1-Hydroxybenzotriazole → HCID 71229372, compound

Lithium hydroxide mono hydrate (43.0 mg, 1.03 mmol) was added to a suspension of methyl 2-(2-(2-(2-((4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I78) (211 mg, 0.344 mmol) in THF (10 mL), MeOH (1.0 mL) and water (1.5 mL) and the resulting mixture was stirred at room temperature for 16 hours. The organics were removed in vacuo then 2 M aqueous NaOH solution (100 mL) was added. The resulting solution was extracted with EtOAc (2×100 mL), then the combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to yield a white solid. The solid was dissolved in dry THF (10 mL) and dry DMF (2 mL) under an atmosphere of nitrogen. To this solution were added 1-hydroxybenzotriazole (72 mg, 0.53 mmol), EDCl (101 g, 0.529 mmol) and N,N-diisopropylethylamine (246 μL, 1.41 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (203 mg, 2.12 mmol) was added in one portion and the reaction was stirred at room temperature for 3 days. The volatiles were removed in vacuo and the residue was taken up in EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL). The combined organic layers were washed with water (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo to give a yellow solid which was dissolved in a small amount of acetone and precipitated with petroleum benzine 40-60° C. to yield the title compound (I79) (138 mg, 65%) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.44 (s, 1H), 7.27-7.12 (m, 4H), 6.96-6.81 (m, 4H), 3.58 (d, J=12.7 Hz, 2H), 3.50 (s, 2H), 3.15-2.93 (m, J=15.2, 6.3 Hz, 4H), 2.67 (t, J=12.0 Hz, 2H), 1.79 (d, J=11.4 Hz, 2H), 1.55-1.42 (m, 2H), 1.39 (s, 9H). LCMS Method C: rt 5.30 min; m/z 599 [M+H]+.

1. customThe organics were removed in vacuo
2. addition2 M aqueous NaOH solution (100 mL) was added
3. extractionThe resulting solution was extracted with EtOAc (2×100 mL)
4. dry with materialthe combined organic extracts were dried (MgSO4)
5. customthe solvent removed in vacuo
6. customto yield a white solid
7. stirringthe resulting mixture was stirred at room temperature for 10 minutes
8. stirringthe reaction was stirred at room temperature for 3 days
9. customThe volatiles were removed in vacuo
10. customThe layers were separated
11. extractionthe aqueous layer was extracted with EtOAc (70 mL)
12. washThe combined organic layers were washed with water (2×100 mL), brine (50 mL)
13. dry with materialdried (MgSO4)
14. concentrationconcentrated in vacuo
15. customto give a yellow solid which
16. customprecipitated with petroleum benzine 40-60° C.

ORD record

ord-aa80767914584d9a9a0e0785d8db73b5

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09421205B2