CN102731530B - Cephalosporin compound and synthetic method thereof and application - Google Patents
Cephalosporin compound and synthetic method thereof and application Download PDFInfo
- Publication number
- CN102731530B CN102731530B CN201110086564.8A CN201110086564A CN102731530B CN 102731530 B CN102731530 B CN 102731530B CN 201110086564 A CN201110086564 A CN 201110086564A CN 102731530 B CN102731530 B CN 102731530B
- Authority
- CN
- China
- Prior art keywords
- compound
- amino
- methyl
- obtains
- acid
- 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.)
- Active
Links
- 0 CC[C@](CCC[C@@]1C=C(C)C*=*C1)C=C(C)C(CCIC=CC=C(CC)ICC)*N Chemical compound CC[C@](CCC[C@@]1C=C(C)C*=*C1)C=C(C)C(CCIC=CC=C(CC)ICC)*N 0.000 description 4
- ZAFOQPUIDUGJIM-GHMZBOCLSA-N CC(C)(CC1=C[C@@H](CC2)[C@@H]2C=C1)Cl Chemical compound CC(C)(CC1=C[C@@H](CC2)[C@@H]2C=C1)Cl ZAFOQPUIDUGJIM-GHMZBOCLSA-N 0.000 description 1
- OHPJGDLKLZFTKY-VEDVMXKPSA-N CCC([C@@H](C)N)C(C)(C)CC Chemical compound CCC([C@@H](C)N)C(C)(C)CC OHPJGDLKLZFTKY-VEDVMXKPSA-N 0.000 description 1
Abstract
The invention provides a kind of novel cephalosporin compound. This compound structure is as shown in general formula I: wherein, and R1The quinary heterocyclic radical that the quinary heterocyclic radical that representative contains nitrogen, sulfur heteroatom or alkyl replace; R2For amino; R3For C1-C6Alkyl or organic acid esters substituted alkyl. The present invention also provides the methods and applications of preparing general formula (I). Gained general formula (I) target compound has certain antibacterial activity to standard gold staphylococcus aureus and standard bacillus canalis capsulatus.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to substituted type cephalosporins derivatives, the cephalosporins derivatives of the structure that particularly a class is new and synthetic method and application.
Background technology
The chemical improvement research work of cynnematin, from the rise of the sixties in last century, starts development the seventies, and reach a climax the eighties, enters the nineties, develops increasingly steady. Synthesize altogether during this period more than 50,000 noval chemical compound, wherein more than 50 kind of has a broad antifungal spectrum, good kind long-acting, resistance to beta-lactamase are gone on the market. But due to the result of abuse of antibiotics, especially in China, people's the not enough shortage with managing of understanding, the drug resistance of bacterium is development with surprising rapidity, not only some old antibiotic kinds lost efficacy successively, even the new antibiotic kind that Time To Market is not long, drug-resistant intensity is clinically also amazing. Threaten greatly so the drug resistance of bacterium has become one of clinical application, limited it and further developed. Rarer new antibiotic kind listing, found new reactive compound and also became very difficult recent years. From current new drug development trend, structure of modification will be certainly one of developing direction from now on.
At present, the main method of acquisition novel cephalosporin derivative is by cephalosporin mother nucleus is carried out to structure of modification. By calculating and clinical data, we can find that 7 side chains of cephalosporin nucleus and 3 various functional groups of introducing can greatly change antibacterial activity; 4 transformations of introducing group are also had to similar report, there is medium antibacterial activity, but relevant research few. But along with the enhancing of bacterial drug resistance, the compound of being badly in need of new chemical structure or new role mechanism occurs, is therefore all the focus that people study to the transformation of 7,3 and 4 groups.
Summary of the invention
An object of the present invention is to provide series of new cephalosporin compound.
Another object of the present invention is to provide the preparation method of these novel cephalosporin derivatives. It obtains a series of noval chemical compounds through condensation, oxidation, Mannich reaction, reduction, esterlysis, enzymolysis, condensation respectively taking GCLE as initiation material.
A further object of the present invention is to provide the pharmaceutical composition of these novel cephalosporin compounds as active component.
A present invention also object is to provide the application of these novel cephalosporin compounds aspect the medicine for the preparation for the treatment of sensitive bacterial infected patient, particularly treats the application of gram-positive bacteria medicine and Gram negative bacteria drugs aspect. The for example bacillus canalis capsulatus in staphylococcus aureus and the Gram-negative bacteria in gram-positive bacteria.
The present invention is synthetic a series of cephalosporins derivatives successfully, and its general formula is as follows:
R1The quinary heterocyclic radical replacing for the quinary heterocyclic radical that contains nitrogen, sulfur heteroatom or alkyl;
R2For amino;
R3For C1-C6Alkyl or C1-C6Organic acid esters substituted alkyl;
General formula (I) compound is following structural compounds preferably:
Wherein: R2For amino; R3For C1-C6Alkyl or C1-C6Organic acid esters substituted alkyl.
C of the present invention1-C6Straight chained alkyl comprises methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, tertiary fourth etc.
The heterocyclic radical of replacement of the present invention refers to and contains five-membered ring, and hetero atom is selected from O, S, N, for example, can be tetrazole, thiadiazoles etc.
A series of cephalosporins derivatives, preferred compound chemistry title is as follows:
7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl group] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methine cephalosporanic acid (Compound I I);
7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl group] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methine cephalosporanic acid (compound III);
7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) acetyl group] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methine cephalosporanic acid (compound IV);
7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) acetyl group] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methine cephalosporanic acid (compound V).
Preparation method, comprises the following steps:
Step 1: by GCLE(3) with the condensation of 1-methyl-5-mercapto tetrazole obtain compound (4) or by GCLE(3) with 2-sulfydryl-5-methyl isophthalic acid, 3,4 thiadiazoles condensations obtain and compound (5);
Step 2: compound (4) obtains compound (6) or compound (5) through oxidation and obtains compound (7) through oxidation;
Step 3: compound (6) obtains compound (8) or compound (7) obtains compound (9) through Mannich reaction through Mannich reaction;
Step 4: compound (8) obtains compound (10) or compound (9) through reduction and obtains compound (11) through reduction;
Step 5: compound (10) obtains compound (12) or compound (11) obtains compound (13) through esterlysis through esterlysis;
Step 6: compound (12) obtains compound (14) or compound (13) obtains compound (15) through enzymolysis through enzymolysis;
Step 7: compound (14) obtains compound (1) with compound (16) and (17) condensation respectively or compound (15) obtains compound (2) with compound (16) or (17) condensation respectively;
Wherein: R2For amino; R3For C1-C6Alkyl or organic acid esters substituted alkyl.
In general formula (I) compound, the preparation method of typical compound (1) and (2) is as follows:
Step 1:
By 1-methyl-5-mercapto tetrazole or 2-sulfydryl-5-methyl isophthalic acid, 3,4 thiadiazoles, respectively with appropriate dissolution with solvents, drip organic base. The settled solution of gained and GCLE(compound 3) react 1 ~ 12h. With the reactant liquor of inorganic alkali solution washing gained, to neutral, concentrate drying obtains respectively compound (4) or (5) solid.
Step 2:
Step 1 gained solid, respectively with suitable organic solvent dissolution, is dripped to acid anhydrides and hydrogen peroxide oxidant reaction. React complete with inorganic base neutralization reaction liquid. Filter and obtain respectively compound (6) or (7) solid.
Step 3:
Step 2 gained solid carries out amine-methylated condensation with diethylamine respectively, and the mol ratio of solid and diethylamine is 1:4, preferably 1:2. Reaction temperature is controlled at 30～60 DEG C, preferably 50～53 DEG C. Reaction time is 1～4h, preferably 2h. Obtain respectively compound (8) or (9) solid.
Step 4:
Step 3 products therefrom is processed to obtain to compound (10) or (11) solid with reducing agent reduction respectively.
Step 5:
Step 4 products therefrom, respectively with suitable organic solvent dissolution, drips trifluoroacetic acid reaction, obtains compound (12) or (13) solid.
Step 6:
Regulate respectively PH that it is dissolved step 5 products therefrom, add acylase, dropping acid solution is finished in reaction, obtains compound (14) or (15) solid.
Step 7:
Step 6 gained solid reacts with MEAM (compound 16) or Cefixime active ester (compound 17) respectively, obtains compound (1) or (2) solid.
Wherein can select suitable organic solvent to have carrene, chloroform, chloroform or toluene etc.; Available organic base has triethylamine, tri-n-butylamine, diethylamine, aniline or TMG etc.; Available acid anhydrides has acetic anhydride, propionic andydride etc.; Available inorganic base has sodium acid carbonate, sodium carbonate, ammoniacal liquor or sodium hydroxide solution; Oxidant means hydrogen peroxide or Peracetic acid; Reducing agent means phosphorus trichloride. Acid means hydrochloric acid, trifluoroacetic acid; Organic acid esters means methyl acetate or tert-butyl acetate; Immobilized penicillin G acylase refers to IPA-750 immobilized penicillin G acylase.
The present invention further discloses series compound application in treatment infectious disease medicament as antiseptic of the cephalosporins derivatives of general formula (I), the infection of the upper respiratory tract that for example staphylococcus aureus or bacillus canalis capsulatus cause, skin soft-tissue infection, acute bronchitis, pneumonia etc. Concrete pharmacological evaluation is as follows:
Sample: Compound I I, III, IV, V
Contrast medicine: Cefixime; Cefdinir; Cephazoline.
Bacterial strain: standard gold staphylococcus aureus (CMCC(B) 26003)
Standard bacillus canalis capsulatus (CMCC(B) 46117), all purchased from Products in China qualification institute.
Instrument and equipment:
Electrothermal pressure steam sterilizer YXQGO2 type; Carbon dioxide water-impermeable incubator; Electronic balance; Pin type filter; Disposable 96 orifice plates.
Compound I I, III, IV, V compound are fine to the antibacterial activity of standard gold staphylococcus aureus, and wherein Compound I I, V are best to the antibacterial effect of standard gold staphylococcus aureus and standard bacillus canalis capsulatus.
The present invention further discloses the compound that contains general formula (I) is the Pharmaceutical composition of active component and pharmaceutically acceptable carrier, excipient or diluent composition.
Series compound of the present invention is normally taken with the form of pharmaceutical composition, can oral or parenteral administration, or with the oral or parenteral administration of compound (as tablet, capsule and sustained release preparation thereof, injection, the solution) safety that forms with pharmaceutically acceptable carrier, excipient and other additive. In the time of oral administration, composition can be mixed with tablet, capsule, granule etc. Can adopt lactose, microcrystalline cellulose or starch to do carrier for preparing combination of oral medication, gelatin, polyvinylpyrrolidone and cellulose family macromolecule compound etc. are as suitable bonding agent or granulating agent. Can select sodium carboxymethylcellulose, sodium carboxymethyl starch, low replacement carboxy-propyl cellulose as disintegrant, normal using talcum powder, colloidal silica gel, tristerin, calcium stearate or magnesium as suitable antiadhesives and lubricant. For example, can prepare tablet by compacting wet granular. Active component and carrier and optionally with a disintegration additive composition mixture; the aqueous solution of this mixture and adhesive; alcohol or aqueous alcohol solution carry out granulating in suitable equipment; dried particles adds other disintegrant subsequently, and lubricant and antiplastering aid are by this mixture compressing tablet. Series compound of the present invention can injection form administration, although dosage changes according to treatment target, administering mode, symptom and other factors. In the time of parenterai administration, composition of the present invention is made into ejection preparation.
Brief description of the drawings:
Fig. 1 is novel cephalosporin compounds structural formula.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further, embodiment is only indicative, never mean that it limits the scope of the invention by any way, the compound of invention is through high performance liquid chromatography (HPLC), thin-layer chromatography (TLC), fusing point (m.p.) detects, can adopt subsequently nuclear magnetic resonance (1HNMR/13Etc. CNMR) further confirm its structure. The present invention GCLE used, MEAM, Cefixime active ester, immobilized penicillin G acylase (IPA-750 immobilized penicillin G acylase) are commercially available.
Embodiment 1
7-phenylacetylamino-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-cephalosporanic acid is synthetic to methoxy benzyl ester (4):
1-methyl-5-mercapto tetrazole 14.5g, carrene 750mL add in reaction bulb, add triethylamine 15mL at 0 DEG C, add GCLE50g(compound 3), reaction 10h, is washed till neutrality with saturated sodium carbonate solution, dry, concentrate to obtain white solid 55.9g, yield 96%.
Embodiment 2
7-phenylacetylamino-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-cephalosporanic acid is synthetic to methoxy benzyl ester-5-oxygen (6):
By compound (4) 29g, toluene 360mL adds in reaction bulb, under 0 DEG C of condition, adds acetic anhydride 27.5mL, hydrogen peroxide (30%) 15mL, after reaction 3h, adds saturated sodium bicarbonate solution and solution of sodium bisulfite to neutral, filter to obtain 25.3g solid, yield 85%.
Embodiment 3
7-phenylacetylamino-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methine-cephalosporanic acid is synthetic to methoxy benzyl ester-5-oxygen (8)
Compound (6) 25g, diethylamine 9mL, trifluoroacetic acid 7mL, formaldehyde (37%) 8.5mL, the 75mL tert-butyl alcohol, 200mL diox are reacted to 3h under 50 DEG C of conditions, then reactant liquor is dropped in water, filter, obtain 20g solid, yield 80%.
Embodiment 4
7-phenylacetylamino-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methine-cephalosporanic acid is synthetic to methoxy benzyl ester (10)
By compound (8) 6g, 100mL carrene, 10mLN, dinethylformamide adds in reaction bulb, adds phosphorus trichloride 3.5mL under condition of ice bath, after 3h, stop reaction, add water and carrene, dichloromethane layer is dry, concentrate to obtain 4.6g solid, yield 80%.
Embodiment 5
7-phenylacetylamino-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methine-cephalosporanic acid (12) synthetic
Compound (10) 1.2g, 50mL methyl phenyl ethers anisole are added in reaction bulb, add trifluoracetic acid 7.5ml under room temperature condition, stir and add ethyl acetate 50ml after 3 hours, filter, appropriate ethyl acetate washed twice, obtains 0.8g solid, yield 64%.
Embodiment 6
7-amino-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methine-cephalosporanic acid (14) synthetic
Compound (12) 4g, 50mL phosphate solution are added in reaction bulb; ammoniacal liquor with 5% regulates pH to 7.8; add immobilized penicillin G acylase 4g, adding ammoniacal liquor to regulate pH value is 7.8, keeps constant; after pH value is constant; with hydrochloric acid adjust pH to 3, separate out white solid, filter; obtain 2.6g solid, yield 80%.
Embodiment 7
7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl group] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methine cephalosporanic acid (II) synthetic
Compound (14) 2g, 10mL acetone, 5mL water are joined in reaction bulb, stir and be cooled to 10 DEG C, drip triethylamine 0.6mL, then add MEAM 2g(compound 16), react 14 hours. After completion of the reaction, boil off solvent, the 10mL that adds water, filters, and filtrate adds activated carbon decolorizing, filters, and salt acid for adjusting pH value to 3, separates out precipitation, hold over night, and suction filtration, proper amount of acetone washing, obtains faint yellow solid 2.5g, yield 81%.
Embodiment 8
7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) acetyl group] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methine cephalosporanic acid (IV) synthetic:
Carrene 13mL, water 1mL and methyl alcohol 0.5mL, be cooled to 0 DEG C, adds 1.6g compound 14 under stirring, drips triethylamine 5mL, after solution clarification, adds Cefixime active ester (compound 17) 2.3g, is warming up to room temperature, stirring reaction 3 hours. React the complete ethyl acetate 13mL that adds, filter, with the each washing of appropriate carrene and ethyl acetate 5mL one time, be dried and obtain pale yellow powder 2.30g, yield 78%.
1H-NMR(DMSO,400MHz)δ:3.67(3H,s),3.88(3H,s),4.38,4.56(2H,dd,J=13.3Hz),
4.68(2H,s)5.04(1H,d,J=4.8Hz),5.54(2H,d,J=13.4Hz),
5.82(1H,dd,J=8.0Hz,J=4.8Hz),6.77(1H,s),7.24(2H,s),
9.63(1H,d,J=6.9Hz).
Embodiment 9
7-phenylacetylamino-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-cephalosporanic acid is synthetic to methoxy benzyl ester (5):
By 2-sulfydryl-5-methyl isophthalic acid, 3,4 thiadiazoles 16.5g, 750mL carrene add in reaction bulb, under 0 DEG C of condition, add triethylamine 15mL, add GCLE50g, reaction 10h, is washed till neutrality with saturated sodium carbonate solution, dry, concentrate to obtain white solid 56.5g, yield 94%.
Embodiment 10
7-phenylacetylamino-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-cephalosporanic acid is synthetic to methoxy benzyl ester-5-oxygen (7):
Compound (5) 30g, 360mL toluene are added in reaction bulb, at 0 DEG C, add acetic anhydride 27.5mL, hydrogen peroxide (30%) 15mL, after 3h, react complete, add saturated sodium bicarbonate solution and solution of sodium bisulfite to neutral, filter to obtain 26g solid, yield 84%.
Embodiment 11
7-phenylacetylamino-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methine-cephalosporanic acid is synthetic to methoxy benzyl ester-5-oxygen (9):
Compound (7) 27g, diethylamine 9mL, trifluoroacetic acid 6.6mL, formaldehyde (37%) 8.5mL, the 75mL tert-butyl alcohol, 205mL diox are reacted to 3h under 50 DEG C of conditions, then reactant liquor is added to the water, filter, obtain 22.8g solid, yield 82%.
Embodiment 12
7-phenylacetylamino-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methine-cephalosporanic acid is synthetic to methoxy benzyl ester (11):
By compound (9) 6.4g, 100mL carrene, 10mLN, dinethylformamide adds in reaction bulb, adds phosphorus trichloride 3.5mL under condition of ice bath, after 3h, add water and stop reaction, washing, carrene extracts water layer, combined dichloromethane layer is dry, concentrates to obtain solid 4.9g, yield 80%.
Embodiment 13
7-phenylacetylamino-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methine-cephalosporanic acid (13) synthetic:
Compound (11) 1.2g, 50mL methyl phenyl ethers anisole are added in reaction bulb, add trifluoracetic acid 7.5ml under room temperature, stir and add ethyl acetate 50ml after 5 hours, filter, appropriate ethyl acetate washed twice for filter cake, obtains 0.8g solid, yield 83%.
Embodiment 14
7-amino-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methylene-cephalo-alkanoic acid (15) synthetic
Compound (13) 5g, 50mL phosphate solution are added in reaction bulb, and 37 DEG C, the ammoniacal liquor with 5% is adjusted pH to 8.0; add immobilized penicillin G acylase 4g; stir, and adding ammoniacal liquor, to regulate pH value be 8, keeps constant; after reaction finishes; with salt acid for adjusting pH value to 3.0, separate out solid, filter; obtain 3g solid, yield 78%.
Embodiment 15
7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl group] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methine cephalosporanic acid (compound III) synthetic:
Compound (15) 2g, 10mL acetone, 5mL water are joined in reaction bulb, stir and be cooled to 10 DEG C, drip triethylamine 0.6mL, then add MEAM (compound 16) 1.8g, react 14 hours. Evaporate to dryness acetone, the 10mL that adds water, adds activated carbon decolorizing and filters in filtrate, and salt acid for adjusting pH value to 3.0, separates out precipitation, and suction filtration obtains faint yellow solid 1.4g, yield 62%.
1H-NMR(DMSO,400MHz)δ:2.66(3H,s),3.84(3H,s),4.37,
4.84(2H,dd,J=15.2Hz),5.12(1H,d，J=4.3Hz)，
5.53(2H,d,J=14.0Hz),5.67(1H,dd,J=7.8Hz,J=3.9Hz),
6.73(1H,s),7.19(2H,s),9.62(1H,d,J=6.9Hz).
Embodiment 16
7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) acetyl group] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methine cephalosporanic acid (compound V) synthetic:
Carrene 13mL, water 1mL and methyl alcohol 0.3mL, add compound (15) 2g at 0 DEG C, adds triethylamine 5mL, adds a gram oxime active ester (compound 17) 2.3g, rises to room temperature, stirs 3 hours. Add ethyl acetate 13mL, filter, wash with carrene and ethyl acetate, vacuum drying obtains pale yellow powder 1.9g, yield 65%.
1H-NMR(DMSO,400MHz)δ:2.66(3H,s),3.76(3H,s),4.37,
4.85(2H,dd,J=13.3Hz),4.68(2H,s)5.14(1H,d,J=4.7Hz),5.55(2H,d，
J=13.8Hz),5.71(1H,dd，J=6.2Hz，J=3.8Hz),.7,6(1H,s),7.23(2H,s)，
9.6,1(1H,d,J=7.1Hz).
Embodiment 17
The every preparation of the tablet containing 100mg active component:
Mg/ sheet
Compound V100
Lactose 50
Microcrystalline cellulose 80
Starch 50
Hydroxypropyl methylcellulose 15
Carboxyrnethyl starch sodium 5
Dolomol 5
By active component, lactose, starch, microcrystalline cellulose are crossed 100 mesh sieves, and fully mix, the 2% hydroxyl methylcellulose aqueous solution is joined in above-mentioned mixed-powder and mixed, cross 20 mesh sieve softwood processed, make wet granular in 45-55 DEG C dry, carboxyrnethyl starch sodium, dolomol are joined to compressing tablet in above-mentioned dried particles.
Embodiment 18
Consumption
Compound I I10g
Appropriate amount of ethanol
Starch 150g
By Compound I I, starch, moistening with 60% ethanol water, the granulation of sieving after mixing, 60 DEG C are dry, whole grain, filled capsules.
After the preferred embodiment describing in detail, being familiar with this technology personage can be well understood to, can carry out various variations and amendment not departing under above-mentioned claim and spirit, any simple modification, equivalent variations and modification that all foundations technical spirit of the present invention is done above embodiment, all belong to the scope of technical solution of the present invention. And the present invention is not also limited to the embodiment of example in description.
Claims (7)
1. cephalosporin compound, its chemical structural formula is:
Wherein: R2For amino; R3For C1-C6Alkyl or C1-C6Organic acid esters substituted alkyl.
2. cephalosporin compound claimed in claim 1, its typical compound is as follows:
7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl group] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methine cephalosporanic acid;
7-[[(2-amino-4-thiazolyl) (methoxyimino) acetyl group] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methine cephalosporanic acid;
7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) acetyl group] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methine cephalosporanic acid;
7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) acetyl group] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methine cephalosporanic acid.
3. the preparation method of cephalosporin compound claimed in claim 1, comprises the following steps:
(I) is by GCLE(3) with the condensation of 1-methyl-5-mercapto tetrazole obtain compound (4) or by GCLE(3) with 2-sulfydryl-5-methyl isophthalic acid, 3,4 thiadiazoles condensations obtain compound (5);
(II) compound (4) obtains compound (6) or compound (5) through oxidation and obtains compound (7) through oxidation;
(III) compound (6) obtains compound (8) or compound (7) obtains compound (9) through Mannich reaction through Mannich reaction;
(IV) compound (8) obtains compound (10) or compound (9) through reduction and obtains compound (11) through reduction;
(V) compound (10) obtains compound (12) or compound (11) obtains chemical combination through esterlysis through esterlysis
Thing (13);
(VI) compound (12) obtains compound (14) or compound (13) obtains compound (15) through enzymolysis through enzymolysis;
(VII) compound (14) obtains compound (1) with compound (16) and (17) condensation respectively, and compound (15) obtains compound (2) with compound (16) or (17) condensation respectively;
Wherein: R2For amino; R3For C1-C6Alkyl or C1-C6Organic acid esters substituted alkyl.
4. the application of the antibacterial combination of cephalosporin compound claimed in claim 1 and pharmaceutically acceptable carrier composition aspect the medicine for the preparation for the treatment of sensitive bacterial infected patient.
5. the application of cephalosporin compound aspect the medicine for the preparation for the treatment of sensitive bacterial infected patient described in claim 1.
6. application claimed in claim 5, is characterized in that the application aspect preparation treatment gram-positive bacteria medicine and Gram negative bacteria drugs.
7. application claimed in claim 6, gram-positive bacteria is wherein staphylococcus aureus, Gram-negative bacteria is bacillus canalis capsulatus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110086564.8A CN102731530B (en) | 2011-04-07 | 2011-04-07 | Cephalosporin compound and synthetic method thereof and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110086564.8A CN102731530B (en) | 2011-04-07 | 2011-04-07 | Cephalosporin compound and synthetic method thereof and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102731530A CN102731530A (en) | 2012-10-17 |
| CN102731530B true CN102731530B (en) | 2016-05-04 |
Family
ID=46987904
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110086564.8A Active CN102731530B (en) | 2011-04-07 | 2011-04-07 | Cephalosporin compound and synthetic method thereof and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102731530B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866703A (en) * | 2017-04-28 | 2017-06-20 | 山东新华制药股份有限公司 | The preparation method of Cefradine oxide D |
| CN114540454B (en) * | 2022-03-09 | 2023-10-17 | 浙江东邦药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride by enzyme method and synthesis intermediate thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4202893A (en) * | 1976-03-25 | 1980-05-13 | Roussel Uclaf | Alkyloximes of 7-amino-thiazolyl-acetamido-cephalosporanic acids |
| WO2000061149A1 (en) * | 1999-04-07 | 2000-10-19 | Takeda Schering-Plough Animal Health K.K. | Long-acting antibacterial composition |
| WO2000063213A1 (en) * | 1999-04-15 | 2000-10-26 | Research Corporation Technologies, Inc. | Beta-lactamase inhibiting compounds |
| WO2004058695A1 (en) * | 2002-12-26 | 2004-07-15 | Lupin Limited | Novel intermediates for synthesis of cephalosporins and process for preparation of such intermediates |
| CN101550150A (en) * | 2009-05-07 | 2009-10-07 | 张锡芬 | Cefmenoxime compound and synthetic method thereof |
| CN101671351A (en) * | 2009-09-23 | 2010-03-17 | 天津市医药集团技术发展有限公司 | Carbon 2-bit substituted cephalosporin derivative as well as synthetic method and application thereof |
-
2011
- 2011-04-07 CN CN201110086564.8A patent/CN102731530B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4202893A (en) * | 1976-03-25 | 1980-05-13 | Roussel Uclaf | Alkyloximes of 7-amino-thiazolyl-acetamido-cephalosporanic acids |
| WO2000061149A1 (en) * | 1999-04-07 | 2000-10-19 | Takeda Schering-Plough Animal Health K.K. | Long-acting antibacterial composition |
| WO2000063213A1 (en) * | 1999-04-15 | 2000-10-26 | Research Corporation Technologies, Inc. | Beta-lactamase inhibiting compounds |
| WO2004058695A1 (en) * | 2002-12-26 | 2004-07-15 | Lupin Limited | Novel intermediates for synthesis of cephalosporins and process for preparation of such intermediates |
| CN101550150A (en) * | 2009-05-07 | 2009-10-07 | 张锡芬 | Cefmenoxime compound and synthetic method thereof |
| CN101671351A (en) * | 2009-09-23 | 2010-03-17 | 天津市医药集团技术发展有限公司 | Carbon 2-bit substituted cephalosporin derivative as well as synthetic method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 2位取代的头孢菌素类新化合物的合成与生物活性的研究;刘晓;《中国协和医科大学中国医学科学院硕士学位论文》;20090715;第16-23页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102731530A (en) | 2012-10-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2727509C2 (en) | Polymorphous and pseudopolymorphous forms of the pharmaceutical compound | |
| CA2538546C (en) | Polymorphic forms of rifaximin, processes for their production and use thereof in medicinal preparations | |
| KR100245938B1 (en) | Triazolylthiomethylthio cephalosporin hydrochloride, its crystalline and the production of the same | |
| KR100435315B1 (en) | Crystallographically stable amorphous cephalosporin compositions and process for producing the same | |
| CN102731530B (en) | Cephalosporin compound and synthetic method thereof and application | |
| CN111620893B (en) | C-3 tetrahydrofuran substituted cephalosporin-siderophore coupling compound and preparation method and application thereof | |
| US4189479A (en) | Cephalosporin esters | |
| CN101418015B (en) | Ceftriaxone phosphorylation derivates | |
| WO2013010297A1 (en) | Method for purifying ceftizoxime sodium | |
| CN102040615B (en) | Pyrrolin naphthene base-containing cephalo antibiotic | |
| JP2575590B2 (en) | Triazolylthiomethylthiocephalosporin hydrochloride and its hydrate crystals and their preparation | |
| CN101397297A (en) | Aminothiazole derivates, preparation method and use thereof | |
| CN101210023B (en) | Novel cephalosporin derivatives | |
| CN102030766B (en) | Flomoxef antibiotic containing pyrrolinheterocycle | |
| CN101230069B (en) | Novel cephalosporin derivant | |
| CN100396688C (en) | Cephems phosphate and preparation process and use thereof | |
| CN101357929B (en) | Cephalosporin derivative containing sulfhydryl thiadiazole | |
| CN101245081B (en) | Novel cephalosporin derivative | |
| CN101245080A (en) | Cephalosporin derivatives containing pyrazole triazole | |
| CN101190922B (en) | Cephalosporin derivative | |
| CN101210022B (en) | Cephalosporin | |
| CN101787022B (en) | Quinoline carboxylic acid hydrochloride-hydrate novel crystal form, and preparation method thereof | |
| SU1060116A3 (en) | Process for preparing derivatives of 7-2-(2-aminothiazol-4-yl)-2-oxyamino-acetamido-4-cephem-4-carboxylic acid, or its esters, or its salts | |
| CN101220041B (en) | Cephalosporin derivant | |
| CN113045498A (en) | 1, 5-diaryl pyrazole derivative, synthesis method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |