Preparation method of imidocarb

Abstract

The invention belongs to the technical field of drug synthesis, and relates to a preparation method of imidocarb, which comprises the following steps: carrying out condensation and cyclization on m-nitrobenzoic acid and ethylenediamine under the action of DCC to obtain 2-(3-nitrophenyl) imidazoline, reducing with zinc powder and ammonium chloride to obtain 2-(3-aminophenyl) imidazoline, and finally condensing with triphosgene to obtain imidocarb. The method has the advantages of low initial material cost, no use of acylation reagents such as thionyl chloride, avoiding of the generation of acidic tail gas, and environmental protection. The technical route provided by the invention is simple in process operation, low in cost and less in three wastes, and the obtained imidocarb product is high in purity and is suitable for industrial production requirements.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method of imidocarb dipropionate. Background Art

[0002] Imidocarb dipropionate is a new type of antiprotozoal chemical drug for animals. Generally, its dipropionate or dihydrochloride is commonly made into preparations and used for intramuscular or subcutaneous injection to treat and prevent various babesiosis, piroplasmosis, trypanosomiasis, eperythrozoonosis, anaplasmosis, and theileriosis. As a veterinary drug, it has the characteristics of small dosage, convenient use, short course of treatment, and low drug resistance. Its structural formula is as follows:

[0003] The chemical synthesis methods of imidocarb dipropionate mainly include the following several: (1) US Patent No. US3338917 discloses a method for preparing imidocarb dipropionate by reacting 2-(3-aminophenyl)imidazoline with phosgene:

[0004] (2) Chinese Patent No. ZL200610083133.5 discloses a method for preparing imidocarb by using m-aminobenzonitrile as a raw material, first forming a diphenylurea structure with triphosgene (BTC), and then reacting with ethylenediamine:

[0005] (3) Chinese Patents CN111574455A, CN106957265A, and ZL202210274805.X disclose a method for preparing imidocarb dipropionate by using m-nitrobenzonitrile as a raw material, first reacting with ethylenediamine to prepare 2-(3-nitrophenyl)imidazoline, then reducing the nitro group, and finally preparing imidocarb dipropionate:

[0006] (4) Chinese Patents ZL201210454778.0 and ZL201410155713.5 disclose a method for preparing imidocarb dipropionate by using m-nitrobenzoic acid / methyl m-nitrobenzoate as a raw material, first reacting with ethylenediamine to prepare 2-(3-nitrophenyl)imidazoline, then reducing the nitro group, and finally preparing imidocarb dipropionate:

[0007] The existing synthesis methods have problems such as high price of starting materials, many reaction steps, and a large amount of three wastes, which ultimately lead to high product cost and lack of market competitiveness. Summary of the Invention

[0008] The object of the present invention is to provide a preparation method of imidocarb dihydrochloride aiming at the deficiencies of the prior art. The technical route has simple process operation, low cost, less three wastes and high product purity, and meets the requirements of industrial production.

[0009] A preparation method of imidocarb dihydrochloride comprises the following steps: (1) Mix m-nitrobenzoic acid and toluene in a mass-volume ratio of 1:3 - 10, g / mL, add dicyclohexylcarbodiimide (DCC) as a condensing agent under stirring. The molar ratio of m-nitrobenzoic acid to DCC is 1:1 - 3, and react at 10 - 30°C for 0.5 - 3 hours. Then add ethylenediamine, the molar ratio of m-nitrobenzoic acid to ethylenediamine is 1:1 - 3, and react at 10 - 30°C for 1 - 4 hours. Raise the reaction temperature and reflux for 1 - 5 hours. During the reaction process, separate out the water generated by the reaction. Cool the reaction solution to -10 - 30°C, filter, wash with toluene, and dry to obtain 2-(3-nitrophenyl)imidazoline; (2) Use methanol as a solvent for 2-(3-nitrophenyl)imidazoline, zinc powder and ammonium chloride as reducing agents, heat to 65 - 70°C and reflux. The reflux reaction time is 1 - 5 hours. Filter while it is hot, concentrate the filtrate to about one-third, cool to 0 - 30°C, filter, wash with methanol, and dry to obtain 2-(3-aminophenyl)imidazoline; (3) Use toluene and water as solvents for 2-(3-aminophenyl)imidazoline, adjust the pH to 8 - 9 with 5% aqueous sodium hydroxide solution, add triphosgene, and carry out a condensation reaction with a molar ratio of 2-(3-aminophenyl)imidazoline to triphosgene of 3 - 9:1. React at 0 - 50°C for 1 - 4 hours, filter, wash with water, and dry to obtain imidocarb dihydrochloride.

[0010] Preferably, in step (1), the mass-volume ratio of m-nitrobenzoic acid to toluene is 1:5 - 6, g / mL.

[0011] Preferably, in step (1), the molar ratio of m-nitrobenzoic acid to DCC and ethylenediamine is 1:(1.1 - 1.3):(1.05 - 1.2).

[0012] Preferably, in step (1), the reaction time of m-nitrobenzoic acid with DCC is 1 - 2 hours, and then add ethylenediamine and react for 2 - 3 hours.

[0013] Preferably, in step (1), the reaction temperature is raised to the reflux temperature of toluene for 2 - 3 hours, and the reflux temperature is 110 - 120°C. During the reaction process, separate out the generated water through a water separation device.

[0014] Preferably, after the reaction in step (1) is completed, cool the reaction solution to 0 - 20°C.

[0015] Preferably, in step (2), the reflux reaction time is 2 - 3 hours.

[0016] Preferably, in step (2), the temperature is lowered to 0-20°C.

[0017] Preferably, in step (3), the molar ratio of 2-(3-aminophenyl)imidazoline to triphosgene is 5:1.

[0018] Preferably, in step (3), the condensation reaction temperature is 10-30°C and the reaction time is 2-3 hours.

[0019] The chemical reaction formula is as follows:

[0020] The preparation method of imidocarb dipropionate according to the present invention has the following advantages compared with the prior art route: (1) The price of starting material m-nitrobenzoic acid is much lower than that of m-nitrobenzonitrile and methyl m-nitrobenzoate, and the process has a cost advantage.

[0021] (2) Using DCC as a condensing agent, m-nitrobenzoic acid is condensed with ethylenediamine without using acylating reagents such as thionyl chloride, avoiding the generation of acidic tail gas and having an environmental protection advantage.

[0022] (3) Water is generated during the cyclization process of m-nitrobenzoic acid and ethylenediamine. In the reaction process of the present invention, the generated water is continuously separated, which is beneficial to the forward reaction, and the reaction yield can reach 96%.

[0023] (4) The present invention uses triphosgene as a raw material. Compared with phosgene, it is safer to operate and easier to store; and it has lower toxicity and is more stable. This technical route has simple process operation, low cost, less three wastes and high product purity, meeting the requirements of industrial production. Specific embodiments

[0024] The present invention will be further described in detail below with reference to specific embodiments, but the scope of the present invention is not limited. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0025] Example 1 A preparation method of imidocarb dipropionate (1) Add m-nitrobenzoic acid (167 g, 1 mol) and 835 mL of toluene to a reaction flask. Stir and add DCC (227 g, 1.1 mol). Stir and react at about 15°C for about 1 hour. Add ethylenediamine (63 g, 1.05 mol) and continue to react at this temperature for about 2 hours; heat up to about 120°C for reflux. During the reaction process, the generated water is continuously separated through a water separator. Reflux and react for about 3 hours, cool to about 10°C, filter, wash with toluene, and dry to obtain 184 g of 2-(3-nitrophenyl)imidazoline with a yield of 96.3%.

[0026] (2) Add 2-(3-nitrophenyl)imidazoline (180 g, 0.94 mol), 1800 mL of methanol, zinc powder (244 g, 3.8 mol), and ammonium chloride (214 g, 4 mol) into the reaction flask. Heat up to about 65 °C and reflux for 2 - 3 hours. Filter while it is hot. Concentrate the filtrate to about one-third, cool down to about 10 °C, filter, wash with methanol, and dry to obtain 129 g of 2-(3-aminophenyl)imidazoline with a yield of 85.1%.

[0027] (3) Add 2-(3-aminophenyl)imidazoline (120 g, 0.74 mol), 240 mL of toluene, and 360 mL of water into the reaction flask. Adjust the pH to 8 - 9 with 5% aqueous sodium hydroxide solution. Add triphosgene (44.5 g, 0.15 mol) and react at room temperature for 2 - 3 hours. Filter, wash with water, and dry to obtain 110 g of imidocarb dipropionate with a yield of 85.3%.

[0028] Example 2 A preparation method of imidocarb dipropionate (1) Add m-nitrobenzoic acid (167 g, 1 mol) and 1000 mL of toluene into the reaction flask. Add DCC (247 g, 1.2 mol) with stirring at about 25 °C and stir for about 1 hour. Add ethylenediamine (66 g, 1.1 mol) and continue to react at this temperature for about 2 hours. Heat up to about 110 °C and reflux. Continuously separate the generated water through the water separator during the reaction. Reflux for about 3 hours, cool down to about 10 °C, filter, wash with toluene, and dry to obtain 185 g of 2-(3-nitrophenyl)imidazoline with a yield of 96.8%.

[0029] (2) Add 2-(3-nitrophenyl)imidazoline (180 g, 0.94 mol), 1800 mL of methanol, zinc powder (257 g, 4 mol), and ammonium chloride (214 g, 4 mol) into the reaction flask. Heat up to about 70 °C and reflux for 2 - 3 hours. Filter while it is hot. Concentrate the filtrate to about one-third, cool down to about 10 °C, filter, wash with methanol, and dry to obtain 130 g of 2-(3-aminophenyl)imidazoline with a yield of 85.8%.

[0030] (3) Add 2-(3-aminophenyl)imidazoline (120 g, 0.74 mol), 360 mL of toluene, and 480 mL of water into the reaction flask. Adjust the pH to 8 - 9 with 5% aqueous sodium hydroxide solution. Add triphosgene (44.5 g, 0.15 mol) and react at room temperature for 2 - 3 hours. Filter, wash with water, and dry to obtain 109 g of imidocarb dipropionate with a yield of 84.6%.

[0031] Example 3 A preparation method of imidocarb dipropionate (1) Add m-nitrobenzoic acid (167 g, 1 mol) and 835 mL of toluene into a reaction flask. While stirring, add DCC (268 g, 1.3 mol). Stir and react at about 20 °C for about 1 hour. Then add ethylenediamine (72 g, 1.2 mol) and continue to react at this temperature for about 2 hours. Heat up to about 110 °C for reflux. During the reaction process, continuously separate the generated water through a water separator. Reflux and react for about 3 hours. Cool to about 10 °C, filter, wash with toluene, and dry to obtain 183 g of 2-(3-nitrophenyl)imidazoline with a yield of 95.8%.

[0032] (2) Add 2-(3-nitrophenyl)imidazoline (180 g, 0.94 mol), 1800 mL of methanol, zinc powder (321 g, 5 mol), and ammonium chloride (267 g, 5 mol) into a reaction flask. Heat up to about 65 °C for reflux and react for 2 - 3 hours. Filter while it is hot. Concentrate the filtrate to about one-third, cool to about 10 °C, filter, wash with methanol, and dry to obtain 131 g of 2-(3-aminophenyl)imidazoline with a yield of 86.4%.

[0033] (3) Add 2-(3-aminophenyl)imidazoline (120 g, 0.74 mol), 360 mL of toluene, and 360 mL of water into a reaction flask. Adjust the pH to 8 - 9 with 5% aqueous sodium hydroxide solution. Add triphosgene (44.5 g, 0.15 mol) and react at room temperature for 2 - 3 hours. Filter, wash with water, and dry to obtain 111 g of imidocarb dipropionate with a yield of 86.1%.

[0034] Example 4 A preparation method of imidocarb dipropionate (1) Add m-nitrobenzoic acid (167 g, 1 mol) and 835 mL of toluene into a reaction flask. While stirring, add DCC (247 g, 1.2 mol). Stir and react at about 20 °C for about 1 hour. Then add ethylenediamine (66 g, 1.1 mol) and continue to react at this temperature for about 2 hours. Heat up to about 110 °C for reflux. During the reaction process, continuously separate the generated water through a water separator. Reflux and react for about 3 hours. Cool to about 10 °C, filter, wash with toluene, and dry to obtain 185 g of 2-(3-nitrophenyl)imidazoline with a yield of 96.8%.

[0035] (2) Add 2-(3-nitrophenyl)imidazoline (180 g, 0.94 mol), 2000 mL of methanol, zinc powder (257 g, 4 mol), and ammonium chloride (214 g, 4 mol) into the reaction flask. Heat up to about 65 °C and reflux for 2 - 3 hours. Filter while it is hot. Concentrate the filtrate to about one-third, cool down to about 10 °C, filter, wash with methanol, and dry to obtain 130 g of 2-(3-aminophenyl)imidazoline, with a yield of 85.8%.

[0036] (3) Add 2-(3-aminophenyl)imidazoline (120 g, 0.74 mol), 480 mL of toluene, and 480 mL of water into the reaction flask. Adjust the pH to 8 - 9 with 5% aqueous sodium hydroxide solution. Add triphosgene (44.5 g, 0.15 mol) and react at room temperature for 2 - 3 hours. Filter, wash with water, and dry to obtain 110 g of imidocarb dipropionate, with a yield of 85.3%.

[0037] Comparative Example 1 Prepare imidocarb dipropionate according to Examples 2 - 3 in a preparation method of imidocarb dipropionate and its intermediate disclosed in the patent application No. 202010411314.6.

[0038] (1) Add 1500 mL of methanol into the reaction flask. While stirring, add m-nitrobenzonitrile (148 g, 1 mo1), sodium sulfide (39 g, 0.5 mol), and ethylenediamine (72 g, 1.2 mol). Heat up to reflux and reflux for 8 hours. Filter while it is hot. Cool the filtrate to about 0 °C and stir for crystallization for 2 hours. Filter, wash with cold methanol, and dry to obtain 2-(3-nitrophenyl)imidazoline (amount: 178 g, yield: 93.1%).

[0039] (2) Add 2-(3-nitrophenyl)imidazoline (170 g, 0.89 mol) and 1400 mL of water into the reaction flask. Carefully add 10% wet palladium-carbon (5 g), slowly heat up and stir to reflux, and slowly dropwise add an aqueous solution of ammonium formate (168 g, 2.67 mol) in water (340 mL). Finish dropping in about 0.5 hour and react for 2 hours. Filter, and directly use the obtained filtrate in the next step.

[0040] (3) Add the reaction solution from the previous step, hydrochloric acid (190 mL, 2.27 mol), and urea (27 g, 0.45 mol) into the reaction flask in sequence. Under nitrogen protection, heat and stir to reflux, react for 8 hours, cool down to about 20 °C, adjust the pH to 9 - 10 with 2 mo1 / L aqueous sodium hydroxide solution, stir for 0.5 hour, filter, wash with water, and dry to obtain imidocarb dipropionate (amount: 99 g, two-step yield: 63.9%).

[0041] Comparative Example 2 The preparation method of imidocarb dipropionate was carried out according to the method of Example 1 in a preparation method of imidocarb dipropionate disclosed in the application No. 201210454778.0.

[0042] (1) Add m-nitrobenzoic acid (167 g, 1 mol) and thionyl chloride (476 g, 4 mol) into the reaction flask, mix and stir, heat up to 80 °C, reflux for 4 hours, control the temperature at about 75 °C, concentrate under reduced pressure to remove thionyl chloride, and dry to obtain 181 g of m-nitrobenzoyl chloride with a yield of 97.5%; (2) Add m-nitrobenzoyl chloride (175 g, 0.94 mol), 800 mL of acetonitrile, and phosphomolybdovanadic heteropolyacid (11 g) into the reaction flask, stir and add ethylenediamine (62 g, 1.03 mol), heat up to 80 °C, reflux for 2 hours, filter, and concentrate the filtrate under reduced pressure at 75 °C to obtain 161 g of 2-(3-nitrophenyl)imidazoline with a yield of 89.6%.

[0043] (3) Add 2-(3-nitrophenyl)imidazoline (153 g, 0.8 mol), 750 mL of water, and 5% palladium-carbon catalyst (12 g) into the reaction flask, carry out reduction hydrogenation reaction for 4 hours under the conditions of temperature 70 °C, hydrogen atmosphere, and pressure 0.4 MPa, filter, adjust the pH of the filtrate to 6 with 6 mol / L hydrochloric acid, cool down to about 0 °C, stand for crystallization for 1 hour, filter, and dry to obtain 2-(3-aminophenyl)imidazoline hydrochloride (142 g) with a yield of 89.8%.

[0044] (4) Add 2-(3-aminophenyl)imidazoline hydrochloride (131 g, 0.66 mol) and 800 mL of N,N-dimethylformamide into the reaction flask, stir and add urea (36 g, 0.6 mol), heat up to 160 °C, react for 5 hours, cool down to about 0 °C, stand for crystallization for 1 hour, filter, wash with water, and dry to obtain 96 g of imidocarb dipropionate with a yield of 83.5%.

[0045] The total yields and main differences of the preparation of imidocarb dipropionate in Examples 1-4 and Comparative Examples 1-2 were statistically analyzed, and the results are shown in Table 1.

[0046] Table 1 Total yields of imidocarb dipropionate and main differences in the preparation methods in Examples 1-4 and Comparative Examples 1-2

[0047] Using the method of this application, not only the total yield of the prepared imidocarb dipropionate is increased, but also the preparation cost is low, the operation is simple, the safety is high, the three wastes are less in the preparation process, and it is suitable for industrial production.

[0048] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Without departing from the scope of the technical solution of the present invention, equivalent embodiments with minor modifications and equivalent changes made using the above technical content still fall within the scope of the technical solution of the present invention and should all be included within the protection scope of the present invention.

Claims

1. A preparation method of imidocarb, characterized in that, The preparation method includes the following steps: (1) Mix m-nitrobenzoic acid and toluene at a mass-to-volume ratio of 1:3 - 10, g / mL. While stirring, add dicyclohexylcarbodiimide (DCC) as a condensing agent. The molar ratio of m-nitrobenzoic acid to DCC is 1:1 - 3. React at 10 - 30 °C for 0.5 - 3 hours. Then add ethylenediamine. The molar ratio of m-nitrobenzoic acid to ethylenediamine is 1:1 - 3. React at 10 - 30 °C for 1 - 4 hours. Raise the reaction temperature and reflux for 1 - 5 hours. During the reaction process, separate out the water generated by the reaction. Cool the reaction solution to -10 - 30 °C, filter, wash with toluene, and dry to obtain 2-(3-nitrophenyl)imidazoline; (2) Use methanol as the solvent for 2-(3-nitrophenyl)imidazoline, and zinc powder and ammonium chloride as reducing agents. Heat up to 65 - 70 °C and reflux. The reflux reaction time is 1 - 5 hours. Filter while it is hot. Concentrate the filtrate to about one-third. Cool to 0 - 30 °C, filter, wash with methanol, and dry to obtain 2-(3-aminophenyl)imidazoline; (3) Use toluene and water as the solvents for 2-(3-aminophenyl)imidazoline. Adjust the pH to 8 - 9 with a 5% aqueous sodium hydroxide solution. Add triphosgene. The molar ratio of 2-(3-aminophenyl)imidazoline to triphosgene is 3 - 9:1 for the condensation reaction. React at 0 - 50 °C for 1 - 4 hours. Filter, wash with water, and dry to obtain imidocarb dipropionate.

2. The preparation method according to claim 1, characterized in that, In the step (1), the mass-to-volume ratio of m-nitrobenzoic acid to toluene is 1:5 - 6, g / mL; the molar ratios of m-nitrobenzoic acid to DCC and ethylenediamine are 1:(1.1 - 1.3):(1.05 - 1.2).

3. The preparation method according to claim 1, characterized in that, In the step (1), the reaction time of m-nitrobenzoic acid with DCC is 1 - 2 hours, and then add ethylenediamine and react for 2 - 3 hours.

4. The preparation method according to claim 1, characterized in that, In the step (1), the reaction temperature is raised to the reflux temperature of toluene for 2 - 3 hours, and the reflux temperature is 110 - 120 °C. During the reaction process, separate out the generated water through a water separation device.

5. The preparation method according to claim 1, characterized in that, After the reaction in the step (1) is completed, cool the reaction solution to 0 - 20 °C.

6. The preparation method according to claim 1, wherein, In the step (2), the reflux reaction time is 2 - 3 hours.

7. The preparation method according to claim 1, characterized in that, In the step (2), cool to 0 - 20 °C.

8. The preparation method according to claim 1, wherein In the step (3), the molar ratio of 2-(3-aminophenyl)imidazoline to triphosgene is 5:

1.

9. The preparation method according to claim 1, characterized in that, In the step (3), the condensation reaction temperature is 10 - 30 °C, and the reaction time is 2 - 3 hours.

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