Phenylacetic Acid → Phenylacetylglutamine t-butyl ester

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Reaction Steps

As shown in reaction scheme I (FIG. 1), phenylacetic acid 1 (1250 mg; 1.84 mmol) was coupled to a protected glutamine 4 (protected in this case by a lower alkyl such as t-butyl group) by first dissolving the phenyl acetic acid in anhydrous dimethylformamide (8 ml). N-hydroxysuccinimide 2 (254 mg; 2.2 mmol) was added followed by addition of dicyclohexylcarbodiimide (456 mg; 2.2 mmol) to produce N-succinimidphenylacetate 3. The reaction mixture was stirred for ten hours and precipitated dicyclohexyl urea was filtered off. The filtrate containing 3 was returned to a reaction flask to which a carboxy-protected glutamine such as L-glutamine t-butyl-ester hydrochloride 4 (439 mg; 1.84 mmol) was added. pH was adjusted to 9 with triethylamine, and the reaction mixture was stirred for 24 hours to produce phenylacetylglutamine t-butyl ester 5. Precipitated crystals were filtered off, and the filtrate containing 5 after concentration in vacuum was purified by column chromatography on silica gel using ethyl acetate-methanol (95:5) as an eluent. Yield 299 mg of desired material, mp. 132°-133° C. 1H-NMR (60 MHz) (CDCl3) δ ppm: 1.4 (s,9H); 1.8-2.4 (mult,4H); 3.6 (s,2H); 4.5 (mult,1H); 5.5 (broad,1H); 6.3 (mult,2H); 7.3 (s,5H). Mass Spectrum (DEI/DIP): 321 (M+H)+, 320 M+, 264 (M-C4H8)+, 247 (M-OC4H9)+. The t-butyl ester 5 (295 mg; 0.924 mmole) of phenylacetylglutamine was deprotected (i.e., the t-butyl carboxy protecting group was removed) by dissolving 5 in methylene chloride (4 ml) and adding trifluoroacetic acid (4 ml). After 45 minutes, the reaction mixture was evaporated in vacuum and the oily residue crystallized from tetrahydrofurane (THF), to give colorless crystals of phenylacetyl glutamine 6. 1H-NMR(300 MHz)(CDCl3 /CD3OD) δ ppm 1.9-2.05 (mult,1H); 2.13-2.36 (mult,3H); 3.58 (s,2H); 4.5 (mult,1H); 7.23-7.38 (mult,5H); Mass Spectrum (pos.FAB, MeOH):265 (M+H)+ (100%).

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