反应详情

The title compound was prepared according to a procedure similar to that described in Procedure G Into a 8-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 2-(5-methylisoxazol-3-yl)but-3-yn-2-ol (515 mg, 3.41 mmol, 3.50 equiv), 13-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (300 mg, 0.97 mmol, 1 equiv) and Pd(PPh3)2Cl2 (205 mg, 0.29 mmol, 0.3 equiv) in DMSO (2 mL) and triethylamine (2 mL). The final reaction mixture was irradiated with microwave radiation for 2 h at 70° C. The resulting mixture was washed with 1×100 mL of water and 2×100 mL of CH3CN. The solids were collected by filtration. The residue was further purified by Chiral-Prep-HPLC with the following conditions (2#-Gilson Gx 281(HPLC-09): Column, Chiralpak IA2*25 cm, 5 um Chiral-P(IA)004IA00CJ-MB003; Phase A:MTBE Phase B:EtOH (0.2% DEA)-HPLC (10.0% EtOH for 60 min, then down to 0%); Detector, uv 254/220 nm. This resulted in 34.2 mg (9%) of 9-[(S)-3-Hydroxy-3-(5-methyl-isoxazol-3-yl)-but-1-ynyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid LC-MS (ES, m/z): 379[M+H]+; 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.536 (s, 1H), 7.802 (s, 1H), 7.558 (br s, 1H), 7.340-7.300 (m, 1H), 7.143 (br s, 1H), 7.040 (d, 1H), 6.504 (s, 1H), 6.360 (s, 1H), 4.492 (s, 4H), 2.365 (s, 3H), 1.920 (s, 3H).

1. customsealed tube
2. custompurged
3. temperaturemaintained with an inert atmosphere of nitrogen
4. customThe final reaction mixture
5. customwas irradiated with microwave radiation for 2 h at 70° C
6. washThe resulting mixture was washed with 1×100 mL of water and 2×100 mL of CH3CN
7. filtrationThe solids were collected by filtration
8. customThe residue was further purified by Chiral-Prep-HPLC with the following conditions (2#-Gilson Gx 281(HPLC-09): Column, Chiralpak IA2*25 cm, 5 um Chiral-P(IA)004IA00CJ-MB003
9. customThis resulted in 34.2 mg (9%) of 9-[(S)-3-Hydroxy-3-(5-methyl-isoxazol-3-yl)-but-1-ynyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid LC-MS (ES, m/z)