CN101054374A - Flouroquinolone-oxazolidone derivative, composition, preparation method and application thereof - Google Patents
Flouroquinolone-oxazolidone derivative, composition, preparation method and application thereof Download PDFInfo
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- CN101054374A CN101054374A CN 200610025603 CN200610025603A CN101054374A CN 101054374 A CN101054374 A CN 101054374A CN 200610025603 CN200610025603 CN 200610025603 CN 200610025603 A CN200610025603 A CN 200610025603A CN 101054374 A CN101054374 A CN 101054374A
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Abstract
The present invention discloses a fluoroquinolone-oxazolidinone derivates and its composition, preparation method and application. Said fluoroquinolone-oxazolidinone derivates is the compounds has as above structural general formula I, wherein, R1 is C1 to C4 alkyl, C3 to C6 cycloalkyl or C1 to C4 halogenated alkyl groups; R2 is H or C1 to C4 alkyl; R3 is H, halogen or C1 to C4 alkoxyl group; or R2 together with R1 form bridge having above structure (formula II), wherein X is S, O or CH2; or R3 together with R1 form bridge having above structure (formula III), wherein Y is S, O or CH2; R4 is H or C1 to C4 alkyl;R5 is H or C1 to C4 alkyl. The fluoroquinolone-oxazolidinone derivates of present invention has well antibiotic action.
Description
Technical field
The invention belongs to the pharmaceutical chemistry synthesis technical field, relate to the application of the medicine of new Flouroquinolone-oxazolidone derivative and composition thereof, preparation method and conduct treatment infected by microbes.
Background technology
In recent years, antibiotic widespread use even abuse, cause the bacterial drug resistance problem serious day by day, especially the resistance of gram-positive microorganism, methicillin resistant staphylococcus aureus (methicillin-resistant Staphylococcus aureus for example, MRSA), penicillin-fast streptococcus pneumoniae (penicillin-resistant Streptococcus pneunoniae, PRSP), vancomycin-resistant enterococcus (vancomycin-resistant Enterococci, VRE) etc.These constitute a threat to human health to the drug-fast bacterium of antiseptic-germicide that routine is used with surprising rapidity.Therefore seeking can be extremely urgent to the effective newtype drug of resistant organism.
The oxazolidone compounds also is the novel complete synthesis antiseptic-germicide of a class, linezolid (Linezolid) for example, act on bacterioprotein synthetic commitment (main action target spot is the 23S rRNA of rrna 50S subunit), mainly show the resisting gram-positive bacteria activity (Li Rongpo of height, Zhou Weicheng; oxazolidine ketone antibacterials structure activity relationship new development. Chinese Journal of New Drugs .2003,12 (9): 694).And on the structural modification of another kind of antimicrobial drug fluoroquinolone, done a large amount of work, tens fluoroquinolone antibacterial agents are successively arranged, as listing (Zhou Weicheng such as norfloxicin (Norfloxacin), Ciprofloxacin (Ciprofloxacin), levofloxacin (Levofloxacin) and Gatifloxacins (Gatifloxacin), Zhou Houyuan. fluoroquinolone antibacterial agent thing progress. Chinese Journal of Pharmaceuticals .2005,5:309-312.).The important structure feature of these medicines is that 7 bit strips of quinolone ring have ring-shaped fat amine, these substituting groups encircle (Zhang Zhenfa by the mother that nitrogen-atoms is attached to fluoroquinolone, Zhou Weicheng. the new development of fluoroquinolone structure activity study. Chinese Journal of Pharmaceuticals .2003,34:36-43.).
Summary of the invention
Therefore ， is attached to the oxazolidone fragment on 7 ring-shaped fat amine of fluoroquinolone by bridge linkage group, forms new Flouroquinolone-oxazolidone derivative, wishes to obtain the novel Flouroquinolone-oxazolidone derivative with anti-microbial effect.
One of purpose of the present invention is to disclose a series of anti-microbial activity De oxazolidone-fluoro quinolone derivatives that have, to satisfy medicine industry field and people's needs;
Two of purpose of the present invention provides the polymorphic form of its pharmacy acceptable salt of said derivative, said derivative solvate, said derivative optical isomer or said derivative;
Three of purpose of the present invention is the polymorphic form of open said derivative or its pharmacy acceptable salt, said derivative solvate, said derivative optical isomer or said derivative and the composition that pharmaceutically acceptable carrier is formed;
Four of purpose of the present invention is preparation methods of open said derivative;
Five of purpose of the present invention is application of open said derivative or its salt.
Purpose of the present invention comprises provides this compounds and salt thereof to be used to prepare the microbial infection of the bacterial infection disease for the treatment of the human or animal, particularly resistance.
Technical conceive of the present invention is such:
The ring-shaped fat amine that 7 bit strips have an alkalescence has material impact to the anti-microbial activity and the pharmacokinetic property of quinolone, and (S)-5-substituted amine methyl-3-substituted-phenyl-oxazolidine-2-ketone is the basic structural unit of oxazolidine ketone antibacterials, the present invention by the methyl carbonyl above-mentioned fluoroquinolone He the oxazolidone fragment link together, thereby synthesized Flouroquinolone-oxazolidone derivative of the present invention.
De oxazolidone-fluoro quinolone derivative of the present invention is the compound with following general structure I:
Formula I
Wherein,
R
1Be C
1～C
4Alkyl, C
3～C
6Cycloalkyl or C
1～C
4Haloalkyl;
R
2Be H or C
1～C
4Alkyl;
R
3Be H, halogen or C
1～C
4Alkoxyl group;
Perhaps, R
2And R
1Form the bridge of following structure together:
Wherein, X is S, O or CH
2
Perhaps, R
3And R
1Form the bridge of following structure together:
Wherein, Y is S, O or CH
2
R
4Be H or C
1～C
4Alkyl;
R
5Be H or C
1～C
4Alkyl.
In the present invention, C
1～C
4Alkyl as the part of a kind of group or group, means and contains the branched-chain or straight-chain alkyl of 4 carbon atoms at the most, and it comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl and the tertiary butyl;
Equally, C
1～C
4Alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert.-butoxy;
C
1～C
4Haloalkyl is meant the C that is replaced by one or more identical or different halogen atoms
1～C
4Alkyl, for example chloromethyl, methyl fluoride, trifluoromethyl, chloroethyl, fluoro ethyl, two fluoro ethyls, chloropropyl etc.;
C
3～C
6Cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Among the present invention, term " halogen " is meant F, Cl, Br or I, preferred F or Cl.
Among the present invention, R
1Preferred ethyl or cyclopropyl;
R
2Preferred H;
R
3Preferred H, fluorine or methoxyl group;
Perhaps, R
1And R
2Form the bridge of following structure together:
Perhaps, R
1And R
3Form the bridge of following structure together:
R
4Preferred H or methyl;
R
5Preferred H or methyl.
In a preferred embodiment of the present invention, Suo Shu De oxazolidone-fluoro quinolone derivative is:
1-cyclopropyl-6-fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 1),
9-fluoro-3-methyl isophthalic acid 0-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (compound 2),
(S)-9-fluoro-3-methyl isophthalic acid 0-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl)-phenyl]-ethanoyl]-piperazine-1-yl }-7-oxo-2; 3-dihydro-7H-pyridine [1; 2,3-de] [1,4] benzoxazine-6-carboxylic acid (compound 3),
1-cyclopropyl-6-fluoro-8-methoxyl group-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 4),
6-fluoro-1-methyl-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1H, 4H-[1,3] sulfur nitrogen heterocycle butane [3,2-a] quinoline-3-carboxylic acid (compound 5),
1-ethyl-6-fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 6),
1-ethyl-6,8-two fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 7),
9-fluoro-3-methyl isophthalic acid 0-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-7-oxo-2; 3-dihydro-7H-pyridine [1; 2,3-de] [1,4] benzoxazine-6-carboxylic acid (compound 8),
(S)-and 9-fluoro-3-methyl isophthalic acid 0-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-7-oxo-2; 3-dihydro-7H-pyridine [1; 2,3-de] [1,4] benzoxazine-6-carboxylic acid (compound 9),
1-cyclopropyl-6-fluoro-8-methoxyl group-7-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 10),
1-ethyl-6,8-two fluoro-7-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 11),
1-cyclopropyl-6,8-two fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 12),
1-cyclopropyl-6,8-two fluoro-7-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 13),
1-ethyl-6,8-two fluoro-7-{3,5-dimethyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (compound 14).
In the present invention, term " pharmaceutically acceptable solvate " means hydrate or C
1～C
4The solvate of pure and mild other organic solvent.
In the present invention, term " pharmacy acceptable salt " comprises the salt that forms with basic metal, as the salt of mineral alkalis such as sodium, potassium, calcium, magnesium.
The compound of being addressed shown in general formula I adopts and comprises that formula II compound and formula III compound carry out prepared in reaction and form, and its synthetic route is as follows:
R
1, R
2, R
3, R
4And R
5Described as defined above.
The preparation method of the formula I compound that reaches of the present invention comprises the steps:
Being reflected at that organic solvent, condensing agent exist down, carrying out under the katalysis of alkali of formula II compound and formula III compound.The preferred tetrahydrofuran (THF) of described organic solvent, pyridine, acetonitrile, N, the mixed solvent of one or more in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone and the methyl-sulphoxide etc., more preferably non-protonic solvent, as acetonitrile or N, dinethylformamide.Mineral alkalis such as the preferred sodium hydroxide of described alkali, potassium hydroxide, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, and/or, organic basess such as triethylamine, pyridine, diisopropyl ethyl amine and composition thereof, more preferably organic bases.Said condensing agent is dicyclohexylcarbodiimide, 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide, methylphosphine acid anhydrides, ethylphosphonic acid acid anhydride, n-propyl phosphonic acid anhydride and/or benzotriazole base diethyl phosphoric acid etc., preferred dicyclohexylcarbodiimide, 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide, ethylphosphonic acid acid anhydride, n-propyl phosphonic acid anhydride etc.The processing condition of reaction are: temperature of reaction is 0 ℃～200 ℃, preferred 20 ℃～100 ℃; The molar ratio of formula II compound and formula III compound is 1: 1～1: 10, preferred 1: 1～1: 3.
In the present invention, the preparation were established of the oxazolidone of De shown in formula III compound is as follows:
1. esterification: (the Chinese patent application CN200510030355.6 of the applicant (Shanghai Institute of Pharmaceutical Industry) in application on October 10th, 2005 seen in the preparation of compound 1a to compound 1a, denomination of invention is Flouroquinolone-oxazolidone new derivatives and the preparation method with anti-microbial activity) under alkaline matter catalysis with trimethyl carbinol generation esterification, be reflected at dewatering agent and carry out under existing.Said alkaline matter is salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide, triethylamine, pyridine, N, N dimethylamine yl pyridines and/or 1,5-diazabicylo [5.4.0] hendecene-5 etc., preferred N, N dimethylamine yl pyridines, 1,5-diazabicylo [5.4.0] hendecene-5.Be reflected in the trimethyl carbinol or non-polar solvent and the trimethyl carbinol mixed system and carry out.Said non-polar solvent is methylene dichloride, tetrahydrofuran (THF) and/or ethyl acetate etc.Said dewatering agent is N, N '-carbonyl dimidazoles, 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide and/or tert-Butyl dicarbonate etc.Reaction process condition: temperature of reaction is-10 ℃～80 ℃, preferred 1: 1～1: 2.5 of the mol ratio of compound 1a and carboxyl activator.
2. nitro-reduction reaction: the nitroreduction of compound 1b can adopt: common metallic reducing agent, as iron powder/hydrochloric acid, tin protochloride etc.; The sulfide reductive agent is as sodium sulphite/water; Contain oxysulfide, as V-Brite B/water etc.; Or, also can adopt the catalytic hydrogenation method.In polarity or non-polar organic solvent, metal catalyst exists down, hydrogenation under normal pressure or the pressurized conditions; Also can use the phase transition hydride process, select hydrogen donor for use, for example hydrazine hydrate, tetrahydrobenzene, Virahol etc.The preferred methylene dichloride of said non-polar organic solvent, tetrahydrofuran (THF) and/or ethyl acetate etc., said polar organic solvent particular methanol, ethanol and/or Virahol etc.Reaction process condition: the Pd/C or the Raney-Ni of catalyzer preferred 5%～10%, carry out hydro-reduction under normal pressure or the pressurization (0～20 normal atmosphere), temperature of reaction is 10 ℃～140 ℃.
3. acylation reaction: the compound 1c with step 2 gained is a raw material, in the mixed system of organic solvent or organic solvent and water, under the effect of alkaline matter, carries out acylation reaction with chloroformic acid benzyl ester.Said organic solvent is a non-polar organic solvent, as toluene, methylene dichloride, tetrahydrofuran (THF), acetonitrile, ethyl acetate etc., and preferred tetrahydrofuran (THF) or ethyl acetate.Said alkaline matter is salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide, triethylamine, pyridine, N, N dimethylamine yl pyridines etc.Reaction process condition: temperature is-10 ℃～40 ℃, preferred 1: 1～1: 1.5 of the mol ratio of compound 1c and chloroformic acid benzyl ester.
4. ring-closure reaction:, in non-polar organic solvent, under the effect and cold condition of strong alkaline substance,, obtain the cyclization product, i.e. compound 1e with (R)-butanic acid glycidic ester condensation with the compound 1d of step 3 gained.Said non-polar organic solvent is tetrahydrofuran (THF), ether etc., preferred tetrahydrofuran (THF).Said strong alkaline substance is n-Butyl Lithium, trimethyl carbinol lithium, lithium diisopropyl amido etc., preferred n-Butyl Lithium.Reaction process condition: temperature of reaction is 20 ℃～-100 ℃, preferred 20 ℃～-80 ℃, compound 1d with (R)-preferred 1: 1～1: 2.5 of the mol ratio of butanic acid glycidyl ester.
5. sulfonylation:, in non-polar organic solvent, under the effect of alkaline matter,, be converted into compound 1f with the methane sulfonyl chloride reaction with the compound 1e of step 4 gained.Said non-polar organic solvent is methylene dichloride, chloroform, tetrahydrofuran (THF), ethyl acetate etc., preferred methylene dichloride.Said alkaline matter is mineral alkalis such as salt of wormwood, sodium bicarbonate, sodium hydroxide, and/or, triethylamine, N, N dimethylamine yl pyridines, N, organic basess such as accelerine, preferred triethylamine and/or N, N dimethylamine yl pyridines.Reaction process condition: temperature of reaction is-20 ℃～50 ℃, preferred 1: 1～1: 2.5 of the mol ratio of compound 1e and methylsulfonyl chloride.
6. azido reaction:,, in organic solvent, carry out azido reaction with an alkali metal azide (as sodiumazide) with the compound 1f of step 5 gained.The processing condition of reaction are as follows: temperature of reaction is 0 ℃～200 ℃, and preferred 20 ℃～100 ℃, said organic solvent can preferentially adopt tetrahydrofuran (THF), acetonitrile, N, dinethylformamide etc., more preferably N, dinethylformamide.
7. reduction reaction: change the azido group of the compound 1g of step 6 gained into amino or acetamido.The catalytic hydrogenation method is adopted in the reduction of compound 1g.This method is in organic solvent, and catalyzer exists down, and hydrogenation under normal pressure or the pressurized conditions can obtain (S)-5-aminomethyl-3-[3-fluoro-4-(tertiary butyl oxygen carbonyl methyl) phenyl]-oxazolidines-2-ketone (compound 1h).Said organic solvent comprises tetrahydrofuran (THF), ethyl acetate, methyl alcohol, ethanol, Virahol etc., preferred tetrahydrofuran (THF).The processing condition of reaction: the Pd/C of catalyzer preferred 5%～10%, carry out hydrogenation under normal pressure or the pressurization (0～20 normal atmosphere).
8. acetylization reaction: the compound 1h that step 7 obtained, in organic solvent, under the alkaline matter effect,, carry out acetylization reaction with acylating reagent (for example diacetyl oxide, Acetyl Chloride 98Min.), form compound 1i.Said organic solvent comprises toluene, methylene dichloride, chloroform, tetrahydrofuran (THF), ethyl acetate etc., preferred tetrahydrofuran (THF).Said alkaline matter is salt of wormwood, yellow soda ash, sodium bicarbonate, sodium hydroxide, triethylamine, pyridine, N, N dimethylamine yl pyridines, preferred triethylamine, pyridine.Preferred 1: 1～1: 3 of the mol ratio of compound 1h and acylating reagent, temperature of reaction are 0 ℃～50 ℃.
9. deprotection reaction: the compound 1i of step 8 gained is carried out the carboxyl deprotection generate (S)-5-ethanamide methyl-3-[3-fluoro-4-(carboxy ethyl) phenyl]-oxazolidines-2-ketone (formula III compound).The reagent of fracture tertiary butyloxycarbonyl base key is preferably dilute hydrochloric acid, trifluoroacetic acid, formic acid etc.
The invention still further relates to a kind of pharmaceutical composition, said composition comprises a kind of and pharmaceutically acceptable carrier in the compound polymorphic form of the optical isomer of compound of solvate, general formula I of compound of pharmacy acceptable salt, general formula I of compound of compound, general formula I of the general formula I for the treatment of significant quantity or general formula I.
Can put on the patient who needs treatment with compound of the present invention and pharmaceutically acceptable carrier with the form of composition, general dosage is 1000～100mg/ kg body weight/sky, specifically can change according to patient's age, the state of an illness etc.
Said carrier is meant the pharmaceutical carrier of pharmaceutical field routine, thinner, vehicle such as water etc.; Tackiness agent such as derivatived cellulose, gelatin, polyvinylpyrrolidone etc., weighting agent such as starch etc., agent such as lime carbonate, sodium bicarbonate burst apart; In addition, can also in composition, add other auxiliarys such as flavouring agent and sweeting agent.
Be used for when oral, it can be prepared into conventional solid preparation such as tablet, pulvis or capsule etc.; When being used to inject, it can be prepared into injection liquid.
The various formulations of composition of the present invention can adopt the method for medical field routine to be prepared, and wherein the content of activeconstituents is 0.1%～99.5% (weight ratio).The composition that compound of the present invention and above-mentioned carrier constitute can put on the patient who needs this treatment by intravenous injection, subcutaneous injection or oral form.In various preparations, the weight content of The compounds of this invention is 0.1%～99.9%, is preferably 0.5%～90%.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment are not any limitation of the invention.The fusing point of compound is measured with the capillary melting point determination instrument among all embodiment, and thermometer is not proofreaied and correct;
1H NMR is interior mark by Varian AM-400 type nmr determination with TMS, and chemical shift is represented with δ (ppm); Mass spectrum is measured with Q-TOF type mass spectrograph; Ultimate analysis is measured by CarloErba1106 type automatic elemental analyzer, and specific rotatory power is measured by Perkin Elmer P-341 polarimeter.The column chromatography used silica gel is that Haiyang Chemical Plant, Qingdao produces (thin-layer chromatography H type), HSGF 254 types that thin layer chromatography board is produced for Yantai Zhifu experiment chemical plant.
Embodiment 1
Synthesizing of the 2-fluoro-4-nitrophenyl-acetic acid tert-butyl ester (compound 1b)
2-fluoro-4-nitrophenyl-acetic acid (compound 1a) (pressing the described preparation of CN200510030355.6) (58.0g, 291.3mmol), N, and the N dimethylamine yl pyridines (46.7g, 381.9mmol), join in the trimethyl carbinol (580.0mL), ice-water bath is chilled to below 0 ℃, in system, drip tert-Butyl dicarbonate (155.2mL, 725.3mmol), about 1h adds, and continues reaction 3h then.Add saturated sodium bicarbonate aqueous solution (160.0mL) in reaction solution, stir 30min, add entry (1000mL), (3 * 500mL), organic phase merges after washing, saturated sodium-chloride washing, anhydrous sodium sulfate drying with ethyl acetate extraction.Filter, remove solvent under reduced pressure, (eluent: the purifying petrol ether/ethyl acetate gradient elution) gets colorless oil compound 1b (71.1g), yield 95.6% to the crude product of gained through column chromatography.
1H NMR(CDCl
3)δ：7.99(1H，dd，J＝8.4Hz，2.4Hz，Ar-H)，7.92(1H，dd，J＝9.2Hz，2.4Hz，Ar-H)，7.45(1H，t，J＝8.4Hz，Ar-H)，3.66(2H，s，CH
2Ph)，1.45(9H，s，C(CH
3)
3)。
Embodiment 2
Synthesizing of the 2-fluoro-4-aminophenyl acetic acid tert-butyl ester (compound 1c)
(51.3g 200.9mmol) is dissolved in methyl alcohol (500mL) to compound 1b, and (35.0mL, 595.0mmol), about 1h adds the hydrazine hydrate of dropping 85% under the room temperature, continues reaction 4h.Filter, remove solvent under reduced pressure, (eluent: petrol ether/ethyl acetate) purifying gets oily compound 1c (37.4g), yield 82.6% to the gained crude product through column chromatography.
1H NMR(CDCl
3)δ：6.34-6.40(2H，m，Ar-H)，6.98(1H，t，J＝8.4Hz，Ar-H)，3.70(2H，br，-NH
2)，3.43(2H，s，CH
2Ph)，1.42(9H，s，C(CH
3)
3)。
Embodiment 3
Synthesizing of 2-fluoro-4-(carbobenzoxy-(Cbz) amido) the toluylic acid tert-butyl ester (compound 1d)
Compound 1c (35.0g 155.3mmol) is dissolved in methylene dichloride (500mL), and the adding pyridine (35.0mL, 443.6mmol), ice-water bath is chilled to below 0 ℃, and (29.4mL, 206.8mmol), about 1h adds, and continues reaction 4h to drip chloroformic acid benzyl ester.System washes with water successively, 0.5molL
-1The salt pickling, saturated sodium-chloride washing.The organic layer anhydrous magnesium sulfate drying.Filter, remove solvent under reduced pressure, the gained crude product gets white solid compound 1d (53.0g) with the petrol ether/ethyl acetate recrystallization, yield 94.9%, 64～66 ℃ of fusing points.
1H NMR(CDCl
3)δ：7.28-7.40(6H，m，Ar-H)，7.14(1H，t，J＝8.2Hz，Ar-H)，6.97(1H，dd，J＝8.2Hz，2.0Hz，Ar-H)，6.69(1H，br，-NH)，5.19(2H，s，OCH
2Ph)，3.50(2H，s，CH
2Ph)，1.42(9H，s，C(CH
3)
3)。
Embodiment 4
(R)-and 5-methylol-3-[3-fluoro-4-(tertiary butyl oxygen carbonyl methyl) phenyl]-oxazolidines-2-ketone (compound 1e)
(53.0g 147.5mmol) is dissolved in the exsiccant tetrahydrofuran (THF) (800mL) compound 1d, is chilled to-78 ℃, and dropping concentration is 1.6molL
-1The n-Butyl Lithium hexane solution (120.0mL, 191.7mmol), about 30min adds, and continues at-78 ℃ of reaction 1h down.(19.6mL, 177.2mmol), about 30min adds, and keeps Nei Wen-78 ℃ of reaction 1h down to drip (R)-butanic acid glycidyl ester in system.Slowly be raised to room temperature, reaction is spent the night.Add saturated aqueous ammonium chloride (20mL) cancellation reaction, add entry (300mL) again, saturated aqueous ammonium chloride (500mL), (3 * 500mL) extractions merge organic phase to ethyl acetate, wash saturated sodium-chloride washing, anhydrous sodium sulfate drying successively with water.Filter, remove solvent under reduced pressure, (eluent: petrol ether/ethyl acetate) purifying gets white solid compound 1e (38.1g), yield 79.4%, 84～86 ℃ of fusing points to the gained crude product through column chromatography.
1H NMR(CDCl
3)δ：7.40(1H，dd，J＝12.0Hz，2.0Hz，Ar-H)，7.20(1H，t，J＝8.2Hz，Ar-H)，7.16(1H，dd，J＝8.2Hz，2.0Hz，Ar-H)，4.65-4.71(1H，m，5-H)，3.89-3.99(3H，m，4-H，5-CH
2OH)，3.68-3.72(1H，m，4-H)，3.51(2H，s，CH
2Ph)，1.38(9H，s，C(CH
3)
3)，2.83(1H，br，OH)。
Embodiment 5
(R)-and 5-mesyloxy methyl-3-[3-fluoro-4-(tertiary butyl oxygen carbonyl methyl) phenyl]-oxazolidines-2-ketone (compound 1f)
Compound 1e (38.0g, 116.8mmol) be dissolved in methylene dichloride (500mL), add triethylamine (51.0mL, 362.9mmol) and N, N dimethylamine yl pyridines (3.0g, 24.6mmol), ice-water bath is chilled to 0 ℃, and the dropping methylsulfonyl chloride (22.6mL, 292.0mmol), about 1h adds, and slowly is raised to room temperature reaction 2h.Washing, 0.5mmolL
-1The salt pickling, saturated sodium-chloride washing, organic phase anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: petrol ether/ethyl acetate) purifying gets oily compound 1f (40.2g), yield 85.3% through column chromatography.
1H NMR(CDCl
3)δ：7.42(1H，dd，J＝11.8Hz，2.0Hz，Ar-H)，7.26(1H，t，J＝8.4Hz，Ar-H)，7.17(1H，dd，J＝8.4Hz，2.0Hz，Ar-H)，4.87-4.91(1H，m，5-H)，4.38-4.39(2H，m，5-CH
2O)，4.11(1H，dd，4-H)，3.89-3.93(1H，m，4-H)，3.54(2H，s，CH
2Ph)，3.08(3H，s，SO
2CH
3)，1.42(9H，s，C(CH
3)
3)。
Embodiment 6
(R)-and 5-azido methyl-3-[3-fluoro-4-(tertiary butyl oxygen carbonyl methyl) phenyl]-oxazolidines-2-ketone (compound 1g)
(37.1g 92.0mmol) is dissolved among the exsiccant DMF (400mL) compound 1f, and (14.9g 229.2mmol), is warmed up to 75 ℃, stirring reaction 4h to add sodiumazide.Be chilled to room temperature, add water (50mL) and stir 30min, add water (2000mL) again, (3 * 500mL) extractions merge organic layer to ethyl acetate, washing, saturated sodium-chloride washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: the purifying petrol ether/ethyl acetate gradient elution) gets oily compound 1g (29.7g), yield 92.2% through column chromatography.
1H NMR(CDCl
3)δ：7.42(1H，dd，J＝11.8Hz，2.0Hz，Ar-H)，7.25(1H，t，J＝8.4Hz，Ar-H)，7.18(1H，dd，J＝8.4Hz，2.0Hz，Ar-H)，4.74-4.78(1H，m，5-H)，4.05(1H，dd，4-H)，3.79-3.83(1H，m，4-H)，3.55-3.70(2H，m，5-CH
2N
3)，3.54(2H，s，CH
2Ph)，1.42(9H，s，C(CH
3)
3)。
Embodiment 7
(S)-and 5-aminomethyl-3-[3-fluoro-4-(tertiary butyl oxygen carbonyl methyl) phenyl]-oxazolidines-2-ketone (compound 1h)
(25.0g 71.4mmol) is dissolved in tetrahydrofuran (THF) (500mL) to compound 1g, adds 10% Pd/C catalyzer (2.5g), feeds hydrogen under the room temperature, stirring reaction 12h.Filter, remove catalyzer, not purifiedly directly carry out next step reaction.
Embodiment 8
(S)-and 5-ethanamide methyl-3-[3-fluoro-4-(tertiary butyl oxygen carbonyl methyl) phenyl]-oxazolidines-2-ketone (compound 1i)
In the reaction solution of embodiment 7 gained, add pyridine (28.8mL, 357.0mmol), ice-water bath is chilled to below 0 ℃, (10.0mL, 107.1mmol), about 30min adds, and slowly is raised to room temperature reaction 3h to drip diacetyl oxide.Remove solvent under reduced pressure, add entry (200mL), (3 * 250mL), organic phase merges, and washes 0.5mmolL successively with water with ethyl acetate extraction
-1The salt pickling, washing, anhydrous sodium sulfate drying is used in saturated sodium-chloride washing again.Filter, remove solvent under reduced pressure,, get white solid compound 1i (19.3g), yield 73.8% (2 steps added up to yield), 100～102 ℃ of fusing points with methylene dichloride/sherwood oil recrystallization.[α]
D 25(c＝0.5，DMSO)：-22。
1H NMR(CDCl
3)δ：7.43(1H，dd，J＝12.0Hz，2.0Hz，Ar-H)，7.25(1H，t，J＝8.0Hz，Ar-H)，7.16(1H，dd，J＝8.0Hz，2.0Hz，Ar-H)，6.28(1H，br，-NH)，4.75-4.79(1H，m，5-H)，4.05(1H，dd，4-H)，3.76-3.80(1H，m，4-H)，3.58-3.72(2H，m，5-CH
2N)，3.56(2H，s，CH
2Ph)，2.03(3H，s，COCH
3)，1.47(9H，s，C(CH
3)
3).ESIMS：389(M
++Na)。
Embodiment 8
(S)-and 5-ethanamide methyl-3-[3-fluoro-4-(carboxy ethyl) phenyl]-oxazolidines-2-ketone (compound III)
(17.7g 48.3mmol) is dissolved in methylene dichloride (340mL) to compound 1i, and ice-water bath is chilled to 0 ℃, and (60.0mL, 807.8mmol), about 1h drips complete, slowly is raised to room temperature reaction 4h to drip trifluoroacetic acid.Remove solvent under reduced pressure, add acetone (20mL), refrigeration.Filter washing with acetone, dry white solid compound III (12.1g), yield 80.7%, 194～196 ℃ of the fusing points of getting.[α]
D 25(c＝0.5，DMSO)：-25。
1H NMR(CDCl
3)δ：7.46(1H，dd，J＝12.0Hz，2.0Hz，Ar-H)，7.26(1H，t，J＝8.0Hz，Ar-H)，7.15(1H，dd，J＝8.0Hz，2.0Hz，Ar-H)，7.66(1H，br，-NH)，4.74-4.80(1H，m，5-H)，4.00(1H，dd，4-H)，3.78-3.82(1H，m，4-H)，3.58-3.60(4H，m，5-CH
2N，CH
2Ph)，1.98(3H，s，COCH
3).ESIMS：333(M
++Na)。
Embodiment 9
1-cyclopropyl-6-fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the preparation of 4-dihydroquinoline-3-carboxylic acid (compound 1)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 1-cyclopropyl-6-fluoro-7-(piperazine-1-yl)-4-oxo-1, and 4-dihydroquinoline-3-carboxylic acid (0.331g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphinylidyne acid anhydride (1.130g, 3.55mmol) the solution of methylene dichloride (1.130g), 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 1 (0.350g).
The physicochemical constant of compound 1 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 10
9-fluoro-3-methyl isophthalic acid 0-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-7-oxo-2; 3-dihydro-7H-pyridine [1; 2,3-de] [the preparation of 1,4] benzoxazine-6-carboxylic acid (compound 2)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 9-fluoro-3-methyl isophthalic acid 0-(piperazine-1-yl)-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (0.347g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphinylidyne acid anhydride (1.130g, methylene dichloride 3.55mmol) (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 2 (0.441g).
The physicochemical constant of compound 2 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 11
(S)-9-fluoro-3-methyl isophthalic acid 0-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl)-phenyl]-ethanoyl]-piperazine-1-yl }-7-oxo-2; 3-dihydro-7H-pyridine [1; 2,3-de] [the preparation of 1,4] benzoxazine-6-carboxylic acid (compound 3)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), (S)-and 9-fluoro-3-methyl isophthalic acid 0-(piperazine-1-yl)-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (0.347g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphonic acid anhydride (1.130g, methylene dichloride 3.55mmol) (1.130g) solution, 70～80 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, (eluent: methyl alcohol/chloroform gradient elution), spent glycol monomethyl ether recrystallization gets white powder target compound 3 (0.100g) to the residue of gained again through column chromatography purification.
The physicochemical constant of compound 3 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 12
1-cyclopropyl-6-fluoro-8-methoxyl group-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the preparation of 4-dihydroquinoline-3-carboxylic acid (compound 4)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 1-cyclopropyl-6-fluoro-8-methoxyl group-7-(piperazine-1-yl)-4-oxo-1, and 4-dihydroquinoline-3-carboxylic acid (0.361g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphinylidyne acid anhydride (1.130g, 3.55mmol) methylene dichloride (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 4 (0.167g).
The physicochemical constant of compound 4 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 13
6-fluoro-1-methyl-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1H, 4H-[1,3] preparation of sulfur nitrogen heterocycle butane [3,2-a] quinoline-3-carboxylic acid (compound 5)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 6-fluoro-1-methyl-7-(piperazine-1-yl)-4-oxo-1H, 4H-[1,3] sulfur nitrogen heterocycle butane [3,2-a] quinoline-3-carboxylic acid (0.349g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphinylidyne acid anhydride (1.130g, 3.55mmol) methylene dichloride (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 5 (0.072g).
The physicochemical constant of compound 5 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 14
1-ethyl-6-fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the preparation of 4-dihydroquinoline-3-carboxylic acid (compound 6)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 1-ethyl-6-fluoro-7-(piperazine-1-yl)-4-oxo-1, and 4-dihydroquinoline-3-carboxylic acid (0.319g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphonic acid anhydride (1.130g, 3.55mmol) methylene dichloride (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 6 (0.229g).
The physicochemical constant of compound 6 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 15
1-ethyl-6,8-two fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the preparation of 4-dihydroquinoline-3-carboxylic acid (compound 7)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 1-ethyl-6,8-two fluoro-7-(piperazine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.337g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphonic acid anhydride (1.130g, methylene dichloride 3.55mmol) (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 7 (0.269g).
The physicochemical constant of compound 7 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 16
9-fluoro-3-methyl isophthalic acid 0-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-7-oxo-2; 3-dihydro-7H-pyridine [1; 2,3-de] [the preparation of 1,4] benzoxazine-6-carboxylic acid (compound 8)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 9-fluoro-3-methyl isophthalic acid 0-(3-methylpiperazine-1-yl)-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (0.361g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphonic acid anhydride (1.130g, methylene dichloride 3.55mmol) (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 8 (0.250g).
The physicochemical constant of compound 8 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 17
(S)-and 9-fluoro-3-methyl isophthalic acid 0-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-7-oxo-2; 3-dihydro-7H-pyridine [1; 2,3-de] [the preparation of 1,4] benzoxazine-6-carboxylic acid (compound 9)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), (S)-and 9-fluoro-3-methyl isophthalic acid 0-(3-methylpiperazine-1-yl)-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (0.361g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphonic acid anhydride (1.130g, methylene dichloride 3.55mmol) (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 9 (0.321g).
The physicochemical constant of compound 9 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 18
1-cyclopropyl-6-fluoro-8-methoxyl group-7-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the preparation of 4-dihydroquinoline-3-carboxylic acid (compound 10)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 1-cyclopropyl-6-fluoro-8-methoxyl group-7-(3-methylpiperazine-1-yl)-4-oxo-1, and 4-dihydroquinoline-3-carboxylic acid (0.375g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphonic acid anhydride (1.130g, 3.55mmol) methylene dichloride (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 10 (0.146g).
The physicochemical constant of compound 10 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 19
1-ethyl-6,8-two fluoro-7-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the preparation of 4-dihydroquinoline-3-carboxylic acid (compound 11)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 1-ethyl-6,8-two fluoro-7-(3-methylpiperazine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.351g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphonic acid anhydride (1.130g, methylene dichloride 3.55mmol) (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography for separation (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 11 (0.156g).
The physicochemical constant of compound 11 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 20
1-cyclopropyl-6,8-two fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the preparation of 4-dihydroquinoline-3-carboxylic acid (compound 12)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 1-cyclopropyl-6,8-two fluoro-7-(piperazine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.349g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphonic acid anhydride (1.130g, methylene dichloride 3.55mmol) (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 12 (0.300g).
The physicochemical constant of compound 12 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 21
1-cyclopropyl-6,8-two fluoro-7-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the preparation of 4-dihydroquinoline-3-carboxylic acid (compound 13)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 1-cyclopropyl-6,8-two fluoro-7-(3-methylpiperazine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.363g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphonic acid anhydride (1.130g, methylene dichloride 3.55mmol) (1.130g) solution, 25～30 ℃ of following stirring reaction 72h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 13 (0.130g).
The physicochemical constant of compound 13 and MS,
1The HNMR data see Table 1 and table 2 respectively.
Embodiment 22
1-ethyl-6,8-two fluoro-7-{3,5-dimethyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the preparation of 4-dihydroquinoline-3-carboxylic acid (compound 14)
With compound III (0.550g, 1.77mmol), N-methylmorpholine (0.682mL, 6.20mmol), 1-ethyl-6,8-two fluoro-7-(3,5-lupetazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.365g, 1.00mmol), join N, in the dinethylformamide (15mL), stir 30min, add again and contain n-propyl phosphonic acid anhydride (1.130g, 3.55mmol) methylene dichloride (1.130g) solution, 25～30 ℃ of following stirring reaction 96h.Remove solvent under reduced pressure, the residue of gained is through column chromatography purification (eluent: methyl alcohol/chloroform gradient elution), use the DMF/ ethyl alcohol recrystallization again, get white powder target compound 14 (0.112g).
The physicochemical constant of compound 14 and MS,
1H NMR data see Table 1 and table 2 respectively.
Embodiment 23
Tablet: (weight part)
1 part of the compound of embodiment 12,1 part of polyvinylpyrrolidone, 5 parts of starch, 0.5 part in lime carbonate becomes tablet according to the preparation of the method for this area routine.
Embodiment 24
Injection: (weight part)
1 part of the compound of embodiment 12 is made into 10 parts of waters for injection with the sodium hydroxide of equimolar amount, becomes injection according to the method preparation of this area routine.
Table 1 has been listed some example of the prepared formula I compound of the present invention, and table 2 listed the MS of these compounds,
1H NMR data.
Table 11,2,8-three replacement-6-fluoro-7-{3,5-two replacement-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the materialization data of 4-dihydroquinoline-3-carboxylic acid (1～14)
A:c=0.2, DMSO; B:c=0.2, N-Methyl pyrrolidone
Table 21,2,8-three replacement-6-fluoro-7-{3,5-two replacement-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1, the MS of 4-dihydroquinoline-3-carboxylic acid (compound 1～14),
1H NMR data
| No. | ESIMS | 1H NMR/δ(DMSO-d 6) |
| 1 | 646 (M ++Na) | 15.12(1H，s，-COOH) a，8.67(1H，s，2-H)，7.93(1H，d，J＝13.2Hz，5-H)， 7.58(1H，J＝7.2Hz，8-H)，1.14-1.15(2H，m，cycl.-CH 2) b，1.31-1.32(2H，m， cycl.-CH 2)，7.46(1H，dd，J＝10.4Hz，2.0Hz，3’-H)，7.29(1H，t，1H，t，J＝8.4 Hz，6’-H)，7.23(1H，dd，J＝8.4Hz，2.0Hz，5’-H)，3.73-3.84(6H，m，cycl.-H， 4”-H，2×CH 2N)，3.36(4H，br，2×NCH 2)，3.78(2H，s，CH 2Ph)，4.12(1H， dd，4”-H)，4.71-4.75(1H，m，5”-H)，3.40-3.43(2H，m，5”-CH 2N)，8.15(1H， br，-NH)，1.83(3H，s，COCH 3) |
| 2 | 640 (M ++1) | 15.09(1H，s，-COOH)，8.94(1H，s，2-H)，7.58(1H，d，J＝12.4Hz，5-H)， 4.90-4.92(1H，m，1-CHCH 3)，1.46(3H，d，J＝6.4Hz，1-CHCH 3)， 4.37-4.59(2H，dd，J＝9.2Hz，9.2Hz，8-OCH 2)，7.46(1H，dd，J＝10.4Hz，2.0 Hz，3’-H)，7.29(1H，t，J＝8.4Hz，6’-H)，7.23(1H，dd，J＝8.4Hz，2.0Hz， 5’-H)，3.64(4H，br，2×CH 2N)，3.30(4H，br，2×NCH 2)，4.12(1H，dd， 4”-H)，3.73-3.76(3H，m，4”-H，CH 2Ph)，4.71-4.75(1H，m，5”-H)， 3.40-3.43(2H，m，5”-CH 2N)，8.15(1H，br，-NH)，1.83(3H，s，COCH 3) |
| 3 | 662 (M ++Na) | 15.10(1H，s，-COOH)，8.95(1H，s，2-H)，7.61(1H，d，J＝12.4Hz，5-H)， 4.91-4.92(1H，m，1-CHCH 3)，1.47(3H，d，J＝6.8Hz，1-CHCH 3)， 4.38-4.60(2H，dd，J＝9.2Hz，9.2Hz，8-OCH 2)，7.46(1H，dd，J＝10.4Hz，2.0 Hz，3’-H)，7.29(1H，t，J＝8.4Hz，6’-H)，7.23(1H，dd，J＝8.4Hz，2.0Hz， 5’-H)，3.62-3.67(4H，m，2×CH 2N)，3.25-3.28(4H，m，2×NCH 2)，4.12(1H， dd，4”-H)，3.73-3.76(3H，m，4”-H，CH 2Ph)，4.71-4.75(1H，m，5”-H)， 3.41-3.42(2H，m，5”-CH 2N)，8.16(1H，br，-NH)，1.83(3H，s，COCH 3) |
| 4 | 654 (M ++1) | 14.83(1H，s，-COOH)，8.71(1H，s，2-H)，7.77(1H，d，J＝12.4Hz，5-H)， 4.13-4.21(1H，m，cycl.-H)，1.04(2H，br，cycl.-CH 2)，1.12-1.14(2H，m， cycl.-CH 2)，3.80(3H，s，8-OCH 3)，7.47(1H，dd，J＝12.0Hz，2.0Hz，3’-H)， 7.29(1H，t，J＝8.4Hz，6’-H)，7.24(1H，dd，J＝8.4Hz，2.0Hz，5’-H)， 3.68-3.78(7H，m，CH 2Ph，2×CH 2N，4”-H)，3.36(4H，br，2×NCH 2)， 4.12(1H，dd，4”-H)，4.72-4.80(1H，m，5”-H)，3.41-3.43(2H，m，5”-CH 2N)， |
| 8.16(1H，br，-NH)，1.83(3H，s，COCH 3) | ||
| 5 | 664 (M ++Na) | 14.82(1H，s，-COOH)，7.83(1H，d，J＝13.2Hz，5-H)，6.39(1H，br， 1-CHCH 3)，2.10(3H，d，J＝3.2Hz，1-CHCH 3)，6.95(1H，br，8-H)，7.46(1H， dd，J＝12.8Hz，1.6Hz，3’-H)，7.29(1H，t，J＝8.4Hz，6’-H)，7.24(1H，dd， J＝8.4Hz，1.6Hz，5’-H)，3.68-3.77(7H，m，CH 2Ph，2×CH 2N，4”-H)， 3.35(4H，br，2×NCH 2)，4.11(1H，dd，4”-H)，4.71-4.75(1H，m，5”-H)， 3.40-3.44(2H，m，5”-CH 2N)，8.16(1H，br，-NH)，1.83(3H，s，COCH 3) |
| 6 | 612 (M ++1) | 15.25(1H，s，-COOH)，8.94(1H，s，2-H)，7.95(1H，d，J＝13.2Hz，5-H)， 4.56-4.61(2H，m，1-Ch 2CH 3)，1.43(3H，t，1-CH 2CH 3)，7.21(1H，d，J＝7.6 Hz，8-H)，7.46(1H，dd，J＝12.4Hz，2.0Hz，3’-H)，7.29(1H，t，J＝8.4Hz， 6’-H)，7.24(1H，dd，J＝8.4Hz，2.0Hz，5’-H)，3.70-3.78(7H，m，CH 2Ph，2× CH 2N，4”-H)，3.37(4H，br，2×NCH 2)，4.11(1H，dd，4”-H)，4.71-4.75(1H， m，5”-H)，3.40-3.43(2H，m，5”-CH 2N)，8.16(1H，br，-NH)，1.84(3H，s， COCH 3) |
| 7 | 630 (M ++1) | 15.25(1H，s，-COOH)，8.92(1H，s，2-H)，7.95(1H，d，J＝12.0Hz，5-H)， 4.58-4.61(2H，m，1-CH 2CH 3)，1.45(3H，t，1-CH 2CH 3)，7.47(1H，dd，J＝12.4 Hz，2.4Hz，3’-H)，7.30(1H，t，J＝8.0Hz，6’-H)，7.24(1H，dd，J＝8.0Hz，2.4 Hz，5’-H)，3.65-3.77(7H，m，CH 2Ph，2×CH 2N，4”-H)，3.37(4H，br，2× NCH 2)，4.12(1H，dd，4”-H)，4.71-4.76(1H，m，5”-H)，3.41-3.43(2H，m， 5”-CH 2N)，8.15(1H，br，-NH)，1.84(3H，s，COCH 3) |
| 8 | 654 (M ++1) | 15.10(1H，s，-COOH)，8.94(1H，s，2-H)，7.59(1H，d，J＝12.4Hz，5-H)， 4.90-4.92(1H，m，1-CHCH 3)，1.47(3H，d，1-CHCH 3)，4.39-4.59(2H，dd， J＝10.4Hz，10.4Hz，8-OCH 2)，7.46(1H，dd，J＝12.4Hz，2.0Hz，3’-H)， 7.27(1H，t，J＝8.0Hz，6’-H)，7.23(1H，dd，J＝8.0Hz，2.0Hz，5’-H)， 3.28-3.77(10H，m，CH 2Ph，CH 2N，-CHCH 3，4”-H，2×NCH 2)，1.27(3H，br， -CHCH 3)，4.14(1H，dd，4”-H)，4.73-4.78(1H，m，5”-H)，3.43-3.46(2H，m， 5”-CH 2N)，8.15(1H，br，-NH)，1.87(3H，s，COCH 3) |
| 9 | 676 (M ++Na) | 15.10(1H，s，-COOH)，8.95(1H，s，2-H)，7.59(1H，d，J＝12.0Hz，5-H)， 4.90-4.92(1H，m，1-CHCH 3)，1.47(3H，d，1-CHCH 3)，4.38-4.59(2H，dd， J＝10.4Hz，10.4Hz，8-OCH 2)，7.46(1H，dd，J＝12.4Hz，2.0Hz，3’-H)， 7.27(1H，t，J＝8.0Hz，6’-H)，7.23(1H，dd，J＝8.0Hz，2.0Hz，5’-H)， 3.28-3.75(12H，m，CH 2Ph，CH 2N，-CHCH 3，4”-H，2×NCH 2，5”-CH 2N)， 1.27(3H，br，-CHCH 3)，4.12(1H，dd，4”-H)，4.72-4.76(1H，m，5”-H)， 8.16(1H，br，-NH)，1.83(3H，s，COCH 3) |
| 10 | 668 (M ++1) | 14.83(1H，s，-COOH)，8.71(1H，s，2-H)，4.15-4.18(1H，m，cycl.-H)， 1.10-1.13(2H，m，cycl.-CH 2)，0.98-0.99(2H，m，cycl.-CH 2)，7.78(1H，d， J＝12.0Hz，5-H)，3.75(3H，s，8-OCH 3)，7.46(1H，dd，J＝12.6Hz，2.0Hz， 3’-H)，7.28(1H，t，J＝8.0Hz，6’-H)，7.24(1H，dd，J＝8.0Hz，2.0Hz，5’-H)， 3.28-3.75(10H，m，CH 2Ph，CH 2N，CH 3CH-，4”-H，2×NCH 2)，1.25(3H，br， CH 3CH-)，3.41-3.43(2H，m，5”-CH 2N)，4.12(1H，dd，4”-H)，4.71-4.75(1H， m，5”-H)，8.18(1H，br，-NH)，1.83(3H，s，COCH 3) |
| 11 | 644 (M ++1) | 14.79(1H，s，-COOH)，8.91(1H，s，2-H)，4.57-4.60(2H，m，1-CH 2CH 3)， 1.45(3H，t，1-CH 2CH 3)，7.88(1H，d，J＝11.6Hz，5-H)，7.46(1H，dd，J＝12.6 Hz，2.4Hz，3’-H)，7.27(1H，t，J＝8.0Hz，6’-H)，7.23(1H，dd，J＝8.0Hz，2.4 Hz，5’-H)，3.28-3.75(10H，m，CH 2Ph，CH 2N，CH 3CH-，4”-H，2×NCH 2)， 1.27(3H，br，CH 3CH-)，3.40-3.43(2H，m，5”-CH 2N)，4.12(1H，dd，4”-H)， |
| 4.71-4.75(1H，m，5”-H)，8.18(1H，br，-NH)，1.83(3H，s，COCH 3) | ||
| 12 | 642 (M ++Na) | 14.64(1H，s，-COOH)，8.69(1H，s，2-H)，1.18-1.22(4H，m，2×cycl.-CH 2)， 7.84(1H，d，J＝12.0Hz，5-H)，7.46(1H，dd，J＝12.6Hz，2.0Hz，3’-H)， 7.28(1H，t，J＝8.0Hz，6’-H)，7.24(1H，dd，J＝8.0Hz，2.0Hz，5’-H)， 3.66-3.75(5H，m，4”-H，2×NCH 2)，3.33-3.38(4H，m，2×CH 2N)，3.78(2H， s，CH 2Ph)，4.10-4.14(2H，m，cycl.-H，4”-H)，4.71-4.75(1H，m，5”-H)， 3.41-3.43(2H，m，5”-CH 2N)，8.16(1H，br，-NH)，1.84(3H，s，COCH 3) |
| 13 | 656 (M ++1) | 14.64(1H，s，-COOH)，8.67(1H，s，2-H)，1.10-1.28(7H，m，cycl.-CH 2， cycl.-CH 2，CH 3CH-)，7.82(1H，d，J＝13.2Hz，5-H)，7.44(1H，dd，J＝11.6 Hz，2.0Hz，3’-H)，7.29(1H，t，J＝8.4Hz，6’-H)，7.21(1H，dd，J＝8.4Hz，2.0 Hz，5’-H)，3.28-3.75(10H，m，CH 2Ph，CH 2N，CH 3CH-，4”-H，2×NCH 2)， 4.10-4.14(2H，m，cycl.-H，4”-H)，4.70-4.74(1H，m，5”-H)，3.41-3.43(2H， m，5”-CH 2N)，8.16(1H，br，-NH)，1.84(3H，s，COCH 3) |
| 14 | 680 (M ++Na) | 14.77(1H，s，-COOH)，8.93(1H，s，2-H)，4.57-4.61(2H，m，1-CH 2CH 3)， 7.91(1H，d，J＝11.6Hz，5-H)，7.46(1H，dd，J＝12.6Hz，2.4Hz，3’-H)， 7.27(1H，t，J＝8.0Hz，6’-H)，7.23(1H，dd，J＝8.0Hz，2.4Hz，5’-H)， 3.28-3.77(9H，m，CH 2Ph，2×CH 3CH-，4”-H，2×NCH 2)，1.39-1.47(9H， m，1-CH 2CH 3，2×CH 3CH-)，3.40-3.43(2H，m，5”-CH 2N)，4.12(1H，dd， 4”-H)，4.71-4.75(1H，m，5”-H)，8.18(1H，br，-NH)，1.83(3H，s，COCH 3) |
A: add D
2Behind the O, blackout; B:cycl.: cyclopropyl
The antibacterial activity in vitro test of effect embodiment 1 The compounds of this invention
1. test method: reference literature (Liu Qing, Zhou Weicheng, Yu Aizhen etc., 7-[4-(2,4-diamino quinazoline-6-yl) piperazine-1-yl]-the synthetic and anti-microbial activity of 6-fluoroquinolone compound, Chinese Journal of Pharmaceuticals, 1996,27:104.), with agar two-fold dilution method the minimum inhibitory concentration (MIC) of strain subject is measured.After the compound that is tried is used the methyl-sulphoxide hydrotropy, use with the sterile purified water wiring solution-forming.
2. positive controls is linezolid (Linezolid) and norfloxicin (Norfloxacin); Medicine group: be respectively compound 1～14 of the present invention.
3. test strain: totally 20 kinds of laboratory standard bacterium (preceding 6 kinds is G
+Bacterium, back 14 kinds is G
-Bacterium).Gold bacterium 26003 (the Staphylococcus aureus) of Portugal, pneumococcus 31002 (Streptococcuspneuminiae), white bacterium 260101 (the Staphylococcus albus) of Portugal, faecalis 32220 (Enterococcusfaecium), gamma streptococcus 32206 (Gamma streptococcus), staphylococcus epidermidis 26069 (Streptococcus epidermidis), intestinal bacteria 44102 (Escherichia coli), Song Shi Shigellae 51081 (Shigella sonnei), Shigella bogdii 51313 (Shigella boydii), Proteus mirabilis 49005, (Proteus mirabilis), proteus vulgaris 49085 (Proteus vulgaris), Morgan Bacillus proteus 49086 (Proteus morganii), Pseudomonas aeruginosa 10124 (Pseudomonasaeruginosa), pneumobacillus 46101 (Klebsiella pneumoniae), Salmonella enteritidis 50041 (Salmonella enteridis), Corynebacterium diphtheriae 50097 (Salmonella typhi), citrobacter 48017 (Salmonella citrobacter), gas bacillus 9221 (Enterobacter aerogenes), emplastic serratia 41002 (Serratia marcescens) and Fu Shi shiga bacillus 92475 (Shigellaflexneri).
The MIC value of The compounds of this invention 1～14 is listed in the table 3.By table 3 as seen, compound of the present invention has the anti-golden Portugal of obvious in-vitro bacterium activity.Most target compounds all are not so good as contrast medicine linezolid to the activity of gram-positive microorganisms such as golden Portugal bacterium, pneumococcus, white Portugal bacterium, faecalis, gamma streptococcus, form staph, but, the bacteriostatic activity of 3,4,9,10 pairs of golden Portugal bacterium of compound is better than or suitable linezolid, and 4 pairs of faecalis of compound also show better antibacterial activity.
Table 3 target compound 1～15 antibacterial activity in vitro data (MIC, μ gmL
-1)
| No. | Sau c | Spn | Sal | Efa | Sga | Sep | Ec | Son | Sbo | Pmi | Pv | Pmo | Pae | Kp | Sae | Sty | Sci | Eae | Sma | Sfl |
| Lzd a Norf b 1 2 3 4 5 6 7 8 9 10 11 12 13 14 | 3.13 0.39 12.5 12.5 3.13 1.56 12.5 ＞25 25 6.25 3.13 3.13 25 6.25 12.5 ＞25 | 0.78 0.39 25 25 ＞25 3.13 25 ＞25 25 ＞25 12.5 6.25 25 12.5 25 ＞25 | 3.13 3.13 25 25 ＞25 ＞25 25 ＞25 ＞25 ＞25 12.5 ＞25 25 ＞25 ＞25 ＞25 | 1.56 6.25 12.5 12.5 ＞25 1.56 12.5 ＞25 12.5 ＞25 ＞25 25 25 25 25 ＞25 | 3.13 6.25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 25 ＞25 25 ＞25 ＞25 | 3.13 0.78 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 0.098 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 ＜0.049 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 25 ＞25 ＞25 | ＞6.25 0.098 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 25 ＞25 ＞25 | ＞6.25 0.39 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 0.39 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 ＜0.049 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 1.56 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 ＜0.049 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 ＜0.049 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 ＜0.049 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 ＜0.049 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 0.098 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 0.39 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 | ＞6.25 0.098 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 ＞25 |
Wherein: the a:Lzd:Linezolid linezolid; The b:Norf:Norfloxacin norfloxicin; C:Sau gold Portugal bacterium; The Spn pneumococcus; The white Portugal of Sal bacterium; The Efa faecalis; The Sga gamma streptococcus; The Sep form staph; The Ec intestinal bacteria; Son Song Shi Shigellae; The Sbo Shigella bogdii; The Pmi Proteus mirabilis; The Pv proteus vulgaris; Pmo Morgan Bacillus proteus; The Pae Pseudomonas aeruginosa; The Kp pneumobacillus; The Sae Salmonella enteritidis; The Sty Corynebacterium diphtheriae; The Sci citrobacter; The Eae gas bacillus; The Sma emplastic serratia; Sfl Fu Shi shiga bacillus
Claims (13)
1. Flouroquinolone-oxazolidone derivative, described Flouroquinolone-oxazolidone derivative is the compound with following general structure I:
Wherein,
R
1Be C
1～C
4Alkyl, C
3～C
6Cycloalkyl or C
1～C
4Haloalkyl;
R
2Be H or C
1～C
4Alkyl;
R
3Be H, halogen or C
1～C
4Alkoxyl group;
Perhaps, R
2And R
1Form the bridge of following structure together:
Wherein, X is S, O or CH
2
Perhaps, R
3And R
1Form the bridge of following structure together:
Wherein, Y is S, O or CH
2
R
4Be H or C
1～C
4Alkyl;
R
5Be H or C
1～C
4Alkyl.
2. Flouroquinolone-oxazolidone derivative according to claim 1 is characterized in that, described halogen is F or Cl.
3. Flouroquinolone-oxazolidone derivative according to claim 1 is characterized in that,
R
1Be ethyl or cyclopropyl;
R
2Be H;
R
3Be H, fluorine or methoxyl group;
Perhaps, R
1And R
2Form the bridge of following structure together:
Perhaps, R
1And R
3Form the bridge of following structure together:
R
4Be H or methyl;
R
5Be H or methyl.
4. Flouroquinolone-oxazolidone derivative according to claim 1 is characterized in that, described Flouroquinolone-oxazolidone derivative is:
1-cyclopropyl-6-fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
9-fluoro-3-methyl isophthalic acid 0-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid,
(S)-9-fluoro-3-methyl isophthalic acid 0-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl)-phenyl]-ethanoyl]-piperazine-1-yl }-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid,
1-cyclopropyl-6-fluoro-8-methoxyl group-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-fluoro-1-methyl-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1H, 4H-[1,3] sulfur nitrogen heterocycle butane [3,2-a] quinoline-3-carboxylic acid,
1-ethyl-6-fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
1-ethyl-6,8-two fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
9-fluoro-3-methyl isophthalic acid 0-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid,
(S)-and 9-fluoro-3-methyl isophthalic acid 0-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid,
1-cyclopropyl-6-fluoro-8-methoxyl group-7-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidines-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
1-ethyl-6,8-two fluoro-7-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
1-cyclopropyl-6,8-two fluoro-7-{4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
1-cyclopropyl-6,8-two fluoro-7-{3-methyl-4-[2-[2-fluoro-4-((5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or,
1-ethyl-6,8-two fluoro-7-{3,5-dimethyl-4-[2-[2-fluoro-44 (5S)-5-ethanamide methyl-2-oxo-oxazolidine-3-yl) phenyl] ethanoyl] piperazine-1-yl }-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
5. one kind contains the composition that each described derivative of claim 1～4 for the treatment of significant quantity and pharmaceutically acceptable carrier are formed.
6. each its pharmacy acceptable salt of described derivative of claim 1～4, solvate, optical isomer or its polymorphic form.
7. its pharmacy acceptable salt of derivative according to claim 6, solvate, optical isomer or its polymorphic form is characterized in that pharmaceutically acceptable solvate is hydrate or C
1～C
4The solvate of alcohol or other organic solvent.
8. its pharmacy acceptable salt of derivative according to claim 6, solvate, optical isomer or its polymorphic form is characterized in that, pharmacy acceptable salt comprises the salt that forms with basic metal.
9. its pharmacy acceptable salt of derivative according to claim 8, solvate, optical isomer or its polymorphic form is characterized in that pharmacy acceptable salt comprises the salt of sodium, potassium, calcium or magnesium mineral alkali.
10. one kind contains the composition that the described salt of the claim 6 for the treatment of significant quantity, solvate, optical isomer or its polymorphic form and pharmaceutically acceptable carrier are formed.
11. the preparation method of Flouroquinolone-oxazolidone derivative according to claim 1 is characterized in that, this method comprises the steps:
Formula II compound and formula III compound are reacted in organic solvent, in the presence of the condensing agent, under the effect of alkali, wherein, temperature of reaction is 0～200 ℃, and the reaction times is 2～120 hours, and the molar ratio of formula II compound and formula III compound is 1: 1～1: 10.
R
1, R
2, R
3, R
4And R
5Described as defined above.
12. method according to claim 11 is characterized in that, described organic solvent is selected from tetrahydrofuran (THF), pyridine, acetonitrile, N, one or more in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone and the methyl-sulphoxide; Described alkali is selected from one or more in the mineral alkalis such as sodium hydroxide, potassium hydroxide, yellow soda ash and sodium bicarbonate, and/or, be selected from pyridine, triethylamine, N, one or more in the organic basess such as N dimethylamine yl pyridines, diisopropyl ethyl amine; Described condensing agent is selected from dicyclohexylcarbodiimide, 1-ethyl-3-[3-(dimethylin) propyl group] in carbodiimide, methylphosphine acid anhydrides, ethylphosphonic acid acid anhydride, n-propyl phosphonic acid anhydride and benzotriazole base diethyl phosphoric acid etc. one or more.
13. the application of each described Flouroquinolone-oxazolidone derivative of claim 1～4 in preparation treatment bacterial infection disease medicine.
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| CN103641847A (en) * | 2013-11-28 | 2014-03-19 | 山东鑫泉医药有限公司 | Preparation method of cefoperazone acid |
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| CN103641847B (en) * | 2013-11-28 | 2016-04-20 | 山东鑫泉医药有限公司 | The preparation method of cefoperazone acid |
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