Reaction #46607

Reaction equation

EDC

(E)-3-(6-amino-pyridin-3-yl)acrylic acid

4,6-dichloro-1-methyl-2-(methylaminomethyl)-1H-indole

HOBt H2O

Et3N

→

title compound

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

Solvents

DMF

Conditions

Workup

1. 1
   Concentrationthe reaction was concentrated to dryness
2. 2
   Concentrationthe residue was re-concentrated from CHCl3/xylenes (2×)
3. 3
   OtherFlash 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. 4
   ConcentrationThis was solidified by re-concentration from MeOH/EtOAc/CHCl3 several times
5. 5
   OtherThis material was triturated with hot EtOAc/MeOH
6. 6
   FiltrationThe title compound was collected by suction filtration
7. 7
   ConcentrationThe filtrate was concentrated
8. 8
   Otherthe residue was triturated with EtOAc

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)+.

Source