Effects of various bases on acid-catalyzed amination of 2-chloro-5-ethylpyrimidine: synthesis of PPARpan agonist GW693085.

A unique buffering effect of various bases, i-Pr(2)NEt and CaCO(3) in particular, was observed for the acid-catalyzed chloro displacement of 2-chloro-5-ethylpyrimidine with a 2-methyl-2-phenylpropanamine. The use of the carefully chosen bases was essential for the progression of the chloro displacement as well as the stability of the product in the presence of HCl formed. Research work leading to an efficient synthesis of PPARpan agonist GW693085 is described, featuring highly selective sequential N- and O-alkylations.

Integration of optimized substituent patterns to produce highly potent 4-aryl-pyridine glucagon receptor antagonists.

Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-hydroxyethyl] and a 2'-hydroxy group. Due to restricted rotation of the phenyl-pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC(50)=10-25 nM.

Optimization of the 4-aryl group of 4-aryl-pyridine glucagon antagonists: development of an efficient, alternative synthesis.

A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.

Tandem Dipolar Cycloaddition-Mannich Cyclization as an Approach to Tricyclic Nitrogen Heterocycles.

A series of 2-diazo-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-hept-6-enoylmalonamides were prepared and treated with a catalytic amount of rhodium(II) perfluorobutyrate. The resultant carbenoids undergo facile cyclization onto the neighboring amide carbonyl oxygen atom to generate isomünchnone-type intermediates. Subsequent 1,3-dipolar cycloaddition across the pendant olefin affords intramolecular cycloadducts in high yield.