Diisopropylethylamine → Methyl 2-((s)-1-((s)-2-(benzyloxycarbonylamino)-3-(4-hydroxyphenyl)propanamido)-2-methylpropyl)-5-(7-bromo-1h-indol-3-yl)oxazole-4-carboxylate

Participants

Reaction Steps

To diisopropylethylamine (225 mL, 1,290 mmol) stirred at 0° C. was added a solution of the title compound of Example 6 (277.5 g, 586.5 mmol), Cbz-L-tyrosine (194.2 g 615.9 mmol) and TBTU (207.2 g, 1.1 eq) in dimethylformamide (anhydrous, 2.77 L). The reaction was allowed to warm to room temperature and stirred for 16 hours at which time HPLC indicated completion of reaction. The reaction solution was slowly poured into saturated aqueous NaHCO3 (12.0 L) and stirred for 30 min. The precipitate was filtered and the filter cake was thoroughly washed with water. The resulting brown material was dried to constant mass in a vacuum oven at 40° C. to yield the title compound (435 g). The title compound was further purified by recrystallization. The title compound was dissolved in isopropanol (9.0 L) at 70° C. The insoluble material was removed by filtration and the filtrate was heated while slowly adding hexanes (9.0 L). The suspension was allowed to cool to room temperature at which time an ice bath was applied. Once cooled the mixture was stirred at ice bath temperature for 30 min and filtered. The solid was washed with hexanes and dried to constant mass at 40° C. in a vacuum oven giving pure title compound (264 g, 61% yield). 1H NMR (CDCl3): consistent with proposed structure.

Provenance & Evidence