N,N-Dimethyl-1,3-propanediamine → N'-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-N,N-dimethylpropane-1,3-diamine

HRID 2112206Notes

Reaction equation

HRID 2112206 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][NH2:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>O1CCOCC1.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:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[O:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:29][CH2:28][CH2:27][CH2:26][N:25]([CH3:30])[CH3:24])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:7]=[CH:6]2

Participants

7

Reactant 4

HCID 7993N,N-Dimethyl-1,3-propanediamineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 574187626-Bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole

Product 1

HCID 57639704N'-[5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-yl]-N,N-dimethylpropane-1,3-diamineYield 69.2%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 6-bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole (15d; Example 110, Steps A-E) (0.030 g, 0.079 mmol), 3-(dimethylamino)propylamine (0.012 g, 0.118 mmol), BINAP (0.009 g, 0.016 mmol), Pd2dba3 (0.007 g, 0.008 mmol), and NaOtBu (0.008 g, 0.087 mmol), in dioxane were mixed in a flask and purged with N2 three times. The reaction mixture was then heated to 100° C. for 16 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (20 mL) and brine (20 mL). The aqueous phase was extracted with ethyl acetate and the combined organics were dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica eluting with acetone/ether (1:1.5) with 0.2% triethylamine. The product was chromatographed again eluting with 5% MeOH in dichloromethane to afford 0.022 g of the product as colorless oil (69% yield). MS (ESI+) m/z 403 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 7.70 (s, 1H), 6.95 (m, 3H), 6.80 (m, 1H), 6.40 (s, 1H), 5.48 (br. s, 1H), 4.06 (d, 2H), 3.28 (m, 2H), 2.43 (m, 2H), 2.35 (m, 1H), 2.20 (s, 6H), 1.86 (m, 2H), 0.94 (d, 6H).

Workup

  1. custompurged with N2 three times
  2. temperatureThe mixture was cooled to room temperature
  3. custompartitioned between ethyl acetate (20 mL) and brine (20 mL)
  4. extractionThe aqueous phase was extracted with ethyl acetate
  5. dry with materialthe combined organics were dried over MgSO4
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was chromatographed on silica eluting with acetone/ether (1:1.5) with 0.2% triethylamine
  8. customThe product was chromatographed again
  9. washeluting with 5% MeOH in dichloromethane

Sources & evidence

ORD record
ord-5fb6209d84ea4d9fb0c75d33708f1bf9
Source dataset
uspto-grants-2009_04
Patent number
US07521447B2

Reaction notes

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