Patent GB-997378-A (GB)
Title: Isothiazole derivatives
Inventor: SLACK RONALD
IPC: C07D275/02
Filed: 1962-03-15
Abstract: The invention comprises compounds of formula <FORM:0997378/C2/1> where R1 represents a hydrogen atom, an alkyl group containing up to 6 carbon atoms, or a carboxyl group, and R2 represents a hydrogen or halogen atom, an alkyl group as defined, or a carboxyl group, which are prepared by reaction of a compound of formula <FORM:0997378/C2/2> where Z represents a hydrogen or halogen atom, with an organo-lithium compound, e.g. butyl or phenyl lithium, in an ether-containing solvent such as tetrahydrofuran, with or without n-hexane, at a temperature below 0 DEG  C., e.g. - 30 DEG  to - 70 DEG  C. Examples specify the reaction of butyl lithium with the above compound when Z is H, m which if R1 is H, R2 is H, Me, Cl, Br, or COOH; if R1 is Me, R2 is H, Cl, Br, I, or COOH; and if R1 is COOH, R2 is H; and also with the compound in which Z is Br, R1 is Me, and R2 is H. Isothiazole-5-carboxylic acids of the general formula <FORM:0997378/C2/3> wherein R1 represents hydrogen or an alkyl or carboxyl group and R2 represents hydrogen or halogen or an alkyl or carboxyl group, are prepared by reacting the corresponding 5-lithium-isothiazole with carbon dioxide.  By this method the following are prepared: isothiazole-5-carboxylic acid; 3- and 4-methylisothiazole - 5 - carboxylic acids; 4 - bromo-, 4 - chloro - and 4 - iodo - 3 - methyl - 5 - carboxylic acids; 4-chloro- and 4-bromo-isothiazole - 5 - carboxylic acid; 3 - methyl - isothiazole-4,5-dicarboxylic acid; and isothiazole-3,5-dicarboxylic acid.  Isothiazole - 5 - aldehydes (and ketones) of the general formula <FORM:0997378/C2/4> wherein R1 and R2 have the above significance and X represents hydrogen or an alkyl group, are prepared by treating the corresponding 5-lithium-isothiazole with a compound of the formula <FORM:0997378/C2/5> wherein X has the above significance, and R3 and R4 represent alkyl groups and when R2 represents hydrogen or halogen and R1 represents a methyl group, the products may be converted to thiosemicarbazones of the general formula <FORM:0997378/C2/6> wherein R21 represents a hydrogen or halogen atom, X1 represents a hydrogen atom or methyl group, and Y represents a hydrogen atom or a b -ethoxyethyl group.  By this method the following are prepared: isothiazole-5-carboxaldehyde; 3- and 4-methyl-isothiazole-5-carboxaldehyde; 4-chloro-, 4-bromo- and 4-iodo-3-methyl-isothiazole-5-carboxaldehyde; 4-chloro- and 4 - bromo - isothiazole - 5 - carboxaldehyde; and 5 - formyl - 3 - methyl - isothiazole-4-carboxylic acid.  The thiosemicarbazones of all these aldehydes are also prepared.  Isothiazole-5-methyl compounds of the general formula <FORM:0997378/C2/7> wherein R1 and R2 have the above significance and R5 represents halogen or an alkyl, cycloalkyl, cycloalkyl-alkyl or aralkyl group, are prepared by treating the corresponding 5-lithium compounds with a halogen or halide of the formula R5Hal wherein R5 has the above significance and Hal represents a halogen such as chlorine, bromine or iodine. By this method the  following  are  prepared: 5-methyl-isothiazole; 4 - bromo - 3,5 - dimethylisothiazole; 4 - bromo - 3 - methyl - 5 - ethyl - (proply and benzyl) - isothiazole; 5 - bromo - isothiazole; 4,5 - dibromo - 3 - methyl - isothiazole; and 5 - bromo - 3 - methyl - isothiazole - 4 - carboxylic acid.  Isothiazole - 4,5 - dicarboxylic acid and the mono-sodium salt thereof are prepared by oxidizing 4 - methyl - isothiazole - 5 - carboxylic acid with potassium permanganate, by oxidizing 5 - aminobenz(d) - 1,2 - isothiazole, and by treating the 5-lithium derivative of isothazole - 4 - carboxylic acid with carbon dioxide, in each case the free carboxylic acid is formed and, when desired, converting the free acid to a mono-sodium salt.  Isothiazole - 3 - carboxylic acid is prepared by oxidizing 3 - methyl - isothiazole with chromium trioxide.  Specifications 997,376 and 997,377 are referred to.