| 85% |
With hydrogenchloride; water; chlorine at 0℃; for 2h; |
1 Pyridine-2-sulfonyl chloride (43)
Example 1 Pyridine-2-sulfonyl chloride (43) A solution of 2-mercaptopyridine (41) (20.0 g, 180.0 mmol) in 140 mL of conc. HCl and 20 mL of water was cooled to 0° C. Cl2 was bubbled through this solution for 2 h. A stream of N2 was then used to remove excess Cl2. The mixture was poured onto ice-water and dichloromethane was added. The reaction mixture was neutralized with solid NaHCO3 while maintaining the temperature at 0° C. by addition of ice. Two phases were separated and the aqueous layer was extracted with cold dichloromethane. The organics were dried over MgSO4, and concentrated in vacuo to provide 27.2 g (85%) of product 43 as a colorless oil which was used immediately. 1H NMR (300 MHz, CDCl3) δ 7.68-7.70 (m, 1H), 8.05-8.10 (m, 2H), 8.82-8.83 (m, 3H). |
| 85% |
With sodium hypochlorite; sulfuric acid Inert atmosphere; Sealed tube; |
|
| 79% |
With sodium hypochlorite; sulfuric acid In water at -5 - 0℃; for 1h; |
|
| 77% |
With sodium hypochlorite; sulfuric acid In water at 0℃; for 2h; |
35
Reference Example 35 2-pyridinesulfonyl chloride; Under ice-cooling, 2-mercaptopyridine (2.0 g) was added to sulfuric acid (50 mL) and the mixture was stirred. Sodium hypochlorite solution (chlorine content 5%, 126 mL) was added dropwise over 1.5 hr, and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was diluted with water (100 mL), and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a colorless oil (yield 2.45 g, 77%). 1H-NMR (CDCl3) δ: 7.69-7.71 (1H, m), 8.06-8.14 (2H, m), 8.83-8.85 (1H, m). |
| 77% |
With sodium hypochlorite In sulfuric acid; water at 0℃; for 0.5h; |
|
| 77% |
With sodium hypochlorite; sulfuric acid In water for 2h; Cooling with ice; |
138 2-Pyridinesulfonyl chloride
Reference Example 138 2-Pyridinesulfonyl chloride Under ice-cooling, 2-mercaptopyridine (2.0 g) was added to sulfuric acid (50 mL). To the mixture was added dropwise an aqueous sodium hypochlorite solution (chlorine content 5%, 126 mL) over 1.5 hr, and the mixture was further stirred at the same temperature for 30 min. The reaction mixture was diluted with water (100 mL), and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a colorless oil (yield 2.45 g, 77%). 1H-NMR (CDCl3)δ: 7.69-7.71 (1H, m), 8.06-8.14 (2H, m), 8.83-8.85 (1H, m). |
| 76% |
With hydrogenchloride; chlorine at 0℃; for 1.5h; |
|
| 74% |
With hydrogenchloride; sodium hypochlorite In dichloromethane; water at 0℃; for 30h; |
|
| 74% |
With hydrogenchloride; sodium hypochlorite In dichloromethane; water at 0℃; for 0.5h; |
2.1 2.2.1. Synthesis of pyridine-2-sulfonyl chloride
Pyridine-2-sulfonyl chloride was prepared according to thepreviously published procedure [49].Typically, a solution of 2-mercaptopyridine (3.24 g, 29.2 mmol) in 20 mL dichloromethane was combined with concentrated hydrochloric acid (81 mL), and the mixture was cooled to 0 °C in an ice bath. Sodium Hypochlorite (14.5%, 178 mL) was added dropwise and the reaction mixture which turned yellow gradually was stirred for another 30 min at 0 °C. The resulting solution mixture was extracted twice with dichloromethane (∼30 mL), and the organic layers were combined and dried over sodium sulfate for half an hour. The solid was filtered off, and the solvent was mostly removed in a rotary evaporator, yielding a colorless liquid (∼3 mL). The resulting pyridine-2-sulfonyl chloride solution was immediately used for preparing the following bis(pyridine-2-sulfonamide) ligands with various substituents due to its moderate stability in the presence of air or water. Yield: 74%. 1H NMR (500 MHz, CDCl3): δ 8.84 (d, J = 4.5 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 8.07 (td, J = 7.3, 1.5 Hz, 1H), 7.71 (ddd, J = 7.1, 4.8, 1.3 Hz, 1H), 5.30 (s, dichloromethane). |
| 72% |
With sodium hypochlorite; sulfuric acid; sodium chloride In water at -15 - 0℃; for 1h; Inert atmosphere; |
|
| 72% |
With sodium hypochlorite; sulfuric acid In water at -15 - 10℃; for 1h; Cooling with ice; |
Pyridine-2-sulfonyl Chloride
Pyridine-2-sulfonyl Chloride [0141] 2-Mercaptopyridine (126 mg, 1 mmol) was dissolved in 5 mL of concentrated sulfuric acid to form a yellow solution, which was cooled to around -15° C. with a sodium chloride/ice (1/3) bath. Aqueous sodium hypochlorite solution (10-15%, 11 mL, 15-20 mmol) was added to the solution slowly enough to maintain the internal temperature of the reaction mixture below 10° C., with vigorous stirring. The reaction mixture was stirred at 0° C. for 1 hour and then 10 mL of water was added, which was then extracted with methylene chloride (20 mL×3). The combined organic phase was washed with water, dried with anhydrous magnesium sulfate, and then concentrated in vacuo. Pyridine-2-sulfonyl chloride (145 mg, 72%) was produced as a yellowish viscous liquid. 1H NMR (CDCl3): δ 7.684-7.729 (m, 1H), 8.043-8.143 (m, 2H), 8.84 (d, J=4.10 Hz, 1H). |
| 71% |
With sodium hypochlorite; sulfuric acid at 0℃; for 0.5h; Inert atmosphere; |
|
| 70% |
With sodium hypochlorite; sulfuric acid In water at 0 - 20℃; for 0.5h; |
68.68A
68A: A solution of 2-Mercaptopyridine (100 mg, 0.9 mmol) in 2.5 mL of concentrated sulfuric acid cooled at 0°C was treated with 5.6 mL of 12.5% sodium hydrochloric solution added dropwise. The mixture was stirred at room temperature for 30 minutes, then poured on ice and water, extracted three times with dichloromethane, dried over magnesium sulfate and concentrated. Compound 68 A was obtained as a colourless oil (1 10 mg, 70%yield). NMR (ppm, CDC13): 7.69 (t, J= 5.9 Hz, 1H), 8.09 (m, 2H), 8.80 (d, J= 3.9 Hz, 1 H). |
| 65% |
With sodium hypochlorite; sulfuric acid at 0℃; for 0.5h; |
|
| 63% |
With water; chlorine In tetrachloromethane at 0℃; for 1h; |
|
| 54% |
With hydrogenchloride; chlorine at 0℃; for 1.5h; |
|
|
With hydrogenchloride; chlorine |
|
|
With hydrogenchloride; chlorine at 0℃; for 2h; |
|
|
With sodium hypochlorite; sulfuric acid at 0℃; for 0.5h; |
|
|
In hydrogenchloride; water |
4.a N2-[4-(4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2-pyridinesulfonamide
a) 2-Pyridinesulfonyl chloride was prepared as described in Heterocycles, 1989, 28, 1115. chlorine gas was bubbled into the solution of 2-pyridinethiol (2.00 g, 17.99 mmol) in concentrated hydrochloric acid (30 ml) at 0° C. for 3 h. The reaction mixture was poured into ice-cold water (40 ml) and the resulting precipitate was collected by filtration. The precipitate was further washed with ice-cold water and then dried over phosphorus pentaoxide in vacuo at 0° C. for 2 h to afford 2-pyridinesulfonyl chloride as white solids (2.00 g, 11.26 mmol). |
|
In hydrogenchloride; ethyl acetate |
7.c c.)
c.) {(S)-1-[3-Hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester Generation of 2-pyridinesulfonylchloride: A solution of 2-mercaptopyridine (2.23 g in 33 ml 9N HCl) was cooled to 0° C. Chlorine gas was bubbled into the solution for 90 min, taking care to maintain the temperature at 0° C. Ice cooled ethyl acetate was added followed by slow addition of ice cooled sat'd NaHCO3 until the pH of the water layer was approximately 9. The organic layer were then washed with brine and dried over MgSO4. Evaporation of the ethyl acetate gave 3.5 g of the crude 2-pyridinesulfonylchloride as a light yellow liquid. |
|
With chlorine In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water |
188.a a)
a) 2- pyridinesulfonylchloride Through a stirring solution of 2-mercaptopyridine (2.235 g, 20 mmol) in water (7.5 mL) and concentrated HCl (26 mL) at 0° C. was bubbled Cl2. After 30 min, 75 mL of ice water was added and extracted with cold ether (2*75 mL). The organic layers were combined and washed successively with cold 10% aqueous NaHCO3, and cold brine. The organic layer was dried (MgSO4), filtered and concentrated to yield the title compound as a clear oil. (3.1 g, 87%). |
|
In hydrogenchloride; ethyl acetate |
1.h h.
h. {(S)-1-[3-Hydroxy-1-(pyridine-2-sulfonyl)-azepan-4ylcarbamoyl]-3-methyl-butyl }-carbamic Acid Tert-butyl Ester Generation of 2-pyridinesulfonylchloride: A solution of 2-mercaptopyridine (2.23 g in 33 ml 9N HCl) was cooled to 0° C. Chlorine gas was bubbled into the solution for 90 min, taking care to maintain the temperature at 0° C. Ice cooled ethyl acetate was added followed by slow addition of ice cooled sat'd NaHCO3 until the pH of the water layer was approximately 9. The organic layer were then washed with brine and dried over MgSO4. Evaporation of the ethyl acetate gave 3.5 g of the crude 2-pyridinesulfonylchloride as a light yellow liquid. |
|
Stage #1: 2-Sulfanylpyridine With hydrogenchloride; water; chlorine at 0℃; for 2h;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 0℃; |
37
Description 37; 2-Pyridinesulfonyl chloride (D37); Chlorine gas was bubbled through a solution of 2-mercaptopyridine (10 g, 90 mmol) in conc. HCl (70 ml) and water (10 ml) at 0° C. for 2 h. The solution was purged with argon for 15 min, prior to pouring into ice-water. DCM (200 ml) was added and the resulting mixture neutralised with solid NaHCO3, keeping the temperature at 0° C. by addition of ice. The phases were separated and the aqueous layer washed with cold DCM (2×100 ml). The combined organics were dried (Na2SO4) and concentrated to give the title compound as a colourless oil (14.8 g) which was either used immediately in the next step, or stored temporarily in the freezer. δH (CDCl3, 250 MHz) 7.70 (1H, m), 8.07 (1H, m), 8.12 (1H, d), 8.84 (1H, m). |
|
With hydrogenchloride; sodium hypochlorite In dichloromethane; water at -10 - -5℃; |
|
|
With hydrogenchloride; water; chlorine at 0℃; for 1h; |
92.1 1. 3-(2-Pyridinylsulfonyl)amino-6-methyl-1-[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone
To a stirred reaction mixture of 2-mercaptopyridine (500 mg, 4.5 mmol) and 1N HCl (5 mL) at 0° C., was bubbled in chlorine gas for 1 hr. The reaction mixture was extracted with methylene chloride (3×50 mL), dried (Na2SO4), and concentrated to yield a clear oil, which was used immediately. N,N-Dimethylaminopyridine (200 mg) is added to a stirred reaction mixture of 2-pyridinesulfonyl chloride (50 mg, 0.178 mmol), and 3-amino-6-methyl-1-[N,N'-di(tert-butoxycarbonyl)][3-(guanidinooxyethyl)aminocarbonyl]-2-pyridinone (78 mg, 0.162 mmol), as prepared in step 3 of Example 30, in methylene chloride (2 mL). Reaction mixture was stirred 16 hrs, concentrated in vacuo and purified on silica gel column chromatrography (4% methanol/96% methylene chloride) to give the title compound as a white solid (34 mg, 30% yield). Mass spectrum (LCMS, ESI) calcd. for C26H37SO9N7: 624.6 (M+H); Found 624.1. |
|
Stage #1: 2-Sulfanylpyridine With hydrogenchloride; water; chlorine at 0℃; for 2h;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 0℃; |
37
Description 37; 2-Pyridinesulfonyl chloride (D37); Chlorine gas was bubbled through a solution of 2-mercaptopyridine (10g, 90mmol) in cone. HCI (70ml) and water (10ml) at 00C for 2h. The solution was purged with argon for 15min, prior to pouring into ice-water. DCM (200ml) was added and the resulting mixture neutralised with solid NaHCθ3 , keeping the temperature at ~ O0C by addition of ice. The phases were separated and the aqueous layer washed with cold DCM (2x 100ml). The combined organics were dried (Na2SO4) and concentrated to give the title compound as a colourless oil (14.8g) which was either used immediately in the next step, or stored temporarily in the freezer. δH (CDCI3, 250MHz) 7.70 (1H, m), 8.07 (1H, m), 8.12 (1 H, d), 8.84 (1H, m). |
|
With sodium hypochlorite solution; sulfuric acid In water at 0℃; for 0.5h; |
|
|
With N-chloro-succinimide; tetrabutyl-ammonium chloride; water In acetonitrile at 0℃; |
|
|
With sodium hypochlorite; sulfuric acid In water at 0℃; for 0.25h; |
|
|
With 1,3-dichloro-5,5-dimethylhydantoin; water; benzyltrimethylammonium chloride In acetonitrile at 0℃; for 0.5h; |
|
|
With sodium hypochlorite; sulfuric acid In water at 0℃; for 0.5h; |
9 General Procedure 9: Pyridine-2-sulfonyl chloride (Intermediate 18)
General Procedure 9: Pyridine-2-sulfonyl chloride (Intermediate 18)Sodium hypochlorite solution (conc., 62 ml) was added dropwise to a stirred solution of pyridine-2-thiol (1.0 g, 8.995 mmol) dissolved in H2SO4 (25 ml) at 0° C. The mixture was stirred for 30 min, water (15 ml) added and the mixture extracted with DCM. The organic phases were combined, dried (MgSO4) and concentrated in vacuo gave the title compound (800 mg, 50%) which was used in the next step without purification. The structure was confirmed by 1H NMR. |
| 0.23 g |
With sodium hypochlorite; sulfuric acid In water at -5 - 0℃; for 0.5h; |
3 Pyridine-2-sulfonyl chloride
Pyridine-2-sulfonyl chloride 2-Mercaptopyridine (available from Sigma-Aldrich; 0.25 g, 2.25 mmol) was added to H2SO4 (8 mL) and the mixture was cooled to about -5° C. Sodium hypochlorite (10% solution; 17 mL) was added and the reaction mixture was stirred for 30 min at about 0° C. Water (10 mL) was added and the mixture was extracted with CH2Cl2 (3*20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure to give crude pyridine-2-sulfonyl chloride (0.23 g, 58%), which was used directly in the next step without further purification. |
|
With hydrogenchloride; sodium hypochlorite In dichloromethane; water at 5℃; for 1.16667h; |
Synthesis of 3-Methyl-2-(pyridine-2-sulfonylamino)-butyricacid tert-butyl ester
To a solution of 2-mercaptopyridine(6 mmol) in CH2Cl2 (30 mL) at 5°Cwas added aqueous HCl (4 mL conc. HCl in 13.4 mL H2O). Aqueous NaClO(20 mL, 11% Cl content) was added to the solution using an addition funnel over10 minutes. The solution was stirred at 5°C for a further 60 minutes and was then extracted with CH2Cl2 (2 x 20 mL),dried over sodium sulphate and filtered to give a pale yellow solution. The solvent was reduced until no colour remained (approximately one third theoriginal volume). To this solution was added valine tertiary butyl ester (6 mmol) and triethylamine (6 mmol). The solution was stood at room temperature for 2 hours and was then quenched with H2O (20 mL)and extracted with CH2Cl2 (2 x 20 mL), dried over sodiumsulphate, filtered and the solvent removed to give a solid. This solid was recrystallised from methanol / H2O to give the title compound as a colourless crystalline solid (1.64 g, 87 %). |
|
With hydrogenchloride; chlorine In dichloromethane Inert atmosphere; |
|
|
With N-chloro-4-methylbenzenesulfonamide; tetrabutyl-ammonium chloride; water In acetonitrile at 0℃; for 0.5h; |
|
|
With sodium chlorite; sulfuric acid at 0℃; for 0.25h; |
|
|
With sodium hypochlorite; sulfuric acid at 0℃; for 1h; |
|
|
With hydrogenchloride; water; chlorine at 0℃; for 1h; |
109.1 (Step 1) Methyl 2-Fluoro-4-[(pyridin-2-ylsulfonyl)amino]benzoate
4-Pyridinethiol (16.7 g, 15.0 mmol) was dissolved in concentrated hydrochloric acid (110 ml) and water (30 ml). After the solution was cooled to 0° C., chlorine gas was injected for 1 hour. The reaction liquid was poured onto ice (80.0 g), and then neutralized slowly by adding sodium hydrogen carbonate. With the solution being cooled to 5 to 10° C., extraction was conducted with methylene chloride (150 ml×3), and the extraction liquids were combined and dried over anhydrous sodium sulfate. Then, with the combined liquid being cooled to 5 to 10° C., the solvent was removed under reduced pressure. |
|
With sodium chlorite; sulfuric acid at 0℃; for 0.25h; |
|
|
With sodium hypochlorite; sulfuric acid In water at 0℃; for 0.25h; |
|
|
With sodium hypochlorite; sulfuric acid at 0℃; for 0.25h; |
|
|
With sodium hypochlorite; sulfuric acid at 0℃; for 0.25h; |
|
|
Multi-step reaction with 2 steps
1: hydrogenchloride; sodium chlorite / water
2: dichloromethane |
|
|
With hydrogenchloride; sodium chlorite In water at 0 - 5℃; for 0.5h; |
4.3. General procedure for the synthesis of sulfonyl chlorides.
General procedure: To a 5-mL round-bottom flask was sequentially added azaarenethiol (2.0 mmol) and concentrated HCl (12 mol/L, 1.0 mL) at 0 oC in an ice bath. Subsequently, sodium chlorite (426 mg, 85% content by weight, 4 mmol) dissolved in 1 mL of water, was added dropwise within 15 min. To maintain the inner temperature of reaction mixture to no more than 5 oC, ice was intermittently added to the flask. After another 15 min, the reaction mixturewas extracted by CH2Cl2, dried over anhydrous Na2SO4 and concentrated in vacuum, andthe corresponding crude azaarenesulfonyl chloride was obtained. 4.3.1. Pyridine-2-sulfonyl chloride (2a)Known compound, CAS No. 66715-65-9. Yellow liquid; Yield: 160mg, 90%. 1HNMR(400MHz, CDCl3) δ 8.81-8.79 (1H, m), 8.11-8.05 (2H, m), 7.72-7.68 (1H, m). |
| 320 mg |
With sodium hypochlorite; sulfuric acid In water at -10 - 0℃; |
|
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