CN105585533A - A preparing method of albendazole - Google Patents
A preparing method of albendazole Download PDFInfo
- Publication number
- CN105585533A CN105585533A CN201410567647.2A CN201410567647A CN105585533A CN 105585533 A CN105585533 A CN 105585533A CN 201410567647 A CN201410567647 A CN 201410567647A CN 105585533 A CN105585533 A CN 105585533A
- Authority
- CN
- China
- Prior art keywords
- nitroaniline
- thiocyanogen
- albendazole
- methyl
- preparation
- 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.)
- Pending
Links
- 0 *C(C=CCC(N=C=S)[N+]([O-])=O)=C Chemical compound *C(C=CCC(N=C=S)[N+]([O-])=O)=C 0.000 description 6
- XJAXNSOWDPIYHF-UHFFFAOYSA-N Nc(ccc(N=C=S)c1)c1N Chemical compound Nc(ccc(N=C=S)c1)c1N XJAXNSOWDPIYHF-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A preparing method of albendazole is disclosed. The method adopts 2-nitro-4-thiocyanatoaniline as a raw material, and includes salifying with an aqueous sodium hydroxide solution in an n-propanol solvent under nitrogen protection, reacting with bromopropane, and separating to obtain an n-propanol solution of 2-nitro-4-(propylthio)aniline, and therefore a problem that an impurity that is methyl 5-(methylthio)benzoimidazol-2-yl carbamate in products is high in content because steps of salifying in methanol with sodium sulfide and then reacting with bromopropane in processes at present is overcome. A technique of reducing the 2-nitro-4-(propylthio)aniline by utilizing hydrazine hydrate is adopted to replace a technique of reducing with sodium sulfide at present, thus overcoming a problem that sulfur-containing waste water is high in amount and difficult to treat in the sodium sulfide reduction technique. A methanol solution of methyl O-methyl isourea formate is adopted as a ring closing agent, thus overcoming a problem that waste water is high in amount in processes at present when cyanamide and an aqueous methyl formate solution are adopted as ring closing agents. The method is advantaged by a small waste water amount, capability of being environmental friendly, high product purity, and the like.
Description
Technical field
Invention relates to a kind of preparation method of albendazole, belongs to broad-spectrum de-worming medicine preparation field.
Background technology
Albendazole ([5-(rosickyite base)-1H-benzimidazolyl-2 radicals-yl] methyl carbamate)
Broad-spectrum de-worming medicine (structure is as follows) as a kind of high-efficiency low-toxicity:Clinically can be used for ascarifuge, pinworm, tapeworm, whipworm, hookworm, excrement strongylid etc. In vivo metabolism be sulfoxide type orAfter sulfone class, suppress the absorption of parasite to glucose, cause polypide glycogen depletion, or suppress fumaric reductase systemSystem, hinders the generation of ATP, and parasite cannot be survived and breed. And as a kind of wide spectrum expelling parasite of high-efficiency low-toxicityMedicine, for future, has wide market and development space.
Summary of the invention
The object of the invention is large for vulcanized sodium reduction technique sulfur-containing waste water amount, environment is poor, the deficiency of poor product qualityA kind of preparation method of high-purity albendazole is provided, and the method wastewater flow rate is little, environmental friendliness, and product purity is high, suitableShould suitability for industrialized production.
The technical solution that realizes the object of the invention is: a kind of preparation method of albendazole, comprises the following steps:
The first step: under nitrogen protection, stir and add 4-thiocyanogen-2-nitroaniline in organic solvent, drip liquid caustic sodaReaction generates salt, then drips bromopropane reaction, through separating preparation 4-rosickyite base-2-nitroaniline;
Second step: 4-rosickyite base-2-nitroaniline, in methanol solvate, turns to catalyst with ferric trichloride or hydrogen-oxygen, livesProperty charcoal is carrier, prepares 4-rosickyite base o-phenylenediamine with hydrazine hydrate reduction;
The 3rd step: 4-rosickyite base o-phenylenediamine, in methanol solvate, makees catalyst with acid, by O-methyl-isourea formic acid firstEster is made cyclizing agent, prepares crude product;
The 4th step: crude product obtains albendazole fine work through refining methanol.
Organic solvent described in the first step be in methyl alcohol, ethanol, isopropyl alcohol and normal propyl alcohol any one, preferably positive thirdAlcohol; Liquid caustic soda is NaOH, and the temperature of dropping liquid alkali reaction is 30-40 DEG C, 3～4 hours reaction time, liquid caustic soda withThe mol ratio of 4-thiocyanogen-2-nitroaniline is 2.0:1～3.0:1; The temperature that drips bromopropane reaction is 50-60 DEG C,In 2～3 hours reaction time, the mol ratio of N-Propyl Bromide and 4-thiocyanogen-2-nitroaniline is 1.1 :～1.5:1; Separate temperatureDegree is 50～60 DEG C.
Catalyst ferric trichloride consumption described in second step is 0.8% of 4-thiocyanogen-2-nitroaniline weight(W/W), catalyst sodium hydroxide concentration is 0.5% (W/W) of 4-thiocyanogen-2-nitroaniline weight, active carbonConsumption is 5% (W/W) of 4-thiocyanogen-2-nitroaniline weight, the rubbing of hydrazine hydrate and 4-thiocyanogen-2-nitroanilineYou are 3.0:1～4.0:1, and reaction temperature is for refluxing.
Acid described in the 3rd step is formic acid or acetic acid, preferably acetic acid; Acid with the mol ratio of 4-thiocyanogen-2-nitroaniline is2.5:1～3.5:1; The mol ratio of O-methyl-isourea methyl carbamate and 4-thiocyanogen-2-nitroaniline is 1.2:1～1.5:1,5 hours reaction time.
Extraction temperature described in the 4th step is 20～30 DEG C.
Compared with prior art, its advantage is in the present invention:
(1) solved existing technique and caused again 5-first in product with bromopropane reaction with vulcanized sodium salify in methyl alcoholThe large problem of sulfenyl benzimidazolyl-2 radicals-methyl carbamate impurity.
(2) adopt hydrazine hydrate reduction 4-rosickyite base-2-nitroaniline technology, substitute existing vulcanized sodium reduction technique, separateLarge, the unmanageable problem of sulfur-containing waste water amount in vulcanized sodium reduction technique of having determined.
(3) do cyclizing agent with O-methyl-isourea methyl formate methanol solution and solved current technology cyanamide and formic acid firstAqueous solution of ester does the large problem of closed loop agent wastewater flow rate.
(4) the product typical purity of the present invention after refining is 98.9-99.6%, and productive rate can reach 60-70% conventionally. ItWhite powder, HPLC purity >=99.0%, content 98.7-99.6%, residue≤0.15%, loss on drying≤0.5%,Meet USP standard.
Detailed description of the invention
Non-limiting real case is to the detailed description of the invention below.
Synthetic chemistry equation of the present invention:
Example 1
The first step, the preparation (replacement, condensation) of 4-rosickyite base-2-nitroaniline
Fill N2Under condition, in reaction bulb, throw pure 4-thiocyanogen-2-nitroaniline 39.0g (0.2mol), normal propyl alcohol100ml, water 30ml, stir, and 30-40 DEG C drip 30% sodium hydroxide solution 53.3g (0.40mol) approximately 1 hour,Drip insulation 2 hours, be heated to 50 DEG C, drip the about 0.5h of N-Propyl Bromide 27.0g (0.22mol), dripComplete continuation insulation 2 hours, after finishing, closes and fills N2Protection, 50-60 DEG C of layerings, discards waste water layer, upper strataRufous liquid, is the normal propyl alcohol solution of 4-rosickyite base-2-nitroaniline.
Second step, the preparation (reduction) of 4-rosickyite base o-phenylenediamine
In reaction bulb, drop into rufous liquid in the first step (4-rosickyite base-2-nitroaniline), heat up, distill positive thirdAlcohol, after having steamed, adds 100ml methyl alcohol after cooling, throw 2.0g active carbon, 0.3g ferric trichloride, 0.2g hydroxideSodium, is heated to backflow, the lower about 1h of hydrazine hydrate 37.8g (0.60mol) that slowly drips that refluxes, and lower insulation refluxes2.5h, cooling, filters, and methyl alcohol filter wash cake is the methanol solution of 4-rosickyite base o-phenylenediamine.
The 3rd step, crude product albendazole (cyclization)
In reaction bulb, drop into second step rufous liquid (4-rosickyite base o-phenylenediamine methanol solution), heat up, decompressionDistillating carbinol to 110 DEG C, cooling, adds new methyl alcohol 100ml, stirs, and adds EDTA0.2g, acetic acid 36.0g(0.6mol), the methanol solution 63.4g (0.24mol) of 50% 0-methyl-isourea methyl carbamate, heating, is warming up to backStream, backflow 5h, fills N2Borehole cooling to 15 DEG C following filtration. Obtain [5-(rosickyite base)-1H-benzimidazolyl-2 radicals-yl] carbamic acidMethyl esters, is albendazole crude product, about 40g.
The 4th step, fine work albendazole
In reaction bulb, drop into, drop into crude product 40g, add methyl alcohol 120ml, 20～30 DEG C are stirred 2～2 hours, filter,The washing of 100ml pure water, 80～95 DEG C of filter cakes are dry, obtain albendazole 33g,Yield 62.3%, purity 99.2%, content 99.12%, fusing point 207-208 DEG C, loss on drying 0.3%, residue 0.1%.
Example 2
The first step, the preparation (replacement, condensation) of 4-rosickyite base-2-nitroaniline
Fill N2Under condition, in reaction bulb, throw pure 4-thiocyanogen-2-nitroaniline 39.0g (0.2mol), normal propyl alcohol100ml, water 30ml, stir, and 30-40 DEG C drip 30% sodium hydroxide solution 80g (0.60mol) approximately 1 hour,Drip insulation 2 hours, be heated to 50 DEG C, drip the about 0.5h of N-Propyl Bromide 37.0g (0.30mol), dripComplete continuation insulation 2 hours, after finishing, closes and fills N2Protection, 50-60 DEG C of layerings, discards waste water layer, upper strataRufous liquid, is the normal propyl alcohol solution of 4-rosickyite base-2-nitroaniline.
Second step, the preparation (reduction) of 4-rosickyite base o-phenylenediamine
In reaction bulb, drop into rufous liquid in the first step (4-rosickyite base-2-nitroaniline), heat up, distill positive thirdAlcohol, after having steamed, adds 100ml methyl alcohol after cooling, throw 2.0g active carbon, 0.3g ferric trichloride, 0.2g hydroxideSodium, is heated under backflow, the lower about 1h of hydrazine hydrate 50g (0.80mol) that slowly drips that refluxes, and lower insulation refluxes2.5h, cooling, filters, and methyl alcohol filter wash cake is the methanol solution of 4-rosickyite base o-phenylenediamine.
The 3rd step, crude product albendazole (cyclization)
In reaction bulb, drop into second step rufous liquid (4-rosickyite base o-phenylenediamine methanol solution), heat up, decompressionDistillating carbinol to 110 DEG C, cooling, adds new methyl alcohol 100ml, stirs, and adds EDTA0.2g, acetic acid 36.0g(0.6mol), the methanol solution 79.3g (0.30mol) of 50% 0-methyl-isourea methyl carbamate, heating, is warming up to backStream, backflow 5h, fills N2Borehole cooling to 15 DEG C following filtration. Obtain [5-(rosickyite base)-1H-benzimidazolyl-2 radicals-yl] carbamic acidMethyl esters, is albendazole crude product, about 42g.
The 4th step, fine work albendazole
In reaction bulb, drop into, drop into crude product 42g, add methyl alcohol 120ml, 20～30 DEG C are stirred 2～2 hours, filter,The washing of 100ml pure water, 80～95 DEG C of filter cakes are dry, obtain albendazole 33.5g,Yield 63.2%, purity 99.3%, content 99.25%, fusing point 207.3-208.5 DEG C, loss on drying 0.2%, residue 0.1%.
Example 3
The first step, the preparation (replacement, condensation) of 4-rosickyite base-2-nitroaniline
Fill N2Under condition, in reaction bulb, throw pure 4-thiocyanogen-2-nitroaniline 39.0g (0.2mol), normal propyl alcohol100ml, water 30ml, stir, and 30-40 DEG C drip 30% sodium hydroxide solution 66.7g (0.50mol) approximately 1 hour,Drip insulation 2 hours, be heated to 50 DEG C, drip the about 0.5h of N-Propyl Bromide 32.0g (0.26mol), dripComplete continuation insulation 2 hours, after finishing, closes and fills N2Protection, 50-60 DEG C of layerings, discards waste water layer, upper strataRufous liquid, is the normal propyl alcohol solution of 4-rosickyite base-2-nitroaniline.
Second step, the preparation (reduction) of 4-rosickyite base o-phenylenediamine
In reaction bulb, drop into rufous liquid in the first step (4-rosickyite base-2-nitroaniline), heat up, distill positive thirdAlcohol, after having steamed, adds 100ml methyl alcohol after cooling, throw 2.0g active carbon, 0.3g ferric trichloride, 0.2g hydroxideSodium, is heated to backflow, the lower about 1h of hydrazine hydrate 43.8g (0.70mol) that slowly drips that refluxes, and lower insulation refluxes2.5h, cooling, filters, and methyl alcohol filter wash cake is the methanol solution of 4-rosickyite base o-phenylenediamine.
The 3rd step, crude product albendazole (cyclization)
In reaction bulb, drop into second step rufous liquid (4-rosickyite base o-phenylenediamine methanol solution), heat up, decompressionDistillating carbinol to 110 DEG C, cooling, adds new methyl alcohol 100ml, stirs, and adds EDTA0.2g, acetic acid 36.0g(0.6mol), the methanol solution 79.3g (0.30mol) of 50% 0-methyl-isourea methyl carbamate, heating, is warming up to backStream, backflow 5h, fills N2Borehole cooling to 15 DEG C following filtration. Obtain [5-(rosickyite base)-1H-benzimidazolyl-2 radicals-yl] carbamic acidMethyl esters, is albendazole crude product, about 43g.
The 4th step, fine work albendazole
In reaction bulb, drop into, drop into crude product 43g, add methyl alcohol 120ml, 20～30 DEG C are stirred 2～2 hours, filter,The washing of 100ml pure water, 80～95 DEG C of filter cakes are dry, obtain albendazole 34.5g,Yield 65.1%, purity 99.4%, content 99.35%, fusing point 207.5-208.9 DEG C, loss on drying 0.4%, residue 0.1%.
Claims (5)
1. a preparation method for albendazole, is characterized in that, comprises the following steps:
The first step: under nitrogen protection, stir and add 4-thiocyanogen-2-nitroaniline in organic solvent, dropping liquid alkali reaction generates salt, then drips bromopropane reaction, through separating preparation 4-rosickyite base-2-nitroaniline;
Second step: 4-rosickyite base-2-nitroaniline, in methanol solvate, turns to catalyst with ferric trichloride or hydrogen-oxygen, and active carbon is carrier, prepares 4-rosickyite base o-phenylenediamine with hydrazine hydrate reduction;
The 3rd step: 4-rosickyite base o-phenylenediamine, in methanol solvate, makees catalyst with acid, makes cyclizing agent with O-methyl-isourea methyl formate, prepares crude product;
The 4th step: crude product obtains albendazole fine work through refining methanol.
2. the preparation method of albendazole as claimed in claim 1, is characterized in that, the organic solvent described in the first step be in methyl alcohol, ethanol, isopropyl alcohol and normal propyl alcohol any one; Liquid caustic soda is NaOH, and the temperature of dropping liquid alkali reaction is 30-40 DEG C, and in 3 ~ 4 hours reaction time, the mol ratio of liquid caustic soda and 4-thiocyanogen-2-nitroaniline is 2.0:1 ~ 3.0:1; The temperature that drips bromopropane reaction is 50-60 DEG C, and in 2 ~ 3 hours reaction time, the mol ratio of N-Propyl Bromide and 4-thiocyanogen-2-nitroaniline is 1.1: ~ 1.5:1; Separation temperature is 50 ~ 60 DEG C.
3. the preparation method of albendazole as claimed in claim 1, it is characterized in that, catalyst ferric trichloride consumption described in second step is 0.8% of 4-thiocyanogen-2-nitroaniline weight, catalyst sodium hydroxide concentration is 0.5% of 4-thiocyanogen-2-nitroaniline weight, activated carbon dosage is 5% of 4-thiocyanogen-2-nitroaniline weight, hydrazine hydrate and 4-thiocyanogen-2-nitroaniline mole be 3.0:1 ~ 4.0:1, reaction temperature is for refluxing.
4. the preparation method of albendazole as claimed in claim 1, is characterized in that, the acid described in the 3rd step is formic acid or acetic acid; Acid is 2.5:1 ~ 3.5:1 with the mol ratio of 4-thiocyanogen-2-nitroaniline; The mol ratio of O-methyl-isourea methyl carbamate and 4-thiocyanogen-2-nitroaniline is 1.2:1 ~ 1.5:1,5 hours reaction time.
5. the preparation method of albendazole as claimed in claim 1, is characterized in that, the extraction temperature described in the 4th step is 20 ~ 30 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410567647.2A CN105585533A (en) | 2014-10-22 | 2014-10-22 | A preparing method of albendazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410567647.2A CN105585533A (en) | 2014-10-22 | 2014-10-22 | A preparing method of albendazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105585533A true CN105585533A (en) | 2016-05-18 |
Family
ID=55925475
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410567647.2A Pending CN105585533A (en) | 2014-10-22 | 2014-10-22 | A preparing method of albendazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105585533A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106629779A (en) * | 2016-08-18 | 2017-05-10 | 连云港市亚晖医药化工有限公司 | Method for recycling sodium bromide and sodium thiocyanate |
| CN109400537A (en) * | 2019-01-03 | 2019-03-01 | 山东国邦药业股份有限公司 | A kind of synthetic method of albendazole |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4152522A (en) * | 1978-01-03 | 1979-05-01 | Ethyl Corporation | Process for the preparation of 2-benzimidazole carbamates |
| CN101270091A (en) * | 2008-04-23 | 2008-09-24 | 常州亚邦齐晖医药化工有限公司 | Method for preparing albendazole |
| CN101270068A (en) * | 2008-04-23 | 2008-09-24 | 常州亚邦齐晖医药化工有限公司 | Method for preparing 2-nitryl-4-propylthioaniline |
-
2014
- 2014-10-22 CN CN201410567647.2A patent/CN105585533A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4152522A (en) * | 1978-01-03 | 1979-05-01 | Ethyl Corporation | Process for the preparation of 2-benzimidazole carbamates |
| CN101270091A (en) * | 2008-04-23 | 2008-09-24 | 常州亚邦齐晖医药化工有限公司 | Method for preparing albendazole |
| CN101270068A (en) * | 2008-04-23 | 2008-09-24 | 常州亚邦齐晖医药化工有限公司 | Method for preparing 2-nitryl-4-propylthioaniline |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106629779A (en) * | 2016-08-18 | 2017-05-10 | 连云港市亚晖医药化工有限公司 | Method for recycling sodium bromide and sodium thiocyanate |
| CN106629779B (en) * | 2016-08-18 | 2018-05-18 | 连云港市亚晖医药化工有限公司 | A kind of method for recycling sodium bromide and sodium sulfocyanate |
| CN109400537A (en) * | 2019-01-03 | 2019-03-01 | 山东国邦药业股份有限公司 | A kind of synthetic method of albendazole |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101357911B (en) | Method for synthesizing (z)-2-(alpha-methoxyimino)furan-ammonium acetate | |
| CN103664561B (en) | The preparation method of a kind of metconazole and intermediate thereof | |
| CN103204823B (en) | Method for purifying 1, 2-benzisothiazole-3-ketone | |
| CN1915976B (en) | Method for preparing 5- chlorine -4 hydroxy -2(1II)- pyridone and intermediate | |
| CN105585533A (en) | A preparing method of albendazole | |
| CN105669642B (en) | Preparation method of loflupridine hydrochloride | |
| CN105037236B (en) | Rui Boxini intermediates and preparation method thereof | |
| CN104650093B (en) | Synthesis method of sildenafil analog | |
| CN102964280B (en) | Preparation method of toluenesulfonylurea | |
| CN105481856A (en) | Preparation method of palipefidone | |
| CN101450951B (en) | Method for producing topiramate | |
| CN100537552C (en) | Method for preparing Repaglinide | |
| CN103360330A (en) | Synthetic method for homopiperazine | |
| WO2017133283A1 (en) | Composite catalyst and application thereof | |
| CN106397347A (en) | Method for producing irganox 565 | |
| CN104557877B (en) | A kind of avanaphil intermediate and its preparation method and application | |
| CN106905234B (en) | A method of the synthesis chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4- | |
| CN102127081A (en) | Preparation method of adenine | |
| CN105523995A (en) | Preparation method for malaridine intermediate 2-methoxy-5-aminopyridine | |
| CN101696185B (en) | Synthesizing method of 6-nitro-S-(-)-indoline-2-carboxylic acid | |
| CN113754650A (en) | High-selectivity synthesis method of rosuvastatin calcium intermediate | |
| CN107739343B (en) | Environment-friendly process for producing quizalofop-p-ethyl | |
| CN105111193B (en) | A kind of preparation method of Lapatinib | |
| CN105061327A (en) | Synthetic method of long-acting sulfonamide | |
| CN105272937A (en) | Production method of hydrochlorothiazide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160518 |
|
| RJ01 | Rejection of invention patent application after publication |