CN103641846B - The preparation method of the amino rocephin of 7- - Google Patents
The preparation method of the amino rocephin of 7- Download PDFInfo
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- CN103641846B CN103641846B CN201310625223.2A CN201310625223A CN103641846B CN 103641846 B CN103641846 B CN 103641846B CN 201310625223 A CN201310625223 A CN 201310625223A CN 103641846 B CN103641846 B CN 103641846B
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- amino
- methylcarbonate
- rocephin
- acetonitrile
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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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention belongs to field of medicaments, be specifically related to the preparation method of the amino rocephin of a kind of 7-.Be suspended in methylcarbonate by 7-amino-cephalosporanic acid, triazine ring and EDTA, add boric carbonic acid dimethyl ester complex trifluoride, reaction, aftertreatment obtains the amino rocephin of 7-.7-ACA and triazine ring is adopted to use green economy solvent methylcarbonate as solvent, boric carbonic acid dimethyl ester complex trifluoride is the amino rocephin of catalyzer synthesis 7-, adopt nontoxic, environmental-protecting performance is excellent, price is low relative to acetonitrile, have aborning safe and convenient to use, pollute less, the methylcarbonate of the easy feature such as transport is as solvent, avoid the use of the noxious solvents such as volatile acetonitrile, make the relative environmental protection of reaction process, the security of operation improves.The relative acetonitrile of price of methylcarbonate is cheap, greatly reduces production cost, and the method adopts low cost and the starting material of environmental protection, and building-up process is simple, and yield is higher.
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] is amino]-8-oxo-3-[[(1,2,5,6-tetrahydrochysene-2-methyl-5,6-dioxo-1,2,4-triazine-3-base) sulfo-[methyl]-5-sulfo--1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid disodium salt three times of semihydrates.Ceftriaxone sodium is Third generation Cephalosporins microbiotic, there is the characteristic of broad-spectrum high efficacy, for urinary tract, biliary tract infection, lower respiratory infection caused by 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 in 1978 by Switzerland Roche Developed, until after its patent term in 1996, ceftriaxone sodium starts to grow up with surprising rapidity at home.In the last few years, ceftriaxone sodium was the maximum kind of the cephalosporin market share, and no matter be bulk drug or preparation, be in cut-throat competition state always, the production cost therefore reducing 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 synthesizing ceftriaxone sodium, optimize its technique and reduce the market competitiveness that its production cost is very beneficial for strengthening ceftriaxone sodium.
Report about the document of 7-ACT and patent is all little, has been summed up following two kinds of methods:
Adopt acetonitrile as solvents in patent CN102702233, boron trifluoride-acetonitrile is catalyzer, makes 7-ACA and triazine ring reaction, then regulates pH crystallization.The shortcoming of this method is: have employed the higher and virose acetonitrile of highly volatile, price as solvent, become to produce cost higher, productive rate is only 90.4%.
In addition, be also adopt acetonitrile technique in patent CN102559829, in Crystallization Process, add cephalosporin esterase control pH to improve the purity of product.The shortcoming of this method is: introduce a kind of raw material (cephalosporin esterase), improve production cost, and productive rate is lower is 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, and 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 nontoxic, environmental protection, excellent performance, price relative to advantages such as acetonitrile are low, and there is use safety, convenience aborning, pollute less, the easy feature such as transport.The method adopts low cost and the starting material of environmental protection, and building-up process is simple, environmentally friendly, and yield is higher; For industrial production, improve the security of operation.
The preparation method of the amino rocephin of 7-of the present invention, joins in methylcarbonate by 7-amino-cephalosporanic acid, triazine ring and EDTA, 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 products.
Temperature of reaction is 15 DEG C-40 DEG C, 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 for adding terminator termination reaction, then adjusts pH crystallization with ammonolysis process, separation, washing, drying.PH crystallization is adjusted to be 2.5-3.8 crystallization for adding ammoniacal liquor to pH with ammonolysis process.In order to the side reaction in preventing from reacting continues reaction, affect quality and the yield of product, so add terminator termination reaction, terminator is preferably the one in the mixture of water, ethanol, water and ethanol, methyl alcohol or acetone.
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.
Preferably add in raw material of the present invention and lay particular stress on sodium bisulfite.
Compared with prior art, the present invention has the following advantages:
(1) 7-ACA and triazine ring is adopted to use green economy solvent methylcarbonate as solvent, boric carbonic acid dimethyl ester complex trifluoride is the amino rocephin of catalyzer synthesis 7-, this approach avoid 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, price is low relative to acetonitrile, there is use safety, convenience aborning, pollute less, the methylcarbonate of the easy feature such as transport is as solvent.
(3) solvent after having reacted can by rectifying by methylcarbonate and terminator recycling, provide cost savings, improve utilization ratio, and the price of methylcarbonate is cheap relative to acetonitrile, greatly reduce production cost, the method adopts low cost and the starting material of 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 comparatively acetonitrile is low, the operation environment safety of workman, be the green solvent integrating spatter property and security, so the present invention is for industrial production, improve the security of operation, improve 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 lay particular stress on sodium bisulfite, uniform stirring in 185mL methylcarbonate, be warming up to 24 DEG C.Add 50g BF
3-methylcarbonate, 30 DEG C are reacted 20 minutes.Reaction terminates, and adds the water of 0 DEG C, and dripping ammoniacal liquor is 2.5 crystallizatioies to pH, growing the grain 30min at 8 DEG C, suction filtration, washing, and ethanol is washed, and dries, 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, be warming up to 25 DEG C.Add 36.0g BF
3-methylcarbonate, 15 DEG C of reaction 60min.Reaction terminates, and adds the ethanol of 0 DEG C, and dripping ammoniacal liquor is 2.9 crystallizatioies to pH, growing the grain 30 minutes at 5 DEG C, suction filtration, washing, and ethanol is washed, and dries, 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, be warming up to 25 DEG C.Add 64.0g BF
3-methylcarbonate, 60 DEG C of reaction 15min.Reaction terminates, and adds the acetone of 0 DEG C, and dripping ammoniacal liquor is 3.8 crystallizatioies to pH, growing the grain 25min at 6 DEG C, suction filtration, and washing is dried, obtained dry product 24.6g.High performance liquid chromatography detection level 99.2%, mass yield is that 1.23(is in 7-ACA).
Claims (1)
1. the preparation method of the amino rocephin of 7-, it is characterized in that: in 500 mL three-necked bottles, add 20 g 7-ACA, 11.7g triazine rings, 0.12 g EDTA and 0.05 g lays particular stress on sodium bisulfite, uniform stirring in 185 mL methylcarbonates, is warming up to 24 DEG C, adds 50 g BF
3-methylcarbonate, 30 DEG C are reacted 20 minutes; Reaction terminates, and adds the water of 0 DEG C, and dripping ammoniacal liquor is 2.5 crystallizatioies to pH, growing the grain 30 min at 8 DEG C, suction filtration, washing, and ethanol is washed, and dries, obtains dry product.
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| CN104130273B (en) * | 2014-08-18 | 2016-10-26 | 哈药集团制药总厂 | A kind of synthetic method of 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 |
-
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- 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 |
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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 |
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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 |