Method for preparing solifenacin succinate

A technology of succinic acid and acid-binding agent, which is applied in the preparation of solifenacin succinate and the preparation of selective muscarinic M3 receptor antagonist drugs, and can solve the problem of unsuitable industrial application and high price of formyldiimidazole , the toxicity of raw material reagents and other problems, to achieve the effect of easy recycling, improving utilization rate and conversion rate, and increasing yield

Active Publication Date: 2014-07-02
CHONGQING KERUI PHARMA GRP
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[0012]3) Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinolin e-2-carbox ylate derivatives as novel muscarinic receptor antagonists, J Med Chem 2005, 48(21): 6597, discloses the preparation of solifenacin succinate using triphosgene pyridine as a reaction system, wherein the toxicity of the triphosgene pyridine reaction system is relatively high, the environ

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  • Method for preparing solifenacin succinate
  • Method for preparing solifenacin succinate
  • Method for preparing solifenacin succinate

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[0045] Sorenacin succinate ((3R)-1-azabicyclo[2.2.2]octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2 -(1H)-carboxylate succinate) preparation method, comprises the steps:

[0046]

Embodiment 1

[0048] 1) Add ionic liquid [bmim]BF in sequence to a 500ml three-neck bottle 4 250ml, 20.9g of formula IV compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 13.8g of potassium carbonate, under the condition of stirring, add 10.8g of chlorine dropwise to the reaction system After the addition of ethyl formate, react at room temperature for 2 hours. After the reaction, the reaction solution is first extracted three times with 50ml of dichloromethane, then washed with water three times, then dried with anhydrous sodium sulfate at room temperature for 2 hours, and finally distilled under reduced pressure. The dichloromethane was removed to obtain 27.0 g of an oily product, that is, compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarboxylic acid ethyl ester of formula III, and the yield was 96.1%.

[0049] 2) Add ionic liquid [bmim]BF in sequence to a 500ml three-neck bottle 4 250ml, formula III compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid ethyl e...

Embodiment 2

[0053] 1) In a 500ml three-necked flask, add 250ml of toluene, 20.9g of the compound of formula IV (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 16.6g of potassium carbonate in sequence, under stirring conditions , add 10.8g of ethyl chloroformate dropwise to the reaction system. After the dropwise addition, react at room temperature for 2h. Sodium was dried at room temperature for 6 hours, and finally dichloromethane was distilled under reduced pressure to obtain 27.11 g of oily substance, namely the compound of formula III (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarboxylic acid ethyl Esters, the yield is 96.5%.

[0054] 2) Add ionic liquid [bmim]BF in sequence to a 500ml three-neck bottle 4 250ml, formula III compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid ethyl ester 20g, DMF0.86g, (R)-3-quinine alcohol 11.7g and hydrogenation Sodium 0.5g, stirring and heating until the reaction system is 100°C, heat preservation reaction for 6h, after the reacti...

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Abstract

The invention relates to a method for preparing a solifenacin succinate ((3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate succinate). The method comprises the following steps: 1) preparing a compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid ethyl ester of formula III from a compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, serving as a raw material, of formula IV; 2) synthesizing a compound (3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate of formula II in an ionic liquid by using the compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid ethyl ester of formula III; and 3) salifying the compound (3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate of formula II in an organic solvent to obtain the compound solifenacin succinate ((3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate succinate) of formula I. The preparation method has the advantages that the process is simple, the method is suitable for industrialized production, the yield of the product is high and the purity of the product is high.

Description

technical field [0001] The invention relates to a preparation process of a selective muscarinic M3 receptor antagonist medicine, in particular to a preparation method of solifenacin succinate, which belongs to the technical field of raw material medicine preparation. [0002] Background technique [0003] Overactive bladder (Overactive bladder, OAB) is one of the common clinical manifestations of voiding dysfunction. In September 2001, the International Continence Society (ICS) defined it as a "symptom syndrome of lower urinary tract dysfunction". Urinary urgency with or without urge incontinence, often accompanied by frequency and nocturia. At present, the incidence of OAB is relatively high. According to statistics, about 1 / 6 of the European population over the age of 40 is troubled by OAB, and the incidence of OAB in the United States has reached 17%. Now countries spend a lot of money on the treatment of OAB every year. In 2000, the United States spent 12.02 billion US...

Claims

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Application Information

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IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 李强刘睿斌刘俊敏秦家川程鹏傅青云朱志平李荣
Owner CHONGQING KERUI PHARMA GRP
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