Potassium Carbonate → 2-[5-(1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl)pyridin-3-yl]-1,1,1-trifluoropropan-2-ol

HRID 1048945Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1048945
[CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[F:13][C:14]([F:27])([F:26])[C:15]([C:18]1[CH:19]=[C:20]([CH:24]=O)[CH:21]=[N:22][CH:23]=1)([OH:17])[CH3:16].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH:1]1([N:4]2[C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=3[N:12]=[C:24]2[C:20]2[CH:19]=[C:18]([C:15]([OH:17])([CH3:16])[C:14]([F:27])([F:13])[F:26])[CH:23]=[N:22][CH:21]=2)[CH2:3][CH2:2]1

Komponenten

8

Edukt 4

HCID 11430Potassium CarbonateHCID 23707502Potassium hydroxy sulfiteHCID 545925541-N-cyclopropyl-5-fluorobenzene-1,2-diamineHCID 867030845-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)pyridine-3-carbaldehyde

Produkt 1

HCID 680535152-[5-(1-cyclopropyl-6-fluoro-1H-benzimidazol-2-yl)pyridin-3-yl]-1,1,1-trifluoropropan-2-ol

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittel2×HCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel2×

Versuchsvorschrift

To a solution of the title compound from Step E (0.058 g, 0.35 mmol) in DMF (1.68 mL) and water (0.06 mL) were added the title compound from Step C (0.076 g, 0.35 mmol) and OXONE® (0.139 g, 0.226 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and water. Solid potassium carbonate was added until the aqueous layer was basic (pH ˜9). Ethyl acetate was then added, and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% acetone in dichloromethane, then 30% acetone in dichloromethane) provided the title compound as a racemic mixture. That racemic mixture was then separated into two enantiomers by HPLC (ChiralCel AS column, 25% MeOH (0.2% DEA)/CO2, 70 mL/min, 100 bar, 35° C.). Data for EXAMPLE 6 (Enantiomer A): LCMS m/z 365.99 [M+H]+; 1 H NMR (500 MHz, CDCl3) δ 9.14 (s, 1 H), 8.85 (s, 1 H), 8.59 (s, 1 H), 7.76 (dd, J=8.8, 4.8 Hz, 1 H), 7.30 (dd, J=8.5, 2.1 Hz, 1 H), 7.11-7.07 (m, 1 H), 4.85 (br s, 1 H), 3.55-3.53 (m, 1 H), 1.79 (s, 3 H), 1.22-1.12 (m, 2 H), 0.80-0.72 (m, 2 H). Data for Example 7 (Enantiomer B): LCMS m/z 365.97 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.16 (s, 1 H), 8.88 (s, 1 H), 8.57 (s, 1 H), 7.76 (dd, J=8.8, 4.8 Hz, 1 H), 7.30 (dd, J=8.5, 2.0 Hz, 1 H), 7.10-7.05 (m, 1 H), 3.91 (br s, 1 H), 3.56-3.55 (m, 1 H), 1.84 (s, 3 H), 1.18-1.15 (m, 2 H), 0.80-0.71 (m, 2 H).

Aufarbeitung

  1. customthe organic layer was separated
  2. washwashed with water and brine
  3. dry with materialdried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification by flash column chromatography on silica gel (10% acetone in dichloromethane

Quellen und Nachweise

ORD-Eintrag
ord-b2cd77cc8a784845af4f77e2004a9892
Quelldatensatz
uspto-grants-2016_07
Patentnummer
US09382226B2

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