Patent GB-783908-A (GB)
Title: Heterocyclic compounds
Filed: 1955-04-21
Abstract: The invention comprises 2,2-disubstituted-3,5-thiamorpholinediones of the formula <FORM:0783908/IV (a)/1> wherein R is an alkyl radical having from 1 to 6 carbon atoms, R1 is an alkyl radical having from 1 to 6 carbon atoms or an aryl radical and R2 is hydrogen or a lower alkyl or lower alkenyl radical having from 1 to 6 carbon atoms or an aralkyl, aralkenyl or acyl radical.  Such compounds are obtained (in method A) by reacting an a ,a -disubstituted - a  - bromoacetyl bromide with ethanol to form the corresponding ethyl a ,a  - disubstituted - a  - bromo - acetate, reacting this with ethanol and then with the sodium or potassium salt of ethyl thioglycollate to form the diethyl ester of the a ,a -disubstituted-thiodiacetic acid, hydrolysing to the free acid and forming the ammonia or amine salt which give respectively, on pyrolysis, the corresponding 2,2 - disubstituted - 3,5 - thiamorpholinedione or the 2,2,4-trisubstituted-3,5-thiamorpholinedione.  An alternative (Method B) comprises reacting an a ,a  - disubstituted - a  - bromoacetyl bromide with thiourea to form a 5,5-disubstituted - 2 - imino - 4 - thiazolidone which is hydrolysed to form a mixture of an a ,a -disubstituted - a  - mercaptoacetic acid and the corresponding a ,a - disubstituted - a  - mercaptoacetamide. This mixture is then reacted with (1) a haloacetic acid to form the corresponding thiodiacetic acid and the monoamide of the thiodiacetic acid (separable by fractional crystallization) or with (2) a haloacetamide to form the corresponding thiodiacetamide and its monoamide (separable in alkaline solution); or (3) with an alkyl ester of a haloacetic acid to form the monoalkyl ester of the a ,a -disubstituted-thiodiacetic acid and the alkyl ester of its monoamide (separable in alkaline medium).  Treatment of the diacetic acid with ammonium hydroxide followed by pyrolysis of the salt yields the 2,2-disubstituted-3,5-thiamorpholinedione or 2,2,4-trisubstituted-3,5-thiamorpholinedione respectively. Alternatively the diacetic acid is converted by treatment with acetic anyhydride to its cyclic anhydride, which is treated with a primary amine to form an N - substituted - a ,a  - disubstituted - thiodiacetic acid monoamide which then is pyrolysed to the desired product.  The mono- or diamides produced by reactions (1) and (2) can be pyrolysed (separately or together) to 2,2-disubstituted - 3,5 - thiamorpholinediones.  The alkyl ester of the a ,a -disubstituted-thiodiacetic acid monoamide heated with a strong mineral acid yields the 2,2-disubstituted-3,5-thiamorpholinedione. The alkyl ester of the a ,a -disubstituted-thiodiacetic acid can be converted with thionyl chloride and then ammonia to its monoamide and pyrolysed (as such or after hydrolysis to the corresponding acid). Alternatively the alkyl ester monoamide can be hydrolysed to the a ,a -disubstituted-thiodiacetic acid which is then converted as above to the diand tri-substituted products.  The products can be acylated at the nitrogen atom using an acyl halide or acid anhydride.  In examples: (1) a  - bromo - a  - ethyl butyryl bromide (from a -ethylbutyric acid treated first with thionyl chloride and then bromine) is converted to the ethyl ester, treatment of which with ethyl thioglycollate and sodium in ethanol gives diethyl a ,a -diethylthiodiacetate.  This is hydrolysed to the acid, which is purified as its benzylamine salt, and then converted to its ammonium salt, pyrolysis of which gives 2,2-diethyl-3,5-thiamorpholinedione; (2) 2,2 - dimethyl - 3,5 - thiamorpholinedione and (4) the corresponding 2,2-dipropyl derivative are prepared analogously; (3) diethyl a ,a -dimethylthiodiacetate is heated with alcoholic ammonia to form the diamide, which is then pyrolysed to give the same product as in (2); (5) a -bromo-a -butylcaproyl bromide (prepared similarly to the bromide of (1)), refluxed with thiourea in acetic acid gives 5,5 - dibutyl - 2 - imino - thiazolidone.  Refluxing this with 15 per cent sodium hydroxide and reacting the product with bromacetic acid gives a ,a  - dibutyl - a  - carboxy - methylmercaptoacetamide (precipitate) and the corresponding diacetic acid (filtrate).  The amide is heated to give 2,2-dibutyl-3,5-thiamorpholinedione; (6) the diacetic acid from (5) is purified, converted to its ammonium salt, and converted to the same product as in (5); (7) 5-ethyl-5-butyl-2-imino-thiazolidone prepared similarly to the thiazolidone of (5) is hydrolysed and the product reacted with chloracetamide.  From the resulting mixture there are separated a -ethyl-a -butylthiodiacetamide which is pyrolysed to 2-ethyl-2-butyl-3,5-thiamorpholine, and a  - ethyl - a  - butyl - a - carbamyl - methylmercaptoacetic acid which, in Example (8) is also pyrolysed to give the same product; (9) 2 - isoamyl - 2 - ethyl - 3,5 - thiamorpholinedione and (10) the 2-ethyl-2-isopropyl derivative are obtained similarly; (11) and (12) 2,2-diethyl-3,5-thiamorpholinedione and (13) and (14) 2,2-dipropyl - 3,5 - thiamorpholinedione are prepared by methods analogous to those of Examples (5) and (6); (15) and (16) by methods corresponding to those of examples (7) and (8) there is prepared 2-ethyl-2-phenyl-3,5-thiamorpholinedione; (17) the methylamine salt of a ,a  - diethylthiodiacetic acid is pyrolysed to give 2,2-diethyl - 4 - methyl - 3,5 - thiamorpholinedione; (18) 2,2,4-trimethyl-3,5-thiamorpholinedione is obtained similarly; (19) to (22) a ,a -diethylthiodiacetic acid is refluxed with acetic anhydride to yield a ,a -diethylthiodiacetic anhydride.  This on heating with the appropriate amine gives a 2,2-diethyl-4-substituted-3,5-thiamorpholinedione in which the 4-substituent is respectively (19) ethyl, (20) allyl, (21) benzyl and (22) cinnamyl; (23) and (24) 2,2-diethyl-3,5-thiamorpholinedione is acylated at the 4-position by reaction with acetic anhydride and benzoyl chloride, respectively; (25) the mixed hydrolysis product of 5,5-diethyl-2-imino-4-4-thiazolidine is reacted with ethyl chloroacetate.  The a ,a -diethyl-a -carbethoxymethylmercaptoacetic acid obtained is converted with thionyl chloride to the acid chloride, this with ammonia gives the corresponding amide, and the latter on heating with concentrated hydrochloric acid gives 2,2-diethyl-3,5-thiamorpholinedione.