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

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...

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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]formylhydrazide with high risk, high cost and difficult operation.

[0010] The Chinese patent application number 201711474200.0 discloses the synthesis method of (S)-N'-(2-benzyloxypropylene)formylhydrazide as shown below, which avoids the use of diisobutylaluminum hydride, However, the atom economy of the entire reaction route is not high, and the use and post-treatment of ethylenediamine will cause certain environmental pressure:

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