A new and efficient synthesis of pyrrolo[2,3-d]pyrimidine anticancer agents: Alimta (LY231514, MTA), homo-Alimta, TNP-351, and some aryl 5-substituted pyrrolo[2,3-d]pyrimidines

J Org Chem. 2003 Dec 26;68(26):9938-47. doi: 10.1021/jo030248h.

Abstract

Alimta, as well as homo-Alimta, a nonbridged analogue of Alimta, and TNP-351 have been prepared by a new method that involves Michael addition of the appropriate 1-nitroalkene with 2,6-diamino-3H-pyrimidin-4-one or 2,4,6-triaminopyrimidine, followed by a Nef reaction of the resulting primary nitro Michael adduct. Spontaneous intramolecular cyclization of the resulting aldehyde with the pyrimidine 6-amino group yields the corresponding pyrrolo[2,3-d]pyrimidine. A series of previously unknown 5-arylpyrrolo[2,3-d]pyrimidines was prepared by the same methodology from the above pyrimidines and nitrostyrenes. It has been found that the intermediate primary nitro Michael adduct can be prepared in a single step by sonication of a mixture of an arylaldehyde, nitromethane, and the 6-aminopyrimidine in acetic acid containing ammonium acetate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Glutamates / chemical synthesis*
  • Glutamates / chemistry
  • Glutamates / pharmacology
  • Guanine / analogs & derivatives*
  • Guanine / chemical synthesis*
  • Guanine / chemistry
  • Guanine / pharmacology
  • Methotrexate / analogs & derivatives*
  • Methotrexate / chemical synthesis*
  • Methotrexate / chemistry
  • Methotrexate / pharmacology
  • Molecular Structure
  • Pemetrexed
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology

Substances

  • Antineoplastic Agents
  • Glutamates
  • Pyrimidines
  • Pyrroles
  • Pemetrexed
  • TNP 351
  • Guanine
  • Methotrexate