CN106518984A - Preparation method for preparing vancomycin from 2-methylpyridine - Google Patents
Preparation method for preparing vancomycin from 2-methylpyridine Download PDFInfo
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- CN106518984A CN106518984A CN201510587036.9A CN201510587036A CN106518984A CN 106518984 A CN106518984 A CN 106518984A CN 201510587036 A CN201510587036 A CN 201510587036A CN 106518984 A CN106518984 A CN 106518984A
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Abstract
The invention discloses a preparation method for preparing vancomycin from 2-methylpyridine. The preparation method comprises the following steps: a, rapidly mixing an antibiotic fermentation mixture with 2-methylpyridine so as to obtain a solution with a pH value of at least about 7.8, and allowing the obtained solution to continue precipitation without stirring; b, crystallizing the precipitate formed in the step a from the solution; and c, dissolving the obtained crystal so as to obtain an aqueous solution, and carrying out crystallization separation through one or more resin chromatographic columns so as to obtain the vancomycin. The vancomycin prepared by using the preparation method provided by the invention has the following advantages: effective components are greatly improved; impurities are greatly reduced; the purity is high; the chromatographic purity can reach 95% or above; meanwhile, the vancomycin has significantly-improved appearance and color, and is applicable to oral or injection administration. The invention has the following advantages: the preparation method is simple and convenient; and the technological process is applicable to mass production.
Description
Technical field
It is the present invention relates to the preparation method technical field of vancomycin, more particularly to a kind of by 2- methyl
Pyridine prepares the preparation method of vancomycin.
Background technology
Vancomycin is one kind of antibiotic, and its molecular formula is C66H74Cl2N9O24.Its half-life：
4～8 hours, renal failure 9 days, invalid to anaerobe and gram negative bacteria, hemodialysis will not be moved
Remove.In " superbug " NDM-1 that the South Asian nations such as India occur, Britain, U.S. has been spread to
The countries such as state, Canada, Australia, Holland, domestic expert claim South Asia superbug not flow greatly
OK, vancomycin can take effect.
Vancomycin belongs to glycopeptide class macromole antibiotic, and the efficacy of a drug of vancomycin is stronger, in other antibiosis
Element can be used when invalid to pathogenic bacteria.It is mainly used in staphylococcuses (including penicillin resistant and Nai Xin penicillium sp
Plain strain), the system infections caused by clostridium difficile etc. and intestinal infection, such as endocarditiss, lose
Mass formed by blood stasis, pseudomembranous enteritiss etc..
For be obtained vancomycin, need by ion exchange, decolouring, chromatographic isolation, ultrafiltration, nanofiltration,
Various Hydrolysis kinetics means such as crystallization, dissolving, lyophilization.Wherein crystallization process can be improved through the ages
Mycin purity, removes the impurity such as partial pigment, but because vancomycin hydrochloride crystal growth is slow, ties
Brilliant process is easily disturbed by impurity, and crystallization difficulty is larger, only by ion exchange and the thick extraction decolourized
Liquid is difficult to crystallize out.
The content of the invention
The purpose of the present invention is to overcome the deficiencies in the prior art, there is provided one kind is prepared by 2- picolines
The preparation method of vancomycin.
Technical scheme is as follows：The present invention provides one kind and prepares vancomycin by 2- picolines
Preparation method, comprise the following steps：
A, antibiotic fermentation mixture is quickly mixed with 2- picolines, obtain pH value at least about 7.8
Solution, and be allowed to without under stirring continue precipitation；
B, by step a formed precipitate crystallize out from solution；
C, the dissolution of crystals for obtaining are aqueous solution, then by being crystallized by one or more chromatography resin posts
Separate, obtain vancomycin.
Currently preferred, according in step a, the pH scopes of the 2- picolines are 1.0～3.0.
It is currently preferred, it is according in step b, miscible with water organic by adding in precipitate
Crystallizing, before crystallization, in solution, vancomycin content is 40%～60.0% to solvent.
Currently preferred, the machine solvent is methanol, ethanol, isopropanol or acetone.
Currently preferred, the machine solvent adding amount is：Methanol is 2～6 times of crystal solution volumes；Second
Alcohol is 1.5～5.5 times of crystal solution volumes；Isopropanol is 1.2～5 times of crystal solution volumes；Acetone be 1.0～
4.5 times of crystal solution volumes.
Currently preferred, according in step b, crystallization process initial temperature is 25～60 DEG C；Crystallization
Course end temperature is 0～30 DEG C；Crystallization process cooling rate is 0.5～5 DEG C/min.
Currently preferred, according in step c, the vancomycin concentration after crystal water dissolution is
50%～80%.
Beneficial effects of the present invention are as follows：
Using such scheme, the present invention prepares gained vancomycin active princlple and is improved significantly, its
Its impurity is substantially reduced, and purity is very high, and chromatographic purity can reach more than 95%, while product appearance face
Color obtains remarkable improvement, is suitable to oral or injection administration；The present invention has manufacture method easy and technique
Flow process is applied to the advantage produced in enormous quantities.
Description of the drawings
Fig. 1 is a kind of stream of preparation method for preparing vancomycin by 2- picolines of the present invention
Cheng Tu.
Specific embodiment
Below in conjunction with the drawings and specific embodiments, the present invention is described in detail.
Fig. 1 is referred to, the present invention provides a kind of preparation method for preparing vancomycin by 2- picolines,
Comprise the following steps：
A, antibiotic fermentation mixture is quickly mixed with 2- picolines, obtain pH value at least about 7.8
Solution, and be allowed to without under stirring continue precipitation；
B, by step a formed precipitate crystallize out from solution；
C, the dissolution of crystals for obtaining are aqueous solution, then by being crystallized by one or more chromatography resin posts
Separate, obtain vancomycin.
Embodiment one：
According in step a, the pH of the 2- picolines is 1.0；According in step b, by
Add organic solvent miscible with water to crystallize in precipitate, before crystallization, in solution, vancomycin content is
40%；The machine solvent is methanol；The machine solvent adding amount is：Methanol is 2 times of crystal solution volumes；
According in step b, crystallization process initial temperature is 25 DEG C；Crystallization process outlet temperature is 0 DEG C；Knot
Brilliant process cooling rate is 2 DEG C/min；According to the vancomycin in step c, after crystal water dissolution
Concentration is 60%.
Embodiment two：
According in step a, the pH of the 2- picolines is 2；According in step b, by heavy
Add organic solvent miscible with water to crystallize in starch, before crystallization, in solution, vancomycin content is
50%；The machine solvent is methanol；The machine solvent adding amount is：Methanol is 3 times of crystal solution volumes；
According in step b, crystallization process initial temperature is 35 DEG C；Crystallization process outlet temperature is 10 DEG C；Knot
Brilliant process cooling rate is 3 DEG C/min；According to the vancomycin in step c, after crystal water dissolution
Concentration is 70%.
Embodiment three：
According in step a, the pH of the 2- picolines is 2.5；According in step b, by
Add organic solvent miscible with water to crystallize in precipitate, before crystallization, in solution, vancomycin content is
55%；The machine solvent is methanol；The machine solvent adding amount is：Methanol is 4 times of crystal solution volumes；
According in step b, crystallization process initial temperature is 55 DEG C；Crystallization process outlet temperature is 20 DEG C；Knot
Brilliant process cooling rate is 4 DEG C/min；According to the vancomycin in step c, after crystal water dissolution
Concentration is 75%.
Example IV：
According in step a, the pH of the 2- picolines is 3；According in step b, by heavy
Add organic solvent miscible with water to crystallize in starch, before crystallization, in solution, vancomycin content is
60%；The machine solvent is methanol；The machine solvent adding amount is：Methanol is 6 times of crystal solution volumes；
According in step b, crystallization process initial temperature is 60 DEG C；Crystallization process outlet temperature is 30 DEG C；Knot
Brilliant process cooling rate is 5 DEG C/min；According to the vancomycin in step c, after crystal water dissolution
Concentration is 80%.
In sum, using such scheme, the present invention prepares gained vancomycin active princlple and obtains significantly
To raising, other impurity are substantially reduced, and purity is very high, and chromatographic purity can reach more than 95%, while
Product appearance color obtains remarkable improvement, is suitable to oral or injection administration；The present invention has manufacture method
Easy and technological process is applied to the advantage produced in enormous quantities.
Presently preferred embodiments of the present invention is these are only, the present invention is not limited to, it is all at this
Any modification, equivalent and improvement for being made within bright spirit and principle etc., should be included in this
Within the protection domain of invention.
Claims (7)
1. a kind of preparation method for preparing vancomycin by 2- picolines, it is characterised in that include
Following steps：
A, antibiotic fermentation mixture is quickly mixed with 2- picolines, obtain pH value at least about 7.8
Solution, and be allowed to without under stirring continue precipitation；
B, by step a formed precipitate crystallize out from solution；
C, the dissolution of crystals for obtaining are aqueous solution, then by being crystallized by one or more chromatography resin posts
Separate, obtain vancomycin.
2. a kind of preparation side for preparing vancomycin by 2- picolines according to claim 1
Method, it is characterised in that according in step a, the pH scopes of the 2- picolines are 1.0～3.0.
3. a kind of preparation side for preparing vancomycin by 2- picolines according to claim 1
Method, it is characterised in that according in step b, it is miscible with water organic molten by adding in precipitate
Crystallizing, before crystallization, in solution, vancomycin content is 40%～60.0% for agent.
4. a kind of preparation side for preparing vancomycin by 2- picolines according to claim 3
Method, it is characterised in that the machine solvent is methanol, ethanol, isopropanol or acetone.
5. a kind of preparation side for preparing vancomycin by 2- picolines according to claim 4
Method, it is characterised in that the machine solvent adding amount is：Methanol is 2～6 times of crystal solution volumes；Ethanol
For 1.5～5.5 times of crystal solution volumes；Isopropanol is 1.2～5 times of crystal solution volumes；Acetone is 1.0～4.5
Times crystal solution volume.
6. a kind of preparation side for preparing vancomycin by 2- picolines according to claim 1
Method, it is characterised in that according in step b, crystallization process initial temperature is 25～60 DEG C；Crystallized
Journey outlet temperature is 0～30 DEG C；Crystallization process cooling rate is 0.5～5 DEG C/min.
7. a kind of preparation side for preparing vancomycin by 2- picolines according to claim 1
Method, it is characterised in that according in step c, the vancomycin concentration after crystal water dissolution is 50%～
80%.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1033997A (en) * | 1987-12-28 | 1989-07-19 | 伊莱利利公司 | Improved vancomycin precipitation process |
| US5149784A (en) * | 1990-07-10 | 1992-09-22 | Abbott Laboratories | Process for making vancomycin |
| US5574135A (en) * | 1990-07-10 | 1996-11-12 | Abbott Laboratories | Process for making vancomycin |
| CN101260134A (en) * | 2007-03-05 | 2008-09-10 | 浙江医药股份有限公司新昌制药厂 | Precipitation method for vancomycin |
| CN104672310A (en) * | 2013-11-27 | 2015-06-03 | 北大医药重庆大新药业股份有限公司 | Preparation method of vancomycin hydrochloride |
-
2015
- 2015-09-15 CN CN201510587036.9A patent/CN106518984A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1033997A (en) * | 1987-12-28 | 1989-07-19 | 伊莱利利公司 | Improved vancomycin precipitation process |
| US5149784A (en) * | 1990-07-10 | 1992-09-22 | Abbott Laboratories | Process for making vancomycin |
| US5574135A (en) * | 1990-07-10 | 1996-11-12 | Abbott Laboratories | Process for making vancomycin |
| CN101260134A (en) * | 2007-03-05 | 2008-09-10 | 浙江医药股份有限公司新昌制药厂 | Precipitation method for vancomycin |
| CN104672310A (en) * | 2013-11-27 | 2015-06-03 | 北大医药重庆大新药业股份有限公司 | Preparation method of vancomycin hydrochloride |
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