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CAS No. : | 56542-67-7 | MDL No. : | MFCD00203480 |
Formula : | C7H4ClNO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BHNRGBRMCNHNQD-UHFFFAOYSA-N |
M.W : | 201.63 | Pubchem ID : | 2801360 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 44.24 |
TPSA : | 66.31 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.32 cm/s |
Log Po/w (iLOGP) : | 1.4 |
Log Po/w (XLOGP3) : | 1.7 |
Log Po/w (WLOGP) : | 2.57 |
Log Po/w (MLOGP) : | 0.88 |
Log Po/w (SILICOS-IT) : | 1.29 |
Consensus Log Po/w : | 1.57 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.47 |
Solubility : | 0.691 mg/ml ; 0.00343 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.71 |
Solubility : | 0.395 mg/ml ; 0.00196 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.03 |
Solubility : | 0.188 mg/ml ; 0.000933 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.15 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3261 |
Hazard Statements: | H314-H317 | Packing Group: | Ⅱ |
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 |
---|---|---|
45% | Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; Stage #2: With sulfur dioxide; copper(l) chloride In water; acetic acid at 0℃; for 1.17 h; |
3-Aminobenzonitrile (2.5g, 21 mmol) was dissolved in conc. HCl (20 mL) and water (20 mL), cooled to 0 °C and a solution of sodium nitrite (1.5 g, 22 mmol) in water (5 mL) was added dropwise. The reaction mixture was stirred for 10 min to complete the diazonium salt formation. In a separate flask was added copper(I) chloride (0.2g) over a saturated solution of sulfur dioxide in AcOH (25 mL) and stirred at 0 °C for 10 min. The resulting solution was added dropwise to the diazonium salt and stirred at 0 °C for 1 h. The reaction mixture poured into ice water and the product was extracted with tert-butylmethylether. The combined organic layer was washed with water and brine. The crude product was purified by column chromatography (silica gel 60-120 mesh using 5percent EtOAc in petroleum ether) to get the pure 3-cyanobenzene-1-sulfonyl chloride (1.9 g, yield 45percent) as an off-white solid. 1H NMR (300MHz, CDCl3) δ 8.35 (t, J = 1.5 Hz, 1 H), 8.31-8.27 (m, 1 H), 8.06-8.02 (m, 1 H), 7.82 (t, J = 7.9 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With ammonia In water; acetonitrile at 20℃; | NH4OH (22ml_, excess) can be added to a solution of 3-cyanobenzene-l-sulfonyl chloride (1.Og, 4.97mmol) in acetonitrile (22ml_) and the reaction stirred overnight at r.t. The reaction can be concentrated and the solid obtained washed with water to give 500mg of product. The water phase can be extracted with AcOEt, dried with MgSO4 anh, filtered and evaporated to give 400mg of product that can be combined with the solid obtained before (0.90g,99percent). |
82% | With ammonia In 1,4-dioxane at 20℃; for 0.5 h; | Step 1: 3-cyanobenzenesulfonamideTo a solution of ammonia in dioxane (0.5 M in dioxane; 50 ml 25 mmol) was added a solution of 3-cyanobenzene-1-sulfonyl chloride (ABCR; 605 mg; 3 mmol) in dioxane (10 ml_) and the mixture was allowed to stir at RT for 30 min. The solvent was removed in vacuo to give the title compound as a white solid (450 mg; 82percent). 1H NMR: (DMSOd6, 400MHz) δ 8.25 (1 H, t, J = 1.7 Hz), 8.18-8.12 (2H, m), 7.85 (1 H, t, J = 7.9 Hz), 7.63 (2H, br s). LC/MS (Method C): 181 (M+H)+. HPLC (Method E) Rt 2.42 min (Purity: 99.3percent). |
75% | for 1 h; | A solution of 3-cyano-benzenesulfonyl chloride (1.07 g) in ammonia (33percent aqueous solution, 40 mL) was stirred for 1 h and then evaporated under reduced pressure to approx. 20 mL and cooled. The precipitate was filtered and washed with water and dried in vaccuo to afford the intermediate (722 mg; 75percent) as a colourless solid. [MH]+=183. |
75% | With ammonia In water at 20℃; for 1 h; | A solution of commercially available 3-cyano-benzenesulfonyl chloride (1.07 g) in a 33percent solution of NH3 in H2O (40 mL) was stirred at room temperature for 1 h, then concentrated to ~ 20 mL and placed in an ice bath. The formed precipitate was separated by filtration, washed with H2O and dried in vacuo to afford the title compound as a colorless solid (722 mg, 75percent). [MH]+ = 183. |
56.6% | With ammonia In methanol at 20℃; for 0.5 h; Inert atmosphere; Cooling with ice | r under the protection, 3-cyanobenzenesulfonyl chloride (400 mg, 2. Ommo 1) Excess ammonia methanol solution (3.5 mL, 17.5 mmol) Ice bath to room temperature reaction, 0.5h after stopping the reaction, steaming solution, adding 10mL of ice water, DCM extracted four times, combined organic phase, recrystallized pale yellow solid (206mg 56.6percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridine In dichloromethane at 20℃; | General procedure: A mixture of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine (3.3 mmol) and pyridine (736 mg, 9.3 mmol) was stirred overnight at room temperature in abs dichloromethane (40 mL). After removal of the solvent at reduced pressure, nitriles B were obtained by flash column chromatography (dichloromethane) and recrystallisation from ethyl acetate/hexane or toluene.#10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With ammonia; In water; acetonitrile; at 20℃; | NH4OH (22ml_, excess) can be added to a solution of 3-cyanobenzene-l-sulfonyl chloride (1.Og, 4.97mmol) in acetonitrile (22ml_) and the reaction stirred overnight at r.t. The reaction can be concentrated and the solid obtained washed with water to give 500mg of product. The water phase can be extracted with AcOEt, dried with MgSO4 anh, filtered and evaporated to give 400mg of product that can be combined with the solid obtained before (0.90g,99%). |
82% | With ammonia; In 1,4-dioxane; at 20℃; for 0.5h; | Step 1: 3-cyanobenzenesulfonamideTo a solution of ammonia in dioxane (0.5 M in dioxane; 50 ml 25 mmol) was added a solution of 3-cyanobenzene-1-sulfonyl chloride (ABCR; 605 mg; 3 mmol) in dioxane (10 ml_) and the mixture was allowed to stir at RT for 30 min. The solvent was removed in vacuo to give the title compound as a white solid (450 mg; 82%). 1H NMR: (DMSOd6, 400MHz) delta 8.25 (1 H, t, J = 1.7 Hz), 8.18-8.12 (2H, m), 7.85 (1 H, t, J = 7.9 Hz), 7.63 (2H, br s). LC/MS (Method C): 181 (M+H)+. HPLC (Method E) Rt 2.42 min (Purity: 99.3%). |
75% | With ammonia; water; for 1h; | A solution of 3-cyano-benzenesulfonyl chloride (1.07 g) in ammonia (33% aqueous solution, 40 mL) was stirred for 1 h and then evaporated under reduced pressure to approx. 20 mL and cooled. The precipitate was filtered and washed with water and dried in vaccuo to afford the intermediate (722 mg; 75%) as a colourless solid. [MH]+=183. |
75% | With ammonia; In water; at 20℃; for 1h; | A solution of commercially available 3-cyano-benzenesulfonyl chloride (1.07 g) in a 33% solution of NH3 in H2O (40 mL) was stirred at room temperature for 1 h, then concentrated to ~ 20 mL and placed in an ice bath. The formed precipitate was separated by filtration, washed with H2O and dried in vacuo to afford the title compound as a colorless solid (722 mg, 75%). [MH]+ = 183. |
56.6% | With ammonia; In methanol; at 20℃; for 0.5h;Inert atmosphere; Cooling with ice; | r under the protection, 3-cyanobenzenesulfonyl chloride (400 mg, 2. Ommo 1) Excess ammonia methanol solution (3.5 mL, 17.5 mmol) Ice bath to room temperature reaction, 0.5h after stopping the reaction, steaming solution, adding 10mL of ice water, DCM extracted four times, combined organic phase, recrystallized pale yellow solid (206mg 56.6%) |
With ammonia; In tetrahydrofuran; water; at 20℃; for 0.5h; | To 3-cyanobenzene sulfonyl chloride (0.37 g, 1.81 mmol) in THF (3 mL), ammonium hydroxide (28% in water, 0.13 g, 3.62 mmol) was added. The reaction was stirred at rt for 30 min. Water was added and the product was extracted with EtOAc. After drying over Na2SO4, the solvent was evaporated to give 0.3 g of Intermediate 5S a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridine; In dichloromethane; at 20℃; | General procedure: A mixture of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine (3.3 mmol) and pyridine (736 mg, 9.3 mmol) was stirred overnight at room temperature in abs dichloromethane (40 mL). After removal of the solvent at reduced pressure, nitriles B were obtained by flash column chromatography (dichloromethane) and recrystallisation from ethyl acetate/hexane or toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In dichloromethane; water; at 0℃; for 0.5h; | Example 97; 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide; Step 1; A flask containing DCM (90 niL) and methylamine in water (40 wt%, 7.5 mmol) is chilled in an ice water bath with magnetic stirring: 3-Cyano-benzenesulfonyl chloride (5 g, 2.49 mmol) is added along with DCM (1OmL) to wash down the sides of the flask. After 30 min, concentrated HCl in water is added at O0C, until the reaction is acidic (pH < 4). Water (50 mL) is added and DCM is removed in vacuo. The residue is filtered to afford 3-cyano-N-methyl-benzenesulfonamide as a solid (99%). MS: 195 (M+H); 1HNMR (300 MHz, CDCl3): delta 2.76 (d, 3H), 4.48 (broad-s, N-H), 7.7 (t, IH), 7.9 (d, IH), 8.13 (d, IH), 8.19 (s, IH). |
In methanol; at 0 - 35℃; | Example 4; 5-chloro-2-imino-1-[3-(methylsulfamoyl)benzyl]-1,2-dihydropyridine-3-carboxamide hydrochloride; (Step 1); To a 40% methylamine methanol solution (5 ml) was added <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (0.88 g) at 0 C., and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure. 10% Palladium carbon powder (0.46 g) was added to a solution (10 ml) of the residue in ethanol, and the mixture was stirred overnight under a hydrogen atmosphere (1 atm). The solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) to give 3-(aminomethyl)-N-methylbenzenesulfonamide (0.38 g) as a colorless oil. 1H NMR (300 MHz, CDCl3) delta ppm 1.70 (2H, br. s.), 2.68 (3H, d, J=4.9 Hz), 3.86 (2H, s), 4.88 (1H, br. s.), 7.39-7.62 (2H, m), 7.76 (1H, dt, J=7.5, 1.6 Hz), 7.89 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine; In dichloromethane; at 20℃; | General procedure: A mixture of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine (3.3 mmol) and pyridine (736 mg, 9.3 mmol) was stirred overnight at room temperature in abs dichloromethane (40 mL). After removal of the solvent at reduced pressure, nitriles B were obtained by flash column chromatography (dichloromethane) and recrystallisation from ethyl acetate/hexane or toluene. |
With triethylamine; In tetrahydrofuran; at 20℃; for 18h; | Preparation 25 N-Benzyl-3-cyanobenzenesulfonamide Benzylamine (1.17g, 10mmol) was added to a solution of 3-cyanobenzene sulphonyl chloride (2g, 10mmol) and triethylamine (3.45ml, 25mmol) in tetrahydrofuran (30ml) and the mixture stirred at room temperature for 18 hours. The mixture was diluted with water (30ml), and extracted with ethyl acetate (50ml). The organic extract was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a solid, 2.53g. 1H NMR (CD3OD, 400MHz) delta: 4.17(s, 2H), 7.17(m, 5H), 7.62(dd, 1H), 7.88(d, 1H), 8.02(m, 2H). LRMS: m/z APCI+ 271 [M+H+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | 3-Aminobenzonitrile (2.5g, 21 mmol) was dissolved in conc. HCl (20 mL) and water (20 mL), cooled to 0 C and a solution of sodium nitrite (1.5 g, 22 mmol) in water (5 mL) was added dropwise. The reaction mixture was stirred for 10 min to complete the diazonium salt formation. In a separate flask was added copper(I) chloride (0.2g) over a saturated solution of sulfur dioxide in AcOH (25 mL) and stirred at 0 C for 10 min. The resulting solution was added dropwise to the diazonium salt and stirred at 0 C for 1 h. The reaction mixture poured into ice water and the product was extracted with tert-butylmethylether. The combined organic layer was washed with water and brine. The crude product was purified by column chromatography (silica gel 60-120 mesh using 5% EtOAc in petroleum ether) to get the pure 3-cyanobenzene-1-sulfonyl chloride (1.9 g, yield 45%) as an off-white solid. 1H NMR (300MHz, CDCl3) delta 8.35 (t, J = 1.5 Hz, 1 H), 8.31-8.27 (m, 1 H), 8.06-8.02 (m, 1 H), 7.82 (t, J = 7.9 Hz, 1 H). | |
With hydrogenchloride; sulfur dioxide; sodium hydrogencarbonate; sodium nitrite;copper(I) chloride; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; diethyl ether; hexane; water; acetic acid; | Production Example 13 3-Cyanobenzenesulfonyl Chloride To a mixed solution of 200 ml of water and 250 ml of concentrated hydrochloric acid was added 25.0 g (212 mmol) of 3-cyanoaniline followed by stirring. An aqueous solution (80 ml) of 15.5 g (223 mmol) of sodium nitrite was added dropwise thereinto at -10 C. The reaction solution was added to acetic acid saturated with sulfur dioxide (prepared by saturating sulfur dioxide in 250 ml of acetic acid followed by adding 2.1 g of cuprous chloride) under ice-cooling and stirring. After 1 hour, the reaction solution was poured onto 500 ml of ice water and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and brine successively, and dried over magnesium sulfate. The solvent was evaporated, a mixed solution of diethyl ether and hexane was added to the residue and the crystals were collected by filtration to give 16.0 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm); 7.55(1H,t,J=8.0 Hz), 7.78(1H,dd,J=8.0,1.2 Hz), 7.86-7.92(2H,m). | |
With hydrogenchloride; sulfur dioxide; acetic acid; sodium nitrite;copper(I) chloride; In ice-water; diethyl ether; hexane; water; | Production Example 13 3-Cyanobenzenesulfonyl chloride 25.0 g (212 mmol) of 3-cyanoaniline was added to a mixed solution of 200 ml of water and 250 ml of concentrated hydrochloric acid and the mixture was stirred. An aqueous solution (80 ml) containing 15.5 g (223 mmol) of sodium nitrite was added dropwise into the mixture at -10C. The reaction solution was added to a sulfur dioxide saturated acetic acid solution (solution prepared by saturating 250 ml of acetic acid with sulfur dioxide and then adding 2.1 g of cuprous chloride thereto) under ice-cooling with stirring. After one hour, the reaction solution was poured into 500 ml of ice-water and extracted with diethyl ether. The extract was successively washed with an aqueous saturated sodium bicarbonate, water and brine, and dried over magnesium sulfate. The solvent was evaporated, and to the residue was added a mixed solution of diethyl ether and hexane. The crystals were collected by filtration, to give 16.0 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm): 7.55 (1H, t, J=8.0Hz), 7.78 (1H, dd, J=8.0, 1.2Hz), 7.86-7.92 (2H, m) |
With concentrated hydrochloric acid; sulfur dioxide; acetic acid; sodium nitrite;copper(I) chloride; In ice-water; diethyl ether; hexane; water; | PRODUCTION EXAMPLE 13 3-Cyanobenzenesulfonyl Chloride 25.0 g (212 mmol) of 3-cyanoaniline was added to a mixed solution of 200 ml of water and 250 ml of concentrated hydrochloric acid and the mixture was stirred. An aqueous solution (80 ml) containing 15.5 g (223 mmol) of sodium nitrite was added dropwise into the mixture at -10 C. The reaction solution was added to a sulfur dioxide saturated acetic acid solution (solution prepared by saturating 250 ml of acetic acid with sulfur dioxide and then adding 2.1 g of cuprous chloride thereto) under ice-cooling with stirring. After one hour, the reaction solution was poured into 500 ml of ice-water and extracted with diethyl ether. The extract was successively washed with an aqueous saturated sodium bicarbonate, water and brine, and dried over magnesium sulfate. The solvent was evaporated, and to the residue was added a mixed solution of diethyl ether and hexane. The crystals were collected by filtration, to give 16.0 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm): 7.55 (1H, t, J=8.0 Hz), 7.78 (1H, dd, J=8.0, 1.2 Hz), 7.86-7.92 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With 4-methyl-morpholine; In dichloromethane; at 0 - 20℃; for 6h; | To a solution of the 6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (28 mg, 0.068 mmol), which had been obtained in Example 351, in dichloromethane (0.5 ml) were successively added N-methylmorpholine (0.015 ml, 0.14 mmol) and <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (22 mg, 0.10 mmol) at 0C. The resulting mixture was stirred at room temperature for 6 hours. After washing with 1N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography and a fraction obtained from the elution portion with hexane:ethyl acetate = 7:3 was concentrated under reduced pressure. The solid thus obtained was washed with hexane and collected by filtration, whereby the title compound (23 mg, 0.040 mmol, 59%) was obtained as a white solid.1H-NMR (400 MHz, CDCl3) delta: 4.26 (2H, d, J = 6.4 Hz), 5.08 (1H, t, J = 6.4 Hz), 5.91 (1H, s), 6.86-7.06 (2H, m), 7.40 (2H, d, J = 8.1 Hz), 7.55 (2H, d, J = 8.1 Hz), 7.57-7.70 (3H, m), 7.81 (1H, d, J = 7.4 Hz), 7.94-8.05 (2H, m), 8.11 (1H, s), 8.46 (1H, s). MS m/z: 574 (M++H). |
59% | With 4-methyl-morpholine; In dichloromethane; at 0 - 20℃; for 6h; | To a dichloromethane (0.5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (28 mg, 0.068 mmol) obtained in Example 63 were added N-methylmorpholine (0.015 ml, 0.14 mmol) and <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (22 mg, 0.10 mmol) sequentially at 0C. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=7:3 eluate was concentrated under reduced pressure. The solid thus obtained was washed with hexane and collected by filtration to give the title compound (23 mg, 0.040 mmol, 59%) as a white solid. 1H-NMR (400MHz, CDCl3) delta: 4.26 (2H,d, J=6.4Hz), 5.08 (1H,t, J=6.4Hz), 5.91 (1H,s), 6.86-7.06 (2H,m), 7.40 (2H,d, J=8.1Hz), 7.55 (2H,d, J=8.1Hz), 7.57-7.70 (3H,m), 7.81 (1H,d, J=7.4Hz), 7.94-8.05(2H,m), 8.11 (1H,s), 8.46 (1H,s). MSm/z: 574(M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In tetrahydrofuran; at 20℃; for 16h; | Methylamine hydrochloride (736 mg, 10.9 mmol) was added to a solution of 3-cyano benzene sulfonyl chloride (2.0g, 9.9 mmol) and triethylamine (3.45 ml,24.7mmol) in tetrahydrofuran (30 ml) and the resulting mixture left to stir atroom temperature under a nitrogen atmosphere for 16h hours. The reactionmixture was diluted with water (30 ml) and ethyl acetate (50 ml). The organicphase was separated and dried (sodium sulfate) and reduced in vacua to givethe title compound as a colourless solid (1.68g, 86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | REFERENCE EXAMPLE 3 Methyl (4S)-1-[(3-Cyanophenyl) sulfonyl]-4-hydroxyprolinate; Methyl (4S)-4-hydroxyprolinate (52. 0 g, 0. 286 mol) was dissolved in 500 rnL CH2C12 and cooled to 0C. Triethylamine (83. 6 mL, 0. 600 mol) was added, followed by <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (55. 0, 0. 273 mol) slowly. The reaction mixture was stirred at room temperature overnight. Water was added, and the aqueous layer was extracted three times with CH2C12. The combined organic layers were washed with 1N HCl, H2O, 1N NaOH, and brine, dried over MgSO4, and concentrated to give a viscous residue. Ethyl acetate (300 mL) was added to completely dissolve the residue. Approximately 100 mL hexanes was added slowly until the solution became slightly cloudy. The mixture was then stirred overnight to allow the product to precipitate. The solid was filtered and rinsed two times with 30% EtOAc/hexanes to give the desired product as an off-white powder (66. 2 g, 78%). 1H-NMR (CDC13, 500MHz) 6 8. 20-8. 18 (m, 1H), 8. 15-8. 12 (m, 1H), 7. 92-7. 89 (m, 1H), 7. 72 (t, 1H), 4. 51-4. 47 (m, 1H), 4. 42 (br s, 1H), 3. 74 (s, 3H), 3. 53-3. 49 (m, 1H), 3. 46-3. 43 (m, 1H), 3. 39 (br s, 1H), 2. 29-2. 25 (m, 1H), 2. 21-2. 02 (m, 1H). MS (ESI) calculated for C13Hl4N2o5S 310. 3, observed m/e 311. 2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | After suspending 2.50 kg (14.6 mol) of <strong>[289483-87-0]7-amino-3-cyano-4-methyl-1H-indole</strong> and 3.24 kg (16.06 mol) of 3-cyanobenzenesulfonyl chloride [CAS No.56542-67-7] in 25 L of methyl acetate, 87.5 L of methyl acetate and 37.5 L of water were added thereto. Next, 1.39 kg (17.52 mol) of pyridine was added dropwise and the mixture was stirred for 2 hours. After adding 0.36 L (4.38 mol) of concentrated hydrochloric acid to the reaction mixture, it was subjected to liquid-liquid separation and the organic layer was washed with a mixture of 37.5 L of water and 8.8 L of ethanol. After adding activated carbon to the organic layer and stirring at 50C for 30 minutes, the mixture was filtered and concentrated. To this was added 30 L of isopropyl alcohol, and after re-concentration, 91 L of isopropyl alcohol and 9.1 L of water were added and the mixture was heated to 70C. Dissolution was confirmed after 2 hours, and then clarifying filtration was performed and 11.4 L of isopropyl alcohol and 1.1 L of water were added. The solution was slowly cooled to 7C at 10C/hr (with introduction of seed crystals at 64C), and after stirring overnight at 7C, the crystals were collected by filtration. The crystals were dried at 70C under reduced pressure to give 3.6 kg of the title compound as a white crystalline powder (yield: 73%). The moisture content of the obtained white crystalline powder was measured by the Karl Fischer method to be 0.1%, confirming that the obtained crystals were anhydrate crystals. HPLC analysis also confirmed that the obtained crystals were N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide.(HPLC conditions) Mobile phase: CH3CN/H2O/70% HClO4 = 500/500/1 (v/v/v)Flow rate: 1.0 ml/minDetection: UV (282 nm)Column: YMC-Pack Pro C 18 250 x 4.6 mmColumn temperature: 25CRetention time: 8.3 min A powder X-ray diffraction pattern for the obtained crystals is shown in Fig. 3, and the diffraction angle (2theta) peak and peak intensity are shown in Table 7. [Table 7] 2 theta (degree) Relative Intensity 11.4 47 13.0 24 14.4 20 15.2 21 16.4 30 17.0 16 19.1 100 19.8 36 20.4 12 20.9 15 22.6 37 24.0 25 24.5 28 25.0 27 25.6 19 26.3 35 26.8 23 28.8 35 31.6 24 32.7 10 A 13C solid-state NMR spectrum for the obtained crystals is shown in Fig. 5, and the chemical shifts are listed in Table 8. [Table 8] Chemical Shift (ppm) 143.4 137.7 136.9 134.2 131.1 128.5 126.4 125.8 124.3 120.0 118.8 115.8 111.0 84.5 19.4 An infrared spectrum (KBr) for the obtained crystals is shown in Fig. 7, and the wavenumbers (cm-1) and transmittances (%T) of the absorption peak are shown in Table 9. [Table 9] Wavenumber (cm-1) %TWavenumber (cm-1) %T 3212 5 1087 23 2954 26 1060 38 2872 26 984 25 2242 22 939 41 2223 7 905 25 1715 47 839 45 1617 49 819 38 1519 29 795 32 1472 42 754 33 1443 12 690 19 1410 20 676 16 1337 12 652 26 1316 17 625 24 1260 32 607 28 1207 33 588 20 1178 32 559 17 1158 6 518 14 1102 32 420 45 | |
47% | Crystals of the title compound were synthesized using the same reaction conditions and recrystallization conditions as for the N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide described in WO00/50359. To a solution of <strong>[289483-87-0]7-amino-3-cyano-4-methyl-1H-indole</strong> (10 g, 58.4 mmol) in tetrahydrofuran (200 ml) were added pyridine (20 ml) and 3-cyanobenzenesulfonyl chloride (12.5 g), followed by stirring at room temperature for 3.5 hours. After further adding 2N hydrochloric acid (100 ml), extraction was performed with ethyl acetate. The organic layer was washed with water (twice) and brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1-3:2). A mixed solvent of ethanol-hexane (1:2) was added thereto, and after sonication, the precipitate was collected by filtration and washed with a mixed solvent of ethanol-hexane (1:3). The mixture was dried overnight under reduced pressure to give the title compound (9.33 g, 27.7 mmol, 47% yield). 1H-NMR spectrum (DMSO-d6) delta (ppm): 2.58 (3H, s), 6.52 (1H, d, J=7.6Hz), 6.80 (1H, d, J=7.6Hz), 7.74 (1H, m), 7.92 (1H, d, J=8.0Hz), 8.12 (2H, m), 8.19 (1H, d, J=3.2Hz), 10.13 (1H, s), 12.03 (1H, s). A powder X-ray diffraction pattern for the obtained crystals is shown in Fig. 2, and the diffraction angle (2theta) peak and peak intensity are shown in Table 6. [Table 6] PEAK No. 2 theta HALF WIDTH d-VALUE INTENSITY RELATIVE INTENSITY 1 5.960 0.235 14.8167 3492 49 2 8.100 0.212 10.9063 2820 40 3 8.440 0.188 10.4677 1968 28 4 11.920. 0.259 7.4184 4067 57 5 14.120 0.282 6.2671 7103 100 6 15.120 0.259 5.8548 2142 30 7 16.400 0.165 5.4006 2330 33 8 17.660 0.141 5.0180 1905 27 9 17.960 0.212 4.9349 1998 28 10 19.240 0.306 4.6093 5707 80 11 21.380 0.235 4.1526 2443 34 12 21.940 0.282 4.0478 5502 77 13 23.020 0.212 3.8603 2602 37 14 23.580 0.165 3.7699 3172 45 15 23.900 0.400 3.7201 3958 56 16 24.540 0.282 3.6245 2812 40 17 25.840 0.165 3.4451 4302 61 18 26.520 0.212 3.3582 3045 43 19 27.540 0.376 3.2361 3265 46 20 28.380 0.118 3.1422 2655 37 21 28.520 0.188 3.1271 2435 34 It was attempted to produce identical crystals by the same process as Example 1B, but the powder X-ray diffraction pattern did not match. In other words, the crystals obtained in Example 1B were presumably not of a single crystal form but were a mixture of multiple crystal forms. Moreover, it is believed that a single crystal form cannot be produced by the process of Example 1B. | |
To a suspension of 5.0 g (29 mmol) of the <strong>[289483-87-0]7-amino-3-cyano-4-methyl-1H-indole</strong> obtained in Example 2A and 6.48 g (32 mmol) of 3-cyanobenzenesulfonyl chloride [CAS No. 56542-67-7] in 150 mL of methyl acetate, were added 75 mL of water and 2.83 mL (35 mmol) of pyridine, followed by stirring for 2 hours and 40 minutes. After adding 0.73 mL (9 mmol) of concentrated hydrochloric acid to the reaction mixture, liquid-liquid separation was performed and the organic layer was washed with a mixture of 75 mL of water and 17.5 mL of ethanol. Activated carbon was added to the organic layer and the mixture was stirred at 45-50C for 30 minutes, and then filtered and concentrated. To thus obtained crude crystals were added 96 mL of 2-butanol and 24 mL of water for dissolution at 75C, and the solution was cooled to 7C at approximately 10C/hr and stirred overnight. The precipitated crystals were collected by filtration and washed twice with 10 mL of 2-butanol to give 8.17 g (wet weight) of crystals of the title compound. The crystals were dried under reduced pressure at 70C for 2 hours to give 7.54 g of crystals of the title compound. HPLC analysis confirmed that the obtained compound was identical to the N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide described in WO00/50395.(HPLC conditions) Mobile phase: CH3CN/H2O/70% HClO4 = 500/500/1 (v/v/v)Flow rate: 1.0 mL/minDetection: UV (282 nm)Column: YMC-Pack Pro C18 250 x 4.6 mm A powder X-ray diffraction pattern for the obtained crystals is shown in Fig. 1, and the diffraction angle (2theta) peak and peak intensity are shown in Table 5. [Table 5] PEAK No. 2 theta INTERPLANAR SPACING INTENSITY HALF WIDTH I/Io 1 11.420 7.74203 2122 0.210 55 2 13.040 6.78363 913 0.210 24 3 14. 380 6.15437 778 0.300 20 4 15.200 5.824I5 717 0.210 19 5 15. 540 5.69748 220 0.210 6 6 16.380 5.40714 1013 0.210 26 7 17.000 5. 21131 960 0.210 25 8 19.080 4.64763 3925 0.240 100 9 19.440 4.56237 505 0.150 13 10 19.780 4.48471 1512 0.240 39 11 20.360 4. 35824 470 0.210 12 12 20.900 4.24684 543 0.210 14 13 22.500 3. 94833 1295 0.150 33 14 22.620 3.92765 1437 0.270 37 15 23.160 3.83728 295 0.124 8 16 23.960 3.71094 920 0.330 24 17 24.400 3.64501 890 0.180 23 18 24.520 3.62744 952 0.150 25 19 24.980 3.56168 917 0.240 24 20 25.560 3.48216 693 0.210 18 21 26.260 3.39090 1230 0.270 32 22 26.760 3.32867 823 0.240 21 23 28.840 3.09315 1277 0.210 33 24 29.620 3.01345 270 0.180 7 |
With pyridine; hydrogenchloride; In tetrahydrofuran; | Example 1 3-Cyano-N-(3-cyano-4-methyl-1H-indole-7-yl)benzenesulfonamide The compound (2.00 g, 11.7 mmol) of Production Example 12 was dissolved in 60 ml of tetrahydrofuran, and then 4.0 ml (49.5 mmol) of pyridine and 2.60 g (12.9 mmol) of the compound of Production Example 13 were added thereto. After stirring at room temperature for 16 hr, a 2N hydrochloric acid was added thereto to adjust to pH 1-2, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated. Then, the resulting residue was purified by silica gel column chromatography to give 3.90 g of the title compound. m.p.: 220-221 C. (recrystallized from ethanol/n-hexane) 1H-NMR(DMSO-d6) delta (ppm); 2.55(3H,s), 6.50(1H,d,J=8.0 Hz), 6.77(1H,d,J=8.0 Hz), 7.71(1H,t,J=8.0 Hz), 7.90(1H,d,J=8.0 Hz), 8.05-8.13(2H,m), 8.16(1H,s), 10.11(1H,brs), 12.01(1H,brs). | |
With pyridine; In acetic acid methyl ester; water; for 2.66667h;Product distribution / selectivity; | Example 3A; Synthesis of N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide; To a suspension of 5.0 g (29 mmol) of the <strong>[289483-87-0]7-amino-3-cyano-4-methyl-1H-indole</strong> obtained in Example 2A and 6.48 g (32 mmol) of 3-cyanobenzenesulfonyl chloride [CAS No. 56542-67-7] in 150 mL of methyl acetate, were added 75 mL of water and 2.83 mL (35 mmol) of pyridine, followed by stirring for 2 hours and 40 minutes. After adding 0.73 mL (9 mmol) of concentrated hydrochloric acid to the reaction mixture, liquid-liquid separation was performed and the organic layer was washed with a mixture of 75 mL of water and 17.5 mL of ethanol. Activated carbon was added to the organic layer and the mixture was stirred at 45-50 C. for 30 minutes, and then filtered and concentrated. To thus obtained crude crystals were added 96 mL of 2-butanol and 24 mL of water for dissolution at 75 C., and the solution was cooled to 7 C at approximately 10 C./hr and stirred overnight. The precipitated crystals were collected by filtration and washed twice with 10 mL of 2-butanol to give 8.17 g (wet weight) of crystals of the title compound. The crystals were dried under reduced pressure at 70 C. for 2 hours to give 7.54 g of crystals of the title compound. HPLC analysis confirmed that the obtained compound was identical to the N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide described in WO00/50395. (HPLC conditions) Mobile phase: CH3CN/H2O/70% HClO4=500/500/1 (v/v/v) Flow rate: 1.0 mL/min Detection: UV (282 nm) Column: YMC-Pack Pro C18 250×4.6 mm | |
Reference Example 4A Synthesis of N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide To a suspension of 250 g (1.46 mol) of the <strong>[289483-87-0]7-amino-3-cyano-4-methyl-1H-indole</strong> obtained in Reference Example 3A in 5 L of tetrahydrofuran (20-fold amount), were added 354 mL (4.38 mol) of pyridine and 312 g (1.55 mol) of 3-cyanobenzenesulfonyl chloride, followed by stirring at an internal temperature of 21 to 34 C. Disappearance of the starting materials was confirmed after 30 minutes. To the reaction mixture were added 2925 mL of water (11.7-fold amount), 5 L of ethyl acetate (20-fold amount) and a mixture of 730 mL of concentrated hydrochloric acid and 730 mL of water (total of 5.8-fold amount), and liquid-liquid separation was performed. The organic layer was washed with 2925 mL of water, and then 125 g of activated carbon was added and the mixture was stirred for 1 hour. The mixture was filtered through celite and washed twice with 1 L of ethyl acetate. To the filtrate were added 5 L of water and 100 mL of 1 N solution of sodium hydroxide, 1 L of ethyl acetate was further added and liquid-liquid separation was performed. Next, 6 L of water and 2 L of ethyl acetate were added to the organic layer and liquid-liquid separation was performed. The aqueous layer was re-extracted with 2 L of ethyl acetate, and both organic layers were combined and concentrated under reduced pressure at 50 C., after which 1 L of 2-propanol was added and azeotropic distillation and concentration was carried out to give the title compound (666 g, wet weight). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydrogencarbonate; sodium sulfite; In tetrahydrofuran; water; at 80℃; | The sodium 3-cyanobenzenesulfinate used in this step was prepared by heating a solution of sodium sulfite (3.2 grams, 25.2 mmoles) in 10 mL water to 80, and adding dropwise thereto a solution of <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (2.55 grams, 12.6 mmoles) in 7 mL THE and a solution of sodium bicarbonate (2.1 grams, 25.2 mmoles) . The mixture was extracted with diethyl ether and the aqueous phase was concentrated under reduced pressure, heated, and filtered through Whatman GF/B glass fiber filter. The filtrate was concentrated under reduced pressure to give 1.92 grams (81%), of sodium 3-cyanobenzenesulfinatem.p. 216-218 C.Following the general procedure of Cacchi et al., J. Organic Chemistry: 69(17): 5608-5614 (2004), a mixture of JR-(6-iodo-l,2,3,4-tetrahydro-naphthlen-l-ylmethyl)- carbamic acid tot-butyl ester (0.4 gram, 1.0 mmole) sodium 3-cyanobenzenesulfinic acid (0.246 gram, 1.3 mmole), tris(dibenzylideneacetone)dipalladium(0) (0.05 gram, 0.054 mmole), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.062 gram, 0.108 mmole), cesium carbonate (0.53 gram, 1.5 mmole), and tetra-n-butyl ammonium chloride (0.362 gram, 1.3 mmole) in 10 mL toluene was heated at 95 for 4 hours. The reaction mixture was diluted with 80 mL ethyl acetate and washed with saturated sodium chloride. The EPO <DP n="109"/>organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to low pressure column chromatography over silica gel 230- 400 mesh eluting with 25% ethyl acetate in hexane. beta-f-^-Cyano-benzenesulfonyl)- l,2,3,4-tetrahydro-naphthalen-l-ylmethyl]-carbamic acid tert-butyl ester was obtained as a foam, 0.2 gram (47%), M+' = 426, [alpha]D = +5 (c = 1, methanol). |
81% | With sodium hydrogencarbonate; sodium sulfite; In tetrahydrofuran; water; at 80℃; | Example 16 i?-3-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl)-benzonitrile The synthetic procedure described in this Example was carried out according to the process shown in Scheme U.SCHEME UStep 1^-[-O-Cyano-benzenesulfonvD-l^^^-tetrahydro-naphthalen-l-ylmethyll-carbamic acid ferf-butyl esterThe sodium 3-cyanobenzenesulfinate used in this step was prepared by heating a solution of sodium sulfite (3.2 grams, 25.2 mmoles) in 10 mL water to 80, and adding dropwise thereto a solution of <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (2.55 grams, 12.6 mmoles) in 7 mL THF and a solution of sodium bicarbonate (2.1 grams, 25.2 mmoles). The mixture was extracted with diethyl ether and the aqueous phase was concentrated under reduced pressure, heated, and filtered through Whatman GF/B glass fiber filter. The filtrate was concentrated under reduced pressure to give 1.92 grams (81%), of sodium 3- cyanobenzenesulfinatem.p. 216-218 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In diethyl ether; dichloromethane; sodium hydrogencarbonate; ethyl acetate; | a 3-(3-Cyanophenylsulfonyloxy)-5-methylphenol <strong>[6153-39-5]Orcinol monohydrate</strong> (1.42 g, 10.0 mmol) and 3-cyanobenzenesulfonyl chloride (2.02 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3*50 mL). The organic phase was washed with brine (2*50 mL) and dried over Na2 SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.40 g, 83%). 1 H-NMR (300 MHz, CDCl3) delta 8.12 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 6.56 (s, 1H), 6.36 (s, 1H), 6.30 (s, 1H), 5.35 (s, 1H), 2.22 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hydrogencarbonate; In diethyl ether; water; at 20℃; | a) 3-(3-Cyanophenylsulfonyloxy)-5-methylphenol Orcinol monohydrate (1.42 g, 10.0 mmol) and <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (2.02 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3 x 50 mL). The organic phase was washed with brine (2 x 50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.40 g, 83%). 1H-NMR (300 MHz, CDCl3) delta 8.12 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H), 6.56 (s, 1H), 6.36 (s, 1H), 6.30 (s, 1 H), 5.35 (s, 1H), 2.22 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 195 3-(3-Cyano-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 121, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-cyanobenzenesulfonyl chloride as starting materials, which is commercially available from Aldrich or Maybridge; m.p. 195-197 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h; | 68A: N-(4-bromophenethyl)-3-cyanobenzenesulfonamide; [00516] To a solution of 2-(4-bromophenyl)ethanamine (600 nig, 3.13 mmol) and TEA (800 mg, 8 mmol) in THF (10 mL), was added a solution of 3-cyano- benzenesulfonyl chloride (580mg, 2.88 mmol) in THF (10 mL) at 0 C. The mixture was stirred at rt for 2 h, quenched with water, and extracted with EtOAc (3 x 20 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated.Purification via flash chromatography (0-50 % EtOAc in hexanes) gives 68A (708 mg, 71%). MS (ESI) m/z 365.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; In dichloromethane; at 20℃; for 12h; | To a solution of the substituted tetrahydroisoquinoline (300 mg5 0.9 mmol) in DCM (10 ml) was added triethylamine (0.14 ml, 0.99 mmol) followed by <strong>[56542-67-7]3-cyanobenzene sulfonyl chloride</strong> (199 mg, 0.99 mmol). The reaction mixture was stirred at rt for 12 h. Saturated aqueous sodium hydrogen C(Ar)bonate (30 ml) was added and DCM (30 ml). The layers were separated and the aqueous layer extracted with DCM (2 x 30 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo. The crude material was purified (flashmaster: 2Og, 100% hex to 50% hex/50% EtOAc over 20 min then to 100% EtOAc over 5 min) to afford the title compound (308 mg, 76%) as a colourless solid. 1H NMR (270 MHz; CDCl3) 1.04 (18H5 d5 J= 6.7 Hz5 6 * CH3CH)5 1.12- 1.32 (3H5 m5 3 x CHCH3), 2.76 (2H5 1, J = 5.7 Hz, CH2), 3.39 (2H5 15 J = 5.9 Hz, CH2), 3.73 (3H, s, OCH3), 4.22 (2H, s CH2), 6.46 (IH5 S5 CH)5 6.54 (IH5 S5 CH), 7.64 (IH5 td, J= 7.9, 0.5 Hz5 CH)5 7.82-7.86 (IH5 m5 CH)5 8.0-8.04 (IH5 m, CH)5 8.11 (IH5 15 J= 1.3 Hz, CH). 13C NMR (67.5 MHz; CDCl3) 12.92 (CH)5 17.98 (CH3), 27.87 (CH2), 43.95 (CH2), 47.37 (CH2), 55.59 (OCH3), 109.47 (CH)5 113.82 (C)5 117.24 (C), 120.33 (CH), 123.24 (C), 124.58 (C), 130.23 (CH)5 131.22 (CH)5 131.48 (CH)5 135.88 (CH)5 138.84 (C), 144.61 (C), 149.85 (C). LC/MS (ES+) tr = 2.59 min, m/z 343.28 (M+-H-SiOiPr3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; In dichloromethane; at 23℃; for 2h; | Step 3: 4-bromo-N-{l-|(3-cyanophenyl)sulfonyl]piperidin-4-yl}-2- (trifluoromethyl)benzenesulfonamide; [0249J 4-bromo-N-piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide hydrochloride (106 mg, 0.25 mmol), <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (50 mg, 0.25 mmol) and triethylamine (d 0.726, 0.105 mL, 0.75 mmol) were combined in dichloromethane (2.5 mL) at 23 0C. After 2 hours, the reaction solution was washed with saturated aqueous sodium bicarbonate (2.5 mL), water (2.5 mL) and saturated brine (2.5 mL). The organic solution was dried (MgSO4) and concentrated under vacuum. The residue was dissolved in a small <n="69"/>volume of dichloromethane, loaded directly onto a 4 g ISCO column (silica gel) and eluted with ethyl acetate-hexanes (30-75 % solution (at) 18 mL/min) to provide 4-bromo-N-{l-[(3- cyanophenyl)sulfonyl]piperidin-4-yl}-2-(trifluoromethyl)benzenesulfonamide (94 mg, 68 %) as a white solid. MS (ES) m/z 551.5 ([M+H]*). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In dichloromethane; at 0 - 25℃; for 16h; | Example 12,2,2-Trifluoro-1-[3-(piperidine-1-sulfonyl)-phenyl]-1-trifluoromethyl-ethylamine; Step A. To a mixture of <strong>[56542-67-7]3-cyano-benzenesulfonyl chloride</strong> (170 mg, 0.84 mmol, 1A) and triethylamine (0.24 mL, 1.69 mmol) in 2 mL dichloromethane at 0 C. was added piperidine (124 muL, 1.26 mmol). The reaction mixture was stirred at 25 C. for 16 h and concentrated to give a yellow oily residue. Flush column chromatography of the residue (silica gel, hexane:ethyl acetate=1:3) provided compound 3-(piperidine-1-sulfonyl)-benzonitrile (189 mg, 90%) as a white solid.1H NMR (400 MHz, CDCl3): delta 1.42-1.52 (m, 2H), 1.62-1.72 (m, 4H), 2.99-3.08 (m, 4H), 7.71 (dd, J=7.83, 7.83 Hz, 1H), 7.89 (d, J=7.83 Hz, 1H), 8.00 (d, J=7.83 Hz, 1H), 8.07 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 15-crown-5; sodium hydride; In tetrahydrofuran; at 0℃; for 3h; | Reference Example 81; tert-butyl ( {5- (2-chloropyridin-3-yl) -1- [ (3- cyanophenyl) sulfonyl] -4-fluoro-lH-pyrrol-3- yl}methyl)methylcarbamate; To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl { [5- (2-chloropyridin-3-yl) -4-fluoro-lH-pyrrol-3- yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran, 15- crown-5 (330 mg) and <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (302 mg) under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane- ethyl acetate=6: 1?3:1) to give the title compound as a pale- yellow oil (yield 490 mg, 97%) . 1H-NMR (CDCl3) delta: 1.50(9H,s), 2.90(3H,s), 4.30 (2H,brs) , <n="121"/>7.32(lH,brs) , 7.39 (IH, dd, J=I .6, 4.8Hz) , 7.55-7.61 (2H,m) , 7.64 (IH, q, J=I.3Hz), 7.82 (lH,dd, J=7.6, 1.8Hz) , 7.85-7.91(1H7In), 8.51 (IH, dd, J=4.7,1.9Hz) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 15-crown-5; sodium hydride; In tetrahydrofuran; at 0℃; for 0.25h; | Reference Example 84; tert-butyl { [1- [ (3-cyanophenyl) sulfonyl] -5- (2-cyanopyridin-3- yl) -4-fluoro-lH-pyrrol-3-yl]methyl Jmethylcarbamate; To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl { [5- (2-cyanopyridin-3-yl) -4-fluoro-lH-pyrrol-3- yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15- crown-5 (330 mg) and <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (302 mg) under ice-cooling and the mixture was stirred for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6: 1?2:1) to give the title compound as a pale-yellow oil (yield 401 mg, 81%) .1H-NMR (CDCl3) delta: 1.49(9H,s), 2.89(3H,s), 4.31 (2H,brs) , 7.29- 7.44(lH,m), 7.48-7.75 (4H,m) , 7.82-8.04 (2H,m) , 8.79(lH,dd, J=4.7,1.5Hz) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 15-crown-5; sodium hydride; In tetrahydrofuran; at 0℃; for 17h; | Reference Example 86; tert-butyl { [l-[ (3-cyanophenyl) sulfonyl] -4-fluoro-5- (2- fluoropyridin-3-yl ) -lH-pyrrol-3-yl] methyl }methylcarbamate; To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl { [4-fluoro-5- (2-fluoropyridin-3-yl ) -lH-pyrrol-3- yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran, 15- crown-5 (330 mg) and <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (302 mg) under ice-cooling and the mixture was stirred for 17 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified <n="124"/>by silica gel column chromatography (eluent: hexane-ethyl acetate=6: 1-»2: 1) to give the title compound as a pale-yellow oil (yield 446 mg, 91%) .1H-NMR (CDCl3) delta: 1.49(9H7S), 2.88(3H,s), 4.28(2H,s), 7.30- 7.39(2H,m), 7.59 (2H, d, J=4.9Hz) , 7.66(lH,s), 7.75-7.93 (2H,m) , 8.34 (IH, d, J=4.7Hz) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Reference Example 98; 3-{ [2- (2-chloropyridin-3-yl)-4-formyl-lH-pyrrol-l- yl]sulfonyl}benzonitrile; To a solution of 5- (2-chloropyridin-3-yl) -lH-pyrrole-3- carbaldehyde (110 mg) in tetrahydrofuran (11 mL) was added sodium hydride (60% in oil, 64 mg) at room temperature and the mixture was stirred for 10 min. 3-Cyanobenzenesulfonyl chloride (215 mg) was added and the mixture was further stirred for 15 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The obtained extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound as colorless crystals (yield 150 mg, 76%) .1H-NMR (CDCl3) delta: 6.76 ( IH, d, J=I .7Hz) , 7.41 (IH, dd, J=7.6, 4.8Hz) , 7.62-7.64(3H,m) , 7.78 (IH, dd, J=7.6, 2. OHz) , 7.91-7.94 (IH,m) f 8.16(lH,d, J=I.9Hz) , 8.54 (IH, dd, J=4.8, 2. OHz) , 9.94(lH,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | 3-Cvano-N-[(2,3-diaza-spiro[4.41non-3-en-2-yl)-ethylamino-methylene1-benzenesulfonamide; To a solution of 3.50 g <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> in 150 ml. DCM were added 17,69 ml_ (6.0 equiv.) DiPEA and 4.00 g (1.0 equiv.) N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carbox- amidine. The reaction mixture was stirred overnight at room temperature and extracted with water. The organic phase was dried over Na2SO4 and evaporated, and the residue was purified by automated flash chromatography (EtOAc/PA 1 :1 ) to give 3.54 g (57%) of a pale yellow oil. 1H NMR (400 MHz, CDCI3) delta 1.17 (t, J=8 Hz, 3H), 1.65-1.86 (m, 8H), 3.41-3.50 (m, 2H), 3.87 (br.s., <n="57"/>2H), 6.70-6.80 (br.s., 1 H), 6.87 (s, 1 H), 7.60 (t, J=8 Hz, 1 H), 7.77 (d, J= 8Hz, 1 H), 8.17 (d, J=8 Hz, 1 H), 8.23 (br.s., 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | 3-Cvano-N-[(4,4-dimethyl-4,5-dihvdro-pyrazol-1-yl)-ethylamino-methylene1-benzenesulfonamide; 500 mg N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboxamidine was suspended in 10 ml_ dichloromethane; 0.92 ml. (2.2 equiv.) DiPEA was added and subsequently 0.49 g (1.0 equiv.) <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong>. The mixture was stirred overnight at room temperature. The reaction mixture was extracted with 5% aqueous NaHCO3 and 2 M aqueous NaOH, dried over Na2SO4 and concentrated under reduced pressure to yield 680 mg (82 %) of a brown oil. 1H NMR (400 MHz, CDCI3) delta 1.18 (t, J=I Hz, 3H), 1.25 (s, 6H), 3.41-3.52 (m, 2H), 3.81 (s, 2H), 6.71 (br s, 1 H), 6.80 (s, 1 H), 7.59 (t, J = 8 Hz, 1 H), 7.73-7.79 (m, 1 H), 8.15-8.21 (m, 1 H), 8.22- 8.26 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In dichloromethane; at 20℃; | [0193j Preparation of SIl: To a solution of (R)-3-amino-1-N-BOC-pyrrolidine (1.00 g, 5.37 mmol) in CH2C12 (40.0 mL, 0.134 M) was added triethylamine (2.25mL, 16.11 mmol)followed by 3-cyanobenzenesuifonyi chloride (1.21 g, 6.0 mmol) at room temperature. The mixture was stirred overnight. The following morning the mixture was diluted with CH2C12 (40 mL) and washed with water (40 mL). The aqueous layer was extracted CH2C12 (2 x 2OmL). The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (40-60%EtOAc/hexanes) to provide SIl as a clear oil (1.70 g, 90%). |
With triethylamine; In dichloromethane; at 20℃; | Example 6 3-cyano-N-[(3R)-1-cyano-3-pyrrolidinyl]benzenesulfonamide To <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (0.1019 g, 0.50 mmol) and triethylamine (0.275 ml, 1.97 mmol) in DCM (2 mL) was added 1,1-dimethylethyl (3R)-3-amino-1-pyrrolidinecarboxylate (0.080 ml, 0.471 mmol). The reaction mixture was stirred at room temperature overnight. Water (1.5 ml) was added to the reaction mixture with stirring. The mixture was then diluted with DCM (2 ml) and water (1.5 ml) and put through a phase separator to dry. Then 4N HCl in 1,4-dioxane (2.0 ml) was added. After 6 hours, the reaction was blown down to dryness. The dry material was then diluted with DCM (10 ml), and mixed with DIEA (0.45 mL, 2.58 mmol) and BrCN (0.40 mL, 1.2 mmol). The resultant mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the solid purified by preparatory HPLC (without TFA) to afford the title compound (0.0665 g). LC-MS: m/z, 277 (M+H), rt 1.40 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine; In tetrahydrofuran; at 20℃; for 17h; | To a solution of lambdaL(3,5-dichloroberLzyl)-1-(4-fluorophenyl)methanamine (1.40 g, 4.91 mmol) in THF (15 mL) was added 3-cyanobenzene-1-supsilonlfonyl chloride (0.9 g, 4.46 mmol) and Et3N (1.22 mL, 8.93 mmol) at rt for 2h. Additional sulfonyl chloride (0.35 g) and Et3N (0.5 mL) were added. The reaction mixture was stirred at rt for 15 h. The mixture was concentrated and the residue was diluted with ethyl acetate and 1 N HCl solution. The organic layer was separated, washed with brine, saturated aq NaHCO^ solution, dried over MgSOphi and concentrated to give a glassy material which was purified by flash silica gel column chromatography on silica gel (ISCO. Column: 24 g. Eluent: A: hexane. B: ethyl acetate. Condition: A to 25 % of B (50 min gradient) to obtain the desired product as a white solid (1.8 g, 81%). 1H NMR (CDCl3): 5 8.08-8.02 (m, 2H), 7.93-7.90 (m, 1H),7.7O (t, J - 8.0 Hz, 1 H), 7.25-7.24 (m, 1H), 7.13-7.09 (m,2H), 6.98 (t, J= 8.0 Hz, 2H), 6.90 (d, /= 4.0 Hz, 2H), 4.38 (s, 2H), 4.30(s, 2H); MS (ESI): [M-H]- = 506.9.F |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 50 - 60℃; for 2h; | Step 3: Scheme 3155Synthesis of 3-((4-(6-(4-fluorophenoxy)picolinoyl)piperazin-l-yl)sulfonyl) benzonitrileA 50 mL round bottom flask was charged with compound 68 (100 mg,0.19 mmol), 3-cyano phenylsulfonyl chloride (Aldrich, 33 mu, 0.19 mmol), DIEA (0.1 mL, 0.7 mmol) and DCM (5 mL). The reaction mixture stirred at 60 C for 2 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was concentrated and the residue was subjected to flash column chromatography (hexanes/EtOAc) to give 3-((4-(6-(4-fluorophenoxy)picolinoyl) piperazin-l-yl)sulfonyl) benzonitrile (compound 55) as white solid (96 mg, yield 83%, (m/z + H) = 467, 1HNMR (CDC13) delta ppm: 6.80-7.90 (m, 11H); 3.6-3.8 (m, 4H); 2.9 (m, 2H); 2.5 (m, 2H)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With pyridine; In dichloromethane; at 0 - 20℃; for 16.5h; | General procedure: To a stirred solution of 17-amino-1,3,5(10)-estratrien-3-ol (0.38 mmol) in dry pyridine (3 mL) at 0 C was added a solution of the sulfonyl chlorides (0.40 mmol) in dichloromethane (1 mL) via a syringe pump over 30 min. After addition, the reaction was stirred for 16 h at room temperature. The pyridine was removed under vacuum, the residue was dissolved in ethyl acetate, washed with water and brine then dried (Na2SO4,), filtered, and concentrated and the residue purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; In dichloromethane; at 20℃; | General procedure: In a solution of 6-(4-aminophenyl)-N-(3-(trifluoromethyl) phenyl) pyrimidin-4-amine (4) (1eq) in DCM (5ml), different substituted sulphonyl chlorides (l.1eq) and triethylamine (1.1eq) were added. Resulting reaction mixture was stirred at room temperature for 1-2 h and progress of reaction monitored by TLC in ethyl acetate- petroleum ether mixture. Resulting reaction mixture was diluted with DCM and water added. Organic layer washed by fresh water and brine, dried on Na2SO4 and concentrated under reduced pressure to afford crude product, which was purified by silica gel (100-200 No.) column chromatography in 10% ethyl acetate petroleum ether as eluent to obtain a title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With pyridine; In dichloromethane; at 20℃; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides D and H (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred overnight at room temperature. After removing of the solvent, the crude product was dissolved in ethyl acetate (100 mL) and the mixture was washed with KHSO4 (1 × 50 mL), NaCl (1 × 50 mL) and was dried over Na2SO4. After evaporation of the solvent, nitriles E and I were obtained by recrystallisation from ethyl acetate/hexane or ethyl acetate/toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With pyridine; In dichloromethane; at 20℃; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides D and H (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred overnight at room temperature. After removing of the solvent, the crude product was dissolved in ethyl acetate (100 mL) and the mixture was washed with KHSO4 (1 × 50 mL), NaCl (1 × 50 mL) and was dried over Na2SO4. After evaporation of the solvent, nitriles E and I were obtained by recrystallisation from ethyl acetate/hexane or ethyl acetate/toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With pyridine; In dichloromethane; at 20℃; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides D and H (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred overnight at room temperature. After removing of the solvent, the crude product was dissolved in ethyl acetate (100 mL) and the mixture was washed with KHSO4 (1 × 50 mL), NaCl (1 × 50 mL) and was dried over Na2SO4. After evaporation of the solvent, nitriles E and I were obtained by recrystallisation from ethyl acetate/hexane or ethyl acetate/toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With pyridine; In dichloromethane; at 20℃; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides D and H (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred overnight at room temperature. After removing of the solvent, the crude product was dissolved in ethyl acetate (100 mL) and the mixture was washed with KHSO4 (1 × 50 mL), NaCl (1 × 50 mL) and was dried over Na2SO4. After evaporation of the solvent, nitriles E and I were obtained by recrystallisation from ethyl acetate/hexane or ethyl acetate/toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With pyridine; In dichloromethane; at 20℃; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides D and H (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred overnight at room temperature. After removing of the solvent, the crude product was dissolved in ethyl acetate (100 mL) and the mixture was washed with KHSO4 (1 × 50 mL), NaCl (1 × 50 mL) and was dried over Na2SO4. After evaporation of the solvent, nitriles E and I were obtained by recrystallisation from ethyl acetate/hexane or ethyl acetate/toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With pyridine; In dichloromethane; at 20℃; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides D and H (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred overnight at room temperature. After removing of the solvent, the crude product was dissolved in ethyl acetate (100 mL) and the mixture was washed with KHSO4 (1 × 50 mL), NaCl (1 × 50 mL) and was dried over Na2SO4. After evaporation of the solvent, nitriles E and I were obtained by recrystallisation from ethyl acetate/hexane or ethyl acetate/toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amines F or K (3 mmol) and DIPEA (388 mg, 3 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent and addition of acetic acid (2 mL) the nitriles G and L were obtained by flash column chromatography (dichloromethane/ethyl acetate = 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amines F or K (3 mmol) and DIPEA (388 mg, 3 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent and addition of acetic acid (2 mL) the nitriles G and L were obtained by flash column chromatography (dichloromethane/ethyl acetate = 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amines F or K (3 mmol) and DIPEA (388 mg, 3 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent and addition of acetic acid (2 mL) the nitriles G and L were obtained by flash column chromatography (dichloromethane/ethyl acetate = 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amines F or K (3 mmol) and DIPEA (388 mg, 3 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent and addition of acetic acid (2 mL) the nitriles G and L were obtained by flash column chromatography (dichloromethane/ethyl acetate = 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amines F or K (3 mmol) and DIPEA (388 mg, 3 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent and addition of acetic acid (2 mL) the nitriles G and L were obtained by flash column chromatography (dichloromethane/ethyl acetate = 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amines F or K (3 mmol) and DIPEA (388 mg, 3 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent and addition of acetic acid (2 mL) the nitriles G and L were obtained by flash column chromatography (dichloromethane/ethyl acetate = 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amines F or K (3 mmol) and DIPEA (388 mg, 3 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent and addition of acetic acid (2 mL) the nitriles G and L were obtained by flash column chromatography (dichloromethane/ethyl acetate = 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amines F or K (3 mmol) and DIPEA (388 mg, 3 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent and addition of acetic acid (2 mL) the nitriles G and L were obtained by flash column chromatography (dichloromethane/ethyl acetate = 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amines F or K (3 mmol) and DIPEA (388 mg, 3 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent and addition of acetic acid (2 mL) the nitriles G and L were obtained by flash column chromatography (dichloromethane/ethyl acetate = 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amines F or K (3 mmol) and DIPEA (388 mg, 3 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent and addition of acetic acid (2 mL) the nitriles G and L were obtained by flash column chromatography (dichloromethane/ethyl acetate = 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides N (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent, acetic acid was added (2 mL) and the nitriles O were obtained by flash column chromatography (ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides N (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent, acetic acid was added (2 mL) and the nitriles O were obtained by flash column chromatography (ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides N (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent, acetic acid was added (2 mL) and the nitriles O were obtained by flash column chromatography (ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides N (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent, acetic acid was added (2 mL) and the nitriles O were obtained by flash column chromatography (ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides N (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent, acetic acid was added (2 mL) and the nitriles O were obtained by flash column chromatography (ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides N (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent, acetic acid was added (2 mL) and the nitriles O were obtained by flash column chromatography (ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | General procedure: A solution of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine hydrochlorides N (3 mmol) and DIPEA (776 mg, 6 mmol) in THF (30 mL) was stirred 1 h at room temperature. After evaporation of the solvent, acetic acid was added (2 mL) and the nitriles O were obtained by flash column chromatography (ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With pyridine; In dichloromethane; at 20℃; | General procedure: A mixture of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine (3.3 mmol) and pyridine (736 mg, 9.3 mmol) was stirred overnight at room temperature in abs dichloromethane (40 mL). After removal of the solvent at reduced pressure, nitriles B were obtained by flash column chromatography (dichloromethane) and recrystallisation from ethyl acetate/hexane or toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With pyridine; In dichloromethane; at 20℃; | General procedure: A mixture of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine (3.3 mmol) and pyridine (736 mg, 9.3 mmol) was stirred overnight at room temperature in abs dichloromethane (40 mL). After removal of the solvent at reduced pressure, nitriles B were obtained by flash column chromatography (dichloromethane) and recrystallisation from ethyl acetate/hexane or toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With pyridine; In dichloromethane; at 20℃; | General procedure: A mixture of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine (3.3 mmol) and pyridine (736 mg, 9.3 mmol) was stirred overnight at room temperature in abs dichloromethane (40 mL). After removal of the solvent at reduced pressure, nitriles B were obtained by flash column chromatography (dichloromethane) and recrystallisation from ethyl acetate/hexane or toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyridine; In dichloromethane; at 20℃; | General procedure: A mixture of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine (3.3 mmol) and pyridine (736 mg, 9.3 mmol) was stirred overnight at room temperature in abs dichloromethane (40 mL). After removal of the solvent at reduced pressure, nitriles B were obtained by flash column chromatography (dichloromethane) and recrystallisation from ethyl acetate/hexane or toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; In dichloromethane; at 20℃; | General procedure: A mixture of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine (3.3 mmol) and pyridine (736 mg, 9.3 mmol) was stirred overnight at room temperature in abs dichloromethane (40 mL). After removal of the solvent at reduced pressure, nitriles B were obtained by flash column chromatography (dichloromethane) and recrystallisation from ethyl acetate/hexane or toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With pyridine; In dichloromethane; at 20℃; | General procedure: A mixture of 3- or 4-cyanobenzenesulfonyl chloride (605 mg, 3 mmol), the amine (3.3 mmol) and pyridine (736 mg, 9.3 mmol) was stirred overnight at room temperature in abs dichloromethane (40 mL). After removal of the solvent at reduced pressure, nitriles B were obtained by flash column chromatography (dichloromethane) and recrystallisation from ethyl acetate/hexane or toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere; | Example 3: 3-cvano-Lambda/-{4-r(1R5SV3-(2-methyl-1 /-/-benzimidazol-1-vn-8- azabicvclobeta^.iloct-delta-yll^-phenylbutyllbenzenesulfonamideTo a solution of <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (39 mg, 0.19 mmol) in dry CH2CI2 (1 ml.) was added a solution of intermediate 6 (75 mg, 0.19 mmol) in dry CH2CI2 (2 ml.) followed by diisopropylethylamine (0.085 ml_, 0.48 mmol) and the solution stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was concentrated in vacuo and purified by silica gel chromatography eluting with 0-5% CH2CI2/Me0H to give the title compound (77 mg, 73% yield) as a white solid. 1H NMR (DMSO-de, 400 MHz) delta 8.08 (d, J = 8.98 Hz, 2 H), 8.02 (d, J = 8.25 Hz, 1 H), 7.93 (t, J = 5.87 Hz, 1 H), 7.76 (t, J = 7.88 Hz, 1 H), 7.48 (d, J = 7.33 Hz, 1 H), 7.38 (d, J = 7.33 Hz, 1 H), 7.23 - 7.29 (m, 2 H), 7.14 - 7.21 (m, 3 H), 7.06 - 7.13 (m, 2 H), 4.53 - 4.65 (m, 1 H), 3.19 - 3.29 (m, 2 H), 2.95 - 3.09 (m, 2 H), 2.78 - 2.87 (m, 1 H), 2.50 (s, 3 H), 2.28 - 2.42 (m, 2 H), 1.89 - 2.01 (m, 4 H), 1.74 - 1.88 (m, 3 H), 1.52 - 1.67 (m, 3 H). HRMS: (M + H)+ calcd for C32H35N5O2S + H, 554.2584; found, 554.2586. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of sulfonyl chloride derivatives (0.025 mmol) in THF (20 mL) is added pyridine (0.05 mmol). The solution is cooled to 0-5 C and water (1 mL) is added. The reaction mixture is left to warm to room temperature, stirred for 2 hr, and then concentrated under reduced pressure. To the residue is added EtOH (20 mL), and the mixture is concentrated under reduced pressure. Then EtOH (10) is added to the residue and a suspension is obtained in a majority of trials. The solid is collected by vacuum filtration and dried. Pyridinium sulfonate salt intermediate are obtained with a yield of 50% w/w and more. If no crystal is form, the solution is directly used with Amberlyst-15 without isolation of the pyridinium sulfonate salt. The solid (pyridinium sulfonate) is then dissolved in MeOH (20 mL) and Amberlyst15 is added. The mixture is stirred for 1 hr at room temperature, then the resin is removed by filtration on Celite and washed with MeOH (5 mL). The resulting mixture is passed through a 0.45 muiotaeta filter, then <strong>[39133-31-8]trimebutine</strong> (1 equivalent vs pyridinium sulfonate intermediate) is added, and the mixture is stirred for 1 hr at room temperature. The resulting solution is divided in 6 equal part parts and transferred to round-bottom flask, and then each flask is concentrated under reduced pressure. Each residue is then treated using one of the following protocols: ? Protocol A: MeOH (5 mL) is added and the mixture is stirred to obtain a solution. ? Protocol B: MeOH (5 mL) and water (1 mL) are added, and the mixture is stirred to obtain a solution. ? Protocol C: EtOH (5 mL) is added and the mixture is stirred to obtain a solution. ? Protocol D: GammaRhoAlpha (5 mL) is added and the mixture is stirred to obtain a solution. ? Protocol E: Acetone (5 mL) is added and the mixture is stirred to obtain a solution. ? Protocol F: Acetone (5 mL) and water (1 mL) is added, and the mixture is stirred to obtain a solution. Each solution is then transferred into a vial and kept open for the solvent(s) to evaporate at room temperature (18-25C) until crystal formation is observed. The solid is then recovered by filtration, washed with solvent and dried under mechanical vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With water; In tetrahydrofuran; at 0 - 20℃; for 2h; | <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (100 g, 0.496 mol) was dissolved in a mixture of THF (1.00 L) and pyridine (82.2 mL, 1.02 mol) at room temperature. The solution was cooled down 0 C and water (50 mL) was added to the solution. The mixture was stirred vigorously for two (2) hours and left to warm to room temperature. The mixture was then concentrated reduced pressure, and residual water was removed by azeotropic distillation using ethanol (2 x 1000 mL). Addition ethanol (400 mL), followed by filtration provided the title compound (78 g, 60% yield) as a solid with purity greater than 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In toluene; at 20℃; for 2h; | General procedure: The appropriate carboxyl chloride, sulfonyl chloride, or carbamoyl chloride (1 mmol), either neat or dissolved in dry toluene (1-2 mL), was added dropwise to a stirred solution of N-tboc-bispidine 13 (230 mg, 1 mmol) and Et3N (101 mg, 1 mmol) in dry toluene (5 mL) at rt. The volatiles were removed under reduced pressure after 2 h and the residue was purified by flash chromatography (silica gel, mixtures of CH2Cl2 and MeOH-40:1, 20:1 or 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: 6-chloro-4-methoxypyridazin-3-amine With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 3-cyanobenzene sulfonyl chloride In tetrahydrofuran at 20℃; for 18h; | N-(6-chloro-4-methoxypyridazin-3-yl)-3-cyanobenzene-l-sulfonamide Toa suspension of potassium 2-methylpropan-2-olate (70 mg, 0.63 mmol) in THF (4mL) at 0°C was added 6-chloro-4-methoxypyridazin-3-amine (100 mg, 0.63 mmol)and stirred for 30 mins. 3-cyanobenzene-l -sulfonyl chloride (126 mg, 0.63mmol) was added to the reaction mixture and was stirred for 18 hrs at roomtemperature. The reaction mixture was diluted with EtOAc (15mL) and washed with1M aqueous HC1 (10 mL). The organic phase was dried using Na2SC>4,filtered and concentrated. The crude residue was purified using silica columnchromatography (DCM: MeOH 90: 10) to yield the title compound (63 mg, 30%); mz=323.0, 325.0 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine; In dichloromethane; at 0 - 20℃; | Et3N (0.15 mL, 1.43 mmol) was added dropwise to an ice cold solution of (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (130 mg, 0.48 mmol) in dry CH2Cl2 (3 mL). The resulting reaction mixture was stirred at 0 C for 5 min, then a solution of <strong>[56542-67-7]3-cyanobenzene-1-sulfonyl chloride</strong> (105 mg, 0.52 mmol) in dry CH2Cl2 (2 mL) was added dropwise. The reaction mixture was further stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 35% EtOAc in petroleum ether) to afford compound 3-cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamide (0.13 g, yield 61%) as an off-white solid. 1H NMR (300 MHz, CDCl3) delta 8.03-7.98 (m, 2H), 7.85-7.76 (m, 3H), 7.59-7.54 (m, 1 H), 7.50-7.38 (m, 4H), 3.87-3.79 (m, 2H), 3.74-3.66 (m, 2H), 3.36 (s, 2H), 2.27-2.19 (ddd, J = 13.5 Hz, 6.7 Hz, 3.5 Hz, 2H), 2.01- 1.93 (ddd, J = 13.8 Hz, 7.5 Hz, 3.7 Hz, 2H). MS (ESI) m/z: Calculated for C22H21N3O3S2: 439.10; found: 440.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.7% | With triethylamine; In dichloromethane; at 20℃; for 2h; | To a solution of compound 9 (100 mg, 0.29 mmol) in dry dichloromethane (5 mL)To the solution was added <strong>[56542-67-7]3-cyanobenzene-1-sulfonyl chloride</strong> (70.4 mg, 0.35 mmol)And TEA (48. 5 mul, 0. 35 mmol)The mixture was stirred at room temperature for 2 hours.The mixed solution was diluted with an aqueous solution of saturated NH4Cl (10 mL)And extracted with dichloromethane (3 x 10 mL).The organic material was dried over MgSO4 and filtered,Concentrate under vacuum.The resultant was purified by silica gel chromatography (CHCl3: MeOH = 50: 1)By refiningTert-butyl 4- (5- (4 - (((3-cyanophenyl) sulfonyl) oxy) phenyl)1H-imidazol-1-yl)Piperidine-1-carboxylate(128 mg, 86.7% yield)obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With pyridine; In dichloromethane; at 20℃; for 18h; | General procedure: To a stirring mixture of 5-amino-2-(4-aminophenyl) benzoxazole (1 eq.) in anhydrous CH2Cl2 (5 mL) was added the respective sulfonyl chloride (2.1 eq.) followed by anhydrous pyridine (2.1 eq.). The reaction was allowed to stir at room temperature for 18 h and was then chromatographed over silica and concentrated. If necessary, the product was further purified by preparatory RP-HPLC (H2O:CH3CN gradient), concentrated, and lyophilized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With borax; In water; at 20℃; | 11 (135 mg, 0.50 mmol), Na2B4O7 (1.00 g, 4.97 mmol) and <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (101 mg, 0.50 mmol) were suspended in H2O (30 mL) under vigorous stirring. The reaction mixture was stirred at rt overnight meanwhile a colorless precipitate was formed. This solid was dissolved by addition of 1 M NaOH and the resulting solution was extracted with CH2Cl2 to remove byproducts. The aqueous layer was treated with conc. HCl to adjust pH value to 1 and the formed precipitate was filtered, washed with H2O and dissolved in THF. After removal of the solvent under reduced pressure, the resulting solid was recrystallized from MeOH/ H2O to yield 5t. Colorless solid, mp 224 C, yield 166 mg (76 %). C22H18N4O4S (434.5). Rf = 0.78 (ethyl acetate, detection: 254 nm). 1H NMR (600 MHz, DMSO-D6): delta [ppm] = 4.16 (s, 2H, NHCH2), 7.38 (d, J = 7.9 Hz, 2H, 2-HB, 6-HB), 7.53 (t, J = 7.6 Hz, 2H, 3-HC, 5-HC), 7.60 (t, J = 7.4 Hz, 1H, 4-HC), 7.79 (t, J = 7.9 Hz, 1H, 5-HA), 7.84 (d, J = 7.9 Hz, 2H, 3-HB, 5-HB), 7.93 (d, J = 7.6 Hz, 2H, 2-HC, 6-HC), 8.06-8.13 (m, 2H, 4-HA, 6-HA), 8.22 (s, 1H, 2-HA), 8.51 (br s, 1H, SO2NHCH2), 10.46 (br s, 2H, ArBCONHNHCOArC). 13C NMR (151 MHz, DMSO-D6): delta [ppm] = 45.7 (1C, NHCH2), 112.4 (1C, C-3A), 117.6 (1C, NC), 127.4 (2C, C-2C, C-6C), 127. 5 (2C, C-3B, C-5B), 127.6 (2C, C-2B, C-6B), 128.5 (2C, C-3C, C-5C), 130.1 (1C, C-2A), 130.7 (1C, C-5A), 130.9 (1C, C-6A), 131.5 (1C, C-4B), 131.9 (1C, C-4C), 132.6 (1C, C-1C), 136.0 (1C, C-4A), 141.4 (1C, C-1B), 142.0 (1C, C-1A), 165.5 (1C, ArBCONHNH), 165.8 (1C, NHNHCOArC). FT-IR: nu [cm-1] = 3283 (N-H), 3071 (C-HAr), 2230 (NC), 1667 (C=O), 1612, 1573, 1516, 1497 (C=CAr), 1339, 1153 (SO2), 864, 799, 756, 721, 687 (Ar-Hout of plane). HRMS (APCI): m/z = 435.1138 (calcd. 435.1122 for C22H19N4O4S [M+H]+). HPLC: tR = 17.5 min, purity 97.0 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridine; In dichloromethane; at 20℃; for 0.5h;Inert atmosphere; | General procedure: To a solution of N-benzyl-4-phenoxyaniline 13 (195 mg,0.708 mmol) in CH2Cl2 were added benzenesulfonyl chloride(162 mg, 0.850 mmol) and pyridine (0.258 mL, 1.42 mmol) under argon. The reaction mixture was stirred at room temperature for 30 min. The reaction was quenched with 1 M HCl (2 mL) and the whole was extracted with EtOAc. The combined organic layer was washed with NaHCO3 and brine, dried over Na2SO4, and concentrated.The crude product was purified by flash silica gel column chromatography (EtOAc/hexane = 1:4). The product wasrecrystallized from CH2Cl2/hexane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | General procedure: Sodium hydride (60% in oil, 440 mg, 11.0 mmol) was washed twice with n-hexane, and suspended in THF (20 mL). To this suspension was added dropwise a solution of tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate 18 in THF (10 mL) at 0 C, and the mixture was stirred at the same temperature for 30 min. 15-Crown-5 (2,45g, 11.1 mmol) was added, and then a solution of 3-fluorobenzenesulfonyl chloride (1.96 g, 10.1 mmol) in THF (5 mL) were added dropwise at the same temperature, and the resulting mixture was stirred at room temperature for 1 h, then diluted with H2O and extracted with EtOAc. The extract was washed with a solution of NaHCO3, H2O and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(n-hexane/EtOAc = 5/1)to produce |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1h;Inert atmosphere; | General procedure: To a stirred solution of <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (1 g, 5 mmol) in dry THF (10 ml_), triethylamine (700 muIota_, 5 mmol, 1 equiv.) and the appropriate amine (1 equiv.) were added at 0C under azote atmosphere. The reaction mixture was stirred for 1 hr at room temperature, then diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2S04, filtered and concentrated under vacuum to provide the expected compound which was used without further purification The following compounds are examples illustrating this procedure: ; N-benzyl-4-cvano-benzenesulfonamide was prepared from <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong>. Yield: 1 .31 g (92%) of the title compound as a white powder |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In dichloromethane; at 0 - 20℃; | General procedure: To a stirred solution of <strong>[56293-29-9]aloperine</strong> (2.0 mmol) and K2CO3(6.0 mmol) in dichloromethane (20 mL), and the substituted benzoylchloride or sulfonyl chloride (2.0 mmol) was added. The reactionmixture was stirred at 0 C for 1e2 h until TLC analysisshowed completion of the reaction. Then the solvent was washedsuccessively with water (20 mL), brine (20 mL). The organic layerwas concentrated and purified by flash column chromatography onsilica gel with CH2Cl2/CH3OH as the eluent to get target compounds3aeb or 4aee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.2% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | General procedure: To an 93 (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 5aa (70.0mg, 0.322mmol) solution in 1.50mL of 119 dichloromethane in a 5mL round-bottom flask, 120 <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (68.6mg, 0.340mmol) and 121 N,N-diisopropylethylamine (0.0590mL, 0.339mmol) were added. Then, the reaction solution was stirred at room temperature overnight before being concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol: dichloromethane=2:98). |
Ca.38.2% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | 300 mg of (3R)-(+)-1-benzyl-3-aminopyrrolidine was added to a 25-mL round-bottomed flask. After 6.00 mL of deionized water and 274 mg of 6-chloro-7-deazapurine were sequentially added thereto, 470 mg of potassium carbonate (K2CO3) was added to the reaction mixture, and then the reaction mixture was refluxed for about 24 hours and then cooled at room temperature. The reaction mixture was extracted three times with 10.0 mL of dichloromethane (CH2Cl2) to collect an organic phase. The collected organic phase was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=2:98). As a result, 292 mg of (R)-N-(1-benzylpyrrolidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained with a yield of about 58.5%. (0225) 294 mg of (R)-N-(1-benzylpyrrolidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 25-mL round-bottomed flask and then dissolved with 4.00 mL of methanol. After 280 mg of a 10w/w% palladium/ carbon (Pd/C) was added thereto, a hydrogen-containing balloon was installed on the reaction flask. The reaction mixture was vigorously stirred overnight and then filtered through a Celite 545 filter agent. The resulting filtrate was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=2:98). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 191 mg of (R)-N-(pyrrolidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was obtained with a yield of about 94.8%. (0226) 60.0 mg of (R)-N-(pyrrolidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 25-mL round-bottomed flask and then dissolved with 1.50 mL of dichloromethane (CH2Cl2). After 59.6 mg of <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> was added to the solution, the reaction mixture was treated with 0.0770 mL of N,N-diisopropylethylamine. The reaction mixture was then stirred overnight at room temperature and then concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=2:98). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 42.0 mg of (R)-3-((3-((7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)pyrrolidine-1-yl)sulfonyl)benzonitrile was obtained with a yield of about 38.2%. (0227) 1H NMR (400 MHz, DMSO) 511.51 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 5.6 Hz, 1H), 7.06(s, 1H), 6.40 (d, J = 1.2 Hz, 1H), 4.43-4.39 (m, 1H), 3.53-3.47 (m, 2H), 3.39-3.26 (m, 2H), 2.14-2.05 (m, 1H), 1.96-1.88 (m, 1H). (0228) LRMS (ESI) calcd for (C17H16N6O2S + H+) 369.1, found 369.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.4% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | To an 93 (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 5aa (70.0mg, 0.322mmol) solution in 1.50mL of 119 dichloromethane in a 5mL round-bottom flask, 120 <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (68.6mg, 0.340mmol) and 121 N,N-diisopropylethylamine (0.0590mL, 0.339mmol) were added. Then, the reaction solution was stirred at room temperature overnight before being concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol: dichloromethane=2:98). Removing the solvent in vacuo provided 88.6mg of 122 (R)-3-((3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)sulfonyl)benzonitrile (72.4% yield). 97.0% purity by HPLC. 1H NMR (400MHz, DMSO-d6) delta 11.68 (s, 1H), 8.32 (d, J=7.8Hz, 1H), 8.23 (d, J=7.7Hz, 1H), 8.17 (d, J=8.0Hz, 1H), 8.06 (t, J=4.6Hz, 1H), 7.88 (td, J=7.8, 2.2Hz, 1H), 7.14 (d, J=2.1Hz, 1H), 6.48 (s, 1H), 5.27 (m, 1H), 3.51 (dd, J=7.6, 4.4Hz, 1H), 3.44 (m, 1H), 3.36 (s, 3H), 3.23 (m, 1H), 3.17 (s, 1H), 2.03 (dd, J=15.0, 7.6Hz, 2H). 13C NMR (100MHz, DMSO-d6) delta 156.8, 151.7, 150.4, 137.1, 136.8, 131.9, 131.0, 130.9, 121.2, 117.6, 112.9, 102.5, 101.3, 54.0, 48.7, 46.8, 31.7, 27.5. HRMS (ESI) calcd for C18H19N6O2S: 383.1290. Obsd: 383.1285. [alpha]D -45.7 (c 0.530, CHCl3). |
Ca.72.4% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | 70.0 mg of (R)-N-methyl-N-(pyrrolidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 5-mL round-bottomed flask and then dissolved with1.50 mL of dichloromethane (CH2Cl2). After 68.6 mg of <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> was added thereto, the reaction mixture was treated with 0.0590 mL of N,N-diisopropylethylamine and then stirred at room temperature for about 1 hour. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=0:100?1:80?1:50). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 88.6 mg of (R)-3-((3-(methyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)pyrrolidine-1-yl)sulfonyl)benzonitrile was obtained with a yield of about 72.4%. 1H NMR (400 MHz, CDCl3) delta10.04 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.10 (t, J = 3.2 Hz, 1H), 6.57 (t, J = 1.6 Hz, 1H), 5.62 (t, J = 7.6 Hz, 1H), 3.75-3.70 (m, 1H), 3.51 (dd, J = 10.4, 8.4 Hz, 1H), 3.40 (dd, J = 10.4, 6.8 Hz, 1H), 3.33 (s, 3H), 3.20-3.13 (m, 1H), 2.27-2.14 (m, 2H). LRMS (ESI) calcd for (C18H18N6O2S + H+) 383.1, found 383.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.3% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | General procedure: To an 93 (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 5aa (70.0mg, 0.322mmol) solution in 1.50mL of 119 dichloromethane in a 5mL round-bottom flask, 120 <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (68.6mg, 0.340mmol) and 121 N,N-diisopropylethylamine (0.0590mL, 0.339mmol) were added. Then, the reaction solution was stirred at room temperature overnight before being concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol: dichloromethane=2:98). |
Ca.73.3% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | 67.0 mg of (R)-N-ethyl-N-(pyrrolidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 5-mL round-bottomed flask and then dissolved with 1.45 mL of dichloromethane (CH2Cl2). After 60.5 mg of <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> was added to the solution, the reaction mixture was treated with 0.0500 mL of N,N-diisopropylethylamine and then stirred at room temperature for about 1 hour. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=0:100?1:80?1:50). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 84.3 mg of (R)-3-((3-(ethyl(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)pyrrolidine-1-yl)sulfonyl)benzonitrile was obtained with a yield of about 73.3%. 1H NMR (400 MHz, CDCl3) delta10.34 (s, 1H), 8.20 (s, 1H), 8.12 (d, J = 10.0 Hz, 2H), 7.94 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 3.6 Hz, 1H), 6.45 (d, J = 3.6 Hz, 1H), 5.32-5.24 (m, 1H), 3.81-3.63 (m, 4H), 3.38-3.27 (m, 2H), 3.27-2.19 (m, 3H), 1.37 (t, J = 7.2 Hz, 3H). LRMS (ESI) calcd for (C19H20N6O2S + H+) 397.1, found 397.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.0% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | General procedure: To an 93 (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 5aa (70.0mg, 0.322mmol) solution in 1.50mL of 119 dichloromethane in a 5mL round-bottom flask, 120 <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> (68.6mg, 0.340mmol) and 121 N,N-diisopropylethylamine (0.0590mL, 0.339mmol) were added. Then, the reaction solution was stirred at room temperature overnight before being concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol: dichloromethane=2:98). |
Ca.61.0% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | 62.0 mg of (R)-N-(cyclopropylmethyl)-N-(pyrrolidine-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was added to a 5-mL round-bottomed flask and then dissolved with 1.20 mL of dichloromethane (CH2Cl2). After 50.4 mg of <strong>[56542-67-7]3-cyanobenzenesulfonyl chloride</strong> was added to the solution, the reaction mixture was treated with 0.0420 mL of N,N-diisopropylethylamine and then stirred at room temperature for about 1 hour. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was purified by flash column chromatography (MeOH:CH2Cl2=0:100?1:80?1:50). The resulting fraction was concentrated under reduced pressure and then further under vacuum. As a result, 62.2 mg of (R)-3-((3-((cyclopropylmethyl)(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)pyrrolidine-1-yl)sulfonyl)benzonitrile was obtained with a yield of about 61.0%. 1H NMR (400 MHz, CDCl3) delta10.08 (s, 1H), 8.20 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H), 5.10-5.06 (m, 1H), 3.72-3.61 (m, 4H), 3.52-3.48 (m, 1H), 3.34-3.28 (m, 1H), 2.31-2.25 (m, 2H), 1.17-1.10 (m, 1H), 0.71-0.67 (m, 2H), 0.38-0.35 (m, 2H). LRMS (ESI) calcd for (C21H22N6O2S + H+) 423.2, found 423.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; | General procedure: To a stirred solution of alcohol intermediate 4 in dichloromethane (20 mL) at 0 C was added trimethylamine (1 eq) and 4-dimethylaminopyridine (0.1 eq). The desired aryl sulfonyl chloride (1.5 eq) was then added and the reaction mixture was stirred for an additional 15 min at 0 C, followed by stirring overnight at room temperature. Upon completion, the reaction mixture was partitioned between dichloromethane and H2O. The organic layer was then washed 3 times with water, dried over Na2SO4, filtered, and removed under reduced pressure. The desired cjoc42 derivatives 5-29 were then purified using column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With triethylamine; In dichloromethane; at 20℃; for 18h; | General procedure: A solution of compound 8 (90 mg, 0.44 mmol), 4-chlorobenzenesulfonyl chloride (103 mg, 0.49 mmol) and triethylamine (68 muL, 0.49 mmol) in dichloromethane (5 mL) was stirred at room temperature for 18 h. The reaction was quenched through the addition of water (20 mL) and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7). The mixture was then diluted with dichloromethane (20 mL) and the separated aqueous layer further extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with aqueous phosphate buffer solution (0.5 M, pH 7) (20 mL), dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 40:1) afforded compound 9a as a beige solid (96 mg, 0.25 mmol, 56%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.65% | With pyridine at 25℃; | 36; 151 Synthesis of 36.2. Into a 50-mL round-bottom flask, was placed 36.1 (557 mg, 1.2 equiv.), 3-cyanobenzene-1-sulfonyl chloride (500 mg, 1 equiv), pyridine (10 mL). The resulting solution was stirred overnight at 25 oC. The pH value of the solution was adjusted to 7-8 with 1 M HCl (aq.). The resulting solution was washed with H2O (20 mL). The resulting solution was extracted with 3 x 15 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 630 mg (70.65%) of 36.2 as a light yellow solid. (ES, m/z): [M-H]- 351.0, 1H -NMR (300MHz, DMSO-d6, ppm): d10.56 (s, 1H), d8.19-8.15 (m, 2H), d8.07-8.04 (m, 1H), d7.84-7.79 (m, 1H), d7.56-7.25 (m, 8H). |
Tags: 56542-67-7 synthesis path| 56542-67-7 SDS| 56542-67-7 COA| 56542-67-7 purity| 56542-67-7 application| 56542-67-7 NMR| 56542-67-7 COA| 56542-67-7 structure
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