Diisopropylethylamine → (S)-4-Amino-6-((1-(6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)pyrimidine-5-carbonitrile

HRID 243403Notes

Reaction equation

HRID 243403 reaction equation
C(O[C:6](=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=2)[C:13]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.[NH2:28][C:29]1[C:34]([C:35]#[N:36])=C(Cl)[N:32]=[CH:31][N:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.CC(O)C.CO>[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:6]([NH:7][C@H:8]([C:10]2[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=3)[C:13]3[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=3[N:11]=2)[CH3:9])[N:32]=[CH:31][N:30]=1

Participants

8

Reactant 3

HCID 81531DiisopropylethylamineHCID 122782624-Amino-6-chloropyrimidine-5-carbonitrileHCID 68157791{(S)-1-[6-Fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester

Product 1

HCID 58459115(S)-4-Amino-6-((1-(6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)pyrimidine-5-carbonitrile

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 3776IsopropanolSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

A mixture of {(S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (165 mg, 0.44 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford a yellow oil. A mixture of this residue, 4-amino-6-chloropyrimidine-5-carbonitrile (68 mg, 0.44 mmol) and DIPEA (230 mL, 1.32 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 0-100% EtOAc in cyclohexane) followed by trituration from EtOAc/cyclohexane/Et2O to afford 277 as an off white solid (73 mg, 42% over 2 steps). 1H NMR (DMSO-d6, 400 MHz): δ 8.66 (1H, d, J=2.64 Hz), 8.62 (1H, s), 8.11-8.03 (1H, m), 7.83 (1H, s), 7.78-7.73 (2H, m), 7.26-7.04 (4H, m), 5.64-5.54 (1H, m), 1.58 (3H, d, J=6.77 Hz). LCMS (Method K): RT 3.40 min [M+H]+ 393

Workup

  1. washwashed with MeOH
  2. concentrationconcentrated in vacuo
  3. customto afford a yellow 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 0-100% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-c8a3c5fceb22427a8ca8df0d72056854
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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