Method for preparing mosapride citrate intermediate

A technology of mosapride citrate and intermediates, applied in the field of medicine, can solve the problems of high production difficulty, high cost, low purity of mosapride citrate and the like, and achieve the effects of reducing production costs and shortening routes.

Active Publication Date: 2018-06-08
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to solve the problems of low purity, high cost and difficult production of mosapride citrate, the invention provides an important intermediate of mosapride citrate 4-(4-fluorobenzyl)-2-ammonia New preparation method of methylmorpholine

Method used

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  • Method for preparing mosapride citrate intermediate
  • Method for preparing mosapride citrate intermediate
  • Method for preparing mosapride citrate intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Preparation of intermediate N-3-[4-fluorobenzyl-2-(hydroxyl-ethylamine)-2-hydroxyisopropyl]phthalamide:

[0031] Add phthalimide potassium salt (33.4g, 0.18mol) and 166ml of absolute ethanol into a 500ml four-neck flask, heat to 60-70°C and stir to dissolve, add 0.216mol of dichloroisopropanol after the material is dissolved , 0.216mol triethylamine, heated and refluxed for 6 hours to generate the intermediate N-(2-hydroxy-3-chloropropyl) phthalimide, cooled to 50-60°C, and added dropwise the intermediate (30.5g , 0.18mol) ethanol solution of 2-(4-fluorobenzylamino)ethanol, keep warm for 3 hours, evaporate the ethanol to dryness under reduced pressure, add ethyl acetate to dissolve, filter with suction, wash the filtrate with water and salt, separate liquid, anhydrous sulfuric acid After drying the magnesium, filter it with suction and evaporate to dryness under reduced pressure to obtain a light yellow oily substance which is the intermediate N-3-[4-fluorobenzyl-2-(hyd...

Embodiment 2

[0033] Preparation of intermediate N-3-[4-fluorobenzyl-2-(hydroxyl-ethylamine)-2-hydroxyisopropyl]phthalamide:

[0034] Add phthalimide potassium salt (33.4g, 0.18mol) and 166ml of absolute ethanol into a 500ml four-neck flask, heat to 60-70°C and stir to dissolve, add 0.27mol of dichloroisopropanol after the material is dissolved , 0.27mol triethylamine, heated and refluxed for 6 hours to generate intermediate N-(2-hydroxyl-3-chloropropyl)phthalimide, cooled to 50-60°C, and added dropwise 0.216mol 2 -(4-Fluorobenzylamino)ethanol solution in ethanol, heat preservation reaction for 3 hours, evaporate the ethanol to dryness under reduced pressure, add ethyl acetate to dissolve, filter with suction, wash the filtrate with water and salt, separate liquid, dry over anhydrous magnesium sulfate, and pump Filter, evaporate to dryness under reduced pressure to obtain light yellow oil intermediate N-3-[4-fluorobenzyl-2-(hydroxyl-ethylamine)-2-hydroxyisopropyl]phthalamide (yield 83.6%, ...

Embodiment 3

[0036] Preparation of intermediate N-3-[4-fluorobenzyl-2-(hydroxyl-ethylamine)-2-hydroxyisopropyl]phthalamide:

[0037]Add phthalimide potassium salt (33.4g, 0.18mol) and 166ml of absolute ethanol into a 500ml four-neck flask, heat to 60-70°C and stir to dissolve, then add 0.3mol of dichloroisopropanol after the material is dissolved , 0.216mol triethylamine, heated and refluxed for 6 hours to generate the intermediate N-(2-hydroxy-3-chloropropyl) phthalimide, cooled to 50-60°C, and added dropwise the intermediate (30.5g , 0.18mol) ethanol solution of 2-(4-fluorobenzylamino)ethanol, keep warm for 3 hours, evaporate the ethanol to dryness under reduced pressure, add ethyl acetate to dissolve, filter with suction, wash the filtrate with water and salt, separate liquid, anhydrous sulfuric acid After magnesium drying, filter with suction and evaporate to dryness under reduced pressure to obtain light yellow oil intermediate N-3-[4-fluorobenzyl-2-(hydroxyl-ethylamine)-2-hydroxyisop...

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Abstract

The invention belongs to the technical field of medicines and particularly relates to a method for preparing a mosapride citrate intermediate IV 4-(4-fluorophenyl)-2-aminomethyl morpholine. The methodcomprises the following steps: phthalimide potassium salt and dichloro-2-propanol react to produce an intermediate II N-(2-hydroxy-3-chloropropyl) phthalimide, then the produced intermediate II and an intermediate I 2-(4-fluorphenylamine)ethyl alcohol are condensed to prepare an intermediate III N-3-[4-fluorophenyl-2-(hydroxy-ethylamine)-2-hydroxypropyl]phthalic diamide, and the intermediate IIIis subjected to cyclization and hydrolysis to obtain the intermediate IV 4-(4-fluorophenyl)-2-aminomethyl morpholine. The method is short in route, lower in production cost and suitable for industrialproduction.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically provides a method for preparing an intermediate 4-(4-fluorobenzyl)-2-aminomethylmorpholine of mosapride citrate. Background technique [0002] With the acceleration of the pace of social life, the improvement of people's living standards and the change of diet structure and other factors, the number of patients with low gastric motility is increasing, and people's quality of life is greatly affected. Mosapride citrate is a selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist, which can promote the production of acetylcholine by exciting the 5-HT4 receptors of choline interneurons and myenteric nerves in the gastrointestinal tract. release, thereby enhancing the motility of the gastrointestinal tract, improving the gastrointestinal symptoms of patients with functional dyspepsia, without affecting the secretion of gastric acid. Mosapride citrate, as a gastric motility drug wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/30
CPCC07D265/30
Inventor 张贵民臧超公艳艳
Owner LUNAN PHARMA GROUP CORPORATION
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