Triethylamine → 7-(4-Bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amide

HRID 500570ノート

反応式

HRID 500570 の反応式
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13]([CH3:20])=[N:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[C:21](O)=[O:22])=[C:4]([Cl:24])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH:42]([O:44][CH2:45][CH2:46][O:47][NH2:48])=[CH2:43].CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH:42]([O:44][CH2:45][CH2:46][O:47][NH:48][C:21]([C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([F:19])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:24])[N:16]=[CH:15][N:14]=[C:13]2[CH3:20])=[O:22])=[CH2:43]

参加物

8

反応物 5

HCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 21867017O-(2-(Vinyloxy)ethyl)hydroxylamineHCID 686372087-(4-Bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid

生成物 1

HCID 865986407-(4-Bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amide収率 44%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 8857Ethyl Acetate溶媒

実験手順

To a solution of 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (47 mg, 0.11 mmol) in DMF (2 mL) was added HOBt (26.0 mg, 0.170 mmol), Et3N (0.060 mL, 0.044 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (15 mg, 0.15 mmol), and EDCI (30 mg, 0.16 mmol) at room temperature. The resulting solution was stirred for 7 days at room temperature. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (1.5 to 2% MeOH in CH2Cl2) to afford 24 mg (42%) of 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amide. To a solution of the vinyl ether (24.0 mg, 0.048 mmol) in EtOH (2 mL) was added 1 N aqueous HCl (0.21 mL) at room temperature. After stirring for 3 hours at room temperature, pH of the reaction mixture was adjusted to 6 to 7 with 1 N aqueous NaOH, and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (5 to 10 to 20% MeOH in CH2Cl2 with 1% Et3N) to afford 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-hydroxyethoxy)-amide (5 mg, 22%). MS APCI (−) m/z 467, 469 (M-, Br, Cl pattern) detected; 1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 8.38 (s, 1H), 7.60 (d, 1H), 7.35 (dd, 1H), 6.86 (dd, 1H), 4.10 (t, 2H), 3.81 (t, 2H), 2.99 (s, 3H).

後処理

  1. washwashed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customto give the crude material which
  6. customwas purified by silica gel flash column chromatography (1.5 to 2% MeOH in CH2Cl2)

出典と根拠

ORDレコード
ord-ed6b9eec41f648da8f9212d4ceb5a231
出典データセット
uspto-grants-2010_08
特許番号
US07772234B2

反応ノート

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