CN103641846A - Preparation method of 7-amino ceftriaxone sodium - Google Patents
Preparation method of 7-amino ceftriaxone sodium Download PDFInfo
- Publication number
- CN103641846A CN103641846A CN201310625223.2A CN201310625223A CN103641846A CN 103641846 A CN103641846 A CN 103641846A CN 201310625223 A CN201310625223 A CN 201310625223A CN 103641846 A CN103641846 A CN 103641846A
- Authority
- CN
- China
- Prior art keywords
- amino
- preparation
- rocephin
- dimethyl carbonate
- ceftriaxone sodium
- 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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention belongs to the field of medicines, and specifically relates to a preparation method of 7-amino ceftriaxone sodium. The preparation method comprises the following steps: suspending 7-aminocephalosporanic acid, a triazine ring and EDTA (Ethylene Diamine Tetraacetic Acid) in dimethyl carbonate; adding a boron trifluoride dimethyl carbonate complex; carrying out reaction; performing post-treating to obtain 7-amino ceftriaxone sodium. By adopting 7-aminocephalosporanic acid (ACA) and triazine ring and using an environment-friendly and economical solvent dimethyl carbonate as a solvent and the boron trifluoride dimethyl carbonate complex as a catalyst to synthesize 7-amino ceftriaxone sodium, use of toxic solvents such as volatile acetonitrile is avoided by adopting dimethyl carbonate which has no toxicity, excellent environment-friendly performance and low cost compared with acetonitrile and has the characteristicsof convenience in use, less pollution, easiness in transportation and the like during production as the solvent, so that the reaction process is relatively environment-friendly, and the operating safety is improved. The price of dimethyl carbonate is cheaper than that of acetonitrile, so that the production cost is greatly lowered. The method adopting the environment-friendly raw materials which are low in cost is simple in synthetic process and higher in yield.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the preparation method of the amino rocephin of a kind of 7-.
Background technology
Ceftriaxone sodium chemical name is (6R, 7R)-7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino]-8-oxo-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-yl) three times of semihydrates of sulfo-[methyl]-5-sulfo--1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt.Ceftriaxone sodium is Third generation Cephalosporins microbiotic, the characteristic with broad-spectrum high efficacy, for urinary tract, biliary tract infection, the lower respiratory infection due to responsive pathogenic bacterium, and the disease such as pelvic infection, abdominal cavity infection, bone and the infection of joint, skin soft-tissue infection, septicemia, meningitis.
Ceftriaxone sodium is at 1978 Nian You Switzerland Roche Developeies, until after its patent in 1996 expires, ceftriaxone sodium starts to grow up with surprising rapidity at home.In the last few years, ceftriaxone sodium was a kind of cephalosporin market share maximum, no matter was bulk drug or preparation, and always in cut-throat competition state, the production cost that therefore reduces ceftriaxone sodium is the Important Action that each manufacturer establishes oneself in an unassailable position.The amino rocephin of 7-ACT(7-) be the intermediate of synthetic ceftriaxone sodium, optimize its technique and reduce the market competitiveness that its production cost is very beneficial for strengthening ceftriaxone sodium.
About the document of 7-ACT and the report of patent all seldom, be summed up following two kinds of methods:
In patent CN102702233, adopt acetonitrile to make solvent, boron trifluoride-acetonitrile is catalyzer, makes 7-ACA and triazine ring reaction, then regulates pH crystallization.The shortcoming of this method is: adopted highly volatile, price is higher and virose acetonitrile as solvent, become to produce cost higher, productive rate is only 90.4%.
In addition, in patent CN102559829, be also to adopt acetonitrile technique, in Crystallization Process, add cephalosporin esterase control pH to improve the purity of product.The shortcoming of this method is: introduced a kind of raw material (cephalosporin esterase), improved production cost, and productive rate lower be only 85%.
In a word, these traditional method raw materials cost are high, and majority is toxic substance, and the shortcoming such as have greater environmental impacts, is unfavorable for Sustainable development.
Summary of the invention
For the deficiencies in the prior art, the object of the present invention is to provide the preparation method of the amino rocephin of a kind of 7-, adopt methylcarbonate as solvent, there is the advantages such as nontoxic, environmental protection, excellent performance, the relative acetonitrile of price be low, and have aborning the safety of use, convenient, pollute less, the easy feature such as transportation.The method adopts the starting material of low cost and environmental protection, and building-up process is simple, environmentally friendly, and yield is higher; For industrial production, improved the security of operation.
The preparation method of the amino rocephin of 7-of the present invention, joins 7-amino-cephalosporanic acid, triazine ring and EDTA in methylcarbonate, adds boric carbonic acid dimethyl ester complex trifluoride, reaction, and aftertreatment obtains the amino rocephin of 7-.
Reaction process is as follows:
Wherein:
Boric carbonic acid dimethyl ester complex trifluoride is commercial product.
Temperature of reaction is 15 ℃-40 ℃, and the time is 15-60min.
The feed ratio of 7-amino-cephalosporanic acid, triazine ring, EDTA and methylcarbonate is 1:0.585-0.614:0.004-0.006:5-15, and wherein 7-amino-cephalosporanic acid, EDTA and triazine ring are in g, and methylcarbonate is in mL.The mass ratio of boric carbonic acid dimethyl ester complex trifluoride and 7-amino-cephalosporanic acid is 1.8-3.2:1.
Aftertreatment is for adding terminator termination reaction, then adjusts pH crystallization with ammonolysis process, separated, washing, dry.With ammonolysis process adjust pH crystallization for add ammoniacal liquor to pH be 2.5-3.8 crystallization.In order to prevent that the side reaction in reaction from continuing reaction, affect quality and the yield of product, so add terminator termination reaction, terminator is preferably a kind of in mixture, methyl alcohol or the acetone of water, ethanol, water and ethanol.
The feed ratio of terminator and 7-amino-cephalosporanic acid is 3-10:1, and wherein terminator is in mL, and 7-amino-cephalosporanic acid is in g.
In raw material of the present invention, preferably add and lay particular stress on sodium bisulfite.
Compared with prior art, the present invention has the following advantages:
(1) adopt 7-ACA and triazine ring to use green economy solvent methylcarbonate as solvent, boric carbonic acid dimethyl ester complex trifluoride is the amino rocephin of the synthetic 7-of catalyzer, this method has been avoided the use of the noxious solvents such as volatile acetonitrile, make the relative environmental protection of reaction process, the security of operation improves.
(2) adopt nontoxic, environmental-protecting performance is excellent, the relative acetonitrile of price is low, have aborning the safety used, convenient, pollute less, easily the methylcarbonate of the feature such as transportation is as solvent.
(3) solvent after having reacted can be by rectifying by methylcarbonate and terminator recycling, provide cost savings, improved utilization ratio, and the relative acetonitrile of the price of methylcarbonate is cheap, greatly reduce production cost, the method adopts the starting material of low cost and environmental protection, and building-up process is simple, environmentally friendly, yield is higher.
(4) because methylcarbonate flash-point is high, steam forces down, Lower Explosive Limit high in air, and toxicity is low compared with acetonitrile, workman's operation environment safety, the green solvent that integrates spatter property and security, so the present invention for industrial production, has improved the security of operation, improved the competitive power of product in the same industry, suitability for industrialized is produced.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1
In 500mL three-necked bottle, add 20g 7-ACA, 11.7g triazine ring, 0.12g EDTA and 0.05g to lay particular stress on sodium bisulfite, uniform stirring in 185mL methylcarbonate, is warming up to 24 ℃.Add 50g BF
3-methylcarbonate, 30 ℃ are reacted 20 minutes.Reaction finishes, and adds the water of 0 ℃, and dripping ammoniacal liquor is 2.5 crystallizatioies to pH, growing the grain 30min at 8 ℃, and suction filtration, washing, ethanol is washed, and dries, and obtains dry product 24g.High performance liquid chromatography detection level 99.5%, mass yield is that 1.20(is in 7-ACA).
Embodiment 2
In 500mL three-necked bottle, add 20g 7-ACA, 12.0g triazine ring, 0.08g EDTA, uniform stirring in 100mL methylcarbonate, is warming up to 25 ℃.Add 36.0g BF
3-methylcarbonate, 15 ℃ of reaction 60min.Reaction finishes, and adds the ethanol of 0 ℃, and dripping ammoniacal liquor is 2.9 crystallizatioies to pH, and at 5 ℃, growing the grain is 30 minutes, suction filtration, and washing, ethanol is washed, and dries, and obtains dry product 25.4g.High performance liquid chromatography detection level 99.0%, mass yield is that 1.27(is in 7-ACA).
Embodiment 3
In 500mL three-necked bottle, add 20g7-ACA, 12.2g triazine ring, 0.10g EDTA, uniform stirring in 300mL methylcarbonate, is warming up to 25 ℃.Add 64.0g BF
3-methylcarbonate, 60 ℃ of reaction 15min.Reaction finishes, and adds the acetone of 0 ℃, and dripping ammoniacal liquor is 3.8 crystallizatioies to pH, growing the grain 25min at 6 ℃, and suction filtration, washing, dries, and obtains dry product 24.6g.High performance liquid chromatography detection level 99.2%, mass yield is that 1.23(is in 7-ACA).
Claims (8)
1. a preparation method for the amino rocephin of 7-, is characterized in that: 7-amino-cephalosporanic acid, triazine ring and EDTA are joined in methylcarbonate, add boric carbonic acid dimethyl ester complex trifluoride, react, aftertreatment obtains the amino rocephin of 7-.
2. the preparation method of the amino rocephin of 7-according to claim 1, it is characterized in that: the feed ratio of 7-amino-cephalosporanic acid, triazine ring, EDTA and methylcarbonate is 1:0.585-0.614:0.004-0.006:5-15, wherein 7-amino-cephalosporanic acid, EDTA and triazine ring are in g, and methylcarbonate is in mL.
3. the preparation method of the amino rocephin of 7-according to claim 1, is characterized in that: the mass ratio of boric carbonic acid dimethyl ester complex trifluoride and 7-amino-cephalosporanic acid is 1.8-3.2:1.
4. the preparation method of the amino rocephin of 7-according to claim 1, is characterized in that: temperature of reaction is 15 ℃-40 ℃, and the time is 15-60min.
5. the preparation method of the amino rocephin of 7-according to claim 1, is characterized in that: aftertreatment is for adding terminator termination reaction, then adjusts pH crystallization with ammonolysis process, separated, washing, is dried.
6. the preparation method of the amino rocephin of 7-according to claim 5, is characterized in that: terminator is a kind of in mixture, methyl alcohol or the acetone of water, ethanol, water and ethanol.
7. the preparation method of the amino rocephin of 7-according to claim 5, is characterized in that: the feed ratio of terminator and 7-amino-cephalosporanic acid is 3-10:1, and wherein terminator is in mL, and 7-amino-cephalosporanic acid is in g.
8. the preparation method of the amino rocephin of 7-according to claim 5, is characterized in that: with ammonolysis process adjust pH crystallization for add ammoniacal liquor to pH be 2.5-3.8 crystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310625223.2A CN103641846B (en) | 2013-11-28 | 2013-11-28 | The preparation method of the amino rocephin of 7- |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310625223.2A CN103641846B (en) | 2013-11-28 | 2013-11-28 | The preparation method of the amino rocephin of 7- |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103641846A true CN103641846A (en) | 2014-03-19 |
| CN103641846B CN103641846B (en) | 2015-08-19 |
Family
ID=50247159
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310625223.2A Active CN103641846B (en) | 2013-11-28 | 2013-11-28 | The preparation method of the amino rocephin of 7- |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103641846B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130273A (en) * | 2014-08-18 | 2014-11-05 | 哈药集团制药总厂 | Method for synthesizing ceftriaxone sodium |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424316A (en) * | 2001-12-11 | 2003-06-18 | 浙江海正药业股份有限公司 | Preparation of cephalosporin compound |
| CN1803803A (en) * | 2006-01-10 | 2006-07-19 | 哈药集团制药总厂 | Process for preparing ceftezode three-position intermediate |
| CN101792453A (en) * | 2010-03-17 | 2010-08-04 | 河北九派制药有限公司 | Method for preparing 7-amino-3-sulfotetrazolthiomethylcephalosporanic acid |
| CN102372729A (en) * | 2011-12-14 | 2012-03-14 | 哈药集团制药总厂 | Novel method for synthesizing cefoperazone sodium compound |
| CN102617606A (en) * | 2012-03-31 | 2012-08-01 | 哈药集团制药总厂 | Method for preparing ceftezole sodium compound |
| CN102627659A (en) * | 2012-04-17 | 2012-08-08 | 黑龙江豪运精细化工有限公司 | Preparation method of cefoperazone intermediate 7-TMCA |
| 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 |
-
2013
- 2013-11-28 CN CN201310625223.2A patent/CN103641846B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424316A (en) * | 2001-12-11 | 2003-06-18 | 浙江海正药业股份有限公司 | Preparation of cephalosporin compound |
| CN1803803A (en) * | 2006-01-10 | 2006-07-19 | 哈药集团制药总厂 | Process for preparing ceftezode three-position intermediate |
| CN101792453A (en) * | 2010-03-17 | 2010-08-04 | 河北九派制药有限公司 | Method for preparing 7-amino-3-sulfotetrazolthiomethylcephalosporanic acid |
| CN102372729A (en) * | 2011-12-14 | 2012-03-14 | 哈药集团制药总厂 | Novel method for synthesizing cefoperazone sodium compound |
| CN102617606A (en) * | 2012-03-31 | 2012-08-01 | 哈药集团制药总厂 | Method for preparing ceftezole sodium compound |
| CN102627659A (en) * | 2012-04-17 | 2012-08-08 | 黑龙江豪运精细化工有限公司 | Preparation method of cefoperazone intermediate 7-TMCA |
| 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130273A (en) * | 2014-08-18 | 2014-11-05 | 哈药集团制药总厂 | Method for synthesizing ceftriaxone sodium |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103641846B (en) | 2015-08-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103539803B (en) | A kind of method preparing ceftriaxone sodium | |
| CN102372729B (en) | Novel method for synthesizing cefoperazone sodium compound | |
| CN103709121B (en) | The preparation method of pharmaceutical grade 2-benzothiazolyl mercaptan and derivative DM thereof | |
| CN104447800B (en) | A kind of synthetic technology of cefoxitin acid | |
| CN105254648A (en) | Convenia synthetic method and Convenia sodium salt synthetic method | |
| CN105131017A (en) | Preparation method for cefcapene pivoxil hydrochloride | |
| CN102030762A (en) | Preparation method of cefprozil | |
| CN101768168B (en) | Method for synthesizing cephalosporin intermediate | |
| CN101210019A (en) | Methoxy cephalosporin intermediate | |
| CN110117291A (en) | A kind of synthetic method of cefotaxime acid | |
| CN103641846B (en) | The preparation method of the amino rocephin of 7- | |
| CN102127068A (en) | Method for synthesizing aztreonam compound | |
| CN102285997B (en) | Method for preparing chloroallyl beta-lactam antibiotic intermediate | |
| CN101130803B (en) | A method for enzymatically synthesizing β-lactam antibiotics in organic solvents | |
| CN106699681A (en) | Method for synthesizing ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate | |
| CN105294734B (en) | A kind of method for preparing cefonicid dibenzylethylenediamsalt salt | |
| CN105669701A (en) | Synthesis method of cefpodoxime proxetil intermediate | |
| CN101851249A (en) | Method for preparing cefcapene pivoxil hydrochloride | |
| CN101544659A (en) | Preparation method of ceftezole and midbody thereof | |
| CN101792453B (en) | Preparation method of 7-amino-3-sulfonic tetrazole thiomethyl cephalosporanic acid | |
| CN105131015B (en) | A kind of preparation method of the cephalosporanic acid of 7 amino, 3 vinyl 4 | |
| CN105017287B (en) | A kind of preparation method of cephamycin intermediate | |
| CN108017658A (en) | A kind of synthetic method of Cefprozil | |
| CN103467358B (en) | The preparation method of Zelnorm | |
| CN101857600B (en) | Method for preparing 7-phenylacetylamino-3-methylcephalosporanic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of 7-aminoceftriaxone Effective date of registration: 20211216 Granted publication date: 20150819 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: SHANDONG XINQUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980015208 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20220721 Granted publication date: 20150819 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: SHANDONG XINQUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980015208 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |