Trifluoroacetic acid → (3S,4S)-benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate

HRID 1487331Notes

Reaction equation

HRID 1487331 reaction equation
[NH2:1][C@H:2]1[C@@H:6]([CH2:7][F:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(O)(C(F)(F)F)=O.[Br:26][C:27]1[N:28]=[C:29]2[C:34](Cl)=[C:33]([C:36]([NH2:38])=[O:37])[CH:32]=[N:31][N:30]2[CH:39]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:26][C:27]1[N:28]=[C:29]2[C:34]([NH:1][C@H:2]3[C@@H:6]([CH2:7][F:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:3]3)=[C:33]([C:36](=[O:37])[NH2:38])[CH:32]=[N:31][N:30]2[CH:39]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 68350298(3S,4S)-benzyl 3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylateHCID 899954732-Bromo-8-chloro-imidazo[1,2-b]pyridazine-7-carboxamide

Product 1

HCID 89995462(3S,4S)-benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylateYield 98%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

A solution of (3S,4S)-benzyl 3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylate, TFA (468 mg, 1.278 mmol) and 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (352 mg, 1.278 mmol), DIEA (1116 μl, 6.39 mmol) in DMA (5110 μl) was heated at 80° C. for 7 hrs. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate solution was washed with saturated NaCl, dried with sodium sulfate, filtered, and concentrated to yield a brown oil. The crude product was purified by flash column (ISCO 12 g, 0-100% EtOAc/hexane) to afford (3S,4S)-benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (615.6 mg, 1.253 mmol, 98% yield) as a faint yellow solid. ESI-MS (analytical LCMS Method B): m/z 493.2 ([M+H]+). HPLC (analytical HPLC Method B) Rt: 3.148 min.

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate and water
  2. washThe ethyl acetate solution was washed with saturated NaCl
  3. dry with materialdried with sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto yield a brown oil
  7. customThe crude product was purified by flash column (ISCO 12 g, 0-100% EtOAc/hexane)

Sources & evidence

ORD record
ord-3107c108a26040bf9c4175f2c5154345
Source dataset
uspto-grants-2016_08
Patent number
US09428511B2

Reaction notes

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