CN109369742A - A kind of refining methd of Etimicin - Google Patents
A kind of refining methd of Etimicin Download PDFInfo
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- CN109369742A CN109369742A CN201811591259.2A CN201811591259A CN109369742A CN 109369742 A CN109369742 A CN 109369742A CN 201811591259 A CN201811591259 A CN 201811591259A CN 109369742 A CN109369742 A CN 109369742A
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- etimicin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
- C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
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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
- C07H1/06—Separation; Purification
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Abstract
The present invention provides a kind of refining methds of Etimicin, comprising the following steps: S1: Etimicin crude product obtains Etimicin ester through esterification；S2: Etimicin ester obtained in step S1 is obtained into Etimicin crystalline esters through solvent dissolving-recrystallization；S3: Etimicin crystalline esters deprotection reaction obtained in step S2 is generated into target product Etimicin fine work.Etimicin obtained by refining methd using a kind of disclosed Etimicin can reach ion-exchange column effect by simple chemical method, and the period is short, and product stability is good.
Description
Technical field
The invention belongs to medical production technical fields, specifically relate to a kind of refining methd of Etimicin.
Background technique
Etimicin (Etimicin), alias E-402, antibiotic 89-07 belong to aminoglycoside.Chemical name is O-2-
Amino-2,3,4,6-four deoxidation-6- amino-α-D- erythros-hexpyranosyl-(1 → 4)-O- [- 3 (first of 3- deoxidation-4-C- methyl
Amino)-β-L- arabopyranose base-(1 → 6)] -2- '-deoxy-n-ethyl-L- streptamine.
Etimicin mechanism of action is to inhibit the normal protein synthesis of sensitive bacteria.For broad-spectrum antibiotic, to most of G+
And G- bacterium has good antibacterial action, especially to Escherichia coli, the white pneumobacillus of Cray, Serratia, proteus mirabilis, sramana
Pseudomonas, bloodthirsty Bacillus influenzae and staphylococcus etc. have higher antibacterial activity, to part gentamicin, micronomicin and cephalo azoles
The drug resistant S. aureus L-forms of quinoline, Escherichia coli and the white pneumobacillus of Cray, external MIC value is still in the blood concentration of this product therapeutic dose
In range.The staphylococcus (MRSA) of part staphylococcus and part low-level methicillin resistance to generation penicillase is also
There is certain antibacterial activity.
Etimicin is obtained by fermentation, generates a large amount of impurity during the fermentation, existing technique mainly by from
Sub- exchange column chromatographic purifying, period are up to the several months, and unstable quality between batch often occurs that medicinal efficacy is not achieved, therefore, exploitation
New purification process is imperative.
Summary of the invention
It is an object of the invention to disclose a kind of refining methd of Etimicin, this method does not use ion-exchange chromatography
Purifying overcomes and causes period length, the problem of stable product quality difference using ion-exchange chromatography purifying in the prior art,
The present invention is that can reach the effect of ion-exchange chromatography purifying by simple chemical method, and the period is shorter, and product is stablized
Property is good.
To achieve the above object, the present invention provides a kind of refining methds of Etimicin, comprising the following steps:
S1: Etimicin crude product obtains Etimicin ester through esterification；
S2: Etimicin ester obtained in step S1 is obtained into Etimicin crystalline esters through solvent dissolving-recrystallization；
S3: Etimicin crystalline esters deprotection reaction obtained in step S2 is generated into target product Etimicin fine work.
As a further improvement of the present invention, esterification described in step S1 are as follows: dichloromethane is sequentially added in reaction flask
Alkane, Etimicin, catalyst and trifluoroacetic acid, magnetic agitation, heating reflux reaction 2h, TLC judgement reaction terminate, filter, filter
Liquid is washed to neutrality, and anhydrous sodium sulfate is dried overnight, and concentration obtains Etimicin trifluoro-acetate.
As a further improvement of the present invention, catalyst is hydrochloric acid, the concentrated sulfuric acid, pyridine, sodium hydroxide, potassium hydroxide, three
The mixture of one or more of ethamine or DMAP arbitrary proportion, DMAP are 4-dimethylaminopyridine.
As a further improvement of the present invention, the specific reaction of step S2 are as follows: Etimicin ester is added in reaction flask, is added molten
Agent is heated to reflux 1h, and heat filters, and filtrate is cooled to room temperature 0 DEG C naturally and is stirred overnight crystallization, filters, a small amount of ethanol washing of filter cake,
Obtain Etimicin crystalline esters.
As a further improvement of the present invention, solvent is methanol, ethyl alcohol, isopropanol, tetrahydrofuran, acetone, acetonitrile, dichloro
One or more of methane, methyl tertiary butyl ether(MTBE), ethyl acetate, hexamethylene, dioxane or water arbitrary proportion
Mixture.
As a further improvement of the present invention, solvent is the mixture of hexamethylene and ethyl acetate.
As a further improvement of the present invention, the volume ratio of hexamethylene and ethyl acetate is 3:1.
As a further improvement of the present invention, the specific reaction of step S3 are as follows: reaction flask be added Etimicin crystalline esters and
Ethyl alcohol, stirring and dissolving continuously add sodium hydroxide, and back flow reaction 12h is filtered, and filtrate concentration, residue dried under vacuum is obtained according to for rice
Star fine work.
Compared with prior art, the beneficial effects of the present invention are: the refining methd of Etimicin disclosed herein is only
It is that can reach the effect of ion-exchange chromatography purifying by simple chemical method, the period is shorter, and product stability is good.
Specific embodiment
Below with reference to each embodiment, the present invention is described in detail, but it should be stated that, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according to these embodiments in made function, method or structure
Equivalent transformation or substitution, all belong to the scope of protection of the present invention within.
The present invention provides a kind of refining methds of Etimicin, comprising the following steps:
S1: Etimicin crude product obtains Etimicin ester through esterification；
S2: Etimicin ester obtained in step S1 is obtained into Etimicin crystalline esters through solvent dissolving-recrystallization；
S3: Etimicin crystalline esters deprotection reaction obtained in step S2 is generated into target product Etimicin fine work.
The equation of above method reaction is as follows:
Specifically includes the following steps:
S1: structural formula Etimicin crude product as shown in formula (1) obtains structural formula as shown in formula (2) according to replacing through esterification
Rice star ester；Esterification described in step S1 are as follows: methylene chloride, Etimicin, catalyst and trifluoro are sequentially added in reaction flask
Acetic acid, magnetic agitation, heating reflux reaction 2h, TLC judgement reaction terminate, filter, and filtrate is washed to neutrality, and anhydrous sodium sulfate is dry
Dry overnight, concentration obtains Etimicin trifluoro-acetate.
Esterification described in step S1 are as follows: methylene chloride, Etimicin, catalyst and trifluoro are sequentially added in reaction flask
Acetic acid, magnetic agitation, heating reflux reaction 2h, TLC judgement reaction terminate, filter, and filtrate is washed to neutrality, and anhydrous sodium sulfate is dry
Dry overnight, concentration obtains Etimicin trifluoro-acetate.
Catalyst is one of hydrochloric acid, the concentrated sulfuric acid, pyridine, sodium hydroxide, potassium hydroxide, triethylamine or DMAP or two
The mixture of kind any of the above ratio, DMAP is 4-dimethylaminopyridine.
S2: Etimicin ester obtained in step S1 is obtained into Etimicin crystalline esters through solvent dissolving-recrystallization；Step S2
Specific reaction are as follows: Etimicin ester is added in reaction flask, and solvent is added, is heated to reflux 1h, and heat filters, and filtrate is down to room temperature naturally
It is stirred overnight crystallization for 0 DEG C afterwards, filters, a small amount of ethanol washing of filter cake obtains Etimicin crystalline esters.Solvent is methanol, ethyl alcohol, isopropyl
In alcohol, tetrahydrofuran, acetone, acetonitrile, methylene chloride, methyl tertiary butyl ether(MTBE), ethyl acetate, hexamethylene, dioxane or water
One or more kinds of arbitrary proportions mixture.Solvent is the mixture of hexamethylene and ethyl acetate.Hexamethylene and acetic acid
The volume ratio of ethyl ester is 3:1.
S3: Etimicin crystalline esters deprotection reaction obtained in step S2 is generated into structural formula mesh as shown in formula (3)
Mark product Etimicin fine work.The specific reaction of step S3 are as follows: Etimicin crystalline esters and ethyl alcohol is added in reaction flask, stirs molten
Solution continuously adds sodium hydroxide, and back flow reaction 12h is filtered, and filtrate concentration, residue dried under vacuum obtains Etimicin fine work.
Embodiment one
The present embodiment is obtained a kind of Etimicin according to the method described above, the specific steps are as follows:
200ml methylene chloride, 10g Etimicin, the 1ml concentrated sulfuric acid and 8ml trifluoroacetic acid, magnetic are sequentially added in 1L reaction flask
Power stirring, heating reflux reaction 2h, TLC judgement reaction terminate, filter, and filtrate is washed to neutrality, and anhydrous sodium sulfate is dried overnight,
Concentration, obtains Etimicin trifluoro-acetate 12.7g.
Etimicin trifluoro-acetate 10g is added in 250ml round-bottomed flask, and cyclohexane/ethyl acetate (3/1) 160ml is added,
It is heated to reflux 1h, heat filters, and filtrate is cooled to room temperature 0 DEG C naturally and is stirred overnight crystallization, filters, and a small amount of ethanol washing of filter cake obtains
White crystal 8.2g, i.e. Etimicin crystalline esters.
10g Etimicin crystalline esters are added in 250ml reaction flask and 100ml ethyl alcohol, stirring and dissolving continuously add sodium hydroxide
1g, back flow reaction 12h.It filters, filtrate concentration, residue dried under vacuum obtains Etimicin fine work 6.4g.
Etimicin fine work purity made from the method according to embodiment one is measured with chemical analysis method to reach
99.37%.
Embodiment two
The present embodiment is obtained a kind of Etimicin according to the method described above, the specific steps are as follows:
200ml methylene chloride, 10g Etimicin, 5ml pyridine and 8ml trifluoroacetic acid, magnetic force are sequentially added in 1L reaction flask
Stirring, heating reflux reaction 2h, TLC judgement reaction terminate, filter, filtrate is washed to neutrality, and anhydrous sodium sulfate is dried overnight, dense
Contracting, obtains Etimicin trifluoro-acetate 11.4g.
Etimicin trifluoro-acetate 10g is added in 250ml round-bottomed flask, and cyclohexane/ethyl acetate (3/1) 160ml is added,
It is heated to reflux 1h, heat filters, and filtrate is cooled to room temperature 0 DEG C naturally and is stirred overnight crystallization, filters, and a small amount of ethanol washing of filter cake obtains
White crystal 8.0g, i.e. Etimicin crystalline esters.
10g Etimicin crystalline esters are added in 250ml reaction flask and 80ml methanol, stirring and dissolving continuously add sodium hydroxide
1g, back flow reaction 12h.It filters, filtrate concentration, residue dried under vacuum obtains Etimicin fine work 6.3g.
Etimicin fine work purity made from the method according to embodiment two is measured with chemical analysis method to reach
99.49%.
The refining methd of Etimicin disclosed herein, being only through simple chemical method can reach ion exchange
The effect of column chromatographic purifying, the period is shorter, and product stability is good.
The series of detailed descriptions listed above only for feasible embodiment of the invention specifically
Protection scope bright, that they are not intended to limit the invention, it is all without departing from equivalent implementations made by technical spirit of the present invention
Or change should all be included in the protection scope of the present invention.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Benefit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent elements of the claims
Variation is included within the present invention.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiments being understood that.
Claims (8)
1. a kind of refining methd of Etimicin, which comprises the following steps:
S1: Etimicin crude product obtains Etimicin ester through esterification；
S2: Etimicin ester obtained in step S1 is obtained into Etimicin crystalline esters through solvent dissolving-recrystallization；
S3: Etimicin crystalline esters deprotection reaction obtained in step S2 is generated into target product Etimicin fine work.
2. preparation method according to claim 1, which is characterized in that esterification described in the step S1 are as follows: reaction
Methylene chloride, Etimicin, catalyst and trifluoroacetic acid are sequentially added in bottle, and magnetic agitation, heating reflux reaction 2h, TLC sentence
Disconnected reaction terminates, and filters, and filtrate is washed to neutrality, and anhydrous sodium sulfate is dried overnight, and concentration obtains Etimicin trifluoroacetic acid
Ester.
3. preparation method according to claim 2, which is characterized in that the catalyst is hydrochloric acid, the concentrated sulfuric acid, pyridine, hydrogen
The mixture of one or more of sodium oxide molybdena, potassium hydroxide, triethylamine or DMAP arbitrary proportion.
4. preparation method according to claim 1, which is characterized in that the specific reaction of the step S2 are as follows: reaction flask adds
Enter Etimicin ester, solvent is added, be heated to reflux 1h, heat filters, and filtrate is cooled to room temperature 0 DEG C naturally and is stirred overnight crystallization, takes out
Filter, a small amount of ethanol washing of filter cake obtain Etimicin crystalline esters.
5. the preparation method according to claim 4, which is characterized in that the solvent is methanol, ethyl alcohol, isopropanol, tetrahydro
One of furans, acetone, acetonitrile, methylene chloride, methyl tertiary butyl ether(MTBE), ethyl acetate, hexamethylene, dioxane or water or
The mixture of two or more arbitrary proportions.
6. preparation method according to claim 5, which is characterized in that the solvent is the mixing of hexamethylene and ethyl acetate
Object.
7. preparation method according to claim 6, which is characterized in that the volume ratio of the hexamethylene and ethyl acetate is 3:
1。
8. preparation method according to claim 1, which is characterized in that the specific reaction of the step S3 are as follows: reaction flask adds
Enter Etimicin crystalline esters and ethyl alcohol, stirring and dissolving continuously adds sodium hydroxide, and back flow reaction 12h is filtered, and filtrate concentration is residual
Slag is dried in vacuo to obtain Etimicin fine work.
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| CN201811591259.2A CN109369742A (en) | 2018-12-25 | 2018-12-25 | A kind of refining methd of Etimicin |
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| CN201811591259.2A CN109369742A (en) | 2018-12-25 | 2018-12-25 | A kind of refining methd of Etimicin |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030060430A1 (en) * | 2001-07-31 | 2003-03-27 | Mitali Ghoshal | Site-specific aminoglycoside derivatives and their use in immunodiagnostic assays |
| CN102432645A (en) * | 2010-09-29 | 2012-05-02 | 无锡济民可信山禾药业股份有限公司 | Purifying method for etimicin sulfate |
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2018
- 2018-12-25 CN CN201811591259.2A patent/CN109369742A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030060430A1 (en) * | 2001-07-31 | 2003-03-27 | Mitali Ghoshal | Site-specific aminoglycoside derivatives and their use in immunodiagnostic assays |
| CN102432645A (en) * | 2010-09-29 | 2012-05-02 | 无锡济民可信山禾药业股份有限公司 | Purifying method for etimicin sulfate |
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