Diisopropylethylamine → 6-[2-[4-(2,6-Difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-nicotinic acid methyl ester

HRID 18979

Reaktionsgleichung

Reaktionsgleichung von HRID 18979
[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:60][O:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66]([NH2:69])=[N:65][CH:64]=1>ClCCl>[CH3:60][O:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66]([NH:69][C:11](=[O:12])[CH:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[CH:6][C:7]2=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:65][CH:64]=1

Komponenten

6

Edukt 4

HCID 81531DiisopropylethylamineHCID 737487Methyl 6-aminonicotinateHCID 2733179PyBroPHCID 668950782-[4-(2,6-Difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid

Produkt 1

HCID 442537566-[2-[4-(2,6-Difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-nicotinic acid methyl esterAusbeute 55 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel2×

Reaktionsbedingungen

Temperatur
25 °C

Versuchsvorschrift

A solution of 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (155 mg, 0.42 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (240 mg, 0.051 mmol), N,N-diisopropylethylamine (165 mg, 0.127 mmol) and 6-aminonicotinic acid methyl ester (80 mg, 0.51 mmol). The reaction mixture was stirred at 25° C. for 18 h under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 6-[2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-nicotinic acid methyl ester (110 mg, 55%), as an off-white solid: LR-ES-MS m/z calculated for C25H25F2N3O6 [M]+ 501, observed [M+H]+ 502; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20-1.95 (m, 7H) 3.11-3.32 (m, 2H) 3.70-3.92 (m, 2H) 3.86 (s, 3H) 4.37 (d, J=18.1 Hz, 1H) 4.64 (d, J=18.1 Hz, 1H) 4.98-5.12 (m, 2H) 7.30-7.51 (m, 3H) 8.13-8.20 (m, 1H) 8.28 (dd, J=8.8, 2.4 Hz, 1H) 8.87 (d, J=2.4 Hz, 1H) 11.33 (s, 1H).

Aufarbeitung

  1. washwashed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution
  2. dry with materiala saturated sodium chloride solution and dried over magnesium sulfate
  3. concentrationThe organic layer was concentrated
  4. customthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-1a44fa3ba5084f518e870f89759fe773
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07741327B2

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