2-Chlorobenzoyl chloride → N-(2-chlorobenzoyl)-(L)-tyrosine ethyl ester

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Reaction Steps

Into a 2L round bottom flask was added 21 g (100 mmol) of (L)-tyrosine ethyl ester (1) (Bachem) and 500 mL of tetrahydrofuran (THF). The mixture was magnetically stirred at room temperature until dissolved, and 500 mL of aqueous NaHCO3 (0.5 M) was added. The mixture was cooled in an ice bath and 19.3 g (110 mmol) of 2-chlorobenzoyl chloride (Aldrich) was added slowly via a glass syringe. The ice bath was removed and the reaction was allowed to warm to room temperature with stirring. After 30 min., the reaction mixture was rotory evaporated under reduced pressure to remove the THF and the remaining aqueous bicarbonate solution was extracted twice with 400 mL ethyl acetate. The combined extracts were washed with 400 mL of satd. aqueous NaHCO3, 400 mL of 0.1 N HCl, 400 mL of water, and 400 mL of satd. aqueous NaCl. The remaining organic layer was dried over Na2SO4 and evaporated to dryness to afford ˜40 g of crude (2) as a pale yellow oil. The crude product (2) was recrystallized from ˜800 mL of boiling ethyl acetate/hexane (˜1:3) and cooled to 4° C. overnight. The resulting crystalline product was filtered and dried under a stream of nitrogen to afford 32 g (92% isolated yield) of purified (2). The N-(2-chlorobenzoyl)-(L)-tyrosine ethyl ester product (2) was confirmed by NMR and electrospray mass spectrometry (see attached) and judged >95% pure by HPLC and TLC (Rf=0.6, 1:1 ethyl acetate/hexane). The remaining 5% impurity (Rf=0.7) was identified as 2-chlorobenzoic acid by HPLC and TLC versus authentic material.

Provenance & Evidence