CN101550146A - Cefetamet pivoxil hydrochloride compound and preparation method thereof - Google Patents
Cefetamet pivoxil hydrochloride compound and preparation method thereof Download PDFInfo
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- CN101550146A CN101550146A CNA2009100149797A CN200910014979A CN101550146A CN 101550146 A CN101550146 A CN 101550146A CN A2009100149797 A CNA2009100149797 A CN A2009100149797A CN 200910014979 A CN200910014979 A CN 200910014979A CN 101550146 A CN101550146 A CN 101550146A
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- cefetamet pivoxil
- hydrochloride compound
- pivoxil hydrochloride
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Abstract
The invention discloses a cefetamet pivoxil hydrochloride compound and a preparation method thereof. In the method, the crude product of cefetamet pivoxil hydrochloride prepared by the prior art is processed by the following steps to obtain a relatively pure cefetamet pivoxil hydrochloride compound: the crude product of cefetamet pivoxil hydrochloride is dissolved in methanol or alcohol, and then sodium hydroxide solution or potassium hydroxide solution is added; the mixed solution is stirred for reaction and hydrolyzed to obtain cefetamet pivoxil sodium salt or cefetamet pivoxil sylvite which is then absorbed with added active carbon and filtered; and then iodo-ester is added and reaction is conducted in the presence of an organic solvent to obtain cefetamet pivoxil; the cefetamet pivoxil dissolves in isopropyl alcohol, hydrochloric acid is added in a dropwise manner and cyclohexane is added, and the mixed solution is stirred to separate out crystal; and the crystal is filtered, washed and dried to obtain cefetamet pivoxil hydrochloride.
Description
Technical field
The present invention relates to a kind of process for purification of cefetamet pivoxil hydrochloride compound, belong to medical technical field.
Background technology
Ro 15-8075, its chemical name is: (6R, 7R)-the 3-methyl-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-formic acid pivalyl oxygen methyl ester hydrochloride, molecular formula: C
20H
25N
5O
7S
2HCl, molecular weight: 548.04, structural formula is:
For oral third generation broad-spectrum cephalosporin class microbiotic, gram-positive microorganism and Gram-negative bacteria all there are very strong anti-microbial activity, stable to bacteriogenic β-Nei Xiananmei.Be applicable to responsive microbial lower respiratory infection, ear, nose, larynx infection and urinary system infection etc. clinically.
Synthetic method about Ro 15-8075, reported for work at polar aprotic solvent N in " Guizhou medical college journal " 2006 31 5 phases of volume, in the dinethylformamide solution, in certain temperature of reaction with under the reaction times, make catalyzer with triethylamine, temperature of reaction 20-23 ℃ is raw material with cefetamet and trimethylacetic acid iodine methyl esters, synthetic cefetamet pivaloyl oxygen methyl esters.The Ro 15-8075 purity of this method preparation is lower, does not reach the limit of standard preparation requirement, be difficult to prepare qualified preparation, and general dissolving crystallized process for purification can not fundamentally improve its purity.
Summary of the invention
The objective of the invention is to overcome the defective that prior art exists, a kind of refining purification process of cefetamet pivoxil hydrochloride compound is provided, fundamentally improved the purity of Ro 15-8075 greatly, guaranteed the quality of preparation.
The process for purification of cefetamet pivoxil hydrochloride compound provided by the invention, this method is the Ro 15-8075 crude product with prior art for preparing, prepare pure relatively cefetamet pivoxil hydrochloride compound through following steps: the Ro 15-8075 crude product is dissolved in methyl alcohol or the ethanol, add sodium hydroxide or potassium hydroxide solution, stirring reaction, hydrolysis get Ro 15-8074/001 or sylvite; Add charcoal absorption, filter, add iodo-ester then, under the condition that organic solvent exists, react, obtain cefetamet pivoxil; Cefetamet pivoxil is dissolved in the Virahol, and dripping hydrochloric acid adds hexanaphthene and stirs, and separates out crystallization, filter, and washing, drying gets Ro 15-8075.
Above-mentioned described process for purification, iodo-ester are trimethylacetic acid iodine methyl esters ICH
2OOCC (CH
3)
3
Above-mentioned described process for purification, organic solvent is selected from acetone, ethanol, methyl alcohol, Virahol, trichloromethane, ethyl acetate, phenylacetate, methyl benzoate, methyl acetate, butylacetate, ether, acetonitrile, methylene dichloride, tetrahydrofuran (THF), N, dinethylformamide, N, N-dimethyl sulfoxide (DMSO), N,N-dimethylacetamide and their mixture.
Above-mentioned described process for purification, the mol ratio of potassium hydroxide or sodium hydroxide and Ro 15-8075 are 2-5: 1, and temperature of reaction is-10-30 ℃.
Above-mentioned described process for purification, the mol ratio of iodo-ester and Ro 15-8075 are 1-3: 1.
Above-mentioned described process for purification, the mol ratio of hydrochloric acid and Ro 15-8075 are 1-2: 1.
The process for purification of above-mentioned described cefetamet pivoxil hydrochloride compound, preferably, the concrete operations step is:
(1) the Ro 15-8075 crude product is dissolved in methyl alcohol or the ethanol, adds sodium hydroxide or potassium hydroxide solution, stirring reaction is 60 minutes under-10-30 ℃ temperature, and crystallization is separated out in hydrolysis, filter, washing, drying, Ro 15-8074/001 or sylvite;
(2) Ro 15-8074/001 or sylvite is soluble in water, add charcoal absorption, filter, add trimethylacetic acid iodine methyl esters ICH then
2OOCC (CH
3)
3And organic solvent, stirring at room reaction 60 minutes adds ethyl acetate and water again, stirs extraction, layering, organic phase is water and saturated sodium carbonate solution washing respectively, uses solid drier again, as dryings such as anhydrous sodium sulphate, anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrouss, filter, concentrating under reduced pressure, drying gets cefetamet pivoxil.
(3) cefetamet pivoxil is dissolved in the Virahol, slow dripping hydrochloric acid, and stirring reaction 60 minutes adds hexanaphthene and stirs, and separates out crystallization, filter, washing, drying gets Ro 15-8075.
The process for purification of cefetamet pivoxil hydrochloride compound provided by the invention has solved the low shortcoming of present technology synthetic Ro 15-8075 purity, has improved the quality of clinical preparation, has ensured the security of medication; This method technology is simple, easy to operate, and cost is low, is suitable for large-scale production.
Embodiment
Below further explain and describe content of the present invention by embodiment, but embodiment is not to be construed as limiting the scope of the invention.
Embodiment 1
(1) Ro 15-8075 crude product 100g is dissolved in the 600ml methyl alcohol, adds 2mol/L sodium hydroxide solution 230ml, stirring reaction is 60 minutes under room temperature, crystallization is separated out in hydrolysis, filters water washing, 50 ℃ of drying under reduced pressure get cefetamet sodium salt 95.4g, yield 95.4%;
(2) the cefetamet sodium salt is dissolved in the 800ml water, added the 8g charcoal absorption 30 minutes, filter decarburization, add trimethylacetic acid iodine methyl esters 88.3g and N then, dinethylformamide 300ml, stirring at room reaction 60 minutes adds 600ml ethyl acetate and 100ml water again, stir extraction, layering, organic phase with 400ml water and saturated sodium carbonate solution washing, are used anhydrous sodium sulfate drying respectively again, filter, concentrating under reduced pressure steams and removes organic solvent, 50 ℃ of drying under reduced pressure, get cefetamet pivoxil 89.5g, yield 93.8%;
(3) cefetamet pivoxil is dissolved in the 500ml Virahol, slow Dropwise 5 mol/L hydrochloric acid soln, stirring reaction 60 minutes adds hexanaphthene 800ml and stirs, and separates out crystallization, filter, water washing, 50 ℃ of drying under reduced pressure get Ro 15-8075 84.5g, yield 94.4%.
Embodiment 2
(1) Ro 15-8075 crude product 100g is dissolved in the 800ml ethanol, adds 2mol/L potassium hydroxide solution 250ml, stirring reaction is 60 minutes under room temperature, crystallization is separated out in hydrolysis, filters water washing, 50 ℃ of drying under reduced pressure get cefetamet sylvite 96.7g, yield 96.7%;
(2) cefetamet sylvite is dissolved in the 1000ml water, added the 10g charcoal absorption 30 minutes, filter decarburization, add trimethylacetic acid iodine methyl esters 102.2g and N then, N-dimethyl sulfoxide (DMSO) 500ml, stirring at room reaction 60 minutes adds 800ml ethyl acetate and 200ml water again, stir extraction, layering, organic phase with 600ml water and saturated sodium carbonate solution washing, are used anhydrous magnesium sulfate drying respectively again, filter, concentrating under reduced pressure steams and removes organic solvent, 50 ℃ of drying under reduced pressure, get cefetamet pivoxil 90.6g, yield 93.7%;
(3) cefetamet pivoxil is dissolved in the 700ml Virahol, slowly drips the 2mol/L hydrochloric acid soln, stirring reaction 60 minutes adds hexanaphthene 1000ml and stirs, separate out crystallization, filter water washing, 50 ℃ of drying under reduced pressure get Ro 15-8075 87.4g, yield 96.5%.
Claims (6)
1, the cefetamet pivoxil hydrochloride compound and the method for making thereof of structure shown in a kind of formula (I),
It is characterized in that comprising the steps: the Ro 15-8075 crude product is dissolved in methyl alcohol or the ethanol, add sodium hydroxide or potassium hydroxide solution, stirring reaction, hydrolysis gets Ro 15-8074/001 or sylvite; Add charcoal absorption, filter, add iodo-ester then, under the condition that organic solvent exists, react, obtain cefetamet pivoxil; Cefetamet pivoxil is dissolved in the Virahol, and dripping hydrochloric acid adds hexanaphthene and stirs, and separates out crystallization, filter, and washing, drying gets Ro 15-8075.
2, the process for purification of cefetamet pivoxil hydrochloride compound as claimed in claim 1 is characterized in that iodo-ester is a trimethylacetic acid iodine methyl esters.
3, the process for purification of cefetamet pivoxil hydrochloride compound as claimed in claim 1, it is characterized in that organic solvent is selected from acetone, ethanol, methyl alcohol, Virahol, trichloromethane, ethyl acetate, phenylacetate, methyl benzoate, methyl acetate, butylacetate, ether, acetonitrile, methylene dichloride, tetrahydrofuran (THF), N, dinethylformamide, N, N-dimethyl sulfoxide (DMSO), N,N-dimethylacetamide and their mixture.
4, the process for purification of cefetamet pivoxil hydrochloride compound as claimed in claim 1, the mol ratio that it is characterized in that potassium hydroxide or sodium hydroxide and Ro 15-8075 is 2-5: 1, temperature of reaction is-10-30 ℃.
5, the process for purification of cefetamet pivoxil hydrochloride compound as claimed in claim 1, the mol ratio that it is characterized in that iodo-ester and Ro 15-8075 is 1-3: 1.
6, the process for purification of cefetamet pivoxil hydrochloride compound as claimed in claim 1, the mol ratio that it is characterized in that hydrochloric acid and Ro 15-8075 is 1-2: 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100149797A CN101550146A (en) | 2009-05-07 | 2009-05-07 | Cefetamet pivoxil hydrochloride compound and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830912A (en) * | 2010-05-07 | 2010-09-15 | 胡建荣 | Cefetamet pivoxil hydrochloride compound and new preparation method thereof |
| CN104800221A (en) * | 2015-05-15 | 2015-07-29 | 苗怡文 | Medicinal cefetamet pivoxil hydrochloride composition for treating sensitive bacteria infectious diseases |
| CN104876947A (en) * | 2015-05-06 | 2015-09-02 | 山东罗欣药业集团股份有限公司 | Cefetamet pivoxil hydrochloride hydrate crystals and dispersible tablet thereof |
| CN104974177A (en) * | 2015-07-29 | 2015-10-14 | 成都倍特药业有限公司 | Cefetamet pivoxil hydrochloride crystal form II and preparation method thereof |
| CN113801141A (en) * | 2020-06-17 | 2021-12-17 | 成都倍特药业股份有限公司 | Preparation method of cefetamet pivoxil hydrochloride |
-
2009
- 2009-05-07 CN CNA2009100149797A patent/CN101550146A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830912A (en) * | 2010-05-07 | 2010-09-15 | 胡建荣 | Cefetamet pivoxil hydrochloride compound and new preparation method thereof |
| CN104876947A (en) * | 2015-05-06 | 2015-09-02 | 山东罗欣药业集团股份有限公司 | Cefetamet pivoxil hydrochloride hydrate crystals and dispersible tablet thereof |
| CN104800221A (en) * | 2015-05-15 | 2015-07-29 | 苗怡文 | Medicinal cefetamet pivoxil hydrochloride composition for treating sensitive bacteria infectious diseases |
| CN106176759A (en) * | 2015-05-15 | 2016-12-07 | 烟台市华文欣欣医药科技有限公司 | A kind of cefetamet pivoxil hydrochloride tablets agent compositions |
| CN106344528A (en) * | 2015-05-15 | 2017-01-25 | 烟台市华文欣欣医药科技有限公司 | Medicine cefetamet pivoxil hydrochloride tablet composition for treating sensitive bacterium infectious diseases |
| CN106420761A (en) * | 2015-05-15 | 2017-02-22 | 烟台市华文欣欣医药科技有限公司 | Pharmaceutical cefetamet pivoxil hydrochloride composition for treating sensitive bacterium infected disease |
| CN104974177A (en) * | 2015-07-29 | 2015-10-14 | 成都倍特药业有限公司 | Cefetamet pivoxil hydrochloride crystal form II and preparation method thereof |
| CN113801141A (en) * | 2020-06-17 | 2021-12-17 | 成都倍特药业股份有限公司 | Preparation method of cefetamet pivoxil hydrochloride |
| CN113801141B (en) * | 2020-06-17 | 2023-01-20 | 成都倍特药业股份有限公司 | Preparation method of cefetamet pivoxil hydrochloride |
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