Synthesis intermediates of halichondrin B analog
A technology for halichondrin and analogs, applied in the field of medicinal chemistry, can solve problems such as difficulty in total synthesis, and achieve the effects of reducing production costs, facilitating industrial production, and reducing costs
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Embodiment 1
[0052] The preparation of embodiment 1 compound F-8
[0053] step 1:
[0054]
[0055] SM2 (29g, 0.095mol) was dissolved in tetrahydrofuran (90ml), cooled to 10°C, LHMDS solution in THF (1M, 95.2ml) was added dropwise, and stirred at 10°C for half an hour. Subsequently, a toluene solution (140 ml) of compound F-1 (35 g, 0.068 mol) was added dropwise, and the reaction was continued at 10° C. for half an hour after the drop was completed. The completion of the reaction was monitored by TLC. The reaction solution was washed with 1M aqueous hydrochloric acid (230ml) and saturated brine (175ml) successively, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude product F-2 (60g).
[0056] MS:667[M+H] + .
[0057] Step 2:
[0058]
[0059] Crude compound F-2 (60g) was dissolved in acetonitrile (200ml) and toluene (200ml), TMSI (60ml) was added, and reacted at 45°C for 2-4h. TLC monitors that the reaction is complete, th...
Embodiment 2
[0082] The preparation of embodiment 2 compound F-9
[0083]
[0084] Compound F-8 (8.8g, 0.023mol) was dissolved in DMF (35ml), imidazole (5.5g, 0.081mol) was added at room temperature, and TBSCl (9g, 0.06mol) was added dropwise below 30°C. After dropping, the reaction was carried out at room temperature, and the reaction was complete as monitored by TLC. The reaction solution was diluted with TBME (88ml), washed with water (44ml), 1M aqueous hydrochloric acid (33ml), water (33ml), aqueous sodium bicarbonate (33ml), and saturated brine (33ml). After drying and concentrating, the compound F-9 (12.4 g) was obtained by column chromatography. Yield 88.6%.
[0085] MS:613[M+H] + .
[0086] 1 H-NMR (CDCl 3 ,400MHz)δ:7.71(d,J=8.2Hz,2H),7.30(d,J=8.1Hz,2H),5.69–5.52(m,1H),4.98–4.82(m,2H),3.84–3.66 (m,3H),3.49(dd,J=10.3,5.6Hz,1H),3.43–3.33(m,2H),3.32(s,3H),2.98–2.91(m,2H),2.39(s,3H ),2.37–2.15(m,3H),1.95–1.83(m,1H),1.72(dt,J=13.7,6.8Hz,1H),0.80(d,J=3.3Hz,18H),0.02–0.06( m,1...
Embodiment 3
[0087] The preparation of embodiment 3 compound F-10
[0088]
[0089] Compound F-9 (2 g, 0.0033 mol) was dissolved in n-hexane (20 ml), cooled to -60° C., and passed through ozone until the solution turned blue. The reaction was complete as monitored by TLC, and the ozone generator was turned off. Nitrogen was passed for 15-30 minutes, the temperature of the reaction solution was raised to 5°C, and Lindlar catalyst (5%Pd / CaCO 3 ) (300mg), after hydrogen replacement for 3 times, reacted at 25°C under 1atm of hydrogen, TLC monitored the reaction to be complete, filtered and concentrated, and separated by column chromatography to obtain compound F-10 (1.7g), with a yield of 85%.
[0090] MS:615[M+H] + .
[0091] 1 H-NMR (CDCl 3 ,400MHz)δ:9.72(s,1H),7.83(t,J=7.4Hz,2H),7.40(d,J=8.1Hz,2H),4.04–3.90(m,2H),3.87–3.74(m ,2H),3.58(dd,J=10.2,5.5Hz,1H),3.52–3.44(m,1H),3.39(s,3H),3.31(dd,J=14.1,5.1Hz,1H),3.08( dt,J=9.5,7.3Hz,1H),2.89(ddd,J=17.5,6.5,1.6Hz,1H),2.78(dd,J=17.5,6.0Hz,1...
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