合成路线1

The oxidation of N-(benzyloxycarbonyl)-D-phenylalaninol (I) with NaOCl catalized by 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaBr in water gives the corresponding aldehyde (II), which is dimerized by means of the Coulton's reagent (VCl3/Zn/THF) to the pinacol (III)(1). The silylation of (III) with triethylsilyl chloride and imidazole in DMF yields the silylated diol (IV), which is submitted to hydrogenolysis with H2 over Pd/C in toluene to afford the free diamine (V). The cyclization of (V) with carbonyldimidazole (CDI) in toluene followed by desilylation with 1N HCl gives (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxyperhydro-1,3-diazepin-2-one (VI), which is treated with 2,2-dimethoxypropane (VII) and p-toluenesulfonic acid in DMF yielding the corresponding acetonide (VIII). The methylation of (VIII) with methyl triflate in refluxing dichloroethane affords the cyclic isourea (IX), which is alkylated with 3-cyano-4-fluorobenzyl bromide (X)/NaH in DMF giving the N-monobenzyl derivative (XI). A new alkylation of (XI) with benzyl bromide (XII) in refluxing acetonitrile yields the disubstituted cyclic urea (XIII), which is finally treated with hydrazine in refluxing butanol to generate the indazole ring and treated with HCl in methanol to eliminate the acetonide group.