Indian Journal of Chemistry

Vol. 51B, October 2012, pp 1470-1488

Eco-friendly, industrial process for synthesis of (S)-3-(aminomethyl)-5methylhexanoic acid [pregabalin]

Bhairab Nath Roy*, Girij Pal Singh, Piyush Suresh Lathi, Manoj Kunjabihari Agrawal,
Rangan Mitra &Vijay Sadashiv Pise
Lupin Research Park, Survey No 46/A & 47/A, Nande Village, Mulshi Taluka, Pune 411 042, India
E-mail: bnroy@lupinpharma.com
Received 14 May 2012; accepted (revised) 21 August 2012
In the present work pregabalin has been synthesized by four novel routes, which have been broadly categorized into
two approaches. In the first strategy, it has been synthesized through a hemiaminal intermediate. In the second approach,
(RS)-ethyl-3-cyano-5-methylhexanoate, a key intermediate, has been synthesized through novel and cost effective routes,
followed by either lipase catalyzed kinetic resolution to optically pure (S)-ethyl-3-cyano-5-methylhexanoate (>99% ee, 85%
yield) or resolution via diastereomeric salt formation with cinchonidine to obtain optically pure (S)-3-cyano-5-methylhexanoic acid (>99% ee, 85% yield), which has been subsequently converted to pregabalin (>99% ee). In addition, for
improvement of atom economy as well as cost effectiveness, an efficient process for complete racemization of (R)-3-cyano5-methyl-hexanoic acid has been developed.

Keywords: Pregabalin, cyano mono ester, resolution, lipase, cinchonidine

Pregabalin, (S)-3-(aminomethyl)-5-methylhexanoic
acid, also known as -isobutyl--aminobutyric acid,
or isobutyl-GABA, is a potent anticonvulsant1,
currently sold under trade name of Lyrica. The
drug, pregabalin has also been 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
disorder2.
Syntheses of pregabalin via asymmetric as well as
achiral pathways are well reported. Generally,
synthesis of (S)-3-(aminomethyl)-5-methylhexanoic
acid is broadly categorized into three major
approaches: (i) resolution of (RS)-3-(aminomethyl)-5methylhexanoic acid via diastereomeric salt
formation3 (ii) synthesis via (S)-ethyl 3-cyano-5methylhexanoate3-7 and (iii) chiral or non-chiral
desymmetrization of 3-isobutyl glutaric anhydride8-10.
Some of the other methods for synthesis of (S)-3(aminomethyl)-5-methylhexanoic
acid
include
reductive amination of mucohalic acid and its
derivatives11, stereo-selective synthesis using chiral
auxiliaries such as (+)-4-methyl-5-phenyl-2-oxazolidinone12 and also through 2,2-dichloro-3-isobutylcyclobutanone13. Most of the above reported methods

are not ecologically friendly and non-benign

chemicals such as alkali cyanides, nitro compounds or
azides have been employed.
Improvement of environmental profile of
manufacturing processes for synthesis of active
pharmaceutical ingredients (APIs) is one of the
important goals in pharmaceutical industry14. This
includes use of eco-friendly benign chemicals,
enhancing efficiency and yield in order to minimize
waste, reduction of solvent usage and reactants, and /
or to develop operational friendly processes. A
number of statistical co-relations with respect to
greenness of chemistry and process efficiency have
been established and are currently practiced15,16.
The present work focuses on two major
approaches for the synthesis of pregabalin. In the
first approach, desired product i.e. pregabalin was
obtained through a hemiaminal intermediate
whereas, the second approach involved the
development of novel process for the synthesis of
(S)-3-cyano-5-methyl hexanoic acid, which was
subsequently converted to pregabalin. In addition to
this, an attempt has been made to assess the
greenness of the developed routes vis--vis
desirability for scale-up for industrial manufacture
through the use of prevalent yard-sticks for
measurement of greenness and efficiency.

ROY et al.: ECO-FRIENDLY, INDUSTRIAL PROCESS FOR PREGABALIN

1471

Scheme I

Results and Discussion

In Scheme I, four reaction sequences for the
synthesis of pregabalin have been shown.
First Approach: Synthesis of pregabalin from
5-hydroxy-4-iso-butyl-5H-furan-2-one [Route 1]
5-Hydroxy-4-iso-butyl-5H-furan-2-one 117 on
reaction with ammonia gave the hemiaminal

intermediate 2, which on subsequent hydrogenation

gave racemic pregabalin. It can be further resolved to
obtain pregabalin as per reported method3. Moreover,
asymmetric synthesis of pregabalin was attempted by
replacing ammonia with chiral amines such as (S)alpha methyl benzylamine and (S)-phenylglycinol,
which resulted in 60% enantiomerically enriched
pregabalin, as depicted in Scheme II, which could be

1472

INDIAN J. CHEM., SEC B, OCTOBER 2012

Scheme II Reagents and conditions: (i) NH3, MeOH, 25C, 1.5 h; (ii) NH2CH(R)Ph, MeOH, 25C, 1 h; (iii) a) H2 (5 atm), 10 mol %
Pd/C (50 % wet and 10 % Pd loading), MeOH, RT, 8 h; (iv) H2 (25 atm), 10 mol % Pd/C (50 % wet and 10 % Pd loading), MeOH, RT,
8 h; (v) resolution as per reported method3

resolved as per reported method3 to obtain optically

pure pregabalin.
Compound 4 was obtained from compound 3
probably because compound 3 existed in equilibrium
with compound 3a i.e. the dienamine intermediate,
which underwent hydrogenation and hydrogenolysis.

methyl-hexanoic acid / ethyl ester to eventually obtain

(S)-3-cyano-5-methyl-hexanoic acid.
(ii) Asymmetric synthesis of (S)-3-cyano-5-methylhexanoic acid/ ester, and
(iii) Racemization of undesired isomer i.e. (R)-3cyano-5-methyl-hexanoic acid/ ester.

Second Approach: Synthesis of pregabalin from

(S)-3-cyano-5-methyl-hexanoic acid

Synthesis of (RS)-ethyl 3-cyano-5-methylhexanoate

from succinic anhydride [Route 2]

The first approach for synthesis of pregabalin

yielded racemic/enantionmerically enriched product
which needed further resolution to obtain pregabalin.
Currently, in the literature there are no reports for
racemization and recycling of undesired isomer of
pregabalin. Hence, the strategy was re-directed
towards the synthesis of the key intermediate of
pregabalin i.e. (S)-3-cyano-5-methyl hexanoic acid
which consisted of the following strategies:
(i) a) synthesis of (RS)-ethyl 3-cyano-5-methylhexanoate and b) resolution of (RS)-3-cyano-5-

Succinic acid diesters 6a-d were converted to

corresponding products 7a-d via Stobbe condensation
with iso-butyraldehyde. Hydrogenation of compounds
7a-c gave the compounds 8a-c which were attempted
upon to convert to the corresponding amide 8d.
However, amidification of the half esters i.e.
compounds 8a-c through ammonolysis failed even
under drastic conditions such as 10 kg/cm2 ammonia
pressure at 50C (Scheme III).
Hence, compound 7d (R=CH2Ph) was converted to
compound 9 by esterification with ethanol in presence

ROY et al.: ECO-FRIENDLY, INDUSTRIAL PROCESS FOR PREGABALIN

1473

Scheme III Reagents and conditions: (i) ROH, pTSA, toluene, reflux; 5 h; (ii) iso-butyraldehyde, potassium tert-butoxide, tertbutanol, RT, 24 h; (iii) H2 (5 atm), 5 mol % Pd/C (50% wet and 10% Pd loading, ethanol, RT, 5 h

Scheme IV Reagents and conditions: (i) Ethanol, pTSA, reflux; 12 h; (ii) H2 (10 atm), 5 mol % Pd/C (50% wet and 10% Pd loading),
Methanol, RT, 10 h; (iii) a) Thionyl chloride, 60C, 10 h; b) DCM, NH3, 1 h; (iv) Thionyl chloride, reflux; 12 h

Scheme V Reagents and conditions: (i) Aq. KOH, RT, 10 h; (ii) LiBH4, THF, reflux; 4 h

of p-toluenesulfonic acid (pTSA), which on

subsequent hydrogenation and hydrogenolysis gave
the compound 10. Compound 10 was converted to
compound 11 via the corresponding acid chloride and
subsequently reacting with ammonia. Dehydration of
compound 11 in presence of thionyl chloride gave
(RS)-ethyl 3-cyano-5-methylhexanoate 14 (Scheme
IV).
Another objective was to convert ester
functionality of the compound 11 to acid through

alkaline hydrolysis and subsequent selective

reduction18 of amide group to obtain 3-(aminomethyl)-5-methylhexanoic acid. Surprisingly, it was
observed that during hydrolysis of compound 11 in
presence of bases such as potassium hydroxide,
sodium hydroxide or lithium hydroxide, only
compound 12 was obtained through migration of
amine functionality presumably via a cyclic imide
intermediate. Structure of compound 12 was
confirmed by reduction of compound 12 with lithium
borohydride to yield compound 1319 (Scheme V).

1474

INDIAN J. CHEM., SEC B, OCTOBER 2012

Scheme VI Reagents and conditions: (i) NaNO2, H2SO4, KBr, water, 14C, 4 h (ii) a) SOCl2, 60C, 10 h; b) DCM, NH3,1 h; (iii)
P2O5, 80C, 12 mm Hg; iv) diethyl malonate, NaH, DMF, RT, 24 h; (v) H2O (1 equiv.), KCl, DMSO, 150C, 6 h.

Scheme VII Reagents and conditions: (i) iso-butyraldehyde, piperidine/acetic acid, H2 (5 atm) 2 mol % Pd/C (50% wet and 10% Pd
loading), methanol, RT, 5 h; (ii) Cs2CO3, ethyl chloro acetate, 65C, 2 h; or K2CO3, ethyl chloro acetate, 90C, 3 h (iii) CsCl, DMSO,
170C, 4 h; (iv) Cs2CO3, thiophenol, DMF, 130C, 4 h.

Synthesis of enantiomerically enriched (S)-ethyl-3cyano-5-methylhexanoate from L-leucine [Route 3]

Synthesis of (RS)-ethyl 3-cyano-5-methylhexanoate

from cyano acetic acid alkyl ester [Route 4]

(S)-2-Bromo-4-methyl-pentanenitrile
18
was
prepared from L-leucine 15 as per reported method20,
which on SN2 displacement with diethyl malonate
gave enantiomerically enriched 2-[(S)-1-cyano-3methyl-butyl]-malonic acid diethyl ester 19. Krapcho
decarboxylation21 of enantiomerically enriched 2-[(S)1-cyano-3-methyl-butyl]-malonic acid diethyl ester 19
gave enantiomerically enriched (S)-ethyl 3-cyano-5methylhexanoate (60% ee) 20 (Scheme VI).

2-Cyano-4-methyl-pentanoic acid alkyl ester 21

was obtained via Knoevenagel condensation of 2methyl-propionaldehyde with cyanoacetic acid alkyl
ester 20, followed by hydrogenation using palladiumon-charcoal22 (Scheme VII).
2-Cyano-4-methyl-pentanoic acid ethyl ester on
reaction with ethyl chloroacetate in presence of alkali
metal carbonates such as potassium carbonate or
cesium carbonate gave diethyl 2-cyano-2-isobutyl

ROY et al.: ECO-FRIENDLY, INDUSTRIAL PROCESS FOR PREGABALIN

succinate 22. It was observed that the rate of reaction

with cesium carbonate was two times faster than with
potassium carbonate; moreover colour of the product
obtained with cesium carbonate was light yellow as
compared to light brown obtained with potassium
carbonate.
Compound 22 was decarboxylated in presence of
cesium chloride or potassium chloride to yield (RS)ethyl 3-cyano-5-methylhexanoate 14. Compound 22
was also decarboxylated at much lower temperature in
presence
of
cesium
carbonate/thiophenol23
(Scheme VII).
Enzymatic resolution of (RS)-ethyl-3-cyano-5methylhexanoate 14 to obtain (S)-ethyl-3-cyano-5methylhexanoate 23
A number of lipase enzymes were screened and
Table I lists the result and stereo-selectivity for the
N
O
14

(i)

(S)

(R)

N
O

23

N
O

24

OH

Scheme VIII Reagents and conditions: (i) Phosphate buffer

(40 mmol, pH 7.2), Lipase, 10C, 4 h.

1475

screened enzymes. Only Candida Antarctica Lipase B

showed desired stereo-selectivity towards the
hydrolysis of (RS)-ethyl 3-cyano-5-methylhexanoate
to (S)-ethyl 3-cyano-5-methylhexanoate in high
enantiomeric purity (99% ee) (Scheme VIII).
Ratio of rate of hydrolysis of (R)-ethyl-3-cyano-5methylhexanoate to that of (S)-ethyl-3-cyano-5methylhexanoate was found to be 2.85 and 10 at 25C
and 10C respectively (Figure 1).
Resolution of (RS)-3-cyano-5-methyl-hexanoic acid
via diastereomeric salt formation
In order to resolve (RS)-3-cyano-5-methylhexanoic acid, diastereomeric salts of optically pure
(S)-3-cyano-5-methyl-hexanoic acid and (R)-3-cyano5-methyl-hexanoic acid were prepared with chiral
amines such as (S)--methyl benzylamine, D-phenyl
glycinol and cinchonidine. (S)--Methyl benzylamine,
and D-phenyl glycinol did not form crystalline solid
either with (S) or (R)-3-cyano-5-methyl hexanoic
acid. Cinchonidine produced nice crystalline high
melting salt with both (S) and (R)-3-cyano-5-methylhexanoic acid.
The temperature dependence solubility for
cinchonidine salts of (R)-3-cyano-5-methyl-hexanoic
acid and cinchonidine salt of (S)-3-cyano-5-methyl
hexanoic acids was found to be 0.12 g/cm3,C and
0.056g/cm3,C respectively.
It was observed that difference in the solubility of
cinchonidine salt of (R)-3-cyano-5-methyl-hexanoic
acid over cinchonidine salt of (S)-3-cyano-5-methylhexanoic acid was more than 6 times at 55C. Hence,
resolution of (RS)-3-cyano-5-methyl hexanoic acid

Table I Screening of lipases

Enzyme

Trade Name

Supplier

% ee

Candida Antarctica Lipase B

Thermomyces langinous
Rhizomucor miehei
Candida antarctica Lipase B
Candida Antarctica Lipase B
Aspergillus niger
Pseudomonas fluorescens
Burkholderia cepacia
Burkholderia cepacia
Candida rugosa
Candida Antarctica Lipase A
Rhizomucor miehei
Thermomyces langinous
@: No specificity observed

Novozym 435
Lipozyme TL IM
Lipozyme RM- IM
CALB
CALB-lyophilized
Amano AS
Amano AK
Amano PS IM
Amano PS SD
Amano AYS
CLEA
Rhizomucor miehei
Thermomyces langinous

Novozyme A/S
Novozyme A/S
Novozyme A/S
C-LETA
C-LETA
Amano enzyme Japan
Amano enzyme Japan
Amano enzyme Japan
Amano enzyme Japan
Amano enzyme Japan
CLEA Techologies
Sigma
Sigma

99%
@
@
96%
99%
@
@
@
@
@
7%
@
@

1476

% conversion of ester to acid

INDIAN J. CHEM., SEC B, OCTOBER 2012

160
140
120
100
80
60
40
20
0
0

50

100

150

Time, min

200

(S)-3-Cyano-5-methylhexanoic acid at 10C; (R)-3-Cyano-5-methylhexanoic acid at 10C; (S)-3-cyano-5-methylhexanoic acid at

25C; (R)-3-cyano-5-methylhexanoic acid at 25C
Figure 1 Rate of formation of (R)-ethyl 3-cyano-5-methylhexanoate and (S)-ethyl 3-cyano-5-methylhexanoate vs. time

(i) 2 % Ethanol
Dry solvent

OH

NaOEt (1.25 eq)

70 0C
(ii) Acetic acid, RT

(iii) Water, RT
N
26

Yield=95%

N
25

Scheme IX

with cinchonidine carried out at about 55C gave 97%

optically pure (S)-3-cyano-5-methyl-hexanoic acid,
which was further re-crystallized to obtain 99%
optically pure (S)-3-cyano-5-methyl-hexanoic acid.
Racemization of undesired isomer i.e. (R)-3-cyano5-methyl-hexanoic acid to (RS)-3-cyano-5-methylhexanoic acid (Scheme IX)
It is needless to mention, that the process
economics could be very significantly improved if the
undesired stereoisomer was recycled i.e. (R)-3-cyano5-methyl-hexanoic acid/ester
was
racemized.
However, base (sodium ethoxide) catalyzed racemization in absolute alcohol did not give satisfactory
results.
Racemization of nitriles such as (+)-2-methyl-3phenyl propionitrile, (-)-2-phenylbutyronitrile and (-)2,2-diphenylcyclopropylnitrile24,25 has been reported
in dry dimethyl sulfoxide doped with 2% ethanol with
1.25 eq of sodium ethoxide at 70C.

In compound 28, pKa of the proton adjacent to

carboxylate functionality was apparently lower as
compared to pKa of the proton adjacent to nitrile
group, which was evident from D2O exchange
reaction26 and formation of acylated product resulting
from generation of anion alpha to the carboxylate
group27.
Surprisingly, smooth racemization of (R)-ethyl-3cyano-5-methylhexanoate to (RS)-3-cyano-5-methylhexanoic acid in practically quantitative yield was
obtained by employing similar conditions i.e.
dimethyl sulfoxide doped with 2% ethanol with 1.25
eq of sodium ethoxide at 70C. Interestingly, although
reaction medium was completely anhydrous during
the course of racemization, the sole product obtained
was (RS)-3-cyano-5-methylhexanoic acid and not its
corresponding ester.
Moreover, rate of racemization in case of tert-butyl
ester of (R)-3-cyano-5-methylhexanoic acid was
considerably slower than that for the corresponding

1477

ROY et al.: ECO-FRIENDLY, INDUSTRIAL PROCESS FOR PREGABALIN

Table II Metrics values for the four routes

Route
Metrics

Route 1

Route 2

Route 3

Route 4

E-Factor
E-Factor (assuming 80% solvent recovery)
Atom economy
Atom efficiency
Reaction Mass efficiency
Carbon efficiency (without considering recycling of undesired isomer)

31.06
9.16
49.93
39.94
22.53
35.33

163.02
29.07
16.23
12.21
3.98
6.31

154.2
55.60
15.09
11.32
2.40
14.37

22.23
4.72
51.70
36.20
29.22
42.37

180
160
140
120
Route 4
Route 1

100

Route 3

80

Route 2

60
40
20
0

E-Factor

E-Factor
(Solvent
Recovery)

Atom
Economy

Atom
Efficiency

Reaction
Mass
Efficiency

Carbon
Efficiency

Figure 2 Graphical representation of metrics calculation for routes 1, 2, 3 and 4

ethyl ester. This could be rationalized by involving

formation of a three member cyclopropanone
intermediate or its equivalent28.
Also, it is to be noted that the solvent system
reported in the literature i.e. dimethyl sulfoxide/ 2%
ethanol could be replaced with other solvents doped
with 2% ethanol such as 2-methyl tetrahydrofuran,
methyl tert-butyl ether, dimethoxy ethane, dimethyl
formamide, and N-methyl-2-pyrrolidone, having
water content in the range of 0.05 to 0.65% to give
efficient racemization of the above mentioned
substrate.
Process metrics for harmonizing green chemistry
and industrial scalability29-31
Having developed a number of alternative novel
processes for the synthesis of (S)-3-(aminomethyl)-5methylhexanoic acid, it would be worthwhile to

assess environmental aspect, greenness, efficiency

and assign relative merits to the developed routes and
based on these, recommend them for further scale up.
A number of criteria or metrics as given below
were used for quick assessment of greenness of
reaction protocols29-31. Table II summarizes the
outcome of the following metrics which are generally
followed for the assessment of a process and Figure 2
gives the graphical representation of metrics
calculations for the four routes developed.
1. E-factor:

E - factor =

Total Waste (Kg)

Kg of Product

In pharmaceutical industry E-factor is normally in

the range to 25-250; lower the value for E-factor more
benign the process.

1478

INDIAN J. CHEM., SEC B, OCTOBER 2012

2. Atom economy is defined as amount of the

reactants incorporated in the final product.
3. Atom efficiency
= Atom economy Over all yield (%)
4. Reaction mass efficiency

Reaction mass efficiency

Mass of the product 100
=
Sum of the masses of the reactants
5. Carbon efficiency

Carbon efficiency
=

Amount of carbon in product 100

Total carbon present in reactants

Higher the value for atom economy, atom

efficiency, reaction mass efficiency and carbon
efficiency, more desirable and efficient the process.
In routes 1 and 4, E-factors are the least whereas
their atom economy, atom efficiency, reaction mass
efficiency and carbon efficiency are also better than
those for routes 2 and 3. According to these factors,
routes 1 and 4 should be the routes of choice from
greener aspects for the synthesis of (S)-3(aminomethyl)-5-methylhexanoic acid. From the
practical point of view also, routes 1 and 4 are easier
to carry out and easier to scale up as both involve less
number of steps and lower amount of reagents per kg
of product and also do not require any special
treatment for the waste generated.
Experimental Section
The enantiomeric excess (ee) for pregabalin was
determined by HPLC using a Shimadzu LC 2010
system equipped with a chiral column [Purosphere
star RP-18e (4.6 150 mm), 5 m], column oven
temperature 25C and UV-Vis detector (UV at
340 nm). Mobile phase was phosphate buffer
(10 mmol) : acetonitrile (55:45) with flow rate 1.0
mL/min, injection volume 20 L. The enantiomeric
excess (ee) was determined by derivatizing with
Marfeys reagent (retention time for R-isomer is 8.4
min and for S-isomer is 11.4 min). NMR spectra were
obtained using 200 MHz Bruker instruments, with
CDCl3, MeOD and DMSO-d6 as solvents. Chemical
shifts () are given in ppm relative to tetramethylsilane ( = 0 ppm). IR spectra were recorded on
Perkin-Elmer Spectrum (Model: Spectrum 100)

instrument and absorption bands are given in cm-1.

The enantiomeric excess (ee) for (S)-ethyl-3-cyano-5methyl-hexanoate was determined by Gas-Liquid
chromatography using a Shimadzu GC 2010 system
equipped with a chiral column [Chiraldex (20 m
0.25 mm 0.12 mm)], and FID detector, retention
time for (R)-ethyl-3-cyano-5-methyl-hexanoate is 21
min and for (S)-ethyl-3-cyano-5-methyl-hexanoate is
24 min. Mass analyses were performed on Shimadzu
LCMS 2010A instrument. Powder X-ray diffraction
was recorded on PANalytical B. V. Netherlands
model PN3040/60X Part Pro. DSC was recorded on
Perkin-Elmer model Diamond DSC at the rate of
10C/min, and endothermic peak was recorded in C.
All chemicals mentioned were obtained from
commercial sources and were used without any
further purification.
5-Hydroxy-4-iso-butyl -5H-furan-2-one17 1
n-Heptane (75.0 mL) and morpholine (17.8 g, 0.20
mol) were introduced in a reactor while stirring at
ambient temperature. The resultant mixture was
cooled to 0C and glyoxylic acid (29.6 g, 0.40 mol, 50
wt % in water) was added slowly over 20 min at 0C.
The mixture was stirred at 20C for 1 h and 4methylvaleraldehyde (20.0 g, 0.20 mol) was added.
The reaction mixture was heated to 45C and stirred
for additional 20 h, after which it was cooled to 20C
and 37% aqueous solution of hydrochloric acid (30
mL) was carefully added and stirring continued for 2
h. n-Heptane phase was removed and aqueous phase
was washed with n-heptane (2 50 mL). The aqueous
phase was extracted with di-iso-propyl ether (3 50
mL). The di-iso-propyl ether layers were combined,
washed with brine, dried and concentrated under
reduced pressure to obtain 5-hydroxy-4-iso-butyl-5Hfuran-2-one 1 (13.0 g, 60%) as light yellow oil. IR
(neat): 3371 and 1738 cm-1; 1H NMR (200 MHz,
CDCl3, Me4Si): 0.87-0.99 (t, 6H), 1.87-2.01 (m,
1H), 2.28-2.32 (d, 2H), 5.82 (s, 1H) and 6.11 (s, 1H);
EI-MS: m/z 155.09 (M+-H. C8H12O3 requires 156.06).
5-Hydroxy-4-iso-butyl-1,5-dihydro-pyrrol-2-one, 2
Ammonia gas was purged through a solution of 5hydroxy-4-iso-butyl-5H-furan-2-one (15.0 g, 0.096
mol) in methanol (50 mL) for 30 min at 25C. The
reaction mixture was stirred for 1 h at 25C and
solvent was evaporated under reduced pressure to
afford
5-hydroxy-4-iso-butyl-1,5-dihydro-pyrrol-2one 2 (14.3 g, 95%) as a dark yellow oil. IR (neat):

ROY et al.: ECO-FRIENDLY, INDUSTRIAL PROCESS FOR PREGABALIN

1479

3243, 2957, 1749, 1574, 1030 cm-1; 1H NMR (200

MHz, CDCl3, Me4Si): 0.93-1.03 (m, 6H), 1.88-2.00
(m, 1H), 2.18-2.26 (t, 2H), 5.57-5.64 (d, 1H), 5.98 (s,
1H); EI-MS: m/z 155.85 (M+ + H. C8H13NO2 requires
155.09).

1544, 1409, 1389 cm-1; 1H NMR (200 MHz, D2O,

Me4Si): 0.87-0.88 (m, 6H), 1.18-1.21 (t, 2H), 1.601.65 (q, 1H), 2.12-2.32 (m, 3H), 2.90-3.01 (m, 2H);
EI-MS: m/z 160.30 (M+ + H. C8H17NO2 requires
159.23); m.p. 182-83C

5-Hydroxy-1-[(S)-phenyl-ethyl]-4-iso-butyl-1,5-dihydro-pyrrol-2-one, 3a

Synthesis of enantiomerically enriched (S)-3(aminomethyl)-5-methylhexanoic acid, 4 from

compound 3a and 3b

To a solution of 5-hydroxy-4-iso-butyl-5H-furan-2one (10.0 g, 64.1 mmol) in iso-propanol (100 mL)

was added (S)--methyl benzyl amine (7.8 g, 64.1
mmol) at 25C. The mixture was stirred at 25C for 1
h after which solvent was evaporated from the
reaction mass under reduced pressure to afford 5hydroxy-1-[(S)-phenyl-ethyl]-4-iso-butyl-1,5-dihydropyrrol-2-one 3a (15.5g, 93%) as a dark yellow oil. IR
(neat): 3319, 2959, 1751, 1166 cm-1; 1H NMR (200
MHz, CDCl3, Me4Si): 0.86-0.94 (t, 3H), 0.96-0.99
(t, 3H), 1.34-1.38 (d, 2H), 1.49-1.53 (d, 1H), 1.751.85 (m, 1H), 2.24-2.27 (d, 2H), 4.27-4.30 (q, 1H),
5.17 (s, 1H), 5.88 (s, 1H), 7.26-7.37 (m, 5H); EI-MS:
m/z 260.30 (M+ + H. C16H21NO2 requires 259.0).
5-Hydroxy-1-(2-hydroxy-1-(S)-phenyl-ethyl)-4-isobutyl-1,5-dihydro-pyrrol-2-one, 3b
To a solution of 5-hydroxy-4-iso-butyl-5H-furan-2one (10.0 g, 64.1 mmol) in methanol (100 mL) was
added (S)-(+) phenylglycinol (8.83 g, 64.1 mmol) at
25C. The mixture was stirred at 25C for 1 h after
which solvent was evaporated from the reaction mass
under reduced pressure to afford 5-hydroxy-1-(2hydroxy-1-phenyl-ethyl)-4-iso-butyl-1,5-dihydro-pyrrol-2-one 3b (14.0 g, 80%)as a dark yellow oil.
IR(neat): 3337, 2933, 1740, 1167, 757 cm-1; EI-MS:
m/z 274.30 (M+ - H. C16H21NO3 requires 275.15).
3-(Aminomethyl)-5-methylhexanoic acid, 4 from
5-hydroxy-4-iso-butyl-1,5-dihydro-pyrrol-2-one, 2
In a Parr autoclave, a solution of 5-hydroxy-4-isobutyl-1,5-dihydro-pyrrol-2-one (10.0 g, 0.064 mmol)
in methanol (50 mL) and 50% wet palladium-oncarbon (1.0 g) was charged. Reactor was purged with
hydrogen gas twice and 5 atm. Hydrogen pressure
was maintained for 8 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
iso-propyl alcohol : water mixture (94:06, 25 mL) to
obtain 3-(aminomethyl)-5-methylhexanoic acid 4 (6.5
g, 64%), as a white solid. IR(neat): 3367, 2956, 1661,

A Parr autoclave was charged with a solution of

compound 3 (0.06 mol) in methanol (50 mL) at 25C
and 50% wet palladium-on-carbon (1.0 g) was
carefully added. Reactor was purged with hydrogen
gas twice and 20 atm. Hydrogen pressure was
maintained for 8 h. The reaction mixture was filtered
through a Celite pad and solvent from filtrate was
evaporated under reduced pressure to leave a semisolid material, which was re-crystallized from isopropyl alcohol:water mixture (94:06, 25 mL) to obtain
(S)-3-(aminomethyl)-5-methylhexanoic acid (60% ee
by chiral HPLC analysis), as a white solid. IR(neat):
3367, 2956, 1661, 1544, 1409, 1389 cm-1; 1H NMR
(200 MHz, D2O, Me4Si): 0.87-0.88 (m, 6H), 1.181.21 (t, 2H), 1.60-1.65 (q, 1H), 2.12-2.32 (m, 3H),
2.90-3.01 (m, 2H) (matches with reference 3); EI-MS:
m/z 160.30 (M+ + H. C8H17NO2 requires 159.23); m.p.
187-88C.
General method for synthesis of succinic acid
diester 6a and 6b
To a solution of succinic anhydride (1.0 mol) in
ethanol (5 v/w of substrate) was added p-toluenesulfonic acid (10% w/w of succinic anhydride) and
alcohol (5 v/w of substrate) at 25C. The mixture was
heated and maintained at a temperature of 75-85C
for 12 h after which it was cooled to RT. Solvent was
evaporated under reduced pressure to leave a semisolid residue. The residue was extracted with ethyl
acetate (500 mL) and the combined organic layer was
washed with 10% aqueous solution of sodium
bicarbonate (250 mL), dried and solvent was
evaporated under reduced pressure to obtain product.
6a: 85% yield, colorless oil; IR (neat): 2983, 2938,
1735, 1394, 1159, 1031, 857 cm-1; 1H NMR (200
MHz, CDCl3, Me4Si): 2.61 (s, 4H), 3.72 (s, 6H)
(matched with reference 32); EI-MS: m/z 146.95
(M+ + H. C6H10O4 requires 146.06).
6b: 85% yield, colorless oil; IR (neat): 2984, 2938,
1733, 1393, 1159, 1031, 857 cm-1; 1H NMR (200
MHz, CDCl3, Me4Si): 1.14-1.22 (t, 6H), 2.54

1480

INDIAN J. CHEM., SEC B, OCTOBER 2012

(s, 4H), 4.02-4.12 (q, 4H) (matched with Ref. 32);

EI-MS: m/z 174.95 (M+ + H. C8H14O4 requires 174.09).
General method for synthesis of succinic acid
diester 6c and 6d
To a solution of succinic anhydride (1.0 mol) in
toluene (5v/w of the substrate) was added p-toluenesulphonic acid (10% w/w of succinic anhydride) and
alcohol (2.0 mol) at 25C. The mixture was heated to
a temperature of 135C for 12 h after which the
reaction mass was cooled to RT. Solvent was
evaporated under reduced pressure to leave a semisolid residue. The residue was extracted with ethyl
acetate (500 mL) and combined organic layer was
washed with 10% aqueous solution of sodium
bicarbonate (250 mL), dried and solvent was concentrated under reduced pressure to afford product.
6c: 90%, white crystalline solid; IR (neat): 2959,
2927, 2862, 1729, 1214, 1167, 983 cm-1; 1H NMR
(200 MHz, CDCl3, Me4Si): 0.71-1.05 (m, 24H),
1.29-1.40 (t, 4H), 1.62-1.69 (d, 4H), 1.81-1.99 (m,
4H), 2.58 (s, 4H), 4.61-4.74 (m, 2H); EI-MS: m/z
417.30 (M++ Na. C24H42O4 requires 394.30); m.p. 6364C.
6d: 86%, off white crystalline solid; IR (neat):
3088, 3031, 1732, 1498, 1156, 1003, 733, 698 cm-1;
1
H NMR (200 MHz, CDCl3, Me4Si): 2.73 (s, 4H),
5.16 (s, 4H), 7.38 (s, 10H); EI-MS: m/z 299.05 (M++
H. C18H18O4 requires 298.0); m.p. 49-50C.
General method for synthesis of 7a-d
A solution of the succinic acid diester(0.67 mol)
and iso-butyraldehyde (48.2 g, 0.67 mol) in tertbutanol (250 mL) was added cautiously and slowly
over 60 min to a solution of potassium tert-butoxide
(82.8 g, 0.74 mol) in tert-butanol (250 mL) at 50C.
The reaction mixture was stirred for 2 h at 70C and
cooled to 25C after which it was further stirred for
another 12 h. Solvent was evaporated under reduced
pressure to obtain a semi-solid residue, which was
dissolved in water (5 v/w of residue). Aqueous layer
was washed with ethyl acetate (2 100 mL) to
remove any un-reacted succinic acid diester. Aqueous
layer was acidified with hydrochloric acid (6 M, 200
mL) and extracted with ethyl acetate (3 100 mL).
Combined organic layer was dried and concentrated
under reduced pressure to afford product.
7a: White crystalline solid; (yield 88%); IR (neat):
2952, 1712, 1416, 1157, 983 cm-1; EI-MS: m/z 186.9
(M+ + H. C9H14O4 requires 186.0); m.p. 72-74C.

7b: Colorless oil (yield 75%); IR(neat): 2965,

2963, 1713,1652, 1447, 1155 cm-1; EI-MS: m/z 240.0
(M+ + K. C10H16O4 requires 200.10).
7c: Yellow color oil; (yield 73%); IR (neat): 2958,
1714, 1256, 1178, 986 cm-1; EI-MS: m/z 333.3 (M+ +
Na. C18H30O4 requires 310.4).
7d: Yellow color oil; (yield 66%); IR (neat): 3500,
2964, 1735, 1708, 1948, 1497, 1379, 1268, 1076, 991
cm-1; EI-MS: m/z 262.9 (M+ + H. C15H18O4 requires
262.0).
General method for hydrogenation of Stobbe
product, 8a-c
A solution of the Stobbe product (0.15 mol) in
ethanol (100 mL) was charged into a Parr reactor
followed by addition of 10 mol% palladium-on-carbon
(10% Pd loading). Reactor was purged with hydrogen
gas twice and 10 atm. hydrogen pressure was
maintained in the Parr autoclave until hydrogen
consumption ceased. The reaction mass was filtered
through a Celite pad to remove Pd/C and solvent from
the filtrate was removed under reduced pressure to
obtain a semi-solid residue. The residue was dissolved
in 1 M aqueous sodium hydroxide solution (150 mL).
Aqueous layer was washed with ethyl acetate to
remove any un-reacted material and was acidified with
aqueous hydrochloric acid (50%, 30 mL) and extracted
with di-iso-propyl ether (3 250 mL). Combined
organic layer was dried and solvent was evaporated
under reduced pressure to obtain the product.
8a: Colorless oil (yield 90%); IR (neat): 2965,
1734, 1711, 1469, 1177, 1015 cm-1; 1H NMR (200
MHz, CDCl3, Me4Si): 0.87-1.01 (m, 6H), 1.23-1.27
(m, 1H), 1.49-1.53 (m, 2H), 2.39-2.44 (m, 1H), 2.632.70 (m, 1H), 2.81-2.83 (m, 1H), 3.62 (s, 3H); EI-MS:
m/z 189.0 (M+ -H. C10H18O4 requires 188.0).
8b: Colorless oil (yield 87%); IR(neat): 2960,
1732, 1713, 1469, 1178, 1015 cm-1; 1H NMR (200
MHz, CDCl3, Me4Si): 0.87-1.01 (m, 6H), 1.23-1.32
(m, 4H), 1.52-1.61 (m, 2H), 2.42-2.47 (m, 1H), 2.602.84 (m, 2H), 4.11-4.16 (m, 2H); EI-MS: m/z 203.0
(M+ -H. C10H18O4 requires 202.0).
8c: Colorless oil (yield 80%); IR (neat): 2927,
1732, 1714, 1455, 1369, 1175, 983 cm-1; EI-MS: m/z
313.4 (M+ -H. C18H32O4 requires 312.2).
3-[(Benzyloxy)carbonyl]-5-methylhex-3-enoic acid
ethyl ester, 9
To a solution of 3-[(benzyloxy)carbonyl]-5methylhex-3-enoic acid (78.0 g, 0.29 mol) in ethanol

ROY et al.: ECO-FRIENDLY, INDUSTRIAL PROCESS FOR PREGABALIN

(500 mL) was added p-toluenesulfonic acid (7.8 g,

10% w/w of substrate) at 25C. The mixture was
heated to 90C and stirred for 12 h after which it was
cooled to RT. Solvent was evaporated under reduced
pressure to obtain a semi-solid residue which was
dissolved in 5% aqueous sodium carbonate solution
(120 mL) and extracted with di-iso-propyl ether (3
100 mL). Combined organic layer was dried and
concentrated under reduced pressure to obtain 3[(benzyloxy) carbonyl]-5-methylhex-3-enoic acid
ethyl ester 9 (61.8 g, 72%) as yellow oil. IR (neat):
3065, 3033, 2962, 1736, 1711, 1649, 1498, 1264,
1171, 1149, 1073, 993, 771, 697 cm-1; 1H NMR (200
MHz, DMSO-d6, Me4Si): 1.02 (d, 3H), 1.03 (d, 3H),
1.20 (t, 3H), 2.58 (m, 1H), 3.37 (s, 2H), 4.10 (t, 2H),
4.5.13 (s, 2H), 6.85(d, 1H), 7.33-7.34 (m, 5H); EIMS: m/z 290.85 (M++H, C17H22O4 requires 290.0).
2-[(Ethoxycarbonyl)methyl]-4-methylpentanoic
acid, 10
A Parr autoclave was charged with a solution of 3[(benzyloxy) carbonyl]-5-methylhex-3-enoic acid
ethyl ester (43.0 g, 0.15 mol) in ethanol (100 mL)
followed by addition of 10 mol% palladium-oncarbon (10% Pd loading). The reactor was purged
with hydrogen gas twice and charged with hydrogen
gas; 10atm.hydrogen pressure was maintained in the
Parr autoclave until hydrogen consumption ceased.
Reaction mixture was filtered through a Celite pad to
remove Pd/C and solvent from the mother liquor was
evaporated under reduced pressure to leave an oily
residue which was dissolved in 1 M aqueous sodium
hydroxide solution (150 mL). Aqueous layer was
washed with ethyl acetate to remove any un-reacted
material. Aqueous layer was acidified with aqueous
hydrochloric acid (50%, 30 mL) and extracted with
di-iso-propyl ether (3 250 mL). Combined organic
layer was dried and solvent was evaporated under
reduced pressure to obtain 2-[(ethoxycarbonyl)methyl]-4-methylpentanoic acid (23.0 g, 77%) as a
light yellow oil. IR(neat): 3451, 2959, 2872, 1735,
1468, 1176, 1033 cm-1; 1H NMR (200 MHz, CDCl3,
Me4Si): 0.82 (d, 3H), 0.86 (d, 3H), 0.98-1.22 (m,
4H), 1.35-1.59(m, 2H), 2.46 (t, 2H), 2.57-2.71(m,
1H), 4.01(t, 2H); EI-MS: m/z 202.90 (M+ + H.
C10H18O4 requires 202.25).
Ethyl 3-carbamoyl-5-methylhexanoate, 11
A solution of 2-[(ethoxycarbonyl)methyl]-4-methylpentanoic acid (21.0 g, 0.1 mol) in cyclohexane

1481

(50 mL) under nitrogen atmosphere was heated to

60C and thionyl chloride (18.6 g, 0.15 mol) was
added carefully over 1 h at 60C. The mixture was
further heated at 80C and stirred for an additional 12
h, after which it was cooled to 25C and
dichloromethane (1000 mL) was added. To the
reaction mixture, ammonia gas was purged for 1-1.5 h
and ammonia solution (500 mL) was added. Organic
layer was separated and aqueous layer was extracted
with dichloromethane (500 mL). Combined organic
layer was dried and solvent was evaporated under
reduced pressure to obtain ethyl 3-carbamoyl-5methylhexanoate as yellow oil (18.0 g, 86%).
IR(neat): 3428, 3354, 2958, 2873, 1733, 1674, 1468,
1414, 1373, 1179, 1034, 787 cm-1; 1H NMR (200
MHz, CDCl3, Me4Si): 0.88 (dd, 6H), 1.12-1.24 (m,
4H), 1.51-1.60 (m, 2H), 2.33 (dd, 1H), 2.56-2.78 (m,
2H), 4.05(t, 2H), 6.08 (s, 1H),6.17 (s,1H); EI-MS: m/z
201.95 (M++H C10H19NO3 requires 201.0).
2-(Carbamoylmethyl)-4-methylpentanoic acid 12
and corresponding tert-butyl amine salt
To an aqueous solution of potassium hydroxide
(11%, 100 mL) was added ethyl 3-carbamoyl-5methylhexanoate (15.0 g, 74.6 mmol) at RT. The
reaction mixture was stirred for 10 h at RT. Reaction
mass was extracted with ethyl acetate (100 mL) and
the aqueous layer was acidified to pH 1.5 by addition
of dilute HCl solution. The aqueous layer was further
extracted with ethyl acetate (3 100 mL). Combined
organic layer was concentrated under reduced
pressure to leave 2-(carbamoylmethyl)-4-methylpentanoic acid) as a white solid (13.6 g). To a solution
of the compound 12 (1.6 g, 9.24 mmol) in ethyl
acetate (15 mL) was added tert-butyl amine (0.68 g,
9.24 mmol) in a dropwise manner over 15 min at RT
and stirred for 30 min. The precipitate obtained was
filtered off and sucked dry to leave the tert-butyl
amine salt of compound 12 as a white crystalline solid
(2.1 g, 92%). IR(neat): 3356, 2956, 1678, 1527, 1409,
1276 cm-1; EI-MS: m/z 247.05 (M+ + H. C12H26N2O3
requires 246.19).
2-(2-Aminoethyl)-4-methylpentanoic acid, 13
To a solution of lithium borohydride (0.76 g, 34.7
mmol) in dry tetrahydrofuran (20 mL) at 0C,was
added slowly in a dropwise manner a solution of 2(carbamoylmethyl)-4-methylpentanoic acid (6.0 g,
34.7 mmol) in dry THF (30 mL). Temperature of the
reaction mass was increased to 65C and was refluxed

1482

INDIAN J. CHEM., SEC B, OCTOBER 2012

for 6 h. After cooling the reaction mixture to RT, it

was quenched carefully by adding a solution of
ammonium chloride (1.8 g, 34.7 mmol) in methanol
(30 mL). The organic layer was concentrated under
reduced pressure and the residue was purified by
column chromatography with the product eluting out
with 15% ethyl acetate in cyclohexane as a white
crystalline solid (0.35g, 49%). IR (neat): 3399, 2956,
1659, 1569, 1415, 1029 cm-1; 1H NMR (200 MHz,
D2O, Me4Si): 0.88 (dd, 6H), 1.17-1.30 (m, 1H),
1.42-1.55 (m, 3H), 2.32-2.51 (m, 3H), 2.69-2.80 (m,
1H); EI-MS: m/z 159.95 (M+ + H. C8H17NO2 requires
159.0)22.
(RS)-Ethyl-3-cyano-5-methylhexanoate, 14 from
ethyl 3-carbamoyl-5-methylhexanoate, 11
A reactor equipped with overhead stirrer was
charged with ethyl 3-carbamoyl-5-methylhexanoate
(15.1 g, 74.6 mmol) and heated to 80C. Thionyl
chloride (10 mL, 137.4 mmol) was added carefully to
the above reaction mixture over 1 h at 80C. The
reaction mixture was stirred for 12 h at 80C, after
which it was cooled to 25C and quenched by
carefully adding water, maintaining the reaction
temperature below 25C. The aqueous layer was
extracted with di-iso-propyl ether (2 50 mL).
Combined organic layer was dried and concentrated
under reduced pressure to obtain crude (RS)-ethyl-3cyano-5-methylhexanoate (11.0 g, 80%) as a yellow
oil. IR (neat): 2961, 2242, 1738, 1469, 1182, 1023
cm-1; 1H NMR (200 MHz, CDCl3, Me4Si): 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); EI-MS: m/z 201.05 (M+ + H2O.
C10H17NO2 requires 183.0).
2-(S)-Bromo-4-methyl-pentanoic acid, 16
To a solution of potassium bromide (2.72 g, 22.9
mmol) in sulphuric acid (162.0 g in 1100 mL of
water) L-leucine (86.0 g, 0.66 mol) was added and the
mixture was cooled to 14C. A solution of sodium
nitrite (70.0 g, 1.01 mol) in water (200 mL) was
added slowly over 2 h and mixture was stirred for 3 h
at 14C, after which it was warmed to 20C and
stirred for another 1.5 h. The reaction mixture was
extracted with dichloromethane (5 500 mL).
Combined organic layers were dried and concentrated
under reduced pressure to obtain 2-(S)-bromo-4methyl-pentanoic acid (108.0 g, 85%) as a light
yellow oil. IR (neat): 3583, 2959, 1718, 1468, 1258

cm-1; 1H NMR (200 MHz, CDCl3, Me4Si): 0.95 (d,

3H), 0.96 (d, 3H), 1.72-1.86 (m, 1H), 1.93 (dd, 2H),
4.29 (t, 1H); EI-MS: m/z 192.80/194.80 (M+ - H.
C6H11BrO2requires 193.0/195.0).
2-(S)-Bromo-4-methyl-pentanoic acidamide, 17
A solution of 2-(S)-bromo-4-methyl-pentanoic acid
in cyclohexane (50 mL) was heated to 60C in an
atmosphere of nitrogen and thionyl chloride was
added carefully over 1 h while stirring. The mixture
was further heated to 80C for 12 h after which it was
cooled to 25C and dichloromethane (1000 mL) was
added. To the reaction mixture, ammonia gas was
purged for 1-1.5 h and ammonia solution (500 mL)
was added. Organic layer was separated and aqueous
layer was extracted with dichloromethane (500 mL).
Combined organic layer was dried and concentrated
under reduced pressure to obtain 2-(S)-bromo-4methyl-pentanoic acidamide as a white solid (61.4
g,77%). IR (neat): 3363, 3188, 2957, 2871, 2364,
1666, 1419, 616 cm-1; 1H NMR (200 MHz, DMSO-d6,
Me4Si): 0.83 (d, 3H), 0.88 (d, 3H), 1.54-81 (m, 3H),
4.35 (t, 1H), 7.26 (s, 1H), 7.76 (s, 1H); EI-MS: m/z
193.85/195.75
(M+.
C6H12BrNO
requires
192.0/194.0); m.p. 114-15C.
2-(S)-Bromo-4-methyl-pentanenitrile, 18
2-(S)-Bromo-4-methyl-pentanoic acid amide (50.0
g, 0.25 mol) and phosphorous pentoxide (80.0 g, 0.56
mol) were mixed thoroughly in a round-bottomed
flask and kept for vacuum distillation at 80C and 12
mm of Hg for 4-5 h to obtain 2-(S)-bromo-4-methylpentanenitrile (43.0 g, 94%) as a colorless oil. IR
(neat): 2963, 2936, 2248, 1756, 1470, 1372, 746 cm-1;
1
H NMR (200 MHz, DMSO-d6, Me4Si): 0.97 (d,
3H), 1.01 (d, 3H), 1.88-1.97 (m, 3H), 4.44 (t, 1H); EIMS: m/z 175.85 (M+. C6H10BrN requires 175.0).
2-(1-Cyano-3-methyl-butyl)-malonic acid diethyl
ester, 19
A reactor was charged with dimethyl formamide
(200 mL) and sodium hydride (5.76 g, 0.145 mol;
60% emulsion in paraffin) was added carefully in
small portions under an atmosphere of nitrogen. The
mixture was cooled to 10-15C and a solution of
diethyl malonate(23.1 g, 0.145 mol) in dimethyl
formamide(50 mL) was added slowly over 30 min by
maintaining temperature below 15C, after which it
was heated to 25C and stirred for 1 h. To the above
reaction mixture was added a solution of 2-bromo-4-

ROY et al.: ECO-FRIENDLY, INDUSTRIAL PROCESS FOR PREGABALIN

methyl-pentanenitrile (28.0 g, 0.145 mol) in dimethyl

formamide (50 mL) over 30 min and stirred for 24 h,
after which the reaction mixture was quenched by
adding water (1000 mL). Aqueous layer was extracted
with dichloromethane (3 500 mL). Combined
organic layer was dried and solvent was evaporated
under reduced pressure to yield 2-(1-cyano-3-methylbutyl)-malonic acid diethyl ester as a yellow oil (40.0
g, 98%). 1H NMR (200 MHz, CDCl3, Me4Si): 0.981.01 (m, 6H), 1.22-1.32 (m, 6H), 1.62-1.69 (m, 1H),
1.77-1.90 (m, 2H), 3.25-3.31 (m, 1H), 3.50-3.52 (d,
1H), 4.15-4.23 (m, 4H); EI-MS: m/z 253.75 (M+ - H.
C13H21NO4 requires 255.15).
Enantiomerically enriched (S)-ethyl-3-cyano-5methylhexanoate, 14 from 2-(1-cyano-3-methylbutyl)-malonic acid diethyl ester, 19
To a solution of 2-(1-cyano-3-methyl-butyl)malonic acid diethyl ester (30.0 g, 0.117 mol), in
dimethyl sulfoxide (300 mL) were added potassium
chloride (9.65 g, 0.13 mol), water (10 mL) and heated
to 150-160C for 6 h after which it was cooled to 3040C and methyl tert-butyl ether (200 mL) was added.
The mixture was further cooled to 0-5C and
quenched with water (1000 mL) maintaining
temperature below 40C and stirred for 30 min. The
aqueous phase was extracted with methyl tert-butyl
ether (3 800 mL). The organic layer was
decolorized by treating with 7.0 g of activated
charcoal. The resultant mixture was filtered and
solvent was evaporated to give enantiomerically
enriched (S)-ethyl-3-cyano-5-methylhexanoate as a
yellow oil (78:22, S:R) (17.5 g, 81%). IR (neat): 2961,
2242, 1738, 1469, 1182, 1023 cm-1; 1H NMR (200
MHz, CDCl3, Me4Si): 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); EI-MS: m/z 201.05 (M+ + H2O. C10H17NO2
requires 183.0).
Methyl-2-cyano-4-methylpentanoate, 21a
Methyl cyano acetate (113.0 g, 1.14 mol) was
dissolved in methanol (125 mL), iso-butyraldehyde
(98.0 g, 1.36 mol) and glacial acetic acid (12 mL)
were added to it at RT. The mixture was cooled to
4C 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 20C. The reaction mixture was
transferred into a Parr autoclave reactor followed by

1483

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 ceased. Reaction was
monitored by TLC. After completion of reaction, the
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 as light yellow
oil (170 g, 90% yield). IR (neat): 2958, 2872, 2642,
2250, 1751, 1468, 1185, 1131, 1010 cm-1; 1H NMR
(200 MHz, CDCl3, Me4Si): 0.92 (d, 3H), 0.99 (d,
3H), 1.74-1.98 (m, 3H), 3.53 (t, 1H) 3.81 (s, 3H).
2-Cyano-4-methyl-valeric acid ethyl ester, 21b
To a solution of ethyl cyano acetate (56.5 g, 0.5
mol) in methanol (100 mL) was added isobutyraldehyde (43.2 g, 0.6 mol) at 25C after which it
was cooled to 4C. A solution of acetic acid (6 mL)
and piperidine (2 mL) in methanol (50 mL) was added
slowly to above reaction mixture over 20 min without
allowing the temperature to increase above 20C. The
reaction mixture was transferred into a Parr autoclave
reactor followed by addition of 2 mol% loading of
palladium-on-carbon (10% Pd). Reactor was purged
with hydrogen gas twice and charged with hydrogen;
3 atm pressure was maintained in the Parr autoclave
until hydrogen consumption ceased, after which it
was filtered through a Celite pad to remove Pd/C and
solvent from the filtrate was evaporated under
reduced pressure to obtain an oily residue, which was
suspended in water (100 mL) and extracted with diiso-propyl ether (3 250 mL). Combined organic
layer was dried and solvent was evaporated under
reduced pressure to obtain 2-cyano-4-methyl-valeric
acid ethyl ester aslight yellow oil (80.0 g, 95%). IR
(neat): 2962, 2249, 1746, 1469, 1186 cm-1; 1H NMR
(200 MHz, CDCl3, Me4Si): 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); EI-MS: m/z 186.85 (M+ + H2O.
C9H15NO2 requires 169.0).
Synthesis of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate, 22a in presence of cesium carbonate
A reactor was charged with methyl 2-cyano-4methylpentanoate 21 (41.0 g, 265.0 mmol), ethyl
chloro acetate (35.7 g, 291 mmol) and benzyl triethyl
ammonium chloride (0.6 g) and the resulting reaction

1484

INDIAN J. CHEM., SEC B, OCTOBER 2012

mixture was stirred for 15-20 min at RT. 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 resulted in rise in
the reaction temperature upto 65 to 70C. After
complete addition of cesium carbonate, reaction
mixture was stirred further for 1 h at 60C. 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 2cyano-2-isobutylsuccinate as light yellow oil (57.5 g,
90% yield). IR(neat): 2958, 2248, 1741, 1637, 1467,
1199, 1025 cm-1; 1H NMR (200 MHz, CDCl3, Me4Si):
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); EI-MS: m/z C9H15NO2: 241; [M+H2O]+:
259.05.
Synthesis of 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate, 22a in presence of potassium carbonate
A reactor was charged with methyl 2-cyano-4methylpentanoate (41.0 g, 265.0 mmol), ethyl
chloroacetate (35.7, 291 mmol) and benzyl triethyl
ammonium chloride (0.6 g) and resulting reaction
mixture was stirred for 15-20 min at RT. To above
reaction mixture activated fine powder of potassium
carbonate (20.3 g, 145.5 mmol) was added slowly in
small portions while stirring over a period of 10-15
min. After complete addition of potassium carbonate,
the reaction mixture was stirred further for 3 h at
90C. 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 and
concentrated to obtain 4-ethyl 1-methyl 2-cyano-2isobutylsuccinate as light brown oil (57.5 g, 90%
yield).
Diethyl 2-cyano-2-isobutylsuccinate, 22b
A reactor equipped with overhead stirrer was
charged with dimethoxy ethane (50 mL) and sodium
hydride (22.0 g, 0.550 mol: 60% emulsion in paraffin)
was added in small portions under nitrogen
atmosphere. The mixture was cooled to 10-15C and
solution of 2-cyano-4-methyl-valeric acid ethyl ester
(80.0 g, 0.474 mol) in dimethoxy ethane (500 mL)
was added slowly over 1 h by maintaining
temperature below 20C after which the reaction

mixture was heated to 50C and stirred further for 1 h.

A solution of ethyl chloro acetate (74.0 g, 0.6 mol) in
dimethoxy ethane (300 mL) was added slowly to the
reaction mixture over 1 h. After complete addition of
the ethyl chloro acetate solution, the reaction mixture
was cooled to RT and stirred for an additional 24 h,
after which reaction mixture was filtered to remove
sodium chloride and filtrate was concentrated under
reduced pressure to obtain 2-cyano-2-isobutylsuccinate as light yellow oil (102.0 g, 84%). IR (neat):
2963, 2248, 1743, 1469, 1195, 1025 cm-1; 1H NMR
(200 MHz, CDCl3, Me4Si): 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);
EI-MS: m/z C9H15NO2: 255, [M+H2O] +: 273.05.
(RS)-Ethyl 3-cyano-5-methylhexanoate, 14
A reactor was charged with diethyl 2-cyano-2isobutylsuccinate (102.0 g, 0.4 mol), cesium chloride
(72.5 g, 0.43 mol) in dimethyl sulfoxide (500 mL) and
heated to 150-160C for 4 h after which the reaction
mixture was cooled to 20 to 30C and methyl tertbutyl ether (200 mL) was added. The mixture was
further cooled to 0-5C and water (1000 mL) was
added in small portions without allowing the
temperature to increase above 40C and was stirred
for 30 min. The aqueous phase was extracted with
methyl tert-butyl ether (3 800 mL), The organic
layer was decolorized by treating with 7.0 g of
activated charcoal. The resultant mixture was filtered
to remove charcoal and solvent was evaporated to
afford(RS)-ethyl 3-cyano-5-methylhexanoate as light
brown oil (66.1 g, 98.5% purity by GC). IR (neat):
2961, 2242, 1738, 1469, 1182, 1023 cm-1; 1H NMR
(200 MHz, CDCl3, Me4Si): 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); EI-MS: m/z 201.05 (M+ + H2O. C10H17NO2
requires 183.0).
Decarboxylation of diethyl 2-cyano-2-isobutylsuccinate, 22 to obtain (RS)-ethyl 3-cyano-5-methylhexanoate, 14 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, 77.0 mmol), cesium carbonate
(5.0 g, 15.4 mmol) and N,N-dimethylformamide
(40 mL). The resulting reaction mixture was heated at
130C and maintained at that temperature for 4 h.

ROY et al.: ECO-FRIENDLY, INDUSTRIAL PROCESS FOR PREGABALIN

Reaction was monitored by GC for conversion of

(RS)-ethyl 3-cyano-5-methylhexanoate.
Screening of enzymes for stereo-selective hydrolysis of (RS)-ethyl-3-cyano-5-methylhexanoate, 14
Screening of enzymes was conducted using HLC
Heating-ThermoMixer (Model No. MHR 11) having
14 vial (14 10 mL) chamber blocks with orbital
shaking. Each 10 mL vial was charged with phosphate
buffer (5 mL) of pH 7.2, (RS) 3-cyano-5methylhexanoic acid ethyl ester (0.5 g, 2.7 mmol) and
enzyme (10% w/w of substrate) as mentioned in
Table I. The reaction mixture was stirred for 4 h,
after which it was extracted with dichloromethane (2
5 mL) and monitored on chiral GC analysis for
stereo-selectivity of enzymes.
Stereo-selective hydrolysis of (RS)-ethyl-3-cyano-5methylhexanoate 14 in presence of Novozym 435 at
10C
A reactor equipped with overhead stirring was
charged with sodium phosphate buffer (500 mL) (40
mM, pH 7.2) and (RS)-3-cyano-5-methylhexanoic
acid ethyl ester (100 g) at 25C and was cooled to
10C. Novozym 435 (6.0 g, 6% w/w of substrate)
immobilized enzyme was added and the resulting
heterogenous reaction mixture was titrated with 1 M
solution of sodium hydroxide to maintain a pH of 7.2.
The extent of reaction was monitored on GC for chiral
purity. After complete hydrolysis of (R)-3-cyano-5methylhexanoic acid ethyl ester, reaction was stopped
by filtering the enzyme. Aqueous layer was extracted
with di-iso-propyl ether (3 100 mL). Combined
organic layer was dried over anhydrous sodium
sulphate and solvent was evaporated under reduced
pressure to obtain (S)-ethyl-3-cyano-5-methylhexanoate as brown oil (40.0 g, 40%, and 99% ee).
Stereo-selective hydrolysis of (RS)-ethyl 3-cyano-5methylhexanoate 14 in presence of Novozym 435 at
25C
A reactor equipped with overhead stirring was
charged with sodium phosphate buffer (500 mL) (40
mM, pH 7.2) and (RS)-3-cyano-5-methylhexanoic
acid ethyl ester (100 g) at 25C. Novozym 435 (6.0 g,
6% w/w of substrate) immobilized enzyme was added
and the resulting heterogenous reaction mixture was
titrated with 1 M solution of sodium hydroxide to
maintain a pH of 7.2. The extent of reaction was
monitored on GC for chiral purity. After complete

1485

hydrolysis of (R)-3-cyano-5-methylhexanoic acid

ethyl ester, reaction was stopped by filtering the
enzyme. Aqueous layer was extracted with di-isopropyl ether (3 100 mL). Combined organic layer
was dried over anhydrous sodium sulphate and
solvent was evaporated under reduced pressure to
obtain (S)-ethyl-3-cyano-5-methylhexanoate as brown
oil (20.0 g, 20%, and 99% ee).
Stereo-selective hydrolysis of enantiomerically
enriched (S)-ethyl-3-cyano-5-methylhexanoate 14
in presence of Novozym 435 at 10C
A reactor equipped with overhead stirring was
charged with sodium phosphate buffer (500 mL) (40
mM, pH 7.2) and enantiomerically enriched (S)-3cyano-5-methylhexanoic acid ethyl ester (78:22) (100
g) at 25C and was cooled to 10C. Novozym 435
(6.0 g, 6% w/w of substrate) immobilized enzyme
was added and the resulting heterogeneous reaction
mixture was titrated with 1 M solution of sodium
hydroxide to maintain a pH of 7.2. The extent of
reaction was monitored on GC for chiral purity. After
complete hydrolysis of (R)-3-cyano-5-methylhexanoic
acid ethyl ester, reaction was stopped by filtering the
enzyme. Aqueous layer was extracted with di-isopropyl ether (3 100 mL). Combined organic layer
was dried over anhydrous sodium sulphate and
solvent was evaporated under reduced pressure to
obtain (S) ethyl-3-cyano-5-methylhexanoate as brown
oil (50.0 g, 50%, and 99% ee).
(S)-Ethyl-3-cyano-5-methylhexanoate
A reactor was charged with (S)-ethyl-3-cyano-5methylhexanoate (52.0 g) and water (250 mL). A
solution of lithium hydroxide (15.0 g) in water (25
mL) was added slowly while stirring. The reaction
mixture was stirred further for 12 h at 60C.
Thereafter, the reaction mixture was cooled to RT and
un-reacted (RS)-3-cyano-5-methylhexanoic acid ethyl
ester, if any was extracted with di-iso-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
anhydrous sodium sulfate and solvent was evaporated
under reduced pressure to obtain (RS)-3-cyano-5methylhexanoic acid as yellow oil (31.1 g). IR (neat):
3118, 2961, 2935, 2875, 2642, 2244, 1715, 1470,
1174, 1113 cm-1; 1H NMR (200 MHz, CDCl3, Me4Si):
0.95 (d, 3H), 0.96 (d, 3H), 1.36-1.38 (d, 1H), 1.591.66 (m, 1H), 1.79-1.85 (m, 1H), 2.59-2.61 (dd, 1H),

1486

INDIAN J. CHEM., SEC B, OCTOBER 2012

2.69-2.75 (dd, 1H), 2.98-3.04 (m, 1H); EI-MS: m/z

C8H13NO2: 155.19, [M-H] -: 154.00, [M+H] +: 156.15.
(S)-3-(Aminomethyl)-5-methylhexanoic acid
from (S)-3-cyano-5-methylhexanoic acid

A solution of (S)-3-cyano-5-methylhexanoic
acid(20.0 g, 0.13 mol) in methanol:water (50:50) (100
mL) was added to a solution of potassium hydroxide
(7.2 g, 0.13 mol) in water (20 mL) at 25C and was
stirred at RT for 2 h. The mixture was then transferred
into a Parr autoclave reactor and 50% wet palladiumon-carbon (1.0 g) was added carefully. 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 recrystallized from iso-propyl alcohol:water mixture
(94:06, 25 mL) to obtain (S)-3-(aminomethyl)-5methylhexanoic acid as a white solid (12.0 g, 60%
and 99% ee).
Resolution of (RS)-3-cyano-5-methylhexanoic acid
through diastereomeric salt formation with cinchonidine (1:1 mol ratio) in ethyl acetate
A reactor was charged with cinchonidine (37.9 g,
129 mmol) and ethyl acetate (500 mL) and resulting
reaction mixture was heated to 70C. A solution of
(RS)-3-cyano-5-methylhexanoic acid (20.0 g, 129.0
mmol) in ethyl acetate (200 mL) was added to 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 RT and stirred further for 12 h. (S)-3-Cyano-5methylhexanoic acid salt of cinchonidine precipitated
out during this period. The resultant mixture was
filtered to give (S)-3-cyano-5-methylhexanoic acid
salt of cinchonidine as a white solid (28.3 g, 97% ee
for (S)-ethyl-3-cynao-5-methylhexanoate by GC
area%), which was further re-crystalized to obtain (S)3-cyano-5-methylhexanoic acid salt of cinchonidine
(25.3 g, 99% ee for (S)-ethyl-3-cyano-5-methylhexanoate by GC area %). Spectral data is given
below.
IR (neat): 3413, 3071, 2955, 2234, 1639, 1595,
1508, 1394, 1102, 915, 785, 759, 619 cm-1; 1H NMR
(200 MHz, DMSO-d6, Me4Si): 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
[2] (Cu K1 = 1.54060 , K2 = 1.54443 , K =
1.39225 ; 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
(10C/min): Peak = 152.49C, Onset = 149.86C.
Racemization of (R)-ethyl-3-cyano-5-methylhexanoateto (RS)-3-cyano-5-methylhexanoic acid in
dimethyl sulfoxide and 2% ethanol
A reactor equipped with overhead stirring was
charged with (R)-ethyl-3-cyano-5 methylhexanoate
(15.8 g, 0.086 mol), dimethyl sulfoxide (158 mL),
ethanol (4 mL) and sodium ethoxide (7.35 g, 0.10
mol) and the resulting reaction mixture was stirred for
4 h at 75C, after which the reaction mixture was
cooled to RT, neutralized with acetic acid and treated
with water (200 mL) in small portions to maintain the
temperature below 30C. The aqueous phase was
extracted with methyl tert-butyl ether (3 200 mL).
Organic phases were combined and dried over
anhydrous sodium sulfate and solvent was evaporated
under reduced pressure to give (RS)-3-cyano-5methylhexanoic acid as light brown oil (12.5 g, 95%
yield and analyzed by chiral GC by converting to the
corresponding ethyl ester).
IR (neat): 3118, 2961, 2935, 2875, 2642, 2244,
1715, 1470, 1174, 1113 cm-1; 1H NMR (200 MHz,
CDCl3, Me4Si): 0.95 (d, 3H), 0.96 (d, 3H), 1.361.38 (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); EI-MS: m/z C8H13NO2: 155.19, [M-H] -: 154.00,
[M+H] +: 156.15.
Racemization
of
(R)-ethyl-3-cyano-5-methylhexanoate to (RS)-3-cyano-5-methylhexanoic acid
in N-methyl pyrrolidone and 2% ethanol
A reactor equipped with overhead stirring was
charged with (R)-ethyl-3-cyano-5 methylhexanoate
(3.0 g), N-methyl pyrrolidone (30 mL), ethanol (0.6
mL) and sodium ethoxide (1.4 g) and the resulting
reaction mixture was stirred for 4 h at 75C, after

ROY et al.: ECO-FRIENDLY, INDUSTRIAL PROCESS FOR PREGABALIN

which the reaction mixture was cooled to RT,

neutralized with acetic acid and treated with water
(200 mL) in small portions to maintain the
temperature below 40C. The aqueous phase was
extracted with methyl tert-butyl ether (3 100 mL).
Organic phases were combined and dried over
anhydrous sodium sulfate and solvent was
evaporated under reduced pressure to give (RS)-3cyano-5-methylhexanoic acid as brown oil (2.4 g,
analyzed by chiral GC by converting to
corresponding ethyl ester).
Racemization
of
(R)-ethyl-3-cyano-5-methylhexanoate to (RS)-3-cyano-5-methylhexanoic acid
in dimethyl formamide and 2% ethanol
A reactor equipped with overhead stirring was
charged with (R)-ethyl-3-cyano-5 methylhexanoate
(3.0 g), dimethyl formamide (30 mL), ethanol (0.6
mL) and sodium ethoxide (1.4 g) and the resulting
reaction mixture was stirred for 4 h at 75C, after
which the reaction mixture was cooled to RT,
neutralized with acetic acid and treated with water
(200 mL) in small portions to maintain the
temperature below 40C. The aqueous phase was
extracted with methyl tert-butyl ether (3 100 mL).
Organic phases were combined and dried over
anhydrous sodium sulfate and solvent was
evaporated under reduced pressure to give (RS)-3cyano-5-methylhexanoic acid as brown oil (2.1 g,
analyzed by chiral GC by converting to
corresponding ethyl ester).
Racemization of (R)-ethyl-3-cyano-5-methylhexanoate to (RS)-3-cyano-5-methylhexanoic acid in
dimethoxy ethane and 2% ethanol
A reactor equipped with overhead stirring was
charged with (R)-ethyl-3-cyano-5 methylhexanoate
(3.0 g), dimethoxy ethane (30 mL), ethanol (0.6 mL)
and sodium ethoxide (1.4 g) and the resulting reaction
mixture was stirred for 4 h at 75C, after which the
reaction mixture was cooled to RT, neutralized with
acetic acid and treated with water (200 mL) in small
portions to maintain the temperature below 40C. The
aqueous phase was extracted with methyl tert-butyl
ether (3 100 mL). Organic phases were combined
and dried over anhydrous sodium sulfate and solvent
was evaporated under reduced pressure to give (RS)3-cyano-5-methylhexanoic acid as brown oil (2.2 g,
analyzed by chiral GC by converting to corresponding
ethyl ester).

1487

Racemization of (R)-ethyl-3-cyano-5-methylhexanoate to (RS)-3-cyano-5-methylhexanoic acid in

methyl-tert-butyl ether and 2% ethanol
A reactor equipped with overhead stirring was
charged with (R)-ethyl-3-cyano-5 methylhexanoate
(3.0 g), methyl-tert-butyl ether(30 mL), ethanol (0.6
mL) and sodium ethoxide (1.4 g) and the resulting
reaction mixture was stirred for 4 h at 75C, after
which the reaction mixture was cooled to RT,
neutralized with acetic acid and treated with water
(200 mL) in small portions to maintain the
temperature below 40C. Organic layer was separated
and aqueous phase was extracted with methyl tertbutyl ether (100 mL). Organic phases were combined
and dried over anhydrous sodium sulfate and solvent
was evaporated under reduced pressure to give (RS)3-cyano-5-methylhexanoic acid as brown oil (2.2 g,
analyzed by chiral GC by converting to corresponding
ethyl ester).
Racemization of enantiomerically enriched (R)ethyl-3-cyano-5-methylhexanoate to (RS) 3-cyano5-methylhexanoic acid in 2-methyl tetrahydrofuran and 2% ethanol
A reactor equipped with overhead stirring was
charged with (R)-ethyl-3-cyano-5 methylhexanoate
(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 75C, after
which the reaction mixture was cooled to RT,
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 (3 300 mL). Organic phases were combined
and dried over anhydrous sodium sulfate and solvent
was evaporated under reduced pressure to give (RS)3-cyano-5-methylhexanoic acid as brown oil (2.0 g,
analyzed by chiral GC by converting to corresponding
ethyl ester).
Conclusion
Four novel routes for the synthesis of (S)-3(aminomethyl)-5-methylhexanoic acid have been
developed which appear to be benign, efficient, ecofriendly and do not employ any explosive or toxic
chemicals. All the developed routes have been
assessed for the greenness and efficiency as per
criteria generally used for such assessment and based
on that, route 4 has been recommended for scale-up.

1488

INDIAN J. CHEM., SEC B, OCTOBER 2012

References
1 Silverman R B, Andruszkiewicz R, Yuen P, Sobieray D M,
Franklin L C & Schwindt M A, US Patent 5563175,
University Northwestern and Warner Lambert Co, 1966.
2 (a) Bueno L, Chovet M, Diop L, Guglietta A, Little H J,
Rafferty M F, Ren J, Taylozr C P & Watson W P, US Patent
6242488, University of Oklahoma and Warner Lambert Co,
2001; (b) Magnus L & Segal C A, US Patent 6326374,
Warner Lambert Co, 2001; (c) Singh L, US Patent 6001876,
Warner Lambert Co, 1999; (d) Akunne H C, Corbin A E,
Dooley D J, Green A L & Heffner T G, US Patent 6194459,
Warner Lambert Co, 2000; (e) Schrier D, Taylor C P &
Westlund H K N, US Patent 6329429, Warner Lambert Co,
2001; (f) Bueno L, Chovet M, Diop L, Guglietta A, Little H,
Rafferty M F, Ren J, Taylor C P & Watson W P, US Patent
6127418, Warner Lambert Co, 2000; (g) Bueno L, Chovet M,
Diop L, Guglietta A, Little H, Rafferty M F, Ren J, Taylor C
P & Watson W P, US Patent 6426368, Warner Lambert Co,
2001; (h) Magnus L & Segal C A, US Patent 6306910,
Warner Lambert Co, 2001; (i) Pande A C, US Patent
6359005, Warner Lambert Co, 2002.
3 Grote T M, Huckabee B K, Mulhern T, Sobieray D M &
Titus R D, US Patent 5637767, Warner Lambert Co, 1997.
4 Shanghui H, Carlos A M, Junhua T, William E T, Patrick K
& Yves D, US Patent 0283023 (A1), Warner Lambert Co,
2005.
5 Burk M J, Goel O, Hoekstra M S, Mich T F, Thomas,
Mulhern J & Ramsden A, US Patent Appl 0212290 A1,
Warner Lambert Co, 2003.
6 Burns M P, Weaver J K & Wong J W, US Patent Appl
0196905(A1), Warner Lambert Co, 2007.
7 Sammis G M & Jacobsen E N, J Am Chem Soc, 125, 2003,
4442.
8 Kansal V K, Chaurasia B P, Rao V G & Tiwari A P, PCT Int
Appl WO 035890 (A1), Teva Pharmaceutical Industries Ltd,
2007.
9 Kansal V K, Chaurasia B P & Tiwari A P, PCT Int Appl WO
035789 (A1), Teva Pharmaceutical Industries Ltd, 2007.
10 Kansal V K, Chaurasia B P, Tiwari A P & Shelke S H, US
Patent Appl 0306292, Teva Pharmaceutical Industries Ltd,
2008.
11 Blazecka P G, Davidson J G & Zhang J, US Patent 6924377,
Warner Lambert Co, 2005.
12 Silverman R B, Andruszkiewicz R, Yuen P W, Sobieray D
M, Franklin L C & Schwindt M A, US Patent 5563175,
University Northwestern and Warner Lambert Co, 1996.
13 Rasparini M, Tufaro R, Marras G, Giovenzana G & Castaldi
G, PCT Int Appl WO 053446 (A2), Chemo Ibrica S.A, 2009.
14 Anastas P T & Warner J C, in Green Chemistry: Theory and
Practice (Oxford University Press, Oxford), 1998.

15 Trost B M, Science, 254, 1991, 1471.

16 Sheldon R A, Pure Appl Chem, 72, 2000, 1233.
17 Bourguignon J J & Wermuth C G, J Org Chem, 46, 1981,
4889.
18 (a) Brown H C & Narasimhan S, J Org Chem, 47, 1982,
1604; (b) Schlesinger H I & Brown H C, J Am Chem Soc, 62,
1940, 342.
19 Belliotti T R, Capiris T, Ekhato I V, Kinsora J J, Field M J,
Heffner T G, Meltzer L T, Schwarz J B, Taylor C P, Thorpe
A J, Vartanian M G, Wise L D, Zhi-Su T, Weber M L &
Wustrow D J, J Med Chem, 48, 2005, 2294.
20 Ichimura K & Ohta M, Bull Chem Soc Japan, 43, 1970, 1443.
21 Krapcho A P, Glynn G A & Grenon B J, Tetrahedron Lett, 8,
1967, 215.
22 Alexander E R & Cope A C, J Am Chem Soc, 66, 1944, 886.
23 Keinan E & Eren D, J Org Chem, 51, 1986, 3165.
24 Cram D J, Rickborn B, Kingsbury C A & Haberfield P, J Am
Chem Soc, 83, 1961, 3678.
25 Youssef A A & Sharaf S M, J Org Chem, 39, 1974, 1705.
26 D2O exchange experimental condition: In a NMR tube, 3cyano-5-methyl hexanoic acid ethyl ester (50 mg), D2O (50
L), ethanol (50 L), dimethyl sulfoxide (1 mL) and sodium
ethoxide (23.2 mg) were heated to 70C and NMR was
recorded. 1H NMR (200 MHz, CDCl3, Me4Si): 0.95 (d, 3H),
0.96 (d, 3H), 1.22-1.24 (m, 4H), 1.58 (m, 1H), 1.83 (m, 1H),
2.49 (d, 1H), 2.98-3.06 (m, 1H), 4.17 (q, 2H).
27 To rationalize the acidity of protons, an experiment was
carried out by treating 3-cyano-5-methyl hexanoic acid ethyl
ester with diethyl oxalate under identical conditions and it
was observed that only one acylation product was obtained
viz. diethyl 2-(1-cyano-3-methylbutyl)-3-oxosuccinate, i.e.
acylation to carboxyl functionality and not acylation at
cyano functionality (Isolated yield: 70%); IR (Neat): 3656,
3475, 2961, 2244, 1757, 1733, 1657, 1469, 1370, 1254, 1092,
1023, 858 cm-1; 1H NMR (CD3OD, 200 MHz, equilibrium
existed for keto and enol form): 0.82-0.88 (m, 3H), 0.95 (d,
3H), 0.97 (d, 3H) 1.22-1.62 (m, 11H), 1.77-1.90 (m, 2H),
3.33 (dd, 1H), 4.24 (q, 2H), 4.35 (q, 2H), 13.02 (enolic OH);
EI-MS: C14H21NO5: m/z 283.32, [M] +m/z = 283.95, [M-H]m/z = 282.05.
28 One might rationalize the formation of (RS)-3-cyano-5methylhexanoic acid from (R)-ethy-3-cyano-5-methylhexanoic acid ester, through a cyclopropanone intermediate
(Tetrahedron: Asymmetry, 13, 2002, 563-567).
29 Constable D J C, Curzons A D & Cunningham V L, Green
Chem, 4, 2002, 521.
30 Curzons A D, Constable D J C, Mortimer D N &
Cunningham V L, Green Chem, 3, 2001, 1.
31 Watson W J W, Green Chem, 14, 2012, 251.
32 Yan J, Travis B R & Borhan B, J Org Chem, 69, 2004, 9299.