CN105348275A - Oxazolidinone compound and synthetic method and medical application of oxazolidinone compound - Google Patents

Oxazolidinone compound and synthetic method and medical application of oxazolidinone compound Download PDF

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CN105348275A
CN105348275A CN201510916298.5A CN201510916298A CN105348275A CN 105348275 A CN105348275 A CN 105348275A CN 201510916298 A CN201510916298 A CN 201510916298A CN 105348275 A CN105348275 A CN 105348275A
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phenyl
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amino
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陈国华
李海妹
王静
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China Pharmaceutical University
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China Pharmaceutical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings

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Abstract

The invention discloses a series of oxazolidinone compounds, and structures of the oxazolidinone compound are as shown in a general formula (I) and a general formula (II), wherein the definitions of R1, R2 and R3 are in the description; the invention also discloses a synthetic method of the compound and application of the compound in treatment of cardiovascular diseases such as thrombosis.

Description

Oxazolidinone compounds and synthetic method thereof and medical applications
Technical field
The present invention relates to and oxazolidinone compounds, and provides the synthetic method of this compounds and the application in antithrombotic thereof.
Background technology
Factor Xa is positioned at the crossover location of exogenous cruor pathway and intrinsic coagulation pathway, zymoplasm can be converted into by catalyze prothrombin, suppress its activity can the effectively generation of Trombin inhibiting and the formation of thrombus, so factor Xa is the important target spot of current anticoagulation medicine research.Xa factor inhibitor is the novel antithrombotics of a class, is used for the treatment of the cardiovascular and cerebrovascular diseases such as thromboembolism clinically.Along with the listing oxazolidinone Xa factor inhibitor of first the oral Xa factor inhibitor razaxaban in the whole world receives much concern, its advantage is that bioavailability is high, treatment window width, dose-effect relationship are stable, with food with the advantage such as drug interaction is little, Clinical practice is convenient.
S1 pocket in Xa factor structure is a darker narrow fissure, Xa factor and substrate specificity binding pocket, asparagicacid residue (Asp189) and tyrosine residues (Tyr228) are arranged at bottom, and wherein the carboxyl of Asp189 can be combined with basic group.Containing strong lipotropy chlorothiophene fragment in razaxaban structure, can interact with the aromatic nucleus of Tyr228, improve the fat-soluble of medicine, improve oral administration biaavailability.When Xun looks for Xin oxazolidinone medicine, we utilize bioisosterism to carry out structure of modification to razaxaban: imagine the chlorothiophene fragment replacing razaxaban with halogen-containing and not halogen-containing lipotropy aromatic structure, expect the fat-soluble and oral administration biaavailability being ensured medicine by aromatic base; Increase basic group, the combination of Jia Qiang oxazolidinone medicine and S1 pocket Asp189 carboxyl simultaneously, strengthen drug effect.Yi Xi Lie oxazolidinone compounds has been designed and synthesized according to this imagination.
Summary of the invention
The object of the present invention is to provide a series of newly there is anticoagulation oxazolidinone compounds.
Another object of the present invention is to the synthetic method that this series compound is provided.
A further object of the present invention is to provide the application of above-claimed cpd in thrombosis treatment.
For solving the problem, the invention provides following technical scheme:
General formula (I) oxazolidinone compounds:
Wherein R 1represent nitro or amino, R 2represent hydrogen, halogen, nitro, cyano group, hydroxyl, C 1~ C 6alkyl, C 1~ C 6alkoxyl group, C 1~ C 6haloalkyl, C 1~ C 6halogenated alkoxy, nothing replace monosubstituted or disubstituted amino, carboxyl, carbonyl and derivative thereof;
Above-mentioned R 2the phenyl ring of general formula (I) can be unit replaces, dibit replaces or multidigit replaces, the R that dibit replaces or multidigit replaces 2can be hydrogen, halogen, nitro, cyano group, hydroxyl, C at the same time or separately 1~ C 6alkyl, C 1~ C 6alkoxyl group, C 1~ C 6haloalkyl, C 1~ C 6halogenated alkoxy, nothing replace monosubstituted or disubstituted amino, carboxyl, carbonyl and derivative thereof.
General formula (II) oxazolidinone compounds:
Wherein R 2definition the same, R 3represent replace or without the alkyl replaced, heterocycle, aromatic nucleus or aralkyl, substituting group can be halogen, nitro, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy, cyano group, hydroxyl, without replacing monosubstituted or disubstituted amino, carboxyl, carbonyl and derivative thereof.
According to the present invention, the compound of preferred general formula (I) and general formula (II) comprising:
I 1: (S)-4-(4-(5-(((4-nitrophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 2: (S)-4-(4-(5-(((the fluoro-4-nitrophenyl of 2-) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 3: (S)-4-(4-(5-(((the fluoro-4-nitrophenyl of 3-) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 4: (S)-4-(4-(5-(((2,4-dinitrophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 5: (S)-4-(4-(5-(((4-aminophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 6: (S)-4-(4-(5-(((4-amino-2-fluorophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 7: (S)-4-(4-(5-(((4-amino-3-fluorophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
II 1: the chloro-N-of (S)-2-(4-(2-chloracetyl amido) phenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) ethanamide
II 2: the chloro-N-of (S)-2-(4-(2-chloracetyl amido)-2-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) ethanamide
II 3: the chloro-N-of (s)-2-(4-(2-chloracetyl amido)-3-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) ethanamide
II 4: (S)-N-(4-benzoylamino phenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) benzamide
II 5: (S)-N-(4-benzoylamino-2-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) benzamide
II 6: (S)-N-(4-benzoylamino-3-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) benzamide
Substitution reaction is there is in the synthetic method one of general formula (I) compound: Compound I a and general formula I b under alkali existence condition; The mol ratio of reaction is Ia: Ib=1: 1 ~ 10; Solvent for use be ethyl acetate, acetonitrile, DMSO, DMF, acetone, tetrahydrofuran (THF), dioxane, toluene, propyl carbinol, Virahol, ethylene glycol, water one or more; The mass volume ratio of Ia and solvent is 1: 5 ~ 50; Alkali used comprises sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide, trimethyl carbinol lithium, potassium hydroxide, lithium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, potassiumphosphate, dipotassium hydrogen phosphate; Temperature of reaction is 25 ~ 150 DEG C;
Wherein, R 2define the same, Y represents halogen.
Above-mentioned synthetic method can add a small amount of cuprous iodide and make catalyzer.
The synthetic method two of general formula (I) compound: carry out reduction reaction by the general formula I c of synthetic method one gained of general formula (I) compound under the condition of reduced iron powder and ammonium chloride; The mol ratio of reaction is Ic: Fe: ammonium chloride=1: 3 ~ 15: 1 ~ 5; Solvent for use is ethanol: water=1 ~ 10: 1; The mass volume ratio of Ic and solvent is 1: 20 ~ 50; Temperature of reaction is 50 ~ 150 DEG C;
Wherein, R 2define the same.
The synthetic method of the compound of general formula (II): by the general formula I Ia of synthetic method two gained of general formula (I) compound, itself and general formula I Ib carry out substitution reaction in the basic conditions; The mol ratio of reaction is IIa: IIb=1: 1 ~ 10; Solvent for use comprises methylene dichloride, dioxane, toluene, DMF, DMSO, tetrahydrofuran (THF), acetonitrile, pyridine; The mass volume ratio of IIa and solvent is 1: 5 ~ 50; Alkali used comprises triethylamine, pyridine, sodium hydride, potassium hydroxide, lithium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate; Temperature of reaction is-10 ~ 120 DEG C;
Wherein, R 2, R 3the same with the definition of Y.
Compound is to the body outer suppressioning experiment of human blood coagulation Xa:
13 oxazolidinone compounds of the present invention to synthesis carry out Pharmacological Activity Screening.Specific experiment scheme can see (Jin Liyuan, the computer aided design (CAD) of coagulation factor xa inhibitors and pharmacology activity research, Master's thesis, Medical University Of Tianjin, Tianjin, 2009).
1. experiment material
1.1 medicines and reagent
Reference substance razaxaban, Compound I 1, I 2, I 3, I 4, I 5, I 6, I 7, II 1, II 2, II 3, II 4, II 5, II 6there is provided by pharmaceutical chemistry teaching and research room of China Medicine University.Human blood coagulation Xa (FXa) enzyme-linked immunoassay kit, magnificent bio tech ltd, Wuhan, production code member CSB-E12696h.Other reagent are analytical pure.
1.2 key instrument
Enzyme micro-plate reader: Bio-Rad company, model: iMark.
2. test method
The preparation of 2.1 standard substance: standard substance are diluted to 1ml by 15min sample diluting liquid before use, repeatedly putting upside down to jolt makes it fully dissolve, its concentration is 20ng/ml, after doing serial doubling dilution, is diluted to 10ng/ml respectively, 5ng/ml, 2.5ng/ml, 1.25ng/ml, 0.625ng/ml, 0.312ng/ml, sample diluting liquid is normal concentration 0ng/ml.
The preparation of 2.2 samples: get 1mg reference substance razaxaban and add 0.5mlDMSO dissolving, and dilute with water 10 doubly to 200 μ g/ml.Oxazolidinone series of samples is dissolved with 0.5mlDMSO respectively, and dilute with water 10 doubly to 200 μ g/ml.Get reference substance razaxaban respectively with oxazolidinone series of samples 200 μ l mixes with 5ng/ml standard enzyme solution 200 μ l, 25 DEG C of incubation 10min.
The preparation of 2.3 working fluids: A working fluid, B working fluid and wash plate liquid and all prepare by test kit specification sheets.
2.4 application of sample measured values:
2.4.1 on 96 hole elisa plates, add the 20ng/ml of 100 μ l respectively, 10ng/ml, 5ng/ml, 2.5ng/ml, 1.25ng/ml, 0.625ng/ml, 0.312ng/ml, each two examples of standard enzyme solution of 0ng/ml, also add each three examples of the sample solution after 100 μ l incubations respectively, overlay film 37 DEG C hatches 120min.
2.4.2 discard liquid, dry.Every hole adds A working fluid 100 μ l, and overlay film 37 DEG C hatches 60min.
2.4.3 discard liquid, dry, wash plate immersion bubble 2min with 400 μ l, wash plate altogether 3 times, dry.
2.4.4 every hole adds B working fluid 100 μ l, and overlay film 37 DEG C hatches 60min.
2.4.5 discard liquid, dry, wash plate immersion bubble 2min with 400 μ l, wash plate altogether 5 times, dry.
2.4.6 sequentially every hole adds substrate solution 90 μ l, 37 DEG C of lucifuge colour developing 30min.
2.4.7 sequentially every hole adds stop bath 50 μ l, termination reaction.The addition sequence of stop buffer is consistent with the addition sequence of substrate solution.
2.4.8 measure the optical density(OD) OD value in each hole successively at 450nm place by microplate reader.
3. experimental result:
As shown in table 1, when standard enzyme amount is 5ng/ml, compared with reference substance razaxaban, Compound I 7show FXa restraining effect more better than razaxaban, Compound I 4and II 3external FXa restraining effect and reference substance razaxaban suitable, comparatively razaxaban is poor for the external FXa restraining effect of other compounds.
Table 1: compound is to the restraining effect (standard enzyme 5ng/ml) of the FXa factor
Specific embodiments
Embodiment 1:(S)-4-(4-(5-(((4-nitrophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone (I 1)
By (S)-4-(4-(5-(amino methyl)-2-Yang Dai oxazolidine-3-base) phenyl) morpholine-3-keto hydrochloride (Ia) (2g, 6.12mmol), p-fluoronitrobenzene (1.73g, 12.23mmol), salt of wormwood (2.54g, 18.36mmol), ethyl acetate (40ml) joins in reaction flask, be heated to backflow, after stirring 24h, reaction mixture filters, filter cake washes with water, obtains filter cake.Filtrate separates organic layer, organic layer is with saturated common salt water washing (30ml × 3), anhydrous sodium sulfate drying, filter, filtrate silica gel column chromatography (ethyl acetate: sherwood oil, 40: 1) obtains yellow solid, merges two portions solid and namely obtains product (1.90g, 75.4%), mp190 ~ 192 DEG C.
Its Structural Identification data are as follows:
ESI-MS(m/z)：435.10[M+23] +
1H-NMR(300MHz，CDCl 3)δ：8.03(d，J＝9.0Hz，2H，Ar-H)，7.49(d，J＝8.9Hz，2H，Ar-H)，7.28(d，J＝8.8Hz，2H，Ar-H)，6.56(d，J＝9.0Hz，2H，Ar-H)，4.82(s，1H，CH)，4.28(s，2H，OCH 2CO)，3.92～4.10(m，3H，OCHCH HNHandOCH 2C H 2N)，3.41～3.81(m，5H，OCHC HHNH，OC H 2CH 2NandOCHC H 2N).
IR(KBr)ν(cm -1)：3420，2963，1736，1654，1602，1517，1475，1408，1313，1261，1232，1016，801，752，694.
Embodiment 2:(S)-4-(4-(5-(((the fluoro-4-nitrophenyl of 2-) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone (I 2)
With reference to I 1synthetic method, obtain yellow solid by Ia and 3,4-difluoro nitrobenzene, yield 70.3%, mp188 ~ 190 DEG C.
Its Structural Identification data are as follows:
EsI-Ms(m/z)：453.10[M+23] +
1H-NMR(300MHz，DMSO-d 6)δ：7.90～8.03(m，2H，Ar-H)，7.56(d，J＝9.0Hz，2H，Ar-H)，7.41(d，J＝9.0Hz，2H，Ar-H)，7.06(t，J＝9.3Hz，1H，Ar-H)，4.91(s，1H，CH)，4.11～4.40(m，3H，OCH 2COandOCHCH HNH)，3.85～4.02(m，3H，OCH 2C H 2NandOCHC HHNH)，3.45～3.78(m，4H，OC H 2CH 2NandOCHC H 2N).
IR(KBr)ν(cm -1)：3415，2963，1725，1655，1617，1549，1518，1503，1474，1423，1336，1312，1261，1101，1039，806，747，618.
Embodiment 3:(S)-4-(4-(5-(((the fluoro-4-nitrophenyl of 3-) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone (I 3)
With reference to I 1synthetic method, obtain yellow solid by Ia and 2,4-difluoro nitrobenzene, yield 80.1%, mp230 ~ 232 DEG C.
Its Structural Identification data are as follows:
EsI-Ms(m/z)：453.10[M+23] +
1H-NMR(300MHz，CDCl 3)δ：8.15～8.26(m，1H，Ar-H)，7.52(d，J＝8.9Hz，2H，Ar-H)，7.31(d，J＝8.9Hz，2H，Ar-H)，6.48～6.60(m，1H，Ar-H)，6.36～6.46(m，1H，Ar-H)，4.88(s，1H，CH)，4.28(s，2H，OCH 2CO)，4.15(t，J＝8.1Hz，1H，OCHCH HNH)，3.98(t，J＝3.9Hz，2H，OCH 2C H 2N)，3.80(t，J＝8.10Hz，1H，OCHC HHNH)，3.54～3.73(m，4H，OC H 2CH 2NandOCHC H 2N).
IR(KBr)ν(cm -1)：3463，2963，1736，1630，1578，1517，1479，1410，1345，1316，1261，1225，1101，1024，801，750.
Embodiment 4:(S)-4-(4-(5-(((2,4-dinitrophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone (I 4)
With reference to I 1synthetic method, obtain yellow solid by Ia and DNF, yield 81.0%, mp236 ~ 238 DEG C.
Its Structural Identification data are as follows:
EsI-Ms(m/z)：480.10[M+23] +
1H-NMR(300MHz，DMSO-d 6)δ：9.04(t，J＝6.0Hz，1H，Ar-H)，8.86(d，J＝2.6Hz，1H，Ar-H)，8.29(dd，J＝9.7，2.7Hz，1H，Ar-H)，7.56(d，J＝8.9Hz，2H，Ar-H)，7.35～7.50(m，2H，Ar-H)，4.99(s，1H，CH)，4.11～4.28(m，3H，OCH 2COandOCHCH HNH)，3.80～4.09(m，5H，OCH 2C H 2N，OCHC HHNHandOC H 2CH 2N)，3.67～3.77(m，2H，OCHC H 2N).
IR(KBr)ν(cm -1)：3421，2963，1747，1649，1618，1517，1414，1341，1313，1261，1228，1092，1032，801，747，609.
Embodiment 5:(S)-4-(4-(5-(((4-aminophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone (I 5)
By I 1(1.0g, 2.43mmol), reduced iron powder (0.68g, 12.15mmol), ammonium chloride (0.23g, 4.37mmol), add (30ml in the mixing solutions of water and ethanol, 1: 2), be heated to backflow, stir 4h, diatomite filtration, filtrate decompression spins off most of solvent, add methylene dichloride (15ml) and water (15ml) extraction, stratification, separate organic layer, with saturated common salt water washing (15ml × 3), anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains pale solid (0.66g, 70.8%), mp190 ~ 192 DEG C.
Its Structural Identification data are as follows:
ESI-MS(m/z)：405.10[M+23] +
1H-NMR(300MHz，CDCl 3)δ：7.54(d，J＝6.0Hz，2H，Ar-H)，7.28(d，J＝6.9Hz，2H，Ar-H)，6.49～6.61(m，4H，Ar-H)，4.82(s，1H，CH)，4.28(s，2H，OCH 2CO)，3.95～4.06(m，3H，OCHCH HNHandOCH 2C H 2N)，3.82(t，J＝6.8Hz，1H，OCHC HHNH)，3.69(t，J＝5.4Hz，2H，OC H 2CH 2N)，3.28～3.46(m，4H，OCHC H 2NandNH 2).
IR(KBr)ν(cm -1)：3410，2962，2873，1742，1655，1522，1433，1414，1348，1329，1249，1233，1120，1076，992，922，832，822，755，549.
Embodiment 6:(S)-4-(4-(5-(((4-amino-2-fluorophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone (I 6)
With reference to I 5synthetic method, by I 2the obtained pale solid of reduction, yield 80.9%, mp170 ~ 172 DEG C.
Its Structural Identification data are as follows:
ESI-MS(m/z)：423.10[M+23] +
1H-NMR(300MHz，CDCl 3)δ：7.53(d，J＝9.0Hz，2H，Ar-H)，7.29(d，J＝7.4Hz，2H，Ar-H)，6.56(t，J＝8.9Hz，1H，Ar-H)，6.22～6.45(m，2H，Ar-H)，4.81(s，1H，CH)，4.28(s，2H，OCH 2CO)，3.93～4.11(m，3H，OCHCH HNHandOCH 2C H 2N)，3.84(t，J＝6.8Hz，1H，OCHC HHNH)，3.69(t，J＝5.3Hz，2H，OC H 2CH 2N)，3.20～3.58(m，4H，OCHC H 2NandNH 2).
IR(KBr)ν(cm -1)：3401，2963，2865，1733，1652，1520，1481，1411，1341，1231，1123，1100，1029，958，921，819，803，754，689，546.
Embodiment 7:(S)-4-(4-(5-(((4-amino-3-fluorophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone (I 7)
With reference to I 5synthetic method, by I 3the obtained pale solid of reduction, yield 81.5%, mp218 ~ 220 DEG C.
Its Structural Identification data are as follows:
ESI-MS(m/z)：423.10[M+23] +
1H-NMR(300MHz，CDCl 3)δ：7.53(d，J＝8.8Hz，2H，Ar-H)，7.29(d，J＝8.9Hz，2H，Ar-H)，6.61～6.73(m，1H，Ar-H)，6.28～6.42(m，2H，Ar-H)，4.88(s，1H，CH)，4.28(s，2H，OCH 2CO)，4.09(t，J＝8.9Hz，1H，OCHCH HNH)，3.98(t，J＝5.3Hz，2H，OCH 2C H 2N)，3.85(t，J＝8.5Hz，1H，OCHC HHNH)，3.69(t，J＝5.4Hz，2H，OC H 2CH 2N)，3.23～3.61(m，4H，OCHC H 2NandNH 2).
IR(KBr)ν(cm -1)：3415，2963，2878，1736，1656，1612，1521，1478，1414，1355，1338，1314，1265，1227，1122，997，922，838，794，709.
Embodiment 8:(S) the chloro-N-of-2-(4-(2-chloracetyl amido) phenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) ethanamide (II 1)
By I 5(0.66g, 0.97mmol), salt of wormwood (0.27g, 1.94mmol) add in methylene dichloride (7ml), under condition of ice bath, drip chloroacetyl chloride (0.33g, 2.90mmol), rise to room temperature gradually, stir 24h, add saturated sodium bicarbonate aqueous solution washing (5ml × 2) after reaction terminates, saturated common salt water washing (5ml × 2), anhydrous sodium sulfate drying, filter, filtrate silica gel column chromatography (methylene dichloride: ethanol, 50: 1) obtains white solid (0.32g, 62.3%), mp100 ~ 102 DEG C.
Its Structural Identification data are as follows:
ESI-MS(m/z)：533.20[M-H] -
1H-NMR(300MHz，CDCl 3)δ：8.60(s，1H，PhNHCO)，7.56(d，J＝8.7Hz，2H，Ar-H)，7.46(d，J＝8.8Hz，2H，Ar-H)，7.22～7.31(m，4H，Ar-H)，4.89(s，1H，CH)，4.27(s，2H，OCH 2CO)，3.93～4.19(m，6H，HNCOC H 2Cl，CH HNCO，OCH 2C H 2NandC HHNCO)，3.63～3.89(m，6H，NCOC H 2Cl，OC H 2CH 2NandOCHC H 2N).
IR(KBr)ν(cm -1)：3415，2963，1752，1655，1638，1618，1515，1407，1313，1262，1099，1023，801，548.
Embodiment 9:(S) the chloro-N-of-2-(4-(2-chloracetyl amido)-2-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) ethanamide (II 2)
With reference to II 1synthetic method, by I 6obtained white solid is reacted, yield 61.3%, mp104 ~ 106 DEG C with chloroacetyl chloride.
Its Structural Identification data are as follows:
ESI-MS(m/z)：551.20[M-H] -
1H-NMR(300MHz，CDCl 3)δ：8.77～8.88(m，1H，PhNHCO)，7.64(t，J＝11.1Hz，1H，Ar-H)，7.46(t，J＝8.8Hz，2H，Ar-H)，7.22～7.37(m，3H，Ar-H)，7.03～7.15(m，1H，Ar-H)，4.73(s，1H，CH)，4.28(s，2H，OCH 2CO)，3.93～4.23(m，6H，HNCOC H 2Cl，CH HNCO，OCH 2C H 2NandC HHNCO)，3.62～3.92(m，6H，NCOC H 2Cl，OC H 2CH 2NandOCHC H 2N).
IR(KBr)ν(cm -1)：3415，2963，1752，1638，1618，1517，1409，1314，1262，1221，1098，1023，865，801，698，612，552.
Embodiment 10:(S) the chloro-N-of-2-(4-(2-chloracetyl amido)-3-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) ethanamide (II 3)
With reference to II 1synthetic method, by I 7obtained white solid is reacted, yield 64.2%, mp96 ~ 98 DEG C with chloroacetyl chloride.
Its Structural Identification data are as follows:
ESI-MS(m/z)：551.10[M-H] -
1H-NMR(300MHz，CDCl 3)δ：8.83(s，1H，PhNHCO)，7.83～8.09(m，1H，Ar-H)，7.44(d，J＝10.4Hz，2H，Ar-H)，7.22～7.32(m，2H，Ar-H)，7.06～7.18(m，1H，Ar-H)，6.86～7.01(m，1H，Ar-H)，4.79(s，1H，CH)，3.91～4.37(m，8H，OCH 2CO，HNCOC H 2Cl，CH HNCO，OCH 2C H 2NandC HHNCO)，3.35～3.87(m，6H，NCOC H 2Cl，OC H 2CH 2NandOCHC H 2N).
IR(KBr)ν(cm -1)：3415，2963，1753，1655，1617，1517，1430，1407，1313，1262，1223，1122，1025，921，800，698，611，552.
Embodiment 11:(S)-N-(4-benzoylamino phenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) benzamide (II 4)
With reference to II 1synthetic method, by I 5obtained white solid is reacted, yield 59.5%, mp136 ~ 138 DEG C with Benzoyl chloride.
Its Structural Identification data are as follows:
ESI-MS(m/z)：589.20[M-H] -
1H-NMR(300MHz，CDCl 3)δ：8.28(s，1H，PhNHCO)，7.71～7.89(m，2H，Ar-H)，7.31～7.53(m，7H，Ar-H)，7.21～7.29(m，2H，Ar-H)，7.07～7.19(m，4H，Ar-H)，6.96～7.05(m，2H，Ar-H)，6.78～6.93(m，1H，Ar-H)，5.01(s，1H，CH)，4.31～4.42(m，1H，OCHCH HN)，4.22(s，2H，OC H 2CO)，3.88～4.12(m，4H，CH HNCO，OCHC HHNandOCH 2C H 2N)，3.76(t，J＝8.40Hz，1H，C HHNCO)，3.65(t，J＝5.4Hz，2H，OC H 2CH 2N).
IR(KBr)ν(cm -1)：3415，2963，2923，2852，1751，1647，1514，1407，1346，1314，1261，1220，1101，1026，922，798，706，600，544.
Embodiment 12:(S)-N-(4-benzoylamino-2-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) benzamide (II 5)
With reference to II 1synthetic method, by I 6obtained white solid is reacted, yield 60.9%, mp120 ~ 122 DEG C with Benzoyl chloride.
Its Structural Identification data are as follows:
ESI-MS(m/z)：607.20[M-H] -
1H-NMR(300MHz，CDCl 3)δ：8.76(s，1H，PhNHCO)，7.95～8.88(m，1H，Ar-H)，7.73(d，J＝7.3Hz，2H，Ar-H)，7.36～7.65(m，5H，Ar-H)，7.28～7.35(m，2H，Ar-H)，7.22～7.27(m，2H，Ar-H)，6.99～7.19(m，6H，Ar-H)，5.06(s，1H，CH)，4.30～4.51(m，1H，OCHCH HN)，4.11～4.28(m，3H，OC H 2COandOCHC HHN)，4.04(t，J＝8.9Hz，1H，C HHNCO)，3.93(t，J＝4.4Hz，2H，OCH 2C H 2N)，3.68～3.82(m，1H，CH HNCO)，3.63(t，J＝4.5Hz，2H，OC H 2CH 2N).
IR(KBr)ν(cm -1)：3415，2963，2922，2844，1753，1655，1514，1407，1312，1261，1220，1122，1026，918，796，707，627.
Embodiment 13:(S)-N-(4-benzoylamino-3-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) benzamide (II 6)
With reference to II 1synthetic method, by I 7obtained white solid is reacted, yield 65.7%, mp106 ~ 108 DEG C with Benzoyl chloride.
Its Structural Identification data are as follows:
ESI-MS(m/z)：607.30[M-H] -
1H-NMR(300MHz，CDCl 3)δ：8.49(s，1H，PhNHCO)，8.04(d，J＝7.1Hz，1H，Ar-H)，7.90(d，J＝7.6Hz，1H，Ar-H)，7.72～7.83(m，1H，Ar-H)，7.37～7.61(m，7H，Ar-H)，7.22～7.33(m，3H，Ar-H)，6.91～7.16(m，5H，Ar-H)，5.06(s，1H，CH)，4.42～4.79(m，1H，OCHCH HN)，4.28(s，2H，OCH 2CO)，3.78～4.21(m，4H，CH HNCO，OCHC HHNandOCH 2C H 2N)，3.55～3.77(m，3H，C HHNCOandOC H 2CH 2N).
IR(KBr)ν(cm -1)：3414，2962，2924，2852，1757，1708，1640，1618，1518，1429，1408，1314，1098.1025.802.708.

Claims (9)

1. general formula (I) oxazolidinone compounds:
Wherein R 1represent nitro or amino, R 2represent hydrogen, halogen, nitro, cyano group, hydroxyl, C 1~ C 6alkyl, C 1~ C 6alkoxyl group, C 1~ C 6haloalkyl, C 1~ C 6halogenated alkoxy, nothing replace monosubstituted or disubstituted amino, carboxyl, carbonyl and derivative thereof.
2. R as claimed in claim 1 2, it can be that unit replaces, dibit replaces or multidigit replaces, the R that dibit replaces or multidigit replaces on the phenyl ring of general formula (I) 2can be hydrogen, halogen, nitro, cyano group, hydroxyl, C at the same time or separately 1~ C 6alkyl, C 1~ C 6alkoxyl group, C 1~ C 6haloalkyl, C 1~ C 6halogenated alkoxy, nothing replace monosubstituted or disubstituted amino, carboxyl, carbonyl and derivative thereof.
3. general formula (II) oxazolidinone compounds:
Wherein R 2definition with claim 1, R 3represent replace or without the alkyl replaced, heterocycle, aromatic nucleus or aralkyl, substituting group can be halogen, nitro, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy, cyano group, hydroxyl, without replacing monosubstituted or disubstituted amino, carboxyl, carbonyl and derivative thereof.
4. the preferred compound of general formula (I) and general formula (II) comprising:
I 1: (S)-4-(4-(5-(((4-nitrophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 2: (S)-4-(4-(5-(((the fluoro-4-nitrophenyl of 2-) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 3: (S)-4-(4-(5-(((the fluoro-4-nitrophenyl of 3-) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 4: (S)-4-(4-(5-(((2,4-dinitrophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 5: (S)-4-(4-(5-(((4-aminophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 6: (S)-4-(4-(5-(((4-amino-2-fluorophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
I 7: (S)-4-(4-(5-(((4-amino-3-fluorophenyl) is amino) methyl)-2-Yang oxazolines-3-base) phenyl) morpholine-3-ketone
II 1: the chloro-N-of (S)-2-(4-(2-chloracetyl amido) phenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) ethanamide
II 2: the chloro-N-of (S)-2-(4-(2-chloracetyl amido)-2-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) ethanamide
II 3: the chloro-N-of (S)-2-(4-(2-chloracetyl amido)-3-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) ethanamide
II 4: (S)-N-(4-benzoylamino phenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) benzamide
II 5: (S)-N-(4-benzoylamino-2-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) benzamide
II 6: (S)-N-(4-benzoylamino-3-fluorophenyl)-N-((2-oxo-3-(4-(3-oxomorpholin-4-base) phenyl) oxazoline-5-base) methyl) benzamide.
5. the synthetic method one of general formula (I) compound, is characterized in that: Compound I a and general formula I b, under alkali existence condition, substitution reaction occurs; The mol ratio of reaction is Ia:Ib=1: 1 ~ 10; Solvent for use be ethyl acetate, acetonitrile, DMSO, DMF, acetone, tetrahydrofuran (THF), dioxane, toluene, propyl carbinol, Virahol, ethylene glycol, water one or more; The mass volume ratio of Ia and solvent is 1: 5 ~ 50; Alkali used comprises sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide, trimethyl carbinol lithium, potassium hydroxide, lithium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, potassiumphosphate, dipotassium hydrogen phosphate; Temperature of reaction is 25 ~ 150 DEG C;
Wherein, R 2definition is with claim 2, and Y represents halogen.
6. the synthetic method two of general formula (I) compound, is characterized in that: under the condition of reduced iron powder and ammonium chloride, carry out reduction reaction by the general formula I c of synthetic method one gained of general formula (I) compound; The mol ratio of reaction is Ic: Fe: ammonium chloride=1: 3 ~ 15: 1 ~ 5; Solvent for use is ethanol: water=1 ~ 10: 1; The mass volume ratio of Ic and solvent is 1: 20 ~ 50; Temperature of reaction is 50 ~ 150 DEG C;
Wherein, R 2definition is with claim 2.
7., in synthetic method as claimed in claim 5, a small amount of cuprous iodide can be added and make catalyzer.
8. the synthetic method of general formula (II) compound, is characterized in that: by the general formula I Ia of synthetic method two gained of general formula (I) compound, itself and general formula I Ib carry out substitution reaction in the basic conditions; The mol ratio of reaction is IIa: IIb=1: 1 ~ 10; Solvent for use comprises methylene dichloride, dioxane, toluene, DMF, DMSO, tetrahydrofuran (THF), acetonitrile, pyridine; The mass volume ratio of IIa and solvent is 1: 5 ~ 50; Alkali used comprises triethylamine, pyridine, sodium hydride, potassium hydroxide, lithium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate; Temperature of reaction is-10 ~ 120 DEG C;
Wherein, R 2define with claim 2, R 3definition is with claim 3, and Y definition is with claim 5.
9. general formula (I), the application of (II) compound in the cardiovascular and cerebrovascular diseases such as treatment thrombosis.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107827882A (en) * 2017-11-27 2018-03-23 浙江永太药业有限公司 A kind of razaxaban analog and its purposes for treating thrombus

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102050819A (en) * 2009-11-10 2011-05-11 天津药物研究院 Oxazolidone derivative as well as preparation method and purposes thereof
US20110135650A1 (en) * 2008-12-05 2011-06-09 Samuel Chackalamannil Morpholinone compounds as factor ixa inhibitors
CN103936763A (en) * 2013-01-18 2014-07-23 中国科学院上海药物研究所 Oxazolidinone compound as well as preparing method and purpose thereof
WO2015043364A1 (en) * 2013-09-29 2015-04-02 华北制药集团新药研究开发有限责任公司 Benzoxazoleoxazine ketone compound as blood coagulation factor xa inhibitor
CN104557900A (en) * 2014-12-23 2015-04-29 中国药科大学 Oxazolidinone compound as well as preparation method and medical application thereof
IN2014MU00196A (en) * 2014-01-21 2015-09-25 Wanbury Ltd

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110135650A1 (en) * 2008-12-05 2011-06-09 Samuel Chackalamannil Morpholinone compounds as factor ixa inhibitors
CN102050819A (en) * 2009-11-10 2011-05-11 天津药物研究院 Oxazolidone derivative as well as preparation method and purposes thereof
CN103936763A (en) * 2013-01-18 2014-07-23 中国科学院上海药物研究所 Oxazolidinone compound as well as preparing method and purpose thereof
WO2015043364A1 (en) * 2013-09-29 2015-04-02 华北制药集团新药研究开发有限责任公司 Benzoxazoleoxazine ketone compound as blood coagulation factor xa inhibitor
IN2014MU00196A (en) * 2014-01-21 2015-09-25 Wanbury Ltd
CN104557900A (en) * 2014-12-23 2015-04-29 中国药科大学 Oxazolidinone compound as well as preparation method and medical application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
李慧，等: "噁唑烷酮醚类化合物的合成及其Xa因子抑制活性", 《中国药科大学学报》 *
江凯，等: "Xa因子抑制剂的研究进展", 《中国新药杂志》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107827882A (en) * 2017-11-27 2018-03-23 浙江永太药业有限公司 A kind of razaxaban analog and its purposes for treating thrombus
CN107827882B (en) * 2017-11-27 2019-12-03 浙江永太药业有限公司 A kind of razaxaban analog and its purposes for treating thrombus

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