抗菌药物合成英文文献和中文翻译(3)
The reaction mixture was cooled andconcentrated. The residue was purified by flash chromato-graphy on silica gel (CH2Cl2/MeOH, 20:1) to yield carbox-ylic acid 14a (1.2 g, 86%): 1H NMR (CD3OD, 300 MHz) δ7.68 (dd, J = 13.2, 2.7 Hz, 1H), 7.44 (t, J = 8.4 Hz, 1H), 7.36(dd, J = 9.3, 2.7 Hz, 1H), 4.83 (m, 1H), 4.20 (t, J = 9.0 Hz,2H), 3.86 (t, J = 7.4 Hz, 2H), 3.60 (d, J = 4.8 Hz, 2H), 2.59(t, J = 7.9 Hz, 1H), 2.27 (m, 2H), 2.00 (s, 3H).N-(4-((S)-5-(Acetamidomethyl)-2-oxo-oxazolidin-3-yl)-2-fluorophenyl)-3-(benzyloxy)-4-hydroxybutanamide (17a).Compound 17a was prepared from 1a and 16 according tothe similar procedure for the preparation of compound 6a(yield 49%): 1H NMR (DMSO-d6, 300 MHz) δ 9.76 (s, 1H),8.28 (t, J = 5.6 Hz, 1H), 7.80 (t, J = 8.8 Hz, 1H), 7.59 (dd, J= 13.2, 2.7 Hz, 1H), 7.27 (m, 5H), 4.82 (t, J = 5.5 Hz, 1H),4.74 (m, 1H), 4.64 ( d, J = 12.0 Hz, 1H), 4.54 ( d, J = 12.0Hz, 1H), 3.91 (m, 1H), 3.74 (dd, J=8.7, 6.6 Hz, 1H), 3.52 (t,J = 5.2 Hz, 2H), 3.43 (t, J = 5.2 Hz, 2H), 2.62 (m, 2H), 1.85(s, 3H).N-(((S)-3-(4-((S)-4-(Benzyloxy)-2-oxo-pyrrolidin-1-yl)-3-fluorophenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide(18a). Compound 18a was prepared from 17a according tothe similar procedure for the preparation of compound 7a(yield 99%): 1H NMR (DMSO-d6, 300 MHz) δ 8.25 (t, J =5.6 Hz, 1H), 7.58 (dd, J = 13.2, 2.2 Hz, 1H), 7.45 (t, J = 8.7Hz, 1H), 7.33 (m, 6H), 4.74 (m, 1H), 4.56 (s, 2H), 4.35 (m,1H), 4.12 (t, J = 9.1 Hz, 1H), 4.03 (m, 1H), 3.75 (m, 2H),3.42 (t, J = 5.5 Hz, 2H), 2.82 (dd, J = 17.3, 6.5 Hz, 1H), 2.49(m, 1H), 1.83 (s, 3H).N-(((S)-3-(3-Fluoro-4-((S)-4-hydroxy-2-oxo-pyrrolidin-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (19a).Compound 19a was prepared 18a according to the similarprocedure for the preparation of compound 8a (yield 73%):1H NMR (DMSO-d6, 300 MHz) δ 8.27 (t, J = 5.7 Hz, 1H),7.59 (dd, J = 13.2, 2.4 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.35(dd, J = 8.7, 2.7 Hz, 1H), 4.76 (m, 1H), 4.44 (m, 1H), 4.15 (t,J = 9.0 Hz, 1H), 4.00 (dd, J = 9.9, 5.1 Hz, 1H), 3.76 (dd, J =9.0, 6.3 Hz, 1H), 3.50 (dd, J = 9.9, 1.8 Hz, 1H), 3.44 (t, J =5.6 Hz, 2H), 2.76 (dd, J = 17.1, 6.6 Hz, 1H), 2.25 (dd, J =16.7, 2.5 Hz, 1H), 1.85 (s, 1H), 1.83 (s, 3H); HRMS (EI+)calcd for C16H18FN3NaO5 (M+): 374.1128, found: 374.1302.N-(((S)-3-(3-Fluoro-4-((S)-4-fluoro-2-oxo-pyrrolidin-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (20a). Compound 20a was prepared 19a according to the similarprocedure for the preparation of compound 9a (yield 33%):1H NMR (CD3OD, 300 MHz) δ 7.61 (dd, J = 13.2, 2.4 Hz,1H), 7.46 (t, J = 12.6 Hz, 1H), 7.35 (dd, J = 8.9, 2.3 Hz, 1H),4.81 (m, 1H), 4.42 (dd, J = 11.6, 5.0 Hz, 1H), 4.20 (t, J = 9.1Hz, 2H), 3.91 (m, 1H), 3.87 (dd, J = 9.0, 6.3 Hz, 1H), 3.50(d, J = 4.8 Hz, 2H), 3.26 (dd, J = 17.4, 6.6 Hz, 1H), 2.74 (dd,J = 16.4, 3.5 Hz, 1H), 2.0 (s, 3H). N-(((S)-3-(4-((S)-4-Chloro-2-oxo-pyrrolidin-1-yl)-3-fluoro-phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (21a).Compound 21a was prepared from 19a according to thesimilar procedure for the preparation of compound 10a(yield 56%): 1H NMR (CD3OD, 300 MHz) δ 7.71 (dd, J =13.2, 2.4 Hz, 1H), 7.47 (t, J = 12.6 Hz, 1H), 7.38 (dd, J =8.9, 2.3 Hz, 1H), 4.86 (m, 1H), 4.42 (dd, J = 11.6, 5.0 Hz,1H), 4.20 (t, J = 9.1 Hz, 2H), 3.92 (m, 1H), 3.87 (dd, J = 9.0,6.3 Hz, 1H), 3.60 (d, J = 4.8 Hz, 2H), 3.26 (dd, J = 17.4, 6.6Hz, 1H), 2.74 (dd, J = 16.4, 3.5 Hz, 1H), 2.0 (s, 3H). N-(((5S)-3-(4-(4-Bromo-2-oxo-pyrrolidin-1-yl)-3-fluoro-phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (22a).Compound 22a was prepared from 19a according to thesimilar procedure for the preparation of compound 11a(yield 80%): 1H NMR (CD3OD, 300 MHz) δ 7.71 (dd, J =12.9, 2.7 Hz, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.38 (dd, J = 9.4,2.3 Hz, 1H), 4.85 (m, 1H), 4.48 (dd, J = 11.8, 5.2 Hz, 1H),4.20 (t, J = 9.1 Hz, 2H), 4.02 (dd, J = 11.7, 1.8 Hz, 1H), 3.87(dd, J = 9.0, 6.3 Hz, 1H), 3.63 (d, J = 4.8 Hz, 2H), 3.34 (m,1H), 2.86 (dd, J = 17.7, 2.1 Hz, 1H), 2.00 (s, 3H); HRMS(EI+) calcd for C16H17BrFN3NaO4 (M+): 436.0284, found:436.0397.N-(((5S)-3-(3-Fluoro-4-(4-methoxy-2-oxo-pyrrolidin-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (23a).Compound 23a was prepared from 19a according to thesimilar procedure for the preparation of compound 12a(yield 42%): 1H NMR (CD3OD, 300 MHz) δ 7.68 (dd, J =13.1, 2.6 Hz, 1H), 7.44 (t, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.8,2.8 Hz, 1H), 5.53 (s, 1H), 4.82 (m, 1H), 4.22 (m, 1H), 4.12(m, 2H), 3.82 (m, 2H), 3.59 (d, J = 4.8 Hz, 2H), 3.42 (s, 3H),2.90 (dd, J = 17.4, 6.3 Hz, 1H), 2.56 (dd, J = 17.6, 2.3 Hz,1H), 2.00 (s, 3H).Biological Assay. MIC (Minimal Inhibitory Concentrations) Determina-tion: Minimal inhibitory concentrations (MICs) were deter-mined by two-fold agar dilution as described by the Clinicaland Laboratory Standards Institute.31 Test strains weregrown for 18 h at 37 °C in tryptic soy broth and diluted withthe same fresh medium to a density of ca. 107 colony form-ing units (CFU)/mL. Suspensions were applied to Mueller-Hinton agar (MHA) plates containing serial dilutions ofantimicrobial agents using a multipoint inoculator to yield105 CFU/spot. Plates were incubated in air at 37 °C for 18 hand were examined for growth. The MIC was considered tobe the lowest concentration that completely inhibited growthon agar plates, disregarding a single colony or a faint hazecaused by the inoculum.MIC (Minimal Inhibitory Concentrations) Determina-tion of Mycobacterium tuberculosis: The MICs of compoundsagainst Mycobacterium tuberculosis (Mtb) H37Rv was deter-mined by the Microplate Alamar Blue Assay.32 Results and DiscussionChemistry. Two types of oxazolidinone starting material,acetamide 1a and 1,2,3-triazole 1b, were synthesized bymodification of literature method.33,34 Oxazolidinone deriva-tives having pyrrolidinone at the C-ring were prepared bycoupling of amino group in 1a and 1b with 4-chlorobutyrylchloride and the subsequent cyclization to form pyrrolidonein good yields as shown in Scheme 1.α-Hydroxy pyrrolidinonyl oxazolidinone 8a and 8b werealso prepared by the condensation of amino group in 1a and1b with 3-(benzyloxy)dihydrofuran-2(3H)-one and followedby intramolecular Mitsunobu-type cyclization and sub-sequent hydrogenation protocol as shown in Scheme 2. α-Hydroxy pyrrolidinone 8a was obtained as inseparable dia-stereomeric mixture, and one of its single diastereomer wasprepared by using optically active 3(R)-3-(benzyloxy)di-hydrofuran-2(3H)-one. The synthesis of other oxazolidinonederivatives having α-substituted pyrrolidinones at C-ring oflinezolid was shown in Scheme 2 too. Halogenation ofalcohol 8a and 8b gave the fluoride, chloride and bromidecompounds 9-11 by using diethylaminosulfur trifluoride(DAST), thionyl chloride and triphenylphosphine withcarbon tetrabromide respectively in moderate to good yields.O-Methylation of α-hydroxy compound 8a with methyliodide in the presence of silver oxide provided α-methoxycompound 12a.N-Aryl-2-oxo-pyrrolidine-3-carboxylic acid 14a weresynthesized by the reaction of arylamine 1a and 6,6-di-methyl-5,7-dioxaspiro[2.5]octane-4,8-dione 13 in toluene at