CN113248445B - Synthesis method of fenbendazole - Google Patents
Synthesis method of fenbendazole Download PDFInfo
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract
A synthetic method of fenbendazole belongs to the technical field of insect repellents, and comprises the following specific steps: 5-chloro-2-nitroaniline and an aqueous solution of thiophenol sodium are subjected to condensation reaction in a mixed solution of n-propanol and water to obtain 5-thiophenyl-2-nitroaniline; the 5-thiophenyl-2-nitroaniline is subjected to reduction reaction in a high-pressure kettle under the catalysis of Raney nickel to generate 4-thiophenyl o-phenylenediamine; 4-thiophenyl o-phenylenediamine and N- (trichloromethyl) methyl carbamate are mixed and then undergo cyclization reaction to obtain fenbendazole; the synthesis method has the advantages that: the method has the advantages of mild conditions, simple and convenient operation, capability of avoiding the generation of ammonium chloride in the cyclization process and low cost of three wastes; the generation of amine salt is avoided, and the cost of three-waste treatment is greatly reduced; the yield of the fenbendazole can reach 84.27-89.99%, and the purity of the fenbendazole can reach 96.39-99.71%.
Description
Technical Field
The invention relates to the technical field of insect repellents, in particular to a synthetic method of fenbendazole.
Background
The fenbendazole belongs to benzimidazole drugs, is a low-toxicity, high-efficiency and broad-spectrum anthelmintic, can kill hookworm, roundworm, whipworm, partial tapeworm, roundworm and other parasites in animal gastrointestinal tracts, has a strong insecticidal action, and has the advantages of lasting drug effect, safety, low toxicity, good palatability and the like.
Patent US3954791 discloses a synthesis method for preparing benzimidazole compounds, which comprises refluxing 5-chloro-2-nitroaniline and thiophenol in DMF to prepare 5-thiophenyl-2-nitroaniline, reducing it to 4-thiophenyl o-phenylenediamine with tin chloride, and finally cyclizing with S-methyl isothiourea methyl formate to obtain benzimidazole, which requires DMF as solvent and has high requirements on equipment and recovery cost; tin chloride used in reduction is corrosive and sensitive to moisture, and has more difficulty in practical use because of explosion risk when being mixed with oxygen or an oxidant in air, and the production cost is higher because methyl ethyl thiourea formate is used as a cyclization agent in cyclization.
Indian patent IN2014MU02203A is an improvement on the basis of the original process, wherein toluene and tetrabutylammonium bromide are used for replacing DMF IN the condensation reaction, a hydrazine system is added IN ferric chloride and water for reduction, and methyl cyanocarbamate is used for replacing S-methyl isothiourea methyl formate IN cyclization. The method needs to use tetrabutylammonium bromide to increase the cost, the three wastes generated by the reduction of ferric chloride pollute the environment, the synthesis cost of the hydrazine hydrate process is higher, and the use of methyl cyanocarbamate as a cyclization agent can reduce the cost, but ammonium chloride is generated and is difficult to separate after being mixed with sodium salts in the three wastes.
At present, the main stream of the cyclization agent is S/O-methyl isothiourea methyl formate and cyancarbamate, but the former of the two has higher production cost, and the latter can generate amine salt in the cyclization process, so that the sodium salt and the amine salt in three wastes are difficult to separate, and the cost of the three wastes is increased.
Disclosure of Invention
Aiming at the defects, the invention provides the method for preparing the fenbendazole, which achieves the purposes of mild conditions and simple and convenient operation, can avoid the generation of ammonium chloride in the cyclization process, greatly reduces the cost of three wastes and is suitable for industrial production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a synthetic method of fenbendazole comprises condensation reaction, reduction reaction and cyclization reaction;
the condensation reaction is carried out, namely 5-chloro-2-nitroaniline and sodium thiophenolate are subjected to condensation reaction to obtain 5-thiophenyl-2-nitroaniline;
in the reduction reaction, 5-thiophenyl-2-nitroaniline is subjected to reduction reaction to generate 4-thiophenyl o-phenylenediamine;
and (3) carrying out cyclization reaction, namely mixing 4-thiophenyl o-phenylenediamine and N- (trichloromethyl) methyl carbamate and then carrying out cyclization reaction to obtain fenbendazole.
And (3) performing cyclization reaction, namely mixing 4-thiophenyl o-phenylenediamine and acetone, heating to 40-60 ℃, dropwise adding N- (trichloromethyl) methyl carbamate, preserving heat at 50-70 ℃ for 2-3h after dropwise adding, filtering, and washing with acetone to obtain fenbendazole.
The dripping time of the N- (trichloromethyl) methyl carbamate is 28-32 min.
Wherein the molar ratio of the 4-thiophenyl o-phenylenediamine to the methyl N- (trichloromethyl) carbamate is 1: 1.1-1.3.
The condensation reaction comprises the steps of mixing 5-chloro-2-nitroaniline, n-propanol, sodium hydroxide and an aqueous solution of thiophenol sodium, uniformly stirring in a nitrogen atmosphere, heating to 80-88 ℃, keeping the temperature for 4.8-5.2h, cooling, filtering and drying to obtain the 5-thiophenyl-2-nitroaniline.
Wherein the mass ratio of the n-propanol to the 5-chloro-2-nitroaniline is 2.8-3.2: 1.
The mass fraction of the thiophenol sodium aqueous solution is 18-22%.
Wherein the molar ratio of the 5-chloro-2-nitroaniline to the sodium thiophenolate is 1: 1.1-1.2.
Raney nickel is used as a catalyst in the reduction reaction.
The mass ratio of the Raney nickel to the 5-thiophenyl-2-nitroaniline is 1: 95-105.
Compared with the prior art, the invention has the beneficial effects that:
(1) the synthesis method of fenbendazole takes 5-chloro-2-nitroaniline as a raw material, prepares the product of fenbendazole through condensation reaction, reduction reaction and cyclization reaction, has mild conditions and simple and convenient operation, can avoid the generation of ammonium chloride in the cyclization process compared with the prior art, has low cost of three wastes, is suitable for industrial production, and is also suitable for cyclization of other benzimidazoles;
(2) according to the synthesis method of fenbendazole, 5-chloro-2-nitroaniline and a sodium thiophenolate aqueous solution with the mass fraction of 20% are reacted under the protection of nitrogen in n-propanol to obtain the 5-thiophenyl-2-nitroaniline, the yield is higher, the purity can reach 100%, the quality reduction of a final product caused by a small amount of disulfide residue is reduced, and a cleaner catalytic hydrogenation process is used during reduction;
(3) according to the synthesis method of fenbendazole, N- (trichloromethyl) methyl carbamate is used as a cyclization agent during cyclization, so that generation of amine salt is avoided, and cost of three-waste treatment is greatly reduced;
(4) according to the synthesis method of fenbendazole, the yield of fenbendazole can reach 84.27-89.99%, and the purity of fenbendazole can reach 96.39-99.71%.
Drawings
FIG. 1 is a reaction formula of a synthetic method of fenbendazole.
Detailed Description
In order to more clearly understand the technical features, objects, and effects of the present invention, specific embodiments of the present invention will now be described.
EXAMPLE 1 preparation of intermediate 5-thiophenyl-2-nitroaniline
Adding 172.57g of 5-chloro-2-nitroaniline, 517.71g of n-propanol, 8.00g of sodium hydroxide and 858.00g of sodium thiophenolate aqueous solution into a 1000ml four-mouth bottle, uniformly stirring, heating to 88 ℃ (reflux temperature), keeping the temperature for 5h, then beginning to stir while cooling to 0 ℃, cooling to separate out, filtering, putting a filter cake into an oven, drying for 5h at 60 ℃ until constant weight is achieved to obtain 218.64g of 5-phenylthio-2-nitroaniline, wherein the yield is 86.14% and the purity is 97.03%.
The mass fraction of the thiophenol sodium aqueous solution is 20%.
EXAMPLE 2 preparation of the intermediate 5-thiophenyl-2-nitroaniline
Adding 172.67g of 5-chloro-2-nitroaniline, 517.71g of n-propanol, 8.00g of sodium hydroxide and 858.00g of sodium thiophenolate aqueous solution into a 1000ml four-neck bottle, replacing the mixture with nitrogen for three times, uniformly stirring, heating to 88 ℃, keeping the temperature for 5h, then beginning to stir while cooling to 0 ℃, cooling to separate out, filtering, and putting a filter cake into an oven to dry for 5h at 60 ℃ to constant weight to obtain 243.50g of 5-thiophenyl-2-nitroaniline, wherein the yield is 98.87%, and the purity is 100%.
The mass fraction of the thiophenol sodium aqueous solution is 20%.
As is clear from examples 1 and 2, when the reaction is not carried out under nitrogen protection, the yield of 5-thiophenyl-2-nitroaniline is significantly reduced because sodium thiophenolate is easily deteriorated in air and water, 5-chloro-2-nitroaniline cannot be completely converted, and the product contains a large amount of diphenyl sulfide produced by condensation of sodium thiophenolate with itself, so that the reaction is carried out under nitrogen protection.
EXAMPLE 3 preparation of the intermediate 5-thiophenyl-2-nitroaniline
Adding 172.67g of 5-chloro-2-nitroaniline, 517.71g of n-propanol, 8.00g of sodium hydroxide and 792.00g of sodium thiophenolate aqueous solution into a 1000ml four-neck bottle, replacing the system with nitrogen for three times, uniformly stirring, heating to 88 ℃, preserving the temperature for 5h, cooling, separating out, filtering, putting a filter cake into an oven, drying for 5h at 60 ℃ until the weight is constant to obtain 242.81g of 5-thiophenyl-2-nitroaniline, wherein the yield is 98.59 percent, and the purity is 100 percent.
The mass fraction of the thiophenol sodium aqueous solution is 20%.
EXAMPLE 4 preparation of the intermediate 5-thiophenyl-2-nitroaniline
Adding 172.67g of 5-chloro-2-nitroaniline, 517.71g of n-propanol, 8.00g of sodium hydroxide and 726.00g of sodium thiophenolate aqueous solution into a 1000ml four-neck bottle, replacing the system with nitrogen for three times, uniformly stirring, heating to 88 ℃, keeping the temperature for 5h, cooling, separating out, filtering, putting a filter cake into an oven, drying for 5h at 60 ℃ until the weight is constant to obtain 235.59g of 5-thiophenyl-2-nitroaniline, wherein the yield is 95.66%, and the purity is 100%.
The mass fraction of the thiophenol sodium aqueous solution is 20%.
EXAMPLE 5 preparation of intermediate 5-thiophenyl-2-nitroaniline
Adding 172.57g of 5-chloro-2-nitroaniline, 517.71g of n-propanol, 8.00g of sodium hydroxide and 693.00g of sodium thiophenolate aqueous solution into a 1000ml four-neck bottle, replacing the system with nitrogen for three times, uniformly stirring, heating to 88 ℃, preserving heat for 5h, cooling, separating out, filtering, putting a filter cake into an oven, drying for 5h at 60 ℃ until the weight is constant to obtain 222.68g of 5-thiophenyl-2-nitroaniline, wherein the yield is 90.01%, and the purity is 100%.
The mass fraction of the thiophenol sodium aqueous solution is 20%. From examples 2-5, it can be seen that when the equivalent weight of sodium thiophenolate is higher than 1.1, the conversion of 5-chloro-2-nitroaniline is more thorough and the yield is higher; however, when the equivalent of sodium thiophenolate is less than 1.1, the 5-chloro-2-nitroaniline cannot react completely within 5h, and the heat preservation time needs to be prolonged, and in consideration of economic benefits, the use amount of the solvent and the raw material cost are increased due to the increase of the use amount of the sodium thiophenolate, so that the molar ratio of the 5-chloro-2-nitroaniline to the sodium thiophenolate is preferably 1: 1.1-1.2.
EXAMPLE 6 preparation of intermediate 5-thiophenyl-2-nitroaniline
Adding 172.57g of 5-chloro-2-nitroaniline, 517.71g of n-propanol, 8.00g of sodium hydroxide and 792.00g of sodium thiophenolate aqueous solution into a 1000ml four-neck bottle, replacing the system with nitrogen for three times, uniformly stirring, heating to 80 ℃, preserving heat for 5 hours, cooling, separating out, filtering, putting a filter cake into an oven, drying for 5 hours at 60 ℃ until the weight is constant to obtain 234.80g of 5-thiophenyl-2-nitroaniline, wherein the yield is 95.34 percent, and the purity is 100 percent.
The mass fraction of the thiophenol sodium aqueous solution is 20%.
EXAMPLE 7 preparation of intermediate 5-thiophenyl-2-nitroaniline
Adding 172.57g of 5-chloro-2-nitroaniline, 517.71g of n-propanol, 8.00g of sodium hydroxide and 792.00g of sodium thiophenolate aqueous solution into a 1000ml four-mouth bottle, replacing the system with nitrogen for three times, uniformly stirring, heating to 75 ℃, preserving the temperature for 5 hours, cooling, separating out, filtering, putting a filter cake into an oven, drying for 5 hours at 60 ℃ until the weight is constant to obtain 217.24g of 5-thiophenyl-2-nitroaniline, wherein the yield is 88.21 percent and the purity is 100 percent.
The mass fraction of the thiophenol sodium aqueous solution is 20%.
As is clear from examples 3, 6 and 7, the condensation reaction of 5-chloro-2-nitroaniline and sodium thiophenolate is endothermic, and the higher the temperature is, the more advantageous the reaction is, the higher the yield is, and 88 ℃ is an azeotropic temperature of n-propanol and water, so the temperature of the condensation reaction is preferably 80 ℃ to 88 ℃.
EXAMPLE 8 preparation of intermediate 4-Phenylthio-O-phenylenediamine
147.77g of toluene, 73.88g of 5-thiophenyl-2-nitroaniline with the purity of 100 percent and 0.74g of raney nickel are added into a 250ml high-pressure reaction kettle, the high-pressure reaction kettle is subjected to nitrogen substitution and then is filled with hydrogen until the pressure is 3MPa, the system pressure is kept at 2-3MPa in the reaction process, the temperature is kept at 80 ℃ for 2 hours for reaction, the catalyst is filtered, and the toluene layer is evaporated after extraction and delamination to obtain 64.54g of 4-thiophenyl o-phenylenediamine with the yield of 98.97 percent and the purity of 99.50 percent.
EXAMPLE 9 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 42.33g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the dropwise addition is completed within 30min, the temperature is kept for 2h, the filtration is carried out after the temperature is kept, the filter cake is washed by acetone and then is placed into an oven to be dried for 2h at 70 ℃, and 45.40g of fenbendazole is obtained, the yield is 73.21% and the purity is 96.55%.
EXAMPLE 10 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 42.33g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the dropwise addition is completed within 30min, then the temperature is raised to 50 ℃, the temperature is kept for 2h, after the temperature is kept, the filtration is carried out, the filter cake is washed by the acetone and then is placed into an oven to be dried for 2h at 70 ℃, and then fenbendazole 50.62g is obtained, the yield is 84.27%, and the purity is 99.67%.
EXAMPLE 11 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 42.33g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the dropwise addition is completed within 30min, then the temperature is raised to 60 ℃, the temperature is kept for 2h, after the temperature is kept, the filtration is carried out, the filter cake is washed by the acetone and then is placed into an oven to be dried for 2h at 70 ℃, 53.46g of fenbendazole is obtained, the yield is 89.03%, and the purity is 99.71%.
EXAMPLE 12 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 42.33g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the dropwise addition is completed within 30min, then the temperature is raised to 70 ℃, the temperature is kept for 2h, after the temperature is kept, the filtration is carried out, the filter cake is washed by the acetone and then is placed into an oven to be dried for 2h at 70 ℃, and then fenbendazole 53.11g is obtained, the yield is 88.45%, and the purity is 99.70%.
EXAMPLE 13 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 42.33g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the dropwise addition is completed within 30min, then the temperature is raised to 80 ℃, the temperature is kept for 2h, after the temperature is kept, the filtration is carried out, the filter cake is washed by the acetone and then is placed into an oven to be dried for 2h at 70 ℃, 44.44g of fenbendazole is obtained, the yield is 66.89%, and the purity is 90.11%.
As can be seen from examples 9 to 13, the yield and purity were improved with the rise in the incubation temperature after the incubation temperature exceeded 50 ℃ but the yield decreased sharply with the rise in the incubation temperature exceeded 80 ℃ due to the decomposition of methyl N- (trichloromethyl) carbamate at an excessively high temperature; while a temperature lower than 50 ℃ will result in slow reaction and low conversion rate, so the optimum value of the holding temperature is 50-70 ℃.
EXAMPLE 14 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 38.48g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the temperature is raised to 60 ℃ after the dropwise addition is completed within 30min, the temperature is kept for 2h, after the temperature is kept, the filtration is carried out, the filter cake is washed by acetone and then is placed into an oven to be dried for 2h at 70 ℃, and then fenbendazole 48.68g is obtained, the yield is 74.99%, and the purity is 92.23%.
EXAMPLE 15 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 46.18g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the temperature is raised to 60 ℃ after the dropwise addition is completed within 30min, the temperature is kept for 2h, after the temperature is kept, the filtration is carried out, the filter cake is washed by acetone and then is placed into an oven to be dried for 2h at 70 ℃, 55.06g of fenbendazole is obtained, the yield is 89.19% and the purity is 96.99%.
EXAMPLE 16 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 50.03g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the temperature is raised to 60 ℃ after the dropwise addition is completed within 30min, the temperature is kept for 2h, after the temperature is kept, the filtration is carried out, the filter cake is washed by the acetone and then is placed into an oven to be dried for 2h at 70 ℃, and then fenbendazole 55.47g is obtained, the yield is 89.99%, and the purity is 97.12%.
EXAMPLE 17 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 53.87g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the temperature is raised to 60 ℃ after the dropwise addition is completed within 30min, the temperature is kept for 2h, after the temperature is kept, the filtration is carried out, the filter cake is washed by acetone and then is placed into an oven to be dried for 2h at 70 ℃, 55.04g of fenbendazole is obtained, the yield is 87.64%, and the purity is 95.33%.
From examples 11 to 17, it is understood that the yield gradually increased with the increase in the cyclizing agent methyl N- (trichloromethyl) carbamate, that the yield was significantly decreased when the cyclizing agent content was less than 1.1 equivalents, and that the yield was not increased any more when the cyclizing agent content was more than 1.2 equivalents, and therefore the molar ratio of 4-phenylthio-o-phenylenediamine to methyl N- (trichloromethyl) carbamate was 1:1.1 to 1.3.
EXAMPLE 18 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 46.18g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the temperature is raised to 60 ℃ after the dropwise addition is completed within 30min, the temperature is kept for 1h, the filtration is carried out after the temperature is kept, a filter cake is washed by acetone and then is placed into an oven to be dried for 2h at 70 ℃, 47.40g of fenbendazole is obtained, the yield is 70.57% and the purity is 89.13%.
EXAMPLE 19 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 46.18g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the temperature is raised to 60 ℃ after the dropwise addition is completed within 30min, the temperature is kept for 3h, after the temperature is kept, the filtration is carried out, the filter cake is washed by acetone and then is placed into an oven to be dried for 2h at 70 ℃, and then fenbendazole 55.32g is obtained, the yield is 89.66%, and the purity is 97.03%.
EXAMPLE 20 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 46.18g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 40 ℃, the temperature is raised to 60 ℃ after the dropwise addition is finished for 30min, the temperature is kept for 4h, the filtration is carried out after the temperature is kept, a filter cake is washed by acetone and then is placed into an oven to be dried for 2h at 70 ℃, 54.78g of fenbendazole is obtained, the yield is 86.21%, and the purity is 94.22%.
From examples 15 and 18 to 20, it is understood that the incubation time after the completion of the dropwise addition of the cyclic mixture N- (trichloromethyl) methyl carbamate is prolonged to 2 to 3 hours, the yield of the reaction can be improved, the reaction of the raw materials is incomplete when the time is less than 2 hours, the purity of the product is reduced when the time is more than 3 hours because impurities in the system are increased, and the incubation time of the ring-closing reaction is preferably 2 to 3 hours.
EXAMPLE 21 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 46.18g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 50 ℃, the temperature is raised to 60 ℃ after the dropwise addition is completed within 30min, the temperature is kept for 3h, after the temperature is kept, the filtration is carried out, the filter cake is washed by acetone and then is placed into an oven to be dried for 2h at 70 ℃, and then fenbendazole 54.96g is obtained, the yield is 89.01%, and the purity is 96.97%.
EXAMPLE 22 preparation of fenbendazole
43.26g of 4-thiophenyl o-phenylenediamine prepared in example 8 and 129.78g of acetone are added into a 250ml four-mouth bottle, 46.18g of N- (trichloromethyl) methyl carbamate is added dropwise after the temperature is raised to 60 ℃, the dropwise addition is completed within 30min, then the heat preservation is continued for 3h, the filtration is carried out after the heat preservation is finished, the filter cake is washed by acetone and then is placed into an oven to be dried for 2h at 70 ℃, and 54.99g of fenbendazole is obtained, the yield is 88.54 percent, and the purity is 96.39 percent.
From examples 19, 21 and 22, it is clear that the temperature at which the cyclization agent methyl N- (trichloromethyl) carbamate is added dropwise is preferably 40 to 60 ℃ because the fenbendazole product obtained at 40 to 60 ℃ is relatively high in both yield and purity, and slightly decreases with increasing temperature.
All percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The synthesis method of fenbendazole is characterized by comprising a condensation reaction, a reduction reaction and a cyclization reaction;
the condensation reaction is carried out, namely 5-chloro-2-nitroaniline and sodium thiophenolate are subjected to condensation reaction to obtain 5-thiophenyl-2-nitroaniline;
in the reduction reaction, 5-thiophenyl-2-nitroaniline is subjected to reduction reaction to generate 4-thiophenyl o-phenylenediamine;
and (3) carrying out cyclization reaction, namely mixing 4-thiophenyl o-phenylenediamine and N- (trichloromethyl) methyl carbamate and then carrying out cyclization reaction to obtain fenbendazole.
2. The synthesis method of fenbendazole according to claim 1, wherein the cyclization reaction comprises the steps of mixing 4-thiophenyl o-phenylenediamine and acetone, heating to 40-60 ℃, dropwise adding methyl N- (trichloromethyl) carbamate, preserving heat at 50-70 ℃ for 2-3 hours after completing dropwise adding, filtering, and washing with acetone to obtain the fenbendazole.
3. The method for synthesizing fenbendazole according to claim 2, wherein the dropping time of the methyl N- (trichloromethyl) carbamate is 28-32 min.
4. The method of synthesizing fenbendazole according to claim 2, wherein the molar ratio of 4-thiophenyl o-phenylenediamine to methyl N- (trichloromethyl) carbamate is 1: 1.1-1.3.
5. The synthesis method of fenbendazole as claimed in claim 1, wherein the condensation reaction comprises mixing 5-chloro-2-nitroaniline, n-propanol, sodium hydroxide and an aqueous solution of thiophenol sodium, stirring uniformly in a nitrogen atmosphere, heating to 80-88 ℃, keeping the temperature for 4.8-5.2h, cooling, filtering and drying to obtain 5-thiophenyl-2-nitroaniline.
6. The synthesis method of fenbendazole according to claim 5, wherein the mass ratio of n-propanol to 5-chloro-2-nitroaniline is 2.8-3.2: 1.
7. The synthesis method of fenbendazole according to claim 5, wherein the mass fraction of the aqueous solution of sodium thiophenolate is 18% -22%.
8. The method for synthesizing fenbendazole according to claim 5, wherein the molar ratio of 5-chloro-2-nitroaniline to sodium thiophenolate is 1: 1.1-1.2.
9. The method for synthesizing fenbendazole according to claim 1, wherein raney nickel is used as a catalyst in the reduction reaction.
10. The synthesis method of fenbendazole according to claim 9, wherein the mass ratio of the raney nickel to the 5-thiophenyl-2-nitroaniline is 1: 95-105.
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