Synthesis of isotopically labelled pyridoindolone 5‐HT₃ receptor antagonists (1)

Abstract

SummarySyntheses of labelled versions of 5-HT3 receptor antagonists, Alosetron and Lurosetron, are described. [14C]Alosetron was prepared by routes utilizing either Fischer indolisation of an amidohydrazine or palladium-mediated cyclisation of an aryl enaminone as key steps. 2H and 13C versions of Alosetron were prepared from suitably labelled imidazoles.Lurosetron was labelled in either the methylene bridge carbon or carbonyl carbon, using 14C-labelled paraformaldehyde or phosgene, respectively.

Sulfuric Acid‐Catalyzed Regioselective Alkylation of Indoles and β‐Naphthols with Ketene Dithioacetal‐Based Allylic Alcohols

“…Thus, a simple cyclization of indoles 3 was examined in the presence of N-chlorosuccinimide (NCS) under basic conditions [14] for the synthesis of pyridoindolone derivatives 4. [15] As summarized in Scheme 2, all the tested cyclizations of 3 furnished 3-[bis(ethylthio)methylene]-4a-chloro-4-methyl-1-aryl-4,4a-dihydro-1H-pyrido[2,3-b]indol-2(3H)-ones 4 in good to high yield. No dehydrochlorination product of 4 was isolated in any of the cases.…”

γ-Carbolines and their hydrogenated derivatives. 2.* Hydrogenated derivatives of γ-carbolines: methods of synthesis (review)

“…In the general case the nature of substitution at the nitrogen atom of the carbonyl component does not have a significant effect on the cyclization process: Both piperid-4-one [41] itself and its N-alkyl [32][33][34][35][36][37][38][39][40][42][43][44][45][46][47][48][49][50] and N-acyl [51,54] derivatives can also take part in the transformation, as can be demonstrated by the synthesis of the C 14 -labeled medical product Alosetron [67]. Of substantial importance for the Fischer reaction is the spatial structure of the piperidine carbonyl component.…”

“…good yield of a mixture of tetrahydro and aromatic γ-carboline derivatives is obtained[77].If the halogen atom in the aromatic ring of the enamine is absent the oxidative variant of the Heck reaction, in which copper salts that simultaneously regenerate the catalyst act as oxidizing agent, is realized successfully[67].…”

The synthesis and physiological activity of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles

“…25 The oxidative nucleophilic addition of N-methylpiperidin-4-one to 3-nitro-6-chloroaniline makes it possible, although in a low yield, to obtain 6-chloro-2-methyl-9nitro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole (23) 34 which is difficult to access by other ways.…”

“…When treated with AlCl 3 it cyclizes to 6-fluoro-5-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indol-1-one (65). 25 Compound 66 protected at position 1 with a tertbutyldimethylsilyl group cyclized to 1-phenyl-2-toluenesulfonyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indol-4-one (67) on bentonite clay. 51 A wide use of homogeneous catalysts containing Group VIII metals of the Periodic system in the synthesis of a variety of heterocyclic compounds could not miss THPI derivatives.…”