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Preparation method of methimazole

A technology of methimazole and methimazole, which is applied in the field of drug synthesis, can solve the problems that methimazole needs to be improved, and achieve the effects of eliminating extraction and washing steps, easy post-processing, and improving reaction yield and purity

Active Publication Date: 2016-05-04
WUHAN CONFORM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Therefore, the preparation method of existing methimazole still needs to be improved

Method used

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  • Preparation method of methimazole
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  • Preparation method of methimazole

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preparation example Construction

[0020] Concrete preparation method of the present invention is as follows:

[0021] N-methylimidazole is dissolved in tetrahydrofuran, and n-butyllithium-n-hexane solution is added dropwise at -15°C to 0°C, and then incubated for 0.5 to 2 hours. Then add elemental sulfur in batches at this temperature, heat up and reflux for 6-10 hours after the addition is complete, no raw material spots are detected by thin-layer chromatography, then quench the reaction in an ice-water bath, add dilute hydrochloric acid to adjust the pH to 5.0-7.0, and then The reaction system was concentrated to dryness. The concentrated solid was added to ethyl acetate and activated carbon, heated and dissolved, stirred at reflux for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to obtain methimazole.

[0022] The synthetic route of the present invention is as follows:

[0023]

[0024] We surprisingly found that N-methylimidazole, n-butyllithium and sulfur powder particip...

Embodiment 1

[0030] Add 8.21 grams (100mmoL) of N-methylimidazole and 80ml tetrahydrofuran into a three-necked reaction flask, then drop the temperature to -15°C and add 48ml of n-butyllithium-n-hexane solution (containing n-butyllithium 120mmoL, 2.5mol / L), after the dropwise addition was completed, it was incubated and reacted at -15°C for 2 hours, then 3.84 grams (120mmoL) of elemental sulfur was added in batches at this temperature, and after the addition was completed, it was slowly raised to room temperature and stirred for 10 hours. Thin-layer chromatography detected no raw material spots, then quenched in an ice-water bath, added dilute hydrochloric acid to adjust the pH to 5.0-5.5, and then concentrated the reaction system to dryness under pressure. Then the concentrated solid was added to ethyl acetate and activated carbon for heating and dissolving, refluxed for decolorization for about 1 hour, filtered, and the filtrate was concentrated under reduced pressure to obtain 9.04 gram...

Embodiment 2

[0032] Add 8.21 grams (100mmoL) of N-methylimidazole and 80ml tetrahydrofuran into a three-necked reaction flask, then drop the temperature to -10°C and add 48ml of n-butyllithium-n-hexane solution (containing n-butyllithium 120mmoL, 2.5mol / L), after the dropwise addition was completed, it was incubated and reacted at -10°C for 1.5 hours, then 4.48 grams (140mmoL) of elemental sulfur was added in batches at this temperature, and the temperature was raised to reflux for 9 hours after the addition was completed. Thin-layer chromatography detected no raw material spots, then quenched in an ice-water bath, added dilute hydrochloric acid to adjust the pH to 5.5-6.0, and then concentrated the reaction system to dryness under pressure. Then the concentrated solid was added to ethyl acetate and activated carbon for heating and dissolving, refluxed for decolorization for about 1 hour, filtered, and the filtrate was concentrated under reduced pressure to obtain 9.52 grams of light yello...

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Abstract

The invention relates to a preparation method of methimazole. The method specifically comprises the following step: enabling reaction of N-methylimidazole, N-butyllithium and powdered sulfur in an organic solvent to obtain methimazole. The preparation method disclosed by the invention is simple in process, mild in condition, simple to operate, easy for post treatment, applicable for industrialized production, and capable of greatly improving the reaction yield of methimazole.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of methimazole. Background technique [0002] Methimazole is an antithyroid drug. It is suitable for various types of hyperthyroidism, especially for patients with mild to moderate thyroid enlargement; adolescents, children and elderly patients; patients who relapse after thyroid surgery and who are not suitable for treatment with radioactive iodine-131 ; Preoperative preparation and as an adjuvant treatment of iodine-131 radiotherapy. [0003] (J.Org.Chem.1994,59,4691-4692) disclose a kind of preparation method of methimazole in the prior art, take N-methylimidazole as raw material, react with n-butyllithium, and then Sulfur powder was added for reflux reaction, and finally the yield of crude methimazole was 42%. The reaction conditions of this method are harsh, and n-butyllithium is added dropwise at -78°C, which is difficult for indus...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/84
CPCC07D233/84
Inventor 周小顺童国富牟东升李进赵志雄
Owner WUHAN CONFORM PHARMA CO LTD
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