Preparation of intermediate (VI) has been reported by two related ways. The nonselective methylation of alkaloid K252a (V) with methyl iodide in the presence of NaH yielded the required O-methyl compound (VI) along with the N-methyl and the N,O-dimethyl derivatives, which were separated by silica gel chromatography. A large-scale process for the regioselective synthesis of ether (VI) was further developed. Selective protection of the amide group of (V) with tert-butyldimethylsilyl chloride gave the N-silyl derivative (VII), which was O-methylated with methyl iodide to afford methyl ether (VIII). Desilylation under acidic conditions then gave (VI). Subsequent reduction of the ester group of (VI) with with NaBH4 in THF/MOH provided alcohol (IX). This was coupled with dipeptide (IV) using DCC and NMM to afford ester (X). The Boc protecting groups were finally cleaved by treatment with HCl in EtOAc.

A new process, able for the large-scale preparation of the title compound has been developed. Selective N-silylation of the amide group of alkaloid (I) with tert-butyl dimethylsilyl chloride afforded (II). Subsequent O-methylation of (II) with iodomethane and LiOH gave methyl ether (III), which was desilylated to (IV) under aqueous acid conditions. Finally, reduction of the ester group of (IV) with NaBH4 afforded the title compound.