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Efinaconazole, preparation method of efinaconazole intermediate and efinaconazole intermediate

A kind of technology of efluconazole and volume, applied in the preparation of efluconazole and its intermediates, and the field of intermediates thereof, and can solve the problems of complicated reaction steps, low yield, poor safety and the like

Active Publication Date: 2017-05-03
SHANGHAI VIWIT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] The technical problem to be solved by the present invention is to overcome the need to use highly toxic reagents, low temperature or high temperature operation, harsh conditions, large amount of reaction reagents, high cost, poor safety, The reaction steps are cumbersome, the yield is low, the defects such as incapable of industrial application, and provide a kind of preparation method of efluconazole and its intermediate, its intermediate

Method used

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  • Efinaconazole, preparation method of efinaconazole intermediate and efinaconazole intermediate
  • Efinaconazole, preparation method of efinaconazole intermediate and efinaconazole intermediate
  • Efinaconazole, preparation method of efinaconazole intermediate and efinaconazole intermediate

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Embodiment 1

[0114] Example 1: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4- Preparation of Triazol-1-yl)butan-2-ol (Efluconazole)

[0115]

[0116] Step 1: Preparation of (2R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2,3-diol.

[0117] To a 500 mL reaction flask was added water (94 mL), potassium ferricyanide (39.5 g, 120 mmol), potassium carbonate (16.6 g, 120 mmol), methanesulfonamide (3.80 g, 40 mmol) , potassium osmate dihydrate (141.5 mg, 0.4 mmol), hydroquinidine 1,4-(2,3-naphthyridine) diether (1.56 g, 2.0 mmol), tert-butanol (94 mL ) and 1-(2-(2,4-difluorophenyl)but-2-enyl)-1H-1,2,4-triazole (9.41 g, 40 mmol). The whole mixture was stirred at room temperature for 40 hours.

[0118] Ethyl acetate (40 mL) and 30% aqueous sodium sulfite (55 mL) were added to the reaction system. The organic phase was separated for use; the aqueous phase was extracted with ethyl acetate (40 mL), and the organic phase was separated; the organic phases wer...

Embodiment 2

[0128] Example 2: 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methylepoxy-2-yl)methyl)-1H-1,2,4- Preparation of triazole (intermediate A)

[0129]

[0130] Step 1: Preparation of (R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propane-1,2-diol

[0131] To a 500 mL reaction flask was added water (66 mL), potassium ferricyanide (29.6 g, 90 mmol), potassium carbonate (12.4 g, 90 mmol), methanesulfonamide (2.85 g, 30 mmol) , potassium osmate dihydrate (106 mg, 0.3 mmol), hydroquinidine 1,4-(2,3-naphthyridine) diether (1.17 g, 1.5 mmol), tert-butanol (66 ml ) and 1-(2-(2,4-difluorophenyl)allyl)-1H-1,2,4-triazole (6.63 g, 30 mmol). The whole mixture was stirred at room temperature for 24 hours.

[0132] Ethyl acetate (30 mL) and 30% aqueous sodium sulfite (45 mL) were added to the reaction system. The organic phase was separated for use; the aqueous phase was extracted with ethyl acetate (30 mL), and the organic phase was separated; the organic phases were combined, washed with ...

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Abstract

The invention discloses efinaconazole, a preparation method of an efinaconazole intermediate and the efinaconazole intermediate. A preparation method of efinaconazole comprises the following step: in a solvent, under the action of a reducing agent, performing reductive amination reaction on a compound shown in the formula 4 and a compound shown in the formula B. The invention also provides the efinaconazole intermediate shown in the formula 4 and the preparation method thereof, and the preparation method comprises the following step: performing oxidizing reaction on a compound shown in the formula 3 to obtain the compound shown in the formula 4. A preparation method of the compound shown in the formula 3 comprises the following step: in a solvent, performing Sharpless asymmetric dihydroxylation on a compound shown in the formula 2 under the actions of a chiral catalyst, an oxidant and a co-oxidant. The efinaconazole and the preparation method of the efinaconazole intermediate are green and environment-friendly, high in security, mild in condition, low in cost, simple in step, high in yield and suitable for industrial application. The formulas 2, 3, 4 and B are as shown in the description.

Description

technical field [0001] The present invention specifically relates to the preparation method of efluconazole and its intermediates, and the intermediates thereof. Background technique [0002] Efluconazole (English name: Efinaconazole, trade name Jublia), chemical name: (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine- 1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, CAS registry number: 164650-44-6, the structural formula is shown in formula Ⅰ: [0003] [0004] Efluconazole is a triazole antifungal drug invented by Kaken Pharmaceutical Company of Japan and developed by Valeant International Pharmaceutical Company of Canada, which is mainly used for the treatment of onychomycosis of toes. The drug was approved in Canada and the United States in October 2013 and June 2014, respectively. [0005] The synthesis method of efluconazole is mainly prepared by reacting chiral epoxy intermediate A and piperidine intermediate B. Patents WO9426734, WO2006059759 and WO2012029836 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06C07D249/08
Inventor 魏彦君蒋宪龙邢艳平其他发明人请求不公开姓名
Owner SHANGHAI VIWIT PHARMA CO LTD
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