Hydrochloric Acid → HCID 86691522, compound

Temperature

0 °C

A solution of R-16 (9.0 mmol, 2.6 g) is dissolved in MeOH (24 mL) and cooled to 0° C. Sodium borohydride (9.0 mmol, 0.34 g) is added slowly to the mixture and the reaction is stirred at room temperature for 3 h. The mixture is concentrated under reduced pressure and the residue is diluted with DCM and water. The organic layer is separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is purified using flash silica gel chromatography to provide R-17 (0.26 g, 100%). To a solution of R-17 (0.91 mmol, 0.26 g) in THF (5 mL) is added TEA (0.14 ml, 1.0 mmol) followed by methanesulfonyl chloride (1.0 mmol, 0.078 ml). The reaction mixture is allowed to stir at room temperature for 16 h. To the mixture is added DBU (1.8 mmol, 0.27 m) and the reaction is allowed to stir at room temperature for 2 h. The mixture is diluted with EtOAc and washed sequentially with a saturated aqueous solution of NH4Cl followed by a 1M solution of HCl. The organic phase is dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide R-18 (0.26 g, 100%). To a solution of trimethylsulfoxonium iodide (1.0 mmol, 0.23 g) in DMSO (24 mL) is slowly added NaH (60% dispersion in mineral oil, 1.0 mmol, 0.042 g). The mixture is stirred at room temperature for 1 h and then a solution of R-18 (0.950 mmol, 0.26 g) in DMSO (0.5 mL) is rapidly added. The reaction mixture is heated to 50° C. for 2 h and then cooled to ambient temperature and stirred for 16 h. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phase is washed with brine then dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide R-19 (0.17 g, 63%). To a solution of R-19 (0.60 mmol, 0.17 g) in a 3:1 mixture of Et2O:DCM (4 ml) is added a solution of HCl in 1,4-dioxane (4M, 4 mmol, 1.0 mL). The mixture is stirred at 45° C. for 3 h then concentrated under reduced pressure. The residue is washed with Et2O and dried to provide the title compound (0.099 g, 75%).

1. concentrationThe mixture is concentrated under reduced pressure
2. additionthe residue is diluted with DCM and water
3. customThe organic layer is separated
4. washwashed with brine
5. dry with materialdried over Na2SO4
6. concentrationconcentrated under reduced pressure
7. customThe residue is purified
8. customto provide R-17 (0.26 g, 100%)
9. stirringto stir at room temperature for 16 h
10. stirringto stir at room temperature for 2 h
11. washwashed sequentially with a saturated aqueous solution of NH4Cl
12. dry with materialThe organic phase is dried over anhydrous Na2SO4
13. concentrationconcentrated under reduced pressure
14. customThe residue is purified by flash silica gel chromatography
15. customto provide R-18 (0.26 g, 100%)
16. stirringThe mixture is stirred at room temperature for 1 h
17. temperatureThe reaction mixture is heated to 50° C. for 2 h
18. temperaturecooled to ambient temperature
19. stirringstirred for 16 h
20. extractionextracted with ethyl acetate
21. washThe combined organic phase is washed with brine
22. dry with materialthen dried over anhydrous sodium sulfate
23. concentrationconcentrated under reduced pressure
24. customto provide R-19 (0.17 g, 63%)
25. stirringThe mixture is stirred at 45° C. for 3 h
26. concentrationthen concentrated under reduced pressure
27. washThe residue is washed with Et2O
28. customdried

ORD record

ord-1c0007841f9a45b99c7fff77b13e52d9

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08815857B2