DE1291740B - 2,4 and 2,6-dihalobenzyl-methyl-sulfoxides and processes for their preparation - Google Patents

Description

The invention relates to new 2,4 or

2,6-dihalobenzyl-methyl-sulfoxides of the general formula where X is chlorine, bromine or fluorine and Y is hydrogen or X is hydrogen and Y is chlorine. The process for the preparation of these new compounds is characterized in that a compound of the general formula oxidized in a manner known per se.

The oxidation proceeds analogously to that in Liebig's Annals of Chemistry, 579, 1953, p. 23, and H 0 u b e n -We y 1, Methods of Organic Chemistry, Vol. IX, 1955, pp. 211-213.

The usual oxidizing agents are suitable for the oxidation: hydrogen peroxide, Manganese dioxide, nitric acid, chromic acid, chromic anhydride, lead tetraacetate, organic Peracids such as peracetic acid and perbenzoic acid, inorganic peracids or their Salts, e.g. B. potassium permanganate, sodium metaperiodate, sodium perchlorate and persulfuric acid, Alcohol hydroperoxides, e.g. B. tert-butyl hydroperoxide and cumene hydroperoxide, halogens, Selenium dioxide, ruthenium tetraoxide, iodosobenzene, N-bromosuccinimide, dinitrogen pentoxide.

The presence of a solvent is not essential, especially in cases where a liquid oxidizing agent is used, however, the Reaction according to the invention usually carried out in the presence of a solvent, to speed up the reaction or to avoid side reactions. As a solvent for example, water, alcohols (e.g. methanol, ethanol), organic ones are suitable Acids (e.g. acetic acid, butyric acid, formic acid), halogenated hydrocarbons (e.g. chloroform, carbon tetrachloride, sithylene chloride), hydrocarbons (e.g. E.g. benzene, toluene, hexane), ethers (e.g. tetrahydrofuran, dioxane), and ketones (e.g. B. acetone, methyl ethyl ketone).

The reaction is pH-independent.

If, for example, hydrogen peroxide or peracids are used as oxidizing agents are used are weakly alkaline conditions for the preparation of the sulfoxide derivatives he wishes.

The reaction temperature will suitably depend chosen from the compounds desired and the oxidizing agents used.

For the preparation of the sulfoxide derivatives according to the invention, the Reaction when using, for example, sodium metaperiodate, cumene hydroperoxide, N-bromosuccinimide is usually carried out at room temperature or with cooling. It is also possible to use less than one sulfoxide derivatives Molecular equivalent of a strong oxidizing agent such as hydrogen peroxide, potassium permanganate, by reaction with cooling, optionally at room temperature or at a temperature below 60 "C, expediently below 40" C.

The new compounds prepared according to the invention are more effective anti-inflammatory agents than the previously known non-steroidal anti-inflammatory agents Medium with low toxicity.

The results of animal experiments to determine the anti-inflammatory effect are summarized in the following table: Anti-inflammatory effect Compound dose inhibition probability LD50 mg'kg%% mglkg Cl Cl w CH2SOCH3 25 40.4 <0.05 250 to 500 Cl CH2SOCH3 50 50.0 <0.01 250 to 500 Cl CH2SOCH3 25 32.8 <0.05 250 to 500 Br continuation Anti-inflammatory effect Compound dose inhibition I probability L4, mg / kg%% ms / ke C1 9 CH2SOCH3 12.5 40.6 <0.01 250 F. 113C Cl HWCH2SOCH3 100 0 0.01 CH2SOCH3 300 58.7 0.01 500 to 1000 The anti-inflammatory effect was determined when administered orally to rats by the carrageenin edema method (Proc. Soc. Exp.

Biol. Med., 3, 544 [1962]).

The mean lethal dose (LD ,,) was given intraperitoneally in mice Administration determined.

The compounds prepared according to the invention also have at the same time with the anti-inflammatory effect an analgesic effect (e.g. in acute or chronic rheumatoid arthritis and other musculoskeletal disorders) and an inhibitory effect on the development of pneumonia from influenza virus on.

The sulfoxides according to the invention are in the usual pharmaceutical Preparations used.

In the following examples all temperatures are uncorrected, and the percentages relate to weight.

Example 1 A solution of 6.2 g of 2,6-dichlorobenzyl methyl sulfide in 20 ml of acetic acid, a solution of 3.6 is obtained within 10 minutes while stirring g of a 3001 own aqueous hydrogen peroxide solution in 20 ml of acetic acid on a added dropwise to a cold water bath. The mixture is left for an additional hour at room temperature touched. An aqueous solution saturated with sodium sulfite is added to the solution, to decompose the excess hydrogen peroxide. The solution is then used for removal the solvent evaporated under reduced pressure. After adding water the mixture is agitated to form the oily residue, crystals separating out. the Crystals are washed with water and then recrystallized from carbon tetrachloride, 6.3 g of 2,6-dichlorobenzylmethyl sulfoxide in the form of needles of melting point 116 to 118 "C. Yield 94 ° / 0.

Example 2 To a solution of 4 g of 2,4-dichlorobenzyl methyl sulfide in 20 ml of acetic acid, a solution of 2 g of a 300 / above aqueous hydrogen peroxide solution in 10 ml of acetic acid added dropwise, being chilled with ice will. The mixture is left for an additional hour at room temperature touched. An aqueous solution saturated with sodium sulfite is used as the reaction solution given to remove excess hydrogen peroxide. The solution obtained is evaporated to remove the solvent under reduced pressure. To the The residue is added to chloroform and water. The mixture is shaken well, whereupon the chloroform layer is separated. The chloroform layer is made with water washed, dried and removed under reduced pressure to remove the solvent evaporated. The oily residue is recrystallized from ether, with 4 g of 2,4-dichlorobenzyl-methylsulfoxide in the form of flakes with a melting point of 59 "C. Yield 93%.

Example 3 A solution of 2.2 g of 2-bromo-6-chlorobenzylmethyl sulfide in 15 ml of acetic acid, a solution of 1.1 g of a 300% aqueous solution is added with stirring Hydrogen peroxide solution in 10 ml of acetic acid was added dropwise to a cold water bath. The mixture is stirred for an additional hour at room temperature. To the reaction solution an aqueous solution saturated with sodium sulfite is added to remove excess To replace hydrogen peroxide. The resulting solution is used to remove the solvent evaporated under reduced pressure.

Water is added to the oily residue. The mixture becomes a precipitate moved by crystals.

The crystals are washed with water and made from carbon tetrachloride recrystallized, with 2.3 g of 2-bromo-6-chlorobenzyl-methyl-sulfoxide in the form of prisms from melting point 122 to 124 "C. Yield 970/0.

Example 4 A solution of 3.8 g of 2-chloro-6-fluorobenzylmethyl sulfide in 30 ml of acetic acid, a solution of 2 g of a 300% aqueous solution is added with stirring Hydrogen peroxide solution in 10 ml of acetic acid was added dropwise to a cold water bath. The mixture is stirred for an additional hour at room temperature.

The resulting solution is used to remove the solvent evaporated under reduced pressure at low temperature. The residue will dissolved in chloroform. The solution is made with an aqueous sodium hydrogen carbonate solution and then washed with an aqueous solution saturated with sodium sulfite. To After drying, the solution is evaporated to remove the chloroform. The received Petroleum ether is added to the residue, whereupon crystals separate out.

The crystals are recrystallized from ligroin, with 3.4 g of 2-chloro-6-fluorobenzyl-methyl-sulfoxide can be obtained in the form of flakes with a melting point of 89 to 91 "C. Yield 830ei.

Example 5 2,6-dichlorobenzyl-methyl-sulfide (4.1 g) is gradually added after added to a solution of 4.3 g of sodium metaperiodide in 80 ml of water, wherein the mixture is stirred and the reaction temperature is not allowed to rise above 5 ° C. with ice After stirring for one hour, the reaction solution is saturated with sodium chloride. The saturated solution is shaken with 200 ml of chloroform. The chloroform layer is separated off, dried and concentrated under reduced pressure; it remains an oily residue which is recrystallized from carbon tetrachloride, wherein 3.2 g of 2,6-dichlorobenzyl-methyl-sulfoxide in the form of needles with a melting point of 116 to 118 C can be obtained.

Example 6 A chloroform solution (30 ml) containing 0.0535 g of perbenzoic acid per ml, gradually becomes a solution of 2.0 g of 2,4-dichlorobenzyl-methyl-sulfide with stirring in 30 ml of chloroform, cooling with ice to the reaction temperature below 5 C. The reaction solution is agitated for 1 hour and then with 10 ml 0.1 N sodium thiosulfate is added, whereupon the mixture is stirred vigorously. The chloroform layer is with 100% potassium carbonate solution and then with a saturated sodium chloride solution washed and dried. The solvent is then distilled off, with 1.8 g 2,4-dichlorobenzyl-methyl-sulfoxide remains behind as an oily substance, which comes from ether is recrystallized, flakes with a melting point of 59 ° C. being obtained.

Example 7 6 ml of a toluene solution containing 0.76 g of cumene hydroperoxide per ml, becomes a solution of 1.9 g of 2-chloro-6-fluorobenzyl-methyl-sulfide added to 20 ml of chloroform, while stirring and cooling with ice. After a The reaction solution is stirred for one hour and left to stand at room temperature for 3 days. The solvent is distilled off under reduced pressure and the residue shaken with a mixture of water and chloroform. The chloroform layer becomes washed with water, dried and distilled to remove the solvent. The residue is recrystallized from ligroin, 1.5 g of 2-chloro g of 2-chloro-6-fluorobenzyl-methyl-sulfoxide in the form of flakes with a melting point of 89 to 91 "C.

Claims (2)

Claims: 1. 2,4- or 2,6-dihalobenzyl-methylsulfoxides of the general formula where X is chlorine, bromine or fluorine and Y is hydrogen or X is hydrogen and Y is chlorine. 2. Process for the preparation of compounds according to Claim 1, characterized in that a compound of the general formula is used oxidized in a manner known per se.