CN100586936C - Chemical synthesis of albendazole-sulfoxide - Google Patents
Chemical synthesis of albendazole-sulfoxide Download PDFInfo
- Publication number
- CN100586936C CN100586936C CN200710051367A CN200710051367A CN100586936C CN 100586936 C CN100586936 C CN 100586936C CN 200710051367 A CN200710051367 A CN 200710051367A CN 200710051367 A CN200710051367 A CN 200710051367A CN 100586936 C CN100586936 C CN 100586936C
- Authority
- CN
- China
- Prior art keywords
- albendazole
- sulfoxide
- reaction
- filter cake
- dinethylformamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A process for chemically synthesizing albendazole sulfoxide includes such steps as oxidizing reaction between albendazole, glacial acetic acid and H2O2 to obtain coarse albendazole sulfoxide, 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-sulfoxide.
Background technology
Albendazole-sulfoxide is that albendazole enters in the body after the metabolic product of first pass effect is metabolized to Albendazole sulfone then, and last metabolism is the amino sulfone (see figure 1) of albendazole-2-.Albendazole-sulfoxide is an albendazole anthelmintic main active ingredient.The development impact test of albendazole-sulfoxide on rat shows to have the toxicity (Committee for veterinary medical products Albendazole sulfoxide EMEA/MRL/094/96-FINAL.June.1996) of teratogenesis tire.So albendazole-sulfoxide is one of target metabolite that detects in the albendazole residue detection.Therefore prepare metabolism, the pharmacological toxicology and residual significant of albendazole-sulfoxide for the research albendazole.
Olivia etc. report with 0.5g albendazole and 0.403g sodium periodate at 0～5 ℃ of prepared in reaction albendazole-sulfoxide, gained albendazole-sulfoxide purity is 97%, 218～220 ℃ of (Studies on the SelectiveS-oxidation of Albendazole of melting range, Fenbendazole, Triclabendazole, and Other BenzimidazoleSulfidesJ.Mex.Chem.Soc; 2005,49 (4), 353-358).Reports such as Xie Jianhua are made oxygenant with sodium periodate, reaction 9～10h, gained albendazole-sulfoxide content is more than 98% (Xie Jianhua etc., the preparation of albendazole activity in vivo metabolite-sulfoxide. journal of Zhejiang university (medicine); Vol.31 No.1.2002).The Italy's Bari scholar of university report is an oxygenant with the tertbutyl peroxide, in diethyl tartrate solution ,-20 ℃ down reaction make albendazole-sulfoxide (A new synthesis of Albendazole-sulfoxide and antifungal activityof Albendazole metabolites.http: //www.eurom.it/medicina/pr/pr9_1-2_09.html).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, the rotation solvent evaporated, albendazole-sulfoxide (Li Yan etc., the synthetic and electrospray ionization mass spectrum analysis of Albendazole's sulphur oxidative metabolism product. Shenyang Pharmaceutical University's journal; Vol.19 No.6 Nov.2002P.413).Huang Lixin etc. report is with m-chloro aniline, oxalic acid etc. for raw material through the reaction of 8 steps make albendazole-sulfoxide (Huang Lixin etc., anti-echinococcus drug research albendazole metabolite and analogue thereof synthetic. Chinese Journal of Pharmaceuticals .1995.26 (2)).Reports such as Xin Wenfen are made oxygenant with chromium sesquioxide, and reaction finishes use chloroform extraction, and the water recrystallization makes albendazole-sulfoxide, yield be 65% (Xin Wenfen etc., the synthesizing of rycobendazole and rosickyite benzene miaow sulfone. health research .1990.19 (4)).
Above method existing problems have:
(1) reaction must be carried out at low temperature, and condition is harsh relatively.(2) other impurity is easily introduced in the adding of solid oxidizing agent.(3) reactions steps is many, and productive rate is low, and it is many and poisonous to consume reagent.(4) purification process complexity must be carried out column chromatography, complex operations such as rotary evaporation.(5) albendazole-sulfoxide is water insoluble, and the water recrystallization can't be realized.
Summary of the invention
The object of the invention is to overcome the shortcoming of existing method, provides that a kind of operation is simple, and reagent is cheap and easy to get, low toxicity or nontoxic, the synthetic method that gained albendazole-sulfoxide purity is high.
The objective of the invention is to reach by following measure:
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 15～50 ℃ of conditions, with 30% hydrogen peroxide of amount of substances such as slow dropping of dropping funnel and albendazole; Reaction finishes with 1～8molL
-1The mixed liquid of sodium hydroxide solution neutralization reaction to pH6.0～7.0, filter, filter cake places 30～50 ℃ of oven dryings, the albendazole-sulfoxide crude product.The albendazole-sulfoxide crude product is made solvent recrystallization 1～3 time with 70%～90% ethanol earlier, again with N, N-2-methylformamide and acetonitrile mixing solutions recrystallization 1～3 time, filter and use N, N-2-methylformamide flush cake, with the dehydrated alcohol flushing, filter cake places 30～50 ℃ of oven dryings to get albendazole-sulfoxide again.
Reaction of the present invention can be carried out under 15～50 ℃, and as preferred version, suitable temperature of reaction is 20～40 ℃.
Recrystallization scheme among the present invention is earlier with 70～90% ethanolic soln recrystallization 1～3 time.As preferred version earlier with 90% ethanolic soln recrystallization 2～3 times.
After product is used the ethanolic soln recrystallization among the present invention, use N again, N-2-methylformamide and acetonitrile mixing solutions recrystallization 1～3 time, as preferred version with N, N-2-methylformamide and acetonitrile mixing solutions (N, the N-2-methylformamide: acetonitrile=5: 1～9: 1, V/V) as solvent recrystallization 2～3 times again;
The present invention compared with prior art has following characteristics:
(1) consumption of accurate controlled oxidation agent reduces the generation of Albendazole sulfone to the full extent, is easy to purify; (2) reactions steps of the present invention is few, and average yield is up to more than 98%; (3) purification process is simple, need not cross complex operations such as post, rotary evaporation; (4) provide the recrystallization method of albendazole-sulfoxide, gained albendazole-sulfoxide purity reaches more than 99.5%, reaches the requirement of chromatographic grade reference substance.
Table 1 the present invention compared with the prior art
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-sulfoxide.
Fig. 3 is the infrared spectrogram (KBr) of albendazole-sulfoxide.
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram (DMSO-d of albendazole-sulfoxide
6).
Fig. 5 is that the nucleus magnetic resonance of albendazole-sulfoxide is talked spectrogram (DMSO-d
6).
Fig. 6 is the electrospray ionization mass spectrum figure (positive ion scanning) of albendazole-sulfoxide.
Fig. 7 is the electrospray ionization mass spectrum figure (negative ion scanning) of albendazole-sulfoxide.
Fig. 8 is the high-efficient liquid phase chromatogram of albendazole-sulfoxide.
Embodiment
Wash bright the present invention below by specific embodiment, but the present invention is not limited by these embodiment.
The 13.25g albendazole is added in the 250mL four-hole bottle, add the 70mL glacial acetic acid again, 15 ℃ are stirred to dissolving.With the slow Dropwise 5 .1mL30% of dropping funnel hydrogen peroxide, dropwise afterreaction 5h.Reaction finishes with 1molL
-1Sodium hydroxide solution neutralization reaction mixed solution to pH6.0, filter, filter cake is placed 30 ℃ of oven for drying.Get 13.76g albendazole-sulfoxide crude product.
With 10.02g albendazole-sulfoxide dissolving crude product in the there-necked flask that spherical condensation tube is housed, 90 ℃ of water-baths, add the 100mL70% ethanolic soln and be stirred to dissolving, suction filtration while hot, filtrate slowly cools to 4 ℃, place 5～10h after-filtration, filter cake gets recrystallization product of albendazole-sulfoxide with alcohol flushing, and product after drying, again with N, the acetonitrile solution of dinethylformamide (N, dinethylformamide: acetonitrile=5: 1, V/V) recrystallization is twice, filter cake is used earlier N respectively, alcohol flushing is used in the dinethylformamide flushing again, places 30 ℃ of oven for drying to get albendazole-sulfoxide 5.13g filter cake.
Embodiment 2
The 13.25g albendazole is added in the 250mL four-hole bottle, add the 70mL glacial acetic acid, 35 ℃ of water-baths are stirred to dissolving.With the slow Dropwise 5 .1mL30% of dropping funnel hydrogen peroxide, dropwise afterreaction 4h.Reaction finishes with 5molL
-1Sodium hydroxide solution neutralization reaction mixed solution to pH6.5, filter, filter cake is placed 40 ℃ of oven for drying.Get 13.85g albendazole-sulfoxide crude product.
With 10.12g albendazole-sulfoxide dissolving crude product in the there-necked flask that spherical condensation tube is housed, 90 ℃ of water-baths, add the 100mL85% ethanolic soln and be stirred to dissolving, suction filtration while hot, filtrate slowly cools to 4 ℃, behind the placement 5-10h, filters, the filter cake alcohol flushing, recrystallization product of albendazole-sulfoxide, product after drying, again with N, the acetonitrile solution of dinethylformamide (7: 1, V/V) recrystallization twice, and filter cake is used earlier N respectively, the dinethylformamide flushing, use alcohol flushing again, place 40 ℃ of oven for drying to get albendazole-sulfoxide 5.27g filter cake.
Embodiment 3
The 13.25g albendazole is added in the 250mL four-hole bottle, add the 70mL glacial acetic acid, 50 ℃ of water-baths are stirred to dissolving.With the slow Dropwise 5 .1mL30% of dropping funnel hydrogen peroxide, dropwise afterreaction 3h.Reaction finishes with 8molL
-1Sodium hydroxide solution be neutralized to pH7.0, filter, filter cake is placed 50 ℃ of oven for drying.Get 13.71g albendazole-sulfoxide crude product.
With 10.07g albendazole-sulfoxide dissolving crude product in the there-necked flask that spherical condensation tube is housed, 90 ℃ of water-baths, add the 100mL90% ethanolic soln and be stirred to dissolving, suction filtration while hot, filtrate slowly cools to 4 ℃, after placing 5-10h, filter, filter cake gets recrystallization product of albendazole-sulfoxide with alcohol flushing, product after drying, again with N, and the acetonitrile solution of dinethylformamide (9: 1, V/V) recrystallization is twice, filter cake is used earlier N respectively, alcohol flushing is used in the dinethylformamide flushing again, places 50 ℃ of oven for drying to get albendazole-sulfoxide 5.09g filter cake.
The raw materials used albendazole bulk drug of the present invention purity 〉=99%; Glacial acetic acid, 30% hydrogen peroxide, dehydrated alcohol, N, dinethylformamide, acetonitrile, sodium hydroxide are analytical pure; Water is distilled water.
Synthetic albendazole-sulfoxide of the present invention 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 melting range: 221-222 ℃ (decomposition).
The ultraviolet spectrogram of albendazole-sulfoxide (methyl alcohol): λ
MaxTwo absorption peaks in 223nm and 294nm 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-sulfoxide (KBr): 3339cm
-1The place is absorbed as by force-stretching vibration of NH-; 2965cm
-1, 2876 liang of stretching vibrations of locating to be respectively two methyl; 1730cm
-1The stretching vibration that is absorbed as C=O by force at place; 1651cm
-1The stretching vibration that is absorbed as C=N by force at place; 1592cm
-1And 1525cm
-1The skeletal vibration that is absorbed as phenyl ring by force at place; 1055cm
-1The stretching vibration that is absorbed as S=O by force at place.See Fig. 3.
Hydrogen nuclear magnetic resonance spectrogram (the DMSO-d of albendazole-sulfoxide
6): δ: 0.96 (3H, t, J=7.6Hz); 1.60 (2H, m, J=7.2Hz); 2.80 (2H, m, J=4.8Hz) 3.82 (3H, s); 7.34 (1H, f, J=1.6); 7.58 (1H, d, J=8.4); 7.74 (1H, s); 11.95 (2H, br, s).See Fig. 4.
Carbon-13 nmr spectra figure (the DMSO-d of albendazole-sulfoxide
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-sulfoxide (positive ion scanning): m/z281.6:[M]; M/z303.7:[M+Na]
+M/z319.7:[M+K]
+See Fig. 6.
The electrospray ionization mass spectrum figure of albendazole-sulfoxide (negative ion scanning): m/z248.1:[M-OCH
3-1]
+M/z280.1:[M-1]
+See Fig. 7.
The high-efficient liquid phase chromatogram of albendazole-sulfoxide: it is a simple spike that product detects through high performance liquid phase.See Fig. 8.
The elemental analyser detected result of albendazole-sulfoxide is as follows: each element percentage composition Error Absolute Value all is no more than 0.5%
Table 2 synthetic albendazole-sulfoxide of the present invention results of elemental analyses
Claims (1)
1, a kind of chemical synthesis process of albendazole-sulfoxide, its step is as follows:
1) in reaction flask, press amount of substance and volume ratio 0.05mol: 70mL and add albendazole and glacial acetic acid, under 20～40 ℃ of conditions of temperature of reaction, be stirred to dissolving, slowly dripping concentration with amount of substance such as albendazole with dropping funnel is 30% hydrogen peroxide, the reaction times timing is from dropwising reaction 3～5h; The reaction finish reaction mixture;
2) with 1～8molL
-1Sodium hydroxide solution conditioned reaction pH of mixed to 6.0～7.0, product is separated out fully, filters, filter cake places 30～50 ℃ of oven dryings, the albendazole-sulfoxide crude product;
3) earlier make solvent to albendazole-sulfoxide crude product recrystallization 1～3 time with 70%～90% ethanol, again with N, dinethylformamide and acetonitrile are 5: 1～9: 1 mixing solutions recrystallizations 1～3 time by volume, filter and use N, the dinethylformamide flushing, with the dehydrated alcohol flushing, filter cake places 30～50 ℃ of oven dryings to get albendazole-sulfoxide again.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710051367A CN100586936C (en) | 2007-01-24 | 2007-01-24 | Chemical synthesis of albendazole-sulfoxide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710051367A CN100586936C (en) | 2007-01-24 | 2007-01-24 | Chemical synthesis of albendazole-sulfoxide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101029030A CN101029030A (en) | 2007-09-05 |
| CN100586936C true CN100586936C (en) | 2010-02-03 |
Family
ID=38714599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200710051367A Expired - Fee Related CN100586936C (en) | 2007-01-24 | 2007-01-24 | Chemical synthesis of albendazole-sulfoxide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100586936C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107935939A (en) * | 2017-11-09 | 2018-04-20 | 华中药业股份有限公司 | A kind of process for purification of albendazole |
-
2007
- 2007-01-24 CN CN200710051367A patent/CN100586936C/en not_active Expired - Fee Related
Non-Patent Citations (9)
| Title |
|---|
| Studies on the Selective S-oxidation ofAlbendazole,Fenbendazole,Triclabendazole,and OtherBenzimidazole Sulfides. Olivia Soria-Arteche,et al.J.Mex.Chem.Soc,Vol.49 No.4. 2005 |
| Studies on the Selective S-oxidation ofAlbendazole,Fenbendazole,Triclabendazole,and OtherBenzimidazole Sulfides. Olivia Soria-Arteche,et al.J.Mex.Chem.Soc,Vol.49 No.4. 2005 * |
| 丙基乙烯基亚砜的合成. 龚张水等.浙江大学学报（自然科学版），第25卷第6期. 1991 |
| 反应温度对吡唑硫醚衍生物选择性氧化的影响. 吴彦超等.化学试剂，第25卷第6期. 2003 |
| 阿苯哒唑硫氧化代谢产物的合成及电喷雾质谱分析. 李岩等.沈阳药科大学学报，第19卷第16期. 2002 |
| 阿苯哒唑硫氧化代谢产物的合成及电喷雾质谱分析. 李岩等.沈阳药科大学学报，第19卷第6期. 2002 |
| 阿苯哒唑硫氧化代谢产物的合成及电喷雾质谱分析. 李岩等.沈阳药科大学学报，第19卷第16期. 2002 * |
| 阿苯达唑体内活性代谢物－亚砜的制备. 谢剑华等.浙江大学学报（医学版），第31卷第1期. 2002 |
| 阿苯达唑体内活性代谢物－亚砜的制备. 谢剑华等.浙江大学学报(医学版)，第31卷第1期. 2002 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101029030A (en) | 2007-09-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ishikawa et al. | Dimerization of indole derivatives with hypervalent iodines (III): a new entry for the concise total synthesis of rac-and meso-chimonanthines | |
| WO2010022690A2 (en) | A method of preparation of highly pure vildagliptin | |
| CN109633041B (en) | Method for measuring dihydrotestosterone in medicine by derivatization HPLC method | |
| CN101279901A (en) | Honokiol series derivates, preparation and use thereof | |
| Kamiński et al. | Synthesis, physicochemical and anticonvulsant properties of new N-phenylamino derivatives of 2-azaspiro [4.4] nonane-and [4.5] decane-1, 3-diones: Part V | |
| CN106153798B (en) | It is a kind of to be used to analyze the purposes for doing reference standard about the HPLC methods and these impurity of material for Buddhist nun's preparation according to Shandong for Buddhist nun and according to Shandong | |
| CN100586936C (en) | Chemical synthesis of albendazole-sulfoxide | |
| CN106153797B (en) | It is a kind of to replace Buddhist nun's preparation Related substance method according to Shandong for Buddhist nun and according to Shandong | |
| Lehmann et al. | Design, parallel synthesis and SAR of novel urotensin II receptor agonists | |
| Flídrová et al. | Anion complexation by calix [4] arene–TTF conjugates | |
| CA2842495C (en) | 5,6,7,8-tetrahydro-6-[n,n-bis[(2-thienyl)ethyl]]amino-1-naphthol, and preparing method and use thereof | |
| CN104280495A (en) | Method for detecting validamycin A in water and rice plants | |
| Zhu et al. | Identification and characterization of related substances in EVT-401 by hyphenated LC–MS techniques | |
| CN100551914C (en) | The chemical synthesis process of Albendazole sulfone | |
| Ivanova et al. | Functionalized Ergot-alkaloids as potential dopamine D3 receptor agonists for treatment of schizophrenia | |
| CN109239253A (en) | A kind of efficient liquid phase detection method of the impurity of Abacavir | |
| CN104122342A (en) | Sertraline hydrochloride intermediates (+/-)-tetralone and chiral chromatographic splitting method thereof | |
| CN100551913C (en) | The chemical synthesis process of the amino sulfone of albendazole-2- | |
| CN112209882A (en) | Levoornidazole impurity C and preparation method and application thereof | |
| CN103910812B (en) | Beta-cyclodextrin derivative and its preparation method and many ureas key cyclodextrin chiral prepared therefrom are fixed phase | |
| Rao et al. | Isolation and characterization of a potential process related impurity of phenazopyridine HCl by preparative HPLC followed by MS–MS and 2D-NMR spectroscopy | |
| CN105330563B (en) | For the reference compound in the control of Kukoamine B quality | |
| BRPI0613680A2 (en) | thiocolchicoside analogues, pharmaceutical compositions and their uses | |
| CN109836367A (en) | A method of cis- Glimepiride is prepared with preparative liquid chromatography separation | |
| CN103804366A (en) | Lafutidine crystal compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100203 Termination date: 20200124 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |