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Preparation method of meptazinol hydrochloride critical impurity

The invention relates to a meptanol hydrochloride and a key technology, which is applied in the field of preparation of key impurity compounds of meptanol hydrochloride, and can solve the problem of unqualified quality of meptanol hydrochloride, inability to remove special impurities, and the process of meptanol hydrochloride. immaturity etc.

Inactive Publication Date: 2013-12-25
BEIJING WANQUAN SUNSHINE MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The drug has been on the market in 1986, but it has not been on the market in my country for nearly 30 years. The possible reasons are: 1. The process for preparing meprotamol hydrochloride is immature; Impurities cannot be removed

Method used

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  • Preparation method of meptazinol hydrochloride critical impurity
  • Preparation method of meptazinol hydrochloride critical impurity
  • Preparation method of meptazinol hydrochloride critical impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 5.39 g of reaction material (III) to a 50 mL three-necked flask, add 25 mL of ethanol, dropwise add 11 mL of 2.0 mol / L aqueous sodium hydroxide solution, and stir the reaction at room temperature. After reacting for about 3 hours, the desalination was completed, concentrated by rotary evaporation, dissolved the concentrated solution with 15 mL of dichloromethane, filtered with suction, concentrated the filtrate to obtain a white solid, dried under reduced pressure at 40°C, weighed 4.34 g, and the yield was 93%, MS : 234 [M+H]+.

Embodiment 2

[0024] Add 5.39 g of reaction raw material (III) to a 50 mL three-necked flask, add 25 mL of ethanol, add 2.76 g of K2CO3, heat and reflux for 8 hours, the salt solution is completed, filter with suction, concentrate the filtrate to obtain a white solid, and dry under reduced pressure at 40°C The constant weight was 3.96 g, the yield was 85%, MS: 234 [M+H]+.

[0025] Implementation example: Preparation of impurity 3-(3-ethoxyphenyl)-3-ethyl-1-methylhomopiperidine

Embodiment 3

[0027] Add 4.67 g of 3-(3-ethyl-1-methyl-1H-hexahydroazepine-3-yl)phenol (II) to a 50 mL three-necked flask, add 30 mL of chloroform, add 2.76 g of K2CO3, and Stir for 1.5 hours, then add bromoethane 3.27 g, control the reaction temperature at 50 ° C, monitor the progress of the reaction by thin layer chromatography (TLC), react for 16 hours, the reaction is basically complete, stop heating, cool, and wash the reaction solution with water. Wash until pH=7, dry the organic phase with anhydrous sodium sulfate, filter with suction, concentrate the filtrate, and obtain the target compound (I) by column chromatography as a colorless oil, dry under reduced pressure at 40°C to a constant weight of 2.82 g , Yield 54%, 1H-NMR (CDCl3) δ 0.58 (t, 3H), 1.40 (t, 3H), 1.54 (q, 2H), 1.61-1.75 (m, 5H), 2.13 (q, 1H), 2.38 (s, 3H), 2.42-2.59 (m, 3H), 2.83 (s, 1H), 4.02 (q, 2H), 6.68(d, 1H), 6.68-6.89 (m, 2H), 7.2 (t, 1H). MS: 262 [M+H]+.

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Abstract

The invention belongs to the field of medicinal chemistry, relates to a preparation method of a meptazinol hydrochloride critical impurity, and particularly relates to the method for preparation of the critical impurity 3-(3-ethoxy phenyl)-3-ethyl-1-methyl homopiperidine with 3-(3-ethyl-1-methyl-1H-hexahydroazepine-3-ly) phenol hydrochloride as a starting material. The corresponding characterization of the compound is carried out, and the method is simple in operation.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new method for preparing the key impurity compound (I) of meptafol hydrochloride. [0002] Background technique [0003] Compound (I) with the above structure is a key impurity of meptafol hydrochloride, and its chemical name is: 3-(3-ethoxyphenyl)-3-ethyl-1-methylhomopiperidine. [0004] The chemical name of meptafol (III) hydrochloride is: 3-(3-ethyl-1-methyl-1H-hexahydroazepine-3-yl)phenol hydrochloride. In 1986, the racemic hydrochloride was listed in the UK, and it was recorded in the British Pharmacopoeia in 1998. It is a substitute for powerful analgesics currently used. Meptafol hydrochloride is one of the six agonist-antagonist analgesics recommended in many countries. The chemical structure of mebutaol hydrochloride is similar to that of morphine, and it is an agonist of opioid μ receptor and an antagonist of μ receptor. Most of the analgesics currently used c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/04
Inventor 王进敏马苏峰赵国磊
Owner BEIJING WANQUAN SUNSHINE MEDICAL TECH CO LTD