合成路线1

In an alternative procedure, the silylether of 3-bromophenol (XIX) was converted to the organolithium compound (XXII) and then coupled to 3-bromobenzaldehyde (XXIII) in THF at -78 C. The resulting benzhydrol (XXIV) was treated with SOCl2 to give chloride (XXV), which was subsequently condensed with piperazine (V) in refluxing acetonitrile. The diastereomeric mixture of benzhydryl piperazines (XXVI) was desilylated with tetraethylammonium fluoride, and the major isomer (XXVII) was isolated by recrystallization from acetonitrile. The bromo substituent of (XXVII) was then substituted for a cyano group upon treatment with CuCN in N-methylpyrrolidinone at 170 C. Basic hydrolysis of nitrile (XXVIII) gave acid (XXIX), which was protected as the tert-butyldimethylsilyl ether and further converted to acid chloride (XXX) by reaction with oxalyl chloride and a catalytic amount of DMF. Finally, acid chloride (XXX) was condensed with N-methyl-3-fluoroaniline (XIV), and the silyl protecting group was removed by treatment with tetraethylammonium fluoride in acetonitrile.