Organic Process Research & Development 2007, 11, 922–923
New Synthetic Approach to Memantine Hydrochloride starting from
1,3-Dimethyl-adamantane
Mukesh K. Madhra,* Mukesh Sharma, and C. H. Khanduri
Chemical Research DiVision, Ranbaxy Research Laboratories, Gurgaon, Haryana 122 001, India
Abstract:
solvent, is toxic and poisonous; when heated to 230 °C with
NaOH, it decomposes exothermally to release explosive hy-
drogen gas and also emits acid smoke and irritating fumes.4
Ether was used both as a solvent for acidification of the free
base and its recrystallization.2a,3a However, the use of ethers
can constitute a hazard because of their highly inflammable
nature and tendency to form peroxides. This process is unsafe
for scale-up and environmentally hazardous, along with produc-
ing low yields. Several other syntheses of 1 have been reported
that are either too long or contain unacceptable operations and
are therefore less suitable for large-scale synthesis.3 A recent
reported method for synthesizing 1 through a key formamide
intermediate also uses bromine as the initiating step.5
A short and practical method for the synthesis of 1-amino-3,5-
dimethyl-adamantane (Memantine hydrochloride) was established
by using tertiary butyl alcohol under Ritter conditions to give
1-acetamido-3,5-dimethyl-adamantane. The 1-acetamido-3,5-di-
methyl-adamantane is hydrolyzed using alkali to give free base
which was then converted into its hydrochloride acid.
Introduction
In the field of Alzheimer’s disease, Donepezil, Galanthamine,
Rivastigmine, and Memantine are the most commonly used
APIs. Memantine hydrochloride is an orally active N-methyl
D-aspartate (NMDA) receptor antagonist. There is increasing
evidence that memory loss and dementia in Alzheimer’s disease
are related to malfunctioning of the signals that pass messages
between the nerve cells in the brain. Memantine works by
blocking the NMDA receptors in the brain. This blocks the
excessive activity of glutamate but still allows the normal
activation of these receptors that occurs when the brain forms
a memory. Memantine can therefore improve brain function in
Alzheimer’s disease and also blocks the glutamate activity that
may further damage the brain cells. Memantine is used to treat
moderately severe to severe Alzheimer’s disease.1
An early method for synthesis of Memantine hydrochloride
(1) discloses a process in which 1,3-dimethyl-adamantane (2)
is brominated to give 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 (Ritter
reaction)2a,4,5 and treatment of 4 in diethylene glycol (DEG) at
reflux conditions (245–250 °C) followed by salt formation
produces Memantine hydrochloride 1 (Scheme 1).2 This pro-
cedure has several disadvantages. The bromination is carried
out under reflux, which can lead to the emission of toxic
bromine vapour. The tertiary bromide 3 should not be stored
for long periods due to issues with stability.4 DEG, used as
Results and Discussion
In this report, 4 is prepared directly from 1,3-dimethyl-
adamantane (2) in the presence of tert-butyl alcohol, acetonitrile,
and sulphuric acid. The reaction is carried out at 60–65 °C.
Quenching is done by charging slowly the precooled reaction
mass into a biphasic water/water-immiscible organic solvent,
from which the strongly acid aqueous phase is discarded. The
organic phase is washed with water and concentrated under
vacuum to give 4. Compound 4 is hydrolyzed using alkali in
PEG-400 to give in situ 5, which is converted into its
hydrochloride salt 1 using IPA-HCl. Conversion of 2 directly
into 4 is a key step in the synthesis of 1.
In summary, the process described in Scheme 2 has the
advantage of a safe and economically competitive synthesis of
1. This process, with a reduced number of stages, an overall
yield of 75%, and no use of bromine has been easily scaled up
and is thus industrially feasible. 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.
Experimental Section
The solvents and reagents were used as such without further
1
purification. H NMR spectra are recorded in DMSO/CDCl3
* To whom correspondence should be addressed. Tel: (91-124) 4011832. Fax:
(91-124) 4011832. E-mail: mukesh.madhra@ranbaxy.com.
(1) Reisberg, B.; Doody, R.; Stöffler, A.; Schmitt, F.; Ferris, S.; Möbius,
H. J. N. Engl. J. Med. 2003, 14, 1333–41.
using 300 MHz on a Bruker 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 Spectrum One spectrophotometer. The
mass spectrum (70 eV) was recorded on an Applied Biosystem
API-2000 LC/MS/MS spectrometer. Gas chromatography was
carried out with a Hewlett Packard instrument (6890 series or
(2) (a) Mills, J.; Krumkalns, E. Eli Lilly. 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. Merz & Co. U.S. Patent 4,122,193, 1978.
(3) (a) James, G. H.; Jeffrey, T. H.; Gianutsos, G. J. Med. Chem. 1982,
25, 51–56. (b) Kraus, G. A. U.S. Patent 5,599,998, 1997. (c) Klimo-
chkin, Ju. N.; Leonova, M. V.; Timofeeva, A. K. (Tsiklan) RU
2,246,4822002. (d) Klimochkin, Yu. N.; Bagrii, E. I.; Dolgopolova,
T. N.; Moiseev, I. K. Bull. Acad. Sci. USSR, DiV. Chem. Sci. 1988, 37,
757–759. (e) Kovacic, P.; Roskos, P. D. J. Am. Chem. Soc. 1969, 91,
6457–6460. (f) Jones, S.; Mellor, J. M. Synthesis 1976, 32.
(4) Periyandi, N.; Kilaru, S.; Thennati, R. WO 05/062724.
(5) Reddy, J. M.; Prasad, G.; Raju, V.; Ravikumar, M.; Himabindu, V.;
Reddy, G. M. Org. Process Res. DeV. 2007, 11, 268–269.
922
•
Vol. 11, No. 5, 2007 / Organic Process Research & Development
10.1021/op700138p CCC: $37.00
2007 American Chemical Society
Published on Web 08/08/2007