CN103360412A - A kind of synthetic method of S 578 - Google Patents
A kind of synthetic method of S 578 Download PDFInfo
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- CN103360412A CN103360412A CN2013102276219A CN201310227621A CN103360412A CN 103360412 A CN103360412 A CN 103360412A CN 2013102276219 A CN2013102276219 A CN 2013102276219A CN 201310227621 A CN201310227621 A CN 201310227621A CN 103360412 A CN103360412 A CN 103360412A
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Abstract
The invention discloses a kind of synthetic method of S 578, comprise that step is: under-10 ~-50 ℃, 7-aminodesacetoxycephalosporanic acid is obtained 7-aminodesacetoxycephalosporanic acid salt with the organic bases dissolving; Generate mixed anhydride and carry out condensation reaction with described 7-aminodesacetoxycephalosporanic acid salt in the reaction of-20 ~-70 ℃ of lower hydroxyl Deng salt and pivaloyl chloride, extraction and the pH value of regulating water layer are separated out with salt again and are regulated the pH value, and crystallization obtains S 578.By the way, the synthetic method of a kind of S 578 provided by the invention, the method technique is simple, does not need to form solvate in building-up process, can be in water direct crystallization, reduced the consumption of organic solvent, reduced production cost, the S 578 productive rate that obtains is high, and every quality index is qualified, meet standards of pharmacopoeia, be conducive to realize suitability for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, particularly relate to a kind of synthetic method of S 578.
Background technology
S 578 is semi-synthetic first-generation oral cephalosporin, the oral cephalosporin analog antibiotic of a kind of wide spectrum, its has a broad antifungal spectrum, anti-microbial activity is similar to Kefzol, effective to staphylococcus, streptococcus pneumoniae and intestinal bacteria etc., also effective to penicillin-fast staphylococcus.Oral absorption is good, is mainly used in urinary tract, biliary tract, and the infection such as respiratory tract, especially is fit to children.
The synthesis technique that now S 578 is commonly used is to be starting raw material by 7-ADCA, via the mixed anhydride condensation that generates with hydroxyl Deng salt and pivaloyl chloride, through hydrochloric acid hydrolysis, with S 578 and solvent such as DMF or the DMAC formation solvate that generates, separate drying, in water, solvate is changed into S 578 again.This synthetic method can consume a large amount of solvents in forming the solvate process, improved greatly production cost, is unfavorable for suitability for industrialized production.
Summary of the invention
The technical problem that the present invention mainly solves provides a kind of synthetic method of S 578, and the method can reduce solvent consumption, Decrease production cost.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: a kind of synthetic method of S 578 is provided, comprises that step is:
(1) under-10 ~-50 ℃, 7-aminodesacetoxycephalosporanic acid is obtained 7-aminodesacetoxycephalosporanic acid salt with the organic bases dissolving;
(2) generate mixed anhydride and carry out condensation reaction with described 7-aminodesacetoxycephalosporanic acid salt at-20 ~-70 ℃ of lower hydroxyl Deng salt and pivaloyl chloride reaction, extraction and the pH value of regulating water layer, again the salt in the described water layer is separated out and regulates the pH value of described water layer, crystallization obtains S 578.
In a preferred embodiment of the present invention, the mol ratio of 7-aminodesacetoxycephalosporanic acid and described tetramethyl guanidine is 1:1 ~ 1.5 described in the step (1), and described solvent temperature is-20 ~-30 ℃.
In a preferred embodiment of the present invention, hydroxyl Deng salt and described pivaloyl chloride react in mixed solvent described in the step (2), and the described mixed anhydride that obtains and the mol ratio of described 7-aminodesacetoxycephalosporanic acid are 1.0 ~ 1.5:1.
In a preferred embodiment of the present invention, described mixed solvent is that methylene dichloride mixes with dimethyl formamide or methylene dichloride mixes with N,N-DIMETHYLACETAMIDE.
In a preferred embodiment of the present invention, the reaction times that generates mixed anhydride described in the step (2) is 0.5 ~ 2.0 hour, and the time of described condensation reaction is 1.5 ~ 5.0 hours.
In a preferred embodiment of the present invention, comprise also in the step (2) that the condensation reaction end is 10 ~ 20% dilute hydrochloric acid hydrolysis afterwards with mass percent, described hydrolysis time is 10 ~ 60 minutes.
In a preferred embodiment of the present invention, extraction process described in the step (2) is with methylene dichloride or ethyl acetate extraction, also comprises after extraction finishes and uses activated carbon decolorizing.
In a preferred embodiment of the present invention, the salt that separates described in the step (2) in the water layer is that the mass ratio of described weakly acidic cation-exchange resin, storng-acid cation exchange resin or liquid resin and described 7-aminodesacetoxycephalosporanic acid is 2 ~ 6:1 with weakly acidic cation-exchange resin, storng-acid cation exchange resin or liquid resin.
In a preferred embodiment of the present invention, described weakly acidic cation-exchange resin is 732 types, 011 type or 001 type, described storng-acid cation exchange resin is 107 types or 113 types, described liquid resin is BR-113, BR-116 or BR-106, and the mass ratio of described weakly acidic cation-exchange resin, storng-acid cation exchange resin or liquid resin and described 7-aminodesacetoxycephalosporanic acid is 3 ~ 5:1.
The invention has the beneficial effects as follows: the synthetic method of S 578 of the present invention, the method technique is simple, in building-up process, do not need to form solvate, can be in water direct crystallization, reduced the consumption of organic solvent, reduced production cost, the S 578 productive rate that obtains is high, every quality index is qualified, meets standards of pharmacopoeia, is conducive to realize suitability for industrialized production.
Embodiment
The below is described in detail preferred embodiment of the present invention, thereby so that advantages and features of the invention can be easier to be it will be appreciated by those skilled in the art that protection scope of the present invention is made more explicit defining.
Embodiment one:
(1) in the reaction flask of drying, add 50ml methylene dichloride and 25g 7-ADCA, be cooled to-20～-30 ℃, add again the 15g tetramethyl guanidine, stirring and dissolving obtains 7-ADCA salt lysate to clarification;
(2) add 50ml methylene dichloride and 50ml DMF in another dry reaction flask, add hydroxyl Deng salt 40g stirring and dissolving again, be cooled to-50～-60 ℃, add the 15g pivaloyl chloride, temperature control-40～-50 ℃ are reacted and were obtained mixed anhydride liquid in 1.5 hours;
(3) be no more than at temperature control under-70 ℃ the condition and add the 7-ADCA salt lysate that step (1) obtains, the reinforced end, temperature control-20～-55 ℃ reaction 3.0 hours, reaction finishes to add 3mol/L hydrochloric acid 120ml, and temperature control is no more than 20 ℃, stir hydrolysis, methylene dichloride is told in layering, and water is used twice of ethyl acetate extraction again, use 100ml at every turn, obtain water layer;
(4) in water layer, add the 2g gac, steam residual organic solvent in the following decolouring of the temperature limit decompression less than or equal to 45 ℃, decolouring was carried out 1 hour, suction filtration, filtrate is regulated pH to 2.5, with the salt in the 732 type Zeo-karbs separation water layer of 80g, washes with purified water again, collect altogether about 350ml of filtrate, filtrate was regulated the pH value to crystallization, and terminal point pH is 5.0～5.5,20 ℃ of lower growing the grains 2 hours, suction filtration, the purified water washing is drained, 45 ℃ of lower vacuum-dryings, obtain S 578 34g, yield is 76.5%.
Embodiment two:
(1) in the reaction flask of drying, add 50ml methylene dichloride and 25g 7-ADCA, be cooled to-20～-30 ℃, add again the 15g tetramethyl guanidine, stirring and dissolving obtains 7-ADCA salt lysate to clarification;
(2) add 50ml methylene dichloride and 50ml DMF in another dry reaction flask, add hydroxyl Deng salt 40g stirring and dissolving again, be cooled to-50～-60 ℃, add the 15g pivaloyl chloride, temperature control-20～-50 ℃ are reacted and were obtained mixed anhydride liquid in 1.5 hours;
(3) be no more than at temperature control under-70 ℃ the condition and add the 7-ADCA salt lysate that step (1) obtains, the reinforced end, temperature control-20～-55 ℃ reaction 3.0 hours, reaction finishes to add 3mol/L hydrochloric acid 120ml, and temperature control is no more than 20 ℃, stir hydrolysis, methylene dichloride is told in layering, and water is used twice of dichloromethane extraction again, use 100ml at every turn, obtain water layer;
(4) in water layer, add the 2g gac, steam residual organic solvent in the following decolouring of the temperature limit decompression less than or equal to 45 ℃, decolouring was carried out 1 hour, suction filtration, filtrate is regulated pH to 2.5, with the salt in the 107 type Zeo-karbs separation water layer of 100g, washes with purified water again, collect altogether about 350ml of filtrate, filtrate was regulated the pH value to crystallization, and terminal point pH is 5.0～5.5,20 ℃ of lower growing the grains 2 hours, suction filtration, the purified water washing is drained, 45 ℃ of lower vacuum-dryings, obtain S 578 33g, yield is 74.2%.
The synthetic method of the S 578 that the present invention discloses, the method is in order to reduce the use of cost, minimizing high boiling solvent, employing without forming solvate in water primary crystallization obtain S 578, increase reflection polarity owing in synthetic, need to add water-soluble solvent such as DMF or DMAC, the sylvite or the sodium salt that also have hydroxyl Deng salt to bring simultaneously, the existence of these materials will cause S 578 can't separate out in system, therefore adopt extraction, regulate pH value, resin isolation sylvite or sodium salt, re-adjustment pH value, the method for crystallization S 578.
The above only is embodiments of the invention; be not so limit claim of the present invention; every equivalent structure or equivalent flow process conversion that utilizes description of the present invention to do; or directly or indirectly be used in other relevant technical fields, all in like manner be included in the scope of patent protection of the present invention.
Claims (9)
1. the synthetic method of a S 578 is characterized in that, comprises that step is:
(1) under-10 ~-50 ℃, 7-aminodesacetoxycephalosporanic acid is obtained 7-aminodesacetoxycephalosporanic acid salt with the organic bases dissolving;
(2) generate mixed anhydride and carry out condensation reaction with described 7-aminodesacetoxycephalosporanic acid salt at-20 ~-70 ℃ of lower hydroxyl Deng salt and pivaloyl chloride reaction, extraction and the pH value of regulating water layer, again the salt in the described water layer is separated out and regulates the pH value of described water layer, crystallization obtains S 578.
2. the synthetic method of S 578 according to claim 1 is characterized in that, the mol ratio of 7-aminodesacetoxycephalosporanic acid and described tetramethyl guanidine is 1:1 ~ 1.5 described in the step (1), and described solvent temperature is-20 ~-30 ℃.
3. the synthetic method of S 578 according to claim 1, it is characterized in that, hydroxyl Deng salt and described pivaloyl chloride react in mixed solvent described in the step (2), and the described mixed anhydride that obtains and the mol ratio of described 7-aminodesacetoxycephalosporanic acid are 1.0 ~ 1.5:1.
4. the synthetic method of S 578 according to claim 3 is characterized in that, described mixed solvent is that methylene dichloride mixes with dimethyl formamide or methylene dichloride mixes with N,N-DIMETHYLACETAMIDE.
5. the synthetic method of S 578 according to claim 1 is characterized in that, the reaction times that generates mixed anhydride described in the step (2) is 0.5 ~ 2.0 hour, and the time of described condensation reaction is 1.5 ~ 5.0 hours.
6. the synthetic method of S 578 according to claim 1 is characterized in that, comprises also in the step (2) that the condensation reaction end is 10 ~ 20% dilute hydrochloric acid hydrolysis afterwards with mass percent, and described hydrolysis time is 10 ~ 60 minutes.
7. the synthetic method of S 578 according to claim 1 is characterized in that, extraction process described in the step (2) is with methylene dichloride or ethyl acetate extraction, also comprises after extraction finishes and uses activated carbon decolorizing.
8. the synthetic method of S 578 according to claim 1, it is characterized in that, the salt that separates described in the step (2) in the water layer is that the mass ratio of described weakly acidic cation-exchange resin, storng-acid cation exchange resin or liquid resin and described 7-aminodesacetoxycephalosporanic acid is 2 ~ 6:1 with weakly acidic cation-exchange resin, storng-acid cation exchange resin or liquid resin.
9. the synthetic method of S 578 according to claim 8, it is characterized in that, described weakly acidic cation-exchange resin is 732 types, 011 type or 001 type, described storng-acid cation exchange resin is 107 types or 113 types, described liquid resin is BR-113, BR-116 or BR-106, and the mass ratio of described weakly acidic cation-exchange resin, storng-acid cation exchange resin or liquid resin and described 7-aminodesacetoxycephalosporanic acid is 3 ~ 5:1.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106588953A (en) * | 2016-11-08 | 2017-04-26 | 山东裕欣药业有限公司 | Anti-infective drug cefadroxil crystal compound and composition thereof |
| CN106588954A (en) * | 2016-11-08 | 2017-04-26 | 山东裕欣药业有限公司 | Anti-infective drug such as cefadroxil crystal compound and composition thereof |
| CN109608477A (en) * | 2018-12-28 | 2019-04-12 | 华北制药股份有限公司 | A kind of synthetic method of cephalosporin |
| CN109836438A (en) * | 2019-03-19 | 2019-06-04 | 河北科技大学 | The synthetic method of cefalexin impurity |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106588953A (en) * | 2016-11-08 | 2017-04-26 | 山东裕欣药业有限公司 | Anti-infective drug cefadroxil crystal compound and composition thereof |
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| CN106588953B (en) * | 2016-11-08 | 2018-11-27 | 山东罗欣药业集团恒欣药业有限公司 | A kind of anti-infectives cefadroxil crystal-form compound and combinations thereof |
| CN106588954B (en) * | 2016-11-08 | 2018-11-27 | 山东罗欣药业集团恒欣药业有限公司 | A kind of anti-infectives amoxycillin crystalline compounds and combinations thereof |
| CN109608477A (en) * | 2018-12-28 | 2019-04-12 | 华北制药股份有限公司 | A kind of synthetic method of cephalosporin |
| CN109836438A (en) * | 2019-03-19 | 2019-06-04 | 河北科技大学 | The synthetic method of cefalexin impurity |
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| CN103360412B (en) | 2015-08-19 |
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