Asymmetric synthesis method of (S)-rivastigmine

A synthetic method and asymmetric technology, applied in the field of chiral drug synthesis, can solve the problems of no rivastigmine and other problems, and achieve the effects of easy availability of raw materials, cost reduction, and mild reaction conditions

Inactive Publication Date: 2008-03-05
JINAN UNIVERSITY
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  • Asymmetric synthesis method of (S)-rivastigmine

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Embodiment 1

[0039] (1) Synthesis of 3-methoxybenzaldehyde (3)

[0040] In a 250ml three-necked flask, add 3-hydroxybenzaldehyde (6.10g, 50mmol) and 15ml of methanol solution, heat to about 65°C under magnetic stirring, and dropwise add dimethyl sulfate (7.41ml, 75mmol) and potassium hydroxide Solution (KOH (5.04 g, 90 mmol), 8 ml water). Continue to stir the reaction for 24h after the addition, stop the reaction, and cool to room temperature. Extracted with ethyl acetate (15ml×3), dried over anhydrous sodium sulfate, rotary evaporated to dryness, and column chromatography gave 3-methoxybenzaldehyde (3) (5.76g, yield: 84.1%) as a yellow oil.

[0041] (2) Synthesis of (R, E)-3-methoxy-benzylidene tert-butylsulfonamide (4)

[0042] Under nitrogen protection, weigh tert-butylsulfinamide (2.40g, 20mmol) and anhydrous copper sulfate (7.00g, 44mmol), put tert-butylsulfinamide into a 100ml three-necked bottle, add 30ml dichloro Methane, anhydrous copper sulfate was added under magnetic stirrin...

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Abstract

The present invention is asymmetrical (S)-carbalatine synthesizing process including the following steps: protecting the phenolic hydroxyl group of m-hydroxy benzaldehyde, reacting with chiral tert-butyl sulfonamide to produce (R, E)-3-methoxyl-phenyl methylene tert-butyl sulfonamide, addition reacting with methyl Grignard reagent, hydrolyzing, Eschweiler-Clarke methylation reaction, demethylating BBr3 to synthesize important intermediate (S)-1-(3-hydroxy phenyl)-N, N-dimethyl ethyl amine, and esterification with methyl ethyl carbamyl chloride to obtain (S)-carbalatine. The present invention has less reaction steps, high yield, total yield up to 21.85 %, and low cost.

Description

technical field [0001] The invention belongs to the technical field of chiral drug synthesis, in particular to a method for synthesizing optically pure (S)-rivastigmine, specifically an asymmetric synthesis method of (S)-rivastigmine. Background technique [0002] Rivastigmine (Rivastigmine) is a new type of anti-senile dementia drug, because rivastigmine is a compound containing a chiral carbon, with (R)- and (S)-two enantiomers. (S)-Rivastigmine is its active ingredient. There are two types of synthesis methods: 1) racemic resolution; 2) asymmetric synthesis. The existing synthetic methods are mostly synthesized by racemic resolution. Representative documents include: "Preparation and use of phenylcarbamate cholinergic agonists as central nervous agents" (Albert, E.DE3805744, 1988); "Tartrate Synthesis of Rivastigmine" (Jiang Yongwen, Hua Zhengmao, Xie Lihua, Princeisaac K.A. Yang Liping. Journal of East China Normal University, 2001, 1, 61-65); "Process for preparing(-...

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Application Information

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IPC IPC(8): C07C271/44C07C269/00
Inventor 陈卫民文富华
Owner JINAN UNIVERSITY
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