Triethylamine → 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-1-(3-hydroxyazetidin-1-yl)-2-methylbut-3-yn-1-one

To a solution of 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoic acid (100 mg, 0.30 mmol) in DMF (3 mL) was introduced O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (225 mg, 0.59 mmol), azetidin-3-ol hydrochloride (65 mg, 0.59 mmol) and triethylamine (0.12 mL, 0.89 mmol). After 18 hr at RT, the solution was re-treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (225 mg, 0.59 mmol), azetidin-3-ol hydrochloride (65 mg, 0.59 mmol) and triethylamine (0.12 mL, 0.89 mmol). After 3 hr at RT, the reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2×5 mL extractions). The combined organic extracts were washed with water (5 mL) and brine (5 ml), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (DCM containing a 2-10% gradient of methanol) furnished the title compound as a colorless solid: 1H NMR (500 MHz, DMSO) delta 1.64 (3H, s), 2.58 (3H, s), 3.58-3.75 (1H, m), 4.09-4.19 (1H, m), 4.19-4.28 (1H, m), 4.49 (1H, s), 4.63-4.76 (1H, m), 5.67-5.81 (1H, m), 6.14 (1H, d, J=17.5 Hz), 6.98 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.38 (1H, d, J=8.7 Hz), 7.87 (1H, dd, J=8.2, 1.8 Hz), 8.27 (1H, d, J=5.5 Hz), 8.87 (1H, s); LC-MS: m/z=+393.05 (M+H)+.

1. waitAfter 3 hr at RT
2. extractionextracted with EtOAc (2×5 mL extractions)
3. washThe combined organic extracts were washed with water (5 mL) and brine (5 ml)
4. dry with materialdried (Na2SO4)
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customPurification of the residue by silica gel flash column chromatography (DCM containing a 2-10% gradient of methanol)

ORDレコード

ord-376891baaaf1479494aad16b4f74b551

出典データセット

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08901313B2