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HazMat fee for 500 gram (Estimated)
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USD 0.00
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USD 15-60
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USD 80+
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Structure of 4025-64-3 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Patent: US2453232, 1943, ,
[2] Journal of the Chemical Society, 1921, vol. 119, p. 1796
2
[ 110-89-4 ]
[ 4025-64-3 ]
[ 7311-93-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 0℃; for 0.5 h;
To a stirred solution of 3-(chlorosulfonyl)benzoic acid (1.10 g, 5.00 mmol) in DCM (10 mL) was added piperidine (1.49 g, 17.5 mmol) at 0° C., and the resulting solution stirred for 30 minutes. The volatiles were then removed in vacuo and the residue treated with aqueous 1N KHSO4. The aqueous phase was then extracted with ethyl acetate (.x.3), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 3-(piperidin-1-ylsulfonyl)benzoic acid (1.22 g, 4.52 mmol, 90percent).1H NMR (d6 DMSO): 13.54 (1H, br), 8.24 (1H, dt, J 8.0 1.4 Hz), 8.18 (1H, t, J 1.8 Hz), 7.97 (1H, dt, J 8.0 1.6 Hz), 7.79 (1H, t, J 7.7 Hz), 2.93-2.88 (4H, m), 1.58-1.50 (4H, m), 1.40-1.32 (2H, m).
90%
at 0℃; for 2 h;
To a stirred solution of 3-(chlorosulfonyl) benzoic acid (0.3 g, 1.36 mmol) in DCM (5 mL) was added piperidine (0.35 g, 0.4ml, 4.08 mmol) at 0° C, and the resulting solution was stirred for 2 hours. The volatiles were then evaporated under reduced pressure and the residue treated with aqueous IN KHSO4. The aqueous phase was then extracted with ethyl acetate (x3), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 3-(piperidin-l-ylsulfonyl)benzoic acid as a white solid (0.34 g, 1.262 mmol, 90percent). NMR (400MHZ, CDCL3): 8.41 (1H, br), 8.26 (1H, dt, J= 8.0Hz , 1.4 - - Hz), 7.94 (1H, dt, J= 8.0Hz , 1.6 Hz), 7.61 (1H, t, J= 7.7 Hz), 2.98-2.96 (4H, m), 1.62-1.56 (4H, m), 1.40-1.34 (2H, m). 13C NMR (100 MHz, CDC13): 170.0, 137,6, 133.9, 132.5, 130.3, 129.4, 129.2, 46.9, 25.2, 23.5.
90%
at 0℃; for 0.5 h;
To a stirred solution of 3-(chlorosulfonyl)benzoic acid (1.10 g, 5.00 mmol) in DCM (10 mL) was added piperidine (1.49 g, 17.5 mmol) at 00C, and the resulting solution stirred for 30 minutes. The volatiles were then removed in vacuo and the residue treated with aqueous IN KHSO4. The aqueous phase was then extracted with ethyl acetate (x3), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 3-(piperidin-l-ylsulfonyl)benzoic acid (1.22 g, 4.52 mmol, 90percent).1H NMR (d6 DMSO): 13.54 (IH, br), 8.24 (IH, dt, J 8.0 1.4 Hz), 8.18 (IH, t, J 1.8 Hz), 7.97 (IH, dt, J 8.0 1.6 Hz), 7.79 (IH, t, J 1.1 Hz), 2.93-2.88 (4H, m), 1.58-1.50 (4H, m), 1.40-1.32 (2H, m).
Reference：
[1] Journal of the Chemical Society, 1946, p. 763,766
[2] Patent: US2453232, 1943, ,
[3] Journal of the Chemical Society, 1921, vol. 119, p. 1796
4
[ 4025-64-3 ]
[ 74-88-4 ]
[ 5345-27-7 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1968, vol. 33, p. 3988 - 3999
5
[ 4025-64-3 ]
[ 636-76-0 ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: With ammonia In water at 0 - 20℃; for 15 h; Stage #2: With hydrogenchloride In water
To ice-cold solution of ammonium hydroxide (25percent, 250ml) is added 3-(chlorosulfonyl) benzoic acid (25g, commercially available, Aldrich) portionwise and the mixture is stirred at room temperature for 15h. The solvent is removed under vacuum to about 50ml and the mixture is acidified with cone. HCl. The precipitate is collected by filtration and dried under vacuum to afford 22g (96percent) of the title compound as a white solid. IH NMR (DMSO-d6) δ 13.44 (br s, IH), 8.38 (s, IH), 8.14 (d, J = 7.5 Hz, IH), 8.04 (d, J = 7.9 Hz, IH), 7.72 (t, J = 7.9 Hz, IH), 7.49 (s, 2H), HPLC (max plot) 97percent; Rt 0.68 min. LC/MS: (ES-): 199.8.
95%
at 0 - 20℃; for 2 h;
To 75 mL of 0 °C cold ammonia (25percent in water) (1002 mmol 30.0 eq) 7.4 g of 3-(chlorosulfonyl)benzic acid, S4,(33.54 mmol, 1.0 eq) was added portion wise. The mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure. The residue was suspended in 25 mL of water and 40 mL of conc. hydrochloric acid were added. The precipitate was collected by vacuum filtration and was washed with water.The crude product was suspended in water and lyophilized to give 6.42 g (95percent) white solid.
64.6%
With ammonia In ethyl acetate at 0℃; for 0.5 h;
General procedure: To a saturated solution of 3-chloro sulfonyl benzoic acid (8 mmol) in ethyl acetate (4 mL) was added cold concentrated ammonia or methylamine aqueous solution. After stirring for 30 min at 0 deg C., the mixture was neutralized with a solution of HCl in dioxane (4M) and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to give a solid which was recrystallized from acetonitrile to give desired compound. 3-Sulfamoyl-benzoic Acid[0234][0235]White solid, yield 64.6percent, 1HNMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H, Ar—H), 8.12 (d, J=8.1 Hz, 1H, Ar—H), 8.03 (d, J=7.8 Hz, 1H, Ar—H), 7.71 (t, J=7.5 Hz, J=7.8 Hz, 1H, Ar—H), 7.5 (s, 2H, SO2NH2)
Reference：
[1] Patent: WO2007/23186, 2007, A1, . Location in patent: Page/Page column 45
[2] European Journal of Medicinal Chemistry, 2014, vol. 89, p. 503 - 523
[3] Journal of the American Chemical Society, 2011, vol. 133, # 40, p. 16235 - 16242
[4] ChemMedChem, 2015, vol. 10, # 9, p. 1548 - 1558
[5] Patent: US2013/35364, 2013, A1, . Location in patent: Paragraph 0233-0235
[6] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6146 - 6155
[7] Fermentforschung, 1931, vol. 12, p. 180,208
[8] Journal of the Chemical Society, 1921, vol. 119, p. 1796
[9] Bulletin de la Societe Chimique de France, 1945, vol. <5>12, p. 954,960
[10] Patent: WO2005/44817, 2005, A1, . Location in patent: Page/Page column 96
[11] Archiv der Pharmazie, 2015, vol. 348, # 6, p. 399 - 407
6
[ 65-85-0 ]
[ 4025-64-3 ]
Yield
Reaction Conditions
Operation in experiment
88.7%
at 100℃; for 0.75 h;
1.22 g (10 mmol) of benzoic acid were weighed into a 50 mL pear-shaped flask and then slowly added10 mL of chlorosulfonic acid was added and stirred at 100 & lt; 0 & gt; C for 45 min. After completion of the reaction, the reaction solution was added dropwise to ice brine,Then vacuum filtration, washing, vacuum drying, in a white solid, yield 88.7percent.
87%
at 65℃; for 4 h;
Chlorosulfonation of benzoic acid derivatives. A mixture of 1 (5 g, 40.94 mmol) or 2 (5 g, 32.86mmol) in chlorosulfonic acid (20 mL) was heated to 65 °C in an oil bath for 4 h, after which time TLC indicated complete conversion of the starting material to the intermediates, 3-(chlorosulfonyl)benzoic acid (3) and 3-(chlorosulfonyl)-4- methoxybenzoic acid (4), respectively. The reaction mixture was slowly poured over ice and filtered. The solid was dried in vacuo to yield intermediates 3 (7.90 g, 87percent) and 4 (6.40 g, 86percent), which were carried forward without further purification.
85%
at 120 - 125℃; for 2 h; Neat (no solvent)
Benzoic acid (250 g, 2.05 mol) was placed in a 1-L round-bottom flask, and chlorosulfonic acid (1 L, 1760 g, 15.1 mol) was added. The mixture was heated with stirring at 120-125° C. for 2 h, allowed to cool to 40-50° C., and added dropwise to an excess of crushed ice. The precipitated product was collected by filtration and dissolved in 1 L of ethyl acetate; then the aqueous layer that formed was separated, and the organic layer was washed with 100 mL of water, dried over sodium sulfate, and concentrated by evaporation to near dryness. After trituration with 300 mL of hexane, the product was collected by filtration, washed on the filter with 200 mL of hexane, and dried in air to give 384.1 g (85percent) of 3-chlorosulfonylbenzoic acid, mp 134-135° C. (lit. mp 134-135° C.); 1H NMR (400 MHz, in CDCl3w/TMS, ppm) 11.43 (broad s, CO2H, 7.81 (t, J=8.0 Hz, H-5), 8.32 and 8.50 (2d, J=8.0 Hz, H4 and H-6), 8.79 (t, J=1.6 Hz, H-2); {1H}13C NMR (100 MHz, in CDCl3w/TMS, ppm) 170.00 (CO), 145.06 (C-3), 136.71 (C-6), 131.92 (C-4), 131.31 (C-1), 130.63 (C-5), 128.91 (C-2).
82%
at 120 - 125℃; for 2 h;
20 mL of Chlorosulfonic acid (300.4 mmol, 7.34 eq) was added to 5.0 g of benzoic acid, S3, (40.9 mmol 1.0 eq) and the mixture was stirred at 120 - 125 °C. After 2 hours the mixture was added dropwise to 200 mL of ice. The resulting precipitate was collected, dissolved in 150 mL of ethyl acetate, washed with water (3 x 25 mL), driedover Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was pestled and washed with hexane to give 7.42 g (82percent) of a white solid.
82%
at 120℃; for 2 h;
Chlorosulfonic acid (2 mL, 300.4 mmol,) was added to125, (500 mg, 40.9 mmol) and the mixture was stirred at 120 °C for 2 h.. After this time the mixture was added dropwise to a mxture of EtOAc (200 mL) and crushed ice. The resulting precipitate was collected, dissolved in ethyl acetate, washed with water (3 x 25 mL) and Brine, dried over Na2SO4, and the solvent was removed under reduced pressure. 1H-NMR (400 MHz, DMSO-d6): (5 = 8.80 (t, J = 1.4 Hz, 1H), 8.40 (m 1H), 8.19 (m, 1H), 7.69 (t, J = 7.5 Hz, 1H).ppm.
80%
at 20 - 130℃; for 2.5 h;
Solid benzoic acid [(50] g, 0.41 mol) in portions was added to [CHLOROSULFONIC] acid (348.7 g, 200 mL, 3 mol) at room temperature. The reaction mixture was heated to [125-130 C] for 2 hr and was then poured into vigorously stirred crushed-ice (1000 g). After 30 min, the white solid was collected, washed with water [(1] L) and air dried to give 72.5 g (80percent) of the title compound. 1H NMR [(CDCL3] : d4-MeOH 4: 1,60 MHz) 8 5.0 (s, 1H), 8.0-9. 1 (m, 4H).
60%
at 5 - 110℃; for 2 h;
Benzoic acid (5 g, 40.9 mmol) was added in portions to chlorosulfonic acid (14.3 g, 122.9 mmol) under stirring at 5–10 C and then stirred at 110 C for 2 h. The reaction mixture was cooled to room temperature, poured on to crushed ice (∼100 g) under stirring during which solids precipitated. These solids were filtered, extracted with ethyl acetate (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the title compound as solid mass (5.4 g, 60percent yield).
54%
at 120℃; for 4 h;
The benzoic acid 1 (12.20g, 10mmol) was added to chlorosulfonic acid (20mL, 30mmol) with stirring. The mixture was heated at 120°C for 4h. After cooling to rt, the mixture was poured into ice-water (100mL), the formed precipitate was collected by filtration and washed with ice-water. The separated solid was dissolved with ethyl acetate (50mL×3). The combined organic extracts were washed with saturated brine (50mL×2) and dried over anhydrous sodium sulfate overnight. After removal of the solvent, the residue was loaded onto a silica gel column and eluted with PE/EA (1:1, v/v) to afford compound 2 (11.93g) in 54percent yield as white solid. H NMR (400MHz, DMSO-d6) δ 12.27 (s, 1H), 8.20 (s, 1H), 7.89 (d, J=7.7Hz, 1H), 7.83 (d, J=7.7Hz, 1H), 7.47 (t, J=7.7Hz, 1H). 13C NMR (101MHz, DMSO-d6) δ 166.92, 148.50, 130.27, 129.73, 129.31, 128.14, 126.45.
851 g
at 90℃; for 11 h;
500g of benzoic acid, 763 g of chlorosulfonic acid was placed in a reactor with a micro-negative pressure alkali absorbing device.Turn on the stirring and add 7.5 g of fuming sulfuric acid.The closed reactor begins to heat up,The temperature was started at 90 ° C, and the GC gas spectrometer was followed. After 11 h, the amount of benzoic acid was ≤ 0.05percent, and the reaction was completed.Reduce the system temperature to 8 ° C,Start adding water while stirring.At first the temperature rose slightly,After the 45g water drop is added,The temperature does not change anymore,Then you can add 45g of water at a time.Stir for a while, let stand, layer,Approximately 862 g of the sulfonated liquid in the lower layer was transferred to another reactor.And adding 86g of anhydrous sodium sulfate and stirring for 1h,After filtration, 851 g of the obtained sulfonated solution was used.The upper aqueous layer is neutralized with alkali and poured into a wastewater tank.
Reference：
[1] Patent: CN105732444, 2016, A, . Location in patent: Paragraph 0031; 0032; 0036; 0037; 0038
[2] Patent: WO2014/100833, 2014, A1, . Location in patent: Paragraph 0076
[3] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 961 - 965
[4] Patent: US2005/49307, 2005, A1, . Location in patent: Page/Page column 5
[5] European Journal of Medicinal Chemistry, 2014, vol. 89, p. 503 - 523
[6] Patent: WO2017/162834, 2017, A1, . Location in patent: Page/Page column 96; 97
[7] Patent: WO2004/9583, 2004, A2, . Location in patent: Page 200-201
[8] New Journal of Chemistry, 2017, vol. 41, # 22, p. 13516 - 13532
[9] Journal of Chemical Sciences, 2015, vol. 127, # 3, p. 439 - 445
[10] European Journal of Medicinal Chemistry, 2018, vol. 148, p. 359 - 371
[11] Journal of the Chemical Society, 1921, vol. 119, p. 1796
[12] Tetrahedron, 2004, vol. 60, # 17, p. 3755 - 3762
[13] Journal of the American Chemical Society, 2013, vol. 135, # 15, p. 5656 - 5668
[14] Patent: WO2016/128541, 2016, A1, . Location in patent: Page/Page column 105
[15] Angewandte Chemie - International Edition, 2017, vol. 56, # 1, p. 248 - 253[16] Angew. Chem., 2017, vol. 129, # 1, p. 254 - 259,6
[17] Letters in Drug Design and Discovery, 2016, vol. 13, # 10, p. 1 - 13
[18] Letters in Drug Design and Discovery, 2017, vol. 14, # 11, p. 1239 - 1251
[19] ChemMedChem, 2018, vol. 13, # 12, p. 1165 - 1171
[20] Patent: CN108395389, 2018, A, . Location in patent: Paragraph 0032; 0034; 0035
7
[ 7790-94-5 ]
[ 65-85-0 ]
[ 4025-64-3 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 65℃; for 4 h;
General procedure: A mixture of 1 (5g, 40.94mmol) or 2 (5g, 32.86mmol) in chlorosulfonic acid (20mL) was heated to 65°C in an oil bath for 4h, after which time TLC indicated complete conversion of the starting material to the intermediates, 3-(chlorosulfonyl)benzoic acid (3) and 3-(chlorosulfonyl)-4-methoxybenzoic acid (4), respectively. The reaction mixture was slowly poured over ice and filtered. The solid was dried in vacuo to yield intermediates 3 (7.90g, 87percent) and 4 (6.40g, 86percent), which were carried forward without further purification.
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 414 - 426
[2] Archiv der Pharmazie, 2015, vol. 348, # 6, p. 399 - 407
8
[ 98-88-4 ]
[ 4025-64-3 ]
Reference：
[1] Patent: US2273974, 1939, ,
9
[ 121-53-9 ]
[ 4025-64-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1858, vol. 106, p. 30
[2] Monatshefte fuer Chemie, 1902, vol. 23, p. 1126,1128
10
[ 25116-40-9 ]
[ 4025-64-3 ]
Reference：
[1] Chemische Berichte, 1957, vol. 90, p. 841,843
Stage #1: for 0.5 h; Stage #2: With hydrogenchloride In tetrahydrofuran; dichloromethane; water
A solution of 3-(chlorosulfonyl) benzoic acid (2.60 g, 12 mmol) in DCM (20 ml) was treated with dimethylamine (2.0 M in TΗF, 20 ml, 40 mmol, 3.3 equiv). After 30 min, the reaction was quenched with 10percent HCl and extracted with EtOAc. The organics were washed with NaCl(sat) and then dried with Na2SO4(s). The organics were then removed under reduced pressure to give 1.80 g, 65percent; m/z 229.
65%
Stage #1: for 0.5 h; Stage #2: With hydrogenchloride In tetrahydrofuran; dichloromethane; water
A solution of 3-(chlorosulfonyl)benzoic acid (2.60 g, 12 mmol) in DCM (20 ml) was treated with dimethylamine (2.0 M in THF, 20 ml, 40 mmol, 3.3 equiv). After 30 min, the reaction was quenched with 10percent HC1 and extracted with EtOAc. The organics were washed with NaCl(Sat) and then dried with Na2S04(S). The organics were then removed under reduced pressure to give 1.80 g, 65percent; m/z 229.
65%
for 0.5 h;
Method 25; 3-[(Dimethylamino)sulfonyr|benzoic acid; A solution of 3-(chlorosulfonyl) benzoic acid (2.60 g, 12 mmol) in DCM (20 ml) was treated with dimethylamine (2.0 M in THF, 20 ml, 40 mmol, 3.3 equiv). After 30 min, the reaction was quenched with 10percent HCl and extracted with EtOAc. The organics were washed with νaCl(sat) and dried with Na2SO4(S). The organics were then removed under reduced pressure to give 1.80 g, 65percent; m/z 229.
65%
at 20℃; for 0.333333 h;
Method 128; 5 3 - \\( Dimethylamino)sulfonyll benzoic acid; A solution of 3-(chlorosulfonyl) benzoic acid (2.60 g, 12 mmol) in DCM (20 ml) was treated with dimethylamine (2.0 M in THF, 20 ml, 40 mmol, 3.3 equiv). After 30 min, the reaction was quenched with 10percent HCl and extracted with EtOAc. The organics were washed with NaCl (sat) and then dried with Na2SO4 (s). The organics were then removed under 10 reduced pressure to give 1.80 g, 65percent; m/z 229.
Reference：
[1] ChemMedChem, 2015, vol. 10, # 9, p. 1548 - 1558
[2] Patent: WO2006/24834, 2006, A1, . Location in patent: Page/Page column 82
[3] Patent: WO2006/24836, 2006, A1, . Location in patent: Page/Page column 30
[4] Patent: WO2007/71963, 2007, A2, . Location in patent: Page/Page column 50
[5] Patent: WO2006/40568, 2006, A1, . Location in patent: Page/Page column 82
[6] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6146 - 6155
[7] Journal of Heterocyclic Chemistry, 1984, vol. 21, p. 1807 - 1816
[8] Tetrahedron, 2004, vol. 60, # 17, p. 3755 - 3762
[9] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 18, p. 4552 - 4557
14
[ 4025-64-3 ]
[ 56542-67-7 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1945, vol. <5>12, p. 954,960
15
[ 4025-64-3 ]
[ 3118-68-1 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1945, vol. <5>12, p. 954,960
16
[ 67-56-1 ]
[ 4025-64-3 ]
[ 63555-50-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 212 - 221
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 3, p. 442 - 454
To ice-cold solution of ammonium hydroxide (25%, 250ml) is added 3-(chlorosulfonyl) benzoic acid (25g, commercially available, Aldrich) portionwise and the mixture is stirred at room temperature for 15h. The solvent is removed under vacuum to about 50ml and the mixture is acidified with cone. HCl. The precipitate is collected by filtration and dried under vacuum to afford 22g (96%) of the title compound as a white solid. IH NMR (DMSO-d6) delta 13.44 (br s, IH), 8.38 (s, IH), 8.14 (d, J = 7.5 Hz, IH), 8.04 (d, J = 7.9 Hz, IH), 7.72 (t, J = 7.9 Hz, IH), 7.49 (s, 2H), HPLC (max plot) 97%; Rt 0.68 min. LC/MS: (ES-): 199.8.
95%
With ammonium hydroxide; at 0 - 20℃; for 2h;
To 75 mL of 0 C cold ammonia (25% in water) (1002 mmol 30.0 eq) 7.4 g of 3-(chlorosulfonyl)benzic acid, S4,(33.54 mmol, 1.0 eq) was added portion wise. The mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure. The residue was suspended in 25 mL of water and 40 mL of conc. hydrochloric acid were added. The precipitate was collected by vacuum filtration and was washed with water.The crude product was suspended in water and lyophilized to give 6.42 g (95%) white solid.
64.6%
With ammonia; In ethyl acetate; at 0℃; for 0.5h;
General procedure: To a saturated solution of 3-chloro sulfonyl benzoic acid (8 mmol) in ethyl acetate (4 mL) was added cold concentrated ammonia or methylamine aqueous solution. After stirring for 30 min at 0 deg C., the mixture was neutralized with a solution of HCl in dioxane (4M) and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to give a solid which was recrystallized from acetonitrile to give desired compound. 3-Sulfamoyl-benzoic Acid[0234][0235]White solid, yield 64.6%, 1HNMR (300 MHz, DMSO-d6) delta 8.38 (s, 1H, Ar-H), 8.12 (d, J=8.1 Hz, 1H, Ar-H), 8.03 (d, J=7.8 Hz, 1H, Ar-H), 7.71 (t, J=7.5 Hz, J=7.8 Hz, 1H, Ar-H), 7.5 (s, 2H, SO2NH2)
With ammonia; In ethyl acetate; at 0℃;
a) To a solution of 3-carboxylbenzenesulfonyl chloride (3. 54 g, 16 mmol) in ethyl acetate (50 mL) at 0 C was added concentrated ammonia (2.5 mL). The reaction was neutralized with HCl in dioance (20 mL), diluted with ethyl acetate (100 mL), dried with anhydrous sodium sulfate and filtered. Concentration of the filtrate yielded the title compound, which was used without purification.
3-Chlorosulfonylbenzoic acid (156.0 g, 0.707 mol), acetic acid (240 mL), and red phosphorus (78.5 g, 2.53 mol) were placed in a 2-L three-neck flask. The mixture was heated to 110 C. and stirred while a solution of iodine (2.82 g, 0.011 mol) in acetic acid (66 mL) was added dropwise over about 30 min, so as to maintain the color of iodine vapor. The stirred mixture was cooled to 100 C. and treated dropwise with 41 mL (2.3 mol) of water over a 10-min period, then heated at reflux temperature for 1.5 h and subsequently cooled to 90 C. Following the addition of saturated sodium chloride solution (250 mL) and water (500 mL), the mixture was kept at 0-5 C. for 1 h and filtered. The damp filter cake was slurried with 450 mL of acetone, and the excess red phosphorus was removed by filtration; then the acetone was evaporated from the filtrate while adding 500 mL of water. The resultant solid was filtered off and dried under vacuum to give 100.1 g (92%) of 3-mercaptobenzoic acid, mp 138-141 C. (lit. mp 138-141 C.); 1H NMR (400 MHz, in CDCl3 w/TMS, ppm) 3.59 (s, SH), 7.36 (t, J=7.8 Hz, H-5), 7.51 and 7.90 (2d, J=7.8 Hz, H4 and H-6), 8.03 (s, H-2); {1H}13C NMR (100 MHz, in CDCl3 w/TMS, ppm) 171.77 (CO), 134.49 (C-4), 132.24 (C-1), 130.86 (C-2), 130.34 C-3), 129.42 (C-5), 127.59 (C-6).
62%
With hydrogenchloride; zinc; In benzene; for 1h;Heating / reflux;
3-MERCAPTO-BENZOIC acid (44a). To a suspension of 3- (chlorosulfonyl) benzoic acid (22.0 g, 0.10 mol) and zinc powder (87.5 g, 1.3 mol) in benzene (150 mL) was added at 0 C, in a dropwise manner, concentrated hydrochloric acid (150 mL, 10 M). The mixture was heated at reflux, stirred for 1 hour, cooled to room temperature, and filtered through a pad of celite, which was subsequently washed with benzene (3 x 50 mL). The organic layer was separated and washed with water (100 mL), and brine (100 mL), dried over anhydrous MGS04, filtered and concentrated under reduced pressure to give a white solid which was recrystallised from aqueous ethanol (9.5 g, 62%) to give the title compound as a solid, mp 147 C.
A solution of 3-(chlorosulfonyl) benzoic acid (2.60 g, 12 mmol) in DCM (20 ml) was treated with dimethylamine (2.0 M in TEtaF, 20 ml, 40 mmol, 3.3 equiv). After 30 min, the reaction was quenched with 10% HCl and extracted with EtOAc. The organics were washed with NaCl(sat) and then dried with Na2SO4(s). The organics were then removed under reduced pressure to give 1.80 g, 65%; m/z 229.
65%
A solution of 3-(chlorosulfonyl)benzoic acid (2.60 g, 12 mmol) in DCM (20 ml) was treated with dimethylamine (2.0 M in THF, 20 ml, 40 mmol, 3.3 equiv). After 30 min, the reaction was quenched with 10% HC1 and extracted with EtOAc. The organics were washed with NaCl(Sat) and then dried with Na2S04(S). The organics were then removed under reduced pressure to give 1.80 g, 65%; m/z 229.
65%
In tetrahydrofuran; dichloromethane; for 0.5h;
Method 25; 3-[(Dimethylamino)sulfonyr|benzoic acid; A solution of 3-(chlorosulfonyl) benzoic acid (2.60 g, 12 mmol) in DCM (20 ml) was treated with dimethylamine (2.0 M in THF, 20 ml, 40 mmol, 3.3 equiv). After 30 min, the reaction was quenched with 10% HCl and extracted with EtOAc. The organics were washed with nuaCl(sat) and dried with Na2SO4(S). The organics were then removed under reduced pressure to give 1.80 g, 65%; m/z 229.
65%
In tetrahydrofuran; dichloromethane; at 20℃; for 0.333333h;
Method 128; 5 3 - ( Dimethylamino)sulfonyll benzoic acid; A solution of 3-(chlorosulfonyl) benzoic acid (2.60 g, 12 mmol) in DCM (20 ml) was treated with dimethylamine (2.0 M in THF, 20 ml, 40 mmol, 3.3 equiv). After 30 min, the reaction was quenched with 10% HCl and extracted with EtOAc. The organics were washed with NaCl (sat) and then dried with Na2SO4 (s). The organics were then removed under 10 reduced pressure to give 1.80 g, 65%; m/z 229.
2.93 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 5℃; for 2h;
Preparation of 3-(N,N-dimethylsulfamoyl)benzoic Acid, Intermediate 13.0 To a round-bottom flask was added dimethylamine (2.0M in THF, 9.1 mL, 18.2 mmol) and DCM (40 mL). The solution was cooled to 0 C. and DIPEA (7.88 mL, 45.3 mmol) was added followed by 3-(chlorosulfonyl)benzoic acid (4.0 g, 18.1 mmol) in portions maintaining the temperature <5 C. The reaction was stirred at 0 C. for 2 h then 1N NaOH (50 mL) was added and the phases were separated. The organics were washed with 1N NaOH (2*50 mL) and the aqueous extracts were collected and acidified with conc. HCl to pH 2. The resulting precipitate was collected by filtration and dried under reduced pressure to give the desired product (2.93 g). 1H NMR (500 MHz, DMSO-d6) delta ppm 13.55 (br s, 1H), 8.23-8.29 (m, 1H), 8.18-8.22 (m, 1H), 7.95-8.06 (m, 1H), 7.74-7.85 (m, 1H), 2.63 (s, 6H). LCMS-ESI (POS.). m/z: 230.2 (M+H)+.
54.A Step A:
Step A: 3-(N,N-Diethylaminosulfonyl)benzoic Acid To a solution of 3-(chlorosulfonyl)benzoic acid (1.02 g, 4.62 mmol) in CH2Cl2 (100 mL) at 0° C. was added diethylamine (2.4 mL, 23 mmol). The resulting mixture was stirred at 0° C. for 3 h then worked up by adding 2N aqueous HCl and extracting 3* with EtOAc. The combined organic was washed with brine then dried over MgSO4 and concentrated under reduced pressure. The residue was used without further purification.
In dichloromethane at 0℃; for 2h;
50A
Diethylamine (Aldrich, 2.5 mL, 24 mmol) was added to a solution of 3- (chlorosulfonyl)benzoic acid (Aldrich, 2.0 g, 9.1 mmol) in anhydrous dichloromethane (20 mL) at 0 0C. The mixture was then stirred at 0 0C for 2 hours. The volatiles were removed under reduced pressure. The residue was treated with aqueous potassium hydrogensulfate (1 M, 10 mL) and then extracted with ethyl acetate (3x50 mL). The combined extracts were dried over magnesium sulfate filtered and then concentrated to give the title compound. 1 H NMR (300 MHz, CD3OD) δ 1 .13 (t, J=7.1 Hz, 6 H), 3.22 - 3.30 (m, 4 H), 7.69 (t, J=7.8 Hz, 1 H), 8.03 (ddd, J=7.9, 1 .9, 1 .4 Hz, 1 H), 8.25 (dt, J=7.8, 1 .4 Hz, 1 H), 8.40 (t, J=1 .7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 275 (M+NH4)+.
In ethyl acetate at 0 - 20℃; Inert atmosphere;
In tetrahydrofuran at 20℃;
In dichloromethane at 0℃; for 2h;
50A
Diethylamine (Aldrich, 2.5 mL, 24 mmol) was added to a solution of 3- (chlorosulfonyl)benzoic acid (Aldrich, 2.0 g, 9.1 mmol) in anhydrous dichloromethane (20 mL) at 0 0C. The mixture was then stirred at 0 0C for 2 hours. The volatiles were removed under reduced pressure. The residue was treated with aqueous potassium hydrogensulfate (1 M, 10 mL) and then extracted with ethyl acetate (3x50 mL). The combined extracts were dried over magnesium sulfate filtered and then concentrated to give the title compound. 1H NMR (300 MHz, CD3OD) δ 1.13 (t, J=7.1 Hz, 6 H), 3.22 - 3.30 (m, 4 H), 7.69 (t, J=7.8 Hz, 1 H), 8.03 (ddd, J=7.9, 1.9, 1.4 Hz, 1 H), 8.25 (dt, J=7.8, 1.4 Hz, 1 H), 8.40 (t, J=I.7 Hz, 1 H) ppm; MS (DCIZNH3) mZz 275 (M+NH4)+.
Preparation of 3-Benzylsulfamoyl-benzoic acid:
Preparation of 3-Benzylsulfamoyl-benzoic acid: 3-Chlorosulfonyl-benzoic acid (300 mg, 1.36mmol), and benzylamine (0.60 mL, 5.49 mmol) were stirred at room temperature in anhydrous CH2Cl2 (10 mL) overnight under N2. The reaction mixture was concentrated in vacuo. Purification of the residue on IR-120 ion exchange resin column (elution with methanol) afforded the title compound (395 mg, 100%) as a white solid.
95%
In dichloromethane at 0℃; for 0.5h;
In acetone Reflux;
2.1. Synthesis of Phenylacetic Acid and Trifluoromethylphenyl Substituted Benzamide Derivatives
General procedure: Dry benzoic acid (0.01 mol) was taken in round-bottom flask equipped with a stirrer in an ice bath chamber and cooled with maintaining the temperature between 10 to 15 °C. Chlorosulfonic acid (8.0 mL) was added and funnel was stoppered with calcium chloride filled with cotton wool tubes and carefully checked to ensure that there was no leaking.The mixture showed exothermic reaction and when whole benzoic acid was dissolved followed by the extinction of exothermic reaction, the flask was heated in a hot water bath at 70-80 °C for 2 h to complete the reaction. The mixture was cooled and transferred to 150 g crushed ice. 3-(chlorosulphonyl)benzoic acid was collected by vacuum filtration and washed with cold water and air dried. 3-(chlorosulphonyl)benzoic acid (0.01 mol) and commercially available aliphatic aromatic, and heteroaromatic amines(0.01 mol) were refluxed in acetone and the completion of reaction was monitored by TLC to get the respective sulphonamides of benzoic acid. The reaction mixture was cooled and precipitates obtained were washed and recrystallized. The different sulphonamides obtained (0.01 mol) were refluxed with thionyl chloride (0.01 mol) for 3 h. While the refluxing got over, the excess of thionyl chloride was distilled off to get the respective benzoyl chlorides. Phenylacetic acid derivatives (1-6) were obtained by refluxing the respective benzoyl chlorides (0.01 mol) and 2-aminophenylacetic acid (0.015 mol) in methanol. The products obtained after evaporation of acetone were recrystallized with ethanol. 2-trifluoromethylphenyl benzamide derivatives(7-26) were obtained by refluxing the respective benzoyl chlorides (0.01 mol) with 2-trifluoromethylaniline (0.015mol) in acetone. The product obtained after evaporation of acetone was recrystallized with ethanol.
In acetone Reflux;
General procedure for preparation of designed molecules
General procedure: Dry benzoic acid (1 mmol) was transferred to a flat baseflask fixed on a magnetic agitator at constant temperaturearound 10 °C. Excess of HClSO3 (8.0 mL) was addedcarefully and observed to avoid any escape. When all theacid was liquefied and the exothermic response terminated,the flat bottom flask was heated at 70-80 °C using waterbath for 2 h followed by cooling. The materials of flask werepoured to crushed ice (150 g) cautiously with stirring andcrystals of 3-(chlorosulphonyl)benzoic acid were filteredemploying vacuum subsequent to cold water wash followedby air drying. The precipitates prepared above (1 mmol)were then reacted with the corresponding aliphatic andaromatic amines (1 mmol) under reflux using acetone tillcompletion of reaction (observed using silica gel G TLC)following cooling and drying of the precipitates. The differentsulphonamides prepared above (1 mmol) wererefluxed for 3 h with sulfinyl chloride (1 mmol) and toreceive equivalent acid chlorides excess sulfinyl chloridewas withdrawn. Acid chlorides prepared above (1 mmol)were refluxed with 2-aminobenzimidazole (1.5 mmol). Theend products (compounds 1-10) obtained by the evaporationof solvent were purified using recrystallization from ethanol[28-30].
535.1 Step 1.
To a solution of 3-chlorosulfonylbenzoic acid (1 g, 4.53 mmol) in DCM (10 mL) was added a solution of 2-methylpropan-2-amine (1.16 g, 15.86 mmol, 1.67 mL). The mixture was stirred at 0°C for 0.5 h and at rt for 2 h. A white solid was formed during the reaction. The solid was filtered and washed with 10 mL of DCM. The solid was poured onto 20 mL of H2O and 5 N aqueous HCl was added slowly (while stirring) until pH~5. The mixture was stirred at rt for 30 min. The mixture was filtered, washed with water and dried under vacuum to give 3-(tert-butylsulfamoyl) benzoic acid (0.9 g, 77.17% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 8.37 (t, J = 1.6 Hz, 1 H) 8.13 (dt, J = 7.6, 1.4 Hz, 1 H) 8.05 (dt, J = 7.6, 1.4 Hz, 1 H) 7.70 (t, J = 7.8 Hz, 2 H) 1.09 (s, 9 H).
71.2%
In dichloromethane at 0 - 20℃; for 2.5h;
82
To a solution of 5.0 g (0.0227 mol) of 3-(chlorosulfonyl)benzoic acid in 80 ml of dichloromethane at O0C, 8.4 ml (0.0799 mol) of tert-butilamine dissolved in 20 ml of dichloromethane were added. The mixture was stirred at O0C for 30 minutes and at room temperature for 2 hours. A white solid was formed during the reaction. The solid was filtered and washed with 10 ml of dichloromethane. The filtrate was discarded. The solid was poured into 100 ml of water and 5N aqueous HCI was added slowly (while stirring) until acidic pH of the solution. The mixture was stirred at room temperature for 30 minutes. A new solid was formed which was filtered, washed with water and dried in a vacuum oven at 450C (P2O5). 4.21 g (72.1%) of the title compound were obtained. (Product described in WO 99/24461 ).
Synthesis of Benzamide Derivatives
General procedure: Dry benzoic acid (0.01 mol) was taken in RBF fitted with a stir bar and a Claisen adapter. The flask was cooled in a cold water bath maintained between 10 and 15 °C. Chlorosulfonic acid (8.0 mL) was added and funnel was stoppered and checked cautiously to confirm no leakage. The reaction showed exothermic reaction and when whole benzoic acid had dissolved and exothermic reaction has subsided, the reaction was completed by heating the flask using water bath at 70-80 °C for 2 hours. The reaction mixture was cooled and transferred to 150 g crushed ice with stirring to break the lumps. The precipitates were filtered using vacuum filtration followed by washing with cold water and product (3-(chlorosulphonyl)benzoic acid) was air dried. 3-(chlorosulphonyl)benzoic acid (0.01 mol) and commercially available aliphatic and aromatic amines (0.01 mol) were refluxed in acetone, until the reaction was completed as observed by TLC. The contents of the flask were cooled and precipitates of sulphonamide of benzoic acid obtained were washed and recrystallized. The different sulphonamides (0.01 mol) as obtained above and thionyl chloride (0.01 mol) were refluxed for 3 hours. On completion of reflux, the excess of thionyl chloride was distilled off to obtain the corresponding benzoyl chlorides. The respective benzoyl chlorides (0.01 mol) and available aromatic and aliphatic amines (0.015 mol) were refluxed in acetone. The final products(benzamide derivatives) received after the evaporation of acetone were purified by recrystallization using ethyl alcohol.
In acetone Reflux;
2.1. Synthesis of Phenylacetic Acid and Trifluoromethylphenyl Substituted Benzamide Derivatives
General procedure: Dry benzoic acid (0.01 mol) was taken in round-bottom flask equipped with a stirrer in an ice bath chamber and cooled with maintaining the temperature between 10 to 15 °C. Chlorosulfonic acid (8.0 mL) was added and funnel was stoppered with calcium chloride filled with cotton wool tubes and carefully checked to ensure that there was no leaking.The mixture showed exothermic reaction and when whole benzoic acid was dissolved followed by the extinction of exothermic reaction, the flask was heated in a hot water bath at 70-80 °C for 2 h to complete the reaction. The mixture was cooled and transferred to 150 g crushed ice. 3-(chlorosulphonyl)benzoic acid was collected by vacuum filtration and washed with cold water and air dried. 3-(chlorosulphonyl)benzoic acid (0.01 mol) and commercially available aliphatic aromatic, and heteroaromatic amines(0.01 mol) were refluxed in acetone and the completion of reaction was monitored by TLC to get the respective sulphonamides of benzoic acid. The reaction mixture was cooled and precipitates obtained were washed and recrystallized. The different sulphonamides obtained (0.01 mol) were refluxed with thionyl chloride (0.01 mol) for 3 h. While the refluxing got over, the excess of thionyl chloride was distilled off to get the respective benzoyl chlorides. Phenylacetic acid derivatives (1-6) were obtained by refluxing the respective benzoyl chlorides (0.01 mol) and 2-aminophenylacetic acid (0.015 mol) in methanol. The products obtained after evaporation of acetone were recrystallized with ethanol. 2-trifluoromethylphenyl benzamide derivatives(7-26) were obtained by refluxing the respective benzoyl chlorides (0.01 mol) with 2-trifluoromethylaniline (0.015mol) in acetone. The product obtained after evaporation of acetone was recrystallized with ethanol.
In acetone Reflux;
General procedure for preparation of designed molecules
General procedure: Dry benzoic acid (1 mmol) was transferred to a flat baseflask fixed on a magnetic agitator at constant temperaturearound 10 °C. Excess of HClSO3 (8.0 mL) was addedcarefully and observed to avoid any escape. When all theacid was liquefied and the exothermic response terminated,the flat bottom flask was heated at 70-80 °C using waterbath for 2 h followed by cooling. The materials of flask werepoured to crushed ice (150 g) cautiously with stirring andcrystals of 3-(chlorosulphonyl)benzoic acid were filteredemploying vacuum subsequent to cold water wash followedby air drying. The precipitates prepared above (1 mmol)were then reacted with the corresponding aliphatic andaromatic amines (1 mmol) under reflux using acetone tillcompletion of reaction (observed using silica gel G TLC)following cooling and drying of the precipitates. The differentsulphonamides prepared above (1 mmol) wererefluxed for 3 h with sulfinyl chloride (1 mmol) and toreceive equivalent acid chlorides excess sulfinyl chloridewas withdrawn. Acid chlorides prepared above (1 mmol)were refluxed with 2-aminobenzimidazole (1.5 mmol). Theend products (compounds 1-10) obtained by the evaporationof solvent were purified using recrystallization from ethanol[28-30].
Multi-step reaction with 2 steps
1: acetone; aqueous sodium sulfite; sodium carbonate / Erwaermen der erhaltenen 3-Sulfino-benzoesaeure mit Natriumcarbonat in wss. Aethanol und mit Methyljodid
2: 230 °C
General procedure: Sulfonyl chloride derivative 1 or 2 (3.99mmol) was added gradually to a mixture of substituted amine (4.39mmol) and pyridine (2mL) in EtOAc with stirring at 0C. The reaction mixture was stirred at room temperature until the TLC indicated complete conversion of the sulfonyl chloride to the sulfonamide intermediate. The reaction mixture was dissolved in DCM and extracted (2×) with 10% NaOH. After the aqueous layer was acidified with 2N HCl, the precipitate was collected by filtration, washed with H2O, and dried in vacuo to give the desired products (5-22, 173, 174), which were carried forward without further purification.
With triethylamine; In methanol; at 0 - 20℃; for 5.5h;
A chilled solution of <strong>[932-96-7]4-chloro-N-methylaniline</strong> (2.77 g, 19.6 mmol, Aldrich) and triethylamine (2.2 mL, 16 mmol) in methanol (10 mL) was added by cannula to solid [3-(chlorosulfonyl)] benzoic acid (2.87 g, 13.0 mmol, Aldrich) with stirring in an ice bath. The ice bath was removed after 45 minutes, and the mixture was stirred at room temperature for 4.75 hours. The mixture was added to a separatory funnel with 60 mL of 1 M aqueous KOH, and this solution was washed with 2 X 60 mL [OF CH2CL2.] The aqueous layer was then acidified with concentrated HC1. The resulting precipitate was collected, washed with water, and recrystallized from hot toluene. The crystals were collected, washed with pentane, and dried at [100 C] under vacuum. Yield was 2.48 g of white solid.
In dichloromethane; at 0 - 20℃; for 12h;
General procedure:To a solution of 3-(chlorosulfonyl)benzoic acid (1.0 equiv, ca. 0.1 M) in dichloromethane, 4-bromo-N-methylaniline (3.1 equiv) was slowly added at 0 C with stirring. The mixture was stirred at room temp for 12 h. The solvent was removed with a nitrogen gas stream, the mixture was treated with 1 M NaOH (> 10 equiv), and was extracted with ether three times. The aqueous fraction was then acidified with 3 M HCl to pH ~1. The mixture turned cloudy during the addition. The resulting precipitate was collected by suction filtration on a Buchner funnel, washed with distilled water, and dried overnight at reduced pressure to give 3-(N-(4-bromophenyl)-N-methylsulfamoyl)benzoic acid (7a, 50-60%), which was used without further purification. To a solution of 7a (1.0 equiv, ca. 0.1 M), was added <strong>[932-96-7]4-chloro-N-methylaniline</strong> (1.1 equiv), EDCI (1.3 equiv), and DMAP (0.1 equiv). The mixture was stirred at room temp for 12 h and then diluted with excess EtOAc. The organic mixture was washed with 1 M aqueous HCl (2 times), 1 M aqueous NaHCO3 (2 times), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield a crude product, which was purified by silica gel column chromatography to give 3a as a thick gel.
In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran at 0℃; for 0.5h;
30.i
A mixture of 3- (chlorosulfonyl) benzoic acid (2. 00g) and DCM (20ml) under nitrogen at 0° was treated with cyclohexylamine (3. 63moi) and the mixture was stirred at 0°C for 0.5 h. The solvent was evaporated in vacuo and the residue was treated with 1 M potassium hydrogen sulfate solution (50mi) and extracted with EtOAc. The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (2.28g). LCMS RT = 3. 16min.
With triethylamine In dichloromethane at 5 - 20℃;
Synthesis of compound 6: Compound 6 To a solution of 3-(chlorosulfonyl)benzoic acid (1 g, 4.53 mmol) in CH2C12 (20 mL) at 5°C, cyclohexanamine (0.899 g, 9.06 mmol) and triethylamine (1.38 g, 13.60 mmol) were successively added drop wise. The solution was stirred at room temperature overnight. The mixture was washed with IN HC1 (50 mL). The organic phase was dried over MgS04 and concentrated resulting in 3-(N-cyclohexylsulfamoyl)benzoic acid as a white solid (1.2 g), which was used in the next step without purification. To a solution of 3-(N-cyclohexylsulfamoyl)benzoic acid (1.2 g, 4.24 mmol) in DMF (15 mL) at 5°C, 4-fluoroaniline (0.52 g, 4.66 mmol) and DIPEA (1.64 g, 12.71 mmol) were successively added.. The mixture was stirred for 20 minutes and then HATU (1.93 g, 5.08 mmol) was added. The solution was stirred at room temperature overnight. To the reaction mixture aqueous NaHC03 (50 mL) was added followed by EtOAc (50 mL). The organic layer washed with HC1 (5%; 50 mL) and brine. The organic layer was dried with MgS04 and concentrated, resulting in a residue. The obtained residue was purified by a silica gel chromatography column (Petroleum ether: EtOAc=2: l) resulting in compound 6 as a white solid (850 mg). Method B; Rt: 4.50 min. m/z : 377.2 (M+H)+ Exact mass: 376.1
1.2 g
With triethylamine In dichloromethane at 5 - 20℃;
Synthesis of compound 6: Compound 6 To a solution of 3-(chlorosulfonyl)benzoic acid (1 g, 4.53 mmol) in CH2C12 (20 mL) at 5°C, cyclohexanamine (0.899 g, 9.06 mmol) and triethylamine (1.38 g, 13.60 mmol) were successively added drop wise. The solution was stirred at room temperature overnight. The mixture was washed with IN HC1 (50 mL). The organic phase was dried over MgS04 and concentrated resulting in 3-(N-cyclohexylsulfamoyl)benzoic acid as a white solid (1.2 g), which was used in the next step without purification. To a solution of 3-(N-cyclohexylsulfamoyl)benzoic acid (1.2 g, 4.24 mmol) in DMF (15 mL) at 5°C, 4-fluoroaniline (0.52 g, 4.66 mmol) and DIPEA (1.64 g, 12.71 mmol) were successively added.. The mixture was stirred for 20 minutes and then HATU (1.93 g, 5.08 mmol) was added. The solution was stirred at room temperature overnight. To the reaction mixture aqueous NaHC03 (50 mL) was added followed by EtOAc (50 mL). The organic layer washed with HC1 (5%; 50 mL) and brine. The organic layer was dried with MgS04 and concentrated, resulting in a residue. The obtained residue was purified by a silica gel chromatography column (Petroleum ether: EtOAc=2: l) resulting in compound 6 as a white solid (850 mg). Method B; Rt: 4.50 min. m/z : 377.2 (M+H)+ Exact mass: 376.1
With sodium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; water;
EXAMPLE 4 Preparation of sodium 3-sulfobenzoate 565.0 g of 3-(chlorosulfonyl)benzoic acid containing 32.9% water (corresponding to 379.1 g (1.72 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 182 g of water and 1170 g of xylene and heated in a water separator. A total of 340 ml of water are distilled off azeotropically with xylene. After cooling the reaction mixture to 25 C. 210 g (1.73 mol) of 33% strength sodium hydroxide solution are added dropwise over 30 minutes. Subsequently another 170 ml of water are expelled. After cooling, the precipitated product is filtered off with suction. After drying at 100 C./100 torr (13.16 kPa) 370.2 g of sodium 3-sulfobenzoate are obtained, the purity determined by titration being 98.3%; this corresponds to a yield of 94.3%.
93.3%
With sodium hydroxide; In water; chlorobenzene;
EXAMPLE 5 Preparation of sodium 3-sulfobenzoate 273.6 g of 3-(chlorosulfonyl)benzoic acid containing 28.6% water (corresponding to 195.3 g (0.89 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 50 g of water and 500 g of chlorobenzene and heated in a water separator. A total of 106 ml of water are expelled. After cooling the reaction mixture to 100 C., 108 g (0.89 mol) of 33% strength sodium hydroxide solution are added dropwise over 30 minutes. Subsequently a further 90 ml of water are expelled. After cooling, the precipitated product is filtered off with suction. After drying at 100 C./100 torr (13.16 kPa) 190.4 g of sodium 3-sulfobenzoate are obtained, the purity determined by titration being 97.3%; this corresponds to a yield of 93.3%.
EXAMPLE 1 Preparation of 3-sulfobenzoic acid 300 g of 3-(chlorosulfonyl)benzoic acid containing 38.8% water (corresponding to 183.6 g (0.83 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 150 g of water and heated at 100 C. for 1 hour. Then 600 g of xylene are added dropwise over 1 hour and a total of 260 ml of water are azeotropically distilled off with xylene. The reaction mixture is cooled and the precipitate is filtered off with suction. After drying at 100 C./100 torr (13.16 kPa) 164.7 g of 3-sulfobenzoic acid are obtained, the purity determined by titration being 97.7%; this corresponds to a yield of 95.6%.
95.4%
In water; toluene;
EXAMPLE 2 Preparation of 3-sulfobenzoic acid 300 g of 3-(chlorosulfonyl)benzoic acid containing 38.8% of water (corresponding to 183.6 g (0.83 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 100 g of water and heated to 100 C. for 1 hour. Then 500 g of toluene are added dropwise over 1 hour and a total of 164 ml of water distilled off azeotropically with toluene. The reaction mixture is cooled and the precipitated product filtered off with suction. After drying at 100 C./100 torr (13.16 kPa) 163.5 g of 3-sulfobenzoic acid are obtained, the purity determined by titration being 98.2%; this corresponds to a yield of 95.4%.
95.6%
In 5,5-dimethyl-1,3-cyclohexadiene; water;
EXAMPLE 3 Preparation of 3-sulfobenzoic acid 250 g of 3-(chlorosulfonyl)benzoic acid containing 35.9% of water (corresponding to 160.2 g (0.73 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 86 g of water and 500 g of xylene and heated in a water separator. A total of 171 ml of water are expelled. The reaction mixture is cooled and the precipitated product filtered off with suction. After drying at 100 C./100 torr (13.16 kPa) 144.3 g of 3-sulfobenzoic acid are obtained, the purity determined by titration being 97.5%; this corresponds to a yield of 95.6%.
Reference Example 7 3-(Methoxycarbonyl)benzenesulfonyl chloride The title compound was obtained by the same procedure as a series of reaction of reference example 6, using 3-carboxybenzenesulfonyl chloride instead of 4-carboxybenzenesulfonyl chloride.
With triethylamine; In tetrahydrofuran; dichloromethane; at 0℃; for 0.5h;
Example 19; 3-Methylsulfamoyl-iV-[5-(3-pyridin-3-yl-5-trifluoromethyl-pyrazol-l- yl)-pyridin-2-yl] -benzamide; Methylamine (1.1 mL of 2 M solution in tetrahydrofuran, 2.2 mralphaol) and triethylamine (0.6 mL, 4.3 mmol) are added to dichloromethane (10 mL) at 0 0C. Then 3- chlorosulfonyl-bcnzoic acid (500 mg, 2.2 mmol) is added in small portions. The mixture is stirred for 30 minutes at 0 0C before 1 M aqueous HCl (8 mL) is added. The mixture is extracted with ethyl acetate (25 mL, 3 x). The organic layers are combined and dried over sodium sulfate. Removal of solvent under vacuum affords 3-methylsulfamoyl- benzoic acid (480 mg) with 92% purity (2.1 mmol, 95 %). This material is used in the next step without further purification.
86%
In tetrahydrofuran; at 0 - 20℃; for 1.25 - 1.33333h;
Example 2The N-nitroso compounds shown below are prepared and then used to generate diazomethane in a suitable apparatus: <n="14"/>Preparation of 3-[(lambda/-nitroso methylamino)sulfonyl] benzoic acidMethylamine was bubbled for 15-20 min through 3-chlorosulfonylbenzoic acid (5 g, 22.7 mmol) in tetrahydrofuran (50 mL) at 0C. The reaction was stirred at room temperature for 1 hour then concentrated to dryness. Water (50 mL) was added, then acidified with cone, hydrochloric acid to precipitate a white solid which was filtered and air-dried to afford, 3-[(methylamino) sulfonyl] benzoic acid (4.2 g, 86%). 1 H NMR 2.57(3H); 7.70- 7.75 (1H); 8.05-8.09 (1H); 8.26-8.30 (1 H); 8.46-8.49 (1H).
54%
In water; ethyl acetate; at 0℃; for 0.5h;
General procedure: To a saturated solution of 3-chloro sulfonyl benzoic acid (8 mmol) in ethyl acetate (4 mL) was added cold concentrated ammonia or methylamine aqueous solution. After stirring for 30 min at 0 deg C., the mixture was neutralized with a solution of HCl in dioxane (4M) and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to give a solid which was recrystallized from acetonitrile to give desired compound.3-Methylsulfamoyl-benzoic Acid[0236][0237]white solid, yield 54%, 1HNMR (300 MHz, DMSO-d6) delta 8.30 (s, 1H, Ar-H), 8.17 (d, J=7.8 Hz, 1H, Ar-H), 7.99 (d, J=8.1 Hz, 1H, Ar-H), 7.75 (t, J=7.8 Hz, 1H, Ar-H), 7.62 (d, J=4.8 Hz, 1H, NH), 2.4 (s, 3H, Me).
43%
In dichloromethane; at 25℃;Inert atmosphere; Schlenk technique;
General procedure: To a stirred solution of 3-(chlorosulfonyl)benzoic acid (1 .0 eq.) in DCM (0.30 M), the amine (2.5 eq.) was added dropwise. The reaction was stirred at 25 C for 6-16.5 h and it was then concentrated under reduced pressure. The residue was diluted with water and HCI (1 M) was added. The resulting precipitate was filtered, washed with water and dried to afford the pure sulfonamide benzoic acids. White solid; Yield: 43 %; mp 211-213 C.
A heterogeneous mixture of 3-chlorosulfonyl-benzoic acid (11.0 g, 50. Ommol) in 18 mL of SOCl2 was refluxed for 3 h. Thereafter the excess of [SOCL2] was removed, the residual brown oil was dissolved in 60 [ML OF CH3CN,] and then 2- (p-tolylsulfonyl) ethanol (9.4 g, 47.0 mmol, 0.95 eq. ) was added. The mixture was heated to reflux temperature for 20 h. Thereafter the most of CH3CN was removed, the resulting oil was purified by short column chromatography (silica gel, [CH2CL2)] to give light brown oil, which was dried further under vacuum to yield 19.1 g (95%) of a light brown solid. 1H NMR (CDCl3, 400 MHz) [52.] 34 (s, 3 H), 3.61 (t, 2 H), 4.73 (t, 2 H), 7.29 (d, 2 H), 7.68 (t, [1] H), 7.81 (d, 2 H), 8.19 (m, 2 H), 8.43 (s, [1] H).
63%
A mixture of 3- (chlorosulfonyl) benzoic acid (Intermediate 73,5. 51 g, 0.025 mol) and thionyl chloride (17.85 g, [11] mL, 0.15 mol) was refluxed for 1 hr. Excess thionyl chloride was distilled off at atmospheric pressure and finally at reduced pressure to give crude acid chloride. To a mixture of the crude acid chloride and 2- (p-tolylsulfonyl) ethanol (4.8 g, 0.024 mol) in dichloromethane (50 [ML)] was added triethylamine (2.52 g, 0.025 mol) at room temperature. TLC showed the reaction mixture was complete after 1 hr. The reaction mixture was washed with water (2 X 25 mL), filtered through [IPS] filter paper and concentrated under reduced pressure to give 10 g of a viscous oil. The oil was purified by flash chromatography (silica gel, 25 to 50% ethyl acetate in hexane) to give 6.1 g (63%) of the title compound as a white solid. ['L-I] NMR [(CDCL3,] 60 MHz) [6] 2.4 (s, 3H), 3.7 (t, 2H, J= 6 Hz), 4.8 [(T,] 2H, J= 6 Hz), 7.3-8. 6 (m, 8H)
With triethylamine In acetonitrile at 20℃; for 60h;
166.a
To a cooled solution of 220 mg (1 mmol) of 3-chlorosulfonyl-benzoic acid in 1 ml acetonitrile were added 745 mg (4 mmol) piperazine-1-carboxylic acid tert-butyl ester and 304 mg (3 mmol) triethylamine and then stirred at ambient temperature for 60 hours. The reaction mixture is concentrated under reduced pressure, the residue taken up in 2N NaOH and extracted with ethyl acetate. The aqueous phase is set to pH 1 with concentrated hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. 4-(3-Carboxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester was obtained as solid: MS (ISN): 368.8 ((M-H)-.).
To a suspension of 3- (chlorosulfonyl) benzoic acid (10.8 g, 49.0 mmol) in CH2Cl2 (105 mL) and three drops [OF DMF] was added oxalyl chloride (12.5 mL) and the reaction was stirred at rt overnight. The solution was concentrated in vacuo, diluted with [CH2C12] (100 mL), and the solution was divided into two reactions. A 50 mL (24.5 mmol) aliquot of the acid chloride was added to a solution of PHA-522499 (4.49 g, 25.5 mmol) dissolved in [CH2C12] (50 mL) and pyridine (3.0 [ML)] and stirred at rt overnight. The solution was diluted with MTBE, washed with 2 N HC1 and brine, concentrated, [TRITURATED WITH MTBE] to afford 7.91 g [(85%)] of methyl [2-[3-] (chlorosulfonyl) benzoyl] [AMINO}-5-CYANOBENZOATE] as a tan [SOLID. 1H NMR (400 MHZ,] [DMSO-D6)] [8] 11.73 (s, 1 H), 8.67 (d, [J=] 9 Hz, [1] H), 8.37 (d, [J=] 2 Hz, 1 H), 8.25 (s, 1 H), 8.12 (dd, J= 9,2 Hz, 1 H), 7.92 (d, J= 8 Hz, [1] H), 7. [88] (d, J= 8 Hz, 1 H), 7.60 (t, [J= 8 HZ, 1 H),] 3.93 (s, 3H).
methyl 5-cyano-2-({3-[(3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)sulfonyl]benzoyl}amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 3- (chlorosulfonyl) benzoic acid (456 mg, 2.07 mmol, Aldrich) in CH2Cl2 (15 [ML)] was added DMF (15 [UL)] followed by oxalyl chloride (270 [; J, L,] 3.10 mmol). After stirring for 1.5 hours, the solvent and excess oxalyl chloride were removed by rotary evaporation. The residue was dissolved in toluene (15 mL), and [METHYL 2-AMINO-5-CYANOBENZOATE (370 MG,] 2.10 mmol) was added. The mixture was heated in a [105 C] oil bath for 2 hours, and the toluene was then removed by rotary evaporation. The residue was dissolved in [CH2CLZ] (6 mL), and a mixture of 3,3- [DIMETHYLINDOLINE,] descrinbed by Kucerovy et al. in Synth. Commun. 1992, 22 (5), 729- 733, (342 mg, 2.32 mmol) and triethylamine (600 [-LL,] 4.31 mmol) in [CH2C12] (6 [ML)] was added. This mixture was stirred overnight and then added to a separatory funnel with 100 mL of [CH2C12.] This solution was washed with 2 X 100 [ML] of 1 M aqueous HC1 and 100 [ML] of brine. The [CH2CK WAS] evaporated in the presence of silica gel, and the product was purified by chromatography using a Biotage Flash 40 M silica cartridge with a gradient from [CHUCK] to [1 % ETOAC] in [CH2C12 AS] eluent. Yield was 728 mg of white solid as the methyl ester. The methyl ester was hydrolyzed according to method D yielding 292 mg of white [SOLID. 1H] NMR (400 MHz, DMSO-d6) [8 12.] 57 (s, [1] H), 8. [80] (d, [J=] 8.7 Hz, [1 H),] 8.41-8. 44 (m, 2 H), 8.24 (d, [J=] 7.9 Hz, 1 H), 8.09- 8.14 (m, 2 H), 7.83 (t, J= 7.9 Hz, [1] H), 7.55 (d, J= 8.1 Hz, 1 [H),] 7.24 (t, J= 7.7 Hz, 1 H), 7.18 (d, [J=] 7.7 Hz, [1] H), 7.02 (t, [J=] 7.5 Hz, [1 H),] 3.73 (s, 2 H), 1. [08] (s, 6 H).
To a stirred solution of 3-(chlorosulfonyl)benzoic acid (1.10 g, 5.00 mmol) in DCM (10 mL) was added piperidine (1.49 g, 17.5 mmol) at 0 C., and the resulting solution stirred for 30 minutes. The volatiles were then removed in vacuo and the residue treated with aqueous 1N KHSO4. The aqueous phase was then extracted with ethyl acetate (×3), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 3-(piperidin-1-ylsulfonyl)benzoic acid (1.22 g, 4.52 mmol, 90%).1H NMR (d6 DMSO): 13.54 (1H, br), 8.24 (1H, dt, J 8.0 & 1.4 Hz), 8.18 (1H, t, J 1.8 Hz), 7.97 (1H, dt, J 8.0 & 1.6 Hz), 7.79 (1H, t, J 7.7 Hz), 2.93-2.88 (4H, m), 1.58-1.50 (4H, m), 1.40-1.32 (2H, m).
90%
In dichloromethane; at 0℃; for 2h;
To a stirred solution of 3-(chlorosulfonyl) benzoic acid (0.3 g, 1.36 mmol) in DCM (5 mL) was added piperidine (0.35 g, 0.4ml, 4.08 mmol) at 0 C, and the resulting solution was stirred for 2 hours. The volatiles were then evaporated under reduced pressure and the residue treated with aqueous IN KHSO4. The aqueous phase was then extracted with ethyl acetate (x3), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 3-(piperidin-l-ylsulfonyl)benzoic acid as a white solid (0.34 g, 1.262 mmol, 90%). NMR (400MHZ, CDCL3): 8.41 (1H, br), 8.26 (1H, dt, J= 8.0Hz , 1.4 - - Hz), 7.94 (1H, dt, J= 8.0Hz , 1.6 Hz), 7.61 (1H, t, J= 7.7 Hz), 2.98-2.96 (4H, m), 1.62-1.56 (4H, m), 1.40-1.34 (2H, m). 13C NMR (100 MHz, CDC13): 170.0, 137,6, 133.9, 132.5, 130.3, 129.4, 129.2, 46.9, 25.2, 23.5.
90%
In dichloromethane; at 0℃; for 0.5h;
To a stirred solution of 3-(chlorosulfonyl)benzoic acid (1.10 g, 5.00 mmol) in DCM (10 mL) was added piperidine (1.49 g, 17.5 mmol) at 00C, and the resulting solution stirred for 30 minutes. The volatiles were then removed in vacuo and the residue treated with aqueous IN KHSO4. The aqueous phase was then extracted with ethyl acetate (x3), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 3-(piperidin-l-ylsulfonyl)benzoic acid (1.22 g, 4.52 mmol, 90%).1H NMR (d6 DMSO): 13.54 (IH, br), 8.24 (IH, dt, J 8.0 & 1.4 Hz), 8.18 (IH, t, J 1.8 Hz), 7.97 (IH, dt, J 8.0 & 1.6 Hz), 7.79 (IH, t, J 1.1 Hz), 2.93-2.88 (4H, m), 1.58-1.50 (4H, m), 1.40-1.32 (2H, m).
With triethylamine; In dichloromethane; at 20℃; for 0.5h;
Example 178 3-[[(3-Bromophenyl)methyl](methyl)amino]sulfonyl}benzoic Acid 1-(3-Bromophenyl)-N-methylmethanamine (0.100 g, 0.5 mmol) in DCM (5 mL) was added TEA (0.139 mL, 1.000 mmol) and 3-(chlorosulfonyl)benzoic acid (0.110 g, 0.500 mmol). The resulting mixture was stirred at room temperature for 0.5 h. The reaction was quenched with HCl (1 N), concentrated and redissolved in EtOAc (10 mL) which was washed with H2O (2*3 mL), brine (3 mL), then dried with Na2SO4. It was then filtered and concentrated to afford the title compound (0.1505 g, 78percent). LC-MS m/z 384 (M+H)+.
126.1 Step 1
Step 1 A solution of N,N-Diisopropylethylamine (0.0078 ml, 0.045 mmol) in THF (1 ml) is added to 4-Isobutoxy-piperidine (0.008 g, 0.05 mmol) followed by a solution of 3-(Chlorosulfonyl)benzoic acid (9.93 mg, 0.045 mmol) and shaken at room temperature for 48 hours. The solution is evaporated under vacuum to afford 3-(4-Isobutoxy-piperidine-1-sulfonyl)-benzoic acid which is used without purification; [M+H]+ 342.00.
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 48h;
126.1
Step 1 A solution of N,N-Diisopropylethylamine (0.0078 ml, 0.045 mmol) in THF (1 ml) is added to 4-Isobutoxy-piperidine (0.008 g, 0.05 mmol) followed by a solution of 3-(Chlorosulfonyl)benzoic acid (9.93 mg, 0.045 mmol) and shaken at room temperature for 48 hours. The solution is evaporated under vacuum to afford 3-(4-Isobutoxy-piperidine-1-sulfonyl)-benzoic acid which is used without purification; [M+H]+342.00
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 48h;
126.1 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [8-[3-(4-isobutoxy-piperidine-1-sulfonyl)-benzoyl]-1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide
A solution of N,N-Diisopropylethylamine (0.0078 ml, 0.045 mmol) in THF (1 ml) is added to 4-Isobutoxy-piperidine (0.008 g, 0.05 mmol) followed by a solution of 3-(Chlorosulfonyl)benzoic acid (9.93 mg, 0.045 mmol) and shaken at room temperature for 48 hours. The solution is evaporated under vacuum to afford 3-(4-Isobutoxy-piperidine-1-sulfonyl)benzoic acid which is used without purification; [M+H]+ 342.00.
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 17h;
85
3-(N-allylsulfamoyl)benzoic acid. To a solution of 3-(chlorosulfonyl)benzoic acid (5g, 22.66 mmol) in THF (50.4 mL) at 0°C was added allylamine (2.038 mL, 27.2 mmol) followed by NaOH (IN aqueous) (49.9 mL, 49.9 mmol). The mixture was allowed to warm to RT over 1 hour and stirred an additional 16 hours. The mixture was diluted with IN HC1 (250 mL), and the aqeuous layer was extracted with EtOAc (300 mL). The organic layer was dried over sodium sulfate and concentrated to dryness to afford 3-(N-allylsulfamoyl)benzoic acid as white solid (5.2 g, 95% yield). MS m/z = 242.0 [M+H]. Calc'd for Ci0H„NO4S: 241.0.
(B) Formation of the sulfonamide bonds
General procedure: Sulfonyl chloride derivative 1 or 2 (3.99mmol) was added gradually to a mixture of substituted amine (4.39mmol) and pyridine (2mL) in EtOAc with stirring at 0°C. The reaction mixture was stirred at room temperature until the TLC indicated complete conversion of the sulfonyl chloride to the sulfonamide intermediate. The reaction mixture was dissolved in DCM and extracted (2×) with 10% NaOH. After the aqueous layer was acidified with 2N HCl, the precipitate was collected by filtration, washed with H2O, and dried in vacuo to give the desired products (5-22, 173, 174), which were carried forward without further purification.
In dichloromethane at 0 - 20℃; for 12h;
3-(N-(4-Bromophenyl)-N-methylsulfamoyl)-N-(4-chlorophenyl)-N-methylbenzamide (3a); representative procedure for 3b-3e and 4a.
General procedure:To a solution of 3-(chlorosulfonyl)benzoic acid (1.0 equiv, ca. 0.1 M) in dichloromethane, 4-bromo-N-methylaniline (3.1 equiv) was slowly added at 0 C with stirring. The mixture was stirred at room temp for 12 h. The solvent was removed with a nitrogen gas stream, the mixture was treated with 1 M NaOH (> 10 equiv), and was extracted with ether three times. The aqueous fraction was then acidified with 3 M HCl to pH ~1. The mixture turned cloudy during the addition. The resulting precipitate was collected by suction filtration on a Buchner funnel, washed with distilled water, and dried overnight at reduced pressure to give 3-(N-(4-bromophenyl)-N-methylsulfamoyl)benzoic acid (7a, 50-60%), which was used without further purification. To a solution of 7a (1.0 equiv, ca. 0.1 M), was added 4-chloro-N-methylaniline (1.1 equiv), EDCI (1.3 equiv), and DMAP (0.1 equiv). The mixture was stirred at room temp for 12 h and then diluted with excess EtOAc. The organic mixture was washed with 1 M aqueous HCl (2 times), 1 M aqueous NaHCO3 (2 times), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield a crude product, which was purified by silica gel column chromatography to give 3a as a thick gel.
General procedure: Sulfonyl chloride derivative 1 or 2 (3.99mmol) was added gradually to a mixture of substituted amine (4.39mmol) and pyridine (2mL) in EtOAc with stirring at 0C. The reaction mixture was stirred at room temperature until the TLC indicated complete conversion of the sulfonyl chloride to the sulfonamide intermediate. The reaction mixture was dissolved in DCM and extracted (2×) with 10% NaOH. After the aqueous layer was acidified with 2N HCl, the precipitate was collected by filtration, washed with H2O, and dried in vacuo to give the desired products (5-22, 173, 174), which were carried forward without further purification.
In dichloromethane; at 0 - 20℃; for 12h;
General procedure:To a solution of 3-(chlorosulfonyl)benzoic acid (1.0 equiv, ca. 0.1 M) in dichloromethane, <strong>[6911-87-1]4-bromo-N-methylaniline</strong> (3.1 equiv) was slowly added at 0 C with stirring. The mixture was stirred at room temp for 12 h. The solvent was removed with a nitrogen gas stream, the mixture was treated with 1 M NaOH (> 10 equiv), and was extracted with ether three times. The aqueous fraction was then acidified with 3 M HCl to pH ~1. The mixture turned cloudy during the addition. The resulting precipitate was collected by suction filtration on a Buchner funnel, washed with distilled water, and dried overnight at reduced pressure to give 3-(N-(4-bromophenyl)-N-methylsulfamoyl)benzoic acid (7a, 50-60%), which was used without further purification. To a solution of 7a (1.0 equiv, ca. 0.1 M), was added 4-chloro-N-methylaniline (1.1 equiv), EDCI (1.3 equiv), and DMAP (0.1 equiv). The mixture was stirred at room temp for 12 h and then diluted with excess EtOAc. The organic mixture was washed with 1 M aqueous HCl (2 times), 1 M aqueous NaHCO3 (2 times), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield a crude product, which was purified by silica gel column chromatography to give 3a as a thick gel.
General procedure:To a solution of 3-(chlorosulfonyl)benzoic acid (1.0 equiv, ca. 0.1 M) in dichloromethane, 4-bromo-N-methylaniline (3.1 equiv) was slowly added at 0 C with stirring. The mixture was stirred at room temp for 12 h. The solvent was removed with a nitrogen gas stream, the mixture was treated with 1 M NaOH (> 10 equiv), and was extracted with ether three times. The aqueous fraction was then acidified with 3 M HCl to pH ~1. The mixture turned cloudy during the addition. The resulting precipitate was collected by suction filtration on a Buchner funnel, washed with distilled water, and dried overnight at reduced pressure to give 3-(N-(4-bromophenyl)-N-methylsulfamoyl)benzoic acid (7a, 50-60%), which was used without further purification. To a solution of 7a (1.0 equiv, ca. 0.1 M), was added 4-chloro-N-methylaniline (1.1 equiv), EDCI (1.3 equiv), and DMAP (0.1 equiv). The mixture was stirred at room temp for 12 h and then diluted with excess EtOAc. The organic mixture was washed with 1 M aqueous HCl (2 times), 1 M aqueous NaHCO3 (2 times), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield a crude product, which was purified by silica gel column chromatography to give 3a as a thick gel.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; for 12h;
General procedure: To a solution of 3-(chlorosulfonyl)benzoic acid (1.0 equiv, ca. 0.1 M) in dichloromethane, was added 4-bromo-N-methylaniline (2.1 equiv), EDCI (1.5 equiv), and DMAP (0.1 equiv) at 0 7 C with stirring. The resulting solution was stirred for 12 h. The mixture was diluted with an excess amount of EtOAc, washed with aqueous 1 M HCl, aqueous saturated NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography by elution with 1:4 EtOAc-hexane to give a thick gel.
To a solution of (5-amino-6-methoxypyridin-3-yl)boronic acid pinacol ester (1.0 g, 3. 99 mmol) in pyridine (13.3 mL) at 0C was added 3-(chlorosulfonyl)benzoic acid (1.11 g, 4.79 mmol). The reaction mixture was stirred at 0C for 3 h. The mixture was concentrated and the residue was purified by column chromatography (Biotage, cHex:EtOAc 100:0 to 0:100) to give Intermediate 1-01 (1.15 g, 82 %).
Stage #1: 3-Carboxybenzenesulfonyl chloride; Cyclopropylamine With triethylamine In tetrahydrofuran at 0 - 20℃; for 3h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water
1
3-(N-cylcopropylaminosulfonyl)benzoic acid (2.2):Cyclopropyl amine (0.26 g, 4.53 mmol) and triethyl amine (1.38 g, 13.6 mmol) are dissolved in tetrahydrofuran (15 ml). To this solution is added dropwise a tetrahydrofuran solution (5 mL) of 3-(chlorosulfonyl)benzoic acid (1 g, 4.53 mmol, subject compound 2.1) at 0°C. After adding, the mixture is heated up to room temperature, and stirred at room temperature for 3 h. After the reaction is completed as indicated by TLC, the reaction mixture is poured into 30 mL of saturated saline, and treated with 1 N hydrochloric acid to pH = 3. The mixture is extracted with ethyl acetate (20 mL x 2), and the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to obtain a light white solid (subject compound 2.2, 0.6 g, 55%).
Compound 102 A mixture of (5)-tetrahydrofuran-3-amine hydrochloride (11.2 g, 90.7 mmol) and NEt3 (50.5 mL, 362.6 mmol) in dry CH2CI2 (400 mL) was stirred for 5 minutes at 20 C. 3-(chlorosulfonyl)benzoic acid (20 g, 90.7 mmol) was added and the mixture was stirred overnight at 20C. The reaction mixture was washed with IN HCl (100 mL), the aqueous layer was extracted with dichloromethane (2 x 200 mL). The combined organic layers were dried over Na2S04 and the solvent was removed in vacuo, resulting in 3-[[(35)-tetrahydrofuran-3-yl]sulfamoyl]benzoic acid (16.3 g). 3-[[(35)-tetrahydro- furan-3-yl]sulfamoyl]benzoic acid (3 g, 11.058 mmol), 3-(difluoromethyl)-4-fluoro- aniline (2.1 g, 13.3 mmol) and triethylamine (3.3 g, 33 mmol) were dissolved in DMF (400 mL). PyBrOP (132705-51-2, 6.2 g , 13.3 mmol) was added at 0C. The mixture was stirred at 50C for 12 hours. The solvent was removed in vacuo and the obtained residue was purified by reversed phase high performance liquid chromatography (mobile phase: CH3CN in water (0.1% TFA) from 30% to 60%). The pure fractions were collected and neutralized with solid NaHC03. The organic solvent was removed in vacuo and the formed precipitate was filtered, washed with H20 (5 mL) and dried under high vacuum. The obtained residue was suspended in water (5 mL) and lyophilized to dryness resulting in compound 102 (2.3 g). Method A; Rt: 5.32 min. m/z : 415.2 (M+H)+ Exact mass: 414.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.53 - 1.68 (m, 1 H) 1.82 - 1.99 (m, 1 H) 3.27 - 3.42 (m, 1 H) 3.51 - 3.90 (m, 4 H) 7.26 (t, J=55 Hz, 1 H) 7.36 - 7.51 (m, 1 H) 7.80 (t, J=7.8 Hz, 1 H) 7.92 - 8.00 (m, 1 H) 8.01 - 8.08 (m, 1 H) 8.08 - 8.15 (m, 2 H) 8.25 (d, J=7.8 Hz, 1 H) 8.40 (s, 1 H) 10.75 (s, 1 H).
0.6 g
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 2h;Cooling with ice;
To an iced-cooled mixture of (5)-tetrahydrofuran-3 -amine hydrochloride (0.500 g, 4.41 mmol) and NaOH (0.485 g, 12.138 mmol) in H20 (5 mL) and THF (5 mL) 3-(chlorosulfonyl)benzoic acid (0.893 g, 4.406 mmol) was added in several portions. Then, the reaction mixture was stirred at 20C for 2 hours. The resulting mixture was diluted with H20 (10 mL) and extracted with ethyl acetate (10 mL). The pH value of aqueous layer was adjusted to 3 by adding IN HC1 and then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed by brine (10 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure resulting in (5)-3-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoic acid (0.60 g). To an ice cooled mixture of (5)-3-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoic acid (600 mg, 2.212 mmol), 4-fluoroaniline (270 mg, 2.433mmol) and HATU (1.01 g, 2.654 mmol) in DMF (5 mL) DIPEA (1.15 mL, 6.636 mmol) was added under N2 atmosphere. The resulting mixture was stirred at 20C for 2 hour. The solvent was removed in vacuo. The mixture was washed with saturated aqueous critic acid (10 mL), brine and dried over Na2S04. The solvent was removed in vacuo. The residue was purified by column chromatography over silica gel (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 10/90). The pure fractions were collected and the solvent was removed in vacuo. The residue was further purified by preparative high performance liquid chromatography over RP-18 (eluent: CH3CN in H20 from 40% to 80%, v/v; 0.06% NH4HC03 as addition). The pure fractions were collected and the volatiles were removed in vacuo. The aqueous layer was lyophilized to dryness resulting in compound 9 (0.48 g) Method A; Rt: 4.6 min. m/z : 365.2 (M+H)+ Exact mass: 364.1;[alpha]eta = +15.56 (c 0.10, MeOH); 1H NMR (400 MHz, 80C, DMSO-d6) delta ppm 10.35 (1 H, br. s), 8.32 - 8.48 (1 H, m), 8.15 - 8.32 (1 H, m), 8.03 (1 H, br. s), 7.83 - 7.94 (1 H, m), 7.68 - 7.83 (3 H, m), 7.06 - 7.31 (2 H, m), 3.70 - 3.87 (2 H, m), 3.51 - 3.70 (2 H, m), 3.32 - 3.48 (1 H, m), 1.85 - 2.04 (1 H, m), 1.59 - 1.78 (1 H, m)
General procedure: Sulfonyl chloride derivative 1 or 2 (3.99mmol) was added gradually to a mixture of substituted amine (4.39mmol) and pyridine (2mL) in EtOAc with stirring at 0C. The reaction mixture was stirred at room temperature until the TLC indicated complete conversion of the sulfonyl chloride to the sulfonamide intermediate. The reaction mixture was dissolved in DCM and extracted (2×) with 10% NaOH. After the aqueous layer was acidified with 2N HCl, the precipitate was collected by filtration, washed with H2O, and dried in vacuo to give the desired products (5-22, 173, 174), which were carried forward without further purification.
(B) Formation of the sulfonamide bonds
General procedure: Sulfonyl chloride derivative 1 or 2 (3.99mmol) was added gradually to a mixture of substituted amine (4.39mmol) and pyridine (2mL) in EtOAc with stirring at 0°C. The reaction mixture was stirred at room temperature until the TLC indicated complete conversion of the sulfonyl chloride to the sulfonamide intermediate. The reaction mixture was dissolved in DCM and extracted (2×) with 10% NaOH. After the aqueous layer was acidified with 2N HCl, the precipitate was collected by filtration, washed with H2O, and dried in vacuo to give the desired products (5-22, 173, 174), which were carried forward without further purification.
General procedure: Sulfonyl chloride derivative 1 or 2 (3.99mmol) was added gradually to a mixture of substituted amine (4.39mmol) and pyridine (2mL) in EtOAc with stirring at 0C. The reaction mixture was stirred at room temperature until the TLC indicated complete conversion of the sulfonyl chloride to the sulfonamide intermediate. The reaction mixture was dissolved in DCM and extracted (2×) with 10% NaOH. After the aqueous layer was acidified with 2N HCl, the precipitate was collected by filtration, washed with H2O, and dried in vacuo to give the desired products (5-22, 173, 174), which were carried forward without further purification.
General procedure: Sulfonyl chloride derivative 1 or 2 (3.99mmol) was added gradually to a mixture of substituted amine (4.39mmol) and pyridine (2mL) in EtOAc with stirring at 0C. The reaction mixture was stirred at room temperature until the TLC indicated complete conversion of the sulfonyl chloride to the sulfonamide intermediate. The reaction mixture was dissolved in DCM and extracted (2×) with 10% NaOH. After the aqueous layer was acidified with 2N HCl, the precipitate was collected by filtration, washed with H2O, and dried in vacuo to give the desired products (5-22, 173, 174), which were carried forward without further purification.
With ammonia In water; ethyl acetate at 0℃; for 0.5h;
In acetone for 8h; Reflux;
Synthesis of Benzamide Derivatives
General procedure: Dry benzoic acid (0.01 mol) was taken in RBF fitted with a stir bar and a Claisen adapter. The flask was cooled in a cold water bath maintained between 10 and 15 °C. Chlorosulfonic acid (8.0 mL) was added and funnel was stoppered and checked cautiously to confirm no leakage. The reaction showed exothermic reaction and when whole benzoic acid had dissolved and exothermic reaction has subsided, the reaction was completed by heating the flask using water bath at 70-80 °C for 2 hours. The reaction mixture was cooled and transferred to 150 g crushed ice with stirring to break the lumps. The precipitates were filtered using vacuum filtration followed by washing with cold water and product (3-(chlorosulphonyl)benzoic acid) was air dried. 3-(chlorosulphonyl)benzoic acid (0.01 mol) and commercially available aliphatic and aromatic amines (0.01 mol) were refluxed in acetone, until the reaction was completed as observed by TLC. The contents of the flask were cooled and precipitates of sulphonamide of benzoic acid obtained were washed and recrystallized. The different sulphonamides (0.01 mol) as obtained above and thionyl chloride (0.01 mol) were refluxed for 3 hours. On completion of reflux, the excess of thionyl chloride was distilled off to obtain the corresponding benzoyl chlorides. The respective benzoyl chlorides (0.01 mol) and available aromatic and aliphatic amines (0.015 mol) were refluxed in acetone. The final products(benzamide derivatives) received after the evaporation of acetone were purified by recrystallization using ethyl alcohol.
In acetone Reflux;
2.1. Synthesis of Phenylacetic Acid and Trifluoromethylphenyl Substituted Benzamide Derivatives
General procedure: Dry benzoic acid (0.01 mol) was taken in round-bottom flask equipped with a stirrer in an ice bath chamber and cooled with maintaining the temperature between 10 to 15 °C. Chlorosulfonic acid (8.0 mL) was added and funnel was stoppered with calcium chloride filled with cotton wool tubes and carefully checked to ensure that there was no leaking.The mixture showed exothermic reaction and when whole benzoic acid was dissolved followed by the extinction of exothermic reaction, the flask was heated in a hot water bath at 70-80 °C for 2 h to complete the reaction. The mixture was cooled and transferred to 150 g crushed ice. 3-(chlorosulphonyl)benzoic acid was collected by vacuum filtration and washed with cold water and air dried. 3-(chlorosulphonyl)benzoic acid (0.01 mol) and commercially available aliphatic aromatic, and heteroaromatic amines(0.01 mol) were refluxed in acetone and the completion of reaction was monitored by TLC to get the respective sulphonamides of benzoic acid. The reaction mixture was cooled and precipitates obtained were washed and recrystallized. The different sulphonamides obtained (0.01 mol) were refluxed with thionyl chloride (0.01 mol) for 3 h. While the refluxing got over, the excess of thionyl chloride was distilled off to get the respective benzoyl chlorides. Phenylacetic acid derivatives (1-6) were obtained by refluxing the respective benzoyl chlorides (0.01 mol) and 2-aminophenylacetic acid (0.015 mol) in methanol. The products obtained after evaporation of acetone were recrystallized with ethanol. 2-trifluoromethylphenyl benzamide derivatives(7-26) were obtained by refluxing the respective benzoyl chlorides (0.01 mol) with 2-trifluoromethylaniline (0.015mol) in acetone. The product obtained after evaporation of acetone was recrystallized with ethanol.
With ammonia In water; ethyl acetate at 0℃; for 0.5h;
In acetone Reflux;
General procedure for preparation of designed molecules
General procedure: Dry benzoic acid (1 mmol) was transferred to a flat baseflask fixed on a magnetic agitator at constant temperaturearound 10 °C. Excess of HClSO3 (8.0 mL) was addedcarefully and observed to avoid any escape. When all theacid was liquefied and the exothermic response terminated,the flat bottom flask was heated at 70-80 °C using waterbath for 2 h followed by cooling. The materials of flask werepoured to crushed ice (150 g) cautiously with stirring andcrystals of 3-(chlorosulphonyl)benzoic acid were filteredemploying vacuum subsequent to cold water wash followedby air drying. The precipitates prepared above (1 mmol)were then reacted with the corresponding aliphatic andaromatic amines (1 mmol) under reflux using acetone tillcompletion of reaction (observed using silica gel G TLC)following cooling and drying of the precipitates. The differentsulphonamides prepared above (1 mmol) wererefluxed for 3 h with sulfinyl chloride (1 mmol) and toreceive equivalent acid chlorides excess sulfinyl chloridewas withdrawn. Acid chlorides prepared above (1 mmol)were refluxed with 2-aminobenzimidazole (1.5 mmol). Theend products (compounds 1-10) obtained by the evaporationof solvent were purified using recrystallization from ethanol[28-30].
With triethylamine; In methanol; at 20 - 25℃; for 4h;Inert atmosphere;
To a solution of compound 1 (12.5 g, 71.42 mmol) in methanol (90 mL) was added triethylamine (10.5 g, 103.78 mmol) followed by 3-(chlorosulfonyl)benzoic acid (15 g, 68.181 mmol) at 20-25 C and stirred for 4 h. After completion of the reaction, the precipitated solid was filtered at the pump and dried. The crude compound was recrystallized from ethanol to obtain the pure compound 3. White solid, Yield: 18 g, 81 %; m.p.: 220-223 C; 1H NMR (500 MHz, DMSO-d6): delta 11.54 (s, 1H), 8.26 (t, J = 1.5 Hz, 1H), 8.22 (d, J = 1.5Hz, 1H), 8.02 (d, J = 6.5 Hz, 1H), 7.76 (t, J = 8.5 Hz, 1H),7.32 (d, J = 4.5 Hz, 1H), 6.86 (d, J = 5.5 Hz, 1H), 4.20 (brs, 2H), 3.42 (brs, 2H), 2.42 (brs, 2H).
3-(4-benzoxazol-2-yl-piperazin-1-sulfonyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With triethylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃;
General procedure: 2-(Piperazin-1-yl)benzazolylderivatives 5a-d (1 equivalent) and triethylamine (1.5 equivalents) were dissolved in25 mL dry CH2Cl2 and cooled to 0C in an ice salt bath. Then the required 3 or 4-Chloro-sulfonylbenzoicacid (1.1 equivalents) dissolved in 15 mL dry THF was added dropwise. After theaddition, the reaction mixture was stirred at 0C for a further 1 h and then allowed to warm toroom temperature and the course of the reaction followed by TLC (CH2Cl2/MeOH/konz. NH3:898/100/2). After indicating the end of the reaction, the mixture was evaporated to dryness, the residue was dissolved in dist. water and made slightly acidic (pH 6) with glacial acetic acid andstirred for about 30 mins. The solid formed was filtered by suction, washed with water andthen with petrol ether. The product was recrystallized from the appropriate solvent; the precipitateformed was filtered under suction and dried at 60C under high vacuum.
3-(4-benzothiazol-2-yl-piperazin-1-sulfonyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With triethylamine In tetrahydrofuran; dichloromethane at 0 - 20℃;
General synthesis of the carboxylic acid derivatives 6a-d and 7a-d
General procedure: 2-(Piperazin-1-yl)benzazolylderivatives 5a-d (1 equivalent) and triethylamine (1.5 equivalents) were dissolved in25 mL dry CH2Cl2 and cooled to 0°C in an ice salt bath. Then the required 3 or 4-Chloro-sulfonylbenzoicacid (1.1 equivalents) dissolved in 15 mL dry THF was added dropwise. After theaddition, the reaction mixture was stirred at 0°C for a further 1 h and then allowed to warm toroom temperature and the course of the reaction followed by TLC (CH2Cl2/MeOH/konz. NH3:898/100/2). After indicating the end of the reaction, the mixture was evaporated to dryness, the residue was dissolved in dist. water and made slightly acidic (pH 6) with glacial acetic acid andstirred for about 30 mins. The solid formed was filtered by suction, washed with water andthen with petrol ether. The product was recrystallized from the appropriate solvent; the precipitateformed was filtered under suction and dried at 60°C under high vacuum.
sodium 3-(N-(5-chloro-4-methyl-2-nitrophenyl)sulfamoyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With pyridine; at 20℃; for 19h;Inert atmosphere;
General procedure: This compound was prepared in 2 steps from <strong>[7149-80-6]5-chloro-4-methyl-2-nitroaniline</strong>. (a) A solution of <strong>[7149-80-6]5-chloro-4-methyl-2-nitroaniline</strong> (500mg, 2,68 mmol) in dry pyridine (5 ml) under argon is cooled in an ice bath. 3-(Chlorosulfonyl)benzoic acid (944 mg, 4.28mmol) is added and the reaction is stirred for 19 hours at room temperature. Water (1 ml) is added and the solvent is removed under reduced pressure. The yellow solid is taken up in water and 1M sodium hydroxide is added followed by ethyl acetate. After standing for a few minutes a yellow precipitate is formed. The precipitate is filtered and washed with water. Sodium 3-(N-(5-chloro-4-methyl-2-nitrophenyl)sulfamoyl)benzoate (12) is obtained as a white solid (760 mg) in 91% yield. (b) A microwave reaction vessel is charged with sodium 3-(N-(5-chloro-4-methyl-2-nitrophenyl)sulfamoyl)benzoate (12) (200 mg, 0.51 mmol), 3-furanylboronic acid (120 mg,1.02 mmol), dimethoxy ethane (4 ml), water (0.4 ml) andsodium carbonate (160 mg, 1.53 mmol). The reaction is degassed and put under argon. Pd(PPh3)4 (92 mg, 0.076 mmol)is added and the reaction is heated in the microwave for 45min at 110C. The reaction is allowed to cool to room temperature,diluted with water and extracted with ethyl acetate.The organic layer is washed with NaHCO3 solution and thecombined aqueous layers are acidified with 1M HCl to pH =2. The aqueous layer is extracted with ethyl acetate (3x). The combined organic layers are dried over magnesium sulfate,filtered and the solvent removed under reduced pressure. The crude product is purified via silica gel chromatography: dichloromethane/methanol 9/1 to 85/15. 3-(N-(5-(Furan-3-yl)-4-methyl-2-nitrophenyl)sulfamoyl)benzoic acid (106 mg) is obtained in 99% purity and 52% yield. 1H NMR (DMSO-d6,500 MHz) 10.81 (s, 1H, COOH), 8.23 (t, J = 1.6 Hz, 1H, H-8), 8.10 (dd, J = 1.0; 1.4 Hz, 1H, H-16), 7.95 (s, 1H, H-5),7.86 (td, J = 1.2; 7.7 Hz, 1H, H-18), 7.82 (m, 2H, H-2, H-20), 7.77 (s, 1H, H-11), 7.50 (t, J = 7.7 Hz, 1H, H-19), 6.88 (dd, J = 0.9; 1.9 Hz, 1H, H-3), 2.44 (s, 3H, CH3); LC-MS ESI (neg): m/z 401 [M - H]-.
With pyridine; for 19.0h;Inert atmosphere; Cooling with ice;
Stage 1 Stage 2 In a first step a solution of <strong>[40371-63-9]5-bromo-4-methyl-2-nitroaniline</strong> in dry pyridine under argon is cooled in an ice bath. 3-(chlorosulfonyl)benzoic acid is added and the reaction is stirred for 19 hours at room temperature. 1 ml water is added and the solvent is removed under reduced pressure. The yellow solid is taken up in water and 1M sodium hydroxide is added followed by EtOAc. After standing for a few minutes a yellow precipitate is formed. Intermediate is obtained as a white solid in 91% yield.
3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
475 g
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
Step 2: Preparation of 3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic Acid, Intermediate 3.1 To a suspension of <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (275 g, 2.32 mol) in DCM (2.8 L) at 0 C. was added triethylamine (1.3 L, 9.28 mol). The mixture was stirred for 10 min at 0 C. then 3-(chlorosulfonyl)benzoic acid (563 g, 2.56 mol, Arbor Chemicals) was slowly added in portions over the period of 1 h (Caution: Exotherm). The reaction mixture was stirred at rt for 3 h and then cooled to 0 C. and quenched with 1N aqueous HCl (4 L). The precipitate was collected by filtration, washed with water (2 L) and dried under vacuum to give 3-((3-cyanoazetidin-1-yl)sulfonyl)benzoic acid (475 g) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 13.65 (bs, 1H), 8.33 (d, J=7.8 Hz, 1H), 8.26 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.87 (dd, J=8.1, 7.8 Hz, 1H), 4.02 (dd, J=8.5, 5.8 Hz, 2H), 3.89 (dd, J=8.5, 5.8 Hz, 2H), 3.68-3.60 (m, 1H). LCMS-ESI (NEG) m/z: 265.0 (M-H)-.
With hydrogenchloride; N-ethyl-N,N-diisopropylamine; methylamine;
(1) To a solution of commercially available 3-chlorosulfonylbenzoic acid (2.01 g) in chloroform (30 mL), N,N-diisopropylethylamine (2.38 mL) and methylamine (9.8 mol/L methanol solution, 980 muL) were added, and the mixture was stirred at room temperature for 2 hours. Thereto, N,N-diisopropylethylamine (2.38 mL) and methylamine (9.8 mol/L methanol solution, 980 muL) were further added, and the mixture was stirred for 2 hours. Water and 2 mol/L hydrochloric acid were added thereto under ice cooling, and the resultant mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3-(methylsulfamoyl)benzoic acid (1.54 g) as a yellow powder. The obtained compound was used for the next reaction without being purified.
With triethylamine In chloroform for 1h; Inert atmosphere; Reflux;
1
Add 6g pyridine complex, 40ml chloroform, 4g prednisolone to the reaction flask,Add 5ml of triethylamine and pass in nitrogen for protection,The temperature was raised to reflux and reacted for 1 hour.It was cooled to room temperature and concentrated to dryness in vacuo.Add 100ml water to dissolve, add 34ml sodium hydroxide aqueous solution,Then add 2ml acetic acid and 100ml saturated sodium acetate aqueous solution,Precipitated in a colloidal state.Re-dissolve it in 50ml water and dilute to 100ml saturated sodium acetate aqueous solution,The precipitated product is ground and filtered, washed with saturated sodium acetate, and dried.5.5g crude product was obtained, the molar yield was 87.5%,HPLC purity is 85.9%, the crude product is recrystallized with 3 times water,Cool in the refrigerator overnight, precipitate and filter, wash with a small amount of water,3.35 g of sodium prednisolone benzoyl sulfonate was obtained by drying.The molar yield is 60.9%, and the HPLC purity is 96.5%.
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