Synthesis method of 3-(3-hydroxyphenyl)-1, 1-dimethylurea, intermediate and application

A technology of dimethylurea and hydroxyphenyl, which is applied in the field of drug synthesis, can solve the problems of drug quality control risks, cumbersome operations, and residues, and achieve the effects of improving reaction processing efficiency, simple operation process, and wide application range

Pending Publication Date: 2021-11-16
ZHEJIANG CHEMSYN PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] 3-(3-Hydroxyphenyl)-1,1-dimethylurea is a process impurity produced during the synthesis of neostigmine methosulfate, which may remain during the purification process, so this impurity has a significant impact on the quality of the drug control poses a greater risk
Patents US41013450, US3383195 and WO2017175258 all report the synthesis method of this compound, using m-aminophenol to directly react with dimethylcarbamoyl chloride, but because the hydroxyl and amino groups on the m-aminophenol have obvious differences in the reaction with dimethylcarbamoyl chloride Competitiveness (reaction equation is as follows), in fact can obtain the mixture of three kinds of structures, need through column chromatography separation, complicated operation, in view of this, it is necessary to traditional 3-(3-hydroxyphenyl)-1,1 -The synthetic method of dimethylurea is improved

Method used

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  • Synthesis method of 3-(3-hydroxyphenyl)-1, 1-dimethylurea, intermediate and application
  • Synthesis method of 3-(3-hydroxyphenyl)-1, 1-dimethylurea, intermediate and application
  • Synthesis method of 3-(3-hydroxyphenyl)-1, 1-dimethylurea, intermediate and application

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Experimental program
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Effect test

Embodiment 1

[0030] A kind of synthetic method of 3-(3-hydroxyphenyl)-1,1-dimethylurea, comprises the following concrete steps:

[0031] S1. Preparation of intermediate compound Ⅰ: Add raw materials m-aminophenol 20g (0.183mol), ethyl acetate 60ml, HDMS (hexamethylsilazane) 32g (0.198mol, 1.08eq) and phosphotungstic acid into a single-necked round bottom flask 0.5g (0.17mmol), heat up to 55-70°C with stirring, keep stirring for 2h, after the reaction, cool down to room temperature, add 100g tap water to wash until pH = 7.0, take the organic phase, add magnesium sulfate for dehydration, and obtain 3- The ethyl acetate solution of trimethylsiloxyaniline, reaction equation is:

[0032]

[0033] S2. Preparation of intermediate compound II: add 19 g of triethylamine (0.187 mol, 1.03 eq) to the ethyl acetate solution of 3-trimethylsiloxyaniline after dehydration, and start to drop 20 g of dimethylcarbamoyl chloride (0.186mol, 1.01eq), heated to 55-70°C, kept stirring for 6h, filtered to remo...

Embodiment 2

[0038] A kind of synthetic method of 3-(3-hydroxyphenyl)-1,1-dimethylurea, comprises the following specific steps:

[0039] S1. Preparation of intermediate compound I: Add 10g (0.092mol) of raw materials m-aminophenol, 40ml of toluene, 15.9g (0.10mol, 1.08eq) of HDMS (hexamethylsilylazide) and 0.26 phosphotungstic acid into a single-necked round bottom flask g (0.08mmol), heated to 55-70°C under stirring, kept stirring for 1.5h, after the reaction, cooled to room temperature, added 70g tap water to wash to PH=7.0, took the organic phase, added magnesium sulfate for dehydration, and obtained 3- The toluene solution of trimethylsiloxyaniline;

[0040] S2. Preparation of intermediate compound II: Add 10.1 g (0.10 mol, 1.09 eq) of triethylamine to the toluene solution of 3-trimethylsiloxyaniline after dehydration, and start to drop 10.8 g of dimethylcarbamoyl chloride (0.10mol, 1.09eq), heated to 55-70°C, kept stirring for 6h, filtered to remove the solid, and washed the organic ...

Embodiment 3

[0043] A kind of synthetic method of 3-(3-hydroxyphenyl)-1,1-dimethylurea, comprises the following concrete steps:

[0044] S1. Preparation of intermediate compound I: Add 30g (0.274mol) of raw materials m-aminophenol, 150ml of acetone, 50g (0.31mol, 1.13eq) of HDMS (hexamethylsilylazide) and 3g of phosphotungstic acid ( 0.001mol), heated to 55-70°C with stirring, kept stirring for 1h, after the reaction was completed, cooled to room temperature, added 75g tap water to wash until PH = 7.0, took the organic phase, added magnesium sulfate for dehydration, and obtained 3-trimethyl Acetone solution of siloxyaniline;

[0045] S2. Preparation of intermediate compound II: Add 35 g of triethylamine (0.346 mol, 1.26 eq) to the acetone solution of dehydrated 3-trimethylsilyloxyaniline, and start to drop 36 g of dimethylcarbamoyl chloride ( 0.335mol, 1.22eq), heated to 55~70℃, kept stirring for 6h, filtered to remove the solid, washed the organic phase twice with 350g water to obtain 1,1,...

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Abstract

The invention discloses a synthesis method of 3-(3-hydroxyphenyl)-1, 1-dimethylurea, an intermediate and application. The synthesis method comprises the steps of: generating 3-trimethylsiloxy phenylamine from m-aminophenol as a raw material under the catalysis of HDMS and phosphotungstic acid, then reacting with dimethylamino formyl chloride to obtain 1, 1,-dimethyl-3-(3-trimethylsiloxy phenyl) urea, and then removing TMS to obtain 3-(3-hydroxyphenyl)-1, 1-dimethylurea. The method has the advantages of simple synthesis route, simplicity in operation, high yield and no pollution.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and specifically relates to a synthesis method, intermediate and application of 3-(3-hydroxyphenyl)-1,1-dimethylurea. Background technique [0002] Neostigmine methosulfate is a commonly used heteroreverse anticholinesterase drug, which is commonly used in various flaccid paralysis, muscle and neurosis in internal medicine, gynecology and ENT. [0003] 3-(3-Hydroxyphenyl)-1,1-dimethylurea is a process impurity produced during the synthesis of neostigmine methosulfate, which may remain during the purification process, so this impurity has a significant impact on the quality of the drug control poses a greater risk. Patents US41013450, US3383195 and WO2017175258 all report the synthesis method of this compound, using m-aminophenol to directly react with dimethylcarbamoyl chloride, but because the hydroxyl and amino groups on the m-aminophenol have obvious differences in the reaction wit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C275/34C07C273/18C07F7/18G01N30/02G01N30/04
CPCC07C273/1854C07F7/1804C07F7/188C07F7/1892G01N30/02G01N30/04G01N2030/027G01N2030/047C07C275/34
Inventor 丁尊良宋瑜叶山海
Owner ZHEJIANG CHEMSYN PHARM
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