Patent GB-960181-A (GB)
Title: Substituted tetrahychroisoquinolines
Inventor: BARTON DEREK HAROLD RICHARD
IPC: C07D217/16
Filed: 1959-07-08
Abstract: 1-substituted 1,2,3,4-tetrahydro-isoquinolines, specifically, <FORM:0960181/C1/1> in which R2 and R3 are hydrogen atoms or hydrocarbon groups and R111 is an alkyl group, a carboxy methyl group or a group <FORM:0960181/C1/2> are prepared by reacting a 3,4-dihydroisoquinoline compound with a methine compound R1R11-CH-Y where R1 and R11, which may be the same or different, are hydrogen atoms, carboxyl groups, hydrocarbon groups, or further groups, or further groups Y, and Y is an elec attracting group, such as a carbonyl, cyan tron nitro group.  Acetone, acetyl-acetone, acetone dicarboxylic acids acetoacetic acid, malonic esters and acids and benzyl cyanide are examples of the reactive methine compounds, and the dihydroisoquinoline may be substituted in the 3,4,5,6,7 and/or 8 position by for example alkyl, aralkyl, aryl, alkenyl, alkoxy, aralkoxy, aryloxy, alkyl, aralkyl or aryl thio or disubstituted amino groups or methylene dioxy groups.  A solvent medium, e.g. acetone, pyridine, or methanol, with an acid catalyst may be used, and as examples describe the preparation of a -bis(1:2:3:4-tetrahydro-6:7-dimethoxyisoquinol-1-yl) acetone, its isomers and acid addition salts; of 6:7-dimethoxy-1:2:3:4-tetrahydroisoquinol-1-yl acetone hydrochloride; and 6:7-dimethoxy-1,2,3,4-tetrahydro-isoquinol-1-yl-acetroacetic acid. The products are suitable as precursors for benzoquinolizine ring compounds of formula <FORM:0960181/C1/3> e.g.emetine, or 2-dehydro-emetine and by reacting with a compound R4CH2.COZ where Z is a halogen atom, azide group, or a -CO.CH2R4 group (and R4 is a hydrocarbon group), or a vinyl ketone R6-CO-CH=CH2 (where R6 is a hydrocarbon group) followed by cyclisation, dehydration and reduction.  Examples describe the preparation of emetine from the corresponding bis-derivatives by the use of (a) acid anhydride or (b) vinyl ketone following the above stages in which a -bis (1:2:3:4-tetrahydro 6:7-dimethoxy-isoquinol-1-yl) acetone and its di-butyryl derivative is prepared, followed by the preparation of 1,3-bis (1:2:3:4-tetrahydro 6:7-dimethoxy-2(3-oxo-but-1-yl)-isoquinol-1-yl) acetone hydrochloride and (1:2:3:4-tetrahydro-6:7-dimethoxy-2-(31-oxo-but-11-yl) isoquinol-1-yl) acetone hydrochloride. 3-acetyl-1:2:3:4:6:7-hexahydro 11 b [H] - 9:10 - dimethoxy - 2 - methylbenzo[a] - quinolizine-2-ol hydrochloride is prepared by sodium methoxide and hydrochloric acid cyclisation. 11:31-bis (2-butyryl-1:2:3:4-tetrahydro-6:7-dimethoxyisoquinol-1-yl) acetone is self condensed to form fractions which yield 3-ethyl-1:4:6:7 - tetrahydro - 9:10 - dimethoxy - 2 - (21 butyryl - 11:21:31:41 - tetrahydro - 61:71-dimethoxyisoquinol-11-yl) methyl-4-oxo-11(b)H-benzo [a] quinolizine and other quinolizines. The preparation of 3-Acetyl-1:4:6:7-tetrahydro-9:10 - dimethoxy - 2 - methyl - 11b[H]-benzo [a] quinolizine, 3-acetyl-1:2:3:4:6:7-hexahydro - 2 - hydroxy - 9,10 - dimethoxy - 2 - [11:21:31:41 tetrahydro-61-71-dimethoxy-21-(311 -oxobutyl) - isoquinol-11-yl] methyl-11b[H]-benzo-[a]-quinolizine, 3-acetyl-1:4:6:7-tetrahydro-9:10-dimethoxy - 2 - [11:21:31:41 - tetrahydro - 61,71 - dimethoxy 21 - (311 - oxobutyl) - isoquinol - 11-yl] methyl - 11b[H] - benzo[a] - quinolozine, and 6:7 - dimethoxy - 1,2,3,4 - tetrahydro - isoquinol - 1-yl-acetoacetic acid is also described.