Attempted resolution of citalopram using (-)-O,O′-Di-p-toluoyl-(R,R)- tartaric acid, and reflections on an alkylation reaction; Comment on an article by Elati et al.

Organic Process Research and Development

Volumn 13, Issue 1, 2009, Pages 23-33

  Dancer, Robert James ^a   Lopez De Diego, Heidi ^a  

^a H LUNDBECK A S   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 61449255477     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op800101z     Document Type: Article

References (18)

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2. That (rac)·DTT and (R)·DTT can be isostructural is because that, although the (S)- and (R)- citalopram enantiomers are quite distinct structurally, significant overlap of gross structural features is possible. As an illustration of this point, it has been observed that the single-crystal X-ray structures of (racemic) citalopram oxalate and (S)-citalopram oxalate are extremely similar (isostructural). Examination of the racemic structure reveals that the (S)- and (R)-isomers are symmetrically placed around the oxalate. Comparison with the (S)-citalopram structure reveals that the overall structure is essentially the same, but with the (R)-citalopram molecules replaced by rotated (S)-citalopram molecules. More specifically, the fluorophenyl group of one isomer is mapped onto the isobenzofuran aromatic ring of the other isomer, but the isobenzofuran oxygen atoms and the basic nitrogen atoms are situated more or less in the same positions in the two enantiomers. (Lopez de Diego, H. et al., manuscript in preparation). Comparison of these findings to the current case of resolution of citalopram may offer a deeper explanation as to why the resolution is not effective.
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4. It is of course not possible in this manner to distinguish between the double addition salt (rac)·DTT and a physical mixture containing equimolar quantities of (S)·DTT and (R)·DTT. For that matter, it would not be possible to distinguish between a solid solution containing (for example) 55 % (S)-citalopram and 45% (R)-citalopram on the one hand, and a conglomerate containing approximately 10 % (S)·DTT and 90% (rac)·DTT on the other. However, the purpose of the experiment was to try to detect time intervals in the precipitation process where (S)·DTT has precipitated out to a significant degree in a significant purity. Therefore, in this context, the precise composition of solid forms containing almost equimolar quantities of (S)- and (R)-citalopram is not relevant.
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