CN102898440A - Technology for preparing 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester - Google Patents
Technology for preparing 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester Download PDFInfo
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- CN102898440A CN102898440A CN2012103837146A CN201210383714A CN102898440A CN 102898440 A CN102898440 A CN 102898440A CN 2012103837146 A CN2012103837146 A CN 2012103837146A CN 201210383714 A CN201210383714 A CN 201210383714A CN 102898440 A CN102898440 A CN 102898440A
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- phenylacetylamino
- methoxybenzyl ester
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Abstract
The invention discloses a technology for preparing a 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester. The 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester product is generated by using 7-phenylacetylamino-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester, sodium bromide, triphenylphosphine, purified water and dichloromethane as raw materials through a series of reaction. The technology has the advantages of safety and high product yield.
Description
Technical field
The present invention relates to a kind of 7-phenylacetylamino-3-vinyl cethalosporanic acid to the preparation technology of methoxybenzyl ester.
Background technology
7-phenylacetylamino-3-vinyl cethalosporanic acid is the key intermediate of making the medicines such as Cefixime Micronized, Cefdinir to methoxybenzyl ester, and its synthesising process research is conducive to the research and development of 3 vinyl cephalosporin medicaments.3 on cephalo ring forms ethylene linkage mainly by propadiene method, 3-fluoroform sulphonyl oxygen method and three kinds of methods of Wittig reaction at present.Front two kinds of conditions are overcritical, rear a kind of mild condition, and yield is high.Present method is that the further improvement of carrying out is being made larger improvement to environmental protection and yield etc. on original Wittig reaction basis.
Summary of the invention
Main task of the present invention is to provide the preparation technology of a kind of 7-phenylacetylamino-3-vinyl cethalosporanic acid to methoxybenzyl ester.
In order to solve above technical problem, a kind of 7-phenylacetylamino of the present invention-3-vinyl cethalosporanic acid is to the preparation technology of methoxybenzyl ester, and it is characterized in that: preparation technology is as follows:
Under the room temperature, add successively 7-phenylacetylamino-3-chloromethyl cephalosporanic to methoxybenzyl ester, Sodium Bromide, triphenylphosphine, purified water, methylene dichloride, behind the stirring at room reaction 3h, be cooled to 20 ℃;
Add successively dimethyl formamide, 37% formaldehyde solution, sodium formiate, 20 ℃ of stirring reaction 6h add the purified water extracting and demixing, get dichloromethane layer, and temperature control is evaporated to dried below 25 ℃, vacuum degree control-0.09～-0.1Mpa;
Add methyl alcohol under the rapid stirring, 35 ℃ are stirred 1h, 1/3 methyl alcohol that temperature control concentrates below 40 ℃;
Temperature control adds purified water below 40 ℃, stirs 1h, is cooled to 5 ℃, and suction filtration is used methanol wash, dries to such an extent that the 7-phenylacetylamino-the 3-vinyl cethalosporanic acid is to methoxybenzyl ester, and reaction formula is as follows:
Further, described 7-phenylacetylamino-3-chloromethyl cephalosporanic is 1-1:1-0.42:1-0.59:1-1:1-8 to the mass ratio of methoxybenzyl ester, Sodium Bromide, triphenylphosphine, purified water, methylene dichloride.
Further, described dimethyl formamide, 37% formaldehyde solution, sodium formiate: 1-5.67:1-1.8:1-0.42.
Technological advantage of the present invention:
1, with dimethyl formamide replaced adopting in the existing report technique inflammable and explosive and be the easy acetone of drugs processed.
2, replaced highly basic sodium hydroxide used in the existing report technique with sodium formiate, reduced structural damage.
3, the method that adopts the secondary decompression to steam methyl alcohol is come the residual of methylene dichloride in the minimizing system, has improved yield.
Embodiment
Embodiment 1
Under 25 ℃, in the 1000ml there-necked flask, add successively GCLE 100g, Sodium Bromide 42g, triphenylphosphine 59g, purified water 100ml, methylene dichloride 600ml, 25 ℃ of stirring reaction 3h, Liquid Detection GCLE＜5% is considered as reaction to be finished, and is cooled to 20 ℃, adds successively dimethyl formamide 600ml, 37% formaldehyde solution 180g, sodium formiate 42g, 20 ℃ of stirring reaction 6h change feed liquid in the 1200ml purified water over to.Stir, leave standstill, layering, get dichloromethane layer, temperature control is evaporated to dried below 25 ℃, adds methyl alcohol 1500ml under the rapid stirring, 35 ℃ are stirred 1h, temperature control is concentrated methyl alcohol 500ml below 40 ℃, and temperature control adds purified water 500ml below 40 ℃, and 40 ℃ are stirred 1h, be cooled to 5 ℃, suction filtration, with methyl alcohol 300ml washing, dry 7_ phenylacetylamino _ 3_ vinyl cethalosporanic acid to methoxybenzyl ester 85g.
Embodiment 2
25 ℃, in the 1000ml there-necked flask, add successively GCLE 100g, Sodium Bromide 42g, triphenylphosphine 59g, purified water 100ml, methylene dichloride 600ml, 25 ℃ of stirring reaction 3h, Liquid Detection GCLE＜5% is considered as reaction to be finished, and is cooled to 20 ℃, adds successively dimethyl formamide 600ml, 37% formaldehyde solution 180g, sodium formiate 42g, 20 ℃ of stirring reaction 6h change feed liquid in the 1200ml purified water over to.Stir, leave standstill, layering, get dichloromethane layer, temperature control is evaporated to dried below 25 ℃, adds methyl alcohol 1500ml under the rapid stirring, 35 ℃ are stirred 1h, temperature control is concentrated methyl alcohol 400ml below 40 ℃, and temperature control adds purified water 500ml below 40 ℃, and 40 ℃ are stirred 1h, be cooled to 5 ℃, suction filtration, with methyl alcohol 300ml washing, dry 7_ phenylacetylamino _ 3_ vinyl cethalosporanic acid to methoxybenzyl ester 82g.
Embodiment 3
25 ℃, in the 1000ml there-necked flask, add successively GCLE 100g, Sodium Bromide 42g, triphenylphosphine 59g, purified water 100ml, methylene dichloride 600ml, 25 ℃ of stirring reaction 3h, Liquid Detection GCLE＜5% is considered as reaction to be finished, and is cooled to 20 ℃, adds successively dimethyl formamide 600ml, 37% formaldehyde solution 180g, 4% sodium hydroxide solution 210ml, 20 ℃ of stirring reaction 6h change feed liquid in the 1200ml purified water over to.Stir, leave standstill, layering, get dichloromethane layer, temperature control is evaporated to dried below 25 ℃, adds methyl alcohol 1500ml under the rapid stirring, 35 ℃ are stirred 1h, temperature control is concentrated methyl alcohol 500ml below 40 ℃, and temperature control adds purified water 500ml below 40 ℃, and 40 ℃ are stirred 1h, be cooled to 5 ℃, suction filtration, with methyl alcohol 300ml washing, dry 7_ phenylacetylamino _ 3_ vinyl cethalosporanic acid to methoxybenzyl ester 79g.
Claims (3)
1. 7-phenylacetylamino-3-vinyl cethalosporanic acid is to the preparation technology of methoxybenzyl ester, and it is characterized in that: preparation technology is as follows:
Under the room temperature, add successively 7-phenylacetylamino-3-chloromethyl cephalosporanic to methoxybenzyl ester, Sodium Bromide, triphenylphosphine, purified water, methylene dichloride, behind the stirring at room reaction 3h, be cooled to 20 ℃;
Add successively dimethyl formamide, 37% formaldehyde solution, sodium formiate, 20 ℃ of stirring reaction 6h add the purified water extracting and demixing, get dichloromethane layer, and temperature control is evaporated to dried below 25 ℃, vacuum degree control-0.09～-0.1Mpa;
Add methyl alcohol under the rapid stirring, 35 ℃ are stirred 1h, 1/3 methyl alcohol that temperature control concentrates below 40 ℃;
Temperature control adds purified water below 40 ℃, stirs 1h, is cooled to 5 ℃, and suction filtration is used methanol wash, dries to such an extent that the 7-phenylacetylamino-the 3-vinyl cethalosporanic acid is to methoxybenzyl ester, and reaction formula is as follows:
2. a kind of 7-phenylacetylamino according to claim 1-3-vinyl cethalosporanic acid is characterized in that the preparation technology of methoxybenzyl ester: described 7-phenylacetylamino-3-chloromethyl cephalosporanic is 1-1:1-0.42:1-0.59:1-1:1-8 to the mass ratio of methoxybenzyl ester, Sodium Bromide, triphenylphosphine, purified water, methylene dichloride.
3. a kind of 7-phenylacetylamino according to claim 1-3-vinyl cethalosporanic acid is characterized in that: described dimethyl formamide, 37% formaldehyde solution, sodium formiate: 1-5.67:1-1.8:1-0.42 the preparation technology of methoxybenzyl ester.
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| CN2012103837146A CN102898440A (en) | 2012-10-11 | 2012-10-11 | Technology for preparing 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester |
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| CN2012103837146A CN102898440A (en) | 2012-10-11 | 2012-10-11 | Technology for preparing 7-phenylacetylamino-3-vinyl cephalosporanic acid p-methoxybenzyl ester |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111454280A (en) * | 2020-04-10 | 2020-07-28 | 佛山市南海北沙制药有限公司 | GVINE synthesis process |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111454280A (en) * | 2020-04-10 | 2020-07-28 | 佛山市南海北沙制药有限公司 | GVINE synthesis process |
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