Diisopropylethylamine → N-(3-fluoropyridin-4-yl)benzamide

Temperatur

80 °C

A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (4.6 g, 14 mmol), 1-benzyl-3,3-difluoropiperidin-4-amine (prepared according to EP2123651 A1, 3.08 g, 13.6 mmol), diisopropylethylamine (6 mL, 34 mmol) in propan-2-ol (100 mL) was heated at 80° C. for 12 hours. The mixture was concentrated, suspended in potassium bisulfate solution (1N, 100 mL), and filtered to yield 7.06 g of a yellow solid (LCMS (Method F, ESI): RT=1.28 min, m+H=528.3). The solid was suspended in ethanol (90 mL) and water (30 mL), iron powder (2.3 g, 41 mmol) and ammonium chloride (3.6 g, 68 mmol) was added, and the mixture was refluxed for 4 hours. The mixture was filtered through CELITE®, thoroughly washing the filter cake with ethanol and ethyl acetate. The filtrate and washings were combined and concentrated under vacuum. The resulting residue was partitioned between ethyl acetate and water, and the organic layer dried with sodium sulfate and concentrated under vacuum. Purification by column chromatography on silica gel (gradient: 0 to 50% (20% methanol in ethyl acetate) in heptanes) affording 4.6 g (68%) of 1-Benzenesulfonyl-N*4*-(1-benzyl-3,3-difluoro-piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine as a purple solid (LCMS (Method F, ESI): RT=0.83 min, m+H=490.3). 1H NMR (400 MHz, DMSO) δ 8.02 (d, J=7.9 Hz, 2H), 7.72-7.62 (m, 2H), 7.57 (t, J=7.7 Hz, 2H), 7.50 (d, J=4.2 Hz, 1H), 7.40-7.22 (m, 5H), 6.82 (d, J=4.2 Hz, 1H), 5.17 (d, J=9.9 Hz, 1H), 4.46 (s, 2H), 4.27-4.08 (m, J=16.0, 13.3, 8.1 Hz, 1H), 3.69-3.52 (m, 2H), 3.04 (dd, J=16.5, 10.6 Hz, 1H), 2.80 (d, J=11.5 Hz, 1H), 2.60-2.42 (m, J=11.9 Hz, 1H), 2.31 (t, J=11.0 Hz, 1H), 1.91 (d, J=13.0 Hz, 1H), 1.85-1.69 (m, 1H).

1. concentrationThe mixture was concentrated
2. filtrationfiltered

ORD-Eintrag

ord-216593ef998b49da96b6ec7d8f51d2f7

Quelldatensatz

uspto-grants-2013_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08461328B2