Diisopropylethylamine → 4-(3-fluoro-4-{[(quinoxalin-2-ylamino)carbonyl]amino}phenoxy)-N-methyl-pyridine-2-carboxamide

HRID 658497ノート

反応式

HRID 658497 の反応式
[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[F:19].ClC(Cl)(O[C:24](=[O:30])OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.[NH2:41][C:42]1[CH:51]=[N:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=1>C1COCC1.CN(C=O)C>[F:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[NH:1][C:24]([NH:41][C:42]1[CH:51]=[N:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=1)=[O:30])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=1

参加物

7

反応物 4

HCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 2245732-AminoquinoxalineHCID 468352194-(4-Amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide

生成物 1

HCID 599874944-(3-fluoro-4-{[(quinoxalin-2-ylamino)carbonyl]amino}phenoxy)-N-methyl-pyridine-2-carboxamide収率 27.5%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
75 °C

実験手順

To a solution of 4-[4-amino-3-(fluoro)phenoxy]-N-methylpyridine-2-carboxamide (150.0 mg, 0.57 mmol) in anhydrous THF (5.7 mL) was added triphosgene (63 mg, 0.21 mmol, 0.37 eq) and diisopropylethyl amine (0.12 mL, 0.69 mmol, 1.2 eq), and the reaction mixture was stirred at 75° C. After 3 h a solution of 2-aminoquinoxaline (83.3 mg, 0.57 mmol, 1.0 eq) in anhydrous DMF (2.8 mL) was added, and the reaction mixture was stirred at 75° C. for 17 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude was absorbed onto silica and purified by MPLC (biotage) eluted with 10% MeOH/EtOAc. Trituration from DCM/MeOH afforded 25.0 mg (10.1%) of the title product as a yellow solid. 1H-NMR (DMSO-d6) δ 11.75 (s, 1H), 10.75 (s, 1H), 8.89 (s, 1H), 8.79 (br q, J=5.1 Hz, 1H), 8.53 (d, J=6.0 Hz, 1H), 8.38 (t, J=9.0 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.82 (d, J=3.9 Hz, 2H), 7.70 to 7.64 (m, 1H), 7.47 to 7.42 (m, 2H), 7.20 (dd, J=5.4, 2.4 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H) 2.78 (d, J=4.8 Hz, 3H); TLC (100% EA), Rf=0.20; MS LC-MS [M+H]+=433), RT=2.86 min.

後処理

  1. stirringthe reaction mixture was stirred at 75° C. for 17 h
  2. customThe reaction mixture was partitioned between EtOAc and water
  3. washthe organic layer was washed with water and brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customThe crude was absorbed onto silica
  8. custompurified by MPLC (biotage)
  9. washeluted with 10% MeOH/EtOAc

出典と根拠

ORDレコード
ord-1aa21a0cfe914306b2f5c7f20f58c455
出典データセット
uspto-grants-2011_12
特許番号
US08076488B2

反応ノート

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