Practical and Large-Scale Synthesis of r ac-(3S,4aR,10aR)- 6-Methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylic Acid Methyl Ester

• Published in: Organic process research & development 2000-11, Vol.4 (6), p.460-466
• Main Authors: Bänziger, Markus, Cercus, Jacques, Stampfer, Wolfgang, Sunay, Ustun
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op0000531

3- Substituted octahydrobenzo[g]quinolines are important intermediates for pharmaceutically active compounds. A short, efficient synthesis, which is feasible for large-scale manufacturing of rac-(3S,4aR,10aR)-6-methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylic acid methyl ester is presented. As starting materials the cheap and readily available 1,6-dimethoxynaphthalene and ethoxymethylenecyanoacetic acid ethyl ester were chosen. All atoms of the skeleton were introduced in the first step, by the reaction of 7-lithiated 1,6-dimethoxynaphthalene with ethoxymethylenecyanoacetic acid ethyl ester. Subsequent hydrogenation, followed by Birch reduction and acidic cyclization gave the 6-methoxy-2,3,4,4a,5,10-hexahydrobenzo[g]quinoline-3-carboxylic acid·hydrochloride in high yield. The trans fusion of the two six-membered rings was established after NaBH4 reduction. After esterification, n-propylation, and kinetic protonation of an intermittantly formed trimethylsilylketene acetal, the desired product was isolated in high yield and excellent purity.