5-bromofuran-2-carboxamide

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

実験手順: In substantially the same manner as in Reference Example 47, 5-bromo-2-furancarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(5-bromo-2-furyl)-4-chloromethyloxazole. The yield was 23%. Recrystallization from diethyl ether-hexane gave colorless needles, mp 90-92° C.

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

実験手順: In a microwave flask, a suspension of 5-bromofuran-2-carboxamide (200 mg, 1.05 mmol), acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (Intermediate-5, 1.04 g, 2.11 mmol), X-PHOS (50.2 mg, 0.105 mmol), Pd2(dba)3 (48.2 mg, 0.052 mmol) and potassium phosphate (894 mg, 4.21 mmol) in dioxane (7 ml) and water (0.7 ml) was degassed with argon for 3-5 min. The mixture was set in a microwave at 125° C. for 30 min. Water was added and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash column chromatography (ethyl acetate in hexanes, gradient to 100% ethyl acetate) to obtain acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(5-carbamoyl-furan-2-yl)-benzyl ester (78.5 mg, 16%). was degassed with argon for 3-5 min Water was added the mixture was extracted with ethyl acetate twice The organic layer was washed with brine dried over sodium sulfate evaporated to dryness The crude material was purified by flash column chromatography (ethyl acetate in hexanes, gradient to 100% ethyl acetate)

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

実験手順: In substantially the same manner as in Reference Example 47, 5-bromo-2-furancarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(5-bromo-2-furyl)-4-chloromethyloxazole. The yield was 23%. Recrystallization from diethyl ether-hexane gave colorless needles, mp 90-92° C.

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

実験手順: In substantially the same manner as in Reference Example 47, 5-bromo-2-furancarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(5-bromo-2-furyl)-4-chloromethyloxazole. The yield was 23%. Recrystallization from diethyl ether-hexane gave colorless needles, mp 90-92° C.

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

実験手順: In the same way as described for Compound 145, step 2 using [4-(4-methyl-piperazin-1-yl)-phenyl]-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (0.068 g, 0.162 mmol) in THF (3 mL), 5-bromo-furan-2-carboxylic acid amide (0.061 g, 0.324 mmol) and Pd(PPh3)4 (0.009 g, 0.008 mmol). The crude reaction mixture is stirred in (1:1) TFA:DCM (2 mL) for 2 hours at room temperature. Purification of the crude by silica gel column chromatography, eluting with DCM followed by 97:3 DCM:NH3 (7M in MeOH), affords the title compound (7.4 mg, 11%). LCMS: Rt 1.81 min (99%) m/z (APCI) 418 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.49-2.53 (4H, m), 3.14 (4H, m), 6.97 (2H, d), 7.28 (1H, d, 7.34 (1H, d), 7.58 (1H, br s), 7.82 (1H, s), 7.90 (2H, d), 8.02 (1H, br s), 8.15 (1H, s), 8.48 (1H, s), 9.62 (1H, s). The crude reaction mixture Purification of the crude by silica gel column chromatography eluting with DCM

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

実験手順: In the same way as described for Compound 145, step 2 using [4-(4-methyl-piperazin-1-yl)-phenyl]-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (0.068 g, 0.162 mmol) in THF (3 mL), 5-bromo-furan-2-carboxylic acid amide (0.061 g, 0.324 mmol) and Pd(PPh3)4 (0.009 g, 0.008 mmol). The crude reaction mixture is stirred in (1:1) TFA:DCM (2 mL) for 2 hours at room temperature. Purification of the crude by silica gel column chromatography, eluting with DCM followed by 97:3 DCM:NH3 (7M in MeOH), affords the title compound (7.4 mg, 11%). LCMS: Rt 1.81 min (99%) m/z (APCI) 418 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.49-2.53 (4H, m), 3.14 (4H, m), 6.97 (2H, d), 7.28 (1H, d, 7.34 (1H, d), 7.58 (1H, br s), 7.82 (1H, s), 7.90 (2H, d), 8.02 (1H, br s), 8.15 (1H, s), 8.48 (1H, s), 9.62 (1H, s). The crude reaction mixture Purification of the crude by silica gel column chromatography eluting with DCM

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

実験手順: In the same way as described for Compound 145, step 2 using [4-(4-methyl-piperazin-1-yl)-phenyl]-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (0.068 g, 0.162 mmol) in THF (3 mL), 5-bromo-furan-2-carboxylic acid amide (0.061 g, 0.324 mmol) and Pd(PPh3)4 (0.009 g, 0.008 mmol). The crude reaction mixture is stirred in (1:1) TFA:DCM (2 mL) for 2 hours at room temperature. Purification of the crude by silica gel column chromatography, eluting with DCM followed by 97:3 DCM:NH3 (7M in MeOH), affords the title compound (7.4 mg, 11%). LCMS: Rt 1.81 min (99%) m/z (APCI) 418 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm).2.26 (3H, s), 2.49-2.53 (4H, m), 3.14 (4H, m), 6.97 (2H, d), 7.28 (1H, d, 7.34 (1H, d), 7.58 (1H, br s), 7.82 (1H, s), 7.90 (2H, d), 8.02 (1H, br s), 8.15 (1H, s), 8.48 (1H, s), 9.62 (1H, s). The crude reaction mixture Purification of the crude by silica gel column chromatography eluting with DCM

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

実験手順: In a microwave flask, a suspension of 5-bromofuran-2-carboxamide (200 mg, 1.05 mmol), acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (Intermediate-5, 1.04 g, 2.11 mmol), X-PHOS (50.2 mg, 0.105 mmol), Pd2(dba)3 (48.2 mg, 0.052 mmol) and potassium phosphate (894 mg, 4.21 mmol) in dioxane (7 ml) and water (0.7 ml) was degassed with argon for 3-5 min. The mixture was set in a microwave at 125° C. for 30 min. Water was added and the mixture was extracted with ethyl acetate twice. The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash column chromatography (ethyl acetate in hexanes, gradient to 100% ethyl acetate) to obtain acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(5-carbamoyl-furan-2-yl)-benzyl ester (78.5 mg, 16%). was degassed with argon for 3-5 min Water was added the mixture was extracted with ethyl acetate twice The organic layer was washed with brine dried over sodium sulfate evaporated to dryness The crude material was purified by flash column chromatography (ethyl acetate in hexanes, gradient to 100% ethyl acetate)

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

実験手順: In substantially the same manner as in Reference Example 47, 5-bromo-2-furancarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(5-bromo-2-furyl)-4-chloromethyloxazole. The yield was 23%. Recrystallization from diethyl ether-hexane gave colorless needles, mp 90-92° C.