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Preparation method of azole antifungal drug

A technology of imidazole and azole oil, which is applied in the field of drug preparation, can solve problems such as complex operation, easy decomposition, and easy deliquescent, and achieve the effects of simplifying the process, increasing the yield, and not easily absorbing water

Pending Publication Date: 2020-11-03
上海福乐医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method solves the problem that 1-(cyanomethyl) imidazole is extremely easy to absorb water and deliquescence, and (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate is unstable at room temperature. , easy to decompose technical problems; solved the technical problems of low conversion rate of luliconazole crystallization and complicated operation

Method used

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  • Preparation method of azole antifungal drug
  • Preparation method of azole antifungal drug
  • Preparation method of azole antifungal drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Embodiment 1, synthesis (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate

[0076]

[0077] Add 6 kg of dichloromethane into a 20-liter four-neck flask, add 2 kg of (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol under stirring, and the inner temperature is 2°C. After adding 0.96 kg of triethylamine, keep the internal temperature at 0-5°C, add 1.06 kg of methanesulfonyl chloride dropwise, control the dropping time to 0.7 hours, and continue stirring for 20 minutes after the dropping is completed.

[0078] Add 2 kg of water to the reaction flask to terminate the reaction, separate the water phase, extract the water phase once with dichloromethane, combine the organic phase, wash the organic phase with 2 mol / L hydrochloric acid solution, wash with saturated sodium bicarbonate solution, and wash with water , adding anhydrous sodium sulfate and drying for 30 minutes.

[0079] The organic phase was distilled to collect 5.6 kg of dichloromethane fractions, and 3 kg of...

Embodiment 2

[0080] Embodiment 2, synthetic 1-(cyanomethyl) imidazoles

[0081]

[0082] Add 1900 grams of acetonitrile, 230 grams of anhydrous sodium sulfate solid, 508 grams of imidazole and 320 grams of sodium hydroxide powder into a 5-liter reaction flask; keep the inner temperature at -5 to 5°C and stir for 10 minutes.

[0083] Control the temperature at -5 to 5°C, add 608 grams of chloroacetonitrile dropwise to the above 5 liter reaction flask, the dropping time is controlled at 1.2 hours, after the dropping is completed, continue to stir and react for 10 minutes. After the stirring reaction finishes, remove the insoluble matter by filtration, the mother liquor is distilled and concentrated to obtain 1070 grams of oil, add 1500 grams of dichloromethane and 850 grams of toluene to the oil, stir for 10 minutes, and separate the organic phase after standing for 10 minutes , Distilled and concentrated to obtain 670 grams of 1-(cyanomethyl) imidazole oil, which was crystallized with 14...

Embodiment 3

[0084] Embodiment 3, synthetic intermediate (VIII)

[0085]

[0086] Add 450 grams of 1-(cyanomethyl) imidazole to a 10-liter reaction flask, add 5 kilograms of DMSO, and stir until a homogeneous solution; add 325 grams of carbon disulfide to the system; keep the internal temperature at 10-35°C, and distribute Add 480 grams of potassium hydroxide in batches, and keep stirring for 0.5 hours after adding.

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Abstract

The invention discloses a preparation method of an azole antifungal drug, which comprises the following steps: (a) reacting (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol with methanesulfonyl chloride, and crystallizing the reaction product to obtain a compound crystal as shown in a formula (III); (b) reacting imidazole with chloroacetonitrile, and crystallizing the reaction product to obtain 1-(cyanomethyl)imidazole crystals; (c) reacting the 1-(cyanomethyl)imidazole with carbon disulfide under an alkaline condition to obtain a compound as shown in a formula (VIII); (d) reacting the compound as shown in the formula (III) with a compound as shown in a formula (VIII) under an alkaline condition to obtain luliconazole oil; and (e) dissolving the luliconazole oil into acetonitrile, dropwise adding water into the solution, separating out crystals, and filtering the mixture while hot to obtain a luliconazole pure product. According to the method, industrially common and cheap raw materials areselected, the luliconazole pure product conforming to the medicine is efficiently prepared, so that the invention solves the technical problems that the luliconazole purification yield is low, 1- (cyanomethyl) imidazole is prone to water absorption and deliquescence, and (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate is unstable and easy to decompose at the normal temperature.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and relates to a preparation method of an azole antifungal drug, in particular to an industrial preparation method of an azole antifungal drug luliconazole. Background technique [0002] Luliconazole (C 14 h 9 C 12 N 3 S 2 )(luliconazole), the chemical name is (-)-(E)-(4R)-4-(2,4-dichlorophenyl)-1,3-dithiolane-2-subsubstituted (1H-imidazole -1-substituted) acetonitrile, as shown in the following general formula (IX): [0003] [0004] Luliconazole is an imidazole antifungal drug developed by Nippon Pesticide Co., Ltd. It was first launched in Japan in 2005. The specifications of cream and lotion are both 1%. It is a widely used azole antifungal drug in clinical practice. Interferes with the synthesis of Ergosterol. [0005] Luliconazole is currently on the market in many countries (the domestic product name is Lulit), and it was approved by the FDA in 2013 for interdigital tinea pedi...

Claims

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Application Information

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IPC IPC(8): C07D409/06C07D233/56C07C303/44C07C309/66
CPCC07B2200/07C07C303/44C07D233/56C07D409/06C07C309/66
Inventor 于晓琳张蕴仪高雅胡雨群
Owner 上海福乐医药科技有限公司
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