Patent GB-633427-A (GB)
Title: Improvements in or relating to the production of aromatic-substituted aliphatic thioamides and the corresponding acids
IPC: C07D295/194
Filed: 1947-02-06
Abstract: Aromatic-substituted aliphatic thioamides are prepared by heating an aryl lower alkyl ketone having in the aryl nucleus one or more hydroxy, amino, acyloxy, acylamino or nitro groups, with sulphur and a primary or secondary amine.  They are hydrolysed to the acids with acid or alkali.  Lower alkyl is defined as having 1 to 4 carbon atoms.  Stable substituent groups such as alkyl, aryl, alkoxy, alkyl-mercapto, and halo may also be present in the ketone. Temperatures are generally 100-200 DEG  C., pressure being employed with lower boiling amines.  Hydrogen sulphide and solvents such as water, primary alcohols, dioxane or hydrocarbons may be present. Amines specified are morpholine, n-heptylamine, piperidine, 2 - ethylhexylamine, cyclohexylamine, benzylamine, aniline, n-butylamine, mono- and di-ethanolamine.  Examples of the process are conversion of amino- and hydroxy-propiophenones with sulphur and piperidine to amino- and hydroxy-phenylthiopropionpiperidides, and of hydroxy-tolyl butyl ketone with sulphur and benzylamine to N-benzyl-hydroxytolylthiobutyramide.  Preferred proportions of reactants are 1 mole. of ketone, 2.5 sulphur, and 2 amine.  Lower ratios of sulphur, e.g. 1 mole, give decreased yields.  Equimolar proportions may be employed.  Times may be 1-2 hours at 100-150 DEG C. or up to 8-10 hours at lower temperatures.  In examples: (1) o-hydroxyacetophenone, sulphur, and morpholine are refluxed for 2 hours, the product taken up in chloroform, washed with water and dilute acid, and o - hydroxyphenylthioacetmorpholide recovered. This is converted to o-hydroxyphenylacetic acid by refluxing with aqueous caustic soda.  Resacetophenone and p-gallacetophenone are similarly converted to 2,4-dihydroxy- and 3,4,5-trihydroxy-phenyl-thioacetmorpholide; (2) and (3) m- and p-hydroxyacetophenone are converted as in (1) to the thioamides and corresponding hydroxyphenylacetic acids, while acetocatechol yields 3,4-dihydroxyphenylacetic acid; (4) m-aminoacetophenone is similarly converted to m-aminophenylthioacetmorpholide, which is refluxed with hydrochloric acid, the filtrate taken to dryness under vacuum, treated with caustic soda, evaporated, treated with acid and again evaporated, leached with alcohol, evaporated, refluxed with acid, acid removed, and the residue dried by azeotropic distillation with toluene to yield m-aminophenylacetic acid hydrochloride.  Ethyl m-aminophenylacetate hydrochloride is obtained if the residue from the alcohol leach liquor is not refluxed with acid; (5) by refluxing m-aminoacetophenone, sulphur, and morpholine for 8 hours, pouring into water, and extracting with ether, m-aminophenylthioacetmorpholide is obtained; (6) p-aminoacetophenone is converted as in (4) to the thioamide and hydrolysed to p-aminophenylacetic acid; (7) and (8) m-acetamidoacetophenone is converted to m-acetoamidophenylthioacetmorpholide, which is hydrolysed to p-aminophenylacetic acid; (9) o-acetamidoacetophenone similarly yields the thioamide, which is refluxed with hydrochloric acid and oxindole recovered; (10) m-nitroacetophenone gives m-nitrophenylthioacetmorpholide; (11) m-acetoxyacetophenone is converted to m-hydroxyphenylthioacetmorpholide.  The Specification as open to inspection under Sect. 91 comprises also the preparation of the aromatic-substituted aliphatic amides, and the use instead of the aryl alkyl ketones of mercaptans, secondary and tertiary alcohols, olefins, and alkyl halides having aromatic substituents and of ammonia instead of amines.  This subject-matter does not appear in the Specification as accepted.