FIELD OF THE INVENTION
The present invention relates to an improved process to prepare Pregabaiin of Formula I

in one-pot.
BACKGROUND OF THE INVENTION
Pregabaiin, which is also called p-isobutyl-y-aminobutyric acid or isobutyl-GABA, is a potent anticonvulsant. Pregabaiin is chemically known as (S)-(+)-3-aminomethyl-5-methyl-l-hexanoic acid or (S)-(+)-3-(2-methylpropyl)-4-aminobutanoic acid or (S)-(+)-3-isobutylGABA of Formula I.
Pregabaiin has been found to activate GAD (L-glutamic acid decarboxylase).
Pregabaiin has a dose dependent protective effect on-seizure, and is a CNS-active compound. Pregabaiin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. Pregabaiin has analgesic, anticonvulsant, and anxiolytic activity. Pregabaiin is marketed under the trade name LYRICA®.
Pregabaiin is disclosed for the first time in US 6,197,819 Bl. US 6,197,819 Bl discloses a process to prepare Pregabaiin, which is as shown below:
2


However, the above process is of limited use for scale-up, principally due to the low temperature required for the reactions, the use of pyrophoric reagent such as butyl lithium, and due to side reactions, which resulted in a low overall yield.
US 5,616,793 discloses a process to prepare Pregabalin, which comprises, combining 3-isobutylglutaric acid and acetic anhydride under reflux to give 3-isobutylglutaric acid anhydride, which is then treated with an aqueous ammonia to give (±)-3-(carbamoylmethyl)-5-methylhexanoic acid. (±)-3-(carbamoylmethyl)-5-methylhexanoic acid is resoluted using (R)-(+)-l-phenylethylamine to give (R)-(+)-l-phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, which is treated with hydrochloric acid to give (R)-(-)-3-(carbamoylmethyl)-
3

5-methylhexanoic acid. (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid was dissolved in water and 50% sodium hydroxide solution and cooled to 5°C. In a separate flask water, 50% sodium hydroxide solution and bromine are combined while maintaining a temperature of less than 10°C. The bromine solution was added to the solution of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and warmed until a temperature of 80°C is reached. The solution was cooled to 45°C and quenched into 37% hydrochloric acid solution. The mixture was heated to 89°C and then cooled to 3°C. The mixture was filtered, washed with water and then dried to give (S)-(+)-3-aminomethyl-5-methylhexanoic acid.
The above process involves preparation of sodium hypobromite first and addition of this reagent into (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid to give (S)-(+)-3-aminomethyl-5-methylhexanoic acid, which is very lengthy and industrially not feasible process. Further, in the above process more amount of bromine i.e 1.20 mole equivalents is used, which is high and resuhs in byproducts, which are difficult to remove from Pregabalin.
This patent also discloses the recovery of 3-isobutylglutaric acid (S)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. The process comprises treating (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (47 kg, 251mol) in chloroform (807 kg) and ethanol (8.8 kg). The mixture was heated to 55°C and (R)-(+)-l-phenylethylamine (16.7 kg) was added. After a solution forms, additional (R)-(+)-1-phenylethylamine (5.5 kg) and (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid seed crystals (100 g) are added. The mixture is cooled to 32°C and filtered. The solid is washed with chloroform (100 kg) and dried under reduced pressure to give the (R)-(+)-l-phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. The solid is dissolved in water (138.5 kg) and concentrated hydrochloric acid (9.4 kg) is added. The mixture is cooled to 0-10°C and filtered. The solid is washed with cold water (20 L) and dried under reduced pressure to give 17.7 kg of (R)-(-)-3-(carbamoyl methyl)-5-methylhexanoic acid as a white solid.

The chloroform filtrate is extracted with aqueous sodium hydroxide solution (25 kg of 50% sodium hydroxide is dissolved in 106 kg water). The aqueous extract is acidified with concentrated hydrochloric acid (94 kg) and heated under reflux for approximately 24 hours. The aqueous mixture is extracted with methyl tert-butyl ether (70.5 kg). The methyl tert-butyl ether solution is concentrated under reduced pressure to give 3-isobutylglutaric acid (27.4 kg) of Formula V

By repeating the above process, the present invention inventors, has found that -30% of 4-isobutylpiperidine-2,6-dione is formed during the recovery of racemic (3-(carbamoylmethyl)-5-methylhexanoic acid).
US 2007/0073085 Al discloses a process to prepare Pregabalin, which comprises, combining an alkali hydroxide with water and adding CMH (3-(carbamoylmethyl)-5-methylhexanoic acid) at a temperature of about 0°C to about 40°C. Thereafter, adding bromine, in a drop-wise manner, at a temperature of about 0°C to about 40°C. Further the reaction mass was heated and reacted with a strong mineral acid and then the reaction mass was extracted with a C4.g alcohol and thereafter precipitated Pregabalin with an amine.
In above process we have to limit the amine content as per the ICH guidelines.
Hence, there is a need in the art for a process for the preparation and purification of Pregabalin and salts thereof
OBJECTIVE
The objective of the present invention is to provide a safe, productive and easy to handle commercial process for preparing Pregabalin.

In yet another objective of the present invention is to provide an improved process for preparing Pregabalin in one-pot.
In yet another objective of the present invention is to provide an improved process for preparing Pregabalin, which is simple, industrially applicable, eco-friendly and economically viable.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparing Pregabalin of Formula I,

in one-pot, which comprises:
a) cooling the aqueous sodium hydroxide solution;
b) addition of bromine to aqueous sodium hydroxide solution;
c) addition of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid;
d) isolating the Pregabalin.
In another embodiment, the present invention also provides a process to prepare highly pure Pregabalin having single individual impurities less than 0.1% in one-pot, which comprises:
a) cooling the aqueous sodium hydroxide solution;
b) addition of bromine to aqueous sodium hydroxide solution;
c) addition of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid;
d) isolating the Pregabalin; and
e) purifying the isolated Pregabalin.

In another embodiment, the present invention also provides, recovery of the racemic 3-(carbamoylmethyl)-5-methylhexanoic acid from non-racemic 3-(carbamoyl-methyl)-5-methylhexanoic acid, obtained during resolution, without isolating intermediates.
In another embodiment, the present invention also provides, recovery of (R)-(+)-1-phenylethylamine from organic layer.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process to prepare Pregabalin, which comprises, cooling the aqueous sodium hydroxide solution to 0-5°C (the sodium hydroxide solution is prepared by dissolving sodium hydroxide in water) and then bromine is added. (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid of compound of Formula II

which is not isolated and treated with carbon at 25-30°C and then the pH of the reaction mass is adjustment to 4.8-5.2 using 50% w/w aqueous sodium hydroxide solution.
The bromine is added in the range of 0.95 to 1.03 mole equivalents with respect to (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid.

The present invention relates to an improved process to prepare highly pure Pregabalin having individual impurity less than 0.1% in one-pot, which comprises, cooling the aqueous sodium hydroxide solution to 0-5 °C and then adding bromine. (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid of compound of Formula II

is added in lot wise at 0-5°C to the above reaction mass. Thereafter, the reaction mass is heated to 60-65°C, while stirring. After completion of reaction, the reaction mass is cooled to 25-30°C and hydrochloric acid is added to give Pregabalin hydrochloride compound of Formula III

which is not isolated and treated with carbon at 25-35°C and then the pH of the reaction mass is adjustment to 4.8-5.2 using 50% w/w aqueous sodium hydroxide solution to give crude Pregabalin. Crude Pregabalin is added to 50% v/v aqueous isopropyl alcohol at 25-35°C and heating the contents to 75-80°C and thereafter cooling to 0-5°C to give pure Pregabalin.
The process to prepare (R)-(-)-3-(carbamoylmethyl)-5-methyihexanoic acid of compound of Formula II

comprises,
a) treating 3-(carbamoylmethyl)-5-methylhexanoic acid of compound of Formula IV


with R-(+)-l-phenylethylamine to give (R)-(+)-l-phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid; b) combining the (R)-(+)-l-phenylethylamine salt of (R)-(-)-3-(carbamoyl-methyl)-5-methylhexanoic acid with an acid to obtain (R)-(-)-3-(carbamoylmethyl)-5 -methylhexanoic acid.
The present invention also relates to recovery of the racemic 3-(carbamoyl-methyl)-5-methylhexanoic acid of compound of Formula IV

from filtrates without isolating the intermediates, which comprises:
a) basification and separation of aqueous layer for 3-(carbamoylmethyl)-5-
methylhexanoic acid and organic layer for (R)-(+)-l-phenylethylamine;
b) addition of sodium hydroxide to aqueous layer and heating under reflux
for- 15 hrs;
c) cooling the reaction mass to 25-35°C and acidifying to obtain 3-
isobutylglutaric acid of Formula V;

d) extracting the reaction mass with toluene and concentrating the toluene
extract followed by addition of acetic anhydride and heating the contents
under reflux to obtain 3-isobutylglutaric acid anhydride of Formula VI;


e) concentrating the reaction mass and diluting with toluene followed by addition of diluted reaction mass to aqueous ammonia solution to give racemic 3-(carbamoyl-methyl)-5-methylhexanoic acid of compovmd of Formula IV; and
f) isolating racemic 3-(carbamoylmethyl)-5-methylhexanoic acid of compound of Formula IV.
The present invention also relates to recovery of (R)-(+)-l-phenylethylamine from organic layer, which comprises:
a) acidification of organic layer and extracting with water;
b) basification of aqueous layer and extracting with methylene chloride;
c) evaporating the methylene chloride to give (R)-(+)-l-phenylethylamine; and
d) isolating the (R)-(+)-l-phenylethylamine.
wherein the organic layer is obtained during recovery of racemic 3-(carbamoylmethyl)-5-methyl-hexanoic acid.
The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.
EXAMPLE!
PREPARATION OF S)-(+)-3-AMINOMETHYL-5-METHYL-l-
HEXANOIC ACID
Bromine (I54g, 0.96 moles) vv^as added to pre-cooled aqueous sodium hydroxide solution [prepared by dissolving sodium hydroxide (212g, 5.3 moles) in DM water 675ml] over a period of -Ihrs at 0-5°C. (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (180g, 0.96 mole) was added in lots to the reaction mass, maintaining temperature at 0-5°C and further stirred for Ihr at this temperature.

Thereafter, the temperature of the reaction was raised to 30°C and allowed to raise the temperature up to 60-65°C by using its exothermicity. After completion of reaction, reaction mass was cooled to 25-30°C and 35% w/w hydrochloric acid (396ml) was added slowly at this temperature to obtained a clear solution. Obtained solution was treated with carbon and 50% w/w aqueous sodium hydroxide solution was added to the filtrate till the pH was 5.1. Thereafter, the temperature of the reaction mass was raised to 55-60°C and stirred for -15 min slowly cooled to 10-15°C. At this temperature the reaction mass was stirred for Ih and the obtained product was filtered, washed with pre-cooled DM water (2 x 90 ml) and dried at 50-60°C under reduced pressure -20mm Hg to a constant weight. Yield: 117g (76% of theory) Chiral Purity: 100% Assay (%w/w, by HPLC): 99.2
EXAMPLE-2
PURIFICATION OF (S)-(+)-3-AMINOMEHYL-5-METHYL-l-HEXANOIC ACID
Pregabalin (lOOg) was suspended in 50% v/v aqueous isopropyl alcohol (900ml)
and heated to 75-80°C to obtain a clear solution. Thus, obtained clear solution was
cooled slowly to 0-5°C and stirred for Ihr to complete the crystallization. Product
was filtered, washed with isopropyl alcohol (2x100ml) and dried at 50-55°C under
reduced pressure ~20mm Hg to a constant weight.
Yield: 85 g (85% of theory)
Chromatographic Purity (by HPLC): 99.92 %
Chiral Purity: 100%
Assay (%w/w, by HPLC): 99.9 %

EXAMPLE-3
PURIFICATION OF (SH+)-3-AMINOMEHYL-5-METHYL-l-HEXANOIC ACID
Pregabalin (3g) was suspended in mixture of 18 ml isopropyl alcohol and 12 ml DM water and heated to 75-80°C to obtained a clear solution. Thus, obtained clear solution was cooled slowly to 0-5 C and stirred for Ihr to complete the crystallization. Product was filtered, washed with isopropyl alcohol (2x3ml) and
o
dried at 50-55 C/~20mm Hg to a constant weight. Yield: 2.77 g (92% of theory) Chromatographic Purity (by HPLC): 99.92 %
EXAMPLE-4
PURIFICATION OF (S)-(+)-3-AMINOMEHYL-5-METHYL-l-HEXANOIC ACID
Pregabalin (5g) was suspended in mixture of 25 ml isopropyl alcohol and 25 ml DM water and heated to 75-80 C to obtained a clear solution. Thus, obtained clear solution was cooled slowly to 0-5°C and stirred for Ihr to complete the crystallization. Product was filtered, washed with isopropyl alcohol (2x5ml) and
o
dried at 50-55 C/~20mm Hg to a constant weight.
Yield: 4.30g g (86% of theory)
Chiral purity: 100%
Chromatographic Purity (by HPLC): 99.95 %
EXAMPLES
RECOVERY OF RACEMIC 3-(CARBAMOYLMETHYL)-5-METHYL-HEXANOICACID
Mixture of aqueous mother liquor (~4000ml) and chloroform mother liquor (-75 00ml) obtained after resolution of 3-(carbamoylmethyl)-5-methyl-
12

hexanoicacid was combined and the pH was adjusted to 12.5 using 50% w/w aqueous sodium hydroxide solution at 25-35°C. Aqueous layer was separated and sodium hydroxide (192g, 4.80moles) was added. Thereafter, the solution was heated under reflux at 95-100°C and stirred at this temperature till starting material, 3-(carbamoylmethyl)-5-methylhexanoic acid is absent. After completion of reaction, the reaction mass was cooled to 20-3 0°C and the pH of the reaction mass was adjusted to 0.5 using sulftiric acid. Thereafter, the reaction mass was extracted with toluene (Ixl200ml,lx600ml) and combined organic layer was concentrated at 35-60°C under reduced pressure (150-10 mm Hg). Acetic anhydride (294g, 2.88 moles) was added to the concentrated mass and contents were heated again to 130-135°C and stirred for 2hrs. The reaction mass was concentrated at 115-135°C under reduced pressure (300-lOmm Hg) to remove excess acetic anhydride and acetic acid byproduct. Thus obtained, concentrated mass was diluted with toluene (600ml) and cooled to 30-35°C and this reaction mass was added to pre-cooled aqueous ammonia solution (9%w/w, 1350ml) by maintaining the pH of the reaction mass >8 at 10-20°C. Thereafter, the aqueous layer was separated and acidified to pH 1 with 35%w/w hydrochloric acid (550ml) and further stirred for 1 hr at 5-10°C to precipitate the product. The precipitated product was filtered, washed with water and dried at 50-55°C under reduced pressure ~20mm Hg to a constant weight. Yield: 325g (85% recovery) Chromatographic Purity (by HPLC): 99.50 % Assay: 99.6 % (%w/w, by titrimetry)
EXAMPLE-6
RECOVERY OF (R)-(+)-l-PHENYLETHYLAMINE
DM water (1800 ml) was added to chloroform layer (-7000 ml, obtained after separation of sodium salt of non-racemic 3-(carbomoylmethyl)-5-methyl-l-hexanoic acid) and adjusting the pH of the biphasic solution to 0.5 with 35% w/w aqueous hydrochloric acid (550 ml) at 25-30°C. The aqueous layer was separated
13

and the organic layer was extracted with DM water (600 ml) at 25-30°C.
Methylene chloride was added to the aqueous layer and the pH of the solution was
adjusted to 12.5 with 50% w/w aqueous sodium hydroxide solution (390 ml) at
25-30°C. Thereafter, the organic layer was separated and extracted the aqueous
layer with methylene chloride (500 ml) at 25-30°C. The obtained organic solvent
layer was concentrated at 25-30°C under reduced pressure (400-70 mm Hg) to
obtain the pure (R)-(+)-l-phenylethylamine.
Yield: 250 g
Chromatograpic purity (by GC): 100%
Assay: 99.5 % (% w/w, by titrimetry)
SOR (Ia]D^° c=10 in ethanol): (+) 30.6°
EXAMPLE-7
PREPARATION OF (R)-(-)-3-(CARBAMOYLMETHYL)-5-METHYL-HEXANOIC ACID
Racemic 3-(carbamoylmethyl)-5-methylhexanoic acid (600g, 3.21 moles)) was suspended in a mixture of chloroform (7200ml) and ethanol (60ml) at 25-35°C. Thereafter, temperature of the contents was raised to 55°C and (R)-(+)-l-phenyl ethylamine (272g, 2.25 moles) was added. Thus, obtained clear solution was cooled slowly to 28-32°C and stirred at this temperature for -90 min to precipitated (R)-(+)-l-phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, which was filtered, washed and dried at 55-65°C under reduced pressure ~20mmHg to a constant weight.
After drying, the obtained product was added to DM water (3180ml) and heated to 35-40°C and pH of thus obtained solution was adjusted to 0.5 with 35% w/w hydrochloric acid, slowly cooled to 5-10°C, and stirred at this temperature for Ihr to precipitate (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, which was filtered, washed with 3% w/w hydrochloric acid (420ml) followed by DM water
14

(420ml) and dried at 60-65°C under reduced pressure ~20mm Hg to a constant
weight.
Yield = 216 g (72% of theory)
Chiral Purity: 100%
Chromatographic Purity (by HPLC): 99.47 %
Assay: 99.5 % (%w/w, by titrimetry)
15

1) An improved process for preparing Pregabalin of Formula I in one-pot,

which comprises:
a) cooling the aqueous sodium hydroxide solution;
b) addition of bromine to aqueous sodium hydroxide solution;
c) addition of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid;
d) isolating the Pregabalin.
2) The process according to claim 1, the sodium hydroxide solution is prepared
by dissolving sodium hydroxide in water and cooled to 0-5°C.
3) The process according to claim 1, the bromine is added in the range of 0.95 to
1.03 mole equivalents.
4) A process to prepare highly pure Pregabalin having individual impurity less
than 0.1% in one-pot, which comprises:
a) cooling the aqueous sodium hydroxide solution;
b) addition of bromine to aqueous sodium hydroxide solution;
c) addition of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid;
d) isolating the Pregabalin; and
e) purifying the isolated Pregabalin.
5) The process according to claim 4, the sodium hydroxide solution is prepared
by dissolving sodium hydroxide in water and cooled to 0-5°C.
16

6) The process according to claim 4, the bromine is added in the range of 0.95 to
1.03 mole equivalents.
7) The process according to claim 4, purification of Pregabalin, comprises:
a) adding crude pregabalin to 50% v/v aqueous isopropyl alcohol at 25-35°C;
b) heating the contents to 75-80°C;
c) cooling to 0-5°C to precipitate Pregabalin; and
d) isolating pure Pregabalin.
8) The process to recover the racemic 3-(carbamoylmethyl)-5-methylhexanoic
acid of Formula IV

from filtrate without isolating the intermediates, which comprises:
a) basification and separation of aqueous layer for 3-(carbamoylmethyl)-5-
methylhexanoic acid and organic layer for (R)-(+)-l-phenylethylamine;
b) addition of sodium hydroxide to aqueous layer and heating under reflux for ~ 15 hrs;
c) cooling the reaction mass to 25-35°C and acidifying to obtain 3-isobutylglutaric acid of Formula V;

d) extracting the reaction mass with toluene and concentrating the toluene
extract followed by addition of acetic anhydride and heating the contents
under reflux to obtain 3-isobutylglutaric acid anhydride of Formula VI;
CH3 L^ O Formula VI
O J
17

e) concentrating the reaction mass and diluting with toluene followed by addition of diluted reaction mass to aqueous ammonia solution to give racemic 3-(carbamoylmethyl)-5-methylhexanoic acid of compound of Formula IV; and
f) isolating racemic 3-(carbamoylmethyl)-5-methylhexanoic acid of compound of Formula IV.
9) The process to recovery the (R)-(+)-l-phenylethylamine from organic layer,
which comprises:
a) acidification of organic layer and extracting with water;
b) basification of aqueous layer and extracting with methylene chloride;
c) evaporating the methylene chloride to give (R)-(+)-l-phenylethylamine; and
d) isolating the (R)-(+)-1 -phenylethylamine.
10) The process according to claim 9, the organic layer is obtained during
recovery of racemic 3-(carbamoylmethyl)-5-methyl-hexanoic acid.