Patent GB-1168350-A (GB)
Title: Heterocyclylmethyl Alkyl Sulfoxides
Inventor: SHEN TSUNG-YING
IPC: C07D233/91
Filed: 1967-11-06
Abstract: 1,168,350. Methyl sulphinyl methyl-heterocyclic compounds. MERCK & CO. Inc. 6 Nov., 1967 [9 Nov., 1966], No. 50359/67. Heading C2C. The invention comprises compounds of the general formula in which " Het " is a heteroaromatic radical containing one or two 5- or 6-membered rings and that contains more than one hetero atom if it is an unsubstituted monocyclic oxa or thia radical and if R 2  and R 3  are both hydrogen; Y is a halogen atom or a C 1-5  alkyl, C 2-5  alkenyl, cyclic C 3-6  alkyl, amino, C 1-5  alkylamino, di- (C 1-5  alkyl)amino, hydroxy, C 1-5  alkoxy, mercapto, C 1-5  alkylmercapto or nitro radical, n is 0, 1 or 2; each of R 2  and R 3  is a hydrogen atom or a C 1-5  alkyl or C 2-5  alkenyl radical and R 4  is a C 1-5  alkyl or C 2-5  alkenyl radical which are prepared by reacting a compound of the formula in which X is a chlorine, bromine or iodine atom and R 2 , R 3  " Het ", Y and n are as defined above with an alkali metal R 4 -mercaptide to form a sulphide compound and subsequently oxidizing the said sulphide compound. When " Het " is an indole ring compounds of Formula I are prepared by reacting an indole compound of the formula in which R and R 1  are each equal to hydrogen or to Y as defined above, with dimethylamine and formaldehyde to produce the corresponding 3-dimethylaminomethyl derivative and subsequently reacting this with an alkali metal R 4 - mercaptide and oxidizing the product to produce a compound of the formula where R 4  is as defined above. When " Het " is a heterocyclic residue containing nitrogen and only one of R 2  and R 3  is hydrogen compounds of Formula I are prepared by reacting a compound of the formula where one of R 5  and R 6  is a hydrogen atom or C 1-5  alkyl or C 2-5  alkenyl, radical with an N- halosuccinimide in the presence of at least a catalytic amount of a peroxide to produce the corresponding halogen substituted compound, reacting this with an alkali metal-R 4 -mercaptide to form a sulphide compound and oxidizing said sulphide compound to form a compound of Formula I. When Y, n, R 2,  R 3  and R 4  are as defined previously and " Het " is a radical containing at least one nitrogen atom, compounds of Formula I are prepared by reacting (Y) n -[Het] with a halogenated compound of the formula in the presence of an alkali or alkaline earth metal hydroxide to form the corresponding heterocyclic sulphide compound and subsequently oxidizing this to produce a compound of Formula I in which the sulphoxide residue is attached to Het " via the nitrogen atom. When " Het " is a heterocyclic residue containing one or more oxygen and/or sulphur atoms and at least one of R 2  and R 3  is other than hydrogen compounds of Formula I are prepared by reacting a compound of the formula with a C 1-5  alkyl or C 2-5  alkenyl iodide in the presence of a strong base. 2- or 4-Chloromethylthiazole is prepared by reacting thionyl chloride with 2- or 4-hydroxythiazole. The 2-hydroxy compound is prepared by reacting thiazole with formalin; the 4- hydroxy compound is prepared by reducing 4-formylthiazole. 3 - Chloromethylpyrdzole (or 4 - chloromethylimidazole) is prepared by reacting thionylchloride with 3-hydroxymethylpyrazole (or 4- chloromethylimidazole) which is prepared by reducing 3-ethoxycarbonylpyrazole (or 4-ethoxycarbonylimidazole). The ester is prepaed by treating 3-carboxypyrazole (or 4-carboxyimidazole with ethanol. 3-Carbozy-pyrazole is prepared by oxidizing 3-methylpyrazole. 4-Carboxy-imidazole is prepared by the acid hydrolysis of 4-anilinocarbonylimidazole which is prepared by reacting aniline with 4,5-dicarboxyimidazole which is obtained by hydrolysis of the corresponding 4,5-diethylester. 2 - Iodomethyl - 1,4 - benzodioxane is prepared by reacting the corresponding 2-chloromethyl compound with sodium iodide. 2 - Methyl - 3 - dimethylaminomethyl - 5 - methoxyindole is prepared by reacting 2-methyl-5- methoxy indole with formalin and dimethylamine. 1 - Methylthiomethylimidazole, optionally substituted at the 2-, 3- or 4-position by C 1-5  alkyl, bromine, methoxy or methylthiomethyl, 1 - methylthiomethylbenzimidazole and 1 - methylthiomethylpyrazole optionally substituted at the 3-, 4- or 5-position by C 1-5  alkyl, chlorine, bromine, ethoxy and nitro, are prepared by reacting the corresponding heterocycle with chloro methylmethylsulphide. 2 - Methylthiomethylthiazole and 4 - hydroxy- 2-methylthiomethylthiazole are prepared by reacting methylthioacetamide with chloroacetaldehyde and chloroacetic acid respectively. 4 - Methoxy - 2 - methylthiasole is prepared by methylating the corresponding 4-hydroxy compound. Pharmaceutical compositions containing compounds of Formula I as active ingredient are administered orally and have analgesic antiinflammatory and antipyretic activity.