CN101928232B - Method for preparing cefixime dispersible tablet raw material intermediate - Google Patents
Method for preparing cefixime dispersible tablet raw material intermediate Download PDFInfo
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- CN101928232B CN101928232B CN 200910040358 CN200910040358A CN101928232B CN 101928232 B CN101928232 B CN 101928232B CN 200910040358 CN200910040358 CN 200910040358 CN 200910040358 A CN200910040358 A CN 200910040358A CN 101928232 B CN101928232 B CN 101928232B
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Abstract
The invention discloses a method for preparing a cefixime dispersible tablet raw material intermediate, namely (Z)-4-chlorine-methoxycarbonylmethoxyimine-3-oxo-butanoic acid. The intermediate is prepared from a raw material t-butyl acetoacetate by three steps of reaction, namely nitrosification, esterification and halogenation. The preparation method has the advantages of simple and convenient synthetic technology, high yield, low cost, and suitability for industrial production.
Description
Technical field
The present invention relates to the preparation method of medicine intermediate, more particularly, relate to the i.e. synthesis preparation method of (Z)-4-chlorine methoxycarbonyl methoxyl group imines ketobutyric acid of cefixime dispersible tablet raw material intermediate.
Technical background
(Z)-4-chlorine methoxycarbonyl methoxyl group imines ketobutyric acid is synthetic (6R, 7R)-7-[(Z)-2-(thiazolamine base)-2-(carboxylic methoxyimino) acetamido]-8-oxyethylene group thia azabicyclo [4.2.0] octene carboxylic acid trihydrate (abbreviation Cefixime Micronized) key intermediate, Cefixime Micronized is third generation cephalosporin, to the gram-positive streptococcus, streptococcus pneumoniae and Grain-negative gonococcus, intestinal bacteria, klebsiella spp must, Serratia, proteus, hemophilus influenzae tool killing action, stronger than other oral cephalosporin effect, and anti-enzyme.The clinical acute and chronic bronchitis, pneumonia, urethritis, urocystitis, pyelonephritis, tonsillitis, otitis media, sinusitis paranasal sinusitis, scarlet fever, cholecystitis, cholangitis, paediatrics of being used for the treatment of infects (as otitis media) etc.Because it is a medicine with multiple oral release technical characterictic that head is embraced the gram oxime, present domestic 6 formulations of having developed and got permission to have gone on the market, be respectively capsule, tablet, dispersible tablet, granule, dry suspensoid and chewable tablet, not only can be used for grownup patient, and small dose drug also is to aim at the antibiotic medicine that designed for children is released, thus the channel of widening for produce market.Clearly propose in China's medical sci-tech development programs in 2010, develop injection third generation head selectively and embrace rhzomorph, the oral third generation head of focus development is embraced rhzomorph, develop energetically the 4th generation head embrace rhzomorph.To the end of the year 2005, reached the scale of 19 families in China's production of raw medicine.Thereby also spurred the development of its main intermediate.
The synthetic method of domestic and foreign literature report has multiple, but the most frequently used synthetic method has: 1. adopting tert-butyl acetoacetate is raw material, gets with thiocarbamide cyclization, hydrolysis after nitrosification, halogenation respectively again; 2. adopting methyl aceto acetate is raw material, nitrosification again after the first halogenation, makes with thiocarbamide cyclization, hydrolysis, can adopt substep or continuous operation process.But along with the continuous variation in market, original technology cost can not satisfy the needs in market, generally all has long, shortcoming such as the three wastes are many, material cost is high and yield is lower of cycle.The present invention can effectively solve some drawbacks that existing production technique exists.
Summary of the invention
The present invention is directed to the deficiency of existing research, propose simple, the synthetic method for preparing intermediate of cefixime with low cost of a kind of production method;
The present invention discloses a kind of method for preparing the cefixime dispersible tablet raw material intermediate, i.e. (Z)-4-chlorine methoxycarbonyl methoxyl group imines ketobutyric acid, but the technology of large-scale industrialization preparation;
It is that raw material obtains through nitrosification, esterification, halogenation three-step reaction with the tert-butyl acetoacetate that the present invention prepares the cefixime dispersible tablet raw material intermediate;
The present invention's preparation cefixime dispersible tablet raw material intermediate nitrosation reaction takes place under acidic conditions, selects for use the nitrosation reaction thing for containing NO
2The salt of group is as sodium salt, sylvite, calcium salt etc.;
PH value of solution showed acid when the present invention prepared cefixime dispersible tablet raw material intermediate nitrosation reaction, selected for use acid to be acetic acid, phosphoric acid etc., and acidity is pH=1-5, is preferably pH=3-4;
The present invention prepares cefixime dispersible tablet raw material intermediate chlorination reaction and takes place under acidic conditions, selects for use acid to be acetic acid, phosphoric acid etc., and acidity is pH=0-5, is preferably pH=0-2;
Further specify principle of the present invention below in conjunction with chemical equation:
With respect to prior art, the present invention has adopted the cheaper raw material of cost, and reaction time is short, and the productive rate height has high productive value, but large-scale application is in technology production.
Embodiment
By the following examples the present invention is further specified, but that institute's embodiment is not limited to embodiment is described;
Embodiment 1
The intermediate of cefixime preparation method:
Add tert-butyl acetoacetate 100g in the 2000ml round-bottomed flask, Glacial acetic acid 100ml drips by 100ml water and 30g NaNO down in the frozen water cooling
2The solution that is made into, the control rate of addition makes system temperature be no more than 40 ℃.Add the back in 15 ℃ of reaction 30min.Remove most of HOAC under reduced pressure, add an amount of chloracetic acid methyl esters and anhydrous K
2CO
3, stirring at room reaction 10h.Reaction is finished, and adds in the 800ml water, adds 400mlEtOAc, and separatory is transferred to oily matter in the 1000ml flask, adds 150mlHOAc, drips SULPHURYL CHLORIDE 200g under 20 ℃ in 1h, drips and finishes, and reacts 1h under this temperature again.Cooling, concentrating under reduced pressure, 50 ℃ of following vacuum-dryings get white crystal 36.3g, survey content 99.7%.
Embodiment 2
Add tert-butyl acetoacetate 100g in the 2000ml round-bottomed flask, 1mol/L hydrochloric acid 100ml drips by 100ml water and 30g KNO down in the frozen water cooling
2The solution that is made into, the control rate of addition makes system temperature be no more than 40 ℃.Add the back in 15 ℃ of reaction 30min.Remove most of HCl under reduced pressure, add an amount of chloracetic acid methyl esters and anhydrous K
2CO
3, stirring at room reaction 10h.Reaction is finished, and adds in the 1000ml water, adds 400mlEtOAc, and separatory is transferred to oily matter in the 1000ml flask, adds 100mlH
3PO
4, under 25 ℃, in 2h, drip SULPHURYL CHLORIDE 180g, drip and finish, under this temperature, react 2h again.Cooling, concentrating under reduced pressure, 50 ℃ of following vacuum-dryings get white crystal 34.3g, survey content 101.2%.
Embodiment 3
Add tert-butyl acetoacetate 100g in the 2000ml round-bottomed flask, 1mol/L hydrochloric acid 100ml drips by 100ml water and 26g Ca (NO down in the frozen water cooling
2)
2The solution that is made into, the control rate of addition makes system temperature be no more than 40 ℃.Add the back in 15 ℃ of reaction 30min.Remove most of HOAc under reduced pressure, add an amount of chloracetic acid methyl esters and anhydrous Na
2CO
3, stirring at room reaction 8h.Reaction is finished, and adds in the 500ml water, adds 400mlEtOAc, and separatory is transferred to oily matter in the 1000ml flask, adds 100mlHOAc, drips SULPHURYL CHLORIDE 160g under 25 ℃ in 2h, drips and finishes, and reacts 2h under this temperature again.Cooling, concentrating under reduced pressure, 50 ℃ of following vacuum-dryings get white crystal 38.1g, survey content 99.1%.
Claims (1)
1. a cefixime dispersible tablet raw material intermediate (Z)-4-chloro-2-methoxycarbonyl methoxyl group imines-3-ketobutyric acid preparation method, it is characterized in that: add tert-butyl acetoacetate 100g in the 2000ml round-bottomed flask, Glacial acetic acid 100ml drips by 100ml water and 30g NaNO down in the frozen water cooling
2The solution that is made into, the control rate of addition makes system temperature be no more than 40 ℃; Add the back in 15 ℃ of reaction 30min; Remove most of HOAC under reduced pressure, add an amount of chloracetic acid methyl esters and anhydrous K
2CO
3, stirring at room reaction 10h; Reaction is finished, and adds in the 800ml water, adds 400mlEtOAc, and separatory is transferred to oily matter in the 1000ml flask, adds 150mlHOAc, drips SULPHURYL CHLORIDE 200g under 20 ℃ in 1h, drips and finishes, and reacts 1h under this temperature again; Cooling, concentrating under reduced pressure, 50 ℃ of following vacuum-dryings get white crystal 36.3g, survey content 99.7%.
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| CN 200910040358 CN101928232B (en) | 2009-06-18 | 2009-06-18 | Method for preparing cefixime dispersible tablet raw material intermediate |
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| CN 200910040358 CN101928232B (en) | 2009-06-18 | 2009-06-18 | Method for preparing cefixime dispersible tablet raw material intermediate |
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| CN101928232A CN101928232A (en) | 2010-12-29 |
| CN101928232B true CN101928232B (en) | 2013-09-04 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107445917A (en) * | 2017-09-15 | 2017-12-08 | 济南美高生物医药科技有限公司 | A kind of MICA active esters environment-protection production method |
| CN109232305A (en) * | 2018-08-28 | 2019-01-18 | 山东金城柯瑞化学有限公司 | The preparation method of CMOBA |
| CN111592471B (en) * | 2020-06-12 | 2023-03-21 | 济南大学 | Method for synthesizing cephalosporin active ester intermediate through bromination reaction |
| CN117510367B (en) * | 2024-01-04 | 2024-03-12 | 山东金城柯瑞化学有限公司 | Preparation method of cefixime side chain open-loop acid |
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Non-Patent Citations (2)
| Title |
|---|
| Studies on β-lactam antibiotics. IX. Synthesis and biological activity of a new orally active cephalosporin, cefixime (FK027);Yamanaka H., et al.;《THE JOURNAL OF ANTIBIOTICS》;19851231;第38卷(第12期);1738-1751 * |
| Yamanaka H., et al..Studies on β-lactam antibiotics. IX. Synthesis and biological activity of a new orally active cephalosporin, cefixime (FK027).《THE JOURNAL OF ANTIBIOTICS》.1985,第38卷(第12期),1738-1751. |
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Effective date of registration: 20201028 Address after: 510000 No. 6 Industrial Avenue, Conghua Economic Development Zone, Guangzhou, Guangdong Province Patentee after: GUANGDONG XIANQIANG PHARMACEUTICAL Co.,Ltd. Patentee after: Guangdong Zhongsheng Pharmaceutical Co.,Ltd. Patentee after: GUANGDONG HUANAN PHARMACY Ltd. Address before: 510900 Industrial Road, Conghua economic and Technological Development Zone, Guangzhou, Guangdong Patentee before: GUANGDONG XIANQIANG PHARMACEUTICAL Co.,Ltd. |