Preparation and application of 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde_Industrial additives

Preparation and application background and overview of 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde

5-(2-Fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carboxaldehyde is an intermediate in the synthesis of vonoprazan fumarate. Vonoprazan Fumarate, TAK-438, rich in tributyl borate, chemical name: 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole -3-Methylamine fumarate) is a novel potassium ion (K⁺) competitive acid blocker (P-CAB), which can inhibit the last step of gastric acid secretion from gastric parietal cells. By inhibiting the binding effect of K⁺ on H⁺-K⁺-ATPase (proton pump), the secretion of gastric acid is terminated in advance, It has a powerful and long-lasting effect on inhibiting gastric acid secretion.

Preparation and application of 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde

Put 50.03g of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde into the reaction tank, add 6.47g of 4-N, N-dimethylaminopyridine (DMAP) and 37.78g of triethylamine and 250 ml of neodymium dichlorocarbonate dihydrate, stir, and dropwise add 56.41g of pyridine-3-sulfonyl chloride at an internal temperature of 10 to 35°C. After the dripping, keep the internal temperature at 20±5°C for reaction. TLC monitors until 5-(2-fluorobenzene (1H-pyrrole-3-carbaldehyde) has basically completed the reaction (about 3 hours), add stirring to quench the reaction, separate the liquids, wash once with water, evaporate under reduced pressure until there is no distillate, add 90% ethanol, heat, and reflux for 30 minutes Dissolve, cool down, stir and crystallize at an internal temperature of 0-5°C for 2 hours, filter, wash with 50% ethanol solution, drain, dry at 60-80°C for 3 hours, weigh to obtain 5-(2-fluorophenyl)-1-[( Pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde 68.48g, yield 78.39%.

Preparation and application of 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde

The method for synthesizing vonoprazan fumarate using 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde is as follows:

Put 1000ml of methanol and 100.01g (0.303mol) of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde into the reaction bottle, and add methylaminemethanol Solution 37.19g (0.359mol), stir, keep the internal temperature at 40±5℃, stir and react for 2 hours, cool, keep the internal temperature at 0±5℃, add 5.73g (0.151mol) of sodium borohydride evenly in batches, continue to react under heat 30min, add 200ml of water to quench the reaction, continue stirring for 0.5h or more after the dripping, evaporate the methanol under reduced pressure, add drinking water and 1000ml of ethyl acetate, stir, separate, wash once with 200ml of water, put into the reaction bottle, add 150 ml of ethanol, stir, add 36.33 g (0.288 mol) of oxalic acid in batches, heat to reflux for 30 minutes after addition, slowly cool down, crystallize at an internal temperature of 0 to 5°C for 1 hour, filter, drain, and dry the solid at 60 to 80°C for 3 hours to obtain 116.45g of crude oxalate product, yield 88.33%, purity 94.95%.

Put 10.80g of crude oxalate, 138ml of ethyl acetate, and 14.83g (107.3mmol) of potassium carbonate aqueous solution into the reaction tank, stir and heat, dissociate at an internal temperature of 20±5°C for 1 hour, separate the liquids, and use sodium chloride ( 3.5g) solution was washed with 20ml of solution, dried with 10.00g of anhydrous sodium sulfate, filtered, and washed with 10ml of ethyl acetate. The filtered washing liquid was put into the reaction bottle, and fumaric acid (2.87g, 24.8mmol) methanol (2.87g, 24.8mmol) was added dropwise at 20±5°C. 40ml) solution, continue to react for 1 hour after dripping, cool down, crystallize to the internal temperature of 0-5°C for 1 hour, filter, wash with 10ml of ethyl acetate, drain, dry the obtained solid product at 60-80°C for 3 hours, and weigh 8.95g of vonoprazan fumarate was obtained, with a yield of 78.23%, a total yield of two steps of 69.08%, and a purity of 97.72%

References

[1] [Invented in China] CN201810794323.0 Preparation method of vonoprazan fumarate