Diisopropylethylamine → 6-{(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionylamino}-nicotinic acid methyl ester

HRID 18978Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 18978
[CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:24][C:23]2=[O:36])[C:9]([NH:11]C2C=CN(CC(O)(C)C)N=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:70][O:71][C:72](=[O:80])[C:73]1[CH:78]=[CH:77][C:76](N)=[N:75][CH:74]=1>ClCCl>[CH3:70][O:71][C:72](=[O:80])[C:73]1[CH:78]=[CH:77][C:76]([NH:11][C:9](=[O:10])[C@@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=3[F:34])=[CH:24][C:23]2=[O:36])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:75][CH:74]=1

Komponenten

6

Edukt 4

HCID 81531DiisopropylethylamineHCID 737487Methyl 6-aminonicotinateHCID 2733179PyBroPHCID 44253752(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

Produkt 1

HCID 442537556-{(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionylamino}-nicotinic acid methyl esterAusbeute 40 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel2×

Reaktionsbedingungen

Temperatur
25 °C

Versuchsvorschrift

A solution of (S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (prepared in Example 36, 90 mg, 0.25 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (138 mg, 0.30 mmol), N,N-diisopropylethylamine (95 mg, 0.74 mmol) and 6-aminonicotinic acid methyl ester (45 mg, 0.30 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-{(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionylamino}-nicotinic acid methyl ester (49 mg, 40%) as a white solid: LR-ES-MS m/z calculated for C26H27F2N3O5 [M]+ 499, observed [M+H]+ 500; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85-1.35 (m, 6H) 1.49-1.88 (m, 7H) 3.86 (s, 3H) 4.31 (d, J=18.3 Hz, 1H) 4.63 (d, J=18.3 Hz, 1H) 5.03 (m, 1H) 5.07 (s, 1H) 7.30-7.52 (m, 3H) 8.16 (d, J=9.1 Hz, 1H) 8.28 (dd, J=9.1, 2.4 Hz, 1H) 8.87 (d, J=2.4 Hz, 1H) 11.32 (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-d21d17dbedd349218b007709cf3e6db1
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07741327B2

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