The Synthesis Of Antithrombotic Drug Ozagrel And Alkaloid Halofuginone

This paper is made up of the synthesis of antithrombotic drug ozagrel and alkaloid halofuginone.The first part is on the synthesis of ozagrel, whose chemical name is a 1-alkylimidazole derivative that acts as a selective inhibitor of thromboxnae A2(TXA2). The beneficial effects of TXA2 inhibition by ozagrel include improved motor coordination after experimental stroke, and antihypertensive effects in spontaneously hypertensive rats. It has been marketed in 1988 as an antithrombotic drug in Japna. A novel approach to the synhtesis of ozagrel is described. The target compound is conveniently prepared from the commrecially available material, imidazole and mehtyl 4-bromomehtyl cinnamate, through the condensation and hydrolyzation. The structures of the target compound was characterized by ~1HNMR. The operation is simple and all raw materials are cheap and friendly to the environment, so the route is suited for industrialization.The other part is on the synthesis of alkaloid halofuginone. Halofuginone, whose chemical name is 3-[3-[3 (S)-HydroxyPiperidin-2 (R)-yl] -2- oxopropyl ] -7-bromo-6-chloro-3,4-dihydroquinazolin-4-one, and febrifugine, whose chemical name is 3-[3-[3 (S)- Hydroxypiperidin-2 (R) -yl]-2-oxopropyl]-3,4-dihydro quinazolin-4-one, and isofebrifugine, whose chemical name is 3-[(3aS,7aS)-2-Hydroxyperhydrofuro [3,2-b] pyridin-2- ylmethyl]-3,4-dihydroquinazolin-4-one, were discovered as alkaloids with excellent biological activity in last century. Halofuginone has been used as an antiparasitic feed additive for the prevention of coccidiosis in poultry production and is now undergoing clinical trials for treatment of scleroderma in human. Febrifugine and isofebrifugine exhibit potent anti-malarial activity and, to date, no parasite resistance to has been reported. Since natural sources are rather limited, there has been strong demand on chemical synthesis. In this paper, a novel and applicable synthetic method of them was discribed :3-hydropyridine was employed as raw material and afforded (2S*,3S*)-phenyl-2-(1, 2-epoxypropyl) -3-benzyloxy- pyridinecarboxylate through N-allylation,O-allylation,reduction,replacement of protective group,rearrangement, reduction, hydroxy protection and epoxy reaction; 7-bromo -6 - chloro - 3,4-dihydroquinazolin-4-one was prepared from m-bromoaniline;and then halofuginone was prepared. The structures of all intermediates were characterized by ~1HNMR. The operation is simple and all raw materials are cheap and friendly to the environment, so the route is suited for industrialization.