4
B. D. VU ET AL.
Memantine hydrochloride (1) from N-formyl-1-amino-3,5-dimethyl-
adamantane (3)
A mixture of water (44 mL), 36% HCl (48 mL) and N-formyl-1-amino-3,5-dimethylada-
mantane (12.65 g, 0.060 mol) was stirred for 10 min, and then heated to reflux for 1 h.
The reaction mixture was concentrated to half volume, then to this reaction mass n-
hexane (20 mL) was added, and the reaction mixture was heated to reflux for 0.5 h. The
ꢀ
reaction mass was cooled to 5-10 C for 1 h, the white solid was separated, filtered and
washed with cold ethyl acetate to obtain a white solid, which was further recrystallized
from a mixture of methanol and ethyl acetate, then dried under vacuum to give
ꢀ
Memantine hydrochloride (1) (10.94 g; 84.65%), which did not melt up to 300 C.
ꢁ
1
Purity (GC-MS) 99.93%. IR (KBr), (cm ): 3441 (N-H); 2943, 2901 (CH); 1364,38 (C-
þ
1
N); MS, m/z: 180.17 [M-HCl þ 1] . H-NMR (500 MHz, CDCl ), d (ppm): 8.34 (s, 3H,
3
NH HCl); 2.20 (m, 1H, C -H); 1.89 (s, 2H); 1.74 (d, J ¼ 11.5, 2H); 1.68 (d, J ¼ 11.5,
2
ꢂ
7
2
H); 1.42 (d, J ¼ 12.5, 2H); 1.31 (d, J ¼ 12.5 2H); 1.22 (d, J ¼ 12.5Hz, 1H,); 1.16 (d,
13
J ¼ 12.5Hz, 1H); 0.86 (s, 6H, 2CH ). C-NMR (125 MHz, CDCl ), d (ppm): 54.4 (C );
3
3
1
4
9.8 (2C, C and C ); 46.4 (C ); 41.8 (2C, C and C ); 39.2 (C ); 32.6 (C and C ); 29.8
2 9 4 6 10 7 3 5
(
C ); 29.6 (2C, C and C12).
8 11
Memantine hydrochloride (1) from 1,3-dimethyladamantane (2)
ꢀ
At 20-25 C, 1,3-dimethyladamantane (222.5 mL, 197.1 g, 1.2 mol) was slowly added to
9
6% sulfuric acid (600 mL, 1098 g; 10.8 mol) over 0.5 h. Then over 0.5 h, 65% HNO3
(56 mL, 77.2 g; 0.8 mol) was added to this reaction mixture. The suspension was main-
tained for 6 h, then formamide (128 mL, 144 g; 3.2 mol) was slowly added over 1 h. After
ꢀ
that, the mixture was heated to 30-35 C for 3 h. After the reaction was finished, which
ꢀ
was indicated by TLC (as above), the reaction mass was cooled to 0-5 C and added to
ice-cold water (800 mL). Then the reaction mixture was extracted with dichloromethane
(1600 mL). The separated organic layer was treated with an ammonia solution to pH 8-
9
and then with chilled water. The organic layer was dried over Na SO , filtered, and
2
4
then the solvent was evaporated to dryness in vacuum to give N-formyl-1-amino-3,5-
dimethyladamantane as an oil. To this oil, a solution of 5 N HCl (1800 mL) was added
and stirred for 10 min, then heated to reflux for 1 h. The reaction mixture was concen-
trated to half volume. To this reaction mass n-hexane (300 mL) was added, the reaction
ꢀ
mixture was heated to reflux for 0.5 h. The reaction mass was cooled to 5-10 C for 1 h;
the white solid was separated, filtered, and washed with cold ethyl acetate and dried
under vacuum to give Memantine hydrochloride (1) (219.61 g, 84.87%) which did not
ꢀ
melt up to 300 C. The product has met United States Pharmacopoeia standard USP 38
with checklist number 1219/KNT-17 of the Preventive Medical Center, Hanoi
Department of Health.
Acknowledgments
This research was financially supported by the Drug R&D Center, Vietnam Military
Medical University.