Triethylamine → 3-(3,4-Bis-difluoromethoxy-phenyl)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid methyl ester

HRID 1367094ノート

反応式

HRID 1367094 の反応式
[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH:17]([F:19])[F:18])[CH:7]=1.C(N(CC)CC)C.C[O:30][C:31](=O)[C:32]1[C:37]([NH:38][C:39]([CH:41]2[CH2:43][CH2:42]2)=[O:40])=[CH:36][CH:35]=[C:34]([Cl:44])[C:33]=1[CH2:45]Br>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH:17]([F:18])[F:19])[CH:7]=1)[N:20]1[CH2:45][C:33]2[C:32](=[C:37]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[CH:36]=[CH:35][C:34]=2[Cl:44])[C:31]1=[O:30]

参加物

5

反応物 3

HCID 8471TriethylamineHCID 669200082-Bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl esterHCID 669203783-Amino-3-(3,4-bis-difluoromethoxy-phenyl)-propionic acid methyl ester

生成物 1

HCID 103701873-(3,4-Bis-difluoromethoxy-phenyl)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid methyl ester収率 17.2%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

反応条件

温度
90 °C

実験手順

To a solution of 3-amino-3-(3,4-bis-difluoromethoxy-phenyl)-propionic acid methyl ester (50 mg, 0.16 mmol) and triethyl amine (0.09 ml, 3.1 mmol) in DMF (2 ml) was added 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (67 mg, 0.19 mmol). The mixture was heated at 90° C. under nitrogen atmosphere overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml). The organic layer was washed with water (30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give 3-(3,4-bis-difluoromethoxy-phenyl)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid methyl ester as a off-white solid (15 mg, 17%). mp, 175-177° C.; 1HNMR (CDCl3): δ 0.88-0.94 (m, 2H, cyclopropyl ring CH2), 1.07-1.13 (m, 2H, cyclopropyl ring CH2), 1.65-1.68 (m, 1H, cyclopropyl ring CH), 3.14 (dd, J=6, 15 Hz, 1H, CHHCO), 3.28 (dd, J=10, 15 Hz, 1H, CHHCO), 3.70 (s, 3H, OCH3), 4.13 (d, J=17 Hz, 1H, CHHN), 4.36 (d, J=17 Hz, 1H, CHHN), 5.79-5.85 (m, 1H, CHN), 6.23 (t, JH-F=75 Hz, 1H, OCF2H), 6.26 (t, JH-F=75 Hz, 1H, OCF2H), 7.28-7.41 (m, 4H, Ar), 8.45 (d, J=9 Hz, 1H, Ar), 10.38 (s, 1H, NHCO); 13C NMR (CDCl3): 8.45, 15.25, 16.16, 36.46, 46.34, 51.62, 52.31, 65.38, 111.38, 111.42, 115.57, 115.61, 118.64, 119.76, 119.80, 121.76, 121.81, 122.77, 125.45, 133.14, 136.89, 137.03, 138.86, 142.29, 142.21, 168.79, 170.20, 172.73; Anal. Calcd. for C24H21ClF4N2O6: C, 52.90; H, 3.88; N, 5.14. Found: C, 52.78; H, 3.80; N, 5.01;

後処理

  1. customThe solvent was removed in vacuo
  2. extractionThe resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml)
  3. washThe organic layer was washed with water (30 ml), brine (30 ml)
  4. dry with materialdried over magnesium sulfate
  5. customThe solvent was removed in vacuo
  6. customthe resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1)

出典と根拠

ORDレコード
ord-7be87dbe65d547f9a87bf259fa69318e
出典データセット
uspto-grants-2011_02
特許番号
US07893102B2

反応ノート

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