CN102286001A - Method for preparing ceftezole sodium - Google Patents
Method for preparing ceftezole sodium Download PDFInfo
- Publication number
- CN102286001A CN102286001A CN2011102526732A CN201110252673A CN102286001A CN 102286001 A CN102286001 A CN 102286001A CN 2011102526732 A CN2011102526732 A CN 2011102526732A CN 201110252673 A CN201110252673 A CN 201110252673A CN 102286001 A CN102286001 A CN 102286001A
- Authority
- CN
- China
- Prior art keywords
- acid
- thiadiazoles
- sodium
- ceftezole
- tetrazoleacetic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a method for preparing ceftezole sodium, belonging to the field of medicinal chemistry. 1H-tetrazole acetic acid and 2-mercapto-1,3,4-thiadiazole are taken as raw materials, and the method disclosed by the invention comprises the following steps of: catalyzing toluenesulfonic acid or dicyclohexylcarbodiimide to generate 1H-tetrazole-acet-1,3,4-thiadiazole-2-thioester (active ester), carrying out a process of boiling in one pot on the active ester and 7-aminocephalosporanic acid to synthesize ceftezole acid under the action of a quaternary ammonium salt phase transfer catalyst, regenerating sodium salt, and further carrying out recrystallization and purification to obtain the high-purity ceftezole sodium. The method for preparing the ceftezole sodium, disclosed by the invention, is simple and is feasible, the atom utilization ratio is high, the product quality is good and the requirements on industrial production are met.
Description
Technical field
The invention belongs to and belong to the pharmaceutical chemistry field, relate to the synthetic method of cefobutazine sodium medicine.
Background technology
Cefobutazine sodium, English name Ceftezole Sodium, molecular weight are 461.9963, molecular formula is C
13H
11N
8NaO
4S
3, chemical name is (6R, 7R)-3-{[(1,3,4-thiadiazoles-2-yl) sulphur] and methyl }-7-[(1H-tetrazole-1-yl) kharophen]-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-formic acid sodium salt.Its structural formula is as follows:
Cefobutazine sodium is a first-generation injection semi-synthetic cephalosporins microbiotic, and mechanism of action is by suppressing the synthetic anti-microbial activity that plays of bacteria cell wall.All relatively more responsive to gram-positive microorganism especially streptococcus aureus, micrococcus scarlatinae, streptococcus pneumoniae, Hemolytic streptococcus, Streptococcus viridans, staphylococcus epidermidis and diphtheria corynebacterium, anthrax bacillus.Better to effects such as some Gram-negative bacteria such as influenzae, intestinal bacteria, klebsiella spp, Proteus mirabilises, Shigella, Salmonella, citrobacter, the positive Bacillus proteus of part indoles also there are anti-microbial effect.Be mainly used in after infection due to the sensitive organism such as pneumonia, bronchitis, septicemia, peritonitis, urinary tract infections and the operation thereof clinically or infection that wound causes.
Cefobutazine sodium is by the exploitation of Japanese rattan pool company, goes on the market with trade(brand)name " Falomesin " in 1978.Nineteen ninety-five enters Chinese market, and clinical consumption increases day by day, improves its synthesis technique line, reduces production costs, and will help industrial production.
" newly organized medicine synthesizes the synthetic method of having reported a kind of cefobutazine sodium in the handbook (by publishing Chemical Industry Press, in August, 2003); with 7-ACA is starting raw material; generate 7-bit amino acylate with the reaction under dicyclohexylcarbodiimide (DCC) effect of 1H-tetrazoleacetic acid; again with 2-sulfydryl-1; 3, ceftezole acid is produced in the reaction of 4-thiadiazoles, and this method is fairly simple; but total recovery is lower, only has 18.3%.
Patent application CN101229129A discloses a kind of above-mentioned similar method; but requiring raw material 1H-tetrazoleacetic acid and the ratio of DCC and 7-ACA is 1.4～1.7:1～1.3:1; the raw material large usage quantity; with methyl-sulphoxide, ethyl acetate, triethylamine is solvent; the acidylate yield has only 72.8%; total recovery increases, and is 55.0%.
Patent application CN1803803A discloses a kind of method for preparing ceftezole 3-position intermediate, with 7-ACA and 2-sulfydryl-1,3, the 4-thiadiazoles reacts in a kind of solvent complex compound, and described solvent complex compound is the complex compound that acetonitrile, formic acid are equal to boron trifluoride.This method has been used and has been cost an arm and a leg and the boron trifluoride of high pollution, has improved production cost, has increased the difficulty that the three wastes are handled.
The amino acylate that patent application JP 56053684A discloses with 7-ACA is a raw material, generates thioether with 2-mercaptobenzimidazole earlier, and then with 2-sulfydryl-1,3, the substitution reaction that the 4-thiadiazoles carries out the thioether alkyl generates ceftezole.This method has been introduced the reaction that generates thioether with 2-mercaptobenzimidazole, has increased reactions steps, has improved production cost.
Patent application CN101544659A discloses a kind of method for preparing ceftezole; with boric acid is catalyzer, with 7-ACA and 2-sulfydryl-1,3; the 4-thiadiazoles reacts in water; obtain to higher yields the intermediate of 3-position, but used a large amount of 2-sulfydryls-1,3; 4-thiadiazoles and boric acid; prepare ceftezole acid with 1H-tetrazole excess acetyl chloride then, the acidylate yield is low, and total recovery is 38%.
Patent application CN101735250A discloses a kind of method for preparing cefobutazine sodium, be tetrazoleacetic acid and 2-sulfydryl-1,3, the condensation of 4-thiadiazoles generates tetrazoleacetic acid-1,3,4-thiadiazoles-2-thioesters, generate cefobutazine sodium with the 7-amino-cephalosporanic acid reaction, this method is at synthetic tetrazoleacetic acid-1,3,4-thiadiazoles-2-thioesters has used expensive reagent isopropyl chlorocarbonate and N-methyl piperidine, has used nitrogen in the reaction of 7-amino-cephalosporanic acid reaction generation cefobutazine sodium, has increased production cost.
The method of synthetic cefobutazine sodium in the prior art, the ubiquity yield is low, shortcomings such as product look differential and industrial production cost height.The difficulty of technology has caused the costliness of hospital preparation price, has caused economical load for medication person, and has used the strong chemical reagent of contaminative in the building-up process, and is bigger to environmental disruption.Be badly in need of at present its synthesis technique is improved, satisfy the suitability for industrialized production demand.
Summary of the invention
The purpose of this invention is to provide a kind of simple, the synthetic method that environmental protection, yield be higher, can satisfy the cefobutazine sodium of suitability for industrialized production demand.
For achieving the above object, technical solution of the present invention is as follows:
The structural formula of cefobutazine sodium is shown in (I):
Its synthetic route is:
Concrete steps are as follows: (1) 1H-tetrazoleacetic acid-1,3, synthesizing of 4-thiadiazoles-2-thioesters (IV): with 1H-tetrazoleacetic acid (II) and 2-sulfydryl-1,3,4-thiadiazoles (III) is dissolved in the organic solvent, adds catalyzer p-methyl benzenesulfonic acid or dicyclohexylcarbodiimide under 0 ℃～4 ℃ temperature, and reaction finishes after-filtration and promptly gets 1H-tetrazoleacetic acid-1,3,4-thiadiazoles-2-thioesters (IV); Used organic solvent is one or more mixing in ethyl acetate, acetone, the tetrahydrofuran (THF); 1H-tetrazoleacetic acid, 2-sulfydryl-1,3, the molar ratio of 4-thiadiazoles and p-methyl benzenesulfonic acid are 1.05～1.10:1.00:0.1.1H-tetrazoleacetic acid, 2-sulfydryl-1,3, the molar ratio of 4-thiadiazoles and dicyclohexylcarbodiimide are 1.05～1.10:1.00:1.10.
(2) ceftezole acid (V) synthetic: 7-amino-cephalosporanic acid and sodium-acetate or sodium bicarbonate are added in entry and the ethanol mixed solvent, add the prepared 1H-tetrazoleacetic acid-1 of step (1) down at 0 ℃ to 5 ℃, 3,4-thiadiazoles-2-thioesters (IV), then temperature rises to 30 ℃ and reacts, with phase-transfer catalyst and organic solvent, temperature rises to 58 ℃ to 62 ℃ reactions again; The HPLC monitoring reaction is finished, and filters, and filtrate is filtered and promptly got ceftezole acid with acid for adjusting pH to 2.0～3.0; Phase-transfer catalyst is quaternary ammonium salt triethyl benzyl ammonia chloride, Tetrabutyl amonium bromide, hexadecyl triethyl ammonium chloride, tetramethyl ammonium chloride or ferrocene quaternary ammonium salt; Used organic solvent is one or more in ethyl acetate, toluene, the hexanaphthene; 7-amino-cephalosporanic acid, 1H-tetrazoleacetic acid-1,3,4-thiadiazoles-2-thioesters (IV), with the molar ratio of phase-transfer catalyst be 1.00:1.05～1.10:0.15; Water and ethanol volume ratio 1:1 in the mixed solvent;
(3) the synthetic and purifying of cefobutazine sodium (I): the ceftezole acid crude of step (2) gained is joined in the sodium bicarbonate aqueous solution and Virahol that contains equimolar amount, boil off solvent, stirring and crystallizing promptly gets cefobutazine sodium.
The quality of described aqueous solvent equals the quality of ceftezole acid, and the volume ratio of water and Virahol is 1:2, and recrystallization temperature is 0 ℃～4 ℃.
Compare advantage of the present invention with existing technology: preferred reactant ratio, reduced the generation of side reaction, improved product yield.Adopt the method for " treating different things alike ", the step that simplifies the operation, the Atom economy height of technology, the recyclable utilization of organic solvent has reduced environmental pollution, environmental protection, simple for process, the quality height of product has reduced production cost, can satisfy the suitability for industrialized production demand.
Embodiment
Further explain and describe content of the present invention by the following examples, but the embodiment that is provided should not be understood that protection scope of the present invention is construed as limiting.
Embodiment 1
1,1H-tetrazoleacetic acid-1,3,4-thiadiazoles-2-thioesters synthetic
With 1H-tetrazoleacetic acid 134.4g(1.05mol) and 2-sulfydryl-1,3,4-thiadiazoles 118.0g(1.00mol) be dissolved in the 1000mL tetrahydrofuran (THF), be cooled to 0 ℃～4 ℃, and then the tetrahydrofuran solution 50mL of adding p-methyl benzenesulfonic acid 17.2g (0.10mol), keep thermotonus 2h, vacuum distillation recovered solvent, be cooled to 0 ℃～4 ℃, filter, obtain the 1H-tetrazoleacetic acid-1,3 of 220.8g, 4-thiadiazoles-2-thioesters, yield 96.8%.
2, ceftezole acid is synthetic
With 7-amino-cephalosporanic acid (7-ACA) 227.0g (0.83mol) and crystallization sodium acetate 112.9g(0.83mol) add in 1500mL water and the 1500mL ethanol, stirring makes dissolving, ice bath is cooled to 0 ℃～4 ℃, add the above-mentioned 1H-tetrazoleacetic acid-1 for preparing with the 1.0:1.2 mol ratio then, 3,4-thiadiazoles-2-thioesters, stirring reaction 0.5h, be warming up to 30 ℃ then and stir 2h, add triethyl benzyl ammonia chloride (TEBA) 28.4g(0.12mol again) and the 300mL ethyl acetate further be warming up to 58 ℃ to 62 ℃, reaction 5h, decompression steams the recovery organic solvent, is cooled to room temperature, filtrate is regulated pH2.0 with 5% hydrochloric acid, at 0 ℃～4 ℃ stirring and crystallizing 2h, filter and promptly get ceftezole acid 326.7g, yield 89.4%.
3, cefobutazine sodium is synthetic and refining
Ceftezole acid 150.0g adding is contained among the sodium bicarbonate aqueous solution 150mL of equimolar amount, add Virahol 300mL again, impurity is separated out in stirring, filters, and boils off solvent, 0 ℃～4 ℃ following stirring and crystallizing, filter, with ice ethanol 50mL washing, 40 ℃ of following drying under reduced pressure, get cefobutazine sodium 137.9g, yield 87.6%.
Embodiment 2
1,1H-tetrazoleacetic acid-1,3,4-thiadiazoles-2-thioesters synthetic
With 1H-tetrazoleacetic acid 134.4g(1.05mol) and 2-sulfydryl-1,3,4-thiadiazoles 118.0g(1.00mol) be dissolved in the 1200mL ethyl acetate, be cooled to 0 ℃～4 ℃, and then add 226.6g (1.10mol) dicyclohexylcarbodiimide (DCC) and ethyl acetate solution 500mL, keep thermotonus 2h, vacuum distillation recovered solvent, be cooled to 0 ℃～4 ℃, filter, obtain the 1H-tetrazoleacetic acid-1,3 of 213.8g, 4-thiadiazoles-2-thioesters, yield 93.7%.
2, ceftezole acid is synthetic
With embodiment 1, phase-transfer catalyst adopts Tetrabutyl amonium bromide; Used organic solvent is a toluene.
3, cefobutazine sodium is synthetic and refining
With embodiment 1.Get cefobutazine sodium 135.6g, yield 86.1 %.
Claims (1)
1. the preparation method of a cefobutazine sodium is characterized in that, described cefobutazine sodium prepares as follows:
(1) 1H-tetrazoleacetic acid-1,3, synthesizing of 4-thiadiazoles-2-thioesters: with 1H-tetrazoleacetic acid and 2-sulfydryl-1,3, the 4-thiadiazoles is dissolved in the organic solvent, adds catalyzer p-methyl benzenesulfonic acid or dicyclohexylcarbodiimide under 0 ℃～4 ℃ temperature, and reaction finishes after-filtration and promptly gets 1H-tetrazoleacetic acid-1,3,4-thiadiazoles-2-thioesters; Used organic solvent is one or more mixing in ethyl acetate, acetone, the tetrahydrofuran (THF); 1H-tetrazoleacetic acid, 2-sulfydryl-1,3, the molar ratio of 4-thiadiazoles and p-methyl benzenesulfonic acid are 1.05～1.10:1.00:0.1; 1H-tetrazoleacetic acid, 2-sulfydryl-1,3, the molar ratio of 4-thiadiazoles and dicyclohexylcarbodiimide are 1.05～1.10:1.00:1.10;
(2) ceftezole acid is synthetic: 7-amino-cephalosporanic acid and sodium-acetate or sodium bicarbonate are added in entry and the ethanol mixed solvent, add the prepared 1H-tetrazoleacetic acid-1 of step (1) down at 0 ℃ to 5 ℃, 3,4-thiadiazoles-2-thioesters, then temperature rises to 30 ℃ and reacts, with phase-transfer catalyst and organic solvent, temperature rises to 58 ℃ to 62 ℃ reactions again; The HPLC monitoring reaction is finished, and filters, and filtrate is filtered and promptly got ceftezole acid with acid for adjusting pH to 2.0～3.0; Phase-transfer catalyst is quaternary ammonium salt triethyl benzyl ammonia chloride, Tetrabutyl amonium bromide, hexadecyl triethyl ammonium chloride, tetramethyl ammonium chloride or ferrocene quaternary ammonium salt; Used organic solvent is one or more in ethyl acetate, hexanaphthene, the toluene; 7-amino-cephalosporanic acid, 1H-tetrazoleacetic acid-1,3,4-thiadiazoles-2-thioesters, with the molar ratio of phase-transfer catalyst be 1.00:1.05～1.10:0.15;
(3) the synthetic and purifying of cefobutazine sodium: the ceftezole acid crude of step (2) gained is joined in the aqueous solution and Virahol of the sodium bicarbonate that contains equimolar amount, stir, boil off partial solvent, stirring and crystallizing is filtered and is promptly got cefobutazine sodium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102526732A CN102286001A (en) | 2011-08-30 | 2011-08-30 | Method for preparing ceftezole sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102526732A CN102286001A (en) | 2011-08-30 | 2011-08-30 | Method for preparing ceftezole sodium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102286001A true CN102286001A (en) | 2011-12-21 |
Family
ID=45332777
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011102526732A Pending CN102286001A (en) | 2011-08-30 | 2011-08-30 | Method for preparing ceftezole sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102286001A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183687A (en) * | 2011-12-30 | 2013-07-03 | 山东天绿制药有限公司 | Phase transfer catalysis method for preparing cefdinir |
| CN105030787A (en) * | 2015-09-15 | 2015-11-11 | 青岛华之草医药科技有限公司 | Ceftezole sodium composition serving as medicine for treating bacterial infection |
| CN105061473A (en) * | 2015-09-15 | 2015-11-18 | 青岛华之草医药科技有限公司 | Sterilization medicine ceftezole sodium compound and preparation method thereof |
| CN105085547A (en) * | 2015-03-05 | 2015-11-25 | 石药集团中诺药业（石家庄）有限公司 | Novel ceftezole sodium compound |
| CN105131018A (en) * | 2015-09-23 | 2015-12-09 | 浙江华方药业股份有限公司 | Preparation method of ceftezole acid |
| CN108129493A (en) * | 2018-02-07 | 2018-06-08 | 宁夏天心医药有限责任公司 | A kind of Cefobutazine sodium compound and its preparation |
| CN109160922A (en) * | 2017-07-20 | 2019-01-08 | 海南灵康制药有限公司 | A kind of 1/2 water Cefobutazine sodium compound |
| CN109336907A (en) * | 2018-11-21 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of cefobutazine sodium |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0004570A1 (en) * | 1978-03-09 | 1979-10-17 | Asahi Kasei Kogyo Kabushiki Kaisha | Thiol esters, process for their preparation, pharmaceutical compositions containing them and a process for preparing cephalosporin compounds using the same |
| US4327211A (en) * | 1980-11-26 | 1982-04-27 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for preparation of cephalosporin compounds |
| CN101696215A (en) * | 2009-08-28 | 2010-04-21 | 海南美大制药有限公司 | Cefazolin sodium pentahydrate compound of new route |
| CN101735250A (en) * | 2009-12-02 | 2010-06-16 | 王明 | Ceftezole sodium compound with novel route |
-
2011
- 2011-08-30 CN CN2011102526732A patent/CN102286001A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0004570A1 (en) * | 1978-03-09 | 1979-10-17 | Asahi Kasei Kogyo Kabushiki Kaisha | Thiol esters, process for their preparation, pharmaceutical compositions containing them and a process for preparing cephalosporin compounds using the same |
| US4327211A (en) * | 1980-11-26 | 1982-04-27 | Asahi Kasei Kogyo Kabushiki Kaisha | Method for preparation of cephalosporin compounds |
| CN101696215A (en) * | 2009-08-28 | 2010-04-21 | 海南美大制药有限公司 | Cefazolin sodium pentahydrate compound of new route |
| CN101735250A (en) * | 2009-12-02 | 2010-06-16 | 王明 | Ceftezole sodium compound with novel route |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183687A (en) * | 2011-12-30 | 2013-07-03 | 山东天绿制药有限公司 | Phase transfer catalysis method for preparing cefdinir |
| CN105085547A (en) * | 2015-03-05 | 2015-11-25 | 石药集团中诺药业（石家庄）有限公司 | Novel ceftezole sodium compound |
| CN105030787A (en) * | 2015-09-15 | 2015-11-11 | 青岛华之草医药科技有限公司 | Ceftezole sodium composition serving as medicine for treating bacterial infection |
| CN105061473A (en) * | 2015-09-15 | 2015-11-18 | 青岛华之草医药科技有限公司 | Sterilization medicine ceftezole sodium compound and preparation method thereof |
| CN105131018A (en) * | 2015-09-23 | 2015-12-09 | 浙江华方药业股份有限公司 | Preparation method of ceftezole acid |
| CN109160922A (en) * | 2017-07-20 | 2019-01-08 | 海南灵康制药有限公司 | A kind of 1/2 water Cefobutazine sodium compound |
| CN108129493A (en) * | 2018-02-07 | 2018-06-08 | 宁夏天心医药有限责任公司 | A kind of Cefobutazine sodium compound and its preparation |
| CN109336907A (en) * | 2018-11-21 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of cefobutazine sodium |
| CN109336907B (en) * | 2018-11-21 | 2020-05-26 | 山东罗欣药业集团股份有限公司 | Preparation method of ceftezole sodium |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102286001A (en) | Method for preparing ceftezole sodium | |
| CN101613361B (en) | Method for preparing cefoxitin sodium | |
| CN102219795B (en) | Method for preparing ceftezole sodium | |
| CN102030762B (en) | Preparation method of cefprozil | |
| CN101696214B (en) | Cefminox sodium compound of new route | |
| CN101619069A (en) | Preparation method of cefotiam hexetil hydrochloride | |
| CN101735250B (en) | Synthesis method of ceftezole sodium compound | |
| CN101704827B (en) | Synthesis method of cefathiamidine compound | |
| CN101747346B (en) | Method for synthesizing coarse salt of ceftriaxone sodium by phase transfer catalysis method | |
| CN103030651A (en) | Method for preparing ceftazidime hydrochloride | |
| CN101220040A (en) | Preparation of cefixime cephalosporin and fine purification method | |
| CN101671349A (en) | New method for preparing cefuroxime sodium compound | |
| CN101585845B (en) | Preparation process of Mezlocillin | |
| CN101550147B (en) | Cefdinir compound and preparation method thereof | |
| CN101337970B (en) | Method for synthesizing antibiotic cefpirome sulfate | |
| CN103193799B (en) | A kind of chemical synthesis process of Cefquinome sulfate | |
| CN110407857B (en) | Preparation process of cefathiamidine | |
| CN102911186B (en) | Ceftizoxime sodium preparation and refining method | |
| CN101798312A (en) | Novel route cefprozil compound | |
| CN108017658B (en) | Synthesis method of cefprozil | |
| CN114805393A (en) | Preparation method of cefprozil | |
| CN101284840B (en) | Synthetic method of cefpirome sulfate | |
| CN108299469B (en) | Preparation method of cefotiam hydrochloride | |
| CN106046024A (en) | Preparation method of cefpodoxime proxetil | |
| CN113801141B (en) | Preparation method of cefetamet pivoxil hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20111221 |