CN108912145A - A kind of preparation method of α-pivaloyl group Cefditoren pivoxil Cephalosporins - Google Patents
A kind of preparation method of α-pivaloyl group Cefditoren pivoxil Cephalosporins Download PDFInfo
- Publication number
- CN108912145A CN108912145A CN201810889118.2A CN201810889118A CN108912145A CN 108912145 A CN108912145 A CN 108912145A CN 201810889118 A CN201810889118 A CN 201810889118A CN 108912145 A CN108912145 A CN 108912145A
- Authority
- CN
- China
- Prior art keywords
- cefditoren pivoxil
- pivoxil cephalosporins
- pivaloyl group
- pivaloyl
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, 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
Abstract
The present invention provides a kind of α-pivaloyl group Cefditoren pivoxil Cephalosporins preparation methods.The method includes the steps：Cefditoren pivoxil Cephalosporins reacts under alkaline condition with pivaloyl chloride generates α-pivaloyl group Cefditoren pivoxil Cephalosporins.Preparation method of the present invention is easy to operate, reaction condition is mild, product yield is high, with high purity, pollution is few; and the high-purity alpha being prepared-pivaloyl group Cefditoren pivoxil Cephalosporins can be controlled directly as impurity reference substance, the quality for the Cefditoren pivoxil Cephalosporins in production process.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation side of α-pivaloyl group Cefditoren pivoxil Cephalosporins
Method.
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, chemical structure is such as
Shown in lower：
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.But since final step reaction temperature is higher, the dosage of iodometyl pivalate is larger, cause to generate such as hydroxyl
(its structure is such as methyl Cefditoren pivoxil Cephalosporins, α-impurity such as pivaloyl group Cefditoren pivoxil Cephalosporins and Cefditoren pivoxil Cephalosporins dimer
Shown in lower), and related impurities content is higher, directly reduces the drug effect and quality of product, and obtained Cefditoren pivoxil Cephalosporins produces
Product are also hardly consistent with the standard of pharmacopeia.
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.).
α-pivaloyl group Cefditoren pivoxil Cephalosporins as Cefditoren pivoxil Cephalosporins quality control in the important impurity that needs to study it
One, the impurity reference substance at present mainly by from Cefditoren pivoxil Cephalosporins crude product separation and Extraction obtain, but this method step
Cumbersome, low yield, purity is low, and the similar impurity of certain structures, which is difficult to be kept completely separate, to come, to influence the accuracy of detection.With
Country to drug agreement work propulsion, determine impurity compound α-pivaloyl group Cefditoren pivoxil Cephalosporins preparation side
Method provides qualified reference substance, can control the quality of Cefditoren pivoxil Cephalosporins and play a positive role.Therefore, research and
The new efficient α-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method of one kind is provided to have a very important significance.
Summary of the invention
For the related important impurity α of current Cefditoren pivoxil Cephalosporins-, pivaloyl group Cefditoren pivoxil Cephalosporins separation and Extraction is difficult, receives
The problem that rate is low, purity is low, the present invention provides a kind of α of simple and effective-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method,
α-pivaloyl group Cefditoren pivoxil Cephalosporins purity with higher of this method preparation can be used for cephalo directly as impurity reference substance
Quality Control Links in appropriate logical sequence pivoxil production process.
Particular technique content of the invention is as follows：
One kind α as shown in formula (I)-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method, includes the following steps：
1) Cefditoren pivoxil Cephalosporins and alkali are added in organic solvent, after mixing evenly, pivaloyl chloride is added dropwise in control temperature
Organic solvent is added dropwise, and temperature control to reaction terminates；
2) reaction solution is filtered, the purified water of pre-cooling is added in filtrate, after mixing evenly, extractant extraction is added, merges
Organic phase is successively used dilute hydrochloric acid, purified water and saturated common salt water washing, is dried, filtered after washing with anhydrous sodium sulfate, filtrate subtracts
Pressure is concentrated to dryness, and can be obtained α-pivaloyl group Cefditoren pivoxil Cephalosporins after obtained solid is dried in vacuo.
Preferred embodiment, organic solvent described in step 1 are tetrahydrofuran, acetone, acetonitrile, Isosorbide-5-Nitrae-dioxane, acetic acid
Ethyl ester, methylene chloride, chloroform, n,N-Dimethylformamide, one of n,N-dimethylacetamide or combinations thereof, wherein especially
It is preferred that tetrahydrofuran.
Preferred embodiment, alkali described in step 1 be sodium carbonate, sodium bicarbonate, saleratus, sodium iso-octoate, triethylamine, N,
N- diisopropyl ethyl amine, one of pyridine or combinations thereof, wherein particularly preferred triethylamine.
The molar ratio of preferred embodiment, the Cefditoren pivoxil Cephalosporins and alkali and pivaloyl chloride is 1: 2~4: 1.05~
1.8, wherein particularly preferred 1: 2.6: 1.4.
The mass volume ratio of preferred embodiment, Cefditoren pivoxil Cephalosporins described in step 1 and organic solvent is 1: 3~12, g/
mL；The mass volume ratio of pivaloyl chloride and organic solvent is 1: 4~10, g/mL in the organic solvent of the pivaloyl chloride.
Preferred embodiment, the temperature that pivaloyl chloride is added dropwise described in step 1 is -15~10 DEG C, wherein particularly preferred 0~5
℃；Reaction temperature is -15~10 DEG C, wherein particularly preferred 0~5 DEG C.
Preferred embodiment, reaction time described in step 1 are 0.5~4h.
Preferred embodiment, the purifying coolant-temperature gage of pre-cooling described in step 2 are 0~10 DEG C.
The mass ratio of preferred embodiment, Cefditoren pivoxil Cephalosporins described in step 2 and purified water is 1: 8~12.
Preferred embodiment, extractant described in step 2 are ethyl acetate, methylene chloride, chloroform, in methyl tertiary butyl ether(MTBE)
One kind or combinations thereof.
Preferred embodiment, the concentration of dilute hydrochloric acid described in step 2 are 0.1~2.0M.
Preferred embodiment, vacuum drying temperature described in step 2 are 35~40 DEG C.
One kind preparing resulting α-pivaloyl group Cefditoren pivoxil Cephalosporins by any the method for the present invention.
Compared with prior art, what the present invention obtained has the technical effect that：
1. provide a simple and effective prepares α-pivaloyl group Cefditoren pivoxil Cephalosporins method, entire preparation method road
Line is short, and operating procedure is simple, and reaction yield is high, and product purity is high；
2. providing a kind of α-pivaloyl group Cefditoren pivoxil Cephalosporins of high-purity, impurity reference substance can be used as, for giving birth to
The quality of Cefditoren pivoxil Cephalosporins during production controls.
Specific embodiment
The present invention is further illustrated below by embodiment, it should which correct understanding is：The embodiment of the present invention is only
Be for illustrating the present invention, rather than limiting the invention, so, to of the invention simple under the premise of method of the invention
It improves and belongs to the scope of protection of present invention.
The present invention measures α-pivaloyl group Cefditoren pivoxil Cephalosporins purity, chromatographic condition using HPLC：[chromatographic column：
Agilent ZORBAX SB-C18 (4.6mm × 250mm, 5.0 μm)；Mobile phase A：Ammonium formate solution (takes ammonium formate 1.58g, adds
Water 900mL adjusts pH to 4.5 with formic acid solution, is diluted with water to 1000mL)-acetonitrile-methanol (45: 25: 25)；Mobile phase B：
Ammonium formate solution (take ammonium formate 1.58g, add water 900mL, with formic acid solution adjust pH to 4.5, be diluted with water to 1000mL)-second
Nitrile-methanol (45: 55: 55), gradient elution (0 → 5min：A100%；5→40min：A100% → 0；40→50min：A0→
100%)；Column temperature：40℃；Detection wavelength：254nm；Flow velocity：1.0mL·min-1；Sample volume：20μL].
Embodiment 1
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), tetrahydrofuran is added in triethylamine (10.52g, 0.104mol)
In (125mL), after mixing evenly, 0~5 DEG C of the temperature control tetrahydrofuran (35mL) that pivaloyl chloride (6.75g, 0.056mol) is added dropwise is molten
Liquid is added dropwise, and after keeping the temperature 0~5 DEG C of reaction 1.0h, 0~5 DEG C of purified water (250mL), heat preservation 0~5 is added in filtering, filtrate
DEG C stirring 10min after, methylene chloride (100mL × 3) extraction, merge organic layer, 1.0M hydrochloric acid (100mL × 2) wash organic layer,
Purified water (100mL × 2) washs organic layer, and saturated salt solution (100mL × 3) washs organic layer, and anhydrous sodium sulfate is dry, mistake
Filter, filtrate decompression are concentrated to dryness, and 40 DEG C of obtained solid are dried under reduced pressure after 16~18h as α-pivaloyl group Cefditoren pivoxil Cephalosporins,
Yield 86.27%, is detected through HPLC, wherein tR=24.515min is α-pivaloyl group Cefditoren pivoxil Cephalosporins, and purity is
96.93%.
Embodiment 2
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), acetone (150mL) is added in triethylamine (8.10g, 0.08mol)
In, after mixing evenly, acetone (40mL) solution of 0~5 DEG C of temperature control dropwise addition pivaloyl chloride (6.75g, 0.056mol) drips
Finish, after keeping the temperature 0~5 DEG C of reaction 1.0h, 0~5 DEG C of purified water (250mL) is added in filtering, filtrate, keeps the temperature 0~5 DEG C of stirring
After 10min, methylene chloride (100mL × 3) extraction merges organic layer, and 1.0M hydrochloric acid (100mL × 2) washs organic layer, purified water
(100mL × 2) wash organic layer, and saturated salt solution (100mL × 3) washs organic layer, and anhydrous sodium sulfate dries, filters, filtrate
It is concentrated to dryness, 35~40 DEG C of obtained solid are dried under reduced pressure after 16~18h as α-pivaloyl group Cefditoren pivoxil Cephalosporins, yield
80.56%, it is detected through HPLC, wherein tR=24.489min is α-pivaloyl group Cefditoren pivoxil Cephalosporins, purity 96.12%.
Embodiment 3
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), acetonitrile (200mL) is added in triethylamine (16.19g, 0.16mol)
In, after mixing evenly, acetonitrile (35mL) solution of 0~5 DEG C of temperature control dropwise addition pivaloyl chloride (6.75g, 0.056mol) drips
Finish, after keeping the temperature 0~5 DEG C of reaction 1.0h, 0~5 DEG C of purified water (250mL) is added in filtering, filtrate, keeps the temperature 0~5 DEG C of stirring
After 10min, methylene chloride (120mL × 3) extraction merges organic layer, and 2.0M hydrochloric acid (100mL × 2) washs organic layer, purified water
(100mL × 2) wash organic layer, and saturated salt solution (100mL × 3) washs organic layer, and anhydrous sodium sulfate dries, filters, filtrate
It is concentrated to dryness, 35~40 DEG C of obtained solid are dried under reduced pressure after 16~18h as α-pivaloyl group Cefditoren pivoxil Cephalosporins, yield
79.86%, it is detected through HPLC, wherein tR=24.522min is α-pivaloyl group Cefditoren pivoxil Cephalosporins, purity 95.34%.
Embodiment 4
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), tetrahydrofuran is added in triethylamine (10.52g, 0.104mol)
In (125mL), after mixing evenly, 0~5 DEG C of the temperature control tetrahydrofuran (35mL) that pivaloyl chloride (5.06g, 0.042mol) is added dropwise is molten
Liquid is added dropwise, and after keeping the temperature 0~5 DEG C of reaction 2.0h, 0~5 DEG C of purified water (250mL), heat preservation 0~5 is added in filtering, filtrate
DEG C stirring 10min after, methylene chloride (100mL × 3) extraction, merge organic layer, 1.0M hydrochloric acid (100mL × 2) wash organic layer,
Purified water (100mL × 2) washs organic layer, and saturated salt solution (100mL × 3) washs organic layer, and anhydrous sodium sulfate is dry, mistake
Filter, filtrate decompression are concentrated to dryness, and 35~40 DEG C of obtained solid are dried under reduced pressure after 16~18h as α-pivaloyl group cefoperon
Ester, yield 79.53%, is detected through HPLC, wherein tR=24.511min is α-pivaloyl group Cefditoren pivoxil Cephalosporins, and purity is
95.97%.
Embodiment 5
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), tetrahydrofuran is added in triethylamine (10.52g, 0.104mol)
In (125mL), after mixing evenly, the tetrahydrofuran of pivaloyl chloride (8.68g, 0.072mol) is added dropwise in temperature control -10~-5 DEG C
(35mL) solution, is added dropwise, and after keeping the temperature -10~-5 DEG C of reaction 1.0h, 0~5 DEG C of purified water is added in filtering, filtrate
(250mL), after keeping the temperature 0~5 DEG C of stirring 10min, methylene chloride (100mL × 3) extraction merges organic layer, 1.0M hydrochloric acid
(100mL × 2) wash organic layer, and purified water (100mL × 2) washs organic layer, and saturated salt solution (100mL × 3) washing is organic
Layer, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated to dryness, and 35~40 DEG C of obtained solid are dried under reduced pressure after 16~18h as
α-pivaloyl group Cefditoren pivoxil Cephalosporins, yield 80.16% detect, wherein t through HPLCR=24.507min is α-pivaloyl group
Cefditoren pivoxil Cephalosporins, purity 95.89%.
Embodiment 6
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), N, N- dimethyl methyl is added in sodium carbonate (9.75g, 0.092mol)
In amide (200mL), after mixing evenly, the N of 0~5 DEG C of temperature control dropwise addition pivaloyl chloride (6.75g, 0.056mol), N- dimethyl methyl
Amide (60mL) solution, is added dropwise, and after keeping the temperature 0~5 DEG C of reaction 3.0h, 0~5 DEG C of purified water is added in filtering, filtrate
(250mL), after keeping the temperature 0~5 DEG C of stirring 10min, methylene chloride (150mL × 3) extraction merges organic layer, 1.0M hydrochloric acid
(150mL × 2) wash organic layer, and purified water (150mL × 2) washs organic layer, and saturated salt solution (150mL × 3) washing is organic
Layer, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated to dryness, and 35~40 DEG C of obtained solid are dried under reduced pressure after 16~18h as
α-pivaloyl group Cefditoren pivoxil Cephalosporins, yield 82.16% detect, wherein t through HPLCR=24.504min is α-pivaloyl group
Cefditoren pivoxil Cephalosporins, purity 96.12%.
Embodiment 7
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), N, N- dimethyl is added in sodium bicarbonate (7.73g, 0.092mol)
Formamide (200mL), after mixing evenly, the N of 0~5 DEG C of temperature control dropwise addition pivaloyl chloride (6.75g, 0.056mol), N- dimethyl methyl
Amide (60mL) solution, is added dropwise, and after keeping the temperature 0~5 DEG C of reaction 3.0h, 0~5 DEG C of purified water is added in filtering, filtrate
(250mL), after keeping the temperature 0~5 DEG C of stirring 10min, methylene chloride (150mL × 3) extraction merges organic layer, 1.0M hydrochloric acid
(150mL × 2) wash organic layer, and purified water (150mL × 2) washs organic layer, and saturated salt solution (150mL × 3) washing is organic
Layer, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated to dryness, and 35~40 DEG C of obtained solid are dried under reduced pressure after 16~18h as
α-pivaloyl group Cefditoren pivoxil Cephalosporins, yield 81.25% detect, wherein t through HPLCR=24.512min is α-pivaloyl group
Cefditoren pivoxil Cephalosporins, purity 96.22%.
Embodiment 8
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), N, N- diformazan is added in sodium iso-octoate (15.30g, 0.092mol)
In base formamide (200mL), after mixing evenly, the N of 0~5 DEG C of temperature control dropwise addition pivaloyl chloride (6.75g, 0.056mol), N- diformazan
Base formamide (60mL) solution, is added dropwise, and after keeping the temperature 0~5 DEG C of reaction 4.0h, 0~5 DEG C of purified water is added in filtering, filtrate
(250mL), after keeping the temperature 0~5 DEG C of stirring 10min, chloroform (150mL × 3) extraction, merging organic layer, 1.0M hydrochloric acid (150mL ×
2) organic layer is washed, purified water (150mL × 2) washs organic layer, and saturated salt solution (150mL × 3) washs organic layer, anhydrous sulphur
Sour sodium dries, filters, and filtrate decompression is concentrated to dryness, and 35~40 DEG C of obtained solid are dried under reduced pressure after 16~18h as α-pivaloyl
Base Cefditoren pivoxil Cephalosporins, yield 80.10%, is detected through HPLC, wherein tR=24.520min is α-pivaloyl group cefoperon
Pivoxil, purity 96.21%.
Embodiment 9
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), N, N- dimethylacetamide is added in pyridine (7.28g, 0.092mol)
In amine (200mL), after mixing evenly, the N of 0~5 DEG C of temperature control dropwise addition pivaloyl chloride (6.75g, 0.056mol), N- dimethylacetamide
Amine (50mL) solution, is added dropwise, and after keeping the temperature 0~5 DEG C of reaction 1.0h, 0~5 DEG C of purified water is added in filtering, filtrate
(250mL), after keeping the temperature 0~5 DEG C of stirring 10min, methyl tertiary butyl ether(MTBE) (150mL × 3) extraction merges organic layer, 0.05M hydrochloric acid
(150mL × 2) wash organic layer, and purified water (150mL × 2) washs organic layer, and saturated salt solution (150mL × 3) washing is organic
Layer, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated to dryness, and 35~40 DEG C of obtained solid are dried under reduced pressure after 16~18h as
α-pivaloyl group Cefditoren pivoxil Cephalosporins, yield 78.12% detect, wherein t through HPLCR=24.525min is α-pivaloyl group
Cefditoren pivoxil Cephalosporins, purity 94.96%.
Embodiment 10
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), tetrahydrofuran is added in butyl lithium (4.61g, 0.072mol)
In (125mL), after mixing evenly, 5~10 DEG C of the temperature control tetrahydrofurans (35mL) that pivaloyl chloride (4.82g, 0.04mol) is added dropwise are molten
Liquid is added dropwise, after keeping the temperature 5~10 DEG C of reaction 1.5h, filtering, and the purified water (250mL) of 5~10 DEG C of filtrate addition, heat preservation 5~
After 10 DEG C of stirring 10min, ethyl acetate (120mL × 3) extraction merges organic layer, and 0.1M hydrochloric acid (100mL × 2) washing is organic
Layer, purified water (100mL × 2) wash organic layer, and saturated salt solution (100mL × 3) washs organic layer, and anhydrous sodium sulfate is dry,
Filtering, filtrate decompression are concentrated to dryness, and 35~40 DEG C of obtained solid are dried under reduced pressure after 16~18h as α-pivaloyl group cefoperon
Pivoxil, yield 60.56%, is detected through HPLC, wherein tR=24.507min is α-pivaloyl group Cefditoren pivoxil Cephalosporins, purity
It is 90.39%.
Embodiment 11
By Cefditoren pivoxil Cephalosporins (24.83g, 0.04mol), Isosorbide-5-Nitrae-dioxane is added in sodium methoxide (9.72g, 0.18mol)
In (200mL), after mixing evenly, Isosorbide-5-Nitrae-dioxane of 5~10 DEG C of temperature control dropwise additions pivaloyl chloride (9.65g, 0.08mol)
(40mL) solution, is added dropwise, and after keeping the temperature 5~10 DEG C of reaction 1.0h, 5~10 DEG C of purified water is added in filtering, filtrate
(250mL), after keeping the temperature 0~5 DEG C of stirring 10min, ethyl acetate (120mL × 3) extraction merges organic layer, 2.0M hydrochloric acid
(100mL × 2) wash organic layer, and purified water (100mL × 2) washs organic layer, and saturated salt solution (100mL × 3) washing is organic
Layer, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated to dryness, and 35~40 DEG C of obtained solid are dried under reduced pressure after 16~18h as
α-pivaloyl group Cefditoren pivoxil Cephalosporins, yield 62.03% detect, wherein t through HPLCR=24.518min is α-pivaloyl group
Cefditoren pivoxil Cephalosporins, purity 91.67%.
Claims (10)
1. a kind of preparation method of the α as shown in formula (I)-pivaloyl group Cefditoren pivoxil Cephalosporins, which is characterized in that specific preparation side
Method is as follows,
2. α as described in claim 1-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method, which is characterized in that including walking as follows
Suddenly：
1) Cefditoren pivoxil Cephalosporins and alkali are added in organic solvent, after mixing evenly, the organic of pivaloyl chloride is added dropwise in control temperature
Solvent is added dropwise, and temperature control to reaction terminates；
2) reaction solution is filtered, the purified water of pre-cooling is added in filtrate, after mixing evenly, extractant extraction is added, merges organic
Phase is successively used dilute hydrochloric acid, purified water and saturated common salt water washing, is dried, filtered after washing with anhydrous sodium sulfate, by filtrate decompression
It is concentrated to dryness, can be obtained α-pivaloyl group Cefditoren pivoxil Cephalosporins after obtained solid is dried in vacuo.
3. α as claimed in claim 2-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method, which is characterized in that described is organic
Solvent is tetrahydrofuran, acetone, acetonitrile, Isosorbide-5-Nitrae-dioxane, ethyl acetate, methylene chloride, chloroform, N, N- dimethyl formyl
Amine, one of n,N-dimethylacetamide or combinations thereof.
4. α as claimed in claim 2-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method, which is characterized in that the alkali is
Sodium carbonate, sodium bicarbonate, saleratus, sodium iso-octoate, triethylamine, N, N- diisopropyl ethyl amine, one of pyridine or its
Combination.
5. α as claimed in claim 2-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method, which is characterized in that the cephalo
The molar ratio of appropriate logical sequence pivoxil and alkali and pivaloyl chloride is 1: 2~4: 1.05~1.8.
6. α as claimed in claim 2-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method, which is characterized in that the cephalo
The mass volume ratio of appropriate logical sequence pivoxil and organic solvent is 1: 3~12, g/mL；Pivaloyl in the organic solvent of the pivaloyl chloride
The mass volume ratio of chlorine and organic solvent is 1: 4~10, g/mL.
7. α as claimed in claim 2-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method, which is characterized in that the dropwise addition
The temperature of pivaloyl chloride is -15~10 DEG C；Reaction temperature is -15~10 DEG C；Reaction time is 0.5~4h.
8. α as claimed in claim 2-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method, which is characterized in that the cephalo
The mass ratio of appropriate logical sequence pivoxil and purified water is 1: 8~12, wherein the purifying coolant-temperature gage being pre-chilled is 0~10 DEG C.
9. α as claimed in claim 2-pivaloyl group Cefditoren pivoxil Cephalosporins preparation method, which is characterized in that the extraction
Agent is ethyl acetate, methylene chloride, chloroform, one of methyl tertiary butyl ether(MTBE) or combinations thereof.
10. preparing resulting α-pivaloyl group Cefditoren pivoxil Cephalosporins by any one of claim 1-9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810889118.2A CN108912145B (en) | 2018-08-06 | 2018-08-06 | Preparation method of alpha-pivaloyl cefditoren pivoxil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810889118.2A CN108912145B (en) | 2018-08-06 | 2018-08-06 | Preparation method of alpha-pivaloyl cefditoren pivoxil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108912145A true CN108912145A (en) | 2018-11-30 |
| CN108912145B CN108912145B (en) | 2020-10-30 |
Family
ID=64394471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810889118.2A Active CN108912145B (en) | 2018-08-06 | 2018-08-06 | Preparation method of alpha-pivaloyl cefditoren pivoxil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108912145B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256464A (en) * | 2019-06-20 | 2019-09-20 | 重庆医药高等专科学校 | The preparation method of Cefditoren pivoxil Cephalosporins open loop dimer |
| CN114014876A (en) * | 2021-12-17 | 2022-02-08 | 浙江东邦药业有限公司 | Preparation method of methoxymethyl cefditoren pivoxil |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006024900A1 (en) * | 2004-08-31 | 2006-03-09 | Ranbaxy Laboratories Limited | Highly pure cefditoren pivoxil |
-
2018
- 2018-08-06 CN CN201810889118.2A patent/CN108912145B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006024900A1 (en) * | 2004-08-31 | 2006-03-09 | Ranbaxy Laboratories Limited | Highly pure cefditoren pivoxil |
Non-Patent Citations (1)
| Title |
|---|
| BRUNO SCHIAVI，ET AL.,: "Synthesis of 5-deazthiogirollines:analogs of a natural antitumor agent", 《TETRAHEDRON》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256464A (en) * | 2019-06-20 | 2019-09-20 | 重庆医药高等专科学校 | The preparation method of Cefditoren pivoxil Cephalosporins open loop dimer |
| CN110256464B (en) * | 2019-06-20 | 2020-03-31 | 重庆医药高等专科学校 | Method for preparing cefditoren pivoxil ring-opening dimer |
| CN114014876A (en) * | 2021-12-17 | 2022-02-08 | 浙江东邦药业有限公司 | Preparation method of methoxymethyl cefditoren pivoxil |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108912145B (en) | 2020-10-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9090631B2 (en) | Process for purifying cefotiam hydrochloride | |
| CN105175432B (en) | Preparation method of cefditore | |
| CN105131017B (en) | A kind of preparation method of Method of cefcapene pivoxil hydrochloride | |
| CN104130273B (en) | A kind of synthetic method of ceftriaxone sodium | |
| CN108912145A (en) | A kind of preparation method of α-pivaloyl group Cefditoren pivoxil Cephalosporins | |
| US20130303754A1 (en) | Refining process of cefamandole sodium | |
| CN103102357B (en) | A kind of synthetic method of Cefuroxime sodium | |
| CN113135939B (en) | Cefixime impurity and preparation method thereof | |
| CN106749258B (en) | Method for purifying ertapenem sodium | |
| CN105440054B (en) | A kind of technique preparing cefathiamidine | |
| CN103319503A (en) | Preparation method of cefdinir | |
| CN103232477B (en) | Cefotiam hydrochloride compound, and preparation method and pharmaceutical composition thereof | |
| CN104277053B (en) | A kind of preparation method of Cefodizime and its intermediate cefodizime acid | |
| CN110143957B (en) | Preparation method of cefditoren pivoxil ring-opening product | |
| CN105481856A (en) | Preparation method of palipefidone | |
| CN101550146A (en) | Cefetamet pivoxil hydrochloride compound and preparation method thereof | |
| CN108727418A (en) | A kind of preparation method of Cefditoren pivoxil Cephalosporins dimer | |
| CN102911186B (en) | Ceftizoxime sodium preparation and refining method | |
| WO2013029497A1 (en) | Preparation process of erythromycin thiocyanate | |
| CN108727410A (en) | A kind of preparation method of methylol Cefditoren pivoxil Cephalosporins | |
| CN102942575B (en) | Method for preparing cefodizime sodium | |
| CN104230956B (en) | A kind of preparation method of cefoxitin | |
| CN102746324B (en) | Purification method of cefotiam hydrochloride and aseptic powder injection of cefotiam hydrochloride | |
| CN109232610A (en) | A kind of refining methd of cefonicid dibenzylethylenediamsalt salt | |
| CN108395444B (en) | Preparation method of 3-ethyl cefadroxil |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |