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Preparation method of vonorazan fumarate

A technology of vonoprazan fumarate and fluorophenyl, which is applied in the field of medicine, can solve the problems of many by-products, troublesome post-processing steps, etc., and achieves the effect of mild reducing agent

Inactive Publication Date: 2018-06-12
海南欣莱医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The invention solves the problems of many by-products and cumbersome post-processing steps in the prior preparation method of vonoprazan fumarate

Method used

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  • Preparation method of vonorazan fumarate
  • Preparation method of vonorazan fumarate
  • Preparation method of vonorazan fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation method of high-purity fumaric acid vonoprazan of the present invention is as follows:

[0028] ①Synthesis of Crude Vonoprazan Fumarate

[0029] Add 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde (660g, 2mol) into 3.5L tetrahydrofuran, and fill with 2mol formaldehyde at 20°C Amine gas and solid gradually dissolved, continued stirring for 30 minutes, cooled to 0°C, added sodium triacetoxyborohydride (1.6mol) in batches, and stirred at 0°C until the raw materials were completely reacted. After post-treatment to obtain an oily substance, fumaric acid (1.6 mol) was added to form a salt to obtain 622 g of vonoprazan fumaric acid crude product, with a yield of 67.4%.

[0030] ②Refinement of crude product of vonoprazan fumarate

[0031] Add 600g crude vonoprazan fumarate into a mixed solvent of 5.8L methanol and 0.7L N,N-dimethylformamide, heat to 60°C to dissolve the solid, filter, cool to 0°C for crystallization for 6 hours, pump Filte...

Embodiment 2

[0033] The preparation method of high-purity fumaric acid vonoprazan of the present invention is as follows:

[0034] ①Synthesis of Crude Vonoprazan Fumarate

[0035] Add 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde (330g, 1mol) into 2.3L acetonitrile, and charge 1.5mol at 30°C under temperature control Methylamine gas, the solid gradually dissolved, and continued to stir for 30 minutes. The temperature was lowered to 5° C., and sodium triacetoxyborohydride (1.2 mol) was added in batches. After the addition, the temperature was maintained and stirred until the reaction of the raw materials was complete. After post-treatment to obtain an oily substance, fumaric acid (1.2 mol) was added to form a salt to obtain 319.8 g of crude product of vonoprazan fumarate, with a yield of 69.3%.

[0036] ②Refinement of crude product of vonoprazan fumarate

[0037] Add 300g crude vonoprazan fumarate into a mixed solvent of 2.4L methanol and 0.2L N,N-dimethylformamide...

Embodiment 3

[0039] The preparation method of high-purity fumaric acid vonoprazan of the present invention is as follows:

[0040] ①Synthesis of Crude Vonoprazan Fumarate

[0041] Add 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde (165g, 0.5mol) into 1.1L of dichloromethane, and control the temperature at 20°C Underfill 0.5mol methylamine gas, the solid gradually dissolves, and continue to stir for 30 minutes. Cool down to 0°C, add sodium tripropionyloxyborohydride (0.5mol) in batches, stir at 0°C until the raw materials are completely reacted after the addition, and then process to obtain an oily substance, add fumaric acid (0.45mol) 164.3 g crude product of vonoprazan fumarate was obtained by salt formation, with a yield of 71.2%.

[0042] ②Refinement of crude product of vonoprazan fumarate

[0043] Add 160g crude vonoprazan fumarate into a mixed solvent of 1.4L methanol and 140mL N,N-dimethylformamide, heat to 62°C to dissolve the solid, filter, cool to 5°C for ...

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Abstract

The invention discloses a preparation method of Vonoprazan fumarate. The preparation method comprises steps as follows: 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3- formaldehyde is dissolved in a solvent, methylamine gas is introduced at the temperature of 20-30 DEG C, the components are stirred, the temperature is reduced to 0-5 DEG C, a reducing agent is added, then the mixture is continuously stirred until the mixture reacts completely, grease is obtained through processing, fumaric acid is added to form salt, and a crude product of Vonoprazan fumarate is obtained; the crude product is added to a methyl alcohol and N,N-dimethylformamide mixed solvent and heated to 60-70 DEG C, solids are dissolved, and white crystals are obtained through filtering, cooling, crystallization, suction filtration and drying. According to the preparation method, reaction by-products can be reduced, high-purity Vonoprazan fumarate is acquired with a new refining technology, and the purity of Vonoprazan fumarate is up to 99.8% through HPLC (high performance liquid chromatography) detection.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of vonoprazan fumarate. Background technique [0002] Peptic ulcer is the most common type of disease in the digestive system. It is also a general term for a type of digestive tract disease caused by excessive gastric acid secretion or sensitivity to gastric acid. The vast majority of ulcers occur in the duodenum and Stomach. Clinical studies in recent years have shown that excessive gastric acid secretion, Helicobacter pylori infection and weakened protective effect of gastric mucosa are the main factors causing peptic ulcer. Proton pump inhibitors (PPIs) are currently the most powerful class of drugs for acid suppression, such as omeprazole, lansoprazole, pantoprazole, rabeprazole, etc. Because PPIs have nocturnal acid breakthrough phenomenon, it will affect the therapeutic effect. [0003] Different from traditional PPIs, potassium ion-competitive aci...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
CPCC07B2200/13C07D401/12
Inventor 邝少轶陈年根张丽杨雪峰陈琳
Owner 海南欣莱医药科技股份有限公司