Method for synthesizing N'-[(2S, 3S)-2-(benzyloxy) pentyl-3-base] formylhydrazine

A synthetic method, the technology of benzyloxypropylene, applied in the field of synthesis of N'-[-2-pent-3-yl]formylhydrazide, can solve the problem of harsh anhydrous conditions, high production risk and difficult operation Large and other problems, to achieve the effect of easy industrial production, improve operational safety, and reduce production costs

Active Publication Date: 2019-05-24
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0009] The method's long preparation steps (up to five steps) will cause many side reactions and low yield. What is more prominent is that diisobutyl aluminum hydride that is expensive and easy to catch fire during post-treatment will be used in its preparation process. Moreover, the reaction conditions require anhydrous conditions to be very harsh, resulting in the production of N'-[(2S,3S)-2-(benzyloxy)pent-3-yl]formylh

Method used

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  • Method for synthesizing N'-[(2S, 3S)-2-(benzyloxy) pentyl-3-base] formylhydrazine
  • Method for synthesizing N'-[(2S, 3S)-2-(benzyloxy) pentyl-3-base] formylhydrazine
  • Method for synthesizing N'-[(2S, 3S)-2-(benzyloxy) pentyl-3-base] formylhydrazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] 1. Add (S)-2-benzyloxypropionic acid (18.02 grams, 0.10mol), thionyl chloride (14.16 grams, 0.12mol) and 150ml toluene in a 250ml round bottom flask, heat to reflux, and use sodium hydroxide for the tail gas The solution absorbs. After 6 hours of reaction, the heating was stopped, and the toluene and excess thionyl chloride were removed by rotary evaporation to obtain 18.87 g (0.095 mol) of (S)-2-benzyloxypropionyl chloride, with a yield of 95%.

[0041]2. 10.00 grams of palladium barium sulfate catalyst (converted into metal palladium 0.01mol) with a palladium content of 10% is added in 100ml o-xylene, and the hydrogen atmosphere (0.1MPa pressure) is refluxed for 20 minutes and then down to room temperature; (1) 19.86 grams (0.10mol) of (S)-2-benzyloxypropionyl chloride prepared, then continue hydrogenation under 0.1MPa hydrogen atmosphere and reflux until the reaction mixture does not absorb hydrogen (hydrogen pressure does not drop in the reaction system ). After t...

Embodiment 2

[0049] 1. Add (S)-2-benzyloxypropionic acid (18.02 grams, 0.10mol), oxalyl chloride (12.70 grams, 0.10mol) and 150ml toluene in a 250ml round bottom flask, heat to reflux, and use sodium hydroxide solution for the tail gas absorb. After 8 hours of reaction, the heating was stopped, and the toluene and excess oxalyl chloride were removed by rotary evaporation to obtain 18.27 g (0.092 mol) of (S)-2-benzyloxypropionyl chloride, with a yield of 92%.

[0050] 2. Add 10.00 grams of palladium barium sulfate catalyst with a palladium content of 10% (converted to 0.01 mol of metal palladium) into 100 ml of toluene, reflux under hydrogen atmosphere (0.1 MPa) for 20 minutes and then cool down to room temperature, add (S)-2 - 19.86 grams (0.10 mol) of benzyloxy propionyl chloride, then continue hydrogenation under 0.1 MPa hydrogen atmosphere and reflux until the reaction mixture does not absorb hydrogen (hydrogen pressure does not drop in the reaction system). After the reaction, the mix...

Embodiment 3

[0056] 1. Add (S)-2-benzyloxypropionic acid (18.02 g, 0.10 mol), phosphorus trichloride (15.07 g, 0.11 mol) and 150 ml of toluene into a 250 ml round bottom flask, heat to reflux, and oxidize the tail gas with hydrogen Sodium solution absorbed. After 7 hours of reaction, the heating was stopped, and the toluene and excess thionyl chloride were removed by rotary evaporation to obtain 19.06 g (0.096 mol) of (S)-2-benzyloxypropionyl chloride, with a yield of 96%.

[0057] 2. Add 12 grams of palladium barium sulfate catalyst with a palladium content of 10% (converted into 0.012 mol of metal palladium) into 100 ml of toluene, reflux under hydrogen atmosphere (0.1 MPa) for 20 minutes and then cool down to room temperature, add (S)-2 - 21.41 grams (0.108 mol) of benzyloxypropionyl chloride, then continue hydrogenation under a hydrogen atmosphere of 0.1 MPa and reflux until the reaction mixture does not absorb hydrogen (the hydrogen pressure in the reaction system does not drop). Aft...

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Abstract

A method for synthesizing N'-[(2S, 3S)-2-(benzyloxy) pentyl-3-base] formylhydrazine comprises the following steps: reacting (S)-2-benzyloxypropionic acid with an acylation reagent to obtain (S)-2-benzyloxy propionyl chloride; adding a palladium barium sulfate catalyst into o-xylene and reacting in hydrogen atmosphere for 15-30 min; adding (S)-2-benzyloxy propionyl chloride hydrogen atmosphere forreflux reaction until hydrogen is not absorbed; after the reaction is finished, the catalyst is filtered and the o-xylene is removed to obtain (S)-2-benzyloxypropionaldehyde; reacting the (S)-2-benzyloxypropionaldehyde with formylhydrazine, removing the solvent after finishing the reaction, and post-treating to obtain (S)-N'-(2 benzyloxypropyl) formylhydrazine; reacting the (S)-N'-(2 benzyloxypropyl) formylhydrazine with a Grignard reagent, and post-treating to obtain N'-((2s,3s)- 2-(benzyloxy) pentyl-3-base] formylhydrazine. According to the invention, an acylating reagent which is low in price and safer and more environment-friendly in reaction and a palladium barium sulfate catalyst which can be recycled for a plurality of times are used as reaction raw materials, so that the reaction process more conforms to the principle of atom economy, and the reaction is milder.

Description

technical field [0001] The invention relates to the technical field of synthesis of posaconazole intermediates, specifically designing a synthesis method of N'-[(2S,3S)-2-(benzyloxy)pentan-3-yl]formylhydrazide. 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 o...

Claims

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Application Information

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IPC IPC(8): C07C241/04C07C243/28
CPCY02P20/584
Inventor 骆成才王春春邵宁
Owner NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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