反応 #9702

反応方程式

ester

methyl (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate

NaOH

→

(1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid

収率 15.0%

溶媒

dioxane THF

反応条件

後処理

1. 1
   workup.ADDITIONwas added
2. 2
   その他The solvent was removed by rotary evaporation, and water (20 mL) and EtOAc (40 mL)
3. 3
   workup.ADDITIONwere added to the residue
4. 4
   その他The aqueous layer was separated
5. 5
   workup.ADDITIONacidified to pH 5 by the addition of 1 N aqueous HCl
6. 6
   抽出extracted with EtOAc (2×60 mL)
7. 7
   洗浄The combined organic phases were washed with saturated NaCl
8. 8
   乾燥dried (Na2SO4)
9. 9
   その他The solvent was removed by rotary evaporation
10. 10
    workup.DISSOLUTIONthe residue was redissolved in DMF (10 mL)
11. 11
    その他The crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA)

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+).

出典