CN104610402A - Preparation method of macrolide impurity - Google Patents
Preparation method of macrolide impurity Download PDFInfo
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- CN104610402A CN104610402A CN201410840070.8A CN201410840070A CN104610402A CN 104610402 A CN104610402 A CN 104610402A CN 201410840070 A CN201410840070 A CN 201410840070A CN 104610402 A CN104610402 A CN 104610402A
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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
The present invention relates to medicinal chemistry art, specifically, the present invention relates to a kind of preparation method of macrolide impurity.
Background technology
Clarithromycin, its chemical structure is such as formula shown in (I), and be the microbiotic of s-generation macrolide, having stronger restraining effect to gram-positive microorganism as streptococcus aureus, suis, streptococcus pneumoniae etc., is current antibiotic main force kind,
Current China produces clarithromycin more than 1000 tons per year, is the major country of production of clarithromycin bulk drug in the world.The production of every a collection of clarithromycin bulk drug all needs to control impurity according to the regulation of pharmacopeia, clarithromycin impurity D, also referred to as nitrogen demethyl clarithromycin, the regulation impurity of American-European pharmacopeia, No. CAS is 101666-68-6, molecular weight 733.93, white solid, its structure is such as formula shown in (II):
The clarithromycin impurity of the synthesis of high purity in contrast quality approach of product to clarithromycin bulk drug has great importance.Current clarithromycin impurity generally adopts following methods to prepare: take clarithromycin as raw material, using sodium acetate as alkali, methanol/water makes solvent, under 70 DEG C of conditions, add iodine and react, react complete, be cooled to-20 DEG C, add ammoniacal liquor, then use dichloromethane extraction, organic layer uses saturated common salt water washing again, after solvent evaporated, then obtain clarithromycin impurity D through purification by column chromatography.Specifically refer to Journal of Labelled Compounds & Radiopharmaceuticals, 47 (2), 95-98; The report of 2004, yield 74%, PCT application open WO2007/25089, WO2008/99368 also report above-mentioned preparation method.This preparation method's complex operation, because by product is many, cannot to be purified by recrystallization, need could obtain higher purity through purification by column chromatography.
Summary of the invention
First object of the present invention explores a kind of novel method preparing clarithromycin impurity D.
The second object of the present invention is to provide the novel method preparing clarithromycin impurity D that a kind of yield is high, purity is high.
It is simple that 3rd object of the present invention is to provide a kind of aftertreatment, without the need to adopt purification by column chromatography can obtain purity higher than 98% the method preparing clarithromycin impurity D.
Clarithromycin impurity D, its structure such as formula the preparation method shown in (II),
it comprises: in non-alkaline solvent, and clarithromycin and the two benzsulfamide of N-fluoro react at low temperatures.
Described non-alkaline solvent is esters solvent, halogenated hydrocarbon solvent or their mixture, and described esters solvent is one or more in ethyl acetate, isopropyl acetate, n-butyl acetate; Described halogenated hydrocarbon solvent is one or more in methylene dichloride, tetracol phenixin, 1,2-ethylene dichloride or chlorobenzene.In certain embodiments, described non-alkaline solvent is methylene dichloride, ethyl acetate or its combination.The volume of described non-alkaline solvent is 3ml/g to 10ml/g relative to clarithromycin, preferred 5ml/g.
Described non-alkaline solvent does not comprise methyl-sulphoxide, DMF (DMF), and N,N-dimethylacetamide (DMAc) etc. show weakly alkaline solvent.
Described low temperature refers to that temperature is about-20 DEG C to about 0 DEG C, and in certain embodiments, described low temperature refers to that temperature is about-15 DEG C to about-10 DEG C.
The two benzsulfamide of described N-fluoro is that about 1.0 equivalents are to about 1.5 equivalents, preferably about 1.2 equivalents relative to clarithromycin.The feed postition of the two benzsulfamide of described N-fluoro, directly can add the two benzsulfamide solid of N-fluoro, also first two for N-fluoro benzsulfamide can be dissolved in non-alkaline solvent and form solution, then two for N-fluoro benzsulfamide solution slowly be instilled in reaction system.
Preparation method of the present invention, react complete after, add bicarbonate aqueous solution cancellation reaction, then separatory, concentrated organic phase obtain clarithromycin impurity D crude product, then using alcoholic solvent as recrystallisation solvent, by recrystallization method purifying clarithromycin impurity D crude product, obtain after recrystallization purity higher than 98% clarithromycin impurity D sterling.
In one embodiment, following steps are adopted to realize object of the present invention: to add in reaction flask by clarithromycin (10g) and ethyl acetate (30ml), be cooled to-15 DEG C, then in system, slowly drip the ethyl acetate solution of the two benzsulfamide of N-fluoro of above-mentioned preparation, dropwise, after stirring 8h, the 3wt% sodium hydrogen carbonate solution adding 30g stirs 30 minutes, leave standstill, separatory, obtain ethyl acetate layer, water layer methyl tertiary butyl ether extraction (20ml x 2), merge methyl tert-butyl ether layers and ethyl acetate layer, concentrating under reduced pressure, obtain clarithromycin impurity D crude product, purity 85.1%.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), stirs 2h, filters.
The present invention obtains following beneficial effect:
The present invention finds to adopt the two benzsulfamide of N-fluoro N-can be gone to methylate obtained clarithromycin impurity D to clarithromycin, this reaction can be under mild conditions, clarithromycin impurity D is generated through single step reaction, then by recrystallization can obtain purity higher than 98% clarithromycin impurity D, the clarithromycin impurity D of gained can use as the reference substance in clarithromycin quality approach.
The term " about " used in the context of the invention, refers to the numerical range of concrete numerical value ± 10%.Such as, phrase " about 50mg " comprise 50 ± 10% or from 45 to 55mg.
In the context of the invention, term " clarithromycin impurity D " its structure is such as formula shown in (II):
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
The reagent that the present invention is used and raw material all can be bought from market and obtain.
The Chinese another name of the two benzsulfamide of N-fluoro: N-fluorobenzenesulfonimide, N-fluoro two benzenesulfonimide, N-fluoro-diphenyl sulfimide, No. Cas: 133745-75-2, buy from sail bio tech ltd of upper Hisense, clarithromycin is bought from Yichang Changjiang Pharmaceutical Co., Ltd..
In the context of the invention, g represents gram, and ml represents milliliter, and h represents hour, and 15 DEG C/h represents cooling per hour 15 DEG C, and wt% represents weight or mass percent.
Embodiment 1 prepares clarithromycin impurity D
The two benzsulfamide solution of preparation N-fluoro: two for the N-fluoro of 5.0g benzsulfamide is dissolved in the ethyl acetate of 15ml, obtains the ethyl acetate solution of the two benzsulfamide of N-fluoro.
Clarithromycin (10g) and ethyl acetate (30ml) are added in reaction flask, be cooled to-15 DEG C, then in system, slowly drip the ethyl acetate solution of the two benzsulfamide of N-fluoro of above-mentioned preparation, dropwise, after stirring 8h, the 3wt% sodium hydrogen carbonate solution adding 30g stirs 30 minutes, standing, separatory, obtain ethyl acetate layer, water layer methyl tertiary butyl ether extraction (20ml x 2), merges methyl tert-butyl ether layers and ethyl acetate layer, concentrating under reduced pressure, obtain clarithromycin impurity D crude product, purity 85.1%.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, filtration, washing, drying obtain 8.8g clarithromycin impurity D, and HPLC purity (peak area) is 98.5%.
Embodiment 2 prepares clarithromycin impurity D
10g clarithromycin is joined in 50mL methylene dichloride, adds the two benzsulfamide of 4.7g N-fluoro, after-10 DEG C of reaction 12h, after completion of the reaction, 3% sodium hydrogen carbonate solution adding 30g stirs 30 minutes, standing, separatory, organic layer evaporate to dryness obtains clarithromycin impurity D crude product, purity 87.2%.In crude product, add 60mL ethanol, be warming up to 70 DEG C, solid all dissolves, gradient cooling to 0 ~ 5 DEG C (15 DEG C/h), stirs 2h, and filtration, washing, drying obtain 8.2g clarithromycin impurity D, and HPLC purity (peak area) 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
Determined wavelength: 205 & 230nm
Working time: 25min
Starting time: 3min
Gradient elution
Time (min) A phase (V/V) B phase (V/V)
0 60 40
10 25 75
15 25 75
Potassium dihydrogen phosphate aqueous solution (the pH5.5)-acetonitrile mixing solutions (80:20, v/v) of A phase: 10mm.
B phase: acetonitrile (HPLC).
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (10)
1. clarithromycin impurity D, its structure such as formula the preparation method shown in (II),
it comprises: in non-alkaline solvent, and clarithromycin and the two benzsulfamide of N-fluoro react at low temperatures.
2. preparation method as claimed in claim 1, described low temperature refers to that temperature is about-20 DEG C to about 0 DEG C.
3. preparation method as claimed in claim 2, described low temperature refers to that temperature is about-15 DEG C to about-10 DEG C.
4. preparation method as claimed in claim 1, the two benzsulfamide of described N-fluoro is that about 1.0 equivalents are to about 1.5 equivalents relative to clarithromycin.
5. preparation method as claimed in claim 4, the two benzsulfamide of described N-fluoro is about 1.2 equivalents relative to clarithromycin.
6. preparation method as claimed in claim 4, the feed postition of the two benzsulfamide of described N-fluoro, is first be dissolved in non-alkaline solvent by two for N-fluoro benzsulfamide to form solution, is then slowly instilled in reaction system by two for N-fluoro benzsulfamide solution.
7. preparation method as claimed in claim 1, described non-alkaline solvent is methylene dichloride, ethyl acetate or its combination.
8. preparation method as claimed in claim 7, the volume of described non-alkaline solvent is 3ml/g to 10ml/g relative to clarithromycin.
9. the preparation method as described in as arbitrary in claim 1-8, react complete after, add bicarbonate aqueous solution cancellation reaction, then separatory, concentrated organic phase obtain clarithromycin impurity D crude product, then using alcoholic solvent as recrystallisation solvent, by recrystallization purifying clarithromycin impurity D crude product, obtain after recrystallization purity higher than 98% clarithromycin impurity D sterling.
10. preparation method as claimed in claim 1, it comprises: add in reaction flask by clarithromycin (10g) and ethyl acetate (30ml), be cooled to-15 DEG C, then in system, slowly drip the ethyl acetate solution of the two benzsulfamide of N-fluoro of above-mentioned preparation, dropwise, after stirring 8h, the 3wt% sodium hydrogen carbonate solution adding 30g stirs 30 minutes, leave standstill, separatory, obtain ethyl acetate layer, water layer methyl tertiary butyl ether extraction (20ml x 2), merge methyl tert-butyl ether layers and ethyl acetate layer, concentrating under reduced pressure, obtain clarithromycin impurity D crude product, purity 85.1%.In crude product, add 60mL ethanol, be warming up to about 70 DEG C, solid all dissolves, and cooling per hour 15 DEG C, is cooled to 0 ~ 5 DEG C, stirs 2h, filters.
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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 |
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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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