CN102675145A - Preparation method of guaiacol sulfonate doxycycline - Google Patents
Preparation method of guaiacol sulfonate doxycycline Download PDFInfo
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- CN102675145A CN102675145A CN2012101284196A CN201210128419A CN102675145A CN 102675145 A CN102675145 A CN 102675145A CN 2012101284196 A CN2012101284196 A CN 2012101284196A CN 201210128419 A CN201210128419 A CN 201210128419A CN 102675145 A CN102675145 A CN 102675145A
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Abstract
The invention relates to a preparation method of guaiacol sulfonate doxycycline, which comprises the following steps: carrying out unreal reaction on guaiacol and concentrated sulfuric acid and bathing in water with a temperature of 60-100 DEG C; adding doxycycline after reaction, and agitating and reacting at a room temperature; ensuring that the molar ratio of a raw material is guaiacol:concentrated sulfuric acid:doxycycline equal to (1-2):(0.5-1):(1-2); and adding an organic solvent with the same volume as reaction liquid for crystallization and washing, and evaporating the organic solvent under reduced pressure. Through measuring the content by using a high-performance liquid chromatography, the purity of a guaiacol sulfonate doxycycline product is more than or equal to 99 percent. The guaiacol sulfonate doxycycline product prepared by the preparation method has the advantages of high purity, high yield, stable product performance, simple and convenient process, small environmental pollution, simple subsequent treatment and reduced production cost.
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, multiple 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 more than single infection more and is seen, 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 the stick effect of intestinal bacteria to respiratory tract.But because the mass-producing of livestock and poultry cultivation; Cause stocking density excessive; Factors such as ventilation effect is bad make respiratory tract disease or the complication followed takes place more and more easily, and 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 the treatment 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-1,4,4a, 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 superior to terramycin, and it is evident in efficacy that livestock and poultry respiratory mucus is too much stopped up tracheae.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 technology subsequent disposal, produces this and brings environmental pollution thereby strengthened.
Summary of the invention
To the deficiency of prior art, the present invention provides a kind of preparation method of Guaiacolsulfonic acid Vibravenos.
Technical scheme of the present invention is following:
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) treat that solution is cooled to room temperature after reaction finishes, add Vibravenos, stirring reaction under the room temperature; The tlc detection reaction is carried out degree;
The mol ratio of the above raw material is a methyl catechol: the vitriol oil: Vibravenos=1～2: 0.5～1: 1～2.
(3) after step (2) reaction finishes, add and the isopyknic organic solvent of reaction solution, the limit edged stirs, and after crystallization is separated out, filters, and filtrating is used organic solvent washing 2～3 times again, and the solid with filtering gained removes organic solvent under reduced pressure, promptly gets.Through high effective liquid chromatography for measuring content, Guaiacolsulfonic acid Vibravenos product purity >=99%.
Preferred according to the present invention, the mol ratio of said raw material is a 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 said tlc detection reaction of step (2) is carried out degree and is; After adding Vibravenos and after it is dissolved fully, whenever once at a distance from 10 fen hour plate, with ammonium acetate-acetonitrile expansion of 9: 1 volume ratios; The iodine colour developing shows that no longer Vibravenos raw material spot is regarded as reaction and accomplishes.
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 a propyl carbinol.
The characteristics of the inventive method: the present invention is sulfonated reagent with the vitriol oil, and preferred suitable usage ratio, and after the methyl catechol sulfonation reaction, remaining sulfuric acid is without separation, and direct and Vibravenos is carried out to reactant salt.After end reaction finishes, adopt crystalline method separation and purification Guaiacolsulfonic acid Vibravenos.Gained Guaiacolsulfonic acid Vibravenos product purity is more than 99%.
Preparing the Guaiacolsulfonic acid Vibravenos through 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
Below in conjunction with embodiment the present invention is described further, but is not limited thereto.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 following among the embodiment:
Material: Hyper 0DS2 C18, flow velocity: 1.0ml/min;
Moving phase: 0.05mol/l ammonium oxalate solution-N-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.Treat that solution is cooled to room temperature after reaction finishes, add 515 gram Vibravenoss again, stirring reaction under the room temperature.After adding Vibravenos and it dissolved fully, every at a distance from 10 fen hour plate, launch iodine colour developing, detection reaction progress with ammonium acetate-acetonitrile (9: 1).Add isopyknic propyl carbinol after reaction finishes, the limit edged stirs, and after crystallization is separated out, filters, and filtrating is washed with propyl carbinol again.After washing 3 times, with the crystal that filters gained, evaporated under reduced pressure promptly 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.Treat that solution is cooled to room temperature after reaction finishes, add 1050 gram Vibravenoss again, stirring reaction under the room temperature.After adding Vibravenos and it dissolved fully, every at a distance from 10 fen hour plate, launch iodine colour developing, detection reaction progress with ammonium acetate-acetonitrile (9: 1).Add isopyknic propyl carbinol after reaction finishes, the limit edged stirs, and after crystallization is separated out, filters, and filtrating is washed with propyl carbinol again.After washing 3 times, with the crystal that filters gained, evaporated under reduced pressure promptly 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.Treat that solution is cooled to room temperature after reaction finishes, add 510 gram Vibravenoss again, stirring reaction under the room temperature.After adding Vibravenos and it dissolved fully, every at a distance from 10 fen hour plate, launch iodine colour developing, detection reaction progress with ammonium acetate-acetonitrile (9: 1).Add isopyknic ether after reaction finishes, the limit edged stirs, and after crystallization is separated out, filters, and filtrating is washed with ether again.After washing 3 times, with the crystal that filters gained, evaporated under reduced pressure promptly gets the Guaiacolsulfonic acid Vibravenos.Through high effective liquid chromatography for measuring content, product purity is 99.4%.
Claims (7)
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) treat that solution is cooled to room temperature after reaction finishes, add Vibravenos, stirring reaction under the room temperature; The tlc detection reaction is carried out degree;
The mol ratio of the above raw material is a methyl catechol: the vitriol oil: Vibravenos=1～2: 0.5～1: 1～2;
(3) after step (2) reaction finishes, add and the isopyknic organic solvent of reaction solution, the limit edged stirs, and after crystallization is separated out, filters, and filtrating is used organic solvent washing 2～3 times again, and the solid with filtering gained removes organic solvent under reduced pressure, promptly gets.
2. the preparation method of Guaiacolsulfonic acid Vibravenos as claimed in claim 1 is characterized in that, the mol ratio of said raw material is a 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 said raw material is a 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 mol ratio of said raw material is 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, the mol ratio of said raw material is 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 is characterized in that, the mol ratio of said raw material is that 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 a propyl carbinol.
7. the preparation method of Guaiacolsulfonic acid Vibravenos as claimed in claim 1; It is characterized in that the said tlc detection reaction of step (2) is carried out degree and is, after adding Vibravenos and it is fully dissolved; Whenever once at a distance from 10 fen hour plate; Ammonium acetate-acetonitrile with 9: 1 volume ratios launches, and the iodine colour developing shows that no longer the raw material spot is the reaction completion.
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| CN 201210128419 CN102675145B (en) | 2012-04-27 | 2012-04-27 | Preparation method of guaiacol sulfonate doxycycline |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292136A (en) * | 2014-09-19 | 2015-01-21 | 浙江科技学院 | Preparation method of sulfogaiacol |
| CN110229084A (en) * | 2019-07-08 | 2019-09-13 | 广西两面针亿康药业股份有限公司 | A kind of preparation method of orthocoll |
Citations (4)
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| ES381588A2 (en) * | 1970-07-08 | 1974-11-01 | Ferrer Labor | Procedure for the manufacture of new tetracycline compounds. (Machine-translation by Google Translate, not legally binding) |
| 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 |
| CN101027279A (en) * | 2004-05-21 | 2007-08-29 | 哈佛大学校长及研究员协会 | Synthesis of tetracyclines and analogues thereof |
| 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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2012
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES381588A2 (en) * | 1970-07-08 | 1974-11-01 | Ferrer Labor | Procedure for the manufacture of new tetracycline compounds. (Machine-translation by Google Translate, not legally binding) |
| CN101027279A (en) * | 2004-05-21 | 2007-08-29 | 哈佛大学校长及研究员协会 | 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 |
Non-Patent Citations (1)
| Title |
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| 胡汉峰: "盐酸多西环素氢化合成研究", 《江苏化工》, vol. 31, no. 4, 31 August 2003 (2003-08-31) * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104292136A (en) * | 2014-09-19 | 2015-01-21 | 浙江科技学院 | Preparation method of sulfogaiacol |
| CN104292136B (en) * | 2014-09-19 | 2016-03-09 | 浙江科技学院 | A kind of preparation method of thiocol |
| CN110229084A (en) * | 2019-07-08 | 2019-09-13 | 广西两面针亿康药业股份有限公司 | A kind of preparation method of orthocoll |
| 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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