Reaction Steps
(R)—N—Boc-pyrrolidine-3-carboxylic acid (700 mg, 3.25 mmol, 1.1 equiv), HBTU (1.23 g, 1.1 equiv) and DIEA (1.53 mL, 3 equiv) were dissolved in DMF (15 mL). The solution was stirred 5 min and then 1,3-thiazole-2-amidoxime (5a) (422 mg, 2.95 mmol, 1 equiv) was added. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with saturated aqueous NaHCO3, once with brine, then dried over MgSO4 and evaporated under reduced pressure. The residue was dissolved in 15 mL of DMF and then heated at 110° C. for 7 h. The solvent was removed under vacuum and the residue was dissolved in AcOEt. The organic layer was washed once with HCl 1N, once with saturated aqueous NaHCO3 and once with brine, then dried over MgSO4 and evaporated under reduced pressure. The obtained product was used in the next step without further purification. Boc intermediate was dissolved in dioxane (10 mL) and HCl 4N solution in dioxane (6 mL) was added. The reaction mixture was stirred overnight at room temperature and then the product was recovered by filtration and washed with petroleum ether to give 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (yield 66% over two steps). 4,4,4-trifluorobutyric acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.4 equiv) and DIEA (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (0.62 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Beige powder; Yield 33%; 1H NMR (CDCl3) δ 8.02-8.00 (m, 1H), 7.57-7.60 (m, 1H), 3.89-4.03 (m, 2H), 3.69-3.87 (m, 2H), 3.53-3.65 (m, 1H), 2.38-2.55 (m, 6H); 13C NMR (CDCl3) cis/trans isomer mixture (60 isomer A/40 isomer B); isomer A δ 180.31, 168.50, 163.98, 153.53, 144.99, 126.94 (q, J=276 Hz), 122.87, 49.24, 45.52, 35.03, 29.05 (q, J=29 Hz), 28.86, 27.07 (q, J=3 Hz); isomer B δ 179.84, 168.31, 163.98, 153.38, 144.94, 126.92 (q, J=276 Hz), 122.81, 49.43, 45.25, 36.82, 30.28, 29.05 (q, J=29 Hz), 27.24 (q, J=3 Hz). tR LCMS 4.6 min. Purity >99%; MS [M+H]+ m/z 347.
