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Halofuginone (halofuginone), Chinese medicine the Changshan extracts febrifugine (febrifugine) derivatives. The halofuginone trade name of speed Dan (Stenorol), and premixes for halofuginone hydrobromide 0.6%, mainly produced by the German company Hoechst-Roussel Agri-Vet and operating. Halofuginone is mainly used for domesticated animals, such as the prevention and treatment of of poultry, livestock coccidiosis and malaria, with a broad spectrum of efficient, irreversible and no recurrence after stopping, no cross-resistance, toxicity, safety and other advantages. Recent studies have found that halofuginone can also be used to prevent liver fibrosis, pulmonary fibrosis, scleroderma and other collagen type I synthesis excessive characteristics of the disease and bladder cancer, prostate cancer, breast cancer, skin cancer, lung cancer and other malignancies and scar treatment, broad market prospects. Halofuginone for imported veterinary drugs fail to achieve its domestic industrial production, due to the complexity of the synthesis process, and therefore expensive. This article refer to the relevant literature on the halofuginone the synthesis process optimization and improved, mainly including the following three aspects: (1) inter-chlorotoluene as the starting material in the ferric chloride catalyzed bromination , after KMnO4 oxidation and cuprous oxide catalyzed aminolysis reaction to generate a 2 - amino-4 - bromo-5 - chloro-benzoic acid, and then with ammonium acetate, triethyl orthoformate cyclization to give 6 - chloro-7 - bromo - 4 (3H) - quinazolinone. Step 4 total yield 46%, the method is simple, low cost, suitable for industrial production. (2) In the commercially available 2 - methyl - 3 - hydroxy pyridine starting material, the addition reaction occurs after methylation with acetonitrile, Rh / C selectively reduced to give (3 - methoxy -2 - piperidinecarboxylic -yl) - acetone, and then after bromoacetate, N-protection and 6 - chloro -7 - bromo -4 (3H) - quinazolinone coupling, the coupling product by a two-step hydrolysis to protect the final product 6 - chloro -7 - bromo-3 - (3 - (3 - hydroxy - 2 - piperidin-yl)-- acetone yl) -4 (3H) - quinazolinone hydrobromide, the total yield of 11.6% of the 6-step reaction, for of halofuginone the industrialized production provides a viable method. (3) an inexpensive and easily obtained methoxy acetone as a starting material, the Michael addition of 4 - methoxy-5 - oxo-hexanenitrile occurs with acrylonitrile, 4 - methoxy-5 - oxo-hexanenitrile Raney Ni catalyzed hydrogenation cyclization 2 - methyl-3 - methoxy-piperidine, the piperidine ring portion successfully constructed. 2 - methyl -3 - methoxypiperidine by aryl isomerization to give 2 - methyl-3 - methoxy-pyridine. Conclusive evidence of the intermediate structure by mass spectrometry and 1H NMR spectra of end products hydrobromide halofuginone structure was confirmed by infrared, mass spectrometry, high resolution mass spectrometry, 1H NMR, nuclear magnetic carbon spectrum. Purity relative peak area of ??HPLC results showed that the purity of the product gt; 97%. The article also focuses on the intermediates and product purification methods, domestic independent production halofuginone it possible. This synthesis process raw materials are readily available, mild reaction conditions, post-processing is simple and suitable for industrial production.
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