A method for the synthesis of toltrazuril

Abstract

The application provides a synthesis method of tolfenpyrad, and belongs to the technical field of medicine synthesis. Methylamine aqueous solution is used for synthesizing methylaminoformic acid ethyl ester with diethyl carbonate. N-[3-methyl-4-(4-trifluoromethylsulfanyl-phenoxy)-phenyl]-urea (arylurea) is used as a starting material to react with the obtained methylaminoformic acid ethyl ester under the action of a catalyst to synthesize biuret. The biuret is subjected to ring closing with diethyl carbonate to generate tolfenpyrad. The synthesis method does not need to use phosgene, is simple to operate, raw materials are easy to obtain, cost is low, and the yield is high.

Description

Technical Field

[0001] This application relates to a method for synthesizing toltrazuril, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] Toltrazuril, 1-[3-methyl-4-(4-trifluoromethylthiophenoxy)phenyl]-3-methyl-1,3,5-triazine-2,4,6[1H,3H,5H]-trione, is an anticoccidial drug effective against Eimeria coccidia in poultry, rabbits, lambs, and piglets. It is widely used due to its high insecticidal efficacy and low toxicity. This drug has a broad anticoccidial spectrum (it can be used for coccidiosis in various animals), affecting the respiratory and metabolic functions of coccidia by interfering with cell division and mitochondrial activity. It has a killing effect on both the schizogony and gametogony stages of coccidia. It has good inhibitory and killing effects on Eimeria tenella, Eimeria spp., Eimeria maxima, Eimeria brevicornuate, Eimeria toxicaria, and Eimeria spp., and does not affect the growth and development of chicks or the development of immunity to coccidia.

[0003] There are multiple routes for the synthesis of tottrizurite, with five routes currently disclosed: 1. US4874860 discloses two synthetic routes. One route uses raw materials such as methyl isocyanate and chlorocarbonyl isocyanate, which are not easily obtained directly from the market. If they are made in-house, phosgene is required, posing significant safety hazards in industrial production and making it difficult to meet the safety requirements of enterprises. The other synthetic route is longer, with high reaction pressures, reaching 90 bar (9 MPa). It uses the highly toxic gas phosgene in the isocyanation process, with harsh process conditions and high operational difficulty in industrial production, which is also unsuitable for the safety requirements of enterprises.

[0004] Patent DE4239000 uses potassium carbonate instead of sodium hydroxide, which improves the condensation reaction process conditions. However, the hydrogenation reaction pressure is high, and the highly toxic gas phosgene is still used in the isocyanate esterification. The process conditions are harsh, the production cost is high, and the production capacity is difficult to expand.

[0005] 3. CN101265236A uses solid phosgene. Although it is solid, bis(trichloromethyl) carbonate still releases phosgene under reaction conditions. In essence, it has not completely deviated from the phosgene route, and still poses significant safety risks and environmental pressures. Moreover, the overall yield of the finished product is about 50%, which is not outstanding among the various routes, meaning that the production cost may be relatively high.

[0006] 4. US20170291880A1 first synthesized a novel intermediate, [(methylamino)carbonyl]phenyl carbamate, which was then reacted with an aromatic amine to generate biuret, which was subsequently cyclized to generate toltrazuril. This route completely avoids the use of phosgene and triphosgene and avoids the generation of unstable isocyanate intermediates. However, the overall process is relatively complex, and the yield of the novel intermediate [(methylamino)carbonyl]phenyl carbamate is only 86%, the yield of toltrazuril is not high, and the cost is high.

[0007] 5. CN102731351A uses aromatic amines as raw materials to synthesize arylurea with cyanate under acidic conditions, and then synthesizes biuret with methylcarbamoyl chloride. The biggest advantage of this route is its green and safe nature. Cyanate is a conventional organic synthesis reagent, and the reaction conditions are mild and the operation is simple. Summary of the Invention

[0008] In view of this, this application provides a method for synthesizing tortezulide, which realizes a complete reaction process without interruption of intermediate transfer, and the synthesis steps are simple, using only one solvent to complete the synthesis of tortezulide.

[0009] Specifically, this application is implemented through the following scheme: A method for synthesizing totruzumab, comprising the following steps: Step 1: Add a methylamine aqueous solution to the reaction vessel, cool to 0-5°C, slowly add diethyl carbonate solution, controlling the adding temperature to not exceed 10°C, and after the addition is complete, react at 5-15°C for 1-3 hours, controlling the water content to below 0.5%, to obtain ethyl methylcarbamate with a molar yield of approximately 90%.

[0010] The molar ratio of methylamine to diethyl carbonate is 1.0:1.0 to 1.3.

[0011] The reaction equation for this step is expressed as follows: .

[0012] Step two: First, dissolve arylurea in a solvent, then add it along with the catalyst to the reaction vessel containing ethyl methylcarbamate. React at 40–90°C for 2–16 h, with a molar ratio of arylurea, ethyl methylcarbamate, and catalyst (CAT) of 1.0:1.0–10:0.5–8.0. After TLC monitoring shows the reaction is complete, add diethyl carbonate and maintain the temperature at 70–120°C for 0.5–12 h, with a molar ratio of arylurea to diethyl carbonate of 1.0:1.5–10. After TLC monitoring shows the reaction is complete, add water at 40–80°C, adjust the pH to neutral using hydrochloric acid, and cool to 0–10°C to precipitate a white solid. Filter, wash, dry, dissolve, and recrystallize to obtain toltrazuril in 85–95% yield.

[0013] The reaction formula for this step is expressed as follows: .

[0014] Furthermore, as a preferred option: The mass concentration of the monomethylamine aqueous solution is 40%.

[0015] The moisture content is controlled by first reducing the pressure to recover the moisture, then adding toluene for entrainment at normal pressure, with the mass ratio of toluene to monomethylamine aqueous solution being 0.5-1.0:1.0.

[0016] The catalyst is any one of sodium methoxide, sodium ethoxide, sodium hydrogen, and sodium isopropoxide.

[0017] The solvent is any one of toluene, xylene, diethyl carbonate, acetonitrile, and ethanol.

[0018] The mass ratio of arylurea to solvent is 1:2 to 8.

[0019] The dissolution refers to the addition of an alcohol for dissolution. More preferably, the alcohol is any one of methanol, ethanol, and isopropanol.

[0020] This application significantly improves product yield, reduces processes, reduces waste, and lowers costs, making it suitable for industrial production. Its beneficial effects are summarized as follows: Tortrazulide is obtained from arylurea through a two-step reaction of amidation and cyclization. The entire reaction is carried out in a fluid form with no solid intermediates produced. The synthesis involves fewer steps and is suitable for industrial production.

[0021] The raw materials used do not involve the use of phosgene or triphosgene, making them green and environmentally friendly.

[0022] (3) The reaction conditions are mild, and the same solvent is used in both steps of the reaction, which reduces the generation of wastewater. Detailed Implementation

[0023] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions of this application will be further described in detail below with reference to specific examples in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0024] Example 1

[0025] 30.00 g of 40% monomethylamine aqueous solution (0.386 mol) was added to a reaction vessel, and the temperature was lowered to around 0°C. 45.60 g of diethyl carbonate solution (0.386 mol) was slowly added dropwise, controlling the addition temperature to not exceed 10°C. After the addition was complete, the reaction was carried out at 10°C for 3 hours. Water was recovered under reduced pressure. After recovery, 30 g of toluene was added under normal pressure to remove entrained water, controlling the water content to ≤0.5%. 34.69 g of ethyl methylcarbamate was obtained, with a molar yield of 87.26% and a purity of 99.21%.

[0026] Example 2

[0027] The setup in this embodiment is the same as in Example 1, except that the amount of diethyl carbonate used is 54.72 g (0.463 mol), yielding 35.87 g of ethyl methacrylate, with a molar yield of 90.23% and a content of 99.11%.

[0028] Example 3

[0029] The setup in this embodiment is the same as in Example 1, except that the amount of diethyl carbonate used is 59.28 g (0.502 mol), yielding 35.48 g of ethyl methacrylate, with a molar yield of 89.25% and a content of 99.01%.

[0030] Example 4

[0031] 20.00 g of arylurea (0.058 mol) was dissolved in 80.00 g of toluene. 11.96 g of ethyl methylcarbamate (0.116 mol, which can be the ethyl methylcarbamate prepared in Example 1) and 3.94 g of sodium ethoxide (0.058 mol) were added to the reaction vessel, and the reaction was carried out at 85 °C for 6 h. After the reaction was complete as monitored by TLC, 20.53 g of diethyl carbonate (0.174 mol) was added, and the mixture was kept at 120 °C for 4 h. After the reaction was complete as monitored by TLC, 40 g of water was added at 65 °C, the pH was adjusted to 7 using hydrochloric acid, the mixture was cooled to 5 °C, filtered, rinsed, dried, and then dissolved and recrystallized using 260 g of anhydrous ethanol. The resulting product was toltrazuril with a molar yield of 91.21% and a purity of 99.93%.

[0032] Example 5

[0033] 20.00 g of arylurea (0.058 mol) was dissolved in 100.00 g of ethanol. 11.96 g of ethyl methylcarbamate (0.116 mol, which can be the ethyl methylcarbamate prepared in Example 1) and 3.94 g of sodium ethoxide (0.058 mol) were added to the reaction vessel, and the reaction was carried out at 85 °C for 12 h. After the reaction was complete as monitored by TLC, 34.21 g of diethyl carbonate (0.29 mol) was added, and the mixture was kept at 85 °C for 10 h. After the reaction was complete as monitored by TLC, 40 g of water was added at 65 °C, the pH was adjusted to 7 using hydrochloric acid, the mixture was cooled to 5 °C, filtered, rinsed, dried, and then dissolved and recrystallized using 260 g of anhydrous ethanol. The resulting product was toltrazuril with a molar yield of 87.13% and a purity of 99.96%.

[0034] Example 6

[0035] 20.00 g of arylurea (0.058 mol) was dissolved in 120.00 g of diethyl carbonate, and 11.96 g of ethyl methylcarbamate (0.116 mol, which can be the ethyl methylcarbamate prepared in Example 1) and 3.94 g of sodium ethoxide (0.058 mol) were added to the reaction vessel and reacted at 120 °C for 16 h. The reaction was monitored by TLC until completion. The pH was adjusted to 7 with acetic acid at 65 °C, 40 g of water was added, the mixture was separated, the aqueous layer was removed, and the solvent diethyl carbonate was recovered and dried to obtain a white solid. The solid was dried and dissolved in 260 g of anhydrous ethanol and recrystallized to obtain toltrazuril with a molar yield of 90.36% and a purity of 99.91%.

[0036] Example 7

[0037] This embodiment is set up the same as in Example 6, except that the catalyst sodium ethoxide is replaced with a 20wt% sodium ethoxide ethanol solution, and it is added dropwise at approximately 50°C for 1.5 hours. The resulting toltrezulli molar yield is 90.68%, and the purity is 99.93%.

[0038] Example 8

[0039] The setup in this embodiment is the same as in Example 6, except that the catalyst sodium ethoxide is replaced with 15.66g of 20wt% sodium methoxide methanol solution, resulting in a molar yield of 87.35% and a content of 99.95% for tortezulli.

[0040] Example 9

[0041] This embodiment uses the same setup as Example 6, except that the recrystallization solvent, anhydrous ethanol, is replaced with methanol. The resulting toltrazuril had a molar yield of 88.23% and a purity of 99.92%.

[0042] The above-described embodiments are merely illustrative of several feasible implementations of the present invention, and their descriptions are relatively specific and detailed. However, they should not be construed as limiting the scope of the present invention, nor are the embodiments intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. All equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for synthesizing toltrazuril, characterized in that, The steps are as follows: Step 1: Under conditions of 0-5℃, diethyl carbonate solution is slowly added dropwise to a methylamine aqueous solution. After the addition is complete, the reaction is carried out at 5-15℃. The water content is controlled below 0.5% to obtain ethyl methylcarbamate. The molar ratio of methylamine to diethyl carbonate is 1.0:1.0-1.

3. Step 2: Add arylurea, solvent, and catalyst to the obtained ethyl methylcarbamate and react at 40–90°C. After the reaction is complete as monitored by TLC, add diethyl carbonate and maintain the temperature at 70–120°C. After the reaction is complete as monitored by TLC, add water and adjust the pH to neutral at 40–80°C. Cool to 0–10°C to precipitate a white solid. Filter, wash, dry, dissolve, and recrystallize to obtain toltrazuril. The molar ratio of arylurea, ethyl methylcarbamate, and catalyst is 1.0:1.0–10:0.5–8.0, and the molar ratio of arylurea to diethyl carbonate is 1.0:1.5–10.

2. The method for synthesizing toltrazuril according to claim 1, characterized in that: The mass concentration of the monomethylamine aqueous solution is 40%.

3. The method for synthesizing toltrazuril according to claim 1, characterized in that, The moisture content is controlled by first reducing the pressure to recover the moisture, then adding toluene for entrainment at normal pressure, with the mass ratio of toluene to monomethylamine aqueous solution being 0.5-1.0:1.

0.

4. The method for synthesizing toltrazuril according to claim 1, characterized in that: The catalyst is any one of sodium methoxide, sodium ethoxide, sodium hydrogen, and sodium isopropoxide.

5. The method for synthesizing toltrazuril according to claim 1, characterized in that: The solvent is any one of toluene, xylene, diethyl carbonate, acetonitrile, and ethanol.

6. The method for synthesizing toltrazuril according to claim 1, characterized in that: The mass ratio of arylurea to solvent is 1:2 to 8.

7. The method for synthesizing toltrazuril according to claim 1, characterized in that: The so-called dissolution refers to the dissolution process by adding alcohols.

8. The method for synthesizing toltrazuril according to claim 7, characterized in that: The alcohol is any one of methanol, ethanol, and isopropanol.