A kind of preparation method of solifenacin succinate

A technology of succinic acid and acid-binding agent, which is applied in the preparation of selective muscarinic M3 receptor antagonist drugs and solifenacin succinate, which can solve the problem that formyldiimidazole is expensive and unsuitable for industrial application , high toxicity of raw material reagents, etc., to achieve the effect of easy recycling, improved utilization rate and conversion rate, and increased yield

Active Publication Date: 2016-02-24
CHONGQING KERUI PHARMA GRP
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Problems solved by technology

[0011] 3) Synthesis and antimuscarinic properties of quinuclidin-3-yl1,2,3,4-tetrahydroisoquinoline-2-carboxylated derivatives as novelmus carinicreceptorantagonists, JMedChem2005,48(21):6597, discloses the preparation of solifenacin succinate using triphosgene pyridine as a reaction system, wherein triphosgene pyridine The toxicity of the reaction system is relatively large, the environment is seriously polluted, and the price of formyldiimidazole is high, and the molecular economy is poor, so it is not suitable for industrialization
[0018] 1. The selected raw material reagents are highly toxic, and a large amount of toxic solvents are used as the reaction system in the preparation process, which seriously pollutes the environment
[0019] 2. Low product yield, not suitable for industrial application

Method used

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  • A kind of preparation method of solifenacin succinate
  • A kind of preparation method of solifenacin succinate
  • A kind of preparation method of solifenacin succinate

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preparation example Construction

[0042] 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:

[0043]

Embodiment 1

[0045] 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%.

[0046] 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

[0049] 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%.

[0050] 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 present invention relates to a kind of sorenacin succinate ((3R)-1-azabicyclo[2.2.2]octane-3-yl(1S)-1-phenyl-3,4-dihydroisoquinone The preparation method of phenoline-2-(1H)-carboxylate succinate) comprises the following steps: 1) Formula IV compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinone Phenyl is used as raw material to prepare ethyl ester of formula III compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinolinecarboxylate; 2) formula III compound (S)-1-phenyl Synthesis of Formula Ⅱ Compound (3R)-1-azabicyclo[2.2.2]octane-3-yl(1S) from Ethyl-1,2,3,4-tetrahydroisoquinolinecarboxylate in Ionic Liquid -1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate; 3) Formula II compound (3R)-1-azabicyclo[2.2.2]octane- 3-base (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate is salified in organic solvent, obtains formula I compound sorenacin succinate (( 3R)-1-azabicyclo[2.2.2]octane-3-yl(1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate succinic acid salt); the preparation method has the advantages of simple process, suitability for industrial production, high product yield and high product purity.

Description

Technical field [0001] The present invention involves the preparation process of selective poisonous pyrodoline M3 receptor antagonist drugs, and it is specific to a new preparation method of amber acid Samena, which belongs to the field of preparation of raw medicines. Background technique [0002] OverActiveBladder (OAB) is one of the common clinical manifestations of urinary dysfunction. In September 2001, the International Incipulation Society (ICS) defined it as "symptoms of lower urinary tract dysfunction".Urine urgency or urgent urgency incontinence is often accompanied by frequent urination and nighturia.At present, the incidence of OAB is high. According to statistics, about 1 / 6 of the European population over 40 years of age is plagued by OAB, and the incidence of OAB in the United States has also reached 17%.At present, there are a lot of expenses for OAB for the treatment of OAB every year. In 2000, the United States only spent on this item of US $ 12.02 billion, acco...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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