Chiral tetrahydropyran derivatives and their preparation and use
A compound, C1-C3 technology, applied in the field of its synthesis method and its intermediate, tetrahydropyran chiral derivatives
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Embodiment 1
[0289]
[0290] Preparation of compound 14-1
[0291] Under anhydrous and oxygen-free conditions, 2,5-difluorobromobenzene (28.7g, 0.149mol) was dissolved in 150mL of anhydrous ether, cooled to -98°C, and n-BuLi (62mL, 99mmol, 1.6M in hexane), after reacting for 10 minutes, add the anhydrous ether solution of intermediate 12-1 (15g, 0.05mol) dropwise. 4 Cl aqueous solution (100mL) quenched the reaction, returned to room temperature, extracted 4 times with TBME (100mL×4), combined the organic layers, dried with anhydrous sodium sulfate, evaporated the organic solvent in vacuo, azeotroped toluene (50mL×2) Water was removed twice, and colorless oil 14-1 (20 g, 0.048 mmol) was obtained by flash preparative chromatography, yield: 97%. 1 H-NMR (400MHz, CDCl 3 )δ7.43–7.33(m,1H),7.03–6.93(m,2H),4.32–4.23(m,2H),4.21(d,J=5.8Hz,1H),4.15(t,J=5.7Hz ,1H),4.08(d,J=12.5Hz,1H),4.02(s,1H),1.53(s,3H),1.36(s,3H),0.74(s,9H),0.06(s,3H) ,-0.30(s,3H).
Embodiment 2
[0293]
[0294] Preparation of compound 15-1
[0295] Under nitrogen protection, intermediate 14-1 (20 g, 0.048 mol) was dissolved in 200 mL of dry CH 2 Cl 2 , cooled to -78°C, added Et 3 SiH (8.4mL, 0.053mol), after stirring for 5min, TMSOTf (10.2mL, 0.053mol) was added dropwise, and reacted for 1h. After the reaction was detected by TLC, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution (100mL), and the aqueous layer was washed with CH 2 Cl 2 (100mL×3) extracted 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, separated and purified on a silica gel column (10:1, 60-90°C petroleumeumether–EtOAc) to obtain a white crystalline solid 15-1 (18.8g, 0.047mol), yield: 98%. M.p.72.1-76.6°C (60-90°C petroleum ether–EtOAc); R f 0.52 (10:1, 60-90°C petroleum ether–EtOAc); [α] D -72.90(c 0.155CHCl 3 ); HPLC t R 4.49min; 1 H-NMR (600MHz, CDCl 3( d, J=9.5Hz, 1H, H-1), 4.26(dd, J=5.6, 2.0Hz, 1H, H-4...
Embodiment 3
[0297]
[0298] Preparation of Compound 16-1
[0299] Intermediate 15-1 (12g, 29.96mmol,) was dissolved in anhydrous tetrahydrofuran (100mL), n-butylammonium fluoride (44.94mL, 44.94mmol, 1M in THF) was added, and stirred overnight at room temperature. After the reaction was complete, THF was evaporated to dryness, diluted with EA (200 mL), the organic layer was washed three times with water (50 mL×3), and the EA layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain an oily product 16-1.
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