Synthesis of 5-Substituted Indole Derivatives, Part II. Synthesis of Sumatriptan through the Japp-Klingemann Reaction

Synthesis of selective 5-HT 1B/1D receptor agonist, sumatriptan (1) was accomplished through decarboxylation of 2-carboxy-3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide (2) in quinoline with copper powder.The preparation of the acid (2) was effected through the Japp-Klingemann method thus avoiding the need for the formation of hydrazine from diazonium salt.Attempted decarboxylation in N,N-dimethylacetamide resulted in the formation of the β-carboline (16).The complex physiological processes of the neurotransmitter serotonin (5-HT, 5-hydroxytryptamine) are becoming increasingly elucidated.In one role it acts as a vasoconstrictor in the brain and, thereby, displays beneficial properties in the treatment of the migraine. 2Over the past few years an extensive effort has been devoted to the development of tryptamines showing 5-HT 1D receptor agonists properties to achieve the desired activity and selectivity for the treatment of migraine. 3Sumatriptan 4 (1) is the first of this class of drugs having been approved for this use, and its discovery initiated the synthesis of a great number of 5substituted tryptamines. 5Many of these works obtained tryptamines directly from Fischer synthesis 6 by the choice of appropriate starting materials.The hydrazones necessary for these Fischer synthesis are prepared either by the condensation of a hydrazine with a 4-aminobutyraldehyde derivative or by the reaction of a diazonium salt with a β-oxo ester.The difficulties encountered when using hydrazine, that is, the need for tin(II) chloride to prepare the hydrazine and the formation of byproducts during the ring closure, are treated in detail in our previous paper on this subject. 1