Réaction #5158

Équation de réaction

(2S, 4S)-2-carbamoyl-1,1-dimethyl-4-mercaptopyrrolidinium

diisopropylethylamine

diphenylphosphoryl chloride

4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate

→

title compound

(5R, 6S)-2-[(2S, 4S)-2-Carbamoyl-1,1-dimethylpyrrolidinium-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate

Solvants

diethyl ether

acetonitrile

Conditions de réaction

Traitement

1. 1
   workup.DISSOLUTIONdissolved in 5 ml of dry acetronitrile
2. 2
   Températurecooling
3. 3
   workup.ADDITIONwas added to the mixture, whilst ice-
4. 4
   Températurecooling
5. 5
   workup.WAITto stand for 4 hours at the same temperature
6. 6
   workup.WAITfor 2 days in a refrigerator
7. 7
   Lavagethe resulting deposit was washed repeatedly by decantation
8. 8
   workup.DISSOLUTIONThe crude product was dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2.5 hours in the presence of 450 mg of 10% w/w palladium-on-charcoal
9. 9
   AutreAt the end of this time, insoluble materials were removed by filtration
10. 10
    Filtrationfilter aid
11. 11
    ConcentrationThe aqueous layer was concentrated by evaporation under reduced pressure
12. 12
    LavageFractions eluted with water
13. 13
    Autrewere collected

Mode opératoire

210 μl of diisopropylethylamine and 250 μl of diphenylphosphoryl chloride were simultaneously added, whilst ice-cooling, to a solution of 400 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate dissolved in 5 ml of dry acetronitrile, and the mixture was stirred for 1 hour, whilst ice-cooling. At the end of this time, a solution of 447 mg of the crude (2S, 4S)-2-carbamoyl-1,1-dimethyl-4-mercaptopyrrolidinium salt prepared as described in Example 1-(1) in 5 ml of dry acetonitrile was added to the mixture, whilst ice-cooling, and then the mixture was allowed to stand for 4 hours at the same temperature and then for 2 days in a refrigerator. The reaction mixture was then poured into diethyl ether and the resulting deposit was washed repeatedly by decantation. The crude product was dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2.5 hours in the presence of 450 mg of 10% w/w palladium-on-charcoal. At the end of this time, insoluble materials were removed by filtration using a Celite filter aid. The aqueous layer was concentrated by evaporation under reduced pressure, and the residue was transferred to a column packed with Diaion HP-20AG (Mitsubishi Chemicals Industries, Ltd.). Fractions eluted with water were collected and lyophilized to afford the title compound as a powder. This was further purified using a Lobar column (Merck, LiChroprep RP-8 size B) and fractions eluted with a 5% by volume aqueous methanolic solution were collected and concentrated by evaporation under reduced pressure followed by lyophilization, to afford 208 mg of the title compound.

Source