反应详情

温度

55 °C

A mixture of ethyl (6-methoxy-4-methylpyridin-3-yl)carbamate (0.593 g, 2.82 mmol) and potassium tert-butoxide (0.275 g, 2.452 mmol) in NMP (4.90 mL) was stirred at RT for 5 min before 1-(((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.69 g, 2.452 mmol) was added. The reaction mixture was stirred at 55° C. for 16 h, then at 70° C. for 2.5 h and then at 85° C. for 16 h. Saturated aq NaHCO3 was added and the mixture was extracted with EtOAc. The organic layer was concentrated and purified via HPLC (Waters, Sunfire C-18 column, OBD, 20-60% MeCN in water (0.1% TFA), 16 min, with at-column dilution, flow rate 45 mL/min). Fractions contained desired products were free based with NaHCO3, extracted with DCM, dried over Na2SO4 and concentrated. The resulted foam was crystallized by stirring with a solution of 1/3 DCM/isopropanol (4 mL total) in an uncapped vial overnight. The resulted cloudy mix was concentrated to ˜2 mL volume and then stirred for 1 h. The resulted light pink solids were collected by filtration and dried on high vacuum for 2 h to yield 1-(((5S,7S)-3-(6-methoxy-4-methylpyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.92 (d, J=8.53 Hz, 1H), 7.78 (s, 1H), 7.59 (dd, J=1.25, 8.28 Hz, 1H), 6.66 (s, 1H), 4.04 (s, 2H), 3.93 (s, 3H), 3.52-3.58 (m, 2H), 2.25 (s, 4H), 2.01 (d, J=13.80 Hz, 2H), 1.63-1.77 (m, 2H), 1.60 (s, 1H), 1.50 (d, J=13.80 Hz, 1H), 1.37-1.42 (m, 4H). MS (m/z) 446.2 (M+H+).

1. additionwas added
2. waitat 70° C. for 2.5 h
3. waitat 85° C. for 16 h
4. extractionthe mixture was extracted with EtOAc
5. concentrationThe organic layer was concentrated
6. custompurified via HPLC (Waters, Sunfire C-18 column, OBD, 20-60% MeCN in water (0.1% TFA), 16 min, with at-column dilution, flow rate 45 mL/min)
7. extractionextracted with DCM
8. dry with materialdried over Na2SO4
9. concentrationconcentrated
10. customThe resulted foam was crystallized
11. stirringby stirring with a solution of 1/3 DCM/isopropanol (4 mL total) in an uncapped vial overnight
12. additionThe resulted cloudy mix
13. concentrationwas concentrated to ˜2 mL volume
14. stirringstirred for 1 h
15. filtrationThe resulted light pink solids were collected by filtration
16. customdried on high vacuum for 2 h