Vonoprazan fumarate intermediate and preparation method thereof

A technology of vonoprazan fumarate and its intermediates, which is applied in the field of medicinal chemistry, can solve the problems of toxic impurities residues, cumbersome operation process, etc., achieve the effect of easy-to-obtain materials and avoid hydrogenation reaction operation

CN113549054APending Publication Date: 2021-10-26LUNAN PHARMA GROUP CORPORATION
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2021-10-26

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Abstract

The invention provides a vonoprazan fumarate intermediate compound, and a preparation method and application thereof. The intermediate compound can be obtained through oxidative hydrolysis reaction and acylating chlorination reaction. Compared with the prior art, the preparation method provided by the invention avoids hydrogenation reaction operation with relatively high dangerousness, and avoids the use of reactants with genotoxicity warning structures such as halogenated hydrocarbon and aldehyde during the reaction of introducing the N-methyl group. According to the technical scheme, starting materials are easy to obtain, cheap and non-toxic, and a safe, efficient, green and environment-friendly technical scheme is provided for preparation of vonoprazan fumarate.
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Description

technical field

[0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a fumaric acid vonoprazan intermediate, a preparation method thereof and the use of the intermediate in preparing fumaric acid vonoprazan. 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] There are many kin...

Examples

Embodiment 1

[0052] Example 1 Preparation of 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-1H-pyrrole-3-carboxamide

[0053] Dissolve 93g of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile in 270mL of tetrahydrofuran solution, add 50g of 20% NaOH aqueous solution, raise the temperature to 55°C, add 57g of 30% hydrogen peroxide solution dropwise, after the dropwise addition, keep warm React for 1 hour, cool down to 5°C after the reaction is complete, add 540 mL of purified water dropwise, solid appears during the dropwise addition, keep stirring for 1 hour after dropwise addition, filter with suction, and vacuum-dry the filter cake at 50-60°C to obtain solid 5-(2 -Fluorophenyl)-1H-pyrrole-3-carboxamide 86.86g. ESI-MS(m / z):204.03[M+H] + ; 1 HNMR (400MHz, DMSO-d 6)δ: 11.84(s,1H), 7.72~7.77(t,J=1.5Hz,1H), 7.47(s,1H), 7.24~7.29(m,3H), 6.86(s,1H); 13 CNMR (100MHz, DMSO-d 6 )δ: 164.9, 159.1, 156.8, 127.7-128.1, 127.3, 126.6, 126.0, 124.4-125.1, 119.4-119.7, 117.5, 116.0-116.3.

[0054] Add 86.86g o...

Embodiment 2

[0057] Example 2 Preparation of 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-1H-pyrrole-3-carboxamide

[0058] Dissolve 93g of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile in 270mL of tetrahydrofuran solution, add 50g of 20% NaOH aqueous solution, raise the temperature to 55°C, add 64g of 40% hydrogen peroxide solution dropwise, after the dropwise addition, keep warm React for 1 hour, cool down to 5°C after the reaction is complete, add 540 mL of purified water dropwise, solid appears during the dropwise addition, keep stirring for 1 hour after dropwise addition, filter with suction, and vacuum-dry the filter cake at 50-60°C to obtain solid 5-(2 -Fluorophenyl)-1H-pyrrole-3-carboxamide 84.93 g. The structural confirmation is the same as in Example 1.

[0059] Add 84.93g of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide to 240mL of acetonitrile pre-dried by molecular sieves, add 42.1g of triethylamine, and add 165.3g of 3-pyridinesulfonyl chloride dropwise at 20-30°C Acetonitrile sol...

Embodiment 3

[0060] Example 3 Preparation of 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-1H-pyrrole-3-carboxamide

[0061] Dissolve 93g of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile in 270mL of tetrahydrofuran solution, add 50g of 20% NaOH aqueous solution, raise the temperature to 55°C, add 114g of 15% hydrogen peroxide solution dropwise, after the dropwise addition, keep warm React for 1 hour, cool down to 5°C after the reaction is complete, add 540 mL of purified water dropwise, solid appears during the dropwise addition, keep stirring for 1 hour after dropwise addition, filter with suction, and vacuum-dry the filter cake at 50-60°C to obtain solid 5-(2 -Fluorophenyl)-1H-pyrrole-3-carboxamide 78.63 g. The structural confirmation is the same as in Example 1.

[0062] Add 78.36g of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide to 240mL of acetonitrile pre-dried by molecular sieves, add 39.2g of triethylamine, and add 150.2g of 3-pyridinesulfonyl chloride dropwise at 20-30°C Acetonitrile so...