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Alpha hydroxy - alpha phenyl phenylacetic acid 8 - aza dicyclo [3. 2. 1] - 3 heptyl ester, midbody compound, and preparation method

A technology of azabicyclo and phenylbenzene, which is applied in the field of drug synthesis, can solve the problems of uneasy operation, mild reaction conditions, and long reaction cycle, and achieve the effects of simple operation, mild reaction conditions, and short reaction cycle

Inactive Publication Date: 2007-07-25
LUJIAN MEDICINS TECH SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] One of the technical problems to be solved in the present invention is to disclose a preparation method of α-hydroxy-α-phenylphenylacetic acid 8-azabicyclo[3.2.1]-3-heptyl ester, to overcome the existing problems in the prior art The reaction conditions are not mild, the operation is not simple, the reaction cycle is long, the pollution is high, the quality of the finished product is unstable, and it is not suitable for large-scale industrial production.

Method used

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  • Alpha hydroxy - alpha phenyl phenylacetic acid 8 - aza dicyclo [3. 2. 1] - 3 heptyl ester, midbody compound, and preparation method
  • Alpha hydroxy - alpha phenyl phenylacetic acid 8 - aza dicyclo [3. 2. 1] - 3 heptyl ester, midbody compound, and preparation method

Examples

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Effect test

Embodiment 1

[0032] Preparation of α-Hydroxy-α-Phenylphenylacetic Acid Tropin Ester (I)

[0033] Tropinol (21.4g, 0.15mol), methyl α-hydroxy-α-phenylphenylacetate (40.5g, 0.16mol), xylene (200ml), 29% sodium methoxide (28.3g, 0.15mol), Heat to distill methanol, the temperature is from 70°C to 120°C, after 5 hours, cool to room temperature, add 1mol / L hydrochloric acid to pH 2~3 after cooling in an ice bath, separate layers, cool the water phase in an ice bath, add potassium carbonate to pH 9~ 10, filtered with suction, washed with water until neutral, and dried to obtain 35.7 g of compound I, with a yield of 67.1%. Melting point: 142°C 144°C. Mass spectrometry m / e: [M+1] + 352.3.

Embodiment 2

[0035] Preparation of α-Hydroxy-α-Phenylphenylacetic Acid Tropin Ester (I)

[0036] Tropinol (21.4g, 0.15mol), methyl α-hydroxy-α-phenylphenylacetate (40.5g, 0.16mol), toluene (200ml), potassium tert-butoxide (16.8g, 0.15mol), heated to reflux After 12 hours, cool to room temperature, add 1 mol / L hydrochloric acid to pH 2-3, separate layers, cool the water phase in an ice bath, add potassium carbonate to pH 9-10, filter with suction, wash with water until neutral, and dry 43.1 g of compound I was obtained with a yield of 81%. Melting point: 142℃~144℃. Mass spectrometry m / e: 352.3.

Embodiment 3

[0038]Preparation of α-hydroxy-α-phenylphenylacetic acid 8-ethoxyformyl-8-azabicyclo[3.2.1]-3-heptyl ester ((II)

[0039] Tropin diphenyl glycolate I (92g, 0.26mol), toluene (300ml), heated to 40°C, and ethyl chloroformate (75ml, 0.78mol) was added dropwise for 5 hours, and the addition was completed. Heat to 50°C, heat to reflux after 2 hours, cool to room temperature after 24 hours, filter with suction, and dry to obtain 107.1 g of compound II with a yield of 99%. Melting point: 130℃~132℃. Mass spectrometry m / e: [M+1] + 410.4.

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Abstract

This invention discloses a method for preparing a key intermediate of trospium chloride, alpha-hydroxy-alpha-phenylphenylacetic acid 8-azabicyclo[3.2.1]-3-heptyl ester, and the intermediates during the preparation process, alpha-hydroxy-alpha-phenyl phenylacetic acid 8-aralkyl oxyl formyl-8-azabicyclo[3.2.1]-3-heptyl ester, and hydrobromide of alpha-Br-phenylphenylacetic acid 8-azabicyclo[3.2.1]-3-heptyl ester. The method comprises: interesterifying between tropinol and alpha-hydroxy-alpha-phenyl phenylacetic acid methyl ester, demethylating and hydrolyzing twice. The method has such advantages as mild reaction conditions, easy operation, short reaction period, little pollution, and stable product quality.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a preparation method of the key intermediate of the medicine trospium chloride α-hydroxy-α-phenylphenylacetic acid 8-azabicyclo[3.2.1]-3-heptyl ester, and the preparation process intermediates. Background technique [0002] Overactive Bladder (OAB) is a common and distressing problem, a common disease affecting normal life of people of different ages, it occurs in both men and women, especially women and the elderly, and the incidence of this disease is currently very high According to the survey in Beijing, my country, the incidence rate of urinary incontinence in men over 50 years old is 16.4%, and the total incidence rate of mixed urinary incontinence and urge incontinence in women over 18 years old is as high as 40.4%. The associated increase in overactive bladder will significantly affect the quality of life of older adults. [0003] The muscarinic receptor antagonist oxybu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08
Inventor 许荣森吴志明宁奇
Owner LUJIAN MEDICINS TECH SHANGHAI
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