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CAS No. : | 6339-87-3 | MDL No. : | MFCD00185853 |
Formula : | C4H5NO2S2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KTFDYVNEGTXQCV-UHFFFAOYSA-N |
M.W : | 163.22 | Pubchem ID : | 72881 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 35.31 |
TPSA : | 96.78 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.5 cm/s |
Log Po/w (iLOGP) : | 0.39 |
Log Po/w (XLOGP3) : | -0.29 |
Log Po/w (WLOGP) : | 1.48 |
Log Po/w (MLOGP) : | -0.86 |
Log Po/w (SILICOS-IT) : | 0.81 |
Consensus Log Po/w : | 0.31 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.01 |
Solubility : | 15.8 mg/ml ; 0.0967 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.28 |
Solubility : | 8.51 mg/ml ; 0.0522 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.22 |
Solubility : | 9.77 mg/ml ; 0.0598 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.67 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With ammonium hydroxide In water at 50℃; for 0.25 h; | Example 2Preparation of thiophene-2-sulphonamide[00156] Thiophene-2-sulfonyl chloride (0.5 g, 2.74 mmol) was added in a 25 percent ammonium hydroxide solution (5 ml_, 33.45 mmol) refluxing at 50 °C, and stirred for 15 minutes. The reaction mixture was filtered while boiling and the residue was washed with boiling 25percent ammonium hydroxide aqueous solution. Ammonium hydroxide solution was removed in vacuo until the ammonia smell disappeared and the target compound was re-crystallised from water (0.328 g, 77percent) as a white solid; mp 145 - 146 °C; vmax (KBr) 3290 (N-H), 3224 (N-H); δΗ (400 MHz, DMSO-de) 7.15 (1 H, dd, J 5.0, 3.7, C(4)H), 7.55 (1 H, dd, J 3.7, 1 .4, C(3)H), 7.66 (2H, s, NH2), 7.85 (1 H, dd, J 5.0, 1 .4, C(5)H); 5C (100 MHz, DMSO-d6) 127.3, 130.0, 131 .1 , 145.7; m/z (ESI") 162 ([M-H] ", 100 percent); HRMS (ESI") C4H4N02S2" ([M-H] ") requires 161 .9689; found 161 .9695. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tetraethoxy orthosilicate In ethanol at 150℃; for 6 h; | A 25 mL round bottom flask containing a mixture of A-106 (2.81 g, 13.5 mmol) and A30 107 (2.00 g, 12.3 mmol) was treated with tetraethyl orthosilicate (2.81 g, 13.5 mmol) and fittedwith a small distillation head and receiving flask. The reaction was heated to 150°C for 6 hours while ethanol was collected in the receiving flask. After cooling to room temperature, the solid formed in the reaction flask was filtered and washed with 100 ml of diethyl ether. Purification by recrystallization (from a 1:3 mixture of ethyl acetate:dichloromethane) afforded pure STF-083010 as green crystals (2.21 g, 57percent): ‘H NMR (400 MHz, CDC13) ö 12.65 (s, 1H), 9.99 (s,1H), 8.20 (d, J= 8.5 Hz, 1H), 8.00 (d, J= 9.1 Hz, 1H), 7.82 (d, J 4.5 Hz, 1H), 7.80 (d, J 8.8Hz, 1H), 7.72 (d, J= 5.0 Hz, 1H), 7.65 (t, J 7.7 Hz, 1H), 7.46 (t, J 7.5 Hz, 1H), 7.16 (d, J8.8 Hz, 1H), 7.15 (t, J 4.5 Hz, 1H)); ‘3C NMR (101 MHz, CDC13) ö 167.0, 165.9, 140.3, 139.4,134.3, 134.2, 133.5, 129.9, 129.7, 128.3, 128.1, 125.1, 119.9, 119.4 108.2; HRMS (ESI-TOF) m/z [M + H] calculated for C,5H,2N03S2 318.0259, found 318.0263. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With ammonium hydroxide; In water; at 50℃; for 0.25h; | Example 2Preparation of thiophene-2-sulphonamide[00156] Thiophene-2-sulfonyl chloride (0.5 g, 2.74 mmol) was added in a 25 % ammonium hydroxide solution (5 ml_, 33.45 mmol) refluxing at 50 C, and stirred for 15 minutes. The reaction mixture was filtered while boiling and the residue was washed with boiling 25% ammonium hydroxide aqueous solution. Ammonium hydroxide solution was removed in vacuo until the ammonia smell disappeared and the target compound was re-crystallised from water (0.328 g, 77%) as a white solid; mp 145 - 146 C; vmax (KBr) 3290 (N-H), 3224 (N-H); deltaEta (400 MHz, DMSO-de) 7.15 (1 H, dd, J 5.0, 3.7, C(4)H), 7.55 (1 H, dd, J 3.7, 1 .4, C(3)H), 7.66 (2H, s, NH2), 7.85 (1 H, dd, J 5.0, 1 .4, C(5)H); 5C (100 MHz, DMSO-d6) 127.3, 130.0, 131 .1 , 145.7; m/z (ESI") 162 ([M-H] ", 100 %); HRMS (ESI") C4H4N02S2" ([M-H] ") requires 161 .9689; found 161 .9695. |
With hydrogenchloride; ammonium hydroxide; In methanol; | Step 1: 2-Thiophenesulfonamide (vi). At 0 C., a concentrated solution of ammonium hydroxide (50 mL, 1.35 mol) was added to a solution of 2-thiophenesulfonyl chloride (50 g, 0.27 mol) in methanol (300 mL). The mixture was stirred at room temperature overnight, cooled in an ice bath, and a concentrated solution of HCl was added until the pH reached 7. The resultant solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford 45 g of a brownish solid. Trituration with methylene chloride-hexanes (1:1) afforded the title compound: 1H NMR (300 MHz, CD3OD) deltaH 7.73 (m, 1H), 7.59 (m, 1H), 7.05 (m, 1H). | |
EXAMPLE 6 Preparation of N-[[(4-chlorophenyl)amino]carbonyl]-2-thiophenesulfonamide The procedure of Example 4A was followed with thiophenesulfonylchloride (5 g) to provide 4.2 g of white solid, 2-thiophenesulfonamide. |
With hydrogenchloride; ammonium hydroxide; In methanol; | Step 1: 2-Thiophenesulfonamide (vi). At 0 C., a concentrated solution of ammonium hydroxide (50 mL, 1.35 mol) was added to a solution of 2-thiophenesulfonyl chloride (50 g, 0.27 mol) in methanol (300 mL). The mixture was stirred at room temperature overnight, cooled in an ice bath, and a concentrated solution of HCl was added until the pH reached 7. The resultant solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford 45 g of a brownish solid. Trituration with methylene chloride-hexanes (1:1) afforded the title compound: 1H NMR (300 MHz, CD3OD) deltaH 7.73 (m, 1 H), 7.59 (m, 1 H), 7.05 (m, 1 H). | |
With hydrogenchloride; ammonium hydroxide; In methanol; | Step 1: 2-Thiophenesulfonamide (vi). At 0 C., a concentrated solution of ammonium hydroxide (50 mL, 1.35 mol) was added to a solution of 2-thiophenesulfonyl chloride (50 g, 0.27 mol) in methanol (300 mL). The mixture was stirred at room temperature overnight, cooled in an ice bath, and a concentrated solution of HCl was added until the pH reached 7. The resultant solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford 45 g of a brownish solid. Trituration with methylene chloride-hexanes (1:1) afforded the title compound: 1H NMR (300 MHz, CD3OD) deltaH 7.73 (m, 1 H), 7.59 (m, 1 H), 7.05 (m, 1 H). | |
With hydrogenchloride; ammonium hydroxide; In methanol; | Step 1: 2-Thiophenesulfonamide (vi). At 0 C., a concentrated solution of ammonium hydroxide (50 mL, 1.35 mol) was added to a solution of 2-thiophenesulfonyl chloride (50 g, 0.27 mol) in methanol (300 mL). The mixture was stirred at room temperature overnight, cooled in an ice bath, and a concentrated solution of HCl was added until the pH reached 7. The resultant solution was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford 45 g of a brownish solid. Trituration with methylene chloride-hexanes (1:1) afforded the title compound: 1H NMR (300 MHz, CD3OD) deltaH 7.73 (m, 1 H), 7.59 (m, 1 H), 7.05 (m, 1 H). | |
EXAMPLE 26; Preparation of 2-thiophenesulfonamide; Prepared from 2-thiophenesulfonyl chloride ( purchased from Aldrich) using the method of Justus Liebigs Ann. Chem., 501, 1933, p.174-182. | ||
Preparation of 2-thiophenesulfonamide The desired product was prepared from 2-thiophenesulfonyl chloride (purchased from Aldrich) using the method described in Justus Liebigs Ann. Chem. 1933, 501, p. 174-182. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; | The procedure of Example 4B was followed with 2-thiophenesulfonamide (4.2 g, 26 mmole) in 40 ml of acetone, 1N NaOH (26 ml, 26 mmole) and 4-chlorophenyl isocyanate (4.0 g, 26 mmole) in 40 ml of acetone. 7 g of named product were obtained PMR (CD3 SOCD3) 10.88 (bs, 1H), 9.07 (s, 1H), 8.04 (d, J=4 Hz, 1H), 7.84 (d, J=4 Hz, 1H), 7.45 (d, J=9 Hz, 2H), 7.34 (d, J=9 Hz, 2H) and 7.23 (dd, J=4,4 Hz, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole; | In the same manner as in Example 1, 3-(2,4-dichlorobenzyl)-2-methyl-5-(2-thiophenesulfonylcarbamoyl)benzo[b]furan (0.33 g) was obtained as white crystals from 5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]furan (0.335 g), N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and 2-thiophene-sulfonamide (0.33 g). 1H-NMR(DMSO-d6, delta ppm): 2.39(3H, s), 4.07(2H, s), 7.15-7.21(2H, m), 7.32(1H, dd, J=8.3 and 2.3 Hz), 7.58(1H, d, J=8.6 Hz), 7.63(1H, d, J=2.2 Hz), 7.78(1H, dd, J=8.6 and 1.8 Hz), 7.83(1H, dd, J=3.7 and 1.1 Hz), 7.95(1H, d, J=1.6 Hz), 8.02(1H, dd, J=4.9 and 0.9 Hz), 12.57(1H, brs). IR(Nujol): 1703 cm-1 mp: 198-199 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; dimethyl sulfoxide; at 20℃; | A mixture of the acid I-7 (170 mg, 0.84 mmol), 2-thiophenesulfonamide (163 mg, 1 mmol), 4-dimethylamino pyridine (207 mg, 1.7 mmol) and EDCI (325 mg, 1.7 mmol) in dichloromethane (20 ml) and DMSO (0.5 ml) was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with methanol/CH2Cl2 as an eluent to give 170 mg of compound I-8. 1H-NMR (500 MHz, DMSO-d6) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; dimethyl sulfoxide; at 20℃; | Synthesis of Thiophene-2-sulfonic acid [(E)-3-(5-fluoro-1H-indol-7-yl)-acryloyl]-amide, I-32. A mixture of the acid I-31 (180 mg, 0.88 mmol), 2-thiophenesulfonamide (172 mg, 1.2 mmol), 4-dimethylamino pyridine (215 mg, 1.77 mmol) and EDCI (336 mg, 1.77 mmol) in dichloromethane (20 ml) and DMSO (0.5 ml) was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with methanol/CH2Cl2 as an eluent to give 150 mg of the sulphonamide I-32. 1H-NMR (500 MHz, DMSO-d6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | A mixture of the acid I-41 (32 mg, 0.085 mmol), 2-thiophenesulfonamide (16 mg, 0.1 mmol), 4-dimethylamino pyridine (21 mg, 0.17 mmol) and EDCI (33 mg, 0.17 mmol) in dichloromethane (5 ml) was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq. (2×10 ml), water (4×10 ml), brine and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with dichloromethane and methanol/dichloromethane as eluents to give 20 mg of compound P160. 1H NMR (CDCl3) 1.90 (d, J=22 Hz, 3H), 5.20 (d, J=16 Hz, 1H), 5.33 (d, J=16 Hz, 1H), 6.02 (d, J=15.0 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 7.15 (m, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.44 (m, 2H), 7.50 (d, J=7 Hz, 1H), 7.70 (m, 2H), 7.75 (m, 2H), 7.87 (s, 1H), 7.92 (m, 1H), 8.00 (d, J=15.0 Hz, 1H). LC/MS (93%) ESI- Calcd. 519.6 m/z Found: 519.3 m/z |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h; | Synthesis of N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-2-oxo-2-(thiophen-2-sulfonylamino)-acetamide, P019: A mixture of N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-oxalamic acid, I-62 (52 mg, 0.14 mmol), thiophene sulfonamide (28 mg, 0.17 mmol), EDCI (33 mg, 0.17 mmol), DMAP (22 mg, 0.17 mmol) in methylene chloride was stirred at room temperature for 24 h. Reaction was diluted with chloroform (10 mL) and washed with 6.0 M HCl (3.0 mL*4), water (3.0 mL). Chloroform layer was concentrated and the residue was purified over silica gel with chloroform:methanol (90:10) as eluant to afford N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-2-oxo-2-(thiophen-2-sulfonylamino)-acetamide, P019 (7.0 mg). 1H NMR (500 MHz, DMSO-d6) 4.59 (s, 2H), 5.35 (s, 2H), 6.84 (dd, J=8.0, 1.5 Hz, 1H), 6.90 (dd, J=8.0, 8.0 Hz, 1H), 7.02 (m, 2H), 7.06 (dd, J=5.0, 3.5 Hz, 1H), 7.44 (m, 1H), 7.56 (s, 1H), 7.61 (dd, J=3.5, 1.5 Hz, 1H), 7.71-7.65 (m, 3H), 7.78 (m, 1H), 10.05 (s, 1H). MS (ESI-) Calcd. (M+) 521.6; Found: 520.7 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 48h; | A solution of (4-naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)-acetic acid, I-64 (102 mg, 0.281 mmol), thiophen-2-sulfonamide (46 mg, 0.281 mmol), EDCI (40 mg, 0.33 mmol), DMAP (40 mg, 0.33 mmol) in CH2Cl2 was stirred at room temperature for 48 h. Reaction mixture was diluted with CH2Cl2 (30.0 mL) and washed with 6N HCl (5 mL*3), water (5 mL), dried (brine, Na2SO4) concentrated and the residue obtained was purified over silica gel with Chloroform:methanol (95:5) as eluant to afford thiophen-2-sulfonic acid[2-(4-naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamino)-acetyl]-amide, P049 (16 mg). 1H NMR (500 MHz, DMSO-d6) 3.76 (s, 2H), 4.48 (s, 2H), 5.39 (s, 2H), 5.52 (br s, 1H), 6.11 (dd, J=8.5, 1.0 Hz, 1H), 6.32 (dd, J=8.5, 1.0 Hz, 1H), 6.74 (t, J=8.5 Hz, 1H), 7.12 (m, 2H), 7.44 (m, 2H), 7.60 (s, 1H), 7.73-7.67 (m, 2H), 7.79 (m, 1H), 7.90 (d, J=4.5 Hz, 1H), 12.45 (br s, 1H). LC/MS=93.8% purity, MS (ESI-) Calcd. (M+) 511.6; Found: 511.5 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | To a mixture of the acid I-73 (36 mg, 0.1 mmol), 2-thiophenesulfonamide (20 mg, 0.12 mmol), 4-dimethylamino pyridine (25 mg, 0.2 mmol) in dichloromethane (5 ml), was added EDCI (38 mg, 0.2 mmol). The reaction mixture was stirred at r.t. over night. The solution was diluted with dichloromethane, washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, the solid was washed with ether to give 35 mg of compound P004. 1H NMR (DMSO-d6) 4.36 (s, 2H), 6.06 (s, 2H), 6.74 (d, J=9 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.16 (m, 2H), 7.34 (d, J=7 Hz, 1H), 7.38-7.42 (m, 3H), 7.63-7.72 (m, 3H), 7.81 (m, 1H), 7.95 (m, 2H). LC/MS (90%) ESI- Calcd. 503.6 m/z Found: 503.4 m/z |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; dimethyl sulfoxide; at 20℃; | To a mixture of the acid I-76 (25 mg, 0.07 mmol), 2-thiophenesulfonamide (14 mg, 0.084 mmol), 4-dimethylamino pyridine (18 mg, 0.15 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was added EDCI (29 mg, 0.15 mmol). The reaction mixture was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, the solid was washed with ether to give 30 mg of compound P-12. 1H-NMR (500 MHz, DMSO-d6), MS (ESI-): 503.3 (M-1), LC-MS: 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; dimethyl sulfoxide; at 20℃; | To a mixture of the acid I-84 (25 mg, 0.07 mmol), 2-thiophenesulfonamide (16 mg, 0.1 mmol), 4-dimethylamino pyridine (24 mg, 0.2 mmol) in dichloromethane (6 ml) and DMSO (0.5 ml) was added EDCI (38 mg, 0.2 mmol). The reaction mixture was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with dichloromethane and 2% methanol/dichloromethane as the eluant to give 7 mg of P015. 1H NMR (DMSO-d6) 1.81 (m, 2H), 2.78 (t, J=6.5 Hz, 2H), 3.03 (m, 2H), 3.62 (s, 2H), 5.12 (s, 2H), 6.66 (d, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.79 (m, 1H), 6.87 (m, 1H), 7.19 (m, 1H), 7.35 (m, 1H), 7.43 (m, 1H), 7.49 (m, 2H), 7.62 (m, 1H), 7.72 (m, 2H), 7.82 (m, 3H). LC/MS (97%) ESI- Calcd. 491.6 m/z Found: 491.2 m/z |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; dimethyl sulfoxide; at 20℃; | A mixture of the acid I-94 (35 mg, 0.1 mmol), 2-thiophenesulfonamide (20 mg, 0.12 mmol), 4-dimethylamino pyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with methanol/dichloromethane as the eluent to give 35 mg of P050. MS (ESI-): 487.4 (M-1), LC-MS: 87%, 1H-NMR (500 MHz, DMSO-d6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; dimethyl sulfoxide; at 20℃; | A mixture of the acid I-97 (37 mg, 0.1 mmol), 2-thiophenesulfonamide (20 mg, 0.12 mmol), 4-dimethylamino pyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with methanol/dichloromethane as the eluent to give 32 mg of compound P051. MS (ESI-): 511.4 (M-1), LC-MS: 89%, 1H-NMR (500 MHz, DMSO-d6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; dimethyl sulfoxide; at 20℃; | A mixture of the acid I-103 (33 mg, 0.1 mmol), 2-thiophenesulfonamide (20 mg, 0.12 mmol), 4-dimethylamino pyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with methanol/dichloromethane as the eluent to give 37 mg of compound P053. 1H NMR (DMSO-d6) 2.11 (s, 3H), 2.24 (s, 3H), 4.58 (s, 2H), 5.13 (s, 2H), 6.69 (m, 2H), 6.92 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 7.04 (m, 2H), 7.18 (m, 1H), 7.73 (m, 1H), 8.01 (m, 1H), 12.5 (bs, 1H). LC/MS (88%) ESI- Calcd. 471.5 m/z Found: 471.4 m/z |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h; | Synthesis of P096. To a mixture of I-106 (21 mg, 0.059 mmol, 1 equiv.) in 0.5 mL dichloromethane were added DMAP (19 mg, 0.157 mmol, 2.6 equiv.), 2-thiophenesulfonamide (13 mg, 0.078 mmol, 1.3 equiv.), and EDCI (30 mg, 0.157 mmol, 2.6 equiv.). The mixture was stirred at room temperature for 16 hours and then quenched with 10% HCl and extracted with EtOAc-CH2Cl2. The extract was washed with water, brine, and then dried over MgSO4. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (2 mL) and filtered. Chromatography on SiO2 (5 g) with EtOAc/Hex (1:1) afforded 10 mg (33%) of sulfonamide P096 as off-white solid. LC-MS (ESI-): 501 (M-1) (98%). 1H-NMR (500 MHz, CDCl3) confirmed the structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 72h; | To a round bottom flask (25 mL) which contained a solution of 2-thiophenesulfonamide, (28 mg, 0.17 mmol), 4-dimethyaminopyridine (DMAP, 23 mg, 0.3 mmol) and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 40 mg, 0.4 mmol) in c (5 mL) was added acrylic acid I-21 (60 mg, 0.16 mmol) at rt. The mixture which resulted was allowed to stir at rt for 72 h, then was cooled to 0 C. After the addition of MeOH (1 mL) and water (5 mL), the reaction mixture was acidified with addition of aq HCl (10%) until pH=1 which was followed by extraction with CH2Cl2/MeOH (9/1, 3×5 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, CH2Cl2/EtOAc/hexane=1:1:4, EtOAc) to afford desired product P085 (35 mg, 40% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3); 2.53 (s, 3H), 5.53 (s, 2H), 6.20 (d, J=15.0 Hz, 1H), 6.42 (d, J=8.5 Hz, 1H), 7.07 (dd, J=8.0, 3.0 Hz, 1H), 7.16 (t, J=4.5 Hz, 1H), 7.26-7.30 (m, 2H), 7.41 (d, J=2.0 Hz, 1H), 7.69 (s, 1H), 7.74 (dd, J=5.5, 1.5 Hz, 1H), 7.91-7.94 (m, 2H), 8.57 (dd, J=7.0, 2.0 Hz, 1H). LC/MS (78%) ESI- Calcd.: 533.5 m/z, found: 535.1 m/z (M). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 72h; | To a round bottom flask (25 mL) which contained a solution of 2-thiophenesulfonamide (9 mg, 0.05 mmol), 4-dimethyaminopyridine (DMAP, 20 mg, 0.2 mmol) and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 25 mg, 0.3 mmol) in c (5 mL) was added acrylic acid I-25 (9 mg, 0.03 mmol) at rt. The mixture which resulted was allowed to stir at rt for 72 h, then was cooled to 0 C. After the addition of MeOH (1 mL) and water (5 mL), the reaction mixture was acidified with addition of aq HCl (10%) until pH=1 which was followed by extraction with CH2Cl2/MeOH (9/1, 3×5 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, CH2Cl2/EtOAc/hexane=1:1:4, EtOAc) to afford desired target P069 (6.3 mg, 45% yield) as a light yellow solid. 1H NMR (500 MHz, methanol-d4); 5.70 (s, 2H), 6.13 (d, J=15.0 Hz, 1H), 6.36 (d, J=8.5 Hz, 1H), 7.09-7.11 (m, 2H), 7.23 (m, 1H), 7.29-7.35 (m, 2H), 7.60 (m, 1H), 7.70 (m, 1H), 7.89-7.94 (m, 2H), 8.34 (dd, J=9.0, 1.5 Hz, 1H), 9.95 (s, 1H). LC/MS (71%) ESI- Calcd.: 519.4 m/z, found: 517.4 m/z (M-2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 48h; | To a round bottom flask (25 mL) which contained a solution of 2-thiophenesulfonamide (35 mg, 0.15 mmol), 4-dimethyaminopyridine (DMAP, 45 mg, 0.5 mmol) and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 60 mg, 0.6 mmol) in CH2Cl2 (5 mL) was added acrylic acid I-27 (25 mg, 0.07 mmol) at rt. The resulting mixture was allowed to stir at rt for 48 h, then was cooled to 0 C. After the addition of MeOH (1 mL) and water (5 mL), the reaction mixture was acidified with addition of aq HCl (10%) until pH=1 which was followed by extraction with CH2Cl2 (3×5 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, CH2Cl2, EtOAc/hexane=1:1, EtOAc) to afford P062 (16 mg, 35% yield) as an off-white solid. MS(ESI-) m/z=519.3, (M-2); LCMS(ESI-)>85%. 1H-NMR (500 MHz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 48h; | To a round bottom flask (25 mL) which contained a solution of 2-thiophenesulfonamide (15 mg, 0.09 mmol), 4-dimethyaminopyridine (DMAP, 20 mg, 0.2 mmol) and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 25 mg, 0,25 mmol) in CH2Cl2 (5 mL) was added acrylic acid I-29 (10 mg, 0.025 mmol) at rt. The resulting mixture was allowed to stir at rt for 48 h, then was cooled to 0 C. After the addition of MeOH (1 mL) and water (5 mL), the reaction mixture was acidified with addition of aq HCl (10%) until pH=1 which was followed by extraction with CH2Cl2 (3×5 mL). The combined organic layers were dried over anhydrous Na2SO4) and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, CH2Cl2, EtOAc/hexane=1:1) to afford P070 (1.5 mg, 10% yield) as an off-white solid. 1H NMR (500 MHz, methanol-d4); 3.39 (s, 3H), 4.67 (s, 2H), 5.70 (s, 2H), 6.16 (d, J=15.5 Hz, 1H), 6.36 (d, J=9.5 Hz, 1H), 7.05 (dd, J=8.0, 3.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 7.20 (m, 1H), 7.25 (m, 1H), 7.31 (m, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.84-7.87 (m, 2H), 7.91 (d, J=15.0 Hz, 1H). LC/MS (78%) ESI- Calcd.: 535.5 m/z, found: 535.0 m/z (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; dimethyl sulfoxide; at 20℃; | A mixture of the acid I-89 (35 mg, 0.1 mmol), 2-thiophenesulfonamide (20 mg, 0.12 mmol), 4-dimethylamino pyridine (25 mg, 0.2 mmol) and EDCI (38 mg, 0.2 mmol) in dichloromethane (5 ml) and DMSO (0.5 ml) was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, the solid was washed with ether to give 30 mg of compound P046. MS (ESI-): 493.4 (M-1), LC-MS: 81%, 1H-NMR (500 MHz, DMSO-d6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 48h; | To a round bottom flask (25 mL) which contained a solution of thiophenesulfonamide (17 mg, 0.11 mmol), 4-dimethyaminopyridine (DMAP, 20 mg, 0.2 mmol) and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 23 mg, 0.3 mmol) in CH2Cl2 (2 mL) was added acrylic acid I-54 (26 mg, 0.11 mmol) at rt. The mixture which resulted was allowed to stir at rt for 2d, then was cooled to 0 C. After the addition of MeOH (2 mL) and water (10 mL), the reaction mixture was acidified with addition of aq HCl (10%) until pH=1 which was followed by extraction with CH2Cl2/MeOH (9/1, 3×10 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, CH2Cl2/EtOAc/hexane=1:1:4, EtOAc) to afford desired product P219 (23 mg, 45%) as a white solid. MS(ESI-)m/z(505.2, M-2); LCMS(ESI-)>95%. 1H-NMR (500 MHz, DMSO-d6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 48h; | To a round bottom flask (25 mL) which contained a solution of thiophene-2-sulfonamide (17 mg, 0.11 mmol), 4-dimethyaminopyridine (DMAP, 20 mg, 0.2 mmol) and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 23 mg, 0.3 mmol) in CH2Cl2 (2 mL) was added acrylic acid I-53 (40 mg, 0.1 mmol) at rt. The mixture which resulted was allowed to stir at rt for 2d, then was cooled to 0 C. After the addition of MeOH (2 mL) and water (10 mL), the reaction mixture was acidified with addition of aq HCl (10%) until pH=1 which was followed by extraction with CH2Cl2/MeOH (9/1, 3×10 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, CH2Cl2/EtOAc/hexane=1:1:4, EtOAc) to afford desired acylsulphonamide P216 (15 mg, 25%) as a white solid. 1H NMR (500 MHz, acetone-d6); 5.04 (s, 2H), 6.15 (d, J=15.0 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H), 7.25-7.27 (m, 2H), 7.33 (t, J=8.6 Hz, 1H), 7.38 (d, J=15.5 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.81 (d, J=4.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 8.10 (d, J=4.0 Hz, 1H). LC/MS (92%) ESI- Calcd.: 543.4 m/z, found: 541.4 m/z (M-2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | To a mixture of the acid I-68 (140 mg, 0.38 mmol), 2-thiophenesulfonamide (76 mg, 0.45 mmol), 4-dimethylamino pyridine (94 mg, 0.77 mmol) in dichloromethane (8 ml), was added EDCI (147 mg, 0.77 mmol). The reaction mixture was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq., water, brine and dried over sodium sulfate. After removal of solvent, the solid was washed with ether to give 135 mg of compound P018. MS (ESI-): 507.5 (M-1), LC-MS: 83%, 1H-NMR (500 MHz, DMSO-d6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | Synthesis of Thiophene-2-sulfonic acid [(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)-acryloyl]-amide, I-35. A mixture of the acid I-34 (100 mg, 0.46 mmol), 2-thiophenesulfonamide (90 mg, 0.55 mmol), 4-dimethylamino pyridine (112 mg, 0.92 mmol) and EDCI (176 mg, 0.92 mmol) in dichloromethane (10 ml) was stirred at rt over night. The solution was diluted with dichloromethane, washed with diluted HCl aq. and water. The resulted solid was filtered and solid washed with water, dichloromethane to give 55 mg of compound 4. The remain dichloromethane mother liquid was purified by column chromatography on silica gel with methanol/CH2Cl2 as an eluent to give 45 mg of acylsulphonamide I-35. Total 100 mg of compound I-35 was obtained. 1H-NMR (500 MHz, DMSO-d6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | To a mixture of the acid I-69 (1.11 g, 5 mmol), 2-thiophenesulfonamide (913 mg, 5.5 mmol), 4-dimethylamino pyridine (1.22 g, 10 mmol) in dichloromethane (200 ml), was added EDCI (1.91 g, 10 mmol). The reaction mixture was stirred at rt over night. The solution was diluted with water and adjusted pH to acidic by adding HCl aq. (2N). The resulted solid was filtered and washed with diluted HCl aq. water, CH2Cl2 and ether. After drying, 1.6 g of compound I-70 was obtained as a white solid. 1H-NMR (500 MHz, DMSO-d6). MS (ESI-): 367.2 (M-1), LC-MS: 96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h; | To a mixture of the acid, I-105 (71 mg, 0.177 mmol, 1 equiv.) in 2 mL dichloromethane were added DMAP (43 mg, 0.354 mmol, 2 equiv.), 2-thiophenesulfonamide (37 mg, 0.225 mmol), and EDCI (82 mg, 0.425 mmol). The mixture was stirred at room temperature for 16 hours and then quenched with NH4Cl (6 mL). The mixture was then extracted with EtOAc (6 mL). The extract was washed with brine, and then dried over MgSO4. The solvent was removed in vacuo. Trituration of the residue with ether (2 mL) afforded 86 mg (86%) of sulfonamide P083 as off-white solid. LC-MS (ESI-): 545 (M-1) (81%). 1H-NMR (500 MHz, CDCl3) confirmed the structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 48h; | 2-Methyl-3-naphthalen-2-ylmethyl-1H-benzoimidazol-4-yloxy)-acetic acid (77 mg, 2.2 mmol), thiophen-2-sulfonamide (36 mg, 2.2. mmol), EDCI (47 mg, 0.25 mmol), DMAP (30 mg, 2.5 mmol) in methylene chloride (2.0 mL) was stirred at room temperature for 48 h. Reaction mixture was concentrated and the residue was purified over silica gel with chloroform:methanol (97:3) as eluant to afford thiophen-2-sulfonic acid [2-(2-methyl-3-naphthalen-2-ylmethyl-3H-benzoimidazol-4-yloxy)-acetyl] amide, P037 (5.2 mg). 1H NMR (500 MHz, CD3OD) 2.47 (s, 3H), 4.50 (s, 2H), 5.86 (s, 2H), 6.60 (d, J=8.0 Hz. 1H), 6.91 (dd, J=5.0, 4.0 Hz, 1H), 7.06 (dd, J=8.5, 8.0 Hz, 1H), 7.26 (m, 2H), 7.32 (s, 1H), 7.36 (dd, J=5.0, 1.0 Hz, 1H), 7.45-7.40 (m, 3H), 7.51 (dd, J=3.5, 1.0 Hz, 1H), 7.68 (m, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.70 (m, 1H). LC/MS=95.7% purity, MS (ESI-) Calcd. (M+) 491.5; Found: 490.5 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diaza-bicyclo-undecene; 1,1'-carbonyldiimidazole; | EXAMPLE 78 Production of 3-(2,4-dichlorobenzyl)-2-methyl-5-(2-thiophenesulfonylcarbamoyl)indole (107) According to the method of Example 59, obtained is 3-(2,4-dichlorobenzyl)-2-methyl-5-(2-thiophenesulfonylcarbamoyl)indole (107) (0.226 g) from 5-carboxy-3-(2,4-dichlorobenzyl)-2-methylindole (0.334 g), N,N'-carbonyldiimidazole (0.275 g), diazabicycloundecene (0.258 g) and 2-thiophenesulfonamide (0.277 g). 1H-NMR (DMSO-d6, delta ppm): 2.28 (3H, s), 4.07 (2H, s), 6.91 (1H, d, J=8.4 Hz), 7.18 (1H, t, J=4.2 Hz), 7.25 (1H, dd, J=2.2 and 8.4 Hz), 7.32 (1H, d, J=8.5 Hz), 7.58 (1H, dd, J=1.6 and 8.6 Hz), 7.61 (1H, d, J=2.1 Hz), 7.82 (1H, dd, J=1.0 and 3.8 Hz), 8.00 (2H, m), 11.39 (1H, brs), 12.31 (1H, brs). IR (Nujol): 1690 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 21 2-ethyl-5,7-dimethyl-3-(4-{2-[([(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl) -3H-imidazo[4,5-b]pyridine The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 2-thiophenesulfonamide (Huang, H. C.; Reinhard, E. J.; Reitz, D. B. Tetrahedron Lett., 1994, 35, 7201.; Graham, S. L.; Scholz, T. H. Synthesis, 1986, 1031). 1H-NMR (CDCl3) delta8.01 (1H, s), 7.78 (1H, dd, J=1.3, 4.9 Hz), 7.63 (1H, dd, J=1.3, 4.9 Hz), 7.22 (2H, d, J=8.3 Hz), 7.14 (2H, d, J=8.3 Hz), 7.09 (1H, dd, J=3.8, 5.0 Hz), 6.92 (1H, s), 6.05 (1H, t, J=5.3 Hz), 3.53 (2H, q, J=6.2 Hz), 2.96 (3H, s), 2.88 (3H, s), 2.87 (2H, t, J=6.2 Hz), 2.67 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.43 (3H, s), 1.20 (3H, t, J=7.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetyl chloride; | Step 1: [2-Phenyl-1-(thiophene-2-sulfonylamino)-ethyl-phosphonic Acid Diethyl Ester (xii). To a suspension of sulfonamide (vi) (500 mg; 0.31 mmol) in acetyl chloride (5 mL) was slowly added diethyl phosphite (400 muL; 0.31 mmol). The reaction was cooled to 0 C. and then phenylacetaldehyde (450 muL; 0.39 mmol) was added dropwise. The reaction was gradually warmed to ambient temperature and after 6 hrs the homogeneous solution was concentrated. The residue was diluted with dichloromethane (25 mL) then washed successively with water (10 mL), saturated sodium bicarbonate (10 mL) and brine (10 mL). The combined organic extracts wre dried (MgSO4), evaporated and initially purified by flash chromatography (ethyl acetate-hexanes; 3:2). A second purification by flash chromatography (acetone-hexanes; 3:7) yielded diethyl phosphonate (xii) (437 mg, 35%) as a colorless solid; 1H NMR (400 MHz, CDCl3) deltaH 1.22 (t, J=7 Hz, 3H, OCH2CH3), 1.26 (t, J=7 Hz, 3H, OCH2CH3), 2.89 (dt, J=8, 14 Hz, 1H, CHPh), 3.12 (dt, J=6, 14 Hz, 1H. CHPh), 3.96-4.23 (m, 5H, NCHP and OCH2CH3), 6.38 (dd, J=2, 9.5 Hz, 1H, NH), 6.92-6.93 (m, 1H, Ar-H), 7.12-7.20 (m, 5H, Ar-H), 7.33-7.34 (m, 1H, Ar-H), 7.43-7.45 (m, 1H, Ar-H). | |
In acetyl chloride; | Step 1: [2-Phenyl-1-(thiophene-2-sulfonylamino)-ethyl]-phosphonic acid diethyl ester (xii). To a suspension of sulfonamide (vi) (500 mg; 0.31 mmol) in acetyl chloride (5 mL) was slowly added diethyl phosphite (400 muL; 0.31 mmol). The reaction was cooled to 0 C. and then phenylacetaldehyde (450 muL; 0.39 mmol) was added dropwise. The reaction was gradually warmed to ambient temperature and after 6 hrs the homogeneous solution was concentrated. The residue was diluted with dichloromethane (25 mL) then washed successively with water (10 mL), saturated sodium bicarbonate (10 mL) and brine (10 mL). The combined organic extracts wre dried (MgSO4), evaporated and initially purified by flash chromatography (ethyl acetate-hexanes; 3:2). A second purification by flash chromatography (acetone-hexanes; 3:7) yielded diethyl phosphonate (xii) (437 mg, 35%) as a colorless solid; 1H NMR (400 MHz, CDCl3) deltaH 1.22 (t, J=7 Hz, 3 H, OCH2CH3), 1.26 (t, J=7 Hz, 3 H, OCH2CH3), 2.89 (dt, J=8, 14 Hz, 1 H, CHPh), 3.12 (dt, J=6, 14 Hz, 1 H, CHPh), 3.96-4.23 (m, 5 H, NCHP and OCH2CH3), 6.38 (dd, J=2, 9.5 Hz, 1 H, NH), 6.92-6.93 (m, 1 H, Ar-H), 7.12-7.20 (m, 5 H, Ar-H), 7.33-7.34 (m, 1 H, Ar-H), 7.43-7.45 (m, 1 H, Ar-H). | |
In acetyl chloride; | Step 1: [2-Phenyl-1-(thiophene-2-sulfonylamino)-ethyl]-phosphonic Acid Diethyl Ester (xii). To a suspension of sulfonamide (vi) (500 mg; 0.31 mmol) in acetyl chloride (5 mL) was slowly added diethyl phosphite (400 muL; 0.31 mmol). The reaction was cooled to 0 C. and then phenylacetaldehyde (450 muL; 0.39 mmol) was added dropwise. The reaction was gradually warmed to ambient temperature and after 6 hrs the homogeneous solution was concentrated. The residue was diluted with dichloromethane (25 mL) then washed successively with water (10 mL), saturated sodium bicarbonate (10 mL) and brine (10 mL). The combined organic extracts were dried (MgSO4), evaporated and initially purified by flash chromatography (ethyl acetate-hexanes; 3:2). A second purification by flash chromatography (acetone-hexanes; 3:7) yielded diethyl phosphonate (xii) (437 mg, 35%) as a colorless solid; 1H NMR (400 MHz, CDCl3) deltaH 1.22 (t, J=7 Hz, 3 H, OCH2CH3), 1.26 (t, J=7 Hz, 3 H, OCH2CH3), 2.89 (dt, J=8, 14 Hz, 1 H, CHPh), 3.12 (dt, J=6, 14 Hz, 1 H, CHPh), 3.96-4.23 (m, 5 H, NCHP and OCH2CH3), 6.38 (dd, J=2, 9.5 Hz, 1 H, NH), 6.92-6.93 (m, 1 H, Ar-H), 7.12-7.20 (m, 5 H, Ar-H), 7.33-7.34 (m, 1 H, Ar-H), 7.43-7.45 (m, 1 H, Ar-H). |
In acetyl chloride; | Step 1: [2-Phenyl-1-(thiophene-2-sulfonylamino)-ethyl]-phosphonic Acid Diethyl Ester (xii). To a suspension of sulfonamide (vi) (500 mg; 0.31 mmol) in acetyl chloride (5 mL) was slowly added diethyl phosphite (400 muL; 0.31 mmol). The reaction was cooled to 0 C. and then phenylacetaldehyde (450 muL; 0.39 mmol) was added dropwise. The reaction was gradually warmed to ambient temperature and after 6 hrs the homogeneous solution was concentrated. The residue was diluted with dichloromethane (25 mL) then washed successively with water (10 mL), saturated sodium bicarbonate (10 mL) and brine (10 mL). The combined organic extracts wre dried (MgSO4), evaporated and initially purified by flash chromatography (ethyl acetate-hexanes; 3:2). A second purification by flash chromatography (acetone-hexanes; 3:7) yielded diethyl phosphonate (xii) (437 mg, 35%) as a colorless solid; 1H NMR (400 MHz, CDCl3) deltaH 1.22 (t, J=7 Hz, 3 H, OCH2CH3), 1.26 (t, J=7 Hz, 3 H, OCH2CH3), 2.89 (dt, J=8, 14 Hz, 1 H, CHPh), 3.12 (dt, J=6, 14 Hz, 1 H, CHPh), 3.96-4.23 (m, 5 H, NCHP and OCH2CH3), 6.38 (dd, J=2, 9.5 Hz, 1 H, NH), 6.92-6.93 (m, 1 H, Ar-H), 7.12-7.20 (m, 5 H, Ar-H), 7.33-7.34 (m, 1 H, Ar-H), 7.43-7.45 (m, 1 H, Ar-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With phosphorous acid trimethyl ester; paraformaldehyde;sodium methylate; In methanol; dichloromethane; | Step 2: [(2-Thiophenesulfonylamino)methyl]phosphonic Acid Dimethyl Ester (vii). To a solution of 2-thiophenesulfonamide (vi) (1.0 g, 6.1 mmol) in methanol (5 mL) was added a catalytic amount of sodium methoxide and paraformaldehyde (200 mg, 6.7 mmol). The reaction was heated to 55 C. for 1 h, and then the homogeneous solution was cooled and trimethyl phosphite (0.8 mL, 6.8 mmol) was added. After heating the reaction mixture for an additional 1 h at 55 C., the reaction mixture was cooled and concentrated. The residue was dissolved in dichloromethane (15 mL), washed with water (10 mL), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (elution with methanol-chloroform; 1:19) yielded (vii) (600 mg, 34%) as a colorless solid: 31P NMR: (162 MHz, CDCl3) deltaP 23.7. Also isolated was the corresponding N-methylated compound, [(2-thiophenesulfonyl-N-methylamino)methyl]-phosphonic acid dimethyl ester (234 mg, 13%) as a colorless solid: 13C NMR (100 MHz, CDCl3) deltaC 36.7, 44.6 (d, J=165 Hz), 53.2 (d, J=6.5 Hz), 127.6, 132.4, 132.6, 135.7. |
13% | With phosphorous acid trimethyl ester; paraformaldehyde;sodium methylate; In methanol; dichloromethane; | Step 2: [(2-Thiophenesulfonylamino)methyl]phosphonic acid dimethyl ester (vii). To a solution of 2-thiophenesulfonamide (vi) (1.0 g, 6.1 mmol) in methanol (5 mL) was added a catalytic amount of sodium methoxide and paraformaldehyde (200 mg, 6.7 mmol). The reaction was heated to 55 C. for 1 h, and then the homogeneous solution was cooled and trimethyl phosphite (0.8 mL, 6.8 mmol) was added. After heating the reaction mixture for an additional 1 h at 55 C., the reaction mixture was cooled and concentrated. The residue was dissolved in dichloromethane (15 mL), washed with water (10 mL), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (elution with methanol-chloroform; 1:19) yielded (vii) (600 mg, 34%) as a colorless solid: 31P NMR: (162 MHz, CDCl3) deltaP 23.7. Also isolated was the corresponding N-methylated compound, [(2-thiophenesulfonyl-N-methylamino)methyl]-phosphonic acid dimethyl ester (234 mg, 13%) as a colorless solid: 13C NMR (100 MHz, CDCl3) deltaC 36.7, 44.6 (d, J=165 Hz), 53.2 (d, J=6.5 Hz), 127.6, 132.4, 132.6, 135.7. |
13% | With phosphorous acid trimethyl ester; paraformaldehyde;sodium methylate; In methanol; dichloromethane; | Step 2: [(2-Thiophenesulfonylamino)methyl]phosphonic Acid Dimethyl Ester (vii). To a solution of 2-thiophenesulfonamide (vi) (1.0 g, 6.1 mmol) in methanol (5 mL) was added a catalytic amount of sodium methoxide and paraformaldehyde (200 mg, 6.7 mmol). The reaction was heated to 55 C. for 1 h, and then the homogeneous solution was cooled and trimethyl phosphite (0.8 mL, 6.8 mmol) was added. After heating the reaction mixture for an additional 1 h at 55 C., the reaction mixture was cooled and concentrated. The residue was dissolved in dichloromethane (15 mL), washed with water (10 mL), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (elution with methanol-chloroform; 1:19) yielded (vii) (600 mg, 34%) as a colorless solid: 31P NMR: (162 MHz, CDCl3) deltaP 23.7. Also isolated was the corresponding N-methylated compound, [(2-thiophenesulfonyl-N-methylamino)methyl]-phosphonic acid dimethyl ester (234 mg, 13%) as a colorless solid: 13C NMR (100 MHz, CDCl3) deltaC 36.7, 44.6 (d, J=165 Hz), 53.2 (d, J=6.5 Hz), 127.6, 132.4, 132.6, 135.7. |
13% | With phosphorous acid trimethyl ester; paraformaldehyde;sodium methylate; In methanol; dichloromethane; | Step 2: [(2-Thiophenesulfonylamino)methyl]phosphonic Acid Dimethyl Ester (vii). To a solution of 2-thiophenesulfonamide (vi) (1.0 g, 6.1 mmol) in methanol (5 mL) was added a catalytic amount of sodium methoxide and paraformaldehyde (200 mg, 6.7 mmol). The reaction was heated to 55 C. for 1 h, and then the homogeneous solution was cooled and trimethyl phosphite (0.8 mL, 6.8 mmol) was added. After heating the reaction mixture for an additional 1 h at 55 C., the reaction mixture was cooled and concentrated. The residue was dissolved in dichloromethane (15 mL), washed with water (10 mL), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (elution with methanol-chloroform; 1:19) yielded (vii) (600 mg, 34%) as a colorless solid: 31P NMR: (162 MHz, CDCl3) deltaP 23.7. Also isolated was the corresponding N-methylated compound, [(2-thiophenesulfonyl-N-methylamino)methyl]-phosphonicAciddimethyl ester (234 mg, 13%) as a colorless solid: 13C NMR (100 MHz, CDCl3) deltaC 36.7, 44.6 (d, J=165 Hz), 53.2 (d, J=6.5 Hz), 127.6, 132.4, 132.6, 135.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; triethylamine; 1,1'-carbonyldiimidazole; In 1,2-dichloro-ethane; | EXAMPLE 2 N-(2-Thienylsulfonyl)-1-methylpyrazole-4-carboxamide 3.8 g of <strong>[5952-92-1]1-methylpyrazole-4-carboxylic acid</strong> and 4.9 g of carbonyldiimidazole in 100 ml of 1,2-dichloroethane are heated at 55° C. for 3.5 h. 4.9 g of 2-thienylsulfonamide and 5.4 ml of triethylamine are added and then the mixture is heated at 55° C. for 13 h. After cooling, 40 ml of 10percent strength aqueous NaOH solution are added and then the pH of the aqueous phase is adjusted to 1. The precipitate is removed and dried under reduced pressure. 5.2 g of N-(2-thienylsulfonyl)-1-methylpyrazole-4-carboxamide with a melting point of 174°-180° C. are obtained (active ingredient Example No. 103). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In acetone; | EXAMPLE 20 Preparation of N-[[(3,4-dichlorophenyl)amino]carbonyl]-2-thiophenesulfonamide <strong>[6339-87-3]2-Thiophenesulfonamide</strong> (1.55 g, 9.5 mmole) was combined with 3,4-dichlorophenyl isocyanate (1.79 g, 9.5 mmole), 1N NaOH (9.5 ml) and acetone (25 ml) followed by 1N HCl (9.5 ml) using the method of Example 4B to give the named product (1.3 g). PMR (CD3 SOCD3) 9.22 (s, 1H), 8.02 (dd, J=2,6 Hz, 1H), 7.82 (dd, J=2,6 Hz, 1H), 7.76 (d, J=3 Hz, 1H), 7.52 (d, J=9 Hz, 1H), 7.34 (dd, J=3,9 Hz, 1H) and 7.02 (dd, J=6,6 Hz, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step b N-[(1-Oxo-2-oxo-2-chloro)ethyl]-(2-thiophene)sulfonamide Combine (2-thiophene)sulfonamide (1.04g, 6.4mmol) and oxalyl chloride (15mL) and reflux for 9 hours. Evaporate the excess oxalyl chloride in vacuo to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; paraformaldehyde; In tetrahydrofuran; nitrogen; | [2] In a nitrogen stream, 8.5 g of the thiophenesulfonamide obtained in the preceding step [1] was dissolved in a solvent mixture comprising 80 ml of dried ethyl ether and 20 ml of dried tetrahydrofuran, and the solution was cooled to -70 C. Then, 77 ml of a n-butyllithium solution (1.55 M) was dropwise added thereto at a temperature of -50 C. or lower. Then, the mixture was reacted at -70 C. for 1 hour. To this reaction product, 100 ml of dried tetrahydrofuran was added. Then, 3.5 g of paraformaldehyde was quickly added thereto at a temperature of -50 C. or lower, and the temperature was gradually raised to room temperature. Then, the mixture was reacted at room temperature for 3 hours. After the completion of the reaction, the reaction product was poured into water, then acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developer: ethyl acetate/hexane=2/3) to obtain 2.98 g of N-tert-butyl-2-hydroxymethyl-3-thiophenesulfonamide as an oily substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; paraformaldehyde; In tetrahydrofuran; nitrogen; | [2] In a nitrogen stream, 2.0 g of the thiophenesulfonamide obtained in the preceding step [1] was dissolved in a solvent mixture comprising 20 ml of dried ethyl ether and 15 ml of dried tetrahydrofuran, and the solution was cooled to -70 C. Then, 9.5 ml of a n-butyllithium solution (1.55 M) was dropwise added at a temperature of -50 C. or lower, and the mixture was reacted at -70 C. for 1 hour. To the reaction product, 15 ml of dried tetrahydrofuran was added, and then 0.6 g of paraformaldehyde was quickly added at a temperature of -50 C. or lower. Then, the temperature was gradually raised to room temperature, and the mixture was reacted at room temperature for 1 hour. After the completion of the reaction, the reaction product was poured into water, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The extract layer was washed with water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developer: ethyl acetate/hexane=1/1) to obtain 1.1 g of N-tert-butyl-4-hydroxymethyl-3-thiophenesulfonamide as an oily substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In trifluoroacetic acid; | [4] 0.33 g of the thiophenesulfonamide obtained in the preceding step [3] was dissolved in 5 ml of trifluoroacetic acid, and reacted at room temperature for 16 hours. After the completion of the reaction, the reaction product was poured into water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract layer was washed with water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer: methylene chloride) to obtain 0.12 g of 3-(2-chloroethoxymethyl)-2-thiophenesulfonamide as oily substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 5,5-dimethyl-1,3-cyclohexadiene; | [2] 372 mg of the thiophenesulfonamide obtained in the preceding step [1] and three drops of n-butyl isocyanate were dissolved in 30 ml of dried xylene, and phosgen was supplied at a refluxing temperature. When the temperature in the flask reached 95 C., the supply of phosgen was stopped, and the reaction was continued at that temperature for 30 minutes. After the completion of the reaction, the reaction product was cooled, and the solvent was distilled off under reduced pressure to obtain 3-(2,2,2-trifluoroethoxymethyl)-2-thiophenesulfonyl isocyanate as a yellow oily substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In trifluoroacetic acid; | [5] 2.2 g of the thiophenesulfonamide obtained in the preceding step [4] was dissolved in 20 ml of trifluoroacetic acid, and reacted at 0 C. for 5 hours. After the completion of the reaction, the reaction product was poured into water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract layer was washed with water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developer: ethyl acetate/hexane=1/1) to obtain 1.21 g of 2-(2-fluoroethoxymethyl)-3-thiophenesulfonamide having a melting point of from 61 to 64 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In trifluoroacetic acid; | [5] 0.7 g of the thiophenesulfonamide obtained in the preceding step [4] was dissolved in 5 ml of trifluoroacetic acid, and reacted at 0 C. for 2 hours. After the completion of the reaction, the reaction product was poured into water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract layer was washed with water, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developer: ethyl acetate/hexane=1/1) to obtain 0.4 g of 4-(2-fluoroethoxymethyl)-3-thiophenesulfonamide having a melting point of from 63.5 to 65.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dichloro-ethane; | Step 3 2-Thiophenesulfonyl isocyanate A mixture of 2-thiophenesulfonylamide (1.5 g) and oxalyl chloride (6 mL) in 10 mL of 1,2-dichloroethane was refluxed for 14 h. The solvent was removed under vacuum and the crude used as is for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8. Preparation of 2-thiophene Sulfonamide Prepared from 2-thiophene sulfonylchloride which was purchased from Aldrich using the method of Steinkopf and Hoepner, Justus Liebigs Ann. Chem., 501, 1933, p.174-182. | ||
Preparation of 2-thiophenesulfonamide The desired product was prepared from 2-thiophenesulfonyl chloride (purchased from Aldrich) using the method described in Justus Liebigs Ann. Chem. 1933, 501, p. 174-182. | ||
Preparation of 2-thiophenesulfonamide The desired product was prepared from 2-thiophenesulfonyl chloride (purchased from Aldrich) using the method described in Justus Liebigs Ann. Chem., 501:174-182 (1933). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Example 9; Thiophene-2-sulfonic acid [17-(6-methoxy-2-phenylpyrimidin-4-yloxy)-13-methyl- 2,14-dioxo-3J3-diaza-tricyclo[13.3.0.0*4,6*loctadec-7-ene-4-carbonyll-amide (9) Compound 7e (27 mg, 0.05 mmol) was dissolved in DCM (3 ml). EDAC (12 mg, 0.06 mmol) was added and the reaction mixture was stirred at RT for 1 h. thiofen- 2-sulfonic amide (9 mg, 0.055 mmol) and DBU ( 16 mul, 0.105 mmol) were added and the reaction mixture was stirred at RT for 2 h. Citric acid (5%) was added, the organic layer was separated, washed with brine, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound. (30 mg, 88 %), MS (M+H)+ 680. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate; In dimethyl sulfoxide; at 60℃; for 24h; | To a solution of <strong>[75806-86-9]2-bromo-5-chloro-3-nitro-pyridine</strong> (CAS RN: 75806-86-9, 360 mg, 1.5 mmol) in DMSO (2 ml) was added thiophene-2-sulfonic acid amide (CAS RN: 6339-87-3, 165 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol). The mixture was stirred at 60C for 24 h, diluted with EtOAc, extracted with 1 M HCl, brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0%-100% EtOAc in hexanes) to yield Intermediate 9 (245 mg, 77%) as light brown solid. 1H NMR (METHANOL-d4) delta: 8.57 - 8.63 (m, 2H), 7.95 (dd, J = 4.0, 1.3 Hz, 1 H), 7.86 (dd, J = 5.0, 1.5 Hz, 1H), 7.14 (dd, J = 5.1, 4.0 Hz, 1H). |
Tags: 6339-87-3 synthesis path| 6339-87-3 SDS| 6339-87-3 COA| 6339-87-3 purity| 6339-87-3 application| 6339-87-3 NMR| 6339-87-3 COA| 6339-87-3 structure
[ 100342-30-1 ]
N-tert-Butyl-2-thiophenesulfonamide
Similarity: 0.72
[ 155731-14-9 ]
5-Chlorothiophene-2-sulfonic acid tert-butylamide
Similarity: 0.62
[ 286932-39-6 ]
N-tert-Butyl 5-bromo-2-thiophenesulfonamide
Similarity: 0.61
[ 100342-30-1 ]
N-tert-Butyl-2-thiophenesulfonamide
Similarity: 0.72
[ 155731-14-9 ]
5-Chlorothiophene-2-sulfonic acid tert-butylamide
Similarity: 0.62
[ 286932-39-6 ]
N-tert-Butyl 5-bromo-2-thiophenesulfonamide
Similarity: 0.61
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