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

HRID 18329Notes

Reaction equation

HRID 18329 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

7

Reactant 5

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 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, 1 H), 7.70-7.90 (2×d, 1 H), 7.57-7.70 (2×s, 1 H), 7.46 (d, J=15.2 Hz, 1 H), 7.18 (s, 1 H), 6.97 (d, J=15.2 Hz, 1 H), 6.45 and 6.15 (2×m, 4 H), 5.02 and 4.82 (2×s, 2H), 3.60-3.80 (2×s, 3 H), 2.99 and 3.11 (2×s, 3 H); MS (ES) m/e 239 and 391 (M+H)+.

Workup

  1. concentrationthe reaction was concentrated to dryness
  2. concentrationthe residue was re-concentrated from CHCl3/xylenes (2×)
  3. 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
  4. concentrationThis was solidified by re-concentration from MeOH/EtOAc/CHCl3 several times
  5. customThis material was triturated with hot EtOAc/MeOH
  6. filtrationThe title compound was collected by suction filtration
  7. concentrationThe filtrate was concentrated
  8. customthe residue was triturated with EtOAc

Sources & evidence

ORD record
ord-872134c200b94c3b9f467c4a6ed23e90
Source dataset
uspto-grants-2010_06
Patent number
US07741339B2

Reaction notes

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