6-Methyl-2-(methylsulfonyl)-1,3-benzoxazole → methyl (1R,2R)-2-({3'-fluoro-4'-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1'-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate

HRID 907745

反応式

HRID 907745 の反応式
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:25].[CH3:26][C:27]1[CH:39]=[CH:38][C:30]2[N:31]=[C:32](S(C)(=O)=O)[O:33][C:29]=2[CH:28]=1>ClC(Cl)C>[F:25][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:32]1[O:33][C:29]2[CH:28]=[C:27]([CH3:26])[CH:39]=[CH:38][C:30]=2[N:31]=1

参加物

4

反応物 2

HCID 219857516-Methyl-2-(methylsulfonyl)-1,3-benzoxazoleHCID 58681300Methyl (1R,2R)-2-[(4'-amino-3'-fluoro-1,1'-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate

生成物 1

HCID 67147332methyl (1R,2R)-2-({3'-fluoro-4'-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1'-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate収率 42.7%

試薬・触媒・溶媒 1

HCID 63651,1-Dichloroethane溶媒

反応条件

温度
85 °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, 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+).

後処理

  1. customThe solvent was removed by rotary evaporation
  2. customthe residue was purified

出典と根拠

ORDレコード
ord-22bfde865e4d425b946618fc904b76c7
出典データセット
uspto-grants-2011_09
特許番号
US08013166B2

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