Patent Watch

September 21, 2009

Resolve citalopram enantiomers with L-tartaric acid. The racemic hydrobromide salt of citalopram (1) is an antidepressant marketed under the brand name Celexa. The (S)-enantiomer is the more potent of the two isomers. Because the original patents have expired, interest in improved methods of resolution or synthesis has increased, and a new synthesis has been developed (Dall’asta, L.; Cotticelli, G. US Patent 7,166,729, 2007). J. Zhu describes a process for producing pure (S)-enantiomer from the racemic mixture by forming the L-tartrate salt.

L-Tartaric acid (LTA) is widely used as a resolving agent, but the inventor claims that it has not been used successfully to resolve 1. The inventive step in this patent is to use formaldehyde in conjunction with LTA to improve the resolution process. The precise mechanism for the improvement is unclear, but one explanation is that a hemiacetal is formed by the reaction of an LTA hydroxyl group with HCHO. This may occur before or after salt formation. An alternative proposal is that HCHO modifies the solvent and provides solubility discrimination between the tartrate diastereomers.

The inventor claims that the HCHO can be used in any convenient form, but the examples use the standard 37% aqueous solution that contains up to 15% MeOH. In the procedure, an aqueous solution of LTA, 1, and HCHO is seeded and stirred overnight at 4 °C. The solids are recovered and suspended in 37% HCHO. The LTA salt of the (S)-enantiomer is obtained in 78.3% ee. A second treatment with HCHO solution increases the enrichment to 95% ee, and a third treatment increases it to 97%.

The tartrate salt can be converted to the free base when treated with an inorganic base such as NaOH. One example describes the production of ~9 kg of (S)-citalopram oxalate. The tartrate salt is initially treated with concd NH₃, and the base recovered as an oily mass. Treating this with (CO₂H)₂ in EtOH solution at 5 °C gives the (S)-oxalate, demonstrating that the process can be scaled up. There is no mention of recovery of the (R)-enantiomer and its racemization to improve yield.

The process provides an effective method for resolving the racemate and obtaining high yields of the more active enantiomer. (Synthon BV [Nijmegen, The Netherlands]. US Patent 7,566,793, July 28, 2009; Keith Turner)

View patent information from CAS.

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