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Method for preparing rivastigmine

A technology of reagents and compounds, which is applied in the field of preparation of rivastigmine for the treatment of Alzheimer's disease, can solve the problems of poor chemical stability, difficult industrialization, and difficult operation, and achieve the application value of large-scale industrial production, short synthetic route, and easy production low cost effect

Active Publication Date: 2011-07-27
SHANGHAI JINGXIN BIOLOGICAL MEDICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] But there are some defectives in above-mentioned method, as: take methylethylamine as starting raw material, there is operational purification difficulty; Some use poisonous and harmful or harsh raw materials (such as phosgene, triphosgene, dimethyl sulfate, methyl iodide etc.) , bringing environmental protection and labor protection problems; and the preparation method of methylethylcarbamoyl chloride is difficult to operate, has poor chemical stability, extremely low yield, and is difficult to industrialize, etc.

Method used

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  • Method for preparing rivastigmine
  • Method for preparing rivastigmine
  • Method for preparing rivastigmine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] R 1 Be the preparation of the formula II compound (N-methyl O-methyl carbamate) of methyl

[0052] Slowly add 9.25 g of the compound of formula IV into 20 ml of anhydrous methanol previously cooled to 0-5°C with an ice-water bath, continue stirring for 0.5 hours after the addition, remove the ice-water bath, continue stirring at 25°C for 0.5 hours, evaporate The solvent was washed with water, and dried under vacuum at 120°C for 5 hours to obtain 7.0 g of the title product, yield: 80%.

[0053] h 1 NMR (CD3OD): 2.90-2.91 (d, 3H); 3.67 (s, 3H);

Embodiment 2

[0055] R 1 Be the preparation of the formula II compound (N-methyl O-methyl carbamate) of methyl

[0056] 2.53 grams of sodium metal and 20 milliliters of anhydrous methanol were prepared by conventional methods to prepare sodium methoxide, cooled to 0-5 ° C with an ice-water bath, slowly added 9.25 grams of compound of formula IV, continued to stir for 0.5 hours after the addition, removed the ice-water bath, and Continue stirring at 25°C for 0.5 hour, filter, distill off the solvent, wash with water, and dry under vacuum at 120°C for 5 hours to obtain 8.0 g of the title product, yield: 90.9%.

Embodiment 3

[0058] R 1 Be methyl, R is the preparation of the formula II compound (N-methyl O-4-nitrophenylcarbamate) of p-nitrophenyl

[0059] Dissolve 13.9 grams of p-nitrophenol in 50 milliliters of anhydrous tetrahydrofuran, cool in an ice-water bath to 0-5 ° C, add 4.8 grams of 60% sodium hydrogen, continue stirring for 0.5 hours after the addition, under the protection of Ar gas, the compound of formula IV 9.25 g was added slowly, continued to stir overnight, the reactant was poured into 50 g of ice water, and filtered to obtain 1.4 g of the title product in the form of light yellow powder, with a yield of 72%;

[0060] h 1 NMR (CDCl 3 ): 2.91-2.92(d, 3H); 5.08(s, 1H); 7.28-7.31(d, 2H); 8.21-8.24(d, 2H);

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Abstract

The invention discloses a method for preparing rivastigmine serving as an Alzheimer disease treatment medicament. The rivastigmine is used as the Alzheimer disease treatment medicament. The method comprises the following steps of: performing methylation or ethylation on a carbamate compound of a formula II to obtain a compound of a formula III, and performing condensation on the compound of the formula III and (S)-3-(N,N-dimethylaminoethyl) phenol (IV) to obtain the rivastigmine. R is aliphatic hydrocarbon alkyl, aromatic ring, substituted aromatic ring, aromatic heterocycle or substituted aromatic heterocycle; R1 is methyl or ethyl; and R2 is ethyl or methyl. The method has short synthetic route, does not need to use toxic or harmful substances, is easy to operate, reduces the production cost, and has great industrial production application value.

Description

technical field [0001] The invention relates to medicine preparation, in particular to a preparation method of rivastigmine, a drug for treating Alzheimer's disease. Background technique [0002] With the trend of economic development and the aging of human society, the number of drug users and the amount of drugs used for diseases of the elderly population are increasing day by day. Alzheimer's disease, also known as Alzheimer's disease (Alzheimer Disease, referred to as AD), is a degenerative disease of the central nervous system that causes dementia. Neuropathology shows that AD is characterized by neurofibrillary tangles and extracellular neuritic plaques in large areas of cortex and subcortex, or plaques of senile amyloid deposition. Some classic forms of AD show a genetic predisposition, but most cases are sporadic with no known exact cause. AD disease has become a common disease of the elderly, and the prevalence of AD in the elderly over 65 years old is about 5%-15...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/44C07C269/00
Inventor 王光强黄悦黄建勋许维嘉洪赟飞林丽娅赵银芬栾国金
Owner SHANGHAI JINGXIN BIOLOGICAL MEDICAL