Rivastigmine preparation suitable for industrial production

A compound and methylation technology, which is applied in the preparation of organic compounds, chemical instruments and methods, and the preparation of carbamic acid derivatives, etc., can solve the problems of large loss, low yield, no synthetic routes and examples, and achieve pollution Small size, easy access to raw materials, and easy operation

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

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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-((

Method used

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  • Rivastigmine preparation suitable for industrial production
  • Rivastigmine preparation suitable for industrial production
  • Rivastigmine preparation suitable for industrial production

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Preparation of 3-((S)-1-((S)-1-phenethylamino) ethyl) phenylethyl (methyl) carbamate (compound 1)

[0035] 10g (0.05mol) of (S)-1-phenethylamine, 5.5g (0.05mol) of (S)-1-phenethylamine, 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 (4) 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 yield of 92% and a purity of 98%.

Embodiment 2

[0036] Embodiment 2: Preparation of (S)-3-(1-aminoethyl) phenylethyl (methyl) carbamate (compound 2)

[0037] Add 10g (0.03mol) of compound (1) and 100ml of methanol into the reactor, add 0.5g of 10% palladium carbon, stir and pass hydrogen, react at 65°C and 15atm for 8 hours, TLC monitors that compound (1) has reacted completely, and cools Suction filtration, the mother liquor was spin-dried at 40°C, added 100ml of 10% potassium carbonate solution and stirred at room temperature for 1 hour, extracted with 50ml of ethyl acetate x 4 times, combined the ethyl acetate layers, washed with 50ml of saturated brine x 3 times, no After drying with sodium sulfate, the product was filtered and spin-dried to obtain 6.7 g of a yellow clear liquid with a yield of 98.5%.

Embodiment 3

[0039] Add 10 g (0.03 mol) of compound (1) and 100 ml of methanol into the reactor, add 1 g of 10% palladium carbon, stir and pass hydrogen, and react for 96 hours at 35 ° C and 2 atm. TLC monitors that the compound (1) has reacted completely. Filter, spin dry the mother liquor at 40°C, add 100ml of 10% potassium carbonate solution and stir at room temperature for 1 hour, extract with 50ml of ethyl acetate x 4 times, combine ethyl acetate layers, wash with saturated brine 50ml x 3 times, anhydrous After drying over sodium sulfate, suction filtration and spin-drying gave 5.8 g of yellow clear liquid with a yield of 85.0%.

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Abstract

The invention belongs to the technical field of a method for preparing Rivastigmine. In the preparation method for the Rivastigmine which is suitable for industrial production, catalytic hydrogenation is carried out on 3-((S)-1-((S)-1-phenethylamine group) ethide) phenylethyl (methyl) carbamate to remove phenylethane group and methylation reaction is carried out to obtain the Rivastigmine. The synthetic route in the invention is the shortest among the current routes of asymmetric synthesis of Rivastigmine, so that huge losses caused by disconnecting route later can be avoided, the problem of deprotection of hydroxide radical caused by first disconnecting route later and then forming ester can be avoided by forming ester first and pollution is lessened. 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
Inventor 袁哲东王强沈裕辉俞雄
Owner SHANGHAI INST OF PHARMA IND
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