Preparation method of chiral tertiary alcohol benzo-fused bicyclo [m.3. 0] alkanone compound
A benzo-fused compound technology, which is applied in the field of preparation of chiral tertiary alcohol benzo-fused bicyclo[m. Excellent chemical selectivity, strong group tolerance, and wide application range
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Embodiment 1
[0052] Catalyst Pd(R-DTBM-SEGPHOS)I 2 [i.e. Pd(L3)I 2 ] preparation
[0053] PdCl 2 +R-DTBM-segphos+2Kl=Pd(R-DTBM-segphos)l 2 +2KCl
[0054] Under nitrogen protection, the PdCl 2 (195mg, 1.1mmol, 1.1eq), (R)-DTBM-SEGPHOS (L3, 1.179g, 1.0mmol, 1.0eq), KI (1.66g, 10mmol, 10.0eq) and DMF (10mL) were added to the dried 25mL Schlenk tube. The reaction mixture was stirred at room temperature for 5 hours; the solution was removed under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain Pd(L3)I 2 1.46 g, 95% yield, as a dark purple solid. 1 H NMR (400MHz, Chloroform-d)δ8.65(s,1H),7.56(d,J=12.7Hz,4H),7.00(s,1H),6.69-6.59(m,2H),6.46-6.40( m, 2H), 5.71(d, J=1.3Hz, 2H), 5.63(d, J=1.2Hz, 2H), 3.69(s, 6H), 3.67(s, 6H), 1.38(s, 72H).
[0055] 13 C NMR (100MHz, Chloroform-d) δ162.5,161.7,149.5,146.3,143.9,142.8,142.7,133.8,129.6,128.9,128.9,119.6,119.1,13,7.4,117.2,107.8,107.7,100.31.8,64 , 32.1.
[0056] 31 P NMR (162MHz, Chlorofor...
Embodiment 14
[0078] 2-(2-Bromobenzyl)-2-methylcyclohexane-1,3-dione (Ia) was prepared with reference to Example 1
[0079] Preparation of (4aR,9aR)-4a-hydroxy-9a-methyl-2,3,4,4a,9,9a-hexahydro-1H-fluoren-1-one (IIa) (gram scale preparation)
[0080]
[0081] Under argon protection, compound Ia (1.0 g, 3.4 mmol, 1.0 eq), Pd(L3)I 2 (261.5mg, 0.17mmol, 0.05eq), L3 (40mg, 0.034mmol, 0.01eq), Et 3 N (1.2 g, 11.9 mmol, 3.5 eq) and dry DMSO (34 mL) were added to a dry Schlenk tube. The resulting reaction mixture was raised to 80 °C, and the reaction was stirred for 48 h. Then the reaction solution was cooled to room temperature, and 60 mL of H was added. 2 O. The aqueous phase obtained by separation was extracted with DCM (15 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and desolubilized. The residue was purified by silica gel column chromatography to obtain 504.2 mg of compound IIa as a white solid, yield 69%, 95% ee. [α] D ...
Embodiment 15
[0084] (4aR,9aR)-4a-hydroxy-6-methoxy-7,9a-dimethyl-2,3,4,4a,9,9a-hexahydro-1H-fluoren-1-one (IIb) preparation
[0085]
[0086] The preparation was carried out with reference to Example 1, and 40.5 mg of white solid IIb was obtained, with a yield of 78% and 98% ee.
[0087] 1 H NMR(500MHz, Chloroform-d)δ7.01(d,J=1.0Hz,1H),6.72(s,1H),3.82(s,3H),3.49(d,J=15.2Hz,1H),2.59 (d, J=15.5Hz, 1H), 2.55–2.47 (m, 1H), 2.32–2.24 (m, 2H), 2.20–2.11 (m, 1H), 2.18 (s, 3H), 1.98–1.89 (m ,1H),1.70(br s,1H),1.50–1.39(m,1H),1.32(s,3H).
[0088] 13 C NMR (126MHz, Chloroform-d) δ213.5, 157.3, 143.3, 133.8, 127.8, 127.4, 103.6, 85.2, 62.5, 55.5, 38.1, 37.6, 32.0, 20.0, 17.9, 16.5.
[0089] ATR-FTIR (cm -1 ): 3447, 2935, 1699, 1943, 1295, 1201, 1001.
[0090] HRMS m / z(ESI): calcd for C 16 H 20 NaO 3 + (M+Na) + 283.1305, found 283.1310.
[0091] [α] D 25 = 12.4 (c = 1.40, CHCl 3 ).
[0092] HPLC (hexane / isopropanol=80:20, flow rate=1.0mL / min, uv-vis detection atλ=254nm)t R =6.8min...
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