WO2003031382A2

WO2003031382A2 - Process for the preparation of hydroxydiphenyl ether compounds

Info

Publication number: WO2003031382A2
Application number: PCT/EP2002/010996
Authority: WO
Inventors: Dieter Reinehr; Werner HÖLZ; Frédéric Brunner; Sonja Riesterer; Rolf Felker
Original assignee: Ciba Specialty Chemicals Holding Inc.
Priority date: 2001-10-09
Filing date: 2002-10-01
Publication date: 2003-04-17
Also published as: AU2002350473A1; WO2003031382A3

Abstract

There is described a process for the preparation of hydroxydiphenyl ether compounds of formula by acylation of a halogenated benzene compound (first step), etherification of the acylated compound with a phenol compound (second step), oxidation of the etherified compound (third step) and hydrolysis of the oxidised compound in a fourth step, corresponding to the following reaction scheme: wherein R1 and R2 are each independently of the others F, CI or Br; R3 and R4 are each independently of the other hydrogen ; or C1-C4alkyl; m is from 1 to 3; and n is 1 or 2. The compounds of formula (1) are used for protecting organic materials and articles from micro-organisms.

Description

Process for the preparation of hvdroxydiphenyl ether compounds

The present invention relates to the preparation of hydroxydiphenyl ether compounds of formula

wherein

Rι, R₂ and R₃ are each independently of the others hydrogen; hydroxy; unsubstituted or hydroxy-substituted CrC₂oall<yl or CrC₂oall<oxy; C₅-C₇cycloalkyl; CrC₆alkylcarbonyl; phenyl; or phenyl-C_rC₃alkyl; and R₄ is hydrogen; unsubstituted or hydroxy-substituted CrC₂₀alkyl; hydroxy; C₅-C₇cycIoalkyl; formyl; acetonyl; C C₆alkylcarbonyI; C₂-C₂₀alkenyl; carboxy; carboxy-CrC₃alkyl;

C Csalkylcarbonyl-CrCaalkyl; or carboxyallyl, and to the use of such compounds as disinfecting agents for protecting organic materials from micro-organisms.

The process according to the invention is a four-step reaction in which in a first step a halogenated benzene compound is acylated, in a second step the acylated compound is etherified with a phenol compound, in a third step the etherified compound is oxidised and in a fourth step the oxidised compound is hydrolysed, in accordance with the following reaction scheme:

4. hydrolysis

(1)

In the above scheme,

R is hydrogen; CrC₂₀alkyI; halo-CrC₂₀alkyl; or C₆-Cι₀aryl;

Rι. R₂. R₃ and R are as defined for formula (1).

CrC₂₀AIkyl radicals are straight-chain or branched alkyl radicals such as, for example, methyl, ethyl, n-propyl, isobutyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, nonadecyl and icosyl.

CrC₂₀Alkoxy radicals are straight-chain or branched alkoxy radicals such as, for example, methoxy, ethoxy, n-propoxy, isobutoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tetradecyloxy, nonadecyloxy and icosyloxy.

CrC₆Alkylcarbonyl radicals are straight-chain or branched carbonyl radicals such as, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl and the like.

In the first reaction step (acylation reaction) compounds of formula (3) are prepared. That reaction is usually carried out in the presence of a Lewis acid such as, for example, an aluminium halide, especially aluminium chloride, the Lewis acid being used in a from 1- to 3- molar amount , preferably in a from 1.25- to 2-molar amount, based on the halogenated compound of formula (2). An acyl halide, especially acetyl chloride, is a suitable acylating reagent for the reaction.

The Lewis acid and acylating reagent are used in the reaction preferably in equimolar amounts. The reaction is carried out in the solvents customary for Friedel-Crafts reactions such as, for example, methylene chloride and ethylene chloride. The reaction time is of secondary importance for this reaction step and can vary within a wide range of, for example, from 1 to 18 hours.

The acyl compound is isolated and then further reacted.

In the second reaction step, the compounds of formula (5) are prepared. Etherification of the free OH group of the phenol compound of formula (4) is usually carried out in an alkaline medium using an organic or, preferably, inorganic base such as, for example, a hydroxide of an alkali or alkaline earth metal, preferably NaOH or KOH, a carbonate or hydrogen carbonate of an alkali metal or alkaline earth metal, preferably Na₂CO₃ or K₂CO₃, a tertiary phosphate of an alkali meal or alkaline earth metal, preferably l<₃PO₄, an organic base such as, for example, pyridine or an alkyl derivative thereof and, optionally, in the presence of a catalyst. Suitable catalysts are, preferably, transition metals or salts thereof, especially Cu, Ni, Pd, more especially Cu or Cu(ll) and Cu(l) salts such as, for example, oxides, chlorides, acetates, carbonates and Pd, PdCI₂, Pd(OAc)₂ and complexes thereof with neutral organic ligands, as described in the literature (for example Angew. Chemie 1999, 111, 3509), preferred ligands being tert-phosphanes having bulky substituents, for example 2-(di-tert- butyl-phosphanyl)-phenyl-benzene.

The second reaction step is preferably carried out in the presence of an inert organic solvent such as, for example, DMF, dimethylacetamide, toluene, xylene or a xylene isomer mixture. The reaction times for this reaction step are usually from 1 to 24 hours, preferably from 2 to 10 hours; the temperature ranges from 80 to 250°C, preferably from 100 to 150°C.

The molar ratio of phenol compound:base is from 5:1 to 0.5:1, preferably from 2:1 to 0.5:1. In the third reaction step (oxidation) compounds of formula (6) are prepared. Oxidation of the ether compound of formula (5) to form the compound of formula (6) (Baeyer-Villiger oxidation) can be carried out using various oxidising agents. Suitable oxidising agents are, for example: a mixture of dilute peracetic acid and acetic anhydride in the presence of a catalytic amount of perchloric acid; m-chloroperbenzoic acid (MCPBA) in water; diperoxydodecanedioic acid (DPDDA); a mixture of dilute peracetic acid and acetic anhydride and sulfuric acid; perbenzoic acid (PBA) a mixture of sodium borate 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 hydrogen peroxide/sulfuric acid/acetic acid; a mixture of K₂S₂O_8> sulfuric acid and a 1 :1 water/methanol mixture; a mixture of acetic acid and the potassium salt of monoperoxomaleic acid; a mixture of trichloromethyane, the potassium salt of monoperoxomaleic acid and sodium hydrogen sulfate; a mixture of maleic anhydride, acetic anhydride, hydrogen peroxide and trichloromethane; a mixture of maleic anhydride, a urea-hydrogen peroxide complex and acetic acid; magnesium monoperphthalate; a mixture of acetic anhydride, sulfuric acid and H₂O₂; a mixture of dichloroacetic acid and H₂O₂.

Preference is given to the use of m-chloroperbenzoic acid (MCPBA) or a mixture of hydrogen peroxide/sulfuric acid/acetic acid for the oxidation.

Where appropriate, a commercially available wetting agent may also be added to the oxidising agent. The reaction times lie over a wide range and extend from about 0.5 to about 15 hours, preferably from 1 to 8 hours. The reaction temperature ranges from -20 to about 100°C, preferably from 0 to about 85°C. The subsequent hydrolysis to form the desired hydroxydiphenyl ether of formula (1) (4th reaction step) is carried out quantitatively in an acid or alkaline medium.

The process according to the invention preferably comprises the preparation of hydroxydiphenyl ether compounds of formula (1) wherein

R_L R₂ and R₃ are each independently of the others hydrogen; CrC₂₀alkyl; C₅-C₇cycloalkyl;

Cι-C₆alkylcarbonyl; or CrCaoalkoxy; and R₄ is hydrogen; unsubstituted or hydroxy-substituted C₁-C₂₀alkyl; hydroxy; C₅-C₇cycloalkyl; formyl; acetonyl; CrCβalkylcarbonyl; or C₂-C₂₀alkenyl.

Special preference is given to compounds of formula (1) wherein

R_L R₂ and R₃ are each independently of the others hydrogen; C_rC₂₀alkyl; or CrC₂₀alkoxy; and

R is hydrogen, at least one of the radicals R_1t R₂ or R₃ not being hydrogen, or more especially to compounds of formula (1) wherein at least one of the radicals R^ R₂ or R₃ is d-C₂₀alkyl.

Preference is given to compounds of formula (1) wherein

Ri and R₃ are each independently of the other CrC₂₀aIkyl, especially CrC₅alkyl and

R₂ and R₄ are hydrogen.

Very especially preferred compounds correspond to formula

Ri and R₃ are each independently of the other C C₂₀alkyl.

Preference is given furthermore to the following compounds:

The diphenyl ether compounds prepared in accordance with the invention are insoluble in water but are soluble to a greater or lesser extent in dilute sodium or potassium hydroxide solution and in practically all organic solvents. By virtue of those solubility characteristics their suitability for use in the control of micro-organisms, especially bacteria, fungi and yeasts, and as disinfecting agents for protecting organic materials and articles from attack by micro-organisms is very wide-ranging. They are accordingly suitable especially for disinfection, deodorisation, and for general and antimicrobial treatment of the skin and mucosa and of integumentary appendages (hair), more especially for the disinfection of hands and wounds.

They are accordingly suitable as antimicrobial active substances and preservatives in personal care preparations such as, for example, shampoos, bath additives, haircare preparations, liquid and solid soaps (based on synthetic surfactants and salts of saturated and/or unsaturated fatty acids), lotions and creams, deodorants, other aqueous or alcoholic solutions, e.g. cleansing solutions for the skin, moist cleansing cloths, oils or powders.

A personal care preparation contains from 0.01 to 15 % by weight, preferably from 0.1 to 10 % by weight, based on the total weight of the composition, of a compound of formula (1), and cosmetically tolerable adjuvants.

Depending upon the form of the personal care preparation, it comprises, in addition to the diphenyl ether compound of formula (1), further constituents such as, for example, sequestering agents, colorants, perfume oils, thickening or solidifying agents (consistency regulators), emollients, UV-absorbers, skin protective agents, antioxidants, additives that improve the mechanical properties, such as dicarboxylic acids and/or aluminium, zinc, calcium or magnesium salts of Cι₄-C₂₂fatty acids.

The personal care preparation may be in the form of a water-in-oil or oil-in-water emulsion, an alcoholic or alcohol-containing formulation, a vesicular dispersion of an ionic or non-ionic amphiphilic lipid, a gel, a solid stick or an aerosol formulation.

As a water-in-oil or oil-in-water emulsion, the cosmetically tolerable adjuvant contains preferably from 5 to 50 % of an oil phase, from 5 to 20 % of an emulsifier and from 30 to 90 % water. The oil phase may comprise any oil suitable for cosmetic formulations, for example one or more hydrocarbon oils, a wax, a natural oil, a silicone oil, a fatty acid ester or a fatty alcohol. Preferred mono- or poly-ols are ethanol, isopropanol, propylene glycol, hexylene glycol, glycerol and sorbitol.

The cosmetic formulations are used in various fields. There come into consideration, for example, especially the following preparations: skin-care preparations, e.g. skin-washing and cleansing preparations in the form of tablet-form or liquid soaps, synthetic detergents or washing pastes, bath preparations, e.g. liquid (foam baths, milks, shower preparations) or solid bath preparations, e.g. bath cubes and bath salts; skin-care preparations, e.g. skin emulsions, multi-emulsions or skin oils; cosmetic personal care preparations, e.g. facial make-up in the form of day creams or powder creams, face powder (loose or pressed), rouge or cream make-up, eye-care preparations, e.g. eyeshadow preparations, mascaras, eyeliners, eye creams or eye-fix creams; lip-care preparations, e.g. lipsticks, lip gloss, lip contour pencils, nail-care preparations, such as nail varnish, nail varnish removers, nail hardeners or cuticle removers; intimate hygiene preparations, e.g. intimate washing lotions or intimate sprays; foot-care preparations, e.g. foot baths, foot powders, foot creams or foot balsams, special deodorants and antiperspirants or callus-removing preparations; light-protective preparations, such as sun milks, lotions, creams or oils, sun-blocks or tropicals, pre-tanning preparations or after-sun preparations; skin-tanning preparations, e.g. self-tanning creams; depigmenting preparations, e.g. preparations for bleaching the skin or skin-lightening preparations; insect-repellents, e.g. insect-repellent oils, lotions, sprays or sticks; deodorants, such as deodorant sprays, pump-action sprays, deodorant gels, sticks or roll-ons; antiperspirants, e.g. antiperspirant sticks, creams or roll-ons; preparations for cleansing and caring for blemished skin, e.g. synthetic detergents (solid or liquid), peeling or scrub preparations or peeling masks; hair-removal preparations in chemical form (depilation), e.g. hair-removing powders, liquid hair-removing preparations, cream- or paste-form hair-removing preparations, hair-removing preparations in gel form or aerosol foams; shaving preparations, e.g. shaving soap, foaming shaving creams, non-foaming shaving creams, foams and gels, preshave preparations for dry shaving, aftershaves or aftershave lotions; fragrance preparations, e.g. fragrances (eau de Cologne, eau de toilette, eau de parfum, parfum de toilette, perfume), perfume oils or perfume creams; dental care, denture-care and mouth-care preparations, e.g. toothpastes, gel toothpastes, tooth powders, mouthwash concentrates, anti-plaque mouthwashes, denture cleaners or denture fixatives; cosmetic hair-treatment preparations, e.g. hair-washing preparations in the form of shampoos, hair conditioners, hair-care preparations, e.g. pretreatment preparations, hair tonics, styling creams, styling gels, pomades, hair rinses, treatment packs, intensive hair treatments, hair-structuring preparations, e.g. hair-waving preparations for permanent waves (hot wave, mild wave, cold wave), hair-straightening preparations, liquid hair- setting preparations, hair foams, hairsprays, bleaching preparations, e.g. hydrogen peroxide solutions, lightening shampoos, bleaching creams, bleaching powders, bleaching pastes or oils, temporary, semi-permanent or permanent hair colorants, preparations containing self-oxidising dyes, or natural hair colorants, such as henna or camomile.

An antimicrobial soap has, for example, the following composition:

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

0.3 to 1 % by weight titanium dioxide,

1 to 10 % by weight stearic acid, soap base ad 100 %, e.g. a sodium salt of tallow fatty acid or coconut fatty acid, or glycerol.

A shampoo has, for example, the following composition: 0.01 to 5 % by weight of a compound of formula (1), 12.0 % by weight sodium laureth-2-sulfate, 4.0 % by weight cocamidopropyl betaine, 3.0 % by weight NaCI and water ad 100 %.

A deodorant has, for example, the following composition:

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

60 % by weight ethanol,

0.3 % by weight perfume oil, and water ad 100 %.

An oral composition contains 0.01 to 15 % by weight, based on the total weight of the composition, of a compound of formula (1), and orally tolerable adjuvants.

Example of an oral composition:

10 % by weight sorbitol,

10 % by weight glycerol,

15 % by weight ethanol,

15 % by weight propylene glycol,

0.5 % by weight sodium lauryl sulfate,

0.25 % by weight sodium methylcocyl taurate,

0.25 % by weight polyoxypropylene/polyoxyethylene block copolymer,

0.10 % by weight peppermint flavouring,

0.1 to 0.5 % by weight of a compound of formula (1), and

48.6 % by weight water.

The oral composition according to the invention may be, for example, in the form of a gel, a paste, a cream or an aqueous preparation (mouthwash).

The oral composition according to the invention may also comprise compounds that release fluoride ions which are effective against the formation of caries, for example inorganic fluoride salts, e.g. sodium, potassium, ammonium or calcium fluoride, or organic fluoride salts, e.g. amine fluorides, which are known under the trade name Olafluor.

The diphenyl ether compounds of formula (1) prepared in accordance with the invention are also suitable for treating, especially preserving, textile fibre materials. Such materials are undyed and dyed or printed fibre materials, e.g. of silk, wool, polyamide or polyurethanes, and especially cellulosic fibre materials of all kinds. Such fibre materials are, for example, natural cellulose fibres, such as cotton, linen, jute and hemp, as well as cellulose and regenerated cellulose. Preferred suitable textile fibre materials are made of cotton.

The diphenyl ether compounds prepared in accordance with the invention are suitable also for treating, especially imparting antimicrobial properties to or preserving, plastics, e.g. polyethylene, polypropylene, polyurethane, polyester, polyamide, polycarbonate, latex etc.. Fields of use therefor are, for example, floor coverings, plastics coatings, plastics containers and packaging materials; kitchen and bathroom utensils (e.g. brushes, shower curtains, sponges, bathmats), latex, filter materials (air and water filters), plastics articles used in the field of medicine, e.g. dressing materials, syringes, catheters etc., so-called "medical devices", gloves and mattresses.

Paper, for example papers used for hygiene purposes, may also be provided with antimicrobial properties using the diphenyl ether compounds prepared in accordance with the invention.

It is also possible for nonwovens, e.g. nappies/diapers, sanitary towels, panty liners, and cloths for hygiene and household uses, to be provided with antimicrobial properties in accordance with the invention.

The diphenyl ether compounds of formula (1) prepared in accordance with the invention are also used in washing and cleaning formulations, e.g. in liquid or powder washing agents or softeners.

The diphenyl ether compounds of formula (1 ) prepared in accordance with the invention can also be used especially in household and general-purpose cleaners for cleaning and disinfecting hard surfaces.

A cleaning preparation has, for example the following composition:

0.01 to 5 % of a compound of formula (1)

3.0 % octyl alcohol 4EO

1.3 % fatty alcohol C₈-C₁₀polyglucoside

3.0 % isopropanol water ad 100 %.

In addition to preserving cosmetic and household products, the preservation of technical products, the imparting of antimicrobial properties to technical products and use as a biocide in technical processes are also possible, for example in paper treatment, especially in paper treatment liquors, printing ink thickeners of starch or cellulose derivatives, surface-coatings and paints. The diphenyl ether compounds of formula (1) prepared in accordance with the invention are also suitable for the antimicrobial treatment of wood and for the antimicrobial treatment of leather, the preserving of leather and the imparting of antimicrobial properties to leather.

The compounds prepared in accordance with the invention are also suitable for the protection of cosmetic products and household products from microbial damage.

The following Examples illustrate, but do not limit, the present invention.

Preparation Examples

Example 1 : Reaction of 4-bromoacetophenone with 2-tert-butyl-5-methylphenol to form 4-(2- tert-butyl-5-methylphenoxy)-acetophenone (101) with Pd catalysis:

In a reaction apparatus provided with a dropping funnel, reflux condenser and stirrer, 1.3 ml (12 mmol) of 2-tert-butyl-5-methylphenol, 1.99 g (10 mmol) of 4-bromoacetophenone, 0.045 g (0.2 mmol) of Pd(OAc)₂, 0.091 g (0.3 mmol) of 2-(di-tert-butyl-phosphanyl)-phenyl- benzene and 4.24 g (20 mmol) of K₃PO.₁ are introduced, under nitrogen, into 30 ml of absolute toluene. The mixture is heated at reflux for 24 hours, with stirring; after cooling, 100 ml of diethyl ether are added and the organic phase is washed first with 100 ml of 1 M NaOH, then with 100 ml of 1M hydrochloric acid and finally with 100 ml of NaCI solution. After drying with Na₂SO₄ and drawing off the solvent, the compound of formula (101) is formed in good purity (> 95 % by area, GO).

Yield: 1.0 g (35 % of theory)

¹H NMR (CDCI,): 6.6-7.9 (m,7H,arom. H), 2.5 (s,3H,CH₃CO), 2.15 (s,3H,CH₃Ph), 1.25 (s,9H,C(CH₃)₃)

Example 2: Reaction of 4-bromacetophenone with 2-tert-butyl-5-methylphenol to form 4-(2- tert-butyl-5-methylphenoxy)-acetophenone (101) with Cu catalysis:

In a reaction apparatus provided with a dropping funnel, reflux condenser with water separator and stirrer, 164.3 g (1.00 mol) of 2-tert-butyl-5-methylphenol and 33.0 g (0.50 mol) of KOH (powder, 85%) are introduced, under nitrogen, into 400 ml of xylene. While heating at reflux, about 15 ml of water are removed in the course of 1.5 hours. Then, at 120°C, 99.1 g (0.50 mol) of 4-bromacetophenone and 0.6 g of basic CuCO₃ are added and the mixture is subsequently heated at reflux for 16 hours.

After cooling to 100°C, the reaction mass is treated with 100 ml of hot water and filtered. The aqueous phase is separated off and the organic phase is washed again, twice, using 100 ml of hot water each time.

Xylene and excess 2-tert-butyl-5-methylphenol are removed by vacuum distillation.

The product residue is distilled in vacuo in a short-path distillation apparatus.

Yield: 50.0 g (35 % of theory)

¹H NMR: identical to reference

Example 3: Reaction of 4-fluoroacetophenone with 2-tert-butyl-5-methylphenol to form 4-(2- tert-butyl-5-methylphenoxy)-acetophenone (A)

(101)

In a reaction apparatus provided with a dropping funnel, reflux condenser and stirrer, 16.7 g (100 mmol) of 2-tert-butyl-5-methylphenol, 14.1 g (100 mmol) of 4-fluoroacetophenone and 14.9 g (120 mmol) of K₂CO₃ are introduced, under nitrogen, into 100 ml of absolute N,N- dimethylacetamide. The batch is heated at 140°C for 6 hours, with stirring. After cooling, 60 ml of water and 50 ml of 4M hydrochloric acid are added, and extraction is carried out using 100 ml of chloroform. The organic phase is washed 6 times using 50 ml of water and dried. After drawing off the solvent, the product is isolated by distillation.

(B.p. 155 - 165°C (0.3 mbar))

Yield: 7.5 g (27 % of theory)

¹H NMR: identical to reference Example 4: Reaction of 4-fluorobenzaldehvde with 2-tert-butyl-5-methylphenol to form 4-(2- tert-butyl-5-methylphenoxy)-benzaldehvde (102):

(102)

In a reaction apparatus provided with a dropping funnel, reflux condenser and stirrer, 16.7 g (100 mmol) of 2-tert-butyl-5-methylphenol, 12.7 g (100 mmol) of 4-fluorobenzaldehyde and 14.9 g (120 mmol) of K₂CO₃ are introduced, under nitrogen, into 100 ml of absolute N,N- dimethylacetamide. The batch is heated at 140°C for 5 hours, with stirring. After cooling, 100 ml of water are added, extraction is carried out 4 times using 50 ml of chloroform each time, and the combined organic phases are dried over MgSO₄. The product is isolated by distillation (b.p. 114 - 129°C/0.05 mbar). Yield: 7.5 g (28 % of theory) ¹H NMR (DMSO-ds): 9.91 (s,1H,CHO), 6.71-7.98 (m,7H, arom. H), 2.22 (s,3H,CH₃); 1.29

(s,9H,C(CH₃)₃) ¹³C NMR (DMSO-d_R): 191.7 (CHO), 117.8 - 163.1 (arom. C), 34.4 (C(CH₃)₃), 30.5

(C(CH₃)₃), 20.5 (CH₃)

Example 5: Alternative synthesis of 4-(2-tert-butyl-5-methylphenoxy)-phenol Reaction scheme:

(101)

(103) 1st step: Ullmann condensation

In a reaction flask, water is removed azeotropically from 132 g (2.00 mol) of potassium hydroxide 85 % and 670 g (4.00 mol) of 2-tert-butyl-5-methyl-phenol 98 % in the presence of 344 g of xylene isomer mixture. About 55 ml of water are removed up to Tj (Tj = internal temperature) 158°C.

At Tj = 140°C, 398 g (2.00 mol) of 4-bromo-acetophenone and 4 g of basic copper(ll) carbonate are added. The reaction mass is subsequently stirred at Tj = 150°C for 17 hours. (GC analysis: 4-bromacetophenone < 1 % by area).

At Tj = 100°C, 400 ml of water are added and the mixture is clarified through filter paper. The reaction flask and the suction filter are subsequently rinsed with 100 g of xylene isomer mixture.

The lower, aqueous phase is separated off from the clarified reaction mixture at Tj = 90°C.

Xylene is distilled off in vacuo from the upper, organic phase using a rotary evaporator.

Excess 2-tert-butyl-5-methyl-phenol is distilled off at 0.6 mbar at T = about 76°C.

The crude product is distilled in a short-path distillation apparatus in the presence of 5 % polyethylene glycol 800 (T_e = 160°C (T_θ= external temperaure), Tj = 70°C under a vacuum of 0.1 mbar).

Yield: 345 g of the compound of formula (101); yellow oil (61 % of theory)

2nd step: Baever-Villiαer oxidation

1) Preparation of the Baever-Villiqer charge

In a cooled reaction flask, 345 g (1.22 mol) of the distilled intermediate are dissolved at Ti = 60°C in 540 g (8.99 mol) of anhydrous acetic acid. The solution is cooled to 25°C, and 246 g (2.40 mol) of sulfuric acid 96 % are added dropwise at Tj = 25°C.

2) Preparation of the Baever-Villiqer reagent

In a cooled glass receptacle, 122.4 g (1.20 mol) of sulfuric acid 96 % are metered into 360 g (6.00 mol) of anhydrous acetic acid at Tj = 15-20°C. Then 127.8 g (1.87 mol) of hydrogen peroxide 50 % are metered in at T-, = 15-20°C in the course of 30 minutes. The solution is subsequently stirred at Ti = 20°C for 1 hour. 3) Baever-Villiqer reaction

The Baeyer-Villiger reagent 2) is evenly metered into the charge 1) at Ti = 20-30°C in the course of 2 hours (strong exotherm). After metering-in, the reaction mixture is heated to 40°C in the course of 1 hour and is subsequently stirred at Tj = 40°C for 1 hour and then at Ti = 50°C for 30 minutes.

4) Quenching and isolation

2000 ml of water and 1000 g of petroleum ether (80-110) are introduced into a reaction flask at T. = 50°C. The reaction mass 3) is metered into the stirred petroleum/water mixture in the course of 10 minutes at T, = 50-55°C.

The lower, aqueous phase is separated off at Tj = 50°C and the upper, organic phase is washed three times using 1000 ml of water each time.

The product phase is washed again, with 1000 ml of NaOH/water at pH = 9.5.

Petroleum ether is distilled off using a rotary evaporator.

The crude mass is distilled in a short-path distillation apparatus in the presence of 5 % polyethylene glycol 800 (T_θ = 170°C, Ti = 98°C under a vacuum of 0.1 mbar).

233 g of the compound of formula (103) are obtained in the form of a yellow melt.

The yellow distillate is crystallised from 1000 g of petroleum ether 80-110, filtered off and washed with cold solvent.

Yield: 165 g of white crystals (53 % of theory); m.p. 99-100°C.

Overall yield over the 2 synthesis steps: 32 % of theory

Claims

What is claimed is:

1. A process for the preparation of a hydroxydiphenyl ether compound of formula

by acylation of a halogenated benzene compound (first step), etherification of the acylated compound with a phenol compound (second step), oxidation of the etherified compound (third step) and hydrolysis of the oxidised compound in a fourth step, corresponding to the following reaction scheme:

4. hydrolysis

wherein

R_L R₂ and R₃ are each independently of the others hydrogen; hydroxy; unsubstituted or hydroxy-substituted C C₂₀alkyl or CrC₂₀alkoxy; C₅-C₇cycloalkyl; C C₆alkylcarbonyl; phenyl; or phenyl-C C₃alkyl; and R₄ is hydrogen; unsubstituted or hydroxy-substituted Cι-C₂₀alkyl; hydroxy; C₅-C₇cycloalkyl; formyl; acetonyl; CrC₆alkylcarbonyl; C₂-C₂₀alkenyl; carboxy; carboxy-CrC₃alkyl;

CrCaalkylcarbonyl-CrCsalkyl; or carboxyallyl.

2. A process according to claim 1 , wherein the acylation reaction (first step) is carried out in the presence of a Lewis acid.

3. A process according to either claim 1 or claim 2, wherein an acyl halide is used for the acylation reaction.

4. A process according to any one of claims 1 to 3, wherein the etherification of the free OH group of the phenol compound of formula (4) is carried out in an alkaline medium.

5. A process according to claim 4, wherein the reaction is carried out using Na₂CO₃ or K₂CO₃.

6. A process according to any one of claims 1 to 5, wherein the etherification of the free OH group of the phenol compound of formula (4) is carried out using a catalyst selected from the transition metals and salts of Cu, Ni and Pd.

7. A process according to any one of claims 1 to 6, wherein the molar ratio of phenol compound:base is from 5:1 to 0.5:1.

8. A process according to any one of claims 1 to 7, wherein the oxidation is carried out in the presence of m-chloroperbenzoic acid.

9. A process according to any one of claims 1 to 7, wherein the oxidation is carried out in the presence of a mixture of sodium borate and trifluoroacetic acid.

10. A process according to any one of claims 1 to 9, comprising the preparation of a hydroxydiphenyl ether compound of formula (1) wherein

Ri, R₂ and R₃ are each independently of the others hydrogen; CrC₂₀alkyl; C₅-C₇cycloalkyl;

CrC₆alkylcarbonyl; or C C₂₀alkoxy; and R₄ is hydrogen; unsubstituted or hydroxy-substituted d-C_∑oalkyl; hydroxy; C₅-C₇cycloalkyl; formyl; acetonyl; CrC₆alkylcarbonyl; or C₂-C₂₀alkenyl.

11. A process according to claim 10, comprising the preparation of a compound of formula (1) wherein R and R₃ are each independently of the other C_t-C^alkyl, and R₂ and R are hydrogen.

12. A process according to claim 11, comprising the preparation of a compound of formula (1 ) wherein

Ri and R₃ are each independently of the other C Csalkyl.

13. A process according to claim 11 , comprising the preparation of a compound of formula

Ri and R₃ are each independently of the other CrC₂₀alkyl.

14. Use of a compound prepared in accordance with the process according to any one of claims 1 to 13 as a disinfecting agent for protecting organic materials from attack by microorganisms.