4-Methylmorpholine → ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate

Participants

Reaction Steps

A solution of 2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoic acid (1.47 g, 4.71 mmol.) in 20 mL of DCM was treated sequentially with ethyl 1(R)-[4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate hydrochloride (prepared in example 5) (1.44 g, 4.71 mmol.), N-methyl morpholine (1.80 mL, 16.34 mmol.), and HATU (2.14 g, 5.53 mmol.). The reaction mixture was stirred at rt under N2 for 3 h, and then concentrated in vacuo. The residue was dissolved in water and 1N HCl was added until the pH=5. This aqueous solution was extracted with EtOAc (3×). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) gave 1.55 g (58%) of ethyl 1(R)-[1-[2(S)-(tert-butoxycarbonylamino)-3-[N-cyclopropyl-N-(pent-4-enyl)amino]propanoyl]-4(R)-hydroxypyrrolidine-2(S)-carboxamido]-2(S)-vinylcyclopropanecarboxylate as a white foam: LC-MS (Phenomenex-Luna S10 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 4 mL/min. Detector Wavelength: 220 nM. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 1.38 min), MS m/z 564 (M++1).

Provenance & Evidence