Ethyl Acetate → 5-Dehydro Tolvaptan

HRID 2389239Notes

Reaction equation

HRID 2389239 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:4][C:3]=1[CH3:18].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:29][CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=2[CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O.[OH-].[Na+].[C:55](OCC)(=[O:57])C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C)C=O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[N:29]([C:55](=[O:57])[C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH3:16])=[CH:4][C:3]=3[CH3:18])[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=2[CH:31]=1

Participants

9

Reactant 6

HCID 8857Ethyl AcetateHCID 11776TriphenylphosphineHCID 14798Sodium HydroxideHCID 825633N-(4-bromo-3-methylphenyl)-2-methylbenzamideHCID 229034837-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-oneHCID 178418416HCID 178418416, compound

Product 1

HCID 113628435-Dehydro TolvaptanYield 85%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Procedure

Well-dried 2-bromo-5-(2-methylbenzoylamino)toluene (3.2 g, 10.5 mM) and 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (1.8 g, 9.2 mM) are entered into a reaction vessel, and thereto are added 1,8-diazabicyclo[5.4.0]undecene-7 (DBU) (2.5 mL) and N,N-dimethylformamide (DMF) (6 mL), and the mixture is stirred at room temperature. To the solution thus obtained are added triphenylphosphine (221 mg) and Pd(OAc)2 (23.5 mg, 0.105 mM), and the mixture is heated under carbon monoxide at 125° C. for 3 hours. The reaction mixture is cooled till room temperature, and thereto is blown argon gas to discharge excess carbon monoxide. Thereafter, to the mixture are added ethyl acetate (150 mL) and 0.5M aqueous NaOH solution (50 mL) to divide into two phases. The organic layer is washed with diluted hydrochloric acid and then with saturated saline and dried over magnesium sulfate. After filtering off magnesium sulfate, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane) to give the desired 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (3.5 g) as pale yellowish white crystalline powder (Yield 85%, purity 99.1%, Mp 134-142° C.).

Workup

  1. customTo the solution thus obtained
  2. temperaturethe mixture is heated under carbon monoxide at 125° C. for 3 hours
  3. temperatureThe reaction mixture is cooled till room temperature
  4. washThe organic layer is washed with diluted hydrochloric acid
  5. dry with materialwith saturated saline and dried over magnesium sulfate
  6. filtrationAfter filtering off magnesium sulfate
  7. concentrationthe filtrate is concentrated under reduced pressure
  8. customthe residue is purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane)

Sources & evidence

ORD record
ord-eca46a8540fa4a1684abf3b0cc9b6131
Source dataset
uspto-grants-2012_09
Patent number
US08273735B2

Reaction notes

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