2-amino-5-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-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 solution of 5-chloroisatoic anhydride (10.0 g, 51 mmol) in tetrahydrofuran (100 ml) at ambient temperature was added a 40% w/w aqueous solution of methylamine (19.80 g, 255 mmol) dropwise. The mixture was stirred at an ambient temperature for 1 hour. Ethyl acetate (100 ml) and water (100 ml) were added and the phases separated. The aqueous layer was back extracted with ethyl acetate (100 ml) and the combined organics were evaporated under reduced pressure to afford a white solid, which was recrystallised from toluene (60 ml) to afford the title compound as a white solid (8.15 g) the phases separated The aqueous layer was back extracted with ethyl acetate (100 ml) the combined organics were evaporated under reduced pressure to afford a white solid, which was recrystallised from toluene (60 ml)

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

Procedure: To a solution of 5-chloroisatoic anhydride (10.0 g, 51 mmol) in tetrahydrofuran (100 ml) at ambient temperature was added a 40% w/w aqueous solution of methylamine (19.80 g, 255 mmol) dropwise. The mixture was stirred at an ambient temperature for 1 hour. Ethyl acetate (100 ml) and water (100 ml) were added and the phases separated. The aqueous layer was back extracted with ethyl acetate (100 ml) and the combined organics were evaporated under reduced pressure to afford a white solid, which was recrystallised from toluene (60 ml) to afford the title compound as a white solid (8.15 g) the phases separated The aqueous layer was back extracted with ethyl acetate (100 ml) the combined organics were evaporated under reduced pressure to afford a white solid, which was recrystallised from toluene (60 ml)

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