Treatment of 4-oxopiperidine (IX) with chloromethyl chloroformate (X) and NaOH in H2O/Et2O provides 4-oxopiperidine-1-carboxylic acid chloromethyl ester (XI), which is then condensed with pivalic acid (XII) in DMF in the presence of K2CO3 to furnish derivative (XIII). Finally, (XIII) is reductively condensed with intermediate (VI) by means of NaBH4, HOAc and Et3N in THF/EtOAc.
Reductive condensation of 2-oxopiperazine (I) with 4-oxopiperidine-1-carboxylic acid t-butyl ester (XIV) in the presence of sodium cyanoborohydride (NaBH3CN) in MeOH/EtOH-HCl yields derivative (XV), which is then coupled to bromo derivative (IV) by means of sodium in refluxing toluene to give compound (XVI). Deprotection of (XVI) by treatment with TFA and anisole provides piperidine derivative (XVII), which is then treated with chloromethyl chloroformate (X) and proton sponge in CH2Cl2 to furnish derivative (XVIII). Finally, (XVIII) is coupled to pivalic acid (XII) by means of K2CO3 in DMF and converted into the corresponding hydrochloride salt by treatment with HCl-EtOH in EtOAc.
Synthesis of intermediate (VI): Treatment of 2-oxopiperazine (I) with di-t-butyl dicarbonate (II) and Et3N in DMF affords 1-t-butoxycarbonyl-3-oxopiperazine (III), which is then condensed with bromo derivative (IV) by means of NaH in THF, providing ethyl phenoxyacetate derivative (V). Treatment of (V) with HCl/EtOAc allows removal of the t-butyloxycarbonyl group, yielding intermediate (VI). Alternatively, intermediate (VI) can be obtained by first formylation of (I) with formic acid and acetic anhydride (Ac2O) in CH2Cl2 to afford derivative (VII), followed by condensation of (VII) with (IV) to give (VIII) by means of NaH in DMF/THF and deformylation by treatment with HCl/EtOAc to afford (VI).