Reaction Steps
To 5-amino-3-methoxy-[1,2,4]thiadiazole (1.31 g, 10 mmol) in dichloromethane (15 mL) at room temperature was added 1,1′-carbonyldiimidazole, CDI, (1.78 g, 11 mmol) followed by triethylamine (2.1 mL, 15 mmol). The resulting suspension was stirred under nitrogen for 2.5 h. Volatile materials were removed in vacuo and the residue was dissolved in DMF (20 mL). The latter was then added to a solution of L-leucine-L-proline methyl ester hydrochloride (4.18 g, 15 mmol) and triethyl amine (2.1 mL, 15.1 mmol) in DMF (25 mL). The resulting mixture was heated at 120° C. for 2 h and then allowed to cool to room temperature. Volatile materials were removed in vacuo and the residue was diluted with ethyl acetate (250 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers was dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a solvent mixture of hexane and ethyl acetate (1/1 and 2/3) afforded {3-methoxy-[1,2,4]-thiadiazol-5-yl}carbamoyl-L-leucine-L-proline methyl ester as a light yellow foam (3.2 g, 76.6%). M.p. 88-90° C.; 1H-NMR (CDCl3) δ 12.75 (s, 1H, NH), 6.70 (d, J=12.0 Hz, 1H, NH), 4.79-4.87 (m, 1H, NCHpro), 4.54-4.59 (dd, J=11.8, 6.0 Hz, 1H, NCH), 4.12 (s, 3H, OMe), 3.64-3.90 (m, 2H, NCH2pro), 1.56-2.26 (m, 6H, 3CH2), 0.94-1.12 (two d, J=9.7 Hz, 7H, 2CH3+CH); 13C-NMR (CDCl3) 178.3 (C3), 172.3, 171.1 (CO2), 165.9 (C5), 153.7 (NHC═ONH), 58.8, 56.6, 52.2, 49.8, 47.0 (CH2), 42.0 (CH2), 29.0 (CH2), 24.8 (CH2), 24.5, 23.2, 22.0; MS (m/z) 400 (M++1), 326, 271, 243, 209, 158, 130, 87.
