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Synthesis process of rivastigmine hydrogen tartrate

A technology of rivastigmine bitartrate and synthesis process, which is applied in the field of medicine, can solve the problems of low yield of rivastigmine bitartrate and the like, and achieves the effects of controllable product quality, strong controllability and stable reaction

Active Publication Date: 2014-10-01
SICHUAN XINSIDUN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to solve the technical problem of low yield of rivastigmine bitartrate in industrialized production, the present invention provides a synthesis process of rivastigmine bitartrate

Method used

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  • Synthesis process of rivastigmine hydrogen tartrate
  • Synthesis process of rivastigmine hydrogen tartrate
  • Synthesis process of rivastigmine hydrogen tartrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] A kind of synthetic technology of rivastigmine hydrotartrate, processing step is as follows:

[0038] A, the synthesis of racemic rivastigmine

[0039] Add tetrahydrofuran and 3-(1-(dimethylamino)ethyl)phenol into the reaction kettle, stir until clear, cool to 20°C, add sodium hydride in batches, cool to 10°C, dropwise add N-ethyl- N-methylcarbamoyl chloride, stirred and reacted at 30°C for 16 hours, and post-treated to obtain racemic rivastigmine;

[0040] B. Resolution of racemic rivastigmine

[0041] Add racemic rivastigmine, D-(+)-p-methyldibenzoyl tartaric acid and methanol solution into the reaction kettle, stir, heat to reflux until the solution is clear, stop heating, cool to 10°C, stir and crystallize , filtered, and dried to obtain a white solid; recrystallize the resulting white solid with methanol solution, filter, and dry to obtain the DTTA salt of rivastigmine, dissolve the DTTA salt in water, add aqueous sodium hydroxide to adjust the pH value, and add di...

Embodiment 2

[0047] A kind of synthetic technology of rivastigmine hydrotartrate, processing step is as follows:

[0048] A. Synthesis of racemic rivastigmine (Ⅱ)

[0049] Add tetrahydrofuran and 3-(1-(dimethylamino)ethyl)phenol (I) into the reaction kettle, stir until clear, cool to 0°C, add sodium hydride in batches, cool to 0°C, drop N- Ethyl-N-methylcarbamoyl chloride, stirred and reacted at 20°C for 24 hours, and post-treated to obtain racemic rivastigmine (II);

[0050]

[0051] B. Resolution of racemic rivastigmine (Ⅱ)

[0052] Add racemic rivastigmine (II), D-(+)-p-methyldibenzoyltartaric acid (D-(+)DTTA) and methanol solution into the reaction kettle, stir and heat to reflux until the solution is clear , stop heating, cool to 0°C, stir to crystallize, filter, and dry to obtain a white solid; recrystallize the obtained white solid with methanol solution, filter, and dry to obtain the DTTA salt (Ⅲ) of rivastigmine, and the DTTA salt ( Ⅲ) Dissolve in water, add sodium hydroxide...

Embodiment 3

[0062] A kind of synthetic technology of rivastigmine hydrotartrate, processing step is as follows:

[0063] A, the synthesis of racemic rivastigmine

[0064] Add tetrahydrofuran and 3-(1-(dimethylamino)ethyl)phenol into the reaction kettle, stir until clear, cool to 10°C, add sodium hydride in batches, cool to 5°C, dropwise add N-ethyl- N-methylcarbamoyl chloride, stirred and reacted at 25°C for 20 hours, and post-treated to obtain racemic rivastigmine;

[0065] B. Resolution of racemic rivastigmine

[0066] Add racemic rivastigmine, D-(+)-p-methyldibenzoyl tartaric acid and methanol solution into the reaction kettle, stir, heat to reflux until the solution is clear, stop heating, cool to 5°C, stir and crystallize , filtered, and dried to obtain a white solid; recrystallize the resulting white solid with methanol solution, filter, and dry to obtain the DTTA salt of rivastigmine, dissolve the DTTA salt in water, add aqueous sodium hydroxide to adjust the pH value, and add di...

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Abstract

The invention aims to solve the technical problem that during industrial production, the yield of rivastigmine hydrogen tartrate is low, and provides a synthesis process of rivastigmine hydrogen tartrate. A racemized raw material is adopted to firstly synthesize racemized rivastigmine, and then direct separation is performed to obtain an optically pure S-shaped isomer, so that racemization in the reaction process is effectively avoided, the optical purity is controllable, and further the product quality is controllable. Through simplified process flow, the optimal reaction solvent, reaction time and reaction temperature can be discovered via exploration, and the method for preparing rivastigmine hydrogen tartrate, which is high in yield, low in cost and simple to operate, has easily accessible raw materials and is suitable for being realized in industrial production, is found.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a synthesis process of an anti-senile dementia drug rivastigmine bitartrate. Background technique [0002] Rivastigmine Hydrogen Tartrate—(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-carbamate phenyl ester, hydrogen-(2R, 3R) - common name for tartaric acid, whose structural formula is [0003] [0004] Rivastigmine bitartrate can be used to treat mild and moderate Alzheimer's dementia. Alzheimer's Disease (Alzheimer's Disease) is a progressive degenerative disease of the central nervous system, which mostly occurs in the elderly over 60 years old. Its clinical manifestations are short-term memory dysfunction first, followed by persistent mental decline, loss of judgment and reasoning ability, aphasia, and movement disorders. The main pathological features are brain atrophy, formation of senile plaques and cerebrovascular deposits in brain tissue, and neurofi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/44C07C269/06C07C269/08C07C59/255C07C51/41C07C51/43
Inventor 庄惠祥杜丰蔡孙均
Owner SICHUAN XINSIDUN PHARMA
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