MICROWAVE SYNTHESIS OF ATORVASTATIN CALCIUM SALT

1. MICROWAVE SYNTHESIS OF ATORVASTATIN CALCIUM SALT Juan Hernando, M. Paz Matía, J. Luis. Novella, Julio Alvarez-Builla* Planta Piloto de Química Fina. Universidad de Alcalá. Ctra. Madrid-Barcelona Km. 33,600. 28871 Alcalá de Henares. Madrid. España. Introduction Atorvastatin, usually marketed under the trade name Lipitor, is a member of the drug class known as statins, used to lower cholesterol synthesis[1]. Atorvastatin inhibits the rate-determining step of the enzyme located in hepatic tissue that produces mevalonate, a small molecule used in the synthesis of cholesterol and related derivatives. This lowers the amount of cholesterol produced, which in turn lowers the total amount of cholesterol.Atorvastatin, commercially available as calcium salt [2],is normally prepared via sodium salt and subsequent reaction with CaCl2[3,4] . We have proposed an alternative route, using microwave irradiation in all steps, for the synthesis of Atorvastatin calcium salt, obtained directly from diol tert-butyl ester (4)by reaction with Ca(OH)2 following the synthetic method indicated in the scheme. The procedure was optimized in a CEM Explorer apparatus –performing batch experiments- and was scaled up using the CEM Voyager flow system, using the best conditions obtained in the batch method. The synthesis of the calcium salt 5was not implemented to flow method, due to the poor solubility of Ca(OH)2 in methanol. a CEM Explorer b CEM Voyager (1 cycle) c CEM Voyager (8 cycles) REFERENCES (PON LAS REFERENCIAS COMPLETAS) [1] B. D, Rorh et al. J. Med, Chem. 1991, 34, 357. [2] WO 02 057 229 [3] K. L. Baumann et al. Tetrahedron Lett. 1992, 17, 2283. [4] WO 06 097 909