2-bromobenzamide

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 0.47 g (2.3 mmol) of 2-bromobenzamide and 0.34 g (2.7 mmol, 1.2 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2-bromobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.64 g (2.3 mmol) of 2-bromo-4-chloro-5-trifluoromethyl aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.25 g (Yield 22%) of the title compound as a solid. The reaction solution was cooled down to room temperature The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure

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

実験手順: The 1-phenyl substituted compound can be prepared as illustrated by the exemplary reaction in Scheme 4. Reaction of 2-bromobenzamide with oxalyl chloride in DCM, followed by addition of methyl 3-aminobenzoate produced methyl 3-(3-(2-bromobenzoyl)ureido)benzoate. Reaction of the benzoate with potassium tert-butoxide in DMF produced 1-(3-methoxycarbonylphenyl)quinazoline-2,4(1H,3H)-dione. Hydrolysis of the ester with NaOH in water-methanol produced 1-(3-carboxyphenyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acid with 2-(piperazin-1-yl)pyrimidine in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(3-(1-(pyrimidin-2-yl)piperazine-4-carbonyl)phenyl)quinazoline-2,4(1H,3H)-dione. as illustrated by the exemplary reaction in Scheme 4

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate F, 1.00 g, 5.3 mmol), 2-bromobenzamide (1.07 g, 5.3 mmol), potassium carbonate (0.89 g, 6.4 mmol), and copper (II) acetate (39 mg, 0.2 mmol) in DMF (20 mL) was heated (150° C.) in a sealed tube for 18 h. After cooling, the solution was adjusted to pH=4 using glacial acetic acid. The reaction mixture was extracted with dichloromethane (3×20 mL), and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 33-50% ethyl acetate/hexane afforded a yellow solid that was washed with diethyl ether to give 2-{[3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzamide (350 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.01 (s, 1H), 7.67 (dd, 1H), 7.32 (m, 7H), 6.77 (ddd, 1H), 6.08 (s, 1H), 2.19 (s, 3H), 2.00 (s, 3H); ES-MS m/z 307.1 (MH+); HPLC RT (min) 2.41. After cooling The reaction mixture was extracted with dichloromethane (3×20 mL) the combined organic extracts were washed with brine dried over anhydrous magnesium sulfate filtered concentrated in vacuo Flash chromatography of the residue over silica gel using 33-50% ethyl acetate/hexane afforded a yellow solid that was washed with diethyl ether

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

実験手順: 2-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzamide. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (52 mg, 0.083 mmol) and 2-bromobenzamide following General Procedure A. Flash chromatography (20-40% EtOAc/hexanes) yielded the title compound as a white solid (39 mg, 100%): 1H NMR (CDCl3, 600 MHz) δ 7.70 (d, 1H, J=7.8 Hz), 7.60 (s, 1H), 7.51-7.48 (m, 2H), 7.39-7.36 (m, 1H), 7.25-7.23 (m, 2H), 7.16-7.13 (m, 3H), 6.48 (br s, 1H), 6.19 (br s, 1H), 4.88 (t, 1H, J=6.0 Hz), 2.57 (t, 2H, J=7.5 Hz), 1.93-1.87 (m, 2H), 1.59-1.56 (m, 2H), 1.44-1.30 (m, 6H), 0.87 (s, 9H), 0.09 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 170.4, 143.6, 137.6, 134.4, 132.5, 131.3, 130.7, 129.7, 129.2, 129.1, 128.6, 128.5, 126.4, 120.1, 69.3, 37.3, 36.8, 32.2, 30.0, 26.6, 26.6, 25.9, 19.0, −4.0, −4.3.

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 2 mL conical vial was charged with Example 22B (10 mg, 0.024 mmol), 2-bromo-benzamide (7 mg, 0.036 mmol) and Pd(PPh3)4 (3 mg). The vial was evacuated and purged with argon. EtOH (0.5 mL) and toluene (0.5 mL) were added, followed by 2M aqueous Na2CO3 (0.036 mL, 0.072 mmol). The reaction was heated to 80° C. until disappearance of the starting material was noted. The reaction was cooled to room temperature and concentrated. The product was purified by reversed-phase HPLC to afford 2-(5-Acetyl-2-chloro-5,6,11,12-tetrahydro-dibenzo[b,f]azocin-9-yl)-benzamide (5.6 mg, 58%). HPLC Rt=1.62(b) min. m/z=405 (M+H+). The vial was evacuated purged with argon EtOH (0.5 mL) and toluene (0.5 mL) were added The reaction was cooled to room temperature concentrated The product was purified by reversed-phase HPLC

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 2 mL conical vial was charged with Example 22B (10 mg, 0.024 mmol), 2-bromo-benzamide (7 mg, 0.036 mmol) and Pd(PPh3)4 (3 mg). The vial was evacuated and purged with argon. EtOH (0.5 mL) and toluene (0.5 mL) were added, followed by 2M aqueous Na2CO3 (0.036 mL, 0.072 mmol). The reaction was heated to 80° C. until disappearance of the starting material was noted. The reaction was cooled to room temperature and concentrated. The product was purified by reversed-phase HPLC to afford 2-(5-Acetyl-2-chloro-5,6,11,12-tetrahydro-dibenzo[b,f]azocin-9-yl)-benzamide (5.6 mg, 58%). HPLC Rt=1.62(b) min. m/z=405 (M+H+). The vial was evacuated purged with argon EtOH (0.5 mL) and toluene (0.5 mL) were added The reaction was cooled to room temperature concentrated The product was purified by reversed-phase HPLC

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

実験手順: The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromobenzamide. MS (ESI): mass calcd. for C17H13FN4O, 308.11; m/z found, 309.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.01 (s, 1H), 7.86 (m, 1H), 7.75 (s, 1H), 7.55-7.26 (m, 7H), 6.70 (s, 2H).

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 0.47 g (2.3 mmol) of 2-bromobenzamide and 0.34 g (2.7 mmol, 1.2 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2-bromobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.64 g (2.3 mmol) of 2-bromo-4-chloro-5-trifluoromethyl aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.25 g (Yield 22%) of the title compound as a solid. The reaction solution was cooled down to room temperature The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure