Toluene → N-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propyl]-L-alanyl-N1-isobutyl-L-valinamide

Participants

Reaction Conditions

Reaction Steps

N-t-Butoxycarbonyl(3,5-difluorophenyl)alanine methyl ester (1.3 g, 4.1 mmol) in toluene (20 mL) is placed under nitrogen and cooled to −78° C. To the stirred solution is added, dropwise over 10 min, 12.0 mL of a 1 M solution of Dibal in toluene. After 1 h, 2 mL of methanol is added dropwise, and the solution is poured into an aqueous solution of Rochelle salts cooled in an ice bath. The mixture is stirred and the organic material is extracted into ethyl ether. The organic phase is washed with water and brine, dried over Na2SO4, and concentrated to N-t-butoxycarbonyl(3,5-difluorophenyl)alanal as a white solid, 1.2 g (quantitative). N-t-Butoxycarbonyl(3,5-difluorophenyl)alanal (700 mg, 2.45 mmol) and L-alanyl-N1-isobutyl-L-valinamide (EXAMPLE 1, 700 mg, 2.87 mmol) are combined with sodium triacetoxyborohydride (1.0 g, 4.7 mmol) in 14 mL of THF containing 0.30 mL (5.0 mmol) of acetic acid. The mixture is allowed to stir 18 h. The reaction is quenched with 1 N NaHCO3 and the product is taken up in 200 mL of ethyl acetate and several mL of methanol. The organic phase is washed with more bicarbonate, and then with brine, and dried over Na2SO4. It is concentrated to a solid, which is chromatographed over silica gel, eluting with 25% to 30% acetone in dichloromethane. The product-containing fractions are concentrated to afford 432 mg (0.84 mmol, 34%) of the title product as a white solid. HRMS (ESI) calcd for C26H42F2N4O4+H1 513.3252, found 513.3259.

Provenance & Evidence