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CHAPTER-5

SYNTHESIS AND CHARACTERIZATION OF

MEMANTINE HYDROCHLORIDE

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5.1 INTRODUCTION

Memantine hydrochloride 1 (Namenda) is a novel class of anti-

Alzheimer’s drugs and chemically known as 1-amino–3,5-dimethyl

adamantane, which is also active towards glutamatergic system. According

to the new medical guidance, Memantine is recommended to use for

people with moderate to severe AD. Memantine can also be used for the

treatment of Alzheimer’s disease as well as Parkinson’s disease.

Memantine acts as NMDA receptors by blocking the NMDA (N-methyl-D-

aspartate) receptors in the brain cells. Blocks the excess actively of

glutamate, but allow the normal activity of the NMDA receptors, which

happen when the brain forms a memory. Therefore, Memantine henhance

the improvement of the brain functioning in AD patients. It is available in

the market as 5mg and 10mg capsule shaped film – coated. Memantine

was approved by FDA in 2003 for Alzheimer’s treatment.

Memantine Hydrochloride’s innovator is Forest Laboratories, Inc.-

HQ and appears world-wide under the brand name Namenda.

Alzheimer’s disease is a progressive brain disorder that gradually

destroys a person’s memory. Compounds such as Donepezil,

Galanthamine, Rivastigmine, and Memantine have dual acetylcholine

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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

5.2 PREVIOUS APPROACHES

First we explain the current synthetic approaches towards the

synthesis of Memantine hydrochloride. A few reports have been disclosed

for the synthesis of this molecule.

Several routes have been reported2,3 for the synthesis of 1 with an

overall low yield. Mills et al, reported the synthesis from compound 2

wherein bromination of 1,3-dimethyladamantane 2 with bromine in

acetonitrile provided 1-bromo-3,5-dimethyl-adamantane 3. Conversion of

3 to N-(3,5-dimethyl-adamantan-1-yl)- acetamide 4 was achieved by using

of sulfuric acid in acetonitrile, and treatment of 4 at reflux conditions in

diethylene glycon followed by salt formation produces the memantine

hydrochloride 1 (Scheme-5.1).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).

The process involves bromination of 1,3-dimethyl adamantane 2

with bromine at reflux temperature to yield 1-bromo-3,5-dimethyl

adamantane 3b, which is furthur reacted with 17 moles of acetinitrile and

35 moles of conc.sulphuric acid at ambient temperature to furnish 1-

acetamido-3,5-dimethyl adamantane 4. Alkaline hydrolysis of amide 4 in

the presence of basic medium (pH is 13 to 14) in diethylene glycol at reflux

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temperature to provide crude memantine 5 and finally converted into

hydrochloride salt 1 (scheme 5.1).5

Scheme-5.1

In this process 1-bromo-3,5-dimethyl adamantane 3b is reacted

with urea in 80% formic acid at 80°C followed by acid hydsrolysis to yield

crude memantine 5, which is furthur tranformed into memantine HCl salt

1 in ethanolic HCl (scheme 5.2).6

Scheme-5.2

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The process involves lithiation of bromoadamentane 3b with Lithium

metal in ether to yield compound 7, which is furthur reacts with NH2Cl

results crude memantine 5. Finally compound 5 converted into

hydrochloride salt 1 with ethanolic HCl (scheme 5.3).7

Scheme-5.3

In this method, reaction of halo compound 3a/3b with potassium

phthalimide in DMF provided phthalimide derivative 8, which on furthur

hydrolysis results crude Memantine 5. Finally, converted into

hydrochloride salt in IPA.HCl 1 (scheme 5.4).8

Scheme-5.4

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All the reported synthetic approaches are either too long or contain

unacceptable operations and are therefore less suitable for large-scale

synthesis.

5.3 PRESENT WORK

To achieve higher yields and purity, herein we have modified the

synthetic scheme, reagents and the process also optimized. In this report

10 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 9, which on treatment with aq HCl gives 1-chloro-3,5-

dimethyladamantane 3a. Conversion of 3a to N-(3,5-dimethyl-adamantan-

1-yl)-formamide 10 is a key step in the synthesis of 1 (scheme 5.5).9

Scheme-5.5

Synthesis of Memantine hydrochloride started from compound 2,

which upon hydroxylation at tertiary position with bromine in the

presence of water to afford 9 in 95% yield and 99.9% purity (scheme 5.6).

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Scheme-5.6

Mass spectrum of 9 showed the protonated molecular ion at m/z

181 and IR spectrum displayed hydroxy stretching at 3323 cm-1. 1H NMR

displayed two multiplets at δ 2.30-2.10 and 1.50-1.10 for the methylene

protons. Six protons of methyl group appeared at 0.85 confirmed the

structure of alcohol 9.

Chlorination of hydroxy compound 9 with aq. HCl in

dichloromethane for 15h yielded chloro derivative 3a in 80% yield with

99.99% purity (scheme 5.7).

Scheme-5.7

EI-MS showed peaks at m/z 197 (M-H) for chloro compound.

Disappearance of alcohol bands and the presence of absorptions at 2923

and 750 for aliphatic C-C and C-H stretching’s. In the 1H NMR spectrum,

three multiplets at δ 2.35-2.20, 1.95-1.60, and 1.45-1.20 ppm and a

singlet at δ 0.84 ppm are due to aliphatic methylene and methyl protons

respectively. The C-H analysis also supporting the structure of chloro

compound.

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To get the amine functionality in the final molecule, amidation of

chloro derivative was achieved with formamide at 100°C for 8h provided

formyl derivative 10 in 98% yield with 99.85% GC purity (scheme 5.8).

Scheme-5.8

The protonated molecular ion appeared at 208 as the base peak in

the mass spectra. 1H NMR showed a doublet at δ 8.20 corresponding to

formyl proton and singlet at δ 0.84 for two methyl six protons. Aliphatic

protons appeared as multiplets in between at d 1.15–2.15. In the IR

spectrum absorption at 1690 cm-1 for carbamte carbonyl group. The

structure of compound 10 was further confirmed by elemental analysis

data.

Finally, cleavage of formyl group and hydrochloride salt formation

was achieved in a single step with aq. hydrochloride afforded Memantine

hydrochloride in 80% yield (scheme 5.9).

Scheme-5.9

Mass spectrum of compound 1 showed peaks at m/z 216

corresponding to the protonated molecular ion. IR spectrum displayed

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characteristic absorptions at 3450 cm-1 corresponding to amine

functionality stretching. In the 1H NMR spectrum of Memantine

hydrochloride 1 disappearance of formyl proton at δ 8.20 and the presence

of singlets at δ 0.85 due to two methyl groups. Other aliphatic protons

observed at their respective regions confirm the Memantine hydrochloride

structure.

In summary, new synthetic route has been developed with safe,

economically competitive process for the preparation of Memantine

hydrochloride. In which final compound obtained from 2 in four steps with

an overall yield of 55% using inexpensive, commercially available, raw

materials and reagents.

5.4 EXPERIMENTAL

5.4.1 3, 5-Dimethyl-adamantan-1-ol (9)

To 1,3-dimethyl-adamantane 2 (250.0 g, 1.52 mol) was added

bromine (390.0 mL, 7.31 mol) slowly for 10-15 min, and the reaction mass

was maintained at reflux temperature for 4-5 h. The reaction mass was

cooled to room temperature, and diethyl ether (100.0 mL) was added

followed by washing with 15% sodium bisulphate solution (4.0 L). The

separated organic layer was evaporated under vacuum to afford compound

9 as white solid.

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Yield: 260.0 g (95%)

GC purity: 99.99%

1H NMR (DMSO-d6, 200 MHz): δ 4.52 (bs, 1H), 2.30-2.10 (m, 1H), 1.50-

1.10 (m, 12H), 0.82 (s, 6H).

IR (KBr, cm-1): 3323, 2944, 1452, 1185, 1032, 880 (OH).

Mass: m/z 181 (M+ + 1).

Anal. calcd for C12H20O: C 79.94, H 11.18. Found: C 79.83, H 11.11.

5.4.2 1-Chloro-3,5-dimethyl-adamantane (3a)

To a soution of 3,5-dimethyl-adamantan-1-ol 9 (250.0 g, 1.39 mol)

in dichloromethane (2.0 L) was added concentrated hydrochloric acid

(1300.0 mL) at ambient temperature; the resulting mixture was

maintained for 12-15 h. After completion of reaction, organic layer was

seperated and the solvent was evaporated under vacuum to yield

compound 3a as oily liquid.

Yield: 216.6 g (80%)

GC purity: 99.99%.

1H NMR (DMSO-d6, 200 MHz): δ 2.35-2.20 (m, 1H), 1.95-1.60 (m, 6H),

1.45-1.20 (m, 6H), 0.84 (s, 6H).

IR (KBr, cm-1): 2923, 1455, 1324, 1174, 750

Mass: m/z 197 (M - 1)

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Anal. calcd for C12H19Cl: C 72.52, H 9.64. Found: C 72.43, H 9.45.

5.4.3 N-(3,5-Dimethyl-adamantan-1-yl) formamide (10)

A mixture of 1-chloro-3,5-dimethyl-adamantane 3a (100.0 g, 0.50

mol) and formamide (500.0 mL) was heated to 150 °C and maintained for 8

h. Ice-cold water was added and the reaction mass was extracted with

methylene chloride (70.0 mL), the separated organic layer was

concentrated, and compound 10 was isolated as a white solid.

Yield: 101 g (98%)

GC purity: 99.85%.

1H NMR (DMSO-d6, 400 MHz): δ 8.20 (d, 1H), 7.84 (s, 1H), 2.15-2.07 (m,

1H), 1.78 (s, 1H), 1.70-1.22 (s, 9H), 1.15 (s, 2H), 0.84 (s, 6H).

IR (KBr, cm-1): 3347, 3197, 2945, 1690, 1451, 1325, 1034, 794.

Mass: m/z 208 (M+ + 1).

Anal. calcd for C13H21NO: C 75.32, H 10.21, N 6.76. Found: C 75.16, H

10.16, N 6.86.

5.4.4 Memantine Hydrochloride (1)

A mixture of N-(3,5-dimethyl-adamantan-1-yl)formamide 10 (75.0 g,

0.36 mol) and concentrated HCl (750.0 mL) was heated under reflux

temperature (100-105 °C) for 6-7 h. The reaction mass was then cooled

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and stirred for 2 h, and a white solid was separated, filtered, and dried

under vacuum to afford 1.

Yield: 58.0 g (74%)

GC purity: 99.99%.

1H NMR (CD3OD, 300 MHz): δ 2.35-2.20 (m, 1H), 1.75 (s, 2H), 1.60-1.40

(m, 8H), 1.30-1.18 (m, 2H), 0.94 (s, 6H).

13C NMR (CD3OD, 75 MHz): δ 54.4, 50.7, 47.3, 42.7, 39.9, 33.4, 31.1,

30.1

IR (KBr, cm-1): 3350, 3100, 2950, 1450, 1310, 1067, 799.

Mass: m/z 180 (M+ + 1).

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5.5 REFERENCES

1. a) Altman, H. J., Alzheimer’s Disease Problems, Prospects and

Prospecti Ves; Plenium Press: New York, 1987.

b) Durnett, S.B.; Fibiger, H.C., 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., 2001, B 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) Gerzon, K.; Krumkalns, E.V.; Brindle, R.L.; Marshall, F.J.; Root,

M.A., J. Med. Chem. 1963, 6, 760-763.

b) Scherin, A.; Homburg, B.; Peteri, D.; Markobel, H., U.S. Patent

4,122,193, 1978.

5. Mills, J.; Krumkalns, E., US 3391142, 1968.

6. Fuli, Z.; Meng, H.; Lizhi, Z.; Mengya. G., EP 1674446.

7. Kraus, G.A.; Iowa, A., US 5599998.

8. Jaroslav, T.; Marija, M.; Frane, V. WO 2008/040560.