Synthesis method of diethyl 2-[2-(2,4-difluorophenyl)allyl]-1,3-malonate

A technology of diethyl malonate and difluorophenyl, applied in the field of 2-[2-allyl]-1, can solve the problems of difficult industrial production and difficult operation, and achieve easy industrial production and easy operation , the effect of high yield

Active Publication Date: 2016-06-01
TIANSHENG PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This reaction requires anhydrous and oxygen-free conditions, is difficult to operate, and is not easy to realize industrial production

Method used

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  • Synthesis method of diethyl 2-[2-(2,4-difluorophenyl)allyl]-1,3-malonate
  • Synthesis method of diethyl 2-[2-(2,4-difluorophenyl)allyl]-1,3-malonate
  • Synthesis method of diethyl 2-[2-(2,4-difluorophenyl)allyl]-1,3-malonate

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Experimental program
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Effect test

Embodiment 1

[0035] 1. Mix 3-chloro-1,2-propanediol (33.16g, 0.30mol) and 1,3-difluorobenzene (34.23g, 0.30mol) at 0°C and add aluminum chloride in batches while stirring (40.00 g, 0.30 mol), react at room temperature for 8 hours after the addition, and then raise the temperature to 60° C. to continue the reaction for 3 hours. After the reaction was completed, the mixture was carefully added to 300ml of hydrochloric acid solution with a concentration of 2mol / l at 0°C, stirred evenly and extracted three times with dichloromethane, 200ml 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, 50.83 g (0.25 mol) of oily product 1-chloro-2-(2,4-difluorophenyl)-3-propanol was obtained, with a yield of 82%.

[0036] 2. Add 41.32g (0.20mol) of 1-chloro-2-(2,4-difluorophenyl)-3-propanol and 29.96g...

Embodiment 2

[0039] 1. Mix 3-chloro-1,2-propanediol (26.53g, 0.24mol) and 1,3-difluorobenzene (22.82g, 0.20mol) at 0°C and add trichloro in 4 batches while stirring Iron oxide (0.24mol), react at room temperature for 8 hours after the addition, and then raise the temperature to 60° C. to continue the reaction for 3 hours. After the reaction was completed, the mixture was carefully added to 200ml of hydrochloric acid solution with a concentration of 2mol / l at 0°C, stirred evenly and extracted three times with dichloromethane, 130ml 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, 33.06 g (0.16 mol) of oily product 1-chloro-2-(2,4-difluorophenyl)-3-propanol was obtained, with a yield of 80%.

[0040] 2. Add 41.32g (0.20mol) of 1-chloro-2-(2,4-difluorophenyl)-3-propanol and 29.96g (0.2...

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Abstract

The invention relates to a synthesis method of diethyl 2-[2-(2,4-difluorophenyl)allyl]-1,3-malonate. The synthesis method comprises the following steps: mixing 3-chloro-1,2-propanediol and 1,3-difluorobenzene, and adding a catalyst to react; adding the mixture into a hydrochloric acid solution at 5 to -5 DEG C, stirring uniformly, extracting 3-5 times by using dichloromethane as an extractant, and washing the extracting solution with a saturated NaHCO3 solution, water and a saturated saline solution; drying with anhydrous Na2SO4, filtering, evaporating the dichloromethane to obtain 1-chloro-2-(2,4-difluorophenyl)-3-propanol, mixing the 1-chloro-2-(2,4-difluorophenyl)-3-propanol and potassium hydrogen sulfate into chlorobenzene, and heating under reflux for 10-16 hours; and washing with water to a neutral state, drying with anhydrous Na2SO4, filtering, distilling to obtain 1-(1-chloromethylvinyl)-2,4-difluorobenzene, dissolving in DMSO (dimethyl sulfoxide), adding diethyl malonate and hydroxide to react, extracting, washing and carrying out reduced pressure distillation to obtain the target product. The synthesis route is disclosed in the specification.

Description

technical field [0001] The invention relates to a synthesis method of 2-[2-(2,4-difluorophenyl)allyl]-1,3-malonic acid diethyl ester. 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 oropharyngeal candida infection. [0005] Diethyl 2-[2-(2,4-difluorophenyl)al...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/343C07C69/65
CPCC07C17/35C07C29/60C07C67/343C07C69/65C07C33/46C07C25/24
Inventor 骆成才危凤库拉里
Owner TIANSHENG PHARMA GROUP
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