propane-2-sulfonamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of propane-2-sulfonamide (18.46 mg, 0.150 mmol), DMAP (0.915 mg, 7.49 μmol) and Hunig's Base (0.065 mL, 0.375 mmol) in DME (2 mL) was added (1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-benzyl 9-(4-(chlorocarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (50 mg, 0.075 mmol). The reaction mixture was stirred for 16 hours. LCMS indicated the formation of the desired product. The reaction mixture was quenched with distilled water, extracted with ethyl acetate and concentrated under reduced pressure to give crude intermediate (1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-benzyl 9-(4-(isopropylsulfonylcarbamoyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate as a yellow solid. LCMS: m/e 754.60 (M+H)+, 2.36 min (method 7). To this intermediate (50 mg, 0.066 mmol) in EtOAc (2 mL) and MeOH (2.00 mL) was added 10% Pd/C (21.17 mg, 0.020 mmol). The reaction mixture was hydrogentated using a Parr shaker at 40 Psi for 17 hours. LCMS indicated the reaction was completed. The reaction mixture was filtered through a pad of celite and concentrated under reduced. The residue was purified by prep HPLC to provide the desired product, (1R,3aS,5aR,5bR,7aR,11aS,13aR,13bR)-9-(4-(isopropylsulfonylcarbamoyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid, as a white solid (12 mg, 26%). LCMS: m/e 664.48 (M+H)+, 2.18 min (method 7). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.91 (s, 6H), 0.96 (s, 3H), 1.00 (d, J=4.27 Hz, 6H), 1.18-1.27 (m, 8H), 1.35-1.55 (m, 13H), 1.60-1.75 (m, 5H), 1.94-2.03 (m, 2H), 2.07-2.14 (m, 1H), 2.22-2.31 (m, 2H), 2.97-3.07 (m, 1H), 3.98-4.08 (m, 1H), 4.61 (s, 1H), 4.74 (s, 1H), 5.28 (d, J=4.88 Hz, 1H), 7.23-7.25 (m, 2H), 7.74 (d, J=8.24 Hz, 2H).

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromonicotinaldehyde (0.930 g, 5 mmol), propane-2-sulfonamide (0.616 g, 5.00 mmol) and titanium(IV) isopropoxide (2.93 mL, 10.00 mmol) in toluene (20 mL) was heated to reflux for 4 h. After concentration, the residue was dissolved in THF (25 mL) and cooled to −40° C. A solution of cyclopropylmagnesium bromide (25 mL, 12.50 mmol) was added dropwise and the resulting mixture was slowly warmed up to 0° C. over 4 h. After quenching with a NH4Cl solution, filtration and extraction with CH2Cl2, the organic phase was dried over Na2SO4, filtered and concentrated, to give a residue which was purified by flash column (ethyl acetate/heptane, v/v, 10%-35%) and to give a yellow solid (1.1 g). ESI-MS m/z: 335.0 [M+1]+. was heated to reflux for 4 h After concentration the residue was dissolved in THF (25 mL) the resulting mixture was slowly warmed up to 0° C. over 4 h After quenching with a NH4Cl solution, filtration and extraction with CH2Cl2 the organic phase was dried over Na2SO4 filtered concentrated to give a residue which was purified by flash column (ethyl acetate/heptane, v/v, 10%-35%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (198 mg) was added to a stirred mixture of 4-(t-butoxycarbonyl)benzoic acid (195 mg), 2-propanesulfonamide (98 mg) and 4-dimethylaminopyridine (126 mg) in dichloromethane (3.7 ml). The mixture was stirred overnight, diluted with ethyl acetate, washed (1N HCl, brine), dried (MgSO4), and evaporated. The crude product was purified by flash chromatography, eluting with acetone:hexanes (75:25), to afford the product (193 mg): TLC, Rf =0.64, acetone:hexanes (75:25): MS, m/e=356(M+29), 330(M+3), 329(M+2), 328(M+1), 272, 223, 222, 205, 204, 166. washed (1N HCl, brine) dried (MgSO4) evaporated The crude product was purified by flash chromatography eluting with acetone:hexanes (75:25)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid (67 mg, 0.10 mmol) was dissolved in 5 mL of THF and treated with CDI (21 mg, 0.13 mmol). (Care was taken to avoid moisture by using oven dried glassware and maintaining a dry N2 atmosphere.) After refluxing the reaction mixture for one hour, it was cooled to rt and treated sequentially with isopropylsulfonamide (16 mg, 0.13 mmol) and DBU (20 mg, 0.13 mmol). After stirring for 24 h at rt, the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and pH 4 buffer. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. Flash chromatography (1–5% MeOH/methylene chloride) gave 50 mg (71%) of the desired product. Further purification by preparative HPLC (YMC ODS-A, S5, 20×100 mm, gradient: 60% to 100% B) gave 30 mg (43%) of [18-(isoquinolin-1-yloxy)-2,15-dioxo-4-(propane-2-sulfonylaminocarbonyl)-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: 1H NMR (300 MHz, CD3Cl3) δ 1.22 (S, 9H), 1.31 (d. J=6.6 Hz, 3H), 1.41 (d, J=6.9 Hz, 3H), 1.20–1.96 (m, 11H), 2.30 (q, J=8.4 Hz, 1H), 2.56 (m, 1H), 2.69 (m, 2H), 3.69 (m, 1H), 4.03 (m, 1H), 4.29 (m, 1H), 4.62 (m, 2H), 4.97–5.06 (m, 2H), 5.68 (q, J=9.5 Hz, 1H), 5.91 (s, 1H), 6.76 (s, 1H), 7.23 (m, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.63 (t, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.97 (d, J=5.9 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 9.89 (s, 1H). LC-MS (Method A, retention time: 3.79 min), MS m/z 670 (M++1). dried glassware maintaining a dry N2 atmosphere ) After refluxing the reaction mixture for one hour the THF was removed by rotary evaporation The residue was partitioned between ethyl acetate and pH 4 buffer The organic phase was dried (MgSO4) concentrated in vacuo to give the crude product

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 100 ml round bottom flask dissolve 13-cyclohexyl-6-(4-(ethoxycarbonyl)-1-ethyl-1H-pyrazol-5-yl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (950 mg, 1.680 mmol), propane-2-sulfonamide (652 mg, 5.29 mmol) and DMAP (655 mg, 5.36 mmol) in dichloromethane (16.8 mL). To the reaction add EDC (508 mg, 2.65 mmol). Place the reaction under a nitrogen atmosphere and stir a room temperature for 64 hours. the reaction under a nitrogen atmosphere

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40.8 mg, 0.072 mmol) was dissolved in THF (1 ml) and CDI (26 mg, 0.160 mmol) added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 50 min then heated in an oil bath at 60 C for 1.5 hrs. The reaction was cooled and propane-2-sulfonamide (46 mg, 0.373 mmol) was added to the reaction followed by DBU (0.022 ml, 0.144 mmol). The reaction was capped under a nitrogen atmosphere and heated at 65 C overnight (16 hr). The reaction was partitioned between dichloromethane and 1.0N aqueous hydrochloric acid. The organic layer was washed sequentially with 1N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4. The organic layer was dried over sodium sulfate and solvent removed in vacuo to yield 50 mg of an amorphous yellow solid. The title was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector. The sample was dissolved in acetonitrile/DMF (1:1) purified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 25 mL/min, a gradient of 70 solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradient time of 12 minutes with a run time of 15 minutes using % A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solvent system. Removal of solvents and drying in vacuo yielded 28.3 mg of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.15-1.28 (m, 1.3H) 1.30-1.46 (m, 2.4H) 1.48-1.61 (m, J=16.48 Hz, 1.2H) 1.77 (d, J=9.77 Hz, 2.3H) 1.87-2.15 (m, 4.8H) 2.22-2.52 (m, 4.6H) 2.78-2.90 (m, 1.1H) 3.37-3.72 (m, 8.9H) 3.76 (s, 6.2H) 3.80-3.89 (m, 3.2H) 3.91 (s, 3.6H) 4.08 (s, 0.3H) 4.13-4.23 (m, 1.0H) 4.42 (d, J=13.73 Hz, 0.9H) 4.65 (d, J=14.95 Hz, 0.1H) 5.55 (d, J=14.04 Hz, 1.0H) 6.97 (d, J=2.44 Hz, 1.0H) 7.07 (dd, J=8.70, 2.59 Hz, 1.0H) 7.27-7.33 (m, 0.2H) 7.38 (s, 0.1H) 7.46-7.55 (m, 2.0H) 7.60 (d, J=9.77 Hz, 1.0H) 7.78 (d, J=8.24 Hz, 0.1H) 7.83 (s, 1.0H) 7.87 (d, J=8.55 Hz, 1H) 8.07 (s, 0.1H) 8.10 (d, J=4.27 Hz, 0.1H) 8.31 (d, J=8.54 Hz, 0.1H) 8.42 (s, 0.9H) 8.94 (d, J=9.16 Hz, 0.1H) 9.55 (s, 0.9H) 9.60 (s, 0.1H). LC-MS retention time 1.63 min; 714 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. The reaction was capped under a nitrogen atmosphere then heated in an oil bath at 60 C for 1.5 hrs The reaction was cooled The reaction was capped under a nitrogen atmosphere heated at 65 C overnight (16 hr) The reaction was partitioned between dichloromethane and 1.0N aqueous hydrochloric acid The organic layer was washed sequentially with 1N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4 The organic layer was dried over sodium sulfate and solvent removed in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40.8 mg, 0.072 mmol) was dissolved in THF (1 ml) and CDI (26 mg, 0.160 mmol) added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 50 min then heated in an oil bath at 60 C for 1.5 hrs. The reaction was cooled and propane-2-sulfonamide (46 mg, 0.373 mmol) was added to the reaction followed by DBU (0.022 ml, 0.144 mmol). The reaction was capped under a nitrogen atmosphere and heated at 65 C overnight (16 hr). The reaction was partitioned between dichloromethane and 1.0N aqueous hydrochloric acid. The organic layer was washed sequentially with 1N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4. The organic layer was dried over sodium sulfate and solvent removed in vacuo to yield 50 mg of an amorphous yellow solid. The title was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector. The sample was dissolved in acetonitrile/DMF (1:1) purified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 25 mL/min, a gradient of 70 solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradient time of 12 minutes with a run time of 15 minutes using % A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solvent system. Removal of solvents and drying in vacuo yielded 28.3 mg of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.15-1.28 (m, 1.2H) 1.29-1.60 (m, 10.9H) 1.59-1.85 (m, 6.7H) 1.86-2.15 (m, 4.7H) 2.78-2.87 (m, 1.0H) 3.37-3.50 (m, 1.4H) 3.51-3.89 (m, 7.3H) 3.91 (s, 3.3H) 4.02-4.12 (m, 1.5H) 4.15-4.26 (m, 0.9H) 4.42 (d, J=13.73 Hz, 0.9H) 4.54 (d, J=15.26 Hz, 0.1H) 5.54 (d, J=14.65 Hz, 0.9H) 6.57 (d, J=14.04 Hz, 0.1H) 6.97 (d, J=2.44 Hz, 0.9H) 7.07 (dd, J=8.55, 2.44 Hz, 1.0H) 7.28-7.35 (m, 0.3H) 7.48-7.54 (m, 2.0H) 7.62-7.67 (m, 1.0H) 7.75 (d, J=7.93 Hz, 0.1H) 7.82 (s, 1.0H) 7.87 (d, J=8.55 Hz, 1.0H) 8.21 (s, 0.9H) 8.31 (s, 0.2H) 8.48 (s, 1.0H) 8.94 (d, J=9.15 Hz, 0.1H) 9.46 (s, 0.9H) 9.86 (s, 0.1H). LC-MS retention time 1.26 min; 671 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. The reaction was capped under a nitrogen atmosphere then heated in an oil bath at 60 C for 1.5 hrs The reaction was cooled The reaction was capped under a nitrogen atmosphere heated at 65 C overnight (16 hr) The reaction was partitioned between dichloromethane and 1.0N aqueous hydrochloric acid The organic layer was washed sequentially with 1N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4 The organic layer was dried over sodium sulfate and solvent removed in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40.8 mg, 0.072 mmol) was dissolved in THF (1 ml) and CDI (26 mg, 0.160 mmol) added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 50 min then heated in an oil bath at 60 C for 1.5 hrs. The reaction was cooled and propane-2-sulfonamide (46 mg, 0.373 mmol) was added to the reaction followed by DBU (0.022 ml, 0.144 mmol). The reaction was capped under a nitrogen atmosphere and heated at 65 C overnight (16 hr). The reaction was partitioned between dichloromethane and 1.0N aqueous hydrochloric acid. The organic layer was washed sequentially with 1N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4. The organic layer was dried over sodium sulfate and solvent removed in vacuo to yield 50 mg of an amorphous yellow solid. The title was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector. The sample was dissolved in acetonitrile/DMF (1:1) purified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 25 mL/min, a gradient of 70 solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradient time of 12 minutes with a run time of 15 minutes using % A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solvent system. Removal of solvents and drying in vacuo yielded 28.3 mg of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.15-1.28 (m, 1.2H) 1.29-1.60 (m, 10.9H) 1.59-1.85 (m, 6.7H) 1.86-2.15 (m, 4.7H) 2.78-2.87 (m, 1.0H) 3.37-3.50 (m, 1.4H) 3.51-3.89 (m, 7.3H) 3.91 (s, 3.3H) 4.02-4.12 (m, 1.5H) 4.15-4.26 (m, 0.9H) 4.42 (d, J=13.73 Hz, 0.9H) 4.54 (d, J=15.26 Hz, 0.1H) 5.54 (d, J=14.65 Hz, 0.9H) 6.57 (d, J=14.04 Hz, 0.1H) 6.97 (d, J=2.44 Hz, 0.9H) 7.07 (dd, J=8.55, 2.44 Hz, 1.0H) 7.28-7.35 (m, 0.3H) 7.48-7.54 (m, 2.0H) 7.62-7.67 (m, 1.0H) 7.75 (d, J=7.93 Hz, 0.1H) 7.82 (s, 1.0H) 7.87 (d, J=8.55 Hz, 1.0H) 8.21 (s, 0.9H) 8.31 (s, 0.2H) 8.48 (s, 1.0H) 8.94 (d, J=9.15 Hz, 0.1H) 9.46 (s, 0.9H) 9.86 (s, 0.1H). LC-MS retention time 1.26 min; 671 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. The reaction was capped under a nitrogen atmosphere then heated in an oil bath at 60 C for 1.5 hrs The reaction was cooled The reaction was capped under a nitrogen atmosphere heated at 65 C overnight (16 hr) The reaction was partitioned between dichloromethane and 1.0N aqueous hydrochloric acid The organic layer was washed sequentially with 1N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4 The organic layer was dried over sodium sulfate and solvent removed in vacuo