N,N'-Dimethylethylenediamine → HCID 68350492, compound

HRID 877751Notes

Reaction equation

HRID 877751 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=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.[O:31]=[C:32]1[C@@H:36]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:35][CH2:34][NH:33]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.CO.ClCCl.[Cu]I>[C:27]([C:8]1[CH:7]=[N:6][N:5]2[CH:30]=[C:2]([N:33]3[CH2:34][CH2:35][C@H:36]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:43])[CH3:42])[C:32]3=[O:31])[CH:3]=[C:4]2[C:9]=1[NH:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH2:13][C:12]1([CH3:25])[CH3:26])(=[O:28])[NH2:29]

Participants

8

Reactant 4

HCID 8070N,N'-DimethylethylenediamineHCID 11430Potassium CarbonateHCID 10750535(S)-tert-Butyl (2-oxopyrrolidin-3-yl)carbamateHCID 68291450HCID 68291450, compound

Product 1

HCID 68350492HCID 68350492, compoundYield 20%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (R)-6-bromo-4-((1-(4-cyanophenyl)-3,3-dimethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.039 mmol), (S)-tert-butyl (2-oxopyrrolidin-3-yl)carbamate (21.6 mg, 0.108 mmol), copper(I) iodide (1.5 mg, 7.70 mmol), potassium carbonate (16.0 mg, 0.116 mmol) in dioxane (0.5 mL) was pumped under vacuum and backfilled with nitrogen twice. N1,N2-dimethylethane-1,2-diamine (8.3 μl, 0.077 mmol) was added. The reaction tube was sealed and heated at 100° C. for 17 h. The mixture was diluted with a 1:1 mixture of methanol-dichloromethane (2 mL) and filtered. The filtrate was concentrated to give crude product (48.3 mg) as brown solid. Part of the material (15.6 mg) was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×100 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water; Mobile Phase B: acetonitrile; Buffer: 20-mM ammonium acetate; Gradient: 15-100% B over 10.9 minutes, then a 4.0 minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give tert-butyl ((S)-1-(3-carbamoyl-4-(((R)-1-(4-cyanophenyl)-3,3-dimethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-2-oxopyrrolidin-3-yl)carbamate (4.4 mg, 20% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.11 (s, 1H), 7.79 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.27 (s, 1H), 6.94 (d, J=8.9 Hz, 2H), 4.41 (t, J=9.4 Hz, 1H), 4.09 (dd, J=10.2, 3.7 Hz, 1H), 3.91-3.72 (m, 3H), 3.57 (d, J=12.9 Hz, 1H), 3.25-3.16 (m, 1H), 2.95 (d, J=13.4 Hz, 1H), 2.66-2.57 (m, 1H), 2.25-2.07 (m, 2H), 1.96-1.84 (m, 1H), 1.44 (s, 9H), 1.16 (s, 3H), 1.08 (s, 3H); MS (ES+) m/z: 587.1 (M+H); LC retention time: 1.78 min (analytical LCMS Method I).

Workup

  1. customThe reaction tube was sealed
  2. filtrationfiltered
  3. concentrationThe filtrate was concentrated
  4. customto give crude product (48.3 mg) as brown solid
  5. customPart of the material (15.6 mg) was purified via preparative LC/MS with the following conditions
  6. customa 4.0 minute hold
  7. additionFractions containing the desired product
  8. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-2a7669d017a84b4f8f18359a0549d149
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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