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Oseltamivir derivative, preparation method and application thereof

A technology of oseltamivir and derivatives, which is applied in the fields of organic compound synthesis and medical application, and can solve problems such as inconvenience for patients

Active Publication Date: 2017-08-18
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current highly pathogenic H5N1 avian influenza virus and various seasonal H1N1 and H3N2 influenza virus strains have developed resistance to it
Zanamivir (zanamivir) and the newly launched peramivir (peramivir) are mainly administered by inhalation or intravenous injection, which is very inconvenient for patients, and drug-resistant virus strains have also emerged

Method used

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  • Oseltamivir derivative, preparation method and application thereof
  • Oseltamivir derivative, preparation method and application thereof
  • Oseltamivir derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] (3R,4R,5S)-4-Acetamido-5-((4-nitrobenzyl)amino)-3-(pentane-3-oxyl)cyclohexene-1-ene-1-carboxy Preparation of ethyl acetate (1)

[0102]

[0103] Weigh oseltamivir phosphate (0.41g, 1mmol), 4-nitrobenzaldehyde (0.15g, 1.2mmol), sodium cyanoborohydride (0.12g, 2mmol) in 20mL ethanol solution, stir at 30°C for 5h (TLC detects that the reaction is complete, developer: ethyl acetate). Evaporate the solvent, add 20mL water, extract three times with 20mL ethyl acetate, dry over anhydrous magnesium sulfate, filter, evaporate the solvent, and perform flash column chromatography to obtain a white solid which is the compound (3R,4R,5S)-4- Ethyl acetamido-5-((4-nitrobenzyl)amino)-3-(pentane-3-oxy)cyclohexene-1-ene-1-carboxylate, yield: 76.3%.

[0104] (3R,4R,5S)-4-Acetamido-5-((4-nitrobenzyl)amino)-3-(pentane-3-oxyl)cyclohexene-1-ene-1-carboxy Preparation of acid (IA-1-1)

[0105]

[0106] (3R,4R,5S)-4-acetamido-5-((4-nitrobenzyl)amino)-3-(pentane-3-oxyl)cyclohexene-1-ene...

Embodiment 2

[0109] (3R,4R,5S)-4-Acetamido-5-((3-trifluoromethylbenzyl)amino)-3-(pentane-3-oxyl)cyclohexene-1-ene-1 - Preparation of ethyl carboxylate (2)

[0110]

[0111] The operating steps are the same as in Example 1, except that the starting material used is 3-trifluoromethylbenzaldehyde.

[0112] The product was obtained as a white solid, yield: 77.1%.

[0113] (3R,4R,5S)-4-Acetamido-5-((3-trifluoromethylbenzyl)amino)-3-(pentane-3-oxyl)cyclohexene-1-ene-1 - Preparation of ethyl carboxylate (IA-1-2)

[0114]

[0115] The operation steps are the same as in Example 1, except that compound 2 is used as the starting material.

[0116] The product was obtained as a white solid, yield: 79.3%.

[0117] 1 H NMR (400MHz, DMSO-d 6 )δ12.71(s,1H),9.90(s,1H),9.53(s,1H),8.22(d,J=9.0Hz,1H),7.99(s,1H),7.87(d,J=7.6 Hz, 1H), 7.76(d, J=7.8Hz, 1H), 7.66(t, J=7.7Hz, 1H), 6.66(s, 1H), 4.30(s, 3H), 4.05(q, J=8.9 Hz,1H),3.53–3.46(m,1H),2.96(dd,J=17.1,4.8Hz,1H),2.77–2.65(m,1H),1.91(s,3H),1.42(q...

Embodiment 3

[0119] Preparation of 4-(Benzo[b]thiophen-2-yl)benzaldehyde (3-1)

[0120]

[0121] Benzo[b]thiophene-2-boronic acid (1.78g, 10mmol), 4-bromobenzaldehyde (1.85g, 10mmol), potassium carbonate (4.1g, 30mmol), tetrakis(triphenylphosphine)palladium (0.08g , 0.069mol), DMSO (30mL) were added into the flask, under nitrogen protection, heated to 120°C, and stirred for 12 hours. The reaction mixture was added to 150 mL of water, extracted 3 times with 50 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, evaporated to remove the solvent, and separated by flash column chromatography to obtain a pale yellow oil which was the compound 4-(benzo[b] Thiophen-2-yl)benzaldehyde (3-1), yield: 82.5%.

[0122] (3R,4R,5S)-4-acetamido-5-((4-(benzo[b]thiophen-2-yl)benzyl)amino)-3-(pentane-3-oxyl) ring Preparation of ethyl hexene-1-ene-1-carboxylate (2)

[0123]

[0124] The operation steps are the same as in Example 1, except that the starting material is 4-(benzo[b]thi...

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Abstract

The invention discloses an oseltamivir derivative, a preparation method and an application thereof. The derivative has a structure shown as formula I. The invention also discloses the preparation method for the oseltamivir derivative, the application thereof as an avian influenza virus neuraminidase inhibitor and the application of a composition containing one or more compounds in preparing anti-influenza virus drugs.

Description

technical field [0001] The invention relates to an oseltamivir derivative, a preparation method thereof and an application as an influenza virus neuraminidase inhibitor, belonging to the technical field of organic compound synthesis and medical application. Background technique [0002] Influenza is referred to as influenza (influenza or flu), which is an acute upper respiratory infectious disease caused by influenza virus. It poses a great threat to human life and health. Tens of thousands of people die from influenza every year in the world. Animal influenza will not only cause the death of a large number of birds, mammals and other animals, but also cause social and economic damage. Heavy losses caused great social panic. Neuraminidase (NA) is a functional protein of influenza virus, which plays an important role in the life process of the virus and is an important target for the design of anti-influenza drugs. Currently the only oral NA inhibitor, oseltamivir phosphate...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C233/52C07D333/58C07D207/325C07D277/28C07D333/20C07C319/20C07C323/32C07C315/04C07C317/32C07C303/40C07C311/20C07C257/18C07C277/08C07C279/16A61K31/196A61K31/381A61K31/402A61K31/426A61P31/16
CPCC07C233/52C07C257/18C07C279/16C07C311/20C07C317/32C07C323/32C07D207/325C07D277/28C07D333/20C07D333/58Y02P20/55
Inventor 刘新泳张健展鹏鞠翰孔秀杰孙卓森
Owner SHANDONG UNIV
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