CN110372727A - Cefoperon acid δ3Isomers and Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers - Google Patents
Cefoperon acid δ3Isomers and Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers Download PDFInfo
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- CN110372727A CN110372727A CN201910536047.2A CN201910536047A CN110372727A CN 110372727 A CN110372727 A CN 110372727A CN 201910536047 A CN201910536047 A CN 201910536047A CN 110372727 A CN110372727 A CN 110372727A
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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
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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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- 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
- C07D501/60—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 3 and 4
Abstract
The invention discloses a kind of cefoperon acid δ3Isomers and Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers, wherein cefoperon acid δ3Isomers is prepared as follows: pure water and tetrahydrofuran being added in the reaction vessel, is cooled to 0-5 DEG C, 7-ATCA δ is added3Isomers and AE active ester (MAEM), it finishes, organic base is added dropwise and controls pH8.0-8.5, needs to add organic base during reaction by pH and is maintained at 8.0-8.5, methylene chloride and water are added after reaction, stirring is extracted, it is then allowed to stand layering, lower organic layer discards, and upper aqueous layer adjusts pH3.0-3.5, agitation and filtration, washing are dried to obtain product.The cefoperon acid δ of preparation method preparation provided by the invention3Isomers and Cefditoren pivoxil Cephalosporins δ3Content of isomer can achieve 93.0% or more.
Description
Technical field
The present invention relates to a kind of cefoperon acid δ3Isomers and Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers, belongs to
Impurity analysis field in pharmaceutical synthesis.
Background technique
Cefditoren pivoxil Cephalosporins (Cefditoren Pivoxil), entitled (6R, 7R) -2,2- dimethyl propylene acyl-oxygen first of chemistry
Base -7- [(Z) -2- (2- amino -4- thiazolyl) -2- methoxyl group imido acetamido] -3- [(Z) -2- (4- methyl-1,3- thiophene
Azoles -5- base) vinyl] -8- oxo -5- thia -1- azabicyclic [4.2.0] oct-2-ene -2- formic acid esters.
Cefditoren pivoxil Cephalosporins is that the ester type of Japanese MingZhi fruit Co., Ltd's exploitation takes orally third generation cephem antibiotics,
It is listed for the first time in Japan within 1994, in April, 2001, trade name Meiact (Meiact) was clinically main to use in Discussion on Chinese Listed
In treatment infection as caused by gram-positive bacteria and Gram-negative bacteria.This product has extensive antibacterial action, especially right
The gram positive bacterias such as staphylococcus, streptococcus (including streptococcus pneumonia), Escherichia coli, catarrh Blanc sweat coccus, Cray are white
The anaerobic bacterias such as the gram-negative bacterias such as Bacillus, Proteus, haemophilus influenzae and Peptostreptococcus, Bacteroides
Antibacterial ability it is more superior than existing cephalosporanic olefinic.The medicine mechanism of action be inhibit bacteria cell wall synthesis, have antibacterial spectrum width,
The features such as significant in efficacy, safety and stability, oral absorption is good, blood concentration is high, internal distribution is wide.
The method for the synthesis Cefditoren pivoxil Cephalosporins reported at present is more, such as WO2005016936 and EP0175610.But it is big
Most techniques mainly use the synthetic method reported in US2006/0173175, and route is as follows:
The route reacts to obtain cefoperon acid with AE active ester with cefoperon parent nucleus 7-ATCA, then in sodium iso-octoate
Alkaline condition under at salt be made cefoperon acid sodium, last cefoperon acid sodium reacts to obtain target production with iodometyl pivalate
Product Cefditoren pivoxil Cephalosporins.
In new drug research and development process, the quality of drug is to measure a major criterion of drug quality, the matter of drug
Amount is decided by the curative effect and toxic side effect of drug itself, the i.e. validity and safety of drug first.The effective component of drug
Content is to reflect the important symbol of pharmaceutical purity, and impurity present in drug directly influences the curative effect of drug and may cause
The generation of toxic side effect.The impurity of drug is other chemicals other than the drug of production, the introduction in storage and transport process or generation
Matter, the presence of impurity not only influence the purity of drug, can also bring the active toxic side effect of non-treatment, it is necessary to be controlled.For
Drug is safely and effectively used, the quality standard of drug has the purity of effective ingredient and the limit of impurity more stringent
Regulation, it is however generally that, impurity of the drug more than 0.1% should be identified and quantitative by process for selective.
For medicament research and development personnel, groundwork is not only only that how to obtain the bulk pharmaceutical chemicals (API) of high quality, open
Send out synthesis technology efficient, it is often more important that dopant species, source and the production for how controlling process impurity in research bulk pharmaceutical chemicals
It is raw.Usual researcher first can generated impurity in controlled syntheses technique, be secondly then exploitation efficient impurity synthesis road
Line, to obtain a large amount of impurity reference substance, guarantee every batch of bulk pharmaceutical chemicals quality detection work development (e.g., impurity HPLC positioning,
Dirt content test etc.).
Major impurity present in Cefditoren pivoxil Cephalosporins has:
Cefoperon δ3Isomers and Cefditoren pivoxil Cephalosporins δ3Isomers as Cefditoren pivoxil Cephalosporins quality control in need
The important impurity of research, the impurity reference substance at present mainly by from Cefditoren pivoxil Cephalosporins crude product separation and Extraction obtain, but
It is this method complex steps, low yield, purity is low, and the similar impurity of certain structures, which is difficult to be kept completely separate, to come, to influence to examine
The accuracy of survey.With the propulsion that country works to drug agreement, impurity compound cefoperon δ is determined3Isomers
And the preparation method of 3 isomers of Cefditoren pivoxil Cephalosporins δ, qualified reference substance is provided, it can be to the quality of Cefditoren pivoxil Cephalosporins
Control plays a positive role.
Summary of the invention
In view of the above technical problems, the first object of the present invention is to provide a kind of cefoperon acid δ3The preparation of isomers
Method, the second object of the present invention are to provide a kind of Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers.
To achieve the goals above, the technical solution of the present invention is as follows: a kind of cefoperon acid δ3The preparation method of isomers,
It is characterized by: pure water and tetrahydrofuran are added in the reaction vessel, it is cooled to 0-5 DEG C, 7-ATCA δ is added3Isomers and AE
Active ester (MAEM), finishes, and organic base is added dropwise and controls pH8.0-8.5, needs to add organic base during reaction and is maintained at by pH
Methylene chloride and water is added in 8.0-8.5 after reaction, and stirring is extracted, and is then allowed to stand layering, lower organic layer discards, upper layer
Water layer adjusts pH3.0-3.5, agitation and filtration, and washing is dried to obtain product.
In above scheme: during reaction, needing to add a certain amount of AE active ester (MAEM).Be conducive to react in this way into
Row, improves the yield and product quality of reaction.
In above scheme, preferably: the 7-ATCA δ being added in first set reaction3Isomers rubs with AE active ester (MAEM's)
, than being 1:1.1-1.3, the amount of the AE active ester added (MAEM) is the 0.1-0.2 for AE active ester (MAEM) amount being added for the first time for you
Times.
In above scheme, 7-ATCA δ3Isomers the preparation method comprises the following steps: 7-ATCA and dichloromethane are added in the reaction vessel
Alkane, is added silylating reagent under nitrogen protection, stirring to all dissolution clarifications, is then cooled to 20 DEG C hereinafter, organic base is added,
It is stirred to react, then is warming up to 25-30 DEG C, continue stirring to fully reacting；
After having reacted, purified water is first added, stirs, is then allowed to stand, separates water layer, water layer is washed with methylene chloride, washing
It is cooling after complete, pH3.5-4.5 is adjusted, is precipitated crystal, is filtered, filter cake pure water, then filter cake is suspended in methanol, is heated
Dissolution, is filtered, filtrate crystallisation by cooling while hot, is filtered, and filter cake acetone washing is finally dried under reduced pressure to obtain product.
In above scheme: the bis- di (trimethyl silicon based) ethanamides of silylating reagent N, O-, hexamethyldisilane amine, double trimethyl silicanes
One of urea, bis- (trimethyl silane) trifluoroacetamides.
In above scheme: the organic base is triethylamine, tri-n-butylamine, diethylamine, diisopropylethylamine, one in pyridine
Kind.
In above scheme: the molar ratio of the 7-ATCA and silylating reagent be 1:1.8-2.2, the 7-ATCA with it is organic
The molar ratio of alkali is 1:1.6-2.0.
The second object of the present invention is achieved in that a kind of Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers, it is special
Sign is: the cefoperon acid δ of any one of claim 1-7 preparation being added in the reaction vessel3Isomers and N, N- dimethyl
Formamide, stirring and dissolving are cooled to -45 DEG C -- and 40 DEG C, excessive iodometyl pivalate is added dropwise, is stirred to react after dripping off, reacts
Reaction solution is added after complete in the ethyl acetate of pre-cooling and the mixed solution of aqueous solution, stirring, is then allowed to stand layering, water layer is abandoned
It goes, organic layer successively uses sodium bicarbonate solution and water washing, and active carbon decoloring, filtering are then added in organic layer, and filtrate subtracts
Pressure distills stirred crystallization after the organic solvent of part, and product is obtained by filtration.
In above scheme: the cefoperon acid δ3The molar ratio of isomers and n,N-Dimethylformamide is 1:1.1-
1.3.The mixed solution of the ethyl acetate and aqueous solution need to be cooled to 0-10 DEG C in advance.
The utility model has the advantages that preparation method step provided by the invention is simple, and it is at low cost, it is appropriate for prepare with scale.This hair
The cefoperon acid δ of the preparation method preparation of bright offer3Isomers and Cefditoren pivoxil Cephalosporins δ3Content of isomer can achieve
93.0% or more, theoretical foundation is provided for drug safety use, the quality standard of Cefditoren pivoxil Cephalosporins is provided effectively
Data are supported, provide effective guarantee for the clinical safety use of drug.
Detailed description of the invention
Fig. 1 is δ prepared by the present invention3The infrared absorpting light spectra of isomers.
Fig. 2 is δ prepared by the present invention3Isomers1H-NMR spectrum.
Fig. 3 is δ prepared by the present invention3Isomers13C-NMR spectrogram.
Fig. 4 is δ prepared by the present invention3The HMBC spectrogram of isomers.
Fig. 5 is δ prepared by the present invention3The mass spectrogram of isomers.
Fig. 6 is 7-ATCA 1H-NMR map.
Fig. 7 is cefoperon acid δ3The mass spectrogram of isomers.
Fig. 8 is cefoperon acid δ3Isomers1H-NMR figure.
Fig. 9 is cefoperon acid δ3Isomers13C-NMR figure.
Figure 10 is Cefditoren pivoxil Cephalosporins δ3The mass spectrogram of isomers.
Figure 11 is Cefditoren pivoxil Cephalosporins δ3Isomers1H-NMR figure.
Specific embodiment
Below by embodiment combination attached drawing, the invention will be further described:
Embodiment 1
7-ATCAδ3The preparation of isomers
7-ATCA 0.1mol and methylene chloride 350ml is added in 1000ml three-necked bottle, BSA is added under nitrogen protection
(the bis- di (trimethyl silicon based) ethanamides of N, O-) 0.18mol, stirring are cooled to 20 DEG C hereinafter, three fourths are then added to all dissolution clarifications
Amine 0.16mol is stirred 40 minutes, is warming up to 25 DEG C -30 DEG C, is stirred to react, and HPLC detects the conversion situation of isomers, has been reacted
350ml purified water is added in Quan Hou, stirs 10 minutes, stands, separates water layer, water layer is washed 3 times with methylene chloride, each 50ml.
Water layer is cooled to 2-5 DEG C, and with 15% salt acid for adjusting pH value 3.5, crystallization is precipitated, stirs 2 hours, and filtering is washed with cold purifying
Filter cake is washed, is filtered dry.Wet product is suspended in 450ml methanol, dissolves by heating, filters while hot, filtrate crystallisation by cooling, is filtered, filter cake
It with acetone washing, is dried under reduced pressure, obtains product, be yellow crystalline powder, purity 93.3%.
Embodiment 2
7-ATCAδ3The preparation of isomers
7-ATCA 0.1mol and methylene chloride 350ml is added in 1000ml three-necked bottle, BSA is added under nitrogen protection
(the bis- di (trimethyl silicon based) ethanamides of N, O-) 0.22mol, stirring are cooled to 20 DEG C hereinafter, diethyl is then added to all dissolution clarifications
Amine 0.2mol is stirred 30 minutes, is warming up to 25 DEG C -30 DEG C, is stirred to react, and HPLC detects the conversion situation of isomers, has been reacted
350ml purified water is added in Quan Hou, stirs 10 minutes, stands, separates water layer, water layer is washed 3 times with methylene chloride, each 50ml.
Water layer is cooled to 2-5 DEG C, and with 10% salt acid for adjusting pH value 4.5, crystallization is precipitated, stirs 2 hours, filtering, the cold purifying of filter cake
Water washing is filtered dry.Wet product is suspended in 450ml methanol, dissolves by heating, filters while hot, filtrate crystallisation by cooling, is filtered, filter cake
It with acetone washing, is dried under reduced pressure, obtains product, be yellow crystalline powder, purity 93.0%.
Embodiment 3
7-ATCAδ3The preparation of isomers
7-ATCA 0.1mol and methylene chloride 350ml is added in 1000ml three-necked bottle, BSA is added under nitrogen protection
(the bis- di (trimethyl silicon based) ethanamides of N, O-) 0.2mol, stirring are cooled to 20 DEG C hereinafter, triethylamine is then added to all dissolution clarifications
0.18mol is stirred 25 minutes, is warming up to 25 DEG C -30 DEG C, is stirred to react, and HPLC detects the conversion situation of isomers, fully reacting
Afterwards, 350ml purified water is added, stirs 10 minutes, stands, separates water layer, water layer is washed 3 times with methylene chloride, each 50ml.Water
Layer is cooled to 2-5 DEG C, and with 10% salt acid for adjusting pH value 4.0, crystallization is precipitated, stirs 2 hours, filtering, the cold purified water of filter cake
Washing, is filtered dry.Wet product is suspended in 450ml methanol, dissolves by heating, filters while hot, filtrate crystallisation by cooling, is filtered, filter cake is used
Acetone washing is dried under reduced pressure, and obtains product, is yellow crystalline powder, purity 93.2%.
Embodiment 4
7-ATCAδ3The preparation of isomers
7-ATCA 0.1mol and methylene chloride 350ml is added in 1000ml three-necked bottle, pregnancy is added under nitrogen protection
Base disilazane 0.2mol, stirring are cooled to 20 DEG C hereinafter, diisopropylethylamine is then added to all dissolution clarifications
0.19mol is stirred 30 minutes, is warming up to 25 DEG C -30 DEG C, is stirred to react, and HPLC detects the conversion situation of isomers, fully reacting
Afterwards, 350ml purified water is added, stirs 10 minutes, stands, separates water layer, water layer is washed 3 times with methylene chloride, each 50ml.Water
Layer is cooled to 2-5 DEG C, and with 10% salt acid for adjusting pH value 4.0, crystallization is precipitated, stirs 2 hours, filtering, the cold purified water of filter cake
Washing, is filtered dry.Wet product is suspended in 450ml methanol, dissolves by heating, filters while hot, filtrate crystallisation by cooling, is filtered, filter cake is used
Acetone washing is dried under reduced pressure, and obtains product, is yellow crystalline powder, purity 93.5%.
Embodiment 5
7-ATCAδ3The preparation of isomers
7-ATCA 0.1mol and methylene chloride 350ml is added in 1000ml three-necked bottle, double three are added under nitrogen protection
Methyl silicon urea 0.2mol, stirring to all dissolution clarification, be cooled to 20 DEG C hereinafter, then be added pyridine 0.2mol, stir 30 points
Clock is warming up to 25 DEG C -30 DEG C, is stirred to react, and HPLC detects the conversion situation of isomers, and after fully reacting, 350ml purifying is added
Water stirs 10 minutes, stands, separates water layer, water layer is washed 3 times with methylene chloride, each 50ml.Water layer is cooled to 2-5 DEG C, uses
Crystallization is precipitated in 16% salt acid for adjusting pH value 4.0, stirs 2 hours, and filtering, the cold purifying water washing of filter cake is filtered dry.By wet product
It is suspended in 450ml methanol, dissolves by heating, filter while hot, filtrate crystallisation by cooling, filter, filter cake acetone washing, decompression is dry
It is dry, product is obtained, is yellow crystalline powder, purity 93.0%.
Embodiment 6
7-ATCAδ3The preparation of isomers
7-ATCA 0.1mol and methylene chloride 350ml is added in 1000ml three-necked bottle, is added under nitrogen protection double
(trimethyl silane) trifluoroacetamide 0.2mol, stirring are cooled to 20 DEG C hereinafter, triethylamine is then added to all dissolution clarifications
0.18mol is stirred 30 minutes, is warming up to 25 DEG C -30 DEG C, is stirred to react, and HPLC detects the conversion situation of isomers, fully reacting
Afterwards, 350ml purified water is added, stirs 10 minutes, stands, separates water layer, water layer is washed 3 times with methylene chloride, each 50ml.Water
Layer is cooled to 2-5 DEG C, and with 20% salt acid for adjusting pH value 4.2, crystallization is precipitated, stirs 2 hours, filtering, the cold purified water of filter cake
Washing, is filtered dry.Wet product is suspended in 450ml methanol, dissolves by heating, filters while hot, filtrate crystallisation by cooling, is filtered, filter cake is used
Acetone washing is dried under reduced pressure, and obtains product, is yellow crystalline powder, purity 93.1%.
7-ATCA 1H-NMR spectrum analysis
The hydrogen nuclear magnetic resonance spectrum of 7-ATCA is tested using Bruker Avance DMX500 NMR spectrometer with superconducting magnet, molten
Agent is DMSO-d6.Test data and chemical shift ownership are shown in Table 1,1H-NMR map and see Fig. 6.The results show that each proton in structure
Chemical shift and the structure of this product coincide, and it is consistent in data in literature (WO2005/016936A2).
C13H13N3O3S2=323.39
1 7-ATCA of table1H-NMR modal data and chemical shift ownership
δ3The structural confirmation of isomers
7-ATCAδ3The chemical structural formula of isomers, molecular formula and molecular weight are as follows:
C13H13N3O3S2=323.39
1, Fourier Transform Infrared Spectroscopy (FT-IR) is analyzed
Test method: KBr tabletting
Table 2 is the ir data and ownership of sample.
Fig. 1 is the infrared absorpting light spectra of sample.
The absorption peak position of sample key functional groups is consistent with structure it can be seen from map and data analysis.
2 sample ir data of table and ownership
| Absorption peak (cm-1) | Ownership |
| 3422 | O-H stretching vibration |
| 1763 | C=O stretching vibration |
| 1618 | C=C stretching vibration |
| 1384 | C-H bending vibration |
| 1080 | C-O stretching vibration |
| 715 | C-H out-of-plane bending vibration |
2, nmr analysis
Test condition: solvent DMSO-d6；TMS is internal standard
Table 3 is sample1H-NMR and13C-NMR spectral data and ownership.
Fig. 2 is sample1H-NMR spectrum.
Fig. 3 is sample13C-NMR spectrogram.
Fig. 4 is the HMBC spectrogram of sample.
It can be seen from map and data analysis compared with 7-ATCA, a proton is had more at 5, has lacked one at 7
The chemical shift of proton, each proton and carbon is consistent with structure, and each proton has correlation with the carbon in structure, illustrates sample structure
For target product.
3 sample of table1H-NMR and13C-NMR spectral data and ownership
3, high resolution mass spectrum
The high resolution mass spectrum figure of acquisition is shown in Fig. 5.As seen from the figure, this product molecular ion peak is 323.0397, with molecular formula
C13H13N3O3S2And molecular weight 323.39 matches.
Embodiment 7
Cefoperon acid δ3The preparation method of isomers,
Pure water 300ml and tetrahydrofuran 60ml is added in the reaction vessel, is cooled to 0-5 DEG C, 7-ATCA δ is added3Isomery
Body 10g (0.03mol) and AE active ester (MAEM) 0.039mol, finishes, and organic bases triethylamine is added dropwise and controls pH8.0-8.5, instead
2h is answered, needs to add triethylamine during reaction and is maintained at 8.0-8.5 by pH.
AE active ester (MAEM) 0.0039mol is added, while adding triethylamine and being maintained at 8.0-8.5 by pH, the reaction was continued
1h。
Methylene chloride 100ml, pure water 100ml are added after reaction, stirs 10min, stratification, lower organic layer is abandoned
It goes, upper aqueous layer adjusts pH3.0-3.5 with hydrochloric acid solution, stirs, filtering.Filter cake is washed with water, and drains, and vacuum drying is produced
Product, purity 93.5%, yield 90%.
Embodiment 8
Cefoperon acid δ3The preparation method of isomers
Pure water 300ml and tetrahydrofuran 60ml is added in the reaction vessel, is cooled to 0-5 DEG C, 7-ATCA δ is added3Isomery
Body 10g (0.03mol) and AE active ester (MAEM) 0.033mol, finishes, and organic base tri-n-butylamine is added dropwise and controls pH8.0-8.5, instead
2h is answered, needs to add tri-n-butylamine during reaction and is maintained at 8.0-8.5 by pH.
AE active ester (MAEM) 0.0078mol is added, while adding tri-n-butylamine and being maintained at 8.0-8.5 by pH, the reaction was continued
1h。
Methylene chloride 100ml, pure water 100ml are added after reaction, stirs 10min, stratification, lower organic layer is abandoned
It goes, upper aqueous layer adjusts pH3.0-3.5 with hydrochloric acid solution, stirs, filtering.Filter cake is washed with water, and drains, and vacuum drying is produced
Product, purity 94.0%, yield 89.5%.
Embodiment 9
Cefoperon acid δ3The preparation method of isomers
Pure water 300ml and tetrahydrofuran 60ml is added in the reaction vessel, is cooled to 0-5 DEG C, 7-ATCA δ is added3Isomery
Body 10g (0.03mol) and AE active ester (MAEM) 0.036mol, finishes, and organic base diisopropylethylamine is added dropwise and controls pH8.0-
8.5,2h is reacted, needs to add diisopropylethylamine during reaction and is maintained at 8.0-8.5 by pH.
AE active ester (MAEM) 0.0072mol is added, while adding diisopropylethylamine and being maintained at 8.0-8.5 by pH, after
Continuous reaction 1h.
Methylene chloride 100ml, pure water 100ml are added after reaction, stirs 10min, stratification, lower organic layer is abandoned
It goes, upper aqueous layer adjusts pH3.0-3.5 with hydrochloric acid solution, stirs, filtering.Filter cake is washed with water, and drains, and vacuum drying is produced
Product, purity 94.2%, yield 88.3%.
Embodiment 10
The appropriate logical sequence acid δ of spore3The preparation method of isomers
Pure water 300ml and tetrahydrofuran 60ml is added in the reaction vessel, is cooled to 0-5 DEG C, 7-ATCA δ is added3Isomery
Body 10g (0.03mol) and AE active ester (MAEM) 0.035mol, finishes, and organic base pyridine is added dropwise and controls pH8.0-8.5, reaction
2h, needs to add pyridine during reaction and is maintained at 8.0-8.5 by pH.
AE active ester (MAEM) 0.0070mol is added, while adding pyridine and being maintained at 8.0-8.5 by pH, the reaction was continued 1h.
Methylene chloride 100ml, pure water 100ml are added after reaction, stirs 10min, stratification, lower organic layer is abandoned
It goes, upper aqueous layer adjusts pH3.0-3.5 with hydrochloric acid solution, stirs, filtering.Filter cake is washed with water, and drains, and vacuum drying is produced
Product, purity 93.8%, yield 87.9%.
Cefoperon acid δ3The structural confirmation of isomers:
Cefoperon δ3[(Z) -2- (2- amino -4- thiazolyl) -2- methoxyl group is sub- by entitled (6R, the 7R) -7- of isomers chemistry
Ammonia acetylamino] -3- [(Z) -2- (4- methylthiazol -5- base) vinyl] -8- oxo -5- thia -1- azabicyclo [4.2.0]
Octyl- 3- alkene -2- carboxylic acid, molecular formula C19H18N6O5S3, molecular weight 506.58, structural formula are as follows:
1, mass spectral analysis
Sample mass spectrum is as follows:
As seen from Figure 7, this product molecular ion peak of acquisition is m/z507.0 (M+1).With this product molecular formula
C19H18N6O5S3It matches with molecular weight 506.58.
2, nuclear magnetic resonance spectroscopy (1H-NMR) and spectrum analysis
(1) instrument for testing: BRUKR company, Switzerland AC-600 Nuclear Magnetic Resonance.
(2) determination condition: with CD3OD is solvent, and TMS is internal standard.
Test map is shown in Fig. 8, is as a result listed in the table below.
| Serial number | Chemical shift | Multiplicity | Proton number | Corresponding proton |
| 1 | 2.41 | s | 3H | 23-CH3 |
| 2 | 3.96 | s | 3H | 16-CH3 |
| 3 | 4.66 | s | 1H | 2-CH |
| 4 | 5.50 | d | 1H | 6-H- |
| 5 | 5.65 | d | 1H | 7-H- |
| 6 | 6.25 | s | 1H | 4-CH |
| 7 | 6.32 | d | 1H | 18-CH= |
| 8 | 6.58 | d | 1H | 19-CH= |
| 9 | 6.88 | s | 1H | 13-CH- |
| 10 | 8.65 | s | 1H | 22-CH- |
2.41 be 23-CH on methylthiazol ring3Corresponding hydrogen signal peak；
3.99 be=NOCH3That is 16-H signal peak；
4.66 be the corresponding hydrogen signal peak 2-CH；
5.50 and 5.65 be respectively 6-H and 7-H signal peak；
6.25 be the corresponding hydrogen signal peak 4-CH；
6.32 be the corresponding hydrogen signal peak 18-CH=；
6.58 be the corresponding hydrogen signal peak 19-CH=；
6.88 be the corresponding hydrogen signal peak 13-CH on aminothiazole ring；
8.65 be the corresponding hydrogen signal peak 22-CH on methylthiazol ring.
3, carbon-13 nmr spectra (13C-NMR)
(1) instrument for testing: BRUKR company, Switzerland AC-600 Nuclear Magnetic Resonance.
(2) determination condition: with CD3OD is solvent.
Map is tested as shown in figure 9, test result is listed in the table below.
| Carbon sequence number | Chemical shift (ppm) | Carbon ownership |
| 1 | 13.83 | 23-CH3 |
| 2 | 53.08 | 7-CH |
| 3 | 54.68 | 6-CH |
| 4 | 59.66 | 2-CH |
| 5 | 61.55 | 16-CH3 |
| 6 | 110.59 | 13-CH |
| 7 | 118.78 | 19-CH= |
| 8 | 118.96 | 4-CH |
| 9 | 123.17 | 20-C |
| 10 | 127.61 | 21-C |
| 11 | 130.39 | 3-C |
| 12 | 142.03 | 18-CH= |
| 13 | 148.37 | 12-C |
| 14 | 151.45 | 11-C |
| 15 | 151.75 | 22-CH |
| 16 | 163.35 | 10-C |
| 17 | 164.06 | 8-C |
| 18 | 169.99 | 14-C |
13.83 be 23-CH on methylthiazol ring3Signal peak；
53.08 and 54.68 be respectively 6-CH and 7-CH signal peak on beta-lactam nucleus；
59.66 being 2-CH signal peak；
61.55 for=NOCH3That is 16-CH3Signal peak；
110.59 be 13-CH signal peak on aminothiazole ring；
118.78 being 19-CH=signal peak；
118.96 being 4-CH signal peak；
123.17 be 20-CH signal peak on methylthiazol ring；
127.61 be 21-C signal peak on methylthiazol ring；
130.39 being 3-C signal peak；
142.03 being 18-CH=signal peak；
148.37 be 12-C signal peak on aminothiazole ring；
151.45 being 11-C=N signal peak；
151.75 be 22-CH signal peak on methylthiazol ring；
163.35 being 10-C=O signal peak；
164.06 be 8-C signal peak on beta-lactam nucleus；
169.99 be 14-C signal peak on aminothiazole ring.
Structural confirmation and cefoperon δ3Isomers is consistent.
Embodiment 11
Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers
The cefoperon acid δ of preparation is added in the reaction vessel3Isomers 0.13mol and n,N-Dimethylformamide
50ml, stirring and dissolving are cooled to -45 DEG C -- 40 DEG C, iodometyl pivalate 0.143mol is added dropwise, temperature is controlled always -45
DEG C -- 40 DEG C, be stirred to react after dripping off, after having reacted by reaction solution be added in advance be cooled to 0-10 DEG C 1000ml ethyl acetate and
In the mixed solution of 950ml aqueous solution, stirring is then allowed to stand layering, the reusable pre- 500ml acetic acid second for being cooled to 0-10 DEG C of water layer
Ester extracts once, and combined ethyl acetate layer, water layer discarded, ethyl acetate layer is again successively with 0.1% sodium bicarbonate solution and washing
It washs, needs first to be cooled to 0-10 DEG C in advance for the sodium bicarbonate solution of washing and the temperature of water, activity is then added in organic layer
Charcoal 7g stirring is decolourized, and 0-10 DEG C of temperature is kept in decolorization, filtering, filtrate is evaporated under reduced pressure to remaining at 30-40 DEG C
500ml, adjustment temperature are 35-40 DEG C of stirred crystallization, are filtered, filter cake is cleaned with ethyl acetate, is dried under reduced pressure to obtain product
0.09mol。
Embodiment 12
Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers
The cefoperon acid δ of preparation is added in the reaction vessel3Isomers 0.13mol and n,N-Dimethylformamide
50ml, stirring and dissolving are cooled to -45 DEG C -- 40 DEG C, iodometyl pivalate 0.17mol is added dropwise, temperature is controlled always at -45 DEG C --
It 40 DEG C, is stirred to react after dripping off, the pre- 1000ml ethyl acetate and 950ml water for being cooled to 0-10 DEG C is added in reaction solution after having reacted
In the mixed solution of solution, stirring is then allowed to stand layering, and the reusable pre- 500ml ethyl acetate for being cooled to 0-10 DEG C of water layer extracts
Once, combined ethyl acetate layer, water layer discarded, ethyl acetate layer successively with 0.1% sodium bicarbonate solution and water washing, are used for again
The sodium bicarbonate solution of washing and the temperature of water need first to be cooled to 0-10 DEG C in advance, and active carbon 7g stirring is then added in organic layer
It decolourizes, 0-10 DEG C of temperature is kept in decolorization, filtering, filtrate is evaporated under reduced pressure to remaining 500ml, adjustment temperature at 30-40 DEG C
Degree is 35-40 DEG C of stirred crystallization, is filtered, and filter cake is cleaned with ethyl acetate, is dried under reduced pressure to obtain product 0.098mol.
Cefditoren pivoxil Cephalosporins δ3The structural confirmation of isomers
Cefditoren pivoxil Cephalosporins δ3Isomers: (6R, 7R) -7- [(Z) -2- (2- amino -4- thiazolyl) -2- methoxyl group imido
Acetylamino] -3- [(Z) -2- (4- methylthiazol -5- base) vinyl] -8- oxo -5- thia -1- azabicyclo [4.2.0]
Octyl- 3- alkene -2- carboxylic acid 2,2- dimethyl propylene acyl-oxygen methyl esters, molecular formula C25H28N6O7S3, molecular weight 620.73, structural formula
Are as follows:
1, mass spectral analysis
Sample mass spectrum such as Figure 10, as seen from the figure, this product molecular ion peak of acquisition are m/z621.1 (M+1).With this
Product molecular formula C19H18N6O5S3It matches with molecular weight 620.73.
2, nuclear magnetic resonance spectroscopy (1H-NMR) and spectrum analysis
(
(2) determination condition: with CD3OD is solvent, and TMS is internal standard.
Sample1H-NMR spectrum is shown in Figure 11, and test result is listed in the table below.
| Serial number | Chemical shift | Multiplicity | Proton number | Corresponding proton |
| 1 | 1.16 | s | 9H | 21-CH3 |
| 2 | 2.45 | s | 3H | 27-CH3 |
| 3 | 3.99 | S | 3H | 16-CH3 |
| 4 | 5.11 | s | 1H | 2-CH |
| 5 | 5.44 | d | 1H | 6-CH |
| 6 | 5.73 | d | 1H | 7-CH |
| 7 | 5.76/5.81 | ABq | 2H | 18-CH2- |
| 8 | 6.15 | d | 1H | 24-CH= |
| 9 | 6.62 | s | 1H | 4-CH |
| 10 | 6.68 | d | 1H | 25-CH= |
| 11 | 6.89 | s | 1H | 13-H |
| 12 | 8.76 | s | 1H | 28-CH |
1.16 be-COOCH2OCOC(CH3)3That is 21-CH3Signal peak；
2.45 being 27-CH3Corresponding hydrogen signal peak；
3.99 be=NOCH3That is 16-H signal peak；
5.11 be the corresponding hydrogen signal peak 2-CH；
5.44 and 5.73 be respectively 6-H and 7-H signal peak；
5.76 and 5.81 be 18-CH2Signal peak；
6.15 be the corresponding hydrogen signal peak 24-CH=；
6.62 be the corresponding hydrogen signal peak 4-CH；
6.68 be the corresponding hydrogen signal peak 25-CH=；
6.89 be the corresponding hydrogen signal peak 13-CH；
8.76 be the corresponding hydrogen signal peak 28-CH.
Structural confirmation and Cefditoren pivoxil Cephalosporins δ3Isomers is consistent.
The present invention is not limited to the above embodiment, it will be understood by those skilled in the art that: do not departing from the present invention
Principle and objective in the case where a variety of change, modification, replacement and modification, the scope of the present invention can be carried out to these embodiments
It is defined by the claims and their equivalents.
Claims (10)
1. a kind of cefoperon acid δ3The preparation method of isomers, it is characterised in that: pure water and tetrahydro furan are added in the reaction vessel
It mutters, is cooled to 0-5 DEG C, 7-ATCA δ is added3Isomers and AE active ester (MAEM), finish, and organic base is added dropwise and controls pH8.0-
8.5, it needs to add organic base during reaction by pH and is maintained at 8.0-8.5, methylene chloride is added after reaction and water, stirring mention
It takes, is then allowed to stand layering, lower organic layer discards, and upper aqueous layer adjusts pH3.0-3.5, agitation and filtration, and washing is dried to obtain production
Product.
2. cefoperon acid δ according to claim 13The preparation method of isomers, it is characterised in that: during reaction, need
Add a certain amount of AE active ester (MAEM).
3. cefoperon acid δ according to claim 23The preparation method of isomers, it is characterised in that: add in first set reaction
The 7-ATCA δ entered3The molar ratio of isomers and AE active ester (MAEM) are 1:1.1-1.3, the AE active ester added (MAEM)
Amount is 0.1-0.2 times of AE active ester (MAEM) amount being added for the first time.
4. any one of -3 cefoperon acid δ according to claim 13The preparation method of isomers, which is characterized in that 7-ATCA
δ3Isomers the preparation method comprises the following steps: 7-ATCA and methylene chloride are added in the reaction vessel, silanization examination is added under nitrogen protection
Agent, stirring to all dissolution clarification, be then cooled to 20 DEG C hereinafter, be added organic base, be stirred to react, then be warming up to 25-30 DEG C,
Continue stirring to fully reacting；
After having reacted, purified water is first added, stirs, is then allowed to stand, separates water layer, water layer is washed with methylene chloride, after having washed
It is cooling, pH3.5-4.5 is adjusted, is precipitated crystal, is filtered, filter cake pure water, then filter cake is suspended in methanol, is heated molten
Solution, is filtered, filtrate crystallisation by cooling while hot, is filtered, and filter cake acetone washing is finally dried under reduced pressure to obtain product.
5. cefoperon acid δ according to claim 43The preparation method of isomers, it is characterised in that: stating silylating reagent is
The bis- di (trimethyl silicon based) ethanamides of N, O-, hexamethyldisilane amine, dual-trimethylsilyl urea, in bis- (trimethyl silane) trifluoroacetamides
It is a kind of.
6. cefoperon acid δ according to claim 53The preparation method of isomers, it is characterised in that: the organic base is three
Ethamine, one of tri-n-butylamine, diethylamine, diisopropylethylamine, pyridine.
7. cefoperon acid δ according to claim 63The preparation method of isomers, it is characterised in that: the 7-ATCA and silicon
The molar ratio of Alkylators is 1:1.8-2.2, and the molar ratio of the 7-ATCA and organic base is 1:1.6-2.0.
8. a kind of Cefditoren pivoxil Cephalosporins δ3The preparation method of isomers, it is characterised in that: claim 1- is added in the reaction vessel
The cefoperon acid δ of any one of 7 preparations3Isomers and n,N-Dimethylformamide, stirring and dissolving are cooled to -45 DEG C -- and 40 DEG C,
Excessive iodometyl pivalate is added dropwise, is stirred to react after dripping off, reaction solution is added to the ethyl acetate and water of pre-cooling after having reacted
In the mixed solution of solution, stirring is then allowed to stand layering, and water layer discarded, organic layer successively uses sodium bicarbonate solution and water washing,
Then active carbon decoloring, filtering are added in organic layer, filtrate decompression distills stirred crystallization after the organic solvent of part, filters
To product.
9. Cefditoren pivoxil Cephalosporins δ according to claim 83The preparation method of isomers, it is characterised in that: the cefoperon
Sour δ3The molar ratio of isomers and n,N-Dimethylformamide is 1:1.1-1.3.
10. Cefditoren pivoxil Cephalosporins δ according to claim 93The preparation method of isomers, it is characterised in that: the ethyl acetate
0-10 DEG C need to be cooled in advance with the mixed solution of aqueous solution.
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| CN111233894A (en) * | 2020-01-13 | 2020-06-05 | 浙江东邦药业有限公司 | Cefditoren pivoxil delta3Process for the preparation of isomers |
| CN113788844A (en) * | 2021-09-08 | 2021-12-14 | 湖北凌晟药业有限公司 | Preparation method of E-type cefditoren sodium |
| CN114014876A (en) * | 2021-12-17 | 2022-02-08 | 浙江东邦药业有限公司 | Preparation method of methoxymethyl cefditoren pivoxil |
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Cited By (4)
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| CN111233894A (en) * | 2020-01-13 | 2020-06-05 | 浙江东邦药业有限公司 | Cefditoren pivoxil delta3Process for the preparation of isomers |
| CN111233894B (en) * | 2020-01-13 | 2021-07-09 | 浙江东邦药业有限公司 | Cefditoren pivoxil delta3Process for the preparation of isomers |
| CN113788844A (en) * | 2021-09-08 | 2021-12-14 | 湖北凌晟药业有限公司 | Preparation method of E-type cefditoren sodium |
| CN114014876A (en) * | 2021-12-17 | 2022-02-08 | 浙江东邦药业有限公司 | Preparation method of methoxymethyl cefditoren pivoxil |
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