CN104693251B - The preparation method of Gamithromycin or its presoma 13- descladinosylation compounds - Google Patents
The preparation method of Gamithromycin or its presoma 13- descladinosylation compounds Download PDFInfo
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- CN104693251B CN104693251B CN201510087675.9A CN201510087675A CN104693251B CN 104693251 B CN104693251 B CN 104693251B CN 201510087675 A CN201510087675 A CN 201510087675A CN 104693251 B CN104693251 B CN 104693251B
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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
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention discloses a kind of Gamithromycin or the preparation method of its 13 descladinosylation compound of presoma, belong to the field of chemical synthesis.The method of the present invention is using Gamithromycin or Gamithromycin presoma as reaction substrate, using rudimentary acid amides, lower ketones or lower alcohol as solvent, reaction substrate and solvent are placed in autoclave, it is 0.5 5 to add acid and control reaction system pH, it is 0.1 0.8Mpa that nitrogen is passed through into autoclave and keeps pressure, controlling reaction temperature is 0 35 DEG C, stirs 1 12h；Present invention process is simple, high selectivity, Gamithromycin or its 13 descladinosylation compound yield of presoma are high.Hydroxyl, ester group and several ehter bonds are included in Gamithromycin and its presoma, but Gamithromycin and its presoma reaction substrate are in acid condition in the method for the present invention, selectivity fracture cladinose and the ehter bond of parent junction, and hydroxyl, ester group do not react under the reaction conditions, high selectivity.
Description
Technical field
The present invention relates to the field of chemical synthesis, more particularly to a kind of Gamithromycin or its presoma 13- descladinosylations
The preparation method of compound.
Background technology
Gamithromycin（Gamithromycin）CAS：145435-72-9 molecular structural formulas are：
Gamithromycin is a kind of new second generation macrolides veterinary antibiotic medicine.Synthesize Gamithromycin intermediate and
Azithromycin synthetic intermediate is the same, is all obtained ring expansion derivative after a kind of erythromycin A-9 oxime ring expansion, and simply both are same point
Isomers.Gamithromycin is mainly used for treating the bacterial diseases such as pasteurella haemolytica, pasteurella multocida, Histophilus
Cattle infected disease caused by substance.
In recent years, as the popularization of new equipment together etc. and the increase of China's science research input, China's pharmaceutical standards carry
High workload is also more and more deep.Not only the medicine such as direct specification bulk pharmaceutical chemicals, injection is in itself for the raising of pharmaceutical standards in pharmacopeia
Standard and safe medication, and the production for medicine has indirect directive function, for eliminating old technique, promoting skill
Art improves and process modification is by immeasurable meaning.
Gamithromycin or its presoma 13- descladinosylations are the major impurity chemical combination in Gamithromycin or its presoma
Thing, preparing for impurity correlative become the basis that standards of pharmacopoeia improves.Related Gamithromycin or its presoma 13- take off carat
The preparation method of fixed sugar impurity thing has no report.
Application publication number discloses a kind of azithromycin or Zitromax for the Chinese invention patent of " 103232501 A of CN "
Plain intermediate sloughs the preparation process of cladinose compound.But the invented technology prepares the yield of descladinosylation compound
Only 44.4%-52.0%.
The content of the invention
To make up above deficiency, the present invention provides a kind of Gamithromycin or its presoma 13- descladinosylation compounds
Preparation method and preparation method thereof.
The technical scheme is that：
The preparation method of a kind of Gamithromycin or its presoma 13- descladinosylation compounds, with Gamithromycin or adds rice
Mycin presoma is reaction substrate, and using rudimentary acid amides, lower ketones or lower alcohol as solvent, reaction substrate and solvent are placed in high pressure
In reaction kettle, it is 0.5-5 to add acid and be used as catalyst and control reaction system pH, and nitrogen is passed through into autoclave and is kept
Pressure is 0.1-0.8Mpa, and controlling reaction temperature is 0-35 DEG C, stirring reaction 1-12h；Specific reaction equation is as follows：
Wherein, R1For H or CH2CH2CH3, R2For H or OH, R3For H or CH3, R4For CH3、H、COCH2CH3, or
SO2C6H4CH3。
Preferably, the mass ratio of solvent and reaction substrate is 1:1-1:10.
Preferably, reaction terminates, and method of purification is specially：Halogenated hydrocarbons, lower member ester or rudimentary ether are added under normal pressure
In one kind and water, it is 8.5-10.5 to adjust pH value with sodium hydroxide solution, and phase inversion to organic layer concentrates, and concentrate addition is rudimentary
Alcohol or lower ketones crystallization, centrifugal filtration.
Preferably, the rudimentary acid amides is n,N-Dimethylformamide or n,N-dimethylacetamide；Lower ketones are C3-C6
Ketone；Lower alcohol is C1-C4Alcohol.
Further, the lower ketones are acetone, methyl ethyl ketone or methyl iso-butyl ketone (MIBK)；The lower alcohol for methanol, ethanol,
Normal propyl alcohol.
Preferably, the acid is organic acid, inorganic acid or the organic acid of 10wt%-60 wt% and the mixed acid of inorganic acid
Aqueous solution；The organic acid is formic acid, acetic acid, oxalic acid, propionic acid, butyric acid；The inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.
Preferably, the halogenated hydrocarbons is C1-C4Halogenated hydrocarbons；The lower member ester is C2-C6Ester；It is described rudimentary
Ether is C2-C6Ether.
Further, the halogenated hydrocarbons is dichloromethane, chloroform, carbon tetrachloride or 1,2- dichloroethanes；The lower member ester
For Ethyl formate, ethyl acetate or isopropyl acetate；The rudimentary ether is ether, propyl ether, isopropyl ether or methyl tertiary butyl ether(MTBE).
Preferably, in method of purification, halogenated hydrocarbons, lower member ester or the mass ratio of rudimentary ether and reaction substrate are 1:1-
1:10；The mass ratio of water and reaction substrate is 1:1-1:10.
Preferably, reaction system pH is 1.5-3, pressure 0.3-0.6Mpa, reaction temperature is 25-30 DEG C, and stirring is anti-
Answer 6-10h.
Beneficial effects of the present invention are：
The Gamithromycin of the present invention or the preparation method of its presoma 13- descladinosylation compounds, technique is simple, selection
Property high, Gamithromycin or its presoma 13- descladinosylations compound yield it is high.
Hydroxyl, ester group and several ehter bonds are included in Gamithromycin and its presoma, but add rice in the method for the present invention
In acid condition, selectivity is broken the ehter bond that is connected with parent of cladinose for mycin and its presoma reaction substrate, and hydroxyl,
Ester group does not react under the reaction conditions, high selectivity.
Embodiment
Embodiment 1
In the autoclave of 250ml, Gamithromycin 7.8g is added（10mmol）, methanol 20ml, stirring and dissolving, be added dropwise
The aqueous hydrochloric acid solution of 4mol/L, adjusts pH between 1.5-2.0, autoclave is passed through N2, keep pressure 0.3Mpa, control temperature
25 DEG C of degree, dichloromethane and each 50ml of water are added after stirring 8h, adjust pH=9.8 with the sodium hydroxide solution of 4mol/L, liquid separation obtains
Concentrated to organic phase, concentration residue adds the filtering of 35ml acetone stirring and crystallizing.The vacuum drying white solid B of 50 DEG C of filter cake
5.4g, yield 86.0%, purity 99.5%.
Embodiment 2
In the autoclave of 250ml, 9- deoxidations-8 α-α of azepine-8-homoerythromycin A 7.4g are added（10mmol）、
Methanol 20ml, stirring and dissolving, is added dropwise the aqueous hydrochloric acid solution of 4mol/L, adjusts pH between 1.5-2.0, autoclave is passed through
N2, pressure 0.5Mpa is kept, controls 30 DEG C of temperature, dichloromethane and each 50ml of water are added after stirring 5h, with the hydrogen-oxygen of 4mol/L
Change sodium solution and adjust pH=9.6, liquid separation obtains organic phase concentration, and concentration residue adds the filtering of 35ml ethanol stirring and crystallizing.Filter cake
50 DEG C of vacuum drying white solid B 5.0g, yield 83.7%, purity 98.4%.
Embodiment 3：
In the autoclave of 250ml, Gamithromycin 7.8g is added（10mmol）, acetone 70ml, be added dropwise 4mol/L's
Sulfuric acid, adjusts pH between 2.5-3.0, autoclave is passed through N2, 30 DEG C of temperature is controlled, keeps pressure 0.4Mpa, stirs 8h
Dichloromethane and each 50ml of water are added afterwards, and pH=9.8 are adjusted with the sodium hydroxide solution of 4mol/L, liquid separation obtains organic phase concentration,
Concentration residue adds the filtering of 35ml ethanol stirring and crystallizing.The vacuum drying white solid B 5.1g of 50 DEG C of filter cake, yield
82.0%, purity 99.6%.
Embodiment 4：
In the autoclave of 250ml, Gamithromycin 7.8g is added（10mmol）, methanol 20ml, be added dropwise 4mol/L's
Hydrochloric acid, adjusts pH between 1.5-2.0, autoclave is passed through N2, 35 DEG C of temperature is controlled, keeps pressure 0.3Mpa, stirs 8h
Methyl tertiary butyl ether(MTBE) and each 50ml of water are added afterwards, adjust pH=9.8 with the sodium hydroxide solution of 4mol/L, liquid separation obtains organic phase
Concentration, concentration residue add the filtering of 35ml ethanol stirring and crystallizing.The vacuum drying white solid B 5.2g of 50 DEG C of filter cake, yield
84.0%, purity 96.6%.
Embodiment 5：
In the autoclave of 250ml, Gamithromycin 7.8g is added（10mmol）, methanol 20ml, stir and lower add water
80ml, is added dropwise the mixed acid of phosphoric acid and oxalic acid, adjusts pH between 1.0-1.5, autoclave is passed through N2, control temperature 25
DEG C, pressure 0.6Mpa is kept, ethyl acetate and each 50ml of water are added after stirring 8h, pH is adjusted with the sodium hydroxide solution of 4mol/L
=9.8, liquid separation obtains organic phase concentration, and concentration residue adds the filtering of 35ml methanol stirring and crystallizing.50 DEG C of filter cake is vacuum drying
White solid B 5.1g, yield 81.6%, purity 99.5%.
Embodiment 6：
In the autoclave of 250ml, Gamithromycin 7.8g is added（10mmol）, n,N-Dimethylformamide 20ml,
Stirring is lower to add water 80ml, and hydrochloric acid is added dropwise, adjusts pH between 2.0-2.5, autoclave is passed through N2, 35 DEG C of temperature is controlled,
Keep pressure 0.5Mpa, ethyl acetate and each 50ml of water added after stirring 6h, with the sodium hydroxide solution of 4mol/L adjust pH=
9.7, liquid separation obtains organic phase concentration, and concentration residue adds the filtering of 35ml methanol stirring and crystallizing.50 DEG C of filter cake is vacuum drying
White solid B 5.2g, yield 80.9%, purity 98.9%.
Claims (7)
1. a kind of-8 α of the Gamithromycin 13- descladinosylations compound or 9- deoxidations-α of azepine-8-homoerythromycin A 13- take off gram
Draw the preparation method for determining sugar compounds, it is characterised in that：Using-8 α of the Gamithromycin or 9- deoxidations-α of azepine-8-homoerythromycin A as
Reaction substrate, using rudimentary acid amides, lower ketones or lower alcohol as solvent, rudimentary acid amides is n,N-Dimethylformamide or N, N- diformazan
Yl acetamide；Lower ketones are C3-C6Ketone；Lower alcohol is C1-C4Alcohol, reaction substrate and solvent are placed in autoclave,
The mass ratio of solvent and reaction substrate is 1:1-1:10, it is 0.5-5, Xiang Gao to add acid and be used as catalyst and control reaction system pH
It is 0.3-0.6 MPa to be passed through nitrogen in pressure reaction kettle and keep pressure, and controlling reaction temperature is 25-35 DEG C, stirring reaction 6-
10h；Reaction terminates, and method of purification is specially：Halogenated hydrocarbons, lower member ester or one kind and water in rudimentary ether are added under normal pressure, uses hydrogen
It is 8.5-10.5 that sodium hydroxide solution, which adjusts pH value, and phase inversion to organic layer concentrates, and concentrate adds lower alcohol or lower ketones crystallization, from
The heart filters.
2.-8 α of the Gamithromycin 13- descladinosylations compound as claimed in claim 1 or 9- deoxidations-α of azepine-8-homotype is red mould
The preparation method of plain A 13- descladinosylation compounds, it is characterised in that：The lower ketones are acetone, methyl ethyl ketone or methyl are different
Butyl ketone；The lower alcohol is methanol, ethanol, normal propyl alcohol.
3.-8 α of the Gamithromycin 13- descladinosylations compound as claimed in claim 1 or 9- deoxidations-α of azepine-8-homotype is red mould
The preparation method of plain A 13- descladinosylation compounds, it is characterised in that：The acid is the organic acid of 10wt%-60 wt%, nothing
Machine acid or the mixed acid aqueous solution of organic acid and inorganic acid；The organic acid is formic acid, acetic acid, oxalic acid, propionic acid, butyric acid；It is described
Inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.
4.-8 α of the Gamithromycin 13- descladinosylations compound as claimed in claim 1 or 9- deoxidations-α of azepine-8-homotype is red mould
The preparation method of plain A 13- descladinosylation compounds, it is characterised in that：The halogenated hydrocarbons is C1-C4Halogenated hydrocarbons；It is described low
Level ester is C2-C6Ester；The rudimentary ether is C2-C6Ether.
5.-8 α of the Gamithromycin 13- descladinosylations compound as claimed in claim 4 or 9- deoxidations-α of azepine-8-homotype is red mould
The preparation method of plain A 13- descladinosylation compounds, it is characterised in that：The halogenated hydrocarbons is dichloromethane, chloroform, four chlorinations
Carbon or 1,2- dichloroethanes；The lower member ester is Ethyl formate, ethyl acetate or isopropyl acetate；The rudimentary ether for ether,
Propyl ether, isopropyl ether or methyl tertiary butyl ether(MTBE).
6.-8 α of the Gamithromycin 13- descladinosylations compound as claimed in claim 1 or 9- deoxidations-α of azepine-8-homotype is red mould
The preparation method of plain A 13- descladinosylation compounds, it is characterised in that：In method of purification, halogenated hydrocarbons, lower member ester or rudimentary ether
Mass ratio with reaction substrate is 1:1-1:10；The mass ratio of water and reaction substrate is 1:1-1:10.
7.-8 α of the Gamithromycin 13- descladinosylations compound as claimed in claim 1 or 9- deoxidations-α of azepine-8-homotype is red mould
The preparation method of plain A 13- descladinosylation compounds, it is characterised in that：Reaction system pH is 1.5-3, reaction temperature 25-
30℃。
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510087675.9A CN104693251B (en) | 2015-02-26 | 2015-02-26 | The preparation method of Gamithromycin or its presoma 13- descladinosylation compounds |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510087675.9A CN104693251B (en) | 2015-02-26 | 2015-02-26 | The preparation method of Gamithromycin or its presoma 13- descladinosylation compounds |
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| CN104693251B true CN104693251B (en) | 2018-05-01 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102993250B (en) * | 2011-07-06 | 2016-02-10 | 洛阳惠中兽药有限公司 | -9-deoxidation-9A-azepine-9A-the a-homoerythromycin A derivatives that C-3 replaces |
| CN103232501A (en) * | 2013-04-11 | 2013-08-07 | 宜昌东阳光药业股份有限公司 | A preparation process for compounds of azithromycin or azithromycin intermediates with cladinose removed |
| CN104119413B (en) * | 2014-07-29 | 2016-08-24 | 华中农业大学 | A kind of soil draws the synthetic method of mycin residual marker |
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Address after: 251500, the south side of the west of plough City Road, Linyi Economic Development Zone, Shandong Province Applicant after: Qilu Synva Pharmaceutical Co., Ltd. Address before: 250000 No. 243 industrial North Road, Shandong, Ji'nan Applicant before: Qilu Synva Pharmaceutical Co., Ltd. |
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