4-(Dimethylaminomethyl)piperidine → 6-(4-((Dimethylamino)methyl)piperidin-1-yl)-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid

HRID 62318Notes

Reaction equation

HRID 62318 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:18][N:19]([CH3:27])[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:18][N:19]([CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]3[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH2:23][CH2:22]1)[CH3:27]

Participants

5

Reactant 3

HCID 111372684-(Dimethylaminomethyl)piperidineHCID 23676156Sodium t-butoxideHCID 674686786-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid

Product 1

HCID 674659296-(4-((Dimethylamino)methyl)piperidin-1-yl)-1-isopropyl-3-methyl-1H-indole-4-carboxylic acidYield 54%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
98 °C

Procedure

To a 10-mL microwave tube were added 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (100 mg, 0.338 mmol), 1,4-dioxane (2 mL), N,N-dimethyl-1-(4-piperidinyl)methanamine (52.8 mg, 0.371 mmol) and sodium tert-butoxide (71.4 mg, 0.743 mmol), and the mixture was degassed for 5 min. Choro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]Pd(11)Me-t-butylether adduct (13.96 mg, 0.017 mmol) was added and the tube was sealed. The mixture was stirred at 98° C. with stirring for 20 h. The mixture was then concentrated and the residue was purified using reverse-phase HPLC (Gemini 5u C18(2) 100A, AXIA; 30×100 mm 5 micron; (30 mL/min, 7% ACN/H2O, 0.1% formic acid to 37% ACN/H2O, 0.1% formic acid) to give the title compound (65 mg, 54%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.34 (m, 2H), 1.39 (d, J=6.57 Hz, 6H), 1.58-1.71 (m, 1H), 1.82 (d, J=11.87 Hz, 2H), 2.23-2.31 (m, 10H), 2.66 (td, J=11.94, 1.89 Hz, 2H), 3.57-3.71 (m, 2H), 4.70 (quin, J=6.63 Hz, 1H), 7.09 (d, J=2.02 Hz, 1H), 7.15 (dd, J=9.60, 1.52 Hz, 2H). MS: (M+H)+=358.2.

Workup

  1. customthe mixture was degassed for 5 min
  2. customthe tube was sealed
  3. stirringwith stirring for 20 h
  4. concentrationThe mixture was then concentrated
  5. customthe residue was purified

Sources & evidence

ORD record
ord-523629c77c1648c8b4460f2deb81de22
Source dataset
uspto-grants-2016_09
Patent number
US09446041B2

Reaction notes

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