N,N'-Dimethylethylenediamine → HCID 88948489, compound

HRID 877722Notes

Reaction equation

HRID 877722 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=4)[CH2:13][C:12]3([CH3:26])[CH3:25])=[C:8]([C:27]([NH2:29])=[O:28])[CH:7]=[N:6][N:5]2[CH:30]=1.[F:31][C:32]([F:37])([F:36])[C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[C:23]([C:20]1[N:19]=[N:18][C:17]([N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:9]3[C:4]4[N:5]([CH:30]=[C:2]([NH:35][C:33](=[O:34])[C:32]([F:37])([F:36])[F:31])[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:27]([NH2:29])=[O:28])[C:12]([CH3:25])([CH3:26])[CH2:13]2)=[CH:22][CH:21]=1)#[N:24]

Participants

7

Reactant 4

HCID 8070N,N'-DimethylethylenediamineHCID 11430Potassium CarbonateHCID 67717TrifluoroacetamideHCID 68290695HCID 68290695, compound

Product 1

HCID 88948489HCID 88948489, compound

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
92.5 °C

Procedure

A mixture of 6-bromo-4-(1-(6-cyanopyridazin-3-yl)-3,3-dimethylpiperidin-4-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 4 of Example 1 (20 mg, 0.043 mmol), 2,2,2-trifluoroacetamide (9.6 mg, 0.085 mmol), copper(I) iodide (1.6 mg, 8.52 μmol), potassium carbonate (11.8 mg, 0.085 mmol) and N1,N2-dimethylethane-1,2-diamine (10 μl, 0.094 mmol) in dioxane (0.5 mL) was pumped and backfilled with nitrogen twice. The reaction vial was sealed and stirred at 90-95° C. for 16 h. LCMS analysis showed the reaction was ˜40% complete. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 20-55% B over 25 minutes, then a 15-minute hold at 55% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound, assumed as TFA salt (4 mg, 15% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.11 (1 H, s), 7.96 (1 H, d, J=1.66 Hz), 7.55-7.58 (1 H, m), 7.15-7.21 (2 H, m), 4.22 (1 H, d, J=13.04 Hz), 4.17 (1 H, dd, J=10.40, 3.75 Hz), 3.42-3.51 (1 H, m), 3.20 (1 H, d, J=13.87 Hz), 2.24 (1 H, dd, J=13.87, 3.61 Hz), 1.85-1.94 (1 H, m), 1.11 (3 H, s), 1.10 (3 H, s); MS (ES+) m/z: 502.13 (M+H); LC retention time: 2.225 min (analytical HPLC Method C).

Workup

  1. customThe reaction
  2. customvial was sealed
  3. customThe crude material was purified via preparative LC/MS with the following conditions
  4. waitGradient: 15-100% B over 25 minutes
  5. customa 5-minute hold
  6. additionFractions containing the desired product
  7. customdried via centrifugal evaporation
  8. customThe material was further purified via preparative LC/MS with the following conditions
  9. waitGradient: 20-55% B over 25 minutes
  10. customa 15-minute hold
  11. additionFractions containing the desired product
  12. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-d8251db214df481db9d74c4becc995a3
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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