Water → Trifluoroacetic acid

HRID 1748222ノート

反応式

HRID 1748222 の反応式
Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1.[CH:16]12[NH:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([O:24][CH2:25][C:26]1[C:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][C:41]([F:44])([F:43])[F:42])=[N:28][O:29][C:30]=1[CH:31]1[CH2:33][CH2:32]1)[CH2:17]2.[F-].[K+].O>CN1C(=O)CCC1>[CH:31]1([C:30]2[O:29][N:28]=[C:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][C:41]([F:42])([F:43])[F:44])[C:26]=2[CH2:25][O:24][CH:18]2[CH2:17][CH:16]3[N:23]([C:2]4[CH:3]=[CH:4][C:5]5[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=5)[N:7]=4)[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH2:32][CH2:33]1.[C:11]([OH:13])([C:41]([F:42])([F:43])[F:44])=[O:12]

参加物

7

反応物 4

HCID 962WaterHCID 522689Potassium FluorideHCID 2779714ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylateHCID 67983256HCID 67983256、化合物

生成物 2

HCID 6422Trifluoroacetic acidHCID 67985078HCID 67985078、化合物

試薬・触媒・溶媒 1

HCID 13387N-methyl-2-pyrrolidone溶媒

反応条件

温度
200 °C

実験手順

To a suspension of commercially available ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (II Farmaco, 1997, 52, 4, 213) (66 mg, 0.255 mmol) in NMP (2.5 mL) was added 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (I-1) (120 mg, 0.29 mmol) and potassium fluoride (51 mg, 0.88 mmol). The mixture was heated at 200° C. for 30 minutes under microwave irradiation. The mixture was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified using mass-triggered reverse phase HPLC using gradient of 40 to 60% acetonitrile/water with 0.05% TFA as modifier to yield ethyl 6-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-b]pyridazine-2-carboxylate as TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.67 (d, J=10.0 Hz, 1H), 7.54 (dd, J=7.6 and 2.0 Hz, 1H), 7.51 (dd, J=7.6 and 0.8 Hz, 1H), 7.40-7.37 (m, 2H), 6.72 (d, J=10.0 Hz, 1H), 4.43 (q, J=7.2 Hz, 4H), 4.32 (bs, 2H), 4.28 (bs, 2H), 3.48 (m, 1H), 2.14-2.07 (m, 1H), 2.05-1.86 (m, 6H), 1.69 (bs, 1H), 1.65 (bs, 1H), 1.42 (t, J=7.2 Hz, 3H), 1.25-1.20 (m, 2H), 1.13-1.08 (m, 2H). MS m/z 598.2 (M+1).

後処理

  1. extractionextracted with ethyl acetate twice
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was purified

出典と根拠

ORDレコード
ord-12c70c17d18445aba0921472310978a4
出典データセット
uspto-grants-2015_10
特許番号
US09150568B2

反応ノート

読み込み中…