Diisopropylethylamine → p-nitrobenzyl (1R,5S,6S)-2-[1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate

To a solution of 3-acetylthio-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (238 mg, 0.73 mmol) (obtained as described in Reference Example 69) in dimethylformamide (7 ml) was added hydrazine acetate (81 mg, 0.88 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (523 mg, 0.88 mmol) in acetonitrile (14 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.51 ml, 2.92 mmol). The mixture was stirred for 2 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (20:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (211 mg, yield 46%) as a pale yellow solid.

1. customthe completion of the reaction
2. stirringThe mixture was stirred for 2 hours
3. additionwere added to the reaction mixture
4. stirringThe resulting mixture was shaken in a separatory funnel
5. customthe ethyl acetate layer was separated
6. washwashed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution
7. dry with materialdried over anhydrous magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure
10. customThe residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (20:1))

ORD record

ord-22e5e31776fc4c26b37ae245d3a6851c

Source dataset

uspto-grants-2006_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07001897B2