DE1668968A1 - New organic compounds - Google Patents

Description

Patent application,

Sandoz AG Dr.W.Schrik.W-Ahe.?. Confused

Basel DipL-iG. G. ur ..- / i..bcr3 - Case 6ΟΟ-6136

Dr. V. Sc'iTii.T · ''. Lyvarzk

Dr. P. Wcii; 'iülJ ,. Dr. D. Gudel

6 FrankiurifM., Gr. Eschenheimer S »r. 39

New organic compounds

The present invention relates to compounds of the general. Formula I, wherein the radical Y has the same meaning and either for the trifluorraethyl or for the 4-chlorophenyl or the phenyl group and R, hydrogen, a salt-forming cation, an alkyl group with 1-4 carbon atoms or a basic radical of the general formula

- (CH ₀ )

means where η is an integer from 0-4, n ^{1 is} 4 or and R is an alkyl group with 1-4 carbon atoms, as well as the acid addition salts or quaternary ammonium compounds of compounds of the general formula I which have the above basic residue included

109842/1863

NeU3 documents (Art. 7 11 para. 2 No. I sentence 3 of the amendment aees.

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According to the invention you can either

a) to compounds of the general formula Ia, in which Y has the above meaning and R _{2 is} a group of the general formula

stands in which n, n ¹ and R, have the above meaning, their quaternary ammonium compounds or their acid addition salts, get by either

i) Compounds of the general formula Ib, in which Y and R_ have the above meaning, with compounds of. general formula IV, in which R _{0 has the} above meaning, converts or

ii) Compounds of the general formula II, in which Y

and R, have the above meaning, with compounds of the general formula IV at temperatures partial decarboxylation occurs, converts or

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iii) Compounds of the general formula IHa, in which Y Has the above meaning and Hal stands for chlorine or bromine, with compounds of the general formula IV or with compounds of the general formula IVa, in which R_ has the above meaning and Me is an alkali metal stands, implements

and the compounds of the general formula Ia thus obtained, optionally subsequently into their quaternary ammonium compounds or converted into their acid addition salts or. .

b) to obtain compounds of the general formula Ib by either

i) 1 mol of compounds of the general formula VI, in which Hai and FU have the above meanings, with at least 2 moles of compounds of the general formula V, in which Y and Me have the above meaning, in one below

reacts with one another under the reaction conditions inert organic solvents or

ii) Compounds of the general formula II partially decarboxylated or

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iii) Compounds of the general formula III, wherein Y is above Has meaning and Q stands for a hydroxyl group, chlorine or bromine, with compounds of the general. Formula VII, wherein R-. has the above meaning,. implements or

iv) Compounds of the general formula IHa with compounds of the general formula VIIa, in which PL · and Me have the above meaning, implements or

c) to compounds of the general formula Ic, wherein Y is above Has meaning, and / or their .Salzen, with salt-forming Cations arrive by either

i) Compounds of the general formula VIII, in which Y has the above meaning, partially decarboxylated or

ii) compounds of the general formula Ib saponified or

iii) compounds of the general formula II at temperatures, partial decarboxylation occurs, saponified or

109842/1863

iv) 1 mole of compounds of the general formula VIa, in which Hai and Me have the above meaning, with at least 2 moles of compounds of the general formula V in one reacts with one another under the reaction conditions inert organic solvents

and liberates the acids of the general formula Ic from the salts obtained, if any, or the acids obtained of the general formula Ic. Formula Ic, optionally then by reaction with appropriate bases in.'i: salts with salt-forming cations convicted.

The reaction of compounds of general formula Ib with compounds of general formula IV described in section a) under i) is preferably carried out in an organic solvent which is inert under the reaction conditions, for example toluene, xylolodobenzene, in the presence of a lower alkali metal alcoholate, preferably sodium methylate or sodium ethylate, at temperatures between 50 and 15O ⁰ C, but preferably at the boiling point of the respective solution is performed.

The conversion of compounds described in section a) under ii) the general. Formula II with compounds of the general. Formula IV is preferably used in one under the reaction conditions inert organic solvent with a boiling point of at least 100 ° C, for example toluene or xylene, in counter-

ORIGlNA INSPECTED 10984? / 1863

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waiting an alkali metal alcoholate "preferably sodium methylate or sodium ethylate performed · Since the required for partial decarboxylation temperature at about 100 ° C, the reaction should preferably be carried out at temperatures of at least 100 ° C, ie between 100 and I5O ⁰ C.

The conversion of compounds described in section a) under iii) of the general formula IHa with compounds of the general formula IV or with compounds of the general formula IVa is preferably in an organic under the reaction conditions Solvents, for example benzene, toluene, chloroform or diethyl ether, at room temperature (20 ° C.) or below, preferably between 5 and -10 ° C. The implementation can also take place at higher temperatures, but this must be done because of the strong heat generated during the reaction be cooled. If compounds of the general formula IV are used for this reaction, it is advisable to use the Reaction resulting halogen-hydrogen with the help of suitable inorganic, basic reagents, for example alkali metal carbonates such as potassium or sodium carbonate or organic, basic reagents such as pyridine. An excess of compounds of the general formula IV can be used instead of basic reagents. In case of connections the general formula IVa is assumed, it is advisable to use their sodium or potassium compounds.

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The compounds of the general formula Ia obtained in this way are prepared in a manner known per se from the corresponding reaction mixtures isolated and purified and, if necessary, then converted into their quaternary ammonium compounds or into their acid addition salts convicted.

The reaction, described in section b) under i), of 1 mol of compounds of the general formula VI with at least 2 mol of compounds of the general formula V, preferably with the sodium or potassium compounds of the compounds of the general formula V, at temperatures between room temperature (20 ° C) and 80 ° C in an inert organic under the reaction conditions Solvent, for example dimethylacetamide, diethylacetaraid or dimethylformamide performed.

The in section b). Partial decarboxylation described under ii) of compounds of the general formula II is expediently carried out in an anhydrous, under the reaction conditions inert organic solvent which has a boiling point of at least 75 ° C, for example toluene or xylene, " by heating to at least 80 ° C. The reaction is preferably carried out in the presence of inorganic hydroxyl groups or organometallic bases, such as, for example, alkali or alkaline earth metal hydrides or alcoholates with 1-4 carbon atoms such as sodium methoxide or potassium tert-butoxide.

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The reaction of acid chlorides or acid chloride of compounds of the General formulas III and IHa with compounds of the general formula VII or VIIa is in an inert organic solvent under the reaction conditions, for example benzene, toluene, Chloroform or diethyl ether, carried out at a temperature of 30 ° C or below. Implementation can also take place at higher temperatures can be carried out, but you have to Pay attention to strong cooling. When using compounds of the general formula VII and in particular of tert. Butyl alcohol must be Halogen-hydrogen formed during the reaction with the aid of suitable basic reagents, for example alkali metal carbonates such as potassium or sodium carbonate or organic, basic reagents such as pyridine. As connections of the general formula VIIa, the potassium or sodium compounds are preferably used. The one under ill) as well described conversion of an acid of the general formula III (Q «OH) with compounds of the general formula VII can either be in an organic solvent inert under the reaction conditions, for example toluene, in the presence of catalytic amounts of an esterification catalyst such as sulfuric acid or a sulfonic acid such as p-toluenesulfonic acid, at temperatures

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between 50 and I3O ⁰ C, but preferably at the boiling temperature, using compounds of the general. formula VII in a üeberschuss of 10 to 100% or without additional solvent, in a far beyond the oe necessary amount of continuous Üeberschuss of compounds of the general. formula VII can be carried out in the presence of an esterification catalyst at the boiling point.

The Connectivity resulting 's the general. Formula Ib are from their reaction mixtures isolated on known manner and purified. ·

The partial decarboxylation described in section c) under i) of compounds of the general formula VIII can, for example, be carried out in such a way that the compounds are either without a solvent or in an organic solvent which is inert under the reaction conditions and has a boiling point of . at least 100 ° C, e.g. toluene or xylene, to temperatures heated above their melting point. Furthermore, the partial decarboxylation in an aqueous-alkaline solution, for example an aqueous potassium or sodium hydroxide solution, optionally in the presence of another, miscible with water organic solvents such as 2-methoxyethanol, at least 70 ° C, but preferably at the boiling point of the respective solution.

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The saponification of compounds of the general formula Ib described in section c) under ii) is preferably carried out in such a way that they are dissolved in water or in a mixture of water and a water-miscible organic solvent such as methanol, ethanol or a cyclic ether such as Dloxan or tetrahydrofuran, with a strong inorganic base at temperatures between 10 and 100 ⁰ C, but preferably between

4th
80 and 100 ° C. Is preferred for saponification. An inorganic base is used which forms a water-soluble salt of the desired acid, such as sodium or potassium hydroxide, for example. The compounds of the general formula Ic are released from the salts obtained in this way by treatment with acids, for example with mineral acids such as hydrochloric acid.

and part. Decarboxylation The saponification / of Compounds of the general formula II is preferably carried out in such a way that that they are in water or in a mixture of water and a water-miscible organic solvent such as methanol, ethanol or a cyclic ether such as dioxane or tetrahydrofuran, with a strong base at temperatures treated by * at least 75 ° C. Preferred saponification

wisely used an inorganic base that forms a water-soluble salt of the desired acid, such as sodium or Potassium hydroxide. The salts obtained in this way become

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the compounds of general formula Ic by treatment with Acids, for example with mineral acids such as hydrochloric acid, released

The reaction, described in section c) under iv), of 1 mol of compounds of the general formula VIa with at least 2 mol of compounds of the general formula V is preferably used with the sodium or potassium compounds of the compounds of the general formula V at temperatures between room temperature (20 ° C) and 80 ° C in an inert organic under the reaction conditions Solvents, for example dirnethylacetamide, diethylacetamide or dimethylformamide. The compounds of the general formula Ic are obtained from the salts obtained in this way by treatment released with acids, for example with mineral acids such as hydrochloric acid.

The compounds of the general formula Ic obtained in this way are selected from the corresponding reaction mixtures isolated and purified in a manner known per se and, if appropriate, subsequently converted into their salts with salt-forming cations by reaction with suitable bases.

The preparation of the in section a) under i) as starting compounds Compounds of the general formula Ib used are described in section b) under i), ii), iii) and iv).

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Those used as starting compounds in section a) under ii) Compounds of the general formula II are new and, like the process described below for their preparation, form an object of the present invention.

Compounds of the general formula II can be obtained by 1 mol of compounds of the general formula IX, wherein Hai and R, above Have meaning, with at least 2 moles of compounds of the general formula V, "preferably their sodium or potassium compounds.

up to 80 ° C, preferably
at temperatures / between room temperature (20 ° C.) and 80 ° C. in an organic solvent which is inert under the reaction conditions, for example dirnethylacetamide, diethylacetamide or dimethylformamide.

Those used as starting compounds in section a) under iii) Compounds of the general formula IHa are new and, like the process described below for their preparation, an object of the present invention.

Compounds of the general formula Ic are preferably in an organic solvent which is inert under the reaction conditions, for example diethyl ether, with suitable chlorination or

Thionyl chloride,
Brominating agents such as / thionyl bromide, phosphorus pentachloride or phosphorus pentabromide, treated at temperatures between room temperature (20 ° C) and the reflux temperature of the reaction mixture. However, the use of a solvent is not essential

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necessary because an excess of the halogenating agent Can replace solvents. The halogenation reaction is caused by the presence of catalytic amounts of dimethylformamide favored.

The compounds of the general formula IV used as starting compounds in section a) under i), ii) and iii) are known and can be used to prepare compounds of the general formula IVa if these are not yet known. The compounds of the general formula IX · required for the preparation of the starting compounds of the general. Formula II used in the Ab ^ ^s Nitt a) under ii) are also known.

The compounds of the general formula VI used as starting compounds in section b) under i) are known. The one in this Section compounds of the general formula V also used as starting compounds are obtained by adding compounds of the general formula X with alkali metal hydrides, preferably sodium or potassium hydrides. The connections of the general Formula X are known.

Those used as starting compounds in section b) under iii) Compounds of the general formula III are in the form of the free acids (Q «OH) identical to the compounds of the general formula III.

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Formula Ic, the preparation of which in section c) under i), ii), iii) and iv). In the form of acid chlorides or acid bromides (Q = chlorine or bromine) the compounds of the general formula III are identical to the compounds of the general formula IHa [Starting compounds for the processes described in sections a) under iii) and b) under iv)], their preparation is described above.

The compounds of the general formula VIII used as starting compounds in section c) under i) are new and also form such as the process described below for their preparation, an object of the present invention.

Compounds of the general formula II are in water or in a mixture of water and a water-miscible organic Solvent, for example methanol, ethanol or a cyclic ether such as doxane or tetrahydrofuran, by treatment saponified with a strong inorganic base at temperatures not exceeding 80 ° C. As inorganic bases those which form a water-soluble salt of the desired acid can be used, e.g., sodium or potassium hydroxide or those that form a water-insoluble salt such as barium hydroxide.

The acids of the general formula VIII can be prepared from the salts obtained in this way by treatment with an acid, for example

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a mineral acid such as hydrochloric acid, in the event that the Barium salt was prepared, preferably by treatment with sulfuric acid, to be released.

The starting compounds used in section c) under iv) the general formula VIa are known. The manufacture of the likewise Compounds of the gen. Formula V is described above. The preparation of the starting compounds in section c) under ii) is also described above compounds of the general formula Ib used and those used as starting compounds in section c) under iii) Compounds of the general formula II.

In the practical execution of the reactions that involve diesters of dicarboxylic acids or of dicarboxylic acids themselves take place as output or intermediate connections, it is understandable that not in every case these intermediate connections need to be isolated. For example, [according to the method specified above under c) iii)] in the Preparation of compounds of general formula Ic either the compounds of general formula II initially to compounds of General formula Ib [process b) ii)] partially decarboxylated and this at the same time or subsequently without isolation Compounds of the general formula Ic [process c) ii)] are saponified, or the compounds of the general formula II to give compounds of the general formula VIII and saponified this without isolation

early or subsequently partially to connections of the general

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Formula Ic are decarboxylated [method c) i)] ·

Some compounds of the general formula Ia have an asymmetric carbon atom and can therefore be obtained both in racemic and in optically active form. Optically active compounds of the general formula Ia can be obtained by resolving racemic compounds of the general formula Ia into their optical antipodes or in their preparation using optically active alcohols or optically active alcoholates as intermediate compounds. The optically active compounds of the general formula Ia obtained in this way can, if appropriate, subsequently be converted into their acid addition salts or quaternary ammonium compounds.

Compounds of the general formula Ia can be converted into their acid addition salts by reaction with suitable organic or inorganic acids and converted into their quaternary ammonium salts with suitable quaternizing agents. For the production of acid addition salts, the following acids have proven to be suitable:

Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, benzoic acid, acetic acid, maleic acid, fumaric acid, p-toluenesulfonic acid and benzenesulfonic acid.

Straight-chain ones have proven to be suitable quaternizing agents

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Alkyl bromides, chlorides and iodides such as methyl bromide, methyl chloride, ethyl bromide, methyl iodide and ethyl iodide and straight-chain dialkyl sulfates such as dimethyl sulfate, have been shown to be suitable

Salts of compounds of the general formula Ic with salt-forming Cations are for example the aluminum salts, non-toxic alkali metal salts, e.g. potassium and sodium salts, non-toxic Alkaline earth metal salts, e.g. magnesium and calcium salts, ammonium salts and corresponding ammonium salts with organic, basic compounds that contain at least 1 nitrogen atom, e.g. physiologically compatible primary, secondary and tertiary amines, such as ethanolamine, diethanolamine, triethanolamine, etc.

The compounds of the general formula prepared according to the invention I have beneficial pharmacodynamic effects and can therefore be used as medicinal products. Own the connections in particular a cholesterol blood level lowering effect and are therefore .for administration as a cholesterol blood level lowering and Blood lipid lowering agents suitable. To achieve the desired therapeutic success, 0.25-2 g of one should be used daily Compound of the general formula I can optionally be administered in several smaller doses of 62.5 to 1000 mg 2-4 times a day.

Each of the compounds obtained according to the invention can e.g.

for oral administration in the form of a tablet with the following

Composition are brought:

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1-3 % binding agent (e.g. tragacanth), 3-10 % starch, 2-10 % talc, 0.25-1 % magnesium stearate, corresponding amount of active substances and ad 100 % filling substance, e.g. lactose.

The o.e. Substituent R «means a heterocyclic ring, the - (CH) - group at every possible position can be bound.

In the following examples, which illustrate the implementation of the process, but in no way limit the invention should, * all temperatures are given in degrees Celsius and have been corrected.

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? H-COOR,

600-6136

vy-ο-

m-cooR,

Yes

Vo,

• CH COOR.

γ- Λ \ yo-

γ-β V> -o.

CH-COOH

Y - // V, -O

Ib

Ic

109842/1863

6OO-6I36

Y-A \ V - <

JOOR,

'CH'

II

COOR.

CH-COQ

III

CH-COHaI

IHa

Y- / TV0

- OH

IV

- OMe

IVa

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Y-J / Vv-O-Me

Ha] ₂ - CH - COOR Ha] ₂ - CH - COOMe ^R 3- OH

VI

Via

VII

- OMe

Vila

COOH VIII

coo:

Hal ₂ -C

COOR, IX

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Example It bis (4-biphenylyloxy) - essip: ethyl acid ester To a solution of 37.8 g (0.22 mol) of 4-phenylphenol in 500 ml of dimethyl acetamide, 5.28 g (0.22 mol) of sodium hydride, obtained from 8.8 g of a 60 J & Lgen sodium hydride suspension in mineral oil (after washing out the mineral oil with petroleum ether). The resulting mixture is stirred for 2 hours at room temperature and then 27 g (0.11 mol) of ethyl dibromoacetate in 25 ml of dimethylacetamide are quickly added dropwise. The mixture is then stirred for 16 hours at room temperature and the solvent is evaporated off in a rotary evaporator under vacuum (water jet pump vacuum) at 70-80 ° C. The residue is taken up in 1500 ml of ethyl acetate and the ethyl acetate solution is extracted first twice with 100 ml of water each time and then twice with 50 ml of an aqueous 2N sodium hydroxide solution each time. The ethyl acetate solution is dried over anhydrous sodium sulfate, filtered and evaporated to give the crude ethyl bis (4-biphenyiyloxy) acetic acid ester.

The product is purified by chromatography on a Silcagel column using chloroform as the eluent. The first portions of the chloroform fraction are collected, the chloroform is evaporated and the product thus obtained is crystallized from isopropyl ether. After renewed recrystallization from isopropyl ether yields the pure bis (4-biphenylyloxy) -acetate, mp 103.5 to 106.5 * ⁰ C.

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Example 2; Bis- (4-biphenylyloxy) -esslp; acid methyl ester Analogously to the process described in Example 1 is obtained

if the ethyl dibromoacetate used therein is replaced by an equivalent amount of methyldibromoacetate to the bis- (4 ~ biphenylyl-

oxy) -acetic acid methyl ester of melting point 108-110 ° C.

Example 3; Bis- (4-biphenylyloxy) -acetic acid-l-methyl-4-pipe-

ridyl ester

A mixture consisting of 12 g (0.0275 mol) of bis (4-bipheny IyI-oxy) -acetic acid methyl ester, 3.2 g (0.0275 mol) of 1-methyl-4-hydroxypiperidine, 100 ml of toluene and 0.2 g of sodium methylate * is distilled under atmospheric pressure until the temperature of the contents of the flask has reached ^{150 ° C. (after about 30 minutes).} This temperature of 150 ° C. is maintained for a further 15 minutes. Then, with the heating switched off, a vacuum (water jet pump vacuum) is carefully applied until the distillation has ceased. The mixture obtained is ^{cooled to 50 °} C. and mixed with 200 ml of benzene. Thereafter, cooling is continued to 20 ^° C. and 200 ml of water are added. The upper oily phase is separated off, washed first with 200 ml v / ater, then with 100 ml of a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The mixture is then evaporated in a rotary evaporator at a vacuum of approximately 100 mm Hg and the residue is recrystallized from 50 ml of isopropanol, the pure l-methyl-4-piperldyl bis (4-biphenylyloxy) acetic acid having a melting point of 114-117 ° C. being obtained .

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The procedure described above is used for replacement. of the bis (4-biphenylyloxy) ethyl acetate used therein by an equivalent amount of bis (4-biphenylyloxy) ~ acetic acid ethyl ester also to bis (4-biphenylyloxy) -acetic acid methyl-4-piperidyl ester.

Example 4; Bis- (4 ~ trifluoromethylphenoxy) acetic acid a) Bis- ^ - trifluoromethylphenoxy ^ -malonic acid diethyl ester

6.7 g of a 56.7% suspension of sodium hydride in mineral oil are washed with dry, low-boiling petroleum ether and the resulting sodium hydride, then suspended in 100 ml of dimethylacetamide. The suspension will cooled to 0 ° and with 25.5 g of p-trifluoromethylphenol in 25 ml Dimethylacetamide is added, the rate of addition being chosen so that the temperature does not exceed 10 ° (if necessary, can be cooled externally with an ice and salt bath). After the addition is complete, the "mixture is still during stirred for one hour and then removed the cooling. Then 23.8 g of diethyl dibromomalonate are added rapidly and allowed the temperature to rise to approximately 32 °. The mixture is then stirred for 88 hours 3/4 of the solvent was evaporated off in vacuo and 1500 ml of ethyl acetate were added to the remainder. After each twice washing the ethyl acetate solution with 1500 ml of water and 750 ml of 2N aqueous sodium hydroxide solution, this is removed

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separated, dried over anhydrous magnesium sulfate, filtered and evaporated, whereby the pure bis (4-trifluoromethylphenoxy) malonic acid diethyl ester from m.p. 55 * 5-5 ^ * 5 ° * b.p. 154-135β ° / 0.05 mm Hg.

b) bis- {4-trifluoromethane-lghenox5r2-njalonic acid

¹ To a ^rf at 20 C with stirring .hergestellten solution of 9.75 g (0.0507 mole) of barium hydroxide (99.5% Ba (OH) ₂ · 8HgO) in 115 ml methanol and 115 ml of water is quickly at the same temperature a solution of 14.756 "g", 0507 mol) of bis (4-trifluoromethylphenoxy) malonic acid diethyl ester in 40 ml of methanol was added with stirring. Three minutes after the solutions have been mixed, 10 ml of water are added with stirring and the mixture is then stirred for a further 15 minutes, the barium salt of bis (4-trifluoromethylphenoxy) malonic acid precipitating out. This is separated by filtration and dried at 6O ⁰ C for 5 hours in vacuo.

A suspension of 16.19 S (0.02895 mole) of barium salt of bis- (4-trifluoromethylphenoxy) malonic acid and 5 g of diatomaceous earth (Celite) in 200 ml methanol at 0 ⁰ C under stirring by adding dropwise a solution of 2, 97 g conc. Acidified sulfuric acid (95-95.5 %) in 5 ml of water. The mixture is then stirred for 20 minutes at room temperature and to

Removal of solid matter filtered. The separated solid components are washed with 100 ml of ethyl acetate. The ethyl acetate phase is combined with the Piltrat and the

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Solvent evaporated in a vacuum (water jet pump vacuum), whereby an oily residue is obtained. This is dissolved in 100 ml of ethyl acetate and twice with a saturated aqueous one Washed sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and then evaporated in vacuo to give an oily residue. This is done three times with 70 ml portions of petroleum ether Washed at 35O-6o ° C, the bis (4-trifluoromethylpherioxy) malonic acid is obtained in solid form with a melting point of 155-156.5 ° C. (with decomposition). After recrystallization from hexane / ethyl acetate (10: 1) the compound melts at 157-158 ° C (with decomposition)

c) bis (4-trifluoromethylphenoxy-2-acetic acid

7 * 3 g (0.01725 mol) of bis (4-trifluoromethylphenoxy) malonic acid are dissolved in a solution of 1.95 g (0.0 ^ 5 mol) of potassium hydroxide in 20 ml of water. Subsequently, the solution is added 60 ml of 2-Methoxyäthoxyäthanol and the resulting mixture heated for 4 hours in an oil bath at 170 ⁰ C to reflux. The mixture is largely freed from water by boiling under atmospheric pressure. The mixture is then heated ^{at 190 °} C. for a further 15 minutes. Thereafter, the 2-Methoxyäthoxyäthanol is largely evaporated in a water pump vacuum at 70 ⁰ C to give the crude potassium salt of bis (4-trifluoromethylphenoxy) acetic acid remains. This is dissolved in 100 ml of water, the solution is treated with charcoal and filtered through Celite. After acidification with 18 ml of 2 N HCl

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The crude bis (4-trifluoromethy! phenoxy) acetic acid separates as an oil that solidifies. The crude bis (4-trifluoromethylphenoxy) - ' acetic acid is collected by filtration and then dissolved in 100 ml of ethyl acetate. The ethyl acetate solution is twice with 50 ml portions of saturated aqueous sodium chloride solution

washed, dried over magnesium sulfate, and evaporated in vacuo to give an oily residue which by. Scratching becomes firm. After washing with 50 ml of petroleum ether at 30-60 ° C bis- (4-trifluoromethylphenoxy) acetic acid, mp. 120-12J obtained ^0C. After recrystallization from cyclohexane / benzene (5il), the compound melts at 127-128.5 ° C.

Example 5: bis (4-trifluoromethylphenoxy) -essip; acid-1-methyl-4-piperidyl ester

a) Bis - ^ - trifluorometh ^ lghenoxjr ^ -acetyl chloride

A mixture of 2.5 g (0.00657 mol) of bis (4-trifluoromethylphenoxy) acetic acid, 100 ml of anhydrous diethyl ether, 0.1 ml of dimethylformamide and 2 g (0.0168 mol) of thionyl chloride is placed in a vessel during k Heated at reflux for hours while a stream of nitrogen gas is passed through to remove hydrochloric acid formed during the reaction. The reaction mixture is then evaporated in a rotary evaporator under vacuum (water jet vacuum) at 45 ° C., an oily residue being obtained. This is dissolved in 60 ml of carbon tetrachloride, the solution is poured over anhydrous magnesium sulfate.

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dries and filtered. The filtrate is used to remove the Evaporated solvent in vacuo, the bis (4-trifluoro ~ methylphenoxy) acetyl chloride remains.

b) Bis - ^ - Trifluoromethylghenox ^^ - acetic acid-l-meth ^ l - ^ - gigeridjlester

A solution of 1.49 ε (0.0129 mol) of l-methyl-4-hydroxypiperidine in 50 ml of dry diethyl ether is added dropwise at 0 ° with stirring to a solution of 2.57 g (0.00645 mol) of bis- ( 4-Trifluoromethylphenoxy) acetyl chloride in 25 ml of dry diethyl ether was added and the mixture was cooled during the addition in order to keep the temperature between 0 ° and 5 ° C. A white solid precipitate begins to form. The mixture is then ^{stirred at 20 °} C. for a further 18 hours. The white solid precipitate (predominantly 1-methyl-4-hydroxypiperidine hydrochloride) is removed by filtration and the filtrate is first mixed with 50 ml

ice-cold aqueous 10 ^ strength sodium bicarbonate, then with JO ml saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and evaporated to leave an oily residue. This is dissolved in 20 ml of chloroform and the chloroform solution on silica gel placed in a sintered glass filter funnel. By eluting with 175 ml Chloroform impurities are removed and by repeated Eluting with 400 ml of ethyl acetate, the product obtained. The ethyl acetate solution is evaporated in vacuo, the

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Bis (4-trifluoromethylphenoxy) acetic acid 1-methyl-4-piperidyl ester is obtained as the free base.

0.977 g (0.00205 mol) of bis (4-trifluoromethylphenoxy) acetic acid methyl 4-piperidyl ester are added to 0.2 ^ 8 g (0.00205 mol) of fumaric acid in 10 ml of isopropanol, the acid addition salt of fumaric acid with bis (4-trifluoromethylphenoxy) acetic acid l-methyl-4-piperidyl ester is formed. After recrystallizing twice from 5 ml of isopropanol and charcoal, it melts the bis (4-trifluoromethyl '* "Bnoxy) -acetic acid-l-methyl-4-piperidyl ester · Fumarate

Example 6; Bis- (4-biphenylyloxy) -essiKäuräthylester A solution of 8.4 g of Kalumäthylat in 85 ml of ethanol with stirring and at a reaction temperature between 20 ° and 30 °, a solution of 41.6 g of bis (4-biphenylyloxy) acetyl chloride in 50 ml abs. Diethyl ether added. After the addition is complete, the mixture is stirred for a further 10 minutes and then evaporated to dryness in vacuo. 200 ml of chloroform, 100 ml of ice-water and 100 ml of a saturated aqueous sodium bicarbonate solution are added to the residue. The organic phase is then separated off, washed with 75 ml of water, dried over magnesium sulfate and evaporated. After recrystallization of the residue from isopropyl ether yields the bis (4-biphenylyloxy) -acetate, mp. 103.5 to 106.5 ⁰ C.

Example 7: bis (4-biphenylyloxy) acetic acid

Analogous to the procedure described in Example 1 and with replacement

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of the ethyl dibromoacetate used therein by an equivalent Amount of sodium salt of dichloroacetic acid. Work-up of the reaction product and the release of the acid from the product obtained Salt by treatment with hydrochloric acid in a manner known per se leads to bis (4-biphenylyloxy) acetic acid from m.p. 179-181 ° C:

Example 8: Bis- (4-biphenylyloxy) -acetic acid ethyl ester 39 g (0.1 mol) of bis- (4-biphenylyloxy) acetic acid are dissolved in 3OO ml of ethanol, which still contains 1 g of p-toluenesulfonic acid, for 14 hours on the reflux condenser Boiling heated. The mixture is then cooled to 60 ° C., 3 g of potassium carbonate are added and finally it is evaporated to dryness in vacuo. The residue obtained in this way is dissolved in 300 ml of benzene. The benzene solution is washed first with 100 ml of water, then with 100 ml of 10% aqueous sodium carbonate solution and then evaporated in vacuo. The residue is recrystallized from 150 ml of isopropanol and washed with ice-cold petroleum ether. The bis "- (4-biphenylyloxy) -acetic acid ethyl ester melts between 103.5 and 106.5 ° C.

Example Q; Bis (4-3iphenylyloxy) acetic acid

To 500 g (1.1 mol) of bis (4-biphenylyloxy) ethyl acetate are added 56.1 g (1 mol) of potassium hydroxide, 40 g (1 mol) of sodium hydroxide and 1500 ml of water. The resulting mixture is heated to boiling and distilling off the liberated methanol at a steam temperature of 65 ⁰ C. According to tempe-

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raturanstieg the steam to about 100 ⁰ C is heated still remaining mixture at reflux during one hour · to boiling. It is then allowed to cool to room temperature, whereupon the salts of bis (4-biphenylyloxy) acetic acid precipitate. This precipitate is filtered off, washed with water and then added to a mixture of 1000 ml of water and 2000 ml of ethyl acetate. The mixture obtained is adjusted to pH 1 with concentrated hydrochloric acid and the organic phase, in which the acid liberated is located, is separated off. After washing with 500 ml of saturated aqueous sodium chloride solution and drying over magnesium sulfate, the organic phase is evaporated, the bis (4-biphenylyloxy) acetic acid having a melting point of 179-181 ° C. crystallizes out.

Example 10; Bis- (4-biphenylyloxy) -acetic acid ethyl ester r ^a )

* 3 β (1 ^M ° l) of a 56.7 #igen suspension of sodium hydride in mineral oil are washed with dry, low-boiling petroleum ether and the sodium hydride obtained in this way is suspended in 1500 ml of dimethylacetamide. The suspension obtained is cooled to ⁰ ° C and then slowly added with 187.2 g (1.1 mol) of p-phenylphenol, that in this case the temperature of 10 ⁰ C does not exceed (external cooling with an ice-salt mixture can, if necessary). After all of the p-phenylphenol is added, that is formed

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Phenolate suspension stirred for a further hour. After removing any cooling bath, which may be used, 159 g (0 »5 mol) of diethyl dibromomalonate are quickly added, the temperature rising to approximately J> 2 ° 0 . The mixture is then stirred for 88 hours, then 5/4 of the solvent is evaporated in vacuo, 1500 ml of ethyl acetate are added and the resulting mixture is washed twice with 1500 ml of water each time and twice with 750 ml of 2N aqueous sodium hydroxide solution each time. The organic phase is separated off, dried over magnesium sulfate, filtered and evaporated to dryness. 500 ml of isopropyl ether are added to the residue obtained in this way, a crystalline product being formed which is washed with cold isopropyl ether. The washed crystals are dried in vacuo ^{at 80 ° C. for one hour.} The bis (4-biphenylyloxy) malonic acid diethyl ester obtained melts at 107-108.5 ° C.

100 g of bis (4-biphenylyloxy) malonic acid diethyl ester are combined with 0.1 g of sodium metal in 100 ml of a mixture consisting of 98 % ethanol and 2 % benzene, and the resulting mixture is heated under atmospheric pressure until 50 ml of the mixture , consisting of 98 % ethanol and 2 % benzene, are distilled off (for about an hour). The remaining reaction mixture is heated to boiling on the reflux condenser for a further hour and then a partial vacuum (vacuum from a water jet pump) is applied with heating.

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to remove the remaining solvent mixture.

Then the crude bis- (4-biphenylyloxy) acetic acid becomes in a high vacuum Eäthy read it is distilled off and uracrystallized from isopropyl ether. The ethyl bis- (4-biphenylyloxy) -acetate, purified in this way, melts between 105.5 and 105.5 ° C.

Example 11; Bis [4- (4-chlorophenyl) phenoxy] acetic acid

The procedure described in Example 4 a) is analogous to the replacement of the p-trifluoromethylphenol used therein by an equivalent amount of 4- (4-chlorophenyl) phenol to bis [4- (4-chlorophenyl) ~ phenoxy] malonic acid diethyl ester vom. M.p. 104-109 ° C.

b) bis [4- £ 4-chlorophenyl) phenoxy] acetic acid A mixture of 14.1 g of bis [4- (4-chlorophenyl) phenoxy] malon

and
acid diethyl ester / 2.8 g potassium hydroxide in 100 ml. A ethanol water (95: 5) solution is refluxed for 2 hours and then the ethanol is evaporated. The remaining phase is treated with a mixture of 100 ml of water and 52 ml of 1N hydrochloric acid, the crude bls- [4- (4-chloropheriyl) phenoxy] acetic acid precipitating out. This is collected on a filter, washed with ice water and crystallized from glacial acetic acid using charcoal. After recrystallization from glacial acetic acid, bis- [4- (4-chlorophenyl) phenoxy] acetic acid with a melting point of 157-167 ° C. is obtained.

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Example 12: Monoethanolamine salt of bis (4-blphenylylox y ) -essi g;

acid

• A mixture of 400 g (1 mol) bis (4-biphenylyloxy) acetic acid, 6l g (1 mol) monoethanolamine and 3000 ml isopropanol / ethanol (3: 1) is heated with stirring, whereby a clear solution (approximately at 8O ⁰ C) is obtained. It is then cooled to room temperature (20 ^° C.). The monoethanolamine salt of bis (4-blphenylyloxy) acetic acid crystallizes from the solution on standing, is collected and recrystallized from isopropanol / ethanol (3: 1). Mp. 135-137 ⁰ C.

Example 13: Triethanolamine salt of bis (4-biphenylyloxy) acetic acid

Analogously to the process described in Example 12, the monoethanolamine used therein is replaced an equivalent amount of triethanolamine to the triethanolamine salt of bis (4-biphenylyloxy) acetic acid. This is collected and recrystallized three times from isopropanol / ethanol (4: 1). M.p. 113.5-114.5 ° C.

Example 3.4: Description of a tablet composition; Bis (4-trifluoromethylphenoxy) acetic acid

acid l-methyl-4-piperidyl ester 50 g

Tragacanth 2 g

Lactose 39 »5 g

Corn starch powder 5 g

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Talk. 3 ε

Magnesium stearate · 0.5 ε

Alcohol SD-30 1

T in the necessary quantities of distilled water J

The weight of the tablets produced depends on the amount of active ingredient to be administered.

Claims (1)

Patent claims: 1. Compounds of the general formula I, in which the radical Y in each case has the same meaning and either for the trifluoromethyl or stands for the 4-chlorophenyl or the phenyl group, and R, hydrogen, a salt-forming cation, a Alkyl group with 1-4 carbon atoms or a basic radical of the general formula means where η is an integer from 0-4, n 'is 4 or 5 and R, stand for an alkyl group with 1-4 carbon atoms, as well as the acid addition salts or quaternary ammonium compounds of compounds of the general formula I, which the o. e. basic residue included. ^ 2. Bis (4-biphenylyloxy) acetic acid ethyl ester. 5. Bis (4-biphenylyloxy) acetic acid methyl ester. 4. Bis (4-biphenylyloxy) acetic acid 1-methyl-4-piperidyl ester. 5. Bis (4-trifluoromethylphenoxy) acetic acid. 6. Bis- (4-trifluoromethylphenoxy) -acetic acid-l-methyl-piperidyl ester ₌ Ne \] -> Ό Π terlääefl ϊλΛ. ^ 11 para. Ι Nh I Satt 3 of the change gee. ν. 4.9. '109847/1863 - 27 - 600-6156 γ. Bis (4-biphenyloxy) acetic acid. 8. Bis [4- (4-chlorophenyl) phenoxy] acetic acid. 9. Therapeutic composition characterized by the content of compounds of the general formula I. 10. Process for the preparation of compounds of the general formula I in which the radical Y has the same meaning owns and either for the trifluoromethyl or for the 4-chlorophenyl or the phenyl group and R is hydrogen, a salt-forming cation, an alkyl group with 1-4 carbon atoms or a basic radical of the general formula 109842/1863 600-6136 denotes in which, η is an integer from 0-4, n ^{1 is} 4 or and R is an alkyl group with 1-4 carbon atoms, as well as acid addition salts or quaternary ammonium compounds of compounds of the general formula I which have the ο ^ e. contain basic radical, characterized in that one either . a) to compounds of the general formula Ia, in which Y has the above meaning and R _{2 represents} a group of the general formula 109842/18 63 _ 39 - 600-613.6 stands, in which η, η ¹ and R, have the above meaning, their quaternary ammonium compounds or their acid addition salts, obtained by either i) Compounds of the general formula Ib, in which Y and R have the same meaning as above, with compounds of the general formula IV, in which Rp has the above meaning owns, implements or ii) Compounds of the general formula II, in which Y and R have the same meaning as above, with compounds of the general formula IV at temperatures, with partial decarboxylation occurring, implements or iii) Compounds of the general formula IHa, in which Y has the above meaning and Hal stands for chlorine or bromine, with compounds of the general formula IV or with compounds of the general formula IVa, in which R _{2 has the} above meaning and Me is an alkali metal stands, implements and the compounds of the general formula Ia thus obtained optionally then into their quaternary ammonium compounds or converted into their acid addition salts or 10984? / 1 86 ** - ^ O- 600-6156 b) to compounds of the general formula Ib obtained by either i) 1 mole of compounds of the general formula VI, in which Hai and R have the above meanings, with at least 2 moles of compounds of the general formula V, in which Y and Me have the above meaning, in one below the reaction conditions inert organic solvents • reacts with one another or iij compounds of the general formula II partially decarboxylated or iii) Compounds of the general formula III, in which Y has the above meaning and Q is a hydroxyl group, Is chlorine or bromine, with compounds of the general formula VII, in which R has the above meaning, implements or iv) Compounds of the general formula IHa with compounds of the general formula VIIa, wherein R-. and Me have the above meaning, implements or c) to compounds of the general formula Ic, in which Y has the above meaning, and / or their salts, with salt-forming Cations can be obtained by either 109842/1863 _ 4l - 600-6136 i) Compounds of the general formula VIII, in which Y Has the above meaning, partially decarboxylated -or ii) saponified compounds of the general formula Ib or iii) compounds of the general formula II at temperatures, with partial decarboxylation occurring, saponified or iv) 1 mole of compounds of the general formula VIa, in which Hai and Me have the above meaning, with at least 2 moles of compounds of the general formula V in one reacts with one another under the reaction conditions inert organic solvents and liberates the acids of the general formula Ic from the salts obtained, if any, or the acids obtained of the general formula Ic. Formula Ic, optionally then by reaction with appropriate bases in their salts with salt-forming cations convicted. 11. The method according to claim 10, characterized in that compounds of the general. Formula Ib with compounds of the general. Formula IV at temperatures between 50 and I5O ⁰ C. 109842/1863 - 42 - 600-6136 12. The method according to claim 10, characterized in that compounds of the general. Formula II with compounds of the general. Formula IV is implemented at temperatures of at least 100 ° C. 15 · The method according to claim 10, characterized in that compounds of the general formula IHa with compounds of the general formula IV or with compounds of the general formula IVa Room temperature (20 ° C) or below. 14. The method according to claim 10 and 13, characterized in that that compounds of the general formula HIa with compounds of the general formula IV in the presence of inorganic or organic, basic reagents or in an excess of compounds of the general formula IV. 1 "5. The method according to claim 10 and 13, characterized in that that compounds of the general formula HIa are reacted with sodium or potassium compounds of the general formula IVa. l6. Process according to claim 10, characterized in that 1 mol of compounds of the general formula VI with 2 mol of potassium or Sodium compounds of the general formula V converts. 17 · The method according to claim 10 and 16, characterized in that the reaction is carried out at temperatures between room temperature (20 ° C) and 80 ° C. 109847/1863 - 6OO-6rs6 18. The method according to claim 10, characterized in that the partial decarboxylation of compounds of the general. Formula II carried out in an inert organic solvent under the reaction conditions by heating to at least 80 ° C will. Process according to Claim 10 and 18, characterized in that the partial decarboxylation is carried out in the presence of hydroxyl-free inorganic or metal-organisctien bases is carried out. 20. The method according to claim 10 characterized in that the reaction of acid chlorides or acid bromides of compounds of the general. Formula III and IIIa with compounds of the general. Formula VII or VIIa at a temperature of 3O ⁰ C or below is carried out. 21. The method according to claim 10 and 20 characterized thereby, that when using tert. Butyl alcohol as a compound of the general formula VII with the resulting hydrogen halide With the help of suitable basic reagents it is bound. 22. The method according to claim 10, characterized in that the reaction of acids of the general formula III (Q «OH) with compounds of the general formula VII in the presence of catalytic amounts of an esterification catalyst. 10980/186? _ j | 4 _ 600-6136 23. The method according to claim 10, characterized in that for partial decarboxylation, compounds of the general formula VIII without a solvent or in one under the reaction conditions inert organic solvents heated to temperatures above their melting point. 24. The method according to claim 10, characterized in that for partial decarboxylation, the aqueous-alkaline Solution of compounds of the general formula VIII heated to the boil. 25. The method according to claim 10, characterized in that the saponification of compounds of the general formula Ib in water or in a mixture of water and a water mix- Help ble organic solvents with / a strong inorganic Base is carried out at temperatures between 10 and 100 ° C. 26. The method according to claim 10, characterized in that the saponification and partial decarboxylation and compounds of the general formula II in water or in a mixture of water and a water-miscible organic solvent and in the presence of a strong base at temperatures of at least 75 ° C is carried out. 1Q984 7 - 45 - 600-6136 27. The method according to claim 10, characterized in that the reaction of 1 mol of compounds of the general formula VIa with at least 2 moles of sodium or potassium compounds of compounds of the general formula V is carried out. 28. The method according to claim 10, 16 and 17, characterized in that that by reacting Äethyldlbromacetat with the sodium compound of 4-phenylphenol to bis (4-biphenylyloxy) -acetic acid ethyl ester got. 29. The method according to claim 10, 16 and 17, characterized in that by reacting methyl dibromoacetate with the sodium compound of 4-phenylphenol to bis (4-biphenylyloxy) -acetic acid methyl ester got. 30. The method according to claim 10 and 11, characterized in that that by reacting bis- (4-biphenylyloxy) -acetic acid methyl ester with 1-methyl-4-hydroxypiperidine to give bis (4-biphenylyloxy) acetic acid 1-methyl-4-piperidyl ester arrives and this optionally then converted into its acid addition salts. 109847/1863 - 46 - 600-6136 2.1 · The method according to claim 10 and 11, characterized in that that by reacting Bls- (4-biphenylyloxy) acetic acid ethyl ester with l-methyl-4-hydroxypiperidine to form bis (4-biphenylyloxy) acetic acid l-methyl-4-piperidyl ester If necessary, this subsequently ends up in its acid addition salts convicted. 32. The method according to claim 10 and 24, characterized in that that partial decarboxylation of bis- (4-trifluoromethylphenoxy) malonic acid reaches bis (4-trifluoromethylphenoxy) acetic acid and this optionally then in their salts transferred. 33 ". Method according to claim 10, 13 and 14". characterized, that by reacting bis (4-trifluoromethylphenoxy) acetyl chloride with l-methyl-4-hydroxypiperidine to form bis (4-trifluoromethylphenoxy) acetic acid 1-methyl-piperidyl ester arrives and this optionally then subsequently in its acid addition salts convicted. 34. Process according to Claim 10 and 20, characterized in that the reaction of bis (4-biphenylyloxy) acetyl chloride with potassium ethylate in the presence of ethanol to bis (4-biphenylyloxy) -ethyl acetate arrives. 1098t? / 1P63 - 47 - 600-6136 35. The method according to claim 10 and 2? characterized, that by reacting sodium dichloroacetate with the sodium compound of 4-phenylphenol and then releasing it the acids from the salt obtained to bis (4-biphenylyloxy) acetic acid got. 36 .. The method according to claim 10 and 22, characterized in that that by reacting bis (4-biphenylyloxy) acetic acid with ethanol in the presence of p-toluene sulphonic acid to form bis (4-biphenylyloxy) acetic acid ethyl ester arrives 37. The method according to claim 10 and 25, characterized in that that by saponification of bis (4-biphenylyloxy) -acetic acid methyl ester reaches bis (4-biphenylyloxy) acetic acid. 38. The method according to claim 10 and iS, characterized in that that by partial decarboxylation of bis (4-biphenylyloxy) malonic acid diethyl ester to the bis (4-biphenylyloxy) acetic acid ethyl ester got. 39. The method according to claim iO and 26, characterized in that that by partial decarboxylation and saponification of bis [4- (4-chlorophenyl) phenoxy] malonic acid diethyl ester for Bis- [4- (4-chlorophenyl) phenoxy] acetic acid arrives and this optionally then converted into its salts. 57OO / ST / SE, _n - _no _ f.) J_U ANDOZ AG.