Process Development and Scale-up of T3-Sulfate, A New Prodrug Alternative to the Conventional Hormone Therapy of Hypothyroidism

摘要

An efficient and scalable preparation of the thyroid hormone analogue O-[3-iodo-4-(sulfooxy)phenyI]-3,5-diiodo-L-tyrosine sodium salt (T3-sulfate, 1) is reported. The synthesis involved monoiodination of 0-(4-hydroxyphenyl)-3,5-diiodo-L-tyrosine to give liothyronine (2) which was sulfated with chlorosulfonic acid in N,N-dimethylacetamide. Crude T3-sulfate was initially purified by chromatography on polystyrene resin Amberlite XAD 1600 and then crystallized with ethanol. This strategy was scaled-up to give a process suitable for the production of kilogram quantities of API, needed to support preclinical and clinical studies.