Field of the Invention:
This invention relates to process for racemization of (R)-3-cyano-5-methyl hexanoic
acid ethyl ester (VII) in presence of a base to obtain directly (RS)-3-cyano-5-methyl
hexanoic acid (III).
Background of the Invention:
The 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" of the present applicant reports the lipase
catalyzed kinetic resolution of (RS) - 3-cyano-5-methyl-hexanoic acid ethyl ester (I)
to obtain (S)- 3-cyano-5-methyl-hexanoic acid ethyl ester (II) , which was further
converted to (S)-pregabalin (VI). In the co-pending Indian patent
application entitled "Novel, cost effective, green and industrial
process for synthesis of (S)-pregabalin" of the present applicant, the inventors
demonstrated the process for resolution of (RS) - 3-cyano-5-methyl-hexanoic acid
(III) with cinchonidine through diastereomeric salt formation to obtain (S) - 3-cyano-
5-methyl-hexanoic acid (IV), which was also further converted into (S)-pregabalin.
The disclosers of above said patents, including prior art are incorporated herein by
reference.
In both the above processes (R) - 3-cyano-5-methyl-hexanoic acid (V) was obtained
as an undesired isomer.
The processes disclosed in the above said patents i.e. PCT/IN2010/000440 and co-
pending Indian patent application entitled "Novel, cost effective,
green and industrial process for synthesis of (S)-pregabalin" are summarized in
scheme A.

It is evident from the prior art that whichever process is utilized for resolution to
obtain optically pure (S) -3-cyano-5-methyl hexanoic acid (IV), about 50 % of
undesired isomer i.e. (R) -3-cyano-5-methyl hexanoic acid (V) will get produced..
Hence, it is imperative that for improvement of overall process efficiency, "atom
economy" and cost, the undesired isomer i.e. (R) - 3-cyano-5-methyl-hexanoic acid
(V) has to be isomerised through racemization to (RS) - 3-cyano-5-methyl-hexanoic
acid (III), which could be resolved through subsequent identical processes described
in application entitled "Novel, cost effective, green and industrial process for
synthesis of (S)-pregabalin" of the present applicant.
In PCT application number PCT/IN2010/000440 dated 28 June 2010, process for
racemization of (R) - 3-cyano-5-methyl-hexanoic acid ethyl ester (VII) to (RS) - 3-

cyano-5-methyl-hexanoic acid ethyl ester (I) was disclosed in presence of catalytic
amount of base such as sodium ethoxide and ethanol as a solvent and summarized in
scheme B

Racemization of nitrile compounds in presence of base (JACS, 1961, 83, 3678-3687;
J. Org. Chem. 1974, 39, 1705-1707) has been reported for benzylic substrates such as
(+)-2-methyl-3-phenyl propionitrile (VIII) , (-)-2-phenylbutyronitrile (IX) and (-) 2,2-
diphenylcyclopropylnitrile (X).

(+)-2-methyl-3-phenyI propionitrile (VIII)

(-)-2-phenylbutyronitrile (IX)


Although, in the said publications, racemization of benzylic nitrile substrates has been
reported but there is no report for the racemization of substrate containing both
carboxyl and cyano functionality i.e. β- cyano esters.
This invention provides a method for racemization of optically active β- cyano ester
directly to corresponding racemic β- cyano acid.
To the knowledge of the inventors, there is no report available for isomerization of
(R) - 3-cyano-5-methyl-hexanoic acid ethyl ester (VII) to (RS) - 3-cyano-5-methyl-
hexanoic acid (III).
Thus, this invention provides a novel, highly cost effective, operation friendly,
"green" process for racemization of (R) - 3-cyano-5-methyl-hexanoic acid ethyl ester
(VII) to (RS) - 3-cyano-5-methyl-hexanoic acid (III).
Objects of the Invention:
The object of the present invention is to provide a process for recycling of (R)-3-
cyano-5-methyl-hexanoic acid (V) via converting into corresponding ester i.e. (R)-3-
cyano-5-methyl-hexanoic acid ethyl ester (VII), followed by racemization to obtain
(RS) - 3-cyano-5-methyl-hexanoic acid (III), which could be reused for resolution
through diastereomeric salt formation with cinchonidine, thereby improving the atom
economy and hence further reduce the cost for the synthesis of (S)-pregabalin.

Summary of Invention:
The present invention is directed towards racemization of (R)-3-cyano-5-methyl
hexanoic acid ethyl ester (VII) to (RS)-3-cyano-5-methyl hexanoic acid (III) with a
base, which is directly utilized for resolution with cinchonidine as mentioned
hereinbefore. The invention is summarized below in scheme C.

The processes for isomerization of (R)-3-cyano-5-methyl hexanoic acid (VII)
(R)-3-cyano-5-methyl hexanoic acid ethyl ester (VII) and 2% absolute ethanol was
heated at 70 °C for 4 hours in organic solvent such as dimethyl sulfoxide, N,N,
dimethylformamide, N-methyl-2-pyrrolidone, 2-methyl tetrahydrofuran, dimethoxy
ethane and methyl tert-butyl ether preferably 2-methyl tetrahydrofuran. dimethoxy
ethane, methyl tert-butyl ether in presence of a base such as alkali earth metal
alkoxides e.g. sodium ethoxide, potassium tert-butoxide, sodium methoxide to obtain
(RS)-3-cyano-5-methyl-hexanoic acid (III).
Detailed Description of the Invention:
It is worthwhile to note that, the substrates reported in literature and mentioned above
contain only one electron withdrawing group i.e. nitrile, hence, when above said
substrates were subjected to racemization in presence of catalytic amount of base,
proton which is attached to carbon bearing optically active center i.e. "Ha", which is
a to cyano functionality only gets abstracted, which results into isomerization of said
nitrile substrates.

In case of substrates like β- cyano ester i.e. 3-cyano-5-methyl hexanoic acid ethyl
ester (XI), where, two vicinal protons are present as shown in the following structure
i.e. "Ha" which is a to carboxyl and "Hb" which is a to cyano functionality, it is
difficult to predict which proton will get abstracted in conditions reported in
literature..

However, surprisingly it was observed that, when (R) -3-cyano-5-methyIhexanoic
acid ethyl ester (VII) was treated with more than 1 equivalent of base such as sodium
ethoxide, in dimethyl sulfoxide and 2 % ethanol, the product was (RS) -3-cyano-5-
methylhexanoic acid (III). The product was analyzed 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 by converting into ester. Retention time for (R)
-3-cyano-5-methylhexanoic acid ethyl ester (VII) is 30.10 min and for (S) -3-cyano-5-
methylhexanoic acid ethyl ester (II) is 31.09 min. Product was also characterized by
NMR and IR having the following spectral data.
NMR spectra (CDC13, 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, lH)and
IR Spectra(neat):3118, 2961,2935, 2875, 2642, 2244, 1715, 1470, 1174, 1 I 13 cm-1.
Moreover, it is to be noted that the solvent system reported in the literature such as
dimethyl sulfoxide/ 2% ethanol could be replaced with other solvent systems such as 2-
methyl tetrahydrofuran/ 2% ethanol, methyl tert-butyl ether/ 2% ethanol, dimethoxy
ethane/ 2% ethanol, dimethyl formamide / 2 % ethanol, and N-Methyl-2-pyrrolidone/ 2 %
ethanol without effecting the efficiency of the process and also it is to be noted that water
content in the solvent used for reaction is in the range of 0.05 to 0.65 %.

Further, it was observed that when (R)-3-cyano-5-methyl hexanoic acid was treated under
similar experimental conditions used for (R)-3-cyano-5-methyl hexanoic acid ethyl ester,
it did not undergo racemization.
To the best of knowledge of the inventors, there are no reports available for one step
racemization of (R) -3-cyano-5-methylhexanoic acid ester (VII) to (RS) -3-cyano-5-
methylhexanoic acid (III).
One might rationalize the formation of (RS) -3- cyano-5-methylhexanoic acid (III)
from (R) -3- cyano-5-methylhexanoic acid ester (VII) with the help of following
plausible reaction mechanism (Scheme D), which proceeds via a cyclopropanone
intermediate.

In literature formation of cyclopropanone through Dieckmann type condensation has
been reported as shown in scheme E (Tetrahedron: Asymmetry 13 (2002) 563-567).
The present proposed reaction mechanism is akin to Dieckmann condensation.


Thus, racemization of (R) -3-cyano-5-methylhexanoic acid (V) to (RS) -3-cyano-5-
methylhexanoic acid (III) comprised of the following steps:
i) compound (V) was converted into corresponding ester i.e. compound (VII)
through esterification reaction such as "mixed-anhydride" technique
employing ethylchloroformate/ triethylamine with ethanol or through Steglich
Esterification or acid catalyzed esterification or esterification by any other
conventional methods.

ii) compound (VII) was racemized to obtain compound (III) in presence of alkali metal
alkoxides in a mixture of organic solvent e.g. methyl tert-butyl ether doped with 2%
ethanol, dimethyl sulfoxide doped with 2% ethanol. dimethylformamide doped with 2%
ethanol, dimethoxyethane doped with 2% ethanol, 2-methyl tetrahydrofuran doped with
2% ethanol and N-Methyl-2-pyrrolidone doped with 2% ethanol. Alkali metal alkoxides

used such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, lithium methoxide, lithium ethoxide, potassium tert-butoxide preferably sodium
methoxide, sodium ethoxide; more preferably sodium ethoxide. Aprotic solvent used such
as dimethyl sulfoxide, dimethylformamide, dimethoxyethane, 2-methyl tetrahydrofuran,
methyl tert-butyl ether and N-Methyl-2-pyrrolidone preferably dimethyl sulfoxide and
methyl tert-butyl ether. Protic solvent used such as methanol, ethanol, propanol and
butanol, preferably ethanol. Ratio of aprotic solvent to protic solvent varied from 1:99 to
99:1, preferably ratio used was 99:1. The quantity of base used was 1.25 mol/per mole of
substrate.

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 (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-methyI-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 CDCl3 as
solvent unless otherwise stated. Chemical shifts (S) are given in ppm relative to
tetramethylsilane (S = 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.
Example 1: Synthesis of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) through
Steglich Esterification.
A reactor equipped with overheard stirring is charged with 50 mL of dichloromethane 50
mL, ethanol (1.24 g), (R) - 3-cyano-5-methylhexanoic acid (2.1 g) and DCC (5.58 g) at 0
°C. The mixture is stirred for 1 h at 0 °C. Further it is stirred for 12 h at 25 °C. The extent
of reaction is monitored on GC for chiral purity for (R) 3-cyano-5-methylhexanoic acid
ethyl ester (1.8 g).
FTIR(neat): 2961,2242, 1738, 1469, 1182, 1023 cm-1.
1H NMR (CDCl3, 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, 1 H), 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 (EI): C10H17NO2: 183; [M+H2O]+: 201.05.

Example 2: Synthesis of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) through
mixed-anhydride.
A reactor equipped with overheard stirring is charged with 100 mL of dichloromethane,
(R) - 3-cyano-5-methylhexanoic acid (26.2 g) and triethyl amine (34.1 g) and resulting
reaction mixture was cooled to 0 °C. A solution of ethyl chloroformate (27.5 g) in
dichloromethane (100mL) was slowly added to the above reaction mixture over a period
of 30 min at 0°C and stirred further for 3 h at 25 °C.
After which reaction mixture was cooled to 0°C and ethanol (15.5 g) was added slowly
over period of 20-25 min and resultant reaction mixture was further stirred for 1 h at 25
°C. The reaction was quenched by adding 100 ml water and organic layer was separated.
Aqueous layer was further extracted with dichloromethane (2* 100ml).Combined organic
layer was dried over sodium sulfate and solvent was evaporated under reduced pressure to
obtain (R) 3-cyano-5-methylhexanoic acid ethyl ester (30.1 g) as yellow oil.
Example 3: Synthesis of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) in
presence of sulfuric acid.
A reactor equipped with overheard stirring is charged with ethanol (100 mL), (R) - 3-
cyano-5-methylhexanoic acid (25.0 g) and concentrated sulfuric acid (0.25 g) and
resulting reaction mixture was refluxed for 6 h. After which reaction was cooled to 25 C,
solvent was evaporated under reduced pressure to obtain crude (R) - 3-cyano-5-
methylhexanoic acid ethyl ester. Crude (R) - 3-cyano-5-methylhexanoic acid ethyl ester
was dissolved in di-iso-propyl ether (100 mL) and washed with 10 % aqueous solution of
sodium bicarbonate. Organic layer was dried over sodium sulfate and solvent was
evaporated under reduced pressure to obtain (R) 3-cyano-5-methylhexanoic acid ethyl
ester (30.1 g) as yellow oil.
Example 4: Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to
(RS) 3-cyano-S-methylhexanoic acid (III) in dimethyl sulfoxide and 2 % ethanol.
A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic
acid ethyl ester (15.8 g, 0.086 mol), dimethyl sulfoxide (158 ml), ethanol (4 mL ) and

sodium ethoxide (7.35 g, 0.10 mol) and resulting reaction mixture was stirred for 4 h at
75 °C. After which reaction mixture was cooled to room temperature neutralized with
acetic acid and treated with water (200 mL) in small portions to maintain the temperature
below 30 °C. The aqueous phase was extracted with methyl tert-butyl ether (3 x 200 mL),
organic phases were combined and dried over sodium sulfate and solvent was evaporated
under reduced pressure to give (RS) - 3-cyano-5-methylhexanoic acid (12.5 g 95 % yield
and analyzed chiral GC by converting in to ethyl ester) light brown color oil.
FTIR (neat): 3118, 2961, 2935, 2875, 2642, 2244, 1715, 1470, 1 174, 11 13 cm-1
1H NMR (CDCl3, 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, 1 H), 2.59-2.61 (dd, 1H), 2.69-2.75 (dd, 1H), 2.98-3.04 (m, 1H).
MS(EI): C8H13NO2: 155.19; [M-H]-: 154.00; [M+H] +: 156.15
Example 5: Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to
(RS) 3-cyano-5-methylhexanoic acid (III) in N-methyl pyrrolidine and 2 % ethanol
A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic
acid ethyl ester (3.0 g), N-methyl pyrrolidine (30 ml), ethanol (0.6 mL ) and sodium
ethoxide (1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C. After which
reaction mixture was cooled to room temperature neutralized with acetic acid and treated
with water (200 mL) in small portions to maintain the temperature below 40 °C. The
aqueous phase was extracted with methyl tert-butyl ether (3 x 100 mL), organic phases
were combined and dried over sodium sulfate and solvent was evaporated under reduced
pressure to give (RS) - 3-cyano-5-methylhexanoic acid (2.4 g, analyzed chiral GC by
converting in to ethyl ester) brown color oil.
Example 6: Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to
{RS) 3-cyano-5-methylhexanoic acid (III) in dimethyl formamide and 2 % ethanol
A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic
acid ethyl ester (3.0 g), dimethyl formamide (30 ml), ethanol (0.6 mL ) and sodium
ethoxide (1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C. After which
reaction mixture was cooled to room temperature neutralized with acetic acid and treated
with water (200 mL) in small portions to maintain the temperature below 40 °C. The

aqueous phase was extracted with methyl tert-bulyl ether (3 x 100 mL), organic phases
were combined and dried over sodium sulfate and solvent was evaporated under reduced
pressure to give (RS) - 3-cyano-5-methylhexanoic acid (2.1 g. analyzed chiral GC by
converting in to ethyl ester) brown color oil.
Example 7: Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to
(RS) 3-cyano-5-methylhexanoic acid (III) in dimethoxy ethane and 2 % ethanol
A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic
acid ethyl ester (3.0 g), dimethoxy ethane (30 ml), ethanol (0.6 mL ) and sodium ethoxide
(1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C. After which reaction
mixture was cooled to room temperature neutralized with acetic acid and treated with
water (200 mL) in small portions to maintain the temperature below 40 °C. The aqueous
phase was extracted with methyl tert-butyl ether (3 x 100 mL), organic phases were
combined and dried over sodium sulfate and solvent was evaporated under reduced
pressure to give (RS) - 3-cyano-5-methylhexanoic acid (2.2 g, analyzed chiral GC by
converting in to ethyl ester) brown color oil.
Example 8: Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to
(RS) 3-cyano-5-methylhexanoic acid (III) in methyl-tert-butyl ether
A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic
acid ethyl ester (3.0 g), dimethoxy ethane (30 ml), ethanol (0.6 mL ) and sodium ethoxide
(1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C. After which reaction
mixture was cooled to room temperature neutralized with acetic acid and treated with
water (200 mL) in small portions to maintain the temperature below 40 °C. Organic layer
was separated and aqueous phase was extracted with methyl tert-butyl ether (100 mL).
organic phases were combined and dried over sodium sulfate and solvent was evaporated
under reduced pressure to give (RS) - 3-cyano-5-methylhexanoic acid (2.2 g, analyzed
chiral GC by converting in to ethyl ester) brown color oil.
Example 9: Racemization of enantiomerically enriched (R) 3-cyano-5-
methylhexanoic acid ethyl ester (VII) to (RS) 3-cyano-5-methylhexanoic acid (III) in
2-methyl tetrahydrofuran

A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic
acid ethyl ester (3.0 g), 2-methyl tetrahydrofuran (30 ml), ethanol (0.6 mL ) and sodium
ethoxide (1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C. After which
reaction mixture was cooled to room temperature neutralized with acetic acid and solvent
was evaporated under reduced pressure to obtain residue. Residue was further suspended
in water (200 mL) and aqueous phase was extracted with methyl tert-butyl ether (3 x 300
mL), organic phases were combined and dried over sodium sulfate and solvent was
evaporated under reduced pressure to give (RS) - 3-cyano-5-methylhexanoic acid (2.0 g,
analyzed chiral GC by converting in to ethyl ester) brown color oil.

We claim:
1) A process of racemization of (R) -3-cyano-5-methylhexanoic acid (V) to obtain
(SR) -3-cyano-5-methylhexanoic acid (III) comprising
i) conversion of (R) -3-cyano-5-methylhexanoic acid (V) into corresponding
ester (VII) through esterification reaction such as "mixed-anhydride"
technique employing ethylchioroformate/ triethylamine with ethanol or
through Steglich esterification or acid catalyzed esterification or esterification
by any other conventional methods;

ii) treatment of compound (VII) with alkali metal alkoxides in a mixture of protic
and aprotic polar solvents, wherein aprotic polar solvent is selected from
dimethyl sulfoxide, dimethylformamide, dimethoxyethane, 2-methyl
tetrahydrofuran, methyl tert-butyl ether and N-Methyl-2-pyrrolidone preferably
dimethyl sulfoxide and methyl tert-butyl ether; and protic polar solvent is
selected from methanol, ethanol, propanol and butanol.

2) The process as claimed in claim 1, wherein the solvent in step (ii) is selected
from methyl tert-butyl ether doped with 2% ethanol, dimethyl sulfoxide doped
with 2% ethanol, dimethylformamide doped with 2% ethanol, dimethoxyethane
doped with 2% ethanol, 2-methyl tetrahydrofuran doped with 2% ethanol and N-
Methyl-2-pyrrolidone doped with 2% ethanol.

3) The process as claimed in claim 1, wherein alkali metal alkoxide in step (ii) is
selected from sodium methoxide, sodium ethoxide. potassium methoxide, potassium
ethoxide, lithium methoxide, lithium ethoxide, and potassium tert-butoxide.
4) A process for conversion of (R) -3-cyano-5-methylhexanoic acid ethyl ester (VII)
to (RS) -3-cyano-5-methylhexanoic acid (III) comprising treatment of compound
(VII) with alkali metal alkoxides in a mixture of protic and aprotic polar solvents,
wherein aprotic polar solvent is selected from dimethyl sulfoxide,
dimethylformamide, dimethoxyethane, 2-methyl tetrahydrofuran, methyl tert-
butyl ether and N-Methyl-2-pyrrolidone preferably dimethyl sulfoxide and
methyl tert-butyl ether; and protic polar solvent is selected from methanol,
ethanol, propanol and butanol.
5) The process as claimed in claim 4, wherein the solvent is selected from methyl
tert-butyl ether doped with 2% ethanol, dimethyl sulfoxide doped with 2%
ethanol, dimethylformamide doped with 2% ethanol, dimethoxyethane doped
with 2% ethanol, 2-methyl tetrahydrofuran doped with 2% ethanol and N-
Methyl-2-pyrrolidone doped with 2% ethanol.
6) The process as claimed in claim I, wherein the alkali metal alkoxide is selected from
sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide,
lithium methoxide, lithium ethoxide, and potassium tert-butoxide.

A novel process for racemization of (R)-3-cyano-5-methyl hexanoic acid ethyl ester
directly to (RS)-3-cyano-5-methyl hexanoic acid has been developed through a base
catalyzed mechanism in a specific solvent system.