CN1962666A - Cepham antibiotics and its intermediate preparation method - Google Patents
Cepham antibiotics and its intermediate preparation method Download PDFInfo
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- CN1962666A CN1962666A CN 200610098099 CN200610098099A CN1962666A CN 1962666 A CN1962666 A CN 1962666A CN 200610098099 CN200610098099 CN 200610098099 CN 200610098099 A CN200610098099 A CN 200610098099A CN 1962666 A CN1962666 A CN 1962666A
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Abstract
The invention discloses a preparing method of cepham compound with general formula (I) as key intermediate of antibiotic drug, which is characterized by the following: substituting 3-position through mother core 7-ACA to obtain intermediate (IV); acylating 7-amino of intermediate (IV); esterifying 4-carboxyl to obtain the product.
Description
Technical field
The present invention relates to prepare the novel method of cephalosporin compound and intermediate thereof.Specifically, be exactly 3 substitution reactions by cephalo parent nucleus 7-ACA, obtain intermediate (IV); 7 bit amino generation acylation reactions of intermediate (IV); obtain intermediate (VI), 4 carboxyl generation esterifications of intermediate (VI) prepare cephalosporin compound.
Background information
Cephalosporin compound is the extremely important antibiotic medicine commonly used of a class, by to 3 of cephalo parent nucleus 7-ACA, 4,7 structural modification, can prepare some important cephalosporins medicines, as (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid pivalyl oxygen methyl esters (C).
At patent US 5; described its preparation method in 144,027, the intermediate that this method obtains (VI) purity is low; there is isomer; and intermediate (VI) is 4 carboxyl esterification reactions earlier, and low, the easy moisture absorption of its product content is unfavorable for suitability for industrialized production; last 7 bit amino acylation reactions; reaction is incomplete, and unreacted reactant is difficult for removing, and product is difficult to purifying.
Summary of the invention
The novel method that the purpose of this invention is to provide a kind of preparation (C).
The detailed description of the invention is as follows: the present invention is the method for preparing structural formula compound shown in the general formula (I) and intermediate thereof,
Wherein:
R
1Be hydrogen atom;
R
2Optional from ethanoyl, 2-(thiazolamine-4-yl)-2-(methoxy imino) ethanoyl, 2-[(4-ethyl-2,3-dioxy-piperazine-1-yl)-formamido group]-2-is to hydroxyphenyl ethanoyl, (2-methylamino-phenyl) ethanoyl, phenylacetyl, benzenesulfonyl or 2-chloracetyl;
R
3Be hydrogen atom or trimethylacetic acid methoxycarbonyl,
This preparation method is: compound (II) generates intermediate (IV) with compound (III) reaction, and intermediate (IV) generates intermediate (VI) with compound (V) reaction, last intermediate (VI) and compound (VII) reacting generating compound (I),
R wherein
2Same compound (I), R
4Optional from hydroxyl, amino, oxyethyl group, benzotriazole-1-oxygen base or benzothiazole-2-sulfenyl
R wherein
3Same compound (I), R
5Be halogen atom
Its reaction conditions is:
(1) compound (II) and compound (III) be in solvent orange 2 A, BF
3Have reaction down, temperature of reaction is-8～40 ℃, and the reaction times is 2 hours to 24 hours;
(2) intermediate (IV) and compound (V) temperature of reaction are-5～40 ℃, and the reaction times is 1 hour to 10 hours, and reaction finishes through the water extraction, and water layer is 1～5 by regulating pH value, gets intermediate (VI);
(3) intermediate (VI) is in the presence of catalyst B with compound (VII) reaction, and temperature of reaction is-15～25 ℃, and the reaction times is 30 minutes to 10 hours; protection of inert gas is reacted; reaction solution is treated, under agitation directly is added drop-wise to crystallization among the solvent D, obtains compound (I).
In the above-mentioned reaction, solvent orange 2 A is ether, toluene, ethyl chloroacetate, ethyl acetate or diethyl oxalate.
Preferred solvent orange 2 A is ethyl chloroacetate or diethyl oxalate, and particularly preferred solvent orange 2 A is an ethyl chloroacetate.
Catalyst B is diethylamine, triethylamine, DBU or dimethylamine.
Preferred catalyst B is triethylamine or DBU.Most preferred catalyst B is DBU.
Solvent D is ether, normal hexane, hexanaphthene, isopropyl ether.
Preferred solvent D is isopropyl ether or normal hexane.Most preferred solvent D is an isopropyl ether.
Preferred compound (V) is A.E. active ester or cefotaxime ethyl ester.
Preferred compound (VII) is trimethylacetic acid iodine methyl esters or chloromethyl pivalate.
Compound (II) is chosen as 25～35 ℃ with compound (III) optimal reaction temperature, and optimum reacting time is chosen as 10 hours to 20 hours.
Intermediate (IV) is chosen as 15～25 ℃ with compound (V) optimal reaction temperature, and optimum reacting time is chosen as 3 hours to 7 hours.
Intermediate (VI) is chosen as 5～10 ℃ with compound (VII) optimal reaction temperature, and optimum reacting time is chosen as 2 hours to 5 hours.
The invention has the beneficial effects as follows easy and simple to handlely, it is all very high that each goes on foot intermediate purity.Method of the present invention can react fully and carry out, and each goes on foot the high and easy purifying of product yield.In addition, the present invention also can be used for suitability for industrialized production.
Embodiment
The present invention will be described below by non-limiting example.
Embodiment 1
(HPLC 95.6%, 0.091mol) is added to 100ml ethyl chloroacetate and 18g BF respectively with 11.5g 5-methyl tetrazole with 25.9g 7-ACA
3In, be warming up to 25 ℃ and kept 20 hours, then reaction solution is joined in the 140g frozen water, concuss, the separating funnel layering, water layer is regulated PH to 2.5 with 30% aqueous sodium hydroxide solution, stirs 10 minutes.
Filter and collect the solid of separating out, filter cake is used 40ml water, the cold washing with alcohol of 20ml successively, and 40 ℃ of following vacuum-dryings obtain 21.8g 7-amino-3-[2-(5-methyl-2H-tetrazole base) methyl] and Cephalosporanic acid (98.2%, HPLC) (yield 79.5%).
With 20g 7-amino-3-[2-(5-methyl-2H-tetrazole base) methyl] (HPLC 98.2%, 0.0664mol) is added in the 130ml toluene, stirs to be suspension for Cephalosporanic acid, 5 ℃ add the 7.59g triethylamine down, add 26.1g cefotaxime ethyl ester after 5 minutes, keep 25 ℃ of temperature, reacted 3 hours.
Reaction solution water 30ml * 2 extractions, layering, water layer is regulated pH value with 3N HCl, pH value is greater than 4.5, the gained sedimentation and filtration is removed, and the gained sedimentation and filtration is collected between the pH value 2.5-4.5, Vanadium Pentoxide in FLAKES vacuum-drying, obtain 22g 7-[2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (96.7%, HPLC) (yield 67%).
With 15g 7-[2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-(HPLC 96.7% for 2-formic acid; 0.0303mol); join in the 100ml ethyl acetate; when being 5 ℃, temperature adds 4.6g DBU (1; 8-diazabicyclo [5.4.0] hendecene); be stirred to dissolving; under nitrogen protection; add 7.33g trimethylacetic acid iodine methyl esters, keep 10 ℃ of reactions of temperature 2 hours.
Reaction solution is used 50ml 10%HCl successively, 50ml 10% sodium hydrogen carbonate solution, the 50ml water washing, layering, organic layer slowly joins in the 300ml isopropyl ether, separate out the white solid precipitation, filter, filter cake washs with the 50ml isopropyl ether, room temperature vacuum-drying filter cake, obtain 10.2g (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid pivalyl oxygen methyl esters (96.1%, HPLC) (yield 54.4%).
Embodiment 2
(HPLC 95.6%, 0.091mol) is added to 150ml diethyl oxalate and 18g BF respectively with 11.5g 5-methyl tetrazole with 25.9g 7-ACA
3In, be warming up to 35 ℃ and kept 10 hours, then reaction solution is joined in the 140g frozen water, concuss, the separating funnel layering, water layer is regulated PH to 4.5 with 30% aqueous sodium hydroxide solution, stirs 10 minutes.
Filter and collect the solid of separating out, filter cake is used 40ml water, the cold washing with alcohol of 20ml successively, and 40 ℃ of following vacuum-dryings obtain 20.1g 7-amino-3-[2-(5-methyl-2H-tetrazole base) methyl] and Cephalosporanic acid (98.2%, HPLC) (yield 73.3%).
With 20g 7-amino-3-[2-(5-methyl-2H-tetrazole base) methyl] (HPLC 98.2%, 0.0664mol) is added in the 130ml methylene dichloride, stirs to be suspension for Cephalosporanic acid, 5 ℃ add the 7.59g triethylamine down, add the 30gA.E. active ester after 5 minutes, keep 15 ℃ of temperature, reacted 7 hours.
Reaction solution water 30ml * 2 extractions, layering, water layer is regulated pH value with 3N HCl, pH value is greater than 4.5, the gained sedimentation and filtration is removed, and the gained sedimentation and filtration is collected between the pH value 2.5-4.5, Vanadium Pentoxide in FLAKES vacuum-drying, obtain 22.2g 7-[2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5 thias-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (95%, HPLC) (yield 66.4%).
With 15g 7-[2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-(HPLC 95% for 2-formic acid; 0.0297mol); join in the 150ml ethyl acetate; when being 10 ℃, temperature adds the 3.4g triethylamine; be stirred to dissolving; under nitrogen protection, add the 6.85g chloromethyl pivalate, keep 5 ℃ of reactions of temperature 5 hours.
Reaction solution is used 50ml 10%HCl successively, 50ml 10% sodium hydrogen carbonate solution, the 50ml water washing, layering, organic layer slowly joins in the 320ml normal hexane, separate out the white solid precipitation, filter, filter cake washs with the 50ml normal hexane, room temperature vacuum-drying filter cake, obtain 9.3g (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid pivalyl oxygen methyl esters (95.7%, HPLC) (yield 50.4%).
Embodiment 3
(HPLC 95.6%, 0.091mol) is added to 100ml ethyl acetate and 20g BF respectively with 11.5g 5-methyl tetrazole with 25.9g 7-ACA
3In, be warming up to 30 ℃ and kept 15 hours, then reaction solution is joined in the 140g frozen water, concuss, the separating funnel layering, water layer is regulated PH to 2.5 with 30% aqueous sodium hydroxide solution, stirs 10 minutes.
Filter and collect the solid of separating out, filter cake is used 40ml water, the cold washing with alcohol of 20ml successively, and 40 ℃ of following vacuum-dryings obtain 22.6g 7-amino-3-[2-(5-methyl-2H-tetrazole base) methyl] and Cephalosporanic acid (98.2%, HPLC) (yield 82.4%).
With 20g 7-amino-3-[2-(5-methyl-2H-tetrazole base) methyl] (HPLC 98.2%, 0.0664mol) is added in the 130ml toluene, stirs to be suspension for Cephalosporanic acid, 5 ℃ add the 7.59g triethylamine down, add 28.4g cefotaxime ethyl ester after 5 minutes, keep 20 ℃ of temperature, reacted 5 hours.
Reaction solution water 30ml * 2 extractions, layering, water layer is regulated pH value with 3N HCl, pH value is greater than 4.5, the gained sedimentation and filtration is removed, and the gained sedimentation and filtration is collected between the pH value 2.5-4.5, Vanadium Pentoxide in FLAKES vacuum-drying, obtain 21.3g 7-[2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid (97.3%, HPLC) (yield 65.3%).
With 15g 7-[2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-(HPLC 97.3% for 2-formic acid; 0.0305mol); join in the 100ml ethyl acetate; when being 5 ℃, temperature adds 4.6g DBU (1; 8-diazabicyclo [5.4.0] hendecene); be stirred to dissolving; under nitrogen protection; add 7.33g trimethylacetic acid iodine methyl esters, keep 8 ℃ of reactions of temperature 4 hours.
Reaction solution is used 50ml 10%HCl successively, 50ml 10% sodium hydrogen carbonate solution, 50ml * 2 water washings, layering, organic layer slowly joins in the 400ml hexanaphthene, separate out the white solid precipitation, filter, filter cake washs with the 50ml isopropyl ether, room temperature vacuum-drying filter cake, obtain 11.7g (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid pivalyl oxygen methyl esters (96.5%, HPLC) (yield 62.6%).
Claims (10)
1. one kind prepares the cephalosporin compound shown in the general formula (I) and the method for intermediate thereof,
Wherein: R
1Be hydrogen atom; R
2Optional from ethanoyl, 2-(thiazolamine-4-yl)-2-(methoxy imino) ethanoyl, 2-[(4-ethyl-2,3-dioxy-piperazine-1-yl)-formamido group]-2-is to hydroxyphenyl ethanoyl, (2-methylamino-phenyl) ethanoyl, phenylacetyl, benzenesulfonyl or 2-chloracetyl; R
3Be hydrogen atom or trimethylacetic acid methoxycarbonyl,
This preparation method is: compound (II) generates intermediate (IV) with compound (III) reaction, and intermediate (IV) generates intermediate (VI) with compound (V) reaction, last intermediate (VI) and compound (VII) reacting generating compound (I),
R
2R
4 (V)
R wherein
2Same compound (I), R
4Optional from hydroxyl, amino, oxyethyl group, benzotriazole-1-oxygen base or benzothiazole-2-sulfenyl
R
3R
5 (VII)
R wherein
3Same compound (I), R
5Be halogen atom
It is characterized in that:
(1) compound (II) and compound (III) be in solvent orange 2 A, BF
3Have reaction down, temperature of reaction is-8～40 ℃, and the reaction times is 2 hours to 24 hours, obtains intermediate (IV);
(2) intermediate (IV) reacts with compound (V), and temperature of reaction is-5～40 ℃, and the reaction times is 1 hour to 10 hours, and reaction finishes through the water extraction, and water layer is 1～5 by regulating pH value, gets intermediate (VI);
(3) intermediate (VI) is in the presence of catalyst B with compound (VII) reaction, and temperature of reaction is-15～25 ℃, and the reaction times is 30 minutes to 10 hours; protection of inert gas is reacted; reaction solution is treated, under agitation directly is added drop-wise to crystallization among the solvent D, obtains compound (I).
2. according to the method for claim 1, it is characterized in that solvent orange 2 A is ether, toluene, ethyl chloroacetate, ethyl acetate or diethyl oxalate; Catalyst B is diethylamine, triethylamine, DBU or dimethylamine; Solvent D is ether, normal hexane, hexanaphthene, isopropyl ether.
3. according to the method for claim 2, it is characterized in that solvent orange 2 A is ethyl chloroacetate or diethyl oxalate; Catalyst B is triethylamine or DBU; Solvent D is isopropyl ether or normal hexane.
4. according to the method for claim 3, it is characterized in that solvent orange 2 A is an ethyl chloroacetate; Catalyst B is DBU; Solvent D is an isopropyl ether.
5. according to the method for claim 1, it is characterized in that compound (V) is A.E. active ester or cefotaxime ethyl ester.
6. according to the method for claim 1, it is characterized in that compound (VII) is trimethylacetic acid iodine methyl esters or chloromethyl pivalate.
7. according to the method for claim 1, it is characterized in that compound (II) and compound (III) temperature of reaction are 25～35 ℃, the reaction times is 10 hours to 20 hours.
8. according to the method for claim 1, it is characterized in that intermediate (IV) and compound (V) temperature of reaction are 15～25 ℃, the reaction times is 3 hours to 7 hours.
9. according to the method for claim 1, it is characterized in that intermediate (VI) and compound (VII) temperature of reaction are 5～10 ℃, the reaction times is 2 hours to 5 hours.
10. according to the method for claim 1, compound shown in the general formula (I) that it is characterized in that preparing for (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) kharophen]-3-[2-(5-methyl-2H-tetrazole base) methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid pivalyl oxygen methyl esters.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351886A (en) * | 2011-09-07 | 2012-02-15 | 山东罗欣药业股份有限公司 | Cefteram pivoxil crystal and preparation method thereof and composition tablets containing crystal |
| CN102633815A (en) * | 2012-03-30 | 2012-08-15 | 李莎 | Cefoxitin esterified prodrug compound and oral preparation thereof |
| CN106046026A (en) * | 2016-06-30 | 2016-10-26 | 济南康和医药科技有限公司 | Preparation method of cefteram pivoxil |
-
2006
- 2006-12-04 CN CN 200610098099 patent/CN1962666A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351886A (en) * | 2011-09-07 | 2012-02-15 | 山东罗欣药业股份有限公司 | Cefteram pivoxil crystal and preparation method thereof and composition tablets containing crystal |
| CN102351886B (en) * | 2011-09-07 | 2013-10-16 | 山东罗欣药业股份有限公司 | Cefteram pivoxil crystal and preparation method thereof and composition tablets containing crystal |
| CN102633815A (en) * | 2012-03-30 | 2012-08-15 | 李莎 | Cefoxitin esterified prodrug compound and oral preparation thereof |
| CN106046026A (en) * | 2016-06-30 | 2016-10-26 | 济南康和医药科技有限公司 | Preparation method of cefteram pivoxil |
| CN106046026B (en) * | 2016-06-30 | 2018-07-06 | 济南康和医药科技有限公司 | A kind of preparation method of cefteram pivoxil |
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Open date: 20070516 |