L-Malic Acid → Sunitinib Malate

HRID 84784

Reaktionsgleichung

Reaktionsgleichung von HRID 84784
[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:38])(=[O:37])[C@H:31]([CH2:33][C:34]([OH:36])=[O:35])[OH:32]>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[CH2:33]([C:34]([OH:36])=[O:35])[C@H:31]([OH:32])[C:30]([OH:38])=[O:37]

Komponenten

4

Edukt 2

HCID 222656L-Malic AcidHCID 5329102Sunitinib

Produkt 1

HCID 6456015Sunitinib MalateAusbeute 90 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 887MethanolLösungsmittel

Versuchsvorschrift

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).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-0d356208797946228aca5fd9ed9cede3
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08846953B2

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