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

HRID 243498Notes

Reaction equation

HRID 243498 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.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=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]([CH3:18])[C:16]3[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=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 66827Phenylboronic AcidHCID 681575724-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile

Product 1

HCID 681576434-amino-6-[[(1S)-1-(6-fluoro-1-methyl-7-phenyl-benzimidazol-2-yl)ethyl]amino]pyrimidine-5-carbonitrileYield 58%

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, (0.10 g, 0.26 mmol), phenylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.013 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 min, then heated for 30 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH then the product eluted with 2M NH3/MeOH. then concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-7% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water). The relevant fractions were concentrated to approximately ⅓ volume and partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give 424 as a white solid (0.058 g, 58%). LCMS (Method K): RT 3.55 min [M+H]+ 388.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.03 (1H, s), 7.66-7.62 (2H, m), 7.52-7.41 (5H, m), 7.30 (2H, s), 7.13 (1H, m), 5.61 (1H, m), 3.15 (3H, s), 1.57 (3H, d, J=6.72 Hz)

Workup

  1. customwas placed in a sealed tube
  2. customdegassed with nitrogen for 5 min
  3. washwashed with MeOH
  4. washthe product eluted with 2M NH3/MeOH
  5. concentrationthen concentrated in vacuo
  6. customThe resulting residue was purified by chromatography (SiO2, 0-7% (2M ammonia in methanol) in DCM)
  7. customC18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water
  8. concentrationThe relevant fractions were concentrated to approximately ⅓ volume
  9. custompartitioned between DCM (3×) and saturated aqueous NaHCO3
  10. dry with materialThe combined DCM extracts were dried (Na2SO4)
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-4972710f6cf64eb1bf688ad3de2ba047
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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