CN101560209B - Oxazolidinone compound containing pyridine and preparation method thereof - Google Patents
Oxazolidinone compound containing pyridine and preparation method thereof Download PDFInfo
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Abstract
The invention provides an oxazolidinone compound containing pyridine shown in the formula I, a preparation method thereof, and an application of the compound in preparation of medicaments for treatingmicrobe-infected diseases.
Description
Technical field:
The present invention relates to the pharmaceutical chemistry field, particularly a kind ofly contain pyrimidine De oxazolidone compound, or its optically active isomer, pharmacy acceptable salt and/or solvate, and the pharmaceutical composition that contains them, 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 has caused the difficulty in the treatment, and present antibacterials can not satisfy needs clinically, is badly in need of having the antibacterials of novel mechanism of action clinically.
Oxazolidine ketone antibacterials are the brand-new chemical complete synthesis antibacterials of a class formation, and such drug effect seldom occurs cross resistance in the commitment of protein synthesis with other antimicrobial drug.The DuP721 of E.I.Du Pont Company's report in 1987 is a lead compound, the general strong company of the U.S. has successfully developed the one oxazolidine ketone antiseptic-germicide---linezolid (Linezolid), the gram positive bacteria infection that is used for the treatment of penicillin resistant, Macrolide and other antibacterials, this medicine go on the market in U.S.'s approval in April, 2000.
But because this medicine has been used for a long time, produced some resistant organisms gradually, its curative effect is reduced, it is necessary therefore seeking new medicine.
Summary of the invention:
The present invention has found a kind of oxazolidone compounds of general formula I, and has found that it compared with prior art has good antimicrobial agent activity through research.
Compound of the present invention comprises its raceme or optically active isomer, also comprises its pharmacy acceptable salt and/or solvate.
Wherein
R
1And R
2Identical or different, be independently selected from hydrogen, C respectively
1-C
10Alkyl, C
3-C
7Cycloalkyl, C
2-C
10Thiazolinyl and C
2-C
10Alkynyl,
Or R
1And R
2Form 5-10 unit heterocyclic radical or 5-10 unit heteroaryl with the nitrogen-atoms that is connected with them, described heterocyclic radical and heteroaryl except with R
1And R
2Outside the nitrogen-atoms that connects, can contain 1-4 heteroatoms that is selected from N, O and S, except R
1And R
2Outside the nitrogen-atoms that is connected, optional 1 or 2 carbon-carbon double bond or three key of comprising of described heterocyclic radical.
R in the preferred compound of the present invention
1And R
2Identical or different, be independently selected from hydrogen, C respectively
1-C
10Alkyl, C
3-C
7Cycloalkyl, or R
1And R
2Form 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, piperidino, 1-pyrrolidyl, 1H-1 with the nitrogen-atoms that is connected with them, 2,4-triazole-1-base, 1-imidazolyl, 2-methyl isophthalic acid-imidazolyl and 1H-tetrazole-1-base.
R in the preferred compound of the present invention
1And R
2Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, or R
1And R
2Form 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, piperidino, 1-pyrrolidyl with the nitrogen-atoms that is connected with them.
The particularly preferred compound of the present invention is R wherein
1And R
2Form 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, piperidino, 1-pyrrolidyl with the nitrogen-atoms that is connected with them.
Most preferred of the present invention is N-[[(5S)-3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide.
According to some usual methods in field under 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, following acid is particularly preferred: hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric 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, isethionic acid, p-methyl benzenesulfonic acid, Phenylsulfonic acid, naphthene sulfonic acid, trifluoroacetic acid and aspartic acid.
The salt of most preferred of the present invention is hydrochloride or mesylate.
The present invention also comprises the solvate of The compounds of this invention, and as ethanol, water etc. wherein, can contain the water of different amounts, as monohydrate, semihydrate, semihydrate, dihydrate or a trihydrate.
The present invention also comprises the prodrug of The compounds of this invention.According to the present invention, prodrug is the derivative of compound of Formula I, they self may have more weak active or even do not have activity, but after administration, (for example by metabolism, solvolysis or other mode) is converted to corresponding biologically active form under physiological condition.
The present invention also comprises racemic modification, optically active isomer, polymorphic forms or its mixture of The compounds of this invention, and they possess useful quality of the present invention.Compound of Formula I of the present invention contains the C-5 position of chiral centre (oxazolidone ring), therefore there are two kinds of enantiomorphs or the racemic mixture of the two.The present invention relates to two kinds of enantiomorphs of useful quality and contain two kinds of mixture of isomers.
Unless otherwise noted, term used herein " alkyl " is meant the alkyl of straight or branched; " cycloalkyl " is meant and replaces or unsubstituted cycloalkyl; " thiazolinyl " is meant the thiazolinyl of straight or branched; " alkynyl " is meant the alkynyl of straight or branched; 5-10 unit heteroaryl comprises and contains one or more N of being selected from, the heteroatoms of O and S, wherein the ring-type system of each heteroaryl can be monocycle or polycyclic, the ring-type system is an aromaticity, contain 5-10 atom altogether, can enumerate for example imidazolyl, 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 the heteroatoms that contains one or more N of being selected from, O and S, wherein the ring-type system of each heteroaryl can be monocycle or polycyclic, but be non-aromaticity, the ring-type system contains 5-10 atom altogether, can choose wantonly and comprise 1 or 2 carbon-carbon double bond or carbon-carbon triple bond, can enumerate for example pyrrolidyl, morpholinyl, piperazinyl, piperidyl, thiazolinyl etc.
The present invention also comprises pharmaceutical composition, and said composition comprises that compound of Formula I and their pharmacy acceptable salts and/or solvate are as activeconstituents and pharmaceutically acceptable carrier; Compound of the present invention can be used in combination with other activeconstituentss, as long as they do not produce other disadvantageous effect, for example anaphylaxis.
The carrier that is used for pharmaceutical composition of the present invention is the available common type of pharmaceutical field, comprising: the tackiness agent that oral preparations is used, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives etc.; The sanitas that injectable formulation is used, solubilizing agent, stablizer etc.; The matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under the stomach condition, it can be mixed with enteric coated tablets.
The present invention comprises that also it is used for the treatment of the particularly application in the medicine of infectation of bacteria of Mammals microorganism in preparation.This application method is given the compound of Formula I of significant quantity, can compound is oral to Mammals in pharmaceutical composition, parenteral, transdermal or topical.
Owing to have particularly antibacterial activity of anti-microbial infection according to general formula I De oxazolidone compounds of the present invention, therefore, it can be as the medicine of preparation treatment Mammals infectation of bacteria, compound according to the present invention can be used as the method that activeconstituents is used to prepare treatment Mammals infectation of bacteria, comprise suffer from or easily suffer from this sick patient significant quantity according to compound of the present invention.
Particularly the accurate amount of the required The compounds of this invention of infectation of bacteria will be different because of the curee for the treatment microorganism, depend on curee's kind, age and general condition, the severity of disease for the treatment of, used specific compound and administering mode, for example the approach of administration and frequency or the like.Those of ordinary skills only utilize the normal experiment method can determine suitable significant quantity.
The dosage of compound can be from about 0.1～100mg/kg body weight every day, preferred 1～50mg/kg body weight/day.Be understandable that dosage can be because of patient's demand, the seriousness of the infectation of bacteria of being treated and employed specific compound and different.And, being understandable that the initial dosage of institute's administration can increase and exceeds the upper limit, purpose is to reach the desired blood level rapidly, and perhaps initial dosage can be less than optimum value, and every day, dosage can increase during treating gradually, and this depends on concrete situation.If necessary, every day, dosage also can be divided into multiple dose administration, for example every day 2-4 time.
Mammals is represented the human or animal.
Activeconstituents, the amount of compound just according to the present invention in pharmaceutical composition and unit dosage thereof can have nothing in common with each other, and depends on the effectiveness and the desired concn of application-specific, specific compound.Generally speaking, the content of activeconstituents will be between 0.5%～90%, by the gross weight of composition.
In conjoint therapy, The compounds of this invention and other compound can be by simultaneously or administration at interval, and at the same time during administration, The compounds of this invention and other compounds can be bonded in the single pharmaceutical composition or in the composition that separates.
The present invention also provides the preparation method of the compound of general formula I, said method comprising the steps of:
With formula II compound and guanidine or R
1And R
2The guanidine that replaces reacts in organic solvent and can make compound of Formula I, and organic solvent can be selected alcohol, acetonitrile, DMF equal solvent, and wherein preferred reaction solvent is an ethanol, and temperature of reaction is 0～100 ℃, preferred 25～80 ℃.
R wherein
1And R
2Define the same.
When needing the pharmacy acceptable salt of compound of Formula I, can described compound and the acid-respons that suits be obtained by using ordinary method.
Below synthetic route 1 preparation of general formula I of the present invention has been described, all raw materials all are the method preparation known by the method for describing in these synoptic diagram, by the organic chemistry filed those of ordinary skill or commercially available.All final compound of the present invention all is to prepare by the method for describing in these synoptic diagram or by method similar with it, and these methods are that the organic chemistry filed those of ordinary skill is known.R in these synoptic diagram
1And R
2Define the same.
With 3-fluoroaniline (VII) is starting raw material; through with methyl chlorocarbonate generation acylation reaction after; obtain (3-fluorophenyl) Urethylane (VI), after carrying out Friedel-Crafts reaction, make compound (4-ethanoyl-3-fluorophenyl) Urethylane (V) with Acetyl Chloride 98Min..In the presence of trimethyl carbinol lithium, methyl alcohol; react with compound N-[(2S)-2-(acetoxyl group)-3-chloropropyl] ethanamide (IV); after the acid neutralization; make compound N-[((5S)-3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1,3-oxazolidine-5-yl) methyl] ethanamide (III).Compound III and N, dinethylformamide dimethylacetal (DMF-DMA) reacts, and obtains Compound I I.Compound I I and guanidine or R
1And R
2The guanidine that replaces carries out cyclization, makes compound of Formula I.
Synthesizing of route 1 Compound I
Wherein the preparation of compound IV as shown in Scheme 2; with the phenyl aldehyde is starting raw material; through making (S)-1-amino-3-chloro-2-propylate hydrochlorate, make N-[(2S with diacetyl oxide generation acylation reaction again with (S)-epoxy chloropropane, ammoniacal liquor reaction, acid hydrolysis)-2-(acetoxyl group)-3-chloropropyl] ethanamide (IV).
Route 2 N-[(2S)-and 2-(acetoxyl group)-3-chloropropyl] ethanamide (IV) synthetic
With (R)-epoxy chloropropane or (R; S)-epoxy chloropropane is a starting raw material; preparation method according to compound IV; can obtain (R)-1-acetamido-3-chloro-2-lithium propoxide or (R respectively; S)-1-acetamido-3-chloro-2-lithium propoxide; then with the reaction of (4-ethanoyl-3-fluorophenyl) Urethylane (V), can obtain the enantiomer or the raceme of compound of Formula I respectively.
The a plurality of compounds of the present invention have been carried out antibacterial activity in vitro research, and the result is as follows:
For becoming a series of concentration with M-H meat soup two-fold dilution after the test agent degerming, maximum concentration is 128mg/L.Add 100 μ LM-H broth cultures in the 12nd hole as blank every row of 96 micropores dilution plate, the 11st hole adds 50 μ LM-H meat soups, according to adding 50 μ L sample test liquids successively from 1 hole, the 10th hole to the from low paramount order.
Picking is tried bacterium in right amount and reference culture is seeded in Mueller-Hinton (M-H) nutrient broth medium that is fit to its growth, cultivate 16-18h in 37 ℃, bacterium liquid after the growth uses physiological saline corrected concentrations to 0.5 Maxwell than turbid standard, use the dilution in 1: 100 of M-H meat soup again, this liquid is as supplying examination bacterium liquid.Inoculate 50 μ L test organisms liquid then in the 1st～11 hole, the jolting mixing is placed in the square tray anth cap that is lined with wet gauze, cultivates 18-20h for 37 ℃.
Observations under the light source of black background is being arranged, having to have the diffusivity muddiness in the hole of bacteria growing or the bottom, hole is clasp sample precipitation, this phenomenon of the nothing hole of asepsis growth in.Contained lowest concentration of drug is minimum inhibitory concentration (MIC) in the hole of asepsis growth.Test-results sees Table 1.
Table 1 part embodiment compound is to the activity of various bacteria
MIC：ug/mL
A: methicillin-resistant gold Portugal bacterium; B: VRSA; C: penicillin resistant streptococcus pneumoniae
The antibacterial activity in vitro test result shows, the compound among the present invention has the how more good anti-microbial activity of oxazolone of Billy, and remarkable to the resistant organism anti-microbial activity, side effect simultaneously is little, bioavailability height, good stability, dissolving is better than the effect of linezolid rapidly.
Embodiment:
Following examples are intended to set forth rather than limit the scope of the invention.The proton nmr spectra of compound is measured with BrukerARX-300, and mass spectrum is measured with Agilent 1100 LC/MSD; Agents useful for same is analytical pure or chemical pure.
Embodiment 1 N-[[(5S)-and 3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide
1.1 N-[(2S)-and 2-acetoxy-3-chloropropyl] preparation of ethanamide (IV)
1.1.1 (S)-preparation of 1-amino-3-chloro-2-propylate hydrochlorate
Phenyl aldehyde 59.0g (0.56mol) is dissolved among the ethanol 150ml, and dropping ammonia 58.0ml (0.55mol) in reaction solution stirs, and drips (S)-epoxy chloropropane 58ml (0.88mol) in reaction solution, and the control rate of addition keeps temperature of reaction to be lower than 40 ℃.Drip and finish, 35-40 ℃ of reaction 6h reduces to reaction solution room temperature then and continues reaction 12h.Decompression steams most of solvent, adds toluene 100ml.Stir, solution is risen to 35-40 ℃, splash into aqueous hydrochloric acid (68ml hydrochloric acid, 77ml water), drip and finish, 35-40 ℃ is stirred 3h.Leave standstill, divide water-yielding stratum, organic layer washing, combining water layer.Add ethanol 40mL, remove ethanol under reduced pressure, add ethanol and steaming repeatedly except that ethanol.Residual solution is separated out white solid in-18 ℃ of freeze overnight, and suction filtration is washed with cold small amount of ethanol, and vacuum-drying gets (S)-1-amino-3-chloro-2-propylate hydrochlorate, 43g, yield 52.7%.
1.1.2 N-[(2S)-and 2-(acetoxyl group)-3-chloropropyl] preparation of ethanamide (IV)
(S)-1-amino-3-chloro-2-propylate hydrochlorate 40g (0.27mol), diacetyl oxide 60ml (0.62mol) are added among the methylene dichloride 100mL, and controlled temperature drips pyridine 28ml (0.34mol) at 35-40 ℃.Drip and finish, under this temperature, react 5h, then room temperature reaction 14h.Reaction is finished, and adds entry 50mL in reaction solution, and the ice-water bath cooling splashes into 47% wet chemical 800mL, and control reaction temperature is lower than 10 ℃.Drip and finish, dichloromethane extraction merges organic layer, washing, anhydrous sodium sulfate drying.Evaporate to dryness gets solid, suction filtration, the octane-iso washing gets solid N-[(2S)-2-(acetoxyl group)-3-chloropropyl] ethanamide 43.7g, yield is 88.3%.
1.2 N-[[(5S)-3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide (III)
The preparation of (1.2.1 3-fluorophenyl) Urethylane (VI)
With 3-fluoroaniline 20.0g (VII, 0.18mol) add among the methylene dichloride 120ml, add pyridine 14.2g (0.18mol), stir, drip the dichloromethane solution (30ml) of methyl-chloroformate 18.7g (0.2mol) in reaction solution, the control rate of addition makes temperature of reaction be lower than 40 ℃.Drip and finish room temperature reaction 5h.Reaction is finished, washed reaction liquid, and the organic layer anhydrous sodium sulfate drying, evaporate to dryness gets white solid 30.1g, yield 98.8%.
The preparation of (1.2.2 4-ethanoyl-3-fluorophenyl) Urethylane (V)
(3-fluorophenyl) Urethylane (VI) 16.9g (0.1mol) is added in the three-necked bottle, add aluminum chloride 40.0g (0.3mol), stir and be warming up to 35-40 ℃, dripping acetyl chloride 15.7g (0.2mol) in reaction flask.Drip and finish, be warmed up to 50-60 ℃ of reaction 3h.Reaction solution is poured in an amount of trash ice, stirred, suction filtration, filter cake 80% recrystallizing methanol gets (4-ethanoyl-3-fluorophenyl) Urethylane (V) 14.9g, yield 70.8%.
1.2.3 N-[[(5S)-3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide (III)
(V 0.1mol) adds among the dry DMF 100mL, and stirring and dissolving adds anhydrous methanol 8.14mL (0.2mol) with compound (4-ethanoyl-3-fluorophenyl) Urethylane (V) 21.1g.Under 20 ℃, drip the dry DMF 100mL solution of trimethyl carbinol lithium 23.7g (0.3mol) in reaction solution, the control rate of addition is kept temperature of reaction and is lower than 24 ℃.Drip and finish, reaction solution is chilled to 0-5 ℃, add N-[(2S)-2-(acetoxyl group)-3-chloropropyl] ethanamide 34.6g (0.2mol).Reaction solution slowly is warming up to 20-25 ℃ 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, drying; the evaporated under reduced pressure solvent gets oily matter, recrystallizing methanol; get N-[[(5S)-3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1; 3-oxazolidine-5-yl] methyl] ethanamide 10.2g, yield 34.7%, [M+H
+]: 295.5.
1.3 N-[[(5S)-3-[4-[(E)-3-(dimethylamino)-2-alkene-propionyl]-the 3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide (II)
With N-[[(5S)-3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1; 3-oxazolidine-5-yl] methyl] ethanamide 20.8g (III; 0.071mol), N, dinethylformamide dimethylacetal (DMF-DMA) 50.5mL (0.38mol) is added among the ethanol 300mL, at N
2Under the protection, heating reflux reaction 5h is chilled to reaction solution room temperature then and continues to stir 10h.Reaction is finished, solvent evaporated, and suction filtration gets solid 11.2g, yield 45.4%, [M+H
+]: 349.9.
1.4 N-[[(5S)-3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide
(10.6g 0.46mol) adds among the ethanol 460mL, and reflux is to dissolving fully with sodium.Add Guanidinium nitrate 56.1g (0.46mol) backflow 1h, cooling, suction filtration obtains the ethanolic soln of guanidine.With compound N-[[(5S)-3-[4-[(E)-3-(dimethylamino)-2-allyl acyl group]-3-fluorophenyl]-2-oxo-1; 3-oxazolidine-5-yl] methyl] (II 0.115mol) adds in the 400mL dehydrated alcohol ethanamide 40g, stirs; in reaction solution, drip the above-mentioned ethanolic soln that makes guanidine; drip and finish, stirring at room 2h separates out a large amount of solids in the reaction solution; suction filtration; ethanol is washed, and gets solid 23.8g, yield 60.3%.mp：238-240℃；
1H-NMR(DMSO-d
6)：δ1.82(s，3H)，3.42(t，2H，J＝5.4Hz，)，3.77(dd，1H，J＝6.7，9.1Hz)，4.16(dd，1H，J＝8.9，9.1Hz)，4.76(m，1H)，6.71(s，2H)，6.94(m，1H)，7.46(dd，1H，J＝1.9，8.8Hz)，7.58(d，1H)，8.04(t，1H，J＝8.9Hz)，8.25(m，1H)，8.29(d，1H，J＝5.4Hz)；[M+H
+]：346.1；[α]
20 D＝-27.2(c＝1.00，DMSO)。
Embodiment 2 N-[[(5S)-and 3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of acetamide hydrochloride
With N-[[(5S)-3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide 5.2g (0.015mol) adds in 80% ethanol, the dripping hydrochloric acid ethanolic soln is to pH=2 under stirring, reflux, decolorizing with activated carbon, suction filtration while hot, dry, get N-[[(5S)-3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] acetamide hydrochloride 5.4g, yield 95.1%.mp：227.3℃；[α]
20 D＝-25.3(c＝1.00，DMSO)。
Embodiment 3 N-[[(5S)-and 3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide mesylate
With N-[[(5S)-3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide 5.2g (0.015mol) adds in 80% ethanol, stir down and drip methylsulfonic acid to pH=2, reflux, decolorizing with activated carbon, suction filtration while hot, dry, get N-[[(5S)-3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide mesylate 6.2g, yield 93.9%.
Embodiment 4 N-[[(5S)-and 3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide isethionate
With N-[[(5S)-3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide 5.2g (0.015mol) adds in 80% ethanol, stir down and drip isethionic acid to pH=2, reflux, decolorizing with activated carbon, suction filtration while hot, dry, get N-[[(5S)-3-fluoro-4-(2-aminopyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide isethionate 6.5g, yield 92.6%.
Embodiment 5 N-[[(5S)-3-fluoro-4-[2-(4-morpholinyl)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide
5.1 the preparation of morpholine-4-guanidine nitrate
Morpholine 1.7g (0.02mol) is added among the dehydrated alcohol 10mL, stir, add nitric acid 1.4mL (0.02mol) and cyanamide 1.3g (0.03mol), heating reflux reaction 15h, reaction is finished, be chilled to room temperature, in reaction solution, add ether 80ml, freeze overnight, separate out white crystals, suction filtration gets morpholine-4-guanidine nitrate 2.9g, yield 75.2%.
5.2 N-[[(5S)-3-fluoro-4-(2-(4-morpholinyl)-pyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide
(6.9g 0.3mol) adds among the ethanol 460mL, and reflux is to dissolving fully with sodium.Add morpholine-4-guanidine nitrate 57.6g (0.3mol) backflow 1h, cooling, suction filtration obtains the ethanolic soln of morpholine-4-carbonamidine.With compound N-[[(5S)-3-[4-[(E)-3-(dimethylamino)-2-allyl acyl group]-3-fluorophenyl]-2-oxo-1; 3-oxazolidine-5-yl] methyl] (II 0.075mol) adds in the 270mL dehydrated alcohol ethanamide 26.1g, stirs; in reaction solution, drip the above-mentioned ethanolic soln that makes morpholine-4-carbonamidine; drip and finish, reflux 5h separates out a large amount of solids in the reaction solution; suction filtration; ethanol is washed, and gets solid 15.5g, yield 60.3%.[M+H
+]：416.1。
Embodiment 6 N-[[(5S)-and 3-fluoro-4-(2-(1-pyrrolidyl)-pyrimidine-4-yl)-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide
According to 5.2 preparation method among the embodiment 5,, make N-[[(5S with Compound I I and Pyrrolidine-1-carbonamidine reaction)-3-fluoro-4-[2-(1-pyrrolidyl)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide, yield 80.2%, [M+H
+]: 410.3.
Embodiment 7 N-[[(5S)-3-fluoro-4-[2-(4-methyl isophthalic acid-piperazinyl)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide
According to 5.2 preparation method among the embodiment 5, with Compound I I and 4-methylpiperazine-1-carbonamidine reaction, make N-[[(5S)-3-fluoro-4-[2-(4-methyl isophthalic acid-piperazinyl)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide, yield 79.0%, [M+H
+]: 429.3.
Embodiment 8 N-[[(5S)-3-fluoro-4-[2-(1H-imidazoles-1-yl)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide
According to 5.2 preparation method among the embodiment 5,, make N-[[(5S with Compound I I and imidazoles-1-carbonamidine reaction)-3-fluoro-4-[2-(1H-imidazoles-1-yl)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide, yield 74.9%, [M+H
+]: 397.2.
Embodiment 9 N-[[(5S)-3-fluoro-4-[2-(cyclohexyl amino)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide
According to 5.2 preparation method among the embodiment 5,, make N-[[(5S with Compound I I and the reaction of 1-cyclohexyl guanidine)-3-fluoro-4-[2-(cyclohexyl amino)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide, yield 82.1%, [M+H
+]: 428.2.
Embodiment 10 N-[[(5S)-3-fluoro-4-[2-(first fourth amino)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide
According to 5.2 preparation method among the embodiment 5,, make N-[[(5S with Compound I I and 1-methyl isophthalic acid-butyl guanidine reaction)-3-fluoro-4-[2-(first fourth amino)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide, yield 79.2%, [M+H
+]: 416.1.
Embodiment 11 N-[[(5S)-3-fluoro-4-[2-(methyl cyclopropylamino)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide
According to 5.2 preparation method among the embodiment 5, with Compound I I and 1-methyl isophthalic acid-cyclopropyl guanidine reaction, make N-[[(5S)-3-fluoro-4-[2-(first cyclopropylamino)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide, yield 77.1%, [M+H
+]: 400.1.
Embodiment 12 N-[[(5S)-3-fluoro-4-[2-(piperidines-1-yl)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide
According to 4.2 preparation method among the embodiment 4,, make N-[[(5S with Compound I I and piperidines-1-carbonamidine reaction)-3-fluoro-4-[2-(piperidines-1-yl)-pyrimidine-4-yl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide, yield 82.3%, [M+H
+]: 414.2.
The preparation of embodiment 13 embodiment 1 compound tablet (250mg/ sheet)
Get embodiment 1 compound 250g, starch 30g, 2%HPMC aqueous solution 80mL, sodium starch glycolate 15g, Magnesium Stearate 2g, according to following steps:
A, preparation 2%HPMC solution are an amount of, standby;
B, former, auxiliary material is suitably dry crosses 100 mesh sieves respectively, and is standby;
C, take by weighing former, auxiliary material by recipe quantity.After embodiment 1 compound, starch, carboxymethylstach sodium mixed, add 2%HPMC solution and make softwood, with 20 mesh sieve system wet granulars;
D, wet granular cool after the drying slightly in about 3 hours of 55 ℃ of dryings, add Magnesium Stearate, with whole of 20 mesh sieves; Measure content, it is heavy to calculate sheet;
E, select 10mm dimple form drift compressing tablet for use, make 1000;
F, inspection after construction, qualified after, packing warehouse-in.
The preparation of embodiment 14 embodiment, 2 compound capsules (125mg/ grain)
Get following component: embodiment 2 compound 125g, starch 15g, lactose 15g, the about 40mL of the 2%HPMC aqueous solution, sodium starch glycolate 7.5g, Magnesium Stearate 1g.Carry out according to following steps:
A, preparation 2%HPMC solution are an amount of, standby.
B, former, auxiliary material is suitably dry crosses 100 mesh sieves respectively, and is standby.
C, take by weighing former, auxiliary material by recipe quantity.After embodiment 2 compounds, starch, lactose, sodium starch glycolate mixed, add 2%HPMC solution system softwood, with 20 mesh sieve system wet granulars.
D, wet granular cool after the drying slightly in about 3 hours of 55 ℃ of dryings, add Magnesium Stearate, with whole of 20 mesh sieves.Measure content, calculate loading amount.
E, select 2# capsule shell can particle for use, 1000 of capsules.
F, with capsule polishing, dedusting.
G, inspection after construction, qualified after, packing warehouse-in.
The preparation of embodiment 15 embodiment, 3 compound dispersible tablets (250mg/ grain)
Get following component: embodiment 3 compound 250g, pregelatinized Starch 50g, Microcrystalline Cellulose 50g, sodium starch glycolate 20g, the about 90ml of the 2%HPMC aqueous solution, micropowder silica gel 20g, stevia glucoside 18g, Magnesium Stearate 2g, be prepared according to following steps:
A, preparation 2%HPMC solution are an amount of, standby.
B, former, auxiliary material is suitably dry crosses 100 mesh sieves respectively, and is standby.
C, take by weighing former, auxiliary material by recipe quantity.After embodiment 4 compounds, pregelatinized Starch, Microcrystalline Cellulose, carboxymethylstach sodium, stevia glucoside mixed, add 2%HPMC solution and make softwood, with 20 mesh sieve system wet granulars.
D, wet granular cool after the drying slightly in 55 ℃ of dryings 3 hours, add micropowder silica gel, Magnesium Stearate, with whole of 20 mesh sieves.Measure content, it is heavy to calculate sheet.
E, select 11mm dimple form drift compressing tablet for use, 1000.
F, inspection after construction, qualified after, packing warehouse-in.
The preparation of embodiment 16 embodiment 4 compound sodium chloride injections (100mL:250mg)
Get following component: embodiment 4 compound 250g, sodium-chlor 825g, citric acid 6.5g, water for injection and add to 100L, carry out according to following steps:
A, take by weighing embodiment 4 compounds, sodium-chlor and the citric acid of recipe quantity.
B, main materials and auxiliary materials is dissolved in the water for injection (about 80 ℃) that accounts for preparation total amount 90%, stirs and to make dissolving fully.
C, adding 0.05% are stirred through 2 hours needle-use activated carbons of 120 ℃ of activation, leave standstill 15 minutes.
Behind d, the titanium rod strainer filtering decarbonization with 0.6 μ m, benefit adds to the full amount of water for injection.
E, detect intermediate color, clarity, pH value, content etc., qualified after, filter with polysulfones strainer coarse filtration and the 0.22 μ m polysulfones strainer essence of 0.45 μ m.
F, 1000 bottles of embeddings, tamponade, rolled lid, 110 ℃ of pressure sterilizings 45 minutes, the lamp inspection, entirely examine qualified, label, pack promptly.
Claims (8)
1. the compound of formula I,
Or its pharmacy acceptable salt, wherein: R
1And R
2Identical or different, be independently selected from hydrogen, C respectively
1-C
10Alkyl, C
3-C
7Cycloalkyl or R
1And R
2Form 4-morpholinyl, piperidino, 1-pyrrolidyl with the nitrogen-atoms that is connected with them.
2. the generalformula of claim 1, wherein R
1And R
2Identical or different, be independently selected from hydrogen, C respectively
1-C
6Alkyl, or R
1And R
2Form 4-morpholinyl, piperidino, 1-pyrrolidyl with the nitrogen-atoms that is connected with them.
3. the described generalformula of claim 1 is N-[[(5S)-3-[3-fluoro-4-(2-aminopyrimidine-4-yl) phenyl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide.
4. the generalformula of claim 1 or its pharmacy acceptable salt, described pharmacy acceptable salt is the salt that forms with acid, described acid is selected from: hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric 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, isethionic acid, p-methyl benzenesulfonic acid, Phenylsulfonic acid, naphthene sulfonic acid, trifluoroacetic acid and aspartic acid.
5. the generalformula of claim 4 or its pharmacy acceptable salt, the wherein said salt that forms with acid is hydrochloride and mesylate.
6. prepare the method for the generalformula of claim 1, may further comprise the steps:
With formula II compound and R
1And R
2The guanidine reaction that replaces, wherein, R
1And R
2Identical or different, be independently selected from hydrogen, C respectively
1-C
10Alkyl, C
3-C
7Cycloalkyl or R
1And R
2Form 4-morpholinyl, piperidino, 1-pyrrolidyl with the nitrogen-atoms that is connected with them.
7. pharmaceutical composition, described composition contains each compound of claim 1-5.
8. each compound of claim 1-5 is used for the treatment of application in the medicine of infectation of bacteria in preparation.
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| CN102702186B (en) * | 2012-06-20 | 2014-11-19 | 安润医药科技（苏州）有限公司 | Synthesis method of rivaroxaban |
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| 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 |
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| 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 |
Non-Patent Citations (3)
| Title |
|---|
| C. S. Lee et al..Carbon-Carbon-Linked (Pyrazolylphenyl)oxazolidinones with Antibacterial Activity Against Multiple Drug Resistant Gram-Positive and Fastidious Gram-Negative Bacteria.《Bioorg. Med. Chem. 》.2001,第9卷(第12期),第3243-3253页. * |
| 孟庆国等.噁唑烷酮类抗菌剂研究进展.《中国新药杂志》.2002,第11卷(第5期),第355-359页. * |
| 翟鑫等.新型噁唑烷酮类抗菌药物的研究进展.《沈阳药科大学学报》.2006,第23卷(第11期),第739-744页. * |
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