合成路线1

Cyclization of 4-phenoxyphthalic acid (I) with glycine (II) at 215 °C gives the phthalimide (III), which by esterification with MeOH and H2SO4 at reflux yields the methyl ester (IV). Subsequent rearrangement of the phthalimidoacetate (IV) by means of Na in BuOH at 97 °C, followed by flash chromatography provides the isoquinoline-2-carboxylate (V). Bromination of compound (V) using POBr3 and NaHCO3 in acetonitrile leads to butyl 8-bromo-3-hydroxy-6-phenoxyisoquinoline-2-carboxylate (VI), which by hydrolysis with NaOH in refluxing H2O/EtOH affords the carboxylic acid (VII). Substitution of bromine in intermediate (VII) using MeI and BuLi in THF at –78 °C, followed by alkylation with PhCH2Br by means of K2CO3 in refluxing acetone yields the 2-methyl isoquinoline (VIII). Ester hydrolysis of compound (VIII) using KOH in MeOH gives the corresponding carboxylic acid (IX), which is then activated with i-BuOCOCl and Et3N in CH2Cl2, followed by condensation with benzyl glycinate hydrochloride (X) to yield the benzyl ester (XI). Finally, compound (XI) is debenzylated with H2 over Pd/C in EtOAc/MeOH .