CN107033095B - The Oxazolidinone derivative of the structure of hydrazone containing piperazine - Google Patents
The Oxazolidinone derivative of the structure of hydrazone containing piperazine Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D263/20—Oxygen atoms attached in position 2
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- C07—ORGANIC CHEMISTRY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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Abstract
The present invention discloses a kind of Oxazolidinone derivative of structure of hydrazone containing piperazine, including compound or its stereoisomer or its pharmaceutically acceptable salt or its solvate or its prodrug containing general formula (I)；Wherein, R1 is hydrogen, fluorine, chlorine or trifluoromethyl；R2 is-NHCOCH3 or-OH；R3 be Ar,Ar is the C5-C10 aryl and heteroaryl that any 1-3 R4 replaces；R4 is hydrogen, hydroxyl, halogen; nitro, amino, cyano; C1-C6 alkyl, C1-C6 alkoxy, optionally by hydroxyl, amino or halogenated C1-C6 alkyl; the amino optionally replaced by hydroxyl, amino or halogenated C1-C6 alkoxy, coverlet or two (C1-C6 alkyl), C1-C6 alkylamidoalkyl; free, at salt, esterification and amidated carboxyl, C1-C6 alkyl sulphinyl, C1-C6 alkyl sulphonyl; C1-C6 alkyl acyl, carbamoyl.The compound can be used for preparing the drug for the treatment of microorganism infection.
Description
Technical field:
The present invention relates to field of medicinal chemistry, in particular to the Oxazolidinone compound of a kind of structure of hydrazone containing piperazine or its
Optical isomer, pharmaceutically acceptable salt and/or solvate, and containing their pharmaceutical composition, preparation method and
Using.
Background technique:
In recent years, the even abuse that is widely used of antibacterials causes the death rate of infectious diseases to steeply rise, and is facing
On bed, the drug resistance problems of bacterium are got worse, and some antibacterials curative effects is caused to reduce, or even invalid, such as methicillin-resistant
Staphylococcus aureus (MR (S) A), the staphylococcus epidermis (MR (S) E) of methicillin-resistant, vancomycin resistance pneumonia intestines
Coccus (VRE).Some non-pathogenic bacterias become conditioned pathogen, such as proteus, pseudomonas aeruginosa.All these drug-fast bacterias
The formation and development of strain brings great difficulty for clinical treatment, and present antibacterials, which have been unable to meet, must clinically need,
Therefore, especially there are the antibacterials for developing novel overriding resistance the antibacterials of novel mechanism of action to seem especially urgent.
Oxazolidinones antimicrobial is that the chemistry that another structure is completely new after sulfamido and Comprecin is complete
Synthetic antibacterial drug drug.Oxazolidinones antimicrobial can be in conjunction with bacterial ribosome 50 (S) methylene, to inhibit bacterioprotein
Seldom there is cross resistance with other antibacterials in the synthesis of matter.E.I.Du Pont Company in 1987 reports 2 completely new oxazolidones
Class antibacterial drug compound DuP721 and DuP105, the two compounds are the representatives of novel oxazolidinones antimicrobial.In this base
On plinth, Pu Qiang company, the U.S. successfully has developed first oxazolidinones antimicrobial --- Linezolid (Linezolid), the medicine
Object is ratified to list in April, 2000 in the U.S., for treating for treating the multiple microbial infection of resistance to Grain-positive.Specially azoles
Amine (Tedizolid) is the oxazolidinones antimicrobial of second listing, is used in June, 2014 through U.S. FDA approval listing
Treat skin infection.
However since listing, with being widely used for they, drug resistance problems have also occurred, and need to do it into one
More novel compound is designed in the optimization of step, to overcome drug resistance.Have no that someone's preparation contains piperazine hydrazone knot in the prior art
The Oxazolidinone derivative of structure, and antibacterial activity especially antimicrobial agent activity research is carried out to it.
Summary of the invention:
It is an object of the present invention to provide a kind of Oxazolidinone derivatives of structure of hydrazone containing piperazine comprising is related to general formula (I)
Compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate or its prodrug,
Wherein,
R1For hydrogen, fluorine, chlorine or trifluoromethyl；
R2Selected from-NHCOCH3Or-OH；
R3For Ar,
Ar is any 1-3 R4(the C replaced5-C10) aryl and heteroaryl；
R4For hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, optionally by hydroxyl, ammonia
Base or halogenated (C1-C6) alkyl or (C1-C6) alkoxy, coverlet or two (C1-C6Alkyl) replace amino, (C1-C6) alkyl acyl
Amido, free, at salt, esterification and amidated carboxyl, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl,
(C1-C6) alkyl acyl, carbamoyl.
Preferably, the Oxazolidinone derivative of the structure of hydrazone containing piperazine,
R1For fluorine；
R2Selected from-NHCOCH3。
R3For Ar,
Ar is any 1-3 R4(the C replaced5-C10) aryl and heteroaryl；
R4For hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, optionally by hydroxyl, ammonia
Base or halogenated (C1-C6) alkyl or (C1-C6) alkoxy, coverlet or two (C1-C6Alkyl) replace amino, (C1-C6) alkyl acyl
Amido, free, at salt, esterification and amidated carboxyl, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl,
(C1-C6) alkyl acyl, carbamoyl.
Preferably, the Oxazolidinone derivative of the structure of hydrazone containing piperazine,
R1For fluorine；
R2Selected from-NHCOCH3；
R3For Ar,
Ar is any 1-3 R4Substituted phenyl, pyridyl group, furyl, thienyl, pyrrole radicals, pyrazolyl, oxazolyl,
Isoxazolyl, thiazolyl, imidazole radicals, triazol radical, pyrazinyl, pyrimidine radicals, pyridazinyl, isoquinolyl, indyl, imidazole radicals,
Triazol radical, naphthalene；
R4For hydrogen, hydroxyl, halogen, nitro, amino, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, optionally by hydroxyl, ammonia
Base or halogenated (C1-C6) alkyl or (C1-C6) alkoxy, coverlet or two (C1-C6Alkyl) replace amino, (C1-C6) alkyl acyl
Amido, free, at salt, esterification and amidated carboxyl, (C1-C6) alkyl sulphinyl, (C1-C6) alkyl sulphonyl,
(C1-C6) alkyl acyl, carbamoyl.
It is further preferable that the Oxazolidinone derivative of the structure of hydrazone containing piperazine,
R1For fluorine；
R2Selected from-NHCOCH3；
R3For Ar,
Ar is any 1-3 R4Substituted phenyl, quinolyl；
R4For 1-3 it is identical or different be selected from hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, amino, cyano, methyl, second
Base, n-propyl, isopropyl, tert-butyl, vinyl, acrylic, 2- methylpropenyl, acetenyl, methoxyl group, ethyoxyl, cyclopropyl
Oxygroup, tert-butoxy, allyl, trifluoromethyl, trifluoromethoxy, methylamino, ethylamino-, dimethylamino, formamido group, acetyl
Amino, propionamido, cyclopropyl acylamino-, carboxyl, methylsulfinyl, sulfonyl, mesyl, formoxyl, acetyl group, propionyl
Base, cyclopropyl acyl group, carbamoyl substituent group.
It is further preferable that the Oxazolidinone derivative of the structure of hydrazone containing piperazine, specifically:
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (pyrroles -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazole
Alkyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (thiophene -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazole
Alkyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (furans -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazole
Alkyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (pyridine -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazole
Alkyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (naphthalene -1- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidine
Base] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (indoles -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazole
Alkyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (phenyl ring -1- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazole
Alkyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((4- methyl) -1- methylene phenyl) aminopiperazine base) phenyl) -2- oxygen
Generation -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((4- fluorine) -1- methylene phenyl) aminopiperazine base) phenyl) -2- oxo -
5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((the chloro- 4- fluorine of 3-) -1- methylene phenyl) aminopiperazine base) phenyl) -2-
Oxo -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- phenyl thiazole) -4- methylene) aminopiperazine base) phenyl) -2- oxygen
Generation -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (3- aminomethyl phenyl) thiazole) -4- methylene) aminopiperazine base) benzene
Base) -2- oxo -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- fluorophenyl) thiazole) -4- methylene) aminopiperazine base) phenyl) -
2- oxo -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (2,4 difluorobenzene base) thiazole) -4- methylene) aminopiperazine base) benzene
Base) -2- oxo -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- tolylthiophene -5- methylene) aminopiperazine base) phenyl) -2- oxo -
5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- methoxyphenyl) thiophene) -5- methylene) aminopiperazine base) benzene
Base) -2- oxo -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- fluorophenyl) thiophene) -5- methylene) aminopiperazine base) phenyl) -
2- oxo -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (2,4 difluorobenzene base) thiophene) -5- methylene) aminopiperazine base) benzene
Base) -2- oxo -5- oxazolidinyl] methyl] acetamide.
The Oxazolidinone derivative of the structure of hydrazone containing piperazine, it is described to be related to the solvate of general formula (I), such as second
Alcohol, water etc., wherein different amounts of water can be contained, such as monohydrate, semihydrate, a semihydrate, dihydrate or three
Hydrate.
According to some usual methods of the art, generalformulaⅰcompound of the invention can generate its medicine with acid
Acceptable salt on.Acid may include inorganic acid or organic acid, and the salt formed with following acid is particularly preferred: hydrochloric acid, hydrogen
Bromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, cream
Acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzene sulfonic acid, naphthalene sulfonic acids, trifluoroacetic acid
And aspartic acid.
The invention also includes the prodrugs of the compounds of this invention.According to the present invention, prodrug is the derivative of generalformulaⅰcompound,
Their own may have weaker activity or even without activity, but upon administration, in physiological conditions (such as pass through
Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
The invention also includes the racemic modification of the compounds of this invention, optical active isomers, polymorphic forms or its mixing
Object, they have useful quality of the present invention.Generalformulaⅰcompound of the present invention contains the chiral centre (C-5 of oxazolidone ring
Position), therefore there are the racemic mixtures of two kinds of enantiomers or both.The present invention relates to two kinds of enantiomers of useful quality and
Containing there are two types of the mixtures of isomers.
Unless otherwise noted, term used herein " alkyl " refers to the alkyl of linear chain or branched chain；" alkoxy " refers to
The alkoxy of linear chain or branched chain；" alkenyl " refers to the alkenyl of linear chain or branched chain；" alkynyl " refers to the alkynyl of linear chain or branched chain；5-10
Unit's heteroaryl includes containing one or more hetero atoms for being selected from N, O and (S), wherein the cyclic annular system of each heteroaryl can be
Monocycle is polycyclic, and cyclic annular system is armaticity, altogether contain 5-10 atom, it can be cited for example that pyridyl group, furyl,
Thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazole radicals, triazol radical, pyrazinyl, pyrimidine radicals, is rattled away at pyrrole radicals
Piperazine base, isoquinolyl, indyl, imidazole radicals, triazol radical, naphthalene.
The invention also includes pharmaceutical composition, the composition includes generalformulaⅰcompound and their pharmaceutically acceptable salts
And/or solvate is as active constituent and pharmaceutically acceptable carrier；The compound of the present invention can be with other activity
Ingredient is applied in combination, as long as they do not generate other unfavorable effects, such as allergic reaction.
Carrier for pharmaceutical composition of the present invention is available common type in pharmaceutical field, comprising: oral preparation
Adhesive, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, non-pigment, corrigent etc.；Injectable system
Preservative, solubilizer, stabilizer of agent etc.；Matrix, diluent, lubricant, preservative of topical formulations etc..Pharmaceutical preparation
It can by oral administration or parenteral (such as in intravenous, subcutaneous, peritonaeum or part) administration, if some drugs are in stomach item
Be under part it is unstable, enteric coated tablets can be configured to.
The invention also includes it to prepare answering in the drug for treating mammal microorganism especially bacterium infection
With.The application method gives a effective amount of generalformulaⅰcompound, can by compound in pharmaceutical composition to mammal mouthful
Clothes, parenteral, transdermal or local administration.
Since the Oxazolidinone derivative of general formula I according to the invention has anti-microbial infection especially antibacterium living
Property, therefore, it may be used as the drug of preparation treatment mammalian bacterial infection, and compound according to the present invention can be used as activity
Ingredient be used to prepare treatment mammalian bacterial infection method, including give suffer from or be susceptible to this disease Case treatment it is effective
The compound according to the present invention of amount.
The precise volume of the compounds of this invention needed for treating microorganism especially bacterium infection will be different because of subject, according to
Rely the type in subject, age and general condition, the seriousness of treated disease, specific compound used and to prescription
Formula, such as the approach and frequency etc. of administration.Those of ordinary skill in the art can determine suitable just with routine experiment method
When effective quantity.
The dosage of compound can be daily from about 0.1~100mg/kg weight, preferably 1~50mg/kg body weight/day.It can
With understanding, dosage can be because of the demand of patient, the seriousness for the bacterium infection treated and used specific compound
And it is different.Also, it is to be understood that the initial dosage being administered can increase beyond the upper limit, it is therefore an objective to be rapidly reached required blood
Liquid is horizontal or initial dosage can be less than optimum value, and daily dosage can gradually increase during treatment, this is dependent on specific
The case where.If necessary, daily dosage can also be divided into multiple dose administration, such as 2-4 times daily.
Mammal indicates human or animal.
Active constituent, that is, amount of the compound according to the present invention in pharmaceutical composition and its unit dosage forms can be each
It is not identical, dependent on specific application, the effect of specific compound and required concentration.In general, the content of active constituent will be
Between 0.5%~90%, it is based on the total weight of the composition.
In conjoint therapy, the compounds of this invention and other compounds can be administered at the same time by simultaneously or doses at intervals
When, the compounds of this invention and other compounds can be bonded in single pharmaceutical composition or in separated composition
In.
Following synthetic route A, B, C, D describe the preparation of general formula I of the present invention, and all raw materials are shown by these
Method described in Italian type, by organic chemistry filed it is well-known to the ordinarily skilled artisan method preparation or it is commercially available.This hair
Bright whole final compounds are prepared by method described in these signal formulas or by similar method, this
A little methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.The whole variable factors applied in these signal formulas are as follows
Definition in definition or such as claim.
Generalformulaⅰcompound according to the invention, in route A, route B, route C and route D, R1For hydrogen, fluorine, chlorine and three
Methyl fluoride；R4For 1-3 it is identical or different selected from hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, amino, cyano, methyl, ethyl,
N-propyl, isopropyl, tert-butyl, vinyl, acrylic, 2- methylpropenyl, acetenyl, methoxyl group, ethyoxyl, cyclopropyl oxygen
Base, tert-butoxy, allyl, trifluoromethyl, trifluoromethoxy, methylamino, ethylamino-, dimethylamino, formamido group, acetyl ammonia
Base, propionamido, cyclopropyl acylamino-, carboxyl, methylsulfinyl, sulfonyl, mesyl, formoxyl, acetyl group, propionyl
Base, cyclopropyl acyl group, carbamoyl substituent group.
The synthesis of route A intermediate compound I
In route A, with R1Substituted 4- fluoronitrobenzene is starting material, and nucleophilic displacement of fluorine occurs with piperazine and obtains intermediate 1-
(2-R1- 4- nitrobenzophenone) piperazine (I a), then react with di-tert-butyl dicarbonate obtained intermediate 1- tertbutyloxycarbonyl-
4- (the fluoro- 4- nitrobenzophenone of 2-) piperazine (I b).In FeCl3·6H2In the presence of O, reduction reaction system occurs for chemical compounds I b and hydrazine hydrate
Obtain intermediate 1- tertbutyloxycarbonyl -4- (2-R1- 4- aminophenyl) piperazine (I c), it is made through acylation occurs with methylchloroformate
Obtain intermediate 1- tertbutyloxycarbonyl -4- (2-R1- 4- ((methoxycarbonyl group) amino) phenyl) piperazine (I d).Exist in tert-butyl alcohol lithium
Under, cyclization reaction then occurs with ((S))-N- [2- acetoxy-3-chloropropyl] acetamide, the tertiary fourth of intermediate (S)-1- is made
Oxygen carbonyl -4- (2-R1- 4- (5- (acetyl aminomethyl) -2- oxo -3- oxazolidinyl) phenyl) piperazine (I e).It is deposited in hydrochloric acid methanol
Under, Boc is removed, intermediate (S)-N- [[3- (3'-R is made1- 4'- (4- piperazinyl) phenyl) -2- oxo -5- oxazolidinyl]
Methyl] acetamide (I f).Intermediate (S)-N- [[3- (3'-R is made through nitrosation in chemical compounds I f'1- 4'- (4- nitroso piperazine
Base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide (I g).In the presence of glacial acetic acid, then it is made with zinc powder reduction
Intermediate (S)-N- [[3- (3'-R1- 4'- (4- aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide
(Ⅰ)。
The synthesis of route B compound I-i
In route B, using aromatic aldehyde as starting material, is reacted with intermediate compound I and compounds of formula I I-i is made.
The synthesis of route C compound I-ii
In route C, with R4Substituted benzonitrile is starting material, anti-with NaHS in the presence of Magnesium dichloride hexahydrate
It should obtain R4Substituted thiobenzamide (C1) then occurs cyclization reaction with ethyl bromide acetone and R is made4Substituted 2-
Phenyl thiazole -4- carboxylic acid, ethyl ester (C2).Compound C2 is reacted with Lithium Aluminium Hydride is made R4Substituted 2- phenyl thiazole -4- methanol
(C3), it then reacts to obtain R with pyridine chlorochromate drone salt (PCC)4Substituted 2- phenyl thiazole -4- formaldehyde (II C).Compound
II C is reacted with intermediate compound I generates compounds of formula I I-ii.
The synthesis of route D compound I-iii
In route D, with R4Substituted acetophenone is starting material, and the chloro- 3- phenyl of (Z) -3- that substitution is made is reacted with DMF
Methacrylaldehyde (D1) then reacts with ethyl thioglycolate and generates R4Substituted 5- tolylthiophene -2- carboxylic acid, ethyl ester (D2).Compound
D2 is reacted with Lithium Aluminium Hydride is made R4Substituted 5- tolylthiophene -2- methanol (D3), then with pyridine chlorochromate drone salt (PCC)
Reaction obtains R4Substituted 5- tolylthiophene -2- formaldehyde (II D).Compound II D reacts the change for generating general formula I with intermediate compound I
Close object I-iii.
Specific embodiment
Following embodiment is intended to illustrate and be not intended to limit the scope of the invention.The nuclear magnetic resonance spectroscopy Bruker of compound
ARX-300 measurement, mass spectrum are measured with 1100 LC/M of Agilent (S) D；Agents useful for same is that analysis is pure or chemical pure.
Embodiment 1 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- (pyrroles -3- methylene) aminopiperazine base) phenyl) -2- oxo -
5- oxazolidinyl] methyl] acetamide preparation
1.1 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] second
The preparation of amide (intermediate I)
1.1.1 the preparation of intermediate 1- (the fluoro- 4- nitrobenzophenone of 2-) piperazine (I a)
At room temperature, Piperazine anhydrous 12.9g (150mmol) is dissolved in 80mL acetonitrile, 3,4- difluoro is slowly added dropwise thereto
Nitrobenzene 7.95g (50mmol), drop finish, and are warming up to 80 DEG C of reaction 3h.Reaction is finished, and reaction solution is cooled to room temperature, and is concentrated under reduced pressure
80mL water is added into residue, is extracted with ethyl acetate (3 × 50mL) for solvent, merges organic layer, with saturated common salt washing (2
× 50mL), anhydrous sodium sulfate is dry, filters, filtrate is evaporated, yellow solid 11.0g, yield 97.7% are obtained.M(S)(E(S)I)
m/z:226.1[M+H]+。
1.1.2 the preparation of intermediate 1- tertbutyloxycarbonyl -4- (the fluoro- 4- nitrobenzophenone of 2-) piperazine (I b)
At room temperature, 2.25g (10mmol) intermediate I a is dissolved in 10mL methylene chloride, 2.62g is added dropwise into reaction solution
Methylene chloride (10mL) solution of (12mmol) di-tert-butyl dicarbonate, drop finish, and are warming up to 40 DEG C of reaction 2h.Reaction is finished, to anti-
Answer liquid cooling but after successively washed (3 × 20mL) with saturated sodium bicarbonate, saturated common salt washes (3 × 20mL), and anhydrous sodium sulfate is dry,
It filters, filtrate is evaporated, yellow solid 3.0g, yield 92.3% are obtained.M(S)(E(S)I)m/z:326.1[M+H]+。
1.1.3 the preparation of intermediate 1- tertbutyloxycarbonyl -4- (the fluoro- 4- aminophenyl of 2-) piperazine (I c)
At room temperature, 3.5g (10mmol) intermediate I b is dissolved in the 90%EtOH of 35mL, is warming up to 70 DEG C, is successively added
0.44g(1.5mmol)FeCl36H2O and 0.038g (3mmol) active carbon, are stirred to react 10min, then 6.73g is added dropwise
The hydrazine hydrate of (100mmol) 80%, drop finish, and are warming up to 90 DEG C of reaction 2h.Reaction is finished, and filters while hot, solvent is evaporated to obtain crude product,
50mL water is added into crude product again, platform stirs 0.5h, filters, and filter cake elutes with a small amount of water, dry faint yellow solid 2.5g,
Yield 78.6%.M(S)(E(S)I)m/z:296.2[M+H]+。
1.1.4 the preparation of intermediate 1- tertbutyloxycarbonyl -4- (the fluoro- 4- of 2- ((methoxycarbonyl group) amino) phenyl) piperazine (I d)
Under ice bath, by 3.0g (10mmol) intermediate I c, 2.1g (16mmol) n,N-diisopropylethylamine (DIPEA) and
30mL methylene chloride is added in 50mL three-necked bottle, hereinafter, 1.54g (16mmol) methylchloroformate is added dropwise, drop finishes 0 DEG C of temperature control,
React at room temperature 1.5h.Reaction is complete, evaporating solvent under reduced pressure, then adds 50mL water thereto, and platform stirs 0.5h, filters, and filter cake is with less
Measure water elution, dry faint yellow solid 2.6g, yield 72.4%.M(S)(E(S)I)m/z:354.2[M+H]+。
1.1.5 intermediate (S) -1- tertbutyloxycarbonyl -4- (the fluoro- 4- of 2- (5- (acetyl aminomethyl) -2- oxo -3- oxazolidine
Base) phenyl) piperazine (I e) preparation
Under nitrogen protection, 7.0g (20mmol) intermediate I d is dissolved in the dry n,N-Dimethylformamide (DMF) of 30mL
In, it stirs at room temperature, adds 4.8g (40mmol) tert-butyl alcohol lithium, be warming up to 30 DEG C of stirring 1h, reaction solution is then cooled to 5
~10 DEG C, 1.3g (40mmol) chromatography methanol is added dropwise, after stirring 1.5h, 7.6g (40mmol) is slowly added dropwise into reaction solution
DMF (15mL) solution of ((S))-N- [2- acetoxy-3-chloropropyl] acetamide, drop finish, and react at room temperature 48h.Reaction is finished, ice
Bath is cooled to 0~5 DEG C, and the saturated aqueous ammonium chloride of 14mL (2eq) is added dropwise, and drop finishes, and stirs 2h, 50mL is added into reaction solution
Water is extracted with dichloromethane (3 × 50mL), merges organic layer, washes (2 × 50mL) with saturated common salt, and anhydrous sodium sulfate is dry,
It filters, filtrate is evaporated, obtain khaki solid 5.2g, yield 59.6% after column chromatographic purifying, obtains yellow solid 2.1g.M(S)
(E(S)I)m/z:437.2[M+H]+。
1.1.6 intermediate (S)-N- [[3- (the fluoro- 4'- of 3'- (4- piperazinyl) phenyl) -2- oxo -5- oxazolidinyl] first
Base] acetamide (I f) preparation
At room temperature, 2.2g (5mmol) intermediate I e is dissolved in the saturation methanol hydrochloride solution of 22mL, is warming up to 30 DEG C and stirs
Mix reaction 1.5h.Reaction is finished, and evaporating solvent under reduced pressure obtains brown oil 1.4g, yield 83.3%.M(S)(E(S)I)m/z:
337.2[M+H]+。
1.1.7 intermediate (S)-N- [[3- (the fluoro- 4'- of 3'- (4- nitroso piperazinyl) phenyl) -2- oxo -5- oxazolidine
Base] methyl] acetamide (I g) preparation
Under ice bath, 1.0g (3mmol) intermediate I f' is dissolved in 10mL tetrahydrofuran, 1.5mL hydrochloric acid is added dropwise thereto
(3M), then the 3mL aqueous solution of 0.5g (7mmol) sodium nitrite is added dropwise, react at room temperature 5h.Reaction is finished, and is filtered, a small amount of water of filter cake
Elution, dry light tan solid 0.4g, yield 36.5%.M(S)(E(S)I)m/z:366.2[M+H]+。
1.1.8 intermediate (S)-N- [[3- (the fluoro- 4'- of 3'- (4- aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl]
Methyl] acetamide (I) preparation
Under ice bath, 1.1g (3mmol) intermediate I g is dissolved in 10mL50% glacial acetic acid solution, is added into reaction solution
0.59g (9mmol) zinc powder continues to be stirred to react 3h under ice bath.Reaction is finished, and filters, filtrate decompression is evaporated, milky oily is obtained
30mL ether is added in object thereto, and platform stirs 0.5h, then filters, and filter cake is eluted with a small amount of ether, dry white solid
0.7g, yield 66.4%.M(S)(E(S)I)m/z:352.2[M+H]+。
[[3- (the fluoro- 4'- of 3'- (4- (pyrroles -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- is disliked 1.2 (S)-N-
Oxazolidinyl] methyl] acetamide preparation
At room temperature, 0.095g (1mmol) 3- pyrrole aldehyde is dissolved in 5mL dehydrated alcohol, is warming up to 78 DEG C, 1 drop is added
Glacial acetic acid adds 0.35g (1mmol) intermediate I after reacting 0.5h, the reaction was continued 4h.Reaction is finished, naturally cold to reaction solution
But, it stands and is precipitated completely to solid, filtered, a small amount of ethanol rinse filter cake, dry yellow powder 0.30g, yield 70.0%.
M.p.:213.1~215.1 DEG C, M (S) (E (S) I) m/z:429.2 [M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 11.01 ((S), 1H), 8.26 (t, J=6.0Hz, 1H), 7.61 ((S),
1H), 7.51 (dd, J=16.0,4.0Hz, 1H), 7.24~7.06 (m, 2H), 6.74 ((S), 1H), 6.22 ((S), 1H), 6.03
~6.05 (m, 1H), 4.76~4.63 (m, 1H), 4.09 (t, J=12.0Hz, 1H), 3.71 (dd, J=12.0,8.0Hz, 1H),
3.40 (t, J=8.0Hz, 2H), 3.15~3.17 (br, 8H), 1.83 ((S), 3H)
Embodiment 2 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- (thiophene -3- methylene) aminopiperazine base) phenyl) -2- oxo -
5- oxazolidinyl] methyl] acetamide preparation
Using 3- thiophenecarboxaldehyde as raw material, (S)-N- [[3- (fluoro- 4'- of 3'- is made according in embodiment 1 1.2 synthetic method
(4- (thiophene -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide, yield 69.6%.
M.p.:238.4~240.2 DEG C, M (S) (E (S) I) m/z:445.4 [M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.25 (t, J=8.0Hz, 1H), 7.93 ((S), 1H), 7.51 (dd, J=
16.0,4.0Hz, 1H), 7.42 (d, J=4.0Hz, 1H), 7.21~7.16 (m, 2H), 7.12 (t, J=8.0Hz, 1H), 7.07
~7.00 (m, 1H), 4.80~4.64 (m, 1H), 4.08 (t, J=12.0Hz, 1H), 3.70 (dd, J=12.0,8.0Hz, 1H),
3.40 (t, J=8.0Hz, 2H), 3.14~3.21 (br, 8H), 1.83 ((S), 3H)
Embodiment 3 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- (furans -3- methylene) aminopiperazine base) phenyl) -2- oxo -
5- oxazolidinyl] methyl] acetamide preparation
At room temperature, 0.096g (1mmol) 3- furtural is dissolved in 5mL dehydrated alcohol, is warming up to 78 DEG C, 1 drop is added
Glacial acetic acid adds 0.35g (1mmol) intermediate I after reacting 0.5h, the reaction was continued 4h.Reaction is finished, naturally cold to reaction solution
But, it stands and is precipitated completely to solid, filtered, a small amount of ethanol rinse filter cake, dry obtained white powder 0.3g, yield 69.9%.
M.p.:223.7~225.6 DEG C, M (S) (E (S) I) m/z:429.1 [M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.28 (t, J=6.0Hz, 1H), 7.66 ((S), 1H), 7.59 ((S),
1H), 7.51 (dd, J=16.0,4.0Hz, 1H), 7.26~7.06 (m, 2H), 6.63~6.48 (m, 2H), 4.78~4.63 (m,
1H), 4.09 (t, J=8.9Hz, 1H), 3.71 (t, J=8.7, Hz, 1H), 3.40 (t, J=5.3Hz, 2H), 3.14~3.22
(br,8H),1.83((S),3H).
Embodiment 4 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- (pyridine -3- methylene) aminopiperazine base) phenyl) -2- oxo -
5- oxazolidinyl] methyl] acetamide preparation
Using 4- pyridine carboxaldehyde as raw material, (S)-N- [[3- (fluoro- 4'- of 3'- is made according in embodiment 1 1.2 synthetic method
(4- (pyridine -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide, yield 72.7%.
M.p.:213.8~215.6 DEG C, M (S) (E (S) I) m/z:441.5 [M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.52 (d, J=8.0Hz, 2H), 8.25 (t, J=5.8Hz, 1H), 7.65
((S), 1H), 7.58~7.45 (m, 3H), 7.25~7.09 (m, 2H), 4.77~4.67 (m, 1H), 4.09 (t, J=9.0Hz,
1H), 3.71 (t, J=8.0Hz, 1H), 3.40~3.41 (m, 2H), 3.40~3.31 (m, 4H), 3.23~3.07 (m, 4H),
1.84((S),3H).
Embodiment 5 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- (naphthalene -1- methylene) aminopiperazine base) phenyl) -2- oxo -5-
Oxazolidinyl] methyl] acetamide preparation
Using 1- naphthaldehyde as raw material, (S)-N- [[3- (fluoro- 4'- of 3'- is made according in embodiment 1 1.2 synthetic method
(4- (naphthalene -1- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide, yield 69.5%.
M.p.:189.9~192 DEG C, M (S) (E (S) I) m/z:490.5 [M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.72 (d, J=8.0Hz, 1H), 8.35 ((S), 1H), 8.25 (t, J=
5.7Hz, 1H), 7.93 (d, J=8.7Hz, 1H), 7.90~7.80 (m, 2H), 7.61~7.46 (m, 4H), 7.23~7.09 (m,
2H), 4.77~4.65 (m, 1H), 4.08 (t, J=8.9Hz, 1H), 3.70 (t J=8.0Hz, 1H), 3.39~3.40 (br,
6H), 3.19~3.21 (br, 4H), 1.82 ((S), 3H)
Embodiment 6 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- (indoles -3- methylene) aminopiperazine base) phenyl) -2- oxo -
5- oxazolidinyl] methyl] acetamide preparation
At room temperature, 0.145g (1mmol) 3- indolecarboxaldehyde is dissolved in 5mL dehydrated alcohol, is warming up to 78 DEG C, 1 drop is added
Glacial acetic acid adds 0.35g (1mmol) intermediate I after reacting 0.5h, the reaction was continued 4h.Reaction is finished, naturally cold to reaction solution
But, it stands and is precipitated completely to solid, filtered, a small amount of ethanol rinse filter cake, dry obtained yellow powder 0.34g, yield 71.1%.
M.p.:221.5~223.4 DEG C, M (S) (E (S) I) m/z:479.6 [M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 11.26 ((S), 1H), 8.24 (t, J=5.8Hz, 1H), 8.16 (d, J=
7.9Hz, 1H), 7.99 ((S), 1H), 7.56 (d, J=2.6Hz, 1H), 7.50 (dd, J=16.0,4.0Hz, 1H), 7.37 (d, J
=8.0Hz, 1H), 7.14~7.15 (br, 3H), 7.05 (t, J=7.5Hz, 1H), 4.78~4.58 (m, 1H), 4.07 (t, J=
8.9Hz, 1H), 3.69 (t, J=8.0,1H), 3.39 (t, J=5.5Hz, 2H), 3.18 ((S), 8H), 1.82 ((S), 3H)
Embodiment 7 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- (phenyl ring -1- methylene) aminopiperazine base) phenyl) -2- oxo -
5- oxazolidinyl] methyl] acetamide preparation
At room temperature, 0.106g (1mmol) benzaldehyde is dissolved in 5mL dehydrated alcohol, is warming up to 78 DEG C, 1 drop ice vinegar is added
Acid adds 0.35g (1mmol) intermediate I after reacting 0.5h, the reaction was continued 4h.Reaction is finished, quiet to reaction solution natural cooling
It sets to solid and is precipitated completely, filter, a small amount of ethanol rinse filter cake, dry obtained white powder 0.3g, yield 68.3%.m.p.:
216.8~218.8 DEG C, M (S) (E (S) I) m/z:440.3 [M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.26 (t, J=5.8Hz, 1H), 7.71 ((S), 1H), 7.59 (d, J=
7.2Hz, 2H), 7.51 (dd, J=16.0,4.0Hz, 1H), 7.36 (t, J=7.5Hz, 2H), 7.28 (t, J=7.3Hz, 1H),
7.18~7.20 (br, 2H), 4.78~4.63 (m, 1H), 4.09 (t, J=9.0Hz, 1H), 3.69~3.71 (m, 1H), 3.41
(t, J=5.5Hz, 2H), 3.27 (t, J=5.6Hz, 4H), 3.17 (t, J=5.0Hz, 4H), 1.83 ((S), 3H)
Embodiment 8 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((4- methyl) -1- methylene phenyl) aminopiperazine base) benzene
Base) -2- oxo -5- oxazolidinyl] methyl] and acetamide preparation
At room temperature, 0.120g (1mmol) 4- tolyl aldehyde is dissolved in 5mL dehydrated alcohol, is warming up to 78 DEG C, be added 1
Glacial acetic acid is dripped, after reacting 0.5h, adds 0.35g (1mmol) intermediate I, the reaction was continued 4h.Reaction is finished, to reaction solution nature
Cooling, standing is precipitated completely to solid, filters, a small amount of ethanol rinse filter cake, dry obtained white powder 0.32g, yield
70.6%.M.p.:261.8~263.1 DEG C, M (S) (E (S) I) m/z:454.4 [M+H]+。
1H NMR(400MHz,DM(S)O-d6)δ8.24((S),1H),7.66((S),1H),7.47(br,3H),7.16
((S),4H),4.69((S),1H),4.07((S),1H),3.69((S),1H),3.39((S),2H),3.18(br,8H),2.28
((S),3H),1.82((S),3H).
Embodiment 9 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((4- fluorine) -1- methylene phenyl) aminopiperazine base) phenyl) -
2- oxo -5- oxazolidinyl] methyl] acetamide preparation
Using 4- fluorobenzaldehyde as raw material, (S)-N- [[3- (fluoro- 4'- of 3'- is made according in embodiment 1 1.2 synthetic method
(4- ((4- fluorine) -1- methylene phenyl) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide, yield
70.0%.M.p.:233.4~235.2 DEG C, M (S) (E (S) I) m/z:458.1 [M+H]+。
1H NMR(400MHz,DM(S)O-d6)δ8.24((S),1H),7.71((S),1H),7.61((S),2H),7.49
(d, J=14.8Hz, 1H), 7.30~7.00 (m, 4H), 4.69 ((S), 1H), 4.07 (t, J=8.0Hz, 1H), 3.68 ((S),
1H), 3.39 ((S), 2H), 3.15~3.24 (br, 8H), 1.82 ((S), 3H)
Embodiment 10 (S)-N- [[3- (fluoro- 4'- of 3'- (4- ((the chloro- 4- fluorine of 3-) -1- methylene phenyl) aminopiperazine base)
Phenyl) -2- oxo -5- oxazolidinyl] methyl] and acetamide preparation
Using the chloro- 4- fluorobenzaldehyde of 3- as raw material, (S)-N- [[3- (3'- is made according in embodiment 1 1.2 synthetic method
Fluoro- 4'- (4- ((the chloro- 4- fluorine of 3-) -1- methylene phenyl) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] second
Amide, yield 69.2%.M.p.:200.3~201.5 DEG C, M (S) (E (S) I) m/z:492.2 [M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.24 (t, J=5.6Hz, 1H), 7.73 (d, J=7.3Hz, 1H), 7.67
((S), 1H), 7.61~7.52 (m, 1H), 7.47~7.50 (br, 1H), 7.40 (t, J=8.9Hz, 1H), 7.09~7.14
(br, 2H), 4.75~4.61 (m, 1H), 4.07 (t, J=8.0Hz, 1H), 3.67~3.70 (m, 1H), 3.39 (t, J=
8.0Hz,2H),3.27((S),4H),3.14((S),4H),1.81((S),3H).
Embodiment 11 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- phenyl thiazole) -4- methylene) aminopiperazine base) benzene
Base) -2- oxo -5- oxazolidinyl] methyl] and acetamide preparation
The preparation of 11.1 intermediate 2- phenyl thiazole -4- formaldehyde (II C)
11.1.1 the preparation of intermediate thiobenzamide (C1)
At room temperature, 4.1g (40mmol) benzonitrile, 4.5g (80mmol) NaHS, 8.1g (40mmol) six are hydrated chlorine
Change magnesium to be added in 50mLDMF, reacts at room temperature 6h.Reaction is finished, and reaction solution is poured into 150mL water, stirs 10min, acetic acid second
Ester extracts (3 × 40mL), merges organic layer, washes (3 × 30mL), and saturated common salt washes (2 × 30mL), and anhydrous sodium sulfate is dry
It is dry, it filters, is evaporated, obtains light yellow solid 5g, yield 91.2%.M(S)(E(S)I)m/z:138.1[M+H]+。
11.1.2 the preparation of intermediate 2- phenyl thiazole -4- carboxylic acid, ethyl ester (C2)
At room temperature, 4.1g (30mmol) intermediate C1 is added in reaction flask, 40mL ethyl alcohol is added, is stirred to dissolve, delayed
It is slow that 6.44g (33mmol) ethyl bromide acetone is added, it finishes, is warming up to 78 DEG C of reaction 5h.Reaction is finished, evaporating solvent under reduced pressure,
50mL water is added, is extracted with dichloromethane (3 × 40mL), organic layer is merged, successively washed with saturated sodium bicarbonate (3 ×
30mL), saturated common salt washing (2 × 30mL), anhydrous sodium sulfate is dry, filters, is evaporated, obtains yellow oil 4.8g, yield
69.0%.M(S)(E(S)I)m/z:234.1[M+H]+。
11.1.3 the preparation of intermediate 2- phenyl thiazole -4- methanol (C3)
2.33g (10mmol) intermediate C2 is dissolved in 25mL dry tetrahydrofuran, under ice bath, is slowly added portionwise
0.57g (15mmol) Lithium Aluminium Hydride, finishes, and reacts at room temperature 1h.Reaction is finished, and is slowly added to 0.6mL water quenching reaction, is added
0.6mL10%NaOH solution adds 1.8mL water process, after stirring 0.5h, filters, and a small amount of tetrahydrofuran washs filter cake, anhydrous
Sodium sulphate dried filtrate is stayed overnight, and is filtered, and solvent evaporated obtains brown solid 1.4g, yield 73.6%.M(S)(E(S)I)m/z:
192.1[M+H]+。
11.1.4 the preparation of intermediate 2- phenyl thiazole -4- formaldehyde (II C)
At room temperature, 1.9g (10mmol) intermediate C3 is dissolved in 20mL methylene chloride, is stirred to dissolve, adds
2.58g (12mmol) pyridine chlorochromate drone salt (PCC) reacts at room temperature 1.5h.Reaction is finished, and the anhydrous second of 20mL is added into reaction solution
Ether stirs 10min, filters, and a small amount of ether washs filter cake, then with saturated common salt water washing filtrate (2 × 20mL), separates organic
Layer, solvent evaporated obtain brown solid 0.95g, yield 50.3%.M(S)(E(S)I)m/z:190.0[M+H]+。
11.2 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- phenyl thiazole) -4- methylene) aminopiperazine base) phenyl) -2-
Oxo -5- oxazolidinyl] methyl] acetamide preparation
At room temperature, 0.19g (1mmol) intermediate II C is dissolved in 5mL dehydrated alcohol, is warming up to 78 DEG C, 1 drop ice is added
Acetic acid adds 0.35g (1mmol) intermediate I after reacting 0.5h, the reaction was continued 4h.Reaction is finished, to reaction solution natural cooling,
Standing is precipitated completely to solid, filters, a small amount of ethanol rinse filter cake, dry obtained khaki powder 0.33g, yield 69.2%.
M.p.:210.3~211.8 DEG C, M (S) (E (S) I) m/z:545.2 [M+Na]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.24 ((S), 1H), 7.94 ((S), 1H), 7.82 ((S), 1H), 7.69~
7.72 (br, 1H), 7.58 (d, J=4.0Hz, 1H), 7.50 (d, J=8.0Hz, 2H), 7.35 ((S), 1H), 7.27 (d, J=
7.3Hz, 1H), 7.22~7.06 (m, 2H), 4.69 ((S), 1H), 4.07 (t, J=8.2Hz, 1H), 3.70 ((S), 1H), 3.39
((S),2H),3.27(br,4H),3.15((S),4H),1.82((S),3H).
Embodiment 12 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (3- aminomethyl phenyl) thiazole) -4- methylene) amino piperazine
Piperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide preparation
Using 3- methyl benzonitrile as raw material, key intermediate is synthesized by embodiment 11 11.1 synthetic method, according still further to
11.2 method synthesizes (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (3- aminomethyl phenyl) thiazole) -4- methylene in embodiment 11
Base) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide, yield 69.2%.M.p.:240.3~
241.5℃,M(S)(E(S)I)m/z:559.1[M+Na]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.27 ((S), 1H), 7.87~7.63 (m, 2H), 7.51 (d, J=
9.0Hz, 1H), 7.45~7.28 (m, 2H), 7.10~7.18 (br, 3H), 4.71 ((S), 1H), 4.09 ((S), 1H), 3.71
((S), 1H), 3.40 ((S), 2H), 3.35~3.05 (m, 8H), 2.31~2.39 (br, 3H), 1.83 ((S), 3H)
Embodiment 13 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- fluorophenyl) thiazole) -4- methylene) aminopiperazine
Base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide preparation
Using 4- fluorobenzonitrile as raw material, key intermediate is synthesized by embodiment 11 11.1 synthetic method, according still further to reality
Apply in example 11 11.2 method synthesis (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- fluorophenyl) thiazole) -4- methylene) ammonia
Base piperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide, yield 61.1%.M.p.:220.3~221.6 DEG C, M
(S)(E(S)I)m/z:540.9[M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.27 ((S), 1H), 8.01 ((S), 1H), 7.86~7.68 (m, 1H),
7.61~7.63 (br, 1H), 7.49~7.53 (br, 1H), 7.36 (t, J=8.0Hz, 1H), 7.16 (br, 3H), 4.71 ((S),
1H), 4.09 (t, J=8.0Hz, 1H), 3.71 ((S), 1H), 3.40 ((S), 2H), 3.21 (br, 8H), 1.83 ((S), 3H)
Embodiment 14 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (2,4 difluorobenzene base) thiazole) -4- methylene) amino
Piperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide preparation
With 2,4- difluorobenzonitrile for raw material, key intermediate is synthesized by embodiment 11 11.1 synthetic method, then press
According in the embodiment 11 11.2 [[(((Asia (2- (2,4 difluorobenzene base) thiazole) -4- 4- the fluoro- 4'- of 3'- 3- method synthesis (S)-N-
Methyl) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide, yield 60.9%.M.p.:202.3~
203.1℃,M(S)(E(S)I)m/z:558.9[M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.27 ((S), 1H), 7.85 (br, 1H), 7.79~7.63 (m, 1H),
7.51 (d, J=14.6Hz, 1H), 7.38~7.25 (m, 1H), 7.16 (br, 3H), 4.71 ((S), 1H), 4.09 (t, J=
8.0Hz, 1H), 3.71 (t, J=8.0Hz, 1H), 3.40 ((S), 2H), 3.24 (br, 8H), 1.83 ((S), 3H)
Embodiment 15 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- tolylthiophene -5- methylene) aminopiperazine base) benzene
Base) -2- oxo -5- oxazolidinyl] methyl] and acetamide preparation
The preparation of 15.1 intermediate 5- tolylthiophene -2- formaldehyde (II D)
15.1.1 the preparation of the chloro- 3- phenylacrolein (D1) of intermediate (Z) -3-
Under ice bath, 18.4g (120mmol) phosphorus oxychloride is added dropwise in the dry DMF of 70mL, temperature is kept to be no more than
It 20 DEG C, drips and finishes stirring 20min, the DMF solution that 25mL contains 3.6g (30mmol) acetophenone is added dropwise thereto, drop finishes, is warming up to
70 DEG C of reaction 2h.Reaction is finished, and is cooled to room temperature to reaction solution, is poured into 20% sodium acetate solution of 100mL, be sufficiently stirred, then use
Ethyl acetate extracts (3 × 40mL), merges organic layer, washed organic layer (3 × 40mL), and saturated common salt washes (2 × 40mL), nothing
Aqueous sodium persulfate is dry, filters, is evaporated, obtains yellow oil 4.8g, yield 96.1%.M(S)(E(S)I)m/z:167.5[M+H]+。
15.1.2 the preparation of intermediate 5- tolylthiophene -2- carboxylic acid, ethyl ester (D2)
At room temperature, 0.46g (20mmol) sodium is added in 40mL methanol, 2.4g (20mmol) mercapto is added dropwise in stirring to Quan Rong
Ethyl, drop finishes, and after 0.5h is stirred at room temperature, 3.33g (20mmol) intermediate D1 is added in reaction solution, is finished, room temperature
After reacting 1h, then 0.46g (20mmol) sodium is added in reaction solution, finished, reacts at room temperature 1h.Reaction is finished, and is filtered, and filter cake is with less
Water elution is measured, filtration cakes torrefaction obtains yellow solid 3.2g, yield 69.0%.M(S)(E(S)I)m/z:232.1[M+H]+。
15.1.3 the preparation of intermediate 5- tolylthiophene -2- methanol (D3)
2.32g (10mmol) intermediate D2 is dissolved in 25mL dry tetrahydrofuran, under ice bath, is slowly added portionwise
0.57g (15mmol) Lithium Aluminium Hydride reacts at room temperature 1h.Reaction is finished, and is slowly added to 0.6mL water, is added 0.6Ml 10%NaOH
Solution adds 1.8mL water process, after stirring 0.5h, filters, and washs filter cake with a small amount of tetrahydrofuran, anhydrous sodium sulfate is dry
Filtrate, filters, and solvent evaporated obtains yellow solid 1.4g, yield 73.7%.M(S)(E(S)I)m/z:191.1[M+H]+。
15.1.4 the preparation of intermediate 5- tolylthiophene -2- formaldehyde (II D)
At room temperature, 1.91g (10mmol) intermediate D3 is dissolved in 20mL methylene chloride, is stirred to dissolve, adds
2.58g (12mmol) pyridine chlorochromate drone salt (PCC) reacts at room temperature 1.5h.Reaction is finished, and the anhydrous second of 20mL is added into reaction solution
Ether stirs 10min, filters, and a small amount of ether washs filter cake, then with saturated common salt water washing filtrate (2 × 20mL), separates organic
Layer, solvent evaporated obtain brown solid 0.95g, yield 50.3%.M(S)(E(S)I)m/z:189.0[M+H]+。
15.2 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- tolylthiophene -5- methylene) aminopiperazine base) phenyl) -2-
Oxo -5- oxazolidinyl] methyl] acetamide preparation
At room temperature, 0.19g (1mmol) intermediate II D is dissolved in 5mL dehydrated alcohol, is warming up to 78 DEG C, 1 drop ice is added
Acetic acid adds 0.35g (1mmol) intermediate I after reacting 0.5h, the reaction was continued 4h.Reaction is finished, to reaction solution natural cooling,
Standing is precipitated completely to solid, filters, a small amount of ethanol rinse filter cake, dry obtained yellow powder 0.33g, yield 63.3%.
M.p.:210.3~212.1 DEG C, M (S) (E (S) I) m/z:522.1 [M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.26 (t, J=5.7Hz, 1H), 7.90 ((S), 1H), 7.65 (d, J=
7.5Hz, 2H), 7.50 (dd, J=16.0,4.0Hz, 1H), 7.44 (d, J=3.6Hz, 1H), 7.39 (t, J=7.6Hz, 2H),
7.29 (t, J=7.2Hz, 1H), 7.14 (br, 3H), 4.78~4.57 (m, 1H), 4.07 (t, J=8.0Hz, 1H), 3.79~
3.62 (m, 1H), 3.39 (t, J=8.0Hz, 2H), 3.15~3.24 (br, 4H), 3.15 ((S), 4H), 1.81 ((S), 3H)
Embodiment 16 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- methoxyphenyl) thiophene) -5- methylene) amino
Piperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide preparation
Using 4- methoxyacetophenone as raw material, key intermediate is synthesized according in embodiment 15 15.1 method, according still further to
15.2 method synthesizes (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- methoxyphenyl) thiophene) -5- methylene in embodiment 15
Base) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide, yield 61.7%.M.p.:195.2~197
℃,M(S)(E(S)I)m/z:552.2[M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.24 (t, J=5.6Hz, 1H), 7.87 ((S), 1H), 7.59 (d, J=
8.0Hz2H), 7.50 (dd, J=16.0,4.0Hz, 1H), 7.30 (d, J=3.6Hz, 1H), 7.17 (br, 1H), 7.11 (br,
2H), 6.96 (d, J=8.0Hz, 2H), 4.77~4.63 (m, 1H), 4.07 (t, J=8.0Hz, 1H), 3.77 ((S), 3H),
3.73~3.63 (m, 1H), 3.39 (t, J=8.0Hz, 2H), 3.13~3.39 (br, 8H), 1.82 ((S), 3H)
Embodiment 17 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- fluorophenyl) thiophene) -5- methylene) aminopiperazine
Base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide preparation
Using 4- fluoro acetophenone as raw material, key intermediate is synthesized according in embodiment 15 15.1 method, according still further to implementation
15.2 method synthesizes (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- fluorophenyl) thiophene) -5- methylene) amino in example 15
Piperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide, yield 63.2%.M.p.:218.5~220.4 DEG C, M
(S)(E(S)I)m/z:540.2[M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.24 (t, J=5.7Hz, 1H), 7.89 ((S), 1H), 7.68~7.70
(m, 2H), 7.50 (dd, J=16.0,4.0Hz, 1H), 7.41 (d, J=3.7Hz, 1H), 7.23 (t, J=8.8Hz, 2H), 7.14
(br, 3H), 4.76~4.61 (m, 1H), 4.07 (t, J=8.0Hz, 1H), 3.67~3.70 (m, 1H), 3.39 (t, J=
8.0Hz, 2H), 3.14~3.39 (br, 8H), 1.82 ((S), 3H)
Embodiment 18 (S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (2,4 difluorobenzene base) thiophene) -5- methylene) amino
Piperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide preparation
With 2,4- difluoro acetophenone for raw material, key intermediate is synthesized according in embodiment 15 15.1 method, according still further to
15.2 method synthesizes N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (2,4 difluorobenzene base) thiophene) -5- methylene) in embodiment 15
Aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] methyl] acetamide, yield 61.0%.M.p.:221.5~223 DEG C, M
(S)(E(S)I)m/z:558.1[M+H]+。
1H NMR(400MHz,DM(S)O-d6) δ 8.24 (t, J=5.5Hz, 1H), 7.91 ((S), 1H), 7.87~7.77
(m, 1H), 7.55~7.43 (m, 2H), 7.36~7.39 (br, 1H), 7.09~7.15 (br, 4H), 4.76~4.63 (m, 1H),
4.07 (t, J=8.9Hz, 1H), 3.77~3.62 (m, 1H), 3.39 (t, J=5.3Hz, 2H), 3.24 ((S), 4H), 3.14
((S),4H),1.81((S),3H).
The preparation of 19 embodiment of embodiment, 1 compound tablet (250mg/ piece)
1 compound 250g of Example, starch 30g, 2%HPMC aqueous solution 80mL, sodium carboxymethyl starch 15g, stearic acid
Magnesium 2g, according to the following steps:
A, it is appropriate to prepare 2%HPMC aqueous solution, it is spare；
B, former, auxiliary material is suitably dry, it sieves with 100 mesh sieve respectively, it is spare；
C, former, auxiliary material is weighed by recipe quantity, after mixing by 1 compound of embodiment, starch, carboxyrnethyl starch sodium, be added
Softwood is made in 2%HPMC solution, with 20 mesh Shai Zhi wet granulars；
D, wet granular is about 3 hours dry in 55 DEG C, slightly cools after dry, magnesium stearate is added, with 20 mesh sieves；Measurement
Content calculates slice weight；
E, the formed punch tabletting of 10mm dimple form is selected, is made 1000；
F, product inspection is packed and stored after qualified.
The preparation of 20 embodiment of embodiment, 2 compound capsule (125mg/)
Take following component: 2 compound 125g of embodiment, starch 15g, lactose 15g, 2%HPMC aqueous solution about 40mL, carboxylic first
Base sodium starch 7.5g, magnesium stearate 1g.It follows the steps below:
A, it is appropriate to prepare 2%HPMC solution, it is spare.
B, former, auxiliary material is suitably dry, it sieves with 100 mesh sieve respectively, it is spare.
C, former, auxiliary material is weighed by recipe quantity, 2 compound of embodiment, starch, lactose, sodium carboxymethyl starch is uniformly mixed
Afterwards, 2%HPMC solution softwood is added, with 20 mesh Shai Zhi wet granulars.
D, wet granular is about 3 hours dry in 55 DEG C, slightly cools after dry, magnesium stearate is added, with 20 mesh sieves.Measurement
Content calculates loading amount.
E, the filling particle of 2# capsule shells is selected, obtains capsule 1000.
F, by capsule polishing, dedusting.
G, product inspection is packed and stored after qualified.
The preparation of 21 embodiment of embodiment, 3 chemical combination composition dispersible tablets (250mg/)
Take following component: 3 compound 250g of embodiment, pregelatinized starch 50g, microcrystalline cellulose 50g, sodium carboxymethyl starch
20g, 2%HPMC aqueous solution about 90ml, superfine silica gel powder 20g, stevia glucoside 18g, magnesium stearate 2g, carry out in accordance with the following steps
Preparation:
A, it is appropriate to prepare 2%HPMC solution, it is spare.
B, former, auxiliary material is suitably dry, it sieves with 100 mesh sieve respectively, it is spare.
C, former, auxiliary material is weighed by recipe quantity.By 4 compound of embodiment, pregelatinized starch, microcrystalline cellulose, carboxymethylstarch
Sodium, stevia glucoside after mixing, are added 2%HPMC solution and softwood are made, with 20 mesh Shai Zhi wet granulars.
D, wet granular is 3 hours dry in 55 DEG C, slightly cools after dry, and superfine silica gel powder, magnesium stearate is added, whole with 20 meshes
Grain.Content is measured, slice weight is calculated.
E, the formed punch tabletting of 11mm dimple form is selected, obtains 1000.
F, product inspection is packed and stored after qualified.
The preparation of 22 embodiment of embodiment, 4 compound sodium chloride injection (100mL: 250mg)
Take following component: 4 compound 250g of embodiment, sodium chloride 825g, citric acid 6.5g, water for injection add to 100L,
It follows the steps below:
A, 4 compound of embodiment, sodium chloride and the citric acid of recipe quantity are weighed.
B, main materials and auxiliary materials are dissolved in and are accounted for about in the water for injection (80 DEG C or so) for preparing total amount 90%, stirring makes to be completely dissolved.
C, 0.05% needle-use activated carbon that 2 hours are activated through 120 DEG C is added, stirring stands 15 minutes.
D, with after 0.6 μm of stud filter filtering decarbonization, benefit adds to the full amount of water for injection.
Embodiment 22 carries out antibacterial activity in vitro research to the compound of the present invention
As a result: with M-H meat soup two-fold dilution at a series of concentration, maximum concentration 128mg/L after test sample degerming.?
100 μ LM-H broth bouillons are added as blank control in every arrange of 96 micropores dilution plate in the 12nd hole, 50 μ LM-H are added in the 11st hole
Meat soup sequentially adds 50 μ L sample test liquids according to from down to high sequence from the 10th hole to the 1st hole.
Tested bacterium and reference culture are seeded in Mueller-Hinton (M-H) nutrient broth for being suitble to it to grow to picking in right amount
In culture medium, in 37 DEG C of culture 16-18h, the bacterium solution after growth with physiological saline corrected concentrations to 0.5 Maxwell than turbid standard, then
It is diluted with M-H meat soup 1: 100, this liquid is used as trying bacterium solution.Then 50 μ L test bacteria liquids, shaking mixing are inoculated in the 1st~11 hole
It is placed in the square tray anth cap for being lined with wet gauze, 37 DEG C of culture 18-20h.
The observation under the light source for having black background is as a result, have diffusivity muddiness or hole bottom in button in the hole for thering is bacterium to grow
Increment precipitates, without this phenomenon in the hole of asepsis growth.Contained lowest concentration of drug is minimum suppression in the hole of asepsis growth
Bacteria concentration (MIC).Test result is shown in Table 1.
Table 1 is activity of the section Example compound to gram-positive cocci
MIC:ug/mL
Note: MR (S) A is the staphylococcus aureus of methicillin-resistant, and MSSA is the golden yellow grape of methicillin-sensitivity
Coccus, LDZ-R1 are the drug resistant enterococcus faecalis of Linezolid, and VRE is the enterococcus faecium of drug resistance of vancomycin.
It is more more excellent than Linezolid that preliminary antibacterial activity in vitro test result shows that the compound in the present invention has
Antibacterial activity, and it is significant to drug-fast bacteria antibacterial activity.
Claims (10)
1. the Oxazolidinone derivative of the structure of hydrazone containing piperazine, which is characterized in that including containing general formula (I) compound or it is vertical
Body isomers or its pharmaceutically acceptable salt；
Wherein,
R1For hydrogen, fluorine, chlorine or trifluoromethyl；
R2For-NHCOCH3Or-OH；
R3For Ar,
Ar is any 1-3 R4Substituted C5-C10Aryl and heteroaryl；
R4For hydrogen, hydroxyl, halogen, nitro, amino, cyano, C1-C6Alkyl, C1-C6Alkoxy, optionally by hydroxyl, amino or halogenated
C1-C6Alkyl, optionally by hydroxyl, amino or halogenated C1-C6Alkoxy, coverlet or two (C1-C6Alkyl) replace amino,
C1-C6Alkylamidoalkyl, free, at salt, esterification and amidated carboxyl, C1-C6Alkyl sulphinyl, C1-C6Alkyl
Sulfonyl, C1-C6Alkyl acyl, carbamoyl.
2. the Oxazolidinone derivative of the structure of hydrazone containing piperazine as described in claim 1, which is characterized in that
R1For fluorine；R2For-NHCOCH3。
3. the Oxazolidinone derivative of the structure of hydrazone containing piperazine as described in claim 1, which is characterized in that
Ar is any 1-3 R4Substituted phenyl, pyridyl group, furyl, thienyl, pyrrole radicals, pyrazolyl, oxazolyl, isoxazole
Base, thiazolyl, imidazole radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, isoquinolyl, indyl, imidazole radicals, triazol radical, naphthalene.
4. the Oxazolidinone derivative of the structure of hydrazone containing piperazine as described in claim 1, which is characterized in that
Ar is any 1-3 R4Substituted phenyl；
R4For 1-3 identical or different substituent groups, it is selected from hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, amino, cyano, methyl, second
Base, n-propyl, isopropyl, tert-butyl, vinyl, acrylic, 2- methylpropenyl, acetenyl, methoxyl group, ethyoxyl, cyclopropyl
Oxygroup, tert-butoxy, allyl, trifluoromethyl, trifluoromethoxy, methylamino, ethylamino-, dimethylamino, formamido group, acetyl
Amino, propionamido, cyclopropyl acylamino-, carboxyl, methylsulfinyl, sulfonyl, mesyl, formoxyl, acetyl group, propionyl
Base, cyclopropyl acyl group, carbamoyl.
5. the Oxazolidinone derivative of the structure of hydrazone containing piperazine as described in claim 1, which is characterized in that specifically:
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (pyrroles -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl]
Methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (thiophene -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl]
Methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (furans -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl]
Methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (pyridine -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl]
Methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (naphthalene -1- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl] first
Base] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (indoles -3- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl]
Methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- (phenyl ring -1- methylene) aminopiperazine base) phenyl) -2- oxo -5- oxazolidinyl]
Methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((4- methyl) -1- methylene phenyl) aminopiperazine base) phenyl) -2- oxo -5-
Oxazolidinyl] methyl] acetamide；
(S) [[3- (the fluoro- 4'- of 3'- (4- ((4- fluorine) -1- methylene phenyl) aminopiperazine base) phenyl) -2- oxo -5- is disliked-N-
Oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((the chloro- 4- fluorine of 3-) -1- methylene phenyl) aminopiperazine base) phenyl) -2- oxo -
5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- phenyl thiazole) -4- methylene) aminopiperazine base) phenyl) -2- oxo -5-
Oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (3- aminomethyl phenyl) thiazole) -4- methylene) aminopiperazine base) phenyl) -2-
Oxo -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- fluorophenyl) thiazole) -4- methylene) aminopiperazine base) phenyl) -2- oxygen
Generation -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (2,4 difluorobenzene base) thiazole) -4- methylene) aminopiperazine base) phenyl) -
2- oxo -5- oxazolidinyl] methyl] acetamide；
(S) [[(the fluoro- 4'- of 3'- (4- ((2- tolylthiophene -5- methylene) aminopiperazine base) phenyl) -2- oxo -5- is disliked 3--N-
Oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- methoxyphenyl) thiophene) -5- methylene) aminopiperazine base) phenyl) -
2- oxo -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (4- fluorophenyl) thiophene) -5- methylene) aminopiperazine base) phenyl) -2- oxygen
Generation -5- oxazolidinyl] methyl] acetamide；
(S)-N- [[3- (the fluoro- 4'- of 3'- (4- ((2- (2,4 difluorobenzene base) thiophene) -5- methylene) aminopiperazine base) phenyl) -
2- oxo -5- oxazolidinyl] methyl] acetamide.
6. the Oxazolidinone derivative of the structure of hydrazone containing piperazine as described in claim 1, which is characterized in that described pharmaceutically
The salt of receiving is the salt formed with acid, and the acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, second
Acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, first
Sulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzene sulfonic acid, naphthalene sulfonic acids, trifluoroacetic acid, aspartic acid.
7. the Oxazolidinone derivative of the structure of hydrazone containing piperazine as claimed in claim 6, which is characterized in that described and sour formation
Salt be hydrochloride and mesylate.
8. a kind of pharmaceutical composition, which is characterized in that the composition contains the compound of any one of claim 1-7.
9. the Oxazolidinone derivative of the structure of hydrazone containing piperazine of any of claims 1-7 is micro- for treating in preparation
Application in the drug of biological infection, which is characterized in that the microorganism infection is bacterium infection.
10. application as described in claim 9, which is characterized in that the bacterium infection is gram positive bacteria infection.
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