Patent GB-744774-A (GB)
Title: Process for the preparation of indole derivatives
Filed: 1953-03-30
Abstract: A process for the preparation of (hydroxy-3-indole)-alkylamines and salts thereof comprises the step of subjecting to hydrogenolysis a (benzyloxy - 3 - indole) - alkylamine having the formula <FORM:0744774/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 Z represents the radical -NR3R4 wherein R3 is hydrogen, alkyl, cycloalkyl, phenyl or aralkyl and R4 is alkyl, cycloalkyl, phenyl or aralkyl or R3 and R4 taken together with the nitrogen are five or six atom mono heterocyclic radicals, and the terms "lower alkyl" and "lower alkoxy" refer to radicals containing 1 to 8 carbon atoms inclusive.  The hydrogenolysis can be effected at hydrogen pressures from below atmospheric to about 2 or 3 atmospheres or higher, and usually at about 25 DEG  C. although temperatures between 0 DEG  C. and the boiling point of the solvent are also suitable.  Suitable solvents are aliphatic ketones and alkanols.  Suitable catalysts include palladium black, palladium-barium sulphate, and palladium-charcoal. The hydrogenolysis can also be effected by the action of sodium in liquid ammonia.  The product may be isolated as the free base, as the acid addition salt obtained by the addition of hydrochloric, picric, tartaric, citric, acetic or sulphuric acids or by the addition of sulphuric acid and creatinine sulphate, or as the quaternary ammonium salt by heating the free amine with an alkyl halide or aralkyl halide in a pressure vessel, and the product is separated by addition of the appropriate precipitating agent.  The starting materials may be obtained by the methods of Specifications 744,772 and 744,773, typical preparations according to those specifications being included.  The hydrogenolysis may also result in the removal of a benzyl radical from the amino group, in which case re-benzylation may be effected by reaction with e.g. benzaldehyde followed by hydrogenation in the presence of a platinum oxide catalyst.  In examples (1) 5 - benzyloxy - 3 - [2 - (N - benzyl-N - methylamino) - ethyl] - indole is treated with hydrogen at 25 DEG  C. in the presence of a palladium-charcoal catalyst to give 5-hydroxy-3 - [2 - (N - methylamino) - ethyl] - indole, which is isolated by adding sulphuric acid and creatinine sulphate to the hydrogenation product. The hydrochloride, picrate, tartrate, citrate, acetate and sulphate can be prepared.  Similarly prepared are (2) 5-hydroxy-3-[2-(N,N-dimethylamino) - ethyl] - indole is prepared by a method similar to example (1); (3) 5-hydroxy-3 - [2 - (N - cyclohexylamino) - ethyl] - indole hydrochloride; (4) 5 - hydroxy - 3 - [2 - (N - phenyl-N-ethylamino)-ethyl]-indole picrate; (5) 5 - hydroxy - 3 - [2 - (1 - piperidino) - ethyl]-indole hydrochloride and a number of similar pyrrolidino, morpholino, and thiomorpholino derivatives, some containing alkyl substituents in the indole nucleus and in the ethylene or propylene chain; (6) 5-hydroxy-3[2-(N,N-dibutyl-amino)-ethyl]-indole hydrochlorides. In further examples (7) 5-hydroxy-3-[3-(N-methylamino)-propyl] indole is prepared by the similar hydrogenolysis of 5-(p,p1-dimethoxybenzhydryloxy)-3 - [3 - (N - methylamino) - propyl] - indole.  In a similar manner the (5-alkyloxybenzyloxy-3-indole)-alkylamines listed in example 8 of Specification 744,773 are converted by hydrogenolysis to the corresponding hydroxy compounds; (8) 2-ethyl-5-hydroxy-3-[2-(N-methylamino)-ethyl]-indole is prepared by the treatment with palladium black and hydrogen at the two atmospheres of 2-ethyl-5(p,p1-dichlorobenzhydryloxy) - 3 - [2 - (N - methyl - N - benzylamino) - ethyl] - indole. Similarly debenzylation is effected of the (5-halobenzyloxy-3-indole)-alkylamines listed in example (7) of Specification 744,773; (9) 5 - hydroxy - 3 - (1 - methyl - 3-aminopropyl)-indole is prepared by the treatment with hydrogen and a palladium-barium sulphate catalyst of 5-(p,p1-dimethylbenzhydryloxy) - 3 - [1 - methyl - 3 -(N,N - dibenzylamino)-propyl] - indole.  Similar hydrogenolysis is effected of the other (5-alkybenzyloxy-3-indole) - alkylamines referred to in example (6) of Specification 744,773; 5-hydroxy-3-(2-aminoethyl)-indole is prepared by treatment with hydrogen and a palladium-barium sulphate catalyst of 5 - benzhydryloxy - 3 - [2 - (N-benzylamino) - ethyl] - indole.  A similar hydrogenolysis is applied to the (5-benzhydryloxy - 3 - indole) - alkylamines produced in example (10) of Specification 744,773; (11) 2-methyl - 5 - hydroxy - 3 - (2 - aminoethyl)-indole is prepared by the treatment with hydrogen and a palladium-charcoal catalyst of 2 - methyl - 5 - benzyloxy - 3 - [2 - (N,N - dibenzylamino) - ethyl] - indole.