CN113956205B - Preparation method of mebendazole - Google Patents
Preparation method of mebendazole Download PDFInfo
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- 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
The invention discloses a preparation method of mebendazole, belonging to the technical field of drug synthesis, and the preparation method comprises acylation reaction and Friedel-crafts reaction; wherein, during the acylation reaction, the trichlorotoluene is heated to 50-90 ℃, then the zinc chloride aqueous solution is dripped, the heat preservation reaction is carried out after the dripping is finished, and after the reaction is finished, the benzoyl chloride is obtained by reduced pressure distillation; the Friedel-crafts reaction is to mix and stir carbendazim, solvent and anhydrous aluminum chloride, then cool the mixture, then drop benzoyl chloride, continue stirring and keep the temperature reaction after the dropping is finished, and then carry out reduced pressure distillation to obtain the product mebendazole; the invention abandons the traditional method of Friedel-crafts and cyclization, takes carbendazim as a reactant, directly synthesizes mebendazole, has high total yield, and has the characteristics of simple flow, mild conditions and high atom utilization rate compared with the traditional process.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of mebendazole.
Background
The mebendazole is white, white-like or yellowish crystalline powder, belongs to benzimidazole carbamate medicines, is synthesized in eighties and is added with clinical anthelmintics, is effective on intestinal worms such as roundworms, hookworms, pinworms, whipworms, tapeworms, strongyloides stercoralis and the like, and has the characteristics of broad spectrum, high efficiency and high safety.
The mebendazole is obtained by taking p-chlorobenzoic acid as a raw material through a series of steps of nitration, Friedel-crafts, ammoniation, reduction and condensation, the process has multiple reaction steps, the yield is low, the atom utilization rate can only reach 49.77%, and dangerous processes such as nitration, ammoniation, reduction and the like are involved, the safety is poor, the approval is difficult, and the industrial feasibility is poor.
Patent CN106083622B describes the reduction of 4-amino-3-nitrobenzophenone by transfer hydrogenation reduction in the presence of a metal supported catalyst such as palladium-nickel with pyrrolidine as the hydrogen donor. Although the reaction temperature and pressure of catalytic hydrogenation are reduced, the catalyst impregnation preparation time is long, the operation is complex, the industrialization difficulty is high, and the catalyst activation is carried out by using a reducing agent such as hydrazine hydrate, so that the cost is high.
In patent CN109467512B, ammoniation of 3-nitro-4-chloro-benzophenone is carried out by using ammonia water instead of liquid ammonia, and 3, 4-diaminobenzophenone is prepared by palladium-carbon catalytic hydrogenation. Although the impurity content is reduced, the method has the disadvantages of strict reaction conditions, higher requirements on equipment, longer reaction time, more treatment steps and complex operation, and is still unsatisfactory.
Moreover, the preparation methods disclosed in the above patents are mainly based on improvement of the existing process, and do not fundamentally solve the problems of long reaction flow, process danger and the like.
Disclosure of Invention
The invention provides a preparation method of mebendazole, which takes trichlorotoluene as a raw material, obtains benzoyl chloride through catalytic hydrolysis, and obtains the mebendazole through Friedel-crafts reaction of the benzoyl chloride and carbendazim.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of mebendazole comprises acylation reaction and Friedel-crafts reaction.
And (2) carrying out acylation reaction, namely heating trichlorotoluene to 50-90 ℃, then dropwise adding a zinc chloride aqueous solution, controlling the dropwise adding time of the zinc chloride aqueous solution to be 50-70min, keeping the temperature at 50-90 ℃ during dropwise adding, continuing to carry out heat preservation reaction for 50-80min after dropwise adding is finished, and carrying out reduced pressure distillation to obtain benzoyl chloride after the reaction is finished.
Wherein the molar ratio of zinc chloride to trichlorotoluene in the zinc chloride aqueous solution is 0.1-0.2: 1.
wherein the molar ratio of water in the zinc chloride aqueous solution to trichlorotoluene is 1.05-1.15: 1.
the Friedel-crafts reaction is characterized in that carbendazim, a solvent and anhydrous aluminum chloride are mixed and stirred, then the temperature is reduced to 10-20 ℃, benzoyl chloride is dripped in the mixture and dripped out for 50-70min, then the mixture is continuously stirred and reacts for 2.5-3.5h under the condition of heat preservation, after the reaction is finished, acetic acid is recovered through reduced pressure distillation to obtain a crude product, and the crude product is washed with water and recrystallized from acetic acid to obtain a product of mebendazole.
Wherein the molar ratio of the anhydrous aluminum chloride to the benzoyl chloride is 1.1-1.3: 1.
wherein the molar ratio of the carbendazim to the benzoyl chloride is 1-1.1: 1.
the solvent is one of formic acid or acetic acid.
The molar ratio of the solvent to the benzoyl chloride is 6.8-8.9: 1.
compared with the prior art, the invention has the beneficial effects that:
(1) the preparation method of mebendazole can obviously shorten the reaction flow, reduce the intermediate loss, does not need high-pressure hydrogenation and ammoniation, has relatively mild reaction conditions and low industrialization difficulty, and has strong development space and competitive power;
(2) according to the preparation method of mebendazole, the atom utilization rate can reach 72.97%, and compared with the existing preparation method using p-chlorobenzoic acid as a raw material, the atom utilization rate is improved by 23.2%;
(3) according to the preparation method of mebendazole, the molar yield of the prepared intermediate benzoyl chloride is 85.44% -96.47%, and the purity of gas phase detection is 100%;
(4) according to the preparation method of the mebendazole, the molar yield of the prepared product mebendazole can reach 89.69-94.51%, the purity of the product is 99.1-99.8% by liquid phase detection, and the total yield is 79.72-90.04%.
Drawings
FIG. 1 is a reaction process for the preparation of mebendazole;
FIG. 2 is a liquid chromatogram of a standard solution;
FIG. 3 is a liquid chromatogram of the mebendazole solution prepared in example 1.
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
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: 4.18g (0.0307 mol) of zinc chloride and 4.05g (0.2251 mol) of water are taken, stirred and dissolved to obtain a zinc chloride aqueous solution, then 40g (0.2046 mol) of trichlorotoluene is taken to be put into a four-neck flask, the temperature is raised to 70 ℃, the zinc chloride aqueous solution is started to be dripped, the dripping time is controlled to be 1h, the temperature is kept at 70 ℃ during the dripping, the heat preservation reaction is continued for 1h after the dripping is finished, after the reaction is finished, the reduced pressure distillation is carried out to obtain 27.61g (0.1964 mol) of benzoyl chloride, the molar yield is 96.00%, and the purity is 100% through gas phase detection.
2. Friedel-crafts reaction: 39.44g (0.2063 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 31.43g (0.2357 mol) of anhydrous aluminum chloride are taken into a flask, stirred and cooled to 15 ℃, the benzoyl chloride prepared in the step 1 is dripped into the flask for 1h, and then the flask is continuously stirred and kept warm for 3 h. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 54.62g of the product mebendazole, wherein the molar yield is 93.79%, the purity of liquid phase detection is 99.6%, and the total yield is 90.04%.
The molar yield is calculated by the formula: n (mebendazole)/n (benzoyl chloride);
the calculation formula of the total yield is as follows: n (mebendazole)/n (trichlorotoluene);
the standard solution and the product mebendazole prepared in this example are dissolved by the same dissolving method to obtain a standard solution and a mebendazole solution, and then the standard solution and the mebendazole solution are subjected to liquid chromatography analysis respectively, wherein a liquid chromatogram of the standard solution is shown in fig. 2, and a liquid chromatogram of the mebendazole solution is shown in fig. 3.
Example 2
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: 2.79g (0.0205 mol) of zinc chloride and 4.05g (0.2251 mol) of water are taken, stirred and dissolved to obtain a zinc chloride aqueous solution, then 40g (0.2046 mol) of trichlorotoluene is taken to be put into a four-neck flask, the temperature is raised to 70 ℃, the zinc chloride aqueous solution is started to be dripped, the dripping time is controlled to be 1h, the temperature is kept at 70 ℃ during the dripping, the heat preservation reaction is continued for 1h after the dripping is finished, after the reaction is finished, 24.58g (0.1748 mol) of benzoyl chloride is obtained by reduced pressure distillation, the molar yield is 85.44%, and the purity is 100% by gas phase detection.
2. Friedel-crafts reaction: adding 35.10g (0.1836 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 27.97g (0.2098 mol) of anhydrous aluminum chloride into a flask, stirring and cooling to 15 ℃, dropwise adding the benzoyl chloride prepared in the step 1, dropwise adding after 1h, and then continuing stirring and keeping the temperature for 3 h. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 48.46g of the product mebendazole, wherein the molar yield is 93.31%, the purity of liquid phase detection is 99.4%, and the total yield is 79.72%.
Example 3
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: 5.58g (0.0409 mol) of zinc chloride and 4.05g (0.2251 mol) of water are taken, stirred and dissolved to obtain a zinc chloride aqueous solution, then 40g (0.2046 mol) of trichlorotoluene is taken to be put into a four-neck flask, the temperature is raised to 70 ℃, the zinc chloride aqueous solution is started to be dripped, the dripping time is controlled to be 1h, the temperature is kept at 70 ℃ during the dripping, the heat preservation reaction is continued for 1h after the dripping is finished, after the reaction is finished, 26.68g (0.1898 mol) of benzoyl chloride is obtained by reduced pressure distillation, the molar yield is 92.74%, and the purity is 100% by gas phase detection.
2. Friedel-crafts reaction: adding 38.10g (0.1993 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 30.36g (0.2277 mol) of anhydrous aluminum chloride into a flask, stirring and cooling to 15 ℃, dropwise adding the benzoyl chloride prepared in the step 1, finishing dropwise adding for 1h, and then continuing stirring and keeping the temperature for 3 h. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 52.87g of the product mebendazole, wherein the molar yield is 93.97%, the purity of liquid phase detection is 99.6%, and the total yield is 87.15%.
Example 4
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: 4.18g (0.0307 mol) of zinc chloride and 3.87g (0.2149 mol) of water are taken, stirred and dissolved to obtain a zinc chloride aqueous solution, 40g (0.2046 mol) of trichlorotoluene is taken to be put into a four-neck flask, the temperature is raised to 70 ℃, the zinc chloride aqueous solution is started to be dripped, the dripping time is controlled to be 1h, the temperature is kept at 70 ℃ during the dripping, the heat preservation reaction is continued for 1h after the dripping is finished, after the reaction is finished, 26.22g (0.1865 mol) of benzoyl chloride is obtained by reduced pressure distillation, the molar yield is 91.15%, and the purity is 100% by gas phase detection.
2. Friedel-crafts reaction: adding 37.45g (0.1958 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 29.84g (0.2238 mol) of anhydrous aluminum chloride into a flask, stirring and cooling to 15 ℃, dropwise adding the benzoyl chloride prepared in the step 1, finishing dropwise adding for 1h, and then continuing stirring and keeping the temperature for 3 h. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 51.54g of the product mebendazole, wherein the molar yield is 92.74%, the purity of a liquid phase detection is 99.1%, and the total yield is 84.53%.
Example 5
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: taking 4.18g (0.0307 mol) of zinc chloride and 4.24g (0.2353 mol) of water, stirring and dissolving to obtain a zinc chloride aqueous solution, taking 40g (0.2046 mol) of trichlorotoluene to a four-neck flask, heating to 70 ℃, starting to dropwise add the zinc chloride aqueous solution, controlling the dropwise adding time to be 1h, keeping the temperature at 70 ℃ during the dropwise adding period, continuing to carry out heat preservation reaction for 1h after the dropwise adding is finished, and after the reaction is finished, carrying out reduced pressure distillation to obtain 25.35g (0.1804 mol) of benzoyl chloride, wherein the molar yield is 88.14% and the purity is 100% through gas phase detection.
2. Friedel-crafts reaction: 36.21g (0.1894 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 28.86g (0.2164 mol) of anhydrous aluminum chloride are taken into a flask, stirred and cooled to 15 ℃, the benzoyl chloride prepared in the step 1 is dripped in the flask for 1h, and then the flask is continuously stirred and kept warm for 3 h. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 50.21g of the product mebendazole, wherein the molar yield is 94.00 percent, the purity of liquid phase detection is 99.7 percent, and the total yield is 82.85 percent.
Example 6
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: 4.18g (0.0307 mol) of zinc chloride and 4.05g (0.2251 mol) of water are taken, stirred and dissolved to obtain a zinc chloride aqueous solution, then 40g (0.2046 mol) of trichlorotoluene is taken to be put into a four-neck flask, the temperature is raised to 50 ℃, the zinc chloride aqueous solution is started to be dripped, the dripping time is controlled to be 50min, the temperature is kept at 50 ℃ during the dripping, the heat preservation reaction is continued for 50min after the dripping is finished, after the reaction is finished, 25.75g (0.1832 mol) of benzoyl chloride is obtained by reduced pressure distillation, the molar yield is 89.51%, and the purity is 100% by gas phase detection.
2. Friedel-crafts reaction: 36.77g (0.1923 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 29.31g (0.2198 mol) of anhydrous aluminum chloride are added into a flask, stirred and cooled to 15 ℃, the benzoyl chloride prepared in the step 1 is added dropwise after 1h of dripping, and then stirring and heat preservation are continued for 3 h. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 50.45g of the product mebendazole, wherein the molar yield is 92.74%, the purity of a liquid phase detection is 99.4%, and the total yield is 82.67%.
Example 7
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: taking 4.18g (0.0307 mol) of zinc chloride and 4.05g (0.2251 mol) of water, stirring and dissolving to obtain a zinc chloride aqueous solution, then taking 40g (0.2046 mol) of trichlorotoluene to a four-neck flask, heating to 90 ℃, starting to dropwise add the zinc chloride aqueous solution, controlling the dropwise adding time to be 70min, keeping the temperature at 90 ℃ during the dropwise adding period, continuing to carry out heat preservation reaction for 80min after the dropwise adding is finished, and after the reaction is finished, carrying out reduced pressure distillation to obtain 27.52g (0.1958 mol) of benzoyl chloride, wherein the molar yield is 95.68% and the purity is 100% through gas phase detection.
2. Friedel-crafts reaction: 39.31g (0.2056 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 31.33g (0.2349 mol) of anhydrous aluminum chloride are taken to be put into a flask, stirred and cooled to 15 ℃, the benzoyl chloride prepared in the step 1 is dripped for 1 hour, and then stirring and heat preservation are continued for 3 hours. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 53.29g of the product mebendazole, wherein the molar yield is 91.63%, the purity of a liquid phase detection is 99.4%, and the total yield is 87.67%.
Example 8
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: taking 4.18g (0.0307 mol) of zinc chloride and 4.05g (0.2251 mol) of water, stirring and dissolving to obtain a zinc chloride aqueous solution, taking 40g (0.2046 mol) of trichlorotoluene to a four-neck flask, heating to 70 ℃, starting to dropwise add the zinc chloride aqueous solution, controlling the dropwise adding time to be 1h, keeping the temperature at 70 ℃ during the dropwise adding period, continuing to carry out heat preservation reaction for 1h after the dropwise adding is finished, and after the reaction is finished, carrying out reduced pressure distillation to obtain 27.40g (0.1949 mol) of benzoyl chloride, wherein the molar yield is 95.26%, and the purity is 100% by gas phase detection.
2. Friedel-crafts reaction: 39.14g (0.2047 mol) of carbendazim, 80g (1.7391 mol) of formic acid and 28.59g (0.2144 mol) of anhydrous aluminum chloride are taken to be put into a flask, stirred and cooled to 15 ℃, the benzoyl chloride prepared in the step 1 is dripped for 1 hour, and then stirring and heat preservation are continued for 3 hours. After the reaction is finished, the formic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 51.90g of the product mebendazole, wherein the molar yield is 89.69%, the purity of liquid phase detection is 99.5%, and the total yield is 85.44%.
Example 9
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: taking 4.18g (0.0307 mol) of zinc chloride and 4.05g (0.2251 mol) of water, stirring and dissolving to obtain a zinc chloride aqueous solution, taking 40g (0.2046 mol) of trichlorotoluene to a four-neck flask, heating to 70 ℃, starting to dropwise add the zinc chloride aqueous solution, controlling the dropwise adding time to be 1h, keeping the temperature at 70 ℃ during the dropwise adding period, continuing to carry out heat preservation reaction for 1h after the dropwise adding is finished, and after the reaction is finished, carrying out reduced pressure distillation to obtain 27.40g (0.1949 mol) of benzoyl chloride, wherein the molar yield is 95.25%, and the purity is 100% by gas phase detection.
2. Friedel-crafts reaction: 39.13g (0.2046 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 33.78g (0.2534 mol) of anhydrous aluminum chloride are taken to be put into a flask, stirred and cooled to 15 ℃, the benzoyl chloride prepared in the step 1 is dripped for 1 hour, and then stirring and heat preservation are continued for 3 hours. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and 54.50g of the product mebendazole is obtained by washing and acetic acid recrystallization, the molar yield is 94.51%, the purity of liquid phase detection is 99.8%, and the total yield is 90.02%.
Example 10
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: taking 4.18g (0.0307 mol) of zinc chloride and 4.05g (0.2251 mol) of water, stirring and dissolving to obtain a zinc chloride aqueous solution, taking 40g (0.2046 mol) of trichlorotoluene to a four-neck flask, heating to 70 ℃, starting to dropwise add the zinc chloride aqueous solution, controlling the dropwise adding time to be 1h, keeping the temperature at 70 ℃ during the dropwise adding period, continuing to carry out heat preservation reaction for 1h after the dropwise adding is finished, and after the reaction is finished, carrying out reduced pressure distillation to obtain 27.45g (0.1953 mol) of benzoyl chloride, wherein the molar yield is 95.42% and the purity is 100% through gas phase detection.
2. Friedel-crafts reaction: 37.33g (0.1953 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 31.24g (0.2343 mol) of anhydrous aluminum chloride are taken to be put into a flask, stirred and cooled to 15 ℃, the benzoyl chloride prepared in the step 1 is dripped for 1 hour, and then stirring and heat preservation are continued for 3 hours. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 52.63g of the product mebendazole, wherein the molar yield is 90.79%, the purity of liquid phase detection is 99.5%, and the total yield is 86.64%.
Example 11
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: taking 4.18g (0.0307 mol) of zinc chloride and 4.05g (0.2251 mol) of water, stirring and dissolving to obtain a zinc chloride aqueous solution, then taking 40g (0.2046 mol) of trichlorotoluene to a four-neck flask, heating to 70 ℃, starting to dropwise add the zinc chloride aqueous solution, controlling the dropwise adding time to be 1h, keeping the temperature at 70 ℃ during the dropwise adding period, continuing to carry out heat preservation reaction for 1h after the dropwise adding is finished, and after the reaction is finished, carrying out reduced pressure distillation to obtain 27.50g (0.1956 mol) of benzoyl chloride, wherein the molar yield is 95.59% and the purity is 100% through gas phase detection.
2. Friedel-crafts reaction: 41.14g (0.2152 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 31.30g (0.2347 mol) of anhydrous aluminum chloride are added into a flask, stirred and cooled to 15 ℃, the benzoyl chloride prepared in the step 1 is dripped into the flask for 1 hour, and then the mixture is continuously stirred and kept warm for 3 hours. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and 54.26g of the product mebendazole is obtained by washing and acetic acid recrystallization, the molar yield is 93.19%, the purity of liquid phase detection is 99.2%, and the total yield is 89.08%.
Example 12
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: taking 4.18g (0.0307 mol) of zinc chloride and 4.05g (0.2251 mol) of water, stirring and dissolving to obtain a zinc chloride aqueous solution, taking 40g (0.2046 mol) of trichlorotoluene to a four-neck flask, heating to 70 ℃, starting to dropwise add the zinc chloride aqueous solution, controlling the dropwise adding time to be 1h, keeping the temperature at 70 ℃ during the dropwise adding period, continuing to carry out heat preservation reaction for 1h after the dropwise adding is finished, and after the reaction is finished, carrying out reduced pressure distillation to obtain 27.74g (0.1973 mol) of benzoyl chloride, wherein the molar yield is 96.44%, and the purity is 100% by gas phase detection.
2. Friedel-crafts reaction: and (3) adding 39.62g (0.2072 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 31.58g (0.2368 mol) of anhydrous aluminum chloride into a flask, stirring and cooling to 10 ℃, dropwise adding the benzoyl chloride prepared in the step 1, dropwise adding after 50min, and then continuing stirring and keeping the temperature for 2.5 h. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 53.84g of the product mebendazole, wherein the molar yield is 91.93%, the purity of a liquid phase detection is 99.5%, and the total yield is 88.66%.
Example 13
As shown in fig. 1, a preparation method of mebendazole specifically comprises the following steps:
1. acylation reaction: taking 4.18g (0.0307 mol) of zinc chloride and 4.05g (0.2251 mol) of water, stirring and dissolving to obtain a zinc chloride aqueous solution, taking 40g (0.2046 mol) of trichlorotoluene to a four-neck flask, heating to 70 ℃, starting to dropwise add the zinc chloride aqueous solution, controlling the dropwise adding time to be 1h, keeping the temperature at 70 ℃ during the dropwise adding period, continuing to carry out heat preservation reaction for 1h after the dropwise adding is finished, and after the reaction is finished, carrying out reduced pressure distillation to obtain 27.75g (0.1973 mol) of benzoyl chloride, wherein the molar yield is 96.47% and the purity is 100% through gas phase detection.
2. Friedel-crafts reaction: and (3) adding 39.63g (0.2073 mol) of carbendazim, 80g (1.3322 mol) of acetic acid and 31.59g (0.2369 mol) of anhydrous aluminum chloride into a flask, stirring, cooling to 20 ℃, dropwise adding the benzoyl chloride prepared in the step 1, dropwise adding for 70min, and then continuing stirring and keeping the temperature for 3.5 h. After the reaction is finished, acetic acid is recovered by reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain 53.47g of the product mebendazole, wherein the molar yield is 91.37%, the purity of a liquid phase detection is 99.6%, and the total yield is 88.15%.
The formulas for calculating the molar yield and the total yield in examples 2 to 13 are the same as those in example 1.
Examples 1-13 data summary sheet
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 (1)
1. The preparation method of the mebendazole is characterized by comprising an acylation reaction and a Friedel-crafts reaction;
the acylation reaction comprises the steps of heating trichlorotoluene to 50-90 ℃, then dropwise adding a zinc chloride aqueous solution, controlling the dropwise adding time of the zinc chloride aqueous solution to be 50-70min, keeping the temperature at 50-90 ℃ during the dropwise adding process, continuing to perform heat preservation reaction for 50-80min after the dropwise adding process is finished, and after the reaction is finished, performing reduced pressure distillation to obtain benzoyl chloride;
the Friedel-crafts reaction is that carbendazim, a solvent and anhydrous aluminum chloride are mixed and stirred, then the temperature is reduced to 10-20 ℃, benzoyl chloride is dripped in the mixture and dripped out for 50-70min, then the mixture is continuously stirred and reacts for 2.5-3.5h under the condition of heat preservation, after the reaction is finished, the solvent is recovered through reduced pressure distillation to obtain a crude product, and the crude product is washed by water and recrystallized by acetic acid to obtain a product of mebendazole;
the solvent is one of formic acid or acetic acid;
the molar ratio of zinc chloride to trichlorotoluene in the zinc chloride aqueous solution is 0.1-0.2: 1;
the molar ratio of water to trichlorotoluene in the zinc chloride aqueous solution is 1.05-1.15: 1;
the molar ratio of the anhydrous aluminum chloride to the benzoyl chloride is 1.1-1.3: 1;
the molar ratio of the carbendazim to the benzoyl chloride is 1-1.1: 1;
the molar ratio of the solvent to the benzoyl chloride is 6.8-8.9: 1.
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