Synthesis of deuterium‐labeled zaleplon‐d₅ as an internal standard

Abstract

Zaleplon is licensed for the short-term treatment of insomnia. Excessive usage causes side effects; hence, the drug is controlled. Identifying zaleplon in a drug abuser requires an isotope-labeled internal standard. This work presents a synthesis of stable isotope-labeled internal standard for zaleplon, zaleplon-d 5 , by a five-step synthetic sequence.

Synthesis of 2H‐ and 13C‐labelled sunitinib and its primary metabolite

“…N-d 5 -ethylation, has been used to stable label a variety of drugs to obtain internal standards for biological quantification. [12][13][14] Between the sunitinib-d 5 , presented herein, and sunitinib itself, neither cross-contribution to analyte ions very similar and the internal standard was considered suitable for the determination of sunitinib. Next to the presented synthesis of a sunitinib-d 5 internal standard, an analogously d 5 -deuterized metabolite, requiring mono-alkylation of ethylenediamine, posed a major chemical challenge, and was therefore not addressed.…”

“…The pyrrolecontaining building block was prepared from commercially available ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate (Ace Synthesis, Woburn, USA). A Vilsmeier reaction, introducing a 12 C-or 13 C-formyl function into the pyrrole, was carried out affording compounds 2a and 2b. Subsequent alkaline hydrolysis of the ethyl ester moiety produced 3a and 3b, which where joined with 1 in a pyrrolidine-catalyzed aldol reaction to obtain key intermediates 4a and 4b.…”

“…Nevertheless, also SU12662 was successfully analysed using the sunitinib-d 5 internal standard. Structural elucidation of the sunitinib scaffold was based particularly on NMR experiments exploiting the unique 1 H, 13 C, and 19 F coupling patterns observed with the prepared 13 C-isotopomers. The convergent synthesis of sunitinib and related indolin-2-one derived structures started from 5-fluoroindolin-2-one (1), which was readily obtained by a Wolff-Kishner-type reduction of the corresponding 5-fluoroisatin (Scheme 1).…”

“…HPLC purity assessment was carried out using a C 18 column (Ziemer Hypersil-ODS, 3 mm, 125 Â 4.6 mm, Langerwehe, Germany) attached to a UV detector (Jasco UV-2075Plus, 220 nm) under isocratic conditions (MeCN/H 2 O, 65/35 v/v). 13 C NMR (125 MHz) and 1 H NMR spectra (500 MHz) were recorded on a Avance DRX 500 spectrometer (Bruker BioSpin, Rheinstetten, Germany) and chemical shifts d are given in ppm referring to the signal centre using the solvent peaks for reference (DMSO-d 6 : 2.49/39.7). To characterize the spin multiplicity the following abbreviations are used: s singlet, bs broad singlet, d doublet, dd doublet of doublets, ddd doublet of doublet of doublets, t triplet, q quartet, dq doublet of quartets, m multiplet.…”

“…In addition, 18 F-sunitinib has been prepared for PET purposes and a 14 C-analogue was synthesized for ADME studies prior to FDA approval. 10,11 The aim of our work was to prepare comparable 13 C/ 2 H-SU11248/SU12662 internal standards for LC-MS determination of sunitinib and its primary metabolite in human blood samples.…”