SK4542001A3 - Process for the preparation of 4,4'-dihalogen-o-hydroxydiphenyl compounds - Google Patents

Abstract

Disclosed is a four-step process for the preparation of 4,4'-dihalogen-o-hydroxydiphenyl compounds of formula (1) by halogenation of a diphenyl compound (step 1a) or by the reaction of p-halophenol and p-dihalobenzene (step 1b), acylation of the dihalogen compound in a Friedel-Crafts reaction (2nd step), oxidation of the acyl compound (3rd step) and hydrolysis (4th step). The compounds of formula (1) are used for protecting organic materials and objects from microorganisms.

Description

Technical field

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

Hal

Hal (D where

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

BACKGROUND OF THE INVENTION

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):

(2)

However, the yield obtained by this process is unsatisfactory, since other chemical reactions may take place competitively.

It is an object of the present invention to provide an inexpensive process for the preparation of 4,4'-dihalo-o-hydroxydiphenyl compounds, wherein: In which undesirable side reactions are suppressed.

SUMMARY OF THE INVENTION

According to the present invention, this objective is achieved by means of a four-year reaction in which, in a first step, the diphenyl compound is halogenated or the p-halophenol is reacted with p-dihalobenzene in the presence of copper and / or copper salts; in the second step, the dihalogenated compound is acylated by a Frie del-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:

oxidation

In the scheme:

^R ^ ° 'Hal (7) · · · · · · · · · · · · · · · · · · · · · · · · · · ·

R is C 1 -C 8 alkyl which is unsubstituted or substituted by 1 to 3 halogen atoms or hydroxyl groups; unsubstituted (C 6 -C 12) aryl; or (C 6 -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.

C 1 -C 8 alkyl is a branched or unbranched alkyl group, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-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 above reaction scheme:

R is an alkyl group having 1 to 4 carbon atoms and preferably a methyl group.

If 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 a catalyst such as dibenzothiophene, methylsulfide, propylsulfide, phenylsulfide, Lewis acid such as aluminum chloride, or mixtures of these compounds. 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 over 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 for 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 the dihalogenated compound of formula 4b are present in a stoichiometric ratio and the alkali metal hydroxide must be present in the less than the equivalent amount (20 to 80%).

The copper catalysts used are preferably the 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-OS-2,242,519.

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 acylated compound of Formula 6. A suitable acylating agent for this reaction is an acyl halide, preferably acetyl chloride. Other preferred acylating agents are, for example:

······································· ·

ο

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 and 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 acylated compound of formula 7 to the compound of formula 8 (Bayer-Villiger oxidation) can be carried out using various oxidizing agents. Suitable oxidizing agents are, for example:

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

excess m-chloroperbenzoic acid (MCPBA) in water;

diperoxydodecanedioic acid (DPDDA);

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

Persiric acid; < tb > ______________________________________ < tb > ______________________________________ < tb >

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

a mixture of m-chloroperbenzoic acid (MCP3A), trifluoroacetic acid and dichloromethane;

a mixture of sodium perborate and trifluoroacetic acid;

a mixture of formic acid, hydrogen peroxide, acetic anhydride, 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 ₈ , sulfuric acid and a 1: 1 mixture of water / methanol;

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

a mixture of trichloromethane, monoperoxomaleinic 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.

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

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

The reaction temperature can be in the range of -20 to approximately 7 ° C. Not 80 ° C. The reaction is preferably carried out at room temperature.

Subsequent hydrolysis to the desired 4,4'-dihalo-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 disinfecting, deodorizing and, in general, antimicrobial treatment of the skin, mucous membrane and exterior (hair), in particular for the disinfection of hands and wounds.

They are particularly useful 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.

Thus, the present invention also relates to body care compositions comprising at least one compound of formula I and cosmetically acceptable carriers or ingredients.

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

Depending on the particular form of the body care composition, the composition contains, in addition to the compound of Formula 1, other ingredients such as sequestrants, colorants, essential oils, thickeners, or consistency-regulating agents. Emollients, UV absorbers, skin protection agents, antioxidants, additives improving 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 active agents.

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

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

The oily phase in this case may comprise any suitable oil-soluble cosmetics, for example one or more 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 a variety of cosmetic compositions. Examples of particularly suitable formulations are:

skin care compositions, for example, skin cleansing and cleansing compositions in the form of solid soaps or liquid soaps and the like, or pastes for washing;

bath preparations, for example, liquid (foam baths, lotions, shower preparations) or solid bath preparations, such as bath beads or bath salts;

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

decorative skin care products, such as, for example, skin care products, e.g. Facial makeup in the form of daily or powdered creams, facial powders (loose or compressed), lipstick or cream makeup, eye care products such as eye shadows, mascara, eyeliner, eye cream or eye fixation creams, lip care compositions such as lipsticks, lip glosses, contouring pencils, nail care compositions such as nail polishes, nail polish removers, nail enhancers or skin removers;

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

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

sunscreen products, such as sun lotions, lotions, creams, oils, sun blocking agents or tropics, pre- and post-sunscreen products;

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 such as antiperspirant sticks, creams or spheres;

non-cleansing and cleansing agents, for example, soaps (solid or liquid), peeling or peeling agents or peeling masks;

chemical depilatory products, 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, shaving foams and gels, pre-shaving means, after-shave or after-shave lotions;

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

oral and dental hygiene compositions 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 example, hair shampoo formers, hair conditioners, hair care products, such as pre-treatment products, hair tonics, hair care creams and gels, pomades, hair rinse agents, deep care products, intensive hair care products (hot waving, mild waving, cold waving), hair straighteners, liquid hair fixatives, hair mousses, lightening agents such as hydrogen peroxide solutions, lightening shampoos, lightening creams, lightening powders, lightening pastes or oils, short-term, semi-long-lasting or permanent hair dyes, compositions containing auto-oxidative dyes or natural hair dyes such as henna or blush.

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

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

0.3 to 1% by weight of titanium dioxide, up to 10% by weight of stearic acid, to 100% by weight of a soap base, for example sodium tallow and coconut fatty acid or glycerols.

·····························

For example, the shampoo composition is:

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

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

4,0% by weight of cocamidopropylbetaine,

3.0% by weight sodium chloride, and up to 100% water.

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

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

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

An example of an oil-in-water emulsion:

(A)

0.01 to 5% by weight of a compound of formula 1,% by weight glyceryl stearate,% by weight paraffin oil,% by weight caprylic / capric acid triglyceride,% by weight glycerol,

0,2% by weight of ECTA disodium salt,

1.0% by weight of citric acid (20%), and

65.8 to 70.8% by weight of science.

(B)

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

3.5% PEG-30 dipolyhydroxystearate,

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

0.2% by weight of EDTA disodium salt,

3.4% glycerol, and

69.9 to 74.9% by weight of water.

In a further aspect, the present invention relates to an oral composition comprising 0.01 to 15% by weight of a compound of general formula (II). The formula 1 based on the total weight of the composition as well as the orally compatible ingredient.

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 a compound of formula 1, and 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 fluoride-ion-releasing compounds that are effective against dental caries, for example inorganic fluoride salts such as sodium, potassium, ammonium or calcium fluorides, or organic fluorides such as ammonium fluorides which are known in the art. under the tradename 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 or 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, rope, jute and hemp and cellulose and regenerated cellulose.

The compounds of formula I, alone or in combination with other antimicrobial agents, are also suitable for the preservation of cosmetics such as shampoos, bath additives, for the treatment of cosmetics. 9 Hair Care, Liquid and Solid Soaps (based on Synthetic Surfactants and Loans) 9 · · · ··· ······· · ········· saturated and / or unsaturated fatty acids); liquid and solid detergents and plasticizers.

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

The novel compounds of the formula I can also be treated with antimicrobial paper, for example sanitary paper.

According to the present invention, non-woven materials such as diapers, sanitary towels and cotton, napkins for sanitary and household use can also be treated antimicrobially.

In particular, the hydroxyphenyl-1,3-propanediones can also be used in households 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% polyglucoside of a C8-C8 fatty alcohol, ··· ·· ·· · ·· ·

3.0% isopropanol, and up to 100% water.

In addition to the preservation of cosmetics and household care products, technical products such as paper-based lacquers, printing thickeners containing starch or cellulose derivatives, coloring systems and paints can be preserved and antimicrobially treated.

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

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

DETAILED DESCRIPTION OF THE INVENTION

Example

reacting

Reaction step 1a of the scheme:

(101b) (101b)

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 4 ° 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 continues to the dia trichloro derivative degree (content of the dichloro derivative is 80%, and the chlorinated derivative content is 80%), The trichlorinated derivative content (20%), the reaction mixture can be directly used for acylation.

Example 2

Acylation (second reaction step):

'Reaction scheme:

(101c) (101c)

To 520 g of ethylene chloride was added 250 g of aluminum chloride at 20-25 ° C with stirring. 170 g of acetyl chloride are added dropwise over a period of 15 to 20 minutes at 25 to 40 ° C and the mixture is stirred for 10 minutes at 40 ° C. A solution of 239 g of 4,4'-dichlorodiphenyl ether in 400 g of ethylene chloride was added dropwise over 1 hour. The reaction mixture is kept for 4 hours at 40 ° C (± 2 ° C) and then added with stirring to a mixture of 2500 ml of ice water and 350 ml of 34% hydrochloric acid. 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) was dissolved in 10 ° C g of isopropyl alcohol at 70 ° C and purified by filtration with a little activated carbon. 350 ml of water are added at 60 ° C with stirring. The solution is cooled slowly, crystallization is induced by seeding with crystals at 45 ° C. The solution is stirred for 15 hours and the crystals are 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 having a melting point of 65-66 ° C are obtained.

··················································· · · · · · ·

Example 3

Bayer-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 over 30 minutes. This reaction solution was added dropwise at 20-25 ° C over 1 hour to a solution of 70 g of acetylated compound 101c in 180 g of acetic acid (100%) and 87 g of concentrated sulfuric acid. The mixture was stirred for 3 hours at 20-25 ° C and slowly warmed to 45 ° C to complete the hydrolysis of the phenyl ester of formula 10ld. This temperature is maintained for 2 hours and the reaction mixture is added to a mixture containing 130 g of water and 360 g of toluene such that the final temperature is 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, the pure product is obtained in the form of colorless crystals, m.p. 74-75 ° C.

Claims (18)

PATENT CLAIMS Process for the preparation of a 4,4'-dihalogen-o-hydroxydiphenyl compound of the general formula 1, characterized in that in step 1a the diphenyl compound is halogenated or in step 1b is reacted, p-halophenol with p-longbenzene in the presence of copper and / or copper salts; in a second step, the dihalogenated compound is acylated using a 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: hydrolysis T OH where R is an alkyl group having 1 to 8 carbon atoms which is an alkyl group having 1 to 8 carbon atoms; Unsubstituted or substituted by 1 to 3 halogen atoms or hydroxyl groups; unsubstituted (C 6 -C 12) aryl; or (C 6 -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. Method according to claim 1, characterized in that R is an alkyl group having 1 to 4 carbon atoms. Method according to claim 2, characterized in that R is methyl. 4th process by any of claims 1 to 3 , confess- ignating sa t atom halogen is atom chlorine. 5th process by claim 4, you z n a č u j ú c i by The process according to claim 1, wherein the chlorination step 1a is carried out using elemental chlorine. The process according to claim 5, characterized in that the chlorination is carried out in the presence of a mixture comprising propyl sulfide and an equimolar amount of aluminum chloride. Process according to any one of claims 1 to 6, characterized in that the copper catalyst used in step 1b is copper oxide, copper oxide, copper carbonate, basic copper carbonate, copper chloride, copper chloride, copper bromide, copper bromide or copper sulfate. . ······················································· ··· ·· Process according to any one of claims 1 to 7, characterized in that the second step acylation reaction is carried out in the presence of acetyl chloride and aluminum chloride, which are used in equimolar amounts. The process 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. The process according to any one of claims 1 to 10, wherein the oxidation in the third step is carried out using a mixture comprising concentrated sulfuric acid, anhydrous acetic acid and hydrogen peroxide as a 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 by the methods of any one of claims 1 to 12 to protect organic materials and objects from attack by microorganisms. 14. Use of a compound of general 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 I in detergents and cleaners. · J • J J J J J J J J J J J J J J J J J J J · · J J J · · · · J • · ·· · 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 of the compound of formula I, based on the total weight of the composition, as well as cosmetically compatible ingredients. An oral composition comprising 0.01 to 15% by weight of the compound of formula 1, based on the total weight of the composition, as well as orally compatible ingredients.