Reacción #5154

Ecuación de reacción

diisopropylethylamine

salt

(2S, 4S)-2-carbamoyl-4-mercapto-1,1-dimethylpyrrolidinium

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

diisopropylethylamine

diphenylphosphoryl chloride

→

title compound

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

Disolventes

tetrahydrofuran

phosphate

palladium-on-charcoal

acetonitrile

acetonitrile

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturacooling
2. 2
   workup.STIRRINGthe mixture was then stirred for 7 hours
3. 3
   workup.WAITto stand for 2 days at the same temperature
4. 4
   workup.DISTILLATIONThe solvent was then distilled off under reduced pressure
5. 5
   Lavadothe residue was washed repeatedly by decantation
6. 6
   Otrodried under reduced pressure
7. 7
   Otroto afford a crude product
8. 8
   OtroAt the end of this time, an insoluble material was removed by filtration with the help of a Celite (trade mark)
9. 9
   Filtraciónfilter aid
10. 10
    Lavadothe filtrate was washed with diethyl ether
11. 11
    ConcentraciónThe aqueous layer was then concentrated by evaporation under reduced pressure
12. 12
    Lavado(Mitsubishi Chemical Industries, Ltd.) and the fractions eluted with a 5% by volume aqueous acetone solution
13. 13
    Concentraciónwere concentrated by evaporation under reduced pressure
14. 14
    Otroto afford a crude product as a yellow powder
15. 15
    OtroThis crude product was purified by chromatography
16. 16
    LavadoThe fractions eluted with 5% and 10% by volume aqueous methanolic solutions
17. 17
    Otrowere collected
18. 18
    Concentraciónconcentrated by evaporation under reduced pressure

Procedimiento

0.20 ml of diisopropylethylamine and 0.24 ml of diphenylphosphoryl chloride were added dropwise, whilst ice-cooling, to a solution of 400 mg of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 4 ml of dry acetonitrile, and the mixture was stirred at the same temperature for 1 hour. At the end of this time, 0.46 ml of diisopropylethylamine and a solution of the salt prepared in step (1) above in 3 ml of acetonitrile were added to the reaction mixture, whilst ice-cooling, and the mixture was then stirred for 7 hours and then allowed to stand for 2 days at the same temperature. The solvent was then distilled off under reduced pressure, and the residue was washed repeatedly by decantation using diethyl ether and dried under reduced pressure to afford a crude product. This crude product was then 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 555 mg of 10% w/w palladium-on-charcoal. At the end of this time, an insoluble material was removed by filtration with the help of a Celite (trade mark) filter aid, and the filtrate was washed with diethyl ether. The aqueous layer was then concentrated by evaporation under reduced pressure. The residue was adsorbed on a column of Diaion (trade mark) HP-20AG (Mitsubishi Chemical Industries, Ltd.) and the fractions eluted with a 5% by volume aqueous acetone solution were concentrated by evaporation under reduced pressure, and the residue was lyophilized to afford a crude product as a yellow powder. This crude product was purified by chromatography using a Lobar column (Merck Co., LiChroprep RP-8, size B). The fractions eluted with 5% and 10% by volume aqueous methanolic solutions were collected and concentrated by evaporation under reduced pressure, and the residue was lyophilized to afford 100 mg of the title compound.

Fuente