CN105585581B - A method of synthesis Ceftriaxone Sodium - Google Patents
A method of synthesis Ceftriaxone Sodium Download PDFInfo
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- CN105585581B CN105585581B CN201610133557.1A CN201610133557A CN105585581B CN 105585581 B CN105585581 B CN 105585581B CN 201610133557 A CN201610133557 A CN 201610133557A CN 105585581 B CN105585581 B CN 105585581B
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- 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
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a kind of methods of synthesis Ceftriaxone Sodium, chemical compounds I and compound ii are added in the reaction vessel for filling dimethyl carbonate, 30~40 DEG C are stirred to react 1~2 hour, and compound III is then added, and PEG 800 is added while stirring, stirring 10~triethylamine is added after twenty minutes, 8~10 DEG C are stirred to react 3~4 hours, and sodium hydroxide solution is then added dropwise to pH=7, excessive propanone is added, white crystals are precipitated, are drying to obtain compound V.7 ACA, thio triazine heterocycle and cefotaxime side chain three parts are carried out one pot reaction, without isolation, continuous condensating by the present invention.Expensive reagent is not used during the reaction, and using the dimethyl carbonate of green low toxicity as reaction dissolvent, in the homogeneous environment that PEG 800 is formed, step is simple, obtains the Ceftriaxone Sodium of high-purity in high yield.Moreover, present invention effectively prevents enlarge-effect, especially suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic methods, and in particular to a kind of method of one pot process Ceftriaxone Sodium.Belong to doctor
Medicine technical field.
Background technology
Ceftriaxone Sodium, Ceftriaxone Sodium (Rocephin) are Third generation Cephalosporins antibiotic, to intestines
Bacteriaceae bacterium has powerful activity.To escherichia coli, Klebsiella Pneumoniae, clostridium perfringen, fluorine labor ground citrobacter, Yin
The MIC90 of diindyl positive proteus, Pu Luweideng Pseudomonas and Serratia is between 0.12~0.25mg/L.Cloaca intestines bar
Bacterium, acinetobacter and pseudomonas aeruginosa are poor to the sensibility of the medicine.To haemophilus influenzae, NEISSERIA GONORRHOEAE and meningitis
Neisseria has stronger antibacterial action, also has good action to hemolytic streptococcus and pneumococcus.To staphylococcus aureus
MIC is 2~4mg/L.Methicillin-resistant Staphylococcus and enterococcus are to the medicine drug resistance.Most bacteroides fragilis are to the medicine drug resistance.
Ceftriaxone Sodium is white or off-white color crystalline powder, odorless, is easy dissolving in water, in methyl alcohol slightly soluble,
It is almost insoluble in chloroform or ether.Its structural formula is as follows：
Ceftriaxone Sodium is by 7- amino cephalos alkane (7-ACA, compound ii) parent nucleus, thio triazine heterocycle and cefotaxime side
Chain three parts are constituted, therefore it can regard as and is condensed and is obtained with both rear respectively by 7-ACA.Widely used at present is first 3
70 synthetic routes afterwards first undergo 3 triazine heterocyclic substituteds, then carry out 7 side chain cefotaxime heterocycles that is, using 7-ACA as raw material
The generation reaction of N- acyls.Ceftriaxone Sodium product is obtained by dilution crystallization separating-purifying again later.Although technique can expire at present
The primary demand produced enough, but product yield, purity etc. still have sizable progressive space, these indexs to directly influence factory
The productivity effect of family.
Invention content
The purpose of the present invention is to overcome above-mentioned the deficiencies in the prior art, provide a kind of method of synthesis Ceftriaxone Sodium.
To achieve the above object, the present invention uses following technical proposals：
A method of chemical compounds I and compound ii are added to and fill the anti-of dimethyl carbonate by synthesis Ceftriaxone Sodium
It answers in container, 30~40 DEG C are stirred to react 1~2 hour, and compound III is then added, and PEG-800, stirring 10 are added while stirring
~triethylamine is added after twenty minutes, 8~10 DEG C are stirred to react 3~4 hours, and sodium hydroxide solution is then added dropwise to pH=7, is added
Excessive propanone is precipitated white crystals, is drying to obtain compound V；Wherein, the substance of chemical compounds I, compound ii, compound III
The ratio between amount is 1：1.1~1.2：1.1~1.2, chemical compounds I and dimethyl carbonate, PEG-800, triethylamine mass ratio be 1：0.2
~0.3：0.2~0.3：0.05~0.1；Its reaction equation is as follows：
Preferably, chemical compounds I, compound ii, compound III the ratio between the amount of substance be 1：1.1：1.1.
Preferably, chemical compounds I and dimethyl carbonate, PEG-800, triethylamine mass ratio be 1：0.2：0.2：0.05.
Preferably, chemical compounds I and compound ii are added in the reaction vessel for filling dimethyl carbonate, 35 DEG C of stirrings are anti-
It answers 1 hour.
Preferably, after compound III being added, PEG-800 is added while stirring, triethylamine is added in stirring after ten minutes.
Preferably, after triethylamine being added, 10 DEG C are stirred to react 4 hours.
Preferably, the mass concentration of sodium hydroxide is 5% in sodium hydroxide solution.
Preferably, the drying is 20~30 DEG C of vacuum drying.
Beneficial effects of the present invention：
The present invention has abandoned the common process that 7-ACA is condensed with thio triazine heterocycle and cefotaxime side chain respectively, but will
7-ACA, thio triazine heterocycle and cefotaxime side chain three parts carry out one pot reaction, without isolation, continuous condensating.It was reacting
It is formed in PEG-800 homogeneous using the dimethyl carbonate of green low toxicity as reaction dissolvent without using expensive reagent in journey
In environment, step is simple, obtains the Ceftriaxone Sodium of high-purity in high yield.Moreover, present invention effectively prevents enlarge-effect, it is special
It Shi Yongyu not industrialized production.
Specific implementation mode
With reference to embodiment, the present invention will be further elaborated, it should explanation, following the description merely to
It explains the present invention, its content is not defined.
The reaction route of the present invention is as follows：
Embodiment 1：
15.9g chemical compounds Is (0.1mol, M.W.159) and 28.49g compound iis (0.11mol, M.W.259) are added to
In the reaction bulb for filling 3.18g dimethyl carbonates, 30 DEG C are stirred to react 1 hour, and 38.5g compound IIIs are then added
3.18g PEG-800 are added in (0.11mol, M.W.350) while stirring, stir and 0.975g triethylamines are added after ten minutes, 8 DEG C
It is stirred to react 3 hours, 5w.t.% sodium hydroxide solutions is then added dropwise to pH=7, excessive propanone is added, be precipitated white crystals, 20
It DEG C is dried in vacuo up to 65.6g compounds V (M.W.661), yield 99.2%, 99.99% or more purity, it is total miscellaneous to be less than
0.01%.
Embodiment 2：
15.9g chemical compounds Is (0.1mol, M.W.159) and 31.08g compound iis (0.12mol, M.W.259) are added to
In the reaction bulb for filling 4.77g dimethyl carbonates, 40 DEG C are stirred to react 2 hours, be then added 42g compound IIIs (0.12mol,
M.W.350), 4.77g PEG-800 are added while stirring, 1.59g triethylamines are added in stirring after twenty minutes, and 10 DEG C are stirred to react 4
Hour, 5w.t.% sodium hydroxide solutions are then added dropwise to pH=7, excessive propanone is added, white crystals are precipitated, 30 DEG C of vacuum are dry
Dry 65.6g compounds V (M.W.661) to obtain the final product, yield 99.2%, 99.99% or more purity are always miscellaneous to be less than 0.01%.
Embodiment 3：
15.9g chemical compounds Is (0.1mol, M.W.159) and 28.49g compound iis (0.11mol, M.W.259) are added to
In the reaction bulb for filling 3.18g dimethyl carbonates, 35 DEG C are stirred to react 1 hour, and 38.5g compound IIIs are then added
3.18g PEG-800 are added in (0.11mol, M.W.350) while stirring, stir and 0.975g triethylamines are added after ten minutes, 10 DEG C
It is stirred to react 4 hours, 5w.t.% sodium hydroxide solutions is then added dropwise to pH=7, excessive propanone is added, be precipitated white crystals, 30
It DEG C is dried in vacuo up to 65.8g compounds V (M.W.661), yield 99.5%, 99.99% or more purity, it is total miscellaneous to be less than
0.01%.
Embodiment 4：
159g chemical compounds Is (1mol, M.W.159) and 284.9g compound iis (1.1mol, M.W.259) are added to and are filled
In the reaction bulb of 31.8g dimethyl carbonates, 35 DEG C are stirred to react 1 hour, be then added 385g compound IIIs (1.1mol,
M.W.350), 31.8g PEG-800 are added while stirring, 9.75g triethylamines are added in stirring after ten minutes, and 10 DEG C are stirred to react 4
Hour, 5w.t.% sodium hydroxide solutions are then added dropwise to pH=7, excessive propanone is added, white crystals are precipitated, 30 DEG C of vacuum are dry
Dry 658g compounds V (M.W.661) to obtain the final product, yield 99.5%, 99.99% or more purity are always miscellaneous to be less than 0.01%.
Embodiment 5：
1590g chemical compounds Is (10mol, M.W.159) and 2849g compound iis (11mol, M.W.259) are added to and are filled
In the reaction bulb of 318g dimethyl carbonates, 35 DEG C are stirred to react 1 hour, be then added 3850g compound IIIs (11mol,
M.W.350), 318g PEG-800 are added while stirring, 97.5g triethylamines are added in stirring after ten minutes, and 10 DEG C to be stirred to react 4 small
When, 5w.t.% sodium hydroxide solutions are then added dropwise to pH=7, excessive propanone is added, white crystals, 30 DEG C of vacuum drying are precipitated
Up to 6580g compounds V (M.W.661), yield 99.5%, 99.99% or more purity is always miscellaneous to be less than 0.01%.
Embodiment 6：
159kg chemical compounds Is (1000mol, M.W.159) and 284.9kg compound iis (1001mol, M.W.259) are added
Into the reaction kettle for filling 31.8kg dimethyl carbonates, 35 DEG C are stirred to react 1 hour, and 385kg compound IIIs are then added
31.8kg PEG-800 are added in (1100mol, M.W.350) while stirring, stir and 9.75kg triethylamines are added after ten minutes, and 10
It DEG C is stirred to react 4 hours, 5w.t.% sodium hydroxide solutions is then added dropwise to pH=7, excessive propanone is added, white crystals are precipitated,
30 DEG C are dried in vacuo up to 657kg compounds V (M.W.661), yield 99.4%, 99.99% or more purity, always miscellaneous to be less than
0.01%.
Although the above-mentioned specific implementation mode to the present invention is described, not to the limit of the scope of the present invention
System, based on the technical solutions of the present invention, those skilled in the art need not make the creative labor can make it is each
Kind modification or deformation are still within protection scope of the present invention.
Claims (5)
1. a kind of method of synthesis Ceftriaxone Sodium, which is characterized in that be added to chemical compounds I and compound ii and fill carbonic acid two
In the reaction vessel of methyl esters, 35 DEG C are stirred to react 1 hour, and compound III is then added, PEG-800 is added while stirring, stirring
10~triethylamine is added after twenty minutes, 8~10 DEG C are stirred to react 3~4 hours, and sodium hydroxide solution is then added dropwise to pH=7, adds
Enter excessive propanone, white crystals are precipitated, are drying to obtain compound V；Wherein, the substance of chemical compounds I, compound ii, compound III
The ratio between amount be 1：1.1：1.1, chemical compounds I and dimethyl carbonate, PEG-800, triethylamine mass ratio be 1：0.2：0.2：
0.05；Its reaction equation is as follows：
2. a kind of method of synthesis Ceftriaxone Sodium according to claim 1, which is characterized in that after compound III is added,
PEG-800 is added while stirring, triethylamine is added in stirring after ten minutes.
3. a kind of method of synthesis Ceftriaxone Sodium according to claim 1, which is characterized in that after triethylamine is added, 10
It DEG C is stirred to react 4 hours.
4. a kind of method of synthesis Ceftriaxone Sodium according to claim 1, which is characterized in that hydrogen in sodium hydroxide solution
The mass concentration of sodium oxide molybdena is 5%.
5. a kind of method of synthesis Ceftriaxone Sodium according to claim 1, which is characterized in that the drying is 20~30
DEG C vacuum drying.
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| CN201610133557.1A CN105585581B (en) | 2016-03-09 | 2016-03-09 | A method of synthesis Ceftriaxone Sodium |
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| CN105585581B true CN105585581B (en) | 2018-10-09 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106366099B (en) * | 2016-08-22 | 2018-08-31 | 山东罗欣药业集团恒欣药业有限公司 | A kind of anti-infectives Ceftriaxone Sodium crystalline compounds 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 |
| CN110393720B9 (en) * | 2018-08-30 | 2020-12-29 | 广东金城金素制药有限公司 | Pharmaceutical preparation of compound of trisufen ceftriaxone sodium and new indication for treating infection of patients with low immune function |
| CN110396101B (en) * | 2018-12-03 | 2021-01-22 | 广东金城金素制药有限公司 | New indication of pharmaceutical preparation of troxofen ceftriaxone sodium for treating bacterial endometritis |
| CN110684038B (en) * | 2019-05-05 | 2021-06-08 | 广东金城金素制药有限公司 | Pharmaceutical preparation of compound of trissofene ceftriaxone sodium and new indication 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 |
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