AN IMPROVED PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY PURE PREGABALIN

FIELD OF THE INVENTION

The present application relates to an improved process for the preparation of enantiomerically pure Pregabalin.

BACKGROUND OF THE INVENTION

Pregabalin generally known for its active (S)-isomer. Pregabalin chemically represented by (S)-(+)-3-aminomethyl-5-methyl hexanoic acid, structurally represented by the structural formula I.

(S)-(+)-Pregabalin (I) is related to the endogenous inhibitory neurotransmitter v-ainino-butyric acid (GABA), which is involved in the regulation of brain neuronal activity . (S)-Pregabalin-(I) exhibits anti-seizure activity and if also thought to be useful for treating amongst other conditions, pain, physiological conditions associated with psychomotor stimulants, inflammation , gastrointestinal damage , alcoholism, insomnia, fibromyalgia and various psychiatric disorders, including mania and bipolar disorders. Pregabalin was marketed under the trade name LYRICA and having dosage of about 20mg, 50mg, 75mg, lOOmg, 150mg, 200mg, 225mg and 300mg.

Pregabalin was disclosed in the EP patent No. 641330 Bl, Various patents disclosed the process for the preparation of Pregabalin by Hoffmann degradation method, enaymatic resolution method and resolution with chiral optically active acids.

Resolution in earlier stages of a synthesis appears to be preferable but depends on how it is feasible for further synthesis of the compound without racemizations. Resolution of intermediates always results in the possibility of carrying out other isomer impurity all along the rest of the process affecting the chiral purity.

Racemizations in the final stage of the process are of advantageous and this was proved in many compounds.

Resolution of racemic Pregabalin with diastereomeric salts was disclosed in US patent No 5637767, This patent disclosed the resolution of racemic Pregabalin with optically active (S)-mandelic acid in presence of alcoholic solvent and water, and precipitating with aprotic polar solvents selected from DMSO and THF.
In International patent application WO 2008/138874 disclosed the process for the resolution of racemic Pregabalin with optically active L-Tartaric acid in presence of water and acids.

In International patent application WO 2009/04409 disclosed the resolution of racemic Pregabalin with chiral optically active (-)DPTTA in presence of organic solvents.

In International patent application WO 2009/122215 disclosed the resolution of racemic Pregabalin with L-Tartaric acid in the presence of alcoholic solvents selected from IPA, t-butanol, and methanol and so on.

Resolution of racemic Pregabalin with chiral optically active compounds in the presence of solvents was disadvantageous. Solvents used in the resolution process may be recovered, but there will be some loss in the recovery. This loss may be evaporated and may consider as a hazardous factor for environment. Apart from this some solvents may undergoes reaction with the reactants resulting in the degradation of the product affecting the purity of both chiral and chemical.

Resolution of racemic Pregabalin with optically active mandelic acid in the presence of water (absence of organic and inorganic solvents) was not disclosed in the literature well known to those skilled in the art.

Therefore there is always a need in the preparation of pharmaceutical compounds to develop a process which is advantageous than the existing process in order to increase the yields, to be eco friendly and most suitable for commercial manufacturing.

SUMMARY OF THE INVENTION

The present patent application relates to a process for the preparation of enantiomerically pure Pregabalin

The present application provides a process for the preparation of enantiomerically pure Pregabalin of formula-I comprising the steps of:

a) reacting racemic Pregabalin [(±)-3-(Aminomethyl)-5-methyl hexanoic acid] of formula II with S-(+)-mandelic acid of formula III in the presence of water to obtain diastereomeric salt, S-(+)-3-aminomethyl-5-methyl hexanoic acid S-mandelic acid salt of formula IV.

b) reacting the diastereomeric salt of Formula IV with caustic lye solution to give(S)-(+)-Pregabalin of Formula-I.

c) Recrystallising the (S)-(+)-Pregabalin of step b with alcoholic solvents to get enantiomerically pure (S)-(+)-Pregabalin of pharmaceutically acceptable grade.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present patent application relates to a process for the preparation of enantiomerically pure Pregabalin

The present application provides a process for the preparation of enantiomerically pure Pregabalin of formula-I comprising the steps of:

a) reacting racemic Pregabalin [(±)-3-(Aminomethyl)-5-methyl hexanoic acid] of formula II with S-(+)-mandelic acid of formula III in the presence of water to obtain diastereomeric salt, S-(+)-3-aminomethyl-5-methyl hexanoic acid S-mandelic acid salt of formula IV.

b) reacting the diastereomeric salt of Formula IV with caustic lye solution to give(S)-(+)-Pregabalin of Formula-I.

c) Recrystallising the (S)-(+)-Pregabalin of step b with alcoholic solvents to get optically pure (S)-(+)-Pregabalin of pharmaceutically acceptable grade.

Step a) involves reacting racemic Pregabalin [(±)-3-(Aminomethyl)-5-methyl hexanoic acid] of formula II with S-(+)-mandelic acid of formula-Ill in the presence of water to form a diastereomeric salt of formula-IV.

Suitably the volume of water used in reaction may be from about 2 times to about 10 times, preferably for about 4 times to the weight of racemic Pregabalin of formula II.

Suitably the reaction mixture can be heated for complete dissolution, preferably at 40-45°C.
Suitable temperature for conducting the reaction can range from about 20-45°C, preferably at room temperature.

The reaction may be carried out for about 5 hours to about 24 hours, preferably for about 10-12 hours.

The diastereomeric salt of Formula IV may be isolated by suitable techniques such as filtration by gravity, or by suction, centrifugation and the like.

The diastereomeric salt obtained in step a) may be further dried. Drying may be suitable carried out in a tray drier, vacuum oven, fluidized bed drier and spin flash drier.

If required, the diastereomeric salt of Formula IV may be further purified by any process. The purified diastereomeric salt of Formula IV may
be isolated by suitable techniques such as filtration by gravity, or by suction, centrifugation and the like.

Step b) involves reacting the diastereomeric salt of Formula IV with caustic lye solution to give(S)-(+)-Pregabalin of Formula-I.

Suitable temperature for conducting the reaction can range from about 80-120 °C, most preferably at about 95-100 °C.

The reaction may be carried out for about 2 to about 10 hours, preferably for about 6-8 hours.
Step c) involves the recrystallisation of the (S)-(+)-Pregabalin of step b with alcoholic solvents to get optically pure (S)-(+)-Pregabalin of pharmaceutically acceptable grade.
Recrystallisation of crude (S)-(+)-Pregabalin from solvent medium comprising solvents such as alcohols selected from isopropyl alcohol and methanol separately or with the mixture of water to get pharmaceutically acceptable grade.
Isolation temperature for recrystallised salt is at 0-5°C for about 5-6 hours. The isolated optically pure (S)-(+)-Pregabalin is dried completely. Drying may be suitable carried out in a tray drier, vacuum oven, fluidized bed drier and spin flash drier.

Thus the process of the present invention of resolution of racemic Pregabalin with S-(+)-mandelic acid is carried out in the absence of any organic or inorganic solvents resulting in the highly pure S-Pregabalin. This made the process more ecofriendly, commercially viable and resulting in the enantiomerically pure compound.

Having thus described the invention with reference to particular preferred embodiments and illustrative example, those in the art may appreciate modification to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set for to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well know to those of ordinary skill in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.

The present application provides a process for the preparation of Enantiomerically pure Pregabalin by using R-mandelic acid, the following steps are comprises:

a) Reaction of racemic pregabalin with R-mandelic acid in presence of water to form the precipitate of (R)-pregabalin(R)-mandelate and filtrate of (S)-pregabalin(R)-mandelate.

b) Reaction of the filtrate of (S)-Pregabalin(R)-mandelate with caustic lye solution to form S-Pregabalin of formula I

c) Recrystallising the S-Pregabalin of step b with alcoholic solvents to get optically pure (S)-Pregabalin of pharmaceutically acceptable grade.

Examples:

Example-1: Preparation of S-(+)-3-aminomethyl-5-methylhexanoic acid (S)-mandelic acid salt of formula-Ill

Charge 400 ml (4times) water and lOOgms DL-Pregabalin in a clean R.B.Flask and added S-(+)-mandelic acid (1.05moles) to the R.M. Heat at 40-45°c for complete dissolution, and slowly cool to RT maintain for 12 hours and then filter and then washed with 50ml water to form a crude material of salt. The salt was dried at 50-55°c to form the compound of formula III.
Yield: 85gms.

Example-2: Preparation of (S)-Pregabalin
Charge water (4 volumes) to 85 gms of Example-1 compound and slowly added 200% lye solution till the pH of the solution reaches to 6.0 to 6.5 and then maintain for 2hrs at RT and then filter. The filtrate was washed with 50ml water and then dry at 50-55°C under the vacuum to give the titled compound

Yield: 41 gms.

Example-3: Recrystallisation of (S)-Pregabalin using methanol and water
About 36.5 gm of (S)-Pregabalin obtained from Example-2 was charged in methanol (694ml) and water (219ml). Heat to 60-65°C to obtain a clear solution. The clear solution was filtered, filtrate was cooled to 0-5°C and stirred at 0-5°C for about 5hrs.The solid obtained was filtered off and dried under vacuum at 40-45°C to give enantiomerically pure Pregabalin.

Yield: 32.8g (90% molar and w/w).

Enantiomeric purity: 100%. S-isomer (as measured by HPLC).
Chemical purity: 99.98% (as measured by HPLC).
No lactam impurity was observed by HPLC.

Example-4: Preparation of S-Pregabalin R-mandelic acid
Charge 400 ml (4times) water and lOOgms DL-Pregabalin in a clean R.B.Flask and added S-(+)-mandelic acid (1.05moles) to the "R.M. Heat at 40-45°c for complete dissolution, and slowly cool to RT maintain for 12 hours and then filter and then washed with 50ml water to form a crude material of salt.

Example-5: Preparation of (S)-Pregabalin
Charge 4 volumes of water to the crude compound of Example-4 and slowly added 200% caustic lye solution till the pH of the R.M. reaches to 6.0 to 6.5, maintain for 2hrs at RT and then filter. The filtrate was washed with 50ml water and then dry at 50-55°C under the vacuum to gives the S-(+)3-aminomethyl-5-methyhexanoic acid.

Example-6: Recrystallisation of (S)-Pregabalin using Isopropanol and water
36.5 gms of (S)-Pregabalin prepared as per the Example-1 and 2 was charged in isopropanol (694ml) and water (219ml) and heated to 60-65°C to obtain a clear solution. The clear solution was filtered, filtrate was cooled to 0-5°C and stirred at 0-5°C for 5hrs.The solid obtained was filtered off and dried under vacuum at 40-45°C.
Yield: 32.8g (90% molar and w/w).

Enantiomeric purity: 100%. S-isomer (as measured by HPLC).

Chemical purity: 99.98% (as measured by HPLC).
No lactam impurity was observed by HPLC.

Claims:

1) A process for the preparation of Enantiomerically pure Pregabalin comprising;

a) reacting racemic Pregabalin [(±)-3-(Aminomethyl)-5-methyl hexanoic acid] of formula II with S-(+)-mandelic acid of formula III
in the presence of water to obtain diastereomeric salt, S-(+)-3-
aminomethyl-5-methyl hexanoic acid S-mandelic acid salt of formula IV.

b) reacting the diastereomeric salt of Formula IV with caustic lye solution to give(S)-(+)-Pregabalin of Formula-I.

c) Recrystallising the (S)-(+)-Pregabalin of step b with alcoholic solvents to get optically pure (S)-(+)-Pregabalin of pharmaceutically acceptable grade.

2) The process of claim 1 step a), wherein the volume of water used in reaction is from 2- 10 times.

3) The process of claim 1 step a), where in the temperature for conducting the reaction can range from 15-60°C

4) The process of claim 1 step a), where in the reaction time carried out from 5-24 hours,

5) The process of claim 1 step b), where in the temperature for conducting the reaction range is from 80-120°C.

6) The process of claim 1 step b), where in the reactiom time is carried out from 2-10 hours.

7) The process of claim 1 step c), where in the solvent for recrystalisation of Pregabalin is selected from isopropyl alcohol and methanol separately or with the mixture of water.

8) The process of claim 1 step c), where in the temperature for conducting the reaction is from 0-10°C and time is 4-8 hours.