Iodine → 1-(3-(dimethylamino)propyl)-4-(4-(tetrahydro-2H-pyran-2-yloxy)benzoyl)pyridin-2(1H)-one

HRID 626203Notes

Reaction equation

HRID 626203 reaction equation
II.C(Br)C.Br[C:7]1[CH:19]=[CH:18][C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[CH3:20][N:21]([CH3:38])[CH2:22][CH2:23][CH2:24][N:25]1[CH:30]=[CH:29][C:28]([C:31](N(OC)C)=[O:32])=[CH:27][C:26]1=[O:37]>C1COCC1>[CH3:38][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][N:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:32])[C:7]2[CH:19]=[CH:18][C:10]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:9][CH:8]=2)=[CH:27][C:26]1=[O:37]

Participants

6

Reactant 4

HCID 807IodineHCID 6332Ethyl BromideHCID 46464362-(4-Bromophenoxy)tetrahydro-2H-pyran2×HCID 896728791-(3-(dimethylamino)propyl)-N-methoxy-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide

Product 1

HCID 896574441-(3-(dimethylamino)propyl)-4-(4-(tetrahydro-2H-pyran-2-yloxy)benzoyl)pyridin-2(1H)-oneYield 80%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
55 °C

Procedure

Mg (440 mg, 3.5 eq) was added to a 3-neck round bottom flask containing 50 mL anhydrous THF, and the mixture was heated to 55° C. Iodine chips (2 grains) were added in one lot followed by 0.1 mL ethyl bromide. 2-(4-Bromophenoxy)-tetrahydro-2H-pyran (4.0 g, 3.0 eq) was dissolved in 30 mL anhydrous THF, and 3 mL of this solution was added at once to the Mg-THF suspension. The reaction was initiated after 30 min and reflux started. the remaining solution of 2-(4-bromophenoxy)-tetrahydro-2H-pyran was added dropwise maintaining the reflux temperature over 5 min. After addition, the reaction mixture was further reflux for 2 h., cooled to rt, 1-(3-(dimethylamino)propyl)-N-methoxy-N-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxamide (1.4 g, 1.0 eq) in 20 mL THF was added dropwise at rt, stirred at rt for 30 min., quenched with sat NH4Cl (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (1.6 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=9.2 Hz, 2H), 7.48 (d, J=6.8 Hz, 1H), 7.11 (d, J=9.2 Hz, 2H), 6.75 (d, J=1.6 Hz, 1H), 6.44 (dd, J=6.8 Hz, 2.0 Hz, 1H), 5.55 (t, J=2.8 Hz, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.82-3.88 (m, 1H), 3.62-3.66 (m, 1H), 2.32 (t, J=6.4 Hz, 2H), 2.24 (s, 6H), 1.88-2.08 (m, 5H), 1.62-1.74 (m, 4H).

Workup

  1. temperaturereflux
  2. temperaturemaintaining the reflux temperature over 5 min
  3. additionAfter addition
  4. temperaturethe reaction mixture was further reflux for 2 h.
  5. temperaturecooled to rt
  6. customquenched with sat NH4Cl (aq)
  7. extractionextracted with EtOAc
  8. customThe extract was dried
  9. concentrationconcentrated
  10. custompurified by column chromatography

Sources & evidence

ORD record
ord-9d1b8c308def4c5f8d455763181f548c
Source dataset
uspto-grants-2016_04
Patent number
US09309211B2

Reaction notes

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