Sodium Hydroxide → (1r,2r)-2-({3'-Fluoro-4'-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1'-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid

HRID 30923

Reaction equation

HRID 30923 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([O:34]C)=[O:33])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>O1CCOCC1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([OH:34])=[O:33])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=2[N:13]=1

Participants

4

Reactant 2

HCID 14798Sodium HydroxideHCID 67147332methyl (1R,2R)-2-({3'-fluoro-4'-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1'-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate

Product 1

HCID 11385583(1r,2r)-2-({3'-Fluoro-4'-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1'-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acidYield 15%

Reagents, catalysts & solvents 1

HCID 22018518Dioxane tetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of methyl (1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate (800 mg, 2.34 mmol, 78% ee) in dichloroethane (15 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (891 mg, 4.22 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 80:20 hexane/EtOAc) to give methyl (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate (472 mg). This ester intermediate was redissolved in 1:1 dioxane/THF (20 mL), a solution of 1 N aqueous NaOH (7.02 mL, 7.02 mol) was added, and the mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation, and water (20 mL) and EtOAc (40 mL) were added to the residue. The aqueous layer was separated, acidified to pH 5 by the addition of 1 N aqueous HCl, and then extracted with EtOAc (2×60 mL). The combined organic phases were washed with saturated NaCl and dried (Na2SO4). The solvent was removed by rotary evaporation and the residue was redissolved in DMF (10 mL) and methanol (20 mL). The crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as an off-white solid (161 mg, 15% yield, 80% ee). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (m, 1H), 8.00-7.60 (m, 6H), 7.30 (d, 2H), 7.00 (d, 1H), 4.05 (m, 1H), 3.20 (m, 1H), 2.40 (s, 3H), 2.20 (m, 1H), 1.95 (m, 1H), 1.80-1.60 (m, 4H); LC-MS ret. time 3.57 min, m/z 459.3 (MH+).

Workup

  1. customThe solvent was removed by rotary evaporation, and water (20 mL) and EtOAc (40 mL)
  2. additionwere added to the residue
  3. customThe aqueous layer was separated
  4. additionacidified to pH 5 by the addition of 1 N aqueous HCl
  5. extractionextracted with EtOAc (2×60 mL)
  6. washThe combined organic phases were washed with saturated NaCl
  7. dry with materialdried (Na2SO4)
  8. customThe solvent was removed by rotary evaporation
  9. dissolutionthe residue was redissolved in DMF (10 mL)
  10. customThe crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA)

Sources & evidence

ORD record
ord-154dac1abc6842328009a9ca5adc8a82
Source dataset
uspto-grants-2008_09
Patent number
US07423156B2

Linked notes

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