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Methimazole synthesizing and purifying method

A technology of methimazole and a purification method is applied in the preparation field suitable for industrial production, can solve problems such as harsh operating conditions, unfavorable industrial production and the like, and achieves the effects of short production cycle, easy industrial production and mild reaction conditions

Active Publication Date: 2017-09-15
CHANGZHOU TIANHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this process needs to use n-butyllithium as a hydrogen extraction reagent, requires strict anhydrous and oxygen-free reaction, and strictly controls the reaction temperature. The operating conditions are extremely harsh and there are serious safety hazards. Therefore, it is not conducive to industrial production.

Method used

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  • Methimazole synthesizing and purifying method
  • Methimazole synthesizing and purifying method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Mix methylaminoacetaldehyde ethylene acetal (294g, 2.0mol, 1.0eq), ammonium thiocyanate (198g, 2.6mol, 1.3eq) and deionized water (200mL) and stir to dissolve, then add benzyl triethyl ammonium chloride (22.8g, 2.6mol, 0.05eq), p-toluenesulfonic acid (38.1g, 0.2mol, 0.1eq), the temperature was raised to 50°C for condensation reaction for 8h, and the disappearance of raw materials was monitored by TLC (V PE / EA =15:1, KMnO 4 Color development), after the reaction is completed, add 200mL saturated saline, tetrahydrofuran (300mL*2), extract, separate liquids, combine the organic layers, dry over anhydrous sodium sulfate, concentrate to obtain 171g of the crude product of light red solid methimazole, the yield 75% with a purity of 94.7%.

[0022] Add 150g of the light red crude product methimazole into 300mL of methanol, heat to dissolve completely, add activated carbon to decolorize, reflux for 30min, filter while hot, cool to 0°C, filter, and vacuum dry at 45°C to obta...

Embodiment 2

[0024] Stir and dissolve methylaminoacetaldehyde ethylene acetal (221g, 1.5mol, 1.0eq), ammonium thiocyanate (206g, 2.7mol, 1.8eq), deionized water (200mL), and then add PEG-2000 (15g) The temperature was raised to 40°C, and then 98% concentrated sulfuric acid (40mL g, 0.74mol) was slowly added thereto, and the addition was completed in 1h, then the temperature was raised to 70°C for 5h, and TLC monitored the disappearance of the raw material (V PE / EA =15:1, KMnO 4 color development), after the reaction was completed, 200mL saturated saline and tetrahydrofuran (300mL*2) were added, extracted, separated, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 139.4g of a light red solid methimazole crude product. The yield is 81.4%, and the purity is 95.8%.

[0025] Add 120g of the light red crude product methimazole into 200mL of ethanol, heat to dissolve completely, add activated carbon to decolorize, reflux for 30min, filter ...

Embodiment 3

[0027] Stir and dissolve methylaminoacetaldehyde ethylene acetal (353g, 2.4mol, 1.0eq), ammonium thiocyanate (274g, 3.6mol, 1.5eq), deionized water (260mL), and then add tetrabutylammonium bromide (38.7g, 0.12mol, 0.05eq) was warmed up to 40°C, and then 37% concentrated hydrochloric acid (50mL, 0.6mol) was slowly added thereto for 1h, then the temperature was raised to 60°C for 6h, and TLC monitored the disappearance of the raw material (V PE / EA =15:1, KMnO 4 color development), after the reaction is completed, add 300mL saturated saline, 1,4-dioxane (450mL*2), extract, separate liquids, combine organic layers, dry over anhydrous sodium sulfate, concentrate to obtain light red solid formazan Thiamimazole crude product 255g, yield 93.2%, purity 96.8%.

[0028] Add 250g of the light red crude product methimazole into 500mL of acetone, heat to dissolve completely, add activated carbon to decolorize, reflux for 30min, filter while hot, cool to 0°C, filter, and vacuum dry at 45...

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Abstract

The invention discloses a methimazole synthesizing and purifying method, and belongs to the field of medicine synthesis. The method comprises the following steps: carrying out a condensation reaction on methylaminoacetaldehyde polyethylene glycol and ammonium thiocyanate which are used as raw materials in the presence of an acid catalyst and a phase transfer catalyst; and adding saturated salt water after the reaction is completed, uniformly mixing the obtained reaction product and the saturated salt water, adding an organic solvent to carry out extraction, drying and concentrating the obtained organic layer to obtain crude methimazole, heating and dissolving the crude product in a solvent, adding active carbon to decolorize the obtained solution, filtering the solution, and drying the filtered solution to obtain purified methimazole. The method is a preparation method simple to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a method for synthesizing and refining methimazole, in particular to a condensation method using methylaminoacetaldehyde ethylene acetal and ammonium thiocyanate as raw materials, hydrochloric acid as a catalyst, and a phase transfer catalyst. The crude product of methimazole is obtained through reaction, and the preparation method suitable for industrial production of methimazole meeting the pharmacopoeia standard is obtained through refining. Background technique [0002] Methimazole (Methimazole), chemical name 2-mercapto-1-methylimidazole, is a commonly used antithyroid drug, clinically used for the treatment of various hyperthyroidism (commonly known as "hyperthyroidism"), especially for the treatment of In patients with mild and moderate thyroid enlargement, its mechanism of action is to inhibit the synthesis of thyroxine and triiodothyronine. [0003] The synthetic method of m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/84
CPCC07D233/84
Inventor 李光文李剑平倪国成
Owner CHANGZHOU TIANHUA PHARMA
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