Diisopropylethylamine → 4-Amino-6-[1-(6-fluoro-1-pyridin-4-yl-1H-benzoimidazol-2-yl)-ethylamino]-pyrimidine-5-carbonitrile

HRID 243414Notes

Reaction equation

[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=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.CO>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][CH:10]([C:8]2[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=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

Conditions

Temperature: 90 °C

Procedure

A mixture of 1-(6-fluoro-1-pyridin-4-yl-1H-benzoimidazol-2-yl)ethylamine (55 mg, 0.22 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (33 mg, 0.22 mmol) and DIPEA (115 μL, 0.64 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 reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 296 as a pale beige solid (21 mg, 26%). LCMS (Method K): RT 3.00 min [M+H]+ 375.06. 1H NMR (DMSO-d6, 400 MHz): δ 8.75-8.71 (2H, m), 7.88 (1H, s), 7.79-7.72 (2H, m), 7.65-7.60 (2H, m), 7.24-7.12 (3H, m), 7.06 (1H, dd, J=8.98, 2.49 Hz), 5.65-7.56 (1H, m), 1.57 (3H, d, J=6.77 Hz)

Workup

temperatureAfter cooling to RT
washThe cartridge was washed with MeOH
concentrationconcentrated in vacuo
customthe resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc)

Sources & evidence

ORD record: ord-fe6ce5d9f9074668ab8e0ed2b513bdad
Source dataset: uspto-grants-2014_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08653089B2

Reaction notes

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