Method for synthesizing luliconazole intermediate-(S)-2,4-dichloro-1-(1,2-dichloroethyl) benzene

A technology of luliconazole and dichloroethyl, which is applied in the field of chemical synthesis technology, can solve the problems of difficult industrialization, high cost, and low yield, and achieve the effect of less organic solvent consumption, high yield, and low dosage

Inactive Publication Date: 2013-04-17
ASTATECH CHENGDU PHARMA
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Problems solved by technology

[0012] The technical problem to be solved in the present invention is that the cost of the existing synthetic method is high, the yield is low, and it is difficult to industrialize

Method used

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  • Method for synthesizing luliconazole intermediate-(S)-2,4-dichloro-1-(1,2-dichloroethyl) benzene
  • Method for synthesizing luliconazole intermediate-(S)-2,4-dichloro-1-(1,2-dichloroethyl) benzene
  • Method for synthesizing luliconazole intermediate-(S)-2,4-dichloro-1-(1,2-dichloroethyl) benzene

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preparation example Construction

[0044] The synthetic method of luliconazole intermediate (S)-2,4-dichloro-1-(1,2-dichloroethyl)benzene comprises the following steps:

[0045] a. Under the protection of nitrogen, heat (S,S)-TsDPEN and the transition metal complex precursor in degassed water to 35-40°C and react for 1-2 hours to make a chiral catalyst; the transition metal The complex precursor is [Ru(p-cymene)Cl 2 ] 2 、[Cp*RhCl 2 ] 2 or [Cp*Ir Cl 2 ] 2 one of

[0046] b. Add ω-chloro-2,4-dichloroacetophenone, surfactant or phase transfer catalyst, and hydrogen source to the chiral catalyst degassed water system described in step a for reaction; the reaction temperature is 10 ~70℃, the reaction time is 6~20 hours;

[0047] c. After the reaction is complete, extract with n-hexane. After the extract is dried, remove the solid by filtration, concentrate the filtrate to dryness, recrystallize with n-hexane, and dry the solid to obtain (R)-2-chloro-1-(2,4- Dichlorophenyl) ethanol;

[0048] d. Under the pro...

Embodiment 1

[0063] a, 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)-TsDPEN into a 250 ml reaction flask, then add 100 ml of degassed water, heat to 40°C, and react for 1 hour.

[0064] b. Add 0.25 grams of CTAB (cetyltrimethylammonium bromide) and 52 grams of HCO to the above reaction solution 2 Na·2H 2 O (sodium formate) and 22 g of ω-chloro-2,4-dichloroacetophenone, the reaction temperature is 28 ° C, and the reaction temperature is maintained for 14 hours.

[0065] c. After the reaction is complete, add n-hexane to extract the product, dry the extract with anhydrous sodium sulfate, filter off the sodium sulfate, concentrate the filtrate to dryness, add 55 ml of n-hexane to heat and dissolve, then drop to room temperature for crystallization, and filter. After drying, 21.2 g of (R)-2-chloro-1-(2,4-dichlorophenyl)ethanol was obtained, with an optical purity of 99.2%.

[0066] d. Synthesis of (S)-2,4-dichl...

Embodiment 2

[0069] The recycling of embodiment 2 catalyst

[0070] After step c of Example 1 extracted the product with n-hexane, the water phase was transferred to a 250 ml reaction flask, and under nitrogen protection, 22 grams of ω-chloro-2,4-dichloroacetophenone was added, 4.1 ml of formic acid was added to adjust the pH value of the reaction solution to 7.2, and the reaction was carried out at 28° C. for 14 hours. After the reaction is complete, other operations are the same as steps c and d of Example 1.

[0071] 21.0 g of the product (S)-2,4-dichloro-1-(1,2-dichloroethyl)benzene was obtained, with a yield of 95.0% and an optical purity of 99.2%.

[0072] The detection conditions of the optical purity of the final product are the same as in Example 1.

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Abstract

The invention belongs to the field of chemical synthesis processes, particularly relates to a method for synthesizing a luliconazole intermediate-(S)-2,4-dichloro-1-(1,2-dichloroethyl) benzene, and solves the technical problems of high cost, lower yield and low possibility of industrialization in the conventional synthesis method. The invention adopts the following technical scheme: the method comprises the steps as follows: a, preparing a chiral catalyst; b, adding a surfactant or a phase transfer catalyst and omega-chloro-2,4-dichloroacetophenone as well as a hydrogen source into the chiral catalyst for reaction; c, extracting and re-crystallizing a reaction solution and drying a solid to obtain (R)-2-chloro-1-(2,4-dichlorophenyl) ethanol; and d, reacting (R)-2-chloro-1-(2,4-dichlorophenyl) ethanol with oxalyl chloride, and extracting, purifying and drying the reaction solution to obtain (S)-2,4-dichloro-1-(1,2-dichloroethyl) benzene as a product. The invention provides a novel method for preparing (S)-2,4-dichloro-1-(1,2-dichloroethyl) benzene with high yield and low cost.

Description

technical field [0001] The invention belongs to the field of chemical synthesis technology. Specifically, it relates to a method for synthesizing luliconazole intermediate (S)-2,4-dichloro-1-(1,2-dichloroethyl)benzene. Background technique [0002] Luliconazole is an imidazole antifungal drug developed by Nippon Shoyaku Co., Ltd. It started non-clinical trials and cream phase I clinical trials earlier, and the first phase of phase II clinical trials, and then stopped the development process due to war reasons. In the 1990s, Nippon Agricultural Chemicals Co., Ltd. and Pola Chemical Co., Ltd. signed an agreement to jointly develop. Pola Chemical Co., Ltd. began the second phase of clinical trials of cream cream in phase II and phase III clinical trials in 2001, and carried out phase I clinical trials of lotions and Comparison test with cream. Finally, the drug was approved in June 2005, and it was listed under the trade name ルリコン (Lulicon) on July 20, 2005. [0003] [0...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C25/02C07C17/16C07C33/46C07C29/143
Inventor 刘卫国王灿辉周家炎吴黎明
Owner ASTATECH CHENGDU PHARMA
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