Reaction #82372

Reaction equation

hydroxybenzotriazole

dicyclohexylcarbodiimide

N-(benzyloxycarbonyl)-3-cyano-L-alanine

N2 [3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide

→

N2 [3(S)-[[N-(benzyloxycarbonyl)-3-cyano-L-alanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide hemihydrate

Yield 23.4%

Solvents

dimethyformamide

dichloromethane

Conditions

Workup

1. 1
   Temperaturecooled in an ice/salt bath
2. 2
   workup.STIRRINGThe mixture was stirred for 5 minutes
3. 3
   workup.STIRRINGwas then stirred overnight
4. 4
   FiltrationThe resulting dicyclohexylurea was filtered off
5. 5
   Washwashed with methylene chloride
6. 6
   OtherThe combined filtrate and washings were evaporated at 40° C. in a vacuum
7. 7
   Otherto give an oil which
8. 8
   Otherwas partitioned between ethyl acetate and water
9. 9
   WashThe organic phase was washed in sequence with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution
10. 10
    Dryingdried over sodium sulphate
11. 11
    OtherThe solvent was removed by evaporation
12. 12
    Otherto give an oil which
13. 13
    Otherwas chromatographed on silica gel using 14% methanol in dichloromethane for the elution
14. 14
    Otherwas recrystallized from diethyl ether/n-hexane

Procedure

0.122 g of N-(benzyloxycarbonyl)-3-cyano-L-alanine was dissolved in 2 ml of dry dimethyformamide. The solution was stirred and cooled in an ice/salt bath and treated with 0.066 g of hydroxybenzotriazole and 0.1 g of dicyclohexylcarbodiimide. The mixture was stirred for 5 minutes and then treated with 0.163 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide in 2.5 ml of dry dichloromethane. The mixture was allowed to warm to room temperature and was then stirred overnight. The resulting dicyclohexylurea was filtered off and washed with methylene chloride. The combined filtrate and washings were evaporated at 40° C. in a vacuum to give an oil which was partitioned between ethyl acetate and water. The organic phase was washed in sequence with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution and then dried over sodium sulphate. The solvent was removed by evaporation to give an oil which was chromatographed on silica gel using 14% methanol in dichloromethane for the elution. There were thus obtained 50 mg of product which was recrystallized from diethyl ether/n-hexane to give 0.045 g of N2 -[3(S)-[[N-(benzyloxycarbonyl)-3-cyano-L-alanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide hemihydrate as a solid of melting point 65°-70° C. (softening).

Source