Binap, (A+-)- → 1,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-[({6-methyl-1-[3-(methyloxy)phenyl]-1H-indazol-4-yl}amino)methyl]-2-pentanol

HRID 418805Notes

Reaction equation

HRID 418805 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]=[C:35]([O:39][CH3:40])[CH:34]=1.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.C(OCC)(=O)C.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]=[C:35]([O:39][CH3:40])[CH:34]=1)([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

8

Reactant 4

HCID 634876Binap, (A+-)-HCID 179365862-(Aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol3×HCID 23676156Sodium t-butoxideHCID 576159671h-Indazole,4-bromo-1-(3-methoxyphenyl)-6-methyl-2×

Product 1

HCID 576159421,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-[({6-methyl-1-[3-(methyloxy)phenyl]-1H-indazol-4-yl}amino)methyl]-2-pentanolYield 85.9%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (Intermediate 18, 743 mg, 2.4 mmol), 4-bromo-6-methyl-1-[3-(methyloxy)phenyl]-1H-indazole (Intermediate 16, 657 mg, 2.07 mmol), tris(dibenzylideneacetone)dipalladium(0) (117 mg, 0.13 mmol), racemic-BINAP (141 mg, 0.23 mmol) and sodium tert-butoxide (429 mg, 4.46 mmol) in toluene (30 mL) was heated under reflux in an atmosphere of nitrogen for 2 hours. The mixture was cooled, combined with crude product from a similar smaller scale preparation (260 mg input of Intermediate 18), and diluted with toluene (100 mL) and ethyl acetate (50 mL). The resulting solution was washed successively with 1M hydrochloric acid (75 mL), 8% aqueous sodium bicarbonate (75 mL) and brine (75 mL), passed through a hydrophobic rit and evaporated under reduced pressure. The residue was purified by silica gel chromatography using the Flashmaster II (70 g cartridge) eluting with a 0:100 to 50:50 cyclohexane:ethyl acetate gradient over 60 minutes to give impure product (970 mg). Further purification using the Flashmaster II (100 g cartridge) eluting with a 100:0 to 75:25 dichloromethane:tert-butyl methyl ether gradient over 50 minutes gave the title compound (72 mg). A quantity of less pure material (137 mg) was also obtained.

Workup

  1. temperatureunder reflux in an atmosphere of nitrogen for 2 hours
  2. temperatureThe mixture was cooled
  3. washThe resulting solution was washed successively with 1M hydrochloric acid (75 mL), 8% aqueous sodium bicarbonate (75 mL) and brine (75 mL)
  4. customevaporated under reduced pressure
  5. customThe residue was purified by silica gel chromatography
  6. washeluting with a 0:100 to 50:50 cyclohexane

Sources & evidence

ORD record
ord-35ae61d8f3d74554ab1063d33dd6f693
Source dataset
uspto-grants-2012_01
Patent number
US08093281B2

Reaction notes

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