CN116813551A

CN116813551A - Preparation method of imidazole phenylurea dipropionate

Info

Publication number: CN116813551A
Application number: CN202311088204.0A
Authority: CN
Inventors: 刘文耀; 徐亚会; 杜万青; 杨程程; 牛续发; 苏月航
Original assignee: QILU SYNVA PHARMACEUTICAL CO Ltd
Current assignee: QILU SYNVA PHARMACEUTICAL CO Ltd
Priority date: 2023-08-28
Filing date: 2023-08-28
Publication date: 2023-09-29

Abstract

The invention relates to the technical field of organic synthesis, and provides a preparation method of imidocarb dipropionate (i.e. imidocarb dipropionate). In the cyclization step, microwave auxiliary reaction is adopted, and the catalyst is matched for use, so that the reaction time is greatly shortened, and the yield of a product is improved; in the condensation step, alkyl carbonate is used for replacing phosgene or triphosgene, the working procedure is reduced, the imidazole phenylurea is produced in one step, the working procedures of crystallization and centrifugal separation of the imidazole phenylurea hydrochloride are reduced, the step of regulating pH by alkali is not needed to obtain the imidazole phenylurea, and the operation working procedures are reduced; meanwhile, the step of adjusting the pH value by using hydrochloride and alkali is not needed, so that the use of raw materials is saved, and the production cost is reduced.

Description

Preparation method of imidazole phenylurea dipropionate

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a preparation method of mizofenozide dipropionate.

Background

The imidazole phenylurea (also called as micola dipropionate) is a chemical for veterinary medicine, is a diphenyl urea diamidine derivative of a piroxicam resistant medicine, is an important compound with biological activity, and is most commonly used as dipropionate. The traditional Chinese medicine composition has the advantages of broad spectrum, low toxicity, wide application range, long acting time, small dosage and the like, has good treatment effect on the livestock pirosis, the plasmacytosis, the eperythrozoonosis of pigs, dogs and the like, and also has good prevention effect. With the wide spread of piroplasmosis around the world, the demand for such drugs is increasing. In face of urgent domestic and overseas demands, a new preparation method suitable for industrial production is sought, rapid development of veterinary medicine industry is promoted, and the requirements at home and abroad are met, so that the method has important economic benefit and social benefit.

The current method for synthesizing the imidazole phenylurea mainly comprises the following steps:

1.3, 3' -dicyanodiphenyl urea reacts with ethylenediamine in diethyl ether-hydrogen sulfuric acid or ethanol-hydrochloric acid system, and the reaction is a very old method, and the raw material dicyano is a highly toxic compound, so that the industrial production is not facilitated. The reaction formula is as follows:

2. the 3,3' -formate diphenyl urea reacts with ethylenediamine in ammonium chloride solution and (R and R ' are alkane groups with less carbon atoms), and the raw material 3,3' -formate diphenyl urea of the method is difficult to obtain and is not beneficial to industrial production.

3. The ethyl m-nitrobenzoate reacts with ethylenediamine in the presence of trimethylaluminum to obtain 2- (3-nitrophenyl) imidazoline, then the 2- (3-aminophenyl) imidazoline is prepared by reduction, and finally the condensation reaction is carried out with phosgene in sodium acetate-water solution. The m-nitrobenzoic acid ethyl ester and the trimethylaluminum of the route are expensive, and phosgene is extremely toxic gas, so that the route is not suitable for industrial production.

Zhang Shouping the cyclization step is improved on the basis, and the cyclization reaction between m-nitrobenzonitrile and ethylenediamine fully occurs under the action of a catalyst.

4. The meta-aminosodium benzoate reacts with ethylenediamine dihydrochloride to prepare 2- (3-aminophenyl) imidazoline, and hydrochloric acid is added dropwise to enable pH to be in the range of 1-2 to carry out condensation reaction with urea:

the reaction raw material m-aminobenzoic acid is mainly obtained by catalytic hydrogenation of m-nitrobenzoic acid or reduction of iron powder. In industry, benzoic acid is used as a raw material, sodium nitrate is used for nitration in the presence of sulfuric acid, and m-nitrobenzoic acid can be obtained with the yield reaching 60%; if benzoic acid is firstly esterified into methyl benzoate in the presence of sulfuric acid, then mixed acid is used for nitration, and finally the hydrolysis yield can reach 70%, but the method is more troublesome. Meanwhile, the catalyst can also be obtained by directly nitrifying mixed acid, the reaction temperature is high, and the yield can reach 60%.

5. M-nitrobenzonitrile is used as a starting material, and is subjected to cyclization, reduction, condensation and salification reaction:

the route is currently studied more, the main improvement points being the improvement of the catalyst and reaction conditions of the cyclization reaction, and the improvement of the condensing agent of the condensation reaction. However, the prior art has the problems of complex post-treatment, low yield, environmental protection and the like.

Therefore, a novel preparation method of the mizofenozide dipropionate suitable for industrial production has important significance.

Disclosure of Invention

The invention aims to provide a preparation method of mizofenozide dipropionate, which aims to solve the technical problems of complex post-treatment, low yield and environmental protection in the prior art.

In order to solve the technical problems, the invention provides a preparation method of the mizofenozide dipropionate, which comprises the following steps:

step one: m-nitrobenzonitrile is used as a raw material and reacts with ethylenediamine under the microwave condition and in the presence of a catalyst to synthesize 2- (3-nitrophenyl) imidazoline (compound 1);

step two: the compound 1 is subjected to reduction reaction to obtain 2- (3-aminophenyl) imidazoline (compound 2);

step three: the compound 2 and dialkyl carbonate undergo condensation reaction to prepare the imidazole phenylurea (compound 3);

step four: the compound 3 reacts with propionic acid to form salt to prepare the mizofenozide dipropionate;

wherein: the catalyst of step one is selected from S, na ₂ S or K ₂ S, and one or more than one of S.

In one embodiment, the molar ratio of intermediate nitrobenzonitrile to ethylenediamine of step one is from 1:1 to 2, preferably from 1:1.1 to 1.3; the first step is carried out in the presence of a solvent selected from at least one of an alcohol solvent, an ester solvent and an ether solvent, preferably at least one of methanol, ethanol, isopropanol and tert-butanol.

In one embodiment, the microwave reaction power of step one is 150 to 250W, preferably 200W; the reaction time of the first step is 2 to 6 hours, preferably 3 to 4 hours;

in one embodiment, the catalyst of step one is used in an amount of 0.05 to 0.6 times, preferably 0.1 to 0.3 times the molar amount of m-nitrobenzonitrile.

In one embodiment, the reduction reaction of step two uses sodium hydrosulfite as a reducing agent under alkaline conditions.

Preferably, the molar ratio of compound 1 to strongpoint II is 1:2-4, preferably 1:3. And the alkali used in the alkaline condition of the second step is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

In one embodiment, the reaction temperature of step two is from room temperature to 100 ℃, preferably 50-60 ℃.

In one embodiment, the reaction of step three is carried out in the presence of a catalyst selected from the group consisting of 1,5, 7-triazabicyclo- [4.4.0] -decen-5-ene (TBD).

In one embodiment, the reaction of step three is carried out in the presence of an organic solvent, preferably at least one selected from the group consisting of N, N-dimethylformamide, N-diethylformamide, ethylene glycol monomethyl ether, dimethyl sulfoxide, N-methylpyrrolidone.

In one embodiment, the molar ratio of compound 3 to dialkyl carbonate in step three is from 1:0.5 to 1.0, preferably 1:0.55; the molar ratio of compound 3 to catalyst is 10-100:1, preferably 30-50:1.

In one embodiment, the dialkyl carbonate of step three is selected from at least one of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, dibutyl carbonate; preferably at least one of dimethyl carbonate and diethyl carbonate.

In one embodiment, the reaction temperature of step three is from 70 to 200 ℃, preferably from 80 to 140 ℃, most preferably from 90 to 110 ℃.

In one embodiment, the post-processing step of step three comprises: after the reaction is finished, cooling, adding hot water at 70-100 ℃, continuously stirring for 15-60 minutes, and filtering out a solid product; optionally, subjecting the solid product to recrystallization purification; preferably, the recrystallization solvent is selected from at least one of methanol, ethanol, isopropanol.

In one embodiment, step four comprises the steps of: and (3) dissolving the compound 3 in a solvent, stirring until the solid is fully dissolved, adding propionic acid, precipitating a large amount of white solid, cooling to 5-10 ℃, stirring for crystallization, filtering, washing a filter cake, and drying to obtain white solid, namely the mizofenozide dipropionate.

Preferably, the solvent in the fourth step is at least one selected from ethyl acetate, dichloromethane, chloroform, methanol, ethanol and propanol; the crystallization time is 0.5-4 hours.

Compared with the prior art, the invention has the advantages that:

in the first step, the microwave-assisted reaction and the catalyst are used together, so that the reaction time is greatly shortened, and the yield of the product is improved. Under microwave radiation, the inside and the outside of the molecule are heated at the same time, and the conduction speed of the molecule is tens of times or thousands of times faster than the conduction speed of the molecule, so that the reaction is accelerated to different degrees, the yield of the product is improved, the reaction time is greatly shortened, and the method is favorable for industrial production. Li Guangbi et al (journal of the Chinese medical industry, 2008, 39 (2), 88) use sulfur powder as a catalyst in the cyclization step, and although the reaction yield can reach 94.3%, the reaction time is as long as 20 hours, which is extremely disadvantageous in industrial production. The invention combines the microwave technology with the catalyst to catalyze the reaction, so that the reaction time is reduced to 3-4 hours, and the production period of the reaction is greatly reduced.

The reduction modes mainly adopted in the industry at present are an iron powder reduction method, a catalytic hydrogenation reduction method, a hydrazine hydrate reduction method and the like. However, the methods have certain problems in application that the reduction of iron powder causes serious pollution to the environment, the catalytic hydrogenation reduction method has high equipment requirement and high catalyst price, and the hydrazine hydrate has volatility and toxicity and is not suitable for large-scale production. In addition, some conventional metal reducing agents or catalytic hydrogenation processes for reducing nitro groups are mostly less tolerant to other functional groups (e.g., reduction reactions may also occur to unsaturated bonds such as c= O, C = C, C =n present in the starting material). Therefore, the reduction of sensitive multifunctional nitro compounds tends to be less selective, resulting in low yields and difficult separation and purification. In many cases, sodium hydrosulfite (sodium hydrosulfite) can specifically reduce nitro groups, and other unsaturated groups (such as C=N double bonds in the imidazoline of the invention) are not affected, so that the intermediate compound 2 can be obtained in high yield and high purity.

In the condensation step, most of the prior art adopts phosgene or triphosgene as a condensation reagent, HCl gas, phosgene and the like can be generated in the reaction process, HCl is easy to react with the imidazole phenylurea to generate corresponding hydrochloride, alkali is also required to be added in the subsequent preparation of the dipropionate imidazole phenylurea, the imidazole phenylurea hydrochloride is converted into the form of imidazole phenylurea free alkali, the operation process is complicated, the operation process is increased, and the labor cost, the time cost and the reagent cost are increased.

In the condensation step, alkyl carbonate is used for replacing phosgene or triphosgene, the working procedure is reduced, the imidazole phenylurea is produced in one step, the working procedures of crystallization and centrifugal separation of the imidazole phenylurea hydrochloride are reduced, the step of regulating pH by alkali is not needed to obtain the imidazole phenylurea, and the operation working procedures are reduced; meanwhile, the step of adjusting the pH value by using hydrochloride and alkali is not needed, so that the use of raw materials is saved, and the production cost is reduced.

In addition, the use of alkyl carbonate as a condensing agent gives very good yields, no salts are produced during the reaction, the only by-product is alkyl alcohol, and no volatile organic compounds are contained in the post-treatment. Meanwhile, acid gases such as HCl and phosgene are not generated in the reaction process, hydrochloric acid is not needed for salifying in the post-treatment, so that the corrosion of strongly acidic equipment is reduced, the dissipation of toxic gases such as phosgene in the centrifugation process is reduced, and the method is beneficial to professional health.

The post-treatment of the condensation reaction is simple, and the imidazole phenylurea can be obtained only by simple filtering operation. Meanwhile, the intermediate product can be recrystallized and purified according to the requirement, and the solid of the imidazole phenylurea which is separated out by recrystallization is easy to separate and can be separated by conventional methods such as centrifugation, filtration and the like.

In addition, the catalyst TBD used in the condensation reaction is easy to recycle and can be reused, thereby meeting the requirements of green environmental protection and saving the cost.

Drawings

Fig. 1: an infrared spectrum of the imidazole phenylurea prepared in example 4;

fig. 2: the imidazole phenylurea produced in example 4 ^I H NMR spectrum.

Detailed Description

Example 1 2 Synthesis of 3-nitrophenyl imidazolines

Methanol 1500 mL was added to a 3 liter three port reaction flask, m-nitrobenzonitrile (148 g,1.0 mol), sulfur powder (3.2 g,0.1 mol) and ethylenediamine (72 g,1.2 mol) were added with stirring, the mixture was placed in a microwave reactor after the addition was completed, the microwave power was adjusted to 200W for reflux reaction, the reaction progress was analyzed by gas chromatography, and the reaction was completed after about 4 hours. Filtering while the filtrate is hot, cooling the filtrate to-5-0 ℃, stirring and crystallizing 2h, filtering, washing a filter cake with a small amount of cold methanol, and vacuum drying the product to obtain light yellow solid 2- (3-nitrophenyl) imidazoline (181 g, yield: 94.9%, purity: 99.0%).

Example 22 Synthesis of 3-nitrophenyl imidazolines

Ethanol 1500 mL was added to a 3 liter three port reaction flask and m-nitrobenzonitrile (148 g,1.0 mol), na was added with stirring ₂ S (15.6 g,0.2 mol) and ethylenediamine (72 g,1.2 mol), and placing the materials in a microwave reactor after the addition, adjusting the microwave power to 200W for reflux reaction, and performing gas chromatography tracking analysis on the reaction progress, wherein the reaction is completed after about 3.5 hours. Filtering while the filtrate is hot, cooling the filtrate to-5-0 ℃, stirring and crystallizing 2h, filtering, washing a filter cake with a small amount of cold methanol, and vacuum drying the product to obtain light yellow solid 2- (3-nitrophenyl) imidazoline (186 g, yield: 97.2%, purity: 98.4%).

Example 3 2 Synthesis of- (3-aminophenyl) imidazolines

To a 500ml three-necked flask were added 19.1: 19.1 g of 2- (3-nitrophenyl) imidazoline (0.1 mol) obtained in example 1 and 200ml of methanol, followed by addition of 24g of sodium hydroxide, stirring and dissolution, and the temperature was kept at 50℃under stirring. 50 g sodium dithionite was weighed out and slowly added dropwise to the flask, and sodium dithionite was added over 30 minutes. The progress of the reaction was monitored by TLC for about 3 hours. After the raw materials are completely reacted, the mixture is cooled, and the mixture is subjected to suction filtration, extraction and recrystallization to obtain 15.3g (yield 95.0%) of 2- (3-aminophenyl) imidazoline.

EXAMPLE 4 Synthesis of imidazole phenylurea

To a 500ml three-necked flask, 2- (3-aminophenyl) imidazoline (8.1 g,50 mmol) and 150ml DMF were added, and the mixture was dissolved with stirring, followed by diethyl carbonate (3.6 g,30 mmol) and TBD (1.3 mmol) as a catalyst, and the mixture was reacted by heating at 110℃for 6 hours under magnetic stirring. The flask was fitted with an air condenser and kept open throughout the reaction. After cooling to 70 ℃, hot water (100 ml) was added and vigorous stirring was continued for another 30 minutes. A large amount of solid was precipitated, and then the solid product was filtered off and purified by recrystallization from methanol, and dried in vacuo to give 8.2g (yield: 93.7%, purity: 99.5%) of imidocarb. The product is verified by infrared spectrogram and 1H-NMR to be the target intermediate imidazole phenylurea.

1H-NMR（400 MHz，DMSO-d6）δ：10.95（s，2H，NH）， 8.19（s，2H，CH），7.64-7.67（d，2H，CH），7.59-7.61（d，2H，CH），7.55-7.58（dd，2H，CH），6.91-6.95（m，2H，NH），3.78（s，8H，CH2）。

EXAMPLE 5 Synthesis of imidazole phenylurea

To a 500ml three-necked flask, 2- (3-aminophenyl) imidazoline (8.1 g,0.1 mol) and 150ml DMF were added, and the mixture was dissolved by stirring, followed by dimethyl carbonate (2.7 g,30 mmol) and TBD (1.3 mmol) as a catalyst, and the mixture was reacted by heating at 95℃for 8 hours under magnetic stirring. The flask was fitted with an air condenser and kept open throughout the reaction. After cooling to 70 ℃, hot water (100 ml) was added and vigorous stirring was continued for another 30 minutes. A large amount of solid was precipitated, and then the solid product was filtered off and purified by recrystallization from methanol, and dried in vacuo to give 8.3g (yield: 95.4%, purity: 99.3%).

EXAMPLE 6 Synthesis of imidocarb dipropionate

Imidazole phenylurea (3.5 g,10 mmol) is added into a 50mL three-mouth bottle sequentially, 20mL of ethyl acetate is added into the bottle, the mixture is heated and stirred until the solid is fully dissolved, the mixture is refluxed and stirred for 0.5h, the mixture is filtered, the filtrate is stirred and cooled to room temperature, propionic acid (1.63 g,22 mmol) is added dropwise, a large amount of white solid is separated out after the dripping, the mixture is cooled to 5-10 ℃ and stirred and crystallized for 2h, the mixture is filtered, a small amount of ethyl acetate is used for washing a filter cake, and the product is dried in vacuum to obtain white solid imidazole phenylurea dipropionate (4.58 g, 92.3%).

Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims

1. The preparation method of the mizofenozide dipropionate comprises the following steps:

step one: m-nitrobenzonitrile is used as a raw material and reacts with ethylenediamine under the microwave condition and in the presence of a catalyst to synthesize 2- (3-nitrophenyl) imidazoline, namely a compound 1;

step two: the compound 1 is subjected to reduction reaction to obtain 2- (3-aminophenyl) imidazoline, namely a compound 2;

step three: the compound 2 and dialkyl carbonate undergo condensation reaction to prepare the imidazole phenylurea, namely the compound 3;

wherein: the catalyst of step one is selected from S, na ₂ S or K ₂ At least one of S;

the catalyst in the third step is 1,5, 7-triazabicyclo- [4.4.0] -decen-5-ene;

the dialkyl carbonate in the step three is at least one selected from dimethyl carbonate, diethyl carbonate, dipropyl carbonate and dibutyl carbonate.

2. The method of manufacturing according to claim 1, characterized in that: the mol ratio of the m-nitrobenzonitrile to the ethylenediamine is 1:1-2; the first step is carried out in the presence of a solvent selected from at least one of an alcohol solvent, an ester solvent and an ether solvent.

3. The method of manufacturing according to claim 1, characterized in that: the microwave reaction power of the first step is 150-250W; the reaction time of the first step is 3-4 hours;

the catalyst dosage in the first step is 0.05-0.6 times of the molar quantity of the m-nitrobenzonitrile.

4. The method of manufacturing according to claim 1, characterized in that: and step two, the reduction reaction is carried out under alkaline conditions, and sodium hydrosulfite is used as a reducing agent.

5. The method of manufacturing according to claim 4, wherein: the mol ratio of the compound 1 to the sodium hydrosulfite in the second step is 1:2-4; the alkali used in the alkaline condition is at least one selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate;

the reaction temperature of the second step is between room temperature and 100 ℃.

6. The method of manufacturing according to claim 1, characterized in that: the reaction in the third step is carried out in the presence of an organic solvent, wherein the organic solvent is at least one selected from N, N-dimethylformamide, N-diethylformamide, ethylene glycol monomethyl ether, dimethyl sulfoxide and N-methylpyrrolidone.

7. The method of manufacturing according to claim 1, characterized in that: in the third step, the molar ratio of the compound 3 to the dialkyl carbonate is 1 (0.5-1.0); the molar ratio of the compound 3 to the catalyst is (10-100): 1.

8. The preparation method according to claim 1 or 6, characterized in that: the reaction temperature in the third step is 70-200 ℃.

9. The preparation method according to claim 1 or 6, characterized in that: the post-treatment step of the third step comprises the following steps: after the reaction is finished, cooling, adding hot water at 70-100 ℃, continuously stirring for 15-60 minutes, and filtering out a solid product; recrystallizing and purifying the solid product; the recrystallization solvent is selected from methanol, ethanol or isopropanol.

10. The method of manufacturing according to claim 1, characterized in that: the fourth step comprises the following steps: dissolving the compound 3 in a solvent, stirring until the solid is fully dissolved, adding propionic acid, precipitating white solid, cooling to 5-10 ℃, stirring for crystallization, filtering, washing a filter cake, and drying to obtain white solid, namely the iprodione dipropionate;

the solvent in the fourth step is at least one of ethyl acetate, dichloromethane, chloroform, methanol, ethanol and propanol; the crystallization time is 0.5-4 hours.