Nitrogen → 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(4-(3-oxo-4-morpholinyl)phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 1408961Notes

Reaction equation

HRID 1408961 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)O1.[NH2:23][C@@:24]1([CH3:45])[CH2:28][CH2:27][C@@H:26]([NH:29][C:30]2[C:31]3[N:32]([CH:39]=[C:40](Br)[CH:41]=3)[N:33]=[CH:34][C:35]=2[C:36]([NH2:38])=[O:37])[C:25]1([CH3:44])[CH3:43].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>CN(C=O)C.CO.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:23][C@@:24]1([CH3:45])[CH2:28][CH2:27][C@@H:26]([NH:29][C:30]2[C:31]3[N:32]([CH:39]=[C:40]([C:9]4[CH:10]=[CH:11][C:12]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][C:16]5=[O:21])=[CH:13][CH:14]=4)[CH:41]=3)[N:33]=[CH:34][C:35]=2[C:36]([NH2:38])=[O:37])[C:25]1([CH3:44])[CH3:43]

Participants

9

Reactant 4

HCID 947NitrogenHCID 62657Potassium Phosphate, TribasicHCID 682922884-((1R,3 S)-3-amino-2,2,3-trimethylcyclopentylamino)-6-bromopyrrolo[1,2-b]-pyridazine-3-carboxamide2×HCID 692342734-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one

Product 1

HCID 682924254-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(4-(3-oxo-4-morpholinyl)phenyl)pyrrolo[1,2-b]pyridazine-3-carboxamide

Reagents, catalysts & solvents 4

HCID 7611Bis(eta-cyclopentadienyl) ironCatalystHCID 167845palladium(II) acetateCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
93 °C

Procedure

A solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one (31.9 mg, 0.105 mmol), 4-((1R,3S)-3-amino-2,2,3-trimethylcyclopentylamino)-6-bromopyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 48, 20 mg, 0.053 mmol), 1,1′-bis(di-t-butyl/diphenylphosphino) ferrocene (2.495 mg, 5.26 μmol), palladium (II) acetate (1.181 mg, 5.26 μmol) and dibasic potassium phosphate (0.079 mL, 0.158 mmol) in DMF (0.5 mL) was purged with N2 for 5 min. The reaction mixture was sealed and heated at 93° C. for 120 min. The reaction mixture was cooled and diluted with methanol and filtered. The filtrate was purified by prep HPLC [Column: YMC 20×100; Mobil phase: B in A: 20%-100% (A: 10% MeOH in H2O with 0.1% TFA, B: 90% MeOH in H2O with 0.1% TFA; gradient time: 15 min., hold time: 5 min] to afford the title compound, assumed to be TFA salt (7.2 mg, 0.012 mmol, 23.18% yield) as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 8.19 (1 H, s), 8.02 (1 H, d, J=1.54 Hz), 7.73-7.87 (2 H, m), 7.42 (2 H, d, J=8.58 Hz), 7.25 (1 H, d, J=1.54 Hz), 4.72 (1 H, t, J=9.02 Hz), 4.31 (2 H, s), 4.00-4.13 (2 H, m), 3.76-3.86 (2 H, m), 2.42-2.65 (1 H, m), 2.11-2.24 (1 H, m), 2.00-2.10 (1 H, m), 1.77-1.92 (1 H, m), 1.50 (3 H, s), 1.18 (3H, s), 1.08 (3H, s). HPLC (condition F): ret. Time 3.143 min.; LC/MS [m/z, (M+H)] 477.1.

Workup

  1. customThe reaction mixture was sealed
  2. temperatureThe reaction mixture was cooled
  3. filtrationfiltered
  4. customThe filtrate was purified by prep HPLC [Column
  5. custom15 min.

Sources & evidence

ORD record
ord-973a1e8af5984d408bc27f728f845e87
Source dataset
uspto-grants-2014_12
Patent number
US08921368B2

Reaction notes

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