Asymmetric synthesis of (S)-mirtazapine: Unexpected racemization through an aromatic ipso-attack mechanism

European Journal of Organic Chemistry

Volumn , Issue 17, 2008, Pages 2989-2997

  Van Der Linden, Marco ^a   Borsboom, Judith ^a   Kaspersen, Frans ^a   Kemperman, Gerjan ^a  

^a Department of Process Chemistry ^*  (Netherlands)

Author keywords

(S) Mirtazapine; Asymmetric synthesis; Isotopic labeling; Reaction mechanisms

Indexed keywords

EID: 53749087674     PISSN: 1434193X     EISSN: 10990690     Source Type: Journal    
DOI: 10.1002/ejoc.200701224     Document Type: Article

References (28)

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22. Economically more viable syntheses for (S)-1-methyl-3- phenylpiperazine have also been identified, which will be reported in a separate paper.
23. 5 was added in portions to 100 g phosphoric acid.
24. It should be noted that in reactions with PPA and DMF (entry 14 in Table 1) a side-product was observed in amounts of up to 26% relative to the product. This side-product was characterized by MS as having a MIM of 338, corresponding to a DMF adduct of a cationic intermediate. The side-product was not isolated or further characterized. However, it is a plausible hypothesis that the piperazine cation was attacked by DMF thereby preventing re-attack of the piperazine cation and thus avoiding formation of racemic mirtazapine.
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27. The NMR spectra were recorded in deuteriated acetone in order to achieve sufficient resolution of the signals of the relevant protons 12 and 13.
28. Because of the small scale of the reaction a little more than the intended 2.5 wt.-equiv. of PPA were used.