Chiral resolution



Chiral resolution in drugs. Other terms with the same meaning are optical resolution and mechanical resolution.

One disadvantage of chiral resolution of racemates compared to direct asymmetric synthesis of one of the enantiomers is that only 50% of a desired enantiomer is obtained. Several methods exist.

Resolution by crystallization

Racemic compounds are known to crystallize as mixtures of supersaturated solution of sodium ammonium tartrate with a d-crystal on one side of the reactor and a l-crystal on the opposite side that crystals of opposite handedness will form on the opposite side of the reactor.

This type of resolution called spontaneous resolution has also been demonstrated with racemic petroleum ether and concentrated. Two millimeter-sized d- and l-crystals are added and after stirring for 125 hours at 40°C two large d- and l-crystals are recovered in 50% yield.

Another form of direct crystallization is preferential crystallization also called resolution by entrainment of one of the enantiomers. For example an added seed of (-)-hydrobenzoin to an optical purity can be obtained.

Chiral resolving agents

Derivatization of racemic compounds is possible with optically pure reagents forming pairs of tartaric acid with optically active (+)-cinchotoxine.

One modern-day method of chiral resolution is used in the Duloxetine [4]:

In one of its steps the hydrochloric acid in toluene. This process is known as RRR synthesis in which the R's stand for Resolution-Racemization-Recycle.

Chiral column chromatography

  • In chiral column chromatography the stationary phase is made chiral with similar resolving agents as described above.

See also

v • d • e
Concepts in Biocatalysis

References

  1. ^ Resolution of chiral drugs William H. Porter Pure & Appl. Chem., Vol. 63, No. 8, pp. 11 19-1 122,1991. Link
  2. ^ Enantiomers, racemates, and resolutions Jean Jacques, André Collet, Samuel H Wilen 1981 ISBN 0-471-08058-6
  3. ^ A Mechanical Resolution of dl-Methadone BaseHarold E. Zaugg J. Am. Chem. Soc.; 1955; 77(10) pp 2910 - 2910; doi:10.1021/ja01615a084 10.1021/ja01615a084
  4. ^ 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 ProcessesYoshito Fujima, Masaya Ikunaka, Toru Inoue, and Jun Matsumoto Org. Process Res. Dev.; 2006; 10(5) pp 905 - 913; (Article) doi:10.1021/op06011
 
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