Patent GB-593024-A (GB)
Title: Production of ª‰-2-thienoylpropionic acids and derivatives thereof
IPC: C07D277/22
Filed: 1944-05-18
Abstract: 4-Arylthiazole- and -selenazole-5-acetic acids and esters and 4-(21-thienyl)-thiazole-5-acetic acids and esters, of the general formula <FORM:0593024/IV/1> where R1 is an aryl group (which may contain nuclear substituents, e.g. a phenyl, tolyl, naphthyl, ethylphenyl isopropylphenyl, xylyl, anisyl, phenetyl or chlorophenyl group) or a 2-thienyl group, R2 is hydrogen or an alkyl or aryl group, R3 is hydrogen or a hydrocarbon radical, R' is hydrogen or an alkyl, alkylthio, aralkylthio or amino group, and X is sulphur or (when R1 is aryl and R' is amino) selenium, are manufactured by condensing b -halogen-b -aryl- or -b -2-thenyl-propionic acids or esters or a -alkyl- or a -aryl derivatives thereof with thiourea, thioamides of aliphatic monocarboxylic acids, or S-alkyl or S-aralkyl dithiocarbamates, or condensing b -halogen-b -arylpropionic acids or esters or a -alkyl or a -aryl derivative thereof with selenourea. The reaction may be effected by bringing the reactants together in a solvent, with heating if necessary and preferably in the presence of alkalis, e.g. alkali carbonates or bicarbonates.  In examples: (1) b -bromo-b -benzoylpropionic acid is shaken with an ethereal solution of thioformamide (prepared by the action of phosphorus pentasulphide on formamide in ether) to produce 4-phenylthiazole-5-acetic acid; (2) 4-phenyl-, 4 - (41 - methyl-, -ethyl-, -isopropyl-, -methoxy-and -chloro-phenyl)- and 4-(21 : 41 - dimethylphenyl) - 2 - methylthiazole - 5 - acetic acids are prepared by the action of thioacetamide on the appropriate b -bromo-b -aroylpropionic acids in isopropyl alcohol with the addition of sodium carbonate; (3) b -bromo-b -thienoyl propionic acid and thioacetamide are dissolved in isopropyl alcohol and allowed to stand, and the resulting hydrobromide is treated with aqueous sodium hydroxide to liberate 4-(21-thienyl)-2-methylthiazole-5-acetic acid; (4) and (5) b -bromo-b -(1- and 2-naphthoyl)-propionic acids are treated as in (2) to give 4-(11-and 21 - naphthyl) - 2 - methylthiazole - 5 - acetic acids; (6) b -bromo-b -benzoylisobutyric acid is treated with thioacetamide in ethanol in the presence of sodium carbonate to yield a  - 5 - (4 - phenyl - 2 - methylthiazole) - propionic acid; (7) methyl b -bromo-b -benzoylpropionate is refluxed with thioacetamide in ethyl alcohol with the addition of sodium carbonate to form methyl 4-phenyl-2-methylthiazole-5-acetate, which may be converted to the free acid by heating with aqueous alcoholic potassium hydroxide; (8) 4-phenyl- and 4 - (41 - methylphenyl) - 2 - aminothiazole - 5 - acetic acids are prepared by heating the appropriate b  - bromo - b - aroylpropionic acids with thiourea in isopropyl alcohol with the addition of sodium carbonate; (9) b -bromo-b -thienoylpropionic acid similarly yields 2-amino-4-(21-thienyl)-thiazole-5-acetic acid; (10) and (11) b  - bromo - b  - (1- and 2-naphthoyl)-propionic acids similarly give 2-amino-4-(11- and 21-naphthyl) - thiazole - 5 - acetic acids; (12) the thioacetamide in (6) is replaced by thiourea, producing a  - 5 - (2 - amino - 4 - phenylthiazole)-propionic acid; (13) methyl b -bromo-b -benzoylpropionate is heated with thiourea in isopropyl alcohol in the presence of sodium carbonate to produce methyl-2-amino-4-phenylthiazole-5-acetate, which may be hydrolysed as in (7); (14) 2-methylthio- and 2-ethylthio-4-phenyl- and 2-methylthio-4-(41-methylphenyl)-thiazole-5-acetic acids are prepared by treating the appropriate b -bromo-b -aroylpropionic acids in the cold with the appropriate S-alkyl dithiocarbamates in isopropyl alcohol; (15) b -bromo-b -(1-naphthoyl)-propionic acid is treated with methyl dithiocarbamate in isopropyl alcohol with the addition of sodium carbonate, producing 2 - methylthio - 4 - (11 - naphthyl) - thiazole - 5 - acetic acid; (16) b  - bromo - b  - (2 - naphthoyl) - propionic acid is treated in the cold with methyl dithiocarbamate in isopropyl alcohol, and 2-methylthio-4-(21-naphthyl)-thiazole-5-acetic acid is liberated from the resulting hydrobromide; (17) b -bromo-b -benzoylpropionic acid is heated with selenourea in isopropyl alcohol in the presence of sodium carbonate, yielding 2-amino-4-phenylselenazole-5-acetic acid.  b  - Bromo - b  - aroylpropionic acids, their a -alkyl and a aryl derivatives and b -bromo-b -2-thienylpropionic acid are obtainable by treating the corresponding non-brominated acids with an equimolecular proportion of bromine using chloroform as solvent, e.g. by gradual addition of bromine to a boiling solution or suspension of the acid in chloroform.  Examples are given of the preparation of the b -bromo-derivatives of b -(1- and 2-naphthoyl)- propionic acids and b - 2 - thienoylpropionic acid.  b -(1- and 2-Naphthoyl)-propionic acids are obtainable by condensing naphthalene with succinic anhydride in nitrobenzene in the presence of aluminium chloride.  An example is given of the separation of the isomers from the resulting mixture.  a -Alkyl- and a -aryl-b -aroylpropionic acids are obtainable by Friedel-Crafts condensation of alkyl and aryl substituted succinic anhydrides with aromatic hydrocarbons, e.g. of methylsuccinic anhydride with benzene to give b -benzoylisobutyric acid.  b  - 2 - Thienoylpropionic acid is obtainable by condensing thiophene with succinic anhydride in nitrobenzene in the presence of aluminium chloride.  Methyl b -bromo-b -benzoylpropionate is obtainable by esterifying b -benzoylpropionic acid with methyl alcohol in the presence of sulphuric acid and treating the ester with bromine in chloroform solution.