New synthesis method of luliconazole key chiral intermediate

A chiral intermediate, luliconazole technology, applied in the field of chemical synthesis, can solve the problems of large amount of carbonyl reductase T, unfavorable industrial production, high equipment cost, etc., and achieve easy industrial production, low product cost and mild reaction conditions Effect

Inactive Publication Date: 2018-07-20
ASTATECH CHENGDU BIOPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, the amount of carbonyl reductase T used is large, and the concentration of the substrate is low, so a large volume of equipment is required to achieve mass production, which will result in high cost of raw materials and equipment, which is not conducive to further industrial production

Method used

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  • New synthesis method of luliconazole key chiral intermediate
  • New synthesis method of luliconazole key chiral intermediate
  • New synthesis method of luliconazole key chiral intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of (R)-2-chloro-1-(2,4-dichlorophenyl)ethanol

[0037] Under nitrogen protection, 0.31 grams of ruthenium complex precursor [Ru(p-cymene)Cl 2 ] 2 Add 0.67 g of optically pure (S,S)-N-p-methylbenzenesulfonyl-1,2-diphenylethylenediamine to a 250 ml reaction flask, add 100 ml of degassed water, and heat to 35 React at -40°C for 1 hour; then add 0.25 g of cetyltrimethylammonium bromide, 52 g of NaHCO 3 2H 2 O and 22 grams of ω-chloro-2,4-dichloroacetophenone, the reaction temperature is 25-35 ° C, and the temperature is maintained for 14 hours. After the reaction is completed, the product is extracted with n-hexane, and the extract is used without Dry over sodium sulfate, filter out sodium sulfate, and concentrate to dryness; add 55 ml of n-hexane and heat to dissolve, then cool down to room temperature for crystallization, filter, and dry to obtain (R)-2-chloro-1-(2,4 - 21.2 grams of dichlorophenyl) ethanol, optical purity 99.2%.

[0038] Catalyst recycling ...

Embodiment 2

[0045] Synthesis of (R)-2-chloro-1-(2,4-dichlorophenyl)ethanol

[0046] Under nitrogen protection, 0.15 grams of ruthenium complex precursor [Ru(p-cymene)Cl 2 ] 2 Add 0.34 g of optically pure (S,S)-N-p-methylbenzenesulfonyl-1,2-diphenylethylenediamine to a 150 ml reaction flask, add 60 ml of degassed water, and heat to 35 -40°C; after 1 hour of reaction, add 0.12 g of cetyltrimethylammonium bromide, 26 g of NaHCO 3 2H 2 O and 11 grams of ω-chloro-2,4-dichloroacetophenone, the reaction temperature is 25-35 ° C, keep the temperature for 12 hours; add n-hexane to extract the product, and the extract is dried with anhydrous sodium sulfate , filtered off sodium sulfate, concentrated to dryness, then added 30 ml of n-hexane and heated to dissolve, then lowered to room temperature for crystallization, filtered, and dried to obtain (R)-2-chloro-1-(2,4-dichlorobenzene Base) 10.6 grams of ethanol, optical purity 99.3%.

Embodiment 3

[0048] Synthesis of (R)-2-chloro-1-(2,4-dichlorophenyl)ethanol

[0049] Under nitrogen protection, 0.15 grams of ruthenium complex precursor [Ru(p-cymene)Cl 2 ] 2 Add 0.34 g of optically pure (S,S)-N-p-methylbenzenesulfonyl-1,2-diphenylethylenediamine to a 150 ml reaction flask, add 60 ml of degassed water, and heat to 35 -40°C; After 1 hour of reaction, add 0.54 g of sodium lauryl sulfate and 26 g of NaHCO 3 2H 2 O and 11 grams of ω-chloro-2,4-dichloroacetophenone, the reaction temperature is 25-35 ° C, keep the temperature for 12 hours, the reaction is complete; add n-hexane to extract the product, the extract is anhydrous Dry over sodium sulfate, filter out sodium sulfate, concentrate to dryness, add 30 ml of n-hexane and heat to dissolve, then cool down to room temperature for crystallization, filter, and dry to obtain (R)-2-chloro-1-(2,4- Dichlorophenyl) ethanol 10.5 grams, optical purity 99.1%.

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Abstract

The invention discloses a new synthesis method of a luliconazole key chiral intermediate, belonging to the field of chemical synthesis. The method comprises the steps of firstly, preparing (R)-2-halogenated-1-(2,4-dichlorobenzyl)ethanol, and then carrying out halogenation on hydroxyl so as to obtain the synthesized luliconazole key chiral intermediate, i.e., (S) -2, 4-dichloro-1-(1,2-dihalogenatedethyl)benzene. According to the method, the preparation method of chiral alcohol is completed in a water phase, and an organic solvent does not need to be used, so that the harm of the organic solvent to the environment is reduced; a smaller amount of chiral catalyst is required by the method and can be recycled under the condition of extraction, so that the reaction cost is greatly lowered; furthermore, the method increases the yield of the final product (S)-2, 4-dichloro-1-(1,2-dihalogenated ethyl)benzene and is beneficial to industrial application.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a new method for synthesizing a key chiral intermediate of luliconazole. Background technique [0002] Luliconazole is an imidazole antifungal drug developed by Nippon Agricultural Chemicals Co., Ltd., which was approved in June 2005 and listed under the trade name ルリコン (Lulicon) since July 20, 2005. The main indication of luliconazole is tinea pedis (i.e. beriberi), which has a very high incidence rate. Compared with previous antifungal topical drugs, the biggest advantage of luliconazole is its high skin retention rate and short medication cycle (for general Half of the drug), good curative effect and not easy to relapse, so it has great competitiveness. [0003] [0004] However, the preparation of the key chiral intermediate (S)-2,4-dichloro-1-(1,2-dihaloethyl)benzene for the synthesis of luliconazole has not been reported in the literature, and the preparation of (S)-2 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C29/143C07C33/46C07C17/16C07C25/02C07B53/00
CPCC07B53/00C07B2200/07C07C17/16C07C29/143C07C33/46C07C25/02Y02P20/584
Inventor 罗建业徐兴兵郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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