Naratriptan synthesis

Scheme 15. Synthesis of naratriptan (3) using the Fischer indole reaction.

The synthesis of a C-labelled version of naratriptan (3b) is highlighted in Scheme The indole ring of naratriptan hydrochloride (3) was oxidatively cleaved using sodium periodate to give ketoformanilide 45. Cyanation of 45 with potassium [ C]cyanide in aqueous ethanol gave the intermediate amidine 46, which was reduced directly with NaBH4 in acetic acid to afford C-labelled naratriptan (3b), which was isolated as the hydrochloride salt. 

Introduction 12.2 Synthesis of sumatriptan 12.3 Synthesis of zolmitriptan 12.4 Synthesis of naratriptan 12.5 Synthesis of rizatriptan 12.6 Synthesis of almotriptan 12.7 Synthesis of frovatriptan 12.8 Synthesis of eletriptan 12.9 References... 

The Heck reactions have been explored in the synthesis of the drugs naratriptan, rizatriptan, almotriptan, and eletriptan on laboratory scale however, none of them have been explored on an industrial scale. 

The key step in the synthesis of naratriptan (12) involved the Heck reaction of bromoin-dolyl piperidine with A methylvinylsulfonamide (11) at 100-1 IOC in a sealed tube vessel to afford indolylsulfenamide 12 [73, 74]. 

Triptans have provided a futile ground for indole synthesis employing both the Heck and the intramolecular Heck reaction. In Glaxo s process synthesis of naratriptan, the reaction of 5-bromoindole with A -methyl-4-piperidone gave the A -methyl-tetrahydropyridinyl substituted indole. The Heck reaction between the 5-bromoindole and the A -methylvinylsulfonamide was carried out on 700-g scales. Both double bonds of the resulting diene were hydrogenated to give naratriptan hydrochloride as white crystals in 71% yield after recrystallization from hot water. 

As Eilbracht and coworkers [38] showed in numerous examples, the reaction cascade hydroformylation—(Fischer indolization) is a useful protocol for the synthesis of three-substituted indoles, including the essential amino acid tryptophan, the tissue hormone melatonin, and the neutrotransmitter serotonin (Figure 5.25). In addition, pharmacologically active tryptamine or homotryptamine derivatives, such as the marketed serotonin agonists sumatriptan, naratriptan, or zolmitriptan, or compounds that show a platelet aggregation inhibitory and antithrombotic effect (vintoperol) can be synthesized by such a protocol. Also active drug components for the treatment of schizophrenia (sertindole) can probably be produced by this approach [39]. It is estimated that the worldwide demand for such indole derivatives is about 20 000 mt/a [40]. 

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