1-fluoro-4-(isocyanatomethyl)benzene

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

実験手順: A solution of 5-(6-bromo-2-phenylquinolin-3-yl)pentanoic acid (1A, 100 mg, 0.260 mmol) in THF (4.00 mL, 49.3 mmol) in a flame dried vial under an atmosphere of nitrogen gas was treated with lithium hexamethyldisilazide (1M/THF, 780 uL). The reaction mixture stirred at RT for 10 min before it was cooled to −78° C. in an acetone/dry ice bath. A solution of nBuLi (2.5M/hexane, 229.0 uL) was slowly added and the reaction progressed for 5 minutes at −78° C. before addition of 4-fluorobenzyl isocyanate (398 uL, 3.12 mmol). The reaction was stirred at −78° C. for 20 minutes, acidified with 10% HCl to pH 1, and diluted with DCM. The biphasic solution was separated and the aqueous layer was extracted with DCM (3×). The combined organic phase was dried over anhydrous sodium sulfate, concentrated and chromatographed (5-100% EtOAc/hexanes) to provide 2 (28 mg; Yield=24%, LCMS (M+H)=439). was cooled to −78° C. in an acetone/dry ice bath The reaction was stirred at −78° C. for 20 minutes The biphasic solution was separated the aqueous layer was extracted with DCM (3×) The combined organic phase was dried over anhydrous sodium sulfate concentrated chromatographed (5-100% EtOAc/hexanes) to provide 2 (28 mg; Yield=24%, LCMS (M+H)=439)

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

実験手順: A solution of 5-(6-bromo-2-phenylquinolin-3-yl)pentanoic acid (1A, 100 mg, 0.260 mmol) in THF (4.00 mL, 49.3 mmol) in a flame dried vial under an atmosphere of nitrogen gas was treated with lithium hexamethyldisilazide (1M/THF, 780 uL). The reaction mixture stirred at RT for 10 min before it was cooled to −78° C. in an acetone/dry ice bath. A solution of nBuLi (2.5M/hexane, 229.0 uL) was slowly added and the reaction progressed for 5 minutes at −78° C. before addition of 4-fluorobenzyl isocyanate (398 uL, 3.12 mmol). The reaction was stirred at −78° C. for 20 minutes, acidified with 10% HCl to pH 1, and diluted with DCM. The biphasic solution was separated and the aqueous layer was extracted with DCM (3×). The combined organic phase was dried over anhydrous sodium sulfate, concentrated and chromatographed (5-100% EtOAc/hexanes) to provide 2 (28 mg; Yield=24%, LCMS (M+H)=439). was cooled to −78° C. in an acetone/dry ice bath The reaction was stirred at −78° C. for 20 minutes The biphasic solution was separated the aqueous layer was extracted with DCM (3×) The combined organic phase was dried over anhydrous sodium sulfate concentrated chromatographed (5-100% EtOAc/hexanes) to provide 2 (28 mg; Yield=24%, LCMS (M+H)=439)

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 1-fluoro-4-(isocyanatomethyl)benzene, the product of Example 73A and the procedure described in Example 73B (white solid, 108 mg, 65%). MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.61; H, 3.35; N, 11.14.

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 1-fluoro-4-(isocyanatomethyl)benzene, the product of Example 73A and the procedure described in Example 73B (white solid, 108 mg, 65%). MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.61; H, 3.35; N, 11.14.

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: Following the procedure of Example 5, making variations only as required to use 4-fluorobezylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white solid (56% yield). 1H NMR (500 MHz, CDCl3) δ 8.13, 7.78, 7.66, 7.60, 7.33, 7.21, 7.09, 6.83, 4.50, 3.91-4.00, 3.73-3.80, 3.34-3.48, 3.05-3.22. MS (ES+) m/z 503 (M+1).

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

実験手順: 4-Fluorobenzylisocyanate (0.130 ml, 1.02 mmol) was added to a solution of 1-ethyl 5-methyl 3-amino-1H-thieno[3,2-c]pyrazole-1,5-dicarboxylate (85 mg, 0.32 mmol) in anhydrous dichloromethane (5 ml). After stirring for 96 h at room temperature, the solvent was removed under reduced pressure, and the residue purified by chromatography over silica gel (eluent dichloromethane 50; methyl alcohol 0.5; 6% aqueous ammonia 0.1) to yield 80 mg of the title compound as a white solid. Chromatographic method A, Rt 6.11, [M+H]+ 621. the solvent was removed under reduced pressure the residue purified by chromatography over silica gel (eluent dichloromethane 50; methyl alcohol 0.5; 6% aqueous ammonia 0.1)

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

実験手順: 1,1-Bis(3-fluorophenyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.18 g, 0.55 mmol) was dissolved in tetrahydrofuran (5 mL). (4-Fluorophenyl)methyl isocyanate (0.15 g, 1.0 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=50:1 to ethyl acetate) to obtain the title compound (0.25 g, yield 96%). The reaction solution was concentrated under reduced pressure The residue was purified with silica gel column chromatography (hexane:ethyl acetate=50:1 to ethyl acetate)

反応条件: temp:0.00; pressure:0.00; stir: