Patent GB-589210-A (GB)
Title: Process for the manufacture of thiophane derivatives
Filed: 1945-03-19
Abstract: Thiophane derivatives, of the general formula <FORM:0589210/IV/1> wherein X represents an alkyl or o -halogenalkyl radical, are manufactured from 3-ketothiophane-4-carboxylic esters of the general formula <FORM:0589210/IV/2> wherein R represents a lower alkyl radical and X1 an alkyl or o -hydroxy-, -alkoxy-, -aryloxy- or -halogen-alkyl radical, by converting such esters into the corresponding cyanhydrins by means of hydrocyanic acid, preparing therefrom, by saponification and esterification with lower aliphatic alcohols, the corresponding 3-hydroxy-3 : 4-dicarboxylic esters, eliminating the hydroxy group by replacing it by halogen by the action of halides of phosphorus or sulphur and subsequent reduction, reacting the resulting 2 - X1 - thiophane - 3 : 4 - dicarboxylic esters with hydrazine hydrate, treating the acid hydrazides with sodium nitrite to obtain the acid azides, decomposing these by reaction with a lower aliphatic alcohol to yield the 3 : 4-diurethanes, converting these by boiling with hydrogen halides into the 3 : 4-diamine hydrohalides with simultaneous replacement of the o -hydroxy-, -alkoxy- or -aryloxy-group, if present, by halogen, and treating the products with phosgene in the presence of alkali. Alternatively, the conversion of the 2-X1-thiophane-3 : 4-dicarboxylic acid lower alkyl esters into the acid azides is effected by saponification, converting the free acids into their chlorides by any method commonly employed for the conversion of dicarboxylic acids into their chlorides, and treating the latter with sodium azide.  In an example, 3 : 4-(21-ketotetrahydroimidazole)-2-methylthiophane is prepared from 2 - methyl - 3 - ketothiophane - 4 - carboxylic acid ethyl ester by each of the alternative processes, using ethyl alcohol for each of the esterification steps, thionyl chloride (in the presence of pyridine) for the replacement of the hydroxy group of the cyanhydrin by chlorine, zinc, acetic acid and sodium iodide for the reduction and hydrobromic acid for the conversion of the diurethane to the diamine dihydrobromide.  Samples have been furnished under Sect. 2 (5) of : (I) 3 : 4 - (imidazolidone - 21) - 2 - (o  - bromobutyl)-thiophane, m. pt. 175.5 DEG  C., prepared from 2 - (o  - methoxybutyl) - 3 - ketothiophane-4-carboxylic acid ethyl ester by the first of the two alternative processes, using the same reagents as are specified in the example above, except that potassium iodide replaced the sodium iodide in the reduction step; (II) an isomer of (I), m. pt. 163-4 DEG C., prepared from an oily compound isolated from the mother liquors after the crystallization of the dihydrazide in the preparation of (I), by converting the oily dihydrazide into the diurethane, dissolving this in benzene, chromotographing the solution on a column of aluminium oxide, eluting with benzene and subjecting the resulting crystalline diurethane to the remaining steps of the process; (III) the same as (I), but prepared from 2-(o -methoxybutyl) - 3 - ketothiophane - 4 - carboxylic acid methyl ester and with the use of methyl alcohol in the first esterification step and sodium iodide in the reduction.  The Specification as open to inspection under Sect. 91 comprises also the manufacture of products containing other o -substituents in the radical X.  Reference is made to the conversion of the 2-X1-thiophane-3 : 4-dicarboxylic acids into their anhydrides by warming with acetic anhydride, and to the separation of further isomers by chromatographing the oily urethanes occurring in the preparation of sample (II).  This subject-matter does not appear in the Specification as accepted.