CN102408438B - Preparation method of cefprozil monohydrate - Google Patents
Preparation method of cefprozil monohydrate Download PDFInfo
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- CN102408438B CN102408438B CN201010295648.8A CN201010295648A CN102408438B CN 102408438 B CN102408438 B CN 102408438B CN 201010295648 A CN201010295648 A CN 201010295648A CN 102408438 B CN102408438 B CN 102408438B
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- ALYUMNAHLSSTOU-CIRGZYLNSA-N (6r,7r)-7-[[(2r)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 ALYUMNAHLSSTOU-CIRGZYLNSA-N 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229960002580 cefprozil Drugs 0.000 claims abstract description 29
- 238000003756 stirring Methods 0.000 claims abstract description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000012453 solvate Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 5
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 claims abstract 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000012046 mixed solvent Substances 0.000 abstract 1
- 239000003960 organic solvent Substances 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 30
- 238000001035 drying Methods 0.000 description 22
- 238000005406 washing Methods 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000003814 drug Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a preparation method of a cefprozil monohydrate. The method comprises: first placing a cefprozil DMF(dimethyl formamide) solvate in a mixed solvent composed of water and an organic solvent and conducting stirring so as to obtain a cefprozil monohydrate crude product, then putting the crude product in another solvent for stirring, thus obtaining a cefprozil monohydrate. The cefprozil monohydrate prepared by the method of the invention has high purity and meets the requirement of pharmacopeia standards at home and abroad, and the proportion of E-isomer in cefprozil is in line with a range prescribed by pharmacopoeias at home and abroad. The method provided in the invention has simple operation and strong controllability, thus meeting industrial production demands.
Description
Technical Field
The invention relates to the field of drug synthesis, and in particular relates to a preparation method of cefprozil monohydrate, a cephalosporin antibiotic.
Background
Cefprozil (cefprozil), with the chemical name of (6R, 7R) -7- [ (2R) -amino (4-hydroxyphenyl) acetamido]-8-oxo-3- (1-propenyl) -5-thioxo-1-azabicyclo [4.2.0]Octyl-2-ene-2-carboxylic acid, pharmaceutically acceptable monohydrate (structure shown as formula (I)), is a cephalosporin broad-spectrum antibacterial drug developed by Behme, Shibaobao, USA, and is used for G+、G-The antibacterial activity of both bacteria and anaerobe is very strong, and the antibacterial activity is G+The bacteria are particularly prominent.
The compound of formula (I) is usually prepared by using cefprozil DMF solvate shown as formula (II) as a raw material.
Wherein x is 0.5, 1, 1.5 or 2, and the (E) isomer accounts for 6-11% of the cefprozil content.
At present, the following two schemes for preparing cefprozil monohydrate from cefprozil DMF solvate have been reported:
the first scheme is as follows: PCT patent WO03011871 reports a method that cefprozil DMF solvate is placed in water at a certain temperature for stirring, and then is cooled, filtered, washed and dried to obtain cefprozil monohydrate.
Scheme II: the method reported in chinese patent CN101024649 is to put cefprozil DMF solvate in water at a certain temperature, adjust the pH of the mixed solution with hydrochloric acid of a certain concentration, then add methanol at a certain temperature, stir, filter, wash with 50% methanol and pure acetone, and obtain cefprozil monohydrate after decompression and drying.
In practical research, the cefprozil monohydrate obtained by the first scheme has low purity which is only about 95 percent and is lower than 98 percent of domestic and foreign standards, and cannot be used as a raw material medicine; and the proportion of the isomer (E) of the cefprozil monohydrate obtained by the scheme II in the cefprozil content is less than 6 percent, and the cefprozil monohydrate does not meet the standard range of 0.06-0.11 in domestic and foreign pharmacopoeias, and cannot be declared as a medicine.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the scheme and provide a preparation method of cefprozil monohydrate, which has high purity and the ratio of the (Z) isomer to the (E) isomer which meets the standard range of domestic and foreign pharmacopoeias.
Accordingly, the present invention provides an improved process for the preparation of cefprozil monohydrate (I),
the method comprises the following steps:
(1) placing the cefprozil DMF solvate (II) in a mixed solution consisting of water and a solvent A at the temperature of-10-50 ℃, stirring, and filtering to obtain a crude product of cefprozil monohydrate;
wherein x is 0.5, 1, 1.5 or 2, and the (E) isomer accounts for 6-11% of the cefprozil content.
(2) And (3) placing the crude cefprozil monohydrate product in a solvent B at the temperature of-10-50 ℃, stirring, and filtering to obtain the cefprozil monohydrate.
The method is shown as a scheme 1:
scheme 1
Wherein,
the solvent A in the step (1) is selected from one of alcohol, ketone and ether, wherein the alcohol is preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, the ketone is preferably acetone and 2-butanone, and the ether is preferably diethyl ether, dioxane, isopropyl ether, methyl tert-butyl ether and tetrahydrofuran.
The temperature range in the step (1) is preferably 15-35 ℃, and more preferably 20-30 ℃.
In the step (1), the volume ratio of the water to the solvent A is 0.5-4.0: 1, preferably 0.5-2.0: 1.
In the step (1), the volume/mass (mL/g) ratio of the mixed solution to the cefprozil DMF solvate is 1-8: 1, and the preferable range is 4-7: 1.
The temperature range in the step (2) is preferably 15-35 ℃, and more preferably 20-30 ℃.
The solvent B in the step (2) is selected from one of water, methanol, ethanol, isopropanol, acetone, diethyl ether, isopropyl ether, tetrahydrofuran, dichloromethane and chloroform.
In the step (2), the volume/mass (mL/g) ratio of the solvent B to the crude cefprozil monohydrate is 0.5-4: 1, and preferably 0.5-2: 1.
The filtration and drying can be carried out by a method conventional in the art.
The raw material cefprozil DMF solvate can be prepared by the methods of documents such as WO03011871, WO2005042544, US20040087786, US20090048460, WO2004039812, WO2004083172 and the like. The contents of the above documents are incorporated herein by reference.
The cefprozil monohydrate obtained by the method has the purity higher than 98 percent and meets the standard requirements of domestic and foreign pharmacopoeia; (E) the proportion of the isomer in the cefprozil content is in accordance with the range of 0.06-0.11 specified by domestic and foreign pharmacopoeias; and the operation is simple and convenient, the controllability is strong, and the requirements of industrial production are met.
Detailed Description
The following examples are intended to illustrate the invention but should not be construed as limiting the scope of the invention.
Example 1: preparation of cefprozil monohydrate
Adding 90L of water and 45L of acetone into a 250L reaction kettle, controlling the internal temperature to be 25-30 ℃, then adding 20kg of cefprozil DMF solvate, keeping the internal temperature at 25-30 ℃, stirring for 2 hours, filtering, washing and drying to obtain 16.6kg of light yellow powdery solid. Adding the solid into 30L of methanol at the temperature of 25-30 ℃, stirring for 1 hour at controlled temperature, filtering, washing and drying to obtain 16.0kg of light yellow powdery solid with the purity of 99.3 percent, the (E) isomer ratio of 0.084, the water content of 4.8 percent and the mass yield of 80.0 percent.
Example 2: preparation of cefprozil monohydrate
Adding 60L of water and 60L of acetone into a 250L reaction kettle, controlling the internal temperature at 20-25 ℃, then adding 20kg of cefprozil DMF solvate, keeping the internal temperature at 20-25 ℃, stirring for 2 hours, filtering, washing and drying to obtain 16.4kg of light yellow powdery solid. Adding the solid into 30L of water at the temperature of 20-25 ℃, stirring for 1 hour at controlled temperature, filtering, washing and drying to obtain 15.9kg of light yellow powdery solid with the purity of 99.2 percent, the (E) isomer ratio of 0.087, the water content of 5.0 percent and the mass yield of 79.5 percent.
Example 3: preparation of cefprozil monohydrate
Adding 50L of water and 100L of methanol into a 250L reaction kettle, controlling the internal temperature at 20-25 ℃, then adding 25kg of cefprozil DMF solvate, keeping the internal temperature at 20-25 ℃, stirring for 1 hour, filtering, washing and drying to obtain 20.5kg of light yellow powdery solid. Adding the solid into 25L of water at the temperature of 20-25 ℃, stirring for 1.5 hours at controlled temperature, filtering, washing and drying to obtain 20.0kg of light yellow powdery solid with the purity of 99.6 percent, the (E) isomer ratio of 0.081, the water content of 4.9 percent and the mass yield of 80.0 percent.
Example 4: preparation of cefprozil monohydrate
Adding 70L of water and 70L of methanol into a 250L reaction kettle, controlling the internal temperature at 15-20 ℃, then adding 25kg of cefprozil DMF solvate, keeping the internal temperature at 15-20 ℃, stirring for 1 hour, filtering, washing and drying to obtain 21.1kg of light yellow powdery solid. Adding the solid into 25L of water at the temperature of 15-20 ℃, stirring for 1.5 hours at controlled temperature, filtering, washing and drying to obtain 20.5kg of light yellow powdery solid with the purity of 99.4 percent, the (E) isomer ratio of 0.091, the water content of 4.5 percent and the mass yield of 82.0 percent.
Example 5: preparation of cefprozil monohydrate
Adding 100L of water and 50L of methanol into a 250L reaction kettle, controlling the internal temperature to be 25-30 ℃, then adding 25kg of cefprozil DMF solvate, keeping the internal temperature to be 25-30 ℃, stirring for 1 hour, filtering, washing and drying to obtain 20.8kg of light yellow powdery solid. Adding the solid into 25L of water at the temperature of 15-20 ℃, stirring for 1.5 hours at controlled temperature, filtering, washing and drying to obtain 20.4kg of light yellow powdery solid with the purity of 99.7 percent, the (E) isomer ratio of 0.073, the water content of 5.2 percent and the mass yield of 81.6 percent.
Example 6: preparation of cefprozil monohydrate
Adding 100L of water and 25L of methanol into a 250L reaction kettle, controlling the internal temperature at 30-35 ℃, then adding 25kg of cefprozil DMF solvate, keeping the internal temperature at 30-35 ℃, stirring for 2 hours, filtering, washing and drying to obtain 20.6kg of light yellow powdery solid. Adding the solid into 20L of methanol at the temperature of 30-35 ℃, stirring for 0.5 hour under controlled temperature, filtering, washing and drying to obtain 19.8kg of light yellow powdery solid with the purity of 99.1 percent, the (E) isomer ratio of 0.094, the moisture content of 4.4 percent and the mass yield of 79.2 percent.
Example 7: preparation of cefprozil monohydrate
Adding 40L of water and 15L of isopropanol into a 250L reaction kettle, controlling the internal temperature at 15-20 ℃, then adding 20kg of cefprozil DMF solvate, keeping the internal temperature at 15-20 ℃, stirring for 2 hours, filtering, washing and drying to obtain 16.4kg of light yellow powdery solid. And adding the solid into 45L isopropyl ether at the temperature of 15-20 ℃, stirring for 2 hours at a controlled temperature, filtering, washing and drying to obtain 15.2kg of light yellow powdery solid. Purity 98.8%, isomer ratio (E) 0.089, water content 5.2%, mass yield 76.0%.
Example 8: preparation of cefprozil monohydrate
Adding 70L of water and 20L of tetrahydrofuran into a 250L reaction kettle, controlling the internal temperature at 30-35 ℃, then adding 25kg of cefprozil DMF solvate, keeping the internal temperature at 30-35 ℃, stirring for 1.5 hours, filtering, washing and drying to obtain 20.3kg of light yellow powdery solid. And adding the solid into 60L dichloromethane at the temperature of 30-35 ℃, stirring for 2 hours at controlled temperature, filtering, washing and drying to obtain 19.1kg of light yellow powdery solid. 99.0% of purity, (E) isomer ratio is 0.077, water content is 4.8%, and mass yield is 76.4%.
Example 9: preparation of cefprozil monohydrate
Adding 60L of water and 20L of diethyl ether into a 250L reaction kettle, controlling the internal temperature to be-10-0 ℃, then adding 20kg of cefprozil DMF solvate, keeping the internal temperature at-10-0 ℃, stirring for 2 hours, filtering, washing and drying to obtain 17.0kg of light yellow powdery solid. And adding the solid into 50L of ethanol at the temperature of-10-0 ℃, stirring for 1 hour at controlled temperature, filtering, washing and drying to obtain 16.5kg of light yellow powdery solid. Purity 98.3%, isomer ratio (E) 0.106, moisture content 5.1%, mass yield 82.5%.
Example 10: preparation of cefprozil monohydrate
Adding 100L of water and 60L of ethanol into a 250L reaction kettle, controlling the internal temperature at 40-45 ℃, then adding 20kg of cefprozil DMF solvate, keeping the internal temperature at 40-45 ℃, stirring for 2 hours, filtering, washing and drying to obtain 15.9kg of light yellow powdery solid. Adding the solid into 60L tetrahydrofuran at the temperature of 40-45 ℃, stirring for 1 hour at controlled temperature, filtering, washing and drying to obtain 14.5kg of light yellow powdery solid. Purity 98.1%, isomer ratio (E) 0.102, moisture content 5.0%, mass yield 72.5%.
Claims (7)
1. A process for the preparation of cefprozil monohydrate of formula (I),
(1) placing the cefprozil DMF solvate (II) in a mixed solution consisting of water and a solvent A at the temperature of 20-30 ℃, stirring, and filtering to obtain a crude cefprozil monohydrate product, wherein the solvent A is selected from one of methanol, ethanol, isopropanol, acetone, tetrahydrofuran and diethyl ether;
x is one of 0.5, 1, 1.5 and 2, and the (E) isomer accounts for 6-11% of the cefprozil content;
(2) and (2) placing the crude cefprozil monohydrate product in a solvent B at the temperature of 20-30 ℃, stirring, and filtering to obtain the cefprozil monohydrate, wherein the solvent B is selected from water, methanol, ethanol, isopropanol, acetone, diethyl ether, isopropyl ether, tetrahydrofuran, dichloromethane and chloroform.
2. The method of claim 1, wherein: in the step (1), the volume ratio of the water to the solvent A is 0.5-4.0: 1.
3. the method of claim 2, wherein: in the step (1), the volume ratio of the water to the solvent A is 0.5-2.0: 1.
4. the method of claim 1, wherein: the volume/mass ratio of the mixed solution to the cefprozil DMF solvate in the step (1) is 1-8: 1.
5. the method of claim 4, wherein: the volume/mass ratio of the mixed solution to the cefprozil DMF solvate in the step (1) is 4-7: 1.
6. the method of claim 1, wherein: in the step (2), the volume/mass ratio of the solvent B to the cefprozil monohydrate crude product is 0.5-4: 1.
7. the method of claim 6, wherein: in the step (2), the volume/mass ratio of the solvent B to the cefprozil monohydrate crude product is 0.5-2: 1.
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| CN108299468B (en) * | 2017-12-29 | 2020-06-16 | 山东裕欣药业有限公司 | Refining method of cefprozil |
| CN108530467A (en) * | 2018-05-02 | 2018-09-14 | 天方药业有限公司 | A kind of process for purification of Cefprozil and products thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4504657A (en) * | 1976-04-27 | 1985-03-12 | Bristol-Myers Company | Cephadroxil monohydrate |
| WO2003011871A2 (en) * | 2001-08-01 | 2003-02-13 | Sandoz Gmbh | Intermediates in cephalosporin production |
| WO2004083172A2 (en) * | 2003-03-21 | 2004-09-30 | Ranbaxy Laboratories Limited | Process for the preparation of 7-amino (p-hydroxyphenylglyclyamido) cephem compounds |
| CN1711271A (en) * | 2002-10-08 | 2005-12-21 | 兰贝克赛实验室有限公司 | Process for the preparation of (Z)-isomer enriched 7-amino-3-propen-1-yl-3-cephem-4-carboxylic acid |
| WO2006048887A1 (en) * | 2004-11-01 | 2006-05-11 | Hetero Drugs Limited | A novel process for preparation of cefprozil intermediate |
| CN101024649A (en) * | 2006-02-23 | 2007-08-29 | 上海医药科技发展有限公司 | Method for preparing oral non-ester-type autibiotic cetprozil |
| CN101798312A (en) * | 2010-01-19 | 2010-08-11 | 海南美大制药有限公司 | Novel route cefprozil compound |
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2010
- 2010-09-26 CN CN201010295648.8A patent/CN102408438B/en active Active
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|---|---|---|---|---|
| US4504657A (en) * | 1976-04-27 | 1985-03-12 | Bristol-Myers Company | Cephadroxil monohydrate |
| WO2003011871A2 (en) * | 2001-08-01 | 2003-02-13 | Sandoz Gmbh | Intermediates in cephalosporin production |
| CN1711271A (en) * | 2002-10-08 | 2005-12-21 | 兰贝克赛实验室有限公司 | Process for the preparation of (Z)-isomer enriched 7-amino-3-propen-1-yl-3-cephem-4-carboxylic acid |
| WO2004083172A2 (en) * | 2003-03-21 | 2004-09-30 | Ranbaxy Laboratories Limited | Process for the preparation of 7-amino (p-hydroxyphenylglyclyamido) cephem compounds |
| WO2006048887A1 (en) * | 2004-11-01 | 2006-05-11 | Hetero Drugs Limited | A novel process for preparation of cefprozil intermediate |
| CN101024649A (en) * | 2006-02-23 | 2007-08-29 | 上海医药科技发展有限公司 | Method for preparing oral non-ester-type autibiotic cetprozil |
| CN101798312A (en) * | 2010-01-19 | 2010-08-11 | 海南美大制药有限公司 | Novel route cefprozil compound |
Non-Patent Citations (2)
| Title |
|---|
| Spectroscopic analytical Study for the Charge-Transfer Complexation of Certain Cephalosporins with Chloranilic Acid;Gamal A.Saleh,等;《ANALYTICAL SCIENCES FEBRUARY》;20030731;第19卷(第2期);第281-287页 * |
| 肖涛,等.头孢丙烯的合成.《中国医药工业杂志》.2004,第35卷(第7期),第388-390页,396页. * |
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