合成路线1

Selective bromide displacement in 2,5-dibromopyridine (I) with NaOMe in refluxing MeOH affords 5-bromo-2-methoxypyridine (II) (1), which alternatively can be obtained by bromination of 2-methoxypyridine (III) with elemental bromine in the presence of NaOAc in EtOAc at 50 °C (2). Metalation of 5-bromo-2-methoxypyridine (II) with BuLi in THF at –75 °C followed by addition of trimethyl borate and aqueous acidic hydrolysis leads to (6-methoxy-3-pyridyl)boronic acid (IV). Subsequent Suzuki coupling of boronic acid (IV) with 2-bromopyridine (V) in the presence of Pd(OAc)2, PPh3 and K2CO3 in DME/H2O at reflux provides 6-methoxy-3,2’-bipyridine (VI) (1). In an alternative method, bipyridine (VI) can be obtained by metalation of 5-bromo-2-methoxypyridine (II) with BuLi in THF at –75 °C followed by condensation with 2-(phenylsulfonyl)pyridine (VII) . Hydrolysis of 6-methoxy-3,2’-bipyridine (VI) by means of aqueous HCl at reflux yields 5-(2-pyridyl)-2-pyridone (VIII) . In a related method, Stille coupling of 5-bromo-2-methoxypyridine (II) with (2-pyridyl)tributyltin (IX) in the presence of Pd(Ph3)4 in DMF at 120 °C followed by methoxy group hydrolysis with concentrated HBr at 110 °C leads to 5-(2-pyridyl)-2-pyridinone (VIII) . N-Arylation of pyridone (VIII) with either phenylboronic acid (X) or its trimeric anhydride 2,4,6-triphenylboroxine (XI) in the presence of Cu(OAc)2 in pyridine/DMF under air blowing conditions gives 1-phenyl-5-(2-pyridyl)-2-pyridinone (XII), which is brominated using NBS in DMF or EtOAc to yield the 3-bromopyridone derivative (XIII). Finally, this compound is subjected to Suzuki coupling with 2-(2-cyanophenyl)-1,3,2-dioxaborinane (XIV) by means of Pd(OAc)2, PPh3, CuI and K2CO3 in DME .
In a different synthetic strategy, Suzuki coupling of 5-bromo-6-methoxy-3,2’-bipyridine (XV) with 2-(2-cyanophenyl)-1,3,2-dioxaborinane (XIV) using Pd(PPh3)4 and Cs2CO3 in DMF at 140 °C gives 3-(2-cyanophenyl)-5-(2-pyridyl)-2-methoxypyridine (XVI), which undergoes methoxy group hydrolysis by means of ClSiMe3 and NaI in acetonitrile to produce the pyridone derivative (XVII). Finally, subsequent N-arylation of pyridone (XVII) with phenylboronic acid (X) in the presence of Cu(OAc)2 and Et3N in CH2Cl2 furnishes perampanel