NXY-059 is synthesized by condensation of N-tert-butylhydroxylamine (I) or its acetate or hydrochloride salts and disodium benzaldehyde-2,4-disulfonate (II) directly in refluxing MeOH or mixtures of MeOH/water or i-PrOH/MeOH/water or by means of MeONa in refluxing MeOH/water or i-PrOH/MeOH/water. N-tert-butylhydroxylamine (I) can be prepared as follows: a) Reduction of 2-methyl-2-nitropropane (III) with either Zn in HOAc/EtOH or aluminum foil and HgCl2 in EtOH/ether/H2O. b) Condensation of benzaldehyde (IV) with tert-butyl-amine (V) in refluxing toluene provides N-benzylidene-N-tert-butylamine (VI), which is oxidized with meta-chloroperbenzoic acid and Na2CO3 in water/toluene/ EtOH to furnish the phenyloxaziridine derivative (VII). Finally, the oxaziridine ring of (VII) is opened by treatment with H2SO4/HOAc in EtOH/H2O. c) Heating of the phenyloxaziridine derivative (VII) at 130 C gives N-tert-butylphenylnitrone (VIII), which is finally treated with H2SO4/HOAc in toluene. Disodium benzaldehyde-2,4-disulfonate (II) can be obtained as follows: a) Heating of 2,4-dichlorobenzaldehyde (IX) with sodium sulfite at 170 癈 in water, followed by oxidation with sodium hypochlorite. b) Reaction of 2,4-dichlorobenzal chloride (X) with sodium sulfite and Na2CO3 or NaHCO3 at 170 C in water, followed by oxidation with sodium hypochlorite.
Reduction of 2-methyl-2-nitropropane (I) with either zinc and acetic acid or aluminum and HgCl2 afforded the corresponding hydroxylamine (II). Subsequent condensation of (II) with aldehyde (III) furnished the title nitrone.
The reaction of 2,4-dichlorophenyl bromide (I) with 14CO2 (II) by means of BuLi in ethyl ether gives the labeled 2,4-dichlorobenzoic acid (III), which is reduced with LiAlH4 in the same solvent to yield 2,4-dichlorobenzyl alcohol (IV). The oxidation of (IV) with lead tetraacetate affords 2,4-dichlorobenzaldehyde (V), which is condensed with sodium sulfite in water at 160 C in a pressure vessel to provide the disulfonate (VI). Finally, the aldehyde group of (VI) is condensed with N-tert-butylhydroxylamine (VII) in hot acetic acid to give rise to the target imine oxide.
The reaction of 14C-labeled acetone (I) with O-benzylhydroxylamine (II) and pyridine in refluxing ethanol gives the corresponding oxime (III), which is methylated with MeLi and BF3.Et2O in toluene to yield labeled N-tert-butyl-O-benzylhydroxylamine (IV). The deprotection of (IV) by hydrogenation with H2 over Pd/C in methanol affords N-tert-butylhydroxylamine (V), which is finally condensed with benzaldehyde 2,4-disulfonic acid sodium salt (VI) in HOAc/water to give rise to the target imine oxide.