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Stage #1: 1-dichlorophosphoryloxy-4-nitro-benzene; alanine isopropyl ester hydrochloride With triethylamine In tetrahydrofuran; dichloromethane at -78℃; for 0.5h;
Stage #2: 4-hydroxy-N,N-dimethyl-benzamide With triethylamine In dichloromethane at -78℃; for 1.5h; |
Intermediate 43. Isopropyl ((4-(dimethylcarbamoyl)phenoxy)(4- nitrophenoxy)phosphoryl)-L-alaninate
To a solution of 4-nitrophenyl phosphorodichloridate (620 mg, 2.422 mmol) and isopropyl L-alanine-HCl (406 mg, 2.422 mmol) in DCM-THF (10:3 mL) was added TEA (0.68 mL, 4.844 mmol) in DCM (3.32 mL) over 30 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C and N,N-dimethyl-4- hydroxybenzamide (400 mg, 2.422 mmol) was added in one portion and TEA (0.34 mL, 2.422 mmol) in DCM (3.66 mL) added over 30 min at -78 °C. The resulting mixture was stirred for 1 h after removal of dry ice bath, then diluted with EtOAc, washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc 0 to 100% in hexanes) to afford the product.1H NMR (400 MHz, Chloroform-d) δ 8.26 - 8.18 (m, 2H), 7.45 - 7.35 (m, 3H), 7.27 (m, 2H), 6.76 (m, 1H), 5.01 (m, 1H), 4.17 - 3.94 (m, 2H), 3.19 - 2.84 (m, 6H), 1.39 (m, 3H), 1.27 - 1.16 (m, 6H).31P NMR (162 MHz, Chloroform-d) δ -3.13, - 3.21. MS m/z = 480 (M+H). LCMS: MS m/z = 480.26 [M+1]; tR = 1.00 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6µ XB-C18100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 µL/min. |
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Stage #1: 1-dichlorophosphoryloxy-4-nitro-benzene; alanine isopropyl ester hydrochloride With triethylamine In tetrahydrofuran; dichloromethane at -78 - 20℃; for 1h;
Stage #2: 4-hydroxy-N,N-dimethyl-benzamide With triethylamine In tetrahydrofuran; dichloromethane at -78 - 20℃; for 1.5h; |
Intermediate 43. Isopropyl ((4-(dimethylcarbamoyl)phenoxy)(4- nitrophenoxy)phosphoryl)-L-alaninate
To a solution of 4-nitrophenyl phosphorodichloridate (620 mg, 2.422 mmol) and isopropyl L-alanine-HCl (406 mg, 2.422 mmol) in DCM-THF (10:3 mL) was added TEA (0.68 mL, 4.844 mmol) in DCM (3.32 mL) over 30 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C and N,N-dimethyl-4- hydroxybenzamide (400 mg, 2.422 mmol) was added in one portion and TEA (0.34 mL, 2.422 mmol) in DCM (3.66 mL) added over 30 min at -78 °C. The resulting mixture was stirred for 1 h after removal of dry ice bath, then diluted with EtOAc, washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc 0 to 100% in hexanes) to afford the product. 1H NMR (400 MHz, Chloroform-d) δ 8.26 - 8.18 (m, 2H), 7.45 - 7.35 (m, 3H), 7.27 (m, 2H), 6.76 (m, 1H), 5.01 (m, 1H), 4.17 - 3.94 (m, 2H), 3.19 - 2.84 (m, 6H), 1.39 (m, 3H), 1.27 - 1.16 (m, 6H). 31P NMR (162 MHz, Chloroform-d) δ -3.13, - 3.21. MS m/z = 480 (M+H). LCMS: MS m/z = 480.26 [M+1]; tR = 1.00 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL/min. |
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Stage #1: 1-dichlorophosphoryloxy-4-nitro-benzene; alanine isopropyl ester hydrochloride With triethylamine In tetrahydrofuran; dichloromethane at -78 - 20℃; for 1h;
Stage #2: 4-hydroxy-N,N-dimethyl-benzamide With triethylamine In tetrahydrofuran; dichloromethane at -78 - 20℃; for 1.5h; |
Intermediate 43. Isopropyl ((4-(dimethylcarbamoyl)phenoxy)(4- nitrophenoxy)phosphoryl)-L-alaninate
To a solution of 4-nitrophenyl phosphorodichloridate (620 mg, 2.422 mmol) and isopropyl L-alanine-HCl (406 mg, 2.422 mmol) in DCM-THF (10:3 mL) was added TEA (0.68 mL, 4.844 mmol) in DCM (3.32 mL) over 30 min at -78 °C. The resulting mixture was stirred for 30 min after removal of dry ice bath and cooled to -78 °C and N,N-dimethyl-4- hydroxybenzamide (400 mg, 2.422 mmol) was added in one portion and TEA (0.34 mL, 2.422 mmol) in DCM (3.66 mL) added over 30 min at -78 °C. The resulting mixture was stirred for 1 h after removal of dry ice bath, then diluted with EtOAc, washed with brine, concentrated in vacuo, and the resulting residue purified by silica gel column chromatography (EtOAc 0 to 100% in hexanes) to afford the product. 1H NMR (400 MHz, Chloroform-d) δ 8.26 - 8.18 (m, 2H), 7.45 - 7.35 (m, 3H), 7.27 (m, 2H), 6.76 (m, 1H), 5.01 (m, 1H), 4.17 - 3.94 (m, 2H), 3.19 - 2.84 (m, 6H), 1.39 (m, 3H), 1.27 - 1.16 (m, 6H). 31P NMR (162 MHz, Chloroform-d) δ -3.13, - 3.21. MS m/z = 480 (M+H). LCMS: MS m/z = 480.26 [M+1]; tR = 1.00 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Phenomenex Kinetex 2.6μ XB-C18100A, 50 x 3.0 mm; Solvents: acetonitrile with 0.1% formic acid, water with 0.1% formic acid; Gradient: 0 min-1.8 min 2-100% acetonitrile, 1.8 min-1.85 min 100%-2% acetonitrile, 1.85 min-2.00 min 2% ACN at 1800 μL/min. |
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