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Preparation method for ravuconazole intermediate

A technology for rifaconazole and intermediates, applied in the field of preparation of rifaconazole intermediates, can solve the problems of low chiral purity, reduced chiral purity, long reaction steps, etc., and achieve high chiral purity and high yield High, easy-to-operate effect

Inactive Publication Date: 2017-05-31
VALIANT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Huang Hanzhong et al in the erythro-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane In the synthesis of bromopropionyl bromide and difluorobenzoylation reaction, then bromine is substituted with hydroxyl, and then the Cole Tchaikovsky reaction is carried out to obtain the product, but the ratio of the threo formula to the erythro formula is 15: 1 or so, the chiral purity is too low to obtain products with high chiral purity, and sodium hydride is used as a hydrogen extraction reagent in the reaction, which is not suitable for large-scale production
[0005] Both WO9839305 and WO2005014583 use R-methyl lactate as a raw material, another chiral center is induced, and the chiral purity of the final product is excessively dependent on the chiral purity of R-methyl lactate, while the reaction steps are long and the intermediates are Partial configuration conversion occurs, resulting in a decrease in the chiral purity of the final product
Raw materials are expensive, but the ee value of the product is reduced, which is not suitable for industrial production

Method used

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  • Preparation method for ravuconazole intermediate
  • Preparation method for ravuconazole intermediate
  • Preparation method for ravuconazole intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Add 100g THF, 100g (0.96mol) methyl lactate, 12g (48mmol) pyridinium p-toluenesulfonate into a 1L three-necked flask, and drop in 86.2g (1.0mol) morpholine. =10, temperature controlled at 10°C and stirred for 3 hours, after the heat preservation and stirring, take a sample for GC (methyl lactate <1%), cool the system down to 5°C, continue to drop 84g (1mol) of 3,4-dihydropyran, drop Stir at 10°C for 15 hours after completion of temperature control (GC detection of intermediates <3%). After incubation, add 300 g of dichloromethane to the reaction solution, and wash the reaction solution once with 200 g of dilute hydrochloric acid with a mass fraction of 5%. Wash once with 5% sodium bicarbonate solution, separate the layers, add anhydrous sodium sulfate and molecular sieves to the organic phase and dry until the water content is less than 1000ppm. The solvent was removed to obtain 221.6 g of light yellow oil compound I, with a yield of 95% and a GC purity of 98%, and 200 ...

Embodiment 2

[0040]Add 100g THF, 100g (0.96mol) methyl lactate, 12g (48mmol) pyridinium p-toluenesulfonate into a 1L three-necked flask, and drop in 86.2g (1.0mol) morpholine. =10, temperature controlled at 10°C and stirred for 3 hours, after the heat preservation and stirring, take a sample for GC (methyl lactate <1%), cool the system down to 5°C, continue to drop 84g (1mol) of 3,4-dihydropyran, drop Stir at 10°C for 15 hours after completion of temperature control (GC detection of intermediates <3%). After incubation, add 300 g of dichloromethane to the reaction solution, and wash the reaction solution once with 200 g of dilute hydrochloric acid with a mass fraction of 5%. Wash once with 5% sodium bicarbonate solution, separate the layers, add anhydrous sodium sulfate and molecular sieves to the organic phase and dry until the water content is less than 1000ppm. The solvent was removed to obtain 221.6 g of light yellow oil compound I, with a yield of 95% and a GC purity of 98%, and 200 g...

Embodiment 3

[0044] Add 100g THF, 100g (0.96mol) methyl lactate, 12g (48mmol) pyridinium p-toluenesulfonate into a 1L three-necked flask, and drop in 86.2g (1.0mol) morpholine. =10, temperature controlled at 10°C and stirred for 3 hours, after the heat preservation and stirring, take a sample for GC (methyl lactate <1%), cool the system down to 5°C, continue to drop 84g (1mol) of 3,4-dihydropyran, drop Stir at 10°C for 15 hours after completion of temperature control (GC detection of intermediates <3%). After incubation, add 300 g of dichloromethane to the reaction solution, and wash the reaction solution once with 200 g of dilute hydrochloric acid with a mass fraction of 5%. Wash once with 5% sodium bicarbonate solution, separate the layers, add anhydrous sodium sulfate and molecular sieves to the organic phase and dry until the water content is less than 1000ppm. The solvent was removed to obtain 221.6 g of light yellow oil compound I, with a yield of 95% and a GC purity of 98%, and 200 ...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method for a ravuconazole intermediate. The preparation method comprises the following steps: enabling D,L-methyl lactate, morpholine and 3,4-dihydropyran to react; enabling a reactant and a Grignard reagent of 2,4-difluorobrmorobenzene to react to prepare a compound III; enabling the compound III to react through asymmetric kortchaikovsky under the catalysis of a catalyst B, namely, L-menthol, and triphenylphosphine; enabling a compound IV to react with 1,2,4-triazole to react; dewatering to cyclise to obtain a ravuconazole intermediate compound V. According to the preparation method for the ravuconazole intermediate, D,L-methyl lactate is used and a catalyst is added for inducing production of a chiral centre; the raw material cost of the reaction is greatly reduced; the yield is high; the purity is high; the preparation method is easy to control, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical technology, in particular to a preparation method of a rifaconazole intermediate. Background technique [0002] The chemical structure of rifuconazole is similar to that of fluconazole and voriconazole. The drug has high bioavailability, long half-life, and broad antibacterial spectrum; it can be taken orally; it is effective against Candida, including Candida krusei and Candida pyrogenes, and Cryptococcus neoformans , Aspergillus, Seidospora and dark fungus have good inhibitory effect, moderate inhibitory activity against Fusarium and Zygomycetes, the market prospect is good. Its key intermediate structure is as follows: [0003] [0004] Huang Hanzhong et al in the erythro-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane In the synthesis of bromopropionyl bromide and difluorobenzoylation reaction, then bromine is substituted with hydroxyl, and then the Kol Tchaikovsky r...

Claims

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Application Information

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IPC IPC(8): C07D405/06
CPCC07D405/06
Inventor 房立平陈阳孙蕊肖景超王晓龙乔磊
Owner VALIANT CO LTD
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