Method for preparing solifenacin intermediate

A technology for solifenacin and intermediates, which is applied in the field of preparation of solifenacin intermediates, can solve the problems of unfavorable industrial production, harsh equipment requirements, and viscous reaction system, etc., and achieve easy industrial production, less waste, and less reaction The effect of mild conditions

Active Publication Date: 2016-05-04
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] These routes all use compound I, and the preparation methods of compound I involved use highly toxic and highly corrosive substances such as polyphosphoric acid / phosphorus pentoxide / phosphorus oxychloride, which require harsh equipment and the reaction The system is viscous, which is not conducive to industrial production; a large amount of strong acid waste gas and waste water are produced during the reaction process and post-treatment process, which seriously pollutes the environment

Method used

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  • Method for preparing solifenacin intermediate
  • Method for preparing solifenacin intermediate
  • Method for preparing solifenacin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Preparation of compound III: Add 26.1g of 2-bromobenzophenone into the reaction flask, then add 130.5ml of ethylene glycol and 0.5g of methanesulfonic acid, heat to 50°C for reaction, after the reaction is completed, add anhydrous sodium sulfate After drying, it was filtered and concentrated under reduced pressure to obtain compound III. 29.8g, yield 97.7%.

[0051] Preparation of Compound IV: Dissolve 30.5g of Compound III in 300ml of tetrahydrofuran, lower the temperature of the low-temperature circulation tank to -55±5°C, add 42.0ml of n-butyllithium (2.5mol / L) dropwise, and then add DMF8.0g dropwise under temperature control , after the completion of the reaction, adjust the acidity of the system with 0.1 mol / L dilute hydrochloric acid to pH = 7 under control < 0°C, and precipitate a solid, filter it with suction, and dry it with air blast to obtain compound IV. 19.8g, yield 77.9%.

[0052] The preparation of compound V: mix 25.4g of compound IV, 254.0ml of methan...

Embodiment 2

[0059] Preparation of compound III: Add 26.1g of 2-bromobenzophenone into the reaction flask, then add 130.5ml of ethylene glycol and 0.5g of methanesulfonic acid, heat to 60°C for reaction, after the reaction is completed, add anhydrous sodium sulfate After drying, it was filtered and concentrated under reduced pressure to obtain compound III. 29.6 g, yield 97.2%.

[0060] Preparation of Compound IV: Dissolve 15.3g of Compound III in 150ml of tetrahydrofuran, cool down to -55±5°C in a low-temperature circulation tank, add 21.0ml of n-butyllithium (2.5mol / L) dropwise, and then add DMF4.0g dropwise under temperature control , after the reaction was completed, adjust the acidity of the system with 0.1 mol / L dilute hydrochloric acid to pH = 8 under control < 0°C, and a solid precipitated, filtered with suction, and was blown-dried to obtain compound IV. 9.8g, yield 77.5%.

[0061] Preparation of Compound V: Mix 25.4g of Compound IV, 254.0ml of methanol, and 6.7g of nitromethane...

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Abstract

The invention belongs to the field of medicine and particularly relates to a method for preparing a solifenacin intermediate. After 2-halogenated diphenyl ketone is used for carbonyl protection, n-butyllithium is used for removing bromine, then the formyl group is added; a condensation reaction with nitromethane and catalytic hydrogenation for reduction are carried out, and then acidification is conducted; later, cyclization is carried out, and a solifenacin intermediate compound I is obtained through alkaline hydrolysis after reduction and chiral resolution. The structural formula of the solifenacin intermediate is shown in the description. According to the method for preparing the solifenacin intermediate, the initial raw materials easy to obtain are utilized, and the production cost is reduced. The process route is advanced, the reaction conditions are mild, the reaction yield is high, less three wastes are caused, expensive and toxic reagents do not exist, reaction solvents can be used repeatedly after distillation, industrial production is facilitated, and implementation value and social, economic and environmental protection benefits are high.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of a solifenacin intermediate. Background technique [0002] Solifenacin, developed by Astellas, Japan, is a new generation of highly selective M-receptor blocker. Compared with similar drugs, it has the highest selectivity to the bladder, so it has stronger curative effect and fewer side effects such as dry mouth. [0003] At present, the relevant patents and literature reports on the synthesis of solifenacin mainly include the following three routes: [0004] Route 1 (using different condensing agents R-OCO 2 -R or OR replaced by acid chloride) [0005] [0006] Route 2 (using different condensing agents R-OCO 2 -R or OR replaced by acid chloride) [0007] [0008] Route three (using different condensing agents R-OCO 2 -R or OR replaced by acid chloride) [0009] [0010] The patents mainly include CN1045601C, CN201210348560.7, WO201108600...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/02
CPCC07D217/02
Inventor 孙滨赵承彪马庆双王晓光
Owner SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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