Triethylamine → Cyclopropanecarboxylic acid {2-[1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amide

HRID 913197Notes

Reaction equation

HRID 913197 reaction equation
[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([NH2:20])[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C[O:22][C:23](=O)[C:24]1[C:29]([NH:30][C:31]([CH:33]2[CH2:35][CH2:34]2)=[O:32])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:36]Br.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([N:20]3[C:23](=[O:22])[C:24]4[C:25](=[CH:26][CH:27]=[CH:28][C:29]=4[NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])[CH2:36]3)[CH2:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 669203212-Bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl esterHCID 674176041-(3-Cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine

Product 1

HCID 11591388Cyclopropanecarboxylic acid {2-[1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amideYield 5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1.0 g, 3.3 mmol) in DMF (18 mL), were added 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.0 g, 3.3 mmol) and triethylamine (1.3 mL, 9.8 mmol). The mixture was heated at 90° C. overnight. The solvent was removed in vacuo. The resulting oil was extracted with ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with water (30 mL×4) and brine (30 mL), and dried over magnesium sulfate. The solvent was removed in vacuo and the resulting oil was purified by silica gel column to give cyclopropanecarboxylic acid {2-[1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (50 mg, 5%): mp 224-226° C.; 1H NMR (CDCl3) δ 0.35-0.39 (m, 2H, c-CH2), 0.60-0.63 (m, 2H, c-CH2), (0.88-0.93 (m, 2H, c-CH2), 1.08-1.12 (m, 2H, c-CH2), 1.25-132 (m, 1H c-CH), 1.63-1.69 (m, 1H, c-CH), 2.95 (s, 3H, CH3), 3.69 (dd, J=5, 15 Hz, 1H, CHH), 3.82 (d, J=4 Hz, 2H, c-CH), 3.86 (s, 3H, CH3), 4.19 (dd, J=10, 17 Hz, 1H, CHH), 4.20 (d, J=17 Hz, 1H, CHHN), 4.43 (d, J=17 Hz, 1H, CHHN), 5.72 (dd, J=5, 10 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.45 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 10.46 (s, 1H, NHCO); 13C NMR (CDCl3) δ 3.3, 3.4, 8.3, 10.2, 16.2, 41.5, 47.9, 51.7, 55.9, 56.0, 74.3, 77.2, 111.8, 113.0, 116.7, 117.1, 117.9, 119.6, 129.4, 133.6, 138.2, 141.3, 149.1, 150.0, 170.1, 172.6. Analy. Calculated for C26H3oN2O6S: C, 62.63; H, 6.06; N, 5.62. Found: C, 62.41; H, 5.95; N, 5.43.

Workup

  1. customThe solvent was removed in vacuo
  2. extractionThe resulting oil was extracted with ethyl acetate (50 mL) and water (30 mL)
  3. washThe organic layer was washed with water (30 mL×4) and brine (30 mL)
  4. dry with materialdried over magnesium sulfate
  5. customThe solvent was removed in vacuo
  6. customthe resulting oil was purified by silica gel column

Sources & evidence

ORD record
ord-565d1384fa734e32bb79725829189ac1
Source dataset
uspto-grants-2011_09
Patent number
US08026269B2

Reaction notes

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