Patent GB-456751-A (GB)
Title: Process for the manufacture of 4-alkyl-5-hydroxy-alkylthiazoles
IPC: C07D277/22
Filed: 1935-05-13
Abstract: 4-Alkyl-5-hydroxyalkyl-thiazoles are prepared by reacting with thiocyanic acid salts upon ketones in which the carbon atom adjacent to the keto-carbon atom is substituted with halogen and also with a hydroxyl group or an etherified or esterified hydroxyl group, condensing the resulting keto-thiocyanates to the corresponding 2-hydroxythiazoles by treatment with strong acids, and converting the etherified or esterified hydroxyl group into the hydroxyl group by saponification.  After the cyclization to the thiazole, the 2-hydroxy group may be replaced with hydrogen by treatment with a phosphorus halide followed by reduction. Suitable ketones are 1-hydroxy-2-halogen-3-oxobutane and 1-hydroxy-3-halogen-4-oxopentane. Ketones may also be employed which contain, instead of the hydroxyl group, a carboxyl or an esterified carboxyl group or an amino group, e.g. 3 - halogen - 4 - oxopentane-carboxylic acid esters and their homologues.  The products may then be converted into the 5-alkylol compounds by reduction of the carboxylic group or treatment of the amino compound with nitrous acid according to Hoffmann's or Curtius' method.  Again, instead of the thiocyanic acid salts may be employed compounds of the formula H2N--C(R)=S, wherein R represents hydrogen or hydroxyl, mercapto, alkoxy, alkylthio or amino groups.  The said groups appearing in the product may then be replaced by hydrogen, in the case of the amino group by the action of nitrite in the presence of an alcohol or by the action of nitrite and hydrohalic acid followed by reduction, and in the case of the remaining groups by treatment first with a phosphorus halide and then with a reducing agent.  According to the examples: (1) 4-methyl-5-hydroxyethylthiazole is obtained by brominating acetopropyl-alcoholacetate, treating with barium thiocyanate, cyclizing to the 2-hydroxy-4-methyl-5-acetoxyethyl-thiazole with concentrated sulphuric acid, heating with phosphorus oxychloride, reducing the 2-chloro compound with zinc and acetic acid, and finally splitting off the acetyl group with alcoholic caustic potash; (2) 4-methyl-5-hydroxyethylthiazole is also obtained by brominating g -acetobutyric acid ethyl ester, treating with barium thiocyanate, ring-closing with sulphuric acid, converting the resulting 2-hydroxy-4-methyl-thiazolyl-5-propionic acid ethyl ester into the 2-chloro compound with phosphorus oxychloride, reducing with zinc and acetic acid, heating the product with methyl alcoholic ammonia to form the 4-methyl-5-thiazolylpropionic acid amide, converting this into 4-methyl-5-aminoethyl-thiazole by treatment with bromine and potassium hydroxide solution, and finally reacting with sodium nitrite and sulphuric acid; the 2-chloro-4-methyl-thiazolyl-5-propionic acid ethyl ester may also be prepared by heating bromo-g -acetobutyric acid ethyl ester with xanthogenic acid amide, converting the resulting 2 - ethoxy - 4 - methylthiazolyl-5-propionic acid ethyl ester into the 2-hydroxy compound by stirring with hydrochloric acid, and treating it with phosphorus oxychloride; furthermore, the 4-methyl-5-aminoethyl-thiazole may also be obtained from the 4-methyl-5-thiazolyl-propionic acid ethyl ester by treatment with hydrazine hydrate, followed by conversion of the hydrazide into the azide with sodium nitrite, and decomposition of the azide with heat; (3) 4-methyl-5-hydroxyethyl-thiazole is further obtained by reacting b -bromolevulinic acid ethyl ester with barium thiocyanate, cyclizing with concentrated sulphuric acid, treating the resulting 2-hydroxy-4-methyl-thiazolyl-5-acetic acid ethyl ester with phosphorus oxychloride, reducing the 2-chloro compound with zinc and acetic acid or with hydrogen in the presence of palladium, and finally reducing the ester group in the product by means of sodium and boiling alcohol; the 4-methylthiazole-5-acetic acid ethyl ester may also be obtained by condensing b -bromo or chloro-levulinic acid ethyl ester with thiourea and treating the resulting 2-amino-4-methylthiazolyl-5-acetic acid ethyl ester hydrohalide with sodium nitrite and concentrated sulphuric acid; (4) 4-methyl-5-hydroxyethyl-thiazole is again obtained by first brominating acetopropyl-alcoholbenzoate, obtained by the action of benzoyl chloride on acetopropyl alcohol, treating the product with potassium or calcium thiocyanate, ring-closing with concentrated sulphuric acid, boiling the 2-hydroxy-4-methyl-5-benzoylhydroxyethyl-thiazole formed with phosphorus oxychloride, reducing the 2-chloro compound with zinc and acetic acid, and finally splitting off the benzoyl group with alcoholic caustic potash; (5) the same product as in the preceding examples is prepared by treating bromopropyl-methylketone first with bromine and then with lead thiocyanate, cyclizing the resulting 1 - bromo - 3 - thiocyan - 4 - ketopentane with sulphuric acid, treating the resulting 2 - hydroxy - 4 - methyl - 5 - b  - bromoethyl - thiazole with anhydrous potassium acetate and acetic acid, and working up the resulting 5-acetoxyethyl compound in the manner described in (1); the 1-bromo-3-thiocyan-4-ketopentane may also be prepared by treating the methyl-1 : 3-dibromopropylketone with an equimolecular amount of sodium iodide and reacting the 1-bromo-3-iodo-4-oxopentane so obtained with lead thiocyanate; instead of lead thiocyanate may be used thiocyanic acid and the equivalent amount of a base such as barium hydroxide, ammonia or triethylamine; ammonium dithiocarbamate may also replace the lead thiocyanate; the 2-hydroxy-4-methyl-5-b -bromoethyl-thiazole may alternatively be prepared by reacting the methyl-1 : 3-dibromopropylketone with methyl xanthogen amide, the methoxy group in the product being hydrolyzed by the acid split off; (6) 4-methyl-5- hydroxyethyl-thiazole is again prepared by condensing methyl-1 : 3-dibromopropylketone with thioformamide and heating the resulting 4-methyl-5-b -bromoethyl-thiazole with potassium carbonate solution; the use of methyl-1 : 2-dibromoethyl-ketone and methyl-1 : 4-dibromobutyl-ketone, prepared by brominating methyl-4 - bromobutyl - ketone, gives rise to the 5-hydroxymethyl and 5-hydroxypropyl bodies respectively.