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 1046029노트

반응식

HRID 1046029 반응식
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]

참가 물질

6

반응물 4

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

생성물 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-carboxamide수율 65%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매2회

실험 절차

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+).

후처리

  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)

출처 및 근거

ORD 기록
ord-bf846f068dfb48fdb86f700566e91ff7
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08569319B2

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