In one of its steps the racemic alcohol 1 is dissolved in a mixture of toluene and methanol to which solution is added optically active (S)-mandelic acid 3. The alcohol (S)-enantiomer forms an insoluble diastereomeric salt with the mandelic acid and can be filtered from the solution. Simple deprotonation with sodium hydroxide liberates free (S)-alcohol. In the meanwhile the (R)-alcohol remains in solution unaffected and is recycled back to the racemic mixture by epimerization with hydrochloric acid in toluene. This process is known asRRR synthesis in which the R’s stand for Resolution-Racemization-Recycle. ref 1,2,3
This is a modern-day method of chiral resolution used in the organic synthesis of the drug Duloxetine: ref 4
References
- William H. Porter (1991). “Resolution of chiral drugs”. Pure Appl. Chem.63 (8): 1119–1122. DOI:10.1351/pac199163081119.
- Enantiomers, racemates, and resolutions Jean Jacques, André Collet, amuel H Wilen 1981ISBN 0-471-08058-6
- Harold E. Zaugg (1955). “A Mechanical Resolution of dl-Methadone Base”. J. Am. Chem. Soc.77 (10): 2910.DOI:10.1021/ja01615a084.
- Yoshito Fujima, Masaya Ikunaka, Toru Inoue, and Jun Matsumoto (2006). “Synthesis of (S)-3-(N-Methylamino)-1-(2-thienyl)propan-1-ol: Revisiting Eli Lilly’s Resolution-Racemization-Recycle Synthesis of Duloxetine for Its Robust Processes”. Org. Process Res. Dev.10 (5): 905–913. http://pubs.acs.org/doi/abs/10.1021/op060118l
(S)-3-(N-methylamino)-1-(2-thienyl)propan-1-ol (1) of 100% ee, an alleged penultimate precursor to duloxetine
