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Synthesis method of oseltamivir

A synthetic method and compound technology, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., to achieve the effects of short steps, cheap and easy-to-obtain reagents, and simple operation

Inactive Publication Date: 2015-05-27
ZHEJIANG NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Professor Ma Dawei (Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem. Int. Ed. 2010, 49, 4656) of Shanghai Institute of Organic Chemistry and others have also done this Excellent work, realized the shortest synthetic route of oseltamivir so far, only needs 5 steps, yield rate is 46%, but, also used above-mentioned comparatively expensive organic amine catalyst, therefore, simple, economical oseltamivir Wei synthetic route still needs to be developed

Method used

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  • Synthesis method of oseltamivir
  • Synthesis method of oseltamivir
  • Synthesis method of oseltamivir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] In a 50mL round bottom flask, add the compound shown in structural formula I (1.54g, 11mmol) and the compound shown in structural formula II (1.5g, 10mmol), heat to 70°C for 4 hours, then cool to room temperature, add Cu(OTf) 2 (181mg, 0.5mmol), PhI=NNs (4.2g, 10mmol), then add 20mL of acetonitrile to dissolve, stir the reaction for 6 hours, stop the reaction, remove the solvent by rotary evaporation, and use silica gel (300-400 mesh) column chromatography to separate the free Color liquid 3.2g, productive rate 67%. colorless liquid 1 H-NMR (CDCl 3 ,600MHz):δ0.75(t,J=7.3Hz,3H),0.91(t,J=7.3Hz3H),1.23(t,J=7.1Hz,3H),1.35-1.39(m,2H),1.49 -1.53(m,2H),1.80-1.85(m,1H),2.56-2.60(m,1H),3.21-3.24(m,1H),3.26-3.30(m,1H),3.34-3.37(m, 1H),3.40-3.42(m,1H),4.11-4.20(m,2H),4.61(s,1H),4.78(dd,J=11.4,3.0Hz,1H),8.16(d,J=9.2Hz ,2H),8.45(d,J=8.4Hz,2H); 13 C-NMR (CDCl 3 ,150MHz):δ8.8,9.5,14.0,25.0,25.2,25.9,35.9,38.8,42.6,61.7,70.5,82.7,83.4,124.7,129.2,143.4,150.9,172.1;Anal.Calcd.forC...

Embodiment 2

[0045] Except that 50°C was used instead of 70°C in Example 1 to carry out the Diels-Alder reaction of the compound shown in the structural formula I and the compound shown in the structural formula II, the rest of the operating steps were the same as in Example 1, and the total yield of oseltamivir was obtained. The rate is 13%, and the product characterization data are the same as in Example 1.

Embodiment 3

[0047] Except that 90°C was used instead of 70°C in Example 1 to carry out the Diels-Alder reaction of the compound shown in structural formula I and the compound shown in structural formula II, the rest of the operating steps were the same as in Example 1, and the total yield of oseltamivir was obtained. The rate is 31%, and the product characterization data are the same as in Example 1.

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Abstract

The invention discloses a synthesis method of oseltamivir. The synthesis method of oseltamivir comprises the following steps: starting from a compound 1,3-butadiene-3-amyl ether and compound 3-nitro-ethyl acrylate, carrying out Diels-Alder reaction, then reacting at room temperature in acetonitrile in the presence of a copper catalyst and PhI-NNs to prepare an aziridine compound in a one-pot method, wherein the mole ratio of the 1,3-butadiene-3-amyl ether to 3-nitro-ethyl acrylate to the copper catalyst is 1.1: 1: 0.025-0.1; and finally synthesizing the oseltamivir for preventing bird flu through the aziridine ring opening, nitryl and p-nitrobenzene sulfonyl removal, acetylation and hydrogenation. The method comprises short steps, the used reagent is cheap and easily available, the operation is simple, the total yield is up to 40%, and the method is a simple and efficient synthesis method of oseltamivir.

Description

technical field [0001] The invention relates to the field of compound synthesis, in particular to a synthesis method of oseltamivir. Background technique [0002] The molecular formula of oseltamivir is C 16 h 28 N 2 o 4 , the chemical name is: (3R,4R,5S)-4-acetamide-5-amino-3-(1-propoxyethyl)-1-cyclohexene-1-carboxylate ethyl ester, the structural formula is as follows: [0003] [0004] Oseltamivir is a neuraminidase inhibitor with a cyclohexene structure. It was synthesized for the first time in 1996 and was mainly developed by Roche. It was launched in Switzerland in 1999 and was approved to be launched in China in 2002. It soon became the World Health Organization And the therapeutic drugs and national strategic reserve drugs for the prevention and control of bird flu in my country. So far, oseltamivir (or oseltamivir phosphate, also known as Tamiflu) is recognized as the most effective drug against avian influenza, so its synthesis is very important. [0005] T...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/12C07C233/52
Inventor 朱钢国杜思全章洁妮程存归
Owner ZHEJIANG NORMAL UNIVERSITY
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