Production methods of luliconazole and hydrochloride thereof

Abstract

The invention discloses production methods of luliconazole and hydrochloride thereof. The production method of the luliconazole hydrochloride comprises the following step of: i, with or without inert gas protection, reacting a luliconazole product with hydrogen chloride in a mixed solvent of an ether solvent and an ester solvent to obtain the luliconazole hydrochloride. The production method of the luliconazole comprises the following step of: a, with or without inert gas protection, reacting the luliconazole hydrochloride with an alkaline substance in a mixed solvent of water and an ester solvent to obtain luliconazole. According to the methods disclosed by the invention, the luliconazole hydrochloride and the alkaline substance react to produce luliconazole, the target product is convenient to separate and purify, a luliconazole product with high purity and high e.e. value can be conveniently obtained, and a brand new process route is provided for the production of luliconazole.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a production method of luliconazole and its hydrochloride. Background technique [0002] Luliconazole, CAS number: 187164-19-8, chemical name: (R,E)-2-(4-(2,4-dichlorophenyl)-1,3-dithiolane-2-ylidene )-2-(1H-imidazol-1-yl)acetonitrile, English name: (R,E)-2-(4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene)-2- (1H-imidazol-1-yl)acetonitrile, its structural formula is as follows: [0003] [0004] Luliconazole is an imidazole antifungal drug, which mainly inhibits the activity of lanosterol demethylase and reduces the level of ergosterol to interfere with the synthesis of fungal cell walls and the growth of fungi, except for the treatment of tinea pedis and jock itch In addition to tinea corporis, it is also developed for onychomycosis (onychomycosis) treatment, etc., and its products have been listed and sold in countries and regions such as Japan, India, China and the Unit...

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Problems solved by technology

[0005] However, for luliconazole (E configuration) as a drug, it is not only necessary to strictly control the content of impurities such as unreacted raw materials and by-products to improve its purity, but also to strictly control its enantiomer (Z configuration). ) content to improve its optical purity, because for luliconazole (E configuration), its enantiomer (Z configuration) is also an impurity, which affects its efficacy

[0006] In order to meet the high requirements of luliconazole (E configuration) in terms of purity and optical purity, Chinese patent CN1194582A provides a milligram-level laboratory preparation method, which is to mix 1-cyanomethylimidazole, carbon disulfide, and potassium hydroxide in The dithiolate solution generated by the reaction in DMSO was added dropwise to the DMSO solution of (S)-1-[(2,4-dichlorophenyl)-2-bromoethyl]methanesulfonate, and the reaction was complete with stirring Finally, the reaction mixture was poured into ice water, extracted with ethyl acetate, the organic phase was washed and dried, and the solvent was removed, the residue was purified by silica gel column chromatography, and then recrystallized with a mixed solvent of ethyl acetate-n-hexane, Obtained 350 mg of product with an optical purity of 95% enantiomeric excess, based on (S)-1-[(2,4-dichlorophenyl)-2-bromoethyl] methanesulfonate, the yield was 36%; it can be seen that this method needs to be purified by silica gel column chromatography, which is not conducive to large-scale mass production, and is only applicable to the laboratory level. After the two measures, the optical purity can reach 95%, which is still not ideal, and the yield is not high at the same time

[0007] The Chinese patent application CN105566309A discloses a synthetic method for luliconazole, in which the reaction solution of cyanomethylimidazole, carbon disulfide and sodium hydroxide in DMSO is added dropwise to compound 4((S)-2,2',4'-tri Chlorobenzene methanesulfonate) in DMSO solution, reacted overnight at room temperature, then added to ice water, added ethyl acetate, stirred and separated, the water layer was extracted with ethyl acetate, combined organic phase, washed with saturated sodium chloride solution , concentrate, add sherwood oil, stir, separate out solid, filter, dry, recrystallize with ethyl acetate, obtain orange-yellow solid 142g, yield 40%; Although this method is improved to the output level of gram, yield also improves slightly , but from the orange-yellow appearance of its products, it is not advisable to sacrifice the quality of the product (eg, purity, optical purity, etc.)

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