc., 124(44),
13097-13105 (2002).
[0014] Other groups have investigated a new class of bifunctional catalysts bearing a
thiourea moiety and an amino group on a chiral scaffold. See 1. Okino, et al., J. Am. Chem.
Soc.,121(1), 119-125 (2005). On the basis of a catalytic Michael addition to the nitroolefm
with enantiomeric selectivity, they were able to prepare a series of analogues of compound
15.
[0015] Thus, there is a need in the art for new processes for the preparation of
(S)-Pregabalin that do not suffer from the disadvantages mentioned above.
[0016]
SUMMARY OF THE INVENTION In one embodiment, the invention encompasses a compound of formula 24
Formula Removed)

wherein Ar is a Ce-io aromatic group selected from the group consisting onaphthyl, phenyl,
and substituted phenyl and R is straight or branched Ci-4 alkyl, ester or carboxylic acid.
[0017] Where Ar is phenyl and R is methyl, the compound of formula 24 corresponds
to (3R)-5-methyl-3-(2-oxo-2{[(lR)-l-phenylmethyl]amino}ethyl)hexanoic acid of formula 24A
[0018] In another embodiment, the invention "encompasses the compound of formula
24A in crystalline form.
[001 9] In another embodiment, the invention encompasses a process for preparing the
compound of formula 24 comprising: combining a chiral amine of formula 23,
(Formula Removed)
an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base to obtain a mixture; cooling the mixture to a temperature of about 10°C to about -70°C; adding to the mixture 3-isobutyl glutaric anhydride of formula 22,
to obtain the compound of formula 24; and recovering the compound of formula 24 from the mixture, wherein Ar is a Ce-io aromatic group selected from the group consisting of .naphthyl, phenyl, and substituted phenyl and R is straight or branched Ci-4 alkyl, ester or carboxylic acid.
[0020] In another embodiment, the invention encompasses a process for preparing
(S)-pregabalin comprising: combining a chiral amine of formula 23,
(Formula Removed)
an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base to obtain a mixture; cooling the mixture to a temperature of about 10°C to about -70°C; adding to the mixture 3-isobutyl glutaric anhydride of formula 22;
to obtain the compound of formula 24; recovering the compound of formula 24 from the mixture; combining the recovered compound of formula 24, water, an ether, ammonia and an alkali metal, at a temperature of about 10°C to about -78°C to obtain a mixture; recovering the compound of formula 25 from the mixture;
(Formula Removed)
combining the recovered compound of formula 25 with bromine, water, and an alkaline hydroxide to obtain a basic mixture; heating the basic mixture to a temperature of about 60°C to about 85°C; adding to the basic mixture a strong mineral acid to obtain an acidic mixture; reacting the acidic mixture with a base to obtain (S)-Pregabalin, and
(Formula Removed)
recovering (S)-Pregabalin; wherein Ar is a Cg.io aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl and R is straight or branched CM alkyl, ester or carboxylic acid.
[0021] hi another embodiment, the invention encompasses a process for preparing
(S)-Pregabalin comprising: combining a chiralamine of formula 23,
(Formula Removed)
an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base to obtain a mixture; cooling the mixture to a temperature of about 10°C to about -70°C; adding to the mixture 3-isobutyl glutaric anhydride of formula 22;
to obtain the compound of formula 24; recovering the compound of formula 24 from the mixture; combining the compound of formula 24 with concentrated sulfuric acid to obtain a mixture; maintaining the mixture at a temperature of about 0°C to about 50°C, for about 10 hours to about 30 hours; recovering the compound of formula 25 from the mixture;
(Formula Removed)
combining the recovered compound of formula 25 with bromine, water, and an alkaline hydroxide to obtain a basic mixture; heating the basic mixture to a temperature of about 60°C to about 85°C; adding to the basic mixture a strong mineral acid to obtain an acidic mixture; reacting the acidic mixture with a base to obtain (S)-Pregabalin, and
(Formula Removed)
recovering (S)-Pregabalin; wherein Ar is a Ce-io aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl and R is straight or branched CM alkyl, ester or carboxylic acid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 illustrates an 'H-NMR spectrum of (3R)-5-methyl-3-(2-oxo-2{[(1R>
1 -phenylethyl] amino} ethyl)hexanoic acid.
[0023] Figure 2 illustrates a 13C-NMR spectrum of (3R)-5-methyl-3-(2-oxo-2{[(1R)-
1 -phenylethyl] amino} ethyl)hexanoic acid.
[0024] Figure 3 illustrates an IR spectrum of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-
phenylethyl] amino} ethyl)hexanoic acid.
[0025] Figure 4 illustrates a powder X-ray diffraction pattern of (3R)-5-methyl-3-(2-
oxo-2 {[(1R)-1 -phenylethyl] amino} ethyl)hexanoic acid.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The invention provides a stereoselective synthesis of (S)-Pregabalin according
to the following scheme: (Scheme Removed)

[0027] The invention encompasses (3R)-5-methyl-3-(2.-oxo-2{[(lR)-l-aryI-
alkyl]amino}ethyl)hexanoic acids of formula 24,
(Formula Removed)
wherein Ar is a Ce-io aromatic group selected from the group consisting of naphthyl, phenyl,
and substituted phenyl, and R is a straight or branched CM alkyl, ester, or carboxylic acid.
Preferably, Ar is phenyl. Preferably, R is a straight or branched CM alkyl, more preferably,
methyl.
[0028] Preferably, the substituted phenyl is a phenyl group substituted with at least
one of alkoxy, halogen, alkyl, carboxylic acid, or ester. A preferred alkoxy phenyl is
methoxyphenyl. Preferred halogenated phenyls are chlorobenzene, bromobenzene, and
fluorobenzene. Preferred alkylated phenyls are either toluene or ethylbenzene.
[0029] Preferably, the CM alkyl is methyl, ethyl, isopropyl, n-butyl, isobutyl or
t-butyl. More preferably, the CM alkyl is methyl or ethyl, most preferably, methyl.
[0030] Preferably, the carboxylic acid substituent is -COOH, -CH2COOH, -
CH(CH3)COOH or -C(CH3)2COOH. Preferably the ester is a methylester, ethylester, isopropylester, n-butylester, isobutyl or t-butyl derivative of one of the above-listed carboxylic acid substituents.
[0031] When Ar is phenyl and R is methyl, the compound of formula 24 is (3R)-5-
methyl-3-(2-oxo-2{[(lR)-l-phenyhnethyl]amino}ethyl)hexanoic acid 24A
(Formula Removed)
which may be characterized by data selected from a 13C-NMR spectrum (CDCls, 75 MHz) having carbon chemical shifts at about 21.74,22.15,22.61,24.12,24.87, 30-.85, 38.1,40.47, 43.38,48.88,126.0,127.2,128.49,143.00,172.02 and 176.66 ppm; an 'H-NMR spectrum (CDCU, 300 MHz) having hydrogen chemical shifts at about 0.84, 1.19,1.44-1.46,1.63, 2.27, 5.09, 6.89-6.91,7.28 and 11.65 ppm; an IR spectrum having peaks at about 3323, 3318.8,2955,1691.98, 1638,1617, 1566 and 761 cm"1. The compound of formula 24A may further be characterized by data selected from a 13C-NMR spectrum substantially as depicted in Figure 2; a !H-NMR spectrum substantially as depicted in Figure 1; and an IR spectrum substantially as depicted in Figure 3.
[0032] The invention also encompasses isolated (3R)-5-methyl-3-(2-oxo-2 {[(1R)-1-
phenyhnethyl]amino}ethyl)hexanoic acid 24A, preferably in.a crystalline form. The
crystalline form of 24A may be characterized by a powder X-ray diffraction ("PXRD")
pattern having peaks at about 4.3°, 6.2° 6.8°, 7.3°, 10.3°, and 17.4° 26 ± 0.2° 28. The
crystalline form of 24A may be further characterized by X-ray powder diffraction peaks at
about 7.7°, 8.2°, 9.7°, 11.3°, 12.8°, 13.9°, 15.1°, 15.7°, 18.6°, 19.1°, 19.6°, 20.9°, 21.8°,
22.4°, and 23.3° 28 ± 0.2° 28. The crystalline form of 24A may be even further characterized
by a powder X-ray diffraction pattern substantially as depicted in Figure 4. Moreover, the
crystalline form of 24A may have a melting range of about 95°C to about 97°C.
[0033] The invention also encompasses (3R)-5-methyl-3-(2-oxo-2{[(lR)-l-
phenyknethyl]amino}ethyl)hexanoic acid 24A having an optical purity of at least about 80
percent area by HPLC, preferably of at least about 93 percent area by HPLC, more preferably
of about 99 percent to about 100 percent area by HPLC.
[0034] The compound of formula 24 may be prepared by combining a chiral amine of

formula 23,

(Formula Removed)

wherein Ar is a Ce-io aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl, and R is a straight or branched C^ alkyi, ester, or carboxylic acid, an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base, to obtain a mixture; cooling the mixture to a temperature of about 0°C to about -70°C; and adding 3-isobutyl glutaric anhydride of formula 22to the mixture to obtain the compound of formula 24,
(Formula Removed)
which is then recovered from the mixture.
[0035] The 3-isobutyl glutaric anhydride of formula 22 may be prepared according to
the process disclosed in U.S. patent No. 5,616,793.
[0036] The chiral amine of formula 23 is commercially available, and is, preferably, a
primary amine. Preferably, the primary amine is selected from a group consisting of 1R,2S-
ephedrine, naphthyl-a-methyl ethylamine, glycine methylester, methylbenzylamine or a
chiral amino acid derivative. Preferably, the primary amine is methylbenzylamine, and more
preferably (R)-methylbenzylamine.
[0037] Preferably, the aromatic hydro'carbon'is a Ce-s aromatic hydrocarbon.
Preferably, Ce-g aromatic aromatic hydrocarbon is toluene, xylene, ethylbenzene, or cumene, more preferably, toluene. Preferably, the ether is a C^s ether. Preferably, the Ca-e ether is tert-butyl methyl ether, tetrahydrofuran, diisopropylether, or diethyl ether, more preferably, tetrahydrofuran. Preferably, the halogenated carbon is a C^ halogenated hydrocarbon. Preferably, the Ci_2 halogenated hydrocarbon is dichloroethane, carbon tetrachloride, or chloroform, more preferably, dichloromethane. Preferably, the alcohol is a €1.4 alcohol. Preferably, the Ci_4 alcohol is isopropyl alcohol, ethanol, methanol or n-butanol, more preferably, n-butanol. Preferably, the ester is a Cs-e ester. Preferably, the C3-e ester is ethyl acetate, isopropyl acetate, or isobutyl acetate, more preferably, ethyl acetate. Preferably, the alkane is a straight, branched or cyclic €5.7 alkane, more preferably, hexane, heptane, or cyclohexane, most preferably, heptane. Preferably, the ketone is a Ca-s ketone. Preferably, the Cs-e ketone is acetone, methyl isobutyl ketone, or methyl ethyl ketone, most preferably, acetone. The more preferred organic solvent is toluene.
[0038] Preferably, the base is an organic base. Preferably, the organic base is a Ci-u
amine. Preferably, the Ci-n amine is selected from the group consisting of diethyl amine, triethyl amine, di-n-propyl amine, di-isopropyl amine, tert-burylamme, tri-n-butylamine, morpholine, piperidine, pyridine, and 4-dimethyl aminopyridine, more preferably, the Ci_i2 amine is 4-dimethyl aminopyridine.
[0039] Preferably, the mixture is cooled to a temperature of about 0°C to about -60°C
before adding the 3-isobutyl glutaric anhydride of formula 22. Preferably, the mixture is maintained at a temperature of about 0°C to about -60°C for at least about one hour, more preferably for about one hour to about two hours, before adding the 3-isobutyl glutaric anhydride of formula 22.
[0040] The order of combining the reacting substances when preparing the compound
of formula 24 may influence the purity and the yield of the final product. Preferably, the chiral amine of formula 23 is combined with the base, prior to the addition of the 3-isobutylglutaric anhydride of formula 22.
[0041] The compound of formula 24 may be recovered by any method known to the
skilled artisan. Such methods include, but are not limited to, extracting the organic phase with an aqueous basic solution to convert the acidic product to a salt, and acidifying the aqueous phase with a mineral acid to obtain back the acid product.
[0042] The compound of formula 24,'obtained by the above-described process, has an
optical purity of at least about 80 percent area by HPLC, preferably of at least about 93
percent area by HPLC, more preferably of about 99 percent to 100 percent area by HPLC.
[0043] The compound of formula 24 may optionally be further purified by
crystallization from an organic solvent selected from at least one of esters, nitriles, ethers, C4-6 straight, branched, or cyclic hydrocarbons, and C&-IQ aromatic hydrocarbons. Preferably, the ester is a C^ ester. Preferably, the C^.& ester, is ethyl acetate or isopropyl acetate. Preferably, the nitrile is a Ca nitrile. Preferably, the Ci nitrile is acetonitrile. Preferably, the ether is a C^ ether. Preferably, the Ca-e ether is methyl t-butyl ether. Preferably, the Ce-io aromatic hydrocarbon is a €7.9 aromatic hydrocarbon. Preferably, the Cy.g aromatic hydrocarbon is toluene' or xylene. Preferably, the C/t-e straight, branched or cyclic hydrocarbon is cyclohexane or hexane, more preferably, cyclohexane. Preferred mixtures are that of xylene and ethyl acetate, hexane and ethyl acetate, cyclohexane and ethyl acetate and toluene and ethyl acetate. The most preferred mixture is that of toluene and ethyl acetate. Most preferably, the solvent is toluene.
[0044] The invention further encompasses a process for preparing (S)-Pregabalin by
the following scheme:
(S)-Pregabalin
The process comprises preparing a compound of formula 24, converting the compound of formula 24 into a compound of the following formula 25;
(Formula Removed)
converting the compound of formula 25 into (S)-Pregablin; and recovering the (S)-Pregabalin.
[0045] Preferably, the compound of formula 24 is prepared by the processes
described above.
[0046] The compound of formula 24 may be converted into the compound of formula
25 by a process comprising combining the compound of formula 24, water, an ether,
ammonia, and an alkali metal at a temperature of about 10°C to about -78°C to obtain a
mixture; and recovering the compound 25 from the mixture.
[0047] Preferably, the compound of formula 24, water, and ether are combined to
form a first mixture, to which ammonia and the alkali metal are then added. Preferably,
combining the compound of formula 24, water and ether provides a first mixture. Preferably,
ammonia and the alkali metal, are then added to the first mixture. Preferably, the compound
of formula 24, water, and ether are combined at a temperature of about 10°C to about -78°C.
Preferably, the mixture containing the compound of formula 24,. water, and ether is combined
with ammonia and an alkali metal at a temperature of about -40°C to about 5°C.
[0048] Preferably, the ether is a €3^ ether. Preferably, the €3-6 ether is
tetrahydrofuran or dioxane.
[0049] Preferably, the ammonia is provided in an aqueous solution, i.e., ammonium
hydroxide.
[0050] The preferred alkali metal is either lithium or sodium.
[0051] Preferably, the reaction mixture is maintained for about 2 to about 10 hours,
more preferably for about 6 to about 10 hours.
[0052] Alternatively, the compound of formula 24 may converted into the compound
of formula 25 by a process comprising combining the compound of formula 24 with
concentrated sulfuric acid to obtain a mixture; maintaining the mixture at a temperature of
about 0°C to about 50°C for about 10 hours to about 30 hours, and recovering the compound
of formula 25 from the mixture.
[0053] Preferably, the concentrated sulfuric acid contains about 96 percent to about
100 percent volume of sulfuric acid and about 0 percent to about 4 percent volume of water,
more preferably, about 100 percent volume of sulfuric acid.
[0054] The preferred amount of the concentrated sulfuric acid is about 2 to about 70
mole equivalents, more preferably, about 15 to about 25 mole, equivalents, and most
preferably, about 15 mole equivalents per mole equivalent of the compound of formula 24.
[0055] Preferably, the reaction is maintained at a temperature of about 0°C to about
50°C, when the amount of the concentrated sulfuric acid is about 2 to about 70 mole
equivalents per mole equivalent of the compound of formula 24. More preferably, the
reaction is maintained at a temperature of ab6ut 25°0 to about 45°C, when the amount of the
concentrated sulfuric acid is about 15 to about 25 mole equivalents per mole equivalent of the
compound of formula 24, and most preferably, the reaction is maintained at a temperature of
about 35°C to about 40°C, when the amount of the concentrated sulfuric acid is about 15 mole
equivalents per mole equivalent of the compound of formula 24.
[0056] The compound of formula 25 may be recovered by any method known to the
skilled artisan. Such methods include, but are not limited to extraction, followed by drying
over anhydrous sodium sulfate.
[0057] The compound of formula 25 may optionally be purified by crystallization
from a polar organic solvent selected from the group consisting of esters, straight and
branched CM alcohols, and ethers. Preferably, the ester is a Ca-e ester. Preferably, the Qs-e
ester is ethyl acetate. Preferably, the straight or branched CM alcohol is ethanol, methanol,
isopropanol, or butanol, more preferably, isopropanol, or n-butanol, and most preferably, n-
butanol. Preferably, the ether is a C^-6 ether. Preferably, the C^ ether is tetrahydrofuran or
dioxane. The most preferred polar organic solvent is ethyl acetate.
[0058] The (R)-3-(carbamoylmethyl)-5-methyl hexanoic acid 25 is obtained by the
above crystallization process having an optical purity of at least about 80 percent area by
HPLC, preferably of at least about 93 percent area by HPLC, and more preferably of about of
about 99 percent to about 100 percent area by HPLC.
[0059] The (R)-3-(carbamoylmethyl)-5-methyl hexanoic acid 25 may be converted
into (S)-Pregabalin by a process comprising combining the (R)-3.-(carbamoyhnethyl)-5-
methyl hexanoic acid 25 with bromine, water, and an alkali hydroxide to form a basic
mixture; heating the basic mixture to a temperature of about 60°C to about 85°C; adding .a
strong mineral acid to the basic mixture to obtain an acidic mixture; adding a base to the
acidic mixture; and recovering (S)-Pregabalin.
[0060] Preferably, the alkali hydroxide is selected from the group consisting of
sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide, more.
preferably, sodium hydroxide.
[0061] Preferably, the alkali hydroxide-and water are combined, first, to obtain a
solution, followed by addition of compound 25 and bromine.
[0062] Preferably, compound 25 is added to the solution at a temperature of about
5°C to about 10°C. After the addition of compound 25, bromine is added, preferably, at a
temperature of about 5°C to about 10°C.
[0063] Preferably, a Cn.g alcohol is added to-the basic mixture prior to the addition of
the strong mineral acid. Preferably, the €4.3 alcohol is selected from the group consisting of
butanol, iso-butanol, 2-butanol, pentanol and iso-pentanol, more preferably, iso-butanol.
[0064] Preferably, the strong mineral acid is selected from a group consisting of
H2S04, HC1, HBr and HsPO^ more preferably, HC1. Preferably, the addition of the strong mineral acid provides a two-phase system, comprising an organic phase and an aqueous phase.
[0065] Preferably, the base is added to the organic phase. The base may be an organic
base. The preferred organic base is a secondary or tertiary amine. Preferably, the secondary
amine is diisopropylamine or dipropylamine, more preferably, diisopropylamihe. Preferably,
the tertiary amine is tributyl amine or triethyl amine, more preferably, tributyl amine.
[0066] The base may be an inorganic base. Preferably, the inorganic base is an alkali
hydroxide or an alkali carbonate. Preferred alkali hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide. More preferably, the alkali hydroxide is sodium hydroxide. Preferred alkali carbonates include, but are not limited to, sodium carbonate, sodium bicarbonate, and potassium carbonate. More preferably, the alkali carbonate is sodium carbonate. The more preferred inorganic base is alkali carbonate, most preferably, sodium carbonate.
[0067] The addition of the base induces the precipitation of S-Pregabalin. The
precipitate of S-Pregabalin may be recovered by any method known to the skilled artisan.
Such methods include, but are not limited to, filtering the precipitate, followed by drying.
[0068] (S)-Pregabalin is obtained by the above process having an optical purity of
about 93 percent to about 100 percent area byHPLC, preferably of about 99 percent to about 100 percent area by HPLC.
[0069] Further, 3-isobutyl glutaric anhydride 22 can be regenerated by a process
comprising combining the filtrate obtained from the recovery of (S)-Pregabalin with an acid, to obtain a first mixture; heating me first mixture to obtain 3-isobutyl glutaric acid of the following formula;
(Formula Removed)
-isobutyl glutaric acid

combining the 3-isobutylglutaric acid with acetic anhydride to obtain a second mixture;
heating the second mixture to obtain 3-isobutyl glutaric anhydride 22; and recovering the 3-
isobutyl glutaric anhydride 22.
[0070] Preferably, the acid is a strong mineral acid, more preferably either 6TST to 12N
hydrochloric acid or 20 percent to 80 percent sulfuric acid.
[0071] Preferably, the first mixture is heated at a temperature of about 100°C to about
125°C. Preferably, when the mineral acid is hydrochloric acid, the first mixture is maintained
at temperature of about 100°C to about 105°C. Preferably, when the mineral acid is sulfuric
acid, the first mixture is maintained at a temperature of about 120°C to about 125°C.
[0072] Preferably, the second mixture of 3-isobutylglutaric acid and acetic anhydride
is heated at a temperature of about 135°C to about 155°C, more preferably at a temperature
about 135°C to about 145°C.
[0073] 3-isobutyl glutaric anhydride of formula 22 may be recovered by any method
known to the skilled artisan. Such methods include, but are not limited to, distilling the
excess of acetic anhydride and cooling. .
[0074] The following non-limiting examples are merely illustrative of the preferred
embodiments of the present invention, and are not to be construed as limiting the invention,
the scope of which is defined by the appended claims.
EXAMPLES .
ChiralHPLC analysis
Instrument: Waters-2487
Column: CHIRAL PACK AI>H, 250 x 4.6 mm, 5un
Mobile phase: 2% TFA in n-Hexane/Ethanol -95/5
Flow: 0.5 ml/minute
Temperature: 30°C
Wavelength: 210 nm/UV visible spectrophotometer
1H-NMR analysis
F2-Acquisition parameters F2-Processing parameters
Instrument dpx 300
Probhd 5mm Dual Z5 SI 32768
Pulprog zg SF 300.1300069MHz

TD
Solvent
NS
DS
SWH
FIDRES
AQ
RG
DW
DE
TE
Dl
PI
SFO1
NUC1
PL1

16384 CDC13 8 0
8992.806 Hz 0.548877 Hz 0.9110004 sec 16
55.600 usec 4.50 \isec 300.0 K 5 seconds 11.35 usec 300.1342018MHz 1H OdB

WDW '
SSB
LB
GB
PC

EM
0
0.01 Hz
0
1.4



5mm Dual Z5
zgdc
16384
CDC13
4959
0
18832.393 Hz 1.149438 Hz 0.4350452 sec 9195.2 26.550 usec 4.50 |j.sec 300.0 K 0.03 second
"C-NMR analysis
F2-Acquisition parameters
Instrument dpx 300
Probhd
Pulprog
TD
Solvent
NS
DS
SWH
FIDRES
AQ
RG
DW
DE
TE
DllF2-Processing parameters
SI 16384
SF 75.4677595MHz
WDW EM
SSB 0
LB 10.00 Hz
GB 0
PC 1.4
PL12
Cpdprg2
PCPD2
SFO2
NUC2
PL2
Dl
PI ,
DE
SF01
NUC1
PL1
17.8Db
waltz 16
90.00 usec
300.1330013MHz
1H
OdB
1 second
9.4 usec
4.4 |isec
75.4767751 MHz 13C
OdB
IR analysis
KBr pellets
Number of sample scans 16
Number of background scans 16
Scanning parameters 4000-500 cm"1
Resolution 4
Sample gain 8
Mirror velocity 0.6329
Aperture 100
X-ray analysis Instrument Copper radiation Scanning parameters Step scan Step time
SIEMENS " Model: D-5000
1.5406 A
2-50° 28.
0.03°
0.5 second
Example 1: Preparation of (3RV5-methvl-3-f2-oxo-2([aRH-phenvlethvl]arnino>e&vl) hexanoic acid compound (24)
[0075] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with toluene (400 ml), (R)-(+)-
phenylethylamine (38.59 g, 0.0.319 mole) an'd 4-dim'ethylaminopyridine (0.358 g, 0.0029 mole). The mixture was cooled to a temperature of -50°C to -60°C, followed by addition of a solution of 3-isobutyl glutaric anhydride (50 g, 0.294 mole) in toluene (100 ml), over a period of 45-60 minutes, and stirring for additional 1.5-2 hours, at a temperature of-50°C to -60°C. The mixture was then .extracted with 3.5-4.0 percent aqueous solution of NaOH (1000 ml), and the aqueous phase was washed with toluene (1 x 250 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a solution hydrochloric acid (1-12N). The aqueous phase was further extracted with ethyl acetate (1 x 300 ml and 1 x 100 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 66 g (77.2 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl) hexanoic acid with an optical purity of 99.91 percent, as measured by chiral HPLC.
Example 2: Preparation of r3RV5-methvl-3-f2-oxo-2([(lRVl-phenylethvl1amino|ethvn hexanoic acid compound C24)
[0076] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and mechanical stirrer, was charged with ethyl acetate (100 ml), (R)-(+)- .• phenylethylamine (26.69 g, 0.0.22mole) and 4-dimethylaminopyridine (2.69 g, 0.15.mole). The mixture was cooled to a temperature of-50 to -60° C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in ethyl acetate (50 ml), over a period of 25-30 minutes, and stirring for additional 1.5-2 hours, at a temperature of-50 to -60°C. The mixture was then extracted with 5-4 percent aqueous solution of NaOH (500 ml), and the aqueous phase was separated. The pH of the aqueous phase was adjusted to 2-2.5 by adding a solution hydrochloric acid (1-12N). The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1 x 100 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvent to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 35.43 g (82.87 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl) hexanoic acid with an optical purity of 99.4 percent, as measured by chiral HPLC.Example 3: Preparation of (3RV5-methvl-3-r2-oxo-2frflRVl-pheavlethvnamiiio^ethvl'i hexanoic acid compound (24")
[0077] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with toluene (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.294 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5°C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in toluene (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0°-5°C. The mixture was then extracted with 2.5-3.0 percent aqueous solution of NaHCOa solution (500 ml), and the aqueous phase was washed with toluene (1 x 100 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1 x 50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 28.4g (66.4 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.6 percent, as measured by chiral HPLC.
Example 4: Preparation of (3R)-5-methvl-3-(2-oxo-2([(lR)-l-phenvlethvl]amino)ethyl) hexanoic acid compound (24)
[0078] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer), was charged with tert-butyl methyl ether (100 ml), (R)-(+)-phenylethylamine (43.05 g, 0.355 mole) and 4-dimethylaminopyridine (0.258 g, 0.0021 mole). The mixture was cooled to a temperature of 0-5°C, followed by addition of a solution of 3-isobutyl glutaric anhydride (40 g, 0.235 mole) in tert-butyl methyl ether (100ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5°C. The mixture was then extracted with 5 percent aqueous solution of NaHCOa solution (700 ml), and the aqueous phase was washed with tert-butyl methyl ether (1 x 100 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 200 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 44.5 g (70 percent yield) of a white solid of (3R)-5-
metliyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amiho}ethyl)hexanoic acid with an optical purity of 99.19 percent, as measured by chiral HPLC.
Example 5: Preparation of (3RV5-methyl-3-(2-oxo-2irflRVl-phenylethyl]amino}ethyl'). hexanoic acid compound (24}
[0079] A three-necked flask equipped with an addition runnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with methylene chloride (100 ml), (R)-(+)-phenylethylamine (53.38 g, 0.44 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5°C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in methylene chloride (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5°C. The mixture was then extracted with 2.5-3 percent aqueous solution of NaHCCh solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1 x 100 ml and 1 x 50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution Of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate. (1 x 150 ml and 1 x 50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 26.2 g (61.3 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-
phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.41 percent, as measured by chiral HPLC.
Example 6: Preparation of f3R)-5-methvl-3-C2-oxo-2(rflRVl-phenvlethvl1amino)ethvn hexanoic acid compound (24):
[0080] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with IPA (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5°C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in PA (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5°C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaHCOs solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1 x 100 ml and 1 x 50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted
with ethyl acetate (1 x 150 ml and 1 x 50 ml)', followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 25.2 g (58.9 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.34 percent, as measured by chiral HPLC.
Example 7: Preparation of (3RV5-methyl-3-(2-oxo-2(r(lR)-l-phenvlethvl1amrno>ethvl') hexanoic acid compound (24)
[0081] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with ethyl acetate (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5°C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in ethyl acetate (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5°C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaHGO3 solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1 x 100 ml and 1 x 50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12 N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1 x 50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 26.6 g (61.5 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.3 percent, as measured by chiral HPLC.
Example 8: Preparation of (3R)-5-methvl-3-f2-oxo-2(r(lR)-l-phenvlethvl1amino)ethvl') hexanoic acid compound (24)
[0082] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with acetone (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in acetone (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5°C. The solvent was
stripped off and the residue was extracted with 2.5-3'percent aqueous solution solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1 x 100 ml and 1 x 50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1 x 50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 24 g (56 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-
phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.32 percent, as measured bychiralHPLC.
Example 9: Preparation
hexanoic acid compound (24)
[0083] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with hexane (100 ml), (R)-(+)-
phenylethylamine (35.58 g, 0.147mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5°C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in hexane (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5°C. The mixture was then extracted with 2.5-3 percent aqueous solution of NaHCOs solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1 x 100 ml and 1 x 50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1 x 50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 22.2 g (51.9 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.27 percent, as measured by chiral HPLC.
Example 10: Preparation of f3R)-5-methvl-3-r2-oxo-2irflR)-l-phenvlethvl1amino>ethvl) hexanoic acid compound (24)
[0084] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying rube and a mechanical stirrer, was charged with a mixture of cyclohexane and toluene
(100 ml) in a ratio of 1 to 1, (R)-(+)-phenylethylamine (35.58 g, 0.147mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in mixture of cyclohexane and toluene (100 ml) in aratio of 1 to 1, (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5°C. The mixture was then extracted with 2.5-3 percent aqueous solution of NaOH solution (500 ml), and the aqueous phase was washed with toluene (1 x 50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1 x 50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 28.7 g (67 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.34 percent, as
measured by chiral HPLC.
t .
Example 11: Preparation of f3RV5-methvl-3-f2-oxo-2iraRVl-phenvlethvl1aminolethvn hexanoic acid compound f24)
[0085] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with methyl isobutyl ketone (100 ml), (R)-(4)-phenylemylamine (35.58 g, 0.147mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5°C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) hi methyl isobutyl ketone (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaHCOs solution (500 ml), followed by washing the aqueous phase with toluene (1 x 100 ml and 1 x 50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1 x 50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 25.2 g (58.9 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.3 percent, as measured by .chiral HPLC.
Example 12: Preparation of r3R)-5-methvl-3-r2-oxo^2(rflRVl-phenvlethvl1amino>ethvn hexanoic acid compound f24)
[0086] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with toluene (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147mole) arid 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5°C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in toluene (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The mixture was then extracted with 2.5-3 percent aqueous solution of NaOH solution (500 ml), and the aqueous phase was washed with toluene (1 x 50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1 x 50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 29.3 g (68.5 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.34 percent, ap measured by chiral HPLC.
Example 13: Preparation of f3R)-5-methvl-3-f2-oxo-2{[flRVl-phenylethvl]amino)ethvn hexanoic acid compound (24)
[0087] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with methanol (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147mole) and 4-dimethylaminopyridine (0.18 g, .0.00147 mole). The mixture was cooled to a temperature of 0-5° C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in methanol (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5°C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaHCO3 solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1 x 100 ml and 1 x 50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1 x 50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 22.2 g (51.76 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-
{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.1 percent, as measured by chiral HPLC.
Example 14: Preparation of f3RV5-methvl-3-(2-oxo-2ir(lR)-l-phenylethvnammo>ethvl1 hexanoic acid compound (24)
[0088] A three-necked flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with ethanol (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in ethanol (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5°C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaOH solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1 x 100 ml and 1 x SO.ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1 x 50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 22.7 g (53.09 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.17 percent, as measured by chiral HPLC.
Example 15: Preparation of (3R)-5-methvl-3-(2-oxo-2(r(lR)-l-phenvlethyl1amino)ethyl) hexanoic acid compound (24)
[0089] A three-neck-flask equipped with an addition funnel, thermometer pocket,
drying tube and a mechanical stirrer, was charged with n-butanol (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5°C, followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in n-butanol (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5°C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaOH solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1 x 100 ml and 1 x 50 ml). The pH of the aqueous phase was adjusted to 2-2.5
by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1 x 150 ml and 1x50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 23.1 g (54.03 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(lR)-l-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.16 percent, as measured by crural HPLC.
Example 16: Preparation of (llV3-carbamovlmethyl-5methyl hexanoic acid compound (25)
[0090] A 2 liter four-necked flask, equipped with a mechanical stirrer, thermometer
pocket and a liquid ammonia inlet, was charged with 24 (7.5 g, 0.0257 mole) from examples
1-13, tetrahydrofuran (112.5 ml) and water (7.5 ml). The reaction mixture was cooled to
-40°C and liquid ammonia (700 ml) was added followed by addition of small pieces of
sodium metal (2.5 g). The resultant reaction mixture was stirred vigorously for 6-10 hours,
until the ammonia had evaporated. Water (100 ml) was added to the reaction mass under N2
atmosphere at 5-10°C, followed by separating the phases. The pH of the aqueous phase was
adjusted to 1.5-1.7 using hydrochloric acid, followed by extractions with methylene
dichloride (2 x 250 ml). The combined methylene dichloride layers were dried over
anhydrous sodium sulfate and the solvent was stripped off. The residue was crystallized from
ethyl acetate to get 1.89 g (39.37 percent yield) of (R)-3-carbamoyhnethyl-5-methylhexanoic
acid with optical purity of 99.81 percent as measured by chiral HPLC.
[0091] Compound 25 is characterized by: 1. IR (KBr) :3436.17, 1712.53, 1644.29
cm'1. 2. 'H NMR (CDC13) : d 0.89-0.90 (d, 6H), 1.24-1.26 (i, 2H), 1.63-1.72 (septet, 1H), 2.04-2.11 (d, 2H), 2.26-2.32 (d, 2H),, 6.50 (s,lH), 6.94 (s,lH). 3.13C NMR (CDC13): 5 21.79,22.02, 22.61,24.27, 29.62, 37.86, 38.82, 39.48,42.71, 174.39, 174.83.
Example 17: Preparation of (T<)-3-carbamovlmethyl-5rnethyl hexanoic acid compound (25}
[0092] A 2 liter four neck-flask, equipped with a mechanical stirrer, thermometer
pocket and a liquid ammonia inlet, was charged with 24 (7.0 g, 0.024 mole) from examples 1-13, tetrahydrofuran (70 ml) and water (5 ml). The reaction mixture was cooled to -40°C . and liquid ammonia (400 ml) was added followed by addition of small pieces of lithium metal (0.667 g, 0.0962 mole). The resultant reaction mixture was stirred vigorously for 6-10 hours until the ammonia had evaporated. Water (50 ml) was added to the reaction mass under N2 atmosphere at 5-10°C, followed by separating the phases. The pH of the aqueous phase
was adjusted to 1.5-1.7 using hydrochloric acid, foll&wed by extractions with ethyl acetate (1 x 150 ml and 1 x 100 ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate and the solvent was stripped off. The residue was crystallized from ethyl acetate to get 2.66 g (59.37 percent yield) of (R)-3-carbamoylmethyl-5-methylhexanoic acid with optical purity of 99.8 percent as measured by chiral HPLC.
Example 18: Preparation of (RV3-carbamovhnethyl-5methvl hexanoic acid compound (25}
[0093] A 250 ml four-necked flask, equipped with thermometer pocket and drying
tube, was charged concentrated sulfuric acid (36.4 g, 0.37 mole) and 24 (2.0 g, 0.0068 mole). The reaction mixture was stirred over night at 25-30°C, and then quenched with crushed ice (150 g) and stirred. The aqueous phase was extracted with ethyl acetate (1 x 150 ml and 1x150 ml), followed by washing the ethyl acetate layer with water, and finally drying over anhydrous sodium sulfate. The solvent was stripped off, and the product was crystallized from ethyl acetate obtaining 0.5 g (39 percent yield) of (R)-3-carbamoylmethyl-5-methylhexanoic acid with optical purity of 99.5 percent as measured by chiral HPLC.
Example 19: Regeneration of 3-isobutylghitaric acid
[0094] A 0.5 liter four necked-flask, equipped with a mechanical stirrer, thermometer
pocket, and condenser, was charged with a residue of the secondary amide after crystallization (5 g) from examples 1-13 and concentrated hydrochloric acid (100 ml). The reaction mixture was refluxed at 100-105°C for 20-24 hours, and then cooled to 20-25°C. The pH of the mixture was adjusted to 10-11 with a 20 percent solution of sodium hydroxide. The aqueous layer was extracted with toluene (2 x 50 ml) and the pH of the aqueous layer was adjusted to 1.5-2 with concentrated hydrochloric acid, followed by extractions with methylene chloride (2x50 ml). The combined methylene chloride layers were dried over anhydrous sodium sulfate and the solvent was stripped off to obtain 3-isobutyl glutaric acid (3.39 g) in purity of 88.48 percent as measured by GC.
[0095] 3-isobutylglutaric acid is characterized by: 1. IR (KBr) : 1713.27 cm"1. 2. 'H
NMR (CDC13): 5 0.89-0.92 (d, 6H), 1.25 (t, 2H), 1.6-1.69 (septet, 1H), 2.42 (s, 4H), 11.96 (s,2H). 3. 13C NMR (CDC13): 5 22.39,25.06, 28.11,29.50, 38.45,43.38, 179.17.
Example 20: Regeneration of 3-isobutvlglutaric acid
[0096] A 0.5 liter four-necked flask, equipped with a mechanical stirrer, thermometer
pocket and a condenser, was charged with the residue of the secondary amide after
crystallization (5 g) from example 1-13, and 70 percent of sulfuric acid (100 ml). The reaction mixture was refluxed at 120-125°C for 1-2 hours, and then it was cooled to 20-25°C, followed by adjusting the pH to 10-11 with a 20 percent solution of sodium hydroxide solution. The aqueous layer was extracted with toluene (2 x 50 ml) and the pH of the aqueous layer was adjusted to 1.5-2 with concentrated. Hydrochloric acid, and then it was extracted with methylene chloride 92 x 50 ml). The combined methylene dichloride layers were dried over anhydrous sodium sulfate and the solvent was stripped off to obtain 3-isobutyl glutaric acid (3.3 g).
Example 21: Converting 3-isobutylglutaric acid to 3-isobutvlglutaric anhydride, compound 22
[0097] A 1 liter four-necked flask equipped with a mechanical stirrer, thermometer
pocket and condenser, was charged with 3-isobutyl glutaric acid (250 g) and acetic anhydride (62.7 g).The reaction mixture was refluxed at 135°-145°C for 2.5-3 hours, followed by distilling out the unreacted acetic anhydride at 147°-155°C, and then the distillation was continued under vacuum to ensure removal of traces of unreacted acetic anhydride. The residue was cooled to 25°-30°C to obtain 220-225 g of 3-isobutylglutaric anhydride.
Example 22: Preparation of (S)-Pregabalin
[0098] A 0.2 liter reactor was loaded with 60 ml of water and 17.65 g of NaOH. The
solution was cooled to from 10° to 15°C, and 15 g of 25 were added. Then, 15 g of Br2 were
added drop-wise over a period of 15 minutes, while maintaining the temperature at less than
20°C. The mixture was heated to 80°C for 15 minutes, and then cooled to room temperature,
i.e., about 20° to about 25°C. An aqueous 32 percent solution of HC1 was added in an
amount sufficient to provide a pH of 1. The solution was then divided to two portions.
[0099] Portion I was extracted with 3 7 ml of iso-butanol, the organic layer was
separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 71 percent yield. Optical purity: 97.2 percent area by HPLC.
[00100] Portion n was extracted with 37 ml of pentanol, the organic layer was
separated, and BusN was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of pentanol. After drying at
55°C under vacuum, (S)-Pregabalin was obtained as'white crystals in a 73 percent yield. Optical purity: 93.1 percent area by HPLC.
Example 23: Preparation of (S)-Pregabalin
[00101] A 0.1 liter reactor was loaded with 60 ml of water and 17.6 g of NaOH. The
solution was cooled to from 10° to 15°C, and 15 g of 25 were added. The mixture was
stirred, and 15 g of Br2 were added drop-wise over a period of 45 minutes, while maintaining
the temperature at less than 20°C. The mixture was heated to 85°C for 15 minutes, and then
was cooled to about 20 to about 25°C. Then, 12.4 ml of HaSO4 were added drop-wise in an
amount sufficient to lower the pH to 1, and the resulting solution was divided to two portions.
[00102] Portion I was extracted with 37 ml of iso-butanol. The organic layer was
separated, and BusN was added in an amount sufficient to provide a pH of 4, precipitating (S)-Pregabalin, which was filtered, and washed with 10 ml of iso-butanol. After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 63 percent yield. Optical purity: 99.1 percent area by HPLC.
[00103] Portion n was extracted with 37 ml of pentanol, the organic layer was
separated; and BusN was added in an amount sufficient to provide a pH of 4. The precipitated (S)-Pregabalin was filtered, and washed with 10 ml of pentanol. After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 61 percent yield. Optical purity: 96.6 percent area by HPLC.
Example 24: Preparation of (SVPregabalin
[00104] A 0.2 liter reactor was loaded with 60 ml of water and 17.65 g of NaOH. The
resulting solution was cooled to from 10° to 15°C, and 15 g of 25 were added. Then, 15 g of Br2 were added drop-wise over 15 minutes, while maintaining the temperature at less than 20°C. The mixture was heated to 80°C for 15 minutes, and then cooled to room temperature, i.e., about 20 to about 25°C. Then, 75 ml of iso-butanol were added, and an aqueous 32 percent solution of HC1 was added in an amount sufficient to provide a pH of 2. The organic phase was separated, and (S)-Pregabalin was precipitated after the addition of 14 ml of Bu3N. The mixture was cooled to 2°C, and the solid Was filtered, washed, and dried at 55 °C under vacuum, providing a 61 percent yield. Optical purity: 98.7 percent area by HPLC.
Example 25: Preparation of (SVPregabalin
[00105] A 0.2 liter reactor was loaded with 60 ml of water and 17.65 g of NaOH. The
solution was cooled to from 10° to 15°C, and 15 g of 25 were added. Then, 15 g of Br2 were added drop-wise over 15 minutes, while maintaining the temperature at less than 20°C. The mixture was heated to 80°C for 15 minutes, and then cooled to room temperature, i.e., about 20 to about 25°C. Then 75 ml of pentanol were added, followed by an aqueous 32 percent of HC1 in an amount sufficient to provide a pH of 2. The organic phase was separated, and (S)-Pregabalin was precipitated after the addition of 14 ml of BusN. The mixture was then cooled to 2°C, and the solid was filtered, washed, and dried at 55°C under vacuum, providing a 52 percent yield. Optical purity: 96.9 percent area by HPLC.
Example 26: Preparation of (S)-Pfegabalin
[00106] A 0.2 liter reactor was loaded with 110 ml of water and 27.65 g of NaOH.
The solution was cooled to from 10° to 15°C, and 23.5 g of 25 were added. Then, 23.5 g of Brz were added drop-wise over 15 minutes, while maintaining the temperature at less than 20°C. The mixture was heated to 80°C for 15 minutes, and then cooled to room temperature, i.e., about 20 to about 25°C. An aqueous 32 percent solution of HC1 was added in an amount sufficient to provide apH of 2. The mixture was then extracted with 138 ml of iso-butanol, and the organic phase was separated. (S)-Pregabalin precipitated after the addition of diisopropylethyl amine in an amount sufficient to provide a pH of 4. The mixture was cooled to 2°C, and the solid was filtered, washed, and dried at 55°C under vacuum, providing a 43 percent yield. Optical purity: 98.4 percent area by HPLC.
Example 27: Preparation of (SVPregabalin
[00107] A reactor (0.2 liter) was loaded with water (50 ml), NaOH (14.7 g). The
solution was cooled to 10-15 °C and 25 (12.5 g) was added. Brz (12.5 g) was added dropwise (15 min) while keeping the temperature below 20°C. The mixture was heated to 80° C for 15 and then cooled to room temperature. Iso-butanol was added (75 ml) then a 66 percent solution of H2SO4 was added to obtain a pH of 2. The organic phase was separated, distilled (to a volume of 50 ml), (S)-Pregabalin was precipitated after addition of Bu3N (11.6 ml). The mixture was cooled to 2°C, and then the solid was filtered, washed, and dried at 55°C under vacuum, providing a 81 percent yield. Optical purity: 98.9 percent area by HPLC.
[00108] While it is apparent that the invention1 disclosed herein is well calculated to
fulfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments as falling within the true spirit and scope of the present invention.

We claim:
1. A compound of formula 24
(Formula Removed)
2. wherein AT is a Cg-io aromatic hydrocarbon group, preferably selected from the group consisting of naphthyl, phenyl, and substituted phenyl; and R is straight or branched Ci^ alkyl, ester or carboxylic acid.
2. A compound according to claim 1, wherein Ar represents unsubstituted phenyl.
3. A compound according to claim 1 or 2, wherein tlie R is straight or branched Ci.4
alkyl.
4. A compound according to claim 3, wherein R represents methyl, ethyl, isopropyl, n-
butyl, isobutyl or t-butyl.
5. A compound according to claim 4, wherein R represents methyl or ethyl.
6. A compound according to claim 5, wherein R represents methyl.
7. A compound according to any preceding claim, wherein Ar represents phenyl
substituted with at least one of alkoxy, halogen, alkyl, carboxylic acid, and ester.
8. A compound according to claim 7, wherein Ar represents methoxyphenyl.
9. A compound according to claim 7, wherein Ar represents chlorophenyl, bromophenyl
or fluorophenyl.
10. A compound according to claim?, wherein Ar represents toluene or ehtylbenzene.
11. A compound according to claim 7, wherein Ar represents phenyl substituted with at
least one of-COOH, -CH2COOH, -CH(CH3)COOH and -C(CH3)2COOH.
12. A compound according to claim 7, wherein Ar represents phenyl substituted with at
least one of methylester, ethylester, isopropylester, n-butylester, isobutyl ester, and t-
butyl ester derivatives of -COOH, -CH2COOH, -CH(CH3)COOH or
-C(CH3)2COOH.
13. A compound according to any preceding claim, having optical purity of at least about
93%areabyHPLC.
14. A compound according to claim 13, having optical purity of about 99% to 100% area
byHPLC.
15. A compound oaccording to claim 13, wherein Ar is phenyl, and R is methyl (Formula
24A).
(Formula Removed)
16. A compound according to claim 15, characterized by data selected from a group .
consisting of: a 13C- NMR spectrum (CDC13, 75 MHz) having carbon chemical shifts at about 21.74, 22.15,22.61,24.12,24.87, 30.85, 38.1, 40.47, 43.38, 48.88,126.0, 127.2, 128.49,143.00, 172.02 and 176.66 ppm; a 13C- NMR spectrum substantially as depicted in Figure 2; an !H-NMR spectrum (CDCls, 300 MHz) having hydrogen chemical shifts at about 0.84,1.19,1.44-1.46,1.63,2.27, 5.09, 6.89-6.91, 7.28 and 11.65 ppm; a 'H- NMR spectrum substantially as depicted in Figure 1; an IR
spectrum having peaks at about 3323,' 3318.8*, 2955,1691.98,1638,1617,1566 and 761 cm"1, and an IR spectrum substantially as depicted in Figure 3.
17. A compound according to claim 15 or 16 in a crystalline form.
18. A compound according to any of claims 15 to 17, characterized by a PXRD pattern
having peaks at about 4.3°, 6.2° 6.8°, 7.3°, 10.3°, and 17.4° 26 ± 0.2° 26.
19. A compound according to claim 18, further characterized by data selected from a
group consisting of: X-ray powder diffraction peaks at about 7.7°, 8.2°, 9.7°, 11.3°,
12.8°, 13.9°, 15.1°, 15.7°, 18.6°, 19.1°, 19.6°, 20.9°, 21.8°, 22.4°, and 23.3° 20 ±0.2°
29; a PXRD pattern substantially as depicted in Figure 4; a melting range of about
95°C to about 97°C.
20. A process for the preparation of the compound of formula 24,
21. (Formula Removed)
comprising:
(a) combining a chiral amine of formula 23,
3. (Formula Removed)
an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base to obtain a mixture;
(b) cooling the mixture to a temperature of about 10°C to about -70°C;
(c) adding to the mixture 3-isobutyl glutaric anhydride of formula 22,
to obtain the compound of formula 24,
(d) recovering the compound of formula 24 from the mixture; wherein Ar is a C&.io aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl and R is straight or branched Ci-4 alkyl, ester or carboxylic acid.
21. The process according to claim 20, wherein Ar represents phenyl.
22. The process according to any of claims 20 to 21 wherein R represents straight or
branched CM alkyl.
23. The process according to claim 22, wherein R represents methyl, ethyl, isopropyl, n-
butyl, isobutyl or t-butyl.
24. The process according to claim 23, wherein R represents methyl or ethyl.
25. The process according to claim 24, wherein R represents methyl.
26. The process according to any of claims 20 to 25 wherein Ar represents phenyl substituted
with at least one of alkoxy, halogen, alkyl, carboxylic acid, and ester.
27. The process according to claim 26, wherein Ar represents methoxyphenyl.
28. The process according to claim 26, wherein Ar represents chlorophenyl, bromophenyl or
fluorophenyl.
29. The process according to claim 26, wherein Ar represents toluene or ethylbenzene.
30. The process according to claim 26, wherein AT represents phenyl substituted with at least
one of-COOH, -CH2COOH, -CH(CH3)COOH and -C(CH3)2COOH.
31. The process according to claim 26, wherein Ar represents phenyl substituted with at least
one of methylester, ethylester, isopropylester, n-butylester, isobutyl ester, and t-butyl ester
derivatives of -COOH, -CH2COOH5 -CH(CH3)COOH or -C(CH3)2COOH.
32. The process according to any of claims 20 to 31 wherein the chiral amine is a primary
amine.
33. The process according to any of claims 20 to 32 wherein the chiral amine is selected from
a group consisting of: lR,2S-Ephedrine, naphthyl-a-methyl ethylamine, Glycine methylester,
methylbenzylamine and a chiral amino acid derivative.
34. The process according to claim 33 wherein the chiral amine is methylbenzylamine.
35. The process according to claim 34, wherein the chiral amine is (R)-methylbenzylamine.
36. The process according to any of the claims 20 to 35 wherein the organic solvent is a Cg-g
aromatic hydrocarbon.
37. • The process according to claim 36 wherein the organic solvent is toluene or xylene.
38. The process according to any of claims 20 to 35, wherein the organic solvent is a Cs-e
ether.
39. The process according to claim 38, wherein the organic solvent is selected from the
group consisting of tert-butyl methyl ether, THF, Diisopropylether, and Diethyl ether.
40. The process according to any of the claims 20 to 35 wherein the organic solvent is a Ci_2
halogenated hydrocarbon.
41. The process according to claim 40 wherein the organic solvent is dichloromethane.
42. The process according to any of the claims 21 to 35, wherein the organic solvent is a
alcohol selected from a group consisting of isopropyl alcohol, ethanol, methanol and n-
butanol.
43. The process according to any of claims 21 to 35 wherein the organic solvent is a ester.
44. The process according to claim 43, wherein the organic solvent is selected from the
group consisting of ethyl acetate, isopropyl acetate, and isobutyl acetate.
45. The process according to any of the claims 21 to 35, wherein the organic solvent is a
straight, branched, or cyclic Cs-Cy alkane.
46. The process according to claim 45, wherein the organic solvent is hexane or
cyclohexane.
47. The process according to any of claims 21 to 35 wherein the organic solvent is a Ca-g
ketone.
48. The process according to claim 47, wherein the organic solvent is selected from the
group consisting of acetone, methyl isobutyl ketone, and methyl ethyl ketone.
49. The process according to claim 48, wherein the organic solvent is acetone.
50. The process according to any of claims 20 to 49 wherein the base is an organic base.
51 . The process according to claim 50, wherein the base is a C\.u amine.
52. The process according to claim 51, wherein the Q_i2 amine is selected from the group consisting of diethyl amine, triethyl amine, di-n-propyl amine, di-isopropyl amine, tert-butylamine morpholine, piperidine, pyridine, and 4-dimethyl aminopyridine.
53. The process according to claim 52, wherein the organic base is 4-dimethyl aminopyridine.
54. The process according to any of claims 20 to 53 wherein the mixture is cooled to a
temperature of about 0°C to about -60°C.
55. The process according to claim 54 wherein the mixture is maintained at a temperature of
about 0°C to about -60°C for about one hour to about two hours, prior to the addition of 3-
isobutyl glutaric anhydride.
56. The process according to any of claims 20 to 55 wherein the recovered compound of
formula 24 has an optical purity of at least about 93%.
57. The process according to claim 56, wherein the recovered compound of formula 24 has
an optical purity of about 99% to about 100% area by HPLC.
58. The process according to any of claims 20 to 57 further comprising purifying the
recovered compound 24 by a process of crystallization from an organic solvent selected from
the group consisting of esters, nitriles, ethers, Ct-t straight, branched or cyclic hydrocarbons,
Ce-io aromatic hydrocarbons and mixtures thereof.
59. The process according to claim 58, wherein the organic solvent is €3.6 ester.
60. The process according to claim 59, wherein the Cs-s ester is ethyl acetate.
61. The process according to claim 58, wherein the organic solvent is acetonitrile.
62. The process according to claim 58, wherein the organic solvent is a C2-6 ether.
63. The process according to claim 62, wherein the C2-6 ether is methyl t-butyl ether.
64. The process according to claim 61, wherein the organic solvent is a C7.9 aromatic
hydrocarbon.
65. The process of claim 64 wherein the Cy.g aromatic hydrocarbon is either toluene or
xylene.
66. The process according to claim 58, wherein the mixtures are that of xylene and ethyl
acetate, hexane and ethyl acetate, cyclohexane and ethyl acetate and toluene and ethyl
acetate.
67. The process according to claim 66, wherein the mixture is that of toluene and ethyl
acetate.
68. The process according to any of claims 20 to 67, further comprising converting the
compound of formula 24 to (S)-Pregabalin.
69. A process according to claim 71 wherein the compound of formula 24 is converted to a
compound of formula 25,
4. (Formula Removed)
and the compound of formula 25 is subsequently converted to (S)-pregabalin
70. A process according to claim 69 wherein the compound of formula 24 is converted to the
compound of formula 25 by a process comprising: combining the compound of formula 24,
water, an ether, ammonia and an alkali metal at a temperature of about 10°C to about ~78°C to
obtain a mixture; and recovering the compound of formula 25 from the mixture.
71. The process according to claim 70 wherein the compound of formula 24, water and ether
are combined, prior to the addition of ammonia and an alkali metal.
72. The process according to claim 72, wherein the ammonia and alkali metal are added to
the compound of formula 24, water, and ether at a temperature of about 5°C to about -40°C.
73. The process according to any of claims 70 to 72 wherein the ether is C2-e ether.
74. The process according to claim 73 wherein the ether is tetrahydrofuran or dioxane.
75. The process according to any of claims 70 to 74 wherein the ammonia is an aqueous
solution of ammonia.
76. The process according to any of claims 70 to 75 wherein the alkali metal is either lithium
or sodium.
77. The process according to claim 69 wherein the compound of formula 24 is converted to
the compound of formula 25 by a process comprising:
a) combining the compound of formula 24 with concentrated sulfuric acid to obtain a
mixture;
b) maintaining the mixture at a temperature of about 0°C to about 50°C, for about 10
hours to about 30 hours, and
c) recovering the compound of formula 25 from the mixture.
78. A process according to any of claims 69 to 77 wherein the conversion of tlie compound of
formula 25 to (S)-pregabalin comprises combining the compound of formula 25 with
bromine, water, and an alkaline hydroxide to obtain a basic mixture; heating the basic
mixture to a temperature of about 60°C to about 85°C; adding to the basic mixture a strong
mineral acid to obtain an acidic mixture; reacting the acidic mixture with a base to obtain (S)-
Pregabalin, and N S-Pregabalin recovering (S)-Pregabalin;
79. The process according to claim 83, wherein the alkaline hydroxide and water are combined to obtain a solution, prior to the addition of the compound of formula 25 and bromine. 80. The process according to any of claims 78 to 79 wherein the alkaline hydroxide is selected from a group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide.
81. The process according to claim 80, wherein the alkaline hydroxide is sodium hydroxide.
82. The process according to any of claims 78 to 81, wherein the compound of formula 25 is
added to the solution at a temperature of about 5°C to about 10°C.
83. The process according to claim 82, wherein the bromine is added to the solution of
alkaline hydroxide and water after the addition of the compound of formula 25.
84. The process according to claim 83, wherein the compound of formula 25 is added to the
solution of alkaline hydroxide and water at a temperature of about 5°C to about 10°C.
85. The process according to any of claims 78 to 84, wherein a C4_8 alcohol is added prior to
the addition of the strong mineral acid.
86. The process according to claim 85 wherein the Ci-g alcohol is selected from the group
consisting of butanol, iso-butanol, 2-butanol, pentanol and iso-pentanol.
87. The process according to claim 86, wherein the €4.5 alcohol is iso-butanol.
88. The process according to any of claims 78 to 87, wherein the strong mineral acid is
selected from a group consisting of H2SC>4, HC1, HBr and H3PO4.
89. The process according to claim 88, wherein the strong mineral acid is HC1.
90. The process according to any of claims 78 to 89, wherein the addition of the strong
mineral acid provides a two-phase system comprising an organic phase and an aqueous
phase.
91. The process according to claim 90, wherein the base is added to the organic phase.
92. The process according to any of claims 78 to 91 wherein the base is an organic base.
93. The process according to claim 92, wherein the organic base is either a secondary or
tertiary amine.
94. The process according to claim 93, wherein the secondary amine is diisopropylamine or
dipropylamine.
95. The process according to claim.94, wherein the secondary amine is diisopropylamine.
96. The process according to claim 93, wherein the tertiary amine is tributyl amine or triethyl
amine.
97. The process according to claim 96, wherein the tertiary amine is tributyl amine.
98. The process according to any of claims 78 to 91 wherein the base is an inorganic base.
99. The process according to claim 98, wherein the inorganic base is either an alkali
hydroxide or ah alkali carbonate.

100. The process according to claim 99, wherein the alkali hydroxide is sodium hydroxide,
potassium hydroxide, lithium hydroxide, or cesium hydroxide.
101. The process according to claim 100, wherein the alkali hydroxide is sodium hydroxide.
102. The process according to claim 99, wherein the inorganic base is alkali carbonate.
103. The process according to claim 102, wherein the alkali carbonate is sodium carbonate,
sodium bicarbonate, or potassium carbonate.
104. The process according to claim 103, wherein the alkali carbonate is sodium carbonate.
105. Use of a process as defined in any of claims 20 to 67 in the manufacture of (S)-
pregabalin.
106. Use of an intermediate as defined in any of claims 1 to 19 in the manufacture of (S)-pregabalin.