Diisopropylethylamine → (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 73732

Reaktionsgleichung

[NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Br:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[C:21]([CH:36]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)=[O:23]>CC(O)C.CCOC(C)=O>[Br:16][C:17]1[C:18]([N:1]2[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]2)=[N:19][CH:20]=[C:21]([CH:36]=1)[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:33])[F:35])=[CH:29][CH:30]=1)=[O:23]

Komponenten

Reaktionsbedingungen

Temperatur: 140 °C

Versuchsvorschrift

(R)-Pyrrolidin-3-ol (17.1 ml, 211.2 mmol) and DIPEA (67.6 ml, 387.6 mmol) were added to a suspension of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.3, 69.6 g, 175.9 mmol) in iPrOH (120 mL) and stirred at 140° C. for 1 h. The mixture was diluted with EtOAc (1 L), washed with 1N HCl (2×200 mL), a sat. solution of NaHCO3 (200 mL) and brine (2×200 mL) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the product was crystallized from EtOAc/iPr2O to afford the title compound as a white crystalline solid. HPLC (Condition 5) tR=6.58 min, UPLC-MS (Condition 6) m/z=446.0/448.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.01 (m, 2H) 3.55 (d, J=11.34 Hz, 1H) 3.64-3.76 (m, 1H) 3.79-3.91 (m, 2H) 4.33 (br. s, 1H) 4.97 (d, J=3.13 Hz, 1H) 7.33 (d, J=9.38 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.30-8.36 (m, 1H) 8.66 (d, J=2.35 Hz, 1H) 10.20 (s, 1H).

Aufarbeitung

washwashed with 1N HCl (2×200 mL)
dry with materiala sat. solution of NaHCO3 (200 mL) and brine (2×200 mL) and dried over Na2SO4
customThe solvent was evaporated off under reduced pressure
customthe product was crystallized from EtOAc/iPr2O

Quellen und Nachweise

ORD-Eintrag: ord-55e5d26bf6d543718ec07beca625a5f9
Quelldatensatz: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patentnummer: US08829195B2

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