1-Hydroxybenzotriazole → tert-Butyl 3-(4-((4-(2-(3-(2-amino-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

1-Hydroxybenzotriazole (20 mg, 0.15 mmol), EDCI.HCl (32 mg, 0.17 mmol) and N,N-diisopropylethylamine (45 μL, 0.26 mmol) were added to a solution of 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetic acid (I149) (29 mg, 0.051 mmol) in dry DMF (5 mL) under an atmosphere of nitrogen. Ammonium carbonate (50 mg, 0.52 mmol) was added in one portion after 10 minutes then stirring was continued at room temperature for 17 hours. Further portions of 1-hydroxybenzotriazole (20.0 mg, 0.15 mmol), EDCI.HCl (32 mg, 0.17 mmol) and N,N-diisopropylethylamine (45 μL, 0.26 mmol) were added, then ammonium carbonate (50 mg, 0.52 mmol) was added in one portion after 10 min. The resulting solution was stirred at 25° C. for 24 hours. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate (10 mL) and saturated sodium hydrogen carbonate (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL) then the combined organic layers were washed with brine (10 mL), dried (MgSO4) and evaporated to dryness. The residue was chromatographed (Biotage Isolera: 10 g silica cartridge, 0-100% EtOAc/petroleum benzine 40-60° C. then 10 g silica cartridge, 50-100% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I150) (0.023 g, 77%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.46 (dd, J=4.8, 1.6 Hz, 1H), 7.77 (br s, 1H), 7.57-7.44 (m, 3H), 7.19 (d, J=8.5 Hz, 2H), 7.14 (dd, J=7.6, 4.8 Hz, 1H), 5.63 (d, J=22.0 Hz, 2H), 4.35-3.96 (m), 3.67 (s, 2H), 3.41-3.33 (m, 2H), 3.27 (t, J=6.9 Hz, 2H), 2.83-2.58 (m, 3H), 2.01-1.99 (m, 1H), 1.80-1.71 (m, 1H), 1.68 (s, 3H), 1.65-1.52 (m, 2H), 1.46 (s, 9H).

1. stirringThe resulting solution was stirred at 25° C. for 24 hours
2. customThe volatiles were removed in vacuo
3. customthe residue was partitioned between ethyl acetate (10 mL) and saturated sodium hydrogen carbonate (10 mL)
4. extractionThe aqueous layer was extracted with ethyl acetate (2×10 mL)
5. washthe combined organic layers were washed with brine (10 mL)
6. dry with materialdried (MgSO4)
7. customevaporated to dryness
8. customThe residue was chromatographed (Biotage Isolera

ORD record

ord-4d1492ceaddc4326a2ee78e0e473e62f

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012461B2