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To a slurry of NaH (0.96 g, 60% in oil) in THF (5.0mL), was added diethyl 1,3-acetonedicarboxylate (2.4 g) slowly at 0-15 oC. After the mixture was stirred for 0.5 h, a total of 1.4 g of Compound 9 was added slowly at 0-15 oC. The mixture was stirred at 20-30 oCfor 1 h, and then heated to reflux. 5 mL of EtOH and 2.4 g of NaOEt solution(20% in EtOH) were added respectively. The resulting mixture was refluxed for 5h. After that, a total of 11.2 g of KOH solution (20% in water) was added slowly, and the reaction mixture was refluxed for another 5 h. The organic solvent in reaction mixture was removed at reduced pressure. The aqueous solution was extracted with MTBE (2 x 10 mL) and then heated to 50-60 oCwith addition of conc. HCl until pH at 2.5-3.5. The resulting mixture wasstirred at 50-60 oC for 2 h and then cooled to 20-30 oC.It was extracted with dichloromethane (3 x 25 mL). The combined organic phase was concentrated at reduced pressure. Then 5.0 mL of MTBE was added to the residue and the resulting slurry was stirred for 0.5 h at 0-10 oC.The solid was collected by filtration, washed with MTBE (5.0 mL), and dried under vacuum. A total of 0.68 g (45% yield) of 2 was obtained as a white solid. |
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To a slurry of NaH (0.96 g, 60 in oil) in THF (5.0 mL) , was added diethyl acetonedicarboxylate (2.4 g) slowly at 0-15 . After it was stirred for 0.5 h, a total of 1.4 g of Compound 12 was added slowly at 0-15 . The mixture was stirred at 20-30 for 1 h, and then heated to reflux. 5 mL of EtOH and 2.4 g of NaOEt solution (20 in EtOH) were added respectively. The resulting mixture was refluxed for 5 h. After that, a total of 11.2 g of KOH solution (20 in water) was added slowly, and the reaction mixture was continuously refluxed for another 5 h. The organic solvent in reaction mixture was removed under vacuum. The aqueous solution was extracted with MTBE (2 x 10 mL) and then heated to 50-60 with addition of conc. HCl until pH at 2.5-3.5. The resulting mixture was stirred at 50-60 for 2 h and then cooled to 20-30 . It was extracted with dichloromethane (3 x 25 mL) . The combined organic phase was concentrated under vacuum. Then 5.0 mL of MTBE was added to the residue and the resulting slurry was stirred for 0.5 h at 0-10 . The solid was collected by filtration, washed with MTBE (5.0 mL) , and dried under vacuum. A total of 0.68 g (45 yield, 98 purity) of Compound 6 was obtained as a white solid.1HNMR(400 MHz, DMSO-d6) delta11.02 (br s, 1H) , 5.17 (s, 1H) , 2.45-2.25 (m, 4H) , 1.90-1.75 (m, 2H) , 1.75-1.65 (m, 4H) 13CNMR(100 MHz, DMSO-d6) delta186.22, 103.55, 44.69, 38.35, 31.48, 14.61 MS (m/z) 152.1. |
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