ChemicalBook CAS DataBase List Memantine HCl

Memantine HCl synthesis

12synthesis methods

Product Name:Memantine HCl
CAS Number:41100-52-1
Molecular formula:C12H22ClN
Molecular Weight:215.76

Memantine (XV) or 1-amino- 3,5-dimethyladamantane hydrochloride was first synthesized by Lilly as an anti-diabetic agent but was ineffective in lowering blood sugar. Several syntheses have been detailed in the literature. However the simplest synthesis of the drug was done in one step from the commercially available 3,5-dimethyl adamantine (122). Treatment of 122 with nitrogen trichloride (CAUTION: very explosive gas!) in the presence of aluminum trichloride (ratio of 1.5:1.2) gave the desired amino adamantine in 86% yield. However, a much safer alternative has been reported by Lilly scientists. Heating the commercially available 3,5-dimethyladamantane 122 in bromine gave the bromo derivative 123 (86%) which was then reacted with sulfuric acid in acetonitrile to provide quantitatively acetyl amino derivative 124 after aqueous workup. Hydrolysis of the acetyl group was done by heating 124 with sodium hydroxide in diethylene glycol to give 1-amino -3,5- adamantane (96%), which was then made into the hydrochloride salt in ether and recrystallized from ether and alcohol mixture to provide the final product memantine hydrochoride XV.

19982-07-1
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$14.00/250mg

41100-52-1
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$14.00/1g

Yield:41100-52-1 99.3%

Reaction Conditions:

Stage #1: 1-acetamido-3,5-dimethyladamantanewith sodium hydroxide in diethylene glycol; for 6 h;Reflux;
Stage #2: with water in dichloromethane;diethylene glycol at 20; for 0.25 h;
Stage #3: with hydrogenchloride in ethyl acetate at 0 - 30; for 6 h;

Steps:

2

l-Acetamido-3,5-dimethyladamantane (44 gm) as obtained in example 1, sodium hydroxide and diethylene glycol are added, and heated to reflux. Then, the contents were maintained for 6 hours at reflux and water (1 175 ml) was added under stirring. The reaction mass was cooled to below 20 C and then added methylene chloride (750 ml), and stirred for 15 minutes at 20°C. The layers were separated and the organic layer was distilled off completely under vacuum at below 45°C to obtain a residue. The residue was dissolved in ethyl acetate (700 ml). Ethyl acetate hydrochloride (160 ml) was added to the reaction mass and stirred for 5 hours at 25 to 30°C. The reaction mass was cooled to 0 to 5°C and stirred for 1 hour at 0 to 5 °C. The separated solid was filtered and dried at 50°C for 2 hours to obtain 87 gm of memantine hydrochloride containing l-amino-3,5,7-trimethyladamantane hydrochloride and l-amino-3-methyladamantane hydrochloride impurity.Memantine hydrochloride: 99.3%;The combined contents of l-amino-3,5,7-trimethyladamantane hydrochloride and 1- amino-3-methyladamantane hydrochloride impurity: 0.5%.

References:

WO2011/125062,2011,A1 Location in patent:Page/Page column 8-9

941-37-7 Synthesis