Reaction #838944

Reaction equation

acid

tert-Butyl (S)-2-[1-((S)-2-{(S)-2-[(2S,4R)-2-((S)-2-benzyloxycarbonylamino-2-carboxy-ethoxycarbonyl)-4-methyl-pyrrolidin-1-yl]-1-methyl-2-oxo-ethylcarbamoyl}-piperidin-1-yl)-methanoyl]-pyrrolidine-1-carboxylate

pentafluorophenol

EDC

→

Benzyl ((3S,9S,13S,15R,19S,22S)-15,19-dimethyl-2,8,12,18,21-pentaoxo-11-oxa-1,7,17,20-tetraaza-tetracyclo[20.4.0.03,7.013,17]hexacos-9-yl)-carbamate

Solvents

dichloromethane

Conditions

Workup

1. 1
   Temperaturewith slow warming to RT
2. 2
   ConcentrationThe reaction solution is concentrated to dryness
3. 3
   workup.ADDITIONthe residue is treated at 0° C. with 4N hydrogen chloride solution in dioxane (80 ml)
4. 4
   workup.STIRRINGThe mixture is stirred for 3 h
5. 5
   Otherthe solvent is subsequently removed in vacuo
6. 6
   workup.DISSOLUTIONThe residue is dissolved in dichloromethane (about 900 ml)
7. 7
   workup.ADDITIONslowly added dropwise at RT to a vigorously stirred two-phase mixture of 1N aqueous sodium hydrogencarbonate solution (700 ml) and dichloromethane (1200 ml)
8. 8
   workup.STIRRINGThe reaction mixture is stirred overnight
9. 9
   OtherThe phases are separated
10. 10
    Extractionthe aqueous phase is extracted three times with dichloromethane
11. 11
    Dryingthe combined organic phases are dried over sodium sulfate
12. 12
    Filtrationfiltered
13. 13
    Concentrationconcentrated to dryness
14. 14
    OtherThe residue (2.7 g of yellow hard foam) is purified by chromatography in 3 portions by means of preparative RP-HPLC
15. 15
    Other1.98 g (60% of th.) of the product are obtained

Procedure

3.95 g (5.41 mm ol) of the acid from example 25A and 3.98 g (21.65 mmol) of pentafluorophenol are dissolved in dichloromethane (13 ml) and cooled to −20° C. under argon. 1.14 g (5.95 mmol) of EDC are added, and the reaction mixture is stirred overnight with slow warming to RT. The reaction solution is concentrated to dryness and the residue is treated at 0° C. with 4N hydrogen chloride solution in dioxane (80 ml). The mixture is stirred for 3 h and the solvent is subsequently removed in vacuo. The residue is dissolved in dichloromethane (about 900 ml) and slowly added dropwise at RT to a vigorously stirred two-phase mixture of 1N aqueous sodium hydrogencarbonate solution (700 ml) and dichloromethane (1200 ml). The reaction mixture is stirred overnight. The phases are separated, the aqueous phase is extracted three times with dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness. The residue (2.7 g of yellow hard foam) is purified by chromatography in 3 portions by means of preparative RP-HPLC using acetonitrile/water (gradient). 1.98 g (60% of th.) of the product are obtained.

Source