CN105294794A - Preparation method of clarithromycin - Google Patents
Preparation method of clarithromycin Download PDFInfo
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- CN105294794A CN105294794A CN201510797901.2A CN201510797901A CN105294794A CN 105294794 A CN105294794 A CN 105294794A CN 201510797901 A CN201510797901 A CN 201510797901A CN 105294794 A CN105294794 A CN 105294794A
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Abstract
The invention relates to a preparation method of clarithromycin. The method is characterized in that erythromycin thiocyanate is subjected to an oximation reaction, an etherification reaction, a silanization reaction, a methylation reaction and a reduction hydrolysis reaction to obtain a clarithromycin methanol reaction solution, methanol is obtained after underpressure distillation is carried out, an organic solvent A and purified water are added for phase splitting, an organic acid solution is fed in a clarithromycinorganic phase solution after phase-splitting, and then a salt forming reaction is carried out, and the obtained clarithromycin salt is recrystallized, filtered and dried to obtain the clarithromycin. The method can realize effective purification and increases product yield, the technical operation is simple, the unit consumption of the solvent is less, the product quality is reliable, and the clarithromycin salt after salt forming is easily dissolved in a mixed solvent system of the organic solvent and water, a heating backflow process is not required, and the reaction can be carried out at normal temperature.
Description
Technical field
The present invention relates to biology and new medical technology, particularly relate to a kind of preparation method of clarithromycin.
Background technology
Clarithromycin is the derivative of erythromycin.At present, generally adopt both at home and abroad and produce clarithromycin with the following method: by Matachrom through oximation reaction, etherification reaction, Silanization reaction, clarithromycin methyl alcohol reaction solution is obtained after methylation reaction and reductive hydrolysis reaction, then pH9 ~ 10 are regulated with sodium hydroxide solution, centrifugal, suction filtration, use the pure crystallization secondary of 95% ethanol again, quality product can meet USP38 version standard, or employing chloroform, methylene dichloride, after extraction into ethyl acetate, washing secondary, evaporated under reduced pressure again, clarithromycin finished product is obtained again by the way of ethyl alcohol recrystallization, aforesaid method yield can be under some influence.Its major cause is to need secondary just can obtain qualified final product quality in clarithromycin recrystallization process, and solvent ratios consumption is large, and material heat sensitivity is strong, very easily separates out and cause yield losses when clarithromycin filters.
Summary of the invention
The object of the invention is to the defect overcoming above-mentioned prior art, provide one effectively to improve product yield, reliable product quality, solvent load is few, the preparation method of the simple clarithromycin of technique.
Technical scheme taked for achieving the above object is:
A kind of preparation method of clarithromycin, it is characterized in that: after the clarithromycin methyl alcohol reaction solution underpressure distillation that Matachrom obtains after the reaction of oximation reaction, etherification reaction, Silanization reaction, methylation reaction and reductive hydrolysis is gone out methyl alcohol, add organic solvent A and purified water carries out phase-splitting, in the clarithromycin organic phase solution of phase-splitting gained, stream adds organic acid soln and carries out salt-forming reaction, and gained clarithromycin salt can obtain clarithromycin through recrystallization, filtration, drying.
In described phase process, the consumption of organic solvent is 6 ~ 12 times of quantity of solvent of solid content, and the consumption of purified water is 2 ~ 3 times of solid content.
Described organic solvent A be in chloroform, methylene dichloride, ethyl acetate and toluene any one or two or more.
Described salt-forming reaction condition is: salify temperature 36 ~ 75 DEG C, salt time 10 ~ 60min, the consumption of organic acid soln adds 0.1 ~ 0.5 liter of organic acid soln according to every 1 liter of clarithromycin organic phase solution and adds, and organic acid soln mass concentration controls 1% ~ 50%.
Described organic acid soln is the aqueous solution of any one or two kinds in tartrate, citric acid, L-glutamic acid, phenylformic acid and lactic acid.
Described recrystallization process is: joined in the organic solvent B aqueous solution by clarithromycin salt, after being warming up to 30 ~ 70 DEG C of stirring and dissolving, slowly drips alkaline solution muddy to solution, growing the grain 0.5 ~ 2h, continues to drip alkaline solution to pH9 ~ 10, cooling.
Described alkaline solution is ammoniacal liquor, sodium hydroxide solution, sodium bicarbonate or saturated solution of sodium carbonate.
Described organic solvent B is ethanol, acetone or Virahol.
The preparation method of clarithromycin of the present invention utilizes clarithromycin to be organic bases, has the principle with organic acid salify, adopt by clarithromycin in organic phase directly and the method for organic acid salify, realize effectively purifying, thus improve product yield, its technological operation is easy, and solvent unit consumption is few, reliable product quality, and the clarithromycin salt after salify is fairly dissolved in the mixed solvent system of organic solvent and water, need not reflux, normal temperature can react.
Embodiment
The present invention is described in further detail by following examples; but the present embodiment the technology contents that describes be illustrative; instead of it is determinate; protection scope of the present invention should do not limited to according to this; within the spirit and principles in the present invention all; any amendment of doing, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
The reductive hydrolysis reaction solution of the clarithromycin in following embodiment is obtain after the reaction of Matachrom oximation reaction, etherification reaction, Silanization reaction, methylation reaction and reductive hydrolysis.
Comparative example 1
Get the reductive hydrolysis reaction solution 300ml of clarithromycin, after underpressure distillation goes out methyl alcohol, add 15% sodium hydroxide solution, suction filtration obtains clarithromycin intermediate 33.4g.Add 10 times of ethanol and be heated to backwash, slow cooling after solution clarification, after being cooled to 5 DEG C, suction filtration obtains 20.3g.Same process is secondary recrystallization again, finally obtains clarithromycin 12.8g.
Comparative example 2
Get the reductive hydrolysis reaction solution 300ml of clarithromycin, after underpressure distillation goes out methyl alcohol, add 100ml purified water and 200ml trichloromethane, phase-splitting after washing secondary.Be evaporated to dry product, suction filtration obtains clarithromycin intermediate 30.8g.Add 10 times of ethanol and be heated to backwash, slow cooling after solution clarification, after being cooled to 5 DEG C, suction filtration obtains 20.2g.Same process is secondary recrystallization again, finally obtains clarithromycin 13.5g.
Embodiment 1
Get the reductive hydrolysis reaction solution 300ml of clarithromycin, after underpressure distillation goes out methyl alcohol, add 100ml purified water and 200ml chloroform, phase-splitting, obtain clarithromycin organic phase.In clarithromycin organic phase, stream adds 20% citric acid solution 60ml, stirs 30min, and period controls salify temperature 60 C.Cooling, suction filtration obtains clarithromycin citric acid wet salt 32g.Clarithromycin citric acid wet salt is joined 50% acetone 200ml and is warming up to 40 DEG C of stirring and dissolving, slowly drip ammoniacal liquor muddy to solution, growing the grain 45min, continue to drip ammoniacal liquor adjust ph to 10, cooling, suction filtration, dries to obtain clarithromycin 15g for 70 DEG C.
Embodiment 2
Get the reductive hydrolysis reaction solution 300ml of clarithromycin, after underpressure distillation goes out methyl alcohol, add 200ml purified water and 300ml ethyl acetate, phase-splitting, obtain clarithromycin organic phase.In clarithromycin organic phase, stream adds 30% tartaric acid solution 50ml, stirs 60min, and period controls salify temperature 70 C.Cooling, suction filtration obtains clarithromycin citric acid wet salt 28.6g.Clarithromycin citric acid wet salt is joined 30% ethanol 300ml and is warming up to 70 DEG C of stirring and dissolving, slowly drip 20% sodium hydroxide solution muddy to solution, growing the grain 1.5h, continue dropping 20% sodium hydroxide solution and regulate pH value to 9, cooling, suction filtration, dries to obtain clarithromycin 13.2g for 70 DEG C.
Embodiment 3
Get the reductive hydrolysis reaction solution 300ml of clarithromycin, after underpressure distillation goes out methyl alcohol, add 250ml purified water and 250ml methylene dichloride, phase-splitting obtains clarithromycin organic phase.In clarithromycin organic phase, stream adds 50% lactic acid solution 10ml, stirs 40min, and period controls salify temperature 40 DEG C.Cooling, suction filtration obtains clarithromycin lactic acid wet salt 30g.Clarithromycin lactic acid wet salt is joined 50% Virahol 400ml and is warming up to 50 DEG C of stirring and dissolving, slowly drip saturated solution of sodium bicarbonate muddy to solution, growing the grain 1h, continue to drip saturated solution of sodium bicarbonate and regulate pH value to 9.5, cooling, suction filtration, dries to obtain clarithromycin 14.5g for 70 DEG C.
Embodiment 4
Get the reductive hydrolysis reaction solution 300ml of clarithromycin, after underpressure distillation goes out methyl alcohol, add 250ml purified water and 100ml trichloromethane and 100ml toluene, phase-splitting obtains clarithromycin organic phase.In clarithromycin organic phase, stream adds 25% citric acid solution 10ml, stirs 30min, and period controls salify temperature 60 C.Cooling, suction filtration obtains clarithromycin lactic acid wet salt 28.3g.Clarithromycin lactic acid wet salt is joined 50% acetone 300ml and is warming up to 40 DEG C of stirring and dissolving, slowly drip ammoniacal liquor muddy to solution, growing the grain 1h, continue to drip saturated solution of sodium bicarbonate and regulate pH value to 9.5, cooling, suction filtration, dries to obtain clarithromycin 14.0g for 70 DEG C.
Claims (8)
1. the preparation method of a clarithromycin, it is characterized in that: after the clarithromycin methyl alcohol reaction solution underpressure distillation that Matachrom obtains after the reaction of oximation reaction, etherification reaction, Silanization reaction, methylation reaction and reductive hydrolysis is gone out methyl alcohol, add organic solvent A and purified water carries out phase-splitting, in the clarithromycin organic phase solution of phase-splitting gained, stream adds organic acid soln and carries out salt-forming reaction, and gained clarithromycin salt can obtain clarithromycin through recrystallization, filtration, drying.
2. according to the preparation method of clarithromycin according to claim 1, it is characterized in that in described phase process, the consumption of organic solvent is 6 ~ 12 times of quantity of solvent of solid content, and the consumption of purified water is 2 ~ 3 times of solid content.
3. according to the preparation method of the clarithromycin described in claim 1 or 2, it is characterized in that described organic solvent A be in chloroform, methylene dichloride, ethyl acetate and toluene any one or two or more.
4. according to the preparation method of clarithromycin according to claim 1, it is characterized in that described salt-forming reaction condition is: salify temperature 36 ~ 75 DEG C, salt time 10 ~ 60min, the consumption of organic acid soln adds 0.1 ~ 0.5 liter of organic acid soln according to every 1 liter of clarithromycin organic phase solution and adds, and organic acid soln mass concentration controls 1% ~ 50%.
5., according to the preparation method of the clarithromycin described in claim 1 or 4, it is characterized in that described organic acid soln is the aqueous solution of any one or two kinds in tartrate, citric acid, L-glutamic acid, phenylformic acid and lactic acid.
6. according to the preparation method of clarithromycin according to claim 1, it is characterized in that described recrystallization process is: joined by clarithromycin salt in the organic solvent B aqueous solution, after being warming up to 30 ~ 70 DEG C of stirring and dissolving, slow dropping alkaline solution is muddy to solution, growing the grain 0.5 ~ 2h, continue to drip alkaline solution to pH9 ~ 10, cooling.
7., according to the preparation method of clarithromycin according to claim 6, it is characterized in that described alkaline solution is ammoniacal liquor, sodium hydroxide solution, sodium bicarbonate or saturated solution of sodium carbonate.
8., according to the preparation method of clarithromycin according to claim 6, it is characterized in that described organic solvent B is ethanol, acetone or Virahol.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111995648A (en) * | 2020-07-31 | 2020-11-27 | 宁夏泰益欣生物科技有限公司 | Method for recovering clarithromycin crystallization mother liquor |
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| CN101875678A (en) * | 2009-04-30 | 2010-11-03 | 浙江华义医药有限公司 | Method for preparing clarithromycin |
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2015
- 2015-11-19 CN CN201510797901.2A patent/CN105294794A/en active Pending
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| CN1580065A (en) * | 2004-05-18 | 2005-02-16 | 湖北工学院 | Clarithromycin amino acid salt, and its preparing method and use |
| CN101045063A (en) * | 2006-03-28 | 2007-10-03 | 广州朗圣药业有限公司 | Clarithromycin water soluber preparation for injection use |
| WO2009023191A2 (en) * | 2007-08-09 | 2009-02-19 | Teva Pharmaceutical Industries Ltd. | An improved process for the preparation of clarithromycin |
| CN101525360A (en) * | 2008-03-06 | 2009-09-09 | 刘力 | Hydrates of macrolides organic acid salts, preparation and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111995648A (en) * | 2020-07-31 | 2020-11-27 | 宁夏泰益欣生物科技有限公司 | Method for recovering clarithromycin crystallization mother liquor |
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Application publication date: 20160203 |