Six 10-hydroxy-4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine derivatives 17a-f have been synthesized as potential analgesics. The synthesis of these compounds involved conversion of 4-(2-dimethylaminoethyl)-6-methoxy alpha tetralone derivatives 12a-f to their N-methyl analogues and the subsequent intramolecular mannich reaction with formaldehyde to give the 7-keto C-ring homobenzomorphans 14a-f from which 17a-f, respectively, were obtained. Compounds 17a-f are as potent as morphine as analgesics (mice).
The parent framework of furo[2,3‐c]pyridine has been synthesized. 3‐Furoic acid chloride (2) was reduced with bis(triphenylphosphine) copper(1) tetrahydroborate to afford 3‐furaldehyde (3) which was condensed with malonic acid to give β‐(3‐furyl)acrylic acid (4). The acrylic acid 4 was converted to the acid azide (5), which in turn was cyclized to give furo[2,3‐c]pyridin‐7(6H)‐one (6) by heating at 180° in diphenylmethane. The pyridone 6 was chlorinated with phosphorus oxychloride, followed by reduction with zinc and acetic acid to give furo[2,3‐c]pyridine (8).
Although the exact nature of forces controlling the binding affinity of analgesics and their antagonists at the opiate receptor site is still poorly understood, recently developed stereochemical studies of analgesics and related
This paper describes the synthesis and chemical properties of some 2‐ and 3‐substituted furo[2,3‐b]pyridines. Reaction of ethyl 2‐chloronicotinate 1 with sodium ethoxycarbonylmethoxide or 1‐ethoxycarbonyl‐1‐ethoxide gave β‐keto ester 2 or ketone 5, respectively. Ketonic hydrolysis of 2 afforded ketone 3, from which furo[2,3‐b]pyridine 4 was obtained by the method of Sliwa. While, 2‐methyl derivative 7 was prepared from 5 by reduction, O‐acetylation and the subsequent pyrolysis. Reaction of ketone 3 with methyllithium gave tertiary alcohol 8 which was O‐acetylated and pyrolyzed to give 3‐methyl derivative 9. Formylation of 4, via lithio intermediate, with DMF yielded 2‐formyl derivative 10, from which 7, was obtained by Wolff‐Kishner reduction. Dehydration of the oxime 11 of 10 gave 2‐cyano derivative 12, which was hydrolyzed to give 2‐carboxylic acid 13. Reaction of 3‐bromo compound 14 with copper(I) cyanide gave 3‐cyano derivative 15. Alkaline hydrolysis of 15 afforded compound 16 and 17, while acidic hydrolysis gave carboxamide 18. Reduction of 15 with DIBAL‐H afforded 3‐formyl derivative 19. Wolff‐Kishner reduction of 19 gave no reduction product 9 but hydrazone 20. Reduction of tosylhydrazone 21 with sodium borohydride in methanol afforded 3‐methoxymethylfuro[2,3‐b]pyridine 22.
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