Improved synthesis of substituted pyrido[2,3-d]pyrimidinediones

Tetrahedron Letters

Volumn 52, Issue 28, 2011, Pages 3657-3661

  Churchill, Gwydion H ^a   Raw, Steven A ^a   Powell, Lyn ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

6 Aminouracil; Enaminone; Heteroannulation; Pyrimidinedione

Indexed keywords

AMINE; PYRIDO[2,3 D]PYRIMIDINEDIONE DERIVATIVE; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG; URACIL DERIVATIVE;

ANNULATION REACTION; ARTICLE; CYCLIZATION; DRUG SYNTHESIS; ELECTRON; METHODOLOGY; POLYMERIZATION; STEREOSPECIFICITY;

EID: 79958263569     PISSN: 00404039     EISSN: 18733581     Source Type: Journal    
DOI: 10.1016/j.tetlet.2011.05.021     Document Type: Article

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18. The structure of 22 was confirmed by 2D NMR and we postulate that its formation is due to residual acetaldehyde present in acetic acid. The formation of 22 may be explained by reaction of 6-aminouracil (2) with acetaldehyde to give species 27. Elimination of water under the acidic conditions could give reactive intermediate 28, which upon β-alkylation of the enamine followed by heteroannulation and elimination of dimethylamine would give 22. We attribute the increased ratio of 22:21 in the neat acetic acid process to an increased rate of reaction of 2 with acetaldehyde and/or greater stability/concentration of intermediate 28 under these conditions. Furthermore, when three equivalents of acetaldehyde were doped into the acetic acid 'all-in' reaction, compound 22 was obtained in 65% yield.