Method for preparing intermediate compound of Rivastigmine and intermediate compound

A technology for compounds and intermediates, which is applied to the preparation of intermediate compounds of rivastigmine and the field of intermediate compounds, can solve the problems of low yield, high cost, and difficulty in applying industrial production.

Active Publication Date: 2012-03-21
CHIRAL QUEST (SUZHOU) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The technical problem to be solved by the present invention is to provide an intermediate compound of rivastigmine in order to overcome the defects of low yield, high cost and difficulty in applying to industrial production in the existing synthetic method of rivastigmine. Preparation method of body compound and a kind of intermediate compound

Method used

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  • Method for preparing intermediate compound of Rivastigmine and intermediate compound
  • Method for preparing intermediate compound of Rivastigmine and intermediate compound
  • Method for preparing intermediate compound of Rivastigmine and intermediate compound

Examples

Experimental program
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Effect test

Embodiment 1

[0076] The preparation of embodiment 1 m-benzyloxyacetophenone (III)

[0077] Put compound (II) 108.8g (0.8mol) into a 1L three-necked flask equipped with a thermometer and a stirrer, DMF 600ml and potassium carbonate 220.8g (1.6mol), and add benzyl chloride 126.6g (1mol) dropwise at room temperature under stirring, and then Heat to 70°C, react overnight, TLC detects that the raw materials have reacted completely, filter after cooling, evaporate the filtrate to dryness under reduced pressure, add 600ml of toluene to dissolve, then wash with saturated brine, dry, and distill under reduced pressure to obtain 164g (HPLC purity 98.4% ). Yield: 91%.

Embodiment 2

[0078] The preparation of embodiment 2 (R)-1-(3-(benzyloxy)phenyl)ethanol (IV)

[0079] Put 2.26g (10mmol) of compound (III) into the hydrogenation kettle, then add 40ml of isopropanol, 0.1ml of 1M potassium tert-butoxide in tert-butanol solution and metal catalyst RuCl under nitrogen atmosphere 2 (s) xylBinap(s)-Daipen (CAS No. 220114-01-2) (50000TON), then add hydrogen, pressure 10bar, react at room temperature for 24 hours. Conversion >99%. After separation and purification, the ee value is 99%, and the HPLC purity is 98.5%.

Embodiment 3

[0080] The preparation of embodiment 3 (R)-1-(3-(benzyloxy)phenyl)ethanol (IV)

[0081] In a 250ml autoclave, 18.08g (80mmol) of compound (III), 60g of isopropanol, 89.6mg (0.8mmol) of potassium tert-butoxide and the chiral metal catalyst RuCl 2 (s) xylBinap(s)-Daipen (TON 5000), then add hydrogen, pressure 50bar, TLC detection of raw material reaction is complete, after vacuum evaporation to dryness 18.4g (HPLC purity 98.5%, ee value 99.9%). Yield: 99.3%.

[0082] 1 H NMR (CDCl 3 , 400M) δ: 1.4(d, 3H); 1.7(d, 1H); 4.8(m, 1H); 5.0(s, 2H); 6.8-7.4(m, 9H).

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Abstract

The invention discloses a method for preparing an intermediate compound VII of Rivastigmine, which is characterized by comprising the step of conducting the reaction of removing a benzyl protection group of hydroxy on a compound VI. The invention also discloses intermediate compounds V and VI of Rivastigmine and hydrochloride of the compound VI. By adopting the preparation method, the product productivity is high, the chemical impurity and optical purity are very high, the cost is low, the postprocessing is simple, and the method can be applicable to industrialization production.

Description

technical field [0001] The present invention specifically relates to a preparation method of an intermediate compound of rivastigmine and the intermediate compound. Background technique [0002] The compound (S)-3-(1-(N,N-dimethylamino)ethyl)phenol is a key intermediate in the synthesis of rivastigmine. Revastigmine has central selective inhibition of cholinesterase activity and can effectively treat Alzheimer's disease. Its tartrate was listed in Switzerland in 1997. The trade name is EXELON, (Formula VIII). [0003] [0004] Formula VIII [0005] Revastigmine contains a chiral carbon atom and has two configurations, R and S. The S configuration is its active ingredient. [0006] According to the existing literature, the synthetic methods of Revastigmine mainly include: [0007] 1. Chiral resolution technology. Use tartaric acid, camphorsulfonic acid, mandelic acid or their derivatives as resolution reagents to perform salt formation, crystallization, and neutrali...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/50C07C213/00C07C43/23C07C41/26C07C69/24C07C69/63C07C67/08C07C67/14C07C303/28C07C309/66C07C309/65C07C309/73B01J31/24B01J31/22C07C271/44C07C269/00
Inventor 吴树林李永超谢银君张伟
Owner CHIRAL QUEST (SUZHOU) CO LTD
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