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4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine and preparation method and application thereof

A technology of alkoxyacyl and alkyl, applied in the field of 4-alkyl-6-aryl-5-alkoxyacyl-1, to achieve high anti-neuraminidase activity effect

Inactive Publication Date: 2010-08-18
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-5-alkoxy acyl 1,3-thiazine and preparation method and application thereof
  • 4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine and preparation method and application thereof
  • 4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1 Preparation of 4-methyl-6-(4-methylphenyl)-5-ethoxyacyl-2-amino-1,3-thiazine and its hydrochloric acid

[0019]

[0020] Dissolve 0.01mol 2-(3-methylbenzylidene) ethyl acetoacetate and 0.012mol thiourea in 30mL methanol, add 1mL concentrated hydrochloric acid, reflux reaction, TLC monitors the reaction, after the reaction is complete, part of the solvent is evaporated to precipitate a solid , recrystallized from ethanol, and dried to obtain 4-methyl-6-(4-methylphenyl)-5-ethoxyacyl-2-amino-1,3-thiazine hydrochloride; the hydrochloride was dissolved in ethanol , add dilute NaOH solution, adjust the pH to 7~8, precipitate solid, recrystallize from ethanol, and dry to obtain 4-methyl-6-(4-methylphenyl)-5-ethoxyacyl-2-amino-1,3- Thiazide, yield 74.5%, m.p.142-145°C. 1 H NMR (400MHz, 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, CH 3 ), 4.17 (q, J=6.8Hz, 2H, OCH 2 ), 5.20 (s, 1H, thiazine ring...

Embodiment 2

[0021] Example 2 Preparation of 4-methyl-6-(4-chlorophenyl)-5-ethoxyyl-2-amino-1,3-thiazine and its hydrobromic acid

[0022]

[0023]0.004mol 2-(4-chlorobenzylidene)ethyl acetoacetate, 0.005mol thiourea and 30mL ethanol, 1mL hydrobromic acid, stirred and refluxed, TLC monitored the reaction, the reaction was completed, and part of the solvent was rotary evaporated, and the solid was precipitated, ethanol Recrystallized and dried to obtain 4-methyl-6-(4-chlorophenyl)-5-ethoxyacyl-2-amino-1,3-thiazine hydrobromide; hydrobromide was dissolved in ethanol, Add dilute sodium carbonate solution, adjust the pH to 7-8, and precipitate a yellow solid, recrystallize from ethanol, and dry to obtain 4-methyl-6-(4-chlorophenyl)-5-ethoxyacyl-2-amino-1,3- Thiazide, yield 87.7%, m.p.149~151℃. 1 H NMR (400MHz, 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, OCH 2 ), 5.27 (bs, 2H, NH 2 ); 5.28 (s, 1H, thiazine ring 6-H), 7.11 (d, J=8.4Hz, 2H, benzen...

Embodiment 3

[0024] Example 3 Preparation of 4-methyl-6-(4-fluorophenyl)-5-ethoxyyl-2-amino-1,3-thiazine and its hydrochloric acid

[0025]

[0026] 0.005mol 2-(4-fluorobenzylidene)ethyl acetoacetate and 0.006mol thiourea, 30mL methanol, 1mL concentrated hydrochloric acid, stirred and refluxed, TLC monitored the reaction, after the reaction was completed, part of the solvent was evaporated, and the solid was precipitated, ethanol Recrystallize and dry to obtain 4-methyl-6-(4-fluorophenyl)-5-ethoxyyl-2-amino-1,3-thiazine hydrochloride; dissolve the hydrochloride in ethanol, add Dilute sodium bicarbonate solution, adjust the pH to 7-8, precipitate a yellow solid, recrystallize from ethanol, and dry to obtain pale yellow 4-methyl-6-(4-fluorophenyl)-5-ethoxyacyl-2-amino-1 , 3-thiazine. Yield 85.7%, m.p.121-122°C. 1 H NMR (400MHz, CDCl 3 ), δ: 1.23 (t, J=6.8Hz, 3H, CH 3 ), 2.49 (s, 3H, CH 3 ), 4.15 (q, J=6.8Hz, 2H, OCH 2 ), 4.80 (bs, 2H, NH 2 ), 5.31 (s, 1H, thiazine ring 6-H), 6.95 (...

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Abstract

The invention discloses 4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine or salts thereof, and the chemical formula of the 4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine is shown in the specification of the invention. The preparation method of the 4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine (I) comprises the steps of: adding 2-benzal acetoacetate and thiourea in an organic solvent and stirring at 55 DEG C-80 DEG C under the catalysis of an acid; detecting reaction process by using TLC (Thin-Layer Chromatography); after finishing the reaction, filtering, washing, and drying to obtain 4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine salt; neutralizing the neutralize salt with an alkali to obtain the 4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine (I); and acylating the 4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine (I) to obtain 4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine (II). The invention also discloses the application of the 4-alkyl-6-aryl-5-alkoxy acyl 1,3-thiazine or the salt thereof in the preparation of neuraminidase inhibitors.

Description

technical field [0001] The present invention relates to a new class of compound and its preparation method and application, specifically 4-alkyl-6-aryl-5-alkoxyacyl-1,3-thiazine and its preparation method and application. 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 inhibitors 327704 and 117...

Claims

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Application Information

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Patent Type & Authority Applications(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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