Diisopropylethylamine → 4-Benzyl 1-tert-butyl (2S)-2-{[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl-amino]carbonyl}-1,4-piperazinedicarboxylate

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Reaction Steps

(2S)-4-[(benzyloxy)carbonyl]-1-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (1, 17.33 g, 47.5 mmol) is dissolved in DMF (800 mL), to which is added diisopropylethylamine (DIEA, 41.5 mL, 0.24 mol). This mixture is stirred at RT for 1.5 h. R-(−)-1,2,3,4-tetrahydro-1-naphthylamine (7.00 g, 47.5 mmol) is added, and stirring continued for a further hour. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 19.84 g, 52.3 mmol) and 1-hydroxybenzotriazole hydrate (HOBt, 7.07 g, 52.3 mmol) are also added and the entire mixture stirred overnight at RT. The reaction mixture is then diluted with EtOAc (1.2 L) and washed sequentially with 1 M citric acid, brine, sat. NaHCO3, brine, water and brine (1 L of each solution). The EtOAc layer is then dried with Na2SO4, filtered, and the solvent removed under reduced pressure to afford a crude off-white solid (23.34 g). This material is purified by flash chromatography on silica gel (CH2Cl2 as eluent initially, followed by 5% Et2O/CH2Cl2 to elute the desired product). The desired coupled product 6 is isolated as a white foam (20.37 g, 87% yield): 1H NMR δ (CDCl3) 7.27-7.42 (m, 5H), 7.06-7.19 (m, 4H), 6.10 (brs, 1H), 5.11-5.25 (br m, 3H), 4.46-4.75 (br m, 2H), 3.77-4.02 (br m, 2H), 3.00-3.31 (br m, 3H), 2.68-2.84 (m, 2H), 1.97-2.07 (br m, 1H), 1.69-1.84 (br m, 3H), 1.43 (s, 9H). LCMS (APCl+) 494.8 (MH+), 438.5 (MH+-tBu), 394.4 (MH+-BOC).

Provenance & Evidence