合成路线1

Protection of 3,4-dihydroxybenzaldehyde (XVI) with t-butyldimethylsilyl chloride and imidazole provided the corresponding bis-silyl ether (XVII) (2). Asymmetric nitroaldol condensation of aldehyde (XVII) with nitromethane in the presence of the chiral samarium tris(binaphthoxide) complex (XV) --prepared from (S)-6,6'-bis(trimethylsilylethynyl)-1,1'-dihydroxy-2,2'-binaphthalene (XIV) and samarium triisopropoxide in the presence of BuLi (2,3)-- gave rise to the (R)-nitro alcohol adduct (XVIII) with high optical purity. Catalytic hydrogenation of the nitro group of (XVIII) furnished the silylated norepinephrine (XIX), which was coupled with acid (XIII) in the presence of diethylphosphoryl cyanide to yield amide (XX). Reduction of amide (XX) with LiAlH4 gave amine (XXI). The silyl and methoxymethyl protecting groups were finally removed under acidic conditions to furnish the title compound.

合成路线2

Reaction of methyl cyanoacetate (I) with benzylamine (II) at 100 C gives N-benzyl cyanoacetamide (III). Subsequent condensation of (III) with 3,4-dihydroxybenzaldehyde (IV) in the presence of NaH provides the title compound.

合成路线3

The title compound was obtained by condensation between 9-ethylcarbazole-3-carboxaldehyde (I), veratraldehyde (III), and O,O'-diaminoethanediol (II). The desired asymmetric bisoxime was separated from the symmetric homodimers by silica gel column chromatography.

合成路线4

Metallation of 1,4-dibromobenzene (I) followed by addition to hexafluoroacetone afforded the bis(trifluoromethyl)carbinol (II), which was subsequently protected as the trimethylsilylethoxymethyl ether (III). 3,4-Dihydroxybenzaldehyde (IV) was alkylated with either chlorodifluoromethane or methyl chlorodifluoroacetate to give the bis(difluoromethyl)ether (V). Addition of either the organolithium or Grignard reagent prepared from aryl bromide (III) to aldehyde (V) furnished the diaryl carbinol (VI), which was converted to chloride (VII) by treatment with SOCl2 and diisopropyl ethylamine. Selective carbomethoxylation of 3,4-dimethylpyridine (VIII) using dimethyl carbonate and LDA afforded (IX). Condensation of chloride (VII) with the lithium anion of (IX) yielded the triarylpropionate derivative (X). Ester group hydrolysis with LiOH, followed by acidification with NH4Cl, provided the decarboxylated compound (XI). After SEM group cleavage by treatment with tetrabutylammonium fluoride, the pyridine ring of the resulting (XII) was finally oxidized to the target N-oxide.

合成路线5