Sodium Hydroxide → Kdi 792

Temperature

40 °C

In an atmosphere of nitrogen, potassium t-butoxide (21.9 g, 0.195 mol) was dissolved in tetrahydrofuran (140 ml) and after the solution was cooled to 0°-5° C., (4-carboxybutyl)triphenylphosphonium chloride (43.3 g, 0.0975 mol) was added thereto. The mixture was warmed to 40° C. and stirred for 1 hour. The reaction mixture was cooled to 0°-5° C. and a solution of (2S,4R)-1-(3-pyridylmethyl)-2-formyl-4-(4-chlorophenylsulfonylamino)pyrrolidine (10.4 g) in tetrahydrofuran (60 ml) was added thereto dropwise. This reaction mixture was stirred at -5°~5° C. for 1 hour, after which it was poured into methylene chloride (200 ml) and 1N-hydrochloric acid (400 ml) for extraction. After phase separation, the methylene chloride layer was extracted with 1N-hydrochloric acid (200 ml) twice. The aqueous layer was combined and adjusted to pH 5.5 with 24% sodium hydroxide in water (pH prior to adjustment=0.25-0.3). The aqueous solution was extracted with ethyl acetate (200 ml), while the aqueous layer was re-extracted with ethyl acetate (100 ml). The ethyl acetate layer was combined and concentrated to dryness under reduced pressure to provide an oil. This oil was dissolved in 1N-hydrochloric acid (70 ml)-purified water (35 ml) and the solution was adjusted to pH 2.2 by dropwise addition of 1N-aqueous sodium hydroxide solution. The mixture was stirred at 20°-25° C. for crystallization and ripening. During this procedure, 1N-aqueous sodium hydroxide solution was added thereto dropwise so as to maintain the solution at pH 2.2. After (about 1 hour of) ripening, 1N-aqueous sodium hydroxide solution was added thereto dropwise so as to adjust the solution to pH 3.5. The solution was then cooled to 5° C. and stirred for 1 hour. The resulting crystal was collected by filtration, washed with cold purified water (10 ml) and dried in vacuo overnight to provide (2S,4R)-2-[(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)-1-(3-pyridylmethyl)pyrolidine hydrochloride (8.0 g) as crude crystal.

1. temperatureafter the solution was cooled to 0°-5° C.
2. temperatureThe reaction mixture was cooled to 0°-5° C.
3. stirringThis reaction mixture was stirred at -5°~5° C. for 1 hour
4. customAfter phase separation
5. extractionthe methylene chloride layer was extracted with 1N-hydrochloric acid (200 ml) twice
6. extractionThe aqueous solution was extracted with ethyl acetate (200 ml), while the aqueous layer
7. extractionwas re-extracted with ethyl acetate (100 ml)
8. concentrationconcentrated to dryness under reduced pressure
9. customto provide an oil
10. stirringThe mixture was stirred at 20°-25° C. for crystallization
11. temperaturedropwise so as to maintain the solution at pH 2.2
12. customAfter (about 1 hour of)
13. temperatureThe solution was then cooled to 5° C.
14. stirringstirred for 1 hour
15. filtrationThe resulting crystal was collected by filtration
16. washwashed
17. customwith cold purified water (10 ml)
18. customdried in vacuo overnight

ORD record

ord-d3545aae46b04dd09d30b7eb840c707c

Source dataset

uspto-grants-1997_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05675011