CN101289457A - Novel process for synthesizing 3-deacetyl cefuroxime sodium (DCCF) - Google Patents
Novel process for synthesizing 3-deacetyl cefuroxime sodium (DCCF) Download PDFInfo
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- CN101289457A CN101289457A CNA2008100677806A CN200810067780A CN101289457A CN 101289457 A CN101289457 A CN 101289457A CN A2008100677806 A CNA2008100677806 A CN A2008100677806A CN 200810067780 A CN200810067780 A CN 200810067780A CN 101289457 A CN101289457 A CN 101289457A
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Abstract
The invention relates to a synthesis art of a chemical product, in particular to a new synthesis art for 3-deacetyl cefuroxime acid (DCCF). The art of the invention uses SMIA acyl chloride and 3-deacetyl cephalosporin acid (D-7-ACA) as the main synthesis ingredients to replace the SMIA acyl chloride and the 7-ACA, which reduces the chemical reaction process needed in the synthesis, shortens the production cycle, reduces the using solvent species, facilitates the solvent recovery and improves the product synthesis rate.
Description
Technical field:
The present invention relates to a kind of synthesis technique of chemical preparations, particularly a kind of 3-deacetyl cefuroxime sodium acid (DCCF) new synthetic process.
Background technology:
3-deacetyl cefuroxime sodium acid (chemical name: (6R; 7R)-7-[2-furyl (methoxyimino) kharophen]-3-methylol-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid or (6R; 7R)-7-[2-furyl (methoxyimino) kharophen]-3-methylol-Cephalosporanic acid, also be called DCCF) be a kind of important source material of pharmacy.At present, 3-deacetyl cefuroxime sodium acid synthetic technology situation is as follows:
(1) SMIA acyl chlorides preparation: after having added 8.4kg phosphorus pentachloride and 70L methylene dichloride stirring and dissolving in the cleaning-drying retort, be cooled to-40 ℃, stream adds 5L DMA, stream adds process control 10-15 minute, and controlled temperature is not higher than-20 ℃, finishes, continue to add the 7.5kg SMIA, control-12～-10 ℃ of stirring reactions 90 minutes, reaction finishes with frozen water washing three times, and it is standby that organic phase is cooled to-5 ℃ of preservations.
(2) go the preparation of acetyl cefuroxime acid: added 26L purified water and 5.4kg 7-ACA in the cleaning reaction jar, be cooled to 0 ℃, stream adds NaOH solution and regulates the PH7.5-8.5 dissolving, and after the dissolving fully, stream adds above (1) prepares the organic phase [1] of SMIA acyl chlorides, control 20-30 minute during this time, temperature: 2-8 ℃, finish 0-15 ℃ and stirred 3 hours, during keep PH6.0-8.5 with NaOH solution, standing demix after reaction finishes, water is temporary; Organic phase adds the extraction of 10L purified water, standing demix, organic phase recycling, merge water, add 100L methyl alcohol, be cooled to-30 ℃, stream adds 6L 15% sodium hydroxide solution, the powerful stirring after 20 minutes between-10～-15 ℃, and stream adds 10L acetic acid and regulates PH to 6.0, stream adds 4N hydrochloric acid and regulates PH to 1.5 crystallization, and crystallization finishes and is cooled to below 5 ℃, stirs 2 hours, centrifugal, wash secondary with frozen water, dry, less than 0.5%, discharging gets 6.5kg DCCF in 45 ℃ of vacuum-dryings to moisture.
Existing explained hereafter 3-deacetyl cefuroxime sodium acid has following problem:
1, the synthetic 3-deacetyl cefuroxime sodium acid of 7-ACA route is longer relatively, and reactions steps is 3 step chemical reactions.
2, the synthetic middle solvent more (methylene dichloride, DMF, methyl alcohol) that uses, solvent reclaims difficulty.
3, yield lower (weight yield is 125%, and molar yield is 89.2%)
4, the production cycle longer, energy consumption is big.
Summary of the invention:
The present invention is a kind of new 3-deacetyl cefuroxime sodium acid (DCCF) synthesis technique of invention in order to solve above-mentioned existing technology deficiency just.
The present invention implements by following technique means:
Main synthetic batching in synthetic 3-deacetyl cefuroxime sodium acid (DCCF) technology replaces SMIA acyl chlorides and 7-ACA by SMIA acyl chlorides and 3-deacetylate Cephalosporanic acid (D-7-ACA).
3-deacetylate Cephalosporanic acid and SMIA acyl chlorides add-on molar ratio are no more than 5: 1.
Concrete mode is:
A. phosphorus pentachloride is dissolved in and is cooled to 10 ℃～-60 ℃ after solvent fully stirs;
B. continue to add SMIA, temperature is controlled at 0 ℃～-40 ℃;
C. fully behind the above-mentioned solution of stirring reaction, the frozen water washing obtains organic phase SMIA acyl chlorides and remaines in 15 ℃～-20 ℃ the temperature;
D. 3-deacetylate Cephalosporanic acid (D-7-ACA) is added and add basic solution or solvent adjustment pH value behind the capacity pure water and dissolve to 7.5-8.5;
E.3-after deacetylate Cephalosporanic acid (D-7-ACA) dissolving fully, stream adds the SMIA acyl chlorides organic phase that above-mentioned steps c prepares, and 3-deacetylate Cephalosporanic acid (D-7-ACA) is no more than 5: 1 with SMIA acyl chlorides mol ratio;
F.3-deacetylate Cephalosporanic acid (D-7-ACA) and SMIA acyl chloride reaction process control solution temperature-5～30 ℃, with basic solution or basic solvent control PH:6.0-8.5 and constantly stir, fully reaction back standing demix keeps water;
G. organic phase is with continuing to keep extraction back water with the pure water extraction after getting layering;
H. after merging all waters, stream adds acidic solution or solvent (example hydrochloric acid, sulfuric acid, nitric acid etc.) is regulated pH value to 1～3 crystallizations;
I. be cooled to after crystallization finishes below 5 ℃, after fully stirring, centrifugal; Product after centrifugal places 30-70 ℃ of vacuum dry with after the frozen water washing, drying.
The present invention can also implement by following measure: solvent can be got the solution that methylene dichloride or ethylene dichloride, trichloromethane etc. can fully dissolve phosphorus pentachloride among the step a of above-mentioned synthesis technique.Can also add auxiliary SMIA dissolved solvents such as DMA, DMF in the whipping process of step a.
The present invention uses 3-deacetylate Cephalosporanic acid (hereinafter referred to as D-7-ACA) as the synthetic 3-deacetyl cefuroxime sodium acid of starting raw material; reduce by a step chemical reaction process; shorten the production cycle and reduced the solvent kind of using; be beneficial to solvent and reclaim, compare with existing technology and have the following advantages:
(1) be that the synthetic DCCF weight yield of raw material improves (weight yield 150%, molar yield are 90.6%) with D-7-ACA
(2) production cycle shortens, and energy consumption reduces.
(3) solvent kind of Shi Yonging and usage quantity reduce, and are beneficial to solvent and reclaim.
Description of drawings:
Fig. 1 is the technology of the present invention process flow sheet.
Specific embodiment:
Example 1:
(1) cephalofruxin side chain (SMFA acyl chlorides) is synthetic: add in the cleaning-drying retort the 4.16kg phosphorus pentachloride (with the D-7-ACA molar ratio range: 1: 1) and 70L methylene dichloride stirring and dissolving after, be cooled to :-15～-50 ℃, stream adds 5L DMF, stream adds process control 10-15 minute, controlled temperature is not higher than-20 ℃, finish, continue to add the 3.72kg SMIA (with the D-7-ACA molar ratio range: 1: 1), controlled temperature was-5 ℃～-25 ℃ stirring reactions 90 minutes, reaction finishes with frozen water washing three times, and it is standby that organic phase is cooled to 15 ℃～-20 ℃ preservations.
(2) go the preparation of acetyl cefuroxime acid: added 26L purified water and 4.65kg D-7-ACA in the cleaning reaction jar, be cooled to 0～10 ℃, stream adds NaOH solution and regulates the PH7.5-8.5 dissolving, after the dissolving fully, stream adds above-mentioned (1) preparation the organic phase that contains the SMIA acyl chlorides, during control 20-30 minute, temperature :-5～30 ℃, finish-5 ℃～30 ℃ and stirred 3 hours, control PH:6.0-8.5 with NaOH solution between the reaction period; After reacting completely, standing demix, water is temporary; Organic phase adds the extraction of 10L purified water, standing demix, organic phase recycling, water and water merging for the first time, stream adds 4N hydrochloric acid and regulates PH to 1.5 crystallization, crystallization finishes and is cooled to below 5 ℃, stirs 2 hours, and is centrifugal, use the frozen water washed twice, dry, less than 0.5%, discharging gets 7.1kg DCCF in 45 ℃ of vacuum-dryings to moisture.
Example 2:
(1) cephalofruxin side chain (SMFA acyl chlorides) is synthetic: after having added 8.4kg phosphorus pentachloride (with the D-7-ACA mol ratio being: 2: 1) and 70L methylene dichloride stirring and dissolving in the cleaning-drying retort, be cooled to :-15～-50 ℃, stream adds 5L DMA, stream adds process control 10-15 minute, controlled temperature is not higher than-20 ℃, finish, continue to add the 7.45kg SMIA (with the D-7-ACA mol ratio be 2: 1), controlled temperature was-5 ℃～-25 ℃ stirring reactions 90 minutes, reaction finishes with frozen water washing three times, and it is standby that organic phase is cooled to 15 ℃～-20 ℃ preservations.
(2) go the preparation of acetyl cefuroxime acid: added 26L purified water and 4.65kg D-7-ACA in the cleaning reaction jar, be cooled to 0～10 ℃, stream adds NaOH solution and regulates the PH7.5-8.5 dissolving, after the dissolving fully, and the organic phase that contains the SMIA acyl chlorides of preparation that stream adds above-mentioned (1), control 20-30 minute during this time, temperature :-5～30 ℃, finish-5 ℃～30 ℃ and stirred 3 hours, control PH:6.0-8.5 between the reaction period, standing demix after reacting completely, water is temporary; Organic phase adds the extraction of 10L purified water, standing demix, organic phase recycling, water and water merging for the first time, stream adds 4N hydrochloric acid and regulates PH to 1.5 crystallization, crystallization finishes and is cooled to below 5 ℃, stirs 2 hours, and is centrifugal, use the frozen water washed twice, dry, less than 0.5%, discharging gets 7.2kg DCCF in 45 ℃ of vacuum-dryings to moisture.
Example 3:
(1) cephalofruxin side chain (SMFA acyl chlorides) is synthetic: after having added 20.84kg phosphorus pentachloride (with the D-7-ACA mol ratio being: 5: 1) and 150L methylene dichloride stirring and dissolving in the cleaning-drying retort, be cooled to :-15～-50 ℃, stream adds 10L DMF, stream adds process control 10-15 minute, controlled temperature is not higher than-20 ℃, finish, continue to add the 18.6kg SMIA (with the D-7-ACA mol ratio be 5: 1), controlled temperature was-5 ℃～-25 ℃ stirring reactions 90 minutes, reaction finishes with frozen water washing three times, and it is standby that organic phase is cooled to 15 ℃～-20 ℃ preservations.
(2) go the preparation of acetyl cefuroxime acid: added 26L purified water and 4.65kg D-7-ACA in the cleaning reaction jar, be cooled to 0～10 ℃, stream adds NaOH solution and regulates the PH7.5-8.5 dissolving, after the dissolving fully, and the organic phase that contains the SMIA acyl chlorides of preparation that stream adds above-mentioned (1), control 20-30 minute during this time, temperature :-5～30 ℃, finish-5 ℃～30 ℃ and stirred 3 hours, during with NaOH solution control PH at 6.0-8.0, the back standing demix reacts completely, water is temporary, and organic phase adds the extraction of 10L purified water, standing demix, the organic phase recycling, water adds 4N hydrochloric acid and regulates PH to 1.5 crystallization with water merging for the first time, stream, and crystallization finishes and is cooled to below 5 ℃, stirred 2 hours, centrifugal, use the frozen water washed twice, dry, less than 0.5%, discharging gets 7.2kg DCCF in 45 ℃ of vacuum-dryings to moisture.
Example 4:
(1) cephalofruxin side chain (SMFA acyl chlorides) is synthetic: after having added 8.4kg phosphorus pentachloride (with the D-7-ACA mol ratio being: 2: 1) and 70L ethylene dichloride stirring and dissolving in the cleaning-drying retort, be cooled to :-15～-50 ℃, add the 7.45kg SMIA (with the D-7-ACA mol ratio be 2: 1), controlled temperature was-5 ℃～-25 ℃ stirring reactions 90 minutes, reaction finishes with frozen water washing three times, and it is standby that organic phase is cooled to 15 ℃～-20 ℃ preservations.
(2) go the preparation of acetyl cefuroxime acid: added 26L purified water and 4.65kg D-7-ACA in the cleaning reaction jar, be cooled to 0～10 ℃, stream adds 15% ammoniacal liquor and regulates the PH7.5-8.5 dissolving, after the dissolving fully, and the organic phase that contains the SMIA acyl chlorides of preparation that stream adds above-mentioned (1), control 20-30 minute during this time, temperature :-5～30 ℃, finish-5 ℃～30 ℃ and stirred 3 hours, stream adds 15% ammoniacal liquor control PH:6.0-8.5 between the reaction period, the back standing demix reacts completely, water is temporary, and organic phase adds the extraction of 10L purified water, standing demix, the organic phase recycling, water adds 4N hydrochloric acid and regulates PH to 1.5 crystallization with water merging for the first time, stream, and crystallization finishes and is cooled to below 5 ℃, stirred 2 hours, centrifugal, use the frozen water washed twice, dry, less than 0.5%, discharging gets 7.3kg DCCF in 45 ℃ of vacuum-dryings to moisture.
This 3-deacetyl cefuroxime sodium provided by the invention acid (DCCF) new synthetic process; improve the loaded down with trivial details production technique of existing synthesis technique greatly; reducing energy consumption and solvent, improved productivity, is the huge advance made on a kind of 3-deacetyl cefuroxime sodium acid (DCCF) synthesis technique in fact.
Claims (5)
1, a kind of 3-deacetyl cefuroxime sodium acid (DCCF) new synthetic process is characterized in that the main synthetic batching in the described synthetic 3-deacetyl cefuroxime sodium acid technology is made of SMIA acyl chlorides and 3-deacetylate Cephalosporanic acid:
2,3-deacetyl cefuroxime sodium according to claim 1 acid (DCCF) new synthetic process is characterized in that described 3-deacetylate Cephalosporanic acid and SMIA acyl chlorides add-on molar ratio are no more than 5: 1.
3,3-deacetyl cefuroxime sodium according to claim 2 acid (DCCF) new synthetic process, its described technology characteristics is:
A. phosphorus pentachloride is dissolved in and is cooled to 10 ℃～-60 ℃ after solvent fully stirs;
B. continue to add SMIA, temperature is controlled at 0 ℃～-40 ℃;
C. fully behind the above-mentioned solution of stirring reaction, the frozen water washing obtains organic phase SMIA acyl chlorides and remaines in 15 ℃～-20 ℃ the temperature;
D. will add basic solution or solvent adjustment pH value behind the 3-deacetylate Cephalosporanic acid adding capacity pure water to 7.5-8.5;
E.3-after the dissolving fully of deacetylate Cephalosporanic acid, stream adds the SMIA acyl chlorides organic phase that above-mentioned steps c prepares;
F. 3-deacetylate Cephalosporanic acid (D-7-ACA) and SMIA acyl chloride reaction process control solution temperature-5～30 ℃, with basic solution or basic solvent control PH:
6.0-8.5 and constantly stir, fully reaction back standing demix keeps water;
G. organic phase is with continuing to keep extraction back water with the pure water extraction after getting layering;
H. after merging all waters, stream adds acidic solution or solvent (example hydrochloric acid, sulfuric acid, nitric acid etc.) is regulated pH value to 1～3 crystallizations;
I. be cooled to after crystallization finishes below 5 ℃, after fully stirring, centrifugal; Product after centrifugal places 30 70 ℃ of vacuum dry with after the frozen water washing, drying.
4,3-deacetyl cefuroxime sodium according to claim 3 acid (DCCF) new synthetic process is characterized in that solvent among the step a of described synthesis technique can get the solvent that methylene dichloride or ethylene dichloride, trichloromethane etc. can fully dissolve phosphorus pentachloride.
5,3-deacetyl cefuroxime sodium according to claim 4 acid (DCCF) new synthetic process, the step a that it is characterized in that described synthesis technique can also add DMA, DMF etc. and can assist SMIA dissolved solvent in whipping process.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928292A (en) * | 2010-09-19 | 2010-12-29 | 苏州致君万庆药业有限公司 | Method for preparing cefuroxime acid |
| CN102702231A (en) * | 2012-06-18 | 2012-10-03 | 山东大学 | Method for preparing 3-descarbamoyl-cefuroxime acid |
| CN103450223A (en) * | 2013-08-16 | 2013-12-18 | 广东立国制药有限公司 | Preparation method of descarbamoyl cefuroxime |
| CN110041346A (en) * | 2019-04-17 | 2019-07-23 | 深圳市立国药物研究有限公司 | A kind of preparation method of the Cefixime of low cost |
| CN110526964A (en) * | 2015-04-17 | 2019-12-03 | 南京济朗生物科技有限公司 | The quick non-invasive monitoring technology of women luteal function |
| CN110950892A (en) * | 2019-12-16 | 2020-04-03 | 山东金城柯瑞化学有限公司 | Method for optimizing and removing impurities from cefuroxime intermediate (3-decarbamoyl-cefuroxime acid) |
-
2008
- 2008-06-13 CN CNA2008100677806A patent/CN101289457A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928292A (en) * | 2010-09-19 | 2010-12-29 | 苏州致君万庆药业有限公司 | Method for preparing cefuroxime acid |
| CN101928292B (en) * | 2010-09-19 | 2013-03-13 | 苏州致君万庆药业有限公司 | Method for preparing cefuroxime acid |
| CN102702231A (en) * | 2012-06-18 | 2012-10-03 | 山东大学 | Method for preparing 3-descarbamoyl-cefuroxime acid |
| CN102702231B (en) * | 2012-06-18 | 2014-10-29 | 山东大学 | Method for preparing 3-descarbamoyl-cefuroxime acid |
| CN103450223A (en) * | 2013-08-16 | 2013-12-18 | 广东立国制药有限公司 | Preparation method of descarbamoyl cefuroxime |
| CN110526964A (en) * | 2015-04-17 | 2019-12-03 | 南京济朗生物科技有限公司 | The quick non-invasive monitoring technology of women luteal function |
| CN110041346A (en) * | 2019-04-17 | 2019-07-23 | 深圳市立国药物研究有限公司 | A kind of preparation method of the Cefixime of low cost |
| CN110041346B (en) * | 2019-04-17 | 2022-06-07 | 广东立国制药有限公司 | Low-cost preparation method of cefixime |
| CN110950892A (en) * | 2019-12-16 | 2020-04-03 | 山东金城柯瑞化学有限公司 | Method for optimizing and removing impurities from cefuroxime intermediate (3-decarbamoyl-cefuroxime acid) |
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