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Chapter-II Section A
113
INTRODUCTION
(S)-3-(Aminomethyl)-5-methylhexanoic acid ((S)-Pregabalin) is a δ -aminobutyric acid
(GABA) analogue, a neurotransmitter and plays a major inhibitory role in the central
nervous system (CNS). Pregabalin “LYRICA” has been developed by Pfizer as a follow-
up compound to Gabapentin (Neurontin) to be used in the treatment of epilepsy, pain,
anxiety and social phobia. Pregabalin has been approved in the US for the treatment of
nerve pain associated with diabetes and shingles. The dosage (capsule, Oral) strength is
25 mg, 50 mg, 75 mg; 100 mg, 150 mg, 200 mg, 225 mg & 300 mg. Due to the high
pharmacological activity of Pregabalin extensive research have been carried out to
develop cost effective, green synthesis of enantiomerically pure (S)-Pregabalin ((S)-
2A.1).
(S)-3-(aminomethyl)-5-methylhexanoic acid
Figure-2A.1. Structure of (S)-Pregabalin.
INTRODUCTION TO GAMMA AMINOBUTYRIC ACID AND MECHANISM
OF ACTION
Pregabalin is closely related to gabapentin (Neurontin; Pfizer), an alkylated analogue of
γ-amino-butyric acid (GABA), which acts as main inhibitory neurotransmitter in the
central nervous system (Figure-2A.2). γ-Aminobutyric acid (GABA) is the chief
inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in
regulating neuronal excitability throughout the nervous system. In humans, GABA is also
directly responsible for the regulation of muscle tone.
Figure-2A.2. Structure of γ-Aminobutyric acid derivatives
Chapter-II Section A
114
Pregabalin is a new antiepileptic drug that is active in animal seizure models. Pregabalin
is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also
has been approved for the treatment of pain from diabetic neuropathy or post-herpetic
neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in
Europe. Pregabalin is structurally related to the antiepileptic drug gabapentin and the site
of action of both drugs is similar, the alpha2-delta (α2-β) protein, an auxiliary subunit of
voltage-gated calcium channels. Pregabalin subtly reduces the synaptic release of several
neurotransmitters, apparently by binding to α2-β subunits, and possibly accounting for its
actions in vivo to reduce neuronal excitability and seizures. Several studies indicate that
the pharmacology of Pregabalin requires binding to α2-β subunits, including structure-
activity analyses of compounds binding to α2-β subunits and pharmacology in mice
deficient in binding at the α2-β Type 1 protein. The preclinical findings to date are
consistent with a mechanism that may entail reduction of abnormal neuronal excitability
through reduced neurotransmitter release.
Figure-2A.3. Structure of calcium channel.
Structure and function of voltage-gated calcium channel subunits are illustrated by a
schematic diagram of a single calcium channel, including the four homologous domains
of the calcium channel α1 subunit (I-IV), the extracellular α2 and linked δ subunits
comprising the α2-δ protein with a single transmembrane domain (red), the completely
cytosolic β subunit (rose) and the less well characterized γ subunit (green) along with the
binding site for Pregabalin is shown.
Chapter-II Section A
115
PHARMACEUTICAL AND PHYSICOCHEMICAL PROPERTIES OF
PREGABALIN 3A.1
Proper or generic name Pregabalin
Chemical name (S)-3-(aminomethyl)-5-methylhexanoic acid
Molecular formula C8H17NO2
Molecular mass 159.23
CAS. Reg. No 148553-50-8
Melting range 129-134° C
Physical description white to off-white, crystalline solid
Solubility water and both basic and acidic aqueous solutions
SYNTHETIC APPROACHES OF PREGABALIN
Pregabalin was synthesized in the flowing four ways
2A.1. Resolution synthetic approaches
2A.2. Symmetrical synthetic approaches
2A.3. Chiral synthetic approaches
2A.4. Asymmetric synthetic approaches
2A.1. Resolution synthetic approaches
Resolution by using chiral resolution agents, in stereochemistry is a process for the
separation of racemic compounds into their enantiomers.
2A.1.1. chemical resolution approaches
2A.1.1.1. γ-isobutylglutaric anhydride as a synthetic intermediate
Huckabee et al approach1
In this approach, ethyl cyanoacetate 2A.2 was condensation with isovaleraldehyde 2A. 3
in presence of di-n-propyl amine yields cyano ester 2A.4, which on condensation with
diethyl malonate gives triester 2A.5. Hydrolysis of triester 2A.5 using aqueous HCl
solution yielded γ-isobutylglutaric acid 2A.6. Dehydrative cyclization of 2A.6 using
acetic anhydride/acetyl chloride yielded cyclic anhydride 2A.7. The 2A.7 cyclic ring was
opened using aqueous ammonia solution to yield amido carboxylic acid intermediate (±)-
2A.8. This (±)-2A.8 on resolution using (+)-α-phenylethylamine yielded (R)-(-)- 2A.8
and finally Hofmann rearrangement of (R)-(-)-2A.8 using sodium hypobromite as
oxidant, yielded Pregabalin (S)-2A.1 with 99.8% optical purity.
Chapter-II Section A
116
Scheme-2A.1. Reagents and conditions: (i) di-n-propyl amine, hexane, 100 °C; (ii) (a) diethyl malonate, di-n-propyl amine, 50°, 1h, 85.4% (b) aqueous HCl solution, 90 °C, 42 h (two stages); (iii) acetyl chloride, 100°C, 16h, 91.5%; (iv) Aqueous ammonia, water, methyl tert-butyl ether, 15 °C to 55 °C, 94.8%; (v) chloroform, ethanol, (R)-(+)-α-phenylethylamine, 55 °C, Conc.Hcl solution, 4 °C, 36.0%; (vi) water, 50 % sodium hydroxide solution, sodium hypobromite, 80 °C, 59.1%. Chen et al approach2, 3 & 4 In this approach, amido carboxylic acid intermediate (±)-2A.8 subjected for Hofmann
rearrangement using sodium hydroxide and bromine, to yield racemic Pregabalin (±)-
2A.1. This (±)-2A.1 on resolution with (S)-(+)-mandalic acid yielded (S)-Pregabalin 2A.1
with an overall yield of 16.1%.
Scheme-2A.2. Reagents and conditions: (i) water, 50 % sodium hydroxide solution, Br2; (ii) (S)-(+)-mandalic acid, 23.9% (two stages).
Zhang et al approach5 & 6
In this approach, γ-isobutylglutaric acid 2A.6 was converted in to cyclic 3-isobutyl-4-
glutarimide 2A.9 by using urea and then 2A.9 was subjected for Hofmann rearrangement
using sodium hypochlorite in presence of sodium hydroxide to yield racemic Pregabalin
(±)-2A.1. This (±)-2A.1 on resolution with (S)-(+)-mandalic acid yielded (S)-Pregabalin
(S)-2A.1 with an overall yield of 33.0%.
OH
HO
O
O HNO O
NH2
COOH
NH2
COOH
i ii iii
2A.6 2A.9 (±)-2A.1 (S)-2A.1
Chapter-II Section A
117
Scheme-2A.3. Reagents and conditions: (i) urea; (ii) water, 50 % sodium hydroxide solution, Br2; (ii) (S)-(+)-mandalic acid, 33.0% (three stages).
Chen et al approach7
In this approach, isovaleryl alcohol 2A.10 on reaction with 40% HBr and followed by
reaction with cumyl amine in presence of K2CO3 and KI yielded compound 2A.10, which
converted to 2A.11 using diketene in presence of THF, followed by p-ABSA in presence
of DBU and hydrolysis by using LiOH in presence of water in three subsequent steps.
Then 2A.11 was converted to pyrrolone derivative 2A.12 using Rh2(OAc)2 in CH2Cl2
solvent. This pyrrolone derivative 2A.12 by hydrolysis with 6 mol HCl yielded racemic
Pregabalin (±)-2A.1. This (±)-2A.1 on resolution with (S)-(+)-mandalic acid yielded (S)-
Pregabalin (S)-2A.1.
CH2OH NH
Ph NPh
ON2
N
O
Ph NH2
COOH
i ii
iii iv
2A.10 2A.11 2A.12
2A.13 (±)-2A.1
Scheme-2A.4. Reagents and conditions: (i) (a) 40 % HBr, (b) Cumyl amine, K2CO3, KI; (ii) (a) Diketene, THF; (b) p-ABSA, DBU; (c) LiOH, H2O (iii) Rh2(OAc)4, CH2Cl2; (iv) 6 mol/L HCl.
3A.1.1.2. Micheal addition followed by resolution approach.
Grote et al approach8 & 9
In this approach, isovaleraldehyde 2A.2 was reacted with diethyl malonate 2A.14in
presence of di-n-propyl amine and glacial acetic acid to obtain the enoic ester derivative
2A.15 in 88.7% yield. Then 2A.15 subjected for Michael addition by potassium cyanide
in presence of ethanol to yield Michael adduct 2A.16 in 93.8%, followed by hydrolysis
and decarboxylation in presence of NaCl, water and DMSO to give compound 2A.17 in
85.7% yield, which on catalytic hydrogenation of yielded racemic Pregabalin (±)-2A.1 in
75.1% yield. This (±)-2A.1 on resolution with (S)-(+)-mandalic acid yielded (S)-
Pregabalin (S)-2A.1 in 99.9% HPLC purity.
Chapter-II Section A
118
Scheme-2A.5. Reagents and conditions: (i) di-n-propyl amine, hexane, glacial acetic acid, 90 °C, 88.7%; (ii) KCN, ethanol, 25-45 °C, 18 h, 93.8%; (iii) NaCl, DMSO, water, 137-148 °C, 8.5 h, 85.7%; (iv) KOH, Raney Ni, Ethanol, water, 50 psi H2 pressure, 20-25 °C, 75.1%; (v) (S)-(+)-mandalic acid. Gore et al approach10 & 11
In this approach, isovaleraldehyde 2A.2 was condensed with nitromethane under basic
conditions to obtain 2-hydroxy-4-methyl-1-nitro-1-pentane 2A.19 in 95 % yield. Then
2A.19 protected with trifluoroacetic anhydride and then reacted with diethyl malonate
2A.14 in presence of sodium methoxide to give nitro ester derivative 2A.20 in 85 %
yield. This 2A.20 on hydrolysis using aqueous hydrochloric acid yielded nitro acid
derivative 2A.21, which on catalytic hydrogenation yielded racemic Pregabalin (±)-2A.1,
This (±)-2A.1 on resolution with (S)-(+)-mandalic acid yielded (S)-Pregabalin (S)-2A.1.
Scheme-2A.6. Reagents and conditions: (i) NaOMe, THF, 0-5 to 25-35 °C, 95 %; (ii) diethyl malonate, NaOMe, trifluoroacetic anhydride, THF, 10 °C, 85%; (iii) water, Aq.HCl solution, 100-105 °C, 6-8 h, 85%; (iv) MeOH, Pd/C, 50 psi H2 pressure, 25-35 °C, 6-8 h, 80%.
2A.1.1. Kinetic resolution approaches
In organic chemistry, kinetic resolution is a means of differentiating two enantiomers in a
racemic mixture. In kinetic resolution, two enantiomers react with different reaction rates
Chapter-II Section A
119
in a chemical reaction with a chiral catalyst or reagant, resulting in an enantioenriched
sample of the less reactive enantiomer.12
Thijs et al approach13
In this approach, isovaleraldehyde 2A.2 was reacted with diethyl malonate 2A.14 in
presence of (S)-proline in DMSO solvent to obtain the ene derivative 2A.15 in 88% yield.
Then 2A.15 subjected for Michael addition with nitromethane in presence DBU in
toluene solvent to yield Michael adduct 2A.20, followed by hydrolysis, decarboxylation
and hydrogenation in presence of acetic acid and Pd/C and Raney-Ni to give racemic
lactone derivative 2A.22. This 2A.22 on enzymatic hydrolysis given (S,S)-isomer of
lactone (S, S)-2A.22. This (S, S)-2A.22 on hydrolysis using aqueous hydrochloric acid
yielded (S)-Pregabalin (S)-2A.1.
Scheme-2A.7. Reagents and conditions: (i) (S)-proline, 90 °C, 88.7%; (ii) CH3NO2, DBU; (iii) acetic acid, Pd/C, Raney-Ni, H2 gas pressure; (iv) Pig liver esterase; (v) 6 mol HCl solution.
Xie et al approach14
The nitrilase enzyme AtNit1 isolated from Arabidopsis thaliana used for selectively
hydrolysis of racemic isobutylsuccinonitrile (R, S)-2A.23 to (3S)-3-cyano-5-methyl-
hexanoate (S)-2A.24 and R-configuration isobutylsuccinonitrile (R)-2A.23, wherein the
obtained compound (S)-2A.24 was converted in to (S)-Pregabalin 2A.1 by catalytic
reduction. Unhydrolyzed R-configuration isobutylsuccinonitrile (R)-2A.23 can be
racemized to give racemic isobutyl- succinonitrile (R, S)-2A.23.
Chapter-II Section A
120
Scheme-2A.8. Reagents and conditions: (i)Nitrilase; (ii) MeOH, Pd/C, 50 psi H2 pressure, 25-35 °C, 6-8 h, 80%.
Martinez et al approach15
In this approach, cyano diester derivative (R, S)-2A.25 was used as the key intermediate
and prepared Pregabalin in three different ways. (R, S)-2A.25 on lipolase enzymatic
hydrolysis for desymmetrization of the prochiral C-2 center of one diastereotopic
carboxyethyl group, gives a single enantiomer in the form of mono sodium salt of acid
(S)-2A.26, in the first route (S)-2A.26 was subjected for hydrolysis followed by reduction
gives diacid derivative 2A.27. This 2A.27 on decarboxylation gives enantioselectively
pure Pregabalin 2A.1. In the second route (S)-2A.26 on decarboxylation gives cyano
ester 2A.28 which was subjected for hydrolysis followed by reduction gives
enantioselectively pure Pregabalin 2A.1. In the third route (S)-2A.26 was subjected for
reduction to give lactone derivative 2A.29. 2A.29 on decarboxylation gives
enantioselectively pure Pregabalin (S)-2A.1. The other isomer of cyano diester (R)-2A.25
was recycled and converted to Pregabalin (S)-2A.1.
Chapter-II Section A
121
COOEt
COOEtCOOEt
COOEt
CNCN
NaOH
Toluene
Lipolase
COONa
COOEt
CN
Raney Ni
H2 NH
COOH
O
COOHCH2NH2
OH-
then Raney Ni, H2COOH
COOH
CH2NH2
H+, -CO2
H+, -CO2-CO2
COOEtCN
1) OH-
2) Raney Ni, H2
COOHCH2NH2COOH
CH2NH2
(R, S)-2A.25
(S)-2A.262A.27
(S)-2A.1
2A.28
(S)-2A.1
(S)-2A.1
2A.29
(R)-2A.25
Scheme-2A.9. Reagents and conditions: (i) Lipolase (8%), 150 mM Ca(OAc)2, >98% ee, 45-50 % conversion; (ii) reflux, 80-80 °C, >99% ee, quantitative conversion; (iv) (a) KOH (aq), RT, 1h; (b) Sponge Ni, H2, H2O/IPA, <5 h. Felluga et al approach16
In this approach, isovaleraldehyde 2A.2 and coupled with Witting reagent 2A.30 to give
alpha, beta-unsaturated ester 2A.31. Then 2A.31 subjected for Michael addition with
nitro methane in presence of DBU to obtain the racemic β-isobutyl-gamma-nitro ester
2A.32, which on hydrolysis with enzyme Novozyme 435 (Candida antarcita) given β-
isobutyl-gamma-nitro acid (S)-(+)-2A.32 by kinetic resolution. Then (S)-(+)-2A.32 was
subjected for hydrogenation in presence of acidic environment given Pregabalin (S)-2A.1
in 92% ee with a total yield of 25%.
Chapter-II Section A
122
Scheme-2A.10. Reagents and conditions: (i) triethyl phosphonoacetate, tert-BuOK, refluxing THF, 20 min; (ii) CH3NO2, DBU, 25-35 °C, overnight; (iii) enzyme, buffer, pH 7.4, 25-35 °C; (iv) Ra-Ni, H2, 1 atm, EtOH/HCl, 25-35 °C, overnight. Sterimbaum et al approach17
In this approach, diacid 2A.6 was converted to monoester 2A.33 using Candida antartica
lipase CAL-B (Candida Antarctic selective ester lipase B, Antarctic Candida lipase B) in
95.5% ee, and then reacted with benzyl chloroformate followed by reaction with
ammonia to obtain amide intermediate 2A.34. Finally the compound 2A.34 was subjected
for Hoffman rearrangement to give Pregabalin (S)-2A.1.
Scheme-2A.11. Reagents and conditions: (i) CaL-B; (ii) Phenyl chloroformate, NH3-
H2O; (ii) NaOCH3, Br2.
Hamrsak et al approach18
In this approach, a convenient stereoselective synthesis of Pregabalin was reported, in
which the key steps was quinine mediate desymmetrization of isobutyl glutaric anhydride
2A.7 with cinnamyl alcohol to give glutarate derivative 2A.35 with 72% ee. This
compound 2A.35 on chemical resolution with R-PEA gives the compound glutarate
derivative 2A.35 with 97% ee. Then compound 2A.35 was subjected for Curtius
Chapter-II Section A
123
rearrangement followed by protected with cinnamyl alcohol and benzyl amine in two
different ways to lead cinnamyl 2A.36 and benzyl amine derivatives 2A.37 respectively.
Then de-protected the cinnamyl protecting group of compound 2A.36 using Pd(OAc)2,
PPh3 and morpholine mediated to give Pregabalin (S)-2A.1. In another approach benzoyl
protected compound 2A.37 on de-benzoylation gives Pregabalin (S)-2A.1.
Hedvati et al approach19
In this method reported quinine-mediated ring opening of 3-isobutylglutaric anhydride
2A.7 with cinnamyl alcohol to give enantioselective product 2A.35 with 90% yield and
95% ee. Then Curtius rearrangement and subsequent deprotection provides (S)-2A.1 in
high yield and excellent enantiomeric excess.
Scheme-2A.12. Reagents and conditions: (i) quinine, toluene, cinnamyl alcohol, -30 °C, 24 h; (ii) resol. (S)-PEA, 72%, 97% ee; (iii) 1. (PhO)2PON3, Et3N 2. benzyl alc. (iv)
Chapter-II Section A
124
1.(PhO)2PON3, Et3N 2. cinnamyl alc. (v) Pd(OAc)2, PPh3, morpholine, EtOH; (vi) Pd(OAc)2, PPh3, morpholine, EtOH; (vii) H2 Pd/C, aq. MeOH, 60%. Connon et al approach20
In this method, the asymmetric ring-opening reaction carried out with isobutyl glutaric
anhydride 2A.7 with cyclohexyl mercaptan 2A.40 using quinine derivatives 2A.41 to
give thioester 2A.42 with 92% ee and then in a series of conversions synthesized
Pregabalin (S)-2A.1.
Scheme-2A.13. Reagents and conditions: Ligand 2A.41.
Park et al approach21
In this method asymmetric ring-opening of isobutyl glutaric anhydride 2A.7 was done
using sulfonamide quinine derivatives 2A.43 to give 2A.44 with 96 % yield and 92 % ee.
Scheme-2A.14. Reagents and conditions: Catalyst 49.
Chapter-II Section A
125
Jung et al approach22
In this approach, CAL-B catalyzed desymmetrization of prochiral 3-alkylglutaric acid
diesters 2A.7a was used to prepare optically active 3-alkylglutaric acid monoesters
bearing various alkyl substituents, including methyl, ethyl, propyl and allyl groups. Allyl
esters showed far better stereoselectivity among the alkyl esters, suggesting possible π–π
interactions between the olefin of the substrate and the Trp104 or His224 side chains at
the enzyme active site. Based on this reaction, the synthesis of (S)-(+)-3-aminomethyl-5-
methylhexanoic acid (Pregabalin) (S)-2A.1 was achieved with a 70% overall yield.
Allyl mono ester 2A.44a was converted in to an amide (R)-(-)-2A.8 in a highly efficient
manner without racemization and no interference of carboxylic acid with Mg3N2 in
methanol. Amide (R)-(-)-2A.8 was recrystallized twice in diethyl ether to afford an
enantiomerically pure product in 93% yield which was used as precursor for the synthesis
of Pregabalin (S)-2A.1.
CO2R
CO2R
R = allyl
(S)CO2H
CO2R
(R)CO2H
CO2R
2A.44a
(R)CO2H
CONH2
ii
i
2A.7a
2A.44b
R-(-)-2A.8
Scheme-2A.14. Reagents and conditions: (i) CAL-B, 0.25 M NaOH, Buffer pH 7, 25 °C,
100% conversion; (ii) Mg3N2, MeOH, 80 °C, 93%.
2A.3. Chiral synthetic approaches
Chiral synthesis is one of the simplest approaches for enantioselective synthesis, as it
does not involve asymmetric induction. Instead a chiral starting material is manipulated
through successive reactions, using achiral reagents, to obtain the desired target molecule.
Izquierdo et al approach23
In this method, D-mannitol bisacetonide 2A.45 was used as a starting material and which
was subjected for oxidative cleavage using sodium periodate afforded D-glyceraldehyde
acetonide 2A.46, which on Wadsworth-Emmons olefination reaction afforded 2A.47.
This 2A.47 on reaction with nitromethane via Michael addition yielded nitro ester 2A.48.
Chapter-II Section A
126
Then 2A.48 nitro group was reduced by hydrogen transfer from ammonium formate
using 20% Pd(OH)2/C as a catalyst in refluxing methanol overnight and the formed
amino ester cyclized in situ to provide lactam 2A.49 in 85% yield. The intermediate
lactam N-H 2A.49 was efficiently protected as a N-Boc derivative by the treatment with
(Boc)2O in the presence of TEA and DMAP quantitatively afforded the NBoc carbamate
2A.50, Subsequently, ketal protection was chemoselectively removed by the treatment of
2A.50 with 90% AcOH providing diol 2A.51 in 100% yield. This diol 2A.51 was then
oxidatively cleaved by NaIO4 in MeOH–H2O to give aldehyde 2A.52. The incorporation
of the isopropyl group into the carbon backbone of the (S)-Pregabalin precursors
achieved through a Wittig condensation of aldehyde 2A.52 with isopropylidenetriphenyl
phosphorane leading to isobutenyl oxazolidin-2-one 2A.53, The lactam-ring was then
opened by the reaction between 2A.53 and 1 M LiOH in THF at room temperature,
afforded acid 2A.54, which is the direct precursor of (S)-Pregabalin, 2A.1. The reduction
of the C–C double bond and the hydrolysis of the N-Boc carbamate were carried out in
one step by the hydrogenation of 2A.54 over 20% Pd(OH)2/C in ethanol, in the presence
of aqueous HCl, under 6 atmospheres pressure at room temperature. In this way,
enantiomerically pure (S)-Pregabalin, (S)-2A.1, was obtained in 28% overall yield.
Scheme-2A.15. Reagents and conditions: NaIO4,THF-H2O; (ii) (EtO)2POCH2CO2Et, t-BuOK/ CH2Cl2 (iii) CH3NO2/TBAF, THF (iv) NH4HCO3, Pd(OH)2/C (v) (Boc)2O, TEA, DMAP (vi) AcOH (vii) NaIO4, MeOH-H2O (viii) isopropylidenetriphenyl phosphorane (ix) 1 mol/L LiOH, THF (x) H2, HCl, Pd(OH)2/C.
Chapter-II Section A
127
Ok et al approach24
In this method a (1R,5S)-bicyclic lactone 2A.55 was used as a key intermediate for the
synthesis of Pregabalin. In this approach first epichlorohydrine 2A.56 and diethyl
malonate 2A.14 was coupled via intramolecular double substitution reaction to obtain
optically pure (1R,5S)-bicyclic lactone 2A.55a and (1S,5R)-bicyclic lactone 2A.55b.
(1R,5S)-bicyclic lactone 2A.55a was coupled with isopropyl cuprate via nucleophilic
addition through bicyclic lactone ring-opening followed by decarboxylation to give (S)-3-
isobutyl-β-butyrolactone 2A.56 in 75% overall yield. The lactone ring was easily opened
by TMS-Br and ethanol to give bromide 2A.57 in 90% yield. Azide substitution,
saponification, and subsequent hydrogenation provided Pregabalin (S)-2A.1 in 85%
overall yield.
Scheme-2A.16. Reagents and conditions: (i)1) i-PrMgCl, CuI, 2) LiCl, H2O (ii) TMSBr, EtOH (iii) NaN3,DMF (iv) 1) LiOH.H2O, 2) H2, Pd/C. Wu et al approach25
In this method, S-(+) -leucine 2A.59 was used as a key staring material for the synthesis
of Pregabalin. S-(+) - leucine 2A.59 was subjected for reduction using LiAlH4 to yield S-
2-amino-4-methyl-pentanol 2A.60, which was subjected for diazotization followed by
substitution reaction with CuBr afforded S-2-bromo-4-methyl-pentanol 2A.61. Then
2A.61 hydroxy group was protected with chlorosilane to obtained Compound 2A.62 and
this was coupled with sodium malonate Salt by substitution reaction afforded 2A.63. This
2A.63 was subjected for hydrolysis to de-protect the trimethylsilyl group using tetrabutyl
Chapter-II Section A
128
ammonium fluoride afforded the compound 2A.64. Then the hydroxyl group of 2A.64
was protected with mesyl group using mesyl chloride afforded 2A.65. Then mesyl
protected 2A.65 subjected for substituted with an amino group followed by
decarboxylation yielded Pregabalin (S)-2A.1.
Scheme-2A.17. Reagents and conditions: (i) LiAlH4 (ii) NaNO2, H2SO4, CuBr (iii) TBSCl (iv) NaCH(COOCH2CH3)2 (v) TBAF (vi) MsCl (vii) NH3 (viii) KOH. 2A.4. Asymmetric synthetic approaches
Asymmetric synthesis or stereoselective synthesis is defined as: a chemical reaction (or
reaction sequence) in which one or more new elements of chirality are formed in a
substrate molecule and which produces the stereoisomeric (enantiomeric or
diastereoisomeric) products in unequal amounts.
2A.4.1. chiral auxiliary induced enantioselective synthesis
Stereoselective auxiliary group is introduced in the substrate to control the reaction.
Yuen et al approach26
In this method, oxazolidinone 2A.66 was obtained by reaction (+)-norephedrine with
diethyl carbonate, and then coupled with isovaleryl chloride 2A.67 yielded compound
2A.68. Then 2A.68 was coupled with benzyl bromoacetate in Evans asymmetric
alkylation reaction to give the product of S-configuration with 53% yield, >95% ee. Then
2A.69 was subjected for protection with p-toluenesulfonyl chloride, then azide
Chapter-II Section A
129
substitution, reduction and deprotection of benzyl group afforded Pregabalin 2A.1 in an
overall yield of 24%.
Scheme-2A.18 Reagents and conditions: (i)THF; (ii) (1) LDA, THF, (2) BrCH2CO2Bn (iii) (1) LiOH, H2O2, THF, (2) Na2SO3, NaHSO3, H2O; (iv) (1) BH3.SMe2, THF 2) TsCl (v) (1) NaN3, DMSO, 2) H2, Pd/C
Rodriguez et al approach27 & 28
In this approach, chiral phosphonium salt (S)-2A.72 was prepared by the reaction of
2A.73 mesylate-phosphonium salt and (S)-phenylethylamine 2A.74 in the presence of
triethylamine. This witting reagent was coupled with isobutarldehyde to yield allylic
amine 2A.75 of the cis and trans isomers in the ratio of 91:9. The allylic amine was
subjected for N-acylation reaction with bromo acetyl bromide afforded allylic amide
2A.76. Then both allylic amide 2A.76 isomers were stereoselectivity subjected for radical
cyclization to afford the compound ratio of (4S,1`,S)-4-isopropylpyrrolidinone 2A.77 and
(4S,1`,R)-4-isopropylpyrrolidinone 2A.78 in 88:12. The compound 2A.77 subjected for
Birch reduction, followed by hydrolysis yielded Pregabalin (S)-2A.1 with 98 % ee.
Chapter-II Section A
130
Scheme-2A.19. Reagents and conditions: (i) NEt2, CH2Cl2 (ii) n-BuLi, THF, -78 °C, 72% (two stages); (iii) BrCH2COBr, DMAP, CH2Cl2, 92%; (iv) n-Bu3SnH/BEt3/O2, BF3.OEt, -78 °C; (v) Birch reduction; (vi) KOH, 68% (two stages). 2A.4.2. Catalytic Asymmetric Synthesis
In general, enantioselective catalysis (known traditionally as asymmetric catalysis) refers
to the use of chiral coordination complexes as catalysts. The catalysts are typically
rendered chiral by using chiral ligands, however it is also possible to generate chiral-at-
metal complexes using simpler achiral ligands. Most enantioselective catalysts are
effective at low concentrations making them well suited to industrial scale synthesis; as
even exotic and expensive catalysts can be used affordably. Perhaps the most versatile
example of enantioselective synthesis is asymmetric hydrogenation, which is able to
reduce a wide variety of functional groups.
2A.4.2.1. Asymmetric Hydrogenation
Burk et al approach29, 30, 31 & 32
In this approach, [(R,R)-MeDuPHOS]Rh(COD)+BF4- was used as chiral ligands for
asymmetric hydrogenation of compound 3-cyano-5-methyl-3-hexenoic potassium salt
2A.80 with 95 % ee to yield (S)-3-cyano-hexanoic acid 2A.81, and then cyano group
subjected for Ni-catalyzed hydrogenation afforded Pregabalin (S)-2A.1 in an overall
yield 61%, 99.8% ee.
Chapter-II Section A
131
Scheme-2A.20 Reagents and conditions: (i) [(R,R)-MeDuPHOS]Rh(COD)+BF4-, H2,
MeOH, 100 % conversion, 95 % ee ; (ii) Raney NI, Aq. KOH solution, EtOH, 50 psi H2 pressure. Then, the group has synthesized new chiral diphosphine ligands 2A.83, for asymmetric
hydrogenation of 2A.80 with conversion rate of 92% and 100% ee for the synthesis of
Pregabalin.
P Rh PBF4
PRhHP
OTf
2A.82 2A.83
Gaitonde et al approach33
In this approach, 5-methyl-3-oxo-hexanoic acid ethyl ester 2A.84 was subjected for
catalytic hydrogenation using [(S)-Ru (BINAP)Cl2]2 catalyst afforded S-configuration
compound 2A.85 with 99% ee. Then 2A.85 on reaction with bromine in presence of
triphenylphosphine yielded S-3-bromo-5-methyl-hexanoic acid ester 2A.86 in 73% yield.
Then 2A.86 on substitution reaction with nitromethane in the presence of DBU afforded
2A.87 in 96% yield of the S-configuration nitro ester 2A.88. Finally, by the LiOH
mediated hydrolysis and catalytic hydrogenation reaction afforded Pregabalin (S)-2A.1
with an overall yield 35% and 99% ee.
Chapter-II Section A
132
Scheme-2A.21. Reagents and conditions: (i) H2, [(S)-Ru(BINAP)Cl2]2 (ii) PPh3, Br2 (iii) CH3NO2, DBU (v) LiOH (vi) Pd/C, H2. 2A.4.2.2 Asymmetric Michael addition reaction
Sammis et al approach34
In this method, Salen-Al 2A.89 was used as catalyst for asymmetric addition of cyano
group to α, β-unsaturated amide 2A.90 as via Michael addition yielded S-configuration
cyano derivative 2A.91, which then subjected for hydrolysis, reduction to obtain
Pregabalin hydrochloride salt 2A.1 HCl. In this method explored solvents and CN-source
effects on rate of the reaction and was found that TMSCN as CN-sources and alcohols as
a reaction solvent can get better yields.
Scheme-2A.22. Reagents and conditions: (i) TMSCN, salen-Al, i-prOH, toluene, 24 °C (ii) 1 mol/L NaOH (iii) PtO2, H2, HCl, H2O. Armstrong et al approach35
In this approach, synthesized the compound 2A.94 by diastereoselective conjugate
addition of cyanide to chiral α,β-unsaturated oxazolidinones 2A.93 catalyzed by
samarium(III) isopropoxide, with 66% de. This 2A.94 on catalytic hydrogenation in the
presence PtO2 yielded pyrrolidone derivative 2A.95 with 75% yield, 96% ee. Finally by
Chapter-II Section A
133
hydrolysis of 2A.95 using 4 mol/L hydrochloric acid afforded Pregabalin hydrochloride
salt (S)-2A.1 HCl in 95% yield, 96% ee.
Scheme-2A.23. Reagents and conditions: (i) Cyano hydrine, acetone, 10 mol% Sm(OiPr)3, Toluene, 25-35 °C. (ii) PtO2, H2, EtOH; (iii) 4 mol/L HCl.
Fujimori et al approach36
In this method, by chiral phosphine catalyst 2A.96 was used to afford asymmetric
Michael addition product β-cyano-N-acyl imidazole 2A.98 by reaction of α, β-
unsaturated N-acyl imidazole 2A.97 with TMSCN in 99% yield and 93% ee. Then 2A.98
subjected for hydrolysis followed by reduction afforded Pregabalin (S)-2A.1.
Scheme-2A.24. Reagents and conditions: (i) Gd(OiPr)3 (5 mol %), Ligand 2A.96 (3 mol %), TMSCN (1.5 equiv), 2,6-Dimethylphenol (1 equiv), EtCN, -20 °C, 99%, 93% ee (ii) 1 M NaOH 94% (iii) PtO2 (cat.) H2 (500 psi), HCl, H2O. Gotoh et al approach37
In this approach, stereoselective addition of nitromethane with α, β-unsaturated aldehyde
2A.101 was done to obtain nitro aldehyde 2A.102 with 68% yield and 91% ee using
organocatalyst triphenyl prolinol silyl ether 2A.100. Then 2A.102 was oxidized using
NaClO2 followed by and reduction in presence of Pd/C afforded Pregabalin (S)-2A.1.
Chapter-II Section A
134
NH
Ph
OTMS
Ph
2A.100
Scheme-2A.25. Reagents and conditions: (i) Catalyst 2A.100, PhCO2H, MeOH, 68%, 91% ee; (ii) NaClO2; (iii) Pd/C, H2. Bassas et al approach and Kataja et al approach38 & 39
In this approach, a quinine derivative 2A.104 was used as a catalyst for asymmetric
Michael addition of meldrum`s acid 2A.105 to nitro olefin 2A.106 afforded compound
2A.107 in the ratio of 87.3: 12.7 of S- and R-configuration, which on hydrogenation
followed by decarboxylation afforded Pregabalin 2A.1 with 80% ee.
Scheme-2A.26. Reagents and conditions: (i) Catalyst 2A.104 (10 mol%), CH2Cl2, 25-35 °C; (ii) Raney-Ni, H2, HOAc, r.t, 22h, 75%; (iii) 6N HCl, 100°C, 28 h, 94%.
Poe et al approach40
In this approach, multi-step one-pot reaction by Aldol asymmetric Michael reaction for
the synthesis of Pregabalin was reported. Polyethyleneimine catalyst microcapsules
2A.109 and a nickel complex 2A.110 was used a catalyst system. The isovaleraldehyde
Chapter-II Section A
135
2A.2, nitromethane and diethyl malonate 2A.14 coupled in tandem Michael addition
passion afforded the product (S)-2A.111 in 94% yield and 72% ee. Then (S)-2A.111 on
reduction by Raney Ni afforded lactone derivative 2A.112. Then 2A.112 on acidic
hydrolysis followed by decarboxylation afforded Pregabalin hydrochloride salt 2A.1.
HCl in 95% yield 72% ee.
Scheme-2A.27. Reagents and conditions: (i) toluene, methanol, rt, 48h, 94%, 72% ee; (ii) Raney Ni, H2 (45 psi), EtOH, rt, 18 h, 96%; (iii) 5 M HCl, 115 °C, 18 h, 95%, 72%.
Liu et al approach41
In this approach, nitroalkene 2A.106, was prepared from the condensation of
isovaleraldehyde 2A.2 with nitromethane. Then 2A.106 reacted with diethyl malonate
2A.14 in the presence of 10 mol % of catalyst 2A.113 under solvent-free conditions at 20
°C for 24 h afforded the key intermediate 2A.111 in 73% yield with 88% ee. Then
hydrogenation of 2A.111 in the presence of Raney-Ni afforded lactone derivative 2A.112
as a white crystalline solid in 72% yield after crystallization from hexane. Then 2A.112
on acidic hydrolysis followed by decarboxylation afforded Pregabalin hydrochloric salt
2A.1.HCl in 92% yield. The overall yield is 44% for four steps.
Chapter-II Section A
136
Catalyst
Scheme-2A.28. Reagents and conditions: (i) (1) CH3NO2, NaOH, EtOH, 0 °C; (2) DCC, CuCl, Et2O, rt; (ii) diethyl malonate, 2 (10 mol %), 20 °C, 24 h; (iii) Raney-Ni, H2, MeOH, rt, 24 h; (iv) 6 N HCl, reflux for 10 h. Baran et al approach42
In this approach, asymmetric organocatalytic 1,4-additions for the synthesis of Pregabalin
is reported. Chiral squaramides efficiently catalyzed enantioselective Michael addition of
1,3-dicarbonyl compounds such as with Meldrum’s acid as a donor to aliphatic
nitroalkenes, with which enantiomeric purity of the Michael adduct 2A.107 as 94% ee
and in high yields. Using this methodology Pregabalin (S)-2A.1 was synthesized in three
steps in overall 52% yield.
Chapter-II Section A
137
Scheme-2A.29. Reagents and conditions: (i) Catalyst 2A.118 (5 mol%), CH2Cl2, 25-35 °C, 96 h, 83%, 94% ee; (ii) Raney-Ni, H2, HOAc, 48 h, 70%; (iii) 6N HCl, 100°C, 28 h, 90%.
2A.4.3. Alcoholization cyanide reaction
Davies et al approach43
In this approach, isovaleraldehyde 2A.2 on reaction with cyanohydrin 2A.114 in the
presence of enzyme Cassava S-Hydroxynitrile Lysae afforded (S)-2A.115 alcohol in 92%
yield, then hydroxyl group was subjected for protected with 2-nitrobenzenesulfonyl
chloride afforded 2-nitrobenzene sulfonate 2A.116 in 92% yield and with 94% ee. This
2A.116 in a substitution reaction with diethyl malonate 2A.14 under the usage of NaH
yielded cyano diethyl ester 2A.117 in 67% yield and 94% ee. This 2A.117 was subjected
for decarboxylation followed by reduction afforded Pregabalin (S)-2A.1.
Scheme-2.30. Reagents and conditions: (i) Cassava S-Hydroxynitrile Lyase, citric acid,
NMTB, 25 °C, 21 h. 92%; (ii) 4-nitrobenzenesulfonyl chloride, triethyamine, MTBE, 0-
10 °C to 15-20 °C, 92%, 94 % ee. (iii) Diethyl amlonate, NAH, 67%, 94% ee.
Chapter-II Section A
138
REFERENCES
1. Huckabee, B. K.; Sobieray, D. M. WO 9638405, 1996.
2. Chen, A.; Zhang, J. J. Chin. J. Pharm. 2004, 35, 195
3. Yang, J.; Huang, Y. J. Chem. Eng. Chin. Univ. 2009, 23, 825
4. Gong, M. Y. Gongdong Chem. Ind. 2009, 36, 129
5. Zhang, G. L.; Yang, X, P.; Liu, B. F. Chin. J. Pharm. 2007, 38, 617
6. Ahirrao, V. D.; Narani, C. P.; Bondge, S. P.; Khunt, M. D.; Pradhan, N. S.;
Sharadchandra, V. J. WO 2009147528, 2009.
7. Chen, Z.; Liu, W.; Chen, Z.; Jiang, Y.; Hu, W. Chin. J. Synth. Chem. 2004, 12,
31.
8. Grote, T. M.; Huckabee, B. K.; Mulhern, T.; Sobieray, D. M.; Titus, R. D. WO
9640617, 1996.
9. Sarin, G. S.; Saini, M.; Chidambaram, V. S.; Wadhwa, L. WO 2010061403, 2010.
10. Gore, V.; Gadakar, M.; Shinde, D. WO 2009147434, 2009.
11. Wang, W. H.; Dong, X. J.; Yang, Y. C. CN 101362696, 2009.
12. http://en.wikipedia.org/wiki/Kinetic_resolution.
13. Thijs, L. WO 2009149928, 2009.
14. Xie, Z. Y.; Feng, J. I.; Garcia, E.; Bernett, M.; Yazbeck, D.; Tao, J. H. J. Mol.
Catal. B: Enzym. 2006, 41, 75.
15. Martinez, C. A.; Hu, S. H.; Dumond, Y.; Tao, J. H.; Kelleher, P.; Tully, L. Org.
Process Res. Dev. 2008, 12, 392.
16. Felluga, F.; Pitacco, G.; Valentin, E.; Venneri, C. D. Tetrahedron Asymmetry.
2008, 19, 945.
17. Sterimbaum, G.; Hedvati, L.; Raizi, Y.; Aminov, R. WO 2009158343, 2009.
18. Hamersak, Z.; Stipetic, I.; Avdagic, A. Tetrahedron Asymmetry. 2007, 18, 1481.
19. Hedvati, L.; Gilboa, E.; Avhar-Maydan, S. WO 2007139933, 2007.
20. Connon, S. J.; Peschiulli, A.; Markey, L. WO 2010086429, 2010.
21. Park, S. E.; Nam, E. H.; Jang, H. B.; Oh, J. S.; Some, S.; Lee, Y. S.; Song, C. E.
Adv. Synth. Catal. 2010, 352, 2211.
22. Jung, J-H.; Yoon, D-H.; Kang, P.; Lee, W. K.; Euma, H.; Ha, H-J. Org. Biomol.
Chem., 2013, 11, 3635
Chapter-II Section A
139
23. Izquierdo, S.; Aguilera, J.; Buschmann, H. H.; Garcia, M.; Torrens, A.; Ortuno, R.
M. Terahedron Asymmetry. 2008, 19, 651.
24. Ok, T.; Jeon, A.; Lee, J.; Lim, J. H.; Hong, C. S.; Lee, H. S. J. Org. Chem. 2007,
72, 7390.
25. Wu, B. F.; Zhang, T.; Du, D. F. CN 101585778, 2009.
26. Yuen, P.; Kanter, G. D.; Taylor, C. P.; Vartanian, M. G. Bioorg. Med. Chem. Lett.
1994, 4, 823.
27. Rodriguez, V.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron Lett. 2007, 48, 4305.
28. Rodriguez, V.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron. 2008, 64, 2750.
29. Burk, M. J.; Goel, O. P.; Hoekstra, M. S.; Mich, T. F.; Mulhern, T. A.; Ramsden,
J. A. WO 2001055090, 2001.
30. Burk, M. J.; DeKoning, P. D.; Grote, T. M.; Hoekstra, M. S.; Hoge, G.; Jennings,
R. A.; Kissel, W. S.; Le, T.; Lennon, I. C.; Mulhern, T. A.; Ramsden, J. A.; Wade,
R. A. J. Org. Chem. 2003, 68, 5731.
31. Hoge, G. J. Am. Chem. Soc. 2003, 125, 10219.
32. Hoge, G. J. Am. Chem. Soc. 2004, 126, 9920.
33. Gaitonde, A.; Datta, D.; Manojkumar, B.; Phadtare, S. WO 200981208, 2009.
34. Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442.
35. Armstrong, A.; Convine, N. J.; Popkin, M. E. Synlett. 2006, 1589.
36. Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.;
Shibasaki, M. Tetrahedron. 2007, 63, 5820.
37. Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307.
38. Bassas, O.; Huuskonen, J.; Rissanen, K.; KosKinen, A. M. P. Eur. J. Org. Chem.
2009, 1340.
39. Kataja, A. O.; Koskinen, A. M. P. Arkivoc. 2010, ii, 205.
40. Poe, S. L.; Kobaslija, M.; McQuade, D. T. J. Am. Chem.Soc. 2007, 129, 9216.
41. Liu, J.-M., Wang, X.; Ge, Z.-M.; Sun, Q.; Cheng, T.-M. Li, R.-T. Tetrahedron. 2011,
67, 636.
42. Baran, R.; Veverkova, E.; Skvorcova, A.; Sebesta, R. Org. Biomol. Chem., 2013.
DOI: 10.1039/c3ob41709c.
43. Davies, B. S.; Guzman, M. M.; Martinez, C. A.; Mcdaid, P. O.; O'Neill, P. M.;
Shanmugam, E. WO 2010070593, 2010.