Patent GB-893798-A (GB)
Title: Dialkoxymethyl-benzoxindoles and process for the manufacture of benz-indoles therefrom
Filed: 1958-07-02
Abstract: The invention comprises 1-dialkoxymethyl-8-amino-1 : 2 : 3 : 4-tetrahydronaphthalene-1-carboxylic acid lactams having a nucleus of formula <FORM:0893798/IV (b)/1> in which R is a dialkoxymethyl group, and their use in the production of benzindoles.  The lactams may be obtained, for example, by heating an 8-amino-1 : 2 : 3 : 4-tetrahydronaphthalene-1-carboxylic acid lactam with an orthoformic acid ester and acetic or other alkanoic acid anhydride, preferably in the presence of a solvent.  The reaction proceeds particularly well if compounds which are acylated, especially acetylated, at the nitrogen in the 8-position are used as starting materials.  The 8-amino-1 : 2 : 3 : 4-tetrahydro-naphthalene-1-carboxylic acid lactams used as starting materials may be further substituted, for example, by free or functionally converted hydroxyl, oxo or carboxyl groups and may, therefore, be esters or ethers, e.g. acetates, benzoates, p-toluene sulphonates, methyl or allyl ethers, or acetal, mercaptal, ketal or thioketal compounds, oximes, semicarbazones, amides, nitriles or imides.  In addition there may be present free or substituted amino groups, e.g. methylamino, dimethylamino, ethylamino, pyrrolidino, piperidino, piperazino or morpholino groups; halogen atoms; saturated or unsaturated hydrocarbon groups; and carbomethoxypropyl, carbomethoxyethinyl and carbomethoxyethenyl groups.  The 1-di-alkyoxymethyl-8-amino- 1 : 2 : 3 : 4-tetrahydronaphthalene-1-carboxylic acid lactams may be converted into benzindoles by treatment with a basic agent which is capable of splitting a lactam ring and acidifying the thus produced a -dialkoxymethylamino carboxylic acid so that carbon dioxide is lost and the 5-membered heterocyclic ring is closed with elimination of water.  Suitable basic agents are, for example, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, quaternary ammonium bases and basic ion-exchangers.  Preferred acid agents are mineral acids, especially hydrochloric acid.  The treatment with alkali is preferably carried out in the presence of a solvent and the acid treatment is preferably carried out in solution with the exclusion of oxygen and at elevated temperature.  The reaction takes place as follows:-N-acetyl-1-diethoxy-methyl-8-1,2,3, 4-, tetrahydro-naphthalene - 1 - carboxylic acid --> <FORM:0893798/IV (b)/2> In Examples (a) N-acetyl-1-diethoxymethyl-8- 1 : 2 : 3 : 4-tetrahydronaphthalene-1-carboxylic acid lactam of formula <FORM:0893798/IV (b)/3> is heated with caustic soda to give an alkaline filtrate and crystals of 1-diethoxymethyl-8-amino- 1 : 2 : 3 : 4-tetrahydro-naphthalene-1-carboxylic acid lactam; the alkaline filtrate is acidified to give 8-acetylamino-1-diethoxymethyl-1 : 2 : 3 : 4-tetrahydro-1-naphthoic acid of formula <FORM:0893798/IV (b)/4> which is boiled with ethanol and neutralised with caustic soda to give 1 : 3 : 4 : 5-tetrahydrobenz-(cd)-indole or alternatively may be cautiously neutralised in the cold with caustic soda to give N-acetyl-1 : 3 : 4 : 5-tetrahydrobenz-(cd)-indole of formula <FORM:0893798/IV (b)/5> the crystals of 1-diehtoxymethyl-8-amino-1 : 2 : 3 : 4-tetrahydro-naphthalene-1-carboxylic acid lactam is treated with caustic potash to give 1 : 3 : 4 : 5-tetrahydrobenz-(cd)-indole of formula <FORM:0893798/IV (b)/6> (b) N-acetyl-1-diethoxymethyl-3-oxo-8-amino-1 : 2 : 3 : 4-tetrahydro-naphthalene-1-carboxylic acid lactam of formula <FORM:0893798/IV (b)/7> is converted similarly into N-acetyl-5-acetoxybenz-(cd)-indole of formula <FORM:0893798/IV (b)/8> and (c) 31 - amino - 1 - methyl - 3 - carbethoxy -7-diethoxy-methyl-1 : 2 : 3 : 4 : 4a : 7 : 8 : 8a-octahydro-5,6-benzoquinoline-7-carboxylic acid lactam of formula <FORM:0893798/IV (b)/9> is converted similarly into a mixture of the stereoisomers of dihydro-lysergic acid hydrochloride of formula <FORM:0893798/IV (b)/100> which may be converted to the free acid. Methods of making the starting materials in the examples are given.