CN103232501A - A preparation process for compounds of azithromycin or azithromycin intermediates with cladinose removed - Google Patents
A preparation process for compounds of azithromycin or azithromycin intermediates with cladinose removed Download PDFInfo
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- CN103232501A CN103232501A CN2013101251661A CN201310125166A CN103232501A CN 103232501 A CN103232501 A CN 103232501A CN 2013101251661 A CN2013101251661 A CN 2013101251661A CN 201310125166 A CN201310125166 A CN 201310125166A CN 103232501 A CN103232501 A CN 103232501A
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- azythromycin
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Abstract
A preparation process for compounds of azithromycin or azithromycin intermediates with cladinose removed is characterized in that: solving the azithromycin or azithromycin intermediates in a lower alcohol, a lower ether, a halogenated hydrocarbon, a lower ketone, or a lower ester, after adding an appropriate amount of water, at a temperature of -5-40 DEG C, dropwise adding an inorganic acid, or an organic acid, or a mixed acid of an inorganic acid and an organic acids for a hydrolysis reaction, with a pH value controlled to be 0 <pH <= 6.0 and a reaction time 0.5-8 hours; and after the reaction is completed, adding sodium hydroxide to adjust the pH value to be 7 <= pH <= 10, concentrating to remove the solvent, separating solid out in an aqueous phase, centrifugating and suction filtering, and purifying a filter cake by crystallization in a mixed system of a lower alcohol with water or a lower ketone with water. Through the preparation process of the invention, compounds of azithromycin or azithromycin intermediates with cladinose removed can be obtained; and the process has a simple flow and a high yield.
Description
Technical field
The present invention relates to the preparation technology that Azythromycin and Azythromycin intermediate take off the cladinose compound.
Background technology
Azythromycin (Azithromycin) CAS:83905-01-5 molecular structural formula is:
First 15 yuan nitrogenous Macrolide new drugs of ring of Zitromax prime system, be described as " 21st century anti-infective cookle ", at first formulated by Yugoslavia Pliva drugmaker, the exploitation listing of U.S. Pfizer drugmaker, clinically be mainly used in treating pharyngitis, tonsillitis, pneumonia, skin and the soft tissue infection that suis, streptococcus pneumoniae cause, the pneumonia that hemophilus influenzae and other sensitive organism cause and light, moderate respiratory system infection.At home and abroad do not appear in the newspapers in the document about the preparation technology who takes off the cladinose compound in the Azythromycin at present.
Summary of the invention
The purpose of this invention is to provide the preparation technology that the intermediate of a kind of Azythromycin and Azythromycin is sloughed the cladinose compound.
The present invention solves the problems of the technologies described above the technical scheme that adopts:
The preparation technology that Azythromycin or Azythromycin intermediate are sloughed the cladinose compound, it is characterized in that: Azythromycin or Azythromycin intermediate are dissolved in lower alcohol, rudimentary ether, halohydrocarbon, lower ketones or the lower member ester, after adding an amount of water, at-5～40 ℃, dropping inorganic acid, perhaps organic acid, perhaps mineral acid and the organic acid mixing acid reaction that is hydrolyzed, the control of reaction solution pH value exists: 0＜PH≤6.0,0.5～8 hour reaction times; Reaction finishes, and adds sodium hydroxide, and pH value is transferred to: 7≤PH≤10, concentrate desolventizing, and aqueous phase is separated out solid, centrifugal suction filtration, filter cake carries out refining crystallization under the mixed system of lower alcohol and water or lower ketones and water.Concrete reaction formula is as follows:
Described Azythromycin or Azythromycin intermediate structure general formula are II, and it is I, wherein R that Azythromycin and Azythromycin intermediate are sloughed cladinose compound structure general formula
1=R
3=CH
3Perhaps H, R
2=H or OH, R
4=CH
3, H, CHO or SO
2C
6H
4CH
3
The usage ratio of described Azythromycin or Azythromycin intermediate and organic solvent can change between 1:1～1:10 (kg/kg), and the usage ratio of organic solvent and water can change between 1:1～1:30 (V/V).
Described lower alcohol refers to C
1～C
4Alcohol, for example: methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol and its isomeric forms.
Described lower ketones refers to C
3～C
6Ketone, for example: acetone, methylethylketone, methyl iso-butyl ketone (MIBK) or analogue compounds.
Described rudimentary ether refers to C
2～C
6Ether, for example: ether, propyl ether, isopropyl ether or analogue compounds.
Described halohydrocarbon refers to C
1～C
4Halohydrocarbon, for example: methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride or analogue compounds.
Described lower member ester refers to C
2～C
6Ester, for example: methyl-formiate, ethyl formate, ethyl acetate, propyl acetate or analogue compounds.
Described mineral acid for hydrolysis, for example: hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid.
Described organic acid for hydrolysis, for example: formic acid, acetic acid, oxalic acid, propionic acid, butanic acid.
Preferred-5～30 ℃ of described temperature of reaction, the reaction solution pH value is preferred 1.0～6.0, preferred 0.5～6 hour of reaction times.
By the preparation technology that the intermediate of Azythromycin provided by the invention or Azythromycin is sloughed the cladinose compound, the intermediate that can obtain Azythromycin and Azythromycin is sloughed the compound of cladinose, and this technical process is simple, yield is high.
Embodiment
Following examples are used for further specifying the present invention, but are not limited to content of the present invention:
Embodiment 1
In the reaction flask of 100ml, add Azythromycin 10g(13.4mmol), methyl alcohol 20ml., stirring and dissolving, add 100ml water, the control temperature slowly drips 4N hydrochloric acid at 10 ℃, transfer between PH=1.0～1.5, after the insulated and stirred 2 hours, transfer PH=9.0,40 ℃ of following concentrating under reduced pressure filtrates with 10% sodium hydroxide, remove methyl alcohol, residue 10ml acetone solution, 35 ℃ of temperature controls slowly drip 30ml water, separate out until solid, be incubated after 1 hour, be down to 8 ℃, suction filtration, filter cake gets white solid I 3.8g, yield 48.2% 45 ℃ of vacuum-dryings.Content 99.5%.Infrared spectra is consistent with standard substance.
Embodiment 2
In the reaction flask of 100ml, add Azythromycin 10g(13.4mmol), acetone 30ml., stirring and dissolving, add 100ml water, the control temperature slowly drips glacial acetic acid at 10 ℃, transfers between PH=1.0～1.5, after the insulated and stirred 5 hours, transfer PH=9.0 with 10% sodium hydroxide, 40 ℃ of following concentrating under reduced pressure remove acetone, suction filtration, filter cake 20ml dissolve with methanol, 30 ℃ of temperature controls slowly drip 60ml water, separate out until solid, be incubated after 1 hour, be down to 8 ℃, suction filtration, 45 ℃ of vacuum-dryings of filter cake get white solid I 4.1g.Yield 52.0%, content 99.2%.Infrared spectra is consistent with standard substance.
Embodiment 3
In the reaction flask of 100ml, add Azythromycin 10g(13.4mmol), ethyl acetate 30ml., stirring and dissolving, add 100ml water, the control temperature slowly drips 4N sulfuric acid at 10 ℃, transfers between PH=0.5～1.0, after the insulated and stirred 3 hours, transfer PH=9.0 with 10% sodium hydroxide, 40 ℃ of following concentrating under reduced pressure go ethyl acetate, suction filtration, filter cake 20ml dissolve with methanol, 30 ℃ of temperature controls slowly drip 60ml water, separate out until solid, be incubated after 1 hour, be down to 8 ℃, suction filtration, 45 ℃ of vacuum-dryings of filter cake get white solid I 3.5g.Yield 44.4% content 99.6%.Infrared spectra is consistent with standard substance.
Embodiment 4
In the reaction flask of 100ml, add Azythromycin 10g(13.4mmol), isopropyl ether 30ml., stirring and dissolving, add 100ml water, the control temperature slowly drips the mixing acid of phosphoric acid and oxalic acid at 40 ℃, transfers to PH=6.0, after the insulated and stirred 8 hours, transfer PH=10.0 with 10% sodium hydroxide, 40 ℃ of following concentrating under reduced pressure remove isopropyl ether, suction filtration, filter cake dissolves with the 20ml methyl iso-butyl ketone (MIBK), 30 ℃ of temperature controls slowly drip 60ml water, separate out until solid, be incubated after 1 hour, be down to 8 ℃, suction filtration, 45 ℃ of vacuum-dryings of filter cake get white solid I 3.5g.Yield 44.4% content 99.6%.Infrared spectra is consistent with standard substance.
Embodiment 5
In the reaction flask of 100ml, add Azythromycin 10g(13.4mmol), methylene dichloride 30ml., stirring and dissolving, add 100ml water, the control temperature slowly drips the mixing acid of phosphoric acid and oxalic acid at 5 ℃, transfers to PH=0.4, after the insulated and stirred 1 hour, transfer PH=7.0 with 10% sodium hydroxide, 40 ℃ of following concentrating under reduced pressure remove methylene dichloride, suction filtration, filter cake 20ml acetone solution, 30 ℃ of temperature controls slowly drip 60ml water, separate out until solid, be incubated after 1 hour, be down to 8 ℃, suction filtration, 45 ℃ of vacuum-dryings of filter cake get white solid I 3.5g.Yield 44.4% content 99.6%.Infrared spectra is consistent with standard substance.
Embodiment 6
In the reaction flask of 100ml, add Azythromycin intermediate 10g(13.4mmol), methylene dichloride 30ml., stirring and dissolving, add 100ml water, the control temperature slowly drips the mixing acid of phosphoric acid and oxalic acid at 3 ℃, transfers to PH=0.8, after the insulated and stirred 5 hours, transfer PH=7.0 with 10% sodium hydroxide, 40 ℃ of following concentrating under reduced pressure remove methylene dichloride, suction filtration, filter cake 20ml acetone solution, 30 ℃ of temperature controls slowly drip 60ml water, separate out until solid, be incubated after 1 hour, be down to 8 ℃, suction filtration, 45 ℃ of vacuum-dryings of filter cake get white solid I 3.5g.Yield 44.4% content 99.6%.Infrared spectra is consistent with standard substance.
Claims (16)
1. Azythromycin or the Azythromycin intermediate preparation technology that sloughs the cladinose compound, it is characterized in that: Azythromycin or synthetic Azythromycin intermediate are dissolved in lower alcohol, rudimentary ether, halohydrocarbon, lower ketones or the lower member ester, after adding an amount of water, at-5～40 ℃, dropping inorganic acid, perhaps organic acid, perhaps mineral acid and the organic acid mixing acid reaction that is hydrolyzed, the control of reaction solution pH value exists: 0＜PH≤6.0,0.5～8 hour reaction times; Reaction finishes, and adds sodium hydroxide, and pH value is transferred to: 7≤PH≤10, concentrate desolventizing, and aqueous phase is separated out solid, centrifugal suction filtration, filter cake carries out refining crystallization under the mixed system of lower alcohol and water or lower ketones and water, and concrete reaction formula is as follows:
2. Azythromycin according to claim 1 or the Azythromycin intermediate preparation technology that sloughs the cladinose compound is characterized in that wherein R
1=R
3=CH
3Perhaps H, R
2=H or OH, R
4=CH
3, H, CHO or SO
2C
6H
4CH
3
3. Azythromycin according to claim 1 or the Azythromycin intermediate preparation technology that sloughs the cladinose compound, the usage ratio that it is characterized in that reaction raw materials and organic solvent can change between 1:1～1:10 (kg/kg), and the usage ratio of organic solvent and water can change between 1:1～1:30 (V/V).
4. Azythromycin according to claim 1 or the Azythromycin intermediate preparation technology that sloughs the cladinose compound is characterized in that described lower alcohol refers to C
1～C
4Alcohol.
5. Azythromycin according to claim 1 or the Azythromycin intermediate preparation technology that sloughs the cladinose compound is characterized in that described lower ketones refers to C
3～C
6Ketone.
6. Azythromycin according to claim 1 or the Azythromycin intermediate preparation technology that sloughs the cladinose compound is characterized in that described rudimentary ether refers to C
2～C
6Ether.
7. Azythromycin according to claim 1 or the Azythromycin intermediate preparation technology that sloughs the cladinose compound is characterized in that described halohydrocarbon refers to C
1～C
4Halohydrocarbon.
8. Azythromycin according to claim 1 or the Azythromycin intermediate preparation technology that sloughs the cladinose compound is characterized in that described lower member ester refers to C
2～C
6Ester.
9. Azythromycin according to claim 1 or the Azythromycin intermediate preparation technology that sloughs the cladinose compound is characterized in that described mineral acid for hydrolysis is hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid.
10. Azythromycin according to claim 1 and the Azythromycin intermediate preparation technology that sloughs the cladinose compound is characterized in that described organic acid for hydrolysis is formic acid, acetic acid, oxalic acid, propionic acid or butanic acid.
11. the preparation technology that Azythromycin according to claim 1 or Azythromycin intermediate are sloughed the cladinose compound is characterized in that described temperature of reaction is-5～30 ℃, the reaction solution pH value is between 1.0～6.0, and the reaction times is 0.5～6 hour.
12. the preparation technology that Azythromycin according to claim 4 or Azythromycin intermediate are sloughed the cladinose compound, peculiar levying is described C
1～C
4Alcohol be methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol or its isomeric forms.
13. the preparation technology that Azythromycin according to claim 5 or Azythromycin intermediate are sloughed the cladinose compound, peculiar levying is described C
3～C
6Ketone be acetone, methylethylketone, methyl iso-butyl ketone (MIBK) or analogue compounds.
14. the preparation technology that Azythromycin according to claim 6 or Azythromycin intermediate are sloughed the cladinose compound, peculiar levying is described C
2～C
6Ether be ether, propyl ether, isopropyl ether or analogue compounds.
15. the preparation technology that Azythromycin according to claim 7 or Azythromycin intermediate are sloughed the cladinose compound, peculiar levying is described C
1～C
4Halohydrocarbon be methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride or analogue compounds.
16. the preparation technology that Azythromycin according to claim 8 or Azythromycin intermediate are sloughed the cladinose compound, peculiar levying is described C
2～C
6Ester be methyl-formiate, ethyl formate, ethyl acetate, propyl acetate or analogue compounds.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104693251A (en) * | 2015-02-26 | 2015-06-10 | 齐鲁晟华制药有限公司 | Preparation method of gamithromycin or 13-descladinosylation compound serving as precursor of gamithromycin |
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| CN104693251A (en) * | 2015-02-26 | 2015-06-10 | 齐鲁晟华制药有限公司 | Preparation method of gamithromycin or 13-descladinosylation compound serving as precursor of gamithromycin |
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Application publication date: 20130807 |