Synthesis method of 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol

A technology of difluorophenyl and synthetic method, which is applied in the field of synthesis of posaconazole intermediates, can solve the problems of affecting the health of experimenters, high production cost of propylene glycol, and difficulty in industrialized production, and achieves low toxicity and easy industrialized production , easy-to-operate effects

Inactive Publication Date: 2016-07-20
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The above method will use expensive trimethylchloromethylsilanes, resulting in the production of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol high cost
In addition, it is more important that Grignard reaction is also used in this method, which requires anhydrous and oxygen-free conditions, is difficult to operate, and is not easy to realize industrial production; in addition, this reaction process also uses the highly irritating compound chlorine Acetyl chloride is relatively polluting and seriously affects the health of experimenters

Method used

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  • Synthesis method of 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol
  • Synthesis method of 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol

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Experimental program
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Effect test

Embodiment 1

[0041] 1. Mix 2-chloromethyl propylene oxide (27.60g, 0.30mol) and 1,3-difluorobenzene (34.23g, 0.30mol) at 0°C and add trichloride in 5 batches while stirring. Aluminum (40.00 g, 0.30 mol) was reacted at room temperature for 7.5 hours after the addition was completed, and then the temperature was raised to 58° C. to continue the reaction for 3 hours. After the reaction was completed, the mixture was carefully added to 300 ml of hydrochloric acid solution with a concentration of 2 mol / l at 0°C, stirred evenly and extracted three times with dichloromethane, 200 ml each time, and the dichloromethane layers were combined, and the dichloromethane layers were sequentially washed with saturated NaHCO 3 Solution, water, and saturated saline were washed once respectively. The washed dichloromethane layer was washed with anhydrous Na 2 SO 4 After drying, filter, and rotary evaporate to remove dichloromethane, 51.65 g (0.25 mol) of oily product 2-(2,4-difluorophenyl)-1-chloro-3-propa...

Embodiment 2

[0046] 1. Mix 2-chloromethyl propylene oxide (22.08g, 0.24mol) and 1,3-difluorobenzene (22.82g, 0.20mol) at 0°C and add trichloride in 4 batches while stirring. Iron (0.24mol), react at room temperature for 8 hours after the addition, then raise the temperature to 60°C and continue the reaction for 3 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, 130 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, 33.06 g (0.16 mol) of oily product 2-(2,4-difluorophenyl)-1-chloro-3-propanol was obtained, with a yield of 80%.

[0047] 2. Add 41.32g (0.20mol) of 2-(2,4-difluorophenyl)-1-chloro-3-propanol and 29.96g...

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Abstract

The invention relates to a synthesis method of 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol. The synthesis method comprises the following steps: mixing 2-chloromethyl epoxy propane with 1,3-difluorobenzene to perform reaction under an effect of catalyst to obtain 2-(2,4-diflurophenyl)-1-chloro-3-propanol; mixing 2-(2,4-diflurophenyl)-1-chloro-3-propanol with potassium hydrogen sulfate and chlorobenzene to perform reaction to obtain 1-(1-chloromethylvinyl)-2,4-difluorobenzene; enabling 1-(1-chloromethylvinyl)-2,4-difluorobenzene to react with diethyl malonate to obtain a product 2-[2-(2,4-diflurophenyl)propenyl]-1,3-diethyl malonate; dissolving 2-[2-(2,4-diflurophenyl)-2-propen-1-yl]-1,3-diethyl malonate in mixed solvent formed by isopropanol and water to react with borohydride to obtain a target product 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol; a synthesis route is as shown in the accompanying drawing.

Description

technical field [0001] The present invention relates to a synthetic method of posaconazole intermediate, in particular to a synthetic method of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol . 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 fluconazole and voriconazole Medicine for orophary...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C29/147C07C33/48C07C29/36C07C33/46C07C17/35C07C25/24C07C67/343C07C69/65
CPCC07C17/35C07C29/147C07C29/36C07C67/343C07C33/46C07C25/24C07C69/65C07C33/483
Inventor 骆成才郑培灿
Owner NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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