Patent GB-677595-A (GB)
Title: Isoquinoline derivatives and process for the manufacture thereof
Filed: 1950-08-16
Abstract: The invention comprises 1-benzyl-5 : 6 : 7 : 8-tetrahydroisoquinoline compounds of the general formula <FORM:0677595/IV (b)/1> (wherein R1 and R2 each represent hydrogen or a hydroxy or alkoxy group), and their methohalides; and a process (in which these compounds are intermediates) for the manufacture of N-methylmorphinanes of the general formul  <FORM:0677595/IV (b)/2> and <FORM:0677595/IV (b)/3> and their salts, which comprises reacting 5 : 6 : 7 : 8 - tetrahydroisoquinoline with sodamide, reacting the resulting 1-amino-5 : 6 : 7 : 8-tetrahydroisoquinoline with a nitrite in the presence of hydrobromic acid and bromine to replace the amino group by bromine, reacting the product (suitably in ether at a low temperature, e.g. -35 DEG  C.) with an alkyl lithium (e.g. butyl lithium), condensing the resulting lithium compound with benzaldehyde or a derivative thereof carrying an alkoxy group in the m- or p-position or both, to produce a carbinol of the formula <FORM:0677595/IV (b)/4> (wherein R1 and R2 each represent hydrogen or an alkoxy group), converting this to a compound of the first formula above by methods known to be capable of converting -CHOH- to -CH2-, reacting the desoxy compound with a methyl halide, reducing the methohalide (e.g. by catalytic hydrogenation) to the corresponding 2-methyl-1-benzyl-1 : 2 : 3 : 4 : 5 : 6 : 7 : 8-octahydroisoquinoline, and cyclizing this by heating with an acid. The conversion of the carbinol compound to the desoxy compound may be effected by one of the following methods: (a) bromination (e.g. with hydrobromic acid) and reduction of the 1-(a -bromobenzyl) compound (e.g. with zinc dust); (b) disproportionation, by heating in tetrahydronaphthalene with palladium charcoal, to an equimolecular mixture of the desoxy compound and the corresponding ketone, and reduction of the latter constituent by the Clemmensen method; (c) oxidation (e.g. with potassium permanganate) to the ketone and reduction thereof as in (b); (d) direct reduction with hydriodic acid and red phosphorus (whereby any alkoxy groups present may be simultaneously converted into hydroxy groups, which may be re-etherified, if desired, before carrying out the next step). The cyclization may be effected with phosphoric, hydrobromic or hydrochloric acid, and conversion of alkoxy to hydroxy groups may occur at this stage also if a hydrogen halide is used.  Examples illustrate the various alternative processes as applied to the preparation of: (1) N-methylmorphinane via 1-benzyl-5 : 6 : 7 : 8-tetrahydroisoquinoline and its methobromide or methiodide; (2) 3-hydroxy-N-methyl morphinane (which may be converted to its methyl ether by the action of diazomethane) via 1 - (41 - hydroxybenzyl) - 5 : 6 : 7 : 8 - tetrahydroisoquinoline and its methyl ether and the methiodide or methochloride of the latter; (3) 4-hydroxy-3-methoxy-N-methylmorphinane (with 2 : 3 - dihydroxy - N - methylmorphinane as by-product) via 1-veratryl-5 : 6 : 7 : 8-tetrahydroisoquinoline (which can be converted to 1-(31 : 41-dihydroxy-benzyl) - 5 : 6 : 7 : 8 - tetrahydroisoquinoline by heating with hydrobromic acid) and its metho-bromide or methiodide. The product of (3), which is dl-tetrahydrodesoxycodeine, may be resolved by means of d-tartaric acid.