CS196334B2 - Method of producing /alpha-aminoacetyl/benzene derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of derivatives (α-aminoacetyl) benzene having the ability inhibit the formation of insoluble fibrin of fibrin.

Description

The invention relates to a process for the preparation of (α-aminoacetyl) benzene derivatives having the ability to inhibit the formation of insoluble fibrin from fibrin.

The present invention relates to a process for the preparation of (N-aminoacetyl) benzene derivatives of the formula I

Y

HJhC X-A-CO-R (I) wherein

Y is hydrogen or C1 to C4 alkoxy,

X represents oxygen, sulfur or a direct bond between the benzene ring and residue A,

A represents a straight-chain or branched C 1 -C 6 alkylene residue and

R is hydroxy, amino, C 1 -C 4 alkoxy, di- (C 1 -C 4 alkyl) amino or α- (C 1 -C 4 alkoxy) carbonyl-C 1 -C 4 alkylamino, or a pharmaceutically acceptable acid addition salt thereof, or in the case of compounds of the formula I, wherein R is hydroxy, of pharmaceutically acceptable base addition salts, characterized in that the compound of formula II

Y

Q-CH _from CO-R-XA-CO-R (II) wherein

Q represents a chlorine, bromine or iodine atom and

X, Y, A and R are as defined above, reacted with hexamethylenetetramine in an inert solvent or diluent at 20 to 60 ° C, and then the resulting hexamine salt is acid hydrolyzed at 40 to 100 ° C, followed by to obtain a pharmaceutically acceptable acid addition salt, the compound of formula I is reacted with an acid capable of providing a pharmaceutically acceptable cation, and, if a pharmaceutically acceptable base addition salt is to be obtained, a compound of formula I wherein R is hydroxy, reacting with a base capable of providing a pharmaceutically acceptable cation.

Those compounds of formula I wherein A has a different meaning to a symmetrical C 1 -C 6 -alkylene group contain an asymmetrically substituted carbon atom and consequently, such compounds and similar compounds of formula I wherein R is a substituent containing an asymmetrically substituted carbon atom can be isolated as racemic and optically active forms. The present invention relates both to the racemic form of the compounds of formula I containing one or more asymmetrically substituted carbon atoms and to all optical isomers having the above-mentioned useful property. Methods for resolving racemic forms and methods for determining the biological properties of individual optical isomers are generally known in the art of chemotherapeutics.

A particularly suitable value of R when this symbol represents a C 1 -C 8 -alkoxy group is, for example, methoxy, ethoxy, n-propoxy-isopropoxy, n-butoxy or n-hexyloxy.

A particularly preferred value of the (C 1 to O 4 -oxycarbonyl group optionally present as a substituent in radical A is, for example, methoxy or ethoxycarbonyl.

A particularly suitable meaning of R when these symbols are α- (C 1 -C 4 alkoxycarbonyl-C 1 -C 4 alkylamino) is, for example, α- (methoxycarbonyl) ethylamino, and a suitable di- (C 1 -C 4 alkyl amino) is, for example, diethylamino.

A particularly preferred meaning of C1 to O4-alkoxy in the meaning of Y. is, for example, methoxy.

A particularly suitable meaning of A when this symbol represents a straight or branched C 1 -C 6 -alkylene radical is, for example, a methylene, ethylene or propylene group or a group of the formula - CH (CH 3) - or - C (C 3) 2 -.

Particularly suitable pharmaceutically acceptable addition salts are, for example, hydrohalides, for example hydrochlorides or hydrobromides, sulfates, phosphates or 2-hydroxyethylsulfonates or salts with carboxylic acids, for example citrates, lactates or acetates.

Particularly suitable base addition salts are, for example, alkali metal or alkaline earth metal salts, for example sodium, potassium or calcium salts, aluminum salts or salts of organic phases giving a pharmaceutically acceptable cation, for example trietbanolamine.

A particular group of compounds of formula (I) are those compounds of formula (I) wherein A is methylene and the pharmaceutically acceptable salts thereof as defined above.

Within this particular group of compounds, one group of preferred compounds are those in which X represents oxygen and the pharmaceutically acceptable salts thereof as defined above and the other group of preferred compounds are those in which X represents sulfur and pharmaceutically acceptable salts thereof as defined above.

Yet another particular group of compounds of formula I are those compounds of formula I wherein X is a direct bond between a benzene moiety and a moiety A, and pharmaceutically acceptable salts thereof, as defined above.

In each of the above groups, R may be as defined above, but preferably R is hydroxy-, methoxy- or α - (methoxycarbonyl) -ethylamino. In addition, in each of the abovementioned groups of compounds, particularly suitable salts are, for example, acid addition salts, for example hydrochlorides.

Specific compounds of formula (I) are described in the Examples, and of these compounds, the following are of particular interest:

4- (Aininoacetyl) phenoxyacetic acid, methyl 4- (aminoacetyl) phenoxyacetate, methyl 4- (aminoacetyl) thiophenoxyacetate, and N- {3- [4- (aminoacetyl) phenyl] propionyl] alanine methyl ester and pharmaceutically acceptable salts thereof as defined above , in particular their acid addition salts.

The reaction with hexamine is conveniently carried out, for example, using equimolar amounts of the reactants in an inert solvent or diluent, for example ether, tetrahydrofuran or chloroform, and at a temperature of, for example, 20 to 60 ° C, for example at room temperature or near.

The acid hydrolysis of the intermediate adduct of the compound of formula (II) with hexamine is conveniently carried out as a separate step in an inert solvent or diluent, for example ethanol, at a temperature of, for example, 40 to 100 ° C. A particularly suitable acid for use in the hydrolysis is, for example, hydrochloric acid, and the compound of formula I is conveniently isolated from the reaction mixture as an acid addition salt derived from the acid used for the hydrolysis.

If the desired compound of formula (I) contains an alkoxy group, the corresponding alcohol is preferably used as the solvent in the hydrolysis step to avoid re-esterification.

All starting materials can be obtained by well-known procedures that are useful for the synthesis of analogous compounds.

The starting materials of the formula II can be obtained from aromatic compounds of the general formula II.

(in) where

X, Y, A and R are as defined above, by Friedel-Grafts reaction using a haloacyl halide such as chloroacetyl chloride or acyl halide followed by direct halogenation. Compounds of formula (II) wherein Y is C 1 -C 4 alkoxy are preferably obtained by alkylation of a suitable 4-hydroxy-3- (C 1 -C 4 alkoxy) acetophenone followed by direct halogenation as described in the Examples.

The compounds of formula (I) may be converted into pharmaceutically acceptable acid addition salts as defined above by reaction with a suitable acid using conventional means compatible with the remaining substituents. Similarly, compounds of formula I wherein R is hydroxy may be converted to the pharmaceutically acceptable base addition salts as defined above by reaction with a suitable base using conventional means compatible with the others. substituents.

As already mentioned, the compounds of formula I inhibit the formation of insoluble fibrin from fibrin. The formation of thrombi or clots in blood plasma is a complex process, but during the last stages of this process, fibrin units combine to form a fully coupled throinb, which is catalytically controlled by the enzyme fibrinoligase (factor XIIIa). While the thrombus still consists of different fibrin units it can be dispersed easily and reversibly in a 1% (w / v) aqueous monochloroacetic acid solution. However, once fully coupled, the thrombus is insoluble in this monochloroacetic acid solution.

The ability to inhibit the insoluble fibrin formation of compounds of formula I can be demonstrated by "in vitro" measurement of the effect of a test compound on the solubility of fibrin clots in a 1% (w / v) aqueous monochloroacetic acid solution. Fibrin clots are obtained by adding porcine thrombin to an aqueous buffered solution of radiolabelled ( ¹²⁵ L) human fibrirrogen, which contains a physiologically effective amount of the fibrinoligase enzyme.

The ability to inhibit the insoluble fibrin formation of the compounds of Formula I can also be demonstrated by administering the test compound to a rabbit and then measuring the solubility of fibrinph clots resulting from the recalcification of rabbit blood plasma samples taken at intervals after test compound administration at 1% In this test, the compounds of formula I increase the solubility of fibrin clots formed after administration at a dose of 100 mg / kg or less, in particular methyl 4- (aminoacetyl) phenoxyacetate exhibits oral activity and plasma samples collected. Twenty-four days after administration of the compound, fibrin precipitates are soluble in 1% (w / v) aqueous monochloroacetic acid.

Thus, the compounds of Formula I have the ability to inhibit the formation of fully associated fibrin clots. This property is very important in the in vivo physiology of thrombus formation, since when the thrombus is formed in the presence of a compound of formula (I), it is more readily dissolved by the protease which is possibly present in the blood. For this reason, the compounds of formula I are useful for inhibiting thrombus formation as well as for reducing the persistence of thrombi formed in the blood of warm-blooded animals.

The ability of the compounds of formula (I) to inhibit the formation of insoluble fibrin is also important in other physiological procedures in which fused fibrin is deposited, since inhibition of this process can be used for a therapeutic effect. For example, in those tumors that require a fibrin network to support, invade other tissues or expand or develop metastases, the compounds of Formula I are capable of reducing the disease process when used alone or in conjunction with cytotoxic agents, antimetabolites or potentiators immunological reaction. The use of the compounds of formula I is demonstrated in the effect of these compounds in reducing the spread and growth of chemically induced or transplanted tumors in immunologically suppressed or normal rodents, or in reducing the formation or formation of tumor embolism or metastasis. Experiments of the latter type are carried out in the rabbit ear chamber injected with a transplantable metastatic tumor, and the test compounds are administered alone or together with other antitumor agents.

For use in inhibiting the formation of insoluble fibrin from fibrin in warm-blooded animals, the compounds of formula I may be administered intravenously or by infusion at a daily dose of 2.5 mg / kg to 25 mg / kg, administered at intervals. Alternatively, the compounds may be administered orally, in which case a suitable daily dose is 5 to 50 mg / kg. In humans, the above-mentioned injected dose is equivalent to a total daily dose of 0.2 to 2.0 g. The above oral dose is equivalent to a total daily dose of 0.4 to 4.0 g in humans. administration is continued as long as there is a risk of thrombus formation.

The compound of formula (I) is used in the formulations preferably in the form of pharmaceutically acceptable acid addition salts.

The invention is illustrated by the following non-limiting examples.

In the examples

(1) NMR spectra are measured in de-DMSO solution with tetramethylsilane as an internal standard;

2) room temperature means a temperature between 18 and 27 ° C;

(3) the petroleum ether used has a boiling point in the range of 40 to 60 ° C, unless otherwise indicated;

4) the melting points reported for acid addition salts are associated with decomposition; and

5) if yields are reported, these are not the maximum achievable yields. The meaning of these data is illustrative only.

Example 1

To a solution of 4- (bromoacetyl) phenoxyacetic acid (26 g) chloroform (150 ml) was added hexamine (14 g) with stirring, and the mixture was stirred at room temperature for 3 days, then filtered and the solid suspended in ethanol (250 ml). Concentrated hydrochloric acid (50 ml) was added and the mixture was stirred at room temperature for 18 hours, then the mixture was filtered and the filtrate was diluted with diethyl ether (1500 ml) and the solid thus formed was filtered, washed with ethanol / diethyl ether. 4- (aminoacetyl) phenoxyacetic acid, m.p. > 250 ° C.

NMR:

<S 7.0 to 7.14, 7.92 to 8.06 each 2H (aromatic protons),

4.5 (2H, NH 3 CH 2 CO) and

4.81 (2H, -OCH2-COOH).

Example 1 a d 2.

A solution of methyl 4- (chloroacetyl) phenoxyacetate (6.7 g in methylene chloride (100 mL) was stirred while hexamine (hexamethylenetetramine) (4.5 g) was added and the mixture was stirred at room temperature for 3 days. Filter (0 g), filter and stir in methanol (60 mL) and concentrated hydrochloric acid (30 mL) at room temperature for 60 hours, and the resulting solid (5.1 g) is filtered off and dissolved in cold methanol (100 mL). The solution was filtered and the filtrate was evaporated to 30 ml, and after cooling, methyl 4- (aminoacetyl) phenoxyacetate hydrochloride (2.0 g, m.p. 202-204 ° C) was collected and further fractions were obtained from the mother liquors.

Examples 3 to 4 *

Using a procedure similar to that described in Example 1, 4- (4- (aminoacetyl) phenyl) propionic acid hydrochloride (Example 3), m.p. 208 DEG C., and 2- (4- (aminoacetyl) phenoxy) hydrochloride are obtained. -2-methylpropionic acid (Example 4), m.p. 188-190 ° C in a yield of 32 ^io / o and 26% when 3- [4- (chloroacetyl) phenyl] propionic acid or 2- (4- ( chloroacetyl) phenoxy] -2-methylpropionic acid.

3- (4- (Chloroacetyl) phenyl] propionic acid is obtained as follows:

A solution of 3-phenylpropionic acid (50 grams) in ethylene dichloride (200 mL) was added with stirring for 1 hour to chloroacetyl chloride (37.7 g) and aluminum chloride (48.9 g) in ethylene dichloride (550 mL) at room temperature.

The resulting mixture was stirred for 1 hour and then poured carefully into a mixture of ice (2 kg) and concentrated hydrochloric acid (55 mL) .After stirring for 16 hours, the crude product was filtered and recrystallized from water to give 3- [4- (chloroacetyl)]. phenyl] propionic acid, m.p. 151-153 ° C.

2- (4- (Chloroacetyl) phenoxy] -2-methylpropionic acid is obtained in a similar manner as a solid having a satisfactory microanalysis.

Examples 5 to 18

Using a similar procedure to that described in Example 2, the following compounds of formula I are obtained as hydrochlorides in a yield of 23 to 48% of the corresponding α-chloro- or n -bromoacetofertones of formula II (Q = Cl or Br). The corresponding alcohol in the hydrolysis step is used.

196

4

Example Y X 5 H O 6 H O 7 MeO O 8 H O 9 H O 10 H direct link 11 H direct link 12 H About ' 13 H O 14 H O 15 Dec H direct link 16 H O 17 H O 18 H WITH

* substance isolated as hygroscopic solid with satisfactory microanalysis:

calculated:

(+ ³ µmol HzO):

H, 6.1%; N, 4.9%;

C 50.0%, H 5.9%, N. 4.9%

-j- substance isolated as a hygroscopic solid with satisfactory microanalysis:

calculated:

(+ Ví mole HzO):

53.4% C, 6.3% H, 4.8% N.

found:

53.1% C, 6.2 O / o H, 4.8% N.

Me = methyl Pr = propyl

Et = ethyl Bu = butyl

The necessary starting α-bromo- or α-chloroacetophenone derivatives can be obtained by the following procedures or analogous thereto:

Isopropyl 4- (bromoacetyl) phenoxyacetate

Potassium carbonate (17.0 g) was added to a solution of isopropyl bromoacetate (24.0 g) and 4-hydroxyacetophenone (17.7 g) in acetone (200 mL). The mixture was refluxed for 24 hours, then cooled and filtered. The filtrate was evaporated to an oil which was dissolved in ether (150 mL). The solution was washed with sodium bicarbonate solution (2 X 30 milliliters of), water (2 X 30 MLJ, dried and evaporated. The residual oil is distilled. Give isopropyl-4-acetylfenoxyacetát, infrared (IR) peaks at 1750 and 1670 cm ^4.

A R Hydrochloride, melting point (° C)

—CHz— i-PrO 167—170 —CHz— n-hexyl-O 122—126 —CHz— MeO 174—175 —CHz— EtO 188—190 —CHz— n-BuO 172—176 —CHz— EtO 183—185 - _(CH2) 2- MeO 188 —CMez— EtO 108—109 —CHMe— EtO + - (CH 2) 3 - MeO 165—169 - _(CH2) 2- —INH. CHMe. . COzMe 187—190 ch ₂ n-PrO 194—197 —CHMe— MeO * CH2 MeO 161—165 (monohydrate) Brom (12 g) is added dropwise to mixed solution isopropyl-4-acetylphenoxyacetate (17.6 g) in benzene (200 mL) for 30 min.

nut. The solution was stirred for an additional 15 minutes and then evaporated. The residue was recrystallized from ether / hexane. Isopropyl 4- (bromoacetyl) phenoxyacetate, m.p. 60-61 ° C.

Methyl 2-methoxy-4- (bromoacetyl) phenoxyacetate

Methyl bromoacetate was reacted with 2-methoxy-4-acetylphenol to give methyl 2-methoxy-4-acetylphenoxyacetate in the same manner as was used to prepare isopropyl 4-acetylphenoxyacetate.

Copper bromide (23.9 g) was then added to a solution of methyl 2-methoxy-4-acetylphenoxyacetate (12.8 g) in a mixture of methyl acetate (150 mL) and chloroform (150 mL). The mixture was stirred and heated to reflux until the copper (I) bromide was substantially completely separated. The mixture was cooled and filtered, and the filtrate was washed with brine (3 X 30 mL), dried and evaporated. The residue was chromatographed on silica gel to give methyl 2-methoxy-4- (bromoacetyl) -phenoxyacetate, mp 105-107 ° C.

n-Hexy 1-4- (bromoacetyl) phenoxyacetate

A mixture of 4-acetylphenoxyacetic acid (20.0 g), n-hexanol (10.5 g) and concentrated sulfuric acid (2 ml) in benzene (100 ml) was heated under reflux for 6 hours using a water separator. The mixture was then evaporated and the residue was dissolved in n-pentane (50 mL). The solution was washed with water (3 X 30 mL) with sodium bicarbonate solution (1 X 50 mL) and again with water (1 X 50 mL). The solution was evaporated and the residue was chromatographed on alumina. N196334 was obtained

-hexyl 4-acetylphenoxyacetate with infrared maxima at 1760 to 1680 cm ^-1 .

Methyl 3- [4- (chloroacetyl) phenyl] propionate

A mixture of 3-phenylpropionic acid (50 g), methanol (250 mL) and concentrated sulfuric acid (12 mL) was heated at reflux for 12 hours, and then the excess methanol was evaporated under reduced pressure. sodium bicarbonate solution (100 ml) containing ice (400 g) and the pH was adjusted to 9 by addition of additional sodium bicarbonate solution, extracted with ether (5 X 100 ml) and the extracts were combined, washed with brine (2 X 50 ml) ), dried and evaporated. to give methyl 3-phenylpropionate as an oil with a maximum at 1740 cm ^-1 in ^the IR spectrum.

Aluminum chloride (225 g) was added to a rapidly stirred mixture of the above ester (41 grams) and chloroacetyl chloride (113 g) in carbon disulfide maintained at 0 ° C. The mixture was allowed to warm to room temperature with stirring over 2 hours and the carbon disulfide was evaporated. The residue was added to a mixture of ice (500 g) and concentrated hydrochloric acid (15 mL), and the mixture was extracted with methylacetate (4 X 200 mL) and then methylene dichloride (2 X 150 mL). The extracts were combined, washed with brine (2 X 100 mL), dried and evaporated. The residue is recrystallized from a 2: 1 mixture of diethyl ether and n-pentane. Methyl 3- [4- (chloroacetyl) phenyl] propionate is obtained, m.p. 90 ° C.

Ethyl 2- (4- (bromoacetyl) phenoxy) -2-methylpropionate

Ethyl 2- [4- (acetylphenoxy) -2-methylpropionate (10 mmol) in a chloroform solution (120 mL) was brominated at 35 ° C, dropwise adding a solution of bromine (10.5 mmol) in chloroform (20 mL). After 1 hour, the reaction mixture was filtered and the filtrate was washed with water (2 X 30 mL), dried and evaporated to give ethyl 3- (4- (bromoacetyl) phenoxy] -2-methylpropionate as an oil which was pure by analysis. thin layer chromatography (TLC) (on silica gel plates, eluting with a mixture of 50% ether and 50% gasoline).

Ethyl 2- [4- (chloroacetyl) phenoxy] propionate

Ethyl 2-phenoxypropionate (0.25 mmol) was dissolved in methylene chloride (20 mL) containing chloroacetyl chloride (0.26 mmol). The solution was cooled to 0% C with rapid stirring and aluminum chloride (0.79 mol) was added portionwise over 30 minutes. The mixture was allowed to warm to room temperature with stirring over 16 hours. The solvent was evaporated and the residue was poured into a mixture of ice (300 g and concentrated hydrochloric acid (15 ml)), extracted with methylene dichloride (5X 100 ml), washed with water (2 X 50 ml), dried and evaporated. ethyl 2- (4-chloroacetyl) phenoxy] propionate is obtained on aluminum oxide as a white solid, which has a satisfactory microanalysis:

calculated:

57.7% C, 5.6% H, 13.1% N, found:

57.7% C, 5.5% H, 13.0% N.

Methyl 4- [- (chloroacetyl) phenoxy] butyrate

Methyl 4-phenoxybutyrate is reacted with acetyl chloride in a manner similar to that described above for the preparation of 3- (4- (chloroacetyl) phenyl) propionic acid, except that the crude product is triturated with petroleum ether. [4- (chloroacetyl) phenoxy] butyrate is obtained as a crystalline solid which is pure by TLC analysis (on silica gel plates using 50% ether / 50% petroleum ether as eluent).

N- {3- [4- (chloroacetyl) phenyl] propionyl-alanine methyl ester

A solution of pivaloyl chloride (4.41 mL) in tetrahydrofuran (30 mL) was added to a stirred solution of 3- (4- (chloroacetyl) phenyl) propionic acid (9.7 g) and trlethylamine (5.5 mL) in tetrahydrofuran (30 mL). ) and acetonitrile (40 ml) cooled to -15 DEG C. The resulting mixture was stirred at -15 DEG C. for 1 hour and then a suspension of DL-alanine methyl ester hydrochloride (5.0 g) in dimethylformamide (30 ml) was added over 15 minutes. The mixture was stirred at -15 ° C for 1 hour and then at room temperature for 16 hours, saturated sodium bicarbonate solution (30 ml) was added, the solution was stirred for 30 minutes and then evaporated in vacuo. The residue was treated with water (150 mL), extracted with chloroform (2 X 100 mL) and washed successively with 10% hydrochloric acid (200 mL), water (200 mL), saturated sodium bicarbonate solution (200 mL), and water (200 mL). ml), dried over magnesium sulphate and evaporated, and the residue was recrystallized from toluene / petroleum. r. There was obtained N- {3- [4- (chloroacetyl) phenyl] propionyl] alanine methyl ester, m.p. 122-124 ° C.

Methyl 4- (chloroacetyl) thio phenoxyacetate

A solution of methylthiophenoxyacetate (60 g) in methylene chloride (100 mL) was added over 20 minutes to a stirred suspension of chlorination of 193333 tyl chloride (45.2 g) and aluminum chloride (134 grams) in methylene chloride (400 mL) at room temperature.

The resulting solution was stirred at room temperature overnight and then poured into a mixture of ice (2 kg) and concentrated hydrochloric acid (50 mL). The mixture was then stirred at room temperature for 1 hour. The methylene chloride phase is separated, dried over magnesium sulphate and evaporated in vacuo. The residue was recrystallized from methanol. There was obtained methyl 4- (chloroacetyl) thiophenoxyacetate (60.1 g), m.p. 61-63 ° C.

Example 10

Similar to Example 1 except that concentrated hydrochloric acid was replaced with 50% aqueous sulfuric acid, methyl 4- (aminoacetyl) phenoxyacetate sulfate was obtained as a solid, mp 125-128 ° C. Examples 20 to 21

Using a similar procedure to that of Example 2, but starting from N, N-diethyl-4- (chloroacetyl) phenoxyacetamide or N, N-diethyl-2-methoxy-4- (bromoacetyl) phenoxyacetamide, N, N- diethyl 4- (aminoacetyl) phenoxyacetamide hydrochloride (Example 20j (m.p. 78-80 ° C)), or N, N-diethyl-2-methoxy-4- (aminoacetyl) phenoxyacetamide;

Claims (3)

SUBJECT A process for the preparation of (N-aminoacetyl) benzene derivatives of the general formula I Y is ^H 2 ^N-CH 2 ^C0 ~ ^^ ~ ^ ~ ^C0 ~ ^A ~ ^R (I) wherein Y is hydrogen or Cl to Cd alkoxy, X represents oxygen, sulfur or a direct bond between the benzene ring and residue A, A represents a straight chained or branched C 1 -C 6 alkylene residue and R is hydroxy, amino, C 1 -C 5 alkoxy, di- (C 1 -C 1 alkyl amino) or α- (C 1 -C 4 alkoxy) carbonyl-C 1 -C 4 alkylamino or pharmaceutically acceptable acid addition salts thereof, or in the case of compounds of formula I wherein R represents a hydroxy group, a pharmaceutically acceptable base addition salt, characterized in that the compound of formula (II) amide hydrochloride (Example 21) (m.p. 113-116 ° C). The starting 4- (haloacetyl) phenoxyacetamides are obtained as follows: N, N-Diethy 1-4- (chloroacetyl) phenoxyacetamide Aluminum chloride (83.3 gj) was added in portions over 30 minutes to a rapidly stirred solution of N, N-diethylphenoxyacetamide (51.6 g) and chloroacetyl chloride (31.0 g) in methylene chloride (200 mL) at 0 ° C. After stirring for 16 hours at room temperature with stirring, the solvent was evaporated and the residue was poured into a mixture of ice (300 g) and concentrated hydrochloric acid (15 ml), extracted with methylene chloride (5X 100 ml) and the extracts washed with water (2X50). The residue was chromatographed on alumina to give N, N-diethyl-4- (chloroacetyl) phenoxyacetamide, m.p. 89-91 ° C. N, N-Diethyl-2-methoxy-4- (bromoacetyl) phenoxyacetamide N, N-Diethyl-2-methoxy-4-acetylphenoxyacetamide is reacted with copper (I) bromide in a similar manner as described above for the preparation of the starting material for the procedure of Example 6. N, N-diethyl-2-methoxy- 4- (bromoacetyl) phenoxyacetamide, m.p. 101-103 ° C. ynAlezu Y Q-CH 2 CO 4 ^-A - ^co - ^R (II) wherein Q represents a chlorine, bromine or iodine atom and X, Y, A and R are as defined above, reacted with hexamethylenetetramine in an inert solvent or diluent at 20 to 60 ° C, and then the resulting hexamine salt is acid hydrolyzed at 40 to 100 ° C, followed by to obtain a pharmaceutically acceptable acid addition salt, reacting a compound of formula I with an acid capable of providing a pharmaceutically acceptable cation and, if a pharmaceutically acceptable base addition salt is to be obtained, a compound of formula I wherein R is hydroxy, reacting with a base capable of providing a pharmaceutically acceptable cation. 2. Process according to claim 1, characterized in that the acid hydrolysis is carried out in the presence of alcohol and hydrochloric acid at a temperature of 40 to 100 ° C. 3. A process according to claim 1, wherein Y is hydrogen, X is oxygen, A is methylene and R is methoxy and acid hydrolysis is carried out in the presence of methanol.