CN101525340B - Method for synthesizing 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl acid p-methoxybenzyl ester - Google Patents
Method for synthesizing 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl acid p-methoxybenzyl ester Download PDFInfo
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- CN101525340B CN101525340B CN2008100143334A CN200810014333A CN101525340B CN 101525340 B CN101525340 B CN 101525340B CN 2008100143334 A CN2008100143334 A CN 2008100143334A CN 200810014333 A CN200810014333 A CN 200810014333A CN 101525340 B CN101525340 B CN 101525340B
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Abstract
The invention belongs to the field of cephalosporin antibiotic medicaments, and in particular relates to a method for synthesizing 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl acid p-methoxybenzyl ester (GCLE). The technical proposal is that the method comprises the following steps: reacting penicillin sulfoxide ester with ammonium benzene sulfinate and 2-mercaptobenzothiazole in dichloromethane, and steaming out a solvent at normal pressure to generate aza-cyclobutanone thiosulfinate intermediate; adding dichloromethane to the intermediate after cooling, stirring and introducing saturated brine ice for cooling, adding trichloro isocyanic acid for reaction so as to generate an allylic chlorination product of the aza-cyclobutanone thiosulfinate; and reducing the pressure and drying the allylic chlorination product by distillation, adding dimethyl formamide to the product, stirring and introducing saturated brine ice for cooling, adding ammonia for reaction, adding water and dichloromethane to the mixture, mixing and stirring the mixture, standing for layering, transferring a dichloromethane layer at the bottom layer to another reactor, and steaming out the solvent at the normal pressure to obtain a dry product which is the GCLE. The method has the advantages of mild reaction condition, few reaction steps, simple operation, short production cycle, and improved production efficiency.
Description
Technical field
The invention belongs to the synthetic field of cephalosporin analog antibiotic medicine, be specially the synthetic method of 7-phenylacetyl ammonia-3-chloromethyl cephalosporin alkyl olefin(e) acid methoxy benzyl ester.
Background technology
The cephalosporin analog antibiotic medicine is powerful and strong fresh combatants in the anti-infectives, and it has characteristics such as curative effect height, side effect is little, anti-microbial activity is strong.Cynnematin is a class semisynthetic antibiotics, three big parent nucleus of traditional synthetic cynnematin are 6-APA, 7-ACA and 7-ADCA, and 7-phenylacetyl ammonia-3-chloromethyl cephalosporin alkyl olefin(e) acid is the 7-ACA that continues to methoxy benzyl ester (being called for short GCLE), the another class novel cephalosporin parent nucleus intermediate feed of synthetic cephalosporin medicament after the 7-ADCA, be one of important parent nucleus of synthetic cephalosporins, its structural formula is:
The synthetic of GCLE is raw material with the potassium salt of penicillin mainly, obtains penicillin sulfoxide ester through esterification, oxidation, and a kind of is the 3-ring exomethylenecepham alkanoic acid ester intermediate that makes through ring expansion, reduction, makes GCLE through chlorination again.The chlorination reaction step is: the 3-that makes is encircled exomethylenecepham alkanoic acid ester intermediate in tetrahydrofuran solvent, react 10min with DBU and chlorizating agent t-butyl hypochlorate down in-80 ℃ of low temperature, add then after trimethyl phosphite is warming up to 0 ℃, get GCLE through aftertreatment again, this chlorination reaction condition is harsh, need under lower-80 ℃ of temperature, to react, the refrigerating apparatus refrigerating capacity of general factory is about-35, do not reach processing requirement, need the newly-built refrigerating apparatus of investment, production capital has high input, and reacts bad control, unstable product quality under-80 ℃ of temperature.
The synthetic method that also has a kind of GCLE: penicillin sulfoxide ester and benzene sulfinic acid ammonium add inorganic salt and acid catalyst and carry out ring-opening reaction earlier in organic solvent, generate azetidinone thiosulfinate intermediate.Open-loop products is dissolved in the organic solvents such as chloroform or methylene dichloride then, add and add the vitriolic sodium chloride saturated solution, in two-phase system, use the platinum electrode electrolytic reaction, controlled temperature is at 15～17 ℃ of reaction 40min, the Cl2 that utilizes electrolysis to produce, HOCl, cl2O isoreactivity halogenating agent encircles the chlorination reaction of outer allylic, after separating, get the allylic chlorizate, get GCLE with the ammoniacal liquor closed loop at last.But the difficult control of this law technology difficulty height, reaction conditions, if reaction conditions control is improper, reaction is difficult to carry out smoothly, can cause more side reaction and influences yield.
Summary of the invention
The objective of the invention is deficiency at present technology, and provide the synthetic method of 7-phenylacetyl ammonia-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester, this method is a chlorizating agent with the trichlorine isocyanic acid, and chlorating processing condition and chlorination reaction parameter have been carried out optimized choice.This method requires not harsh to temperature of reaction, the reaction conditions gentleness is easy to control.
Technical scheme of the present invention comprises with the potassium salt of penicillin being raw material, obtain penicillin sulfoxide ester through esterification and oxidizing reaction, make 7-phenylacetyl ammonia-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester through open loop, chlorination and ring-closure reaction again, it is characterized in that: penicillin sulfoxide ester and benzene sulfinic acid ammonium, 2-sulfydryl phenylpropyl alcohol thiazole are reacted in methylene dichloride, steam solvent under the normal pressure, generate azetidinone thiosulfinate intermediate; The cooling back adds methylene dichloride, opens and stirs the logical full icy salt solution cooling of closing, and adds the trichlorine isocyanate reaction, generates azetidinone thiosulfinate allylic chlorizate; Evaporated under reduced pressure, add dimethyl formamide, open and stir the logical full icy salt solution cooling of closing, after adding the ammoniacal liquor reaction, add water and methylene dichloride, mix and stir the back static layering, the bottom dichloromethane layer is transferred to another retort, steam solvent under the normal pressure, the gained dry product is 7-phenylacetyl ammonia-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester.
Chemical equation is:
R
1＝PhCH
2CO R
2＝PCh
3OC
6H
4CH
2
Concrete operations of the present invention and reaction conditions are as follows: add penicillin sulfoxide ester 40 weight parts and benzene sulfinic acid ammonium 18 weight parts, 2-sulfydryl phenylpropyl alcohol thiazole 13 weight parts in the retort respectively, add methylene dichloride 120 weight parts again, opening the stirring intensification reacted 4-4.5 hour down at 38-40 ℃, normal pressure steams solvent under 39-42 ℃, generate azetidinone thiosulfinate intermediate; This retort tap water cooling 1-1.5 hour, suction methylene dichloride 150 weight parts then, open to stir and logically fullly close icy salt solution and be cooled to-15--20 ℃, add 30 weight part trichlorine isocyanic acids, at-15--20 ℃ stirring reaction 1-1.2 hour, generate azetidinone thiosulfinate allylic chlorizate; This reaction solution is under 0.06 ~ 0.08MPa after the evaporated under reduced pressure, add dimethyl formamide 150 weight parts, open to stir and logically fullly close icy salt solution and be cooled to-15--20 ℃, the ammoniacal liquor that adds 15 weight part 16-18%, after-15--20 ℃ stirring reaction 2.5-3 hour, in this retort, add water 200 weight parts and methylene dichloride 150 weight parts, stirred 0.5-0.8 hour, static 4-5 hour layering, the bottom dichloromethane layer is transferred to another retort, normal pressure steams solvent under 39-42 ℃, the gained dry product is 7-phenylacetyl ammonia-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester.
The invention has the beneficial effects as follows, owing to be chlorizating agent in this synthetic method with the trichlorine isocyanic acid, chlorination reaction temperature requires not too harsh, under-15--20 ℃ temperature, react, the refrigerating apparatus refrigerating capacity of general factory is about-35 ℃, can reach processing requirement, need not carry out new investment and build refrigerating apparatus; Reaction conditions is gentle, be easy to control, this overall yield of reaction can reach 55-65%, can propose 5-10 percentage point than prior art, greatly reduces production cost, and the reactions steps of this synthetic method is few, easy and simple to handle, with short production cycle, enhance productivity, this shows that the present invention has outstanding substantive distinguishing features and obvious improvement.
Embodiment
Embodiment 1
Add penicillin sulfoxide ester 40kg and benzene sulfinic acid ammonium 18kg, 2-mercaptobenzothiazole 13kg in the retort respectively, add methylene dichloride 120kg again, open the stirring intensification and reacted 4 hours down at 38 ℃, normal pressure steams solvent under 39 ℃, generates azetidinone thiosulfinate intermediate; This retort tap water cooling 1 hour, suction methylene dichloride 150kg then opens to stir and logically fullly closes icy salt solution and be cooled to-15 ℃, adds 30kg trichlorine isocyanic acid ,-15 ℃ of stirring reactions 1 hour, generates azetidinone thiosulfinate allylic chlorizate; This reaction solution is under 0.06MPa after the evaporated under reduced pressure, add dimethyl formamide 150kg, open to stir and logically fullly close icy salt solution and be cooled to-15 ℃, the ammoniacal liquor that adds 15kg16%, at-15 ℃ of stirring reactions after 2.5 hours, in this retort, add water 200kg and methylene dichloride 150kg, stirred 0.5 hour, layering in static 4 hours, the bottom dichloromethane layer is transferred to another retort, normal pressure steams solvent under 39 ℃, the gained dry product is 7 one phenylacetylaminos, one 3 one chloromethyl cephalosporin alkyl olefin(e) acids to methoxy benzyl ester.Total recovery is 58%.
Embodiment 2
Add penicillin sulfoxide ester 40kg and benzene sulfinic acid ammonium 18kg, 2-mercaptobenzothiazole 13kg in the retort respectively, add methylene dichloride 120kg again, open the stirring intensification and reacted 4.5 hours down at 40 ℃, normal pressure steams solvent under 42 ℃, generates azetidinone thiosulfinate intermediate; This retort tap water cooling 1.5 hours, suction methylene dichloride 150kg then opens to stir and logically fullly closes icy salt solution and be cooled to-20 ℃, adds 30kg trichlorine isocyanic acid,-20 ℃ of stirring reactions 1.2 hours, generate azetidinone thiosulfinate allylic chlorizate; This reaction solution is under 0.08MPa after the evaporated under reduced pressure, add dimethyl formamide 150kg, open to stir and logically fullly close icy salt solution and be cooled to-20 ℃, the ammoniacal liquor that adds 15kg18%, at-20 ℃ of stirring reactions after 3 hours, in this retort, add water 200kg and methylene dichloride 150kg, stirred 0.8 hour, layering in static 5 hours, the bottom dichloromethane layer is transferred to another retort, normal pressure steams solvent under 42 ℃, the gained dry product is 7 one phenylacetylaminos, one 3 one chloromethyl cephalosporin alkyl olefin(e) acids to methoxy benzyl ester.Total recovery is 65%.
Embodiment 3
Add penicillin sulfoxide ester 40kg and benzene sulfinic acid ammonium 18kg, 2-sulfydryl phenylpropyl alcohol thiazole 13kg in the retort respectively, add methylene dichloride 120kg again, open the stirring intensification and reacted 4.2 hours down at 39 ℃, normal pressure steams solvent under 40 ℃, generates azetidinone thiosulfinate intermediate; This retort tap water cooling 1.2 hours, suction methylene dichloride 150kg then opens to stir and logically fullly closes icy salt solution and be cooled to-18 ℃, adds 30kg trichlorine isocyanic acid,-18 ℃ of stirring reactions 1.1 hours, generate azetidinone thiosulfinate allylic chlorizate; This reaction solution is under 0.07MPa after the evaporated under reduced pressure, add dimethyl formamide 150kg, open to stir and logically fullly close icy salt solution and be cooled to-18 ℃, the ammoniacal liquor that adds 15kg17%, at-18 ℃ of stirring reactions after 2.8 hours, in this retort, add water 200kg and methylene dichloride 150kg, stirred 0.7 hour, layering in static 4.5 hours, the bottom dichloromethane layer is transferred to another retort, normal pressure steams solvent under 40 ℃, the gained dry product is 7-phenylacetyl ammonia-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester.Total recovery is 60%.
Claims (5)
1. 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl olefin(e) acid is to the synthetic method of methoxy benzyl ester, comprise with the potassium salt of penicillin being raw material, obtain penicillin sulfoxide ester through esterification and oxidizing reaction, make 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester through open loop, chlorination and ring-closure reaction again, it is characterized in that: penicillin sulfoxide ester and benzene sulfinic acid ammonium, 2-mercaptobenzothiazole are reacted in methylene dichloride, steam solvent under the normal pressure, generate azetidinone thiosulfinate intermediate; The cooling back adds methylene dichloride, opens and stirs the logical full icy salt solution cooling of closing, and adds the trichlorine isocyanate reaction, generates azetidinone thiosulfinate allylic chlorizate; Evaporated under reduced pressure, add dimethyl formamide, open and stir the logical full icy salt solution cooling of closing, after adding the ammoniacal liquor reaction, add water and methylene dichloride, mix and stir the back static layering, the bottom dichloromethane layer is transferred to another retort, steam solvent under the normal pressure, the gained dry product is 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester.
2. 7-phenylacetylamino according to claim 1-3-chloromethyl cephalosporin alkyl olefin(e) acid is to the synthetic method of methoxy benzyl ester, it is characterized in that, the concrete operations and the reaction conditions of described synthetic method are as follows: add penicillin sulfoxide ester 40 weight parts and benzene sulfinic acid ammonium 18 weight parts, 2-mercaptobenzothiazole 13 weight parts in the retort respectively, add methylene dichloride 120 weight parts again, opening the stirring intensification reacted 4-4.5 hour down at 38-40 ℃, normal pressure steams solvent under 39-42 ℃, generate azetidinone thiosulfinate intermediate; This retort tap water cooling 1-1.5 hour, suction methylene dichloride 150 weight parts then, open to stir and logically fullly close icy salt solution and be cooled to-15--20 ℃, add 30 weight part trichlorine isocyanic acids, at-15--20 ℃ stirring reaction 1-1.2 hour, generate azetidinone thiosulfinate allylic chlorizate; This reaction solution is under 0.06-0.08MPa after the evaporated under reduced pressure, add dimethyl formamide 150 weight parts, open to stir and logically fullly close icy salt solution and be cooled to-15--20 ℃, the ammoniacal liquor that adds 15 weight part 16-18%, after-15--20 ℃ stirring reaction 2.5-3 hour, in this retort, add water 200 weight parts and methylene dichloride 150 weight parts, stirred 0.5-0.8 hour, static 4-5 hour layering, the bottom dichloromethane layer is transferred to another retort, normal pressure steams solvent under 39-42 ℃, the gained dry product is 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester.
3. 7-phenylacetylamino-3 one chloromethyl cephalosporin alkyl olefin(e) acid according to claim 1 and 2 is to the synthetic method of methoxy benzyl ester, it is characterized in that, the concrete operations and the reaction conditions of described synthetic method are as follows: add penicillin sulfoxide ester 40 weight parts and benzene sulfinic acid ammonium 18 weight parts, 2-mercaptobenzothiazole 13 weight parts in the retort respectively, add methylene dichloride 120 weight parts again, opening the stirring intensification reacted 4 hours down at 38 ℃, normal pressure steams solvent under 39 ℃, generate azetidinone thiosulfinate intermediate; This retort tap water cooling 1 hour, suction methylene dichloride 150 weight parts are then opened to stir and are logically fullly closed icy salt solution and be cooled to-15 ℃, add 30 weight part trichlorine isocyanic acids,-15 ℃ of stirring reactions 1 hour, generate azetidinone thiosulfinate allylic chlorizate; This reaction solution is under 0.06MPa after the evaporated under reduced pressure, add dimethyl formamide 150 weight parts, open to stir and logically fullly close icy salt solution and be cooled to-15 ℃, the ammoniacal liquor that adds 15 weight parts 16%, at-15 ℃ of stirring reactions after 2.5 hours, in this retort, add water 200 weight parts and methylene dichloride 150 weight parts, stirred 0.5 hour, layering in static 4 hours, the bottom dichloromethane layer is transferred to another retort, normal pressure steams solvent under 39 ℃, the gained dry product is 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester.
4. 7-phenylacetylamino-3 one chloromethyl cephalosporin alkyl olefin(e) acid according to claim 1 and 2 is to the synthetic method of methoxy benzyl ester, it is characterized in that, the concrete operations and the reaction conditions of described synthetic method are as follows: add penicillin sulfoxide ester 40 weight parts and benzene sulfinic acid ammonium 18 weight parts, 2-mercaptobenzothiazole 13 weight parts in the retort respectively, add methylene dichloride 120 weight parts again, opening the stirring intensification reacted 4.5 hours down at 40 ℃, normal pressure steams solvent under 42 ℃, generate azetidinone thiosulfinate intermediate; This retort tap water cooling 1.5 hours, suction methylene dichloride 150 weight parts are then opened to stir and are logically fullly closed icy salt solution and be cooled to-20 ℃, add 30 weight part trichlorine isocyanic acids,-20 ℃ of stirring reactions 1.2 hours, generate azetidinone thiosulfinate allylic chlorizate; This reaction solution is under 0.08MPa after the evaporated under reduced pressure, add dimethyl formamide 150 weight parts, open to stir and logically fullly close icy salt solution and be cooled to-20 ℃, the ammoniacal liquor that adds 15 weight parts 18%, at-20 ℃ of stirring reactions after 3 hours, in this retort, add water 200 weight parts and methylene dichloride 150 weight parts, stirred 0.8 hour, layering in static 5 hours, the bottom dichloromethane layer is transferred to another retort, normal pressure steams solvent under 42 ℃, the gained dry product is 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester.
5. 7-phenylacetylamino according to claim 1 and 2-3-chloromethyl cephalosporin alkyl olefin(e) acid is to the synthetic method of methoxy benzyl ester, it is characterized in that, the concrete operations and the reaction conditions of described synthetic method are as follows: add penicillin sulfoxide ester 40 weight parts and benzene sulfinic acid ammonium 18 weight parts, 2-mercaptobenzothiazole 13 weight parts in the retort respectively, add methylene dichloride 120 weight parts again, opening the stirring intensification reacted 4.2 hours down at 39 ℃, normal pressure steams solvent under 40 ℃, generate azetidinone thiosulfinate intermediate; This retort tap water cooling 1.2 hours, suction methylene dichloride 150 weight parts are then opened to stir and are logically fullly closed icy salt solution and be cooled to-18 ℃, add 30 weight part trichlorine isocyanic acids,-18 ℃ of stirring reactions 1.1 hours, generate azetidinone thiosulfinate allylic chlorizate; This reaction solution is under 0.07MPa after the evaporated under reduced pressure, add dimethyl formamide 150 weight parts, open to stir and logically fullly close icy salt solution and be cooled to-18 ℃, the ammoniacal liquor that adds 15 weight parts 17%, at-18 ℃ of stirring reactions after 2.8 hours, in this retort, add water 200 weight parts and methylene dichloride 150 weight parts, stirred 0.7 hour, layering in static 4.5 hours, the bottom dichloromethane layer is transferred to another retort, normal pressure steams solvent under 40 ℃, the gained dry product is 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl olefin(e) acid to methoxy benzyl ester.
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| CN2008100143334A CN101525340B (en) | 2008-03-04 | 2008-03-04 | Method for synthesizing 7-phenylacetylamino-3-chloromethyl cephalosporin alkyl acid p-methoxybenzyl ester |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2795556A1 (en) * | 2010-05-10 | 2011-11-17 | Basilea Pharmaceutica International Ltd. | Oxidation process for preparing 3-formyl-cephem derivatives |
| CN102344459B (en) * | 2011-07-27 | 2014-08-06 | 山西新天源医药化工有限公司 | Preparation method of cephalosporin intermediate GCLE |
| CN102690243B (en) * | 2012-05-25 | 2014-07-16 | 伊犁川宁生物技术有限公司 | Method for recovering raw materials in preparation process of 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl |
| CN107033162B (en) * | 2016-02-03 | 2020-05-01 | 湖北凌晟药业有限公司 | Preparation of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester |
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| CN1580058A (en) * | 2003-08-01 | 2005-02-16 | 日本化学工业株式会社 | Method for preparig 3-chloromethyl-3-cephem derivative crystalline |
| CN1849324A (en) * | 2003-09-09 | 2006-10-18 | 日本化学工业株式会社 | Process for producing 3-chloromethyl-3-cephem derivative |
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Patent Citations (3)
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| US4058521A (en) * | 1976-01-23 | 1977-11-15 | Shionogi & Co., Ltd. | 2-Halomethyl-2-nucleophilic substituted methyl penicillins |
| CN1580058A (en) * | 2003-08-01 | 2005-02-16 | 日本化学工业株式会社 | Method for preparig 3-chloromethyl-3-cephem derivative crystalline |
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| Title |
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| JP昭58-74689A 1983.05.06 |
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