Reaktion #5681

Reaktionsgleichung

5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine

dimethylaminopyridine

dimethylaminopyridine hydrochloride

N-benzyloxycarbonyl-L-valine

dicyclohexylcarbodiimide

→

5-L-valyloxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine

Ausbeute 38.5%

Lösungsmittel

acetic acid

methanol

acetic acid

ethyl acetate

chloroform

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.STIRRINGthe mixture is stirred at room temperature for 30 minutes
2. 2
   SonstigeThe insoluble materials are removed by filtration
3. 3
   workup.ADDITIONto the filtrate is added 5% aqueous sodium hydrogen sulfate solution
4. 4
   Extraktionfurther extracted with dichloromethane
5. 5
   WaschenThe extract is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine
6. 6
   Trocknendried over magnesium sulfate
7. 7
   workup.DISTILLATIONthe solvent is distilled off under reduced pressure
8. 8
   Sonstigeto give crude 5-N-benzyloxycarbonyl-L-valyloxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.0 g)
9. 9
   Sonstigeis subjected to hydrogenation at ordinary room temperature under atmospheric pressure
10. 10
    SonstigeAfter hydrogenation, the catalyst is removed by filtration
11. 11
    Einengenthe filtrate is concentrated
12. 12
    SonstigeThe resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate)

Vorschrift

To a solution of 5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.0 g), dimethylaminopyridine (1.26 g) and dimethylaminopyridine hydrochloride (1.10 g) in chloroform (20 ml) are added N-benzyloxycarbonyl-L-valine (672 mg) and dicyclohexylcarbodiimide (1.42 g), and the mixture is stirred at room temperature for 7 hours. To the mixture are added methanol (3 ml) and acetic acid (0.7 ml), and the mixture is stirred at room temperature for 30 minutes. The insoluble materials are removed by filtration, and to the filtrate is added 5% aqueous sodium hydrogen sulfate solution, and further extracted with dichloromethane. The extract is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure to give crude 5-N-benzyloxycarbonyl-L-valyloxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.0 g). This product is dissolved in a mixture of acetic acid (15 ml) and ethyl acetate (15 ml), and thereto is added 5% Pd-C (0.3 g). The mixture is subjected to hydrogenation at ordinary room temperature under atmospheric pressure. After hydrogenation, the catalyst is removed by filtration, and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate) to give Isomer A (0.48 g) and Isomer B (0.47 g) of 5-L-valyloxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.

Quelle