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Method for preparing efinaconazole intermediate

A technology for chiral ligands and compounds is applied in the field of preparation of efluconazole intermediates, and can solve the problems of high cost, large amount of reaction reagents, cumbersome reaction steps and the like

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

AI Technical Summary

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 a kind of preparation method of the intermediate of efluconazole is provided

Method used

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  • Method for preparing efinaconazole intermediate
  • Method for preparing efinaconazole intermediate
  • Method for preparing efinaconazole intermediate

Examples

Experimental program
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Effect test

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 a method for preparing an efinaconazole intermediate. The method comprises the following step: in a solvent, performing Sharpless asymmetric dihydroxylation on a compound as shown in the formula 2 under the actions of a chiral catalyst, an oxidant and a co-oxidant to prepare a compound as shown in the formula 3, wherein R<1> is halogen or 1,2,4-triazolyl, and R<2> is hydrogen or methyl. The method is 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 formula 2 and the formula 3 are as shown in the description.

Description

technical field [0001] The present invention specifically relates to a preparation method of an efluconazole intermediate. 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 report such synthetic methods. Seconda...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08C07D401/06
CPCC07B2200/07C07D249/08C07D401/06
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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