CN101029029A - Chemical syntheis of albendazole-sulphone - Google Patents
Chemical syntheis of albendazole-sulphone Download PDFInfo
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- CN101029029A CN101029029A CNA2007100513661A CN200710051366A CN101029029A CN 101029029 A CN101029029 A CN 101029029A CN A2007100513661 A CNA2007100513661 A CN A2007100513661A CN 200710051366 A CN200710051366 A CN 200710051366A CN 101029029 A CN101029029 A CN 101029029A
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Abstract
A process for chemically synthesizing albendazole sulfone includes such steps as oxidizing reaction between albendazole, glacial acetic acid and H2O2 to obtain coarse albendazole sulfone, and recrystallizing.
Description
Technical field
The invention belongs to chemical process synthetic drugs metabolite field, be specifically related to the chemical synthesis process of one of albendazole cylinder metabolism-ure Albendazole sulfone.
Background technology
Albendazole is an albendazole-sulfoxide through the first pass effect metabolism at first after entering in the body, and albendazole-sulfoxide is metabolized to Albendazole sulfone then, and last metabolism is the amino sulfone of albendazole-2-.The main metabolic process is as shown in Figure 1 in vivo for albendazole.Albendazole sulfone is one of major objective metabolite of albendazole residue detection.Therefore it is significant for metabolism, pharmacological toxicology and the residual research of albendazole to prepare Albendazole sulfone.
About the existing following pertinent literature of Albendazole sulfone preparation method's report.Reports such as Olivia prepare Albendazole sulfone with 1.0g albendazole and 2.015g sodium periodate at 25 ℃ of reaction 22h, products obtained therefrom purity is 90%, 226～227 ℃ of (Olivia etc. of melting range, Studies on the Selective S-oxidation of Albendazole, Fenbendazole, Triclabendazole, and OtherBenzimidazole SulfidesJ.Mex.Chem.Soc.2005,49 (4), 353-358).1g albendazole and the reaction of 4mL hydrogen peroxide under report such as the Li Yan room temperature, make the mixture of albendazole-sulfoxide and Albendazole sulfone, again through column chromatography for separation, make Albendazole sulfone (Li Yan etc., synthetic and the electrospray ionization mass spectrum analysis of Albendazole's sulphur oxidative metabolism product, Shenyang Pharmaceutical University's journal, Vol.19 No.6 Nov.2002 are P.413).Huang Lixin etc. report is with m-chloro aniline, and oxalic acid etc. make Albendazole sulfone (Huang Lixin etc., anti-echinococcus drug research albendazole metabolite and analogue thereof synthetic, Chinese Journal of Pharmaceuticals, 1995.26 (2)) for raw material through the reaction of 10 steps.Reports such as Xin Wenfen are dissolved in the 15ml acetate with the 1g Albendazole, with hydrogen peroxide as oxidant, 90 ℃ of reactions finish to have precipitation to separate out, and cold filtration gets product Albendazole sulfone, yield is 85%, 274～278 ℃ of melting ranges have molecular ion peak m/z265 (Xin Wenfen etc., rycobendazole and propanethiophenyl imidzole sulfone synthetic of Albendazole's raw material in its mass spectrograph measured result, health research, 1990.19 (4)).
The subject matter that the described method of above document exists has:
(1) long reaction time, products therefrom purity is low.(2) reactions steps is many, and productive rate is low, and it is many and poisonous to consume reagent.(3) temperature of reaction is low, in have a large amount of sulfoxides to generate, be difficult to purifying.Have material to separate out in the reaction, raw material is separated out in the lump, causes impurity many, and purity is low.(4) purification process complexity must be carried out complex operations such as column chromatography.
Summary of the invention
The object of the invention is to overcome existing method defective, provides that a kind of operation is simple, and reagent is cheap and easy to get, low toxicity or nontoxic, and purification process is simple, the synthetic method that gained Albendazole sulfone purity is high.
The objective of the invention is to reach by following measure respectively:
In being housed, the reaction flask of spherical condensation tube adds albendazole and glacial acetic acid by amount of substance and volume ratio 0.05mol: 120mL, in the dissolving extremely fully of 60～100 ℃ of stirring in water bath, divide 2 times and in reaction flask, add 30% hydrogen peroxide, add 1～4 times earlier to the hydrogen peroxide of albendazole amount of substance, behind reaction 4～6h, add 1～4 times of hydrogen peroxide again to the albendazole amount of substance; React 4～6h again; Question response finish reaction mixture; With 1～8molL
-1The mixed liquid of sodium hydroxide solution neutralization reaction to pH5.0～7.0, filtration drying, the Albendazole sulfone crude product.Products therefrom promptly gets the Albendazole sulfone reference substance through methyl-sulphoxide and aqueous solution recrystallization.
In the reaction of the present invention, this reaction is to finish in 60～100 ℃ of scopes, as preferred version, makes to be reflected in 70～90 ℃ and carries out.
In the reaction of the present invention, in reaction flask, add the total amount of substance of 30% hydrogen peroxide and be 2～8 times of Albendazole's amount of substance,, add 4 times of hydrogen peroxide with Albendazole's amount of substance as preferred version.
In the reaction of the present invention, this is reflected at 8～12h and finishes, and as preferred version, the suitable reaction times is 8h.
Product recrystallization solvent for use is that (methyl-sulphoxide: water=5: 1～9: 1, V/V), as preferably, recrystallization solvent is that methyl-sulphoxide and water volume ratio are 9: 1 mixing solutions to the methyl-sulphoxide aqueous solution among the present invention.
The present invention compared with prior art has following characteristics:
(1) the present invention adds oxygenant in batches, has avoided the loss of hydrogen peroxide decomposes.(2) add the reaction medium glacial acetic acid of appropriate amount, avoid separating out of raw material and Albendazole's sulfoxide in the reaction process.(3) single step reaction obtains Albendazole sulfone with the albendazole exhaustive oxidation, and reactions steps is few, and average yield is up to more than 97%.(3) purification process is simple, need not cross complex operations such as column chromatography, rotary evaporation.(4) provide the recrystallization method of Albendazole sulfone, products therefrom purity reaches more than 99.5%, reaches the purity requirement of chromatographic grade reference substance.
The present invention is compared with the prior art and sees Table 1
Table 1 the present invention be compared with the prior art
| Technology | Temperature of reaction (℃) | Reaction times (h) | Oxygenant | Number of steps | Yield (%) | Purity | Melting range (℃) | Characteristics | |
| The present invention | 70-90 | 8 | 30% | 1 | 97 | Crude product is a single chromatographic peak, reaches more than 99.5% behind the recrystallization. | 271-272 | Single step reaction, product is single, mild condition. | |
| Olivia etc. report synthetic method | 25 | 22 | | 1 | 90 | - | 226-227 | The solid oxidizing agent difficulty is removed, and fusing point and actual value difference are very big. | |
| Li Yan etc. report synthetic | Room temperature | 1 | | 1 | 26.5 | Mixture for Albendazole's sulfoxide and sulfone | - | Obtain mixture, separate and to cross post, operations such as rotary evaporation. | |
| Huang Lixin etc. report synthetic method | - | - | - | 7 | 80-86 | - | - | Polystep reaction, yield is low. | |
| Xin Wenfen etc. report | 90 | 2 | 30% | 1 | 85 | - | 274-278 | There is impurity to separate out in the lump in the reaction process, is difficult to the removal of impurity with product. |
Description of drawings
Fig. 1 is an albendazole main metabolic process in vivo.
Fig. 2 is the ultraviolet spectrogram (solvent is a methyl alcohol) of Albendazole sulfone.
Fig. 3 is the infrared spectrogram (KBr) of Albendazole sulfone.
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram (DMSO-d of Albendazole sulfone
6).
Fig. 5 is the carbon-13 nmr spectra figure (DMSO-d of Albendazole sulfone
6).
Fig. 6 is the electrospray ionization mass spectrum figure (positive ion scanning) of Albendazole sulfone.
Fig. 7 is the electrospray ionization mass spectrum figure (negative ion scanning) of Albendazole sulfone.
Fig. 8 is the high-efficient liquid phase chromatogram of Albendazole sulfone.
Embodiment
Further specify the present invention below by embodiment, but not limited by these embodiment.
The 13.25g albendazole is added 500ml be equipped with in the four-hole bottle of spherical condensation tube, add the 120mL glacial acetic acid again, 60 ℃ of water-baths are stirred to dissolving.Add the 12mL30% hydrogen peroxide, 6h adds the 12mL hydrogen peroxide more at interval, reacts 6h again.The reaction finish reaction mixture.Use 1molL
-1Sodium hydroxide solution in and the mixed liquid of above-mentioned reaction to pH5.0, filter, filter cake is placed oven for drying.Get 13.07g Albendazole sulfone crude product.
With 10.07g Albendazole sulfone dissolving crude product in the there-necked flask that spherical condensation tube is housed, 90 ℃ of water-baths, add 100mL dimethyl sulfoxide solution (methyl-sulphoxide: water=5: 1, V/V) be stirred to dissolving, suction filtration while hot, filtrate places under the room temperature slowly that cooling is placed on 4 ℃ of refrigerator 5h, filter recrystallization product of Albendazole sulfone, after the product drying, (methyl-sulphoxide: water=5: 1, V/V) recrystallization gets Albendazole sulfone 4.10g 4 times with the 100mL dimethyl sulfoxide solution again.
The 13.25g albendazole is added 500ml be equipped with in the four-hole bottle of spherical condensation tube, add the 120mL glacial acetic acid again, 80 ℃ of water-baths are stirred to dissolving.Add the 18mL30% hydrogen peroxide, 5h adds the 18mL hydrogen peroxide more at interval, reacts 5h again.The reaction finish reaction mixture.Use 4molL
-1Sodium hydroxide solution in and the mixed liquid of above-mentioned reaction to pH6.5, filter, filter cake is placed oven for drying.Get 14.03g Albendazole sulfone crude product.
With 10.10g Albendazole sulfone dissolving crude product in the there-necked flask that spherical condensation tube is housed, 90 ℃ of water-baths, add 100mL methyl-sulphoxide (methyl-sulphoxide: water=7: 1, V/V) solution stirring is to dissolving, suction filtration while hot, and filtrate places under the room temperature slowly that cooling is placed on 4 ℃ of refrigerator 5h, filter recrystallization product of Albendazole sulfone, after the product drying, (methyl-sulphoxide: water=7: 1, V/V) recrystallization gets Albendazole sulfone 4.52g 3 times with the 100mL dimethyl sulfoxide solution again.
Embodiment 3
The 13.25g albendazole is added 500ml be equipped with in the four-hole bottle of spherical condensation tube, add the 120mL glacial acetic acid, 100 ℃ of water-baths are stirred to dissolving.Add the 24mL30% hydrogen peroxide, 6h adds the 24mL hydrogen peroxide more at interval, reacts 6h again.The reaction finish reaction mixture.Use 8molL
-1Sodium hydroxide solution in and the mixed liquid of above-mentioned reaction to pH7.0, filter, filter cake is placed oven for drying.Get 14.18g Albendazole sulfone crude product.
With 10.05g Albendazole sulfone dissolving crude product in the there-necked flask that spherical condensation tube is housed, 90 ℃ of water-baths, add 100mL dimethyl sulfoxide solution (methyl-sulphoxide: water=9: 1, V/V) be stirred to dissolving, suction filtration while hot, filtrate places under the room temperature slowly that cooling is placed on 4 ℃ of refrigerator 5h, filter recrystallization product of Albendazole sulfone, after the product drying, (methyl-sulphoxide: water=9: 1, V/V) recrystallization gets Albendazole sulfone 2 times with the 100ml dimethyl sulfoxide solution again.
The raw materials used albendazole bulk drug of the present invention purity 〉=99%; Glacial acetic acid, 30% hydrogen peroxide, dehydrated alcohol, sodium hydroxide, methyl-sulphoxide are analytical pure; Water is distilled water.
The synthetic Albendazole sulfone of the present invention institute is as follows through fusing point instrument, ultraviolet spectrophotometer, infrared spectrophotometer, nuclear magnetic resonance analyser, mass spectrograph, elemental analyser and high performance liquid chromatograph detected result:
The fusing point instrument is measured fusing point, and melting range is: 271～272 ℃ (decomposition).
The ultraviolet spectrogram of Albendazole sulfone (solvent is a methyl alcohol): λ
MaxTwo absorption peaks in 223nm and 292nm place are that phenyl ring E, B band is subjected on the imidazole ring two nitrogen-atoms to influence the result of red shift.See Fig. 2.
The infrared spectrogram of Albendazole sulfone (KBr): 3346cm
-1The absorption at place is-stretching vibration of NH-; 2962cm
-1Be absorbed as CH by force in the place
3-stretching vibration 1703cm
-1The stretching vibration that is absorbed as C=O by force at place; 1653cm
-1The stretching vibration that is absorbed as C=N by force at place; 1458cm
-1, 1529cm
-1And 1597cm
-1The skeletal vibration that is absorbed as phenyl ring by force at place; 1133cm
-1The stretching vibration that is absorbed as O=S=O by force at place.See Fig. 3.
Hydrogen nuclear magnetic resonance spectrogram (the DMSO-d of Albendazole sulfone
6): δ: 0.90 (3H, t, J=7.6Hz); 1.55 (2H, six, J=7.6Hz); 3.22 (2H, t, J=8Hz); 3.83 (3H, s); 7.60 (2H, m, J=1.6Hz); 7.91 (1H, s); 11.98 (2H, bf, s).See Fig. 4.
Carbon-13 nmr spectra figure (the DMSO-d of Albendazole sulfone
6): δ: 12.49 (CH
3-); (16.41 the carbon of intermediary methylene radical); (52.73 the carbon of methoxyl group); (57.10 the carbon of the methylene radical that links to each other with sulfoxide group); (114.14-154.16 the carbon on the phenyl ring).See Fig. 5.
The electrospray ionization mass spectrum figure of Albendazole sulfone (positive ion scanning): m/z297.8:[M]; M/z319.5:[M+Na]
+M/z335.7:[M+Kr]
+See Fig. 6.
The electrospray ionization mass spectrum figure of Albendazole sulfone (negative ion scanning): m/z264.0:[M-CH
3OH]
+M/z296.1:[M-H]
+See Fig. 7.
The high-efficient liquid phase chromatogram of Albendazole sulfone: detecting through high performance liquid phase is a simple spike.See Fig. 8.
The synthetic Albendazole sulfone of the present invention institute is as shown in table 2 through the elemental analyser detected result, and each element percentage composition Error Absolute Value all is no more than 0.5%.
The results of elemental analyses of table 2 synthetic Albendazole sulfone of the present invention
| Element | Theoretical value | Measured value | Error Absolute Value (%) |
| C | 48.47 | 48.64 48.77 | 0.17 0.30 |
| N | 14.14 | 14.62 14.39 | 0.48 0.25 |
| S | 10.78 | 10.98 11.21 | 0.20 0.43 |
| H | 5.085 | 5.051 4.986 | 0.034 0.099 |
Claims (5)
1, a kind of chemical synthesis process of Albendazole sulfone, its step is as follows:
1) in being housed, the reaction flask of spherical condensation tube adds albendazole and glacial acetic acid by amount of substance and volume ratio 0.05mol: 120mL, under 60～100 ℃ of conditions of temperature of reaction, be stirred to dissolving, dividing and add concentration for 2 times in reaction flask is 30% hydrogen peroxide, add 2～4 times earlier to the hydrogen peroxide of albendazole amount of substance, behind reaction 4～6h, add 2～4 times of hydrogen peroxide again to the albendazole amount of substance; React 4～6h again;
2) reaction finishes with 1～8molL
-1The mixed liquid of alkali lye neutralization reaction to pH5.0～7.0, filter, filter cake is placed 75～90 ℃ of oven for drying, the Albendazole sulfone crude product;
3) with methyl-sulphoxide and water mixed solution as solvent with Albendazole sulfone crude product recrystallization 3～5 times, must Albendazole sulfone.
2, the chemical synthesis process of Albendazole sulfone according to claim 1 is characterized in that: the step 1) temperature of reaction is 70～90.
3, the chemical synthesis process of Albendazole sulfone according to claim 1 is characterized in that: the hydrogen peroxide amount of substance that is added in the step 1) is 4: 1 with the ratio of the amount of substance of albendazole; Begin to react 8h from adding hydrogen peroxide for the first time.
4, the chemical synthesis process of Albendazole sulfone according to claim 1 is characterized in that: step 2) used alkali lye is sodium hydroxide solution.
5, the chemical synthesis process of Albendazole sulfone according to claim 1 is characterized in that: the used methyl-sulphoxide aqueous solution of Albendazole sulfone crude product recrystallization in the step 3), methyl-sulphoxide and water are 5: 1～9: 1 by volume.
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| CN115073380A (en) * | 2022-04-13 | 2022-09-20 | 青海大学 | 2-amide substituted benzo five-membered nitrogen-containing heterocyclic compound and preparation method and application thereof |
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| CN115073380A (en) * | 2022-04-13 | 2022-09-20 | 青海大学 | 2-amide substituted benzo five-membered nitrogen-containing heterocyclic compound and preparation method and application thereof |
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