CN102276595A - Oxazolidinone antibiotic containing five-membered heterocycles - Google Patents
Oxazolidinone antibiotic containing five-membered heterocycles Download PDFInfo
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- CN102276595A CN102276595A CN2011101097439A CN201110109743A CN102276595A CN 102276595 A CN102276595 A CN 102276595A CN 2011101097439 A CN2011101097439 A CN 2011101097439A CN 201110109743 A CN201110109743 A CN 201110109743A CN 102276595 A CN102276595 A CN 102276595A
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- 0 C*(C***)C(*1)=C(*)C(*)=C1c(c(*)c1*)c(*)c(*)c1N(CC(C*)O1)C1=O Chemical compound C*(C***)C(*1)=C(*)C(*)=C1c(c(*)c1*)c(*)c(*)c1N(CC(C*)O1)C1=O 0.000 description 7
- XQCCGSZSXRJZNT-AWEZNQCLSA-N CC(NC[C@@H](CN1c2ccc(-c3ccc(C[n]4nncc4)[s]3)c(F)c2)OC1=O)=O Chemical compound CC(NC[C@@H](CN1c2ccc(-c3ccc(C[n]4nncc4)[s]3)c(F)c2)OC1=O)=O XQCCGSZSXRJZNT-AWEZNQCLSA-N 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C Chemical compound CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- CLSHQIDDCJTHAJ-UHFFFAOYSA-N N#CCc1ccc[s]1 Chemical compound N#CCc1ccc[s]1 CLSHQIDDCJTHAJ-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention which belongs to the technical field of medicines concretely relates to an oxazolidinone antibiotic containing five-membered heterocycles represented by a general formula (I), pharmaceutically acceptable salts thereof or stereo isomers thereof, and in the general formula (I), R1, R2, R3, R4, R5, R6, R7, R8, A, X or n are defined in the specification. The invention also relates to a preparation method of above compounds, a pharmaceutical composition containing the compounds, and purposes of the compounds in preparing medicaments for treating and/or preventing infectious diseases.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to contain five-membered ring De oxazolidone antibiotic, its pharmacy acceptable salt or its steric isomer, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent purposes in the medicine of infectious diseases in preparation.
2, background technology
Oxazolidine ketone antimicrobial drug is the complete synthesis antimicrobial drug of developing after sulfamido and fluoroquinolones of a class new chemical, has the effect that suppresses the multidrug resistant gram-positive microorganism.
Linezolid is first listing De oxazolidone antibiotics,
It has stronger restraining effect to gram-positive microorganism, does not have cross resistance with other antimicrobial drugs.Its mechanism of action uniqueness can suppress bacterioprotein synthetic commitment.Linezolid is mainly used in the infectious diseases that treatment is caused by the resistance gram-positive microorganism, also can be used for the surgical infection treatment of diseases.
Yet the clinical application kind of the more and more serious ， oxazolidone antibiotics of the resistance situation of gram-positive microorganism is single clinically, can not satisfy clinical demand, and the resistance situation of Linezolid occurs constantly also.Therefore, be badly in need of developing to the effective antibacterials of drug tolerant bacteria height.
3, summary of the invention
The invention provides a class anti-infective compounds, have better antibacterial activity, concrete technical scheme is as follows:
Compound shown in the general formula (I):
Wherein, R
1Be acetamido, hydroxyl, amino, C
1-6Alkyl amine group, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3, R
4, R
5Be hydrogen atom independently respectively, halogen atom, C
1-6Alkyl, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido or C
1-6Alkoxyl group;
A is the saturated or undersaturated nitrogen heterocyclic of 5-6 unit;
X is S, O or NR
9, R wherein
9Be hydrogen atom, C
1-6Alkyl, hydroxyl C
1-6Alkyl or amino C
1-6Alkyl;
R
6, R
7, R
8Be hydrogen atom independently respectively, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, hydroxyl C
1-6Alkyl or amino C
1-6Alkyl;
N is 1～3 integer.
Be preferably:
Wherein, R
1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3, R
4, R
5Be hydrogen atom independently respectively, halogen atom, C
1-3Alkyl, C
1-3Alkyl amine group, two (C
1-3Alkyl) amido or C
1-3Alkoxyl group;
A is a 5-6 unit unsaturated nitrogen heterocycle;
X is S, O or NR
9, R wherein
9Be hydrogen atom or C
1-3Alkyl;
R
6, R
7, R
8Be hydrogen atom independently respectively, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, hydroxyl C
1-4Alkyl or amino C
1-4Alkyl;
N is 1 or 2.
More preferably:
Wherein, R
1Be acetamido, hydroxyl or 1,2,3-triazol radical;
R
2, R
3, R
4, R
5Difference is hydrogen atom or fluorine atom independently;
A is 1,2,3-triazol radical, 1,2,4-triazol radical, pyrazolyl, imidazolyl, 1,2,3,4-tetrazole base, pyridyl or pyrazinyl;
X is S, O or NR
9, R wherein
9Be hydrogen atom, methyl, ethyl, propyl group, cyclopropyl or sec.-propyl;
R
6, R
7, R
8Be hydrogen atom independently respectively, fluorine atom, chlorine atom, methyl, methoxyl group, methylol or aminomethyl;
N is 1.
More preferably:
Wherein, R
1Be acetamido;
R
2, R
3, R
4, R
5Be hydrogen atom or fluorine atom independently;
A is 1,2,3-triazol radical or 1,2,3,4-tetrazole base;
X is S, O or NR
9, R wherein
9Be hydrogen atom or methyl;
R
6, R
7, R
8Be hydrogen atom or methyl independently respectively;
N is 1.
Another technical scheme of the present invention is as follows:
Wherein, R
1Be acetamido, hydroxyl, amino, C
1-6Alkyl amine group, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3, R
4, R
5Be hydrogen atom independently respectively, halogen atom, C
1-6Alkyl, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido or C
1-6Alkoxyl group;
A is the saturated or undersaturated nitrogen heterocyclic of 5-6 unit;
X is S, O or NR
9, R wherein
9Be hydrogen atom, C
1-6Alkyl, hydroxyl C
1-6Alkyl or amino C
1-6Alkyl;
R
6, R
7, R
8Be hydrogen atom independently respectively, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, hydroxyl C
1-6Alkyl or amino C
1-6Alkyl;
N is 1～3 integer.
Be preferably:
Wherein, R
1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3, R
4, R
5Be hydrogen atom independently respectively, halogen atom, C
1-3Alkyl, C
1-3Alkyl amine group, two (C
1-3Alkyl) amido or C
1-3Alkoxyl group;
A is a 5-6 unit unsaturated nitrogen heterocycle;
X is S, O or NR
9, R wherein
9Be hydrogen atom or C
1-3Alkyl;
R
6, R
7, R
8Be hydrogen atom independently respectively, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, hydroxyl C
1-4Alkyl or amino C
1-4Alkyl;
N is 1 or 2.
More preferably:
Wherein, R
1Be acetamido, hydroxyl or 1,2,3-triazol radical;
R
2, R
3, R
4, R
5Difference is hydrogen atom or fluorine atom independently;
A is 1,2,3-triazol radical, 1,2,4-triazol radical, pyrazolyl, imidazolyl, 1,2,3,4-tetrazole base, pyridyl or pyrazinyl;
X is S, O or NR
9, R wherein
9Be hydrogen atom, methyl, ethyl, propyl group, cyclopropyl or sec.-propyl;
R
6, R
7, R
8Be hydrogen atom independently respectively, fluorine atom, chlorine atom, methyl, methoxyl group, methylol or aminomethyl;
N is 1.
More preferably:
Wherein, R
1Be acetamido;
R
2, R
3, R
4, R
5Be hydrogen atom or fluorine atom independently;
A is 1,2,3-triazol radical or 1,2,3,4-tetrazole base;
X is S, O or NR
9, R wherein
9Be hydrogen atom or methyl;
R
6, R
7, R
8Be hydrogen atom or methyl independently respectively;
N is 1.
" halogen atom " of the present invention is meant fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" C of the present invention
1-6Alkyl, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl " in " C
1-6Alkyl " the expression straight chain; side chain or cyclic contain the alkyl of 1-6 carbon atom; as methyl; ethyl; n-propyl; sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, neo-pentyl, the 1-ethyl propyl, n-hexyl, isohexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 2-ethyl-butyl, 1-methyl-2-methyl-propyl, cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.
" the saturated or undersaturated nitrogen heterocyclic of 5-6 unit " of the present invention comprises pyrryl, Pyrrolidine base, imidazolidyl, pyrazolidine, imidazolyl, pyrazolyl, 4,5-pyrazoline, 1,2,3-triazol radical, 1,2,4-triazol radical, 1,2,3,4-tetrazyl, 1,2,3,5-tetrazyl, pyridyl, piperidyl, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazines base, 1,2,4,5-tetrazine base etc.
Particularly preferred compound comprises:
The present invention also provides the preparation method of above-claimed cpd:
Reaction equation:
Reactions steps:
The preparation of step 1 intermediate 1
Under the nitrogen protection, raw material 1, raw material 2, potassium acetate are joined among the DMSO (or dioxane, DMF, toluene), to wherein adding Pd (dppf)
2Cl
2(or Pd (PPh
3)
4), mixture 50-120 ℃ of down reaction 0.5-18 hour, reduce to room temperature after, remove solid to wherein adding the ethyl acetate after-filtration, mother liquor is with the saturated common salt water washing, dry back steam desolventize intermediate 1.
The preparation of step 2 formula I compound
Under the nitrogen protection, with intermediate 1, raw material 3, Na
2CO
3And water dissolution is in DMSO (perhaps dioxane, DMF), to wherein adding Pd (dppf)
2Cl
2(perhaps Pd (PPh
3)
4), mixture is in down reaction 3-10 hour of 50-120 ℃ of nitrogen protection, adds entry after being chilled to room temperature, and the solid crude product column chromatography purification gets formula I compound.
Raw material 1 in the above reaction equation, raw material 3 transform through simple functional group by the raw material that is easy to get and make.Have in the structure of part material 3 and contain protecting group (as 2; 4-dimethoxy-benzyl or trityl); the compound of this class formation is dissolved in the trifluoroacetic acid after reacting with intermediate 1, and 20-50 ℃ stirring is concentrated after 5-16 hour down, and the crude product column chromatography gets institute's corresponding (I) compound.R in the above reaction equation
1, R
2, R
2, R
4, R
5, R
6, R
7, R
8, A, X or n such as preamble define.
The compounds of this invention " pharmacy acceptable salt " is meant by the salt of pharmaceutically acceptable, non-toxic bases or acid preparation, comprises organic acid salt, inorganic acid salt, organic alkali salt, inorganic base salts.Organic acid salt comprises formate, acetate, propionic salt, benzene sulfonate, benzoate, tosilate, 2,3-dyhydrobutanedioic acid salt, camsilate, Citrate trianion, mesylate, esilate, propanesulfonic acid salt, fumarate, gluconate, glutaminate, isethionate, lactic acid salt, maleate, malate, mandelate, mucate, embonate, pantothenate, succinate, tartrate etc., preferred especially benzoate, benzene sulfonate, tosilate, mesylate, Citrate trianion, maleate, fumarate, tartrate.Inorganic acid salt comprises hydrogen chlorate, hydrobromate, hydriodate, vitriol, phosphoric acid salt, nitrate etc., preferred especially hydrogen chlorate, hydrobromate, vitriol, phosphoric acid salt.Organic alkali salt comprises primary, the second month in a season and tertiary amine, be substituted amine and comprise naturally occurring replacement amine, cyclammonium and basic ion exchange resin, be selected from arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylin ethanol, the 2-dimethylamino-ethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, the polyamides resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, the salt that Trometamol etc. form.Inorganic base salts comprises the basic cpd of ammonium salt and lithium salts, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, barium salt, aluminium salt, molysite, mantoquita, ferrous salt, manganese salt, manganous salt etc., preferred especially ammonium salt and sodium salt, sylvite, calcium salt, magnesium salts.
The compounds of this invention contains one or more asymmetric centers, thereby can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.The compounds of this invention has asymmetric center, and each will produce two optical isomers independently this class asymmetric center, and scope of the present invention comprises all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all stereoisomeric forms in any ratio of these compounds.
Compound of the present invention unless stated otherwise, the present invention includes cis-isomeride and trans-isomer(ide) if contain olefinic double bonds.
Compound of the present invention can exist with tautomeric forms, and it has the tie point of different hydrogen by one or more double-bond shifts.Each tautomer and composition thereof all is included in the compound of the present invention.
Compound and the intermediate in preparation process thereof shown in the formula for example of the present invention (I), the A representative
The time, change can take place, when having prepared one of them, be equivalent to prepare its tautomer.The compounds of this invention and preparation intermediate thereof that all relate to above-mentioned situation are considered as being equal to, and all are included in the scope of the invention.
That is:
For example prepare compound 1, be equivalent to prepare compound 1 '.
Compound 1 '
The present invention is the claimed pharmaceutical composition that comprises arbitrary compound recited above, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner further.Described composition can be made clinically or pharmaceutically acceptable arbitrary formulation, is preferably oral preparations, injection.
The compounds of this invention, its pharmacy acceptable salt or its steric isomer can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1mL, 2mL, 5mL, 10mL, 20mL, 50mL, 100mL, 200mL, 250mL, 500mL etc., and wherein large volume (generally the being not less than 100mL) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The present invention also provides and has contained the purposes that five-membered ring De oxazolidone antibiotic is used for preparing the medicine that treats and/or prevents infectious diseases.De oxazolidone antibiotic of the present invention has good antibacterial activity to gram-positive microorganism, and the Gram-positive resistant organism is also had good antibacterial activity, can be used for treating and/or preventing the various diseases that is caused by gram-positive microorganism.
Below further set forth the The compounds of this invention beneficial effect by antibacterial activity test, but this should be interpreted as that The compounds of this invention only has following beneficial effect.
The antibacterial activity in vitro of experimental example The compounds of this invention
For trying bacterial classification: following clinical isolates strain is all bought in public institution.
Methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), vancomycin-resistant enterococcus (VRE)
Trial-product: part of compounds of the present invention, its chemical name and preparation method are seen the preparation embodiment of each compound;
Experimental technique: agar dilution, with reference to National Committee for Clinical Laboratory Standards.2006.Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard--Seventh Edition M7-A7.
Experimental result and conclusion:
The anti-microbial activity of table 1 The compounds of this invention
The anti-microbial activity of table 2 The compounds of this invention
By table 1-2 experimental result as seen, test compound of the present invention all has better antibacterial activity to above strains tested, and The compounds of this invention has clinical application potentiality preferably.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1N-[[(S)-and 3-[3-fluoro-4-[5-[(1-methyl isophthalic acid H-tetrazolium-5-yl) methyl] thiophene-2-yl] phenyl]-2-Yang Dai oxazole
Alkane-5-yl] methyl] preparation of ethanamide (compound 1)
(1) three normal-butyl azide tin
200mL t-butyl methyl ether and three normal-butyl chlorination tin (15g) are joined NaN
3In water (34g) (200mL) solution, mixture stirring at room 1 hour, separatory collects organic phase and with anhydrous magnesium sulfate drying, getting product after concentrating is oily matter (15g, 97%).
(2) 2-(5-bromothiophene-2-yl) acetonitrile
Under the room temperature, (31.6g 0.178mol) joins 2-(thiophene-2-yl) acetonitrile (20g with NBS, 0.163mol) DMF solution in, mixture back flow reaction 5 hours, cooling back is with water and NaOH solution washing, concentrate after the organic phase drying, it is oily matter (21g, 64%) that the crude product column chromatography gets product.
(3) methyl 5-[(5-bromothiophene-2-yl)]-the 1H-tetrazolium
With 2-(5-bromothiophene-2-yl) acetonitrile (7.8g, 0.038mol) and tri-n-butyl tin trinitride (15.2g, 0.046mol) join in the dioxane (200mL), mixture refluxed 12 hours, with 1N salt acid elution, ethyl acetate (150mL) extraction, organic phase concentrates, it is solid (9.06g, 97%) that crude product gets product through column chromatography purification.
(4) (R)-3-(4-bromo-3-fluorophenyl)-5-(methylol) oxazolidine-2-ketone
The n-Butyl Lithium (200mL) and the trimethyl carbinol (50mL) are joined among the 340mL THF, stir 1 hour standby, get half above-mentioned solution and join isobutyl-4-bromo-3-fluorophenyl carbamate (50g, 0.1724mol) THF (200mL) solution in, all the other solution join (S)-3-chloropropane-1,2-glycol (20g, 0.2mol) THF (150mL) solution in, after 3 hours, with (S)-3-chloropropane-1, the mixture of 2-glycol splashes in the mixture of isobutyl-4-bromo-3-fluorophenyl carbamate, be reflected at 0 ℃ and stir down after 12 hours, with the THF extraction, saturated NaCl washing, it is solid (44.1g, 90%) that crude product gets product through column chromatography purification
(5) [(R)-and 3-(4-bromo-3-fluorophenyl)-2-Yang Dai oxazolidine-5-yl] methyl 4-toluene sulfonic acide ester
With (R)-3-(4-bromo-3-fluorophenyl)-5-(methylol) oxazolidine-2-ketone (44.1g, 0.152mol) and TsOCl (27.5g, 0.166mol) join in the methylene dichloride (400mL), then to wherein adding triethylamine (57mL), stirred 5 hours under the room temperature, decompression removes behind the solvent crude product, and to get product with the methylene dichloride recrystallization be white solid (64g, 95%).
(6) (R)-5-(azido-methyl)-3-(4-bromo-3-fluorophenyl) oxazolidine-2-ketone
Will [(R)-3-(4-bromo-3-fluorophenyl)-2-Yang Dai oxazolidine-5-yl] methyl 4-toluene sulfonic acide ester (36g, 0.081mol) and NaN
3(10.8g 0.166mol) joins among the DMF (200mL), and mixture refluxed 12 hours, then to wherein adding ethyl acetate (200mL), and saturated aqueous common salt (150mL * 3) washing, organic phase removes and obtains product behind the solvent is yellow solid (22g, 84.6%).
(7) (S)-5-(amino methyl)-3-(4-bromo-3-fluorophenyl) oxazolidine-2-ketone
With (R)-5-(azido-methyl)-3-(4-bromo-3-fluorophenyl) oxazolidine-2-ketone (20g, 0.063mol) and triphenyl phosphorus (18.3g, 0.07mol) join among the THF (300mL), mixture stirs after 3 hours and concentrates, add entry (200mL) in resistates, with ethyl acetate (200mL) extraction, organic phase is with anhydrous magnesium sulfate drying, getting product after steaming desolventizes is solid (18g, 99%).
(8) N-[[(S)-and 3-(4-bromo-3-fluorophenyl)-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide
With (S)-5-(amino methyl)-3-(4-bromo-3-fluorophenyl) oxazolidine-2-ketone (18g, 0.0625mol), diacetyl oxide (10mL, 0.09mol) and triethylamine (40mL, 0.29mol) join in the methylene dichloride (200mL), mixture stirring at room 5 hours, obtaining product behind the thick product recrystallization is white solid (18g, 90%).
(9) N-[[(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide
With N-[[(S)-3-(4-bromo-3-fluorophenyl)-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide (6g, 0.0182mol), two valeryl two boron (9.2g, 0.036mol), (7.1g 0.072mol) joins among the DMSO (50mL) potassium acetate, to wherein adding 1gPd (dppf)
2Cl
2, mixture 80-100 ℃ of down reaction 90 minutes, reduce to room temperature after, remove solid to wherein adding ethyl acetate (100mL) after-filtration, mother liquor is with the saturated common salt water washing, steams after desolventizing to such an extent that crude product be oily matter (3.5g, 50.9%).
(10) methyl 5-[(5-bromothiophene-2-yl)]-1-methyl isophthalic acid H-tetrazolium
With 5-[(5-bromothiophene-2-yl) methyl]-the 1H-tetrazolium (0.5g, 0.002mol), K
2CO
3(0.6g, 0.004mol) join among the DMF (100mL), stirred 2 hours down for back 0 ℃ to wherein adding methyl iodide (0.32g), add entry (500mL) and ethyl acetate (50mL) then, organic phase is washed with saturated aqueous common salt (100mL * 3), removing behind the solvent resistates column chromatography under reduced pressure, to get product be solid (0.4g, 40%).
(11) N-[[(S)-and 3-[3-fluoro-4-[5-[(1-methyl isophthalic acid H-tetrazolium-5-yl) methyl] thiophene-2-yl] phenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide
With N-[[(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide (0.8g, 0.002mol), 5-[(5-bromothiophene-2-yl) methyl]-1-methyl isophthalic acid H-tetrazolium (0.5g, 0.0019mol), Na
2CO
3(0.4g, 0.0037mol) and the 10mL water dissolution in 10mL DMSO, to wherein adding 0.1gPd (dppf)
2Cl
2, mixture is in down reaction 4 hours of 90 ℃ of nitrogen protections, adds 40mL water after being chilled to room temperature.The solid crude product column chromatography purification gets yellow solid (0.14g, 15.4%).
Molecular formula: C
19H
19FN
6O
3S molecular weight: 430.456 mass spectrums (M+H): 431
1H-NMR?DMSO(-d6，400MHz)：δ1.82(s，3H)，3.41(t，2H)，3.75(dd，1H)，4.02(s，3H)，4.13(t，1H)，4.61(s，2H)，4.72-4.75(m，1H)，7.04(dd，1H)，7.36-7.40(m，2H)，7.55-7.59(m，1H)，7.75(t，1H)，8.23(t，1H).
Embodiment 2N-[[(S)-and 3-[4-[5-[(1H-tetrazolium-5-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl]
Methyl] preparation of ethanamide (compound 2)
(1) 2-(5-bromothiophene-2-yl) acetonitrile
With reference to embodiment 1 (2), getting product is oily matter (21g, 64%).
(2) methyl 5-[(5-bromothiophene-2-yl)]-the 1H-tetrazolium
With reference to embodiment 1 (3), getting product is solid (9.06g, 97%).
(3) N-[[(S)-and 3-[4-[5-[(1H-tetrazolium-5-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide
With N-[[(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide (1.2g, 0.003mol), 5-[(5-bromothiophene-2-yl) methyl]-the 1H-tetrazolium (0.8g, 0.003mol), Na
2CO
3(0.68g, 0.006mol) and the 5mL water dissolution in 20mL DMSO, to wherein adding 0.5g Pd (dppf)
2Cl
2, mixture is in down reaction 3 hours of 90 ℃ of nitrogen protections, adds 100mL water after being chilled to room temperature, filters, and the resistates column chromatography purification gets white solid (0.25g, 20%).
Molecular formula: C
18H
17FN
6O
3S molecular weight: 416.429 mass spectrums (M+H): 417
1H-NMR(DMSO-d6，400MHz)：δ1.82(s，3H)，3.41(t，2H)，3.75(dd，1H)，4.13(t，1H)，4.55(s，2H)，4.72-4.75(m，1H)，7.02(d，1H)，7.35-7.39(m，2H)，7.57(dd，1H)，7.74(t，1H)，8.23(t，1H).
Embodiment 3N-[[(S)-and 3-[4-[5-[(3H-1,2,3-triazole-4-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine
-5-yl] methyl] preparation of ethanamide (compound 3)
(1) 2-bromo-5-(chloromethyl) thiophene
The 30mL sherwood oil is joined in the formaldehyde solution (18mL) of concentrated hydrochloric acid (18mL) and 37%, be chilled to 5 ℃, to wherein adding 2-bromothiophene (30g, 0.185mol), under the vigorous stirring to wherein feeding HCl gas and keeping system temperature below 10 ℃, merge organic phase behind the petroleum ether extraction, obtain yellow oil (34g, 87%) after concentrating.
(2) [3-(5-bromothiophene-2-yl)-1-proyl] trimethyl silane
With trimethylsilyl acetylene (6.7mL, 0.047mol) and ethylmagnesium bromide (15mL, 0.047mol) be dissolved among the THF (30mL), mixture stirred after 0.5 hour, to wherein add CuBr (0.3g, 2.4mmol) and 2-bromo-5-(chloromethyl) thiophene (10g, 0.047mmol), refluxed 3 hours, with saturated NH
4The Cl cancellation, ethyl acetate extraction, saturated common salt water washing organic phase, it is yellow oil (6.6g, 51.4%) that column chromatography purification obtains product.
(3) 2-bromo-5-(2-propynyl) thiophene
With [3-(5-bromothiophene-2-yl)-1-proyl] trimethyl silane (1g, 0.0037mol), K
2CO
3(1g 0.0074mol) joins in the methyl alcohol (10mL), stirring at room 12 hours, and mixture washs three times with 3N hydrochloric acid (50mL), ethyl acetate extraction, the saturated common salt water washing, it is oily matter (0.3g, 44.7%) that concentrated back preparation plate purifying gets product.
(4) methyl 1-(2, the 4-dimethoxy-benzyl)-5-[(5-bromothiophene-2-yl)]-1H-1,2, the 3-triazole
With 2-bromo-5-(2-propynyl) thiophene (0.42g, 0.0022mol) and 1-(azido-methyl)-2,4-dimethoxy benzene (0.4g, 0.0022mol) be dissolved in the dioxane (20mL), mixture stirred 12 hours, and it is solid (1.4g, 63%) that concentrated back crude product column chromatography gets product.
(5) N-[[(S)-and 3-[4-[5-[[3-(2, the 4-dimethoxy-benzyl)-3H-1,2,3-triazole-4-yl] methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide
With reference to having a try example 1 (11), throw 1-(2, the 4-dimethoxy-benzyl)-5-[(5-bromothiophene-2-yl) methyl]-1H-1,2, and the 3-triazole (0.7g, 0.0018mol), N-[[(S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide (0.68g, 0.0018mol), getting product is yellow solid (0.7g, 67%).
(6) N-[[(S)-and 3-[4-[5-[(3H-1,2,3-triazole-4-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl] methyl) ethanamide
With N-[[(S)-3-[4-[5-[[3-(2, the 4-dimethoxy-benzyl)-3H-1,2,3-triazole-4-yl] methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide (0.7g, 0.00124mol) be dissolved among the TFA (20mL), stirring is concentrated after 12 hours down in 50 ℃ for mixture.It is yellow solid (0.22g, 43%) that the crude product column chromatography gets product.
Molecular formula: C
19H
18FN
5O
3S molecular weight: 415.441 mass spectrums (M+H): 416
1H-NMR(DMSO-d6，400MHz)：δ1.81(s，3H)，3.40(m，2H)，3.74(t，1H)，4.12(t，1H)，4.24(s，2H)，4.71-4.74(m，1H)，6.93(s，1H)，7.33-7.35(m，2H)，7.53-7.57(m，1H)，7.64(s，1H)，7.68-7.73(t，1H)，8.22(t，1H).
Embodiment 4 (S)-N-[[3-[4-[5-[(1H-1,2, the 3-triazol-1-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine
-5-yl] methyl] preparation of acetamide hydrochloride (compound 4 hydrochlorides)
(1) 2-bromo-5-(brooethyl) thiophene
In the exsiccant reaction flask, (5g 25.4mmol) is dissolved in 50mL CCl with 2-bromo-5-thiotolene
4In, to wherein add NBS (4.97g, 27.9mmol) and AIBN (0.5g, 3.05mmol), mixture stirs down at 80 ℃ and spends the night, the mixture that obtains is not purified to be directly used in next step reaction.
(2) methyl 1-[(5-bromothiophene-2-yl)]-1H-1,2, the 3-triazole
In the exsiccant reaction flask, and 2-bromo-5-(brooethyl) thiophene that previous step is obtained (3g 11.72mmol) is dissolved in the 20mL acetonitrile, to wherein adding 1H-1, and 2, the 3-triazole (0.81g, 11.72mmol) and K
2CO
3(1.62g, 11.72mmol), mixture heating up refluxed 3 hours, added entry and ethyl acetate in mixture, ethyl acetate extraction, merge organic phase, the organic phase anhydrous sodium sulfate drying filters, be concentrated into dried, (EA: PE=10: 1) purifying gets product white solid (2.2g, 76.9%) to residue through silica gel column chromatography.
(3) (S)-and N-[[3-[4-[5-[(1H-1,2, the 3-triazol-1-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide
In the exsiccant reaction flask, with 1-[(5-bromothiophene-2-yl) methyl]-1H-1,2,3-triazole (0.5g, 2.05mmol) be dissolved in (dioxane: water=5: 1))-3-[3-fluoro-4-(4,4 in the mixed solvent of 55mL dioxane and water to wherein adding N-[[(S, 5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) phenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide (1g, 2.65mmol), 0.05gPd (dppf)
2Cl
2And Na
2CO
3(0.43g, 4.1mmol), mixture adds entry and ethyl acetate in 80 ℃ of down heating 6 hours in mixture, and ethyl acetate extraction merges organic phase, the organic phase anhydrous sodium sulfate drying, filtration is concentrated into driedly, and residue is through silica gel column chromatography (MeOH: CH
2Cl
2=1: 25) purifying gets product white solid (200mg, 24.9%).
Molecular formula: C
19H
18FN
5O
3S molecular weight: 415.44 mass spectrums (M+H): 416
1H-NMR(CDCl
3，600MHz)：δ7.73(s，1H)，7.60(s，1H)，7.56-7.53(m，2H)，7.31(d，1H)，7.22(d，1H)，7.10(d，1H)，5.92(t，1H)，5.75(s，2H)，4.81(b，1H)，4.07(t，1H)，3.66-3.61(m，1H)，3.75-3.71(m，1H)，3.81-3.79(m，1H)，2.03(s，3H).
(4) (S)-and N-[[3-[4-[5-[(1H-1,2, the 3-triazol-1-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl] methyl] acetamide hydrochloride
In the exsiccant reaction flask, with (S)-N-[[3-[4-[5-[(1H-1,2, the 3-triazol-1-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide 60mg is dissolved in the 10mL methylene dichloride, to wherein feeding hydrogenchloride, mixture at room temperature stirred 6 hours, and the solvent evaporate to dryness is got product white solid (50mg, 83%).
With reference to above-mentioned preparation method, can also prepare following compound.
Claims (9)
1. the compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer:
Wherein, R
1Be acetamido, hydroxyl, amino, C
1-6Alkyl amine group, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3, R
4, R
5Be hydrogen atom independently respectively, halogen atom, C
1-6Alkyl, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido or C
1-6Alkoxyl group;
A is the saturated or undersaturated nitrogen heterocyclic of 5-6 unit;
X is S, O or NR
9, R wherein
9Be hydrogen atom, C
1-6Alkyl, hydroxyl C
1-6Alkyl or amino C
1-6Alkyl;
R
6, R
7, R
8Be hydrogen atom independently respectively, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, hydroxyl C
1-6Alkyl or amino C
1-6Alkyl;
N is 1～3 integer.
2. compound as claimed in claim 1, its pharmacy acceptable salt or its steric isomer:
Wherein, R
1Be acetamido, hydroxyl, 1,2,3-triazol radical Huo isoxazole oxygen base;
R
2, R
3, R
4, R
5Be hydrogen atom independently respectively, halogen atom, C
1-3Alkyl, C
1-3Alkyl amine group, two (C
1-3Alkyl) amido or C
1-3Alkoxyl group;
A is a 5-6 unit unsaturated nitrogen heterocycle;
X is S, O or NR
9, R wherein
9Be hydrogen atom or C
1-3Alkyl;
R
6, R
7, R
8Be hydrogen atom independently respectively, halogen atom, C
1-4Alkyl, C
1-4Alkoxyl group, hydroxyl C
1-4Alkyl or amino C
1-4Alkyl;
N is 1 or 2.
3. compound as claimed in claim 2, its pharmacy acceptable salt or its steric isomer:
Wherein, R
1Be acetamido, hydroxyl or 1,2,3-triazol radical;
R
2, R
3, R
4, R
5Difference is hydrogen atom or fluorine atom independently;
A is 1,2,3-triazol radical, 1,2,4-triazol radical, pyrazolyl, imidazolyl, 1,2,3,4-tetrazole base, pyridyl or pyrazinyl;
X is S, O or NR
9, R wherein
9Be hydrogen atom, methyl, ethyl, propyl group, sec.-propyl or cyclopropyl;
R
6, R
7, R
8Be hydrogen atom independently respectively, fluorine atom, chlorine atom, methyl, methoxyl group, methylol or aminomethyl;
N is 1.
4. compound as claimed in claim 3, its pharmacy acceptable salt or its steric isomer:
Wherein, R
1Be acetamido;
R
2, R
3, R
4, R
5Be hydrogen atom or fluorine atom independently;
A is 1,2,3-triazol radical or 1,2,3,4-tetrazole base;
X is S, O or NR
9, R wherein
9Be hydrogen atom or methyl;
R
6, R
7, R
8Be hydrogen atom or methyl independently respectively;
N is 1.
5. compound as claimed in claim 4, its pharmacy acceptable salt or its steric isomer, described compound is:
N-[[(S)-and 3-[3-fluoro-4-[5-[(1-methyl isophthalic acid H-tetrazolium-5-yl) methyl] thiophene-2-yl] phenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide,
N-[[(S)-and 3-[4-[5-[(1H-tetrazolium-5-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide,
N-[[(S)-and 3-[4-[5-[(3H-1,2,3-triazole-4-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide, or
(S)-and N-[[3-[4-[5-[(1H-1,2, the 3-triazol-1-yl) methyl] thiophene-2-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-yl] methyl] ethanamide.
6. as each described compound of claim 1～5, its pharmacy acceptable salt or its steric isomer, its pharmacy acceptable salt is benzoate, benzene sulfonate, tosilate, mesylate, Citrate trianion, maleate, fumarate, tartrate, hydrogen chlorate, hydrobromate, vitriol, phosphoric acid salt, ammonium salt, sodium salt, sylvite, calcium salt, magnesium salts.
7. the pharmaceutical composition that comprises each described compound of claim 1～5, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner is characterized in that described pharmaceutical composition is for clinically or pharmaceutically acceptable arbitrary formulation.
8. pharmaceutical composition as claimed in claim 7 is characterized in that being oral preparations or injection.
9. each described compound of claim 1～5, its pharmacy acceptable salt and steric isomer thereof treat and/or prevent application in the medicine of infectious diseases in preparation.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014528946A (en) * | 2011-09-29 | 2014-10-30 | 山東軒竹医薬科技有限公司 | Oxazolidone antibacterials substituted with biaryl heterocycles |
| CN106045934A (en) * | 2015-10-27 | 2016-10-26 | 博瑞生物医药（苏州）股份有限公司 | Crystal form of intermediate used for synthesis of tedizolid |
| CN111320618A (en) * | 2018-12-17 | 2020-06-23 | 好医生药业集团有限公司 | Novel anti-staphylococcus small molecule compound and preparation method and application thereof |
| CN115785020A (en) * | 2022-11-24 | 2023-03-14 | 济宁福顺化工有限公司 | Synthetic method of 2-chloro-5-chloromethyl thiazole |
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| WO1993009103A1 (en) * | 1991-11-01 | 1993-05-13 | The Upjohn Company | Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents |
| WO2006018682A2 (en) * | 2004-08-11 | 2006-02-23 | Ranbaxy Laboratories Limited | Oxazolidinone derivatives as antimicrobials |
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| CN1894242A (en) * | 2003-12-18 | 2007-01-10 | 东亚制药株式会社 | Novel oxazolidinone derivatives |
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2011
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| WO1993009103A1 (en) * | 1991-11-01 | 1993-05-13 | The Upjohn Company | Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2014528946A (en) * | 2011-09-29 | 2014-10-30 | 山東軒竹医薬科技有限公司 | Oxazolidone antibacterials substituted with biaryl heterocycles |
| CN106045934A (en) * | 2015-10-27 | 2016-10-26 | 博瑞生物医药（苏州）股份有限公司 | Crystal form of intermediate used for synthesis of tedizolid |
| CN111320618A (en) * | 2018-12-17 | 2020-06-23 | 好医生药业集团有限公司 | Novel anti-staphylococcus small molecule compound and preparation method and application thereof |
| CN115785020A (en) * | 2022-11-24 | 2023-03-14 | 济宁福顺化工有限公司 | Synthetic method of 2-chloro-5-chloromethyl thiazole |
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