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A method of synthesizing 2-methylpropionic acid-[(2s)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-penten-1-yl] ester

A technology of difluorophenyl and methylpropionic acid, applied in the field of preparation of posaconazole intermediates, can solve the problems of difficult industrialized production, difficult operation, large pollution, etc., and achieves easy industrialized production, easy operation, and reduced production cost effect

Active Publication Date: 2017-12-26
山东汉申化工科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This reaction requires anhydrous and oxygen-free conditions, is difficult to operate, and is not easy to realize industrial production; in addition, the highly irritating compound chloroacetyl chloride will be used in this method, and the pollution is relatively large

Method used

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  • A method of synthesizing 2-methylpropionic acid-[(2s)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-penten-1-yl] ester
  • A method of synthesizing 2-methylpropionic acid-[(2s)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-penten-1-yl] ester
  • A method of synthesizing 2-methylpropionic acid-[(2s)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-penten-1-yl] ester

Examples

Experimental program
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Effect test

Embodiment 1

[0043] 1. Add 1,2,3-trichloropropane (29.40g, 0.20mol) dropwise to 1,3-difluorobenzene (22.82g, 0.20mol) at 0°C, and continue stirring the reaction mixture for 30min before dividing Aluminum trichloride (26.66 g, 0.20 mol) was added in 5 batches, and gas was emitted after the addition. After the addition, react at 0°C for 1 hour, and then continue to react at room temperature (20-35°C) for 6 hours. After the reaction was completed, the mixture was carefully added to 200 ml of hydrochloric acid solution with a concentration of 2 mol / l at 0°C, stirred evenly, extracted three times with dichloromethane, 200 ml each time, combined the dichloromethane layers, and washed with saturated NaHCO 3 Solution, water, and saturated saline were washed once respectively. Anhydrous Na for organic layer 2 SO 4 After drying, filter, and remove methylene chloride by rotary evaporation, 38.26 g (0.17 mol) of oily product 1,3-dichloro-2-(2,4-difluorophenyl)propane was obtained, with a yield of 8...

Embodiment 2

[0049] 1. Add 1,2,3-trichloropropane (26.54g, 0.18mol) dropwise to 1,3-difluorobenzene (17.11g, 0.15mol) at 0°C, and continue stirring the reaction mixture for 30 minutes before dividing Aluminum trichloride (24.00 g, 0.18 g) was added in 4 batches, and gas was emitted after the addition. After the addition, the reaction was carried out at 0°C for 1 hour, and then the reaction was continued at room temperature for 6 hours. After the reaction was completed, the mixture was carefully added to 150ml of hydrochloric acid solution with a concentration of 2mol / l at 0°C, stirred evenly and extracted three times with dichloromethane, 150ml each time, the dichloromethane layers were combined, and saturated NaHCO 3 Solution, water, and saturated saline were washed once respectively. Anhydrous Na for organic layer 2 SO 4 After drying, filter, and remove methylene chloride by rotary evaporation, 29.26 g (0.13 mol) of oily product 1,3-dichloro-2-(2,4-difluorophenyl)propane was obtained,...

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Abstract

The invention provides a method for synthesizing 2-methyl propionate-[(2S)-4-(2,4-diflurophenyl)-2-hydroxymethyl-4-amylene-1-group] ester.The method includes the steps that 1,2,3-trichloropropane is added dropwise to 1,3-difluorobenzene, and aluminum trichloride is added for a reaction; the mixture is added to a hydrochloric acid solution for extraction, and washing is conducted with a saturated NaHCO3 solution, water and saturated salt solution in sequence; anhydrous Na2SO4 is used for drying and filtering, evaporation is conducted for solvent removal, and 1,3-dichloro-2-(2,4-diflurophenyl) propane is obtained; 1,3-dichloro-2-(2,4-diflurophenyl) propane and potassium hydroxide are added to tert butyl alcohol, and reflux is conducted for 3.5-6 h; tert butyl alcohol is removed, ice water is added, the mixture is neutralized with hydrochloric acid at the temperature of 5 to -5 DEG C to be neutral, dichloromethane is used for three times of extraction, anhydrous Na2SO4 is used for drying and filtering, a distillation product is dissolved in DMSO, a product obtained after diethyl malonate and diethyl malonate react are added and a product obtained after lithium chloride and sodium borohydride react are added and dissolved in methylbenzene, and sodium bicarbonate, Novo SP 435 esterifying enzymes and isobutyric anhydride are added for a reaction; the target product is obtained after washing, crystallization and drying are conducted.The synthesis path is shown in the description.

Description

technical field [0001] The present invention relates to the preparation method of posaconazole intermediate, specifically a method for synthesizing 2-methylpropionic acid-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4 -Penten-1-yl] ester method. Background technique [0002] Posaconazole (chemical name: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-tri Azol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3 -base]-1,2,4-triazole-3-ketone, English name: Posaconazole), the structural formula is as follows: [0003] [0004] Developed by the Schering-Plough Company of the United States and approved by the FDA in September 2006, it is a broad-spectrum triazole antifungal drug with high lipophilicity. The trade name is Noxafil (Nuo Kefei), oral suspension, mainly used to prevent invasive aspergillus and candida infections in patients aged thirteen and over, and to treat oropharyngeal candida infections and resistance to fluconaz...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/08C07C69/28
CPCC07C17/25C07C17/269C07C29/147C07C67/08C07C67/343C07C25/13C07C25/24C07C69/65C07C33/48C07C69/28
Inventor 库拉里
Owner 山东汉申化工科技有限公司
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