CN104788471B - A kind of synthetic method of Cefditoren pivoxil Cephalosporins parent nucleus - Google Patents
A kind of synthetic method of Cefditoren pivoxil Cephalosporins parent nucleus Download PDFInfo
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- CN104788471B CN104788471B CN201510126136.1A CN201510126136A CN104788471B CN 104788471 B CN104788471 B CN 104788471B CN 201510126136 A CN201510126136 A CN 201510126136A CN 104788471 B CN104788471 B CN 104788471B
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Abstract
The invention discloses a kind of synthetic method of Cefditoren pivoxil Cephalosporins parent nucleus, the synthetic method is by the carboxylic acid of 7 amino, 3 vinyl, 3 cephem 4 shown in quantitative formula (I), the halo thiazole of 4 methyl 5 shown in formula (II), ionic liquid shown in formula (III), inorganic base or organic base, palladium and triphenylphosphine are added in reactor, terminate within 1~10 hour in reaction at 10~150 DEG C, the post-treated Cefditoren pivoxil Cephalosporins parent nucleus obtained shown in formula (IV) again, in formula (III), R is the alkyl of carbon number 1~10, L‑It is BF4 ‑Or BF6 ‑,
Description
Technical field
The present invention relates to a kind of medicine intermediate, the particularly synthetic method of Cefditoren pivoxil Cephalosporins parent nucleus.
Background technology
Cefditoren is third generation oral cephalosporin class antibiotic, is to be developed by Japanese Meiji Seika Kaisba company for 1994
, for treating the infection caused by gram-positive bacteria and Gram-negative bacteria, especially to staphylococcus, including pneumonia
Streptococcus interior streptococcus gram-positive bacteria, Escherichia coli, branhamella catarrhalis, Kleb, deformation
The anaerobism such as the Gram-negative bacterias such as Bacillus, haemophilus influenzae and Peptostreptococcus, propionibacterium acnes, Bacteroides
Bacterium, all shows very strong antibacterial activity.Due to cefditoren has a broad antifungal spectrum, thus it is widely used in clinic.Cephalo
Appropriate entitled (6R, the 7R) -7- amino -3- of logical sequence pivoxil parent nucleus chemistry [(1Z) -2- (4- methyl-5-thiazoles) vinyl] -8- oxos -5-
Sulphur -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acids, are the important intermediates for producing cefditoren.In recent years, Wo Menzheng
It is devoted to the synthesis and application of ionic liquid, is used for ionic liquid as reaction medium in the synthesis technique of cephalosporins medicine,
It is economical and practical environment-friendly clean manufacturing new technology.
Ionic liquid (ionicil quids) is made up of organic cation and inorganic or organic anion two parts,
The ionic system being in a liquid state under room temperature and adjacent temperature.Ionic liquid has the advantages that many other materials are incomparable, such as liquid
State temperature range is wide, does not have significant vapour pressure, and heat endurance is good, has to many inorganic compounds and organic compound etc. good
Good dissolubility, electrochemical window is wide etc..Based on these features, ionic liquid is in the side such as extract and separate, catalytic reaction, electrochemistry
Face has a wide range of applications.Used as a kind of friendly reaction medium of novel environmental, ionic liquid can avoid organic solvent from volatilizing
Environment is polluted, while reactivity can be improved, is easily separated with product, there is wide answering in organic synthesis industry
With prospect, its developmental research is just being increasingly subject to the extensive concern of people.
Heck reactions are the important methods for synthesizing alkenyl substituted arene compound by halogenated aryl hydrocarbon under catalyzing by metal palladium.
With ionic liquid as reaction medium, in the presence of metal palladium catalyst, ME1207 is synthesized using Heck
There is not been reported so far for pivoxil parent nucleus.
The content of the invention
The technical problems to be solved by the invention are to provide one kind using Heck reactions, and antibiosis is synthesized in ionic liquid
The method of plain class medicine.
Technical scheme：The synthetic method of Cefditoren pivoxil Cephalosporins parent nucleus disclosed in this invention：By quantitative formula
(I) the 7- amino -3- vinyl -3- cephem -4- carboxylic acids shown in, the 4- methyl -5- halo thiazoles shown in formula (II), formula (III)
Shown ionic liquid, inorganic base or organic base, palladium and triphenylphosphine are added in reactor, in reacting 1 at 10~150 DEG C
~10 hours terminate, then the post-treated Cefditoren pivoxil Cephalosporins parent nucleus obtained shown in formula (IV),
In formula (III), R is the alkyl of carbon number 1~10, L-It is BF4 -Or BF6 -。
Reaction equation is as follows：
Further, X is chlorine, the bromine or iodine in halogen in the formula (II).
Further, it is described to post-process as reaction terminates, saturated sodium bicarbonate solution is added, adjust pH=8~10, reaction solution
Extracted with dichloromethane, extract anhydrous sodium sulfate drying, filtering, concentration, ethyl alcohol recrystallization is obtained as shown in formula (IV)
Cefditoren pivoxil Cephalosporins parent nucleus product.
Further, the 4- methyl -5- halo thiazoles and 7- amino -3- vinyl -3- cephem -4- carboxylic acids feed intake thing
The ratio of the amount of matter is (1~1.5)：1.
Further, the quality that feeds intake of the ionic liquid and the 7- amino -3- vinyl -3- cephem -4- carboxylic acids
Than being (5~20)：1.
Further, described inorganic or organic base is sodium carbonate, potassium carbonate or triethylamine.
Further, the sodium carbonate, potassium carbonate or triethylamine and 7- amino -3- vinyl -3- cephem -4- carboxylic acids are thrown
The ratio of the amount of material matter is (1~1.5):1.
Further, the palladium and triphenylphosphine and 7- amino -3- vinyl -3- cephem -4- carboxylic acids feed intake thing
The ratio of the amount of matter is (0.01~1)：(0.01~1)：1.
The present invention changes reaction process condition by the use of ionic liquid as reaction medium, has innovated a kind of new cephalo appropriate
Logical sequence pivoxil parent nucleus synthetic method, the technology is easy to operate, and reactions steps are few, and convenient post-treatment, product purity is high, and ionic liquid can be again
Life is used, and is economical and practical green environmental protection technique, is a kind of green synthesis method for studying antibiotics.
Specific embodiment
Embodiment 1：In 100 milliliters of there-necked flasks, 7- amino -3- vinyl -3- cephem -4- carboxylic acids 2.26g is added
(10mmol), 4- methyl-5-chloro thiazoles 1.34g (10mmol), 1- methyl -3- butyl imidazole tetrafluoroborate ion liquids
22.6g, palladium 0.224g (1mmol), triphenylphosphine 0.26g (1mmol), triethylamine 1.0g (10mmol) add reactor
In, to be reacted 10 hours at 50 DEG C, reaction terminates, and adds saturated sodium bicarbonate solution, adjusts pH=8~10, reaction solution dichloro
5 × 3mL of methane is extracted 3 times, extract anhydrous sodium sulfate drying, and concentration, ethyl alcohol recrystallization obtains faint yellow solid product
2.62g, yield 81%.Purity 99%.Fusing point：220 DEG C of decomposition.MS：M/e=323 (M+)。
Embodiment 2：In 100 milliliters of there-necked flasks, 7- amino -3- vinyl -3- cephem -4- carboxylic acids 2.26g is added
(10mmol), 4- methyl -5- bromo thiazoles 1.78g (10mmol), 1- methyl -3- butyl imidazole tetrafluoroborate ion liquids
22.6g, palladium 0.224g (1mmol), triphenylphosphine 0.26g (1mmol), triethylamine 1.0g (10mmol) add reactor
In, to be reacted 5 hours at 50 DEG C, reaction terminates, and adds saturated sodium bicarbonate solution, adjusts pH=8~10, reaction solution dichloromethane
5 × 3mL of alkane is extracted 3 times, extract anhydrous sodium sulfate drying, and concentration, ethyl alcohol recrystallization obtains faint yellow solid product
2.72g, yield 84%.Purity 99%.Fusing point：220 DEG C of decomposition.MS：M/e=323 (M+)。
Embodiment 3：In 100 milliliters of there-necked flasks, 7- amino -3- vinyl -3- cephem -4- carboxylic acids 2.26g is added
(10mmol), 4- methyl -5- iodine thiazoles 2.25g (10mmol), 1- methyl -3- butyl imidazole tetrafluoroborate ion liquids
22.6g, palladium 0.224g (1mmol), triphenylphosphine 0.26g (1mmol), triethylamine 1.0g (10mmol) add reactor
In, to be reacted 10 hours at 10 DEG C, reaction terminates, and adds saturated sodium bicarbonate solution, adjusts pH=8~10, reaction solution dichloro
5 × 3mL of methane is extracted 3 times, extract anhydrous sodium sulfate drying, and concentration, ethyl alcohol recrystallization obtains faint yellow solid product
2.65g, yield 82%.Purity 99%.Fusing point：220 DEG C of decomposition.MS：M/e=323 (M+)。
Embodiment 4：In 100 milliliters of there-necked flasks, 7- amino -3- vinyl -3- cephem -4- carboxylic acids 2.26g is added
(10mmol), 4- methyl-5-chloro thiazoles 2.0g (15mmol), 1- methyl -3- hexyl imidazolium tetrafluoroborate ion liquid 45g,
Palladium 0.25g (1.1mmol), triphenylphosphine 0.29g (1.1mmol), triethylamine 1.0g (10mmol) are added in reactor,
Reacted 1 hour at 100 DEG C, reaction terminates, add saturated sodium bicarbonate solution, adjust pH=8~10, reaction solution dichloromethane 5
× 3mL is extracted 3 times, extract anhydrous sodium sulfate drying, and concentration, ethyl alcohol recrystallization obtains faint yellow solid product 2.62g, is received
Rate 81%.Purity 99%.Fusing point：220 DEG C of decomposition.MS：M/e=323 (M+)。
Embodiment 5：In 100 milliliters of there-necked flasks, 7- amino -3- vinyl -3- cephem -4- carboxylic acids 2.26g is added
(10mmol), 4- methyl -5- bromo thiazoles 1.78g (10mmol), 1- methyl -3- octylimidazole tetrafluoroborate ion liquid 12g,
Palladium 0.224g (1mmol), triphenylphosphine 0.26g (1mmol), triethylamine 1.0g (10mmol) are added in reactor, 50
Reacted 10 hours at DEG C, reaction terminates, addition saturated sodium bicarbonate solution, tune pH=8~10, reaction solution dichloromethane 5 ×
3mL is extracted 3 times, extract anhydrous sodium sulfate drying, and concentration, ethyl alcohol recrystallization obtains faint yellow solid product 2.65g, yield
82%.Purity 99%.Fusing point：220 DEG C of decomposition.MS：M/e=323 (M+)。
Embodiment 6：In 100 milliliters of there-necked flasks, 7- amino -3- vinyl -3- cephem -4- carboxylic acids 2.26g is added
(10mmol), 4- methyl-5-chloro thiazoles 1.34g (10mmol), 1- methyl -3- decyl tetrafluoroborate ionic liquids
22.6g, palladium 0.224g (1mmol), triphenylphosphine 0.26g (1mmol), potassium carbonate 1.4g (10mmol) add reactor
In, to be reacted 5 hours at 150 DEG C, reaction terminates, and adds saturated sodium bicarbonate solution, adjusts pH=8~10, reaction solution dichloro
5 × 3mL of methane is extracted 3 times, extract anhydrous sodium sulfate drying, and concentration, ethyl alcohol recrystallization obtains faint yellow solid product
2.65g, yield 82%.Purity 99%.Fusing point：220 DEG C of decomposition.MS：M/e=323 (M+)。
Embodiment 7：In 100 milliliters of there-necked flasks, 7- amino -3- vinyl -3- cephem -4- carboxylic acids 2.26g is added
(10mmol), 4- methyl -5- bromo thiazoles 2.2g (12mmol), 1- methyl -3- hexyl imidazolium tetrafluoroborate ion liquids
22.6g, palladium 0.224g (1mmol), triphenylphosphine 0.26g (1mmol), sodium carbonate 1.1g (10mmol) add reactor
In, to be reacted 5 hours at 100 DEG C, reaction terminates, and adds saturated sodium bicarbonate solution, adjusts pH=8~10, reaction solution dichloro
5 × 3mL of methane is extracted 3 times, extract anhydrous sodium sulfate drying, and concentration, ethyl alcohol recrystallization obtains faint yellow solid product
2.8g, yield 87%.Purity 99%.Fusing point：220 DEG C of decomposition.MS：M/e=323 (M+)。
Claims (8)
1. the synthetic method of Cefditoren pivoxil Cephalosporins parent nucleus of the one kind as shown in formula (IV), it is characterised in that：The synthetic method be by
7- amino -3- vinyl -3- cephem -4- carboxylic acids shown in quantitative formula (I), the 4- methyl -5- halo thiophenes shown in formula (II)
Azoles, the ionic liquid shown in formula (III), inorganic base or organic base, palladium and triphenylphosphine are added in reactor, in 10~150
Reaction terminates for 1~10 hour at DEG C, then the post-treated Cefditoren pivoxil Cephalosporins parent nucleus obtained shown in formula (IV),
In formula (III), R is the alkyl of carbon number 1~10, L-It is BF4 -Or BF6 -。
2. the synthetic method of the Cefditoren pivoxil Cephalosporins parent nucleus as shown in formula (IV) according to claim 1, it is characterised in that：
X is chlorine, the bromine or iodine in halogen in the formula (II).
3. the synthetic method of the Cefditoren pivoxil Cephalosporins parent nucleus as shown in formula (IV) according to claim 1, it is characterised in that：
The post processing terminates for reaction, adds saturated sodium bicarbonate solution, adjusts pH=8~10, and reaction solution is extracted with dichloromethane, extraction
Liquid anhydrous sodium sulfate drying is taken, is filtered, concentration, the Cefditoren pivoxil Cephalosporins parent nucleus that ethyl alcohol recrystallization obtains as shown in formula (IV) is produced
Product.
4. the synthetic method of the Cefditoren pivoxil Cephalosporins parent nucleus as shown in formula (IV) according to claim 1, it is characterised in that：
4- methyl -5- the halo thiazoles and 7- amino -3- vinyl -3- cephem -4- carboxylic acids feed intake material amount ratio for 1~
1.5：1.
5. the synthetic method of the Cefditoren pivoxil Cephalosporins parent nucleus as shown in formula (IV) according to claim 1, it is characterised in that：
The mass ratio that feeds intake of the ionic liquid and the 7- amino -3- vinyl -3- cephem -4- carboxylic acids is 5~20：1.
6. the synthetic method of the Cefditoren pivoxil Cephalosporins parent nucleus as shown in formula (IV) according to claim 1, it is characterised in that：
Described inorganic or organic base is sodium carbonate, potassium carbonate or triethylamine.
7. the synthetic method of the Cefditoren pivoxil Cephalosporins parent nucleus as shown in formula (IV) according to claim 6, it is characterised in that：
The sodium carbonate, potassium carbonate or triethylamine and 7- amino -3- vinyl -3- cephem -4- carboxylic acids feed intake material amount ratio be 1
~1.5:1.
8. the synthetic method of the Cefditoren pivoxil Cephalosporins parent nucleus as shown in formula (IV) according to claim 1, it is characterised in that：
The palladium and triphenylphosphine and 7- amino -3- vinyl -3- cephem -4- carboxylic acids feed intake material amount ratio for 0.01~
1：0.01~1：1.
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| WO2005100369A1 (en) * | 2004-04-13 | 2005-10-27 | Ranbaxy Laboratories Limited | Depletion of e-isomers in preparation of z-enriched 3-(2-substituted vinyl) cephalosporins |
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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. Applicant after: Pei Wen Address before: Taizhou City, Zhejiang province 318020 gate Huangyan Jiangkou Road Economic Development Zone No. 10 Applicant before: Shandong Changyi Sifang Pharmaceutical Co., Ltd. Applicant before: Pei Wen |
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