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Method for preparing isoquinolyl substituted pyrimidine derivative

A technology of tetrahydroisoquinoline and pyrimidine, which is applied in the field of medicine, can solve problems such as darkening of color, unfavorable storage, insufficient reduction, etc., and achieve the effect of simple operation, simple process and high purity

Active Publication Date: 2013-01-09
天津泰普制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are two chlorines in 2,4-dichloro-5,6-dimethylpyrimidine. When preparing, it is necessary to use twice the equivalent of phosphorus oxychloride as the reaction substrate; and two chlorine atoms, that is, two reactive Center, when reacting with 1-methyl-1,2,3,4-tetrahydroisoquinoline, by-products with similar structures will inevitably be produced, which affects the yield of the reaction and makes the reaction product difficult to refine
[0011] 1-Methyl-1,2,3,4-tetrahydroisoquinoline is obtained by reduction of 1-methyl-3,4-dihydroisoquinoline. There is a problem of insufficient reduction. The structure of raw materials and products Similar, difficult to separate and purify
The 1-methyl-1,2,3,4-tetrahydroisoquinoline prepared by this method is usually a brown nearly tan liquid, and 1-methyl-1,2,3,4-tetrahydro Isoquinoline is a secondary amine, if placed in contact with air at room temperature, it will easily oxidize and deteriorate over time, and the color will become darker, which is not conducive to storage

Method used

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  • Method for preparing isoquinolyl substituted pyrimidine derivative
  • Method for preparing isoquinolyl substituted pyrimidine derivative
  • Method for preparing isoquinolyl substituted pyrimidine derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0023] 20g of 1-methyl-3,4-dihydroisoquinoline, 28.8g of 5,6-dimethyl-2-(4-fluorophenylamino)pyrimidine, in 200mL of dry toluene, add a stirring, In the reaction bottle of the thermometer, reflux condenser, and drying tube, under the protection of nitrogen, heat to reflux, turbidity begins to occur, and react for 30 hours. Filter and wash with anhydrous ether. The solid was quickly dissolved with 200 mL of absolute ethanol, and NaBH was added in portions 4 After adding 4.8g, continue to stir at room temperature for 1h. Evaporate the solvent under reduced pressure, add 200 mL of water to the residue, adjust the pH to >10 with concentrated ammonia water, extract with dichloromethane, wash with water, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, dissolve in acetone, and pass through dry HCl gas, A solid precipitated out. Filtrate, dissolve the solid with absolute ethanol, decolorize with activated carbon, filter, freeze and crystallize to obt...

Embodiment 2

[0025] 15g of 1-methyl-3,4-dihydroisoquinoline, 21.6g of 5,6-dimethyl-2-(4-fluorophenylamino)pyrimidine, in 150mL of dry toluene, add a stirring, In the reaction bottle of the thermometer, reflux condenser, and drying tube, under the protection of nitrogen, heat to reflux, and turbidity begins to occur, and react for 24 hours. Filter and wash with anhydrous ether. The solid was quickly dissolved with 150 mL of absolute ethanol, and NaBH was added in portions 4 After adding 3.6g, continue to stir at room temperature for 1h. Evaporate the solvent under reduced pressure, add 150 mL of water to the residue, adjust the pH to >10 with concentrated ammonia water, extract with dichloromethane, wash with water, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, dissolve in acetone, and pass through dry HCl gas, A solid precipitated out. Filtrate, dissolve the solid with absolute ethanol, decolorize with activated carbon, filter, freeze and crystallize to...

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Abstract

The invention provides a preparation method of 5,6-dimethyl-2-(4-fluorophenyl amino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-group) pyrimidine and its hydrochloride. The method comprises the following steps: 1-methyl-3,4-dihydroisoquinoline is reacted to 5,6-dimethyl-2-(4-fluorophenyl amino)pyrimidine to obtain quaternary ammonium salt, quaternary ammonium salt is not dissolved in an organic solvent, and is easy to separate the raw material with good dissolvability in the organic solvent and the generated by-product, thereby high purity 5,6-dimethyl-2-(4-fluorophenyl amino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-group) pyrimidine and its hydrochloride can be obtained by reduction. The preparation method of the present invention has the advantages of simple technology and simple operation, and is used for large scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinone The preparation method of pyrimidine and hydrochloride thereof. Background technique [0002] 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl) shown in formula I Pyrimidine and its hydrochloride is a reversible proton pump inhibitor, a potassium-competitive acid pump inhibitor with a novel and unique mechanism of action, which makes it more effective in inhibiting acid, faster onset, and less side effects. Gastritis, duodenal ulcer, gastric ulcer and gastroesophageal reflux have certain advantages. [0003] [0004] CN95194599.8 disclosed the compound and its preparation method for the first time, and CN97194367.2 disclosed another preparation method of the compound. [0005] The preparation method disclosed in CN95194599.8 is as follows: [0006] [0007...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 黄淑云李兴伟黄铭辉罗振福谢应
Owner 天津泰普制药有限公司