An Improved Process For Preparation Of S (+) 3 (Aminomethyl) 5 Methyl Hexanoic Acid

Abstract

An improved method for preparation of S-(+)-3-(aminomethyl)-5-methyl hexanoic acid (I) of high purity by treating (S)-mandelic acid salt of S-(+)-3-(aminomethyl)-5-methyl hexanoic acid with a base in an organic solvent.

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Specification

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


"AN IMPROVED PROCESS FOR PREPARATION OF S-(+>3-(AMINOMETHYL)-5-METHYL HEXANOIC ACID"
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 PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:

Field of the invention:
The present invention relates to an improved method for preparation of S-(+)-3-(aminomethyl)-5-methyl hexanoic acid (I) of high purity by treating (S)-mandelic acid salt of S-(+)-3-(aminomethyl)-5-methylhexanoic acid with a base in an organic solvent.
Background of the invention
(S)-3-(Aminomethyl)-5-methylhexanoic acid also known as p-isobutyl-y-aminobutyric acid or isobutyl gamma-aminobutyric acid (GABA) is an anticonvulsant drug, generally used for the treatment of neuropathic pain by oral administration. It is a structural derivative of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) and generically known as Pregabalin of formula (I).

There are several methods disclosed for the preparation of Pregabalin.
US 5,616,793 discloses a stereoselective preparation of (S)-(+)-3-aminomethyl)-5-methythexanoic acid using isovaleraldehyde and alkyl cyanoacetate as starting materials. The subsequent (±)-3-(carbamoylmethyl)-5-methylhexanoic acid which is formed is resolved with (R)-(+)-a-phenylethylamine to obtain (R)-(+)-a-phenylethyIamine salt of R-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. The desired isomer is liberated from the salt by treatment with aqueous HCl. Pregabalin is obtained by treating the intermediate carbamoyl derivative with a Hofmann reagent.
Another method for preparation of Pregabalin involves preparing racerriic 3-(aminomethyl)-5-methylhexanoic acid and then, resolving with suitable agents such as enzymes or chemical resolving agents to give S-(+)-3-(aminomethyl)-5-methylhexanoic acid i.e. Pregabalin.

Conventionally, resolution with chemical reagents involves treatment of the racemic compound with an acidic or basic resolving agent to form a diastereomeric salt, which is fractionally crystallized to obtain selectively the salt of the desired isomer.
US 2005283023 Al and WO 2005100580 disclose enzymatic methods for resolution of intermediates useful for the synthesis of Pregabalin. The enzymes used are NIT-101, NIT-102, NIT-103 and nitrilase from Arabidopsis thaliama. However, enzymatic methods are not practical on an industrial scale since enzymes are quite costly, require stringent conditions of pH, temperature etc. which are quite difficult to maintain on a commercial scale.
US 5,637,767, US 5,840,956, WO 2008/117305 Al and WO2008062460A1 disclose a method for obtaining Pregabalin from racemic (±)-3-(aminomethyl)-5-methylhexanoic acid, comprising, of treating racemic 3-(aminomethyl)-5-methyIhexanoic acid with (S)-mandelic acid in water, an alcohol, or mixture thereof to form the diastereomeric salt and selectively crystallizing out the desired diastereomeric salt. Pregabalin is isolated from the precipitated salt by heating it with a mixture of THF and water in a temperature range of 65-80°C. Although the specification mentions that desalification of the diastereomeric salt can be carried out at 0-45°C, but the present inventors have found that the desalification of the salt at lower temperature is quite slow thereby consuming precious time for each batch run and making the process very expensive on commercial scale.
A major disadvantage of the method as mentioned in the specification is the formation of the impurity of formula (II) on prolonged heating.


Further, THF as a solvent is highly flammable and is liable to develop peroxides on standing, which then become explosive, during solvent recovery.
US 4,198,524 and US 4,224,239 disclose a method for isolation of an optically amino acid from the corresponding diastereomeric salt of the optically active amino acid and mandelic acid complex using a column loaded with DIAION WA 30 resin.
The present inventors have replicated this method for isolating Pregabalin from its corresponding mandelic acid salt by passing through DIAION WA 30 resin. However, it was found that there was incomplete breaking of salt and hence, gave the desired pregabalin in low yield. Further, the use of resin column for a batch process is not practical, since considerable time is required for isolating the desired product from the column by concentration of the eluant, erection of a column on commercial scale requires lot of capital investment, voluminous amount of solvent is required for elution of the product, which makes the overall operation very expensive, time-consuming and tedious on an industrial scale.
Therefore, prior art methods suffer from the following drawbacks, which are overcome by the present invention.
i) Use of enzymes, which require stringent conditions of pH and temperature
and are very costly for commercial use,
ii) Separation of Pregabalin from its mandelic acid salt is carried out at a high temperature, which leads to the formation of an impurity of formula (II),
iii) Use of a DIAION WA 30 resin loaded column did not lead to separation of Pregabalin from its mandelic acid salt. Further, use of a column is not practical on an industrial scale due to large amount of resin, large amount of solvents required and also due to the large amount of time required for isolation of the product by recovery of a large amount of solvent.
Thus, there is a need to develop a process for preparation of S-(+)-3-(aminomethyl)-5-methylhexanoic acid which overcomes the above mentioned problems and yields

Pregabalin of formula (I) with high yield, purity (both chemical and optical) and devoid of associated impurities.
The present invention provides a method for isolation of S-(+)-3-(aminomethyl)-5-
methylhexanoic acid from (S)-mandelic acid salt of S-(+)-3-(aminomethyl)-5-
methylhexanoic acid by using a base in the presence of solvent and at ambient temperature.
It is pertinent to mention that the use of a base for separation of the desired Pregabalin did not result in formation of the undesired isomer of S-(+)-3-(aminomethyl)-5-methylhexanoic acid thereby, yielding the desired product with high optical purity.
Further, it should also be noted that heating if required, for obtaining the product did not yield the lactam impurity of formula (II) as observed in prior art methods. Thus, the present invention provides a process which is simple, high yielding, cost effective, and provides a chirally pure product in high enantiomeric excess.
Object of the Invention:
An object of the invention is to provide a cost-effective method for separation of S-(+)-3-(aminomethyl)-5-methylhexanoic acid from its mandelic acid complex in high yield.
Another object of the invention is to provide S-(+)-3-(aminomethyl)-5-methylhexanoic acid of high purity and devoid of associated impurities.
Summary of the invention:
An aspect of the invention is to provide an improved method for preparation of S-(+)-3-(aminomethyl)-5-methylhexanoic acid with high yield and purity from the (S)-mandelic acid salt of S-(+)-3-(aminomethyl)-5-methylhexanoic acid by treating with a base in an organic solvent.
Detailed Description of the Invention:

The (S)-mandelic acid salt of S-(+)-3-(aminomethyl)-5-methylhexanoic acid was prepared by the method disclosed in US 5,840,956, which comprises of treating racemic 3-(aminomethyl)-5-methylhexanoic acid with S-(+)-mandelic acid in an aqueous alcohol. The resulting mixture was heated to about 65-80°C and then cooled to selectively crystallize out (S)-mandelic acid salt of S-(+)-3-(aminomethyl)-5-methylhexanoic acid.
The present invention relates to an improved method for isolation of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid from (S)-mandelic acid salt of (S)-(+)-3-(aminomethyl)-5-methyIhexanoic acid with high yield and purity.
In a specific embodiment, the separation of S-(+)-3-(aminomethyl)-5-methylhexanoic acid from its (S)-mandelic acid salt was carried out by adding (S)-mandelic acid salt of S-(+)-3-(aminomethyl)-5-methylhexanoic acid to an organic solvent at ambient temperature.
The solvents were selected from the group comprising of alcohols, ketones, ethers, nitriles, esters etc.
The alcohols were selected from the group comprising of methanol, ethanol, n-propanol, isopropanol and isobutanol but preferably methanol and isopropanol or mixtures thereof
The ketones were selected from the group comprising of acetone, ethyl methyl ketone or mixtures thereof but preferably acetone.
The ethers were selected from the group comprising of 1,2-dimethoxyethane, tetrahydrofuran, tertiary butyl methyl ether but preferably tetrahydrofuran.
The nitrile was preferably acetonitrile.
The ester was preferably ethyl acetate.

A base was gradually added to the solvent at ambient temperature.
The base was selected either an organic or inorganic base.
The inorganic base was selected from the group comprising of aqueous ammonia, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide etc.
The organic bases were selected from the group comprising of di-isopropyl ethylamine, triethylarnine, l,8-Diazabicyclo[5.4.0]undec-7-ene, tromethamine etc.
The inorganic base was preferably aqueous ammonia, sodium bicarbonate, sodium carbonate, potassium carbonate and sodium hydroxide.
The organic base was preferably di-isopropyl ethylamine and triethylarnine.
The reaction was carried out at a temperature ranging frcim 5°C to 35°C, preferably at 15-30 °C.
The reaction mixture was stirred till completion of reaction as monitored by HPLC.
On completion of reaction, S-(+)-3-(aminomethyl)-5-methylhexanoic acid was found to separate out, which was then filtered, dried and optionally purified.
The results showed that use of an inorganic or organic base in a protic or aprotic solvent or mixture thereof gave Pregabalin which was not less than 99 % enantiomerically pure.
It is very pertinent to note that use of a base either at ambient temperature or higher temperature did not result in loss of optical purity and also the lactam impurity of formula (II), which was normally encountered at higher temperature was below detectable limits, thereby providing an improved cost-effective process for obtaining S-(+)-3-

(aminomethyl)-5-methylhexanoic acid of high optical and chemical purity. The product obtained was having chemical purity above 98%, which was then optionally purified.
Pregabalin (I) formed is optionally purified by recrystallization using a suitable solvent such as alcohols, water or mixture thereof.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Examples
Example 1:
Preparation of Pregabalin:
In a round bottom flask, IPA (25ml) was charged. Pregabalin mandalate salt (5 gms;
0.016meq) was charged at 25-30°C. The reaction mass was stirred at 25-30°C for 30
minutes. Aqueous ammonia (5ml; 0.073meq) was added at 25-30°C. The reaction mass
was stirred at 25-30°C for 1.0 hrs, filtered and dried under suction for 30 minutes. The
wet cake was washed with PA (5ml) and dried.
Yield: 2.32 gm
Chiral Purity: 100 % e.e.
Example 2
Preparation of Pregabalin:
In a round bottom flask; methanol (25ml) was charged. Pregabalin Mandalate salt (5 gms; 0.016meq) was charged at 25-30°C. The reaction mass was stirred at 25-30°C for 30 minutes. Aqueous ammonia (5ml; 0.073meq) was added at 25-30°C. The reaction mass

was stirred at 25-30°C for 1.0 hrs, filtered and dried under suction for 30 minutes. The
wet cake was washed with methanol (5ml) and dried.
Yield: 2.01 gm
Chiral Purity: 100%e.e.
Example 3
Preparation of Pregabalin:
In a round bottom flask; acetone (25ml) was charged. Pregabalin Mandalate salt (5 gms;
0.016meq) was charged at 25-30°C. The reaction mass was stirred at 25-30°C for 30
minutes. Aqueous ammonia (5ml; 0.073meq) was added at 25-30°C. The reaction mass
was stirred at 25-30°C for 1.0 hr, filtered and dried under suction for 30 minutes. The wet
cake was washed with acetone (5 ml) and dried.
Yield: 2.31 gm
Chiral Purity: 100 % e.e.
Example 4
Preparation of Pregabalin:
In a round bottom flask; ethyl acetate (25 ml) was charged. Pregabalin Mandalate salt (5
gms; 0.016 meq) was charged at 25-30°C. The reaction mass was stirred at 25-30°C for
30 minutes. Aqueous ammonia (5 ml; 0.073 meq) was added at 25-30°C. The reaction
mass was stirred at 25-30°C for 1.0 hr, filtered and dried under suction for 30 minutes.
The wet cake was washed with ethyl acetate (5 ml) and dried.
Yield: 1.33 gms
Chiral Purity: 100% e.e
Example 5
Preparation of Pregabalin:
In a round bottom flask acetonitrile (25 ml) was charged. Pregabalin Mandalate salt (5 gms; 0.016 meq) was charged at 25-30°C. The reaction mass was stirred at 25-30°C for 30 minutes. Aqueous ammonia (5 ml; 0.073 meq) was added at 25-30°C. The reaction

mass was stirred at 25-30°C for 1.0 hrs, filtered and dried under suction for 30 minutes.
The wet cake was washed with acetonitrile (5 ml) and dried.
Yield: 2.45 gms
Chiral Purity: 100%e.e
Example 6:
Preparation of Pregabalin:
In a round bottom flask; methanol (25ml) was charged. Pregabalin Mandalate salt (5
gms; 0.016meq) was charged at 25-30°C. The reaction mass was stirred at 25-30°C for 30
minutes. Aqueous ammonia (5ml; 0.073meq) was added and the reaction mass was
refluxed for 1 hr. The reaction mass was filtered and dried under suction for 30 minutes.
The wet cake was washed with methanol (5 ml) and was dried under suction.
Yield: 1.8 gm
Chiral Purity: 100%e.e
Example 7:
Preparation of Pregabalin:
In a round bottom flask; acetone (25ml) was charged. Pregabalin Mandalate salt (5 gms;
0.016meq) was charged at 25-30°C. The reaction mass was stirred at 25-30°C for 30
minutes. Aqueous ammonia (5ml; 0.073meq) was added and the reaction mass was
refluxed for 1 hr. The reaction mass was filtered and dried under suction for 30 minutes.
The wet cake was washed with acetone (5 ml) and was dried under suction.
Yield: 2.31 gm
Chiral Purity: 100 % e.e
Example 8:
Preparation of Pregabalin:
In a round bottom flask; IPA (25ml) was charged. Pregabalin Mandalate salt (5 gms; 0.016meq) was charged at 25-30°C. The reaction mass was stirred at 25-30°C for 30

minutes. Aqueous ammonia (5ml; 0.073meq) was added and the reaction mass was
refluxed for 1 hr. The reaction mass was filtered and dried under suction for 30 minutes.
The wet cake was washed with IPA (5ml) and was dried under suction.
Yield: 1.98 gm
Chiral Purity: 99.98 %e.e
Example 9 -14.
Preparation of Pregabalin:
Isolation of 3-(Amino methyl)-5-methyl hexanoic acid from corresponding (S)-(+)-Mandalate salt was carried out using different organic and inorganic bases in isopropanol as follows:
Mandalate salt (5 gms) was added to iso-propanol at 25-30°C. The reaction mass was stirred at 25-30°C for 30 minutes. A base was added and the reaction mass was refluxed for 1 hour. The reaction mass was filtered and dried under suction for 30 minutes. The wet cake was washed with iso-propanol (5 ml) and was dried under suction. Results are illustrated in Table 1:

No (S,S)- MandelicAcid
salt
(gms) Base Chiral purity % Yield (gms)
9 5.0 NaHCO3 99.98 1.27
10 5.0 Diisopropylethyl amine 99.97 1.87
11 5.0 Triethyl amine 99.98 1.51
12 5.0 DBU 99.98 1.27
13 5.0 Tromethamine 99.96 1.63
14 5.0 K2CO3 99.97 1.71
Example 15:
Purification of Pregabalin:
In a round bottom flask 154 ml Isopropyl alcohol and DM Water (154 ml) was charged at 25-30 °C. The reaction mass was stirred at 25-30°C for 15.0 minutes To this crude Pregabalin (44gms) was charged 25-30°C. The reaction mass was heated to 75-80 °C and

was stirred for 30.0 minutes. The reaction mass was filtered at 75-80 °C and was cooled slowly at 0-5 °C. The reaction mass was stirred farther at 0-5 °C for 1.0 hrs and was filtered and was dried under suction for 30.0 minutes. The wet cake was washed with mixture of Isopropyl alcohol and DM Water (88 ml) and was dried under suction for 30 minutes. The material was dried in oven at 50-55°C till LOD is NMT 0.5%.
Dry wt Yield = 30-40 gms. Chemical Purity = 99.90% Any individual impurity = NMT 0.10%

We claim:
1. A process for preparation of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid by treating (S)-mandelic acid salt of S-(+)-3-(aminomethyl)-5-methylhexanoic acid with a base in an organic solvent.
2. A process as claimed in claim 1 wherein, the base is an organic or inorganic base.
3. A process as claimed in claim 1 wherein, the inorganic base is selected from the group comprising of ammonia, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
4. A process as claimed in claim 1 wherein, the organic base is selected from the group comprising of di-isopropyl ethylamine, triethylamine, 1,8-Diazabicyclo[5.4.0]undec-7-ene and tromethamine.
5. A process as claimed in claim 1 and 3 wherein the inorganic base is preferably aqueous ammonia, sodium bicarbonate, sodium carbonate, potassium carbonate and sodium hydroxide.
6. A process as claimed in claim 1 and 4 wherein the organic base is preferably di-isopropyl ethylamine and triethylamine.
7. A process as claimed in claim 1 wherein the solvent is selected from the group comprising of alcohols, ketones, ethers, nitriles, esters or mixtures thereof.
8. A process as claimed in claim 1 and 7 wherein the solvent is preferably methanol, isopropanol, acetone, tetrahydrofuran and acetonitrile, ethyl acetate or mixtures thereof.

9. A process as claimed in claim 1 wherein the temperature is ranging from 5°C to 35°C preferably in the range of 15°C and 30°C.
10. A process as claimed in claim 1-9 wherein, the lactam compound of formula (II) is less than 0.5%.
Dated this 18th day of March, 2009

(Signed).
Dr. Mukund. K. Gurjar Chief Scientific Officer Emcure Pharmaceuticals Ltd.
To
The Controller of Patents
The Patent Office Branch, Mumbai

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