Synthesis method of solifenacin succinate

Abstract

The invention discloses a synthesis method of solifenacin succinate. The synthesis method comprises the following processing steps: (1) respectively dissolving (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, organic alkali and triphosgene into a proper amount of high-boiling-point solvent, dropwise adding the (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and a solution of the organic alkali to the solution of the triphosgene, so as to obtain an intermediate (S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-formyl chloride, and finally adding a proper amount of organic alkali and high-boiling-point solvent, adding (R)-3-quinuclidinol, heating to 100-200 DEG C and carrying out temperature control reaction, so as to prepare solifenacin; and (2) dissolving the solifenacin into a mixed solvent of ethyl acetate and ethyl alcohol, adding new seed crystal of the solifenacin succinate, stirring and crystallizing, so as to prepare the solifenacin succinate. The synthesis method of the solifenacin succinate has the advantages that two-step condensation reaction is carried out by virtue of a one-pot operation in the synthesis method, so that the troublesome azeotropic separation operation reported in the literature is avoided; and homogeneous catalysis is carried out by selecting soluble organic alkali, so that the reaction efficiency is improved.

Description

technical field [0001] The invention relates to a new synthesis method of solifenacin succinate bulk drug. [0002] Background technique [0003] Solifenacin Succinate, CAS No. 242478-38-2, chemical name 1-azabicyclo[2.2.2]octane-8-yl-(1S)-1-phenyl-3,4 -Dihydro-1H-isoquinoline-2-carboxylate succinate is a selective muscarinic M3 receptor antagonist developed by Japan Astellas Company. It was first launched in the Netherlands, Germany, the United Kingdom and Denmark in 2004. It was launched in China in 2009 and has been marketed in more than 50 countries and regions around the world so far. It has become an important drug for the treatment of overactive bladder (OAB) in Europe, the United States and Japan. It is recommended by many authoritative organizations and guidelines. The structural formula is as follows: [0004] [0005] For the new synthesis of Solina: [0006] Patent WO2007076116 uses (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline to condense with ethyl 1-chlor...

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Problems solved by technology

Although this method utilizes the condensation reaction to replace the transesterification reaction and avoids the azeotropic separation operation that is difficult to control, it still needs to use a highly active NaH strong base in the reaction, because NaH will react with alcohol during the reaction to release hydrogen. It is not conducive to industrialized safe production, but also increases the risk of storage and transportation of raw materials and the cost of raw materials, etc.

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