CN104693217B - Method for preparing cefixime - Google Patents
Method for preparing cefixime Download PDFInfo
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- CN104693217B CN104693217B CN201510090398.7A CN201510090398A CN104693217B CN 104693217 B CN104693217 B CN 104693217B CN 201510090398 A CN201510090398 A CN 201510090398A CN 104693217 B CN104693217 B CN 104693217B
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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
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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
- C07D501/02—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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
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 2-10 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
Technical field
The present invention relates to the synthetic method of a kind of cefixime, particularly by 7-phenyl acetamide-3-
Methoxy benzyl ester (GCLE) is set out and prepares cefixime by chloromethyl-3-cephem-4-carboxylic acid
Method.
Background technology
Cefixime (Cefixime) be Japan Fujisawa Pharmaceutical in 1980 exploitation and
The third generation put goods on the market in 1987 is administered orally cephem antibiotics, is characterized in wide spectrum, height
Effect, resistance to enzyme, blood drug level are high and persistently, and the half-life is more than Cefaclor and cefadroxil,
Dosage is little, adverse effect is low, thus is widely used clinically.Chemistry is entitled
(6R, 7R)-7-[[(Z)-2-(2-amino-4-thiazolyl)-2-(Carboxvmethoxv) imido grpup] second
Acyl group] amino]-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 is mainly to cefixime parent nucleus and cefixime side chain
Numerous studies are carried out in synthesis.Cefixime side chain oneself realize industrialized production, can conveniently buy and
Low price, and to the study on the synthesis of cefixime parent nucleus always the most perfect, sum up
Following several approach: 1) with deacetylation cephalosporin as initiation material, through hydrolysis,
Phenyllacetyl chloride is acylated, and diphenyl diazomethane is esterified, halogenation, and Wittig reacts, deaminizating system
?；2) with 7-amino-3-acetyl-o-methyl-3-cephem-4-carboxylic acid (7-ACA) as raw material, warp
Hydrolysis, phenyllacetyl chloride is acylated, and diphenyl triazonmethane is esterified, bromo, and Wittig reacts,
Deprotection prepares.Or first through silicon etherification reaction and 4-position carboxy protective carry out again above-mentioned instead
Should.3) with benzylpenicillin as raw material, through esterification, after oxidation prepares penicillin sulfoxide ester, then
Through open loop, chlorination, cyclization, reduction, bromo, Wittig reaction and deaminizating, decarboxylation system
?.4) with 7-phenyl acetamide-3-chloromethyl-3-cephem-4-carboxylic acid to methoxy benzyl ester (GCLE)
For raw material, after Wittig reacts, slough 7-bit amino protection group, then make with m-methyl phenol
Prepare with sloughing 4-position carboxyl-protecting group；Or it is after Wittig reacts, de-under phenol effect
Remove 4-position carboxyl-protecting group, then under PA ase effect, slough 7-bit amino protection group
Prepare.
Summary of the invention
The technical problem to be solved is to provide the system of a kind of new synthesis cefixime
Preparation Method, by changing reaction scheme and reaction condition, the green conjunction of research antibiotics
One-tenth method, applies it to the synthesis field of antibiotics.
Technical scheme: for solving above technical problem, cefixime of the present invention
Preparation method, comprise the steps:
A, in reaction vessel, add the quantitative 7-phenyl acetamide-3-as shown in formula I
Chloromethyl-3-cephem-4-carboxylic acid is to methoxy benzyl ester, magnesium powder and solvent, in 10～100 DEG C of temperature
The lower reaction of degree 1～5 hour；
B, in reaction system, add quantitative formaldehyde, react at a temperature of 10～100 DEG C 1～
5 hours；
C, it is cooled to room temperature, drips appropriate trifluoroacetic acid, stirring, post-treated to the end
Spore gram oxime parent nucleus；
D, gained cefixime parent nucleus is dissolved in appropriate solvent, at a temperature of 10～30 DEG C,
It is slowly added to quantitative cefixime side chain, reacts 1～5 hour；
E, post processing, obtain cefixime trihydrate,
Solvent described in step A, D is oxolane, containing carbon atom 1～10 but do not comprise carbon
Atom is the ethers of 1 and containing the alkyl tetrahydro furan of carbon atom 1～10.
Concrete reaction equation is as follows:
Described cefixime side chain is 2-(2-amino-4-thiazole)-2-(Carboxvmethoxv) imines
Base] chloroacetic chloride, its structural formula is as shown in formula II.
Further, in step A, the weight consumption of solvent for use is 7-phenyl acetamide-3-chloromethane
To methoxy benzyl ester weight consumption 1～10 times of base-3-cephem-4-carboxylic acid.
Further, described magnesium powder, formaldehyde and 7-phenyl acetamide-3-chloromethyl-3-cephem-4-
Carboxylic acid is 1～1.5:1～1.5:1 to methoxy benzyl ester molar ratio.
Further, the mole dosage of described cefixime side chain is 7-phenyl acetamide-3-chloromethane
To methoxy benzyl ester mole dosage 1～1.5 times of base-3-cephem-4-carboxylic acid.
Further, post processing described in step C is to subtract the reactant after stirring successively
Pressure is evaporated off solvent, adds second alcohol and water, under cryosel bath cooling, uses saturated sodium bicarbonate solution
Regulation pH=7, separates out faint yellow solid, filters, and washs with ether, at phosphorus pentoxide
In the presence of, it is dried to obtain cefixime parent nucleus in room temperature in vacuo.
Further, post processing described in step E includes removing under reduced pressure solvent successively, adds appropriate
Isopropanol dissolves, and with 15% hydrochloric acid regulation pH=2～3, places, slowly analyse at 0～5 DEG C
Go out crystallization and obtain cefixime trihydrate.
The technology of the present invention easily operates, and the three wastes are few, convenient post-treatment, it is provided that one prepares cephalo
The new approaches of gram oxime, are economical and practical new techniques.
Detailed description of the invention
Embodiment 1
In 500 milliliters of there-necked flasks, add 7-phenyl acetamide-3-chloromethyl-3-cephem-4-carboxylic acid
To methoxy benzyl ester 4.9 grams (0.01 mole), magnesium powder 0.28 gram (0.012 mole), first
Base oxolane 20 grams, after reacting 2 hours at 50 DEG C, by 0.4 gram of formaldehyde (0.012 mole)
Methyltetrahydrofuran solution 20 milliliters be slowly added drop-wise in reaction system, at 50 DEG C react 2
Hour, reaction terminates, and is cooled to room temperature, drips trifluoroacetic acid 35 milliliters, is stirred at room temperature 30
Minute, remove solvent under reduced pressure, add 70% ethanol water 150 milliliters, under cryosel bath cooling,
Regulate pH=7 with saturated sodium bicarbonate solution, gradually separate out faint yellow solid, filter, use second
Ether washs, in the presence of phosphorus pentoxide, dried in room temperature in vacuo, is dissolved in methyl tetrahydrochysene furan
Mutter in 100 milliliters, at 10 DEG C, be slowly added into cefixime side chain 3 grams (0.012 mole),
After reacting 5 hours, remove solvent under reduced pressure, add isopropanol 300 milliliters dissolving, by 15% (matter
Amount) hydrochloric acid regulation pH=2～3, places at 0～5 DEG C, slowly separates out crystallization and obtain cephalo
Gram oxime trihydrate 4.5 grams, yield 88%, fusing point: 218～223 DEG C, use liquid chromatograph HPLC
Measuring, purity is 99.8%.
Test condition:
Detector: Waters2487；
Chromatographic column: Symmetry-C18,4.6 × 250mm；
Column temperature: 40 DEG C；
Flowing phase: (8 grams of TBAH are dissolved in 800mL water to buffer solution 75%, and phosphoric acid is adjusted
PH=6.5；
It is diluted with water to 1000mL, then adds 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-phenyl acetamide-3-chloromethyl-3-cephem-4-carboxylic acid
To methoxy benzyl ester 4.9 grams (0.01 mole), magnesium powder 0.36 gram (0.015 mole), first
Base oxolane 30 grams, after reacting 5 hours at 30 DEG C, by 0.45 gram of formaldehyde, (0.015 rubs
You) methyltetrahydrofuran solution 20 milliliters be slowly added drop-wise in reaction system, anti-at 10 DEG C
Answering 5 hours, reaction terminates, and is cooled to room temperature, drips trifluoroacetic acid 35 milliliters, is stirred at room temperature
30 minutes, remove solvent under reduced pressure, add 70% (quality) ethanol water 150 milliliters, at ice
Under salt bath cooling, regulate pH=7 with saturated sodium bicarbonate solution, gradually separate out faint yellow solid,
Filter, wash with ether, in the presence of phosphorus pentoxide, dried in room temperature in vacuo, it is dissolved in
In methyltetrahydrofuran 100 milliliters, it is slowly added into cefixime side chain at 20 DEG C 3 gram (0.012
Mole), after reacting 3 hours, remove solvent under reduced pressure, add isopropanol 300 milliliters dissolving, use
15% (quality) hydrochloric acid regulation pH=2～3, places at 0～5 DEG C, slowly separates out and crystallizes
To cefixime trihydrate 4.4 grams, yield 87%.Fusing point: 218～223 DEG C, uses liquid phase color
Spectrum HPLC measures, and purity is 99.8%.
Test condition: with embodiment 1, repeat no more.
Embodiment 3
In 500 milliliters of there-necked flasks, add 7-phenyl acetamide-3-chloromethyl-3-cephem-4-carboxylic acid
To methoxy benzyl ester 4.9 grams (0.01 mole), magnesium powder 0.26 gram (0.011 mole), first
Base oxolane 49 grams, after reacting 2 hours at 50 DEG C, by 0.4 gram of formaldehyde (0.012 mole)
Methyltetrahydrofuran solution 20 milliliters be slowly added drop-wise in reaction system, at 50 DEG C react 2
Hour, reaction terminates, and is cooled to room temperature, drips trifluoroacetic acid 35 milliliters, is stirred at room temperature 30
Minute, remove solvent under reduced pressure, add 70% (quality) ethanol water 150 milliliters, at cryosel
Under bath cooling, regulate pH=7 with saturated sodium bicarbonate solution, gradually separate out faint yellow solid,
Filter, wash with ether, in the presence of phosphorus pentoxide, dried in room temperature in vacuo, it is dissolved in
In methyltetrahydrofuran 100 milliliters, at 10 DEG C, it is slowly added into cefixime side chain 3.9 grams
(0.015 mole), after reacting 5 hours, removes solvent under reduced pressure, adds isopropanol 300 milliliters
Dissolve, regulate pH=2～3 with hydrochloric acid 15% (quality), place at 0～5 DEG C, slowly analyse
Go out crystallization and obtain cefixime trihydrate 4.7 grams, yield 89%, fusing point: 218～223 DEG C,
Measuring by liquid chromatograph HPLC, purity is 99.8%.
Test condition: with embodiment 1, repeat no more.
Claims (7)
1. the preparation method of a cefixime, it is characterised in that this preparation method includes as follows
Step:
A, in reaction vessel, add quantitative 7-phenyl acetamide-3-chloromethyl-3-cephem-4-
Carboxylic acid, to methoxy benzyl ester, magnesium powder and solvent, reacts 1～5 little at a temperature of 10～100 DEG C
Time；
B, in reaction system, add quantitative formaldehyde, react at a temperature of 10～100 DEG C 1～
5 hours；
C, it is cooled to room temperature, drips appropriate trifluoroacetic acid, stirring, post-treated to the end
Spore gram oxime parent nucleus；
D, gained cefixime parent nucleus is dissolved in appropriate solvent, at a temperature of 10～30 DEG C,
It is slowly added to quantitative cefixime side chain, reacts 1～5 hour；
E, post processing, obtain cefixime trihydrate,
Solvent described in step A, D is oxolane, containing carbon atom 1～10 but do not include carbon
Atom is the ethers of 1 and containing the alkyl tetrahydro furan of carbon atom 1～10.
The preparation method of cefixime the most according to claim 1, it is characterised in that institute
Stating cefixime side chain is 2-(2-amino-4-thiazole)-2-(Carboxvmethoxv) imido grpup] acetyl
Chlorine.
The preparation method of cefixime the most according to claim 1, it is characterised in that step
In rapid A, the weight consumption of solvent for use is 7-phenyl acetamide-3-chloromethyl-3-cephem-4-carboxylic acid
To methoxy benzyl ester weight consumption 1～10 times.
The preparation method of cefixime the most according to claim 1, it is characterised in that institute
State magnesium powder, formaldehyde with 7-phenyl acetamide-3-chloromethyl-3-cephem-4-carboxylic acid to methoxy benzyl ester
Molar ratio is 1～1.5:1～1.5:1.
The preparation method of cefixime the most according to claim 1 and 2, its feature exists
Mole dosage in described cefixime side chain is 7-phenyl acetamide-3-chloromethyl-3-cephem-4-
To methoxy benzyl ester mole dosage 1～1.5 times of carboxylic acid.
The preparation method of cefixime the most according to claim 1, it is characterised in that step
Post processing described in rapid C is that the reactant after stirring is removed under reduced pressure solvent successively, adds
Second alcohol and water, under cryosel bath cooling, regulates pH=7 with saturated sodium bicarbonate solution, analysis
Go out faint yellow solid, filter, wash with ether, in the presence of phosphorus pentoxide, true in room temperature
Sky is dried to obtain cefixime parent nucleus.
The preparation method of cefixime the most according to claim 1, it is characterised in that step
Post processing described in rapid E includes removing solvent under reduced pressure successively, adds appropriate isopropanol and dissolves, uses
15% hydrochloric acid regulation pH=2～3, places at 0～5 DEG C, slowly separates out crystallization and obtain cephalo
Gram oxime trihydrate.
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| 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 |
| CN115326950A (en) * | 2022-07-27 | 2022-11-11 | 广州白云山医药集团股份有限公司白云山制药总厂 | Method for detecting dissolution rate of cefixime |
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| WO2001023393A1 (en) * | 1999-09-30 | 2001-04-05 | 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 |
| MX2007007476A (en) * | 2004-12-21 | 2007-08-15 | Lupin Ltd | Process for the preparation of cefixime. |
| CN101319246B (en) * | 2008-07-17 | 2012-02-15 | 浙江昂利康制药有限公司 | Process for preparing cefixime |
| CN103923104B (en) * | 2014-04-25 | 2016-04-13 | 湖北凌晟药业有限公司 | 7-phenylacetylamino-3-vinyl-4-cephemcarboxylic acid is to the preparation method of methoxy benzyl ester |
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Address after: Taizhou City, Zhejiang province 318020 gate Huangyan Jiangkou Road Economic Development Zone No. 10 Applicant after: ZHEJIANG HUAFANG PHARMACEUTICAL CO., LTD. Address before: Taizhou City, Zhejiang province 318020 gate Huangyan Jiangkou Road Economic Development Zone No. 10 Applicant before: Shandong Changyi Sifang Pharmaceutical Co., Ltd. |
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