Method of producing bis(4-alkylthiophenyl) disulfides

Details Method of producing bis(4-alkylthiophenyl) disulfides Method of producing bis(4-alkylthiophenyl) disulfides

1996-09-23

1999-11-16

Geist, Gary

Organic compounds -- part of the class 532-570 series

Organic compounds

Sulfur containing

568 26, C07C32100

Patent

active

059861436

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel method of producing bis(4-alkylthiophenyl) disulfides useful as intermediates in synthesis of pharmaceutical products and organic industrial products on an industrial scale.


BACKGROUND ART

The inventors have already disclosed in Publication No. WO93/05052 that a series of compounds having alkylthiophenyl groups have various useful pharmacological functions as pharmaceuticals. Alkylthiophenyl groups are generally introduced into those compounds by reacting bis(alkylthiophenyl) sulfides with various nucleophilic reagents. ##STR2##
The above publication discloses a method according to the above formulae for synthesizing bis(4-alkylthiophenyl) disulfides among disulfides which are used for the above-described purposes. However, such a method of synthesizing disulfides through a Grignard reaction has the drawback that it is difficult to carry out the method on an industrial scale.
Another method of synthesizing bis(4-alkylthiophenyl) disulfides is disclosed in Synth. Commun., 5(3), 173(1975) in which thioanisole is reacted with disulfur dichloride in the presence of silica gel to obtain bis(4-methylthiophenyl) disulfide. However, this method produces a large amount of bis(4-methylthiophenyl) sulfide as a by-product which cannot be easily removed from the disulfide, and it is difficult to obtain high-purity disulfides. Therefore, this method cannot be used for synthesizing disulfides which are raw materials for the above pharmaceutical products.
A method which is capable of producing high-purity bis(4-alkylthiophenyl) disulfides useful as intermediates in synthesis of pharmaceutical products and organic industrial products on an industrial scale has not been known yet. There is thus strong demand for a novel useful production method.
A method of obtaining 4-alkylthiobenzenethiols from alkyl phenyl sulfides through 4-alkylthiobenzenesulfonyl chlorides is also disclosed in Coltect. Czech. Chem. Commun., 29, 2161(1964)., 39, 3338(974)., 47, 1382(1982). However, this method employs reaction using 5 equivalents of chlorosulfuric acid. In the reaction, therefore, excess chlorosulfuric acid must be decomposed by water after completion of reaction. However, this treatment has the drawback that irritant gases and heat are evolved, and a large amount of waste liquid containing acids is produced.
An object of the present invention is to provide an industrial method of producing bis(4-alkylthiophenyl) disulfides useful as intermediates in synthesis of pharmaceutical products and organic industrial products.


DISCLOSURE OF THE INVENTION

The present invention has the following construction. The present invention relates to a method of producing bis(4-alkylthiophenyl) disulfides comprising (a) directly reducing 4-alkylthiobenzenesulfonyl chlorides or (b) reducing 4-alkylthiobenzenesulfonyl chlorides, and then oxidizing the resultant 4-alkylthiobenzenethiols.


BEST MODE FOR CARRYING OUT THE INVENTION

The method of producing bis(4-alkylthiophenyl) disulfides is represented by the following formulae: ##STR3##
Each step of the reactions is described in detail below.
(1) Sulfonation or silyl sulfonation of alkyl phenyl sulfide
An alkyl phenyl sulfide used in the present invention preferably has a lower alkyl group having 1 to 4 carbon atoms, and methyl phenyl sulfide (thioanisole), ethyl phenyl sulfide, n-propyl phenyl sulfide, and isopropyl phenyl sulfide are particularly preferable.
The amount of chlorosulfuric acid used for sulfonating an alkyl phenyl sulfide must be 1 to 1.5 equivalents to alkyl phenyl sulfide. The object can satisfactorily be achieved by using chlorosulfuric acid in an excess amount of 1.05 to 1.1 equivalents. A suitable reaction solvent is an aliphatic halogenated hydrocarbon having 1 to 3 carbon atoms. Particularly, dichloromethane and 1,2-dichloroethane are preferable. The reaction temperature is preferably 40.degree. C. or lower, more preferably within the range of -10.degree. C. to 15.degree. C.
A preferable silyl sulfonating agent used for

REFERENCES:
Feher, Z. Naturforschg B , "Uber den nucleophilen Abbau von Aryltrisulfanen mit Triphenylphosphin", pp. 1030-1033, Feb. 1968.
Schuler, Spectra, Ionization Constants, and Rates of Oxidation of 1,4-Dimercaptobenzene and Properties of the p-Mercaptohenylthiyl Anion Radicals, vol. 97, pp. 5611-5617, Apr. 1993.
Chemical Abstracts CA:85:62748, Abstr of "Synthesis of phenylene-1-2-,-1,3-,and-1,4--dithiols and related compounds". Rodionov, 1974.
Chemical Sources p. 775, 1994.
March, Advanced Organic Chemistry, 1968.

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