Regioisomeric products of propranolol metabolism. The monomethyl ethers of 3,4-dihydroxypropranolol and of 3,4-dihydroxypropranolol glycol.
Regioisomeric monomethyl ethers of the 3,4-catechol of propranolol (1) and its 3-aryloxypropane-1,2-diol (glycol) metabolite were prepared to prove the structures of these putative products of oxidative metabolism. The ring regioisomer 4-methoxy-3-hydroxypropranolol (3) was prepared from 1-acetoxy-3-acetyl-4-methoxynaphthalene (8). Baeyer-Villiger oxidation was the key step in converting the 3-acetyl functionality to the desired 3-naphthol. The ring regioisomer 4-hydroxy-3-methoxypropranolol (4) was prepared from 3-methoxy-1,4-dihydroxynaphthalene (13) by selective 1-O-acylation with trimethylacetyl chloride. 4-O-Benzylation, followed by hydrolysis, and side chain elaboration afforded the 4-O-benzyl ether of 4. Similar methods afforded glycols 5 and 6, with the side chain obtained by osmium tetroxide oxidation of an O-allyl group. GC/MS analysis using the trifluoroacetyl derivatives of these known standards showed both 3 and 4 were metabolites of 1 in the rat. From a single dose study in man, 4 was identified as a minor urinary metabolite, and both regioisomeric glycol metabolites 5 and 6 were observed. In addition, another regioisomeric hydroxymethoxyglycol metabolite was found.
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D007536:Isomerism; D008297:Male; D009284:Naphthols / Q000378:metabolism*; D011433:Propranolol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D011409:Propylene Glycols / Q000378:metabolism*; D051381:Rats
D009284:Naphthols; D011409:Propylene Glycols; C056310:1-((3-hydroxy-4-methoxy)-1-naphthoxy)-2,3-propanediol; C041850:3,4-dihydroxypropranolol; D011433:Propranolol