Patent GB-997376-A (GB)
Title: Isothiazole derivatives
Inventor: SLACK RONALD
IPC: C07D275/03
Filed: 1961-03-16
Abstract: The invention comprises isothiazole derivatives of the general formula <FORM:0997376/C2/1> wherein R1 represents a lower alkyl group, R2 represents a hydrogen or halogen atom and R3 represents a hydrogen atom, a lower alkyl group or a -CH(R4)COOR5 or -CH(R4)COR51 group wherein R4 and R5 represent hydrogen atoms or lower alkyl groups and R51 represents a lower alkyl group (lower alkyl groups contain at the most 6 carbon atoms), and the preparation thereof in the case where R3 represents a hydrogen atom by reducing nitriles of the general formula <FORM:0997376/C2/2> wherein R1 and R2 have the above significance, with a lithium trialkoxy aluminium hydride and by reacting halo compounds of the general formula <FORM:0997376/C2/3> wherein R1 and R2 have the above significance, with a lithium alkyl and reacting the lithium derivative so produced with dimethyl formamide; the preparation of the isothiazole derivatives of the first general formula above wherein R3 represents a lower alkyl group by reacting the nitriles of the above general formula with the required alkyl Grignard reagent; the preparation of the isothiazole derivatives of the first general formula above wherein R3 represents the group of the formula -CH(R4)COOR5, by reacting an isothiazole-5-carboxylic acid halide of the formula <FORM:0997376/C2/4> wherein R1 and R2 have the above significance with an alkanol of the formula HOR51 (R51 has the above significance), and treating the resulting ester with an ester containing a reactive methylene group in the a -position of the formula R4CH2COOR51, wherein R4 and R51 have the above significance, in the presence of the sodium alkoxide corresponding to the above alkanol and when required, hydrolysing the resulting ester containing the group -CH(R4)COOR15 to form the free acid of the first general formula above in which R15 is hydrogen, by reacting the above isothiazole-5-carboxylic acid halide with a sodio-derivative of a b -keto ester and hydrolysing the keto-ester thus produced in accordance with the reaction scheme <FORM:0997376/C2/5> wherein R1, R2, R4, R5 and and R51 have the above significance and R represents a lower alkyl group, and by reacting the above isothiazole-5-carboxylic acid halide with the sodio-derivative of a cyanacetic ester, hydrolysing the resulting a -cyanoester to form an isothiazoloyl-5-malonic acid, and decarboxylating this compound to form acids of the first general formula above wherein R4 and R5 represents hydrogen atoms and, when required, converting the free acids to the corresponding esters in which R4 represents hydrogen and R5 represents an alkyl group, the total synthesis being represented as follows <FORM:0997376/C2/6> wherein R1, R2 and R51 have the above significance; and in the case where R4 represents a lower alkyl group and R5 represents a hydrogen atom or a lower alkyl group by reacting the corresponding compound in which R4 represents hydrogen with an alkylating agent such as a lower alkyl halide; and the preparation of the isothiazole derivatives of the first general formula above wherein R3 represents the group -CH(R4)COR5 by reacting a carboxylic ester of the formula <FORM:0997376/C2/7> with a ketone of the formula R4CH2COR51 in the presence of a basic condensing agent (R, R1, R2, R4 and R51 having the above significance), and also by reacting a carboxylic acid halide of the general formula above with a sodio-derivative of a b -keto-ester, and hydrolysing the keto-ester thus produced in accordance with the following reaction scheme <FORM:0997376/C2/8> wherein R, R1, R2, R4 and R5 have the abov significance.  Isothiazole-5-carboxylic acid halides of the fourth general formula above are prepared by halogenating the corresponding free carboxylic acids, e.g. with thionyl chloride.  3 - Alkyl - 4 - halo - isothiazole - 5 - carboxylic acids are prepared by halogenating the corresponding 4-unsubstituted acids-bromine is a suitable halogenating agent.  Specifications 997,377 and 997,378 are referred to.