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Preparation process of taytrolazole

A technology of tetraprazole and methoxyimidazole, which is applied in the field of novel H+/K+-ATPase inhibitors, can solve the problems of cumbersome preparation process, troublesome post-processing, violent reaction, etc., and achieves easy availability of raw materials and good product purity , the effect of simple operation

Inactive Publication Date: 2008-03-26
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The intermediate [(3,5-dimethyl-4-methoxyl-pyridyl) methyl]-thioformic acid preparation process used in method one is loaded down with trivial details, post-processing trouble, and yield is also low; Method two first 2 , 3,5-trimethyl-4-nitropyridine nitrogen oxide methoxylation, and then rearrangement to 2-hydroxymethyl-4-methoxy-3,5-lutidine, the reaction is more violent , more by-products, lower yield

Method used

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  • Preparation process of taytrolazole

Examples

Experimental program
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Effect test

Embodiment 1

[0021] 1) Preparation of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine

[0022] Mix 50g (0.27mol) of 2,3,5-trimethyl-4-nitropyridine-N-oxide and 40g of glacial acetic acid, stir and heat to 90°C, slowly add 41g (0.40mol) of acetic anhydride dropwise, approximately After 50 minutes of dripping, control the reaction temperature to 90°C, continue the reaction for 2h, after the reaction is complete, recover the solvent under reduced pressure, cool to 70°C, add 150g of hydrochloric acid with a mass concentration of 15%, keep the reaction for 2h, and use the mass percentage for the reaction. The 10% sodium carbonate aqueous solution was neutralized to pH 8, the aqueous layer was extracted with chloroform (100ml×3), the extracts were combined, concentrated, and dried to obtain 39.5g of white powdery solid, yield: 79%, mp: 65.2~66 ℃.

[0023] 2) Preparation of 2-chloromethyl-3,5-dimethyl-4-nitropyridine hydrochloride

[0024] Mix 20g (0.11mol) of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridin...

Embodiment 2

[0032] 1) Preparation of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine

[0033] Mix 50g (0.27mol) of 2,3,5-trimethyl-4-nitropyridine-N-oxide and 75g of propionic acid, stir and heat to 120°C, slowly add 75g (0.577mol) of propionic anhydride, approximately After 50 minutes of dripping, control the reaction temperature to 120°C, continue the reaction for 1 hour, after the reaction is complete, recover the solvent under reduced pressure, cool to 60°C, add 100 g of hydrochloric acid with a mass percentage of 20%, keep the reaction temperature for 1.5 hours, and use the mass after the reaction is completed A 10% sodium carbonate aqueous solution was neutralized to pH 8, the aqueous layer was extracted with dichloromethane (100ml×3), the extracts were combined, concentrated, and dried to obtain 40.5g of white powdery solid, yield: 81% , Mp: 65.2~66℃.

[0034] 2) Preparation of 2-chloromethyl-3,5-dimethyl-4-nitropyridine hydrochloride

[0035] Mix 20g (0.11mol) of 2-hydroxymethyl-3,5-dime...

Embodiment 3

[0043] 1) Preparation of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine

[0044] Mix 50g (0.27mol) of 2,3,5-trimethyl-4-nitropyridine-N-oxide and 125g of butyric acid, stir and heat to 90°C, slowly add 100g (0.63mol) of butyric anhydride dropwise, approximately After 1h dripping, control the reaction temperature to 70℃ and continue the reaction for 2.5h. After the reaction is completed, the solvent is recovered under reduced pressure, and the temperature is reduced to 50℃. 280g sulfuric acid with a mass concentration of 10% is added. The concentration of 10% sodium carbonate aqueous solution was neutralized to pH 8, the aqueous layer was extracted with 1,2-dichloroethane (100ml×3), the extracts were combined, concentrated, and dried to obtain 40.7g of white powdery solid. Yield : 81.4%, mp: 65.2~66°C.

[0045] 2) Preparation of 2-chloromethyl-3,5-dimethyl-4-nitropyridine hydrochloride

[0046] Mix 20g (0.11mol) of 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine and 50g of 1,2-dichloroe...

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Abstract

A process for preparing Taituolazuo includes such steps as reforming and hydrolyzing 2,3,5-trimethyl-4-nitropyridine oxynitride to obtain 2-hydroxymethyl-3,5-drimethyl -4-nitropyridine, chlorinating reaction to obtain 2-chloromethyl-3,5-dimethyl-4- nitropyridine, condensation reaction on 2-mercapto-5-methoxyimidazo [4,5-b] pyridine to obtain 2-(3,5-dimethyl-4-nitropyridine-2-ylmethylthio)-5-methoxyimidazo [4,5-b] pyridine, reacting on sodium methylate to obtain 2-(3,5-dimethyl-4-methoxypyridine- 2-ylmethylthio)-5-methoxyimidazo [4,5-b] pyridine, and oxidizing by peracid in organic acid.

Description

Technical field [0001] The invention relates to a preparation method for preparing a novel H+ / K+-ATPase inhibitor tytoprazole for treating digestive ulcers. Background technique [0002] There are two main methods for preparing Tetoprazole: Method one (Span.ES 550070, Span.ES534 275) is based on 2,3-diamino-6-methoxypyridine and [(3,5- Dimethyl-4-methoxy-pyridyl)methyl]-thioformic acid is directly condensed to give intermediate 2-[2-(3,5-dimethyl)-4-methoxypicolinyl sulfide -5-Methoxy]imidazo[4,5-b]pyridine, and then oxidized to obtain Tetoprazole; Method 2 (EP254588) uses the intermediate 2,3,5-trimethyl-4-nitropyridine nitrogen Oxide is used as the raw material, firstly methoxylated to obtain 2,3,5-trimethyl-4-methoxypyridine nitrogen oxide, then rearranged and chlorinated to obtain 2-chloromethyl-4-methoxy -3,5-dimethylpyridine hydrochloride, and then condensed with 2-mercapto-5-methoxyimidazo[4,5-b]pyridine under basic conditions to give intermediate 2-[2-(3 ,5-Dimethyl)-4-me...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
Inventor 戴立言王晓钟陈英奇
Owner ZHEJIANG UNIV
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