1-Hydroxybenzotriazole → 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amide

HRID 516682Notes

Reaction equation

HRID 516682 reaction equation
[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:18]([OH:20])=O)[C:9]2[CH:10]=[CH:11][N:12]([CH:15]([CH3:17])[CH3:16])[C:13]=2[CH:14]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:53][CH2:54][C:55]1[C:56](=[O:65])[NH:57][C:58]([CH3:64])=[CH:59][C:60]=1[CH2:61][CH2:62][CH3:63]>CN(C=O)C.O>[CH3:64][C:58]1[NH:57][C:56](=[O:65])[C:55]([CH2:54][NH:53][C:18]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]([CH:15]([CH3:16])[CH3:17])[C:13]=3[CH:14]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:21])[CH:7]=2)=[O:20])=[C:60]([CH2:61][CH2:62][CH3:63])[CH:59]=1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 671241403-(Aminomethyl)-6-methyl-4-propylpyridin-2(1H)-oneacetateHCID 674640256-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid

Product 1

HCID 546702686-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amideYield 19.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Procedure

To a cooled (0° C.) mixture of 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (400 mg, 1.37 mmol) in DMF (10 mL) was added EDC.HCl (310 mg, 1.65 mmol) and HOBt.H2O (250 mg, 1.65 mmol). The reaction was stirred for 15 min, then DIPEA (1.2 mL, 6.89 mmol) and 3-aminomethyl-6-methyl-4-propyl-1H-pyridin-2-one (240 mg, 1.37 mmol) were added. The reaction was allowed to warm to RT and stirred for 16 h, at which time it was diluted with water (20 mL) and extracted with DCM (2×15 mL). The combined DCM layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography eluting with 3% MeOH in chloroform and then further purified by preparative HPLC to furnish 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (6-methyl-2-oxo-4-propyl-1,2-dihydro-pyridin-3-ylmethyl)-amide (120 mg, 19%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.92-0.88 (t, 3H), 1.43-1.41 (d, J=6.8 Hz, 6H), 1.56 (m, 2H), 2.12 (s, 3H), 2.22 (s, 6H), 2.55-2.53 (m, 2H), 2.06 (m, 2H), 4.11-4.09 (t, 2H), 4.36-4.34 (d, J=4.8 Hz, 2H), 4.76-4.73 (m, 1H), 5.90 (s, 1H), 6.74-6.73 (d, J=2.8 Hz, 1H), 7.04 (s, 1H), 7.20 (s, 1H), 7.43-7.42 (d, J=3.2 Hz, 1H), 8.10-8.07 (bs, 1H), 11.55 (bs, 1H). LCMS (ES+): m/z=453.23[M+H].

Workup

  1. temperatureTo a cooled
  2. stirringstirred for 16 h, at which time it
  3. extractionextracted with DCM (2×15 mL)
  4. dry with materialThe combined DCM layer was dried over Na2SO4
  5. concentrationconcentrated
  6. customThe residue was purified by flash column chromatography
  7. washeluting with 3% MeOH in chloroform
  8. customfurther purified by preparative HPLC

Sources & evidence

ORD record
ord-0ad2ddc9f6df4af2abee00f35a038d27
Source dataset
uspto-grants-2015_08
Patent number
US09114141B2

Reaction notes

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