HU196906B - Process for production of derivatives of new substituated diaryl-sulpholid and medical compositions containing these compounds as active substances - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel substituted diaryl sulfoxide derivatives of formula I wherein Y is nitro, amino or trifluoromethyl, R1, R2, R3, R4, R5, R7, R 'and R9 are the same or different. , namely hydrogen or halogen, or C 1-4 alkyl, C 1-4 alkoxy, amino or thiophenyl, and acid addition salts thereof. -1-

Description

The present invention relates to novel substituted diaryl sulfoxide derivatives of general formula (I):

Y is nitro, amino or trifluoromethyl,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ^8, and R 'are the same or different and are hydrogen or halogen or C 1-4 alkyl, C 1-4 alkoxy , an amino or thiophenyl group, and an acid addition salt thereof, by reacting a benzenesulfonyl halide derivative of formula (II) wherein Y, R *, R ² , R ³ and R ⁴ have the same meaning as in formula (I) and X 'is halogen, reduced with an alkali metal sulfite to form a benzene sulfinic acid derivative of formula (111) wherein Y, R ¹ , R ² , R ³ and R ⁴ are as defined for formula (I) and M is an alkali metal, after conversion to the corresponding benzenesulfinic acid, is treated with a thionyl chloride halogenating agent to form a novel benzenesulfinyl halide of formula (IV) wherein Y, R ¹ , R ² , R ³ and R ⁴ are as defined in formula (I). picture and X ² is halogen, with a benzene derivative of formula (V): wherein R ⁵ , R ⁷ , R ⁷ , R ⁸ and R 'are as defined in formula (I) in the presence of an AlCl in this case, the resulting substituted diaryl sulfoxide derivative of formula (I) wherein Y is nitro and R ¹ , R ² , R ⁴ , R ⁵ , R ⁴ , R ⁷ , R ⁸ and R ⁹ are as defined above is reduced. or optionally converting the resulting compound (1) substituted diaryl sulfoxide derivatives of general formula - wherein Y represents a nitro group and as defined above R ', R ^2, R ^3, R ^4, R ^3, R®, ^{R7, R8} and At least one of R ⁹ is halogen, reacted with ammonium or alkaline hydroxide and / or thiophenol or, if desired, the resulting substituted diaryl sulfoxide derivative of formula (1) wherein Y is nitro and at least one of R ¹ , R ² , R ³ , R ³ , R ⁷ , R ⁷ , R ⁸ and R 'having the meaning given above is reacted with boron trihalide and then if desired, the resulting substituted diaryl sulfoxide derivative of formula (I) wherein Y is nitro and the groups R ¹ , R ² , R ³ , R ⁴ , R ³ , R ⁷ , R ⁷ , R ⁹ and R ^{9 are as} defined above. at least one of which is amino is treated with an acid.

The novel compounds of formula (I), on the one hand, have therapeutic properties and are useful in both human and veterinary medicine as nematocidal, fungicidal and anthelmintic agents. They are particularly effective against human fungi (dermalis). For example, (2,4-dichloro-5-nitro) -phenyl 4-chlorophenylsulfoxide (Example 3) has a MIC of 1.56 pg / ml for Trichophyton terrestre, which should be evaluated as a very strong antifungal effect. d- and 1-Ketoconazole base with a MIC of 3.12 pg / ml. Moderately potent antifungal activity is (2,4-dichloro-5-nitrophenyl) phenylsulfoxide (Example 2), Trichophyton terrestre, 4- (4'-chlorophenylsulfinyl) -2-nitrophenol (Example 5). Trichophyton gypseum and (5-amino-2,4-dichloro) phenyl-phenylsulfoxide (Example 6) on Candida albicans. The corresponding MIC values are 25, 25, 12.5 pg / ml, respectively.

The MIC values were determined according to the method described in EP 0 163 606.

Λ (2,5 - Dimethyl) phenyl - (4 - chloro - 3 - nitro) ferlyl sulfoxide exhibits a repellent (negative chemotactic behavior) effect on Caenorhabdit 's elegant (laboratory nematode).

In addition, the compounds of formula I are valuable intermediates for other bioactive facial sulfoxide derivatives.

The compounds of formula I are novel. So far, diaryl sulfoxides have been known which electronically withdraw substituents such as nitro, trifluoromethyl, cyano and the like at the para or ortho position relative to the sulfmyl group. or derivatives thereof such as amino and the like. groups. When the sulfinyl group and said substituents are in a meta position with respect to each other, only derivatives containing a substituted ortho group, a hydroxyl group, and a halogen atom in an ortho or para position with respect to the electron withdrawing group are described. the other benzene ring is unsubstituted or contains hydroxy or nitro.

E'aryl sulfoxides are mostly produced by oxidation of diaryl sulfoxides [Bér. 41, 2836 (1908),

J. Ajn. Chem. Soc. 70, 1381 (1948)]. As oxidizing agents, explosive peracids and peroxtds are used and the resulting product is often contaminated with dyaryl. A further disadvantage is that the diaryl sulfides are hardly accessible substances; e.g. arylsulfenyl halides and benzene derivatives may be prepared by the Friedel-Crafts reaction or the corresponding thiophenol and benzene derivatives containing activated halogen. Both arylsulfenic: hear and activated halobenzene can be prepared by multiple step synthesis at an unfavorable yield [Bér. 52, 2170 (1919) and Synthesis 385 (1975) and J. Am. Chem. Soc. 70, 138 (1948)].

Arylsulfonyl halides, widely used in organic chemistry, readily form diaryl sulfones in the Friedel-Crafts reaction with benzene derivatives, the reduction of which in most cases results in diaryl sulfides [Canad. J. Chem., 51, 1419 (1973)], so this pathway is not suitable for the rational preparation of diaryl sulfoxides.

Nor is it of practical importance to prepare diaryl sulfoxides from arylsulfic acids and benzene derivatives because the process is carried out with only a few active reaction partners in acceptable yield [Bér. 36, 113 (1903)]. It only comes in the preparation of optically active diaryl sulfoxides

196-06 to the reaction of optically active arylsulfinic acid esters with arylmagnesium halides [Compr. Org. Chem., 1979, 3, 169].

In the formula (I), R ¹ , R ¹ , R ³ , R ', R ⁵ , R ⁶ , R ⁷ , R * and R' are selected from halogen, fluorine, chlorine, bio or iodine, preferably chlorine, C 1-4 alkoxy; as a radical any alkoxy group containing straight or branched alkyl groups such as methoxy, ethoxy, η-propoxy, i-propoxy, η-butoxy, sec-butoxy, tert-butoxy, i-butoxy, preferably methoxy. as a C 1-4 alkyl group, any straight or branched chain group such as methyl, ethyl, π-propyl, i-propyl, η-butyl, sec-butyl, tert-butyl, ί -butyl.

In the compounds of formula (III), M can be potassium or sodium as the alkali metal.

(II) and compound of formula (IV), X ¹ and ^X! halogen may be fluorine, chlorine, bromine or iodine, preferably chlorine.

The intermediates of formula (IV) are novel.

The reduction of the arylsulfonyl halides of the formula (II) with alkali metal sulfites is conveniently carried out in an aqueous medium using 1.1 to 4 moles of alkali metal sulfite per small molar amount of arylsulfonyl halide. The reduction can be carried out at a temperature of 20 to 40 'C, preferably 22 to 28' C. The reduction is conveniently carried out under mildly basic conditions, preferably in the pH range of 7 to 9, preferably 7.5 to 8.5, for example by simultaneous addition of an alkali metal hydrogencarbonate, alkali metal carbonate or alkali metal to the reaction mixture. hydroxide is added or pre-introduced into the reaction mixture. These basic agents simultaneously serve as an acid scavenger. The alkali metal bicarbonate, carbonate or hydroxide may be used in solid form, in the form of a saturated aqueous solution, or both.

Optional acid treatment of compounds of general formula (III) is preferably with a strong mineral acid, preferably concentrated aqueous hydrochloric acid, sulfuric acid and the like. It can be carried out. The mineral acid used is preferably used in excess. The arylsulfinic acid obtained after acid treatment is very pure (at least 98% purity) and extremely stable, unlike other arylsulfinic acids obtained by other processes, which are known previously. The yields of the compounds are also very high, exceeding the methods known so far (Houben-Weyl, Vol. 9, p. 307).

Both the arylsulfinate of formula (III) and the arylsulfinic acid optionally obtained therefrom can be reacted with a halogenating agent, both of which result in the corresponding arylsulfinyl halide of formula (IV). The halogenating agent may be an inorganic or organic halogenating agent. Inorganic halogenating agents include, for example, halogen compounds of sulfur or phosphorus, or compounds of halogen and oxygen. Examples of such compounds are thionyl chloride, phosphorus trichloride, phosgene, phosphorus pentachloride, phosphorus oxychloride, phosphorus oxychloride and chlorine. As the organic halogenating agent, for example, an organic acid halide such as oxalyl chloride may be used. The arylsulfinyl halides of formula (IV) are novel compounds and are substantially more stable than other, differently substituted, known arylsulfinyl halides.

The Lewis acid metal halide catalyst used in the reaction of the compounds of formula (IV) and (V) may be any catalyst conventionally used in Friedel-Crafts acylation, such as aluminum trichloride. The reaction may also be carried out by reacting compounds of formula IV with compounds of formula V without isolation, only after removal of the halogenating agent. The reaction may conveniently be carried out using 1.1 to 1.8 moles of a Lewis acid metal halide catalyst per mole of arylsutinyl halide of formula IV. The reaction may be carried out at a temperature of from 20 to 80 'C, preferably from 25 to 42' C.

The process of the present invention provides the diaryl sulfoxides of general formula (I) in very good purity (minimum of 98% purity) in 90% to 96% yield of the corresponding arylsulfinic acid. Certain operations of the process according to the invention can be carried out simply on an industrial scale.

Compounds of formula (I) wherein Y is nitro may be subjected to subsequent reduction. The reduction can be accomplished by a variety of methods known in the art, such as, for example, catalytic hydrogenation using a chemical reducing agent. Preferably, the reducing agent is an alkali metal sulfide, ammonium sulfide, alkali metal hydrogen sulfide, or alkali metal polysulfide. The reaction is suitably a C 1-4 aliphatic alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol and the like. and in a mixture of water.

The reduction may also be carried out with titanium trichloride (Synthesis 1974, 45, Houben-Weyl 4 (ld), or with iron powder in the presence of iron sulfate (J. Med. Chem. 1975, 1164).

The compounds of formula (I) wherein R ¹ and / or R ³ and / or R ^{4 are} halogen are subsequently nucleophilized. substitution reactions so that the halogen atom can be replaced by various other groups by methods known per se. Such a reaction may be, for example, an amination reaction in which an aqueous solution of ammonium hydroxide is suitably used, or another aliphatic primary amine such as methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine or the like. an aliphatic secondary amine such as dimethylamine, diethylamine, diisopropylamine or dibutylamine is the reagent used. The amination may be carried out in an organic solvent, such as a C 1-8 aliphatic monovalent or polyhydric alcohol, their water miscible monoalkyl ethers or cyclic ethers, or mixtures thereof. Nucleophilic substitution with C 1-6 alkanol and phenol may also be carried out in a manner known per se, preferably in the presence of potassium hydroxide.

However, the preparation of the compounds of formula (I) or their subsequent conversion to other compounds of formula (I) may be carried out by any method known per se, but is not limited to the foregoing. The present invention encompasses all possible methods.

For example, the following acids may be used to form acid addition salts of compounds of formula (I). Inorganic acids such as hydrogen halides such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, perhalic acids such as perchloric acid and the like. Organic carboxylic acids such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, succinic acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylenedioic acid, amino salicylic acid, etc. Alkyl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and the like. Cycloaliphatic sulfonic acids such as cyclohexylsulfonic acid. Arylsulfonic acids such as p-toluenesulfonic acid, naphthylsulfonic acid, sulfanylic acid and the like. Amino acids such as aspartic acid, glutamic acid, N-acetyl aspartic acid, N-acetylglutaric acid and the like.

The salt formation may be carried out in an inert organic solvent, such as an aliphatic alcohol having from 1 to 6 carbon atoms, by dissolving the compound of formula (I) in the above solvent and then adding the appropriate acid or acid to the solvent. until the mixture becomes slightly acidic (about pH 5-6). The precipitated acid addition salt may then be isolated from the reaction mixture by any suitable means, such as filtration.

The compounds of formula (I) obtained by the process according to the invention or their salts may, if desired, undergo further purification, such as recrystallization. The range of solvents suitable for recrystallization is determined by the solubility and crystallization properties of the material to be crystallized.

The active ingredient of the formula (1) is formulated in pharmaceutical compositions with non-toxic, inert, solid or liquid carriers and / or excipients which are suitable for parenteral or enteral administration in pharmaceutical formulations. Suitable carriers include, for example, water, gelatin, lactose, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like. It can be used. The active ingredient may be in the form of conventional and pharmaceutical preparations, for example solid (round or square tablets, dragees, capsules such as hard gelatin capsules, pills, suppositories, etc.) or liquid (e.g., oily or aqueous solution, suspension, emulsion, syrup, pse4 latin capsule, injectable oily or aqueous solution or suspension, etc.). The amount of solid carrier can vary within wide limits, preferably from about 25 mg to about 1 g. The compositions may optionally contain conventional pharmaceutical excipients such as preservatives, salts for adjusting the osmotic pressure, buffers, flavoring agents, perfumes, and the like. may also be included. The compositions may also optionally contain other pharmaceutically acceptable compounds of known value without exhibiting synergistic activity. Preferably, the composition is formulated in dosage units appropriate to the desired route of administration. The pharmaceutical compositions may be prepared by conventional techniques, which include, for example, sifting, mixing, granulating, and pressing or dissolving the ingredients in the appropriate compositions. The compositions may be subjected to further pharmaceutical operations (e.g., sterilization).

The invention is further illustrated by the following non-limiting examples.

Example 1

2,4-Dichloro-5-nitro-benzene-sulfinic acid

35.9 gm. sodium sulfite and 12 g of sodium bicarbonate are dissolved in 150 ml of water. Add 33.1 g (0.114 mol) of 2.4 dichloro-5-nitrobenzenesulfuryl chloride over a period of 1.5 hours at 35 ° C and maintain the pH of the solution at 8 to 9 with 40% sodium hydroxide solution. . The reaction mixture was then stirred at 35 ° C for 6 hours and then with toluene (100 ml) for another half hour, cooled to 20 ° C with stirring, filtered, dried. 17.9 g (85.4% potassium permanganate assay) of sodium 2,4-dichloro-5-nitrobenzenesulphinate are obtained, which is dissolved in 90 ml of water at 40 DEG C. and filtered at the same temperature. The filtrate, cooled to 10-15 ° C, was acidified by the addition of concentrated aqueous hydrochloric acid (30 ml), cooled to 5 ° C, filtered, and dried at a temperature below 40 ° C.

14.2 g of 2,4-dichloro-5-nitrobenzenesulfinic acid are obtained.

Active ingredient content: 99%.

Melting point: 139-141 ° C.

44.8% of theory based on sulfonyl chloride.

Example 2 (2,4-Dichloro-5-nitrophenyl) phenylsulfoxide

10.37 g (0.040 mol) were prepared according to Example 1

2,4 dichloro-5-nitrobenzenesulfinic acid, 15 ml dichloroethane, 3.8 ml thionyl chloride and 0.04 ml triethylamine are refluxed for 2 hours and the solvent is removed in vacuo. To the 10.9 g of the sulfinyl chloride derivative (m.p. 61-5 ° C) were added 10 ml of dichloroethane, 96906, rinsed with 15 ml of water, acidified with hydrochloric acid, allowed to stand overnight, the precipitate was filtered and washed with 10.4 g of ethanol. m.p.

The production is 79% of theory.

Melting point: 134-6 'C.

7.03 g (0.052 mol) vm. aluminum chloride was added and 9 mL of benzene was added over 0.5 h. The mixture was stirred at 50 ° C for 2 hours, cooled, diluted with chloroform (100 ml), poured into ice water, the organic phase separated, the aqueous phase extracted with chloroform, the combined chloroform phases were evaporated and the residue was recrystallized from methanol.

10.9 g of white (2,4-dichloro-5-nitro-phenyl) -phenyl are thus obtained. - preparing sulfoxide.

Melting point: 151-3 ° C.

The product was 98% pure (by HPLC).

Production is 85% of theory.

Example 3 (2,4-Dichloro-5-nitrophenyl) - (4-chlorophenyl) sulfoxide

10.9 g of 2,4-dichloro-5-nitrobenzenesulfinyl chloride (0.04 mol) prepared in Example 2 are dissolved in 25 ml of chlorobenzene and 8.4 g (0.063 mol) of vm are cooled. aluminum chloride is added. The reaction mixture was stirred for 5 hours at 50 ° C and worked up as in Example 2. Recrystallization from methanol gave 11.8 g of the title compound as a white solid.

The yield is 84% of theory.

Melting point: 166-168 ° C.

Example 4 (2,5-Dimethylphenyl) - (4-chloro-3 nitrophenyl) sulfoxide

No. 195,949. 36 g of 4-chloro-3-nitrobenzenesulfinic acid (0.1625 moles), 75 ml of dichloroethane, 15.1 ml of thionyl chloride and 0.1 ml of triethylamine (50 g) were stirred at 50 ° C for 1 hour. The solvent was removed in vacuo at a temperature below 60 ° C. The approx. To 40 g of residue, 20 ml of dichloroethane and 28.2 g of vm. Aluminum chloride was added and 61 ml of p-xylene was added with cooling at 25 ° C, stirred for 2 hours at 25-30 ° C, cooled, poured into 150 ml of ice water, extracted twice with 100 ml of benzene, anesthetized, filtered, evaporated, recrystallize from methanol. 44.3 g of (2,5-dimethylphenyl) (4-chloro-3-nitrophenyl) sulfoxide are obtained in the form of a white solid,

The production is 88% of theory.

Melting point: 121-2'C.

Example 5

(4 - Chlorophenylsulfinyl) - 2 - nitrophenol

No. 195,949. A mixture of 14.1 g of (4-chloro-3-nitrophenyl) -4 (chlorophenyl) sulfoxide (0.05 mol), 16.8 g of potassium hydroxide, 30 ml of water and 15 ml of dimethyl sulphoxide, prepared according to Hungarian Patent Specification Stir at C for 4 hours in an autoclave, cool 6. Example 5 (5-Amino-2,4-dichlorophenyl) phenylsulfoxide

15.8 g of the product prepared according to Example 2 (2,4-dichloro-5

- Nitrophenyl) phenylsulfoxide (0.05 mol), a mixture of 5 ml of concentrated hydrochloric acid, 100 ml of methanol and 2 g of 5% palladium on carbon was hydrogenated at room temperature (about 3.4 liters of hydrogen) and the reaction mixture was stirred at room temperature. the filtrate was made basic with methanolic ammonia at a temperature below 40 ° C under vacuum. evaporate to one third, cool to 5 'C, filter, wash with water. 11.2 g of the title compound are obtained.

The production is 78% of theory.

Melting point: 157-9'C.

Example 7 (5-Amino-2,4-dichlorophenyl) (4-chlorophenyl) sulfoxide

All proceed as in Example 6, except that starting material is 17.6 g (0.05 mol) of (2,4-dichloro-5-nitrophenyl) - (4-chloro)

(phenyl) sulfoxide is used.

The production is 77% of theory.

Melting point: 158-160'C.

Example 8 (4-Phenylthio-3-nitrophenyl) phenylsulfoxide

To a mixture of (4-chloro-3-nitrophenyl) phenylsulfoxide (56.3 g, 0.2 mol) in ethanol (120 ml) and stirring at 70 ° C with a solution of potassium hydroxide (12.2 g) in ethanol (160 ml), and at the same time 24.2 g of iophenol are added. The reaction mixture is refluxed for 7 hours, the slurry is slowly cooled to 20 ° C, filtered, washed thoroughly with taste. The crude product is boiled in 300 ml of? Ketone, born at 40 ° C, and dried.

50.6 g of the title compound are obtained.

The production is 71% of theory.

Mp 136-8'C.

Example 9 (3-Nitro-4-chlorophenyl) - (5-chloro-2-methoxyphenyl) sulfoxide

Example 4 was repeated except that 24.3 g (0.17 mol) of p-chloroanisole was used as starting material instead of p-xylene. The addition and reaction temperature were 25 'C.

Production is 87% of theory.

Melting point: 128-130 ° C.

Example 10 (3-Nitro-4-chlorophenyl) - (4-hydroxyphenyl) sulfoxide g (0.625 mol) 4-chloro-3-nitrobenzene sulfinic acid (see Example 4), 75 mL of dichloroethane; Thionyl chloride (15.1 ml, 0.205 mol) and triethylamine (0.1 ml) were stirred at 50 ° C for 1 hour and then solvent was removed in vacuo at a temperature below 60 ° C.

Phenol (g, 0.18 mol) was dissolved in dichloroethane (35 mL), treated with anhydrous aluminum chloride (21.7 g) at 0 ° C, and a solution of the previously obtained sulfinyl chloride diluted in dichloroethane (30 mL) was added to the suspension. The reaction mixture was stirred at 0 ° C for 4 hours and worked up as described in Example 4.

g of the title compound is obtained.

The production is 91% of theory.

Melting point: 164-5 'C.

Example 11 (3-Nitro-4-chlorophenyl) - (4-hydroxyphenyl) sulfoxide

No. 195,949, incorporated herein by reference. A solution of 15.6 g of (4-chloro-3-nitrophenyl) (4-methoxyphenyl) sulfoxide (0.05 mol) in chloroform (50 ml) was added dropwise at 10 ° C.

A mixture of boron tribromide (5.5 ml, 0.055 mol) and chloroform (20 ml) was added. The temperature of the reaction mixture was slowly raised to 35 ° C (gas evolution) and stirred for 1 hour at 35 ° C. While cooling, ethanol (10 mL) was added followed by water (50 mL). The chloroform phase is separated and the aqueous phase is extracted with chloroform. The combined organic phases were evaporated and recrystallized twice from methanol.

8.2 g of the title compound are obtained.

The production is 55% of theory.

Melting point: 164-5 ° C.

Example 12 (4-Hydroxy-3-nitrophenyl) - (4-methoxyphenyl) sulfoxide

15.6 g (4-chloro-3-nitrophenyl) - (4-methoxyphenyl) sulfoxide (0.05 mol) (Example 11), 16.8 g potassium hydroxide, 30 ml water and 35 ml The dimethylsulfoxide mixture was refluxed for 1 hour, cooled, diluted with 20 mL of water and acidified with concentrated hydrochloric acid (pH -Ι). The precipitated mixture was stirred at room temperature for 2 hours, filtered, washed with water, slurried with 20 ml of methanol at 0 ° C and filtered. 14.1 g of the title compound are obtained.

The yield is 96% of theory.

Melting point: 131-132'C.

Example 13 (4-Hydroxy-3-nitro-phenyl) - (2,5-dimethyl-phenyl)

sulfoxide

All were prepared according to Example 12 except that (2,5-dimethylphenyl) (4-chloro-3-nitrophenyl) sulfoxide prepared according to Example 4 was used as starting material.

The production is 91% of theory.

Melting point: 124-125 ° C.

Example 14 (4-Chloro-3-nitro-phenyl) - (2-hydroxy-5-chloro-phenyl) sulfoxide

All were prepared in the same manner as in Example 10 except that 12.9 g (0.18 mol) of p-chlorophenol was used as starting material instead of phenol. The aluminum chloride used was 39 g (0.29 mol).

46.7 g of the title compound are obtained.

The production is 86% of theory.

Melting point: 226-228 ° C.

Example 15 (4-Chloro-3-nitrophenyl) - (2-hydroxy-5-fluorophenyl) sulfoxide

Like Example 10.

Starting material: 4 - fluorophenol.

Aluminum chloride used was 43.3 g.

Production is 76% of theory.

Melting point: 206-210 ° C.

Example 16 (4-Chloro-3-nitrophenyl) (2-hydroxy-3,5-dichlorophenyl) sulfoxide

Like Example 10.

Starting material: 2,4 - dichlorophenol.

4.3.3 g aluminum chloride, reaction temperature 'C.

Yield: 76%.

Melting point: 143-144 ° C.

Example 17 (4-Chloro-3-nitro-phenyl) - (2,4-dimethoxyphenyl) sulfoxide

Like Example 10.

Starting material: resorcinol dimethyl ether. Yield: 84%.

138-140 ° C.

611 ml of i-propanol at 100 ° C were reacted for 10 hours. The reaction mixture was slowly cooled to 40 ° C, and water (15 mL) was added dropwise with stirring, stirred at room temperature for half an hour, filtered, washed with water and dried.

27.3 g of the title compound are obtained.

The production is 94% of theory.

Melting point: 208-9 'C.

Example 18 (4-Chloro-3-nitro-phenyl) - (2-methoxy-5-fluorophenyl) sulfoxide

Like Example 9.

Starting material; p-anisole.

Yield: 86%.

Melting point: 113-114'C.

Example 19

methyl 3 - nitrobenzenesulphonic acid

A solution of 36.2 g of sodium pyrosulfite, 17.4 g of sodium hydroxide in 220 ml of water is dissolved in 16 g of sodium bicarbonate and 36 g (0.164 mol) of 3-nitro-4 toluenesulfonyl chloride (Chem. Abstr. 57: 14987I; m.p. 33-34 ° C) and stirred at this temperature for 4 hours. The pH of the reaction mixture is maintained between 8 and 9 by addition of 40% aqueous sodium hydroxide solution. The excellent sodium sulfinate derivative was born, dissolved in 100 mL of 40 ° C water, and decanted to remove the small amount of oil. The aqueous solution was heated at 15 'C with 34 ml cc. acidified with aqueous hydrochloric acid and stirred for 30 minutes at 5 'C.

g of the title compound is obtained.

The production is 72.8% of theory.

Melting point; 93-5 'C.

Example 4 (4-Methyl-3-nitro-phenyl) -phenylsulfoxide

To a mixture of 18.1 g (0.09 mol) of 4-methyl-3-nitrobenzenesulfinic acid (Example 19), 20 ml of dichloroethane and 0.1 ml of triethylamine, 13.68 g (0.114 mol) of thionyl chloride is added dropwise and 50 ° C is added. stir for 1 hour. The dichloroethane thionyl chloride mixture was evaporated in vacuo, to the residue was added 10 ml of dichloroethane and 18 g (0.135 mol) of aluminum chloride were added at 40 ° C, then 30 ml of benzene was added at 40 ° C (about 15 minutes). stirring the reaction mixture. The reaction mixture was poured into 150 ml of ice-water and diluted with 100 ml of benzene. The organic layer was separated and the solvent was removed in vacuo.

18.6 g of the expected product are obtained.

The production is 79.2% of theory.

Melting point: 78-9 'C.

Example 21 (4-Amino-3-nitrophenyl) (2,5-dimethylphenyl) sulfoxide

30.95 g of (2,5-dimethylphenyl) (4-chloro-3-nitrophenyl) sulfoxide (0.1 mol) prepared in Example 4 were added to 76.5 ml of 20 g / 100 ml. aqueous ammonium hydroxide solution (0.9 mol) and 93.5

Example 22

trifluoromethylphenylsulfoxide

8.4 g of 3-trifluoromethylbenzenesulfinic acid (0.04 mol, prepared by Zsum. Org. Khim. 1977, 13 (10) page 2235) are reacted and processed as described in Example 2.

g of the title compound is obtained.

The production is 74% of theory.

Melting point: 90-92 'C.

Example 23 (5-Amino-2,4-dichlorophenyl) phenylsulfoxide Hydrochloride

2.86 g (0.01 mol) of (5-amino-2,4-dichlorophenyl) phenylsulfoxide prepared in Example 6 are dissolved in 10 ml of chloroform and 0.011 mol of methanolic hydrochloric acid are added dropwise. The precipitate was slowly cooled, with stirring, filtered and dried.

3.0 g of the hydrochloride amine salt are obtained.

The yield is 93% of theory.

Melting point: 163-165 ° C.

Claims

Claims (2)

A process for the preparation of a novel substituted diaryl sulfoxide derivative of general formula (I) wherein: Y is nitro, amino or trifluoromethyl, R ¹ , R ² , R ³ , R 1, R ⁶ , R ⁷ , R ⁸ and R ⁹ are the same or different and are selected from hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, , an amino or thiophenyl group, and an acid addition salt thereof, characterized in that a benzenesulfonyl halide derivative of the formula (I) - in which Y, R ¹ , R ² , R ³ and R * have the same meaning as in formula (I) and X ¹ is halogen, reduced with an alkali metal sulfite to form the resulting benzenesulfinic acid derivative of formula (III): wherein Y, R ¹ , R ² , R ³ and R ⁴ are as defined in formula (1) and M is alkali metal - after conversion to the corresponding benzene sulfinic acid, the thionyl chloride is treated with a halogenating agent to give the t -713 benzenesulfinyl halide, wherein Y, R ¹ , R ² , R ³ and R ⁴ are as defined for formula I and X ² is halogen, with a benzene derivative of formula V wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined in formula I in the presence of a C ₁ -C ₃ catalyst, and if desired, the resulting substituted diaryl sulfoxide derivative of formula ¹ wherein Y is nitro and R ¹ R ^2, R, R \ R ', R ^h, R', R * and R 'are as defined above - optionally reducing or converting the resulting compound (I) substituted diaryl sulfoxide derivatives of general formula - wherein Y represents nitro, and at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R 'having the meaning given above is reacted with halogen - ammonium or alkali hydroxide and / or thiophenol, or, if desired, the resulting substituted diaryl sulfoxide derivative of formula (I) wherein Y is nitro and R ', R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R At least one of the radicals is a C 1 -C 4 alkoxy group which is reacted with a boron trihalide and, if desired, the resulting substituted diaryl sulfoxide derivative of formula (I) wherein Y is nitro and R * is as defined above. At least one of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R 'is amino - treated with an acid. 2. A process for the preparation of a fungicidal and nematocidal pharmaceutical composition comprising: A substituted diaryl sulfoxide derivative of the formula I according to claim ¹ , wherein Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R and R ⁹ are as defined in claim 1. and / or acid addition salts thereof, as hereinbefore defined, with pharmaceutically acceptable carriers and / or other excipients and converting them to a pharmaceutical composition.