合成路线1

Various new routes for the large-scale synthesis of Ro-31-8959 have been described: 1) The condensation of N-protected-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) gives the keto ester (III), which is enantioselectively reduced with NaBH4 to yield the hydroxy ester (IV). The reaction of (IV) with 2,2-dimethoxypropane (V) by means of p-toluenesulfonic acid affords the oxazolidine (VI), which is hydrolyzed with NaOH in ethanol/water to the corresponding acid (VII). The treatment of (VII) with oxalyl chloride, mercaptopyridine-N-oxide (MPO) and bromotrichloromethane affords the bromomethyloxazolidine (VIII), which, without isolation, is treated with acetic acid to give the N-protected 3(S)-amino-2-bromo-4-phenyl-2(S)-butanol (IX). The reaction of (IX) with KOH in methanol yields the epoxide (X), which is condensed with (3S,4aS,8aS)-N-tert-butyldecahydroisoquinoline-3-carboxamide (XI), yielding the protected condensation product (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C affords the amino derivative (XIII), which is condensed with N-benzyloxycarbonyl-asparagine (XIV) in the usual way, giving the protected peptide (XV). The deprotection of (XV) as before yields compound (XVI), with a free amino group that is finally condensed with quinoline-2-carboxylic acid (XVII) by means of dicyclohexylcarbodiimide and hydroxybenzotriazole.