FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
An improved process for the preparation of Pregabalin
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY: An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad -382210, Gujarat, India
3. PREAMBLE TO THE DESCRITION
PROVISIONAL SPECIFICATION COMPLETE SPECIFICATION
The following specification describes the The-feliowing specifiGation-partiGulaFly
invention. dee^^es^e-invention-and the manner-m
whiGhH^i&-to-toe-performed
4. DESCRIPTION
(Description starts from next page)

FIELD OF f HE INVENTION
Pregabalin is useful for the treatment and prevention of seizure disorders, pain, and psychotic disorders. The present invention relates to an improved process for the preparation of Pregabalin involving the use of a mixture of two acids one of which is mandelic acid and second is achiral organic acid or a mineral acid for the resolution of racemic pregabalin.
BACKGROUND OF THE INVENTION
(S)-(+)-3-(Aminomethyl)-5-methylhexanoic acid is known generically as Pregabalin. The compound is also called (SH+)-p-isobutyl-v-aminobutyric acid, (S)-isobutyl-GABA, and CI-1008. Pregabalin is related to the endogenous inhibitory neurotransmitter y-aminobutyric acid or GABA, which is involved in the regulation of brain neuronal activity. Pregabalin has anti-seizure activity, as described by Silverman et al., U.S. Pat. No. 5,563,175.
The anticonvulsant effect of racemic isobutyl-GABA is attributable to the S-enantiomer (pregabalin). That is, the S-enantiomer of isobutyl-GABA shows better anticonvulsant activity than the R-enantiomer (see, for example, Yuen et al., Bioorganic & Medicinal Chemistry Letters, 1994; 4:823). Thus, the commercial utility of pregabalin requires an efficient method for preparing the S-enantiomer substantially free of the R-enantiomer.
Several methods have been reported to prepare pregabalin. Typically, the racemic mixture is synthesized and then subsequently resolved into its R- and S-enantiomers (U.S. Pat. No. 5,563,175 for synthesis via an azide intermediate). Another method uses potentially unstable nitro compounds, including nitromethane, and an intermediate that is reduced to an amine in a potentially exothermic and hazardous reaction. This synthesis also uses lithium bis(trimethylsilylamide) in a reaction that must be carried out at -78° C. (Andruszkiewicz et al., Synthesis, 1989:953). More recently, the racemate has been prepared by a "malonate" synthesis, and by a Hofmann synthesis (U.S. Pat. Nos. 5,840,956; 5,637,767; 5,629,447; and 5,616,793). The classical method of resolving a racemate is used to obtain pregabalin according to these methods. Classical resolution involves preparation of a salt with a chiral resolving agent to separate and purify the desired S-enantiomer. This involves significant processing, and also substantial additional cost associated with the resolving agent. Partial recycle of the resolving agent is feasible, but requires additional processing cost, as well as associated waste generation. Recycling of the resolving agent is described in WO2009001372 and US2008062460 which involves 5 steps.
Thus there is need to provide a process for resolution of Pregabalin which is cost effective. The object of the instant invention is to provide a novel process for resolution of Pregabalin which involves half mole of resolving agent.
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SUMMARY OF THE INVENTION
The main object of the invention is to provide an improved process for the preparation of Pregabalin from racemic pregabalin.
Yet another object of the invention is to provide an alternative process for the resolution of (S)-(+) pregabalin.
Yet another object of the invention is to reduce the consumption of resolving agent.
Yet another object of the invention is to provide a process of resolution of racemic pregabalin wherein , racemic pregabalin is resolved by making salt with a mixture of two acids, one of which is (S)-(+)mandelic acid , the other being a mineral acid or an organic acid, followed by separating (S)-pregabalin-(S)(+) mandelic acid salt , followed by optional purification and cleaving the salt using prior art process to produce (S)-(+) pregabalin.
In one of the preferred embodiments, racemic Pregabalin is resolved to get the (S)-(+)-Pregabalin involving salt formation using two acids ; one is optically active mandelic acid, and other is achiral acid which is hydrochloric acid, during the process', (S)-isomer of pregabalin forms a salt with mandelic acid and is precipitated out from the reaction mass and (R)-isomer of pregabalin forms the salt with hydrochloric acid which goes in filtrate, (S)-{+) pregabalin being obtained by salt cleavage using prior art process.
DETAILED DESCRIPTION OF THE INVENTION
Resolution is known process for separating optically active compounds from corresponding racemic compounds such as acid, amines by preparing salts and separating diasterermeric salts and regenerating required optically active compound by treatment with acid or base.
In asymmetric synthesis, in many cases , we do not get desired enantiomeric excess, hence it further requires enrichment of desired isomer.
In the resolution we can select right resolving agent, proper solvent so as to select a solvent providing maximum solubility difference of two diastereomeric salts, so as to effectively resolve two salts from which desired optical isomer can be obtaine'd by treatment with an acid or a base.
It is desired that to improve commercial economics of the process, the consumption of the expensive reagents should be reduced. Chiral resolving agents are value added compounds, which themselves are prepared by a separate resolution process.
It is preferable to reduce their consumption. We have found out that by adding an achiral organic acid or a mineral acid along with optically active acid, such as (S)-(+) mandelic acid, which is used for the resolution of racemic pregabalin, we could successfully reduce the consumption of chiral resolving agent.
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The preserit invention is depicted as per scheme mentioned below. Scheme-1
Racemic pregabalin + (S) {+)-Mandelic acid + mineral acidorachiral organic acid
(S)(+) Pregabalin {SW+)Mande)ate salt+ R(-) Pregabalin. mineral acid or achiral organic acid salt
Present invention discloses a novel and improved process for resolution of racemic pregabalin, a compound of of formula I, to give (S)-(+)-Pregabalin i.e. [(S)- (+)-3-(aminomethyl)-5-methylhexanoic acid] , a compound of formula IV , via the di acid addition salt, mandelate salt of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, compound of formula II and achiral acid addition salt, preferably hydrochloride salt of (R)- (-)-3-(aminomethyl)-5-methylhexanoic acid - compound of of formula III.

(III) (IV)
The achiral acid can be either a mineral acid such as HCI, HBr, HI, H3PO4, HNO3, H2S04 or other organic acids.
The achiral organic acid is further defined as monocarboxylic or dicarboxylic compounds such as formic acid, acetic acid, oxalic acid, fumaric acid, succinic acid.
The general resolution scheme-1 is further exemplified by specific example, as scheme-2 as follows.
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Scheme-2 The solvents used in the resolution process are polar solvents, or a mixture of polar and non polar solvents. The polar solvents include, but not limited to , water, alcohols and other moderately polar organic solvents The alcohols can be d to Ce alcohols. The temperature of the reaction for preparing salt can be from 0-150°C. The salt formed may be optionally purified to provide optical enrichment of desired salt. The salt is cleaved to give desired isomer by treatment with acid / base. The present invention is further illustrated by following non-limiting examples.
Example-1 Preparation of {S)-(+>-Pregabalin mandelate salt
Racemic pregabalin [5.0 gm] was taken in a flask and 3% aqueous IPA [35.46 ml] was added to it at room temperature.(S)-(+) mandelic acid [2.73 gms] was added at 25-30°C . Hydrochloric acid in IPA [9.11 % wt / vol ; 6.0 ml] was added at 25-30°C. The reaction mass was heated to about 70°C and maintained for 30 minutes. The reaction mass was then cooled to25-30°C The solid mass separated at about 35°C , the reaction mass was then cooled to 0-5°C and stirred at same temperature for about one hour. The reaction mass was filtered, washed with 3% aqueous IPA [5 ml] and the obtained product was dried. Wt= 4.0 gm
Example 2 Purification of (S)-(+)-Pregabalin mandelate salt
To 3% aqueous IPA [ 25 ml] at about 25-30 °C was added 0.98 gm [0.2 mol equivalent] (S)-{+) mandelic acid under stirring at same temperature.The reaction mixture was stirred at 25-30°C for about 15 minutes. The reaction mass was clear at 25-30°C after 15 minutes of stirring. (S)-(+)-Pregabalin mandelate salt obtained in example-1 [2.75 gm] was added with stirring at 25°C .The reaction mass was heated to about 70°C arid stirred at
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same temperature for about 30 minutes. At 70°C, clear solution was obtained. The reaction mass was cooled to 25-30°C, the material was precipitated at 50-55°C. The reaction mass was further cooled to 0 to -5°C and stirred for about one hour at 0 to -5°C.The resultant solid was filtered , washed with 3% aqueous chilled IPA [ 5 ml] and dried Wt= 2.0 gm
The purified (SH+)-Pregabalin mandelate salt was converted to (S)-(+)-Pregabalin by us\r\g pnov art process •

For, Cadila Pharmaceuticals Ltd.,
Dr. Bakuiesh M. Khamar Executive Director - Research
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