Trimethylsilyl iodide → 6-bromo-4-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877761Notes

Reaction equation

HRID 877761 reaction equation
I[Si](C)(C)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14]([NH:15][C@H:16]3[C@@H:20]([CH3:21])[CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH2:17]3)=[C:13]([C:32](=[O:34])[NH2:33])[CH:12]=[N:11][N:10]2[CH:35]=1.BrC1C=C2C(Cl)=C(C(N)=O)C=NN2C=1.N[C@H]1[C@@H](C)CN(C(OCC2C=CC=CC=2)=O)C1>C(#N)C>[Br:6][C:7]1[CH:8]=[C:9]2[C:14]([NH:15][C@H:16]3[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]3)=[C:13]([C:32]([NH2:33])=[O:34])[CH:12]=[N:11][N:10]2[CH:35]=1

Participants

6

Reactant 4

HCID 85247Trimethylsilyl iodideHCID 682911926-Bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamideHCID 68350278(3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylateHCID 68350361(3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate

Product 1

HCID 682908116-bromo-4-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Iodotrimethylsilane (6.23 mL, 45.8 mmol) was added dropwise to a suspension of (3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (8.65 g, 18.31 mmol, prepared by coupling Intermediate 2 and enantiopure Intermediate 5 as previously described in Example 52) in acetonitrile (60 mL). The resulting mixture turned to a homogeneous solution several minutes after completion of addition and gradually turned to brown suspension. After 2 h at room temperature, the resulting mixture was quenched with methanol (10 mL), stirred for 5 min and concentrated in vacuo. The solid residue was diluted with ether (80 mL) and dichloromethane (80 mL), stirred for 30 min and filtered. The filter cake was washed with ether-dichloromethane (1:1 mixture, 160 mL), and dried under vacuum to give the desired 6-bromo-4-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide as yellow powder, assumed as HI salt (10.64 g). 1H NMR (400 MHz, methanol-d4) δ ppm 8.20 (s, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 5.03-4.92 (m, 1H), 3.83-3.72 (m, 1H), 3.67 (dd, J=12.0, 7.8 Hz, 1H), 3.49-3.40 (m, J=2.4 Hz, 1H), 3.14 (t, J=11.3 Hz, 1H), 2.85-2.71 (m, J=7.3 Hz, 1H), 1.25 (d, J=7.0 Hz, 3H); MS (ES+) m/z: 338.0 (M+H); LC retention time: 2.485 min (analytical HPLC Method H).

Workup

  1. customprepared
  2. customturned to a homogeneous solution several minutes
  3. additionafter completion of addition
  4. customthe resulting mixture was quenched with methanol (10 mL)
  5. concentrationconcentrated in vacuo
  6. additionThe solid residue was diluted with ether (80 mL) and dichloromethane (80 mL)
  7. stirringstirred for 30 min
  8. filtrationfiltered
  9. washThe filter cake was washed with ether-dichloromethane (1:1 mixture, 160 mL)
  10. customdried under vacuum

Sources & evidence

ORD record
ord-046249891d8040feb9b44029e07fd2c9
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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