Patent GB-781390-A (GB)
Title: Preparation of 3-(2-aminoethyl)-indoles
Filed: 1955-04-12
Abstract: The invention comprises the 3-(2-N-morpholinylethyl) - and (2 - N - benzyl - N - ethylaminoethyl)-indoles and the 6-methoxy-3-[2-(7-hydroxy - 1 - decahydroisoquinolyl) - ethyl] -, 4 - chloro - 3 - (2 - N:N - dibenzylaminoethyl) -, 2 - methyl - 3 - (2 - N - hexamethyleneiminoethyl)-, 5:6 - dimethoxy - 3 - (2 - N:N - dibenzylaminoethyl)-, 5:6-dimethoxy-3-(2-N-hexamethyleneiminoethyl)-, 1 - benz - (g) - 3 - (2 - piperidylethyl)- and 3 - [2 - N - benzyl - N - (2-ethylhexyl)-aminoethyl]-indoles; and comprises also a process for the preparation of 3-(2-aminoethyl)-indoles in general and their acid addition salts, which includes the step of reducing a 3-indoleglyoxylamide or a 3-indoleglycolamide with lithium aluminium hydride.  Suitably the starting material is a 3-indoleglyoxylylamide of the formula <FORM:0781390/IV (a)/1> wherein R2 is hydrogen, or an aryl, substituted aryl, aralkyl, or substituted aralkyl radical, preferably containing not more than fifteen carbon atoms, or an alkyl radical of not more than eight carbon atoms, R3 is hydrogen or a halogen atom, or a cyano, carboxy, carbalkoxy (wherein the alkyl group contains 1-8 carbon atoms), dialkylamino or alkyl or alkoxy group (containing 1-8 carbon atoms), or a substituted or unsubstituted aryl, aralkyl, aryloxy, benzyloxy or benzhydryloxy group, an acyloxy (wherein the acyl group is from an organic carboxylic acid containing from 1-8 carbon atoms) or a fused arylene radical, R3 being preferably a group of not more than fifteen carbon atoms, n is zero or an integer from one to four, and Z is a primary secondary or tertiary amido radical suitably derived from ammonia, a primary or secondary alkyl, cycloalkyl, aralkyl or aryl amine or a heterocyclic amine such as piperidine, morpholine, thiamorpholine, pyrrolidine, hexamethyleneimine, tetrahydroisoquinoline or hexahydroisoquinoline.  The 3-indoleglyoxylamide is reduced with lithium aluminium hydride, either directly, or stepwise by preliminary reduction to a 3-indolglycolamide by means of reducing agents other than lithium aluminium hydride, e.g. sodium borohydride, lithium borohydride, aluminium amalgam and catalytic reduction, followed by reduction to the amine by lithium aluminium hydride. Reduction to the amine is suitably carried in an inert solvent such as ether, tetrahydrofuran, N-ethylmorpholine or dibutyl ether. Reduction of 3-indoleglyoxylamides wherein R3 is an acyloxy, cyano, carboxy or lower carbalkoxy group results in the conversion of these groups to a hydroxy, aminomethyl, methylol and methylol radical respectively.  The reduction of the 3-indoleglyoxylamides may be effected in a stepwise manner if desired, whereby the 3-indoleglyoxylamide is first treated with a reducing agent other than lithium aluminium hydride, e.g. sodium borohydride, lithium borohydride, aluminium amalgam and catalytic means such as platinum oxide, to effect reduction of the ring-attached carbonyl group to a carbinol group and reducing the 3-indoleglycolamide obtained, by means of lithium aluminium hydride to give the 3-(2-aminoethyl)-indole.  The products may be isolated as the free bases or as acid addition salts such as hydrochlorides, hydrobromides, sulphates, acetates, tartrates or citrates. Quaternary salts such as the methobromide, ethobromide and benzyl chloride may also be prepared from the tertiary amines of the invention.  Examples describe the preparation of 3-(2-aminoethyl)-indoles by reduction of 3-indoleglyoxylamides of the above general formula I to give corresponding products wherein R2 is chosen from hydrogen, phenyl, benzyl, methyl, ethyl and p-chlorophenyl; R3 is chosen from benzyloxy, benzyl, phenoxy, phenyl, methyl, methoxy, hydroxy, aminomethyl, methylol, chloro, diethylamino and fused phenylene radicals and Z is chosen from dibenzylamino, benzylamino, amino, benzylethylamino, diethylamino, morpholino, dimethylamino, diphenylamino, anilino, N-benzyl-N-2-ethylhexylamino, hexamethyleneimino, piperidino, methylamino, 7 - hydroxy - 2 - decahydroisoquinolyl, cyclohexylamino, and dibutylamino radicals. Many other substituents are specified.  Starting materials.  3 - Indoleglyoxyl amides are made by treating a 3-indoleglyoxylyl halide with ammonia or a primary or secondary amine.  Specified products include 3-indoleglyoxylamide itself and the 5-benzyloxy-N:N-dibenzyl-, 5-benzyloxy - N - benzyl -, N - benzyl - N - ethyl-, N:N-diethyl-, N-benzyl-, 5-benzyloxy-N:N-dimethyl-, 5:6 - dimethoxy - N:N - dibenzyl-, 5 - benzyloxy - N - phenyl -, 2 - methyl - N:N - hexamethylene-, 5:6 - dimethoxy - N:N - hexamethylene- and N - methyl-, derivatives and also 3-indole-glyoxylic acid morpholide, 1 - benz - (g) - 3 - indoleglyoxylic acid piperidide and 2-(6 - methoxy - 3 - indoleglyoxylyl) - 7 - hydroxy - decahydroisoquinoline.  3 - Indoleglyoxylyl halides such as those corresponding to the above glyoxylamides are made by reacting an indole with an oxalyl halide. N-Methyl-3-indoleglycolamide and N-benzyl-3-indoleglycolamide are made by reducing the corresponding glyoxylamides by catalytic hydrogenation. Specifications 720,584, 728,013, 744,765 and 744,774 are referred to.