Triethylamine → N-(4-(2-[bis[(1,1-dimethylethoxy)carbonyl]amino]-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide

HRID 1046029Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1046029
S(Cl)(Cl)=O.[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:10](=[O:21])[C:9]=1[C:22](Cl)=[O:23])[CH3:6].[NH2:25][C:26]1[C:59]([F:60])=[CH:58][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:32]=2[C:52]2[CH:53]=[N:54][N:55]([CH3:57])[CH:56]=2)=[C:28]([F:61])[CH:27]=1.CCN(CC)CC>C1COCC1>[CH3:50][C:48]([CH3:51])([O:47][C:45]([N:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:33]1[C:32]([C:52]2[CH:53]=[N:54][N:55]([CH3:57])[CH:56]=2)=[C:31]([O:30][C:29]2[C:28]([F:61])=[CH:27][C:26]([NH:25][C:22]([C:9]3[C:10](=[O:21])[N:11]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[CH:12]=[CH:13][C:8]=3[O:7][CH2:5][CH3:6])=[O:23])=[C:59]([F:60])[CH:58]=2)[CH:36]=[CH:35][N:34]=1)=[O:46])[CH3:49]

Komponenten

6

Edukt 4

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 67468806HCID 67468806, VerbindungHCID 866675054-Ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride

Produkt 1

HCID 68009418N-(4-(2-[bis[(1,1-dimethylethoxy)carbonyl]amino]-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamideAusbeute 65 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel2×

Versuchsvorschrift

Using the method of Example 4, thionyl chloride (5 mL) and Example B2 (0.19 g, 0.7 mmol) were combined to prepare 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride as a solid. This solid was dissolved in THF (3 mL) and added to a solution of Example A6 (0.18 g, 0.35 mmol) and Et3N (0.2 ml, 1.4 mmol) in THF (3 mL). The resultant mixture was stirred at RT for 2 h. The mixture was partitioned between EtOAc (20 mL) and sat aq NaHCO3 (30 mL). The aqueous layer was further extracted with EtOAc (15 ml) and the combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc-hexanes) to afford N-(4-(2-[bis[(1,1-dimethylethoxy)carbonyl]amino]-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide as colorless foam (175 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 8.33 (dd, J=12.7 Hz, 7.2 Hz, 1H), 8.20 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 7.48 (m, 4H), 7.36 (t, J=8.8 Hz, 2H), 6.83 (d, J=5.6 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 3.86 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.26 (s, 18H); MS (ESI) m/z: 777.2 (M+H+).

Aufarbeitung

  1. customThe mixture was partitioned between EtOAc (20 mL)
  2. extractionThe aqueous layer was further extracted with EtOAc (15 ml)
  3. washthe combined organics were washed with brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by silica gel chromatography (EtOAc-hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-bf846f068dfb48fdb86f700566e91ff7
Quelldatensatz
uspto-grants-2013_10
Patentnummer
US08569319B2

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