反应详情

To a 1 L flask was added 1-{[(1S,3S)-3-hydroxy-3-(hydroxymethyl)-1-methylcyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (21.2 g, 70.8 mmol) and DCM (698 mL) and the temperature was lowered to 5° C. Next DMAP (6.49 g, 53.1 mmol), tosyl-Cl (20.25 g, 106 mmol) and triethylamine (20.23 mL, 145 mmol) were added. The solution was allowed to stir and warm to RT. Stirring was continued for 18 h and then the solution was added to a separatory funnel and diluted with saturated aq NaHCO3 (1 L). The DCM was separated, and washed sequentially with saturated aq NH4Cl, then saturated aq NaHCO3. The DCM was then passed over a phase separator to remove leftover water, concentrated, and taken directly onto the next step. To the yellow residue was added methanol (698 mL) followed by K2CO3 (10.77 g, 78 mmol). The mixture was stirred at RT for 3 h. Following completion, the solution was filtered, and the solids were washed with MeOH. The mixture was then diluted with DCM (500 mL) and saturated aq NaHCO3 (1 L). The solution was added to a 3 L separatory funnel, and the aqueous layer extracted three times with DCM. The combined DCM extracts were washed with brine and then dried over Na2SO4, filtered and concentrated. The crude solid was azeotroped with EtOAc two times to give a yellow residue. The residue was dried under reduced pressure to give 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile as a yellow solid (19.9 g, 95% yield). MS (m/z) 282.2 (M+H+).

1. customwas lowered to 5° C
2. stirringStirring
3. additionthe solution was added to a separatory funnel
4. customThe DCM was separated
5. washwashed sequentially with saturated aq NH4Cl
6. customto remove leftover water
7. concentrationconcentrated
8. additionTo the yellow residue was added methanol (698 mL)
9. stirringThe mixture was stirred at RT for 3 h
10. filtrationthe solution was filtered
11. washthe solids were washed with MeOH
12. additionThe mixture was then diluted with DCM (500 mL) and saturated aq NaHCO3 (1 L)
13. additionThe solution was added to a 3 L separatory funnel
14. extractionthe aqueous layer extracted three times with DCM
15. washThe combined DCM extracts were washed with brine
16. dry with materialdried over Na2SO4
17. filtrationfiltered
18. concentrationconcentrated
19. customThe crude solid was azeotroped with EtOAc two times
20. customto give a yellow residue
21. customThe residue was dried under reduced pressure