An Efficient and Selective 1-N-Monoethylation of Sisomicin:  Process Development of Netilmicin

With a new reagent developed for the selective monoethylation at the 1-amino group of sisomicin (1), a new process suitable for the mass production of netilmicin under conditions less sensitive to air and moisture has also been developed. Three of the amino groups, at the C-3, C-2‘, and C-6‘ positions of the four amino groups of sisomicin, were selectively protected by using Zn(OAc)2 and acetic anhydride in methanol. Development efforts focused on optimising the conditions for ethylation to give an improved product (96% yield) according to the new and concise synthetic route.