Pivalic acid → (R)-4-((1-cyclobutylethyl)amino)-2-(4-isopropylpyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile

HRID 81086

Reaction equation

HRID 81086 reaction equation
C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C(O)(=O)C(C)(C)C.[F-].[Cs+].Br[C:36]1[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[CH:39]=[CH:38][N:37]=1.[CH:45]1([C@H:49]([NH:51][C:52]2[C:57]3[N:58]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([C:68]([F:71])([F:70])[F:69])=[CH:64][CH:63]=4)[CH:59]=[N:60][C:56]=3[C:55]([CH3:72])=[C:54]([C:73]#[N:74])[N:53]=2)[CH3:50])[CH2:48][CH2:47][CH2:46]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:45]1([C@H:49]([NH:51][C:52]2[C:57]3[N:58]([CH2:61][C:62]4[CH:63]=[CH:64][C:65]([C:68]([F:71])([F:70])[F:69])=[CH:66][CH:67]=4)[C:59]([C:36]4[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[CH:39]=[CH:38][N:37]=4)=[N:60][C:56]=3[C:55]([CH3:72])=[C:54]([C:73]#[N:74])[N:53]=2)[CH3:50])[CH2:48][CH2:47][CH2:46]1

Participants

8

Reactant 5

HCID 6417Pivalic acidHCID 25953Cesium fluorideHCID 11371790Bis(adamantan-1-yl)(butyl)phosphaneHCID 457879862-Bromo-4-isopropylpyridineHCID 86724464(R)-4-((1-cyclobutylethyl)amino)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile

Product 1

HCID 86724465(R)-4-((1-cyclobutylethyl)amino)-2-(4-isopropylpyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
70 °C

Procedure

To a vial containing palladium(II) acetate (4.3 mg, 0.019 mmol) and butyldi-1-adamantylphosphine (13.9 mg, 0.039 mmol) was added 1,4-dioxane (300 ul). The vial was evacuated and refilled with Ar (3×). The solution was warmed to 70° C. for 20 minutes. In a separate vial were combined pivalic acid (9.9 mg, 0.097 mmol), cesium fluoride (44 mg, 0.29 mmol), 2-bromo-4-isopropylpyridine (purchased from CombiPhos Catalysts, Inc.) (29 mg, 0.15 mmol), (R)-4-((1-cyclobutylethyl)amino)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (40 mg, 0.097 mmol) and 1,4-dioxane (0.5 mL). The mixture was degassed with Ar for 15 minutes, and the catalyst solution was added to the mixture. The resulting mixture was stirred at 130° C. for 3 days. The mixture was cooled to room temperature and concentrated. The residue was dissolved in DCM and purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to give (R)-4-((1-cyclobutylethyl)amino)-2-(4-isopropylpyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C30H31F3N6 [M+H]+ 533. found 533.

Workup

  1. customThe vial was evacuated
  2. additionrefilled with Ar (3×)
  3. customThe mixture was degassed with Ar for 15 minutes
  4. additionthe catalyst solution was added to the mixture
  5. temperatureThe mixture was cooled to room temperature
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in DCM
  8. custompurified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient)

Sources & evidence

ORD record
ord-25ba329731bc4cecab261f438551a9a2
Source dataset
uspto-grants-2014_09
Patent number
US08846657B2

Linked notes

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