Synthesis method of oseltamivir

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

Inactive Publication Date: 2014-06-04
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 represented by structural formula I (1.54g, 11mmol) and the compound represented by structural formula II (1.5g, 10mmol), heat to 70℃ and react for 4 hours, then cool to room temperature and add Cu(OTf) 2 (181mg, 0.5mmol), PhI=NNs (4.2g, 10mmol), add 20mL of acetonitrile to dissolve, stir the reaction for 6 hours, stop the reaction, remove the solvent by rotary evaporation, and separate with silica gel (300-400 mesh) column chromatography. 3.2g of colored liquid, 67% yield. 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...

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 represented by structural formula I and the compound represented by structural formula II, the rest of the operation steps were the same as in Example 1, to obtain the total production of oseltamivir The rate was 13%, and the product characterization data were 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 represented by structural formula I and the compound represented by structural formula II, the rest of the operation steps were the same as in Example 1, to obtain the total production of oseltamivir The rate was 31%, and the product characterization data were 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 method for synthesizing oseltamivir. Background technique [0002] The molecular formula of oseltamivir is C 16 H 28 N 2 O 4 , Chemical name: (3R, 4R, 5S)-4-acetamide-5-amino-3-(1-propoxyethyl)-1-cyclohexene-1-carboxylic acid ethyl ester, the structural formula is as follows: [0003] [0004] Oseltamivir is a neuraminidase inhibitor with a cyclohexene structure. It was first synthesized in 1996. It was mainly developed by Roche and listed in Switzerland in 1999. It was approved to be launched in China in 2002 and soon became the World Health Organization. And my country's national defense and control of bird flu therapeutic drugs and national strategic reserve drugs. 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] The synthetic route jointly developed b...

Claims

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Application Information

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Patent Type & Authority Applications(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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