1) Alkylation of diethyl malonate (II) with 1 6-dibromohexane (I) results in diethyl 6-bromohexylmaionate (III). Compound (II) is hydrolyzed to the monoester (IV), followed by condensation with paraformaldehyde in ethanol/piperidine/2-methylquinoline to yield ethyl 8-bromo-2-methyleneoctanoate (V), which is oxidized with permaleic acid to (VI). Subsequent reaction with 4-chlorophenolate produces etomoxir.
2) Alternatively, etomoxir can be prepared as follows: Alkylation of 4-chlorophenol with 1,6-dibromohexane (I) yields 1 bromo-6-(4-chlorophenoxy)hexane (VII). Diethyl malonate (II) is alkylated by (VII), yielding (VIII), followed by hydrolysis to the monoester (IX), which is condensed with para formaldehyde/pyridine/piperidine to give ethyl 8-(4-chlorophenoxy)-2-methyleneoctanoate (IX). Oxidation with m-chloroperbenzoic acid produces etomoxir.