1,2-Dichloroethane → N-Methyl-N-(1-methyl-1H-indol-2-ylmethyl)-3-(5,7,8,9-tetrahydro-6-oxa-1,9-diaza-benzocyclohepten-3-yl)-acrylamide

HRID 1879980Notes

Reaction equation

HRID 1879980 reaction equation
C(Cl)CCl.Cl.[N:6]1[C:11]2[NH:12][CH2:13][CH2:14][O:15][CH2:16][C:10]=2[CH:9]=[C:8]([CH:17]=[CH:18][C:19]([OH:21])=O)[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:32][NH:33][CH2:34][C:35]1[N:36]([CH3:44])[C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:32][N:33]([CH2:34][C:35]1[N:36]([CH3:44])[C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:19](=[O:21])[CH:18]=[CH:17][C:8]1[CH:7]=[N:6][C:11]2[NH:12][CH2:13][CH2:14][O:15][CH2:16][C:10]=2[CH:9]=1

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 11401058methyl((1-methyl-1H-indol-2-yl)methyl)amineHCID 684149593-(5,7,8,9-Tetrahydro-6-oxa-1,9-diaza-benzocyclohepten-3-yl)-acrylic acid hydrochloride

Product 1

HCID 68410444N-Methyl-N-(1-methyl-1H-indol-2-ylmethyl)-3-(5,7,8,9-tetrahydro-6-oxa-1,9-diaza-benzocyclohepten-3-yl)-acrylamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
35 °C

Procedure

EDC (0.10 g, 0.52 mmol) was added to a solution of 3-(5,7,8,9-Tetrahydro-6-oxa-1,9-diaza-benzocyclohepten-3-yl)-acrylic acid hydrochloride (0.11 g, 0.43 mmol), HOBt (64 mg, 0.47 mmol), Methyl-(1-methyl-1H-indol-2-ylmethyl)-amine (128 mg, 0.47 mmol) and (i-Pr)2EtN (0.36 mL, 2.15 mmol) in DMF (6 mL). The mixture was allowed to stir overnight at 35° C. The mixture was cooled to 0° C. and diluted with H2O (15 mL) with rapid stirring. The resulting gummy precipitate was filtered, washed with H2O (30 mL) then with Et2O (20 mL). The solid was dissolved in dichloromethane (100 mL), washed with H2O (50 mL), brine (50 mL), dried over MgSO2, and treated with charcoal. The mixture was filtered and the filtrate was passed through a plug of silica gel. The silica gel was washed with ethyl acetate (50 mL) then with 5% methanol: dichloromethane (50 mL). The combined organic fractions were concentrated to give an oil. The resulting oil was triturated with ether:hexanes (20 mL) until the oil was converted to a beige solid. Yield: 40 mg (25%) as a mixture of amide rotamers; 1H NMR (400 MHz, DMSO-d6) δ 8.24 (br s, 1H), 7.92 and 7.85 (2×s, 1H), 7.50-7.39 (m, 3H), 7.18-6.92 (m, 3H), 6.78 (br s, 1H), 6.41 and 6.20 (2×s, 1H), 5.07 and 4.83 (2×s, 2H), 4.52 and 4.45 (2×s, 2H), 3.71-3.61 (m, 5H), 3.50-3.40 (m, 2H), 3.10 and 2.95 (2×s, 3H); ESI MS m/z 377 [C22H24N4O2+H]+

Workup

  1. temperatureThe mixture was cooled to 0° C.
  2. filtrationThe resulting gummy precipitate was filtered
  3. washwashed with H2O (30 mL)
  4. dissolutionThe solid was dissolved in dichloromethane (100 mL)
  5. washwashed with H2O (50 mL), brine (50 mL)
  6. dry with materialdried over MgSO2
  7. additiontreated with charcoal
  8. filtrationThe mixture was filtered
  9. washThe silica gel was washed with ethyl acetate (50 mL)
  10. concentrationThe combined organic fractions were concentrated
  11. customto give an oil
  12. customThe resulting oil was triturated with ether
  13. additionYield: 40 mg (25%) as a mixture of amide rotamers

Sources & evidence

ORD record
ord-fcecf984c23d4adca73a6213d3e61ed7
Source dataset
uspto-grants-2012_11
Patent number
US08318720B2

Reaction notes

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