An Efficient Process For Synthesis Of Pregabalin

Abstract

The present invention provides a simple and cost effective method for synthesis of pregabalin. The undesired S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid, produced during resolution step in synthesis of pregabalin is racemized to obtain a racemic 3-(carbamoylmethyl)-5-methylhexanoic acid. The said racemic mixture of 3-(carbamoylmethyl)-5-methylhexanoic acid, then again can be converted to pregabalin.-1 JUN 2009

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FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)


"An Efficient Process for Synthesis of Pregabalin"
Emcure Pharmaceuticals Limited.,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.

THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND
THE MANNER IN WHICH IT IS TO BE PERFORMED '

FIELD OF INVENTION

The present invention relates to a cost effective method for synthesis of pregabalin. In particular, the present invention relates to a method for racemization of S-3-(carbamoylmethyl)-5-methylhexanoic acid from a mixture of corresponding R and S-isomer, enriched in S-isomer, of 3-(carbamoylmemyl)-5-methylhexanoic acid.
BACKGROUND OF THE INVENTION
(5)-3-Aminomethyl-5-methylhexanoic acid (Pregabalin, l) has been reported as a more potent substitute of gabapentin. It has anticonvulsant, an.xiolytic-like and analgesic action and is currently approved for neuropathic pain associated with diabetic peripheral inawcpa&j; post beepietie nswzdgfc, as a atfmc&iv&&?apy foradult patients with partial onset seizures and for fibromyalgia. Though, pregabalin. is commercially marketed in its racemic form, under the brand name of Lyrica®, the biological activity of pregabalin is known to reside in its (S)-(+) enantiomer.

Various researchers have attempted to synthesize the active (S)-(+) enantiomer of pregabalin. One of the most preferred processes of pregabalin manufacturing comprises resolution of an isobutylglutaric acid derivative. Huckabee et al in WO 96/38405 discloses a process for Pregabalin manufacturing (Schenle 1) comprising aminolysis of 3-isobutylglutaric anhydride obtained from 3-isobutylglutaric acid, followed by resolution of the intermediary amide with (R)-(+)- 1-phenylethyiamine in chloroform. The R-enantiomer of 3-(carbamoylmethyl)-5-methylhexanoic acid preferentially crystallizes out which is then transformed into pregabalin by using a Hofmann reagent.


However, such an approach, though useful in giving the desired isomer, provides a yield of 37.5% based on racemate, of salt containing desired R-isomer. Further, the documents, though provides a method for regeneration 3-isobutylglutamic acid, however, is silent on racemization of S-isomer, which, apparently, is discarded as undesired isomer. Thus, the prior art method of synthesis of pregabalin from 3-(carbamoyImethyI)-5-rnethylhexanoic acid is economically particularly not viable, because of loss of one of the isomer, which in turn results in poor overall yield of pregabalin.
Martinez and coworkers in Organic Process Research and Development, 2008,12, 392-398, have tried to improve upon the disadvantages associated with the abovementioned process of pregabalin synthesis by taking recourse to a chemoenzymatic process for synthesis of pregabalin (Scheme 2). In this process, commercially available lipase was employed to resolve racemic-2-carboxyefhyl-3-cyano-5-methylhexanoic acid ethyl ester to give (5)-2-carboxyethyl-3-cyano-5-methylhexanoic acid, which was subsequently subjected to decarboxylation and reduction to provide pregabalin. The process involves recycling of unwanted R-enantiomer by reacting it with sodium ethoxide in ethanol in the presence of toluene. The reaction is carried by heating the mixture at 80°C for 8-16 hrs-.
-1 JUN 2009
However, the abovementioned process of using sodium ethoxide in ethanol results in only partial racemization yielding only 5-10% racemized product in 16 hours.


It is clearly evident from the above, that the racemizatipn processes reported in prior art are far from satisfactory as it require number of steps, hazardous reagents and long reaction time. Therefore, there exists a need to develop an alternative, cost effective and safe method of racemization of S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid.
OBJECTS OF THE INVENTION
An object of the present invention is to provide a simple, cost effective process for synthesis of pregabalin.
Another object of the present invention is to provide a commercially viable process for synthesis of pregabalin by recycling the undesired isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid.
Yet another object of the present invention is to provide a cost effective process for racemization of S-3-(carbamoylmethyl)-5-methylhexanoic acid.
A further object of the present invention is to provide a one pot reaction for racemization of S-3-(carbamoylmethyl)-5-methylhexanoic acid.

SUMMARY OF THE INVENTION
In their endeavor to prepare a simple, cost effective method for synthesis of pregabalin, the present inventors have found that pregabalin could be synthesized from resolution of an isobutylglutaric acid derivative and the undesired S- isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid could be racemized with an organic base and then resolved to increase the yield of for preparation of pregabalin of formula (1).
Typically, pregabalin is synthesized by aminolysis of 3-isobutylglutaric anhydride obtained from 3-isobutylglutaric acid, followed by resolution of the intermediary amide with (.R)-(+)-l-phenylethylamine in chloroform. Typically, the process comprises of condensing isovaleraldehyde with an alkyl cyanoacetate to form a 2-cyano-5-methylhex-2-enoic acid alkyl ester; reacting the 2-cyano-5-methylhex-2-enoic acid alkyl ester with a dialkyl malonate to form 3-isobutylglutaric acid; forming the anhydride of 3-isobutylglutaric acid; reacting the anhydride with ammonia to form 3-(carbamoylmethyl)-5- methylhexanoic acid; reacting 3 - (carbamoylmethyl) - 5-methylhexanoic acid with (RH+)-a-phenylethylamine to obtain the (R)-(+)-a-phenylethylamine salt of (R) - (-) -3-(carbamoylmethyl) -5-methylhexanoic acid; combining the salt with an acid to obtain (R)-(-)-3 (carbamoylmethyl)-5-methylhexanoic acid; and reacting the (R) - (-) -3-(carbamoylmethyl) -5-methylhexanoic acid with a Hofmann reagent to obtain (S)-(+)-3-(aminomethyl)-5 -methylhexanoic acid.
In the above procedure, the R-enantiomer of 3-(carbamoylmethyl)-5-methylhexanoic acid preferentially crystallizes out leaving the undesired S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid in reaction mixture.
The present invention provides a simple method for racemization of S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid in reaction mixture to obtain a racemic 3-(carbamoylmethyl)-5-methylhexanoic acid. The said racemic mixture of 3-(carbamoylmethyl)-5-methylhexanoic acid, then again can be converted to pregabalin by following the above described procedure.
-1 JUN 2009

Thus, in one aspect the present invention provides a simple cost effective process for synthesis of pregabalin.
In another aspect, the present invention provides a Commercially viable process for synthesis of pregabalin by using 3-(carbamoylmemy|)_5_methylhexanoic acid as an intermediate.
In still further aspect, the present invention provides a COst effective process for racemization of S-3-(carbamoylmethyI)-5-methylhexanoic acid
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a simple, economical and commercially viable process for the preparation of pregabalin. Preferably, pregabalin is synthesized by aminolysis of 3-isobutylglutaric anhydride obtained from 3-isobulylglutaric acid followed by resolution of the intermediary amide with (R)(+)-l-pWylemylamine in chloroform, which is then transformed into pregabalin by using Hofmann reagent.
In the above procedure, the R-enantiomer of 3-(carbamoyimetriyl)-5-methylhexanoic acid preferentially crystallizes out leaving the undesired S-is comer 0f 3-(carbamoylmethyl)-5-methylhexanoic acid in the mother liquor. Typically it was observed that, the mother liquor, after separation of R-enantiomer as a phenylalanine salt, approximately contains 15-20 % of R-enantiomer and about 80-.g5% 0f S-enantiomer of 3-(carbamoyImethyl)-5-methylhexanoicacid.
The present invention provides a method for ractzation 0f S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid, remaining in mother liquor. Typically, racemization is carried out by converting the S-isorner 0f 3-(carbamoylmethyl)-5-methylhexanoic acid into a symmetrical cyclic imide and men hydrolyzing the same to produce a racemic compound.

Preferably, the S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid was converted to a symmetrical cyclic imide and then hydrolyzed in situ with an alkali to produce racemic 3-(carbamoylmethyl)-5-methylhexanoic acid, as depicted in Scheme - 3.

Racemization of (S)-3-(carbamoylmethyl)-5-methylhexanoic acid involves reacting (S)-3-(carbamoylmethyl)-5-methylhexanoic acid with a base, such as piperidine, in the presence of solvent, such as toluene, under reflux for 8-12 hrs to give a cyclic imide compound, which upon hydrolysis with aqueous solution of an alkali and then on acidifying with an acid gives racemic 3-(carbamoylmethyl)-5-methylhexanoic acid. Preferably, the reaction of racemization is carried out in one pot.
Thus, the present invention provides a efficient, simple and cost effective method for conversion of (S) enantiomer of 3-(carbamoylmethyl)-5-methylhexanoic acid into a racemic 3-(carbamoylmethyl)-5-methylhexanoic acid. The said racemic compound can then be further converted into pregabalin.
Although, piperidine is the preferred base for the racemization process, however, other bases such as diisopropylamine, diisopropylethylamine, triethyl amine, 1,8-Diazabicyclo (5.4.0)undec-7-Ene (DBU) can also successfully used. Preferably, mild organic bases are selected for converting the S-isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid into a cyclic imide compound. The effect of various bases on racemization of S-isomer of 3-(carbamoyImethyl)-5-methylhexanoic acid is summarized in Table -1. For the purpose of present invention, chiral HPLC method was used for analysis and the chromatogram was

recorded by using chiral column AD-H (250X4.6mm) at 210 nm and eluted with n-hexane : ethanol: Trifluroacetic acid (950:50:1).
Upon addition of the base to the reaction mixture enriched in (S) enantiomer of 3-(carbamoylmethyl)-5-methylhexanoic acid, the reaction mixture is refluxed in a suitable solvent for a period of about 8 to 12 hrs. to obtain a cyclic imide derivative.
Table 1: Effect of various bases on Racemization of S-isomer of 3-(carbamoylmethyl)-
5-methylhexanoic acid refluxing in toluene.

Sr. No. Base Solvent Temp °C Yield g Chiral purity by HPLC
1 Piperidine Toluene 110-120 3.5 R isomer-50.01, S isomer-49.99
2 DBU Toluene 110-120 1.2 R isomer-50.01, S isomer-49.98
3 Diisopropylamine Toluene 110-120 3.2 R isomer-50.86, S isomer-49.14
4 Diisopropylethylamine Toluene 110-120 3.2 R isomer-47.21, S isomer-52.78
5 Triethylamine Toluene 110-120 3.4 R isomer-37.57, S isomer-62.42
6 Diisopropylethylamine MTBE 60-65 2.4 R isomer-33.25, S isomer-66.74
The solvent used for racemization reaction is selected from low boiling organic solvents, such as toluene, methyl t-butyl ether (MTBE), n-hexane, ethyl acetate and chloroform. The solvent is preferably toluene. Use of toluene as a refluxing solvent provides additional advantage as it removes water in the form of azeotrop thereby effecting the cyclization step.
The cyclic imide compound was then hydrolyzed. Typically hydrolysis is carried out in presence of aqueous solution of strong base such as sodium hydroxide by heating the solution at 60 °C for about an hour. This was followed by acidification of the reaction mixture to give racemic 3-(carbamoylmethyI)-5-methylhexanoic acid.
Thus, the present invention provides a method for synthesis of pregabalin, comprising the steps of:

a. resolving (±)-3-(carbamoylmemyl)-5-methylhexanoic acid with (R) - (+) - a -
phenylethylamine to obtain the solid (R) - (-) - 3-(carbamoylmethyl)-5-
methylhexanoic acid;
b. reacting (R) - (-) - 3-(carbamoyhnethyl)-5-methylhexanoic acid with sodium
hydroxide and bromine to form pregabalin; and
c. racemizing the (S) - 3-(carbamoylmethyl)-5-methylhexanoic acid obtained in step
(a).
Particularly, the racemization reaction is carried out under reflux for 10 h to form glutarimide. The mixture was cooled to 60 °C and was further reacted with aqueous solution of sodium hydroxide. After 1 h at 60 °C, the reaction mixture was cooled to ambient temperature and layers were separated. The aqueous layer was cooled to 0-5 °C and acidified with cone. HC1. The solid obtained was filtered and washed with cold water and dried at 50-55°C to give racemic 3-(carbamoylmethyl)-5-methyl hexanoic acid.
The crude racemic 3-(carbamoylmethyl)-5-methyl hexanoic acid is further recrystallized from a solvent such as acetone, ethyl acetate to give crystalline racemic compound. The yield of the racemic compound obtained by said method is typically in the range of 75-80%.
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.

EXAMPLES:
Example 1
Racemization of S-3-(carbamoylmethyl)-5-methylhexanoic acid
A mixture of piperidine (0.68 g, 8 mmol), (5)-3-(carbamoylmethyl)-5-methylhexanoic acid (containing -15% of ^?-enantiomer) (40.0 g, 213 mmol) and toluene (200 mL) was heated under reflux for 10 h. It was cooled to 60 °C and 10% sodium hydroxide solution (200 mL) added. After 1 h at 60 °C, the reaction mixture was cooled to ambient temperature and layers separated. The aqueous layer was cooled to 0-5 °C and acidified with cone HC1 (-64 mL). The solid obtained was filtered and washed with cold water and dried at 50-55 °C to give crude 3-(carbamoylmethyl)-5-methyl hexanoic acid. Recrystallization from ethyl acetate gave the racemic product 4 (31 g, 78%), as a white solid, mp: 108-110 °C, IR (KBr): 3356, 3211, 2963, 2511, 1700, 1668, 1587, 1461 cm"1, MS (m/z): 126, 142, 168, 186, !H NMR (DMSO-^6): 6 0.85(d, 6H) 1.10-1.20 (m, 2 H), 1.50-1.70 (m, 1 H), 2.0-2.2 (m, 5 H), 6.75 (s, 1 H), 7.25 (s, 1 H), 12.0 (s, 1 H)
Example 2
Racemization of S-3-(carbamoylmethyI)-5-methylhexanoic acid.
A mixture of DBU (0.2ml, 1.3 mmol), (»S)-3-(carbamoylmethyl)-5-methylhexanoic acid (containing -15% of i?-enantiomer) (5gm, 26.73 mmol) and toluene (25 ml) was heated under reflux for 10 h. It was cooled to 60 °C and 10% sodium hydroxide solution (200 mL) added. After 1 h at 60 °C, the reaction mixture was cooled to ambient temperature and layers separated. The aqueous layer was cooled to 0-5 °C and acidified with cone HC1 (-64 mL). The solid obtained was filtered and washed with cold water and dried at 50-55 °C to give crude 3-(carbamoylmethyl)-5-methyl hexanoic acid. Recrystallization from ethyl acetate gave the racemic product (1.2 gm), as a white solid, mp: 108-110 °C
Example 3
Racemization of S-3-(carbamoyImethyl)-5-methylhexanoic acid.
A mixture of Diisopropyl amine (0.2ml, 2mmoi), (5)-3-(carbamoylmethyl)-5-methylhexanoic acid (containing -15% of fl-enantiomer) (5gm, 26.73 mmol) and toluene

(25 ml) was heated under reflux for 10 h. It was cooled to 60 °C and 10% sodium hydroxide solution (200 mL) added. After 1 h at 60 °C, the reaction mixture was cooled to ambient temperature and layers separated. The aqueous layer was cooled to 0-5 °C and acidified with cone HCl (-64 mL). The solid obtained was filtered and washed with cold water and dried at 50-55 °C to give crude 3-(carbamoylmethyl)-5-methyl hexanoic acid. Recrystallization from ethyl acetate gave the racemic product (2.5gm), as a white solid, mp: 108-110 °C

Claims:
1. A method for synthesis of pregabalin, comprising the steps of:
a. resolving (±)-3-(carbamoylmemyI)-5-methylhexanoic acid with (R) - (+) -
a - phenylethylamine to obtain the solid (R) - (-) - 3-(carbamoylmethyl)-
5-methylhexanoic acid;
b. reacting (R) - (-) - 3-(carbamoylmethyl)-5-methylhexanoic acid with
sodium hydroxide and bromine to form pregabalin; and
c. racemizing the (S) - 3-(carbamoylmethyl)-5-methylhexanoic acid obtained
in step (a).
2. A process for racemization of (S)-3-(carbamoylmethyl)-5-methylhexanoic acid, as
claimed in claim -1, comprising the steps of:
a. reacting (S)-3-(carbamoylmethyl)-5-methylhexanoic acid with a base in
the presence of solvent under reflux for 8-12 hrs;
b. treating the reaction mixture with aqueous alkali solution; and acidifying
the reaction mixture to give racemic 3-(carbamoylmethyl)-5-
methylhexanoic acid.
3. A process for racemization of (S)-3-(carbamoylmethyl)-5-methylhexanoic acid, as claimed in claim -2, wherein the (S)-3-(carbamoylmethyI)-5-methylhexanoic acid is reacted with a base in the presence of solvent to form a cyclic imide compound.
4. A process for racemization as claimed in claim 2 wherein the said reaction is carried out in the presence of a selected from piperidine, 1, 8 - diazabicyclo [5.4.0] undec-7-ene, di-isopropyl amine, di-isopropylethylamine or Triethylamine.
5. A process for racemization as claimed in claim 4 wherein the said base is piperidine.
6. A process for racemization as claimed in claim 2, wherein the said reaction is carried out in the presence of a solvent selected from toluene, methyl tert-butyl ether (MTBE), n-hexane, ethyl acetate or chloroform.
7. A process for racemization as claimed in claim 6 wherein the said solvent is toluene.

1 JUN 2009
8. A process for racemization as claimed in claim 2 wherein the said (S)-3-(carbamoylmethyl)-5-methylhexanoic acid is present as a mixture along with the corresponding (R)-isomer.
9. A process for racemization as claimed in claim 8 wherein the said reaction mixture is enriched (S)-isomer of 3-(carbamoylm.emyi)_5_methylhexanoic acid.

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