Preparation method of methimazole

Abstract

The invention provides a preparation method of methimazole, and relates to the field of medicinal chemistry. The method comprises the following steps: by taking 1-methylimidazole, ethyl chloroformate and sulfur as raw materials, reacting under an alkaline condition to generate an intermediate 3-methyl-2-thio-2, 3-dihydro-1H-imidazole-1-carboxylic acid ethyl ester; and then hydrolyzing under an alkaline condition to generate methimazole. The method is simple to operate, mild in condition and suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a method for preparing methimazole, a raw material medicine. Background Art

[0002] 2-Mercapto-1-methylimidazole (CAS: 60-56-0, C4H6N2S, methimazole) is a widely used antithyroid drug. Its mechanism of action is to inhibit thyroid peroxidase, thereby hindering the oxidation of iodide absorbed into the thyroid gland and the coupling of tyrosine, and hindering the synthesis of thyroxine (T4) and triiodothyronine (T3). Animal experiments have observed that the drug can inhibit the synthesis of antibodies by B lymphocytes, reduce the level of thyroid stimulating antibodies in the blood circulation, and restore the function of inhibitory T cells to normal. It is suitable for various types of hyperthyroidism, including Graves' disease, thyroid adenoma, nodular goiter and thyroid cancer.

[0003] J.Am.Chem.Soc., 71, 4000. (1949) discloses a method for preparing a derivative of 2-mercapto-1-methylimidazole by reacting substituted aminoacetal with thiocyanic acid, but the method only relates to a small amount of laboratory-scale reaction, and the document does not disclose a complete synthesis scheme of 2-mercapto-1-methylimidazole. The synthesis method of methimazole currently mainly includes the following two types: 1) using methylaminoacetaldehyde ethylene glycol as raw material and potassium thiocyanate aqueous solution to carry out condensation reaction under acidic conditions, after the reaction is completed, decompression distillation is performed to remove moisture, then ethyl acetate is added to dissolve the substrate, insoluble matter is removed by filtration, ethyl acetate is removed by decompression distillation, solid is separated out, and then purified water is added for recrystallization to obtain the product methimazole. Although the process has a shorter synthetic route, the operating process is complicated, methimazole is highly water-soluble, and decompression dehydration is required after the reaction is completed, so energy consumption is large, production cycle is long, and potassium thiocyanate is expensive to use, and production cost is high, which is unfavorable for industrial application. 2) 1-methylimidazole is used as raw material, and n-butyl lithium is used for hydrogen extraction reaction in n-hexane solution under low temperature conditions, and then sulfur powder is added in batches, and the reaction is reacted at room temperature for 10 hours, and then water is added to quench the reaction, and the crude methimazole is obtained by acidification and concentration, and then ethyl acetate is added for recrystallization to obtain a light yellow product methimazole with a purity of more than 99%. However, this process requires the use of n-butyl lithium as a hydrogen extraction reagent, as well as strict anhydrous and oxygen-free reaction, strict control of reaction temperature, and extremely harsh operating conditions, which have serious safety hazards and are also unfavorable for industrial production. Therefore, a method for developing a methimazole synthesis route that is simple in steps, easy to obtain raw materials, mild in reaction conditions, and short in production cycle and suitable for industrial production has become a technical problem to be solved in this area. Summary of the invention

[0004] In view of the above problems, the present application provides a method for preparing methimazole with simple operation and mild conditions to improve the yield and product purity of the synthetic route.

[0005] Specifically, the present application is implemented through the following technical routes: First, the present application provides a preparation method of methimazole, and the preparation steps are as follows:

[0006] 1) Add 1-methylimidazole to solvent I, control the internal temperature at 10-15°C, add ethyl chloroformate and base I dropwise in sequence, react at 25°C-35°C for 1h after the addition is complete; then add sulfur powder (particle size preferably <100 μm), continue to react at 25°C-35°C until the reaction of 1-methylimidazole is complete (the remaining mass is less than 0.5% of the initial amount); cool to 5°C-10°C, stir and crystallize, filter the reaction solution, take the filter cake and rinse with solvent I to obtain the intermediate product 3-methyl-2-thio-2,3-dihydro-1H-imidazole-1-carboxylic acid ethyl ester (IV);

[0007] The solvent I comprises at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether and toluene, preferably 2-methyltetrahydrofuran;

[0008] The base I comprises at least one of triethylamine, N,N-diisopropylethylamine, DMAP and pyridine, preferably triethylamine;

[0009] The molar ratio of ethyl chloroformate to 1-methylimidazole added in the above step is 1 to 1.5:1, preferably 1.2:1;

[0010] The molar ratio of the added base I to 1-methylimidazole is 1 to 2.0:1, preferably 1.05:1;

[0011] The molar ratio of the added sulfur to 1-methylimidazole is 1 to 1.5:1, preferably 1:1;

[0012] 2) adding a base II solution to the ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate (IV) obtained in step 1) at 0°C-5°C, stirring and reacting at 25°C-35°C, and hydrolyzing the intermediate product (IV) under alkaline conditions until the reaction of the intermediate ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate (IV) is completed (the remaining amount is less than 0.5% of the initial amount);

[0013] The base II comprises at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and sodium hydride, preferably sodium hydroxide;

[0014] The molar ratio of the added base II to ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate is 1.0-3.0:1, preferably 1.5:1.

[0015] 3) The reaction solution is heated to 60° C. to 70° C. and concentrated to dryness, and then the residue obtained by extraction and concentration is extracted with solvent II, filtered to obtain a filter cake and a filtrate; the filter cake is washed with solvent II, the washing liquid and the filtrate are combined, and concentrated to dryness at 40° C. to 50° C. to obtain a crude methimazole;

[0016] The solvent II comprises at least one of dichloromethane, ethyl acetate, methyl tert-butyl ether and toluene, preferably dichloromethane;

[0017] 4) Add solvent III to the crude methimazole, heat to 65°C-75°C, add activated carbon, stir for reaction and filter, take the filtrate for crystallization at 5°C-10°C; take the filter cake after filtration and rinse with solvent III, and then heat at 50°C

[0018] The obtained white solid is the target product methimazole (2-mercapto-1-methylimidazole).

[0019] The solvent III includes at least one of methanol, ethanol, isopropanol, acetonitrile and acetone, preferably isopropanol.

[0020] The chemical equations involved in the above reactions are as follows:

[0021]

[0022] The present invention uses 1-methylimidazole, ethyl chloroformate and sulfur as raw materials, reacts under alkaline conditions to generate an intermediate 3-methyl-2-thio-2,3-dihydro-1H-imidazole-carboxylic acid ethyl ester; then hydrolyzes under alkaline conditions to generate the final product methimazole. Compared with the existing synthesis method, the synthesis route of the present invention has the following application effects:

[0023] 1) The first step of the reaction route of the present application uses 2-methyltetrahydrofuran as the reaction solvent, and the amount of the solvent is 8.1 times the volume of 1-methylimidazole, which can ensure that the reaction is fully stirred and the reaction effect is better.

[0024] 2) The feeding amount of ethyl chloroformate is 1.2 equivalents of 1-methylimidazole, and the reaction of 1-methylimidazole is basically completed, thereby improving the yield.

[0025] 3) The present application uses sulfur powder for the reaction, which increases the contact rate between the reaction materials, can reduce the reaction time and reduce energy consumption.

[0026] 4) After the second step reaction, the conventional method uses activated carbon to decolorize the extract, but the decolorization effect is poor. The reaction route of the present application heats the crude product with isopropanol and then adds activated carbon, and decolorizes while refining. The color of the finished product is white, which proves that it has a high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Attached Figure 1 is a high performance liquid chromatogram of the intermediate IV prepared in Example 1;

[0028] Attached Figure 2 is a high performance liquid chromatogram of the target product V prepared in Example 2;

[0029] Attached Figure 3 The target product V prepared in Example 2 1 H-NMR spectrum. DETAILED DESCRIPTION

[0030] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available.

[0031] The raw material 1-methylimidazole (I) was purchased from Shanghai Anaiji Chemical Co., Ltd.; ethyl chloroformate (II) and sulfur (III) were purchased from Shanghai MacLean Biochemical Technology Co., Ltd.

[0032] The "water" used in the following examples refers to purified water prepared by conventional methods.

[0033] Example 1 Preparation of 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylic acid ethyl ester

[0034] 1) 455 g of 2-methyltetrahydrofuran and 65 g (0.791 mol, 1.0 eq) of 1-methylimidazole were added to a 2L three-necked flask, stirred evenly, cooled to 10°C (in the specific implementation, the initial reaction temperature can achieve the purpose of the invention within the range of 10-15°C), and 103.07 g (0.95 mol, 1.2 eq) of ethyl chloroformate was added dropwise, and the addition was completed in about half an hour. The internal temperature was controlled at 10-15°C during the addition process, and the reaction was stirred for half an hour after the addition was completed; then 84.11 g (0.831 mol, 1.05 eq) of triethylamine was slowly added dropwise, and the internal temperature was continued to be controlled at 10-15°C. The addition was completed in about half an hour, and then the temperature was controlled at 25°C-35°C and the reaction was stirred for 1 hour, and the stirring rate was 480 rpm.

[0035] 2) Then add 25.38g (0.791mol, 1.0eq) sulfur powder (crushed to a particle size of <100μm), control the temperature at 25℃~35℃ and stir to react for about 20 hours. Sampling and detection (chromatograph: Agilent; chromatographic column: 4.6mmx25cm, 5um (C18 column); mobile phase A: 0.02mol / L potassium dihydrogen phosphate, pH value adjusted to 3.2; B: methanol; A:B 70:30, isocratic elution; wavelength 210nm, column temperature 30℃, flow rate 0.5ml / min. Same below), until the residual mass of 1-methylimidazole is less than 0.5%, which is the end point of the reaction.

[0036] The reaction mixture was cooled to 10°C (in the specific implementation, cooling to 5°C to 10°C can achieve the purpose of crystallization), stirred for 1 hour, the precipitated solid was filtered, and the filter cake was rinsed with 65 ml of 2-methyltetrahydrofuran. The obtained solid was the crude intermediate (IV).

[0037] 3) The crude product was stirred and slurried with 325 g of purified water at 25° C. to 35° C. for 1 h, filtered, and the filter cake was dried at 60° C. to 70° C. for 6 h to obtain 130 g of ethyl 3-methyl-2-thio-2,3-dihydro-1H-imidazole-1-carboxylate (IV) as a white solid. The purity of the solid was 98.40% by chromatography, and the yield was 88.2%. The chromatogram was as follows: Figure 1 shown.

[0038] Example 2

[0039] 1) Into a 2L three-necked flask, 400 g of water and 100 g (0.536 mol, 1.0 eq) of ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate (IV) prepared in Example 1 were added, stirred for 15 minutes, and then cooled to 0°C (in the specific implementation, 0°C-5°C is acceptable).

[0040] 2) Add 100 g of water and 32.21 g (0.804 mol, 1.5 eq) of sodium hydroxide to the reaction system to prepare an alkaline solution with a concentration of 24.4%, stir and react at 25° C. to 35° C. for 2 to 3 h, and detect the reaction solution (chromatograph: Agilent; chromatographic column: 4.6 mm x 25 cm, 5 um (C18 column); mobile phase A: 0.02 mol / L potassium dihydrogen phosphate, adjusted to pH 3.2; B: methanol; A: B 70:30, isocratic elution; wavelength 210 nm, column temperature 30° C., flow rate 0.5 ml / min. Same below) until the intermediate 3-methyl-2-thio-2,3-dihydro-1H-imidazole-1-carboxylic acid ethyl ester (IV) remains less than 0.5%, indicating that the reaction is complete.

[0041] 3) The reaction solution was concentrated to dryness at 60°C-70°C, 800 g of dichloromethane was added to the obtained residue, and the mixture was stirred for half an hour and filtered to obtain a filter cake and a filtrate; the filter cake was washed with 100 g of dichloromethane, the washing liquid was combined with the filtrate, and concentrated to dryness at 40°C-50°C to obtain a crude methimazole.

[0042] 4) Add 200g of isopropanol to the crude methimazole, heat to 65°C to dissolve the system, then add 5g of activated carbon, continue stirring at 65°C to 75°C for 30 minutes, filter while hot, cool the filtrate to 5°C to 10°C and stir for crystallization for 2 to 3 hours. Filter, rinse the filter cake with 50g of isopropanol, and dry at 50°C to 60°C for about 4 hours to obtain 54.6g of white solid, which is the target product methimazole (V), with a purity of 99.98% and a yield of 89%. Its chromatogram is as follows Figure 2 As shown, 1 H-NMR images Figure 3 As shown, the NMR spectrum shows that 3H is on the methyl group, the two adjacent 1Hs are on the double bond methine group, and the low-field 1H is the hydrogen on the thiol group, proving that it is the target product methimazole.

[0043] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing methimazole, characterized in that: The specific steps are as follows: 1) Add 1-methylimidazole to solvent I, and then drop ethyl chloroformate and base I in sequence at 10-15°C. After the dropwise addition is completed, react at 25°C-35°C for 1 hour; then add sulfur powder and react at 25°C-35°C until the reaction of 1-methylimidazole is complete; then cool to 5°C-10°C, crystallize, filter, take the filter cake and rinse with solvent I to obtain an intermediate product; The solvent I comprises at least one of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether and toluene; The base I comprises at least one of triethylamine, N,N-diisopropylethylamine, DMAP, and pyridine; The molar ratio of the added ethyl chloroformate to 1-methylimidazole is 1 to 1.5:1; the molar ratio of the added base I to 1-methylimidazole is 1 to 2.0:1; the molar ratio of the added sulfur to 1-methylimidazole is 1 to 1.5:1; 2) adding alkali II solution to the intermediate product prepared in step 1) at 0°C-5°C, reacting at 25°C-35°C until the intermediate product is completely reacted, concentrating the reaction solution to dryness to obtain a residue; The base II includes at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and sodium hydride; the molar ratio of the added base II to the intermediate product is 1.0 to 3.0:1; 3) Add solvent II to the residue, filter, and obtain filter residue and filtrate; wash the filter residue with solvent II, combine the eluate and the filtrate, and concentrate to dryness at 40°C to 50°C to obtain crude methimazole; The solvent II includes at least one of dichloromethane, ethyl acetate, methyl tert-butyl ether and toluene; Add solvent III to the crude methimazole, heat to 65°C-75°C, add activated carbon, stir for reaction and filter, take the filtrate for crystallization at 5°C-10°C; filter, take the filter residue and wash it with solvent III and then dry it to obtain the methimazole; the solvent III includes at least one of methanol, ethanol, isopropanol, acetonitrile and acetone.

2. The method for preparing methimazole according to claim 1, characterized in that: In step 1), the molar ratio of ethyl chloroformate to 1-methylimidazole added is 1.2:

1.

3. The preparation method of methimazole according to claim 1, characterized in that In step 1), the molar ratio of the added base I to 1-methylimidazole is 1.05:

1.

4. The method for preparing methimazole according to claim 1, wherein In step 1), the molar ratio of sulfur to 1-methylimidazole added is 1:

1.

5. The method for preparing methimazole according to claim 1, characterized in that: In step 2), the molar ratio of the added base II to the intermediate product is 1.5:

1.

6. The method for preparing methimazole according to claim 1, characterized in that: In step 4), the drying refers to drying at 50°C to 60°C.

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