ChemInform Abstract: Reaction of 1,3,4‐Oxadiazolones with Free L‐α‐Amino Acids: A Facile Synthesis of Novel 3,5‐Disubstituted Hydantoins.

Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement

“…Pent-4enohydrazide (6). To a solution of pent-4-enoic acid (3.96 g, 39.6 mmol) 25 (3.92 g, 24.9 mmol) was added to a solution of 6 (1.9 g, 16.6 mmol) in dioxane (10 mL), and the resulting mixture was stirred 3 h at RT. The volatiles were then removed under reduced pressure, and the residue was purified by SiO 2 gel chromatography (PE/EtOAc = 1/1) to obtain 8 as a pale-yellow oil (3.0 g, 66% yield).…”

“…Methyl (3R,5S,8S,16-E)-8-Isopropyl-7-oxo-2, 27-dioxa-6,9,11, 12,24-pentaazapentacyclo[16.6.2.1 3,6 .1 10,13 .0 21,25 ]octacosa-1(24), 10, 12,16,18,20,22,25-octaene-5-carboxylate (12). To a solution of 11 (0.1 g, 0.19 mmol) in DCE (20 mL) at 80 °C was added the Zhan 1 23 catalyst (25 mg, 0.038 mmol), and the resulting reaction mixture was stirred at 80 °C for 2 h (only E-isomer detected by UPLC-MS analysis).…”

“…1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 5.9 Hz, 1H), 7.78 (bs, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 8.3, 1.7 Hz, 1H), 7.16 (d, J = 5.9 Hz, 1H), 6.47 (d, J = 16.0 Hz, 1H), 5.85 (ddd, J = 16.0, 8.8, 6.6 Hz, 1H), 5.74 (t, J = 3.3 Hz, 1H), 5.38 (d, J = 9.9 Hz, 1H), 4.68 (dd, J = 9.9, 8.1 Hz, 1H), 4.61-4.53 (m, 2H), 3.92 (dd, J = 11.4, 3.3 Hz, 1H), 3.75 (s, 3H), 2.96-2.86 (m, 2H), 2.67-2.60 (m, 2H), 2.26 (m, 1H), 2.14 (m, 1H), 1.16 (d, J = 6.7 Hz, 3H), 1.14 (d, J = 6. 7 Hz,3H) 27-dioxa-6,9,11,12,24pentazapentacyclo[16.6.2.1 3,6 .1 10,13 .0 21,25 ]octacosa-1(24), 10,12, 18,20,22,25-heptaene-5-carboxamide (4). To a solution of 12 (55 mg, 0.047 mmol) in EtOH (10 mL) was added 10% Pd/C (0.005 mg, 10% w/w), and the resulting reaction mixture was stirred at RT under an atmosphere of H 2 for 2 h. The catalyst was filtered off, and the volatiles were removed under reduced pressure to give methyl (3R,5S,8S)-8-isopropyl-7-oxo-2, 27-dioxa-11-thia-6,9,11,12,24-pentaazapentacyclo[16.6.2.1 3,6 .1 10,13 .0 21,25 ]octacosa-1(24),10,12,18,20,22,25-heptaene-5-carboxylate as a colorless oil (49 mg, 89% yield).…”

“…7 Hz,3H) 27-dioxa-6,9,11,12,24pentazapentacyclo[16.6.2.1 3,6 .1 10,13 .0 21,25 ]octacosa-1(24), 10,12, 18,20,22,25-heptaene-5-carboxamide (4). To a solution of 12 (55 mg, 0.047 mmol) in EtOH (10 mL) was added 10% Pd/C (0.005 mg, 10% w/w), and the resulting reaction mixture was stirred at RT under an atmosphere of H 2 for 2 h. The catalyst was filtered off, and the volatiles were removed under reduced pressure to give methyl (3R,5S,8S)-8-isopropyl-7-oxo-2, 27-dioxa-11-thia-6,9,11,12,24-pentaazapentacyclo[16.6.2.1 3,6 .1 10,13 .0 21,25 ]octacosa-1(24),10,12,18,20,22,25-heptaene-5-carboxylate as a colorless oil (49 mg, 89% yield).…”

“…HCl (1N aq) was then added dropwise until pH = 2 was reached and the mixture was extracted with EtOAc. The organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure to obtain (3R,5S,8S)-8-isopropyl-7-oxo-2, 27dioxa-6,9,11,12,24-pentaazapentacyclo[16.6.2.1 3,6 .1 10,13 .0 21,25 ]octacosa-1(24),10,12,18,20,22,25-heptaene-5-carboxylic acid as a white solid (47 mg, 99% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.91 (d, J = 6.1 Hz, 1H), 7.71 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 6.1 Hz, 1H), 5.96 (m, 1H), 4.75 (t, J = 9.0 Hz, 1H), 4.61 (d, J = 11.8 Hz, 1H), 4.40 (d, J = 6.8 Hz, 1H), 3.99 (dd, J = 11.9, 3.2 Hz, 1H), 2.98-2.82 (m, 4H), 2.67-2.53 (m, 2H), 2.…”