Patent GB-471416-A (GB)
Title: Process for the manufacture of thiazolium compounds
Filed: 1936-01-30
Abstract: N-Pyrimidylalkyl-thiazolium compounds are prepared by (1) rendering thiazoles containing a hydroxyalkyl or esterified hydroxyalkyl group quaternary by interaction with an alkylpyrimidine having a reactive substituent in the alkyl group; or (2) causing the formation of a quaternary thiazole nucleus in N-pyrimidylalkyl-thioamides by the action of an a -halogenated carbonyl compound substituted at the halogenated carbon atom by a hydroxyalkyl or esterified hydroxyalkyl group.  Advantageously, the starting materials are chosen to give products containing in addition an alkyl group attached to the thiazole nucleus, preferably in the 4-position, and also an amino group in the pyrimidine nucleus, preferably in the orthoposition to the alkylene bridge.  Other substituents, such as alkyl and hydroxyl groups may be present, and when a pyrimidylalkylthiazolium compound containing a hydroxyl group in the pyrimidine nucleus is obtained, the hydroxyl group may be converted into halogen by means of a phosphorus halide and then into an amino group by treatment with ammonia or an amine.  The products possess therapeutic properties, the N - (2<1> - methyl - 4<1> - aminopyrimidyl - 5<1> - methyl) - 4 - methyl - 5 - hydroxyethyl-thiazolium chloride having the attributes of aneurin (vitamin B1) obtained from yeast.  Examples are given of the preparation of thiazolium compounds by (1) interaction of 2-methyl-4-amino-6-bromo- or chloro-methylpyrimidine and 4 - methyl - 5 - hydroxyethylthiazole; (2) reacting 2-amino-4-bromomethyl-6-methyl-pyrimidine with 4-methyl-5-hydroxyethyl-thiazole; (3) heating 2-methyl-4-amino-5-chloro- or bromo-methyl-pyrimidine with 4-methyl-5-hydroxyethyl-thiazole; the same product is obtained by treating the thiazole compound with the benzenesulphonic acid ester of 2 - methyl - 4 - amino - 5 - hydroxymethylpyrimidine and saponifying with hydrochloric acid; similar products are produced when 2-methyl-4-amino-5-b -bromoethyl-pyrimidine and 4 - amino - 5 - chloromethyl - pyrimidine are used as starting materials; (4) reacting 2-methyl - 4 - hydroxy - 6 - chloromethyl - pyrimidine with 4-methyl-5-hydroxyethyl-thiazole, treating the product first with phosphorus oxychloride and then with dimethylamine to give N - (2<1>-methyl-4<1>-dimethylaminopyrimidyl-6<1>-methyl) - 4 - methyl - 5 - hydroxyethyl - thiazolium chloride; (5) treating 4-amino-5-bromomethyl-6-methyl-pyrimidine with 4-methyl-5-hydroxyethyl-thiazole; (6) heating N-(2-methyl-4-aminopyrimidyl-5-methyl)-thioformamide with g -bromo-g -acetopropyl alcohol benzoate and saponifying the product to give N-(2<1>-methyl-4<1> - aminopyrimidyl - 5<1> - methyl) - 4 - methyl - 5 - hydroxyethyl - thiazolium bromide; the benzoate may be replaced by g -bromo- or chloro-g -acetopropyl alcohol, in which case saponification is unnecessary; (7) interaction of 2-methyl-4-amino-5-bromomethyl-pyrimidine with 4 - methyl - 5 - g  - hydroxypropyl - thiazole or 2 : 4-dimethyl-5-hydroxyethyl-thiazole, and of 2-ethyl-4-amino-5-bromomethyl-pyrimidine with 4-methyl-5-hydroxyethyl-thiazole; the first reaction product is also obtained when N - (2 - methyl - 4 - aminopyrimidyl - 5 - methyl)-thioformamide is heated with 4-bromo-4-acetobutyl-alcohol-1; (8) treating 2 : 4-diamino-6-methyl - 5 - b  - bromoethyl - pyrimidine with 4-methyl - 5 - hydroxyethyl - thiazole; (9) interaction of 2-methyl- or ethyl-4-amino-5-bromomethyl-pyrimidine and 4-ethyl-5-hydroxyethylthiazole, and of 2-methyl-4-amino-5-bromomethyl-pyrimidine and 4-methyl-5-hydroxymethyl - thiazole; (10) melting together 2-methyl - 4 - amino - 5 - bromomethyl - pyrimidine and 4-methyl-5-benzoyloxyethyl-thiazole and saponifying the product; (11) heating 2-methyl-4 - amino - 5 - bromomethyl - pyrimidine with 4-hydroxymethyl-thiazole; (12) interaction of 2-phenyl-4-amino-5-bromomethyl-pyrimidine and 4-methyl-5-hydroxyethyl-thiazole; (13) treating 2-methyl-4-amino-5-bromomethyl-pyrimidine with 4 - methyl - 5 - acetoxyethylthiazole.  A phenylurethane derivative of vitamin B1 is obtained when 4 - methyl - 5 - hydroxyethyl-thiazole is heated with phenyl isocyanate and the resulting 4-methyl-5-phenylaminocarbethoxyethyl - thiazole reacted with 2-methyl-4-amino-5-bromomethyl-pyrimidine.  The thiazolium halides prepared as above may be converted into their salts with other acids by double decomposition, e.g. with silver nitrate, phosphate, sulphate, acetate, lactate or benzoate.  Specification 456,735 is referred to.  Pyrimidines.--2 - Methyl - 4 - amino - 6 - chloro-and bromomethyl-pyrimidines are prepared by condensing g -ethoxy-acetoacetic ethylester with acetamidine, heating the resulting 2-methyl-4-hydroxy - 6 - ethoxymethyl - pyrimidine with hydrochloric acid to give a mixture of 2-methyl-4-hydroxy-6-hydroxymethyl- and chloromethylpyrimidines, separating the former compound and heating it first with acetic anhydride to give 2-methyl-4-hydroxy-6-acetoxymethyl-pyrimidine, then with phosphorus oxychloride to form 2-methyl-4-chloro-6-acetoxymethyl-pyrimidine, then with methyl alcoholic ammonia to give 2-methyl-4-amino-6-hydroxymethyl-pyrimidine and finally with hydrochloric and hydrobromic acids respectively. 2-Amino-4-bromomethyl-6-methyl-pyrimidine is obtained when 2-amino-4 : 6-dimethyl-pyrimidine is brominated in glacial acetic acid. 2-Methyl-4-amino-5-aminomethyl-pyrimidine is prepared by condensing formylsuccinic acid ethylester with acetamidine, converting the 2-methyl-4-hydroxypyrimidyl-5-acetic ester formed into the 4-chloro compound by means of phosphorus oxychloride, treating the latter with ammonia to give 2-methyl-4-aminopyrimidyl-5-acetamide and subjecting it to Hofmann's reaction; treatment with nitrous acid produces 2 - methyl - 4 - amino - 5 - hydroxymethyl-pyrimidine, which may be converted into its benzenesulphonic acid ester.  2-Methyl-4 - amino - 5 - chloro- and bromo - methyl-pyrimidines are formed when 2-methyl-4-amino-5-aminomethyl-pyrimidine is reacted with sodium nitrate in the presence of concentrated hydrochloric and hydrobromic acid respectively. 2-Methyl-4-amino-5-b -bromoethyl-pyrimidine is prepared by condensing formylglutaric acid ethylester with acetamidine, treating the resulting 2 - methyl - 4 - hydroxypyrimidine - 5 - propionic acid ethylester with phosphorus oxychloride, reacting the 4-chloro compound with methyl alcoholic ammonia, subjecting the 2-methyl-4-aminopyrimidyl-5-propionamide to Hofmann's reaction, and decomposing the resulting 2-methyl-4-amino-5-b -aminoethyl-pyrimidine with nitrous acid in hydrobromic acid solution.  4 - Amino - 5 - chloromethyl-pyrimidine is formed by condensing formylsuccinic acid ethylester with thiourea, treating the 2 - mercapto - 4 - hydroxypyrimidyl - 5 - acetic acid ethylester with hydrogen peroxide to eliminate the mercapto group, reacting on the product with phosphorus oxychloride, treating the resulting 4-chloro compound with methyl alcoholic ammonia, subjecting the 4-aminopyrimidyl-5-acetamide to Hofmann's reaction and reacting the 5-aminomethyl product with nitrous acid in hydrochloric acid solution.  4-Amino-5-bromomethyl-6-methyl-pyrimidine is prepared by boiling 2 : 4 - dihydroxy - 5-hydroxymethyl - 6 - methyl - pyrimidine with a solution of phosphorus pentachloride in phosphorus oxychloride, extracting the 2 : 4-dichloro-5-chloromethyl-6-methyl-pyrimidine with ether, boiling with sodium iodide, reacting the 2 : 4-dichloro - 5 - iodomethyl - 6 - methyl - pyrimidine with silver acetate, heating the 5-acetoxymethyl product with alcoholic ammonia and then with hydrochloric acid, treating the resulting mixture with zinc dust to give 2-chloro-4-amino-5-hydroxymethyl-6-methyl-pyrimidine, then boiling with zinc dust in aqueous solution to eliminate the 2-chloro atom and finally reacting with hydrobromic acid on the product. 2-Ethyl - 4 - amino - 5 - bromomethyl - pyrimidine is obtained by reacting upon the 5-aminomethyl compound first with nitrous acid and then with hydrogen bromide; the starting material is prepared in the same way as 2-methyl-4-amino-5-aminomethyl-pyrimidine (see above) but using propionic acid amidine instead of acetamidine for the condensation.  2 : 4-Diamino-6-methyl-5-bromoethyl-pyrimidine is formed by condensing urea with a -acetobutyrolacetone, treating the resulting 2 : 4-dihydroxy-6-methyl-5-hydroxyethyl-pyrimidine with phosphorus oxychloride, exchanging the halogen atoms of the 2 : 4 - dichloro - 6 - methyl - 5 - b  - chloroethyl-pyrimidine with alcoholic ammonia for amino groups, transforming the 5-aminoethyl group into the hydroxyethyl group by means of sodium nitrite and finally treating with hydrobromic acid.  2 - Phenyl - 4 - amino - 5 - bromomethyl-pyrimidine is prepared by interacting formylsuccinic acid ethylester with benzamidine, treating the 2-phenyl-4-hydroxypyrimidyl-5-acetic acid ethylester so formed with phosphorus oxychloride, decomposing the 4-chloro compound with alcoholic ammonia, subjecting the resulting 2 - phenyl - 4 - aminopyrimidyl - 5-acetamide to Hofmann's reaction, and treating the 2-phenyl-4-amino-5-aminomethyl-pyrimidine first with nitrous acid to give the 5-hydroxymethyl compound and then with hydrogen bromide. Thioformamides.--N - (2 - Methyl - 4 - aminopyrimidyl - 5 - methyl) - thioformamide is obtained by reacting 2-methyl-4-amino-5-aminomethyl-pyrimidine with formic acid ester and treating the 5-formylaminomethyl product with phosphorus pentasulphide.  Thiazoles.--2 : 4 - Dimethyl - 5 - hydroxyethylthiazole is prepared by reacting upon g -bromog -acetopropyl alcohol with thioacetamide. 4-Ethyl-5-hydroxyethyl-thiazole is obtained by dropping 1 - benzoyloxy - 3 - thiocyano - 4 - oxohexane, prepared from the corresponding 3-bromo compound and barium rhodanide, into concentrated sulphuric acid, treating the resulting 2 - hydroxy - 4 - ethyl - 5 - benzoyloxyethyl-thiazole with phosphorus oxychloride, eliminating the halogen from the 2-chloro compou