FIELD OF THE INVENTION
The present invention relates to the process for resolving pregabalin by means of chiral acids. In
carrying out the process, racemic pregabalin is contacted with a chiral acid thereby precipitating
one of the enantiomers acid addition salt of pregabalin.
BACKGROUND OF THE INVENTION
Pregabalin is chemically described as 3-aminomethyl-5-methyl-1-hexanoic acid. It is also known
as 3-(-2-methylpropyl)-4-aminobutanoic acid. Pregabalin increases the concentration of GABA
by activating GAD and therefore is useful as therapeutic agent for the treatment of pain,
convulsions, general anxiety related disorders and epileptic seizures. The (S)-(+)-enantiomer of
pregabalin has been found to be about 40 times more active when compared with (R)-(-)-
enatiomer. The (S)-(+)-pregabalin is represented below as a formula I.

Considering the importance of (S)-(+)-enantiomer, various syntheses have been developed.
Literature search revealed that (S)-(+)-pregabalin was obtained by making use of chiral
oxazolidinone and using resolving agents. US6197819 discloses the stereospecific synthesis of
(S)-(+)-pregabalin using chiral oxazolidinone but the process is not feasible for production on
industrial scale. Another approach to obtain (S)-(+)-pregabalin is resolution of racemic
pregabalin. US 5637767, WO 2006136087 and US 2006/270871 discloses the resolution of
racemic pregabalin using (S)-(+)-mandelic acid. US 5616793 and WO2006122259 discloses the
resolution of 3-(carbamoylmethyl)-5-methylhexanoic acid using (R)-(+)-a-phenylethylamine and
1R, 2S-(-)-ephedrine respectively. US 5637767, WO 2006136087 and US 2006/270871 discloses
the resolution of pregabalin using S-(+)-mandelic acid which involves the use of polar aprotic
solvent (tetrahydrofuran) and water in one of the step of resolution. The S-(+)- pregabalin
obtained needs to be further recrystallized by using aqueous isopropanol.
Thus there is a need to provide a process for resolution of pregabalin with reduced number of
steps and hence cost effective and yet achieving 100% optical purity.

The present inventors have found that unlike the known art process comprising use of ammonia in
a mixture of polar protic solvent (isopropanol) with water avoids the further crystallization step
and yet the optical purity of S-(+)-pregabalin obtained by this process is 100%. Hence the
isolation of S-(+)-pregabalin is cost effective.
OBJECT OF THE INVENTION
One object of present invention is resolution of racemic pregabalin by using O,O-dibenzoyl-L-
tartaric acid and (S)-(+)-mandelic acid.
Second object of invention relates to use of diastereomeric salt of formula II in the preparation of
(S)-(+)-pregabalin.
Third object of the invention relates to acid addition salt of (S)-(+)-pregabalin with O, O-
dibenzoyl-L-tartaric acid of formula II.

SUMMARY OF THE INVENTION
The present invention relates to the resolution of pregabalin by using chiral acids, preferably O,
O-dibenzoyl-L-tartaric acid and (S)-(+)-mandelic acid . An advantage of the process of the
present invention is that resolving agent can be easily recovered in a state of high purity, such that
it can be re-used in one or more subsequent resolution processes. In particular, O, O-dibenzoyl-L-
tartaric acid and (S)-(+)-mandelic acid are used as resolving agent for the purpose of the
invention.
An aspect of the invention is to provide method of obtaining (S)-3-(aminomethyl)-5-
methylhexanoic acid from (±)-3-(aminomethyl)-5-methylhexanoic acid, the method comprising a)
reacting a (±)-3-(aminomethyl)-5-methylhexanoic acid in a polar solvent with a solution of O, O-
dibenzoyl-L-tartaric acid in polar solvent and allowing to form a precipitate b) introducing the

precipitate in a mixture of polar solvent with water to form slurry c) treating the cooled with base
in polar solvent d) adjusting the pH by water soluble acid e) filtering the solid and adding organic
solvent or mixture thereof to obtain S-(+)-pregabalin.
A further aspect is to provide a method of obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid
from (±)-3-(aminomethyl)-5-methylhexanoic acid, the method comprising a) reacting a (±)-3-
(aminomethyl)-5-methylhexanoic acid in a polar solvent with a solution of O, O-dibenzoyl-L-
tartaric acid in polar solvent and allowing to form a precipitate b) introducing the precipitate in a
mixture of polar solvent with water c) treating with base in polar solvent d) filtering the solid.
A method of obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (±)-3-(aminomethyl)-5-
methylhexanoic acid, the method comprising a) reacting a (±)-3-(aminomethyl)-5-methylhexanoic
acid in a polar protic solvent with a solution of S- (+)-mandelic acid in polar protic solvent b)
allowing to form a precipitate c) introducing the precipitate in a mixture of polar protic solvent
and water to form slurry d) treating with base in polar protic solvent and filtering the solid.
A further aspect is to provide a monobasic acid addition salt, O, O-dibenzoyl-L-tartarate salt of
(S)-(+)-pregabalin of formula II

DETAILED DESCRIPTION OF THE INVENTION
The preferred chiral acids for use in the process of this invention is O, O-dibenzoyl-L-tartaric acid
and (S)-(+)-mandelic acid because the S-enantiomer of pregabalin can be selectively precipitated
from an enantiomeric mixture with these acids in relatively high optical purity. These acids can be
easily prepared or can be commercially, obtained at relatively low cost. Furthermore, these acids
can be easily and nearly quantitatively recovered after completion of the resolution.

In accordance with the present invention, there is a provided a process for resolution of
pregabalin. In typical experiment, racemic pregabalin can be treated with resolving agent in a
polar solvent. Thus racemic pregabalin in polar solvent was treated with a solution of O, O-
dibenzoyl-L-tartaric acid monohydrate (1.0 mol equivalent) in polar solvent. The resultant
reaction mixture was heated to reflux to obtain clear solution and then slowly cooled and stirred
for 10-12 h at ambient temperature to obtain crystals of diastereomeric salt of pregabalin. The salt
thus obtained was taken in tetrahydrofuran -water and was treated with aqueous ammonia and the
pH was adjusted to alkaline . The solid obtained was filtered and dried. The polar solvent is
selected from the group of acetone, methanol, ethanol, isopropanol, tetrahydrofuran, water and
mixture thereof. Alternatively diastereomeric salt was treated with KOH solution in isopropanol.
The resultant mixture was treated with acetic acid. The precipitated O, O-dibenzoyl-L-tartaric
acid was filtered and washed with isopropanol-water. The filtrate was concentrated under
vacuum. To the residue was added acetone and stirred for 4-6 h at ambient temperature. The solid
obtained was filtered and washed with acetone and dried under vacuum to get (S)- (+)-pregabalin.
Another aspect of the invention relates to the process of resolution of racemic pregabalin using
(S)-(+)-mandelic acid. In typical embodiment, a solution of racemic pregabalin in polar protic
solvent was treated with a (S)-(+)-mandelic acid to form a precipitate. The precipitate thus
obtained was suspended in polar protic solvent and treated with ammonia to obtain (S)-(+)-
pregabalin. The optical purity obtained for (S)-(+)-pregabalin is 100%. The polar protic solvent
used for the purpose of invention can be selected from isopropanol, methanol, ethanol, water and
mixtures thereof.
DETAILED DESCRIPTION OF THE DRAWINGS
FIG.l provides an XRPD pattern of diastereomeric salt of (S)-(+)-pregabalin with O, O-
dibenzoyl-L-tartaric acid
The present invention is illustrated by the following non-limiting examples
Example 1: Preparation of S- (+)-pregabaIin
A) Preparation of O,O-dibenzoyl tartarate salt
To a mixture of methanol (80 ml) and acetone was added O,O-dibenzoyl-L-tartaric acid (47.5 g)
and racemic pregabalin (20 g). This reaction mixture was heated to reflux and then cooled slowly
and stirred for 10-12 h at ambient temperature to obtain crystals of dibenzoyl tartarate salt of

pregabalin. These crystals were filtered and washed with acetone (40 ml). SOR: -74 ° (c = 0.5,
MeOH), Yield: 40%, M.P.: 149.7-150.9 °C, IR (cm-1): 3426.86, 3377.97, 2958.67, 1724.29,
1694.00, 1600.43, 1246.0, 718.40 1H NMR (MeOD, 400MHz): 8 8.14(d, J = 7.2 Hz, 4H), 7.63(t, J
= 7.2 Hz, 2H), 7.50(, 4H), 5.92(s, 2H), 3.65(m, 1H), 2.92(d, J = 6.4 Hz, 1H), 2.37(m, 2H), 2.16(m,
1H), 1.69(m, 1H), 1.25(m, 2H), 0.9(m, 6H). Chiral HPLC: 98.22% S, 1.78% R.
B) Cleavage of O,O-dibenzoyl tartarate salt
Method 1: A slurry of O,O-dibenzoyl tartarate salt (20 g) in a mixture of isopropanol-water (97:3,
300 ml) was cooled to 0-5 °C and pH was adjusted to slightly basic with KOH solution in
isopropanol. Stirred the reaction mass for 30-40 minutes and then added acetic acid (10 ml).
Stirred for 30 minutes and then filtered and washed with isopropanol-water (40 ml). The filtrate
was concentrated under vacuum up to 2 volumes. To this was added acetone (300 ml) and stirred
for 4-6 h at ambient temperature. The solid obtained was filtered and washed with acetone (40 ml)
and dried under vacuum.
Yield: 20%, M.P.: 175 °C Water (Karl Fischer): 0.6% by weight, HPLC: 99.00% w/w; Chiral
HPLC: 99.57% S, 0.43 % R (limit of detection: 0.05 %).
Method 2: A solution was prepared by dissolving O,O-dibenzoyl tartarate salt (5 g) in
tetrahydrofuran- water (65 ml/5 ml) at ambient temperature. To this solution was added ammonia
solution to basic pH. The mixture was stirred for 2 h at ambient temperature. The solid thus
obtained was filtered and washed with tetrahydrofuran-water (10 ml) and isopropanol (5 ml). The
solid thus obtained was recrystallized from isopropanol-water and dried under vacuum.
Yield: 40%, M.P.: 180.7-181.5 °C Water (Karl Fischer): 0.5% by weight, HPLC: 99.3 w/w; Chiral
HPLC: 99.94% S, 0.06 % R (limit of detection: 0.05%).
Example 2: Preparation of S- (+)-pregabalin
A) Preparation of mandelate salt
To a solution of 3% v/v aqueous isopropanol (1000 ml) was added racemic pregabalin
(100 g) and S- (+)-mandelic acid (132.5 g). The resultant mixture was heated at 75- 80 °C
to get clear solution. The solution was cooled to 0-5 °C to obtain solid. The solid thus
obtained was filtered and washed with 3% aqueous isopropanol. A solution of damp solid
in aqueous isopropanol (500 mL) was treated with S- (+)-mandelic acid (19.5 g). The

mixture was heated at 75- 80 °C to get clear solution and cooled to 0-5 °C. The solid
obtained was filtered, washed with aqueous isopropanol (100 ml) and dried under vacuum
at 55-60 °C for 7-8 h to get madelate salt of pregabalin.
B) Cleavage of mandelate salt
A slurry of mandelate salt of pregabalin (100 g) in a mixture of isopropanol-water was
stirred at 25-30 °C and then adjusted to pH = 5.3-5.7 with aqueous ammonia. The mixture
was heated to 70-75 °C and stirred for 5-10 minutes. The mixture was then gradually
cooled to 25-30 °C and stirred for 60 minutes and then filtered and washed with
isopropanol (2 x 100 ml). The solid was dried at 50-55 °C under vacuum. SOR: +11.0 ° (c
= 1.06,H2O)
Yield: 46%, M.P.: 184.6 °C, Water (Karl Fischer): 0.22% by weight, HPLC: 99.5 % w/w;
Chiral HPLC: 100% S, R isomer not detected (limit of detection: 0.05%)

We claim:
1. A method of obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (+)-3-
(aminomethyl)-5-methylhexanoic acid, the method comprising a) reacting a (±)-3-
(aminomethyl)-5-methylhexanoic acid in a polar solvent with a solution of O, O-
dibenzoyl-L-tartaric acid in polar solvent and allowing to form a precipitate b) introducing
the precipitate in a mixture of polar solvent with water to form slurry c) treating the cooled
with base in polar solvent d) adjusting the pH by water soluble acid e) filtering the solid
and f) adding organic solvent or mixture thereof to the filtrate to obtain S-(+)-pregabalin
2. The method as claimed in claim 1, wherein the polar solvent is selected from the group
consisting of acetone, isopropanol, methanol, tetrahydrofuran, water and mixtures thereof.
3. The method as claimed in claim 1, wherein the base is selected from the group of sodium
hydroxide, potassium hydroxide and ammonia.
4. The method as claimed in claim 3, wherein the base is potassium hydroxide.
5. The method as claimed in claim 1, wherein water-soluble acids are selected from the
group of formic acid, acetic acid, propionic acid, butyric acid.
6. The method as claimed in claim 5, wherein water-soluble acid is acetic acid.
7. The method as claimed in any one of preceding claims wherein the precipitation is formed
by heating to reflux, cooling and stirring for 10-12 h at ambient temperature.
8. The method as claimed in any one of preceding claims wherein the slurry is cooled to 0-5
°C.
9. A method of obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (±)-3-
(aminomethyl)-5-methylhexanoic acid, the method comprising a) reacting a (±)-3-
(aminomethyl)-5-methylhexanoic acid in a polar solvent with a solution of O, O-
dibenzoyl-L-tartaric acid in polar solvent and allowing to form a precipitate b)
introducing the precipitate in a mixture of polar solvent with water c) treating with base in
polar solvent d) filtering the solid.
10. The method as claimed in claim 7, wherein the polar solvent is selected from the group
consisting of acetone, isopropanol, methanol, ethanol ,tetrahydrofuran, water and mixtures
thereof.
11. The method as claimed in claim 7, wherein the base is selected from the group of sodium
hydroxide, potassium hydroxide and ammonia.
12. The method as claimed in claim 7, wherein the base is ammonia.

13. The method as claimed in any one of claims 9 to 12 wherein the precipitation is formed by
heating to reflux, cooling and stirring for 10-12 h at ambient temperature
14. A method of obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (±)-3-
(aminomethyl)-5-methylhexanoic acid, the method comprising a) reacting a (±)-3-
(aminomethyl)-5-methylhexanoic acid in a polar protic solvent with a solution of S- (+)-
mandelic acid in polar protic solvent b) allowing to form a precipitate c) introducing the
precipitate in a mixture of polar protic solvent and water to form slurry d) treating with
base in polar protic solvent and filtering the solid.
15. A method as claimed in claim 11, wherein the polar protic solvent is selected from the
group consisting of isopropanol, methanol, ethanol, water and mixtures thereof
16. A method as claimed in claim 11, wherein the base is selected from the group of sodium
hydroxide, potassium hydroxide and ammonia.
17. A method as claimed in claim 13, wherein the base is ammonia.
18. The method as claimed in any one of claims 14 to 17 wherein the precipitation is formed
by heating to reflux, cooling and stirring for 10-12 h at ambient temperature.
19. The method as claimed in any one of claims 14 to 18 wherein the slurry is cooled to 0-5
°C
20. A monobasic acid addition salt, O, O-dibenzoyl-L-tartarate salt of (S)-(+)-pregabalin of
formula II

21. A monobasic acid addition salt as claimed in claim 20, characterized by X-ray powder
diffraction peaks at about 8.41, 9.76, 14.16, 16.34, 17.55, 19.53, 24.14 and 31.42 ± 0.2 0.

A novel process for the resolution of pregabalin by means of chiral acids. According to
the process, racemic pregabalin is contacted with a chiral acid to precipitate a salt of the
chiral acid with one of the enantiomer. The chiral acid for the purpose of the invention is
selected from O, O-dibenzoyl-L-tartaric acid and (S)-(+)-mandelic acid. A novel
diastereomeric salt of (S)-(+)-pregabalin with O, O-dibenzoyl-L-tartaric acid and its use
to prepare (S)-(+)-pregabalin.