Patent GB-778823-A (GB)
Title: 3-(2-hydroxyethyl)-indoles and the manufacture thereof
IPC: C07D209/12
Filed: 1955-04-06
Abstract: The invention comprises (1) the production of 3 - (2 - hydroxyethyl) - indoles (tryptophols) by lithium aluminium hydride reduction of the corresponding indole-3-glyoxylic acids (or salts, esters, halides or anhydrides thereof) or indole-3-glycollic acids (or salts or esters thereof); (2) compounds of the formula: <FORM:0778823/IV(b)/1> where R2 is hydrogen, C1-C8 alkyl, aryl o aralkyl (not over 15 carbon atoms), n is 1-4 and R is hydroxy, methylol, aminomethyl, dialkylamino, halogen, aryl, aralkyl, aryloxy, benzyloxy (which may be substituted) or a fused arylene radical attached at e, f, or g, R3 containing not more than 15 carbon atoms; and (3) the compound 5 : 6-dimethoxy-tryptophol. The process of (1) is particularly applicable to compounds of the formula: <FORM:0778823/IV(b)/2> where Y is a glyoxylic or glycollic group as above, R2 is as above and R3 is carboxylic acid or ester (reduced to methylol), cyano (reduced to aminomethyl), acyloxy (hydrolysed to hydroxy), C1-C8 alkoxy, dialkylamino, halogen, C1-C8 alkyl, aryl, aralkyl, aryloxy, benzyloxy (which may be substituted) or a fused arylene group.  Examples are given of the production of tryptophol itself and the following substituted tryptophols: 6-methyl, 2 : 4-diphenyl, 2 : 5-dibenzyl, 2-phenyl-6-hydroxy, 4-methylol, 2-phenethyl - 5 - methylol, 5 : 6 - dimethoxy, 5-phenoxy, 5 - benzyloxy, 4 - aminomethyl, 4-diethylamino, 5 - chloro and 1 - benz - (g)-tryptophol.  Other products are mentioned in which R2 is H, methyl, ethyl, propyl, phenyl, tolyl, biphenylyl, benzyl, phenethyl, p-methylbenzyl, naphthyl, p-chlorophenyl or p-chlorobenzyl, and R3 is methyl, ethyl, propyl, butyl, phenyl, naphthyl, benzyl, phenethyl, p-methoxybenzyl, methylol, aminomethyl, hydroxy, ethoxy, propoxy, butoxy, phenoxy, naphthoxy, chloro, bromo, dimethylamino, diethylamino, dipropylamino, benz - (e) benz - (f) - or benz-(g).  Many other starting materials are listed in which R2 is in addition hexyl, p-propylphenyl, p - ethoxyphenyl, p - ethylbenzyl, p - methoxybenzyl, p - ethoxybenzyl, p - bromobenzyl, methylnaphthyl, ethoxynaphthyl and chloronaphthyl, and R3 is additionally hexoxy, p-methylbenzyloxy, p - methoxybenzyloxy, p-chlorobenzyloxy and benzhydryloxy, the last optionally para-substituted by methyl, methoxy, ethoxy, chlorine or bromine.  It is also stated that R2 may be octyl and R3 may be iodo, methylbutylamino or a fused naphthalene ring.  Tryptamines are made from the above products by successive treatment with phosphorus tribromide and ammonia or an amine.  If R3 is benzyloxy it may be converted to hydroxyl by catalytic hydrogenation (see Specification 744,774) to give serotonin or an isomer or derivative thereof. Similarly if R3 is alkoxy it may be dealkylated with aluminium chloride.  A number of tryptamines are mentioned, with or without a nuclear hydroxyl group.  They may be reacted with thiocyanic or perthiocyanic acid and then condensed with aldehydes to give pickling inhibitors.  Indole - 3 - glyoxylic acid derivatives are made by condensing indole or a substituted indole with an oxalyl halide and converting the resulting indole-3-glyoxylyl halide into the free acid or salt, ester or anhydride (simple or mixed) by normal methods. Examples show the production of indole-3-glyoxylyl chloride and conversion to the corresponding methyl, ethyl, diethylaminoethyl and benzyl esters, and of 5-benzyloxyindole - 3 - glyoxylyl chloride and the corresponding ethyl ester.  Other products are mentioned, variously substituted, the functional groups being the free acid; sodium, potassium and barium salts; methyl, ethyl, propyl, butyl, phenyl and benzyl esters; acid chloride and bromide; acid anhydride, and mixed anhydrides with acetic, propionic, butyric and benzoic acids.  Indole - 3 - glycollic acids and their salts and esters are made by partial reduction of the corresponding glyoxylic compounds, e.g. with sodium or lithium borohydride, aluminium amalgam or hydrogen with a catalyst.  An example is given of the preparation of methyl indole-3-glycollate.  Bz - benzyloxy - indoles are prepared from the hydroxy - 2 - nitrobenzaldehydes by O-benzylation and carrying out the successive steps described in Specifications 720,584, 728,013 and 744,765.  Typical products are mentioned, in which the benzyl group may be substituted.  Bz - substituted indoles are similarly obtained by reduction of 2 : b -dinitro-styrenes substituted by acyloxy, halo, cyano, carboxy, carbalkoxy, dialkylamino, alkyl, aryl aralkyl and aryloxy groups.  Typical products are mentioned.  2 - substituted indoles, e.g. 2 - methyl, 2-phenyl, 2-benzyl and 2-naphthyl are made from phenylhydrazine (or a substituted phenylhydrazine) and the corresponding methyl ketones. Other 2-alkyl-indoles are made as in Specification 728,013.  Typical products are mentioned.