studies on the synthesis of anti-convulsant drug,...
TRANSCRIPT
Chapter II
O OH
NH2
Studies on the synthesis of
anti-convulsant drugs,
Pregabalin
INTRODUCTION:
The anticonvulsants (also commonly known as antiepileptic drugs) are a diverse group
of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also
increasingly being used in the treatment of bipolar disorder, since many seem to act as mood
stabilizers, and for the treatment of neuropathic pain. The goal of an anticonvulsant is to
suppress the rapid and excessive firing of neurons that start a seizure. Failing this, an effective
anticonvulsant would prevent the spread of the seizure within the brain and offer protection
against possible excitotoxic effects, that may result in brain damage. Anticonvulsants are more
accurately called antiepileptic drugs (abbreviated "AEDs"), and are sometimes referred to
as anti-seizure drugs.
γ-Amino butyric acid (GABA) and L-glutamic acid are the two major neurotransmitters in the
mammalian central nervous system (CNS),[1-2]
the first one being the major inhibitory and the
later the excitatory transmitter.[3]
The concentration of GABA is regulated by two pyridoxal 5’-
phosphate dependent enzymes, L-glutamic acid decarboxylase (GAD; EC 4.1.1.15), which
catalyzes the conversion of L-glutamate to GABA and GABA aminotransferase (EC; 2.6.1.19),
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 82
Chapter - II
which degrades inhibitory neurotransmitter GABA to succinic semialdehyde.[4]
Compounds that
inactivate this enzyme have been shown to exhibit anti-convulsant activity.[5]
Table-2.1
GABAA receptor
agonist
Barbiturates (Barbexaclone, Metharbital, Methylphenobarbital,
Pentobarbital, Phenobarbital, Primidone)
Benzodiazepines (Clobazam, Clonazepam, Clorazepate, Diazepam,
Flutoprazepam, Lorazepam, Midazolam, Nimetazepam, Nitrazepam,
Temazepam)
Other GABA agents Aromatic allylic alcohols (Stiripentol)
Carbonic
anhydrase inhibitor
Sulfa drugs (Acetazolamide, Ethoxzolamide, Sultiame, Topiramate,
Zonisamide)
Channel blockers
Primary sodium, Hydantoins (Ethotoin, Fosphenytoin, Mephenytoin,
Phenytoin)
Primary sodium, Carboxamides (Carbamazepine, Eslicarbazepine
acetate, Oxcarbazepine, Oxitriptyline, Rufinamide)
Primary calcium, Succinimides (Ethosuximide, Mesuximide,
Phensuximide)
AMPA receptor (Perampanel)
Unknown/ungrouped: Phenyltriazine (Lamotrigine),
Oxazolidinediones (Ethadione, Paramethadione, Trimethadione),
Ureas (Phenacemide, Pheneturide), Monosaccharide (Topiramate)
Channel openers Potassium (Retigabine)
Indirect GABA
agents
Carboxylic acids/Fatty acid derivatives: GABA transaminase
inhibitor (Valproic acid [Sodium valproate & Valproate
semisodium], Valpromide, Valnoctamide, Valproate pivoxil)
Carboxylic acids/Fatty acid derivatives: GABA reuptake inhibitor (Tiagabine)
GABA analogs (Gabapentin, Pregabalin, Progabide, Tolgabide,
Vigabatrin)
Unknown/
multiple/unsorted
Carbamates (Emylcamate, Felbamate, Meprobamate, Carisbamate)
Pyrrolidines (Brivaracetam, Levetiracetam, Nefiracetam,
Seletracetam)
Propionates (Beclamide, Lacosamide)
Aldehydes (Paraldehyde)
Bromides (Potassium bromide, Sodium bromide)
It has been shown that convulsions can occur when the level of GABA in the brain diminishes
below a critical amount.[6]
Despite the fact that increasing the brain concentration of GABA
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 83
Chapter - II
prevents convulsive seizures, the low lipophilicity of this compound is probably responsible for
its inefficiency as anti-convulsant drug, because it very inefficiently crosses the blood-brain
barrier (BBB),[7-9]
a protective membrane that prevents xenobiotics from entering the brain.
Many GABA mimetic substances such as GABA receptor agonists, GABA reuptake inhibitors
and GABA metabolism inhibitors have been developed[10-11]
as potent anti-convulsant agents
Table-2.1 and a number of GABA analogs such as Gabapentin, Vigabatrin and Pregabalin have
been introduced as medicines against epilepsy, neuropathic pain and anxiety[12]
which is
summarized in Table-2.2.
Table-2.2
Sr.
no.
Generic name
Systematic (IUPAC) name Structure
1 Pregabalin (1)
(S)-3-(aminomethyl)-5-methylhexanoic acid NH2
O OH
2 Gabapentin (2)
2-[1-(aminomethyl)cyclohexyl]acetic acid
H2N
O
OH
3 Vigabatrin (3)
(RS)-4-aminohex-5-enoic acid OH
O
NH2
4
Progabide (4)
4-[(4-chlorophenyl)-(5-fluoro-2-hydroxy-
phenyl)-methylidene]aminobutanamide
F
OH
Cl
N
O
NH2
5
Tolgabide (5)
4-{[(Z)-(3-chloro-5-methyl-6-oxocyclohexa-
2,4-dien-1-ylidene)(4-
chlorophenyl)methyl]amino}butanamide
Cl
O
Cl
HN
O
NH2
γ-Amino acids i.e. Gabapentin (2) and Pregabalin (1) both have anti-convulsant, anxiolytic-like,
analgesic actions.[12]
Originally developed as an add-on therapy for the treatment of partial
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 84
Chapter - II
seizures, Gabapentin (2) has shown efficacy in the treatment of post herpetic neuralgia (a type
of neuropathic pain) and activity in several preclinical models of neuropathic pain.[13-15]
Pregabalin (1) has been developed as a follow up compound to Gabapentin. Pregabalin has
more potent and robust activity than Gabapentin in preclinical models of epilepsy,[16-18]
neuropathic pain[15]
and anxiety.[19]
In placebo-controlled clinical studies, Pregabalin reduces the
incidence of partial seizures, reduces pain from post herpetic neuralgia[20]
and tooth
extraction,[21]
and reduces symptoms of generalized anxiety disorder[22]
with modest side effects
including dizziness and somnolence.[23]
Pregabalin binds with high affinity to the α2-δ subunits
of voltage-gated calcium channels in central nervous system tissues.[24-25]
As a consequence
calcium influx is modulated at nerve terminals, which in turn reduces the release of several
neurotransmitters including glutamate. It activates GAD (L-glutamic acid decarboxylase)
promoting the production of GABA.[12,24]
Pregabalin (1) is known as (S)-(+)-3-aminomehyl-5-methyl-1-hexanoic acid or (S)-(+)-3-(2-
methylpropyl)-4-aminobutanoic acid or (S)-(+)-3-isobutylGABA. Pregabalin is a commercially
marketed pharmaceutically active substance, under the brand name LYRICA by Pfizer in
capsules 25, 50, 75, 150, 200, and 300mg dose in the United State of America and is known to
be useful as therapeutic agent for treatment of pain, convulsions, general anxiety related
disorder and epileptic seizures. It’s molecular formula is C8H17NO2 and molecular weight is
159.23amu. Sales reached a record $3.063 billion in 2010.[26]
REVIEW OF LITERATURE:
Number of methods has been developed for racemic and asymmetric synthesis of Pregabalin.
Process, in which racemic Pregabalin is intermediate,[27-39]
used to resolve finally with chiral
resolving agent[28, 34, 40-45]
, e.g. (S)-(+)-mandelic acid. The existing asymmetric synthesis of
Pregabalin involves use of chiral precursors,[46-55]
enantioselective catalytic conjugate addition
of cyanide,[56-62]
to α, β-unsaturated imides, enantioselective catalytic conjugate addition of
nitromethane[63-64]
and diethylmalonate[65]
to α, β-unsaturated aldehyde and nitro compound,
rhodium catalyzed asymmetric hydrogenation of an unsaturated Pregabalin precursors,[66-71]
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 85
Chapter - II
enantioselective ring opening of 3-isobutylglutaric acid anhydride,[72-78]
or chemical[79-89]
and
chemoenzymetic[90-101]
resolution by setting the stereo centre early in the synthesis and enabling
the facile racimization and reuse of unwanted enantiomers.
Pregabalin 1 was first synthesized by Silverman and Andruszkiewicz in 1989.[27]
It first involved
a conjugate addition of nitromethane to ethyl 5-methyl-hexenoate (6) to give nitro ester 7, which
was hydrogenated to give amino ester 8. Hydrolysis of 8 under acidic conditions gave racemic
Pregabalin 1 in 58% overall yield (Scheme-2.1).
CO2Et CO2Et
NO2
CO2H
NH2
MeNO2, DBU
rt, 48h
40-74%
H2/Pd-C/AcOH
rt, 2-4h
6N HCl
reflux, 3h
78-86%
(6) (±)-(7) (±)-(8)
(±)-(1)
CO2Et
NH2
…..Scheme-2.1
Pregabalin can also be prepared from diethyl malonate, 10 as shown in scheme-2.2.[28]
Diethyl
malonate (10) was condensed with isovaleraldehyde (9) followed by Michael addition of
potassium cyanide to the unsaturated diester (11) to give β-cyanodiester 12. The diester was
then saponified, the resulting malonic acid was decarboxylated and the cyano acid (13)
hydrogenated using a nickel catalyst to give (±)-3-isobutyl GABA (1). The key step of this
process was a mandelic acid resolution of racemic 3-isobutyl GABA to give Pregabalin.
Although the (R)-enantiomer generated as a by-product in this late-stage resolution cannot be
recycled efficiently, this process is still the most cost-effective process to produce Pregabalin
thus far.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 86
Chapter - II
CHOCO2Et
CO2Et
CO2Et
CO2Et
CN
CO2EtEtO2C
CN
CO2K CO2H
NH2
+n-Pr2NH
AcOH
KCN
79-88%
KOH Sponge Ni, H2
72-83%
reflux, 89%
(S)-mandelic acid
CO2H
NH2
(9) (10) (11) (12)
(±)-(1) (1)(13)
…..Scheme-2.2
The first enantioselective synthesis of Pregabalin (1) was developed by Yuen and co-workers[46]
at Pfizer using Evan's chiral oxazolidinone chemistry. 4-methylpentanoic acid (14) was
converted into the corresponding acid chloride and then coupled with Evan's chiral auxilary.
The resulting acyloxazolidinone 15 was then alkylated with benzyl bromoacetate to give the
benzyl ester intermediate 16. The chiral auxilary was removed by peroxide treatment followed
by a modified bisulfite work-up at pH 7 to give the corresponding acid intermediate. Under the
usual acidic bisulfite work-up conditions, a significant amount of diacid by-product was formed
due to an undesired hydrolysis of the benzyl ester. Borane reduction of the resulting acid
intermediate gave alcohol 17 in good yield. The alcohal was then converted to the
corresponding azide (18) under standard conditions. With catalytic hydrogenation, the benzyl
group was removed and the azide was simultaneously reduced to the amine to give Pregabalin
(1) in 99.5% ee and 65% chemical yield (Scheme-2.3).
OH
ON
O
OH
O
O
N
O
O
O
O
O
O
O
N3
O
O
1) SOCl2, CHCl3
2) HN O
Ph
O
THF, -78°C, 64%
LDA, THF, -78°C
Br
O
OBn
65%
1) LiOH, H2O2
2) Na2SO3, NaHSO3, pH 7
3) BH3.SMe2
73%
1) TsCl, Pyridine
2) NaN3, DMSO, 68°C
76%
NH2
O
OH
H2 (50 psi), Pd/C
HCl, THF
65%, 99.5% ee
(14)
(15)(16)
(17) (18) (1)
….. Scheme-2.3
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 87
Chapter - II
While trying to scale-up the synthesis to kilogram quantities, Pfizer process chemists
encountered unexpected difficulties. A significant amount of lactone was formed after the
borane reduction step, leading to a 10% overall yield. By replacing benzyl bromoacetate with t-
butyl bromoacetate as the alkylating agent, this problem was solved and the overall yield was
increased to 33%.[47]
However, the cost of goods was too high to be practical. Therefore, other
synthetic routes to produce Pregabalin were considered.
The first approach investigated was the L-leucine approach,[47]
as shown in Scheme-2.4, in
which L-leucine (19) was converted to the bromoester (20). The bromide was displaced with
excess diethyl sodiomalonate to give triester (21) in good yield. The t-butyl ester was
deprotected by formic acid treatment and the resulting acid was reduced with borane to the
corresponding alcohol. The diester alcohol was treated with aqueous hydrochloric acid to effect
hydrolysis of the ester followed by decarboxylation and formation of lactone 22. This was
opened up to the iodoester with trimethylsilyl iodide in ethanol and the iodide was further
converted to azidoester 23. Saponification followed by catalytic hydrogenation of the azedoester
gave Pregabalin 1 in 29% overall yield.
OH
O
NH2
O
O
Br
O
O
EtO2C CO2Et
O
O N3
CO2Et
NH2
CO2H
1) NaNO2, NaBr, H2SO4
2) t-BuOAc, BF3.HOAc,
63%
NaCH(CO2Et)2
THF, reflux, 93%
1) HCO2H, 35%
2) BH3. SMe3
3) HCl, H2O, 87%
1) TMSI, EtOH
2) NaN3, CH3CN, 88%
1) KOH, EtOH, H2O
2) H2, Pd/C, 65%
(19) (20) (21)
(22) (23) (1)
….. Scheme-2.4
In 2003, Jacobsen and co-workers[56]
published their work on a novel enantioselective synthesis
of Pregabalin 1. The Harvard group was able to promote conjugate addition of hydrogen
cyanide into the unsaturated imide 24 using 10mol% of the (R,R)-aluminum salen catalyst to
give the (S)-cyanoimide 25 in 96% ee and 93% chemical yield. Imide 25 was hydrolyzed to
give cyanoacid 26. The cyanoacid was then hydrogenated in the presence of platinum oxide to
give Pregabalin hydrochloride, as seen in Scheme-2.5, in 84% overall yield from the
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 88
Chapter - II
unsaturated imide. However, considering the cost of TMSCN and the high-pressure requirement
of the hydrogenation reaction, it was deemed commercially impractical.
O
NH
Ot-Bu O
N N
t-BuO
t-But-Bu
Al
Cl
, TMSCN
i-PrOH, PhMe, 93%, 96% ee
O
NH
O
CN
O
OH
CN
O
OH
NH2.HCl
1N NaOH
THF, 94%
H2 (500 psi), PtO2
HCl, H2O, 92%, 96% ee
(24) (25)
(26) (1)
….. Scheme-2.5
Kissel and other researchers at Pfizer published a novel chiral synthesis of Pregabalin in 2003
on asymmetric hydrogenation.[68-69]
The synthesis started with the condensation of
isobutyraldehyde (27) with acrylonitrile under Baylis-Hillman conditions to give allylic alcohol
28. This alcohol was activated as the carbonate 29 and subjected to palladium-catalyzed
carbonylation conditions to give cyanoester 30. The ester was hydrolyzed and converted to the
corresponding t-butyl ammonium salt 31, which was hydrogenated with the (R,R)-
methylDuPHOS rhodium catalyst to give the chiral cyanoacid ammonium salt (32) in 98% ee.
Hydrogenation of nitrile over nickel gave Pregabalin in greater than 99% ee (Scheme-2.6).
CHO
OH
CN
OCO2Et
CNCN
CO2Et
CN
CO2 H3N
CN
O
O NH3 NH2
CO2H
(1)
CN DABCO, H2O
t-Bu
t-Bu
OHMe , 97%
EtOCOCl
Pyridine, 95%
Pd(OAc)2, PPh3
EtOH, CO, 83%
LiOH, H2O
t-BuNH2
P
P
Rh BF4
H2 (45 psi), MeOH, 100%, 97.7% ee
H2 (50psi), Ni
KOH, H2O, EtOH
HOAc, 61%,
99.8% ee
(27) (28) (29) (30)
(31) (32)
….. Scheme-2.6
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 89
Chapter - II
Huckabee and Sobieray at Pfizer was developed the γ-isobutylglutaric acid approach in 1997.[79]
Ethyl cyanoacetate 33 was first condensed with isovaleraldehyde (9) to give the unsaturated
ester 34. Michael addition of diethyl malonate 10, followed by acid-induced decarboxylation
gave glutaric acid 35, which was then converted to the amide acid 37 via the anhydride
intermediate 36. Acid can be resolved with (R)-methylbenzylamine 38 to give the chiral acid 39
in 98% ee. Hofmann rearrangement of 39 gave Pregabalin in good yield (Scheme-2.7). The
antipode of acid from the resolution step can be hydrolysed back to glutaric acid 35 and
recycled.
EtOCN
OCHO , n-Pr2NH
Heptane, 98%CN
CO2Et
EtO2C CO2Et
n-Pr2NH
HBr, H2O, 82%
O
OH
O OH
H
O
NH2
O OH
H
O
O
O
H
AC2O NH3(aq), MTBE
H2N
Aq. HCl, 75%, 98% ee
O
NH2
O OH
NaOH, Br2
NH2
O OH
reflux, 92% HCl, 95%
EtOH, CHCl3
HCl, 59%, 99% ee
(33)
(9)
(34)
(10)
(35)
(36) (37)
(38)
(39) (1)
….. Scheme-2.7
Hu and co-workers[91]
developed a process to prepare Pregabalin 1 via enzymatic resolution
(Scheme-2.8). The Pfizer researchers investigated a large number of commercially available
hydrolases to catalyze the hydrolysis of β-cyanodiester 12, an intermediate from the malonate
route, to form (3S)-3-cyano-2-ethoxcarbonyl-5-methylhexanoic acid potassium salt 40
enantioselectively. With this enzyme screening study, they determined that LIPOLASE 100L,
type EX, was the most effective hydrolase for the large scale preparation of monoester 40.
Hydrogenation of nitrile over Raney nickel followed by acid treatment gave the pyrrolidinone-
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 90
Chapter - II
3-carboxylic acid 42 in 97% ee. Acid was then decarboxylated and hydrolyzed with
hydrochloric acid to give crystalline Pregabalin 1 in greater than 99.5% ee. The (R)-3-cyano-2-
ethoxycarbonyl-5-methylhexanoic acid ethyl ester 41 left over from the LIPOLASE-catalyzed
hydrolysis reaction can be recycled back to the β-cyanodiester 12 by sodium ethoxide in ethanol
treatment, providing a 50% savings in cost of goods over the malonate approach described
above.
CO2Et
CO2Et
CN
LIPOLASE 100L
Ca(OAc)2 buffer, KOH, pH 7CO2K
CO2Et
CN
CO2Et
CO2Et
CN
+
CO2H
NH
O NH2
CO2H
(1)
H2 (50psi), Ra-Ni, H2O
HCl, H2O, pH 3,
40-42%, 97% ee
HCl, H2O,HOAc, 80°c
KOH, pH 5.2-5.5
80-85%, >99.5% ee
(12) (40) (41)
(42)
….. Scheme-2.8
PRESENT WORK:
The object of the present work was to uncover and overcome the many disadvantages of the
prior art. Present work details the journey towards development of a simple, safe, productive,
eco-friendly and easy to handle commercial process, having controls via Hofmann degradation
of R-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. Hence, we have developed and
optimized the process, impurities formed in the process were identified, prepared and
characterized. A new process was developed for the preparation of Pregabalin (1) using alcohols
as reaction medium in Hofmann degradation. Still another object of the present invention was to
recover racemic 3-(carbamoylmethyl)-5-methylhexanoic acid 37 from non-racemic 3-
(carbamoylmethyl)-5-methylhexanoic acid, obtained during resolution, without isolation of any
intermediate.
Another aspect of invention was to provide highly pure (S)-Pregabalin 1 having single
individual impurities less than 0.10%, chromatographic and chiral purity > 99.9% each. Yet
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 91
Chapter - II
another aspect of invention was to provide highly pure (S)-Pregabalin having Chromatographic
and chiral purity > 99.9% each.
RESULTS AND DISCUSSION:
Three synthetic approaches are described herein, among which approach A deals with 4-steps
preparation of Pregabalin, having controls via Hofmann degradation of R-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid 39 for large scale synthesis of Pregabalin 1. Process
development and identification of impurities also included in this approach. Additionally, force
degradation study of Pregabalin was also carried out. A mechanistic rationale for the formation
of the various impurities and degradation products has also been provided. Approach B
discloses a new manufacturing process with improved yield of Pregabalin. It was developed
using alcohols as reaction medium in Hofmann degradation of R-(-)-3-(carbamoylmethyl)-5-
methylhexanoic acid 39 followed by hydrolysis of corresponding carbamates. Approach C
depicted efficient racimization process of non-racemic mixture of 3-(carbamoylmethyl)-5-
methylhexanoic acid in basic medium.
APPROACH A:
One of the preferred process of Pregabalin manufacturing comprises aminolysis of 3-
isobutylglutaric anhydride 36 (obtained from 3-isobutylglutaric acid, 35), followed by
resolution of intermediary amide 37 with (R)-(+)-1-phenylethylamine 38 in chloroform
(Scheme-2.9). The (R)-enantiomer of 3-(carbamoylmethyl)-5-methylhexanoic acid 39
preferentially crystallizes out which was then transformed into Pregabalin 1 through Hofmann
degradation.[79]
Although, the relation between synthetic route and impurity identity is often
assumed and investigated during development, the results are seldom made public. The purpose
of this report was to investigate the existed route and identification, synthesis (or isolation) and
characterization of impurities and degradents during the process development of important drug,
Pregabalin.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 92
Chapter - II
O
OH
O OH
H
O
NH2
O OH
H
O
O
O
H
AC2O NH3
H2N
Aq. HCl
O
NH2
O OH
NaOH, Br2
NH2
O OH
(1)
(35) (36) (37)
(39)
(38)
….. Scheme-2.9
PROCESS DEVELOPMENT AND IMPURITY PROFILE:
From the chemical synthesis point of view, key steps in this process for the preparation of
Pregabalin are, resolution of 3-(carbamoylmethyl)-5-methylhexanoic acid (Pregabalin
monoamide 37) and Hofmann degradation of resolved Pregabalin monoamide i.e. (R)-
Pregabalin monoamide, 39. During the resolution of 37, presence of four potent impurities was
observed. These impurities arise mainly due to heating of diaestereisomeric salt in
chloroform/ethanol and carrying through the synthesis to contaminate the finished product i.e.
Pregabalin 1. Further, in addition to this, during Hofmann degradation twelve degradation
products were detected by LCMS study. The reported yield in this particular stage was only
66%.[79]
Hofmann found that yields of amine fell off because of two side reactions. Loss of yield
was attributes to formation of nitrile having one less carbon atom than the starting amide and
was due mainly to formation of alkylacyl ureas. It was thought that the loss from urea formation
was largely due to the physical properties of the organic compounds. As molecular weight
increases, the isocyanate, the proximate rearrangement product, the product amine and the
earlier intermediates have an increasing tendency to extract each other from solution, whereby
the isocyanate is increasingly likely to react with other substances than hydroxide ion.[102]
Some
of the reported side reactions during Hofmann degradation are formation of urea and acylurea
which can surface by reacting amine and amide respectively with isocyanate,[103-104]
while
oxidation of amine group present in Pregabalin can end result in corresponding nitrile
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 93
Chapter - II
impurity.[105]
The presence of impurities in an active pharmaceutical ingredient (API) can have a
significant impact on the quality and safety of the drug products. Consequently, it was a
regulatory requirement to isolate and characterize these substances. Furthermore, ICH
guidelines require that drug substances and drug products be stressed to aid in the development
of stability-indicating analytical methods.
Resolution of Pregabalin monoamide 37: For the process development of Pregabalin 1,
Pregabalin monoamide 37 was selected as a key raw material because of its commercial
availability. It was also well documented in the chemical literature that, 37 can be resolved
easily with (R)-1-Phenylethylamine 38 as a chiral reagent to yield enantiopure diastereoisomeric
salt 43 in 1-2%v/v ethanol in chloroform. Thereafter, 43 can be transformed into highly
enantiopure 39 using hydrochloric acid in water.
Initially, as the part of the process development study, resolution of 37 was tried in different
solvent(s) or mixture of solvent(s) using 38 as resolving agent. The detailed study revealed that
none of the solvents can resolve Pregabalin monoamide except chloroform or chloroform-
ethanol mixture. Hence, chloroform emerges as a unique solvent to resolve 37 using 38 as a
resolving agent (Table-2.3).
Table-2.3
S.
No
.
BATCH
No.
(R)-1-
PHENYL
ETHYLA
MINE 38
(m. eq.)
SOLVENTS YIELDS
(w/w)
CHIRAL
PURITY
(%)
1 PRE(918)08 0.70 2%v/v ethanol in chloroform
(11.5 volume) 0.62 97.34
2 PRE(918)42 0.70
2%v/v ethanol in ethylene
dichloride
(17 times)
1.20 50.84
3 PRE(918)43 0.70 Ethylene dichloride (22
volume) 1.10 52.21
4 PRE(918)44 0.70 Methylene dichloride (20 1.00 51.21
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 94
Chapter - II
volume)
5 PRE(918)45 0.70 Ethyl acetate (17 volume) 1.30 49.86
6 PRE(918)46 0.70 Acetone (7 volume) 0.80 50.70
7 PRE(918)47 0.70 1,4-Dioxane (7 volume) 0.80 47.99
8 PRE(918)48 0.70 Tetrahydrofuran (7 volume) 0.90 49.26
9 PRE(918)49 0.70 n-butanol (7 volume) 0.25 50.46
10 PRE(918)50 0.70 Methyl isobutyl ketone
(10volume) 1.15 50.12
11 PRE(918)51 0.70 2%v/v Ethanol in isopropyl
acetate(16 volume) 0.75 49.54
12 PRE(918)52 0.70 2%v/v Ethanol in toluene
(10 volume) 1.00 51.00
13 PRE(918)53 0.70 5%v/v 1,4-dioxane (4
volume) 0.35 49.03
14 PRE(918)54 0.70 Isopropyl alcohol (5 volume) 0.60 49.70
15 PRE(918)55 0.70 Acetonitrile (10 volume) 0.90 50.81
16 PRE(918)67 0.70
2% v/v Methanol in
methylene chloride
(10 volume)
0.30 51.01
17 PRE(918)63 0.70 Methyl tert-butylether (10
volume) No solid -
18 PRE(918)64 0.70 Diisopropyl ether (10
volume) No solid -
19 PRE(918)68 0.70 1,4-Dibromobutane (5
volume) No solid -
20 PRE(918)69 0.70
10%v/v Methanol in
methylene chloride
(5 volume)
No solid -
Next, our target was to optimize the resolution step by varying mole equivalents of (R)-1-
Phenylethylamine 38 (resolving agent), reaction temperature, mode of addition of 38 and
stirring time. In these experiments, addition of 38 was done in 11.5 volumes of 2%v/v ethanolic
chloroform in two lots at 55-58°C. The use of 0.70 equivalents of 38 was found to be ideal for
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 95
Chapter - II
getting the required compound 43 with high chiral purity with good yield. The results of those
experiments are summarized in Table-2.4.
Table-2.4
Sr.
no.
(R)-1-
Phenylethylamine 38
(mole eq.)
Stirring time /
temperature
Yield (%) Chiral purity
(%)
1 0.50 lot wise addition 25-30°C / 5h 52 98.50
2 0.50 lot wise addition 18-20°C / 5h 85 79.58
3 0.60 lot wise addition 18-20°C / 3h 82 87.22
4 0.60 lot wise addition 25-30°C / 2h 65 96.95
5 0.70 18-20°C / 5h 77 95.33
6 0.80 28-32°C / 1h 98 89.50
7 0.90 28-32°C / 1h 122 66.10
8 1.00 28-32°C / 1h 137 59.10
During the process optimization, we paid great attention to optimize the stirring time and
temperature of the reaction mass during resolution. The study clearly indicates that, at constant
temperature prolong stirring during resolution of 37 results in lesser yield (Table-2.5). One of
the reasons of lowering the yield may be due to formation of impurities, mainly dehydrated
impurity 44, which liberates water (Scheme-2.10) during its generation. The diastereoisomeric
salt 43, which is highly water soluble, may remained in solution and results in the low yield.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 96
Chapter - II
Table-2.5
Sr.
no.
Stirring
Yields
(%)
Chiral purity
(%) Time
(hrs)
Temp.
(0C)
1 1 28-30 79 93.64
2 2 28-30 77 96.06
3 3 28-30 71 95.00
4 4 28-30 70 96.79
To know the impact of prolong stirring on the resolution of (RS)-Pregabalin monoamide 37,
after addition of (R)-1-phenylethylamine 38 (0.70 m. eq.), reaction mixture was stirred at 31-
32°C which summarizes in (Table-2.6).
Table-2.6
S.No. EXPERIMENTAL DETAILS
(FILTRATE)
ENANTIOMIERIC
RATIO (R / S)
1 At 42°C 29.67 / 70.33
2 At 32°C / 0 hrs 20.64 / 79.36
3 At 31-32°C / 1 hrs 19.91 / 80.09
4 At 31-32°C / 2 hrs 20.57 / 79.43
5 At 31-32°C / 5 hrs 20.87 / 79.13
6 At 31-32°C / 21 hrs 20.60 / 79.40
7 Filtered Product 97.93 / 2.07
It was clear from above study that chiral purity of (R)-Pregabalin monoamide (R)-PEA salt 43
does not decrease with prolong stirring at 30-32°C.
Detection and origin of impurities during resolution of 37: Four process impurities were
detected by LCMS with a mass of 290, 291, 169 and 188. The structures 44, 45, 46 and 35 were
proposed for these compounds. Origin of these impurities is briefly described in Scheme-2.10.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 97
Chapter - II
O
NH2
O O H3N.
(43)
Aq. HCl
Dehydration
O
NH2
OHN
(44)
Hydrolysis
- NH3
O
OHN
OH
(45)
Cyclisation
O
NH
O
(46)
- 38
Hydrolysis
Hydrolysis
- 38
O
NH2
O OH
H
(37)
H2N
(38)
O
NH2
O OH
(39)
O
OH
O OH
H
(35)
….. Scheme-2.10
Impurity 44 was thought to arise by dehydration of 43, the enantiomerically pure
diastereoisomeric salt during heating in chloroform. Impurity 45, PEA-Pregabalin acid may be
formed due to hydrolysis of amide group by liberated water during formation of PEA-
Pregabalin amide 44. Pregabalin diacid, 35 may be regenerated due to hydrolysis of 37, 39 or
45. Pregabalin imide 46, which was more potent in this step of reaction, was anticipated to form
by the cyclization of 44, librating 38 again.
Preparation of these impurities are described in the literature.[106-120]
Attempt to prepare 44 was
made, concordant to its origin, i.e. acid group of 37 or 39 was activated with haloformates and
then replaced by 38. Mass and 1H-NMR data supports the assigned structure. PEA Pregabalin
acid, 45 was conveniently prepared from Pregabalin diacid anhydride 36, by reacting with 38 at
-10 to -15°C, where as Pregabalin imide, 46 was prepared by refluxing 37 or 39 in acetic
anhydride. Preparation of these impurities are summarized schematically in Scheme-2.11.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 98
Chapter - II
O
NH2
O OH
H
(37)O
NH2
OHN
(44)TEA / ECF
H2N
(38)
H
O
O
O
(36)
H2N
(38)
O
OHN
OH
(45)
TEA / ECF
AmmoniaO
NH2
OHN
(44)
H
O
O
O
(36)
H2N
(38)
O
OHN
OH
(45)
O
NH2
O OH
H
(37)
O
NH
O
(46)
AC2O
….. Scheme-2.11
Another study was carried out at 55-58°C to enable the origin of these impurities after addition
of 38. Here, reaction mass was stirred for 2hr at 55-58°C and monitored by qualitative HPLC.
Results of HPLC revealed that some impurities get increased with time while stirring the
reaction mass at 55-58°C for longer time (Table-2.7). Some of these impurities are getting
carried in Hofmann degradation step forming further new byproducts 47, 48, 49 and 50.
Table-2.7
Sr.
no.
Reaction
conditions
Pregabalin
imide, 46
(%)
Pregabalin
diacid, 35
(%)
PEA-
Pregabalin
amide, 44
(%)
PEA-
Pregabalin
acid, 45
(%)
HPLC
purity
(%)
1 Pregabalin
monoamide 37 0.48 0.03 - - -
2
After addition of
38, at 55-58°C (0
hr)
1.95 Not
detected 2.48
Not
detected -
3 At 55-58°C (1 hr) 6.02 Not 2.65 0.18 -
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 99
Chapter - II
detected
4 At 55-58°C (2 hr) 9.50 Not
detected 3.16 0.22 -
5
R-PEA
Pregabalin
monoamide 43
0.19 Not
detected 0.83 0.19 98.35
6 Mother liquor 14.32 Not
detected 5.87 5.87 56.70
7 R-Pregabalin
monoamide 39 0.03 0.01 Not detected 0.22 99.66
The above obtained diastereoisomeric salt 43 was taken into water and treated with aqueous
hydrochloric acid to liberate highly enantiopure 39 with 100% chiral purity. In this step, many
experiments revealed that the use of more quantity of water could increase the chiral purity of
39 due to more solubility of unwanted isomer towards water. It was also observed that after
adjusting pH ~1.5 in water, presence of 38 was detected on HPLC in isolated (R)-Pregabalin
monoamide. Therefore, pH of the reaction mass was kept highly acidic (~0.5) to remove the
residual (R)-1-Phenylethylamine 38 as its hydrochloride salt in water. The results of some
performed experiments are summarized in Table-2.8.
Table-2.8
S.
No.
INPUT
BATCH No.
43
Chiral
Purity
BATCH
No.
Water
(Volume)
Yield
(w/w)
39
Chiral
purity
1 PRE(918)104 96.50% PRE(918)104 3 times 0.54 99.96%
2 PRE(918)139 98.35% PRE(918)146 6 times 0.54 99.87%
3 PRE(918)140 98.28% PRE(918)147 6 times 0.54 99.82%
4 PRE(918)141 95.42% PRE(918)144 8 times 0.54 99.97%
5 PRE(918)147,138 98.12% PRE(918)145 8 times 0.55 99.96%
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 100
Chapter - II
Based on above experiments we preset 8 volumes of water to be used w.r.t. to 43. Having
worked out the resolution of 37 into 39, we devoted our effort to recycling the off-enantiomer
67 to improve throughput of the overall resolution process which will summarize in part C.
Hofmann degradation of (R)-Pregabalin monoamide 39: (R)-Pregabalin monoamide 39 was
treated with sodium hypobromite to form N-bromoamide derivative, which was converted to
corresponding isocyanate via Hofmann rearrangement. Subsequent hydrolysis with hydrochloric
acid provides Pregabalin hydrochloride, which on neutralization with base yields Pregabalin 1.
During the process optimization, a series of preliminary experiments were carried out to profile
the reaction in terms of molar ratio of the reagents and optimum reaction temperature. Initially,
when 39 was made to react with sodium hypobromite using 1.2 and 1.3 mole equivalent of
bromine and sodium hydroxide (5.0-5.2 mole eq.) in water at 0-5°C, the temperature of the
reaction mass was then allowed to rise up to 55-60°C using its own exothermicity and further
increased to 85-90°C. After workup procedures, isolated Pregabalin crude showed its HPLC
purity 94.36%, which on purification with 50%v/v aqueous isopropyl alcohol resulted
Pregabalin with HPLC purity of 99.75%, having 0.25% unknown impurities. The results are
summarized in Table-2.9.
Table-2.9
Sr.
no.
Water
volume
(times)
Bromine
(Mole eq.)
Sodium hydroxide
(mole eq.)
Impurity
1.20 RRT (%)
Impurity
1.32 RRT (%)
1 5.5 1.2 5.2 0.42 Not detected
2 8.5 1.3 6 0.15 0.14
3 10 1.2 6 0.08 0.11
4 4 1.2 6 0.32 0.32
5 8 1.2 6 0.17 0.15
6 4 1.2 6 0.27 0.23
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 101
Chapter - II
Then purification studies were undertaken to remove the above said impurities by re-
crystallization using different ratios of aqueous isopropyl alcohol, various solvents and by
making different salts of Pregabalin (Table-2.10). Results of this study show that, none of the
purification method was effective to remove these undesired products.
Table-2.10
Sr.
no.
Solvent (volume) / acid for salt
formation
Pregabalin crude Pregabalin pure
1.20 RRT
(%)
1.32 RRT
(%)
1.20 RRT
(%)
1.32 RRT
(%)
1 Aq. IPA 50% v/v (9) 0.24 0.24 0.26 0.15
2 Aq. IPA 40% v/v (8) 0.08 0.11 0.14 0.12
3 Aq. IPA 30% v/v (10) 0.08 0.11 0.13 0.12
4 Aq. IPA 18% v/v (17) - - 0.36 0.05
5 Aq. IPA 10% v/v (50) 0.08 0.11 0.55 0.10
6 Aq. methanol 50% v/v (8) 0.12 0.04 0.17 Not
detected
7 Acetone / S-mandelic acid 0.24 0.24 0.21 0.17
8 Aqueous THF / Salt free 0.21 0.17 0.16 0.08
9 IPA / N-acetyl proline 0.24 0.24 0.35 0.60
10 Aq. IPA / succinic acid 0.24 0.24 0.25 0.12
11 IPA / malonic acid No salt precipitation
12 IPA / citric acid No salt precipitation
To identify these impurities present at RRT 1.20 and 1.32, samples were subjected for LCMS
study, which gave m/z 316 and 236 respectively.[121]
Proposed structures of these impurities
were shown in Chart-2.1. The results of this study prove that these impurities were not able to
get removed by solvent purification or by its salt formation. Therefore, it was necessary to avoid
the formation of these impurities in reaction itself. As these impurities may form due to over
oxidation of Pregabalin by sodium hypobromite, it was decided to decrease the molar ratio of
bromine and reaction temperature to arrest their formation. Further, efforts were made by
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 102
Chapter - II
carrying out some more experiments by varying water volume, workup temperature and mole
ratio of reagents to minimize/avoid the formation of these impurities.
N
Br
OHO
O OH
mass : 236
RRT: 1.32
mass : 316
RRT: 1.20
NH
HN
O
OH
Chart 2.1: Proposed impurities due to over oxidation of 1
Surprisingly, when reaction was carried out by mixing bromine (1.0 mole eq.) and sodium
hydroxide (5.5 mole eq.) at 0-5°C followed by addition of 39 in lots, the temperature of the
reaction mass was allowed to raise up to 55-60°C using its own exothermicity and stirring was
continued at this temperature to complete the reaction. After workup, isolated Pregabalin crude
showed its HPLC purity in the range of 90-97%. To examine the impact of recrystallization of
the drug itself, 50%v/v aqueous isopropyl alcohol was chosen as good solvent system due to its
low toxicity and ability to achieve a recovery of at least 90% by simple heating and cooling of
1. All impurities are effectively removed or minimized by this re-crystallization, which provides
Pregabalin 1 with 100% purity and chiral purity by HPLC (see Table-2.11).
Table-2.11
Sr.
no.
Bromine
(mole
eq.)
Sodium
hydroxide
(mole eq.)
Pregabalin crude Pregabalin pure
1.20 RRT
(%)
1.32 RRT
(%)
1.20 RRT
(%)
1.32 RRT
(%)
1 1.0 5.1 1.10 Not
detected
Not
detected
Not
detected
2 1.0 5.1 0.11 Not
detected
Not
detected
Not
detected
3 1.0 5.1 0.15 Not
detected
Not
detected
Not
detected
4 1.0 5.1 Not
detected
Not
detected
Not
detected
Not
detected
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 103
Chapter - II
Further, Pregabalin crude was subjected for LCMS study to identify this modified process
related impurities. Around twelve impurities have been identified, the origin of these impurities
has also been studied systematically as represented in Scheme-2.12.
Detection and origin of impurities during Hofmann degradation of 39: Twelve process
impurities formed mainly in this stage (Hofmann degradation / rearrangement) were detected by
LCMS (Figure- 1) with mass numbers (m/z) 159, 328, 300, 262, 173, 155, 202, 344, 372, 326,
155 and 141. The structures 47 to 58 were proposed for these compounds. Origin of these
impurities was schematically given in Scheme-2.12.
Figure 1: LCMS of Pregabalin (Crude)
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 104
Chapter - II
NH2
OHN
Hofmann
Degradation
O
HN
O OH
Br
N
O OH
NH2
O OH
NH
O OH
CO
O
OH
A Bromoamide
An isocyanate
A carbamic acid
Hofmann
Degradation
O
NH
O OH
Br
NH2
O OH
NH
O
NH
O OH
C
O
NH2
NH3
Hydrolysis
-HBr
Hydrolysis
-NH3
Hydrolysis
-HBr-N
H3
Hofm
ann
Degradation
NH2
O OHO NH2
O
HN
O
OH
NH2
O
HN
O
OH
NH
O OH
O NH
NH
O OH
O N
O
NH
O
CN
O OH
NH
O OH
O NH
O O
OH
H2O
O-B
romination
OH
O
Hofmann
Degradation
Reduction
Dehydration
Deh
ydra
tion
DehydrationOxidation
Decarboxylation
1. Resolution
2. aq. HCl
1
(47)
(48)
(49)
(58)
(37 or 39)
(1)
(1)
(37 or 39)
(54)
(56)
(55)
(50)
(51)
(52)
(53)
(1)(57) (58)
O
NH2
O OH
H
(37)
H2N
(38)
O
NH2
O OH
(39) O
OHN
OH
(45)O
NH2
OHN
(44)
O
OH
O OH
H
(35)
O
NH
O
(46)
…..Scheme-2.12
The racemic Pregabalin 47 could arise due to Hofmann degradation of Pregabalin imide 46.
Another possibility of racimizing Pregabalin is the presence of 37 in 39 which also give 47 via
Hofmann degradation. When 46 reacts with Pregabalin 1 or Pregabalin lactum 58, (obtained
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 105
Chapter - II
from cyclization of Pregabalin 1) reacts with unreacted 37 or 39 could result in the formation of
Pregabalin amide dimer 48 and further it converts to degradant 49 during Hofmann degradation.
On the other hand 49 could also arise due to the reaction of 58 with Pregabalin 1. Similarly,
PEA Pregabalin 50 was the degradation product of 44 which was the impurity carried from the
resolution step. The origin of unexpected Pregabalin homolog 51 in this process was unclear, as
we predicted that most probably it could be formed due to o-bromination of 39, instead of
forming N-bromoamide in Hofmann degradation, finally it reduces to give 51. Further it
undergoes dehydration to surface new six membered lactum, Pregabalin piperidinone 52. N-
bromoamide is the reactive intermediate rearranges to give isocyanate with libration of heat. It
undergoes nucleophilic attack by a variety of functional groups like, ammonia, amine and amide
linkages present in the reaction medium. Isocyanate reacts with ammonia which was liberated
from hydrolysis of 37 or 39 gives Mono Pregabalin urea 53, whereas reaction with functional
groups like amine of Pregabalin 1 and amide of 37 or 39 could result in the formation of
corresponding di Pregabalin urea 54 and Pregabalin acyl urea 55 respectively. The reaction with
water gives the desired intermediate, a carbamic acid which decarboxylates to give Pregabalin
1. Further 54 and Pregabalin 1 undergo dehydration to give Pregabalin lactum urea 56 and
Pregabalin lactum 58. Pregabalin could oxidize partially with sodium hypobromite and gives
Pregabalin nitrile 57.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 106
Chapter - II
TEA / ECF /
Hydrolysis
NH2
O OCH3
(59)
O
NH2
O OH
H
(37)
O
NH
O
(46)
NaOH, Br2
'or'
NH2
O OH
(47)
O
NH2
O OH
(39)
O NH2
O
HN
O
OH
(48)
NH2
O
HN
O
OH
(49)
NH2
OHN
(50)
NaOH, Br2
NaOH, Br2
O NH2
O
HN
O
OH
(48)
O
NH2
OHN
(44)
Hofmann degradation
Hofmann degradation
Hofmann degradation
…..Scheme-2.13
Preparation of 49 was given in the literature.[122]
Synthetically 47, 49 and 50 were prepared by
Hofmann degradation of 46, 48 and 44 respectively (Scheme-2.13). 48 was synthesized by
making mixed an-hydride of 37 or 39 in dichloromethane using TEA/ethylchloroformate and
subsequently reacting with 59, which after hydrolysis in basic medium results Pregabalin amide
dimer 48.
MeOH
O
OH
O OCH3
(60)
TEA / ECF / NH3
O
NH2
O OCH3
(61)
Py / TsCl
CN
O OCH3
(62)
Hydrolysis
CN
O OH
(63)
Hydrogenation
H
O
O
O
(36)
NH2
O OH
(51)
NH2
O OH
(51)
NH
O
(52)
Dehydration
…..Scheme-2.14
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 107
Chapter - II
Pregabalin homolog 51 was prepared starting from 36 (Scheme-2.14). 3-Isobutylglutaric
anhydride 36 was reacted with methanol to give Pregabalin diacid monomethyl ester 60.
Pregabalin amide ester 61 was prepared by making mixed an-hydride of 60 in dichloromethane
using TEA/ethylchloroformate and then reacting with 20%w/w aqueous ammonia solution.
Pregabalin cyanomethyl acid 63 was achieved, first by amide group dehydration to yield 62,
then ester hydrolysis. 63 on hydrogenation with Raney Nickel give Pregabalin homolog 51,
which was unstable and immediately liberates water to give more stable six membered lactum
52.
Curtius rearrangement
NH3 / Hydrolysis
Curtius rearrangement
H2 O / Hydrolysis
Curtius
rearrangement
37 or 39 / Hydrolysis
O
OH
O OCH3
(60)
NH
O OH
C
O
NH2
(53)
NH
O OH
O NH
OH
O
(54)
NH
O OH
O NH
O O
OH
(55)
…..Scheme-2.15
Pregabalin diacid monomethyl ester 60 was very useful intermediate, from which we have
prepared impurities 53, 54 and 55 (Scheme-2.15). Through Curtius rearrangement we are able
to isolate useful reactive intermediate isocyanate, which reacts with ammonia, 1 and 37 to give
53, 54 and 55 respectively.
Di Pregabalin urea 54, on heating in basic condition liberates water to give new molecule 56.
Pregabalin on prolong reflux in alkaline medium cyclized, liberating water to result in 58
(Scheme-2.16). Diethyl malonate (10) was condensed with isovaleraldehyde (9) followed by
Michael addition of potassium cyanide to the unsaturated diester (11) to give β-cyanodiester 12.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 108
Chapter - II
The diester was then saponified, the resulting malonic acid was decarboxylated to the
Pregabalin nitrile 57 (Scheme-2.17). All of the prepared impurities were characterized by IR,
1H-NMR and mass, of which the results and data are concordant to the assigned structures.
NH
O OH
O NH
OH
O
(54)
NH
O OH
O N
O
(56)
NH2
O OH
(1)
NH
O
(58)
Dehydration
Dehydration
…..Scheme-2.16
CHO+
O OC2H5
O
OC2H5
O
O
OC2H5
OC2H5
O
O
OC2H5
OC2H5
CN O
OC2H5
CN
Hydrolysis
(11)
(12) (64)
(9)(10)
CN
O OH
(57)
n-Pr2NH
AcOH
reflux
KCN
KOH
…..Scheme-2.17
Degradents: Pregabalin is a relatively stable compound, no degradation was observed upon
exposure to photolytic degradation [exposure to white fluorescent light (10K Lux / 120 hours)
followed by UV light, 200 watt-hours / meter2] as well as humidity degradation [90%RH / 25°C
/ 120 hours]. Mild degradants were observed upon exposure to acid, thermal and peroxide
conditions, whereas severe degradation was happening in basic condition. 1, with 99.89%
chromatographic purity was kept for acid degradation in 5M HCl at 85°C for 120 minutes.
Practically no major degradation was noticed except the formation of 58 (2.01%) along with 57
and 56 (0.14 and 0.12% respectively, by HPLC, by area normalization). Again 58 was the major
degradant (4.22%) under thermal degradation condition (105°C / 120 hours), besides with 57
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 109
Chapter - II
and some unknown polymeric impurities (in the range of 0.1 to 0.2%). Under peroxide
condition (30% H2O2 / 85°C / 60min), no major degradation observed, but 58 was again the
main degradant (27.77%), with 57 (0.99%) under basic degradation condition (5M NaOH /
85°C / 120 minutes).
From above results, it was concluded that, the Pregabalin drug substance is susceptible to
degradation under base hydrolysis, while it is moderately stable to acid hydrolysis and thermal
stress. Study also revealed that 1 is stable to remaining stress conditions and 58 is a potential
degradant.
Metabolite: The metabolite of Pregabalin[30]
and its preparation[123]
was disclosed in the
literature. We prepared this metabolite starting with 1 and charecterized (Scheme-2.18).
O
OH
HN
N-methyl-1
O
OH
NH2
O
OH
HN
O
O
O
OH
N
O
O
K2CO3, Water
Toluene, DIBOC
THF, MeI, NaH
EtOAc, citric acid,
sodium thiosulfate
Trifluoroacetic acid
(1) (66)
(67)
…..Scheme-2.18
Simple and cost-viable process for large-scale synthesis of Pregabalin: The process for the
preparation of Pregabalin 1 used in the scale-up experiment consists of four separate operations
Scheme-2.19.
O
OH
O OH
H
O
NH2
O OH
HNH2
O OH2 steps 2 steps
(35) (37)(1)
….. Scheme-2.19
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 110
Chapter - II
Pregabalin manufacturing comprises aminolysis of 3-isobutylglutaric anhydride 36 (obtained
from 3-isobutylglutaric acid, 35) to get (RS)-3-(carbamoylmethyl)-5-methylhexanoic acid 37 in
the first step. 37 was resolved easily with (R)-1-Phenylethylamine 38 as a chiral reagent to yield
enantiopure diastereoisomeric salt 43 in 1-2%v/v ethanol in chloroform. Thereafter, 43 was
transformed into highly enantiopure 39 using hydrochloric acid in water. In the second step,
Pregabalin 1, was prepared in one pot, which comprises the i) cooling of aqueous sodium
hydroxide solution to 0-5°C; ii) addition of bromine; iii) addition of 39 and heating to 60-65°C;
iv) neutralization and isolation of Pregabalin crude. In the final stage, crude Pregabalin was
added to 50%v/v aqueous isopropyl alcohol and heated to 75-80°C and thereafter cooled to give
pure Pregabalin with chromatographic purity >99.90% and enantiomeric purity almost 100%.
Further, racimization process of 65 into 37, without isolating the intermediates, makes the
overall process, safe, economic, controlled and throughput (Figure-2).
(RS)-Pregabalin monoamide (37)
0.78w/w (after one recycle)
(78% of theory)
(R)-Pregabalin monoamide (39)
0.66w/w
(78% of theory)
Pregabalin-crude (1)
0.85 w/w
(85% of theory)
Pregabalin (1)
Overall yield: 0.437 w/w based on 37 (50.6% of theory)
Figure 1: Synthesis of Pregabalin
APPROACH B:
In approach A, we have optimized synthetic process for the preparation of Pregabalin, starting
from γ-isobutylglutaric acid derivative. Knovengial condensation of isovaleraldehyde 9 with
cyano acetic acid ethyl ester 33 followed by Michal addition of diethyl malonate 10 in presence
of dipropyl amine in refluxing heptanes, after decarboxylation in aqueous hydrochloric acid
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 111
Chapter - II
gives 3-isobutylglutaric acid 35 in 80% yield. Thus obtained compound was converted to 3-
(carbamoylmethyl)-5-methylhexanoic acid 37, key raw material for the preparation of
Pregabalin, by successive treatment with acetic anhydride and ammonium hydroxide.
Pregabalin monoamide 37 was then resolved using suitable resolving agent, e.g., R-1-
phenylethyl amine 38 in 35% yield and then subjected to Hofmann degradation in aqueous
alkaline medium at 60-65°C. After workup the overall yield was only 78% of theory, due to lot
many side reactions.
Although this route was safe, scalable, controlled, selective and widely applicable, there are
possibilities for improvement in terms of economy and high throughput: the use of non-aqueous
reaction medium in Hofmann degradation reaction and racimisation of non racimic mixture of
3-(carbamoylmethyl)-5-methylhexanoic acid in basic medium to improve quality and quantity
of product. The process development described herein aimed at using relatively mild conditions
for Hofmann degradation to provide highly pure Pregabalin having chromatographic and chiral /
optical purity >99.9% each. This part describes the successful realization of all of these goals,
resulting in an efficient synthesis of 1.
The classical Hofmann rearrangement was the conversion of primary carboxamide to a primary
amine using aqueous NaOH and Bromine.[124]
In order to improve the reaction conditions and
yield, many modifications have been made by using oxidative reagents including iodine (III)
species,[125]
lead tetraacetate,[126]
benzyltrimethylammonium tribromide,[127]
NBS-Hg(OAc)2,[128]
CH3OBr,[129]
and NBS-DBU.[130]
When methanol was used as a solvent, the corresponding
methyl carbamate was produced.
Part-A: Treatment of a solution of sodium methoxide in methanol at -40°C with bromine causes
rapid decolorization and results in a pale yellow solution. This solution upon warming results in
the rapid development of a precipitate at ~ -20°C with concurrent loss in activity as far as
usefulness in the Hofmann rearrangement was concerned. We have not characterized the
substance that was formed in this reaction as methyl hypobromite but we believe that it was
present
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 112
Chapter - II
NaOCH3+ Br2 + NaBr[H3COBr]
and that was functions as the source of positive bromide for the Hofmann rearrangement, since
addition of an amide 39 to this cold, basic solution, followed by gentle heating at ~ 50°C, results
in high yields of the expected carbamate 68 (Scheme-2.20).
O
NH2
O OH
NH
O OH
O
ONaOCH3/CH3OH/Br2,-40°C to -15°C
(39) (68)
….. Scheme-2.20
To study the reaction in details, we used different alcohols as reaction medium, which was
selected from, methanol, ethanol, n-propanol, iso-propanol, n-butanol and tert-butanol. To
alcohols, under nitrogen atmosphere added piece of sodium metal and stirred to get a solution.
39 was added to the obtained sodium alkoxides solution and are cooled to -40° to -50°C.
Bromine was added maintaining the temperature < -40°C and after addition, raised the
temperature to 60-65°C to complete the reaction. The Table-2.12 shows the typical results
obtained upon application of this reaction using different alcohols.
Table-2.12
Solvent Product Yield (%)
Methanol
NH
O OH
O
O
(68)
97
Ethanol
NH
O OH
O
O
(69)
89
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 113
Chapter - II
n-Propanol
NH
O OH
O
O
(70)
78
Iso-Propanol
NH
O OH
O
O
(71)
30
n-Butanol
NH
O OH
O
O
(72)
61
tert-Butanol
NH
O OH
O
O
(73)
No reaction
Methanol
HN
O
OH
O
O
(74)
99
It was clear from the above that, isocyanate the main intermediate of the reaction was reactiong
fast with the alcohols having less no. of carbons compare to more no. of carbons. It was further
clear that, linear alcohols reacting fast compare to branched alcohols. After work-up as
described in the experimental section, carbamates were converted to Pregabalin by refluxing in
aqueous hydrochloric acid.
Part-B: Kajigaeshi and co-workers[131]
have reported the use of DBU as a base for the Hofmann
rearrangement and it appears as though DBU was particularly well studied to effect the
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 114
Chapter - II
rearrangement. Furthermore, when an attempt was made to use triethylamine in place of DBU,
no rearrangement was even at higher temperature. Apparently NEt3, while only slightly less
basic than DBU, was not a strong enough base to promote the rearrangement.
O
NH2
O OH
NH
O OH
O
ONBS, DBU, MeOH, reflux
(39) (68)
….. Scheme-2.21
Table-2.13
Solvent Product Yield (%)
Methanol
NH
O OH
O
O
(68)
95
Ethanol
NH
O OH
O
O
(69)
88
Iso-Propanol
NH
O OH
O
O
(71)
40
Treatment of 39, in methanol with N-Bromosuccinimide (NBS) and DBU at 20-55°C, under
mild conditions gives 68 in excellent yield (Scheme-2.21, Table-2.13). The reaction was
spontaneous, which completes after addition of DBU completes, in methanol. For long chain
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 115
Chapter - II
aliphatic amides, a large volume of methanol was used in order to avoid the formation of N,N-
dialkylurea 54. It was thought that the loss from urea formation was largely due to the physical
properties of the organic compounds (Scheme-2.12). As molecular weight increases, the
isocyanate, the proximate rearrangement product, the product amine 1 and the earlier
intermediates have an increasing tendency to extract each other from solution, whereby the
isocyanate was increasingly likely to react with other substances than hydroxide ion.[102]
APPROACH C:
The known[79]
racimisation process of 65, was carried out in hydrochloric acid under reflux for
approximately 24 hours. During our experimental observations, we found that, lot of impurities
were formed during hydrolysis of 65 in acidic medium, mainly formation of 46 (~23%,
Scheme-2.22), which reduces the yield of hydrolyzed product 35, and incase, 46 carried through
Hofmann degradation, may rearrange to 47 and reduces optical purity as well as overall yield.
O
NH2
O OH
(65)
H
O
OH
O OH
HHCl, reflux
24h
(35)
+
O
NH
O
(46)
….. Scheme-2.22
The basic premise of our objective was to convert 65 into 37, without isolating the intermediates
(Scheme-2.23). Typically, the mother liquor, obtained after isolation of 43, was basified and
aqueous layer was separated for recovery of 37 and organic layer for recovery of 38. Sodium
hydroxide was added to aqueous layer and heated under reflux for ~15hrs, then cooled to 25-
30°C, acidified, extracted with toluene and concentrated to get 35. Addition of acetic anhydride
and heating under reflux gives 36, which was converted to 37 in 85% yield, by treating with
aqueous ammonia solution. The comparisons of racimization process are given in Table-2.14.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 116
Chapter - II
O
NH2
O OH
(65)
O
OH
O OH
H
O
NH2
O OH
H
O
O
O
H
AC2O
NH3
(35) (36)
(37)
Aq. NaOH
H
O
NH2
O O H3N.
(43)
Aq. HCl
O
NH2
O OH
H
(37)
H2N
(38)
O
NH2
O OH
(39)Mother
liquor /
Aq. NaOH
O
NH2
O O H3N.organic layer
aq. layer
H2N
(38)
reflux, 15h reflux
….. Scheme-2.23
Table-2.14
Sr.
no. Reaction conditions
Pregabalin
imide, 46
(%)
PEA-
Pregabalin
amide, 44
(%)
PEA-
Pregabalin
acid, 45
(%)
Pregabal
in diacid,
35
(%)
Pregabalin
monoamid
e, 37
(%)
1 Acid hydrolysis of 65, for
24hr 23.10
Not
detected 0.15 76.39 0.13
2 Base hydrolysis of 65, for
12hr 0.06 0.03 3.15 76.25 0.17
3 After concentration, 35 Not
detected 0.06 4.60 93.69 0.11
4 Anhydride preparation, for
2hr 2.96 0.06 0.76 0.18
Not
detected
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 117
Chapter - II
5 Monoamide preparation,
for 1hr 9.96 0.08 0.31 0.10 85.77
6 Organic layer 15.94 0.83 2.78 Not
detected
Not
detected
7 Aqueous layer 14.63 0.08 0.30 0.12 81.03
8 Recovered Pregabalin
monoamide, 37 0.05 0.01 0.12 0.01 99.72
9 Mother liquor 11.14 0.93 2.86 0.91 53.20
APPROACH D:
Possible isomers of Pregabalin have been prepared starting with 2-methyl butyraldehyde (75),
valeraldehyde (76), trimethyl acetaldehyde (77) instead of isovaleraldehyde (9) used for the
preparation of pregabalin. This is summarized schematically in Scheme-2.24.
CHO
(9)
CHO
(75)
CHO
(76)
CHO
(77)
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
CONH2
COOH
CONH2
COOH
CONH2
COOH
CONH2
COOH
NH2
COOH
NH2
COOH
NH2
COOH
NH2
(35) (37) (47)
(78)
(79)
(80)
(81)
(82)
(83)
(84)
(85)
(86)
….. Scheme-2.24
Ethyl cyanoacetate (33) was condensed with different aldehydes 9, 75, 76 and 77 which after
Michael addition of diethyl malonate 10, followed by acid-induced decrboxylation gave glutaric
acids 35, 78, 79 and 80. These di-acids was then converted to amide 37, 81, 82 and 83, via
corresponding anhydride intermediates. Hofmann rearrangement of these amides gave isomers
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 118
Chapter - II
of Pregabalin 47, 84, 85 and 86. The characterization data and detailed experimental procedure
given in details in experimental section.
CONCLUSION:
Hence we have developed a simple, safe, productive, eco-friendly and easy to handle
commercial process, having controls via Hofmann degradation of R-(-)-3-(carbamoylmethyl)-
5-methylhexanoic acid. Further, we have optimized the process, impurities formed in the
process were identified, prepared and characterized. A new process was developed for the
preparation of Pregabalin (1) using alcohols as reaction medium in Hofmann degradation. We
have recovered racemic 3-(carbamoylmethyl)-5-methylhexanoic acid 37 from non-racemic 3-
(carbamoylmethyl)-5-methylhexanoic acid, obtained during resolution, without isolation of any
intermediate. We have provided highly pure (S)-Pregabalin 1 having single individual
impurities less than 0.10%, chromatographic and chiral purity > 99.9% each.
EXPERIMENTAL SECTION:
3-Isobutylpentanedioic acid (Pregabalin diacid, 35)
After suspending ethylcyanoacetate 33 (62.4g, 0.55mole), isovaleraldehyde 9 (52.11g,
0.61mole), and di-n-propylamine (0.55g) sequentially in cyclohexane (80ml) at 25 to 30°C,
temperature of the contents was raised to reflux (85 to 90°C) to remove water azeotropically
(11ml during 3hr). Thereafter, reaction mass was cooled, concentrated under reduced pressure
to remove solvent. Diethylmalonate 10 (105.7g, 0.66mole) and di-n-propylamine (5.6g) were
added sequentially to the remaining oil (mainly 2-cyano-5-methylhex-2-enoic acid ethyl ester,
34) and contents were stirred at 50 to 55°C for 3hr to form 2-cyano-4-ethoxycarbonyl-3-
isobutylpentanedioic acid diethyl ester. Thereafter, aqueous hydrobromic acid (1300ml,
47%w/w) was added and contents were further refluxed at 100 to 125°C for 10hr. Reaction
mass was cooled to 25 to 30°C and extracted with toluene (2x250ml; 1x100ml). Finally,
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 119
Chapter - II
combined toluene extracts was concentrated under reduced pressure to give 105.3g of 35 as oil,
which on stirring with hexanes, yielded 35 as low melting solid. Yield 104g (91.3%). IR (KBr,
cm-1
): 3042, 2957, 2935, 2867, 2711, 2614, 1702, 1464, 1447, 1419 and 1409. 1HNMR (CDCl3,
300 MHz, δ ppm): 0.92 (2d, 6H), 1.20 (t, 2H), 1.63 (m, 1H), 2.10-2.20 (q, 2H), 2.46-2.50 (q,
2H), 2.59 (m, 1H). Exact Mass (m/z, 188.1); Observed: (in –ve ion mode) m/z; 187.2 [(M+-H)
-].
Following same procedure, 78, 79 and 80 was prepared, see (Table-2.15) for characterization
data.
Table-2.15
Sr.
no. Compound Data
1 78
1HNMR (CDCl3, 300 MHz, δ ppm): 0.86 (d, 3H), 0.95 (t, 3H), 1.21 (m,
1H), 1.38 (m, 1H), 1.45 (m, 1H), 2.20 (m, 1H), 2.32-2.59 (m, 4H).
Exact Mass (m/z, 188.1); Observed: (in –ve ion mode) m/z; 187.2 [(M+-
H)-].
2 79
1HNMR (CDCl3, 300 MHz, δ ppm): 0.91 (t, 3H), 1.35 (m, 6H), 2.23-
2.52 (m, 5H). Exact Mass (m/z, 188.1); Observed: (in –ve ion mode)
m/z; 187.2 [(M+-H)
-].
3 80
1HNMR (CDCl3, 300 MHz, δ ppm): 0.93 (s, 9H), 2.19 (m, 2H), 2.35
(m, 1H), 2.65 (m, 2H). Exact Mass (m/z, 188.1); Observed: (in –ve ion
mode) m/z; 187.2 [(M+-H)
-].
3-Carbamoylmethyl-5-methylhexanoic acid (Pregabalin monoamide, 37)
Acetic anhydride (65g, 0.64mole) was added to 35 (100g, 0.53mole) and then heated under
reflux for 3hr. Thereafter, reaction mass was placed under vacuum distillation to remove acetic
acid and acetic anhydride. Undistilled 3-isobutylglutaric acid anhydride, 36 was cooled to 30 to
35°C and diluted with di-isopropyl ether (200ml). Obtained solution was added slowly to
precooled aqueous ammonia solution (300ml, 12%w/w) at 15 to 20°C. After stirring bi-phasic
solution for 1hr, organic layer was separated and aqueous layer was placed under vacuum to
remove volatile impurities. Thereafter, pH of the aqueous mass was adjusted to 1 and cooled the
obtained slurry to 0 to 5°C. After stirring at 0 to 5°C for 1hr, product was filtered, washed with
chilled water and then dried at 55 to 60°C. Yield 91.25g (91.7%). IR (KBr, cm-1
): 3366, 3222,
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 120
Chapter - II
2963, 2924, 2879, 2851, 2795, 2622, 2514, 1897, 1704, 1669, 1586, 1461 and 1428. 1HNMR
(DMSO-d6, 300 MHz, δ ppm): 0.83 (2d, 6H), 1.11 (t, 2H), 1.60 (m, 1H), 1.95-2.25 (m, 5H), 6.74
& 7.27 (2brs, 2H), 12.01 (brs, 1H). Exact Mass (m/z, 187.12); Observed: (in –ve ion mode) m/z;
186.2 [(M+-H)
-]. Following same procedure, 81, 82 and 83 was prepared, see (Table-2.16) for
characterization data.
Table-2.16
Sr.
no. Compound Data
1 81
IR (KBr, cm-1
): 3410, 2934, 2877, 1704, 1663, 1603, 1310, 1211,
1174. 1HNMR (CDCl3, 300 MHz, δ ppm): 0.87 (t, 3H), 0.92 (d, 3H),
1.19 & 1.34 (2m, 2H), 1.52 (m, 1H), 2.16 -2.35 (m, 5H), 6.10 & 6.77
(brs, 2H). Exact Mass (m/z, 187.12); Observed: (in –ve ion mode)
m/z; 186.2 [(M+-H)
-].
2 82
IR (KBr, cm-1
): 3416, 3221, 2959, 2936, 2858, 1711, 1649, 1592,
1457, 1416, 1225. 1HNMR (CDCl3, 300 MHz, δ ppm): 0.41 (t, 3H),
0.84 (m, 6H), 1.82 (m, 5H), 5.65 & 6.34 (2brs, 2H). Exact Mass (m/z,
187.12); Observed: (in –ve ion mode) m/z; 186.2 [(M+-H)
-].
3 83
IR (KBr, cm-1
): 3459, 3405, 3324, 2968, 2874, 1712, 1651, 1582,
1412, 1311, 1221, 1168. 1HNMR (DMSO-d6, 300 MHz, δ ppm): 0.85
(s, 9H), 1.84 (m, 1H), 2.04-2.24 (m, 4H), 6.73 & 7.28 (2brs, 2H),
11.98 (brs, 1H). Exact Mass (m/z, 187.12); Observed: (in –ve ion
mode) m/z; 186.2 [(M+-H)
-].
R-(-) - 1-Phenylethyl ammonium 3- carbamoylmethyl-5-methylhexanoate (R-PEA Pregabalin
monoamide, 43)
After suspending 37 (600g, 3.21mole) in chloroform (7200ml) and ethanol (60ml) at 25 to
30°C, contents were heated to 52 to 55°C and (R)-(+)-1-phenylethylamine, 38 (272g, 2.25mole)
was added. Thereafter, obtained clear solution was cooled slowly to 28 to 30°C and stirred at
this temperature for 90min. Precipitated salt was filtered, washed with chloroform (2x600ml)
and dried at 60 to 65°C under reduced pressure to give 43. Yield 352g (71.2%). Melting range
117-125°C. SOR α
D20 (c=1 in water) +4.9
°. IR (KBr, cm
-1): 3499, 3377, 3189, 3035, 2956, 2933,
2903, 2869, 2843, 2780, 2688, 2538, 2215, 1660, 1634, 1563, 1525, 1468, 1447 and 1434 .
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 121
Chapter - II
1HNMR (DMSO-d6, 300 MHz, δ ppm): 0.83 (d, 6H), 1.10 (t, 2H), 1.27 (m, 3H), 1.62 (m, 1H),
2.02 (d, 2H), 2.08-2.17 (m, 3H), 4.07 (m, 1H), 6.71 (brs, 1H), 7.19-7.39 (m, 5H). Exact Mass
(m/z, 308.2); Observed: (in +ve ion mode) m/z; 309.2 [(MH)+].
R-(-) - 3-Carbamoylmethyl-5-methylhexanoic acid (R-Pregabalin monoamide, 39)
After adding 43 (350g) in water (2800ml) at 25 to 30°C pH of the obtained solution was
adjusted to 0.5 with concentrated hydrochloric acid (250ml, 37%w/w). Thereafter, obtained
product slurry was slowly cooled to 5 to 10°C, stirred at this temperature for 1hr. Product was
filtered , washed successively with chilled 3%w/w hydrochloric acid solution (350ml) followed
by chilled water (350ml) and dried at 60 to 65°C under reduced pressure to yield 39. Yield
198g (93.2%). IR (KBr, cm-1
): 3436, 3227, 2930, 1712, 1643 and 1591. 1HNMR (DMSO-d6,
300 MHz, δ ppm): 0.83 (2d, 6H), 1.11 (t, 2H), 1.60 (m, 1H), 1.95-2.25 (m, 5H), 6.74 & 7.27
(2brs, 2H), 12.01 (brs, 1H). Exact Mass (m/z, 187.12); Observed: (in –ve ion mode) m/z; 186.2
[(M+-H)
-].
3-Isobutyl-n’-(1-phenylethyl) pentanediamide (PEA-Pregabalin amide, 44)
Triethyl amine (70.2g, 0.69mole) was added to a suspension of 37 or 39 (100g, 0.53mole) in
dichloromethane (700ml) at 25 to 30°C. Obtained clear solution was cooled to 0 to 5°C and
added ethylchloroformate (69.6g, 0.64mole) in 30min. After stirring the contents for ~15 min,
38 (77.6g, 0.64mole) was added and temperature was raised slowly to 25 to 30°C. Thus,
precipitated product was filtered, washed with ethyl acetate followed by hexanes, and dried at
55 to 60°C under reduced pressure to a constant weight. Yield 70g (45%). IR (KBr, cm-1
): 3297,
3175, 3068, 3033, 2962, 2950, 2911, 2870, 1668, 1644, 1548, 1495, 1467 and 1421. 1HNMR
(DMSO-d6, 300 MHz, δ ppm): 0.73-0.82 (m, 6H), 1.05 (m, 2H), 1.32 (d, 3H), 1.59 (m, 1H), 1.99
& 2.08 (2d, 4H), 2.20 (m, 1H), 4.92 (m, 1H), 6.72 & 7.27 (2brs, 2H), 7.17- 7.30 (m, 5H), 8.26
(d, 1H). Exact Mass (m/z, 290.2); Observed: (in +ve ion mode) m/z; 291.2 [(MH)+].
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 122
Chapter - II
5-Methyl-3-[(1-phenylethylcarbamoyl)-methyl]hexanoic acid (PEA-Pregabalin acid, 45)
After suspending 35 [Pregabalin diacid (25g, 0.13mole)] in acetic anhydride (16.27g, 0.15mole)
at 25°C contents were heated to reflux and stirred for 2.5hr at this temperature. Thereafter,
reaction mass was concentrated to remove acetic acid and acetic anhydride and undistilled 36
was cooled to 30°C under vacuum and diluted with toluene (30ml). In another flask, 38 (32g,
0.26mole) and 4-dimethylamino pyridine (0.2g) were added sequentially in toluene (60ml) and
obtained solution was cooled to -10 to -15°C. Thereafter, solution of 36 as prepared above was
added in ~45min. and contents were stirred for 1.5hr at this temperature. Thereafter, reaction
mass was quenched by adding 10% aqueous sodium hydroxide solution (150ml) and aqueous
layer was separated and washed with toluene. Further, after adjusting pH of aqueous layer to 2
and product was extracted with ethyl acetate (1x200ml; 1x100ml) and dried on sodium sulphate.
Organic layer was concentrated under reduced pressure and digested in toluene (200ml) at 65 to
70°C. Obtained product was cooled to 10 to 15°C, stirred for 1hr, filtered, washed with chilled
toluene and dried at 45 to 50°C under reduced pressure to a constant weight. Yield 38g (98.2%).
IR (KBr, cm-1
): 3321, 3087, 3067, 3031, 2957, 2931, 2906, 2869, 2521, 1995, 1694, 1607,
1563, 1495 and 1453. 1HNMR (CDCl3, 300 MHz, δ ppm): 0.86 (2d, 6H), 1.20 (m, 2H), 1.47 (m,
1H), 1.49 (d, 2H), 1.64 (m, 1H), 2.23-2.38 (2m, 5H), 5.13 (m, 1H), 6.16 (d, 1H), 7.16-7.36 (m,
5H). Exact Mass (m/z, 291.18); Observed: (in –ve ion mode) m/z; 290.2 [(M+-H)
-].
4-Isobutylpiperidine-2,6-dione (Pregabalin imide, 46)
After suspending 37 (100g, 0.53mole) in acetic anhydride (65g, 0.64mole) at 25°C contents
were heated to reflux and stirred for 3 hr at this temperature. Thereafter, reaction mass was
concentrated to remove acetic acid and acetic anhydride and undistilled 4-isobutyl
dihydropyran-2,6-dione , 46 was cooled to 30°C under vacuum . Thus, Obtained solid was
diluted with di-isopropyl ether (300ml), cooled to 0 to 5°C, and stirred of 2hr. product was
filtered, washed with chilled di-isopropyl ether (2x50ml) and dried at 45 to 50°C under reduced
pressure to a constant weight. Yield 57g (63%). IR (KBr, cm-1
): 3355, 3201, 3089, 2955, 2924,
2891, 2866, 2844, 2717, 1732, 1683, 1464, 1448, 1422 and 1411. 1HNMR (DMSO-d6, 300
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 123
Chapter - II
MHz, δ ppm): 0.84 (2d, 6H), 1.14 (m, 2H), 1.61 (m, 1H), 2.08-2.25 (m, 3H), 2.45 (m, 2H), 10.67
(brs, 1H). Exact Mass (m/z, 169.11); Observed: (in –ve ion mode) m/z; 168 [(M+-H)
-].
3-Aminomethyl-5-methyl-1-hexanoic acid (RS-Pregabalin, 47)
46 (162g, 0.96mole) or 37 (180g, 0.96mole) was added in lots to sodium hypobromite solution
prepared by adding bromine (154g, 0.96mole) to pre-cooled aqueous sodium hydroxide
solution [(212g, 5.3mole) in water (675ml)] at 0 to 5°C and stirred for 1hr at this temperature.
Thereafter, temperature of the reaction was raised to 30°C and allowed to rise of the
temperature to 60 to 65°C by using its exothermicity. After completion of reaction, reaction
mass was cooled to 25 to 30°C and 35%w/w hydrochloric acid is added to it slowly at this
temperature to obtain a clear solution. 50%w/w aqueous sodium hydroxide solution is added to
the reaction mass to adjust its pH 5.1. Thereafter, temperature, of the reaction mass is raised to
55 to 60°C, stirred for 15min and again slowly cooled to 10 to 15°C. After stirring for 1hr,
product was filtered, washed with pre-cooled water (2x90ml) and dried at 50 to 60°C under
reduced pressure to a constant weight. Yield 117g (72.2%). IR (KBr, cm-1
): 3338, 2956, 2909,
2870, 2785, 2590, 2177, 1662, 1636, 1542, 1468 and 1408. 1HNMR (D2O, 300 MHz, δ ppm):
0.88 (m, 6H), 1.21 (m, 2H), 1.65 (m, 1H), 2.11-2.35 (m, 3H), 2.97 (m, 2H). Exact Mass (m/z,
159.13); Observed: (in +ve ion mode) m/z; 160.2 [(MH)+]. Following same procedure, 84, 85
and 86 was prepared, see (Table-2.17) for characterization data.
Table-2.17
Sr.
no. Compound Data
1 84
IR (KBr, cm-1
): 3339, 2964, 2916, 2876, 1661, 1538, 1461, 1408, 1395. 1HNMR (D2O, 300 MHz, δ ppm): 0.84 (t, 3H), 0.86 (d, 3H), 1.19 & 1.34
(2m, 2H), 1.49 (m, 1H), 2.08 (m, 1H), 2.11 & 2.32 (2m, 2H), 2.87- 3.07
(m, 2H). Exact Mass (m/z, 159.13); Observed: (in +ve ion mode) m/z;
160.1 [(MH)+].
2 85
IR (KBr, cm-1
): 3376, 3109, 2953, 2929, 2860, 1664, 1628, 1542, 1440,
1405, 1386. 1HNMR (D2O, 300 MHz, δ ppm): 0.86 (t, 3H), 1.35 (m,
6H), 2.08 (m, 1H), 2.19 -2.35 (m, 2H), 2.90 -3.04 (m, 2H). Exact Mass
(m/z, 159.13); Observed: (in +ve ion mode) m/z; 160.1 [(MH)+].
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 124
Chapter - II
3 86
IR (KBr, cm-1
): 3376, 3053, 2961, 2872, 2778, 2625, 1635, 1558, 1513,
1473, 1386, 1329. 1HNMR (D2O, 300 MHz, δ ppm): 0.91 (s, 9H), 1.80
(m, 1H), 2.19 (dd, 1H), 2.55 (dd, 1H), 2.79 (dd, 1H), 3.27 (d, 1H). Exact
Mass (m/z, 159.13); Observed: (in +ve ion mode) m/z; 160.1 [(MH)+].
3-{[3-(2-Carbamoylethyl)-5-methylhexanoylamino]-methyl}-5-methylhexanoic acid
(Pregabalin amide dimer, 48)
Triethyl amine (94.5g, 0.93mole), was added to a suspension of 39 (50g, 0.27mole) in
dichloromethane (300ml) at 25 to 30°C. Obtained clear solution was cooled to 0 to 5°C and
added ethylchloroformate (34.81g, 0.32mole) in 30min. Thereafter, a solution of Pregabalin
methyl ester hydrochloride, 59 (61g, 0.29mole) in dichloromethane (100ml) was added to it at
0 to 5°C and contents were stirred further for 1hr at this temperature to complete the reaction,.
Thereafter, reaction mass was washed with 5% aqueous sodium bicarbonate solution (150ml)
followed by water (150ml). Thus obtained, organic layer was concentrated under reduced
pressure to yield oil, which was further treated with 15%w/w aqueous sodium hydroxide
solution for 2hr at 25 to 30°C. Thus obtained solution was washed with dichloromethane and
pH of the aqueous layer was adjusted to 4. Product was extracted in dichloromethane,
concentrated under reduced pressure to obtained viscous oil. Yield 25g (28.5%). IR (neat, cm-1
):
3333, 3092, 2957, 2933, 2872, 2627, 2248, 1924, 1712, 1652, 1553, 1469, 1442 and 1424.
1HNMR (CDCl3, 300 MHz, δ ppm): 0.88-0.94 (m, 12H), 1.18 (m, 2H), 1.33 (m, 2H), 1.64 (m,
2H), 2.15-2.61 (m, 8H), 3.02-3.51 (m, 2H). Exact Mass (m/z, 328.24); Observed: (in +ve ion
mode) m/z; 329.2 [(MH)+].
3-{[3-(2-aminoethyl)-5-methylhexanoylamino]-methyl}-5-methylhexanoic acid (Pregabalin
dimer, 49)
To aqueous sodium hydroxide solution (43.4g, 0.54mole) diluted with water (120ml), 48 (35g,
0.11mole) was added and resulting solution was further cooled to 0 to 2°C. Thereafter, bromine
(18.7g, 0.11mole) was added slowly in 1hr at 0 to 5°C and temperature was raised to 60-65°C.
After maintaining at 65°C for 1hr, reaction mass was cooled to 25°C and adjusted pH 4.5 to 5
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 125
Chapter - II
with hydrochloric acid. Thereafter, product was extracted in dichloromethane (2x200ml) and
concentrated under reduced pressure. Yield 20g (62.5%). IR (neat, cm-1
): 3061, 2957, 2871,
2620, 2248, 1945, 1711, 1651, 1553, 1469, 1455 and 1416. 1HNMR (CDCl3, 300 MHz, δ ppm):
0.84 (2d, 12H), 1.11-1.29 (m, 4H), 1.53-1.60 (m, 2H), 1.98-2.55 (m, 8H), 2.88-3.44 (m, 2H),
6.51 (brs, 3H). Exact Mass (m/z, 300.24); Observed: (in +ve ion mode) m/z; 301.2 [(MH)+].
3-Aminomethyl-5-methylhexanoic acid (1-phenylethyl) amide (PEA Pregabalin, 50)
Bromine (27.5g, 0.17mole) was added to pre-cooled aqueous sodium hydroxide solution
[prepared by dissolving sodium hydroxide (34.4g, 0.86mole) in water 200ml] over a period of
1hr at 0 to 5°C. 3-isobutyl-n’-(1-phenylethyl) pentanediamide 44 (50g, 0.17mole) was added in
lots to the reaction mass maintaining temperature 0 to 5°C and further stirred for 1hr at this
temperature. Thereafter, temperature of the reaction mass was raised to 30°C and allowed
raising of temperature to 60-65°C by using its exothermicity. After completion of reaction,
reaction mass was cooled to 25 to 30°C and adjusted pH 5 with 35%w/w hydrochloric acid
(20ml). To obtained sticky solid methanol (300ml) is added and heated to 50°C. Obtained slurry
is slowly cooled to 25 to 30°C, filtered and washed with methanol. After drying under reduced
pressure, it is recrystallized with methanol. Yield 5g (11%). IR (KBr, cm-1
): 3334, 3087, 3066,
3030, 2959, 2933, 2871, 1682, 1645, 1531, 1495, 1468, 1450 and 1422. 1HNMR (DMSO-d6,
300 MHz, δ ppm): 0.78 (2d, 6H), 1.04 (m, 2H), 1.32 (d, 3H), 1.58 (m, 1H), 1.97-2.24 (m, 4H),
3.12 (m, 1H), 4.91 (m, 1H), 7.20-7.28 (m, 5H), 8.28 & 8.42 (2brs, 2H), 10.28 (brs, 1H). Exact
Mass (m/z, 262.2); Observed: (in +ve ion mode) m/z; 263.2 [(MH)+].
3-(2-Aaminoethyl)-5-methylhexanoic acid (Pregabalin homolog, 51)
3-Cyanomethyl 5-methylhexanoic acid 63 (29g, 0.17mole) was added to aqueous sodium
hydroxide solution [prepared by dissolving sodium hydroxide (13.73g, 0.34mole) in water
290ml] at 25 to 30°C. Thereafter, contents were hydrogenated using Raney nickel (2.9g,
10%w/w) at 4-5kg pressure at 25 to 30°C for 4Hrs. After completion, catalyst was removed by
filtration, and filtrate was neutralized and concentrated. Yield 29.68g (100%). IR (KBr, cm-1
):
3197, 2963, 2948, 2929, 2912, 2868, 2842, 2714, 2529, 2222, 1870, 1848, 1775, 1633, 1529,
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 126
Chapter - II
1471, 1429 and 1401. 1HNMR (D2O, 300 MHz, δ ppm): 0.87 (d, 6H), 1.16 (m, 2H), 1.53-1.74
(m, 3H), 1.94 (m, 1H), 2.07 & 2.22 (2m, 2H), 3.02 (t, 2H). Exact Mass (m/z, 173.14); Observed:
(in –ve ion mode) m/z; 172.1 [(M+-H)
-].
4-Isobutylpiperidin-2-one (Pregabalin piperidinone, 52)
It was prepared by stirring 3-(2-aminoethyl)-5-methylhexanoic acid 51 (50g, 0.29mole) with
20%w/w aqueous sodium hydroxide solution (200ml) at 45 to 50°C. IR (KBr, cm-1
): 2964,
2949, 2929, 2913, 2868, 2843, 2764, 2544, 2210, 1630, 1567, 1528, 1469, 1430 and 1402.
1HNMR (DMSO-d6, 300 MHz, δ ppm): 0.85 (d, 6H), 1.11 (m, 2H), 1.25 (m, 1H), 1.58-1.79 (m,
4H), 2.18 (m, 1H), 3.12 (m, 2H), 7.40 (brs, 1H). Exact Mass (m/z, 155.13); Observed: (in +ve
ion mode) m/z; 156.2 [(MH)+].
5-Methyl-3-uriedomethylhexanoic acid (Mono Pregabalin urea, 53)
After adding triethyl amine (45.75g, 0.45mole) to a solution of Pregabalin diacid monomethyl
ester 60 (61g, 0.30mole) in dry acetone (250ml) at -10°C under nitrogen atmosphere.,
ethylchloroformate (39.31g, 0.36mole) was also added slowly at -10°C, and reaction mass was
stirred at -10°C for 30min. Therafter, sodium azide solution [prepared by dissolving sodium
azide (29.5g, 0.45mole) in water (100ml)] was added slowly while maintaining the temperature
to -5°C. After completion of reaction, diluted the reaction mass with water (700ml) and
continued stirring at 0 to -5°C for 15min. Azide intermediate was extracted in toluene
(1x500ml; 1x300ml) at 0 to 5°C and dried on sodium sulphate at 0 to 4°C. Toluene (50ml) was
taken in another flask and heated to reflux at 108 to 110°C. To this, added above dried toluene
extracts slowly at 80 to 100°C to facile rearrangement. After maintaining for 30min at reflux,
reaction mass was slowly cooled to 0 to 5°C and then purged dry ammonia gas in it for 30 min.
After complete conversion of isocyanate to urea, toluene was removed under reduced pressure.
Obtained concentrated mass was stirred with 15% aqueous sodium hydroxide solution for 4hr,
diluted with water and washed with toluene. Thereafter, pH of the aqueous layer was adjusted to
1.5 and stirred the precipitated product at 0 to 5°C for 30min. Filtered the product under suction,
washed with chilled water and dried at 50 to 55°C under reduced pressure. Yield 31.7g (52%).
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 127
Chapter - II
IR (KBr, cm-1
): 3404, 3343, 3232, 2958, 2928, 2911, 2873, 2739, 2527, 1891, 1705, 1652,
1574, 1503, 1467, 1449 and 1412. 1HNMR (DMSO-d6, 300 MHz, δ ppm): 0.84 (d, 6H), 1.07
(m, 2H), 1.63 (m, 1H), 1.88 (m, 1H), 2.02 & 2.19 (2m, 2H), 2.86 & 3.00 (2m, 2H), 5.40 (brs,
2H), 5.99 (brs, 1H), 12.11 (brs, 1H). Exact Mass (m/z, 202.13); Observed: (in –ve ion mode)
m/z; 201.2 [(M+-H)
-].
3-[({[2-(carboxymethyl)-4-methylpentyl]carbamoyl}amino)methyl]-5-methylhexanoic acid (Di
Pregabalin urea, 54)
Pregabalin diacid monomethyl ester 60 (161g, 0.80mole) was added to dry acetone (600ml) and
cooled the resulting solution to -10°C under nitrogen atmosphere. Added triethyl amine (121g,
1.2mole) slowly in 15min, followed by ethylchloroformate (104g, 0.96mole) during 30min at -
10°C. Stirred the reaction mass at -10°C for 30min and added sodium azide solution [prepared
by mixing sodium azide (77.8g, 1.2mole) in water (250ml)] slowly while maintaining the
temperature to -5°C. After completion of reaction, diluted reaction mass with water (2000ml)
and continued stirring at 0 to -5°C for 15min. Obtained azide intermediate was extracted in
toluene (2x500ml) at 0 to 5°C and dried on sodium sulphate. Toluene (50ml) was taken in
another flask and heated to reflux at 108 to 110°C. Dried toluene extracts as obtained above was
added slowly to it by maintaining temperature 80 to 100°C to facile rearrangement. After
maintaining for 30min at reflux, water (200ml) was added slowly under reflux and maintained
for another 30min. Toluene was removed under reduced pressure, diluted with methanol (50ml),
added 15% w/w aqueous sodium hydroxide solution (500ml) and maintained stirring for 2hr.
After hydrolysis, diluted reaction mass with water and washed with dichloromethane. To
washed aqueous layer added dichloromethane and adjusted pH 1.5, with hydrochloric acid.
Product was extracted in dichloromethane and concentrated. Yield 124.27g (90.7%). IR (neat,
cm-1
): 3311, 2957, 2931, 2872, 2641, 1715, 1563 and 1468. 1HNMR (CDCl3, 300 MHz, δ ppm):
0.88 (2d, 12H), 1.16 (m, 4H), 1.66 (m, 2H), 2.05-2.41 (m, 6H), 3.10 & 3.21 (2m, 4H), 5.84 (brs,
2H), 9.49 (brs, 2H). Exact Mass (m/z, 344.23); Observed: (in –ve ion mode) m/z; 343.3 [(M+-
H)-].
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 128
Chapter - II
3-{[(4-Isobutyl-2-oxo-pyrrolidine-1-carbonyl)-amino]-methyl}-5-methylhexanoic acid
(Pregabalin lactam urea, 56)
3-[({[2-(Carboxymethyl)-4-methylpentyl]carbamoyl}amino)methyl]-5-methylhexanoic acid, 54
on heating with aqueous sodium hydroxide solution yields 56. IR (neat, cm-1
): 3303, 3095,
2957, 2872, 1717, 1548, 1484 and 1469. 1HNMR (CDCl3, 300 MHz, δ ppm): 0.91 (2d, 12H),
1.21 (m, 2H), 1.35 (m, 2H), 1.64 (m, 2H), 2.18 (m, 2H), 2.32 (m, 2H), 2.43 (m, 1H), 2.68 (m,
1H), 3.27 (m, 2H), 3.38 (m, 2H), 4.04 (m, 1H), 8.54 (t, 1H). Exact Mass (m/z, 326.22);
Observed: (in –ve ion mode) m/z; 325.2 [(M+-H)
-]; (in +ve ion mode) m/z; 327.1 [(MH)
+], m/z;
349.2 [(MH)++Na].
3-Cyano-5-methylhexanoic acid (Pregabalin nitrile, 57)
3-Cyano-5-methylhexanoic acid ethyl ester 64 (410g, 2.24mole) was added to ethanol (430ml)
and stirred the contents at 25-30°C for homogenization. Potassium hydroxide solution
[potassium hydroxide (150.55g, 2.69mole) dissolved in water (460ml)] was added slowly and
maintained stirring for 2hr. Thereafter, reaction mass was diluted with water (2000ml) and
washed with methyl tert-butyl ether (1x1000ml, 1x750ml). Adjusted the pH of the washed
aqueous layer to 1 using concentrated hydrochloric acid, extracted the product in toluene
(1x750ml; 1x500ml) and concentrated under reduced pressure to give an oil, which solidified
upon holding. Yield 327.1g (94.2%). IR (neat, cm-1
): 3212, 2961, 2874, 2639, 2243, 1860, 1786,
1714, 1662, 1605, 1470 and 1416. 1HNMR (DMSO-d6, 300 MHz, δ ppm): 0.91 (m, 6H), 1.34
(m, 1H), 1.56 (m, 1H), 1.71 (m, 1H), 2.60 (d, 2H), 2.99 (m, 1H), 12.65 (brs, 1H). Exact Mass
(m/z, 155.09); Observed: (in –ve ion mode) m/z; 154.2 [(M+-H)
-].
4-Isobutyl pyrrolidin-2-one (Pregabalin lactum, 58)
Added sodium hydroxide (111.2g, 2.78mole) to water (500ml) and cooled the contents to 5 to
10°C. After adding Pregabalin diacid monoamide 39 (100g, 0.53mole), cooled the contents to
0°C. Thereafter, bromine (94g, 0.59mole) was added slowly at 0 to 5°C during 1hr and
temperature of the reaction mass was raised slowly to 85 to 90°C. After 2hr, reaction mass was
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 129
Chapter - II
further heated to reflux at 105 to 110°C for 20hrs. Cooled the reaction mass to 25 to 30°C and
adjusted pH 9 with hydrochloric acid. Extracted the product in 1, 2-dichloroethane (2x200ml;
2x100ml; 2x50ml), washed with little water (100ml) and concentrated under reduced pressure to
obtain oil. Product was purified by distillation at 120°C/1mmHg, which solidified on cooling.
Yield 46g (61%). IR (neat, cm-1
): 3232, 3103, 2956, 2901, 2871, 2844, 2311, 1695, 1490, 1467,
1450 and 1426. 1HNMR (CDCl3, 300 MHz, δ ppm): 0.90 (d, 6H), 1.35 (t, 2H), 1.58 (m, 1H),
2.00 & 2.43 (2m, 2H), 2.54 (m, 1H), 3.00 & 3.49 (2m, 2H), 6.62 (brs, 1H). Exact Mass (m/z,
141.12); Observed: (in +ve ion mode) m/z; 141.9 [(MH)+].
3-Aminomethyl-5-methylhexanoic acid methyl ester hydrochloride (Pregabalin methyl ester.
HCl, 59)
Pregabalin 1 (30g, 0.19mole) is added to methanol (150ml) at 25°C. Dimethylformamide (1ml)
is added and cooled the slurry to 0 to 5°C. Thereafter, thionyl chloride (26.94g, 0.23mole) is
added slowly during 1hr, maintaining temperature below 15°C. Obtained reaction mass is
heated to reflux (60 to 65°C) and maintained for 3hr. Reaction mass is concentrated and diluted
with isopropyl ether (100ml). Obtained slurry again cooled to 0 to 5°C, maintained for 2hr and
filtered. Isolated product is washed with isopropyl ether (2x30ml) and dried at 40 to 45°C under
reduced pressure. Yield 39.48g (99.8%). IR (KBr, cm-1
): 3455, 2922, 2853, 1734, 1625, 1461,
1377, 1198. 1HNMR (DMSO-d6, 300 MHz, δ ppm): 0.86 (2d, 6H), 1.08 (m, 1H), 1.24 (m, 1H),
1.59 (m, 1H), 2.17 (m, 1H), 2.35 &2.54 (2m, 2H), 2.75 (m, 2H), 3.61 (s, 3H), 8.28 (brs, 3H).
Exact Mass (m/z, 173); Observed: (in +ve ion mode) m/z; 174.1 [(MH)+].
3-Isobutylpentanedioic acid mono methyl ester (Pregabalin diacid mono methyl ester, 60)
3-Isobutylpentanedioic acid [Pregabalin diacid 35 (200g, 1.06mole)] was suspended in acetic
anhydride (130.2g, 1.28mole) at 25°C. Thereafter, temperature of the contents was raised to
reflux for 2.5hr. Removed acetic acid/acetic anhydride under under reduced pressure. Cooled
the residual 4-isobutyl dihydro-pyran-2, 6-dione 36 to 30°C and methanol (250ml) was added to
it. Temperature of the contents was raised to reflux for 5hr. After completion, reaction mass was
cooled to 45°C and excess of methanol was removed at 45-65°C under reduced pressure to give
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 130
Chapter - II
Pregabalin diacid mono methyl ester 60 as oil. Yield 214.5g (100%). IR (neat, cm-1
): 2958,
2873, 2673, 2007, 1739, 1710, 1469, 1438 and 1416. 1HNMR (CDCl3, 300 MHz, δ ppm): 0.89
(d, 6H), 1.21 (m, 2H), 1.63 (m, 1H), 2.39 (m, 5H), 3.67 (s, 3H). Exact Mass (m/z, 202.12);
Observed: (in –ve ion mode) m/z; 201.1 [(M+-H)
-].
3-Carbamoylmethyl 5-methylhexanoic acid methyl ester (Pregabalin amide ester, 61)
After adding Pregabalin diacid mono methyl ester 60 (100g, 0.5mole) to dichloromethane
(600ml), resulting solution was cooled the to 0-5°C. Added triethyl amine (75g, 0.74mole),
followed by ethyl chloroformate (64.5g, 0.59mole) sequentially and slowly in ~30min.
Maintained reaction mass at 0-5°C for 1hr and then quenched slowly with 20% aqueous
ammonia solution (300ml) at 0-5°C. Organic layer was separated and extracted the aqueous
layer with dichloromethane (100ml). Washed the combined dichloromethane extracts with
water (200ml) and concentrated it at 45-55°C under reduced pressure. Obtained concentrated
mass becomes solid on standing. Yield 99g (98.5%). IR (nujol, cm-1
): 3416, 3192, 2955, 2917,
2872, 2762, 2727, 2597, 1727, 1667, 1621, 1465, 1439 and 1405. 1HNMR (CDCl3, 300 MHz, δ
ppm): 0.89 (d, 6H), 1.21 (m, 2H), 1.62 (m, 1H), 2.20-2.48 (m, 5H), 3.66 (s, 3H), 5.91 (brs, 2H).
Exact Mass (m/z, 201.14); Observed: (in –ve ion mode) m/z; 201.2 [(M+-H)
-], (in +ve ion mode)
m/z; 202.3 [(MH)+], m/z; 223.9 [(MH)
++Na].
3-Cyanomethyl 5-methylhexanoic acid methyl ester (Pregabalin cyanomethyl ester, 62)
To Pregabalin amide ester 61 (50g, 0.25mole) suspended in toluene (100ml), pyridine (43.3g,
0.55mole) and p-toluene sulfonyl chlorides (57g, 0.29mole) were added sequentially at 25-
30°C. Thereafter, temperature of the reaction mass was raised to 85-90°C and maintained for
2hr. The reaction mass was cooled to 25-30°C and diluted with water (100ml). Organic layer
was separated, washed with water (2x100ml) and concentrated under reduced pressure to get
oil. Yield 45.82g (45.5%). IR (neat, cm-1
): 2958, 2873, 2852, 2610, 2247, 1738, 1595, 1492,
1469 and 1437. 1HNMR (CDCl3, 300 MHz, δ ppm): 0.91 (d, 6H), 1.32 (m, 2H), 1.61 (m, 1H),
2.27 (m, 1H), 2.40-2.52 (m, 4H), 3.69 (s, 3H). Exact Mass (m/z, 183.13); Observed: (in –ve ion
mode) m/z; 182.0 [(M+-H)
-], (in +ve ion mode) m/z; 185.2 [(M2H)
+], m/z; 202.3 [(MH)
++NH3].
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 131
Chapter - II
3-Cyanomethyl 5-methylhexanoic acid (Pregabalin cyanomethyl acid, 63)
10% aqueous sodium hydroxide solution (200ml) was added to Pregabalin cyanomethyl ester 62
(45g, 0.24mole) in methanol (50ml) at 25-30°C. Obtained mass was stirred at 25-30°C for 3hr
and diluted with water (100ml). Thereafter, reaction mass was washed with toluene and
acidified with concentrated hydrochloric acid. Finally, extracted the product in dichloromethane
and concentrated under reduced pressure. Yield 31.16g (75%). IR (neat, cm-1
): 3114, 2959,
2935, 2874, 2669, 2248, 1712, 1470 and 1417. 1HNMR (CDCl3, 300 MHz, δ ppm): 0.92 (d,
6H), 1.35 (m, 2H), 1.65 (m, 1H), 2.30 (m, 1H), 2.45-2.57 (m, 4H), 10.65 (brs, 1H). Exact Mass
(m/z, 169.11); Observed: (in –ve ion mode) m/z; 168.1 [(M+-H)
-].
2-(3-Methylbutylidene) malonic acid diethyl ester (11)
Isovaleraldehyde 9 (260g, 3.02mole) was combined with a mixture of diethylmalonate 10
(460g, 2.87mole), cyclohexane (400ml) and di-n-propylamine (2.75g) and contents were heated
to reflux at 85 to 90°C to remove water azeotropically (55ml of water was collected during
24hr). Thereafter, reaction mass was cooled to 25 to 30°C, diluted with water and neutralized
with aqueous ammonia. Organic layer was separated, washed with water and concentrated
under vacuum at 45 to 60°C. Finally, product was collected by fractional distillation at 90 to
110°C / 1mmHg as light yellow viscous oil. Yield 621.39g (90.2%). IR (neat, cm-1
): 3436, 2962,
2874, 2351, 1732, 1646 and 1467. 1HNMR (CDCl3, 300 MHz, δ ppm): 0.93 (d, 6H), 1.28 &
1.31 (2t, 6H), 1.80 (m, 1H), 2.19 (m, 2H), 4.21 & 4.27 (2m, 4H), 6.99 (t, 1H). Exact Mass (m/z,
228.14); Observed: (in +ve ion mode) m/z; 229.2 [(MH)+].
2-(1-Cyano-3-methylbutyl) malonic acid diethyl ester (12)
Potassium cyanide (154.2g, 2.37mole) was added to a solution of 2-(3-methylbutylidene)
malonic acid diethyl ester 11 (600g, 2.63mole) in absolute ethanol (800ml) and stirred at 35 to
40°C for 36hr. Thereafter, cooled the reaction mass to 25°C and diluted with hexanes (780ml).
Acetic acid (175g) was added slowly at <35°C followed by water (710ml) with stirring.
Separated the organic layer and extracted aqueous layer is with hexanes (780ml). Combined
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 132
Chapter - II
organic layer was washed with water (400ml) and concentrated at 35 to 45°C under reduced
pressure, to yield orange oil. Yield 597.4g (89%). IR (neat, cm-1
): 3465, 2963, 2940, 2875,
2244, 1737, 1649, 1469 and 1449. 1HNMR (DMSO-d6, 300 MHz, δ ppm): 0.91 (2d, 6H), 1.20
(2t, 6H), 1.29 (m, 1H), 1.55-1.78 (m, 2H), 3.28 (m, 1H), 3.96 (d, 1H), 4.15-4.24 (2m, 4H). Exact
Mass (m/z, 255.15); Observed: (in +ve ion mode) m/z; 256.1 [(MH)+]; (in –ve ion mode) m/z;
253.9 [(M+-H)
-].
3-Cyano-5-methylhexanoic acid ethyl ester (64)
To dimethylsulfoxide (1760ml), added sodium chloride (155.7g, 2.66mole), 2-(1-cyano-3-
methylbutyl)malonic acid diethyl ester 12 (590g, 2.31mole) and water (79ml) at 30 to 35°C and
heated the contents to 138 to 148°C and maintained for 10hr. Thereafter, mixture was cooled to
25°C, diluted with methyl-tert-butyl ether (920ml) and again cooled to 5 to 10°C. After adding
water (1180ml) slowly at <40°C, organic layer was separated. After extracting aqueous layer
with methyl-tert-butyl ether (920ml), combined extracts are washed with water (590ml) and
concentrated at 35 to 40°C under reduced pressure to result dark brown oil. Yield 417.1g
(98.5%). IR (neat, cm-1
): 3459, 2962, 2938, 2874, 2728, 2603, 2392, 2242, 1736, 1648, 1468
and 1420. 1HNMR (CDCl3, 300 MHz, δ ppm): 0.97 (2d, 6H), 1.29 (t, 3H), 1.35 & 1.63 (2m,
2H), 1.84 (m, 1H), 2.53 & 2.68 (2m, 2H), 3.05 (m, 1H), 4.22 (q, 2H). Exact Mass (m/z, 183.13);
Observed: (in –ve ion mode) m/z; 182.1 [(M+-H)
-].
3-{[(tert-butoxycarbonyl)amino]methyl}-5-methylhexanoic acid (66)
To aqueous solution of Potassium carbonate (108.5g, 0.7861 mole, in DM water 200ml), added
Pregabalin (50g, 0.3144 mole) and toluene (200ml) at 25-30°C. Added DIBOC (82.5g, 0.3773
mole) to the stirred solution and maintain stirring for ~16h to complete the reaction. Diluted
reaction mass with DM water (500ml), and stirred for 30min. Separated toluene layer and
aqueous layer was washed with toluene (100ml). Added toluene (300ml) to the aqueous layer
and adjusted pH 1.5 with con. hydrochloric acid. Aqueous layer separated and extracted again
with toluene (100ml). Combined organic layer washed with water, dried on sodium sulfate and
concentrated. yield 81.4g (100%). 1HNMR (CDCl3, 300 MHz, δ ppm): 0.90 (d, 6H), 1.17 (m,
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 133
Chapter - II
2H), 1.45 (s, 9H), 1.66 (m, 1H), 2.10 (m, 1H), 2.33 (m, 2H), 3.06-3.26 (m, 2H), 4.78 & 6.21
(2brs, 1H). Exact Mass (m/z, 259); Observed: (in –ve ion mode) m/z; 258.1 [(M+-H)
-].
3-{[(tert-butoxycarbonyl)N-methylamino]methyl}-5-methylhexanoic acid (67)
N-Boc Pregabalin 66 (81g, 0.3127mole) and methyl iodide (355g, 2.5019mole) was taken into
dry THF (500ml) and cooled the reaction mass to 0-5°C. Added sodium hydride (41g,
0.9382mole) in portions with vigorous stirring in 30 min. After addition, stirred the mass at 25-
30°C for ~24h. The reaction mass is quenched by addition of ethyl acetate (700ml), and water
(150ml). The reaction mass was concentrated to residue under reduced pressure. The oily
residue taken into water (500ml) and washed with ether (200ml). The ether extracts washed
with sat. sodium bi carbonate (200ml). Combined aqueous layer acidified with citric acid and
product extracted in ethyl acetate (2x200ml), washed with water (2x100ml), 5% aq. sodium
thiosulfate (2x100ml) and water (2x100ml). Organic layer dried on sodium sulfate and
evaporated to give a pale yellow oil. Yield 79.24g (92.8%). 1HNMR (D2O, 300 MHz, δ ppm):
0.91 (2d, 6H), 1.26 (t, 2H), 1.49 (s, 9H), 1.65 (m, 1H), 2.28 (m, 1H), 2.42 (d, 2H), 2.75 (s, 3H),
2.06 (d, 2H). Exact Mass (m/z, 273.1); Observed: (in –ve ion mode) m/z; 272.1 [(M+-H)
-].
3-N-Methylaminomethyl-5-methyl-1-hexanoic acid (N-Methyl-1)
N-methyl Boc-Pregabalin 67 (79g, 0.2893mole) was taken to methylene chloride (250ml) and
cooled the solution to 0-5°C. Added trifluoro acetic acid (79ml) in ~15min and raised the
temperature to 25-30°C. Stirred the content for ~20hr and concentrated under reduced pressure.
1HNMR (CDCl3, 300 MHz, δ ppm): 0.92 (2d, 6H), 1.07 (t, 2H), 1.58 (m, 1H), 2.10 (m, 1H),
2.17 & 2.44 (2m, 2H), 2.58 (s, 3H), 2.70 & 2.88 (2m, 2H). Exact Mass (m/z, 173.13); Observed:
(in +ve ion mode) m/z; 174.4 [(MH)+].
Resolution of 37:
Racemic 3-(carbamoylmethyl)-5-methylhexanoic acid 37 (600g, 3.21 moles)) was suspended in
a mixture of chloroform (7200ml) and ethanol (60ml) at 25-35°C. Thereafter, temperature of the
contents was raised to 55°C and (R)-(+)-α-phenyl ethylamine 38 (272g, 2.25 moles) was added
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 134
Chapter - II
.Thus, obtained clear solution was cooled slowly to 28-32°C and stirred at this temperature for
90min. Precipitated product i.e. (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, (R)-(+)-α-
phenyl ethylamine salt 43 was filtered, washed and dried at 55-65°C/~20mmHg to a constant
weight. After drying, obtained product was added to DM water (3180ml) and heated to 35-
40°C. pH of thus obtained solution was adjusted to 0.5 with (35% w/w) hydrochloric acid,
slowly cooled to 5-10°C, and stirred at this temperature for 1hrs to complete the precipitation.
Precipitated product was filtered, washed with 3% w/w hydrochloric acid (420ml) followed by
Dm water (420ml) and dried at 65-65°C/~20mm Hg to a constant weight. Yield = 216 g (72%
of theory). Chromatographic Purity (by HPLC): 99.47%. Chiral Purity: 100%. Assay: 99.5%
(%w/w, by titrimetry). Melting Range 130.9-132.4°C. IR (KBr, cm-1
): 3436, 3227, 2930, 1712,
1643 and 1591. 1H-NMR( DMSO-d6): δ 0.82-0.85 (d, 6H), 1.09-1.13 (m, 2H), 1.59-1.63 (m,
1H), 2.01-2.24 (m, 5H), 6.75 (s, 1H), 7.28 (s, 1H). SOR: [α]20
D : -1.20 o (c=1, in methanol).
Preparation of (S)-(+)-3-Aminomethyl-5-methyl-1-hexanoic acid (Pregabalin, 1)
Bromine (154g, 0.96 moles) was added to pre-cooled aqueous sodium hydroxide solution
[prepared by dissolving sodium hydroxide (212g, 5.3 moles) in DM water 675ml] over a period
of 1hrs at 0-5°C. (R)-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid 39 (180g, 0.96 mole)
was added in lots to the reaction mass maintaining temperature 0-5°C and further stirred for 1hr
at this temperature. Thereafter, temperature of the reaction was raised to 30°C and allowed the
raise of the temperature to 60-65°C by using its exothermicity. After completion of reaction,
reaction mass was cooled to 25-30°C and 35%w/w hydrochloric acid (396ml) was added to it
slowly at this temperature to obtained a clear solution. Obtained solution was treated with
carbon and 50% w/w aqueous sodium hydroxide solution was added to the filtrate to adjust its
pH 5.1. Thereafter, temperature of the reaction mass was raised to 55-60°C, stirred for ~15 min
and again slowly cooled to 10-15°C. After stirring at 10-15°C for 1h, product was filtered,
washed with pre-cooled DM water (2 x 90ml) and dried at 50-60°C/~20mm Hg to a constant
weight. Yield: 117g (76% of theory). Chiral Purity: 100%. Assay (%w/w, by HPLC): 99.2%.
Melting Range: 170-171°C. IR (KBr, cm-1
): 2922, 2896, 2208, 1644, 1563 and 1556. 1H-NMR
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 135
Chapter - II
(D2O, 300 MHz): δ 0.78-0.84 (m, 6H), 1.10-1.15 (t, 2H), 1.54-1.59 (m, 1H), 2.07-2.22 (m, 3H),
2.86-2.95(m, 2H).
Purification of (S)-(+)-3-aminomethyl-5-methyl-1-hexanoic acid (Pregabalin, 1)
Pregabalin (110g) was suspended in 50% v/v aqueous isopropyl alcohol (900ml) and heated to
75-80°C to obtained a clear solution. Thus, obtained clear solution was cooled slowly to 0-5°C
and stirred for 1hr to complete the crystallization. Product was filtered, washed with isopropyl
alcohol (2x100ml) and dried at 50-55°C/~20mm Hg to a constant weight. Yield: 85 g (85% of
theory). Chromatographic Purity (by HPLC) : 99.92 %. Chiral Purity: 100%. Assay (%w/w, by
HPLC): 99.9 %. Melting Range: 183-185°C. SOR: [α]25
D: +10.8° (c =1, in water). IR (KBr,
cm-1
): 2922, 2896, 2208 and 1644. 1H-NMR (D2O, 300 MHz): δ 0.72-0.78 (m, 6H), 1.04-1.09 (t,
2H), 1.30-1.60 (m, 1H), 2.01-2.16 (m, 3H), 2.80-2.89(m, 2H).
Recovery of racemic 3-(carbamoylmethyl)-5-methylhexanoic acid 37 from the mother liquor
obtained after isolation of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid 39:
pH of the mixture of aqueous mother liquor (~4000ml) and chloroform mother liquor(~7500ml)
was raised to 12.5 with 50% w/w aqueous sodium hydroxide solution at 25-35°C. Aqueous
layer was separated and sodium hydroxide (192g, 4.80moles) was added to it. Thereafter,
contents were heated under reflux at 95-100°C and stirred at this temperature till starting
material, 3-(carbamoylmethyl)-5-methylhexanoic acid 65 is absent. After completion of
reaction, reaction mass was cooled to 20-30°C and acidified to pH 0.5 with sulfuric acid.
Thereafter, reaction mass was extracted with toluene (1x1200ml,1x600ml) and combined
organic layer was concentrated at 35-60°C under reduced pressure(150-10mm Hg). Acetic
anhydride (294g, 2.88 moles) was added to the concentrated mass and contents were heated
again to 130-134°C. Stirring of reaction mass was continued for 2hrs at 130-134°C and further
concentrated at 115-134°C under reduced pressure (300-10mm Hg) to remove excess acetic
anhydride and acetic acid byproduct. Thus obtained, concentrated mass was diluted with toluene
(600ml), cooled to 30-35°C, and added to pre-cooled aqueous ammonia solution (9%w/w,
1350ml) maintaining pH >8 and temperature 10-20°C. Thereafter, aqueous layer was separated,
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 136
Chapter - II
acidified to pH 1 with 35%w/w hydrochloric acid (550ml) and further stirred for 1 hr at 5-10°C
to precipitate the product. Precipitated product was filtered, washed with water and dried at 50-
55°C/~20mm Hg to a constant weight. Yield: 325g (85% recovery). Chromatographic Purity
(by HPLC): 99.5 %. Melting Range: 106-107°C. Assay: 99.6 % (%w/w, by titrimetry). SOR:
[α]20
D:-0.31° (c =1, in methanol). IR (KBr, cm
-1): 3364, 3220, 2962, 1703, 1668 and 1585.
1H
NMR (DMSO-d6, 300 MHz): δ 0.82-0.87 (m, 6H), 1.09-1.13 (t, 2H), 1.42-1.70 (m, 1H), 2.01-
2.24 (m, 5H), 6.7 (s, 1H), 7.28 (s, 1H), 12.02 (s, br, 1H).
General procedure for the preparation of carbamates using sodium alkoxides:
Sodium metal (59g, 2.57 moles) was added slowly to methanol (1800 ml) at 25-55°C, under
nitrogen atmosphere and stirred to obtain a clear solution. Thus, obtained resultant sodium
methoxide solution in methanol was cooled to -40° to -50°C, under nitrogen. (R)-(-)-3-
(carbamoylmethyl)-5-methylhexanoic acid 39 (120 g, 0.64 moles) and bromine (107.8 g, 0.67
moles) were added sequentially maintaining temperature -40° to -50°C. Thereafter, reaction
mass temperature was raised to 65-75°C and contents were stirred for 2 hrs at this temperature.
After completion of reaction, reaction mass was concentrated at 45-75°C/300-20mmHg. DM
water (1000ml) was added to the concentrated mass and obtained solution was washes with
methylene chloride (2x200ml). Obtained aqueous layer was acidified and product was extracted
with methylene chloride (2x500ml). Thereafter, combined organic layer was concentrated at 30-
55°C/300-20mm Hg. Characterization data given in Table-2.18.
Table-2.18
Sr.
no. Compound Data
1 68
1H NMR (CDCl3, 300 MHz): δ 0.89 (2d, 6H), 1.18 (m, 2H), 1.66 (m,
1H), 2.16 (m, 1H), 2.32 (m, 2H), 3.11 & 3.28 (2m, 2H), 3.66 (s, 3H),
5.02 & 6.22 (2brs, 1H). Exact Mass (m/z, 217); Observed: (in –ve ion
mode) m/z; 216.3 [(M+-H)
-], (in +ve ion mode) m/z; 218.3[(MH)
+].
2 69
1H NMR (CDCl3, 300 MHz): δ 0.90 (2d, 6H), 1.17 (m, 2H), 1.24 (t, 3H),
1.67 (m, 1H), 2.18 (m, 1H), 2.34 (m, 2H), 3.12 & 3.25 (2m, 2H), 4.12 (m,
2H), 4.97 & 6.20 (2brs, 1H). Exact Mass (m/z, 231); Observed: (in –ve
ion mode) m/z; 230.2 [(M+-H)
-], (in +ve ion mode) m/z; 232.2 [(MH)
+].
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 137
Chapter - II
3 70
1H NMR (CDCl3, 300 MHz): δ 0.91 (2d, 6H), 0.95 (t, 3H), 1.16 (q, 2H),
1.61 (m, 3H), 2.15 (m, 1H), 2.34 (m, 2H), 3.03 & 3.27 (2m, 2H), 4.01 (t,
2H), 4.98 & 6.15 (2brs, 1H). Exact Mass (m/z, 245); Observed: (in –ve
ion mode) m/z; 244.1 [(M+-H)
-], (in +ve ion mode) m/z; 246.2 [(MH)
+].
4 71
1H NMR (CDCl3, 300 MHz): δ 0.89 (2d, 6H), 1.21 (m, 8H), 1.67 (m,
1H), 2.10 (m, 1H), 2.31 (m, 2H), 2.51 (m, 1H), 3.08 & 3.27 (2m, 2H),
4.89 & 6.09 (2brs, 1H). Exact Mass (m/z, 245); Observed: (in –ve ion
mode) m/z; 244.2 [(M+-H)
-], (in +ve ion mode) m/z; 246.2 [(MH)
+].
5 72
1H NMR (CDCl3, 300 MHz): δ 0.89 (2d, 6H), 0.95 (m, 3H), 1.18 & 1.25
(2m, 2H), 1.38 (m, 2H), 1.56-1.72 (m, 3H), 2.34 (m, 3H), 3.06 & 3.22
(2m, 2H), 4.06 (t, 2H), 4.90 & 5.97 (2brs, 1H). Exact Mass (m/z, 259);
Observed: (in –ve ion mode) m/z; 258.2 [(M+-H)
-], (in +ve ion mode)
m/z; 260.4[(MH)+].
6 74
1H NMR (CDCl3, 300 MHz): δ 1.25-1.50 (m, 10H), 2.33 (s, 2H), 3.23 (d,
2H), 3.67 (s, 3H), 5.25 & 6.09 (2brs, 1H). Exact Mass (m/z, 229);
Observed: (in –ve ion mode) m/z; 228.2 [(M+-H)
-], (in +ve ion mode)
m/z; 229.1. [(MH)+].
General procedure for the preparation of carbamates using NBS-DBU:
(R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid 39 (25 g, 0.13moles), N-bromo-
succinamide (35.70g,0.20moles) and DBU(81.41g, 0.54 moles) were added sequentially to
methanol (250ml) at 25-35°C. Thereafter, the contents were heated to reflux and stirred for ~1hr
at this temperature. After completion of reaction, reaction mass was concentrated at 45-75°C/
300-20mmHg. Obtained concentrated mass was dissolved in ethyl acetate (200ml) and washed
with 6N hydrochloric acid followed by DM water. Thereafter, washed organic layer was
concentrated at 30-55°C/300-20mm Hg.
Characterization data given in Table-2.18.
General procedure for the preparation of (S)-(+)-3-Aminomethyl-5-methyl-1-hexanoic acid
(Pregabalin, 1), and its analogs through hydrolysis of carbamates:
Hydrochloric acid (60ml, ~35%w/w) and DM water (90ml) were added to 3-
{[(methoxycarbonyl)amino]methyl}-5-methylhexanoic acid 68 (30 g) at 25-35°C. Thereafter,
the contents were heated to reflux and stirred for ~15hr at this temperature. After completion of
reaction, reaction mass was cooled to 25-35°C and 50% w/w sodium hydroxide was added to
adjust its pH 5. Thereafter, contents were cooled to 10-15°C and stirred for 1 hr to complete the
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 138
Chapter - II
precipitation of Pregabalin. Product was filtered, washed with DM water, and dried at 50-
55°C/~20mm Hg to a constant weight. Yield: 17.34 g (80% of theory).
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 139
Chapter - II
SPECTRA:
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 35
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 140
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 37
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 141
Chapter - II
…..IR AND 1H NMR SPECTRUM OF COMPOUND 43
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 142
Chapter - II
…..IR, 1H NMR,
13C NMR AND MASS SPECTRUM OF COMPOUND 1
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 143
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 44
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 144
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 45
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 145
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 46
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 146
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 48
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 147
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 49
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 148
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 50
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 149
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 51
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 150
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 52
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 151
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 53
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 152
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 54
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 153
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 56
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 154
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 57
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 155
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 58
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 156
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 68
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 157
Chapter - II
…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 74
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 158
Chapter - II
REFERENCES:
1. Lin, Z and Kadaba, P. K. Med. Res. Rev. 1997, 17, 537-572.
2. Roberts, E. Biochem. Pharmacol. 1974, 23, 2637-2649.
3. McGeer, E. G.; McGeer, P. L.; Thompson, S. GABA and Glutamate Enzymes. In: Hertz,
L.; Kvamme, E.; McGeer, E. G.; Schousboe, A. editors. Glutamine, Glutamate, and
GABA in the Central Nervous System. Liss; New York: 1983. pp. 3–17.
4. Baxter, C. F.; Roberts, E. J. Biol. Chem. 1958, 233, 1135-1139.
5. Schechter, P. J.; Tranier, Y.; Grove, J. Adv. Exp. Med. Biol. 1979, 123, 43-57.
6. Krnjevic, K.; Schwartz, S. Exp. Brain Res. 1967, 3, 320-336.
7. Andus, K. L.; Chikale, P. J.; Miller, D. W.; Thomson, S. E.; Borcardt, R. T. Adv. Drug.
Res. 1992, 23, 1-63.
8. Madrid, Y.; Langer, L. F.; Breue, H.; Langer, R. Adv. Pharmacol. 1991, 22, 299-324.
9. Pardridge, W. M. Ann. Rep. Med. Chem. 1985, 20, 305-313.
10. Gatti, G.; Bonomi, I.; Jannuzzi, G.; Perucca, E. Curr. Pharm. Design. 2000, 6, 839.
11. Lopes Lima, J. M. Curr. Pharm. Design. 2000, 6, 873.
12. Bryans, J. S.; Wustrow, D. J. Med. Res. Rev. 1999, 19, 149-177.
13. Xiao, W. H.; Bennett, G. J. Analgesia. 1996, 2(5/6), 267-273.
14. Hwang, J. H.; Yaksh, T. L. Reg. Anesth. 1997, 22, 249-256.
15. Field, M. J.; Oles, R. J.; Lewis, A. S.; McCleary, S.; Hughes, J.; Singh, L. Br. J.
Pharmacol. 1997, 121, 1513-1522.
16. Silverman, R. B.; Andruszkiewicz, R.; Nanavati, S. M.; Taylor, C. P.; Vartanian, M. G. J.
Med. Chem. 1991, 34, 2295-2298.
17. Taylor, C. P.; Vartanian, M. G.; Yuen, P. W.; Kanter, G. D.; Bigge, C.; Suman-Chauhan,
N.; Hill, D. R. Epilepsy Res. 1993, 14, 11-15.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 159
Chapter - II
18. Yuen, P. W.; Kanter, G. D.; Taylor, C. P.; Vartanian, M. G. Bioorg. Med. Chem. Lett.
1994, 4, 823-826.
19. Singh, L.; Field, M. J.; Ferris, P.; Hunter, J. C.; Oles, R. J.; Williams, R. G.; Woodruff, G.
N. Psychopharmacology. 1996, 127, 1-9.
20. Dworkin, R. H. P.; Corbin, A. E. M.; Young, J. P. J.; Sharma, U.; LaMoreaux, L.;
Bockbrader, H.; Garofalo, E. A. M.; Poole, R. M. Neurology, 2003, 60, 1274-1283.
21. Hill, C. M.; Balkenohl, M.; Thomas, D. W.; Walker, R.; Mathe, H.; Murray, G. Eur. J.
Pain. 2001, 5, 119-124.
22. Pande, A. C.; Crockatt, J. G.; Feltner, D. E.; Janney, C. A.; Smith, W. T.; Weisler, R.;
Londborg, P. D.; Bielski, R. J.; Zimbroff, D. L.; Davidson, J. R. Am. J. Psychiatry. 2003,
160, 533-540.
23. Lauria-Horner, B. A.; Pohl, R. B. Expert Opin. Invest. Drugs. 2003, 12, 663-672.
24. Belliotti, T. R.; Capiris, T.; Ekhato, V.; Kinsora, J. J.; Field, M. J.; Heffner, T. G.;
Meltzer, L. T.; Schwart, J. B.; Taylor, C. P.; Thorpe, A. J.; Vartanian, M. G.; Wise, L. D.;
Su, T. Z.; Weber, M. L.; Wustrow, D. J. J. Med. Chem. 2005, 48, 2294.
25. Schwart, J. B.; Gibbons, S. E.; Graham, S. R.; Colbry, N. L.; Guzzo, P. R.; Le, V. D.;
Vartanian, M. G.; Kinsora, J. J.; Lotarski, S. M.; Li, Z.; Dickerson, M. R.; Su, T. Z.;
Weber, M. L.; El-Kattan, A.; Thorpe, A. J.; Donevan, S. D.; Taylor, C. P.; Wustrow, D. J.
J. Med. Chem. 2005, 48, 3026.
26. http://www.sec.gov/Archives/edgar/data/78003/000119312511048877/dex13.htm
(Portions of The Pfizer Inc. 2010 Financial Report). Retrieved 2011-11-06.
27. Andruszkiewicz, R.; Silverman, R. B. Synthesis, 1989, 953-955.
28. Grote, T. M.; Huckabee, B. K.; Mulhern, T.; Sobieray, D. M.; Titus, R. D. [P]. US
5,637,767. Jun.10, 1997. (assigned to Warner-Lambert Company).
29. Chen, Z.; Chen, Z.; Jiang, Z.; Hu, W. Synlett, 2004, 10, 1763-1764.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 160
Chapter - II
30. Blazecka, P. G.; Davidson-III, J. G.; Zhang, J. [P]. US 6,924,377. Aug.02, 2005.
(assigned to Warner-Lambert Company).
31. Zhang, G.; Yang, X.; Ma, Y.; Shi, S.; Duan, L.; Zhu, Y. [P]. WO 2006/136087. Dec.28,
2006. (assigned to NHWA Pharma Corporation).
32. Przewosny, M. T.; Putz, C. [P]. US 7,141,695. Nov.28, 2006. (assigned to Grunenthal
GmbH).
33. Gallos, J. K.; Alexandraki, E. S.; Stathakis, C. I. Heterocycles, 2007, 71(5), 1127-1134.
34. Bobba, V. S. K.; Sanikommu, S. R.; More, B. M.; Metil, D. S.; Kulkarni, P. B.; Prabahar,
K. J.; Khan, M. [P]. WO 2008/117305. Oct.02, 2008. (assigned to Glenmark
Pharmaceuticals Ltd).
35. Gaitonde, A.; Valdya, C.; Khairnar, P. [P]. US 2009/286880. Nov.19, 2009. (assigned to
Generics [UK] Ltd, and Merck Development Centre Pvt. Ltd).
36. Gore, V.; Gadakar, M.; Shinde, D. [P]. WO 2009/147434. Dec.10, 2009. (assigned to
Generics [UK] Ltd, and Mylan Development Centre Pvt. Ltd).
37. Thijs, L. [P]. US 2009/0312560. Dec.17, 2009. (assigned to Synthon IP Inc).
38. Rasparini, M.; Tufaro, R.; Castaldi, G.; Marras, G.; Giovenzana, G. [P]. WO 2009/53446.
Apr.30, 2009. (assigned to Chemo Iberica, S. A).
39. Gaitonde, A.; Datta, D.; Manojkumar, B.; Phadtare, S. [P]. WO 2009/81208. Jul.02, 2009.
(assigned to Generics [UK] Ltd, and Mylan Development Centre Pvt. Ltd).
40. Roberto, T.; Giovanni, M. [P]. WO 2008/138874. Nov.20, 2008. (assigned to Chemo
Iberica, S. A).
41. Konakanchi, D. P.; Pilli, R.; Pula, S. R.; Gongalla, B.; Sikha, K. B.; Chowdary, V. N. [P].
WO 2009/044409. Apr.09, 2009. (assigned to Natco Pharma Ltd).
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 161
Chapter - II
42. Gore, V.; Debashish, D.; Maheshkumar, G.; Kiran, P.; Viraj, M.; Sneha, W. [P]. WO
2009/122215. May.26, 2011. (assigned to Generics [UK) Ltd, and Mylan Development
Centre Pvt. Ltd).
43. Sarin, G. S.; Saini, M.; Chidambaram, V. S.; Wadhwa, L. [P]. WO 2010/061403. Jun.03,
2010. (assigned to Ind-swift Laboratories Ltd).
44. Chavan, A. A.; Padwal, S. B.; Joshi, A. V.; Bhanu, M. N. [P]. WO 2009/87674. Jul.16,
2009. (assigned to Watson Pharma Pvt. Ltd).
45. Xu, J.; Zhang, D.; Ye, M.; Chen, J.; Guo, Y.; Hu, Y. [P]. WO 2009/082861. Jul.09, 2009.
(assigned to Zhejiang Jiuzhou Pharmaceutical Co).
46. Yuen, P.; Kanter, G. D.; Taylor, C. P.; Vartanian, M. G. Bioorg. Med. Chem. Lett. 1994,
4(6), 823-826.
47. Hoekstra, M.S.; Sobieray, D.M.; Schwindt, M.A.; Mulhern, T. A.; Grote, T. M.;
Huckabee, B.K.; Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Kirrick, G. L. Org.
Pro. Res & Dev. 1997, 1, 26-38.
48. Silverman, R. B.; Andruszkiewicz, R. [P]. US 6,197,819. Mar.06, 2001. (assigned to
Northwestern University).
49. Rodriguez-soria, V.; Quintero, L.; Sartillo-piscil, F. Tetrahedron, 2008, 64, 2750-2754.
50. Maymon, A.; Kansal, V. K.; Hedvati, L. [P]. US 2007/66846. Mar.22, 2007. (assigned to
Teva).
51. Ok, T.; Jeon, A.; Lee, J.; Lim, J. H.; Hong, C. S.; Lee, H. S. J. Org. Chem. 2007, 72,
7390-7393.
52. Rodriguez, V.; Quintero, L.; Sartillo-piscil, F. Tetrahedron letters, 2007, 48, 4305-4308.
53. Izquierdo, S.; Aguilera, J.; Buschmann, H. H.; Garcia, M.; Torrens, A.; Ortuno, R. M.
Tetrahedron: Asymmetry, 2008, 19, 651-653.
54. Lee, H. S.; Lee, J.; Ok, T. [P]. US 2010/286442. Nov.11, 2010. (assigned to Kaist).
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 162
Chapter - II
55. Ortuno, R. M.; Izquierdo, S.; Buschmann, H. H.; Jover, A. T.; Lopez, M. G. [P]. US
2010/197939. Aug.05, 2010. (assigned to Laboratorios Del Dr. Esteve, S.A).
56. Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442-4443.
57. Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 514-515.
58. Armstrong, A.; Convine, N. J.; Popkin, M. E. Synlett. 2006, 10, 1589-1591.
59. Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.; Shibasaki,
M. Tetrahedron, 2007, 63, 5820-5831.
60. Shibasaki, M.; Kanai, M.; Mita, T. [P]. JP 2006-151839. Jun.15, 2006. (assigned to Univ.
of Tokyo).
61. Shibasaki, M.; Kanai, M.; Fujimori, I.; Yamatsugu, K.; Kamijo, S. [P]. US 7,820,862.
Oct.26, 2010. (assigned to Univ. of Tokyo).
62. Davies, B. S.; Guzman, M. M.; Martinez, C. A.; McDaid, P. O., O'Neill, P. M.;
Shanmugam, E. [P]. WO 2010/70593. Jun. 24, 2010. (assigned to Pfizer Ireland
Pharmaceuticals).
63. Yujiro, H. [P]. JP 2009-091257. Apr. 30, 2009. (assigned to Tokyo Univ. of Science).
64. Yujiro, H. [P]. JP 2009-263233. Nov. 12, 2009. (assigned to Tokyo Univ. of Science).
65. Poe, S. L.; Kobaslija, M.; McQuade, D. T. J. Am. Chem. Soc. 2007, 129, 9216-9221.
66. Hoge, G. J. Am. Chem. Soc. 2003, 125, 10219-10227.
67. Hoge, G. J. Am. Chem. Soc. 2004, 126, 9920-9921.
68. Hoge, G.; Wu, H.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao, J. J. Am. Chem. Soc.
2004, 126, 5966-5967.
69. Burk, M. J.; Goel, O. P.; Hoekstra, M. S.; Mich, T. F.; Mulhern, T.; Ramsden, J. A. [P].
US 6,891,059. May.10, 2005. (assigned to Warner-Lambert company).
70. Hoge, G. S. [P]. US 7,390,931. Jun.24, 2008. (assigned to Pfizer Inc).
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 163
Chapter - II
71. Bao, J.; Beylin, V. G.; Greene, D.; Hoge, G. S.; Kissel, W.; Marlatt, M. E.; Pflum, D. A.;
Wu, H. [P]. US 2009/124820. May.14, 2009., and US 2005/228190. Oct.13,
2005.(assigned to Pfizer Inc).
72. Avdagic, A.; Hamersak, Z. [P]. WO 2008/9897. Jan.24, 2008. (assigned to Pliva
Istrazivanje I Razvoj D. O. O).
73. Kansal, V. K.; Chaurasia, B. P.; Tiwari, A. P. [P]. US 7,465,826. Dec.16, 2008. (assigned
to TEVA).
74. Kansal, V. K.; Chaurasia, B. P.; Tiwari, A. P.; Shelke, S. H. [P]. US 2008/118427.
Oct.02, 2008. (assigned to TEVA).
75. Kansal, V. K.; Chaurasia, B. P.; Rao, V. G.; Tiwari, A. P. [P]. US 7,446,220. Nov.04,
2008. (assigned to TEVA).
76. Hedvati, L.; Gilboa, E.; Avhar-Maydan, S. [P]. US 7,462,738. Dec.09, 2008. (assigned to
TEVA).
77. Razzetti, G.; Allegrini, P.; Pastorello, D. [P]. US 2010/292506. Nov.18, 2010. (assigned
to Dipharma Francis s. r. l).
78. Connon, S. J.; Peschiulli, A.; Markey, L. [P]. WO 2010/86429. Aug.05, 2010. (assigned
to The Provost).
79. Huckabee, B. K.; Sobieray, D. M. [P]. US 5,616,793. Apr.01, 1997. (assigned to Warner-
Lambert Company).
80. Hidvati, L.; Noor, Z. D.; Singer, C.; Palarski, G.; Raizi, Y.; Tomer, S. [P]. US 7,462,737.
Dec.09, 2008. (assigned to TEVA).
81. Hidvati, L.; Noor, Z. D.; Singer, C.; Palarski, G.; Raizi, Y.; Tomer, S. [P]. US 7,488,846.
Feb.10, 2009. (assigned to TEVA).
82. Hamersak, Z.; Stipetic, I.; Avdagic, A. Tetrahedron: Asymmetry, 2007, 18, 1481-1485.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 164
Chapter - II
83. Hidvati, L.; Noor, Z. D.; Singer, C.; Palarski, G. [P]. US 7,678,938. Mar.16, 2010.
(assigned to TEVA).
84. Riva, S.; Allegrini, P.; Serafini, E.; Razzetti, G.; Mantegazza, S.; Pastorello, D. [P]. US
2008/311635. Dec.18, 2008. (assigned to Dipharma Francis s. r. l).
85. Bernardino, M. [P]. WO 2009/68967. Jun.04, 2009. (assigned to Medichem. S. A).
86. Allegrini, P.; Mantegazza, S.; Pastorello, D.; Razzetti, G. [P]. US 2009/143615. Jun.04,
2009. (assigned to Dipharma Francis s. r. l).
87. Ahirrao, V. D.; Narani, C. P.; Bondge, S. P.; Khunt, M. D.; Pradhan, N. S.; Valgeirsson,
J. [P]. US 2009/147528. Dec.10, 2009. (assigned to Actavis Group PTC EHF).
88. Salvi, A.; Nardi, A.; Angelis, B. D. [P]. US 2009/192331. Jul.30, 2009. (assigned to
Chimico Internazionale).
89. Reddy, M. S.; Rajan, S, T.; Eswaraiah, S.; Satyanarayana, R. [P]. US 2010/179345
Dec.10, 2009. (assigned to MSN).
90. xie, Z.; Feng, J.; Garcia, E.; Bernett, M.; Yezbeck, D.; Tao, J. Journal of molecular
catalysis B: Enzymatic, 2006, 41, 75-80.
91. Martinez, C. A.; Hu, S.; Dumond, Y.; Tao, J.; Kelleher, P.; Tully, L. Org. Proc. Res. Dev.
2008, 12, 392-398.
92. Felluga, F.; Pitacco, G.; Valentin, E.; Venneri, C. D. Tetrahedron: Asymmetry, 2008,
19(8), 945-955.
93. Hedvati, L. [P]. US 2008/15385. Jan.17, 2008. (assigned to TEVA).
94. Hedvati, L.; Fishman, A. [P]. US 2008/26433. Jan.31, 2008. (assigned to TEVA).
95. Notz, W. R. L.; Scott, R. W.; Zhao, L.; Tao, J. [P]. WO 2008/127646. Oct.23, 2008.
(assigned to Bioverdant, Inc).
96. Chaudhari, K.; Yeole, M.; Batchu, C.; Ratnam, R.; Aurora, S.; Gupta, M. N.; Mujumdar,
A. B. [P]. WO 2009/087650. Jul.16, 2009. (assigned to B. V. Medicare Pvt. Ltd).
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 165
Chapter - II
97. Albert, M.; Zepeck, F.; Berger, A.; Riethorst, W.; Schwab, H.; Luschnig, D.; Remler, P.;
Salchenegger, J.; Osl, D.; Desouza, D. [P]. WO 2009/141362. Nov.26, 2009. (assigned to
Sandoz AG).
98. saswata, L.; Hussain, M.; Datta, D. [P]. WO 2010/4577. Jan.14, 2010. (assigned to Matrix
Laboratories Ltd).
99. Hedvati, L.; Sterimbaum, G.; Raizi, Y.; Aminov, R. [P]. US 2010/87525. Apr.08, 2010.
(assigned to TEVA).
100. Burns, M. P.; Weaver, J. K.; Wong, J. W. [P]. US 7,727,749. Jun.01, 2010. (assigned to
Pfizer, Inc).
101. Hu, S.; Martinez, C. A.; Tao, J.; Tully, W. E.; Kelleher, P.; Dumond, Y. [P]. US
7,838,686. Nov.23, 2008. (assigned to Pfizer Inc.)
102. Magnien, E.; Baltzly, R. J. Org. Chem., 1958, 23, 2029-2032.
103. Wiley, P. F. J. Am. Chem. Soc., 1949, 71 (4), 1310–1311.
104. Shkapenko, G.; Gmitter, G. T.; Gruber, E. E. Ind. Eng. Chem., 1960, 52 (7), 605–608.
105. Yamazaki, S. Synthetic Communications, 1997, 27(20), 3559-3564.
106. Kansal, V. K.; Chaurasia, B. P.; Shelke, S. H.; Tiwari, A. P. [P]. WO 2008118427.
Oct.02, 2008. (assigned to Teva.)
107. Tiwari, A. P.; Kansal, V. K.; Chaurasia, B. P.; Rao, V. G. [P]. WO 2007035890. Mar.29,
2007. (assigned to Teva.)
108. Allegrini, P.; Mantegazza, S.; Pastorello, D.; Razzetti, G. [P]. IT 2007M10655. Jun.30,
2007.
109. Allegrini, P.; Mantegazza, S.; Pastorello, D.; Razzetti, G. [P]. IT 2007M10654. Jun.30,
2007.
110. Tiwari, A. P.; Kansal, V. K.; Chaurasia, B. P. [P]. WO 2007035789. Mar.29, 2007.
(assigned to Teva.)
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 166
Chapter - II
111. Zhang, G.; Yang, X.; Liu, B. Zhongguo Yiyao Gongye Zazhi., 2007, 38(9), 617-618.
112. Chavan, A. B.; Maikap, G. C.; Gurjar, M. K. Org. Proc. Res. Dev., 2009, 13(4), 812-814.
113. Wu, T.; Gao, M.; Ye, B.; Shen, Y. Chinese Journal of Chemistry., 2009, 27(5), 983-986.
114. Prasad, K. D.; Ramakrishna, P.; Rao, P. S.; Naveena, T.; Muddasani, P. R.; Nannapaneni,
V. C. [P]. IN 2007CH02207. Mar.19, 2010.
115. Kumar, K. S.; Reddy, K. T.; Reddy, G. J.; Omprakash, G.; Dubey, P. K. Pharmacia
Sinica., 2011, 2(6), 127-131.
116. Moriyama, K.; Ishida, K.; Togo, H., Org. Lett., 2012, 14(3), 946-949.
117. Moriyama, K.; Ishida, K.; Togo, H., Chem. Comm., 2012, 48(68), 8574-8576.
118. Sun, F.; Sorensen, T. S., J. Am. Chem. Soc., 1993, 115(1), 77-81.
119. Huckabee, B. K.; Sobieray, D. M. [P]. WO 9638405. Dec.05, 1996.
120. Chen, A.; Zhang, J. Zhongguo Yiyao Gongye Zazhi., 2004, 35(4), 195-196.
121. Ahmed, I.; Rauf, A. M. A.; Saeed, K. M. journal fur praktische Chemie., 1984, 326(1),
23-28.
122. Shi, W.; Liu, H.; Zhong, B. Zhongguo Xinyao Zazhi., 2007, 16(19), 1593-1599.
123. Bassas, O.; Huuskonen, J.; Rissanen, K.; Koskinen, A. M. P., European Journal of
Organic Chemistry., 2009, 9, 1340-1351.
124. Wallis, E. S.; Lane, J. F. Org. React. 1946, 3, 267-306.
125. Moriarty, R. M.; Chany, C. J., II; Vaid, R. K.; Prakash, O.; Tuladhar, S. M. J. Org. Chem.
1993, 58, 2478-2482.
126. Baumgarten, H. E.; Smith, H. L.; Staklis, A. J. Org. Chem. 1975, 40, 3554-3561.
127. Kajigaeshi, S.; Asano, K.; Fujisaki, S.; Kakinami, T.; Okamoto, T. Chem. Lett. 1989,
463-464.
MD. UMAR KHAN Thesis
Studies on the synthesis of anti-convulsant drug, Pregabalin 167
Chapter - II
128. Jew, S. S.; Park, H. G.; Park, H. J.; Park, M. S.; Cho, Y. S. Tetrahedron lett., 1990, 31,
1559-1562.
129. Radlick, P.; Brown, L. R. Synthesis. 1974, 290-292.
130. Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997, 62(21), 7495-7496.
131. Fujisaki, S.; Tomiyasu, K.; Nishida, A.; Kajigaeshi, S. Bull. Chem. Soc. Jpn. 1988, 61,
1401-1403.