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Preparation method for intermediate of Vonoprazan fumarate

A strong acid and reaction technology, applied in the direction of organic chemistry, can solve the problems of being unsuitable for industrialized large-scale production, difficult to guarantee production safety, and poor reagent safety, so as to achieve the protection of personnel and the environment, and the safety of production and reaction. mild effect

Active Publication Date: 2016-12-07
JIANGXI SYNERGY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] All there is route too long in above-mentioned two kinds of synthetic routes, and total yield is low; And there is the shortcoming of poor security, expensive price in the reagent used, as: two routes have all used highly toxic, volatile liquid bromine, palladium charcoal, thunderbolt Nickel and diisobutylaluminum hydride (DIBAL) are also flammable and expensive raw materials
In addition, both methods require hydrogenation special equipment
In a word, the preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde in the prior art is not suitable for large-scale industrial production due to defects such as difficult production safety and high cost.

Method used

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  • Preparation method for intermediate of Vonoprazan fumarate
  • Preparation method for intermediate of Vonoprazan fumarate
  • Preparation method for intermediate of Vonoprazan fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde

[0047] 1) In a 1000ml reaction flask, add 2-fluorobenzonitrile (50g, 0.41mol), 300ml ethanol, and 200ml ethanol solution containing 30-35% hydrogen chloride by mass. After reacting at 20-30℃ for 12 hours, reduce pressure The solvent was recovered to obtain the compound of structural formula II-A (light yellow oil), which was directly used in the next step without further purification.

[0048]

[0049] 2) Put the compound of structural formula II-A, furan (280g, 4.1mol), silver trifluoromethanesulfonate (0.2g) and 400ml ethanol obtained in the previous step into a 1000ml reaction flask, and react at 40~50℃ for 12 hours Add 500ml of water and stir, then use ethyl acetate to extract three times (100ml*3), combine the organic layers and concentrate to dryness under reduced pressure. The crude product is purified with ethyl acetate / n-heptane to obtain 66.4g of the target product (light yellow solid) . Yie...

Embodiment 2

[0051] Example 2 Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde

[0052] 1) In a 1000ml reaction flask, add 2-fluorobenzonitrile (50g, 0.41mol), 500ml n-propanol, and pass hydrogen chloride gas into it. After reacting at 10-20°C for 8 hours, the solvent is recovered under reduced pressure to obtain structural formula II -B compound (light yellow oil), without further purification, was directly used in the next reaction.

[0053]

[0054] 2) The compound of structural formula II-B obtained in the previous step, furan (245g, 3.6mol), PtCl 2 (0.1g) and 400ml ethyl acetate were put into a 1000ml reaction flask, reacted at 50~60℃ for 12 hours, 500ml water was added and stirred, and then extracted with ethyl acetate three times (100ml*3), the organic layers were combined and concentrated under reduced pressure to Dry, the crude product was refined with ethyl acetate / n-heptane to obtain 65.5 g of the target product (light yellow solid). Yield 84%, HPLC purity: 99.0%.

[005...

Embodiment 3

[0056] Example 3 Preparation of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde

[0057] 1) In a 1000ml reaction flask, add 2-fluorobenzonitrile (50g, 0.41mol), 300ml methanol, 200ml 30-35% hydrogen chloride methanol solution, react at 30-40°C for 12 hours, and recover the solvent under reduced pressure to obtain The compound of structural formula II-C (light yellow oil), without further purification, was directly used in the next reaction.

[0058]

[0059] 2) Put the compound of structural formula II-C, furan (421g, 6.2mol), silver trifluoromethanesulfonate (0.2g) and 400ml methanol obtained in the previous step into a 1000ml reaction flask, and react at 30-40°C for 12 hours , Add 500ml of water and stir, then use ethyl acetate to extract three times (100ml*3), the organic layer is concentrated under reduced pressure to dry, the crude product is purified with ethyl acetate / n-heptane to obtain 67g of the target product (light yellow solid). The yield was 86%, and the purity detect...

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Abstract

The invention provides a preparation method for 5-(2-fluorophenyl)-1H-pyrrolyl-3-formaldehyde represented by a structural formula I shown in the description. The method comprises the following steps: (1) carrying out an alcoholysis reaction: subjecting 2-fluorobenzonitrile, which serves as a raw material, to a reaction with C1-4 saturated fatty alcohol in the presence of strong acid, so as to obtain a compound represented by a structural formula II shown in the description, wherein R is C1-4 straight-chain alkyl; (2) carrying out a cycloaddition reaction: subjecting the compound represented by the structural formula II to a cycloaddition reaction with furan in the presence of a catalyst, thereby obtaining 5-(2-fluorophenyl)-1H-pyrrolyl-3-formaldehyde represented by the structural formula I. The invention further provides a preparation method for Vonoprazan fumarate. The preparation method comprises the step of preparing 5-(2-fluorophenyl)-1H-pyrrolyl-3-formaldehyde by the preparation method. According to the preparation methods provided by the invention, the number of reaction steps is small, the process route is simple, the reaction conditions are mild, severely-toxic or expensive reagents are not used, and no special requirements on equipment exists; therefore, the preparation methods are applicable to industrial production.

Description

Technical field [0001] The invention belongs to the field of organic chemistry, and specifically relates to a preparation method of voronolazan fumarate intermediate. Background technique [0002] Vonoprazan fumarate (TAK-438) is the second reversible proton pump inhibitor, which can inhibit potassium (K) in the last step of gastric acid secretion by parietal cells. + ) To H + -K + -The combination of ATPase stops the secretion of gastric acid in advance. Vonourazan fumarate was developed by Takeda Pharmaceuticals of Japan, and was launched in Japan on December 26, 2014, under the trade name Takecad, for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer and eradication of Helicobacter pylori . [0003] Compared with traditional irreversible proton pump inhibitors (such as omeprazole, esomeprazole), voronolazan fumarate has obvious advantages: 1) The onset of action is rapid, and it will be achieved within the first day of administration. The greatest acid suppre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/333C07D401/12
CPCC07D207/333C07D401/12
Inventor 黄伟平庞泽远刘亮亮蒋慧纲徐烘材
Owner JIANGXI SYNERGY PHARMA