1,2-Dichloroethane → (E)-3-(6-aminopyridin-3-yl)-N-(4,6-dichloro-1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide

HRID 1297455Notes

Reaction equation

HRID 1297455 reaction equation
C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]2[C:19]=1[CH:20]=[C:21]([CH2:29][NH:30][CH3:31])[N:22]2[CH3:28].C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:30]([CH2:29][C:21]2[N:22]([CH3:28])[C:23]3[C:19]([CH:20]=2)=[C:18]([Cl:17])[CH:26]=[C:25]([Cl:27])[CH:24]=3)[CH3:31])=[O:16])=[CH:8][CH:7]=1

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 962WaterHCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 10487224(2E)-3-(6-aminopyridin-3-yl)prop-2-enoic acidHCID 221390824,6-dichloro-1-methyl-2-(methylaminomethyl)-1H-indole

Product 1

HCID 9952280(E)-3-(6-aminopyridin-3-yl)-N-(4,6-dichloro-1-methyl-1H-indol-2-ylmethyl)-N-methylacrylamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

EDC (84.4 mg, 0.44 mmole) was added all at once to a solution of (E)-3-(6-amino-pyridin-3-yl)acrylic acid (65.7 mg, 0.40 mmole), 4,6-dichloro-1-methyl-2-(methylaminomethyl)-1H-indole (107.0 mg, 0.44 mmole), HOBt.H2O (59.5 mg, 0.44 mmole), and Et3N (0.14 mL, 1.0 mmole) in anhydrous DMF (4 mL) at RT. After 17 hr, the reaction was concentrated to dryness and the residue was re-concentrated from CHCl3/xylenes (2×). Flash chromatography on silica gel (7% MeOH in 1:1 EtOAc/CHCl3) gave the Rf 0.44 component (10% MeOH in 1:1 EtOAc/CHCl3) as a foam. This was solidified by re-concentration from MeOH/EtOAc/CHCl3 several times. This material was triturated with hot EtOAc/MeOH, and the mixture was cooled to 0° C. The title compound was collected by suction filtration. The filtrate was concentrated and the residue was triturated with EtOAc to afford additional title compound. The combined desired solids were dried in high vacuum at 50-60° C. to afford the title compound (108.9 mg, 70%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) 1.8:1 mixture of amide rotamers; δ 8.08-8.20 (2×s, 1H), 7.70-7.90 (2×d, 1H), 7.57-7.70 (2×s, 1H), 7.46 (d, J=15.2 Hz, 1H), 7.18 (s, 1H), 6.97 (d, J=15.2 Hz, 1H), 6.45 and 6.15 (2×m, 4H), 5.02 and 4.82 (2×s, 2H), 3.60-3.80 (2×s, 3H), 2.99 and 3.11 (2×s, 3H); MS (ES) m/e 239 and 391 (M+H)+.

Workup

  1. customat RT
  2. concentrationthe reaction was concentrated to dryness
  3. concentrationthe residue was re-concentrated from CHCl3/xylenes (2×)
  4. customFlash chromatography on silica gel (7% MeOH in 1:1 EtOAc/CHCl3) gave the Rf 0.44 component (10% MeOH in 1:1 EtOAc/CHCl3) as a foam
  5. concentrationThis was solidified by re-concentration from MeOH/EtOAc/CHCl3 several times
  6. customThis material was triturated with hot EtOAc/MeOH
  7. filtrationThe title compound was collected by suction filtration
  8. concentrationThe filtrate was concentrated
  9. customthe residue was triturated with EtOAc

Sources & evidence

ORD record
ord-1e7d39f0486e44e483aa2774ae486611
Source dataset
uspto-grants-2007_07
Patent number
US07250424B2

Reaction notes

Loading…