Reaction #1441

Reaction equation

t-butoxycarbonylglycine

1-hydroxybenztriazole

N-methylmorpholine

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

4'-[(2-amino-5,6-dihydro-4H-thiazolo[5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide hydrobromide

→

4'-[(2-glycylamino-5,6-dihydro-4H-thiazolo[5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide 2-propylalcohol hydrochloride

Yield 55.7%

Solvents

water

dichloromethane

triethylamine

dichloromethane

Conditions

Workup

1. 1
   workup.ADDITIONwas added to the resulting solution
2. 2
   workup.STIRRINGstirred for 60 minutes
3. 3
   TemperatureTo this reaction solution, again cooled on an ice bath
4. 4
   workup.DISSOLUTIONhad been dissolved
5. 5
   workup.STIRRINGstirring at room temperature
6. 6
   workup.STIRRINGstirred for 60 minutes
7. 7
   Othersubjected to phase separation
8. 8
   OtherThe dichloromethane layer was separated
9. 9
   Washwashed with a saturated sodium bicarbonate aqueous solution
10. 10
    Dryinga saturated sodium chloride aqueous solution once for each and then dried over anhydrous magnesium sulfate
11. 11
    OtherAfter removing the solvent
12. 12
    workup.DISTILLATIONby distillation
13. 13
    TemperatureWith cooling on an ice bath
14. 14
    workup.ADDITIONthe suspension was mixed with 4.4 ml of 4N hydrochloric acid-dioxane
15. 15
    workup.STIRRINGstirred for 3 hours
16. 16
    ConcentrationThereafter, the reaction solution was concentrated
17. 17
    Otherthe thus obtained residue was recrystallized from 2-propyl alcohol

Procedure

After dissolving 176 mg of t-butoxycarbonylglycine, 205 mg of 1-hydroxybenztriazole and 0.15 ml of N-methylmorpholine in 3.5 ml of dichloromethane, 192 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to the resulting solution with stirring on an ice bath, and the mixture was warmed up to room temperature and stirred for 60 minutes. To this reaction solution, again cooled on an ice bath, was added dropwise 4 ml of dichloromethane in which 400 mg of the 4'-[(2-amino-5,6-dihydro-4H-thiazolo[5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide hydrobromide described in Example 1 and 0.103 ml of triethylamine had been dissolved, followed by overnight stirring at room temperature. The reaction solution was mixed with water, stirred for 60 minutes and then subjected to phase separation. The dichloromethane layer was separated, washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution once for each and then dried over anhydrous magnesium sulfate. After removing the solvent by distillation, the thus obtained residue was suspended in 3 ml of methyl alcohol. With cooling on an ice bath, the suspension was mixed with 4.4 ml of 4N hydrochloric acid-dioxane and stirred for 3 hours. Thereafter, the reaction solution was concentrated and the thus obtained residue was recrystallized from 2-propyl alcohol to obtain 250 mg of 4'-[(2-glycylamino-5,6-dihydro-4H-thiazolo[5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide 2-propylalcohol hydrochloride.

Source