CN103601724A - Novel oxazolidinone compound, as well as preparation method and application thereof - Google Patents

Novel oxazolidinone compound, as well as preparation method and application thereof Download PDF

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CN103601724A
CN103601724A CN201310566144.9A CN201310566144A CN103601724A CN 103601724 A CN103601724 A CN 103601724A CN 201310566144 A CN201310566144 A CN 201310566144A CN 103601724 A CN103601724 A CN 103601724A
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CN103601724B (en
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陈卫民
阮志雄
陈艳
皇甫德胜
孙平华
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Guangxi Wuzhou Pharmaceutical Group Co Ltd
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Jinan University
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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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The invention belongs to the field of medicines, and discloses a novel oxazolidinone compound, as well as a preparation method and application thereof. The compound has a chemical structure shown in the formula (I), wherein R1 and R2 are hydrogen, fluorine or chlorine; R3 is -OR4, -NR5R6, -NHCOR7, fluorine, azide group, primary amine group, triazole, triazole containing side chain radicals, mono-phosphate, metal phosphate, sulfonate or metal sulfonate. The novel oxazolidinone compound can be applied to preparation of antibacterial agents or active vasodilator agents.

Description

A kind of novel oxazolidinone compounds and its preparation method and application
Technical field
The invention belongs to field of medicaments, particularly a kind of novel oxazolidinone compounds and its preparation method and application.
Background technology
Due to the increase of antibiotic resistance, wherein, the resistance of gram-positive microorganism is particularly serious, in the treatment that bacterium infects in the urgent need to thering are the novel type antibacterials of brand new and new role pattern.At present, the one oxazolidine ketone antiseptic-germicide Linezolid (Linezolid, ZyvoxR) goes on the market in U.S.'s approval in April, 2000, is used for the treatment of the infection that multidrug resistant gram-positive microorganism causes.Oxazolidinone compounds is the antimicrobial drug of the novel treatment bacterial infection of a class, its action site is on bacterial ribosome 50S subunit near the position of peptidy transeferace center (PTC) and peptide acyl position (P), partly overlap with the action site existence of peptidy transeferace inhibitor (as lincomycin and paraxin), but both have marked difference by mechanism of action, the synthetic initial period of the former selectivity arrestin matter, and the inhibition activity to peptidy transeferace is extremely faint, therefore be difficult for the antimicrobial drug generation cross resistance synthetic with other arrestin.Although take this medicine, as representing oxazolidone, can be used for treating infected by microbes, but after life-time service, occurred clinically the infection that streptococcus aureus and faecalis by resistance to Linezolid cause, their application is because severe side effect is restricted simultaneously.As the restraining effect of monoamine oxidase, make itself and many medicines, as serotonin reuptake inhibitor or other antidepressives etc. cannot be used simultaneously, and and follow the side reactions such as thrombopenia, bone marrow depression, if with adrenin drug combination, cause hypertensive crisis.
The resistance situation of gram-positive microorganism is more and more serious clinically, and the clinical use kind of oxazole alkanes antibacterials is single.Linezolid has played certain effect as novel antibacterial medicine to overcoming bacterial resistance, but the resistance situation of Linezolid is more and more serious, simultaneously due to toxic side effect such as its monoamine oxidase restraining effect, bone marrow depression, hypertensive crises, limited its use range, can not meet clinical demand far away, therefore, be badly in need of expanding the antibiotic clinical application kind of large oxazolidine ketone, develop antibacterials effective to resistance gram-positive microorganism height and that toxic side effect is low.
Bacterium infects and easily brings out inflammation, for the treatment of inflammation, mainly adopts clinically nonsteroidal anti-inflammatory drug (NSAIDs).Peroxisome proliferation-activated receptors (PPARs), especially PPAR γ is found can be used as the target spot of novel anti-inflammatory medicinal design, studies have shown that PPAR gamma agonist has anti-inflammatory and anti-microbial effect.
For meeting clinical demand, the Ligustrazine structural unit that plan introducing has diastolic blood vessel activity removes to transform Linezolid, using the classical architecture rosiglitazone of PPAR gamma agonist as new drug design template compound, simultaneously in conjunction with bacterium 50S ribosome receptor and PPAR γ acceptor, use the novel oxazolidinone compounds of Computer-Aided Drug Design software design, make synthetic compound there is antibacterial, anti-inflammatory action, improve the side effects such as Linezolid hypertensive crisis simultaneously.
Summary of the invention
In order to overcome the shortcoming and deficiency of above-mentioned prior art, primary and foremost purpose of the present invention is to provide a kind of novel oxazolidinone compounds.This compounds contains Ligustrazine structural unit, can overcome the hypertensive crisis side-effect problem of Linezolid.
Another object of the present invention is to provide a kind of preparation method of above-mentioned novel oxazolidinone compounds.The method has the Ligustrazine structural unit transformation Linezolid of diastolic blood vessel activity by introducing, using the classical architecture rosiglitazone of PPAR gamma agonist as new drug design template compound, the interaction design new compound of binding partner and bacterium 50S ribosome receptor and PPAR γ acceptor, synthetic preparing has compound antibacterial, anti-inflammatory action, improves its improvement to Linezolid side effect (hypertensive crisis) simultaneously.
Another object of the present invention is to provide the application of above-mentioned novel oxazolidinone compounds in antibacterial, diastolic blood vessel activity.
Object of the present invention realizes by following proposal:
A novel oxazolidinone compounds, has the chemical structure as shown in formula I:
Figure BDA0000413517150000021
Wherein, R 1and R 2for hydrogen, fluorine or chlorine.
R 3for-OR 4,-NR 5r 6,-NHCOR 7, fluorine, azido-, primary amine groups, triazole, containing triazole, phosplate, phosphoric acid ester metal-salt, sulphonate or the sulphonate metal-salt of side chain radical.
R 4alkyl for hydrogen or 1～3 carbon atom.
R 5and R 6alkyl or ethanoyl for hydrogen, 1～3 carbon atom.
R 7represent single halogenated methyl, two halogenated methyl, methoxymethyl, adamantyl or heterocycle.
Above-mentioned heterocycle is furans, halo furans, thiophene or halogenated thiophene.
The halogen of above-mentioned halo is chlorine or fluorine.
The preparation method of above-mentioned novel oxazolidinone compounds, specifically according to following operation steps:
(1) a kind of by p-NP and 2-fluoro-4-nitrophenol, reacts with bromo Ligustrazine (TMP-Br), salt of wormwood and dry DMF, cooling, filters, and obtains respectively compd A 1 and compound B-11;
(2) by compd A 1 and compound B-11 respectively with the Pd/C(palladium-carbon catalyst of mass percent 10%) at THF(tetrahydrofuran (THF)) and in dissolve, after vacuumizing, in nitrogen atmosphere, react, filter, filtrate decompression is spin-dried for; Mix with aqueous sodium carbonate and acetone, under nitrogen atmosphere, drip Carbobenzoxy Chloride, after reaction, decompression is spin-dried for, extraction, and recrystallization, obtains respectively compd A 2 and compd B 2;
(3) by compd A 2 and compd B 2 respectively at 100 ℃ with benzene band water, then by benzene evaporate to dryness; Under nitrogen protection, inject anhydrous THF, be placed under-78 ℃ of agitation conditions and inject two (trimethyl silicon based) Lithamides, (the R)-Glycidyl Butyrate that reinjects reaction 1h relief reaction system, to room temperature, adds NH after reaction 4the cancellation of Cl solution, extraction, decompression is spin-dried for, recrystallization, get is Dao oxazolidinone compounds 1a with oxazolidinone compounds 1b respectively;
(4) are Jiang oxazolidinone compounds 1a with oxazolidinone compounds 1b is dissolved in respectively in anhydrous methylene chloride, triethylamine reinjects, inject subsequently fluoro reagent diethylin sulfur trifluoride (DAST), stirring at room reaction 24h, add after completion of the reaction shrend to go out, extraction, is spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 2a and white solid compound 2b;
(5) are Jiang oxazolidinone compounds 1a with oxazolidinone compounds 1b is placed on stirring at 0 ℃ with methylene dichloride dissolving respectively, inject triethylamine, stir after 5 minutes, inject methylsulfonyl chloride, after be transferred to room temperature reaction, spend the night, extraction after reacting completely, decompression is spin-dried for, and purification by silica gel column chromatography obtains respectively methanesulfonates intermediate 3a and methanesulfonates intermediate 3b;
(6) by methanesulfonates midbody compound 3a and methanesulfonates midbody compound 3b respectively with sodium methylate, anhydrous methanol in normal-temperature reaction 48h; After reacting completely, extraction, is spin-dried for, and purification by silica gel column chromatography, obtains respectively white solid compound 4a and white solid compound 4b;
(7) methanesulfonates midbody compound 3a and methanesulfonates midbody compound 3b are placed in to constant temperature stirring reaction 48h at 60 ℃ with Dimethylammonium chloride, salt of wormwood and dry DMF respectively, after, extraction, decompression is spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 5a and white solid compound 5b;
(8) the sodium hydride powder that is 60% by methanesulfonates midbody compound 3a and dry DMF, mass content, and 1H-1,2,4-triazole and 1H-1, a kind of in 2,3-triazole, after room temperature reaction 48h, extract, be spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 6a, white solid compound 7a-1 and white solid compound 7a-2;
The sodium hydride powder that is 60% by methanesulfonates midbody compound 3b and dry DMF, mass content, and 1H-1,2,4-triazole and 1H-1, a kind of in 2,3-triazole, after room temperature reaction 48h, extract, be spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 6b, white solid compound 7b-1 and white solid compound 7b-2;
(9) by methanesulfonates midbody compound 3a and methanesulfonates midbody compound 3b respectively with dry DMF and sodiumazide heated constant temperature at 90 ℃ react 3h, extraction after reacting completely, decompression is spin-dried for, and purification by silica gel column chromatography, obtains respectively triazo-compound 8a and triazo-compound 8b fast;
(10) triazo-compound 8a and triazo-compound 8b are placed in to reactor with water, beta-cyclodextrin and Salzburg vitriol respectively, 1-hexin reinjects, add subsequently sodium ascorbate, stirring at normal temperature reaction 5-10 minute, stopped reaction, extraction, is spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 9a and white solid compound 9b;
(11) triazo-compound 8a and triazo-compound 8b are reacted to 24h with malonamide nitrile, salt of wormwood and dimethyl sulfoxide (DMSO) (DMSO) in stirring at room respectively, extraction after reacting completely, and use saturated common salt water washing, be spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 10a and white solid compound 10b;
(12) by triazo-compound 8a and triazo-compound 8b respectively with the Pd/C(palladium-carbon catalyst of mass percent 10%) in tetrahydrofuran (THF) (THF), dissolve, at 0 ℃, vacuumize, inflated with nitrogen, uses H after 3 times repeatedly 2displacement, after under room temperature stirring reaction; After completion of the reaction, filter, extraction, is spin-dried for, and obtains respectively primary amine 11a and primary amine 11b;
(13) primary amine 11a is dissolved with anhydrous methylene chloride, at 0 ℃, drip anhydrous triethylamine, after stirring 5min, drip the acyl chlorides reagent of 0.5～2.1mmol, after, after stirring 10min, be transferred to room temperature reaction 24h.Stopped reaction, adds shrend and goes out, and extraction, is spin-dried for, and purification by silica gel column chromatography, obtains respectively white solid compound 12a, 13a, 14a, 15a, 16a, 17a, 18a;
Primary amine 11b is dissolved with anhydrous methylene chloride, at 0 ℃, drip anhydrous triethylamine, after stirring 5min, drip the acyl chlorides reagent of 0.5～2.1mmol, after, after stirring 10min, be transferred to room temperature reaction 24h; Stopped reaction, adds shrend and goes out, and extraction, is spin-dried for, and purification by silica gel column chromatography, obtains respectively white solid compound 12b, 13b, 14b, 15b, 16b, 17b and 18b;
Described acyl chlorides reagent is Acetyl Chloride 98Min., chloroacetyl chloride, dichloroacetyl chloride, methoxyacetyl chloride, diamantane acyl chlorides, 2 furoyl chloride or the chloro-2-acyl chlorides of 5-thiophene.
The structural formula of each compound is as follows:
Figure BDA0000413517150000061
Synthetic route as shown in Figure 1.
The application of above-mentioned novel oxazolidinone compounds in preparation antibacterials or diastolic blood vessel activity medicine.
Mechanism of the present invention is:
The present invention take antibacterials Linezolid as lead compound and the exogenous part rosiglitazone with PPAR γ agonist activity be new drug design template compound, retain Linezolid oxazolidone part, introduce Ligustrazine (TMP) structural unit, computer ancillary drug design molecular docking simulation, by principle design such as molecular structure similarity, pharmacophore displacement, the displacement of R substituting group, bioisostere displacements a series of compounds.By retrosynthetic analysis, adopt practicable synthetic method and suitable reagent to design the synthetic route of target compound.
The present invention, with respect to prior art, has following advantage and beneficial effect:
Synthetic route of the present invention has been applied green chemical reaction, and more environmental protection, has more Atom economy.Compound of the present invention combines raising anti-microbial activity and diastolic blood vessel activity, has effectively solved the hypertensive crisis side effect when prodrug Linezolid.
Accompanying drawing explanation
Fig. 1 is synthetic route chart of the present invention, wherein reaction conditions: (a) NBS, Ph (CO 2) 2, hv, reflux; (b) K 2cO 3, DMF, 85 ℃; (c) H 2, 10%Pd/C, THF; (d) Cbz-Cl, Na 2cO 3, acetone-H 2o (10:1); (e) LiN (Si (CH 3) 3) 2, (R)-glycidyl butylate, THF ,-78 ℃ of to rt; (f) DAST, Et 3n, CH 2cl 2, rt; (g) MeSO 2cl, Et 3n, CH 2cl 2, 0 ℃ of to rt; (h) NaOMe, MeOH, rt, 24h; (i) K 2cO 3, Dimethylamine hydrochloride, DMF, 60 ℃; (j) NaH, triazole, DMF, rt; (k) NaN 3, DMF, 90 ℃, 3h; (l) 2-cyanoacetamide, K 2cO 3, DMSO, rt; (m) 1-hexyne, CuSO 4.5H 2o, sodium assorbate, β-CD, H 2o; (o) H 2, 10%Pd/C, THF, 24h; (n) R 2cOCl, Et 3n, CH 2cl 2, 0 ℃ of to rt.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Embodiment 1:2,3,5-trimethylammonium-6-((4-nitro-phenoxy) methyl) preparation of pyrazine (A1)
Figure BDA0000413517150000071
In bis-mouthfuls of flasks of 50mL, add TMP-Br(1.188g, 5.52mmol, TMP-Br is made by currently known methods, can reference literature Journal of Fudan University, 1980,4:390-394.), p-NP (0.640g, 4.60mmol), salt of wormwood (1.279g, 9.20mmol), and add 5.5mL dry DMF to dissolve, be heated to 85 ℃, stirring reaction 5～7h, stopped reaction.Reaction solution is cooled to room temperature, in the frozen water of 50 times of volumes of impouring, separates out white floss, filter, obtain white solid, vacuum-drying obtains yellowing look (log look) solid A1(1.173g, 93.4%).
1H?NMR(300MHz,CDCl 3):δ8.15(d,J=8.0Hz,2H),7.06(d,J=9.1Hz,2H),5.23(s,2H),2.56(s,3H),2.49(s,6H).
The fluoro-4-nitrophenoxy of embodiment 2:2-((2-) methyl)-3,5, the preparation of 6-trimethylpyrazine (B1)
Figure BDA0000413517150000081
Take 2-fluoro-4-nitrophenol and TMP-Br as raw material, and preparation method, with embodiment 1, obtains faint yellow solid B2(6.0g, 95.2%).
1H?NMR(300MHz,CDCl 3):δ8.01(ddd,J=9.0,2.6,1.4Hz,1H),7.95(dd,J=10.5,2.7Hz,1H),7.27(dd,J=11.3,5.8Hz,1H),5.33(s,2H),2.59(s,3H),2.50(d,J=2.2Hz,6H).
Embodiment 3:4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group) preparation of benzyl carbamate (A2)
Figure BDA0000413517150000082
By A1(6.0g, 22mmol, preparation method is with embodiment 1) and 10%Pd/C(0.6g) join in two mouthfuls of round-bottomed flasks of 100mL, add again THF(35mL) stirring and dissolving, by T-valve, make reaction system under atmosphere of hydrogen, at 0 ℃, vacuumize, with nitrogen replacement 2 times, hydrogen exchange once, after, be placed under normal temperature stirring reaction 24 hours.Through diatomite filtration, washing with acetone 3 times, is spin-dried for filtrate decompression, directly drops into next step.Upper step gained is placed in to two mouthfuls of round-bottomed flasks of 100mL, with the H of 4mL 2o dissolves sodium carbonate (2.6g, 2.2mmol), joins in reaction flask, add again 40mL acetone, under nitrogen atmosphere, slowly drip Carbobenzoxy Chloride (10mL, 66mmol), within 10 minutes, dropwise, naturally rise to room temperature, react after 18 hours, the acetone decompression in reaction solution is spin-dried for, then (30mL * 3) extraction that adds methylene chloride, decompression is spin-dried for, and obtains faint yellow solid, with normal hexane and ethyl acetate mixed solvent (3:1) recrystallization, obtain white powder A2(7.5g, 90%).
1H?NMR(400MHz,CDCl 3):δ7.41-7.26(m,7H),6.94(d,J=8.9Hz,2H),6.72(s,1H),5.17(s,2H),5.11(s,2H),2.57(s,3H),2.50(s,6H).
The fluoro-4-((3 of embodiment 4:3-, 5,6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenylcarbamic acid benzyl ester (B2)
Take B1(preparation method with embodiment 2) be raw material, preparation method, with embodiment 3, obtains white solid B2(7.2g, 88%).
1H?NMR(300MHz,CDCl 3):δ7.41-7.29(m,5H),7.03(t,J=8.8Hz,1H),6.95(d,J=8.8Hz,1H),6.78(s,1H),5.17(d,J=3.1Hz,4H),2.60(s,3H),2.50(d,J=3.0Hz,6H).
Embodiment 5:(R)-5-(methylol)-3-(4-((3,5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (1a)
By A2(1.17g, 3.1mmol, preparation method is with embodiment 3) at 100 ℃ with benzene band water, then by benzene evaporate to dryness.Under nitrogen protection, inject anhydrous THF(12mL), be placed at-78 ℃ and stir.Slowly inject two trimethyl silicon based Lithamide (5.76mL, 5.76mmol), minute injection several times (surpassing 10min), after, stirring reaction 30min, slowly inject again (R)-Glycidyl Butyrate (0.66mL, 4.5mmol), after, in-78 ℃ of reaction 1h relief reaction systems, be naturally warming up to room temperature, reaction 24h, stopped reaction, adds the saturated NH of 5mL 4the cancellation of Cl solution, with ethyl acetate (40mL * 3) extraction, decompression is spin-dried for to obtain crude product.With acetone: normal hexane=1:4 mixed solvent recrystallization, the cooling white solid of separating out; Or be that eluent carries out purification by silica gel column chromatography with sherwood oil: acetone=2:1, obtain white solid 1a(0.85g, 79.9%).
1H?NMR(300MHz,DMSO-d6):δ7.56-7.41(m,2H),7.13-6.94(m,2H),5.19(t,J=5.7Hz,1H),5.14(s,2H),4.66(dq,J=6.4,3.9Hz,1H),4.04(t,J=8.9Hz,1H),3.79(dd,J=8.8,6.4Hz,1H),3.67(ddd,J=12.2,5.5,3.5Hz,1H),3.56(ddd,J=12.3,5.7,4.2Hz,1H),2.49(s,3H),2.45(s,6H).
Embodiment 6:(R) the fluoro-4-((3 of-3-(3-, 5, the 6-trimethylpyrazine-2-yl) methoxyl group) phenyl) preparation of-5-Qiang Jia Ji oxazolidine-2-ketone (1b)
Take B2(preparation method with embodiment 4) be raw material, preparation method, with embodiment 5, obtains faint yellow solid 1b(0.887g, 72.3%).
1H?NMR(300MHz,CDCl 3):δ7.47-7.39(m,1H),7.15-7.02(m,2H),5.17(s,2H),4.75-4.64(m,1H),4.01-3.87(m,3H),3.78-3.65(m,1H),3.36(d,J=5.6Hz,1H),2.59(s,3H),2.49(d,J=2.3Hz,6H).
Embodiment 7:(R)-5-(methyl fluoride)-3-(4-((3,5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (2a)
Figure BDA0000413517150000101
Jiang oxazolidinone compounds 1a(110mg, 0.32mmol, preparation method is with embodiment 5) be dissolved in the anhydrous methylene chloride of 10mL, the reinject triethylamine of 0.09mL, injects fluorination reagent DAST(0.05mL, 0.32mmol subsequently), stirring at room reaction 24h, after completion of the reaction, adds suitable quantity of water cancellation, with methylene dichloride (10mL * 3) extraction, be spin-dried for, through purification by silica gel column chromatography, eluent is sherwood oil: acetone=4:1, gradient elution, obtains white solid 2a(85mg, 76.9%).
1H?NMR(300MHz,CDCl 3):δ7.42-7.35(m,2H),7.02-6.95(m,2H),5.10(s,2H),4.74(d,J=3.2Hz,1H),4.70(d,J=3.2Hz,0.5H),4.64-4.53(m,1H),4.46(d,J=3.7Hz,0.5H),4.05(td,J=9.1,0.9Hz,1H),3.88(dd,J=8.9,6.4Hz,1H),2.54(s,3H),2.48(s,6H).
Embodiment 8:(R) the fluoro-4-((3 of-3-(3-, 5, the 6-trimethylpyrazine-2-yl) methoxyl group) phenyl) preparation of-5-(methyl fluoride) oxazolidine-2-ketone (2b)
Yi oxazolidinone compounds 1b(270mg, 0.5mmol, preparation method is with embodiment 6) be raw material, preparation method, with embodiment 7, obtains white solid 2b(160mg, 88.0%).
1H?NMR(300MHz,CDCl 3):δ7.43(dd,J=13.6,1.7Hz,1H),7.18-7.05(m,2H),5.19(s,2H),4.90-4.72(m,2H),4.67-4.57(m,1H),4.48(dd,J=10.6,3.5Hz,1H),4.07(t,J=9.0Hz,1H),3.91(dd,J=8.7,6.4Hz,1H),2.60(s,3H),2.50(d,J=1.9Hz,6H).
Embodiment 9:(R)-(2-oxo-3-(4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl) oxazolidine-5-yl) preparation of methylmethanesulfonate ester (3a)
Figure BDA0000413517150000111
Jiang oxazolidinone compounds 1a(1.00g, 2.92mmol, preparation method is with embodiment 5) join in two mouthfuls of flasks of 100mL, add 20mL methylene dichloride to dissolve, be placed at 0 ℃ and stir, inject triethylamine (0.73mL, 5.84mmol), stir after 5 minutes, slowly inject methylsulfonyl chloride (0.8mL, 5.84mmol), after be transferred to room temperature reaction, spend the night (12h), TLC detection reaction is complete, stopped reaction.Add H 2o(15mL), methylene dichloride (15mL * 3) extraction, decompression is spin-dried for, and obtains faint yellow oily matter, directly drops into next step reaction.As further quick silica gel column chromatography (sherwood oil: acetone=2:1) separation and purification obtains faint yellow solid 3a(1.19g, 97.0%).
1H?NMR(300MHz,CDCl 3):δ7.46-7.36(m,2H),7.06-6.96(m,2H),5.14(s,2H),4.89(ddd,J=13.3,6.1,4.1Hz,1H),4.44(m,1.5H),4.12(t,J=9.1Hz,1H),3.97-3.87(m,1H),3.71(q,J=7.0Hz,0.5H),3.09(s,3H),2.58(s,3H),2.52(s,6H).
Embodiment 10:(R)-(the fluoro-4-((3 of 3-(3-, 5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl)-2-Yang Dai oxazolidine-5-yl) preparation of methylmethanesulfonate ester (3b)
Yi oxazolidinone compounds 1b(2.0g, 5.54mmol, preparation method is with embodiment 6) be raw material, preparation method, with embodiment 9, obtains faint yellow solid 3b(2.24g, 92.0%).
1H?NMR(300MHz,CDCl 3):δ7.42(dd,J=12.9,2.4Hz,1H),7.16-7.03(m,2H),5.18(s,2H),4.88(ddd,J=13.2,6.1,4.0Hz,1H),4.46(dd,J=11.7,3.6Hz,1H),4.38(dd,J=11.7,4.3Hz,1H),4.08(t,J=9.1Hz,1H),3.87(dd,J=9.1,6.2Hz,1H),3.07(s,3H),2.58(s,3H),2.49(d,J=2.3Hz,6H).
Embodiment 11:(R)-5-(methoxymethyl)-3-(4-((3,5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (4a)
Figure BDA0000413517150000121
By methanesulfonates intermediate 3a(110mg, 0.261mmol, preparation method is with embodiment 9) and sodium methylate (70mg, 1.3mmol) join in the round-bottomed flask of 50mL, then add anhydrous methanol (10mL), in normal-temperature reaction 48h.After, add the H of 10mL 2o, with ethyl acetate (10mL * 3) extraction, is spin-dried for, and with sherwood oil: acetone=3:1, is eluent purification by silica gel column chromatography, obtains white solid 4a(50mg, 51%).
1H?NMR(300MHz,CDCl 3):δ7.45-7.39(m,2H),7.02-6.96(m,2H),5.12(s,2H),4.71(ddt,J=9.0,6.3,4.6Hz,1H),4.00(t,J=8.8Hz,1H),3.86(dd,J=8.7,6.4Hz,1H),3.61(d,J=4.6Hz,2H),3.41(s,3H),2.56(s,3H),2.49(s,6H).
Embodiment 12:(R) the fluoro-4-((3 of-3-(3-, 5, the 6-trimethylpyrazine-2-yl) methoxyl group) phenyl) preparation of-5-(methoxymethyl) oxazolidine-2-ketone (4b)
Take methanesulfonates intermediate 3b(preparation method with embodiment 10) be raw material, preparation method, with embodiment 11, obtains white solid 4b(30mg, 45%).
1H?NMR(300MHz,CDCl 3):δ7.15-6.93(m,3H),5.20(s,2H),3.92(dd,J=14.8,3.7Hz,1H),3.70(s,3H),3.51(dd,J=14.8,6.1Hz,1H),3.24-3.17(m,1H),2.79(t,J=4.4Hz,1H),2.60(s,3H),2.51(d,J=3.0Hz,7H).
Embodiment 13:(S)-5-((dimethylamino) methyl)-3-(4-((3,5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (5a)
Figure BDA0000413517150000131
By methanesulfonates intermediate 3a(212mg, 0.50mmol, preparation method is with embodiment 9), Dimethylammonium chloride (61.5mg, 0.756mmol) and salt of wormwood (207mg, 1.50mmol) is mixed in two mouthfuls of bottles of 50mL, adds dry DMF (4mL) to dissolve.Reaction system is placed in to constant temperature stirring reaction 48h at 60 ℃, after, add suitable quantity of water, ethyl acetate (15mL * 3) extraction, decompression is spin-dried for, purification by silica gel column chromatography, eluent is sherwood oil: acetone=3:1, obtains white solid 5a(93mg, 50%).
1H?NMR(300MHz,CDCl 3):δ7.46-7.38(m,2H),7.03-6.94(m,2H),5.12(s,2H),4.78-4.66(m,1H),4.03(t,J=8.7Hz,1H),3.81-3.64(m,1H),2.66(dd,J=6.0,3.8Hz,2H),2.56(s,3H),2.50(s,6H),2.34(s,6H).
Embodiment 14:(S)-5-((dimethylamino) methyl) the fluoro-4-((3 of-3-(3-, 5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (5b)
Take methanesulfonates intermediate 3b(preparation method with embodiment 10) be raw material, preparation method, with embodiment 13, obtains white solid 5b(114mg, 60.6%).
1H?NMR(300MHz,CDCl 3):δ7.50-7.34(m,1H),7.15-6.94(m,2H),5.18(s,2H),4.83(dq,J=5.6,4.0Hz,1H),4.40-4.21(m,2H),4.06(t,J=9.0Hz,1H),3.79(dd,J=8.9,5.7Hz,1H),2.85(d,J=16.3Hz,6H),2.59(s,3H),2.49(d,J=2.1Hz,6H).
Embodiment 15:(R)-5-((1H-1,2,4-triazole-1-yl) methyl)-3-(4-((3,5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (6a)
Figure BDA0000413517150000141
By methanesulfonates intermediate 3a(234mg, 0.556mmol, preparation method is with embodiment 9) and 1H-1,2,4-triazole (130mg, 1.88mmol) be placed in the round-bottomed flask of 50mL, then add 5mL dry DMF to dissolve, adding subsequently content is 60% NaH powder (78mg, 1.95mmol), room temperature reaction 48h, after, add H 2o, ethyl acetate (10mL * 3) extraction, is spin-dried for, purification by silica gel column chromatography, eluent is sherwood oil: acetone=2:1, obtains white powder solid 6a(143mg, 65.5%).
1H?NMR(300MHz,CDCl 3):δ8.21(s,1H),7.90(s,1H),7.30-7.22(m,2H),7.00-6.88(m,2H),5.08(s,2H),4.94(td,J=10.9,4.9Hz,1H),4.49(d,J=4.8Hz,2H),4.07(t,J=9.1Hz,1H),3.90(dd,J=9.2,6.2Hz,1H),2.52(s,3H),2.46(s,6H).
Embodiment 16:(R)-5-((1H-1,2,4-triazole-1-yl) methyl) the fluoro-4-((3 of-3-(3-, 5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (6b)
Take methanesulfonates intermediate 3b(preparation method with embodiment 10) be raw material, preparation method, with embodiment 15, obtains white solid 6b(186mg, 72.8%).
1H?NMR(300MHz,CDCl 3):δ8.19(s,1H),7.87(s,1H),7.27(dd,J=12.8,2.6Hz,1H),7.04(t,J=8.9Hz,1H),6.93(ddd,J=9.0,2.6,1.2Hz,1H),5.12(s,2H),4.94(td,J=10.9,4.9Hz,1H),4.48(d,J=4.8Hz,2H),4.04(t,J=9.1Hz,1H),3.88(dd,J=9.2,6.2Hz,1H),2.52(s,3H),2.43(d,J=3.2Hz,6H).
Embodiment 17:(R)-5-((2H-1,2,3-triazole-2-yl) methyl)-3-(4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group) phenyl) oxazolidine-2-ketone (7a-1) and (R)-5-((1H-1,2,3-triazole-2-yl) methyl)-3-(4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (7a-2)
Figure BDA0000413517150000151
By methanesulfonates intermediate 3a(421mg, 1.00mmol, preparation method is with embodiment 9) be placed in two mouthfuls of round-bottomed flasks of 50mL, add again 5mL dry DMF to dissolve, adding content is 60% NaH powder (44mg again, 1.10mmol), under nitrogen atmosphere, slowly inject subsequently about 0.1mL(1.5equiv mol) 1H-1, 2, 3-triazole, room temperature reaction 48h under nitrogen atmosphere, after completion of the reaction, add H2O, ethyl acetate (20mL * 3) extraction, be spin-dried for, purification by silica gel column chromatography, eluent is sherwood oil: acetone=4:1, obtain white solid 7a-1(90mg, 21.8%) and white solid 7a-2(165mg, 40.0%).
7a-1: 1H?NMR(300MHz,CDCl 3):δ7.62(s,2H),7.37-7.29(m,2H),7.01-6.92(m,2H),5.10(s,2H),5.09-5.03(m,1H),4.82(dd,J=14.0,4.8Hz,1H),4.72(dd,J=14.0,6.7Hz,1H),4.06(t,J=8.9Hz,1H),3.95(dd,J=9.3,5.5Hz,1H),2.55(s,3H),2.49(s,6H).
7a-2: 1H?NMR(300MHz,CDCl 3):δ7.73(d,J=0.9Hz,1H),7.67(d,J=0.9Hz,1H),7.22-7.13(m,2H),6.96-6.85(m,2H),5.05(s,2H),4.96(ddt,J=8.8,6.0,4.4Hz,1H),4.70(dd,J=4.2,1.6Hz,2H),4.06(t,J=9.1Hz,1H),3.82(dd,J=9.4,6.1Hz,1H),2.50(s,3H),2.45(d,J=1.5Hz,6H).
Embodiment 18:(R)-5-((2H-1,2,3-triazole-2-yl) methyl) the fluoro-4-((3 of-3-(3-, 5,6-trimethylpyrazine-2-yl) methoxyl group) phenyl) oxazolidine-2-ketone (7b-1) and (R)-5-((1H-1,2,3-triazole-2-yl) methyl) the fluoro-4-((3 of-3-(3-, 5,6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (7b-2)
Take methanesulfonates intermediate 3b(preparation method with embodiment 10) be raw material, preparation method, with embodiment 17, obtains white solid 7b-1(85mg, 21.0%) and white solid 7b-2(140mg, 43.2%).
7b-1: 1H?NMR(300MHz,CDCl 3):δ7.64(s,2H),7.36(dd,J=13.0,2.4Hz,1H),7.18-7.00(m,2H),5.19(s,2H),5.16-5.03(m,1H),4.85(dd,J=14.0,4.6Hz,1H),4.74(dd,J=14.0,6.8Hz,1H),4.10-3.92(m,2H),2.60(s,3H),2.50(d,J=2.7Hz,6H).
7b-2: 1H?NMR(300MHz,CDCl 3):δ7.76(s,1H),7.71(s,1H),7.30(dd,J=12.8,2.6Hz,1H),7.07(t,J=9.0Hz,1H),6.95-6.88(m,1H),5.16(s,2H),5.01(dt,J=10.1,4.4Hz,1H),4.80-4.66(m,2H),4.09(t,J=9.1Hz,1H),3.85(dd,J=9.3,6.1Hz,1H),2.57(s,3H),2.48(d,J=2.8Hz,6H).
Embodiment 19:(R)-5-(azido-methyl)-3-(4-((3,5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazole-2-ketone (8a)
Figure BDA0000413517150000161
By methanesulfonates intermediate 3a(1.2g, 2.92mmol, preparation method is with embodiment 9) be dissolved in the dry DMF of 10mL, add NaN 3(0.6g, 9.23mmol), heated constant temperature reaction 3h at 90 ℃, TLC detection reaction is complete, adds H 2o(50mL), ethyl acetate (15mL * 3) extraction, decompression is spin-dried for, quick purification by silica gel column chromatography, eluent is sherwood oil: acetone=2:1, obtains white solid 8a(0.986g, 91.8%).
1H?NMR(300MHz,CDCl 3):δ7.42-7.31(m,2H),7.02-6.90(m,2H),5.09(s,2H),4.71(ddt,J=8.9,6.2,4.5Hz,1H),4.00(t,J=8.9Hz,1H),3.75(dd,J=9.0,6.3Hz,1H),3.62(dd,J=13.3,4.3Hz,1H),3.50(dd,J=13.3,4.6Hz,1H),2.52(s,3H),2.46(s,6H).
Embodiment 20:(R)-5-(azido-methyl) the fluoro-4-((3 of-3-(3-, 5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (8b)
Take methanesulfonates intermediate 3b(preparation method with embodiment 10) be raw material, preparation method, with embodiment 19, obtains white solid 8b(0.75g, 86.3%).
1H?NMR(300MHz,CDCl 3):δ7.48-7.38(m,1H),7.17-7.05(m,2H),5.19(s,2H),4.76(ddt,J=9.0,6.2,4.5Hz,1H),4.03(t,J=8.9Hz,1H),3.80(dd,J=8.9,6.2Hz,1H),3.69(dd,J=13.2,4.5Hz,1H),3.57(dd,J=13.2,4.4Hz,1H),2.60(s,3H),2.50(d,J=2.2Hz,6H).
Embodiment 21:(R)-5-((4-butyl-1H-1,2,3-triazole-1-yl) methyl)-3-(4-((3,5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (9a)
Figure BDA0000413517150000171
By triazo-compound 8a(230mg, 0.625mmol, preparation method is with embodiment 19) be placed in the reactor of 3mL, add the H of 1mL 2the beta-cyclodextrin of O, 18mg and Salzburg vitriol (7.8mg, 0.031mmol), 1-hexin (0.077mL reinjects, 0.656mmol), add subsequently sodium ascorbate (20mg, 0.094mmol), stirring at normal temperature reaction 5～10 minutes, stopped reaction, add 5mL water, methylene dichloride (5mL * 3) extraction, merges organic phase, be spin-dried for, obtain yellow-green colour crude product.Crude product carries out purification by silica gel column chromatography, and eluent is sherwood oil: acetone=3:1, and purifying obtains 9a(261mg, and 92.8%).
1H?NMR(300MHz,CDCl 3):δ7.50(s,1H),7.31-7.22(m,2H),6.97(d,J=9.1Hz,2H),5.12(s,2H),5.00(td,J=10.0,4.4Hz,1H),4.74-4.60(m,2H),4.10(t,J=9.1Hz,1H),3.87(dd,J=9.3,6.1Hz,1H),2.73-2.65(m,2H),2.56(s,3H),2.51(s,6H),1.61(dt,J=15.3,7.6Hz,2H),1.31(dt,J=14.6,7.4Hz,2H),0.89(t,J=7.3Hz,3H).
Embodiment 22:(R)-5-((4-butyl-1H-1,2,3-triazole-1-yl) methyl) the fluoro-4-((3 of-3-(3-, 5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (9b)
Take triazo-compound 8b(preparation method with embodiment 20) be raw material, preparation method, with embodiment 21, obtains white solid 9b(120mg, 90.3%).
1H?NMR(300MHz,CDCl 3):δ7.48(s,1H),7.32(dd,J=12.8,2.7Hz,1H),7.07(t,J=9.0Hz,1H),6.91(ddd,J=9.0,2.6,1.4Hz,1H),5.17(s,2H),5.00(m,1H),4.68(dd,J=4.2,1.5Hz,2H),4.08(t,J=9.1Hz,1H),3.86(dd,J=9.3,6.1Hz,1H),2.73-2.62(m,2H),2.58(s,3H),2.49(d,J=3.0Hz,6H),1.59(dt,J=15.3,7.5Hz,2H),1.30(m,2H),0.87(t,J=7.3Hz,3H).
Embodiment 23:(R)-5-amino-1-((2-oxo-3-(4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group) phenyl) oxazolidine-5-yl) methyl isophthalic acid H-1, the preparation of 2,3-triazole-4-methane amide (10a)
Figure BDA0000413517150000181
By triazo-compound 8a(100mg, 0.27mmol, preparation method is with embodiment 19), malonamide nitrile (27mg, 0.324mmol) and salt of wormwood (149mg, 1.08mmol) join in the round-bottomed flask of 25mL, the DMSO solvent that adds again 2mL, stirring at room, stopped reaction after reaction 24h, add 10mL water, with methylene dichloride (10mL * 3) extraction, saturated common salt water washing once, is spin-dried for, purification by silica gel column chromatography, eluent is chloroform: methyl alcohol=40:1, and purifying obtains white solid 10a(100mg, 81.9%).
1H?NMR(300MHz,CDCl 3):δ7.44(d,J=9.1Hz,3H),7.08(dd,J=9.9,6.4Hz,3H),6.46(s,2H),5.14(s,2H),5.09-4.96(m,1H),4.56(qd,J=15.0,5.7Hz,2H),4.19(t,J=9.1Hz,1H),3.85(dd,J=9.2,5.9Hz,1H),2.49(s,3H),2.45(s,6H).
Embodiment 24:(R)-fluoro-4-((3 of 5-amino-1-((3-(3-, 5,6-trimethylpyrazine-2-yl) methoxyl group) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl isophthalic acid H-1, the preparation of 2,3-triazole-4-methane amide (10b)
Take triazo-compound 8b(preparation method with embodiment 20) be raw material, preparation method, with embodiment 23, obtains white solid 10b(110mg, 61.6%).
1H?NMR(300MHz,CDCl 3):δ7.55(dd,J=13.6,2.6Hz,1H),7.45(s,1H),7.33(t,J=9.3Hz,1H),7.19(d,J=9.0Hz,1H),7.10(s,1H),6.46(s,2H),5.22(s,2H),5.13-4.99(m,1H),4.56(m,2H),4.20(t,J=9.1Hz,1H),3.85(dd,J=9.2,5.9Hz,1H),2.51(s,3H),2.45(d,J=3.7Hz,6H).
Embodiment 25:(S)-5-(aminomethyl)-3-(4-((3,5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (11a)
Figure BDA0000413517150000191
Triazo-compound 8a(0.675g, 1.83mmol, preparation method is with embodiment 19) with the THF of 15mL, dissolve, add 10% Pd/C powder (70mg), at 0 ℃, through biexhaust pipe, vacuumize, inflated with nitrogen, 3 times repeatedly, uses H for the last time 2replace once, after, be placed under room temperature and react 24h.After completion of the reaction, reaction solution is filtered through sand core funnel (being covered with one deck diatomite), methylene dichloride for reaction solution (10mL * 3) washs three times, collect filtrate, add again 10% aqueous hydrochloric acid tune left and right, pH to 2～3, with methylene dichloride (10mL * 3) extraction, water intaking layer, again water layer is adjusted to pH to 9～10 with saturated sodium hydroxide solution, finally use again methylene dichloride (10mL * 3) extraction, get organic layer, be spin-dried for, white solid 11a(561mg, 89.5%) be directly used in next step reaction.
1H?NMR(300MHz,CDCl 3):δ7.51-7.35(m,2H),7.04-6.92(m,2H),5.12(s,2H),4.75-4.48(m,1H),4.00(t,J=8.7Hz,1H),3.79(dd,J=8.7,6.7Hz,1H),3.07(dd,J=13.6,4.0Hz,1H),2.96(dd,J=13.7,6.0Hz,1H),2.56(s,3H),2.50(s,6H).
Embodiment 26:(S)-5-(aminomethyl) the fluoro-4-((3 of-3-(3-, 5, the 6-trimethylpyrazine-2-yl) methoxyl group) preparation of phenyl) oxazolidine-2-ketone (11b)
Take triazo-compound 8b(preparation method with embodiment 20) be raw material, preparation method, with embodiment 25, obtains white solid 11b(730mg, 93.6%).
1H?NMR(300MHz,CDCl 3):δ7.43(d,J=13.0Hz,1H),7.15-6.99(m,2H),5.16(s,2H),4.80-4.48(m,1H),3.96(t,J=8.7Hz,1H),3.82-3.71(m,1H),3.06(dd,J=13.5,3.6Hz,1H),2.92(dd,J=13.6,5.6Hz,1H),2.57(s,3H),2.47(s,6H).
Embodiment 27:(S)-N-((2-oxo-3-(4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl) oxazolidine-5-yl) methyl) preparation of ethanamide (12a)
Figure BDA0000413517150000201
By primary amine 11a(0.469g, 1.37mmol, preparation method is with embodiment 25) be placed in two mouthfuls of round-bottomed flasks of 50mL, add anhydrous methylene chloride (20mL) to dissolve, at 0 ℃, drip anhydrous triethylamine (0.38mL, 2.74mmol), after stirring 5min, slowly drip Acetyl Chloride 98Min. (0.16mL, 2.06mmol), after, be transferred to room temperature reaction 24h after stirring 10min at 0 ℃.Stopped reaction, adds 5mL shrend and goes out, and methylene dichloride (15mL * 3) extraction, is spin-dried for, purification by silica gel column chromatography, eluent is sherwood oil: acetone: triethylamine=2:1:1, obtains white solid 12a(250mg, 48.5%).
1H?NMR(300MHz,CDCl 3):δ8.09(dd,J=7.0,1.7Hz,2H),7.79(dd,J=7.0,1.7Hz,2H),6.34(d,J=1.5Hz,2H),6.12-5.98(m,1H),5.47(td,J=6.9,1.6Hz,1H),5.32-5.24(m,1H),5.16(s,2H),4.35(d,J=1.4Hz,3H),4.31(d,J=1.5Hz,6H),3.91(d,J=1.7Hz,3H).
Embodiment 28:(S) the fluoro-4-((3 of-N-((3-, 5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) preparation of ethanamide (12b)
Take primary amine 11b(preparation method with embodiment 26) be raw material, preparation method, with embodiment 27, obtains white solid 12b(124mg, 33.5%).
1H?NMR(300MHz,CDCl 3):δ7.43(dd,J=13.0,2.5Hz,1H),7.15-6.95(m,2H),6.66(s,1H),5.17(s,2H),4.83-4.65(m,1H),3.98(t,J=9.0Hz,1H),3.73(dd,J=9.1,6.7Hz,1H),3.62(dd,J=7.2,4.1Hz,2H),2.58(s,3H),2.48(d,J=2.1Hz,6H),1.99(s,3H).
Embodiment 29:(S) the chloro-N-((2-oxo-3-(4-((3 of-2-, 5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl) oxazolidine-5-yl) methyl) preparation of ethanamide (13a)
Figure BDA0000413517150000211
Take primary amine 11a and chloroacetyl chloride as raw material, and preparation method, with embodiment 27, obtains white solid 13a(140mg, 88.1%).
1H?NMR(300MHz,CDCl 3):δ7.42-7.34(m,2H),7.18(t,J=6.0Hz,1H),7.04-6.95(m,2H),5.12(s,2H),4.77(dtd,J=9.7,6.4,3.4Hz,1H),4.12-3.98(m,3H),3.83-3.68(m,2H),3.61(dt,J=14.5,6.2Hz,1H),2.56(s,3H),2.50(s,6H).
Embodiment 30:(S) the fluoro-4-((3 of the chloro-N-((3-of-2-, 5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) preparation of ethanamide (13b)
Take primary amine 11b and chloroacetyl chloride as raw material, and preparation method, with embodiment 27, obtains white solid 13b(94mg, 78.4%).
1H?NMR(300MHz,CDCl 3):δ7.43(dd,J=12.9,2.5Hz,1H),7.19-7.01(m,3H),5.19(s,2H),4.78(m,1H),4.16-3.99(m,3H),3.81-3.58(m,3H),2.60(s,3H),2.50(d,J=3.2Hz,6H).
Embodiment 31:(S)-2, the chloro-N-((2-oxo-3-(4-((3 of 2-bis-, 5,6-trimethylpyrazine-2-yl) methoxyl group) phenyl) oxazolidine-5-yl) methyl) preparation of ethanamide (14a)
Figure BDA0000413517150000221
Take primary amine 11a and dichloroacetyl chloride as raw material, and preparation method, with embodiment 27, obtains white solid 14a(150mg, 77%).
1H?NMR(300MHz,CDCl 3):δ7.59(br,s,1H),7.35(d,J=9.1Hz,2H),6.98(d,J=9.0Hz,2H),6.01-5.98(m,1H),5.11(s,2H),4.81(ddt,J=9.0,6.3,4.5Hz,1H),4.05(t,J=9.1Hz,1H),3.81-3.63(m,3H),2.55(s,3H),2.50(s,6H).
Embodiment 32:(S)-2, the fluoro-4-((3 of the chloro-N-((3-of 2-bis-, 5,6-trimethylpyrazine-2-yl) methoxyl group) phenyl)-2-oxygen is for oxazolidine-5-yl) methyl) preparation of ethanamide (14b)
Take primary amine 11b and dichloroacetyl chloride as raw material, and preparation method, with embodiment 27, obtains white solid 14b(110mg, 74%).
1H?NMR(300MHz,CDCl 3):δ7.46(dd,J=13.0,2.4Hz,1H),7.15-7.00(m,2H),6.12(t,J=6.0Hz,1H),5.19(s,2H),4.72(dt,J=8.9,4.3Hz,1H),3.98(t,J=9.0Hz,1H),3.77-3.59(m,3H),2.61(s,3H),2.51(d,J=4.1Hz,6H).
Embodiment 33:(S)-2-methoxyl group-N-((2-oxo-3-(4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl) oxazolidine-5-yl) methyl) preparation of ethanamide (15a)
Figure BDA0000413517150000222
Take primary amine 11a and methoxyacetyl chloride as raw material, and preparation method, with embodiment 27, obtains white solid 15a(145mg, 79.6%).
1H?NMR(300MHz,CDCl 3):δ7.39-7.31(m,2H),7.05(t,J=6.2Hz,1H),6.99-6.90(m,2H),5.08(s,2H),4.76-4.65(m,1H),3.99(t,J=9.0Hz,1H),3.92-3.77(m,2H),3.69(ddd,J=9.4,6.5,3.9Hz,2H),3.57(dt,J=13.0,6.2Hz,1H),3.33(s,3H),2.52(s,3H),2.46(s,6H).
Embodiment 34:(S) the fluoro-4-((3 of-N-((3-, 5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) preparation of-2-methoxyl acetamide (15b)
Take primary amine 11b and methoxyacetyl chloride as raw material, and preparation method, with embodiment 27, obtains white solid 15b(85mg, 63.8%).
1H?NMR(300MHz,CDCl 3):δ7.44(dd,J=13.0,2.5Hz,1H),7.16–6.97(m,3H),5.18(s,2H),4.83–4.67(m,1H),4.01(t,J=9.0Hz,1H),3.95–3.82(m,2H),3.77–3.68(m,2H),3.62(dt,J=14.5,6.1Hz,1H),3.38(s,3H),2.60(s,3H),2.50(d,J=2.9Hz,6H).
Embodiment 35:(S)-N-((2-oxo-3-(4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl) oxazolidine-5-yl) methyl) preparation of diamantane-1-methane amide (16a)
Figure BDA0000413517150000231
Take primary amine 11a and diamantane acyl chlorides is raw material, and preparation method, with embodiment 27, obtains white solid 16a(160mg, 81.4%).
1H?NMR(300MHz,CDCl 3):δ7.44-7.34(m,2H),7.03-6.95(m,2H),6.13(t,J=6.1Hz,1H),5.12(s,2H),4.73(ddt,J=8.8,6.2,4.3Hz,1H),4.01(t,J=9.0Hz,1H),3.75(dd,J=9.1,6.2Hz,1H),3.64(dd,J=6.0,4.4Hz,2H),2.56(s,3H),2.51(s,6H),1.82-1.59(m,15H).
Embodiment 36:(S) the fluoro-4-((3 of-N-((3-, 5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) preparation of diamantane-1-methane amide (16b)
Take primary amine 11b and diamantane acyl chlorides is raw material, and preparation method, with embodiment 27, obtains white solid 16b(55mg, 43.8%).
1H?NMR(300MHz,CDCl 3):δ7.46(dd,J=13.0,2.4Hz,1H),7.15-6.99(m,2H),6.12(t,J=6.0Hz,1H),5.19(s,2H),4.72(dt,J=8.9,4.3Hz,1H),3.98(t,J=9.0Hz,1H),3.78-3.60(m,3H),2.61(s,3H),2.51(d,J=4.1Hz,6H),1.85-1.51(m,15H).
Embodiment 37:(S)-N-((2-oxo-3-(4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl) oxazolidine-5-yl) methyl) preparation of furans-2-methane amide (17a)
Figure BDA0000413517150000241
Take primary amine 11a and 2-furoyl acyl chlorides is raw material, and preparation method, with embodiment 27, obtains white solid 17a(96mg, 76.2%).
1H?NMR(300MHz,CDCl 3):δ7.38(dd,J=13.3,5.0Hz,3H),7.16-6.88(m,4H),6.45(dd,J=3.4,1.7Hz,1H),5.09(s,2H),4.87-4.73(m,1H),4.04(dd,J=15.6,6.6Hz,1H),3.92-3.60(m,3H),2.53(s,3H),2.47(s,6H).
Embodiment 38:(S) the fluoro-4-((3 of-N-((3-(3-, 5,6-trimethylpyrazine-2-yl) methoxyl group) phenyl) the 2-Yang Dai oxazolidine-5-yl) methyl) preparation of furans-2-methane amide (17b)
Take primary amine 11b and 2-furoyl acyl chlorides is raw material, and preparation method, with embodiment 27, obtains white solid 17b(90.6mg, 71.8%).
1H?NMR(300MHz,CDCl 3):δ7.43(dt,J=10.2,2.8Hz,2H),7.17-7.00(m,3H),6.92(t,J=6.2Hz,1H),6.50(ddd,J=8.6,3.5,1.7Hz,1H),5.18(s,2H),4.90-4.75(m,1H),4.04(t,J=8.9Hz,1H),3.92-3.72(m,3H),2.60(s,3H),2.50(d,J=3.6Hz,6H).
Embodiment 39:(S) the chloro-N-((2-oxo-3-(4-((3 of-5-, 5,6-trimethylpyrazine-2-yl) methoxyl group) the phenyl) oxazolidine-5-yl) methyl) preparation of thiophene-2-carboxamide derivatives (18a)
Figure BDA0000413517150000251
The chloro-2-acyl chlorides of primary amine 11a and the 5-thiophene of take is raw material, and preparation method, with embodiment 27, obtains white solid 18a(134mg, 82.5%).
1H?NMR(300MHz,CDCl 3):δ7.35(td,J=9.2,3.7Hz,3H),7.02-6.90(m,3H),6.85(d,J=4.0Hz,1H),5.13(s,2H),4.84(m,1H),4.06(t,J=9.0Hz,1H),3.92-3.66(m,3H),2.58(s,3H),2.52(d,J=1.5Hz,6H).
Embodiment 40:(S) the chloro-N-((3-(4-((3 of-5-, 5,6-trimethylpyrazine-2-yl) methoxyl group) phenyl) 2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives (18b)
The chloro-2-acyl chlorides of primary amine 11b and the 5-thiophene of take is raw material, and preparation method, with embodiment 27, obtains white solid 18b(90.6mg, 69.5%).
1H?NMR(300MHz,CDCl 3):δ7.43(dd,J=12.9,2.6Hz,1H),7.34(d,J=4.0Hz,1H),7.10(t,J=8.8Hz,1H),7.02(dd,J=9.0,1.6Hz,1H),6.95-6.87(m,1H),6.87(d,J=4.0Hz,1H),5.19(s,2H),4.92-4.77(m,1H),4.05(t,J=9.0Hz,1H),3.92-3.67(m,3H),2.60(s,3H),2.50(d,J=3.2Hz,6H).
The bacteriostasis property of embodiment 41: novel oxazolidinone compounds is measured
The compound that embodiment 1～40 is prepared carries out minimum inhibitory concentration (MIC) test of resisting gram-positive bacteria and Gram-negative bacteria, with the positive contrast of Linezolid (the results are shown in Table 1).
The bacteriostasis property of table 1 novel oxazolidinone compounds
Figure BDA0000413517150000252
Figure BDA0000413517150000261
Figure BDA0000413517150000271
MRSA,methicillin-resistant?Staphylococcus?aureus(ATCC43300);SA,Staphylococcus?aureus(ATCC25923);SE,Staphylococcus?epidermidis(ATCC12228);EF,Enterococcus?faecalis(ATCC29212);EC,E.coli(ATCC25922);PA,Pseudomonas?aeruginosa(ATCC27853).
From table 1, compound 1b, 7a-2,7b-2,9b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 17a and 17b all demonstrate good bacteriostatic activity to methicillin resistant staphylococcus aureus (ATCC43300), wherein the MIC of compound 7b-2,12a 50value reaches below 8 μ g/mL, and the MIC of compound 12b, 13a, 13b, 14a, 14b 50value reaches below 4 μ g/mL.Active to the inhibition of streptococcus aureus (ATCC25923), compound 1b, 7a-2,7b-2,12a, 12b, 13a, 13b, 14a, 14b, 15b, 17a and 17b all have certain bacteriostatic activity, wherein the MIC of compound 12b, 13a, 13b, 14a, 14b 50value reaches below 8 μ g/mL.In Vitro Bacteriostatic to staphylococcus epidermidis (ATCC12228), compound 1b, 7a-2,7b-2,12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 17a and 17b demonstrate good bacteriostatic activity, the MIC of compound 7b-2,13a, 14a 50value reaches below 8 μ g/mL, and the MIC of compound 12b, 13b, 14b 50value reaches 2 μ g/mL left and right substantially.In Vitro Bacteriostatic to enterococcus faecalis (ATCC29212), compound 1b, 7a-2,7b-2,12a, 12b, 13a, 13b, 14a, 14b, 15b and 17b all demonstrate certain bacteriostatic activity, wherein the MIC of compound 12b, 13b, 14b 50value reaches below 8 μ g/mL.Therefore, from above result, can judge that 12b, 13b, these three compounds of 14b have good In Vitro Bacteriostatic to positive bacteria.
The diastole capillary blood vessel active testing of embodiment 41: novel oxazolidinone compounds
1, experimental technique
Rat dislocation is put to death, and the rapid separated Renal artery, is placed in 0～4 ℃ of oxygen-saturated Kreb's liquid.Remove periphery reticular tissue, make the long vascular circle of 1.8～2.0mm.By vascular circle, with two parallel diameters, be that 40 μ m tungsten filaments are fixed on and are equipped with in hyperchannel antiotasis mensuration system.Setting initial tension is 2mN, 37 ℃ of temperature, and past groove interior (5mL Kreb's liquid is housed) passes into the mixed gas of 95%O2 and 5%CO2 incessantly, and pH value is adjusted to 7.4.Use 60mmolL -1kCl vasoconstriction is washed till baseline with Kreb's liquid after stable, balance 15min, repeat above step until double shrinkage amplitude similar (differ be less than double contraction cause mean tension changing value 10%), maintenance initial tension is constant.After balance 40min, add 0.5 μ molL -1phe vasoconstriction, after shrinking balance, concentration accumulation adds various testing drugs to test, and after end to be tested, uses Kreb's liquid eluting vascular tension force to baseline.
2, experimental result
Experimental result (table 2) shows that Ligustrazine has the active (EC of faint diastole capillary blood vessel 50>300 μ M), diastole activity is not remarkable, and the diastole capillary blood vessel activity of compound in the present invention is greatly improved, as the diastole capillary blood vessel activity of compound 16a, 17a and 17b reaches EC 50<15 μ M, the diastole capillary blood vessel with highly significant is active, and other compound all has good diastole capillary blood vessel activity, coordinates mutually with anti-microbial activity, is conducive to solve the hypertensive crisis side effect of Linezolid.
The diastole capillary blood vessel of table 2 novel oxazolidinone compounds is active
Compound N o. EC 50(μM) ? Compound N o. EC 50(μM)
Ligustrazine >300 ? 12a 92.65
1a 224.32 ? 12b 66.79
1b 24.75 ? 13a 78.17
2a 37.85 ? 13b 32.75
2b 18.90 ? 14a 35.17
4a 152.51 ? 14b 24.49
6a 23.78 ? 15a 109.78
6b 31.63 ? 15b 52.28
7a-1 46.43 ? 16a 2.46
7a-2 111.81 ? 16b 18.33
7b-1 19.50 ? 17a 3.10
7b-2 20.09 ? 17b 12.30
9a 33.20 ? 18a 22.98
10a 134.01 ? 18b 86.96
10b 60.00 ? ? ?
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.

Claims (3)

1. a novel oxazolidinone compounds, is characterized in that: described novel oxazolidinone compounds has the chemical structure as shown in formula I:
Figure FDA0000413517140000011
Wherein, R 1and R 2for hydrogen, fluorine or chlorine;
R 3for-OR 4,-NR 5r 6,-NHCOR 7, fluorine, azido-, primary amine groups, triazole, containing triazole, phosplate, phosphoric acid ester metal-salt, sulphonate or the sulphonate metal-salt of side chain radical;
R 4alkyl for hydrogen or 1～3 carbon atom;
R 5and R 6alkyl or ethanoyl for hydrogen, 1～3 carbon atom;
R 7represent single halogenated methyl, two halogenated methyl, methoxymethyl, adamantyl or heterocycle;
Above-mentioned heterocycle is furans, halo furans, thiophene or halogenated thiophene;
The halogen of above-mentioned halo is chlorine or fluorine.
2. the preparation method of novel oxazolidinone compounds according to claim 1, is characterized in that according to following operation steps:
(1) a kind of by p-NP and 2-fluoro-4-nitrophenol, reacts with bromo Ligustrazine, salt of wormwood and dry DMF, cooling, filters, and obtains respectively compd A 1 and compound B-11;
(2) compd A 1 and compound B-11 are dissolved in THF with the Pd/C of mass percent 10% respectively, after vacuumizing, in nitrogen atmosphere, react, filter, filtrate decompression is spin-dried for; Mix with aqueous sodium carbonate and acetone, under nitrogen atmosphere, drip Carbobenzoxy Chloride, after reaction, decompression is spin-dried for, extraction, and recrystallization, obtains respectively compd A 2 and compd B 2;
(3) by compd A 2 and compd B 2 respectively at 100 ℃ with benzene band water, then by benzene evaporate to dryness; Under nitrogen protection, inject anhydrous THF, be placed under-78 ℃ of agitation conditions and inject two (trimethyl silicon based) Lithamides, (the R)-Glycidyl Butyrate that reinjects reaction 1h relief reaction system, to room temperature, adds NH after reaction 4the cancellation of Cl solution, extraction, decompression is spin-dried for, recrystallization, get is Dao oxazolidinone compounds 1a with oxazolidinone compounds 1b respectively;
(4) are Jiang oxazolidinone compounds 1a with oxazolidinone compounds 1b is dissolved in respectively in anhydrous methylene chloride, triethylamine reinjects, inject subsequently fluoro reagent diethylin sulfur trifluoride, stirring at room reaction 24h, add after completion of the reaction shrend to go out, extraction, is spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 2a and white solid compound 2b;
(5) are Jiang oxazolidinone compounds 1a with oxazolidinone compounds 1b is placed on stirring at 0 ℃ with methylene dichloride dissolving respectively, inject triethylamine, stir after 5 minutes, inject methylsulfonyl chloride, after be transferred to room temperature reaction, spend the night, extraction after reacting completely, decompression is spin-dried for, and purification by silica gel column chromatography obtains respectively methanesulfonates midbody compound 3a and methanesulfonates midbody compound 3b;
(6) by methanesulfonates midbody compound 3a and methanesulfonates midbody compound 3b respectively with sodium methylate, anhydrous methanol in normal-temperature reaction 48h; After reacting completely, extraction, is spin-dried for, and purification by silica gel column chromatography, obtains respectively white solid compound 4a and white solid compound 4b;
(7) methanesulfonates midbody compound 3a and methanesulfonates midbody compound 3b are placed in to constant temperature stirring reaction 48h at 60 ℃ with Dimethylammonium chloride, salt of wormwood and dry DMF respectively, after, extraction, decompression is spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 5a and white solid compound 5b;
(8) the sodium hydride powder that is 60% by methanesulfonates midbody compound 3a and dry DMF, mass content, and 1H-1,2,4-triazole and 1H-1, a kind of in 2,3-triazole, after room temperature reaction 48h, extract, be spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 6a, white solid compound 7a-1 and white solid compound 7a-2;
The sodium hydride powder that is 60% by methanesulfonates midbody compound 3b and dry DMF, mass content, and 1H-1,2,4-triazole and 1H-1, a kind of in 2,3-triazole, after room temperature reaction 48h, extract, be spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 6b, white solid compound 7b-1 and white solid compound 7b-2;
(9) by methanesulfonates midbody compound 3a and methanesulfonates midbody compound 3b respectively with dry DMF and sodiumazide heated constant temperature at 90 ℃ react 3h, extraction after reacting completely, decompression is spin-dried for, and purification by silica gel column chromatography, obtains respectively triazo-compound 8a and triazo-compound 8b fast;
(10) triazo-compound 8a and triazo-compound 8b are placed in to reactor with water, beta-cyclodextrin and Salzburg vitriol respectively, 1-hexin reinjects, add subsequently sodium ascorbate, stirring at normal temperature reaction 5-10 minute, stopped reaction, extraction, is spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 9a and white solid compound 9b;
(11) triazo-compound 8a and triazo-compound 8b are reacted to 24h with malonamide nitrile, salt of wormwood and dimethyl sulfoxide (DMSO) in stirring at room respectively, extraction after reacting completely, and use saturated common salt water washing, be spin-dried for, purification by silica gel column chromatography, obtains respectively white solid compound 10a and white solid compound 10b;
(12) triazo-compound 8a and triazo-compound 8b are dissolved in tetrahydrofuran (THF) with the Pd/C of mass percent 10% respectively, at 0 ℃, vacuumize, inflated with nitrogen, uses H after 3 times repeatedly 2displacement, after under room temperature stirring reaction; After completion of the reaction, filter, extraction, is spin-dried for, and obtains respectively primary amine 11a and primary amine 11b;
(13) primary amine 11a is dissolved with anhydrous methylene chloride, at 0 ℃, drip anhydrous triethylamine, after stirring 5min, drip the acyl chlorides reagent of 0.5～2.1mmol, after, after stirring 10min, be transferred to room temperature reaction 24h; Stopped reaction, adds shrend and goes out, and extraction, is spin-dried for, and purification by silica gel column chromatography, obtains respectively white solid compound 12a, 13a, 14a, 15a, 16a, 17a and 18a;
Primary amine 11b is dissolved with anhydrous methylene chloride, at 0 ℃, drip anhydrous triethylamine, after stirring 5min, drip the acyl chlorides reagent of 0.5～2.1mmol, after, after stirring 10min, be transferred to room temperature reaction 24h; Stopped reaction, adds shrend and goes out, and extraction, is spin-dried for, and purification by silica gel column chromatography, obtains respectively white solid compound 12b, 13b, 14b, 15b, 16b, 17b and 18b;
Described acyl chlorides reagent is Acetyl Chloride 98Min., chloroacetyl chloride, dichloroacetyl chloride, methoxyacetyl chloride, diamantane acyl chlorides, 2 furoyl chloride or the chloro-2-acyl chlorides of 5-thiophene;
The structural formula of each compound is as follows:
Figure FDA0000413517140000041
3. the application of novel oxazolidinone compounds according to claim 1 in preparation antibacterials or diastolic blood vessel activity medicine.
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