Tetrahydrofuran → 2-(3-Chloro-4-fluorophenyl)-N5-(2-(3,3-difluorocyclobutyl)propan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide

Temperature

70 °C

To a stirred solution of Intermediate 226B (18.14 mg, 0.102 mmol) in toluene (1 mL) at RT under nitrogen was added TEA (0.043 mL, 0.305 mmol), DPPA (0.047 mL, 0.204 mmol) and the mixture was heated at 70° C. for 2 h. The reaction mass was cooled to RT and to it was added a solution of Intermediate 185B (30 mg, 0.102 mmol) in THF (1 mL) and stirred for 16 h. The reaction mass was diluted with EtOAc (5 mL), the organic layer was separated, washed successively with a 10% aqueous solution of NaHCO3, water and brine, then dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford Compound 226 as a pale yellow solid (20 mg, 41% yield). HPLC retention times are 1.528 min. and 1.525 min. (Methods E and L respectively). MS(ES): m/z=470.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (d, J=7.28 Hz, 1H), 7.63-7.71 (m, 1H), 7.47 (d, J=9.29 Hz, 1H), 7.12-7.4 (bs, 2H), 6.21 (s, 1H), 4.68 (s, 2H), 4.12 (s, 2H), 3.79 (s, 2H) 2.65-2.83 (m, 1H), 2.27-2.47 (m, 4H), 1.23 (s, 6H).

1. temperatureThe reaction mass was cooled to RT and to it
2. customthe organic layer was separated
3. washwashed successively with a 10% aqueous solution of NaHCO3, water and brine
4. dry with materialdried over Na2SO4
5. filtrationfiltered
6. concentrationthe filtrate concentrated under reduced pressure
7. customThe crude product was purified by preparative HPLC

ORD record

ord-06ed7a873a854dc2828fab0f853a4b15

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09273058B2