CN104693217A - Method for preparing cefixime - Google Patents

Method for preparing cefixime Download PDF

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Publication number
CN104693217A
CN104693217A CN201510090398.7A CN201510090398A CN104693217A CN 104693217 A CN104693217 A CN 104693217A CN 201510090398 A CN201510090398 A CN 201510090398A CN 104693217 A CN104693217 A CN 104693217A
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CN
China
Prior art keywords
cefixime
cefixime micronized
micronized
cephem
phenylacetamide
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CN201510090398.7A
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CN104693217B (en
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孙会
金城
顾士崇
裴文
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Shandong Changyi Sifang Pharmaceutical Chemical Co., Ltd.
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SHANDONG CHANGYI SIFANG PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D501/06—Acylation of 7-aminocephalosporanic acid

Abstract

The invention discloses a method for preparing cefixime. The method comprises the following steps: (A), adding quantitative 7-phenylacetamide-3-chloromethyl-3-cephem-4-p-methoxybenzyl carboxylate, magnesium powder and a solvent into a reaction container, and reacting at the temperature of 10-100 DEG C for 1-5 hours; (B), adding quantitative formaldehyde into the reaction system, and reacting at the temperature of 10-100 DEG C for 1-5 hours; (C) cooling to room temperature, dripping a proper amount of trifluoroacetic acid, stirring, performing after-treatment, thereby obtaining the mother nucleus of cefixime; (D) dissolving the obtained mother nucleus of cefixime in a proper amount of solvent, slowly adding quantitative cefixime side chain at the temperature of 10-30 DEG C, and reacting for 1-5 hours; and (E), performing after-treatment, thereby obtaining a cefixime trihydrate, wherein the solvents in the steps A and D refer to tetrahydrofuran, ethers with the carbon atom number of 1-10 and alkyl tetrahydrofuran with the carbon atom number of 1-10. The method disclosed by the invention is easy to operate, fewer in three wastes and convenient in aftertreatment and is an economical and practical technology.

Description

A kind of preparation method of Cefixime Micronized
Technical field
The present invention relates to a kind of synthetic method of Cefixime Micronized, particularly by 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid to the method preparing Cefixime Micronized methoxy benzyl ester (GCLE).
Background technology
Cefixime Micronized (Cefixime) is that Japanese Fujisawa Pharmaceutical developed and the oral cephem antibiotics of the third generation put goods on the market in 1987 in 1980, be characterized in that wide spectrum, efficient, resistance to enzyme, Plasma Concentration are high and lasting, transformation period is greater than Cefaclor and S 578, dosage is little, adverse drug reaction is low, is thus widely used clinically.(6R, 7R)-7-[[(Z)-2-(2-amino-4-thiazolyl)-2-(Carboxvmethoxv) imido grpup] ethanoyl] by name is amino for chemistry]-3-vinyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-carboxylic acid trihydrate.Structural formula is as shown in formula III:
At present, the synthesis of Cefixime Micronized mainly carries out large quantity research to the synthesis of Cefixime Micronized parent nucleus and Cefixime Micronized side chain.Cefixime Micronized side chain oneself realize suitability for industrialized production, can conveniently buy and low price, and to the study on the synthesis of Cefixime Micronized parent nucleus always constantly perfect, sum up and be mainly following several approach: 1) with deacetylation cynnematin for starting raw material, through hydrolysis, phenyllacetyl chloride acidylate, diphenyl diazomethane esterification, halogenation, Wittig reacts, and deaminizating obtains; 2) with 7-amino-3-acetyl-o-methyl-3-cephem-4-carboxylic acid (7-ACA) for raw material, through hydrolysis, phenyllacetyl chloride acidylate, the esterification of phenylbenzene triazonmethane, bromo, Wittig react, Deprotection obtain.Or first carry out above-mentioned reaction again through silicon etherification reaction and 4-position carboxy protective.3) take penicillin G as raw material, through esterification, after the obtained penicillin sulfoxide ester of oxidation, then through open loop, chlorination, Guan Huan, reduction, bromo, Wittig reaction and deaminizating, decarboxylation obtains.4) with 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid to methoxy benzyl ester (GCLE) for raw material, through Wittig reaction after, slough 7-bit amino protecting group, then with m-methyl phenol effect slough 4-position carboxyl-protecting group obtain; Or through Wittig reaction after, under phenol effect, slough 4-position carboxyl-protecting group, then slough under penicillin acylase effect 7-bit amino protecting group obtain.
Summary of the invention
Technical problem to be solved by this invention is, provides a kind of preparation method of synthesis Cefixime Micronized newly, and by changing reaction scheme and reaction conditions, the green synthesis method of research antibiotics, applies it to the synthesis field of antibiotics.
Technical scheme of the present invention: for solving above technical problem, the preparation method of Cefixime Micronized of the present invention, comprises the steps:
A, in reaction vessel, add the quantitative 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid as shown in formula I to methoxy benzyl ester, magnesium powder and solvent, react 1 ~ 5 hour at 10 ~ 100 DEG C of temperature;
B, in reaction system, add quantitative formaldehyde, react 1 ~ 5 hour at 10 ~ 100 DEG C of temperature;
C, be cooled to room temperature, drip appropriate trifluoroacetic acid, stir, obtain Cefixime Micronized parent nucleus through aftertreatment;
D, gained Cefixime Micronized parent nucleus is dissolved in appropriate solvent, at 10 ~ 30 DEG C of temperature, slowly adds quantitative Cefixime Micronized side chain, react 1 ~ 5 hour;
E, aftertreatment, obtain cefixime trihydrate,
Solvent described in steps A, D is tetrahydrofuran (THF), the ethers containing carbon atom 1 ~ 10 and the alkyl tetrahydro furans containing carbon atom 1 ~ 10.
Concrete reaction formula is as follows:
Described Cefixime Micronized side chain is 2-(2-amino-4-thiazole)-2-(Carboxvmethoxv) imido grpup] Acetyl Chloride 98Min., its structural formula is as shown in formula II.
Further, in steps A, the weight consumption of solvent for use is that 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid is to 1 ~ 10 of methoxy benzyl ester weight consumption times.
Further, described magnesium powder, formaldehyde and 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid are 1 ~ 1.5:1 ~ 1.5:1 to methoxy benzyl ester molar ratio.
Further, the mole dosage of described Cefixime Micronized side chain is that 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid is to 1 ~ 1.5 of methoxy benzyl ester mole dosage times.
Further, aftertreatment described in step C be to stir after reactant remove solvent under reduced pressure successively, add second alcohol and water, under cryosel bath cooling, regulate pH=7 with saturated sodium bicarbonate solution, separate out faint yellow solid, filter, with washed with diethylether, under Vanadium Pentoxide in FLAKES exists, obtain Cefixime Micronized parent nucleus in room temperature in vacuo drying.
Further, aftertreatment described in step e comprises successively and removes solvent under reduced pressure, adds appropriate Virahol and dissolves, regulate pH=2 ~ 3 with 15% hydrochloric acid, and placement at 0 ~ 5 DEG C, slowly crystallization obtains cefixime trihydrate.
The technology of the present invention is easy to operate, and the three wastes are few, convenient post-treatment, provides a kind of new approaches preparing Cefixime Micronized, is economical and practical new technology.
Embodiment
Embodiment 1
In 500 milliliters of there-necked flasks, add 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid to methoxy benzyl ester 4.9 grams (0.01 mole), 0.28 gram, magnesium powder (0.012 mole), methyltetrahydrofuran 20 grams, react at 50 DEG C after 2 hours, the methyltetrahydrofuran solution 20 milliliters of 0.4 gram, formaldehyde (0.012 mole) is slowly added drop-wise in reaction system, react 2 hours at 50 DEG C, reaction terminates, be cooled to room temperature, drip trifluoroacetic acid 35 milliliters, stirring at room temperature 30 minutes, remove solvent under reduced pressure, add 70% aqueous ethanolic solution 150 milliliters, under cryosel bath cooling, pH=7 is regulated with saturated sodium bicarbonate solution, separate out faint yellow solid gradually, filter, with washed with diethylether, under Vanadium Pentoxide in FLAKES exists, after room temperature in vacuo drying, be dissolved in methyltetrahydrofuran 100 milliliters, Cefixime Micronized side chain 3 grams (0.012 mole) is slowly added at 10 DEG C, react after 5 hours, remove solvent under reduced pressure, add Virahol 300 milliliters dissolving, pH=2 ~ 3 are regulated with 15% (quality) hydrochloric acid, place at 0 ~ 5 DEG C, slowly crystallization obtains cefixime trihydrate 4.5 grams, yield 88%, fusing point: 218 ~ 223 DEG C, measure with liquid chromatography HPLC, purity is 99.8%.
Test condition:
Detector: Waters2487;
Chromatographic column: Symmetry-C18,4.6 × 250mm;
Column temperature: 40 DEG C;
Moving phase: (8 grams of TBAH are dissolved in 800mL water to buffered soln 75%, and phosphoric acid adjusts pH=6.5;
Be diluted with water to 1000mL, then add 25% second eyeball;
Sample size: 20 μ l;
Flow velocity: 1.0Ml/min;
Wavelength: 253nm.
Embodiment 2
In 500 milliliters of there-necked flasks, add 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid to methoxy benzyl ester 4.9 grams (0.01 mole), 0.36 gram, magnesium powder (0.015 mole), methyltetrahydrofuran 30 grams, react at 30 DEG C after 5 hours, the methyltetrahydrofuran solution 20 milliliters of 0.45 gram, formaldehyde (0.015 mole) is slowly added drop-wise in reaction system, react 5 hours at 10 DEG C, reaction terminates, be cooled to room temperature, drip trifluoroacetic acid 35 milliliters, stirring at room temperature 30 minutes, remove solvent under reduced pressure, add 70% (quality) aqueous ethanolic solution 150 milliliters, under cryosel bath cooling, pH=7 is regulated with saturated sodium bicarbonate solution, separate out faint yellow solid gradually, filter, with washed with diethylether, under Vanadium Pentoxide in FLAKES exists, after room temperature in vacuo drying, be dissolved in methyltetrahydrofuran 100 milliliters, Cefixime Micronized side chain 3 grams (0.012 mole) is slowly added at 20 DEG C, react after 3 hours, remove solvent under reduced pressure, add Virahol 300 milliliters dissolving, pH=2 ~ 3 are regulated with 15% (quality) hydrochloric acid, place at 0 ~ 5 DEG C, slowly crystallization obtains cefixime trihydrate 4.4 grams, yield 87%.Fusing point: 218 ~ 223 DEG C, measure with liquid chromatography HPLC, purity is 99.8%.
Test condition: with embodiment 1, repeat no more.
Embodiment 3
In 500 milliliters of there-necked flasks, add 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid to methoxy benzyl ester 4.9 grams (0.01 mole), 0.26 gram, magnesium powder (0.011 mole), methyltetrahydrofuran 49 grams, react at 50 DEG C after 2 hours, the methyltetrahydrofuran solution 20 milliliters of 0.4 gram, formaldehyde (0.012 mole) is slowly added drop-wise in reaction system, react 2 hours at 50 DEG C, reaction terminates, be cooled to room temperature, drip trifluoroacetic acid 35 milliliters, stirring at room temperature 30 minutes, remove solvent under reduced pressure, add 70% (quality) aqueous ethanolic solution 150 milliliters, under cryosel bath cooling, pH=7 is regulated with saturated sodium bicarbonate solution, separate out faint yellow solid gradually, filter, with washed with diethylether, under Vanadium Pentoxide in FLAKES exists, after room temperature in vacuo drying, be dissolved in methyltetrahydrofuran 100 milliliters, Cefixime Micronized side chain 3.9 grams (0.015 mole) is slowly added at 10 DEG C, react after 5 hours, remove solvent under reduced pressure, add Virahol 300 milliliters dissolving, pH=2 ~ 3 are regulated with hydrochloric acid 15% (quality), place at 0 ~ 5 DEG C, slowly crystallization obtains cefixime trihydrate 4.7 grams, yield 89%, fusing point: 218 ~ 223 DEG C, measure with liquid chromatography HPLC, purity is 99.8%.
Test condition: with embodiment 1, repeat no more.

Claims (7)

1. a preparation method for Cefixime Micronized, is characterized in that this preparation method comprises the steps:
A, in reaction vessel, add quantitative 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid to methoxy benzyl ester, magnesium powder and solvent, react 1 ~ 5 hour at 10 ~ 100 DEG C of temperature;
B, in reaction system, add quantitative formaldehyde, react 1 ~ 5 hour at 10 ~ 100 DEG C of temperature;
C, be cooled to room temperature, drip appropriate trifluoroacetic acid, stir, obtain Cefixime Micronized parent nucleus through aftertreatment;
D, gained Cefixime Micronized parent nucleus is dissolved in appropriate solvent, at 10 ~ 30 DEG C of temperature, slowly adds quantitative Cefixime Micronized side chain, react 1 ~ 5 hour;
E, aftertreatment, obtain cefixime trihydrate,
Solvent described in steps A, D is tetrahydrofuran (THF), the ethers containing carbon atom 1 ~ 10 and the alkyl tetrahydro furans containing carbon atom 1 ~ 10.
2. the preparation method of Cefixime Micronized according to claim 1, is characterized in that described Cefixime Micronized side chain is 2-(2-amino-4-thiazole)-2-(Carboxvmethoxv) imido grpup] Acetyl Chloride 98Min..
3. the preparation method of Cefixime Micronized according to claim 1, is characterized in that the weight consumption of solvent for use in steps A is that 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid is to 1 ~ 10 of methoxy benzyl ester weight consumption times.
4. the preparation method of Cefixime Micronized according to claim 1, is characterized in that described magnesium powder, formaldehyde and 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid are 1 ~ 1.5:1 ~ 1.5:1 to methoxy benzyl ester molar ratio.
5. the preparation method of Cefixime Micronized according to claim 1 and 2, is characterized in that the mole dosage of described Cefixime Micronized side chain is that 7-phenylacetamide-3-chloromethyl-3-cephem-4-carboxylic acid is to 1 ~ 1.5 of methoxy benzyl ester mole dosage times.
6. the preparation method of Cefixime Micronized according to claim 1, it is characterized in that aftertreatment described in step C be to stir after reactant remove solvent under reduced pressure successively, add second alcohol and water, under cryosel bath cooling, regulate pH=7 with saturated sodium bicarbonate solution, separate out faint yellow solid, filter, with washed with diethylether, under Vanadium Pentoxide in FLAKES exists, obtain Cefixime Micronized parent nucleus in room temperature in vacuo drying.
7. the preparation method of Cefixime Micronized according to claim 1, it is characterized in that aftertreatment described in step e comprises successively and remove solvent under reduced pressure, add appropriate Virahol and dissolve, regulate pH=2 ~ 3 with 15% hydrochloric acid, place at 0 ~ 5 DEG C, slowly crystallization obtains cefixime trihydrate.
CN201510090398.7A 2015-02-28 2015-02-28 Method for preparing cefixime Active CN104693217B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111592557A (en) * 2020-05-09 2020-08-28 河北合佳医药科技集团股份有限公司 One-step environment-friendly preparation method of 7-amino-3-vinyl cephalosporanic acid

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1227100A1 (en) * 1999-09-30 2002-07-31 Otsuka Kagaku Kabushiki Kaisha 3-cephem derivative crystal and method for preparing the same
WO2005100367A1 (en) * 2004-04-13 2005-10-27 Ranbaxy Laboratories Limited Intermediates useful in the synthesis of 3-(2-substituted vinyl) cephalosporins
WO2006067806A1 (en) * 2004-12-21 2006-06-29 Lupin Limited Process for the preparation of cefixime
CN101319246A (en) * 2008-07-17 2008-12-10 浙江昂利康制药有限公司 Process for preparing cefixime
CN103923104A (en) * 2014-04-25 2014-07-16 河北科技大学 Preparation method of 7-phenylacetamido-3-vinyl-4-p-methoxy benzyl ester cefotaximate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1227100A1 (en) * 1999-09-30 2002-07-31 Otsuka Kagaku Kabushiki Kaisha 3-cephem derivative crystal and method for preparing the same
WO2005100367A1 (en) * 2004-04-13 2005-10-27 Ranbaxy Laboratories Limited Intermediates useful in the synthesis of 3-(2-substituted vinyl) cephalosporins
WO2006067806A1 (en) * 2004-12-21 2006-06-29 Lupin Limited Process for the preparation of cefixime
CN101319246A (en) * 2008-07-17 2008-12-10 浙江昂利康制药有限公司 Process for preparing cefixime
CN103923104A (en) * 2014-04-25 2014-07-16 河北科技大学 Preparation method of 7-phenylacetamido-3-vinyl-4-p-methoxy benzyl ester cefotaximate

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111592557A (en) * 2020-05-09 2020-08-28 河北合佳医药科技集团股份有限公司 One-step environment-friendly preparation method of 7-amino-3-vinyl cephalosporanic acid

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