Patent GB-668562-A (GB)
Title: Improvements in or relating to diaryl-tertiary-aminoalkyl-methyl alkyl or cycloalkyl sulfones and their preparation
Filed: 1949-05-12
Abstract: Basic sulphones of the formula B-X-C(Ar)(Ar1)-SO2-R, where B is a dialkylamino group (the alkyl groups containing 1-4 carbon atoms) or an N-piperidino, N-morpholino or N-pyrrolidino radical, Ar and Ar1 are benzene nuclei (which may be linked to form a fluorene ring), X is an alkylene group of 2-6 carbon atoms and R is an alkyl or cycloalkyl group of 1-8 carbon atoms (if cyclic, containing 3-6 ring carbon atoms), are prepared by condensing CH(Ar)(Ar1)-SO2-R with B-X-halogen in the presence of a basic condensing agent.  The aryl radicals may be substituted by non-interfering atoms or groups, e.g. hydroxy, alkyl, alkoxy, dialkylamino, chlorine, bromine or iodine. Sodium amide is the preferred condensing agent (others are listed) and an inert solvent such as toluene is preferably used.  The product may be isolated as the free base or as a salt with a non-toxic acid, e.g. hydrochloric, hydrobromic, sulphuric, sulphamic, phosphoric, tartaric, citric, succinic, acetic, oleic or benzoic. Alternatively, a quaternary salt may be formed, by reaction with, e.g., methyl iodide, ethyl bromide or benzyl chloride.  Examples show the preparation of the following sulphones: 3 - (1 - piperidyl) - 1 : 1 - diphenylpropyl ethyl sulphone, 3-(1-piperidyl)-1 : 1-diphenylpropyl methyl sulphone, 3-dimethylamino-1 : 1 - diphenylbutyl ethyl sulphone, 3 - diethylamino - 1 : 1 - diphenylpropyl ethyl sulphone, 9 - (2 - (1 - piperidyl) ethyl) - 9 - fluorenyl ethyl sulphone, 4-(1-piperidyl)-1 : 1-diphenylbutyl ethyl sulphone, 3-dimethylamino-1 : 1-diphenylbutyl n-propyl sulphone, 3-dimethylamino-1 : 1-diphenylbutyl isopropyl sulphone, 3 - dimethylamino - 1 : 1 - diphenylpropyl ethyl sulphone, 3 - dimethylamino - 1 : 1 - diphenylbutyl cyclopentyl sulphone, 3-(1-piperidyl)-1 : 1-diphenylpropyl isobutyl sulphone and 3-(1-piperidyl)-1 : 1-diphenylbutyl ethyl sulphone.  Other products are mentioned, including those with dimethylaminophenyl, anisyl and phenetyl groups, and other suitable groups are given for B, X and R. 3-Dimethylamino-1 : 1-diphenylbutyl ethyl sulphone may be resolved into its optically active forms with the aid of d-tartaric acid.  In connection with establishing the structure of the products, the following reactions are carried out: (1) diphenylmethane thiol is condensed with 1-bromo-3-chloropropane to give diphenylmethyl 3-chloropropyl sulphide, which is oxidized to diphenylmethyl 3-chloropropyl sulphone; the latter is treated with piperidine yielding diphenylmethyl 3-(1-piperidyl)-propyl sulphone; (2) 3-dimethylamino-1 : 1-diphenylbutyl ethyl sulphone is refluxed with Raney nickel to give 3-dimethylamino-1 : 1-diphenylbutane; the latter is also obtained from 3-dimethylamino - 1 : 1 - diphenyl - 1 - cyanobutane by heating with sodamide.  Sulphones CH(Ar)(Ar1)-SO2-R are obtained by (1) oxidizing the corresponding sulphides, or (2) treating CH(Ar)(Ar1).OH or CH(Ar)(Ar1) Hal with a sulphinic acid R.SO2H.  Examples show the preparation of the following benzhydryl sulphones: methyl, ethyl, propyl, isopropyl, isobutyl and cyclopentyl; also of 9-fluorenyl ethyl sulphone and bis-(4-methoxyphenyl)-methyl n-propyl sulphone.  Sulphides CH(Ar)(Ar1)-SR are obtained from (1) the corresponding thiol and R-Hal; or (2) RSH and CH(Ar)(Ar1)-Hal.  Examples show the preparation of the following benzhydryl sulphides: methyl, ethyl, propyl, isopropyl, isobutyl and cyclopentyl; also of 9-fluorenyl ethyl sulphide.  Diphenylmethane thiol is prepared by treating benzhydryl chloride with thiourea to give the isothiouronium salt and hydrolysing this with alkali.  9-Fluorene thiol is prepared similarly.  According to the Specification as open to inspection under Sect. 91, Ar and Ar1 may be joined through atoms such as carbon, oxygen, sulphur or nitrogen, to give such rings as those of 9 : 10-dihydroanthracene, xanthene, thioxanthene and acridane.  A typical product is 10 - (2 - dimethylamino - 1 - propyl) - 10 - thioxanthenyl ethyl sulphone.  The Specification also refers to compounds of the formula B-X-SO2-CH(Ar)(Ar1), the symbols having the same meaning as above.  These may be made by (1) condensing CH(Ar) (Ar1)SH with a dihalo-paraffin to give CH(Ar) (Ar1)-S-X-Hal, oxidizing to the sulphone and reacting with the appropriate secondary amine, or (2) condensing CH(Ar)(Ar1)SH with B-X-Hal and oxidizing. The products may be converted into salts as above.  In further examples, benzhydryl mercaptan is condensed with ethylene chlorobromide and the product oxidized to benzhydryl 2-chloroethyl sulphone.  This may then be condensed with dimethylamine, di-n-butylamine, piperidine, 2-methylpiperidine and morpholine. Other products mentioned are benzhydryl 2-diethylaminoethyl sulphone, di - p - anisylmethyl 4 - dimethylaminobutyl sulphone, 3 - (1 - piperidyl) - propyl 9-fluorenyl sulphone, benzhydryl 3-(4-morpholinyl)-propyl sulphone and phenyl-(3-ethoxyphenyl) - methyl 2 - di - n - butylaminoethyl sulphone.  This subject-matter does not appear in the Specification as accepted.