Trifluoroacetic acid → 2-[4-[5-Amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-2-pyridyl]-2-methyl-propanenitrile

HRID 331512Notes

Reaction equation

HRID 331512 reaction equation
[NH2:1][C:2]1[C:3]([C:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][N:31](C)[C:32](=O)OC(C)(C)C)=[CH:26][CH:25]=3)=[N:21][N:20]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:9]=2)=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([CH3:16])([CH3:15])[C:17]#[N:18])[CH:9]=2)=[N:4][C:3]=1[C:19]1[O:23][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH:31][CH3:32])=[CH:28][CH:29]=2)=[N:21][N:20]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 70819550tert-butyl N-[[4-[5-[3-amino-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate

Product 1

HCID 665634862-[4-[5-Amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-2-pyridyl]-2-methyl-propanenitrileYield 43.32%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

tert-butyl N-[[4-[5-[3-amino-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (199.3 mg, 0.3785 mmol) was dissolved in dichloromethane (5 mL) followed by the addition of trifluoroacetic acid (500 μL, excess). The mixture was stirred at ambient temperature for 2 hours and then concentrated in vacuo to an oil. Azeotroped with dichloromethane/methanol. Compound was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% trifluoroacetic acid in water; solvent B: acetonitrile) over 16 minutes at 25 mL/minutes], combined fractions were then freeze-dried to give 2-[4-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-2-pyridyl]-2-methyl-propanenitrile Compound I-4 as a pale yellow powder (mono trifluoroacetic acid salt) (88.6 mg, 43.32% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.80 (s, 6H), 2.64 (t, J=5.0 Hz, 3H), 4.28 (t, J=5.4 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 8.12 (dd, J=1.5, 5.3 Hz, 1H), 8.25 (d, J=8.3 Hz, 2H), 8.41 (s, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.91 (s, 2H) and 9.18 (s, 1H) ppm; LC/MS m/z 427.0 [M+H]+.

Workup

  1. concentrationconcentrated in vacuo to an oil
  2. customAzeotroped with dichloromethane/methanol
  3. customCompound was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% trifluoroacetic acid in water; solvent B: acetonitrile) over 16 minutes at 25 mL/minutes]
  4. customwere then freeze-dried

Sources & evidence

ORD record
ord-a3d52ca5d698488d817fa933cb04dd9e
Source dataset
uspto-grants-2014_11
Patent number
US08877759B2

Reaction notes

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