Water → (4-{3-[(1S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1,3-dimethyl-1H-pyrazol-5-yl)methanol

HRID 2095666

Reaktionsgleichung

Reaktionsgleichung von HRID 2095666
Br[C:2]1[C:3]([CH3:11])=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([OH:9])=O.C1COCC1.B.C1COCC1.[Cl:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[C:25]=1[C@H:33]([C:35]1[C:43]2[C:38](=[N:39][CH:40]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:42]=2)[NH:37][CH:36]=1)[CH3:34].C([O-])([O-])=O.[K+].[K+].O>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[C:25]=1[C@H:33]([C:35]1[C:43]2[C:38](=[N:39][CH:40]=[C:41]([C:2]3[C:3]([CH3:11])=[N:4][N:5]([CH3:10])[C:6]=3[CH2:7][OH:9])[CH:42]=2)[NH:37][CH:36]=1)[CH3:34]

Komponenten

9

Edukt 6

HCID 962WaterHCID 8028Tetrahydrofuran2×HCID 11430Potassium CarbonateHCID 2723981Borane;tetrahydrofuranHCID 27798334-bromo-1,3-dimethyl-1H-pyrazole-5-carboxylic acidHCID 670040713-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

Produkt 1

HCID 54674985(4-{3-[(1S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1,3-dimethyl-1H-pyrazol-5-yl)methanol

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

To a solution of 4-bromo-1,3-dimethyl-1H-pyrazole-5-carboxylic acid (20.0 mg, 0.0913 mmol) in THF (3 mL, 30 mmol) was added 1.0 M of BH3.THF in THF (0.456 mL, 0.456 mmol), and the mixture was heated to 60° C. overnight. The material was extracted with EtOAc, and washed with sat. NaHCO3 (3×). The organic layer was concentrated in vacuo. 3-[(S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (15.0 mg, 0.0348 mmol), (1,1′bis-(diphenylphosphino)-ferrocene) palladium dichloride (3.34 mg, 0.00456 mmol), K2CO3 (18.9 mg, 0.137 mmol) and 4:1 dioxane:H2O (1 mL, 10 mmol) were added, and the mixture was heated to 95° C. for 30 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.80 (d, J=7.1 Hz, 3H), 2.04 (s, 3H), 3.64 (br. s., 3H), 3.89 (s, 3H), 4.46 (s, 2H), 5.05-5.15 (m, 1H), 6.88 (dd, J=9.1, 4.3 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.38 (br. s., 1H), 8.07 (d, J=2.0 Hz, 1H). MS (ES+): m/z=429.14/431.15 (100/50) [MH+]. HPLC: tR=1.38 min (polar—3 min, UPLC-ACQUITY).

Aufarbeitung

  1. extractionThe material was extracted with EtOAc
  2. washwashed with sat. NaHCO3 (3×)
  3. concentrationThe organic layer was concentrated in vacuo
  4. temperaturethe mixture was heated to 95° C. for 30 min
  5. customThe solution was used directly for HPLC purification
  6. additionthe fractions containing the pure product
  7. concentrationwere concentrated in vacuo

Quellen und Nachweise

ORD-Eintrag
ord-ad417f4751f04a6393e7d99cfeec59a3
Quelldatensatz
uspto-grants-2013_05
Patentnummer
US08445510B2

Verknüpfte Notizen

Wird geladen…