N,N-二乙基亚磷酰胺二叔丁酯

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a room temperature solution of 1-H-tetrazole (0.45M in acetonitrile, 56 mL, 25.3 mmol, solvent removed in vacuo prior to using) in tetrahydrofuran (100 mL) was added example 1, (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, (5.00 g, 9.39 mmol) and di-t-butyl N,N-diethylphosphoramidite (2.11 g, 8.45 mmol). The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was then cooled to −40° C. and a slurry of m-chloroperoxybenzoic acid (85% in CH2Cl2, 2.74 g, 12.2 mmol) was added while keeping the reaction temperature below 0° C. The reaction mixture was allowed to warm to room temperature and stir for 10 min and then an aqueous.solution of NaHSO3 (10%, 40 mL) was added. After stirring for an additional 1 h at room temperature, the reaction was transferred to a separatory funnel and extracted with EtOAc. The organic layer was washed with NaHCO3 (2×50 mL), dried (NaSO4) and concentrated. The crude material was purified via column chromatography (CH2Cl2:2 M NH3 in MeOH, 98:2), followed by recrystallization (CH2Cl2/hexanes) to afford 3.57 g (52%) of the desired product as a white crystalline material. MS m/z 724.9 (M+H)+; Retention time (LC-MS): 3.74 min. To a room temperature solution of 1-H-tetrazole (0.45M in acetonitrile, 56 mL, 25.3 mmol, solvent removed in vacuo was added example 1 The reaction mixture was then cooled to −40° C. the reaction temperature below 0° C to warm to room temperature stir for 10 min After stirring for an additional 1 h at room temperature the reaction was transferred to a separatory funnel extracted with EtOAc The organic layer was washed with NaHCO3 (2×50 mL) dried (NaSO4) concentrated The crude material was purified via column chromatography (CH2Cl2:2 M NH3 in MeOH, 98:2) followed by recrystallization (CH2Cl2/hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared by starting with 200 mg of Ac-Tyr(Bzl)-Val-Ala-N(C6H13)2 which was reduced with hydrogen under high pressure with 20% Pd/C catalyst in methanol. The catalyst was filtered. The solution was concentrated under reduced pressure, dissolved, and lyophilized (15B mg). The peptide was phosphotitylated with 1H-tetrazole (79.0 mg, 4.0 eq.) and di-t-butyl diethylphosphoramidite (312 mL, 4.0 eq.) in DCM (50 mL) while stirring at room temperature for 1 hour. The compound was then treated with 2.0 mL 70% aqueous t-butyl-hydroperoxide to the solution for 1 hour. The solution was then concentrated under reduced pressure. The peptide was deprotected with 95% TFA/5% water (20 mL) while stirring for 1 hour. The solution was then concentrated under reduced pressure and purified by preparative RP-HPLC using a gradient of 20% to 50% B over 120 minutes. The appropriate fractions were combined and lyophilized yielding Ac-Tyr(PO3H2)-Val-Ala-N(C6H13)2 (11.0 mg, MS=639.3, Calculated=640.43). The catalyst was filtered The solution was concentrated under reduced pressure dissolved The solution was then concentrated under reduced pressure while stirring for 1 hour The solution was then concentrated under reduced pressure purified by preparative RP-HPLC over 120 minutes

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