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 9606

反応式

HRID 9606 の反応式
[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

参加物

4

反応物 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

生成物 1

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

試薬・触媒・溶媒 1

HCID 22018518Dioxane tetrahydrofuran溶媒

反応条件

温度
50 °C

実験手順

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, 1 H), 8.00–7.60 (m, 6 H), 7.30 (d, 2 H), 7.00 (d, 2 H), 4.05 (m, 1 H), 3.20 (m, 1 H), 2.40 (s, 3 H), 2.20 (m, 1 H), 1.95 (m, 1 H), 1.80–1.60 (m, 4 H); LC-MS ret. time 3.57 min, m/z 459.3 (MH+).

後処理

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

出典と根拠

ORDレコード
ord-c7b3e4962de241219997253920a4eda7
出典データセット
uspto-grants-2006_08
特許番号
US07091228B2

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