合成路线1

Reaction of bromoacetyl bromide (I) with phenol at 80 °C gives the phenyl ester (II) , which by cyclization with (S)-(+)-phenylglycinol (III), previously treated with DIEA, in acetonitrile provides 5(S)-phenylmorpholin-2-one (IV) . Treatment of compound (IV) with HCl affords the corresponding HCl salt (V), which is reacted with NaHCO3 followed by coupling with benzodioxane-6-carboxaldehyde (VI) in refluxing EtOAc/toluene to yield the oxazine adduct (VII). Oxazine derivative (VII) can also be obtained by direct coupling of 5(S)-phenylmorpholin-2-one (IV) with aldehyde (VI) in refluxing toluene. Opening of adduct (VII) with pyrrolidine (VIII) in CH2Cl2, CHCl3 or refluxing THF followed by addition of HCl in refluxing MeOH leads to 3-(1,4-benzodioxan-6-yl)-3(R)-hydroxy-2(R)-(2-hydroxy-1-phenylethylamino)-1-(pyrrolidin-1-yl)propanone (IX), which is reduced with LiAlH4 in refluxing THF to give diol (X). Cleavage of diol (X) by means of H2 and Pd(OH)2 in the presence of either CF3COOH or HCl in MeOH or EtOH/H2O provides amine (XI), which is finally coupled with octanoic acid N-hydroxysuccinimide ester (XII) in CH2Cl2 . Ester (XII) is prepared by condensation of octanoyl chloride (XIII) with N-hydroxysuccinimide (XIV) by means of Et3N in CH2Cl2 .