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 1694279노트

반응식

HRID 1694279 반응식
[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]

참가 물질

5

반응물 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

생성물 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 ester수율 17.2%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

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온도
90 °C

실험 절차

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;

후처리

  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)

출처 및 근거

ORD 기록
ord-206e32e1f9cb44fea21a3234bb1f97d9
출처 데이터셋
uspto-grants-2012_04
특허 번호
US08158672B2

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