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Method for preparing 2-hydroxy-2,2-diphenylacetic acid-3alpha-(8-aza-bicyclo(3,2,1))-3-trioctyl

A technology of diphenylacetic acid and methyl diphenylglycolic acid, which is applied in the field of drug synthesis, can solve the problems of long reaction time, high equipment requirements, and high risk, and achieve short reaction time, low equipment requirements, and low environmental pollution. Effect

Inactive Publication Date: 2013-03-13
SICHUAN UNIVERSITY OF SCIENCE AND ENGINEERING
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The whole reaction takes a long time and the yield is low, and the reagents such as methyl chloroformate, ethyl chloroformate, and benzyl chloroformate used in the N-formylation demethylation step belong to the No. Flammable liquids with medium flash point in category 3.2 / category B-class organic highly toxic drugs, which are highly toxic and are controlled by the public security department according to the "Regulations on the Safety Management of Hazardous Chemicals"; and the deformylation step reacts in a strong acid environment, Long time, high requirements on equipment, high risk of production

Method used

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  • Method for preparing 2-hydroxy-2,2-diphenylacetic acid-3alpha-(8-aza-bicyclo(3,2,1))-3-trioctyl
  • Method for preparing 2-hydroxy-2,2-diphenylacetic acid-3alpha-(8-aza-bicyclo(3,2,1))-3-trioctyl
  • Method for preparing 2-hydroxy-2,2-diphenylacetic acid-3alpha-(8-aza-bicyclo(3,2,1))-3-trioctyl

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Preparation of Diphenylglycolic Acid

[0037] Weigh 2g of dibenzoyl into a 100ml three-necked flask, then measure 5ml of water and 5ml of absolute ethanol into the three-necked flask, and stir to dissolve the dibenzoyl. Slowly add saturated NaOH solution (containing 1.5g NaOH) dropwise in a water bath at 80°C while heating, and stop heating after reflux for 30 minutes after dropping. Cool, add 6% hydrochloric acid solution dropwise to the beaker with stirring until pH = 2-3, filter with suction, dissolve the solid with 10% NaOH solution, add activated carbon for decolorization for 5 minutes, and then filter with suction. Slowly add 6% hydrochloric acid solution dropwise to the filtrate until pH=2-3, filter the precipitated white precipitate with suction, and dry to obtain 2.1 g of the compound with a yield of 97%. Melting point: 149~151℃.

Embodiment 2

[0038] Example 2 Preparation of methyl diphenyl glycolate

[0039] Weigh 16g (0.07mol) of diphenylglycolic acid into a 250ml three-neck flask, add 100ml of methanol and stir to dissolve the diphenylglycolic acid. Add 10ml of DMC and 1ml of DBU, and place in a microwave reaction device for reflux reaction for 15 minutes. After the reaction, recover most of the methanol (about 95% by volume), cool the distillate and transfer it to a 250ml beaker, add distilled water 3 times the volume of the distillate to the beaker under stirring, and adjust the pH value of the solution to 9-10, a white solid is produced during the process, the solid is filtered out with suction, and dried at 50°C to obtain the crude methyl diphenylglycolate. Crude product with V 乙酸乙酯 :V 石油醚 =1:3.5 The mixed solution was recrystallized, filtered and dried to obtain 15.24 g of compound, with a yield of 90%. Melting point: 68~70℃.

Embodiment 3

[0040] Example 3 Preparation of Tropin Diphenylglycolate

[0041] Weigh 2.8g (0.02mol) of tropinol into a 250ml three-neck flask, add 60ml of fresh anhydrous toluene, and slowly distill half of the solvent using a distillation device. Then take 1.3g of sodium methoxide and 6g (0.025mol) of methyl diphenylglycolate into the three-necked flask, add 70ml of fresh anhydrous toluene, and reflux for 15h under stirring. After the reaction, put the reaction solution in an ice-water bath to cool to below room temperature, add 40ml of ice water while stirring, and then stir again until solid precipitates. Put the reaction solution in the refrigerator to cool and crystallize for 24 hours, and the precipitated solid was washed twice with 5ml of cold anhydrous toluene to obtain a crude product of tropine diphenylglycolate, which was then recrystallized to obtain 4.2 g of a white solid, with a yield of 60% . Melting point 146-148°C, mass spectrometry m / e: [M+1]+352.3.

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Abstract

The invention discloses a method for preparing 2-hydroxy-2,2-diphenylacetic acid-3alpha-(8-aza-bicyclo(3,2,1))-3-trioctyl. The method comprises the following steps of: by taking dibenzoyl as a raw material, carrying out rearrangement on the raw material so as to obtain dihydroxy-phenylacetic acid; reacting dihydroxy-phenylacetic acid with dimethyl carbonate under the DBU catalysis and microwave actions so as to obtain methyl benzilate; reacting the methyl benzilate with tropine so as to obtain tropine benzilate; and carrying out N formylation and alcoholysis on the obtained tropine benzilate so as to obtain nor-tropine benzilate. Compared with the prior art, the total reaction time of the method disclosed by the invention is greatly reduced, the total yield is increased greatly, and the reaction condition is more simple, and therefore, the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a key intermediate for the preparation of anticholinergic trospium chloride (trospium chloride) 2-hydroxy-2,2-diphenylacetic acid-3α-(8-azabicyclo[3,2 , 1])-3-octyl ester preparation method. . Background technique [0002] Currently, overactive bladder (OAB) is a common and frequently occurring disease that seriously affects people's normal life, especially among women and the elderly. As my country enters the ranks of aging countries, the increase of this disease will significantly affect the quality of life of the elderly. [0003] Trospium chloride is a novel potent muscarinic receptor antagonist that significantly improves daily urinary frequency and incontinence episodes in OAB patients with a good efficacy / tolerability ratio, 2-hydroxy-2,2- Diphenylacetic acid-3α-(8-azabicyclo[3,2,1])-3-octyl ester is a key intermediate for the preparation of trospium chloride. [0004] T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D451/10
Inventor 张利范明才罗荣珍易学文
Owner SICHUAN UNIVERSITY OF SCIENCE AND ENGINEERING
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