Synthesis of a substance P antagonist: An efficient synthesis of 5-substituted-4-N,N-dimethylamino-1,2,3-triazoles

Michel Journet, Dongwei Cai, David L. Hughes, Jason J. Kowal, Robert D. Larsen, Paul J. Reider

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

A highly efficient synthesis of the substance P antagonist 1 is reported starting from the optically pure morpholine acetal derivative 2. The 5-dimethylaminomethyl-1,2,3-triazole moiety is elaborated via a 1,3-dipolar cycloaddition between an activated acetylenic intermediate and sodium azide. Two approaches to the construction of the triazole moiety of 1 have been designed. The first approach is linear affording the side chain in four steps and 85-92% overall yield. The reactive acetylenic aldehyde 5 allowed for a mild azide cyclization. A simple reductive amination of the triazole aldehyde completed the synthesis of 1. An alternative, more efficient, convergent synthesis using analogous methodology developed from the linear synthesis was designed to improve the overall efficiency of the process as well as remove the concerns with the handling of azide. The triazole adduct was prepared offline in a two-step, one-pot operation as the building block 4-N,N-dimethyl-aminomethyl-1, 2,3-triazole-aldehyde 3. Formylation of N,N-dimethylaminopropyne and azide cyclization were carried out as a through process to afford the triazole aldehyde 3 in 90% assay yield. The product was isolated in overall yields ranging from 67 to 81% depending on method. The aldehyde group of 3 was used for coupling to the morpholine building block through a reductive amination with NaBH(OAc)3 in near quantitative yield to afford the substance P antagonist 1 as a hydrochloride salt in 95% yield from 2.

Original languageEnglish (US)
Pages (from-to)490-498
Number of pages9
JournalOrganic Process Research and Development
Volume9
Issue number4
DOIs
StatePublished - Jul 1 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Organic Chemistry

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