CN105585581A - Method for synthesizing ceftriaxone sodium - Google Patents
Method for synthesizing ceftriaxone sodium Download PDFInfo
- Publication number
- CN105585581A CN105585581A CN201610133557.1A CN201610133557A CN105585581A CN 105585581 A CN105585581 A CN 105585581A CN 201610133557 A CN201610133557 A CN 201610133557A CN 105585581 A CN105585581 A CN 105585581A
- Authority
- CN
- China
- Prior art keywords
- compound
- add
- ceftriaxone sodium
- synthetic
- stirring
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a method for synthesizing ceftriaxone sodium. The method includes the steps that a compound I and a compound II are added into a reaction vessel containing dimethyl carbonate, a stirring reaction is carried out for 1-2 h at 30-40 DEG C, then a compound III is added, PEG-800 is added with stirring, triethylamine is added after stirring is carried out for 10-20 min, a stirring reaction is carried out for 3-4 h at 8-10 DEG C, then a sodium hydroxide solution is dripped till the pH is 7, excessive acetone is added, white crystals are separated out, and a compound V is obtained after drying. According to the method, 7-ACA, sulfo-triazine heterocycle and cefotaxime side chains are subjected to a one-pot reaction, and successive condensation is carried out without separation; no expensive agent is used in the reaction process, environment-friendly low-toxicity dimethyl carbonate is adopted as a reaction solvent, and in a homogeneous-phase environment formed by PEG-800, high-purity ceftriaxone sodium is obtained at a high yield through simple steps; in addition, the magnification effect is effectively avoided, and the method is particularly suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method, be specifically related to the method for the synthetic Ceftriaxone Sodium of a kind of one kettle way. Belong to medical skillArt field.
Background technology
Ceftriaxone Sodium, CeftriaxoneSodium (Rocephin) is Third generation Cephalosporins antibiotic, thin to enterobacteriaceaeBacterium has powerful activity. To EHEC, Klebsiella Pneumoniae, clostridium perfringen, fluorine labor ground citrobacter, indoles sunThe MIC90 of property proteus, Pu Luweideng Pseudomonas and Serratia is between 0.12～0.25mg/L. Enterobacter cloacae,Acinetobacter and pseudomonas aeruginosa are poor to the sensitiveness of this medicine. To haemophilus influenzae, NEISSERIA GONORRHOEAE and meningitis howPlucked instrument bacterium has stronger antibacterial action, and hemolytic streptococcus and pneumococcus are also had to good action. To the MIC of staphylococcus aureusBe 2～4mg/L. Methicillin-resistant Staphylococcus and enterococcus are to this medicine resistance. Most bacteroides fragilis are to this medicine resistance.
Ceftriaxone Sodium is white or off-white color crystalline powder, and odorless easily dissolves in water, slightly soluble in methyl alcohol,Almost insoluble in chloroform or ether. Its structural formula is as follows:
Ceftriaxone Sodium is by 7-amino cephalo alkane (7-ACA, compound ii) parent nucleus, sulfo-triazine heterocycle and cefotaxime side chainThree parts form, and obtain respectively therefore it can be regarded as by 7-ACA with rear both condensations. What extensively adopt at present is first 3Rear 70 synthetic routes, taking 7-ACA as raw material, first experience 3 triazine heterocyclic substituted, then carry out 7 side chain ammonia thiophenesThe N-acyl of oxime heterocycle is for reaction. Obtain Ceftriaxone Sodium product by dilution crystallization separating-purifying more afterwards. Although technique at presentCan meet the primary demand of production, but product yield, purity etc. still have sizable progressive space, these indexs are directHave influence on the productivity effect of producer.
Summary of the invention
The object of the invention is, for overcoming above-mentioned the deficiencies in the prior art, provides a kind of method of synthetic Ceftriaxone Sodium.
For achieving the above object, the present invention adopts following technical proposals:
A method for synthetic Ceftriaxone Sodium, joins by chemical compounds I and compound ii the reaction appearance that fills dimethyl carbonateIn device, 30～40 DEG C of stirring reactions 1～2 hour, add compound III subsequently, add while stirring PEG-800, stir 10～After 20 minutes, add triethylamine, 8～10 DEG C of stirring reactions 3～4 hours, then drip sodium hydroxide solution to pH=7, addExcessive propanone, separates out white crystals, is drying to obtain compound V; Wherein, chemical compounds I, compound ii, compound IIIThe ratio of amount of substance is 1:1.1～1.2:1.1～1.2, the quality of chemical compounds I and dimethyl carbonate, PEG-800, triethylamineThan being 1:0.2～0.3:0.2～0.3:0.05～0.1; Its reaction equation is as follows:
Preferably, the ratio of the amount of substance of chemical compounds I, compound ii, compound III is 1:1.1:1.1.
Preferably, the mass ratio of chemical compounds I and dimethyl carbonate, PEG-800, triethylamine is 1:0.2:0.2:0.05.
Preferably, chemical compounds I and compound ii are joined in the reaction vessel that fills dimethyl carbonate to 35 DEG C of stirring reactions 1Hour.
Preferably, add after compound III, add while stirring PEG-800, stir and add triethylamine after 10 minutes.
Preferably, add after triethylamine 10 DEG C of stirring reactions 4 hours.
Preferably, in sodium hydroxide solution, the mass concentration of NaOH is 5%.
Preferably, described being dried is 20～30 DEG C of vacuum drying.
Beneficial effect of the present invention:
The present invention abandoned 7-ACA respectively with the common process of sulfo-triazine heterocycle and the condensation of cefotaxime side chain, but will7-ACA, sulfo-triazine heterocycle and cefotaxime side chain three parts are carried out one pot reaction, without separation, and continuous condensating. InsteadAnswer in process and do not use expensive reagent, adopt the dimethyl carbonate of green low toxicity as reaction dissolvent, form at PEG-800Homogeneous phase environment in, step is simple, high yield obtains highly purified Ceftriaxone Sodium. And the present invention has effectively avoided puttingLarge effect, is specially adapted to suitability for industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further elaborated, should be noted that following explanation is only in order to explainThe present invention, does not limit its content.
Reaction scheme of the present invention is as follows:
Embodiment 1:
15.9g chemical compounds I (0.1mol, M.W.159) and 28.49g compound ii (0.11mol, M.W.259) are addedEnter to filling in the reaction bulb of 3.18g dimethyl carbonate, 30 DEG C of stirring reactions 1 hour, add 38.5g compound III subsequently(0.11mol, M.W.350), adds 3.18gPEG-800 while stirring, and stir and add 0.975g triethylamine after 10 minutes,8 DEG C of stirring reactions 3 hours, then drip 5w.t.% sodium hydroxide solution to pH=7, add excessive propanone, separate out white knotCrystalline substance, 20 DEG C of vacuum drying obtain 65.6g compound V (M.W.661), productive rate 99.2%, purity is more than 99.99%, always assortedBe less than 0.01%.
Embodiment 2:
15.9g chemical compounds I (0.1mol, M.W.159) and 31.08g compound ii (0.12mol, M.W.259) are addedEnter to filling in the reaction bulb of 4.77g dimethyl carbonate, 40 DEG C of stirring reactions 2 hours, add 42g compound III subsequently(0.12mol, M.W.350), adds 4.77gPEG-800 while stirring, and stir and add 1.59g triethylamine after 20 minutes,10 DEG C of stirring reactions 4 hours, then drip 5w.t.% sodium hydroxide solution to pH=7, add excessive propanone, separate out white knotCrystalline substance, 30 DEG C of vacuum drying obtain 65.6g compound V (M.W.661), productive rate 99.2%, purity is more than 99.99%, always assortedBe less than 0.01%.
Embodiment 3:
15.9g chemical compounds I (0.1mol, M.W.159) and 28.49g compound ii (0.11mol, M.W.259) are addedEnter to filling in the reaction bulb of 3.18g dimethyl carbonate, 35 DEG C of stirring reactions 1 hour, add 38.5g compound III subsequently(0.11mol, M.W.350), adds 3.18gPEG-800 while stirring, and stir and add 0.975g triethylamine after 10 minutes,10 DEG C of stirring reactions 4 hours, then drip 5w.t.% sodium hydroxide solution to pH=7, add excessive propanone, separate out white knotCrystalline substance, 30 DEG C of vacuum drying obtain 65.8g compound V (M.W.661), productive rate 99.5%, purity is more than 99.99%, always assortedBe less than 0.01%.
Embodiment 4:
159g chemical compounds I (1mol, M.W.159) and 284.9g compound ii (1.1mol, M.W.259) are joinedFill in the reaction bulb of 31.8g dimethyl carbonate, 35 DEG C of stirring reactions 1 hour, add subsequently 385g compound III (1.1mol,M.W.350), add while stirring 31.8gPEG-800, stir and add 9.75g triethylamine after 10 minutes, 10 DEG C are stirred anti-Answer 4 hours, then drip 5w.t.% sodium hydroxide solution to pH=7, add excessive propanone, separate out white crystals, 30 DEG C trueSky is drying to obtain 658g compound V (M.W.661), productive rate 99.5%, and purity is more than 99.99%, and total mixing is less than 0.01%.
Embodiment 5:
1590g chemical compounds I (10mol, M.W.159) and 2849g compound ii (11mol, M.W.259) are joinedFill in the reaction bulb of 318g dimethyl carbonate, 35 DEG C of stirring reactions 1 hour, add subsequently 3850g compound III (11mol,M.W.350), add while stirring 318gPEG-800, stir and add 97.5g triethylamine after 10 minutes, 10 DEG C of stirring reactions4 hours, then drip 5w.t.% sodium hydroxide solution to pH=7, add excessive propanone, separate out white crystals, 30 DEG C of vacuumBe drying to obtain 6580g compound V (M.W.661), productive rate 99.5%, purity is more than 99.99%, and total mixing is less than 0.01%.
Embodiment 6:
By 159kg chemical compounds I (1000mol, M.W.159) and 284.9kg compound ii (1001mol, M.W.259)Join in the reactor that fills 31.8kg dimethyl carbonate, 35 DEG C of stirring reactions 1 hour, add 385kg compound subsequentlyIII (1100mol, M.W.350), adds 31.8kgPEG-800 while stirring, stirs and after 10 minutes, adds 9.75kg tri-secondAmine, 10 DEG C of stirring reactions 4 hours, then drip 5w.t.% sodium hydroxide solution to pH=7, add excessive propanone, separate out whiteLook crystallization, 30 DEG C of vacuum drying obtain 657kg compound V (M.W.661), productive rate 99.4%, purity is more than 99.99%,Total mixing is less than 0.01%.
Although above-mentioned, the specific embodiment of the present invention is described, not limiting the scope of the invention,On the basis of technical scheme of the present invention, those skilled in the art do not need to pay the various amendments that creative work can be madeOr distortion is still in protection scope of the present invention.
Claims (8)
1. a method for synthetic Ceftriaxone Sodium, is characterized in that, chemical compounds I and compound ii are joined and fill carbonic acidIn the reaction vessel of dimethyl ester, 30～40 DEG C of stirring reactions 1～2 hour, add compound III subsequently, add while stirringPEG-800, stirs and adds triethylamine after 10～20 minutes, and 8～10 DEG C of stirring reactions 3～4 hours, then drip hydroxideSodium solution, to pH=7, adds excessive propanone, separates out white crystals, is drying to obtain compound V; Wherein, chemical compounds I, changeThe ratio of the amount of substance of compound II, compound III is 1:1.1～1.2:1.1～1.2, chemical compounds I and dimethyl carbonate, PEG-800,The mass ratio of triethylamine is 1:0.2～0.3:0.2～0.3:0.05～0.1; Its reaction equation is as follows:
2. the method for a kind of synthetic Ceftriaxone Sodium according to claim 1, is characterized in that, chemical compounds I, chemical combinationThe ratio of the amount of substance of thing II, compound III is 1:1.1:1.1.
3. the method for a kind of synthetic Ceftriaxone Sodium according to claim 1, is characterized in that, chemical compounds I and carbonic acidThe mass ratio of dimethyl ester, PEG-800, triethylamine is 1:0.2:0.2:0.05.
4. the method for a kind of synthetic Ceftriaxone Sodium according to claim 1, is characterized in that, by chemical compounds I and changeCompound II joins in the reaction vessel that fills dimethyl carbonate, 35 DEG C of stirring reactions 1 hour.
5. the method for a kind of synthetic Ceftriaxone Sodium according to claim 1, is characterized in that, add after compound III,Add while stirring PEG-800, stir and add triethylamine after 10 minutes.
6. the method for a kind of synthetic Ceftriaxone Sodium according to claim 1, is characterized in that, add after triethylamine,10 DEG C of stirring reactions 4 hours.
7. the method for a kind of synthetic Ceftriaxone Sodium according to claim 1, is characterized in that, in sodium hydroxide solutionThe mass concentration of NaOH is 5%.
8. the method for a kind of synthetic Ceftriaxone Sodium according to claim 1, is characterized in that, described be dried be 20～30 DEG C of vacuum drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610133557.1A CN105585581B (en) | 2016-03-09 | 2016-03-09 | A method of synthesis Ceftriaxone Sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610133557.1A CN105585581B (en) | 2016-03-09 | 2016-03-09 | A method of synthesis Ceftriaxone Sodium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105585581A true CN105585581A (en) | 2016-05-18 |
| CN105585581B CN105585581B (en) | 2018-10-09 |
Family
ID=55925520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610133557.1A Expired - Fee Related CN105585581B (en) | 2016-03-09 | 2016-03-09 | A method of synthesis Ceftriaxone Sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105585581B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106366099A (en) * | 2016-08-22 | 2017-02-01 | 山东罗欣药业集团恒欣药业有限公司 | Anti-infection medicine ceftriaxone sodium crystal compound and preparation method thereof |
| CN107955021A (en) * | 2017-10-27 | 2018-04-24 | 苏州盖德精细材料有限公司 | A kind of production method of the Ceftriaxone Sodium of low impurity |
| CN110393720A (en) * | 2018-08-30 | 2019-11-01 | 广东金城金素制药有限公司 | Qu Suofen Ceftriaxone Sodium pharmaceutical preparation treats the new indication of immunity function immunocompromised patients infection |
| CN110396101A (en) * | 2018-12-03 | 2019-11-01 | 广东金城金素制药有限公司 | Qu Suofen Ceftriaxone Sodium pharmaceutical preparation treats the new indication of bacillary intimitis |
| CN110684038A (en) * | 2019-05-05 | 2020-01-14 | 广东金城金素制药有限公司 | New indication of pharmaceutical preparation of troxofen ceftriaxone sodium for treating pelvic inflammation |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004111059A1 (en) * | 2003-06-19 | 2004-12-23 | Orchid Chemicals & Pharmaceuticals Ltd | A process for the preparation of a cephalosporin antibiotic |
| US20050059821A1 (en) * | 2003-09-17 | 2005-03-17 | Debashish Datta | Method for manufacture of ceftriaxone sodium |
| CN103539803A (en) * | 2013-07-27 | 2014-01-29 | 珠海保税区丽珠合成制药有限公司 | Method for preparing ceftriaxone sodium |
| CN104130273A (en) * | 2014-08-18 | 2014-11-05 | 哈药集团制药总厂 | Method for synthesizing ceftriaxone sodium |
| CN105061472A (en) * | 2015-08-18 | 2015-11-18 | 齐鲁安替（临邑）制药有限公司 | One-pot synthesis method of ceftriaxone sodium |
-
2016
- 2016-03-09 CN CN201610133557.1A patent/CN105585581B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004111059A1 (en) * | 2003-06-19 | 2004-12-23 | Orchid Chemicals & Pharmaceuticals Ltd | A process for the preparation of a cephalosporin antibiotic |
| US20050059821A1 (en) * | 2003-09-17 | 2005-03-17 | Debashish Datta | Method for manufacture of ceftriaxone sodium |
| CN103539803A (en) * | 2013-07-27 | 2014-01-29 | 珠海保税区丽珠合成制药有限公司 | Method for preparing ceftriaxone sodium |
| CN104130273A (en) * | 2014-08-18 | 2014-11-05 | 哈药集团制药总厂 | Method for synthesizing ceftriaxone sodium |
| CN105061472A (en) * | 2015-08-18 | 2015-11-18 | 齐鲁安替（临邑）制药有限公司 | One-pot synthesis method of ceftriaxone sodium |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106366099A (en) * | 2016-08-22 | 2017-02-01 | 山东罗欣药业集团恒欣药业有限公司 | Anti-infection medicine ceftriaxone sodium crystal compound and preparation method thereof |
| CN107955021A (en) * | 2017-10-27 | 2018-04-24 | 苏州盖德精细材料有限公司 | A kind of production method of the Ceftriaxone Sodium of low impurity |
| CN110393720A (en) * | 2018-08-30 | 2019-11-01 | 广东金城金素制药有限公司 | Qu Suofen Ceftriaxone Sodium pharmaceutical preparation treats the new indication of immunity function immunocompromised patients infection |
| CN110396101A (en) * | 2018-12-03 | 2019-11-01 | 广东金城金素制药有限公司 | Qu Suofen Ceftriaxone Sodium pharmaceutical preparation treats the new indication of bacillary intimitis |
| CN110684038A (en) * | 2019-05-05 | 2020-01-14 | 广东金城金素制药有限公司 | New indication of pharmaceutical preparation of troxofen ceftriaxone sodium for treating pelvic inflammation |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105585581B (en) | 2018-10-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105585581A (en) | Method for synthesizing ceftriaxone sodium | |
| CN101613361B (en) | Method for preparing cefoxitin sodium | |
| CN101696213B (en) | Synthetic method of 7-MAC intermediate | |
| CN100500671C (en) | Synthesis process of cefpirome sulfate as antibiotic | |
| CN108264480B (en) | Preparation method of avibactam sodium intermediate | |
| CN109180704A (en) | A kind of synthetic method of Cefditoren pivoxil Cephalosporins | |
| CN104193765B (en) | A kind of synthetic method of cefixime | |
| CN102391291B (en) | Cefmetazole acid preparation method | |
| CN104447755A (en) | Hexahydropyrrole[2,3-b]indole carboxylate compound and synthesis method thereof | |
| CN105693748A (en) | Synthesis method of 7-amino-3-chloro-3-cephalosporin-4-carboxylic acid | |
| CN102993114B (en) | A kind of production method of 1H-TETRAZOLE-5-acetic acid | |
| CN105646544B (en) | A kind of preparation method of Cefotetan Disodium and its intermediate | |
| CN106279207A (en) | A kind of synthetic method of cefdinir | |
| JP2010059090A (en) | Method for producing glucosamine derivative | |
| CN101284840B (en) | Synthetic method of cefpirome sulfate | |
| CN104292222B (en) | Novel synthetic method of tebipenem pivoxil side chain | |
| CN102503853A (en) | Synthesis method of benzophenone hydrazone | |
| CN102532168A (en) | Synthesis method of cefoperazone acid | |
| CN105385746A (en) | Method for synthesizing cefoxitin acid | |
| CN102285997B (en) | Method for preparing chloroallyl beta-lactam antibiotic intermediate | |
| CN102757430B (en) | A kind of preparation method of tebipenem | |
| CN105254650A (en) | Synthesis method of antibacterial drug cefoxitin | |
| CN115322191B (en) | Synthetic method of moxifloxacin hydrochloride | |
| JP2001131146A (en) | Method for acylation | |
| CN113185538B (en) | Preparation method of cefpodoxime acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200512 Address after: Room 201, building 2, No. 500, Caobao Road, Xuhui District, Shanghai 200000 Patentee after: SHANGHAI BIOSUNDRUG SCIENCE & TECHNOLOGY Co.,Ltd. Address before: 200030, room 4, building 333, 712 Guiping Road, Shanghai, Xuhui District Patentee before: SHANGHAI NINGRUI BIOCHEMICAL TECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181009 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |