HK1015357B - Process for the preparation of halogenated hydroxy diphenyl compounds - Google Patents

Description

The present invention relates to the production of halogenated hydroxydiphenyl compounds of the formula: In which R1 and R2Cl;m2; and n 1 or n 1; and the use of these compounds as disinfectants to protect organic materials from microorganisms.

The preparation of halogenated hydroxydiphenyl compounds, in particular 2-hydroxy-2',4,4'-trichloroethylene (triclosan; compound of formula (3)), is usually carried out by diazotizing and subsequent hydrolysis of 2-amino-2',4,4'-trichloroethylene (TADE; compound of formula (2)). Other

However, the yield from this production method is unsatisfactory because of the different competing chemical reactions that can take place.

In the Journal of Medicinal Chemistry (1983), 1354-1360 the production of 2-phenoxyphenyl) acetic acids is described by acylation of a phenolate, etherisation to the phenoxyphenylacetyl compound and subsequent oxidation to the corresponding phenoxyphenylacetic acid.

EP-A-0.384.043 describes a method for the production of brominated diphenyl ether compounds by the reaction of a substituted phenol compound with a halogenated phenyl carbonyl compound in an alkaline medium using the base in equimolar quantities or in excess, depending on the phenol compound used.

The present invention is therefore based on the objective of finding an economic method of producing halogen hydroxydiphenyl compounds which will suppress undesirable side reactions.

The problem is solved in accordance with the invention by a four-step reaction in which a halogenated benzene compound is acylated in the first step, the acylated compound is etherised in the second step with a halogenated phenolic compound, the etherised compound is oxidised in the third step and the oxidized compound is hydrolysed in the fourth step, according to the following reaction scheme: characterised by the second step being carried out in the presence of a strong organic or inorganic base, a copper catalyst and an inert organic solvent selected from toluene and xylol isomer mixtures,

In the above diagram, R1, R2, m and n have the meanings given in formula (1).

The first reaction step (acyllation reaction) produces compounds of formula (5), usually in the presence of a Lewis acid, such as aluminium halides, especially aluminium chloride. The Lewis acid is used in 1 to 3, preferably 1.25 to 2 molar quantities, based on the halogenated compound of formula (5). An acyl halide, especially acetyl chloride, is used as an acyl reaction agent. Lewis acid and acyl reaction agent are preferably used in equimolar quantities. The reaction is carried out in the solvent used for Friedel-Craft reactions, e.g. chloride or methylene.

The second reaction step is to produce the compounds of formula (7); the etherisation of the free OH group of the halogenated phenol compound of formula (6) is usually carried out in an alkaline medium using a strong organic or preferably inorganic base, e.g. NaOH or KOH, and in the presence of a copper catalyst and an organic solvent, e.g. toluene or a xylol-lysomer mixture. The reaction times for this reaction step are usually 1 to 24 hours, preferably 2 to 10 hours, and the temperature ranges from 80 to 250 °C, preferably 100 to 170 °C.

The third reaction step (oxidation) produces compounds of formula (8) and the oxidation of the acyl compound of formula (7) to the compound of formula (8) (Baeyer-Villiger oxidation) can be carried out with various oxidizers. Mix of diluted peroxyacetic acid and acetic acid in the presence of a catalytic amount of perchloric acid;m-chloroperenzoic acid ((MCPBA) in water;di-peroxydecandidoic acid (DPDDA);mix of diluted peroxyacetic acid and acetanide and sulphuric acid;perbenzoic acid (PBA)mix of sodium borate and trifluoric acid;mix of formic acid, hydrogen peroxide, acetanide, phosphoric oxide and acetic acid;mix of acetic acid, hydrogen peroxide, acetanide and phosphoric oxide;methacrylate carbonate2S2O28, sulphuric acid and potassium 1:1/methacrylate hydrogen peroxyacetic acid/methacrylate hydrogen peroxyacetic acid and trifluoric acid;methacrylate oxide and methacrylate oxide;methacrylate oxide and monohydrogen peroxyacetic acid;methacrylate oxide and methacrylate oxide;methacrylate oxide and methacrylate oxide;methacrylate oxide oxide;methacrylate oxide and methacrylate oxide;methacrylate oxide oxide;methacrylate oxide oxide and methacrylate oxide;methacrylate oxide;methacrylate oxide oxide and methacrylate oxide;methacrylate oxide;methalate oxide;methalate oxide oxide and methalate oxide;methalate oxide;methalate oxide;methalate oxide and methalate oxide;methalate oxide;methalate oxide;methalate oxide;methalate oxide;methalate oxide;methalate oxide;methalate oxide;methalate oxide;methalate oxide;methalate oxide;methalate oxide;methaate oxide;methaate oxide;methaate oxide;methaate oxide;methaate oxide;methaate oxide;methaate;methaate;methaate;metha

Preferably, m-chloropeptobenzoic acid (MCPBA) is used for oxidation, a mixture of sodium borate and trifluoric acid or a mixture of acetic anhydride and H2O2. If necessary, a commercial net agent can be added to the oxidizer. The reaction times range from about 0.5 to about 15, preferably 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 the desired halogen hydroxydiphenyl ether of formula (1) is carried out quantitatively in the acid or alkaline medium.

In particular, compounds of formula (1) are preferred to the formula or Other

The halogenated hydroxy-diphenyl compounds manufactured in accordance with the invention are insoluble in water, but soluble in dilute sodium and potassium hydroxide solution and in virtually all organic solvents. These solubility conditions make them very versatile for use in the control of microorganisms, particularly bacteria, and as disinfectants to protect organic materials and objects from microorganisms. They can be used, for example, in combination with dispersants, such as soap or synthetic solutions for disinfecting and cleaning human skin and hands, hard objects, and in dental nets, in this form, diluted or undiluted.

The following examples illustrate the invention without limiting it to them.

Manufacture from materials of any heading, except that of the product Example 1: Production of 2,5-Dichloroacetophenone (first reaction step) The reaction schedule:

In an apparatus with a drip funnel, stirrer and backflow cooler, 147 g (1.0 mol) of p-dichlorobenzene is completely melted at 60 °C. 120 g (0.9 mol) of anhydrous AlCl3 is added to the melt. Then 39.3 g (0.5 mol) of acetyl chloride is dripped to the well-stirred suspension at 60 °C for about 1 hour, slowly forming a clear solution. After heating to 110 °C, stirring at this temperature for 7 hours. After cooling to room temperature, the brown reaction mass is drawn out through a transparent drain onto a mixture of 200 ml of water and 200 ml of hydrolyzed ice. The temperature of the mixture is maintained during hydrolysis by cooling between 30 and 40 °C. The p-p-p is then held under a separate water separation phase, with 400 ml of organic p-p being removed before re-activation.

The following shall be added to the list of active substances:

Example 2: Production of 1- ((5-Chloro-2- ((2,4-Dichlorophenoxy) -phenyl ethanoon (second reaction step) The reaction schedule:

The red-brown clear solution is then cooled to 100°C, mixed with 189 g of 2,5-dichlorophenone (compound of formula 101) and 0,8 g of basic copper carbonate, heated to 140°C and stirred at this temperature for 8 hours. The reaction solution turns dark red-brown and a white precipitate is produced which is filtered. After distillation of the largest part of the xylenol product in a light water vacuum, a fraction of 208 g is obtained, corresponding to the initial 2,4-dichlorophenone (D.O.P.H.O.P.H.O.P.H.O.) at 165°C. (Th.H.O.P.H.O.P.H.O.P.H.O.P.H.O.) and some 8 mg of Xylenol (Th.H.O.P.H.O.P.H.O.) at 160°C. (Th.H.O.P.H.O.P.H.O.) at 82°C. (Th.H.O.O.P.H.O.O.P.H.O.) at 165°C. (Th.H.O.O.P.P.H.O.O.P.H.O.) at 85, and some 8 mg of Xylenol is still present at 30°C.H.P.P.H.O.P.H.O.P.H.O.O.P.H.O.P.H.O.) at 165°C. (Th.H.P.P.P.H.O.P.H.O.) at 160°C.H.H.H.H.O.O.H.O.H.O.H.H.O.H.O.O.O.O.H.O.O.O.H.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O. Other

	C	H	Cl	Q
Berechnet [%]	53,28	2,87%	33,7%	10,14
Gefunden [%]	53,31	2,85	33,37	10,31

Example 3: Production of 1- ((5-Chloro-2- ((4-Chlorophenoxyl-phenyl) ethanoon (second reaction) (see also

The procedure described in example 2 shall be followed, but using 128,6 g of 4-chlorophenol instead of 163 g of dichlorophenol.

After a reaction time of 2 hours at 140°C and the subsequent treatment described in example 2, a pre-fraction of 223 g (Sdp. 30-112°C/1 mm Hg) yields a main fraction of 91 g (Sdp. 112°C-173°C/1 mm Hg) which, in addition to the parent product 2,5-dichloroacetophenone, makes up more than 80% of the reaction product of the formula Contains a white powder which, when cooled, solidifies (Fp = 64°C). Other

	C	H	Cl	O
Berechnet [%]	59,81	3,59	25,22	11,38
Gefunden [%]	59,74	3,48	25,49	11,29

Example 4: Production of 5-Chloro-2- (2,4-Dichlorophenoxy) phenol by Baeyer-Villiger oxidation with m-Chlorperbenzoic acid (MCPBA) (third and fourth reaction steps) The reaction schedule:

6.3 g of the acetyl compound of formula (102) are slurried in 40 ml of deionized water at 20°C. 9.8 g of m-chlorophenic acid (MCPBA) are added and the mixture is heated by stirring.

To destroy the excess peroxide, add 0.5 g of sodium hydrogen sulphite. Add 50 ml of ethylene chloride and 4 g of 10N NaOH to obtain two clear phases. Separate the water phase with a pH of about 12, wash the solvent phase with neutral water. After distillation of the solvent, 5.5 g of crystallizing compound of the formula (104) (phenolester intermediate) remain.

For hydrolysis, the phenolester is dissolved in 50 ml of ethylene chloride and 10 ml of 5N sodium brine. It is heated to 70-73°C, maintained at this temperature for 15 minutes, then the pH is set to about 4 with acetic acid and the phases are separated.

After clarification and recrystallization from petroleum ether 80/110 the pure product is obtained in colourless crystals and with a melting point of 56 to 57 °C.

Example 5: Production of 5-Chloro-2- (2,4-dichlorophenoxy) phenol by Baeyer-Villiger oxidation with NaBO3 (third and fourth reaction steps)

6.3 g of the acetyl compound of formula (102) are suspended in 20 ml of trifluoroacetic acid and added at 20°C to 9.3 g of sodium perborate tetrahydrate. Heat to 40°C and keep this temperature for 90 minutes under good stirring. After hydrolysis of the phenoester formed and processing in analogy to example 4, 5.4 g of the raw product of formula (105) is obtained.

Example 6: Production of 5-chloro-2- (2,4-dichlorophenoxy) phenol by Baeyer-Villiger oxidation with acetic anhydride/H2O2

18 ml of acetic anhydride is mixed at -5°C with 4.5 ml of 98% sulphuric acid. 4.2 ml of 30% hydrogen peroxide is dripped for 25 minutes under very strong stirring at -5 to -3°C. The milky emulsion is mixed at -5°C with 12.5 ml of methyl chloride to form a clear solution.

The reaction mixture is two-phase and dark. The reaction is maintained at 0 to 5°C for one hour, then 10°C for 4 hours and 15°C for 1 hour. The final reaction is carried out at 20°C for 20 hours, with the intermediate phenolester of formula (104) partially hydrolyzing to the phenolester derivative of formula (105). After destruction of the excess hydrogen peroxide, the methylene chloride is distilled. For complete hydrolysis, the temperature is maintained at 100°C for 4 hours. The product is obtained by methylene chloride extraction.

Example 7: Production of 5-chloro-2- ((4-chloro-phenoxy) phenol (third and fourth reaction steps) The reaction schedule:

14 g of the acetyl compound of formula (103) are slurred with a net in 100 ml of deionized water at 20°C. 29 g of 70% 3-chloroperthobenzoic acid (MCPBA) are added and the mixture is heated by stirring.

To destroy the excess peroxide, add 0.5 g of sodium hydrogen sulphite, add 50 ml of xylol lysomeric mixture and 9 g of NaOH 10N to obtain two clear phases, separate the water phase with a pH of about 12 and wash the solution phase containing formula (106) with water neutrally.

The xylol phase is then separated and the light brown water phase is placed at 25°C with 4 g 34% hydrochloric acid at a pH of about 3. The product then falls out in a sandy, beige form and can be thoroughly washed with water after filtration on the nut. After drying, 5 g of the raw product of the formula (107) with a melting point of 73 to 74°C is obtained.

After recrystallization from petroleum ether 80/110 the pure substance is obtained in colourless crystals with a melting point of 74 to 74,5 °C.

Examples 8 to 14: In the same way as the manufacturing process described above, the following compounds are available:

Claims (7)

1. A process for the preparation of halogenated hydroxydiphenyl compounds of the formula by acylation of a halogenated benzene compound (first stage), 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 a fourth stage, according to the following reaction scheme: characterized in that the second stage is carried out in the presence of a strong organic or inorganic base, a copper catalyst and an inert organic solvent selected from the group consisting of tolvene and xylene isomer mixtures, where

   R₁ and R₂ are Cl;

   m is 2; and

   n is 1; or

   m and n are 1.
2. A process according to claim 1 characterized in that the acylation reaction (first stage) is carried out in the presence of a Lewis acid.
3. A process according to either one of claims 1 and 2, characterized in that an acyl halide, preferably acetyl chloride, is used for the acylation reaction.
4. A process according to any one of claims 1 to 3, characterized in that the oxidation is carried out in the presence of m-chloroperbenzoic acid.
5. A process according to any one of claims 1 to 3, characterized in that the oxidation is carried out in the presence of a mixture of sodium borate and trifluoroacetic acid.
6. A process according to any one of claims 1 to 5, characterized in that it relates to the preparation of the compound of the formula
7. A process according to any one of claims 1 to 5, which relates to the preparation of the compound of the formula