FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"AN IMPROVED METHOD FOR PREPARATION OF (S)-PREGABALIN AND INTERMEDIATE THEREOF"
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad - 380015, Gujarat, India.
The following specification particularly describes the nature of the invention:
1

FIELD OF THE INVENTION
The present invention is directed to the processes for preparing of (S)- Pregabaine of formula (I)

COOH
(I)
The present invention further relates to the process for the preparation of an intermediate 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl, tetraethyl ester of formula (P-02), which is useful for the preparation of (S)-Pregabalin

The present invention also relates to (S)-Pregabalin having a low level of impurities, determined area percentage of HPLC.
BACKGROUND OF THE INVENTION:
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
2

(S)-Pregabalin, which is chemically, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid and represented by below mentioned formula (I)


,,^v

NHc

COOH
0)
(S)-Pregabalin is a gamma.-amino butyric acid or (S)-3-isobutyl (GABA) analogue. (S)-Pregabalin
has been found to activate GAD (L-glutamic acid decarboxylase). (S^Pregabalin has a dose dependent protective effect on-seizure, and is a CNS-active compound. (S)-Pregabalin 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. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.
(S)-Pregabalin is marketed under the name LYRICA.RTM. by Pfizer, Inc., in tablets of 25, 50, 75, 150, 200, and 300 mg doses.
The preparation of (S)-Pregabalin from 3-isbutylglutaric acid is disclosed in DRUGS OF THE FURTURE, 24 (8), 862-870 (1999), and in U.S. Pat. No. 5,616,793, and is described by the following Scheme-1:
SCHEME-1

or ^o' ^O.

COOH S-(+) Prgabalin

YYT°
XOOH2
p-oe

R-{+)-a phenytethyl
amine H2Nv^5.0

3

Accordingly, 3-isobutylglutaric acid, compound I, is converted into the corresponding anhydride, compound 2, by treatment with acetic anhydride. The reaction of the anhydride with NH4OH produces the glutaric acid mono-amide, compound 3, which is resolved with (R)-l-phenylethylamine, yielding the (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid, compound 3-salt. Combining the salt with an acid liberates the R enantiomer, compound 4. Finally, Hoffmann degradation with Br2/NaOH, followed by precipitation of (S)-Pregabalin, after addition of HC1.
A very similar process is disclosed in U.S. Patent No. 5,616,793, wherein (S)-Pregabalin is also obtained by Hoffman degradation, followed by precipitation of (S)-Pregabalin, after addition of HC1. The product is further purified by crystallization from a mixture of isopropanol and water.
Various patent applications US 2007/0073085 Al, US 2007/0066846 Al, US 2006/0281816 Al, US 2006/0276544 Al etc. discloses various process for the preparation of (S)-Pregabalin via the above discussed isobutyl glutaric acid intermediate followed by Hoffman degradation at the end.
WO 2006/122259 Al discloses the optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid via Ephedrine salt and Norephedrine salt. WO 2007/035890 Al discloses an asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid.
In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct
4

reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of an API, such as (S)-Pregabalin, it must be analyzed for purity, typically, by HPLC or TLC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, is as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
Generally, side products, by-products, and adjunct reagents (collectively "impurities") are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. (Strobel p. 953, Strobel, H. A; Heineman, W. R_, Chemical Instrumentation: A Systematic Approach, 3rd ed. (Wiley & Sons: New York 1989)). Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the "retention time."
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Thus, there is a need in the art for Pregabalin and (S)-Pregabalin having a low level of impurities through a pure intermediate and for a process for preparation thereof.
Therefore, there is a need to have simple process, that allow for preparation of highly pure Pregabalin and (S)-Pregabalin in a facile manner on an industrial scale, which yields Pregabalin and (S)-Pregabalin by resolution of 3-(carbamoylmethyl)-5-methylhexanoic acid and in high purity.
The inventors of the present invention has found that the use of this new intermediate for preparation of Pregabalin enables to prepare isobutyl glutaric acid in a highly pure form.
5

OBJECT OF INVENTION:
It is an object of the present invention to overcome or substantially ameliorate one or more of the disadvantages of the prior art or at least to provide a useful alternative.
It is an object of the present invention to provide a process for preparing (S)-Pregabalin that yields highly pure (S)-Pregabalin with every single individual impurities less than 0.1% by area percentage of HPLC.
Yet another object of the present invention to provide (S)-Pregabalin having overall purity more than 99.94%
It is also an object of the present invention to provide a useful intermediate for the preparation of isobutyl glutaric acid in pure form.
Further object of the present invention is to provide a process for preparing (S)-Pregabalin by using the intermediate as discussed herein.
Further object of the present invention is to provide a novel process for preparing (S)-Pregabalin which is cost effective, eco-friendly, non-hazardous and applicable for large scale productions.
6

SUMMARY OF INVENTION:
In one embodiment, the invention encompasses 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl,
tetraethyl ester of formula P-02
OC2H5 0=/ OCzHg
CZHBOOCV-^
C2H500C y
(P-02)
In another embodiment, the invention encompasses (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid in crystalline form, which is characterized by XRD and Dt-La another embodiment, the present invention provides a novel process for the preparation of compound P-02.
In another embodiment, the present invention provides a novel process for preparation of P-02 intermediate by condensation of isovaleraldehyde with diethyl succinate in presence of basic catalyst.
In another embodiment, the present invention provides a process for preparation of isobutylglutaric anhydride by cyclization of isobutylglutaric acid with thionyl chloride.
It another embodiment, the invention provides a process for preparing (S)-Pregabalin, which provides highly pure (S)-Pregabalin with single every single individual impurities less than 0.1% by area percentage of HPLC.
7

BRIEF DESCRIPTION OF FIGURES:

A preferred embodiment of the invention will now be described, by way of example only, with
reference to the accompanying figures in which:
FIG.l: X-ray diffraction of (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-
methylhexanoic acid
FIG.2: FTIR of (R)-phenylethylamine salt of (R>3-(carbamoylmethyl)-5-methylhexanoic acid
FIG.3: Chiral HPLC chromatogram of (S)-Pregabalin.
FIG.4: GC chromatogram of 2-carboxyethyl-5-methylhex-2-enoic acid (P-01)
FIG.5: GC chromatogram of 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl, tetraethyl ester (P-02)
FIG.6: GC chromatogram of isobutylglutaric acid (P-03)
DETAILED DESCRIPTION:
According to the most preferred embodiment of the present invention there is provided an
intermediate (P-02) for preparation of isobutylglutaric acid.
OC2H5 0=< OCzHg C2H5OOC
C2H500C
(P-02)
According to the most preferred embodiment of the present invention, there is provided a method of making (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, the method comprising:
a. condensing isovaleraldehyde with an dialkyl malonate to form a 2-carboxyethyl-5-methylhex-2-
enoic acid, ethyl ester (P-01);
b. reacting the 2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester (P-01) with a dialkyl malonate
to form of 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl, tetraethyl ester (P-02) in presence of
basic catalyst;

c. hydrolyzing 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl, tetraethyl ester (P-02) in presence of
an acid and subsequently decarboxylating to give isobutylglutaric acid (P-03);
d. forming (±)-3-(Carbamoylmethyl)-5-methylhexanoic acid (P-04) via formation of anhydride of
3-isobutylglutaric acid;
e. reacting (±)-3-(Carbamoylmethyl)-5-methylhexanoic acid (P-04) with (R)-(+)-"% |pOC2H5 O
P-01
To a solution of 100 g of Isovaleraldehyde in 450 ml methylene dichloride was added 180 g of diethyl malonate in round bottom flask fitted with a dean-stark. 11.8 g of morpholine and 8.3 gm of acetic acid were added twice. The reaction mixture was heated at reflux temperature 45°C-50°C for 4-5 hours till azeotropic removal of water and was cooled to 25°C-30°C. 225 ml of water was added to the reaction mixture, stirred & settled for 15 minutes. Separated organic layer was treated with 150 ml of 10% HC1 Solution. The aqueous layer and organic layer are separated. The separated organic layer is then treated with 100 ml of 2% NaHC03 solution and with 225 ml of water, stirred and settled. Finally separated organic layer is filtered through hyflow bed, washed with methylene dichloride. The excess of methylene dichloride is distilled under vacuum by hot water below 40°C-50°C. [% Yield = 87%; G.C purity = 84-86%, isomer = 1-2%].
IR (Nujol-mull, v cm-1) : ^C-H stretch: 2980,2960, 2935; CO : 1724; C=C stretch: 1649 'H NMR (CDCI3, 300 MHz): 5 0.90-1.01 (m, 6H), 1.24-1.35 (m, 6H), 1.77-1.84 (m, 1H), 2.16-2.22 (m, 2H), 4.17-4.34 (m, 4H), 6.99-7.04 (t, 1H, J = 7.9 Hz) MS: m/z-228.28 (M+l).
15

Purity of 2-carbethoxy-5-methyl hex-2-enoic acid ethyl ester (P-01) can be determined by using the following gas chromatography apparatus and procedures:

Column & Packing
Injector Temperature : 210°C Detector Temperature: 230°C

: Fused silica capillary column Elite-5 of Perkin Elmer or equivalent Length: 30 m Diamter: 0.53 mm Film thickness : 5 μm

Oven temperature Time (min) Temperature
Initial 0 100°C
Final 44 220°C
Temp Programme rate: 20°C/minute
Equilibrium time 1.0 minute
Injection Volume 0.5^1
Carrier gas Nitrogen
Split Flow Detector 60ml/min. FID
A sample Chromatogram is shown in FIG.4
Example-2: Preparation of 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl, tetraethyl ester of formula P-02

0C2H5O—1L 0c -OC2H5 0=C2H500C PC2H5 =/ OC2H5
>-
X C2H500C \ P-02
P-01
16

98.23 g of diethyl malonate, 22.38 g of piperidine were taken in a round bottom flask. The above prepared intermediate P-01, 100 g was added dropwise at room temperature. After the addition was completed the reaction mixture was heated to 50°C to 52°C and maintained. The reaction mixture was cooled to room temperature and the product P-02, was isolated (215 g).
Purity of 1,1,3,3-Propanetetracarboxylic acid, 2-isobutyl, tetraethyl ester (P-02) can be determined by using the following gas chromatography apparatus and procedures:
Column & Packing : Fused silica capillary column Elite-5 of Perkin Elmer
or equivalent
Length: 30 m
Diamter: 0.53 mm
Film thickness : 5 μm Injector Temperature : 210°C Detector Temperature: 230°C

Oven temperature Time (min) Temperature
Initial 0 100°C
Final 44 220°C
Temp Programme rate: 20°C/minute
Equilibrium time 1.0 minute
Injection Volume 0.5 /A
Carrier gas Nitrogen
Split Flow 60ml/min.
Detector FID
A sample Chromatogram is shown in FTG.5
17

ExampIe-3: Preparation of Isobutylglutaric acid (P-03)
OC2H5 0=^ OC2H5
C2H500C V-^
C2H5OOC y

p-02
OH
O P-03

100 g of P-02 intermediate as prepared above was taken in a round bottom flask and 300 ml cone. HC1 was added. The reaction mixture was heated to reflux at 100°C to 105°C slowly for 72 hours. The reaction mixture was cooled to 85-90°C. The reaction mixture was extracted with toluene at 70°C to 80°C and stirred for 30 min. The product was filtered through hyflow bed and washed with toluene. The excess toluene was distilled under vacuum at 60°C to 70°C to isolate P-03,35 g. Purity of Isobutylglutaric acid (P-03) can be determined by using the following gas chromatography apparatus and procedures:

Column & Packing : Fused silica capillary column Elite-5 of Perkin Elmer or equivalent Length: 30 m Diamter: 0.53 mm Film thickness : 5 fan
Injector Temperature 210°C
Detector Temperature 230°C
Oven temperature Time (min) Temperature
Initial 0 100°C
Final 44 220°C
Temp Programme rate: 20°C/minute
Equilibrium time : 1.0 minute
Injection Volume 0.5 /A
Carrier gas Nitrogen
Split Flow Detector 60ml/min. FID
A sample Chromatogram is shown in FIG.6
18

Example-4: Preparation of (±)-3-(Carbamoylnoiethyl)-5-Methylhexanoic Acid (P-04) (Without Isolation and Purification 3-Isobutylglutaric Acid Anhydride)

3-Isobutylglutaric acid (68.8 kg) and thionyl chloride (445 kg) are combined and placed under reflux for 0.5 hours. The mixture is placed under atmospheric distillation followed by vacuum distillation to remove thionyl chloride. The undistilled 3-isobutylglutaric acid anhydride is dissolved in methyl tert-butyl ether (63 kg) and added to a solution of aqueous ammonia (49 kg of 28% ammonium hydroxide) and water (92 kg) at a temperature of 25°C or less. The mixture is stirred for 35 minutes and the layers are separated. The aqueous layer is placed under vacuum distillation to remove any remaining volatile nonaqueous solvent. Concentrated hydrochloric acid (51 kg) is added to the aqueous mixture to obtain a pH of 1.5. The mixture is cooled to 0°C-10°C. and filtered. The solid is washed with water (50 L) and dried under reduced pressure. The solid is then dissolved in hot (70°C) ethyl acetate (237 kg) and filtered. The solution is cooled to 0°C-5°C and the product is collected by filtration. The solid is washed with cold ethyl acetate (45 kg) and dried under reduced pressure to give 47.5 kg of (±)-3-(Carbamoylmethyl)-5-methylhexanoic acid as an off-white solid having a melting point in the range of 106°C to about 108°C.

Example-5: Preparation of (R)-(-)-3-(Carbamoyllmethyl)-5-Methyl Hexanoic Acid, (R)-(+)-.alpha.-phenylethylamine Salt (P-05)
O NH2

H2Kk ^.0
HO.
Y
O P-04
O NH3
P-05
R-(+)-a phenylethyl amine
19

(±)-3-(Carbamoylmethyl)-5-methylhexanoic acid (17.0 g) is placed in chloroform (292 g) and ethanol (3.2 g) is added. The mixture is heated to 55°C and (R)-(+)-a-phenylethylamine (6.0 g) is added. After a solution forms additional (R)-(+)-a-phenylethylamine (2.0 g) and (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid seed crystals (50 mg) are added. The mixture is cooled to 32°C and filtered. The solid is washed with chloroform (30 ml). The solid is dried under reduced pressure to give 10.5 g of the (R)-(+)-a-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid as a white solid having a melting point in the range of about 123° C to about 126°C (Chiralpak AD-H (250 mm X 4.6 mm, 5u) n-Hexane/Isopropyl alcohol/Formic acid-80/20/0.1) enantiomeric purity >99% (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
Example-6: Preparation of (R)-(-)-3-(Carbamoylmethyl)-5-Methylhexanoic Acid (P-06)
'»'..

■ xx
XOOH2
© JL P_06
o
P-05 The (R)-(+)-a-phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (10.9 g) is placed in water (35 ml). The mixture is acidified to pH 1.7 at 31°C with concentrated hydrochloric acid. The mixture is cooled to 4°C and filtered. The solid is washed with cold (4°C) 1M hydrochloric acid (10 ml) and dried under reduced pressure to give 6.2 g of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid as a white solid having a melting point in the range of about 130°C to about 133°C (Chiralpak AD-H (250 mm X 4.6 mm, 5|i) n-Hexane/Isopropyl alcohol/Formic acid-80/20/0.1) enantiomeric purity >99% (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid.
Example-7: Preparation of (SH+)~^Aiuinomethyl-5-Mcthylhexanoic Acid

(R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid (30 g) is dissolved in water (28 g) and 50% sodium hydroxide solution (12.6 g) and cooled to 5°C. In a separate flask water (85 g), 50% sodium

hydroxide solution (53 g), and bromine (30.6 g) are combined while maintaining a temperature of less than 10°C. The bromine solution is added to the solution of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and warmed until a temperature of 80°C is reached. The solution is cooled to 45°C and quenched into 37% hydrochloric acid solution (42 g). The mixture is heated to 89°C. and then cooled to 3°C. The mixture is filtered and the solid is washed with water (30 mL). The solid is dried under reduced pressure to give 16.7 grams of (S)-(+)-3-aminomethyl-5-methylhexanoic acid. The solid (16.3 g) is recrystallized from a mixture of isopropanol (54 g) and water (54 g) to give 14.7 g of recrystallized (S)-(+)-3-aminomethyl-5-methylhexanoic acid having a melting point in the range of about 184°C to about 186°C-decomposes.
Enantiomeric purity can be established by the following chiral HPLC method:
High-performance liquid chromatography was performed using a Shimadzu LC2010C HPLC system

Column
Mobile Phase : Flow Rate Column oven temp Run Time Detector Wavelength Injection Volume Diluent

Chiralpak AD-H (250 mm X 4.6 mm, 5u)
or equivalent
n-Hexane/Isopropyl alcohol/Formic acid-80/20/0.1
l.Oml/min.
25°C
30 mintues
dual wavelength UV-VIS
264 nm
10//1 n-Hexane/Isopropyl alcohol-50/50.

Mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
HPLC shows purity > 99.5% having R-isomer content NMT 0.5%, unknown impurity NMT 0.1% and total impurity NMT 0.50%.
21

Advantages of the Invention:-
1. The present invention provides a very cost-effective, eco-friendly, non-hazardous and large scale applicable method
2. The present invention provides a method for preparation of (S)-(+)-3-aminomethyl-5-methylhexanoic acid which encompasses through a new intermediate P-02.
3. The present invention provides crystalline (R)-(+)-a-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid which is well characterized by XRD and IR
4. The present invention provides (S)-(+)-3-aminomethyl-5-methylhexanoic acid in substantially pure form having purity greater than 99.5% as measured by area percentage of HPLC.
5. The present invention provides crystalline (R)-(+)-a-phenylethylamine salt of (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid in substantially pure form having purity greater than 99.5% as measured by area percentage of HPLC.
22