• Conference Proceeding

Challenges and Difficulties in Synthesis of Tritium Labeled Fluocinolone Acetonide


Zhong, D. S., & Lewin, A. H. (2010). Challenges and Difficulties in Synthesis of Tritium Labeled Fluocinolone Acetonide. In [53], pp. 260–265. .


Tritium labeled fluocinolone acetonide was synthesized through five-step procedure. Many challenges and difficulties were encountered in the synthesis, especially in the regeneration of 1,2 double bond from reaction of oxidative de-hydrogenation of tritium labeled 4-ene analog. Selenium oxide oxidative de-hydrogenation of 11,21-dihydroxy un-protected 4-ene fluocinolone acetonide analog gave a complex product mixture. The reaction gave a clean unlabeled intermediate after protection of 21-hydroxy group by acetylation, but the same procedure failed to give desired tritium labeled intermediate due to fast tritium-hydrogen exchange reaction. The de-hydrogenation proceeded well with DDQ in refluxing benzene for unlabeled intermediate, but no reaction at all for the tritium labeled one. Benzeneseleninic anhydride/toluene refluxed with tritium labeled 4-ene analog was found to be the best de-hydrogenation reaction conditions after exploring suitable conditions. Detailed examination of the de-hydrogenation product, 1,4-diene analog by radio-HPLC, HPLC-MS, proton and tritium NMR found that not only had the de-hydrogenation taken place, but also 11-hydroxy group was oxidized to ketone at the same time. This problem was resolved by acetylation protection of both 11,21-dihydoxy groups. De-protection of tritium labeled 11,21-diacetyl 1,4-diene intermediate in K2CO3/CH3OH/H2O gave expected final product, [1,2-H-3]fluocinolone acetonide with a specific activity of 36.8 Ci/mmol (radiochemical purity: 97%) after purification.