CN100406455C - Oxazolidinone analog compound containing triazol radical and its preparation method and uses - Google Patents
Oxazolidinone analog compound containing triazol radical and its preparation method and uses Download PDFInfo
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- CN100406455C CN100406455C CNB2006100239906A CN200610023990A CN100406455C CN 100406455 C CN100406455 C CN 100406455C CN B2006100239906 A CNB2006100239906 A CN B2006100239906A CN 200610023990 A CN200610023990 A CN 200610023990A CN 100406455 C CN100406455 C CN 100406455C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The present invention relates to an oxazolidinone analog compound containing triazol, which has a structural formula. The present invention also relates to the pharmaceutical acceptable salts of the compound, a preparation method and the application for preparing medicines for treating infectious diseases, particularly the infectious diseases because of multi-medicine resistance germs. The oxazolidinone analog compound containing triazol and the pharmaceutical acceptable salts thereof of the present invention have good antibacterial activity inside and outside bodies and good medicine metabolism characteristics, so the compound and the slat can reduce the rejection capability of C-5 position acetamide oxazolidinone compounds to MAO-A and can reduce the clinical side reaction of the medicines.
Description
Technical field
The invention belongs to field of pharmacology, relate to pharmaceutical chemistry and area of pharmacology, more specifically, relate to and contain triazol radical De oxazolidone compounds and preparation method thereof and the purposes in the microbial infectious disease medicament of preparation treatment infectious diseases, particularly multidrug resistance.
Background technology
The Mycobacterium tuberculosis of methicillin resistant staphylococcus aureus (MRSA) that occurs in the world wide and staphylococcus epidermidis (MRSE), resistance streptococcus pneumoniae, multidrug resistance and vancomycin resistance intestines ball (VRE) are stubborn problem [Exp.Opin.Ther.Patents the most in the current clinical anti-infective therapy, 2000,10 (9): 1405; Exp.Opin.Ther.Patents, 2004,14 (9): 1309].In the face of the challenge that the multidrug resistance cingula is come, must develop the antibacterials of brand-new mechanism of action.
Oxazolidone is the brand-new antibacterials of a class, it is to the gram-positive microorganism of multidrug resistance, as the streptococcus aureus of methicillin resistant staphylococcus aureus, vancomycin resistance, the faecalis of vancomycin resistance, penicillin-fast streptococcus pneumoniae etc. and responsive gram-positive microorganism, all have very strong anti-microbial activity (Angew.Chem.Int.Ed.2003,42:2010; Current Topics inMedicinal Chemistry, 2003,3:1021).Oxazolidone suppresses bacterioprotein synthetic initial stage, and its antibacterial mechanisms that is different from present existing antibiotic brand new and uniqueness has attracted the concern (Bioorg.﹠amp of numerous drugmakers; Med.Chem.Lett.2003,13:4179; Bioorg.﹠amp; Med.Chem.Lett.2005,15:4261).Wherein at first in U.S.'s listing, commodity are called Zyvox, become the oxazolidone medicine that first gets permission to enter clinical application through the FDA approval for linezolid 2000.Oxazolidone might develop into the complete synthesis antibacterials of the third-largest class after sulfa drug and quinolone, and research emphasis is a novel compound of finding that antimicrobial spectrum is wider, anti-microbial activity is stronger and side reaction is littler at present.
Zao Qi oxazolidone compounds structure activity study shows that the acetamido of the C-5 position of oxazolidone is that pharmaceutical activity is necessary, along with deepening continuously of research, discovery replaces the acetamido of C-5 position with triazol radical, anti-microbial activity and antimicrobial spectrum [Exp.Opin.Ther.Patents that not only can Bao Liu oxazolidone compounds, 2004,14 (9): 1309], and might reduce the inhibition activity of the Yi Xian An oxazolidinone compounds of C-5 position, thereby reduce the clinical side reaction of this class medicine to MAO-A.
Summary of the invention
The purpose of this invention is to provide have anti-microbial activity, active novel triazol radical De oxazolidone compounds or its pharmacy acceptable salt of containing of anti-multidrug resistance bacterium particularly.
Another object of the present invention provides the above-mentioned active novel preparation method who contains triazol radical De oxazolidone compounds or its pharmacy acceptable salt of anti-microbial activity, particularly anti-multidrug resistance bacterium that has.
A further object of the present invention provides above-mentioned contain triazol radical De oxazolidone compounds or the application of its pharmacy acceptable salt in the medicine of preparation treatment infectious diseases, the particularly microbial infectious diseases of multidrug resistance.
The invention provides have a following structural formula (I) contain triazol radical De oxazolidone compounds or its pharmacy acceptable salt:
Wherein, R
1And R
2Be hydrogen or fluorine separately;
N is the integer of 1-3;
M is the integer of 1-2;
R
3Fragrant heterocyclic radical for aryl, fragrant heterocyclic radical or the replacement of alkyl, aryl or the replacement of alkyl or replacement.
The invention provides the preparation method who contains triazol radical De oxazolidone compounds of structural formula (II),
This method comprises: in polar aprotic solvent, (R)-3-(3-fluoro-4-piperazinyl phenyl)-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-keto hydrochloride and R
3CHO reaction, what obtain structural formula (II) contains triazol radical De oxazolidone compounds; R wherein
3Definition as mentioned above;
Or in polar aprotic solvent, in the presence of alkali, (R)-3-(3-fluoro-4-piperazinyl phenyl)-5-(1,2,3-triazol-1-yl methyl) oxazolidine-2-keto hydrochloride and the benzyl chlorine of replacement or the benzyl bromine reaction of replacement, what obtain structural formula (II) contains triazol radical De oxazolidone compounds.
The prepared structural formula of aforesaid method (II) contains triazol radical De oxazolidone compounds, its R according to the present invention
3On active function groups can be further reduction amination, the reduction of aldehyde radical, the aldehyde radical of catalytic hydrogenation, aldehyde radical and various secondary amine of reduction reaction, benzyloxy by nitro become reactions such as oxime to derive to obtain the different triazol radical De oxazolidone compounds that contains of the present invention.
Structural formula of the present invention (I) contain triazol radical De oxazolidone compounds or its pharmacy acceptable salt, have good inside and outside anti-microbial activity and drug metabolism characteristic, can be used for preparing treatment infectious diseases, the particularly medicine of the microbial infectious diseases of multidrug resistance.
The present invention's related De oxazolidone compounds or its pharmacy acceptable salt might reduce the inhibition activity of the Yi Xian An oxazolidinone compounds of C-5 position to MAO-A, thereby reduce the clinical side reaction of this class medicine.
Embodiment
Unless dated especially, term definition used among the present invention is as follows:
Described alkyl is represented saturated or undersaturated, the alkyl of the straight or branched of replacement or non-replacement, can enumerate particularly as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, the 1-methyl butyl, the 2-methyl-propyl, hexyl, isohexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, the 2-methyl butyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl etc.In these groups, preferred carbonatoms is 1-4 alkyl, for example methyl, ethyl, propyl group, sec.-propyl or butyl etc., more preferably methyl, ethyl or propyl group, most preferable or ethyl.
" aryl " expression aromatic hydrocarbyl, the aryl of preferred 6-14 carbon atom is in particular phenyl, tolyl, xylyl, xenyl, naphthyl, indenyl, anthryl or phenanthryl, more preferably phenyl or naphthyl, most preferably phenyl.
" fragrant heterocyclic radical " expression contains 1-4 heteroatomic five yuan or the six membered heteroaryl that is selected from Sauerstoffatom, nitrogen-atoms or sulphur atom, for example furyl, thienyl, pyrryl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazyl etc.In these groups, preferred thienyl, furyl, pyridyl, oxazolyl, isoxazolyl or thiazolyl, more preferably thienyl, furyl or pyridyl.
" alkyl of replacement ", " aryl of replacement " and " fragrant heterocyclic radical of replacement " represent respectively above-mentioned " alkyl ", " aryl " and " fragrant heterocyclic radical " can randomly be selected from halogen atom, alkyl, alkoxyl group, acyloxy ,-OH ,-NH
2,-NO
2,-NHAc ,-CH
2NR
4R
5,-CH
2OR
6,-CH=NR
7Group replace.Wherein, R
4And R
5Be respectively hydrogen or alkyl, perhaps R
4And R
5With nitrogen-atoms to form the saturated or unsaturated ring system of 4-10 unit; R
6Be hydrogen or alkyl; R
7Amido for hydroxyl, amino, alkoxyl group or alkyl replacement.
In the oxazolidone compounds that contains triazol radical shown in the structural formula of the present invention (I), representative compound title and structural formula are as follows,
Particular compound is shown in the table 1, wherein R
1Be fluorine, R
2Be hydrogen, R
3As shown in table 1, n is 1, and m is 1.
Table 1
The pharmacy acceptable salt that contains triazol radical De oxazolidone compounds of the present invention, can enumerate the salt of mineral acids such as above-claimed cpd and hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid particularly, with the acid salt of organic acids such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, ethyl sulfonic acid and acidic amino acids such as aspartic acid, L-glutamic acid.
The invention provides the preparation method who contains triazol radical De oxazolidone compounds of structural formula (II),
This method comprises: in polar aprotic solvent, (R)-3-(3-fluoro-4-piperazinyl phenyl)-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-keto hydrochloride and R
3CHO reaction, what obtain structural formula (II) contains triazol radical De oxazolidone compounds; R wherein
3Definition as mentioned above;
Or in polar aprotic solvent, in the presence of alkali, (R)-3-(3-fluoro-4-piperazinyl phenyl)-5-(1,2,3-triazol-1-yl methyl) oxazolidine-2-keto hydrochloride and the benzyl chlorine of replacement or the benzyl bromine reaction of replacement, what obtain structural formula (II) contains triazol radical De oxazolidone compounds.
The prepared structural formula of aforesaid method (II) contains triazol radical De oxazolidone compounds, its R according to the present invention
3On active function groups can be further reduction amination, the reduction of aldehyde radical, the aldehyde radical of catalytic hydrogenation, aldehyde radical and various secondary amine of reduction reaction, benzyloxy by nitro become reactions such as oxime to obtain the different triazol radical De oxazolidone compounds that contains of the present invention.
The preparation method who contains triazol radical De oxazolidone compounds of structural formula of the present invention (II) is more specifically described below.
In the present invention, employed (R)-3-(3-fluoro-4-piperazinyl phenyl)-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-keto hydrochloride can make by following route:
Wherein, CBZ is a carbobenzoxy-(Cbz); A represents NaN
3, DMF, 100 ℃; B represents vinyl acetate between to for plastic, 80 ℃; C represents H
2/ Pd/C;
1. (J.Med.Chem.1996 39:673-679) can make intermediate (S)-3-(3-fluoro-(4-carbobenzoxy-(Cbz)) piperazinyl-phenyl) 5-(methylsulfonic acid ylmethyl) oxazolidine-2-ketone for Brickner, S.J.et al to press currently known methods.
2. (methylsulfonic acid ylmethyl) oxazolidine-2-ketone is at N for 5-for (S)-3-(3-fluoro-(4-carbobenzoxy-(Cbz)) piperazinyl-phenyl), dinethylformamide, N, in N-diethylformamide, acetonitrile or the methyl-sulphoxide isopolarity aprotic solvent, obtained compound (R)-3-(3-fluoro-(4-carbobenzoxy-(Cbz)) piperazinyl-phenyl) 5-(azido-methyl) oxazolidine-2-ketone in 2-24 hour with the metal azide reaction in 40-120 ℃.Top condition is that with N, dinethylformamide is a solvent, at 100 ℃ and NaN
3Reacted 12 hours.
3. (azido-methyl) oxazolidine-2-ketone and vinyl acetate between to for plastic are in the presence of molecular sieve for 5-for (R)-3-(3-fluoro-(4-carbobenzoxy-(Cbz)) piperazinyl-phenyl), be heated to 40-80 ℃ of reaction and obtained compound (R)-3-(3-fluoro-(4-carbobenzoxy-(Cbz)) piperazinyl)-phenyl in 12-84 hour) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-2-ketone.Top condition is, selects 4 for use
Molecular sieve, heating reflux reaction 84 hours.
4. 5-(1 (R)-3-(3-fluoro-(4-carbobenzoxy-(Cbz)) piperazinyl)-phenyl), 2,3-triazol-1-yl methyl) oxazolidine-2-ketone is in the presence of metal catalyst, with methylene dichloride, methyl alcohol, ethanol, tetrahydrofuran (THF) or their two components or polycomponent is solvent, obtained (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1 in 6-24 hour at the normal temperature and pressure hydrogenation, 2,3-triazol-1-yl methyl) oxazolidine-2-keto hydrochloride.Top condition is for being catalyzer with 10%Pd-C, is solvent with the mixed solvent of methylene dichloride and methyl alcohol, and hydrogenation is 12 hours at normal temperatures and pressures.
With (R)-3-(3-fluoro-4-piperazinyl phenyl)-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-keto hydrochloride is basic raw material, can prepare compounds more of the present invention according to route I:
Route I
Wherein, represent can substituted aryl or can substituted fragrant heterocyclic radical for R; D represents nitrobenzaldehyde, HCO
2H, DMF, 100 ℃; E represents H
2/ Pd/C; F represents RCHO, HCO
2H, DMF, 100 ℃; G represents 5-nitro-2 furan carboxyaldehyde, Ti (O
iPr)
4, NaBH
4H represents benzyloxy substituted benzyl chlorine, Et
3N, DMF; I represents H
2/ Pd/C.
(1) (R)-3-(3-fluoro-4-piperazinyl phenyl)-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-keto hydrochloride, in polar aprotic solvent, N for example, dinethylformamide, N, N-diethylformamide or acetonitrile etc., with the aldehyde of various replacements in 20～120 ℃ of reactions 1-24 hour, top condition be with N, dinethylformamide is that solvent reacted 2-24 hour in 100 ℃, obtain compound 1-3,7-18,24,36.
(2) (R)-3-(3-fluoro-4-piperazinyl phenyl)-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-keto hydrochloride and 5-nitro-2 furan carboxyaldehyde be at Ti (O
iPr)
4Have reaction down, generate the transition state intermediate of metal titanium, this transition state intermediate is again through NaBH
4Reduction obtains compound 19; Optimum reaction condition is to make solvent with methyl alcohol, adding Et
3N and Ti (O
iPr)
4, under nitrogen protection, after 6 hours, generate the transition state intermediate of metal titanium, again through NaBH in room temperature reaction
4Reduction obtains compound 19.
(3) compound 1-3 carries out catalytic hydrogenation and obtains compound 4-6 in polar solvent in the presence of metal catalyst.More specifically, compound 1-3 is a solvent with methylene dichloride, methyl alcohol, ethanol, tetrahydrofuran (THF) or their two components or polycomponent, with palladium/carbon or other contains palladium or nickeliferous metal catalyst is a catalyzer, obtain compound 4-6 through catalytic hydrogenation at normal temperatures and pressures.The top condition of reaction is that the mixed solvent with methyl alcohol and methylene dichloride is a solvent, and palladium/carbon of 5% or 10% is catalyzer, catalytic hydrogenation under the normal temperature and pressure.
(4) with the hydroxy benzaldehyde be raw material, press currently known methods (Bio.Med.Chem.Lett.11 (2001) 2205-2208) through some step synthetic intermediate benzyloxy substituted benzyl chlorine, again with (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-2-keto hydrochloride reaction obtains compound 20,21.Selectable solvent is N, dinethylformamide, N, N-diethylformamide, acetonitrile or methyl-sulphoxide isopolarity aprotic solvent, with triethylamine, pyridine, Anhydrous potassium carbonate or anhydrous sodium carbonate is alkali, reaction times is 1-24 hour, and top condition is, with N, dinethylformamide is a solvent, and triethylamine is alkali reaction 2 hours.
(5) compound 20,21 carries out catalytic hydrogenation and obtains compound 22,23 in polar solvent in the presence of metal catalyst.Be solvent for example, with palladium/carbon or other contains palladium or nickeliferous metal catalyst is a catalyzer, obtain compound 22,23 through catalytic hydrogenation at normal temperatures and pressures with methylene dichloride, methyl alcohol, ethanol, tetrahydrofuran (THF) or their two components or polycomponent.The top condition of reaction is that the mixed solvent with methyl alcohol and methylene dichloride is a solvent, and palladium/carbon of 5% or 10% is catalyzer, catalytic hydrogenation under the normal temperature and pressure.
According to route II, the resulting compound of route I can further be derived by the conventional chemical reaction and be obtained different compounds of the present invention:
Route II:
Wherein, a represents R
4R
5NH, CH
3CN, HCOOH, 80 ℃; B represents NaBH
4, CH
2Cl
2, MeOH, rm, 2h; C represents NH
2OHHCl, K
2CO
3, CH
2Cl
2, MeOH, 2h; D represents NH
2NH
2H
2O, con.H
2SO
4, CH
2Cl
2, MeOH, 12h.
(1) compound 24 and replacement secondary amine in 60～100 ℃ of reactions 12-84 hour, obtain compound 25-31 in polar aprotic solvent; Top condition is, is solvent with the acetonitrile, heating reflux reaction 12-84 hour.
(2) compound 36 and replacement secondary amine in 60～100 ℃ of reactions 12-84 hour, obtain compound 37-42 in polar aprotic solvent; Top condition is, is solvent with the acetonitrile, heating reflux reaction 12-84 hour.
(3) compound 24,36 and NaBH
4Or LiAlH
4In polar solvent, obtain compound 32,44 Deng reductive agent in-10-30 ℃ a reaction; Top condition is, with NaBH
4Being reductive agent, is solvent with methyl alcohol and methylene dichloride, room temperature reaction 2 hours.
(4) compound 24,36 and oxammonium hydrochloride obtain compound 33,43 in 0-60 ℃ of reaction in polar solvent.For example, compound 24,36 and oxammonium hydrochloride, with methylene dichloride, methyl alcohol, ethanol, tetrahydrofuran (THF) or their two components or polycomponent is solvent, in the presence of mineral alkalis such as Anhydrous potassium carbonate, anhydrous sodium carbonate, obtained compound 33,43 in 2-12 hour in-10-60 ℃ of reaction; Top condition is, is solvent with methyl alcohol or methylene dichloride, is alkali with the Anhydrous potassium carbonate, is heated to 40 ℃ of reactions 2 hours.
(5) compound 32 and hydrazine hydrate obtain compound 35 in room temperature reaction in polar solvent.For example, compound 32 and hydrazine hydrate are in the solvent in methylene dichloride, methyl alcohol, ethanol, tetrahydrofuran (THF) or their two components or polycomponent, obtain compound 35 in-10-60 ℃ a reaction.Optimum reaction condition is, is solvent with methyl alcohol or methylene dichloride, with dilute sulphuric acid catalysis, in room temperature reaction 12 hours.
According to the triazol radical De oxazolidone compounds that contains of the present invention, adopt pharmaceutically ordinary method, can make its corresponding pharmacy acceptable salt.
The present invention is further elaborated below in conjunction with embodiment, but these embodiment never are any limitation of the invention.Among all embodiment, fusing point is measured with MEL-TEMP fusing point instrument, and thermometer is not proofreaied and correct;
1H-NMR Varian Mercury 400 nuclear magnetic resonance analyser records, chemical shift is represented with δ (ppm); Separate and use silica gel, the undeclared 200-300 order that is.
Embodiment 1:(R)-N-3-[3-fluoro-4-[4-(4-nitrophenyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (1)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(3.8g 10.0mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (50ml), add triethylamine (2ml), bathe under the cooling, add in batches nitrobenzyl chlorine (2.06g at cryosel, 12mmol), after adding, room temperature reaction 3 hours, TLC (CH
2Cl
2/ MeOH=20: monitoring reaction 1 (V/V)).After question response is finished, stopped reaction, pressure reducing and steaming N, dinethylformamide; Residue dissolves with methylene dichloride 100ml, and water 200ml washes again, and water layer is extracted with methylene dichloride 50ml * 2; Merge organic phase, this organic phase water 200ml * 2 is again washed, and saturated nacl aqueous solution 200ml washes, and anhydrous sodium sulfate drying is spin-dried for, and carries out column chromatography (CH
2Cl
2/ CH
3OH=25: 1 (V/V)) separate, use methylene dichloride and sherwood oil (1: 4 (V/V)) recrystallization at last, get product 1.937g, productive rate 65.2%.
Fusing point: 181-182 ℃.
1H-NMR(CDCl
3)：δ8.18(d，J＝8.6Hz，2H)，7.80(d，J＝0.98Hz，1H)，7.75(d，J＝0.78Hz，1H)，7.54(d，J＝8.61Hz，2H)，7.27(dd，J＝14.18Hz，2.44Hz，1H)，6.95(dd，J＝8.90Hz，2.64Hz，1H)，6.88(t，J＝8.91Hz，1H)，5.05(m，1H)，4.78(m，2H)，4.13(t，J＝9.19Hz，1H)，3.90(dd，J＝9.27Hz，6.17Hz，1H)，3.66(s，2H)，3.08(brs，4H)，2.65(brs，4H)。
Embodiment 2:(R)-N-3-[3-fluoro-4-[4-(3-nitrophenyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (2)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1; 2; (0.385g 1mmol) is dissolved in N to 3-triazol-1-yl methyl) oxazolidine-2-keto hydrochloride, in the dinethylformamide (5ml); add m-nitrobenzaldehyde (0.6g; 3.97mmol), formic acid (0.10g, 2.17mmol); under nitrogen protection, be heated to 120 ℃ of reactions 2 hours, TLC (CH
2Cl
2/ MeOH=20: monitoring reaction 1 (V/V)).After question response was finished, stopped reaction added water 50ml dilution, and is neutralized to weakly alkaline (pH ≈ 8) with saturated sodium bicarbonate solution, used methylene dichloride 25ml * 2 extractions again; Gained organic layer water 100ml is successively washed, and saturated nacl aqueous solution 100ml washes, and anhydrous sodium sulfate drying carries out column chromatography (CH again
2Cl
2/ MeOH=50: 1 (V/V)) separate, use ethyl acetate and sherwood oil (1: 3 (V/V)) recrystallization at last, get product 0.39g, productive rate 81.1%.
Fusing point: 127-128 ℃.
1H-NMR(CDCl
3)：δ8.13(t，J＝1.77Hz，1H)，8.12(m，1H)，7.80(d，J＝0.98Hz，1H)，7.74(d，J＝0.98Hz，1H)，7.70(d，J＝7.43Hz，2H)，7.48(t，J＝7.92Hz，1H)，7.27(dd，J＝14.09Hz，2.54Hz，1H)，6.94(dd，J＝9.19Hz，2.54Hz，1H)，6.88(t，J＝8.90Hz，1H)，5.05(m，1H)，4.87(m，2H)，4.12(t，J＝9.10Hz，1H)，3.88(dd，J＝9.39Hz，6.06Hz，1H)，3.66(s，2H)，3.06(t，J＝4.70Hz，4H)，2.65(t，J＝4.30Hz，4H)。
Embodiment 3:(R)-N-3-[3-fluoro-4-[4-(2-nitrophenyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (3)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (5ml), the adding Ortho Nitro Benzaldehyde (0.6g, 3.97mmol), formic acid (0.09g, 1.95mmol), press embodiment 2 described methods, get product 0.24g, productive rate 50.0%.
Fusing point: 136-137 ℃.
1H-NMR(CDCl
3)：δ7.82(d，J＝7.97Hz，1H)，7.78(d，J＝0.96Hz，1H)，7.74(d，J＝0.96Hz，1H)，7.56(m，2H)，7.42(m，1H)，7.27(dd，J＝14.15Hz，2.33Hz，1H)，6.94(dd，J＝9.13Hz，2.40Hz，1H)，6.87(t，J＝8.92Hz，1H)，5.05(m，1H)，4.88(m，2H)，4.12(t，J＝9.13Hz，1H)，3.84-3.90(m，3H)，3.06(brs，4H)，2.60(brs，4H)。
Embodiment 4:(R)-N-3-[3-fluoro-4-[4-(4-aminophenyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (4)
(193mg 0.4mmol) is dissolved in the mixed solvent (30ml) of methylene dichloride and methyl alcohol (V/V=1), adds 10%Pd-C (40mg), room temperature hydrogenation reaction 3 hours, TLC (CH with 1
2Cl
2/ MeOH=20: monitoring reaction 1 (V/V)).After question response was finished, stopped reaction filtered, and filter residue is washed with a little methylene dichloride, and the combined dichloromethane layer carries out column chromatography (CH with it after concentrated
2Cl
2/ MeOH=25: 1 (V/V)) separate, use methylene dichloride and sherwood oil (1: 3 (V/V)) recrystallization again, get product 54mg, productive rate 30.0%.
Fusing point: 191-192 ℃.
1H-NMR(CDCl
3)：δ7.78(s，1H)，7.74(s，1H)，7.27(dd，J＝14.08Hz，2.34Hz，1H)，7.14(d，J＝8.05Hz，2H)，6.95(dd，J＝8.96Hz，2.02Hz，1H)，6.88(t，J＝8.79Hz，1H)，6.68(t，J＝8.79Hz，1H)，5.04(m，1H)，4.87(m，2H)，4.12(t，J＝9.03Hz，1H)，3.87(dd，J＝9.27Hz，6.10Hz，1H)，3.64(brs，2H)，3.52(s，2H)，3.10(brs，4H)，2.66(brs，4H)。
Embodiment 5:(R)-N-3-[3-fluoro-4-[4-(3-aminophenyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (5)
With 2 (200mg 0.41mmol) is dissolved in the mixed solvent (30ml) of methylene dichloride and methyl alcohol (V/V=1), adds 10%Pd-C (40mg), and room temperature hydrogenation reaction 3 hours press embodiment 4 described methods, must product 120mg, and productive rate 53.5%.
Fusing point: 189-191 ℃.
1H-NMR(DMSO-d6)：δ8.13(d，J＝0.78Hz，1H)，7.72(d，J＝0.78Hz，1H)，7.34(dd，J＝14.86Hz，2.53Hz，1H)，7.07(dd，J＝8.80Hz，2.34Hz，1H)，6.99(t，J＝9.29Hz，1H)，6.92(t，J＝7.63Hz，1H)，6.54(d，J＝1.77Hz，1H)，6.44(m，2H)，5.08(m，1H)，4.95(brs，2H)，4.17(t，J＝9.19Hz，1H)，3.83(dd，J＝9.19Hz，5.77Hz，1H)，3.36(s，2H)，2.96(brs，4H)，2.48(brs，4H)。
Embodiment 6:(R)-N-3-[3-fluoro-4-[4-(2-aminophenyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (6)
With 3 (200mg 0.41mmol) is dissolved in the mixed solvent (30ml) of methylene dichloride and methyl alcohol (V/V=1), adds 10%Pd-C (40mg), and room temperature hydrogenation reaction 1.5 hours press embodiment 4 described methods, product 146mg, product 78.0%.
Fusing point: 201-202 ℃.
1H-NMR(DMSO-d6)：δ8.16(d，J＝0.78Hz，1H)，7.74(d，J＝0.78Hz，1H)，7.36(dd，J＝14.96Hz，2.40Hz，1H)，7.08(dd，J＝9.10Hz，2.25Hz，1H)，7.02(t，J＝9.29Hz，1H)，6.95(t，J＝7.34Hz，2H)，6.62(d，J＝8.02Hz，1H)，6.49(t，J＝6.85Hz，1H)，5.10(m，1H)，4.80(d，J＝5.09Hz，2H)，4.18(t，J＝9.19Hz，1H)，3.83(dd，J＝9.19Hz，5.77Hz，1H)，3.44(brs，2H)，3.36(s，2H)，2.96(brs，4H)，2.48(brs，4H)。
Embodiment 7:(R)-N-3-[3-fluoro-4-[4-(2-furyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (7)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(5.738g 15mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (100ml), the adding furfural (2.88g, 30mmol), formic acid (2.07g, 45mmol), press embodiment 2 described methods, get product 5.19g, productive rate 81.2%.
Fusing point: 148-149 ℃.
1H-NMR(CDCl
3)：δ7.78(d，J＝0.98Hz，1H)，7.73(d，J＝0.98Hz，1H)，7.39(dd，J＝8.74Hz，1.01Hz，1H)，7.27(dd，J＝14.09Hz，2.54Hz，1H)，6.93(dd，J＝8.86Hz，2.40Hz，1H)，6.87(t，J＝8.86Hz，1H)，6.32(dd，J＝3.13Hz，1.95Hz，1H)，6.24(d，J＝2.93Hz，1H)，5.05(m，1H)，4.77(m，2H)，4.11(t，J＝9.19Hz，1H)，3.88(dd，J＝9.29Hz，6.16Hz，1H)，3.62(s，2H)，3.08(t，J＝4.79Hz，4H)，2.65(t，J＝4.69Hz，4H)。
Embodiment 8:(R)-N-3-[3-fluoro-4-[4-(3-furyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (8)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(1.15g 3mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (20ml), adding 3-furtural (0.576g, 6mmol), formic acid (0.276g, 6mmol), press embodiment 2 described methods, get product 0.708g, productive rate 55.2%.
Fusing point: 156-157 ℃.
1H-NMR(CDCl
3)：δ7.78(d，J＝1.10Hz，1H)，7.74(d，J＝0.96Hz，1H)，7.27(dd，J＝14.16Hz，2.32Hz，1H)，6.94(dd，J＝8.93Hz，2.47Hz，1H)，6.88(t，J＝8.72Hz，1H)，6.24(d，J＝3.16Hz，1H)，6.10(d，J＝3.16Hz，1H)，5.04(m，1H)，4.77(m，2H)，4.12(t，J＝9.14Hz，1H)，3.87(dd，J＝9.34Hz，6.18Hz，1H)，3.58(s，2H)，3.08(t，J＝4.81Hz，4H)，2.66(t，J＝4.74Hz，4H)。
Embodiment 9:(R)-N-3-[3-fluoro-4-[4-(5-methyl-2-furyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (9)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (5ml), adding 5-methyl-2 furan carboxyaldehyde (0.44g, 4.0mmol), formic acid (0.10g, 2.17mmol), press embodiment 2 described methods, get product 0.10g, productive rate 22.7%.
Fusing point: 139-140 ℃.
1H-NMR(CDCl
3)：δ7.78(d，J＝0.96Hz，1H)，7.74(d，J＝0.97Hz，1H)，7.27(dd，J＝8.98Hz，2.42Hz，1H)，6.94(dd，J＝8.89Hz，2.42Hz，1H)，6.87(t，J＝8.87Hz，1H)，6.10(d，J＝2.89Hz，1H)，5.90(dd，J＝3.01Hz，1.00Hz，1H)，5.04(m，1H)，4 .77(m，2H)，4.12(t，J＝9.15Hz，1H)，3.87(dd，J＝9.34Hz，6.18Hz，1H)，3.75(s，2H)，3.10(t，J＝4.82Hz，4H)，2.65(t，J＝4.61Hz，4H)，2.28(s，3H)。
Embodiment 10:(R)-N-3-[3-fluoro-4-[4-(5-chloro-2-furyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (10)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (10ml), adding 5-chloro-2 furan carboxyaldehyde (0.552g, 4.00mmol), formic acid (0.09g, 1.95mmol), press embodiment 2 described methods, get product 0.19g, productive rate 41.5%.
Fusing point: 135-137 ℃.
1H-NMR(CDCl
3)：δ7.78(d，J＝0.97Hz，1H)，7.74(d，J＝1.10Hz，1H)，7.27(dd，J＝14.10Hz，2.41Hz，1H)，7.14(d，J＝1.37Hz，1H)，6.85-6.97(m，3H)，5.04(m，1H)，4.77(m，2H)，4.11(t，J＝9.08Hz，1H)，3.88(dd，J＝9.35Hz，6.19Hz，1H)，3.73(s，2H)，3.07(t，J＝4.82Hz，4H)，2.67(t，J＝4.75Hz，4H)。
Embodiment 11:(R)-N-3-[3-fluoro-4-[4-(2-thienyl methene)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (11)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (10ml), the adding 2 thiophene carboxaldehyde (0.45g, 3.68mmol), formic acid (0.18g, 3.9mmol), press embodiment 2 described methods, get product 0.33g, productive rate 74.7%.
Fusing point: 156-157 ℃.
1H-NMR(CDCl
3)：δ7.78(d，J＝1.10Hz，1H)，7.74(d，J＝0.96Hz，1H)，7.23-7.30(m，2H)，6.85-6.97(m，4H)，5.05(m，1H)，4.77(m，2H)，4.11(t，J＝9.08Hz，1H)，3.87(dd，J＝9.35Hz，6.19Hz，1H)，3.80(s，2H)，3.08(t，J＝4.82Hz，4H)，2.67(t，J＝4.75Hz，4H)。
Embodiment 12:(R)-N-3-[3-fluoro-4-[4-(3-thienyl methene)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (12)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (10ml), adding 3-thiophenecarboxaldehyde (0.45g, 3.68mmol), formic acid (0.09g, 1.95mmol), press embodiment 2 described methods, get product 0.31g, productive rate 70.1%.
Fusing point: 149-151 ℃.
1H-NMR(CDCl
3)：δ7.78(d，J＝0.96Hz，1H)，7.74(d，J＝1.10Hz，1H)，7.24-7.30(m，2H)，7.15(dd，J＝3.02Hz，1.10Hz，1H)，7.08(dd，J＝4.88Hz，1H)，6.95(dd，J＝9.07Hz，2.47Hz，1H)，6.88(t，J＝8.80Hz，1H)，5.05(m，1H)，4.77(m，2H)，4.11(t，J＝9.08Hz，1H)，3.87(dd，J＝9.35Hz，6.19Hz，1H)，3.80(s，2H)，3.08(t，J＝4.82Hz，4H)，2.67(t，J＝4.75Hz，4H)。
Embodiment 13:(R)-N-3-[3-fluoro-4-[4-(5-bromo-2-thienyl methene)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (13)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (10ml), adding 5-bromo-2 thiophene carboxaldehyde (0.76g, 3.97mmol), formic acid (0.09g, 1.95mmol), press embodiment 2 described methods, get product 0.26g, productive rate 50.0%.
Fusing point: 151-152 ℃.
1H-NMR(CDCl
3)：δ7.78(d，J＝0.97Hz，1H)，7.74(d，J＝1.10Hz，1H)，7.27(dd，J＝14.10Hz，2.41Hz，1H)，7.14(d，J＝1.37Hz，1H)，6.85-6.97(m，3H)，5.04(m，1H)，4.77(m，2H)，4.11(t，J＝9.08Hz，1H)，3.88(dd，J＝9.35Hz，6.19Hz，1H)，3.73(s，2H)，3.07(t，J＝4.82Hz，4H)，2.67(t，J＝4.75Hz，4H)。
Embodiment 14:(R)-N-3-[3-fluoro-4-[4-(3-methyl-2-thienyl methene)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (14)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmo1) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (10ml), adding 3-methyl-2 thiophene carboxaldehyde (0.50g, 3.96mmol), formic acid (0.09g, 1.95mmol), press embodiment 2 described methods, get product 0.30g, productive rate 65.8%.
Fusing point: 131-133 ℃.
1H-NMR(CDCl
3)：δ7.78(d，J＝0.96Hz，1H)，7.73(d，J＝0.82Hz，1H)，7.27(dd，J＝14.10Hz，2.27Hz，1H)，7.14(d，J＝5.09Hz，1H)，6.95(dd，J＝8.87Hz，2.26Hz，1H)，6.88(t，J＝8.80Hz，1H)，6.80(d，J＝5.09Hz，1H)，5.05(m，1H)，4.77(m，2H)，4.11(t，J＝9.14Hz，1H)，3.87(dd，J＝9.28Hz，6.26Hz，1H)，3.78(s，2H)，3.08(t，J＝4.54Hz，4H)，2.67(t，J＝4.60Hz，4H)，2.12(s，3H)。
Embodiment 15:(R)-N-3-[3-fluoro-4-[4-(5-methyl-2-thienyl methene)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (15)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (10ml), adding 3-methyl-2 thiophene carboxaldehyde (0.50g, 3.96mmol), formic acid (0.09g, 1.95mmol), press embodiment 2 described methods, get product 0.30g, productive rate 65.8%.
Fusing point: 153-154 ℃.
1H-NMR(CDCl
3)：δ7.78(d，J＝1.10Hz，1H)，7.74(d，J＝1.10Hz，1H)，7.27(dd，J＝14.16Hz，2.34Hz，1H)，6.95(dd，J＝8.86Hz，2.40Hz，1H)，6.88(t，J＝8.71Hz，1H)，6.72(d，J＝3.30Hz，1H)，6.59(m，1H)，5.05(m，1H)，4.87(m，2H)，4.11(t，J＝9.07Hz，1H)，3.87(dd，J＝9.35Hz，6.16Hz，1H)，3.71(s，2H)，3.08(t，J＝4.81Hz，4H)，2.65(t，J＝4.61Hz，4H)，2.45(s，3H)。
Embodiment 16:(R)-N-3-[3-fluoro-4-[4-(2-pyridyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (16)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (5ml), adding 2-pyridylaldehyde (0.43g, 4.0mmol), formic acid (0.10g, 2.17mmol), press embodiment 2 described methods, get product 0.258g, productive rate 59.0%.
Fusing point: 140-142 ℃.
1H-NMR(CDCl
3)：δ8.58(m，J＝1.08Hz，1H)，7.78(d，J＝0.95Hz，1H)，7.74(d，J＝1.10Hz，1H)，7.66(t，J＝7.63Hz，1H)，7.45(d，J＝7.70Hz，1H)，7.27(dd，J＝14.16Hz，2.47Hz，1H)，7.18(m，1H)，6.94(dd，J＝8.94Hz，2.75Hz，1H)，6.87(t，J＝8.94Hz，1H)，5.04(m，1H)，4.77(m，2H)，4.12(t，J＝9.14Hz，1H)，3.87(dd，J＝9.35Hz，6.18Hz，1H)，3.75(s，2H)，3.08(t，J＝4.54Hz，4H)，2.72(brs，4H)。
Embodiment 17:(R)-N-3-[3-fluoro-4-[4-(4-pyridyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (17)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (5ml), adding 4-pyridylaldehyde (0.43g, 4.0mmol), formic acid (0.10g, 2.17mmol), press embodiment 2 described methods, get product 0.242g, productive rate 55.4%.
Fusing point: 151-152 ℃.
1H-NMR(CDCl
3)：δ8.56(d，J＝5.50Hz，1H)，7.78(d，J＝0.79Hz，1H)，7.74(d，J＝0.79Hz，1H)，7.34(d，J＝5.36Hz，2H)，7.27(dd，J＝14.16Hz，2.34Hz，1H)，6.95(dd，J＝8.87Hz，2.40Hz，1H)，6.88(t，J＝8.87Hz，1H)，5.04(m，1H)，4.77(m，2H)，4.12(t，J＝9.15Hz，1H)，3.87(dd，J＝9.35Hz，6.12Hz，1H)，3.78(s，2H)，3.08(brs，4H)，2.75(brs，4H)。
Embodiment 18:(R)-N-3-[3-fluoro-4-[4-(3-pyridyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (18)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.38g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (5ml), adding 3-pyridylaldehyde (0.43g, 4.0mmol), formic acid (0.10g, 2.17mmol), press embodiment 2 described methods, get product 0.216g, productive rate 49.4%.
Fusing point: 158-159 ℃.
1H-NMR(CDCl
3)：δ8.57(d，J＝2.01Hz，1H)，8.52(dd，J＝4.75Hz，1.64Hz，1H)，7.78(d，J＝0.92Hz，1H)，7.74(d，J＝0.91Hz，1H)，7.71(d，J＝8.68Hz，2H)，7.27(m，2H)，6.94(dd，J＝8.96Hz，2.74Hz，1H)，6.87(t，J＝9.06Hz，1H)，5.03(m，1H)，4.77(m，2H)，4.12(t，J＝9.06Hz，1H)，3.87(dd，J＝9.33Hz，6.22Hz，1H)，3.78(s，2H)，3.07(t，J＝4.48Hz，4H)，2.64(t，J＝4.21Hz，4H)。
Embodiment 19:(R)-N-3-[3-fluoro-4-[4-(5-nitro-2-furyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (19)
(0.38g 1mmol) is dissolved in the anhydrous methanol (6ml), adds triethylamine (0.3g), Ti (O with (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-keto hydrochloride
iPr)
4(0.6ml), 5-nitro-2 furan carboxyaldehyde (0.28g, 2mmol), room temperature reaction is 6 hours under nitrogen protection, treat that raw material disappears substantially after, stopped reaction adds NaBH in above-mentioned system
4(0.3g), reaction is spent the night, TLC (CH
2Cl
2/ MeOH=20: monitoring reaction 1 (V/V)); After question response is finished, stopped reaction adds ammoniacal liquor 15ml, bathes under the cooling at cryosel and stirs 10 minutes, stirring at room is 10 minutes again, filter, filter residue is washed with a little methyl alcohol, and filtrate extracts with methylene dichloride 50ml * 2, organic layer more successively water 100ml wash, saturated NaCl solution 100ml washes, and anhydrous sodium sulfate drying carries out column chromatography (first CH after concentrating
2Cl
2, back CH
2Cl
2/ MeOH=100: 1) separate, products therefrom is dissolved in methyl alcohol, activated carbon decolorizing, and methylene dichloride and sherwood oil (1: 3 (V/V)) recrystallization gets product 42mg, productive rate 9.0%.
Fusing point: 128-130 ℃.
1H-NMR(CDCl
3)：δ7.79(d，J＝0.96Hz，1H)，7.73(d，J＝0.97Hz，1H)，7.27(m，2H)，6.95(dd，J＝8.94Hz，2.55Hz，1H)，6.88(t，J＝8.87Hz，1H)，6.74(d，J＝3.58Hz，1H)，5.05(m，1H)，4.78(m，2H)，4.12(t，J＝9.15Hz，1H)，3.89(dd，J＝9.35Hz，6.19Hz，1H)，3.71(s，2H)，3.09(t，J＝4.82Hz，4H)，2.71(t，J＝4.82Hz，4H)。
Embodiment 20:(R)-N-3-[3-fluoro-4-[4-(4-benzyloxy phenylmethylene)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (20)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2, (0.492g 1.29mmol) is dissolved in N to 3-triazol-1-yl methyl) oxazolidine-2-keto hydrochloride, in the dinethylformamide (30ml), add Anhydrous potassium carbonate (0.8g, 5.8mmol), add again 4-benzyloxy benzyl chlorine (0.7g, 3mmol), spend the night TLC (CH in room temperature reaction
2Cl
2/ MeOH=20: monitoring reaction 1 (V/V)), treat that raw material disappears substantially after, stopped reaction, evaporated under reduced pressure solvent; Residue dissolves with methylene dichloride 50ml, and water 100ml washes successively again, and saturated aqueous common salt 100ml washes, and anhydrous sodium sulfate drying carries out column chromatography (CH after concentrating
2Cl
2/ MeOH=50: 1 (V/V)) separate, get product 0.639g, productive rate 91.3%.
Fusing point: 157-158 ℃.
1H-NMR(CDCl
3)：δ7.79(d，J＝0.96Hz，1H)，7.75(d，J＝0.96Hz，1H)，7.25-7.45(m，7H)，6.85-6.97(m，5H)，5.08(s，2H)，5.03(m，1H)4.87(m，2H)，4.12(t，J＝9.14Hz，1H)，3.87(dd，J＝9.42Hz，6.12Hz，1H)，3.58(s，2H)，3.08(t，J＝4.47Hz，4H)，2.55(brs，4H)。
Embodiment 21:(R)-N-3-[3-fluoro-4-[4-(3-benzyloxy phenylmethylene)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (21)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1,2,3-triazol-1-yl methyl) oxazolidine-(0.382g 1mmol) is dissolved in N to the 2-keto hydrochloride, in the dinethylformamide (20ml), (0.276g 2mmol), adds 3-benzyloxy benzyl chlorine (0.7g again to add Anhydrous potassium carbonate, 3mmol), press embodiment 20 described methods, get product 0.417g, productive rate 87%.
Fusing point: 159-160 ℃,
1H-NMR (CDCl
3): δ 7.79 (d, J=0.96Hz, 1H), 7.75 (d, J=0.96Hz, 1H), 7.21-7.47 (m, 7H), 7.02 (s, 1H), 6.85-6.97 (m, 4H), 5.08 (s, 2H), 4.87 (m, 2H), 4.13 (t, J=9.07Hz, 1H), 3.87 (dd, J=9.35Hz, 6.19Hz, 1H), 3.56 (s, 2H), 3.06 (brs, 4H), 2.62 (brs, 4H).
Embodiment 22:(R)-N-3-[3-fluoro-4-[4-(4-hydroxy phenyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (22)
(0.418g 0.768mmol) is dissolved in the mixed solvent of methylene dichloride (15ml) and methyl alcohol (30ml), adds 10% Pd-C (0.125g), and hydrogenation reaction is 12 hours under the normal temperature and pressure, TLC (CH with 20
2Cl
2/ MeOH=20: 1, V/V) monitoring reaction, after question response is finished, stopped reaction, filter, filtrate adds methylene dichloride 50ml, adds saturated sodium bicarbonate solution 200ml again, layering, water layer merges organic layer with methylene dichloride 50ml * 2 extractions, and anhydrous sodium sulfate drying carries out column chromatography (CH again
2Cl
2/ MeOH=25: 1 (V/V)) separate, get product 0.145g, productive rate 42%.
Fusing point: 235-236 ℃ (blackening).
1H-NMR(DMSO-d6)：δ8.17(d，J＝0.74Hz，1H)，7.76(d，J＝0.73Hz，1H)，7.38(dd，J＝14.83Hz，2.38Hz，1H)，7.00-7.14(m，4H)，6.72(d，J＝8.43Hz，2H)，5.10(m，1H)，4.92(d，J＝4.76Hz，2H)，4.00(t，J＝9.17Hz，1H)，3.84(dd，J＝9.53Hz，5.87Hz，1H)，3.38(m，4H)，2.95(brs，4H)。
Embodiment 23:(R)-N-3-[3-fluoro-4-[4-(3-hydroxy phenyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (23)
(0.312g 0.5748mmol) is dissolved in the mixed solvent of methylene dichloride (20ml) and methyl alcohol (15ml), adds 10% Pd-C (94mg), and hydrogenation reaction is 12 hours under the normal temperature and pressure, gets product 0.166g, productive rate 64% by embodiment 22 described methods with 21.
Fusing point: 229-230 ℃ (blackening),
1H-NMR (DMSO-d6): δ 8.16 (d, J=0.884Hz, 1H), 7.77 (d, J=0.88Hz, 1H), 7.38 (dd, J=14.95Hz, 2.34Hz, 1H), 7.00-7.16 (m, 3H), 6.73 (m, 2H), 6.64 (dd, J=7.62Hz, 1.46Hz, 1H), 5.12 (m, 1H), 4.82 (d, J=4.98Hz, 2H), 4.18 (t, J=9.23Hz, 1H), 3.83 (dd, J=9.24Hz, 5.71Hz, 1H), 3.45 (s, 2H), 3.33 (m, 4H), 2.97 (brs, 4H).
Embodiment 24:(R)-N-3-[3-fluoro-4-[4-(4-formyl radical phenylmethylene)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (24)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1; 2,3-triazol-1-yl methyl) oxazolidine-(3.83g 10mmol) is dissolved in N to the 2-keto hydrochloride; in the dinethylformamide (50ml); the adding terephthalaldehyde (2.01g, 15mmol), formic acid (0.92g; 20mmol); under nitrogen protection, be heated to 100 ℃ of reactions 10 hours, TLC (CH
2Cl
2/ CH
3OH=20: monitoring reaction 1 (V/V)); After question response is complete, stopped reaction, the evaporated under reduced pressure solvent, residue dissolves with methylene dichloride 100ml, wash with saturated sodium bicarbonate solution 200ml again, water layer merges organic layer with methylene dichloride 50ml * 2 extractions, organic layer more successively water 200ml wash, saturated aqueous common salt 200ml washes, anhydrous sodium sulfate drying is spin-dried for, and then carries out column chromatography (CH
2Cl
2/ CH
3OH=100: 1 (V/V)) separate, use methylene dichloride and sherwood oil (1: 4 (V/V)) recrystallization again.Get product 3.48g, productive rate 75%.
Fusing point: 161-162 ℃;
1H-NMR (CDCl
3): δ 10.00 (s, 1H), 7.85 (d, J=8.05Hz, 2H), 7.78 (s, 1H), 7.74 (s, 1H), 7.53 (d, J=8.05Hz, 2H), 7.27 (dd, J=14.09Hz, 2.57Hz, 1H), 6.95 (dd, J=8.78Hz, 2.38Hz, 1H), 6.88 (t, J=8.78Hz, 1H), 5.04 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.33Hz, 6.22Hz, 1H), 3.64 (s, 2H), 3.08 (t, J=4.76Hz, 4H), 2.65 (t, J=4.76Hz, 4H).
Embodiment 25:(R)-and N-3-[3-fluoro-4-[4-[4-(N, N-dimethylated methylene base) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (25)
(232mg 0.5mmol) is dissolved in N, and in the dinethylformamide (10ml), (82mg, 1mmol), (92mg 2mmol), under nitrogen protection, is heated to 100 ℃ of reactions 6 hours, TLC (CH to formic acid to add dimethylamine hydrochloride with 24
2Cl
2/ CH
3OH=10: monitoring reaction 1 (V/V)); After question response is complete, solvent evaporated, residue dissolves with methylene dichloride 50ml, and saturated sodium bicarbonate solution 100ml washes, and water layer extracts with methylene dichloride 25ml * 2, merge organic layer, this organic layer more successively water 200ml wash, saturated aqueous common salt 200ml washes, anhydrous sodium sulfate drying, be spin-dried for, then carry out column chromatography (CH
2Cl
2/ CH
3OH=20: 1 (V/V)) separate, obtain product 109mg, productive rate 44%.
Fusing point: 162-163 ℃;
1H-NMR (CDCl
3): δ 7.79 (d, J=0.91Hz, 1H), 7.74 (d, J=0.73Hz, 1H), 7.34 (m, 4H), 7.27 (dd, J=14.09Hz, 2.38Hz, 1H), 6.94 (dd, J=8.69Hz, 2.56Hz, 1H), 6.87 (t, J=8.69Hz, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.42Hz, 6.13Hz, 1H), 3.61 (s, 2H), 3.57 (s, 2H), 3.08 (t, J=4.58Hz, 4H), 2.62 (t, J=4.49Hz, 4H), 2.38 (s, 6H).
Embodiment 26:(R)-and N-3-[3-fluoro-4-[4-[4-(N, N-diethyl methylene radical) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (26)
With 24 (232mg 0.5mmol) is dissolved in the dry acetonitrile (10ml), add diethylamine hydrochloride (110mg, 1mmol), formic acid (92mg, 2mmol), under nitrogen protection, heating reflux reaction 60 hours, TLC (CH
2Cl
2/ CH
3OH=10: monitoring reaction 1 (V/V)); After question response is complete, solvent evaporated, residue dissolves with methylene dichloride 50ml, and saturated sodium bicarbonate solution 100ml washes, and water layer extracts with methylene dichloride 25ml * 2, merge organic layer, this organic layer more successively water 200nl wash, saturated aqueous common salt 200ml washes, anhydrous sodium sulfate drying, be spin-dried for, then carry out column chromatography (CH
2Cl
2/ CH
3OH=20: 1 (V/V)) separate, obtain product 96mg, productive rate 36.8%.
Fusing point: 146-147 ℃;
1H-NMR (CDCl
3): δ 7.78 (s, 1H), 7.74 (s, 1H), 7.34 (m, 4H), 7.23-7.35 (m, 5H), 6.95 (dd, J=8.88Hz, 2.47Hz, 1H), 6.88 (t, J=8.79Hz, 1H), 5.05 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.87 (dd, J=9.33Hz, 6.04Hz, 1H), 3.61 (s, 2H), 3.57 (s, 2H), 3.08 (t, J=4.67Hz, 4H), 2.52-2.66 (m, 8H), 1.09 (t, J=7.14Hz, 6H).
Embodiment 27:(R)-and N-3-[3-fluoro-4-[4-[4-(1-pyrryl methylene radical) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (27)
(232mg 0.5mmol) is dissolved in the dry acetonitrile (10ml), and (107mg, 1.5mmol), (138mg 3mmol), presses embodiment 26 described methods to formic acid, and the reaction times is 24 hours to add tetramethyleneimine with 24.Get product 187mg, productive rate 72.6%.
Fusing point: 158-159 ℃;
1H-NMR (CDCl
3): δ 7.78 (s, 1H), 7.74 (s, 1H), 7.39 (d, J=8.05Hz, 2H), 7.32 (d, J=7.86Hz, 2H), 7.27 (dd, J=14.18Hz, 2.47Hz, 1H), 6.95 (dd, J=8.88Hz, 2.48Hz, 1H), 6.88 (t ,=8.87Hz, 1H), 5.05 (m, 1H), 4.77 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.87 (dd, J=9.33Hz, 6.22Hz, 1H), 3.79 (s, 2H), 3.56 (s, 2H), 3.08 (t, J=4.67Hz, 4H), 2.74 (brs, 4H), 2.61 (t, J=4.67Hz, 4H), 1.92 (brs, 4H).
Embodiment 28:(R)-and N-3-[3-fluoro-4-[4-[4-(1-hexahydropyridine methylene) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (28)
(232mg 0.5mmol) is dissolved in the dry acetonitrile (10ml), and (128mg, 1.5mmol), (138mg 3mmol), presses embodiment 26 described methods to formic acid, and the reaction times is 24 hours to add hexahydropyridine with 24.Get product 204mg, productive rate 76.7%.
Fusing point: 173-174 ℃;
1H-NMR (CDCl
3): δ 7.78 (d, J=1.10Hz, 1H), 7.74 (d, J=1.10Hz, 1H), and 7.23-7.30 (m, 5H), 6.95 (dd, J=8.88Hz, 2.47Hz, 1H), 6.88 (t, J=8.79Hz, 1H), 5.04 (m, 1H), 4.77 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.43Hz, 6.13Hz, 1H), 3.67 (s, 2H), 3.64 (s, 2H), 3.08 (t, J=4.76Hz, 4H), 2.62 (t, J=4.67Hz, 4H), 2.45 (brs, 4H), 1.64 (t, J=5.49Hz, 4H), 1.46 (t, J=4.76Hz, 2H).
Embodiment 29:(R)-and N-3-[3-fluoro-4-[4-[4-(4-morpholinyl methylene radical) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (29)
(232mg 0.5mmol) is dissolved in the dry acetonitrile (10ml), and (174mg, 2mmol), (184mg 4mmol), presses embodiment 26 described methods to formic acid, and the reaction times is 72 hours to add morpholine with 24.Get product 172mg, productive rate 64%.
Fusing point: 182-183 ℃;
1H-NMR (CDCl
3): δ 7.78 (s, 1H), 7.74 (s, 1H), 7.29-7.40 (m, 5H), 6.94 (dd, J=9.08Hz, 2.48Hz, 1H), 6.88 (t, J=8.89Hz, 1H), 5.04 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.07Hz, 1H), 3.88 (dd, J=9.34Hz, 6.23Hz, 1H), 3.74 (brs, 4H), 3.63 (s, 2H), 3.53 (s, 2H), 3.11 (brs, 4H), 2.66 (brs, 4H), 2.45 (brs, 4H).
Embodiment 30:(R)-and N-3-[3-fluoro-4-[4-[4-(4-thiomorpholine methylene) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (30)
(232mg 0.5mmol) is dissolved in the dry acetonitrile (10ml), and (206mg, 2mmol), (184mg 4mmol), presses embodiment 26 described methods to formic acid, and the reaction times is 72 hours to add thiomorpholine with 24.Get product 165mg, productive rate 59%.
Fusing point: 165-166 ℃;
1H-NMR (CDCl
3): δ 7.78 (d, J=0.92Hz, 1H), 7.74 (d, J=0.92Hz, 1H), 7.25-7.36 (m, 5H), 6.94 (dd, J=9.17Hz, 2.38Hz, 1H), 6.88 (t, J=8.89Hz, 1H), 5.04 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.08Hz, 1H), 3.87 (dd, J=9.35Hz, 6.05Hz, 1H), 3.74 (brs, 4H), 3.63 (s, 2H), 3.54 (s, 2H), 3.10 (brs, 4H), 2.62-2.78 (m, 12H).
Embodiment 31:(R)-and N-3-[3-fluoro-4-[4-[4-(4-methyl isophthalic acid-piperazinyl methylene radical) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (31)
(232mg 0.5mmol) is dissolved in the dry acetonitrile (10ml), and (200mg, 2mmol), (184mg 4mmol), presses embodiment 26 described methods to formic acid, and the reaction times is 36 hours to add methylpiperazine with 24.Get product 163mg, productive rate 59.5%.
Fusing point: 178-179 ℃;
1H-NMR (CDCl
3): δ 7.78 (s, 1H), 7.74 (s, 1H), 7.23-7.33 (m, 5H), 6.95 (dd, J=8.87Hz, 2.47Hz, 1H), 6.88 (t, J=8.79Hz, 1H) 5.05 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.42Hz, 6.13Hz, 1H), 3.55 (s, 2H), 3.54 (s, 2H), 3.08 (t, J=4.76Hz, 4H), 2.54-2.74 (m, 12H), 2.43 (s, 3H).
Embodiment 32:(R)-N-3-[3-fluoro-4-[4-(4-hydroxymethyl phenyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (32)
(162mg 0.35mmol) is dissolved in mixed solvent (the 30ml) (V/V=1: 1), bathe under the cooling at cryosel, slowly add NaBH of methylene dichloride and methyl alcohol with 24
4(65mg 1.7mmol), adds, room temperature reaction 2 hours, TLC (CH
2Cl
2/ MeOH=15: monitoring reaction 1 (V/V)); After question response is finished, dilute hydrochloric acid is adjusted to neutrality, solvent evaporated, residue dissolves with methylene dichloride 50ml, and saturated sodium bicarbonate solution 100ml washes, water layer is used methylene dichloride 25ml * 2 extractions again, merge organic layer, this organic layer more successively water 200ml wash, saturated aqueous common salt 200ml washes, anhydrous sodium sulfate drying then carries out column chromatography (CH
2Cl
2/ MeOH=25: 1 (V/V)) separate, use methyl alcohol again, the mixed solvent recrystallization of methylene dichloride and ether (1: 2: 4 (V/V/V)).Get product 150mg, productive rate 92%.
Fusing point: 190-191 ℃;
1H-NMR (CDCl
3): δ 7.79 (s, 1H), 7.75 (s, 1H), 7.34 (m, 4H), 7.27 (dd, J=14.09Hz, 2.47Hz, 1H), 6.94 (dd, J=8.87Hz, 2.47Hz, 1H), 6.88 (t, J=8.78Hz, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.69 (s, 2H), 4.11 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.24Hz, 6.13Hz, 1H), 3.57 (s, 2H), 3.06 (t, J=4.76Hz, 4H), 2.62 (t, J=4.67Hz, 4H).
Embodiment 33:(R)-and N-3-[3-fluoro-4-[4-[4-(N-hydroxyl methyne) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (33)
With 24 (46mg 0.1mmol) is dissolved in the mixed solvent of small amount of methanol and methylene dichloride, add oxammonium hydrochloride (24mg, 0.35mmol) and Anhydrous potassium carbonate (48mg 0.35mmol), is heated to 40 ℃ and reacted TLC (CH 2 hours
2Cl
2/ MeOH=10: monitoring reaction 1 (V/V)); After question response is finished, solvent evaporated, residue dissolves with methylene dichloride 50ml, water 100ml washes again, and water layer merges organic phase with methylene dichloride 25ml * 2 extractions, this organic phase is washed with saturated aqueous common salt 100ml again, and anhydrous sodium sulfate drying then carries out column chromatography (CH
2Cl
2/ MeOH=25: 1 (V/V)) separate, suspend with methylene dichloride 5ml again, obtain product 38mg, productive rate 79%.
Fusing point: 219-221 ℃,
1H-NMR (CDCl
3): δ 8.13 (s, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.54 (d, J=7.50Hz, 2H), 7.37 (d, J=8.05Hz, 2H), 7.24-7.30 (m, 1H), 6.85-6.97 (m, 2H), 5.05 (m, 1H), 4.77 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.87 (dd, J=8.87Hz, 6.45Hz, 1H), 3.57 (s, 2H), 3.08 (brs, 4H), 2.64 (brs, 4H).
Embodiment 34:(R)-and N-3-[3-fluoro-4-[4-[4-(acetoxyl group methylene radical) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (34)
(117mg 0.25mmol) is dissolved in the methylene dichloride (30ml), and cryosel is bathed cooling, and (40mg 0.5mmol), adds, room temperature reaction 0.5 hour, TCL (CH slowly to add Acetyl Chloride 98Min. with 32
2Cl
2/ MeOH=15: monitoring reaction 1 (V/V)); After question response is finished, add water 100ml, again with methylene dichloride 50ml extraction, water layer merges organic layer with methylene dichloride 25ml * 2 extractions, this organic layer more successively water 200ml wash, saturated aqueous common salt 200ml washes, anhydrous sodium sulfate drying then carries out column chromatography (CH
2Cl
2/ MeOH=50: 1) separate, get product 113mg, productive rate 88%.
Fusing point: 105-106 ℃;
1H-NMR (CDCl
3): δ 7.80 (s, 1H), 7.72 (s, 1H), 7.34 (m, 4H), and 7.22-7.40 (m, 5H), 6.84-6.96 (m, 2H), 5.01-5.14 (m, 3H), 4.78 (brs, 2H), 4.12 (t, J=8.97Hz, 1H), 3.87 (t, J=7.69Hz, 1H), 3.59 (s, 2H), 3.08 (brs, 4H), 2.64 (brs, 4H), 2.10 (s, 3H).
Embodiment 35:(R)-and N-3-[3-fluoro-4-[4-[4-(the amino methyne of N-) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (35)
With 24 (140mg 0.3mmol) is dissolved in the mixed solvent of small amount of methanol and methylene dichloride, add entry and hydrazine (85%) (75mg 1.5mmol), adds a dilute sulphuric acid catalysis, under nitrogen protection, room temperature reaction 12 hours, TLC (CH
2Cl
2/ MeOH=15: monitoring reaction 1 (V/V)); After question response is finished, stopped reaction, concentrate, the residue 50ml dissolving that adds methylene chloride is washed with saturated sodium bicarbonate 100ml solution again, water layer extracts with methylene dichloride 25ml * 2, merge organic phase, this organic phase more successively water 200ml wash, saturated aqueous common salt 200ml washes, use anhydrous sodium sulfate drying again, carry out column chromatography (CH at last
2Cl
2/ MeOH=50: 1 (V/V)) separate, get product 77mg, productive rate 53%.
Fusing point: 274-276 ℃ (blackening);
1H-NMR (CDCl
3): δ 7.74-7.80 (m, 3H), 7.30 (d, J=7.86Hz, 2H), 7.24-7.36 (m, 3H), 6.95 (dd, J=8.78Hz, 2.38Hz, 1H), 6.88 (t, J=8.60Hz, 1H), 5.51 (s, 2H), 5.03 (m, 1H), 4.77 (m, 2H), 4.11 (t, J=9.06Hz, 1H), 3.88 (dd, J=8.78Hz, 6.22Hz, 1H), 3.56 (s, 2H), 3.06 (brs, 4H), 2.61 (brs, 4H).
Embodiment 36:(R)-N-3-[3-fluoro-4-[4-(3-formyl radical phenylmethylene)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (36)
With (R)-3-(3-fluoro-4-piperazinyl phenyl) 5-(1; 2,3-triazol-1-yl methyl) oxazolidine-(3.83g 10mmol) is dissolved in N to the 2-keto hydrochloride; in the dinethylformamide (50ml); the adding m-terephthal aldehyde (2.01g, 15mmol), formic acid (0.92g; 20mmol); under nitrogen protection, be heated to 100 ℃ of reactions 16 hours, TLC (CH
2Cl
2/ CH
3OH=20: monitoring reaction 1 (V/V)); After question response is complete, stopped reaction, the evaporated under reduced pressure solvent, residue dissolves with methylene dichloride 100ml, wash with saturated sodium bicarbonate solution 200ml again, water merges organic layer with methylene dichloride 50ml * 2 extractions, this organic layer more successively water 300ml wash, saturated aqueous common salt 300ml washes, anhydrous sodium sulfate drying is spin-dried for again, then carries out column chromatography (CH
2Cl
2/ CH
3OH=100: 1 (V/V)) separate, use methylene dichloride and sherwood oil (1: 4 (V/V)) recrystallization again.Get product 2.702g, productive rate 58%.
Fusing point: 120-121 ℃;
1H-NMR (CDCl
3): δ 10.03 (s, 1H), 7.87 (s, 1H), 7.76-7.82 (m, 2H), 7.74 (s, 1H), 7.64 (d, J=7.50Hz, 2H), 7.50 (t, J=7.59Hz, 1H), 7.27 (dd, J=14.18Hz, 2.47Hz, 1H), 6.95 (dd, J=8.88Hz, 2.47Hz, 1H), 6.88 (t, J=8.78Hz, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.42Hz, 6.13Hz, 1H), 3.64 (s, 2H), 3.12 (t, J=4.76Hz, 4H), 2.64 (t, J=4.76Hz, 4H).
Embodiment 37:(R)-and N-3-[3-fluoro-4-[4-[3-(N, N-dimethylated methylene base) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (37)
With 36 (186mg 0.4mmol) is dissolved in the dry acetonitrile (20ml), add dimethylamine hydrochloride (82mg, 1mmol), formic acid (92mg, 2mmol), under nitrogen protection, heating reflux reaction 12 hours, TLC (CH
2Cl
2/ CH
3OH=10: monitoring reaction 1 (V/V)); After question response is complete, solvent evaporated, residue is washed with saturated sodium bicarbonate solution 100ml with methylene dichloride 50ml dissolving again, and water layer extracts with methylene dichloride 25ml * 2, merge organic layer, this organic layer more successively water 200ml wash, saturated aqueous common salt 200ml washes, anhydrous sodium sulfate drying, be spin-dried for, then carry out column chromatography (CH
2Cl
2/ CH
3OH=10: 1 (V/V)) separate, obtain product 134mg, productive rate 68%.
Fusing point: 171-172 ℃;
1H-NMR (CDCl
3): δ 7.78 (d, J=0.73Hz, 1H), 7.74 (d, J=0.91Hz, 1H), 7.18-7.32 (m, 5H), 6.95 (dd, J=8.79Hz, 2.56Hz, 1H), 6.88 (t, J=8.79Hz, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.42Hz, 6.13Hz, 1H), 3.58 (s, 2H), 3.42 (s, 2H), 3.08 (t, J=4.76Hz, 4H), 2.62 (t, J=4.67Hz, 4H), 2.42 (s, 6H).
Embodiment 38:(R)-and N-3-[3-fluoro-4-[4-[3-(N, N-diethyl methylene radical) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (38)
(186mg 0.5mmol) is dissolved in the dry acetonitrile (20ml), and (110mg, 1mmol), (92mg, 2mmol), as embodiment 37 described methods, the reaction times is 80 hours to formic acid, obtains product 94mg, productive rate 45.2% to add diethylamine hydrochloride with 36.
Fusing point: 106-107 ℃;
1H-NMR (CDCl
3): δ 7.78 (s, 1H), 7.73 (s, 1H), 7.18-7.30 (m, 5H), 6.94 (dd, J=8.96Hz, 2.38Hz, 1H), 6.87 (t, J=8.78Hz, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.33Hz, 6.04Hz, 1H), 3.58 (s, 2H), 3.55 (s, 2H), 3.05 (t, J=4.67Hz, 4H), 2.62 (t, J=4.48Hz, 4H), 2.54 (d, J=7.08Hz, 4H), 1.06 (t, J=7.04Hz, 6H).
Embodiment 39:(R)-and N-3-[3-fluoro-4-[4-[3-(1-pyrryl methylene radical) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (39)
(186mg 0.4mmol) is dissolved in the dry acetonitrile (20ml), and (71mg, 1mmol), (92mg, 2mmol), as embodiment 37 described methods, the reaction times is 24 hours to formic acid to add tetramethyleneimine with 36.Get product 126mg, productive rate 60.8%.
Fusing point: 161-163 ℃;
1H-NMR (CDCl
3): δ 7.79 (s, 1H), 7.75 (s, 1H), 7.22-7.33 (m, 5H), 6.95 (dd, J=8.88Hz, 2.28Hz, 1H), 6.88 (t, J=8.78Hz, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.33Hz, 6.04Hz, 1H), (3.68 s, 2), 3.57 (s, 2H), 3.08 (t, J=4.40Hz, 4H), 2.50-2.64 (m, 8H), 1.82 (brs, 4H).
Embodiment 40:(R)-and N-3-[3-fluoro-4-[4-[3-(1-hexahydropyridine methylene) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (40)
(186mg 0.4mmol) is dissolved in the dry acetonitrile (20ml), and (85mg, 1mmol), (92mg, 2mmol), as embodiment 37 described methods, the reaction times is 24 hours to formic acid to add hexahydropyridine with 36.Obtain product 181mg, productive rate 86%.
Fusing point: 165-166 ℃;
1H-NMR (CDCl
3): δ 7.79 (d, J=1.10Hz, 1H), 7.74 (d, J=0.92Hz, 1H), and 7.19-7.30 (m, 5H), 6.94 (dd, J=8.97Hz, 2.38Hz, 1H), 6.88 (t, J=8.79Hz, 1H), 5.04 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.33Hz, 6.22Hz, 1H), 3.57 (s, 2H), 3.48 (s, 2H), 3.08 (t, J=4.67Hz, 4H), 2.62 (t, J=4.67Hz, 4H), 2.48 (brs, 4H), 1.58 (m, 4H), 1.44 (m, 4H).
Embodiment 41:(R)-and N-3-[3-fluoro-4-[4-[3-(4-methyl isophthalic acid-piperazinyl methylene radical) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (41)
(186mg 0.4mmol) is dissolved in the dry acetonitrile (20ml), and (100mg, 1mmol), (92mg, 2mmol), as embodiment 37 described methods, the reaction times is 48 hours to formic acid to add methylpiperazine with 36.Get product 105mg, productive rate 48%.
Fusing point: 103-105 ℃;
1H-NMR (CDCl
3): δ 7.78 (s, 1H), 7.74 (s, 1H), 7.10-7.22 (m, 5H), 6.79-6.90 (m, 2H), 4.97 (m, 1H), 4.72 (m, 2H), 4.08 (t, J=9.15Hz, 1H), 3.80 (dd, J=9.15Hz, 6.40Hz, 1H), 3.50 (s, 2H), 3.44 (s, 2H), 2.98 (brs, 4H), 2.36-2.64 (m, 12H), 2.24 (s, 3H).
Embodiment 42:(R)-and N-3-[3-fluoro-4-[4-[3-(4-morpholinyl methylene radical) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (42)
(186mg 0.4mmol) is dissolved in the dry acetonitrile (20ml), and (87mg, 1mmol), (92mg, 2mmol), as embodiment 37 described methods, the reaction times is 80 hours to formic acid to add morpholine with 36.Get product 162mg, productive rate 76%.
Fusing point: 147-148 ℃;
1H-NMR (CDCl
3): δ 7.79 (s, 1H), 7.74 (s, 1H), 7.20-7.30 (m, 5H), 6.95 (dd, J=8.88Hz, 2.47Hz, 1H), 6.88 (t, J=8.87Hz, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.87 (dd, J=9.33Hz, 6.22Hz, 1H), 3.72 (t, J=4.67Hz, 4H), 3.57 (s, 2H), 3.48 (s, 2H), 3.08 (t, J=4.67Hz, 4H), 2.62 (t, J=4.58Hz, 4H), 2.44 (t, J=4.58Hz, 4H).
Embodiment 43:(R)-and N-3-[3-fluoro-4-[4-[3-(N-hydroxyl methyne) phenyl] methylene radical]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (43)
With 36 (186mg 0.4mmol) is dissolved in the mixed solvent of small amount of methanol and methylene dichloride, add oxammonium hydrochloride (139mg, 2mmol) and Anhydrous potassium carbonate (276mg 2mmol), is heated to 40 ℃ and reacted FLC (CH 2 hours
2Cl
2/ MeOH=20: monitoring reaction 1 (V/V)); Solvent evaporated, residue dissolves with methylene dichloride 50ml, and water 100ml washes, and water layer merges organic phase with methylene dichloride 25ml * 2 extractions, and this organic phase is washed with saturated aqueous common salt 200ml again, and anhydrous sodium sulfate drying then carries out column chromatography (CH
2Cl
2/ MeOH=25: 1 (V/V)) separate, use methyl alcohol at last, the mixed solvent recrystallization of methylene dichloride and ether (1: 2: 4 (V/V/V)) obtains product 163mg, productive rate 85%.
Fusing point: 186-187 ℃;
1H-NMR (CDCl
3): δ 8.14 (s, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.59 (s, 1H), 7.47 (m, 1H), 7.34-7.38 (m, 2H), 7.27 (dd, J=14.09Hz, 2.38Hz, 1H), 6.95 (dd, J=8.88Hz, 2.38Hz, 1H), 6.88 (t, J=8.87Hz, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.52Hz, 6.22Hz, 1H), 3.58 (s, 2H), 3.08 (t, J=4.76Hz, 4H), 2.64 (t, J=4.67Hz, 4H).
Embodiment 44:(R)-N-3-[3-fluoro-4-[4-(3-hydroxymethyl phenyl methylene radical)]-the 1-piperazinyl] phenyl-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-ketone (44)
(162mg, (V/V=1: 1), cryosel is bathed cooling, slowly adds NaBH 0.35mmol) to be dissolved in the mixed solvent (30ml) of methyl alcohol and methylene dichloride with 36
4(65mg 1.7mmol), adds, room temperature reaction 2 hours, TLC (CH
2Cl
2/ MeOH=15: monitoring reaction 1 (V/V)); Dilute hydrochloric acid is adjusted to neutrality, solvent evaporated, residue dissolves with methylene dichloride 50ml, wash with saturated sodium bicarbonate solution 100ml, water layer is used methylene dichloride 25ml * 2 extractions again, merges organic layer again, this organic layer more successively water 200ml wash, saturated aqueous common salt 200ml washes, and uses anhydrous sodium sulfate drying again, then carries out column chromatography (CH
2Cl
2/ MeOH=25: 1 (V/V)) separate, use methyl alcohol at last, the mixed solvent recrystallization of methylene dichloride and ether (1: 2: 4 (V/V/V)).Get product 149mg, productive rate 91%.
Fusing point: 179-180 ℃;
1H-NMR (CDCl
3): δ 7.79 (d, J=0.91Hz, 1H), 7.74 (d, J=1.10Hz, 1H), 7.23-7.36 (m, 5H), 6.95 (dd, J=8.88Hz, 2.42Hz, 1H), 6.88 (t, J=8.78Hz, 1H), 5.03 (m, 1H), 4.78 (m, 2H), 4.70 (s, 2H), 4.12 (t, J=9.15Hz, 1H), 3.88 (dd, J=9.43Hz, 6.12Hz, 1H), 3.58 (s, 2H), 3.08 (t, J=4.76Hz, 4H), 2.62 (t, J=4.67Hz, 4H).
Experimental example
Antibacterial activity in vitro is measured:
1. test method: adopt the agar doubling dilution to measure series compound of the present invention and positive control medicine vancomycin minimum inhibitory concentration (MIC) to the examination bacterial strain.In the agar plate surface that contains different pharmaceutical concentration, every some inoculation bacterium amount is about 10 to employing multiple spot inoculation instrument (DenleyA400) with microbionation
6CFU/ml is hatched 18-24 hour observations for 37 ℃, is the minimum inhibitory concentration (MIC value) of medicine to this bacterium with contained drug minimum concentration in the plate substratum of asepsis growth.
2. test strain: used test strain is the clinical separation pathogenic bacterium of collecting in the area, Sichuan year February in December, 2002 to 2004, use through conventional method is identified again after.Test-compound all adds the DMSO of 2ml earlier, can help it to dissolve fully well, adds aseptic double-distilled water again to desired concn; Vancomycin directly use distilled water can excellent dissolution to desired concn, adding the 20ml heating and melting in each adds the culture dish of soup is liquid MH substratum, makes that medicine final concentration in the culture dish is 8,4,2,1......0.002,0.001,0.0005ug/ml.
3. positive controls is LZ and vancomycin.
Wherein 22 carried out the external activity test, this series compound is to the MIC of test strain
50, MIC
90, and MIC
RangeThe results are shown in Table 2.
In 22 test-compounds, compound 3,4,6,8,11,12,13,16 all has better antibiotic vigor to try 20 strain gram-positive microorganisms as shown in Table 2, and is active suitable with vancomycin with contrast medicine LZ; The activity of compound 2,4,7,19 is better than positive control LZ and vancomycin.
This series compound of table 2 is to the MIC of experimental strain
50/ MIC
90
*The gold Portugal represents streptococcus aureus, and the lung chain is represented streptococcus pneumoniae, and the intestines ball is represented faecalis; Comprise the MSSA5 strain in streptococcus aureus 10 strains, the MRSA3 strain.
Antibacterial activity in vivo is measured:
1. experimental strain: the bacterium that is used for infection animal is streptococcus aureus 05-02, is the clinical separation pathogenic bacterium of collecting from the area, Chengdu in 2004～2005 years, and identifies again through the API method.
2. laboratory animal: select healthy Kunming mouse SPF level for use, body weight 18-22 gram, male and female half and half are provided by Sichuan Industrial Institute of Antibiotics animal reproduction chamber.Animal conformity certification number: No. the 005th, the real kinoplaszm pipe in river.
3. infect and the treatment experimental technique: laboratory animal is evenly divided into groups at random by sex, body weight, every group of 10 mouse, male and female half and half, give mouse peritoneal infectable infection bacterium liquid respectively, 0.5ml/ mouse, infected back 1 hour, that gives mouse oral administration gavage or intravenous injection different concns respectively is subjected to reagent liquid, every mouse 0.5ml/20g.The mouse of oral administration gavage is irritated stomach once in first administration after 4 hours again, observes the death condition of record mouse after the administration.Establish the infection control group simultaneously, record infects dead mouse number in back seven days.
4. Data Processing in Experiment: respectively be subjected to the reagent thing that the endogenous protective effect of experimental strain infecting mouse is calculated median effective dose ED by the Bliss method
50And 95% fiducial limit.Experimental result sees Table 3.
Test-compound has good therapeutic action to the infection of staphylococcus aureus mouse as shown in Table 3, and its interior curative effect is similar with vancomycin or better to LZ.
Antibacterial experiment result in the body of table 3 part of compounds
Pharmacokinetics test in the rat body:
Test-compound is a compound 2,4 and 8.Each compound adopts two kinds of route of administration (irritating stomach and intravenous injection), and gastric infusion adopts two dosage groups (10mg/kg and 50mg/kg), and intravenous injection dosage is 10mg/kg.Every group with 4 of healthy SD rats, male female half and half, body weight 220-280g.Test-results sees Table 4.
Give the C that low, high two dosage groups obtain to rat oral gavage
Max, AUC
0-tBe linear dependence (R with dosage
2＞0.81, P＜0.05).AUC with 10mg/kg dosage group
0-tMean value calculation, compound 2 is 61.5% at the intravital absolute bioavailability of rat.
Give the C that low, high two dosage groups obtain to rat oral gavage
Max, AUC
0-tBe linear dependence (R with dosage
2=0.7793, P＜0.05).AUC with 10mg/kg dosage group
0-tMean value calculation, compound 4 is 43.8% at the intravital absolute bioavailability of rat.
Give the C that low, high two dosage groups obtain to rat oral gavage
Max, AUC
0-tBe linear dependence (R with dosage
2=0.8863, P＜0.05).AUC with 10mg/kg dosage group
0-tMean value calculation, compound 8 is 62.7% at the intravital absolute bioavailability of rat.
Pharmacokinetics test-results in the rat body of table 4 part of compounds
| Compound | Route of administration | Dosage mg/kg | C max μg/ml | T max h | t 1/2β h | AUC 0-t μg·h/ml | MRT h | CL/F ml/min·kg |
| 2 | Irritate stomach | 10 | 3.24 ±0.68 | 1.4 ±0.8 | 2.36±0.56 | 16.10±5.98 | 3.63±0.94 | 11.7±4.99 |
| Irritate stomach | 50 | 10.77 ±2.15 | 2.3 ±0.5 | 5.34±2.56 | 74.5±21.9 | 7.68±1.91 | 11.3±3.58 | |
| Quiet notes | 10 | - | - | 2.95±0.46 | 26.16±8.24 | 3.41±0.77 | 6.98±2.73 | |
| 4 | Irritate stomach | 10 | 1.20 ±0.47 | 0.75 ±0.29 | 3.40±0.24 | 3.10±0.46 | 2.99±0.77 | 54.4±8.0 |
| Irritate stomach | 50 | 2.32 ±0.77 | 1.0± 0.0 | 4.67±0.98 | 18.1±6.5 | 7.17±1.23 | 49.0±17.5 | |
| Quiet notes | 10 | - | - | 3.52±0.52 | 7.08±1.07 | 1.94±0.33 | 23.9±4.24 | |
| 8 | Irritate stomach | 10 | 3.04 ±0.12 | 0.88 ±0.25 | 2.76±0.52 | 16.4±3.5 | 4.70±0.73 | 10.5±2.5 |
| Irritate stomach | 50 | 10.7± 3.0 | 1.9 ±1.0 | 8.60±3.15 | 85.8±20.0 | 11.8±3.9 | 8.86±3.03 | |
| Quiet notes | 10 | - | - | 2.95±0.46 | 26.2±8.2 | 3.41±0.77 | 6.98±2.73 |
Claims (10)
1. the oxazolidone compounds that contains triazol radical or its pharmacy acceptable salt with following structural formula (I):
Wherein, R
1And R
2Be hydrogen or fluorine separately;
N is 1;
M is 1;
R
3Fragrant heterocyclic radical for aryl, fragrant heterocyclic radical or the replacement of aryl, replacement; The aryl of described replacement and the fragrant heterocyclic radical of replacement be respectively aryl and fragrant heterocyclic radical randomly be selected from halogen atom, alkyl, alkoxyl group, acyloxy ,-OH ,-NH
2,-NO
2,-NHAc ,-CH
2NR
4R
5,-CH
2OR
6,-CH=NR
7Group replace; Wherein, R
4And R
5Be respectively hydrogen or alkyl, perhaps R
4And R
5Form the saturated or unsaturated ring system of 4-10 unit with nitrogen-atoms; R
6Be hydrogen or alkyl; R
7Amido for hydroxyl, amino, alkoxyl group or alkyl replacement;
Wherein, described alkyl is a methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, the 1-methyl butyl, the 2-methyl-propyl, hexyl, isohexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, the 2-methyl butyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl or 1-ethyl-2-methyl-propyl;
Described aryl is phenyl, tolyl, xylyl, xenyl, naphthyl, indenyl, anthryl or phenanthryl;
Described fragrant heterocyclic radical is furyl, thienyl, pyrryl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl or tetrazyl.
2. triazol radical De oxazolidone compounds or its pharmacy acceptable salt of containing as claimed in claim 1 is characterized in that described alkyl is methyl, ethyl, propyl group, sec.-propyl or butyl; Described aryl is a phenyl or naphthyl; Described fragrant heterocyclic radical is thienyl, furyl, pyridyl, oxazolyl, isoxazolyl or thiazolyl.
3. triazol radical De oxazolidone compounds or its pharmacy acceptable salt of containing as claimed in claim 2 is characterized in that described alkyl is methyl, ethyl or propyl group; Described aryl is a phenyl; Described fragrant heterocyclic radical is thienyl, furyl or pyridyl.
4. as each described triazol radical De oxazolidone compounds or its pharmacy acceptable salt of containing in the claim 1～3, it is characterized in that described R
1Be fluorine; R
2Be hydrogen.
5. triazol radical De oxazolidone compounds or its pharmacy acceptable salt of containing as claimed in claim 4 is characterized in that described R
3Be the 4-nitrophenyl, the 3-nitrophenyl, the 2-nitrophenyl, the 4-aminophenyl, the 3-aminophenyl, the 2-aminophenyl, the 2-furyl, the 3-furyl, 5-methyl-2-furyl, 5-chloro-2-furyl, the 2-thienyl, the 3-thienyl, 5-bromo-2-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, the 2-pyridyl, the 4-pyridyl, the 3-pyridyl, 5-nitro-2-furyl, the 4-hydroxy phenyl, the 3-hydroxy phenyl, 4-(N, N-dimethylated methylene base) phenyl, 4-(N, N-diethyl methylene radical) phenyl, 4-(1-pyrryl methylene radical) phenyl, 4-(1-hexahydropyridine methylene) phenyl, 4-(4-morpholinyl methylene radical) phenyl, 4-(4-thiomorpholine methylene) phenyl, 4-(4-methyl isophthalic acid-piperazinyl methylene radical) phenyl, the 4-hydroxymethyl phenyl, 4-(N-hydroxyl methyne) phenyl, 4-(the amino methyne of N-) phenyl, 3-(N, N-dimethylated methylene base) phenyl, 3-(N, N-diethyl methylene radical) phenyl, 3-(1-pyrryl methylene radical) phenyl, 3-(1-hexahydropyridine methylene) phenyl, 3-(4-methyl isophthalic acid-piperazinyl methylene radical) phenyl, 3-(4-morpholinyl methylene radical) phenyl, 3-(N-hydroxyl methyne) phenyl or 3-hydroxymethyl phenyl.
6. as claim 1 or 5 described triazol radical De oxazolidone compounds or its pharmacy acceptable salts of containing, it is characterized in that described pharmacy acceptable salt is the salt that contains triazol radical De oxazolidone compounds and hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, ethyl sulfonic acid, aspartic acid or L-glutamic acid.
7. the oxazolidone compounds that contains triazol radical or its pharmacy acceptable salt with following structural formula (I):
Wherein, n is 1; M is 1; R
1Be fluorine; R
2Be hydrogen; R
3Be 4-benzyloxy phenyl, 3-benzyloxy phenyl, 4-formyl radical phenyl, 3-formyl radical phenyl or 4-(acetoxyl group methylene radical) phenyl.
8. one kind as claim 4 or 7 described preparation methods with oxazolidone compounds that contains triazol radical of following structural formula (II), it is characterized in that,
This method comprises: in polar aprotic solvent, (R)-3-(3-fluoro-4-piperazinyl phenyl)-5-(1,2,3-triazoles-1-ylmethyl) oxazolidine-2-keto hydrochloride and R
3CHO reaction, what obtain structural formula (II) contains triazol radical De oxazolidone compounds; R wherein
3Definition as described in claim 4 or 7;
Or in polar aprotic solvent, in the presence of alkali, (R)-3-(3-fluoro-4-piperazinyl phenyl)-5-(1,2,3-triazol-1-yl methyl) oxazolidine-2-keto hydrochloride and the benzyl chlorine of replacement or the benzyl bromine reaction of replacement, what obtain structural formula (II) contains triazol radical De oxazolidone compounds.
9. preparation method according to claim 8 is characterized in that, this method further comprises: resulting triazol radical De oxazolidone compounds, its R of containing
3On active function groups further the reduction of reduction amination, the aldehyde radical of catalytic hydrogenation, aldehyde radical and the various secondary amine of the reduction reaction by nitro, benzyloxy or aldehyde radical become the oxime reaction to derive to obtain the different triazol radical De oxazolidone compounds that contain.
10. each described oxazolidone compounds or its pharmacy acceptable salt purposes in the medicine of preparation treatment infectious diseases that contains triazol radical of a claim 1 to 7.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1206410A (en) * | 1996-02-26 | 1999-01-27 | 法玛西雅厄普约翰美国公司 | Azolyl piperazinyl phenyl oxazolidinone antimicrobials |
| WO2001094342A1 (en) * | 2000-06-05 | 2001-12-13 | Dong A Pharm. Co., Ltd. | Novel oxazolidinone derivatives and a process for the preparation thereof |
| CN1510032A (en) * | 2002-12-25 | 2004-07-07 | 中国科学院上海药物研究所 | Oxazolidone compound, preparing method and use thereof |
| CN1594298A (en) * | 2003-09-12 | 2005-03-16 | 中国科学院上海药物研究所 | Pyridine ring containing oxazolidinone compounds and preparation process and application thereof |
| WO2005058886A1 (en) * | 2003-12-18 | 2005-06-30 | Dong-A Pharm.Co.,Ltd. | Novel oxazolidinone derivatives |
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| GB0009803D0 (en) * | 2000-04-25 | 2000-06-07 | Astrazeneca Ab | Chemical compounds |
| WO2006035283A1 (en) * | 2004-09-27 | 2006-04-06 | Ranbaxy Laboratories Limited | Oxazolidinone derivatives as antimicrobials |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1206410A (en) * | 1996-02-26 | 1999-01-27 | 法玛西雅厄普约翰美国公司 | Azolyl piperazinyl phenyl oxazolidinone antimicrobials |
| WO2001094342A1 (en) * | 2000-06-05 | 2001-12-13 | Dong A Pharm. Co., Ltd. | Novel oxazolidinone derivatives and a process for the preparation thereof |
| CN1510032A (en) * | 2002-12-25 | 2004-07-07 | 中国科学院上海药物研究所 | Oxazolidone compound, preparing method and use thereof |
| CN1594298A (en) * | 2003-09-12 | 2005-03-16 | 中国科学院上海药物研究所 | Pyridine ring containing oxazolidinone compounds and preparation process and application thereof |
| WO2005058886A1 (en) * | 2003-12-18 | 2005-06-30 | Dong-A Pharm.Co.,Ltd. | Novel oxazolidinone derivatives |
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Address after: No. 1, Heng Fei Road, Nanjing economic and Technological Development Zone, Jiangsu Province, China: 210038 Patentee after: Chang'ao Science and Technology of Medical Industry Co., Ltd., Nanjing Address before: Jiangsu province Nanjing city Qinhuai District dajiaochang road 30, zip code: 210007 Patentee before: Chang'ao Science and Technology of Medical Industry Co., Ltd., Nanjing |
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Granted publication date: 20080730 Termination date: 20120220 |