Hydrochloric Acid → Bortezomib

HRID 525289

Reaktionsgleichung

Reaktionsgleichung von HRID 525289
[O:1]1CCNCC[O:3][B:2]1[C@@H:9]([NH:14][C:15](=[O:33])[C@@H:16]([NH:24][C:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH:11]([CH3:13])[CH3:12].Cl>CO>[B:2]([OH:3])([OH:1])[C@@H:9]([NH:14][C:15]([C@@H:16]([NH:24][C:25]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:33])[CH2:10][CH:11]([CH3:13])[CH3:12]

Komponenten

4

Edukt 2

HCID 313Hydrochloric AcidHCID 53327095(2S)-N-[(1R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl]-3-phenyl-2-(pyrazin-2-ylformamido)propanamide

Produkt 1

HCID 387447BortezomibAusbeute 82,3 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 887MethanolLösungsmittel

Versuchsvorschrift

A 100 ml three neck round bottom flask is equipped with a stir bar, thermocouple and nitrogen inlet/outlet then charged with 5.0 g (10.4 mmol) of (2S)—N-[(1R)-1-(1,3,6,2-dioxazaborocan-2-yl)-3-methylbutyl]-3-phenyl-2-(pyrazin-2-ylformamido)propanamide (i.e., diethanolamine ester of bortezomib), 50 ml of methanol and 10.4 ml of 2N aqueous hydrochloric acid. The reaction is stirred at room temperature overnight before removing the solvent in vacuo at 40° C. The resulting residue is dissolved in 50 ml of ethyl acetate and washed with saturated sodium bicarbonate (1×50 mL) before once again concentrating the organic layer to dryness in vacuo. The residue is then triturated overnight at room temperature with 50 mL of pentane under nitrogen. The resulting free flowing solids are collected by vacuum filtration, washed with pentane (1×20 ml) then dried in a vacuum oven at 30° C. overnight to provide 3.29 g (8.56 mmol, 82.3%) of the title compound as a white solid with chemical purity >99.8 A % and a 93.5:6.5 ratio of diastereomers (i.e., 87% de). 1H NMR (d4-MeOH, 400 MHz) δ 9.15 (d, 1H, J=1.36 Hz), 8.77 (d, 1H, J=2.48 Hz), 8.68 (dd, 1H, J=1.52, 2.44 Hz), 7.27 (m, 4H), 7.21 (m, 1H), 5.05 (t, 1H, J=7.68 Hz), 3.2 (m, 2H), 2.66 (t, 1H, J=7.56 Hz), 1.39 (m, 1H), 1.17 (t, 2H, J=7.12 Hz), 0.83 (dd, 6H, J=5.32, 6.40 Hz).

Aufarbeitung

  1. custombefore removing the solvent in vacuo at 40° C
  2. dissolutionThe resulting residue is dissolved in 50 ml of ethyl acetate
  3. washwashed with saturated sodium bicarbonate (1×50 mL)
  4. concentrationbefore once again concentrating the organic layer to dryness in vacuo
  5. customThe residue is then triturated overnight at room temperature with 50 mL of pentane under nitrogen
  6. filtrationare collected by vacuum filtration
  7. washwashed with pentane (1×20 ml)
  8. customthen dried in a vacuum oven at 30° C. overnight

Quellen und Nachweise

ORD-Eintrag
ord-36ec0a7b8eba41389780ff6ccdedcc2e
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09340559B2

Verknüpfte Notizen

Wird geladen…