CN1047172C - Improved purification method for quinolone compounds - Google Patents
Improved purification method for quinolone compounds Download PDFInfo
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- CN1047172C CN1047172C CN93110380A CN93110380A CN1047172C CN 1047172 C CN1047172 C CN 1047172C CN 93110380 A CN93110380 A CN 93110380A CN 93110380 A CN93110380 A CN 93110380A CN 1047172 C CN1047172 C CN 1047172C
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- carbostyril compound
- ammonium salt
- compound
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Abstract
The present invention belongs to the field of organic compound preparation technologies, particularly to an improved refining method for quinolone compounds, which mainly comprises the processes of salt forming, dissolution, decolorization, crystallization, etc. A quinolone compounds or an acid salt crude product thereof is prepared into an ammonium salt water solution, and a complexing agent is used for removing metal ions, decoloring, filtering, deaminizing and crystallizing to prepare a quinolone compound fine product. The present invention is suitable for refining pipemidic acid, norfloxacin, enoxacin, ciprofloxacin, etc. Compared with a neutralization method or an organic solvent recrystallization method, the method has the advantages of high product purity, good quality, low consumption, few pollution, etc.
Description
The present invention relates to a kind of preparation technology of new organic compound, particularly a kind of carbostyril compound or its acid-salt as shown in the formula structure:
In the formula,
Deng basic group, B
1=C, N; B
2=C, N; Work as B
1During=C,
R
2=-C
2H
5,
Alkyl, cycloalkyl, substituted aryl etc.; B
1During=N, R
1Do not have; Work as B
2During=C, Y=F; B
2During=N, Y does not have.
Its reaction process is:
Be applicable to all compounds, as pipemidic acid (Pipemidic acid), Norxin (Norfloxacin), fluorine pyridine acid (Enoxacin), Ciprofloxacin (Ciproflo-xacin) etc. with said structure.
Prior art is that to adopt neutralisation be that the acid-salt of compound (I) neutralizes with alkali when refining above-mentioned all compound, compound (I) basic salt with the acid neutralization; Or with organic solvent to its recrystallization.
The deficiencies in the prior art are:
It is inhomogeneous that neutralisation is separated out crystallization, local-crystalized very fast, may be enclosed with impurity such as inorganic salt in the crystallization, influential to inspection items such as the purity of finished product, residue on ignition.
And organic solvent recrystallization method, then solvent consumption height, cost height.
And the process for purification of prior art all has the three-waste pollution problem.
Purpose of the present invention overcomes the deficiencies in the prior art exactly, develops a kind of crystallization and separates out evenly, and finished product purity height, quality are good, consumes lowly, reduces the process for purification that pollutes.
Task of the present invention is implemented with following technical scheme:
Development and design is a kind of mainly to comprise processes such as salify, dissolving, decolouring, crystallization, and the improved process for purification of carbostyril compound is characterized in that:
1. starting raw material can be carbostyril compound or its acid-salt with following formula structure,
In the formula,
Deng basic group, B
1=C, N; B
2=C, N; Work as B
1During=C,
R
2=-C
2H
5,
Alkyl, cycloalkyl, substituted aryl etc.; B
1During=N, R
1Do not have; Work as B
2During=C, Y=F; B
2During=N, Y does not have.
2. its technological process is to make ammonium salt aqueous solution, complexing agent to remove deamination crystallization behind metal ion, the decolorization filtering, makes the carbostyril compound highly finished product.
The improved process for purification of above-mentioned carbostyril compound, described preparation ammonium salt is meant the ammonium salt solution of the solution of ammonium hydroxide effect of carbostyril compound or its acid-salt and 5～20% being made carbostyril compound.
The improved process for purification of above-mentioned carbostyril compound, the ratio of described carbostyril compound and solution of ammonium hydroxide are 1: 3～10.
The improved process for purification of above-mentioned carbostyril compound is describedly removed metal ion with complexing agent, is meant that carbostyril compound and the ratio of EDTA are 1: 0.001～0.006.
The improved process for purification of above-mentioned carbostyril compound, the decoloration process of the ammonium salt solution of described carbostyril compound is carbostyril compound: gac=1: 0.01～0.03,40～80 ℃ of bleaching temperatures, bleaching time 10～60min.
The improved process for purification of above-mentioned carbostyril compound, the deamination technology of the ammonium salt solution of described carbostyril compound be, pressure 0.098～0.01MPa, temperature≤90 ℃, terminal point pH value 7～8.
The improved process for purification of above-mentioned carbostyril compound, the deamination technology of the ammonium salt solution of described carbostyril compound be, temperature≤90 ℃, terminal point pH value 7～8.
The foundation of the present invention design is, has acidic-group (as carboxyl) and basic group (as imido grpup) in the molecular structure of compound (I), can form inner salt; And the amine salt of compound (I) belongs to unsettled salt, that is:
This reaction is a reversing process, and the ammonium salt of compound (I) is in the deamination process, and balance moves to the right, takes off to the greatest extent until ammonia, and compound (I) is separated out fully.
Advantage of the present invention mainly is that crystallization purity height, good crystalline, residue on ignition are low; The ammonia water of deviating from absorbs to be applied mechanically, thereby ammonium hydroxide consumption is low, cost is low.
Be example now, the contrast effect of prior art and the inventive method be described with the refining of pipemidic acid:
Fusing point, big deamination method 255～256 0.03 off-white colors, 88 treatment capacities are little for ℃ residue on ignition % outward appearance productive rate %# waste water situation neutralisation 252～253 0.2 faint yellow 88 treatment capacities
Results of comparison under (notes) # similarity condition is all calculated the primary crystallization rate, and the mother liquor recovery article does not count.
Practice shows that item indexs such as quality, consumption, environmental protection all obviously are better than prior art, and quality and benifit, environmental benefit and remarkable in economical benefits have reached intended purposes of the present invention satisfactorily.
The present invention is further elaborated below in conjunction with embodiment:
The ammonium salt process of [embodiment one] pipemidic acid is refining
30 parts of three water pipemidic acid crude products, 200 parts of 10% ammoniacal liquor, be warming up to 50～60 ℃ under stirring and make dissolving, add 0.09 part of EDTA, complex reaction 10min, add 0.3 part of gac in 50～60 ℃ of decolouring 60min, be cooled to 20～25 ℃ of filtrations, filtrate under pressure 0.015～0.01MPa, 20～25 ℃, the deamination crystallization, control terminal point PH7.5,25 ℃ of filtrations, washing, dry, get 26.4 parts of finished product three water pipemidic acids, productive rate 88%, mp255～256 ℃ (d), residue on ignition 0.03%, other is checked and all meets the pharmacopeia relevant regulations.
The ammonium salt process of [embodiment two] pipemidic acid is refining
30 parts of Pipemidate hydrochlorate crude products, 150 parts of 15% ammoniacal liquor, 50～60 ℃ of dissolvings, add 0.18 part of EDTA, complex reaction 10min adds 0.9 part of gac, 50～60 ℃ of decolouring 10min, 20～25 ℃ of filtrations, filtrate is in 20～50 ℃ of deamination crystallizations, control terminal point PH8.0,25 ℃ of filtrations, washing, drying gets 26.25 parts of three water pipemidic acids, productive rate 87.5%, mp255～256 ℃ (d), residue on ignition 0.04%, other is checked and all meets the pharmacopeia relevant regulations.
The ammonium salt process of [embodiment three] fluorine pyridine acid is refining
30 parts of three water fluorine pyridine acid crudes, 160 parts of 13% ammoniacal liquor, 50～60 ℃ of dissolvings, add 0.09 part of EDTA, complex reaction 10min adds 70～80 ℃ of decolourings of 0.5 part of gac 20min, be cooled to 20～25 ℃ of filtrations, filtrate under pressure 0.098～0.01MPa, 70～90 ℃, the deamination crystallization, control terminal point PH7.5,40 ℃ of filtrations, washing and drying gets 26.2 parts of finished product fluorine pyridine acid, productive rate 87.3%, mp225～226.5 ℃ (d), residue on ignition 0.025%, other is checked and all meets the pharmacopeia relevant regulations.
The ammonium salt process of [embodiment four] fluorine pyridine acid is refining
30 parts of anhydrous fluorine pyridine acid crudes, 90 parts of 18% ammoniacal liquor are warming up to 40～50 ℃ under stirring and make dissolving, add 0.09 part of EDTA, complex reaction 10min adds 0.5 part of gac in 40～50 ℃ of decolouring 30min, be cooled to 20～25 ℃ of filtrations, filtrate under pressure 0.098～0.01MPa, 70～90 ℃, the deamination crystallization, control terminal point PH7.6,45 ℃ are filtered washing, drying gets 27 parts of finished product fluorine pyridine acid, productive rate 90%, mp255～256 ℃ (d), residue on ignition 0.03%, other all meets the pharmacopeia relevant regulations.
The ammonium salt process of [embodiment five] Norxin is refining
30 parts of Norxin crude products, 300 parts of 5% ammoniacal liquor, be warming up to 50～60 ℃ under stirring and make dissolving, add 0.18 part of EDTA, complex reaction 10min, add 0.5 part of gac in 50～60 ℃ of decolouring 30min, be cooled to 20～25 ℃ of filtrations, filtrate under pressure 0.098～0.01MPa, 50～60 ℃ of deamination crystallizations, control terminal point PH7.2,25 ℃ of filtrations, washing, drying, get 26.5 parts of finished product Norxins, productive rate 88.3%, mp～℃ (d), residue on ignition 0.%, 226～227 ℃, other is checked and all meets the pharmacopeia relevant regulations.
The ammonium salt process of [embodiment six] Norxin is refining
30 parts of Norxin crude products, 150 parts of 15% ammoniacal liquor are warming up to 50～60 ℃ under stirring and make dissolving, add 0.03 part of EDTA, complex reaction 10min, add 0.6 part of gac in 50～60 ℃ of decolouring 30min, be cooled to 20～25 ℃ of filtrations, filtrate is under pressure 0.098～0.01MPa, 50～60 ℃, the deamination crystallization, control terminal point PH7.1,25 ℃ of crystallizations, filter, washing, drying gets 26.4 parts of finished product Norxins, productive rate 88%, mp226～227 ℃, residue on ignition 0.03%, other all meets the pharmacopeia relevant regulations.
The ammonium salt process of [embodiment seven] Ciprofloxacin is refining
30 parts of Ciprofloxacin crude products, 90 parts of 20% ammoniacal liquor, 50～60 ℃ of dissolvings, add 0.03 part of EDTA, complex reaction 10min adds 50～60 ℃ of decolourings of 0.5 part of gac 50min, be cooled to 20～25 ℃ of filtrations, filtrate under pressure 0.098～0.01MPa, 40～60 ℃, the deamination crystallization, control terminal point PH7.2,25 ℃ of filtrations, washing, drying gets 26.4 parts of elaboration Ciprofloxacins, productive rate 88%, mp256～257 ℃.
The ammonium salt process of [embodiment eight] Ciprofloxacin is refining
30 parts of Ciprofloxacin crude products, 160 parts of 13% ammoniacal liquor, 50～60 ℃ of dissolvings, add 0.05 part of EDTA, complex reaction 10min adds 50～60 ℃ of decolourings of 0.5 part of gac 30min, be cooled to 20～25 ℃ of filtrations, filtrate under pressure 0.098～0.01MPa, 30～60 ℃, the deamination crystallization, control terminal point PH7.0,25 ℃ of filtrations, washing, drying gets 26.55 parts of elaboration Ciprofloxacins, productive rate 88.5%, mp256～257 ℃.
Claims (6)
1, a kind of process for purification of carbostyril compound comprises following formula: compound:
In the formula,
B
1=C, N, B
2=C, N,
Work as B
1During=C,
R
2=C
2H
5,
Alkyl,
Cycloalkyl, substituted aryl,
Work as B
1During=N, R
1No,
Work as B
2During=C, Y=F,
Work as B
2During=N, Y does not have, and makes ammonium salt aqueous solution earlier, removes metal ion with complexing agent again, and behind the decolorization filtering, deamination, crystallization again makes the carbostyril compound highly finished product.
2. according to the process of claim 1 wherein that the preparation ammonium salt is with carbostyril compound or its acid-salt, prepare ammonium salt aqueous solution with solution of ammonium hydroxide, the weight ratio of carbostyril compound and 5～20% solution of ammonium hydroxide is 1: 3～10.
3. according to the process of claim 1 wherein that when removing metal ion with complexing agent EDTA, the weight ratio of carbostyril compound and EDTA is 1: 0.001～0.006.
4. according to the process of claim 1 wherein carbostyril compound ammonium salt aqueous solution when decolouring, the weight ratio of carbostyril compound and gac is 1: 0.01～0.03,40～80 ℃ of bleaching temperatures, bleaching time 10～60min.
5. when the process of claim 1 wherein the crystallization of carbostyril compound ammonium salt aqueous solution deamination, temperature≤90 ℃, terminal point pH7～8.
6. according to the method for claim 5, wherein during the crystallization of carbostyril compound ammonium salt aqueous solution deamination, pressure is 0.098～0.01MPa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93110380A CN1047172C (en) | 1993-04-07 | 1993-04-07 | Improved purification method for quinolone compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93110380A CN1047172C (en) | 1993-04-07 | 1993-04-07 | Improved purification method for quinolone compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1093364A CN1093364A (en) | 1994-10-12 |
| CN1047172C true CN1047172C (en) | 1999-12-08 |
Family
ID=4988253
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93110380A Expired - Lifetime CN1047172C (en) | 1993-04-07 | 1993-04-07 | Improved purification method for quinolone compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1047172C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321121C (en) * | 2005-04-21 | 2007-06-13 | 浙江医药股份有限公司新昌制药厂 | Post processing method for preparing levo-ofloxacin |
| CN102746223B (en) * | 2012-07-30 | 2013-10-23 | 浙江新东港药业股份有限公司 | Separation method of norfloxacin and chloro pipradrol |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4910520A (en) * | 1972-05-31 | 1974-01-30 | ||
| JPS5049286A (en) * | 1973-09-04 | 1975-05-01 | ||
| JPS6157538A (en) * | 1984-08-30 | 1986-03-24 | Mitsui Toatsu Chem Inc | Preparation of stabilized methacrylamide |
-
1993
- 1993-04-07 CN CN93110380A patent/CN1047172C/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4910520A (en) * | 1972-05-31 | 1974-01-30 | ||
| JPS5049286A (en) * | 1973-09-04 | 1975-05-01 | ||
| JPS6157538A (en) * | 1984-08-30 | 1986-03-24 | Mitsui Toatsu Chem Inc | Preparation of stabilized methacrylamide |
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| Publication number | Publication date |
|---|---|
| CN1093364A (en) | 1994-10-12 |
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| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
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Expiration termination date: 20130407 Granted publication date: 19991208 |