Patent GB-769261-A (GB)
Title: Novel thiamorpholone compounds and the manufacture of same
Filed: 1955-04-07
Abstract: The invention comprises 2-alkyl-thiamorpholones of the general formula <FORM:0769261/IV(b)/1> wherein R2-R7 represent hydrogen atoms or lower alkyl groups and R1 is a lower alkyl group, said alkyl groups containing from one to four carbon atoms, and three processes for their preparation: (a) by reacting ethylene imine, any or all of the hydrogen atoms of which may be replaced by lower alkyl groups, with a lower alkyl ester of an a -(lower alkyl)- or a ,a -di-(lower alkyl)-a -mercaptoacetic acid; (b) by reacting an alkali metal salt of b -mercaptoethyl amine, any or all of the hydrogen atoms attached to the carbon atoms of which may be replaced by lower alkyl groups, or an N-mono (lower alkyl) derivative thereof, with a lower alkyl ester of an a -(lower alkyl)- or a ,a -di-(lower alkyl)-a -halogenoacetic acid; or (c) of thiamorpholones in which R3 is H, by reacting a lower alkanoic acid ester of b -nitro-ethanol, in which alcohol any or all of the hydrogen atoms are replaced by lower alkyl groups, with a lower alkyl ester of an a -(lower alkyl)- or an a ,a -di-(lower alkyl)-a -mercaptoacetic acid, and subjecting the resulting nitro-ester to a reductive internal condensation by treatment with iron in glacial acetic acid.  In examples: (1) ethyl a -mercaptopropionate and ethylene imine are mixed with cooling, and after 2 hours at 60 DEG  C. the mixture is left to stand, when 2-methyl - 3 - keto - thiamorpholine crystallizes on chilling; (2) to (5) similarly are prepared 2,2 - dimethyl - 3 - keto -, 2 - ethyl - 3 - keto, 2 - propyl - 3 - keto - and 2,2 - diethyl - 3 - ketothiamorpholine (in the last case ethyl a -(b -aminoethylmercapto) - a ,a  - diethylacetate is isolated as an intermediate and cyclized by heating to 200 DEG  C.); (6) to (21), using 2-methyl-, 2,2-dimethyl-, 2-ethyl-, and N-methyl-ethylene imines, the following 3-keto-thiamorpholines are produced: 2,5-dimethyl-, 2,2,5-trimethyl-, 2,5,5-trimethyl-, 2,2,5,5-tetramethyl-, 2-ethyl-5-methyl-, 2-ethyl-5,5-dimethyl-, 2-propyl-5-methyl-, 2-propyl-5,5-dimethyl-, 2-methyl-5-ethyl-, 2,2-dimethyl-5-ethyl-, 2,5-diethyl-, 2,2,5-triethyl-, 2-propyl-5-ethyl-, 2,2-diethyl-4-methyl-, 2,2-diethyl-5-methyl-, (after isolation of the intermediate ethyl a -(b -aminopropylmercapto) - a ,a  - diethyl - acetate) and 2,2-diethyl-5,5-dimethyl-, (after isolation of the intermediate ethyl a -(b -amino-isobutylmercapto)-a ,a -diethyl-acetate); (22) sodium and b -mercapto ethyl amine are refluxed in dioxan, ethyl a -bromoisobutyrate added and after further refluxing the mixture is left to stand, when sodium bromide separates and the residue on concentration yields 2,2-dimethyl-3-keto-thiamorpholine; (23) as in (22), using ethyl a -bromoisovalerate to give 2-isopropyl-3-keto-thiamorpholine; (24) sodium in methanol is added slowly to cooled ethyl a -mercaptobutyrate in methanol, followed by 1-nitro-2-acetoxypropane and after standing the solvent is evaporated and the remaining ethyl a -[(2-nitro - isopropyl) - mercapto] - butyrate after purification is reduced with iron and acetic acid to 2-ethyl-6-methyl-3-keto-thiamorpholine.  Starting materials.  a ,a -diethyl-a -mercaptoacetic acid ethyl ester is prepared by treating a ,a -diethyl-a -bromoacetic acid in water with potassium ethyl xanthate and reacting the resulting a  - (thionocarbethoxymercapto) - a ,a -diethylacetic acid with concentrated ammonia, when a ,a  - diethyl - a  - mercaptoacetic acid is obtained on acidification and is esterified with ethanol-H2SO4.  Other esters similarly prepared are ethyl a -mercapto-propionate, -butyrate, -isobutyrate, and -valerate.