Trifluoroacetic acid → HCID 178461936, compound

HRID 243477Notes

Reaction equation

HRID 243477 reaction equation
C(O)(C(F)(F)F)=O.C(O[C:13](=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.ClC1[N:43]=[CH:42][N:41]=[C:40]2[C:36]=1[N:37]=[CH:38][N:39]2C1CCCCO1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CC(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:19]2[N:18]=[C:17]([C@@H:15]([NH:14][C:13]3[N:43]=[CH:42][N:41]=[C:40]4[C:36]=3[N:37]=[CH:38][NH:39]4)[CH3:16])[N:21]([C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)[C:20]=2[CH:28]=1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 977406-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineHCID 68157081HCID 68157081, compound

Product 1

HCID 178461936HCID 178461936, compoundYield 50%

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 (187 mg, 0.52 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, 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (126 mg, 0.53 mmol) and DIPEA (280 μL, 1.59 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 24 h. After cooling to RT, 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, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) followed by trituration with EtOAc to afford 403 as a pale brown solid (98 mg, 50% over 2 steps). LCMS (Method K): RT 2.84 min [M+H]+ 378.03. 1H NMR (DMSO-d6, 400 MHz): δ 8.21-8.11 (2H, m), 7.94-7.81 (2H, m), 7.75-7.66 (1H, m), 7.19-7.08 (2H, m), 6.61 (1H, d, J=2.29 Hz), 5.89-5.73 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=6.84 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 24 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 DCM)

Sources & evidence

ORD record
ord-1219479ec8f0461ab7fd46ff1f6dc603
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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