Binap, (A+-)- → N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-1-(piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

HRID 1522612Notes

Reaction equation

HRID 1522612 reaction equation
I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:3]=12.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:70][C:71]1[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][C:72]=1[C:78]1[CH:83]=[C:82]([NH2:84])[CH:81]=[CH:80][N:79]=1.CC(C)([O-])C>O1CCOCC1.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:70][C:71]1[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][C:72]=1[C:78]1[CH:83]=[C:82]([NH:84][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[N:9][N:10]([CH:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)[C:3]=23)[CH:81]=[CH:80][N:79]=1

Participants

8

Reactant 4

HCID 634876Binap, (A+-)-2×HCID 45749132-Methylpropan-2-olateHCID 674695782-(2-Fluoro-5-methylphenyl)pyridin-4-amineHCID 67470458tert-Butyl 4-(7-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)piperidine-1-carboxylate

Product 1

HCID 54670503N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-1-(piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineYield 63%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

tert-Butyl 4-(7-iodo-1H-pyrazolo[4,3-b]pyridin-1-yl)piperidine-1-carboxylate (57.0 mg, 0.067 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (41.4 mg, 0.067 mmol), 2-(2-fluoro-5-methylphenyl)pyridin-4-amine (40.4 mg, 0.200 mmol) and t-butoxide (17.91 mg, 0.186 mmol) were dissolved in dioxane (3 mL) and sparged with N2. Palladium(II) acetate (29.9 mg, 0.133 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (41.4 mg, 0.067 mmol) were added next and the mixture was heated at 120° C. for 2 hours. The reaction was cooled to room temperature and diluted with methanol. This mixture was filtered and the filtrate was purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 15-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to give N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-1-(piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (17 mg, 32%)

Workup

  1. customsparged with N2
  2. temperatureThe reaction was cooled to room temperature
  3. filtrationThis mixture was filtered
  4. customthe filtrate was purified by preparative HPLC
  5. washeluting with a gradient of 15-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA)

Sources & evidence

ORD record
ord-38c9781ce8d74613a07b1857674aa8db
Source dataset
uspto-grants-2015_07
Patent number
US09073918B2

Reaction notes

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