3-Methylpyrrolidin-3-ol hydrochloride → 3-Bromo-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-benzamide

HRID 923842ノート

反応式

HRID 923842 の反応式
[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].Cl.[CH3:24][C:25]1([OH:30])[CH2:29][CH2:28][NH:27][CH2:26]1>CS(C)=O.CC(OC)(C)C.CCOC(C)=O.Cl.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:27]1[CH2:28][CH2:29][C:25]([OH:30])([CH3:24])[CH2:26]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]

参加物

7

反応物 2

HCID 533465593-Methylpyrrolidin-3-ol hydrochlorideHCID 867025923-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide

生成物 1

HCID 899066683-Bromo-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-benzamide

試薬・触媒・溶媒 4

HCID 313Hydrochloric Acid溶媒HCID 679Dimethyl Sulfoxide溶媒HCID 18176222EtOAc MTBE溶媒HCID 57417360Sodium chloride; water溶媒

反応条件

温度
90 °C

実験手順

A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 100 mg, 0.264 mmol), 3-methylpyrrolidine-3-ol hydrochloride (72.8 mg, 0.529 mmol), and TEA (147 μL, 1.058 mmol) in DMSO (199 μL) was stirred at 90° C. for 16 h. Additional TEA (73.7 μL, 0.529 mmol) was added to the mixture and stirring was continued for 72 h at 100° C. The cooled RM was diluted with TBME/EtOAc (1:1)(30 mL), sequentially washed 0.5 M HCl (3×5 mL), brine (5 mL) and then evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 20% to 60% EtOAc-EtOH+0.1% NH4OH (9:1)) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.98 min, m/z=459/461.0 [M+H]+, m/z=457/459 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 3H) 1.77-1.95 (m, 2H) 3.32-3.35 (m, 1H) 3.37-3.48 (m, 1H) 3.65 (d, J=10.03 Hz, 1H) 3.75 (td, J=9.41, 7.09 Hz, 1H) 4.79 (s, 1H) 6.90 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.81-7.91 (m, 3H) 8.13 (d, J=1.96 Hz, 1H) 10.17 (s, 1H).

後処理

  1. stirringstirring
  2. waitwas continued for 72 h at 100° C
  3. customevaporated to dryness under reduced pressure
  4. customThe crude product was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 20% to 60% EtOAc-EtOH+0.1% NH4OH (9:1))

出典と根拠

ORDレコード
ord-3324aea94ae34e029c311a2a6e053b87
出典データセット
uspto-grants-2016_03
特許番号
US09278981B2

反応ノート

読み込み中…