NO117370B - - Google Patents

Description

Process for the production of therapeutically effective substituted acetic acid derivatives.

The invention relates to a process for the production of therapeutically effective (3-(substituted-thio)-acylphenoxyacetic acids with the formula

and salts, esters and amides thereof where R is lower alkyl, hydroxyl lower alkyl, halogen-lower alkyl, lower alkanoylamido lower alkyl, lower alkanoylamido-substituted carboxy lower alkyl, amino lower alkyl, amino-substituted carboxy lower alkyl, phenyl, carboxyphenyl, lower al-

kaonyl, or 2-(gamma-L-glutamyl-amino)-2-(N-carboxymethylcarbamoyl)-lower alkyl, R<1>is hydrogen or lower alkyl,

R<2> is hydrogen, lower alkyl, halogen substituted lower alkyl, trihalomethyl substituted lower alkyl, cycloalkyl, phenyl or phenoxy,

R3 and R<4>, which may be the same or different, are hydrogen, halogen, trihalomethyl, lower alkyl, lower alkoxy, nitro, lower alkanoylamido, or R<3> and R<4> on adjacent carbon atoms in the benzene ring may be the same as the ring carbon atoms to which they are attached, form a 5- or 6-membered carbocyclic ring.

It is known from the Journal of Medicinal and Pharmaceutical Chemistry 5 (1962), 660-662 that e.g. 2,3-dichloro-4-(2-methylenebutyryl)-phenoxyacetic acid has diuretic, natriuretic and chloruretic activity. These known compounds contain a 2-alkylidene alkanoyl group. It has now been shown that compounds which, instead of the latter group, have a 2-hydrocarbylthioalkyl-alkanoyl group, give less tissue irritation when injected than the previously known compounds, and they are therefore more advantageous than the known compounds.

The compounds produced by the present method have diuretic, natriuretic and chloruretic properties and are therefore useful in the treatment of many disorders resulting from excessive retention of electrolytes, such as edema and the like.

Compounds produced according to the invention, which have been shown to have particularly good natriuretic properties, and which cause less tissue irritation, have the formula:

where R<2> is lower alkyl. X<2> is hydrogen, halogen or lower alkyl, X<3> is halogen or lower alkyl, and R° is lower alkanoyl, amino-substituted carboxy-lower alkyl, lower alkanioylamldo-substituted carboxy-lower alkyl, carboxyphenyl or 2-(gamma -L-glutamylamino)-2-(N-carboxymethylcarbamoyl)-lower alkyl.

Among these compounds, those where X<2> and X3 are the same and are chlorine or methyl are preferred. The three preferred process compounds are the acetyl-cysteine adduct, the glutathione adduct and the cysteine adduct of 2,3-dichloro-4-(2-methylenebutyryl)-phenoxyacetic acid.

It will be understood that the dosage of the new compounds produced by the present process will vary over a wide range depending on the age and weight of the patient to be treated, the particular disorder to be treated, and the relative potency of the diuretic agent selected. For this reason, tablets, pills, capsules and the like containing e.g. from approx. 25 to approx. 500 ml or more of the active substance is made available for symptomatic adjustment of the dose to the individual patient. These doses appear to be well below the toxic dose of the new compounds prepared according to the method.

The compounds of formula A are prepared according to the present method in that a compound of formula:

is reacted with a mercaptan of the formula RSH, where R, R<1>, R<2>, R<3> and R<4> are as indicated above, and the compounds obtained are optionally transferred in their salts, esters or amides onto and in a familiar way.

The reaction is advantageously carried out under gentle heating which need only be sufficient to melt the reactants. Upon cooling, the product is generally obtained in solid form. In the event that the mercaptan, R—SH, is volatile, an excess is used to ensure that sufficient mercaptan is present in the reaction to give a considerable yield of the product. Heating of the reaction mixture is not necessary when the mercaptan and the α-alkylidene acyl compound react easily. In general, the reaction can be carried out either with or without a solvent and either with or without heating.

Alternatively, when both reactants are soluble in sodium bicarbonate solution, each of them can be dissolved in a separate aqueous sodium carbonate solution, the solutions combined and allowed to stand, preferably at room temperature, until the reaction is practically complete.

When the mercaptan, R—SH, is not soluble in sodium bicarbonate solution, it is added to the sodium bicarbonate solution of the α-alkylidene acyl compound and the reaction mixture is stirred or shaken until the soluble product is formed and all or practically all of the undissolved mercaptan disappears.

When the reaction product contains a basic group, such as an amino group, it is isolated by acidifying the reaction mixture, evaporating to dryness and separating the product from inorganic salts by extraction with an organic solvent. When the product has only acidic groups, it is separated from the reaction mixture by acidification.

The preferred compounds of formula C° above are prepared by using as starting materials a compound of formula:

where R<2>is lower alkyl, X<2>is hydrogen, halogen or lower alkyl and X<3>is halogen or lower alkyl, and a mercaptan, RSH, where R is lower alkanoyl, amino substituted carboxy-lower alkyl, lower alkanoylamido-substituted carboxy-lower alkyl, carboxyphenyl or 2-(gamma-L-glutamylamino)-2-(N-carboxymethylcarbamoyl)-lower alkyl, and preferably a compound of formula C is used where X<2> and X<3> are like and is chlorine or methyl. The three preferred compounds are prepared by reacting 2,3-dichloro-4-(2-methylenebutyryl)-phenoxyacetic acid with respectively acetyl-cysteine hydrochloride, glutathione hydrochloride and levo-cysteine hydrochloride monohydrate.

The mercaptan starting materials are known and can either be obtained commercially or they can be produced by methods described in the literature.

The α-methyleneacylphenoxy and α-methyleneacylphenyl mercapto derivatives of organic carboxylic acids and especially organic monocarboxylic acids, which have been used in the preceding reaction, can

produced in several ways, some of which are shown below.

When the mercaptan, R—SH, is not soluble in sodium bicarbonate solution, it is added to the sodium bicarbonate solution of the α-alkylidene acyl compound and the reaction mixture is stirred or shaken until the soluble product is formed and all or practically all of the insoluble mercaptan disappears.

When the reaction product contains a basic group, such as an amino group, it is isolated by acidifying the reaction mixture, evaporating to dryness and separating the product from inorganic salts by extraction with an organic solvent. When the product has only acidic groups, it is separated from the reaction mixture by acidification.

The mercaptan starting materials are known and can either be obtained commercially or they can be produced by methods described in the literature.

The α-methyleneacylphenoxy and α-methyleneacylphenylmercapto derivatives of organic carboxylic acids and especially organic monocarboxylic acids, which are used in the preceding reaction, can be prepared in several ways, some of which are shown below.

The above reaction scheme shows that α-alkylidene acylphenoxyacetic acid compound (X) can be prepared from saturated acylphenoxyacetic acid compounds (VII) by two methods, the choice in principle depending on whether Z is equal to H or whether Z is equal to CH3 or -CH2 alkyl.

When Z = H, the saturated acylphenoxyacetic acids (VII) are transferred to α-methyleneacylphenoxyacetic acids (X) by first preparing the Mannich derivative (VIII) which, on treatment with sodium bicarbonate, is transferred into the desired compound (X).

Mannich derivative is advantageously prepared by reacting the saturated acyl compound (VII) with a salt of a secondary amine such as a di-lower alkylamine or a salt of a cyclic amine such as piperidine, morpholine or the like, in the presence of formaldehyde or paraformaldehyde. The treatment of the Mannich salt with a base such as aqueous sodium carbonate or preferably sodium bicarbonate, either with or without heating, gives the desired unsaturated acyl compound (X).

Dehydrohalogenation of a-bromoacylphenoxy-acetic acids with an unsymmetrical branched chain in which the a-carbon in the acyl group also has two alkyl substituents will proceed in such a way that the unring is introduced into the longer chain if one of the a-alkyl groups is a methyl group and only one product can be obtained. If the α-carbon is unsymmetrically substituted and the groups are ethyl or higher, the double bond will form randomly in one or the other chain, but the isomers that are formed can often be separated. If the α-carbon is symmetrically substituted with ethyl or higher groups, only one unsaturated product will be obtained.

When Z = CH3, or especially when Z = CH2-alkyl, the saturated acylphenoxyacetic acid (II) is transferred to the unsaturated compound X by halogenating compound VII and then treating the halogenated compound IX with a dehydrohalogenating agent. This method is particularly useful when the saturated acylphenoxy or saturated acylphenyl mercapto derivative (VII) has the structure R 2 = Z = CHS. The saturated acyl compound (VII) is advantageously brominated to compound IX which is then transferred to compound X by treatment with a dehydrohalogenating agent, such as preferably lithium bromide or lithium chloride in dimethylformamide or silver acetate or silver fluoride 1 benzene and the like. If in the starting material VII indicated above, R<2> = CH 3 and Z = ethyl or a higher alkyl group, the predominant product (denoted below by X—A) will have the double bond in the longer chain. The isomeric compound (denoted below by X—B) is generally the product that occurs in the least amount.

Similarly, when in the above starting material R<2> and Z are not identical and are an ethyl or a higher alkyl group, the predominant product will generally have the double bond in the longer chain.

Compounds having an unsaturated acyl group of the type

where Q is an unsubstituted or substituted aryl (ie phenyl) group and R<2> is hydrogen or a group included in the above definition of R<2>, is preferably prepared by condensing benzaldehyde, e.g. in an alkaline medium with compound vn (where Z = H) followed by acidification of the reaction mixture.

Preparation of saturated acylphenoxyacetic acids (VII)

The intermediate product, saturated acylphenoxyacetic acid (VII), can generally be prepared by one of two methods from the known phenols (I).

The first method involves heating the phenol (I) with an excess of the chloroacetic acid in the presence of at least two moles of an alkali metal hydroxide to form phenoxyacetic acid (VI).

The phenoxyacetic acids (VI) are then transferred to the saturated acylphenoxyacetic acids (VII) by a Frie-del-Craft reaction using an acyl halide, R<2>CHCOCl, and the compound VI in the presence of aluminum chloride. The reaction can be carried out either with or without a solvent, such as carbon disulphide. Although this method has limited applicability, it is usually the one chosen where it is applicable as it is the most direct way.

The second method, although it is longer, has a wider applicability. In this method, phenol (I) is transferred to the corresponding anisole (II) (or fenetol) in a known manner, such as by reaction with dimethylsulphate or diethylsulphate in the presence of a base such as sodium or potassium hydroxide. The anisole (II) (or phenetole) is then reacted with acyl halide, R2 —

Z

CHCOC1, in the presence of anhydrous aluminum chloride and a solvent such as ligroin or carbon disulfide. The acylanisole (III) (or -phenetole) is then transferred to the corresponding acylphenol

(IV) during subsequent treatment and more

aluminum chloride in a solvent such as heptane.

The acylphenol (IV) is then transferred to the metadeacylphenoxyacetic acid (VII) by reaction with a haloaliphatic acid (preferably chloroacetic acid) in the presence of sodium or potassium hydroxide.

Alternatively, the compounds VII can be prepared from the compound IV by a two-step process whereby the acylphenol (IV) is treated with a suspension of sodium hydride in ethylene dimethyl ether (glyme) (or sodium ethoxyde in ethanol) followed by reaction with a haloaliphatic acid ester, such as ethyl bromoacetate , forming an acylphenoxyacetic acid ester (V). Hydrolysis of the ester V with an aqueous or alcoholic base gives the compound VII.

Although the reaction scheme that shows

position of the α-alkylidene acylphenoxyacetic acids for simplicity shows the preparation of para-acylphenoxyacetic acid compounds, the above illustrated and described methods can also be used to prepare other positional isomers. However, it is sometimes easier to prepare the orthoisomers by a Fries rearrangement as shown below. The R groups in the following formulas are attached to the phenyl ring so that one of the ortho positions is unsubstituted.

In the Fries rearrangement procedure shown above, the phenol (I) is first esterified by reaction with the acyl halide,

during the formation of the corresponding phenol ester (VII) which is rearranged to the ortho-acylphenol (IVa) by heating with aluminum chloride. The conversion of the ortho-acylphenol (IVa) to the desired ortho-acylphenoxyacetic acid (Vila) by either

(a) to treat with chloroacetic acid in the presence

of a base or

(b) -reacting IVa with sodium hydride or sodium alkoxide followed by reaction with a haloacetic acid ester to form Va which is hydrolyzed to Vila follows practically the same procedures described above for the transfer of IV to VII or for the transfer of IV to V to VII . Although the Fries rearrangement is particularly useful at

preparation of the ortho-isomers, it can also be used to prepare the para-isomers.

The methods described above for the production of α-alkylidene acylphenoxyaliphatic acids in their generality can likewise be used for the production of α-alkylidene acylphenylmercaptoaliphatic acids.

The term "Mannich compound" used in the following examples denotes the salts of the Mannich bases prepared by a process step described in the particular example. In the examples, all melting points are corrected while the boiling points are uncorrected. The melting points of some of the compounds are difficult to determine as the compounds decompose over a wide range.

The following process illustrates the production of (α-alkylidene acyl)-phenoxyacetic acid starting materials which are used in the production of the new compounds according to the present process.

Procedure I

Production of 3-chloro-4-(2-methylene-burytyl)-acetic acid.

Step A: Preparation of 3-chloro-4-butyryl-phenoxy acetic acid

Powdered aluminum chloride (217 g, 1.625 mol) and carbon disulfide (400 mL) were placed in a 1 liter, 4-necked flask equipped with a stirrer, separatory funnel, reflux condenser and internal thermometer. 3-Chlorophenoxyacetic acid (93.3 g, 0.5 mol) is added in portions with stirring and then n-butyryl chloride (66.6 g, 0.625 mol) is added dropwise with stirring over a period of V2 hour at a temperature of approx. 22-26 °C. After stirring for 1 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 disulphide was then decanted and the resulting tough reaction product was added to a mixture of ice (1 kg) and concentrated hydrochloric acid (100 ml). A solid is separated and dissolved in saturated sodium bicarbonate solution (1.5 1). The solution was filtered and the clear yellow filtrate was acidified with hydrochloric acid. The yellow oil that separates slowly solidifies into a solid that melts at 76-85°C. After recrystallization from benzene, 66.7 g, 51%, of 3-chloro-4-butyrylphenoxyacetic acid, m.p. 89-90°C.

Analysis calculated for C12H13C104:

C 56.15, H 5.10, C 13.81

Found: C 56.24, H 5.43, Cl 13.57.

Step B: Preparation of 3-chloro-4-[_2-(dimethylaminomethyl)butyryl~\phenoxyacetic acid hydrochloride

In a 100 mL round bottom flask fitted with a tube for applying a vacuum, an intimate mixture of 3-chloro-4-butyrylphenoxyacetic acid (5.12 g, 0.02 mol), paraformaldehyde (0.7 g, 0.022 mol), dry Dimethylamine hydrochloride (1.78 g, 0.02 mol) and acetic acid (4 drops) heated on a steam bath for approx. 1.5 hours, five or six times during this time a vacuum was applied for 1 minute. On cooling, a solid was obtained which, after grinding with acetone, gave a white solid. By recrystallization from acetonitrile and from isopropyl alcohol, 3-chloro-4-[2-(dimethylaminomethyl)-butyryl]-phenoxyacetic acid hydrochloride was obtained, m.p. 127-129°C.

Analysis calculated for C15H20ClNO4HCl:

C 51.44, H 6.04, Cl 20.25,

Found: C 51.32, H 5.90, Cl 20.19.

Step C: Preparation of 3-chloro-4-(2-methylenebutyryl)-phenoxyacetic acid The Mannich compound prepared as described in step B was dissolved in 25 ml of water and the solution made weakly basic by adding 10% sodium bicarbonate solution. This solution was heated for approx. 25 minutes on a steam bath, cooled and acidified with 6N hydrochloric acid whereby a 69% yield of an impure product was obtained, m.p. 108-109.5°C. After recrystallization from a

mixture of cyclohexane and benzene gave 3-chloro-4-(2-methylenebutyryl)-phenoxyacetic acid, in the form of colorless crystals, m.p. 109-111°C.

Analysis calculated for C13H13C104:

C 58.11, H 4.88, Cl 13.20,

Found: C 57.87, H 5.05, Cl 13.02.

Procedure II

Preparation of 3-chloro-4-methacryloyl-phenoxyacetic acid

Step A: Preparation of 3-chlorophenoxyacetic acid m-chlorophenol (64.27 g, 0.5 mol) was added to a solution of sodium hydroxide (75g, 1.875 mol) in 150 ml of water. To this was added slowly at 40° C. a solution of chloroacetic acid (80.5 g, 0.852 mol) in 80.5 ml of water. When the addition was finished, the mixture was heated with stirring on a steam bath for 1 hour, after which the reaction mixture was cooled and 1 liter of water was added. The solution was filtered and acidified to Congo red with concentrated hydrochloric acid and the pink oil which separated was extracted with ether. The ether solution was then extracted with a total of 400 ml. 10% sodium bicarbonate solution in several portions to remove the product from unreacted phenol. Acidification of the sodium bicarbonate extract gave an oil which soon solidified. The solid was collected and dried in an oven at 65 °C, whereby 67.8 g (73 percent), 3-chlorophenoxyacetic acid, m.p. 110-111° C.

Step B: Preparation of 3-chloro-4-isobutyryl-phenoxyacetic acid

This compound was prepared by following substantially the same procedure as described under Method I, Step A, using the following compounds: 3-chlorophenoxyacetic acid 37.3 g, 0.20 mol isobutyryl chloride 26.6 g, 0.025 mol powdered aluminum chloride 83 .9 g, 0.63 mol carbon disulphide 200 ml A yield of 17.3% (8.93 g) of 3-chloro-4-isobutyrylphenoxyacetic acid was obtained, m.p. 137— 139° C.

Analysis calculated for C12H13C104:

C 56.15, H 5.10, Cl 13.82,

Found: C 56.04, H 5.34, Cl 14.05.

Step C: Preparation of 3-chloro-4-(2-bromiso-butyryl)-phenoxyacetic acid

3-Chloro-4-isobutyrylphenoxyacetic acid (10.7 g, 0.0397 mol) was added to 250 ml of glacial acetic acid at room temperature. Bromine (6.34 g, 0.0397 mol) in 30 mL of glacial acetic acid was added dropwise to the reaction mixture at ca. 25° C with stirring during 1 hour. Stirring was continued for another 1 hour and the treatment was then added to a mixture of 300 g of ice and 500 ml of water. The crude product thus prepared was crystallized from a mixture of hexane and benzene. On cooling the mixture to 5° C for 1 hour, the product precipitated and was collected

light and dried at 65° C, whereby 8.39 g (63 per cent) of 3-chloro-4-(2-bromoisobutyryl)-phenoxyacetic acid were obtained, m.p. 124.5—125° C.

Analysis calculated for C12<H>12BrC104:

C 42.94, H 3.61, Br 23.81,

Found: C 43.33, H 3.78, Br 23.22.

Step D: Preparation of 3-chloro-4-methacryloyl-phenoxyacetic acid

The brominated compound from step C (5 g, 0.0149 mol) was dissolved in benzene (200 mL) and silver acetate (5 g, 0.0299 mol) was added. The mixture was stirred and refluxed for 4 hours and then cooled. Water (150 ml) and concentrated hydrochloric acid (15 mol) were added whereupon silver salts precipitated and were removed by filtration. The benzene solution was then evaporated to a small volume, diluted with hexane and the solid product that separated was collected on a filter, with which 2.8 g, m.p. 125-127° C. After four recrystallizations from benzene, 1.05 g of 3-chloro-4-methacryloylphenoxyacetic acid was obtained, m.p. 128-129° C.

Analysis calculated for C]2HnC104:

C 56.54, H 4.35, Cl 13.93,

Found: C 56.31, H 4.45, Cl 14.10.

Procedure III

Preparation of 2, 3-dichloro-4-(2- methylenebutyryl)-phenoxyacetic acid

Step A: Preparation of 2,3-dichloro-4-butyryl-phenoxyacetic acid

This compound was prepared using practically the same technique and apparatus as described under method I, step A, using the following compounds: 2,3-dichlorophenoxyacetic acid 22.1 g, 0.1 mol n-butyryl chloride 21.3 g, 0.2 mol Powdered aluminum chloride 53.3 g, 0.4 mol The 2,3-dichlorophenoxyacetic acid and n-butyryl chloride were placed in the reaction vessel and stirred while aluminum chloride was added portionwise over 45 minutes. The mixture was then heated on a steam bath for 3 hours and allowed to cool to room temperature. The produced salable product was added to a mixture of 300 g of crushed ice and 30 ml of concentrated hydrochloric acid. This mixture was extracted with ether and the extract evaporated under reduced pressure. The residue was suspended in boiling water and dissolved by adding at least 40% sodium hydroxide. After treatment with decolorizing charcoal and filtration, the hot filtrate was acidified against King red paper and cooled in ice. The oil that separates was extracted with ether, the extract dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was dissolved in boiling benzene (75 ml), treated with decolorizing charcoal, filtered, treated with boiling cyclohexane (275 ml) and cooled to give 22.3 g of 2,3-dichloro-4-butyrylphenoxyacetic acid. After several recrystallizations from a mixture of benzene and cyclohexane, then from methylcyclohexane, then from a mixture of acetic acid and water and finally from methylcyclohexane, the product melted at 110— 111°C.

Analysis calculated for C12H12C12O4:

C 49.51, H 4.15, Cl 24.36,

Found: C 49.81, H 4.22, 1 24.40.

Step B: Preparation of 2,3-a,ichloro-4-[2-dimethylaminomethyl)-butyryl]-phenoxy-acetic acid hydrochloride

This compound was prepared by following substantially the same procedure as described under Method I, Step B, using the following compounds:

2,3-dichloro-4-buryryl-

Phenoxyacetic acid 5.20 g, 0.0179 mol Paraformaldehyde 0.63 g, 0.0209 mol Dimethylamine hydrochloride (dry) 1.59 g, 0.0195 mol Acetic acid 4 drops

The impure reaction product was triturated with ether, whereby 5.8 g (85%) of 2,3-dichloro-4-[2-(dimethylaminomethyl)-buryryl])phenoxy-acetic acid hydrochloride was obtained in the form of a white solid fabric. After two recrystallizations from a mixture of methanol and ether, the product melted at 165-167°C,

Analysis calculated for C15H20Cl3NO4:

C 46.83, H 5.24, Cl 27.65, N 3.64, Found: C 46.69, H 5.31, Cl 27.59, N 3.53.

Step C: Preparation of 2,3-dichloro-4-(2-methylenebutyryl)-phenoxyacetic acid

The above-described Mannich compound was treated with aqueous sodium bicarbonate by approximately the same procedure as described under procedure I, step C, whereby 2,3-dichloro-4-(2-methylenebutyryl)-phenoxyacetic acid was obtained, m.p. 115-118°C. Two recrystallizations from a mixture of benzene and cyclohexane gave a white solid melting at 118.5-120.5°C.

Analysis calculated for C13H12C1204:

C 51.51, H 3.99, Cl 23.39,

Found: C 51.23, H 4.18, Cl 23.39.

Procedure IV

Preparation of 2,3-dimethyl-4-(2-methylenebutyryl)-phenoxyacetic acid

Step A: Preparation of 2,3-dimethyl-4-butyryl-phenoxyacetic acid

This compound was prepared by following practically the same procedure as described under procedure I, step A, using the following substances: 2,3-dimethylphenoxyacetic acid 90 g n-butyryl chloride 66.6 g carbon disulfide 400 ml powdered aluminum chloride 217 g This procedure gives 83.7 g (67 per cent) of crude product which, after recrystallization from a mixture of benzene and cyclohexane, gives 2,3-dimethyl-4-butyrylphenoxyacetic acid, m.p. 87-88° C.

Analysis calculated for C14H1304:

C 67.18, H 7.25,

Found: C 67.14, H 7.27.

Step B: Preparation of 2, 3- dimethyl- 4-\ 2-( dimethylaminomethyl) - butyryl) -

phenoxyacetic acid hydrochloride

This Mannich compound was prepared by following substantially the same procedure as described under Method I, Step B, using the following materials:

The thus produced viscous homogeneous mixture was dissolved in 90 ml of ethyl alcohol, filtered and precipitated with 150 ml of ether. The product was recrystallized from a mixture of ethyl alcohol and ether, filtered and dried in vacuo over phosphorus pentoxide, whereby 11.8 g (90 percent) of 2,3-dimethyl-4-[2-(dimethylaminomethyl)-buryryl)-phenoxy were obtained -acetic acid hydrochloride, m.p. 178.5—180° C.

Analysis calculated for C17H26C1N04:

C 59.38, H 7.62, N 4.07,

Found: C 59.52, H 7.35, N 3.87.

Step C: Preparation of 2,3-dimethyl-4-(2-methylenebutyryl)-phenoxyacetic acid This compound was prepared by practically the same procedure as described under procedure I, step C, using 28.1 g of the Mannich compound prepared in step B. The crude product was recrystallized several times from 250 ml of methylcyclohexane, whereby 7.0 g (33 percent) of 2,3-dimethyl-4-(2-methylenebutyryl)-phenoxyacetic acid was obtained, m.p., 83.5-84 .5°C.

Analysis calculated for C15H1804:

C 68.68, H 6.92,

Found: C 68.46, H 7.24.

Method V 2, 3-dichloro-4-(2-ethylidenebutyryl)-phenoxyacetic acid

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

A mixture of 2,3-dichloroanisole (53.11 g, 0.3 mol), carbon disulfide (350 mL) and 2-ethylbutyryl chloride (80.77 g, 0.6 mol) was, under anhydrous conditions, added aluminum chloride powder (40 g, 0.3 mol) over 5 min 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 hydrogen chloride evolution ceased (1 Va Mme), was cooled to room temperature and treated, under anhydrous conditions, with aluminum chloride powder (40 g, 0.3 mol) during 5 min with stirring . The mixture was then heated in a 55° C. water bath with stirring for 1½ hours. Carbon disulfide was removed under reduced pressure and an equal volume of dry heptane was added to the residue. The prepared mixture was heated on a steam bath with stirring for 3 hours. After cooling to room temperature, the heptane was decanted and the residue was added

a mixture of ice (450 g) and concentrated hydrochloric acid

(45 ml). The oil thus produced was extracted with ether, dried over anhydrous sodium sulfate and the ether removed under reduced pressure. The remaining material was treated with an excess of 5% aqueous sodium hydroxy solution and heated under reflux for 1 hour, then cooled and extracted with ether to remove insoluble oil. The clear aqueous solution was acidified with concentrated hydrochloric acid and the oil formed was extracted with ether, the ether solution was dried over anhydrous sodium sulfate and the ether was again removed under reduced pressure. Distillation of the remaining oil gave 34.45 g (44 per cent) of the product in the form of a liquid with a boiling point of 140-142° C at 0.5 mm pressure. After three recrystallizations from hexane, 2-ethyl-2',3'-dichloro-4'-hydroxybutyrylphenol was obtained in the form of white needles with m.p. 85-86° C.

Analysis calculated for C12H14C12O2:

C 55.19, H 5.40, Cl 27.15,

Found: C 55.21, H 5.64, Cl 26.98.

Step B: Preparation of 2, 3-dichloro-4-(2-ethylbutyryl)-phenoxyacetic acid

A solution of sodium (2.53 g, 0.11 mol) in absolute ethanol (300 mL) was treated first with 2-ethyl-2',3'-dichloro-4'-hydroxybutyrophenone (26.12 g, 0, 1 mol) and then with ethyl bromoacetate (20.04 g, 0.12 mol) and the resulting clear solution was heated under reflux and stirring for 2 hours. Aqueous 5% sodium hydroxide (11.22 g, 0.2 mol) was then added and coking under reflux with stirring was continued for another 1 hour. The alcohol was removed by distillation at atmospheric pressure and the boiling aqueous residue was acidified to Congo red paper by the addition of concentrated hydrochloric acid. An oil separated out which solidified after cooling at room temperature. It was extracted with ether, the ether extract was dried over anhydrous sodium sulfate and the ether was then removed under reduced pressure, whereby 31.9 g (100%) of 2,3-dichloro-4(2-ethylbutyryl)-phenoxyacetic acid was obtained in the form of a white solid with m.p.

128-139° C. A recrystallization from a mixture of benzene and cyclohexane gave 28.7 g (90 per cent) of the product in the form of needles melting at 144.5-145.5° C.

Analysis calculated for C]4H10Cl2O4:

C 52.68, H 5.05, 1 22.22,

Found: C 52.75, H 5.00, Cl 22.08.

Step C: Preparation of 2,3-dichloro-4-(2-bromo-2-ethylbutyryl)-phenoxyacetic acid This compound was prepared by practically the same method as described under method II, step C, using the following compounds:

This procedure gave 23.71 g (99 percent) of 2,3-dichloro-4-(2-bromo-ethylbutyryl)-phenoxy-acetic acid in the form of a white solid with m.p. 151.5—152.5° C.

A recrystallization from benzene gave the product in the form of white needles of m.p. 151.5— 152.5° C.

Analysis calculated for C14H15BrCl204:

C 42.24, H 3.80, Cl 17.81, Found: C 42.53, H 4.00, Cl 17.73.

Step D: Preparation of 2,3-dichloro-4-(2-ethylidene-butyryl)-phenoxyacetic acid The bromoketone prepared as described in step C, (19.91 g, 0.05 mol) was dissolved in dimethylformamide (140 ml ) and anhydrous lithium chloride (6.36 g, 0.15 mol) were added. The mixture was heated on a steam bath for 2 hours with occasional shaking, cooled and poured into 1 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, freed from solids by filtration and acidified. The solid material which then separated was recrystallized from a mixture of benzene and cyclohexane, whereby 14.52 g (92%) of 2,3-dichloro-4-(2-ethylidenebutyryl)-phenoxyacetic acid was obtained in the form of white needles with sm .p. 124-125.5° C. A renewed recrystallization from the same solvent did not change the melting point.

Analysis calculated for C14H14C1204:

C 53.02, H 4.45, Cl 22.36, Found: C 53.28, H 4.43, Cl 22.34.

The following examples illustrate the preparation of the new compounds by the present method.

Example 1 illustrates the reaction of a mercaptan and an α-methyleneacylphenoxyacetic acid without the use of a solvent.

Example 1

in

3- chloro- 4-[ 2-( isopropylthiomethyl)- butyryl] -

phenoxyacetic acid

3-Chloro-4-(2-methylenebutyryl)-phenoxyacetic acid from Method I, (2.68 g, 0.01 mol) was added to isopropyl mercaptan (0.76 g, 0.01 mol). The mixture was heated at 80-90° C under reflux. Due to the volatility of the mercaptan, further amounts of this were added to ensure sufficient mercaptan in the reaction mixture. After a clear reaction mixture had formed, the mixture was heated for another 5 minutes, the excess mercaptan was then driven off and the residue was allowed to cool, whereupon it solidified. After the solid material was recrystallized from a 1:2 mixture of benzene and hexane, 2.25 g (48 percent) of 3-chloro-4-[2-(isopropylthio-methyl)-butyryl]-phenoxyacetic acid were obtained, sm. p. 77— 79° C.

Analysis calculated for C16H2tC104S:

C 55.73, H 6.14, Cl 10.28, Found: C 55.78, H 5.73, Cl 10.69.

The following example illustrates the reaction of a mercaptan and an α-methyleneacylphenoxyacetic acid in an organic solvent.

Example 2

3-chloro-4-[2-(ethylthiomethyl)-butyryl~\ -

phenoxyacetic acid

3-Chloro-4-(2-methylenebutyryl)-phenoxyacetic acid (4.03 g, 0.015 mol), from Method I, and ethyl mercaptan (12.4 g, 0.2 mol) were dissolved in dry ether (15 mL) and the recorked vessel with the solution was allowed to stand at room temperature for 48 hours. The volatile compounds were evaporated

at room temperature and a white solid was recovered which weighed 4.65 g (70 percent) and had a melting point of 86-89° C. Several recrystallizations of this material from a mixture of benzene and cyclohexane gave 3-chloro-4 -[2-(ethylthiomethyl)-butyryl]-phenoxyacetic acid, m.p. 88-90° C.

Analysis calculated for C15H19C104S:

C 54.46, H 5.79,

Found: C 54.94, H 5.90.

Example 3 illustrates the reaction of a mercaptan and an α-methyleneacylphenoxyacetic acid in aqueous solution.

Example 3

3-chloro-4-[2-(o-carboxyphenylthiomethyl)-butyryl]-phenoxyacetic acid

3-Chloro-4-(2-methylenebutyryl)-phenoxyacetic acid prepared as described under method I, (2.68 g, 0.01 mol) was suspended in water (25 ml) and sufficient 10% sodium bicarbonate solution was added to dissolve it. In another vessel, thiosalicylic acid (0.01 mol) was suspended in water (5 ml) and the solution made basic by adding 10% sodium bicarbonate. The solution was mixed and kept at 25-30°C for 4 hours. On acidification with hydrochloric acid, a solid precipitated which, after recrystallization from a 2:3 mixture of isopropyl alcohol and water, gave 2.25 g of 3-chloro-4-[2-(o-carboxyphenyl-thiomethyl)-butyryl]-phenoxyacetic acid, sm. p. 172 -173.5° C.

Analysis calculated for C20H19C100S:

C 56.80, H 4.53, Cl 8.38, Found: C 56.99, H 4.75, Cl 8.18.

The following example illustrates the reaction of an amphoteric mercaptan and an α-methyleneacylphenoxyacetic acid.

Example 4

3- chloro- 4-[ 2-( 2- amino- 2- carboxyethylthio-methyl)- butyryl]- phenoxyacetic acid hydrochloride

By replacing the thiosalicylic acid used in example 3 with an equimolar amount of cysteine hydrochloride and using practically the same method as described in example 3, a tough precipitate was obtained by acidification with hydrochloric acid. The precipitate was dissolved by the addition of more acid and water was then removed by lyophilization, after which the residue was extracted with boiling absolute alcohol. The insoluble sodium chloride was removed by filtration, the alcoholic filtrate was concentrated and by adding absolute ether, 3.3 g of 3-chloro-4-[2-(2-amino-2-carboxyethylthiomethyl)-butyryl were separated. ] - phenoxyacetic acid hydrochloride as a colorless powder. The product melted indistinctly between 110-130° C. It is very easily soluble in alcohol and acetone and is soluble in acids and bases, but is insoluble in water.

Analysis calculated for C10H2nClNO4SHCl:

C 45.07, H 4.96, Cl 16.69, N 3.28, S 7.52, Found: C 44.29, H 5.28, Cl 15.95, N 3.39, S 7, 85.

Example 5 2,3-dimethyl-4-[2-(2-amino-2-carboxyethyl-thiomethyl)-butyryl\-phenoxyacetic acid-

hydrochloride

By replacing the 3-chloro-4-(2-methylenebutyryl)-phenoxyacetic acid and thiosalicylic acid used in Example 3 with equimolar amounts of 2,3-dimethyl-4-(2-methylenebutyryl)-phenoxyacetic acid from method IV and cysteine hydrochloride, and by using practically the same method as described in example 3 (except that the processing of the final product was carried out as described in example 4) 2,3-dimethyl-4-[2-(2-amino-2-carboxyethylthiomethyl)-butyryl was obtained ]-phenoxyacetic acid hydrochloride.

Example 6

3- chloro- 4-[ 2-( 2, 2- dichloroethylthiomethyl)-butyryl]- phenoxyacetic acid

By replacing the thiosalicylic acid used in example 3 with an equimolar amount of 2,2-dichloroethyl mercaptan and using practically the same procedure as described in example 3, 3-chloro-4-[2-(2,2-dichloroethylthio- methyl)-butyryl]-phenoxyacetic acid.

Example 7

2-( 2- amino- 2- carboxye thylthio )- 3-( 2, 3- dichloro-4- carboxymethoxybenzoyl)- pentane hydrochloride Reaction of equimolar amounts of cysteine hydrochloride and 2,3-dichloro-4-(2- ethylidenebutyryl)-phenoxyacetic acid (from procedure V) by practically the same procedure as in example 4, gave 2-(2-amino-2-carboxy-ethylthio)-3-(2,3-dichloro-4-carboxymethoxybenzoyl) -pentane hydrochloride.

Example 8

The glutathione adduct of 2,3-dimethyl-4-(2-methylenebutyryl)-phenoxyacetic acid Reaction of equimolar amounts of glutathione hydrochloride and 2,3-dimethyl-4-(2-methylenebutyryl)-phenoxyacetic acid (from method IV) by practically the same procedure as in Example 4 gave the glutathione adduct of 2,3-dimethyl-4-(2-methylenebutyryl)-phenoxyacetic acid.

Other new compounds produced by practically the same methods as described in previous examples are indicated in the following table, from which it is clear which method was used in each individual case.

The table also indicates the acylphenoxyacetic acid

The radicals R<2>, R, X and Y in the acetylphenoxyacetic acid and the mercaptan are retained in the products formed and are indicated in columns 2-5 of the table. The molar ratios, reaction conditions and the procedure for isolating each product are practically the same as indicated in the example referred to in Table 1.

Example 20

[ 2, 3- dichloro- 4- l2-( methylthiomethyl)-

butyryU - f enoxy] - acetic acid

3.03 g (0.01 mol) of [2,3-dichloro-4-(2-methylenebutyryl)-phenoxy]-acetic acid is suspended in 25 ml of water and sufficient 10% sodium carbonate solution to bring the compound in solution. The solution is stirred and a stream of gaseous methyl mercaptan is introduced below the surface of the solution for 15 minutes. The addition of methyl mercaptan is then continued while the stirred solution is heated on a steam bath for 1.5 hours.

After cooling the reaction mixture to room temperature, it is acidified against Congo red paper by adding 6N hydrochloric acid. The gum formed is extracted with ether and the combined extracts are dried over anhydrous magnesium sulphate. The ether is evaporated under reduced pressure, whereby a slightly solid substance with melting

point 82-86° C. Recrystallization from a mixture of benzene and cyclohexane gives 15.0 g (86 per cent)

[2,3-dichloro-4-[2-methylthiomethyl)-butyryl:-phenoxy]-acetic acid in the form of white prisms with a melting point of 86-89° C.

Analysis for C14H16C1204S:

Calculated: C 47.87; H 4.59; S 9,13;

Found: C 48.13; H 4.56; S 9.07

Example pe 121

( 2, 3- dichloro- 4-[ 2- L( 2- thio- 3- hydroxypropyl)-thiomethyU- butyryl] - phenoxy)- acetic acid

ammonium salt

3.03 g (0.01 mol) [2,3-dichloro-4-(2-methylenebutyryl)-phenoxy]-acetic acid is suspended in 90 ml of water and 28% ammonia water is added dropwise while shaking until the acid dissolves. To this is added a mixture of freshly distilled 2,3-dithiopropanol and 1 ml of 28% ammonia water. The mixture is shaken carefully, heated

at 80-90° C for one hour and kept at 20° C for 24 hours. The solvent is evaporated under reduced pressure (20 mm) at 40-45° C. The light brown oily solid is then dried in vacuum at 0.5 mm until it solidifies. The glassy solid thus obtained is triturated several times with absolute ether to obtain the ammonium salt of (2,3-dichloro-4-[2-[(2-thio-3-hydroxypropyl)-thiomethyli-butyryl]-phenoxy)-acetic acid (2.9

<g>)<.>

Analysis for C^H^ClaNOgS,,:

Calculated: C 43.24; H 5.21; N 3.15;

Found: C 43.65; H 5.41; N 2.92.

Example 22

( 2, 3- dichloro- 4- [2- [ ( 3- amino- 3- carboxypropyl) - thiomethyU- butyryl~]- phenoxy) acetic acid disodium salt

To 3.032 g (0.01 mol) [2,3-dichloro-4-(2-methylenebutyryl)-phenoxy]-acetic acid dissolved in 30 ml of an oxygen-free water solution and containing 0.84 g (0.01 mol) sodium bicarbonate is added a solution of 1.352 g (0.01 mol) of D,L-homocysteine in 30 ml of oxygen-free water containing 0.84 g (0.01 mol) of sodium bicarbonate. The resulting solution is stirred at room temperature for one hour in a nitrogen atmosphere and then concentrated to dryness under reduced pressure at room temperature. 4.82 g (100 per cent) of the disodium salt of (2,3-dichloro-4-[2-[(3-amino-carboxypropyl)-thiomethyl-butyryl]phenoxy)acetic acid are obtained, m.p. 163-168°C.

Analysis for Cj^gClgNNagOeS:

Calculated: C 42.33; H 3.97; S 6.65;

Found: C 41.83; H 4.11; S 6.21.

Example 23

( 2, 3- dichloro- 4- [3- [ ( 2- amino- 2- carboxyethyl) -

thiol- propionyl]-} enoxy ) - acetic acid hydrochloride

Step A: 2', 3'- dichloro- 4'- hydroxyacetophenone A two-liter four-necked resin flask equipped with a mechanical stirrer, condenser, calcium chloride drying tube and Gooch funnel is dried in a stream of nitrogen and introduced into it 71 g (0, 4 mol) of 2,3-dichloroanisole, 440 ml of carbon disulphide and 63 g (0.8 mol) of acetyl chloride.

106 g (0.8 mol) of powdered aluminum chloride are added via the Gooch funnel over 10 minutes. The mixture is stirred at room temperature for 5 hours and allowed to stand overnight.

The mixture is then heated for one hour at 55° C in a water bath, cooled to 25° C, treated with 53 g of aluminum chloride and heated for one hour at 55° C. The condenser is set to reflux, 350 ml of heptane (dried over aluminum chloride) is added and the mixture is heated on a steam bath. The carbon disulphide is collected and heating is continued for 3 hours under reflux. After cooling, the heptane is decanted and the solid product is scraped onto 500 g of ice containing 45 ml of concentrated hydrochloric acid. The product is extracted with 600 ml of ether in several portions, evaporated to dryness, treated with 1.2 ml of 5% aqueous sodium hydroxide and heated for one hour under reflux. The cooled solution is extracted with ether and then acidified with concentrated hydrochloric acid to Congo red. The product is extracted in 600 ml of ether, dried over sodium sulphate and evaporated in vacuo. The residue is recrystallized from benzene whereby 60 g (73 per cent) of 2',3'-dichloro-4'-hydroxyacetophenone is obtained which melts at 153-155°C.

Analysis for C8H0Cl2O2:

Calculated: C 46.86; H 2.95;

Found: C 47.69; H 3.01.

Step B: (2,3-dichloro-4-acetylphenoxy)-acetic acid In a one-liter, round-bottomed, three-necked flask equipped with a cooler and drying tube, a nitrogen inlet tube and a dropping funnel, introduce 450 ml of ethanol and 3.79 g (0.165 mol ) sodium metal. When the sodium has dissolved, 30.75 g (0.15 mol) of 2',3'-dichloro-4'-hydroxyacetophenone and 30.06 g (0.18 mol) of ethyl bromoacetate are added and the mixture is refluxed for two hours. A solution of 16.83 g (0.3 mol) of potassium hydroxide in water is added and the mixture is refluxed for one hour. The ethanol is distilled from the reaction mixture at atmospheric pressure. The remaining aqueous solution is acidified (against Congo red paper) with concentrated hydrochloric acid, cooled and extracted four times with 300 ml portions of ether. The combined ether extracts are dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from 500 ml of xylene, whereby 32.2 g (85 per cent) of (2,3-dichloro-4-acetylphenoxy)-acetic acid is obtained which melts at 154-156° C.

Analysis for C10H8Cl2O4:

Calculated: C 45.67; H 3.07; Cl 26.96;

Found: C 45.60; H 2.92; Cl 26.78.

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

15.8 g (0.06 mol) (2,3-dichloro-4-acetyl-phenoxy)-acetic acid, 4.94 g (0.06 mol) dimethylamine hydrochloride, 1.98 g (0.066 mol) paraformaldehyde and 2 ml of glacial acetic acid are combined and heated under anhydrous conditions on a steam bath for two hours while occasionally applying a partial vacuum to remove the water formed by the reaction. The solid product is dissolved in 500 ml of 90% aqueous ethanol, filtered and treated

with 400 ml of ether, which gives 9.9 g (46 per cent)

[2,3-dichloro-4-(3-dimethylaminopropionyl)-phenoxy]-acetic acid hydrochloride melting at 194-196°C.

Analysis for C^H^Clc.NOx.HCl:

Calculated: C 43.78; H 4.52; N 3.93;

Found: C 43.91; H 4.57; N 3.71.

Step D: (2,3-dichloro-4-[3-12-amino-2-carboxyethyl)-thiol-propionyl]-phenoxy)-acetic acid hydrochloride

835 mg (0.00234 mol) of [2,3-dichloro-4-(3-dimethylaminopropionyl)-phenoxy-acetic acid hydrochloride are suspended in 25 ml of water and treated with vigorous stirring with a solution of 394 mg of sodium bicarbonate and 10 ml of water. Then

a solution containing 410 mg (0.00234 mol) of L-cysteine hydrochloride monohydrate and 394 mg of sodium bicarbonate in 10 ml of water is added.

The reactants are quickly heated to 60 0 C on

steam bath, then removed and allowed to cool to 25° C. The solution is treated with 4 N hydrochloric acid to obtain a pH of 1.5. (2,3-dichloro-4-[3-[2-amino-2-carboxyethyl)-thiol-propionyl]-phenoxy)

The acetic acid hydrochloride that is secreted (900 mg,

89 per cent) is dissolved in 16 ml of ethanol containing 0.5 ml of 6N hydrochloric acid, filtered and treated slowly with 220 ml of ether. The product is filtered and dried and has a melting point of 176-177° C.

Analysis for C14H15C12N06S.HC1:

Calculated: C 38.86; H 3.73; N 3.24; Cl 24.58;

Found. C 38.70; H3.93; N3.18; Cl 24.74.

Example 24

[ 2, 3- dichloro- 4- 12- carboxymethylthiomethyl)-

butyryU - f enoxy]- acetic acid

A mixture of 3.03 g (0.01 mol) [2,3-dichloro-

4-(2-methylenebutyryl)-phenoxy]-acetic acid and 1.0 g (0.0108 mol) thioglycolic acid were heated at 80-90° C. for 5 minutes. The viscous melt solidifies on cooling and the solid crystal

is lysed from benzene containing a trace of ethyl-

acetate with which 2.0 g of [2,3-dichloro-4-[2-(carboxymethylthiomethyl)-butyryl! -f enoxy] -

acetic acid. After careful drying, the [2,3-dichloro-4-C2-(carboxymethylthiomethyl)-butyryU-phenoxy]-acetic acid melts at 128-129°C.

Analysis for C^HjgClcjOeS:

Calculated: C 45.59; H 4.08; Cl 17.95;

Found: C 45.54; H 4.15; Cl 18.07.

Example 25

[ 2, 3- dichloro- 4- 12- ( 2- amino- 2- carboxyethylthio-butyryU- phenoxy]- acetic acid

3.03 g (0.01 mol) [2,3-dichloro-4-(2-methylenebutyryl)-phenoxy]-acetic acid and 1.1 g (0.01 mol) 3-chloropropyl mercaptan are mixed in a large rea-

gene glass. The mixture is heated at 80-90°C

until the mixture melts and the mixture heats

mes then for another 5 minutes. The mixture up-

is then dissolved in 20 ml of benzene and hexane is added at 20° C until precipitation begins. The mixture is kept at 5° C until fusion is complete. After two recrystallizations from a solvent consisting of 4 parts of benzene and 3 parts of hexane, 2.0 g of [2,3-dichloro-4-[2-(3-chloropropylthiomethyl)-

butyryD- f enoxy]- acetic acid m.p. 74-76° C.

Analysis for C16H19C1304S:

Calculated: C 46.45; H 4.62;

Found: C 46.83; H 4.70.

Example 26

[ 2, 3- dichloro- 4- 12-( 2- amino- 2- carboxyethylthio-methyl)- butyryl\ - phenoxy]- acetic acid-

hydrochloride

Two solutions were prepared. The first

was prepared by adding 3.03 g (0.01 mol)

[2,3-dichloro-4-(2-methylenebutyryl)-phenoxy]-

acetic acid to a solution of 0.84 g (0.01 mol) of sodium bicarbonate in 30 ml of water. The other was prepared by adding 1.76 g (0.01 mol) of L-cystem hydrochloride monohydrate to a soln.

ning of 1.68 g (0.02 mol) of sodium bicarbonate in 30 ml of water. The solutions were mixed and obtained

allowed to stand for one hour at room temperature.

3 ml of concentrated hydrochloric acid was then added and

the solution evaporated to dryness in vacuum obtain-

fat of a water jet pump. The residue was then up-

dissolved in 60 ml of isopropyl alcohol, the solution was filtered and the filtrate diluted with 600 ml of ether to precipitate the product. The cleaning was carried out by dissolving the product in a mixture of 15 ml of water and 2 ml of 5% hydrochloric acid. The solution was file-

tert and 5 ml of concentrated hydrochloric acid were added for

>to trap [2,3-dichloro-4-[2-(2-amino-2-carboxy-ethylthiomethyl)-butyryl! -phenoxy] -acetic acid-

hydrochloride. The product was collected and

dried at 65° C, whereby 1.7 g of [2,3-dichloro-4-12-(2-amino-2-carboxyethyl-thio-methyl)-butyryl]-phenoxy]-acetic acid was obtained

hydrochloride with m.p. 183.5—186.5° C.

Analysis for C16H19Cl2NO0S.HCl:

Calculated: C 41.74; H4.38; N3.04; Cl 23.08;

Found: C 41.85; H4.50; N2.89; Cl 22.88.

Claims (7)

1. Procedure for the preparation of a therapeutically active compound with formula: where R is lower alkyl, hydroxyl lower alkyl, halo lower alkyl, lower alkanoylamido lower alkyl, lower alkanoylamido-substituted carboxy lower alkyl, amino lower alkyl, amino substituted carboxy lower alkyl, phenyl, carboxyphenyl, lower alkanoyl or 2-(gamma-L-glutamylamino)-2-(N-carboxymethylcarbamoyl) lower alkyl, R<1>er hydrogen or lower alkyl, R<2> is hydrogen, lower alkyl, halogen-substituted lower alkyl, trihalomethyl-substituted lower alkyl, cycloalkyl, phenyl, or phenoxy, R<3> and R<4>, which may be the same or different, are hydrogen, halogen, trihalomethyl, lower alkyl, lower alkoxy, nitro, lower alkanoylamido, or R<3> and R<4> on neighboring carbon atoms in the benzene ring can together with the ring carbon atoms to which they are attached, form a 5- or 6-membered carbocyclic ring, and salts, esters and amides of these compounds, characterized in that a compound of formula: is reacted with a mercaptan of the formula RSH, where R, R<1>, R<2>, R<3> and R<4> are as indicated above, and the compounds obtained are optionally transferred in their salts, esters or amides onto and in a familiar way. 2. Method according to claim 1, characterized in that a compound with formula is used as starting material: where R<2> is lower alkyl, X<2> is hydrogen, halogen or lower alkyl, and X<3> is halogen or lower alkyl, and a mercaptan, RSH, where R is lower alkanoyl, amino substituted carboxy-lower alkyl, lower alkanoylamido-substituted carboxy-lower alkyl, carboxyphenyl or 2-(gamma-L-glutamylamino)-2-(N-carboxymethylcarbamoyl)-lower alkyl. 3. Method according to claim 2, characterized in that a compound of the formula C is used where X<2> and X<3> are halogen. 4. Method according to claim 2, characterized in that a compound of the formula C is used where X<2> and X<3> are methyl. 5. Process according to claims 1-3, characterized in that 2,3-dichloro-4-(2-methylenebutyryl)-phenoxyacetic acid is reacted with acetylcysteine hydrochloride. 6. Process according to claims 1-3, characterized in that 2,3-chloro-4-(2-methylenebutyryl)-phenoxyacetic acid is reacted with glutathione hydrochloride. 7. Process according to claims 1-3, characterized in that 2,3-dichloro-4-(2-methylenebutyryl)-phenoxyacetic acid is reacted with levo-cysteine hydrochloride monohydrate.