L-N-Boc-phenylalanineamide synthesis

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Yield:88463-18-7 100%

Reaction Conditions:

Stage #1: N-tert-butoxycarbonyl-L-phenylalaninewith chloroformic acid ethyl ester;triethylamine in tetrahydrofuran at 0; for 0.5 h;
Stage #2: with ammonia hydrochloride in tetrahydrofuran;lithium hydroxide monohydrate at 0; for 0.5 h;

Steps:

4.3.5 4.3. Typical procedure for the primary amidation of Cbz-l-Phe-OH 3a with NH4Cl

General procedure: To a colorless solution of 150mg (0.50mmol) of Cbz-L-Phe-OH 3a in 10mL of THF were added 67μL (0.70mmol, 1.4equiv) of ClCO₂Et and 209μL (1.5mmol, 3.0equiv) of Et₃N at 0°C.
After stirring for 30min at 0°C, 0.75 ml of a 1.0M aqueous solution of NH₄Cl (0.75mmol, 1.5equiv) were added at 0°C to the colorless suspension.
The mixture was stirred for 30min at 0°C and 5mL of H₂O was added to the resulted mixture.
The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc.
The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO₄.
The crude product was chromatographed on silica gel with EtOAc to afford 129mg (86% yield) of Cbz-L-Phe-NH₂ 4a. 4.3.5
Boc-l-Phe-NH₂ 4c
132?mg (quant.); >99% ee; colorless solid; mp: 142-144?°C; [α]²³_D?=?+12.9 (c 1.00, MeOH); ¹H NMR (400?MHz, DMSO-d⁶): δ 1.30 (s, 9H, CH₃ *3), 2.72 (dd, J?=?10.2, 13.8?Hz, 1H, CH_AC₆H₅), 2.95 (dd, J?=?4.4, 13.8?Hz, 1H, CH_BC₆H₅), 4.08 (ddd, J?=?4.4, 8.8, 10.2?Hz, 1H, CH), 6.81 (d, J?=?8.8?Hz, 1H, NHCH), 7.01 (br, 1H, CONH_A), 7.16-7.21, 7.24-7.28 (m, m, 1H, 4H, C₆H₅), 7.37 (br, 1H, CONH_B); ¹³C NMR (100?MHz, DMSO-d⁶): δ 28.1, 37.5, 55.6, 77.9, 126.1, 128.0, 129.2, 138.3, 155.2, 173.6; IR (KBr, v_max/cm^-1)?=?3390 (CONH), 3346 (CONH), 3192 (CONH), 1684 (CON), 1660 (CON); HRMS (ESI-TOF): Calcd for C₁₄H₂₀N₂O₃Na (M+Na)⁺: 287.1366, found: 287.1351; The enantiomeric ratio was determined by HPLC (Chiralcel AD: hexane/2-propanol?=?95/5): T_r 20.7?min.