MXPA98000977A - Process for the preparation of hydroxidiphenyl or halogen compounds - Google Patents

Abstract

The present invention relates to a process for the preparation of halohydroxydiphenyl compounds of the formula (See Formula) by means of the acylation of a halogenated benzene compound (first step), the etherification of the acylated compound with a halogenated phenol compound ( second stage), oxidation of the etherified compound (third stage) and hydrolysis of the oxidized compound in the fourth stage, according to the following reaction scheme.

Description

PROCESS FOR THE PREPARATION OF HALOGENATED HYDROXIDPHENYL COMPOUNDS The present invention relates to the preparation of halogenated hydroxydiphenyl compounds of the formula wherein R 1 and R 2 independently of each other are F, Cl or Br; R3 and R4 independently of each other are hydrogen; or C? -C4 alkyl; m is between 1 and 3; and n is 1 or 2; and the use of these compounds as disinfectants to protect organic materials from microorganisms. The preparation of halogenated hydroxydiphenyl compounds, in particular of 2-hydroxy-2 ', 4,4'-tpflorodiphenyl ether (Triclosan, compound of the formula (3)) is generally carried out by diazotization and subsequent hydrolysis of 2-amino -2 ', 4,4'-tpclorodiphenyl ether (TADE, compound of the formula (2)).

However, the performance in this method of preparation is not satisfactory, since several competitive chemical reactions take place. The present invention is therefore based on the objective of finding an economical process for the preparation of haiohydroxydiphenyl compounds, in which the unwanted side reactions are suppressed. The objective is achieved according to the invention by means of a four stage reaction, in which a halogenated benzene compound is acylated in the first stage, in the second stage the acylated compound is etherified using a halogenated phenol compound, in a third stage the etherified compound is oxidized and in a fourth stage the oxidized compound is hydrolyzed, according to the following reaction scheme.

In the above scheme, R ^ R2, R3, R4 and m are as indicated in formula d). In the first reaction step (acylation reaction), the compounds of the formula (5) are prepared. Usually, this reaction is carried out in the presence of a Lewis acid, for example, aluminum halide, in particular aluminum chloride. The Lewis acid is in this case used in a molar amount of 1 to 3, preferably 1, 25 to 2, based on the halogenated compound of the formula (5). A possible acylating reagent for this reaction is an acyl halide, in particular an acetyl chloride. The Ci-C4 alkyl or is preferably an unbranched or branched chain alkyl radical, for example methyl ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tere-butyl. The Lewis acid and the acylating reagent are preferably used in equimolar amounts. The reaction is carried out in the normal solvents for the Friedel-Crafts reactions, for example, methylene chloride or ethylene chloride. The reaction time for this reaction stage plays a minor part and can vary within a wide range, for example, from 1 to 18 hours. In the second step of the reaction, the compounds of the formula (7) are prepared. The etherification of the free OH group of the halogenated phenol compound of the formula (6) is generally carried out in an alkaline medium using a strong or preferably inorganic organic base, for example, NaOH or KOH, and in the presence of a copper and an inert organic solvent, for example, a mixture of xylene isomer or toluene. The reaction times for this reaction step are usually between 1 to 24 hours, preferably between 2 and 10 hours; The temperature ranges are between 80 and 250 ° C, preferably 100 to 170 ° C. In the third reaction step (oxidation), the compounds of the formula (8) are prepared. The oxidation of the acyl compound of the formula (7) with the compound of the formula (8) (Baeyer-Villinger oxidation) can be carried out using various oxidizing agents. Suitable oxidizing agents are, for example, a mixture of peracetic acid and acetic anhydride diluted in the presence of a catalytic amount of perchloric acid; - m-chloroperbenzoic acid (MCPBA) in water; diperoxidedecanedioic acid (DPDDA); - a mixture of diluted 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 K2S2Oß, sufuric acid and 1: 1 water / metapol mixture; - a mixture of acetic acid and potassium salt of monoperoximeleic acid; - a mixture of trichloromethane, potassium salt and monoperoximeleic acid and sodium hydrogen sulfate; - a mixture of maleic anhydride, acetic anhydride, hydrogen peroxide and trichloromethane; - a mixture of maleic anhydride, a complex of urea - hydrogen peroxide and acetic acid; - a mixture of acetic anhydride, sulfuric acid and H2O2; - a mixture of dichloroacetic acid and H2O2. M-chloroperbenzoic acid (MCPBA), a mixture of sodium borate and trifluoroacetic acid or a mixture of acetic anhydride and H2O2 is preferably used for oxidation. If desired, a commercially available wetting agent may additionally be added to the oxidizing agent. The reaction times are in a wide range and range between about 0.5 to about 15 hours, preferably 1 to 8 hours. The ranges of reaction temperature are between -20 to about 100 ° C, preferably between 0 to about 85 ° C. The subsequent hydrolysis which gives the desired halohydroxydiphenyl ether of the formula (1) proceeds quantitatively in the acidic or alkaline medium. The process according to the invention preferably relates to the preparation of haiohydroxydiphenyl compound of the formula (1), in which the particularly preferred compounds of the formula (1) are those in which m is 2 and n is 1 and are 1. The most preferred compounds of the formula (1) have the formula wherein RT and R2 are Cl; and m is 2 and n is 1; and in particular the compound of the formula The acyl compounds formed in the second stage of the reaction (Ullmann condensation) are in some cases new compounds. These are the compounds of the formula wherein R? \ R2 ', and R3' independently of each other are F, Cl or Br; and R and R5 'independently of one another are hydrogen; or C1-C5 alkyl.

In particular, the new compounds of the formula Preferred are those in which R? ', R2', and R3 'independently of one another are F, Cl or Br. The halogenated hydroxydiphenyl compounds prepared according to the invention are insoluble in water, but soluble in dilute sodium hydroxide and a solution of potassium hydroxide and in virtually all organic solvents. Due to these solubility requirements, its applicability for the control of microorganisms, in particular of bacteria, and as disinfectants to protect organic materials and articles from the attack of microorganisms is very versatile. In this way, they can be applied on them in the diluted or undiluted form, for example, together with wetting or dispersing agents, for example, as solutions of soap or synthetic detergent for the disinfection and cleaning of human skin and hands, in composition for dental hygiene and hard articles. The following examples illustrate the invention without restricting it to them. Preparation examples Example 1: Preparation of 2,5-dichloroacetophenone (first step of the reaction) Scheme of the reaction: 147 g (1.0 mole) of p-dichlorobenzene are completely melted at 60 ° C in an apparatus having an attached dropping funnel, a stirrer and a reflux condenser. 120 g (0.9 mol) of anhydrous AICI3 were added to the melt. 39.3 g (0.5 mol) of acetyl chloride and then added as drops to the stirred suspension at 60 ° C over the course of the hour, slowly resulting in a clear solution. After heating to 110 ° C, the mixture was stirred at this temperature for 7 hours. After cooling to room temperature, the brown reaction mass was hydrolyzed by careful decanting in a mixture of 200 ml of water and 200 g of ice. The temperature of the mixture was maintained between 30 and 40 ° C during hydrolysis by external cooling. After the separation of the phases, the lower, organic phase was washed with 400 ml of water and, after a fresh phase separation, subjected to a fractional distillation. The aqueous phases were discarded. Yield: 66 g of 2,5-dichloroacetophenone (70% theory, based on acetyl chloride).Example 2: Preparation of 1- (5-chloro-2- (2,4-dichlorophenoxy) phenylethanone (second step of the reaction) Reaction scheme: 163 g of 2,4-dichlorophenol were initially introduced together with 22.0 g of 85% KOH and 167 ml of a mixture of xylene isomer. The whole was heated to reflux and the water was removed by azeotropic distillation. The light reddish brown solution was then cooled to 100 ° C, treated with 189 g of 2,5-dichloroacetophenone (compound of formula (101) and 0.8 g of basic copper carbonate, heated to 140 ° C). C and stirred at this temperature for 8 hours.In the course of this reaction, the solution of the reaction becomes dark reddish brown and a white precipitate is deposited, precipitate that is filtered.After distilling most of the xylene in a vacuum by water jet, a 208 g fraction was obtained, which in addition to the starting products 2,4-dichlorophen and 2,5-dichloroacetophenone additionally contains some xylene (bp 30-85 ° C / 0.5-1) mm Hg) 82 g of a second slightly yellowish fraction (bp 165 - 175 X / 1 mm Hg) of the compound of the formula (102), corresponding to a yield of 82% of the theory, based on the KOH used, were added. (mp = 91 ° C).

Analysis for CHHn-CI - O? (MW = 315.58): CH CJ O Calculated f% 1 53.28 2.87 33.7 10.14 Found f% l 53.31 2.85 33.37 10.3 Example: Preparation of 1- (5- chloro-2- (4-chlorophenoxy) phenyl) ethanone (second step of the reaction) The procedure is the same as that described in Example 2, but using 128.6 g of 4-chlorophenol instead of 163 g of dichlorophenol. After a reaction time of 2 hours at 140 X and a subsequent preparation as described in Example 2, a main fraction of 91 g (bp 112 X-173 X / 1 mm Hg) was obtained, after a preliminary fraction of 223 g (bp 30 - 112 X / 1 mm Hg), which in addition to the starting material of 2,5-dichloroacetophenone contains more than 80% of the product of the reaction of the formula that on cooling solidifies to give a white powder (p.f. = 64 X). Analysis for Ci.iHinCI-.O-. (MW = 281.14): £ H CJ O Calculated% 1 59.81 3.59 25.22 11, 38 Found% 1 59.74 3.48 25.49 11, 29 Example 4: Preparation of 5-chloro -2- (2,4-dichlorophenoxy) phenol by Baever-Villiqer oxidation with m-chloroperbenzoic acid (MCPBA) (third and fourth stage of the reaction) Scheme of the reaction: (105) 6.3 g of the acetyl compound of the formula (102) were suspended in 40 ml of deionized water at 20 X. 9.8 g of m-chloroperbenzoic acid (MCPBA) were dispersed and the mixture was heated with stirring. A resin / water phase formed at 52 X; the mixture was heated to around 80 X and this temperature was maintained for 6 hours. The mixture was treated with 0.5 g of sodium hydrogen sulfite to remove excess peroxide. Two clear phases were obtained by adding 50 ml of ethylene chloride and 4 g of 10N NaOH. The water phase having a pH of about 12 was separated; The solvent phase was washed with water until neutral.

After distillation of the solvent, 5.5 g of the crystallizing compound of the formula (104) (intermediate of the phenol ester) remain. For hydrolysis, the phenol ester was dissolved in 50 ml of ethylene chloride and 10 ml of 5N of a sodium hydroxide solution. The solution was heated to 70-73 X, this temperature was maintained for 15 minutes, then the pH was adjusted to about 4 using acetic acid and the phases were separated. After the removal of the solvents, 4.9 g of the beige colored raw product of the formula (105) were obtained. After clarifying the filtrate and recrystallization of petroleum ether 80 / 110, the pure product was obtained in colorless crystals and with a melting point of 56 to 57 X. Example 5: Preparation of 5-chloro-2- (2,4-dichlorophenoxy) phenol by Baever-Villiqer oxidation with NaBO ^ (third v fourth stage of the reaction). 6.3 g of the acetyl compound of the formula (102) were suspended in 20 ml of trifluoroacetic acid and the suspension was treated at 20 X with 9., 3 g of sodium perborate tetrahydrate. It was heated to 40 X and this temperature was maintained for 90 minutes with good agitation. After the hydrolysis of the phenol ester formed and the preparation analogous to that of Example 4, 5.4 g of the crude product of the formula (105) were obtained. Example 6: Preparation of 5-chloro-2- (2,4-dichlorophenoxy) phenol by means of Baever-Villiger oxidation with acetic anhydride / H7Q? 18 ml of acetic anhydride was mixed at -5 X with 4.5 ml of 98% sulfuric acid. 4.2 ml of 30% hydrogen peroxide was added dropwise with vigorous stirring at -5 to -3 X over the course of 25 minutes. The milky emulsion was treated at -5 X with 12.5 ml of methylene chloride, a clear solution formed. Then, with vigorous stirring over the course of 3 minutes, a mixture of 7.9 g of the acetyl compound of the formula (102), 15 ml of methylene chloride, 18 ml of 100% acetic acid was added, and 13.5 ml of 98% sulfuric acid, at a temperature between 0 to -5 X. The reaction mixture is two-phase dark. The reaction was maintained between 0 and 5 X for one hour, then at 10 X for 4 hours and at 15 X for 1 hour. Finally, it was allowed to react until the reaction to 20 X for 20 hours, the intermediate formed the phenol ester of the formula (104) also partially hydrolyzed to the phenol derivative of the formula (105).

After the destruction of the excessive hydrogen peroxide, the methylene chloride was distilled. For complete hydrolysis, the temperature was maintained at 100 X for 4 hours. The product was recovered by extraction with methylene chloride. After distillation of the solvent, an oily residue of 7 g of the crude product of the formula (105) remains, which after normal purification gives a product with a melting point between 56 and 57 X.

Example 7: Preparation of 5-chloro-2- (4-chlorophenoxy) phenol (third and fourth stage of the reaction Reaction scheme: (107) 14 g of the acetyl compound of the formula (103) were suspended in 100 ml of 20 X deionized water using a wetting agent. 29 g of 70% 3-chloroperbenzoic acid (MCPBA) were dissected and the mixture was heated with stirring. A resin / water phase was formed at 52 X; the mixture was heated to around 80 X and kept at this temperature for 7 hours. It was treated with 0.5 g of sodium hydrogen sulfite to remove excess peroxide. Two clear phases were obtained by the addition of 50 ml of a mixture of xylene isomer and 9 g of 10N NaOH. The water phase with a pH of about 12 was separated; the phase of the solvent comprising the compound of the formula (106) was washed with water until neutral. To hydrolyze the ester, the xylene phase was treated with 24 g of 10% NaOH and stirred until refluxing (around 95 X) for 5 hours. The xylene phase was then separated and the pale brown water phase was adjusted to a pH of about 3 using 4 g of 34% hydrochloric acid at 25 X. In the course of this process, the product is precipitated in a beige, sandy, and after filtering can be washed carefully with water on the suction filter. After drying, 5 g of the crude product of the formula (107) were obtained with a melting point of between 73 to 74 X. After recrystallization of the petroleum ether 80/110, the pure substance was obtained in colorless crystals which they have a melting point of between 74 and 74.5 X. Examples 8 to 14: The following compounds were obtained analogously to the preparation of the process described above:

Claims (17)

1. Process for the preparation of halogenated hydroxydiphenyl compounds of the formula: by means of the acylation of a halogenated benzene compound (first stage), the etherification of the compound added with a halogenated phenol compound (second stage), oxidation of the etherified compound (third stage) and the hydrolysis of the oxidized compound in the fourth stage , according to the following reaction scheme: where Ri and R2 independently of each other are F, Cl or Br; Ra and R4 independently of each other are hydrogen; or C1-C4 alkyl; m is between 1 and 3; and n is between 1 or 2.

2. A process according to Claim 1, wherein in the acylation reaction (first step) the compound of the formula (5) was formed.

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

4. A process according to any of Claims 1 to 3, wherein the acyl halide, preferably acetyl chloride, was used for the acylation reaction.

5. A process according to any of Claims 1 to 4, wherein the etherification (second step) the compound of the formula (7) was formed.

6. A process according to any of Claims 1 to 5, wherein the etherification of the free OH group of the halogenated phenol compound of the formula (6) was carried out in an alkaline medium using a strong base, preferably NaOH or KOH.

7. A process according to any of Claims 1 to 6, wherein in the oxidation (third step) the compound of the formula (8) is formed.

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

9. A process according to any of Claims 1 to 8, wherein the oxidation was carried out in the presence of a mixture of sodium borate and trifluoroacetic acid.

A process according to any of Claims 1 to 9, which relates to the preparation of compounds of the formula (1) wherein

11. A process according to any of Claims 1 to 10, which relates to the preparation of the compounds of the formula (1) wherein m is 2 and n is 1.

12. A process according to any of Claims 1 to 10, which relates to the preparation of the compounds of the formula (1) wherein m and m are 1.

13. A process according to any of Claims 1 to 11, which relates to the preparation of the compounds of the formula wherein R < And R2 are Cl; and m is 2 and n is 1.

14. A process according to any of Claims 1 to 11 or 13, which relates to the preparation of the compound of the formula

15. A process according to any of Claims 1 to 12, which relates to the preparation of the compound of the formula

16. A compound of the formula wherein R, R2 ', and R3' independently of each other are F, CL or Br; and R4 ', and Rs independently of each other are hydrogen; or C1-C5 alkyl.

17. The use of the compounds prepared by the process according to any of Claims 1 to 15 as disinfectants to protect organic materials from attack by microorganisms. SUMMARY A process for the preparation of haiohydroxydiphenyl compounds of the formula is described by means of the acylation of a halogenated benzene compound (first stage), the etherification of the compound added with a halogenated phenol compound (second stage), oxidation of the etherified compound (third stage) and the hydrolysis of the oxidized compound in the fourth stage , according to the following reaction scheme: where Ri and R2 independently of each other are F, Cl or Br; R3 and R- independently of each other are hydrogen; or C? -C4 alkyl; m is between 1 and 3; and n is between 1 or 2. The compounds of formula (1) are used to protect organic materials and organic articles from microorganisms.