Synthesis of certain metabolites and analogs of vitamin B6 and their ring‐chain tautomerism

Abstract

AbstractPyridoxol and pyridoxal on benzylation with dimethylphenylbenzylammonium hydroxide (“leucotrope”) gave 3‐O‐benzylpyridoxol (IV) and 3‐O‐benzylpyridoxal (V), respectively. As a possible mechanism of this reaction an ion pair intermediate has been postulated. Oxidation of IV and V with chromic oxide‐pyridine‐acetic acid complex gave 3‐O‐benzyl‐4‐pyridoxic acid lactone (VI), which could also be obtained by benzylation of 4‐pyridoxic acid. Treatment of VI with dimethylamine gave 2‐methyl‐3‐benzyloxy‐5‐hydroxymethylpyridine‐4‐N,N‐dimethylcarbox‐amide (X) which oxidized to form the 5‐formyl derivative (XI). The latter on hydrolysis yielded the metabolite, 2‐methyl‐3‐hydroxy‐5‐formylpyridine‐4‐carboxylic acid (I). When reacted with liquid ammonia, VI gave 3‐O‐benzyl‐4‐pyridoxamide (VII) which was then oxidized to give 2‐methyl‐3‐benzyloxypyridine‐4,5‐dicarboxylic acid cyclicimide(IX). Acid hydrolysis of IX gave another metabolite, 2‐methyl‐3‐hydroxypyridine‐4,5‐dicarboxylic acid (XIII), which could also be obtained by oxidizing XI with potassium permanganate in water to yield 2‐methyl‐3‐benzyloxy‐5‐carboxypyridine‐4‐N,N‐dimethylcarboxamide (XII) and subsequent hydrolysis with hydrochloric acid. A positional isomer of I, 2‐methyl‐3‐hydroxy‐4‐formylpyridine‐5‐carboxylic acid (XVII) was synthesized starting from 3‐O‐benzyl‐5‐pyridoxic acid lactone (XIV) following similar reaction sequences used for the preparation of I. Ring‐chain tautomerism has been studied in I, XVII, opianic acid (XVIII), phthalaldehydic acid (XIX) and (2‐carboxy‐4,5‐dimethoxy)‐phenylacetaldehyde (XX) in different solvents by nmr and in the solid state by ir spectroscopy. A direct and reliable differentiation between the open form (aldehyde proton in low field) and the ring form (lactol proton in the intermediate field) has been obtained by nmr spectroscopy. In sodium deuteroxide and pyridine‐d5 the open chain form existed exclusively (except for homolog (XX) which is in cyclic form in pyridine‐d5), whereas in 18% hydrogen chloride in deuterium oxide all the compounds are completely in the cyclic form. In hexafluoroacetone hydrate‐d2, XVIII, XIX, and XX exist in the cyclic form whereas I is in the open form. In DMS0‐d6 both cyclic and open‐chain forms have been observed in XVIII, XIX and XX. Definite peak assignment for the two forms could not be made in I due to broadening or superimposition with C6‐H. The metabolite I, isometabolite (XVII) and opianic acid (XVIII) form cyclic acetyl derivatives which give a sharp lactol peak. In the solid state XVIII, XIX are in the cyclic form and I and XX in the open‐chain form as observed by ir spectroscopy.