FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2006
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention -"A NOVEL PROCESS FOR THE SYNTHESIS OF
PREGABALIN VIA NOVEL INTERMEDIATES"
2. Applicant(s)
(a) NAME: Cipla Ltd.
(b) NATIONALITY: An Indian company
(c) ADDRESS: 289 Bellasis Road, Mumbai Central. Mumbai 400008
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Field of the Invention
The present invention relates to a novel process for the preparation of pregabalin (formula 1)
"■"TY"
Formula 1
The invention also relates to novel intermediates which are produced during the course of carrying out the novel process.
Background of the Invention
y-Aminobutyric acid ("GABA") is one of the most widely distributed inhibitory neurotransmitters involved in the regulation of brain neuronal activity. The concentration of GABA is regulated by two pyridoxal 5'-phosphate dependent enzymes; L-glutamic acid decarboxylays ("GAD"), which catalyses conversion of 1-glutamic acid to GABA and GABA aminotransferase, which degrades GABA to succinic semialdehyde. When the concentration of GABA diminishes below a threshold level in the brain, convulsions may result and, conversely, raising the GABA level appears to terminate seizures.
(S)-3-(aminomethyl)-5-methylhexanoic acid, commonly known as pregabalin; having structural formula 1,


Formula 1
is a 3-substituted y-aminobutyric acid (GABA) analog that acts as an anticonvulsant believed to have a mechanism of action similar to that of Neurontin, a drug introduced to the market by Parke-Davis in 1994.
It has a dose dependent protective effect on-seizure, and is a CNS-active compound. (S)- pregabalin has analgesic, anticonvulsant and anxiolytic activity. It is found to be 40 times more active when compared with R (-) enantiomer of pregabalin.
The earliest known synthesis of pregabalin was first disclosed in the WO 93/23383. The patent discloses a process starting from 4-methylvaleric acid that requires 8 steps. The process involves chlorination with thionyl chloride to yield acid chloride which is reacted with stoichiometric (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidnone that may be recycled ; at -78°C in the presence of n-butyl lithium to give acyloxazolidinone. The compound is further reacted with Benzyl a- bromoacetate using LDA at -78°C in the presence of dry THF to give benzylated acyloxazolidinone. The compound is hydrolyzed and oxidized simultaneously in the presence of hydrogen peroxide -lithium hydroxide to yield the acid. The acid further reduced to alcohol using borane -dimethylsulfide. The hydroxyl group is then protected with tosyl chloride in pyridine. The tosylate is further reacted with sodium azide in dry dimethyl sulfoxide to give azide. The azide on further hydrogenation in the presence of hydrogen gas yields pregabalin.


However, the process has several drawbacks, due to the low temperature required for the reactions, hazardous reactions involving thionyl chloride, hydrogen peroxide and sodium azide, the use of pyrophoric reagent, such as butyl lithium, to side reactions leading to overall low yield.
Several other approaches are also described in the literature to make pregabalin. For
example;
US 5629447 disclose the preparation of pregabalin using 3-carbomoylmethyl-5-
methyl hexanoic acid. The synthetic method employed is depicted in the following
reaction scheme 1.


«*> YTY™ m"
Ethand
O

HQ

( + )-3<^il3amcylmethyl (RH+)-Phenyl
-5-methyl hexanoic acid etnylarrine

OH O
H/4
6 \ 0
YYV «< ^TY

Pregabalin
WO 96/40617, WO00/76958, WO 01/55090, WO 03/093220, WO2006136087 Al and US patent 6306910 provide several processes for the preparation of pregabalin.
WO2006136087 Al makes use of 3-isobutyl glutaric acid to convert to anhydride using acetic anhydride which undergoes Hoffman rearrangement using toxic bromine


to yield pregabalin. The synthetic method employed is depicted in the following reaction scheme 2.


Hoffman Rearrangement
Bromine
3-lsobutyl pjutaric anhydide
HO "O Raceme pregabalin

Resolution

Pregabalin

US6924377 discloses a process for preparing highly functionalized gamma-butyrolactams and gamma.-amino acids by reductive animation of mucohalic acid or its derivatives, and discloses a process for preparing pregabalin, a GABA analog with desirable medicinal activity. US6924377 discloses a process to prepare pregabalin comprising i) reacting mucohalic acid with benzyl alcohol to yield 5-benzyloxy-3,5-dihalo-5H-furan-2-one ii) reacting with isobutyl magnesium halide in presence of copper iodide at -15 to -20°C to yield 5-benzyloxy-3-halo-4-isopropyl-5H-furan-2-one , or reacting with 2-methyl-l-propenyl- boronic acid , cesium fluoride, PdCl2(PPh3)2 & triethylbenzyl ammonium chloride iii) reducing compound to yield 5-benzyloxy-4-isopropyl-dihydro-furan-2-one iv) reductive animation in presence of ammonium formate & [Ir(COD)Cl]2 to yield pregabalin. But the process has many disadvantages .All these steps involve costly reagents & solvents. Further, all the intermediate steps are purified by column chromatography. Further pregabalin obtained is contaminated with 4-isopropyl-pyrrolidin-2-one which requires base hydrolysis to yield pure pregabalin.


The processes disclosed in the prior art are cumbersome. Therefore, there exists a need for a more economical and efficient method of making pregabalin, which is suitable for industrial, scale up.
The processes of the present invention is convergent than the prior art route. It avoids use of reagents such as butyl lithium, acetic anhydride, bromine, thionyl chloride, etc and allows substantial reduction in the number of problems associated with these reagents.
The present invention is an attempt to provide a simple and industrially scalable route for the synthesis of pregabalin.
Objects of the Invention
Accordingly, one object of the present invention is to provide a novel process for
preparing pregabalin.
Another object of the present invention is to provide a novel process via new
intermediates for the synthesis of pregabalin.
Another object of the present invention is to provide novel intermediates of formula
3,4, 5, and 6 and the process for preparing these intermediates.
Yet another object of the present invention is to provide a process, which is simple,
economical & suitable for industrial scale up.
Summary of the Invention
According to one aspect of the present invention there is provided a process for the synthesis of highly pure pregabalin, said process comprising steps of: i) Reacting the lactone of formula 2



2
with an inorganic acid HX to obtain 3-halomethyl-5-methyl-hexanoic acid of formula 3;
O^OH 3
wherein, X is halo atom;
ii) Esterifying the compound of formula 3 with alcohol R-OH, in the presence of an acid or acid addition salt to obtain compound alkyl-3-halomethyl-5-methyl-hexanoate of formula 4
O^OR
4
wherein R is C1-C6 alkyl, straight or branched chain and X has the meaning above; or
reacting the lactone of formula 2 with anhydrous inorganic acid in the presence of a suitable alcoholic solvent to obtain compound alkyl-3-halomethyl-5-methyl-hexanoate of formula 4;


iii) Reacting the compound of formula 4 with potassium phthalimide in polar aprotic solvent to obtain alkyl-l-3-phthalimidomethyl-5-methyl-hexanoate of formula 5;

wherein R has the meaning above;
iv) Hydrolyzing the ester of formula 5 with base to obtain 3-phthalimidomethyl-5-methyl-hexanoic acid of formula 6;
O.

v) Hydrolyzing the acid of formula 6 in the presence of an acid or base to yield racemic pregabalin of formula 7.
NH„

OH

and;

Racemic pregabalin


vi) Separating isomers using chiral resolving agent to obtain pregabalin of formula 1.

H2N

. OH O

Formula 1
Another aspect of the present invention is to provide a novel process via new intermediates for the synthesis of pregabalin.
In yet another aspect, the invention provides novel intermediates of formula 3, 4, 5, and 6 and the process for preparing these intermediates.
The process according to the invention will now be described in more details below.
Detailed description of the invention
In accordance with the above objective the present invention provides a novel synthesis for preparation of pregabalin involving novel intermediates comprising the steps of;
i) Reacting the lactone of formula 2 with an inorganic acid HX, to obtain 3-halomethyl-5 -methyl-hexanoic acid of formula 3 ;
-X inorganic acid

O OH



wherein, X is halo atom;

ii) Esterifying the compound of formula 3 with alcohol R-OH in the presence of an acid or acid addition salt to compound alkyl-3-halomethyl-5-rnethyl-hexanoate of formula 4
X ^X
alcohol, acid

wherein R and X have the above meaning;
or;
Reacting the lactone of formula 2 with anhydrous inorganic acid in the presence of a
suitable alcoholic solvent to obtain compound alkyl-3-halomethyl-5-methyl-
hexanoate of formula 4;
iii) Reacting compound of formula 4 with potassium phthalimide in a polar aprotic solvent to obtain alkyl-l-3-phthalimidomethyl-5-methyl-hexanoate formula 5;



O


4 Potassium phthalimide 5
wherein R has the above meaning;
iv) Hydrolyzing ester of formula 5 in the presence of a suitable base to obtain 3-phthalimidomethyl-5-methyl-hexanoic acid of formula 6;




Hydrolysis

O OH

v) Hydrolyzing 3-phthalimidomethyl-5-methyl-hexanoic acid of formula 6 in the presence of an acid or base to yield racemic pregabahn of formula 7.



Hydrolysis

vi) Separating enantiomers of formula 7 by chiral resolution to obtain pregabahn of formula 1.


NH„
O' 0H
Racemic pregabalin

Resolution

The improved synthesis of pregabalin from lactone by the present invention is depicted below in reaction scheme 3.



Inorganic acid

O^OH

Alcohol, Acid

O OR 4

NH,
Hydrolysis
O^OH

Hydrolysis
e

o' OH Racemic pregabalin

Resolution


Potassium phthalimide ,NH,


The starting material of the above process, the lactone of formula 2, which is a key intermediate in the synthesis of pregabalin, can be prepared by the process described in the prior art. For example Synth. Commun. 1990,159.
i) In the present invention, in step (a), the lactone of formula 2 is reacted with an inorganic acid HX, to obtain 3-halomethyl-5-methyl-hexanoic acid of formula 3. The inorganic acid used, is selected from hydrochloric acid, hydrobromic acid, with hydrobromic acid preferred. The reaction may be carried out with or without water. In the preferred embodiment, the reaction is carried out using aqueous hydrobromic


acid. The reaction can be carried out at a temperature between ambient temperature and reflux temperature, but it is preferred that the temperature be between 80-100°C. ii) In step (b), the compound of formula 3 is esterified with alcohol in the presence of an acid or acid addition salt to compound alkyl-3-halomethyl-5-methyl-hexanoate of formula 4.
The alkanol may include one or more of primary, secondary and tertiary alcohol having from one to six carbon atoms. The lower alkanol may include one or more of methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol , isobutanol and t-butanol. The preferred alkanol is ethanol, methanol, isopropanol, most preferably ethanol and methanol. The catalytic amount of acid used in the process of the present invention is selected from organic acids such as acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, formic acid, etc and inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, pivalic acid or phosphoric acid. In particular, sulfuric acid is preferred.
The preferred acid addition salts are selected from the group comprising of pyridinium p-toluene sulfonate, pyridine hydrochloride, pyridine hydrobromide with pyridinium p-toluene sulfonate being preferred. The reaction is preferably carried out at a temperature ranging from ambient temperature to the reflux temperature of the solvent used.
Alternatively, the compound alkyl-3-halomethyl-5-methyl-hexanoate of formula 4; may be prepared by reacting the lactone of formula 2 with anhydrous inorganic acid in the presence of a suitable solvent. The reaction is performed without isolating the intermediate 3-hamomethyl-5-methyl-hexanoic acid of formula 3. The anhydrous inorganic acid used is selected from hydrochloric acid, hydrobromic acid and the like in the form of gas or gaseous solution. The reaction is preferably carried out in alkanolic solvent which is preferably a C1 to C6 straight chain or branched chain


alcohol, especially methanol, ethanol, or isopropanol, with ethanol and methanol being preferred. The reaction can be carried out at a temperature between 0°C and reflux temperature of the solvent used. The preferred temperature is between 0°C and 30°C.
iii) In step (c), the compound of formula 4 is reacted with potassium phthalimide in the presence of a polar aprotic solvent to obtain alkyl-l-3-phthalimidomethyl-5-methyl-hexanoate of formula 5.
Typically such a polar aprotic solvents include acetone, tetrahydrofuran (THF), methyl ethyl ketone, acetonitrile, ethyl acetate, N,N-dimethylformamide(DMF), Dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and mixtures thereof, preferably dimethyl formamide and dimethyl acetamide. However, it was found that DMF is particularly useful. The reaction is carried out at a temperature from 20-30°C to an elevated temperature such as the reflux temperature of the solvent used, preferably from 20 to 40°C.
iv) In step (d), the ester of formula 5 is hydrolyzed with base to obtain 3-phthalimidomethyl-5-methyl-hexanoic acid of formula 6 in a suitable solvent.
Hydrolysis is carried out using various inorganic bases such as alkali metal hydroxides, carbonates, alkoxides or organic bases such as tertiary amines. A preferred alkali hydroxide is sodium hydroxide, potassium hydroxide, lithium hydroxide, or cesium hydroxide. More preferably, the alkali hydroxide is sodium hydroxide. The solvent may be one or more alkanol, or mixture thereof. The lower alkanol may include one or more of primary, secondary and tertiary alcohol having from one to six carbon atoms. The lower alkanol may include one or more of methanol, ethanol, denatured spirit, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol.


v) In step (e), 3-phthalimidomethyl-5-methyl-hexanoic acid of formula 6 is hydrolyzed in the presence of an acid or base to yield recemic pregabalin of formula
7;
For example, when acid hydrolysis is carried, the suitable acids include sulphuric acid, para toluene sulphonic acid, methane sulphonic acid, hydrochloric acid, hydrobromic acid etc., in alcohols, ketones or, water as such or in combination with water. In the preferred embodiment, the acid used is aqueous hydrochloric acid. The reaction is performed at a temperature ranging from 25°C to 100°C.
Base hydrolysis may be carried out using inorganic or organic bases such as amines. A preferred amine is primary, secondary or tertiary amine. The primary amine is monomethylamine, The secondary amine is selected from diisopropylamine or n-dipropylamine. The tertiary amine is triethylamine. Most preferably, the amine is monomethyl amine. The solvent may be one or more alkanol or water as such or in combination with water. In the preferred embodiment methanolic solution of methyl amine is used preferably at a temperature of 35°C, or lower.
vi) In step (f), racemic pregabalin of formula 7 is separated using chiral resolving agent to obtain pregabalin of formula 1.
The racemic prgabalin i.e. the enantiomers is separated, by selective crystallization with chiral resolving agent preferably (S)-mandelic acid in a solvent such as an alcohol or water or a mixture thereof. Example of suitable alcohol includes metahnol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and the like.
The present invention also provides novel intermediates of formula 3, 4, 5, and 6 and the process to synthesize these intermediates.


Non limiting intermediates of 3-halomethyl-5-methyl-hexanoic acid of formula 4 include,
3 -chloromethyl- 5 -methyl-hexanoic acid 3 -bromomethyl-5 -methyl-hexanoic acid 3-iodomethyl-5-methyl-hexanoicacid
Non limiting intermediates of alkyl-3-halomethyl-5-methyl-hexanoate of formula 5 include,
Methyl-3-bromomethyl-5-methyl-hexanoate Ethyl-3 -bromomethyl-5 -methyl-hexanoate n-Propyl-3 -bromomethyl-5 -methyl-hexanoate Isopropyl-3-bromomethyl-5-methyl-hexanoate n-Butyl-3-bromornethyl-5-methyl-hexanoate Isobutyl-3-bromomethyl-5-methyl-hexanoate t-Butyl-3-bromomethyl-5-methyl-hexanoate
Methyl-3-chloromethyl-5-methyl-hexanoate
Ethyl-3-chloromethyl-5-methyl-hexanoate
n-Propyl-3-chloromethyl-5-methyl-hexanoate
Isopropyl-3-chloromethyl-5-methyl-hexanoate
n-Butyl-3-chloromethyl-5-methyl-hexanoate
Isobutyl-3-chloromethyl-5-methyl-hexanoate
t-Butyl-3-chloromethyl-5-methyl-hexanoate
Non limiting intermediates of alkyl-l-3-phthalimidomethyl-5-methyl-hexanoate of formula 6 include,


Methyl-3-phthalimidomethyl-5-methyl-hexanoate Ethyl -1-3 -phthalimidomethyl-5 -methyl-hexanoate n-Propyl -1-3 -phthalimidomethyl-5-methyl-hexanoate Isopropyl -l-3-phthalimidomethyl-5-methyl-hexanoate n-Buty 1 -1-3 -phthalimidomethyl-5 -methyl-hexanoate Isobutyl -l-3-phthalimidomethyl-5-methyl-hexanoate t-Butyl -l-3-phthalimidomethyl-5-methyl-hexanoate
Non limiting intermediate of formula 7 include,
3-phthalimidomethyl-5-methyl-hexanoicacid
The present invention also provides a process for preparing pharmaceutical formulation comprising pregabalin, prepared according to the process of the present invention, and a pharmaceutically acceptable carrier.
The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. It will be apparent to those skilled in the art that many modifications, both to material and methods, may be practiced without departing from the scope of the invention.


EXAMPLES

Example 1 : Preparation of 3-bromomethyl-5-methyl-hexanoic acid

JUO-—■
Lactone (100 g, 0.70 mol) and 48 % aqueous HBr solution (250 ml) were added in a 500 ml flask. The reaction mass was heated to 80 - 85 °C for 6 hrs and then cooled to RT. Extracted with 2 X 500 ml MDC. Combined MDC layers were washed with 2 X 250 ml water. The organic phase was concentrated completely under reduced pressure below 40°C to yield 3-bromomethyl-5-methyl-hexanoic acid. Efficiency:- 63.7 %
Example 2 : Preparation of Methyl-3-bromomethyl-5-methyl-hexanoate
Br
Br
Cr^OMe
Method A
3-Bromomethyl-5-methyl-hexanoic acid (100 g, 0.44 mol) and methanol (500 ml)
were added in a 1 lit. flask under nitrogen atmosphere. Cone, sulphuric acid (10 ml) was added slowly. The reaction mass was heated to reflux for 10 hrs and then cooled to 25-30°C. The solvent was distilled completely under reduced pressure below 40°C. To the residue, was charged 500 ml ethyl acetate. The organic phase was washed with 2 X 200 ml water followed by 200 ml of 5 % sodium bicarbonate solution and finally with 200 ml water. The reaction mass was concentrated


completely to remove ethyl acetate under reduced pressure below 40°C to yield
methyl-3-bromomethyl-5-methyl-hexanoate.
Efficiency:- 94.1 %
Method B
3-Bromomethyl-5-methyl-hexanoic acid (365 g, 1.63 mol) and methanol (3.65 lit) were added in a 5-lit RB flask. To the stirred solution was added 10% pyridinium p-toluene sulfonate (36 g, 0.143 mol). The reaction mass was heated to reflux for 3 hrs and then cooled to 45°C. The solvent was removed under reduced pressure. To the residue was added 1 lit ethyl acetate. The organic phase was separated and washed with 3x 500 ml water. The solvent was removed completely under reduced pressure below 50°C to yield methyl-3-bromomethyl-5-methyl-hexanoate. Efficiency:- 94.60%
Example 3: Preparation of Methyl-3-bromomethyl-5-methyl-hexanoate without isolating intermediate 3-bromomethyl-5-methyl-hexanoic acid
XJO-—- ^A
cr^OMe
The lactone ( 6g, 42 mol) was dissolved in dry methanol (32ml) and dry HBr gas was bubbled at 0-5 °C over 4 hr and then the reaction mixture was stirred for 15 hr. Reaction mixture was then diluted with water (80ml) and extracted with diethyl ether. The ether layer was concentrated and the residue obtained was purified by column chromatography to afford methyl-3-bromomethyl-5-methyl-hexanoate. Efficiency:- 78 %


Example 4: Preparation of Methyl-3-phthalimidomethyl-5-methyl-hexanoate


0Me COOCH3

Method A
Potassium phthalimide (4.37 g, 23mmol) and dry DMF(15 ml) were added in a 2-
necked RB flask under nitrogen. A solution of methyl-3-bromomethyl-5-methyl-hexanoate ( 4.00 g, 18 mmol) in dry DMF (10 ml) was added with stirring at RT and the resultant mixture was stirred at RT for 20 hr. The resultant reaction mass was diluted with water and extracted with diethyl ether. Combined organic phases and concentrated diethyl ether under reduced pressure. Purification by column chromatography afforded methyl-3-phthalimidomethyl-5-methyl-hexanoate. Efficiency:- 67.5%
Method B
Potassium phthalimide (109 g, 0.59mol) and 400 ml DMF were added in a 1-lit flask
under nitrogen atmosphere. To the stirred reaction mass was charged a solution of methyl-3-bromomethyl-5-methyl-hexanoate (100 g, 0.42 mol) in 200 ml DMF in 30 min at 25-30°C. The reaction mass was further stirred for 20 hours at 25-30°C. The resultant reaction mass was diluted with 3.0 lit ice water and extracted with 3 X 500 ml ethyl acetate. Combined organic phases were washed with 2 X 200 ml water. The organic solvent was removed by distillation completely under reduced pressure to yield methyl-3-phthalimidomethyl-5-methyl-hexanoate. Efficiency:- 88.4 %


Example 5 : Preparation of 3-phthalimidomethyl-5-methyl-hexanoic acid
CL C),

VCOOCH3 C00H
Method A
The ester, methyl-3-phthalimidomethyl-5-methyl-hexanoate (2.60 g, 8.5 mmol) was stirred with sodium hydroxide (0.514 g, 12.8 mmol) in ethanol (25 ml) at RT for 10 hr. It was then acidified with 6 N HC1 and extracted with ethyl acetate ( 2X50 ml). The solvent was removed under reduced pressure and the residue was purified by column chromatography to yield 3-phthalimidomethyl-5-methyl-hexanoic acid. Efficiency:- 80.97%
Method B
Sodium hydroxide (19.8 g, 0.49 moles) and 800 ml methanol were added in a clean, dry 2-lit flask under nitrogen atmosphere. The reaction mass was cooled to RT and methyl-3-bromomethyl-5-methyl-hexanoate (lOOg, 0.33mol) was added. The reaction mass was stirred at RT for 10 hrs. The solvent was removed by distillation under reduced pressure below 40°C. The residue was stirred with 500 ml water and cooled to 10°C. The reaction mass was acidified with cone. HC1 and extracted with 2 X 500 ml ethyl acetate. Combined organic phases were washed with 200 ml water. The organic solvent removed completely by distillation under reduced pressure below 40°C to yield 3-phthalimidomethyl-5-methyl-hexanoic acid.
Efficiency:-99.61%


Example 6: Preparation of Racemic pregabalin


NH2.HCI COOH

Method A
The phthalimido acid (100 g, 0.34 mol) was suspended in 500 ml cone. HCl in a 2-lit RB flask. The reaction mass was heated to reflux for 10 hours , cooled to 25-30°C and then diluted with 500 ml water. The reaction mass was stirred at 25-30°C for 30 min. The precipitated phthalic acid was removed by filtration and washed with 100 ml of 1 M HCl. The filtrate and washings were combined together & distilled out water completely under reduced pressure below 60°C to yield racemic pregabalin. Efficiency:- 59.13 %
Method B
The phthalimido acid (100 g, 0.34 mol) was suspended in 300 ml methanol in a 1 lit RB flask under nitrogen atmosphere. A solution of 100 ml of methyl amine in methanol solution was added and the reaction mass was further stirred at RT for 1 hr. The solvent was removed completely by distillation under vacuum below 40°C. To the residue was added 300 ml water followed by 300 ml ethyl acetate. pH of the reaction mass was adjusted to about 1 with cone. HCl. The aqueous phase was separated and washed with ethyl acetate. It was then basified with 50% sodium hydroxide solution, extracted with ethyl acetate. The organic phase was washed with 200 ml water. The solvent was removed by distillation under reduced pressure below 40°C to yield recemic pregabalin. Efficiency:- 63.62%


Example 7 : Preparation of (S)- pregabalin
Racemic pregabalin (175 g, 1.1 mol), S-(+) - mandelic acid (231.5 g, 1.52 mol) were mixed with 3%v/v water/ isopropyl alcohol solution (1438 g) in a 3 lit RB flask. The reaction mass was heated to reflux, cooled to 20°C. The solid obtained was collected by filtration, washed with 3%v/v water/ isopropyl alcohol solution (127 g).
The wet cake was stirred with 3%v/v water/ isopropyl alcohol solution (713 g) and S-(+) - mandelic acid (34 g, 0.22 mol). The reaction mass was heated to reflux, cooled to 20°C. The solid obtained was collected by filtration, washed with 3%v/v water/ isopropyl alcohol solution (198 g).
The wet salt was mixed with solution of THF (1150 ml) and water (59 ml). The reaction mass was heated to 60°C and cooled to 0-5°C for 1 hr. The pure (S)-(+)-prgabalin was collected by filtration, washed with solution of THF:water (175ml:6ml).The solid was dried under vacuum at 35-40°C to give (S)-(+)-prgabalin. Yield:- 43 g.