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Preparation method of low-impurity Vonoprazan fumarate

A technology of vonorazan fumarate and impurities, applied in the field of medicine, can solve the problems of difficult realization, unrealistic feeding weight, low yield, etc., and achieve the effects of prolonging the process cycle, saving energy, and reducing the introduction of organic solvents

Pending Publication Date: 2019-12-20
JILIN HUIKANG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Chinese patent application CN107778286A, the application is prepared by the above synthetic route, and the purity reaches more than 99.7% after 4 times of refining and purification, and the yield is relatively low
The examples 1-6 of this patent all refer to the addition of methylamine calculated by weight, but methylamine itself is a gas, and it is unrealistic to accurately weigh the weight of the addition, so the experiment is repeated according to the methylaminoalcohol solution commonly used in the prior art. 1-6
Difficult to achieve by dropping dilute hydrochloric acid to adjust the pH to precipitate solids to obtain Vonorazan hydrochloride

Method used

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  • Preparation method of low-impurity Vonoprazan fumarate
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  • Preparation method of low-impurity Vonoprazan fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Voronolazan was prepared with reference to Comparative Example 7, HPLC purity 94.45%, impurity content: the sum of impurity A and impurity C was 0.71%, impurity B was not detected, impurity D was 0.31%, and impurity E was 0.14%. Add 15.0 kg of ethanol to the residue, add 1.53 kg of 48% hydrobromic acid dropwise at room temperature, after the dropwise addition, stir at room temperature for 1 h, filter, rinse the filter cake with 9.0 kg of ethanol, and dry the filter cake to obtain Vonuolazan hydrobromide. 2.95kg, the yield was 76.22%. HPLC purity 98.38%, impurity content: impurity A is 0.03%, impurity B is 0.01%, impurity C is 0.01%, impurity D is 0.01%, and impurity E is 0.13%.

[0090] Add 12.5 kg of ethyl acetate, 1.65 kg of ammonia, 12.5 kg of purified water, and 2.5 kg of voronolazan hydrobromide to a 50L reaction kettle. After stirring until the system is free of solids, continue to stir for 15 minutes, stand for phase separation, and add 6.25 to the water phase. kg ...

Embodiment 2

[0093] Voronolazan was prepared with reference to Comparative Example 7, HPLC purity 94.54%, impurity content: the sum of impurity A and impurity C was 0.61%, impurity B was not detected, impurity D was 0.22%, and impurity E was 0.12%. Add 15.0 kg of ethanol to the residue, add 1.53 kg of 48% hydrobromic acid dropwise at room temperature, after the dropwise addition, stir at room temperature for 1 h, filter, rinse the filter cake with 9.0 kg of ethanol, and dry the filter cake to obtain Vonuolazan hydrobromide. 2.98kg, the yield was 76.99%. HPLC purity 98.03%, impurity content: impurity A is 0.11%, impurity B is not detected, impurity C is not detected, impurity D is not detected, impurity E is 0.06%.

[0094] Add 12.5 kg of ethyl acetate, 1.65 kg of ammonia, 12.5 kg of purified water, and 2.5 kg of voronolazan hydrobromide to a 50L reaction kettle. After stirring until the system is free of solids, continue to stir for 15 minutes, stand for phase separation, and add 6.25 to the ...

Embodiment 3

[0103] Example 3 Preparation of impurity D. 15.0g of Voronolazan was dissolved in 50mL of methanol, and 15.0g of sodium borohydride was added dropwise to 100mL of N,N-dimethylacetamide solution under stirring. After the addition was completed, stirred at room temperature for 12h, and 1mL was taken to react. Add 5ml of purified water and 1ml of ethyl acetate, shake well, let stand, take the organic phase, HPLC detection, the organic phase appears 4 large over-reduced impurity peaks, followed by impurity B (relative retention time RTT=0.28), impurity C (RTT=0.52), impurity A (RTT=0.54), impurity D (RTT=0.73), add 500 mL of purified water and 250 mL of ethyl acetate to the reaction system, stir and stand for phase separation, and concentrate the organic phase under reduced pressure to obtain An oily substance was prepared and separated to obtain 0.90 g of impurity D. Purity 95.06%, MS (ESI) m / z (M+H) + :347.9; 1 H NMR(400MHz, DMSO-d 6 ) δ8.15(s,1H),7.43(dd,J=1.0Hz,6.8Hz,1H), 7.30(...

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Abstract

The invention provides a preparation method of low-impurity Vonoprazan fumarate. A method for removing impurities A-E during preparation of Vonoprazan comprises the steps: preparing Vonoprazan hydrobromide from Vonorazan, and removing the impurities A-E which are difficult to remove by using a recrystallization purifying method, wherein the method for removing the impurities A-E during preparationof Vonoprazan has good selectivity to the impurities A-E. The preparation method of low-impurity Vonoprazan fumarate comprises the steps: performing a reaction on 5-(2-fluorophenyl)-1-(pyridyl-3-ylsulfonyl)-1H-pyrrole-3-formaldehyde and methylamine or a salt of methylamine, then performing reduction so as to obtain Vonoprazan, then preparing Vonoprazan hydrobromide, then performing salt dissociation so as to obtain Vonoprazan free alkali, preparing Vonoprazan fumarate with a purity of 99.7% or above, and then performing recrystallization refining so as to obtain Vonoprazan fumarate with a purity of 99.9% or above. The invention provides an impurity D, a preparation method of the impurity D and application of the impurity D as an impurity reference substance in Vonoprazan fumarate.

Description

Technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of low-impurity fumarate voronolazan. Background technique [0002] Voronolazan fumarate was developed by Takeda Pharmaceutical Co., Ltd., and is mainly used to treat gastric ulcer, duodenal ulcer, reflux esophagitis, and inhibit the recurrence of gastric ulcer or duodenal ulcer. Voronolazan fumarate is a novel potassium ion (K + ) Competitive acid blocker (P-CAB), which can inhibit K in the last step of gastric acid secretion by parietal cells + Right H + -K + -The combination of ATPase (proton pump) stops the secretion of gastric acid in advance, and has a strong and long-lasting effect of inhibiting gastric acid secretion. [0003] Chinese patent application CN102421753A discloses that 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde is used as a raw material and reacted with pyridine-3-sulfonyl chloride to obtain intermediate 5-(2-fluorophenyl)-1 -(Pyridin-3-ylsul...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C57/15C07C51/41C07C51/43G01N33/15
CPCC07D401/12
Inventor 王志军牛玉乐甄志彬胡伟建冯斌孙会谦
Owner JILIN HUIKANG PHARM CO LTD
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