Hydrochloric Acid → tert-Butyl (3R)-3-hydroxypyrrolidine-1-carboxylate

Temperatur

30 °C

Preparation B: A reactor, maintained under a nitrogen atmosphere, was charged with 200 proof ethanol (5.50 kg) and 21% (by weight) sodium ethoxide in ethanol (7.00 kg, 21.6 mol). The mixture was stirred and warmed to 30° C. Diethyl malonate (3.50 kg, 21.9 mol) was added over a 20 min period. The reaction mixture was then warmed at 40° C. for 1.5 h. A solution of tert-butyl (R)-3-(methylsulfonyloxyl)pyrrolidine-1-carboxylate (3.00 kg of the product from Example 2, Procedure B, 10.7 mol) in 200 proof ethanol (5.50 kg) was added, and the resulting mixture was heated at reflux (78° C.) for 2 h. Both GC and TLC analysis (ninhydrin stain) indicated that no starting material remained. The stirred mixture was then cooled to 25° C., diluted with water (2.25 kg), and treated slowly with a solution of concentrated hydrochloric acid (1.27 kg, 12.9 mol) in water (5.44 kg). This mixture was washed twice with methyl tert-butyl ether (MTBE) (14.1 kg and 11.4 kg), using 15 min of stirring and 15 min of settling time for each wash. The combined MTBE washes were dried over anhydrous sodium sulfate (1 kg), filtered and concentrated under vacuum at 50° C. for 6 h. The residue (red oil) weighed 4.45 kg and was 49% desired product by GC analysis (62% overall yield from tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate).

1. customPreparation B
2. temperatureA reactor, maintained under a nitrogen atmosphere
3. temperatureThe reaction mixture was then warmed at 40° C. for 1.5 h
4. temperaturethe resulting mixture was heated
5. temperatureat reflux (78° C.) for 2 h
6. temperatureThe stirred mixture was then cooled to 25° C.
7. washThis mixture was washed twice with methyl tert-butyl ether (MTBE) (14.1 kg and 11.4 kg)
8. stirringof stirring and 15 min
9. dry with materialThe combined MTBE washes were dried over anhydrous sodium sulfate (1 kg)
10. filtrationfiltered
11. concentrationconcentrated under vacuum at 50° C. for 6 h

ORD-Eintrag

ord-486310cd566c49d39d6b9c2ce5ad79ee

Quelldatensatz

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08633227B2