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Procedure: Charge acetic anhydride, (2.8 vol, 3.0 wt, 5.0 eq.) to a vessel and commence stirring. Cool the solution to -5 to 5 C., targeting -4 C. Charge 1-methylimidazole, (0.2 vol, 0.21 wt, 0.5 eq.) to the mixture at -5 to 5 C. Caution: very exothermic. If necessary, adjust the temperature to 0 to 5 C. Charge ZX008 acid, (1.00 wt, 1.0 eq.) to the mixture at 0 to 5 C. Caution: exothermic. Stir the mixture at 0 to 5 C. until ?2.1% area ZX008 acid by HPLC analysis, typically 7 to 9 hours. Charge 15% w/w sodium chloride solution (2.0 vol) to the mixture at 0 to 5 C., 60 to 90 minutes. Caution: very exothermic which will be slightly delayed. Warm the mixture to 18 to 23 C. over 45 to 60 minutes and continue stirring for a further 30 to 45 minutes at 18 to 23 C. Charge TBME, (5.0 vol, 3.7 wt) to the mixture and stir for 10 to 15 minutes at 18 to 23 C. Separate the aqueous layer and retain the organic layer. Back-extract the aqueous layer with TBME, (2×3.0 vol, 2×2.2 wt) at 18 to 23 C. retaining each organic layer. Adjust the pH of the combined organic layer to pH 6.5 to 9.0, targeting 7.0 by charging 20% w/w sodium hydroxide solution (5.3 to 8.3 vol) at 18 to 23 C. Caution: exothermic. Separate the aqueous layer and retain the organic layer. Wash the organic layer with 4% w/w sodium hydrogen carbonate solution (2×3.0 vol) at 18 to 23 C. Determine the residual ZX008 acid content in the organic layer by HPLC analysis, pass criterion ?0.10% area ZX008 acid. Wash the organic layer with purified water, (2×3.0 vol) at 18 to 23 C. Concentrate the organic layer under reduced pressure to ca. 2 vol at 40 to 45 C., targeting 43 C. Determine the w/w assay of ZX008 ketone (WIP) in the mixture by 1H-NMR analysis for information only and calculate the contained yield of ZX008 ketone (WIP) in the mixture. Note: This step can be removed from the process since the process is robust and consistently delivers 80 to 90% th yield. The achieved yield was factored into the charges of the subsequent steps.
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