1,2-Dichloroethane → 1-(2-(4-tert-butyloxycarbonylphenyl)-2-hydroxy-2-phenylethanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide

Participants

Reaction Steps

To a stirred solution of (4-tert-butoxycarbonylphenyl)(hydroxy)phenylacetic acid from the previous step (0.030 g, 0.09 mmol, HPLC RT=2.53 min), L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (0.037 g, 0.1 mmol) and HOBT hydrate (0.015 g, 0.1 mmol) in DMF (1 mL) was added EDC (0.021 g, 0.1 mmol). Diisopropylethylamine was then added in portions (˜0.06 mL total) to bring the pH of the solution to 6-7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 2 days, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (40 mL) and saturated aqueous NaHCO3 (10 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the oil residue was purified by preparative on a Waters PrepPak using 10-100% CH3CN in H2O with 0.1% TFA as eluant over 60 min. Product-containing fractions were combined and the acetonitrile was removed under reduced pressure. The water layer was basicified with saturated aqueous NaHCO3, extracted with 4×20 mL CH2Cl2, dried over Na2SO4 and filtered. The filtrate solvent was removed under reduced pressure to give 1-(2-(4-tert-butyloxycarbonylphenyl)-2-hydroxy-2-phenylethanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide as a white solid. (0.030 g, 46%; HPLC RT=3.25 min, method B; LC-MS M+H=678).

Provenance & Evidence