Triethylamine → (1S)-cyclopropanecarboxylic acid {7-bromo-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amide

HRID 1797245Notes

Reaction equation

HRID 1797245 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C[O:20][C:21](=O)[C:22]1[C:27]([NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:26][CH:25]=[C:24]([Br:34])[C:23]=1[CH2:35]Br.C(N(CC)CC)C>CN(C=O)C>[Br:34][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:29]([CH:31]2[CH2:32][CH2:33]2)=[O:30])=[C:22]2[C:23]=1[CH2:35][N:18]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:21]2=[O:20]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 11282264(1S)-1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamineHCID 686904882-Bromomethyl-3-bromo-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester

Product 1

HCID 10099083(1S)-cyclopropanecarboxylic acid {7-bromo-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amideYield 74.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (0.35 g, 1.2 mmol) in DMF (10 ml) was added 2-bromomethyl-3-bromo-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (0.45 g, 1.1 mmol) and triethyl amine (0.5 ml, 3.3 mmol). The mixture was heated at 90° C. overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with water (30 ml×2), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel column to give (1S)-cyclopropanecarboxylic acid {7-bromo-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (450 mg, 74%): mp, 219–221° C.; 1H NMR (CDCl3) δ 0.89–0.93 (m, 2H, c-CH2), 1.08–1.14 (m, 2H, c-CH2), 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 1.65–1.70 (m, 1H, c-CH), 2.98 (s, 3H, CH3SO2), 3.70 (dd, J=5, 15 Hz, 1H, CHH), 3.87(s, 3H, OCH3), 4.06–4.14 (m, 3H, NCHH+OCH2CH3), 4.19 (dd, J=10, 15 Hz, 1H, CHH), 4.55 (d, J=17 Hz, 1H, CH), 5.75–5.81 (m, 1H, CHN), 6.86–6.96 (m, 3H, Ar), 7.53 (d, J=9 Hz, 1H, Ar), 8.40(d, J=9 Hz, 1H, Ar), 10.38 (s, 1H, NHCO). 13CNMR (CDCl3): δ 9.1, 9.2, 15.4, 16.9, 42.2, 49.1, 52.0, 56.1, 56.7, 65.3, 110.1, 112.3, 112.8, 119.5, 119.9, 120.7, 129.7, 136.8, 138.1, 142.0, 149.6, 150.5, 170.0, 173.3; Anal Calcd for C24H27BrN2O6S: C, 52.27; H, 4.94; N, 5.08. Found: C, 52.57; H, 4.68; N, 4.95.

Workup

  1. customThe solvent was removed in vacuo
  2. extractionThe resulted oil was extracted with ethyl acetate (50 ml) and water (30 ml)
  3. washThe organic layer was washed with water (30 ml×2), 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 column

Sources & evidence

ORD record
ord-c52ab737934f45c6b73ef3006a611048
Source dataset
uspto-grants-2006_04
Patent number
US07034052B2

Reaction notes

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