CN106589023A - Roxithromycin impurity and synthetic method thereof - Google Patents
Roxithromycin impurity and synthetic method thereof Download PDFInfo
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- CN106589023A CN106589023A CN201611046328.2A CN201611046328A CN106589023A CN 106589023 A CN106589023 A CN 106589023A CN 201611046328 A CN201611046328 A CN 201611046328A CN 106589023 A CN106589023 A CN 106589023A
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- roxithromycin
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- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention relates to a roxithromycin impurity and a synthetic method thereof. The synthetic method comprises the following main steps: taking methyl chloride methyl ether (formula II) as a starting material to react with erythromycin oxime in an appropriate solvent at a low temperature under an alkaline condition, performing an appropriate treatment to obtain a crude product, and refining the crude product to obtain a pure target compound (formula I). The invention provides a first report of identifying and synthetic methods of the roxithromycin impurity, and meanwhile, the synthetic route is simple and feasible, the yield is good, the product is high purity, a requirement of daily detection serving as a work standard product can be met, and a more scientific and effective means is provided for quality control of roxithromycin.
Description
Technical field
The present invention relates to field of medicine and chemical technology, and in particular to a kind of Roxithromycin impurity and its synthetic method.
Background technology
Roxithromycin, structural formula is shown in formula IV, and English name is Roxithromycin, is in the semi-synthetic big ring of the first generation
Esters antibiotic, antimicrobial spectrum and antibacterial action are similar with erythromycin.Mainly act on gram positive bacteria, anaerobe, chlamydia
With mycoplasma etc..Although Time To Market is for a long time, but still is one of current three most widely used big antibiotic.
Heretofore described Roxithromycin impurity, also known as 9- (E)-methoxy erythromycin A-9 oxime, according to European Pharmacopoeia
Detection method, its relative retention time in liquid chromatograph is about 0.92, and open report is there are no before this.Send out under study for action
Existing, the impurity is proportionate with the impurity component in Roxithromycin side chain, and Jing LC-MS isolation identification confirms its structural formula.Pass through
Controlled syntheses obtain the working standard of the impurity, and study its physicochemical property and minimizing technology, for Roxithromycin product
The control and lifting of quality has great importance.
The content of the invention
The invention mainly relates to a kind of Roxithromycin impurity, its structure is as follows：
The synthetic method of described Roxithromycin impurity, is synthesized according to following route：
Comprise the following steps：
1) with methylchlormethyl ether be compound II as starting material, be compound III in reaction dissolvent with erythromycin A-9 oxime
Middle addition alkali is reacted, and reaction adjusts pH to 6～7 after terminating, and reaction dissolvent is fallen in vacuum distillation, adds in recrystallisation solvent
Row crystallization, filtration, drying obtain crude product；
2) crude product adds recrystallisation solvent, the solution recrystallization obtained after stirring, filtration, and filtration, drying obtain target chemical combination
Thing I.
Preferably, the step 1) alkali is Feldalat NM or Sodium ethylate or potassium tert-butoxide.
Preferably, the step 1) reaction temperature be -20 DEG C～-10 DEG C.
Preferably, the step 1) reaction dissolvent is dimethyl sulfoxide or DMF or acetone or tetrahydrochysene furan
Mutter.
Preferably, the step 1) mol ratio of methylchlormethyl ether and erythromycin A-9 oxime is 1.1～1.6：1, the alkali with
The mol ratio of erythromycin A-9 oxime is 1.0～1.5：1, the reaction dissolvent volume is 3～8 times of erythromycin A-9 oxime weight.
Preferably, the step 1), step 2) recrystallisation solvent is ethanol-water system or acetone water solution or ethyl acetate
Or DMF；
The ethanol is 1 with water volume ratio：0.5～1.5；The acetone is 1 with water volume ratio：0.5～1.5；The knot
Brilliant temperature is -10 DEG C～0 DEG C.
Preferably, the step 2) in crude product except adding recrystallisation solvent, be also added into the 1%～1.2% of crude product weight
Activated carbon.
Preferably, the step 2) stirring when temperature be 50 DEG C～55 DEG C.
Beneficial effects of the present invention：
1st, a kind of structure of the Roxithromycin impurity (Formulas I) that report is not disclosed before this is illustrated, it is analyzed in European Pharmacopoeia
Appearance time in method be the position of relative retention time 0.92, be Roxithromycin crude drug miscellaneous Mass Spectra with the addition of it is new
Content.
The 2nd, the synthetic method of one simply and easily Roxithromycin impurity is provided, is obtained by controlled syntheses and polishing purification
Working standard, be conducive to lifted Roxithromycin crude drug inherent quality and quality control level.
3rd, methylchlormethyl ether is one of starting material, and the side chain of target product is formed after reaction；Erythromycin A-9 oxime is target
The main ring structure of product；Alkali reacts with compound III, seizes the H in oxime hydroxyl+, the higher alcoxyl anion of nucleophilicity is formed,
Directly, there is S in the carbon with positive electrical effect on attack compound IIN2 nucleophilic substitutions generate target product.Be not added with alkali or
Its alkalescence of the alkali of person's addition is too weak, and reaction then can not occur, or rarely product is generated.Limit the ratio model of the amount of each material
Enclose, within this range, it is possible to obtain optimal reaction result.
4th, reaction temperature is -20 DEG C～-10 DEG C, and in the temperature range, reaction is well on, and impurity is less.Higher than this
Temperature range, reaction can produce more impurity；Less than the temperature range, reaction is carried out slowly, is unfavorable for the generation of product.
5th, the selection of reaction dissolvent has a major impact to reaction, because this reaction belongs to classical SN2 nucleophilic displacement of fluorine
Reaction mechanism, therefore polar non-solute is conducive to the generation of reaction.
6th, different recrystallisation solvents may can obtain the product of different quality, and can be obtained using recrystallisation solvent of the present invention
Obtain higher yields, highly purified product.The fine setting of ratio be in order to obtain in high yield with high-quality balance.
7th, used as industrial conventional adsorbent, Main Function is, for adsorbing contaminant, to decolourize to activated carbon, and drainage is removed not
Soluble solids etc. are acted on.Contribute to here improving the quality of product, remove the various insoluble impuritiess adhered in product.
8th, the purpose of crystallization stirring is to aid in dissolving crude product in recrystallisation solvent, while in this 50 DEG C～55 DEG C temperature ranges
Under, dissolving is thorough, does not have insoluble product and loses when filtering, and higher than the temperature range stablizing for product is unfavorable for,
It is not complete less than the temperature dissolving crude product.
Description of the drawings
Fig. 1, the LC-MS collection of illustrative plates of Roxithromycin impurity；
In figure：MS(ESI):793.5082(M+H)+
Specific embodiment
The present invention is further illustrated with reference to embodiment, but the scope of protection of present invention is not limited to implement
The scope of example statement.
Embodiment 1:The synthesis of 9- (E)-methoxy erythromycin A-9 oxime
The erythromycin oxime (formula III) of 10g, DMF are sequentially added in the four-hole bottle that 250ml is dried
30ml, methanol solution of sodium methylate (28%) 3.6g, open stirring, and reactant liquor is placed at -20 DEG C, when Inner temperature drops are to -10 DEG C, drop
Methylate chloromethylether (Formula II) 1.3g, is controlled after one hour of reaction with TLC.After the raw material point of erythromycin oxime disappears, eventually
Only react.The Deca acetic acid toward reaction bulb, adjusts pH to 6-7.Vacuum distillation, evaporates the N in reaction system, N- dimethyl formyls
Amine, adds 60ml ethanol and 40ml water, and molten clear rear slow cooling obtains white powder to -10 DEG C～0 DEG C crystallization after filtering drying
Last 7.2g, yield 68.0%.
Embodiment 2：The synthesis of 9- (E)-methoxy erythromycin A-9 oxime
The erythromycin oxime (formula III) of 10g, DMF are sequentially added in the four-hole bottle that 250ml is dried
40ml, Feldalat NM 1.0g, open stirring, and reactant liquor is placed at -20 DEG C, when Inner temperature drops are to -10 DEG C, Deca methylchlormethyl ether
(Formula II) 1.3g, with control in TLC (thin layer chromatography) after one hour of reaction.After the raw material point of erythromycin oxime disappears, terminate
Reaction.The Deca acetic acid toward reaction bulb, adjusts pH to 6-7.Vacuum distillation, evaporates the N in reaction system, N- dimethyl formyls
Amine, adds 60ml ethanol and 40ml water, and molten clear rear slow cooling obtains white powder to -10 DEG C～0 DEG C crystallization after filtering drying
Last 6.4g, yield 60.5%.
Embodiment 3：The synthesis of 9- (E)-methoxy erythromycin A-9 oxime
The erythromycin oxime (formula III) of 10g, dimethyl sulfoxide 30ml, ethanol are sequentially added in the four-hole bottle that 250ml is dried
Sodium 1.3g, opens stirring, and reactant liquor is placed at -20 DEG C, when Inner temperature drops are to -10 DEG C, Deca methylchlormethyl ether (Formula II)
1.3g, with control in TLC (thin layer chromatography) after one hour of reaction.After the raw material point of erythromycin oxime disappears, terminating reaction.It is past
Deca acetic acid in reaction bulb, adjusts pH to 6-7.Vacuum distillation, evaporates the dimethyl sulfoxide in reaction system, adds 60ml second
Alcohol and 40ml water, molten clear rear slow cooling obtains white powder 6.8g, yield to -10 DEG C～0 DEG C crystallization after filtering drying
64.3%.
Embodiment 4：The synthesis of 9- (E)-methoxy erythromycin A-9 oxime
The erythromycin oxime (formula III) of 10g, tetrahydrofuran 60ml, Feldalat NM are sequentially added in the four-hole bottle that 250ml is dried
1.0g, opens stirring, and reactant liquor is placed at -20 DEG C, when Inner temperature drops are to -10 DEG C, Deca methylchlormethyl ether (Formula II) 1.3g,
With control in TLC (thin layer chromatography) after one hour of reaction.After the raw material point of erythromycin oxime disappears, terminating reaction.Toward reaction
Deca acetic acid in bottle, adjusts pH to 6-7.Vacuum distillation, evaporates the tetrahydrofuran in reaction system, add 60ml ethanol and
40ml water, molten clear rear slow cooling obtains white powder 5.8g, yield 54.8% to -10 DEG C～0 DEG C crystallization after filtering drying.
Embodiment 5：The synthesis of 9- (E)-methoxy erythromycin A-9 oxime
The erythromycin oxime (formula III) of 10g, tetrahydrofuran 60ml, the tert-butyl alcohol are sequentially added in the four-hole bottle that 250ml is dried
Potassium 2.1g, opens stirring, and reactant liquor is placed at -20 DEG C, when Inner temperature drops are to -10 DEG C, Deca methylchlormethyl ether (Formula II)
1.3g, with control in TLC (thin layer chromatography) after one hour of reaction.After the raw material point of erythromycin oxime disappears, terminating reaction.It is past
Deca acetic acid in reaction bulb, adjusts pH to 6-7.Vacuum distillation, evaporates the tetrahydrofuran in reaction system, adds 60ml ethanol
With 40ml water, molten clear extremely -10 DEG C～0 DEG C crystallization of rear slow cooling, white powder 6.0g, yield are obtained after filtering drying
56.7%.
Embodiment 6:9- (E)-methoxy erythromycin A-9 oxime crude product it is refined
Crude product 10g is taken, adds acetone 40ml to be dissolved in reaction bulb, stirred at 50 DEG C of temperature control, be slowly added dropwise water 40ml, it is molten
Activated carbon 0.1g is added in liquid, continues to stir half an hour, filtered while hot, mother solution is poured in reaction bulb and is incubated and is naturally cooling to
Room temperature (25 DEG C), then -10 DEG C of crystallizations are cooled to, filtering drying obtains sterling target compound 8.5g, yield 85%, purity
98.5%.
Embodiment 7:9- (E)-methoxy erythromycin A-9 oxime crude product it is refined
Crude product 10g is taken, adds ethyl acetate 30ml to be dissolved in reaction bulb, stirred at 50 DEG C of temperature control, added in solution and live
Property charcoal 0.1g, continue to stir half an hour, filtered while hot, mother solution pours in reaction bulb and is incubated and is naturally cooling to room temperature (25
DEG C), then -10 DEG C of crystallizations are cooled to, filtering drying obtains sterling target compound 7.8g, yield 78%, purity 98.0%.
Embodiment 8:9- (E)-methoxy erythromycin A-9 oxime crude product it is refined
Crude product 10g is taken, DMF 20ml is dissolved in reaction bulb, stirred at 50 DEG C of temperature control, added in solution
Enter activated carbon 0.1g, continue to stir half an hour, filtered while hot, mother solution is poured in reaction bulb and is incubated and is naturally cooling to room temperature
(25 DEG C), then -10 DEG C of crystallizations are cooled to, filtering drying obtains sterling target compound 6.8g, yield 68%, purity 97.9%.
Embodiment 9:9- (E)-methoxy erythromycin A-9 oxime crude product it is refined
Crude product 10g is taken, ethanol is with water according to 1:0.5 ratio 50ml is dissolved in reaction bulb, is stirred at 50 DEG C of temperature control, molten
Activated carbon 0.1g is added in liquid, continues to stir half an hour, filtered while hot, mother solution is poured in reaction bulb and is incubated and is naturally cooling to
Room temperature (25 DEG C), then -10 DEG C of crystallizations are cooled to, filtering drying obtains sterling target compound 8.6g, yield 86%, purity
98.2%.
The above embodiments are only the preferred technical solution of the present invention, and are not construed as the restriction of the present invention, this Shen
Please in embodiment and the feature in embodiment in the case where not conflicting, can mutual combination in any.The protection model of the present invention
Enclose the equivalent side of technical characteristic in the technical scheme that should be recorded with claim, including the technical scheme of claim record
Case is protection domain.Equivalent i.e. within this range is improved, also within protection scope of the present invention.
Claims (9)
1. a kind of Roxithromycin impurity, its structure is as follows：
2. the synthetic method of the Roxithromycin impurity described in claim 1, it is characterised in that synthesized according to following route：
Comprise the following steps：
1) with methylchlormethyl ether be compound II as starting material, with erythromycin A-9 oxime be compound III in reaction dissolvent plus
Enter alkali to be reacted, reaction adjusts pH to 6～7 after terminating, and reaction dissolvent is fallen in vacuum distillation, adds in recrystallisation solvent and is tied
Brilliant, filtration, drying obtain crude product；
2) crude product adds recrystallisation solvent, the solution recrystallization obtained after stirring, filtration, and filtration, drying obtain target compound I.
3. the synthetic method of Roxithromycin impurity according to claim 2, it is characterised in that：The step 1) alkali be methanol
Sodium or Sodium ethylate or potassium tert-butoxide.
4. the synthetic method of Roxithromycin impurity according to claim 2, it is characterised in that：The step 1) reaction temperature
For -20 DEG C～-10 DEG C.
5. the synthetic method of Roxithromycin impurity according to claim 2, it is characterised in that：The step 1) reaction dissolvent
For dimethyl sulfoxide or DMF or acetone or tetrahydrofuran.
6. the synthetic method of Roxithromycin impurity according to claim 2, it is characterised in that：The step 1) methyl chloromethane
Base ether is 1.1～1.6 with the mol ratio of erythromycin A-9 oxime：1, the alkali is 1.0～1.5 with the mol ratio of erythromycin A-9 oxime：1, institute
It is 3～8 times of erythromycin A-9 oxime weight to state reaction dissolvent volume.
7. the synthetic method of Roxithromycin impurity according to claim 2, it is characterised in that：The step 1), step 2)
Recrystallisation solvent is ethanol-water system or acetone water solution or ethyl acetate or DMF；
The ethanol is 1 with water volume ratio：0.5～1.5；The acetone is 1 with water volume ratio：0.5～1.5；The crystallization
Temperature is -10 DEG C～0 DEG C.
8. the synthetic method of Roxithromycin impurity according to claim 2, it is characterised in that：The step 2) in crude product also
Add the 1%～1.2% of crude product weight activated carbon.
9. the synthetic method of Roxithromycin impurity according to claim 2, it is characterised in that：The step 2) stirring when
Temperature is 50 DEG C～55 DEG C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006050943A1 (en) * | 2004-11-11 | 2006-05-18 | Glaxo Group Limited | Macrolone compounds |
| WO2006050941A1 (en) * | 2004-11-11 | 2006-05-18 | Glaxo Group Limited | Macrolone compounds |
| WO2006050940A1 (en) * | 2004-11-11 | 2006-05-18 | Glaxo Group Limited | Macrolone compounds |
| CN101098881A (en) * | 2004-11-11 | 2008-01-02 | 葛兰素集团有限公司 | Macrolones - amino substituted quinolones |
-
2016
- 2016-11-22 CN CN201611046328.2A patent/CN106589023A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006050943A1 (en) * | 2004-11-11 | 2006-05-18 | Glaxo Group Limited | Macrolone compounds |
| WO2006050941A1 (en) * | 2004-11-11 | 2006-05-18 | Glaxo Group Limited | Macrolone compounds |
| WO2006050940A1 (en) * | 2004-11-11 | 2006-05-18 | Glaxo Group Limited | Macrolone compounds |
| CN101098881A (en) * | 2004-11-11 | 2008-01-02 | 葛兰素集团有限公司 | Macrolones - amino substituted quinolones |
Non-Patent Citations (1)
| Title |
|---|
| JEAN-CLAUDE GASC，ET AL.: ""NEW ETHER OXIME DERIVATIVES OF ERYTHROMYCIN A A STRUCTURE-ACTIVITY RELATIONSHIP STUDY"", 《THE JOURNAL OF ANTIBIOTICS》 * |
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Application publication date: 20170426 |