Diisopropylethylamine → 1-(2,2-Dimethylpropyl)-5-[2-(isoxazol-3-ylcarbonyl)-2-azabicyclo[2.2.2]-oct-5-en-5-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

HRID 629867Notes

Reaction equation

HRID 629867 reaction equation
[CH:1]12[CH2:25][CH2:24][CH:4]([C:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:23])[C:14](=[O:22])[N:15]([CH2:16][CH:17]5[CH2:19][C:18]5(F)F)[C:10]4=[CH:9][CH:8]=3)=[CH:6]1)[CH2:3][NH:2]2.[O:26]1[CH:30]=[CH:29][C:28]([C:31]([OH:33])=O)=[N:27]1.[CH3:34]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1>[CH3:34][C:17]([CH3:18])([CH3:19])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([C:5]3[CH:4]4[CH2:24][CH2:25][CH:1]([CH:6]=3)[N:2]([C:31]([C:28]3[CH:29]=[CH:30][O:26][N:27]=3)=[O:33])[CH2:3]4)=[CH:8][CH:9]=2)[N:13]([CH3:23])[C:14]1=[O:22]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 112864533-Isoxazolecarboxylic acidHCID 71128767HCID 71128767, compound

Product 1

HCID 711367461-(2,2-Dimethylpropyl)-5-[2-(isoxazol-3-ylcarbonyl)-2-azabicyclo[2.2.2]-oct-5-en-5-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

5-(2-Azabicyclo[2.2.2]oct-5-en-5-yl)-1-[(2,2-difluorocyclopropyl)-methyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (6-3, 40 mg, 0.12 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 21 mg, 0.18 mmol, 1.5 equiv), DIPEA (64 μL, 0.36 mmol, 3.0 equiv) and HATU (69 mg, 0.18 mmol, 1.5 equiv) were added to anhydrous 1,4-dioxane (12 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 2-7 as a white solid. MS m/z (M+H): calculated=442.1685; observed=442.1682. 1H NMR δ (ppm)(CHCl3-d): 8.41 (1H, dd, J=27.39, 1.68 Hz), 7.26-7.21 (1H, m), 7.18 (1H, dd, J=8.10, 1.54 Hz), 6.99 (1H, ddd, J=22.62, 6.35, 2.02 Hz), 6.70 (1H, dd, J=12.85, 1.68 Hz), 5.56-5.52 (0.4H, m), 5.41 (0.6H, m), 4.24-4.16 (1H, m), 3.95 (0.4H, dd, J=11.04, 2.28 Hz), 3.90-3.84 (1H, m), 3.75 (1H, dd, J=15.06, 7.88 Hz), 3.62 (0.6H, dd, J=12.35, 2.29 Hz), 3.58-3.52 (0.4H, m), 3.48 (3H, d, J=3.78 Hz), 3.36 (0.6H, d, J=12.38 Hz), 2.22-2.11 (1H, m), 2.05-1.9 (1H, m), 1.91-1.80 (1H, m), 1.61-1.46 (3H, m), 1.29-1.24 (1H, m). (Mixture of rotamers at RT)

Workup

  1. customconsumption of starting material
  2. customPurification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O)

Sources & evidence

ORD record
ord-5372c47ffab440849c889212fa8abb49
Source dataset
uspto-grants-2016_04
Patent number
US09315518B2

Reaction notes

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