Studies On The Synthesis Of Olprinone

Olprinone, a specific phosphodiesterase (PDE) Ⅲ inhibitor, was developed in Japan for the treatment of acute heart failure or early heart failure following cardiac surgery. In China, Amrinone and Milrinone are the similar drugs of Olprinone. Compared with Amrinone and Milrinone, Olprinone has better curative effect and less side effects. At present, China has no import or production of Olprinone and its preparations. Thus it is important to study the synthesis of Olprinone.Referencing multiple documents, this thesis is aimed at improving research on the synthetic route of Olprinone, to design a synthetic route with good repeatability, high yield and safety. Olprinone was synthesized from 2-Amino-5-bromopyridine by cyclization, Grignard reaction, ozonization, methylenation, cyclization and salt formation.In the cyclization, the repeatability of the synthesis of OP-1 was realized by the adding of concentrated hydrochloric acid; In the Grignard reaction, the water content of THF (<0.1%) was determined to control the initation of the Grignard Reagen, which is helpful to industrial production; the molar ratio of ethyl bromide to OP-1 is 3:1, which can initate the reaction and decrease the production of impurities; In the ozonization, the temperatue (-5～0℃), stirring speed (1000RPM) and the concentration of hydrochloric acid (molar ration of HCl to OP-2 is 1.2:1) were determined to increase the yield, and the purifications of OP-2, OP-3 were simplified, increasing the yield from 74% to 82%; In the methylenation, the temperature (the best is 80℃) was determined, increasing the yield from 55.1% to 78.6%; In the last cyclization, the molar ratio of sodium methoxide to OP-4(1.2) and the reaction temperature (80℃) were also determined to reduce the generation of impurities.The optimised synthetic route of Olprinone contains such highlights:good yield, simple operation, relative friendly process to the environment and suitable for industrial production. In addition, the structures of the product and each intermediate compounds were confirmed by 1H NMR and 13C NMR.