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Preparation method of cimetidine

A technology of cimetidine and methylimidazole is applied in the field of preparation of cimetidine, can solve the problems of low production yield of cimetidine, existence of environmental pollution, a large amount of methyl mercaptan and the like, and achieves easy operation, The effect of low environmental pollution and short synthesis route

Active Publication Date: 2021-08-03
SHIJIAZHUANG POLEE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But existing cimetidine production technology can produce a large amount of methyl mercaptan with stench smell, causes environmental pollution
Although the production company has adopted the treatment methods of methyl mercaptan alkali absorption and tail gas combustion, environmental pollution still exists
In addition, the production yield of cimetidine is also on the low side

Method used

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  • Preparation method of cimetidine
  • Preparation method of cimetidine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] 207.7 g (1 mol) 2- (5-methylimidazole-4-yl) methyl sulfide hydrochloride and 303 g (3.3 mol) Et3n were added to 2.5 L of ethyl acetate and water (volume ratio 3: 1) In the mixed solvent, stirring, the reaction liquid was cooled to 10-15 ° C, and 79.8 g (1.05 mol) CS2 was added dropwise, and the dropwise addition was added, the reaction was 1 h, and the temperature was 10 ° C, and 228 g (1.2 mol) pyrazoloxyl chloride, stir The reaction was 0.5 h and then at room temperature for 4 h. The filtrate was transferred to pH 2-3 with 6N hydrochloride, and the organic layer was separated, the aqueous layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, decompression distillation, and intermediate (I). The aqueous phase was alkated with 30% NaOH solution, and the ET3N was recovered by distillation. The intermediate (I) yield was 94.3%, and the ET3N recovery was 79.3%. 1HNMR (400 MHz, CDCl3) δ2.35 (S, 3H), 2.54-2.61 (m, 2H), 3.70 (S, 2H),...

Embodiment 2

[0020] 207.7 g (1 mol) 2- (5-methylimidazole-4-yl) methyl sulfide hydrochloride and 496.8 g (3.6 mol) K2CO3 were added to 3 l Chloromethane and water (volume ratio 3: 1) In the mixed solvent, stirring, the reaction liquid was cooled to 10-15 ° C, add 91.2 g (1.2 mol) CS2, add 0.5 h, and 50 ° C, 10 ° C, add 152 g (1.2 mol) chloride. The solution was stirred at 0.5 h, and then at room temperature for 6 h. The reaction solution was filtered, and the organic layer was separated, the aqueous phase was extracted with dichloromethane, dried over anhydrous sulfate, filtered, concentrated, decreased pressure distillation, the intermediate (I), yield 93.6%.

[0021] 213 g (1 mol) intermediate (I) to 2.5 L of mass fraction of 60% ethanol, stirred, a methylamine solution of 40% of mass fraction was added 116.2 g (1.5 mol), and reacted at 40-50 ° C for 2-3 hours. Concentrate under reduced pressure, cool the crystallization, and crude product. Ethanol recrystallization and produce intermediate ...

Embodiment 3

[0024] 207.7 g (1 mol) 2- (5-methylimidazole-4-yl) methyl sulfide hydrochloride and 360.4 g (3.4 mol) Na2CO3 were added to mixed solvents of toluene and water (volume ratio 3: 1). In the mixing, stirring, the reaction liquid was cooled to 10-15 ° C, and 83.6 g (1.1 mol) CS2 was added dropwise, and the dropwise addition was 0.5-1 h, and the temperature was 10 ° C, and 417.9 g (1.2 mol) of a water sulfate saturation. The solution was stirred for 0.5 h, and then at room temperature for 5 h. The reaction liquid was filtered, and the organic layer was separated, the aqueous phase was extracted with toluene, dried over anhydrous sodium sulfate, concentrated, decomposed distillation, the intermediate (I), yield 94.0%.

[0025] 213 g (1 mol) intermediate (I) was added to a 2.5 L mass fraction of 65% ethanol aqueous ethanol, stirred, and an methylamine solution of a mass fraction of 40% was added to 155 g (2.0 mol), and reacted at 40-50 ° C for 2-3 hours. Concentrate under reduced pressure...

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Abstract

The invention discloses a preparation method of cimetidine. The preparation method comprises the following steps of (1) condensing 2-(4-methylimidazole-4-yl) methyl thioethylamine hydrochloride and CS2 in the presence of alkali, and preparing an intermediate (I) under the action of a desulfurization reagent, (2) reacting the intermediate (I) with monomethylamine to prepare an intermediate (II), and (3) in the presence of a desulfurization reagent, carrying out amination on the intermediate (II) and cyanamide to prepare cimetidine.

Description

Technical field [0001] The present invention relates to the field of biomedicine technology, and more particularly to a method of preparing a kind of Westernine. Background technique [0002] Wesi is currently the most widely used drugs for the treatment of ulcer diseases, nearly 100 national applications. However, the existing Wom Trim production technology produces a large amount of methyl thiol with malodorous odor, causing environmental pollution. Although the production enterprise uses methyl thioline absorption and exhaust gas combustion, environmental pollution still exists. In addition, the production yield of Wesi Timin is also low. Therefore, it is of great significance to develop Wymphidine preparation methods with no environmental pollution. Inventive content [0003] SUMMARY OF THE INVENTION It is an object of the present invention to overcome the deficiencies of the prior art, provide a method of preparing Wesi Timotidine, which has a small environmental pollution,...

Claims

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Application Information

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IPC IPC(8): C07D233/64
CPCC07D233/64
Inventor 秦晓辉史兰香张之奎秦建辉刘胜昔杨旭翠秦正浩秦少博
Owner SHIJIAZHUANG POLEE PHARMA CO LTD
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