Organic Process Research & Development 2007, 11, 268−269
Technical Notes
An Improved Synthesis of Memantine Hydrochloride: Anti-Alzheimer’s Drug†
Jambula Mukunda Reddy,‡ Ganji Prasad,‡ Veeramalla Raju,‡ Mylavarapu Ravikumar,‡ Vurumidi Himabindu,§ and
Ghanta Mahesh Reddy*,‡
Department of Research and DeVelopment, Dr. Reddy’s Laboratories Ltd., Integrated Product DeVelopment, Unit-III, Plot
No. 116, S.V. Co-Op. Industrial Estate, Bollaram, Jinnaram, Medak District 502 325, A.P., India, and Institute of Science
and Technology, Center for EnVironmental Science, J. N. T. UniVersity, Kukatpally, Hyderabad 500 072, India
Abstract:
formation produces the memantine hydrochloride 1 (Scheme
1).4 This procedure results in relatively low yield and for
large scale has an additional safety concern of a step run at
high temperature (200-250 °C). Several other syntheses of
1 have been reported which are either too long or contain
unacceptable operations and are therefore less suitable for
large-scale synthesis.
An economical new process route has been developed for the
large-scale synthesis of memantine hydrochloride (1) an anti-
Alzheimer’s drug. The procedure involves the conversion of 1,3-
dimethyl adamantane (2) to formamide intermediate 8 as a key
step, followed by hydrolysis to (1-amino-3,5-dimethyl adaman-
tane) hydrochloride (1) in good yield.
Results and Discussion
Introduction
In this report 8 is identified as a suitable intermediate to
prepare 1 via bromination of 1,3-dimethyl-adamantane 2 in
aqueous medium to afford 3,5-dimethyl-adamantan-1-ol (6),
which on treatment with aq HCl gives 1-chloro-3,5-dimethyl-
adamantane (7). Conversion of 7 to N-(3,5-dimethyl-ada-
mantan-1-yl)-formamide (8) is a key step in the synthesis
of 1.
In summary, Scheme 2 represents a safe, economically
competitive synthesis of 1, which may be obtained from 2
in four steps with an overall yield of 55% using inexpensive,
commercially available, raw materials and reagents. To the
best of our knowledge, this protocol is economically
advantageous over the earlier reported synthesis owing to
high yields and the use of less expensive raw materials.
Alzheimer’s disease is a progressive brain disorder that
gradually destroys a person’s memory. Alzheimer’s is the
most common form of dementia, a group of conditions that
gradually destroy brain cells and lead to progressive decline
in mental function. Compounds such as Donepezil, Galan-
thamine, Rivastigmine, and Memantine have dual acetyl-
choline esterase inhibitory and monoamine oxidase inhibitory
activities; therefore, they are expected to have potential
activity for the treatment of Alzheimer’s disease and other
neurodegenerative disorders.1 (1-Amino-3,5-dimethyl ada-
mantane)hydrochloride (1) is one of a small group of tricyclic
antiviral drugs (TAV).2 It also provides good and persistent
activation of central nervous N-methyl-D-aspartate (NMDA)
receptors and thus can be used in the treatment of Parkinson’s
and Alzheimers diseases. Memantine was approved by FDA
in 2003 for Alzheimer’s treatment.
Experimental Section
The 1H NMR spectra were measured in CDCl3 using 200
MHz on a Varian Gemini FT NMR spectrometer; the
chemical shifts are reported in δ ppm relative to TMS. The
FT-IR spectra were recorded in the solid state as KBr
dispersion using a Perkin-Elmer 1650 FT-IR spectropho-
tometer. The mass spectrum (70 eV) was recorded on HP-
5989A LC/MS spectrometer. The CHN analysis was carried
out on a Perkin-Elmer model 2400S analyzer. The solvents
and reagents were used without further purification.
3,5-Dimethyl-adamantan-1-ol (6). Bromine (390.0 mL,
7.31 mol) was slowly added to 1,3-dimethyl-adamantane (2,
250.0 g, 1.52 mol) for 10-15 min, and the reaction mass
was maintained at reflux temperature for 4-5 h, then cooled
to room temperature, and diethyl ether (100.0 mL) was added
Several groups have reported3 the synthesis of 1 with an
overall low yield, whereby bromination of 1,3-dimethyl-
adamantane (2), yields 1-bromo-3,5-dimethyl-adamantane
(3). Conversion of 3 to N-(3,5-dimethyl-adamantan-1-yl)-
acetamide (4) in the presence of sulfuric acid in acetonitrile,
and treatment of 4 at reflux conditions followed by salt
† Dr. Reddy’s Communication #-IPDO-IPM-00043.
* Corresponding author. E-mail: reddyghanta@yahoo.com. Telephone: +
91 9849250324. Fax: +91 40 2373 1955.
‡ Dr. Reddy’s Laboratories Ltd.
§ J. N. T. University.
(1) (a) Altman, H. J. Alzheimer’s Disease Problems, Prospects and Prospec-
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Prog. Brain Res. 1993, 98, 413-420.
(2) (a) Reicova, N.; Pazourek, J.; Polaskova, P.; Havel, J. Electrophoresis. 2002,
23(2), 259-262. (b) Suckow, R. F. J. Chromatogr., B 2001, 764, 313-
325.
(3) (a) Sasaki, T.; Eguchi, S.; Katada, T.; Hiroaki, O. J. Org. Chem. 1977, 42,
3741-3743. (b) Kovacic, P.; Roskos, P. D. J. Am. Chem. Soc. 1969, 91,
6457-6460.
(4) (a) Mills, J.; Krumkalns, E. U.S. Patent 3,391,142, 1968. (b) Gerzon, K.;
Krumkalns, E. V.; Brindle, R. L.; Marshall, F. J.; Root, M. A. J. Med.
Chem. 1963, 6, 760-763. (c) Scherin, A.; Homburg, B.; Peteri, D.;
Markobel, H. U.S. Patent 4,122,193, 1978.
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Vol. 11, No. 2, 2007 / Organic Process Research & Development
10.1021/op060246+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/15/2007
Reddy, Jambula Mukunda
