Field of the Invention:
The invention relates to novel, cost effective, green and industrial process for
synthesis of (S)-pregabalin.
Background of the Invention:
(S)-3-(Aminomethyl)-5-methylhexanoic acid [CAS No. 148553-50-8], which is also
known as β-isobutyl-γ- aminobutyric acid, isobutyl-GABA, or pregabalin (I) is a potent
anticonvulsant. As discussed in U.S. Patent No. 5,563,175, pregabalin exhibits anti-
seizure activity and is found to be useful for treatment of various other conditions, like
pain, fibromyalgia, physiological conditions associated with psychomotor stimulants,
inflammation, gastrointestinal damage, insomnia, alcoholism and various psychiatric
disorders, including mania and bipolar disorder. (U.S. Patent No. 6,242,488; U.S.
Patent No. 6,326,374; U.S. Patent No. 6,001,876; U.S. Patent No. 6,194,459; U.S.
Patent No. 6, 329, 429; U.S. Patent No. 6, 127,418; U.S. Patent No. 6,426, 368; U.S.
Patent No. 6,306,910; U.S. Patent No. 6,359,005).

(S)-3-Cyano-5-methyl-hexanoic acid (II) is one of the key intermediates for the
synthesis of (S)-pregabalin. A number of approaches for synthesis of racemic as well
as enatiomerically pure compound (II) are reported in the literature. However,
majority of processes suffer from the drawback of using potassium cyanide or its
equivalent during synthesis, thus rendering the process not eco-friendly and
environmentally benign.

Our previous PCT application number PCT/IN2010/000440 dated 28 June 2010
entitled "Improved synthesis of optically pure (S) - 3-cyano-5-methyl-hexanoic acid

alkyl ester, an intermediate of (S)-pregabalin", emphasized on the novel, cost
effective, eco-friendly, industrial process for synthesis of (RS) - 3-cyano-5-methyl-
hexanoic acid ethyl ester without using any harmful, hazardous and poisonous
chemicals. Further, (RS) - 3-cyano-5-methyl-hexanoic acid ethyl ester was resolved
through lipase catalyzed kinetic resolution to obtain (S) - 3-cyano-5-methyl-hexanoic
acid ethyl ester, which was hydrolyzed to obtain (S) - 3-cyano-5-methyl-hexanoic
acid and subsequently converted to S-pregabalin, disclosers of which, including prior
art are incorporated herein by reference.
It is evident from prior art published before our PCT application PCT/IN2010/000440
dated 28 June 2010 that the crucial feature in the manufacture of pregabalin is the
synthesis of the key intermediate "(S) - 3-cyano-5-methyl-hexanoic acid" and the
processes reported in the literature for its synthesis are not very attractive in view of
cost, use of undesirable toxic reagents and eco-hazardous operations.
In the present invention, further improvement in the process disclosed in PCT
application number PCT/IN2010/000440 dated 28 June 2010 for synthesis of (RS) -
3-cyano-5-methyl-hexanoic acid ethyl ester has been carried out with the object of
improving the "greenness" of the process, energy consumption, and solvent usage,
all of which have direct implications on the economic aspect of the process by
reducing its over all cost.
In addition to above, a novel process for resolution of (RS) - 3-cyano-5-methyl-
hexanoic acid through diastereomeric salt formation to obtain (S) - 3-cyano-5-methyl-
hexanoic acid is developed. Furthermore, recovery/reuse of chiral resolving agent
was developed to improve the process efficiency, atom economy, carbon efficiency,
and E-factor, thereby significantly reducing the overall cost for the synthesis of the
title compound.
Thus, this invention provides an improved, highly cost effective, operation friendly,
"green" process for the title compound, thus satisfying almost all the criteria outlined
for "green chemistry" (Green Chemistry: Theory and Practice Paul T. Anastas and
John C. Warner)
This invention relates to;
1) Synthesis of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII); and diethyl 2-
cyano-2-isobutylsuccinate (X) in presence of cesium carbonate and without

solvent, thus improving the "greenness" and efficiency of the process for
synthesis of title compound.
2) Improved, cost effective and user friendly process for synthesis of (RS)-3-
cyano-5-methyl hexanoic acid ethyl ester (XI) from diethyl 2-cyano-2-
isobutylsuccinate (X) in presence of cesium chloride and dimethyl sulfoxide,
thus improving the "greenness" and efficiency of the process for synthesis of
title compound.
3) Improved, cost effective and user friendly process for synthesis of (RS)-3-
cyano-5-methyl hexanoic acid ethyl ester (XI) from diethyl 2-cyano-2-
isobutylsuccinate (X) in presence of cesium carbonate/thiol and
dimethylformamide, thus improving efficiency of the process for synthesis of
title compound.
4) Easy to operate at industrial scale process for synthesis of (RS)-3-cyano-5-
methyl hexanoic acid ethyl ester (XI) from 4-ethyl 1-methyl 2-cyano-2-
isobutylsuccinate (VII), thus improving the "energy consumption" and "atom
economy" of the process for synthesis of title compound.
5) Synthesis of a novel compound 2-cyano-2-isobutylsuccinic acid (XVI) from 4-
ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII) or from diethyl 2-cyano-2-
isobutylsuccinate (X) though a base catalyzed hydrolysis.
6) Efficient process for conversion of (RS)-2-cyano-2-isobutylsuccinic acid (XVI)
to (RS)-3-cyano-5-methyl hexanoic acid (XII) by acid catalyzed
decarboxylation.
7) Resolution of (RS)-3-cyano-5-methyl hexanoic acid (XII) to obtain
enantiomerically pure (S)-3-cyano-5-methyl hexanoic acid (II) through
diastereomeric salt formation with cinchonidine (XIII).
8) Synthesis of (S)-Pregabalin from (S)-3-cyano-5-methyl hexanoic acid (II) via
hydrogenation in presence of metal catalysts from group VIM such as Nickel
and Platinum.
9) Recovery and reusability of resolving agent i.e. cinchonidine (XIII)

Objects of the Invention:
The object of this invention is to provide resolution of (RS) - 3-cyano-5-methyl-
hexanoic acid (XII) through diastereomeric salt formation with cinchonidine (XIII) to
obtain optically pure (S) - 3-cyano-5-methyl-hexanoic acid (II), having excellent yield
and high optical purity (99 % ee) and further conversion of it to (S)-pregabalin (I) in
high yield and high optical purity (>99 % ee).
Yet another object of the present invention is synthesis of the novel compound 4-
ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII) through a novel method and further
conversion of it to (S)-pregabalin (I).
Yet another object of the present invention is synthesis of diethyl 2-cyano-2-
isobutylsuccinate (X) through solvent-free, green, eco-friendly and novel method.
Yet another object of the present invention is enhancement in the rate of
decarboxylation of diethyl 2-cyano-2-isobutylsuccinate (X) to obtain (RS)-3-cyano-5-
methyl hexanoic acid ethyl ester (XI).
Yet another object of the present invention is to investigate the effect of carbon chain
length of the substrates on the decarboxylation. Decarboxylation of 4-ethyl 1-methyl
2-cyano-2-isobutylsuccinate (VII) to obtain (RS)-3-cyano-5-methyl hexanoic acid
ethyl ester (XI) requires the reaction temperature around 140 °C whereas, for
decarboxylation of diethyl 2-cyano-2-isobutylsuccinate (X) to obtain (RS)-3-cyano-5-
methyl hexanoic acid ethyl ester (XI) requires the reaction temperature around 170
°C.
Yet another object of the present invention is synthesis of the novel compound 2-
cyano-2-isobutylsuccinic acid (XVI) through a novel method and further conversion of
it to (S) - 3-cyano-5-methyl-hexanoic acid (II)
An also important object of the present invention is to provide a process for recovery
of resolving agent i.e. cinchonidine (XIII) through basification and reusability of
recovered cinchonidine (XIII), thereby improving the atom economy, process
efficiency and hence cost.
Summary of the invention:
The present invention is directed towards synthesis of (S)-Pregabalin. The invention
is summarized below in scheme A and scheme B.

In scheme A, detailed schematic representations of improved process for synthesis
of (RS)-3-cyano-5-methyl hexanoic acid (XII) and further conversion to (S)-pregabalin
(I) are given.
In scheme B, detailed schematic representations of resolution of (RS)-3-cyano-5-
methyl hexanoic acid (XII) through diastereomeric salt formation with cinchonidine
(XIII) to obtain (S)-3-cyano-5-methyl hexanoic acid (II) and method for recovery &
reusability of cinchonidine (XIII) are given.

A) The processes for preparation of (S)-pregabalin (I) from (S)-3-cyano-5-
methyl hexanoic acid (II).
This has been achieved through two routes:
Route I: Compound (V) was prepared by condensation of 2-methyl-propionaldehyde
(IV) with cyano acetic acid methyl ester (III) in presence of cesium acetate, followed
by hydrogenation using palladium on charcoal catalyst. Compound (V) was further
reacted with haloacetic acid ethyl ester (VI) in presence of cesium carbonate without
solvent or optionally in an organic solvent such as dimethyl sulfoxide to give 4-ethyl
1-methyl 2-cyano-2-isobutylsuccinate (VII). Compound (VII) was then treated with
cesium chloride in organic solvent such as dimethyl sulfoxide to get 3-cyano-5-
methyl-hexanoic acid ethyl ester (XI), which was further converted to (RS)-3-cyano-5-
methyl-hexanoic acid (XII) through hydrolysis with lithium hydroxide.
Alternatively, compound (VII) was converted into compound (XVI) through base
catalyzed hydrolysis and which was further decarboxylated to give (f?S)-3-cyano-5-
methyl-hexanoic acid (XII) in presence of mineral acid such as sulfuric acid in organic
solvent such as ethyl acetate.
Racemic 3-cyano-5-methyl-hexanoic acid (XII) was resolved through diastereomeric
salt formation with cinchonidine (XIII) to obtain (S)-3-cyano-5-methyl-hexanoic acid
(II). Compound (II) was converted to compound (I) through hydrogenation in
presence of Raney Nickel.
Route II: Compound (IX) was prepared by condensation of 2-methyl-
propionaldehyde (IV) with cyano acetic acid ethyl ester (VIII) in presence of cesium
acetate, followed by hydrogenation using palladium on charcoal catalyst. Compound
(IX) was further reacted with halo acetic acid ethyl ester (VI) in presence of cesium
carbonate without any solvent or optionally in an organic solvent such as dimethyl
sulfoxide to give diethyl 2-cyano-2-isobutylsuccinate (X). Compound (X) was then
treated with cesium carbonate and thiophenol in organic solvent such as N,N-
dimethylformamide to get 3-cyano-5-methyl-hexanoic acid ethyl ester (XI) or
alternatively, compound (XI) was also obtained through decarboxylation in organic
solvent such as dimethylsulfoxide of diethyl 2-cyano-2-isobutylsuccinate (X) in
presence of cesium chloride, which was further converted to 3-cyano-5-methyl-
hexanoic acid (XII) through base catalyzed hydrolysis.

Alternatively, compound (X) was also converted into compound (XVI) through base
catalyzed hydrolysis, which was further decarboxylated to give (RS)-3-cyano-5-
methyl-hexanoic acid (XII) in presence of mineral acid and in organic solvent such as
ethyl acetate.
(RS)-3-cyano-5-methyl-hexanoic acid (XII) was resolved through diastereomeric salt
formation with cinchonidine (XIII) to obtain (S) 3-cyano-5-methyl-hexanoic acid (II).
Compound (II) was converted to compound (I) through hydrogenation in presence of
Raney Nickel.
B) The processes for resolution of (RS)-3-cyano-5-methyl-hexanoic acid (XII)
to obtain (S)-3-cyano-5-methyl-hexanoic acid (II) through diastereomeric
salt formation with cinchonidine (XIII).
Resolution of racemic 3-cyano-5-methyl-hexanoic acid (XII) through diastereomeric
salt formation with cinchonidine (XIII) is depicted in scheme B. (RS)-3-cyano-5-
methyl-hexanoic acid (XII) was refluxed with cinchonidine (XIII) in organic solvents
such as ethyl acetate. During the reaction (S)-3-cyano-5-methyl-hexanoic acid salt of
cinchonidine (XIV) precipitated out and (R)-3-cyano-5-methyl-hexanoic acid salt of
cinchonidine (XV) remained soluble in ethyl acetate. (S)-3-cyano-5-methyl-hexanoic
acid (II) was obtained from (S)-3-cyano-5-methyl-hexanoic acid salt of cinchonidine
(XIV) via decomposition in biphasic mixture of aqueous mineral acid such as dilute
aqueous hydrochloric acid and organic solvent such as ethyl acetate,
dichloromethane, methyl fert-butyl ether; preferably ethyl acetate. Cinchonidine (XIII)
from aqueous acid solution was also recovered through basification and reused to
improve the over all atom economy and process efficiency.
The invention can be briefly described as follows:
First aspect of the invention is a process for synthesis of pregabalin (I)

from cyano acetic acid alkyl ester of formula (A)


Wherein,
R = CH3: Compound III
R = C2H5: Compound VIM
comprising,
a) condensation of 2-methyl-propionaldehyde (IV) with cyano acetic acid alkyl ester
(A) in presence of organic or inorganic base such as piperidinium acetate, cesium
acetate, and further hydrogenation using noble metal catalyst such as platinum
oxide, palladium on carbon palladium hydroxide on carbon and also with Raney
nickel in polar solvent such as methanol, ethanol, water, 1,4-dioxane,
tetrahydrofuran, dimethoxy ethane and diglyme under hydrogen pressure of about 1
kg/cm2 to 5 kg/cm2 with subsequent isolation of the product 2-cyano-4-methyl-
pentanoic acid alkyl ester (B) in solution form from the catalyst by filtration;

b) reaction of compound of formula (B) with halo acetic acid ethyl ester (VI),
wherein halo group includes chloro, bromo and iodo, in presence of base such as
sodium carbonate, potassium carbonate, cesium carbonate, preferably cesium
carbonate without solvent or in an organic solvent selected from N, N-dimethyl
formamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and dimethoxy
ethane, preferably N, N-dimethyl formamide and dimethyl sulfoxide at
temperature of about 10 to 90 °C to give 4-ethyl 1-alkyl-2-cyano-2-
isobutylsuccinate (C);


c) reaction of compound (C) with alkalimetal chloride such as cesium chloride,
potassium chloride or sodium chloride in an organic solvent such as dimethyl
sulfoxide at temperature of about 130°C to 180°C OR reaction of compound of
formula (C) with cesium carbonate alongwith thiol at temperature of about 130 -
150°C to get (RS)-3-cyano-5-methyl-hexanoic acid ethyl ester (XI);

d) hydrolysis of compound (XI) in presence of base such as lithium hydroxide,
potassium hydroxide or sodium hydroxide, preferably with lithium hydroxide
at temperature of about 20 to 80 °C to get (RS)-3-cyano-5-methyl-hexanoic
acid (XII);

e) treatment of compound (XII) with cinchonidine(XIII) in presence of organic
solvent such as methanol, ethanol, 1,4-dioxane, ethyl acetate,
tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxy ethane and diglyme at
temperature of about 20°C to 80°C to precipitate out (S) 3-cyano-5-
methylhexanoic acid salt of cinchonidine (XIV), followed by separation of
compound (XIV) through known separation techniques such as filtration,
centrifugation, sedimentation, followed by optional purification of (S)-3-cyano-
5-methylhexanoic acid salt of cinchonidine (XIV) in ethyl acetate or through
re-salt formation;


f) treatment of (S) 3-cyano-5-methylhexanoic acid salt of cinchonidine (XIV) with
triphasic mixture of ethyl acetate: dilute hydrochloric acid (1:1) at room
temperature to obtain (S)-3-cyano-5-methylhexanoic acid (II) from ethyl
acetate layer optionally accompanied with recovery of cinchonidine (XIII) from
aqueous phase through basification with sodium hydroxide, potassium
hydroxide;

g) hydrogenation of optically pure (S) - 3-cyano-5-methyl-hexanoic acid (II) in
presence of Raney Nickel.

such that at each step the intermediates were optionally isolated and purified with
suitable processes.

Another aspect of the invention is a process for synthesis of pregabalin (I)

from cyano acetic acid alkyl ester of formula (A)

Wherein,
R = CH3: Compound III
R = C2H5 : Compound VIM
comprising,
a) condensation of 2-methyl-propionaldehyde (IV) with cyano acetic acid alkyl ester
(A) in presence of organic or inorganic base such as piperidinium acetate, cesium
acetate, and further hydrogenation using noble metal catalyst such as platinum
oxide, palladium on carbon, palladium hydroxide on carbon and also with Raney
nickel in polar solvent such as methanol, ethanol, water, 1,4-dioxane,
tetrahydrofuran, dimethoxy ethane and diglyme under hydrogen pressure of about 1
kg/cm2 to 5 kg/cm2 with subsequent isolation of the product 2-cyano-4-methyl-
pentanoic acid alkyl ester (B) in solution form from the catalyst by filtration;

b) reaction of compound of formula (B) with halo acetic acid ethyl ester (VI),
wherein halo group includes chloro, bromo and iodo, in presence of base such as
sodium carbonate, potassium carbonate, cesium carbonate, preferably cesium
carbonate without solvent or in an organic solvent selected from N, A/-dimethyl
formamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and dimethoxy ethane,

preferably N, N-dimethyl formamide and dimethyl sulfoxide at temperature of about
10 to 90 °C to give 4-ethyl 1-alkyl-2-cyano-2-isobutylsuccinate (C);

c) hydrolysis of compound (C) in presence of base such as lithium hydroxide,
potassium hydroxide or sodium hydroxide, preferably with lithium hydroxide
at temperature of about 20 to 80 °C, preferably at 65 to 70 °C to get 2-cyano-
2-isobutylsuccinic acid (XVI)

d) compound (XVI) was decarboxylated in presence of mineral acid such as
sulfuric acid in organic solvent such as ethyl acetate to obtain compound (XII)
at about temperature 70 to 80 °C.

e) treatment of compound (XII) with cinchonidine(XIII) in presence of organic
solvent such as methanol, ethanol, 1,4-dioxane, ethyl acetate,
tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxy ethane and diglyme at
temperature of about 20°C to 80°C to precipitate out (S) 3-cyano-5-
methylhexanoic acid salt of cinchonidine (XIV), followed by separation of
compound (XIV) through known separation techniques such as filtration,
centrifugation, sedimentation, followed by optional purification of (S)-3-cyano-

5-methylhexanoic acid salt of cinchonidine (XIV) in ethyl acetate or through
re-salt formation;

f) treatment of (S) 3-cyano-5-methylhexanoic acid salt of cinchonidine (XIV) with
biphasic mixture of ethyl acetate: dilute hydrochloric acid (1:1) at room
temperature to obtain (S)-3-cyano-5-methylhexanoic acid (II) from ethyl
acetate layer optionally accompanied with recovery of cinchonidine (XIII) from
aqueous phase through basification with sodium hydroxide, potassium
hydroxide;

g) hydrogenation of optically pure (S) - 3-cyano-5-methyl-hexanoic acid (II) in
presence of Raney Nickel.


such that at each step the intermediates were optionally isolated and purified with
suitable processes.
Yet another aspect of the invention is a process for synthesis of pregabalin (I)

from (RS)-3-cyano-5-methyl-hexanoic acid (XII);

comprising;
a) treatment of compound (XII) with cinchonidine(XIII) in presence of organic
solvent such as methanol, ethanol, 1,4-dioxane, ethyl acetate,
tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxy ethane and diglyme at
temperature of about 20°C to 80°C to precipitate out (S) 3-cyano-5-
methylhexanoic acid salt of cinchonidine (XIV), followed by separation of
compound (XIV) through known separation techniques such as filtration,
centrifugation, sedimentation, followed by optional purification of (S)-3-cyano-
5-methylhexanoic acid salt of cinchonidine (XIV) in ethyl acetate or through
re-salt formation;


b) treatment of (S) 3-cyano-5-methylhexanoic acid salt of cinchonidine (XIV) with
biphasic mixture of ethyl acetate: dilute hydrochloric acid (1:1) at room
temperature to obtain (S)-3-cyano-5-methylhexanoic acid (II) from ethyl
acetate layer optionally accompanied with recovery of cinchonidine (XIII) from
aqueous phase through basification with sodium hydroxide, potassium
hydroxide;

c) hydrogenation of optically pure (S) - 3-cyano-5-methyl-hexanoic acid (II) in
presence of Raney Nickel.

such that at each step the intermediates were optionally isolated and purified with
suitable processes.
Detailed Description of the Invention:
This invention provides
i) Resolution via diastereomeric salt formation between (RS) - 3-
cyano-5-methyl-hexanoic acid (XII) and cinchonidine (XIII) to
obtain optically pure (S) - 3-cyano-5-methyl-hexanoic acid (II) in
excellent yield and high optical purity (>99 % ee) and further

conversion to (S)-pregabalin (I) in high yield and high optically
purity (>99 % ee).
ii) Synthesis of the novel compound 4-ethyl 1-methyl 2-cyano-2-
isobutylsuccinate (VII) through a novel method as an intermediate
for the title compound.
iii) A novel method for decarboxylation of 4-ethyl 1-methyl 2-cyano-2-
isobutylsuccinate [VII] and diethyl 2-cyano-2-isobutylsuccinate [X]
in presence of thiol/cesium carbonate.
iv) Green, eco-friendly, solvent free process for the synthesis of
diethyl 2-cyano-2-isobutylsuccinate (X).
v) Synthesis of the novel compound 2-cyano-2-isobutylsuccinic acid
(XVI) through a novel method as an intermediate for the title
compound,
vi) A novel method for decarboxylation of 2-cyano-2-isobutylsuccinic
acid (XVI) in presence of mineral acid such as sulfuric acid and in
organic solvent such as ethyl acetate.
vii) A method for recovery of cinchonidine (XIII) through basification
and utilization of recovered cinchonidine (XIII) for resolution of
(RS) - 3-cyano-5-methyl-hexanoic acid (XII), thereby improving the
process efficiency and hence cost.
A) Process for synthesis of (RS) 3-cyano-5-methylhexanoic acid of formula
(XII)
Route I:
1) A process for synthesis of (RS) 3-cyano-5-methylhexanoic acid of formula (XII)


from cyano acetic acid methyl ester of formula (III)

comprising,
a) condensation of 2-methyl-propionaldehyde (IV) with cyano acetic acid methyl
ester (III) in presence of organic or inorganic base such as piperidinium acetate,
cesium acetate, and further hydrogenation using noble metal catalyst such as
platinum oxide, palladium on carbon, palladium hydroxide on carbon and also with
Raney nickel preferably palladium on carbon and palladium hydroxide on carbon in
polar solvent such as methanol, ethanol, water, 1,4-dioxane, tetrahydrofuran,
dimethoxy ethane and diglyme, preferably methanol under hydrogen pressure of
about 1 kg/cm2 to 5 kg/cm2, preferably about 2 kg/cm2, with subsequent isolation of
the product in solution form from the catalyst by filtration;

b) reaction of compound of formula (V) with halo acetic acid ethyl ester (VI),
wherein halo group includes chloro, bromo and iodo, in presence of base
such as sodium carbonate, potassium carbonate, cesium carbonate,
preferably cesium carbonate without solvent or optionally in a organic solvent
selected from N, N-dimethyl formamide, tetrahydrofuran, 1,4-dioxane,
dimethyl sulfoxide, and dimethoxy ethane, preferably N, N-dimethyl
formamide and dimethyl sulfoxide, more preferably dimethyl sulfoxide at
temperature of about 10 to 90 °C, preferably 50 to 60 °C to give 4-ethyl 1-
methyl 2-cyano-2-isobutylsuccinate (VII).


c) reaction of compound (VII) with cesium chloride, potassium chloride or
sodium chloride preferably with cesium chloride in an organic solvent such as
dimethyl sulfoxide at temperature of about 130°C to 150°C, preferably at
140°C to 145°C to get (RS)-3-cyano-5-methyl-hexanoic acid ethyl ester (XI);

d) hydrolysis of compound (XI) in presence of base such as lithium hydroxide,
potassium hydroxide or sodium hydroxide, preferably with lithium hydroxide
at temperature of about 20 to 80 °C, preferably at 50 to 60 °C to get (RS)-3-
cyano-5-methyl-hexanoic acid (XII)

such that at each step the intermediates were optionally isolated and purified with
suitable processes.
2) A process for synthesis of (RS) 3-cyano-5-methylhexanoic acid of formula (XII)


from cyano acetic acid methyl ester of formula (III)

comprising,
a) compound (VII) was obtained as per the process described in step 'a' and 'b'
in Part '1' of route I.
b) hydrolysis of compound (VII) in presence of base such as lithium hydroxide,
potassium hydroxide or sodium hydroxide, preferably with lithium hydroxide
at temperature of about 20 to 80 °C, preferably at 65 to 70 °C to get 2-cyano-
2-isobutylsuccinic acid (XVI)

c) compound (XVI) was decarboxylated in presence of mineral acid such as
sulfuric acid in organic solvent such as ethyl acetate to obtain compound (XII)
at about temperature 70 to 80 °C; or decarboxylated through reported
methods such as base catalyzed decarboxylation (J.Org. Chem, 1961, 83,
2354)


Route II:
1) A process for synthesis of (RS) 3-cyano-5-methylhexanoic acid of formula (XII)

from cyano acetic acid ethyl ester of formula (VIM)

comprising,
a) condensation of 2-methyl-propionaldehyde (IV) with cyano acetic acid ethyl ester
(VIII) in presence of organic or inorganic base such as piperidinium acetate, cesium
acetate and further hydrogenation using noble metal catalyst such as platinum
oxide, palladium on carbon, palladium hydroxide on carbon and also with Raney
nickel preferably palladium on carbon and palladium hydroxide on carbon in polar
solvent such as methanol, ethanol, 1,4-dioxane, tetrahydrofuran, dimethoxy ethane
and diglyme, preferably methanol under hydrogen pressure of about 1 kg/cm2 to 5
kg/cm2, preferably about 2 kg/cm2, with subsequent isolation of the product in
solution form from the catalyst by filtration;

b) reaction of compound of formula (IX) with halo acetic acid ethyl ester (VI),
wherein halo group include chloro, bromo and iodo, in presence of base such

as potassium carbonate, sodium carbonate and cesium carbonate preferably
cesium carbonate without solvent or optionally in a organic solvent selected
from N, N-dimethyl formamide, tetrahydrofuran, 1,4-dioxane, dimethyl
sulfoxide, and dimethoxy ethane, preferably N, N-dimethyl formamide and
dimethyl sulfoxide, more preferably dimethyl sulfoxide at temperature of about
10 to 80 °C, preferably at 50 to 60 °C to give diethyl 2-cyano-2-
isobutylsuccinate (X).

It was observed that rate of reaction was faster in presence of cesium carbonate
as compared to potassium carbonate and sodium carbonate and also it was
worthwhile to note that reaction temperature with cesium carbonate was much
lower as compared to potassium carbonate and sodium carbonate; details are
summarized in Table 1. Thus, use of cesium carbonate makes the process more
eco-friendly and increases the process efficiency; moreover reaction was carried
out without using any organic solvent, which resulted in overall decrease in the
process cost for the synthesis of title compound.


c) reaction of compound (X) with alkali metal chloride such as sodium chloride,
potassium chloride, cesium chloride preferably cesium chloride in an organic
solvent such as dimethylsulfoxide at temperature of about 140°C to 180°C,
preferably at 160°C to 170°C to get 3-cyano-5-methyl-hexanoic acid ethyl
ester (XI).
It was observed that rate of Krapcho decarboxylation in presence of cesium
chloride is high as compared to potassium chloride and sodium chloride.

Or
reaction of compound (X) with thiol/cesium carbonate in an organic solvent such as
N,N-dimethylformamide at temperature of about 130°C to 150°C, preferably at 130°C
to 140 °C to get 3-cyano-5-methyl-hexanoic acid ethyl ester (XI), thiol being obtained
from thiophenol or diethyl amine ethane thiol; preferably thiophenol.

In literature, decarboxylation of activated esters in presence of thiol/cesium
carbonate (J. Org. Chem. 1986, 51, 3165-31369) is reported for benzylic substances
but there is no report of decarboxylation of compound (X) or similar substances in
presence of thiolate/cesium carbonate.
The decarboxylation of compound (X) in presence of thiol/cesium carbonate was
carried out at lower temperature as compared to decarboxylation in presence of alkali
metal chloride/DMSO, which results in overall decrease in the energy consumption,
hence reducing the overall process cost for synthesis of title compound.

It was also observed that decarboxylation of 4-ethyl 1-methyl 2-cyano-2-
isobutylsuccinate (VII) occurs at lower temperature as compared to decarboxylation
of diethyl 2-cyano-2-isobutylsuccinate (X). Comparison of different methods for
decarboxylation is given in Table 2.



from cyano acetic acid ethyl ester of formula (VIII)

comprising,
a) compound (X) was obtained as per the process described in step a and b in
Part 1 of route II.
b) hydrolysis of compound (X) in presence of base such as lithium hydroxide,
potassium hydroxide or sodium hydroxide, preferably with lithium hydroxide
at temperature of about 20 to 80 °C, preferably at 65 to 70 °C to get 2-cyano-
2-isobutylsuccinic acid (XVI)

c) compound (XVI) was decarboxylated in presence of mineral acid such as
sulfuric acid in organic solvent such as ethyl acetate to obtain compound (XII)
at about temperature 70-80 °C or decarboxylated through reported methods
such as base catalyzed decarboxylation (J.Org. Chem, 1961, 83, 2354)


B) Resolution of (RS)-3-cyano-5-methyl-hexanoic acid (XII) to obtain optically
pure (S) - 3-cyano-5-methyl-hexanoic acid (II) via diastereomeric salt formation
with cinchonidine (XIII).
WO2007/143152 A2, reports the optical resolution of (RS)-3-cyano-5-methylhexanoic
acid (XII) through diastereomeric salt formation with (S)-phenyl ethyl amine to obtain
(S)-3 - cyano -5-methyl hexanoic acid (II) in acetone.
Following the experimental conditions reported in the said patent, it has not been
possible to obtain precipitate of the desired diastereomeric salt crystallizing out, and
in spite of varying the experimental conditions such as solvent, reaction temperature
and ratio between reactants, no precipitation of desired diastereomeric salt was
obtained. Further other chiral amines have also been suggested in the said patent for
resolution of (RS)-3-cyano-5-methylhexanoic acid (XII) to obtain (S)-3-cyano-5-
methylhexanoic acid (II) through diastereomeric salt formation but no enablement
whatsoever has been reported i.e. one does not know how to perform these
speculative experiments.
Hence there was need for identifying suitable resolving agents, which could give the
excellent separation to obtain optically pure compound (II) in high % ee and yield.
Further, the process must be easy to operate in industrial scale i.e. one could
separate the desired diastereomeric salt through efficient crystallization in high
optical purity and yield. Furthermore, to improve the process efficiency, the recovery
of the resolving agent along with its reuse should be easy and efficient.
After a series of experimentation, it was observed that resolution of (RS)-3-cyano-5-
methylhexanoic acid (XII) via diastereomeric salt with cinchonidine (XIII) provides the
desired separation in high optical purity and yield.
Thus, resolution through diastereomeric salt between (RS)-3-cyano-5-
methylhexanoic acid (XII) with cinchonidine (XIII) comprised of the following steps:
a) compound (XII) was treated with cinchonidine(XIII) in presence of organic
solvent such as methanol, ethanol, 1,4-dioxane, ethyl acetate,
tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxy ethane and diglyme,
preferably ethyl acetate at temperature of about 20°C to 80°C, preferably at
70°C to 80 °C to precipitate out (S) 3-cyano-5-methylhexanoic acid salt of

cinchonidine (XIV), followed by separation of compound (XIV) through known
separation techniques such as filtration, centrifugation, sedimentation, etc.
b) (S)-3-cyano-5-methylhexanoic acid salt of cinchonidine (XIV) was further
purified through reflux in ethyl acetate or through re-salt formation in order to
dissolve occluded (R)-3-cyano-5-methylhexanoic acid salt of cinchonidine
(XV) thereby improving enantiomeric purity of (S)-3-cyano-5-methylhexanoic
acid (II).
(S) 3-cyano-5-methylhexanoic acid salt of cinchonidine (XIV) was
characterized by the powder X-ray diffraction peaks at the 2-theta values
5.84, 7.27, 7.69, 10.72, 11.65, 13.79, 14.92, 15.39,15.73, 16.69, 17.31, 17.41,
17.58, 17.99, 19.48, 20.03, 20.71, 21.18, 21.92, 23.18, 24.93, 25.29, 25.95,
26.38, 27.07, 27.91, 28.79, 31.06, 31.65, 35.36, 38.00 and 39.35; specific
optical rotation value -54.29 ° (c=1 in DMSO at 25 °C); DSC (differential
scanning calorimetry) peak at 152.49 ° C (onset =149.86 ° C).
c) (S) 3-cyano-5-methylhexanoic acid salt of cinchonidine (XIV) was
decomposed in a biphasic mixture of ethyl acetate: dilute hydrochloric
acid (1:1) at room temperature. (S)-3-cyano-5-methylhexanoic acid (II)
was obtained from ethyl acetate layer and cinchonidine (XIII) was
recovered from aqueous phase through basification with sodium
hydroxide, potassium hydroxide and was reused for resolution.
d) Mother liquor of salt formation i.e. ethyl acetate layer, which contains the
(R)-3-cyano-5-methylhexanoic acid salt of cinchonidine (XV) was treated
with aqueous dilute mineral acid such as hydrochloric acid to recovered
cinchonidine.
e) Optically pure (S) - 3-cyano-5-methyl-hexanoic acid (II) was converted
into S-pregabalin (I) by hydrogenation in presence of Raney Nickel.


Nomenclatures used for the compounds mentioned herein are as understood from
the CambridgeSoft® ChemOffice software ChemDraw Ultra version 6.0.1.
Analytical Methods:
The enantiomeric excess (ee) for pregabalin is determined by HPLC using a
Shimadzu LC 2010 system equipped with a chiral column (Purosphere star RP-18e
(4.6 x 150mm), 5pm), column oven temperature 25 °C and UV visible detector (UV at
340nm). Mobile phase is buffer: acetonitrile (55:45) with flow rate 1.0 mL/min,
injection volume 20 nl. The enantiomeric excess (ee) is determined by derivatized by
reacting with Marfey's reagent.
The enantiomeric excess (ee) for (S) - 3-cyano-5-methyl-hexanoic acid ethyl ester is
determined by Gas-Liquid chromatography using a Shimadzu GC 2010 system
equipped with a chiral column (Chiraledex (20m x 0.25mm x 0.12mm)), and FID
detector.
The enantiomeric excess (ee) for (S) or (R) - 3-cyano-5-methyl-hexanoic acid is
determined via converting into corresponding ester and analyzed on Gas-Liquid
chromatography using a Shimadzu GC 2010 system equipped with a chiral column
(Chiraledex (20m x 0.25mm x 0.12mm)), and FID detector.
NMR spectra are obtained at 200 and 400 MHz Bruker instruments, with CDCI3 as
solvent unless otherwise stated. Chemical shifts (<5) are given in ppm relative to
tetramethylsilane (6 = 0 ppm). IR spectra are recorded on Perkin Elmer Spectrum
(Model: Spectrum 100) and absorption bands are given in cm"1. Mass analyses are
performed on Shimadzu LCMS 2010A instrument. Powder X-ray diffraction is
recorded on PANalytical B. V. Netherlands model PN3040/60X'Part Pro. DSC is
recorded on Perkin Elmer model Diamond DSC at the rate of 10 °C/min, and
endothermic peak is recorded in °C.
Brief Description of Accompanying Drawings
Figure 1: PXRD of (S)-3-cyano-5-methyl hexanoic acid salt of cinchonidine (XIV)
Figure 2: DSC of (S)-3-cyano-5-methyl hexanoic acid salt of cinchonidine (XIV)
Example 1: Synthesis of ethyl 2-cyano-4-methylpentanoate (IX) from condensation
of ethyl cyano acetate (VIII) with iso-butyraldehdye (IV) in presence of piperidine /
acetic acid

Ethyl cyano acetate (VIII) (56.5 g, 0.5 mol) was dissolved in methanol (100 mL) and iso-
butyraldehyde (IV) (43.2 g, 0.6 mol) was added to it at room temperature. The mixture
was cooled to 4 °C and a solution of acetic acid (12 mL) and piperidine (2 mL) in 50 mL
of methnaol was added slowly over a period of 20 min by maintaining temperature below
20 °C. The reaction mixture was transferred into a Parr autoclave reactor followed by
addition of 2 % catalyst palladium on carbon (50 % wet (10% Pd loading)). Reactor was
purged with hydrogen gas two times and charged with hydrogen, 3 kg/cm2 pressure was
maintained in the Parr autoclave until hydrogen consumption ceases. Reaction was
monitored by TLC. After completion of reaction, reaction mixture was filtered through
Celite bed to remove Pd/C and filtrate was concentrated under reduced pressure to
remove solvent. Residue was suspended in 100 mL water. Organic layer was separated
to obtain ethyl 2-cyano-4-methylpentanoate (IX) (80 g, 95 % yield) as light yellow oil.
FTIR(neat): 2962, 2249, 1746, 1469, 1186 cm-1.
1H NMR(CDCI3, 200 MHz): δ 0.95 (d, 3H), 0.96 (d, 3H), 1.28 (t, 3H), 1.17-1.87 (m, 3H),
3.49 (q, 1H),4.22(q, 2H).
MS (El): C9H15NO2: 169.0; [M+H2O]+: 186.85 and [M]-: 167.80
Example 2: Synthesis of ethyl 2-cyano-4-methylpentanoate (IX) from condensation
of ethyl cyano acetate (VIII) with iso-butyraldehdye (IV) in presence of cesium
acetate /methanol

Reaction was carried out as per process described in example 1 by replacing piperidine/
acetic acid with cesium acetate.

Example 3: Synthesis of ethyl 2-cyano-4-methylpentanoate (IX) from condensation
of ethyl cyano acetate (VIII) with iso-butyraldehdye (IV) in presence of cesium
acetate /water

Reaction was carried out as per process described in example 1 by replacing piperidine/
acetic acid with cesium acetate in aqueous media.
Example 4: Synthesis of diethyl 2-cyano-2-isobutylsuccinate (X) from ethyl 2-
cyano-4-methylpentanoate (IX) and ethyl chloro acetate (VI) in presence of cesium
carbonate.

A reactor was charged with ethyl 2-cyano-4-methylpentanoate (IX) (103.0 g, 609 mmol),
ethyl chloro acetate (VI) ( (82.1, 670 mmol) and benzyl triethyl ammonium chloride (1.4
g, 6.09 mmol) and resulting reaction mixture was stirred for 15-20 min at room
temperature. To above reaction mixture activated fine powder of cesium carbonate
(198.0 g, 609 mmol) was added slowly in small portions while stirring over a period of 10-
15 min, addition of cesium carbonate result into rise in the reaction temperature upto 60
to 65 °C. After complete addition of cesium carbonate, reaction mixture was stirred
further for 1 h at 60 °C. Reaction was monitored by TLC for complete consumption of
starting materials and after completion of reaction; it was quenched by adding 100 mL
water and organic layer was separated to obtain diethyl 2-cyano-2-isobutylsuccinate (X)
(155.0 g, 88% yield) as yellow oil.

FTIR(neat): 2963, 2248, 1743, 1469, 1195, 1025 cm'1.
1H NMR (CDCl3, 200 MHz): δ 0.95 (d, 3H), 0.96 (d, 3H), 1.23 (t, 3H), 1.28 (t, 3H), 1.70-
1.89 (m, 3H), 2.80 (d, 1H), 3.02 (d, 1H), 4.16 (q, 2H), 4.28 (q, 2H).
MS (El): C9H15NO2: 255; [M+H2O]+: 273.05.
Example 5: Synthesis of diethyl 2-cyano-2-isobutylsuccinate (X) from ethyl 2-
cyano-4-methylpentanoate (IX) and ethyl chloro acetate (VI) in presence of
potassium carbonate.

Reaction was carried out as per the procedure described in example 4 with activated fine
powder of potassium carbonate at temperature 90 °C for 120 min to obtain diethyl 2-
cyano-2-isobutylsuccinate (X) as dark brown oil.
Example 6: Synthesis of diethyl 2-cyano-2-isobutylsuccinate (X) from ethyl 2-
cyano-4-methylpentanoate (IX) and ethyl chloro acetate (VI) in presence of sodium
carbonate.

Reaction was carried out as per the procedure described in example 4 with activated fine
powder of sodium carbonate at temperature 90 °C for 180 min to obtain diethyl 2-cyano-
2-isobutylsuccinate (X).

Example 7: Synthesis of methyl-2-cyano-4-methylpentanoate (V) from
condensation of methyl cyano acetate (III) with iso-butyraldehdye (IV) in presence
of piperidine / acetic acid

Methyl cyano acetate (III) (113.0 g, 1.14mol) was dissolved in methanol (125 mL), iso-
butyraldehyde (IV) (98.0 g, 1.36 mol) and glacial acetic acid (12 mL) was added to it at
room temperature. The mixture was cooled to 4 °C and a solution of acetic acid (12 mL)
and piperidine (4 mL) in 50 mL of methanol was added slowly over a period of 20 min by
maintaining temperature below 20 °C. The reaction mixture was transferred into a Parr
autoclave reactor followed by addition of 2 % catalyst palladium on carbon (50 % wet
(10% Pd loading)). Reactor was purged with hydrogen gas two times and charged with
hydrogen, 3 kg/cm2 pressure was maintained in the Parr autoclave until hydrogen
consumption ceases. Reaction was monitored by TLC. After completion of reaction,
reaction mixture was filtered through Celite bed to remove Pd/C and filtrate was
concentrated under reduced pressure to remove solvent. Residue was suspended in 100
mL water. Organic layer was separated to obtain methyl-2-cyano-4-methylpentanoate
(V) (170 g, 90 % yield) as light yellow oil.
FTIR (neat): 2958, 2872, 2642, 2250, 1751, 1468, 1185, 1131, 1010 cm-1
1H NMR (CDCI3, 200 MHz): δ 0.92 (d, 3H), 0.99 (d, 3H), 1.74-1.98 (m, 3H), 3.53 (t, 1H)
3.81 (s, 3H)
MS (El): C9H15NO2: 169.11; [M+H]+: 170.15
Example 8: Synthesis of methyl-2-cyano-4-methylpentanoate (V) from
condensation of methyl cyano acetate (III) with ;'so-butyraldehdye (IV) in presence
of cesium acetate in methanol


Reaction was carried out as per process described in example 7 by replacing piperidine/
acetic acid with cesium acetate to obtain methyl-2-cyano-4-methylpentanoate (V.
Example 9: Synthesis of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII) from
methyl-2-cyano-4-methylpentanoate (V) and ethyl chloro acetate (VI) in presence of
cesium carbonate.

A reactor was charged with methyl 2-cyano-4-methylpentanoate (V) (41.0 g, 265.0
mrmol), ethyl chloro acetate (VI) (35.7, 291 mmol) and benzyl triethyl ammonium chloride
(0.6 g) and resulting reaction mixture was stirred for 15-20 min at room temperature. To
above reaction mixture activated fine powder of cesium carbonate (47.3 g, 145,5 mmol)
was added slowly in small portions while stirring over a period of 10-15 min, addition of
cesium carbonate result into rise in the reaction temperature upto 65 to 70 °C. After
complete addition of cesium carbonate, reaction mixture was stirred further for 1 h at 60
°C. Reaction was monitored by TLC for complete consumption of starting materials and
after completion of reaction; it was quenched by adding 100 mL water and organic layer
was separated to obtain 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII) (57.5 g, 90%
yeild) as light yellow oil.

FTIR(neat): 2958,2248, 1741, 1637, 1467, 1199, 1025 cm"1.
1H NMR (CDCl3, 200 MHz): δ 0.88 (d, 3H), 0.92 (d, 3H), 1.05 (t, 3H), 1.70-1.89 (m, 3H),
2.79 (d, 1H), 3.03 (d, 1H), 3.84 (s, 3H), 4.18 (q, 2H).
MS (El): C9H15NO2: 241; [M+H2O]+: 259.05.
Example 10: Synthesis of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII) from
methyl-2-cyano-4-methylpentanoate (V) and ethyl chloro acetate (VI) in presence of
potassium carbonate.
Reaction was carried out as per the procedure described in example 9 with activated fine
powder of potassium carbonate at temperature 90 °C to obtain 4-ethyl 1-methyl 2-cyano-
2-isobutylsuccinate (VII) as light brown oil.
Example 11: Synthesis of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII) from
methyl-2-cyano-4-methylpentanoate (V) and ethyl chloro acetate (VI) in presence of
sodium carbonate.
Reaction was carried out as per the procedure described in example 9 with activated fine
powder of sodium carbonate at temperature 90 °C to obtain 4-ethyl 1-methyl 2-cyano-2-
isobutylsuccinate (VII) as light brown oil.
Example 12: Decarboxylation of diethyl 2-cyano-2-isobutylsuccinate (X) to obtain
(RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of KCI/DMSO

A 1 L reactor was charged with diethyl 2-cyano-2-isobutylsuccinate (X) (102 g).
potassium chloride (32.5 g), dimethyl sulphoxide (500 mL) and water (7.5 mL). The
resulting reaction mixture was heated at 170 °C and maintained at that temperature for 4
h. Reaction was monitored by TLC for complete consumption of starting material. The
reaction mixture was cooled to 40 to 50 °C and treated with methyl fert-butyl ether (200
mL). The mixture was further cooled to 0 to 5 °C and treated with water (1 L) in small

portions to maintain the temperature below 40 °C. After stirring for 30 min the phases
were separated. The aqueous phase was extracted with methyl tert-butyl ether (3 x 800
mL), Organic phases were combined and washed twice with 100 mL water. The organic
layer was decolorized by treating with 7.0 g of activated charcoal. The resultant mixture
was filtered to remove charcoal and filtrate was evaporated to give (RS) - 3-cyano-5-
methylhexanoic acid ethyl ester (VII) 76.1 g (98.5 % purity by GC area %) as light brown
color oil.
FTIR(neat): 2961,2242, 1738, 1469, 1182, 1023 cm-1.
1H NMR (CDCI3, 200 MHz): δ 0.95 (d, 3H), 0.96 (d, 3H), 1.22-1.24 (m, 4H), 1.58 (m, 1H),
1.83 (m, 1H), 2.49 (dd, 1H), 2.65 (dd, 1H), 2.98-3.06 (m, 1H), 4.17 (q, 2H). 13C NMR
(CDCI3, 50 MHz): 14.1, 21.2, 22.8, 25.8, 26.0, 37.1, 40.7, 61.4, 121.1, 169.7.
MS (El): C10H17NO2: 183; [M+H2O]+: 201.05.
Example 13: Decarboxylation of diethyl 2-cyano-2-isobutylsuccinate (X) to obtain
(RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of CsCI/DMSO
Reaction was carried out as per procedure described in example 12 by replacing
potassium chloride with cesium chloride to obtain (RS) - 3-cyano-5-methylhexanoic acid
ethyl ester (XI).
Example 14: Decarboxylation of diethyl 2-cyano-2-isobutylsuccinate (X) to obtain
(RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of NaCI/DMSO
Reaction was carried out as per procedure described in example 12 by replacing sodium
chloride with cesium chloride to obtain (RS) - 3-cyano-5-methylhexanoic acid ethyl ester
(XI).
Example 15: Decarboxylation of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII)
to obtain (RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of
KCI/DMSO

A 50 mL reactor was charged with 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII)
(57.5 g), potassium chloride (18.5 g), dimethyl sulphoxide (300 mL) and water (4.3 mL).
The resulting reaction mixture was heated at 140 °C and maintained at that temperature
for 4 h. Reaction was monitored by TLC for complete consumption of starting material.
The reaction mixture was cooled to 40 to 50 °C and treated with methyl tert-butyl ether
(200 mL). The mixture was further cooled to 0 to 5°C and treated with water (1 L) in small
portions to maintain the temperature below 40 °C. After stirring for 30 min the phases are
separated. The aqueous phase was extracted with methyl tert-butyl ether (3 x 800 mL).
Organic phases are combined and washed twice with 100 mL water. The organic layer
was decolorized by treating with 5.0 g of activated charcoal. The resultant mixture was
filtered to remove charcoal and filtrate was evaporated to give (RS) - 3-cyano-5-
methylhexanoic acid ethyl ester (XI) 40.1 g as light brown color oil.
FTIR(neat): 2961, 2242, 1738, 1469, 1182, 1023 cm-1.
1H NMR (CDCI3, 200 MHz): δ 0.95 (d, 3H), 0.96 (d, 3H), 1.22-1.24 (m, 4H), 1.58 (m, 1H),
1.83 (m, 1H), 2.49 (dd, 1H), 2.65 (dd, 1H), 2.98-3.06 (m, 1H), 4.17 (q, 2H). 13C NMR
(CDCI3, 50 MHz): 14.1,21.2, 22.8, 25.8,26.0, 37.1,40.7,61.4, 121.1, 169.7.
MS (El): C10H17NO2: 183; [M+H2O]+: 201.05.
Example 16: Decarboxylation of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII)
to obtain (RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of
CsCI/DMSO
Reaction was carried out as per procedure described in example 15 with cesium chloride
instead of potassium chloride to obtain (RS) - 3-cyano-5-methylhexanoic acid ethyl ester
(XI).
Example 17: Decarboxylation of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII)
to obtain (RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of
NaCI/DMSO

Reaction was carried out as per procedure described in example 15 with sodium chloride
instead of potassium chloride to obtain (RS) - 3-cyano-5-methylhexanoic acid ethyl ester
(XI).
Example 18: Decarboxylation of diethyl 2-cyano-2-isobutylsuccinate (X) to obtain
(RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of
thiophenol/cesium carbonate in dimethylformamide.

A 250 mL reactor was charged with diethyl 2-cyano-2-isobutylsuccinate (13.1 g, 51.3
mmol), thiophenol (8.47, 77.0mmol), cesium carbonate (5.0 g, 15.4 mmol) and N,N-
dimethylformamide (40 mL). The resulting reaction mixture was heated at 130 °C and
maintained at that temperature for 4 h. Reaction was monitored by GC for conversion of
(RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) .
Example 19: Decarboxylation of diethyl-2-cyano-2-isobutylsuccinate (X) to obtain
(RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of diethyl amine
ethane thiol/cesium carbonate

Reaction was carried out as per procedure described in example 18 with diethyl amine
ethane thiol/cesium carbonate to obtain {RS) - 3-cyano-5-methylhexanoic acid ethyl

ester (XI) and reaction was monitored on GC for conversion of (RS) - 3-cyano-5-
methylhexanoic acid ethyl ester (XI) .
Example 20: One pot synthesis of (RS) - 3-cyano-5-methylhexanoic acid ethyl ester
(XI) from methyl-2-cyano-4-methylpentanoate (V)

A reactor was charged with methyl-2-cyano-4-methylpentanoate (V) (41.0 g, 265.0
mmol), ethyl chloro acetate (VI) (35.7 g, 291 mmol), benzyl triethyl ammonium chloride
(0.6 g, 2.64 mmol) and dimethyl sulfoxide (63 mL). The resulting reaction mixture was
stirred for 15 -20 min at room temperature. Activated powder of cesium carbonate was
added slowly in small portions to the above reaction mixture while stirring. Addition of
cesium carbonate result into increase in the reaction temperature upto 60 to 65 °C. The
reaction mixture was stirred further for 2 h at 60 °C. Reaction was monitored by TLC for
complete consumption of starting materials. After which reaction mixture was heated to
135- 140 °C and stirred further at that temperature for 4 h. The reaction mixture was
cooled to 40 to 50 °C and treated with methyl fert-butyl ether (200 mL). The mixture was
further cooled to 0 to 5°C and treated with water (1 L) in small portions to maintain the
temperature below 40 °C. After stirring for 30 min the phases were separated. The
aqueous phase was extracted with methyl fert-butyl ether (3 x 800 mL); Organic phases
were combined and washed twice with 100 mL water. The organic layer was decolorized
by treating with 7.0 g of activated charcoal. The resultant mixture was filtered to remove
charcoal and filtrate was evaporated to give (RS) - 3-cyano-5-methylhexanoic acid ethyl
ester (XI) (39.1 g) as light brown color oil.
Example 21: Synthesis of (RS) - 3-cyano-5-methylhexanoic acid (XII) through
hydrolysis of (RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of
lithium hydroxide.


A reactor was charged with (RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) (52.0
g,) and water (250 mL). A solution of lithium hydroxide (15.0 gm) in water (25 mL) was
added slowly while stirring. The reaction mixture was stirred further for 12 h at 60 °C.
After which reaction mixture was cooled to room temperature and un-reacted (RS) - 3-
cyano-5-methylhexanoic acid ethyl ester, if any was extracted with di-/'so propyl ether.
Aqueous layer was acidified with dilute hydrochloric acid upto pH 2 and extracted with
dichloromethane (3 *150 mL). Combined organic layer was dried over sodium sulfate
and solvent was evaporated under reduced pressure to obtain (RS) - 3-cyano-5-
methylhexanoic acid (XII) (31.1 gm) as yellow oil.
FTIR (neat): 3118, 2961, 2935, 2875, 2642, 2244, 1715, 1470, 1174, 1113 cm-1
1H NMR (CDCI3, 200 MHz): δ 0.95 (d, 3H), 0.96 (d, 3H), 1.36-1.38 (d, 1H), 1.59-1.66 (m,
1H), 1.79-1.85 (m, 1H), 2.59-2.61 (dd, 1H), 2.69-2.75 (dd, 1H), 2.98-3.04 (m, 1H).
MS (El): C8H13N02: 155.19; [M-H]-: 154.00; [M+H]+: 156.15
Example 22: Synthesis of (RS) - 3-cyano-5-methylhexanoic acid (XII) through
hydrolysis of (RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of
NaOH
Reaction was carried our as per process given in example 21 by replacing lithium
hydroxide with sodium hydroxide.
Example 23: Synthesis of (RS) - 3-cyano-5-methylhexanoic acid (XII) through
hydrolysis of (RS) - 3-cyano-5-methylhexanoic acid ethyl ester (XI) in presence of
KOH
Reaction was carried our as per process given in example 21 by replacing lithium
hydroxide with Potassium hydroxide.

Example 24: Synthesis of 2-cyano-2-isobutylsuccinic acid (XVI) through hydrolysis
of diethyl 2-cyano-2-isobutylsuccinate (X) in presence of Lithium hydroixde

A reactor was charged with diethyl 2-cyano-2-isobutylsuccinate (X) (200.0 g,) and water
(300 mL). A solution of lithium hydroxide (72.3 gm) in water (350 mL) was added slowly
while stirring. The reaction mixture was stirred further for 12 h at 70 °C. After which
reaction mixture was cooled to room temperature and un-reacted diethyl 2-cyano-2-
isobutylsuccinate, if any was extracted with di-/'so propyl ether. Aqueous layer was
acidified with dilute hydrochloric acid upto pH 2 and extracted with ethyl acetate (3 *350
mL). Combined organic layer was dried over sodium sulfate and solvent was evaporated
under reduced pressure to obtain 2-cyano-2-isobutylsuccinic acid (XVI) (140.1 gm) as off
white solid.
FTIR (KBr): cm-1 3429, 2962, 2271, 1742, 1703, 1469, 1438, 1402, 1214, 910, 844 and
642
1H NMR (DMSO-d6, 200 MHz): δ 0.82-0.89 (d, 3H), 0.96-0.97 (d, 3H), 1.64-1.75 (m, 3H),
2.86 (s, 2H), 13.15 (s, 2H); 13C NMR (DMSO-d6, 50 MHz): 23.4, 23.6, 25.6, 41.7, 45.1,
120.6, 170.4, 171.1
MS (El): C9H13NO4: 199.2; [M-H]-: 197.80; [M+H2O]+: 216.90
Example 25: Synthesis of 2-cyano-2-isobutylsuccinic acid (XVI) through hydrolysis
of diethyl 2-cyano-2-isobutylsuccinate (X) in presence of KOH
Reaction was carried our as per process given in example 24 by replacing lithium
hydroxide with Potassium hydroxide to obtain 2-cyano-2-isobutylsuccinic acid (XVI).
Example 26: Synthesis of 2-cyano-2-isobutylsuccinic acid (XVI) through hydrolysis
of diethyl 2-cyano-2-isobutylsuccinate (X) in presence of NaOH

Reaction was carried our as per process given in example 24 by replacing lithium
hydroxide with Potassium hydroxide to obtain 2-cyano-2-isobutylsuccinic acid (XVI).
Example 27: Synthesis of 2-cyano-2-isobutylsuccinic acid (XVI) through hydrolysis
of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII) in presence of Lithium
hydroxide.

A reactor was charged with 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII) (100.0 g,)
and water (150 mL). A solution of lithium hydroxide (36.5 gm) in water (150 mL) was
added slowly while stirring. The reaction mixture was stirred further for 12 h at 70 °C.
After which reaction mixture was cooled to room temperature and un-reacted diethyl 2-
cyano-2-isobutylsuccinate, if any was extracted with di-iso propyl ether. Aqueous layer
was acidified with dilute hydrochloric acid upto pH 2 and extracted with ethyl acetate (3
*350 mL). Combined organic layer was dried over sodium sulfate and solvent was
evaporated under reduced pressure to obtain 2-cyano-2-isobutylsuccinic acid (XVI) (72.1
gm) as off white solid.
FTIR (KBr): cm-1 3429, 2962, 2271, 1742, 1703, 1469, 1438, 1402, 1214, 910, 844 and
642
1H NMR (DMSO-d6, 200 MHz): δ 0.82-0.89 (d, 3H), 0.96-0.97 (d, 3H), 1.64-1.75 (m, 3H),
2.86 (s, 2H), 13.15 (s, 2H); 13C NMR (DMSO-d6, 50 MHz): 23.4, 23.6, 25.6, 41.7, 45.1,
120.6, 170.4, 171.1
MS (El): C9H13NO4: 199.2; [M-H]-: 197.80; [M+H2O]+: 216.90
Example 28: Synthesis of 2-cyano-2-isobutylsuccinic acid (XVI) through hydrolysis
of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII) in presence of potassium
hydroxide

Reaction was carried our as per process given in example 27 by replacing lithium
hydroxide with Potassium hydroxide to obtain 2-cyano-2-isobutylsuccinic acid (XVI)
Example 29: Synthesis of 2-cyano-2-isobutylsuccinic acid (XVI) through hydrolysis
of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate (VII) in presence of sodium
hydroxide
Reaction was carried our as per process given in example 27 by replacing lithium
hydroxide withsodium hydroxide to obtain 2-cyano-2-isobutylsuccinic acid (XVI)
Example 30: Synthesis of (RS) - 3-cyano-5-methylhexanoic acid (XII) through
decarboxylation of 2-cyano-2-isobutylsuccinic acid (XVI)
H
A reactor was charged with 2-cyano-2-isobutylsuccinic acid (XVI) (6.0 g,) and
concentrated sulfuric acid (0.6 g, 10 w/w) and ethyl acetate (60 mL) and resulting
reaction mixture was refluxed for 4 h. After completion of reaction, solvent was
evaporated under reduced pressure to crude (RS) - 3-cyano-5-methylhexanoic acid (XII).
Crude (RS) - 3-cyano-5-methylhexanoic acid (XII) was suspended in water (25 mL) and
stirred for 30 min. Aqueous layer was extracted with ethyl acetate (2x 25 mL) and
combined organic layer was dried over sodium sulfate and solvent was evaporated
under reduced pressure to obtain (RS) - 3-cyano-5-methylhexanoic acid (XII) (3.1 gm)
as yellow oil.

Example 31: Resolution of (RS) - 3-cyano-5-methylhexanoic acid (XII) through
diastereomeric salt formation with cinchonidine (1: 0.5).

A reactor was charged with cinchonidine (XIII) (18.95, 64.5 mmol) and ethyl acetate (500
ml) and resulting reaction mixture was heating to 70 °C. A solution of (RS) - 3-cyano-5-
methylhexanoic acid (XII) (20.0 g, 129.0 mmol) in ethyl acetate (200 mL) was added into
above reaction mixture over a period of 15- 20 min and reaction mixture was further
stirred for 5 h at reflux temperature. After which reaction mixture was cooled to room
temperature and stirred further for 12 h. (S)-3-cynao-5-methylhexanoic acid salt of
cinchonidine precipitate out. The resultant mixture was filtered to give (S) - 3-cyano-5-
methylhexanoic acid salt of cinchonidine as a white solid (23.0 g, 95% ee for (S)-3-cynao
5-methylhexanoic acid as GC analysis).

Example 32: Resolution (RS) - 3-cyano-5-methylhexanoic acid (XII) through
diastereomeric salt formation with cinchonidine (XIII) (1: 1 mol ratio) in ethyl
acetate

A reactor was charged with cinchonidine (XIII) (37.9, 129 mmol) and ethyl acetate (500
ml) and resulting reaction mixture was heating to 70 °C. A solution of (RS) - 3-cyano-5-
methylhexanoic acid (XII) (20.0 g, 129.0 mmol) in ethyl acetate (200 mL) was added into
above reaction mixture over a period of 15- 20 min and reaction mixture was further
stirred for 5 h at reflux temperature. After which reaction mixture was cooled to room
temperature and stirred further for 12 h. (S)-3-cynao-5-methylhexanoic acid salt of
cinchonidine precipitated out. The resultant mixture was filtered to give (S) - 3-cyano-5-
methylhexanoic acid salt of cinchonidine (XIV) as a white solid (28.3 g, 97% ee for (S)-3-
cynao 5-methylhexanoic acid ethyl ester by GC area %).
Example 33: Resolution (RS) - 3-cyano-5-methylhexanoic acid (XII) through
diastereomeric salt formation with cinchonidine (XIII) (1: 1 mol ratio) in 2-methyl
tetrahydrofuran


A reactor was charged with cinchonidine (XIII) (11.2 g) and 2-methyl tetrahydrofuran
(196 ml) and resulting reaction mixture was heating to 70 °C. A solution of (RS) - 3-
cyano-5-methylhexanoic acid (XII) (5.9 g,) in 2-methyl tetrahydrofuran (45 mL) was
added into above reaction mixture over a period of 15- 20 min and reaction mixture was
further stirred for 1 h at reflux temperature. After which reaction mixture was cooled to
0°C and stirred further for 2 h. (S)-3-cynao-5-methylhexanoic acid salt of cinchonidine
precipitated out. The resultant mixture was filtered to give (S) - 3-cyano-5-
methylhexanoic acid salt of cinchonidine (XIV) as a white solid (7.1 g, 93% ee for (S)-3-
cynao 5-methylhexanoic acid ethyl ester by GC area %).
Example 34: Resolution (RS) - 3-cyano-5-methylhexanoic acid (XII) through
diastereomeric salt formation with cinchonidine (XIII) (1: 1 mol ratio) in dimethoxy
ethane


A reactor was charged with cinchonidine (XIII) (11.2 g) and dimethoxy ethane (196 ml)
and resulting reaction mixture was heating to 70 °C. A solution of (RS) - 3-cyano-5-
methylhexanoic acid (XII) (5.9 g) in dimethoxy ethane (45 mL) was added into above
reaction mixture over a period of 15- 20 min and reaction mixture was further stirred for 2
h at reflux temperature. After which reaction mixture was cooled to room temperature
and stirred further for 5 h. (S)-3-cynao-5-methylhexanoic acid salt of cinchonidine
precipitated out. The resultant mixture was filtered to give (S) - 3-cyano-5-
methylhexanoic acid salt of cinchonidine (XIV) as a white solid (28.3 g, 92% ee for (S)-3-
cynao 5-methylhexanoic acid ethyl ester by GC area %).
Example 35: Purification (S) - 3-cyano-5-methylhexanoic acid salt of cinchonidine
(through refluxing in ethyl acetate).
A reactor was charged with (S) - 3-cyano-5-methylhexanoic acid salt of cinchonidine as a
white solid (28.3 g, 97% ee for (S)-3-cynao 5-methylhexanoic acid) and ethyl acetate
(200 ml) and resulting reaction mixture was heating for 5 h at reflux temperature. After
which reaction mixture was cooled to room temperature and stirred further for 12 h. (S)-
3-cynao-5-methy!hexanoic acid salt of cinchonidine precipitate out. The resultant mixture
was filtered to give (S) - 3-cyano-5-methylhexanoic acid salt of cinchonidine as a white
solid (24.5 g, 98.5% ee for (S)-3-cynao 5-methylhexanoic acid ethyl ester by GC area
%).

Example 36: Purification (S) - 3-cyano-5-methylhexanoic acid salt of cinchonidine
(resait formation)
A reactor was charged (S) - 3-cyano-5-methylhexanoic acid salt of cinchonidine, (23.0 g)
dichlormethane (100 mL) and aqueous dilute hydrochloric acid (100mL). Resulting
heterogeneous mixture was stirred for 1 hr. Organic layer was separated and aqueous
layer was washed with dichloromethane. Combined organic layer was dried over sodium
sulfate and solvent was evaporated under reduced pressure to (S) - 3-cyano-5-
methylhexanoic acid (7.5 g). Cinchonidine was recovered from aqueous layer through
basification (14.5gm).
A reactor was charged with recovered cinchonidine (14.01) and ethyl acetate (200 ml)
and resulting reaction mixture was heating to 70 °C. A solution of enantiomeric excess
(S) - 3-cyano-5-methylhexanoic acid (7.5 g,) in ethyl acetate (50 mL) was added into
above reaction mixture over a period of 15- 20 min and reaction mixture was further
stirred for 5 h at reflux temperature. After which reaction mixture was cooled to room
temperature and stirred further for 12 h. (S)-3-cynao-5-methylhexanoic acid salt of
cinchonidine precipitate out. The resultant mixture was filtered to give (S) - 3-cyano-5-
methylhexanoic acid salt of cinchonidine as a white solid (20.3 g, 99.82 % ee for (S)-3-
cynao 5-methylhexanoic acid ethyl ester by GC area %).
FTIR (KBr): 3413, 3071, 2955, 2234, 1639, 1595, 1508, 1394, 1102, 915, 785, 759,
619 cm-1.
1H NMR (DMSO-D6, 200 MHz): δ 0.89 (d, 3H), 0.91 (d, 3H), 1.30-1.45 (m, 1H), 1.52-1.59
(m, 3H), 1.69-1.82 (m, 4H), 2.38 (bs, 1 H), 2.43-2.55 (dd, 3H), 2.60-2.68 (m, 2H), 2.97-
3.07 (m, 2H), 3.25 (s, 1H), 3.49 (s, 1H), 4.93 (d, 1H), 4.99 (d, 1H), 5.64 (d, 1H), 5.78-
5.87 (m, 1H), 7.60-7.64 (m, 2H), 7.75 (t, 1H), 8.04 (d, 1H), 8.36 (d, 1H), 8.86 (d, 1H). 13C
NMR (DMSO-D6, 50 MHz): 21.6, 22.1, 23.2, 26.2, 26.3, 26.4, 27.6, 38.3, 38.9, 42.3,
55.1, 60.5, 69.4, 115.3, 119.4, 123.0, 124.4, 125.9, 126.9, 129.3, 130.1, 141.6, 148.2,
149.6, 150.5, 172.9.
Powder x-ray diffraction pattern PXRD [29] (Cu Kα1 = 1.54060 A, Kα2 = 1.54443
A, KP = 1.39225 A; 40 mA, 45 kV): 5.84, 7.27, 7.69, 10.72, 11.65, 13.79, 14.92,
15.39,15.73, 16.69, 17.31, 17.41, 17.58, 17.99, 19.48, 20.03, 20.71, 21.18, 21.92,
23.18, 24.93, 25.29, 25.95, 26.38, 27.07, 27.91, 28.79, 31.06, 31.65, 35.36, 38.00
and 39.35
DSC Value: Peak = 152.49 °C Onset = 149.86°C.
49

Example 37: Decomposition of (S) - 3-cyano-5-methylhexanoic acid salt of
cinchonidine to obtain (S) - 3-cyano-5-methylhexanoic acid
A reactor was charged with (S) - 3-cyano-5-methylhexanoic acid salt of cinchonidine,
(20.0g) dichlormethane (100 mL) and aqueous dilute hydrochloric acid (100mL).
Resulting heterogeneous mixture was stirred for 1 hr. Organic layer was separated and
aqueous layer was washed with dichloromethane. Combined organic layer was dried
over sodium sulfate and solvent was evaporated under reduced pressure to give (S) - 3-
cyano-5-methylhexanoic acid (7.5 g).
Example 38: Recovery of Cinchonidine through basification
Cinchonidine (14.5gm) was obtained through basification of aqueous layer of example
28 which contain the hydrochloric acid salt of cinhonidine.
Example 39: Synthesis of (S)-Pregabalin from (S)-3-cyano-5-methyl hexanoic acid.
A solution of (S)-3-cyano-5-methyl hexanoic acid (II) (20.0 g, 0.13 mol) in methanol:
water (50:50) (100 cm3) was added into a solution of potassium carbonate (9.8 g,
0.071 mol) in water (20 cm3) at 25 °C and was stirred at room temperature for 2 h.
The mixture was then transferred into a Parr autoclave reactor and carefully raney
nickel (10.0 g) was added. Reactor was purged with hydrogen gas twice and then 10
atm. hydrogen pressure was maintained for 24 h. The reaction mixture was filtered
through a Celite pad and solvent from filtrate was evaporated under reduced
pressure to leave a semi-solid material, which was re-crystallized from /so-propyl
alcohol: water mixture (94:06, 25 cm3) to obtain (S)-pregabalin (10.0 g, 48 % and 99
% ee as perchiral HPLC analysis), as a white solid.
FTIR (KBr): 3400, 2956, 1645, 1551, 1489, 1278 cm'1
1H NMR (CD3OD, 200 MHz): 0.91-0.96 (m, 6H), 1.22-1.23 (q, 2H), 1.64-1.74 (q, 1H),
2.20-2-48 (m, 3H), 2.79-3.00 (m, 2H).
13C NMR (CDCI3, 50 MHz): 21.4,21.9, 24.3, 31.6,40.5,40.6,43.5, 181.1.
MS(EI):C8H17NO2: 159.13; [M+H]+= 159.96.
Example 40: Synthesis of (S)-Pregabalin from (S)-3-cyano-5-methyl hexanoic acid
and isolation by using dimethoxy ethane.
A solution of (S)-3-cyano-5-methyl hexanoic acid (II) (20.0 g, 0.13 mol) in methanol:
water (70:30) (100 cm3) was added into a solution of potassium carbonate (7.2 g,

0.13 mol) in water (20 cm3) at 25 °C and was stirred at room temperature for 2 h. The
mixture was then transferred into a Parr autoclave reactor and carefully raney nickel
(10.0 g) was added. Reactor was purged with hydrogen gas twice and then 10 atm.
hydrogen pressure was maintained for 24 h. The reaction mixture was filtered
through a Celite pad and resulting filtrate was acidified with acetic acid (8.52 mL,
0.013 mol) and stirred for 10 min. solvent from resulting reaction mixture was
evaporated under reduced pressure to leave a semi-solid material, which further
suspended in dimethoxy ethane (100 mL) and stirred for 2 h at 70 °C. After which
reaction mixture was allow to cool at 5 °C and stirred for 5 h at 5 °C to obtain (S)-
pregabalin (12.0 g, 60 % and 99.81 % ee as per chiral HPLC analysis), as a white
solid.

We claim
1) A process for synthesis of pregabalin (I)

from cyano acetic acid alkyl ester of formula (A)

Wherein,
R = CH3 : Compound III
R = C2H5 : Compound VIII
comprising,
a) condensation of 2-methyl-propionaldehyde (IV) with cyano acetic acid alkyl ester
(A) in presence of organic or inorganic base such as piperidinium acetate, cesium
acetate, and further hydrogenation using noble metal catalyst such as platinum
oxide, palladium on carbon palladium hydroxide on carbon and also with Raney
nickel in polar solvent such as methanol, ethanol, water, 1,4-dioxane,
tetrahydrofuran, dimethoxy ethane and diglyme under hydrogen pressure of about 1
kg/cm2 to 5 kg/cm2 with subsequent isolation of the product 2-cyano-4-methyl-
pentanoic acid alkyl ester (B) in solution form from the catalyst by filtration;

b) reaction of compound of formula (B) with halo acetic acid ethyl ester (VI),
wherein halo group includes chloro, bromo and iodo, in presence of base
such as sodium carbonate, potassium carbonate, cesium carbonate,
preferably cesium carbonate without solvent or in an organic solvent selected
from N, N-dimethyl formamide, tetrahydrofuran, 1,4-dioxane, dimethyl

sulfoxide, and dimethoxy ethane, preferably N, N-dimethyl formamide and
dimethyl sulfoxide at temperature of about 10 to 90 °C to give 4-ethyl 1-alkyl-
2-cyano-2-isobutylsuccinate (C);
i

c) reaction of compound (C) with alkalimetal chloride such as cesium chloride,
potassium chloride or sodium chloride in an organic solvent such as dimethyl
sulfoxide at temperature of about 130°C to 180°C OR reaction of compound
of formula (C) with cesium carbonate alongwith thiol at temperature of about
130 - 150°C to get (RS)-3-cyano-5-methyl-hexanoic acid ethyl ester (XI);

d) hydrolysis of compound (XI) in presence of base such as lithium hydroxide,
potassium hydroxide or sodium hydroxide, preferably with lithium hydroxide
at temperature of about 20 to 80 °C to get (RS)-3-cyano-5-methyl-hexanoic
acid (XII);

e) treatment of compound (XII) with cinchonidine(Xlll) in presence of organic
solvent such as methanol, ethanol, 1,4-dioxane, ethyl acetate,
tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxy ethane and diglyme at
temperature of about 20°C to 80°C to precipitate out (S) 3-cyano-5-
methylhexanoic acid salt of cinchonidine (XIV), followed by separation of
compound (XIV) through known separation techniques such as filtration,

centrifugation, sedimentation, followed by optional purification of (S)-3-cyano-
5-methylhexanoic acid salt of cinchonidine (XIV) in ethyl acetate or through
re-salt formation;

f) treatment of (S) 3-cyano-5-methylhexanoic acid salt of cinchonidine (XIV) with
biphasic mixture of ethyl acetate: dilute hydrochloric acid (1:1) at room
temperature to obtain (S)-3-cyano-5-methylhexanoic acid (II) from ethyl
acetate layer optionally accompanied with recovery of cinchonidine (XIII) from
aqueous phase through basification with sodium hydroxide, potassium
hydroxide;

g) hydrogenation of optically pure (S) - 3-cyano-5-methyl-hexanoic acid (II) in
presence of Raney Nickel.


such that at each step the intermediates were optionally isolated and purified with
suitable processes.
2) A process for synthesis of pregabaline (I)

from cyano acetic acid alkyl ester of formula (A)

Wherein,
R = CH3 : Compound III
R = C2H5 : Compound VIII
comprising,
a) condensation of 2-methyl-propionaldehyde (IV) with cyano acetic acid alkyl ester
(A) in presence of organic or inorganic base such as piperidinium acetate, cesium
acetate, and further hydrogenation using noble metal catalyst such as platinum
oxide, palladium on carbon, palladium hydroxide on carbon and also with Raney
nickel in polar solvent such as methanol, ethanol, water, 1,4-dioxane,
tetrahydrofuran, dimethoxy ethane and diglyme under hydrogen pressure of about 1
kg/cm2 to 5 kg/cm2 with subsequent isolation of the product 2-cyano-4-methyl-
pentanoic acid alkyl ester (B) in solution form from the catalyst by filtration;

b) reaction of compound of formula (B) with halo acetic acid ethyl ester (VI),
wherein halo group includes chloro, bromo and iodo, in presence of base
such as sodium carbonate, potassium carbonate, cesium carbonate,

preferably cesium carbonate without solvent or in an organic solvent selected
from N, N-dimethyl formamide, tetrahydrofuran, 1,4-dioxane, dimethyl
sulfoxide, and dimethoxy ethane, preferably N, N-dimethyl formamide and
dimethyl sulfoxide at temperature of about 10 to 90 °C to give 4-ethyl 1-alkyl-
2-cyano-2-isobutylsuccinate (C);

c) hydrolysis of compound (C) in presence of base such as lithium hydroxide,
potassium hydroxide or sodium hydroxide, preferably with lithium hydroxide
at temperature of about 20 to 80 °C, preferably at 65 to 70 °C to get 2-cyano-
2-isobutylsuccinic acid (XVI)

d) compound (XVI) was decarboxylated in presence of mineral acid such as
sulfuric acid in organic solvent such as ethyl acetate to obtain compound (XII)
at about temperature 70 to 80 °C.

e) treatment of compound (XII) with cinchonidine(XIII) in presence of organic
solvent such as methanol, ethanol, 1,4-dioxane, ethyl acetate,
tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxy ethane and diglyme at
temperature of about 20°C to 80°C to precipitate out (S) 3-cyano-5-

methylhexanoic acid salt of cinchonidine (XIV), followed by separation of
compound (XIV) through known separation techniques such as filtration,
centrifugation, sedimentation, followed by optional purification of (S)-3-cyano-
5-methylhexanoic acid salt of cinchonidine (XIV) in ethyl acetate or through
re-salt formation;

f) treatment of (S) 3-cyano-5-methylhexanoic acid salt of cinchonidine (XIV) with
biphasic mixture of ethyl acetate: dilute hydrochloric acid (1:1) at room
temperature to obtain (S)-3-cyano-5-methylhexanoic acid (II) from ethyl
acetate layer optionally accompanied with recovery of cinchonidine (XIII) from
aqueous phase through basification with sodium hydroxide, potassium
hydroxide;

g) hydrogenation of optically pure (S) - 3-cyano-5-methyl-hexanoic acid (II) in
presence of Raney Nickel.


such that at each step the intermediates were optionally isolated and purified with
suitable processes.
3. A process for synthesis of pregabaline (I)

from (RS)-3-cyano-5-methyl-hexanoic acid (XII);

comprising;
a) treatment of compound (XII) with cinchonidine(XIII) in presence of organic
solvent such as methanol, ethanol, 1,4-dioxane, ethyl acetate,
tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxy ethane and diglyme at
temperature of about 20°C to 80°C to precipitate out (S) 3-cyano-5-
methylhexanoic acid salt of cinchonidine (XIV), followed by separation of
compound (XIV) through known separation techniques such as filtration,
centrifugation, sedimentation, followed by optional purification of (S)-3-cyano-
5-methylhexanoic acid salt of cinchonidine (XIV) in ethyl acetate or through
re-salt formation;

b) treatment of (S) 3-cyano-5-methylhexanoic acid salt of cinchonidine (XIV) with
biphasic mixture of ethyl acetate: dilute hydrochloric acid (1:1) at room
temperature to obtain (S)-3-cyano-5-methylhexanoic acid (II) from ethyl
acetate layer optionally accompanied with recovery of cinchonidine (XIII) from

aqueous phase through basification with sodium hydroxide, potassium
hydroxide;

c) hydrogenation of optically pure (S) - 3-cyano-5-methyl-hexanoic acid (II) in
presence of Raney Nickel.

such that at each step the intermediates were optionally isolated and purified by
conventional processes.

Improved process for the synthesis of (S)-pregabalin having more than 99% ee
through (S) - 3-cyano-5-methyl-hexanoic acid has been developed. In addition to
above, a novel process for resolution of (RS) - 3-cyano-5-methyl-hexanoic acid
through diastereomeric salt formation with cinchonidine to obtain (S) - 3-cyano-5-
methyl-hexanoic acid in high yield and high optical purity has been developed and
furthermore process for recovery/ reuse of cinchonidine is also developed to improve
the overall process efficiency.