Cesium carbonate → HCID 178461950, compound

HRID 243505Notes

Reaction equation

HRID 243505 reaction equation
Br[C:2]1[C:7]2[N:8]([CH3:23])[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:24].[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>[F:24][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])[N:8]([CH3:23])[C:7]=2[C:2]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 66827Phenylboronic AcidHCID 178461925N-[(1S)-1-(7-bromo-6-fluoro-1-methyl-benzimidazol-2-yl)ethyl]-9H-purin-6-amine

Product 1

HCID 178461950HCID 178461950, compoundYield 76%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
140 °C

Procedure

A mixture of [(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine, (0.10 g, 0.26 mmol), phenylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 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 minutes, then heated for 45 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-10% (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 431 as a white solid (0.075 g, 76%). LCMS (Method K): RT 3.21 min [M+H]+ 388.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.98 (1H, s), 8.26-8.11 (2H, m), 7.93-7.86 (1H, m), 7.64 (1H, dd, J=8.82, 4.74 Hz), 7.54-7.39 (5H, m), 7.15-7.08 (1H, m), 5.82-5.71 (1H, m), 3.21 (3H, s), 1.65 (3H, d, J=6.74 Hz). Signals split due to presence of tautomers

Workup

  1. customwas placed in a sealed tube
  2. customdegassed with nitrogen for 5 minutes
  3. washthen washed with MeOH
  4. washthe product eluted with 2M NH3/MeOH
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by chromatography (SiO2, 0-10% (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-3e9167e3dff34bbaafa3ec23e4265773
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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