Tesis doctoral de José Andrés Marcos Escribano
This thesis describes a synthetic route for obtaining exemestane and fluorometholone, compounds that have recently achieved an outstanding reputation as drugs, due to aromatase inhibitor and corticosteroid ophthalmic activity respectively. exemestane obtaining is described by a novel synthetic route, by c-6 functionalization of testosterone through a mannich reaction in a one pot process. The development of an specific dehydrogenation method for 6-methylandrostanes, by acid treatment with chloranil, bstfa and tfoh under reflux of toluene, makes possible to obtain the c-1,2 olefin. This compound can be easily transformed into exemestane by oxidation of c-17 hydroxide with jones reagent. The overall yield of the sintetic route is 70%. on the way to obtaining fluorometholone, funcionalization at c-6 of different progestanes through the same conditions optimized in the synthesis of exemestane leads to 6-methylene derivatives. The development of an efficient selective catalytic hydrogenation method of 6-methylene double bound without affecting the remaining double bonds in the molecule, by using wet (10%) pd on carbon and triethylamine led to the corresponding 6¿-methyl-pregnane in good yield. Catalytic dehydrogenation is performed in basic medium with tfotbdms, dipea, chloranil and pyridine, and ¿1,2 double bond compound is obtained. Afterwards, selective epoxidation of the ¿9,(11) double bond was achieved through a bromohydrin, generated with ddh, perchloric acid and subsequent treatment with k2co3. Finally, the opening of the epoxide with hf allows obtaining fluorometholone with the proper stereochemistry, and an overall yield of 45% path. the high yields of these synthetic routes, as well as its innovation and scalability have led both have been subject to patent and are currently in industrial use.
Datos académicos de la tesis doctoral «Síntesis de esteroides de alta actividad«
- Título de la tesis: Síntesis de esteroides de alta actividad
- Autor: José Andrés Marcos Escribano
- Universidad: Salamanca
- Fecha de lectura de la tesis: 21/05/2010
Dirección y tribunal
- Director de la tesis
- Francisco Bermejo Gonzalez
- Tribunal
- Presidente del tribunal: manuel Grande benito
- bernardo Herradon garcia (vocal)
- María asunción Barbero pérez (vocal)
- Antonio Mouriño mosquera (vocal)