抗菌药物合成英文文献和中文翻译(2)
1H MMR (DMSO-d6,300 MHz) δ 9.52 (s, 1H), 8.02 (t, J = 5.5 Hz, 1H), 7.56 (t, J =8.9 Hz, 1H), 7.34 (dd, J = 13.3, 2.3 Hz, 1H), 6.98 (m, 1H),4.50 (m, 1H), 3.88 (t, J = 8.9 Hz, 1 H), 3.50 (m, 3H), 3.19 (t,J = 5.4 Hz, 2H), 2.39 (t, J = 5.4 Hz, 2H ), 1.82 (m, 2H), 1.61(s, 3H).(S)-N-((3-(3-Fluoro-4-(2-oxo-pyrrolidin-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (3a). Amide 2a(200 mg, 0.54 mmol) was dissolved in ethanol (5 mL) andpotassium hydroxide (45.4 mg, 0.81 mmol) was added.Reaction mixture was stirred at room temperature for 3 h.Solvent was concentrated, and the mixture was extractedwith chloroform (10 mL × 2). The combined organic layerswere washed with brine, dried over MgSO4 and concen-trated under reduced pressure. The residue was purified by flash chromatography on silica gel (CHCl3/MeOH, 10:1) toyield lactam 3a (110 mg, 63%): 1H MMR (DMSO-d6, 300MHz) δ 8.29 (t, J = 5.6 Hz, 1H), 7.65-7.36 (m, 3H), 4.81 (m,1H), 4.19 (t, J = 9.3 Hz, 1H), 3.78 (m, 3H), 3.48 (t, J = 5.4Hz, 2H), 2.50 (t, J = 8.2 Hz, 2H), 2.22 (m, 2H), 1.89 (s, 3H).N-(4-((S)-5-(Acetamidomethyl)-2-oxo-oxazolidin-3-yl)-2-fluorophenyl)-2-(benzyloxy)-4-hydroxybutanamide (6a).Intermediate 1a (3.3 g, 12.2 mmol) was dissolved in CH2Cl2(35 mL) at room temperature and 1 M solution of dimethyl-aluminium chloride in hexane (29.2 mL, 14.4 mmol) wasadded. The mixture was stirred till the solution was trans-parent. 3-(Benzyloxy)dihydrofuran-2(3H)-one 5 (2.81 g,14.64 mmol) was added to the reaction mixture and wasstirred for 4 h at the same temperature. Phosphate buffer (pH7, 20 mL) was added to the reaction mixture, and themixture was extracted with CH2Cl2 (20 mL × 2). The com-bined organic layers were dried over MgSO4 and concen-trated under reduced pressure. The residue was purified byflash chromatography on silica gel (CH2Cl2/MeOH, 25:1) toafford amide 6a (4.48 g, 79%) as white solid: 1H NMR(CD3OD, 300 MHz) δ 7.89 (t, J = 8.8 Hz, 1H), 7.68 (dd, J =13.7, 2.7 Hz, 1H), 7.40 (m, 6H), 4.84 (m, 1H), 4.74 (d, J =11.6 Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H), 4.20 (m, 2H), 3.86(dd, J = 9.0, 6.3 Hz, 1H), 3.77 (t, J = 6.3 Hz, 2H), 3.60 (d, J= 5.1 Hz, 2H), 2.05 (m, 2H), 1.99 (s, 3H).N-(((5S)-3-(4-(3-(Benzyloxy)-2-oxo-pyrrolidin-1-yl)-3-fluorophenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (7a).Compound 6a (3.7 g, 8.3 mmol) and triphenyl phosphine(2.6 g, 9.8 mmol) were dissolved in CH2Cl2 (100 mL) anddiethyl azodicarboxylate (1.7 g, 9.8 mmol) was addedslowly for 20 min at ice bath temperature. The reactionmixture was stirred at room temperature for 4 h. Water (20mL) was added and the mixture was extracted with CH2Cl2(100 mL × 2). The combined organic layers were dried overMgSO4 and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel(CH2Cl2/MeOH, 25:1) to yield lactam 7a (2.98 g, 84%): 1HNMR (DMSO-d6, 300 MHz) δ 8.28 (t, J = 5.7 Hz, 1H), 7.61(dd, J = 13.2, 2.1 Hz, 1H), 7.50 (t, J = 8.7 Hz, 1H), 7.35 (m,6H), 4.87 (part A of AB, J = 11.9 Hz, 1H), 4.71 (part B ofAB, J = 11.9 Hz, 1H), 4.76 (m, 1H), 4.33 (t, J = 7.6 Hz, 1H),4.15 (t, J = 8.9 Hz, 1H), 3.76 (dd, J = 8.7, 6.6 Hz, 1H), 3.70(dd, J = 7.9, 5.3 Hz, 1H), 3.43 (t, J = 5.2 Hz, 2H), 2.5 (m,1H), 2.08 (m, 1H), 1.85 (s, 3H).N-(((5S)-3-(3-Fluoro-4-(3-hydroxy-2-oxo-pyrrolidin-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (8a).Benzyl ether 7a (1.0 g, 2.26 mmol) was dissolved in ethylalcohol (50 mL), and palladium hydroxide in activatedcharcoal (0.16 g, 5 mol %) and cyclohexene (10 mL) wereadded. Reaction mixture was refluxed for 3 d, cooled toroom temperature and filtered through celite. The filtratewas concentrated and the residue was purified by flashchromatography on silica gel (CH2Cl2/MeOH, 10:1) to yieldalcohol 8a (0.73 g, 92%): 1H NMR (DMSO-d6, 300 MHz) δ8.28 (t, J = 5.8 Hz, 1H), 7.57 (dd, J = 13.3, 2.6 Hz, 1H), 7.48(t, J = 8.7 Hz, 1H), 7.36 (dd, J = 8.7, 2.1 Hz, 1H), 4.76 (m,1H), 4.32 (m, 1H), 4.12 (t, J = 9.1 Hz, 1H), 3.76 (dd, J = 8.7, 6.6 Hz, 1H), 3.65 (dd, J = 10.7, 4.1 Hz, 1H), 3.44 (t, J = 5.2Hz, 2H), 2.43 (m, 1H), 1.92 (m, 1H), 1.85 (s, 3H); HRMS(EI+) calcd for C16H18FN3NaO5 (M+): 374.1128, found:374.1290.N-(((5S)-3-(3-Fluoro-4-(3-fluoro-2-oxo-pyrrolidin-1-yl)-phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (9a). Asolution of diethylaminosulfur trifluoride (60 µL) in CH2Cl2(2 mL) was added dropwise to a solution of alcohol 8a (120mg, 0.34 mmol) in CH2Cl2 (12 mL) at −78 oC. The reactionmixture was warmed to room temperature gradually andstirred for 24 h. Saturated aqueous NaHCO3 (5 mL) wasadded and the mixture was extracted with CH2Cl2 (12 mL ×2). The combined organic layers were dried over MgSO4 andconcentrated under reduced pressure. The residue was puri-fied by flash chromatography on silica gel (CH2Cl2/MeOH,15:1) to yield fluoride 9a (24 mg, 20%): 1H NMR (DMSO-d6, 300 MHz) δ 7.63 (dd, J = 13.2, 2.1 Hz, 1H), 7.51 (t, J =8.9 Hz, 1H), 7.38 (dd, J = 9.1, 2.0 Hz, 1H), 4.87 (dd, J = 7.7,5.5 Hz, 1H), 4.76 (m, 1H), 4.16 (t, J = 8.7 Hz, 1H), 3.77 (m,3H), 3.43 (d, J = 5.1 Hz, 1H), 2.79 (m 1H), 2.30 (m, 1H),1.85 (s, 1H), 1.83 (s, 3H).N-(((5S)-3-(4-(3-Chloro-2-oxo-pyrrolidin-1-yl)-3-fluoro-phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide (10a).Thionyl chloride (60 µL) was added dropwise to a solutionof alcohol 8a (120 mg, 0.34 mmol) in acetonitrile (8 mL) atroom temperature. The reaction mixture was refluxed for 24h, cooled to room temperature and concentrated underreduced pressure. The residue was purified by flash chromato-graphy on silica gel (CH2Cl2/MeOH, 10:1) to yield chloride10b (70.6 mg, 56%): 1H NMR (CD3OD, 300 MHz) δ 7.71(dd, J = 13.2, 3.0 Hz, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.39 (dd,J = 8.9, 1.6 Hz, 1H), 4.84(m, 1H), 4.74 (dd, J = 7.7, 5.0 Hz,1H), 4.20 (t, J = 9.0 Hz, 1H), 3.96 (m, 1H), 3.87 (m, 2H),3.60 (d, J = 4.8 Hz, 2H), 2.85 (m, 1H), 2.42 (m, 1H), 2.00 (s,3H); HRMS (EI+) calcd for C16H17ClFN3NaO4 (M+): 392.0789,found: 392.0781.N-[[(5S)-3-[4-(3-Bromo-2-oxo-1-pyrrolidinyl)-3-fluoro-phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide (11a).Triphenylphosphine (194 mg, 0.74 mmol) and carbon tetra-bromide (245 mg, 0.74 mmol) were added to a solution ofalcohol 8a (120 mg, 0.34 mmol) in acetonitrile (8 mL) atroom temperature. The reaction mixture was refluxed for 24h and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel (CH2Cl2/MeOH, 10:1) to yield bromide 11a (45 mg, 32%): 1H NMR (DMSO-d6, 300 MHz) δ 8.27 (t, J = 5.7 Hz, 1H),7.64 (dd, J = 16.0, 4.9 Hz, 1H), 7.51 (t, J = 8.4 Hz, 1H), 7.39(dd, J = 8.9, 1.6 Hz, 1H), 4.88 (m, 1H), 4.77 (m, 1H), 4.16 (t,J = 9.0 Hz, 1H), 3.88 (m, 1H), 3.77 (m, 2H), 3.44 (d, J = 5.1Hz, 2H), 2.83 (m, 1H), 2.38 (m, 1H), 1.85 (s, 3H); HRMS(EI+) calcd for C16H17BrFN3NaO4 (M+): 436.0284, found:436.0271.N-[[(5S)-3-[3-Fluoro-4-(3-methoxy-2-oxo-1-pyrrolidin-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (12a).Silver oxide (95 mg, 0.4 mmol) and methyl iodide (42 μL,2.0 equiv) were added to a solution of alcohol 8a (120 mg,0.34 mmol) in CH2Cl2 (8 mL), and stirred for 1.5 h at roomtemperature. The reaction mixture was filtered through celiteand the filtrate was concentrated. The residue was purifiedby flash chromatography on silica gel (CH2Cl2/MeOH, 20:1)to yield methyl ether 12a (37 mg, 30%): 1H NMR (CD3OD,300 MHz) δ 7.7 (dd, J = 13.2, 2.4 Hz, 1H), 7.46 (t, J = 8.6Hz, 1H), 7.37 (dd, J = 8.7, 2. 7 Hz, 1H), 4.85 (m, 1H), 4.22(m, 2H), 3.86 (dd, J = 9.3, 6.6 Hz, 1H), 3.79 (dd, J = 8.2, 5.0Hz, 2H), 3.60 (s, 3H), 3.44 (d, J = 5.1 Hz, 2H), 2.62 (m, 1H),2.14 (m, 1H), 2.0 (s, 3H).N-[[(5S)-3-[4-(3-Carboxy-2-oxo-1-pyrrolidinyl)-3-Fluoro-phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide (14a).To a solution of aniline 1a (1.0 g, 3.7 mmol) in toluene (20mL), 6,6-dimethyl-5,7-dioxaspiro [2.5] octane-4,8-dione(0.95 g, 5.6 mmol) was added, and the reaction mixture wasrefluxed for 24 h.