CZ20011156A3 - A process for preparing 4,4'-dihalo-o-hydroxydiphenyl compounds, compositions containing them, and uses thereof - Google Patents

Abstract

A four-step process for the preparation of 4,4'-dihalo-ohydroxydiphenyl compounds of formula 1 is described, in step 1 and by halogenation of a diphenyl compound or in step 1b by reaction of p-halophenol and p-dihalobenzene, in the second step by acylation of the dihalogenated compound via the Friedel-Crafts reaction, in the third step by oxidation of the acyl compound and in the fourth step by hydrolysis. Compounds of formula 1 are used for the protection of organic materials and objects against microorganisms.

Description

A process for the preparation of 4,4 ' -dihalogen-o-hydroxydiphenyl compounds, compositions containing them and their use

Qblaat techniques

The present invention relates to a process for the preparation of 4,4'-dihalo-o-hydroxy-diphenyl compounds of formula 1

where

Hal is a halogen atom, and the use of these compounds to protect organic materials and objects from microorganisms.

The prior art techniques

The preparation of 4,4'-dihalogen-o-hydroxydiphenyl compounds is usually carried out by diazotization followed by hydrolysis of 2-amino-4,4'-dichlorodiphenyl ether (compound of formula 2):

However, the yield obtained by this process is unsatisfactory because other chemical reactions may be competitive.

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It is an object of the present invention to provide an inexpensive process for the preparation of 4,4'-dihalogen-o-hydroxydiphenyl compounds, wherein unwanted side reactions are suppressed.

SUMMARY OF THE INVENTION

According to the present invention, this object is achieved by a four-step reaction wherein in the first step the diphenyl compound is halogenated or the p-halophenol is reacted with p-dihalophenol in the presence of copper and / or copper salts; in a second step, the dihalogenated compound is acylated by Friedel Crafts reaction; in the third step the acylated compound is oxidized and in the fourth step the oxidized compound is hydrolyzed according to the following scheme:

Hal

Hal • 0 · 1 ·

00 0 · 0 0

In the scheme:

R is an alkyl group having 1 to 8 carbon atoms which is unsubstituted or substituted by 1 to 3 halogen atoms or hydroxyl groups; unsubstituted C 6 -C 12 aryl; or a (C 6 -C 12) aryl group which is substituted with (C 1 -C 3) atoms, (C 1 -C 5) alkyl groups or (C 1 -C 8) alkoxy groups, or combinations thereof; and

Hal is a halogen atom;

(C až-C) alkyl is a branched or unbranched alkyl group, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, 2-ethylbutyl , n-pentyl, isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, isoheptyl, 1,1,3,3-tetramethylbutyl, 1-methylheptyl, 3-methylheptyl, 2-ethylhexyl or n-octyl.

C1-C8alkoxy is a straight or branched group, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy.

The halogen atom is a fluorine atom, a bromine atom or preferably a chlorine atom.

In Formulas 6 and 7, in the reaction scheme above, the reaction scheme above. · ··················

R is C 1 -C 4 alkyl and preferably methyl.

When the halogen atom is preferably a chlorine atom, the chlorinating agent in reaction step 1a is, for example, sulfuryl chloride or preferably chlorine gas. The reaction is preferably carried out in the presence of a catalyst such as dibenzothiophene, methylsulfide, propylsulfide, phenylsulfide, a Lewis acid such as aluminum chloride or mixtures thereof. A particularly preferred catalyst. is a mixture of propyl sulfide and an equimolar amount of aluminum chloride.

The reaction temperature of the first step may be varied within a wide range, for example -10 to 50 ° C. The reaction is preferably carried out at a temperature of 0 to 40 ° C.

The reaction time may also vary within wide limits. The reaction is usually carried out for 1 to 48 hours, preferably 2.5 to 10 hours.

The reaction of step 1b is usually carried out at a temperature of 120 to 200 ° C, preferably 130 to 170 ° C, whereby the phenol compound of formula 4a and dihalogen compound 4b must be present in a stoichiometric ratio and the alkali metal hydroxide must be present in a lower than an equivalent amount (20 to 80%).

The copper catalysts used are preferably copper salts commonly used in Ullmann synthesis, for example, copper oxide, copper oxide, copper carbonate, basic copper carbonate, copper chloride, copper chloride, copper bromide, copper bromide or copper sulfate.

Further details of reaction step 1b are given in DE-OS2,242,519.

·· φ φ φ • · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

The acylation reaction (second step) is usually carried out in the presence of a Lewis acid such as aluminum chloride. In this case, the Lewis acid is used in an amount of 1 to 3, preferably 1.25 to 2 molar equivalents, relative to the halogenated acyl compound of formula 5. A suitable acylating agent for this reaction is an acyl halide, preferably acetyl chloride. Other suitable acylating agents are, for example

Cl h ₅ cc.

Cl Cl I I

Cl - c - c.

I o H

H ₃ C h ₃ co

/

O or f

O

Cl Cl I I ci — c—

I '' O Cl

In this case, the Lewis acid and the acylating agent are preferably used in equimolar amounts. The reaction is carried out in solvents customary in Friedel-Crafts reactions, such as halogenated solvents, preferably dichloromethane or ethylene chloride.

In a particular embodiment of the present invention, the acylation reaction is carried out in the presence of acetyl chloride and aluminum chloride, which are used in equimolar amounts.

The reaction time for this reaction is of minor importance and can be varied within a wide range, for example 1 to 18 hours.

The halogenation reaction (first step) and the acylation reaction (second step) as well as the optionally repeated chlorination reaction are preferably carried out in the same reaction vessel and are therefore a single reaction vessel.

The oxidation of the acyl compound of formula 6 to the compound of formula 7 (Baeyer-Villiger oxidation) can be carried out using various oxidizing agents. Suitable oxidizing agents are, for example:

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an equimolar mixture of dilute peracetic acid and acetic anhydride in the presence of a catalytic amount of perchloric acid;

excess of 3-chloroperbenzoic acid in. water;

di-peroxydodecanedioic acid (DPDDA);

a mixture of dilute peracetic acid and acetic anhydride and sulfuric acid;

- persulfic acid;

- a mixture of concentrated sulfuric acid, anhydrous acetic acid and hydrogen peroxide;

a mixture of m-chloroperbenzoic acid (MCPBA), trifluoroacetic acid and dichloromethane;

a mixture of sodium perborate and trifluoroacetic acid;

- a mixture of formic acid, hydrogen peroxide, acetic anhydride, phosphorus pentoxide (phosphorus pentoxide) and acetic acid;

a mixture of acetic acid, hydrogen peroxide, acetic anhydride and phosphorus pentoxide;

a mixture of K ₂ S ₂ O _a , sulfuric acid and a 1: 1 water / methanol mixture;

a mixture of acetic acid and a monoperoxomaleic acid potassium salt;

a mixture of trichloromethylene, monoperoxomaleic acid potassium salt and sodium bisulfate;

a mixture of maleic anhydride, acetic anhydride, hydrogen peroxide and trichloromethane;

a mixture of maleic anhydride, urea-hydrogen peroxide complex and acetic acid;

- Mg-monoperphthalate.

Preferably a mixture of concentrated sulfuric acid, anhydrous acetic acid and hydrogen peroxide is used for the oxidation.

• 'fy

· · 44 · 4 · 4 · 4 · 4 · 4 · 4444

If appropriate, a commercially available wetting agent may be added to the oxidizing agent.

The reaction time can be varied within a wide range of 1 to 24 hours, preferably 1 to 5 hours.

The reaction temperature may be -20 to 80 ° C. The reaction is preferably carried out at room temperature.

The subsequent hydrolysis of the desired 4,4'-dihalogen-o-hydroxydiphenyl ether of formula 1 proceeds quantitatively.

The 4,4'-dihalogen-o-hydroxydiphenyl compounds prepared according to the present invention are insoluble in water, but are soluble in dilute sodium hydroxide and potassium hydroxide solutions and in virtually all organic solvents. Due to these solubility properties, the compounds are very versatile in combating microorganisms, especially bacteria, and in protecting organic materials and objects from microorganisms. They are therefore particularly suitable for disinfection, deodorization and general antimicrobial treatment of the skin, mucosa and exterior (hair), particularly suitable for disinfecting hands and injuries.

They are particularly suitable as antimicrobial active ingredients in personal care products such as shampoos, bath additives, hair care products, liquid and solid soaps (based on synthetic surfactants and salts of saturated and / or unsaturated fatty acids), lotions and creams , deodorants, other aqueous and alcoholic solutions, for example, skin cleansers, wet wipes, oils or powders.

i.i <··;

R · r r r r · r r r r r r r r r r

Accordingly, the present invention also relates to body care compositions comprising at least one compound of Formula 1 and cosmetically acceptable carriers or ingredients. -. . . . '

The new body care composition contains 0.01 to 15% by weight, preferably 0.5 to 10% by weight, based on the total weight of the composition, of the compound of formula 1 as well as cosmetically compatible ingredients.

Depending on the particular form of the body care composition, the composition contains other ingredients, in addition to the compound of Formula 1, for example sequestrants, colorants, essential oils, thickeners or consistency regulators, emollients, UV absorbers, skin protection agents, antioxidants, enhancers mechanical properties such as dicarboxylic acids and / or salts of aluminum, zinc, calcium, magnesium of C 14 -C 22 fatty acids, and optionally other antimicrobial actives.

The new body care compositions can be formulated as water-in-oil or oil-in-water emulsions, as alcohol or alcohol-containing compositions, as blister dispersions of ionic or non-ionic amphiphilic lipids, such as gel, solid stick or aerosol composition.

The water-in-oil or oil-in-water emulsions containing the compound of formula I preferably contain, as cosmetically compatible ingredients, 5 to 50% of the oil phase, 5 to 20% of an emulsifier and 30 to 90% of water.

The oil phase may in this case comprise any suitably oil-soluble cosmetic compositions, for example one or more.

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9 * 9 9 9 9 • 9 9 9 9 9 9 • 999 9 9 9 • 9 99 »9 999 Several hydrocarbon oils, waxes, natural oil, silicone oil, fatty acid ester or fatty alcohol. Preferred mono- and polyols are ethanol, isopropanol, propylene glycol, hexylene glycol, glycerol and sorbitol.

The compounds of the present invention may be present in various cosmetic compositions. Examples of particularly suitable formulations are as follows:

- means of care. o skin, for example, compositions for washing and cleaning the skin in the form of solid soaps or liquid soaps, and the like, or washing pastes;

bath compositions, for example liquids (foam baths, lotions, showers) or solid bath compositions such as bath beads or bath salts;

skin care products such as skin emulsions, multi-component emulsions or skin oils;

- decorative skin care products, such as facial make-up in the form of daily or powdered creams, facial powders (loose or compressed), roses or cream make-up, eye care products such as eye shadows, mascara, eyeliner, eye creams or eye fixation creams; lip care compositions such as lip glosses, lip glosses, lip liners, nail care compositions such as nail polishes, nail polish removers, nail enhancers or cuticle removers;

- feminine hygiene products, such as feminine hygiene lotions or sprays;

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foot care products, such as foot baths, foot powders, foot creams or foot balms, special deodorants and antiperspirants, or peeling agents;

sunscreen products such as sun lotions, lotions, creams, oils, sun blocking agents or tropics, before and after tanning agents;

self-tanning agents, for example self-tanning creams;

- depigmenting agents, for example skin whitening or brightening agents;

insect repellents, for example oils, water, sprays or insect sticks;

deodorants, for example deodorant sprays, non-aerosol sprays, deodorant gels, sticks and spheres;

antiperspirants, for example antiperspirant sticks, creams or spheres;

- cleaning and care products. impure skin, for example, soaps (solid or liquid), peeling or exfoliating agents or peeling masks;

chemical depilation means, for example depilatory powders, liquid depilatory products, cream or paste depilatory products, depilatory gels or aerosol foams;

- shaving preparations, for example, shaving soaps, shaving foams, non-foaming shaving creams, shaving foams and shaving gels,

«Pre-dry shaving, aftershave or aftershave;

fragrances, for example perfumes (Eau de Cologne, Eau de Toilette, Eau de Perfume, Perfume de Toilette, perfume), perfumed oils or perfumed creams;

- dental and dental hygiene products as well as denture hygiene, for example toothpastes, dental gels, dental powders, concentrated mouthwashes, dental plaque mouthwashes, denture cleansers or denture adhesives;

- cosmetic products for the treatment of denture, for example hair washing products in the form of shampoos, hair conditioners, hair care products, for example hair pre-treatment products, hair tonic, hair creams and gels, pomades, hair rinsing products, deep care products, intensive hair care products (hot waving, mild waving, cold waving), hair straighteners, liquid hair fixatives, hair mousses, lightening agents such as peroxide, hydrogen, lightening shampoos, lightening creams, lightening powders, lightening pastes or oils, short-lived, long-lasting or permanent hair dyes, compositions containing self-oxidizing dyes or natural hair dyes such as henna or camomile.

For example, the composition of the antimicrobial soap is as follows:

0.01 to 5% by weight of the compound of formula (1),

0.3 to 1% by weight of titanium dioxide, up to 10% by weight of stearic acid,

Up to 100% of a soap base, for example sodium tallow and coconut fatty acid or glycerol.

Shampoo composition is as follows:

0.01 to 5% by weight of the compound of formula 1,

12.0% by weight of sodium laureth-2-sulphate,

4,0% by weight of cocamidopropyl betaine,

3.0% by weight sodium chloride and up to: 10% water.

The composition of the deodorant is, for example, as follows:

0.01 to 5% by weight of the compound of formula 1,% by weight of ethanol,

0.3% by weight of perfumed oil and up to 100% water.

An example of an oil-in-water emulsion:

(a):

0.01-5% by weight of the compound of formula 1,% by weight glyceryl stearate,% by weight paraffin oil,% by weight caprylic / capric acid triglyceride,% by weight glycerols,

0.2% by weight of disodium EDTA,

1.0 wt% citric acid (20%) and 65.8-70.8 wt% water.

(b):

0.01-5% by weight of the compound of formula 1,

3.5% by weight of PEG-30 dipolyhydroxystearate; . . · · · .. · · .. ·.:. ···· ·· ·· **

10.0% w / w paraffin oil,% w / w caprylic / capric triglyceride,% w / w dicaprylether,

0.2% by weight of the disodium EDTA salt,

3.4 wt% glycerol and 69.9-74.9 wt% water.

In another aspect, the present invention relates to an oral composition comprising 0.01 to 15% by weight, based on the total weight of the composition, of a compound of Formula 1 as well as orally compatible ingredients.

An example of an oral composition is:

% sorbitol,% glycerol,% ethanol,% propylene glycol,

0,5% by weight of sodium lauryl sulphate,

0,25% methyl sodium alkyl taurate sodium,

0.25% by weight of a polyoxypropylene / polyoxyethylene block copolymer

0,10% menthol flavor,

0.1 to 0.5% by weight of the compound of formula 1 a

48.6% by weight of water.

For example, the novel oral composition may be in the form of a gel, a paste, a cream or an aqueous composition (mouthwash).

The novel oral composition may further comprise compounds that release fluoride ions that are effective against caries, for example, inorganic fluoride salts such as

Sodium, potassium, ammonium or calcium fluorides or organic fluorides such as ammonium fluorides, which are known under the trade name Olafluor.

The compounds of the formula I used according to the invention are furthermore suitable for the antimicrobial treatment of textile fiber materials. Such materials are uncoloured and dyed or printed fibrous materials, for example silk, wool, polyamide, polyester, polypropylene or polyurethanes, preferably fibrous materials containing cellulose of all kinds. These fibrous materials are, for example, natural cellulose fibers such as cotton, flax, jute and hemp and cellulose and regenerated cellulose.

The compounds of formula 1, alone or in combination with other antimicrobial agents, are also suitable for the preservation of cosmetics such as shampoos, bath additives, hair care products, liquid and solid soaps (based on synthetic surfactants and saturated salts). and / or unsaturated fatty acids), lotions and creams, deodorants, other aqueous and alcoholic solutions such as skin cleansing solutions, wet wipes, oils or powders, and household care products such as detergents and cleaning agents such as liquid and solid detergents and plasticizers.

The compounds of formula 14 used in the present invention are also suitable for antimicrobial finishing of synthetic materials, for example polyethylene, polypropylene, polyurethane, polyester, polyamide, polycarbonate, latex and the like. The application sites for these substances are typically floors, plastic coatings, containers of plastic materials and packaging materials; kitchen and bathroom utensils (for example brushes, shower curtains; sponges, bath mats), latex filter materials (air and water filters), plastic products used in the medical field, for example dressing materials, syringes, catheters and the like, so-called medical devices , gloves and mattress.

Paper, such as sanitary paper, can also be antimicrobially treated with the novel compounds of formula 1.

According to the present invention, it is also possible to antimicrobially treat nonwoven materials, such as diapers, sanitary towels and cotton, sanitary and household wipes.

In particular, hydroxyphenyl-1,3-propanediones can also be used in the home and in multi-purpose cleaners used for cleaning and disinfecting solid surfaces.

For example, the composition of the cleaning agent is as follows:

0.01 to 5% of a compound of formula 1,

3,0% octyl alcohol 4EO,

1.3% of a C8-C10 fatty alcohol polyglucoside,

3.0% isopropanol, to 100% water. .

In addition to the preservation of cosmetic and household care products, it is also possible to preserve and antimicrobially treat technical products such as paper treatment lacquers, printing thickeners containing starch or cellulose derivatives, coloring systems and paints.

The compounds of formula 1 are also suitable for antimicrobial treatment of wood and for antimicrobial treatment and skin treatment.

4

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Reaction step 1a

Reaction scheme:

(101a)

or ₂

(101b)

Cl

Cl

170 g of diphenyl ether are placed in a reaction vessel and melted with stirring at 30 to 40 ° C. Then 4.7 g of dipropylsulfide and 4.8 g of aluminum chloride are added. The chlorination is carried out by introducing chlorine at a temperature of 35 to 40 ° C until the desired degree of chlorination of the reaction mixture is achieved. The reaction is monitored by gas chromatography or HPLC. The reaction mixture can be separated by distillation and the monochlorodiphenyl ether can be recycled. If the chlorination proceeds to the di- and trichlorine stage (80% dichloro derivative content and 20% trichlorinated derivative content), the reaction mixture can also be used directly for acylation.

Example 2

Acylation (second reaction step):

Reaction scheme:

290 g of aluminum chloride are added to 520 g of ethylene chloride with stirring at 20-25 ° C. 170 g of acetyl chloride are added dropwise at 25 to 40 ° C over 15 to 20 minutes and the mixture is stirred at 40 ° C for 10 minutes. A solution of 239 g of 4,4'-dichlorodiphenylether in 400 g of ethylene chloride was added dropwise over 1 hour. The reaction mixture is kept at 40 ° C (± 2 ° C) for 4 hours and then 2500 ml of ice water and 350 ml of 34% hydrochloric acid are added with stirring. The phases were separated at 15-20 ° C. Ethylene chloride was distilled off from the organic phase.

The residue containing the crude acylated derivative (= 300 g) is dissolved in 1000 g of isopropyl alcohol at 70 ° C and purified by filtration with a little activated carbon. 350 ml of water are added with stirring at 60 ° C. The solution is cooled slowly, crystallization is induced by seeding the crystals at 45 ° C. The solution was stirred for 15 hours and the crystals were filtered off at 25 ° C and washed with a mixture containing 210 g of isopropyl alcohol and 70 ml of water. After drying under vacuum at 50 ° C, 192.5 g of a light beige, crystalline product 101c is obtained, m.p. 65-66 ° C.

Example 3

Baeyer-Villiger oxidation

Reaction scheme:

130 g of acetic acid (100%) are placed in a reaction vessel and 31 g of concentrated sulfuric acid are added under cooling at 15 to 20 ° C. At this temperature, 30 g of 50% hydrogen peroxide are added to the mixture over 30 minutes. This reaction solution was added dropwise at 20-25 ° C over one hour to a solution of 70 g of the acetylated compound of formula 101c dissolved in 180 g of 100% acetic acid and 87 g of concentrated sulfuric acid. The mixture was stirred at 20-25 ° C for 3 hours and slowly warmed to 45 ° C to complete the hydrolysis of the phenol ester of the compound of formula 10ld. This temperature was maintained for 2 hours and the reaction mixture was added to a mixture containing 130 g of water and 360 g of toluene such that the final temperature was 25-30 ° C. The phases are separated, the organic phase is washed with water until neutral and the toluene is distilled off. A residue of 143 g containing crude product 101 is obtained. After recrystallization from petroleum ether 80/110. pure product is obtained in the form of colorless. 74-75 ° C.

Claims (20)

PATENT RULES Process for the preparation of 4,4'-dihalogen-o-hydroxydiphenyl compounds, characterized in that in step 1a of halogen it is a diphenyl compound or in step 1b reacts phalogenphenol and p-dihalobenzene in the presence of copper and / or copper salts, in in the second step the dihalogenated compound is acylated by Friedel-Crafts reaction, in the third step the acylated compound is oxidized and in the fourth step the product is hydrolyzed according to the following reaction scheme: acylation where R is an alkyl group containing 1 to 5 carbon atoms 8 carbon atoms which is unsubstituted or substituted by 1 to 3 halogen atoms or hydroxyl groups; unsubstituted C 6 -C 12 aryl; or a C 8 -C 12 aryl group substituted with 1 to 3 halogen atoms, C 1 -C 5 alkyl groups or C 1 -C 8 alkoxy groups, or combinations thereof; and Hal is a halogen atom. A method according to claim 1, characterized in that R is an alkyl group having 1 to 4 carbon atoms. A method according to claim 2, characterized in that R is methyl. A process according to any one of claims 1 to 3, wherein the halogen atom is a chlorine atom. Process according to claim 4, characterized in that the chlorination step 1a is carried out with elemental chlorine. 6. The process of claim 5, wherein the chlorination is carried out in the presence of a mixture comprising propylsulfide and an equimolar amount of aluminum chloride. The process according to any one of claims 1 to 6, wherein the copper catalyst used in step 1b is copper oxide, cuprous oxide, cuprous carbonate, cuprous cuprous carbonate, cuprous chloride, cuprous chloride, cuprous bromide, cuprous bromide or cuprous sulfate. . Process according to any one of claims 1 to 7, characterized in that the acylation reaction is carried out in a second step . ·· .. ·::. . . Aluminum chloride, which is carried out in the presence of acetyl chloride and is used in equimolar amounts. The method of claim 8, wherein the acylation reaction is carried out in the presence of a halogenated solvent. Process according to any one of claims 1 to 9, characterized in that the halogenation in the first step and the acylation in the second step are carried out as a reaction in a single reaction vessel. Process according to any one of claims 1 to 10, characterized in that the oxidation is carried out. the third step is carried out using a mixture comprising concentrated sulfuric acid, anhydrous acetic acid and hydrogen peroxide as solvent. The method of claim 11, wherein the oxidation reaction time is 1 to 24 hours when the oxidation is carried out at room temperature. Use of compounds prepared according to the methods of any one of claims 1 to 12 for protecting organic materials and articles from attack by microorganisms. Use of a compound of formula 1 for antimicrobial treatment of skin, mucosa and hair. Use of a compound of formula 1 for antimicrobial treatment of textile fiber materials. Use of a compound of formula 1 in detergents. ···· 9 · Use of a compound of formula 1 for antimicrobial treatment of plastic materials, paper, nonwovens, wood or leather. Use of a compound of formula 1 for the preservation of cosmetic products. 19. A body care composition comprising 0.01 to 15% by weight, based on the total weight of the composition, of the compound of formula 1 as well as cosmetically compatible ingredients. 20. An oral composition comprising 0.01 to 15% by weight, based on the total weight of the composition, of the compound of formula 1 as well as the orally compatible ingredients.