Synthesis
Preparation of Example 9 (S)-2-Amino-3-methylbutyramide hydrochloride: anhydrous ammonia was passed into 150 mL of cooled dichloromethane (ice bath) at 0°C until the solution was saturated. The mixture was cooled to 5°C and trimethylaluminum (136.2 mL of a 2M hexane solution, 272.4 mmol) was added slowly and dropwise under nitrogen protection. The resulting turbid solution was warmed to room temperature and stirred for 22 hours. L-valine (10.6 g, 90.79 mmol) was added in batches and stirring was continued at room temperature for 18 hours. The reaction mixture was cooled to 0 °C (ice-water bath) and 190 mL of 6N hydrochloric acid was added slowly and dropwise until the pH reached 2. The mixture was warmed to room temperature and stirred for 2 h. Subsequently, the pH was adjusted to 11-12 with 10% aqueous sodium hydroxide. 100 mL of dichloromethane and 100 mL of water were added to the alkaline solution, the organic layer was separated, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and acidified by passing hydrogen chloride gas. The solid formed was collected by filtration and dried under reduced pressure to give 6.8 g (49% yield) of L-valine amide hydrochloride with melting point 258°-260°C. IR (Nujol, cm-1 ) showed C=O (1686) and N-H (3387,3241) absorption peaks.1H NMR and 13C NMR (CDCl3 ) data were consistent with the target product. Elemental analysis (C5H13ClN2O) Calculated values: C, 39.35; H, 8.59; N, 18.35; Cl, 23.23; Measured values: C, 39.82; H, 8.52; N, 18.40; Cl, 23.13. Mass spectra (MS): m/e 117 (M+-Cl).
