In an alternative procedure, 2,2-dimethylsuccinic anhydride (II) was reacted with p-methoxybenzyl alcohol (V) in the presence of dicyclohexylamine to afford the beta,beta-dimethyl p-methoxybenzyl ester (VI) as the major product, along with minor amounts of the alpha,alpha-dimethyl regioisomer. Condensation of hemiester (VI) with AZT (IV) by using DCC and DMAP produced diester (VII). The p-methoxybenzyl group of (VII) was then removed by treatment with trifluoroacetic acid to give (VIII). Acid (VIII) was finally coupled with the dipeptide amide (I) in the presence of BOP and HOBt.
The title compound was prepared following two alternative synthetic sequences: Condensation of the known dipeptide amide (I) with 2,2-dimethylsuccinic anhydride (II) in the presence of DMAP produced regioselectively the succinic monoamide (III). This was then coupled to AZT (IV) by using DCC and DMAP to furnish the corresponding AZT ester.