FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION [See section 10, rule 13]
AN IMPROVED PROCESS FOR RACEMIZATION OF (S)-3-(CARBAMOYLMETHYL)-5-METHYLHEXANOICACID
PIRAMAL HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Piramal Tower, Ganpatrao Kadam Marg, Lower Parel, Mumbai - 400 013, State of Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to a process for producing a key intermediate used for the synthesis of (S)-3-Aminomethyl-5-methylhexanoic acid (Pregabalin or the compound of formula II). In particular, the present invention provides an improved process for the conversion of the (S)-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid ("referred to herein as the compound of formula I") to its racemic form, which is used as the key intermediate for the synthesis of Pregabalin by methods known in the art.
BACKGROUND OF THE INVENTION
Pregabalin, (S)-3-Aminomethyl-5-methylhexanoic acid, represented by the following formula II is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. Pregabalin is marketed under the name LYRICA.RTM by Pfizer, Inc.


Formula I
3-(carbamoylmethyl)-5-methylhexanoic acid is represented by the following formula I. Racemic form of the compound of formula I (3-(carbamoylmethyi)-5-methylhexanoic acid) is used as an important intermediate in the preparation of the compound of formula II (Pregabalin).

There are several methods known in the art for the preparation of the compound of formula II (Pregabalin). One of the most preferred processes is disclosed in US patent no. US5629447. This patent also discloses racemic form of the compound of formula I.
The US patent no. US5629447 describes the process for the synthesis of the compound of formula II comprising condensation of isovaleraldehyde with alkyl cyanoacetate to form 2-cyano-5-methylhex-2-enoic acid alkyl ester. The 2-cyano-5-methylhex-2-enoic acid alkyl ester is reacted with dialkyl malonate to form 3-isobutylglutaric acid, which is reacted with acetic anhydride to form 3-isobutylglutaric anhydride. The resulting 3-isobutylglutaric anhydride is reacted with ammonia to form the racemic compound of formula I which is resolved by using (R)-(+)-a-phenylethylamine to obtain the corresponding (R)-(+)-a-phenylethylamine salt of the (R)-isomer of the compound of formula I, which is then filtered, leaving the undesired (S)-isomer in the filtrate. The (R)-(+)-a-phenylethylamine salt of the (R)-isomer of the compound of formula I is then treated with an acid to obtain the (R)-isomer of the compound of formula I and this (R)-isomer of the compound of formula I is then transformed into the compound of formula II by using Hofinann reagent. The process disclosed in the said patent though useful in providing the desired isomer (i.e. the (R)-isomer) of the compound of formula I, does not teach racemization of the (S)-isomer of the compound of formula I present in the filtrate, which, apparently, is discarded as an undesired isomer. Thus, the prior art method for the synthesis of the compound of formula II from the racemic compound of formula I is economically not viable, because of loss of one of the isomer, which in turn results in poor overall yield of the compound of formula II.
The general process for the synthesis of the compound of formula II disclosed in US5629447 is depicted in Scheme-I herein below


Scheme-I
PCT patent application no. WO96/38405 discloses a method that addresses the disadvantages associated with the above mentioned process. WO96/38405 discloses a process for the recyclization of the (S)-isomer of the compound of formula I which is discarded as undesired isomer during the process for the synthesis of the compound of formula II (Pregabalin). The process involves an extraction of the (S)-isomer of the compound of formula I from the filtrate

which is obtained after filtration of (R)-(+)-a-phenylethylamine salt of the (R)-isomer of the compound of formula I with aqueous sodium hydroxide solution followed by acidification of an aqueous layer with concentrated hydrochloric acid. The resulting acidic solution is further heated under reflux for 24 hours, extracted with methyl tert-butyl ether and concentrated to obtain 3-isobutylglutaric acid, which is then transformed into the racemic compound of formula I and is further converted to the compound of formula II by the method disclosed in the US5629447. The process disclosed in said patent involves use of hazardous solvent for recyclization of the (S)-isomer of the compound of formula I. Also, the process involves numerous steps and is lengthy which renders the process industrially not viable.
The process for the recyclization of the (S)-isomer of the compound of formula I disclosed in WO96/38405 is depicted in Scheme-II herein below


Scheme-II

Indian patent application no. 1327/mum/2009 discloses a process for the racemization of the (S)-isomer of the compound of formula I by reacting it with an organic base such as piperidine, in toluene as a solvent and the resulting reaction mixture is heated at reflux temperature. The reaction mixture is then treated with an aqueous alkali solution. The two layers formed are separated and the aqueous layer is acidified to obtain the compound of formula I in its racemic form. The process disclosed in the said patent application involve use of an organic base as a reagent for racemization of the compound of formula I, which in turn renders the process costlier and less eco-friendly.
Hence, there is a continuous need to develop simple, commercially advantageous and industrially viable process for the racemization of the (S)-isomer of the compound of formula I that reduces on the number of reaction steps and overall reaction time.
The inventors of the present invention have now found that the compound of formula I in its racemic form can be obtained in good yield and purity from its (S)-isomer through an improved process of racemization involving use of a metal salt as a catalyst.
OBJECT OF THE INVENTION:
An object of the present invention is to provide an improved process for producing the racemic compound of formula I from the corresponding (S)-isomer of the compound of formula I, using a metal salt as a catalyst.
Another object of the present invention is to provide an improved process for producing the racemic compound of formula I from the (S)-isomer of the compound of formula I involving less number of reaction steps.
Yet another object of the present invention is to provide an improved process for producing the racemic compound of formula I from the (S)-isomer of the

compound of formula I involving carrying out the reaction at a shorter duration of time.
Further object of the present invention is to provide an improved process for producing the racemic compound of formula I from the (S)-isomer of the compound of formula I avoiding use of an organic base such as piperidine thereby rendering the process environment friendly.
SUMMARY OF THE INVENTION
In accordance with an aspect of the present invention, there is to provided an improved process for producing the racemic compound of formula I comprising the steps of,
a. heating the (S)-isomer of the compound of formula I in the
presence of a metal salt as a catalyst in an organic solvent at a
temperature of 80-140°C to obtain the racemic compound of
formula I, wherein said (S)-isomer may be substantially free of
the (R)-isomer or may be a mixture of the (R)- and (S)-isomer of
the compound of formula I wherein the (S)-isomer is present in
predominant amount;
b. isolating the racemic compound of formula I from the reaction
mixture obtained in the step (a).
The process for producing the racemic compound of formula I is depicted in Scheme-Ill herein below


DETAIL DESCRIPTION OF THE INVENTION:
Pregabalin (the compound of the formula II) is synthesized by aminolysis of 3-isobutylglutaric anhydride obtained from 3-isobulylglutaric acid followed by resolution of the resulting racemic compound of formula I with (R)-(+)-a-phenylethylamine in an organic solvent, the resulting (R)-isomer of the compound of formula I is then converted into the compound of formula II by using Hofmann reagent.
In the procedure as described above, the (R)-isomer of the compound of formula I preferentially crystallize out leaving the undesired (S)-isomer of the compound of formula I in the mother liquor. Typically it was observed that, the mother liquor, after separation of the (R)-isomer as (R)-(+)-a-phenylethylamine salt, approximately contains 15-20 % of the (R)-isomer and about 80-.85% of the (S)-isomer of the compound of formula I.
Accordingly, the present invention relates to an improved process for producing the racemic compound of formula I from the (S)-isomer of the compound of formula I.

According to the present invention, the improved process for producing the racemic compound of formula I from the (S)-isomer of the compound of formula I involves use of readily available raw materials and reagents.
In accordance with an aspect of the present invention, an improved process for producing the racemic compound of formula I comprising the steps of,

a) heating the (S)-isomer of the compound of formula I in the presence of a metal salt as a catalyst in an organic solvent at a temperature of 80-140°C to obtain the racemic compound of formula I, wherein said (S)-isomer may be substantially free of the (R)-isomer or may be a mixture of the (R)- and (S)-isomer of the compound of formula I wherein the (S)-isomer is present in predominant amount;
b) isolating the racemic compound of formula I from the reaction mixture obtained in the step (a).
In the context of the present invention, the (S)-isomer of the compound of formula I used in the process of the present invention is either substantially free of the (R)-isomer of the compound of formula I or is a mixture of the (R)- and the (S)-isomer of the compound of formula I wherein the (S)-isomer is present in predominant amount. Particularly, the term the (S)-isomer of the compound of formula I which is substantially free of the (R)-isomer of the compound of formula I refers to the (S)-isomer of the compound of formula I containing less than 10% the (R)-isomer of the compound of formula I, preferably less than 1%

the (R)-isomer of the compound of formula I, more preferably essentially free of the (R)-isomer of the compound of formula I.
Essentially free of the (R)-isomer of the compound of formula I means that no (R)-isomer of the compound of formula I can be detected through HPLC analysis.
Further, in the context of the present invention the term (S)-isomer of the compound of formula I is present in the mixture in 'predominant amount' refers to the (S)-isomer of the compound of formula I containing less than 50% the (R)-isomer of the compound of formula I, preferably less than 40% the (R)-isomer of the compound of formula I, more preferably less than 20% the (R)-isomer of the compound of formula I.
In accordance with an embodiment of the present invention, the (S)-isomer of the compound of formula I which is subjected to heating in the step (a) is substantially free of the (R)-isomer of the compound of formula I.
In accordance with an embodiment of the present invention, the (S)-isomer of the compound of the formula I is the mixture of the (R)- and the (S)-isomer of the compound of formula I wherein the (S)-isomer is present in predominant amount.
In accordance with an embodiment of the present invention, the metal salt used in the step (a) is a basic metal salt, selected from the group consisting of sodium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate and sodium methoxide.
In accordance with an embodiment of the present invention, the metal salt used in the step (a) is selected from the group consisting of lithium chloride, copper sulphate, ferric chloride, zinc sulphate, zinc chloride, sodium chloride and ferrous sulphate.

In accordance with an embodiment of the present invention, the metal salt used in the step (a) ranges from 0.03 to 0.05 molar equivalents based on the (S)-isomer of the compound of formula I.
In accordance with an embodiment of the present invention, the organic solvent used in the step (a) is selected from the group consisting of toluene, methyl tert-butyl ether (MTBE), n-hexane and ethyl acetate.
In accordance with an embodiment of the present invention, the organic solvent used in the step (a) ranges from 1 to 10 volumes based on the (S)-isomer of the compound of formula I.
In another embodiment of the present invention, the racemic compound of formula I as obtained in the step (a) is further isolated in the step (b) from the reaction mixture.
In accordance with an embodiment of the present invention, wherein the isolation of the racemic compound of formula I from the reaction mixture as obtained in step (a) (as described herein above) comprises the steps of:
i. treating the reaction mixture of the step (a) with aqueous alkali
solution, ii. separating the aqueous layer from the resulting reaction mixture
of above step (i) at 25-30°C, iii. precipitating the racemic compound of formula I by adjusting the
pH of the aqueous layer obtained in the above step (ii) using IN
hydrochloric acid (HC1).
In a specific embodiment of the present invention, in the process for the isolation of the compound of formula I, in the step (iii) the pH of the aqueous layer is adjusted to 1.0 - 1.5.
The starting material of the process, i.e. the (S)-isomer of the compound of formula I is a known compound and can be obtained as undesired isomer during

the synthesis of Pregabalin (the compound of formula II) by following methods described in the literature. For example, the process described in WO96/38405. The said process comprises condensation of isovaleraldehyde with alkyl cyanoacetate to obtain 2-cyano-5-methylhex-2-enoic acid alkyl ester, which was reacted with dialkyl malonate to obtain 3-isobutylglutaric acid, which in turn was reacted with acetic anhydride to obtain 3-isobutylglutaric anhydride. The resulting 3-isobutylglutaric anhydride was reacted with ammonia to form the racemic compound of formula I which was further resolved by using (R)-(+)-oc-phenylethylamine to obtain the (R)-(+)-a-phenylethylamine salt of the (R)-isomer of the compound of formula I, leaving the undesired (S)-isomer of the compound of formula I in the mother liquor. This mother liquor was concentrated under vacuum to give an oily residue. This oily residue was dissolved in 10% sodium hydroxide solution and was acidified with concentrated hydrochloric acid to give the (S)-isomer of the compound of formula I.
According to present invention, the process for the racemization of the (S)-isomer of the compound of formula I involves charging of the (S)-isomer or the mixture of the (R)- and the (S)-isomer in the ratio of (20:80) of the compound of formula I, metal salt as a catalyst and toluene as a solvent to the reaction flask and the reaction mixture was heated to a temperature of 80-140°C for 3 to 8 hours. To the reaction mixture then 10% sodium hydroxide solution was charged at 80°C. The two layers formed were separated at 25°C. The pH of the aqueous layer was then adjusted to 1.0-1.5 with IN hydrochloric acid at 0°C to precipitate the solid. The resulting solid was filtered, and washed with IN hydrochloric acid solution. The solid was dried under vacuum at 50-55 °C to produce the racemic compound of formula I.
The detailed process for producing the racemic compound of formula I from the (S)-isomer of the compound of formula I is depicted in Scheme-IV herein below


Scheme-IV
The inventors of the present invention have observed that the process for racemization of the compound of formula I when carried out in the presence of a metal salt as a catalyst, racemization takes place without any major impurity

formation thereby providing the racemic compound of formula I with good yield and purity. The said racemic compound of formula I can then be further used for the process of synthesis of Pregabalin.
It has been observed that both basic metal salts such as sodium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, sodium methoxide and metal salts which are not basic such as lithium chloride, ferric chloride, copper sulphate, zinc sulphate, zinc chloride, sodium chloride and ferrous sulphate can be used for racemization of the (S)-isomer of the compound of formula I. The effect of various metal salts on racemization of the (S)-isomer of the compound of formula I is summarized in Table -1.
Table 1: Effect of various metal salts on racemization of the (S)-isomer of the compound of formula I.

Sr.
No. Catalyst Input
(gm) Output (gm) Molar ratio of
the substrate
to catalyst Molar yield Chiral purity byHPLC
1 Sodium carbonate 10 7.3 1:0.034 73.00 51.02:48.98
2 Sodium methoxide 10 7.0 1:0.034 70.00 50.49:49.51
3 Lithium chloride 10 7.2 1:0.047 72.00 49.22:50.78
4 Ferric chloride 10 7.1 1:0.047 71.00 49.47:50.53
The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended for illustrative purpose only and should not be construed in any way to limit the scope of the present invention.

Example- 1
In a round bottom flask, the mixture of the (R)- and the (S)-isomer of the compound of formula I in the ratio of 17:83 (10 gm; 0.053 moles), sodium carbonate (0.19 gm; 0.0017 moles) in toluene (50 ml) was charged and the reaction mixture was gradually heated to 80-140°C for 6 hours. After completion of the reaction, 10% sodium hydroxide solution (50ml) was added to the reaction mixture at 80°C. The two layers formed were separated. To the aqueous layer was then added IN hydrochloric acid and the pH of the reaction mixture was adjusted to 1-1.5 to precipitate solid. The precipitated solid was filtered and washed with IN hydrochloric acid (50 ml). The solid was dried under vacuum at a temperature of 50-55°C to yield the racemic compound of formula I. Yield 73%, chiral purity 51.02:48.98.
Example- 2
In a round bottom flask, the mixture of the (R)- and the (S)-isomer of the compound of formula I in the ratio of 17:83 (10 gm; 0.053 moles), sodium methoxide (0.09 gm; 0.0016 moles) in toluene (50 ml) was charged and the reaction mixture was gradually heated to 80-140°C for 6 hours. After completion of the reaction, 10% sodium hydroxide solution (50ml) was added to the reaction mixture at 80°C. The two layers formed were separated. To the aqueous layer was then added IN hydrochloric acid and the pH of the reaction mixture was adjusted to 1-1.5 to precipitate solid. The precipitated solid was filtered and washed with IN hydrochloric acid (50 ml). The solid was dried under vacuum at a temperature of 50-55°C to yield the racemic compound of formula I. Yield 70%, chiral purity 50.49:49.51.
Example- 3
In a round bottom flask, the mixture of the (R)- and the (S)-isomer of the compound of formula I in the ratio of 17:83 (10 gm; 0.053 moles), lithium chloride (O.llgm; 0.0025 moles) in toluene (50 ml) was charged and the

reaction mixture was gradually heated to 80-140°C for 6 hours. After completion of the reaction, 10% sodium hydroxide solution (50ml) was added to the reaction mixture at 80°C. The two layers formed were separated. To the aqueous layer was then added IN hydrochloric acid and the pH of the reaction mixture was adjusted to 1-1.5 to precipitate solid. The precipitated solid was filtered and washed with IN hydrochloric acid (50 ml). The solid was dried under vacuum at a temperature of 50-55°C to yield the racemic compound of formula I. Yield 72%, chiral purity 49.22:50.78.
Example- 4
In a round bottom flask, the mixture of the (R)- and the (S)-isomer of the compound of formula I in the ratio of 17:83 (10 gm; 0.053 moles), ferric chloride (0.40 gm; 0.0024 moles) in toluene (50 ml) was charged and the reaction mixture was gradually heated to 80-140°C for 6 hours. After completion of the reaction, 10% sodium hydroxide solution (50ml) was added to the reaction mixture at 80°C. The two layers formed were separated. To the aqueous layer was then added IN hydrochloric acid and the pH of the reaction mixture was adjusted to 1-1.5 to precipitate solid. The precipitated solid was filtered and washed with IN hydrochloric acid (50 ml). The solid was dried under vacuum at a temperature of 50-55°C to yield the racemic compound of formula I. Yield 71%, chiral purity 49.47:50.53.
Details for HPLC analysis:
Chiral Column: Chiralpak AD-H, 250 X 4.6mm, 5um (P/N-19325) Mobile Phase: n-Heptane: Ethanol: Trifluoroacetic acid (85: 15: 0.1) Detector: UV, 205nm Flow: 0.5 ml/min Temperature: 25°C Run Time: 25mins

Injection Volume: IOµ1
Diluent: - Mobile phase
Blank preparation: Use diluents as blank.
Procedure: Inject separately 10ml of blank, reference and sample Preparation, and record the chromatogram. In the sample preparation chromatogram disregard any peak due to the Blank.
Calculation: Area %
Informative Retention time: R-Isomer:- ~ 12.7 min
S-Isomen- ~ 13.7 min

WE CLAIM,
\. A process fox producing a racemic compound of formula I (3-(carbamoylmethyl)-5-methylhexanoic acid),

a. heating the (S)-isomer of the compound of formula I in the
presence of a metal salt in an organic solvent at a temperature of
80-140°C to obtain the racemic compound of formula I, wherein
the said (S)-isomer may be substantially free of the (R)-isomer or
may be a mixture of the (R)- and the (S)-isomer of the compound
of formula I wherein the (S)-isomer is present in predominant
amount;
b. isolating the racemic compound of formula I from the reaction
mixture obtained in the Step (a).
2. The process as claimed in claim 1, wherein the (SHsomer of the compound of formula I which is subjected to heating in the step (a) is substantially free of the (R)-isojner of the compound of formula I.
3. The process as claimed in claim 1, wherein the (SHsomer of the compound of the formula I which is subjected to heating in the step (a) is the mixture of the (R)- and the (S)-isomer of the compound of formula I wherein the (S)-isomer is preset in predominant amount.

4. The process as claimed in claim 1, wherein the said metal salt is a basic metal salt selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate and sodium methoxide.
5. The process as claimed in claim 1, wherein the said metal salt is selected from the group consisting of lithium chloride, sodium chloride, copper sulphate, zinc sulphate, zinc chloride and ferrous sulphate.
6. The process as claimed in claim 1, wherein the said metal salt is used in an amount ranging from 0.03 to 0.05 molar equivalents based on the (S)-isomer of the compound of formula I.
7. The process as claimed in claim 1, wherein the said organic solvent used in the step (a) is selected from the group consisting of toluene, methyl tert-butyl ether (MTBE), n-hexane and ethyl acetate.
8. The process as claimed in claim 1, wherein said organic solvent is used in an amount ranging from 1 to 10 volumes based on the (S)-isomer of the compound of formula I.
9. The process as claimed in claim 1, wherein the step (b) involving isolation of the racemic compound of formula I from the reaction mixture obtained in the step (a) comprises the steps of:
i. treating the reaction mixture of the step (a) with aqueous alkali
solution, ii. separating the aqueous layer from the resulting reaction mixture
of above step (i) at 25-30°C, iii. precipitating the racemic compound of formula I by adjusting the
pH of the aqueous layer obtained in the above step (ii) using IN
hydrochloric acid.

10. The process as claimed in claim 9, wherein in the step (iii) the pH of the aqueous layer is adjusted to 1-1.5.