Water → Trifluoroacetic acid

HRID 1748222Notes

Reaction equation

HRID 1748222 reaction equation
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]

Participants

7

Reactant 4

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

Product 2

HCID 6422Trifluoroacetic acidHCID 67985078HCID 67985078, compound

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
200 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-12c70c17d18445aba0921472310978a4
Source dataset
uspto-grants-2015_10
Patent number
US09150568B2

Reaction notes

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