反应详情

温度

100 °C

Two identical reactions were set up: To a 1 L flask containing 2-(5-chloropyrazin-2-yl)propan-2-ol (18.29 g, 106 mmol) was added reagents in the following order: first potassium phosphate tribasic (36.0 g, 170 mmol), followed by 1-(((5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (27.5 g, 85 mmol). Next 1,4-dioxane (424 mL) was added followed by N1,N2-dimethylethane-1,2-diamine (7.47 g, 85 mmol). To the resulting white slurry was added copper(I) iodide (8.07 g, 42.4 mmol). The slurry was put under nitrogen and heated to 100° C. (Reaction 1=44 h, Reaction 2=68 h). After completion, the mixture was cooled to RT, diluted with DCM and water and 7N NH3 in MeOH and allowed to stir for 10 min. The layers were separated and the aqueous layer was extracted with DCM (2×). The combined DCM extracts were diluted with 7N NH3 in MeOH (300 mL) (to remove residual copper ions), and then washed with water (2×500 mL), and dried over Na2SO4, filtered, and concentrated. Each residue was purified on the ISCO: 4×330 g silica, 0-10% MeOH/DCM over 10 CV. Fractions containing product were concentrated, dissolved in DCM, and washed one final time with water/7N NH3 in MeOH to remove any leftover copper. The resulting layers were separated, the aqueous layer extracted with DCM (2×), and the combined DCM extracts were dried over Na2SO4, filtered, and concentrated. The residue was then azeotroped with MeCN (300 mL) and then diluted to a volume of ˜650 mL. The solution was heated to 70° C. (all solids went into solution affording a yellow solution), then allowed to cool to RT with stirring and crystals started to form. After stirring at RT for ˜2 h, the slurry was diluted with 2 L water. Stirring was continued overnight before the slurry was filtered and the solids dried under reduced pressure to 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (71.3 g, 91%) as a white solid. MS (m/z) 461.2 (M+H+) 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.82 (d, J=8.28 Hz, 1H), 7.58 (d, J=8.28 Hz, 1H), 5.41 (s, 1H), 4.16 (br. s., 2H), 3.77-3.96 (m, 2H), 1.98 (d, J=7.03 Hz, 1H), 1.82-1.93 (m, 1H), 1.72 (d, J=14.56 Hz, 2H), 1.58-1.67 (m, 2H), 1.28-1.57 (m, 8H), 1.06 (s, 3H). MS (m/z) 461.0 (M+H+).

1. additionwas added reagents in the following order
2. custom(Reaction 1=44 h, Reaction 2=68 h)
3. temperatureAfter completion, the mixture was cooled to RT
4. customThe layers were separated
5. extractionthe aqueous layer was extracted with DCM (2×)
6. additionThe combined DCM extracts were diluted with 7N NH3 in MeOH (300 mL) (to remove residual copper ions)
7. washwashed with water (2×500 mL)
8. dry with materialdried over Na2SO4
9. filtrationfiltered
10. concentrationconcentrated
11. customEach residue was purified on the ISCO
12. additionFractions containing product
13. concentrationwere concentrated
14. dissolutiondissolved in DCM
15. washwashed one final time with water/7N NH3 in MeOH
16. customto remove any leftover copper
17. customThe resulting layers were separated
18. extractionthe aqueous layer extracted with DCM (2×)
19. dry with materialthe combined DCM extracts were dried over Na2SO4
20. filtrationfiltered
21. concentrationconcentrated
22. customThe residue was then azeotroped with MeCN (300 mL)
23. additiondiluted to a volume of ˜650 mL
24. temperatureThe solution was heated to 70° C. (all solids
25. customaffording a yellow solution),
26. temperatureto cool to RT
27. stirringwith stirring
28. customto form
29. stirringAfter stirring at RT for ˜2 h
30. stirringStirring
31. waitwas continued overnight before the slurry
32. filtrationwas filtered
33. dry with materialthe solids dried under reduced pressure to 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (71.3 g, 91%) as a white solid