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

HRID 418804Notes

Reaction equation

HRID 418804 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]([O:39][CH3:40])=[CH:35][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.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][C:36]([O:39][CH3:40])=[CH:35][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

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 576159621h-Indazole,4-bromo-1-(4-methoxyphenyl)-6-methyl-2×

Product 1

HCID 576159261,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-[({6-methyl-1-[4-(methyloxy)phenyl]-1H-indazol-4-yl}amino)methyl]-2-pentanolYield 59.3%

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, 200 mg, 0.65 mmol) and 4-bromo-6-methyl-1-[4-(methyloxy)phenyl]-1H-indazole (Intermediate 15, 190 mg, 0.6 mmol) in toluene (3 mL) were added tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol), racemic-BINAP (37 mg, 0.06 mmol) and sodium tert-butoxide (85 mg, 0.84 mmol). The mixture was heated in a microwave at 120° C. for 30 min and then cooled and partitioned between ethyl acetate (60 mL) and 1M hydrochloric acid (60 mL). The organic layer was separated, washed sequentially with aqueous sodium bicarbonate (30 mL) and brine (30 mL), passed through a hydrophobic frit and evaporated under reduced pressure. The residue was dissolved in dichloromethane (1.5 mL) and loaded onto a silica SPE cartridge and eluted with a gradient of ethyl acetate:petroleum ether (1:9 to 1:4) to give the title compound (194 mg).

Workup

  1. temperaturecooled
  2. custompartitioned between ethyl acetate (60 mL) and 1M hydrochloric acid (60 mL)
  3. customThe organic layer was separated
  4. washwashed sequentially with aqueous sodium bicarbonate (30 mL) and brine (30 mL)
  5. customevaporated under reduced pressure
  6. dissolutionThe residue was dissolved in dichloromethane (1.5 mL)
  7. washeluted with a gradient of ethyl acetate:petroleum ether (1:9 to 1:4)

Sources & evidence

ORD record
ord-3f9a0139820b429d8fdf4fcb6f5044c6
Source dataset
uspto-grants-2012_01
Patent number
US08093281B2

Reaction notes

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