CS199699B2 - Method of producing esters of phenylethylamine derivatives - Google Patents

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to methods for producing esters of phenylethylamine derivatives which exhibit anti-inflammatory activity when applied topically to the site of inflammation.

The novel esters of the phenylethylamine derivatives of the formula I, the same different from them, mean a hydrogen atom or a methyl group,

A represents a direct bond or a methylene group,

Z is hydrogen or chlorine and Q is a radical of formula II or III,

in which

R ^{* 1} represents an alkyl group having 1 to 11 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkyl moiety, or a phenyl group optionally substituted on the nucleus with a methyl or methoxy group, one R @ ² and R @ ³ are hydrogen and the other one is R @ 10 CO. Where R ¹ is as defined above, each of R ⁶ and R ⁷ may be

in which

R ⁸ represents a hydrogen atom or a methyl group,

X is a direct oxygen atom, and the benzene ring Y is optionally substituted on the nucleus with a halogen atom, a trifluoromethyl group, a C 1 -C 3 alkyl group or a C 1 -C 3 alkoxy group, and their pharmaceutically acceptable salts are prepared by the process of the invention, wherein the compound of formula IV is

in which

R @ ¹ , R @ ² , R @ ³ , R @ ⁶ , R @ ⁷ , A, Z and Q are as hereinbefore defined, or an acid addition salt thereof, subjected to reduction, followed by conversion of the optionally obtained free base ester acid provides a pharmaceutically acceptable anion to their pharmaceutically acceptable acid addition salt.

Suitable alkyl groups having 1 to 11 carbon atoms represented by R ¹ as a linear alkyl group having 1 to 11 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl, or branched alkyl group with 3-11 carbon atoms such as isopropyl, isobutyl, tert-butyl, 1-methyl-2,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl or 1,1-diethylpropyl, of which isopropyl, isobutyl and tert-butyl groups are particularly preferred .butylová.

A suitable cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkyl moiety as R ¹ is, for example, (cyclopentyl) methyl.

Suitable alkyl groups having 1 to 3 carbon atoms and alkoxy groups having 1 to 3 carbon atoms present as optional substituents on the benzene ring Y are, for example, methyl or methoxy.

Particularly suitable R ^O ^ when A is a direct bond is, for example, a pivaloyl, isobutyryl or isovaleryl group, and when A is a methylene group, for example an acetyl group.

A suitable halogen atom which is present as an optional substituent on the benzene ring Y is, for example, a fluorine, chlorine or bromine atom.

A suitable radical Y is, for example, phenyl, 4-chloro-, 4-fluoro-, 4-methoxy-, 3-trifluoromethyl- or 4-methylphenyl.

A particularly suitable radical for Q when it represents a group of formula (II) above wherein X is a direct bond is, for example, phenylacetyl, 4-fluoro-, 4-chloro- or 4-methoxyphenylacetyl or 2-phenylproplonyl.

A particularly suitable radical for Q when it represents a group of the above formula (II) wherein X is oxygen is, for example, phenoxyacetyl or (3-trifluoromethylphenoxy) acetyl.

A particularly suitable radical of formula (Q) above is, for example, benzoyl, 4-chlorobenzoyl, 4-methylbenzoyl or 4-methoxybenzoyl.

Particular groups of esters produced according to the invention, which are particularly important are those compounds of formula I wherein (R ² also is a radical of formula R? O. O and R ³ is hydrogen, (bj R ² is hydrogen and R ³ is a radical of the formula R ¹ CO, O-, (cj A represents a direct bond, (d) A represents a methylene group, (e) Z represents a hydrogen atom or (fj Z represents a chlorine atom, in each of the above cases the remaining R @ ¹ , R @ ² , R @ ³ , R @ ⁶ , R @ ⁷ , R @ ⁸ , A, Z and Q, any of the aforementioned general or particularly uplifted meanings, as well as pharmaceutically acceptable acid addition salts of all compounds .

A particularly preferred group of esters are the compounds of formula (I) as defined in the above groups (a) and (cj taken together) wherein R ¹ is furthermore isopropyl, tert-butyl, isohutyl or (cyclopentyl) methyl, R ⁶ and R ⁷ are each both a hydrogen atom or a methyl group; and Q represents a phenylacetyl, a phenoxyacetyl or benzoyl group.

Particularly suitable acid addition salts of esters of the formula I are those derived from acids giving a pharmaceutically acceptable anion, for example from inorganic acids such as hydrochloric, hydrobromic, phosphoric or sulfuric acids, or from organic acids such as oxalic, tartaric, lactic acid , fumaric, lemon, acetic, salicylic, benzoic, β-naphthoic, methanesulfonic or adipic.

It will be appreciated that the esters of formula I contain at least one asymmetric carbon atom, which is a carbon bearing a hydroxyl group, and that they can therefore exist in racemic form or in optically active forms. Depending on the nature of the substituents R ⁶ , R ⁷ and R ⁸ , the esters of formula I may contain up to three other asymmetric carbon atoms and may therefore exist in the corresponding other racemic or optically active forms. It should be pointed out that the invention encompasses a process for the preparation of both the racemic forms of the aforementioned esters and all optically active forms which exhibit anti-inflammatory activity. It is generally known how racemic forms can be resolved into the corresponding optically active forms, or how optically active forms can be obtained by synthesis starting from optically active starting materials, and how pharmacological properties can be determined using standard assays described below.

The specific esters of formula (I) are described below in the Examples, but the following are particularly preferred of these esters:

1- [3,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol,

1- [3,4-bis (pivaloyloxy) phenyl] -2 [1,1-dimethyl-2- (2-phenylacetamido) ethylamino] ethanol,

1- [3,4-bis (pivaloyloxy) phenyl] -2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol,

1- [3,4-bis (pivaloyloxy) phenyl] -2- (2- (2-phenoxyacetamido) ethylaminobenzoyl),

1- [3,4-bis (isovaleryloxy) phenyl] -2- [2- (2-phenylaicetamido) ethylamino] ethanol,

1- [3,4-bis (3,3-dimethylbutyryloxy) phenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol, and pharmaceutically acceptable acid addition salts thereof.

The reduction according to the invention can be carried out by the action of any agent generally known for reducing aromatic ketones, but not reducing the ester moiety on the carboxyl group. Thus, the reduction may be carried out by treatment with an alkali metal borohydride, for example sodium borohydride, in an inert diluent or solvent, for example methanol, ethanol or 2-propanol (this reduction method is preferred), or catalytic hydrogenation, for example hydrogenation in the presence of palladium, platinum or % of a nickel catalyst, in a diluent or solvent, for example ethanol or acetic acid. In both cases, the reaction temperature is, for example, from -20 ° C to 30 ° C, conveniently operating at or near room temperature, for example at a temperature of 15 ° C to 30 ° C.

The starting materials of the general formula (IV) can be obtained by the reaction of the phenacyl halide of the general formula (V),

in which

Hal represents a chlorine or bromine atom and the remaining general symbols have the meanings given above, with an amino compound of the general formula VI, R®

H2N — C — CH2 — NHQ »

R ⁷ (VI), wherein each general symbol is as defined above.

The reaction is conveniently carried out at or near room temperature, for example at a temperature between 15 ° C and 30 ° C, in a diluent or solvent, for example ethanol, dioxane or acetonitrile. Said reaction can also be carried out in the presence of an acid binding agent, for example an alkali metal carbonate or acid carbonate, or an excess of the amino compound of formula VI.

Compounds of formula (VI) may be obtained by selective acylation of a diamine of formula (VII).

R®

NH2-C-CH2-NH2

R ⁷ (VII), wherein R ⁷ and R ⁷ are the same as defined above, by the action of an acylating agent structurally derived from the cyeeline of formula Q. OH, wherein Q is as defined above, for example as described in the examples.

Alternatively, the starting materials of formula (IV) may be prepared by acylation of the dlhydroxy compound of formula (BUT),

wherein one of G ¹ and G ² is a hydrogen atom and the other is a hydroxyl group, and the remaining general symbols are as defined above by the action of an acylating agent structurally derived from an acid of formula R ¹ . CO 2 H, wherein R ¹ is as defined above, for example the chloride or bromide thereof, preferably in the presence of a strong acid to minimize the tendency to acylate on nitrogen, for example using the corresponding dihydroxy compound in the form of hydrochloride, hydrobromide or trifluoroacetic acid salt. The necessary dihydroxy compounds can be obtained, for example, by acid hydrolysis of the corresponding di-O-acetylderivatives or by hydrogenemolysis of the corresponding di-O-benzyl derivatives, as described in Example 2 below.

The phenacyl halides of formula (V) may be obtained by conventional side chain halogenation of the corresponding acylbenzenes corresponding to formula (V) but in which, instead of Hal, hydrogen is present.

The optically active forms of the esters of formula (I) can be obtained by conventional resolution of the corresponding racemic form.

The free base ester of formula (I) may be converted to a pharmaceutically acceptable acid addition salt by reaction with a suitable acid as defined above under conventional conditions in which the ester is not hydrolyzed. Alternatively, for the preparation of salts with hydrochloric or hydrobromic acid, the salts are conveniently obtained by preparing a steehiometric amount of the corresponding hydrogen halide in situ by catalytic hydrogenation of the corresponding benzyl halide in the presence of esters of formula I, preferably in an inert solvent or diluent, e.g. , at or about room temperature.

The esters of formula (I) are conveniently used in the form of their pharmaceutically acceptable acid addition salts.

As mentioned above, the esters of formula I exhibit anti-inflammatory activity when applied topically to the site of inflammation and are therefore particularly useful in the treatment of inflammatory diseases or inflammatory skin conditions in warm-blooded animals.

Anti-inflammatory properties can be demonstrated by a standard test of inhibiting croton oil-induced ear inflammation in mice. In this assay, the specific esters of Formula I described herein cause marked inhibition of inflammation when administered topically at a dose of 0.30 mg / ear or at an even lower dose.

In the above test, no appreciable toxic effects were observed when the test compounds were administered at effective doses.

In general, the esters of formula (I) may be used to treat inflammatory diseases or inflammatory conditions of the skin in an analogous manner to the use of topical anti-inflammatory agents such as topical steroids.

When used for topical treatment of the site of inflammation on the skin of a warm-blooded animal, for example a human, the ester of the formula I can be applied externally at a dose of 10 µg to 15 mg / cm ² , or an equivalent dose using a pharmaceutically acceptable addition salt thereof. An acid ester, wherein, if necessary, this dose can be repeated at intervals of, for example, 4 to 12 hours. It will be understood that the total daily dosage of the ester of Formula I depends on the extent and severity of the inflammation being treated.

For example, when using 1- [3,4-bis (pivaloyloxy) phenyl] -2- [1,1-dimethyl-2- (2-phenoxyacetamidioethylamino) ethanol for topical treatment of the site of inflammation on the skin of a warm-blooded animal such as man, the compound is administered topically at a dose of 1 µg to 5 mg / cm ² , or an equivalent dose using the corresponding pharmaceutically acceptable acid addition salt, repeated, if necessary, at intervals of 4 to 12 hours.

The invention is illustrated by the following non-limiting examples. The following rules apply to these examples:

(I) unless otherwise stated, all operations are carried out at room temperature (in the range of 18 to 26 ° C) and at atmospheric pressure and all evaporations are carried out on a rotary evaporator under reduced pressure;

(IIJ, optionally present IR spectra values are reported in absorbance values (Umax) for characteristic groups;

(III) NMR spectra, if any, are reported as chemical shifts (? Values) for characteristic protons, relative to tetriamethylsilane as a standard, detected using perdeuterodimethylsulfoxide as solvent (unless otherwise specified) at 100 MHz;

(IV) optionally the yields shown are illustrative only and in no way represent the maximum achievable yields.

The terms "volume / volume", "weight / volume", respectively. The "weights / weights" used in the examples to describe the composition of the various compositions, to indicate concentrations, and the like have, in accordance with common practice, the following meanings:

(VJ refers to a mixture in which both components are measured by volume. For example, a 1:19 (v / v) mixture of ethyl acetate and toluene contains 1 volume of ethyl acetate together with 19 volumes of toluene. % (v / v) aqueous ethanol contains 70 parts by volume of ethanol in 100 parts by volume of the total mixture;

(VI) 'mass / volume' describes a mixture in which the first component is measured by weight and the second component by volume. For example, a 10% (w / v sodium carbonate solution contains 10 parts by weight of sodium carbonate in 100 parts by volume of the solution;

(VII) 'weight / weight' describes a mixture in which both components are measured by weight. For example, 10% (w / w) palladium on carbon contains 10 parts by weight of palladium together with 90 parts by weight of coal.

Example 1

A suspension of 3.3 g of 2- [1,1-dimethyl-2- (2-phenoxyacetaimido) ethyl, amino] -3 ', 4'-bis (pivailoyloxy) acetophenone trifluoroacetate in 25 ml of 2-propanol is cooled to -10 ° 0.56 g of sodium borohydride are added in two portions, in which 10 ml of methanol are added, followed by reaction at 50 ° C for 50 minutes, 50 ml of saturated aqueous sodium chloride solution are added to the mixture, and the resulting mixture is extracted three times. Evaporation of the ethereal extracts dried over magnesium sulphate gave 3.2 g of the free basic 1- [3,4-bis (pivoyloxy) phenyl] -2- [1,1-diimethyl-2- (2-phenoxyacetiamido) amino]. To this ethanolic solution was added 0.6 ml of benzyl bromide and the mixture was hydrogenated under atmospheric pressure at room temperature for 3 hours in the presence of 0.5 g of 10% palladium on carbon. The catalyst is filtered off through diatomaceous earth, the residue on f The filtrate is washed with 20 ml of ethanol and the ethanolic filtrate combined with the washings is evaporated. Trituration of the residue with 200 ml of ether gives 2.1 g of 1- (3,4-bis (pivaloyloxy) phenyl) -2- [1,1-dimethyl-2- (2-phenoxy-acetamido) ethylamino] ethanolhydrohromide, m.p. of ethanol-ether at 156-158 ° C.

By analogy, except that benzyl bromide is replaced with an equivalent amount of benzyl chloride, the Od10 corresponding hydrohydrochloride is obtained as a solid, m.p. 129 DEG-132 DEG.

In a manner similar to that described for the preparation of the corresponding 2- (2-phenylacetamido) ethylamino compound in Example 2, with the acylation of 2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] -3 ', 4'-dihydroxyacetophenone pivaloyl chloride in trifluoroacetic acid yields the necessary starting 2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] -3 ', 4'-bis (pivaloyloxy) acetophenine trifluoroacetate, melting at 183-185 in 85% yield. Deň: 32 ° C.

The starting 2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] -3 ', 4'-dihydroxyacetophenone itself is obtained in the form of a foam, a pure product of sufficient purity for further acylation by hydrogenolysis of 2- [1, 1-Dimethyl 1-2- (2-phenoxyacetamido) ethylamino] -3 ', 4'-bis (benzyloxy) acetophenone hydrobromide, carried out in an analogous manner to that described in Example 2 for 2- [1,1-dimethyl-2- ( 2-phenylacetamidoethylamino] -3 ', 4'-bis (benzyloxy) acetophenhydrobromide.

The starting 3 ', 4'-bis (benzyloxy jacetophenone derivative) was also prepared in 67% yield in a manner analogous to that described in Example 2 for the preparation of the corresponding compound from 2-bromo-3', 4'-biS (benzyloxy) acetophenone and N- (2-amino-2-methylpropyl) -2-phenoxyacetamide, m.p. 137-139 ° C.

N- (2-Amino-2-methylpropyl) -2-phenoxyacetaimide may be prepared in an analogous manner to that described in Example 2 for the preparation of N- (2-amino-2-methylpropyl) -2-phenylacetamide. The product melts after recrystallization from aqueous ethanol at 55 to 56 ° C.

Example 2

Using a procedure analogous to that described in Example 1, reduction of the corresponding acetophenone derivatives of formula X

with an excess of sodium borohydride and subsequent catalytic hydrogenation in the presence of a stoichiometric amount of benzyl bromide to in situ addition of hydrobromic acid salts in the form of hydrobromides in yields of 45 to 80% yield the following diesters corresponding to formula IX:

R CO.O "Á> RCO.O OH and CH ₃ -CH-C -CHCHjWH NHCOCHgC ^ ^ _CH2 "(ix) compound number position of substituents on ring B R10 melting point (° C)

1 3.4 isopropyl foam*) 2 3.4 1-ethylpropyl 70 to 75 3 3.4 tert-butyl 134 to 136 4 3.4 2,2-dimethylpropyl 105 to 111 5 3.4 1- (2-: methylpropyl) -3-ethylbutyl 79 to 82 6 3.4 1-methyl-2,2-dimethylpropyl 109 to 110 7 3.4 phenyl 113 to 117 (decomposition) 8 3.4 4 ^J methoxyphenyl 168 to 170 9 3.4 isobutyl 80 to 85 10 3.5 tert-butyl 173 to 175 11 3.5 1-methyl-2,2-dimethylpropyl 150 to 152 12 3,5 ' 4-methoxyphenyl 140 to 145 13 3.5 cyiklopeintylmethyl 160 to 162 14 3.5 2,2-dimethyl-propyl 124 to 127 15 Dec 3.5 isopropyl 106 to 110 Legend: flights, (CH3) 2CH and —NHC (CH3) 2]

*) Product isolated in the form of foam:

NMR (dimeithylsulfoxide, δ values): 7.4 to 7.1 (8H, complex, aromatic protons), 5.0 (1H, complex, CH.OH), 3.6-3.0 (6H, complex, CH 2 NH) and CH 2 CONH), 3.0-2.6 (2H, complex, CHCO), 1.26, 1.20 [18H, two singHOs]

The necessary starting ketones of formula X above are obtained by acylating the corresponding phenol derivative of formula XI

CH,

HIM

COCJi _from NH-C-CH ₂ NHCOCH _from 0 _& Ης hydrobromide, by reaction with the appropriate acyl chloride or acylbromideim general formula R ¹⁰ CO. Cl or R @ ¹⁰ CO. Br. This acylation is illustrated by the following description of the preparation of the intermediate acetophenone required for the preparation of compound 10 above.

To a suspension of 1.8 g of 2- [1,1-dimethyl-2- (2-phenylacetamido) ethyl] amino-3,5,5-dihydroxyacetophenone in 10 ml of trifluoroacetic acid was added 1.85 ml of pivaloyl chloride. The mixture was stirred at room temperature for 5 minutes, then heated at reflux for 45 minutes, evaporated, and the oily residue triturated with ether (100 ml) and ethanol (1 ml). The mixture was cooled to 0-5 ° C for 18 hours, whereupon 1.3 g of 2- [1,1-diimethyl-2- (2-phenylacetamido) ethyl] amino-3 ', 5'- bis (pivaloyloxy) acetophenone trifluoroacetate, m.p. 155-156 ° C.

Using the analogous procedure, the following acetophenone derivatives corresponding to the general formula (X) in the form of trifluoroacetate are obtained in yields of 30 to 70%:

14

Intermediate for the compound C. . position of the substituents on ring B R10 melting point (° C) 1 3.4 isopropyl 136 to 138 2 3.4 1-ethylpropyl 140 to 142 3 3.4 tert-butyl 205 to 208 4 3.4 2,2-dimethylpropyl 112 to 115 5 3.4 1- (2-methylpropyl) -3-methylbutyl 130 to 135 6 3.4 1-methyl-2,2-diimethylpropyl 190 to 194 7 3.4 phenyl 110 to 111 8 3.4 4-methoxyphenyl 125 to 130 9 3.4 isobutyl 140 to 141 11 3.5 1-methyl-2,2-dimethylpropyl 195 to 200 12 3.5 4-Imethoxyphenyl 90 to 95 (decomposition) 13 3.5 cyclopentylmethyl 175 to 178 14 3.5 2,2-dimethylpropyl 148 to 154 15 Dec 3.5 isopropyl 175 to 180

The phenolic starting materials of formula XI are obtained as follows:

1) 2- [1,1-Diimethyl-2- (2-phenylacetamido) ethyl] amino-3‘, 4‘-dihydroxyacetophenone

A solution of 5.24 g of 2-bromo-3 ', 4'-bis (benzyloxy) acetophenone and 5.5 g of N- (2-amino-2-methylpropyl) -2-phenylacetamide in 25 ml of dioxane was stirred at room temperature for 2 hours. The reaction mixture was diluted with dry ether (200 mL) and the precipitated N- (2-amino-2-methylpropyl) -2-phenylacetaimidhydroibromiide was filtered off, washed with water (3 x 50 mL, brine), dried (MgSO4). A saturated ethereal hydrogen bromide solution is then added until the solution is acidic, and after standing at 0-5 ° C for 18 hours, the precipitate formed is filtered off to give 6.85 g of 2- [1,1-dimethyl-2]. (2-Phenylacetamido) ethyl] amino-3 ', 4'-bis (benzyloxy) aceitophenone hydrobromide as a solid, m.p. 155-160 ° C. 5.0 g of this hydrobromide are dissolved in 300 ml of absolute ethanol and the solution is dissolved in ethyl acetate. hydrogenate at atmospheric pressure using 3.0 g of 10% (w / w) palma After the hydrogen consumption has elapsed (about 3 hours), the catalyst is filtered off and the ethanolic filtrate is evaporated at a temperature below 30 DEG C. to give 3.7 g of 2- [1,1-dimethyl-2- (2-phenylacetamido). Ethyl] amino-3 ', 4'-dihydroxyacetophenone hydrobromide in the form of a foamy residue which is directly used for further acylation.

2) 2- [1,1-Diimethyl-2- (2-phenylacetamido) ethyl] amino-3‘, 5‘-dihydroxyeetophenone

This compound was obtained in a yield of 98% as a foaming agent suitable for further acylation in an analogous manner to the previous paragraph using 2-bromo-3 ', 5'-bis (benzyloxy jacetophenone and N- (2-amino-2)). methyl-propyl) -2-phenylacetamide starting materials and isolating the intermediate 2- (1,1-dimethyl-2- (2-phenylacetamido) ethyl] amimo-3 ', 5'-bis (benzyloxy) acetophenone hydrobromide, m.p. Mp 150-153 ° C.

N- (2-Amino-2-methylpropyl-2-phenylacetamide) was obtained as follows:

A solution of 8.8 g of 1,1-dimethylethylenediamine in 250 ml of ether was added over 2 hours to a solution of 15.4 g of phenylacetyl chloride in 250 ml of ether, and the mixture was stirred at room temperature for a further 2 hours. The precipitated solid is filtered off, dissolved in 150 ml of warm water, the solution is filtered, the filtrate is rendered alkaline by the addition of 50 ml of saturated aqueous sodium carbonate solution and extracted three times with 250 ml of chloroform each time. The extracts were dried over magnesium sulphate and evaporated to an oily residue which crystallized upon addition of a mixture of equal volumes of ether and petroleum ether (b.p. 60-80 ° C).

There was obtained 13.1 g of N- (2-amino-2-methylpropyl) -2-phenylacetamide, melting after recrystallization from aqueous ethanol at 68-71 ° C.

Example 3

In an analogous manner to Example 1, 2-J [1- [1-dimethyl-2- (2-phenoxyacetamidoethyl) amino] -2'-chloro-3 ', 4'-bis (pivaloyloxy) or -3', 4'-bis (isovaleryloxy) acetophenone trifluoroacetate yields 58% solid 1- [3,4-bis (pivaloyloxy) -2-chlorophenyl] -2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol hydrobromide in 58% yield. m.p. 163 DEG-164 DEG C., or 49% yield of solids;

- [3,4-bis (isovaleryloxy) -2-chlorophenyl] -2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] -ethanol hydrobromide, m.p. 176-179 ° C.

The desired trifluoroacetates are obtained in the form of a viscous substance (used in the above procedure without further purification) in yields of 70 to 80% in an analogous manner to that described in Example 2 by reaction of 2 - {[1,1-dlmethyl-2- ( 2-phenoxyacetamido) ethyl] amino] -2'-chloro-3 ', 4'-dihydroxyacetophenone 1999999 hydrobromide (A) with pivaloyl or isovaleryl chloride in trifluoroacetic acid.

The above-mentioned acetophenone derivative (A) is prepared in 85% yield as a solid, m.p. 141-143 ° C by a method analogous to that described for the preparation of a similar starting material in Example 2, except starting from 2- ( [1,1-Dimethyl-2- (2-phenoxyacetamido) ethyl] amino] -2'-chloro-3 ', 4'-bis (beinzyloxy) acetophenone hydrobromide The latter compound is obtained in a yield of 40% as a solid in 16% yield. mp 61-63 ° C from N- (2-amino-2-methylpropyl) -2-phenoxy and 2-bromo-3 ', 4'-bib (ben ⁱ benzyloxy) -2'-chloracet'Ofenoin) U using a procedure analogous to that described in Example 2.

Example 4

The following esters of formula (XII) are obtained in the form of their hydrochlorides in a yield of 38 to 75% in an analogous manner to that described in Example 1:

rJco.o,

OH

CHCH 2 NHCH 2 CH ₂ NHCOCH ₂

(KH)

R.CO.O

compound number the position of the n and N-ring suhstituents Ri melting point (° C)

1 3.4 2,2-dimethylpropyl 141 to 142 (hydrate) 2 3.5 T-butyl oil ¹ ) 3 3.5 2,2-dimethylpropyl oil ² ) 4 3.5 cyclopentylmethyl oil ³ ) 5 3.4 n-propyl 102 to 104 6 3.4 isopropyl 116 to 117 7 3.4 heptyl oil ⁴ ) 8 3.4 isobutyl 124 to 128 9 3.4 1-ethylpropyl 102 to 105 10 3.4 1- (2-methylpropyl) -3-methylbutyl ^j 98 to 105 11 3.4 1-methyl-2,2-dimethylpropyl 111 to 114 12 3.4 1-ethyl-2,2-dimethylpropyl oil ⁵ ) 13 3.4 1,1-diethylpropyl foam ⁶ ) 14 3.4 phenyl oil ⁷ ) 15 Dec 3.4 4-methylphenyl foam ⁸ ) 16 3.4 4-methoxyphenyl oil ⁹ ) Legend: ⁴ ) NMR (δ values): 9.0 8.5 (2H, broad

1) NMR (δ values): 8.17 (1H, —NHCO—), 7.2 - 6.7 (8H, complex, aromatic protons), 5.0 (1H, broad singlet, —CHOH—), 3 4 to 2.6 (complex, -CH 2 -), 1.1 (18H, singlet, C-CH 3);

+ signal, NH 2), 8.32 (1H, broad signal, NHCO), 7.5-7.1 (8H, singlet, aromatic protons], 5.0 (1H, doublet, CHOH], 3.6-2 , 8 (complex, CH 2 NH and CH 2 CONH), 2.5 (4H, multiplet,

CH 3 (CH 2) 5 CH 2 CO), 1.8 - 1.0 (20H, complex, ² J NMR (δ values): 8.38 (1H, —NHCO—),

7.4 - 6.7 (8H, complex, aromatic protons), 5.0 (1H, broad singlet, —CH.OH—),

3.7-2.6 (complex, —CH2 -), 2.45 (4H, singlet, —CH2 CO--), 1.06 (18H, singlet,

C (CH 3);

³ ) NMR (δ values): 8.38 (1H, —NHCO—), 7.4 - 6.75 (8H, complex, aromatic protons), 5.0 (1H, broad singlet, —C1. OH) -),

3.9-2.7 (complex, -CH 2 -), 2.5 (4H, complex, -CH 2 CO-1, 2.0-1.0 (—CH 2 -, cyclopentyl ring));

CH3 (CH2) 5CH2CO), 0.88 (6H, broad triplet, CH3 (CH2) 5CH2CO);

⁵ ) NMR (δ values): 9.0-8.5 (2H, broad +)

signal, NH 2), 8.3 (1H, broad signal, NHCO), 7.6-7.0 (8H, complex, aromatic protons), 5.05 (1H, doublet, CHOH), 3.6-2, 7 (6H, complex, CH2N.H and CH2CONH), 2.26 [2H, triplet (J = 7Hz), CH-CO], 1.65 [4H, triplet, (J = 7Hz), CH2-CH —CO], 1.04 [18H, singlet, (CH3) 3C], 0.9 (6H, triplet, CH3CH2);

⁶ J NMR (δ S): 8.9-8.5 (2H, complex + plex, NH 2), 8.35 (1H, complex, NHCO), 7.4-7.1 (8H, complex, aromatic protons ), 5.0 (1H, doublet, CHOH), 3.6-2.8 (8H, complex, CH 2 NH and CH 2 CONH), 1.85-1.20 [12H, complex, (CH 3 CH 2) 5 C, CO], 1.1 - 0.5 [18H, complex, (Cl + CH2) C, CO];

⁷ ) NMR (values <5): 9.0 - 8.6 (broad signal, 2H, NH2), 8.4 (1H, broad signal, NHCO), 8.1 - 7.1 (18H, complex, aromatic) protons), 5.1 (1H, doublet, CHOH), 3.6 to 5

2.9 (complex, CH 2 NH and CH 2 CONH);

⁸ ) NMR ( ^δ ): 9.0-8.5 (2H, broad + NH2), 8.38 (1H, broad, NHCO), 8.0-7.0 (16H, complex, aromatic) protons), 5.06 (1H, doublet, CHOH), 3.6-2.8 (complex, CH 2 NH and CH 2 CONH), 2.34 (6H, singlet, 4-CH 3 -Ph);

⁹ ) NMR (hodnoty3 values): 8.35 (1H, broad signal, NHCO), 8.0-6.8 (16H, complex, aromatic protons), 5.2 (1H, doublet, CH.OH) ,

3.8 (6H, singlet, 4-CH 3 O-Ph), 3.7-2.9 (8H, complex, CH 2 NH and CH 2 CONH).

The necessary ketone starting materials of formula IV can be obtained by careful acylation of the corresponding dihydroxyacetophenone derivatives of formula VIII in the presence of trifluoroacetic acid in a manner similar to that described for the preparation of analogous starting materials of formula XI in Example 2. .

The desired dihydroxyacetophenone derivatives of formula VIII can be prepared by hydrogenolysis of the corresponding O, N-tribenzyl derivatives of formula XIII,

PhC / 1.0

7 &lt; - &gt; - COCH.N-CH _of CH3HCOCH _of PI

Ph-CH 2 O catalysed by 10% (w / w) palladium on carbon, and preferably used in situ for the acylation.

Derivatives of the above formula XIII are obtainable by reacting 2-bromo-3 ', 4'-bis (benzyloxy) - or ^2-bromo-3', 5 '-bis (benzyloxy) acetophenone with N- [2- (benzylamino) eithyl] -2-phenylacetamide using a procedure analogous to that described in Example 2 for the preparation of 2- [1,1-dimethyl-2- (2-phenylacetamido) ethyl] amino-3 ', 4'-bis (benzyloxy Jacetophenone) .

N- [2- (B-benzylamino) ethyl] -2-phenylacetamide was prepared as a solid as follows:

A mixture of 100 g (0.61 mol) of ethyl phenylacetate and 120 ml (1.86 mol) of ethyleindiamine was heated on a steam bath for 4 days. Excess ethylenediamine is evaporated under reduced pressure, the residue is dissolved in 500 ml of water and all insoluble material is filtered off. Evaporation of the filtrate gave 96.8 g of crude N- (2-aminoethyl) -2-phenylacetamide which was used without further purification.

To a solution of 113.5 g (0.637 mol) of N- (2-aminoethyl) -2-phenylacetamide was added 67.5 g (0.637 mol) of benzaldehyde, the mixture was stirred at room temperature for 18 hours and then added portionwise 2 g of sodium borohydride and the resulting mixture was stirred for an additional 1.5 hours.

I (XJII)

Excess borohydride was quenched by the addition of acetic acid, the reaction mixture basified by addition of 2N sodium hydroxide solution and extracted three times with 500 ml of ethyl acetate each time. The extracts were washed with brine (300 ml), dried (MgSO4) and filtered. Hydrogen chloride gas was added to the ethyl acetate filtrate until acidic (pH ca. 2), the resulting mixture was allowed to stand at Q ° C for 4 hours, then the precipitate was filtered off. There was obtained 46.2 g of N- [2- (benzylaimino) ethyl] -2-phenylacetamide hydrochloride, m.p. 183-185 ° C.

The free base is liberated from 15 g of this hydrochloride by basifying the hydrochloride solution in 150 ml of water with solid sodium carbonate. The aqueous mixture was extracted with ethyl acetate (3.times.100 ml), dried (MgSO4) and evaporated. 13.0 g of oily N- [2- (benzylamino) ethyl] -2-phenylacetamide are obtained, which crystallizes slowly.

Example 1 a d 5

In a similar manner to that described in Example 1, the following compound of formula XIV can be obtained in a yield of 42-65%:

co.o.

(ChfoC.CO.O p

_from NHCH CH _of CH _of NH-COR ¹¹ (XIV) ·

compound number position of substituents on ring B R ¹¹ Melting point (C ^c 1 3.4 4-chlorophenyl 102 to 104 2 3.4 4-methoxyphenyl foam ³ ' 3 3.4 4-fluorobenzyl 174 to 175 4 3.4 4-methoxybenzyl 105 to 108 5 3.4 4-chlorobenzyl 156 to 158 6 3.4 α-methylbenzyl 79 to 86 7 3.4 phenoxymethyl 162 to 165 8 3.4 3-trifluoromethylphenoxymethyl 80 to 81 9 3.4 phenyl 166 to 169 (hydrate) 10 3.5 4-methoxybenzyl oil ^b) 11 3.4 3-fluorobenzyl 174 to 176 (hemihydrate) Legend: Necessary acetophenone starting materials

^(a) product isolated in the form of a foam;

NMR (CDCl3): 8.1 (1H, broad signal, NHCO), 8.0-6.6 (7H, complex, aromatic protons);

5.3 (1H, broad signal, CHOH),

3.7 (3H, singlet, 4-CH 3 O-CeHi), 3.8-2.9 (complex, CH 2 NH),

1.28 [18H, singlet, (CH3) 3C];

IV can be prepared in a manner analogous to that described for the preparation of the analogous intermediates in Example 2 from the corresponding amines VI and 2-bromo-3 ', 4'-bis (pivaloyloxy) - or 2-bromo-3', 5'-bis (pivaloyloxy) acetophenone.

The amines of formula VI can be obtained by hydrogenolysis of N-benzyl-N--acylethylenediamines of formula XV,

PI1CH2NHCH2CH2NHCOR ¹¹ , (XV) ^{b> the} product isolated as an oil;

NMR (deuterochloroform, δ values):

9.1-8.5 (2H, broad signal, N + Fk),

8.4 (1H, broad singlet, NHCO),

7.5-6.6 (7H, complex, aromatic protons),

3.7 (3H, singlet, 4-CH3O-CeHa),

3.9-2.7 (complex, CH 2 NH and CH 2 CONH), 1.28 [18H, singlet, (CH 3) 3 C).

wherein Ph represents a phenyl residue catalyzed by 10% (w / w) palladium on carbon.

The amino derivatives of formula (XV) can be obtained in an analogous manner to that described in Example 4 for the preparation of N- [2- (benzylaminoethyl) -2-phenyl-lacetamide, and their hydrochlorides have the following properties:

The starting compounds R ¹¹ Mp (° C) Number

1 4-chlorophenyl 234 to 236 2 4-methoxyphenyl 198 to 200 3 4-fluorobenzyl 194 to 195 4, 10 4-methoxybenzyl 196 to 197 5 4-chlorobenzyl 54 to 55 6 α-methylbenzyl syrup ³¹ 7 phenoxymethyl 182 to 184 8 3-trifluoromethylphenoxymethyl 147 to 149 9 phenyl 54 to 56 11 4-fluorobenzyl 194 to 195

Legend:

*) melting point of the free base.

The required 2-bromoacetophenone derivatives can be prepared as follows:

A suspension of 3,4-dihydroxyacetophenone (13.1 g, 0.08 mol) in chloroform (320 ml) was cooled to 0 ^DEG- 5 ^DEG C. in ice and a solution of 19.2 ml (0.16 ml) was added dropwise with stirring over 10 minutes. mole) of pivaloyl chloride in 80 ml of chloroform and a solution of 22.2 ml of triethylamine (0.16 mol) in 80 ml of chloroform. The reaction mixture was stirred at 0-5 ° C for 1 hour and then poured into a mixture of 100 ml of 2N hydrochloric acid and 200 g of ice. The aqueous mixture is extracted three times with 150 ml of chloroform each, the extracts are washed successively with 100 ml of water, 100 ml of 10% (w / v) sodium carbonate solution, 100 ml of water and 100 ml of sodium chloride solution, dried over magnesium sulphate and evaporated. 23.1 g of crude oily 3 ', 4'-bis (pivaloyloxy) acetophenone are obtained, which is used without further purification.

To a solution of 19.5 g of 3 ', 4'-bis (pivaloyloxy) acetophenone (19.5 g, 0.061 mol) and 8.2 ml (0.06 mol) of tert-butyl acetate in 150 ml of chloroform containing a catalytic amount (0 A solution of 3.15 ml (0.061 mol) of bromine in 50 ml of chloroform was added dropwise while stirring at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, then 75 g of chromatography on silica gel was added and the resulting mixture was evaporated in vacuo. The solid residue is applied to a 1 kg dry silica gel column first deactivated by adding 1 part by weight of water for every 10 parts by weight of silica gel and then equilibrated with 1 part by volume of ethyl acetate and toluene (1:19 by volume) for every 10 parts by weight of silica gel. The column was first eluted with 1.1 L of ethyl acetate / toluene (1:19 by volume) and then eluted twice with 500 mL of ethyl acetate each time, and the fractions collected were monitored by TLC on a solvent system consisting of an equal volume of ethyl acetate and toluene. The later eluted fractions were combined and evaporated to give 14.2 g of oily 2-bromo-3 ', 4'-bis (pivaloyloxy) acetophenone, which crystallized rapidly to give a solid, m.p. 64-66 ^° C.

In a similar manner, 2-bromo-3‘, 5‘-bis (pivaloyloxy) acetoifenone, melting at 112-114 ° C, can be obtained from 3 3, 5‘-dihydroxyacetophenone.

Example 1 a d 6

In analogy to Example 1, 1- [3,4-bis (pivaloyloxy) -2-chlorophenyl] -2 can be obtained in the yields of 40 to 60% of the corresponding starting compounds of the formula IV as their trifluoroacetic acid salts. - [2- (2-Phenylacetamido) ethylamino] ethanol-hydrobromide, m.p. 139-142 ° C and 1- [3,4-bis (isovaleryloxy) -222

Chlorophenyl] -2- [2- (2-phenylacetamido) ethylamino] ethanol-hydrobromide, m.p. 128-131 ° C.

The necessary starting materials of formula (IV) can be obtained in an analogous manner to the starting materials of Example 4, i.e. by careful acylation of the corresponding dihydroxyacetophenone derivative with pivaloyl chloride or isovaleryl chloride in the presence of trifluoroacetic acid. The dihydroxyacetophenone derivative of formula (VIII) is obtained by catalytic hydrogenolysis of 2- {N-benzyl-N- [2- (2-phenylacetamido) ethyl] amino] -2'-chloro-3 ', 4'-bis (benzyloxy) acetophenone hydrobromide. The latter compound is prepared as follows:

An ethereal diazomethane solution was directly distilled into a mixture of 25.0 g of 3,4-bis (benzyloxy) -2-chlorobenzoyl chloride and 200 ml of ether while maintaining the temperature at -25 ° C. The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 4 hours, and saturated ethereal hydrogen bromide (eca 150 mL) was carefully added until the nitrogen evolution ceased. After adding 125 g of silica gel for chromatography, the mixture is evaporated and the residue is applied to a dry column of 900 g of silica gel for chromatography, previously deactivated by adding 1 part by weight of water to 10 parts by weight of silica gel and then. equilibrated with ethyl acetate / toluene (1:19 by volume) in a volume ratio of 1 volume per 10 parts by weight of silica gel. Fraction elution first with 1.1 L of the above solvent mixture and then 1.5 L of ethyl acetate. Evaporation of the appropriate fractions eluted with ethyl acetate (followed by thin layer chromatography) afforded 28.1 g of 2-bromo-3 ‘, 4‘-bis (benzyloxy) -2‘-chloroacetophenone as a solid, m.p. 94-96 ° C.

An ethereal solution of diazomethane is prepared by a standard procedure by adding dropwise a solution of 45.0 g of N-methyl-N-nitrosotoluenesulfonamide in 300 ml to a solution of 12.9 g of potassium hydroxide in 21 ml of water while stirring and maintaining the temperature at 50-55 ^° C. of ether at a rate such that the losses due to distillation of the ethereal diazomethane solution are compensated.

The starting benzoyl chloride is obtained in 90% yield by conventional reaction of 2-chloro-3,4-bis (benzyloxy) benzoic acid with thionyl chloride and has a melting point of 124 to 126 ° C. 2-chloro-3,4-bis (benzyloxy) -benzoic acid was prepared in 80% yield as a ¹ · a solid, mp 159-162 ° C, the oxidation of 2-chloro-3,4-bis (benzyloxy) benzaldehyde (which is It is prepared by the procedure described by Kaiser et al. in J. Medicinal Chemistry 1974, 17, 1071) with chromium trioxide dissolved in sulfuric acid (Jones reagent).

A mixture of 2.95 g of 2-bromo-3 ', 4'-bis (benzyloxy) -2-chloroacetophenone and 3.7 g of N- [2- (benzylamino) ethyl] -2-phenylacetamide in 20 ml of dioxane was stirred at room temperature for 3 hours. then diluted with 200 ml of dry ether and the precipitated N- [2- (benzylamino) ethyl) -2-phenylacetamide hydrobromide was filtered off. The filtrate was washed with water (3.times.50 ml) and brine (100 ml), dried (MgSO4), filtered and then treated with a fresh solution of hydrogen bromide in ether until acidic pH. The mixture was allowed to stand at 0-5 ° C for 16 hours, after which the viscous product was triturated with a mixture of ethanol and ether. 4.2 g of 2-yn-benzyl-N- [2- (2-phenylacetamido) -ethyl] aminophenyl-2'-chloro-3 ', 4'-bis (benzyloxy) acetofenonliydrobromidu mp 162-164 ^C C.

Example 1 a d 7

Using a procedure analogous to that described in Example 1 (omitting the final hydrobromide preparation), the following compounds corresponding to the general formula can be prepared in a yield of 30 to 60%.

Compound number

NHC (CH, NHCO. R

OF *

R ¹² Melting point (° C)

1 tert-butyl benzyl 2 methyl benzyl 3 isobutyl benzyl 4 n-butyl benzyl 5 methyl phenoxymethyl

Legend:

^(a) NMR (deuterochloroform, δ values):

7.8-6.9 (8H, complex, aromatic protons),

6.3-5.8 [2H, broad singlet, CH (OH) CH2 and CH2 NHC (CH3) 2],

5.0 [3H, broad singlet, COCH2 a

CH (OH) CH 2],

3.5 (2H, sharp singlet, C6H5CH2CO), 3.35-3.2 [2H, doublet, (CH2CH2CH2NH), 3.05-2.8 [2H, complex, CH2OH3CH2NH],

2.25 (3H, sharp singlet, CH 3 COO),

2.0 (3H, sharp singlet, CH 3 COOCH 2),

1.2 [6H, doublet, NHCl (CH3) 2] CH2;

H 105-107 *) (acid salt methanesulfone) methyl oil ⁸ ' methyl oil ^b) methyl oil ^c) methyl oil ^d) 6.4-6.1 [2H, broad singlet, CH (OH) CH 2

CH 2 NHC (CH 3) 2],

5.0 [3H, broad singlet,

CO2CH ₂ CH (OH) CH ₂ ],

3.6 (2H, broad doublet, CaH5CH2CO),

3.4 [2H, broad doublet, C (CH3) 2CH2NH],

3.2-2.8 [2H, complex, CH (OH) CH2 NH],

2.6 [2H, triplet, CH2CH2CH3CH2CO2],

2.2 [2H, triplet, CH 3 (CH 2) 2 CH 2 CO 2 CH 2],

1.8-1.2 (8Η, complex,

CH3CH2CH2CH2CO2),

1.2 [6H, doublet, NH-C (CH3) 2CH2], ~ ~ ”

1.1-0.8 [6H, overlapping triplets,

CH3 (CH2) 3CO2];

^(b) NMR (deuterochloroform, δ j values):

7.5-7.0 (8H, complex, aromatic protons),

6.8-6.6 [2H, broad singlet, CH (OH) CH2 and CH2 NHC (CH3),

5.0 [3H, broad singlet, CO2CH2 and CH (OH) CH2],

3.5 (2H, sharp singlet, C6H5ClHCO),

3.4 [2H, broad doublet, (CH3) 2C.CH2NH3,

3.2-2.8 [2H, complex, CH 2 OH 3 CH 2 NH 3,

2.3 (2H, doublet, CH2CO2),

2.1 (2H, doublet, CH2CO2CH2),

1.2 [6H, doublet, NHCl (CH3CH3CH2)],

1.1-0.8 [12H, two doublets, (CF3) CH2];

^(c) NMR (deuterochloroform, δ-values):

7.5-7.0 (8H, complex, aromatic protons), ^d) NMR (deuterochloroform, δ values):

7.9-6.8 (8H, complex, aromatic protons),

6.2-5.6 [2H, broad singlet, CH (OH) CH2 and CH2 NHCCH3],

5.0 (2H, sharp singlet, CH3CO2CH2),

4.5 (2H, sharp singlet, C6H5OCH2CO),

3.6-3.4124, broad doublet, C (CH 3) 2 CH 2 NH],

3.3- 2.8 [2H, complex, CH 2 OH 3 CH 2 NH],

2.25 (3H, sharp singlet, CH 3 CO 2),

2.0 (3H, sharp singlet, CH5CO2CH2),

1.3 [6H, doublet, NHC (CH3) 2 CH2];

all of the oily products as shown by thin layer chromatography (silica gel, ethanol / chloroform 1: 9 or 1: 4 by volume as solvent system);

*) The methanesulfonic acid salt is obtained by dissolving the free base (after reaction with borohydride) in a minimum volume of isopropyl acetate and adding methanesulfonic acid up to pH 4-5. The methanesulfonic acid salt then crystallizes from solution at 0-5 ^° C.

The desired starting materials of formula IV can be obtained by reacting the corresponding 2-bromoacetophenone of formula V with an amine of formula VI using a procedure analogous to that described in Example 2 to prepare analogous starting materials.

The desired 2-bromoacetophenones of formula V can be prepared as follows:

(1j) To a mixture of 54 g of anhydrous sodium acetate, 500 ml of glacial acetic acid and 250 ml of acetic anhydride was added 108 g of 3'-chloromethyl-4'-hydroxyacetophenone, the resulting mixture was heated at 95 ° C for 4 hours. The resinous residue was dissolved in 500 ml of water and the aqueous solution was extracted three times with 300 ml of chloroform each time, and the combined extracts were dried over magnesium sulphate, filtered and evaporated to a yellow oily residue. acetoxymethyl-4'-acetoxyacetophenone as a colorless viscous liquid, boiling at 143-147 ° C / 40 Pa.

To a solution of 11.0 g of 3 20-acetoxymethyl-4‘-acetoxyacetophenone in 150 ml of chloroform is added dropwise a solution of 7.1 g of bromine in 20 ml of chloroform with stirring at room temperature. After the addition was complete, the resulting solution was washed twice with 150 ml of water and 100 ml of brine each time, the organic phase was dried over magnesium sulphate and evaporated after filtration. 10.0 g of 3'-acetoxymethyl-4'-acetoxy-2-bromoacetophenone are obtained which, according to IR spectroscopy and thin layer chromatography [silica gel, a mixture of equal volumes of ethyl acetate and petroleum ether (b.p. 60-80 ° C) as solvent system] sufficiently pure for subsequent use without further purification or characterization.

(II) To 150 ml of valeric acid 2.0 g of sodium hydride was added portionwise with stirring over 15 minutes, then 40 g of 3-acetoxymethyl-4-acetoxyacetophenone was added, the resulting mixture was heated to 160 ^° C and 15 ^° C at this temperature. hours of stirring. The reaction mixture was concentrated by distillation under reduced pressure while maintaining the temperature at 160 ° C, and the gummy residue was separated. Cool and dissolve in 500 mL of ether. The solution is washed first with 3 times 250 ml of 10% (v / v) sodium carbonate solution, then twice with 500 ml of water and finally with 250 ml of saturated sodium chloride solution, the organic phase is dried over magnesium sulphate and evaporated after filtration. The brown oily residue yielded 16.0 g (30%) of 3'-valeryloxymethyl-4'-valeryloxyacetophenone as a colorless viscous liquid by high vacuum distillation.

NMR (deuterochloroform, <5):

7.9-7.0 (3H, aromatic ring substitution, type 1,2,4),

5.0 (2H, sharp singlet, CO2CH2),

2.5 (3H, sharp singlet, COCH3),

2.55-2.15 [4H, complex,

CH3 (CH2) ₂ CH2 CO2 CH3 (CH2) aCH2CO2CH2]

1.8-1.2 (8H, complex, CH3CH2CH2CH2CO2O),

1.1-0.8 [6H, overlapping triplets, CH3 (CH2) 3CO2].

To the cooled solution of 8.5 g of 3‘-valeryloxymethyl-4‘-valeryloxyacetophenone in 100 ml of chloroform was added dropwise with stirring

4.2 g of bromine in 20 ml of chloroform while maintaining the temperature of the reaction mixture at 0 to 5 ° C by adding small pieces of solid carbon dioxide. The resulting solution was washed first with 100 ml of 10% (w / v) sodium carbonate solution each time, then twice with 100 ml of water and then with 100 ml of saturated sodium chloride solution, the organic phase was dried over magnesium sulphate and evaporated. 6 g (57%) of 3'-valeryloxymethyl-4'-valeryloxy-2-bromoacetophenone are obtained which, according to IR spectroscopy and thin layer chromatography [silica gel, a mixture of equal volumes of ethyl acetate and petroleum ether (b.p. 60-80 ° C). (as solvent system) sufficiently pure for subsequent use without further purification or characterization.

(III) 3-Isovaleryloxymethyl-4'-isovaleryloxy-2-bromoacetophenone is obtained in an analogous manner to that described in (II) above, except that isovaleric acid is used in the first reaction step in place of valeric acid. The desired 2-bromoacetophenone derivative is isolated as an oil with satisfactory IC spectrum which is pure according to thin layer chromatography [silica gel, mixture of equal volumes of ethyl acetate and petroleum ether (bp 60-80 ^° C) as solvent system].

The intermediate 3‘-isovaleryloxymethyl-4‘-isovaleryloxyacetophenone was also isolated:

NMR (CDCl3):

7.9- 7.0 (3H, aromatic ring substitution, type 1,2,4),

5.0 (2H, sharp singlet, CO2CH2),

2.5 (3H, sharp singlet, COCH3),

2.4 (2H, doublet, CH2CO2),

2.1 (2H, doublet, CH2CO2CH2),

1.1-0.8 [12H, complex. (CHsjaCHj.

Claims (8)

I will invent the subject A process for the preparation of phenylethylamine derivatives of the general formula I, in which R ¹ represents an alkyl group having 1 to 11 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkyl portion, or a phenyl group optionally substituted on the nucleus with a methyl or methoxy group, one of R ² and R ³ represent a hydrogen atom and the other of these radicals R ¹ C0.0-, wherein R ¹ is as defined above, each of R ⁶ and R ⁷ , which may be the same or different, represents a hydrogen atom or methyl group A represents a direct bond or a methylene group, Z is hydrogen or chlorine; and Q represents a radical of formula II or III in which R ⁸ represents a hydrogen atom or a methyl group, X is a direct bond or an oxygen atom and the benzene ring Y is optionally substituted on the nucleus with a halogen atom, a trifluoromethyl group, a C 1 -C 3 alkyl group or a C 1 -C 3 alkoxy group, and pharmaceutically acceptable salts thereof; A compound of formula IV wherein: R @ ¹ , R @ ² , R @ ³ , R @ ⁶ , R @ ⁷ , A, Z and Q are as defined above, or an acid addition salt thereof is subjected to reduction, after which the optionally obtained free base ester of formula I is converted by reaction with an acid providing a pharmaceutically acceptable anion to its pharmaceutically acceptable acid addition salt. 2. The process of item 1 for the preparation of compounds of the above general formula I, wherein: R ¹ represents an alkyl group having 1 to 11 carbon atoms or a cycloalkylalkyl group having from 3 to 6 carbon atoms in the cycloalkyl portion and from 1 to 5 carbon atoms in the alkyl portion, one of R ² and R ³ being a hydrogen atom and the other wherein R ¹ and R ⁷ are as defined above, each of R ⁶ and R ⁷ , which may be the same or different, represents a hydrogen atom or a methyl group; A represents a direct bond or a methylene group, Z is hydrogen and Q represents a residue of the above general formula (II) in which R ⁸ represents a hydrogen atom or a methyl group, X is a direct bond or an oxygen atom and the benzene ring Y is optionally substituted on the nucleus with a halogen atom, a trifluoromethyl group, a C 1 -C 3 alkyl group or a C 1 -C 3 alkoxy group, and pharmaceutically acceptable salts thereof; A compound of the above formula (IV) wherein R ¹ , R ² , R ³ , R ⁶ , R ⁷ , A, Z and Q are as defined above is subjected to reduction, followed by optionally obtaining an ester of the formula (I) in the form of the free base is converted by treatment with an acid giving a pharmaceutically acceptable anion to its pharmaceutically acceptable acid addition salt. 3. The process of claim 1 wherein the reduction is carried out by treatment with an alkali metal borohydride in an inert diluent or solvent at a temperature of from -20 [deg.] C to 30 [deg.] C. 4. The process of claim 2 wherein the reduction is carried out by treatment with an alkali metal borohydride in an inert diluent or solvent at a temperature of from -20 ° C to 30 ° C. 5. The process of claim 1 wherein the reduction is carried out by catalytic hydrogenation in an inert diluent or solvent, at a temperature of from -20 ° C to 30 ^° C. 6. The process of claim 2 wherein the reduction is carried out by catalytic hydrogenation in an inert diluent or solvent at a temperature of from -20 ° C to 30 ° C. 7. Process according to claim 1, 3 or 5, characterized in that the starting materials of the aforementioned general formula (IV) are used in which R ¹ is isopropyl, tert-butyl, isobutyl or (cyclopentyl) methyl; R ³ represents hydrogen, R ⁶ and R ⁷ are either hydrogen or methyl, A means a direct bond, Q represents a phenylacetyl, phenoxyacetyl or benzoyl group and the remaining general symbols are as in point 1. 8. A process as claimed in claim 2, 4 or 6, wherein the starting materials of the above-mentioned general formula (IV) are used, in which R ¹ represents an isopropyl, tert-butyl, isobutyl or: (cyclopentyl) methyl group, R ³ represents hydrogen, R ⁶ and R ⁷ are either hydrogen or methyl, A means a direct bond, Q represents a phenylacetyl or phenoxyacetyl group and the remaining general symbols are as defined in 2.