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New preparation method of Vonoprazan

A technology of amides and compounds, applied in the new field of preparation, can solve the problems of many operation steps, expensive, ultra-low temperature for reaction, etc., and achieve the effect of reducing costs

Active Publication Date: 2018-04-17
CHANGZHOU NO 4 PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the expensive and air-sensitive reagent diisobutylaluminum hydride (DIBAL-H) ​​is used to reduce the ester group, and the reaction needs to be carried out at -78°C, and the conditions are harsh.
Diisobutylaluminum hydride reagent is highly flammable, and the reaction requires ultra-low temperature, so it is not suitable for industrial production operations
Therefore, the reaction product of this step is more complex
In addition, Raney nickel is very active, and it is easy to burn when exposed to air, and there are serious safety hazards in industrial production.
In short, the reduction of cyano group to aldehyde is difficult to control, the whole process has many steps, the production cycle is prolonged, and Raney nickel is flammable and unsafe, so it is difficult to realize industrialization of this process

Method used

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  • New preparation method of Vonoprazan
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  • New preparation method of Vonoprazan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1.5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylic acid ethyl ester

[0077]

[0078] To a solution of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (4 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.5 g), and the mixture was Stir for 30+ minutes. Pyridine-3-sulfonyl chloride hydrochloride (1 g) was added, followed by stirring for more than 3 hours. After the reaction was completed, it was quenched with saturated brine, and the mixture was extracted with 50 mL of ethyl acetate. The extract was washed with saturated brine and concentrated. Add methyl tert-butyl ether and ethyl acetate (1:1) for crystallization, and obtain colorless crystals (yield 80%, purity 96%).

[0079] l H-NMR (CDC1 3 )δ: 1.35 (3H, t, J = 7.2Hz), 4.30 (2H, q, J = 7.2Hz), 6.69 (1H, d, J = 1.8Hz), 6.99-7.09 (lH, m), 7.19- 7.19(2H,m),7.40-7.39(1H,m),7.46-7.52(1H,m),7.61-7.75(1H,m),8.15(1H.d,J=1.8Hz),8.59-8.61( lH, m), 8.82-8.84 (lH, m).

Embodiment 2

[0080] Example 2.5-(2-fluorophenyl)-N-methyl 1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxamide

[0081]

[0082] Add 37g of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate into 400mL of water, add dropwise 10mL of 40% methylamine aqueous solution, raise the temperature to about 75°C, and react for more than 4 hours. After the reaction, cool down to 0-10° C., stir for more than 12 hours to precipitate an off-white solid, filter, and dry to obtain 33 g of the product, with a yield of 94% and a purity of 95%. l H-NMR (CDC1 3 )δ: 2.65(3H), 6.33(1H, d, J=1.8Hz), 7.28(2H, m), 7.49-7.75(4H, m), 8.15(1H.d, J=1.8Hz), 8.42- 8.45(2H,m), 8.91(lH,s).

Embodiment 3

[0083] Example 3.5-(2-fluorophenyl)-N-methyl 1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxamide

[0084]

[0085] Add 4 g of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate into 40 mL of water, add dropwise 1 mL of 40% methylamine aqueous solution, heat up to about 55°C, and react for more than 4 hours. After the reaction, cool down to 0-10°C, stir for more than 12 hours to precipitate an off-white solid, filter, and dry to obtain 3 g of the product with a yield of 79% and a purity of 94%.

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Abstract

The invention discloses an improved preparation method of Vonoprazan, and particularly discloses a preparation method of a compound Vonoprazan with a structure shown in the description. According to the method, a compound 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylic ester is taken as a raw material and subjected to amination with water as a solvent, a product is reduced, and Vonoprazan is prepared.The technology adopts short steps, and is low in cost, environmentally friendly and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a new preparation method of Vonorazan. It belongs to the field of drug synthesis. Background of the invention [0002] Acid-related diseases (ARDs) are a group of upper gastrointestinal diseases closely related to gastric acid and pathogenesis, including gastroesophageal reflux disease, dyspepsia, gastrointestinal ulcers, gastritis, duodenitis and some anti-inflammatory drugs of gastrointestinal diseases. The incidence of ARDs is increasing year by year worldwide. In China, ARDs have become one of the major diseases, seriously affecting the quality of life of patients and bringing a greater economic burden to patients. Clinically, proton pump inhibitors (PPIs) have been widely used in the treatment of ARDs and are the main therapeutic drugs for such diseases. [0003] Vonorazan is a potassium ion competitive blocker, and the in vitro activity test shows that the ability of the compound to inhibit the proton pump is 400 time...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07C51/41C07C57/15A61P1/04
CPCC07D401/12
Inventor 范新华屠永锐贺赟刘传军周岳宇唐文生马俊朱季张翔张明洁
Owner CHANGZHOU NO 4 PHARMA FACTORY
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