Study On The Synthetic Technique Of Anti-coccidiosis Halofuginone

Halofuginone, derived from Chinese hydrangea "ChangShan", is an excellent anti-coccidiosis for poultry with exceptionally low dosages and little side effect. In recent research, it is found that halofuginone can be used as a new specifical inhibitor of the synthesis of collagen al (I). Halofuginone is also effective in treating human malignancies including vesica, prostate, mammary, and so on. Because of the complicated synthesis, the price of halofuginone is exceedingly expensive. At present, the demand of halofuginone mostly depends on import in China, thus developing a new synthetic route, which can be adapted to plant-scale production, is very valuable.Compared with existed synthetic approaches, we improved the synthetic techniques in three major aspects:(1) 7-bromo-6-chloroquinazolin-4(3H)-one was synthesized from 1-chloro-3-methylbenzene by substitution of bromine, oxidation and ammonolysis to give 2-amino-4-bromo-5-chlorobenzoic acid, which was then subjected to cyclization to afford the product. The total yield of the four steps is 46%.(2) The synthesis of Halofuginone was started from 2-methylpyridin-3-ol by methylation, addition and selective catalytic reduction to give 1-(3-methoxypiperidin-2-yl) propan-2-one, which was then subjected to bromination, N-protection, substitu-tion to afford allyl 2-(3-(7-bromo-6-chloro-4-oxo-quinazolin-3(4H)-yl)-2-oxopropyl)-3-methoxypiperidine-l-carboxylate, and finally hydrolization with acid to give the product. The total yield of the product is 11.6%.(3) 1-methoxypropan-2-one was reacted with acrylonitrile to give 4-methoxy-5-oxohexanenitrile which was then hydrogenated and coupled to afford 3-methoxy-2-methylpiperidine.3-methoxy-2-methylpiperidine was then subject to aromatization to form 3-methoxy-2-methyl-pyridine.The final product was confirmed by IR, MS, 1H-NMR,13C-NMR. In addition, we checked the purity of halofuginone, which was carried out by HPLC, and the result was above 97.0%.The discussion of thesis emphasized on purification of the final product and intermediates, which shall guarantee the possibility halofuginone production. The advantagement of this process is that the reaction conditions are mild, and workup is simple.