1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) → 2-(6-fluoro-7-(3'-fluoro-5,6'-dimethyl-2,2'-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)acetamide

HRID 1522617Notes

Reaction equation

HRID 1522617 reaction equation
[F:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12]([NH:14]C(=O)OC(C)(C)C)=[O:13])[N:10]=[C:4]2[C:3]=1I.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].[F:71][C:72]1[C:73]([C:79]2[CH:84]=[C:83]([NH2:85])[C:82]([CH3:86])=[CH:81][N:80]=2)=[N:74][C:75]([CH3:78])=[CH:76][CH:77]=1>O1CCOCC1.O.CS(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12]([NH2:14])=[O:13])[N:10]=[C:4]2[C:3]=1[NH:85][C:83]1[C:82]([CH3:86])=[CH:81][N:80]=[C:79]([C:73]2[C:72]([F:71])=[CH:77][CH:76]=[C:75]([CH3:78])[N:74]=2)[CH:84]=1

Participants

9

Reactant 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 23676156Sodium t-butoxideHCID 674696193'-Fluoro-5,6'-dimethyl-2,2'-bipyridin-4-amineHCID 67469676tert-butyl 2-(6-fluoro-7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)acetylcarbamate

Product 1

HCID 682126662-(6-fluoro-7-(3'-fluoro-5,6'-dimethyl-2,2'-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)acetamide

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of tert-butyl 2-(6-fluoro-7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)acetylcarbamate (62 mg, 0.148 mmol) in dioxane (4 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (21.34 mg, 0.037 mmol), Pd2(dba)3 (33.8 mg, 0.037 mmol), sodium tert-butoxide (42.5 mg, 0.443 mmol), and 3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-amine (35.3 mg, 0.162 mmol) and the mixture was heated at 110° C. for 3 hours. The solution was then cooled, diluted with water and extracted with EtOAc (3×75 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to give a residue which was suspended in DMSO and purified by preparative HPLC using a gradient of 20-65% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to give the title compound. The title compound was combined with 1N HCl (4 mL) and lyophilized to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H), 2.60 (s, 3H) 3.43-3.58 (m, 1H) 3.61-3.79 (m, 1H) 7.29 (d, J=2.53 Hz, 1H) 7.35 (br. s., 1H) 7.53-7.65 (m, 1H) 7.71 (br. s., 1H) 7.82 (dd, J=11.12, 8.59 Hz, 1H) 8.52 (s, 1H) 8.76 (d, J=3.03 Hz, 1H) 8.87 (s, 1H) 10.14 (br. s., 1H). MS [M+H] found 410.4.

Workup

  1. temperatureThe solution was then cooled
  2. extractionextracted with EtOAc (3×75 mL)
  3. dry with materialThe combined organics were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give a residue which
  7. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-8deaef0b7fc74d849323ad293a9570cb
Source dataset
uspto-grants-2015_07
Patent number
US09073918B2

Reaction notes

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