CN101619061B - Cyanopyridyl-replaced oxazolidinone compound - Google Patents
Cyanopyridyl-replaced oxazolidinone compound Download PDFInfo
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- CN101619061B CN101619061B CN200910013060.6A CN200910013060A CN101619061B CN 101619061 B CN101619061 B CN 101619061B CN 200910013060 A CN200910013060 A CN 200910013060A CN 101619061 B CN101619061 B CN 101619061B
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- 0 CC(NC[C@@](CN1c2ccc(*)c(I)c2)OC1=O)=O Chemical compound CC(NC[C@@](CN1c2ccc(*)c(I)c2)OC1=O)=O 0.000 description 7
- GOJJPJCUSDMTAT-SSDOTTSWSA-N CC(NC[C@@H](CCl)OC(C)=O)=O Chemical compound CC(NC[C@@H](CCl)OC(C)=O)=O GOJJPJCUSDMTAT-SSDOTTSWSA-N 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N O=Cc1ccccc1 Chemical compound O=Cc1ccccc1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- PHFWZIAEQLVDMM-CEXMDJMXSA-N O[C@@H](C/N=C/c1ccccc1)CCl Chemical compound O[C@@H](C/N=C/c1ccccc1)CCl PHFWZIAEQLVDMM-CEXMDJMXSA-N 0.000 description 1
Abstract
The invention relates a cyanopyridyl-replaced oxazolidinone compound with a general formula (I); wherein, R1 is hydrogen, fluorine, chlorine or trifluoromethyl and R2 is shown in the specification. The invention also provides a preparation method of the compound shown in the general formula (I) and medicinal salts of the compound and an application thereof for curing microbial infections, in particular to bacterial infection diseases. Preliminary antibacterial activity tests in vitro show that the compound of the invention has better antibacterial activity compared with linezolid and obvious antibacterial activity to drug-resistant bacteria.
Description
Technical field:
The present invention relates to medicinal chemistry art, particularly a kind of cyanopyridine-based oxazolidinone compounds or its pharmacy acceptable salt, and containing they pharmaceutical composition, preparation method and application.
Background technology:
In recent decades, the abuse of antibacterials causes the mortality ratio of infectious diseases sharply to rise.Clinically, the resistance of cell increases year by year, causes some antibacterials curative effects to reduce, even invalid, as methicillin-resistant golden staphylococci, methicillin-resistant epidermis Portugal Portugal coccus and vancomycin-resistant enterococcus etc.; Some non-pathogenic bacterias become conditioned pathogen, as Bacillus proteus, Pseudomonas aeruginosa etc.The formation and development of all these Resistant strain, result in the difficulty in treatment, and present antibacterials can not meet needs clinically, is badly in need of the antibacterials with novel mechanism of action clinically.
Oxazolidinone antibacterials act on the commitment of protein synthesis, seldom occur cross resistance with other antimicrobial drug.The DuP721 of E.I.Du Pont Company's report in 1987 is lead compound, Pu Qiang company of the U.S. has successfully developed the one oxazolidinone antiseptic-germicide---linezolid (Linezolid), be used for the treatment of the gram positive bacteria infection of penicillin resistant, Macrolide and other antibacterials, this medicine goes on the market in April, 2000 in U.S.'s approval.
Contain cyanopyridine-based replacement oxazolidinone compounds there are no people's preparation in prior art, and anti-microbial activity particularly antimicrobial agent activity research is carried out to it.
Summary of the invention
The present invention relates to general formula I oxazolidinone compounds or its pharmacy acceptable salt,
Wherein,
R
1for hydrogen, fluorine, chlorine and trifluoromethyl;
R
2for
R
3for NR
4r
5;
R
4and R
5identical or different, be separately selected from hydrogen, amino, C
1-C
10alkyl, C
3-C
7cycloalkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, they can by the individual identical or different R of 1-3
6optional replacement;
Or R
4and R
5form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl together with the nitrogen-atoms connected with them, described heterocyclic radical and heteroaryl except with R
4and R
5outside the nitrogen-atoms connected, the heteroatoms of N, O and S can be selected from containing 1-4, except R
4and R
5outside the nitrogen-atoms connected, described heterocyclyl comprises 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl can by 1 ~ 3 identical or different R
6optional replacement;
R
6for C
1-C
4alkyl, C
1-C
4alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group and nitro.
The present invention preferably relates to the compound of Formula I or its pharmacy acceptable salt that are defined as follows,
Wherein, R
1for fluorine;
R
2for
R
3for NR
4r
5;
R
4and R
5identical or different, be separately selected from hydrogen, amino, C
1-C
10alkyl, C
3-C
7cycloalkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, they can by the individual identical or different R of 1-3
6optional replacement;
Or R
4and R
5form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl together with the nitrogen-atoms connected with them, described heterocyclic radical and heteroaryl except with R
4and R
5outside the nitrogen-atoms connected, the heteroatoms of N, O and S can be selected from containing 1-4, except R
4and R
5outside the nitrogen-atoms connected, described heterocyclyl comprises 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl can by 1 ~ 3 identical or different R
6optional replacement;
R
6for C
1-C
4alkyl, C
1-C
4alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group and nitro.
The present invention preferably also relates to the compound of Formula I or its pharmacy acceptable salt that are defined as follows,
Wherein,
R
1for fluorine;
R
2for
R
3for NR
4r
5;
R
4and R
5identical or different, be separately selected from hydrogen, amino, C
1-C
4alkyl and C
3-C
6cycloalkyl, they can by the individual identical or different R of 1-3
6optional replacement;
Or R
4and R
5form guanidine radicals and 5-10 unit heterocyclic radical together with the nitrogen-atoms connected with them, described heterocyclic radical except with R
4and R
5outside the nitrogen-atoms connected, the heteroatoms of N, O and S can be selected from containing 1-2, except R
4and R
5outside the nitrogen-atoms connected, described heterocyclyl comprises 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical can by 1 ~ 3 identical or different R
6optional replacement;
R
6for C
1-C
4alkyl.
The present invention particularly preferably relates to the compound of Formula I or its pharmacy acceptable salt that are defined as follows,
Wherein,
R
1for fluorine;
R
2for
R
3for NR
4r
5;
R
4and R
5identical or different, be separately selected from hydrogen, amino and C
1-C
4alkyl;
Or R
4and R
5morpholine-4-base, piperidin-1-yl, 4-methylpiperazine-1-yl and pyrrolidin-1-yl is formed together with the nitrogen-atoms connected with them;
R
3be preferably dimethylamino, methylethylamino, morpholine-4-base, piperidin-1-yl, 4-methylpiperazine-1-yl and pyrrolidin-1-yl.
The present invention very particularly preferably relates to the compound of Formula I or its pharmacy acceptable salt that are defined as follows,
1) (S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide;
2) (S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
The present invention particularly preferably relates to the compound of Formula I or its pharmacy acceptable salt that are defined as follows,
(S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
Scope of the present invention also comprises the hydrate forms of the compounds of this invention, and it contains the water of different amount, as monohydrate, semihydrate, a semihydrate and dihydrate.
According to some usual methods in field belonging to the present invention, compound of Formula I of the present invention can generate its pharmacy acceptable salt with acid.Acid can comprise mineral acid or organic acid, the salt formed with following acid is particularly preferred: hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, 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, toluenesulphonic acids, Phenylsulfonic acid, naphthene sulfonic acid, trifluoroacetic acid and aspartic acid.
In addition, the present invention also comprises the prodrug of the compounds of this invention.According to the present invention, prodrug is the derivative of formula I, they self may have more weak activity or even not have activity, but upon administration, (such as by metabolism, solvolysis or other mode) is converted to corresponding biologically active form in physiological conditions.
Be understandable that, any racemize of the compounds of this invention, optically active, polymorphic forms or its mixture are contained in the present invention, and they possess useful quality as herein described.Compound of Formula I of the present invention contains the C-5 position of chiral centre (oxazolidone ring), therefore there is two kinds of enantiomorphs or the racemic mixture of the two.The present invention relates to the two kinds of enantiomorphs possessing useful quality described herein and the mixture containing two kinds of isomer.
Unless otherwise noted, term used herein " alkyl " refers to the alkyl of straight or branched, " cycloalkyl " refers to substituted or unsubstituted cycloalkyl, " thiazolinyl " refers to the thiazolinyl of straight or branched, " alkynyl " refers to the alkynyl of straight or branched, 5-10 unit heteroaryl comprises and is selected from N containing one or more, the heteroatoms of O and S, wherein the ring-type system of each heteroaryl can be monocycle or many rings, ring-type system is aromaticity, altogether containing 5-10 atom, such as imidazolyl can be enumerated, pyridyl, pyrimidyl, pyrazolyl, (1, 2, 3)-and (1, 2, 4)-triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrryl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl-, benzothiazolyl, indyl, quinolyl etc., 5-10 unit heterocyclic radical comprises containing one or more heteroatoms being selected from N, O and S, wherein the ring-type system of each heteroaryl can be monocycle or many rings, but be nonaromatic, ring-type system is altogether containing 5-10 atom, optionally can comprise 1 or 2 carbon-carbon double bond or carbon-carbon triple bond, such as pyrrolidyl, morpholinyl, piperazinyl, piperidyl, thiazolinyl etc. can be enumerated.
The present invention also comprises pharmaceutical composition, and said composition comprises compound of Formula I and their pharmacy acceptable salts and/or solvate as activeconstituents and pharmaceutically acceptable carrier; Compound of the present invention can use with other active ingredient combinations, such as, as long as they do not produce other disadvantageous effect, anaphylaxis.
Carrier for pharmaceutical composition of the present invention is available common type in pharmaceutical field, comprising: the tackiness agent, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives etc. of oral preparations; The sanitas, solubilizing agent, stablizer etc. of injectable formulation; The matrix, thinner, lubricant, sanitas etc. of topical formulations.Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable under stomach condition, can be mixed with enteric coated tablets.
The present invention also comprises its application in the medicine for the preparation for the treatment of Mammals infected by microbes particularly bacteriological infection.This application method gives the compound of Formula I of significant quantity, can compound is oral to Mammals in pharmaceutical composition, parenteral, transdermal or topical.
Owing to there is anti-microbial infection particularly antibacterial activity according to general formula I oxazolidinone compounds of the present invention, therefore, it can be used as the medicine that preparation treatment mammalian bacterial infects, compound according to the present invention can be used as activeconstituents for the preparation for the treatment of mammalian bacterial infect method, comprise the patient significant quantity suffering from or easily suffer from this disease according to compound of the present invention.
The precise volume of the compounds of this invention for the treatment of microorganism particularly needed for bacteriological infection will be different because of curee, depend on the kind of curee, age and general condition, the seriousness of institute's disease therapy, specific compound used and administering mode, the approach and frequency etc. of such as administration.Those of ordinary skill in the art only utilize normal experiment method can determine suitable significant quantity.
The dosage of compound can from about 0.1 ~ 100mg/kg body weight every day, preferably 1 ~ 50mg/kg body weight/day.Be understandable that, dosage can because of the demand of patient, the seriousness of the bacteriological infection for the treatment of and the specific compound that uses and different.And be understandable that, the initial dosage of institute's administration can increase and exceeds the upper limit, and object reaches rapidly desired blood level, or initial dosage can be less than optimum value, and every per daily dose can increase gradually at treatments period, and this depends on concrete situation.If necessary, every per daily dose also can be divided into multiple dose administration, such as every day 2-4 time.
Mammals represents human or animal.
Activeconstituents, namely the amount of compound according to the present invention in pharmaceutical composition and unit dosage thereof can be different, depends on application-specific, the effect of specific compound and desired concn.Generally speaking, the content of activeconstituents will between 0.5% ~ 90%, by the total weight of composition.
In conjoint therapy, the compounds of this invention and other compound can by simultaneously or doses at intervals, and at the same time during administration, the compounds of this invention and other compounds can be bonded in single pharmaceutical composition or in the composition separated.
Synthetic route A below, B and C describe the preparation of compound of Formula I of the present invention, and all raw materials are all methods by describing in these schematic diagram, prepared by the method known by organic chemistry filed those of ordinary skill or commercially available.Whole finalization compound of the present invention is all method by describing in these schematic diagram or is prepared by similar method, and these methods are that organic chemistry filed those of ordinary skill is known.The whole variable factors applied in these schematic diagram are as definition hereafter or as the definition in claim.
According to compound of Formula I of the present invention, in route A and route B, R
1for hydrogen, fluorine, chlorine and trifluoromethyl; R
3for NR
4r
5; R
4and R
5identical or different, be separately selected from hydrogen, amino, C
1-C
10alkyl, C
3-C
7cycloalkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, they can by the individual identical or different R of 1-3
7optional replacement; Or R
4and R
5form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl together with the nitrogen-atoms connected with them, described heterocyclic radical and heteroaryl except with R
4and R
5outside the nitrogen-atoms connected, the heteroatoms of N, O and S can be selected from containing 1-4, except R
4and R
5outside the nitrogen-atoms connected, described heterocyclyl comprises 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl can by 1 ~ 3 identical or different R
6optional replacement; R
6for C
1-C
4alkyl, C
1-C
4alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group and nitro.
The synthesis of route A Compound I-i and I-ii
The synthesis of route B Compound I-iii and I-iv
In route A, with R
1replace aniline (1) be starting raw material, through with methyl-chloroformate generation acylation reaction after, obtain R
1the phenylcarbamate (2) replaced, obtains 4-ethanoyl-3-Fluorophenylamino methyl-formiate (3) of replacement then with Acetyl Chloride 98Min. generation Friedel-Crafts reaction.Under trimethyl carbinol lithium exists, compound 3 and S-N-[2-(acetoxyl group)-3-chloropropyl] ethanamide (4) react, obtained compound N-[[(5S)-3-(4-ethanoyl-3-R
1-phenyl)-2-oxo-1,3-oxazolidine-5-base] methyl] ethanamide (5).Under hexamethyldisilazane exists, compound 5 and propane dinitrile react obtained compound 6, and compound 6 and DMF dimethylacetal (DMF-DMA) react, and obtain compound 7.Compound 7 and ammoniacal liquor generation ring-closure reaction, obtained compound of Formula I I-i (works as R
3for-NH
2time).Compound I-the ii that Compound I-i obtains general formula I through diazotization, bromo, substitution reaction (works as R
3as defined in the claims, but-NH
2except).
In route B, compound 5 and DMF-DMA react, obtained compound 9.Compound 9 and propane dinitrile generation ring-closure reaction, obtained compound of Formula I I-iii (works as R
3for-NH
2time).Compound I-iii obtains Compound I-iv (work as R through diazotization, bromo, substitution reaction
3as defined in the claims, but-NH
2except).
In route A; the preparation of compound 4 is as shown in route C; with (S)-epoxy chloropropane for starting raw material, through reacting with phenyl aldehyde, ammoniacal liquor and the obtained chloro-2-propanol hydrochloride of (S)-1-amino-3-after acid hydrolysis, then obtain with diacetyl oxide generation acylation reaction.
The synthesis of route C compound 4
Carried out antibacterial activity in vitro research to compound of the present invention, result is as follows:
1) the degerming rear M-H meat soup two-fold dilution of test sample becomes a series of concentration, and maximum concentration is 128mg/L.Often arrange in the 12nd hole at 96 micropore dilution plates and add 100 μ LM-H broth cultures as blank, the 11st hole adds 50 μ LM-H meat soups, adds 50 μ L sample test liquids successively according to from low paramount order from the 10th hole to the 1st hole.
The appropriate tested bacterium of picking and reference culture are seeded in Mueller-Hinton (M-H) nutrient broth medium of its growth applicable, 16-18h is cultivated in 37 DEG C, bacterium liquid physiological saline corrected concentrations to 0.5 Maxwell after growth is than turbid standard, use M-H meat soup 1: 100 to dilute again, this liquid is as supplying examination bacterium liquid.Then inoculate 50 μ L test organisms liquid in 1st ~ 11 holes, jolting mixing is placed on and is lined with in the square tray anth cap of wet gauze, cultivates 18-20h for 37 DEG C.
Observations under the light source having black background, has in the hole of bacteria growing to have bottom diffusivity muddiness or hole and precipitates in clasp sample, without this phenomenon in the hole of asepsis growth.Lowest concentration of drug contained in the hole of asepsis growth is minimum inhibitory concentration (MIC).Test-results is in Table 1-3.
Table 1 embodiment 1 and 2 compound is to the anti-microbial activity MIC value (ug/mL) of S. aureus L-forms
| ATCC-25923 | SA2 | SA3 | SA4 | SA5 | MRSA2 * | MRSA7 | MRSA8 | |
| Linezolid | 4 | 4 | 4 | 4 | 2 | 2 | 4 | 4 |
| Embodiment 1 compound | 2 | 2 | 2 | 2 | 2 | 2 | 1 | 2 |
| Embodiment 2 compound | 1 | 2 | 1 | 1 | 2 | 2 | ＜0.25 | ＜0.25 |
Note: SA is streptococcus aureus;
*mRSA is methicillin resistant staphylococcus aureus
Table 2 embodiment 1 and 2 compound is to the anti-microbial activity MIC value (ug/mL) of streptococcus pneumoniae
| ATCC-25923 | SPN2 | SPN11 | SPN22 | PRSP3 | PRSP4 | |
| Linezolid | 4 | ＜0.5 | 1 | 4 | ＜0.5 | ＜0.5 |
| Embodiment 1 compound | 1 | ＜0.5 | ＜0.5 | 1 | ＜0.5 | ＜0.5 |
| Embodiment 2 compound | 1 | 2 | ＜0.5 | 1 | 1 | ＜0.5 |
Note: SPN is streptococcus pneumoniae, and PRSP is penicillin-fast streptococcus pneumoniae
Table 3 embodiment 1 and 2 compound is to enterococcal anti-microbial activity MIC value (ug/mL)
| ATCC-25923 | ATCC-25922 | Efa6 | Efa7 | Efm1 | Efm3 | |||
| Linezolid | 2 | 32 | 1 | 1 | 1 | 1 | 4 | 1 |
| Embodiment 1 compound | 1 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | ＜0.25 |
| Embodiment 2 compound | 1 | 2 | 0.5 | 1 | 0.5 | 1 | 1 | ＜0.25 |
Note: Efa is enterococcus faecalis; Efm is faecium
Preliminary antibacterial activity in vitro test result shows, the compound in the present invention has the anti-microbial activity more more excellent than linezolid, and remarkable to resistant organism anti-microbial activity.
Embodiment:
Following examples are intended to set forth instead of limit the scope of the invention.The proton nmr spectra of compound measures with Bruker ARX-300, and mass spectrum Agilent 1100 LC/MSD measures; Agents useful for same is analytical pure or chemical pure.
Embodiment 1 (S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
The preparation of the chloro-2-propanol hydrochloride of step 1 (S)-1-amino-3-
Phenyl aldehyde 59.0g (0.56mol) is dissolved in ethanol 150ml, ammoniacal liquor 58.0ml (0.55mol) is dripped in reaction solution, stir, in reaction solution, drip (S)-epoxy chloropropane 58ml (0.88mol), control rate of addition and keep temperature of reaction lower than 40 DEG C.Drip and finish, 35-40 DEG C of reaction 6h, then reaction solution is down to room temperature and continues reaction 12h.Decompression steams most of solvent, adds toluene 100ml.Stir, solution is risen to 35-40 DEG C, instillation aqueous hydrochloric acid (68ml hydrochloric acid, 77ml water), drip and finish, 35-40 DEG C is stirred 3h.Leave standstill, point water-yielding stratum, organic layer is washed, combining water layer.Add ethanol 40mL, remove ethanol under reduced pressure, repeatedly add ethanol and steam except ethanol.Residual solution is in-18 DEG C of freeze overnight, and separate out white solid, suction filtration, washes with cold a small amount of ethanol, vacuum-drying, obtains (S)-1-amino-3-chloro-2-propanol hydrochloride 43g, yield 52.7%
The preparation of step 2 S-N-[2-(acetoxyl group)-3-chloropropyl] ethanamide (4)
Add in methylene dichloride 100mL by (S)-1-amino-3-chloro-2-propanol hydrochloride 40g (0.27mol), diacetyl oxide 60ml (0.62mol), control temperature drips pyridine 28ml (0.34mol) at 35-40 DEG C.Drip and finish, at this temperature, react 5h, then room temperature reaction 14h.Reaction is finished, and adds water 50mL in reaction solution, and ice-water bath cools, and instills 47% wet chemical 800mL, controls temperature of reaction lower than 10 DEG C.Drip and finish, dichloromethane extraction, merge organic layer, washing, anhydrous sodium sulfate drying.Evaporate to dryness, obtains solid, suction filtration, and octane-iso washs, and obtain solid N-[(2S)-2-(acetoxyl group)-3-chloropropyl] ethanamide 43.7g, yield is 88.3%.
The preparation of step 3 (3-fluorophenyl) Urethylane
3-fluoroaniline 20.0g (0.18mol) is added in methylene dichloride 120ml, add pyridine 14.2g (0.18mol), stir, in reaction solution, drip the dichloromethane solution 30mL of methyl-chloroformate 18.7g (0.2mol), control rate of addition and make temperature of reaction lower than 40 DEG C.Drip and finish, room temperature reaction 5h.Reaction is finished, and washed reaction liquid, organic over anhydrous dried over sodium sulfate, evaporate to dryness, obtains white solid 30.1g, yield 98.8%.
The preparation of step 4 (4-ethanoyl-3-fluorophenyl) Urethylane (V)
(3-fluorophenyl) Urethylane (VI) 16.9g (0.1mol) is added in three-necked bottle, add aluminum chloride 40.0g (0.3mol), stirring is warming up to 35-40 DEG C, drips Acetyl Chloride 98Min. 15.7g (0.2mol) in reaction flask.Drip and finish, be warmed up to 50-60 DEG C of reaction 3h.Reaction solution is poured in appropriate trash ice, stir, suction filtration, filter cake 80% recrystallizing methanol, obtain (4-ethanoyl-3-fluorophenyl) Urethylane (V) 14.9g, yield 70.8%.
The preparation of step 5 S-N-[[3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1,3-oxazolidine-5-base] methyl] ethanamide
Method 1: add in dry DMF 100mL by compound (4-ethanoyl-3-fluorophenyl) Urethylane (V) 21.1g (V, 0.1mol), stirring and dissolving, adds anhydrous methanol 8.14mL (0.2mol).At 20 DEG C, in reaction solution, drip the dry DMF 100mL solution of trimethyl carbinol lithium 23.7g (0.3mol), control rate of addition, maintain temperature of reaction lower than 24 DEG C.Drip and finish, reaction solution is chilled to 0-5 DEG C, adds N-[(2S)-2-(acetoxyl group)-3-chloropropyl] ethanamide 34.6g (0.2mol).Reaction solution is slowly warming up to 20-25 DEG C of reaction 21h.Reaction is finished, and drips saturated ammonium chloride solution 100mL in reaction solution, stirs; add 200mL water and 200mL methylene dichloride again, separatory, water layer dichloromethane extraction; merge organic layer, saturated nacl aqueous solution is washed, dry; evaporated under reduced pressure solvent, obtains oily matter, recrystallizing methanol; obtain S-N-[[3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1; 3-oxazolidine-5-base] methyl] ethanamide 10.2g, yield 34.7%, [M+H
+]: 295.5.
Method 2: trimethyl carbinol lithium 18.3g (0.23mol) is added in 100mL tetrahydrofuran (THF); be cooled to 0 ~ 5 DEG C; absolute methyl alcohol 6.3mL (0.15mol) is dripped in solution; drip Bi Jixu and stir 1h, then add the acetonitrile 100mL solution of N-[(2S)-2-(acetoxyl group)-3-chloropropyl] ethanamide 3.0g (0.15mol) and (4-ethanoyl-3-fluorophenyl) Urethylane 16.3g (0.08mol).Reaction solution stirs 0.5h in 0 ~ 5 DEG C, is then warming up to 18 DEG C of stirring reaction 18h.Reaction is finished, and drips glacial acetic acid 9.0mL (0.15mol) in reaction solution, controls rate of addition, makes reacting liquid temperature lower than 25 DEG C, drips to finish to stir 0.5h.Evaporated under reduced pressure reaction solvent; 50ml water is added in resistates; be stirred to and disperse completely; suction filtration, washing, ethanol filter wash cake; obtain yellow solid S-N-[[3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1; 3-oxazolidine-5-base] methyl] ethanamide 15.1g, yield 66.5%, [M+H
+]: 295.5.
The preparation of step 6:S-N-[[3-[4-(1,1-dicyano-1-propylene-2-base)-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-base] methyl] ethanamide
To in 50ml glacial acetic acid, drip hexamethyldisilazane 4.3ml (20.4mmol), drip and finish, be warming up to 65-70 DEG C and stir 30min.S-N-[[3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1 is dripped in this reaction solution; 3-oxazolidine-5-base] methyl] the 25ml glacial acetic acid solution of ethanamide and propane dinitrile 2.3g (34mmol); drip and finish, 65-70 DEG C of committee 48h.Reaction is finished, and adds 100mL water, dichloromethane extraction in reaction solution, merge organic layer, washing, saturated nacl aqueous solution is washed, anhydrous magnesium sulfate drying, solvent evaporated, must revolve solvent evaporated, obtains S-N-[[3-[4-(1,1-dicyano-1-propylene-2-base)-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-base] methyl] ethanamide 5.9g, yield 51.2%, [M+H
+]: 343.1.
The preparation of step 7S-N-[[3-[4-[1,1-dicyano-4-(dimethylamino)-1,3-butadiene-2-base]-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-base] methyl] ethanamide
By S-N-[[3-[4-(1,1-dicyano-1-propylene-2-base)-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-base] methyl] ethanamide 2.0g (5.8mmol) adds in DMF-DMA 20mL, and stir, add trifluoroacetic acid 0.2mL.Reaction is warming up to 85 DEG C of reaction 6h.Reaction is finished, and is cooled to room temperature, adds water 50mL in reaction solution, dichloromethane extraction, merges organic layer, washing, saturated nacl aqueous solution is washed, anhydrous magnesium sulfate drying, solvent evaporated, obtain S-N-[[3-[4-[1,1-dicyano-4-(dimethylamino)-1,3-butadiene-2-base]-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-base] methyl] ethanamide 1.46g, yield 63.6%, [M+H
+]: 398.2
The preparation of step 8 (S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
By S-N-[[3-[4-[1,1-dicyano-4-(dimethylamino)-1,3-divinyl-2-base]-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-base] methyl] ethanamide 1.0g (2.5mmol) adds in methyl alcohol 40mL, then adds ammoniacal liquor 12mL (150mmol).Reaction solution back flow reaction 2h.Reaction is finished, and be cooled to room temperature, suction filtration, proper amount of methanol is washed, and obtains crude product.With recrystallizing methanol, obtain (S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 0.58g, yield 63.6%, [M+H
+]: 370.2
1H-NMR：(DMSO)：1.84(s，3H)，3.43(t，2H)，4.18(t，2H)，4.77(m，1H)，6.67(s，1H)，7.01(d，1H)，7.51(m，1H)，7.66(d，1H)，8.26(t，1H).
Embodiment 2 (S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Step 1:(S, E)-N-[[3-[the fluoro-4-of 3-[(3-dimethylamino-2-propylene) acyl group] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
By S-N-[[3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1; 3-oxazolidine-5-base] methyl] ethanamide 5.0g (17mmol) and DMF-DMA13.6ml (102mmol) adds in 50ml acetonitrile, is warming up to return stirring reaction 7h.Reaction is finished, and reaction solution is cooled to room temperature, suction filtration, acetonitrile is washed, and obtains yellow solid 5.1g, yield 86%, [M+H
+]: 350.1
Step 2:(S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
By (S; E)-N-[[3-[the fluoro-4-of 3-[(3-dimethylamino-2-propylene) acyl group] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 5g (14.3mmol), the third two eyeball 1.1g (17.2mmol) and ammonium acetate 5.5g (71.6mmol) add in 20ml ethanol, are warming up to return stirring reaction 6h.Reaction is finished, and is cooled to room temperature, suction filtration, ethanol is washed, acetonitrile/water recrystallization, obtains (S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 1.8g, yield: 51.4%, [M+H
+]: 370.1.
1H-NMR：(DMSO)：1.83(s，3H)，3.78(t，1H)，4.17(t，1H)，4.77(m，1H)，6.99(s，1H)，7.07(d，1H)，7.97(m，2H)，8.25(t，1H)
Embodiment 3 (S)-N-[[3-[the fluoro-4-of 3-[2-(piperidino)-3-cyano group-4-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Step 1:(S)-N-[[3-[the fluoro-4-of 3-(the bromo-3-cyano group of 2--4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Embodiment 1 compound 1.0g (2.7mmol) is added in pyridine 10mL, stir, be cooled to-10 DEG C, be added dropwise in the 6mL aqueous solution containing Sodium Nitrite 0.94g (13.5mmol) and vitriol oil 6.8mL in reaction solution, control rate of addition and make reacting liquid temperature be-10 DEG C.Drip and finish, reaction solution is warming up to 0 DEG C of reaction 1h.Reaction is finished, and adds the 3.5mL aqueous solution of KBr1.94g (16.2mmol), room temperature reaction 16h in reaction solution.Reaction is finished, suction filtration, washing filter cake, obtains (S)-N-[[3-[the fluoro-4-of 3-[2-(piperidino)-3-cyano group-4-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 0.41g, yield: 35.3%, [M+H
+]: 433.1.
Step 2:(S) preparation of N-[[3-[the fluoro-4-of 3-[2-(piperidino)-3-cyano group-4-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Under room temperature, (S)-N-[[3-[the fluoro-4-of 3-(the bromo-3-cyano group of 2--4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 0.5g (1.1mmol) is dissolved in 10ml acetone, add Anhydrous potassium carbonate 0.24g (1.65mmol), piperidines 0.099g (1.2mmol), finish, be warming up to back flow reaction 3h.Reaction is finished, and suction filtration, by filtrate decompression evaporate to dryness, obtains crude product, do recrystallization by ethanol in proper amount, obtains product 0.23g, yield 48.9%, [M+H
+]: 438.2.
Embodiment 4 (S)-N-[[3-[the fluoro-4-of 3-[2-(1-pyrrolidyl)-3-cyano group-4-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
(S)-N-[[3-[the fluoro-4-of 3-(the bromo-3-cyano group of 2--4-pyridyl) the phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide obtained with step 1 in embodiment 3 is for raw material, according to the method for embodiment 3 step 2, substitution reaction is carried out with tetramethyleneimine, (S)-N-[[3-[the fluoro-4-of 3-[2-(1-pyrrolidyl)-3-cyano group-4-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide can be obtained, yield 61.3%, [M+H
+]: 424.2.
Embodiment 5 (S)-N-[[3-[the fluoro-4-of 3-(2-dimethylamino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
With embodiment 2 compound for starting raw material, according to the method for step 1 in embodiment 3, first obtained (S)-N-[[3-[the fluoro-4-of 3-(the bromo-3-cyano group of 2--6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide; With it for raw material, according to the method for embodiment 3 step 2, substitution reaction is carried out with diformazan ammonia, (S)-N-[[3-[the fluoro-4-of 3-(2-dimethylamino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide can be obtained, yield 52.6%, [M+H
+]: 398.2.
According to the method for embodiment 5, embodiment 6-7 compound can be obtained.
Embodiment 6 (S)-N-[[3-[the fluoro-4-of 3-[2-(4-morpholinyl)-3-cyano group-6-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
[M+H
+]：440.2。
Embodiment 7 (S)-N-[[3-[the fluoro-4-of 3-[2-(4-methyl isophthalic acid-piperazinyl)-3-cyano group-6-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
[M+H
+]：453.2
Embodiment 8 (S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide bitartrate salt
(S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 1.0g (2.7mmol) obtained in embodiment 1 is added in 25ml methyl alcohol, add 0.49g (3.3mmol) tartrate, backflow 15min, cooling, separate out solid, suction filtration, the a small amount of methanol wash column of solid, obtain white flaky crystals (S)-N-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide bitartrate salt 1.02g, yield 72.3%.
Claims (5)
1. formula I oxazolidinone compounds or its pharmacy acceptable salt,
Ⅰ
Wherein,
R
1for fluorine;
R
2for
,
;
R
3for NR
4r
5;
R
4and R
5identical or different, be separately selected from hydrogen, amino and C
1-C
4alkyl.
2. the generalformulaⅰcompound of claim 1 or its pharmacy acceptable salt, this compound is:
1) (
s)-
n-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide;
2) (
s)-
n-[[3-[the fluoro-4-of 3-(2-Amino 3 cyano-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
3. a pharmaceutical composition, described composition contains the compound of any one of claim 1-2.
4. the compound of the formula I in claim 1-2 described in any one or the application of the composition of claim 3 in the medicine for the preparation for the treatment of infected by microbes, described infected by microbes is bacteriological infection.
5. the compound of the formula I in claim 1-2 described in any one or the application of the composition of claim 3 in the medicine for the preparation for the treatment of S. aureus L-forms, streptococcus pneumoniae, enterococcal infection.
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|---|---|---|---|---|
| WO1998001447A1 (en) * | 1996-07-06 | 1998-01-15 | Zeneca Limited | Pyridyl-piperazinyl-phenyl-oxazolidinone derivatives and their use as antibacterials |
| CN1261889A (en) * | 1997-07-11 | 2000-08-02 | 法玛西雅厄普约翰美国公司 | Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agent |
| CN1433413A (en) * | 2000-06-05 | 2003-07-30 | 东亚制药株式会社 | Novel oxazolidinone derivatives and process for the preparation thereof |
| US20040087633A1 (en) * | 2002-10-29 | 2004-05-06 | Korea Institute Of Science And Technology | Methylidene oxazolidinone compound and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998001447A1 (en) * | 1996-07-06 | 1998-01-15 | Zeneca Limited | Pyridyl-piperazinyl-phenyl-oxazolidinone derivatives and their use as antibacterials |
| CN1261889A (en) * | 1997-07-11 | 2000-08-02 | 法玛西雅厄普约翰美国公司 | Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agent |
| CN1433413A (en) * | 2000-06-05 | 2003-07-30 | 东亚制药株式会社 | Novel oxazolidinone derivatives and process for the preparation thereof |
| US20040087633A1 (en) * | 2002-10-29 | 2004-05-06 | Korea Institute Of Science And Technology | Methylidene oxazolidinone compound and preparation method thereof |
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