合成路线1

The intermediate chiral aldehyde (XIV) has been obtained as follows: Acylation of sarcosine methyl ester (II) with 3,5-dichlorobenzoyl chloride (I) provides the N-benzoyl aminoester (III). The dilithium derivative of 3,4-dichlorophenylacetic acid (IV) is condensed with ester (III) to furnish, after acidic work-up, the N-benzoyl amino ketone (V). Subsequent alkylation of (V) with 1-bromo-3-methyl-2-butene (VI) affords (VII). Treatment of ketone (VII) with hydroxylamine yields a mixture of E- and Z- oximes, from which the Z-isomer (VIII) is isolated by column chromatography. Resolution of racemic (VIII) is then accomplished by two procedures. Coupling of (VIII) with N-Boc-D-phenylglycine (IX) produces a diastereomeric mixture of O-acyl oximes, from which isomer (X) can be separated by recrystallization. Hydrazinolysis of the N-acyl oxime (X) furnishes the target (R)-enantiomer (XI). Alternatively, oxime (VIII) is acylated by pivaloyl chloride, and subsequently separated into enantiomers by means of chiral chromatography. The desired isomer (XII) is then subjected to hydrazinolysis, yielding (XI)