The reaction of 4-(pivaloyl)benzoic acid (I) with refluxing SOCl2 gives the corresponding acyl chloride (II), which is condensed with methoxyamine (III) by means of NaOH in THF to yield N-methoxy-4-(pivaloyl)benzamide (IV). Finally, this compound is condensed with more acyl chloride (II) by means of triethylamine in toluene.
Radiolabeled SDZ-FOX-988 has been synthesized as follows: The condensation of 4-bromotoluene (I) with [14C]-cuprous cyanide in DMSO at 180 C gives the labeled 4-methylbenzonitrile (II), which by a Grignard reaction with tert-butylmagnesium chloride in THF yields the ketone (IV). The oxidation of (IV) with KMnO4 in tert-butanol affords the labeled 4-pivaloylbenzoic acid (V), which by reaction with refluxing SOCl2 gives the corresponding acyl chloride (VI). The reaction of (VI) with methoxyamine (VII) and triethylamine in toluene yields the corresponding amide (VIII), which is finally condensed with more acyl chloride (VI), by means of triethylamine in toluene.