Binap, (A+-)- → 1,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-2-({[1-(2-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-4-methyl-2-pentanol

HRID 418808Notes

Reaction equation

HRID 418808 reaction equation
[NH2:1][CH2:2][C:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].Br[C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39].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(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:5][C:4]([F:7])([F:6])[C:3]([CH2:2][NH:1][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])([OH:21])[CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10]

Participants

7

Reactant 4

HCID 634876Binap, (A+-)-HCID 179365862-(Aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol2×HCID 23676156Sodium t-butoxideHCID 576159291h-Indazole,4-bromo-1-(2-fluorophenyl)-6-methyl-2×

Product 1

HCID 118491111,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-2-({[1-(2-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-4-methyl-2-pentanolYield 22.5%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

To a mixture of 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (Intermediate 18, 49.5 mg, 0.16 mmol) and 4-bromo-1-(2-fluorophenyl)-6-methyl-1H-indazole (Intermediate 26, 45.8 mg, 0.15 mmol) in toluene (0.75 mL) were added tris(dibenzylideneacetone)dipalladium(0) (6.9 mg, 0.075 mmol), racemic-BINAP (9.3 mg, 0.015 mmol) and sodium tert-butoxide (18.5 mg, 0.192 mmol). The mixture was heated in a microwave at 120° C. for 30 min and then cooled and partitioned between water and dichloromethane. The organic layer was separated, dried and purified by silica gel chromatography using the Flashmaster II (20 g cartridge) eluting with a 0:100 cyclohexane:ethyl acetate gradient over 60 minutes to give crude product (43.6 mg) which was purified further by mass-directed autopreparation to give the title compound (18 mg).

Workup

  1. temperaturecooled
  2. custompartitioned between water and dichloromethane
  3. customThe organic layer was separated
  4. customdried
  5. custompurified by silica gel chromatography
  6. washeluting with a 0:100 cyclohexane
  7. customethyl acetate gradient over 60 minutes to give crude product (43.6 mg) which
  8. customwas purified further by mass-directed autopreparation

Sources & evidence

ORD record
ord-857f13ae6f1442dea8067c6494c93a74
Source dataset
uspto-grants-2012_01
Patent number
US08093281B2

Reaction notes

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