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A crystal form of a proton pump inhibitor, its preparation intermediate, its synthesis method and its medical application

A crystal form and drug technology, which is applied in the preparation of carboxylate salts, active ingredients of heterocyclic compounds, drug combinations, etc., can solve problems such as ulcers, and achieve the effect of stable crystal form properties and good market prospects

Active Publication Date: 2017-06-06
连云港恒运药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when certain factors damage a link in the protective mechanism, gastric acid and protease may erode the self-mucosa and cause ulcer formation.

Method used

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  • A crystal form of a proton pump inhibitor, its preparation intermediate, its synthesis method and its medical application
  • A crystal form of a proton pump inhibitor, its preparation intermediate, its synthesis method and its medical application
  • A crystal form of a proton pump inhibitor, its preparation intermediate, its synthesis method and its medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)- N-methylacetamide 10g, be dissolved in the mixed solvent of isopropanol (80ml) and absolute ethanol (20ml), add fumaric acid 1.26g under the condition of stirring, then heat to 50 ℃ and reflux for 30 minutes, in Naturally cooled to room temperature with stirring, stirred for 2 hours, filtered, and dried to obtain 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrole- 1-yl)sulfonyl)phenoxy)-N-methylacetamide hemifumarate, the target crystal form was obtained, named as crystal form 1, weighing 9.8g, mass yield 98%, its 1H-NMR Spectrum such as figure 1 As shown, the XRD pattern is as figure 2 shown.

Embodiment 2

[0037] Example 2: 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)- 10g of N-methylacetamide, dissolved in isopropanol (80ml), added ethanol solution of fumaric acid (1.26g / 20ml), heated to reflux, all solids dissolved, naturally cooled to room temperature under stirring conditions, stirred for 2 hours, filtered and dried to give 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy) -N-methylacetamide hemifumarate, the target crystal form was obtained, named as crystal form 1, weighed 9.6g, and the mass yield was 96%. Its 1H-NMR spectrum was basically the same as figure 1 The same, the XRD pattern is basically the same as figure 2 Consistent with the characteristics of crystal form 1.

Embodiment 3

[0038]Example 3: 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N -Preparation of methylacetamide hemifumarate intermediate and free base

[0039]

[0040] first step

[0041] tert-Butyl((5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbonate (3.0g, 10mmol) and 3-(2-(methylamino)- Add 2-oxoethoxy)phenyl-1-sulfonyl chloride (2.64mg, 10mmol) into acetonitrile, add DIEA and stir for 2-5 hours. The temperature of the reaction solution was cooled, dilute hydrochloric acid was added to adjust the pH to 4-5, and purified water was added for crystallization to obtain compound III, 4.9 g, yield: 92.3%.

[0042] second step

[0043] Compound III (4.5 g) was dissolved in 15 mL of ethyl acetate, the temperature of the reaction liquid was cooled to 10° C. in an ice bath, hydrochloric acid gas was added, and the reaction was stirred for 1 hour. Use sodium bicarbonate to adjust pH to alkaline, wash with saturated sodium chloride solution, dry ov...

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Abstract

The invention discloses a crystal form of a proton pump inhibitor, preparation of a midbody, a synthesis method and a medical application of the crystal form, and particularly relates to a hemi-fumarate salt crystal form as shown in a formula (1) of a proton pump inhibitor containing a pyrrole ring, a midbody, a preparation method and a medical application of the hemi-fumarate salt crystal form. An XRD spectrum characteristic peak of the hemi-fumarate salt crystal form has 2theta angles (+ / -0.2 degrees) of 7.858, 9.456, 13.202, 14.836, 15.099, 15.749, 15.050 and 19.948. The new crystal form disclosed by the invention has the advantages of significant medicine effect, small side effect and the like. The formula (1) is as shown in the specification.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a proton pump inhibitor, namely 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrole-1- Base) sulfonyl) phenoxy) -N-methylacetamide hemifumarate crystal form, preparation intermediate and preparation method thereof, and pharmaceutical composition containing the therapeutically effective amount of the crystal form and use thereof. Background technique [0002] Peptic ulcer refers to the tissue damage of the gastrointestinal mucosa beyond the muscularis mucosa caused by the digestion of gastric digestive juice itself. It can occur in any part of the digestive tract, among which the stomach and duodenum are the most common, namely gastric ulcer and duodenum The etiology, clinical symptoms and treatment methods of digital ulcers are basically similar, and the definite diagnosis mainly depends on gastroscopy. Gastric ulcer is the most common type of peptic ulcer, which mainly refers t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/48C07C57/15C07C51/41A61K31/40A61P1/04
CPCC07D207/48
Inventor 朱强余俊杨宝海
Owner 连云港恒运药业有限公司
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