A new enantioselective synthesis of the anticonvulsant drug pregabalin (lyrica) based on a hydrolytic kinetic resolution method

Article abstract of DOI:10.1002/chir.22253

A practical and efficient enantioselective synthesis of the anticonvulsant drug pregabalin is described for the first time using Jacobsen's hydrolytic kinetic resolution of a terminal epoxide as a key step and a source of chirality.

Full text of DOI:10.1002/chir.22253

CHIRALITY 25:965–969 (2013)
A New Enantioselective Synthesis of the Anticonvulsant Drug Pregabalin
(
Lyrica) Based on a Hydrolytic Kinetic Resolution Method
MOHAMMAD MUJAHID, AND MURUGAN MUTHUKRISHNAN*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune, India
ABSTRACT
A practical and efficient enantioselective synthesis of the anticonvulsant drug
pregabalin is described for the first time using Jacobsen’s hydrolytic kinetic resolution of a terminal
epoxide as a key step and a source of chirality. Chirality 25:965–969, 2013. © 2013 Wiley Periodicals, Inc.
KEY WORDS: pregabalin; anticonvulsant drug; hydrolytic kinetic resolution
INTRODUCTION
report a new and simple synthesis of pregabalin employing
Jacobsen’s HKR strategy as a key step and a source of
chirality.
γ-Aminobutyric acid (GABA) is an important neurotrans-
mitter that plays a major inhibitory role in the central nervous
system. An imbalance of GABA levels in the central ner-
vous system is responsible for many diseases that exhibit sev-
eral nervous system dysfunctions such as epilepsy, anxiety
1,2
EXPERIMENTAL
Chemicals and Reagents
All chemicals were purchased from Sigma Aldrich (St. Louis, MO)
in the highest quality commercially available. Solvents were purified
and dried by standard procedures prior to use. Tetrabutylammonium
fluoride (TBAF) was used as a 1.0 M solution in tetrahydofuran
3
disorders, neuropathic pain, social phobia, etc. Hence, ana-
logs of GABA have significant therapeutic potential and in
the last two decades numerous GABA mimetics (Fig. 1) were
designed with the intention that they would be able to cross
the blood–brain barrier and interact with GABAergic systems
(
THF). Isopropyl magnesium chloride was used as a 2.0 M solution
4
in THF.
and enhance GABA-mediated inhibition. Pregabalin (Lyrica
(
S)-1) is an important lipophilic, chiral analogue of GABA, ap-
Instrumentation
proved by the U.S. FDA for the management of fibromyalgia,
neuropathic pain associated with diabetic peripheral neuropa-
Infrared (IR) spectra were obtained with a Perkin–Elmer (Boston,
1
MA) Spectrum one spectrophotometer. H nuclear magnetic resonance
thy, postherpetic neuralgia, and as an adjunctive therapy for
1
3
epilepsy.5,6 Due to its unique mode of action it became
(NMR) and C NMR spectra were recorded with a Bruker (Billerica,
MA) AC-200 NMR spectrometer. Spectra were obtained in CDCl . Mon-
itoring of reactions was carried out using thin-layer chromatography
TLC) plates, Merck (Darmstadt, Germany) Silica Gel 60 F254, and vi-
sualization with UV light (254 and 365 nm), I and anisaldehyde in eth-
3
Pfizer’s best-selling drug, with worldwide sales of $4.15 bil7-
lion in 2012, showing a 12% increase from the previous year.
To date, several methods for the synthesis of enantiomerically
pure pregabalin have been reported. Generally, the method in-
(
2
anol as development reagents. Optical rotations were measured with a
Jasci (Tokyo, Japan) P 1020 digital polarimeter. Mass spectra were
recorded at ionization energy 70 eV on API Q Star Pulsar spectrometer
using electrospray ionization. High-resolution mass spectrometry
8
–10
cludes chiral pool approaches,
classical resolution pro-
cesses,1
1–15
or using stereospecific procedures.
16–24
However,
some of these methods have their own intrinsic disadvantages,
such as expensive chiral starting materials, undesired side prod-
ucts, tedious and time-consuming experiments, and so on.
Therefore, a new, practical, and expeditious stereoselective syn-
thesis of pregabalin is still desirable.
(
HRMS) (electrospray ionization, ESI) were recorded on an ORBITRAP
mass analyzer (Thermo Scientific, Pittsburgh, PA; Q Exactive). Enantio-
meric excess (ee) was determined by chiral high-performance liquid
chromatography (HPLC).
In this context, as part of our ongoing program aimed at
utilizing Jacobsen’s hydrolytic kinetic resolution strategy
Preparation
HKR)2
5–28
(S)-2-(2-(benzyloxy)ethyl)oxirane (S)-3a. A mixture of 2-(2-
(benzyloxy)ethyl)oxirane 2 (10 g, 56.1 mmol) and (S,S)
salen Co(III)OAc complex-A (0.1 g, 0.14 mmol) was vigor-
ously stirred for 15 min, then cooled to 0°C, and water added
(
for the synthesis of various pharmaceutically im-
29–34
portant compounds for industrial applications,
we herein
(
0.6 mL, 31 mmol) over a period of 15 min through a
microsyringe. The reaction mixture was stirred at room tem-
perature for 12 h, and then additional (S,S) salen Co(III)OAc
complex-A (0.1 g, 0.14 mmol) was added and stirring was con-
tinued for an additional 12 h. The reaction mixture was di-
luted with ethyl acetate, dried over Na SO , and evaporated
2
4
under reduced pressure. The residue was purified by column
*
Correspondence to: M. Muthukrishnan, Division of Organic Chemistry,
CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008,
India. E-mail: m.muthukrishnan@ncl.res.in
Received for publication 15 July 2013; Accepted 26 August 2013
DOI: 10.1002/chir.22253
Published online 23 October 2013 in Wiley Online Library
(wileyonlinelibrary.com).
Fig. 1. Pharmaceutically important GABA mimetics.
2013 Wiley Periodicals, Inc.
©

9
66
MUJAHID AND MUTHUKRISHNAN
chromatography (silica gel, petroleum ether/acetone, 95:5).
3421, 2958, 2871, 2236, 1603, 1496, 1455, 1368, 1116; NMR
The less polar epoxide (S)-3a eluted first as a colorless oil
(200 MHz, CDCl ): δ 0.92 (d, J = 5.2 Hz, 3H), 0.95 (d, J = 5.4
3
H
5
26
25
(
(
2
4.0 g, 40%); [α]2 = À15.2 (c 2.5, CHCl ) {lit. [α]D = À15.7
Hz, 3H), 1.23-1.37 (m, 1H), 1.53-1.67 (m, 1H), 1.76-1.97 (m,
D
3
-
1
c 4.06, CHCl )}; IR (CHCl , cm ): ν
3435, 3013, 2923,
861, 1720, 1495, 1453, 1411, 1362, 1102; NMR (200 MHz,
3H), 2.79-2.94 (m, 1H), 3.63 (apparent t, J = 6.1 Hz, 2H), 4.53
3
3
max
l3
(d, J = 11.8 Hz, 2H), 7.26-7.41 (m, 5H); C NMR(50 MHz,
CDCl ): δ 1.69-2.04 (m, 2H), 2.51 (dd, J = 5.1, 2.7 Hz, 1H),
CDCl ): δ 138.0 (C), 128.5 (CH, 2 carbons), 127.7 (CH, 3 car-
3
H
3
C
2
.76 (dd, J = 5.2, 4.0 Hz, 1H), 3.03-3.12 (m, 1H), 3.60-3.66
bons), 122.1 (C), 73.3 (CH ), 66.9 (CH ), 41.2 (CH ), 33.0
2 2 2
(
ddd, J = 7.0, 5.6, 1.0 Hz, 2H), 4.53 (s, 2H), 7.27-7.37 (m, 5H);
(CH ), 26.7 (CH), 26.2 (CH), 23.0 (CH ), 21.5 (CH ); MS:
2 3 3
l3
+
C NMR(50 MHz, CDCl ): δ 138.3 (C), 128.4 (CH, 2 car-
m/z 254 [M + Na] ; HRMS (ESI): m/z calculated for
3
C
+
bons), 127.7 (CH, 3 carbons), 73.1 (CH ), 67.1 (CH ), 50.1
(
by diol (R)-3b as a colorless oil (4.7 g, 43%); [α] = +18.0 (c 2.0,
EtOH) {lit. [α]D = +22.7 (c 5.16, EtOH)}; IR (CHCl , cm ):
C H NO [M + Na] 254.1515, found 254.1514.
2
2
15 21
+
CH), 47.2 (CH ), 33.0 (CH ); MS: m/z 201 [M + Na] ; followed
2 2
2
5
(S)-tert-butyl (2-(2-hydroxyethyl)-4-methylpentyl)carbamate (S)-6.
D
37
25
-1
To a solution of (S)-5 (2.0 g, 8.6 mmol) and Boc O (2.0 g, 9.5
2
3
mmol) in methanol (30 mL) was added activated Raney-nickel
catalyst (200 mg) and the reaction mixture was stirred under
hydrogen (60 psi) for 20 h. After completion of the reaction (in-
dicated by TLC), the catalyst was filtered over a plug of celite
bed (EtOAc as an eluent) and the solvent was evaporated un-
der reduced pressure. The crude product was purified over col-
umn chromatography (silica gel, petroleum ether/ethyl
acetate, 70:30) to yield (S)-6 as a colorless oil (1.8 g, 86%);
νmax 3600, 3435, 3013, 2923, 2861, 1495, 1453, 1411, 1362,
1
1
102; H NMR (200 MHz, CDCl ): δ 1.70-1.79 (m, 2H), 3.47-
.67 (m, 5H), 3.88 (m, 1H), 4.50 (s, 2H), 7.27-7.36 (m, 5H);
3
H
3
l3
C NMR (50 MHz, CDCl ): δ 137.7 (C), 128.3 (CH, 2 car-
3
C
bons), 127.6 (CH, 3 carbons), 73.0 (CH ), 70.6 (CH), 67.7
2
+
(
CH ), 66.2 (CH ), 32.9 (CH ); MS: m/z 219 [M + Na] .
2 2 2
(R)-1-(benzyloxy)-5-methylhexan-3-ol (R)-4. To a precooled
25
-1
[
α] = +1.8 (c = 1.4,CHCl ); IR (CHCl , cm ): ν
3457, 3019,
(
À20°C) solution of epoxide (S)-3a (3.8 g, 21.2 mmol) and
D
3
3
max
2
959, 2931, 1698, 1513, 1393, 1367, 1168; NMR (200 MHz,
CuI (0.1 g) in dry THF (30 mL) was added isopropyl magne-
sium chloride (2 M in THF, 15.8 mL, 31.8 mmol) in THF
for about 30 min. Subsequently, the reaction mixture was
allowed to attain ambient temperature and the stirring contin-
ued for an additional 2 h. After completion of the reaction (in-
CDCl ): δ 0.88 (apparent t, J = 6.2 Hz, 6H), 1.06-1.18 (m, 2H),
3
H
1
.44 (s, 9H), 1.47-1.74 (m, 4H), 2.25 (bs, 1H), 3.10 (apparent t,
l3
J = 5.6 Hz, 2H), 3.65-3.79 (m, 2H), 4.80 (bs, 1H); C NMR(50
MHz, CDCl ): δC 156.5 (CO), 79.5 (C), 60.7 (CH ), 44.0
3
2
(
CH ), 42.0 (CH ), 34.7 (CH ), 33.6 (CH), 28.4 (CH , 3 car-
dicated by TLC), aqueous NH Cl was added, after which the
2 2 2 3
4
bons), 25.2 (CH), 22.8 (CH ), 22.7 (CH ); MS: m/z 268
reaction mixture was filtered and washed with ethyl acetate.
The solvent was removed under reduced pressure and the
crude product was subjected to column chromatography (sil-
ica gel, petroleum ether/ethyl acetate, 85:15) to yield (R)-4 as
3
3
+
[
[
M + Na] ; HRMS (ESI): m/z calculated for C H NO
M + Na] 268.1883, found 268.1883.
13 27
3
+
(
(
0
S)-3-(((tert-butoxycarbonyl)amino)methyl)-5-methylhexanoic acid
S)-7. A mixture of (S)-6 (1 g, 4.0 mmol), TEMPO (0.05 g,
2
5
a colorless oil. (4.2 g; 90%); [α] = + 17.5 (c 2.2, CHCl ); IR
D
3
-1
(
CHCl , cm ): ν
3502, 3018, 2957, 1603, 1454, 1366, 1307,
3
max
.32 mmol), acetonitrile (20 mL), and sodium phosphate
1
1
092; NMR (200 MHz, CDCl ): δH 0.91 (d, J = 6.6 Hz, 6H),
.12-1.29 (m, 1H), 1.38-1.58 (m, 1H), 1.73 (dd, J = 11.7, 5.6
3
buffer (16 mL, 0.67 M, pH 6.7) was heated to 35°C. Then so-
dium chlorite (1.3 g dissolved in 2 mL water, 14.6 mmol) and
dilute bleach (4–6%, 1 mL diluted in 2 mL water) were added
simultaneously over 1 h. The reaction mixture was stirred at
Hz, 2H), 1.74-1.85 (m, 1H), 2.84 (bd, J = 2.6 Hz, 1H), 3.60-
3
5
.78 (m, 2H), 3.82-3.96 (m, 1H), 4.53 (s, 2H), 7.27-7.37 (m,
l3
H); C NMR(50 MHz, CDCl ): δ 138.0 (C), 128.5 (CH, 2
3
C
3
5°C until the reaction was complete (5 h, TLC), then cooled
carbons), 127.7 (CH, 3 carbons), 73.4 (CH ), 69.4 (CH), 69.3
2
to room temperature. Water (30 mL) was added and the pH is
adjusted to 8 with 2 N NaOH. The reaction was quenched by
(
(
CH ), 46.7 (CH ), 36.9 (CH ), 24.5 (CH), 23.4 (CH ), 22.2
2 2 2 3
+
CH ); MS: m/z 245 [M + Na] ; HRMS (ESI): m/z calculated
3
pouring into ice-cold Na SO solution maintained at <20°C.
+
2
3
for C H O [M + Na] 245.1512, found 245.1513.
1
4
22
2
After stirring for 30 min at room temperature, ethyl acetate
30 mL) was added and the stirring continued for an addi-
(
(S)-2-(2-(benzyloxy)ethyl)-4- methylpentanenitrile (S)-5. To a
tional 15 min. The organic layer was separated and discarded.
More ethyl acetate (30 mL) was added and the aqueous layer
was acidified with 2 N HCl to pH 3–4. The organic layer was
separated, washed with water (2 x 15 mL), brine (20 mL),
and concentrated under reduced pressure to afford the car-
precooled (0°C) solution of alcohol (R)-4 (4.0 g, 17.9 mmol) in
dry dichlormethane (DCM) (50 mL) was added triethylamine
(
5.4 mL, 39.3 mmol) followed by a slow addition of
methanesulfonyl chloride (19.6 mmol, 1.5 mL) dropwise. The re-
action mixture was stirred at 10°C for 2 h before quenching with
water. The organic layer was washed with water (3 x 10 mL),
brine, and evaporated under reduced pressure. The crude prod-
uct was used for the next step without purification.
25
boxylic acid (S)-7 (0.88 g, 85%); [α] = À 8.6 (c 1.1, CHCl )
D
3
6b
25
-1
{
3
lit. [α]D = À 1.4 (c 3.3, EtOH)}; IR (CHCl , cm ): ν
3
max
450, 3020, 2927, 1646, 1521, 1423; NMR (200 MHz, CDCl ):
3
δH 0.90 (apparent t, J = 6.8 Hz, 6H), 1.16-1.19 (m, 2H), 1.45 (s,
Trimethylsilyl cyanide (3.3 mL, 26.8 mmol) and TBAF (1 M
in THF, 26.7 mL, 26.8 mmol) were added to a stirring solution
of crude mesylated product as obtained above in acetonitrile
under nitrogen atmosphere at room temperature. The reac-
tion mixture was stirred at 60°C for 24 h. After completion
of the reaction (indicated by TLC), the solvent was removed
under reduced pressure and the crude product was subjected
to column chromatography (silica gel, petroleum ether/ethyl
acetate, 92:8) to yield (S)-5 as a colorless oil. (2.9 g; 71%, 2
9
3
H), 1.62-1.69 (m, 1H), 2.10-2.35 (m, 3H), 3.05-3.09 (m, 1H),
.21-3.25 (m, 1H), 4.78 (bs, 1H); C NMR(50 MHz, CDCl3):
l3
δ 177.8 (CO), 156.5 (CO), 79.7 (C), 43.8 (CH ), 41.4 (CH ),
C
2
2
3
2
7.1 (CH ), 33.8 (CH), 28.4 (CH , 3 carbons), 25.2 (CH),
2.7 (CH , 2 carbons); MS: m/z 282 [M + Na]
2
3
+
3
(S)-3-(aminomethyl)-5-methylhexanoic acid hydrochloride (Pregabalin)
(S)-1. To a solution of compound (S)-7 (0.25 g, 1 mmol) in ac-
etone (5 mL) was added Conc. HCl (1 mL) and the reaction mix-
ture was stirred at 60°C for 3 h, after which the solvent was
steps); [α]2 = + 17.9 (c 1.08, CHCl ); IR (CHCl , cm ): ν
5
-1
D
3
3
max
Chirality DOI 10.1002/chir

SYNTHESIS OF ANTICONVULSANT DRUG PREGABALIN
967
evaporated under reduced pressure. The residue was dissolved
in water (10 mL) and extracted with DCM (2 x 5 mL). Heating
of the aqueous layer with activated charcoal followed by filtra-
tion through Celite and concentration of the aqueous layer
to dryness under reduced pressure furnished a residue that
was dried at 50°C for 48 h to afford pregabalin hydrochloride
For the purpose of ee determination of pregabalin (S)-1, N-
benzyl amide of protected amino acid (S)-8 was prepared and
analyzed by chiral HPLC.
t
Method for the determination of ee: (S)- butyl (2-(2-(benzylamino)-
2-oxoethyl)-4-methylpentyl)carbamate (S)-8. To a solution of
2
5
36
25
acid (S)-7 (0.11 g, 0.42 mmol) in dry THF was added N-
methylmorpholine (50 μL, 0.46 mmol) at À78°C under argon
atmosphere. After 5 min, isobutyl chloroformate (60 μL, 0.46
mmol) was added and the content stirred for another 5 min.
To this reaction mixture benzylamine (50 μL, 0.46 mmol)
was added at À78°C and the reaction mixture allowed to
stir at room temperature for 2 h. After completion of the reac-
tion, the reaction mixture was filtered and washed with
ethylacetate. The solvent was removed under reduced pres-
sure and the crude product was subjected to column chroma-
tography (silica gel, petroleum ether/ethylacetate, 65:35) to
(
S)-1 (0.18 g, 95%); [α]D = + 7.8 (c 1.1, H O) {lit. [α]D = + 7.0
2
-1
(c 1.03, H O)}; IR (Neat, cm ): ν
3448, 3211, 3130, 1720,
2
max
1
3
1
431, 1215; NMR (200 MHz, D O): δH 0.87 (d, J = 4.7 Hz,
H), 0.90 (d, J = 4.6 Hz, 3H), 1.25 (apparent t, J = 6.7 Hz, 2H),
2
.58-1.75 (m, 1H), 2.22-2.28 (m, 1H), 2.50 (m, 2H), 3.02 (d,
l3
J = 5.6 Hz, 2H); C NMR(50 MHz, CD OD): δ 175.7 (CO),
3
C
4.2 (CH ), 41.7 (CH ), 37.0 (CH ), 32.3 (CH), 25.8 (CH),
2 2 2
+
2.9 (CH ), 22.2 (CH ); MS: m/z 160 [M + H] ; HRMS
3
3
+
8 18 2
1
60.1333.
yield N-benzyl amide (S)-8 (0.12 g, 85%); [α]2 = À 3.5 (c 0.8,
5
D
CHCl ); ee >99% (The ee was determined by chiral HPLC
3
analysis: Chiralcel OJ-H [250 x 4.6 mm] column; eluent: pet
ether/ethanol [90:10], flow rate 0.5 mL/min, detector: 220
nm, [(R)-isomer- t : 8.20 min; (S)-isomer- t : 8.80 min]).
R
R
RESULTS AND DISCUSSION
A retrosynthetic analysis of pregabalin (S)-1 is outlined in
Scheme 1. We envisaged that the secondary alcohol (R)-4
would be an ideal intermediate for the synthesis which can
be extended to the Boc-protected amino alcohol (S)-6 via
Scheme 1. Retrosynthetic analysis of pregabalin (S)-1.
Scheme 2. Synthesis of pregabalin (S)-1.
Chirality DOI 10.1002/chir

9
68
MUJAHID AND MUTHUKRISHNAN
cyanation and hydrogenolysis. Simple oxidation and
deprotection of compound (S)-6 can lead to the target mole-
cule (S)-1. Further, the key intermediate (R)-4 in turn can
be accessed from the enantiopure epoxide (S)-3a by
employing regioselective ring opening using Grignard re-
agent. The enantiopure epoxide (S)-3a can be easily obtained
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2
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with high enantiopurity from its racemic epoxide
2
4
employing Jacobsen’s HKR method.
Accordingly, the substrate for HKR, the rac-epoxide 2, was
35
prepared from 3-buten-1-ol using the standard procedure.
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mol%) at ambient temperature for 24 h (Scheme 2). After comple-
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D
26
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3
3
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1
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3
DCM, 0°C) to afford mesylate and (ii) cyanation (TMSCN, TBAF,
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1
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2
anol furnished the protected amino alcohol derivative (S)-6.
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sodium chlorite catalyzed by TEMPO and bleach in an acetoni-
trile-phosphate buffer (pH 6.8) condition and afforded the
corresponding acid (S)-7 in 85% yield. Finally, simple Boc-
deprotection of (S)-7 using conc. HCl/ acetone completes the
synthesis of pregabalin (S)-1 in excellent enantioselectivity
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3
6
(
>99 % ee) {[α] = +7.8 (c 1.1, H O); lit [α] = +7.0 (c 1.1,
D 2 D
cyanoacrylate esters using ene-reductases.
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J
Org Chem
H O)}. The structure of Pregabalin (S)-1 was confirmed by its
2
1
13
IR, H NMR, C NMR, and mass spectral analysis. The enantio-
1
1
1
1
6. For a review of stereoselective syntheses of pregabalin and its analogs,
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CONCLUSION
In conclusion, we have demonstrated the use of a Jacobsen’s
HKR strategy for the simple synthesis of pregabalin (S)-1 for
the first time. Simple procedures, high enantioselectivities,
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M.M. thanks the CSIR, New Delhi, for a research fellowship.
The authors thank Mrs. S.S. Kunte for chiral HPLC analysis.
Financial support from the CSIR Network projects (CSC0130,
CSC0108 and BSC0121) is gratefully acknowledged.
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