Water → Trifluoroacetic acid

HRID 1748222노트

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HRID 1748222 반응식
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]

참가 물질

7

반응물 4

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

생성물 2

HCID 6422Trifluoroacetic acidHCID 67985078HCID 67985078, 화합물

시약·촉매·용매 1

HCID 13387N-methyl-2-pyrrolidone용매

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온도
200 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-12c70c17d18445aba0921472310978a4
출처 데이터셋
uspto-grants-2015_10
특허 번호
US09150568B2

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