CN108129493A - A kind of Cefobutazine sodium compound and its preparation - Google Patents
A kind of Cefobutazine sodium compound and its preparation Download PDFInfo
- Publication number
- CN108129493A CN108129493A CN201810122551.3A CN201810122551A CN108129493A CN 108129493 A CN108129493 A CN 108129493A CN 201810122551 A CN201810122551 A CN 201810122551A CN 108129493 A CN108129493 A CN 108129493A
- Authority
- CN
- China
- Prior art keywords
- sodium
- acid
- preparation
- cefobutazine
- cefobutazine sodium
- 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.)
- Pending
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
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—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, cefaclor, or cephalexine
- A61K31/546—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, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- 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
- C07D501/12—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a kind of Cefobutazine sodium compound, the Cefobutazine sodium compound is prepared using the assembling of particle process crystal product molecule with form optimisation technique.This compound has the characteristics that purity is high, color grade is good, stability is good.Meanwhile the invention also discloses a kind of preparation-Ceftezole sodium used for injection prepared using above-mentioned cefobutazine sodium.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of using the assembling of particle process crystal product molecule and form
Cefobutazine sodium compound and its preparation prepared by optimisation technique.
Background technology
Cefobutazine sodium is the semi-synthetic cephalosporin antibiotics for being synthesized and being developed by Japanese rattan pool drug company, in 1978
April in year is with the trade name list marketing of Ceolslin.It is mainly used for treating staphylococcus aureus, micrococcus scarlatinae, pneumonia
Infection caused by coccus, coliform, pneumobacillus etc., as caused by septicemia, pneumonia, bronchitis, bronchiectasis infection
The hair sexuality dye of chronic respiratory system, pulmonary abscess, peritonitis, pyelonephritis, cystitis etc..This medicine in China using later,
Breathing out within 2002 medicine and Tianjin Xinfeng has bulk pharmaceutical chemicals and preparation production, and in recent years, usage amount annual growth is 399%.With cephalo
For the extensive clinical practice of azoles sodium and growing utilization rate, therefore have to the study on the synthesis of cefobutazine sodium very great
Meaning.
The synthetic method of the cefobutazine sodium of document report has：(1) it using 1H-tetrazole-1-acetic acid as starting material, is first made
Acyl chlorides, then reacted with 7-amino-cephalosporanic acid (7-ACA) and important intermediate 7- (1H- tetrazoles acetylamino) cephalo alkane is made
Acid, 7- (1H- tetrazoles acetylamino) cephalosporanic acids and 2- sulfydryls -1,3,4- thiadiazoles is in the phosphate buffer that pH is 6.4
Ceftezole acid is made in middle generation nucleophilic substitution.But this chloride method can cause environmental pollution, cost is higher, yield compared with
It is low, it uses less at present.(2) using 7-ACA as starting material, in N, N'- dicyclohexylcarbodiimides (DCC) be under catalyst with
1H-tetrazole-1-acetic acid react, generate 7- (1H- tetrazoles acetylamino) cephalosporanic acid, then with 2- sulfydryls -1,3,4- thiadiazoles
Reaction generation ceftezole acid.The route is simple, but yield is relatively low, and total recovery is only 18%.(3) with mixed anhydride method, mould
Element is acylated enzyme process etc. to synthesize 7 acylated intermediates, these methods equally exist the shortcomings of yield is low, of high cost；In addition, 3
Nucleophilic substitution system is water phase, easily causes beta-lactam nucleus open loop, and side reaction is more, and product purity is relatively low, and color is deeper,
Not easy purification.Using lewis acids such as boron trifluoride ether as catalyst, aqueous medium can be avoided and complete 3 substitution reactions, but be catalyzed
Agent is expensive, and for application value less (4) with 1H-tetrazole-1-acetic acid and 2- sulfydryls -1,3,4 thiadiazoles carry out dehydrating condensation generation
1H-tetrazole-1-acetic acid -1,3,4- thiadiazoles -2- thioesters, 1H-tetrazole-1-acetic acid -1,3,4- thiadiazoles -2- thioesters is directly and 7-
ACA reactions directly obtain ceftezole acid, but the method is low there is also yield, and by-product is more, not the shortcomings that easy purification.
The stability of cefobutazine sodium is poor, and to temperature and photo-labile, purity is relatively low, polymer and other impurity contents
The problems such as height, color is deeper, the reason of occurring may be in final product in be mingled with the reasons such as part by-product, residual solvent.Solution
Certainly this problem must research and develop novel crystallization production technology, to optimize the processes such as solvent, temperature, reaction time, additive
Parameter makes crystallization carry out under the suitable conditions, so as to ensure the quality of product.
Present invention is generally directed to problem above existing for Cefobutazine sodium compound, to solvent, temperature during Crystallization
On the basis of the factors such as degree, external force, additive are fully investigated, skill is optimized with form using the assembling of particle process crystal product molecule
Art has obtained the Cefobutazine sodium compound that a kind of purity is high, color grade is good, stability is good, the more previous preparation of the synthesis step
Journey more focuses on the control of the reagent and parameter in building-up process, and step is simple, raw material used etc. be it is cheap, nontoxic or
Low-toxicity product, suitable for industrial-scale production.Using preparation made of heretofore described compound, more previous preparation has
Better stability.
Invention content
The first object of the present invention is to provide a kind of Cefobutazine sodium compound, which uses particle process crystal
Products molecule assembling is prepared with form optimisation technique, has the characteristics that purity is high, color grade is good, stability is good.
Cefobutazine sodium crystal compound of the present invention is measured with X-ray powder diffraction, is represented with the 2 θ angles of diffraction
X-ray powder diffraction pattern at 11.4 ° ± 0.2 °, 13.2 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.8 ° ± 0.2 °, 19.2 ° ±
0.2 °, 19.4 ° ± 0.2 °, 20.6 ° ± 0.2 °, 22.3 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.3 ° ± 0.2 °, 23.6 ° ± 0.2 °,
23.9 ° ± 0.2 °, 24.3 ° ± 0.2 °, 24.6 ° ± 0.2 °, 26.2 ° ± 0.2 °, 27.0 ° ± 0.2 °, 27.2 ° ± 0.2 °, 31.7 °
Characteristic diffraction peak is shown at ± 0.2 °, 34.8 ° ± 0.2 °.
Cefobutazine sodium compound preparation of the present invention includes the following steps：
(1) by tetrazoleacetic acid and 2- sulfydryls -1,3,4- thiadiazoles is dissolved in solvent 1, is slowly added into dicyclohexyl carbon two
Imines is reacted under ice bath, is filtered to remove 1,3-, bis- ring ethyl carbamides, and filtrate decompression concentration adds in solvent 2, stirring, and filtration drying obtains
Yellow powder object active ester；
(2) 7-ACA is added in chloroform and triethylamine, the active ester reaction of above-mentioned preparation is added under condition of ice bath, is added in
Water, point water intaking layer, acid solution adjust pH value, ice bath stirring, and filtering purifies water washing, is dried in vacuo to obtain 7- (1H- tetrazole second
Acylamino-) cephalosporanic acid；
(3) it is 3 to weight ratio:In 1 7- (1H- tetrazoles acetylamino) -1,3,4 thiadiazoles of cephalosporanic acid and 2- sulfydryls
Acetic acid is added in, is slowly added into methanesulfonic acid, heating water bath is concentrated under reduced pressure into thick, and pH value is adjusted with aqueous slkali, stirring,
Filtering washing, vacuum drying obtain ceftezole acid；
(4) ceftezole acid is added in sodium bicarbonate solution, stirring and dissolving, adds in ethyl alcohol, ice bath stirring, filtering is washed
It washs, is dried in vacuo, obtains cefobutazine sodium.
Preferably, in above-mentioned preparation method, in step (1) reagent 1 for tetrahydrofuran, ether, acetone, one kind in benzene or
Their mixture of person, reagent 2 is petroleum ether, a kind of or their mixture in chloroform, absolute ethyl alcohol.
Preferably, it is 2 that volume ratio is added in above-mentioned preparation method, in step (2):1~15:2 chloroform and three second
Amine.
Preferably, in above-mentioned preparation method, acid solution is the aqueous solution of hydrochloric acid, glacial acetic acid, nitric acid in step (2).
Preferably, in above-mentioned preparation method, acid solution adjusts pH value to 2.0~3.0 in step (2).
Preferably, in above-mentioned preparation method, aqueous slkali is sodium hydroxide, sodium bicarbonate, sodium carbonate, ammonium hydroxide in step (3)
Aqueous solution.
Preferably, it is 1.5~2.5 that aqueous slkali, which adjusts pH value range, in above-mentioned preparation method, in step (3).
Preferably, in above-mentioned preparation method, a concentration of 5%~10% sodium bicarbonate of step (4) sodium bicarbonate solution.
The second object of the present invention is to provide a kind of preparation for including Cefobutazine sodium compound of the present invention, the system
The more previous product of agent has better stability and Small side effects.
The preparation of ceftezole preparation of sodium of the present invention is mainly to above-mentioned prepared Cefobutazine sodium compound
Carry out it is aseptic subpackaged, specification be 0.25~4.0g.
Description of the drawings
The X-ray powder diffraction figure of Fig. 1 cefobutazine sodium crystal compounds, diffraction maximum numbers corresponding 2 θ values in figure
Referring to table 1.
Specific embodiment
Below will by specific embodiment, the present invention will be further described, but not therefore limit the present invention to institute
In the scope of embodiments stated, it should be understood by those skilled in the art that the equivalent replacement done to the content of present invention or changing accordingly
Into still falling within protection scope of the present invention.
Embodiment 1：The preparation of Cefobutazine sodium compound
(1) by 2.56kg tetrazoleacetic acids and 2.43kg 2- sulfydryls -1,3,4- thiadiazoles is dissolved in tetrahydrofuran, slowly
5.04kg N, N'- dicyclohexylcarbodiimides are added in, 2h is reacted under ice bath, is filtered to remove 1,3-, bis- ring ethyl carbamides, filtrate decompression
Concentration, adds in 25L chloroforms, stirring, and filtration drying obtains yellow powder object active ester 4.1Kg；
(2) it is 2 4.44Kg 7-ACA to be added in 60L volume ratios:In 1 chloroform and triethylamine, added under condition of ice bath
The active ester reaction 5h of above-mentioned preparation, adds in 400L water, and point water intaking layer, it is 2.0 to adjust pH value with the glacial acetic acid solution of 2mol/L,
Ice bath stirring 1h, filtering purify water washing, are dried in vacuo to obtain 7- (1H- tetrazoles acetylamino) cephalosporanic acid 6.23Kg；
(3) 50L is added in into 7- (1H- tetrazoles acetylamino) -1,3,4 thiadiazoles of cephalosporanic acid and 2.08Kg2- sulfydryls
Acetic acid, is slowly added into 50L methanesulfonic acids, 40 DEG C of heating water bath 2h, be concentrated under reduced pressure into it is thick, with ammonia spirit adjust pH value to
2.0,1h, filtering washing are stirred, vacuum drying obtains ceftezole acid 6.45Kg；
(4) ceftezole acid is added in the sodium bicarbonate solution of 25.4L5%, stirring and dissolving adds in 15L ethyl alcohol, and ice bath stirs
2h is mixed, is filtered, is washed, vacuum drying obtains cefobutazine sodium 5.44Kg.
The new crystal form of head cefobutazine sodium is studied and characterized using x-ray powder diffraction (XRPD).
Instrument and equipment：EMPYREAN (sharp shadow) X-ray diffractometer (Dutch Panalytical companies).
Measurement result：The X-ray powder diffraction pattern of 1 cefobutazine sodium of embodiment the 2 θ angles of diffraction be 11.4 °, 13.3 °,
16.5 °, 17.7 °, 19.2 °, 19.4 °, 20.6 °, 22.3 °, 22.7 °, 23.3 °, 23.6 °, 23.9 °, 24.3 °, 24.6 °,
Characteristic diffraction peak is shown at 26.2 °, 27.0 °, 27.3 °, 31.7 °, 34.8 °.Referring specifically to Figure of description 1.
The specific data of the XRPD diffraction are as shown in the table：
1 cefobutazine sodium diffraction data of table
Embodiment 2：The preparation of Cefobutazine sodium compound
(1) by 30.33g tetrazoleacetic acids and 31.11g 2- sulfydryls -1,3,4- thiadiazoles is dissolved in tetrahydrofuran, slowly
61.77g N, N'- dicyclohexylcarbodiimides are added in, 2h is reacted under ice bath, is filtered to remove 1,3-, bis- ring ethyl carbamides, filtrate decompression
Concentration, adds in 700ml tetrahydrofurans, stirring, and filtration drying obtains yellow powder object active ester 59.24g；
(2) it is 15 58.34g 7-ACA to be added in 1400ml volume ratios:In 2 chloroform and triethylamine, under condition of ice bath
The active ester reaction 4h of above-mentioned preparation is added in, adds in 600ml water, point water intaking layer, adjusting pH value with the hydrochloric acid solution of 1mol/L is
2.5, ice bath stirring 1h, filtering purify water washing, are dried in vacuo to obtain 7- (1H- tetrazoles acetylamino) cephalosporanic acid 94.79g；
(3) it is added in into 7- (1H- tetrazoles acetylamino) cephalosporanic acids and -1,3,4 thiadiazoles of 31.06g 2- sulfydryls
1500ml acetic acid, is slowly added into 152ml methanesulfonic acids, 50 DEG C of heating water bath 1h, is concentrated under reduced pressure into thick, is adjusted with ammonia spirit
PH value stirs 2h, filtering washing, vacuum drying obtains ceftezole acid 89.75g to 1.5；
(4) ceftezole acid is added in the sodium bicarbonate solution of 189ml 10%, stirring and dissolving adds in 170ml ethyl alcohol, ice
Bath stirring 1h, filters, washs, and vacuum drying obtains cefobutazine sodium 56.51g.
Measurement result, the X-ray powder diffraction pattern of 2 cefobutazine sodium of embodiment are 11.3 ° in the 2 θ angles of diffraction, 13.4 °,
16.4 °, 17.9 °, 19.1 °, 19.4 °, 20.6 °, 22.2 °, 22.7 °, 23.3 °, 23.5 °, 23.8 °, 24.3 °, 24.6 °,
Characteristic diffraction peak is shown at 26.1 °, 27.0 °, 27.1 °, 31.7 °, 34.8 °.
Embodiment 3：The preparation of Cefobutazine sodium compound
(1) by 32.06g tetrazoleacetic acids and 30.79g 2- sulfydryls -1,3,4- thiadiazoles is dissolved in tetrahydrofuran, slowly
60.42g N, N'- dicyclohexylcarbodiimides are added in, 2h is reacted under ice bath, is filtered to remove 1,3-, bis- ring ethyl carbamides, filtrate decompression
Concentration, adds in 700ml absolute ethyl alcohols, stirring, and filtration drying obtains yellow powder object active ester 60.33g；
(2) it is 5 60.12g 7-ACA to be added in 1500ml volume ratios:In 1 chloroform and triethylamine, add under condition of ice bath
Enter the active ester reaction 4h of above-mentioned preparation, add in 600ml water, point water intaking layer, adjusting pH value with the salpeter solution of 1mol/L is
3.0, ice bath stirring 1h, filtering purify water washing, are dried in vacuo to obtain 7- (1H- tetrazoles acetylamino) cephalosporanic acid 94.23g；
(3) it is added in into 7- (1H- tetrazoles acetylamino) cephalosporanic acids and -1,3,4 thiadiazoles of 32.22g 2- sulfydryls
1500ml acetic acid, is slowly added into 150ml methanesulfonic acids, 45 DEG C of heating water bath 1.5h, be concentrated under reduced pressure into it is thick, with ammonia spirit tune
PH value is saved to 2.5, stirs 2h, filtering washing, vacuum drying obtains ceftezole acid 89.44g；
(4) ceftezole acid is added in the sodium bicarbonate solution of 192ml 8%, stirring and dissolving adds in 170ml ethyl alcohol, ice
Bath stirring 1h, filters, washs, and vacuum drying obtains cefobutazine sodium 57.49g.
Measurement result, the X-ray powder diffraction pattern of 2 cefobutazine sodium of embodiment are 11.4 ° in the 2 θ angles of diffraction, 13.3 °,
16.4 °, 17.7 °, 19.3 °, 19.3 °, 20.7 °, 22.2 °, 22.7 °, 23.4 °, 23.7 °, 23.8 °, 24.2 °, 24.7 °,
Characteristic diffraction peak is shown at 26.3 °, 27.1 °, 27.3 °, 31.6 °, 34.9 °.
Embodiment 4：The preparation of Ceftezole sodium used for injection
Cefobutazine sodium compound is prepared according to the step of embodiment 1, Ceftezole sodium used for injection is prepared using this raw material,
Specification 1.0g.
Prescription：
Preparation process：
(1) it stocks up：After bulk pharmaceutical chemicals content and moisture conversion, cefobutazine sodium is weighed by recipe quantity；
(2) it dispenses：It is sub-packed in and is cleaned and in the cillin bottle of dry sterilization under the protection of nitrogen charging, tamponade；
(3) lid is rolled；
Comparative example 1：The preparation of Cefobutazine sodium compound
Cefobutazine sodium compound is prepared according to the synthetic method (2) of document report.
Preparation process：
2.01kg7-ACA is dissolved in 22L chloroforms, is slowly added to 1.92kgN, N'- dicyclohexylcarbodiimides (DCC) and
2.0.3kg1H- tetrazoleacetic acid, ice bath reaction 2h, adds in 20L water, and point water intaking layer adjusts pH value with the hydrochloric acid solution of 1mol/L
It is 2.0, ice bath stirring 1h, filtering purifies water washing, is dried in vacuo to obtain 7- (1H- tetrazoles acetylamino) cephalosporanic acid
2.47kg, by 7- (1H- tetrazoles acetylamino) cephalosporanic acids and 906g2- sulfydryls -1,3,4- thiadiazoles is added in 50L acetic acid,
40 DEG C of heating water bath 1h, are concentrated under reduced pressure into thick, adjust pH value to 2.0 with ammonia spirit, stir 2h, filtering washing is made
Ceftezole acid, is added in the sodium bicarbonate solution of 5L8% by ceftezole acid 1.62kg, and stirring and dissolving adds in 4L ethyl alcohol, ice bath
1h is stirred, is filtered, washing is dried in vacuo to obtain cefobutazine sodium 1.27g.
Comparative example 2：The preparation of Ceftezole sodium used for injection
Take in proportion 1 method prepare Cefobutazine sodium compound, Ceftezole sodium used for injection, specification are prepared using this raw material
0.25g。
Prescription：
Preparation process：
(1) it stocks up：After bulk pharmaceutical chemicals content and moisture conversion, cefobutazine sodium is weighed by recipe quantity；
(2) it dispenses：It is sub-packed in and is cleaned and in the cillin bottle of dry sterilization under the protection of nitrogen charging, tamponade；
Roll lid；
Test example 1：Hygroscopicity is investigated
The present inventor grinds Cefobutazine sodium compound hygroscopicity prepared by the embodiment of the present invention 1 and comparative example 1
Study carefully.Investigation condition is relative humidity 92.5% (RH), and temperature is 40 DEG C, and inspection target is aqueous in Cefobutazine sodium compound
Amount.
Water content testing result：
Conclusion：Cefobutazine sodium compound itself water content prepared by the embodiment of the present invention 1 is low and hygroscopicity is significantly lower than
Cefobutazine sodium compound prepared by comparative example 1.Illustrate that Cefobutazine sodium compound of the present invention has good stability, be suitble to
The manufacture of pharmaceutical preparation and long-term storage.
Test example 2：Purity detecting
The present inventor has carried out purity inspection to the Cefobutazine sodium compound prepared by the embodiment of the present invention 1 and comparative example 1
It surveys.
Purity detecting result：
| Embodiment | Purity (%) |
| Embodiment 1 | 98.92 |
| Comparative example 1 | 95.73 |
Conclusion：Cefobutazine sodium compound purity prepared by the embodiment of the present invention 1 is apparently higher than the cephalo of the preparation of comparative example 1
For azoles sodium compound.
Test example 3：Study on the stability
The present inventor to the Ceftezole sodium used for injection prepared by the embodiment of the present invention 4 and comparative example 2 accelerate steady
It is qualitative to investigate experiment.Investigation condition is 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%.Place 6 months, respectively at 0,1,2,
3rd, 6 the end of month sampled.Inspection target is character, clarity, solution colour, moisture, acidity, content and related substance.
Accelerated test investigates result：
Conclusion：At the conditions of the experiments described above place 6 months, the embodiment of the present invention 4 prepare product all indicators are better than
The product of comparative example 2, stability is good, reliable in quality.The superiority of the technology of the present invention is absolutely proved.
Claims (10)
1. a kind of Cefobutazine sodium compound, which is characterized in that existed with the X-ray powder diffraction pattern that the 2 θ angles of diffraction represent
11.4 ° ± 0.2 °, 13.2 ° ± 0.2 °, 16.5 ° ± 0.2 °, 17.8 ° ± 0.2 °, 19.2 ° ± 0.2 °, 19.4 ° ± 0.2 °, 20.6 °
± 0.2 °, 22.3 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.3 ° ± 0.2 °, 23.6 ° ± 0.2 °, 23.9 ° ± 0.2 °, 24.3 ° ±
0.2 °, 24.6 ° ± 0.2 °, 26.2 ° ± 0.2 °, 27.0 ° ± 0.2 °, 27.2 ° ± 0.2 °, 31.7 ° ± 0.2 °, 34.8 ° ± 0.2 °
Place shows characteristic diffraction peak.
2. Cefobutazine sodium compound as described in claim 1, it is characterised in that be prepared using following methods：
(1) by tetrazoleacetic acid and 2- sulfydryls -1,3,4- thiadiazoles is dissolved in solvent 1, is slowly added into dicyclohexylcarbodiimide,
It is reacted under ice bath, is filtered to remove 1,3-, bis- ring ethyl carbamides, filtrate decompression concentration adds in solvent 2, stirring, and filtration drying obtains yellow
Powdered object active ester；
(2) 7-ACA is added in chloroform and triethylamine, the active ester reaction of above-mentioned preparation is added under condition of ice bath, adds in water, point
Water intaking layer, acid solution adjust pH value, ice bath stirring, and filtering purifies water washing, is dried in vacuo to obtain 7- (1H- tetrazole acetyl ammonia
Base) cephalosporanic acid；
(3) it is 3 to weight ratio:It is added in 1 7- (1H- tetrazoles acetylamino) -1,3,4 thiadiazoles of cephalosporanic acid and 2- sulfydryls
Acetic acid, is slowly added into methanesulfonic acid, heating water bath, is concentrated under reduced pressure into thick, and pH value is adjusted with aqueous slkali, stirring, filtering washing,
Vacuum drying obtains ceftezole acid；
(4) ceftezole acid is added in sodium bicarbonate solution, stirring and dissolving, adds in ethyl alcohol, ice bath stirring filters, washing, very
Sky is dry, obtains cefobutazine sodium.
3. the preparation method of cefobutazine sodium as claimed in claim 2, it is characterised in that reagent 1 is tetrahydrochysene furan in step (1)
Mutter, a kind of or their mixture in ether, acetone, benzene, reagent 2 for petroleum ether, chloroform, one kind in absolute ethyl alcohol or
Their mixture of person.
4. the preparation method of cefobutazine sodium as claimed in claim 2, it is characterised in that volume ratio is added in step (2)
It is 2:1~15:2 chloroform and triethylamine.
5. the preparation method of cefobutazine sodium as claimed in claim 2, it is characterised in that in step (2) acid solution for hydrochloric acid,
The aqueous solution of glacial acetic acid, nitric acid.
6. the preparation method of cefobutazine sodium as claimed in claim 2, it is characterised in that acid solution adjusts pH value in step (2)
To 2.0~3.0.
7. the preparation method of cefobutazine sodium as claimed in claim 2, it is characterised in that aqueous slkali is hydroxide in step (3)
Sodium, sodium bicarbonate, sodium carbonate, ammonium hydroxide aqueous solution.
8. the preparation method of cefobutazine sodium as claimed in claim 2, it is characterised in that aqueous slkali adjusts pH value in step (3)
Ranging from 1.5~2.5.
9. the preparation method of cefobutazine sodium as claimed in claim 2, it is characterised in that sodium bicarbonate solution in step (4)
A concentration of 5%~10% sodium bicarbonate.
10. a kind of Ceftezole sodium used for injection, it is characterised in that its contain Cefobutazine sodium compound described in claim 1 or
Cefobutazine sodium compound made from preparation method described in claim 2~9 any one, specification are 0.25~4.0g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810122551.3A CN108129493A (en) | 2018-02-07 | 2018-02-07 | A kind of Cefobutazine sodium compound and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810122551.3A CN108129493A (en) | 2018-02-07 | 2018-02-07 | A kind of Cefobutazine sodium compound and its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108129493A true CN108129493A (en) | 2018-06-08 |
Family
ID=62430525
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810122551.3A Pending CN108129493A (en) | 2018-02-07 | 2018-02-07 | A kind of Cefobutazine sodium compound and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108129493A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219795A (en) * | 2011-07-28 | 2011-10-19 | 哈药集团制药总厂 | Method for preparing ceftezole sodium |
| CN102286001A (en) * | 2011-08-30 | 2011-12-21 | 郑州大学 | Method for preparing ceftezole sodium |
| CN102617606A (en) * | 2012-03-31 | 2012-08-01 | 哈药集团制药总厂 | Method for preparing ceftezole sodium compound |
-
2018
- 2018-02-07 CN CN201810122551.3A patent/CN108129493A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219795A (en) * | 2011-07-28 | 2011-10-19 | 哈药集团制药总厂 | Method for preparing ceftezole sodium |
| CN102286001A (en) * | 2011-08-30 | 2011-12-21 | 郑州大学 | Method for preparing ceftezole sodium |
| CN102617606A (en) * | 2012-03-31 | 2012-08-01 | 哈药集团制药总厂 | Method for preparing ceftezole sodium compound |
Non-Patent Citations (1)
| Title |
|---|
| 张秋荣，等: "头孢替唑钠的合成工艺研究", 《中国药物化学杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105254648B (en) | A kind of synthetic method of cephalo dimension star and its sodium salt | |
| CN103524532B (en) | Ceftizoxime sodium compound crystal form, and preparing method and pharmaceutical preparation thereof | |
| CN103012434B (en) | Cefathiamidine compound crystal and preparation method as well as pharmaceutical composition thereof | |
| CN109134506A (en) | One water cefotiam hydrochloride compound of one kind and its pharmaceutical composition | |
| CN103601739A (en) | Cefoxitin sodium compound and preparation method thereof | |
| CN103304582B (en) | Cefoxitin sodium compound, preparation method and pharmaceutical composition thereof | |
| CN108129493A (en) | A kind of Cefobutazine sodium compound and its preparation | |
| CN106317080A (en) | Ceftazidime compound prepared by adopting coupling crystallization technology and preparation thereof | |
| CN106565748B (en) | The preparation method of Cefuroxime Sodium and its preparation | |
| CN104622695A (en) | Cefoxitin sodium powder preparation for injection | |
| CN112645912A (en) | Preparation method of high-purity M2 crystal form meclofenol sodium | |
| CN109369683B (en) | Preparation method of cefpiramide sodium | |
| CN109160922A (en) | A kind of 1/2 water Cefobutazine sodium compound | |
| CN109293680B (en) | Preparation method of cefoperazone acid | |
| KR970010068B1 (en) | Process for the preparation of sterile beta-lactam antibiotice | |
| CN106317078A (en) | Ceftriaxone sodium compound prepared by adopting supermolecular mechanism and preparation thereof | |
| CN109824700A (en) | A kind of preparation method of Cefotetan Disodium | |
| CN108033971A (en) | A kind of synthetic method of Method of cefcapene pivoxil hydrochloride | |
| WO2017140073A1 (en) | Cefathiamidine novel crystal compound using particle process crystal product molecular assembly and morphology optimisation technology and formulation thereof | |
| CN109912625B (en) | Process method for reducing ceftazidime impurity H | |
| CN109438477B (en) | Method for refining cefpiramide acid | |
| CN113025679A (en) | Enzymatic preparation process of t-butoxycarbonyl cefcapene precursor acid | |
| CN109096309B (en) | One kind 43/4His acridine compound of head spore and its pharmaceutical composition | |
| CN109160924A (en) | Two water cefotiam hydrochloride compounds of one kind and its drug combination preparation | |
| CN115093431B (en) | Method for synthesizing cefpodoxime proxetil |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180608 |
|
| WD01 | Invention patent application deemed withdrawn after publication |