12-KETOLITHOCHOLIC ACID ACETATE, METHYL ESTER synthesis
- Product Name:12-KETOLITHOCHOLIC ACID ACETATE, METHYL ESTER
- CAS Number:5143-55-5
- Molecular formula:C27H42O5
- Molecular Weight:446.62
Yield:5143-55-5 268 g
Reaction Conditions:
Stage #1: Deoxycholic acidwith pyridine;sulfuric acid in methanol at 55 - 64;
Stage #2: acetic anhydridewith pyridine;dmap;sulfuric acid in methanol;water;ethyl acetate at 25 - 40;
Steps:
2 Synthesis of (3a, 5p)-3-acetoxy-12-oxo-cholan-24-oic acid methyl ester (VIIB)
To a solution of deoxycholic acid (referred to herein as compound (XB), 500 g, 1.27 mol) in MeOH (1.5 L) was charged H2SO4 (0.68 mL, 12.7 mmol) and the reaction heated to 64 °C until complete. The reaction was cooled to 55 °C and pyridine (2.06ml_, 25.4 mmol) was charged. MeOH (800 mL) was removed by distillation and the reaction cooled to 50 °C. EtOAc (500 mL) was charged and the distillation continued. This co-evaporation was repeated until the MeOH content was <0.5%. The reaction was cooled to 40 °C and EtOAc (1.0 L) was charged followed by pyridine (134 mL, 1.65 mol) and DMAP (1.1 g, 8.89 mmol). Acetic anhydride (150 mL, 1.58 mmol) was added dropwise and the reaction vessel stirred at 40 °C until complete. The reaction was cooled to 22 °C and 2M aq. H2S04 (1500 mL) added maintaining the temperature below 25 °C. The aqueous phase was removed and the organic phase washed with water (1.2 L), sat. aq. NaHC03 solution (1.2 L x 2) and water (1.2 L). AcOH (1.0 L) was charged to the organic layer, followed by NaBr (6.6 g, 63.5 mmol). Aq. 16.4% NaOCI solution (958 mL, 2.54 mol) was charged dropwise maintaining the reaction temperature below 25 °C. The reaction was stirred until complete, then cooled to 10 °C and stirred for 90 mins. The resulting solids were collected by filtration, washed with water (3 x 500 mL) and the filter cake dried under vacuum at 40 °C. The solids were crystallised from MeOH (10 vol) to give the title compound as an off white solid (268 g).
References:
WO2017/199036,2017,A1 Location in patent:Page/Page column 68
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