Patent GB-891157-A (GB)
Title: ª+-carbolines and process for their manufacture
IPC: C07D491/04
Filed: 1958-07-03
Abstract: The invention comprises 1-hydroxy-1,2,3,4-tetrahydro-g -carbolines which are N-substituted by an alkyl group having up to 5 carbon atoms, an amino-substituted alkyl group having up to 5 carbon atoms or a benzyl group.  These compounds may be made by reacting an a -indolyl-lithium compound, which is N-substituted by a lower alkyl group, an amino-substituted lower alkyl group or a benzyl group, w th an a -aminoaldehyde or ketone; the indole compound so obtained, which contains tertiary nitrogen in the side chain is converted by catalytic hydrogenation into an indole compound containing secondary nitrogeno; and the secondary nitrogen atom is condensed by means of a carbonyl compound with the b -methylene group of the indole.  If desired the hydrogenated carboline so obtained may be converted into a fully aromatic g -carboline by quaternation and heating with the splitting off of water and a hydrocarbon.  The reaction can be represented, when 1-methyl-indolyl-(2)-lithium and benzyl-ethylamino acetone are used as starting materials as follows:-  <FORM:0891157/IV (b)/1> <FORM:0891157/IV (b)/2> <FORM:0891157/IV (b)/3> <FORM:0891157/IV (b)/4> The basic nitrogen of the a -amino-ketones an aldehydes used as starting materials may form part of a ring system as, for example, in pyridine.  The substituents at the nitrogen atom in these aldehydes and ketones may be, for example, alkyl, aralkyl or cycloalkyl.  Ring closure between the methylene group in the b -position of the indole molecule and the side chain carrying the secondary nitrogen atom is carried out with the aid of a carbonyl compound, e.g. a carboxylic acid or anhydride, halide or ester thereof or an aldehyde or ketone, advantageously formaldehyde. The quaternary ammonium salts obtained may be converted by known methods to other quaternary ammonium salts.  The indolyl-2-lithium compounds used as starting materials may be obtained by reacting n-butyl lithium with the corresponding indole compound.  Examples are given as follows: (a) N-methyl-indole is reacted with n-butyl-lithium to give 1-methyl-indolyl-(2)-lithium which is reacted with benzyl-ethylaminoacetone, the product is hydrogenated and subjected to ring closure as shown above to give 1.9 - dimethyl - 1 - hydroxy - 3 - ethyl - 1,2,3,4 - tetrahydro - g  - carboline; (b) N - (b  - diethylamino ethyl)-indolyl-(2)-lithium (obtained from n-butyl lithium and N-[b -diethyl-amino-ethyl)-indole] is reacted with N-benzyl-N-methyl amino acetone to give the compound of formula <FORM:0891157/IV (b)/5> this is catalytically hydrogenated to give the compound of formula <FORM:0891157/IV (b)/6> which is then subjected to ring closure to give the compound of formula <FORM:0891157/IV (b)/7> (c) 1-methyl-indolyl-(2)-lithium is reacted with 2-acetyl pyridine to give the compound of formula <FORM:0891157/IV (b)/8> this is catalytically hydrogenated to give the compound of formula <FORM:0891157/IV (b)/9> which is subjected to ring closure to give the compound of formula <FORM:0891157/IV (b)/100> this is converted to the carbolinium iodide of formula <FORM:0891157/IV (b)/111> which on heating gives the compound of formula <FORM:0891157/IV (b)/122>