Hydrochloric Acid → (+/-)-2-(1-Amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)benzo[d]oxazole-5-carbonitrile

Temperature

50 °C

To a suspension of (±)-tert-butyl 4-((tert-butylsulfinylimino)(5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (56 mg, 0.105 mmol) and tetramethylammonium fluoride (29.3 mg, 0.314 mmol) in THF (1 mL), TESCF3 (38.6 mg, 0.209 mmol) was added at 0° C. Then, the reaction mixture was allowed to reach rt. After stirring for 2 h, additional tetramethylammonium fluoride (9.76 mg, 0.105 mmol) and TESCF3(38.6 mg, 0.209 mmol) were added. After stirring for 0.5 h at rt, the reaction was diluted with aq. NH4Cl and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was dissolved in HCl (1.25 M in MeOH) (0.840 mL, 1.050 mmol) and stirred at rt for 15 min. At this point the reaction was warmed to 50° C. and heated at this temperature for 45 minutes. The mixture was concentrated and the resulting residue was dissolved in MeOH (1 mL). Cs2CO3 (137 mg, 0.420 mmol) was added and the mixture was stirred at 60° C. for 1.5 h. At this point an additional aliquot of Cs2CO3 (137 mg, 0.420 mmol) was added. After stirring for 50 min, the reaction mixture was cooled to rt, concentrated, and then diluted with aq. NH4Cl, brine and EtOAc. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 35:65). 1H NMR (400 MHz, CD2Cl2) δ ppm 8.15-8.17 (br. m, 1H), 8.02 (d, J=1.26 Hz, 1H), 7.57 (m, 1H), 7.48 (m, 1H), 7.18 (dd, J=3.03, 2.78 Hz, 1H), 6.95 (br. s, 1H), 6.62 (s, 1H), 3.28 (s, 3H), 2.43 (s, 3H). HRMS calcd. for C20H15F3N4O2 (M+H)+ 401.1220. found 401.1221.

1. additionwas added at 0° C
2. customto reach rt
3. stirringAfter stirring for 0.5 h at rt
4. customThe layers were separated
5. extractionthe aqueous layer was extracted with EtOAc
6. washThe organic layer was washed with brine
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated
10. stirringstirred at rt for 15 min
11. temperatureheated at this temperature for 45 minutes
12. concentrationThe mixture was concentrated
13. dissolutionthe resulting residue was dissolved in MeOH (1 mL)
14. stirringthe mixture was stirred at 60° C. for 1.5 h
15. stirringAfter stirring for 50 min
16. temperaturethe reaction mixture was cooled to rt
17. concentrationconcentrated
18. additiondiluted with aq. NH4Cl, brine and EtOAc
19. customThe layers were separated
20. extractionthe aqueous layer extracted with EtOAc
21. washThe combined organic layers were washed with brine
22. dry with materialdried over Na2SO4
23. filtrationfiltered
24. concentrationconcentrated
25. customThe resulting residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 35:65)

ORD record

ord-5c0956f6710d478996341c5ed7b9494f

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09056874B2