Study On Synthetic Process Of The Intermediate Of Halofuginone And Pilot-scale

Halofuginone was a febrifugine derivative extracted from the Chinese herbChangShan. The premixes of0.6%halofuginone hydrobromide whose brand name isStenorol were saled on the market. At present, halofuginone was mainly used as feedadditives to treat and prevent diseases such as coccidiosis and malaria in domesticatedpoultry and livestock. It had many advantages such as broad-spectrum, non-toxic, nocross resistance, no reversibility and no recurrence after drug withdrawal. Some latestresearchs indicated that halofuginone can be used for the treatment and prevention ofhuman diseases such as liver fibrosis, pulmonary fibrosis, scar and scleroderma, and itcan also be used to treat human malignant neoplasm of bladder cancer, breast cancer,prostate cancer, lung cancer, skin cancer. So halofuginone had a broad marketprospects. However, nowadays halofuginone used in China mostly depended onimport for its complex synthesis process, and there were no domestic manufacturers,so the price was relatively expensive.The main contents of this paper were divided into two parts:(1)7-bromo-6-chloro-4(3H)-quinazolinone was synthesized from M-chloroto-luene by substitution of bromine, oxidation, ammonolysis and then subjected tocyclization to afford the product. The total yield of four steps is50.61%, the structuresof all the intermediates and product were confirmed by MS and NMR, the purity ofthe compounds was determined by HPLC. Based on the above synthetic route, thefurther experiments in pilot-scale were taken. Some problems in pilot-scale weresolved, and the pilot conditions been optimized and improved, the total yield is50.52%. In these reaction, the raw materials is cheap and available, the process issimple, and easily to operate. So it is suitable for industrial production.(2) The synthesis of piperdine ring was started from3-hydroxypyridine byMannich reaction, acetylation, hydrobromicacid hydrolysis and finally got2-bromo-3-hydroxypyridine. Then through methylation reaction, addition with acetonitrile andselective catalytic by Rh/C, bromination, amino-protection. After making a series ofimprovements and optimization to this process, the final product still can’t achieved.It showed that this route was invalid and further research was still needed.