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Synthetic method of N-rimantadine

A technique for the synthesis of methylamantadine, which is applied to the preparation of amino compounds, chemical instruments and methods, purification/separation of amino compounds, etc., and can solve problems such as unstable imines and difficulty in separation

Inactive Publication Date: 2013-03-13
ZHEJIANG NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0008] It is generally believed that primary amines condense with aldehydes or ketones to form imines, which are unstable and difficult to separate

Method used

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  • Synthetic method of N-rimantadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Put 2g of amantadine hydrochloride raw material into a 50ml round-bottomed flask, add 20mL of ethanol, add 5mL of 37% formaldehyde aqueous solution dropwise for about 5 minutes, and stir magnetically at room temperature. After the addition of formaldehyde, 6M NaOH solution was added dropwise to adjust the pH=10. After 40 minutes, a sample was taken from the reaction system and extracted with water and ethyl acetate. The reaction yield was 85% according to GC analysis. The methyleneation reaction is substantially complete. The yield of the continued reaction does not change much, and the system has reached a dynamic equilibrium.

[0025] Pour the reaction solution into 30mL of ice water, separate it with a separatory funnel, wash the imine with a 33% ethanol aqueous solution at 0-5°C, after washing, add 10mL of ethanol to dissolve the imine, weigh 0.5g of sodium borohydride and add 5mL of water was dissolved, and the reduction reaction was carried out in an ice-water ba...

Embodiment 2

[0028] Add 2g of amantadine hydrochloride raw material into a 50mL round bottom flask, add 20mL of ethanol, add dropwise 7.5mL of 37% formaldehyde aqueous solution in about 5 minutes, and stir magnetically at room temperature. 40 minutes after the addition of formaldehyde, the reaction system was sampled, alkali was added to adjust the pH, the sample was extracted with ethyl acetate and analyzed by GC, and the reaction yield was 55%. The possible reason is that amantadine forms a salt, which reduces the reactivity of nucleophilic addition.

[0029] The reaction product was separated with a separatory funnel, and the obtained imine was washed with 33% ethanol solution at 0-5° C. after washing, the imine was dissolved in 10 mL of ethanol, and 0.5 g of sodium borohydride was weighed and dissolved in 5 mL of water. Under the reduction reaction. After 30 minutes of reaction, a sample was extracted with ethyl acetate and injected into GC for analysis. The content of the by-product ...

Embodiment 3

[0031] Put 2g of newly prepared amantadine raw material into a 50mL round bottom flask, add 20mL of ethanol, add dropwise 7.5mL of 37% formaldehyde aqueous solution in about 5 minutes, and stir magnetically at room temperature. 40 minutes after the addition of formaldehyde was completed, the reaction system was sampled, alkali was added to adjust the pH, the sample was extracted with ethyl acetate and analyzed by GC, and the reaction yield was 85%. The possible reason is the high reactivity of free amantadine. However, amantadine is easy to form carbonate in the air, which affects the normal progress of the reaction.

[0032] The reaction product was separated with a separatory funnel, and the obtained imine was washed with 33% ethanol solution at 0-5° C. after washing, the imine was dissolved in 10 mL of ethanol, and 0.5 g of sodium borohydride was weighed and dissolved in 5 mL of water. Under the reduction reaction. After 30 minutes of reaction, a sample was extracted with...

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Abstract

The present invention discloses a synthetic method of N-rimantadine. Adamantanamine hydrochloride or admantadine is dissolved in water and / or water-soluble organic solvent, and then, formalin is added to make methylenation reaction; after the methylenation reaction is end, generated admantadine amine-methylene are dissolved into the ater-soluble organic solvent after being extracted, separated and washed, and sodium borohydride is added to make reduction reaction to obtain a N- rimantadine crude product by separation after the reduction reaction; and the N- rimantadine crude product is purified. A synthetic method of organic compound replaced by single methyl of hydrogen on admantadine with high selection and high generation rate is obtained by the reaction provided by the present invention. The reaction conditions are worm, and a noble metal catalyst and a tetrahydro lithium aluminum reducing agent are avoided to use.

Description

technical field [0001] The invention relates to a synthesis method of N-methylamantadine, which belongs to the field of chemical synthesis. Background technique [0002] Amantadine (amantadine) is a symmetrical tricyclodecanylamine. In the early 1960s, it was discovered that amantadine had an inhibitory effect on type A influenza virus. In 1966, the United States approved amantadine for influenza virus subtype H2N2. Influenza prevention. Afterwards, compounds with similar structures, such as amantadine and 1,3-dimethylamantadine, have been used clinically in different areas around the world. It is also suitable for primary Parkinson's disease, Parkinson's syndrome after encephalitis, Parkinson's syndrome after carbon monoxide poisoning, and Parkinson's syndrome with cerebral arteriosclerosis in the elderly. In recent years, people have carried out further research on amantadine and other derivatives from biological activity to synthesis method. Therefore, it is of practic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C211/38C07C209/52C07C209/86
Inventor 胡晓春孔黎春
Owner ZHEJIANG NORMAL UNIVERSITY
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