propanamide

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: Similarly from equivalent amounts of 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionic acid, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionic acid, 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionic acid, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propionic acid, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-ethoxy-4-cyclohexyloxyphenyl)propionic acid, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-methoxy-4-cyclohexyloxyphenyl)propionic acid, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionic acid, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-cyclohexyloxy)-4-methoxyphenyl)propionic acid, 3-(1,3)-dioxobenzo[f]isoindolin-2-yl-3-(3-cyclopentyloxy-4-ethoxyphenyl)propionic acid, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-cyclohexyloxy)-4-ethoxyphenyl)propionic acid, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propionic acid, 3(1,3-dioxo4-azaindolin-2-yl )-3)-(3-ethoxy-4-cyclohexyloxyphenyl)propionic acid, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-methoxy-4-cyclohexyloxyphenyl)propionic acid, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionic acid, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-cyclohexyloxy)-4-methoxyphenyl)propionic acid, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-ethoxyphenyl)propionic acid, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-cyclohexyloxy)-4-ethoxyphenyl)propionic acid, 3-(1,3-dioxo-azaindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propionic acid, 3(1,3-dioxo-azaindolin-2-yl)-3-(3ethoxy-cyclohexyloxyphenyl)propionic acid, 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-methoxy-4-cyclohexyloxyphenyl)propionic acid, 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionic acid, 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-cyclohexyloxy)-4-methoxyphenyl)propionic acid, 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-ethoxyphenyl)propionic acid, and 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-cyclohexyloxy)-4-ethoxyphenyl)propionic acid, there are respectively obtained according to the forgoing procedure 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamide, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamide, 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamide, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propionamide, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-ethoxy-4-cyclohexyloxyphenyl)propionamide, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-methoxy-4-cyclohexyloxyphenyl)propionamide, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamide, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-cyclohexyloxy)-4-methoxyphenyl)propionamide, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-cyclopentyloxy-4-ethoxyphenyl)propionamide, 3-(1,3-dioxobenzo[f]isoindolin-2-yl)-3-(3-cyclohexyloxy)-4-ethoxyphenyl)propionamide, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propionamide, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-ethoxy-4-cyclohexyloxyphenyl)propionamide, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-methoxy-4-cyclohexyloxyphenyl)propionamide, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamide, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-cyclohexyloxy)-4-methoxyphenyl)propionamide, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamide, 3-(1,3-dioxo-4-azaindolin-2-yl)-3-(3-cyclohexyloxy)-4-ethoxyphenyl)propionamide, 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-ethoxy-4-cyclopentyloxyphenyl)propionamide, 3-(1,3-dioxo-5-azaindolin-2-yl )-3-(3-ethoxy-4-cyclohexyloxyphenyl)propionamide, 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-methoxy-4-cyclohexyloxyphenyl)propionamide, 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-methoxy-4-methoxyloxyphenyl)propionamide, 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamide 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-cyclo hexyloxy)-4-methoxyphenyl)propionamide 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-cyclopentyloxy -4-ethoxyphenyl)propionamide, and 3-(1,3-dioxo-5-azaindolin-2-yl)-3-(3-cyclohexyloxy)-4-ethoxyphenyl)propionamide.

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

Procedure: Using the procedure of Example 12, N-(5-chloro-4-((2-chloropyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.05 g, 0.094 mmol), propionamide (10 mg, 0.14 mmol), Cs2CO3 (0.05 g, 0.14 mmol), Xantphos (6 mg, 0.010 mmol), Pd2(dba)3 (5 mg, 0.005 mmol) and dioxane (2 mL) were combined to obtain N-(5-chloro-2-fluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (9 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1 H), 10.46 (s, 1 H), 8.46 (d, J=7.8 Hz, 1 H), 8.13 (d, J=5.7 Hz, 1 H), 7.87 (d, J=7.8 Hz, 1 H), 7.57 (d, J=2.4 Hz, 1 H), 7.45 (m, 3 H), 7.31 (t, J=8.7 Hz, 2 H), 6.62 (dd, J=5.7, 2.4 Hz, 1 H), 6.50 (d, J=7.9 Hz, 1 H), 4.23 (q, J=7.0 Hz, 2 H), 2.28 (q, J=7.5 Hz, 2 H), 1.29 (t, J=7.0 Hz, 3 H), 0.95 (t, J=7.5 Hz, 3 H); MS (ESI) m/z: 569.1 (M+H+).

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(4-((2-Chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide (180 mg, 0.340 mmol), Cs2CO3 (400 mg, 1.228 mmol), propionamide (200 mg, 2.74 mmol) and Xantphos (20 mg, 0.035 mmol) were combined in dioxane (10 mL), sparged with argon under sonication, treated with Pd2(dba)3 (15 mg, 0.016 mmol) and heated to 90° C. overnight. The solids were collected by filtration and washed with DCM and MeCN. The filtrate was evaporated and the residue purified by silica gel chromatography (0-100% EtOAc/DCM) to provide N-(2,5-difluoro-4-((2-propionamidopyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide (95 mg, 49.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1 H), 10.52 (s, 1 H), 8.30 (dd, J=12.6, 7.2 Hz, 1 H), 8.18 (d, J=5.7 Hz, 1 H), 7.87 (d, J=7.9 Hz, 1 H), 7.68 (d, J=2.4 Hz, 1 H), 7.51-7.48 (m, 3 H), 7.35 (t, J=8.7 Hz, 2 H), 6.72 (dd, J=5.7, 2.4 Hz, 1 H), 6.55 (d, J=8.0 Hz, 1 H); 4.85 (m, 1 H), 2.34 (q, J=7.5 Hz, 2 H), 1.31 (d, J=6.0 Hz, 6 H), 0.99 (t, J=7.5 Hz, 3 H); MS (ESI) m/z: 567.1 (M+H+). sparged with argon under sonication The solids were collected by filtration washed with DCM and MeCN The filtrate was evaporated the residue purified by silica gel chromatography (0-100% EtOAc/DCM)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Example A1 (35 g, 122 mmol) in anhydrous 1,4-dioxane (900 mL) was degassed with nitrogen for 10 min and to it was added propionamide (10.5 g, 143 mmol), 1,1′-bis(diphenylphosphino) ferrocene (dppf, 6.6 g, 12.0 mmol, 0.1 equiv.), Cs2CO3 (58.4 g, 179 mmol) and Pd2(dba)3 (5.47 g, 5.97 mmol). The mixture was degassed with nitrogen for another 15 min and then heated to 85° C. (internal temp) and stirred at that temp for 4 h. The reaction mixture was cooled to RT, filtered through a bed of diatomaceous earth and washed with EtOAc (1 L). The combined filtrates were concentrated under reduced pressure and purified by a silica gel chromatography (EtOAc/hexanes) to afford 30 g. This material was further purified by a trituration with diisopropyl ether (600 mL) and drying under vacuum at 40° C. to provide N-(4-(2,5-difluoro-4-nitrophenoxy)pyridin-2-yl)propionamide (27.2 g, 69% yield). MS (ESI): m/z 324.1 (M+H+). This material was carried to next step without further purification. The mixture was degassed with nitrogen for another 15 min The reaction mixture was cooled to RT filtered through a bed of diatomaceous earth washed with EtOAc (1 L) The combined filtrates were concentrated under reduced pressure purified by a silica gel chromatography (EtOAc/hexanes) to afford 30 g This material was further purified by a trituration with diisopropyl ether (600 mL) drying under vacuum at 40° C.

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Example A1 (35 g, 122 mmol) in anhydrous 1,4-dioxane (900 mL) was degassed with nitrogen for 10 min and to it was added propionamide (10.5 g, 143 mmol), 1,1′-bis(diphenylphosphino) ferrocene (dppf, 6.6 g, 12.0 mmol, 0.1 equiv.), Cs2CO3 (58.4 g, 179 mmol) and Pd2(dba)3 (5.47 g, 5.97 mmol). The mixture was degassed with nitrogen for another 15 min and then heated to 85° C. (internal temp) and stirred at that temp for 4 h. The reaction mixture was cooled to RT, filtered through a bed of diatomaceous earth and washed with EtOAc (1 L). The combined filtrates were concentrated under reduced pressure and purified by a silica gel chromatography (EtOAc/hexanes) to afford 30 g. This material was further purified by a trituration with diisopropyl ether (600 mL) and drying under vacuum at 40° C. to provide N-(4-(2,5-difluoro-4-nitrophenoxy)pyridin-2-yl)propionamide (27.2 g, 69% yield). MS (ESI): m/z 324.1 (M+H+). This material was carried to next step without further purification. The mixture was degassed with nitrogen for another 15 min The reaction mixture was cooled to RT filtered through a bed of diatomaceous earth washed with EtOAc (1 L) The combined filtrates were concentrated under reduced pressure purified by a silica gel chromatography (EtOAc/hexanes) to afford 30 g This material was further purified by a trituration with diisopropyl ether (600 mL) drying under vacuum at 40° C.

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

Procedure: 3-Chloropentane-2,4-dione (46.5 g), propionamide (50 g) and propionic acid (151 g) were heated at 145° C. for 5 hours. The mixture was cooled to room temperature, then basified to pH 10 using 10M aqueous sodium hydroxide, and extracted with dichloromethane. The combined extracts were washed with brine, dried and the solvent removed to leave a brown oil which was purified by vacuum distillation, b.p. 70° C. at 2 mbar. extracted with dichloromethane The combined extracts were washed with brine dried the solvent removed to leave a brown oil which was purified by vacuum distillation, b.p. 70° C. at 2 mbar

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

Procedure: 3-Chloropentane-2,4-dione (46.5 g), propionamide (50 g) and propionic acid (151 g) were heated at 145° C. for 5 hours. The mixture was cooled to room temperature, then basified to pH 10 using 10M aqueous sodium hydroxide, and extracted with dichloromethane. The combined extracts were washed with brine, dried and the solvent removed to leave a brown oil which was purified by vacuum distillation, b.p. 70° C. at 2 mbar. extracted with dichloromethane The combined extracts were washed with brine dried the solvent removed to leave a brown oil which was purified by vacuum distillation, b.p. 70° C. at 2 mbar

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

Procedure: N-(1H-pyrrolo[2,3-c]pyridin-7-yl)propanamide (Intermediate 8, yield: 15%) was synthesized from 7-chloro-1H-pyrrolo[2,3-c]pyridine using propanamide.

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

Procedure: N-(1H-pyrrolo[2,3-c]pyridin-7-yl)propanamide (Intermediate 8, yield: 15%) was synthesized from 7-chloro-1H-pyrrolo[2,3-c]pyridine using propanamide.