3-Pyridinesulfonic acid

white to almost white crystalline powder

A mixture of A 3-pyridine sulfonyl chloride is synthesized by using Pyridine-3-sul on l chloride (A4) A3 A4 To a mixture of A3 (9.00 g, 56.6 mmol) in SOCl2 (108.00 mL) was added DMF (5.00 mL) in one portion at 25C under N2. The mixture heated to 80 C and stirred for 12 hours, after which LCMS analysis indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give A4 (9.00 g, yield: 89.6%), which was used in the next step without further purification. 1H NMR (400 MHz, CDC13) delta: 8.98(s, 1H), 8.91 (d, / = 5.6 Hz, 1H), 8.72 (d, / = 8.0 Hz, 1H), 8.07-8.10 (m, 1H).Pyridine-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 (93% pure; 88% 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. HO0C) 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/40C) and yellow semi-solid EPO (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±5C 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±5C. The reaction solution was added dropwise at not more than an inside temperature of 15C, 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±5C, 50% aqueous potassium carbonate solution (39 mL) was added dropwise at not more than an inside temperature of 20C, and the mixture was adjusted to pH 7.5±0.5. After partitioning at room temperature, the organic layer was washed with 5% 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, 87.9%, total amount 20.3 g, 52.7 w/w% 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±5C. After stirring at an inside temperature of 45±5C 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±5C 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±5C in advance, and dried at an outer temperature of 50C under reduced pressure to give the title compound (15.5 g, isolation yield 88.7%). 1H NMR (500 MHz, CDCl3) delta 6.68 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 8.2 Hz, 1H), 7.14-7.19 (m, 2H), 7.38 (dd, J = 8.2, 4.9 Hz, 1H), 7.44-7.48 (m, 1H), 7.72 (ddd, J = 8.2, 2.5, 1.6 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.82 (dd, J = 4.7, 1.6 Hz, 1H), 9.90 (s, 1H).Reference Example 18: Pyridine-3-sulfonyI chloride. A mixture of In 100mL four-necked flask, Step 1: Preparation of pyridin-3-sulfonyl chloride Pyridin-3-sulfonic acid (5.0 g, 31.4 mmol) was added with phosphorous pen- tachloride (9.8 g, 47.1 mmol) and phosphorous oxychloride (10 ml), stirred underreflux for 4 hours, and then the mixture was concentrated to remove phosphorous oxy chloride. The reaction mixture was added with ice water and diethyl ether, stirred, and then extracted into the organic layer. The resulting separated organic layer was washedwith a saturated sodium bicarbonate solution, and the organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4.1 g of a title compound (yield: 75%).[563] 1H NMR (500 MHz, CDCb): 8.91 (s, lH), 8.84 (d, lH), 8.43 (dd, lH), 7.57 (t, lH) [564]3-Pyridine sulfonic acid (4.0 g, 25.1 mmol, 1 eq) and PCl5 (5.75 g, 27.70 mmol, 1.1 eq) were heated at 130 C for 20 h. After cooling, ice was added and the mixture was extracted with EtOAc (*3). The combined organic layers were washed with saturated aqueous NaHCO3 (*1), brine (*1) and dried over sodium sulphate. After filtration and evaporation of the solvent a yellow oil is obtained. (2.94 g, 66%). 1H NMR (300 MHz, CDCl3) delta 9.17 (d, J = 2.4 Hz, 1-H) 8.91 (dd, J = 4.9/1.5 Hz, 1-H), 8.26 (ddd, J = 8.3/2.5/1.8 Hz, 1-H), 7.57 (ddd, J = 8.3/4.9/0.6 Hz, 1-H); 13C NMR (75 MHz, CDCl3) delta 155.6, 147.5, 141.0, 139.7, 124.4; IR (KBr) 3045, 1625, 1522, 1375, 1247, 1173 cm-1.[0310] A mixture of pyridine-3 -sulfonic acid (5.0 g, 31.4 mmol, 1.0 eq) and PC15 (14.2 g, 69.1 mmol, 2.2 eq) was refluxed at 135 C for 2.5 hrs. The resulting mixture was cooled to r.t., triturated with chloroform, filtered and dried to give 3.6 g of Compound Int-18 (64% yield) as a white solid.a) 3-Pyridinesulfonyl chloride was prepared as described in J. Heterocyclo. Chem. 1992, 29, 61. A mixture of STR121 3-Pyridylsulfonyl chloride (23-10) 3-Pyridylsulfonic acid (30 g, 0.188 mole) was added to PCl5 (46.8 g, 0.225 mole), suspended in 150 mL toluene and heated to reflux overnight. The suspension was cooled and concentrated to yield a yellow oil, which was diluted with benzene, filtered through a pad of celite and concentrated to give 30.7 g (92%) of 23-10 as a yellow oil, which was used in the next step without purification. 1 H NMR (300 MHz, CDCl3) delta 9.27 (1H, s), 8.98 (1H, d, 8.35 (1H, d), 7.62 (1H, dd).3-Pyridylsulfonyl chloride (5-6) 3-pyridylsulfonic acid 5-5 (30 g, 0.188 mole) was added to PCl5 (46.8 g, 0.225 mole) suspended in 150 mL toluene and heated to reflux ovemight. The suspension was cooled and concentrated to yield a yellow oil, which was diluted with benzene, filtered through a pad of celite and concentrated to give 5-6 as a yellow oil that was used in the next step without purification. 1 H NMR (300 MHz, CDCl3) a 9.27 (1H, s), 8.98 (1H, d, 8.35 (1H, d), 7.62 (1H, dd).PREPARATION 55 3-Pyridine sulfonyl chloride To 1.2 g of (A) Preparation of Pyridine-3-Sulphonyl chloride A mixture of General Procedure 8: Pyridine-3-sulfonyl chloride (Intermediate 17)Phosphorus pentachloride (3.0 g, 14.6 mmol) was added to a solution of Pyridine-3-sulfonyl chloride Phosphorus pentachloride (1.57 g, 7.5 mmol) was added to a stirred solution of Pyridine-3-sulfonic acid (1.11 g, 6.97 mmol) was treated with 7.00 mL thionyl chloride (96.5 mmol) and catalytic amounts of DMF. The reaction mixture was heated at 75 C for 1.5 h. Then the solvent was removed under reduced pressure and the resulting solid was resuspended in CH2Cl2 and transferred dropwise to a saturated NaHCO3 solution (50 mL) and ice (50 g). This mixture was stirred for 5 min, afterwards it was extracted with CH2Cl2 twice. The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to yield pyridine-3-sulfonyl chloride as a red oil, which was used without further purification (yield: 296 mg, 24 %). Pyridine-3-sulfonyl chloride (22 mg, 0.125 mmol) was added to a mixture of the trifluoroacetate salt of 11 (48 mg, 0.125 mmol) and sodium tetraborate (400 mg, 1.99 mmol). After addition of H2O (30 mL), the reaction mixture was treated with ultra-sonication for 5 min meanwhile the formation of a solid occured. Afterwards, it was stirred at rt overnight. The suspension was treated with conc. HCl to adjust pH value to 1. The resulting solution was neutralized by addition of saturated NaHCO3 solution and cooled to 0 C. The formed solid was filtered, washed with H2O and CH2Cl2 to remove byproducts, and was dissolved in THF. Removal of the solvent under reduced pressure gave 6g. Pale yellow solid, mp 223 C, yield 33 mg (64 %).

Molecular Weight:159.17
XLogP3:-0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:158.99901420
Monoisotopic Mass:158.99901420
Topological Polar Surface Area:75.6
Heavy Atom Count:10
Complexity:193
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes