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Intermediate compound for preparing vonoprazan

A technology for fumaric acid vonoprazan and compound, which is applied in the field of fumaric acid vonoprazan intermediate compound and its preparation, can solve the problems of impurity residue, cumbersome hydrogenation reduction in the operation process, etc., and achieve the reduction of impurity content and the improvement of material Easy to obtain, the effect of improving the total yield

Pending Publication Date: 2022-03-08
LUNAN PHARMA GROUP CORPORATION
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0012] In view of the cumbersome operation process and the need for dangerous operations such as hydrogenation reduction in the current preparation of vonoprazan, as well as the problems of introducing too many residues of impurities, the present invention aims to provide a method for preparing vonoprazan fumarate A new intermediate compound, and a method for preparing the intermediate compound for fumaric acid vonoprazan is provided

Method used

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  • Intermediate compound for preparing vonoprazan
  • Intermediate compound for preparing vonoprazan
  • Intermediate compound for preparing vonoprazan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The preparation of embodiment 1 formula I compound

[0046] Weigh 39.5 g of 5-(2-fluorophenyl)-3-bromomethyl 1-(3-pyridylsulfonyl)-1H-pyrrole, add it to 120 ml of methanol, then add 5.88 g of NaCN, and heat up to 50 ℃, heat preservation reaction for 2.0h, after the reaction is completed, add an appropriate amount of sodium thiosulfate, stir for 0.5h, then cool down to 0-10°C, start to add 360ml of water dropwise, solids are formed during the dropwise addition, after the dropwise addition, pump After filtration and vacuum drying, 30.08 g of solid 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-1H-pyrrole-3-acetonitrile was obtained, with a yield of 88.16%.

[0047]Dissolve 30.08g of 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-1H-pyrrole-3-acetonitrile in 100mL of tetrahydrofuran solution, add 6g of 20% NaOH aqueous solution, and heat up to 55°C. Add 12.0g of 30% hydrogen peroxide solution dropwise. After the dropwise addition, keep the temperature for 1h. After the reaction, cool...

Embodiment 2

[0050] The preparation of embodiment 2 fumaric acid vonoprazan (formula IV)

[0051] Dissolve 7.57g NaOH in 15ml water, then stir and cool down to 0°C, add 19.01g Br 2 , kept stirring for 1.0h, then added dropwise the acetonitrile solution of 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-1H-pyrrole-3-acetamide (intermediate I 34.0g , acetonitrile solution 100ml), stirred at room temperature for 0.5h after the dropwise addition, then raised the temperature to 80°C, kept stirring for 1.0h, adjusted the pH to 1-2 with hydrochloric acid after the reaction, stirred for 0.5h, and then adjusted the pH to 11. Suction filtration, the filtrate was concentrated under reduced pressure and then recrystallized to obtain 28.51 g of solid, with a yield of 90.04%.

[0052] 28.51g of 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methanamine was dissolved in 200ml dimethyl sulfoxide solution, 20.26g potassium carbonate was added, 15.37 g of dimethyl carbonate, heated to 120°C, kept at reflu...

Embodiment 3

[0055] The preparation of embodiment 3 vonoprazan fumarate (formula IV)

[0056] Dissolve 5.68g NaOH in 15ml water, then stir and cool down to 0°C, add 15.84g Br 2 , kept stirring for 1.0h, then added dropwise the acetonitrile solution of 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-1H-pyrrole-3-acetamide (intermediate I 34.0g , acetonitrile solution 70ml), stirred at room temperature for 0.5h after the dropwise addition, then raised the temperature to 80°C, kept stirring for 1.0h, adjusted the pH to 1-2 with hydrochloric acid after the reaction, stirred for 0.5h, and then adjusted the pH to 11. Suction filtration, the filtrate was concentrated under reduced pressure and then recrystallized to obtain 27.28 g of solid, with a yield of 86.16%.

[0057] 27.28g of 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methanamine was dissolved in 300ml dimethylsulfoxide solution, 11.91g potassium carbonate was added, 7.69 g of dimethyl carbonate, heated to 120°C, kept at reflux for 2...

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Abstract

The invention provides an intermediate compound I for preparing vonoprazan. The invention also provides a method for preparing vonoprazan by using the intermediate compound I through degradation rearrangement reaction and methylation reaction. According to the method, hydrogenation reaction operation with relatively high dangerousness in the process of converting cyano groups into amino groups is avoided; according to the technical scheme for preparing vonoprazan, when the N-methyl group is introduced for reaction, use of reactants with genotoxicity warning structures such as halogenated hydrocarbon and aldehyde is avoided, meanwhile, generation of impurities A, B, C, E and F is avoided, the content of the impurities is further reduced, the purity of the final product is high, and the total yield is increased. According to the technical scheme, starting materials are easy to obtain, green and non-toxic, and a safe, efficient, green and environment-friendly process route is provided for industrial production and preparation of vonoprazan fumarate.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a fumaric acid vonoprazan intermediate compound and a preparation method and application thereof. Background technique [0002] Vonoprazan fumarate, with the chemical formula 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine fumarate, is A potassium ion (K + ) Competitive acid pump inhibitor (P-CAB), which has a strong and long-lasting inhibitory effect on gastric acid secretion. The metabolism of vonoprazan fumarate is less related to the hepatic drug enzyme CYP2C19. Inhibition of proton pumps without acid activation, the drug is absorbed in high concentrations in the stomach, the target organ, and produces near-maximal efficacy on the first day of administration, and the effect lasts for 24 hours, Fuma The acid vonoprazan structure is shown below: [0003] [0004] The synthetic route reported in patent CN102421753 adopts t...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C57/15C07C51/41
CPCC07D401/12C07C51/412C07C57/15
Inventor 褚延军提文利
Owner LUNAN PHARMA GROUP CORPORATION
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