One pot synthesis of tetrazole derivatives of rapamycin

Abstract

A single-step, one-pot process to obtain zotarolimus and other rapamycin derivatives on large scale is presented, which improves currently available synthesis schemes. In one embodiment, dried rapamycin is dissolved in isopropylacetate (IPAc). The solution is cooled, and 2,6-Lutidine is added, followed slowly adding triflic anhydride at −30° C. Salts are then removed by filtration. Tetrazole, followed by a tert-base diisopropylethylamine (DIEA) is added to the triflate solution. After incubation at room temperature, the product is concentrated and purified by a silica gel column using THF/heptane as eluant. The fractions containing the product are collected, concentrated, and purified again using an acetone/heptane column. The product containing fractions are concentrated. The product is dissolved in t-BME and precipitated with heptane. The solids are dissolved in acetone, treated with butylated-hydroxy toluene (BHT), and the solution concentrated. The process is repeated twice with acetone to remove solvents. At least one stabilizing agent is added, such as BHT at 0.5% before drying.