CN104610402B - Preparation method of macrolide impurity - Google Patents
Preparation method of macrolide impurity Download PDFInfo
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- CN104610402B CN104610402B CN201410840070.8A CN201410840070A CN104610402B CN 104610402 B CN104610402 B CN 104610402B CN 201410840070 A CN201410840070 A CN 201410840070A CN 104610402 B CN104610402 B CN 104610402B
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- clarithromycin
- impurity
- preparation
- fluoro
- double
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Abstract
The invention relates to a preparation method of macrolide impurity, in particular to a preparation method of clarithromycin impurity D. The preparation method comprises the following step: in a non-alkaline solvent, allowing clarithromycin to react with N-fluorobenzenesulfonimide under a low temperature. The clarithromycin impurity D can be generated through a single-step reaction under mild conditions, then the clarithromycin impurity D with the purity of higher than 98% can be obtained through recrystallization, and the obtained clarithromycin impurity D can be taken as a reference substance in the quality research of clarithromycin.
Description
Technical field
A kind of the present invention relates to medicinal chemistry art, in particular it relates to preparation method of macrolide impurity.
Background technology
Clarithromycin, shown in its chemical constitution such as formula (i), is the antibiotic of second filial generation macrolide, to Gram-positive
Bacterium such as staphylococcus aureuses, streptococcus, streptococcus pneumoniae etc. have stronger inhibitory action, are main force's kinds of current antibiotic,
More than 1000 tons of China's annual output clarithromycin, are the majoies country of production of clarithromycin crude drug in the world at present.Often
The production of a collection of clarithromycin crude drug is required for controlling impurity, clarithromycin impurity d according to the regulation of pharmacopeia, and also referred to as nitrogen goes
Methyl clarithromycin, is the regulation impurity of American-European pharmacopeia, and No. cas is 101666-68-6, molecular weight 733.93, white solid, its
Shown in structure such as formula (ii):
The clarithromycin impurity of synthesis of high purity has important as reference substance to the quality research of clarithromycin crude drug
Meaning.At present clarithromycin impurity commonly used following methods preparation: with clarithromycin as raw material, using sodium acetate as alkali,
Methanol/water makees solvent, under the conditions of 70 DEG C, adds iodine to be reacted, reaction finishes, and is cooled to -20 DEG C, adds ammonia, then use
Dichloromethane extracts, and organic layer uses saturated common salt water washing again, and after solvent evaporated, then it is miscellaneous to obtain clarithromycin through column chromatography purification
Matter d.Specifically refer to journal of labelled compounds＆radiopharmaceuticals, 47 (2), 95-98；
2004 report, yield 74%, pct application open wo2007/25089, wo2008/99368 also report above-mentioned preparation side
Method.This preparation method complex operation, due to by-product many it is impossible to be purified by recrystallization, just can need to obtain through column chromatography purification
Obtain higher purity.
Content of the invention
First purpose of the present invention is to explore a kind of new method preparing clarithromycin impurity d.
The second object of the present invention is the new method preparing clarithromycin impurity d providing a kind of high income, purity high.
Third object of the present invention is to provide a kind of post processing simple, need not can obtain purity using column chromatography purification
The method preparing clarithromycin impurity d higher than 98%.
Clarithromycin impurity d, preparation method as shown in formula (ii) for its structure,
Comprising: in non-alkaline solvent, clarithromycin and n-
The double benzsulfamide of fluoro is reacted at low temperature.
Described non-alkaline solvent is esters solvent, halogenated hydrocarbon solvent or their mixture, and described esters solvent is acetic acid
One or more of ethyl ester, isopropyl acetate, n-butyl acetate；Described halogenated hydrocarbon solvent be dichloromethane, carbon tetrachloride, 1,
One or more of 2- dichloroethanes or chlorobenzene.In certain embodiments, described non-alkaline solvent is dichloromethane, acetic acid
Ethyl ester or a combination thereof.The volume of described non-alkaline solvent is 3ml/g to 10ml/g with respect to clarithromycin, preferably 5ml/g.
Described non-alkaline solvent does not include dimethyl sulfoxide, n, n- dimethylformamide (dmf), n, n- dimethyl acetylamide
Etc. (dmac) show weakly alkaline solvent.
Described low temperature refers to that temperature is about -20 DEG C to about 0 DEG C, in certain embodiments, described low temperature refer to temperature be about -
15 DEG C to about -10 DEG C.
The double benzsulfamide of described n- fluoro is about 1.0 equivalents to about 1.5 equivalents with respect to clarithromycin, and preferably from about 1.2 work as
Amount.The feed postition of the double benzsulfamide of described n- fluoro, can be directly added into the double benzsulfamide solid of n- fluoro it is also possible to first will
The double benzsulfamide of n- fluoro is dissolved in formation solution in non-alkaline solvent, is then slowly dropped into double for n- fluoro benzsulfamide solution
In reaction system.
Preparation method of the present invention, after reaction finishes, adds bicarbonate aqueous solution that reaction, Ran Houfen are quenched
Liquid, concentration organic faciess obtain clarithromycin impurity d crude product, then using alcohols solvent as recrystallisation solvent, by recrystallization method
Purification clarithromycin impurity d crude product, obtains the clarithromycin impurity d sterling that purity is higher than 98% after recrystallization.
In one embodiment, realize the purpose of the present invention using following steps: by clarithromycin (10g) and acetic acid second
Ester (30ml) adds in reaction bulb, is cooled to -15 DEG C, is then slowly added dropwise the double benzene sulfonyl of n- fluoro of above-mentioned preparation toward in system
The ethyl acetate solution of amine, completion of dropping, after stirring 8h, add the 3wt% sodium bicarbonate solution of 30g to stir 30 minutes, quiet
Put, divide liquid, obtain ethyl acetate layer, water layer extracts (20ml x 2) with methyl tertiary butyl ether(MTBE), merge methyl tert-butyl ether layers and second
Ethyl acetate layer, concentrating under reduced pressure, obtain clarithromycin impurity d crude product, purity 85.1%.Add 60ml ethanol toward in crude product, heat up
To about 70 DEG C, solid all dissolves, gradient cooling to 0～5 DEG C (15 DEG C/h), stirs 2h, filters.
The present invention following beneficial effect of acquirement:
Present invention discover that it is mould using the double benzsulfamide of n- fluoro, clarithromycin can be carried out with the n- prepared carat that methylates
Plain impurity d, this reaction can generate clarithromycin impurity d through single step reaction under mild conditions, then passes through recrystallization
Obtain the clarithromycin impurity d that purity is higher than 98%, the clarithromycin impurity d of gained can be used as in clarithromycin quality research
Reference substance use.
Term " about " used in the context of the invention, refers to the numerical range of concrete numerical value ± 10%.For example, short
Language " about 50mg " includes ± the 10% of 50 or from 45 to 55mg.
In the context of the invention, shown in term " clarithromycin impurity d " its structure such as formula (ii):
Specific embodiment
In order that those skilled in the art more fully understands technical scheme, disclose some further below non-
The present invention is described in further detail to limit embodiment.
Reagent used by the present invention and raw material all can be purchased from the market and obtain.
The Chinese nickname of the double benzsulfamide of n- fluoro: n- fluorobenzenesulfonimide, n- fluoro two benzenesulfonimide, n- fluoro are double
Benzenesulfonimide, No. cas: 133745-75-2, buy from sail bio tech ltd of upper Hisense, clarithromycin is bought from preferably
Prosperous the Changjiang river pharmaceutcal corporation, Ltd.
In the context of the invention, g represents gram, ml represents milliliter, and h represents hour, and 15 DEG C/h represents and lowers the temperature 15 DEG C per hour,
Wt% represents weight or mass percent.
Embodiment 1 prepares clarithromycin impurity d
Prepare the double benzsulfamide solution of n- fluoro: double for the n- fluoro of 5.0g benzsulfamides are dissolved in the ethyl acetate of 15ml
In, obtain the ethyl acetate solution of the double benzsulfamide of n- fluoro.
Clarithromycin (10g) is added in reaction bulb with ethyl acetate (30ml), is cooled to -15 DEG C, then toward in system
It is slowly added dropwise the ethyl acetate solution of the double benzsulfamide of n- fluoro of above-mentioned preparation, completion of dropping, after stirring 8h, add 30g
3wt% sodium bicarbonate solution stir 30 minutes, standing, point liquid, obtain ethyl acetate layer, water layer methyl tertiary butyl ether(MTBE) extracts
(20ml x 2), merges methyl tert-butyl ether layers and ethyl acetate layer, concentrating under reduced pressure, obtains clarithromycin impurity d crude product, purity
85.1%.Toward in crude product add 60ml ethanol, be warming up to about 70 DEG C, solid all dissolves, gradient cooling to 0～5 DEG C (15 DEG C/
H), stir 2h, filter, wash, being dried to obtain 8.8g clarithromycin impurity d, hplc purity (peak area) is 98.5%.
Embodiment 2 prepares clarithromycin impurity d
10g clarithromycin is added in 50ml dichloromethane, adds the double benzsulfamide of 4.7g n- fluoro, -10 DEG C of reactions
After 12h, after completion of the reaction, 3% sodium bicarbonate solution adding 30g stirs 30 minutes, standing, point liquid, and organic layer is evaporated and obtains
Clarithromycin impurity d crude product, purity 87.2%.Add 60ml ethanol toward in crude product, be warming up to 70 DEG C, solid all dissolves, ladder
Degree is cooled to 0～5 DEG C (15 DEG C/h), stirs 2h, filters, washes, being dried to obtain 8.2g clarithromycin impurity d, hplc purity (peak
Area) it is 99.1%.
Embodiment 3hplc purity detecting condition
Chromatographic column: waters beh x bridge c18 4.6*100mm, 2.5um
Flow velocity: 1.2ml/min
Column temperature: 60 DEG C
Detection wavelength: 205＆230nm
Run time: 25min
Equilibration time: 3min
Gradient elution
Time (min) a phase (v/v) b phase (v/v)
0 60 40
10 25 75
15 25 75
The potassium dihydrogen phosphate aqueous solution (ph5.5) of a phase: 10mm-acetonitrile mixed solution (80:20, v/v).
B phase: acetonitrile (hplc).
The method of the present invention is described by preferred embodiment, related personnel substantially can present invention,
In spirit and scope, method described herein and application are modified or suitably change and combine, to realize and to apply the present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter and realize.Specifically, institute
There is similar replacement and change apparent to those skilled in the art, they are considered as including in the present invention
Interior.
Claims (6)
1. the preparation method of clarithromycin impurity d, comprising: in non-alkaline solvent, clarithromycin double benzsulfamides with n fluoro
Reacted at low temperature, described low temperature refers to that temperature is -15 DEG C to -10 DEG C, the double benzsulfamide of described n- fluoro with respect to gram
Mycin is drawn to be 1.0 equivalents to 1.5 equivalents, shown in described clarithromycin its structure of impurity d such as formula (ii)
2. preparation method as claimed in claim 1, the double benzsulfamide of described n- fluoro is 1.2 equivalents with respect to clarithromycin.
3. preparation method as claimed in claim 1, the feed postition of the double benzsulfamide of described n fluoro, is first by double for n fluoro benzene
Sulfonamide is dissolved in formation solution in non-alkaline solvent, then double for n- fluoro benzsulfamide solution is slowly dropped into reaction system
In.
4. preparation method as claimed in claim 1, described non-alkaline solvent is dichloromethane, ethyl acetate or a combination thereof.
5. preparation method as claimed in claim 1, the volume of described non-alkaline solvent is with respect to clarithromycin for 3ml/g extremely
10ml/g.
6. described preparation method as arbitrary in claim 1-5, after reaction finishes, adds bicarbonate aqueous solution to be quenched instead
Should, then divide liquid, concentration organic faciess to obtain clarithromycin impurity d crude product, then using alcohols solvent as recrystallisation solvent, by weight
Crystallization purifying clarithromycin impurity d crude product, obtains the clarithromycin impurity d sterling that purity is higher than 98% after recrystallization.
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|---|---|---|---|
| CN201410840070.8A CN104610402B (en) | 2014-12-30 | 2014-12-30 | Preparation method of macrolide impurity |
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| CN201410840070.8A CN104610402B (en) | 2014-12-30 | 2014-12-30 | Preparation method of macrolide impurity |
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| CN104610402A CN104610402A (en) | 2015-05-13 |
| CN104610402B true CN104610402B (en) | 2017-01-25 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008099368A1 (en) * | 2007-02-15 | 2008-08-21 | Ranbaxy Laboratories Limited | Macrolide derivatives as antibacterial agents |
| WO2008111020A3 (en) * | 2007-03-14 | 2008-11-13 | Ranbaxy Lab Ltd | Macrolide derivatives as antibacterial agents |
| WO2009006403A3 (en) * | 2007-06-29 | 2010-01-07 | Georgia Tech Research Corporation | Non-peptide macrocyclic histone deacetylase (hdac) inhibitors and methods of making and using thereof |
-
2014
- 2014-12-30 CN CN201410840070.8A patent/CN104610402B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008099368A1 (en) * | 2007-02-15 | 2008-08-21 | Ranbaxy Laboratories Limited | Macrolide derivatives as antibacterial agents |
| WO2008111020A3 (en) * | 2007-03-14 | 2008-11-13 | Ranbaxy Lab Ltd | Macrolide derivatives as antibacterial agents |
| WO2009006403A3 (en) * | 2007-06-29 | 2010-01-07 | Georgia Tech Research Corporation | Non-peptide macrocyclic histone deacetylase (hdac) inhibitors and methods of making and using thereof |
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| CN104610402A (en) | 2015-05-13 |
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