Synthesis of memantine hydrochloride

A technology of memantine hydrochloride and concentrated hydrochloric acid, which is applied in the field of memantine hydrochloride, can solve the problems of long reaction time, complicated post-treatment, severe heat release, etc., and achieve the effects of low production cost, shortened reaction time, and lowered reaction temperature

Inactive Publication Date: 2013-02-27
陕西方舟制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In method 5, bromodimethyladamantane is used to react with nitriles, concentrated sulfuric acid and organic acids. The reaction time is long, the exotherm is severe, and reddish-brown gas is released, the toxicity is high, and the post-treatment is more complicated

Method used

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  • Synthesis of memantine hydrochloride
  • Synthesis of memantine hydrochloride
  • Synthesis of memantine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] First, buy 1-chloro-3,5-dimethyladamantane on the market (require its GC≥98%. The appearance is colorless or light yellow liquid) or use self-made 1-chloro-3,5-dimethyl Adantane; the applicant uses self-made 1-chloro-3,5-dimethyladamantane, and its self-made method is as follows:

[0041] Preparation of 1-Hydroxy-3,5-Dimethyladamantane

[0042] Take 250g (1.52mol) of 1,3-dimethyladamantane in a three-necked flask, connect the drying pipe and exhaust gas absorption device, add 390mL (7.31mol) of bromine water dropwise at room temperature (the dropwise addition is completed in about 10-15 minutes), drop After completion, the mixture was heated to 90°C and refluxed for 5 h, cooled to room temperature, extracted by adding 100 mL of ether, washed with 4 L of 15% sodium bisulfite, separated the organic layer, dried over anhydrous sodium sulfate, concentrated to obtain a white solid, washed with petroleum ether , and dried to give 1-hydroxy-3,5-dimethyladamantane (260 g) in p...

Embodiment 2

[0048] Mix (10g, 0.05mol) 1-chloro-3,5-dimethyladamantane and (51mL, 1.30mol) formamide, heat to 150°C for 8 hours, cool to room temperature, add 30ml of ice water at 0°C , 70 mL of chloroform, extracted, separated the organic phase, and dried over anhydrous sodium sulfate. Concentration gave a white solid, which was dried under vacuum at 35°C to give 1-carboxamido-3,5-dimethyladamantane (9.9 g). Yield 95%, purity (99.7% GC). Continue to add it to 80mL concentrated hydrochloric acid, heat to reflux at 100°C for 7h, cool the reaction solution, stir at room temperature for 2h, a white solid is produced, filter with suction, and dry under vacuum at 50°C to obtain memantine hydrochloride (8.3g) with purity (99.8% GC) The total yield is 76.5%.

[0049] The difference from Example 1 is that the amount of aminating agent formamide changes, but basically does not affect the product purity and yield.

Embodiment 3

[0051] Mix (20g, 0.10mol) 1-chloro-3,5-dimethyladamantane and formamide (100mL, 2.50mol), heat and react at 150°C for 8 hours, then add 70ml of ice water at 0°C, chloroform 100 mL was extracted, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated to obtain a white solid, and dried under vacuum at 35°C to obtain 1-formamido-3,5-dimethyladamantane (20.2 g). Yield 97.1%, purity (98.9% GC). Add it to 190mL concentrated hydrochloric acid, heat to 100°C and reflux for 7h, cool the reaction solution, stir at room temperature for 2h, a white solid is produced, filter it with suction, and dry it under vacuum at 50°C to obtain memantine hydrochloride (16.8g) with purity (99.85% GC) , a total yield of 77.6%.

[0052] The difference from Example 1 is that the amination reaction conditions remain unchanged, and the hydrolysis of 1-formyl 3,5-dimethyladamantane with concentrated hydrochloric acid becomes 10 times the specific product yield and purity.

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Abstract

The invention relates to a medicine-memantine hydrochloride synthesized from 1-chloro-3,5-dimethyladamantane as an initial raw material. At present, many synthesis methods for preparing memantine hydrochloride, such as urea method, digestive catalytic reduction method, acetamide method and acetonitrile method, have the problems of high bromide / urea reaction temperature, long time, great environmental pollution and the like to different degrees. The invention aims to develop a synthesis technique of the medicine memantine hydrochloride. The technical scheme is as follows: the technique comprises the following steps: by using 1-chloro-3,5-dimethyladamantane as the initial raw material and formamide as an aminating agent, carrying out amination reaction to generate a key intermediate 1-formamido-3,5-dimethyladamantane, hydrolyzing with concentrated hydrochloric acid, salifying, and carrying out vacuum drying to obtain the memantine hydrochloride. The reaction between the formamide and 1-chloro-3,5-dimethyladamantane shortens the reaction time, lowers the reaction temperature, and provides higher product yield and purity (the product yield is higher than 76%, and the purity is higher than 99%).

Description

1. Technical field [0001] The invention relates to a synthesis process of memantine hydrochloride, which specifically refers to memantine hydrochloride synthesized from 1-chloro-3,5-dimethyladamantane as a starting material. 2. Background technology [0002] Alzheimer's disease (Alzheimer's disease, referred to as AD) is one of the common diseases of the elderly, mainly manifested as memory loss and recognition impairment, and is a progressive neurodegenerative disorder. In 2010, there were more than 35 million Alzheimer's patients in the world, and more than 15 million patients in China. The aging of the population increases the number of patients. In 2020, there will be one patient for every 85 people. Currently, there is no drug that can effectively treat Alzheimer's, and the mortality rate is increasing year by year. From 2000 to 2008, death rates from major diseases all declined, with only Alzheimer's mortality rates rising significantly. In 2010, the sales volume in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/38C07C209/62C07C231/08C07C233/03
Inventor 王宇杜小英
Owner 陕西方舟制药有限公司
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