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 1046029ノート

反応式

HRID 1046029 の反応式
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]

参加物

6

反応物 4

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

生成物 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-carboxamide収率 65%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

実験手順

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+).

後処理

  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)

出典と根拠

ORDレコード
ord-bf846f068dfb48fdb86f700566e91ff7
出典データセット
uspto-grants-2013_10
特許番号
US08569319B2

反応ノート

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