Water → 1-[1-Benzyloxycarbonyl-4-(R)-methoxy-3-(S)-pyrrolidinyl]cyclopropanecarboxylic acid

Temperature

0 °C

Under a nitrogen atmosphere, 60% sodium hydride (0.149 g, 3.73 mmol) was suspended in anhydrous tetrahydrofuran (20 ml) to which, after cooling to 0° C., was subsequently added dropwise a dry tetrahydrofuran (20 ml) solution of 1-benzyloxycarbonyl-3-(S)-hydroxy-4-(R)-(1-ethoxycarbonylcyclopropyl)pyrrolidine (0.98 g, 2.92 mmol) over a period of 5 minutes. After 15 minutes of stirring in an ice bath, dimethyl sulfate (0.441 ml, 4.66 mmol) was added dropwise to the reaction solution which was cooled in the ice bath. The reaction solution was stirred at room temperature for 4 hours and then mixed with water (0.5 ml), followed by evaporating tetrahydrofuran under reduced pressure. The thus obtained residue was dissolved in ethanol (40 ml), and a 1 M sodium hydroxide aqueous solution (8.76 ml) was added dropwise to the resulting solution at room temperature. The reaction solution was heated under reflux for 2 hours and then ethanol was evaporated under reduced pressure. The resulting residue was cooled in an ice bath, acidified by adding dropwise a 1 M hydrochloric acid aqueous solution (15 ml) and then extracted with ethyl acetate (50 ml×3). All of the organic layers were combined, washed with a 1 N hydrochloric acid aqueous solution (50 ml) and saturated brine (50 ml) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 0.935 g (quantitative) of the title compound as a colorless amorphous substance.

1. stirringThe reaction solution was stirred at room temperature for 4 hours
2. customby evaporating tetrahydrofuran under reduced pressure
3. dissolutionThe thus obtained residue was dissolved in ethanol (40 ml)
4. additiona 1 M sodium hydroxide aqueous solution (8.76 ml) was added dropwise to the resulting solution at room temperature
5. temperatureThe reaction solution was heated
6. temperatureunder reflux for 2 hours
7. customethanol was evaporated under reduced pressure
8. temperatureThe resulting residue was cooled in an ice bath
9. additionby adding dropwise a 1 M hydrochloric acid aqueous solution (15 ml)
10. extractionextracted with ethyl acetate (50 ml×3)
11. washwashed with a 1 N hydrochloric acid aqueous solution (50 ml) and saturated brine (50 ml)
12. dry with materialdried over anhydrous sodium sulfate
13. filtrationAfter filtration
14. concentrationthe filtrate was concentrated under reduced pressure

ORD record

ord-db4cc4b8a528433d86ea464ae3b0a302

Source dataset

uspto-grants-2000_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06121285