A kind of preparation method of Isoladine maleate

A technology of Isoladine maleate and its intermediates, applied in the field of chemical pharmacy, can solve the problems of uneven ulcer healing quality and easy recurrence, and achieve the effects of less reaction time, high purity and high yield

Inactive Publication Date: 2019-06-07
安徽省公众检验研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] At present, proton pump inhibitors (PPIs) are mainly used to treat peptic ulcer in clinical practice. The acid-suppressing effect is fast and obvious, but there are problems such as unbalanced ulcer healing quality and easy recurrence. In terms of gastric mucosal protection, bismuth and Sucralfate-based

Method used

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  • A kind of preparation method of Isoladine maleate
  • A kind of preparation method of Isoladine maleate
  • A kind of preparation method of Isoladine maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment one: the preparation of Isoladine maleate

[0028] (1) Preparation of Intermediate II (Isoladine)

[0029] 447g (2.6mol) of 2,5-dichlorobenzonitrile, 894ml of 1,3-dimethyl-2-imidazolinone (DMI), heated to 65-70°C, adding 227g (2.7mol) of dicyandiamide and tungsten 85.8g (0.26mol) of sodium nitrite, keep stirring at 65-70°C for 2 hours, TLC to identify the reaction end point (developing solvent: n-butanol-acetic acid-water=5:2:0.5), after the reaction is completed, cool to room temperature, add Deionized water 894ml, stirred for 20min, filtered, the solid was washed with deionized water, and dried under vacuum at 70-75°C for 4h to obtain white solid intermediate II (Isoladine) (635g, 2.48mol), with an HPLC content of 98.9%. Yield 95.4%, Mp: 264-267°C, directly used in the next step.

[0030] (2), preparation of crude product of Isoladine maleate

[0031] Intermediate II (Isoladine) 630g (2.46mol), glycerin formal 1260ml, heat to 45-50°C, add maleic acid 285...

Embodiment 2

[0035] Embodiment two: the preparation of Isoladine maleate

[0036] (1) Preparation of Intermediate II (Isoladine)

[0037]44.7g (0.26mol) of 2,5-dichlorobenzonitrile, 90ml of hexamethylphosphoramide (HMPA), heated to 65-70°C, 22.7g (0.27mol) of dicyandiamide and 8.6g (0.026 mol), keep stirring at 65-70°C for 2 hours, and identify the end point of the reaction by TLC (developing agent: n-butanol-acetic acid-water=5:2:0.5), after the reaction is completed, cool to room temperature, add 90ml of deionized water, and stir After 20 minutes, filter, wash the solid with deionized water, and dry under vacuum at 70-75°C for 4 hours to obtain white solid intermediate II (Isoladine) (66 g, 0.258 mol), HPLC content 98.6%, yield 99.2%, Mp: 265-269°C, directly used in the next step.

[0038] (2), preparation of crude product of Isoladine maleate

[0039] Intermediate II (Isoladine) 63g (0.246mol), glycerin formal 130ml, heat to 45-50°C, add maleic acid 29g (0.246mol), keep stirring for ...

Embodiment 3

[0042] Embodiment three: the preparation of Isoladine maleate

[0043] (1) Preparation of Intermediate II (Isoladine)

[0044] 44.7g (0.26mol) of 2,5-dichlorobenzonitrile, 90ml of hexamethylphosphoramide (HMPA), heated to 65-70°C, added 22.7g (0.27mol) of dicyandiamide and 13g of silica-alumina molecular sieve, and maintained at 65 Stir and react at ~70°C for 2 hours, TLC to identify the reaction end point (developing agent: n-butanol-acetic acid-water=5:2:0.5), after the reaction is completed, cool to room temperature, filter, add 90ml of deionized water to the filtrate, stir for 20min, Filter, wash the solid with deionized water, and dry it under vacuum at 70-75°C for 4 hours to obtain white solid intermediate II (Isoladine) (62g, 0.242mol), HPLC content 98.1%, yield 93.0%, Mp: 264~ 268°C, directly used in the next step.

[0045] (2), preparation of crude product of Isoladine maleate

[0046] Intermediate II (Isoladine) 60g (0.234mol), glycerin formal 130ml, heated to 45-...

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Abstract

The invention provides a preparation method for irsogladine maleate, and belongs to the technical field of medicinal and chemical synthesis. The method comprises the following steps: carrying out a condensation reaction between 2,5-dichlorobenzonitrile and dicyandiamide in a non-protic strong polarity solvent with the existence of a basic catalyst to obtain an intermediate II, and enabling the intermediate II and maleic acid to salify in glyceroformol; re-crystallizing a salt in an acetic acid-acetone mixed solution to obtain the irsogladine maleate. The preparation method is easy to operate, high in yield and high in purity, can effectively shorten reaction time, and has a good industrial application value.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and relates to a preparation method of a novel aminotriazine gastric mucosal protective agent isoladine maleate. Background technique [0002] At present, proton pump inhibitors (PPIs) are mainly used to treat peptic ulcer in clinical practice. The acid-suppressing effect is fast and obvious, but there are problems such as unbalanced ulcer healing quality and easy recurrence. In terms of gastric mucosal protection, bismuth and Sucralfate-based. Isoladine maleate is a new type of aminotriazine gastric mucosal protective agent, which can protect gastric mucosa through various mechanisms. Clinical data show that Isoladine is effective in treating gastritis, gastric ulcer and preventing gastric cancer. curative effect. Isoladine maleate achieves the effects of mucosal protection and anti-ulcer through a series of reactions by increasing the level of cAMP in human neutrophils and increasin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D251/18C07C57/145C07C51/41C07C51/43
CPCC07D251/18
Inventor 徐奎童成亮王亚丽刘经星
Owner 安徽省公众检验研究院有限公司
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