CN101357927A - 7-amino-3-non-3-cephalosporin-4-carbosylic acid preparation method - Google Patents
7-amino-3-non-3-cephalosporin-4-carbosylic acid preparation method Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention provides a preparation method of 7-amino-3-non-cephem-4-carboxylic acid which is 7-ANCA for short. The preparing procedures are as follows: 7-phenyl acetamide-3-hydroxy-3-cephem-4-carboxylic acid-p-nitrobenzyl ester is taken as raw material; firstly, metal borohydride is used to reduce the double bonds between the 3-parental nucleus and the 4-parental nucleus; sulfuryl etheride is used to esterify the 3-hydroxy, then alkali is used to remove the 3-methanesulfonic acid ester group to restore the double bonds between the 3-parental nucleus and the 4-parental nucleus; finally, a catalytic hydrogenation method is used to remove the protecting group on the 4-carboxyl of the parental nucleus, an enzyme method is used to remove the protecting group on the 7-amino of the parental nucleus, thus obtaining the product 7-ANCA. The invention has the advantages of being simple and feasible technology, improving production quality, reducing production cost and reducing environment pollution.
Description
Technical field
The present invention relates to 7-amino-3-does not have-technology of preparing of 3-cephalo-4-carboxylic acid (hereinafter to be referred as 7-ANCA), and it is the common parent nucleus of ceftizoxime (Ceftizoxime) and Ceftibuten (Ceftibuten).
Background technology
Ceftizoxime and Ceftibuten belong to third generation cephalosporin analog antibiotic, and its synthetic method is divided four kinds, and synthetic route is as follows:
1. the reaction formula of synthetic route one is as follows:
Said synthesis route is a raw material with 7-phenylacetyl ammonia-3-hydroxyl-3-cephalo-4-carboxylic acid-α-phenyl benzyl ester 2; earlier get intermediate 3 with the two keys between 3 and 4 of the sodium borohydride reduction parent nucleus; get intermediate 4 with 3 hydroxyls of Methanesulfonyl chloride esterification then; the protecting group that removes on 7 bit aminos with phosphorus pentachloride and pyridine gets intermediate 5; remove 3 methylsulphonic acid ester groups with alkali again and get intermediate 6, remove 4 protecting groups on the carboxyl to obtain product 7-ANCA 1 with trifluoroacetic acid at last with the two keys that recover between 3 and 4 of the parent nucleus.Document is seen US4647658; US3989695; US5660711 and Pure ﹠amp; Appl.Chem., 1987,59 (8): 1041-1046.Its shortcoming is that the industrialization yield is general, and product appearance is bad, and produces a large amount of phosphorous refuses, trifluoroacetic acid expensive raw material price.
2. the reaction formula of synthetic route two is as follows:
This method adopts phosphorus pentachloride and pyridine to remove protecting group on 7 bit aminos, removes protecting group on the carboxyl of 4-position with trifluoroacetic acid.Different is utilizes dimension alkene (Wittig) reaction of loving and respect one's elder brother to come closed loop to form intermediate 10.Document US 4430498; Chemistryand Biology of β-Lactam Autibiotics Penicilins and Cephalosporins Volume 1, P170; Helvetica Chimica Acta1972,55 (43): 423～429.Shortcoming is that starting raw material is difficult to obtain, and product appearance is poor, produces phosphorous refuse, and the trifluoroacetic acid valency is expensive.
3. the reaction formula of synthetic route three is as follows:
This method adopts phosphorus pentachloride and pyridine to remove protecting group on 7 bit aminos, removes protecting group on the carboxyl of 4-position with trifluoroacetic acid.The different tributyl tins that are to use remove chlorine on 3 of the potential parent nucleus, come closed loop to form intermediate 14 with benzene sulfinic acid copper.Document is seen CN7190714; J.Chem.Soc.Perkin Trans 1,1999, (23): 3463.Its shortcoming is that tributyl tin costs an arm and a leg, and the working conditions harshness produces a large amount of cuprics, stanniferous and phosphorated refuse, and metal ion neutralization product is residual too high
4. the reaction formula of synthetic route four is as follows:
Article four, synthetic route adopts phosphorus pentachloride and pyridine to remove protecting group on 7 bit aminos equally, adopts trifluoroacetic acid to remove 4 protecting groups on the carboxyl.Different is to add 3 sulphonates of acid reduction elimination with zinc powder to get intermediate 18.Pertinent literature is seen Pure ﹠amp; Apple.Chem., 1987,59 (8): 1041-1046; Clear 54-3087; US4013651; US3925372.Its shortcoming is that product appearance is bad, produces to contain zinc and phosphorated refuse in a large number, and trifluoroacetic acid and zinc metal price are all higher.
Summary of the invention
The object of the present invention is to provide a kind of new method for preparing 7-ANCA, overcome the shortcoming that exists among the above-mentioned preparation method.
7-amino-3-of the present invention do not have-preparation method of 3-cephalo ring-4-carboxylic acid; with 7-phenylacetyl ammonia-3-hydroxyl-3-cephalo-4-carboxylic acid of being easy to get on the market-to nitrobenzyl ester 19 is raw material; earlier get intermediate 20 with the two keys between 3 and 4 of the metal borohydride reduction parent nucleus; get intermediate 21 with 3 hydroxyls of sulfuryl halide esterification then; remove 3 sulphonates with alkali again and get intermediate 22 with the two keys that recover between 3 and 4; remove 4 protecting groups on the carboxyl with catalytic hydrogenation method at last and get intermediate 23, the protecting group that removes on 7 bit aminos with enzymolysis process obtains product 7-ANCA.Each step reaction formula is as follows:
R is methyl, ethyl or p-methylphenyl in the formula, and X is a chlorine or bromine.
In step (A), use appropriate reductant to reduce two keys between 3 and 4 of the parent nucleus, suitable temp is-70 ℃-50 ℃, suitable solvent is halogenated hydrocarbon solvent, protonic solvent or low boiling-point and polarity aprotic solvent.
In step (B); use suitable low alkane sulfonyl compound to remove 3 hydroxyls; use suitable organic bases or mineral alkali to make acid binding agent, suitable temperature is-55 ℃-50 ℃, and suitable solvent is halogenated hydrocarbon solvent, protonic solvent or low boiling-point and polarity aprotic solvent.
In step (C), use suitable alkali to remove sulphonate.
In step (D), use catalytic hydrogenation method to remove 4 protecting groups on the carboxylic acid, suitable pH value scope is 5-11.
In step (E), use suitable fixedly acylase to remove protecting group on 7 bit aminos, suitable pH value scope is 6-9.
In step (A), appropriate reductant is POTASSIUM BOROHYDRIDE or sodium borohydride etc.Suitable solvent is halogenated hydrocarbon solvent, protonic solvent or low boiling-point and polarity aprotic solvent, and wherein halogenated hydrocarbon solvent comprises: methylene dichloride, chloroform, 1,2-ethylene dichloride, 1, one or more mixing of 2-monobromethane etc.; Protonic solvent comprises: one or more mixing of methyl alcohol, ethanol, propyl alcohol, butanols etc.; The low boiling-point and polarity aprotic solvent comprises: amides, sulfoxide class, nitrile and ethers.Wherein amides is N, and dinethylformamide, N,N-dimethylacetamide etc., sulfoxide class are dimethyl sulfoxide (DMSO) etc., and nitrile is an acetonitrile etc., and ethers is tetrahydrofuran (THF), dioxane, diethylene glycol monoethyl ether, the two ether of glycol ether etc.
In step (B), suitable low alkane sulphonyl thing is Methanesulfonyl chloride, ethyl chloride, sulfonyloxy methyl bromine, ethyl sulfuryl bromide, Tosyl chloride etc.Suitable organic bases comprises: triethylamine, tri-n-butylamine, trioctylamine, pyridine, pyrimidine, methylmorpholine, N, and accelerine, sodium methylate, sodium ethylate etc., suitable mineral alkali comprises: sheet alkali, potassium hydroxide, yellow soda ash, sodium bicarbonate etc.Suitable solvent is halogenated hydrocarbon solvent, protonic solvent or low boiling-point and polarity aprotic solvent, and wherein halogenated hydrocarbon solvent comprises: methylene dichloride, chloroform, 1,2-ethylene dichloride, 1, one or more mixing of 2-monobromethane etc.; Protonic solvent comprises: one or more mixing of methyl alcohol, ethanol, propyl alcohol, butanols etc.; Polar aprotic solvent comprises: amides, sulfoxide class, nitrile, ethers and ketone.Wherein amides is N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE etc., the sulfoxide class is a dimethyl sulfoxide (DMSO) etc., nitrile is an acetonitrile etc., ethers is tetrahydrofuran (THF), dioxane, diethylene glycol monoethyl ether, the two ether of glycol ether etc., and ketone is one or more mixing such as acetone, mibk, butanone;
In step (C), suitable alkali is organic bases and mineral alkali.Suitable organic bases comprises: triethylamine, diethylamine, tri-n-butylamine, trioctylamine, pyridine, pyrimidine, methylmorpholine, N, accelerine, sodium methylate, sodium ethylate, potassium ethylate etc., suitable mineral alkali comprises: sheet alkali, potassium hydroxide, yellow soda ash, sodium bicarbonate etc.
In step (D), the used suitable metal catalyst of shortening is for making platinum, palladium, rhodium catalyst or the Raney's nickel catalyst of carrier with activated carbon, and suitable pH value is 5.0-11.
In step (E), suitable fixedly acylase, fixedly acylase is PGK-400, suitable pH value is 6-9.
The present invention finds in test: if employing 7-phenylacetyl ammonia-3-hydroxyl-3-cephalo-4-carboxylic acid-the nitrobenzyl ester is made starting raw material, then under cold condition during with the two key between 3 and 4 of POTASSIUM BOROHYDRIDE or the sodium borohydride reductions, 4 ester groups are not reduced into alcohol.More ironically, when using catalytic hydrogenation method to remove 4 carboxy protectives, the two keys between 3 and 4 are not reduced.
The present invention reclaims and uses noble metal catalyst and enzyme catalyst, and the mode friendly with environment obtains product 7-ANCA.It avoids using PCl
5Deng the bigger raw material of environmental pollution, avoid using raw materials such as expensive trifluoroacetic acid simultaneously.Whole simple for process, both improved quality product, reduce production cost again, and reduced environmental pollution.
Embodiment
Following examples are intended to illustrate essence of the present invention, unrestricted implementation of the present invention.
Reaction raw materials: 7-phenylacetyl ammonia-3-hydroxyl-3-cephalo-4-carboxylic acid-to the nitrobenzyl ester, hereinafter to be referred as 3-hydroxy-cepham compound 19
Embodiment 1
There-necked flask (band thermometer, mechanical stirring) at 500ml takes by weighing 46.9g 3-hydroxy-cepham compound 19 (0.1mol), adds the dissolving of 200ml tetrahydrofuran (THF).Cool to-30 ℃, add 5.4g POTASSIUM BOROHYDRIDE (0.1mol).Continue to cool to-60 ℃, slowly drip 100ml ethanol.Dropwise the back and continue reaction 1 hour, sampling is carried out HPLC and is detected, control reaction raw materials 19 content≤0.5%.Add the 400ml purified water, slowly be warmed up to room temperature, separate out solid.Reclaim under reduced pressure tetrahydrofuran solvent at room temperature.Filter, drying gets 42.39g white solid product 20 (molar yield is 90%, and HPLC area normalization method content is 98%).
In the there-necked flask of 1000ml, add 42.3g the said products 20 (0.09mol), add the dissolving of 300ml tetrahydrofuran (THF).Cool to-15 ℃, add 13.7g Methanesulfonyl chloride (0.12mol), stirred 10 minutes.Drip 13.1g triethylamine (0.13mol) and form intermediate 21.Sampling is carried out HPLC and is detected, control reaction raw materials 20 content≤0.4%.Add 20.8ml diethylamine (0.2mol), stir adding 100ml water after 2 hours under the room temperature, separate out solid phase prod 22.Filter, add the 600ml tetrahydrofuran (THF), be warmed up to 40-50 ℃ of dissolving filter cake.With soda ash control pH value is 7.5-8.0, adds 10g palladium/carbon metal catalyst (palladium content weight ratio is 5%).Drive air away with nitrogen, normal pressure fed hydrogen 3-4 hour.Sampling is carried out HPLC and is detected, control reaction raw materials 22 content≤1.0%.Filtered and recycled palladium/carbon.At room temperature in the reclaim under reduced pressure filtrate behind the tetrahydrofuran solvent, add 300ml water dissolution viscous material 23.Add fixedly acylase PGK-400 of 40g, keep 30-33 ℃, use 5%Na
2CO
3Solution control pH value 7-8.Sampling is carried out HPLC and is detected, control reaction raw materials 23 content≤0.5%.Filtered and recycled is acylase fixedly.Collect filtrate, filtrate is cooled to 0 ℃.Regulate pH value to 2.5 with 2N hydrochloric acid, separate out white solid.Filter, drying under reduced pressure obtains white solid powder-product 7-ANCA 8.1g (calculate with intermediate 20, molar yield is 45%).
The product optical value :+247 °～+ 253 ° (the 1%7-ANCA product is dissolved in 0.1N Na
2CO
3Solution).
IR(Nicolet，KBr)：3182cm
-1，1803cm
-1，1614cm
-1，1547cm
-1，1531cm
-1，1417cm
-1，1350cm
-1。
1HNMRδ(Bruke?Adance500MHz，D
2O+NaHCO
3，ppm)：3.28(1H，d，J＝18.81，6.31Hz)；3.52(1H，d，J＝18.84，2.48Hz)；4.65(1H，d，J＝4.92Hz)；4.91(1H，d，J＝4.98Hz)；6.12(1H，d，J＝8.82，2.49Hz)。
Embodiment 2
There-necked flask (band thermometer, mechanical stirring) at 500ml takes by weighing 46.9g 3-hydroxy-cepham compound 19 (0.1mol), adds methylene dichloride 200ml dissolving.Cool to-30 ℃, add 4.18g sodium borohydride (0.11mol).Continue to cool to-55 ℃, slowly drip 100ml methyl alcohol.Dropwise the back and continue reaction 1 hour, sampling is carried out HPLC and is detected, control reaction raw materials 19 content≤0.5%.Add the 400ml purified water, slowly be warmed up to room temperature, separate out solid.At room temperature reclaim under reduced pressure methylene dichloride and methanol solvate.Filter, drying gets 41.5g white solid product 20 (molar yield is 88%, and HPLC area normalization method content is 98.5%).
In the there-necked flask of 1000ml, add 41.4g the said products 20 (0.088mol), add the dissolving of 350ml tetrahydrofuran (THF).Cool to-15 ℃, add 22.8g Tosyl chloride (0.12mol), stirred 10 minutes.Drip the 25ml tri-n-butylamine and form intermediate 21.Sampling is carried out HPLC and is detected, control reaction raw materials 20 content≤0.4%.Add 20.1g dipropyl amine (0.2mol), stirring at room adds 100ml water after 2 hours, separate out solid phase prod 22.Filter, add 600ml 1,4-dioxane dissolving filter cake is warmed up to room temperature.At 6.5-8.0, add 10g 5% platinum/carbon with soda ash control pH value.Drive air away with nitrogen, fed hydrogen 3-4 hour.Sampling is carried out HPLC and is detected, control reaction raw materials 22 content≤1.0%.Filtered and recycled platinum/carbon.At room temperature in the reclaim under reduced pressure filtrate behind the solvent, add 300ml water dissolution viscous material 23, add fixedly acylase PGK-400 of 40g then.Keep 30-33 ℃, use 5%Na
2CO
3Solution control pH value 7-8.Sampling is carried out HPLC and is detected, control reaction raw materials 23 content≤0.5%.Filtered and recycled is acylase fixedly.Collect filtrate, filtrate is cooled to 0 ℃.Regulate pH value to 2.5 with 2N hydrochloric acid, separate out white solid.Filter, drying under reduced pressure obtains product 7-ANCA 11.79g (0.059mol calculates with intermediate 20, and molar yield is 67%).
Embodiment 3
There-necked flask (band thermometer, mechanical stirring) at 500ml takes by weighing 46.9g 3-hydroxy-cepham compound 19 (0.1mol), adds the dissolving of 100ml methylene dichloride and 100ml tetrahydrofuran (THF).Cool to-30 ℃, add 5.4g POTASSIUM BOROHYDRIDE (0.1mol) (0.11mol).Continue to cool to-60 ℃, slowly drip 100ml ethanol.Dropwise the back and continue reaction 1 hour, sampling is carried out HPLC and is detected, control reaction raw materials 19 content≤0.5%.Add the 400ml purified water, slowly be warmed up to room temperature, separate out solid.At room temperature reclaim under reduced pressure methylene dichloride and tetrahydrofuran solvent.Filter, drying gets 43g white solid 20 (molar yield is 91.3%, and HPLC area normalization method content is 98.7%).
In the there-necked flask of 1000ml, add 43g the said products 20 (0.0913mol), add 1,4-dioxane 300ml.Cool to-15 ℃, add 19.3g ethyl chloride (0.15mol), stirred 10-25 minute.Drip 15.15g triethylamine (0.15mol) and form intermediate 21.Sampling is carried out HPLC and is detected, control reaction raw materials 20 content≤0.4%.Add 10.8g sodium methylate (0.2mol), stirring at room adds 100ml water after 2 hours, separate out solid phase prod 22.Filter, filter cake washing back adds 600ml dissolve with methanol filter cake, is warmed up to room temperature.At 6.5-8.0, add 10g 5% palladium/carbon with soda ash control pH value.Drive air away with nitrogen, fed hydrogen 3-4 hour.Sampling is carried out HPLC and is detected, control reaction raw materials 22 content≤1.0%.Reclaim palladium/carbon.At room temperature in the reclaim under reduced pressure filtrate behind the solvent, add 300ml water dissolution viscous material 23, add fixedly acylase PGK-400 of 40g then.Keep 30-33 ℃, with 5% sodium hydroxide solution control pH value 7-8.Sampling is carried out HPLC and is detected, control reaction raw materials 23 content≤0.5%.Reclaim fixedly acylase.Collect filtrate, filtrate is cooled to 0 ℃.Regulate PH to 2.5 with 2N hydrochloric acid, separate out white solid.Filter, drying under reduced pressure obtains product 7-ANCA 14.5g (calculate with intermediate 20, molar yield is 79.2%).
Embodiment 4
Be prepared into 43g white solid 20 with embodiment 3.
In the there-necked flask of 1000ml, add 150mll tetrahydrofuran (THF) and 150ml acetone solution 43g white solid 20 (0.0913mol).Cool to-15 ℃, add 19.1g sulfonyloxy methyl bromine (0.12mol), stirred 10 minutes.Drip 10.1g pyridine (0.128mol) and form intermediate 21.Sampling is carried out HPLC and is detected, control reaction raw materials 20 content≤0.4%.Add 13.6g sodium ethylate (0.2mol), stirring at room adds 100ml water after 2 hours, separate out solid phase prod 22.Filter, add 300mL dissolve with ethanol filter cake, be warmed up to room temperature.At 6.5-8.0, add 10g 5% palladium/carbon with soda ash control pH value.Drive air away with nitrogen, fed hydrogen 3-4 hour.Sampling is carried out HPLC and is detected, control reaction raw materials 22 content≤1.0%.Reclaim palladium/carbon.At room temperature in the reclaim under reduced pressure filtrate behind the solvent, add 300ml water dissolution viscous material 23.Add fixedly acylase PGK-400 of 40g, keep 30-33 ℃.With 5% soda ash solution control pH value is 7-8.Sampling is carried out HPLC and is detected, control reaction raw materials 23 content≤0.5%.Reclaim fixedly acylase.Collect filtrate, filtrate is cooled to 0 ℃.Regulate PH to 2.5 with 2N hydrochloric acid, separate out white solid.Filter, drying under reduced pressure obtains product 13.02g 7-ANCA (calculate with intermediate 20, molar yield is 70%).
Embodiment 5
Be prepared into 43g white solid 20 with embodiment 3.
In the there-necked flask of 1000ml, add 150ml methyl alcohol and 150ml acetone solution 43g white solid 20 (0.0913mol).Cool to-15 ℃, add 14.8 Methanesulfonyl chlorides (0.13mol), stirred 10 minutes.Drip 13.2gN-methylmorpholine (0.13mol) and form intermediate 21.Sampling is carried out HPLC and is detected, control reaction raw materials 20 content≤0.4%.Add 27.1g dibutylamine (0.21mol), stirring at room adds 100ml water after 2 hours, separate out solid 22.Filter, add 30ml water and 300ml acetonitrile, be warmed up to 40-50 ℃ of dissolving.At 7.5-8.0, add 2g 50% Raney's nickel with soda ash control pH value.Drive air away with nitrogen, fed hydrogen 3-4 hour.Sampling is carried out HPLC and is detected, control reaction raw materials 22 content≤1.0%.Nitrogen purging, the filtered and recycled Raney's nickel.At room temperature in the reclaim under reduced pressure filtrate behind the acetonitrile, add 300ml water dissolution viscous material 23.Add fixedly acylase PGK-400 of 40g, keep 30-33 ℃.With 5% soda ash solution control pH value is 7-8.Sampling is carried out HPLC and is detected, control reaction raw materials 23 content≤0.5%.Reclaim fixedly acidylate enzyme.Collect filtrate, filtrate is cooled to 0 ℃.Regulate PH to 2.5 with 2N hydrochloric acid, separate out white solid.Filter, the decompression drying at room temperature gets product 7-ANCA 14.6g (calculate with intermediate 20, molar yield is 80%).
Claims (9)
1, a kind of 7-amino-3-does not have-preparation method of cephalo-4-carboxylic acid, it is characterized in that: with 7-phenylacetyl ammonia-3-hydroxyl-3-cephalo-4-carboxylic acid-to nitrobenzyl ester 19 is raw material, gets intermediate 20 with the two keys between 3 and 4 of the metal borohydride reduction parent nucleus earlier; Get intermediate 21 with 3 hydroxyls of sulfuryl halide esterification then; Remove 3 methylsulphonic acid ester groups with alkali again and get intermediate 22 with the two keys that recover between 3 and 4; Remove 4 protecting groups on the carboxyl with the shortening method at last and get intermediate 23; The protecting group that removes on 7 bit aminos with enzymolysis process gets product 7-ANCA1; The reaction formula of each step is as follows:
R is methyl, ethyl or p-methylphenyl in the formula, and X is a chlorine or bromine.
2, preparation method according to claim 1, it is characterized in that: in step (A), two used reductive agents of key are POTASSIUM BOROHYDRIDE or sodium borohydride between 3 and 4 of the parent nucleus of reduction, temperature of reaction is-70 ℃-50 ℃, and reaction solvent is halogenated hydrocarbon solvent, protonic solvent or low boiling-point and polarity aprotic solvent.
3, preparation method according to claim 2 is characterized in that: described halogenated hydrocarbon solvent comprises: methylene dichloride, chloroform, 1,2-ethylene dichloride, 1, one or more mixing of 2-monobromethane; Protonic solvent comprises: one or more mixing of methyl alcohol, ethanol, propyl alcohol, butanols; The low boiling-point and polarity aprotic solvent comprises: amides, sulfoxide class, nitrile or ethers; Described amides is N, dinethylformamide, N,N-dimethylacetamide; The sulfoxide class is a dimethyl sulfoxide (DMSO); Nitrile is an acetonitrile; Ethers is the two ether of tetrahydrofuran (THF), dioxane, diethylene glycol monoethyl ether or glycol ether.
4, preparation method according to claim 1 is characterized in that: in step (B), described etheride is Methanesulfonyl chloride, ethyl chloride, sulfonyloxy methyl bromine, ethyl sulfuryl bromide or Tosyl chloride; Alkali be organic bases or mineral alkali as acid binding agent, temperature of reaction is-55 ℃-50 ℃, reaction solvent is halogenated hydrocarbon solvent, protonic solvent or low boiling-point and polarity aprotic solvent.
5, preparation method according to claim 4 is characterized in that: described organic bases comprises: triethylamine, tri-n-butylamine, trioctylamine, pyridine, pyrimidine, methylmorpholine, N, accelerine, sodium methylate, sodium ethylate; Mineral alkali comprises: sheet alkali, potassium hydroxide, yellow soda ash, sodium bicarbonate.
6, preparation method according to claim 4 is characterized in that: described halogenated hydrocarbon solvent comprises: methylene dichloride, chloroform, 1,2-ethylene dichloride, 1, one or more mixing of 2-monobromethane; Protonic solvent comprises: one or more mixing of methyl alcohol, ethanol, propyl alcohol, butanols; The low boiling-point and polarity aprotic solvent comprises: amides, sulfoxide class, nitrile and ethers; Described amides is N, dinethylformamide, N,N-dimethylacetamide; The sulfoxide class is a dimethyl sulfoxide (DMSO); Nitrile is an acetonitrile; Ethers is the two ether of tetrahydrofuran (THF), dioxane, diethylene glycol monoethyl ether or glycol ether.
7, preparation method according to claim 1, it is characterized in that: in step (C), removing the used alkali of sulphonate comprises: triethylamine, diethylamine, tri-n-butylamine, trioctylamine, pyridine, pyrimidine, methylmorpholine, N, accelerine, sodium methylate, sodium ethylate, potassium ethylate, sheet alkali, potassium hydroxide, yellow soda ash or sodium bicarbonate.
8, preparation method according to claim 1 is characterized in that: in step (D), the used catalyzer of shortening comprises: make platinum, rhodium, palladium catalyst or the Raney's nickel catalyst of carrier with activated carbon, the pH value scope is 5-11.
9, preparation method according to claim 1 is characterized in that: in step (E), remove that the used fixedly acylase of protecting group is PGK-400 on 7 bit aminos, the pH value scope is 6-9.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102021211A (en) * | 2010-11-18 | 2011-04-20 | 浙江普洛得邦制药有限公司 | Method for preparing 7-amino-3-nor-3-cephalo-4-carboxylic acid |
| CN102140103A (en) * | 2011-01-24 | 2011-08-03 | 石家庄柏奇化工有限公司 | Method for preparing 7-amino-3-hydro cephalosporanic acid by taking penicillin G/K as raw material |
| CN102180888A (en) * | 2011-03-02 | 2011-09-14 | 河北科技大学 | Preparation method for 7-amino-3-non-3-cephem-4-carboxylic acid(7-ANCA) |
| CN102558198A (en) * | 2011-12-29 | 2012-07-11 | 北京通瑞源医药研究院有限公司 | Novel process for synthesizing 7-amiro-3-nor-cephem-4-carboxyl icacid (7-ANCA) |
| CN102702229A (en) * | 2011-08-04 | 2012-10-03 | 重庆天地药业有限责任公司 | Preparation of ceftizoxime sodium key intermediate and preparation of high-content ceftizoxime sodium |
| CN105315299A (en) * | 2015-09-22 | 2016-02-10 | 盐城开元医药化工有限公司 | Synthesis method of ceftizoxime mother nucleus 7-ANCA |
| CN107383062A (en) * | 2017-08-31 | 2017-11-24 | 湖北凌晟药业有限公司 | The ANCE of Ceftibuten parent nucleus 7 preparation method |
| CN113563365A (en) * | 2021-08-17 | 2021-10-29 | 华中药业股份有限公司 | Preparation method of 7-amino-3-methoxy-4-cephalosporanic acid |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102021211A (en) * | 2010-11-18 | 2011-04-20 | 浙江普洛得邦制药有限公司 | Method for preparing 7-amino-3-nor-3-cephalo-4-carboxylic acid |
| CN102140103A (en) * | 2011-01-24 | 2011-08-03 | 石家庄柏奇化工有限公司 | Method for preparing 7-amino-3-hydro cephalosporanic acid by taking penicillin G/K as raw material |
| CN102180888A (en) * | 2011-03-02 | 2011-09-14 | 河北科技大学 | Preparation method for 7-amino-3-non-3-cephem-4-carboxylic acid(7-ANCA) |
| CN102180888B (en) * | 2011-03-02 | 2014-02-12 | 河北科技大学 | Preparation method for 7-amino-3-non-3-cephem-4-carboxylic acid(7-ANCA) |
| CN102702229A (en) * | 2011-08-04 | 2012-10-03 | 重庆天地药业有限责任公司 | Preparation of ceftizoxime sodium key intermediate and preparation of high-content ceftizoxime sodium |
| CN102558198B (en) * | 2011-12-29 | 2016-08-10 | 中科医药行业生产力促进中心有限公司 | A kind of preparation method of 7-ANCA |
| CN102558198A (en) * | 2011-12-29 | 2012-07-11 | 北京通瑞源医药研究院有限公司 | Novel process for synthesizing 7-amiro-3-nor-cephem-4-carboxyl icacid (7-ANCA) |
| CN105315299A (en) * | 2015-09-22 | 2016-02-10 | 盐城开元医药化工有限公司 | Synthesis method of ceftizoxime mother nucleus 7-ANCA |
| CN105315299B (en) * | 2015-09-22 | 2017-06-27 | 盐城开元医药化工有限公司 | A kind of synthetic method of the ANCA of Ceftizoxime parent nucleus 7 |
| CN107383062A (en) * | 2017-08-31 | 2017-11-24 | 湖北凌晟药业有限公司 | The ANCE of Ceftibuten parent nucleus 7 preparation method |
| CN107383062B (en) * | 2017-08-31 | 2019-11-05 | 湖北凌晟药业有限公司 | The preparation method of Ceftibuten parent nucleus 7-ANCE |
| CN113563365A (en) * | 2021-08-17 | 2021-10-29 | 华中药业股份有限公司 | Preparation method of 7-amino-3-methoxy-4-cephalosporanic acid |
| CN113563365B (en) * | 2021-08-17 | 2024-05-28 | 华中药业股份有限公司 | Preparation method of 7-amino-3-methoxy-4-cephalosporanic acid |
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