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4-alkyl-6-aryl-2-acylamino-1,3-thiazine-5-formic ether, and preparation method and application thereof

A 2-OCH3, 2-F technology, applied in the direction of antiviral agents, active ingredients of heterocyclic compounds, etc., to achieve high anti-neuraminidase activity effect

Inactive Publication Date: 2012-03-14
HUNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compounds designed against the active site SA and 430-Cavity of neuraminidase NA are rarely reported. The computer-simulated NA double-active site SA and 430-Cavity inhibitors 327704 and 117079 target SA through the N atom. Connected with the group of 430-Cavity, the simulated inhibition constant K of compound 327704, 117079 i 0.406μmol / L and 0.497μmol / L respectively

Method used

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  • 4-alkyl-6-aryl-2-acylamino-1,3-thiazine-5-formic ether, and preparation method and application thereof
  • 4-alkyl-6-aryl-2-acylamino-1,3-thiazine-5-formic ether, and preparation method and application thereof
  • 4-alkyl-6-aryl-2-acylamino-1,3-thiazine-5-formic ether, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Preparation of ethyl 4-methyl-6-(4-methylphenyl)-2-acetylamino-1,3-thiazine-5-carboxylate

[0021]

[0022] (1) Preparation of ethyl 4-methyl-6-(4-methylphenyl)-2-amino-1,3-thiazine-5-carboxylate

[0023] Dissolve 0.01mol 2-(4-methylbenzylidene)ethyl acetoacetate and 0.012mol thiourea in 30mL methanol, 1mL concentrated hydrochloric acid, reflux, after the reaction is complete, part of the solvent is evaporated, and the solid is precipitated, recrystallized from ethanol, and dried Obtain 4-methyl-6-(4-methylphenyl)-2-amino-1,3-thiazine-5-carboxylic acid ethyl ester hydrochloride; dissolve the hydrochloride in ethanol, adjust pH with dilute NaOH solution 7-8, precipitated solid, recrystallized from ethanol, dried to obtain 4-methyl-6-(4-methylphenyl)-2-amino-1,3-thiazine-5-carboxylic acid ethyl ester, yield 74.5% , m.p.142~145℃. 1 H NMR (400M Hz, CDCl 3 ), δ: 1.24 (t, J=6.8Hz, 3H, CH 3 ), 2.14(s, 3H, COCH 3 ), 2.30(s, 3H, benzene ring CH 3 ), 2.55(s, 3H...

Embodiment 2

[0026] Example 2 Preparation of ethyl 4-methyl-6-(4-chlorophenyl)-2-acetylamino-1,3-thiazine-5-carboxylate

[0027]

[0028] (1) Preparation of ethyl 4-methyl-6-(4-chlorophenyl)-2-amino-1,3-thiazine-5-carboxylate

[0029] 0.004mol 2-(4-chlorobenzylidene)ethyl acetoacetate, 0.005mol thiourea and 30mL ethanol, 1mL hydrochloric acid, stirred and refluxed, after the reaction was completed, part of the solvent was evaporated, and the solid was precipitated, recrystallized from ethanol, and dried to obtain 4- Methyl-6-(4-chlorophenyl)-2-amino-1,3-thiazine-5-carboxylic acid ethyl ester hydrochloride; hydrochloride is dissolved in ethanol, dilute sodium carbonate solution to adjust pH 7~8 , a yellow solid was precipitated, recrystallized from ethanol, and dried to obtain ethyl 4-methyl-6-(4-chlorophenyl)-2-amino-1,3-thiazine-5-carboxylate with a yield of 87.7%, m.p.149 ~151°C. 1 H NMR (400M Hz, CDCl 3 ), δ: 1.23 (t, J=7.2Hz, 3H, CH 3 ), 2.48(s, 3H, CH 3 ), 4.15 (q, J=7.2Hz, 2H...

Embodiment 3

[0032] Example 3 Preparation of ethyl 4-methyl-6-(4-fluorophenyl)-2-acetylamino-1,3-thiazine-5-carboxylate

[0033]

[0034] (1) Preparation of ethyl 4-methyl-6-(4-fluorophenyl)-2-amino-1,3-thiazine-5-carboxylate

[0035] 0.005mol 2-(4-fluorobenzylidene)ethyl acetoacetate and 0.006mol thiourea, 30mL methanol, 1mL concentrated hydrochloric acid, stirred and refluxed, after the reaction was completed, part of the solvent was evaporated, and the solid was precipitated, recrystallized from ethanol, and dried to obtain 4 -Methyl-6-(4-fluorophenyl)-2-amino-1,3-thiazine-5-carboxylic acid ethyl ester hydrochloride; hydrochloride dissolved in ethanol, dilute sodium bicarbonate solution to adjust pH 7 ~8, a yellow solid was precipitated, recrystallized from ethanol, and dried to obtain pale yellow ethyl 4-methyl-6-(4-fluorophenyl)-2-amino-1,3-thiazine-5-carboxylate. Yield 85.7%, m.p.121-122°C. 1 H NMR (400M Hz, CDCl 3 ), δ: 1.23 (t, J=6.8Hz, 3H, CH 3 ), 2.49 (s, 3H, CH 3 ), 4.15...

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Abstract

The invention discloses 4-alkyl-6-aryl-2-acylamino-1,3-thiazine-5-formic ether having the following chemical structural formula shown in the specification. The preparation method of the 4-alkyl-6-aryl-2-acylamino-1,3-thiazine-5-formic ether (I) comprises the following steps of: adding 2-benzal-2-acyl acetate and thiourea in organic solvent, stirring at 55-80 DEG C under acid catalysis, filtering and washing after reacting completely, and drying to obtain 4-alkyl-6-aryl-2-amino-1,3-thiazine-5-formic ether salt; neutralizing the 4-alkyl-6-aryl-2-amino-1,3-thiazine-5-formic ether salt with alkali to obtain 4-alkyl-6-aryl-2-amino-1,3-thiazine-5-formic ether; and acylating the 4-alkyl-6-aryl-2-amino-1,3-thiazine-5-formic ether to obtain the 4-alkyl-6-aryl-2-acylamino-1,3-thiazine-5-formic ether (I). The invention also discloses an application of the 4-alkyl-6-aryl-2-acylamino-1,3-thiazine-5-formic ether in preparing the drug of neuraminidase inhibitor.

Description

technical field [0001] The present invention relates to a new class of compounds and their preparation methods and applications, specifically 4-alkyl-6-aryl-2-amido-1,3-thiazine-5-carboxylates and their preparation methods and applications . Background technique [0002] According to the latest report on the 2009 Influenza A (H1N1) global situation released by the World Health Organization on February 26, 2010, at least 16,226 patients in 213 countries and regions have died from this pandemic. Neuraminidase (NA) inhibitors are the first-line drugs against novel influenza viruses. Neuraminidase (NA) inhibitors include compounds such as Zanamivir, Oseltamivir and Peramivir, among which Oseltamivir is widely used. However, some studies have found that Oseltamivir has developed resistance to some virus strains. Compounds designed against the active site SA and 430-Cavity of neuraminidase NA are rarely reported. The computer-simulated NA dual-active site SA and 430-Cavity inhi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D279/06A61K31/54A61P31/16
Inventor 胡艾希谭卫清夏林李婉叶姣
Owner HUNAN UNIV
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