Hydrochloric Acid → HCID 86712697, compound

HOBt (0.036 g, 0.27 mmol), EDCl.HCl (0.052 g, 0.27 mmol) and DIPEA (0.18 mL, 1.0 mmol) were added to a solution of 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)-4-methylphenyl)acetic acid (A89) (0.12 g, 0.21 mmol) in dry THF (6 mL) and dry DMF (1 mL) under a nitrogen atmosphere. After 10 minutes ammonium carbonate (0.10 g, 1.0 mmol) was added in one portion and the resulting mixture stirred at room temperature for 20 hours. The volatiles were removed in vacuo and the residue dried under high vacuum. The resulting residue was taken up in dry THF (5 mL) and dry DMF (4 mL) under a nitrogen atmosphere and HOBt (0.036 g, 0.27 mmol), EDCl.HCl (0.052 g, 0.27 mmol) and DIPEA (0.18 mL, 1.0 mmol) were added. After 10 minutes ammonium carbonate (0.10 g, 1.0 mmol) was added in one portion and the resulting mixture was stirred at 25° C. for 22 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (65 mL) and saturated aqueous NaHCO3 (65 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, the volatiles removed in vacuo and the residue absorbed onto silica gel and purified by column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A90 as a white solid (0.106 g, 86%); 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.88 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.13 (d, J=7.6 Hz, 1H), 7.08-7.01 (m, 2H), 5.78 (s, 1H), 5.47 (s, 1H), 4.39-4.15 (m, 2H), 3.66 (s, 2H), 3.04 (apparent s, 4H), 2.79 (t, J=12.2 Hz, 2H), 2.62 (tt, J=12.0, 3.3 Hz, 1H), 2.32 (s, 3H), 1.81 (d, J=12.7 Hz, 2H), 1.60 (qd, J=12.8, 4.2 Hz, 2H), 1.48 (s, 9H). LCMS-A: rt 6.63 min; m/z 598.4 [M+H]+.

1. customThe volatiles were removed in vacuo
2. customthe residue dried under high vacuum
3. stirringthe resulting mixture was stirred at 25° C. for 22 hours
4. customThe volatiles were removed in vacuo
5. customthe residue was partitioned between EtOAc (65 mL) and saturated aqueous NaHCO3 (65 mL)
6. customThe layers were separated
7. extractionthe aqueous layer was extracted with EtOAc (2×50 mL)
8. washThe combined organic layers were washed with brine (50 mL)
9. dry with materialdried over MgSO4
10. customthe volatiles removed in vacuo
11. customthe residue absorbed onto silica gel
12. custompurified by column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

ORD record

ord-c4f2a079ac934ffc8153cfac8388d010

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09266864B2