3-Pyridinesulfonyl chloride

A mixture of pyridine-3-sulfonic acid (10.3 g, 64.8 mmol), phosphorus pentachloride (20.82 g, 100 mmol) and phosphorus oxychloride (10 mL, 109 mmol) was heated to reflux for 3 h (according to J. Org. Chem. 1989, 54(2), 389.). Evaporated to dryness to give a yellow solid, dissolved in ice water and methyl-tert-butyl ether, added cautiously sat. NaHCOA 3-pyridine sulfonyl chloride is synthesized by using 3-pyridine sulfonic acid as a starting material in U.S. Patent Nos. CN200680040789, US2006 / 217387, Merck & apos; s US5416099A1, Method for 3-pyridine sulfonic acid in phosphorus pentachloride and phosphorus oxychloride reflux for 8 hours or more to be completed after the reaction with a greater amount of water quenching reaction, After the extraction, distillation, Distillation method to obtain high purity 3-pyridyl sulfonyl chloride, The yield of this method can reach more than 90percent.Pyridine-3-sul on l chloride (A4) A3 A4 To a mixture of A3 (9.00 g, 56.6 mmol) in SOClPyridine-3-sulfonic acid (125 g, 0.78 m) was placed in a 1L, 3-necked flask equipped with mechanical stirrer, reflux condenser, thermometer and nitrogen inlet. Next, the phosphorus pentachloride (250 g, 1.19 m, 1.5 eq) was added, followed immediately by the phosphorus oxychloride (330 ml, 3.8 m, 4.5 eq). The contents of flask were initially stirred at ambient temperature for 30 min, then brought slowly to gentle reflux (internal temp. approx. 110° C.) over the next hour, kept at this temperature for approx. 3.5 hr then allowed over the next 12 hr to cool back to ambient temperature. Gas evolution was observed during this time. The volatiles were stripped under reduced pressure (at 12 mmHg/40° C.) and yellow semi-solid residue was diluted with DCM (1 L). The slurry was poured slowly into the stirred, ice-cold sat. aq. bicarbonate, maintaining pH=7. Gas evolution was observed. The organic layer was separated and aqueous layer was back-extracted with DCM. The combined extracts were washed with cold sat. aq. bicarbonate, brine and dried with magnesium sulfate. The solids were filtered off and filtrate evaporated, leaving pyridine-3-sulfonyl chloride as a pale yellow, oily liquid, 123 g (93percent pure; 88percent theory).Pyridine-3 -sulfonic acid (125 g, 0.78 m) was placed in a IL, 3 -necked flask equipped with mechanical stirrer, reflux condenser, thermometer and nitrogen inlet. Next, the phosphorus pentachloride (250 g, 1.19 m, 1.5 eq) was added, followed immediately by the phosphorus oxychloride (330ml, 3.8 m, 4.5 eq) . The contents of flask were initially stirred at ambient temperature for 30 min, then brought slowly to gentle reflux (internal temp, approx. HO(chlorobenzene solvent) 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0141) Pyridine-3-sulfonic acid (10.7 g, 68.5 mmol) and phosphorus pentachloride (15.7 g, 75.4 mmol) were suspended in chlorobenzene (15 mL) at room temperature. After heating and stirring at an inside temperature of 105±5°C for about 3 hr, the mixture was cooled to room temperature. Toluene (50 mL) and water (30 mL) were added into another kolben, and the mixture was cooled to an inside temperature of 5±5°C. The reaction solution was added dropwise at not more than an inside temperature of 15°C, and the dropping funnel was washed well with a mixed solution of toluene and water (1:1, 20 mL). After cooling to an inside temperature of 5±5°C, 50percent aqueous potassium carbonate solution (39 mL) was added dropwise at not more than an inside temperature of 20°C, and the mixture was adjusted to pH 7.5±0.5. After partitioning at room temperature, the organic layer was washed with 5percent brine (40 mL), and concentrated to about 20 mL under reduced pressure. Toluene (40 mL) was added and the mixture was concentrated again to about 20 mL. An operation of adding acetonitrile (40 mL) and concentrating the mixture to about 20 mL was repeated three times to give an acetonitrile solution of pyridine-3-sulfonylchloride (quantified yield 10.7 g, 87.9percent, total amount 20.3 g, 52.7 w/wpercent acetonitrile solution). (0142) To the acetonitrile solution (total amount) of pyridine-3-sulfonylchloride obtained above were added acetonitrile (45 mL), 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (10.0 g, 52.9 mmol), N, N-dimethylpyridin-4-amine (0.646 g, 5.29 mmol) and triethylamine (10.4 mL, 74.1 mmol), and the mixture was heated to an inside temperature of 45±5°C. After stirring at an inside temperature of 45±5°C for 1.5 hr, the mixture was cooled to room temperature, and water (30 mL) was added dropwise. The mixture was adjusted to pH 4 - 5 with 0.5M hydrochloric acid (about 20 mL). The seed crystal of the title compound was added and, after confirmation of crystal precipitation, water (60 mL) was added dropwise. After stirring at room temperature for 30 min and at 5±5°C for 1 hr, the precipitated crystals were collected by filtration. The crystals were washed twice with a mixed solution of acetonitrile and water (1:2, 30 mL) cooled to 5±5°C in advance, and dried at an outer temperature of 50°C under reduced pressure to give the title compound (15.5 g, isolation yield 88.7percent). Reference Example 18: Pyridine-3-sulfonyI chloride. A mixture of pyridine-3-sulfonic acid (3 g, 18.8 mmol), phosphorus pentachloride (6.04 g, 29.0 mmol) and phosphorus oxychloride (15 mL) was heated at12OIn 100mL four-necked flask, pyridine-3-sulfonic acid 15.9g (0.100 mol) and put the monochlorobenzene 23.9g, was heated with stirring to 120 ° C. While maintaining the internal temperature at 119~122 ° C, it was placed in every 5 minutes for 20 split the phosphorus pentachloride 20.4g (0.098 mol). After the addition completion of the phosphorus pentachloride and stirred for an additional 1 hour. When the reaction liquid was subjected to gas chromatography (GC) analysis of the concentration of the pyridine-3-sulfonyl chloride was 29.5 wtpercent. Moreover, it was calculated from the amount of the reaction liquid (54.3 g), pyridine-3-sulfonyl chloride The yield in the reaction solution is 90.2percent by-produced 5-chloropyridine-3-sulfonyl chloride area by GC analysis ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) was 0.02percent.The reaction solution was concentrated under reduced pressure to 3.6kPa at 90 ° C, followed by distilling off the monochlorobenzene and by-product phosphorus oxychloride. Then, 94 ° C, then vacuum distillation under the conditions of 0.4 kPa, to give a pyridine-3-sulfonyl chloride 14.9 g. Pyridine-3-sulfonyl chloride yield was 83.9percent. The area ratio by GC analysis and pyridine-3-sulfonyl chloride 99.99percent 5-chloro-3-sulfonyl chloride was 0.01percent.Step 1: 3-Pyridine sulfonic acid (4.0 g, 25.1 mmol, 1 eq) and PCl[0310] A mixture of pyridine-3 -sulfonic acid (5.0 g, 31.4 mmol, 1.0 eq) and PC1STR121 Pyridine-3-sulfonyl chloride Step A: Add 400 kg of water to the reactor, drop to 0 ° C and then drop 109.24 kg of thionyl chloride. After dropping thionyl chloride, the control temperature is at 4 ° C. After the dropwise addition, 232 g of cuprous chloride , To obtain an aqueous solution of sulfurous acid, stand-by;Step B: Add 82.04 kg of hydrochloric acid to 36percent hydrochloric acid in another reactor, add 20 kg of 3-aminopyridine, cool to -5 ° C, drop an aqueous solution of sodium nitrite (containing 15.84 kg of sodium nitrite, 32 kg of water) Dropping the process to control the temperature at 0 , after the drop is completed, the temperature control at 0 , stand;Step C: The solution obtained in Step B was added dropwise to the reactor of Step A. The reaction temperature was dropwise at 0 ° C, after completion of the dropwise addition, the mixture was stirred at 0 ° C for 1.5 h. After completion of the reaction, 300 L of dichloromethane , The mixture was stirred and allowed to stand for three times. The resulting organic phase was distilled, cooled to 0 ° C, stirred with water (350 L), and the resulting organic phase was dried with anhydrous sodium sulfate.Step D: The organic phase obtained in step C was evaporated to dryness to give 3-pyridylsulfonyl chloride.50.0 g (0.53 mol) of 3-aminopyridine was added to 34.9 g of 35percent hydrochloric acid and stirred to prepare an aqueous hydrochloric acid solution of 3-aminopyridine. In addition, 35.9 g (0.52 mol, 0.98 mol equivalent to 3-aminopyridine) of sodium nitrite was added to 54.0 g of water and stirred to prepare an aqueous solution of sodium nitrite. 131 g of hydrochloric acid was placed in a 500 mL four-necked brown colben and cooled to -20 ° C. An aqueous hydrochloric acid solution of 3-aminopyridine and an aqueous solution of sodium nitrite were simultaneously added dropwise to hydrochloric acid in a temperature range of -20 ± 2 ° C. over 2 hours with stirring. After completion of the dropwise addition, the mixture was further stirred for 30 minutes in a temperature range of -20 ± 2 ° C. to obtain an aqueous solution of pyridine-3-diazonium salt650 g of dichloromethane was placed in 1000 mL four-necked brown bottle and cooled to 0 ° C., and 119 g (1.86 mol) of sulfur dioxide gas was blown into the solution to dissolve. 0.9 g (0.006 mol) of copper (II) chloride dihydrate was added and cooled to -5 ° C., and an aqueous solution of pyridine-3-diazonium salt was added over a period of 1 hour at a temperature range of -5 ± 2 ° C. Was added dropwise. After completion of the dropwise addition, the mixture was further stirred for 1 minute at a temperature range of -5 ± 2 ° C. The copper catalyst was removed by filtration while maintaining the temperature of the reaction solution at -5 ± 5 ° C., and then the organic layer and the aqueous layer were separated. It was extracted with 195 g of dichloromethane × 3 times at a temperature of -5 ± 5 ° C. and mixed all together to obtain 1353 g of an organic layer. GC analysis of this organic layer revealed that the concentration of pyridine-3-sulfonyl chloride was 3.76percent by mass and the yield was 54.0percent. The obtained organic layer was washed with 50 g of water while maintaining the temperature at 3 ± 2 ° C., and then dehydrated using 20 g of magnesium sulfate at room temperature. After removing the magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure (30 to 35 ° C., > 67 kPa) to remove dichloromethane. Subsequently, distillation under reduced pressure (110 ° C., 1.3 kPa) gave 49.0 g (0.276 mol, yield 52.1percent) of pyridine-3-sulfonyl chloride.21.4 g (0.100 mol) of pyridine-3-sulfonyl chloride hydrochloride and 42.8 g of monochlorobenzene were placed in a 200 mL four-necked flask, and the slurry Liquid). The internal pressure was adjusted to 23 kPa using a vacuum pump and heated to 85 ± 5 ° C. for 5 hours (dehydrochlorination). After 5 hours, the contents of the flavor became almost transparent liquid. Thereafter, monochlorobenzene was distilled off under reduced pressure (100 ° C., 27 kPa). Subsequently, distillation under reduced pressure (110 ° C., 1 kPa) gave 16.5 g (0.0929 mol, yield 92.9percent) of pyridine-3-sulfonyl chloride.5-[2-(Piperidin-4-yl)ethyl]thieno-[2, 3-b]thiophene-2-N-[3-2(S)-(2-ethoxyethanesulfonylamino)propionic acid]carboxamide (2-14)

Molecular Weight:177.61
XLogP3:0.9
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:176.9651272
Monoisotopic Mass:176.9651272
Topological Polar Surface Area:55.4
Heavy Atom Count:10
Complexity:196
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes