Metabolic formation and synthesis of 1-(3-chlorophenyl)-2-(4-hydroxyphenyl)-1-methyl-2-(2-pyridine)ethanol. A potential hypocholesteremic agent

Abstract

1-(3-Chlorophenyl)-2-(4-hydroxphenyl)-1-methyl-2(2-pyridine)ethanol (8a) has been synthesized and found to be the major urinary metabolite following intraperitoneal administration of 1-(3-chlorophenyl)-1-methyl-2-phenyl-2-(2-pyridine)ethanol (1) to rats. This metabolite has a hypocholesteremic effect in rats similar to that of the parent drug.

An example of the amine catalyzed retro-aldol reaction. Dehydration and cleavage of 1-(3-chlorophenyl)-1-methyl-2-phenyl-2-(2-pyridine)ethanol. A case of kinetic and thermodynamic competition

“…For reaction number 6 the oil product mixture was dissolved in n-hexane-acetone (10:1) and 2-(3-chlorophenyl)-l-phenyl-l-(2pyridine) propene (3) as a mixture of Z and E isomers (1.2 g, 20%) was obtained as a white, crystalline solid (mp 107-108 °C): NMR 2.11, 2.15 (two s, 3 ), 6.70-7.80 (broad m, 12 H, aromatic ), 8.30-8.75 (broad m, 1 H, pyridine H).…”

“…Silicon has a high affinity for ylide carbanions and exerts a stabilizing effect on these carbanions.1'2 Phosphorus, arsenic, and sulfur ylides having a silicon substituent directly attached to the carbanion have been synthesized as distillable oils. 3 The stabilizing effect of silicon upon a nitrogen ylide is not well investigated. In an earlier paper4 we reported that the reaction of N-(trimethylsilylmethyl)dimethylamine (Id) with benzyne gave predominantly JV-methyl-Y -(1 -trimethylsilylethyl)aniline (2d) which was produced by the Stevens rearrangement of a silyl ylide intermediate (9d).…”

“…Only the higher melting racemate (la) possesses significant ability to lower blood cholesterol levels in the rat. One of a number of likely candidates for a metabolite of 1 is the conjugated alkene, 2-(3-chlorophenyl)l-phenyl-l-(2-pyridine)propene (3), derived from 1 by the loss of water. An earlier report1 describes dehydration of a number of 2-(2-pyridyl)-l,2-diarylalkanols by treatment with 85% phosphoric acid at 100 °C for 3 h. Conjugated alkenes analogous to 3 were the only reported products.1 The present study involves investigation of the behavior of alcohol 1 to treatment with phosphoric acid both as a pathway to the synthesis of possible metabolite 3 and to gain knowledge of its acid sensitivity with respect to decomposition.…”