反应详情

温度

80 °C

4-[3-chloro-5-(chloroethyl)-6-ethoxy-2-fluorophenyl]-1,3-oxazolidin-2-one (160 mg, 0.50 mmol) (from Step 11) was stirred in N,N-dimethylformamide (21 mL) with cesium carbonate (324 mg, 0.99 mmol) and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (89 mg, 0.60 mmol) was added. The mixture was heated to 80° C. for 1.5 hours and cooled to rt. The mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by preparative LCMS (pH 10) using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) separated the two diastereomers (peak 1 [compound 353] Rt=4.9 min. and peak 2 [compound 354] Rt=5.6 min.); providing compound 354 as the desired single enantiomer, 28 mg, 13%. peak 2: LCMS calculated for C19H21ClFN6O3 (M+H)+: m/z=435.1; found: 435.1. 1H NMR (300 MHz, CD3OD): δ 8.15 (s, 1 H), 7.62 (m, 1 H), 6.31 (m, 1 H), 5.39 (m, 1 H), 4.79 (m, 1 H), 4.40 (m, 1 H), 3.95 (m, 1 H), 3.80 (m, 1 H), 2.60 (s, 3 H), 1.80 (m, 3 H), 1.40 (m, 3 H).

1. additionwas added
2. temperaturecooled to rt
3. extractionextracted with ethyl acetate
4. washThe extracts were washed with brine
5. dry with materialdried over sodium sulfate
6. filtrationfiltered
7. customevaporated
8. customPurification by preparative LCMS (pH 10)
9. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min)
10. customseparated the two diastereomers (peak 1 [compound 353] Rt=4.9 min. and peak 2 [compound 354] Rt=5.6 min.)