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 42423Notes

Reaction equation

HRID 42423 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-3bdd8b32046847278e5773e48c674e4d
Source dataset
uspto-grants-2013_09
Patent number
US08536179B2

Reaction notes

Loading…