Heterocyclic compounds and their use in preventing or treating bacterial infections
A compound, heterocyclic technology, used in the prevention or treatment of bacterial infections, β-lactamase inhibitors and/or antibacterial agents, can solve the problem of low efficiency of bacterial strains
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Embodiment 1
[0301] Example 1: [7-oxo-3-(2-oxo-thiazol-3-yl)-1,6-diaza-bicyclo[3.2.1]oct-3-en-6-yl] Synthesis of Sodium Sulfate
[0302]
[0303] Step 1: Preparation of intermediate (1-benzyl-5-oxo-2,6-dihydropyridin-3-yl) triflate (1b)
[0304] Under nitrogen atmosphere, tBuOK (2.7 g, 24.07 mmol) was dissolved in anhydrous THF (180 mL) in a 500 mL round bottom flask, and the resulting solution was cooled to 0 °C. Add N-benzyl-N-acetonylglycine ethyl ester (1a) dissolved in anhydrous THF (60ml) with a dropping funnel within 5 minutes (according to records in literature (J.Org.Chem.2006, 71( 21), 8256, J..Med.Chem.2012, 55(11), 5403, WO2013 / 181741) to synthesize (6g, 24.07mmol).Stir the resulting viscous solution at 0°C for 30 minutes (LC / MS showed formation of the corresponding diketone m / z ([M+H] + 204, [M+H 2 O+H] + 222,[M-H] - 202).
[0305] At 0°C, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide (Comins reagent) (9.7 g, 24.07 mmol) dissolved in THF (20 mL) was add...
Embodiment 2
[0340] Example 2: [7-oxo-3-(triazol-1-yl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]sodium sulfate Synthesis
[0341]
[0342] Step 1a: Intermediate 6-allyloxy-3-(triazol-1-yl)-1,6-diazabicyclo[3.2.1]oct-3-ene-7- Preparation of ketone (2a) and 6-allyloxy-3-(triazol-2-yl)-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (2b)
[0343] Under argon, intermediate (1 g) (629 mg, 2.05 mmol), 1H-1,2,3-triazole (237 μL, 4.10 mmol), di-tert-valerylmethane (86 μL, 0.41 mmol), CuI (37 mg , 0.20mmol) and dry K 2 CO 3 (567 mg, 4.40 mmol) in DMSO (20 mL) was heated (80°C-100°C) for several hours (1 hour-30 hours). The mixture was concentrated to dryness under nitrogen flow. The residue was purified on silica gel (DCM / EtOAc: 100 / 0 to 0 / 100) to give intermediate (2a) (243 mg, 0.982 mmol, 48%) as yellow oil and intermediate (2b) as yellow oil ( 131 mg, 0.530 mmol, 26%).
[0344] 6-allyloxy-3-(triazol-1-yl)-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (2a)
[0345] MS m / z ([M+H] + )248, ([2M+H] + )4...
Embodiment 3
[0360] Example 3: [7-oxo-3-(triazol-2-yl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]sodium sulfate Synthesis
[0361]
[0362] Step 1: [7-Oxo-3-(triazol-2-yl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]sodium sulfate (solid Embodiment 3) preparation
[0363] Intermediate (2b) (180 mg, 0.725 mmol) was converted to Example (3) (102 mg, 0.330 mmol, 46%) as a white solid after lyophilization using the procedure described in Example 2 (Step 2).
[0364] MS m / z ([M+H] + )288.
[0365] MS m / z ([M-H] - )286.
[0366] 1 H-NMR (300MHz, D 2 O): δ (ppm) 3.39 (d, J = 11.3Hz, 1H), 3.58-3.66 (m, 1H), 4.40 (d, J = 1.6Hz, 2H), 4.54 (dd, J = 5.7, 2.7Hz , 1H), 6.89 (dd, J=5.4, 1.5Hz, 1H), 7.81 (s, 2H).
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