Unlock instant, AI-driven research and patent intelligence for your innovation.

Preparation method of revaprzan hydrochloride

A technology of loflupridine and dimethylpyrimidine, which is applied in the field of preparation of loflupridine, can solve the problems of cumbersome operation, high cost, and long reaction time

Inactive Publication Date: 2014-09-03
SHANDONG UNIV +1
View PDF2 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, this method needs to go through addition reaction, pyrimidine cyclization, electrophilic substitution reaction, etc., the operation is cumbersome, the cost is high, and the reaction time is long, and pyridine is used as an acid-binding agent to promote pyrimidine cyclization, which pollutes the environment.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of revaprzan hydrochloride
  • Preparation method of revaprzan hydrochloride
  • Preparation method of revaprzan hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0040] The invention provides a preparation method of loflupridine, comprising the following steps: A) mixing guanidinium salt, basic substance and ethyl 2-methylacetoacetate, heating and reacting in the first solvent to obtain 2-amino -4-hydroxyl-5,6-dimethylpyrimidine, the basic substance is sodium methoxide or sodium ethoxide; B) the 2-amino-4-hydroxyl-5,6-dimethylpyrimidine and halogenated The reagents are mixed and reacted by heating to obtain 2-amino-4-halo-5,6-dimethylpyrimidine; C) combining the 2-amino-4-halo-5,6-dimethylpyrimidine with 1- Methyl-1,2,3,4-tetrahydroisoquinoline is mixed, heated in the second solvent for 4-position electrophilic substitution reaction to obtain 2-amino-4-[3,4-dihydro-1-methanol base-2(1H)-isoquinolinyl]-5,6-dimethylpyrimidine; D) the 2-amino-4-[3,4-dihydro-1-methyl-2(1H) -Isoquinolinyl]-5,6-dimethylpyrimidine is mixed with an acylating reagent for acylation reaction, then adding halogenated p-fluorobenzene and a catalyst, heating in a t...

Embodiment 1

[0087] 1.1 Mix 25g (0.2mol) of guanidine nitrate, 33g (0.6mol) of sodium methoxide with 150mL of methanol, heat up and reflux for 2 hours, then cool down to 20°C, filter with suction to remove the solid sodium nitrate, add 65g (0.44mol) to the filtrate Ethyl 2-methylacetoacetate was heated to reflux and gradually precipitated from the solid. After 2 hours of reaction, the temperature was lowered to 20°C, filtered with suction, the solid was washed with water, and dried to obtain 2-amino-4-hydroxy-5,5 -Dimethylpyrimidine 22.5g, the yield is 80%.

[0088] 1.2 Mix 20g (0.144mol) of 2-amino-4-hydroxy-5,5-dimethylpyrimidine obtained in 1.1 with 176g (1.15mol) of phosphorus oxychloride, heat up to reflux for 2 hours, and the color turns brownish red , evaporate phosphorus oxychloride to dryness under reduced pressure, add 100mL of water dropwise under ice bath conditions, adjust the pH value of the solution to neutral with lye, filter with suction, wash the solid with water, and dry...

Embodiment 2

[0095] 2.1 Mix 25g (0.2mol) of guanidine nitrate, 33g (0.6mol) of sodium methoxide with 150mL of methanol, heat up and reflux for 2 hours, then cool down to 20°C, add 65g (0.44mol) of ethyl 2-methylacetoacetate, heat up Return to reflux, react for 2 hours, cool down to 20°C, filter with suction, wash the solid with water, and dry to obtain 25.5 g of 2-amino-4-hydroxy-5,5-dimethylpyrimidine with a yield of 92%.

[0096] 2.2 Mix 20g (0.144mol) of 2-amino-4-hydroxy-5,5-dimethylpyrimidine obtained in 2.1 with 100g (0.653mol) of phosphorus oxychloride, heat up to reflux for 2 hours, and the color turns brownish red , evaporate phosphorus oxychloride to dryness under reduced pressure, add 100mL of water dropwise under ice bath conditions, adjust the pH value of the solution to neutral with lye, filter with suction, wash the solid with water, and dry to obtain 2-amino-4 -Chloro-5,6-dimethylpyrimidine 19g, the yield is 85%.

[0097] 2.3 Mix 10g (0.0635mol) of 2-amino-4-chloro-5,6-dim...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides a preparation method of revaprzan hydrochloride. The method includes: mixing guanidine salt, an alkaline substance and 2-methylacetoacetic acid ethyl ester, performing pyrimidine cyclization, mixing with a halogenated reagent, heating, reacting to obtain a halogenated compound, mixing with 1-methyl-1, 2, 3, 4-tetrahydro naphthalene, heating, reacting to obtain a substitution product, finally adding halogenated fluorine benzene and a catalyst after acylation reaction, heating and reacting to obtain revaprzan hydrochloride. Compared with the prior art, the preparation method uses guanidine salt as an starting raw material, the pyrimidine cyclization is performed, no pyridine is needed, cost is reduced, and environmental pollution is reduced; secondly, after the pyrimidine cyclization, halogenating reaction is performed, 4 bit and 2 bit electrophilic substitution reactions are performed, amino is acylated to generated an amide compound in the 2 bit electrophilic substitution reaction, then the electrophilic substitution reaction is performed, the reaction is performed easily, reaction time is shortened, reaction period is shortened, and yield is improved.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of loflupridine. Background technique [0002] Loflupridine was developed by South Korea's Yuhan Company and has independent intellectual property rights. The drug was approved by the Korean FDA in September 2005 for the treatment of duodenal ulcer and gastritis. In 2007, it was approved for the treatment of gastric ulcer, gastroesophageal reflux disease, functional dyspepsia and indications for Hp eradication. At present, GlaxoSmithKline has obtained the worldwide development and marketing license for the drug outside South Korea and North Korea. [0003] As a reversible inhibitor of gastric acid secretion, lorflupridine can quickly pass through the cell membrane of the gastric parietal cell, accumulate in the strongly acidic secretory tubules, and be converted into sulfenamide compounds. + 、K + The sulfhydryl group of -ATPase is co...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
Inventor 宋伟国杨大伟夏艳吕伟香张晓攀徐文方
Owner SHANDONG UNIV