Pyridopyrimidinone derivatives

Ozone oxidation of 6-aryl-2-methylthiopyrido[2,3-methyl sulfone with /ra j-4-aminocyclohexanol afforded the amino pyridopyrimidinone derivative 176 <2002W02002018380>. Amination of 6-dimethoxyphenyl-8-ethyl-2-methylthiopyrido[2,3-t7 pyrimidin-7-one with 4-aminopyridine and LiNH2 in THF at 50°C produced the 2-[(4-pyridyl)amino] derivative 177 <2003W02003027110>. 

Apparently related to the aforementioned xanthine analogs, pyridopyrimidinone (X =X2=X3=CH or CR) and aza-pyridopyrimidinone (X1 or X3=N, X2=CH or CR) derivatives (M), exemplified by compounds 41 and 42 respectively, were discovered as GPR109A agonists [94,95]. So far no biological data has been provided for this class of molecules. The calculated pKa of the N-H group present in compounds 41 and 42 ranges from 8 to 9 [82]. 

The heats of formation of the lithiated derivatives 14 and 15 calculated by the semi-empirical Li/PM3 method indicated that the C-5-lithiated intermediate 15 is the more stable isomer. This was in agreement with the result obtained from their reaction with various electrophiles to give regioselectively the respective thermodynamically preferred 5-substituted pyridopyrimidinone at higher temperature and longer reaction time, while the second 8-substituted isomer needed milder conditions <2004T4107>. 

Acetyl-4//-pyrido[ 1,2-a]pyrimidin-4-one 186 was formed in the reaction of ethyl iV-(2-pyridyl)formimidate 187 (R = H) and ketene in acetone at ambient temperature for 2 days in 12% yield (83H597). It was assumed that diketene formed first from ketene, then it reacted with the formimidate 187 (R = H). When excess ketene gas was passed over formimidates 187 (R = H and Me) at 75°C for 0.5-1.5 hours without solvent, 4//-pyrido[ 1,2-a]pyrimidin-4-ones 188 and 7V-(2-pyridyl)formamides were obtained in 25-85% and 0-45% yields, respectively. From the 5-methyl derivative of the formimidate 187 (R = 5-Me) only pyridopyrimidinone 188 (R = 7-Me) was obtained. It was proposed that both products were formed by 1,4-... 

In an approach toward heterocycle synthesis two different three-step methods for solid-phase preparation of aminopropenones and aminopropenoates have been developed [29]. The first involved formation of the respective ester from N-protected glycine derivatives and Merrifield resin (Scheme 16.5) whereas the second used a different approach, use of simple aqueous methylamine solution for functionalization of the solid support [29]. The desired heterocycles were obtained by treatment of the generated polymer-bound benzylamine with the corresponding acetophenones, using N,N-dimethylformamide diethylacetal (DMEDEA) as reagent. The final step in the synthesis of the pyridopyrimidinones involved release of the products from the solid support by intramolecular cyclization. 

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