FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
“A NOVEL PROCESS FOR PREPARING PREGABALIN AND ITS ACID ADDITION SALTS”
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
1

BACKGROUND OF THE INVENTION
1. TECHNICAL FIELD
The present invention relates to a method of making (±)-3-(aminomethyl)-5-methyl hexanoic acid and to a method of obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (±)-3-(aminomethyl)-5-methyl hexanoic acid.
2. DESCRIPTION OF RELATED ART
(S)-Pregabalin, 3-(aminomethyl)-5-methyl-(3S)-hexanoic acid, has the empirical formula C8H17N02 and a molecular weight of 159, and may be represented by the chemical structure:

HX
NH2- l.NaOBr
HO ^O
HO ^O

CH,
HX
2-"J°+ HO^O

VI VII VIII
wherein (R)-(-)-3-(carbamoyl methyl)-5-methyIhexanoic acid is converted to (S)-

Wherein ®-(-)-3-(carbamoyl methyl)-5-methylhexanoic acid is converted to (S)-Pregablin via a Hoffmann degradation with sodium hypobromite followed by precipitation of (S)-pregabalin, after addition of HCL. The product is further purified by crystallization from a mixture of isopropanol and water.
Hence there is a need in the art for a process for the preparation of Pregabalin and salts thereof.
SUMMARY OF THE INVENTION
The present invention provides a process for synthesis of pregabalin and also provides a process for obtaining (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid from (±)-3-(aminomethyl)-5-methylhexanoic acid. Said process comprising condensing isovaleraldehyde with nitro alkane to form a compound of formula-(II); reacting the compound of formula - (II) with the compound of Formula - (III), to form compound of formula-(IV), which upon hydrolysis using an acid/base gives compound of formula -(V). Decarboxylation of compound of formula - (V) with an acid/base gives compound of
3

formula-VI. Reduction of compound of formula - (VI) affords racemic pregabalin, which upon resolution with suitable resolving agents either alone or mixtures thereof, produces (S)-Pregabalin.
The present invention also provides the novel compounds 2, 2-dimethyl-5-[3-methyl-1 -(nitromethyl) butyl]-1, 3-dioxane-4, 6-dione and 3-methyl-l-(nitro methyl) butyl] malonic acid.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the present invention provides a process for the preparation
of (S)-Pregabalin. In accordance with Scheme below, the present invention provides an
efficient process for synthesis of pregabalin and also provides a process for obtaining (S)-
(+)-3-(aminomethyl)-5-methylhexanoic acid from (±)-3-(aminomethyl)-5-
methylhexanoic acid.
4

The method of above scheme generally comprises,
a) condensing isovaleraldehyde with nitro alkane to form Formula-II,

5

Formula-II
b) reacting compound of the formula-II with Meldrum acid or a derivative thereof represented by a compound of formula III, to form a compound of formula-IV,

c) hydrolysis of compound of formula-II using an acid/base gives compound of formula -V.

d) decarboxylation of compound of formula III using an acid/base produces compound of formula-VI

e) reduction of compound of formula VI affords racemic Pregabalin.
6

Racemic Pregabalin
f) resolution of racemic pregabalin with suitable resolving agents either alone or mixture thereof, produces (S)-Pregabalin.

In another embodiment, the present invention provides process for the preparation of Pregabalin as depicted in scheme II below.
7


:

In one step of the process, isovaleraldehyde is condensed with nitro alkane, preferably nitro methane, to form 4-methyl-1-nitropent-l-ene. In general this reaction is carried out in the presence of an organic or inorganic base such as selected from the group consisting of suitable bases include, but are not limited to, C1-C6 mono-, di- or tri-alkyl amines wherein the alkyl groups may be the same or different, e.g., triethylamine (TEA), C3-C25 cyclic amines, e.g., pyridine; alkali metal carbonate and bicarbonates, e.g., sodium, potassium or lithium carbonates or bicarbonates, and the like and mixtures thereof or an acid and base combination, in a polar solvents selected from the group consisting of alcohols, ketones, acetonitrile, THF, DMSO or DMF and mixtures thereof; or non polar solvents selected from the group consisting of chloroform, dichloromethane, diethyl ether, benzene, toluene and hexane or mixtures thereof.
In another step of the process compound of formula II reacts with cyclic anhydride, represented by formula III, like Meldrum's acid or a derivatives thereof in presence of organic base selected from the group consisting of mono alkyl diakyl and trialkyl, amines or their mixtures thereof, wherein alkyl denotes C1-C4 branched or straight chain; or inorganic bases selected from the group consisting of alkali or alkaline hydroxides and carbonates or their mixtures thereof produces compound of formula IV.
Cyclic anhydride represents by formula III, wherein Rl and R2 are the same or different represents alkyls, aralkyl or benzyl or hydrogen. Alkyl denotes C1-C4 brached or straight chain.
In another step of the process, hydrolysis of compound of formula IV is carried out with mineral acid selected from the group consisting of Hydrochloric acid, sulphuric acid, ortho phosphoric acid or their mixtures thereof; or organic acid selected from the group consisting of C1-C4 alkyl acids like formic, acetic, propanoic and butanoic acids or their mixtures thereof, wherein alkyl denotes C1-C4 branched or straight chain; results in compound of formula V.
In another step of the process, hydrolysis of compound of formula V is carried out with aqueous or non aqueous mineral acids or organic acid produces compound of formula VI.
Racemic Pregabalin can be obtained by catalytic hydrogenation of compound of formula VI with an appropriate hydrogenating agent selecting from the group consisting
9

of Pd/C, hydrazine hydrate, tin chloride or mixtures thereof in alcohol selected from the group consisting of CM straight or branched chain alcohols.
In another embodiment of the invention, the racemic pregabalin can be resolved
in to (S)- pregabalin substantially free of (R)-Pregabalin, by using appropriate resolving
reagents selected from the group consisting of acids such as Di-p-Toluoyl-D-Tartaric
acid, Di-p-Toluoyl-L-Tartaric acid, Dibenzoyl-D-Tartaric acid monohydrate, Dibenzoyl-
L-Tartaric acid monohydrate, Di-p-Anisoyl-D-Tartaric acid , Di-p-Anisoyl-L-Tartaric
acid, D-Tartaric acid mono-p-chloroanilide , L-Tartaric acid mono-p-chloroanilide,
Dibenzoyl-D-Tartaric acid monodimethylamide, Dibenzoyl-L-Tartaric acid
monodimethylamide, Malic acid, 10-camphorsulfonic acid, 3-bromocamphor-10-sulfonic
acid, ortho-Chloromandelic acid, para-Methylmandelic acid, Isobutyl lactate, 2-
Hydroxymethylhexanoic acid, 2-Hydroxymethylbutanoic acid, 2-
Hydroxymethylpropanoic acid, Lysine hydrochloride, (1 S,2 R,4 R)-(-)-2,10-
camphorsultam, dichlorophthalic acid, 2-methoxy-2-(l-naphthyl)propionic acid; and
amines such as 1 -phenyl propanamine, Amphetamine, 1 -phenylethylthiuronium,
Tyrosinamide, Threo-l-(4-Nitrophenyl)-2-amino-l,3-propanediol, N-methyl-D-
glucamine, l-(4-Nitrophenyl)ethylamine. 1-phenylethylamine, 2-phenylglycinol. α -
fenchylamine. 2-Amino-l-butanol, L-Leucinamide, Galactamine, Brucine, Quinine.
Yohimbine, Cinchoniine, Ephedrine, strychnine. 1-Phenylbutylamine, 1-(1-
Naphthyl)ethylamine, 1 -Aminotetraline, 1-Aminoindane, 1 -(2-Naphthyl)ethylamine, 1-
Phenylethylhydroxylamine, Bis-(l-phenylethyl)amine, 1-Phenylethylisocyanate, N-
Benzyl-1 -phenylethylamine, 2-(Phenylmethoxy)cyclohexaneamine, 2-
(Phenylmethoxy)cyclopentaneamine, l-Methoxy-2-aminopropane, galanthamine, morphine, codeine, Nicotine, Nornicotine, Sparteine, veratraman, tubulosan, Vobasan, Spirosolane, tubocuraran, pancracine, rodiasine, Matridine, lythran, Lythrancine, Hasubanan, Kopsan, Formosana, R(+)-1-phenyl ethyl amine.(S)-Pregabalin obtained by this process is substantially free of (R)-Pregabalin.
10

The following examples are intended to illustrate particular embodiments of the invention, and are not intended to limit the specification, in any manner.
Example-1
Preparation of (1Z)-4-methyl -1- nitropent-1-ene (Formula-II)
150 g of isovalaraldehyde was charged into round bottom flask containing 93 ml of nitro methane in 1200 ml methanol solution. The mixture was cooled to -5 to 0°C and added sodium hydroxide solution (72 g NaOH flakes dissolved in 150 ml water) at -5 to 0°C over a period of 30 min. Maintain the reaction for 30 min, check reaction progress with TLC monitoring. After completion of reaction, quenched in to aqueous HC1 (1500 ml) slowly at 10-15 °C extracted the reaction mixture with 5 volumes of dichloromethane and evaporate the dichloromethane resulted 200 g of formula-II as crude material.
EXAMPLE-2
Preparation of 2, 2-dimethyl-5-(3-methyl-l-(nitro methyl)-l, 3-dioane-,6-dione (Formula-II)
150 g of (lZ)-4-methyl -1- nitropent-1-ene (from example-1) charged in to round bottom flask containing 750 ml of dichloromethane and 193 g meld rum's acid. Added 140 g of triethyl amine to the mixture at 20-30°C and maintained reaction at reflux for 3 hours with TLC monitoring. After completion of reaction wash the mixture with 300 ml water followed by 300 ml 5% aq.Hydrochloric acid .evaporate the solvent under reduced pressure would gave a solid residue. This residue was isolated with 150 ml isopropyl ether and dried the compound in air oven yielded 150 g of formula-IV.
EXAMPLE-3
Preparation of [3-methyl-l-(nitro methyl) butyl] malonic acid (Formula-V):
150 g of 2, 2-dimethyl-5-(3-methyl-l-(nitro methyl)-1, 3-dioane-, 6-dione (from example-2) was charged in to round bottom flask containing 750 ml con. Hydrochloric acid and heated to 60-65°C for 1-2 hours with TLC monitoring. Cooled to 0-10°C for 2hours.fiItered the compound and washed with 25 ml chilled water .Dry the material in oven at 60-65° gave 100 g of 5-methyl-3-(nitro methyl) hexanoic acid .
11

EXAMPLE-4
Preparation of 5-methyl-3-(nitro methyl) hexanoic acid (Formula-VI):
100 g of 3-methyl-l-(nitro methyl) butyl] malonic acid_[from example-3) was charged in to round bottom flask containing 500 ml con. Hydrochloric acid and heated to reflux for 6 hours. After completion of reaction cooled the mixture to 0-5°C for 2 hours. Filtered the compound on Buchner funnel and wash with chilled water followed by 100 ml hexane to get 60 g of formula-VI.
EXAMPLE-5
Preparation of racemic 3-(Amino methyl)-5-methyl hexanoic acid:
100 g of 5-methyl-3-(nitro methyl) hexanoic acid into round bottom flask containing 500 ml methanol, 10 g charcoal and l.0g iron(III) chloride hexa hydrate and heat to 50°C. Add 132.2 g of hydrazine hydrate drop wisely at 50-55°C.maintain the reaction mixture at reflux for 8 hours .Completion of reaction was monitored by TLC, cooled the mass to 25-30°C and filtered the charcoal and along with undissolved material .concentrate the methanol under vacuum to dryness to gave oil mass. This oily mass dissolved in 100 ml water and added this solution to 25 ml Con. Hydrochloric acid at 50-55°C.stir the reaction mixture to 50-55 °C for 1 hour and cooled to 0-5°C for 1 hour. Filtered the compound and wash with 25 ml chilled water. Dry the material at below 40°C under vacuum, gave 40 g of racemic pregabalin as white powder.
The present invention is particularly denoted by:
A. A process for the preparation of (S)-3-(Amino methyl)-5-methylhexanoic acid, the compound of formula I comprising:

12

i.) condensing isovaleraldehyde with nitro methane to form a compound of formula II

Formula-II
ii) reacting the compound of formula II with meldrum acid or a derivative thereof represented by a compound of formula III, to obtain a compound of formula IV,

wherein R1 and R2 are independently selected from the group consisting of C1-C4 straight or branched or cyclic alkyl groups
iii) converting the compound of formula IV to a compound of formula V by subjecting to hydrolysis,

iv) converting the compound of formula V to compound of formula VI by subjecting to
hydrolysis,
13

v). converting the compound of formula VI to (±) 3-(aminomthyl)-5-methylhexanoic acid.
vi) resolving (±) 3-(aminomthyl)-5-methylhexanoic acid to obtain (S) - 3-(aminomthyl)-5-methylhexanoic acid, a compound of formula I.

B. (S)-3-(Amino methyl)-5-methylhexanoic acid prepared by a process as defined in A
above.
C. The process as defined in A above, wherein hydrolysis is done using an acid or base
D. The process as defined in A above, wherein the compound of formula II is reacted
with a compound of formula III wherein R1 - CH3, R2 = CH3 to obtain a compound of
formula IV, wherein R1 =CH3 and R2 = CH3.
E. A compound of formula IV.
14

F. A compound as defined in claim E, above wherein R1 = CH3 and R2 = CH;

Formula IVA
G. A process for the preparation of (S)-3-(Amino methyl)-5-methylhexanoic acid, the compound of formula I comprising:

i) converting the compound of formula IV to a compound of formula V by subjecting to hydrolysis,
15

ii) converting the compound of formula V to compound of formula VI by subjecting to
decarboxylation,

iii). converting the compound of formula VI to (±) 3-(aminomthyl)-5-methylhexanoic acid.
iv) resolving (±) 3-(aminomthyl)-5-methylhexanoic acid to obtain (S) - 3-(aminomthyl)-
5-methylhexanoic acid, a compound of formula I.

H. A process for the preparation of compound of formula IV as claimed in claim E comprising
16

i.) condensing isovaleraldehyde with nitro methane to form a compound of formula II

ii) reacting the compound of formula II with meldrum acid or a derivative thereof represented by a compound of formula III, to obtain a compound of formula IV,

wherein R1 and R2 are defined as above.
I. A compound of formula V.

J. A process for the preparation of (S)-3-(Amino methyl)-5-methylhexanoic acid, the compound of formula I comprising:

17

Formula I
i) converting the compound of formula V to compound of formula VI by subjecting to decarboxylation,

ii). converting the compound of formula VI to (±) 3-(aminomthyl)-5-methylhexanoic acid.
iii) resolving (±) 3-(aminomthyl)-5-methylhexanoic acid to obtain (S) - 3-(aminomthyl)-5-methylhexanoic acid, a compound of formula I.

H. A process for the preparation of compound of formula V as claimed in claim I comprising
i.) condensing isovaleraldehyde with nitro methane to form a compound of formula II

18

ii) reacting the compound of formula II with meldrum acid or a derivative thereof represented by a compound of formula III, to obtain a compound of formula IV,

wherein R1 and R2 are defined above
iii) converting the compound of formula IV to a compound of formula V by subjecting to hydrolysis,

19

ABSTRACT:
The present invention provides novel intermediates of Pregabalin and process for their preparation. The present invention also provides for the preparation of (S)-Pregabalin or a pharmaceutically acceptable salt or solvate thereof using the intermediates.
20