CN102675145B - Preparation method of guaiacol sulfonate doxycycline - Google Patents
Preparation method of guaiacol sulfonate doxycyclineDownload PDFInfo
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- CN102675145B CN102675145BCN 201210128419CN201210128419ACN102675145BCN 102675145 BCN102675145 BCN 102675145BCN 201210128419CN201210128419CN 201210128419CN 201210128419 ACN201210128419 ACN 201210128419ACN 102675145 BCN102675145 BCN 102675145B
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Abstract
Description
Technical field
The present invention relates to a kind of preparation method of Guaiacolsulfonic acid Vibravenos, belong to the veterinary drug technical field.
Background technology
Respiratory disease of chicken is the common a kind of illness of poultry, and its sickness rate is high, and range of infection is wide, and velocity of propagation is fast.Under the large-scale cultivation condition, the many reasons such as virus, bacterium, mycoplasma, immunosuppression disease pathogen and adverse environmental factors all can cause respiratory tract disease or polyinfection.The respiratory tract disease that this multi-pathogenesis causes is more common than Simple infection, and the diagnosis difficulty strengthens.
At present, be usually used in treating and cough the medicine of breathing heavily and mainly contain tetracyclines, quinolones and Macrolide.Tetracyclines and quinolones mainly have certain effect to mycoplasma and intestinal bacteria; Macrocyclolactone lactone kind medicine mainly has special efficacy to mycoplasma, and wherein tylosin can stop intestinal bacteria to the adhesion of respiratory tract.But because the mass-producing of livestock and poultry cultivation; cause stocking density excessive; the factors such as ventilation effect is bad, so that respiratory tract disease or the complication followed more and more easily occur, the too high dosage of medicine frequency is excessive to have caused livestock and poultry that most of medicines have all been produced resistance.Therefore, a kind ofly can effectively alleviate the cough shape, reduce the medicine of mucus secretion and demand exploitation urgently.
Vibravenos (Doxycycline Hyclate) belongs to tetracyclines Broad spectrum antibiotics class, clinical mycoplasmosis, colibacillosis, salmonellosis, Bacillus pasteurii disease and the psittacosis etc. that are mainly used in treating livestock and poultry.Methyl catechol is a kind of important fine-chemical intermediate, is widely used in the synthetic of medicine, spices and dyestuff.It can be used to synthetic Phenylsulfonic acid methyl catechol (thiocol), as local anesthetic or sanitas, can also eliminate the phlegm and treat maldigestion.The widespread use in people's medicine of its derived products thiocol is mainly used in the treatment of chronic bronchitis.The Guaiacolsulfonic acid Vibravenos, chemical name: 6-methyl-4-(dimethylamino)-3,5,10,12,12a-penta hydroxy group-1,11-dioxo-Isosorbide-5-Nitrae, 4a, 5,5a, 6,11,12a-octahydro-2-tetracene methane amide Guaiacolsulfonic acid salt half ethanol semihydrate; Have the broad-spectrum antibacterial effect, its bacteriostatic activity is better than terramycin, livestock and poultry respiratory mucus is too much stopped up tracheae evident in efficacy.When synthesizing guaiacol sulfonic acid Vibravenos, at first to prepare Guaiacolsulfonic acid salt, sulfonation reaction is reversible reaction, industrial production often adopts and adds the abundant reaction that the excessive vitriol oil guarantees raw material, therefore can remain excessive sulfuric acid, this has brought inconvenience for the technique subsequent disposal, produces this and brings environmental pollution thereby strengthened.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of preparation method of Guaiacolsulfonic acid Vibravenos.
Technical scheme of the present invention is as follows:
A kind of preparation method of Guaiacolsulfonic acid Vibravenos comprises the steps:
(1) methyl catechol is joined in the reaction vessel, add the vitriol oil of massfraction 95～98%, the limit edged stirs, and water-bath 60-100 ℃, reaction times 1-3.5 hour;
(2) reaction treats that solution is cooled to room temperature after complete, adds Vibravenos, stirring reaction under the room temperature; The tlc detection reaction is carried out degree;
The mol ratio of the above raw material is methyl catechol: the vitriol oil: Vibravenos=1～2: 0.5～1: 1～2.
(3) step (2) reaction complete after, add and the isopyknic organic solvent of reaction solution, the limit edged stirs, and behind the crystallization, filters, filtrate is used organic solvent washing 2～3 times again, with filtering the solid of gained, removes organic solvent under reduced pressure, and get final product.Through high effective liquid chromatography for measuring content, Guaiacolsulfonic acid Vibravenos product purity 〉=99%.
Preferred according to the present invention, the mol ratio of described raw material is methyl catechol: the vitriol oil: Vibravenos=1: 0.7～0.9: 1.
Further preferred, methyl catechol: the vitriol oil: Vibravenos mol ratio=1: 0.85: 1.
Preferred according to the present invention, the used vitriol oil of step (1) is massfraction 98% sulfuric acid.
Preferred according to the present invention, step (1) temperature of reaction is 65～80 ℃ of water-baths, reacts 1～1.5 hour.
Preferred according to the present invention, the described tlc detection reaction of step (2) is carried out degree and is, after adding Vibravenos and after it is dissolved fully, every 10 minute hour plate once, launch with the ammonium acetate of 9: 1 volume ratios-acetonitrile, the iodine colour developing shows that no longer Vibravenos raw material spot is considered as reaction and finishes.
Preferred according to the present invention, the described organic solvent of step (3) is propyl carbinol, trichloromethane, methylene dichloride or acetonitrile.Further preferred, the described organic solvent of step (3) is propyl carbinol.
The characteristics of the inventive method: the present invention is take the vitriol oil as sulfonated reagent, and preferred suitable usage ratio, and after the methyl catechol sulfonation reaction, remaining sulfuric acid is without separation, and direct and Vibravenos carries out salt-forming reaction.After end reaction is complete, adopt the method separation and purification Guaiacolsulfonic acid Vibravenos of crystallization.Gained Guaiacolsulfonic acid Vibravenos product purity is more than 99%.
Preparing the Guaiacolsulfonic acid Vibravenos by the inventive method, to have preparation technology simple, the characteristics that environmental pollution is little.After the separation and purification of reaction surplus stock process, reusable edible.The inventive method can effectively simplify subsequent disposal and assurance reacts completely, and the product yield is high.
Description of drawings
Fig. 1 is the high-efficient liquid phase chromatogram of embodiment 1 product.Ordinate zou is voltage (mV), X-coordinate be the time (minute), peak 1 is the solvent impurity peak, peak 2 is Guaiacolsulfonic acid Vibravenos peaks.
Fig. 2 is the high-efficient liquid phase chromatogram of embodiment 2 products.Ordinate zou is voltage (mV), X-coordinate be the time (minute), peak 1 is the solvent impurity peak, peak 2 is Guaiacolsulfonic acid Vibravenos peaks.
Embodiment
The invention will be further described below in conjunction with embodiment, but be not limited to this.All raw materials, reagent are commercial product among the embodiment.Wherein vitriol oil mass concentration is 98%.
The experiment condition of product high effective liquid chromatography for measuring is as follows among the embodiment:
Material: Hyper 0DS2 C18, flow velocity: 1.0ml/min;
Moving phase: 0.05mol/l ammonium oxalate solution-dimethyl formamide-0.2mol/l ammonium dibasic phosphate solution (65: 30: 5);
Pressure: 14.0MPa, column length: 250mm, detector: UV280nm, post footpath: 4.6mm, sample size: 20 μ l.
Embodiment 1:
The 123.2g methyl catechol is joined in the round-bottomed flask, slowly add the 45ml vitriol oil again, the limit edged stirs, and 80 ℃ of water-baths were reacted 1 hour.React and treat that solution is cooled to room temperature after complete, add again 515 gram Vibravenoss, stirring reaction under the room temperature.After adding Vibravenos and it is dissolved fully,, launch iodine colour developing, detection reaction progress every 10 minute hour plate with ammonium acetate-acetonitrile (9: 1).React and add isopyknic propyl carbinol after complete, the limit edged stirs, and behind the crystallization, filters, and filtrate is washed with propyl carbinol again.After washing 3 times, will filter the crystal of gained, evaporated under reduced pressure namely gets the Guaiacolsulfonic acid Vibravenos.Through high effective liquid chromatography for measuring content, product purity is 99.0%.
Embodiment 2:
The 248g methyl catechol is joined in the round-bottomed flask, slowly add 90 milliliters of vitriol oils again, the limit edged stirs, and 65 ℃ of water-baths were reacted 1.5 hours.React and treat that solution is cooled to room temperature after complete, add again 1050 gram Vibravenoss, stirring reaction under the room temperature.After adding Vibravenos and it is dissolved fully,, launch iodine colour developing, detection reaction progress every 10 minute hour plate with ammonium acetate-acetonitrile (9: 1).React and add isopyknic propyl carbinol after complete, the limit edged stirs, and behind the crystallization, filters, and filtrate is washed with propyl carbinol again.After washing 3 times, will filter the crystal of gained, evaporated under reduced pressure namely gets the Guaiacolsulfonic acid Vibravenos.Through high effective liquid chromatography for measuring content, product purity is 99.2%.
Embodiment 3:
The 124g methyl catechol is joined in the round-bottomed flask, slowly add 53 milliliters of vitriol oils again, the limit edged stirs, and 75 ℃ of water-baths were reacted 1.2 hours.React and treat that solution is cooled to room temperature after complete, add again 510 gram Vibravenoss, stirring reaction under the room temperature.After adding Vibravenos and it is dissolved fully,, launch iodine colour developing, detection reaction progress every 10 minute hour plate with ammonium acetate-acetonitrile (9: 1).React and add isopyknic ether after complete, the limit edged stirs, and behind the crystallization, filters, and filtrate is washed with ether again.After washing 3 times, will filter the crystal of gained, evaporated under reduced pressure namely gets the Guaiacolsulfonic acid Vibravenos.Through high effective liquid chromatography for measuring content, product purity is 99.4%.
Claims (2)
1. the preparation method of a Guaiacolsulfonic acid Vibravenos comprises the steps:
(1) methyl catechol is joined in the reaction vessel, add the vitriol oil of massfraction 95 ~ 98%, the limit edged stirs, and water-bath 60-100 ℃, reaction times 1-3.5 hour;
(2) reaction treats that solution is cooled to room temperature after complete, adds Vibravenos, stirring reaction under the room temperature; The tlc detection reaction is carried out degree;
The mol ratio of the above raw material is methyl catechol: the vitriol oil: Vibravenos=1 ~ 2:0.5 ~ 1:1 ~ 2;
(3) step (2) reaction complete after, add and the isopyknic organic solvent of reaction solution, the limit edged stirs, and behind the crystallization, filters, filtrate is used organic solvent washing 2 ~ 3 times again, with filtering the solid of gained, removes organic solvent under reduced pressure, and get final product;
Described organic solvent is propyl carbinol.
2. the preparation method of Guaiacolsulfonic acid Vibravenos as claimed in claim 1 is characterized in that, the mol ratio of described raw material is methyl catechol: the vitriol oil: Vibravenos=1:0.7 ~ 0.9:1.
3.The preparation method of Guaiacolsulfonic acid Vibravenos as claimed in claim 1 is characterized in that, the mol ratio of described raw material is methyl catechol: the vitriol oil: Vibravenos mol ratio=1:0.85:1.
4.The preparation method of Guaiacolsulfonic acid Vibravenos as claimed in claim 1 is characterized in that, the used vitriol oil of step (1) is massfraction 98% sulfuric acid.
5.The preparation method of Guaiacolsulfonic acid Vibravenos as claimed in claim 1 is characterized in that, step (1) temperature of reaction is 65 ~ 80 ℃ of water-baths, reacts 1 ~ 1.5 hour.
6.The preparation method of Guaiacolsulfonic acid Vibravenos as claimed in claim 1, it is characterized in that, the described tlc detection reaction of step (2) is carried out degree and is, after adding Vibravenos and it fully dissolved, every 10 minute hour plate once, launch with the ammonium acetate of 9:1 volume ratio-acetonitrile, the iodine colour developing shows that no longer the raw material spot finishes for reaction.
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| CN 201210128419CN102675145B (en) | 2012-04-27 | 2012-04-27 | Preparation method of guaiacol sulfonate doxycycline |
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| CN104292136B (en)* | 2014-09-19 | 2016-03-09 | 浙江科技学院 | A kind of preparation method of thiocol |
| CN110229084B (en)* | 2019-07-08 | 2021-09-21 | 广西两面针亿康药业股份有限公司 | Preparation method of guaiacol potassium sulfonate |
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| CA2566464C (en)* | 2004-05-21 | 2012-04-03 | Andrew G. Myers | Synthesis of tetracyclines and analogues thereof |
| CN1843505A (en)* | 2005-04-06 | 2006-10-11 | 广州威尓曼新药开发中心有限公司 | Compound Doxycycline lysozyme enteral capsule |
| CN101357341A (en)* | 2007-07-31 | 2009-02-04 | 顾鸣海 | Hydrogenation technique rhodium catalyst for producing antibiotic doxycycline and use thereof |
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