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[2-(1h)-quinolinone-3-yl]aminomethylphosphonate and its preparation method and application

A technology of aminomethyl phosphonate and diethyl anilinomethyl phosphonate, applied in phosphorus organic compounds, antiviral agents, etc., can solve drug resistance, severe side effects of the central nervous system, and clinical application limitations And other issues

Inactive Publication Date: 2018-06-15
HUNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

M2 ion channel inhibitors are prone to drug resistance, have serious side effects on the gastrointestinal tract and central nervous system, and are only effective for type A, so their clinical application is greatly limited

Method used

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  • [2-(1h)-quinolinone-3-yl]aminomethylphosphonate and its preparation method and application
  • [2-(1h)-quinolinone-3-yl]aminomethylphosphonate and its preparation method and application
  • [2-(1h)-quinolinone-3-yl]aminomethylphosphonate and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of [2-(1H)-quinolinone-3-yl]anilinomethylphosphonic acid diethyl ester

[0028]

[0029] (1) Preparation of 3-formyl-2-(1H)-quinolinone

[0030] 98ml POCl 3 Add dropwise to 7ml of N,N-dimethylformamide, stir at 0-5°C for 30min, add 50mmol of acetanilide, raise the temperature to 90°C, and react for 16h. After cooling, the reaction was also poured into 500ml of ice water, filtered with suction, and washed with water. Add 200ml of 70% acetic acid solution to the solid, and react at 95°C for 4h. After cooling the reaction solution, flocculent solids were precipitated, filtered, washed with water, and dried to obtain 3-formyl-2-(1H)-quinolinone with a yield of 73.8%, m.p.303-305°C.

[0031] (2) Preparation of [2-(1H)-quinolinone-3-yl]anilinomethylphosphonic acid diethyl ester

[0032]2mmol 3-formyl-2-(1H)-quinolinone, 2mmol aniline and 15ml toluene, stirred at room temperature for 10min, added 2mmol diethyl phosphite, refluxed for 4h (monitored by TLC), c...

Embodiment 2

[0034] Preparation of [2-(1H)-quinolinone-3-yl]benzylaminomethylphosphonic acid diethyl ester

[0035]

[0036] 2mmol 3-formyl-2-(1H)-quinolinone, 2mmol benzylamine and 15ml toluene, stirred at room temperature for 10min, added 2mmol diethyl phosphite, refluxed for 1h (monitored by TLC); 石油醚 :V 乙酸乙酯 =1:1 Column chromatography, drying to give [2-(1H)-quinolinon-3-yl]benzylaminomethylphosphonic acid diethyl ester, yield 67.5%, m.p.113-116°C. 1 H NMR (400MHz, CDCl 3 )δ: 12.34(s, 1H, NH), 8.10(d, J=3.2Hz, 1H), 7.61(d, J=7.6Hz, 2H), 7.51(t, J=7.6Hz, 1H), 7.40( d, 1H, J=8.4Hz, 1H), 7.65(d, J=7.6Hz, 1H), 7.34~7.26(m, 4H), 7.24~7.21(m, 2H), 4.80~4.75(m, 1H, NCHP), 4.32~4.20(m, 2H, OCH 2 ), 4.11~4.00 (m, 2H, OCH 2 ), 3.90~3.69 (m, 2H, CH 2 ), 1.32(t, J=6.8Hz, 3H, CH 3 ), 1.18(t, J=6.8Hz, 3H, CH 3 ); 13 C NMR (100MHz, CDCl 3 )δ: 163.61, 139.44, 138.01, 130.53, 128.40, 128.35, 127.95, 127.12, 122.69, 119.92, 115.96, 109.38, 63.46, 62.88, 51.97, 51.82, 18.35, 16.351, and 16. ...

Embodiment 3

[0038] Preparation of [2-(1H)-quinolinone-3-yl]-2-methylanilinomethylphosphonic acid diethyl ester

[0039]

[0040] 2mmol 3-formyl-2-(1H)-quinolinone, 2mmol 2-methylaniline and 15ml toluene, stirred at room temperature for 10min, added 2mmol diethyl phosphite, refluxed for 3h (monitored by TLC); 石油醚 :V 乙酸乙酯 =1:1 column chromatography, dried to give [2-(1H)-quinolinon-3-yl]-2-methylanilinomethylphosphonic acid diethyl ester, yield 86.3%, m.p.191~193℃ . 1 H NMR (400MHz, CDCl 3 )δ: 11.59(s, 1H, NH), 8.01(d, J=3.6Hz, 1H), 7.54(d, J=7.9Hz, 1H), 7.49(t, J=7.6Hz, 1H), 7.20( t, J=7.4Hz, 1H), 7.05(d, J=7.2Hz, 1H), 6.97(t, J=7.7Hz, 1H), 6.65(t, J=7.3Hz, 1H), 6.58(d, J=8.0Hz, 1H), 5.56~5.50(m, 1H, NCHP), 4.86(s, 1H, NH), 4.31~4.26(m, 2H, OCH 2 ), 4.14~3.99 (m, 2H, OCH 2 ), 2.30 (s, 3H, CH 3 ), 1.34(t, 3H, J=7.0Hz, CH 3 ), 1.15(t, 3H, J=6.9Hz, CH 3 ); 13 C NMR (100MHz, CDCl 3 )δ:163.37、143.92、138.35、138.02、130.58、130.30、128.49、128.17、127.23、123.02、122.78、119.98、118.31、115.8...

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Abstract

The present invention relates to [2-(1H)-quinolinone-3-yl]aminomethyl phosphonate or its salts shown in chemical structural formula I: R is selected from: C1~C2 alkyl, C3~C4 linear alkane Base or branched chain alkyl; X1, X2 are selected from: hydrogen, deuterium, C1~C2 alkyl; X3, X7 are selected from: hydrogen, deuterium, C1~C2 alkyl, fluorine, chlorine, bromine, iodine or nitro; X4 and X6 are selected from: hydrogen, deuterium, C1-C2 alkyl; X5 are selected from: hydrogen, deuterium, C1-C2 alkyl or nitro; n=0 or 1. Application of [2-(1H)-quinolinone-3-yl]aminomethylphosphonate or its salt in the preparation of neuraminidase inhibitors.

Description

technical field [0001] The invention relates to the preparation and application of a class of novel compounds; specifically, the preparation of [2-(1H)-quinolinone-3-yl]aminomethylphosphonate and its application as an influenza virus neuraminidase inhibitor. Background technique [0002] Avian influenza virus (AIV) belongs to type A influenza virus and can be divided into 16 H (H 1 -H 16 ) subtypes and nine N(N 1 -N 9 ) subtype, among many subtypes of influenza A virus, H 5 and H 7 highly pathogenic avian influenza virus. H 5 N 1 、H 7 N 2 、H 7 N 3 、H 7 N 7 、H 9 N 2 、H 10 N 7 、H 7 N 9 And in December 2013, a new bird flu H was discovered in Jiangxi, my country 10 N 9 Subtype. Symptoms of these subtypes vary and can mainly manifest as respiratory symptoms, conjunctivitis, and even death. Highly pathogenic H 5 N 1 Subtype and the new avian influenza H first detected in humans in March 2013 7 N 9 Subtypes are of particular interest. [0003] In 1997, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/60A61K31/675A61P31/16
Inventor 胡艾希方毅林李水师叶姣刘艾林连雯雯
Owner HUNAN UNIV
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