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Preparation method of high-purity Vonoprazan fumarate

A technology for vonorasan fumarate and vonorasan maleate is applied in the field of preparation of high-purity vonorasan fumarate, can solve problems such as being unfavorable to industrialized production, and achieves simple operation and easy-to-obtain raw materials. , the effect of high product purity

Pending Publication Date: 2021-12-31
ZHEJIANG CHIRAL MEDICINE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Not conducive to industrial production

Method used

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  • Preparation method of high-purity Vonoprazan fumarate
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  • Preparation method of high-purity Vonoprazan fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: Preparation of free alkaline Voro Late (Intermediate II)))

[0066] 100 g (0.3 mol) of 5- (2-fluorophenyl) -1 [(pyridin-3-yl) sulfonyl] -1H-pyrrole-3-formaldehyde was added to 800 g of methanol, and then 30% (quality) %) The methanol solution of the methal alcohol is about 34.54 g (methylamine 0.33 mol) 20 ° C for 4 h, cooling to 5 ° C, sodium borohydride 11.3 g (0.3 mol), 0-5 ° C insulation reaction 1 h; 2 mol / L hydrochloric acid was adjusted to be 5, and 200 g of saturated sodium chloride solution was added, and it was filtered to 0 ° C, and 83 g of free alkaline volfonora was obtained.

[0067] 83 g of free alkaline volfonola was added to 498 g of methanol 40 ° C dissolved, and the pH of 30% hydrochloric acid was 8.0, and 498 g of water was added dropwise, and the temperature was lowered to 0 ° C for 2 h, and the free alkaline volfonora boutique 61g (purity) ≥ 99.8%), yield 58.34% (with starting materials - 5- (2-fluorophenyl) -1 [(pyridin-3-yl) sulfonyl] -1...

Embodiment 2

[0068] Example 2: Preparation of free alkaline Vorora

[0069] 100 g (0.3 mol) of 5- (2-fluorophenyl) -1 [(pyridin-3-yl) sulfonyl] -1H-pyrrole-3-formaldehyde was added to 800 g of methanol, and 30% of the addition of 30% The amine methanol solution is about 62.8 g (0.60 mol) at 10 ° C for 2 h and 0.45 g (0.36 mol) of sodium borohydride, 1 h, and 2 mol / L hydrochloric acid is adjusted by 2 mol / L hydrochloride. 5. Add 200g of saturated sodium chloride solution, cool down to 0 ° C, resulting in free alkaline voltanolas. 76g.

[0070] 76 g of free alkaline volfonola was added to 304 g of methanol dissolved at 40 ° C, and the pH of 30% hydrochloric acid was 8.0, and 456 g of water was added dropwise, and the temperature was cooled to 0 ° C for 2 h, and filtered to obtain free alkaline voltanora boutique 67g ( Purity ≥99.8%), yield 64.07%.

Embodiment 3

[0071] Example 3: Preparation of high purity fumarate volcornsiii III

[0072] The free alkaline volfonola obtained in Example 1 was dissolved in 610 g (0.18 mol) in 610 g of ethanol, and 25.55 g (0.19 mol) was added to 73 ° C for 1 h, and the temperature was fired to 10 ° C for 1 h filtration, obtained Crude product 76g.

[0073] The above-mentioned crude product was added to 50% by volume of methanol solution to 50 ° C for 10 minutes filtration, and the resulting filtrate was lowered to 5 ° C for 2 h. Drying 72 g of rollandavila (yield 88.34%, with intermediate II).

[0074] Detection by high efficiency chromatography, the chromatogram figure 1 , HPLC purity> 99.9%, and only one impurity.

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Abstract

The invention discloses a preparation method of high-purity Vonoprazan fumarate, which comprises the following steps: by taking 5-(2-fluorophenyl)-1[(pyridine-3-yl)sulfonyl]-1H-pyrrole-3-formaldehyde as an initial raw material, dissolving the initial raw material in a reaction solvent I, and reacting the solution with methylamine to generate Schiff base; reacting the solution with a reducing agent, salting out the product to obtain a free alkali Vonorazan crude product, and refining the product to obtain free alkali Vonorazan; and salifying the free alkali Vonorazan and fumaric acid in a reaction solvent II, and refining the product to obtain Vonorazan fumarate, wherein the HPLC purity of the product is greater than 99.9%.

Description

Technical field [0001] The present invention belongs to the field of pharmaceutical compound preparation, and more particularly to a preparation method of high purity (HPLC purity> 99.9%) rolland galvanola. Background technique [0002] Fumanrate (rich martyrogamate, Tak-438, Vonoprazan Fumarate) is a new type of inhibitor (PPI) developed by Japan, China, called potassium competition acid blocker (P- CAB) for the treatment of non-erosive gastroesophageal reflux, duodenal ulcer, gastric ulcer, erosive esophagitis (cure and maintenance treatment). It is currently listed in Japan, China, the Philippines, Thailand, Singapore and many other countries. [0003] Existing PPIs, such as Lan Solarazole, is converted to active substances in the presence of acid, and is irreversible to combine with the SH group of the proton pump, thereby inhibiting the activity of the enzyme, and the alkali ratio of rollandavila The existing PPI is high, high concentrations aggregated in the secretion of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07C57/15C07C51/41
CPCC07D401/12C07C51/412C07C57/15
Inventor 何匡朱银龙袁晓虎吴依阳程超黄凯金靖杰
Owner ZHEJIANG CHIRAL MEDICINE CHEM
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