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Preparation method of efinaconazole

A technology of efeconazole and difluorophenyl, which is applied in the field of preparation of toe onychomycosis drug efeconazole, can solve the problems of low cost, long steps of intermediate A, increased difficulty of compound synthesis, etc., and achieve process environmental protection The effect of economy, promotion of development, and simple process

Active Publication Date: 2015-02-04
旌德君创科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] It can be seen from this that no matter which scheme is selected, the preparation of intermediate A has disadvantages such as long steps, rare raw materials and catalysts, and low yield. The difficulty of synthesis, thus hindering the industrialization process of triazole antifungal drugs such as efeconazole

Method used

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  • Preparation method of efinaconazole
  • Preparation method of efinaconazole
  • Preparation method of efinaconazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] In the three-neck reaction flask, add nitroethane (3.0g, 40mmol), cuprochrome (0.3g, 1mmol), benzoic acid (0.13g, 1mmol) and solvent N, N-dimethylacetamide (DMA ) (10mL), cooled to -10°C, and added dropwise 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (II ) (2.3g, 10mmol) in DMA (15mL) solution, kept the temperature for 6-8 hours, and TLC detected that the reaction was complete. Add 20 mL of 1N dilute hydrochloric acid, extract 3 times with ethyl acetate (10 mL x 3), combine the organic phases, and dry over anhydrous sodium sulfate. Concentrated under reduced pressure, the resulting oil was recrystallized from n-hexane and dichloromethane (1:1, V / V), and dried in vacuo to obtain off-white solid (2R,3R)-3-nitro-2-(2,4- Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (III) 2.6g, yield 87.2%, mp.141-143℃, FAB-MS m / z: 299[M+H] + .

Embodiment 2

[0030] Add (2R,3R)-3-nitro-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)- 2-butanol (III) (1.5g, 5mmol), iron trichloride (0.14g, 0.5mmol), activated carbon 0.2g and ethanol 25mL, add 80% hydrazine hydrate (0.63g, 10mmol) dropwise at room temperature, and complete the addition Afterwards, heat up to 50-60°C, react for 4-5 hours, filter, concentrate to remove ethanol, and recrystallize the residue with ethanol and water (1:1) to obtain off-white solid (2R, 3R)-3-amino-2 -(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (IV) 1.2g, yield 90.0%, mp.95- 98℃, FAB-MS m / z: 270[M+H] + .

Embodiment 3

[0032] Add (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2 into a three-necked reaction flask -Butanol (IV) (1.4g, 5mmol), diisopropylethylamine (1.4g, 11mmol) and 20mL of N,N-dimethylacetamide, heated to 50-55°C, stirred until the system was dissolved uniformly. Slowly add 1,5-dichloro-3-methylenepentane (V) (0.8 g, 5.5 mmol) in 20 mL of N, N-dimethylacetamide solution dropwise into the reaction liquid, and the drop is completed in about 0.5 hours. The temperature was raised to 80° C., and the reaction was continued for 24 hours, and the reaction was detected by TLC. The solvent was recovered under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with 10% sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Ethyl acetate was recovered under reduced pressure, and the residue was recrystallized from acetone to obtain 1.4 g of white solid Efeconazole (I), yield 80.1%, mp...

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Abstract

The invention discloses a preparation method of efinaconazole (I). The preparation method comprises the following steps: performing asymmetric addition reaction on 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl)aceton (II) and nitroethane in the presence of a catalyst cupreine and a promoter benzoic acid to generate (2R,3R)-3-nitro-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol (III); performing nitro reduction reaction on the intermediate (III) to generate (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol (IV); and performing cyclization reaction on the intermediate (IV) and 1,5-di-halogen-3-methylene pentane (V) to prepare efinaconazole (I). The preparation method is easily available in raw materials and concise in process, is economical and environment-friendly and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of efeconazole, a drug for treating toe fungus onychomycosis. Background technique [0002] Efinaconazole is a small molecule triazole antifungal drug originally developed by Kaken Pharmaceuticals in Japan and developed by Valeant Pharmaceuticals International in Canada. The drug was approved for marketing in Canada and the United States in October 2013 and June 2014, respectively, for the treatment of onychomycosis of the toes. This drug is the first topical triazole antifungal drug to be marketed. Because the compound does not have a standard Chinese translation name, the applicant hereby transliterates it as "Efeconazole". [0003] The chemical name of Efinaconazole is: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-( 1H-1,2,4-triazol-1-yl)butane-2-alcoh...

Claims

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Application Information

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IPC IPC(8): C07D401/06
CPCC07D249/08C07D401/06
Inventor 许学农
Owner 旌德君创科技发展有限公司
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