Trifluoroacetic acid → HCID 68158045, compound

HRID 243476Notes

Reaction equation

HRID 243476 reaction equation
C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:21]([C:22]2[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[C:20]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:19]=2[N:18]=1)[CH3:16])(C)(C)C.[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39](Cl)[N:38]=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CC(O)C>[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39]([NH:14][C@H:15]([C:17]2[N:21]([C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)[C:20]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:19]=3[N:18]=2)[CH3:16])[N:38]=[CH:37][N:36]=1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 122782624-Amino-6-chloropyrimidine-5-carbonitrileHCID 68157081HCID 68157081, compound

Product 1

HCID 68158045HCID 68158045, compoundYield 54%

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent

Procedure

TFA (1 mL) was added to a stirring solution of {(S)-1-[6-fluoro-1-(1-methyl-1H-pyrazol-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (126 mg, 0.35 mmol) in DCM (3 mL). After stirring at RT for 3 h, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to give a brown oil. A mixture of this residue, 4-amino-6-chloropyrimidine-5-carbonitrile (60 mg, 0.39 mmol) and DIPEA (205 μL, 1.17 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) followed by trituration with EtOAc to afford 402 as a white solid (71 mg, 54% over 2 steps). LCMS (Method K): RT 3.27 min [M+H]+ 378.04. 1H NMR (DMSO-d6, 400 MHz): δ 7.97 (1H, s), 7.91 (1H, d, J=2.31 Hz), 7.73 (1H, dd, J=8.66, 4.85 Hz), 7.61 (1H, d, J=7.64 Hz), 7.25 (2H, s), 7.17-7.08 (2H, m), 6.54 (1H, d, J=2.31 Hz), 5.77-5.67 (1H, m), 3.89 (3H, s), 1.52 (3H, d, J=6.87 Hz)

Workup

  1. washThe cartridge was washed with MeOH
  2. concentrationconcentrated in vacuo
  3. customto give a brown oil
  4. temperaturewas heated at 90° C. in a sealed vial for 16 h
  5. temperatureAfter cooling to RT
  6. washThe cartridge was washed with MeOH
  7. concentrationconcentrated in vacuo
  8. customthe resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc)

Sources & evidence

ORD record
ord-8833bd96fbd24922a7023ff5247d8b35
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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