2-(3-Oxetanylidene)acetonitrile → 2-(3-((1S,3S,4R)-3-(3H-imidazo[1, 2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)oxetan-3-yl)acetonitrile

HRID 1969666Notes

Reaction equation

HRID 1969666 reaction equation
[CH3:1][C@H:2]1[C@@H:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16](COCC[Si](C)(C)C)[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH2:5][C@@H:4]([NH2:27])[CH2:3]1.[O:28]1[CH2:31][C:30](=[CH:32][C:33]#[N:34])[CH2:29]1>CN(C=O)C>[CH:18]1[C:12]2[N:11]3[C:7]([C@@H:6]4[C@H:2]([CH3:1])[CH2:3][C@H:4]([NH:27][C:30]5([CH2:32][C:33]#[N:34])[CH2:31][O:28][CH2:29]5)[CH2:5]4)=[CH:8][N:9]=[C:10]3[CH:15]=[N:14][C:13]=2[NH:16][CH:17]=1

Participants

4

Reactant 2

HCID 533465742-(3-Oxetanylidene)acetonitrile2×HCID 58558094(1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine

Product 1

HCID 585577262-(3-((1S,3S,4R)-3-(3H-imidazo[1, 2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)oxetan-3-yl)acetonitrileYield 47.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (1S,3R,4S)-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (0.605 g, 1.569 mmol, prepared using FFFFF from Preparation #33, GGGGG with Preparation #E.1.1, KKKK with PFPAA, D with NaOH, KK, Y) in DMF (6 mL) was added 2-(oxetan-3-ylidene)acetonitrile (0.298 g, 3.14 mmol, J. Med. Chem. 2010, 53(8), 3227) and the reaction mixture was heated at about 80° C. for about 15 h. 2-(Oxetan-3-ylidene)acetonitrile (0.149 g, 1.569 mmol) was added and the reaction mixture was heated at about 80° C. for about 3.5 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0% to 10% MeOH in DCM. A second purification by silica gel chromatography eluting with 50% to 100% EtOAc in heptane followed by 10% MeOH in DCM yielded 2-(3-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentylamino)oxetan-3-yl)acetonitrile (0.262 g, 33%) as a sticky brown solid: LC/MS (Table 1, Method n) Rt=0.75 min; MS m/z 481 (M+H)+.

Workup

  1. temperaturethe reaction mixture was heated at about 80° C. for about 3.5 h
  2. temperatureThe reaction mixture was cooled to ambient temperature
  3. concentrationconcentrated in vacuo
  4. customthe residue was purified by silica gel chromatography
  5. washeluting with 0% to 10% MeOH in DCM
  6. customA second purification by silica gel chromatography
  7. washeluting with 50% to 100% EtOAc in heptane

Sources & evidence

ORD record
ord-f048fcc0e3a14a6cb54edde61b1e6e48
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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