FIELD OF THE INVENTION
The present invention relates to a process for preparing substituted acrylic acid ester
and the use thereof to prepare (S)-3-(aminomethyl)-5-methylhexanoic acid generically
known as pregabalin.
BACKGROUND OF THE INVENTION
Pregabalin, (S)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the
following chemical structure of formula I

Formula I is also known as y-amino butyric acid or (S)-3-isobutyl GABA. Pregabalin,
marketed under the name Lyrica®, has been found to activate GAD (L-glutamic acid
decarboxylase). Pregabalin has a dose dependent protective effect on-seizure, and is a
CNS-active compound. 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 brain synapses. Pregabalin has
analgesic, anti-convulsant, and anxiolytic activity.
Pregabalin was first reported in US 6197819 along with its chiral syntheses another
process for preparing pregabalin was reported in US 5637767, which describes the
condensation of isovaleraldehyde with diethyl malonate. The 2-carboxy-2-alkanoic acid
thus formed was reacted with a cyanide source, specifically potassium cyanide. The
cyano diester product was decarboxylated by heating with sodium chloride in dimethyl
sulfoxide and water and hydrolyzed using potassium hydroxide using potassium
hydroxide to give potassium salt of a cyano acid. This hydrogenated in situ using Raney
nickel and neutralized with hydrochloric acid to give racemic pregabalin further the
racemic pregabalin was resolved with (S)-mandelic acid. A disadvantage of this process
is the (S)-mandelic acid is expensive and the yield of the resolved enantiomer leads to
very less.

US 7141695 discloses a process for the preparation of racemic pregabalin
hydrochloride. This process involved a Wittig-Horner reaction between isovaleraldehyde
and triethylphosphonoacetate to give ethyl 2-alkenoate. Addition of nitromethane using
tetrabutyl ammonium fluoride followed by hydrogenation using Raney nickel afforded the
lactam, which was hydrolyzed using hydrochloric acid to form the hydrochloride salt of
the amino acid. A disadvantage of this process, the use of alkali metal hydrides for the
preparation of substituted acrylic acid esters in the first reaction stage, which makes it
necessary to use absolute organic solvents and to perform the procedure under
protective gas and the formation of hydrochloride salt of racemic pregabalin necessitates
an aqueous work-up, which leads to poor yields and lengthy workup procedures.
OBJECT OF THE INVENTION
One of the object of the present invention is to provide a process for preparing the
substituted acrylic acid ester.
Another object of the present invention is use of the substituted acrylic acid ester in the
preparation of (S)-3-(aminomethyl)-5-methylhexanoic acid.
A further object of the present invention is to provide a commercial viable synthetic
process for (S)-3-(aminomethyl)-5-methylhexanoic acid.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing the substituted acrylic acid ester

The process for preparing (S)-3-(aminomethyl)-5-methylhexanoic acid, comprises the
steps of:
i) condensing isovaleraldehyde with an trialkylphosphonoester (a) in presence of base
to form a (2E)-5-methyl-hex-2-ene-carboxylic acid alkyl ester (b);

ii) reacting said (2E)-5-methyl-hex-2-ene-carboxylic acid alkyl ester (b) with a cyanide
source to form a 3-cyano-5-methylhexanoic acid alkyl ester (c),
iii) hydrolyzing said 3-cyano-5-methylhexanoic acid, alkyl ester (c) with an alkali or
alkaline earth metal hydroxide to form an alkali or alkali earth metal carboxylate salt
(d) which is then hydrogenated to form (+)-3-(aminomethyl)-5-methylhexanoic acid
(e);
iv) treating said (+)-3-(aminomethyl)-5-methylhexanoic acid (e) with (L)-dibenzoyl
tartaric acid in ketone, an alcohol, or a mixture of ketone and an alcohol;
v) heating the reaction mixture at 40° C to 60° C and cooling to obtain precipitate of
dibenzoyl tartrate salt of (S)-3-(aminomethyl)-5-methylhexanoic acid (f);
vi) treating said dibenzoyl tartrate salt of (S)-3-(aminomethyl)-5-methyl-hexanoic acid
(V) into a polar protic solvent or a mixture of polar aprotic solvent and water with a
base; and
vii) isolating (S)-3-(aminomethyl)-5-methylhexanoic acid (g).
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided an improved process for
preparation of (S)-3-(aminomethyl)-5-methylhexanoic acid as depicted in scheme I:


The isovaleraldehyde reacted with a trialkyl phosphonoester (a) in the presence of alkali
metal carbonate, alkali metal hydroxide, to form the compound (b) 5-methyl-hex-2-ene
carboxylic acid alkyl ester. The trialkyl phosphonoester used for the purpose of the
invention are selected from the group of compound wherein R is methyl, ethyl, butyl
group preferably ethyl group. The alkali metal carbonate used for preparation of
compound (b) are selected from sodium carbonate, sodium bicarbonate, potassium
carbonate preferably potassium carbonate. The alkali metal hydroxide used for
preparation of compound (b) are selected from sodium hydroxide, potassium hydroxide
preferably sodium hydroxide.

The compound (b) reacted with a cyanide source in polar amide solvent, to form the
compound (c) 3-cyano-5-methylhexanoic acid alkylester. The group of compound
wherein R is methyl, ethyl, butyl group preferably ethyl group.
The Examples of suitable cyanide sources include, but not limited to hydrogen cyanide,
potassium cyanide, sodium cyanide. The polar amide solvent used for preparation of
compound (c) are selected from N,N'-dimethylformamide, N,N'-dimethylacetamide,
preferably N,N'-dimethylformamide. This reaction carried out in the presence of
ammonium chloride and then acidified with acetic acid, hydrochloric acid and nitric acid,
preferably acetic acid. The compound of the general formula (c).

The compound (c) can be hydrolyzed to form the compound (d) with an alkali metal
hydroxide or an alkaline earth metal hydroxide to form an alkali or alkaline earth metal
carboxylate salt. The alkali or alkaline earth metal hydroxide can be any alkali or alkaline
earth metal hydroxide known to those skilled in the art. Examples of suitable alkaline

earth metal hydroxides include calcium hydroxide and magnesium hydroxide. The
reaction usually takes place in a suitable polar protic solvent such as water or a mixture
of water and polar protic solvent such as methanol, ethanol, or isopropanol.

The carboxylate salt of the general formula (d) can be reduced to give the alkali or
alkaline earth metal salt of (+)-3-(aminomethyl)-5-methylhexanoic acid of the general
formula (e). The carboxylate salt can be protonated with mineral acids or carboxylic
acids to give the carboxylic acid and then the nitrite group of the carboxylic acid can be
reduced. Conversely, the nitrile group of the carboxylate salt can be reduced, and
subsequently protonated to form the carboxylic acid. The salt can be treated with mineral
acids or carboxylic acids to give (+)-3-(aminomethyl)-5-methylhexanoic acid. Those
skilled in the art are familiar with the reduction of nitrile functional groups. One common
method of reducing a nitrile uses a hydrogenation catalyst, such as sponge nickel, in the
presence of hydrogen. Other catalysts include palladium, platinum, rhodium, cobalt, and
nickel. In general, the reaction is run in a solvent system such as a mixture of water and
an aprotic solvent.

The racemic product (+)-3-(aminomethyl)-5-methylhexanoic acid thus obtained can be
resolved by the methods known in the art. One of such method for resolution of (+)-3-
(aminomethyl)-5-methylhexanoic acid by selective crystallization with (L)-dibenzoyl
tartaric acid. (+)-3-(aminomethyl)-5-methyl -hexanoic acid and (L)-dibenzoyl tartaric acid
can be combined in a solvent such as ketone, an alcohol or mixture of ketone and an
alcohol to form a salt. Examples of suitable ketone includes acetone and examples of
suitable alcohols include methanol, ethanol, isopropanol, butanoland the like. In general,
the S,S salt precipitates from the solution, and the diastereomers, the R,S salt, stay in

solution. It forms dibenzoyl tartrate salt of 3-(aminomethyl)-5-methylhexanoic acid of the
general formula (f)

It is also contemplated that the compounds of the present method can be found or
isolated in the form of hydrates or solvates, which are considered to fall within the scope
of the present invention.
The examples below are intended to illustrate specific embodiments of the invention and
are not intended to limit the scope of the specification, including the claims, in any
manner.
EXAMPLE
Preparation of (2E)-5-methyl-hex-2-ene carboxylic acid ethyl ester
100 gm of isovaleraldehyde and 312.5 gm of triethyl phosphonoacetate was taken into
flask. The Aqueous potassium carbonate solution (401.3 gm of potassium carbonate
dissolved in 800 ml DM water) was added and heated at 70° C to 75°C for 6 to 8 hrs.
After completion of reaction, the reaction mixture was cooled at room temperature for 20
mins to 30 mins. The mixture of ethyl acetate and water was added and stirred for 10
mins to 15 mins. The aqueous layer was separated and extracted twice with ethyl
acetate. The combined ethyl acetate layer (organic layer) was washed twice with water

and dried over sodium sulphate. Concentration under reduced pressure at 50° C to 55°
C gave 150 gm (2E)-5-methyl-hex-2-ene carboxylic acid ethyl ester.
Preparation of 3-cyano-5-methylhexanoic acid ethyl ester
In a clean flask 2.0 L N,N'-dimethylformamide was taken and 100 gm of (2E)-5-methyl-
hex-2-ene carboxylic acid ethyl ester was added. In the above reaction mixture, 51.4 gm
ammonium chloride and 83.2 gm potassium cyanide was added. The above reaction
mixture was diluted with 200 ml water and heated at 95° C to 100° C for 6 to 8 hrs. The
reaction mixture was cooled at 10° C to 15° C for 15 mins to 20 mins. The reaction
mixture was neutralized using acetic acid and concentrated it. The concentrated residue
was diluted with 1.0 L water and 1.0 L dichloromethane and it was stirred for 15 mins to
20 mins. The aqueous layer was separated and extracted with 1.0 L dichloromethane.
The combined dichloromethane layer was twice washed with water. Concentration under
reduced pressure at 70° C to 75° C gave 95 gm 3-cyano-5-methylhexanoic acid ethyl
ester.
Preparation of (+)-3-(aminomethyl)-5-methylhexanoic acid
In a flask 100 gm 3-cyano-5-methylhexanoic acid ethyl ester was dissolved in 140 ml
methanol and cooled at 0° C to 5° C for 15 mins to 20 mins. Potassium hydroxide
solution (58 gm potassium hydroxide was dissolved in 160 ml water) was added and
stirred at 25° C to 30° C for 2 hrs. The above reaction mixture was treated with Raney
nickel (50 gm Raney nickel was dissolved in mixture of 50 ml water and 60 ml methanol)
and hydrogenated at 10 kg to 11 kg pressure. After completion of reaction, the reaction
mixture was filtered, washed with 50 ml methanol and cooled at 0° C to 5° C for 15 mins
to 30 mins. The pH was adjusted to 7.5 to 8 using acetic acid. The reaction mixture was
filtered and twice washed with 100 ml isopropanol. This (+)-3-(aminomethyl)-5-
methylhexanoic acid was recrystallized with isopropanol and water. This product yield
amounted to 32 gm.
Preparation of dibenzoyl tartrate salt of 3-(aminomethyl)-5-methylhexanoic acid
100 gm (+)-3-(aminomethyl)-5-methylhexanoic acid was dissolved in 400 ml methanol;
(L)-dibenzoyl tartaric acid solution (240 gm (L)-dibenzoyl tartaric acid was dissolved in
2500 ml acetone) was added and heated at 50° C to 55° C for half an hour. It was
cooled to 25° C to 30° C for 60 mins to 90 mins; 0.01 gm of dibenzoyl tartrate salt of 3-

(aminomethyl)-5-methylhexanoic acid was seeded and stirred for 4 hrs. The salt was
filtered and washed with 200 ml acetone. The salt was dried under reduced pressure till
the water content not more than 2.0%. 120 gm of solid was obtained.
Preparation of (S)-3-(aminomethyl)-5-methylhexanoic acid
100 gm dibenzoyl tartrate salt of 3-(aminomethyl)-5-methylhexanoic acid was dissolved
in mixture of 928 ml tetrahydrofuran and 72 ml water and stirred to get clear solution.
The pH was neutralized (pH 7 to 7.5) using aqueous ammonia and it was stirred at 25° C
to 30° C for 2 hrs. The solid was filtered and washed with 100 ml isopropanol. The solid
was dried under reduced pressure till the loss of drying not more than 3.0%. The product
was recrystallized with isopropanol and water. 20 gm of solid was obtained.

We Claim
1. A process for preparing (S)-3-(aminomethyl)-5-methylhexanoic acid, comprising the
steps of:
i) condensing isovaleraldehyde with an trialkylphosphonoester (a) in presence of base
to form a (2E)-5-methyl-hex-2-ene-carboxylic acid alkyl ester (b); ii) reacting said (2E)-5-
methyl-hex-2-ene-carboxylic acid alkyl ester (b) with a cyanide source to form a 3-cyano-
5-methylhexanoic acid alkyl ester (c),
iii) hydrolyzing said 3-cyano-5-methylhexanoic acid, alkyl ester (c) with an alkali or
alkaline earth metal hydroxide to form an alkali or alkali earth metal carboxylate salt (d)
which is then hydrogenated to form (+)-3-(aminomethyl)-5-methylhexanoic acid (e); iv)
treating said (+)-3-(aminomethyl)-5-methylhexanoic acid (e) with (L)-dibenzoyl tartaric
acid in ketone, an alcohol, or a mixture of ketone and an alcohol; v) heating the reaction
mixture at 40° C to 60° C and cooling to obtain precipitate of dibenzoyl tartrate salt of
(S)-3-(aminomethyl)-5-methylhexanoic acid (f);
vi) treating said dibenzoyl tartrate salt of (S)-3-(aminomethyl)-5-methyl-hexanoic acid
(V) into a polar protic solvent or a mixture of polar aprotic solvent and water with a base;
and
vii) isolating (S)-3-(aminomethyl)-5-methylhexanoic acid (g).
2 A process as claimed in claim 1 wherein step (i) said trialkylphosphonoester is
selected from triethylphosphonoacetate, trimethylphosphonoacetate and
tributylphosphonoacetate, preferably triethylphosphonoacetate.
3 A process as claimed in claim 1 wherein in step (ii) said cyanide source is selected
from hydrogen cyanide, or an alkali metal or alkaline earth metal cyanide, such as
sodium cyanide, potassium cyanide, or magnesium cyanide.
4 A process as claimed in claim 1 wherein in step (iii), said alkali or alkaline earth
metal hydroxide is potassium hydroxide.
5 A process as claimed in claim 1 wherein in step (iv), said ketone is acetone.

6 A process as claimed in claim 1 wherein in step (iv), said alcohol is methanol.
7 A process as claimed in claim 1 wherein in step (vi), said aprotic solvent is
tetrahydrofuran.
8 A process as claimed in claim 1 wherein in step (vi), said base is ammonia.
9 A process for preparing (S)-3-(aminomethyl)-5-methylhexanoic acid, comprising the
steps of:
i) combining (+)-3-(aminomethyl)-5-methylhexanoic acid with (L)-Dibenzoyl -tartaric
acid in water, ketone, an alcohol, or a mixture of ketone and alcohol;
ii) allowing a precipitate to form;
iii) the precipitate into a polar aprotic solvent or a mixture of polar aprotic solvent and
water to form a slurry; and
iv) treating with a base;
v) collecting the solid from the slurry.
10 The process of claim 9 wherein in step (i) (+)-3-(aminomethyl)-5-methylhexanoic -
acid and L-dibenzoyl tartaric acid are combined in acetone and methanol.
11 The process of claim 9 wherein in step (iii) the polar aprotic solvent is
tetrahydrofuran.
12 The process of claim 9 wherein in step (iv) the base is ammonia.

The present invention relates to a process for preparing substituted acrylic acid ester
and the use thereof to prepare (S)-3-(aminomethyl)-5-methylhexanoic acid generically
known as pregabalin.