The reaction of hydrocortisone (I) with ethyl orthopropionate (EOP) / p-toluenesulfonic acid (p-TsOH) in DMF yields the orthoester (II), which is cleaved by treating with a trisodium citrate (TSC) - HCl buffer to hydrocortisone 17-propionate (III). Subsequent acetylation by acetic anhydride/1,4-diazabicyclo[2.2.2]octane (DABCO) in DMF yields hydrocortisone 17-propionate 21-acetate.