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

HRID 2095664

Reaktionsgleichung

Reaktionsgleichung von HRID 2095664
Br[C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]([OH:10])=O.[NH4+].[Cl-].C[N:14](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[Cl:49][C:50]1[C:55]([F:56])=[CH:54][CH:53]=[C:52]([O:57][CH3:58])[C:51]=1[C@H:59]([C:61]1[C:69]2[C:64](=[N:65][CH:66]=[C:67](B3OC(C)(C)C(C)(C)O3)[CH:68]=2)[NH:63][CH:62]=1)[CH3:60].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:49][C:50]1[C:55]([F:56])=[CH:54][CH:53]=[C:52]([O:57][CH3:58])[C:51]=1[C@H:59]([C:61]1[C:69]2[C:64](=[N:65][CH:66]=[C:67]([C:2]3[CH:6]=[N:5][N:4]([CH3:7])[C:3]=3[C:8]([NH2:14])=[O:10])[CH:68]=2)[NH:63][CH:62]=1)[CH3:60]

Komponenten

11

Edukt 8

HCID 962WaterHCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 6736864-Bromo-1-methyl-1H-pyrazole-5-carboxylic acidHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 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 546749864-{3-[(1S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-methyl-1H-pyrazole-5-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 2

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

Versuchsvorschrift

A mixture of 4-bromo-2-methyl-2H-pyrazole-3-carboxylic acid (20.0 mg, 0.0976 mmol), NH4Cl (52.2 mg, 0.976 mmol), TBTU (62.6 mg, 0.195 mmol), DIPEA (0.170 mL, 0.976 mmol) and DMF (2 mL, 20 mmol) was stirred at rt for 10 min. The material was extracted with EtOAc, and washed with sat. NaHCO3 (3×) to remove carboxylic acid starting material. 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 (3.57 mg, 0.00488 mmol), K2CO3 (20.2 mg, 0.146 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=1.79 (d, J=7.3 Hz, 3H), 3.70 (br. s., 3H), 3.99 (s, 3H), 5.09-5.16 (m, 1H), 6.90 (dd, J=9.2, 4.2 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.34 (s, 1H), 7.50 (s, 1H), 7.59 (br. s., 1H), 8.20 (br. s., 1H). MS (ES+): m/z=428.11/430.12 (100/50) [MH+]. HPLC: tR=1.34 min (polar—3 min, UPLC-ACQUITY).

Aufarbeitung

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

Quellen und Nachweise

ORD-Eintrag
ord-499ff6834bbd4026bdc6f147f7298bbf
Quelldatensatz
uspto-grants-2013_05
Patentnummer
US08445510B2

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