WO1999010310A1

WO1999010310A1 - Process for producing diphenylethers and esters

Info

Publication number: WO1999010310A1
Application number: PCT/US1998/017873
Authority: WO
Inventors: Gerhardus Johannes Lourens
Original assignee: The Dow Chemical Company
Priority date: 1997-08-29
Filing date: 1998-08-28
Publication date: 1999-03-04
Also published as: EP1007501A1; AU9124798A

Abstract

An improved synthesis of diphenylethers, and in particular, the bacteriostat 2,4,4'-trichloro-2'-hydroxydiphenylether, is described wherein 2'-acetyl-2,4,4'-trichlorodiphenylether is oxidised under Baeyer-Villiger conditions to produce 2'-acetoxy-2,4,4'-trichlorodiphenylether in near quantitative yield. Best oxidative conditions include the use of anhydrous permaleic acid produced in situ. The ester is purified readily by simple recrystallization, as no dibenzofurans and only minor amounts of byproducts are formed in the process. The ester is converted into the desired halogenated phenolic diphenylether, 2,4,4'-trichloro-2'-hydroxydiphenylether, by hydrolysis or transesterification. The final product is purified to a high degree by vacuum distillation and crystallization to meet current purity standards for approved applications.

Description

PROCESS FOR PRODUCING DIPHENYLETHERS AND ESTERS

The bacteriostat 2,4,4'-trichloro-2'-hydroxydiphenylether and its esters, covered by US Pat. No. 3, 506, 720 (1966) and US Pat. No. 3, 629, 477 (1967), are well established for use in soaps, cosmetics, detergents and other personal care formulations. The established synthetic route, improved through additional patents on purification procedures (US Pat. No. 4, 467, 1 17 (1984) and US Pat. No. 4, 486, 610 (1984), and Eur. Pat. No. 86745 (1983)) suffers from the fact that large quantities of chlorinated dibenzofurans are produced during the acid catalyzed hydrolysis of an intermediate diazonium salt formed from 2,4,4'-trichloro-2-aminodiphenylether (TADE) thereby requiring elaborate purification procedures. Furthermore, large quantities of acid effluent require further treatment in the known process.

The fundamental steps of the known process are shown in Scheme I below:

SCHEME I

Purification

TRICLOSAN (2,4,4'-trichloro-2'-hydroxydiphenylether) Some noteworthy features of the patented synthetic steps are:

1 ) Nitration of 1 ,4-dichlorobenzene gives one main product, 2,5-dichloronitrobenzene. The electron-withdrawing nitro-group activates the ortho-chlorine for selective nucleophilic displacement; the meta-chlorine is not activated.

2) The diphenylether is formed in good yield due to the activating effect of the nitro-group. Some dioxins may form under the conditions of condensation.

3) Reduction of the nitro-group can be effected in many ways, for example catalytic hydrogenation, or by reduction with hydrazine.

4) Diazotization.

5) Hydrolysis of the diazonium salt requires relatively high temperatures in concentrated acid. These conditions create large volumes of undesirable acid effluent, large amounts of chlorinated dibenzofuran byproducts (up to 30 percent), and some chloro-substituted dioxins.

Trichlorodibenzofuran forms through nucleophilic arylation by the neighbouring phenyl group on the carbon bearing the diazonium group:

The problems of purifying the very crude product of the known synthetic process (Scheme I) are addressed in U.S. Pat. No. 4, 476, 1 17 (1984), U.S. Pat. No. 4, 486, 610 (1984) and Eur. Pat. 86745 (1983).

Users of triclosan require material that complies with the stringent specifications of purity that have been established during the lifetime of the cited patents. To attain the required levels of purity the following purification steps are essential:

1. The crude organic layer from the hydrolysis of the diazonium salt (Scheme I, step 5) is fractionally distilled.

2. The fraction distilling at 195 - 197°C/4mm is purified further:

(i) The product is dissolved in tetrachloroethylene.

(ii) The mixture is extracted with aqueous base at pH 13 to obtain an aqueous solution of the salts of the phenolic product (triclosan) as well as other contaminating phenol salts.

(iii) The layers are separated - the organic phase contains the non-phenolic impurities including the 2,4,8-trichlorodibenzofuran, which may be as much as 28 percent by mass of crude product.

(iv) The aqueous solution of the desired product is extracted with at least three further portions of trichloroethylene.

(v) The aqueous layer is neutralized to pH 5 - 7 which precipitates the free phenolic product as a bottom layer.

(vi) Final purification of this layer to produce material that conforms to the set specification requires:

a) residual solvent removal by stripping at 150°C/100mm;

b) vacuum steam stripping to remove any residual 2,4-dichlorophenol and 4- chlorophenol;

c) crystallization in water. Because of stringent quality specifications for 2,4,4'-trιchloro-2'-hydroxydιphenylether for use in personal care products and other dermal contact applications, a synthetic route that produces less byproduct waste and effluent and that requires less elaborate purification procedures was developed Comparative analytical data of a commercial sample of 2,4,4'- trιchloro-2'-hydroxydιphenylether produced by the diazonium route and a sample produced by the route that is the subject of this invention are shown in Table A It is clear that the two samples are of at least equal quality

This invention relates to a process for the production of the bacteπostat 2,4,4' tπchloro-2'-hydroxydιphenylether The process involves the oxidation of a 2'-acyl-2,4,4'- tπchlorodiphenylether to the corresponding 2-acyloxy derivative under Baeyer-Vilhger conditions The ester is transestenfied or hydrolyzed to the desired phenol Advantages of the process include high yields in the final synthetic steps, absence of dibenzofuran impurities and ease of purification of the product

According to a first aspect of this invention, a method is provided for the synthesis of an ester of the diphenylether of the general formula

in which R¹ is selected from H, linear or branched, substituted or unsubstituted, aliphatic or ahcyclic groups consisting of one to twenty carbon atoms, including linear or branched primary alkyl groups and aralkyl groups, and carboxyl groups having the formula -C0₂R" wherein R" is H, alkyl, alkoxy, aryloxy Examples of R¹ include substituted or unsubstituted methyl, ethyl, propyl, isopropyl, isobutyl, butyl, pentyl, cyclopentyl and cyclohexyl groups Suitable substituents are those that allow the oxidation of the aryloxyphenylketone (or aldehyde) to an ester, such as carboxyl, carbalkoxy, carbamino, halogen, ammo, blocked ammo, nitro, hydroxyl, alkyloxy and aryloxy groups R², R³, R⁴ and R⁵ are selected from H, halogen, nitro, ammo, substituted am o, carboxyl and substituted or unsubstituted aliphatic groups. Suitable substituents again are those that allow the oxidation of the aryloxyphenylketone (or aldehyde) to an ester, such as carboyxl, carbalkoxy, carbamino, halogen, amino, blocked amino, nitro, hydroxyl, alkyloxy and aryloxy groups. Preferably R², R³, R⁴ and R⁵ are hydrogen or chloro, most preferably chloro. The method includes the oxidation of a substituted diphenylether aldehyde or ketone of the general formula:

in which R\ R², R³, R⁴ and R⁵ have the meanings given above, with a peroxy reagent such as a simple or complex peroxide, an alkylhydroperoxide, a dialkylperoxide (a peroxyether), an acylhydroperoxide (a peroxyacid), or a diacylperoxide (a peroxyanhydride), under conditions of oxidation, commonly known in the art as the Baeyer-Villiger oxidation, under neutral, basic or acidic conditions. Simple and complex peroxides include hydrogen peroxide and perborate and persulfate salts. Suitable alkylhydroperoxides icnlude isopropyl, triphenylmethyl- and tertiary butylhydroperoxide. The dialkylperoxide may be di-tert- butylperoxide. Suitable acylhydroperoxides include performic acid, peracetic acid, perpropionic acid, perbenzoic acid, substituted perbenzoic acid such as m-chloroperbenzoic acid, perphthalic acid, pertrifluoroacetic acid, perfumaric acid and permaleic acid. Diacylperoxides corresponding to the peracids listed may be selected.

According to a further aspect of the invention, the ketone to be oxidized, such as 2'-acyl-2,4,4'-trichloro-diphenylether, may be masked as a derivative of the aldehyde or ketone such as an acetal or a ketal group or an imino group, a ketalgroup, or an iminogroup that will undergo oxidation to an ester directly, or via an intermediate aldehyde or ketone formed in situ under the conditions of the reaction; the acetal or ketal will have the general formula:

in which R\ R², R³, R⁴ and R⁵ have the meanings as above and R⁶ and R⁷ may be linear or branched aliphatic groups such as methyl, ethyl, propyl or isobutyl groups, preferablyl methyl, ethyl or propyl, and may form part of a cyclic acetal or ketal structure of 5 or 6 members such as a dioxolane group or a 1 ,3-dioxane group, and the imino compound may have the general formula:

wherein R¹, R², R³, R⁴ and R⁵ may have the meanings as above and R⁶ includes alkoxy- groups such as methoxy and ethoxy.

The invention further includes the circumstances in which a diphenylether such as 2,4,4'-trichlorodiphenylether bearing an alkyl, substituted alkyl or carboxyalkyl substituent in the 2'-position may be oxidised, or be otherwise converted into a 2'-ketone prior to performance of the Baeyer-Villiger oxidation procedure. For example, the following scheme, starting with (2-(2',4'-dichlorophenoxy)-5-chlorophenyl) acetic acid or a suitablly blocked α-ketoacid, is within the scope of the present invention: SCHEME II The oxidative route to triclosan

The ester of the phenolic diphenylether may be 2'-acetoxy-2,4,4'- trichlorodiphenylether (triclosan acetate), which according to the general formula will require R¹ = CH₃, R² = 4'-chloro, R³= H, R⁴ = 2-chloro and R⁵ = 4-chloro. According to the method this ester is produced via the oxidation of 2'-acetyl-2,4,4'-trichlorodiphenylether (which is a known substance described by DC Atkinson ef al in Journal of Medicinal Chemistry 26 (1983) 1353 - 1360); Scheme II. Another aspect of the invention includes the further step of converting the ester of the phenolic diphenyl ether to the corresponding phenol, in particular the conversion of 2'-acetoxy-2,4,4'-trιchlorodιphenylether (triclosan acetate) to 2,4,4'-trιchloro-2'- hydroxydiphenylether (triclosan). The hydrolysis may be affected in aqueous solvents using an acidic catalyst such as a mineral acid, a sulphonic acid, a Lewis acid, or a solid acid such as an acidic ion exchange resin. Suitable mineral acids include hydrogen chloride, hydrogen bromide, sulphuric acid and nitric acid Suitable sulphonic acids include methanosulphonic acid and p-toluenesulphonic acid. Suitable Lewis acids include aluminum chloride, aluminum bromide, boron tπfluoπde, boron trichloride, ferric chloride, tin chloride and titanium tetrachlonde. Suitable ion exchange resins include strong acid ion exchange resins such as Dow 50, Amber te IR120, Amberlyst 15 and Amberlyst 36. Preferably the conversion of the ester into the phenol is accomplished by transesterification using an alcohol as the recipient of the acyl group and an acid catalyst which may be a mineral acid, a sulphonic acid, a Lewis acid, a solid acid such as an acidic ion exchange resin, or a titanium tetra-alkoxide. The phenol may also be obtained from the ester by aminolysis using ammonia or a primary amme in a suitable solvent, such as anhydrous ammonia in hexane or heptane.

In another aspect of the invention a method is provided for the synthesis of an acylated substitued diphenylether by condensation of a halogen substitued aromatic aldehyde or ketone with a salt of a substituted phenol The general formula for the aldehyde or ketone is:

wherein R , R², R³, R⁴ and R⁵ have the meanings given above Particularly, the hydrogen substitued aromatic ketone may be an 1-acyl-2,5-dιchlorobenzene as represented by the general formula:

in which R¹ has the meaning as above. The salt of the substituted phenol is a metal salt, or a quaternary ammonium salt, or any other salt including salts formed in phase transfer catalysis.

The method for condensation further provides for the use of catalysts in the formation of the diphenylether. The usual catalysts employe in the Ullmann ether condensation apply; these include metallic copper, cuprous (Cu I) and cupric (Cu II) salts, such as oxides, hydroxides, halides, alkanoates, sulphates, nitrates. Also included is the use of these copper catalysts conjugated on carrier matrixes such as clays, silicates and other mineral carriers.

In particular, the invention extends to the condensation of 2,5- dichloroacetophenone with salts of 2,4-dichlorophenol under conditions of the Ullmann condensation as described above (Scheme II). In this particular instance the selectivity of the condensation resides in the electron-withdrawing character of the acyl-substituent, which renders the 2-chloro-atom of the substituted 2,5-dichloroketone much more susceptible to nucleophilic substitution by the attacking phenolate ion than the 5-chloro-atom. This principle is prevalent in all 1 -acyl-2,5-dichlorobenzenes referred to above.

A further aspect of the invention provides a method for the oxidation of a substituted diphenyletherketone particularly 2'-acyl-2,4,4'-trichlorodiphenylether, under Baeyer-Villiger conditions, by use of commercial peroxy-reagents preferably peracids, or peracids generated in situ. This method also includes the steps of oxidizing an organic anhydride with aqueous hydrogen peroxide to form an organic peracid. As a particular example of this method the thus generated peracid solution is rendered anhydrous by reacting the water present in the peracid solution with an added organic anhydride in a hydrolysis step. As a more definite example, the anhydride used to form the peracid is selected from acetic anhydride, maleic anhydride and trifluoroacetic anhydride and the anhydride employed in the hydrolytic removal of water is selected from the same anhydrides.

A specific example of the invention for the production of triclosan is depicted in Scheme II. Some specific features of the process steps are:

1 ) Acylation of 1 ,4-dichlorobenzene under Friedel-Crafts reaction conditions allows facile access to a synthon in which the ortho-chlorine is activated for displacement by a nucleophile due to the electron withdrawing properties of the acyl group; the meta- chlorine is relatively inert to displacement. Many acyl groups are suitable for subsequent

Baeyer-Villiger oxidation.

2) The condensation of 2,5-dichloroacetophenone and 2,4-dichlorophenol to produce 3- chloro-6-(2',4'-dichlorophenoxy)acetophenone can be affected under basic conditions; the base used is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide. The reaction may be catalyzed by theusual catalysts of the Ullmann ether condensation and is selected from metallic copper powder, Cu I and Cu II oxides, halides and acetates. The reaction may be performed in a melt of the reactants, or in a solvent selected from toluene, xylene, butanols, ethylene glycol, polyethylene glycol, N-methylpyrrolidone, N,N-dimethylformamide, or dimethylsulfoxide.

The reaction temperature may be between 100 and 150^QC and the reaction time may be 15 to 100 hours. The molar ratio of 2,4-dichlorophenol to 2,5-dichloroacetophenone employed may be between 1 :1 and 5:1 , preferably 2:1 and most preferably 1.1 :1 . The molar ratio of base employed to the quantity of 2,5-dichloroacetophenone used may be 0.5:1 to 5:1 in the case of the carbonates and 1 :1 to 10:1 in the case of the hydroxides; preferably this ratio will be betwen 0.55:1 and 1 :1 for the carbonates and between 1.1 :1 and 1 .1 :2 for the hydroxides; most preferably the ratio will be 0.55:1 for the alkali metal carbonates and 1 .1 :1 for their hydroxides; that is, most preferably the quantity of base employed will be chemically equivalent to the quantity of 2,4-dichlorophenol used. The quantity of copper catalyst used may be between 0.5g and 10g of Cu per mole of 2,4- dichloroacetophenone employed, preferably between 1 and 5g per mole and most preferably between 2 and 3g of Cu per mole.

3-Chloro-6-(2,4'-dichlorophenoxy)aceotphenone is a new molecular entity and forms part of the claims of this invention. In its formation, no contaminating dibenzofurans are formed and with the preferred temperature of the reaction (120 - 130^s) the formation of other undesired by-products, such as dioxins, is minimal. The intermediate is readily purified by a single crystallization.

3) In this step the acetyl-group of 3-chloro-6-(2',4'-dichlorophenoxy)acetophenone is oxidized to an acetoxy-group by means of a peroxy reagent. The common Baeyer- Villiger oxidants such as percarboxylic acids, alkylhydroperoxides, inorganic peracids or complex peroxygen carriers may be employed in solvents such as organic carboxylic acids, aliphatic hydrocarbons, chlorinated hydrocarbons and alcohols. Catalysts such as inorganic acids, sulphonic acids, or metal ions may be employed. The molar ratio of

6-(2',4'-dichlorophenoxy)acetophenone to oxidant may be 1 :0.2 to 1 :5 oxidation in 1 to 8 volumes of solvent at a temperature of between 20 and 80°C and a reaction time of between 5 and 50 hours. Preferably the oxidation of 3-chloro-6-(2',4'- dichlorophenoxy)acetophenone is performed with one or more of permaleic acid, peracetic acid, perphthalic acid or pertrifluoroacetic acid at a molar ratio of 1 :2 to 1 :3 in two or four volumes of a chlorinated aliphatic solvent such as dichloromethane, dichloroethane or chloroform at a temperature of between 35 and 45°C and a reaction time of between 12 and 24 hours; the reaction mixture may contain carboxylic acids or carboxylic acid anhydrides which may have been employed in the in situ generation of the essentially anhydrous peracid. Most preferably 3-chloro-6-(2' ,4'- dichlorophenoxy)acetophenone is oxidized with anhydrous permaleic acid in a molar ratio of 1 :2 in 2.5 volumes of dichloromethane at 40°C for 16 hours.

Under the latter conditions the oxidative transformation is virtually quantitative. The product, triclosan acetate, is obtained in high purity by simple work-up procedure and one final crystallization. At this stage the levels of undesired contaminants are at acceptably low levels.

4) The conversion of 2'-acetoxy-2,4,4'-trichlorodiphenylether (triclosan acetate) into the corresponding phenol, 2,4,4'-trichloro-2'-hydroxydiphenylether (triclosan) may be accomplished by acid catalyzed hydrolysis, or better by transesterification in excess aliphatic primary alcohol using an acid catalyst such as a mineral acid, a sulfonic acid, a Lewis acid, an acidic resin or a titanium tetra-alkoxide. The transesterification is effected by treatment of one molar equivalent of the ester in 2 to 50 molar equivalents of an aliphatic primary alcohol containing 0.02 to 1 molar equivalents of acid catalyst at a temperature of between 20°C and the boiling point of the alcohol for 4 to 12 hours. Preferably the transesterification is performed in 6 to 8 molar equivalents of methanol, ethanol or propanol containing 0.02 to 0.05 molar equivalents of mineral acid or sulphonic acid at a temperature of between 50°C to the boiling point of the alcohol for between 5 to 9 hours. Most preferably the reaction is performed by refluxing 1 molar equivalent of the ester in 7 molar equivalents of methanol containing 0.03 equivalents of hydrochloric acid for 6 hours.

Removal of the solvent and acid catalyst followed by one distillation and one recrystallization affords pure triclosan. A typical analysis of the material is shown in

Table A.

TABLE A

TEST SPECIFICATION RESULTS PRIOR ART

Appearance Fine Powder Fine Powder Fine Powder

Color White White White

Odor Trace aromatic Odorless Trace aromatic

Identify (IR Conforms Conforms Conforms

Spectroscopy)

Purity 99.0-100.0 percent 99.8 99.8 (m/m)

Hazen value (0.05 M max. 150 apha < 5 40 solution in 0.1 N

NaOH)

Solubiltiy (0.05 M Trace turbidity Clear Clear solution in 0.1 N

NaOH)

2,4-dichlorophenol max. 10 ppm Not detected < 10 ppm

(HPLC) p-chlorophenol max. 50 ppm Not detected < 10 ppm

4,4'-dichloro-2- max. 0.1 percent 0.05 0.05 hydroxydiphenyl ether (GC)

2,3,7,8-tetrachlorodi- max. 0.001 ppb Not detected < 0.001 benzo-p-dioxin (GC-

MS)

2,3,7,8-tetrachlorodi- max. 0.001 ppb Not detected < 0.001 benzofuran (GC-MS)

2,8-dichlorodibenzo- max. 0.5 ppm 0.1 < 0.10 p-dioxin (HPLC)

1 ,3,7-trichlorodi- max. 0.25 ppm Not detected < 0.05 benzo-p-dioxin

(HPLC)

2,8-dichlorodibenzo- max. 0.25 ppm Not detected < 0.05 furan (HPLC)

2,4,8-trichlorodi- max. 0.5 ppm Not detected 0.12 benzofuran (HPLC)

Melting point 56-58⁹C Conforms 56.9⁹C

Ash max. 0.1 percent < 0.1 0.04 (m/m)

Total Heavy Metals max. 20 ppm < 10 < 10

The following examples serve to illustrate aspects of the invention by the synthesis of 2'-acetoxy-2,4,4'-trichlorodiphenylether (triclosan acetate) and its transesterification to 2,4,4'-trichloro-2'-hydroxydiphenylether (triclosan).

EXAMPLE 1 2,5-DICHLOROACETOPHENONE (2,5-DICAP):

A 3-necked, one liter flask was placed in a heatable oil bath and fitted with a reflux condenser topped with a calcium chloride drying tube, an efficient stirrer and a dropping funnel. The flask was charged with 49.5g (336.7 mmoles, 1 equivalent) of 1 ,4- dichlorobenzene and 1 12.5g (843 mmoles, 2.5 equivalents) of anhydrous aluminum chloride. The mass was warmed to 47⁹C and stirred. To the mixture was added dropwise 40g (509.5 mmoles, 1.5 equivalents) of acetyl chloride at a rate (ca 1 hour) that would maintain the exothermic reaction temperature at approximately 60^QC. The mixture was heated to 100⁹C and stirred at that temperature for a further 5 hours. When the reaction was complete, as determined by gas chromatography, the mixture wsa poured into 500g of ice water with vigorous stirring. The product was extracted with two 100 ml portions of dichloromethane and the combined extract was washed to neutrality with saturated aqueous sodium bicarbonate followed by washing with 70 ml of water. Evaporation of the solvent gave 63.5g of brown liquid. Distilliation at 125-130⁹C/20mm gave 60g (94.3percent, 97 percent purity by gas chromatography) of 2,5-dichloroacetophenone which was suitable for further transformation.

EXAMPLE 2 3-CHLORO-6-(2',4'-DICHLOROPHENOXY)ACETOPHENONE (DCPCAP):

A one liter 3-necked flask, equiped with a Dean-Stark water trap, thermometer, stirring magnet and a nitrogen gas inlet extending into the reaction mixture, was place in an oil bath on a magnetic stirrer/hot plate. The flask was charged with 269g (1.65 moles) of 2,4-dichlorophenol, 225 ml of xylene and 114g (0.825 moles) of anhydrous potassium carbonate. The stirred mixture was heated to 120^QC while a slow stream of nitrogen was introduced and 283.5g (1.5 moles) of 2,5-dichloroacetophenone was added. To the mixture at 120°C was added 9g (0.09 moles) of copper (I) chloride. The mixture was refluxed gently and azeotroped water was collected during 2 hours (6 ml total). The rate of product formation was followed by gas chromatographic analysis. The reaction was complete 8 hours after addition of the copper catalyst. The mixture was cooled to 25⁹C and filtered. The filter cake was washed with 200 ml of xylene. The solvent was evaporated in vacuum. The remaining brown oil crystallized on stirring with 250 ml of hexane at 5°C. The product was collected on a filter and washed with four 50 ml portions of hexane (5⁹C). The filter cake was resuspended in 250 ml hexane, stirred at the boiling point, cooled to 5⁹C and again collected on a filter. The dried product (228.5g; 48.5 percent yield; 97 percent purity by gas chromatography) was suitable for further transformation.

EXAMPLE 3 3-CHLORO-6-(2',4'-DICHLOROPHENOXY)ACETOPHENONE (DCPCAP):

A two liter 3-necked flask, equiped with a Dean-Stark apparatus, thermometer, stirrer and nitrogen inlet, was charged with 358.6g (2.2 moles) of 2,4- dichlorophenol, 250 ml of toluene and 151.8g (2.2 moles) of anhydrous potassium carbonate. The mixture was stirred and heated to boiling. When no more water was collected in the trap, the mixture was cooled to 90⁹C and 378g (2 moles) of 2,5- dichloroacetophenone was added. The mixture was purged with nitrogen to remove dissolved oxygen and 5.6g (0.04 mole) of cuprous oxide was added. The mixture was heated under reflux with the water trap in place. The course of formation of product was monitored by gas chromatography. When less than 3 per cent 2,5-dichloroacetophenone remained, the mixture was cooled to 30⁹C and filtered through a pad. The filter cake was washed with 150 ml of toluene. Solvent was evaporated under vacuum. A light fraction containing 2,4-dichlorophenol, 2,5-dichloroacetophenone and other unwated by-products was distilled from the product at 110 - 120⁹C/6mm. The residue was dissolved in 400 ml of toluene at 90⁹C and cooled to 10⁹C. The crystalline product was collected on a filter and washed with 100 mi of methanol Recrystallization from toluene gave 278g (44.3 percent yield, purity 98.8 percent by quantitative gas chromatography using an internal standard).

EXAMPLE 4 2 -ACETOXY-2,4,4 -TRICHLORODIPHENYLETHER:

A three-necked three liter reaction vessel, equipped with a stirrer, thermometer and dropping funnel was charged with 136.8g (1 .98 moles; 4.4 equivalents) of 49.2 percent aqueous hydrogen peroxide. To the stirred solution was added 175.5g (1 .8 moles, 4 equivalents) of solid maleic anhydride over 30 minutes. The internal temperature was maintained at 23 + 2°C with occasional external cooling. Stirring was continued at this temperature for 90 minutes. To the stirred solution was added 395g

(3.87 moles; 8.6 equivalents) of acetic anhydride at a rate that allowed the temperature of the mixture to be maintained at 27 ± 3°C with external cooling. Stirring was continued for one hour at 30°C after the addition of the anhydride.

The reaction mixture was warmed to 40°C and 141 .3g (0.45 mole) of 3- chloro-6-(2',4'-dichlorophenoxy)acetophenone was added in portions over a period of 30 minutes while maintaining the temperature of the exothermic reaction between 45° and 50⁹C. Progress of the reaction was monitored by gas chromatography. When conversion was complete (after approximately 18 hours) 20ml of water was added to destroy excess anhydride and the mixture was extracted with four 150ml-portions of hexane. The combined extract was treated with 10 percent aqueous sodium bisulphite until free of peroxides (test paper) and washed with aqueous sodium bicarbonate to neutrality. Evaporation of the solvent gave 158g of a solid that was recrystallized from hexane to give 152g (97.6 percent yield; 99.4percent purity) of colourless crystals. EXAMPLE 5

2 -ACETOXY-2,4,4^,-TRICHLORODIPHENYLETHER (DICHLOROMETHANE ROUTE):

A 500ml three-neck flask was equipped with a magnetic stirred, a 5⁹C condenser and a thermometer. The flask was charged with 80g of dichloromethane and 179g (1.8 mole) of maleic anhydride. The stirred mixture was heated to 25⁹C and 47.9g (0.88 mol; 4.4 mol. parts) of 62.5 percent aqueous hydrogen peroxide was added dropwise over 30 minutes. The mixture was refluxed for 90 minutes, cooled to 30°C and 65g (0.2 mole; 1 mole part) of 3-chloro-6-(2',4'-dichlorophenoxy)acetophenone was added in small portions during 40 minutes. The reaction mixture was stirred under reflux for 16 hours. Crystalline maleic acid was filtered off and the cake was washed with 50ml of dichloromethane. The filtrate was treated successively with aqueous sodium bisulphite until free of peroxides and with aqueous sodium bicarbonate to neutrality. The solvent was evaporated and the residue crystallized from methanol to give 63.5g (96.2 percent; purity 99.4 percent by gas chromatography) of colourless crystals.

EXAMPLE 6 2,4,4 -TRICHLORO-2^'-HYDROXYDIPHENYLETHER:

To a stirred solution of 461.7g (1 .08 mole) of 2'-acetoxy-2,4,4'- trichlorodiphenylether in 923ml of methanol was added 5.9ml of 35 percent aqueous hydrochloric acid. The reaction mixture was maintained at 40 - 50⁹C and the course of the transesterification was monitored by gas chromatography. When no ester remained (after approximately 5 hours) the solvent was removed in vacuum. The product was purified by distillation at 60⁹C under 0.1 mm vacuum to remove volatile material and the main fraction boiling at 142 - 145⁹C (0.1 mm) was collected. The fraction was poured into 100ml of hexane at 50⁹C with stirring. The product which crystallized on cooling to 15⁹C was collected on a filter and dried; yield 81 g (93.7percent of 99.7 percent purity).

Claims

What is claimed is:

1. A method of preparing an ester of a phenolic diphenylether of the formula:

in which R¹ is selected from the group consisting of H, linear or branched, substituted or unsubstituted aliphatic and alicyclic groups consisting of one to twenty carbon atoms, and - C0₂R" where R" is H, alkyl, alkoxy and aryloxy, and R², R³, R" and R⁵ are independently selected from the group consisting of H, halogen, nitro, amino, substituted amino, carboxyl and substituted or unsubstituted aliphatic groups, the method comprising oxidizing a diphenyl ether aldehyde or ketone of the formula:

wherein A is -C(O)R\ -C(OR⁶)(OR⁷)R¹ or -C(=NR^╬▓)R\

R¹, R², R³, R⁴ and R⁵ have the meanings given above, R⁶ iand R⁷ independently may be a linear or branched aliphatic group or may form part of a cyclic ketal structure of 5 or 6 members, and R⁸ is hydrogen or alkoxy.

2. The method of claim 1 , wherein said oxidation is carried out with a peroxy reagent selected from the group consisting of peroxyether, peroxide, peroxyanhydride and peroxy acid.

3. The method of claim 1 , wherein said ketone is masked as a derivative of a ketone effective to undergo oxidation to an ester directly or via an intermediate ketone formed in situ under the conditions of the reaction.

4. A method as claimed in claims 1 and 2, further comprising hydrolysing said diphenylether phenol ester to produce the corresponding phenol.

5. A method as claimed in claim 4, wherein said hydrolysis of the ester to form the phenol comprises transesterification using an alcohol as the recipient of the acyl group and using an acid catalyst selected from the group consisting of a mineral acid, a sulphonic acid, a Lewis acid, and a solid acid.

6. A method as claimed in claim 4, wherein said hydrolysis of said ester to form said phenol comprises hydrolysis using a base selected from the group consisting of alkali metal hydroxides, alkali metal amides, alkali metal alkoxides, alkali earh metal hydroxides, alkali earth metal amides, alkali earth metal alkoxides, ammonia and primary amines.

7. A method as claimed in claim 1 , wherein said diphenyl ether or ketone is produced by condensing an acylated halogen substituted aromatic compound with a salt of a substituted or unsubstituted phenol.

8. A method as claimed in claim 7 in which said acylated halogen substituted aromatic compound is a 2,5-dichlorophenyl ketone of the general formula:

in which R¹ is selected from H, linear or branched substituted or unsubstituted aliphatic or alicyclic groups consisting of one to twenty carbon atoms, and -C0₂R" where R" is H, alkyl, alkoxy or aryloxy .

9. A method as claimed in claim 8, wherein said 2,5-dichlorophenyl ketone is 2,5-dichloroacetophenone.

10. A method as claimed in claim 7, wherein said salt of the phenol is selected from the group consisitng of metal salt, quaternary ammonium salt and salts formed in phase transfer catalysis of 2,4-dichlorophenol.

11. A method as claimed in claim 7, wherein said acylated substituted diphenylether is a 1 -acyl-3-chloro-2-(2',4'-dichlorophenoxy)benzene of the formula:

wherein R¹ is selected from the group consisting of H, linear or branched substituted or unsubstituted aliphatic or alicyclic groups consisting of one to twenty carbon atoms, and - C0₂R" where R" is H, alkyl, alkoxy or aryloxy.

12. A method as claimed in claim 11 , wherein R¹ is a methyl group.

13. A method as claimed in claim 1 in which the oxidation is carried out with a peracid solution oxidizing agent generated in situ by oxidizing an organic anhydride with aqueous hydrogen peroxide to form an organic peracid.

14. A method as claimed in claim 13 in which the generated, organic peracid solution is rendered anhydrous by reacting all of the water present with an organic anhydride in a hydrolysis step.

15. A method as claimed in claim 13 in which the organic anhydride used in the oxidation step is selected from the group consisting of acetic anhydride, maleic anhydride and trifluoroacetic anhydride and the anhydride used in the hydrolytic removal of water is selected from the group consisitng of maleic, trifluoroacetic and acetic anhydrides.

16. A method as claimed in claim 13 in which the mole ratio of said diphenylether ketone and the oxidizing peracid is between 1 :0.2 and 1 :5.

17. A compound represented by the following formula:

wherein R¹ is selected from the group consisting of linear or branched substituted or unsubstituted aliphatic or alicyclic groups consisting of one to twenty carbon atoms and CO R" where R" is H, alkyl, alkoxy or aryloxy.