Trifluoroacetic acid → (S)-4-(2-amino-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamide

HRID 595934Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 595934
Br[C:2]1[C:3]([NH2:15])=[N:4][CH:5]=[C:6]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[F:16][C:17]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C@@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][OH:24])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:15][C:3]1[C:2]([C:33]2[CH:32]=[CH:31][C:18]([C:19]([NH:21][C@@H:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][OH:24])=[O:20])=[C:17]([F:16])[CH:34]=2)=[CH:7][C:6]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][N:4]=1

Komponenten

8

Edukt 4

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 1180457983-bromo-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amineHCID 123975973(S)-2-fluoro-N-(2-hydroxy-1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Produkt 1

HCID 118045845(S)-4-(2-amino-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamideAusbeute 34,5 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418807HCID 178418807, VerbindungKatalysatorHCID 80711,2-DimethoxyethaneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

To a solution of 3-bromo-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (70 mg, 0.26 mmol) in DME (4 mL) was added (S)-2-fluoro-N-(2-hydroxy-1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (298 mg, 0.77 mmol) and sodium carbonate (0.64 mL, 1.29 mmol). The mixture was purged with nitrogen for 10 min, then PdCl2(dppf)-CH2Cl2 (31.6 mg, 0.039 mmol) was added. The reaction mixture was heated to 120° C. in an oil bath for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography on silicagel (ISCO) eluting with 0-100% ethyl acetate in heptane to give 70 mg crude product, which was purified by HPLC to give (S)-4-(2-amino-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamide (40.8 mg, 0.089 mmol, 34.5% yield) as TFA salt. LCMS (m/z): 450 (MH+), 0.61 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (t, J=7.83 Hz, 1H) 7.77-7.65 (m, 2H) 7.50 (dd, J=11.74, 7.43 Hz, 1H) 7.42-7.36 (m, 4H) 7.33 (d, J=7.43 Hz, 2H) 7.21 (d, J=11.74 Hz, 1H) 5.33 (d, J=4.70 Hz, 1H) 4.08-3.94 (m, 2H) 3.83-3.65 (m, 4H) 1.97 (ddd, J=13.40, 8.12, 5.09 Hz, 2H) 1.72 (d, J=13.69 Hz, 2H) 1.35 (s, 3H)

Aufarbeitung

  1. customThe mixture was purged with nitrogen for 10 min
  2. washwashed with water, brine
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated
  5. customThe resulting residue was purified by flash column chromatography on silicagel (ISCO)
  6. washeluting with 0-100% ethyl acetate in heptane
  7. customto give 70 mg crude product, which
  8. customwas purified by HPLC

Quellen und Nachweise

ORD-Eintrag
ord-c2de10ee74314ecd8c6bc39e078a82b6
Quelldatensatz
uspto-grants-2016_01
Patentnummer
US09242996B2

Notizen zur Reaktion

Wird geladen…