CN106632550A - Method for preparing clarithromycin impurity I - Google Patents
Method for preparing clarithromycin impurity I Download PDFInfo
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- CN106632550A CN106632550A CN201610866537.5A CN201610866537A CN106632550A CN 106632550 A CN106632550 A CN 106632550A CN 201610866537 A CN201610866537 A CN 201610866537A CN 106632550 A CN106632550 A CN 106632550A
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- ethanol
- cla
- mixed alcohols
- alcohols solvent
- impurity
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- 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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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of pharmaceutical and chemical industry and particularly relates to a method for preparing an clarithromycin impurity I. The method includes: placing clarithromycin into a mixed alcohol solvent, adding acid, controlling reaction temperature and reaction time to selectively remove cladinose, and refining and purifying to obtain the high-purity clarithromycin impurity I (larger than 99%). The method has the advantages that acid selection is coordinated with the reaction temperature, and cladinose removing specificity in the mixed alcohol solvent is achieved; meanwhile, the understanding of a clarithromycin production process is further increased by researching the clarithromycin impurity I.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of preparation method of CLA impurity I.
Background technology
CLA (clarithromycin) is the quaternary macrolide antibiotics of the second generation ten, and it is stable to acid, is inhaled
High income, good effect, Small side effects, it is considered to be current most safely and effectively one of broad-spectrum antibiotic, No. CAS is 81103-
11-9。
There is inhibitory action to gram-positive bacteria such as staphylococcus aureus, streptococcus, pneumococcus etc., blue is removed from office to part
Family name's negative bacterium such as haemophilus influenzae, Bordetella pertussis, NEISSERIA GONORRHOEAE, legionella pneumophilia and part anaerobic bacteria intend bar as fragile
Bacterium, peptostreptococcus, propionibacterium acnes etc. also have inhibitory action, also have inhibitory action to mycoplasma in addition.With definite
Curative effect, relatively low toxic and side effect.
With being continuously increased for China's CLA bulk drug export volume in recent years, many enterprises are all to itself CLA
The quality of product is put forward higher requirement, and has especially put into the plenty of time in the research of some CLA known impurities,
But in terms of the research of CLA impurity I, report without Patents both at home and abroad at present.
Its structural formula of CLA impurity I is as follows：At present both at home and abroad without the report of the impurity I that can be inquired about, its is main
Reason has two aspects：1st, CLA impurity I contents in the middle of current production technology both domestic and external are relatively small；2nd, preparing
When CLA impurity I carries out desugar reaction, selectivity is inadequate, it is difficult to accomplish selectively to slough cladinose, so as to increase
The difficulty for preparing impurity I is added.
Impurity I
The content of the invention
The invention mainly relates to a kind of preparation method of CLA impurity, is conducive to improving the matter of CLA bulk drug
Amount control.
Technical solution of the present invention：
A kind of method for preparing CLA impurity, its structure is as follows：
Characterized in that, synthesis path is as follows：
Methods described is CLA in mixed alcohols solvent, adds acid reaction, selectively sloughs cladinose preparation
CLA impurity I.
Preferably, described mixed alcohols solvent is methanol/ethanol system or methyl alcohol-n-butanol system or methyl alcohol-isopropyl
Alcohol system or ethanol-glycol system or ethanol-Isopropanol Solvent or other, both ratio regular meetings in mixed solvent affect carat
Mycin impurity I separates out crystal formation, purity.
It is further preferred that it is 0.10～0.17g/mL that CLA accounts for the concentration of solvent.
It is further preferred that when described mixed alcohols solvent is methanol/ethanol system, the volume ratio of methyl alcohol and ethanol
For 1：0.8～1.2；
When described mixed alcohols solvent is ethanol-n-butanol system, ethanol is 1 with the volume ratio of n-butanol：1.0～
2.0；
When described mixed alcohols solvent is ethanol-Isopropanol Solvent, ethanol is 4 with the volume ratio of isopropanol：1.0～
3.0
When described mixed alcohols solvent is methyl alcohol-n-butanol system, methyl alcohol is 10 with the volume ratio of n-butanol：1.0～
2.0；
When described mixed alcohols solvent is methanol-isopropanol system, methyl alcohol is 2 with the volume ratio of isopropanol：1.5～
2.5；
When described mixed alcohols solvent is ethanol-glycol system, ethanol is 5 with the volume ratio of ethylene glycol：1.0～
1.5；
Preferably, described acid be hydrochloric acid or sulfuric acid or sulfurous acid or ice ethanol or formic acid or other.
Preferably, described reaction temperature is -20～100 DEG C.
Preferably, the described reaction time is 2～24h.
Preferably, described CLA：Sour mol ratio is 1:0.5～5.
Beneficial effects of the present invention：
1) for suitable soda acid and reaction temperature and the reasonable coordination of time is selected for different solvents, could, reach
Cladinose is sloughed to selective, so as to generate CLA impurity I.
2) different dicyandiamide solutions has an impact to elimination reaction, and according to different dicyandiamide solutions suitable reaction temperature is determined
Degree and time.
3) the CLA impurity I crude products purity 90% or so obtained using the application, mycin impurity I purity ＞ after refining
99%.
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
Add in 500ml four-hole boiling flasks and be to slowly warm up under CLA 50g, methyl alcohol 150ml, ethanol 150ml, stirring
40 ± 3 DEG C, hydrochloric acid 10ml is then slowly added dropwise, insulated and stirred 8h adds dichloromethane 200ml to extract once, water layer after cooling
After with liquid adjusting PH with base to 8, each 200ml ethyl acetate is extracted 2 times, and organic layer is evaporated and obtains 30g CLA impurity I, HPLC
Purity ＞ 95%, ethyl alcohol recrystallization purity ＞ 99%.
Embodiment 2
Add in 500ml four-hole boiling flasks and slowly heated up under CLA 50g, ethanol 200ml, n-butanol 150ml, stirring
To 50 ± 3 DEG C, glacial acetic acid 20ml is then slowly added dropwise, insulated and stirred 16h adds dichloromethane 200ml to extract once after cooling,
After water layer is with liquid adjusting PH with base to 8, each 200ml ethyl acetate is extracted 2 times, and organic layer is evaporated and obtains 35g CLA impurity I,
HPLC purity ＞ 93%, ethyl alcohol recrystallization purity ＞ 99%.
Embodiment 3
Add in 500ml four-hole boiling flasks and slowly heated up under CLA 50g, ethanol 200ml, isopropanol 100ml, stirring
To 40 ± 3 DEG C, the common 25g of sulfurous acid is then dividedly in some parts, is warming up to 70 DEG C, insulated and stirred 20h under reflux state is cooled to room temperature
First dichloromethane 200ml is added to extract once with hydrochloric acid tune pH to 5 afterwards, water layer uses again liquid adjusting PH with base to after 8, each 200ml second
Acetoacetic ester is extracted 2 times, and organic layer is evaporated and obtains 25g CLA impurity I, HPLC purity ＞ 94%, ethyl alcohol recrystallization purity ＞
99%.
Embodiment 4
Add in 500ml four-hole boiling flasks and slowly heated up under CLA 50g, methyl alcohol 150ml, isopropanol 150ml, stirring
To 25 ± 3 DEG C, the common 18g of sulfurous acid is then dividedly in some parts, is warming up to 70 DEG C, insulated and stirred 20h under reflux state is cooled to room temperature
First dichloromethane 200ml is added to extract once with hydrochloric acid tune pH to 5 afterwards, water layer uses again liquid adjusting PH with base to after 8, each 200ml second
Acetoacetic ester is extracted 2 times, and organic layer is evaporated and obtains 32g CLA impurity I, HPLC purity ＞ 96%, ethyl alcohol recrystallization purity ＞
99%.
Embodiment 5
Add in 500ml four-hole boiling flasks and slowly heated up under CLA 50g, ethanol 250ml, ethylene glycol 50ml, stirring
To 45 ± 3 DEG C, the common 15ml of formic acid is then dividedly in some parts, is warming up to 70 DEG C, insulated and stirred 10h under reflux state is added after cooling
Dichloromethane 200ml is extracted once, and again with liquid adjusting PH with base to after 8, each 200ml ethyl acetate is extracted 2 times water layer, and organic layer steams
It is dry to obtain 35g CLA impurity I, HPLC purity ＞ 95%, ethyl alcohol recrystallization purity ＞ 99%.
Embodiment 6
Add in 500ml four-hole boiling flasks and slowly heated up under CLA 50g, methyl alcohol 270ml, n-butanol 30ml, stirring
To 25 ± 3 DEG C, the common 18g of glacial acetic acid is then dividedly in some parts, is warming up to 70 DEG C, insulated and stirred 20h under reflux state is cooled to room temperature
First dichloromethane 200ml is added to extract once with hydrochloric acid tune pH to 5 afterwards, water layer uses again liquid adjusting PH with base to after 8, each 200ml second
Acetoacetic ester is extracted 2 times, and organic layer is evaporated and obtains 32g CLA impurity I, HPLC purity ＞ 88%, ethyl alcohol recrystallization purity ＞
99%.
Embodiment 7
Add in 500ml four-hole boiling flasks and slowly heated up under CLA 50g, methyl alcohol 270ml, n-butanol 30ml, stirring
To 25 ± 3 DEG C, the common 18g of glacial acetic acid is then dividedly in some parts, is warming up to 100 DEG C, insulated and stirred 10h under reflux state is cooled to room
Wen Houxian adjusts pH to 5 with hydrochloric acid, adds dichloromethane 200ml to extract once, and water layer uses again liquid adjusting PH with base to after 8, each 200ml
Ethyl acetate is extracted 2 times, and organic layer is evaporated and obtains 32g CLA impurity I, HPLC purity ＞ 88%, ethyl alcohol recrystallization purity
＞ 99%.
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 mutually be combined.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 method for preparing CLA impurity I, its structure is as follows：
Characterized in that, synthesis path is as follows：
Methods described is CLA in mixed alcohols solvent, adds acid reaction, selectively sloughs cladinose, post-treated
CLA impurity I is prepared after purification.
2. method according to claim 1, it is characterised in that：Described mixed alcohols solvent be methanol/ethanol system or
Ethanol-n-butanol system or ethanol-Isopropanol Solvent or methyl alcohol-n-butanol system or methanol-isopropanol system or ethanol-second two
Alcohol system or ethanol-Isopropanol Solvent or other.
3. method according to claim 2, it is characterised in that：CLA account for mixed alcohols solvent concentration be 0.10～
0.17g/mL。
4. method according to claim 3, it is characterised in that：When described mixed alcohols solvent is methanol/ethanol system,
Methyl alcohol is 1 with the volume ratio of ethanol：0.8～1.2；
When described mixed alcohols solvent is ethanol-n-butanol system, ethanol is 1 with the volume ratio of n-butanol：1.0～2.0；
When described mixed alcohols solvent is ethanol-Isopropanol Solvent, ethanol is 4 with the volume ratio of isopropanol：1.0～3.0；
When described mixed alcohols solvent is methyl alcohol-n-butanol system, methyl alcohol is 5 with the volume ratio of n-butanol：0.5～1.0；
When described mixed alcohols solvent is methanol-isopropanol system, methyl alcohol is 2 with the volume ratio of isopropanol：1.5～2.5；
When described mixed alcohols solvent is ethanol-glycol system, ethanol is 5 with the volume ratio of ethylene glycol：1.0～1.5.
5. method according to claim 1, it is characterised in that：Described acid is hydrochloric acid or sulfuric acid or sulfurous acid or ice ethanol
Formic acid or other.
6. method according to claim 1, it is characterised in that：Described reaction temperature is -20～100 DEG C.
7. method according to claim 1, it is characterised in that：The described reaction time is 2～24h.
8. method according to claim 1, it is characterised in that：Described CLA：Sour mol ratio is 1:0.5～5.
9. method according to claim 1, it is characterised in that：CLA is cold after mixed alcohols solvent and acid reaction
But pH to 5～8 is adjusted afterwards, dichloromethane extraction is added, and water layer reuses ethyl acetate extraction again with liquid adjusting PH with base to after 8, has
Machine layer is evaporated and obtains drawing mycin impurity I.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610866537.5A CN106632550B (en) | 2016-09-30 | 2016-09-30 | A kind of method for preparing CLA impurity I |
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| CN201610866537.5A CN106632550B (en) | 2016-09-30 | 2016-09-30 | A kind of method for preparing CLA impurity I |
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| CN106632550A true CN106632550A (en) | 2017-05-10 |
| CN106632550B CN106632550B (en) | 2018-03-06 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105524132A (en) * | 2014-09-30 | 2016-04-27 | 中国医学科学院药物研究所 | Erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, and preparation methods and applications thereof |
| CN103619849B (en) * | 2011-03-01 | 2016-05-25 | 沃克哈特有限公司 | The preparation method of ketone lactone intermediate |
-
2016
- 2016-09-30 CN CN201610866537.5A patent/CN106632550B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103619849B (en) * | 2011-03-01 | 2016-05-25 | 沃克哈特有限公司 | The preparation method of ketone lactone intermediate |
| CN105524132A (en) * | 2014-09-30 | 2016-04-27 | 中国医学科学院药物研究所 | Erythromycin A ketolide antibiotic derivatives containing quinoline substituent group, and preparation methods and applications thereof |
Non-Patent Citations (1)
| Title |
|---|
| 赵贞贞: "《STN检索记录》", 24 January 2017 * |
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Effective date of registration: 20200908 Address after: No.62, Lucheng Binjiang Road, Yidu City, Yichang City, Hubei Province Patentee after: Yichang dongyangguang Biochemical Pharmaceutical Co., Ltd Address before: 443300, No. 38, Binjiang Avenue, Lu Town, Yidu, Yichang, Hubei Patentee before: HEC PHARM Co.,Ltd. |
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