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Synthesis method for 2-methylpropionate-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-pentene-1-yl]ester

A technology of difluorophenyl and methylpropionic acid, applied in the field of posaconazole intermediate synthesis, can solve the problems of affecting the health of experimenters, difficult to industrialized production, high production cost, and achieves low toxicity, easy industrialized production, Easy-to-operate effects

Inactive Publication Date: 2016-07-13
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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  • Abstract
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  • Claims
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Problems solved by technology

[0009] The above method will use expensive trimethylchloromethylsilanes, resulting in 2-methylpropionic acid-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl- The production cost of 4-penten-1-yl] ester has increased significantly
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 for 2-methylpropionate-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-pentene-1-yl]ester
  • Synthesis method for 2-methylpropionate-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-pentene-1-yl]ester
  • Synthesis method for 2-methylpropionate-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-pentene-1-yl]ester

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Experimental program
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Embodiment 1

[0044] 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

[0050] 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%.

[0051] 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 provides a synthesis method for 2-methylpropionate-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-pentene-1-yl]ester.The synthesis method comprises the steps that 2-chloromethyl epoxypropane and 1,3-difluorobenzene are mixed and react under a catalyst to obtain 2-(2,4-difluorophenyl)-1-chloro-3-propanol; 2-(2,4-difluorophenyl)-1-chloro-3-propanol is mixed with potassium bisulfate and chlorobenzene for a reaction to obtain 1-(1-cholomethyl vinyl)-2,4-difluorophenyl; 1-(1-cholomethyl vinyl)-2,4-difluorobenzene reacts with diethyl malonate to obtain 2-[2-(2,4-difluorophenyl)allyl]-1,3-diethyl malonate; 2-[2-(2,4-difluorophenyl)-2-propene-1-yl]-1,3-diethyl malonate is dissolved into mixed solvent of isopropanol and water and then reacts with hydroboron to obtain a product 2-[2-(2,4-difluorophenyl)-2-propene-1-yl]-1,3-propylene glycol; 2-[2-(2,4-difluorophenyl)-2-propene-1-yl]-1,3-propylene glycol is mixed with an esterifying enzyme and isobutyric anhydride for a reaction to obtain the target product; the specific synthesis path comprises the following steps (please see the steps in the description).

Description

technical field [0001] The invention relates to the technical field of posaconazole intermediate synthesis, in particular to a 2-methylpropionic acid-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4- Synthetic method of penten-1-yl] 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 ...

Claims

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Application Information

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IPC IPC(8): C12P7/62
CPCC12P7/62
Inventor 骆成才郑培灿
Owner NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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