Patent GB-450737-A (GB)
Title: Process for the manufacture of cyclohexenylalkylhydantoins
IPC: C07D233/72
Filed: 1935-10-01
Abstract: 5 : 5 - Disubstituted hydantoins possessing therapeutic value and particularly low toxic action are prepared by treating cyclohexenylalkylmalonamides or cyclohexenylalkylcyanacetamides with hypohalides in the presence of acid binding agents.  The 5 : 5-cyclohexenylalkylhydantoins so produced have the general formula <FORM:0450737/IV/1> where R1 is a cyclohexenyl group, R2 is a saturated or unsaturated alkyl residue and R3 and R4 are hydrogen or a saturated or unsaturated alkyl residue or an aralkyl group. They may be further alkylated or aralkylated by methods described for example in Specification 430,255.  The alkylation or aralkylation may be carried out in a solvent such as water, ethanol, methanol, acetone, benzene, or ether, according to the agent used, examples of which are alkylhalides, dialkyl-sulphates, p-toluene sulphonic acid esters, and aralkylhalides.  It is preferred to carry out the reaction in the presence of an acid binding medium such as sodium bicarbonate or carbonate, caustic soda, pyridine, quinoline or dimethylaniline.  As cyclohexenyl residues the D -1 : 2- and D -2 : 3-compounds are mentioned, and as alkyl or aralkyl residues methyl, ethyl, propyl, allyl, bromallyl, benzyl, halogen-benzyl, and nitrobenzyl are mentioned. The cyclohexenylalkylcyan-acetic or malonic acid derivatives which are used are made from cyclohexenyl-alkylcyanic or malonic acid esters by known methods such as by the action of ammonia.  In examples: (1) D -1 : 2-cyclohexenylmethylcyan-acetamide is treated with sodium hypobromite in the presence of bromine and caustic soda.  The product is treated with sodium bisulphite and the 5 : 5-(D -1 : 2)-cyclohexenylmethylhydantoin precipitated by hydrochloric acid and recrystallized from water.  (2) If the D -1 : 2-cyclohexenylmethyl cyanacetamide of example 1 is replaced by the equivalent amount of D 1 : 2 - cyclohexenylethyl - cyanacetamide, the 5 : 5-(D  - 1 : 2) - cyclohexenylethyl - hydantoin is obtained.  (3) The hydantoin of example 1 on treatment with dimethyl sulphate yields 3-methyl-(D -1 : 2)-cyclohexenylmethylhydantoin.  If the dimethyl sulphate is replaced by ethyl bromide, or allyl bromide, or benzyl chloride, there is obtained respectively the corresponding 3-ethyl-, or -allyl- or -benzyl-compounds.  (4) If the 5 : 5-(D -1 : 2)-cyclohexenylmethylhydantoin is replaced by the corresponding amount of 5 : 5-(D -1 : 2)-cyclohexenylethylhydantoin, the corresponding 3-methyl-compound is produced.  (5) The 3-methyl-5 : 5-(D  - 1 : 2) - cyclohexenylmethyl - hydantoin of example 3 on further methylation with dimethyl sulphate yields the 1 : 3-dimethyl compound.  This compound may also be produced directly from the unmethylated parent material by using an excess of the dimethyl sulphate.  If the dimethyl sulphate is replaced by ethyl bromide, or allyl bromide, or benzyl chloride, there is obtained respectively the 3-methyl-1-ethyl- or allyl or benzyl compounds. (6) In the same manner as in example 5 the 1 : 3-dimethyl-5 : 5-(D -1 : 2)-cyclohexenyl-ethyl-hydantoin is obtained from 3-methyl-compound. The D -1 : 2-cyclohexenylmethylcyan - acetamide may be obtained either by the saponification of the D -1 : 2-cyclohexenylmethylcyan-acetic ester to the acid, converting the same into the acid chloride and converting the latter into the amide by treatment with ammonia or by the direct conversion of the ester into the amide by ammonia.  The D  - 1 : 2 - cyclohexenylethylcyanacetic ester may be prepared by a method analogous to that for the methyl compound.