An efficient methodology for the synthesis of 1-(trimethylammoniummethyl) cyclohexaneacetic acid iodide: A trimethylammonium iodide salt of gabapentin

Full text of DOI:10.1080/00304940903523991

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An Efficient Methodology
for the Synthesis of 1-
(Trimethylammoniummethyl)cyclohexaneace
Acid Iodide: A Trimethylammonium
Iodide Salt of Gabapentin
Morshed A. Chowdhury a , Peter A. Smith b & Edward E. Knaus a
a Faculty of Pharmacy and Pharmaceutical Sciences , University of
Alberta , Edmonton, Alberta, Canada
b Department of Pharmacology , University of Alberta , Edmonton,
Alberta, Canada
Published online: 03 Feb 2010.
To cite this article: Morshed A. Chowdhury , Peter A. Smith & Edward E. Knaus (2010) An Efficient
Methodology for the Synthesis of 1-(Trimethylammoniummethyl)cyclohexaneacetic Acid Iodide: A
Trimethylammonium Iodide Salt of Gabapentin, Organic Preparations and Procedures International:
The New Journal for Organic Synthesis, 42:1, 103-106, DOI: 10.1080/00304940903523991
To link to this article: http://dx.doi.org/10.1080/00304940903523991
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Organic Preparations and Procedures International, 42:103–106, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903523991
OPPI BRIEFS
An Efficient Methodology for the Synthesis
of 1-(Trimethylammoniummethyl)cyclohexaneacetic
Acid Iodide: A Trimethylammonium Iodide Salt
of Gabapentin
Morshed A. Chowdhury,1 Peter A. Smith,2 and Edward E. Knaus1
1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta,
Edmonton, Alberta, Canada
2Department of Pharmacology, University of Alberta, Edmonton, Alberta,
Canada
The gabapentinoids pregabalin and gabapentin are structurally related to the inhibitory
neurotransmitter γ -aminobutryic acid (GABA). These two agents, originally introduced as
anticonvulsant (antepileptic) drugs, are now approved and commonly used in the treatment
of neuropathic pain. Neuropathic pain is characteristically resistant to the analgesic actions
of opioids and non-steroidal anti-inflammatory drugs. The accepted mechanism of action
of gabapentinoids is based on their transport into neurons via a non-specific amino acid
transporter where they bind with the alpha 2 delta subunit of voltage gated Ca2+ channels.1,2
It has also been shown that TRPV1 channels, which are present on nociceptive neurons
and are opened by agonists such as capsaicin,3–5 allow the permeation of small organic
molecules such as local anesthetics.6 Accordingly, it is possible that opening of TRPV1
channels may provide a means to deliver gabapentinoids to their intracellular site of action.
This concept may constitute a more effective alternative than reliance on the amino acid
transporter and it may selectively target the gabapentinoids to nociceptive neurons. To test
whether gabapentinoids pass through TRPV1 channels, a charged analog of gabapentin
could be used to replace all Na+ and Ca2+ ions in the extracellular fluid. For this reason, it
was necessary to synthesize a quaternary salt of gabapentin 1. We now describe an efficient
methodology for the synthesis of 1-(trimethylammoniummethyl)cyclohexaneacetic acid
iodide (2) using a four-step reaction sequence free of time consuming chromatography in
81% overall isolated yield starting from gabapentin (see structures in Scheme 1).
Submitted September 10, 2009
Address correspondence to Edward E. Knaus, Faculty of Pharmacy and Pharmaceutical Sciences,
University of Alberta, Edmonton, Alberta, Canada T6G 2N8. E-mail: eknaus@pharmacy.ualberta.ca
103

104
Chowdhury, Smith, and Knaus
MeI, MeOH
KHCO3
HCHO, H2
10% Pd/C
CO2H
NMe3
CO2H
4a, MeI
CO2H
R
2
MeOH
or
X
NH2
Me2SO4
NaOH
2 (X = I)
3 (X = MeSO4)
1
4a, R = NMe2 (98%)
HCl, MeOH
4b, R = NMe2.HCl (95%)
i) 4a, AcCl, MeOH
ii) NaHCO3
CO2Me
NMe3 I
CO2Me
HI
MeI
2 (100%)
Me2CO
NMe2
6 (95%)
5 (87%)
Scheme 1
The synthetic strategy used for the synthesis of (1-(trimethylammoniummethyl)-
cyclohexaneacetic acid iodide (2) is illustrated in Scheme 1. N-quaternization of the amino
group present in gabapentin 1 was initially investigated using methods reported to be
successful for the N-methylation of GABA. For instance, treatment of gabapentin 1
with either methyl iodide and potassium bicarbonate,7 or dimethyl sulphate and sodium
hydroxide,8 did not furnish the respective trimethylammonium salt 2 or 3, presumably due
to the low basicity of the amino group. 1-(Dimethylaminomethyl)cyclohexaneacetic acid
(4a) was subsequently prepared via reductive alkylation of 1 with aqueous formaldehyde
in the presence of 10% Pd/C and H2 gas at 15 psi to increase the basicity of the amino
group.8 However, reaction of 4a with methyl iodide5 to produce the trimethylammonium
salt 2 did not proceed. The failure of this reaction is attributed to the likelihood that the
aminoacid 4a exists as a non-reactive zwitterionic species. The amino acid 4a was converted
to its hydrochloride salt 4b, that was used for analytical characterization, upon treatment
with HCl.9 To circumvent the non-reactivity of 4a, the carboxylic group was esterified
by treatment with acetyl chloride in MeOH10 to afford methyl 1-(dimethylaminomethyl)-
cyclohexaneacetate hydrochloride which on treatment with NaHCO3 furnished the free base
methyl 1-(dimethylaminomethyl)cyclohexaneacetate (5). The subsequent N-methylation of
5 with methyl iodide using acetone as solvent, rather than MeOH,8 proceeded efficiently
to give methyl 1-(trimethylammoniummethyl)cyclohexaneacetate iodide (6). Subsequent
deprotection of the methyl ester group in 6 using aqueous hydriodic acid furnished the
target product 1-(trimethylammoniummethyl)cyclohexaneacetic acid iodide (2).
Experimental Section
Melting points were determined on a Thomas-Hoover capillary apparatus and are uncor-
rected. 1H NMR spectra were measured on a Bruker AM-300 spectrometer. Microanalyses
(MicroAnalytical Service Laboratory, Department of Chemistry, University of Alberta)
were performed for C, H and N and were within 0.3% of theoretical values for all
elements listed. 1-(Aminomethyl)cyclohexaneacetic acid (1, gabapentin) was purchased
from TCI America. All other reagents, purchased from the Aldrich Chemical Company
(Milwaukee, WI), were used without further purification.

1-(Trimethylammoniummethyl)cyclohexaneacetic Acid Iodide
105
1-(Dimethylaminomethyl)cyclohexaneacetic Acid (4a) and 1-(Dimethylaminomethyl)-
cyclohexaneacetic Acid Hydrochloride (4b)
To a solution of 1-(aminomethyl)-cyclohexaneacetic acid (1, 15.0 g, 87.7 mmol) in methanol
(900 mL) was added 37% aqueous formaldehyde (15 mL, 185.0 mmol) and 10% Pd/C
(1.73 g). The reaction mixture was stirred at 25◦C under H2 gas (15 psi) for 5 h, the
catalyst was removed by filtration through celite, and the filtrate was concentrated in vacuo
to dryness. The residue was recrystallized from a mixture of acetone-hexanes to furnish
1
4a (17.11 g, 98%) as colorless needle shaped crystals, mp 88–90◦C; H NMR (D2O): δ
1.20–1.55 (m, 10H, cyclohexyl H-2, H-3, H-4, H-5, H-6), 2.52 (s, 2H, CH2CO2H), 2.82 (s,
6H, NMe2), 3.05 (s, 2H, CH2NMe2).
For compound characterization, a solution of concentrated HCl was added dropwise
to a solution of 4a (200 mg, 1 mmol) in methanol (5 mL) with stirring at 25◦C until
the pH was about 2. The resulting mixture was concentrated in vacuo to dryness and the
residue was recrystallized from a mixture of acetone-hexanes to afford 4b (225 mg, 95%)
1
as a white solid, mp 139–141◦ (lit.9 140–142◦C); H NMR (CD3OD): δ 1.35–1.55 (m,
10H, cyclohexyl H-2, H-3, H-4, H-5, H-6), 2.68 (s, 2H, CH2CO2H), 2.99 (s, 6H, NMe2),
3.26–3.35 (m, 2H, CH2NMe2). This 1H NMR spectral data is in agreement with literature
data.9
Methyl 1-(Dimethylaminomethyl)cyclohexaneacetate (5)
Acetyl chloride (8.8 mL, 123.9 mmol) was added to a solution of 4a (18.0 g, 90.45 mmol)
in methanol (200 mL) at 0◦C and the reaction mixture was stirred at 60◦C for 16 h. The
mixture was then concentrated in vacuo to dryness to yield the hydrochloride salt of 5 to
which a solution of saturated aqueous NaHCO3 (200 mL) was added. The solution was
extracted with EtOAc (3 × 300 mL), the combined EtOAc extracts were successively
washed with water and brine, and the organic fraction was dried (MgSO4). Filtration and
then removal of the solvent in vacuo from the organic fraction afforded 5 as a colorless
1
liquid (16.34 g, 87%), bp 130◦C (1.5 mm Hg); H NMR (D2O): δ 1.20–1.55 (m, 10H,
cyclohexyl H-2, H-3, H-4, H-5, H-6), 2.64 (s, 2H, CH2CO2Me), 2.95 (s, 6H, NMe2), 3.28
(s, 2H, CH2NMe2), 3.69 (s, 3H, CO2Me).
Anal. Calcd for C12H23NO2: C, 67.57; H, 10.87; N, 6.57. Found C, 67.75; H, 10.70;
N, 6.61.
Methyl 1-(Trimethylammoniummethyl)cyclohexaneacetate Iodide (6)
Methyl iodide (23.50 mL, 375.6 mmol) was added to a solution of 5 (16.0 g, 75.1 mmol)
in acetone (25 mL) and the reaction mixture was stirred at 25◦C for 16 h. During this time
a white solid formed which was filtered off, the white solid was washed several times with
diethyl ether, and the solid was dried in vacuo to yield 6 as a white solid (25.46 g, 95%),
1
mp 105–107◦C; H NMR (D2O): δ 1.20–1.70 (m, 10H, cyclohexyl H-2, H-3, H-4, H-5,
H-6), 2.82 (s, 2H, CH2CO2Me), 3.22 (s, 9H, N+Me3I−), 3.50 (s, 2H, CH2N+Me3I−), 3.69
(s, 3H, CO2Me).
Anal. Calcd for C13H26INO2: C, 43.95; H, 7.38; N, 3.94. Found C, 43.77; H, 7.55; N,
3.90.

106
Chowdhury, Smith, and Knaus
1-(Trimethylammoniummethyl)cyclohexaneacetic Acid Iodide (2)
Aqueous hydriodic acid (30 mL of 37% w/v) was added to 6 (15.0 g, 42.2 mmol) and
the reaction mixture was refluxed for 2 h. The mixture was then concentrated in vacuo to
dryness to furnish a reddish solid which upon recrystallion from acetone-hexanes afforded
2 as white crystals, (14.41 g, 100%), mp 160–162◦C; 1H NMR (DMSO-d6): δ 1.15–1.75
(m, 10H, cyclohexyl H-2, H-3, H-4, H-5, H-6), 2.68 (s, 2H, CH2CO2H), 3.18 (s, 9H,
N+Me3I−), 3.49 (s, 2H, CH2N+Me3I−), 12.48 (s, 1H, CO2H that exchanges with D2O).
Anal. Calcd for C12H24INO2: C, 42.24; H, 7.09; N, 4.10. Found: C, 42.39; H, 7.31; N,
4.10.
Acknowledgements
We are grateful to the Canadian Institutes of Health Research (Grant No. MOP-14712) for
financial support of this research, and to Dr. Terry Snutch from the University of British
Columbia who gave us our first few grams of gabapentin.
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