Patent GB-744772-A (GB)
Title: Indole derivatives
IPC: C07D209/18
Filed: 1953-03-30
Abstract: The invention comprises (5-benzyloxy-3-indole)-alkanoylamides having the formula <FORM:0744772/IV(a)/1> wherein X is phenyl, halophenyl, lower alkoxyphenyl, or lower alkylphenyl, Y is hydrogen or one of the radicals represented by X, R1 and R2 are alike or different and represent hydrogen or lower alkyl, n is 0 or 1, and R3 and R4 are alike or different and represent hydrogen, alkyl, cycloalkyl, aralkyl, or phenyl, at least one of R3 and R4 being other than hydrogen, or such a compound wherein the radicals R3 and R4 together with the - N = form a five or six atom monoheterocyclic radical, the terms "lower alkyl" and "lower alkoxy" denoting radicals of 1 to 8 carbon atoms.  The invention also comprises a process for the preparation of a (benzyloxy-3-indole)-alkanoylamide, comprising the steps of mixing a benzyloxyindole with a Grignard reagent and reacting the thus-produced benzyloxy-indolemagnesium halide with a secondary or tertiary a -haloacetamide or b -halopropionamide. Radicals which -NR3R4 in the above formula (when cyclic) can represent include piperidino, morpholino, thiomorpholino and pyrrolidino.  The preferred starting materials have the formula <FORM:0744772/IV(a)/2> and X1-CHR1-(CH2)n-COZ (wherein X1 is halogen) respectively.  The reaction is usually effected in a solvent such as ether, dibutyl, ether, benzene, toluene or anisole at the boiling point of the solvent, although other temperatures between about 0 DEG and 150 DEG  C. may be used.  The benzyloxy-indoles used as starting materials may be prepared by the method of Specification 744,765 by the reductive cyclization of 5-benzyloxy - b ,2 - dinitrostyrenes, prepared in turn by the dehydration (as in Specification 720,584) of the 5-benzyloxy-2-nitro-a -[1-(1-nitroalkyl)] benzyl alcohols, obtained as in Specification 728,013 by the condensation of 5-benzyloxy-2-nitrobenzaldehydes with a 1-nitroalkane.  Starting materials with the benzyloxy group in other positions are prepared similarly.  The haloalkanoylamides are obtained by reacting an acid halide in cooled ether with an amine.  A list of such bromo, iodo and chloro amides is given, containing at R3 and R4 various radicals selected from H, methyl, isopropyl, ethyl, butyl, benzyl, cyclohexyl and phenethyl groups.  The products may be used in the processes of Specifications 744,773 and 744,774 for the production of 5-hydroxytryptamine (serotonin) and analogous compounds.  In example (1) a -3-(5 - benzyloxyindole) - N - benzyl - N - methylacetamide is prepared by reacting a -chloro-N-benzyl - N - methylacetamide with the reaction product from methyl magnesium iodide and 5-benzyloxyindole.  Similarly prepared are (2) a  - 3 - (5 - benzyloxyindole) - N,N - dibenzylacetamide; (3) a  - 3 - (5 - benzyloxyindole - N-benzylacetamide; (4) a  - 3 - (5 - benzyloxy - 2-methylindole) - N - methylacetamide, a  - 3 - (5-benzyloxy - 2 - ethylindole) - N,N - dibenzylacetamide, a  - 3 - (5 - benzyloxy - 2 - propylindole) - N - cyclohexylacetamide, a  - 3 - (5-benzyloxy - 2 - ethylindole) - 2 - methyl - N-benzylacetamide and b  - 3 - (5 - benzyloxy - 2-methylindole) - N - benzylpropionamide; (5) b  - 3 - [5 - (p,p1 - dimethylbenzhydryloxy)-indole] - b  - methyl - N,N - dibenzylpropionamide, a  - 3 - [5 - (p,p1 - diethylbenzhydryloxy)-indole - a  - propyl - N - methyl - N - cyclohexylacetamide, a  - 3 - [5 - (p - methylbenzyloxy)-indole - N - benzylacetamide, a  - 3 - [5 - (p-ethybenzyloxy) - 2 - methyl indole] - N - phenylacetamide, a  - 3 - [5 - ( - p - propylbenzyloxy)-indole - N - isopropyl - N - benzylacetamide, a -3 - [5 - (p,p1 - dimethylbenzhydryloxy) - indole]-N - isopropylacetamide and b  - 3 - [5 - (p-ethylbenzyloxy) - indole] - b  - methyl - N - benzylpropionamide; (6) a  - 3 - (5 - benzhydryloxyindole) - N - benzylacetamide, a , - 3 - (5-benzhydryloxyindole) - N - cyclopentyl - N-ethylacetamide, a  - 3 - (5 - benzhydryloxyindole) - a  - ethyl - N,N - diphenylacetamide, a  - 3 - (5 - benzhydryloxy - 2 - ethylindole) - N-benzyl - N - methylacetamide, b  - 3 - (5 - benzhydryloxyindole) - N - methyl - N - benzylpropionamide and b  - 3 - (5 - benzhydroloxyindole)-b  - ethyl - N - methyl - propionamide; (7) a  - 3-[5 -(p,p1 - dichlorobenzhydryloxy) - 2 - ethylindole] - N - methyl - N - benzylacetamide, a  - 3-[5 - (p,p1 - dichlorobenzhydryloxy) - indole] - a -ethyl-N-methyl-N-benzylacetamide, a -3 - [5 - (p - iodobenzyloxy) - indole] - N,N - dicyclohexylacetamide, b  - 3 - [5 - (p,p1 - dichlorobenzhydryl - oxy) - indole] - N - isopropylpropionamide and b - 3 - [5 - (p - bromobenzyloxy)-indole] - b  - ethyl - N - methylpropionamide; (8) b  - 3[5 - (p,p1 - dimethoxybenzhydryloxy)-indole] - N,N - dibenzylpropionamide, a  - 3-[5 - (p,p1 - dimethoxybenzhydryloxy) - indole]a -propyl - N - ethyl - N - cyclohexylacetamide, a -3 - [5 - (p - propoxybenzyloxy) - indole - N-benzyl - N - cyclopentylacetamide, a  - 3 - [5 - (p-ethoxybenzyloxy) - 2 - propylindole] - N - benzylacetamide, a  - 3 - [5 - (p,p1 - dimethoxybenzhydryloxy) - indole] - N,N - dibenzylacetamide, and b  - 3 - [5 - (p - ethoxybenzyloxy) - indole]-b  - ethyl - N - benzylpropionamide; (9) a  - 3-(5 - benzyloxyindole) - N - benzyl - N - isopropylacetamide, a  - 3 - (5 - benzyloxyindole) - N,N-dibutylacetamide and a  - 3 - (5 - benzyloxyindole) - or - benzyl - N - cyclohexylacetamide; (10) b  - 3 - (5 - benzyloxyindole) - N,N - diethylpropionamide and the corresponding N - isopropyl, N,N - dimethyl, and N - methyl - N-benzyl derivatives and b  - 3 - (5 - benzyloxyindole) - b  - methyl - N - benzylpropionamide; (11) a  - 3 - (5 - benzyloxyindole) - acetopiperidide, a  - 3 - (5 - benzyloxyindole) - a  - methylacetopiperidide, a  - 3 - (5 - benzyloxy - 2 - ethyl indole) - acetopiperidide, a  - 3 - (5 - benzyloxyindole) - acetopyrrolidide, a - 3 - (5 - benzyloxyindole) - acetomorpholide, a  - 3 - (5 - benzyloxyindole) - acetothiomorpholide and b  - 3 - (5-benzyloxyindole) - b  - ethyl - propinopyrrolidide.