Binap, (A+-)- → (2S)-4-(2,3-Dihydro-1-benzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-pentanol

HRID 418803Notes

Reaction equation

HRID 418803 reaction equation
[NH2:1][CH2:2][C@@:3]([OH:21])([CH2:8][C:9]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([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][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]>[O:19]1[C:20]2[C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][C@@:3]([CH2:2][NH:1][C:23]3[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]4[C:24]=3[CH:25]=[N:26][N:27]4[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([OH:21])[C:4]([F:6])([F:7])[F:5])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1

Participants

7

Reactant 4

HCID 634876Binap, (A+-)-HCID 15605604(2S)-2-(Aminomethyl)-4-(2,3-dihydro-1-benzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-pentanol2×HCID 23676156Sodium t-butoxideHCID 576159611h-Indazole,4-bromo-6-methyl-1-phenyl-2×

Product 1

HCID 57615959(2S)-4-(2,3-Dihydro-1-benzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-{[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]methyl}-2-pentanolYield 28.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

To a mixture of (2S)-2-(aminomethyl)-4-(2,3-dihydro-1-benzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-pentanol (Intermediate 31, 87 mg, 0.3 mmol) and 4-bromo-6-methyl-1-phenyl-1H-indazole (Intermediate 33, 92 mg, 0.32 mmol) in toluene (3.5 mL) were added tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.04 mmol), racemic-BINAP (28 mg, 0.04 mmol) and sodium tert-butoxide (45 mg, 0.47 mmol). The mixture was heated in a microwave at 120° C. for 15 min and then cooled and partitioned between ethyl acetate (30 mL) and water (20 mL). The organic layer was separated, washed with water (20 mL), passed through a hydrophobic frit and evaporated. The residue was purified by two sequential SPE cartridge purifications eluting with a gradient of ethyl acetate:petroleum:ether (1:6 to 1:4) to give the title compound as a yellow foam (43 mg).

Workup

  1. temperaturecooled
  2. custompartitioned between ethyl acetate (30 mL) and water (20 mL)
  3. customThe organic layer was separated
  4. washwashed with water (20 mL)
  5. customevaporated
  6. customThe residue was purified by two sequential SPE cartridge purifications
  7. washeluting with a gradient of ethyl acetate:petroleum:ether (1:6 to 1:4)

Sources & evidence

ORD record
ord-07cbd7371bc144a7a4bfbe3e58ce3d6d
Source dataset
uspto-grants-2012_01
Patent number
US08093281B2

Reaction notes

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