3-chloro-N-methylbenzamide

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (E)-3,4-bis(difluoromethoxy)phenyl-2-propenoic acid (0.10 g, 0.42 mmol) in CH2Cl2 (5 mL) was treated with oxalyl chloride (0.14 mL, 1.7 mmol) and catalytic DMF (1 drop). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. A solution of the acid chloride (0.42 mmol) in pyridine (2.0 mL) was added to a cooled solution of 2-amino-4-chloro-N-methylbenzamide (0.12 g, 0.63 mmol) in pyridine (2.0 mL) at 0° C. The suspension was stirred at 0° C. for 1 h, warmed to rt and stirred for 16 h and then acidified with 1 M HCl. The precipitate was collected by filtration and recrystallised from EtOH/water providing (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]-5-chloro-N-methylbenzamide (95 mg, 51%) as a pale brown crystalline solid; mp 191.5-195.5° C.; δH (500 MHz, DMSO-d6) 2.82 (d, J=4.5 Hz, 3H, NHCH3), 6.94 (d, J=15.6 Hz, 1H, CH═CHCO), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.28 (t, J=73 Hz, 1H, OCHF2), 7.26 (dd, J5,6=8.0, J3,5=1.6 Hz, 1H, H5), 7.39 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.59 (d, J=15.6 Hz, 1H, CH═CHCO), 7.69 (dd, J5′,6′=8.5, J2′,6′=2.5 Hz, 1H, H6′), 7.77 (d, J5,6=2.5 Hz, 1H, H6), 7.80 (d, J2′,6′=2.5 Hz, 1H, H2′), 8.67 (d, J3,5=2.5 Hz, 1H, H3), 8.84 (m, 1H, NHCH3), 11.82 (s, 1H, NH); δC (125 MHz, DMSO-d6) 26.3, 116.3 (t, J=259 Hz), 116.5 (t, J=259 Hz), 119.2, 119.9, 119.9, 120.7, 122.6, 123.4, 126.8, 129.6, 132.7, 136.2, 139.7, 140.2, 141.9, 142.8, 163.5, 167.8; HRMS (ESI+) calculated for C19H15ClF4N2O4 [M+Na]+ 469.0549, found 469.0546; νmax 1038, 1113, 1260, 1505, 1578, 1626, 3025, 3382 cm−1. warmed to rt stirred for 16 h The precipitate was collected by filtration recrystallised from EtOH/water

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (E)-3,4-bis(difluoromethoxy)phenyl-2-propenoic acid (0.10 g, 0.42 mmol) in CH2Cl2 (5 mL) was treated with oxalyl chloride (0.14 mL, 1.7 mmol) and catalytic DMF (1 drop). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. A solution of the acid chloride (0.42 mmol) in pyridine (2.0 mL) was added to a cooled solution of 2-amino-4-chloro-N-methylbenzamide (0.12 g, 0.63 mmol) in pyridine (2.0 mL) at 0° C. The suspension was stirred at 0° C. for 1 h, warmed to rt and stirred for 16 h and then acidified with 1 M HCl. The precipitate was collected by filtration and recrystallised from EtOH/water providing (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]-5-chloro-N-methylbenzamide (95 mg, 51%) as a pale brown crystalline solid; mp 191.5-195.5° C.; δH (500 MHz, DMSO-d6) 2.82 (d, J=4.5 Hz, 3H, NHCH3), 6.94 (d, J=15.6 Hz, 1H, CH═CHCO), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.28 (t, J=73 Hz, 1H, OCHF2), 7.26 (dd, J5,6=8.0, J3,5=1.6 Hz, 1H, H5), 7.39 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.59 (d, J=15.6 Hz, 1H, CH═CHCO), 7.69 (dd, J5′,6′=8.5, J2′,6′=2.5 Hz, 1H, H6′), 7.77 (d, J5,6=2.5 Hz, 1H, H6), 7.80 (d, J2′,6′=2.5 Hz, 1H, H2′), 8.67 (d, J3,5=2.5 Hz, 1H, H3), 8.84 (m, 1H, NHCH3), 11.82 (s, 1H, NH); δC (125 MHz, DMSO-d6) 26.3, 116.3 (t, J=259 Hz), 116.5 (t, J=259 Hz), 119.2, 119.9, 119.9, 120.7, 122.6, 123.4, 126.8, 129.6, 132.7, 136.2, 139.7, 140.2, 141.9, 142.8, 163.5, 167.8; HRMS (ESI+) calculated for C19H15ClF4N2O4 [M+Na]+ 469.0549, found 469.0546; νmax 1038, 1113, 1260, 1505, 1578, 1626, 3025, 3382 cm−1. warmed to rt stirred for 16 h The precipitate was collected by filtration recrystallised from EtOH/water

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (E)-3,4-bis(difluoromethoxy)phenyl-2-propenoic acid (0.10 g, 0.42 mmol) in CH2Cl2 (5 mL) was treated with oxalyl chloride (0.14 mL, 1.7 mmol) and catalytic DMF (1 drop). The solution was stirred at rt for 1 h and the solvent was removed under reduced pressure to give the acid chloride as a yellow solid. A solution of the acid chloride (0.42 mmol) in pyridine (2.0 mL) was added to a cooled solution of 2-amino-5-chloro-N-methylbenzamide (0.12 g, 0.63 mmol) in pyridine (2.0 mL) at 0° C. The suspension was stirred at 0° C. for 1 h, warmed to rt and stirred for 16 h and then acidified with 1 M HCl. The precipitate was collected by filtration and recrystallised from EtOH/water providing (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]-5-chloro-N-methylbenzamide (80 mg, 43%) as a pale brown crystalline solid; mp 185.5-187.5° C.; δH (500 MHz, DMSO-d6) 2.81 (d, J=4.5 Hz, 3H, NHCH3), 6.93 (d, J=15.6 Hz, 1H, CH═CHCO), 7.26 (t, J=73 Hz, 1H, OCHF2), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.37 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.57 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 7.59 (d, J=15.6 Hz, 1H, CH═CHCO), 7.66 (dd, J3,4=8.5, J4,6=2.0 Hz, 1H, H4), 7.80 (m, 2H, H2′, H6), 8.56 (d, J3,4=8.5 Hz, 1H, H3), 8.85 (m, 1H, NHCH3), 11.54 (s, 1H, NH); δC (125 MHz, DMSO-d6) 26.3, 116.3 (t, J=259 Hz), 116.5 (t, J=259 Hz), 119.9, 120.7, 122.5, 122.6, 123.5, 126.6, 126.7, 127.7, 131.4, 132.8, 137.7, 139.4, 141.9, 142.7, 163.3, 167.3; HRMS (ESI+) calculated for C19H15ClF4N2O4 [M+Na]+ 469.0549, found 469.0549; νmax 1052, 1267, 1508, 1633, 1684, 3303 cm−1. warmed to rt stirred for 16 h The precipitate was collected by filtration recrystallised from EtOH/water

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

Procedure: To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature utility solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. The organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+ 332 It was then heated to 110° C. for 12 h After cooling to ambient temperature the solvent was distilled off the resulting solid was extracted for 48 h The organic layer was cooled to 0° C. when the product crystallized from the ethyl acetate

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

Procedure: To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature utility solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. the organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+ 332 It was then heated to 110° C. for 12 h After cooling to ambient temperature the solvent was distilled off the resulting solid was extracted for 48 h. was cooled to 0° C. when the product crystallized from the ethyl acetate

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

Procedure: To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature utility solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. The organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+ 332 It was then heated to 110° C. for 12 h After cooling to ambient temperature the solvent was distilled off the resulting solid was extracted for 48 h The organic layer was cooled to 0° C. when the product crystallized from the ethyl acetate

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

Procedure: To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature utility solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. the organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+ 332 It was then heated to 110° C. for 12 h After cooling to ambient temperature the solvent was distilled off the resulting solid was extracted for 48 h. was cooled to 0° C. when the product crystallized from the ethyl acetate

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

Procedure: To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature until it solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. The organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS:MH+332 It was then heated to 110° C. for 12 h After cooling to ambient temperature the solvent was distilled off the resulting solid was extracted for 48 h The organic layer was cooled to 0° C. when the product crystallized from the ethyl acetate

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

Procedure: To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature until it solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. the organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS:MH+332 It was then heated to 110° C. for 12 h After cooling to ambient temperature the solvent was distilled off the resulting solid was extracted for 48 h. was cooled to 0° C. when the product crystallized from the ethyl acetate

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

Procedure: To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature utility solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. The organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+332 It was then heated to 110° C. for 12 h After cooling to ambient temperature the solvent was distilled off the resulting solid was extracted for 48 h The organic layer was cooled to 0° C. when the product crystallized from the ethyl acetate

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

Procedure: To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature utility solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. the organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+332 It was then heated to 110° C. for 12 h After cooling to ambient temperature the solvent was distilled off the resulting solid was extracted for 48 h. was cooled to 0° C. when the product crystallized from the ethyl acetate

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

Procedure: To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol(1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature until it solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. The organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS:MH+332 It was then heated to 110° C. for 12 h After cooling to ambient temperature the solvent was distilled off the resulting solid was extracted for 48 h The organic layer was cooled to 0° C. when the product crystallized from the ethyl acetate