Determination of the activation parameters and the mechanism for atropisomerization of (S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethylpyridin-2-yl)vinyl]-6-fluoroquinazolin-4(3H)-one

摘要

Compounds containing quinazolinone ring systems exhibit anlarge variety of biological effects,1 such as antiinflammatory,2nantimalarial,3 anticonvulsive 4 and hypotensive 5 activities. Oncenit was recognized that substituents at the 2 and 3 positionsnmodulate the hypertensive and antiinflammatory activities,5,6na large number of 2-alkyl-3-arylquinazolin-4(3H)-ones werensynthesized and screened to develop new drugs. However, innmany of these studies it was not recognized that the 2-alkyl-n3-arylquinazolin-4(3H)-ones were stereochemically analogousnto the ortho substituted biphenyls and therefore isolatablenrotational isomers might exist. The first observation ofnrestricted internal rotation in the 3-aryl C–N bond was reportednin 1975 based on 1H NMR evidence.7 Later it was shown thatnthese types of atropisomers 8 are resolvable and stable at roomntemperature but racemize at elevated temperatures.9nWe report here activation parameters for atropisomerizationnof (S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethylpyridin-n2-yl)vinyl]-6-fluoroquinazolin-4(3H)-one 1 (Scheme 1) andnpropose a mechanism for the process. It has been shownnin the literature that the biological effects of atropisomers cannbe different 10 and because the atropisomers can interconvertnduring synthesis and formulation development, we determinednthe activation parameters in order to estimate the atropisomerizationnrate constants at different temperatures.