CN109232305A - The preparation method of CMOBA - Google Patents
The preparation method of CMOBA Download PDFInfo
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- CN109232305A CN109232305A CN201810989858.3A CN201810989858A CN109232305A CN 109232305 A CN109232305 A CN 109232305A CN 201810989858 A CN201810989858 A CN 201810989858A CN 109232305 A CN109232305 A CN 109232305A
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- cmoba
- preparation
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- chlorine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
Abstract
The present invention relates to the preparation methods of CMOBA a kind of, belong to chemical intermediate preparation field.The preparation method, the following steps are included: hydrocarbonylation object is dissolved in solvent A, activator is first added at a set temperature to be activated, it is passed through chlorine again after the activation and carries out chlorination acidolysis generation CMOBA, after reaction by the way that solvent B dilute filtration is added after vacuum distillation removal solvent and byproduct of reaction, CMOBA is obtained.Preparation method provided by the present invention, it is scientific and reasonable, it is simple and easy, have the characteristics that high income, quality, solves the problems, such as that chlorine reaction activity is low, yield is low.
Description
Technical field
The present invention relates to the preparation methods of CMOBA a kind of, belong to chemical intermediate preparation field.
Background technique
Cefixime (Cefixime) is Third generation Cephalosporins antibiotic for oral use, is suitable for treatment sensitive bacteria institute
The infection at the positions such as breathing, uropoiesis and the biliary tract of cause.Cefixime has height to the beta-lactamase that gram negative bacilli generates
Stability is spent, the first generation and second generation cephalosporin are better than to gram negative bacilli antibacterial action, to gram-positive cocci antibacterial
Effect is not so good as the first generation and second generation cephalosporin.The Cefixime drug of State Food and Drug Administration's approval at present has
A variety of dosage forms such as tablet, capsule, dispersible tablet, dry suspensoid agent and granule, are prescription medicine.
CMOBA is an important intermediate for producing Cefixime, to use sulfonic acid chloride in production process, reaction end gas contains
There are a large amount of sulfur dioxide, SO 2 tail gas can cause great pressure to environmental protection, and because contain dioxy in tail gas hydrochloric acid
Change sulphur and be not used to other products for needing hydrochloric acid, on the one hand causes to waste, on the other hand cause environmental protection pressure.
Chlorine is relative to sulfonic acid chloride cheaper, and exhaust gas component is single, is easy to carry out recycling and reusing to tail gas.
But in CMOBA preparation process, chlorine is reduced relative to sulfonic acid chloride reactivity, makes reaction be not easy to cause, reaction speed is slow, instead
It should be not thorough, yield is low, and purity is low.
Summary of the invention
In view of the deficiencies of the prior art, the object of the present invention is to provide the preparation methods of CMOBA a kind of, scientific and reasonable, letter
It is single easy, have the characteristics that high income, quality, solves the problems, such as that chlorine reaction activity is low, yield is low.
The preparation method of CMOBA of the present invention, comprising the following steps:
Hydrocarbonylation object is dissolved in solvent A, activator is first added at a set temperature and is activated, leads to again after the activation
Enter chlorine and carry out chlorination acidolysis generation CMOBA, after reaction by being added after vacuum distillation removal solvent and byproduct of reaction
Solvent B dilute filtration, obtains CMOBA.
In the step 1, reaction temperature is 20-60 DEG C, and the reaction time is 10-25 hours.
The mass ratio of chlorine and hydrocarbonylation object is 0.5~1:1 in the step 1.
The mass ratio of activator and hydrocarbonylation object is 0.01~0.05:1 in the step 1.
In the step 1 activator be sulfonic acid chloride, phosphorus oxychloride, phosphorus pentachloride, hydrogen chloride, the concentrated sulfuric acid, alchlor,
One of ferric trichloride, reaction mother liquor or tail gas are a variety of.
Solvent A is one or more of acetic acid, methyl acetate, ethyl acetate or butyl acetate in the step 1；It is molten
Agent A mass and hydrocarbonylation amount of substance ratio are 0.3-1:1.
In the step 1, solvent B is one or more of methylene chloride, chloroform, toluene, hexamethylene or n-hexane；
Solvent B mass and hydrocarbonylation amount of substance ratio are 0.3-2:1.
1 in the step, reduced vacuum degree is >=-0.085MPa.
In the step 1, after dilute filtration, adds solvent B and eluted.
Further, when being eluted, 0.6-1.5 times that quality is hydrocarbonylation amount of substance is added in the solvent B.
Vapo(u)rizing temperature in the step 1 is 35~65 DEG C.
In the step 1, filtration temperature is 0-5 DEG C.
In the step 1, drying temperature is 40-50 DEG C.
Reaction solution in step 1 after reaction adds solvent dilution after byproduct of reaction is removed in distillation processing, with
Improve yield.
Using the abundant priming reaction liquid of activator is added, react it sufficiently with chlorine in a mild condition, reaction yield
Height, product purity is high, and tail gas is pure, containing only hydrogen chloride, can recycle for other reactions.
Reaction temperature is controlled at 20-60 DEG C, excessively high influence yield, too low influence reactivity, is reacted in dry sealing
It is carried out under environment.Activator is first added before logical chlorine reaction, abundant priming reaction liquid, the reactant after activation is easier and chlorine
It is reacted, can be reacted under mild conditions, prevent the generation of side reaction, be conducive to improve product yield and purity,
It is persistently slowly introducing chlorine in insulating process, guarantees that reaction sufficiently carries out.Reaction terminates will be big to product solubility by distillation
By-product steam, the solvent small to product solubility is added and dilutes crystallization, to improve yield.
Compared with prior art, the invention has the following beneficial effects:
1. reacting raw material first with activator by the way that the abundant priming reaction liquid of activator is added and generating intermediate, intermediate
It can realize under mild conditions with chlorine reaction and carry out chlorination acidolysis reaction purpose with chlorine merely, pure, tail gas
Containing hydrogen chloride facilitates recycling, can be used for other products, and technical process is environmentally protective；
Preparation method described in 2., it is scientific and reasonable, it is simple and easy, solve the problems, such as that chlorine reaction activity is low, yield is low.
Specific embodiment
The present invention will be further explained with reference to the examples below.
Embodiment 1
In the 500ml four-hole boiling flask equipped with electric stirring and thermometer, it is separately added into hydrocarbonylation object 160g, puts into acetic acid
40g, methyl acetate 60g after opening stirring addition phosphorus pentachloride 8g, 35 DEG C of reaction 30min of temperature control, then start logical chlorine, common
Enter chlorine 90g, leading to the chlorine time is 9h, and logical chlorine terminates to keep the temperature 15h, and 10h maintains 1g/h slowly to lead to chlorine before insulating process, protects
Temperature terminates vacuum distillation, and distillation to temperature 60 C is added hexamethylene 50g dilution after being cooled to room temperature, continues to be cooled to 5 DEG C of pumpings
Filter, then eluted with hexamethylene 100g, product 110g, purity 99.2% are obtained after 40 DEG C of drying.
Embodiment 2
In the 500ml four-hole boiling flask equipped with electric stirring and thermometer, it is separately added into hydrocarbonylation object 100g, puts into acetic acid
80g, ethyl acetate 20g open 30 DEG C of temperature control of stirring, are passed through tail gas 4g and carry out after causing priming reaction 30min, control temperature 30
DEG C start logical chlorine, it is common enter chlorine 80g, speed 10g/h, be 4h to be further continued for the logical chlorine time after crystallization, lead to chlorine knot
Shu Baowen 15h, 10h maintains 1g/h slowly to lead to chlorine before insulating process, and heat preservation terminates vacuum distillation, distillation to temperature 50 C, drop
Methylene chloride 100g dilution is added after warming to room temperature, continues to be cooled to 0 DEG C of suction filtration, is eluted with methylene chloride 150g, 45 DEG C of drying
After obtain product 107g, purity 99.3%.
Embodiment 3
In the 500ml four-hole boiling flask equipped with electric stirring and thermometer, it is separately added into hydrocarbonylation object 200g, puts into acetic acid first
Ester 50g, butyl acetate 70g after opening stirring addition phosphorus oxychloride 7g, 40 DEG C of reaction 30min of temperature control, then start logical chlorine, control
40 DEG C of temperature processed start logical chlorine, it is common enter chlorine 100g, leading to the chlorine time is 10h, and logical chlorine terminates to keep the temperature 10h, keep the temperature
Cheng Qian 5h maintains 1g/h slowly to lead to chlorine, and heat preservation terminates vacuum distillation, distills to 55 DEG C of temperature, is cooled to room temperature and toluene is added
90g dilution, continues to be cooled to 2 DEG C of suction filtrations, is eluted with toluene 130g, obtains product 108g, purity 99.1% after 50 DEG C of drying.
Embodiment 4
In the 500ml four-hole boiling flask equipped with electric stirring and thermometer, it is separately added into hydrocarbonylation object 300g, puts into acetic acid
80g, toluene 80g, open stirring and are passed through hydrogen chloride 10g reaction 30min, then start logical chlorine, control temperature 45 C by 45 DEG C of temperature control
Start logical chlorine, it is common enter chlorine 170g, leading to the chlorine time is 11h, and logical chlorine terminates to keep the temperature 10h, and 5h is maintained before insulating process
Slowly logical chlorine, heat preservation terminate vacuum distillation to 1g/h, distill to 40 DEG C of temperature, and addition butyl acetate 150g is dilute after being cooled to room temperature
It releases, continues to be cooled to 5 DEG C of suction filtrations, eluted with butyl acetate 200g, obtain product 106g, purity 99.4% after 48 DEG C of drying.
Claims (9)
1. a kind of preparation method of CMOBA, it is characterised in that: the following steps are included:
1) hydrocarbonylation object is dissolved in solvent A, activator is first added at a set temperature and carries out priming reaction, after the activation again
It is passed through chlorine progress chlorination acidolysis and generates CMOBA, after reaction by adding after vacuum distillation removal solvent and byproduct of reaction
Enter solvent B dilute filtration, obtains CMOBA.
2. the preparation method of CMOBA according to claim 1, it is characterised in that: in step 1, reaction temperature 20-60
DEG C, the reaction time is 10-25 hours.
3. the preparation method of CMOBA according to claim 1, it is characterised in that: the quality of chlorine and hydrocarbonylation object in step 1
Than for 0.5~1:1.
4. the preparation method of CMOBA according to claim 1, it is characterised in that: the matter of activator and hydrocarbonylation object in step 1
Amount is than being 0.01~0.05:1.
5. the preparation method of CMOBA according to claim 1, it is characterised in that: activator is sulfonic acid chloride, three in step 1
One of chlorethoxyfos, phosphorus pentachloride, hydrogen chloride, the concentrated sulfuric acid, alchlor, ferric trichloride, reaction mother liquor or tail gas are a variety of.
6. the preparation method of CMOBA according to claim 1, it is characterised in that: solvent A is acetic acid, acetic acid first in step 1
One or more of ester, ethyl acetate or butyl acetate；Solvent A quality and hydrocarbonylation amount of substance ratio are 0.3-1:1.
7. the preparation method of CMOBA according to claim 1, it is characterised in that: the vapo(u)rizing temperature in step 1 is 35~65
℃。
8. the preparation method of CMOBA according to claim 1, it is characterised in that: in step 1, temperature is 0-5 when filtering
℃。
9. the preparation method of CMOBA according to claim 1, it is characterised in that: in step 1, solvent B be methylene chloride,
One or more of chloroform, toluene, hexamethylene or n-hexane, solvent B mass and hydrocarbonylation amount of substance ratio are 0.3-2:1.
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| CN201810989858.3A CN109232305A (en) | 2018-08-28 | 2018-08-28 | The preparation method of CMOBA |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112624939A (en) * | 2020-12-30 | 2021-04-09 | 山东金城柯瑞化学有限公司 | Synthesis method of cefixime side chain ring-opening acid |
| CN114369041A (en) * | 2021-12-24 | 2022-04-19 | 山东金城柯瑞化学有限公司 | Method for synthesizing antibiotic intermediate by continuous flow reactor |
| CN117510367A (en) * | 2024-01-04 | 2024-02-06 | 山东金城柯瑞化学有限公司 | Preparation method of cefixime side chain open-loop acid |
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| JPS62103091A (en) * | 1985-10-29 | 1987-05-13 | Fujisawa Pharmaceut Co Ltd | Production of 3-cephem compound |
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2018
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| US4452851A (en) * | 1981-02-02 | 1984-06-05 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds |
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| CN1036563A (en) * | 1988-03-24 | 1989-10-25 | 赫彻斯特股份公司 | The preparation method of 4-halo-3-oxo-2-alkoxyimino butanoic acid ester |
| CN101928232A (en) * | 2009-06-18 | 2010-12-29 | 广东先强药业有限公司 | Method for preparing cefixime dispersible tablet raw material intermediate |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112624939A (en) * | 2020-12-30 | 2021-04-09 | 山东金城柯瑞化学有限公司 | Synthesis method of cefixime side chain ring-opening acid |
| CN114369041A (en) * | 2021-12-24 | 2022-04-19 | 山东金城柯瑞化学有限公司 | Method for synthesizing antibiotic intermediate by continuous flow reactor |
| CN114369041B (en) * | 2021-12-24 | 2023-10-03 | 山东金城柯瑞化学有限公司 | Method for synthesizing antibiotic intermediate by continuous flow reactor |
| CN117510367A (en) * | 2024-01-04 | 2024-02-06 | 山东金城柯瑞化学有限公司 | Preparation method of cefixime side chain open-loop acid |
| CN117510367B (en) * | 2024-01-04 | 2024-03-12 | 山东金城柯瑞化学有限公司 | Preparation method of cefixime side chain open-loop acid |
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Application publication date: 20190118 |