Binap, (A+-)- → Phenylmethyl 3-(4-{[(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoate

HRID 549519Notes

Reaction equation

HRID 549519 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:34]=[C:35]([CH:46]=[CH:47][CH:48]=1)[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].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:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][C@:3]([OH:21])([C:4]([F:7])([F:6])[F:5])[CH2:2][NH:1][C:23]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]3[C:24]=2[CH:25]=[N:26][N:27]3[C:33]2[CH:34]=[C:35]([CH:46]=[CH:47][CH:48]=2)[C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH:17]=1

Participants

7

Reactant 4

HCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 57672640phenylmethyl 3-(4-bromo-6-methyl-1H-indazol-1-yl)benzoateHCID 59010010(2R)-2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol

Product 1

HCID 57672651Phenylmethyl 3-(4-{[(2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoateYield 18.7%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

A mixture of (2R)-2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (54.7 mg, 0.177 mmol), phenylmethyl 3-(4-bromo-6-methyl-1H-indazol-1-yl)benzoate (65.3 mg, 0.155 mmol), tris(dibenzylideneacetone)dipalladium(0) (14.2 mg, 0.0155 mmol), racemic-BINAP (9.7 mg, 0.0155 mmol) and sodium tert-butoxide (20.9 mg, 0.217 mmol) in anhydrous toluene (0.9 mL) was heated in a microwave reactor at 120° C. (power set at 400 Watts, 30 seconds pre-stirring) for 15 min. The reaction mixture was filtered and the filtrate was partitioned between water and ethyl acetate (40 mL of each). The organic phase was separated, washed with brine, dried through a hydrophobic frit and evaporated and purified by mass directed autopreparation (System B). Product containing fractions were partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous layer was re-extracted with dichloromethane and the combined organic extracts were washed successively with water and brine, dried through a hydrophobic frit and evaporated in vacuo to give the title compound (18.8 mg).

Workup

  1. filtrationThe reaction mixture was filtered
  2. customthe filtrate was partitioned between water and ethyl acetate (40 mL of each)
  3. customThe organic phase was separated
  4. washwashed with brine
  5. customdried through a hydrophobic frit
  6. customevaporated
  7. custompurified by mass
  8. additionProduct containing fractions
  9. customwere partitioned between dichloromethane and aqueous sodium bicarbonate
  10. extractionThe aqueous layer was re-extracted with dichloromethane
  11. washthe combined organic extracts were washed successively with water and brine
  12. customdried through a hydrophobic frit
  13. customevaporated in vacuo

Sources & evidence

ORD record
ord-29c785a890a5410ab731d75c0694718c
Source dataset
uspto-grants-2011_05
Patent number
US07943651B2

Reaction notes

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