Use if Aqueous Organic Solvents in Resolution Processes

30 June 2003

When carrying out a resolution process of, for example, an amine using a resolving agent such as an organic acid, the success of the initial screening can be affected by the choice of solvent. Rather than use anhydrous solvents, Collet recommends the use of 95% ethanol as solvent, since salts readily form in this solvent and dissolve on heating. Many salts crystallise as hydrates and the presence of water increases the chance of getting crystals at this early stage. The use of anhydrous alcohols at this stage is not recommended. For more details see “Enantiomers, Racemates and Resolutions” by J Jacques, A Collet and S H Wilen, Krieger, Malabar (Fl), 1994, pp 380-388.

One of the problems with the scale up of resolutions is that the separation of two diastereoisomers by crystallisation will be a time dependent process. So a successful lab process may not translate to a successful production process. In the lab, the first diastereoisomer may crystallise in high d.e., but in the plant a slow filtration of the required diastereoisomer may be accompanied by crystallisation of the second diastereoisomer, resulting in a lower d.e. The amount of water present in the solvent will critically affect the rate of crystallisation of the second diastereoisomer and thus the d.e. of the product. The amount of water should therefore be considered as a critical process parameter.

For examples see “Chirality in Industry”, Volume 1, A N Collins, G N Sheldrake and J Crosby (eds), Wiley, Chichester, 1992, p75.

For a recent handbook on resolution methods see CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation ed D Kozma (CRC Press), 2002, ISBN 0-8493-0019-3.