NO161548B - EQUIPMENT FOR REPLACEMENT, FILLING AND CLOSING OF VALVE BAGS. - Google Patents

Abstract

Equipment for erecting, filling and sealing valve bags, particularly for dangerous materials, with which no personnel has to come near the machine, having a filling device (400) which is provided with an obliquely mounted turntable carrying an even number of filling tubes diametrally to the centre line, each extending substantially horizontally in the erected position and substantially vertically in the filling position.

Description

Process for the production of therapeutically active (4_(2-alkylidenealkanoyl)-aryloxyj -alkanoic acids.

The present invention relates to a new process for the production of [4-(2-alkylidenealkanoyl)-aryloxy]-alkanoic acids, which have diuretic, natriuretic and chloruretic properties and which are therefore useful in the treatment of many disorders caused by excessive retention of electrolytes .

It has been shown that 2-alkylidenealkanoyl)-aryloxy]-alkanoic acids can be prepared by dehydrohalogenation of 4-(halogenalkanoyl)-aryloxyalkanoic acids which contain halogen atoms on neighboring carbon atoms in one or both of the 2- and 3-st Ulins in the alkanoyl chain. The elimination of the hydrogen halide leads to the unbinding of the acyl unit and thus causes a bond of the olefin type between the carbon atoms, to which the reactive hydrogen and halogen atoms are bound.

According to the invention, compounds of the general formula are produced:

where R is hydrogen, halogen, lower alkyl, phenyl or benzyl,

R<1> is hydrogen, lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, etc., phenyl, chloro- or hydroxy-substituted phenyl or phenoxy, R<2>is hydrogen or lower alkyl, or together may

R 1 and R 2 form an alkylene chain with 3 - 5 carbon atoms, X^, , X^- and X^, which may be the same or different, are hydrogen, halogen,

lower alkyl, lower alkoxy or together, X^ and X^ or X^ and X^ may be united to form a hydrocarbylene chain containing 4 carbon atoms between its attachment points, e.g. tet raw hylene, 1,3-butadienylene (ie -CH=CH-CH=CH-), etc, and n is an integer from

1 to 5, as well as salts, esters and amides thereof, in that a compound of the formula: 12 in where R, R , R , X^> ' X5» x6 °9 n is as indicated above, and Z and Z , which are the same or different, are hydrogen or halogen, at least one of which is a halogen, is reacted with a dehydrohalogenating agent, and that the acid obtained, if desired, is transferred to a salt, an ester or the amide thereof in and of itself known way.

In general, any reagent capable of cleaving hydrogen halide can be used as dehydrohalogenating agent in the present process. These include e.g. tertiary alkylamines, pyridine, lutidine, quinoline and other tertiary amines, potassium tertiary butoxide in tertiary butanol, potassium hydroxide in lower alkanols, such as methanol, ethanol or propanol, metal-

halides, alkali metal acetates, alkali metal carbonates, etc.

However, it has been shown that the following dehydrohalogenating agents are particularly suitable in the present process: anhydrous lithium chloride, lithium bromide, silver acetate, potassium acetate, silver fluoride and potassium carbonate.

The choice of solvent in which the method can be carried out is not critical, and various solvents such as dimethylformamide, acetic acid, benzene and methanol have been used for this purpose with equally good results. likewise, the choice of suitable reaction temperature is a matter of taste and depends mainly on the reactivity of the halogen compound to be dehydrohalogenated.

In general, the reaction temperature and the time during which the reaction is carried out depend on the reactivity of the reactants used, and where the reactants are relatively inert or it is desirable to facilitate the separation of the hydrogen halide by-product, heating should be used until the reaction is complete.

The [4~(2-haloalkanoyl)-phenoxy]-alkanoic acid reactants in the present process can be prepared in different ways. One of these methods consists in Friedel Craft<*>'s reaction of an alkanoyl halide with a phenoxyalkanoic acid to form the corresponding (4-alkanoylphenoxy)alkanoic acid, followed by reaction of this acid with a halogenating agent, e.g. bromine, chlorine, etc., to replace the hydrogen in the 2-position of the alkanoyl chain with halogen. Another method incorporating Friedel Craft<*>'s method of synthesis involves the reaction of an alkanoic acid halide, which is substituted in the 2-position of the alkyl chain with a halogen atom, with a phenoxyalkanoic acid to form the desired [4-(2-haloalkanoyl )-phenoxy]-alkanoic acid compound. When R in any of the structural formulas shown above is halogen, e.g. chlorine, bromine etc, and R<1> is phenyl, the reactants are advantageously prepared by reaction of benzaldehyde, with the appropriate (4-alkanoylphenoxy)-alkanoic acid to prepare the corresponding omega-phenylmethylene derivative of (4-alkanoylphenoxy)-alkanoic acid, and this derivative is then halogenated, e.g. with bromine in acetic acid, to form the desired [4-(omega-phenyl-alpha,beta-dihaloalkanoyl)-phenoxy]-alkanoic acid reactant. On the other hand, those reactants are prepared in which R is different from halogen, e.g. lower alkyl, and R is phenyl, readily by reaction of benzaldehyde, with the appropriate (4-alkanoylphenoxy)-alkanoic acid to form the corresponding omega - phenylmethylene derivative of 4-alkanoylphenoxy-alkanoic acid, and this derivative

is then hydrogenated to reduce the benzylidene group to a corresponding benzyl group, the saturated intermediate thus produced is condensed with formaldehyde or paraformaldehyde in the presence of a secondary amine, e.g. dimethylamine hydrochloride, forming the corresponding Mannich amine which is then dehydroaminated to the corresponding 4-(2-benzylidenealkanoyl)-phenoxyalkanoic acid, and this methylene intermediate is then hydrogenated to the corresponding 4-(2-benzylidenealkanoyl)- phenoxy-alkanoic acid and halogenated with bromine or chlorine to

introduce halogen instead of hydrogen in the 2-position of the alkanoyl chain. The compound thus formed is the desired 4-(2-bromo-2-benzylalkanoyl)-phenoxy-alkanoic acid reactant. When the radical R is a group other than phenyl, e.g. hydrogen, lower alkyl or phenoxy, the corresponding [4~(2-haloalkanoyl)-phenoxy]-alkanoic acid starting materials are prepared by reacting the appropriate core-substituted or core-unsubstituted phenoxyalkanoic acid with the appropriate alkanoyl halide to form the corresponding (4-alkanoylphenoxy)-alkanoic acid , followed by condensation of this acid with formaldehyde or paraformaldehyde and dimethylamine hydrohalide to form the corresponding Mannich amine derivative, i.e. [4-(2-dimethylaminomethylalkanoyl)-phenoxy]-alkanoic acid hydrohalide, followed by deamination of the amine by reacting it with a weak base, e.g. sodium bicarbonate, and hydrogenating the thus formed [4-(2-methylenealkanoyl)-phenoxy]-alkanoic acid to form a [4-(2-methylalkanoyl)-phenoxy]-alkanoic acid which is then halogenated with a halogenating agent, e.g. chlorine," bromine, etc., to form the desired [4-(2-haloalkanoyl)-phenoxy]-alkanoic acid. The omega-phenoxyalkanoyl halide used in the preceding synthesis is prepared by reacting an appropriate omega-haloalkanoyl acid with an appropriate core substituted or core-unsubstituted sodium phenoxide, followed by reaction of the omega-phenoxy-alkanoic acid thus formed with a suitable halogenating agent, eg thionyl chloride. When it is desired to prepare a product in which the radical R is methyl, and the radical R1 is one of the above indicated organic radicals, the reactants in the process are prepared by condensation of the corresponding 2-methyl-substituted alkanoyl halides with the appropriate phenoxyalkanoic acid to form the corresponding (4-alkanoylphenoxy)-alkanoic acid intermediate, followed by halogenation with bromine or chlorine to form the corresponding [4 -(2-halo-2-methylalkanoyl)-phenoxy]-alkanoic acid reactant Yet another method in the preparation of [4-(2-haloalkanoyl)-phenoxy]-alkanoic acid reactant the ten consists in the reaction of an alkanoyl halide

with a phenyl alkyl ether, e.g. an anisole, to form the corresponding 4-alkanoyl substituted phenyl alkyl ether, which is then either converted to the corresponding phenol by treatment with aluminum chloride, followed by reaction of the phenol with an appropriate omega-haloalkanoic acid, or an ester thereof, to form the desired 4- alkanoyl-substituted phenoxyalkanoic acid, or if the omega-haloalkanoic acid used is the ester derivative, the 4-alkanoyl-substituted phenoxyalkanoic acid ester thus formed is hydrolysed to the corresponding acid. Also, when both Z groups in the starting materials listed above are halogen, and R is lower alkyl, and R 1 and R 2 are both hydrogen, the reactants are prepared by reacting an alpha-halo-alpha-(halomethyl)-alkanoyl halide with an appropriate phenoxyalkanoic acid to form the corresponding |4_[2-halo-2-(halomethyl)-alkanoyl]-phenoxy|-alkanoic acid reactant. From the preceding description, the procedures for producing the starting materials in the present method will be obvious to a person skilled in the art. However, other methods can also be used in the preparation of these reactants.

The present invention also relates to the production of the acid addition salts of the phenoxyalkanoic acids produced according to the invention, which are produced by reacting these acids with a base with one non-toxic pharmaceutically acceptable cation. In general, any base which will form an acid addition salt with a carboxylic acid and whose pharmacological properties will not cause any adverse physiological effect when absorbed into the body system is considered to be within the scope of the present invention, and suitable bases thus include e.g. the alkali metal and alkaline earth metal hydroxides, carbonates, etc; ammonia; primary, secondary and tertiary amines, such as monoalkylamines, dialkylamines and trialkylamines; and heterocyclic amines, e.g. piperidine, etc. The acid addition salts thus prepared are the functional equivalents of the corresponding phenoxyalkanoic acids and to the extent that the phenoxyalkanoic acids prepared according to the invention are useful in therapy, the acid addition salts covered by the invention are only limited by the criterion that the bases used in forming the salts , are both non-toxic and physiologically acceptable.

Pharmacological studies of the products produced by the present method show that they are effective diuretic and saluretic agents, and that they are thus useful in the treatment of conditions caused by an excessively high concentration of electrolyte in the body, such as in the treatment of dropsy conditions caused by e.g. e.g. heart failure.

Example 1

[3-chloro-4-(2-methylcrotonoyl)-phenoxy]-acetic acid

Step A: (3-chloro-4-butyrylphenoxy)-acetic acid

217 9 (1.625 mol) of powdered aluminum chloride and 4o0 ml of carbon disulfide are placed in a 1-liter, 4-necked flask equipped with a stirrer, dropper, reflux condenser, and internal thermometer. 93.3 g (0.5 mol) of (3-chlorophenoxy)-acetic acid is added in portions while stirring and then 66.6 g (0.625 mol) of n-butyryl chloride is added in portions while stirring over the course of half an hour at a temperature of about. 22 - 26°C. After stirring for one hour at room temperature, the reaction flask is placed in a water bath, and the temperature is maintained at 50°C for 3 hours. The carbon disulphide is then decanted off, and the remaining aluminum complex is added to a mixture of 1 kg of ice and 100 ml of concentrated hydrochloric acid. A solid is separated and dissolved in 1.5 l of saturated sodium bicarbonate solution. The solution is filtered, and the clear, yellow filtrate is acidified with hydrochloric acid. The yellow oil that is secreted slowly solidifies to form. a solid that melts at 76 - 85°C. After recrystallization from benzene, 66.7 g (51%) of (3-chloro-4-butyrylphenoxy)-acetic acid with a melting point of 89 - 90°C was obtained.

Step B: [3-chloro-4-(2-dimethylaminomethylbutyryi)-phenoxy]-acetic acid hydrochloride

In a lOO ml round-bottomed flask fitted with an outlet tube suitable for the application of occasional suction, heat an intimate mixture of 5.12 g (0.02 mol) of (3-chloro-4-butyrylphenoxy)-acetic acid, 0.7 g (0.022 mol) paraformaldehyde, 1.78 g (0.02 mol) dimethylamide hydrochloride and 4 drops of acetic acid on a steam bath for approx. 1.5 hours, during which a minute's worth of suction is applied 5 or 6 times. On cooling, a solid is formed which is crystallized from acetonitrile and from isopropanol, whereby one obtains [3-chloro-4-(2-dimethylaminomethylbutyryl)-phenoxy]-acetic acid hydrochloride with a melting point of 127 - 129°C.

Step C: [ 3- chloro- 4-( 2- methylenebutyryl)- phenoxy]- acetic acid

The Mannich compound obtained as described in step B is dissolved in 25 ml of water, and the solution is made weakly basic by the addition of 10% sodium bicarbonate solution. The resulting solution is heated for 25 minutes on a steam bath, cooled and acidified with 6 N hydrochloric acid, whereby 3.7 g (69%) of crude product with melting point I08 - 109.5°C is obtained. After recrystallization from a mixture of cyclohexane and benzene, [3-chloro-4-{2-methylenebutyryl)-phenoxy]-acetic acid is obtained in the form of a colored crystal with a melting point of 109 - 111°C.

Step D: [3-chloro-4-(2-methylbutyryl)-phenoxy]-acetic acid

57.1 g (0.212 mol) of [3-chloro-4-(2-methylenebutyryl)-phenoxy]-acetic acid is dissolved in 200 ml of isopropanol, and 3.0 g of 5% palladium on carbon is added. The mixture is hydrogenated at an initial pressure of o 2.4 kg/cm 2 overpressure on o a Parr apparatus. within 40 minutes, the required amount of hydrogen is absorbed. The solution is heated and filtered to remove the catalyst, the alcohol is evaporated and the residue is crystallized from benzene. 41.2 g of [3~chloro-4-(2-methylbutyryl)-phenoxy]-acetic acid with a melting point of 13° - 139.5°C is obtained. A sample further purified by crystallization from benzene melts at 139 - 140°C.

Step E: [3~chloro-4-(2-bromo-2-methylbutyryl)-phenoxy]-acetic acid

10 g (0.037 mol) of [3-chloro-4-(2-methylbutyryl)-phenoxy]-acetic acid is dissolved in 200 ml of acetic acid, and 6^0 g (0.037 mol) of bromine in 50 ml of acetic acid is added dropwise with stirring during ld - 15 minutes. (The reaction is initiated at the beginning by adding 2 drops of 48% hydrogen bromide). The mixture is added to 1 liter of water containing a little sodium bisulphite. The solid which separates is collected, washed with water, dried in air at 65°C and crystallized from benzene. The product, [3-chloro-4-(2-bromo-2-methyl-butyryl)-phenoxy]-acetic acid (10.9 g), melts at 123 - 124°C

Step F: [ 3- chloro- 4-( 2- methylcrotonoyl)- phenoxy]- acetic acid

14 g (0.04 mol) of the bromine compound prepared in step B,

5.1 g (0.12 mol) of lithium chloride and dimethylformamide were mixed and heated at 80-90°C for 4 hours. The mixture was poured into 500 ml of water. The solid that separates is separated twice from sodium bicarbonate and crystallized from benzene, whereby 4.5 g of [3-chloro-4-(2-methylcrotonoyl)-phenoxy]-acetic acid with a melting point of 114 - 116°C is obtained.

Example 2

(3-chloro-4-orethacryloylphenoxy)-acetic acid

Step A: (3-chloro-4-isobutyrylphenoxy)-acetic acid

A 1-litre, 4-necked flask is provided with an efficient stirrer, dropping funnel, reflux condenser and internal thermometer. The flask is flame-dried while purging with nitrogen gas. 83.9 g (0.63 mol) of powdered aluminum chloride was placed in a flask along with 200 ml of carbon disulfide. 37.3 g (0.20 mol) of 3-chlorophenoxyacetic acid was added in portions with stirring. 26.6 g (0.25 mol) of isobutyryl chloride was then added dropwise with stirring over the course of 30 minutes. The temperature rose slowly from 22°C to 26°C, and the carbon disulphide slowly boiled under reflux. After stirring for one hour at room temperature, the reaction flask was immersed in a water bath, and the water bath temperature was maintained at 50°C for 3 hours. After an hour, the separation of a viscous precipitate made stirring impossible.

After the heating period was over, the carbon disulfide was decanted off, and the viscous aluminum complex was scraped from the flask and added in portions to a mixture of 500 g of ice and 125 ml of concentrated hydrochloric acid. A yellow solid is separated. When the ice had melted, the mixture was extracted with 250 ml of benzene. At this point, an insoluble solid formed on the interface between benzene and water. The aqueous layer was separated and the benzene solution containing the suspended insoluble solid was cooled in an ice bath and then filtered to give 23.9 g of a moist crude product. The solid was added slowly to 200 mL of saturated sodium bicarbonate solution and triturated until nearly all dissolved. When the effervescence ceased, a small amount of undissolved, yellow, soft, solid remained. This was removed by filtration, and the filtrate was carefully acidified with concentrated hydrochloric acid. After cooling the mixture in an ice bath, a certain precipitate was collected by filtration and dried in an oven at 65°C. The yield was 8.93 g (17.3%) of (3-chloro-4-isobutyrylphenoxy)-acetic acid with a melting point of 137-139°C (corrected).

Step B: [3-chloro-4-(2-bromisobutyryi)-phenoxy]-acetic acid

10.17 g (0.0397 mol) (3-chloro-4-isobutyryl enoxy)-acetic acid was dissolved in 250 ml glacial acetic acid at room temperature in a 500 ml round-bottomed flask fitted with a stirrer, dropping funnel and outlet tube. 6.34 g (0.0397 mol) bromine in 30 ml glacial acetic acid was added dropwise to the reaction

tion mixture at 25°C with stirring during one hour. The bromine reacted readily, and some hydrogen bromide was evolved. Stirring was continued for a further hour, and then the mixture was added to a mixture of 300 g of ice and 500 ml of water. A white, solid substance separated and was filtered off by suction after the ice had melted. The solid was washed on the filter with a little water and dried at 65°C to constant weight. The crude product was crystallized from 70 ml of benzene and the mixture cooled to room temperature over 30 minutes and cooled at 5°C for one hour. 8.39 g (63%) of [3~chloro-4-(2-bromoisobutyryl)-phenoxy]-acetic acid was collected by suction filtration and dried at 65°C and had a melting point of 124.5 - 125°C (corrected) .

Step C: (3-chloro-4-methacryloylphenoxy)-acetic acid

•5 g (0.0149 mol) of the brominated compound from step B was dissolved in 200 ml of benzene in a 500 ml round-bottomed flask fitted with a stirrer and a reflux condenser. 5 g (0.02990 mol) of silver acetate was added and the mixture was stirred and refluxed for 3 hours. The mixture was cooled and 150 ml of water and 15 ml of concentrated hydrochloric acid were added. The water phase was separated, and the benzene layer was dried over sodium sulfate and concentrated to 50 ml. On cooling, 2.8 g of a solid with a melting point of 125 - 127°C are separated. The solid was crystallized four times from benzene to give 1.05 g of (3-chloro-4-methacryloylphenoxy)-acetic acid, mp 128-129°C (corrected).

Example 3

(4-methacryloylphenoxy)-acetic acid

Step A: (4-isobutyrylphenoxy)-acetic acid

160 g (1.2 mol) of powdered aluminum chloride and 200 ml of carbon disulfide were placed in a 1-liter, 4-necked flask equipped with a stirrer, dropping funnel, reflux condenser, and internal thermometer. 6l g (0.4 mol) of phenoxyacetic acid was added in portions with stirring and then 53.5 g (0.5 mol) of isobutyryl chloride was added dropwise with stirring during half an hour at a temperature of approx. 22 - 26°C. After stirring for one hour at room temperature, the reaction flask was placed in a water bath and the temperature maintained at 50°C for 3 hours. The carbon disulfide was then decanted off, and the remaining aluminum complex was added to a mixture of 500 g of ice and 125 ml of concentrated hydrochloric acid. The yellow oil which formed was separated to give

51.6 g (4-isobutyrylphenoxy)-acetic acid with boiling point 185 - 190°C

(1 mm pressure).

Step B: [4~(2-bromisobutyryl)-phenoxy]-acetic acid

35.6 g (0.16 mol) of (4-isobutyrylphenoxy)-acetic acid was added to 125 ml of glacial acetic acid at room temperature. 25.7 g (0.16 mol) of bromine in 30 ml of glacial acetic acid was added dropwise to the reaction mixture at 25°C with stirring over the course of one hour. Stirring was continued for a further hour, and then the mixture was added to a mixture of 300 g of ice and 500 ml of water. The solid which separated was collected on a filter, washed and recrystallized from benzene, whereby 33 g of [4-(2-bromoisobutyryl)-phenoxy]-acetic acid with a melting point of 144-145°C was obtained.

Step C: (4-methacryloylphenoxy)-acetic acid

12 g (0.04 mol) of the brominated compound obtained in step B was dissolved in 800 ml of benzene, and 15 g (0.09 mol) of silver acetate was added. The mixture was stirred and refluxed for 4 hours and then cooled. 150 ml of water and 15 ml of concentrated hydrochloric acid were added, after which the silver salts were precipitated and removed by filtration. The benzene was then evaporated to a small volume, diluted with hexane, and the solid that separated was crystallized from benzene, whereby (4-methacryloylphenoxy)-acetic acid with a melting point of 124.5 - 126.5°C was obtained in a yield of 4 .1 g.

Example 4

[3-chloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid

Step A: 3-chloro-4-(2-ethylbutyryl)-phenol

To a mixture of 31.52 g (0.2 mol) 3-chlorophenetol and 26.92 g (0.2 mol) alpha-ethyl-butyryl chloride in petroleum ether, 73.34 g (0.6 mol) aluminum chloride was added gradually under stirring at 5°C during 0.5 hours. The mixture was stirred at 5°C for 20 minutes and then allowed to warm to 25°C with stirring for an additional 3 hours. The mixture was then kept at 25-30°C for 48 hours. The petroi ether was then decanted off and the residue added to 500 g of ice containing 40 ml of concentrated hydrochloric acid. The dark oil which separated was extracted with ether and the ether solution washed with water and extracted with 2.5% sodium hydroxide. The sodium hydroxide extract was treated with Norite, filtered free of carbon and acidified with hydrochloric acid, whereby a green oil was obtained which was then extracted with ether. The ether extract was dried over sodium sulphate, the ether evaporated and the residue distilled at 148 - 181°C at 0.3 mm pressure, whereby 11.44 g (25%) of 3-chloro-4-(2-ethylbutyryl)-phenol was obtained.

Step B: [3-chloro-4-(2-ethylbutyryl)-phenoxy]-acetic acid

11.44 g (0.050 mol) of 4-(2-ethylbutyryl)-3-chlorophenol in sufficient glycol dimethyl ether to dissolve it was added slowly to a suspension of 2.42 g (0.05 mol) of sodium hydride (51% in mineral oil) in glycol dimethyl ether. The mixture is stirred for 15 minutes, and 8.45 g (0.050 mol) of ethyl bromoacetate is added dropwise with stirring. The mixture is then refluxed for 2.5 hours, and the glycol dimethyl ether is evaporated under reduced pressure at (8o - 90°C. 4.14 g (0.101 mol) of sodium hydroxide in 30 ml of water is added to the residue, the mixture is stirred and heated at 90°C for 1.5 hours, and the remaining mineral oil is extracted with ether from the cooled solution. The aqueous layer is acidified with hydrochloric acid, and the solid material which separates is dissolved in sodium bicarbonate solution and treated with "Nor it e", filtered and. acidified, thereby obtaining 12.3 9 (85%) [3-chloro-4-(2-ethylbutyryl)-phenoxy-acetic acid, which after drying in air melted at 146 - 147° C. Crystallization from benzene gave a product melting at 147 - 149 °C.

Step C: f 3-chloro-4-(2-ethyl-2-bromobutyryl)-phenoxy]-acetic acid

To a solution of 10.64 g (0.0374 mol) [3-chloro-4-(2-ethyl-butyryl)-phenoxy]-acetic acid in 200 ml of acetic acid, 2 drops of 48% hydrogen bromide are added with stirring, followed by the dropwise addition of 6.0 g (0.0374 mol) of bromine in 50 ml of acetic acid. After the addition was finished, the mixture was stirred for 15 minutes and then poured into one liter of water containing 2 g of sodium bisulphite. The solid which separated was collected on a filter, washed with water, dried in air and crystallized from 55 ml of benzene to give 10.16 g of [3-chloro-4-(2-ethyl-2-bromobutyryl)- phenoxy]-acetic acid which melted at 130 - 131°C.

Step D; [3-Chloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid

6 g (0.0185 mol) of the bromoketone prepared in step B was dissolved in 400 ml of hot benzene. 7 g (0.042 mol) of powdered silver acetate was added slowly with mechanical stirring. The mixture was heated for approx. 5.5 hours and then acidified with 6 N hydrochloric acid. The silver salts which were formed were removed by filtration, the benzene layer was separated, and

2 g "Darco" was added and the mixture was kept at 25-30°C i

48 hours. The solution was then filtered, diluted with ether and extracted with 5% sodium bicarbonate solution. The water extract was treated with "Norite", and the acid, whereby [3-chloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid was obtained which, after drying in air at 65°C and recrystallization from benzene, melted at 118 - 119°C. The yield was 2.9 g.

Example 5

[3-Chloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid

8.3 g (0.0228 mol) of the bromoketone prepared in Example 5, step C, was dissolved in 60 ml of dimethylformamide, and 2.9 g (0.0684 mol) of anhydrous lithium chloride was added. The mixture was heated on a steam bath for 2 hours with occasional shaking, cooled and poured into one liter of cold water. The solid that separated was collected by filtration, washed with 500 ml of water and then dissolved in dilute sodium bicarbonate solution. The solution was shaken with "Norite" filtered free of solids and the acid. The solid which separated was dried in air, whereby 5 9 [3-chloro-4-(2-ethylidene-butyryl)-phenoxy]-acetic acid was obtained which, after recrystallization from benzene, melted at 118 - 119°C. The yield was 2.9 g.

Example 6

[3-Chloro-4~(crotonoyl)-phenoxy]-acetic acid

Step A: [3-chloro-4-(3-chlorobutyryl)-phenoxy]-acetic acid

To a suspension of 33.3 9 (0.25 mol) aluminum chloride and

9.4 g (0.05 mol) of 3-chlorophenoxyacetic acid was added to a solution of 7.75 g (0.055 mol) of 3-chlorobutyryl chloride in 25 ml of carbon disulfide over 15 minutes at room temperature. The mixture was stirred at room temperature for 30 minutes and the carbon disulphide decanted off. The residue was cooled in an ice bath and treated with 125 ml of ice water and 25 ml of concentrated hydrochloric acid. The product was extracted with ether, the ether extract was washed with water, dried over sodium sulfate, filtered and evaporated to dryness on a steam bath. The residue was crystallized from a mixture of benzene and hexane, whereby [3-chloro-4-(3-chlorobutyryl)-phenoxy]-acetic acid with a melting point of 102.5 - 104°C was obtained.

Step B: [3-chloro-4-(crotonoyl)-phenoxy]-acetic acid

A solution of 1.5 g (0.005 mol) of [3-chloro-4-(3-chlorobutyryl)-phenoxy]-acetic acid in 10 ml of methanol containing 1.5 g (0.015 mol) of freshly melted potassium acetate was allowed to stand room temperature for 5 hours and then evaporated to dryness in vacuo at room temperature. The residue was dissolved in water, acidified with dilute hydrochloric acid, and the product extracted with ether. The ether extract was washed with water, dried over sodium sulfate, filtered and evaporated to dryness on a steam bath The residue was crystallized from a mixture of benzene and methylcyclohexane, whereby [3-chloro-4~(crotonoyl)-phenoxy]-acetic acid with a melting point of 117 - 119°C was obtained.

Example 7

[3-methyl-4-(2-bromocrotonoyl)-phenoxy]-acetic acid

Step A: (3-methyl-4-crotonoylphenoxy)-acetic acid

40 g (0.3 mol) of aluminum chloride in portions over the course of 45 minutes. The mixture was kept at a temperature of between 0 - 15°C for 5 hours and then at room temperature for 18 hours. The yellow complex was collected on a filter and added portionwise to a mixture of 250 mg of ice and 50 ml of concentrated hydrochloric acid. The solid material produced was extracted with ether, and the ether extract was washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was crystallized from a mixture of benzene and methylcyclohexane, whereby (3-methyl-4-crotonoylphenoxy)-acetic acid with a melting point of 85 - 87°C was obtained.

Step B: [ 3~ methyl- 4-( 2, 3- dibromobutyryl)- phenoxy]- acetic acid

A solution of 3.2 g (0.02 mol) bromine in 25 ml chloroform was added dropwise over 30 minutes to a solution of 4.7 9 (0.02 mol) [3-methyl-4 -(crotonoyl)-phenoxy]-acetic acid in 50 ml of ether cooled in an ice bath. After stirring for 45 minutes at room temperature, the solution was evaporated to dryness in vacuo, and the residue was crystallized from a mixture of benzene and methylcyclohexane, whereby [3-methyl-4-(2,3-dibromobutyryl)-phenoxy]-acetic acid was obtained with melting point 119 - 121°c.

Step C: [3-methyl-4-(2-bromocrotonoyl)-phenoxy]-acetic acid

A solution of 3.9 g (0.01 mol) [3-methyl-4-(2,3-dibromo-butyryl)-phenoxy]-acetic acid in 50 ml of methanol containing 3.0 g

(0.03 mol) of potassium acetate was stirred at room temperature for 48 hours, filtered and evaporated to dryness in vacuo. The residue was dissolved in water, acidified with dilute hydrochloric acid, and the product was extracted with ether. The ether extract was washed with water, dried over sodium sulfate, filtered, concentrated and eluted with petroleum ether, thereby obtaining [3-methyl-4-(2-bromocrotonoyl)-phenoxy]-acetic acid with a melting point of 137 - 140°C.

Example 8

[ 3-chloro-4-(2-bromo-3-phenylacryloyl)-phenoxy]-acetic acid Step A: ( 3-chloro-4~ acetylphenoxy)-acetic acid

43.5 g (0.325 mol) of powdered aluminum chloride and 150 mL of carbon disulfide were placed in a 1-liter, 4-necked flask equipped with a stirrer, dropping funnel, reflux condenser, and internal thermometer.

17.06 g (0.1 mol) of (3-chlorophenoxy)-acetic acid was added portionwise with stirring, and then 7.85 g (0.125 mol) of acetyl chloride was added dropwise with stirring over 0.5 hours at a temperature of about. 22 - 26°C. After stirring for one hour at room temperature, the reaction flask was placed in a water bath and the temperature was maintained at 50°C for 3 hours. The carbon disulphide was then decanted off, and the remaining aluminum complex was added to a mixture of 500 g of ice and 125 ml of concentrated hydrochloric acid. The product obtained was precipitated again from a sodium bicarbonate solution by acidification with hydrochloric acid to give a white solid which, when recrystallized from benzene, gave 4.94 g of (3-chloro-4-acetylphenoxy)-acetic acid, m.p. 107 - 109°C.

Step B: [3-Chloro-4-(3-phenylacryloyl.)-phenoxy]-acetic acid

4.4 g (0.0193 mol) (3-chloro-4-acetylphenoxy)-acetic acid and 2.1 g (0.0193 mol) benzaldehyde were dissolved in a mixture of 1.8 g (0.45 mol) sodium hydroxide in 160 ml of water and 10 ml of ethanol. The solution was kept at 25-30°C for 16 hours. It was then acidified, and the solid which separated was collected, dried at 65°C and crystallized from benzene to give 1.2 g of [3-chloro-4-(3-phenylacryloyl)-phenoxy]-acetic acid of m.p. 139 - 140°C.

Step C: f 3-chloro-4-(2, 3-dibromo-3-phenylpropiony1)-phenoxy j-acetic acid

23.8 g (0.075 mol) of [3-chloro-4-(3-phenylacryloyl)-phenoxy|-acetic acid, prepared as described in step B, was dissolved in 300 ml of acetic acid at 50°C, and 12 g (0.075 mol ) bromine in 20 ml of acetic acid was added dropwise with stirring at 4o - 50°C during 30 minutes. The reaction mixture was then poured into one liter of water containing 1-2 g of sodium bisulphite. An unfilterable, bulky, white solid formed and was extracted with ether. The ether extract was washed with water and dried over sodium sulfate. A sample of the dried ether extract was extracted to give a pale yellow solid which was identified as [3-chloro-4-(2,3-dibromo-3-phenylpropiony1)-phenoxy J-acetic acid, m.p. 157 - 158 °C after crystallization from benzene.

Step D: [3-chloro-4-(2-bromo-3-phenylacryloyl)-phenoxy]-acetic acid

300 ml of acetic acid was added to the dried ether solution obtained in step C. The mixture was heated on a steam bath in an open flask to evaporate the ether. The precipitate that first formed slowly dissolved. When the ether was completely evaporated, 18.8 g (0.135 mol) of anhydrous sodium carbonate was carefully added. The mixture was then heated on a steam bath for 5 hours, cooled and poured into one liter of water, and the pale yellow solid that formed was collected by filtration, washed with one liter of water in small portions and crystallized from a mixture of isopropyl alcohol and water , thereby obtaining 18 g of [3-chloro-4-(2-bromo-3~phenylacryloyl)-phenoxyj-acetic acid with a melting point of 159 - 16o°C A small sample recrystallized two more times from a mixture of isopropyl alcohol <p>g water melted at 160 - 161°C.

Example 9

[2,3-Dichloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid

Step A: 2- ethyl- 2', 3'- dichloro- 4'- hydroxybutyrophenone

A mixture of 53.11 g (0.35 mol) of 2,3-dichloroanisole, 350 ml of carbon disulfide and 80.77 g (0.6 mol) of 2-ethylbutyryl chloride was treated under anhydrous conditions with 40.00 g (0.3 mol) aluminum chloride powder for 5 minutes with stirring. The mixture was stirred for 6 hours at room temperature and then allowed to stand at room temperature overnight. The reaction mixture was heated with stirring in a 55°C water bath until evolution of hydrogen chloride ceased.

(1.5 hours), cooled to room temperature and treated under anhydrous conditions with 40.00 g (0.3 mol) aluminum chloride powder for 5 minutes with stirring. The carbon disulphide was then removed under reduced pressure by distillation. An equal volume of dry heptane was added and the mixture was heated on a steam bath with stirring for 3 hours. After cooling to room temperature, the heptane was decanted off, and the gummy residue was added to a mixture of 450 g of ice and 45 ml of concentrated hydrochloric acid. The oil formed was extracted with ether, dried over anhydrous sodium sulfate, and the ether was then removed under reduced pressure, whereby a semi-solid residue was obtained. This material was treated with an excess of 5% aqueous sodium hydroxide solution and heated under reflux for one hour, then cooled and extracted with ether to remove insoluble oil. The clear aqueous solution was acidified with concentrated hydrochloric acid, the resulting oil was extracted with ether, and the remaining oil was distilled to give 34.45 g (44%) of product as a liquid, boiling point 140 - 142°C at 0.5 mm pressure. After three recrystallizations from hexane, 2-ethyl-2',3'-dichloro-4'-hydroxybutyrophenone was obtained in the form of white needles with a melting point of 85 - 86°C.

Step B: [2,3-dichloro-4-(2-ethylbutyryi)-phenoxy]-acetic acid

A solution of 2.53 g (0.11 mol) of sodium in 300 ml of absolute ethanol was treated first with 26.12 g (0.1 mol) of 2-ethyl-2',3'-dichloro-4'-hydroxybutyrophenone and then with 20.04 g (0.12 mol) of ethyl bromoacetate, and the resulting clear solution was heated under reflux with stirring for 2 hours. Then 11.22 g (0.2 mol) of potassium hydroxide in the form of a 5% aqueous solution was added, and refluxing with stirring was continued for a further hour. The alcohol was removed by distillation at atmospheric pressure, and the boiling, aqueous residue was acidified against Congo red paper by the addition of concentrated hydrochloric acid. An oil is separated as solidified on cooling to room temperature. It was extracted with ether, the ether extract was dried over anhydrous sodium sulfate, and the ether was removed under reduced pressure to give 31.9 g (100%) of [2,3-dichloro^4-(2-ethylbutyryl)-phenoxy]- acetic acid in the form of a white solid with a melting point of 128 - 139°C. A recrystallization from a mixture of benzene and cyclohexane gave 28.7 g (90%) of the product in the form of needles melting at 144.5 - 145.5°C.

Step C: [2,3-dichloro-4-(2-bromo-2-ethylbutyryl)-phenoxy]-acetic acid

This product was prepared in substantially the same manner as described in Example 4, Step B, using the following reagents: 19.26 g (0.0603 mol) [2,3-dichloro-4-(2-ethylbutyryl)-phenoxy ]-acetic acid, 9.64 g (0.0603 mol) of bromine and 530 ml of glacial acetic acid.

The above procedure gives 23.71 9 (99%) [2,3-dichloro-4-(2-bromo-2-ethylbutyryl)-phenoxy]-acetic acid in the form of a solid white substance with melting point 151.5 - 152.5 °C.

A recrystallization from benzene gave the product in the form of white needles with a melting point of 151.5 - 152.5°C.

Step D: |"2 ,3-Dichloro-4-(2-ethylidenbuty ryi)-phenoxy]-acetic acid

This product was prepared in substantially the same manner as described in Example 4, Step C, using the following reagents: 19.91 g (0.05 mol) [2,3-dichloro-4-(2-bromo-2- ethylbutyryl)-phenoxy]-acetic acid, 6.36 g (0.15 mol) lithium chloride and 140 ml of dimethylformamide.

A recrystallization from a mixture of benzene and cyclohexane gave 14.52 g (92%) [2,3-dichloro-4-(2-ethylidenebutyryi)-phenoxy]-acetic acid in the form of white needles, m.p. 124 - 125.5° C. Another recrystallization from the same solvent mixture did not change the melting point.

Example IO

[ 2- methyl-3-chloro-4~(2-ethyl idenbutyryl)-phenoxy]-acetic acid

Step Ai [2-methyl-3-chloro-4-(2-ethylbutyryl)-phenoxy]-acetic acid

36.0 g (0.15 mol) of 2-ethyl-2'-methyl-3'-chloro-4'-hydroxybutyrophenone in 120 ml of water was combined with a solution of 24 g (0.60 mol) of sodium hydroxide in 5 ml water. To the solution formed at 45°C, a solution of 28.3 g (0.30 mol) of chloroacetic acid in 10 ml of water was added with stirring over the course of one hour at a temperature of 40 - 45°C. The temperature was raised to 100°C over 30 minutes and stirring continued at 100°C for 40 minutes. The reaction mixture at 100°C was treated with a solution of 5.2 g (0.055 mol) of chloroacetic acid in 10 ml of water for 2 hours. At the same time and during the following 3 hours of stirring at 100°C, a solution of 4.4 g (0.11 mol) of sodium hydroxide in 10 ml of water was added at intervals when necessary to keep the reaction mixture basic. The boiling one

solution was acidified with concentrated hydrochloric acid. The oil that separated after cooling in an ice bath to room temperature was extracted with ether, dried over anhydrous sodium sulfate, and the ether was evaporated under reduced pressure to give an oil. The oil was dissolved in benzene, and the benzene was removed under reduced pressure, yielding a waxy solid. The crude product obtained was recrystallized from 300 ml of benzene and 500 ml of cyclohexane, whereby 20.0 g (45% yield) of [2-methyl-3-chloro-4-(2-ethyl-butyryl)-phenoxy]-acetic acid was obtained as melted at 143 - 144°C.

Step B: [2-methyl-3-chloro-4~(2-bromo-2-ethylbutyryl)-phenoxy]-acetic acid

To a solution of 14.8 g (0.06 mol) [2-methyl-3-chloro-4-(2-ethylbutyryl)-phenoxy]-acetic acid in 350 ml of acetic acid, 2 drops of 48% hydrogen bromide were added with stirring followed by the dropwise addition of 9.63 g (0.06 mol) of bromine in 50 ml of acetic acid. After the addition was finished, the mixture was stirred for 15 minutes and then poured into one liter of water containing 2 g of sodium bisulphite. The solid which separated was collected on a filter, washed with water, dried in air and crystallized from 55 ml of benzene. The crude product thus obtained (19.2 g, 85%) was recrystallized from 100 ml of benzene and 350 ml of cyclohexane, whereby 16 g of [2-methyl-3-chloro-4~(2-bromo-2-ethylbutyryl)- phenoxy]-acetic acid which melted at 136 - 137°C.

Step C: [2-methyl-3-chloro-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid.

13.0 g (0.0345 mol) of [2-methyl-3-chloro-4-(2-bromo-2-ethylbutyryl)-phenoxy]-acetic acid, prepared as described above, was dissolved in 90 ml of dimethylformamide, and 4 .4 Q (0.104 mol) of anhydrous lithium chloride was added. The mixture was heated on a steam bath with occasional shaking for 2 hours, cooled and poured into one liter of cold water. The solid that separated was collected by filtration, washed with 500 ml of water and dissolved in dilute sodium bicarbonate solution. The solution was shaken with "Nor it e", filtered free of solid matter and the acid. The crude product (9.8 g, 96%) separated by acidification was recrystallized from 100 ml of benzene and 300 ml of cyclohexane, whereby 9.0 g of [2-methyl-3-chloro-4-(2-ethylidenebutyryi)- phenoxy]-acetic acid which melted at 132.5 - 133.5°C.

Example 11

[2,3-dimethyl-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid Step A: [2,3-dimethyl-4~(2-ethylbutyryl)-phenoxy]-acetic acid

The above product was prepared by substantially the same procedure as described in Example 3, step A, using the following materials: 90 g (0.50 mol) (2,3-dimethylphenoxy)-acetic acid, 84 g (0.62 mol) 2-ethylbutyryl chloride, 400 ml of carbon disulphide and 217 g (1.63 mol) of aluminum chloride.

In this way, 65 g (47%) of [2,3-dimeth<y>1^-^-ethyl-butyryl)-phenoxy]-acetic acid was obtained which, after recrystallization from methylcyclohexane, melted at 97 - 98°C.

Step B: [2,3-dimethyl-4-(2-bromo-2-ethylbutyryl)-phenoxy]-acetic acid

The above product was prepared by practically the same procedure as in Example 4, step B, using the following materials: 10.4 Q (0.0374 mol) [2,3-dimethyl-4-(2-ethyl-butyryl )-phenoxy]-acetic acid, 6.0 g (0.0374 mol) bromine and 250 ml glacial acetic acid.

The product, 13.4 g (100%) of [2,3-dimethyl-4-(2-bromo-2-ethyl-butyryl)-phenoxy]-acetic acid, obtained by the above procedure, melted after recrystallization from 160 ml of cyclohexane at 117 - 118°C.

Step C: [2,3-dimethyl-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid

This product was prepared by practically the same procedure as described in Example 5 using the following materials: 8.15 g (0.0228 mol) [2,3-dimethyl-4-(2-bromo-2-ethylbutyryl)-phenoxy ]-acetic acid, 2.90 g (0.0684 mol) of anhydrous lithium chloride and 60 ml of dimethylformamide.

The product (6.0 g, 74%) obtained as described was recrystallized from 180 ml of methylcyclohexane to give 5.0 g of [2,3-dimethyl-4-(2-ethylidenebutyryl)-phenoxy]-acetic acid which melted at 103 - 104°C.

Example 12

[3-chloro-4-(2-propylidenevaleryl)-phenoxy]-acetic acid

Step A: 3'-chloro-4'-hydroxy-2-propylvalerophenone

To a mixture of 31.52 g (0.2 mol) of 3-chloroanisole and 26.92 g (0.2 mol) of 2-propylvaleryl chloride in petroleum ether was added gradually with stirring at 5°C over half an hour 73, 34 g (0.6 mol) aluminum chloride. The mixture was stirred at 5°C for 20 minutes and then allowed to warm to 25°C with stirring for an additional 3 hours. The mixture was then kept at 25-30°C for 48 hours. The petroleum ether was then decanted and the residue added to 500 g of ice containing 40 ml of concentrated hydrochloric acid. The dark oil which separated was extracted with ether, the ether solution was washed with water and extracted with 2.5% sodium hydroxide. The sodium hydroxide extract was treated with "Norite" and filtered free of carbon, acidified with hydrochloric acid, whereby a green oil was obtained which was then extracted with ether. The ether extract was dried over sodium sulfate, the ether was evaporated and the residue distilled, whereby 12.96 g of 3'-chloro-4'-hydroxy-2-propylvalerophenone was obtained in the form of a viscous oil with a boiling point of 140°C at 0, 5 mm pressure.

Step B: [ 3 - chloro - 4-( 2 - propy 1 val er yl.) - phenoxy ] - acetic acid

13.21 g (0.0518 mol) of 3'-chloro-4'-hydroxy-2-propylvalerophenone was added to a solution of 1.19 g (0.0518 mol) of sodium dissolved in 100 ml of absolute ethanol. The mixture was heated and stirred while 8.66 g (0.0518 mol) ethyl bromoacetate was added over 10 minutes. After heating for 6 hours on a steam bath, the ethanol was removed under reduced pressure and the residue treated with sodium hydroxide and worked up in practically the same way as described in example 5, whereby 7.7 g of [3-chloro-4-(2-propylvaleryl) -phenoxy]-acetic acid which after recrystallization from benzene melted at 134 - 135°C

Step C: [ 3- chloro~ 4-( 2- propyl- 2- bromovaleryl)- phenoxy]- acetic acid

7.2 g (0.023 mol) of the compound obtained in step A was dissolved in 100 ml of acetic acid and brominated by practically the same procedure as in example 4, step B, whereby 8.05 Q [3-chloro-4-( 2-propyl-2-bromovaleryl)-phenoxy]-acetic acid which after crystallization from a .9:2 mixture of cyclohexane and benzene melted at 125 - 125.5°C.

Step D: [ 3- chloro- 4~( 2- propylidenevaleryl)- phenoxy]- acetic acid

7 g (0.02 mol) of the bromine compound obtained in step B was dissolved in 40 ml of dimethylformamide. and 5.6 g (0.064 mol) of lithium bromide was added. The mixture was heated at 80 - 90°C for 4 hours and then worked up by practically the same method as in example 4, whereby 3 g of [3-chloro-4-(2-propylidenevaleryl)-phenoxy]-acetic acid was obtained which, after crystallization from benzene, melting at 114 - 114.5°C.

Example 13

[3-chloro-4~(2-isopropylidenepropionyl)-phenoxy]-acetic acid Step A: ( 3-chloro-4-isovalerylphenoxy)-acetic acid

By using the following reagents instead of those used in Example 8, step A, and by following practically the same procedure as described there, (3-chloro-4-isovalerylphenoxy)-acetic acid is obtained: 32.6 g (0.272 mol ) isovaleryl chloride, 44.7 g (0.24 mol)

(3-chlorophenoxy)-acetic acid, 101 g (0.755 mol) aluminum chloride and 250 ml of carbon disulphide.

The raw product is obtained in the form of a rubbery, solid substance that was triturated with one liter of hot 5% sodium bicarbonate, and the resulting solution was filtered for insoluble aluminum salts. The filtrate was treated with 5 g "Darco" (decolorizing charcoal) and acidified with hydrochloric acid. The solid which separated was dried and crystallized from benzene, whereby 33.8 g of (3-chloro-4-isovalerylphenoxy)-acetic acid with a melting point of 107 - 108°C was obtained.

Step B: [3-chloro-4~(2-dimethylaminomethylisovaleryl)-phenoxy]-acetic acid hydrochloride

In a 100 ml round bottom flask fitted with an outlet tube suitable for the application of occasional suction, an intimate mixture of 27 g (0.1 mol) (3-chloro-4-isovalerylphenoxy)-acetic acid, 3 g (0.1 mol) paraformaldehyde, 8.15 g (0.1 mol) dry dimethylamine hydrochloride and 0.5 ml acetic acid heated on a steam bath for approx. 1.5 hours, during which suction of approximately 1 minute's duration was occasionally applied 5 or 6 times. The hot reaction mixture was dissolved in 50 ml of hot acetone. The solid (22 g) which separated on cooling, melted at 159-163°C. After digesting this product in hot acetone, the purified [3-chloro-4-(2-dimethylaminomethyl)-isovalerylphenoxy]-acetic acid hydrochloride with a melting point of 167 - 169°C was obtained.

Step C: [ 3- chloro- 4-( 2- methyleneisovaleryl)- phenoxy]- acetic acid

19 g (0.052 mol) of the Mannich compound obtained as described above was dissolved in 25 ml of water and the solution made weakly basic by the addition of 10% sodium bicarbonate solution. The resulting solution was heated for 25 minutes on a steam bath, cooled and acidified with 6 N hydrochloric acid, whereby [3-chloro-4-(2-methyleneisovaleryl)-phenoxy]-acetic acid was obtained which, after crystallization from benzene, melted at 122, 5 - 123.5°C in a yield of 9 g.

Step D: [ 3- chloro- 4~( 2, 3- dimethylbutyryi)- phenoxy]- acetic acid

10 g (0.0355 mol) [3-chloro-4-(2-methyleneisovaleryl)-phenoxy]-acetic acid was dissolved in 275 ml of isopropanol and hydrogenated in the presence of 5% palladium on charcoal at 26°C and 756 mm press a Parr device. During approx. 4o minutes hydrogen was absorbed. The solution was heated and filtered to remove the catalyst, the alcohol evaporated and the residue crystallized from benzene to give 8.4 g of [3-chloro-4-(2,3-dimethylbutyryl)-phenoxy]-acetic acid which melted at 132.5 - 133.5°C.

Step E: [3-chloro-4-(2,3-dimethyl-2-bromobutyryl)-phenoxy]-acetic acid

2.96 g of [3-chloro-4-(2,3-dimethylbutyryl)-phenoxy]-acetic acid prepared by the procedure in step D was brominated by following practically the same procedure as in Example 4, step B, whereby one obtained 2.8 g of [3~chloro-4-(2,3-dimethyl-2-bromobutyryl)-phenoxy]-acetic acid which, after crystallization from benzene, melted at 151.5 - 152°C.

Step F: [3-chloro-4-(2-isopropylidenepropionyl)-phenoxy]-acetic acid

6.5 g (0.018 mol) of the compound obtained in step E was dissolved in 40 ml of dimethylformamide, 2.3 g (0.054 mol) of lithium chloride was added, and the compound was dehydrobrominated by practically the same procedure as in Example 4, whereby 1.5 g of [3-chloro-4-(2-isopropylidenepropionyl)-phenoxy]-acetic acid was obtained which, after repeated crystallizations from benzene, melted at 144 - 146°C.

Example 14

[3-chloro-4-(2-isopropylidenebutyryl)-phenoxy]-acetic acid and

[ 3- chloro-4-(2-ethylidene- 3- methylbutyry1)- phenoxy]- acetic acid Step A: 2'- chloro- 4'- hydroxy- 2- isopropylbutyrophenone

To a mixture of 38.8 g (0.272 mol) of 3-chloroanisole and 25 g (0.168 mol) of 2-isopropylbutyryl chloride in 250 ml of carbon disulphide, 46.6 g (0.35 mol) of aluminum chloride were added with stirring. The mixture was then heated at 50-6o°C for 5 hours. The carbon disulphide was then removed by distillation, 300 ml of heptane and 26.67 g (0.2 mol) of aluminum chloride were added and the mixture stirred and heated on a steam bath for 2 hours. The solvent was then decanted, and 400 ml of ice water was added slowly under external cooling in an ice bath. This was followed by the addition of 40 ml of concentrated hydrochloric acid and extraction with ether. The ether extract was washed with water, dried over sodium sulfate, and the ether was then evaporated and the residue distilled. The fraction boiling at 156-167°C at 0.5 mm pressure (15.8 g) was collected. The product solidified, and after crystallization from cyclohexane, 7.14 9 2 *-chloro-4'-hydroxy-2-isopropylbutyrophenone with melting point 75 - 77°C was obtained.

Step B: [3-chloro-4-(2-isopropylbutyryl)-phenoxy]-acetic acid

By replacing the phenol used in example 4, step A, with an equimolar amount of 2'-chloro-4'-hydroxy-2-isopropylbutyrophenone and by following practically the same procedure as described in step A of example 4, [3- chloro-4-(2-isopropylbutyryl)-phenoxy]-acetic acid which, after crystallization from a mixture of benzene and hexane, melts at 136 - 137°C.

Step C: [3-chloro-4-(2-bromo-2- isopropylbutyryl)-phenoxy]-acetic acid

6.6l g (0.0221 mol) of the product obtained in step B was brominated by practically the same procedure as in example 4, step B, whereby 4 9 [3-chloro-4-(2-bromo-2- isopropylbutyryl)-phenoxy]-acetic acid which, after crystallization from a mixture of benzene and hexane, melted at 126 - 127°c.

.Step D: [ 3- chloro-4~( 2- isopropylidenebutyryl 1)- phenoxy]- acetic acid

and

[ 3- chloro- 4-( 2- ethylidene- 3- methylbutyryl)- phenoxy]- acetic acid

4 g (0.0106 mol) of the compound obtained in step C in 25 ml of dimethylformamide was dehydrobrominated by practically the same method as in example 4> whereby a solid material was obtained which melted at 91 - 94°C. The solid material was extracted with 800 ml of hot hexane in four portions. By combining and cooling, 1.2 g of a mixture of [3-chloro-4~(2-isopropylidenebutyryl)-phenoxy]-acetic acid and [3-chloro-4-(2-ethylidene-3-methylbutyryl)-phenoxy ]-acetic acid in the form of colorless crystals with a melting point of 95 - 97°C. Nuclear magnetic resonance spectra showed that the product was an essentially 1:1 mixture of the compounds.

Example 15

[3-methyl-4-(2-isopropylidene-3-methylbutyryl)-phenoxy]-acetic acid Step A: 2-isopropyl-3,2'-dimethyl-4'-hydroxybutyrophenone

To a stirred mixture of 24.43 g (0.2 mol) of 3-methoxytoluene, 32.53 g (0.2 mol) of 2-isopropyl-3-methylbutyryl chloride and 200 ml of carbon disulfide in a 1 liter flask fitted with a reflux condenser and stirrer, 26.6 g (0.2 mol) of aluminum chloride was added slowly with stirring at 10-20°C using an Erlenmeyer flask connected to a Gooch sleeve to the neck of the reaction flask. The mixture was then gently boiled for 6.5 hours, and the carbon disulphide was then removed by distillation. 100 ml of n-heptane and 26.67 g of aluminum chloride were then added and the mixture refluxed for 7 hours, cooled, and 400 ml of ice water was added carefully while stirring and cooling in an ice bath. The mixture was then acidified with 40 ml of concentrated hydrochloric acid and the organic components extracted with ether. The ether solution was washed with water and extracted with an excess of 10% sodium hydroxide in several portions. The basic extracts were combined and washed with ether and acidified with hydrochloric acid. The light brown, solid material that separated (melting point 114 - H9°C, 12.85 g) was crystallized from benzene, whereby 9.67 g of 2-isopropyl-3,2•-dimethyl-4'-hydroxy-butyrophenone was obtained with melting point 123 - 124.5°C.

Step B: [3-methyl-4-(2-isopropyl-3-methylbutyryl)-phenoxy]-acetic acid

0.8l6 g (0.0355 g atom) of sodium was dissolved in 100 ml of anhydrous ethanol in a suitable apparatus and 8.30 g (0.0355 mol) of the product prepared

set in step A was added to the solution. The mixture was heated to boiling, and 5.93 g (0.0355 mol) of ethyl bromoacetate was added and the mixture heated for 4 hours. The alcohol was then evaporated and the residue heated at 8o - 90°C with 50 ml of 10% sodium hydroxide for 4 hours. The mixture was cooled, extracted with ether and acidified with hydrochloric acid, and the solid which separated was extracted with ether. The ether extract was separated, washed with water and dried over sodium sulphate, the ether was evaporated and the residue crystallized from a mixture of benzene and cyclohexane, whereby 1.9 g of [3-methyl-4~(2-isopropy1-3-methylbutyry1)- phenoxy]-acetic acid with a melting point of 95 - 95.5°C.

Step C: [3~methyl-4-(2-bromo-2-isopropyl-3-methylbutyryl)-phenoxy]-acetic acid 5 g (0.017 mol) of the product prepared in step B was dissolved in 40 ml of acetic acid and the solution heated to 50°C and a few drops of a solution of 2.56 g (0.016 mol) of bromine in 20 ml of acetic acid were added. The bromine color persisted for 30 minutes, at which time 0.5 ml of 48% hydrogen bromide was added, and the red bromine color slowly disappeared. The mixture was allowed to cool to 20 - 25°C, and approx. half of the remaining bromine solution was added over 30 minutes. After a further 2 hours at 20 - 30°C, the reaction mixture, which was again pale yellow, was heated to 50°C, and the rest of the bromine solution was added over the course of 30 minutes. The mixture was kept at 20 - 25°C for 17 hours, and then poured into water containing a little sodium bisulphite. The precipitated solid was collected by filtration, washed well with water to give 6.3 g of [3-methyl-4-(2-bromo-2-isopropyl-3-methylbutyryl)-phenoxy]-acetic acid of m.p. about. 140 - 141°C. As the compound is unstable, it was used directly in the next step.

Step D-, [ 3 -meth hy 1 -4-(2-isopropyl lidene -3-meth hy lbut y ry 1) -phenoxy ] -acetic acid

5.2 g (0.0141 mol) of the bromine compound prepared in step C and 3.59 g (0.0411 mol) of lithium bromide were placed in 34 ml of dimethylformamide and heated to 80-90°C for 5 hours. The mixture was then added to water, and the solid which separated was collected and crystallized from a mixture of hexane and benzene, being at the same time decolorized with activated carbon, whereby 1.8 g of [3-methyl-4-( 2-isopropylidene-3-methylbutyryl)-phenoxy]-acetic acid with melting point HO - 112°C.

Example 16

j" 3-chloro-4-(3-methylcrotonoyl)-phenoxy]-acetic acid

Step A: [3-chloro-4-(2-bromosovaleryl)-phenoxy]-acetic acid

14.6 g (0.0054 mol) of the (3-chloro-4-isovalerylphenoxy)-acetic acid prepared as described in Example 13, step A, was dissolved in approx. 100 ml of acetic acid, and 8.7 Q (0.054 mol) of bromine in 20 ml of acetic acid were added dropwise with stirring during 10 - 15 minutes. The reaction was initiated by adding 2 drops of 48% hydrogen bromide. The mixture was added to approx. 1 liter of water containing a little sodium bisulphite, and the solid which separated was collected, washed with water and dried. The product obtained was crystallized from isopropyl alcohol, whereby 17.0 g of [3-chloro-4-(2-bromoisovaleryl)-phenoxy]-acetic acid with a melting point of 171 - 172°C was obtained.

Step B: f 3- chloro- 4~( 3- methylcrotonoyl)- phenoxy]- acetic acid

12.3 g (0.035 mol) of [3-chloro-4-(2-bromoisovaleryl)-phenoxy]-acetic acid was added to a solution of 23.6 g (0.4 mol) of trimethylamine in 150 ml of absolute ethanol. The solution was enclosed in a glass-lined autoclave and heated at 80°C for 18 hours. On cooling and opening the autoclave, it turned out that the reaction mixture consisted of a reddish-brown solution and a white crystalline precipitate of trimethylamine hydrobromide. The solid was removed by filtration and the filtrate concentrated to a small volume by evaporation on a steam bath. When the residue was added to water, a cloudy solution of the trimethylamine salt of the product was formed. On acidification with 6 N hydrochloric acid, a solid precipitate formed which was collected by filtration and dissolved in diluted sodium bicarbonate. The solution was shaken with decolorizing charcoal, filtered and acidified with hydrochloric acid. The dark amber solid that separated (7.3 g with melting point 120 - 130°C) was crystallized from a mixture of 50 ml of cyclohexane and 70 ml of benzene, and then from benzene, whereby 1.4 g of [3- chloro-4-(3-methylcrotonoyl)-phenoxy]-acetic acid with melting point 134 - 136°C.

Example 17

[ 3-Chloro-4~(2-propy1idenpropionyl)-phenoxy]-acetic acid Step A: ( 3-Chloro-4-n-valerylphenoxy)-acetic acid

A dry 1-liter round bottom flask was fitted with a stirrer and reflux condenser. 36.2 g (0.30 mol) of n-valeryl chloride, 44.7 g (0.24 mol) of (3-chlorophenoxy)-acetic acid and 240 ml of carbon disulphide were placed in the flask. 100 g (0.755 mol) of powdered aluminum chloride was added in small portions at 10°C with mechanical stirring. After half of the aluminum chloride had been added, the mixture became rather viscous, and the rest of the aluminum chloride was added while stirring by hand. When the mixture became mobile enough, mechanical stirring was resumed and continued for one hour. The mixture was then heated below 50°C with stirring for a further 3 hours. The carbon disulfide was decanted off,

and the residue was added to a mixture of 1 kg of ice and 30 ml of concentrated hydrochloric acid. The oil which separated was extracted with ether,

and the ether extract was then extracted with 10% sodium bicarbonate solution. The bicarbonate extract was acidified with concentrated hydrochloric acid, and the crude product obtained was crystallized from a 2:1 mixture of ligroin and benzene, whereby 30 g of (3-chloro-4-n-valerylphenoxy)-acetic acid with a melting point of 82.5 - 83 was obtained, 5°C (corrected).

Step B: / h~[ 2-( diraethylaminomethyl) -valeryl] -3-chlorophenoxy_/-acetic acid - hydrochloride

In a 100 ml round bottom flask fitted with an outlet tube suitable for the application of occasional suction, an intimate mixture of 6.76 g (0.025 mol)

(3-chloro-4-n-valerylphenoxy)-acetic acid, 0.825 g (0.0275 mol) paraformaldehyde, 2.24 g (0.0275 mol) dry dimethylamine hydrochloride and 4 drops of acetic acid heated on a steam bath for approx. 1.5 hours, during which suction was applied for a period of approx. 1 minute five or six times. The resulting syrupy residue was triturated with ether, whereby 5.4 g of /3-chloro-4-[2-(dimethylaminomethyl)-valeryl]-phenoxy/-acetic acid hydrochloride was obtained in the form of a solid which was collected and used in the next step without further purification.

Step C: [ 3- chloro- 4-( 2- methylenevaleryl)- phenoxy]- acetic acid

The /3-chloro-4-[2-(dimethylaminomethyl)-valeryl]-phenoxy_/-acetic acid hydrochloride prepared as described above was dissolved in water

and filtered to remove fading. The clear resolution was then

made basic with sodium bicarbonate and heated for 25 minutes on a steam bath. The resulting solution was then cooled and acidified with 6 N hydrochloric acid, whereby 1.8 g of [3-chloro-4-(2-methylenevaleryl)-phenoxy]-acetic acid was obtained in the form of a solid, which after crystallization from benzene, gave 1.4 g of purified [3-chloro-4-(2-methylenevaleryl)-phenoxy]-acetic acid with melting point 101 - 102°C.

Step D: [ 3- chloro- 4-( 2- methylvaleryl)- phenoxy]- acetic acid

8.7 g of [3-chloro-4-(2-methylenevaleryl)-phenoxy]-acetic acid, prepared as described in step C, was dissolved in 250 ml of isopropyl alcohol and 3 g of 5% apalladium on charcoal was added. The mixture was hydrogenated at an initial pressure of about 2.4 kg/cm 2 in a Parr apparatus. During approx. In 40 minutes, the required amount of hydrogen had been absorbed. The solution was heated and filtered to remove the catalyst, the alcohol evaporated and the residue crystallized from benzene to give 4.8 g of [2-chloro-4-(2-methyl-valeryl)-phenoxy]-acetic acid which, after crystallization from benzene, melted at 123 - 124.5°C

Step E: [3-chloro-4~(2-bromo-2-methylvalery1)-phenoxy]-acetic acid

2.15 g (0.0075 mol) of the [3-chloro-4-(2-methylvalery1)-phenoxy]-acetic acid obtained in step D was brominated by following practically the same procedure as described in Example 10, step B, whereby 2.1 g of [3-chloro-4-(2-bromo-2-methyl valeryl 1)-phenoxy]-acetic acid was obtained which, after crystallization from a 2:1 mixture of cyclohexane and benzene, melted at 115 - 117°C.

Step F: [ 3- chloro- 4~( 2- propylidenepropionyl)- phenoxy]- acetic acid

12.8 g (0.0352 mol) of [3-chloro-4-(2-bromo-2-methylvaleryl)-phenoxy]-acetic acid prepared as described in step E was dissolved in 60 ml of dimethylformamide, and 2.9 g (0.0684 mole) of anhydrous lithium chloride was added. The mixture was heated on a steam bath with occasional shaking for 2 hours, cooled and poured into one liter of cold water. The solid that separated was collected by filtration, washed with 500 ml of water and then dissolved in dilute sodium bicarbonate solution. The solution was shaken with "Norite", filtered free of solids and the acid. The solid which separated was dried in air to give 2.2 g of [3-chloro-4-(2-propylidenepropionyl)-phenoxy]-acetic acid which, after crystallization from a mixture of ether and ligroin, melted at 96 - 97°C.

Example 18

[3-chloro-4-(2-isobutylidenepropionyl)-phenoxy]-acetic acid Step A: [ 3-chloro-4-(4-methylvaleryl)-phenoxy]-acetic acid

This product was prepared by following substantially the same procedure as described in Example 20, Step A, using the following reactants: 134.6 g (0.272 mol) 4-methylvaleryl chloride, 44.8 g (0.24 mol) ( 3-chlorophenoxy)-acetic acid, 108 g (0.755 mol) aluminum chloride and 250 ml carbon disulfide.

the product, [3-chloro-4-(4-methylvaleryl)-phenoxy]-acetic acid, was obtained as a colorless solid, and, after crystallization from a mixture of ether and ligroin, 20 g of [3-chloro -4-(4-methylvaleryl)-phenoxy]-acetic acid with melting point 89.5 - 90°C.

Step B: [3-chloro-4-(2-methylene-4-methylvaleryl)-phenoxy]-acetic acid

A mixture of 17.5 g (0.063 mol) [3-chloro-4-(4-methylvalery1)-phenoxy]-acetic acid, 1.91 g (0.063 mol) paraformaldehyde, 5.15 g (0.063 mol) dimethylamine hydrochloride and 0.5 ml of acetic acid was heated at 90-100°C for 4 hours. The mixture was then dissolved in 40 ml of acetone and ether added until no further precipitate formed. The ether-acetone mixture (a) was decanted off and the residue dissolved in water. The aqueous solution (b) was extracted with ether, basified with 10% sodium bicarbonate, heated at 80-90°C for 15 minutes and acidified. The solid which separated was collected by filtration, and had a melting point of 114 - 116°C. The ether-acetone extract (a) was extracted with 5% sodium bicarbonate solution in portions until acidification of the aqueous extract gave no further precipitate. The bicarbonate extracts were combined and acidified with hydrochloric acid, whereby a solid with a melting point of 111 - 114°C was obtained. The two yields of solid material were dried in air at 65°C and then crystallized from a 9:10 mixture of cyclohexane and benzene and then from benzene to give 14.1 g of [3-chloro-4-(2-methylene -4-methyl-valeryl)-phenoxy]-acetic acid with melting point 115 - 116°C.

Step C: [ 3- chloro- 4-( 2- isobutylpropiony1)- phenoxy]- acetic acid

19.05 g (0.0642 mol) of [3-chloro-4-(2-methylene-4-methylvaleryl)-phenoxy]-acetic acid, prepared as described in step B, was hydrogenated by practically the same procedure as described in Example 17, step D, whereby 13.1 g of [3-chloro-4-(2-isobutyl-propionyl)-phenoxy]-acetic acid was obtained which, after crystallization from benzene, melted at 127-128.5°C.

Step P: [3-chloro-4-(2-bromo-2- isobutylpropiony1)-phenoxy]-acetic acid

To a solution of 12.1 g (0.0405 mol) [3-chloro-4-(2-isobutyl-propionyl)-phenoxy]-acetic acid in 200 ml of acetic acid, 2 drops of 48% hydrogen bromide were added with stirring, followed by dropwise addition of 6.0 g (0.0374 mol) bromine in 50 ml acetic acid. After the addition was finished, the mixture was stirred for 15 minutes and then poured into one liter of water containing 2 g of sodium bisulphite. The solid which separated was collected on a filter, washed with water, dried in air and crystallized from 55 ml of benzene to give 14.4 g of [3-chloro-4-(2-bromo-2-isobutylpropionyl)- phenoxy]-acetic acid with a melting point of 115 - 116°C.

Step E: [ 3-chloro-4-(2-isobutylidenepropionyl)-phenoxy]-acetic acid

9.5 g (0.025 mol) of [3-chloro-4-(2-bromo-2-isobutylpropionyl)-phenoxy]-acetic acid, prepared as described in step D, was dissolved in 60 ml of dimethylformamide and 2.9 g (0 .0684 mol) anhydrous lithium chloride

was added. The mixture was heated on a steam bath with occasional shaking for 2 hours, cooled and poured into one liter of cold water. The solid that separated was collected by filtration, washed with 500 ml of water and then dissolved in dilute sodium bicarbonate solution. The solution was shaken with "Norite", filtered free of solids and the acid. The solid which separated was dried in air, whereby 1.8 g of [3-chloro-4-(2-isobutylidenepropionyl)-phenoxy]-acetic acid was obtained which, after crystallization from benzene, melted at 123 - 124°C.

Example 19

[ 3-chloro-4~(3-bromo-2-ethylidene-propionyl)-phenoxy]-acetic acid

Step A: /3-chloro-4-[2-(dimethylaminomethyl)-buty ry 1 ]-phenoxy_7-acetic acid

In a 100 ml round bottom flask fitted with an outlet tube suitable for the application of occasional suction, an intimate mixture of 14.52 g (0.06 mol)

(3-Chloro-4-butyrylphenoxy)-acetic acid, prepared by the method described in Example 1, step A, 2.1 g (0.072 mol) paraformaldehyde, 5.34 g (0.066 mol) dry dimethylamine hydrochloride and 4 drops of acetic acid heated in a steam bath for approx. 1.5 hours during which time suction was applied for approx. 1 minute periods five or six times. Upon cooling, 19 g of a solid was obtained which was triturated with acetone. The white solid that was formed was crystallized from acetonitrile and isopropyl alcohol to give /3-chloro-4-[2-dimethyl-aminomethyl)-butyryl]-phenoxy_/-acetic acid hydrochloride with a melting point of 127 - 129°C.

Step B: [3-chloro-4-(2-methylenebutyryl)-,phenoxy]-acetic acid

1 g (0.003 mol) of the Mannich compound obtained as described in step A was dissolved in 25 ml of water and the solution was made weakly basic by the addition of 10% sodium bicarbonate solution. The resulting solution was heated for 25 minutes on a steam bath, cooled and acidified with 6 N hydrochloric acid, whereby 0.7 g of solid [3-chloro-4-(2-methylenebutyryl)-phenoxyacetic acid was obtained. After recrystallization from a mixture of cyclohexane and benzene, [3-chloro-4~(2-methylenebutyryl)-phenoxy]-acetic acid was obtained in the form of colorless crystals with a melting point of 109 - H0°C.

Step C: /3-chloro-4-[2-bromo-2-(bromomethyl)-butyryl enoxy_/-acetic acid

4.03 g (0.015 mol) of [3-chloro-4-(2-methylenebutyryl)-phenoxy]-acetic acid was dissolved in 150 ml of boiling carbon tetrachloride and a solution of 2.4 g (0.015 mol) bromine in 50 ml of carbon tetrachloride was added over 5 minutes. The bromine color disappeared quickly after addition to the boiling solution. The solution was cooled and the white solid which separated was removed by filtration and washed with fresh carbon tetrachloride to give 5.94 9 (92%) of /3-chloro-4-[2-bromo-2-(bromomethyl) -butyryl]-phenoxy7-acetic acid with melting point 146 - 149°C. The product was recrystallized alternately from toluene and then acetonitrile, whereby a material was obtained which melted at 153.5 - 155°C (corrected).

Dehydrohalogenation of /3-chloro-4-[2-bromo-2-(bromomethyl)-butyryl]-phenoxy/-acetic acid following practically the same procedure as described in Example 4, step D, gave the compound [3-chloro- 4-(3-Bromo-2-ethylidene-propionyl)-phenoxy]-acetic acid.

Example 20

[3-Chloro-4~(3-methylerotonoyl)-phenoxy]-acetic acid

A mixture of 5.8 g (0.0165 mol) of [3-chloro-4-(2-bromoisovaleryl)-phenoxy]-acetic acid obtained as described in step A of Example 16, and 2.12 g (0.05 mol ) lithium chloride was dissolved in 60 ml of dimethylformamide and heated on a steam bath for 3 hours. The colorless solution obtained was added to 500 ml of water, and the solid which separated was crystallized from benzene, whereby 4.0 g of [3-chloro-4-(2-chloroisovaleryl)-phenoxy]-acetic acid was obtained with melting point 146 - 147°C.

Dehydrohalogenation of [3-chloro-4-(2-chloroisovaleryl)-phenoxy]-acetic acid following substantially the same procedure as described in Example 16, step D, gave the compound [3-chloro-4-(3-methylcroton-oy1 )-phenoxy]-acetic acid.

Claims (1)

Procedure for the preparation of a therapeutically active compound of the formula: where R is hydrogen, halogen, lower alkyl, phenyl or benzyl, R"*" is hydrogen, lower alkyl, phenyl, chloro- or hydroxy-substituted phenyl or phenoxy, R 2 is hydrogen or lower alkyl, or together R 1 and R 2 form an alkylene chain with 3 - 5 carbon atoms, Y~ 2> ^3» ^5 oa; x6' which may be the same or different, is hydrogen, halogen, lower alkyl, lower alkoxy or together X_ and X~ or X- and X^ may be united to form a hydrocarbylene chain containing 4 carbon atoms between its attachment points, and n is a whole number from 1 to 5, as well as salts, esters and amides thereof, characterized in that a compound of the formula: 12 where R, R , R , X^, X^, X^, X^ and n are as indicated above, and Z and Z<2>, which are the same or different, are hydrogen or halogen, at least one of which is halogen, is reacted with a dehydrohalogenating agent, and that the acid obtained, if desired, is transferred to a salt, an ester or the amide thereof in a manner known per se.