Реакция #5681

Уравнение реакции

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

Выход 38.5%

Растворители

acetic acid

methanol

acetic acid

ethyl acetate

chloroform

Условия реакции

Обработка

1. 1
   workup.STIRRINGthe mixture is stirred at room temperature for 30 minutes
2. 2
   ДругоеThe insoluble materials are removed by filtration
3. 3
   workup.ADDITIONto the filtrate is added 5% aqueous sodium hydrogen sulfate solution
4. 4
   Экстракцияfurther extracted with dichloromethane
5. 5
   ПромывкаThe extract is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine
6. 6
   Сушкаdried over magnesium sulfate
7. 7
   workup.DISTILLATIONthe solvent is distilled off under reduced pressure
8. 8
   Другоеto 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
   Другоеis subjected to hydrogenation at ordinary room temperature under atmospheric pressure
10. 10
    ДругоеAfter hydrogenation, the catalyst is removed by filtration
11. 11
    Концентрированиеthe filtrate is concentrated
12. 12
    ДругоеThe resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate)

Методика

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.

Источник