Application overview of 4-chloro-3-pyridinesulfonamide
4-Chloro-3-pyridine-sulfonamide is an intermediate in the synthesis of torasemide. Torsemide is a new antihypertensive diuretic that has been on the market in many European countries since 1993. It is widely used clinically to treat various edema diseases such as hypertension, heart failure, renal failure, chronic heart failure, and hepatic ascites. (Such as liver, lung, renal edema, etc.) and diabetes insipidus.
Application and preparation of 4-chloro-3-pyridinesulfonamide
Add 250g concentrated sulfuric acid, 250g fuming sulfuric acid, and 5g mercury sulfate into a reaction bottle containing 1 L of barium metaborate, stir and heat to 140°C, slowly add 100g (1.053mol) 4-hydroxypyridine in batches, and react for 4 hours. . Pour the reactant into about 2000g of crushed ice, stir and dissolve, adjust to pH=3~4 with an appropriate amount of barium hydroxide, filter with suction, concentrate the filtrate under reduced pressure to an appropriate amount, cool and crystallize, collect the crystals, and dry to obtain 118.4g of white color Solid 4-hydroxypyridine 3-sulfonic acid. The yield is 64.2%, the purity (HPLC) is 98%, m.p. 304~305℃ (literature value: m.p. 305℃).
Add 50g (10.285mol) 4-hydroxypyridine-3-sulfonic acid, 200g (0.960mol) phosphorus pentachloride, and 120g (0.783mol) phosphorus oxychloride into the reaction bottle, reflux for 4 hours, and pour into the crushed In ice, extract with diethyl ether, vent the extract through ammonia gas until it is saturated, precipitate out, and filter with suction to obtain 36.9g of 4-chloropyridine-3-sulfonamide. The yield is 67.4%, the purity (HPLC) is 98%, m.p.157～158℃ (literature value: m.p.157～158℃).
Applications of 4-chloro-3-pyridinesulfonamide
Used in the synthesis of torsemide.
Add 50g (0.260mol) 4-chloropyridine-3-sulfonamide, 33g (0.310mol) m-toluidine, and 260mL methanol into a 500mL reaction bottle and reflux for 3 hours. Filter with suction, dissolve the solid matter with 10% sodium hydroxide solution, and then adjust the pH to 7 with sulfuric acid to precipitate a white precipitate. Filter with suction to obtain 45.1g of 4-(3-toluylamino)-3-pyridine sulfonamide, with a yield of 94.0%. , m.p.168.5~170℃ (literature value: m.p.170~172℃).
Add 45g (0.170mol) 4-(3-toluylamino)-3-pyridinesulfonamide, 35g (0.300mol) isopropylcarbamate, 38g potassium carbonate, 500mL ethylene glycol diethyl ether, and 30mL pyridine 1L reaction bottle, reflux reaction for 30 hours, suction filtration, dissolve the obtained solid in water, adjust pH to 5 with acetic acid, precipitate, and suction filtration to obtain 55.6g of torasemide crystals, yield 93.1%, m.p. 162 ~163℃ (literature value: m.p.162~163℃), elemental analysis Cl6H20N4O3S, measured value (theoretical value)/%: C55.26 (55.17), H7.10 (7.15), N16.04 (16.09). 1HNMR (CDCl3), δ: 0.99 (d, 6H, -CH3), 1.86 (m, -CH- on 1H isopropyl), 6.74 ( s, 3H, -CH-), 7.23～8.54 (m, 4H, -CH-), 10.21～10.98 (s, 2H, N-H).
