After-treatment for solifenacin and method for preparing succinic acid solifenacin

Abstract

The invention discloses an after-treatment method for solifenacin. The method comprises the steps that strong acid is slowly dripped into total synthesis liquid of solifenacin, after a pH value is adjusted to be 1.0-2.0, temperature is raised, water is added, and an extracting agent is used for extraction; after a water phase is cooled, a saturated sodium carbonate solution is added to alkalinity, dichloromethane is added to carry out graded extraction, extract liquor is washed with water, and a drying agent is added for drying, so that a dry product is obtained; the dry product is steamed at low temperature to be dry to obtain an oily substance solifenacin. By optimizing the after-treatment technology, isopropyl ether and dichloromethane are only used in the after-treatment technology of solifenacin, types of solvent are reduced, operation and recycle are facilitated, and cost is saved greatly. Strong base or strong acid is not used in the alkali efflorescence process of hydrochloric acid solifenacin, a saturated NaCO3 solution is used, the reaction is mild, temperature can be controlled easily, most importantly, generation of isomers is greatly reduced, and the content of the isomers of a non-structure type (1S and 3R) is reduced.

Description

technical field [0001] The invention relates to the technical field of preparation and purification technology of synthetic drugs, in particular to a post-treatment of solifenacin and a method for preparing solifenacin succinate. Background technique [0002] Solifenacin succinate is a selective muscarinic M3 receptor antagonist, which is clinically used to treat overactive bladder with symptoms of urgency and frequent urination. Systemic adverse reactions of drugs, such as dry mouth, constipation, dilated pupils, and tachycardia. The chemical name of solifenacin succinate is (3R)-1-azabicyclo[2.2.2]octane-3-yl(1S)-1-phenyl-3,4-dihydroisoquinoline- 2-(1H)-carboxylate succinate; molecular formula: C 23 h 26 N 2 o 2 C 4 h 6 o 4 ;Molecular weight: 480.56. [0003] At present, the preparation methods of solifenacin succinate mainly include: [0004] 1) Patent WO2007076116 uses (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline to condense with ethyl 1-chloroformate, and then ...

AI Technical Summary

Problems solved by technology

Although this method utilizes the condensation reaction to replace the transesterification reaction, avoiding the azeotropic separation operation that is difficult to control, it still needs to use highly active NaH strong base in the reaction, because NaH is a flammable and explosive active strong base, in the reaction During the process, it will react with alcohol to release hydrogen gas, which is not conducive to industrial safety production, and also increases the risk of storage and transportation of raw materials and the cost of raw materials, etc.

[0006] There are many synthetic routes of solifenacin succinate, and the one-pot method is used to synthesize solifenacin base first, including the original research route. There are many problems in the post-treatment of solifenacin base: (1) post-treatment process In the process, the DMF solvent and related impurities cannot be removed well, which greatly affects the subsequent salt formation and crystal precipitation.

(2) The use of strong bases, such as sodium hydroxide, can easily cause racemization, thereby affecting the purity of the finished product and resulting in unstable product quality

(3) There are many types of organic solvents used, and the treatment is complicated, which is not conducive to operation and recycling, resulting in increased costs

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