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
- 22 November 2003
- journal article
- research article
- Published by American Chemical Society (ACS) in The Journal of Organic Chemistry
- Vol. 68 (26), 9938-9947
- https://doi.org/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.Keywords
This publication has 11 references indexed in Scilit:
- A New Route to 7-Substituted Derivatives of N-{4-[2-(2-Amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- ethyl]benzoyl}-l-glutamic Acid [ALIMTA (LY231514, MTA)]1The Journal of Organic Chemistry, 2001
- A Practical Synthesis of Multitargeted Antifolate LY231514Organic Process Research & Development, 1999
- A Ring-Transformation/Ring-Annulation Strategy for the Synthesis of the DHFR Inhibitor, TNP-351: A CorrectionThe Journal of Organic Chemistry, 1996
- A One-Step Ring Transformation/Ring Annulation Approach to Pyrrolo[2,3-d]pyrimidines. A New Synthesis of the Potent Dihydrofolate Reductase Inhibitor TNP-351The Journal of Organic Chemistry, 1995
- A convenient method for regioselective C‐5 halogenation of 4(3H)‐oxo‐7H‐pyrrolo[2,3‐d]pyrimidinesJournal of Heterocyclic Chemistry, 1994
- A novel synthetic approach to pyrrolo[2,3-d]pyrimidine antifolatesThe Journal of Organic Chemistry, 1993
- A dideazatetrahydrofolate analog lacking a chiral center at C-6: N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5yl)ethyl[benzoyl]-L-glutamic acid is an inhibitor of thymidylate synthaseJournal of Medicinal Chemistry, 1992
- Novel pyrrolo[2,3-d]pyrimidine antifolates: synthesis and antitumor activitiesJournal of Medicinal Chemistry, 1991
- New pathways from pteridines. Design and synthesis of a new class of potent and selective antitumor agentsJournal of Heterocyclic Chemistry, 1990
- Synthesis of the antileukemic agents 5,10-dideazaaminopterin and 5,10-dideaza-5,6,7,8-tetrahydroaminopterinJournal of Medicinal Chemistry, 1985