2-Chloroethanol → HCID 118277055, compound

Participants

Reaction Steps

Variant B: Adapting literature known protocols (Palmer, et al., J. Med. Chem. 1990, 33(1), 112-121; Coggiola, et al., Bioorg. Med. Chem. Lett., 2005, 15(15), 3551-3554; Verny et al., Cmpds Radiopharm., 1988, 25(9), 949-955; and Lin, Bioorg. Med. Chem. Lett., 2011, 21(3), 940-943), a reaction mixture of tert-butyl 3-(5-amino-2-methyl-phenyl)-4-(tert-butoxycarbonylamino)butanoate (9d) (3.65 g, 10.0 mmol) and commercial 2-chloroethanol (2.68 mL, 3.22 g, 40.0 mmol) or commercial 2-bromoethanol (2.84 mL, 5.0 g, 40.0 mmol), calcium carbonate (CaCO3) (2.0 g, 20.0 mmol, 2.0 equivalents) in water (about 35 mL), and a catalytic amount of potassium iodide (KI) (166 mg, 1.0 mmol, 10 mol-%) is heated at reflux for about 12-24 hours. The reaction is followed by TLC and/or LC/MS to completion. Additional amounts of 2-halogeno ethanol and CaCO3 may be added and the reaction times may be extended an additional 8-24 h for completion. The pH of the reaction mixture is adjusted to ˜7 with a 2.5 M (10 wt-%) aqueous solution of sodium hydroxide (NaOH). The aqueous phase is extracted with ethyl acetate (4×) and the combined organic extracts are washed with 1.0 M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3), and brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents removed under reduced pressure using a rotary evaporator to yield the target compound tert-butyl 3-[5-(bis(2-hydroxyethyl)amino)-2-methyl-phenyl]-4-(tert-butoxycarbonylamino)butanoate (9e). The crude residue may be further purified by silica gel column chromatography using EtOAc, methanol (MeOH), dichloromethane (DCM), and hexanes, or mixtures of any of the foregoing to furnish the purified target compound.

Provenance & Evidence