Binap, (A+-)- → N-(6-(2,5-difluorophenyl)-2,3-dimethylpyridin-4-yl)-1-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine

HRID 1522625Notes

Reaction equation

HRID 1522625 reaction equation
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.I[C:48]1[CH:53]=[CH:52][N:51]=[C:50]2[CH:54]=[N:55][N:56]([CH2:57][C:58]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=3)[C:49]=12.I[C:67]1[CH:72]=[CH:71][N:70]=[C:69]2[CH2:73][NH:74][N:75]([CH2:76][C:77]3[CH:82]=[CH:81][C:80]([O:83][CH3:84])=[CH:79][CH:78]=3)[C:68]=12.[F:85][C:86]1[CH:91]=[CH:90][C:89]([F:92])=[CH:88][C:87]=1[C:93]1[N:98]=[C:97]([CH3:99])[C:96]([CH3:100])=[C:95]([NH2:101])[CH:94]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C>[F:85][C:86]1[CH:91]=[CH:90][C:89]([F:92])=[CH:88][C:87]=1[C:93]1[N:98]=[C:97]([CH3:99])[C:96]([CH3:100])=[C:95]([NH:101][C:48]2[CH:53]=[CH:52][N:51]=[C:50]3[CH2:54][NH:55][N:56]([CH2:57][C:58]4[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=4)[C:49]=23)[CH:94]=1.[F:85][C:86]1[CH:91]=[CH:90][C:89]([F:92])=[CH:88][C:87]=1[C:93]1[N:98]=[C:97]([CH3:99])[C:96]([CH3:100])=[C:95]([NH:101][C:67]2[C:73]3[C:69](=[CH:68][N:75]([CH2:76][C:77]4[CH:78]=[CH:79][C:80]([O:83][CH3:84])=[CH:81][CH:82]=4)[N:74]=3)[N:70]=[CH:71][CH:72]=2)[CH:94]=1

Participants

9

Reactant 5

HCID 634876Binap, (A+-)-2×HCID 23676156Sodium t-butoxide2×HCID 674695606-(2,5-Difluorophenyl)-2,3-dimethylpyridin-4-amineHCID 674704207-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridineHCID 867043687-iodo-1-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine

Product 2

HCID 67469537N-(6-(2,5-difluorophenyl)-2,3-dimethylpyridin-4-yl)-1-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amineHCID 67469608N-(6-(2,5-difluorophenyl)-2,3-dimethylpyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 1140TolueneSolvent2×

Conditions

Temperature
40 °C

Procedure

Diacetoxypalladium (6.90 mg, 0.031 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (77 mg, 0.123 mmol) were combined in toluene (4 mL) and the solution was stirred at 40° C. for 10 minutes. A mixture of 7-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine and 7-iodo-1-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine (290 mg, 0.794 mmol) in toluene (4 mL), 6-(2,5-difluorophenyl)-2,3-dimethylpyridin-4-amine (72 mg, 0.307 mmol) and sodium 2-methylpropan-2-olate (29.5 mg, 0.307 mmol) were added. The reaction mixture was heated at 100° C. for 20 hours. A further 0.2 eq of diacetoxypalladium, 0.4 eq of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 2 eq of sodium 2-methylpropan-2-olate were added and the reaction heated at 100° C. for 12 hours. The solvent was then evaporated in vacuo to give a residue which was purified via preparative HPLC using a gradient of 5-30% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to give N-(6-(2,5-difluorophenyl)-2,3-dimethylpyridin-4-yl)-1-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and N-(6-(2,5-difluorophenyl)-2,3-dimethylpyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazol[4,3-b]pyridin-7-amine which was used without further purification.

Workup

  1. additionwere added
  2. temperatureThe reaction mixture was heated at 100° C. for 20 hours
  3. temperaturethe reaction heated at 100° C. for 12 hours
  4. customThe solvent was then evaporated in vacuo
  5. customto give a residue which
  6. customwas purified via preparative HPLC

Sources & evidence

ORD record
ord-e513a82ede8441bda7d81841b1ec65d0
Source dataset
uspto-grants-2015_07
Patent number
US09073918B2

Reaction notes

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