Preparation method of ponazuril

Abstract

The invention relates to a preparation method of ponazuril which is an anti-coccidiosis drug. The method includes syntheses of 3-methyl-4-(4-phenoxy trifluoromethyl sulfide)-nitrobenzene, 3-methyl-4-(4-phenoxy trifluoromethyl sulfide)-aniline, 3-methyl-4-(4-phenoxy trifluoromethyl sulfide)-phenyl isocyanate, 1-[3-methyl-4-(4-phenoxy trifluoromethyl sulfide)-m-methylphenyl]-1,3,5-triazine-2,4,6-trione and ponazuril. Dangerous articles such as raney nickel, methyl isocyanate, chloroformylisocyanate, phosgene, triphosgene and hydrazine hydrate are not used during the reaction processes, and the operation is safe and reliable; raw materials are easy to obtain, the production cost and pollution are low, and the production process is environment-friendly; and the preparation method is simple, special equipment is not needed, a total yield of ponazuril product can reach above 60%, and large-scaleindustrial production is facilitated.

Description

Technical field: [0001] The invention belongs to the technical field of preparation of veterinary drugs, and relates to a preparation method of patopazuril, an anti-coccidiosis drug. Background technique: [0002] Coccidiosis is the most common and most invasive disease in poultry, and it is quite harmful to the aquaculture industry. At present, the main means of controlling this disease is still drug control. Patozuril (also known as Pona Zhuli, toltrazuril sulfone, toltrazuril sulfone or toltrazuril sulfone) is a new anti-coccidiosis drug developed by Bayer Company in Germany. The drug was approved by the US FDA in 2001 for the treatment of mammalian central diseases caused by coccidia such as Neospora hughsi and Sarcocystis. Compared with Li, the biggest feature of Patopazuril is that it can penetrate the blood-brain barrier and directly kill the protozoa located in the brain and cerebrospinal fluid, effectively alleviating the symptoms of EPM. Studies have shown that w...

AI Technical Summary

Problems solved by technology

[0006] The advantage of this route is: fewer reaction steps, higher overall yield; but the disadvantage of this route is: the reduction reaction in the route uses Raney-Nickel (Raney-Nickel), which is flammable and explosive, and the operation is more dangerous; while in isocyanate The flammable, explosive and highly toxic methyl isocyanate (CH 3 NCO), chloroformyl isocyanate (ClCONCO) and other dangerous goods, which have high safety requirements and are not conducive to industrial production

[0009] The advantage of this route is that it avoids the use of dangerous goods such as flammable, explosive and highly toxic methyl isocyanate and chloroformyl isocyanate; but the disadvantage of this route is that the reduction reaction in the route still uses Raney nickel, which is flammable. Explosive, the operation is more dangerous; while in The highly toxic phosgene (COCl 2 ), so this route is still not conducive to industrial production

[0012] The advantage of this route is that compared with route 2, the yield has been greatly improved; but the disadvantage of this route is: the reduction reaction in the route still uses flammable and explosive Raney nickel; Highly toxic methyl isocyanate and phosgene, so this route is not conducive to industrial production

[0015] The advantage of this route is that compared with the aforementioned production method, it avoids the use of some highly toxic substances, the operation is relatively simple, and it is easy to industrialized production, but the disadvantage of this route is that the relatively toxic hydrazine hydrate (N 2 h 4 ·H 2 O) as a reactant, and the operation is relatively cumbersome; In the synthesis of phosgene, solid phosgene is used instead of phosgene. Although it is less polluting and easy to operate than the aforementioned route, the reaction is usually added dropwise with solid phosgene at -10°C~-5°C, and then heated to reflux, which is cumbersome to operate , and requires HCl tail gas absorption equipment; in the oxidation reaction, hydrogen peroxide with relatively high price and low stability is used as the oxidant; therefore, this route still needs to be improved in industrial production

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