Method for preparing rivastigmine hydrogen tartrate and application thereof

A technology for rivastigmine bitartrate and its effect is applied in the field of pharmaceutical synthesis, can solve the problems of long reduction amide reaction time, limited industrialized production, troublesome post-processing and the like, and achieves the advantages of low cost, simple and easy-to-obtain reagents, and simple and easy operation. Effect

Inactive Publication Date: 2009-11-18
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this method, expensive lithium aluminum hydride and red aluminum are used, the reaction time required for

Method used

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  • Method for preparing rivastigmine hydrogen tartrate and application thereof
  • Method for preparing rivastigmine hydrogen tartrate and application thereof
  • Method for preparing rivastigmine hydrogen tartrate and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Synthesis of 1-(3-methoxyphenyl)ethanol

[0067] Add 100g (0.66mol) of m-methoxyacetophenone into a 1000mL double-necked flask, then add 400mL methanol and 10mL water to dissolve, add NaBH in batches under stirring 4 12.5 g (0.33 mol). After the reaction is complete, distill off methanol, add 150mL of water to shake, adjust the pH to neutral, then extract three times with ethyl acetate or toluene, combine the organic phases, dry over anhydrous sodium sulfate, distill off the solvent to obtain a colorless viscous oil 100g, yield 99%.

Embodiment 2

[0069] Synthesis of 1-(chloroethyl)-3-methoxybenzene

[0070] Add 100 g (0.65 mol) of 1-(3-methoxyphenyl) ethanol into a 500 mL three-necked bottle, slowly add SOCl dropwise 2 60mL (0.82mol), after the dropwise addition, continue to react at room temperature for 1-2h, the reaction is complete, and a yellow turbid liquid is obtained, and the residual SOCl is removed under reduced pressure 2 Add 150mL of water until no bubbles are generated in the bottle, extract three times with 300mL petroleum ether, combine the extracts, wash once with saturated sodium bicarbonate solution and water, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain a yellow transparent oil 107g, yield 95%.

Embodiment 3

[0072] Synthesis of 1-(3-methoxyphenyl)-N,N-dimethylethylamine

[0073] Dissolve 107 g (0.63 mol) of 1-(chloroethyl)-3-methoxybenzene in 900 mL of acetonitrile, add 77 g (0.94 mol) of dimethylamine hydrochloride and 126 g (1.26 mol) of potassium bicarbonate, and heat slowly. Reflux reaction for 12 hours, turn into a yellow solution, filter, distill off the solvent to obtain a red oil, add 200mL of water, stir to lower the pH to 2, extract twice with 400mL ethyl acetate, adjust the pH of the aqueous layer to 10, and then use 500mL ether Extracted three times, combined the organic layers, washed once with water, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 99.4 g of a light red oily substance with a yield of 88%.

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Abstract

The invention relates to a method for preparing rivastigmine hydrogen and tartrate thereof, which comprises the following steps: taking metamethoxyacetophenone as an initial raw material, and obtaining 1-(3-methoxyphenyl)ethanol by the reduction; then performing the chlorination to obtain 1-(chloroethyl)-3-methoxyphenyl; then reacting the1-(chloroethyl)-3-methoxyphenyl with dimethylamine hydrochloride to obtain 1-(3-methoxyphenyl)-N, N-dimethylethanamine; demethylating the reaction product to obtain 3-[1-(dimethylamino)ethyl]phenol; then performing salt formation resolution with (s)-(+)-camphor-10-sulfonic acid, recrystallizing, and dissociating to obtain (s)-3-[1-(dimethylamino)ethyl]phenol; then taking ethylamine as a raw material to react with ethyl formate to obtain formylethylamine; then reacting the formylethylamine with phosphorus oxychloride to obtain an imine intermediate; reducing the imine intermediate by sodium borohydride to obtain ethyl methyl amine; then reacting the ethyl methyl amine with triphosgene to obtain N-methyl-N-ethylformyl chloride; and finally using (s)-3-[1-dimethylamino)ethyl]phenol to condensate with the N-methyl-N-ethylformyl chloride, and then performing salt formation with levotartaric acid to obtain the rivastigmine hydrogen tartrate. The method has the advantages of easily-obtained raw materials, simple and convenient operation, low cost, high yield and small pollution, and is a brandnew synthesis route at present.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of rivastigmine bitartrate. It also relates to the preparation method of intermediates (s)-3-[1-(dimethylamino)ethyl]phenol, methylethylamine and analogues thereof for preparing rivastigmine bitartrate. Background technique [0002] Rivastigmine (Rivastigmine), chemical name (S)-N-ethyl-3-[(1-dimethylamino)acetyl]-N-methylcarbamate phenyl ester, also known as Esner and Liss , is a carbamate reversible cholinesterase inhibitor, an anti-senile dementia (AD) drug developed by Novartis, Switzerland. Rivastigmine belongs to the third-generation drug for improving the function of the choline system. In addition to inhibiting acetylcholinesterase, it can also inhibit butyrylcholinesterase, exerting dual inhibitory effects, and has a definite and stable curative effect. It went on the market in Switzerland in 1997. In June 2000, my country's State Drug and Food Admini...

Claims

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Application Information

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IPC IPC(8): C07C271/44C07C269/00C07B57/00A61P25/28
Inventor 孙铁民张扬蔡志强祝春燕
Owner SHENYANG PHARMA UNIVERSITY
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