1,2-Dichloroethane → 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-1H-indole-4-carboxamide

HRID 516711Notes

Reaction equation

HRID 516711 reaction equation
Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:20](O)=[O:21])[C:6]2[C:7]([CH3:19])=[C:8]([CH2:15][N:16]([CH3:18])[CH3:17])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.[NH2:23][CH2:24][C:25]1[C:26](=[O:35])[NH:27][C:28]([CH3:34])=[CH:29][C:30]=1[CH2:31][CH2:32][CH3:33].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C)C=O.ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([C:20]([NH:23][CH2:24][C:25]2[C:26](=[O:35])[NH:27][C:28]([CH3:34])=[CH:29][C:30]=2[CH2:31][CH2:32][CH3:33])=[O:21])[C:6]2[C:7]([CH3:19])=[C:8]([CH2:15][N:16]([CH3:18])[CH3:17])[N:9]([CH:12]([CH3:13])[CH3:14])[C:10]=2[CH:11]=1

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 181649HOAtHCID 671241403-(Aminomethyl)-6-methyl-4-propylpyridin-2(1H)-oneacetateHCID 674684516-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid hydrochloride salt

Product 1

HCID 674642276-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-1H-indole-4-carboxamideYield 63.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid hydrochloride salt (0.42 g, 1.216 mmol), 3-(aminomethyl)-6-methyl-4-propylpyridin-2(1H)-one (0.22 g, 1.221 mmol), HOAt (0.17 g, 1.249 mmol) was added Dichloromethane (16 mL), N,N-Dimethylformamide (4 mL) and N-methylmorpholine (135 μL, 1.228 mmol). The mixture was stirred and EDC free base (0.20 g, 1.288 mmol) was added. After stirring for 2 hr LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum and purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 8% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness then taken up in 20% EtOAc in hexanes. Scratching crystallized out the product which was filtered and washed with hexanes to give the product 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-1H-indole-4-carboxamide (362 mg, 0.769 mmol, 63.2% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.49 (s, 1H), 8.24 (t, J=4.9 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 6.83 (d, J=1.8 Hz, 1H), 5.89 (s, 1H), 4.91 (quin, J=7.0 Hz, 1H), 4.31 (d, J=5.1 Hz, 2H), 3.47 (s, 2H), 2.52 (2H under DMSO), 2.14 (s, 6H), 2.12 (s, 3H), 2.10 (s, 3H), 1.62-1.53 (m, 2H), 1.51 (d, J=7.1 Hz, 6H), 0.94 (t, J=7.3 Hz, 3H). MS(ES)+ m/e 471.3 [M+H]+.

Workup

  1. stirringAfter stirring for 2 hr LCMS
  2. customThe reaction was evaporated to dryness under vacuum
  3. custompurified by silica gel chromatography (Analogix
  4. customevaporated to dryness
  5. customScratching crystallized out the product which
  6. filtrationwas filtered
  7. washwashed with hexanes

Sources & evidence

ORD record
ord-a5fe042508c440158cd40a17355b93df
Source dataset
uspto-grants-2015_08
Patent number
US09114141B2

Reaction notes

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