4-Methylmorpholine → HCID 89123998, compound

Participants

Reaction Steps

A solution of (S)-5-cyclopropyl-4,4-difluoro-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)-pentanoic acid (0.5 g; 1.35 mmol) in dry dichloromethane (16 mL) under nitrogen was treated with HOBt (228 mg; 1.49 mmol; 110 mol %), EDC hydrochloride (286 mg; 1.49 mmol; and (3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide hydrochloride (311 mg; 1.49 mmol; 110 mole %). N-methylmorpholine (NMM; 210 μL; 301 mg; 2.97 mmol; 220 mole %) was added and resulting mixture was stirred for 20 h at ambient temperature. The dichloromethane was removed by distillation and the residue partitioned between ethyl acetate (50 mL) and washed in sequence with 10% aqueous citric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated aqueous sodium chloride (20 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give 740 mg of the crude product which was chromatographed on silica gel (5 g), eluting with ethyl acetate/hexane, 1:2 followed by 1:1, to give 469 mg (66.2%) of (25)-5-cyclopropyl-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxopentan-3-yl)-4,4-difluoro-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)pentanamide. LC-MS, positive ion mode: m/z=524 [M+H]+ (100%). Methods for the preparation of starting materials are disclosed in U.S. Pat. Nos. 7,488,848 and 7,893,112.

Provenance & Evidence