CN101270090A - Method for preparing albendazole oxide - Google Patents
Method for preparing albendazole oxide Download PDFInfo
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- CN101270090A CN101270090A CNA2008100239661A CN200810023966A CN101270090A CN 101270090 A CN101270090 A CN 101270090A CN A2008100239661 A CNA2008100239661 A CN A2008100239661A CN 200810023966 A CN200810023966 A CN 200810023966A CN 101270090 A CN101270090 A CN 101270090A
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Abstract
The present invention relates to a preparation method of oxygen albendazole. In the preparation method, albendazole is dissolved in formic acid through stirring; the mixture of activated carbon and chromatographic silica gel is added; after stirring, the albendazole oxidized by hydrogen peroxide is dropped into the mixture; the reaction temperature is controlled between 40 DEG C and 60 DEG C; after the reaction is completed, the mixture is filtered and the filtrate is separated; the formic acid is then used for leaching the mixture of activated carbon and chromatographic silica gel; the lotion and the filtrate are mixed; the solution of sodium hydroxide or the solution of potassium hydroxide is added into the mixed solution to prepare crude albendazole; deionized water is used for leaching the crude albendazole to prepare pure albendazole. The preparation method has the advantages of high yield of the product, low cost, clean process, high purity of the product and suitability for industrialization.
Description
One, technical field
The present invention relates to a kind of preparation method of benzimidazole carbamate compounds, be specifically related to the preparation method of parasiticide bulk drug albendazoloe oxide.
Two, background technology
Albendazoloe oxide; have another name called albendazole-sulfoxide; chemistry 5-third sulfinyl-1 H-benzimidazole by name-2-Urethylane; be after albendazole enters in the body; one of main active metabolite that produces through the effect of liver particulate enzyme; and the further metabolism of quilt is an Albendazole sulfone (English name: Albendazole Sulfone; chemical name: 5-third alkylsulfonyl-1H-benzimidazolyl-2 radicals-Urethylane); last metabolism is the amino sulfone (chemical name: 5-third alkylsulfonyl-2 '-amino benzoglyoxaline) of albendazole-2-; but Albendazole sulfone does not have insecticidal activity, and the insecticidal activity of albendazole is mainly derived from albendazoloe oxide.
Albendazoloe oxide preparation technology is simple relatively, goes on foot by oxidation albendazole one to prepare.But,, directly have influence on product yield and quality so process control is very crucial because in the oxidising process, product can be produced Albendazole sulfone by peroxidation, or forms the oxynitride of albendazole, albendazoloe oxide and Albendazole sulfone.At present, the albendazoloe oxide preparation technology of report is mainly following a few class both at home and abroad:
1, use the solid inorganic oxygenant, as sodium periodate, chromium trioxide, the oxidation albendazole makes the albendazoloe oxide product.
2, use the liquid organic oxidizing agent, as tertbutyl peroxide, the oxidation albendazole makes the albendazoloe oxide product.
3, use liquid inorganic oxidizer, as hydrogen peroxide, the oxidation albendazole makes the albendazoloe oxide product.Wherein, when using the above-mentioned the 1st and the 2nd prepared albendazoloe oxide product, there is the following problem:
(1), be reflected under the cold condition and carry out, condition is harsh relatively; (2), some other impurity are introduced in the affiliation that adds of solid inorganic oxygenant; (3), purifying products method complexity, what have uses complex operations such as column chromatography; (4), reagent consumption is many, product yield and quality are low.
For avoiding above-mentioned shortcoming, Yuan Zonghui etc. have reported and have used the hydrogen peroxide oxidation albendazole to make the method (number of patent application: 200710051367.6 of albendazoloe oxide, publication number: CN 101029030A), i.e. the 3rd albendazoloe oxide preparation technology, concrete grammar is as follows:
In reaction flask, press amount of substance and volume ratio 0.05mol: 70mL and add albendazole and glacial acetic acid, be stirred to dissolving under the 15-50 ℃ of condition, with 30% hydrogen peroxide of amount of substances such as slow dropping of dropping funnel and albendazole; Reaction finishes sodium hydroxide solution neutralization reaction mixed solution with 1-8mol/L to pH6.0-7.0, filters, and filter cake places 30-50 ℃ of oven drying, the albendazole-sulfoxide crude product.The albendazole-sulfoxide crude product is done solvent recrystallization 1-3 time with 70%-90% ethanol earlier, again with N.N-dimethyl formamide and acetonitrile mixing solutions recrystallization 1-3 time, filter and use N, the dinethylformamide flush cake, with the dehydrated alcohol flushing, filter cake places 30-50 ℃ of oven drying to get albendazole-sulfoxide again.
But present method also comes with some shortcomings, mainly be that the albendazoloe oxide crude product that obtains needs through recrystallization repeatedly, simultaneously since albendazoloe oxide only at acid solvent, example hydrochloric acid, formic acid, acetate, solubleness is preferably arranged, and the technology of report only uses 90% ethanol, DMF, acetonitrile and dehydrated alcohol to the product solubility difference to carry out aftertreatment, can consume a large amount of solvents.
Three, technology contents
At above-mentioned shortcoming, the object of the present invention is to provide that a kind of yield height, cost are low, the process cleaning, product purity is high and can realize industrialized albendazoloe oxide preparation method.
Technology contents of the present invention is: a kind of preparation method of albendazoloe oxide, and its preparation process is as follows:
Adding concentration in albendazole is the formic acid of 75～90 weight %, and the ratio of the volume of formic acid and albendazole weight is 3～5; Add 1～10% gac and chromatographic silica gel mixture of albendazole gross weight again, the weight percent hundred of gac is 5～95% in gac and the chromatographic silica gel mixture; Stir after 0.5～1 hour, 1～1.2 times of concentration that drips the albendazole molar weight again is 27～50 weight % hydrogen peroxide oxidation albendazoles, and the drop rate of hydrogen peroxide is 1.0～3.0 gram/minute; And make temperature of reaction be controlled at 40～60 ℃, and the HPLC follow-up control reaction times is complete to raw material reaction, and reaction finishes, and filters, and tells filtrate, is formic acid drip washing gac and the chromatographic silica gel mixture of 75～90 weight % again with concentration; Washing lotion and filtrate are merged, and it is 25～35 ℃ that cooling makes the temperature that merges solution; Dripping concentration in merging solution is sodium hydroxide or the potassium hydroxide solution of 30～50 weight %, making the pH value that merges solution is 6.5～8.5, finish and stirred 0.5～1 hour, filtration obtains the albendazoloe oxide crude product, use deionized water drip washing albendazoloe oxide crude product again, vacuum-drying gets the pure product of albendazoloe oxide.
The chemical equation that reacts among the present invention is as follows:
In the preparation method of above-mentioned albendazoloe oxide, when adding formic acid in albendazole, the ratio of the volume of formic acid and albendazole weight is preferably 4～5, and the concentration of formic acid is preferably 80-85%.
In the preparation method of above-mentioned albendazoloe oxide, the add-on of gac and chromatographic silica gel mixture is preferably 3～6% of albendazole gross weight, and the weight percent hundred of gac is preferably 40～60% in gac and the chromatographic silica gel mixture.
In the preparation method of above-mentioned albendazoloe oxide, the add-on of the hydrogen peroxide of oxidation albendazole is preferably 1～1.1 times of albendazole molar weight, the concentration of hydrogen peroxide is preferably 30～35%, and drop rate is preferably 2～2.5 gram/minute, and temperature of reaction is preferably 45～55 ℃.
In the preparation method of above-mentioned albendazoloe oxide, the concentration of sodium hydroxide or potassium hydroxide solution is preferably 40 weight %, and the pH value of merging filtrate is preferably 7.0～8.0.
The advantage that the present invention is compared with prior art had is as follows:
1, in the reaction process, adopts formic acid to substitute dissolving albendazoles such as acetate, solvent load is reduced to 3-5 times of volume of albendazole weight, reduced solvent load.
2, reaction process coupling purification process by add gac and chromatographic silica gel mixture in system, not only provides carrier, the promotes oxidn reaction; And the direct purification product, the product that obtains does not need recrystallization, and is simple to operate.The product content that obtains reaches more than 99%, and product yield reaches more than 98%, avoids using some price height, difficult recovered solvent simultaneously, as acetonitrile, dimethyl formamide DMF etc.
Four, specific embodiment
The present invention is further detailed explanation below in conjunction with embodiment.
Embodiment 1,
In 500 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, add albendazole 53 gram albendazoles successively, 250 ml concns are 85 weight % formic acid; Add 1.8 gram gacs and 1.3 gram chromatographic silica gel mixtures again, stir after 0.5 hour heating; After being warming up to 50 ℃, beginning to drip 21.3 gram concentration is the hydrogen peroxide oxidation albendazole of 35 weight %; In the hydrogen peroxide dropping process, the control drop rate is 2.0～2.2 gram/minute, and the control temperature of reaction system is at 50～55 ℃; The HPLC follow-up control reaction times is complete to raw material reaction, and reaction finishes, and filters; Tell filtrate, use formic acid drip washing gac and chromatographic silica gel mixture again; Washing lotion and filtrate are merged, and cooling merges solution to 25 ℃; Dripping concentration in merging solution is 40 weight % sodium hydroxide solutions, regulate the pH value to 7 that merges solution, finish and stirred 0.5 hour, filtration obtains the albendazoloe oxide crude product, again with 4 gram methyl alcohol drip washing albendazoloe oxide crude products, vacuum-drying obtains the pure product of 55.6 gram albendazoloe oxides, and yield is 98.9%, and content is greater than 99%.
Embodiment 2,
In 500 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, add albendazole 53 gram albendazoles successively, 250 ml concns are 80 weight % formic acid; Add 1.8 gram gacs and 1.3 gram chromatographic silica gel mixtures again, stir after 0.5 hour heating; After being warming up to 50 ℃, beginning to drip 24.0 gram concentration is the hydrogen peroxide oxidation albendazole of 30 weight %; In the hydrogen peroxide dropping process, the control drop rate is 2.0～2.2 gram/minute, and the control temperature of reaction system is at 50～55 ℃; The HPLC follow-up control reaction times is complete to raw material reaction, and reaction finishes, and filters; Tell filtrate, use formic acid drip washing gac and chromatographic silica gel mixture again; Washing lotion and filtrate are merged, and cooling merges solution to 25 ℃; Dripping concentration in merging solution is 40 weight % sodium hydroxide solutions, regulate the pH value to 7 that merges solution, finish and stirred 0.5 hour, filtration obtains the albendazoloe oxide crude product, again with 4 gram ethanol drip washing albendazoloe oxide crude products, vacuum-drying obtains the pure product of 55.2 gram albendazoloe oxides, and yield is 98.2%, and content is greater than 99%.
Embodiment 3,
In 500 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, add albendazole 53 gram albendazoles successively, 260 ml concns are 85 weight % formic acid; Add 1.3 gram gacs and 1.3 gram chromatographic silica gel mixtures again, stir after 0.5 hour heating; After being warming up to 50 ℃, beginning to drip 21.1 gram concentration is the hydrogen peroxide oxidation albendazole of 35 weight %; In the hydrogen peroxide dropping process, the control drop rate is 2.3～2.5 gram/minute, and the control temperature of reaction system is at 50～51 ℃; The HPLC follow-up control reaction times is complete to raw material reaction, and reaction finishes, and filters; Tell filtrate, use formic acid drip washing gac and chromatographic silica gel mixture again; Washing lotion and filtrate are merged, and cooling merges solution to 25 ℃; Dripping concentration in merging solution is 50 weight % sodium hydroxide solutions, regulate the pH value to 7 that merges solution, finish and stirred 0.5 hour, filtration obtains the albendazoloe oxide crude product, again with 4 gram methyl alcohol drip washing albendazoloe oxide crude products, vacuum-drying obtains the pure product of 55.7 gram albendazoloe oxides, and yield is 99.1%, and content is greater than 99%.
Claims (2)
1, a kind of preparation method of albendazoloe oxide, its preparation process is as follows:
Adding concentration in albendazole is the formic acid of 75～90 weight %, and the ratio of the volume of formic acid and albendazole weight is 3～5; Add 1～10% gac and chromatographic silica gel mixture of albendazole gross weight again, the weight percent hundred of gac is 5～95% in gac and the chromatographic silica gel mixture; Stir after 0.5～1 hour, 1～1.2 times of concentration that drips the albendazole molar weight again is 27～50 weight % hydrogen peroxide oxidation albendazoles, and the drop rate of hydrogen peroxide is 1.0～3.0 gram/minute; And make temperature of reaction be controlled at 40～60 ℃, and the HPLC follow-up control reaction times is complete to raw material reaction, and reaction finishes, and filters, and tells filtrate, is formic acid drip washing gac and the chromatographic silica gel mixture of 75～90 weight % again with concentration; Washing lotion and filtrate are merged, and it is 25～35 ℃ that cooling makes the temperature that merges solution; Dripping concentration in merging solution is sodium hydroxide or the potassium hydroxide solution of 30～50 weight %, making the pH value that merges solution is 6.5～8.5, finish and stirred 0.5～1 hour, filtration obtains the albendazoloe oxide crude product, use deionized water drip washing albendazoloe oxide crude product again, vacuum-drying gets the pure product of albendazoloe oxide.
2, the preparation method of albendazoloe oxide according to claim 1 is characterized in that the volume of the formic acid that adds and the ratio of albendazole weight are preferably 4～5 in albendazole, the concentration of formic acid is 80-85%; The add-on of gac and chromatographic silica gel mixture is 3～6% of an albendazole gross weight, and the weight percent hundred of gac is 40～60% in gac and the chromatographic silica gel mixture; The add-on of the hydrogen peroxide of oxidation albendazole is 1～1.1 times of albendazole molar weight, and the concentration of hydrogen peroxide is 30～35%, and the hydrogen peroxide drop rate is 2～2.5 gram/minute, and temperature of reaction is 45～55 ℃; The concentration of sodium hydroxide or potassium hydroxide solution is 40 weight %; The pH value of merging filtrate is 7.0～8.0.
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| CN2008100239661A CN101270090B (en) | 2008-04-23 | 2008-04-23 | Method for preparing albendazole oxide |
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| CN2008100239661A CN101270090B (en) | 2008-04-23 | 2008-04-23 | Method for preparing albendazole oxide |
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| CN101270090A true CN101270090A (en) | 2008-09-24 |
| CN101270090B CN101270090B (en) | 2011-12-28 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109762483A (en) * | 2018-12-25 | 2019-05-17 | 苏州义铠轩电子科技有限公司 | Vertical conduction is pyrolyzed adhesive tape and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109762483A (en) * | 2018-12-25 | 2019-05-17 | 苏州义铠轩电子科技有限公司 | Vertical conduction is pyrolyzed adhesive tape and preparation method thereof |
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Owner name: CHANGZHOU QIHUI PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: CHANGZHOU YABANG QIHUI FINE CHEMICALS CO., LTD. |
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Address after: 213127, Jinlong Road, Xinbei Town, Xinbei District, Jiangsu, Changzhou, 18 Patentee after: Changzhou Qi Hui pharmaceutcal corporation, Ltd Address before: 213127, Changzhou, Jiangsu Province town of new North Wei Village Riverside Industrial Park Patentee before: Changzhou Yabang Qihui Fine Chemicals Co., Ltd. |