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Novel rivastigmine preparation

A compound and methylation technology, applied in the preparation of organic compounds, chemical instruments and methods, preparation of carbamate derivatives, etc., can solve the problems of no synthesis route and examples, low yield, large loss, etc., and achieve pollution. Small, high reaction yield, easy to operate

Inactive Publication Date: 2009-07-15
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Bull.Chem.Soc.Jpn., 66,3414-3418 reports to further prepare rivastigmine after splitting 1-(3-methoxyphenyl)ethylamine with (S) mandelic acid; Simple and easy, but huge loss and low yield
[0010] WO2007104359 reported the asymmetric synthesis of a 3-((S)-1-((S)-1-phenethylamino)ethyl)phenylethyl(methyl)carbamate by ytterbium-type Lewis acid The compound of the general formula points out that the compound of the general formula can be used to prepare rivastigmine, but there are no specific synthetic routes and examples

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Preparation of 3-((S)-1-((S)-1-phenethylamino) ethyl) phenylethyl (methyl) carbamate (compound 1)

[0039] 10g (0.05mol) of 3-acetylphenylethyl (methyl) carbamate (formula 5), ​​5.5g (0.05mol) of (S)-1-phenylethylamine, tetraisotitanate 19g (0.07mol) of propyl ester and 85ml of ethyl acetate were stirred and reacted at 30°C for 2 hours, 0.5g of 10% palladium carbon was added, hydrogen was passed, and the reaction was carried out at 65°C and 15atm for 15 hours, and the reaction of compound (5) was monitored by TLC. Cooling and suction filtration, add 100ml of 1N sodium hydroxide solution to the mother liquor, stir at room temperature for 1 hour, suction filtration, separate layers of the mother liquor, extract the water layer with 50ml of ethyl acetate twice, combine the ethyl acetate layers, and wash with saturated saline 80ml× Washed 3 times, dried with anhydrous sodium sulfate, then sucked and spin-dried to obtain 13.5 g of a yellow clear liquid with a yiel...

Embodiment 2

[0040] Example 2: 3-((S)-1-(methyl((S)-1-phenylethyl)amino)ethyl)phenylethyl(methyl)carbamate (compound 2) preparation

[0041] Put 10g (0.03mol) of compound (1) into the reactor, 1.8g (0.06mol) of paraformaldehyde and 5ml (0.11mol) of 88% formic acid, heat and stir at 95°C for 8 hours, cool, and spin dry at 60°C , add 30ml of 10% sodium hydroxide solution and 30ml of ethyl acetate, stir at room temperature for 0.5 hours, separate the layers, extract the water layer with 30ml of ethyl acetate x 2 times, separate the layers, combine the ethyl acetate layers, and wash with saturated saline 50ml ×Washed twice, dried with anhydrous sodium sulfate, then suction filtered and spin-dried to obtain 9.5 g of light yellow clear liquid with a yield of 91%.

Embodiment 3

[0042] Example 3: 3-((S)-1-(methyl((S)-1-phenylethyl)amino)ethyl)phenylethyl(methyl)carbamate (Compound 2) preparation

[0043] Put into the reactor 10g (0.03mol) of compound (1), 1.8g (0.06mol) of paraformaldehyde and 5ml (0.11mol) of 88% formic acid, heat and stir at 45°C for 42 hours, spin dry at 60°C, add 30ml of 10% sodium hydroxide solution and 30ml of ethyl acetate, stirred at room temperature for 0.5 hours, separated into layers, extracted the water layer with 30ml of ethyl acetate x 2 times, separated into layers, combined the ethyl acetate layers, and washed with saturated saline 50ml x 2 Washed for three times, dried with anhydrous sodium sulfate, and then sucked and spin-dried to obtain 8.6 g of light yellow clear liquid with a yield of 82%.

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Abstract

The invention belongs to the technical field of a method for preparing Rivastigmine, comprising the following steps: methylation reaction is carried out on 3-((S)-1-((S)-1-phenethylamine group) ethide) phenyl-ethyl (methyl) carbamate, then catalytic hydrogenation is carried out to remove phenylethane group and the methylation is carried out again to obtain the Rivastigmine. By adopting the synthetic route in the method, huge losses caused by disconnecting route later can be avoided, the problem of deprotection of hydroxide radical caused by first disconnecting route and then forming ester is avoided by forming ester first and pollution is lessened. The obtained final product has high purity and simple post-treatment. In every step of the method, reaction yield is relatively high, raw material is accessible, no special equipment is needed, operation is simple and convenient, pollution is little and integrated cost is low, therefore, the method is suitable for domestic industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of rivastigmine. Background technique [0002] Rivastigmine bitartrate is a second-generation selective central, reversible, long-acting non-competitive inhibitor of acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) developed by Novartis. It is suitable for treating mild and moderate Alzheimer's dementia (AD), and can be used for treating mild and moderate Parkinson's dementia. It has a more significant curative effect on patients with advanced severe AD, and is currently internationally recognized and the highest-rated drug for improving symptoms of Alzheimer's dementia. With the aging of the global population, the number of patients with senile dementia is also increasing rapidly. The market for this drug is huge. However, due to the high production cost of this drug, the final market price is high, which increases the economic burden of long-term use by elderly patients....

Claims

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Application Information

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IPC IPC(8): C07C271/44C07C269/06
CPCY02P20/55
Inventor 袁哲东王强沈裕辉俞雄
Owner SHANGHAI INST OF PHARMA IND
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