3-chloro-2-fluorobenzoyl chloride

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound of example 204 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-chloro-2-fluoro benzoyl chloride.

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-chloro-2-fluorobenzoyl chloride (2.2 g; 11.4 mmol) in di-methylformamide (5 ml) was added triethylamine (1.7 mL; 11.7 mmol) and (S)-(+)-2-pyrrolidinemethanol (1.13 mL; 11.4 mmol). The mixture was stirred for 1 h then caesium carbonate (7.4 g; 22.7 mmol) was added and the reaction heated at 120° C. for 5 hours. The reaction was cooled to room temperature then diluted with water and extracted with ethyl acetate The organics were washed with water and dried (Na2SO4) evaporated in vacuo. The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane). On removal of solvent the pure amide crystallised and heptane/ether was added and the title compound collected (0.26 g). M.p., 89-90° C.; EIMS: m/z=238 [M+H]+ The reaction was cooled to room temperature extracted with ethyl acetate The organics were washed with water dried (Na2SO4) evaporated in vacuo The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane) On removal of solvent the pure amide crystallised heptane/ether was added the title compound collected (0.26 g) M.p., 89-90° C.

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-chloro-2-fluorobenzoyl chloride (2.2 g; 11.4 mmol) in di-methylformamide (5 ml) was added triethylamine (1.7 mL; 11.7 mmol) and (S)-(+)-2-pyrrolidinemethanol (1.13 mL; 11.4 mmol). The mixture was stirred for 1 h then caesium carbonate (7.4 g; 22.7 mmol) was added and the reaction heated at 120° C. for 5 hours. The reaction was cooled to room temperature then diluted with water and extracted with ethyl acetate The organics were washed with water and dried (Na2SO4) evaporated in vacuo. The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane). On removal of solvent the pure amide crystallised and heptane/ether was added and the title compound collected (0.26 g). M.p., 89-90° C.; EIMS: m/z=238 [M+H]+ The reaction was cooled to room temperature extracted with ethyl acetate The organics were washed with water dried (Na2SO4) evaporated in vacuo The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane) On removal of solvent the pure amide crystallised heptane/ether was added the title compound collected (0.26 g) M.p., 89-90° C.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound of example 204 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-chloro-2-fluoro benzoyl chloride.

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Chloro-2-fluorobenzoic acid (10.0 g, 0.06 mol), thionyl chloride (31 ml, 50 g, 0.4 mol) and dry toluene (40 ml) were heated at reflux for 3 h. The solution was cooled and the volatiles were removed in vacuo. The residue was azeotroped with toluene (2×30 ml) to give the product (11.5 g) as a clear yellow oil. at reflux for 3 h The solution was cooled the volatiles were removed in vacuo The residue was azeotroped with toluene (2×30 ml)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Chloro-2-fluorobenzoic acid (10.0 g, 0.06 mol), thionyl chloride (31 ml, 50 g, 0.4 mol) and dry toluene (40 ml) were heated at reflux for 3 h. The solution was cooled and the volatiles were removed in vacuo. The residue was azeotroped with toluene (2×30 ml) to give the product (11.5 g) as a clear yellow oil. at reflux for 3 h The solution was cooled the volatiles were removed in vacuo The residue was azeotroped with toluene (2×30 ml)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Chloro-2-fluorobenzoic acid (10.0 g, 0.06 mol), thionyl chloride (31 ml, 50 g, 0.4 mol) and dry toluene (40 ml) were heated at reflux for 3 h. The solution was cooled and the volatiles were removed in vacuo. The residue was azeotroped with toluene (2×30 ml) to give the product (11.5 g) as a clear yellow oil. at reflux for 3 h The solution was cooled the volatiles were removed in vacuo The residue was azeotroped with toluene (2×30 ml)

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-chloro-2-fluorobenzoyl chloride (2.2 g; 11.4 mmol) in dimethylformamide (5 ml) was added triethylamine (1.7 mL; 11.7 mmol) and (S)-(+)-2-pyrrolidinemethanol (1.13 mL; 11.4 mmol). The mixture was stirred for 1 h then caesium carbonate (7.4 g; 22.7 mmol) was added and the reaction heated at 120° C. for 5 hours. The reaction was cooled to room temperature then diluted with water and extracted with ethyl acetate The organics were washed with water and dried (Na2SO4) evaporated in vacuo. The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane). On removal of solvent the pure amide crystallised and heptane/ether was added and the title compound collected (0.26 g). M.p., 89-90° C.; EIMS: m/z=238 [M+H]+ The reaction was cooled to room temperature extracted with ethyl acetate The organics were washed with water dried (Na2SO4) evaporated in vacuo The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane) On removal of solvent the pure amide crystallised heptane/ether was added the title compound collected (0.26 g) M.p., 89-90° C.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (R)-Benzyl 3-(1-(7-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl)but-3-ynylamino)propylcarbamate (0.28 g, 0.53 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (0.22 mL, 1.60 mmol) was added followed by the addition of 2-fluoro-3-chlorobenzoyl chloride (0.112 g, 0.58 mmol). The reaction was stirred under a nitrogen atmosphere until the reaction was complete (LC/MS) (total of 5 min). The mixture was stirred for an additional 10 min, diluted with dichloromethane (50 mL) and washed with aqueous sodium bicarbonate (5 mL), water (5 ml×2) and brine solution and dried over anhydrous sodium sulfate. The solid was removed by filtration and the solvent removed under vacuum to provide (R)-benzyl 3-(3-chloro-N-(1-(7-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl)but-3-ynyl)-2-fluorobenzamido)propyl-carbamate as an orange solid (0.31 g, 0.45 mmol, 84%). mp 103-105° C. 1H-NMR (DMSO-d6): δ 9.41-8.94 (m, 1H), 8.21-5.62 (m, 16H), 5.35-4.80 (m, 2H), 3.46-1.15 (m, 11H). LC/MS: 686 [M+H]. (LC/MS) (total of 5 min) The mixture was stirred for an additional 10 min washed with aqueous sodium bicarbonate (5 mL), water (5 ml×2) and brine solution dried over anhydrous sodium sulfate The solid was removed by filtration the solvent removed under vacuum

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-chloro-2-fluorobenzoyl chloride (2.2 g; 11.4 mmol) in di-methylformamide (5 ml) was added triethylamine (1.7 mL; 11.7 mmol) and (S)-(+)-2-pyrrolidinemethanol (1.13 mL; 11.4 mmol). The mixture was stirred for 1 h then caesium carbonate (7.4 g; 22.7 mmol) was added and the reaction heated at 120° C. for 5 hours. The reaction was cooled to room temperature then diluted with water and extracted with ethyl acetate The organics were washed with water and dried (Na2SO4) evaporated in vacuo. The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane). On removal of solvent the pure amide crystallised and heptane/ether was added and the title compound collected (0.26 g). M.p., 89-90° C.; EIMS: m/z=238 [M+H]+ The reaction was cooled to room temperature extracted with ethyl acetate The organics were washed with water dried (Na2SO4) evaporated in vacuo The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane) On removal of solvent the pure amide crystallised heptane/ether was added the title compound collected (0.26 g) M.p., 89-90° C.