反应详情

温度

18 °C

To a 3 L flask was added 1-{[(3R,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (94.7 g, 337 mmol). The material was azeotroped two times with EtOAc to remove any trace amounts of MeOH from the SFC. Next, to the residue was added DMF (731 mL) and water (731 mL). The solution was cooled to ˜18° C. (with an ice water bath). Next, a solution of TFA (51.9 mL, 673 mmol) in water (731 mL) added (pre-cooled to ˜10° C.). The entire solution was then cooled with an ice water bath to ˜10° C. The temperature was held around 10° C. for about 2.5 h then allowed to warm to RT and stir overnight. The next day, DCM (500 mL) was added, and the solution was made basic by slowly adding 6N NaOH. The mixture was added to a separatory funnel, the DCM separated and the aqueous layer diluted with 6N NaOH (300 mL), and then extracted with DCM (8×250 mL). The combined organic extracts were concentrated under reduced pressure to remove as much DMF as possible. The residue was dissolved in DCM (250 mL) and stirred at RT to crystallize the trans diol. After stirring overnight, the solution was cooled to ˜10° C., and the solids were filtered off, washed with DCM and dried under reduced pressure. This yielded 49.15 g of 1-{[(1S,3S)-3-hydroxy-3-(hydroxymethyl)-1-methylcyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (trans diol) as a white solid. The filtrate (˜60 g material, a mixture of cis-diol, trans-diol, and elimination side products) was concentrated, loaded onto silica gel and split into 3 equal portions and purified on the ISCO RF (3×330 g column): 0-5% MeOH/DCM over 15 min, hold at 5% for 10 min, then 5-25% over 10 min, then hold at 25%. The trans diol product was combined with the solids from the crystallization and used without further purification. MS (m/z) 300.2 (M+H+).

1. customThe material was azeotroped two times with EtOAc
2. customto remove any trace amounts of MeOH from the SFC
3. additionNext, to the residue was added DMF (731 mL) and water (731 mL)
4. temperature(pre-cooled to ˜10° C.)
5. temperatureThe entire solution was then cooled with an ice water bath to ˜10° C
6. temperatureto warm to RT
7. additionThe mixture was added to a separatory funnel
8. customthe DCM separated
9. additionthe aqueous layer diluted with 6N NaOH (300 mL)
10. extractionextracted with DCM (8×250 mL)
11. concentrationThe combined organic extracts were concentrated under reduced pressure
12. customto remove as much DMF as possible
13. dissolutionThe residue was dissolved in DCM (250 mL)
14. stirringstirred at RT
15. customto crystallize the trans diol
16. stirringAfter stirring overnight
17. temperaturethe solution was cooled to ˜10° C.
18. filtrationthe solids were filtered off
19. washwashed with DCM
20. customdried under reduced pressure
21. additionThe filtrate (˜60 g material, a mixture of cis-diol, trans-diol, and elimination side products)
22. concentrationwas concentrated
23. customsplit into 3 equal portions
24. custompurified on the ISCO RF (3×330 g column)
25. wait0-5% MeOH/DCM over 15 min
26. waithold at 5% for 10 min
27. wait5-25% over 10 min
28. customThe trans diol product was combined with the solids from the crystallization
29. customused without further purification