Cesium carbonate → LX-1031

Temperature

100 °C

To a 3-neck 250 ml round-bottom flask equipped with a mechanical stirrer, a thermocontroller, was charged compound 3 (8.62 g, 1.2 equiv), 8 (10.00 g, 25.46 mmol), tetrabutylammonium bisulfate (0.86 g, 10 mol %), and cesium carbonate (29.04 g, 3.5 equiv). Dioxane (50 ml) was added and the resulting mixture was heated at 100° C. for 18 hours. HPLC analysis showed 99% conversion of the starting material 8. The mixture was cooled down to 60° C. and water (60 ml) was added. The top organic layer was diluted with THF (80 ml), washed with brine (50 ml), transferred to a 500 ml round-bottom flask, and 80 ml of 6 N hydrochloric acid was added. The mixture was stirred at room temperature for 16 hours. LC-MS analysis of the reaction mixture showed complete consumption of the intermediate compound 9. The reaction mixture was transferred to a 500 ml separatory funnel. The round-bottom flask was washed with water (2×40 ml) and the washes were also transferred to the funnel. The mixture was washed with ethyl acetate (2×100 ml) and the aqueous layer was collected and concentrated at 40° C. (bath temperature) under 80 mbar vacuum to remove any remaining organic solvents. The resulting aqueous solution was then transferred to a 500 ml three-necked round-bottom flask equipped with a mechanical stirrer, a pH meter, a thermocontroller and an addition funnel. At 60° C., a solution of 50% aqueous sodium hydroxide solution was added slowly until pH=4, then a solution of 1N aqueous sodium hydroxide was added until pH reached 6.5. The mixture was stirred at 60° C. for additional 30 minutes and the yellow solids were collected by filtration. HPLC analysis of this solid showed a purity of about 95%. The solids were dried under vacuum at 50° C. overnight to give the crude product compound 10 as a yellow solid (9.48 g, 69% overall yield).

1. customTo a 3-neck 250 ml round-bottom flask equipped with a mechanical stirrer
2. temperatureThe mixture was cooled down to 60° C.
3. washwashed with brine (50 ml)
4. customtransferred to a 500 ml round-bottom flask
5. addition80 ml of 6 N hydrochloric acid was added
6. customconsumption of the intermediate compound 9
7. customThe reaction mixture was transferred to a 500 ml separatory funnel
8. washThe round-bottom flask was washed with water (2×40 ml)
9. washThe mixture was washed with ethyl acetate (2×100 ml)
10. customthe aqueous layer was collected
11. concentrationconcentrated at 40° C. (bath temperature) under 80 mbar vacuum
12. customto remove any remaining organic solvents
13. customThe resulting aqueous solution was then transferred to a 500 ml three-necked round-bottom flask
14. customequipped with a mechanical stirrer
15. additionAt 60° C., a solution of 50% aqueous sodium hydroxide solution was added slowly until pH=4
16. additiona solution of 1N aqueous sodium hydroxide was added until pH
17. stirringThe mixture was stirred at 60° C. for additional 30 minutes
18. filtrationthe yellow solids were collected by filtration
19. customThe solids were dried under vacuum at 50° C. overnight

ORD record

ord-890bde75257c4132a39a395b7a132be1

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07897763B2