cyclopropanecarboxamide

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: A mixture of the title compound of Step B (127 mg, 0.29 mmol), cyclopropanecarboxamide (74 mg, 0.87 mmol), trifluoroacetic acid (0.07 mL, 0.87 mmol) and triethylsilane (0.14 ml, 0.87 mmol) in toluene (2 mL) was gently refluxed overnight. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using hexane/EtOAc as eluent to provide the title compound, a compound of this invention, as a white foamy solid (113 mg, 77% yield). The reaction mixture was then concentrated under reduced pressure the residue was purified by column chromatography on silica gel

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: A solution of 7.96 g. of 5-bromovaleric acid chloride, 3.40 g. of cyclopropanecarboxamide, 3.16 g. of pyridine, and 20 ml. of 1,2-dimethoxyethane was heated to reflux under nitrogen for 1.5 hours, then was concentrated by rotary evaporation. The resultant semi-solid was triturated with methylene chloride (2X). The combined methylene chloride layers were washed with saturated brine, were dried (anhydrous magnesium sulfate), were treated with activated charcoal, and were filtered. The filtrate was concentrated on a steam-bath with addition of hexane until crystallization started. Thus, 3.98 g. (40% yield) of white, crystalline N-cyclopropanecarbonyl-5-bromovaleramide was obtained melting at 114°-115°C. to reflux under nitrogen for 1.5 hours was concentrated by rotary evaporation The resultant semi-solid was triturated with methylene chloride (2X) The combined methylene chloride layers were washed with saturated brine were dried (anhydrous magnesium sulfate) were treated with activated charcoal were filtered The filtrate was concentrated on a steam-bath with addition of hexane until crystallization

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), cyclopropancarboxamide (12 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-4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (27 mg, 48.4% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1 H), 10.88 (s, 1 H), 8.50 (d, J=7.8 Hz, 1 H), 8.19 (d, J=5.7 Hz, 1 H), 7.92 (d, J=7.8 Hz, 1 H), 7.59 (d, J=2.4 Hz, 1 H), 7.50 (m, 3 H), 7.36 (t, J=8.7 Hz, 2 H), 6.68 (dd, J=5.7, 2.4 Hz, 1 H), 6.55 (d, J=7.9 Hz, 1 H), 4.28 (q, J=7.0 Hz, 2 H), 1.95 (m, 1 H), 1.33 (t, J=7.0 Hz, 3 H), 0.76 (t, J=5.9 Hz, 4 H); MS (ESI) m/z: 581.1 (M+H+).

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), cyclopropancarboxamide (12 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-4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (27 mg, 48.4% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1 H), 10.88 (s, 1 H), 8.50 (d, J=7.8 Hz, 1 H), 8.19 (d, J=5.7 Hz, 1 H), 7.92 (d, J=7.8 Hz, 1 H), 7.59 (d, J=2.4 Hz, 1 H), 7.50 (m, 3 H), 7.36 (t, J=8.7 Hz, 2 H), 6.68 (dd, J=5.7, 2.4 Hz, 1 H), 6.55 (d, J=7.9 Hz, 1 H), 4.28 (q, J=7.0 Hz, 2 H), 1.95 (m, 1 H), 1.33 (t, J=7.0 Hz, 3 H), 0.76 (t, J=5.9 Hz, 4 H); MS (ESI) m/z: 581.1 (M+H+).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.100 g, 0.194 mmol, see: Example 1), cyclopropanecarboxamide (0.033 g, 0.388 mmol), Cs2CO3 (0.095 g, 0.291 μmol) and Xantphos (5.05 mg, 8.72 μmol) in dioxane (2 mL) was sparged with argon, treated with Pd2(dba)3 (2.66 mg, 2.91 μmol), sparged again with argon, then fitted with a reflux condensor capped with an argon-filled balloon and heated to 100° C. overnight. The mixture was cooled to RT and partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (33 mg, 30% yield) as a solid. MS (ESI) m/z: 565.2 (M+H+). was sparged with argon sparged again with argon fitted with a reflux condensor capped with an argon- filled balloon The mixture was cooled to RT partitioned between water and EtOAc The organic layer was washed with brine dried over MgSO4 concentrated to dryness purified via silica gel chromatography (EtOAc/Hex)

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

Procedure: A mixture of Example A2 (100 mg, 0.39 mmol), cyclopropanecarboxamide (100 mg, 1.17 mmol), Xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] (23 mg, 0.039 mmol), Cs2CO3 (254 mg, 0.78 mmol) and Pd2(dba)3 (22 mg, 0.023 mmol) in dioxane (10 mL) was heated at 100° C. for 2 hours. The mixture was cooled to RT and filtered to remove inorganic salts. The filtrate was concentrated under vacuum. The residue was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography to afford N-(4-(4-amino-2,5-difluorophenoxy)pyridin-2-yl)cyclopropanecarboxamide (56 mg, 47% yield). MS (ESI): m/z 306.1 (M+H+). filtered to remove inorganic salts The filtrate was concentrated under vacuum The residue was diluted with water (100 mL) extracted with EtOAc (3×100 mL) The combined organics were washed with brine dried over Na2SO4 concentrated in vacuo The crude product was purified by silica gel chromatography