CN106699823B - A kind of preparation method of Gamithromycin - Google Patents
A kind of preparation method of Gamithromycin Download PDFInfo
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- CN106699823B CN106699823B CN201710004655.XA CN201710004655A CN106699823B CN 106699823 B CN106699823 B CN 106699823B CN 201710004655 A CN201710004655 A CN 201710004655A CN 106699823 B CN106699823 B CN 106699823B
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- reaction
- gamithromycin
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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
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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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The present invention relates to technical field of medicine synthesis, more particularly to a kind of preparation method of Gamithromycin, the preparation method is using 9- deoxidation -8a- azepine-a-homoerythromycin A and positive propionic aldehyde as raw material, using hydrogen as reducing agent, reaction is under the catalytic action of Pd/NiO to get the Gamithromycin.The preparation method reaction process is mild, is not necessarily to extraordinary hydrogenation equipment, is easy to amplify production；And catalyst can repeatedly recycle use, reduce production cost, and more economical environmental protection is suitble to the needs of scale industrial production.
Description
Technical field
The present invention relates to technical field of medicine synthesis more particularly to a kind of preparation methods of Gamithromycin.
Background technique
Gamithromycin (Gamithromycin) is the veterinary antibiotic of 2007 Nian9Yue European Union approval, is French Cimmeria
(Merial) the newest animal specific macrolides semisynthetic antibiotics researched and developed are antibacterial essence injecta ZactranR's for animals
Principle active component is mainly used for preventing and treating and be drawn by pathogens such as Mannheimia haemolytica, Pasteurella and Histophilus
The respiratory disease of the non-cow in milk risen.Gamithromycin antibacterial action is better than azithromycin, especially to gram-negative positive bacteria
There is very strong antibacterial activity, approved is used to treat the upper respiratory disease of ox.There is Gamithromycin animal specific, single to give
Medicine, absorb rapidly, bioavilability it is high and low residual, it is safe and efficient the advantages that, livestock and poultry cultivation production in have it is boundless
Application prospect.
There are many synthetic method of Gamithromycin at present, the difference is that the reaction condition of final step synthesis is different.In
State patent application CN102239174 disclose one kind using 9- deoxidation -8a- azepine -8a- a-homoerythromycin A and propionic aldehyde as raw material, with
Pd/C is catalyst, the method for obtaining Gamithromycin by the method for high-pressure hydrogenation.Chinese patent application CN103554201 is disclosed
It is a kind of to dissolve in 9- deoxidation -8a- azepine -8a a-homoerythromycin A in solvent, it is added dropwise to propionic aldehyde, after HPLC detects fully reacting, drop
Temperature is added dropwise to pyridine borane to -5 DEG C -5 DEG C, reacts the method for obtaining Gamithromycin.Chinese patent application CN105646618 is public
One kind is opened using 9- deoxidation -8a-8- azepine Erythromycin A and positive propionic aldehyde as raw material, hydrogen silane is reducing agent, organotin or inorganic tin
Reagent is catalyst, the method that Gamithromycin is made through reduction amination.
The problem of that there is reagent prices in the synthetic method of existing disclosed Gamithromycin is expensive, equipment requirement is high etc..
Summary of the invention
The purpose of the present invention is in view of the defects existing in the prior art and insufficient, provide a kind of reaction condition it is mild plus rice
The preparation method of mycin, specifically adopts the following technical scheme that
A kind of preparation method of Gamithromycin, using 9- deoxidation -8a- azepine-a-homoerythromycin A and positive propionic aldehyde as raw material, with hydrogen
Gas is reducing agent, and reaction is under the catalytic action of Pd/NiO to get the Gamithromycin.
The reaction equation of above-mentioned reaction is as follows:
Preferably, in the catalyst Pd and 9- deoxidation -8a- azepine-a-homoerythromycin A molar ratio be 1:(100~
500), further preferably 1:(200~300), most preferably 1:250.
Preferably, the temperature of the reaction is 25-50 DEG C.It is further preferred that the temperature of the reaction is 35 DEG C.
Preferably, the hydrogen partial pressure of the reaction is 1-2 atmospheric pressure.
Preferably, the molar ratio of 9- deoxidation -8a- azepine-a-homoerythromycin A and positive propionic aldehyde is 1:(1-3).
Preferably, it is described reaction carry out in a solvent, the solvent in ethyl alcohol, isopropanol, toluene, dimethylbenzene one
Kind.Most preferably, the solvent of the reaction is ethyl alcohol.
Preferably, the preparation method further includes the steps that post-processing reaction solution after reaction, after described
Processing specifically: filter the reaction solution, gained catalyst recovery；It is carried out after gained concentrating filter liquor by solvent of methanol
Recrystallization.
The commercially available acquisition of Pd/NiO catalyst of the present invention, or be prepared according to method disclosed in the prior art,
Or it is prepared using infusion process well known in the art.For example, impregnating Pd on the carrier using nanoscale NiO as carrier
Noble metal.
On the basis of common knowledge of the art, above-mentioned each optimum condition can be combined with each other each preferably to get the present invention
Example.
The present invention relates to the commercially available acquisition of raw materials and reagents.
The present invention achieves following good effect: the preparation method reaction process is mild, is not necessarily to extraordinary hydrogenation equipment, easily
It is produced in amplification；And catalyst can repeatedly recycle use, and verified, when using 5 times, the yield of Gamithromycin is still up to 90%
More than, production cost, and more economical environmental protection can be significantly reduced, the needs of scale industrial production are suitble to.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..Operation involved in embodiment
It unless otherwise specified, is this field customary technical operation.The catalyst being related in embodiment is prepared into the following method
It arrives:
By 0.067mL H2PdCl4Aqueous solution (35mg/mL) is added in 5mL distilled water, and 1.2mL PVA aqueous solution is added
Freshly prepared 0.1M NaBH is added after stirring 30min in (5mg/mL)4Solution (NaBH4The molar ratio of/Pd is 4:1), stirring
After 30min, 100mg nanoscale NiO powder is added, the pH value of regulation system stirs 2h, obtained solid is washed with distilled water to 1
Three times, 80 DEG C of dry 2h, obtain Pd/NiO catalyst, be computed: the load capacity of Pd is 1.1wt%.
Embodiment 1
A kind of preparation method of Gamithromycin: by 9- deoxidation -8a- azepine -8a- a-homoerythromycin A (5.0g, 6.8mmol) and
Positive propionic aldehyde (0.6g, 10.3mmol) is added in 100mL toluene, 263mgPd/NiO is then added, in 35 DEG C of temperature in hydrogen
Under the conditions of, it stirs 12 hours, TLC detection, to after reaction, filter, decompression is spin-dried for, and 60mL water and 100mL dichloromethane is added
Alkane, stirring to solid it is complete it is molten after, stand liquid separation, abandon water layer, organic layer is washed twice, and anhydrous sodium sulfate is dry, and decompression is spin-dried for,
Gained crude product obtains white solid 4.7g, yield 89.0%, HPLC detection purity: 98.8% with recrystallizing methanol.
Embodiment 2
A kind of preparation method of Gamithromycin: by 9- deoxidation -8a- azepine -8a- a-homoerythromycin A (5.0g, 6.8mmol) and
Positive propionic aldehyde (0.6g, 10.3mmol) is added in 100mL dimethylbenzene, 263mgPd/NiO is then added, in 25 DEG C of temperature in hydrogen
It under the conditions of gas, stirs 12 hours, TLC detection, to after reaction, filter, decompression is spin-dried for, and 60mL water and 100mL dichloro is added
Methane, stirring to solid it is complete it is molten after, stand liquid separation, abandon water layer, organic layer is washed twice, and anhydrous sodium sulfate is dry, decompression rotation
Dry, gained crude product obtains white solid 4.6g, yield 87.1%, HPLC detection purity: 98.9% with recrystallizing methanol.
Embodiment 3
A kind of preparation method of Gamithromycin: by 9- deoxidation -8a- azepine -8a- a-homoerythromycin A (5.0g, 6.8mmol) and
Positive propionic aldehyde (0.6g, 10.3mmol) is added in 100mL isopropanol, 263mgPd/NiO is then added, in 35 DEG C of temperature in hydrogen
It under the conditions of gas, stirs 12 hours, TLC detection, to after reaction, filter, decompression is spin-dried for, and 60mL water and 100mL dichloro is added
Methane, stirring to solid it is complete it is molten after, stand liquid separation, abandon water layer, organic layer is washed twice, and anhydrous sodium sulfate is dry, decompression rotation
Dry, gained crude product obtains white solid 4.8g, yield 90.9%, HPLC detection purity: 99.0% with recrystallizing methanol.
Embodiment 4
A kind of preparation method of Gamithromycin: by 9- deoxidation -8a- azepine -8a- a-homoerythromycin A (5.0g, 6.8mmol) and
Positive propionic aldehyde (0.6g, 10.3mmol) is added in 100mL ethyl alcohol, 132mgPd/NiO is then added, in 25 DEG C of temperature in hydrogen
Under the conditions of, it stirs 12 hours, TLC detection, to after reaction, filter, decompression is spin-dried for, and 60mL water and 100mL dichloromethane is added
Alkane, stirring to solid it is complete it is molten after, stand liquid separation, abandon water layer, organic layer is washed twice, and anhydrous sodium sulfate is dry, and decompression is spin-dried for,
Gained crude product obtains white solid 4.6g, yield 87.1%, HPLC detection purity: 99.0% with recrystallizing methanol.
Embodiment 5
A kind of preparation method of Gamithromycin: by 9- deoxidation -8a- azepine -8a- a-homoerythromycin A (5.0g, 6.8mmol) and
Positive propionic aldehyde (0.6g, 10.3mmol) is added in 100mL ethyl alcohol, 526mgPd/NiO is then added, in 50 DEG C of temperature in hydrogen
Under the conditions of, it stirs 12 hours, TLC detection, to after reaction, filter, decompression is spin-dried for, and 60mL water and 100mL dichloromethane is added
Alkane, stirring to solid it is complete it is molten after, stand liquid separation, abandon water layer, organic layer is washed twice, and anhydrous sodium sulfate is dry, and decompression is spin-dried for,
Gained crude product obtains white solid 4.8g, yield 90.9%, HPLC detection purity: 98.3% with recrystallizing methanol.
Embodiment 6
A kind of preparation method of Gamithromycin: by 9- deoxidation -8a- azepine -8a- a-homoerythromycin A (5.0g, 6.8mmol) and
Positive propionic aldehyde (0.6g, 10.3mmol) is added in 100mL ethyl alcohol, 263mgPd/NiO is then added, in 35 DEG C of temperature in hydrogen
Under the conditions of, it stirs 12 hours, TLC detection, to after reaction, filter, decompression is spin-dried for, and 60mL water and 100mL dichloromethane is added
Alkane, stirring to solid it is complete it is molten after, stand liquid separation, abandon water layer, organic layer is washed twice, and anhydrous sodium sulfate is dry, and decompression is spin-dried for,
Gained crude product obtains white solid 4.9g, yield 92.8%, HPLC detection purity: 99.2% with recrystallizing methanol.
The catalyst that conditions above filters out can be reused directly, without other processing, by taking embodiment 6 as an example, repeat
Above-mentioned experimentation, catalyst reuses number and yield see the table below 1:
Table 1: catalyst circulation number and yield
| Number | 1 | 2 | 3 | 4 | 5 | 6 |
| Yield (%) | 92.8 | 91.7 | 91.4 | 91.0 | 90.9 | 61.8 |
Although above having used general explanation, specific embodiment and test, the present invention is made to retouch in detail
It states, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Range.
Claims (2)
1. a kind of preparation method of Gamithromycin, it is characterised in that: be with 9- deoxidation -8a- azepine-a-homoerythromycin A and positive propionic aldehyde
Raw material, using hydrogen as reducing agent, reaction is under the catalytic action of Pd/NiO to get the Gamithromycin；
The molar ratio of 9- deoxidation -8a- azepine-a-homoerythromycin A and positive propionic aldehyde is 1:(1-3)；
Pd and 9- deoxidation -8a- azepine-a-homoerythromycin A molar ratio are 1:250 in the catalyst；
The temperature of the reaction is 35 DEG C；
The hydrogen partial pressure of the reaction is 1-2 atmospheric pressure；
The reaction carries out in a solvent, and the solvent is ethyl alcohol.
2. preparation method according to claim 1, it is characterised in that: further include after being carried out to reaction solution after reaction
The step of processing, the post-processing specifically: filter the reaction solution, gained catalyst recovery；Gained concentrating filter liquor
It is recrystallized afterwards by solvent of methanol.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102239174A (en) * | 2008-10-24 | 2011-11-09 | 梅里亚有限公司 | Method of synthesizing macrolide compounds |
| CN104437467A (en) * | 2014-10-27 | 2015-03-25 | 杭州聚力氢能科技有限公司 | Hydrogenation catalyst, application of hydrogenation catalyst, dehydrogenation catalyst and application of dehydrogenation catalyst |
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| US8445726B2 (en) * | 2010-04-07 | 2013-05-21 | Basf Se | Process for preparing unsymmetric secondary tert-butylamines in the liquid phase |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102239174A (en) * | 2008-10-24 | 2011-11-09 | 梅里亚有限公司 | Method of synthesizing macrolide compounds |
| CN104437467A (en) * | 2014-10-27 | 2015-03-25 | 杭州聚力氢能科技有限公司 | Hydrogenation catalyst, application of hydrogenation catalyst, dehydrogenation catalyst and application of dehydrogenation catalyst |
Non-Patent Citations (1)
| Title |
|---|
| ReductiveAminationofAldehydesandAmineswithanEfficientPd/NiOCatalyst;Yang,HM，等;《SyntheticCommunications》;20140328;第44卷(第9期);摘要，表2，表3，表4 * |
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