GB845034A - Improvements in or relating to the production of heterocyclic compounds - Google Patents

Abstract

The invention comprises a process for the preparation of indole derivatives of the general formula: <FORM:0845034/IV(b)/1> (wherein R is an alkyl or aralkyl group, R1 and R2 are alkyl groups containing at most 4 carbon atoms and R3 is a hydrogen atom or an alkyl group containing at most 4 carbon atoms) in which a di-lower alkyl a -acylaminomalonate is added to acrylic aldehyde to produce a 3:3-di-(carbalkoxy) - 3 - acylaminobutyraldehyde, this is condensed with a 4-alkoxy- or 4-aralkoxy-phenyhydrazine and the 4-alkyl- or 4-aralkyl-phenylhydrazone is cyclized with elimination of ammonia. The addition process is advantageously effected by heating equimolecular proportions of the reactants at less than 45 DEG C., the formation of the phenylhydrazone is preferably carried out at an elevated temperature using equimolecular proportions of the reactants and the final cyclization is desirably effected with sulphuric acid, boron trifluoride or zinc chloride, and most desirably with excess sulphuric acid at an elevated temperature. The intermediate products in the above process need not be isolated, and all the reactions may be carried out in a nuclearly-chlorinated aromatic hydrocarbon, such as chlorobenzene or o-dichlorobenzene or a mixture thereof. The above process may be combined with a process for the preparation of 5-hydroxytryptophan, by converting the indole derivative of the above general formula into 5-hydroxytryptophan by known methods of hydrolysis and decarboxylation of substituted malonic esters, followed by hydrolysis (where necessary) of the acylamino group and reductive fission of the group R by known methods. If R3 is a hydrogen atom the formylamino group is hydrolysed simultaneously with the ester groups R1 and R2. An example describes the preparation of ethyl a -acetylamino-a -carbethoxy-,b -(5-benzyloxyindolyl-3) -propionate and the conversion of this to 5-hydroxy-tryptophan via a -acetylamino-a -carboxy - b - (5-benzyloxy-indolyl-3)-propionic acid, a -acetylamino - b (5-benzyloxy-indolyl-3)-propionic acid and 5-benzyloxytryptophan. 4-Alkoxy- and 4-aralkoxy-phenylhydrazines are prepared by diazotizing the appropriately substituted anilines and reducing the resultant diazo compounds. The preparation of 4-benzyloxyphenylhydrazine hydrochloride is described. In the Provisional Specification this compound is prepared by diazotizing 4-benzyloxyaniline hydrochloride, reacting the product with sodium meta bisulphite, sodium acetate and sodium hydroxide to form sodium 4-benzyloxyphenyl diazonium sulphonate, reducing this with zinc and acetic acid to the hydrazosulphonate and hydrolysing this with ethanol and hydrochloric acid.