Hydrochloric Acid → Bortezomib

HRID 1625687

Reaktionsgleichung

Reaktionsgleichung von HRID 1625687
[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)propanamide2×

Produkt 1

HCID 387447BortezomibAusbeute 82,3 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 887MethanolLösungsmittel

Versuchsvorschrift

A 100 ml three neck round bottom flask was 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)propan-amide (i.e., Compound 13), 50 ml of methanol and 10.4 ml of 2N aqueous hydrochloric acid. The reaction was stirred at room temperature overnight before removing the solvent in vacuo at 40° C. The resulting residue was dissolved in 50 ml of ethyl acetate and washed with saturated sodium bicarbonate (1×50 mL) before once again concentrating the organic to dryness in vacuo. The residue was then triturated overnight at room temperature with 50 mL of pentane under nitrogen. The resulting free flowing solids were 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. HPLC analysis indicated 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 was dissolved in 50 ml of ethyl acetate
  3. washwashed with saturated sodium bicarbonate (1×50 mL)
  4. concentrationbefore once again concentrating the organic to dryness in vacuo
  5. customThe residue was then triturated overnight at room temperature with 50 mL of pentane under nitrogen
  6. filtrationwere 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-327043a320de4557aabb4cc30ecb9dbd
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08785418B2

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