Method of synthesizing (S)-N'-(2-benzyloxy propylidene) formylhydrazine

A technology of benzyloxypropylene and benzyloxyethyl, which is applied in the field of synthesis of posaconazole intermediates, can solve the problems of harsh anhydrous conditions, high production risk, and long preparation steps, and achieve less side reactions , less preparation steps, easy to operate

Active Publication Date: 2018-06-22
东营睿港投资服务有限责任公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This method has long preparation steps, many side reactions, and low yield. What is more prominent is that the preparation process will use diisobutyl aluminum hydride which is expensive and easy to catch fire during post-treatment, and the reaction conditions require anhydrous conditions. Harsh, resulting in the production of (S)-N'-(2-benzyloxypropylene)formylhydrazide is dangerous and costly

Method used

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  • Method of synthesizing (S)-N'-(2-benzyloxy propylidene) formylhydrazine
  • Method of synthesizing (S)-N'-(2-benzyloxy propylidene) formylhydrazine
  • Method of synthesizing (S)-N'-(2-benzyloxy propylidene) formylhydrazine

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Experimental program
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Effect test

Embodiment 1

[0029] 1. Add (S)-2-benzyloxypropionic acid (18.02 grams, 0.10mol), ethylenediamine (7.21 grams, 0.12mol) and 150ml toluene to a 250ml round bottom flask equipped with a water separator, and heat to reflux And divide the water. When the separated water reached 1.60ml (0.09mol), the heating was stopped, and the toluene was removed by rotary evaporation, and the resulting reaction mixture was heated to 150°C for two hours under a pressure of 10 mm Hg to obtain (S)-2-(1-benzyl Oxyethyl)-4,5-dihydro-1H-imidazole 17.77 g (0.087mol), yield 87%; (S)-2-(1-benzyloxyethyl)-4,5-dihydro The NMR data of -1H-imidazole are: 1H NMR (400MHz, CDCl3): δ=1.19(d, 3H), 2.77(t, 2H), 3.41(t, 2H), 3.92(q, 1H), 4.49(s , 2H), 6.97(s, 1H), 7.27~7.35(br, 5H); HRMS(ESI) calcd for C12H16N2O[M+H]+205.1336, found 205.1358; fully confirmed (S)- The structure of 2-(1-benzyloxyethyl)-4,5-dihydro-1H-imidazole is consistent.

[0030] 2. Dissolve 20.43 g (0.10 mol) of (S)-2-(1-benzyloxyethyl)-4,5-dihydro-1H-imid...

Embodiment 2

[0033] 1. Add (S)-2-benzyloxypropionic acid (0.10mol), ethylenediamine (0.13mol) and 160ml toluene into a 250ml round bottom flask equipped with a water separator, heat to reflux and separate water. When the separated water reached 1.70ml, the heating was stopped, and the toluene was removed by rotary evaporation, and the resulting reaction mixture was heated to 150° C. for two hours under a pressure of 10 mm Hg to obtain (S)-2-(1-benzyloxyethyl )-4,5-dihydro-1H-imidazole 17.36 g, yield 85%; (S)-2-(1-benzyloxyethyl)-4,5-dihydro-1H-imidazole NMR data is : 1H NMR (400MHz, CDCl3): δ=1.19(d, 3H), 2.77(t, 2H), 3.41(t, 2H), 3.92(q, 1H), 4.49(s, 2H), 6.97(s, 1H), 7.27~7.35 (br, 5H); HRMS (ESI) calcd forC12H16N2O[M+H]+205.1336, found 205.1358; fully confirmed (S)-2-(1-benzyloxyethyl base)-4,5-dihydro-1H-imidazole structure is consistent.

[0034] 2. Dissolve 0.10mol of (S)-2-(1-benzyloxyethyl)-4,5-dihydro-1H-imidazole in 100ml of absolute ethanol, add metal sodium wire, 0.30mol unde...

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Abstract

The invention discloses a method of synthesizing (S)-N'-(2-benzyloxy propylidene) formylhydrazine. The method comprises the steps of: (1) allowing (S)-2-benzyloxy propionic acid and ethidene diamine to react to form (S)-2-(1-benzyloxy ethyl)-4,5-dihydro-1H-imidazole, (2) dissolving (S)-2-(1-benzyloxy ethyl)-4,5-dihydro-1H-imidazole in absolute ethyl alcohol, adding metallic sodium for stirring andreaction under nitrogen protection, removing alcohol after the reaction, slowly adding residue into a saturated oxalic acid solution under the nitrogen protection, giving a backflow reaction after uniform stirring, performing extraction, drying and filtration after the reaction, and removing a solvent to form (S)-2-benzyloxy propionaldehyde, and (3) allowing (S)-2-benzyloxy propionaldehyde and formylhydrazine to react, removing a solvent after the reaction and performing post treatment to form the product (S)-N'-(2-benzyloxy propylidene) formylhydrazine. The method has the advantages that anorgano-aluminum compound that is high in price and unsafe is not used, the preparation cost is low, the post treatment is simple, and the method is easy and simple to operate.

Description

technical field [0001] The invention relates to the technical field of synthesis of posaconazole intermediates, specifically designing a method for synthesizing (S)-N'-(2-benzyloxypropylene)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 Schering-Plough Corporation 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 oroph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C241/04C07C243/28C07D233/22C07C45/56C07C47/198
CPCC07B2200/07C07C45/562C07C241/04C07D233/22C07C243/28C07C47/198
Inventor 郑培灿王春春田伟
Owner 东营睿港投资服务有限责任公司
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