propanedioyl dichloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A quantity of 3.85 g of 1-t.butyl-3-phenylurea is stirred at 0° C. in 50 ml of dry diethyl ether. 1.95 ml of malonylchloride are slowly added dropwise to this solution. After the addition of a little triethylamine the reaction mixture is slowly heated to approximately 30° C. After 2 hours 50 ml of water are added. The ether layer is separated, washed with water, dried and evaporated. After recrystallisation from ethanol, 1-phenyl-3-t.butyl-barbituric acid is obtained in a yield of 0.6 g; melting-point 118°-125° C. The resulting product is acetylated as described in Example III, the title compound (28) being obtained; melting-point 145°-148° C. The ether layer is separated washed with water dried evaporated After recrystallisation from ethanol, 1-phenyl-3-t

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

Procedure: Malonyl dichloride (1.48 mL) in THF (50 mL) is added dropwise over 35 min to a 0° C. solution of N-Isopropyl-N-(3-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Part C, (5.45 g, 14.1 mmol) in THF (140 mL) and the resultant mixture allowed to attain RT overnight. The solvents were removed in vacuo and the residue diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium hydrogen carbonate (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), and concentrated in vacuo. The resulting oil is purified by silica gel flash column chromatography using 3% methanol in methylene chlorideas eluent to afford 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(3-methoxy-phenyl) acetamide (2.4 g) as an amber foam: 1H NMR (300 MHz, CDCl3) δ7.3-7.1 (m, 10H), 7.02 (t, 1H, J=7.2), 6.92 (dd 1H, J=8.6,2.4), 6.83 (d, 1H, J=7.2), 4.95 (m, 1H, J=6.8), 4.38 (m, 1H), 4.02 (m, 1H), 3.78 (s, 3H), 3.48 (dd, 2H, J=39.3, 11.9), 1.06 (m, 6H). The solvents were removed in vacuo the residue diluted with ethyl acetate (100 mL) washed with saturated aqueous sodium hydrogen carbonate (100 mL), water (100 mL), brine (100 mL) dried (MgSO4) concentrated in vacuo The resulting oil is purified by silica gel flash column chromatography

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

Procedure: Malonyl dichloride (0.50 mL) in THF (22 mL) is added dropwise over 35 min to a 0° C. solution of N-Isopropyl-N-(2-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Part C, (1.90 g, 4.87 mmol) in THF (45 mL) and the resultant mixture allowed to attain RT overnight. The solvents were removed in vacuo and the residue purified by silica gel flash column chromatography using 2% methanol in methylene chlorideas eluent to afford 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(2-methoxy-phenyl) acetamide (770 mg) as a cream foam, which exists as 3:2 mixture of rotamers (major rotamer recorded): 1H NMR (300 MHz, CDCl3) δ7.60-6.90 (m, 13H), 5.05 (m, 1H, J=6.9), 4.60-3.40 (m, 7H), 1.12 (m, 6H). The solvents were removed in vacuo the residue purified by silica gel flash column chromatography

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

Procedure: A solution of 5.62 g 2-(4,5-difluoro-2-phenylamino-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, (13.2 mmol) in 50 mL of tetrahydrofuran is transferred to an addition funnel. A solution of 1.60 mL of malonyl dichloride (16.53 mmol, 1.25 equiv) in 50 mL tetrahydrofuran is transferred to a separate addition funnel. Each solution of each reagent is simultaneously added dropwise over 20 min. to 250 mL of tetrahydrofuran at ambient temperature under nitrogen with vigorous agitation. After stirring 16 hrs. at ambient temperature, the reaction mixture is concentrated in vacuo. The residue is purified on flash grade silica gel using 40-50% ethyl acetate in hexane. The appropriate fractions were combined, evaporated in vacuo, dried under high vacuum for 2 hrs., and then triturated with hexane. The hexane is removed in vacuo and the residual solid is dried under high vacuum to provide 2.340 g of 2-(7,8-Difluoro-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an off-white solid: 1H NMR (300 MHz, CDCl3) δ7.37 (m, 7H), 7.15 (m, 1H), 7.01 (m, 2H), 6.76 (dd, 1H, J=7.8, 11.1), 5.04 (m, 1H), 4.36 (d, 1H, J=16.3), 4.00 (d, 1H, J=16.5), 3.89 (s, 3H), 3.62 (d, 1H, J=12.2), 3.54 (d, 1H, J=12.2), 1.14 (m, 6H); low resolution MS (FAB)m/e 494 (MH+). is transferred to an addition funnel at ambient temperature, the reaction mixture is concentrated in vacuo The residue is purified on flash grade silica gel using 40-50% ethyl acetate in hexane evaporated in vacuo dried under high vacuum for 2 hrs , and then triturated with hexane The hexane is removed in vacuo the residual solid is dried under high vacuum

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

Procedure: A solution of 1.72 g of 2-(2-amino-4-fluoro-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part C, (5.20 mmol) in 15 mL of tetrahydrofuran is transferred to an addition funnel. A solution of 0.506 mL of malonyl dichloride (5.20 mmol, 1.0 equiv) in 15 mL tetrahydrofuran is transferred to a separate addition funnel. Each solution of each reagent is simultaneously added dropwise over 30 min. to 100 mL of tetrahydrofuran at ambient temperature under nitrogen with vigorous agitation. After stirring for 20 min. at ambient temperature, an additional 0.506 mL of malonyl dichloride (5.20 mmol, 0.1 equiv) is added in a single portion. The reaction is allowed to stir an additional 2.5 hrs. and then evaporated in vacuo to a residue. The residue is purified on flash grade silica gel with 1:3 ethyl acetate/hexane followed by 3:1 ethyl acetate/hexane. The appropriate fractions were combined, evaporated in vacuo to a residue and triturated with hexane. The hexane is removed in vacuo and the residual solid is dried under high vacuum to provide 1.06 g of 2-(7-Fluoro-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a tan solid: 1H NMR (300 MHz, CDCl3) δ8.14 (s, br, 1H), 7.45 (dd, 1H, J=5.5. 9.2), 7.29 (m, 1H), 7.05 (m, 1H), 6.94 (m, 3H), 6.78 (m, 1H), 4.99 (m, 1H), 4.37 (d, 1H, J=16.4), 3.82 (s, 3H), 3.69 (d, 1H, J=16.0), 3.40 (m, 2H), 1.09 (d, 6H, J=6.8); low resolution MS (FAB)m/e 400 (MH+). is transferred to an addition funnel to stir an additional 2.5 hrs and then evaporated in vacuo to a residue The residue is purified on flash grade silica gel with 1:3 ethyl acetate/hexane evaporated in vacuo to a residue triturated with hexane The hexane is removed in vacuo the residual solid is dried under high vacuum

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

Procedure: To a stirred solution of 419 mg (1.01 mmol) N-Cyclopentyl-N-(4-methoxy-phenyl)-2-(6-phenylamino-cyclohexa-2,4-dienylamino)-acetamide, prepared as in Part B, in 5 mL THF is added 170 mg (1.21 mmol, 1.2 equiv) Malonyl dichloride dissolved in 2 mL THF dropwise at 0° C. The reaction is stirred 1 h at 0° C. followed by 18 h at ambient temperature. The solvent is removed in vacuo and the residue purified by flash chromatography on 15 g silica gel eluted with EtOAc/Hexanes (1:1, 300 mL). Appropriate fractions were combined and concentrated in vacuo to give 249 mg (0.515 mmol) of N-Cyclopentyl-2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-(4-methoxy-phenyl)-acetamide as a clear glass: 1H NMR (CDCl3, 300 MHz) δ7.43-7.20 (m, 8H), 7.09 (m, 2H), 6.97 (m, 3H), 4.95 (m, 1H), 4.38 (d, 1H, J=16.4), 4.06 (d, 1H, J=16.3), 3.84 (s, 3H), 3.59 (d, 1H, J=12.0), 3.49 (d, 1H, J=11.9), 1.90 (m, 2H), 1.52 (m, 4H), 1.35 (m, 2H); TLC Rf =0.16 (EtOAc/Hexanes, 1:1). followed by 18 h at ambient temperature The solvent is removed in vacuo the residue purified by flash chromatography on 15 g silica gel eluted with EtOAc/Hexanes (1:1, 300 mL) concentrated in vacuo

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

Procedure: To 60 mL of THF at 0° C. is added dropwise over 20 min simultaneously a solution of 2.0 g (4.68 mmol) of N-Isopropyl-2-(2-phenylamino-phenylamino)-N-(4-trifluoromethyl-phenyl) acetamide, prepared as in Part A, in 30 mL of THF and 590 μL (6.08 mmol, 1.3 equiv) of malonyl dichloride in 30 mL of THF. The resulting solution is stirred at RT for 20 h and the solvent removed in vacuo. Purification of the resulting brown oil by silica gel flash column chromatography using hexane/EtOAc 3/2 as eluent afforded 1.35 g of the title compound as a light tan solid: mp 186°-188° C.; 1H NMR (CDCl3, 400 MHz) δ7.74 (d, 2H, J=8.1), 7.42 (d, 2H, J=8.1), 7.36 (m, 3H), 7.25 (m, 4H), 7.08 (ddd, 1H, J=1.4, 8.4, 8.4), 6.90 (dd, 1H, J=1.2, 8.2), 5.06 (m, 1H), 4.12 (dd, 2H, J=14.4, 95.5), 3.52 (dd, 2H, J=12.0, 34.5), 1.11 (d, 6H, J=6.6); low resolution MS (FAB)m/e 496 (MH+), 293, 265; Anal. (C27H24F3N3O3) Calcd. C, 65.45; H, 4.88; N, 8.48; Found C, 65.16; H, 4.95; N, 8.33. the solvent removed in vacuo Purification of the resulting brown oil by silica gel flash column chromatography

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

Procedure: To a stirred solution of 10 g (37.14 mmol) of 2-(2-Aminophenylamino)-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 45, in 100 mL of THF is added 5.2 g (37.14 mmol, 1 equiv.) of malonyl dichloride. The resulting solution is stirred at RT for 2 h and the solvent removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 6.1 g of the title compound as an oil: 1H NMR (CDCl3, 300 MHz) δ9.65 (s, 1H), 7.4 (bd, 1H, J=9), 7.30-6.93 (m, 7H), 5.09-4.95 (m, 1H), 4.42 (d, 1H, J=16), 3.68 (d, 1H, J=17), 3.36 (d, 2H, J=4), 1.09 (d, 6H, J=7). the solvent removed in vacuo Purification by silica gel flash column chromatography

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

Procedure: To 100 mL of THF at 0° C. is added dropwise over 20 min simultaneously a solution of 8.0 g (20.5 mmol) of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Intermediate 43, in 100 mL of THF and 2.40 mL (24.6 mmol, 1.2 equiv) of malonyl dichloride in 100 mL of THF. The resulting solution is stirred at RT for 20 h and the solvent removed in vacuo. Purification of the resulting brown oil by silica gel flash column chromatography afforded 7.5 g of the title compound as a light tan solid: 1H NMR (CDCl3, 300 MHz) δ7.44-6.86 (m, 13H), 5.02 (m, 1H), 4.38 (d, 1H, J=16.6), 4.04 (d, 1H, J=16.6), 3.84 (s, 3H), 2.55 (m, 2H), 1.10 (d, 6H, J=6.8); Rf =0.15 in hexane/EtOAc 1/1. the solvent removed in vacuo Purification of the resulting brown oil by silica gel flash column chromatography

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

Procedure: To 20 mL of THF at 0° C. is added dropwise over 10 min simultaneously a solution of 1.97 g (5.48 mmol) of N-isopropyl-N-phenyl-2-(2-phenylamino-phenylamino) acetamide in 20 mL of THF and 0.53 mL (5.48 mmol) of malonyl dichloride in 20 mL of THF. The resulting red-brown solution is stirred at RT for 5.5 h and the solvent removed in vacuo. Purification of the resulting brown oil by silica gel flash chromatography (50 to 75% ethyl acetate/petroleum ether) followed by recrystallization from ethyl acetate/petroleum ether gave 0.84 g of the title compound as a white powder: mp. 199°-200° C.; 1H NMR (CDCl3, 300 MHz) δ7.6-7.2 (m, 12H), 7.09 (t, 1H, J=8), 6.90 (d, 1H, J=8), 5.05 (m, 1H), 4.38 (d, 1H, J=17), 4.04 (d, 1H, J=17), 3.54 (dd, 2H, J=5, 22), 1.10 (d, 6H, J=7); low resolution MS (FAB) m/e 428 (MH+). the solvent removed in vacuo Purification of the resulting brown oil by silica gel flash chromatography (50 to 75% ethyl acetate/petroleum ether) followed by recrystallization from ethyl acetate/petroleum ether

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

Procedure: A solution of 1-phenyl-1-trimethylsiloxyethylene (25.0 g, 130 mmol) in absolute ether (400 mL) was cooled to −78° C., and malonyl dichloride (6.40 mL, 65.0 mmol) was added dropwise to the resulting solution by using a dropping funnel. The mixture was gradually heated to room temperature, stirred at room temperature (5 to 10° C.) for 14 hours, and further stirred at 30° C. for 24 hours. The thus-produced yellow precipitate was filtered and washed with absolute ether to give the target 4-hydroxy-6-methyl-2-pyrone (8.40 g, 67%) as a yellow solid. further stirred at 30° C. for 24 hours The thus-produced yellow precipitate was filtered washed with absolute ether