Binap, (A+-)- → (2R)-2-({[1-(2,4-Difluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-Pentanol

HRID 418802Notes

Reaction equation

HRID 418802 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][C:36]([F:39])=[CH:35][C:34]=1[F:40].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:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[N:27]1[C:28]2[C:24](=[C:23]([NH:1][CH2:2][C@:3]([OH:21])([CH2:8][C:9]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5])[CH:31]=[C:30]([CH3:32])[CH:29]=2)[CH:25]=[N:26]1

Participants

7

Reactant 4

HCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 576159461h-Indazole,4-bromo-1-(2,4-difluorophenyl)-6-methyl-2×HCID 59010010(2R)-2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol2×

Product 1

HCID 57615927(2R)-2-({[1-(2,4-Difluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-PentanolYield 20.7%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

A solution of (2R)-2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (Intermediate 21, 20 mg, 0.065 mmol), 4-bromo-1-(2,4-difluorophenyl)-6-methyl-1H-indazole (Intermediate 13, 18.3 mg, 0.057 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.6 mg, 0.0028 mmol), racemic-BINAP (3.6 mg, 0.0056 mmol) and sodium tert-butoxide (7.7 mg, 0.081 mmol) in toluene (0.4 mL) was heated in a microwave at 120° C. for 15 min. The mixture was then cooled, partitioned between ethyl acetate (20 mL) and aqueous ammonium chloride (20 mL). The organic layer was separated, washed successively with aqueous sodium bicarbonate, water and brine, passed through a hydrophobic frit and evaporated. The residue was purified by mass-directed autopreparation to give the title compound (6.5 mg).

Workup

  1. temperatureThe mixture was then cooled
  2. custompartitioned between ethyl acetate (20 mL) and aqueous ammonium chloride (20 mL)
  3. customThe organic layer was separated
  4. washwashed successively with aqueous sodium bicarbonate, water and brine
  5. customevaporated
  6. customThe residue was purified by mass-directed autopreparation

Sources & evidence

ORD record
ord-7589f114058147e493c67e984f537779
Source dataset
uspto-grants-2012_01
Patent number
US08093281B2

Reaction notes

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