* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With chromium(VI) oxide; sulfuric acid In water at 20℃; for 24 h;
To solution chromium trioxide (20.4 g, 0.204 mol) in water (150 mL) was added concentrated sulfuric acid (190 mL) dropwise in the ice bath. 2-Methyl-5-nitrobenzenesulfonamide (10 g, 46.3 mmol) was added and the mixture was stirred at room temperature for 24 h. The mixture was filtered and the residue washed with water, dissolved in sodium bicarbonate solution and filtered under vacuum. The filtrate was acidified with concentrated HCl. After the precipitated product was filtered and washed with abundant cold water, it was dried in the vacuum-oven at 40 °C. The product was obtained a white powder in 72percent yield. Mp 205.6-205.8 °C, (lit.36 205-207 °C); IR: 3103, 1720, 1608, 1541, 1354, 1340, 1184, 1128 cm-1; 1H NMR (DMSO-d6, 300 MHz) δ/ppm: 8.02 (1H, d, J = 8.5 Hz), 8.56 (1H, d, J = 8.2 Hz), 8.71 (1H, s), 10.2 (1H, br, NH); 13C NMR (DMSO-d6, 75 MHz) δ/ppm: 117.2, 126.4, 129.8, 135.2, 143.0, 151.7, 162.2.
71.4%
With potassium permanganate; N-benzyl-N,N,N-triethylammonium chloride In water at 95℃; for 8 h;
2-Methyl-5-nitrobenzene sulfonamide (3, 26.1 g, 0.10 mol), benzyl triethyl ammonium chloride (TEBA) (1.2 g, 5.2 mmol) and water (250 mL) were mixed together and heated to 95 °C. The potassium permanganate (15.7 g, 0.1 mmol) was added in batches and then added water (50 mL) finally. The reaction mixture was heated to 95 °C for 8 h. The reaction residue was filtered and washed with hot water (80 mL) twice, the solution was acidified with concentrated hydrochloric acid to pH 2. A white solid was filtered off and recrystallized from ethyl alcohol to give 6-nitrosaccharin (4, 16.3 g, 71.4 percent yield), m.p.: 205.5-206.9 °C (lit. [11,12]m.p.: 212-214 °C). 1H NMR (DMSO-d6, 300 MHz) δ, ppm:7.93 (1H, d, J = 8.4 Hz), 8.41 (1H, dd, J = 1.6, 2.1 Hz), 8.47(1H, s), 10.6 (1H, br, NH).
68%
With chromium(VI) oxide; sulfuric acid In water at 20℃; for 42 h;
Step C: 6-Nitro-l,l-dioxo-l,2-dihydro-llambda*6*-benzo[i/|isothiazol-3-oneTo a solution of Cr03 (20.8 g, 208 mmol) in water (150 mL) was slowly added concentrated sulfuric acid (190 mL). To the resulting mixture was added 2-methyl-5-nitrobenzenesulfonamide (10.0 g, 46.3 mmol) and the mixture was stirred at rt for about 42 h. The mixture was filtered and the filter cake was washed with water (100 mL). The solid was dissolved in 10percent aqueous NaHCC>3, filtered and the filtrate acidified with 2 N HC1 (pH = 1). The precipitate was collected by filtration and washed with water (2 x 50 mL) to provide 6-nitro-l,l-dioxo-l,2-dihydro- llambda*6*-benzo[i/]isothiazol-3-one (7.2 g, 68percent). .H NMR (DMSO- ) δ: 8.42-8.53 (m, 2H), 8.00 (s, 1H), 3.70 (br s, 1H).
55%
With chromium(VI) oxide; sulfuric acid In water at 20℃; for 24 h;
5.1.1 6-Nitrobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (4) To a solution of chromium trioxide (9.0 g, 900 mmol) in water (67 ml), concentrated sulfuric acid (83.5 ml) was added gradually. The mixture was added 2-methyl-5-nitrobenzenesulfonamide 3 (4.32 g, 20 mmol) and then stirred at room temperature for 24 h. Crude product was obtained by filtration and then washed with water. The filter cake was stirred in 10percent sodium bicarbonate solution and the insoluble residue was removed by filtration. The filtrate was acidified with 5percent hydrochloric acid solution to generate the purified product with 55percent yield, mp: 203-205 °C. 1H NMR (DMSO-d6) δ 7.91 (d, J = 8.4 Hz, 1H), 8.47 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 8.54 (s, 1H). MS (ESI) m/z: 227.1 [M-H]-.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 9, p. 2811 - 2821
[2] Asian Journal of Chemistry, 2017, vol. 29, # 7, p. 1622 - 1624
[3] Patent: WO2012/48222, 2012, A1, . Location in patent: Page/Page column 98
[4] Tetrahedron, 2006, vol. 62, # 33, p. 7902 - 7910
[5] Bulletin of the Chemical Society of Japan, 1982, vol. 55, # 12, p. 3824 - 3827
[6] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 5, p. 1529 - 1538
[7] Chemical Communications, 2011, vol. 47, # 29, p. 8301 - 8303
[8] Journal of Medicinal Chemistry, 2014, vol. 57, # 8, p. 3522 - 3531
[9] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 19, p. 676
[10] Patent: WO2008/24634, 2008, A1, . Location in patent: Page/Page column 167
[11] Journal of Enzyme Inhibition and Medicinal Chemistry, 2014, vol. 29, # 1, p. 118 - 123
[12] Journal of Agricultural and Food Chemistry, 2017, vol. 65, # 35, p. 7661 - 7668
2
[ 121-02-8 ]
[ 6269-91-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
With ammonium hydroxide In diethyl ether at 0℃; for 42 h; Inert atmosphere
Step B: 2-Methyl-5-nitrA solution of 2-methyl-5-nitrobenzenesulfonyl chloride (10.0 g, 43.7 mmol) and Et20 (300 mL) under N2 was cooled to about 0 °C and concentrated. NH4OH (40 mL) was added. After stirring for about 42 h, the mixture was filtered and then diluted with DCM (600 mL). The organic layer was separated and dried over MgS04. The solution was then concentrated under reduced pressure to afford 2-methyl-5-nitrobenzenesulfonamide (9.2 g, 100percent). .H NMR (DMSO- ) δ: 8.60 (d, J = 2.4 Hz, 1H), 8.34 (dd, J = 8.0, 2.4 Hz, 1H), 7.77 (br s, 2H), 7.70 (d, J = 8.4 Hz, 1H), 2.71(s, 3H).
88%
With ammonia In diethyl ether; water at 10 - 40℃; for 2.3 h;
To a solution of 2-methyl-5-nitrobenzenesulfonylchloride (10 g, 0.43 mol) in diethyl ether (200 mL) was added aqueous ammonia solution (35percent solution, 40 mL) dropwise over 20 min keeping the temperature below 10 °C, then the mixture was stirred at 40 °C for 2 h and diethyl ether was evaporated. After the precipitated product was filtered and washed with abundant cold water, it was dried in the vacuum-oven at 40 °C. The product was provided a fawn-colored solid in 88percent yield. 1H NMR (CDCl3, 300 MHz) δ/ppm: 2.79 (3H, s), 7.22 (2H, s, NH2), 7.52 (1H, d, J = 8.5 Hz), 8.24 (1H, d, J = 8.2 Hz), 8.80 (1H, s); 13C NMR (CDCl3, 75 MHz) δ/ppm: 20.6, 122.9, 126.0, 133.5, 143.4, 144.6, 145.7.
Reference：
[1] Patent: WO2012/48222, 2012, A1, . Location in patent: Page/Page column 98
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 9, p. 2811 - 2821
[3] Russian Journal of Applied Chemistry, 2012, vol. 85, # 10, p. 1581 - 1585[4] Zh. Prikl. Khim. (S.-Peterburg, Russ. Fed.), 2012, vol. 85, # 10, p. 1648 - 1652,5
[5] Bioorganic and medicinal chemistry, 2002, vol. 10, # 3, p. 639 - 656
[6] American Chemical Journal, 1886, vol. 8, p. 169
[7] Justus Liebigs Annalen der Chemie, 1874, vol. 172, p. 235
[8] Bulletin of the Chemical Society of Japan, 1982, vol. 55, # 12, p. 3824 - 3827
[9] Patent: WO2008/24634, 2008, A1, . Location in patent: Page/Page column 166-167
[10] Patent: US2011/28503, 2011, A1, . Location in patent: Page/Page column 11
[11] Journal of Enzyme Inhibition and Medicinal Chemistry, 2014, vol. 29, # 1, p. 118 - 123
[12] Patent: US2014/73659, 2014, A1, . Location in patent: Paragraph 0116
[13] Journal of Agricultural and Food Chemistry, 2017, vol. 65, # 35, p. 7661 - 7668
[14] Patent: EP2683385, 2018, B1, . Location in patent: Paragraph 0106; 0107
3
[ 99-99-0 ]
[ 6269-91-6 ]
Yield
Reaction Conditions
Operation in experiment
81.2%
Stage #1: With chlorosulfonic acid In 1,2-dichloro-ethane at 50 - 60℃; for 6.5 h; Stage #2: at 10 - 40℃; for 2 h;
To a mixtureof p-nitrotoluene (27.4 g, 0.20 mol) in 1,2-dichloroethane (120 mL) was heated to 50 °C, chlorosulfonic acid (35.4 g, 0.3mol) was added drop-wise with stirring for over 30 min. The mixture was heated to 60 °C for 6 h. Ice water (500 mL) was added at the end of the reaction with stirring. The aqueous mixture was extracted three times with 1,2-dichloromethane (75 mL), 25 percent ammonium hydroxide (25 mL, 0.33 mol) was added drop-wise combined the organic layers at 10 °C, the mixture was heated to 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure in the end of the reaction. The crude residue was taken up in water (80 mL) and filtered, washed with water to afford off-white solid 3 (35.1 g, 81.2 percent yield), m.p.: 183.2-184.8 °C (lit. [10] m.p.: 183-185 °C) 1HNMR (CDCl3, 300 MHz) δ, ppm: 2.78 (3H, s), 7.24 (2H, s,NH2), 7.55 (1H, d, J = 8.4 Hz), 8.26 (1H, d, J = 8.4 Hz), 8.82(1H, s).
Reference：
[1] Asian Journal of Chemistry, 2017, vol. 29, # 7, p. 1622 - 1624
[2] Chemical Communications, 2011, vol. 47, # 29, p. 8301 - 8303
[3] Patent: WO2012/48222, 2012, A1,
[4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 9, p. 2811 - 2821
[5] Patent: US2012/232106, 2012, A1,
[6] Journal of Enzyme Inhibition and Medicinal Chemistry, 2014, vol. 29, # 1, p. 118 - 123
[7] Patent: US2014/73659, 2014, A1,
[8] Journal of Medicinal Chemistry, 2014, vol. 57, # 8, p. 3522 - 3531
[9] Patent: US2014/206708, 2014, A1, . Location in patent: Paragraph 0086; 0087
[10] Patent: EP2683385, 2018, B1,
4
[ 99-55-8 ]
[ 6269-91-6 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2017, vol. 65, # 35, p. 7661 - 7668
With chromium(VI) oxide; sulfuric acid; In water; at 20℃; for 24h;
To solution chromium trioxide (20.4 g, 0.204 mol) in water (150 mL) was added concentrated sulfuric acid (190 mL) dropwise in the ice bath. 2-Methyl-5-nitrobenzenesulfonamide (10 g, 46.3 mmol) was added and the mixture was stirred at room temperature for 24 h. The mixture was filtered and the residue washed with water, dissolved in sodium bicarbonate solution and filtered under vacuum. The filtrate was acidified with concentrated HCl. After the precipitated product was filtered and washed with abundant cold water, it was dried in the vacuum-oven at 40 C. The product was obtained a white powder in 72% yield. Mp 205.6-205.8 C, (lit.36 205-207 C); IR: 3103, 1720, 1608, 1541, 1354, 1340, 1184, 1128 cm-1; 1H NMR (DMSO-d6, 300 MHz) delta/ppm: 8.02 (1H, d, J = 8.5 Hz), 8.56 (1H, d, J = 8.2 Hz), 8.71 (1H, s), 10.2 (1H, br, NH); 13C NMR (DMSO-d6, 75 MHz) delta/ppm: 117.2, 126.4, 129.8, 135.2, 143.0, 151.7, 162.2.
71.4%
With potassium permanganate; N-benzyl-N,N,N-triethylammonium chloride; In water; at 95℃; for 8h;
<strong>[6269-91-6]2-Methyl-5-nitrobenzene sulfonamide</strong> (3, 26.1 g, 0.10 mol), benzyl triethyl ammonium chloride (TEBA) (1.2 g, 5.2 mmol) and water (250 mL) were mixed together and heated to 95 C. The potassium permanganate (15.7 g, 0.1 mmol) was added in batches and then added water (50 mL) finally. The reaction mixture was heated to 95 C for 8 h. The reaction residue was filtered and washed with hot water (80 mL) twice, the solution was acidified with concentrated hydrochloric acid to pH 2. A white solid was filtered off and recrystallized from ethyl alcohol to give 6-nitrosaccharin (4, 16.3 g, 71.4 % yield), m.p.: 205.5-206.9 C (lit. [11,12]m.p.: 212-214 C). 1H NMR (DMSO-d6, 300 MHz) delta, ppm:7.93 (1H, d, J = 8.4 Hz), 8.41 (1H, dd, J = 1.6, 2.1 Hz), 8.47(1H, s), 10.6 (1H, br, NH).
68%
With chromium(VI) oxide; sulfuric acid; In water; at 20℃; for 42h;
Step C: 6-Nitro-l,l-dioxo-l,2-dihydro-llambda*6*-benzo[i/|isothiazol-3-oneTo a solution of Cr03 (20.8 g, 208 mmol) in water (150 mL) was slowly added concentrated sulfuric acid (190 mL). To the resulting mixture was added <strong>[6269-91-6]2-methyl-5-nitrobenzenesulfonamide</strong> (10.0 g, 46.3 mmol) and the mixture was stirred at rt for about 42 h. The mixture was filtered and the filter cake was washed with water (100 mL). The solid was dissolved in 10% aqueous NaHCC>3, filtered and the filtrate acidified with 2 N HC1 (pH = 1). The precipitate was collected by filtration and washed with water (2 x 50 mL) to provide 6-nitro-l,l-dioxo-l,2-dihydro- llambda*6*-benzo[i/]isothiazol-3-one (7.2 g, 68%). .H NMR (DMSO- ) delta: 8.42-8.53 (m, 2H), 8.00 (s, 1H), 3.70 (br s, 1H).
55%
With chromium(VI) oxide; sulfuric acid; In water; at 20℃; for 24h;
5.1.1 6-Nitrobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (4) To a solution of chromium trioxide (9.0 g, 900 mmol) in water (67 ml), concentrated sulfuric acid (83.5 ml) was added gradually. The mixture was added <strong>[6269-91-6]2-methyl-5-nitrobenzenesulfonamide</strong> 3 (4.32 g, 20 mmol) and then stirred at room temperature for 24 h. Crude product was obtained by filtration and then washed with water. The filter cake was stirred in 10% sodium bicarbonate solution and the insoluble residue was removed by filtration. The filtrate was acidified with 5% hydrochloric acid solution to generate the purified product with 55% yield, mp: 203-205 C. 1H NMR (DMSO-d6) delta 7.91 (d, J = 8.4 Hz, 1H), 8.47 (dd, J = 7.8 Hz, 1.8 Hz, 1H), 8.54 (s, 1H). MS (ESI) m/z: 227.1 [M-H]-.
With chromium(VI) oxide; sulfuric acid; In water; at 20℃; for 18.5h;
To a solution of chromium trioxide (40.7g, 0.407mol) in water (30OmL) was added concentrated sulphuric acid (374mL) dropwise over 30 minutes keeping the temperature below 45C. <strong>[6269-91-6]2-methyl-5-nitrobenzenesulfonamide</strong> (2Og, 92.5mmol) was added and the mixture stirred at room temperature for 18.5 hours. The mixture was filtered through a sinter funnel and the residue washed with water, dissolved in sodium bicarbonate solution and filtered under vacuum. The reaction filtrate was acidified with concentrated hydrochloric acid and a precipitate collected by filtration. This was dried under vacuum at 40C to give 5.37g of the title compound. The residue from the basic filtration was washed with water and dried at 50C for 12 hours. The filtrates from the basification and acidification were combined and a precipitate filtered off and the filtrate evaporated under vacuum to give a solid. The residue, precipitate and solid were combined, washed with acetone and filtered. The filtrate was evaporated under vacuum to give 6g of the title compound. A representative NMR is given below. IH NMR (400 MHz, DMSOD6) delta ppm 7.97 (d, ,7=8 Hz, 1 H) 8.51 (dd, J=S & 2 Hz, 1 H) 8.64 (d, J=I.5 Hz, 1 H). MS m/z 227 (M- 1)
With hydrogenchloride; tin(ll) chloride; In diethylene glycol dimethyl ether; water; for 0.75h;
To a stirred solution of 2-methyl-5-nitrobenzenesulfonamide (4.6 g, 0.021 mol) in 2-methoxyethyl ether (43 mL), at [0] C, was added a solution of 16.1 g [OF TIN (II)] chloride in 32 mL of concentrated HCI dropwise over 15 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 130 mL of diethyl ether was added to reaction. The mixture was stirred vigorously for 1 h. The mixture was basified with a solution of [NAOH] and [NAHCO3,] and extracted with ethyl acetate (x 3). The combined ethyl acetate layers were dried over anhydrous [MGS04,] filtered and concentrated to give crude product. Trituation of the crude product with methanol provided 2.4 g of pure [5-AMINO-2-METHYLBENZENESULFONAMIDE] as light brown [SOLID.APOS;H] NMR (300 MHz, DMSO-d6) [# 7.11-7. ] 10 (m, 3H), 6.95 (d, J = 8. 1 Hz, [1 H),] 6.60 (dd, J = 8.1 [# 2.4 HZ, 1H),] 5.24 (s, 2H), 2.36 (s, 3H). MS [(ES+,] m/z) 187 (M+H).
With hydrogen;palladium 10% on activated carbon; In methanol; dichloromethane; under 2585.81 Torr; for 0.25h;
To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10percent Pd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87percent; MS (m/e): 187 (MH+).
palladium-carbon; In methanol; dichloromethane;
To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10percent Pd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes.The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol.The combined organic solvents were concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87percent; MS (m/e): 187 (MH+).
With palladium 10% on activated carbon; hydrogen; In methanol; dichloromethane; under 2585.81 Torr; for 0.25h;
To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10percent Pd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87percent; MS (m/e): 187 (MH+).
With palladium 10% on activated carbon; hydrogen; In methanol; dichloromethane; under 2585.81 Torr; for 0.25h;
To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10percent Pd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87percent; MS (m/e): 187 (M+).
With palladium 10% on activated carbon; hydrogen; In methanol; dichloromethane; under 2585.81 Torr; for 0.25h;
To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10 percentPd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered throughdiatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentratedunder reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87percent; MS (m/e): 187 (MH+).
To a stirred solution of 2-methyl-5-nitrobenzenesulfonamide (4.6 g, 0.021 mol) in 2-methoxyethyl ether (43 mL), at 0° C., was added a solution of 16.1 g of tin(II) chloride in 32 mL of concentrated HCl dropwise over 15 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 130 mL of diethyl ether was added to reaction. The mixture was stirred vigorously for 1 h. The mixture was basified with a solution of NaOH and NaHCO3, and extracted with ethyl acetate (*3). The combined ethyl acetate layers were dried over anhydrous MgSO4, filtered and concentrated to give crude product. Trituation of the crude product with methanol provided 2.4 g of pure 5-amino-2-methylbenzenesulfonamide as light brown solid. 1H NMR (300 MHz, DMSO-d6) delta 7.11-7.10 (m, 3H), 6.95 (d, J=8.1 Hz, 1H), 6.60 (dd, J=8.1 and 2.4 Hz, 1H), 5.24 (s, 2H), 2.36 (s, 3H). MS (ES+, m/z) 187 (M+H).
With hydrogenchloride; tin(ll) chloride; In diethyl ether; diethylene glycol dimethyl ether; water; at 0℃; for 1.75h;
Intermediate Example 5 Preparation of 5-amino-2-methylbenzenesulfonamide Procedure 1 To a stirred solution of 2-methyl-5-nitrobenzenesulfonamide (4.6 g, 0.021 mol) in 2-methoxyethyl ether (43 mL), at 0 °C, was added a solution of 16.1 g of tin(II) chloride in 32 mL of concentrated HCI dropwise over 15 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 130 mL of diethyl ether was added to reaction. The mixture was stirred vigorously for 1 h. The mixture was basified with a solution of NaOH and NaHC03, and extracted with ethyl acetate (x 3). The combined ethyl acetate layers were dried over anhydrous MgS04, filtered and concentrated to give crude product. Trituation of the crude product with methanol provided 2.4 g of pure 5-amino-2- methylbenzenesulfonamide as light brown solid.
To a mixtureof p-nitrotoluene (27.4 g, 0.20 mol) in 1,2-dichloroethane (120 mL) was heated to 50 C, chlorosulfonic acid (35.4 g, 0.3mol) was added drop-wise with stirring for over 30 min. The mixture was heated to 60 C for 6 h. Ice water (500 mL) was added at the end of the reaction with stirring. The aqueous mixture was extracted three times with 1,2-dichloromethane (75 mL), 25 % ammonium hydroxide (25 mL, 0.33 mol) was added drop-wise combined the organic layers at 10 C, the mixture was heated to 40 C for 2 h. The reaction mixture was concentrated under reduced pressure in the end of the reaction. The crude residue was taken up in water (80 mL) and filtered, washed with water to afford off-white solid 3 (35.1 g, 81.2 % yield), m.p.: 183.2-184.8 C (lit. [10] m.p.: 183-185 C) 1HNMR (CDCl3, 300 MHz) delta, ppm: 2.78 (3H, s), 7.24 (2H, s,NH2), 7.55 (1H, d, J = 8.4 Hz), 8.26 (1H, d, J = 8.4 Hz), 8.82(1H, s).
With chlorosulfonic acid; ammonium hydroxide; In ethyl acetate;
Example 2 5-amino-2-methylbenzenesulfonamide 4-methylnitrobenzene (20 mmol) is treated at 0 C. with chlorosulfonic acid (5.29 mL, 80 mmol) and then, after bringing the homogeneous solution to room temperature, it was stirred at 110 C. for 24 hours. The resulting slurry was then poured over ice water (100 gm), extracted with diethyl ether (3*75 mL), and the organic phase washed with water (75 mL), then dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to afford the crude sulfonyl chloride which was taken up in ethyl acetate and stirred with ammonium hydroxide overnight at room temperature. After the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The oil obtained was purified by column chromatography (silica gel, hexanes then 10%, 20%, up to 50% ethyl acetate in hexanes to afford 3-aminosulfonyl-4-methylnitrobenzene, LCMS: purity: 95%; MS (m/e): 217 (MH+).
4-methylnitrobenzene (20 mmol) was treated at 0 C. with chlorosulfonic acid (5.29 mL, 80 mmol) and then, after bringing the homogeneous solution to room temperature, the solution was stirred at 110 C. for 24 hours. The resulting slurry was then poured over ice water (100 gm), extracted with diethyl ether (3×75 mL), and the organic phase washed with water (75 mL), then dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to afford the crude sulfonyl chloride which was taken up in ethyl acetate and stirred with ammonium hydroxide overnight at room temperature. After the ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The oil obtained was purified by column chromatography (silica gel, hexanes then 10%, 20%, up to 50% ethyl acetate in hexanes to afford 3-aminosulfonyl-4-methylnitrobenzene, LCMS: purity: 95%; MS (m/e): 217 (MH
2-(5-allyl-2,7-dichloro-4-((4-(2-((1,1-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-2-oxoethyl)piperazin-1-yl)methyl)-6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid[ No CAS ]
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