1-Hydroxybenzotriazole → 7-(4-methylphenyl)-N-[1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidin-4-yl]-2,3-dihydro-1-benzooxepine-4-carboxamide

HRID 1169408Notes

Reaction equation

HRID 1169408 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:46][CH:47]1[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][N:55]([CH3:62])[CH:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[CH2:49][CH2:48]1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:46][CH:47]4[CH2:48][CH2:49][N:50]([CH2:53][CH2:54][N:55]([CH3:62])[CH:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)[CH2:51][CH2:52]4)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 105646997-(4-Methylphenyl)-2,3-dihydrobenzooxepine-4-carboxylic acidHCID 229899814-amino-1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidine dihydrochloride

Product 1

HCID 229901477-(4-methylphenyl)-N-[1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidin-4-yl]-2,3-dihydro-1-benzooxepine-4-carboxamideYield 36.7%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 8471TriethylamineSolvent

Procedure

Into a solution of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (0.14 g) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g), and the resulting mixture was stirred for one hour. Into the reaction mixture was added a solution of 4-amino-1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidine dihydrochloride (282 mg), triethylamine (0.15 ml.) and diazabicyclo[5,4,0]-7-undecene (0.37 g) in acetonitrile (15 ml), and the resulting mixture was stirred for 18 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was evaporated to remove the solvent, and then the residue was subjected to purification using column chromatography (triethylamine/ethanol/ethyl acetate 1:10:10) and further to recrystallization (ethyl acetate/hexane) to obtain 7-(4-methylphenyl)-N-[1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidin-4-yl]-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 62) (99 mg) as colorless crystals.

Workup

  1. stirringthe resulting mixture was stirred for 18 hours
  2. concentrationAfter the reaction mixture was concentrated under reduced pressure, water
  3. additionwas added to the residue
  4. extractionthe resulting mixture was extracted with ethyl acetate
  5. washThe organic layer was washed with an aqueous saturated solution of sodium chloride
  6. dry with materialwas dried with magnesium sulfate
  7. customThe resulting organic layer was evaporated
  8. customto remove the solvent
  9. customthe residue was subjected to purification
  10. customfurther to recrystallization (ethyl acetate/hexane)

Sources & evidence

ORD record
ord-453d39eabfa84d4d969ec316f3bb04f6
Source dataset
uspto-grants-2003_09
Patent number
US06627651B1

Reaction notes

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