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

A technology of solifenacin and strong acid, applied in the field of preparing solifenacin succinate, can solve problems such as being unfavorable to operation and recycling, affecting salt formation and precipitation of crystals, affecting the purity of finished products, etc., and achieving easy operation and recycling. , the effect of reducing residual solvents and impurities, and simplifying the operation of post-processing

Active Publication Date: 2016-05-11
成都华宇制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Preparation of solifenacin by one-pot method

[0028] Add (R)-(-)-3-quinine alcohol (381g) and N,N-dimethylformamide (1.52L) into a 10L reactor, protect with nitrogen, stir at 30°C to dissolve; Bis(4-nitrophenyl) carbonate (1090 g) was added at 30°C. During the addition, the color of the solution turned into bright brownish yellow. After the addition was completed, the temperature was controlled at 30°C and reacted for 3 hours. TLC monitors that the raw material (R)-(-)-3-quinine alcohol reacts completely, and the raw material (R)-(-)-3-quinine alcohol is completely consumed.

[0029] Add (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (816 g) in batches to the first step reaction system, control the temperature at 30°C, and react for 3 hours. TLC monitors the reaction status of raw material (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and intermediates, such as (S)-1-phenyl-1,2,3,4-tetra If hydroisoquinoline disappears and intermediate I remains, (S)-1-phenyl-1...

Embodiment 2

[0030] Example 2: Post-treatment of the total synthetic solution of solifenacin prepared by the one-pot method

[0031] Slowly add about 3.5L of dilute hydrochloric acid solution to the reaction kettle containing the synthetic total solution, the internal temperature rises during the dropping process, the dropping speed ensures that the temperature rise does not exceed 30°C, and the measured pH value is 1.7. Add 22L of water and 11L of isopropyl ether (about half the volume of water) to the reaction kettle; extract 3 times with isopropyl ether (the amount of water and isopropyl ether for each extraction is 2:1), and collect the extracted aqueous phase , add saturated sodium carbonate solution to adjust the pH value to 9, add dichloromethane and extract twice. The dichloromethane phase is washed 3 times with about an equal volume of water, and the dichloromethane phase is put into a plastic beaker to add sodium sulfate (the consumption of sodium sulfate is about 20% of the solv...

Embodiment 3

[0032] Embodiment 3: the preparation of solifenacin succinate

[0033] Add acetone to dissolve the oil obtained above; add succinic acid and stir at 60°C for 1 hour; stop heating and stirring and let it cool down to room temperature naturally; drop to 20°C and stir for about 2 hours to crystallize; suction filter to obtain a white solid, wash with acetone; Linacin-API crude product.

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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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 罗朝斌万久磊
Owner 成都华宇制药有限公司
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