CN105153198B - A kind of preparation method of Ceftibuten - Google Patents
A kind of preparation method of Ceftibuten Download PDFInfo
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- CN105153198B CN105153198B CN201510595691.9A CN201510595691A CN105153198B CN 105153198 B CN105153198 B CN 105153198B CN 201510595691 A CN201510595691 A CN 201510595691A CN 105153198 B CN105153198 B CN 105153198B
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention provides a kind of preparation method of Ceftibuten, including toward adding Cefaclor parent nucleus in reactor, methyltetrahydrofuran and magnesium powder, after reaction disappears to magnesium powder, add appropriate distilled water, stirring, stratification, the drying of organic layer anhydrous magnesium sulfate is separated, after filtering, D301 types weak-base ion-exchange resin and 2 (base of 2 benzyloxycarbonyl amino thiazole 4) penetenoic acids of 5 benzyloxycarbonyl group 2 is added, reacted under uniform temperature and time, after reaction terminates, weak-base ion-exchange resin is filtered, then hydrolyze prepared target product Ceftibuten.The method is a kind of new method for preparing Ceftibuten, and its high income, purity is high, easy to operate, is a production technology for green cleaning, is suitable for the industrialized production of certain scale；And Cefaclor parent nucleus is our company's main product, the technology that Tenth Five-Year Plan Period focus development kind Ceftibuten is our company's sustainable development is prepared using the product of our company.
Description
Technical field
The invention belongs to field of medicine and chemical technology, more particularly to one kind is by Cefaclor parent nucleus, in D301 type alkalescents
The method that Ceftibuten is prepared under anion-exchange resin catalyst effect.
Background technology
Ceftibuten (Ceftibuten) is the oral broad-spectrum cephalosporin of the third generation developed by Yan Yeyi company of Japan, right
Most of gram-Negative bacilluses and some positive coccus have stronger antibacterial action, to plasmid-mediated beta-lactamase highly
Stabilization, and with post antibiotic effect；With has a broad antifungal spectrum, antibacterial activity is strong, bioavilability is high the features such as, for treat by
The various infection that sensitive strain causes, including the infection of the upper respiratory tract, ALRI, the urinary system that oozes infection, enteritis and stomach and intestine
Inflammation etc..
The chemical name of Ceftibuten is (+)-(6R, 7R) -7 β-[(Z) -2- (2- amino -4- thiazoles) -4- carboxyls -2-
(Z)-crotonamide] -8- oxygen bicyclic water the things of [4.2.0] oct-2-ene -2- carboxylic acids two of -5- sulphur -1- nitrogen, structural formula such as formula (I) institute
Show：
Listed extensively in Ceftibuten world wide including including Japan, Tenth Five-Year Plan Period is classified as by China
Focus development kind.
At present, the preparation according to side chain can be divided into three kinds of routes：
(1) with 2- chloracetyl diethyl malonates as raw material, through cyclisation, amido protecting, Michael additions-elimination, alkali
Property hydrolysis and selective esterification reaction be obtained.Although this synthetic route process is simple, reaction condition is gentle, is easily achieved industrialization
Produce, but reaction raw material 2- chloracetyls diethyl malonate used and chlorine diethyl methylenemalonate are difficult to buy,
And intermediate reaction is related to hydrolysis, decarboxylation, rearrangement etc., cause whole process reaction yield low；
(2) with 2- chloracetyl acetic acid benzhydryl esters as raw material, through Michael additions-elimination, cyclisation and selective hydrolysis
Reaction is obtained.Although this synthetic route is brief, mild condition, reaction raw material 2- chloracetyl acetic acid benzhydryl ester used,
3- carbonyl propionic acids (3- base -2- butylene) ester and benzyloxycarbonyl group thiocarbamide are difficult to buy, and repeatedly use post separation in course of reaction, make
Into answering yield low, treating capacity is small, does not have practical value；
(3) with 2- amino -4- methylthiazols as raw material, add through amido protecting, low temperature conversion, carboxy protective, Michael
Into-eliminate, Witting reactions and selective hydrolysis etc. are obtained.This synthetic route reactions steps is long, and overall yield of reaction is low,
Reaction condition requirement is harsh.
Developing rapidly and in the application of chemical industry, being handed over using new and effective ion with ion-exchange resin technique
Resin is changed as catalyst, the concern of people is received in the research of catalytic reaction, by the use of ion exchange resin as catalysis
Agent, swelling due to resin in reaction system, the characteristics of with homogeneous catalytic reaction, i.e., reaction condition is gentle, and side reaction is few,
Selectivity is good, sometimes up to the degree of Quantitative yield, and the reaction mechanism mechanism of reaction and activated centre are relatively easy and illustrate；Have again simultaneously many
The characteristics of phase catalytic reaction, compensate for the deficiency of homogeneous catalysis.Multiphase can be urged as catalyst by the use of ion exchange resin
Change homogeneousization, with the deficiency for keeping original advantage He make up itself, improve catalytic efficiency, be that homogeneous catalysis and heterogeneous catalysis exist
A promising research direction during production application, is a kind of green chemical synthesis technology.Using D301 types from
Sub-exchange resin as catalyst, by the Cefaclor chloro- 3- cephems -4- carboxylic acids of parent nucleus 7- amino -3- for raw material prepares cephalo
There is not been reported for the method for cloth alkene, and the synthesis of cephalosporin nucleus 7-ANCA mainly uses PCs and cephalosporins as original
Material is prepared.
The content of the invention
The invention solves the problems that purpose be to provide a kind of new technology of green syt Ceftibuten, by select D301 types from
Sub-exchange resin as catalyst, using Cefaclor parent nucleus for raw material prepares Ceftibuten.The technology is one easy to operate
With environment-friendly Green Chemistry technology of preparing, the homegrown resource of company is taken full advantage of, be company's sustainable development
Technology.
To reach above-mentioned purpose, the present invention is adopted the following technical scheme that：
A kind of preparation method of Ceftibuten, including toward adding Cefaclor parent nucleus (II), methyl tetrahydrochysene furan in reactor
Mutter and magnesium powder, after reaction to magnesium powder disappears, add appropriate distilled water, stirring, stratification to separate methyltetrahydrofuran organic layer
Dried with anhydrous magnesium sulfate, after filtering, add weak-base ion-exchange resin (III) and 2- (2- benzyloxycarbonyl amino thiazoles -4-
Base) -5- benzyloxycarbonyl group -2- penetenoic acids, reacted under uniform temperature and time, after reaction terminates, filter weakbase ion
Exchanger resin, then prepared target product Ceftibuten is hydrolyzed,
Wherein, R in formula (III)1、R2Methyl or hydrogen atom each are stood alone as, n represents basic structure in the degree of polymerization, i.e. molecule
The number of times for repeating.If the mixture of the homologue that same chemical composition and the degree of polymerization are not waited, then n is the average poly- of the mixture
It is right, i.e. the average value of the degree of polymerization.
Weak-base ion-exchange resin of the present invention is commercially available prod, described weak-base ion-exchange resin (III)
For D301 R Styrene-DVB, D301 T Styrene-DVB, D301G Styrene-DVB, D392 Styrene-DVB or
One kind in D380 Styrene-DVB.
Reaction temperature in the reactions steps of heretofore described addition weak-base ion-exchange resin (III) is 5~50
DEG C, preferably 10~30 DEG C；Reaction time is 1~10 hour, preferably 3~5 hours.
The quality consumption of described weak-base ion-exchange resin (III) catalyst for cephalosporin nucleus quality consumption 10~
50%, preferably 20~30%.
Heretofore described hydrolysis is that the reaction solution for having filtered out weak-base ion-exchange resin (III) is carried out
Distillation, removes methyltetrahydrofuran, and isopropanol, NaOH solution are then added at room temperature, is warming up to 20~50 DEG C of reactions 1~5 small
When, 20 DEG C are then cooled to, then extracted with dichloromethane, obtain aqueous layer and adjust pH=5~6 with dense HCl at 0 DEG C, stand analysis
Go out crystallization, filtering, dry target product.
Compared with prior art, its advantage is embodied in the present invention：
1. by the use of weak-base ion-exchange resin (III) as catalyst, by Cefaclor parent nucleus for raw material prepares cephalo cloth
Alkene is a new preparation method, and its high income, purity is high, easy to operate, is a production technology for green cleaning, is suitable for
The industrialized production of certain scale；
2. Cefaclor parent nucleus is our company's main product, and Tenth Five-Year Plan Period focus development is prepared using the product of our company
Kind Ceftibuten is the technology of our company's sustainable development.
Specific embodiment
With reference to specific embodiment, the invention will be further described, but protection scope of the present invention is not limited to this.
Embodiment 1
In 100 milliliters of there-necked flasks, addition 2.4 grams of parent nucleus of Cefaclor (0.01 mole), 15 milliliters of methyltetrahydrofuran,
0.4 gram of magnesium powder (0.017 mole), after 30 DEG C of reactions disappear to magnesium powder, adds 10 milliliters of distilled water, stirs 10 minutes, stands
Layering, separates the drying of methyltetrahydrofuran organic layer anhydrous magnesium sulfate, after filtering, adds Styrene-DVB (D301 R) trees
0.7 gram of fat, 2- 5 grams of penetenoic acids of (2- benzyloxycarbonyl aminos thiazole-4-yl) -5- benzyloxycarbonyl group -2- (0.011 mole), at 30 DEG C
Reaction 3 hours, reaction end filters Styrene-DVB (D301 R) resin, and methyltetrahydrofuran is distilled off, and 20 DEG C of additions are different
10 milliliters of isopropanol, 20 milliliters of NaOH (30%) aqueous solution reacts 1 hour at 30 DEG C, is cooled to 20 DEG C.With dichloromethane 10 ×
3 milliliters extract three times, and aqueous layer is added dropwise dense HCl and adjusts pH=5~6 at 0 DEG C, stand and separate out crystallization, filtering, dry that target is produced
(I) 3.55 gram of thing Ceftibuten, yield 86.7%, HPLC：98.5%.Fusing point：178~181 DEG C.HRMS(ESI)：M/e=410
(M+)。IR(KBr)cm-1：3574,3247,3051,2957,1771,1699,1651,1544,1364,1255.
Embodiment 2
In 100 milliliters of there-necked flasks, addition 2.4 grams of parent nucleus of Cefaclor (0.01 mole), 15 milliliters of methyltetrahydrofuran,
0.4 gram of magnesium powder (0.017 mole), after 50 DEG C of reactions disappear to magnesium powder, adds 10 milliliters of distilled water, stirs 10 minutes, stands
Layering, separates the drying of methyltetrahydrofuran organic layer anhydrous magnesium sulfate, after filtering, adds Styrene-DVB (D301 R) trees
1.2 grams of fat, 2- 5 grams of penetenoic acids of (2- benzyloxycarbonyl aminos thiazole-4-yl) -5- benzyloxycarbonyl group -2- (0.011 mole), at 30 DEG C
Reaction 1 hour, reaction end filters Styrene-DVB (D301 R) resin, and methyltetrahydrofuran is distilled off, and 30 DEG C of additions are different
10 milliliters of isopropanol, 20 milliliters of NaOH (30%) aqueous solution reacts 1 hour at 30 DEG C, is cooled to 20 DEG C.With dichloromethane 10 ×
3 milliliters extract three times, and aqueous layer is added dropwise dense HCl and adjusts pH=5~6 at 0 DEG C, stand and separate out crystallization, filtering, dry that target is produced
(I) 3.57 gram of thing Ceftibuten, yield 86.9%, HPLC：99.0%.
Embodiment 3
In 100 milliliters of there-necked flasks, addition 2.4 grams of parent nucleus of Cefaclor (0.01 mole), 15 milliliters of methyltetrahydrofuran,
0.4 gram of magnesium powder (0.017 mole), after 30 DEG C of reactions disappear to magnesium powder, adds 10 milliliters of distilled water, stirs 10 minutes, stands
Layering, separates the drying of methyltetrahydrofuran organic layer anhydrous magnesium sulfate, after filtering, adds Styrene-DVB (D301 T) trees
0.7 gram of fat, 2- 5 grams of penetenoic acids of (2- benzyloxycarbonyl aminos thiazole-4-yl) -5- benzyloxycarbonyl group -2- (0.011 mole), at 10 DEG C
Reaction 3 hours, reaction end filters Styrene-DVB (D301 T) resin, and methyltetrahydrofuran is distilled off, and 20 DEG C of additions are different
10 milliliters of isopropanol, 20 milliliters of NaOH (30%) aqueous solution reacts 1 hour at 20 DEG C, with 10 × 3 milliliters of extractions three of dichloromethane
Secondary, aqueous layer is added dropwise dense HCl and adjusts pH=5~6 at 0 DEG C, stands and separates out crystallization, filtering, dry target product Ceftibuten
(I) 3.56 gram, yield 86.8%, HPLC:99.1%.
Embodiment 4
In 100 milliliters of there-necked flasks, addition 2.4 grams of parent nucleus of Cefaclor (0.01 mole), 15 milliliters of methyltetrahydrofuran,
0.4 gram of magnesium powder (0.017 mole), after 30 DEG C of reactions disappear to magnesium powder, adds 10 milliliters of distilled water, stirs 10 minutes, stands
Layering, separates the drying of methyltetrahydrofuran organic layer anhydrous magnesium sulfate, after filtering, adds Styrene-DVB (D301 G) trees
0.3 gram of fat, 2- 5 grams of penetenoic acids of (2- benzyloxycarbonyl aminos thiazole-4-yl) -5- benzyloxycarbonyl group -2- (0.011 mole), at 30 DEG C
Reaction 3 hours, reaction end filters Styrene-DVB (D301 G) resin, and methyltetrahydrofuran is distilled off, and 20 DEG C of additions are different
10 milliliters of isopropanol, 20 milliliters of NaOH (30%) aqueous solution reacts 1 hour at 10 DEG C, with 10 × 3 milliliters of extractions three of dichloromethane
Secondary, aqueous layer is added dropwise dense HCl and adjusts pH=5~6 at 0 DEG C, stands and separates out crystallization, filtering, dry target product Ceftibuten
(I) 3.50 gram, yield 85.3%, HPLC：99.2%.
Embodiment 5
In 100 milliliters of there-necked flasks, addition 2.4 grams of parent nucleus of Cefaclor (0.01 mole), 15 milliliters of methyltetrahydrofuran,
0.4 gram of magnesium powder (0.017 mole), after 30 DEG C of reactions disappear to magnesium powder, adds 10 milliliters of distilled water, stirs 10 minutes, stands
Layering, separates the drying of methyltetrahydrofuran organic layer anhydrous magnesium sulfate, after filtering, adds Styrene-DVB (D392) resin
0.7 gram, 2- 5 grams of penetenoic acids of (2- benzyloxycarbonyl aminos thiazole-4-yl) -5- benzyloxycarbonyl group -2- (0.011 mole) is anti-at 30 DEG C
Answer 3 hours, reaction end filters Styrene-DVB (D392) resin, methyltetrahydrofuran, 20 DEG C of addition isopropyls is distilled off
10 milliliters of alcohol, 20 milliliters of NaOH (30%) aqueous solution reacts 1 hour at 30 DEG C, is cooled to 20 DEG C.With the milli of dichloromethane 10 × 3
Extraction three times is risen, aqueous layer is added dropwise dense HCl and adjusts pH=5~6 at 0 DEG C, stands and separates out crystallization, filtering, dry target product
(I) 3.57 gram of Ceftibuten, yield 87.1%, HPLC：98.6%.
Claims (7)
1. a kind of preparation method of Ceftibuten, it is characterised in that including toward adding Cefaclor parent nucleus (II), first in reactor
Base tetrahydrofuran and magnesium powder, after reaction to magnesium powder disappears, add appropriate distilled water, stirring, stratification to separate methyl tetrahydrochysene furan
Organic layer anhydrous magnesium sulfate of muttering is dried, and after filtering, adds weak-base ion-exchange resin (III) and 2- (2- benzyloxycarbonyl aminos
Thiazole-4-yl) -5- benzyloxycarbonyl group -2- penetenoic acids, reacted under uniform temperature and time, after reaction terminates, filter weak base
Property ion exchange resin, then prepared target product Ceftibuten is hydrolyzed,
Wherein, R in formula (III)1、R2Methyl or hydrogen atom each are stood alone as, n represents the degree of polymerization.
2. the preparation method of Ceftibuten according to claim 1, it is characterised in that described addition weakbase ion is handed over
The reaction temperature changed in the reactions steps of resin (III) is 5~50 DEG C, and the reaction time is 1~10 hour.
3. the preparation method of Ceftibuten according to claim 2, it is characterised in that reaction temperature is 10~30 DEG C；Reaction
Time is 3~5 hours.
4. the preparation method of Ceftibuten according to claim 1, it is characterised in that described weakbase ion exchanges tree
The quality consumption of fat catalyst (III) is the 10~50% of cephalosporin nucleus quality consumption.
5. the preparation method of Ceftibuten according to claim 4, it is characterised in that described weakbase ion exchanges tree
The quality consumption of fat catalyst (III) is the 20~30% of cephalosporin nucleus quality consumption.
6. according to the preparation method of any described Ceftibuten of claim 1 to 5, it is characterised in that described weakbase ion
Exchanger resin (III) is D301R Styrene-DVB, D301 T Styrene-DVB, D301 G Styrene-DVB, D392
One kind in Styrene-DVB or D380 Styrene-DVB.
7. the preparation method of Ceftibuten according to claim 1, it is characterised in that described hydrolysis is to mistake
The reaction solution for leaching weak-base ion-exchange resin is distilled, remove methyltetrahydrofuran, then at room temperature add isopropanol,
NaOH solution, is warming up to 20~50 DEG C and reacts 1~5 hour, is then cooled to 20 DEG C, then is extracted with dichloromethane, obtains water-soluble
Liquid layer adjusts pH=5~6 at 0 DEG C with dense HCl, stands and separates out crystallization, filtering, dry target product.
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397455B (en) * | 2016-08-30 | 2018-08-31 | 山东罗欣药业集团恒欣药业有限公司 | A kind of anti-infectives Ceftibuten crystalline compounds and combinations thereof |
| CN106397454B (en) * | 2016-08-30 | 2018-08-24 | 山东罗欣药业集团股份有限公司 | A kind of anti-infectives Ceftibuten crystal-form compound and combinations thereof |
| CN106432272A (en) * | 2016-09-21 | 2017-02-22 | 临沂草之美医药科技有限公司 | Method for preparing drug ceftibuten crystal compound for treating surgical operation infection |
| CN106397457A (en) * | 2016-09-21 | 2017-02-15 | 临沂草之美医药科技有限公司 | Drug ceftibuten crystal compound for treating surgical operation infection |
| CN106432270A (en) * | 2016-09-21 | 2017-02-22 | 临沂草之美医药科技有限公司 | Method for preparing medicine ceftibuten crystal compound for treating surgical infection |
| CN106432271A (en) * | 2016-09-21 | 2017-02-22 | 临沂草之美医药科技有限公司 | Pharmaceutical ceftibuten crystal compound for treating surgical infection |
| CN106420617A (en) * | 2016-09-21 | 2017-02-22 | 临沂草之美医药科技有限公司 | Medicine ceftibuten powder injection for treating surgical infection |
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|---|---|---|---|---|
| CN1178220A (en) * | 1996-10-02 | 1998-04-08 | 大化学株式会社 | Process for producing cefazolin |
| CN101186602A (en) * | 2007-11-28 | 2008-05-28 | 浙江工业大学 | Method for synthesizing 2-methyl-2-aryl-1,3-dioxolane compound |
| CN101186566A (en) * | 2007-11-23 | 2008-05-28 | 浙江工业大学 | Method for preparing acetylacetone by using D301 type alkalescent anion exchange resin as catalyst |
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2015
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Patent Citations (3)
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|---|---|---|---|---|
| CN1178220A (en) * | 1996-10-02 | 1998-04-08 | 大化学株式会社 | Process for producing cefazolin |
| CN101186566A (en) * | 2007-11-23 | 2008-05-28 | 浙江工业大学 | Method for preparing acetylacetone by using D301 type alkalescent anion exchange resin as catalyst |
| CN101186602A (en) * | 2007-11-28 | 2008-05-28 | 浙江工业大学 | Method for synthesizing 2-methyl-2-aryl-1,3-dioxolane compound |
Non-Patent Citations (1)
| Title |
|---|
| Ceftibuten: Development of a Commercial Process Based on Cephalosporin C. Part III. Process for the Conversion of 3-Exomethylene-7(R)-glutaroylaminocepham-4-carboxylic Acid 1(S)-Oxide to Ceftibuten;Ermanno Bernasconi,et al.;《Organic Process Research & Development》;20020216;第6卷(第2期);第169-177页 * |
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