CN102225906B - Crystallization method of valnemulin hydrochloride - Google Patents
Crystallization method of valnemulin hydrochloride Download PDFInfo
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- CN102225906B CN102225906B CN201110122421.8A CN201110122421A CN102225906B CN 102225906 B CN102225906 B CN 102225906B CN 201110122421 A CN201110122421 A CN 201110122421A CN 102225906 B CN102225906 B CN 102225906B
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- valnemulin
- valnemulin hydrochloride
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Abstract
The invention mainly discloses a crystallization method of valnemulin hydrochloride. The method comprises the following steps: dissolving valnemulin in an organic solvent; adding a certain amount of dried hydrogen chloride gas or hydrogen chloride organic solution; separating out crystals; and collecting the obtained crystals, and drying so as to obtain valnemulin hydrochloride. The method is convenient for operation, is suitable for industrial production on large scale, has low cost and can be used for purifying the product. The chromatograph content of the valnemulin hydrochloride obtained by the method in the invention is improved by 1-5% as compared with the chromatograph content of the corresponding valnemulin.
Description
Technical field
The invention provides a kind of crystallization method of valnemulin hydrochloride.
Background technology
Valnemulin (Valnemulin) belongs to animal specific s-generation pleuromulins (pleuromutilins) semisynthetic antibiotics, belongs to terpenes, belongs to same class medicine with Tiamulin.Be mainly used in preventing and treating mycoplasmosis and the gram positive bacteria infection of pig, ox, sheep and poultry.First 1984 utilize pleuromutilin by Sandoz company is the semisynthetic microbiotic of raw material.
Because valnemulin is unstable, be generally made into clinically valnemulin hydrochloride pre-mixture and use.1999, valnemulin hydrochloride pre-mixture was at U.S.'s Initial Public Offering, trade(brand)name Econor.It is also the veterinary drug pre-mixture of first all Europe approval simultaneously, is listed in prescription drugs for animals.
US5164526 adopts spray-drying process to make valnemulin hydrochloride solid; CN101597248 and CN101735123 all adopt lyophilization to make valnemulin hydrochloride solid.
But all there is obvious limitation in two kinds of above-mentioned methods: first, these two kinds of methods are only processes of sloughing solvent, to the product effect of not purifying, therefore very high to the content requirement of valnemulin salt acid salt aqueous solution; Secondly, valnemulin salt acid salt aqueous solution is stronger acidity, and the main material of spray drying device is generally stainless steel, and life-time service is very serious to the corrosion of equipment; Finally, spray drying device and freeze-drier are expensive, and energy consumption is high, and use cost and maintenance cost are higher.
Summary of the invention
A kind of method of preparing the crystallization of valnemulin hydrochloride that the invention provides comparatively easy economy, concrete technical characterictic is as follows:
Valnemulin is dissolved in organic solvent, then adds a certain amount of dry hydrogen chloride gas or hydrogenchloride organic solution, crystallize out, the crystal of collection gained, dry, obtain valnemulin hydrochloride.
Described organic solvent is the arbitrary combination of derivative, halogenated alkane and the above-mentioned organic solvent of ether, benzene.
Described ether is methyl tertiary butyl ether, ether, tetrahydrofuran (THF), preferable methyl tertbutyl ether.
The derivative of described benzene is toluene, dimethylbenzene.
Described halogenated alkane is the halogenated alkane of 1 ~ 3 carbon atom.
Described halogenated alkane is methylene dichloride, trichloromethane, 1,1-ethylene dichloride, 1,2-ethylene dichloride.
The described temperature that adds dry hydrogen chloride gas or hydrogenchloride organic solution is-20 DEG C-50 DEG C, preferably 0-20 DEG C.
The solution that described hydrogen chloride solution obtains in organic solvent for hydrogenchloride is dissolved in, this organic solvent is a kind of of methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, acetone, methylethylketone, butanone, methylene dichloride, chloroform or their arbitrary combination, particular methanol or ethanol.
Described valnemulin is 1:0.5-1:50 with the amount of substance of hydrogenchloride ratio, preferably 1:10-1:20.
The valnemulin hydrochloride crystallization method of preparing provided by the invention, compared with existing disclosed method, has following features:
1, easy and simple to handle, utilize chemically general crystallization technique to prepare valnemulin hydrochloride, be applicable to industrial scale operation.
2, with low cost, without adopting expensive equipment, adopt common reactor, whizzer, the drying machine of pharmaceutical industry.
3, product is had to refining effect.The chromatogram content of the valnemulin hydrochloride making by method provided by the invention has improved 1-5% than corresponding valnemulin.
Embodiment
embodiment 1
Get 10.0g(0.0177mol) valnemulin (HPLC content: 95.0%), be dissolved in completely in 100mL methyl tertiary butyl ether, be chilled to 0 DEG C, stir methanol solution (the containing hydrogen chloride 6.5g of the lower 21.7g of dropping hydrogenchloride, 0.178mol), drip and finish, stir filtration under diminished pressure 2 hours, appropriate methyl tertiary butyl ether rinsing for filter cake, dry, obtain valnemulin hydrochloride 10.1g(yield 94.9%, HPLC content 98.2%).
embodiment 2
Get 10.0g(0.0177mol) valnemulin (HPLC content: 95.0%), be dissolved in completely in 100mL methylene dichloride, be chilled to-20 DEG C, under stirring, slowly pass into dry hydrogen chloride 0.65g(0.0178mol), logical finishing, stir 2 hours, filtration under diminished pressure, appropriate methyl tertiary butyl ether rinsing for filter cake, dries, obtain valnemulin hydrochloride 7.8g(yield 73.3%, HPLC content 96.5%).
embodiment 3
Get 10.0g(0.0177mol) valnemulin (HPLC content: 95.0%), be dissolved in completely in 100mL toluene, be warming up to 40 DEG C, under stirring, slowly pass into dry hydrogen chloride 12.9g(0.353mol), logical finishing, stir 2 hours, filtration under diminished pressure, appropriate methyl tertiary butyl ether rinsing for filter cake, dries, obtain valnemulin hydrochloride 9.0g(yield 84.6%, HPLC content 96.8%).
embodiment 4
Get 10.0g(0.0177mol) valnemulin (HPLC content: 95.0%), be dissolved in completely in the mixed solvent of 100mL methyl tertiary butyl ether and toluene (volume ratio 1:1), be warming up to 50 DEG C, under stirring, slowly pass into dry hydrogen chloride 32.3g(0.885mol), logical finishing, stir 2 hours, filtration under diminished pressure, appropriate methyl tertiary butyl ether rinsing for filter cake, dries, obtain valnemulin hydrochloride 9.7g(yield 91.2%, HPLC content 97.0%).
embodiment 5
Get 10.0g(0.0177mol) valnemulin (HPLC content: 95.0%), be dissolved in completely in 100mL methyl tertiary butyl ether, maintain the temperature at 20 DEG C, stir ethanolic soln (the containing hydrogen chloride 12.9g of the lower 43.0g of dropping hydrogenchloride, 0.354mol), drip and finish, stir filtration under diminished pressure 2 hours, appropriate methyl tertiary butyl ether rinsing for filter cake, dry, obtain valnemulin hydrochloride 9.4g(yield 88.3%, HPLC content 97.8%).
embodiment 6
Get 10.0g(0.0177mol) valnemulin (HPLC content: 95.0%), be dissolved in completely in 100mL tetrahydrofuran (THF), maintain the temperature at 20 DEG C, stir methanol solution (the containing hydrogen chloride 0.324g of the lower 1.08g of dropping hydrogenchloride, 0.00888mol), drip and finish, stir filtration under diminished pressure 2 hours, appropriate tetrahydrofuran (THF) rinsing for filter cake, dry, obtain valnemulin hydrochloride 4.8g(yield 45.1%, HPLC content 97.3%).
embodiment 7
Get 10.0g(0.0177mol) valnemulin (HPLC content: 95.0%), be dissolved in completely in 100mL chloroform, maintain the temperature at 5 DEG C, stir chloroformic solution (the containing hydrogen chloride 0.324g of the lower 1.08g of dropping hydrogenchloride, 0.00888mol), drip and finish, stir filtration under diminished pressure 2 hours, appropriate tetrahydrofuran (THF) rinsing for filter cake, dry, obtain valnemulin hydrochloride 4.8g(yield 45.1%, HPLC content 97.3%).
embodiment 8
Get 10.0g(0.0177mol) valnemulin (HPLC content: 95.0%), be dissolved in completely in 100mL ether, maintain the temperature at 15 DEG C, stir methanol solution (the containing hydrogen chloride 9.67g of the lower 32.2g of dropping hydrogenchloride, 0.265mol), drip and finish, stir filtration under diminished pressure 2 hours, the appropriate ether rinse of filter cake, dry, obtain valnemulin hydrochloride 9.6g(yield 90.2%, HPLC content 98.0%).
Claims (3)
1. a crystallization method for valnemulin hydrochloride, is characterized in that: get 10.0g valnemulin, its HPLC content: 95.0%, be dissolved in completely in 100mL methyl tertiary butyl ether, be chilled to 0 DEG C, stir the methanol solution of the lower 21.7g of dropping hydrogenchloride, wherein containing hydrogen chloride 6.5g, drips and finishes, and stirs 2 hours, filtration under diminished pressure, appropriate methyl tertiary butyl ether rinsing for filter cake, dries, and obtains valnemulin hydrochloride 10.1g, yield 94.9%, HPLC content 98.2%.
2. the crystallization method of a valnemulin hydrochloride, it is characterized in that: get 10.0g valnemulin, its HPLC content: 95.0%, be dissolved in completely in the mixed solvent of 100mL methyl tertiary butyl ether and toluene, the wherein volume ratio 1:1 of methyl tertiary butyl ether and toluene, be warming up to 50 DEG C, under stirring, slowly pass into dry hydrogen chloride 32.3g, logical finishing, stirs 2 hours, filtration under diminished pressure, appropriate methyl tertiary butyl ether rinsing for filter cake, dries, and obtains valnemulin hydrochloride 9.7g, yield 91.2%, HPLC content 97.0%.
3. a crystallization method for valnemulin hydrochloride, is characterized in that: get 10.0g valnemulin, its HPLC content: 95.0%, be dissolved in completely in 100mL ether, maintain the temperature at 15 DEG C, stir the methanol solution of the lower 32.2g of dropping hydrogenchloride, wherein containing hydrogen chloride 9.67g, drips and finishes, and stirs 2 hours, filtration under diminished pressure, the appropriate ether rinse of filter cake, dries, and obtains valnemulin hydrochloride 9.6g, yield 90.2%, HPLC content 98.0%.
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| CN201110122421.8A CN102225906B (en) | 2011-05-12 | 2011-05-12 | Crystallization method of valnemulin hydrochloride |
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| CN201110122421.8A CN102225906B (en) | 2011-05-12 | 2011-05-12 | Crystallization method of valnemulin hydrochloride |
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| CN102225906B true CN102225906B (en) | 2014-07-30 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288694B (en) * | 2013-06-28 | 2015-06-17 | 宁夏泰瑞制药股份有限公司 | Preparation method of pleuromutilin synthetic derivate salt crystal |
| CN103483232B (en) * | 2013-09-25 | 2015-05-13 | 宁夏泰瑞制药股份有限公司 | Refining method of valnemulin hydrochloride |
| CN103641702B (en) * | 2013-11-18 | 2015-11-18 | 宁夏泰瑞制药股份有限公司 | A kind of method for hydrolysis of pleuromutilin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5284967A (en) * | 1989-10-03 | 1994-02-08 | Biochemie Gesellschaft M.B.H. | Pleuromutilins |
| CN101107224A (en) * | 2005-01-26 | 2008-01-16 | 诺瓦提斯公司 | Valnemulin salts with organic acids |
| CN101880252A (en) * | 2010-06-29 | 2010-11-10 | 金河生物科技股份有限公司 | Preparation method of valnemulin hydrochloride |
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- 2011-05-12 CN CN201110122421.8A patent/CN102225906B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5284967A (en) * | 1989-10-03 | 1994-02-08 | Biochemie Gesellschaft M.B.H. | Pleuromutilins |
| CN101107224A (en) * | 2005-01-26 | 2008-01-16 | 诺瓦提斯公司 | Valnemulin salts with organic acids |
| CN101880252A (en) * | 2010-06-29 | 2010-11-10 | 金河生物科技股份有限公司 | Preparation method of valnemulin hydrochloride |
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