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A technology of solifenacin succinate and synthesis method, which is applied in the field of synthesis of solifenacin succinate, and can solve the problems of increasing the risk of raw material storage and transportation, raw material cost, unfavorable industrialized safe production, etc.
Inactive Publication Date: 2015-03-25
JINGCHU UNIV OF TECH
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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 reactio
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Embodiment 1
[0033] Dissolve 2.6 g of triphosgene in 40 mL of xylene, cool to 0°C, and slowly add (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline ( I ) 4g, 3.3g of 4-dimethylaminopyridine dissolved in 40mL of xylene solution. After the dropwise addition was completed, it was raised to room temperature to continue the reaction for 3 h, filtered, and the resulting filtrate contained unisolated (S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-formyl chloride ( II ).
[0034] Add 2.8 g of (R)-3-quinuclidinol, 4.8 g of 4-dimethylaminopyridine, and 40 mL of xylene to the solution obtained in the previous step, raise the temperature to 140° C., and stir for 30 h. After cooling to room temperature, add 150 mL of saturated saline, separate the layers, acidify the organic layer with 10% hydrochloric acid, extract with water, then alkalinize with saturated potassium carbonate solution until the pH is approximately equal to 10, extract with ethyl acetate, anhydrous magnesium sulfate Drying, spin-drying solve...
Embodiment 2
[0037] Dissolve 15g of triphosgene in 200mL of xylene, cool to 0°C, add dropwise (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline ( I ) 25g, 20g of 4-dimethylaminopyridine dissolved in 250mL of DMF to form a solution. After the dropwise addition was completed, the reaction was continued at room temperature for 3 h. Add 1 L of water to the reaction liquid in batches to wash and separate the liquids. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and spin-dried to obtain 28 g of a light yellow oil, which is (S)-1-phenyl-3 , 4-dihydro-1H-isoquinoline-2-formyl chloride ( II)Crude.
[0038] Gained (S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-formyl chloride ( II ) crude product, 16g of (R)-3-quinuclidinol, and 30g of 4-dimethylaminopyridine were added into 500mL of DMF, the temperature was raised to 140°C, and the reaction was stirred for 30h. After cooling to room temperature, add 500 mL of ethyl acetate and 500 mL of water each. After sep...
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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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