Method for preparing 2-hydroxyl-2,2-diphenyl acetic acid-3alpha-(8-azabicyclo[3,2,1]-3-octyl ester

A technology of diphenylacetic acid and tropin diphenylglycolate, applied in 2-hydroxy-2,2-diphenylacetic acid-3α-(8-azabicyclo[3,2,1]-3- The field of preparation of octyl esters can solve the problems of difficulty in industrial production, inconvenient storage and transportation, and impact, and achieve the effect of easy reaction and suitable for industrial scale production

Inactive Publication Date: 2010-02-10
北京迈劲医药科技有限公司
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This method has the following problems in the process of implementation: 1, when preparing diphenylglycolic acid tropine ester, transesterification needs to use sodium methylate or potassium tert-butoxide, because these two kinds of materials have certain safety instability 2. Also in this reaction, methanol and toluene must be evaporated to dryness at the end of the reaction, so that the resulting toluene always contains a small amount of methyl alcohol. Complete separation has a certain degree of difficulty in industrial production; 3, when hydrobromic acid is used to remove formyl from N--ethoxycarbonyl diphenylglycolic acid tropinate, it also brings bromolysis while acidolysis 4. The use of bromide may not only cause certain industrial pollution and inconvenient storage and transportation, but also adversely affect the quality of the product.

Method used

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  • Method for preparing 2-hydroxyl-2,2-diphenyl acetic acid-3alpha-(8-azabicyclo[3,2,1]-3-octyl ester

Examples

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Embodiment 1

[0020] 2-Hydroxy-2,2-diphenylacetylimidazole (compound 1, diphenylglycolyl imidazole)

[0021] Add carbonylimidazole (350g, 2.160mol) into dichloromethane (1500ml), start stirring to dissolve the solid, control the temperature at 20-25°C, add diphenylglycolic acid (490g, 2.149mol) in batches, and react at room temperature for 4- It was filtered for 5 hours, and the solid was washed with an appropriate amount of dry dichloromethane. Vacuum drying and recrystallization from acetone gave 485.1 g of white solid, yield: 81.2%, melting point: 147-148°C.

Embodiment 2

[0023] N-methyl 2-hydroxy-2,2-diphenylacetic acid-3α-(8-azabicyclo[3,2,1]-3-octyl ester (compound 2, diphenylglycolic acid tropin ester)

[0024] Add α-tropine alcohol (240g, 1.702mol) into 1000ml of acetone, stir, heat, and under reflux, add diphenylglycol imidazole (482g, 1.734mol) in batches. About half of the solvent was removed, cooled to 0°C, filtered, and the solid was washed thoroughly with acetone at 0°C, and dried naturally. Obtained white crystals: 390.7g, yield: 65.4%, melting point 146~147°C; mass spectrum data m / e: [M]351 (12%), 124 (100%); HPLC purity: 95.87% (t R , 6.844).

Embodiment 3

[0026] N-ethoxycarbonyl-2-hydroxy-2,2-diphenylacetic acid-3α--(8-azabicyclo[3,2,1]-3-octyl ester (compound 3, N-ethoxycarbonyl di Tropinate Phenylglycolate)

[0027] Tropin diphenylglycolate (256g, 0.729mol) and 1,2-dichloroethane (2000ml) were mixed and stirred, and ethyl chloroformate (270ml, 307.8g, 2.837mol) was added dropwise. After dropping, the temperature was naturally raised to reflux for 48 hours, and concentrated under reduced pressure. Evaporated to dryness to give a white solid, yield close to theoretical value: 298.2g, melting point 137-138°C; mass spectrometry data m / e: [M+1] 410 (8%), 183 (100%); HPLC purity: 99.27% (t R , 19.579).

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Abstract

The invention discloses a method for preparing 2-hydroxyl-2,2-diphenyl acetic acid-3alpha-(8-azabicyclo[3,2,1]-3-octyl ester which is a key intermediate of trospium chloride of an anticholinergic agent. The method comprises the following steps that: firstly, 2-hydroxyl-2,2-diphenyl acetic acid serving as a raw material is mixed with carbonyl imidazole for activation of acyl radicals; secondly, theresulting product reacts with tropine alcohol to form 2-hydroxyl-2,2-diphenyl acetic acid tropine ester; and finally, the resulting product of the previous step undergoes N formylation and acidulation reaction to obtain the 2-hydroxyl-2,2-diphenyl acetic acid-3alpha-(8-azabicyclo[3,2,1]-3-octyl ester. The method has the advantages of mild reaction conditions, little pollution and easy realizationof industrialized production.

Description

technical field [0001] The invention discloses a key intermediate 2-hydroxy-2,2-diphenylacetic acid-3α-(8-azabicyclo[3,2,1]-3 for preparing anticholinergic drug trospium chloride - Process for the preparation of octyl esters. Background technique [0002] Trospium chloride, an M-type choline receptor antagonist, is clinically used to treat symptoms such as urinary incontinence and frequent urination. Nortropine diphenylglycolate is a key intermediate for the preparation of trospium chloride. [0003] The synthetic method of nortropine diphenylglycolate has been reported in the literature. People such as Xu Rongsen reported in CN101003535A that take tropin alcohol as raw material through transesterification, prepare diphenyl glycolate tropin ester, carry out N formylation demethylation with ethyl chloroformate again, use the method for hydrobromic acid hydrolysis at last Preparation of 2-hydroxyl-2,2-diphenylacetic acid-3α-(8-azabicyclo[3,2,1]-3-octyl ester. The synthetic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/10
Inventor 钟加胜黄剑卢晓燕马超
Owner 北京迈劲医药科技有限公司
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