Cesium carbonate → 4-amino-6-[[(1S)-1-[7-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-1-methyl-benzimidazol-2-yl]ethyl]amino]pyrimidine-5-carbonitrile

HRID 243506Notes

Reaction equation

HRID 243506 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]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:34][CH2:35][O:36][CH2:37][CH:38]=2)O1.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]([CH3:18])[C:16]3[C:19]([C:33]4[CH2:38][CH2:37][O:36][CH2:35][CH:34]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 112180533,6-Dihydro-2H-pyran-4-boronic acid pinacol esterHCID 681575724-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile

Product 1

HCID 681582864-amino-6-[[(1S)-1-[7-(3,6-dihydro-2H-pyran-4-yl)-6-fluoro-1-methyl-benzimidazol-2-yl]ethyl]amino]pyrimidine-5-carbonitrileYield 15.6%

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-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (122 mg, 0.31 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (85 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium (36 mg, 10 mol %) and caesium carbonate (204 mg, 0.63 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 0-100% EtOAc in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-75%, 0.1% NH4OH in acetonitrile/water) to afford 432 as a white solid (19 mg, 15%). LCMS (Method K): RT 2.79 min [M+H]+ 394.16. 1H NMR (DMSO-d6, 400 MHz): δ 8.07 (1H, s), 7.69 (1H, m), 7.55 (1H, dd, J=8.76, 4.82 Hz), 7.30 (2H, br s), 7.04 (1H, dd, J=10.42, 8.75 Hz), 5.87 (1H br s), 5.70 (1H, m), 4.24 (2H, s), 3.86 (2H, m), 3.73 (3H, s), 2.45-2.23 (2H, m), 1.58 (3H, d, J=6.72 Hz)

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 0-100% EtOAc in DCM)

Sources & evidence

ORD record
ord-eab5b26fbc12433696851c0426fad923
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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