CN103755728B - Cefazolin derivatives and preparation method thereof, oral antibiotic preparation - Google Patents
Cefazolin derivatives and preparation method thereof, oral antibiotic preparation Download PDFInfo
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Abstract
The invention discloses a kind of cefazolin derivatives and preparation method thereof and oral antibiotic preparation.This cefazolin derivatives molecular structural formula is following (I), and its preparation method includes preparing the cefazolin parent nucleus low-temp reaction thing mixed solution sour with cefazolin and the heating of described low-temp reaction thing solution carrying out the step of condensation reaction.This oral antibiotic preparation contains the cefazolin derivatives that this structural formula is following (I).While the cefazolin derivatives of the present invention has cefazolin pharmaceutically active, there is suitable lipid, be suitable for intestines and stomach administration.Wherein preparation method reaction condition is easily-controllable, and technique is simple, and efficiency of pcr product is high.Oral antibiotic preparation good drug efficacy, is used conveniently and safely, and can effectively reduce the incidence rate of abuse of antibiotics, has widened the scope that domestic oral disposition antibiotic selects simultaneously.
Description
Technical field
The invention belongs to antibiotic medicine technical field, particularly relate to a kind of cefazolin derivatives and preparation method thereof and a kind of oral antibiotic preparation.
Background technology
Infectious disease is a modal class disease clinically, is one of modal reason causing death.According to World Health Organization (WHO) 1997 annual report, suffer from the 33.3% of dead number up to all kinds of reason death toll summations of infectious disease.In China, due to the swift and violent growth of population, the acceleration of aging process, the increase of immunosuppressed host and accumulation, and the deterioration of ecological environment, the increase of movement of population, socio-economic development imbalance, frequent generation plus calamity, and vast rural population and still also very backward medical health protection system, the principal disease of harm people ' s health is still by the various microbial infectious diseases that cause a disease, and is also cause to disable and main causes of death.Some have disappeared and have started to revive close to the infectious disease disappeared, and new pathogen and new infectious disease are constantly found, and China is faced with the new threat of infectious disease.The powerful mean that anti-infective is the mankind struggles with infectious disease, its quantity is maximum, most species, with fastest developing speed, and the market demand of this respect medicine is always very vigorous.According to statistics, the sales volume of anti-infection drug accounts for about the 15% of world's medicine sales volume, is only second to cardiovascular drugs.In China, anti-infective accounts for the market share of whole medicine sales about 14%, ranks first in all medicine types.
From the antibiotic medication development trend of developed country, oral formulations will be the developing direction of clinical application.In antibacterial field, the share of the oral medication on international market to be far longer than injecting drug use, and for the oral incidence rate that can also effectively reduce abuse of antibiotics of antibiotic.Therefore, oral antibiotic obtains the clinical expansion of great dynamics in various countries.The U.S. progressively promotes oral class antibiotic part after the nineties in 20th century and replaces injection antibiotic so that antibiotics resistance phenomenon relatively eighties of child substantially reduced in the past.At home, sold by antibiotic medicine Regulation Policy limit, limit the use of, the impact of " three limits " policy of price limit, along with the antibiotic standardization of clinical practice, clinical endpoint advocates the drive of rational use of drug (economic medication, sequential therapy etc.) demand and the promotion that " new agriculture conjunction, basic medical security for urban residents " is universal.In recent years, the oral antibiotic crude drug volume of production and marketing such as cefalexin, cefradine, cefaclor, cefixime, Ro-15-8075 and import & export quantity entered the passage of quickly growth.Oral cephalosporins in the national medical insurance catalogue of new revision has reached 8 (cefalexin, cefradine, cefadroxil, cefuroxime, cefprozil, cefaclor, cefdinir, cefiximes).Therefore, following domestic antibiotic market is bound to progressively draw close to international market, and oral medicine increase-volume is imperative.
But at present at home, the cephalosporins applied clinically is mostly injecting drug use, only 10 kinds (cefalexin, cefadroxil, cefaclor, cefprozil, cefixime, Ro-15-8075, Cefditoren pivoxil Cephalosporins, Cefteram Pivoxil, ceftibuten, cefdinirs) of sample hospital cephalo-type for oral use in 2012, also have 3 kinds of both orally available also injectable kinds (cefradine, cefpodoxime, cefuroxime), be badly in need of developing new oral kind to provide new medication to select.
Summary of the invention
It is an object of the invention to overcome the above-mentioned deficiency of prior art, it is provided that cefazolin derivatives of a kind of good to eat medication and preparation method thereof, with solve existing antibiotic be mostly water solublity and adopt injecting drug use technical problem.
Another object of the present invention is to provide the oral antibiotic preparation of this cefazolin derivatives a kind of.
In order to realize foregoing invention purpose, technical scheme is as follows:
A kind of cefazolin derivatives, its molecular structural formula is following (I):
And, the preparation method of a kind of cefazolin derivatives, comprise the steps:
It is cooled to lower than 5 DEG C after cefazolin parent nucleus and cefazolin acid are dissolved in reaction dissolvent, adds condensing agent, obtain reactant mixed solution；
Described reactant mixed solution is warming up to 20～30 DEG C and carries out condensation reaction, until reaction terminates；Again
Add frozen water to precipitate, solid-liquid separation, purification process, obtain the described cefazolin derivatives of following molecular structure formula I:
And, a kind of oral antibiotic preparation, its above-mentioned cefazolin derivatives containing effective dose or the cefazolin derivatives prepared by above-mentioned cefazolin derivatives preparation method.
Compared with existing cefazolin antibiotic, the cefazolin derivatives of the present invention is to adopt cefazolin parent nucleus that the carboxyl of cefazolin acid is carried out condensation and modification product, while making it have cefazolin pharmaceutically active, there is suitable lipid, be suitable for intestines and stomach administration.Therefore, it effectively changes the water soluble characteristic of spore azoles woods acid, can be used for preparing oral antibiotic medicine.
Above-mentioned cefazolin derivatives preparation method adopts cefazolin acid to be reaction raw materials, the carboxyl utilizing cefazolin parent nucleus sour with cefazolin carries out condensation and modification, make product cefazolin derivatives while maintaining former cefazolin pharmaceutically active, have a suitable lipid, and efficiency of pcr product and purity high.It addition, the reaction condition between this reactant is easily-controllable, technique is simple, and by-product is low, and production efficiency and purity are high, are suitable to industrialized production.
Above-mentioned oral antibiotic preparation is due to the above-mentioned cefazolin derivatives effective ingredient containing effective dose, therefore oral antibiotic preparation good drug efficacy, it is used conveniently and safely, and can effectively reduce the incidence rate of abuse of antibiotics, widened the scope that domestic oral disposition antibiotic selects simultaneously.
Detailed description of the invention
In order to make the technical problem to be solved in the present invention, technical scheme and beneficial effect clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein is only in order to explain the present invention, is not intended to limit the present invention.
Current cephalosporin for injections contains water miscible hydroxy-acid group, such as cefotiam, Cefazolin sodium etc., therefore, its molecular polarity is big, good water solubility, but the medicine that polarity is big is generally more difficult by cell membrane, cause that existing cephalosporin great majority adopt drug administration by injection, it is impossible to for peroral dosage form.If able to the water miscible polar group changed in existing cephalosporin molecules, as carboxylic group carried out modification to strengthen the fat-soluble of cephalosporin compound, so be conducive to it to pass through the transport of cell membrane, enter internal performance drug effect, thus may be used for preparing oral formulations.
Based on the Research idea of foregoing invention people, the invention provides the cefazolin derivatives of a kind of liposoluble, its molecular structural formula is following (I):
So, this cefazolin derivatives is with cefazolin acid for main group, its hydroxy-acid group is by the amino condensation and modification of cefazolin parent nucleus, while making it retain cefazolin pharmaceutically active, there is suitable lipid, that can pass through digestive tract cell membrane is conveyed into internal performance drug effect, thus widening its administering mode, is suitable for intestines and stomach administration.Partition coefficient through the n-octyl alcohol-aqueous systems of detection cefazolin derivatives is 4.37, and apparent partition coefficients is moderate, and relative molecular mass is less, it is appreciated that in intestinal absorption, can prepare for peroral dosage form antibiotic medicine preparation.
Correspondingly, present invention also offers a kind of synthetic method of above-mentioned cefazolin derivatives, the method comprises the steps:
S01. the low-temp reaction thing mixed solution of cefazolin parent nucleus and cefazolin acid is prepared: be cooled to lower than 5 DEG C after being dissolved in reaction dissolvent by cefazolin parent nucleus and cefazolin acid, add condensing agent, obtain low-temp reaction thing mixed solution；
S02. the heating of described low-temp reaction thing solution is carried out condensation reaction: the low-temp reaction thing mixed solution of preparation in step S01 is warming up to 20～30 DEG C and carries out condensation reaction, question response terminates rear frozen water and precipitates, solid-liquid separation, purification process, obtains the described cefazolin derivatives of following molecular structure formula I:
Specifically, in above-mentioned steps S01, it is cooled to lower than 5 DEG C after cefazolin parent nucleus and cefazolin acid are dissolved in reaction dissolvent in order that avoid working as condensing agent and add, react rapidly between reactant cefazolin parent nucleus and cefazolin acid, condensing agent can be uniformly dispersed in reaction dissolvent, thus the generation of the by-product effectively reduced between two reactant cefazolin parent nucleus and cefazolin acid.
Accordingly, in a preferred embodiment, the cefazolin parent nucleus in this step S01 and cefazolin acid are cooled to 0 DEG C after being dissolved in reaction dissolvent.
In this step S01, can be added dissolving according to reactant molar ratio in following chemical equation (1) when dissolving reactant cefazolin parent nucleus with cefazolin acid.In a preferred embodiment, the acid of cefazolin parent nucleus and cefazolin according to mol ratio be 1:(1～1.2) ratio be added dissolving.This mol ratio advantageously carries out in both forwards of reaction.After dissolving, cefazolin acid mass concentration in low-temp reaction thing mixed solution is preferably 0.05～0.15g/ml.
In another preferred embodiment, adopt when adding condensing agent and be slowly added to condensing agent and make it carry out Homogeneous phase mixing with reactant.In a particular embodiment, it is possible to adopt the mode of dropping to add condensing agent.Being slowly added to condensing agent, its purpose is also for preventing two to be swift in response reaction, thus producing more by-product, the yield causing target product is low, purification difficult.It is 1:(1.05～1.2 that the addition of this condensing agent is preferably the mol ratio of cefazolin parent nucleus and condensing agent).
It is preferred that in embodiment, this condensing agent selects 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl), O-(7-azepine BTA-1-base)-two (dimethylamino) carbon hexafluorophosphate (HATU), O-(BTA-1-base)-two (dimethylamino) carbon hexafluorophosphate (HBTU), O-(BTA-1-base)-two (dimethylamino) carbon tetrafluoroborate (TBTU), at least one in O-(N-succimide base)-two (dimethylamino) carbon tetrafluoroborate (TSTU).In further preferred embodiment, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate selected by this condensing agent.Select this 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate as the condensing agent in above-described embodiment, while enabling to two reactant generation condensation reactions, the generation of by-product can also be reduced, improve the yield of target product, and be easily product purification, the by-product of 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate can be dissolved in water, after need in purification, can be dissolved in frozen water, so that by-product separates with target product.
In above-mentioned steps S02, when the temperature of reaction solution rises to 20～30 DEG C, two reactants response speed under the effect of condensing agent increases, and the chemical equation of two reactants is as follows:
As the presently preferred embodiments, it is 25 DEG C that the temperature of reaction solution controls, so that the by-product in formula 1 is down to minimum.After treating two reactant reactions, as reacted after 12 hours at 25 DEG C, add frozen water so that product cefazolin derivatives generation partial crystallization and precipitate.This frozen water can remove the cefazolin acid etc. of inorganic salt and no reaction, reaches precipitation target product, the purpose of remove impurity simultaneously.
After to be precipitated, precipitate is carried out solid-liquid separation, purification process.Wherein, the method for purification process is preferably as follows:
Described filter cake chloroform after washing is dissolved by the alkaline wash that filter cake pH is 7～8 through solid-liquid separation gained again, is separated by silicon dioxide chromatography post and obtain described cefazolin derivatives.Wherein, the pH of alkaline solution is 7.5.
In a preferred embodiment, this alkaline solution is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, at least one solution in sodium hydroxide.
From the above, above-mentioned cefazolin derivatives preparation method adopts cefazolin acid to be reaction raw materials, the carboxyl utilizing cefazolin parent nucleus sour with cefazolin carries out condensation and modification, product cefazolin derivatives is made to have suitable lipid while maintaining former cefazolin pharmaceutically active, as described above, the partition coefficient of the n-octyl alcohol-aqueous systems of this product cefazolin derivatives is 4.37, apparent partition coefficients is moderate, relative molecular mass is less, it is very beneficial for intestinal absorption, can prepare for peroral dosage form.This process products yield and purity are high, it addition, the reaction condition between this reactant is easily-controllable, technique is simple, and by-product is low, and production efficiency and purity are high, are suitable to industrialized production.
On the basis of above-mentioned cefazolin derivatives and preparation method, the embodiment of the present invention additionally provides cefazolin derivatives prepared by a kind of oral antibiotic preparation, its cefazolin derivatives described above containing effective dose or cefazolin derivatives preparation method described above.
As the presently preferred embodiments, this cefazolin derivatives percentage by weight in oral antibiotic preparation is 30～90%.
Specifically, this oral antibiotic preparation is solid preparation, containing cefazolin derivatives active ingredient mentioned above and be suitable for making the excipient substance of solid preparation, wherein the percentage by weight of cefazolin derivatives is 30-90%, and the percentage by weight of adjuvant is 10-70%.This cefazolin derivatives solid preparation every preferably comprises cefazolin derivatives 100-400mg.
Wherein, excipient substance is selected from disintegrating agent, filler, binding agent, lubricant, surfactant, sweeting agent, wherein the percentage by weight of filler is 20-90%, and the percentage by weight of disintegrating agent is 5-30%, the percentage by weight of binding agent be 1-35%, lubricant percentage by weight be 0.1-5%, the percentage by weight of surfactant is 0.1-5%, and the percentage by weight of lubricant is 0.1-5%.
So, owing to above-mentioned oral antibiotic preparation contains cefazolin derivatives effective ingredient mentioned above, and this and cefazolin derivatives have pharmaceutically active as described above and suitable lipid, therefore, after this oral antibiotic preparation is taken, can be absorbed by the transport of digestive tract cell membrane, be played its drug effect, thus effectively reducing the incidence rate of abuse of antibiotics, widen the scope that domestic oral disposition antibiotic selects.It addition, be used conveniently and safely.
In conjunction with embodiment, the present invention is further elaborated.
Embodiment 1
A kind of cefazolin derivatives and synthetic method thereof
Cefazolin parent nucleus (3.4g) and cefazolin acid (4.5g) solvent are in tetramethyl guanidine (30ml), temperature is down to 0 DEG C, reaction solution is slowly added into and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (2.2g), it is sufficiently stirred for dissolving, temperature is increased to 25 DEG C, stirring reaction 12 hours；Reaction stops, and is poured into by reactant liquor in 1000ml frozen water, is filtrated to get a large amount of white solid, the sodium carbonate liquor drip washing of filter cake pH7.5；Filter cake chloroform dissolves, and is separated by silicon dioxide chromatography post and obtains cefazolin derivatives (Formulas I) 5.8 grams, and purity is 99.3%, and its mass yield is 171%.
The cefazolin derivatives embodiment of the present invention 1 prepared carries out hydrogen nuclear magnetic resonance Spectrum Analysis and mass spectral analysis, analyzes result as follows:
1HNMR(500MHz,DMSO-d6):9.67(d,1H,CONH),9.55(d,1H,CONH),9.37(s,1H,ArH),5.53(m,2H,CH),5.40(m,2H,CH2),5.31(m,1H,CH),5.22(m,1H,CH),5.00-5.19(d,d,2H,CH2),4.37-4.50(d,d,2H,CH2),3.91-4.22(d,d,2H,CH2),3.38-3.61(d,d,2H,CH2),2.68(s,3H,CH3),2.66(s,3H,CH3)；Mass (ESI): m/z781 [M]+。
By this analysis result it can be seen that cefazolin derivatives molecular structure prepared by the present embodiment is defined as the compound shown in above-mentioned molecular structure formula I.
Embodiment 2
Cefazolin parent nucleus (3.4g) and cefazolin acid (5.0g) solvent are in tetramethyl guanidine (100ml), temperature is down to 2 DEG C, reaction solution is slowly added into and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (2.6g), it is sufficiently stirred for dissolving, temperature is increased to 22 DEG C, stirring reaction 12 hours；Reaction stops, and is poured into by reactant liquor in 1000ml frozen water, is filtrated to get a large amount of white solid, the sodium carbonate liquor drip washing of filter cake pH7.8；Filter cake chloroform dissolves, and is separated by silicon dioxide chromatography post and obtains cefazolin derivatives (Formulas I) 5.2 grams, and purity is 99.5%, and its mass yield is 153%.
Embodiment 3
Cefazolin parent nucleus (3.4g) and cefazolin acid (4.5g) solvent are in tetramethyl guanidine (50ml), temperature is down to 5 DEG C, reaction solution is slowly added into and O-(7-azepine BTA-1-base)-two (dimethylamino) carbon hexafluorophosphate (HATU) (3.8g), it is sufficiently stirred for dissolving, temperature is increased to 20 DEG C, stirring reaction 12 hours；Reaction stops, and is poured into by reactant liquor in 1000ml frozen water, is filtrated to get a large amount of white solid, the sodium carbonate liquor drip washing of filter cake pH7.8；Filter cake chloroform dissolves, and is separated by silicon dioxide chromatography post and obtains cefazolin derivatives (Formulas I) 5.6 grams, and purity is 99.7%, and its mass yield is 165%.
Embodiment 4
Cefazolin parent nucleus (3.4g) and cefazolin acid (5.4g) solvent are in tetramethyl guanidine (50ml), temperature is down to 0 DEG C, reaction solution is slowly added into and O-(BTA-1-base)-two (dimethylamino) carbon tetrafluoroborate (TBTU) (3.3g), it is sufficiently stirred for dissolving, temperature is increased to 20 DEG C, stirring reaction 12 hours；Reaction stops, and is poured into by reactant liquor in 1000ml frozen water, is filtrated to get a large amount of white solid, the sodium carbonate liquor drip washing of filter cake pH7.8；Filter cake chloroform dissolves, and is separated by silicon dioxide chromatography post and obtains cefazolin derivatives (Formulas I) 4.3 grams, and purity is 99.5%, and its mass yield is 126%.
Oral antibiotic example of formulations
1000 cefotiam hexetil dispersible tablets are made with the raw material of following weight proportion
Preparation method:
First raw material pulverizing is crossed 100 mesh sieves, by cefazolin derivatives, microcrystalline Cellulose, it is sufficiently mixed after uniformly, add appropriate water soft material, 18 mesh sieves are granulated, 60 DEG C after dry 3-4 hour, 24 mesh sieve granulate, outer addition disintegrating agent carboxymethyl base Starch Sodium, aspartame, Fructus Citri tangerinae essence, silicon dioxide, magnesium stearate, after mixing, it is pressed into cefazolin derivatives dispersible tablet.
The pharmaceutically active experiment of cefazolin derivatives
The cefazolin derivatives prepared by above-described embodiment carries out antibacterial activity in vitro experiment, and concrete grammar is as follows:
Test strain: MSSA (judges with oxazacillin), antibacterial both passes through flat board before the test and turns and live point pure, is used for testing with new fresh thalli.Test is used that reference culture (staphylococcus aureus ATCC29213) is as sensitization test Quality Control bacterium every time;With the plate without antibacterials as test strain growth control；
Antibacterials: the cefazolin derivatives that embodiment 1 improves；
Comparison antibacterials: Cefazolin sodium pentahydrate. (Shenzhen China Resources Gosun Pharmaceutical Co., Ltd.)；
Antibacterial activity in vitro experimental technique: adopt two times of agar dilutions to measure cefazolin derivatives and Cefazolin sodium pentahydrate. to the minimum inhibitory concentration of MSSA and MIC value, two kinds of antibiotic are diluted to different concentration with sterile PBS buffer respectively, take each concentration liquid 10ml, it is added separately to dissolve and be cooled in the M-H agar of about 50 DEG C, it is poured into plate immediately so that the drug level of culture medium is between 0.06-32mg/L.Instrument is inoculated by 1 × 10 with trace multiple spot5CFU/mL bacterial suspension inoculation, to the antibiotic above-mentioned agar plate surface of variable concentrations, is placed in 35 DEG C of incubators and hatches 20h, measure each antibacterials minimum inhibitory concentration to various pathogenic bacterium.
Experimental configuration: it is 0.25mg/L that experiment records the Cefazolin sodium pentahydrate. MIC50 value to MSSA, and the MIC50 value of MSSA is 2.12mg/L by the cefazolin derivatives that embodiment 1 provides, illustrate that two kinds of antibiotic all represent higher bacteriostatic activity.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all any amendment, equivalent replacement and improvement etc. made within the spirit and principles in the present invention, should be included within protection scope of the present invention.
Claims (7)
1. a preparation method for cefazolin derivatives, comprises the steps:
It is cooled to lower than 5 DEG C after cefazolin parent nucleus and cefazolin acid are dissolved in organic reaction solvent, adds condensing agent, obtain reactant mixed solution；Wherein, described condensing agent is at least one in 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, O-(7-azepine BTA-1-base)-two (dimethylamino) carbon hexafluorophosphate, O-(BTA-1-base)-two (dimethylamino) carbon hexafluorophosphate, O-(BTA-1-base)-two (dimethylamino) carbon tetrafluoroborate, O-(N-succimide base)-two (dimethylamino) carbon tetrafluoroborate；The molecular structural formula of described cefazolin parent nucleus is such as following (I 0):
Described reactant mixed solution is warming up to 20～30 DEG C and carries out condensation reaction, until reaction terminates；Add frozen water to precipitate, solid-liquid separation, purification process, obtain the described cefazolin derivatives of following molecular structure formula I:
2. the preparation method of cefazolin derivatives according to claim 1, it is characterised in that: being dissolved with the temperature after the reaction dissolvent cooling that described cefazolin parent nucleus is sour with cefazolin is 0 DEG C；And/or described reactant mixed solution is warming up to 25 DEG C.
3. the preparation method of cefazolin derivatives according to claim 1 and 2, it is characterised in that: the mol ratio that described cefazolin parent nucleus is sour with cefazolin is 1:(1～1.2).
4. the preparation method of cefazolin derivatives according to claim 1 and 2, it is characterised in that: the mol ratio of described cefazolin parent nucleus and condensing agent is 1:(1.05～1.2).
5. the preparation method of cefazolin derivatives according to claim 1 and 2, it is characterised in that: described condensing agent is 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate.
6. the preparation method of cefazolin derivatives according to claim 1 and 2, it is characterized in that: described purification process is by the alkaline wash that filter cake pH is 7～8 through solid-liquid separation gained, again the described filter cake chloroform after washing is dissolved, separated by silicon dioxide chromatography post and obtain described cefazolin derivatives.
7. the preparation method of cefazolin derivatives according to claim 6, it is characterised in that: described alkaline solution is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, at least one solution in sodium hydroxide.
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