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Process for preparing 2,4-disubstituted heterocyclo [4,5-e][1,2,4] thiadiazine derivatives

A disubstitution, 5-e technology, applied in the field of chemistry, can solve the problems of single target purity, long reaction steps, and limited number of changes

Inactive Publication Date: 2006-09-27
SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although this synthetic method can obtain target single, higher purity N 2 A single-substituted thieno[4,5-e][1,2,4]thiadiazine derivative intermediate, but due to the longer reaction steps, the limitation of the reaction raw material (substituted) benzylamine species makes N 2 The variable number of single substituents is limited, so it cannot meet the requirements of structural diversity required for structure-activity relationship research

Method used

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  • Process for preparing 2,4-disubstituted heterocyclo [4,5-e][1,2,4] thiadiazine derivatives
  • Process for preparing 2,4-disubstituted heterocyclo [4,5-e][1,2,4] thiadiazine derivatives
  • Process for preparing 2,4-disubstituted heterocyclo [4,5-e][1,2,4] thiadiazine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1.2-p-nitrobenzyl-4-benzyl-7-methyl-1,1,3-trioxy-2,4-dihydropyrazol[4,5-e][1,2,4 ] Preparation of thiadiazine (3.01)

[0062] Dissolve 1 equivalent of 7-methyl-1,1,3-trioxo-2,4-dihydropyrazolo[4,5-e][1,2,4]thiadiazine in dry di In methylformamide (DMF), in N 2 Under protection, slowly add 2 equivalents of sodium hydride containing 60% mineral oil, keep the temperature below 10°C, after the addition is complete, stir for a long enough time until a white precipitate appears, and slowly add 1 equivalent of benzyl bromide. The reaction mixture was stirred for an additional 12 h at 35 °C. Thin layer (TLC) detection, after the reaction is complete, add 1 equivalent of p-nitrobenzyl bromide to the reaction solution, raise the temperature to 50°C, continue the reaction for 12 hours, TLC detection, after the reaction is complete, cool, and evaporate under reduced pressure solvent. The residue was washed with water and purified by recrystallization from ethanol. Yiel...

Embodiment 2

[0064] Example 2.2-o-bromobenzyl-4-benzyl-7-methyl-1,1,3-trioxy-2,4-dihydropyrazol[4,5-e][1,2,4] Preparation of Thiadiazine (3.02)

[0065] Dissolve 1 equivalent of 7-methyl-1,1,3-trioxo-2,4-dihydropyrazolo[4,5-e][1,2,4]thiadiazine (1) in In dry dimethylformamide (DMF), in N 2 Under protection, slowly add 2 equivalents of sodium hydride containing 60% mineral oil, keep the temperature below 10°C, after the addition is complete, stir for a long enough time until a white precipitate appears, and slowly add 1 equivalent of benzyl bromide. The reaction mixture was stirred for an additional 12 h at 35 °C. Thin layer (TLC) detection, after the reaction is complete, add 1 equivalent of o-bromobenzyl bromide to the reaction solution, raise the temperature to 50°C, continue the reaction for 12h, TLC detection, after the reaction is complete, cool, and evaporate the solvent under reduced pressure . The residue was washed with water and purified by recrystallization from ethanol. Yi...

Embodiment 3

[0068] Example 3.2-p-bromobenzyl-4-o-bromobenzyl-7-methyl-1,1,3-trioxy-2,4-dihydropyrazol[4,5-e][1,2, 4] Preparation of Thiadiazine (3.03)

[0069] Dissolve 1 equivalent of 7-methyl-1,1,3-trioxo-2,4-dihydropyrazolo[4,5-e][1,2,4]thiadiazine (1) in In dry dimethylformamide (DMF), in N 2 Under protection, slowly add 2 equivalents of sodium hydride containing 60% mineral oil, keep the temperature below 10°C, after the addition, stir for a long enough time until a white precipitate appears, slowly add 1 equivalent of o-bromo bromide benzyl. The reaction mixture was stirred for an additional 12 h at 40 °C. Thin layer (TLC) detection, after the reaction is complete, add 1 equivalent of p-bromobenzyl bromide to the reaction solution, raise the temperature to 50°C, continue the reaction for 12h, TLC detection, after the reaction is complete, cool, and evaporate the solvent under reduced pressure . The residue was washed with water and purified by recrystallization from ethanol. Y...

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Abstract

The invention discloses a 2, 4-disubstituted heterocycle parallel [4,5-e][1,2,4] thiadiazines derivant preparing method in the chemical technique domain, which comprises the following steps: dissolving heterocycle parallel [1,2,4] thiadiazines parent in dimethyl formamide; adding in sodium hydride; stiring under 10 deg.c to white sediment; filling in halocarbon R2X; stirring and reacting; adding halocarbon R1X in liquor; reacting at 25-60deg.c for 10-24 hours; reducing pressure and steaming dissolvant; rinshing leavings; recrystallizating by organic solvent. R1, R2 represents bromine benzyl, double-bromine-bromine-benzyl, meta- bromine-bromine-benzyl and so on. The invention simplifies the operation, which has high yield.

Description

(1) Technical field [0001] The present invention relates to a preparation method of 2,4-disubstituted heterocyclo[4,5-e][1,2,4]thiadiazine derivatives, in particular to 1,1,3-trioxo-2,4-di Hydrogen heterocyclo[4,5-e][1,2,4]thiadiazine N 2 , N 4 - A "one-pot" preparation method for disubstituted derivatives, which belongs to the field of chemical technology. (2) Background technology [0002] N 2 , N 4 -Disubstituted thienothiadiazines derivatives (TTDs) are a class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis of TTDs is based on the parent ring 1,1,3-trioxo-2,4-dihydrothieno[4,5-e][1,2,4]thiadiazine in the presence of sodium hydride First in the N of the mother ring 2 Substituents are introduced at the position to obtain N 2 -monosubstituted thieno[4,5-e][1,2,4]thiadiazine derivative intermediates; monosubstituted derivatives are separated and purified by column chromatography, and then continue to be purified under N 4 position in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04C07D515/04
Inventor 刘新泳徐文方闫任章
Owner SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD
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