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

HRID 243437Notes

Reaction equation

HRID 243437 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 122782624-Amino-6-chloropyrimidine-5-carbonitrileHCID 68158079(S)-1-(6-Fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)ethylamine

Product 1

HCID 58459229(S)-4-Amino-6-((1-(6-fluoro-1-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)pyrimidine-5-carbonitrile

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of (S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)ethylamine (80 mg, 0.31 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (51 mg, 0.33 mmol) and DIPEA (0.16 mL, 0.93 mmol) in IPA (0.7 mL) was heated in a sealed tube for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue 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—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to give a pale yellow oil. The residue was taken up in EtOAc and product triturated with cyclohexane. The solid was filtered to afford 348 as an off white solid (31 mg, 26%). LCMS (Method K): RT 3.04 min [M+H]+ 3.75. 1H NMR (DMSO-d6, 400 MHz): δ 8.73 (1H, d, J=2.5 Hz), 8.64 (1H, dd, J=5.0, 1.5 Hz), 8.01-7.98, (1H, m), 7.81 (1H, s), 7.76-7.73 (2H, m), 7.55 (1H, ddd, J=8.0, 5.0, 1.0 Hz), 7.18 (2H, bs), 7.12 (1H, ddd, J=10.0, 9.0, 2.5 Hz), 6.93 (1H, dd, J=7.0, 2.5 Hz), 7.48 (1H, dq, 7.0, 7.0 Hz), 1.55 (3H, d, J=7.0 Hz)

Workup

  1. temperatureAfter cooling to RT
  2. customthe volatiles were removed under reduced pressure
  3. washThe cartridge was washed with MeOH
  4. concentrationconcentrated in vacuo
  5. customthe resulting residue purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM)
  6. customto give a pale yellow oil
  7. customproduct triturated with cyclohexane
  8. filtrationThe solid was filtered

Sources & evidence

ORD record
ord-5d2c547d32054801a2421c7f0c8b02e6
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

Loading…