CN102731530A - Novel cephalosporin compound and its synthesis method and use - Google Patents
Novel cephalosporin compound and its synthesis method and use Download PDFInfo
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Abstract
The invention provides a novel cephalosporin compound. The novel cephalosporin compound has a general structural formula I, wherein in the general structural formula I, R1 represents nitrogen and sulfur heteroatom-containing five-membered heterocyclic radical or alkyl-substituted five-membered heterocyclic radical; R2 represents amino; and R3 represents C1-6 alkyl or organic acid ester-substituted alkyl. The invention also provides a synthesis method and a use of the novel cephalosporin compound having the general structural formula I. The novel cephalosporin compound having the general structural formula I has a certain activity of resisting standard staphylococcus aureus and standard klebsiella pneumoniae.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to the substituted type cephalosporins derivatives, particularly the cephalosporins derivatives of one type of new structure and compound method thereof and application.
Background technology
The chemical improvement research work of cynnematin from the rise of the sixties in last century, begins development the seventies, and reach a climax the eighties, gets into the nineties, develops steady day by day.Synthetic altogether during this period more than 50,000 new compound, wherein more than 50 kind of has a broad antifungal spectrum, good kind long-acting, anti-β-Nei Xiananmei are able to listing.But because the result of abuse of antibiotics; Especially in China; People's the insufficient recognition and the shortage of management, drug-resistance of bacteria be development with surprising rapidity, and not only some old microbiotic kinds lost efficacy successively; Even the new microbiotic kind that Time To Market is not long, drug-resistant intensity clinically is also amazing.Threaten greatly so drug-resistance of bacteria has become one of clinical application, limited it and further developed.Rarer new microbiotic kind listing recent years is sought new active compound and is also become very difficult.From present new drug development trend, structure of modification undoubtedly will be one of developing direction from now on.
At present, the main method of acquisition novel cephalosporin derivative is through cephalosporin mother nucleus is carried out structure of modification.Through calculating and clinical data, we can find that 7 side chains of cephalo parent nucleus and 3 various functional groups of introducing can greatly change anti-microbial activity; 4 transformations of introducing group also there is similar report, has medium anti-microbial activity, but relevant research and 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, and therefore the transformation to 7,3 and 4 groups all is the focus that people study.
Summary of the invention
An object of the present invention is to provide a series of novel cephalosporin compounds.
Another object of the present invention provides the preparation method of these novel cephalosporin derivatives.It is starting raw material with GCLE, obtains a series of new compounds through condensation, oxidation, Mannich reaction, reduction, esterlysis, enzymolysis, condensation respectively.
A purpose more of the present invention provides the pharmaceutical composition of these novel cephalosporin compounds as activeconstituents.
The present invention also purpose provides the application aspect these novel cephalosporin compounds are used to treat the sensitive bacterial infected patient in preparation the medicine, particularly treats the application of gram-positive microorganism medicine and Gram negative bacteria drugs aspect.For example streptococcus aureus in the gram-positive microorganism and the bacillus canalis capsulatus in the Gram-negative bacteria.
The successfully synthetic a series of cephalosporins derivatives of the present invention, its general formula is following:
R
1Be quinary heterocyclic radical or the substituted quinary heterocyclic radical of alkyl that contains nitrogen, sulfur heteroatom;
R
2Be amino;
R
3Be C
1-C
6Alkyl or C
1-C
6The organic acid acetic substituted alkyl;
The preferred following structural compounds of logical formula I compound:
Wherein: R
2Be amino; R
3Be C
1-C
6Alkyl or C
1-C
6The organic acid acetic substituted alkyl.
C of the present invention
1-C
6Straight chained alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, uncle's fourth or the like.
Substituted heterocyclic radical according to the invention refers to and contains five-ring, and heteroatoms is selected from O, S, N, for example can be tetrazole, thiadiazoles or the like.
A series of cephalosporins derivatives, preferred compound chemistry title is following:
7-[[(2-amino-4-thiazolyl) (methoxyimino) ethanoyl] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methyne Cephalosporanic acid (compound I I);
7-[[(2-amino-4-thiazolyl) (methoxyimino) ethanoyl] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methyne Cephalosporanic acid (compound III);
7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) ethanoyl] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methyne Cephalosporanic acid (compound IV);
7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) ethanoyl] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methyne Cephalosporanic acid (compound V).
The preparation method may further comprise the steps:
Step 1: GCLE (3) and 1-methyl-5-mercapto tetrazole condensation are obtained compound (4) or with GCLE (3) and 2-sulfydryl-5-methyl isophthalic acid, 3,4 thiadiazoles condensations obtain and compound (5);
Step 2: compound (4) obtains compound (6) or compound (5) obtains compound (7) through oxidation through oxidation;
Step 3: compound (6) obtains compound (8) or compound (7) obtains compound (9) through Mannich reaction through Mannich reaction;
Step 4: the reduction of compound (8) warp obtains compound (10) or compound (9) 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: R
2Be amino; R
3Be C
1-C
6Alkyl or organic acid acetic substituted alkyl.
The preparation method of exemplary compounds (1) and (2) is following in general formula (I) compound:
Step 1:
With 1-methyl-5-mercapto tetrazole or 2-sulfydryl-5-methyl isophthalic acid, 3,4 thiadiazoles drip organic bases respectively with an amount of dissolution with solvents.The settled solution of gained and GCLE (compound 3) react 1 ~ 12h.Reaction solution with inorganic alkali solution washing gained is extremely neutral, and concentrate drying obtains compound (4) or (5) solid respectively.
Step 2:
Step 1 gained solid respectively with suitable organic solvent dissolution, is dripped the reaction of acid anhydrides and hydrogen peroxide oxidant.Reaction finishes with mineral alkali neutralization reaction liquid.Filter and obtain compound (6) or (7) solid respectively.
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, preferred 1:2.Temperature of reaction is controlled at 30～60 ℃, preferred 50～53 ℃.Reaction times is 1～4h, preferred 2h.Obtain compound (8) or (9) solid respectively.
Step 4:
With the step 3 products therefrom respectively with reductive agent reduction handle compound (10) or (11) solid.
Step 5:
The step 4 products therefrom drips the trifluoroacetic acid reaction respectively with suitable organic solvent dissolution, obtains compound (12) or (13) solid.
Step 6:
The step 5 products therefrom is regulated PH respectively make its dissolving, add acylase, the dropping acid solution is finished in reaction, obtains compound (14) or (15) solid.
Step 7:
Step 6 gained solid reacts with AE active ester (compound 16) or Cefixime Micronized active ester (compound 17) respectively, obtains compound (1) or (2) solid.
Wherein can select for use appropriate organic solvent that methylene dichloride, trichloromethane, chloroform or toluene etc. are arranged; Available organic bases has triethylamine, Tributylamine, diethylamine, aniline or tetramethyl guanidine etc.; Available acid anhydrides has diacetyl oxide, propionic anhydride etc.; Available mineral alkali has sodium hydrogencarbonate, yellow soda ash, ammoniacal liquor or sodium hydroxide solution; Oxygenant means hydrogen peroxide or Peracetic Acid; Reductive agent means phosphorus trichloride.Acid means hydrochloric acid, trifluoroacetic acid; Organic acid acetic means methyl acetate or tert.-butyl acetate; The immobilized penicillin G acylase refers to IPA-750 immobilized penicillin G acylase.
The series compound of cephalosporins derivatives that the present invention further discloses general formula (I) as antiseptic-germicide in the application of treatment in the infectious disease medicament; The upper respiratory tract infection that causes of streptococcus aureus or bacillus canalis capsulatus for example; Skin soft-tissue infection; Acute bronchitis, pneumonia or the like.Concrete pharmacological evaluation is following:
Sample: compound I I, III, IV, V
Contrast medicine: Cefixime Micronized; Cefdinir; Kefzol.
Bacterial strain: standard gold staphylococcus aureus (CMCC (B) 26003)
Standard bacillus canalis capsulatus (CMCC (B) 46117) is all identified institute available from the Chinese biological goods.
Instrument and equipment:
Electric heating pressure steam sterilizer YXQGO2 type; Carbonic acid gas water isolation type incubator; Electronic balance; The pin type filter; Disposable 96 orifice plates.
：
| Compound | The standard bacillus canalis capsulatus | The standard gold staphylococcus aureus |
| Cefixime Micronized | 8 | 4 |
| Cefdinir | 8 | 4 |
| Kefzol | 4 | 2 |
| Compound I I | 8 | 4 |
| Compound III | 16 | 4 |
| Compound IV | 32 | 8 |
| Compound V | 8 | 4 |
Compound I I, III, IV, V compound are fine to the anti-microbial 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 medicinal compsns that activeconstituents and pharmaceutically acceptable carrier, vehicle or thinner are formed.
Series compound of the present invention is normally taken with the form of pharmaceutical composition; Taking orally or non-oral administration are perhaps with the oral or non-oral administration of compound (like tablet, capsule and sustained release preparation thereof, injection, the solution) safety that forms with pharmaceutically acceptable carrier, vehicle and other additive.When oral administration, compsn can be mixed with tablet, capsule, granule etc.For the preparation combination of oral medication can adopt lactose, Microcrystalline Cellulose or starch to do carrier, gelatin, Vinylpyrrolidone polymer and cellulose family macromolecule compound etc. are as suitable wedding agent or granulating agent.Can select Xylo-Mucine, sodium starch glycolate, the low carboxy-propyl cellulose that replaces for use as disintegrating agent, normal with talcum powder, colloidal silica gel, stearin, calcium stearate or magnesium as suitable antiadhesives and lubricant.For example, can prepare tablet through the compacting wet granular.Activeconstituents and carrier and optionally with a disintegration additive composition mixture; The aqs soln of this mixture and tackiness agent; Alcohol property or aqueous alcohol property solution carry out prilling in suitable device; Dried particles adds other disintegrating agent subsequently, and lubricant and antisticking agent are with this mixture compressing tablet.Series compound of the present invention can the injection form administration, though dosage changes according to treatment target, administering mode, symptom and other factor.When parenterai administration, compsn of the present invention is made into injection formulations.
Description of drawings:
Fig. 1 is the novel cephalosporin compounds structural formula.
Embodiment
Below in conjunction with embodiment the present invention is done further explanation; It is indicative that embodiment is merely; Mean that never it limits scope of the present invention by any way, the compound of invention is through performance liquid chromatography (HPLC), thin-layer chromatography (TLC); Fusing point (m.p.) detects, can adopt subsequently nucleus magnetic resonance (
1HNMR/
13CNMR) etc. further prove conclusively its structure.The used GCLE of the present invention, AE active ester, Cefixime Micronized 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, methylene dichloride 750mL add in the reaction flask, add triethylamine 15mL under 0 ℃, add GCLE50g (compound 3); Reaction 10h is washed till neutrality with saturated sodium carbonate solution, drying; Concentrate 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):
With compound (4) 29g, toluene 360mL adds in the reaction flask, adds diacetyl oxide 27.5mL under 0 ℃ of condition; Hydrogen peroxide (30%) 15mL behind the reaction 3h, adds saturated sodium bicarbonate solution and sodium sulfite solution to neutral; Cross and filter the 25.3g solid, yield 85%.
Embodiment 3
7-phenylacetylamino-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methyne-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 trimethyl carbinol, 200mL diox are reacted 3h under 50 ℃ of conditions, will react drop then to water, filter, get the 20g solid, yield 80%.
Embodiment 4
7-phenylacetylamino-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methyne-Cephalosporanic acid is synthetic to methoxy benzyl ester (10)
With compound (8) 6g, 100mL methylene dichloride, 10mLN, dinethylformamide adds in the reaction flask, adds phosphorus trichloride 3.5mL under the condition of ice bath; Stopped reaction behind the 3h adds entry and methylene dichloride, and dichloromethane layer is dry; Concentrate the 4.6g solid, yield 80 %.
Embodiment 5
Synthesizing of 7-phenylacetylamino-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methyne-Cephalosporanic acid (12)
Compound (10) 1.2g, 50mL methyl-phenoxide are added in the reaction flask, add trifluoracetic acid 7.5ml under the room temperature condition, stir adding ETHYLE ACETATE 50ml after 3 hours, filter, an amount of ETHYLE ACETATE washed twice gets the 0.8g solid, yield 64%.
Embodiment 6
Synthesizing of 7-amino-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methyne-Cephalosporanic acid (14)
Compound (12) 4g, 50mL aqueous phosphate solution are added in the reaction flask, and the ammoniacal liquor with 5% is regulated pH to 7.8, adds immobilized penicillin G acylase 4g; Adding ammoniacal liquor, to regulate the pH value be 7.8, keeps constant, treat that the pH value is constant after; With hydrochloric acid adjust pH to 3, separate out white solid, filter; Get the 2.6g solid, yield 80%.
Embodiment 7
Synthesizing of 7-[[(2-amino-4-thiazolyl) (methoxyimino) ethanoyl] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methyne Cephalosporanic acid (II)
Compound (14) 2g, 10mL acetone, 5mL water are joined in the reaction flask, stir and be cooled to 10 ℃, drip triethylamine 0.6mL, add AE active ester 2g (compound 16) again, reacted 14 hours.After reaction finishes, boil off solvent, add water 10mL, filtration, filtrating adds activated carbon decolorizing, filters, and salt acid for adjusting pH value to 3 is separated out deposition, hold over night, suction filtration, the proper amount of acetone washing gets faint yellow solid 2.5g, yield 81%.
Embodiment 8
Synthesizing of 7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) ethanoyl] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methyne Cephalosporanic acid (IV):
Methylene dichloride 13mL, water 1mL and methyl alcohol 0.5mL are cooled to 0 ℃, stir down to add 1.6g compound 14, drip triethylamine 5mL, treat that solution clarification back adds Cefixime Micronized active ester (compound 17) 2.3g, is warming up to room temperature, stirring reaction 3 hours.Reaction finishes and adds ETHYLE ACETATE 13 mL, filters, and respectively washs one time with an amount of methylene dichloride and ETHYLE ACETATE 5mL, and drying obtains 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):
With 2-sulfydryl-5-methyl isophthalic acid, 3,4 thiadiazoles 16.5g, 750mL methylene dichloride add in the reaction flask, add triethylamine 15mL under 0 ℃ of condition; Add GCLE50g, reaction 10h is washed till neutrality with saturated sodium carbonate solution; Drying, concentrate 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 the reaction flask; 0 ℃ adds diacetyl oxide 27.5mL, hydrogen peroxide (30%) 15mL down, and the 3h afterreaction finishes, and adds saturated sodium bicarbonate solution and sodium sulfite solution to neutral; Cross and filter the 26g solid, yield 84%.
Embodiment 11
7-phenylacetylamino-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methyne-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 trimethyl carbinol, 205mL diox are reacted 3h under 50 ℃ of conditions, then reaction solution is added in the entry, filter, get the 22.8g solid, yield 82%.
Embodiment 12
7-phenylacetylamino-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methyne-Cephalosporanic acid is synthetic to methoxy benzyl ester (11):
With compound (9) 6.4g, 100mL methylene dichloride, 10mLN, dinethylformamide adds in the reaction flask, adds phosphorus trichloride 3.5mL under the condition of ice bath; Add the water stopped reaction behind the 3h, washing, dichloromethane extraction water layer; The combined dichloromethane layer is dry, concentrate solid 4.9g, yield 80%.
Embodiment 13
Synthesizing of 7-phenylacetylamino-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methyne-Cephalosporanic acid (13):
Compound (11) 1.2g, 50mL methyl-phenoxide are added in the reaction flask, add trifluoracetic acid 7.5ml under the room temperature, stir adding ETHYLE ACETATE 50ml after 5 hours, filter, filter cake gets the 0.8g solid, yield 83% with an amount of ETHYLE ACETATE washed twice.
Embodiment 14
Synthesizing of 7-amino-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methylene radical-cephalo-alkanoic acid (15)
Compound (13) 5g, 50mL aqueous phosphate solution are added in the reaction flask, and 37 ℃, the ammoniacal liquor with 5% is transferred pH to 8.0, adds immobilized penicillin G acylase 4g; Stir, and adding ammoniacal liquor, to regulate the pH value be 8, keeps constant; Reaction with salt acid for adjusting pH value to 3.0, is separated out solid after finishing; Filter, get the 3g solid, yield 78%.
Embodiment 15
Synthesizing of 7-[[(2-amino-4-thiazolyl) (methoxyimino) ethanoyl] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methyne Cephalosporanic acid (compound III):
Compound (15) 2g, 10mL acetone, 5mL water are joined in the reaction flask, stir and be cooled to 10 ℃, drip triethylamine 0.6mL, add AE active ester (compound 16) 1.8g again, reacted 14 hours.Evaporate to dryness acetone adds water 10mL, adds activated carbon decolorizing in the filtrating and filters, and salt acid for adjusting pH value to 3.0 is separated out deposition, and suction filtration gets 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
Synthesizing of 7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) ethanoyl] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methyne Cephalosporanic acid (compound V):
Methylene dichloride 13mL, water 1mL and methyl alcohol 0.3mL, 0 ℃ adds compound (15) 2g down, adds triethylamine 5mL, adds gram oxime active ester (compound 17) 2.3g, rises to room temperature, stirs 3 hours.Add ETHYLE ACETATE 13 mL, filter, wash with methylene dichloride and ETHYLE 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
Every tablet prepn that contains the 100mg activeconstituents:
The mg/ sheet
Compound V 100
Lactose 50
Microcrystalline Cellulose 80
Starch 50
Hypromellose 15
Carboxymethylstach sodium 5
Magnesium Stearate 5
With activeconstituents; Lactose, starch, Microcrystalline Cellulose are crossed 100 mesh sieves; And abundant mixing, the 2% hydroxyl methylcellulose aqueous solution joined in the above-mentioned mixed powder mix, cross 20 mesh sieve system softwoods; Make wet granular in 45-55 ℃ of drying, carboxymethylstach sodium, Magnesium Stearate are joined compressing tablet in the above-mentioned dried particles.
Embodiment 18
Consumption
Compound I I 10g
Ethanol is an amount of
Starch 150g
With compound I I, starch, moistening with 60% aqueous ethanolic solution, the granulation of sieving behind the mixing, 60 ℃ of dryings, whole grain, filled capsules.
After the preferred embodiment that specifies; Being familiar with this technological personage can be well understood to; Do not break away from above-mentioned claim with spirit under can carry out various variations and modification; All foundations technical spirit of the present invention all belongs to the scope of technical scheme of the present invention to any simple modification, equivalent variations and modification that above embodiment did.And the embodiment that the present invention also is not subject in the specification sheets to be given an actual example.
Claims (8)
1. the novel cephalosporin compound that has the formula I structure:
R
1Be quinary heterocyclic radical or the substituted quinary heterocyclic radical of alkyl that contains nitrogen, sulfur heteroatom;
R
2Be amino;
R
3Be C
1-C
6Alkyl or C
1-C
6The organic acid acetic substituted alkyl.
2. the described novel cephalosporin compound of claim 1, its typical chemical structural formula is:
Wherein: R
2Be amino; R
3Be C
1-C
6Alkyl or C
1-C
6The organic acid acetic substituted alkyl.
3. claim 1 or 2 described cephalosporin compounds, its exemplary compounds is following:
7-[[(2-amino-4-thiazolyl) (methoxyimino) ethanoyl] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methyne Cephalosporanic acid;
7-[[(2-amino-4-thiazolyl) (methoxyimino) ethanoyl] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methyne Cephalosporanic acid;
7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) ethanoyl] amino]-3-[[(1-methyl isophthalic acid H-5-tetrazole base) sulphur] methyl]-4-methyne Cephalosporanic acid;
7-[[(2-amino-4-thiazolyl) (methoxycarbonyl methoxyimino) ethanoyl] amino]-3-[[2-(5-methyl isophthalic acid, 3,4 thiadiazolyl groups) mercapto] methyl]-4-methyne Cephalosporanic acid.
4. the preparation method of the described novel cephalosporin compound of claim 2 may further comprise the steps:
(ⅰ) GCLE (3) and 1-methyl-5-mercapto tetrazole condensation are obtained compound (4) or with GCLE (3) and 2-sulfydryl-5-methyl isophthalic acid, 3,4 thiadiazoles condensations obtain compound (5);
(ⅱ) compound (4) obtains compound (6) or compound (5) obtains compound (7) through oxidation 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 compound (13) through esterlysis through esterlysis;
(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: R
2Be amino; R
3Be C
1-C
6Alkyl or organic acid acetic substituted alkyl.
5. antibacterial combination, it is made up of each described compound of claim 1～3 and pharmaceutically acceptable carrier.
6. each said compound of claim 1～3 is used to treat the application aspect the medicine of sensitive bacterial infected patient in preparation.
7. the described application that is applied in preparation treatment gram-positive microorganism medicine and Gram negative bacteria drugs aspect of claim 6.
8. the described application of claim 7, gram-positive microorganism wherein are streptococcus aureus, and Gram-negative bacteria is a 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)
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| 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 |
| CN114540454A (en) * | 2022-03-09 | 2022-05-27 | 浙江东邦药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride by enzyme method and synthetic intermediate thereof |
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| CN114540454A (en) * | 2022-03-09 | 2022-05-27 | 浙江东邦药业有限公司 | Method for synthesizing cefcapene pivoxil hydrochloride by enzyme method and synthetic intermediate thereof |
| 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 |
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