tert-butyl N-[(2S)-1-amino-1-oxopropan-2-yl]carbamate

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

実験手順: To a solution containing Boc-L-alanine (1.0 g, 5.29 mmol) in a mixture of tetrahydrofuran (25 mL) and N,N-dimethylformamide (5 mL) were added EDAC (1.5 g, 7.82 mmol) and N-hydroxysuccinimide (0.91 g, 7.91 mmol) and the mixture was stirred at room temperature for 16 hours. Aqueous ammonium hydroxide solution (15 mL, 28%) was added and the mixture was stirred for 0.5 hours at room temperature. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the product (0.483 g, 49% yield), which was used without further purification. the mixture was stirred for 0.5 hours at room temperature The reaction was partitioned between ethyl acetate and water the organic was washed with brine dried over MgSO4 filtered evaporated

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

実験手順: To a solution containing Boc-L-alanine (1.0 g, 5.29 mmol) in a mixture of tetrahydrofuran (25 mL) and N,N-dimethylformamide (5 mL) were added EDAC (1.5 g, 7.82 mmol) and N-hydroxysuccinimide (0.91 g, 7.91 mmol) and the mixture was stirred at room temperature for 16 hours. Aqueous ammonium hydroxide solution (15 mL, 28%) was added and the mixture was stirred for 0.5 hours at room temperature. The reaction was partitioned between ethyl acetate and water, and the organic was washed with brine and dried over MgSO4, filtered and evaporated to give the product (0.483 g, 49% yield), which was used without further purification. the mixture was stirred for 0.5 hours at room temperature The reaction was partitioned between ethyl acetate and water the organic was washed with brine dried over MgSO4 filtered evaporated

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

実験手順: To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester 3.94 g, 20.9 mmol) in DCM (20 mL) was added triethyloxonium tetrafluoroborate (3.35 g, 17.6 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (20 mL). Acetic acid 3-amino-6-fluoro-2-phenylaminobenzyl ester (2.3 g, 8.38 mmol) was added and the reaction heated at 75° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as an off white solid. LCMS (Method C): RT=3.37 min, [M+H-tBu]+=372, 100%, [M+H]+=428, 40%. dissolved The reaction mixture was concentrated in vacuo the residue dissolved in ethanol (20 mL) the reaction heated at 75° C. for 1 h The reaction mixture was concentrated in vacuo the residue dissolved in water the product extracted with EtOAc (3×20 mL) The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane)

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

実験手順: To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester 3.94 g, 20.9 mmol) in DCM (20 mL) was added triethyloxonium tetrafluoroborate (3.35 g, 17.6 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (20 mL). Acetic acid 3-amino-6-fluoro-2-phenylaminobenzyl ester (2.3 g, 8.38 mmol) was added and the reaction heated at 75° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as an off white solid. LCMS (Method C): RT=3.37 min, [M+H-tBu]+=372, 100%, [M+H]+=428, 40%. dissolved The reaction mixture was concentrated in vacuo the residue dissolved in ethanol (20 mL) the reaction heated at 75° C. for 1 h The reaction mixture was concentrated in vacuo the residue dissolved in water the product extracted with EtOAc (3×20 mL) The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane)

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

実験手順: To a suspension of ((S)-1-carbamoyl-ethyl)carbamic acid tert-butyl ester (1.81 g, 9.63 mmol) in DCM (20 mL) was added triethyloxonium tetrafluoroborate (1.54 g, 8.08 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (20 mL). 3-Amino-6-fluoro-2-(5-fluoropyridin-3-ylamino)benzonitrile (948 mg, 3.86 mmol) was added and the reaction heated at 70° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as an off white solid. LCMS (Method C): RT=3.20 min, [M+H-tBu]+=344, 100%, [M+H]+=400, 10%. dissolved The reaction mixture was concentrated in vacuo the residue dissolved in ethanol (20 mL) the reaction heated at 70° C. for 1 h The reaction mixture was concentrated in vacuo the residue dissolved in water the product extracted with EtOAc (3×20 mL) The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane)

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

実験手順: To a suspension of ((S)-1-carbamoyl-ethyl)carbamic acid tert-butyl ester (1.81 g, 9.63 mmol) in DCM (20 mL) was added triethyloxonium tetrafluoroborate (1.54 g, 8.08 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (20 mL). 3-Amino-6-fluoro-2-(5-fluoropyridin-3-ylamino)benzonitrile (948 mg, 3.86 mmol) was added and the reaction heated at 70° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as an off white solid. LCMS (Method C): RT=3.20 min, [M+H-tBu]+=344, 100%, [M+H]+=400, 10%. dissolved The reaction mixture was concentrated in vacuo the residue dissolved in ethanol (20 mL) the reaction heated at 70° C. for 1 h The reaction mixture was concentrated in vacuo the residue dissolved in water the product extracted with EtOAc (3×20 mL) The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane)

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

実験手順: To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (435 mg, 2.31 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (369 mg, 1.94 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (5 mL). (3-Amino-6-fluoro-2-phenylaminophenyl)acetonitrile (223 mg, 0.92 mmol) was added and the reaction heated at 70° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) LCMS (Method C): RT=3.36 min, [M+H]+=395. The product was dissolved in HCl in dioxane (4N, 10 mL) and the reaction stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title product as an off white solid (227 mg, 67%). LCMS (Method C): RT=1.88 min, [M+H]+=295. dissolved The reaction mixture was concentrated in vacuo the residue dissolved in ethanol (5 mL) the reaction heated at 70° C. for 1 h The reaction mixture was concentrated in vacuo the residue dissolved in water the product extracted with EtOAc (3×20 mL) The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) LCMS (Method C) The product was dissolved in HCl in dioxane (4N, 10 mL) the reaction stirred at RT for 1 h The reaction mixture was concentrated in vacuo

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

実験手順: To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (435 mg, 2.31 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (369 mg, 1.94 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (5 mL). (3-Amino-6-fluoro-2-phenylaminophenyl)acetonitrile (223 mg, 0.92 mmol) was added and the reaction heated at 70° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) LCMS (Method C): RT=3.36 min, [M+H]+=395. The product was dissolved in HCl in dioxane (4N, 10 mL) and the reaction stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title product as an off white solid (227 mg, 67%). LCMS (Method C): RT=1.88 min, [M+H]+=295. dissolved The reaction mixture was concentrated in vacuo the residue dissolved in ethanol (5 mL) the reaction heated at 70° C. for 1 h The reaction mixture was concentrated in vacuo the residue dissolved in water the product extracted with EtOAc (3×20 mL) The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) LCMS (Method C) The product was dissolved in HCl in dioxane (4N, 10 mL) the reaction stirred at RT for 1 h The reaction mixture was concentrated in vacuo

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

実験手順: To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (779 mg, 4.1 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (671 mg, 3.5 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (5 mL). 4-Fluoro-3-methoxy-N2-phenylbenzene-1,2-diamine (283 mg, 1.2 mmol) was added and the reaction heated at 70° C. for 1.5 hours. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (349 mg, 74%). LCMS (Method C): RT=3.52 min, [M+H]+=386. dissolved The reaction mixture was concentrated in vacuo the residue dissolved in ethanol (5 mL) the reaction heated at 70° C. for 1.5 hours The reaction mixture was concentrated in vacuo the residue dissolved in water the product extracted with EtOAc (3×20 mL) The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane)

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

実験手順: To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (779 mg, 4.1 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (671 mg, 3.5 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (5 mL). 4-Fluoro-3-methoxy-N2-phenylbenzene-1,2-diamine (283 mg, 1.2 mmol) was added and the reaction heated at 70° C. for 1.5 hours. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (349 mg, 74%). LCMS (Method C): RT=3.52 min, [M+H]+=386. dissolved The reaction mixture was concentrated in vacuo the residue dissolved in ethanol (5 mL) the reaction heated at 70° C. for 1.5 hours The reaction mixture was concentrated in vacuo the residue dissolved in water the product extracted with EtOAc (3×20 mL) The combined organic extracts were washed with brine dried (MgSO4) concentrated in vacuo The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane)

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

実験手順: Triethyloxonium tetrafluoroborate (1.06 g, 5.60 mmol) was added to a solution of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (1.26 g, 6.67 mmol) in DCM (20 mL) at 20° C. under nitrogen and the resultant mixture stirred for 3 h then concentrated in vacuo. The resultant residue was dissolved in ethanol (20 mL) and 4-fluoro-N2-(2-methyl-2H-pyrazol-3-yl)-benzene-1,2-diamine (0.55 g, 2.67 mmol) added, and the reaction mixture stirred at reflux for 16 h under nitrogen. The reaction mixture was concentrated in vacuo and residue partitioned between DCM (×3) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM) to give the title compound as a yellow oil (1.25 g, 100%). LCMS (Method C): RT 3.08 min [M+H]+ 360.2. 310091751 then concentrated in vacuo The resultant residue was dissolved in ethanol (20 mL) at reflux for 16 h under nitrogen The reaction mixture was concentrated in vacuo and residue partitioned between DCM (×3) and saturated aqueous NaHCO3 The combined DCM extracts were dried (Na2SO4) concentrated in vacuo The resultant residue was purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM)

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

実験手順: Triethyloxonium tetrafluoroborate (1.06 g, 5.60 mmol) was added to a solution of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (1.26 g, 6.67 mmol) in DCM (20 mL) at 20° C. under nitrogen and the resultant mixture stirred for 3 h then concentrated in vacuo. The resultant residue was dissolved in ethanol (20 mL) and 4-fluoro-N2-(2-methyl-2H-pyrazol-3-yl)-benzene-1,2-diamine (0.55 g, 2.67 mmol) added, and the reaction mixture stirred at reflux for 16 h under nitrogen. The reaction mixture was concentrated in vacuo and residue partitioned between DCM (×3) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM) to give the title compound as a yellow oil (1.25 g, 100%). LCMS (Method C): RT 3.08 min [M+H]+ 360.2. 310091751 then concentrated in vacuo The resultant residue was dissolved in ethanol (20 mL) at reflux for 16 h under nitrogen The reaction mixture was concentrated in vacuo and residue partitioned between DCM (×3) and saturated aqueous NaHCO3 The combined DCM extracts were dried (Na2SO4) concentrated in vacuo The resultant residue was purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM)