反应详情

Under N2, crude sunitinib (98.5 g, 0.247 mol, 1.0 eq. 99.2% by HPLC) and MeOH (3113 g, 3940 mL, 40 P w.r.t. crude sunitinib) were charged into a flask with a mechanical stirrer and a thermometer at ambient temperature. The heterogeneous mixture was stirred for 30 min at ambient temperature and L-malic acid (34.8 g, 0.259 mol, 1.05 eq.) was added at about 25° C. The mixture turned clear after 5 to 30 min and was vacuum filtered. The filtrate was stirred for 8 h at about 25° C. The mixture was vacuum filtered at ambient temperature, washed with MeOH (156 g, 197 mL, 2 P w.r.t. crude sunitinib) and dried in vacuo (relative vacuum NLT 0.095 MPa) at about 40° C. for 15 to 18 h to give 118.0 g of crude sunitinib malate with 99.5% purity by HPLC analysis and 0.40% by LOD in 90% yield. m.p. 195.0 to 196.0° C. Under N2, DMSO (506 g, 460 mL, 4 P w.r.t. crude sunitinib malate) was charged into a flask with a mechanical stirrer and a thermometer at ambient temperature and heated to about 45° C. for 5 to 10 min. Crude Sunitinib malate (115 g, 0.216 mol, 1.0 eq.) was charged and DMSO (64 g, 58 mL, 4 P w.r.t. crude sunitinib malate) was used to assist the transformation and after 5 to 10 min the mixture almost turn clear and was vacuum filtered. MIBK (1104 g, 1380 mL, 12 P w.r.t. crude sunitinib malate) was charged into the flask, and the solution was allowed to cool about 20° C. and was stirred for a further 30 h at about 20° C. The mixture was vacuum filtered and washed with MIBK (368 g, 460 mL, 4 P w.r.t crude sunitinib malate) and dried in vacuo (relative vacuum NLT 0.095 MPa) at about 40° C. for 30 to 40 h to give 98.1 g of pure sunitinib malate as a yellow powder with 99.8% purity by HPLC analysis and 0.27% by LOD in 85.3% yield. No individual impurities were present at greater than 0.10% by HPLC analysis. 1H NMR (300 MHz, DMSO-d6) δ: 0.98 (t, 6H, J=7.2 Hz, CH3), 2.31˜2.38 (dd,1H, J=5.8 Hz, 15.75 Hz, CH2), 2.43, 2.45 (s. 6H, CH3), 2.56˜2.62 (m, 1H, CH2), 3.03˜3.12 (m, 6H, 3*CH2), 3.51˜3.55 (t, 3H, CH2), 3.95˜3.99 (dd, 1H, CH).

1. customat ambient temperature
2. waitThe mixture turned clear after 5 to 30 min
3. filtrationfiltered
4. stirringThe filtrate was stirred for 8 h at about 25° C
5. filtrationfiltered at ambient temperature
6. washwashed with MeOH (156 g, 197 mL, 2 P w.r.t. crude sunitinib)
7. customdried in vacuo (relative vacuum NLT 0.095 MPa) at about 40° C. for 15 to 18 h