✍ Scribed by Cor G.M. Janssen; Jos B.A. Thijssen; Jos J.P. Heykants
No coin nor oath required. For personal study only.
Sabeluzole, (+)-4-(2-benzothiazolylmethylamino)-~[(p-fluorophenoxy) methyl]-l-piperidineethanol, effectively protects against several types of hypoxia, displays antiepileptic activity and shows unique effects on memory and learning. Metabolic studies required the synthesis of the drug, 14C-labelled in the benzothiazolyl moiety. As retrosynthetic analysis showed the feasibility of a short reaction sequence starting with phenyl isothio[T4C]cyanate, investigations were directed towards the latters" synthesis. Contrary to literature, where CS2 was only used in excess, we wanted to examine its synthesis with the 1 equivalent of CS2 theoretically required. Of the 3 possible methods offered in practice, viz. thermal decomposition of lithium N-lithio-N-phenyldithiocarbamate, reaction of C52 with phenyl iminophosphorane and elimination of H2S from phenyl dithiocarbamic acid, only the latter proved susceptible to modification. When maintaining the original reaction conditions, use of only 1 equiv, of C52 gave a variety of sideproducts which lowered the phenyl-NCS yield. Improving the formation of the intermediate phenyl dithiocarbamic acid by altering the reaction conditions and, most important, the in situ use of the subsequently formed phenyl isothiocyanate in the reaction with the necessary secondary amine, enabled us to attain an 81% yield over 2 steps, based on CS2. Utilizing 14C-CS2, the envisioned route provided w4C-sabeluzole in an overall radiochemical yield of 49.8%.
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