Heterocyclic antiviral compounds
A compound, oxo generation technology, applied in antiviral agents, organic chemistry, medical preparations containing active ingredients, etc., can solve problems such as side effects
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Embodiment 1
[0187] N-{2-[3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydro-pyridin-3-yl)-phenyl]-4-oxo-4H -Chromene-6-yl]-methanesulfonamide (I-1)
[0188]
[0189] 5-Bromo-3-tert-butyl-2-methoxy-benzaldehyde (20)
[0190] step a - To a solution of 3-tert-butyl-2-hydroxybenzaldehyde (CASRN24623-65-2, 5.00 g) and DCM (20 mL) at 0 °C was added Br dropwise over 30 minutes 2 (1.45 mL) in DCM (15 mL). After the addition was complete, the reaction was stirred for 1 hour, then the organic volatiles were removed under reduced pressure to afford 7.23 g of 5-bromo-3-tert-butyl-2-hydroxybenzaldehyde (21) as a pale yellow solid.
[0191] step b -Compound 21 (3.83g), MeI (2.32mL), K 2 CO 3 (6.18 g) and DMF (50 mL) was heated at 50°C for 1 hour, then cooled to RT and diluted with ether and water. The organic layer was washed three times with water, then brine, and dried (MgSO 4 ), concentrated to afford 3.99 g of 20 as a yellow solid.
[0192] 2-oxo-1,2-dihydropyridine-3-boronic acid ( 28) -...
Embodiment 2
[0199] N-{2-[3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydro-pyridin-3-yl)-phenyl]-4H-chromene-6 -yl]-methanesulfonamide (I-2)
[0200]
[0201] step 1- To a solution of 26c (100 mg, 0.209 mmol) in THF (5 mL) cooled to 0 °C was added LiALH 4 (0.420 mL, 0.420 mmol, 1.0 M in THF). The reaction was gradually warmed to RT over 1.5 h, then cooled to 0 °C and washed with 1 mL NaHCO 3 The aqueous solution was quenched. The resulting suspension was diluted with EtOAc, washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. The crude residue was passed through SiO2 eluting with an EtOAc / hexane gradient (20%-30% EtOAc). 2 Purification by chromatography afforded 40 mg (41%) of N-[2-(5-bromo-3-tert-butyl-2-methoxy-phenyl)-4H-chromen-6-yl]-methanesulfonamide ( 27), as an orange oil.
[0202] step 2 - The palladium catalyzed cross-coupling of 27 and 28 was carried out following the procedure of step 5 of Example 1. The crude product was developed by preparative SiO wit...
Embodiment 3
[0204] N-{2-[3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydro-pyridin-3-yl)-phenyl]-4H-chroman Pyran-6-yl]-methanesulfonamide (I-3)
[0205]
[0206] 2-Benzyloxy-pyridin-3-ylboronic acid (30) - 2-benzyloxy-3-bromo-pyridine (2.50eq, 9.47mmol), Pd(II)Cl 2 (PPh 3 ) 2 (232mg, 28mmol), KOAc (2.32g, 23.67mmol), bis-(pinacolate)diborane (2.95g, 11.36mmol) and DME (75mL) was heated at 70°C for 26 hours. The reaction mixture was cooled in Et 2 Partitioned between O and water. The organic phase was separated, dried and evaporated. The crude product was passed through SiO2 eluting with an EtOAc / hexane gradient (0-5% EtOAc). 2 Chromatographic purification,
[0207] 1.81 g of 2-benzyloxy-pyridin-3-ylboronic acid are obtained, containing a small amount of bis-(pinacolate)diborane.
[0208] step 1 - 27 (75 mg, 0.156 mmol), 30 (53 mg, 0.231 mmol), Pd(PPh 3 ) 4 (19mg, 0.016mmol), Na 2 CO 3 (43mg, 0.406mmol), the sealed tube was irradiated in a microwave reactor at 115°C for 30 mi...
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