Zolmitriptan synthesis and in-process control by HPLC methods

Katarzyna Badowska-Rosłonek ,  Joanna Zagrodzka ,  Justyna Chmiel ,  Paweł Pyć ,  Anna Rosa ,  Łukasz S. Kaczmarek 

Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland

Abstract

Zolmitriptan (Zomig®), a single enantiomer 4(S)-[dimethylamino)ethyl]-1H-indol-5-ylmethyl] oxazolidin-2-one is a novel serotonin 5-hydroxytryptamine receptor agonist that has shown, in an extensive clinical trial program, to be highly effective in the acute oral treatment of migraine with or without aura [1,2]. It works by stimulating serotonin receptors in the brain.

Zolmitriptan is a synthetic indole derivative, which can be obtained by six steps method of synthesis: ZL1 → ZL2 → ZL3 → ZL4 → ZL5 → {[ZL6] + ZL7} → ZL8.

The esterification of L-4-nitrophenylalanine (ZL1) with methanol gives the corresponding ester (ZL2), which is reduced to the (S)-2-amino-3-(4-nitrophenyl)-1-propanal (ZL3). Reduction of the nitro group in ZL3 yielded the corresponding amino derivative ZL4 (step 3), which is cyclized to ZL5 in next step. The diazotation of ZL5 affords the expected hydrazine derivative (ZL6). Finally, hydrazine derivative (ZL6) is reacted with 4-(dimethylamino) butanal diethylacetal (ZL7) to obtain desired product – Zolmitriptan (ZL8).

Different polarity of all products (ZL1-ZL8) determinates application of high selective analytical method for in-process control. Analysis were carried out by reverse phase chromatography (RP-HPLC) with a gradient mobile phase composed of: at first acetonitrile:diethylamine (in a ratio 1:0,1 v/v), and finally water:diethylamine (1:0,1 v/v), on a Phenomenex Gemini C6-Phenyl column. Zolmitriptan (ZL8) and its potential impurities were baseline resolved in the optimized method.

[1] R. Yates, K. Niarn, R. Dixon, J.V. Kemp, J. Clin. Pharmacol. 42, 2002, 1244-1250.
[2] A.D. Dolman, L.A. Smith, H.J. McQuay, R.A. Moore, Plain 97, 2002, 247-457.

 

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Presentation: Poster at VI Multidyscyplinarna Konferencja Nauki o Leku, by Katarzyna Badowska-Rosłonek
See On-line Journal of VI Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2008-04-21 09:59
Revised:   2009-06-07 00:48