6-Chloro-N-methylnicotinamide → 6-[(3-Boc-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)oxy]-N-methylnicotinamide

HRID 645787Notes

Reaction equation

HRID 645787 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][CH3:34])=[O:32])=[CH:29][N:28]=1>C(O)(C)(C)C>[CH3:34][NH:33][C:31]([C:30]1[CH:35]=[CH:36][C:27]([O:19][C:16]2[CH:17]=[CH:18][C:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=3[CH:15]=2)=[N:28][CH:29]=1)=[O:32]

Participants

5

Reactant 3

HCID 123642306-Chloro-N-methylnicotinamideHCID 18173274tert-butyl 7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine-3-carboxylateHCID 23665647Potassium tert-butoxide

Product 1

HCID 592579286-[(3-Boc-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)oxy]-N-methylnicotinamide

Reagents, catalysts & solvents 1

HCID 6386tert-ButanolSolvent

Procedure

7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (8.7 g, 33 mmol) was dissolved in tert-butanol and treated with potassium-tert-butoxide (4 g, 36 mmol). After stirring for 30 minutes at room temperature, 6-chloro-N-methyl-nicotinamide (D10) (5.1 g, 30 mmol) was added and the reaction mixture was stirred at reflux for 20 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Ice/water was added to the crude residue resulting in a precipitate which was collected by filtration. The solid precipitate was dissolved in ethyl acetate, washed with brine and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:1) to afford the title compound (D39). NMR (CDCl3) 8.52 (1H, d, J=2.4), 8.12 (1H, dd, J=8.8), 7.16 (1H, m), 6.95-6.81 (3H, m), 6.02 (1H, br), 3.57 (4H, br), 3.02 (3H, d, J=2.4), 2.89 (4H, br), 1.49 (9H, s).

Workup

  1. stirringthe reaction mixture was stirred
  2. temperatureat reflux for 20 hours
  3. temperatureThe reaction mixture was cooled to room temperature
  4. concentrationconcentrated in vacuo
  5. additionIce/water was added to the crude residue
  6. customresulting in a precipitate which
  7. filtrationwas collected by filtration
  8. dissolutionThe solid precipitate was dissolved in ethyl acetate
  9. washwashed with brine
  10. dry with materialdried (magnesium sulfate)
  11. filtrationThe organic layer was filtered
  12. concentrationconcentrated in vacuo
  13. customthe resulting residue was purified by column chromatography
  14. washeluting with a mixture of ethyl acetate:hexane (1:1)

Sources & evidence

ORD record
ord-7590ebcb8beb4f268b5201b138b21c32
Source dataset
uspto-grants-2010_04
Patent number
US07704994B2

Reaction notes

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