INTRODUCTION:
The anticonvulsants (also commonly known as antiepileptic drugs) are a diverse group
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’-
catalyzes the conversion of L-glutamate to GABA and GABA aminotransferase (EC; 2.6.1.19),
MD. UMAR KHAN Thesis 82
Studies on the synthesis of anti-convulsant drug, Pregabalin
Table-2.1
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
Chapter - II
MD. UMAR KHAN Thesis 83
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
O OH
Pregabalin (1)
1
(S)-3-(aminomethyl)-5-methylhexanoic acid
NH2
H2N
Gabapentin (2) OH
2
2-[1-(aminomethyl)cyclohexyl]acetic acid
O
NH2
Vigabatrin (3) O
3
(RS)-4-aminohex-5-enoic acid OH
OH
O
Progabide (4) N
F NH 2
4 4-[(4-chlorophenyl)-(5-fluoro-2-hydroxy-
phenyl)-methylidene]aminobutanamide
Cl
O
Tolgabide (5) H O
N
Cl NH2
5 4-{[(Z)-(3-chloro-5-methyl-6-oxocyclohexa-
2,4-dien-1-ylidene)(4-
chlorophenyl)methyl]amino}butanamide
Cl
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
Chapter - II
MD. UMAR KHAN Thesis 84
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
calcium influx is modulated at nerve terminals, which in turn reduces the release of several
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
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
Chapter - II
MD. UMAR KHAN Thesis 85
Studies on the synthesis of anti-convulsant drug, Pregabalin
chemoenzymetic[90-101] resolution by setting the stereo centre early in the synthesis and enabling
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
6N HCl CO2H
reflux, 3h
NH2
78-86%
(±)-(1)
…..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.
recycled efficiently, this process is still the most cost-effective process to produce Pregabalin
thus far.
Chapter - II
MD. UMAR KHAN Thesis 86
Studies on the synthesis of anti-convulsant drug, Pregabalin
CO2Et CO2Et CN
CHO + n-Pr2NH KCN
CO2Et AcOH CO2Et 79-88% EtO2C CO2Et
reflux, 89%
(9) (10) (11) (12)
CN
KOH Sponge Ni, H2 NH2 (S)-mandelic acid NH2
…..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
O
OH 1) SOCl2, CHCl3 LDA, THF, -78°C O 1) LiOH, H2O2
O O
O
O 1) TsCl, Pyridine H2 (50 psi), Pd/C
O
OH OH
2) NaN3, DMSO, 68°C N3 HCl, THF
NH2
65%, 99.5% ee
76%
(17) (18) (1)
….. Scheme-2.3
Chapter - II
MD. UMAR KHAN Thesis 87
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
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
O CO2Et CO2H
1) TMSI, EtOH 1) KOH, EtOH, H2O
O 2) NaN3, CH3CN, 88% N3 2) H2, Pd/C, 65% NH2
(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
Chapter - II
MD. UMAR KHAN Thesis 88
Studies on the synthesis of anti-convulsant drug, Pregabalin
unsaturated imide. However, considering the cost of TMSCN and the high-pressure requirement
N N
Al O O
O O
t-Bu O Cl O t-Bu
N N
H t-Bu t-Bu , TMSCN H
CN
i-PrOH, PhMe, 93%, 96% ee
(24) (25)
O O
1N NaOH H2 (500 psi), PtO2
OH OH
THF, 94% HCl, H2O, 92%, 96% ee NH2.HCl
CN
(26) (1)
….. Scheme-2.5
Kissel and other researchers at Pfizer published a novel chiral synthesis of Pregabalin in 2003
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).
OH OCO2Et
CN DABCO, H2O EtOCOCl Pd(OAc)2, PPh3
CO2Et
CHO t-Bu Pyridine, 95% EtOH, CO, 83% CN
CN CN
Me OH , 97%
(27) (28) (29) (30)
t-Bu
P
Rh BF4
P O
H2 (50psi), Ni CO2H
LiOH, H2O CO2 H3N O NH3 KOH, H2O, EtOH
NH2
t-BuNH2 CN H2 (45 psi), MeOH, 100%, 97.7% ee HOAc, 61%,
CN 99.8% ee
(31) (32) (1)
….. Scheme-2.6
Chapter - II
MD. UMAR KHAN Thesis 89
Studies on the synthesis of anti-convulsant drug, Pregabalin
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.
H2N
O O OH
AC2O (38) EtOH, CHCl3
NH3(aq), MTBE
O
reflux, 92% HCl, 95% H NH2
H Aq. HCl, 75%, 98% ee
O O
(36) (37)
O OH
O OH
NaOH, Br2
NH2
HCl, 59%, 99% ee
O NH2
(39) (1)
….. Scheme-2.7
hydrolases to catalyze the hydrolysis of β-cyanodiester 12, an intermediate from the malonate
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-
Chapter - II
MD. UMAR KHAN Thesis 90
Studies on the synthesis of anti-convulsant drug, Pregabalin
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-
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.
CN CN CN
CO2Et LIPOLASE 100L CO2Et + CO2Et
Ca(OAc)2 buffer, KOH, pH 7
CO2Et CO2K CO2Et
(12) (40) (41)
NH CO2H
HCl, H2O,HOAc, 80°c
O NH2
KOH, pH 5.2-5.5
CO2H 80-85%, >99.5% ee
(42) (1)
….. 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
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
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
Chapter - II
MD. UMAR KHAN Thesis 91
Studies on the synthesis of anti-convulsant drug, Pregabalin
another aspect of invention was to provide highly pure (S)-Pregabalin having Chromatographic
Three synthetic approaches are described herein, among which approach A deals with 4-steps
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
APPROACH A:
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.
Chapter - II
MD. UMAR KHAN Thesis 92
Studies on the synthesis of anti-convulsant drug, Pregabalin
O OH O O OH
AC2O NH3
O
H OH H NH2
H
O
O O
(35) (36) (37)
H2N
O OH O OH
(38) NaOH, Br2
Aq. HCl NH2
NH2
O
(39) (1)
….. Scheme-2.9
From the chemical synthesis point of view, key steps in this process for the preparation of
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
chloroform/ethanol and carrying through the synthesis to contaminate the finished product i.e.
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
Chapter - II
MD. UMAR KHAN Thesis 93
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
guidelines require that drug substances and drug products be stressed to aid in the development
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
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-
Table-2.3
(R)-1-
S. PHENYL CHIRAL
BATCH YIELDS
No ETHYLA SOLVENTS PURITY
No. (w/w)
. MINE 38 (%)
(m. eq.)
Chapter - II
MD. UMAR KHAN Thesis 94
Studies on the synthesis of anti-convulsant drug, Pregabalin
volume)
5%v/v 1,4-dioxane (4
13 PRE(918)53 0.70 0.35 49.03
volume)
2% v/v Methanol in
16 PRE(918)67 0.70 methylene chloride 0.30 51.01
(10 volume)
1,4-Dibromobutane (5
19 PRE(918)68 0.70 No solid -
volume)
10%v/v Methanol in
20 PRE(918)69 0.70 methylene chloride No solid -
(5 volume)
Next, our target was to optimize the resolution step by varying mole equivalents of (R)-1-
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
Chapter - II
MD. UMAR KHAN Thesis 95
Studies on the synthesis of anti-convulsant drug, Pregabalin
getting the required compound 43 with high chiral purity with good yield. The results of those
Table-2.4
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.
Chapter - II
MD. UMAR KHAN Thesis 96
Studies on the synthesis of anti-convulsant drug, Pregabalin
Table-2.5
Stirring
Sr. Yields Chiral purity
no. Time Temp.
(%) (%)
0
(hrs) ( C)
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-
Table-2.6
It was clear from above study that chiral purity of (R)-Pregabalin monoamide (R)-PEA salt 43
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.
Chapter - II
MD. UMAR KHAN Thesis 97
Studies on the synthesis of anti-convulsant drug, Pregabalin
H2N
O OH O O . H3N O OH
(38)
H NH2 Aq. HCl
NH2 NH2
O O O
(37) (43) (39)
Dehydration
Hydrolysis
H H
O O N O N O OH
Cyclisation Hydrolysis Hydrolysis
NH
O - 38 - NH3 - 38 H OH
NH2 OH
O O O
(46)
(44) (45) (35)
….. Scheme-2.10
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
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
Chapter - II
MD. UMAR KHAN Thesis 98
Studies on the synthesis of anti-convulsant drug, Pregabalin
H2 N
O OH H
O N
H NH2 (38)
NH2
O
TEA / ECF O
(37) (44)
H2N H
O H
O N O N
O
(38) TEA / ECF
H OH NH2
O Ammonia
O O
(36) (45) (44)
H2 N H
O O N
O (38)
H OH
O
O
(36) (45)
O OH
O
AC2O NH
H NH2
O
O
(37) (46)
….. 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
PEA- PEA-
Pregabalin Pregabalin HPLC
Sr. Reaction Pregabalin Pregabalin
imide, 46 diacid, 35 purity
no. conditions amide, 44 acid, 45
(%) (%) (%)
(%) (%)
Pregabalin
1 0.48 0.03 - - -
monoamide 37
After addition of
Not Not
2 38, at 55-58°C (0 1.95 2.48 -
detected detected
hr)
Chapter - II
MD. UMAR KHAN Thesis 99
Studies on the synthesis of anti-convulsant drug, Pregabalin
detected
Not
4 At 55-58°C (2 hr) 9.50 3.16 0.22 -
detected
R-PEA
Not
5 Pregabalin 0.19 0.83 0.19 98.35
detected
monoamide 43
Not
6 Mother liquor 14.32 5.87 5.87 56.70
detected
R-Pregabalin
7 0.03 0.01 Not detected 0.22 99.66
monoamide 39
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
monoamide. Therefore, pH of the reaction mass was kept highly acidic (~0.5) to remove the
Table-2.8
43 39
S. INPUT BATCH Water Yield
Chiral No. Chiral
No. BATCH No. (Volume) (w/w)
Purity purity
Chapter - II
MD. UMAR KHAN Thesis 100
Studies on the synthesis of anti-convulsant drug, Pregabalin
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.
treated with sodium hypobromite to form N-bromoamide derivative, which was converted to
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
Water
Sr. Bromine Sodium hydroxide Impurity Impurity
volume
no. (Mole eq.) (mole eq.) 1.20 RRT (%) 1.32 RRT (%)
(times)
Chapter - II
MD. UMAR KHAN Thesis 101
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
Table-2.10
Not
6 Aq. methanol 50% v/v (8) 0.12 0.04 0.17
detected
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
Chapter - II
MD. UMAR KHAN Thesis 102
Studies on the synthesis of anti-convulsant drug, Pregabalin
carrying out some more experiments by varying water volume, workup temperature and mole
O OH
HO O
H
N
N O
N H
OH
Br
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
Chapter - II
MD. UMAR KHAN Thesis 103
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
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
Chapter - II
MD. UMAR KHAN Thesis 104
Studies on the synthesis of anti-convulsant drug, Pregabalin
O OH
H NH2
O
(37)
H2N
1. Resolution
2. aq. HCl
(38)
O OH O OH
O Hydrolysis H H
-NH3 O N O N
NH
H OH
O NH2
O O OH NH2
(46)
(35) O
(39) O
(45) (44)
O-
H Hy Hydrolysis Br
De ofm dr om
gr an -H oly -HBr Hofmann in
ad n ati Hofmann
ati -N Br sis Degradation on
1 on H Degradation
3
O NH2 O OH H
O OH O OH O N
O
O H NH
OH N Br
NH2 O
HN Br NH2
(47) O
(37 A Bromoamide (50)
(48) or 3 Re
9) du
ct i
Hofmann on
Degradation (58)
NH2 ( 1) O OH O OH
NH3 O OH
O O
O
O C C
OH N N NH2 NH2
HN H
An isocyanate (51)
(53)
(3
(49) 7o
) r3 Dehydration
O OH (1 H2O 9)
O OH
O OH O
NH NH
O NH
O NH O NH
OH OH (52)
N
on
ati H O O
dr O
ehy A carbamic acid OH
D (54) (55)
O OH
Decarboxylation
NH O
O N
O OH O OH
Oxidation Dehydration
(56) O
CN NH
NH2
(57) (1) (58)
…..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
Chapter - II
MD. UMAR KHAN Thesis 105
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
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
Chapter - II
MD. UMAR KHAN Thesis 106
Studies on the synthesis of anti-convulsant drug, Pregabalin
O OH
O O OH
NH NaOH, Br2
H NH2 'or'
O Hofmann degradation
O NH2
(46)
(37) (47)
O OCH3
O NH2
O OH
TEA / ECF / (59) O
NH2 O
NH2 OH
Hydrolysis HN
O
(39)
(48)
O NH2 NH2
O O
O NaOH, Br2 O
OH OH
HN Hofmann degradation HN
(48) (49)
H H
O N O N
NaOH, Br2
…..Scheme-2.13
Preparation of 49 was given in the literature.[122] Synthetically 47, 49 and 50 were prepared by
subsequently reacting with 59, which after hydrolysis in basic medium results Pregabalin amide
dimer 48.
O
O OCH3 O OCH3
O
MeOH TEA / ECF / NH3 Py / TsCl
H
O OH NH2
O O
(36) (60) (61)
O OCH3 O OH O OH
Hydrolysis Hydrogenation
CN NH2
CN
(51)
(62) (63)
O OH
O
Dehydration
NH
NH2
(52)
(51)
…..Scheme-2.14
Chapter - II
MD. UMAR KHAN Thesis 107
Studies on the synthesis of anti-convulsant drug, Pregabalin
anhydride 36 was reacted with methanol to give Pregabalin diacid monomethyl ester 60.
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.
O OCH3 O OH
Curtius rearrangement O
OH NH3 / Hydrolysis C
N NH2
O H
(60) (53)
Cu
rtiu
H s re
Curtius 2O arr
/H ang
rearrangement yd em
rol ent
ysi
37 or 39 / Hydrolysis s
O OH
O OH
NH
NH O NH
O NH OH
O O O
OH
(54)
(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
Di Pregabalin urea 54, on heating in basic condition liberates water to give new molecule 56.
(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.
Chapter - II
MD. UMAR KHAN Thesis 108
Studies on the synthesis of anti-convulsant drug, Pregabalin
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.
O OH
O OH
NH NH O
Dehydration
O NH O N
OH
O
(56)
(54)
O OH
Dehydration O
NH
NH2 (58)
(1)
…..Scheme-2.16
O OC2H5
O OC2H5
CHO n-Pr2NH OC2H5 KCN
+ OC2H5
AcOH O
(9) O reflux
(10) (11)
O OC2H5
O OH
OC2H5 KOH OC2H5 Hydrolysis
CN O CN O
CN
(12) (57)
(64)
…..Scheme-2.17
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
Chapter - II
MD. UMAR KHAN Thesis 109
Studies on the synthesis of anti-convulsant drug, Pregabalin
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 /
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
O
O
OH
OH
K2CO3, Water THF, MeI, NaH
Toluene, DIBOC EtOAc, citric acid,
HN O
NH2 sodium thiosulfate
(1) O
(66)
O O
OH OH
Trifluoroacetic acid
N O HN
O N-methyl-1
(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 2 steps O OH 2 steps O OH
H OH H NH2
NH2
O O
(35) (1)
(37)
….. Scheme-2.19
Chapter - II
MD. UMAR KHAN Thesis 110
Studies on the synthesis of anti-convulsant drug, Pregabalin
the first step. 37 was resolved easily with (R)-1-Phenylethylamine 38 as a chiral reagent to yield
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
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)
APPROACH B:
In approach A, we have optimized synthetic process for the preparation of Pregabalin, starting
cyano acetic acid ethyl ester 33 followed by Michal addition of diethyl malonate 10 in presence
Chapter - II
MD. UMAR KHAN Thesis 111
Studies on the synthesis of anti-convulsant drug, Pregabalin
gives 3-isobutylglutaric acid 35 in 80% yield. Thus obtained compound was converted to 3-
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
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
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,
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)
CH3OBr,[129] and NBS-DBU.[130] When methanol was used as a solvent, the corresponding
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
Chapter - II
MD. UMAR KHAN Thesis 112
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
O OH O OH
NaOCH3/CH3OH/Br2,-40°C to -15°C O
NH2
N O
O H
(39) (68)
….. Scheme-2.20
To study the reaction in details, we used different alcohols as reaction medium, which was
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
Table-2.12
O OH
O
Methanol 97
N O
H
(68)
O OH
O
Ethanol 89
N O
H
(69)
Chapter - II
MD. UMAR KHAN Thesis 113
Studies on the synthesis of anti-convulsant drug, Pregabalin
O OH
O
n-Propanol 78
N O
H
(70)
O OH
O
Iso-Propanol 30
N O
H
(71)
O OH
O
n-Butanol 61
N O
H
(72)
O OH
O
tert-Butanol No reaction
N O
H
(73)
HN O
Methanol OH 99
O
(74)
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
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
Chapter - II
MD. UMAR KHAN Thesis 114
Studies on the synthesis of anti-convulsant drug, Pregabalin
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 OH O OH
….. Scheme-2.21
Table-2.13
Methanol O OH 95
O
N O
H
(68)
Ethanol O OH 88
O
N O
H
(69)
Iso-Propanol O OH 40
O
N O
H
(71)
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
Chapter - II
MD. UMAR KHAN Thesis 115
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
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
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 OH O OH O
HCl, reflux + NH
H NH2 H OH
24h O
O O
(46)
(65) (35)
….. 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.
Chapter - II
MD. UMAR KHAN Thesis 116
Studies on the synthesis of anti-convulsant drug, Pregabalin
H2N
O OH . H3N O OH
O O
(38)
H NH2 Aq. HCl
NH2 NH2
O O O
(37) Mother (43) (39)
liquor /
Aq. NaOH
O O . H3N
organic layer H2N
NH2
O
(38)
aq. layer
O OH O
O OH
Aq. NaOH AC2O O
H OH
H NH2 reflux, 15h reflux H
O
O
O
(35) (36)
(65)
O OH
NH3
H NH2
O
(37)
….. Scheme-2.23
Table-2.14
Not
3 After concentration, 35 0.06 4.60 93.69 0.11
detected
Chapter - II
MD. UMAR KHAN Thesis 117
Studies on the synthesis of anti-convulsant drug, Pregabalin
Monoamide preparation,
5 9.96 0.08 0.31 0.10 85.77
for 1hr
Not Not
6 Organic layer 15.94 0.83 2.78
detected detected
Recovered Pregabalin
8 0.05 0.01 0.12 0.01 99.72
monoamide, 37
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
….. 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
Chapter - II
MD. UMAR KHAN Thesis 118
Studies on the synthesis of anti-convulsant drug, Pregabalin
of Pregabalin 47, 84, 85 and 86. The characterization data and detailed experimental procedure
CONCLUSION:
Hence we have developed a simple, safe, productive, eco-friendly and easy to handle
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
impurities less than 0.10%, chromatographic and chiral purity > 99.9% each.
EXPERIMENTAL SECTION:
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
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-
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,
Chapter - II
MD. UMAR KHAN Thesis 119
Studies on the synthesis of anti-convulsant drug, Pregabalin
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.
Compound Data
no.
1
HNMR (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).
1 78
Exact Mass (m/z, 188.1); Observed: (in –ve ion mode) m/z; 187.2 [(M+-
H)-].
1
HNMR (CDCl3, 300 MHz, δ ppm): 0.91 (t, 3H), 1.35 (m, 6H), 2.23-
2 79 2.52 (m, 5H). Exact Mass (m/z, 188.1); Observed: (in –ve ion mode)
m/z; 187.2 [(M+-H)-].
1
HNMR (CDCl3, 300 MHz, δ ppm): 0.93 (s, 9H), 2.19 (m, 2H), 2.35
3 80 (m, 1H), 2.65 (m, 2H). Exact Mass (m/z, 188.1); Observed: (in –ve ion
mode) m/z; 187.2 [(M+-H)-].
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,
Chapter - II
MD. UMAR KHAN Thesis 120
Studies on the synthesis of anti-convulsant drug, Pregabalin
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.
Compound Data
no.
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 81 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)-].
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),
2 82
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)-].
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
3 83 (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)-].
monoamide, 43)
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 αD20 (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 .
Chapter - II
MD. UMAR KHAN Thesis 121
Studies on the synthesis of anti-convulsant drug, Pregabalin
HNMR (DMSO-d6, 300 MHz, δ ppm): 0.83 (d, 6H), 1.10 (t, 2H), 1.27 (m, 3H), 1.62 (m, 1H),
1
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)+].
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)-].
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)+].
Chapter - II
MD. UMAR KHAN Thesis 122
Studies on the synthesis of anti-convulsant drug, Pregabalin
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)-].
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
Chapter - II
MD. UMAR KHAN Thesis 123
Studies on the synthesis of anti-convulsant drug, Pregabalin
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)-].
46 (162g, 0.96mole) or 37 (180g, 0.96mole) was added in lots to sodium hypobromite solution
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
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
Table-2.17
Sr.
Compound Data
no.
IR (KBr, cm-1): 3339, 2964, 2916, 2876, 1661, 1538, 1461, 1408, 1395.
1
HNMR (D2O, 300 MHz, δ ppm): 0.84 (t, 3H), 0.86 (d, 3H), 1.19 & 1.34
1 84 (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)+].
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,
2 85
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)+].
Chapter - II
MD. UMAR KHAN Thesis 124
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
3 86
(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
dichloromethane (300ml) at 25 to 30°C. Obtained clear solution was cooled to 0 to 5°C and
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
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.
HNMR (CDCl3, 300 MHz, δ ppm): 0.88-0.94 (m, 12H), 1.18 (m, 2H), 1.33 (m, 2H), 1.64 (m,
1
2H), 2.15-2.61 (m, 8H), 3.02-3.51 (m, 2H). Exact Mass (m/z, 328.24); Observed: (in +ve ion
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
Chapter - II
MD. UMAR KHAN Thesis 125
Studies on the synthesis of anti-convulsant drug, Pregabalin
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)+].
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
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
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)+].
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,
Chapter - II
MD. UMAR KHAN Thesis 126
Studies on the synthesis of anti-convulsant drug, Pregabalin
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:
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.
HNMR (DMSO-d6, 300 MHz, δ ppm): 0.85 (d, 6H), 1.11 (m, 2H), 1.25 (m, 1H), 1.58-1.79 (m,
1
4H), 2.18 (m, 1H), 3.12 (m, 2H), 7.40 (brs, 1H). Exact Mass (m/z, 155.13); Observed: (in +ve
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%).
Chapter - II
MD. UMAR KHAN Thesis 127
Studies on the synthesis of anti-convulsant drug, Pregabalin
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)
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,
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
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)-].
Chapter - II
MD. UMAR KHAN Thesis 128
Studies on the synthesis of anti-convulsant drug, Pregabalin
3-{[(4-Isobutyl-2-oxo-pyrrolidine-1-carbonyl)-amino]-methyl}-5-methylhexanoic acid
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 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)-].
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
Chapter - II
MD. UMAR KHAN Thesis 129
Studies on the synthesis of anti-convulsant drug, Pregabalin
further heated to reflux at 105 to 110°C for 20hrs. Cooled the reaction mass to 25 to 30°C and
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,
HCl, 59)
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)
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
Chapter - II
MD. UMAR KHAN Thesis 130
Studies on the synthesis of anti-convulsant drug, Pregabalin
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);
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),
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)
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].
Chapter - II
MD. UMAR KHAN Thesis 131
Studies on the synthesis of anti-convulsant drug, Pregabalin
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)-].
(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
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,
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
Chapter - II
MD. UMAR KHAN Thesis 132
Studies on the synthesis of anti-convulsant drug, Pregabalin
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)-].
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);
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,
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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)-].
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)-].
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.
HNMR (CDCl3, 300 MHz, δ ppm): 0.92 (2d, 6H), 1.07 (t, 2H), 1.58 (m, 1H), 2.10 (m, 1H),
1
2.17 & 2.44 (2m, 2H), 2.58 (s, 3H), 2.70 & 2.88 (2m, 2H). Exact Mass (m/z, 173.13); Observed:
Resolution of 37:
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
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.Thus, obtained clear solution was cooled slowly to 28-32°C and stirred at this temperature for
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]20D : -1.20 o (c=1, in methanol).
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
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,
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
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(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).
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
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,
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
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,
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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-
(by HPLC): 99.5 %. Melting Range: 106-107°C. Assay: 99.6 % (%w/w, by titrimetry). SOR:
[α]20D:-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).
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-
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.
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-
Table-2.18
Sr.
Compound Data
no.
1
H 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),
1 68
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)+].
1
H 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,
2 69
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)+].
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1
H 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,
3 70
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)+].
1
H 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 71
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)+].
1
H 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
5 72 (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)+].
1
H 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);
6 74
Observed: (in –ve ion mode) m/z; 228.2 [(M+-H)-], (in +ve ion mode)
m/z; 229.1. [(MH)+].
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
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
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precipitation of Pregabalin. Product was filtered, washed with DM water, and dried at 50-
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SPECTRA:
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REFERENCES:
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.
5. Schechter, P. J.; Tranier, Y.; Grove, J. Adv. Exp. Med. Biol. 1979, 123, 43-57.
7. Andus, K. L.; Chikale, P. J.; Miller, D. W.; Thomson, S. E.; Borcardt, R. T. Adv. Drug.
8. Madrid, Y.; Langer, L. F.; Breue, H.; Langer, R. Adv. Pharmacol. 1991, 22, 299-324.
10. Gatti, G.; Bonomi, I.; Jannuzzi, G.; Perucca, E. Curr. Pharm. Design. 2000, 6, 839.
12. Bryans, J. S.; Wustrow, D. J. Med. Res. Rev. 1999, 19, 149-177.
15. Field, M. J.; Oles, R. J.; Lewis, A. S.; McCleary, S.; Hughes, J.; Singh, L. Br. J.
16. Silverman, R. B.; Andruszkiewicz, R.; Nanavati, S. M.; Taylor, C. P.; Vartanian, M. G. J.
17. Taylor, C. P.; Vartanian, M. G.; Yuen, P. W.; Kanter, G. D.; Bigge, C.; Suman-Chauhan,
Chapter - II
MD. UMAR KHAN Thesis 159
Studies on the synthesis of anti-convulsant drug, Pregabalin
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.
20. Dworkin, R. H. P.; Corbin, A. E. M.; Young, J. P. J.; Sharma, U.; LaMoreaux, L.;
21. Hill, C. M.; Balkenohl, M.; Thomas, D. W.; Walker, R.; Mathe, H.; Murray, G. Eur. J.
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.
26. http://www.sec.gov/Archives/edgar/data/78003/000119312511048877/dex13.htm
28. Grote, T. M.; Huckabee, B. K.; Mulhern, T.; Sobieray, D. M.; Titus, R. D. [P]. US
29. Chen, Z.; Chen, Z.; Jiang, Z.; Hu, W. Synlett, 2004, 10, 1763-1764.
Chapter - II
MD. UMAR KHAN Thesis 160
Studies on the synthesis of anti-convulsant drug, Pregabalin
30. Blazecka, P. G.; Davidson-III, J. G.; Zhang, J. [P]. US 6,924,377. Aug.02, 2005.
31. Zhang, G.; Yang, X.; Ma, Y.; Shi, S.; Duan, L.; Zhu, Y. [P]. WO 2006/136087. Dec.28,
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,
Pharmaceuticals Ltd).
35. Gaitonde, A.; Valdya, C.; Khairnar, P. [P]. US 2009/286880. Nov.19, 2009. (assigned to
36. Gore, V.; Gadakar, M.; Shinde, D. [P]. WO 2009/147434. Dec.10, 2009. (assigned to
38. Rasparini, M.; Tufaro, R.; Castaldi, G.; Marras, G.; Giovenzana, G. [P]. WO 2009/53446.
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].
Chapter - II
MD. UMAR KHAN Thesis 161
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
43. Sarin, G. S.; Saini, M.; Chidambaram, V. S.; Wadhwa, L. [P]. WO 2010/061403. Jun.03,
44. Chavan, A. A.; Padwal, S. B.; Joshi, A. V.; Bhanu, M. N. [P]. WO 2009/87674. Jul.16,
45. Xu, J.; Zhang, D.; Ye, M.; Chen, J.; Guo, Y.; Hu, Y. [P]. WO 2009/082861. Jul.09, 2009.
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.
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.
54. Lee, H. S.; Lee, J.; Ok, T. [P]. US 2010/286442. Nov.11, 2010. (assigned to Kaist).
Chapter - II
MD. UMAR KHAN Thesis 162
Studies on the synthesis of anti-convulsant drug, Pregabalin
55. Ortuno, R. M.; Izquierdo, S.; Buschmann, H. H.; Jover, A. T.; Lopez, M. G. [P]. US
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,
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.
62. Davies, B. S.; Guzman, M. M.; Martinez, C. A.; McDaid, P. O., O'Neill, P. M.;
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.
68. Hoge, G.; Wu, H.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao, J. J. Am. Chem. Soc.
69. Burk, M. J.; Goel, O. P.; Hoekstra, M. S.; Mich, T. F.; Mulhern, T.; Ramsden, J. A. [P].
Chapter - II
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71. Bao, J.; Beylin, V. G.; Greene, D.; Hoge, G. S.; Kissel, W.; Marlatt, M. E.; Pflum, D. A.;
72. Avdagic, A.; Hamersak, Z. [P]. WO 2008/9897. Jan.24, 2008. (assigned to Pliva
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.
75. Kansal, V. K.; Chaurasia, B. P.; Rao, V. G.; Tiwari, A. P. [P]. US 7,446,220. Nov.04,
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
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.
81. Hidvati, L.; Noor, Z. D.; Singer, C.; Palarski, G.; Raizi, Y.; Tomer, S. [P]. US 7,488,846.
82. Hamersak, Z.; Stipetic, I.; Avdagic, A. Tetrahedron: Asymmetry, 2007, 18, 1481-1485.
Chapter - II
MD. UMAR KHAN Thesis 164
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
86. Allegrini, P.; Mantegazza, S.; Pastorello, D.; Razzetti, G. [P]. US 2009/143615. Jun.04,
87. Ahirrao, V. D.; Narani, C. P.; Bondge, S. P.; Khunt, M. D.; Pradhan, N. S.; Valgeirsson,
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
90. xie, Z.; Feng, J.; Garcia, E.; Bernett, M.; Yezbeck, D.; Tao, J. Journal of molecular
91. Martinez, C. A.; Hu, S.; Dumond, Y.; Tao, J.; Kelleher, P.; Tully, L. Org. Proc. Res. Dev.
92. Felluga, F.; Pitacco, G.; Valentin, E.; Venneri, C. D. Tetrahedron: Asymmetry, 2008,
19(8), 945-955.
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.
96. Chaudhari, K.; Yeole, M.; Batchu, C.; Ratnam, R.; Aurora, S.; Gupta, M. N.; Mujumdar,
Chapter - II
MD. UMAR KHAN Thesis 165
Studies on the synthesis of anti-convulsant drug, Pregabalin
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
104. Shkapenko, G.; Gmitter, G. T.; Gruber, E. E. Ind. Eng. Chem., 1960, 52 (7), 605–608.
106. Kansal, V. K.; Chaurasia, B. P.; Shelke, S. H.; Tiwari, A. P. [P]. WO 2008118427.
107. Tiwari, A. P.; Kansal, V. K.; Chaurasia, B. P.; Rao, V. G. [P]. WO 2007035890. Mar.29,
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.)
Chapter - II
MD. UMAR KHAN Thesis 166
Studies on the synthesis of anti-convulsant drug, Pregabalin
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,
115. Kumar, K. S.; Reddy, K. T.; Reddy, G. J.; Omprakash, G.; Dubey, P. K. Pharmacia
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.
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
125. Moriarty, R. M.; Chany, C. J., II; Vaid, R. K.; Prakash, O.; Tuladhar, S. M. J. Org. Chem.
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.
Chapter - II
MD. UMAR KHAN Thesis 167
Studies on the synthesis of anti-convulsant drug, Pregabalin
128. Jew, S. S.; Park, H. G.; Park, H. J.; Park, M. S.; Cho, Y. S. Tetrahedron lett., 1990, 31,
1559-1562.
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.
Chapter - II