Cesium carbonate → 4-amino-6-[[(1S)-1-[1-cyclopropyl-6-fluoro-7-(3-pyridyl)benzimidazol-2-yl]ethyl]amino]pyrimidine-5-carbonitrile

HRID 243488Notes

Reaction equation

HRID 243488 reaction equation
[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21](Br)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 27343783-Pyridinylboronic acidHCID 681578024-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile

Product 1

HCID 681579934-amino-6-[[(1S)-1-[1-cyclopropyl-6-fluoro-7-(3-pyridyl)benzimidazol-2-yl]ethyl]amino]pyrimidine-5-carbonitrileYield 43.7%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of 4-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (68 mg, 0.16 mmol), pyridine-3-boronic acid (26 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium (19 mg, 10 mol %) and caesium carbonate (106 mg, 0.33 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into 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 10-90%, 0.1% NH4OH in acetonitrile/water) to afford 414 as a white solid (29 mg, 43%). LCMS (Method K): RT 2.80 min [M+H]+ 415.06. 1H NMR (CDCl3 400 MHz): δ 8.74 (1H, s), 8.66 (1H, dd, J=4.86, 1.69 Hz), 8.17 (1H, s), 7.86 (1H, s), 7.70 (1H, dd, J=8.79, 4.66 Hz), 7.43 (1H, dd, J=7.83, 4.85 Hz), 7.13 (1H, dd, J=10.24, 8.78 Hz), 6.45-6.14 (1H, br m), 5.97 (1H, m), 5.36 (2H, s), 2.95 (1H, m), 1.70 (3H, d, J=6.73 Hz), 1.02-0.09 (4H, m)

Workup

  1. customwas purged with argon gas
  2. temperatureAfter cooling to RT
  3. additionthe reaction mixture was diluted with MeOH
  4. washThe cartridge was washed with MeOH
  5. concentrationconcentrated in vacuo
  6. customthe resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc)

Sources & evidence

ORD record
ord-13fd85720ebf42c9a64b1c000b2a8630
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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