Method for stereoselectively producing substituted polycyclic pyridone derivative
A compound and internal cyclization technology, which can be used in organic chemical methods, pharmaceutical formulations, organic active ingredients, etc., and can solve problems such as undisclosed pyrone compounds
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Embodiment 1
[0574]
[0575] step 1
[0576] To a suspension of NaH (3.96 g, 99 mmol) in DMF (36 mL) was added a solution of Boc-L-serine (9.27 g, 45 mmol) in DMF (45 mL) dropwise under ice-cooling under nitrogen atmosphere over 30 min, then Bromoacetaldehyde dimethyl acetal (10.6 mL, 90 mmol) was added dropwise over 10 minutes. The mixture was warmed to room temperature over 3 hours, and the mixture was stirred for 5 hours. The mixture was poured into water (90 g) and concentrated. Wash the aqueous layer with Et 2 O wash and the pH was adjusted to 3.3 by adding hydrochloric acid. The aqueous layer was extracted with ethyl acetate (100 mL). The aqueous layer was extracted again with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give crude compound 2 (9.52 g).
[0577] 1H-NMR (CDCl 3 )δ: 5.54-5.52 (br m, 1H), 4.50 (t, J=5.1Hz, 1H), 4.44-4.42 (br m, 1H), 4.01-3.99 (br m, 1H), 3.74 (dd, J = 9.7, 4.1 H...
Embodiment 2
[0602]
[0603] step 1
[0604] Add WSCD·HCl (288mg, 1.50 mmol), and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound 12 (203 mg, 80% yield).
[0605] 1 H-NMR (CDCl 3 )δ: 7.90-7.79 (m, 4H), 7.35 (d, J = 7.7Hz, 1H), 6.20 (d, J = 7.7Hz, 1H), 5.81 (d, J = 13.3Hz, 1H), 5.41 ( d, J=3.5Hz, 1H), 5.07-5.01(m, 1H), 4.74(d, J=12.2Hz, 1H), 4.28-4.17(m, 3H), 3.90(dd, J=16.1, 7.1Hz , 1H), 3.40(t, J=10.8Hz, 1H), 1.80-1.68(m, 2H), 1.40-1.24(m, 6H), 0.83(t, J=6.9Hz, 3H).
[0606] step 2
[0607] To a mixture of compound 12 (51 mg, 0.10 mmol) and zinc powder (3.27 mg, 50 μmol) were added THF (0.5 mL) and 2-propanol (51 μL) under nitroge...
Embodiment 3
[0609]
[0610]Compound 13 (37.1 mg, 1.00 mmol) (which was synthesized in the same manner as described in Step 1 to Step 8 of Example 1) and 3-hydroxy-4-methylthiazole-2 (3H )-thione (22.1mg, 1.50mmol) in N-methylpyrrolidone (0.9mL) solution was added DABCO (44.9mg, 4.00mmol) and T3P (255mg, 4.00mmol), the mixture was stirred at room temperature for 2 hours, A solution of compound 14 was obtained. To the mixture was added t-nonanthiol (0.9 mL, 74 mmol) under nitrogen atmosphere, and the mixture was stirred at 55°C for 2 hours. The mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 15 (27 mg, 83% yield).
[0611] 1 H-NMR (DMSO) δ: 2.80-3.00 (m, 1H), 3.10-3.18 (m, 1H), 3.38-3.50 (m, 1H), 3.98-4.08 (m, 2H), 4.10-4.20 (m, 1H), 4.76-4.84(m, 1H), 5.04-5.14(m, 2H), 6.22(m, J=7.6Hz, 1H), 7.27-7.40(m, 4H), 7.56-7.60(m, 2H) , 7.70 (d, J=7.6Hz, 1H).
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