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Oseltamivir amino derivative as well as preparation method and application thereof

A technology of Wei amino and derivatives, applied in the fields of organic synthesis and medical applications, can solve the problems of inconvenient administration, invisible, low bioavailability and the like

Inactive Publication Date: 2021-08-06
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the oral bioavailability of zanamivir is low and administration is inconvenient; with the long-term use of oseltamivir, a variety of virus strains resistant to oseltamivir have been found clinically, such as the H274Y mutant (H1N1 -H274Y and H5N1-H274Y), these defects make the use of existing drugs face a bottleneck, so the research and development of new NA inhibitors is very urgent
[0004] The present invention discloses a new class of amino derivatives of oseltamivir with no relevant reports in the prior art

Method used

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  • Oseltamivir amino derivative as well as preparation method and application thereof
  • Oseltamivir amino derivative as well as preparation method and application thereof
  • Oseltamivir amino derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Target compound (3R,4R,5S)-4-acetamido-3-(pentane-3-oxyl)-5-((2-chloro-4-(2-thiophene)benzyl) Preparation of amino)cyclohexane-1-enecarboxylic acid (9a)

[0038]

[0039] 2-thiophene boronic acid (1) (0.64g, 5.0mmol), 4-bromo-2-chlorobenzaldehyde (3a) (1.09g, 5.0mmol, 1.0equiv), K 2 CO 3 (3.1g, 22.5mmol, 4.5equiv.) and Pd(PPh 3 ) 4 (0.064g, 0.055mmol, 0.011equiv.) was dissolved in 20mL of DMSO, with N 2 Protection, vacuuming 2-3 times, reflux for 10h. TLC detects that after the reaction is completed, 150 mL of water is added to the reaction solution, extracted with ethyl acetate (50 mL×3), the combined organic phase is washed with saturated sodium chloride solution, the organic phase is retained and dried with anhydrous magnesium sulfate, filtered, and the filtrate Concentrated under reduced pressure, the resulting crude product was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:petroleum ether=1:50 syste...

Embodiment 2

[0045] Example 2: Target compound (3R,4R,5S)-4-acetamido-3-(pentane-3-oxyl)-5-((2-chloro-4-(3-thiophene)benzyl) Preparation of amino)cyclohexane-1-enecarboxylic acid (10a)

[0046]

[0047] The preparation of compound 10a, the operation steps are the same as in Example 1, the difference is that the raw material for preparing compound 5a in Example 1 is replaced by 3-thiophene boronic acid to prepare 6a, and after obtaining 6a, follow the same steps to prepare 8a, and after obtaining 8a 10a was prepared following the same procedure.

[0048] White powdery solid, total yield 67.3%, mp: 160-162°C.

[0049] Spectral data:

[0050] 1 H NMR (400MHz, CD 3 OD)δ7.83(d,J=1.5Hz,1H),7.78(d,J=1.5Hz,1H),7.70(dd,J=8.0,1.6Hz,1H),7.61–7.42(m,3H) ,6.86(s,1H),4.34(d,J=15.7Hz,2H),4.22(d,J=7.8Hz,1H),4.11(d,J=10.7Hz,1H),3.59–3.39(m, 3H), 3.12–2.96(m, 1H), 2.61(dd, J=17.6, 9.8Hz, 1H), 2.05(s, 3H), 1.53(dd, J=11.9, 6.1Hz, 4H), 0.91(dt ,J=10.2,7.4Hz,6H).C 25 h 31 ClN 2 o 4 S, ESI-MS: m / z...

Embodiment 3

[0051] Example 3: Target compound (3R,4R,5S)-4-acetamido-3-(pentane-3-oxyl)-5-((5-chloro-4-(2-thiophene)benzyl) Preparation of amino)cyclohexane-1-enecarboxylic acid (9b)

[0052]

[0053] The preparation of compound 9b, the operation steps are the same as in Example 1, the difference is that the raw material for preparing compound 5a in Example 1 is replaced by 4-bromo-3-chlorobenzaldehyde to prepare 5b, and after obtaining 5b, follow the same steps to prepare 7b , to obtain 7b and then follow the same procedure to prepare 9b.

[0054] White powdery solid, total yield 77%, mp: 166-169°C.

[0055] Spectral data:

[0056] 1 H NMR (400MHz, CD 3 OD)δ7.80–7.61(m,2H),7.54(dd,J=5.1,1.0Hz,1H),7.47–7.38(m,2H),7.14(dd,J=5.1,3.7Hz,1H), 6.86(s,1H),4.37(d,J=13.3Hz,1H),4.25–4.06(m,3H),3.62–3.38(m,3H),3.13–2.91(m,1H),2.61(dd, J=17.3,9.7Hz,1H),2.04(d,J=7.0Hz,3H),1.54(dt,J=11.5,5.8Hz,4H),0.91(q,J=7.5Hz,6H).C 25 h 31 ClN 2 o 4 S, ESI-MS: m / z 491.00[M+H] + .

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Abstract

The invention provides an oseltamivir amino derivative as well as a preparation method and application thereof. The compound has a structure represented by a general formula I. The invention also relates to the preparation method of the derivative and the application of the derivative as a neuraminidase inhibitor in preparation of anti-influenza virus drugs.

Description

technical field [0001] The invention relates to an oseltamivir derivative and a preparation method thereof, in particular to the preparation of an oseltamivir amino derivative and its application in the field of anti-influenza drugs, and belongs to the technical field of organic synthesis and medical application. Background technique [0002] Influenza is an acute respiratory infectious disease caused by influenza virus. It has the characteristics of strong infectivity, rapid transmission and high incidence. Infants, young children, the elderly, and patients with basic cardiopulmonary diseases or low immunity are all high-risk groups. Such influenza patients Easy to cause pneumonia or other complications and life-threatening. Influenza infection can be prevented and controlled with vaccination and antiviral drugs. However, due to the large number of subtypes of influenza viruses, which are prone to mutation, the development and production of vaccines requires at least six m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/20C07D333/24A61K31/381A61P31/16
CPCC07D333/20C07D333/24A61P31/16C07B2200/07
Inventor 刘新泳鞠翰展鹏侯凌欣张莹
Owner SHANDONG UNIV