Potassium Fluoride → methyl (2S)-3-[4-(3-amino-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanoate

Temperature

95 °C

Butyl di-1-adamantylphosphine (1.07 g, 2.98 mmol), Pd(OAc)2 (0.33 mg, 1.49 mmol), dioxane (12 mL) and water (2.4 mL) were added to an oven-dried flask and stirred for 10 minutes. 3-bromo-5-methylaniline (1.58 g, 8.51 mmol), methyl (2S)-2-hydroxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate (3.5 g, 10.64 mmol), and potassium fluoride (1.24 g, 21.3 mmol) were added followed by additional dioxane (12 mL). The mixture was heated to 95° C. overnight then cooled to room temperature, filtered and diluted with water. The mixture was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 80% EtOAc/hexanes) to afford methyl (2S)-3-[4-(3-amino-5-methylphenyl)-1H-pyrazol-1-yl]-2-hydroxypropanoate. MS ESI calcd. for C14H18N3O3 [M+H]+ 276. found 276. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.67 (s, 1H), 6.51 (s, 2H), 6.21 (s, 1H), 5.90 (d, J=6.1 Hz, 1H), 4.93 (s, 2H), 4.43 (tt, J=4.6 Hz, 9.2 Hz, 1H), 4.36 (d, J=4.2 Hz, 1H), 4.27-4.21 (m, 1H), 3.63 (s, 3H), 2.14 (s, 3H).

1. temperaturethen cooled to room temperature
2. filtrationfiltered
3. additiondiluted with water
4. extractionThe mixture was extracted with EtOAc (3×)
5. washthe combined organic layers were washed with brine
6. dry with materialdried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe residue was purified by column chromatography on silica gel (0 to 80% EtOAc/hexanes)

ORD record

ord-b985566fb09b4c0ea7577fcf454c6140

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09242984B2