Antibacterial cyclopenta[c]pyrrole-substituted 3,4-dihydro-1h-[1,8]naphthyridones
一种化合物、药学的技术，应用在抗细菌药、含有效成分的医用配制品、药物组合等方向
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Examples
Embodiment A1
[0162]
[0163] Stir 6-bromo-3,4-dihydro-1 H -[1,8]naphthyridin-2-one (1.0 g, 4.4 mmol), tert-butyl acrylate (2.56 ml, 17.62 mmol) and N,N -A solution of diisopropylethylamine (1.46 ml, 8.81 mmol) in acetonitrile (20 ml) and DMF (7 ml) and degassed with nitrogen for 10 minutes. Add tri-o-tolylphosphine (0.27 g, 0.88 mmol) and palladium(II) acetate (47% on Pd) (0.099 g, 0.44 mol) and microwave the resulting mixture (1600 W, 180°C, 35 minutes). The reaction mixture was evaporated to dryness, dissolved in a mixture of DCM / methanol (8 / 2) (50 ml), filtered through a short pad of celite and washed with DCM. The organic layer was washed with water, dried (MgSO4), filtered and evaporated to dryness. The residue was treated in cold ethanol (10 ml) and stirred at 5°C for 5 minutes. The precipitate was filtered off, washed with cold ethanol (3 ml) and dried under vacuum to obtain 950 mg of intermediate (1).
[0164]
[0165] Intermediate (1) (4.1 g, 14.95 mmol) was dissolved in a mixture...
Embodiment A2
[0169]
[0170] Stir allyl-prop-2-ynyl-carbamic acid tert-butyl ester (CAS 147528-20-9, 45 g, 0.23mol), cobalt carbonyl (17.5 g, 46.1 mmol) and 1,1,3,3 -Tetramethyl-2-thiourea (36.6 g, 0.277 mol) in toluene (1.8 L) and heated in high pressure under CO pressure (2-3 bar) at 70 °C for 5 hours. The resulting mixture was filtered through a short pad of celite and evaporated to dryness. The residue was treated in DCM and filtered through a short pad of celite to get a clear solution. It was evaporated to dryness to give 85.7 g of crude residue. It was purified by preparative liquid chromatography (silica gel 20-45µm, 1000 g, mobile phase (DCM / AcOEt gradient from 95 / 5 to 80 / 20). Collect the pure fractions and evaporate the solvent to obtain 36.5 g of intermediate Body (4).
[0171]
[0172] A mixture of intermediate (4) (37.6 g, 0.168 mol) and 10% palladium on carbon (7.5 g) in ethyl acetate (750 ml) was hydrogenated in a closed vessel reactor at room temperature and 3 bar for 30 mi...
Embodiment A3
[0186]
[0187] A solution of intermediate (6) (44.4 g, 111.82 mmol) and 3-thiopheneboronic acid (17.17 g, 134.19 mmol) in potassium carbonate 2M (112 ml) and ethylene glycol dimethyl ether (444 ml) in the open Pass into the container of N 2 Purge for 10 minutes, then add tetrakistriphenylphosphine palladium (12.92 g, 223.65 mmol). The solution was heated using a multi-mode resonator microwave CEMMARS system with an output power ranging from 0 to 400W at 78°C for 1 hour. The solution was cooled to room temperature, and water and EtOAc were added. The mixture was filtered through a pad of Celite. The organic layer was separated, washed with water and brine successively, and washed with MgSO 4 Dry and evaporate to dryness. The residue was purified by preparative liquid chromatography on (silica gel 20-45 µm, 1000 g, mobile phase (80% heptane, 20% AcOEt)). The pure fractions were collected and concentrated to obtain 16 g of intermediate (11).
[0188]
[0189] Trifluoroacetic ac...
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