A Simple and Expedient Procedure for the Preparation of Gabapentin Lactam (2-Aza-spiro[4,5]decan-3-one)

Article abstract of DOI:10.1021/acs.oprd.6b00246

A novel process has been described on 100 g scale for the preparation of gabapentin lactam which is a penultimate intermediate for the preparation of gabapentin, comprising a Hofmann reaction of 1,1-cyclohexanediacetic acid monoamide using chlorinating agents such as trichloroisocyanuric acid, sodium dichloroisocyanurate, 1,3-dichloro-5,5-dimethylhydantoin, and N-chlorosuccinimide, which have not been employed so far for making this molecule. Reactions done in aqueous alkali on the 1,1-cyclohexanediacetic acid monoamide led to a solution of gabapentin sodium salt which on heating led to the formation of the gabapentin lactam in good yield.

Full text of DOI:10.1021/acs.oprd.6b00246

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Communication
A Simple and Expedient Procedure for the Preparation
of Gabapentin Lactam (2-aza-spiro[4,5]decan-3-one)
Jashuva V P Katuri, Vadiraj S Ekkundi, and Kuppuswamy Nagarajan
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00246 • Publication Date (Web): 12 Sep 2016
Downloaded from http://pubs.acs.org on September 13, 2016
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A Simple and Expedient Procedure for the Preparation
of Gabapentin Lactam (2-aza-spiro[4,5]decan-3-one)
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Jashuva V. P. Katuri,*b,c Vadiraj S. Ekkundib and Kuppuswamy Nagarajan*a
aHikal Ltd, 3rd Floor, Grey Rock, No.10, 24th Main, J.P. Nagar 2nd Phase, Bangalore 560078, Karnataka,
India.
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bHikal Ltd, 3A, International Biotech Park, Hinjewadi, Pune 411057, Maharashtra, India.
cDepartment of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology (CSIR-
IICT), Hyderabad 500007, Telangana, India.
AUTHOR EMAIL ADDRESS jashuva@iict.res.in, k_nagarajan@hikal.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
TITLE RUNNING HEAD A Simple and Expedient Procedure for the Preparation of Gabapentin
Lactam
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ABSTRACT
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A novel process has been described on 100 g scale for the preparation of gabapentin lactam which is a
penultimate intermediate for the preparation of gabapentin, comprising Hofmann reaction of 1,1-
cyclohexanediacetic acid monoamide using chlorinating agents such as trichloroisocyanuric acid,
sodium dichloroisocyanurate, 1,3-dichloro-5,5-dimethylhydantoin and N-chlorosuccinimide, which
have not been employed so far for making this molecule. Reactions done in aqueous alkali on the 1,1-
cyclohexanediacetic acid mono amide led to a solution of gabapentin sodium salt which on heating led
to the formation of the gabapentin lactam in good yield.
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KEYWORDS Hofmann reaction, gabapentin, gabapentin lactam, trichloroisocyanuric acid, sodium
dichloroisocyanurate, 1,3-dichloro-5,5-dimethyl hydantoin, N-chlorosuccinimide.
INTRODUCTION
Gabapentin 1 is a therapeutically important drug in the treatment of certain forms of epilepsy, faintness
attacks, cranial traumas, hypokinesia and which additionally brings about an improvement on certain
cerebral functions.1 Extensive and wide spread applications of gabapentin have given it a “blockbuster’
status. There are several processes available for the synthesis of 1 among which one using gabapentin
lactam 4 as a precursor is widely employed.2 Lactam 4 by itself has interesting and potentially useful
biological activities, eg. it is a K+ channel activator and is neuroprotective,3 neurotrophic4 and enhances
new bone formation in vitro.5 Lactam 4 is also useful for the preparation of N-substituted
spirolactams.2b The first synthesis of 4 was reported by Sircar in 1928 by the Hofmann reaction of the
1,1-cyclohexanediacetic acid monoamide 2 with alkaline sodium hypobromite at 55 °C for 2 h.6 The
reaction mixture was then acidified with HCl and evaporated to dryness. The residue was washed with
ether to remove free organic acids and extracted with acetone. The acetone extract was evaporated to
dryness. The residue was neutralized with alkali and extracted into ether. Evaporation of ether afforded
gabapentin lactam 4 in only 46% yield. This process is not useful for commercial production of 4
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because of the number of steps and the low yield of the desired product, making the process expensive
and unviable for commercial production of gabapentin 1 for which 4 is the crucial precursor. Later some
commercial processes for the preparation of gabapentin lactam 4 have been reported. Geibel et al.
disclosed the synthesis of lactam 4 from cyclohexanone in three steps7 - conversion of cyclohexanone
into ethyl cyclohexylidene acetate, followed by addition of nitromethane to form ethyl 1-
nitromethylcyclohexane acetate and finally catalytic reduction of the nitro ethyl derivative. In this
process hazardous nitromethane and costly Wittig reagents are used. In addition explosive and
inflammable hydrogen gas and pyrophoric catalyst such as 10% Pd-C are also employed. Steiner et al.
disclosed a synthesis of 4 from cyclohexanone in four steps8 - conversion of cyclohexanone into diethyl
cyclohexylidene malonate, addition of sodium cyanide to form diethyl 1-cyanocyclohexyl malonate,
hydrolysis of diethyl 1-cyanocyclohexyl malonate to 1-cyanocyclohexyl malonic acid and finally
catalytic hydrogenation of the cyclohexyl malonic acid at elevated temperature resulting in
decarboxylative lactamization. In this process the disadvantages are handling of highly poisonous
sodium cyanide and use of rhodium or pyrophoric Raney nickel as catalyst in the final step. Recently
we have reported a chemo-enzymatic process for making 4 from cyclohexanone.9 This method again
requires the use of highly poisonous sodium cyanide, explosive & inflammable hydrogen gas and use of
Raney nickel as catalyst. Alternatively 4 has been made from monoamide 2 using sodium
hypobromite.10 This process requires expensive and corrosive bromine for the preparation of sodium
hypobromite. Parsons and co-workers reported a new approach for the preparation of 4 on a small
scale,11 wherein 1-cyclohexene-1-carboxaldehyde was condensed with benzoyl hydrazine to form the
corresponding hydrazone. This hydrazone was reduced with dimethylamine-borane/methane sulfonic
acid to get the hydrazine which was then N-acylated with trichloroacetyl chloride to give the
corresponding hydrazide. This was subjected to 5-exo-trig halogen atom transfer radical cyclization
mediated by copper (I) chloride and TMEDA (tetramethylethylenediamine) to form
trichlorospirolactam. Treatment of this trichlorospirolactam with wet Raney nickel gave 4. This
procedure suffers from a few obvious draw backs such as number of chemical steps and scale up
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problems including chromatography. Hu and co-workers reported a transition metal catalyzed C-H
insertion reaction catalyzed by Rh2(cap)4 to prepare N-tert-butyl gabapentin lactam.12 This procedure is
handicapped by the use of expensive Rh2(cap)4. Each of the above procedures suffers therefore from
various limitations. We hence felt that there was a genuine need for synthesizing 4 in higher yields and
of high purity at a low cost, which are commercial requirements so that the process can be used directly
for the production of gabapentin on large scale. In the present work chlorinating agents such as
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trichloroisocyanuric acid, sodium dichloroisocyanurate, 1,3-dichloro-5,5-dimethylhydantoin and
N-
chlorosuccinimide are reported for Hofmann reaction of 1,1-cyclohexanediacetic acid monoamide to get
lactam 4 in good yields.
RESULTS AND DISCUSSION
1,1-Cyclohexanediacetic acid monoamide 2 was prepared in high yield from commercially available
1,1-cyclohexanediacetic acid by following the literature procedure.13 The use of chloro derivatives in
place of bromo derivatives in the Hofmann Reaction will make it economical from a cost perspective at
the production level.
As part of our work, initial experiments for the Hofmann reaction were performed using
trichloroisocyanuric acid (TCCA). TCCA has been widely applied in organic synthesis.14 It has been
used for the Hofmann reaction in methanol in order to get methyl carbamates15 but has not been utilized
for the synthesis of gabapentin. The advantages involved in the use of trichloroisocyanuric acid are i) it
is a solid having high melting point 246-247 °C, which can be handled easily ii) it is an inexpensive and
easily available reactant, iii) it can be used in the molar ratio of 0.33 to 1 of reagent to substrate iv) the
byproduct cyanuric acid can be recycled to make the starting material TCCA and this process can be
repeated for a number of times. In addition to this, a significant advantage in using TCCA is that it can
be stored at room temperature for many days unlike 10-15% sodium hypochlorite solution which has to
be prepared freshly before starting the reaction and has to be stored below 5 °C. Also since the volumes
of the reaction using TCCA are less compared to the common process using 10-15% sodium
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hypochlorite process (~3 volumes less), batch throughputs can be usefully increased. Encouraged by the
above potential advantages, N-chlorination of 1,1-cyclohexanediacetic acid monoamide 2 was
performed on its methanol solution with TCCA as described in the experimental section. The byproduct
cyanuric acid precipitated as solid. After disappearance of starting material 2, as confirmed by TLC
analysis, the reaction mixture was filtered to remove the byproduct cyanuric acid which was obtained
quantitatively. The methanolic filtrate was evaporated to dryness using a rotary evaporator at 50 °C
under vacuum to get N-chloro cyclohexanediacetic acid monoamide 3 as a solid in quantitative yield.
This hitherto unknown N-chloroamide, 3 was characterized completely by NMR and mass spectral
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analysis. In H-NMR (300 MHz, DMSO-d6) a peak at 12.00 ppm showed the presence of –COOH
group. Proton resonating at 9.96 ppm showed the presence of –NH-Cl pattern. Protons resonating at
2.43 and 2.39 ppm showed the presence of two methylene groups as singlets. Multiplet seen in the
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region 1.52 – 1.27 ppm represents the cyclohexyl group. In C-NMR (75 MHz, DMSO-d6) carbonyl
carbons of acid and amide groups were seen at 172.9 & 169.3 ppm respectively. Methylene carbons
which are attached to carboxylic acid and amide groups were seen at 40.7 & 40.3 ppm respectively. The
signal of the quaternary carbon atom in the cyclohexyl group was seen at 35.1 ppm. The other five
carbons of cyclohexyl group were seen at 35.0, 25.5 and 20.9 ppm. The structure of the compound was
further confirmed by high resolution mass spectral analysis which showed the molecular ion peak at m/z
256 (M+Na). Thus the compound was unambiguously established to be N-chloro-1,1-
cyclohexanediacetic acid monoamide 3. This was subjected to the Hofmann Reaction by adding it
portion wise to aqueous sodium hydroxide solution at 0 – 5 °C over a period of 1 h. The resulting
reaction mass was processed as described in the experimental section. The solution containing the
sodium salt of gabapentin was subjected to cyclization under the experimental conditions to give lactam
4 which was extracted by toluene. Evaporation of toluene at reduced pressure afforded 4 in 90% yield
with HPLC purity >99% (Scheme 1).
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Scheme 1 Hofmann reaction using TCCA
Although the above process gave lactam 4 in 90% yield it has a few limitations for use in production
level such as, i) one isolation step involved (N-chlorination) including complete distillation of solvent
and ii) obligatory use of methanol for keeping the monoamide in solution for N-chlorination. In order to
overcome the above drawbacks, reactions were planned for using TCCA in water which is a green
solvent and executed successfully. Accordingly, a solution of the sodium salt of 1,1-
cyclohexanediacetic acid monoamide, prepared by adding the monoamide 2 to excess 12% sodium
hydroxide solution (4.4 equivalent of NaOH with respect to 2; this excess NaOH is required for sodium
salt formation of monoamide, Hofmann rearrangement including the liberated CO2 quenching to
Na2CO3) was added dropwise to a suspension of TCCA in water (1.5 V of water with respect to 2) over
a period of 1 h at 0-5 °C and the Hofmann reaction conducted under well defined conditions as
described in the experimental section. Lactam 4 was obtained by evaporation of the toluene solution in
vacuo in 75% yield with HPLC purity >98%. Cyanuric acid was recovered significantly from the TCCA
reaction as described in the experimental section. To the best of our knowledge, trichloroisocyanuric
acid has not been employed as chlorinating agent for making lactam 4 by Hofmann reaction. The
generality of the method was extended to other chlorinating agents such as sodium dichloroisocyanurate
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(NaDCC), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) and
(NCS).
N-chlorosuccinimide
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Sodium dichloroisocyanurate (NaDCC) is used widely for treating potable water, waste water, water
in swimming pools and many other industrial water systems.16 Benjamin Staskun reported the use of
NaDCC for the Hofmann degradation of 4-chlorobenzamide to 4-chloroaniline17 and also Pallavicini et
al. have reported for N-chlorination.18 Unlike trichloroisocyanuric acid, it is highly soluble in water (25
g in 100 mL water). We have examined its synthetic utility for making gabapentin lactam for the first
time under conditions given in the experimental section and were gratified to find that it proceeded very
well to afford 4 in 85% yield with HPLC purity >99%. Obviously the homogenous nature of reaction
mass using the solution of the sodium dichloroisocyanurate compared to the non-homogeneity in the
case of trichloroisocyanuric acid is the reason for the superior performance of the former reagent.
Cyanuric acid was recovered significantly from the sodium dichloroisocyanurate reaction as described
in the experimental section. These chloroisocyanuric acids are very interesting from the perspective of
green chemistry,19 as these are alternative reagents to generate organic compounds without using
hazardous chlorine gas every time as these reagents can be prepared in bulk and can be stored at room
temperature for long time and used on call.20 They also have advantages from the atom economy point
of view, as they can transfer majority of their mass to the substrate, for example trichloroisocyanuric
acid can transfer up to 46% of its mass. They are not expensive and can be regenerated from recovered
cyanuric acid.
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We have also examined the synthetic utility of 1,3-dichloro-5-5-dimethyl hydantoin (DCDMH) for
the Hofmann reaction in water. The reagent has been extensively used as a bleaching agent for
industrial and domestic water.21 Recently Zou et al. have reported the use of DCDMH for selective
preparation of α-mono and α,α-dichloro ketones.22 We have undertaken to study its synthetic utility for
Hofmann reaction in the present work. Following the standard procedure for gabapentin lactam 4, using
DCDMH, 4 was obtained in only 55% yield with HPLC purity >99%. N-Chlorosuccinimide (NCS) has
been widely used as electrophilic chlorinating agent in organic synthesis.23 NCS in water was used for
the synthesis of pregabalin.24 In our hands, use of NCS for the Hofmann reaction of 2 afforded 4 in 46%
yield (Scheme 2).
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Scheme 2 Hofmann reaction using TCCA, NaDCC, DCDMH and NCS in water
The quality of gabapentin lactam 4 is critical for the purity of derived gabapentin. HPLC data of
lactam 4 obtained from these processes are listed in Table 1. Typical minor unknown impurities seen
are at 0.74, 0.84 and 0.94 RRT and pleasingly, the levels are near nonsignificant. To the best of our
knowledge there is no report available thus far in the literature for the use of TCCA, NaDCC, DCDMH
and NCS to make gabapentin lactam in water and with high purity.
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Table 1. HPLC purity of gabapentin lactam (4)
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Entry Source
HPLC
Single
Unknown
Purity (%) Impurity (RRT, %)
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9
0.74
0.04
0.84
0.02
0.94
0.09
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Example 1 99.75
(via N-
chloro
derivative)
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Example 2 98.40
Example 3 99.50
Example 4 99.43
0.05 0.02
ND*
ND*
ND*
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ND*
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Example 5 98.00
0.22
0.13
ND*
*ND: Not detected
Gabapentin lactam 4 obtained from monoamide 2 and trichloroisocyanuric acid in methanol through
the N-chloroamide 3 was converted to gabapentin 1 by following the procedure reported by us in a
patent25 (Scheme 3, Table 2). 1 was obtained in 79.5% overall yield from 4, with more than 99.5%
purity and a single unknown impurity <0.05%, matching well with samples obtained by a commercial
process using NaOBr for the Hofmann Reaction and was superior to 1 made using NaOCl for the
conversion of 4.26
Scheme 3 Gabapentin lactam (4) to gabapentin (1)
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Table 2. HPLC purity of gabapentin (1) obtained from gabapentin lactam (4)
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Entry Source
HPLC
Single
Unknown
Purity (%) Impurity (%, RRT)
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1
99.46
obtained
0.0244 (3.7 RRT)
0.0094 (0.85 RRT)
0.0107 (0.89 RRT)
1
from
example
gabapentin
lactam
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CONCLUSIONS
In conclusion, we have developed novel methodologies for the preparation of gabapentin lactam (4) in
good yield using chlorinating agents such as trichloroisocyanuric acid, sodium dichloroisocyanurate,
1,3-dichloro-5,5-dimethylhydantoin and N-chlorosuccinimide. Recoverability of the precursors,
recycling and use of water as solvent make these routes particularly attractive from an environmental
point of view. The potential of these reagents for Hofmann Reaction in water with other amides is under
study.
EXPERIMENTAL SECTION
General Information: Reactions were monitored by TLC on silica plates using Iodine chamber for
1
visualization. H NMR and 13C NMR spectra were recorded in CDCl3 solvent on 300 MHz NMR
spectrometer using TMS as internal reference. Chemical shifts δ and coupling constants J are given in
ppm (parts per million) and Hz (hertz) respectively. Chemical shifts are reported relative to residual
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13
1
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solvent as an internal standard for H and C (CDCl3 δ 7.26 ppm for H and δ 77.0 ppm for C). The
following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, and br = broad. HPLC analyses were performed with Atlantis T-13 column (150
x 4.6 x 3u). Mobile phase:50:50/0.05% formic acid in water:methanol. Column temperature was
programmed at 40 °C, with detector wavelength 210 nm. Flow rate was 0.6 mL/min and injection
volume was 20 μL. Purity is given as area%. Melting points were recorded on a Veego melting point
apparatus and are uncorrected. FT-IR spectrum was recorded using a FTLA 2000 spectrometer. TCCA,
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NaDCC, DCDMH, NCS, sodium hydroxide, sulphuric acid, hydrochloric acid, toluene, methanol and
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3
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isopropyl alcohol were of commercial grade and used as such. All compounds are characterized by H
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NMR and 13C NMR. All known compounds data are in consistent with the given literature reports.
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Experimental Procedures
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Example 1: Preparation of gabapentin lactam 4 using N-chloroamide 3
(a) Preparation of N-chloroamide 3 from monoamide 2 in methanol: A suspension of monoamide 2 (100
g, 0.5025 mol) in methanol (6 V, 600 mL) was heated to 45 - 50 °C and stirred for 0.5 h, when a clear
solution resulted. The solution was cooled to 20 - 25 °C, and then treated with TCCA (38.47 g, 0.166
mol) in three portions over a period of 45 min under stirring. Reaction mass became turbid during the
course of the addition and was stirred for 1 h until TLC showed the disappearance of the starting
material 2. The reaction mixture was then filtered off. The solid obtained was cyanuric acid which was
recovered quantitatively. The filtrate was evaporated in vacuo to dryness using a rotovap at 50 °C to get
3 in quantitative yield as a solid. The product was completely characterized by IR, NMR and mass
spectral analysis. Melting point: 109 – 111 °C ; IR (ν, cm-1 ): 3186, 2932, 2854, 1702, 1663, 1453,
1
1397, 1322, 1242, 1191, 1075, 968, 797, 678, 628; H NMR (CDCl3, 300 MHz): δ 12.00 (s, 1H, -
COOH), 9.96 (s, 1H, -CONHCl), 2.43 (s, 2H, -CH2COOH), 2.39 (s, 2H, -CH2CONHCl), 1.52-1.27
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(unresolved multiplet, 10 H, cyclohexyl group); C NMR (CDCl3, 75 MHz), δ 172.9 (-COOH), 169.3
(-CONHCl), 40.7 (-CH2COOH), 40.3 (-CH2CONHCl), 35.1, 35.0, 25.5, 20.9 ppm (cyclohexyl group);
HRMS [M+Na]+ for C10H16ClNO3Na calcd, 256.0711; found, 256.07.
Cyanuric acid which was filtered off was washed with methanol to remove impurities (recovery 100%)
and converted to the trichloro derivative by a known procedure27 and reused for a fresh reaction.
(b) Preparation of 4 from 3: 750 g of 12% sodium hydroxide solution [4.5 equivalents of NaOH with
respect to 2 in (a)] was cooled to 0 - 5 °C and treated with 3 (117.3 g, 0.5025 mol) by adding in three
portions over a period of 1 h at the same temperature. Reaction was continued at 0 - 5 °C for more 2 h.
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Then temperature of the reaction mass was increased to 15 - 20 °C under continued stirring for two
more hours. The temperature was now raised to 50 °C and toluene (2 V, 200 mL) charged in one lot.
Then the reaction mass temperature was raised to 80 °C and maintained for 8 h. After 8 h of stirring at
80 °C, the temperature was decreased to 50 °C and the toluene layer separated. The aqueous layer was
extracted with further amounts of toluene (1 V, 100 mL) and the toluene layer separated. The combined
toluene layers were washed with 30% brine (100 mL). The toluene solution was evaporated to dryness
completely using a rotary evaporator under reduced pressure to get gabapentin lactam 4 (69.2 g, 90%)
as a solid with HPLC purity >99%. The product was identical to standard lactam 4.10 Melting point: 89
– 90 °C (reported: 90 – 91 °C); 1H NMR (CDCl3, 300 MHz): δ 6.05 (bs, 1H, -NH), 3.15 (s, 2H, -CH2-
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NH-), 2.18 (s, 2H, -CH2CO-), 1.67-1.31 (unresolved m, 10H, cyclohexyl group), C NMR (CDCl3, 75
MHz), δ 178.4 (-NHCO-), 53.8 (-CH2NH), 43.3 (-CH2CO-), 39.2, 36.7, 25.6, 22.8 (cyclohexyl group).
Example 2
Preparation of 4 from 2 using TCCA in water:
Monoamide 2 (100 g, 0.5025 mol) and 12% NaOH solution (750 g, 4.4 equivalents of NaOH with
respect to 2) were stirred together for 30 min at 25-30 °C. The resulting solution was added to a stirred
mixture of TCCA (38.47, 0.165 mol) and 150 mL water (1.5 V) at 0 - 5 °C during 1 h. Then the reaction
mixture was stirred for another 2 h at 0 – 5 °C. The temperature of the reaction mixture was slowly
raised to 15 - 20 °C and maintained for 2 h. Then the reaction mass temperature was increased to 50 °C
and toluene (2 V, 200 mL) was charged. The temperature was further raised to 80 °C and maintained for
8 h. The reaction mass was cooled to 50 °C and the toluene layer separated from the aqueous layer.
Further work up as in example 1 gave 4 (57.6 g, 75%) with HPLC purity >98%.
The aqueous solution having a pH of 14 was acidified to pH 2 with 70% H2SO4. The precipitated
cyanuric acid was washed with methanol to remove impurities (recovery 80%) and converted to the
TCCA by a known procedure27 and reused.
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Example 3
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Preparation of 4 using NaDCC:
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To a solution of NaDCC (60.8 g, 0.276 mol) in 150 mL water (150 mL, 1.5 V with respect to 2) at 0 - 5
°C was added a solution of 2 (100 g, 0.5025 mol) in 12% NaOH (750 g) at 0 – 5 °C. The reaction was
conducted further as in example 2 to yield 4 (65.3 g, 85%) with HPLC purity of 99%.
The aqueous alkaline layer was acidified to pH 2 and the precipitated cyanuric acid filtered off and
washed with methanol. The recovered cyanuric cid (80%) was converted to the NaDCC by a known
procedure27 and reused.
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Example 4
Preparation of 4 using DCDMH:
Hofmann Reaction was conducted on monoamide 2 (100 g) dissolved in 12% sodium hydroxide (750
g) and DCDMH (54.4 g) in water (150 mL) as usual. The solution was heated as before in toluene. 4
was isolated as in example 2 to yield 4 (42.3 g, 55%) with HPLC purity >99%.
Recovery of byproduct dimethylhydantoin was not done because of its high solubility in methanol
unlike cyanuric acid.
Example 5
Preparation of 4 using NCS:
Monoamide 2 (100 g in 750 g of 12% sodium hydroxide) was reacted with NCS (73.51 g) in water (150
mL) as usual and the solution processed as earlier in toluene. Evaporation of toluene layer gave 4 (35.7
g, 46%) with HPLC purity >98%.
Recovery of byproduct succinimide was not done because of its high solubility in methanol unlike
cyanuric acid.
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ACKNOWLEDGMENTS
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The authors thank Hikal Ltd management for providing necessary facilities. JVPK is thankful to Dr. R.
Sridharan for discussion on this project. Special thanks are extended to the Analytical Department of
Hikal Ltd. for providing analytical support.
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SUPPORTING INFORMATION
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Characterization (1H, 13C NMR and HRMS) for compounds 3 & 4 and HPLC chromatograms for
compounds 4 & 1 (PDF).
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26. In our hands, quality of gabapentin obtained using NaOCl did not match with samples obtained
by a commercial process using NaOBr for the Hofmann Reaction.
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