CN111039873B - Preparation method of fenbendazole sulfoxide - Google Patents
Preparation method of fenbendazole sulfoxide Download PDFInfo
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- CN111039873B CN111039873B CN201911329380.2A CN201911329380A CN111039873B CN 111039873 B CN111039873 B CN 111039873B CN 201911329380 A CN201911329380 A CN 201911329380A CN 111039873 B CN111039873 B CN 111039873B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- 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
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
- C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
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- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
Abstract
The invention relates to the technical field of chemicals, in particular to a preparation method of fenbendazole sulfoxide. The fenbendazole-containing aqueous solution is prepared by taking fenbendazole as a raw material, taking a sulfuric acid aqueous solution as a reaction solvent and taking potassium dichromate as an oxidant. The reaction process is simple, the reaction conditions are easy to control, and the method can be used for batch preparation in production scale. The obtained product has high biological activity and more obvious insect-resistant effect, and can be used as a new insect-resistant medicament.
Description
Technical Field
The invention belongs to the technical field of chemicals, and particularly relates to a preparation method of fenbendazole sulfoxide.
Background
Echinococcosis, also known as echinococcosis, is a zoonosis caused by the parasite of echinococcus tapeworm in human and livestock, and is one of the countries with the highest incidence rate in China. The disease is widely distributed, the current treatment means mainly comprises surgical operations, but the medicine treatment has great practical significance for patients with multiple diseases, hydatid cyst of multiple organs, poor operation tolerance, postoperative recurrence and late-stage alveolar echinococcus.
The echinococcosis medication is the first choice among benzimidazole drugs. Fenbendazole is a fat-soluble benzimidazole broad-spectrum anthelmintic, has high anthelmintic activity on gastrointestinal nematodes, has a good effect on parasites such as tapeworms, roundworms, hookworms, whipworms, trematodes and the like, has the advantages of wide anthelmintic spectrum, safety, low toxicity, good palatability and the like, and is one of the first-choice anthelmintics in modern animal husbandry. Studies show that fenbendazole only serves as a precursor drug in animals, and is rapidly metabolized to a sulfoxide metabolite fenbendazole sulfoxide (also known as oxfendazole) with activity in vivo after oral administration, wherein the fenbendazole sulfoxide is an active substance for the function of the fenbendazole. The fenbendazole sulfoxide is a derivative with good activity, but related reports such as preparation of the fenbendazole sulfoxide and the like do not exist at home and abroad at present.
Disclosure of Invention
Aiming at the problem of low metabolic rate of fenbendazole sulfoxide metabolized by fenbendazole at present, the invention provides a preparation method of fenbendazole sulfoxide.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a process for preparing fenbendazole sulfoxide includes reaction of fenbendazole with potassium bichromate in aqueous solution of sulfuric acid.
The reaction process is simple, the reaction conditions are easy to control, and the method can be used for batch preparation in production scale. The obtained product has high biological activity and more obvious insect-resistant effect, and can be used as a new insect-resistant medicament. The reaction equation is as follows:
preferably, the volume percentage concentration of the sulfuric acid in the sulfuric acid aqueous solution is 10-12.6%. The combination of sulfuric acid and potassium dichromate can exert synergistic oxidation effect, so that the reaction has the best product yield and purity in the sulfuric acid aqueous solution.
Preferably, the molar ratio of sulfuric acid in the aqueous sulfuric acid solution to the fenbendazole is (1.25-1.63): (0.179-0.190). When the amount of the sulfuric acid is too small, the synergistic oxidation effect of the sulfuric acid is difficult to be sufficiently exerted, so that the product yield is low, and when the amount of the sulfuric acid is too large, side reactions are increased, and the yield is also reduced.
Preferably, the molar ratio of sulfuric acid in the aqueous sulfuric acid solution to the fenbendazole is 1.55: 0.189. The product yield is highest at this ratio.
Preferably, the molar ratio of the potassium dichromate to the fenbendazole is (0.186-0.206) to (0.179-0.190). Within the preferable dosage proportion range, the method is favorable for smoothly carrying out the preparation method to obtain the fenbendazole sulfoxide, the reaction is not complete when the potassium dichromate is too low, but side reactions can occur when the dosage is too high, for example, the fenbendazole sulfone without biological activity is generated, so that the yield of the target product is reduced.
Preferably, the molar ratio of the potassium dichromate to the fenbendazole is 0.195: 0.189.
Preferably, the reaction time is 2-8 h. This time frame allows higher yields to be obtained, and longer times increase side reactions.
Preferably, the reaction time is 6 h.
Preferably, the reaction temperature is 4-10 ℃.
Preferably, the temperature of the reaction is 8 ℃.
Preferably, the preparation method is specifically operated as follows: dissolving the fenbendazole in the sulfuric acid aqueous solution, controlling the temperature of the sulfuric acid aqueous solution to be 4-10 ℃, adding potassium dichromate, reacting for 2-8 h, adjusting the pH of a reaction solution to 8-9.5, crystallizing, and carrying out solid-liquid separation to obtain the fenbendazole. Wherein the solid-liquid separation can adopt a conventional filtration or centrifugation mode. The pH value of the reaction liquid is adjusted to be alkaline, so that most of fenbendazole sulfoxide can be separated out in 2 hours, the separation is increased along with the prolonging of the crystallization time, and the fenbendazole sulfoxide is basically and completely separated out in 4 hours. The pH of the reaction solution is preferably adjusted to 9.0 with an aqueous NaOH solution.
Preferably, the preparation method further comprises refining the product obtained by the reaction.
Preferably, the refining is washing with water, followed by drying at 50-80 ℃. Fenbendazole sulfoxide is not particularly stable, so the drying temperature range is selected to avoid the formation of byproducts by other reactions of the product at high temperature.
Preferably, the temperature of the drying is 60 ℃.
Drawings
FIG. 1 is a mass spectrum of fenbendazole sulfoxide according to an embodiment of the present invention;
FIG. 2 is a scanning infrared spectrum of fenbendazole sulfoxide according to an embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
This example provides a method for preparing fenbendazole sulfoxide.
1. Apparatus and feedstock
Liquid chromatography tandem mass spectrometry: an Agilent 6400 series triple quadrupole LC-MS system; nicolet5700/6700 infrared chromatograph; an electric stirrer; SH2D model water circulation vacuum pump; HH type constant temperature water bath.
The content of the fenbendazole bulk drug is more than 98 percent by Shanghai-sourced leaf biotechnology limited; 92% (v/v) sulfuric acid, analytically pure; potassium dichromate with the content of 99 percent, and is analytically pure; sodium hydroxide, analytically pure.
2. The test method comprises the following steps:
600ml of distilled water was put into a 1000ml three-necked flask equipped with a stirrer, 95ml (1.63mol) of concentrated sulfuric acid (92 v/v%) was added with stirring, and the mixture was cooled to room temperature (28 ℃ C.) to obtain acid water; 55.69g (0.186mol) of fenbendazole was added and stirred until completely dissolved. And (2) placing the acid water in an ice water bath kettle to control the temperature, stirring and slowly adding 54.71g (0.186mol) of potassium dichromate under the condition of keeping the reaction liquid at 4 ℃, reacting for 4h, then adjusting the pH of the reaction liquid to 8.5 by using 15% (W/W) NaOH, crystallizing at room temperature, carrying out suction filtration after 4h, washing a filter cake with 100mL of water for three times, and drying at 50 ℃ to constant weight to obtain the fenbendazole sulfoxide. The yield of fenbendazole sulfoxide was 97.83%.
Example 2
This example provides a method for preparing fenbendazole sulfoxide. The apparatus and the raw materials were the same as in example 1.
The test method comprises the following steps:
600ml of distilled water was put into a 1000ml three-necked flask equipped with a stirrer, 87ml (1.49mol) of concentrated sulfuric acid (92 v/v%) was added thereto with stirring, and the mixture was cooled to room temperature (28 ℃ C.) to obtain acid water; fenbendazole 56.87g (0.190mol) was added and stirred until completely dissolved. Placing the acid water in an ice water bath kettle to control the temperature, stirring and slowly adding 55.89g (0.190mol) of potassium dichromate under the condition of keeping the reaction liquid at 10 ℃, reacting for 8h, then adjusting the pH of the reaction liquid to 8 by using 15% (W/W) NaOH, crystallizing at room temperature, carrying out suction filtration after 2h, washing a filter cake with 100mL of water for three times, and drying at 80 ℃ to constant weight to obtain fenbendazole sulfoxide. The yield of fenbendazole sulfoxide was 95.82%.
Example 3
This example provides a method for preparing fenbendazole sulfoxide. The apparatus and the raw materials were the same as in example 1.
The test method comprises the following steps:
600ml of distilled water was put into a 1000ml three-necked flask equipped with a stirrer, 73ml (1.25mol) of concentrated sulfuric acid (92 v/v%) was added with stirring, and the mixture was cooled to room temperature (28 ℃ C.) to obtain acid water; 53.60g (0.179mol) of fenbendazole was added and stirred until completely dissolved. Placing the acid water in an ice water bath kettle to control the temperature, stirring and slowly adding 60.56g (0.206mol) of potassium dichromate under the condition of keeping the reaction liquid at 6 ℃, reacting for 2h, then adjusting the pH of the reaction liquid to 9.5 by using 15% (W/W) NaOH, crystallizing at room temperature, carrying out suction filtration after 4h, washing a filter cake with 100mL of water for three times, and drying at 70 ℃ to constant weight to obtain fenbendazole sulfoxide. The yield of fenbendazole sulfoxide was 96.14%.
Example 4
This example provides a method for preparing fenbendazole sulfoxide. The apparatus and the raw materials were the same as in example 1.
The test method comprises the following steps:
600ml of distilled water was put into a 1000ml three-necked flask equipped with a stirrer, and 90ml (1.55mol) of concentrated sulfuric acid (92 v/v%) was added with stirring and cooled to room temperature (28 ℃ C.) to obtain acid water; fenbendazole 56.54g (0.189mol) was added and stirred until completely dissolved. And (2) placing the acid water in an ice water bath kettle to control the temperature, stirring and slowly adding 57.32g (0.195mol) of potassium dichromate under the condition of keeping the reaction liquid at 8 ℃, reacting for 6h, then adjusting the pH of the reaction liquid to 9 by using 15% (W/W) NaOH, crystallizing at room temperature, carrying out suction filtration after 2h, washing a filter cake with 100mL of water for three times, and drying at 60 ℃ to constant weight to obtain the fenbendazole sulfoxide. The yield of fenbendazole sulfoxide was 98.28%.
Structural analysis
1. Mass spectrometric determination
The product prepared in the example is prepared into 1 mu g/mL methanol solution, a needle pump sample injection mode is adopted, a positive ion mode is adopted for full scanning, and [ M + H ] is found from a map]+An excimer ion peak 316 and other fragment peaks are assigned, and the product obtained in the preliminary determination example is the target compound fenbendazole sulfoxide, and the mass spectrogram of the product is shown in figure 1.
2. Infrared spectrometry
The product obtained in the example was tabletted with KBr and then scanned with an infrared spectrum, the scanning spectrum of which is shown in FIG. 2, wherein 3400cm-1Is amide nitrogen hydrogen absorption peak, 3000cm-1Characteristic peak of heterocyclic hydrogen, 2900--1Methyl absorption Peak, 1760cm-1Absorption peak of carbon-oxygen double bond, 1600-1400cm-1Is an absorption peak of carbon-carbon double bond on the ring, 1000--1The peak is the characteristic peak of the sulfur-oxygen double bond in the sulfoxide, so the product prepared in the example is further determined to be the target compound fenbendazole sulfoxide.
Biological activity
First, in vitro anti-hydatid activity
1. Material
1.1 Echinococcus granulosus Procoenurus and vesicles
Echinococcus granulosus protocephaliasis is obtained from hepatocyst of slaughtered sheep in Gansu Gannan Maqu slaughter house, and protocephalic activity is above 92%. And forming vesicles with the diameter of 1-3 after the metacercaria is cultured in vitro for 2-3 months.
1.2 reagents and instruments
Tween 80 (pharmaceutical grade), analytically pure; fetal bovine serum, zhengzhou jiulong bioproduct factory; fenbendazole sulfoxide, fenbendazole bulk drug, Shanghai-sourced leaf Biotechnology Limited, with a content of 98%; the remainder were purchased from chemical company.
2. Method of producing a composite material
2.1 preparation of the drug
The tween 80 is used as a cosolvent to help dissolve the fenbendazole and the fenbendazole sulfoxide prepared in the embodiment of the invention. Weighing 1g of each of 2 medicines, respectively placing into a 100ml volumetric flask, respectively adding Tween 80 solution with the concentration of 0.1% (v/v), mixing the solutions, placing into a constant temperature culture oscillator, shaking for 24h, taking out, and standing at room temperature.
2.2 in vitro Effect test of Procercaria and vesicles
Placing Echinococcus granulosus metacercaria and vesicle in RDMI 1640 culture solution containing 20% Fetal Bovine Serum (FBS), 10mg/ml penicillin, and 10mg/ml streptomycin, respectively, at 37 deg.C and 5% (v/v) CO2Culturing under the condition. The fenbendazole and the Tween 80 solution of fenbendazole sulfoxide are filtered by a 0.22 mu m microporous filter membrane for later use. The experiment is totally provided with 8 groups, namely a fenbendazole test group, a fenbendazole sulfoxide test group, a cosolvent control group and a blank control group of the metacercaria, and a fenbendazole test group, a fenbendazole sulfoxide test group, a cosolvent control group and a blank control group of the vesicle, wherein each group is provided with 2 parallel groups. The number of the metacercaria is 3000 per group, and the volume of the culture solution is 25 ml. The number of vesicles per group was about 40, and the culture volume was 50 ml. The above drug solution, cosolvent solution (Tween 80 containing 0.1% (v/v)), and distilled water were added to the corresponding group of culture solutions at the same volume, respectively.
The metacercaria group was observed 1 time every 1d smear: taking 1ml of each group of culture solution, staining the culture solution with 0.1% eosin solution for 3-5 min, smearing the smear after the original metacercaria is precipitated, observing and counting under an inverted microscope, and staining the metacercaria sections with red color, accompanied with structural damage and no activity; the viable head node is resistant to staining and not stained, and has motility or secretory activity. Counting about 200 metacercaria in each group, and calculating the mortality of metacercaria with the experimental period of 10 days.
The vesicle group was observed 1 time per 5 d: and (4) observing each group of culture solution under an inverted microscope, and recording the collapse condition of all vesicles in the group for an experiment period of 20 d.
2.3 statistical analysis
The P test was performed using SPSS17.0 statistical software, and α was 0.05.
3. Results
3.1 comparison of in vitro Echinococcus granulosus Elongaria Procoenuraria resistance
The effect of the two drugs against Echinococcus granulosus metacercaria is shown in Table 1. The difference of the mortality rates of the two drug groups and the control group respectively has statistical significance (P is less than 0.01) through P test; the difference in the mortality rate of metacercaria between the two drug groups was statistically significant (P < 0.05). The results show that the fenbendazole sulfoxide prepared by the embodiment of the invention has stronger effect on resisting echinococcus granulosus metacercaria in vitro than fenbendazole.
TABLE 1 mortality of Primary metacercaria (x. + -. s,%) at different times for each group of drugs
| Group of | 2d th | 4d th | 6d th | 8d th | 10d th |
| Blank control group | 3.69±3.0 | 5.13±0.7 | 5.35±0.2 | 5.47±1.0 | 6.93±1.0 |
| Cosolvent control group | 2.41±0.4 | 3.06±0.4 | 3.11±0.4 | 3.25±0.5 | 5.21±0.5 |
| Fenbendazole test group | 19.0±0.21 | 30.90±2.6 | 32.12±9.7 | 42.49±1.2 | 46.17±4.9 |
| Fenbendazole sulfoxide test group | 19.3±0.41 | 37.55±0.34 | 38.56±10.3 | 45.61±7.2 | 47.91±0.0 |
3.2 comparison of Echinococcus granulosus-resistant vesicles with two drugs
The anti-echinococcus granulosus vesicle effect of the two drugs is shown in table 2. Through P test, the difference of the vesicle collapse rate of the metacercaria of the two drug groups and the vesicle collapse rate of the metacercaria of the control group respectively has statistical significance (P is less than 0.01); the difference in the vesicle collapse rate of the metacercaria between the two drug groups was statistically significant (P < 0.01). The results indicate that the collapse rate of fenbendazole sulfoxide vesicles is higher than that of fenbendazole. With the prolonging of the action time, the collapse rate of the vesicles in each drug group is gradually increased.
Table 2 vesicle collapse Rate (x. + -. s,%) of each group of drugs at different times
The results prove that the effect of the bendazole sulfoxide prepared by the embodiment of the invention on in-vitro anti-metacercaria and vesicle is stronger than that of fenbendazole.
Second, practical application
The echinococcosis secondary to 12 goats and 10 sheep were treated with fenbendazole sulfoxide in Qinghai Tongde county in a tracking way, and the primary joint survival rate was checked to find that the symptoms were significantly improved, and 22 sheep survived and had good growth conditions.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (6)
1. A preparation method of fenbendazole sulfoxide is characterized in that fenbendazole and potassium dichromate react in a sulfuric acid water solution to form the fenbendazole sulfoxide;
the volume percentage concentration of the sulfuric acid aqueous solution is 10-12.6%;
the molar ratio of the sulfuric acid in the sulfuric acid aqueous solution to the fenbendazole is (1.55-1.63) to (0.186-0.189);
the molar ratio of the potassium dichromate to the fenbendazole is (0.186-0.195) to (0.186-0.189);
the preparation method is specifically operated as follows: dissolving the fenbendazole in the sulfuric acid aqueous solution, controlling the temperature of the sulfuric acid aqueous solution to be 4-8 ℃, adding potassium dichromate, reacting for 4-6 h, adjusting the pH of a reaction solution to 8.5-9.0, crystallizing, and carrying out solid-liquid separation to obtain the fenbendazole.
2. The method for producing fenbendazole sulfoxide according to claim 1, wherein a molar ratio of sulfuric acid in the aqueous sulfuric acid solution to fenbendazole is 1.55: 0.189; and/or
The molar ratio of the potassium dichromate to the fenbendazole is 0.195: 0.189.
3. The method for producing fenbendazole sulfoxide according to claim 1, wherein the reaction time is 6 hours; and/or
The temperature of the reaction was 8 ℃.
4. The method for producing fenbendazole sulfoxide according to claim 1, further comprising refining a product obtained by the reaction.
5. The method for producing fenbendazole sulfoxide according to claim 4, wherein the purification is washing with water and then drying at 50 to 80 ℃.
6. The method for producing fenbendazole sulfoxide according to claim 5, wherein the temperature for drying is 60 ℃.
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| CN102131776A (en) * | 2008-06-25 | 2011-07-20 | 拜耳先灵制药股份公司 | Substituted 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethyl indoles and use thereof |
| CN106380452A (en) * | 2016-08-25 | 2017-02-08 | 江苏宝众宝达药业有限公司 | Method for significant reduction of solvent dosage in oxfendazole production process |
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