CN107162983B

CN107162983B - Synthesis and refining method of methimazole

Info

Publication number: CN107162983B
Application number: CN201710439119.2A
Authority: CN
Inventors: 李光文; 李剑平; 倪国成
Original assignee: Changzhou Tianhua Pharmaceutical Co ltd
Current assignee: Changzhou Tianhua Pharmaceutical Co ltd
Priority date: 2017-06-12
Filing date: 2017-06-12
Publication date: 2020-04-28
Anticipated expiration: 2037-06-12
Also published as: CN107162983A

Abstract

The invention discloses a method for synthesizing and refining methimazole, belonging to the field of medicine synthesis. In the method, methylamino acetaldehyde ethylene acetal and ammonium thiocyanate are used as raw materials, and condensation reaction is carried out in the presence of an acid catalyst and a phase transfer catalyst; after the reaction is finished, adding saturated salt water, mixing uniformly, then adding an organic solvent for extraction, drying and concentrating the obtained organic layer to obtain crude methimazole, heating and dissolving the obtained crude methimazole in the solvent, adding activated carbon for decoloring, filtering and drying to obtain refined methimazole. The method is a preparation method which is simple and convenient to operate and suitable for industrial production.

Description

Synthesis and refining method of methimazole

Technical Field

The invention belongs to the field of medicine synthesis, relates to a method for synthesizing and refining methimazole, and particularly relates to a preparation method which takes aminoacetaldehyde ethylene glycol and ammonium thiocyanate as raw materials, takes hydrochloric acid as a catalyst, performs condensation reaction under the action of a phase transfer catalyst to obtain a methimazole crude product, and obtains methimazole meeting pharmacopoeia standards through refining, wherein the preparation method is suitable for industrial production.

Background

Methimazole (Methimazole), the chemical name of which is 2-mercapto-1-methylimidazole, is a commonly used antithyroid drug, is clinically used for treating various hyperthyroidism (commonly called hyperthyroidism), is particularly suitable for patients with mild disease and mild and moderate enlargement of thyroid gland, and has an action mechanism of inhibiting the synthesis of thyroxine and triiodothyronine.

At present, the synthesis method of methimazole mainly comprises the following two methods: the method comprises the following steps:

performing condensation reaction on methylamino acetaldehyde ethylene acetal as a raw material and a potassium thiocyanate aqueous solution under an acidic condition, removing water by reduced pressure distillation after the reaction is finished, adding ethyl acetate to dissolve a substrate, filtering to remove insoluble substances, removing ethyl acetate by reduced pressure distillation, separating out solids, and adding purified water to recrystallize to obtain the product methimazole. The process has the advantages of short route and high yield, but the operation process is complex, the water solubility of the methimazole is high, and the reduced pressure dehydration is needed after the reaction is finished, so the energy consumption is high, the production period is long, and the production cost is increased by using the raw material with expensive potassium thiocyanate.

And (II) performing hydrogen extraction reaction on N-methylimidazole serving as a raw material by adopting N-hexane solution of N-butyllithium at a low temperature, adding sulfur powder in batches, reacting at room temperature for 10 hours, adding water for quenching reaction, acidifying, concentrating to obtain a crude methimazole product, and adding ethyl acetate for recrystallization to obtain a light yellow product methimazole with the purity of over 99%. However, the process needs to apply n-butyllithium as a hydrogen extraction reagent, needs strict anhydrous and anaerobic reaction, strictly controls the reaction temperature, has extremely strict operating conditions and has serious potential safety hazard, and is not beneficial to industrial production.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides the production method which has the advantages of simple process, easily obtained raw materials, mild reaction conditions and short production period and can be suitable for industrialization.

A method for synthesizing and refining methimazole, which takes methylamino acetaldehyde ethylene acetal and ammonium thiocyanate as raw materials to carry out condensation reaction in the presence of acid catalyst and phase transfer catalyst; after the reaction is finished, adding saturated salt water, mixing uniformly, then adding an organic solvent for extraction, drying and concentrating the obtained organic layer to obtain crude methimazole, heating and dissolving the obtained crude methimazole in the solvent, adding activated carbon for decoloring, filtering and drying to obtain refined methimazole.

The technical scheme of the invention is as follows: the mol ratio of the methylamino acetaldehyde ethylene acetal to the ammonium thiocyanate is 1: 1.2-1: 3.

the technical scheme of the invention is as follows: the acid catalyst selected in the condensation reaction is hydrochloric acid, sulfuric acid or p-toluenesulfonic acid; preferably, the method comprises the following steps: the molar ratio of the acid catalyst to the methylamino acetaldehyde ethylene acetal selected in the condensation reaction is 0.05: 1-0.8: 1.

the technical scheme of the invention is as follows: the phase transfer catalyst selected for the condensation reaction is tetrabutylammonium bromide or benzyltriethylammonium chloride. Preferably, the method comprises the following steps: the molar ratio of the phase transfer catalyst selected in the condensation reaction to the methylamino acetaldehyde ethylene acetal is 0.01: 1-0.25: 1.

in other embodiments: the phase transfer catalyst selected by the condensation reaction is polyethylene glycol, and the mass ratio of the polyethylene glycol to the methylaminoacetaldehyde ethylene acetal is 0.01-1: 1.

the technical scheme of the invention is as follows: the condensation reaction temperature is 30-100 ℃, and the preferable reaction temperature is 40-70 ℃; the condensation reaction time is 4-8 h.

The technical scheme of the invention is as follows: the organic solvent used for extraction is tetrahydrofuran or 1, 4-dioxane.

The technical scheme of the invention is as follows: the solvent used for dissolving the crude product is one or a mixture of methanol, ethanol, tetrahydrofuran, acetone and 1, 4-dioxane.

Advantageous effects

The method is an effective method which has the advantages of mild reaction conditions, safe operation, simple operation process, convenient post-treatment, high product yield up to 90.6 percent, low cost and short production period and is easy for industrialized production, and the refined product meets the pharmacopoeia standards.

Detailed Description

The present invention is further illustrated by the following examples, but the scope of the invention is not limited thereto.

Example 1

Mixing methylaminoacetaldehyde ethylene acetal (294g, 2.0mol, 1.0eq), ammonium thiocyanate (198g, 2.6mol, 1.3eq) and deionized water (200mL), stirring for dissolving, adding benzyltriethylammonium chloride (22.8g, 2.6mol, 0.05eq), p-toluenesulfonic acid (38.1g, 0.2mol, 0.1eq), heating to 50 ℃ for condensation reaction for 8h, and monitoring disappearance of raw materials by TLC (V is monitored by TLC_PE/_EA＝15：1，KMnO₄Color development), after completion of the reaction, 200mL of saturated saline and tetrahydrofuran (300mL × 2) were added, extracted, separated,the organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give 171g of crude methimazole as a pale red solid in 75% yield and 94.7% purity.

150g of light red crude methimazole product is added into 300mL of methanol, after the mixture is heated and completely dissolved, activated carbon is added for decolorization, reflux is carried out for 30min, the mixture is filtered while the mixture is hot, the mixture is cooled to 0 ℃, the filtration is carried out, and vacuum drying is carried out at 45 ℃ to obtain 139g of white solid methimazole, wherein the yield is 92.7%. Measurement of m.p: 145 ℃ and the purity is 99.6 percent.

Example 2

Dissolving methylaminoacetaldehyde ethylene acetal (221g, 1.5mol, 1.0eq), ammonium thiocyanate (206g, 2.7mol, 1.8eq) and deionized water (200mL) under stirring, adding PEG-2000(15g), heating to 40 ℃, slowly adding 98% concentrated sulfuric acid (40mL, 0.74mol) into the solution for 1h, heating to 70 ℃ for reaction for 5h, and monitoring the disappearance of raw materials by TLC (V)_PE/_EA＝15：1，KMnO₄Color development), after the reaction was completed, 200mL of saturated saline solution and tetrahydrofuran (300mL × 2) were added, extraction and liquid separation were performed, organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 139.4g of crude methimazole as a pale red solid, which was 81.4% in yield and 95.8% in purity.

Adding 120g of light red crude methimazole into 200mL of ethanol, heating to completely dissolve, adding activated carbon for decolorization, refluxing for 30min, filtering while hot, cooling to 0 ℃, filtering, and vacuum drying at 45 ℃ to obtain 115g of white solid methimazole, wherein the yield is 95.8%. Measurement of m.p: the purity is 99.6 percent at 146 ℃.

Example 3

Dissolving methylaminoacetaldehyde ethylene acetal (353g, 2.4mol, 1.0eq), ammonium thiocyanate (274g, 3.6mol, 1.5eq) and deionized water (260mL) under stirring, adding tetrabutylammonium bromide (38.7g,0.12mol, 0.05eq) to the solution, heating to 40 ℃, slowly adding 37% concentrated hydrochloric acid (50mL, 0.6mol) to the solution for 1h, heating to 60 ℃ to react for 6h, and monitoring by TLC that the raw materials disappear (V)_PE/_EA＝15：1，KMnO₄Color development), after the reaction was completed, 300mL of saturated saline solution, 1, 4-dioxane (450 mL. multidot.2) was added, extraction was performed, liquid separation was performed, organic layers were combined, dried over anhydrous sodium sulfate, and concentration was performed to obtain a light solution255g of red solid crude methimazole, the yield is 93.2 percent, and the purity is 96.8 percent.

Adding 250g of light red crude methimazole into 500mL of acetone, heating to completely dissolve, adding activated carbon for decolorization, refluxing for 30min, filtering while hot, cooling to 0 ℃, filtering, and vacuum drying at 45 ℃ to obtain 243g of white needle-like crystal methimazole, wherein the yield is 97.2%. Measurement of m.p: the purity is 99.7 percent at 146 ℃.

Claims

1. A method for synthesizing and refining methimazole is characterized in that: 294g, 2.0mol of methylaminoacetaldehyde ethylene acetal, 198g, 2.6mol of ammonium thiocyanate and 200mL of deionized water are mixed and stirred for dissolution, then 22.8g, 2.6mol of benzyltriethylammonium chloride, 38.1g and 0.2mol of p-toluenesulfonic acid are added, the temperature is raised to 50 ℃ for condensation reaction for 8 hours, and TLC monitors that the raw materials disappear: v_PE/_EA=15：1，KMnO₄Developing, after the reaction is finished, adding 200mL of saturated saline solution and 300mL of tetrahydrofuran 2, extracting, separating liquid, combining organic layers, drying by anhydrous sodium sulfate, and concentrating to obtain 171g of pale red solid thiamazole crude product with the yield of 75% and the purity of 94.7%;

adding 150g of light red crude methimazole into 300mL of methanol, heating to completely dissolve, adding activated carbon for decolorization, refluxing for 30min, filtering while hot, cooling to 0 ℃, filtering, and vacuum drying at 45 ℃ to obtain 139g of white solid methimazole, wherein the yield is 92.7%; measurement of m.p: 145 ℃ and the purity is 99.6 percent.

2. A method for synthesizing and refining methimazole is characterized in that: 221g of methylamino acetaldehyde ethylene acetal, 1.5mol of methylamino acetaldehyde ethylene acetal, 206g of ammonium thiocyanate and 200mL of deionized water are stirred and dissolved, then 15g of PEG-2000 is added, the temperature is raised to 40 ℃, then 40mL of 98% concentrated sulfuric acid and 0.74mol are slowly added into the mixture, the addition is finished after 1h, the temperature is raised to 70 ℃, the reaction is carried out for 5h, and TLC monitors that the raw materials disappear: v_PE/_EA=15：1，KMnO₄Developing color; after the reaction was completed, 200mL of saturated brine and 300mL of 2-tetrahydrofuran were added, followed by extraction, liquid separation, combination of organic layers, drying over anhydrous sodium sulfate, and concentration to obtain light red139.4g of a crude product of the solid methimazole with the yield of 81.4 percent and the purity of 95.8 percent;

adding 120g of light red crude methimazole into 200mL of ethanol, heating to completely dissolve, adding activated carbon for decolorization, refluxing for 30min, filtering while hot, cooling to 0 ℃, filtering, and vacuum drying at 45 ℃ to obtain 115g of white solid methimazole, wherein the yield is 95.8%; measurement of m.p: the purity is 99.6 percent at 146 ℃.

3. A method for synthesizing and refining methimazole is characterized in that: 353g of methyl, 2.4mol of aminoacetaldehyde ethylene acetal, 274g of ammonium thiocyanate and 260mL of deionized water are stirred and dissolved, then 38.7g of ammonium tetrabutylbromide is added, 0.12mol of ammonium tetrabutylbromide is heated to 40 ℃, then 50mL of 37% concentrated hydrochloric acid and 0.6mol of ammonium tetrabutyl bromide are slowly added into the mixture, 1h of the ammonium tetrabutyl bromide is added, then the mixture is heated to 60 ℃ to react for 6h, and TLC monitors that the raw materials disappear: v_PE/_EA=15：1，KMnO₄Developing color; after the reaction is finished, 300mL of saturated saline solution and 450mL of 1, 4-dioxane 2 are added, extraction and liquid separation are carried out, organic layers are combined, anhydrous sodium sulfate is dried, and concentration is carried out, so that 255g of light red solid thiamazole crude product is obtained, the yield is 93.2%, and the purity is 96.8%;

adding 250g of light red crude methimazole into 500mL of acetone, heating to completely dissolve, adding activated carbon for decolorization, refluxing for 30min, filtering while hot, cooling to 0 ℃, filtering, and vacuum drying at 45 ℃ to obtain 243g of white needle-like crystal methimazole, wherein the yield is 97.2%; measurement of m.p: the purity is 99.7 percent at 146 ℃.