Lithium Hydroxide → HCID 71225442, compound

To a solution of tert-butyl 4-(3-fluoro-4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I60) (0.206 g) in THF (5 mL) was added aqueous 2 M LiOH (0.500 mL, 1.00 mmol) and water (0.5 mL) and the resulting solution was stirred for 16 hours at room temperature. Aqueous LiOH (1.5 M; 0.5 mL) was added and the reaction stirred for a further 20 hours at room temperature. The mixture was then heated to 50° C. and methanol (1 mL) added before stirring for 20 hours. The volatiles were evaporated under reduced pressure and the residue azeotroped with toluene twice before addition of THF (4 mL), solid lithium hydroxide (0.021 g, 0.87 mmol), water (1 mL) and methanol (1 mL). The resulting mixture was stirred at room temperature for 5 hours and then heated to 50° C. for 16 hours. The volatiles were evaporated under reduced pressure and the residue diluted with water. The aqueous solution was extracted with EtOAc (2×20 mL) before acidifying to a pH of 3 with aqueous HCl. The resulting precipitate was collected as a pellet by centrifugation then dissolved in methanol and concentrated under reduced pressure. The residue was azeotroped with toluene then taken up in DMF (6 mL) to which EDCl (0.080 g, 0.42 mmol), HOBT (0.061 g, 0.45 mmol) and DIPEA (0.29 mL, 1.67 mmol) were added. The mixture was stirred at room temperature for 30 minutes under nitrogen before addition of ammonium carbonate (0.129 g, 1.66 mmol). The resulting mixture was stirred at 30° C. for 20 hours before the volatiles were evaporated under reduced pressure. Water (20 mL) was added and the resulting suspension was extracted with EtOAc (3×20 mL). The combined organic extracts were concentrated under reduced pressure and the residue chromatographed on silica gel (0-100% EtOAc/petroleum benzine 40-60° C. then 70-100% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I61) (0.049 g, 24%); 1H NMR (400 MHz, d6-Acetone) δ 8.71 (s, 1H), 8.60 (s, 1H), 7.98 (dd, J=8.4, 8.4 Hz, 1H), 7.29 (m, 1H), 7.17 (m, 5H), 6.66 (s, 1H), 6.22 (s, 1H), 4.21 (m, 1H), 3.63 (s, 2H), 3.16 (m, 4H), 2.09 (m, 2H), 1.87 (m, 3H), 1.59 (qd, J=12.7, 4.4 Hz, 2H), 1.46 (s, 9H); LCMS Method C: rt 6.46 min; m/z 602.1 [M+H]+, 624.1 [M+Na]+, 546.1 [(M-t-Bu)+H]+, 502.1 [(M-Boc)+H]+.

1. stirringthe reaction stirred for a further 20 hours at room temperature
2. temperatureThe mixture was then heated to 50° C.
3. stirringbefore stirring for 20 hours
4. customThe volatiles were evaporated under reduced pressure
5. stirringThe resulting mixture was stirred at room temperature for 5 hours
6. temperatureheated to 50° C. for 16 hours
7. customThe volatiles were evaporated under reduced pressure
8. additionthe residue diluted with water
9. extractionThe aqueous solution was extracted with EtOAc (2×20 mL)
10. customThe resulting precipitate was collected as a pellet by centrifugation
11. dissolutionthen dissolved in methanol
12. concentrationconcentrated under reduced pressure
13. customThe residue was azeotroped with toluene
14. additionwere added
15. stirringThe resulting mixture was stirred at 30° C. for 20 hours before the volatiles
16. customwere evaporated under reduced pressure
17. additionWater (20 mL) was added
18. extractionthe resulting suspension was extracted with EtOAc (3×20 mL)
19. concentrationThe combined organic extracts were concentrated under reduced pressure
20. customthe residue chromatographed on silica gel (0-100% EtOAc/petroleum benzine 40-60° C.

ORD record

ord-e46594a8f5cc416aa24c81ba6fc4aa23

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09120761B2