反应详情

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.

1. stirringthe mixture is stirred at room temperature for 30 minutes
2. customThe insoluble materials are removed by filtration
3. additionto the filtrate is added 5% aqueous sodium hydrogen sulfate solution
4. extractionfurther extracted with dichloromethane
5. washThe extract is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine
6. dry with materialdried over magnesium sulfate
7. distillationthe solvent is distilled off under reduced pressure
8. customto 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. customis subjected to hydrogenation at ordinary room temperature under atmospheric pressure
10. customAfter hydrogenation, the catalyst is removed by filtration
11. concentrationthe filtrate is concentrated
12. customThe resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate)