Diisopropylethylamine → 2-Amino-4-{(S)-1-[6-fluoro-1-(5-fluoro-pyridin-3-yl)-1H-benzoimidazol-2-yl]-ethylamino}-6-methyl-pyrimidine-5-carbonitrile

HRID 243447Notes

Reaction equation

HRID 243447 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]=[C:17]([F:19])[CH:18]=3)[C:6]=2[CH:20]=1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:21][C:22]1[N:27]=[C:26]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:6]3[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 68157511(S)-1-[6-Fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]ethylamineHCID 754124462-Amino-4-chloro-6-methyl-5-pyrimidinecarbonitrile

Product 1

HCID 681573402-Amino-4-{(S)-1-[6-fluoro-1-(5-fluoro-pyridin-3-yl)-1H-benzoimidazol-2-yl]-ethylamino}-6-methyl-pyrimidine-5-carbonitrileYield 15%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 3776IsopropanolSolvent

Procedure

A mixture of (S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]-ethylamine.2HCl (165 mg, 0.48 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (60 mg, 0.36 mmol) and DIPEA (315 μL, 1.82 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 18 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 0-100% EtOAc in cyclohexane) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-75%, 0.1% NH4OH in acetonitrile/water) to afford 364 as a white solid (21 mg, 15%). LCMS (Method K): RT 3.04 min [M+H]+ 407.04. 1H NMR (DMSO-d6, 400 MHz): δ 8.66 (1H, d, J=2.64 Hz), 8.61 (1H, d, J=1.63 Hz), 8.02 (1H, d, J=9.22 Hz), 7.77 (1H, dd, J=8.80, 4.84 Hz), 7.55 (1H, d, J=7.75 Hz), 7.15 (1H, ddd, J=9.84, 8.79, 2.50 Hz), 7.07 (1H, dd, J=8.96, 2.48 Hz), 7.05-6.58 (2H, m), 5.53 (1H, m), 2.18 (3H, s), 1.54 (3H, d, J=6.75 Hz)

Workup

  1. washThe cartridge was washed with MeOH
  2. concentrationconcentrated in vacuo
  3. customthe resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-a5834edd048e444c98cc6cecf9959a67
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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