Solifenacin succinate raw medicine synthesis process

Abstract

The invention discloses a solifenacin succinate raw medicine synthesis process. 2-phenylethylamine and 3-quinuclidinone hydrochloride are respectively used as starting raw materials for synthesizing afragment A and a fragment B; then, condensation reaction occurs to generate solifenacin; through salt formation, the solifenacin succinate is obtained. The process is characterized in that straight-chain paraffin and water are used as reaction solvents; alkali metal hydroxides or carbonate and bicarbonates of the alkali metal hydroxides are used as acid-binding agents; phenylethylamine and benzoyl chloride take acylation reaction to generate midbodies 1 of solid precipitation fragments A insoluble in reaction solvents; in the post treatment process, filtering is directly performed; isomers ofthe fragment A are subjected to catalytic racemization through alkali metal hydroxides by using dimethylsulfoxide as a solvent, so that the byproduct isomers can be recovered and utilized; in the second-step reaction post treatment of the fragment B, a conventional pressure reduced distillation method is used for obtaining high-purity and high-yield 3-acetoxyquinine acetate. The invention provides a novel synthesis process with the advantages of high yield and economic and environment-friendly effects, and is suitable for industrial mass production.

Description

technical field [0001] The invention relates to a new raw material drug synthesis process of solifenacin succinate, and belongs to the technical field of drug synthesis. Background technique [0002] Solifenacin succinate (solifenacin succinate, see structural formula I), chemical name (3R)-1-azabicyclo[2.2.2]octan-3-yl(1S)-1-phenyl-3, 4-Dihydroisoquinoline-2-(1H)-carboxylate succinate, trade name Vesicare, is a selective muscarinic M3 receptor antagonist developed by Japan Astellas (Chinese translation name: Yamanouchi) company, 2004 In August 2008, it was launched in the Netherlands, Germany, the United Kingdom, France and Denmark for the first time. It was approved by the FDA in 2005 to be marketed in the United States and in China in 2009. It is clinically used for the treatment of overactive bladder with symptoms of urgency and frequency. This product can selectively relax the detrusor muscle of the bladder and reduce the systemic adverse reactions of previous antichol...

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Problems solved by technology

[0012] In the second step acetylation post-processing method of Fragment B, the presence of excess acetic anhydride in the reaction will affect the yield and crystallization speed of the next step of salt-forming resolution process, so most of the references and patents are neutralized by adding alkali. Solvent extraction is used to obtain the acetylated product. As a result, it is found that because the acetylated product has better water solubility, repeated extractions are required, the operation is cumbersome, a large amount of organic solvent is wasted, and the yield is low, such as US5387409, Synth Commun., 1992, 22( 13): 1895-1911 and J. Labelled. Comp. Radiopharm., 1989, 27(9): 983-993

In the master's thesis of Zhejiang University of Technology "Research on the racemization process of 1-substituted dihydroindene and 3-substituted quinuclidine", although it is proposed to use vacuum distillation to remove excess acetic anhydride, the actual effect of using toluene to bring out acetic anhydride is not Unsatisfactory, because there is no azeotropic relationship between the two, and residual toluene will affect the next step of salt formation and resolution, affecting the optical purity of the final product Fragment B

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