Title of Invention

PROCESS FOR THE PRODUCTION OF HALOGENO-O-HYDROXYDIPHENY1 COMPOUNDS

Abstract

There is described a four step process for the production of halogeno-o-hydroxydiphenyl compounds having the formula in which X is-0-or-CH2-; m is 1 to 3; and n is 1 or 2; wherein in the first step, a diphenyl compound is chlorinated; in a second step the chlorinated compound is acylated in a Friedel-Crafts reaction and optionally again chlorinated after the acylation; in a third step the acyl compound is oxidised; and in a fourth step the oxidised compound is hydrolysed. The compounds of formula (1) are useful for the protection of organic materials against I microorganisms.

Full Text

The present invention relates to tine production of halogeno-o-hydroxydiphenyl compounds • in which X is -O- or -CH2-; m is 1 to 3; and n is 1 or 2; as well as to the use of these compounds for the protection of organic materials against microorganisms or in e.g. cosmetic compositions. The production of halogeno-o-hydroxydiphenyl compounds, especially of 2-hydroxy-2",4,4"-trichlorodiphenylether (Triclosan; compound of formula (3) below), is usually effected by diazotisation and subsequent hydrolysis of 2-amino-2",4,4"-trichlorodiphenylether (TADE; compound of formula (2) below): The yields obtained by this production method are unsatisfactory, however, since various chemically competing reactions can occur. The object of the present invention, therefore, is the provision of an economic process for the production of halogeno-o-hydroxydiphenyl compounds in which undesired side-reactions are suppressed. According to the present invention, there is provided a four-step process for the production of halogeno-o-hydroxydiphenyl compounds in which, in the first step, a diphenyl compound is chlorinated; in a second step the chlorinated compound is acylated in a Friedel-Crafts reaction and optionally again chlorinated after the acylation; in a third step the acyl compound is oxidised; and in a fourth step the oxidised compound is hydrolysed; according to the following reaction scheme: In the above scheme: R is unsubstituted C-CsalkyI or C1-C8alkyI substituted by 1 to 3 halogen atoms or hydroxy; or unsubstituted C6-C12aryl or C6-C12garyl substituted by 1 to 3 halogen atoms, C1C5alkyl or C1-C8alkoxy or combinations thereof; X is -O- or -CH2-; m is 1 to 3; and n is 1 or 2. C1-C8alkyI denotes branched or unbranched alkyl such as 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 are straight-chain or branched residues such as methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octoxy. Halogen denotes fluorine, bromine or, preferably, chlorine. In the above reaction scheme, in formulae (6) and (7), preferably R is Ci-C4alkyl, especially methyl. For the first reaction step, there may be used, as chlorinating agent, e.g. sulfuryl chloride or, preferably, gaseous chlorine. The reaction is preferably conducted in the presence of a catalyst, such as dibenzothiophene, methyl sulfide, propyl sulfide, phenyl sulfide, a Lewis acid, such as aluminium chloride, or mixtures of these compounds. Especially suitable as catalyst for the chlorination reaction according to the invention is a mixture of propyl sulfide and an equimolar amount of aluminium chloride. For the reaction in the first step, the temperature can be selected from within a wide range, e.g. from -10 to 50°C. Preferably, the reaction is conducted at a temperature from 0 to 40°C. The reaction time can also vary within a wide range. Usually the reaction is conducted within a time span of 1 to 48, preferably 2.5 to 10 hours. The acylation reaction (2. step) is usually conducted in the presence of a Lewis acid, e.g. aluminium chloride. The Lewis acid may be used in amounts of 1 to 3 molar, preferably 1.25 to 2 molar amounts, based on the chlorinated compound of formula (5). A suitable acylating reagent for use in this reaction is an acyl halide, preferably acetyl chloride. Further suitable acylating agents are e.g. The Lewis acid and acylating reagents are preferably used in equimolar amounts. The reaction may be effected in solvents which are conventionally used for Friedel-crafts reactions, such as methylene chloride or ethylene chloride. The reaction time for this reaction step is of secondary importance and can be varied within a wide range, e.g. from 1 to 18 hours. After the acylation reaction, the reaction mixture may be optionally subjected to a further chlorination reaction, in an analogous manner to the first reaction step, especially if, in the first reaction step, mixtures of differently chlorinated diphenyl compounds are obtained, such as mixtures of 4,4"-dichlorodiphenyl- and 2,4,4"-trichlorodiphenyl compounds. By the subsequent chlorination, uniformly chlorinated acyl compounds are produced. The chlorination reaction (first step) and the acylation reaction (second step) and the optional further chlorination reaction are preferably conducted in the same reaction vessel, that is in one-pot reactions. The oxidation of the acyl compound of formula (6) to give the compound of formula (7) (Baeyer-Villiger oxidation), may be effected with various oxidizing agents. Suitable oxidizing agents are, e.g.: an equimolar mixture of dilute peracetic acid and acetic anhydride in the presence of a catalytic amount of perchloric acid; an excess of 3-chloro-perbenzoic acid in water; di-peroxydodecanedioic acid (DPDDA); a mixture of dilute peracetic acid and acetic anhydride and sulfuric acid; a mixture of m-chloroperbenzoic acid (MCPBA), trifluoroacetic acid and dichloromethane; 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 K2S20a, sulfuric acid and a 1:1 water/methanol mixture: a mixture of acetic acid and the potassium salt of monoperoxomaleic acid; a mixture of tricfiloromethylene, 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; and Mg-mono-perphthalate. Preferably there is used for the oxidation, a mixture of maleic anhydride, a urea-hydrogen peroxide complex and acetic acid as solvent. If desired, a commercially available wetting agent may be added to the oxidizing agent. The reaction times lie within a wide range and may vary from about 1 hour to about a week, from 4 to 6 days being preferred. The reaction temperature ranges from -20°C. to about 80°C. Preferably, the reaction is conducted at room temperature. The final hydrolysis to the desired haiogeno-o-hydroxydiphenylethers of formula (1) proceeds quantitatively. Preferably, the process according to the present invention relates to the production of halogeno-o-hydroxydiphenyl compounds having the formula (1) in which X is oxygen, and especially those compounds in which m is 2 and n is 1. in which R is unsubstituted Ci-Caaikyl or Ci-C8all In formula (8), preferably R is CrC4alkyl, especially methyl. These new compounds represent a further aspect of the present invention. The halogeno-o-hydroxydiphenyl compounds produced according to the invention are insoluble in water but are soluble in dilute sodium- and potassium hydroxide solution and in practically all organic solvents. Due to these solubility properties, the application of the compounds in combatting microorganisms, especially bacteria, and in protecting organic materials against the attack microorganisms is very versatile. Thus, they can be used, e.g. together with wetting- or dispersing agents, as soaps or synthetic detergent solutions for the disinfection and cleaning of human skin and hands, or they can be applied to these from solid articles in diluted or undiluted form. The following Examples further illustrate the invention, but without limiting it. Example 1a): Chlorination of diphenylether and direct use of the reaction product for reaction with acetyl chloride: Reaction scheme: A mixture of 265 g (1.56 mol) of diphenylether (formula 101a), 7.36 g (0.06 mol) of dipropyl sulfide and 7.46 g (0.06 mol) of AICI3 are placed in a reaction vessel and melted by stirring and warming to 30°C. The chlorination is conducted by introducing gaseous chlorine at such a rate the reaction mixture can be held at a temperature below 40°C. by external cooling. The reaction is monitored using gas- or liquid chromatography. The chlorination is stopped when the content of 2,4,4"-trichlorodiphenylether (formula 101b) reaches 80 area-% (about 6 hours introduction time). For the acetylation, 265 g (3.37 mol) of acetyl chloride are added, dropwise, on to 450 g (3.37 mol) of AICI3 in 1100 mis of 1,2-dichloroethane, at 20° to 40°C. The reaction mixture is stirred for 15 minutes at 40°C. Finally, the solution is added, dropwise, to the chlorination reaction mixture in 800 mis of dichloroethane at a temperature of 40°C. over about 1 hour. The reaction mixture is then stirred for 10 hours at about 40°C. The reaction mixture is worked up by treating it witli about 4 kg of ice and 550 mis of cone. HCI and extracting it for a sliort time. An aqueous phase and an organic phase are formed which are separated. After distilling off the solvent from the organic phase, there remains a dark, viscous residue which crystallises on standing. Yield: about 490 g of reaction mixture; content of main component about 340 g, corresponding to about 70% of theory, based on diphenylether (formula 101a) used. Main component: 2-acetyl-2,4,4"-trichlorodiphenylether corresponding to formula (101c). Composition of the reaction mixture (area % GC or LC): about 70% main component, about 15% 2,2",4,4"-tetrachlorodiphenylether with the rest being unknown compounds. The reaction mixture can be used directly for the subsequent Baeyer-Villiger oxidation (Example lb). Example 1b): Baeyer-Villiger oxidation Reaction scheme: 6.32 g of the 2-acetyl-2,4,4"-trichlorodiphenylether corresponding to formula 101c) produced in Example 1 a) and 6.88 g of m-chloroperbenzoic acid (MCPBA) are dispersed with a wetting agent in 40 mis of water at 20 to 25°C. The suspension is heated to 80°C. and held at this temperature, with vigorous stirring, for 3 hours. 30 mis of tetrachloroethylene are added, whereupon two clear phases are formed. The excess peracid is decomposed by adding 0.5 g of sodium liydrogen sulfite, the mixture is adjusted to a pH value of about 8 with NaOH and the aqueous phase (containing m-chloroperbenzoic acid) is separated. The phenolether of formula (101d) can be recovered, as a white powder of m.pt. 48-49°C., by crystallisation from the organic phase For the hydrolysis, some water is added to the organic phase and the pH value is adjusted to 12 with sodium hydroxide. The end product of formula (101) is obtained from the intermediate product of formula (lOld). The pH value is adjusted to about 1 with hydrochloric acid, the aqueous phase is separated and the tetrachloroethylene phase is concentrated. 5.7 g of a yellowish oil are obtained which contains about 80 area % of the compound of formula 101. After recrystallisation from petrol ether, the product is obtained as a white powder having a melting point of 55 to 56°C. The data agree with those of the original compound. Example 1c): Alternative Baeyer-Villiqer oxidation in anhydrous medium To a solution of 3 g (10 mmol) of 2-acetyl-2,4,4"-trichlorodiphenylether corresponding to formula (101c) in 20 mis of anhydrous dichloromethane, there are added 4.5 g (13 mmol) of m-chloroperbenzoic acid. The mixture is cooled to 0°C. and 0.77 ml (10 mmol) of trifluoroacetic acid is added. The reaction mixture is allowed to slowly warm to room temperature. After a reaction time of 8 hours at room temperature, the reaction mixture is cooled with a sodium sulfite solution and washed with a saturated sodium bicarbonate solution. The dichloromethane layer is washed several times with water, dried over anhydrous sodium sulfate and concentrated until an oily residue is obtained. This residue is hydrolysed by boiling it for 15 hours, under reflux, in 10 mis of IN NaOH solution. There are obtained 2 g of a crude reaction product which, after acidification, is purified by column chromatography. In this way, there are formed 1.5 g (54% theory) of the compound of formula (101), as a white crystalline powder. Alternative hydrolysis 0.9 g of the crude product obtained from the Baeyer-Villiger oxidation is boiled, for 4 hours under reflux, in 5 mis of ethanol which contains a few drops of concentrated HCI. The reaction is monitored by thin layer chromatography. After completion of the reaction, the alcohol is distilled off under vacuum. The oily residue is dissolved in 10 mis of dichloroethane and the solution is repeatedly washed with water. The organic phase is dried over anhydrous Na2S04 and concentrated. There is formed 0.8 g of the crude compound of formula (101). By recrystallisation from petrol ether, there is obtained 0.64 g (70% theory) as a crystalline powder. Example 2: The procedure of Example 1a) is repeated except that the chlorination is conducted in an about 30% solution of diphenylether in 1,2-dichloroethane. Examples 3 to 6: For the acylation reaction described in Example la), in addition to acetyl chloride, the acylating agents set out in the following Table 1 can also be used: Example 7: Acylation of a mixture of 2.4.4"-trichlorodiphenvlether and 4.4"-dichlorodiphenylether and a further chlorination reaction Example 7a: Acylation Reaction scheme: Into a three-necked sulfonation vessel equipped with a pressure-balanced dropping funnel, a nitrogen gas inlet tube, a stirrer and a safety tube, there are placed 480 mis of anhydrous 1,2-dichloroethane and 221.8 g (11.456 mol) of 88% aluminium chloride. The mixture is stirred and cooled in an ice bath under an atmosphere of nitrogen. To this mixture there are added 104 mis of freshly distilled acetyl chloride (114.4 g, 1.456 mol) over a period of 15 to 20 minutes. The exothermic reaction is allowed to cool to room temperature and the mixture is stirred for 30 minutes. A homogeneous dark brown mixture is formed, to which there is added, dropwise, with stirring at room temperature over 15 to 30 minutes, 251.9 g of a mixture containing 2,4,4"-trich!orodiphenylether (79%) and 4,4"-dichlorodiphenylether (9%), dissolved in 480 mis of anhydrous 1,2-dichloroethane. The reaction is monitored by gas chromatography. After stirring for about 15 hours at room temperature, the mixture is added to 500 mis of ice water containing 50 mis of concentrated HCI. After stirring for 15 minutes, the organic phase is separated from the aqueous phase. The aqueous phase is extracted twice with 1,2-dichloroethane, using 100 mis of 1,2-dichloroethane each time. The combined organic phases are washed 6 times with water using 500 mis of water each time and dried over anhydrous sodium sulfate. After removing tlie solvent, there are obtained 244 g of a mixture containing the compound of formula (101c) and the compound of formula: This reaction mixture is used for the subsequent chlorination reaction. Example 7b: Further chlorination Into a sulfonation vessel equipped with a dropping funnel, a chlorine gas inlet tube, a stirrer, a safety tube and also a purification system for acidic vapors , there are placed 0.077 g (0.65 mmol) of propylsulfide and 88% aluminium chloride in 120 mis of anhydrous 1,2-dichloroethane. Chlorine gas is introduced into this mixture for 15 minutes with stirring. After interrupting the gas supply, there are added, dropwise over 1.5 to 2 hours, 244 g of a mixture containing 2-acetyl-2,4,4"-trichlorodiphenylether (84.4%) and 2-acetyl-4,4"-dichlorodiphenylether (1.9%), dissolved in 120 mis of anhydrous 1,2-dichloroethane. Chlorine gas is introduced, witli stirring, for one hour. The reaction is monitored using gas chromatography. After completion of the reaction, the mixture is added to 500 mis of ice water containing about 15% HCI, The organic phase is separated and the aqueous phase is washed twice with 1,2-dichloroethane, using 100 mis of 1,2-dichloroethane each time. The combined organic phases are washed five times with a saturated sodium bicarbonate solution, using 200 mis of sodium bicarbonate solution each time, then washed five times with water, using 200mls of water each time, and dried over sodium sulfate. Finally, the solvent is removed under vacuum. There are obtained 240 g of a crude product containing the compounds of formulae (101c) and (lOlf). WE CLAIM: 1. A process for the production of halogeno-o-hydroxydiphenyl compounds comprising the steps of chlorinating a diphenyl compound, acylating in a Friedel-Crafts reaction the chlorinated compound and optionally further chlorinating after the acylation, oxidizing the acyl compound; and hydrolysing the oxidized compound according to the following reaction scheme: In the above scheme: R is unsubstituted Ci-Cgalkyl or Ci-Cg alkyl substituted by 1 to 3 halogen atoms or hydroxy; or unsubstituted C6-Ci2aryl or Ce-Cuaryl substituted by 1 to 3 halogen atoms, Ci-C salkyl or Ci-Cs alkoxy or combinations thereof; Xis-0-or-CH2-; m is 1 to 3; and n is 1 or 2. 2. The process according to claim 1, wherein R is Ci-C4alkyi. 3. The process according to claim 2, wherein R is methyl. 4. The process according to any one of the preceding claims 1 to 3, wherein the chlorination is conducted with elemental chlorine. 5. The process according to any one of the preceding claims 1 to 4, wherein the chlorination is conducted in the presence of a mixture of propyl sulfide and an equimolar amount of aluminium chloride. 6. The process according to any one of the preceding claims 1 to 5, wherein the acylation reaction is conducted in the presence of acetyl chloride and aluminium chloride, whereby acetyl chloride and aluminium chloride are used in equimolar amounts. 7. The process according to claim 6, wherein the acylation reaction is conducted in the presence of an halogenated solvent. 8. The process according to any one of the preceding claims 1 to 7, wherein the chlorination, the acylation reaction and optionally the further chlorination are conducted as a one-pot reaction. 9. The process according to any one of the preceding claims 1 to 8, wherein the oxidation is conducted with a mixture of maleic anhydride, a urea-hydrogen peroxide complex and acetic acid as solvent. 10. The process according to claim 9, wherein the reaction time for the oxidation ranges from 1 hour to 1 week and the oxidation is conducted at room temperature. 11. The process according to any one of the preceding claims 1 to 10, wherein X is oxygen. 12. The process according to any one of the preceding claims 1 to 11, wherein m is 2 and n is 1. 13. A process for the production of halogeno-o-hydroxydiphenyl compounds substantially as herein described and exemplified.

Documents:

0290-mas-1997 abstract-duplicate.pdf

0290-mas-1997 abstract.pdf

0290-mas-1997 claims-duplicate.pdf

0290-mas-1997 claims.pdf

0290-mas-1997 correspondence-others.pdf

0290-mas-1997 correspondence-po.pdf

0290-mas-1997 description (complete)-duplicate.pdf

0290-mas-1997 description (complete).pdf

0290-mas-1997 form-1.pdf

0290-mas-1997 form-26.pdf

0290-mas-1997 form-4.pdf

0290-mas-1997 others.pdf

0290-mas-1997 petition.pdf

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