CS199700B2 - Method of producing esters of phenylethylamine derivatives - Google Patents

Description

The present invention relates to a process for the preparation of esters of phenylethylamine derivatives which exhibit anti-inflammatory activity when applied topically to the site of inflammation. >

New esters of phenylethylamine derivatives o-

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 methyl or methoxy, one of R ^2, and R ³ represents a hydrogen atom and the other symbols of the radical of the formula R-O. Where 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 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,

(Uf) in which

R @ 5 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 their pharmaceutically acceptable salts are prepared according to method

199 according to the invention, wherein the carbonyl derivative of the general formula IV,

in which

R ¹ , R ² , R ³ , A and Z are as defined above, condenses under reducing conditions with an amine of formula V,

R ⁶

AND

HzN — C — CH2 — NHQ

Ø ⁷ t ^V )>

in which

R ⁶ , R ⁷ and Q are as defined above, whereupon the optionally obtained free base ester of the formula I is converted by reaction with an acid giving a pharmaceutically acceptable anion to its 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 is from 3 to 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 are particularly preferred.

A suitable cycloalkylalkyl group 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 10 CO - 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 moiety for Q is that when it is a group of formula II, wherein X is a direct bond, is, for example, phenylalethyl, 4-fluoro-, 4-chloro- or 4-methoxyphenylacetyl or 2-phenylpropionyl.

A particularly suitable radical for Q when it is a group of formula (II) in which 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 by the process of the invention of particular interest are those compounds of formula I wherein (a) R ² is a radical of formula R ⁴ CO. O- and R ³ is hydrogen, (b) R ² is hydrogen and R ³ is a radical of formula R ^X CO. O-, (c) A represents a direct bond, (d) A represents a methylene group, (e) Z represents a hydrogen atom or (f) Z represents a chlorine atom, in each of the above cases the remainder of the symbols R ¹ , R 2 being ² , R ³ , R ⁶ , R ⁷ , R ⁸ , A, Z and Q of any of the aforementioned general or particularly praised meanings, as well as pharmaceutically acceptable acid addition salts of all compounds of each of the above cases.

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

Particularly suitable acid addition salts of the 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 , 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 or 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 additional asymmetric carbon atoms and may therefore exist in the corresponding other racemic or optically active forms. It should be noted that the invention encompasses a process for the production of both racemic forms of the above esters and all optically active forms having 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.

Specific esters of the formula I are described in the Examples below, but the following compounds 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-J 3,4-bis (pivaloyloxyphenyl) -2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol,

1- [3,4-bis (pivaloyloxyphenyl) -2- [2- (2-phenoxyacetamido) ethylamino] ethanol,

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

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

Particularly suitable reducing conditions in the process according to the invention are achieved by using, for example, an alkali metal or an alkali metal cyanoborohydride, for example sodium borohydride or sodium cyanoborohydride, of which cyanoborohydride is particularly preferred, suitably in an inert solvent or diluent, for example acetonitrile, methanol, ethanol or 2- propanol, at a temperature in the range, for example, from -20 ° C to 30 ° C. When using sodium cyanoborohydride, the reaction is preferably carried out at or around pH 4, for example in the presence of acetic acid.

Obviously, the processes of the above general type are known as reductive alkylations and take place at least in part via intermediates of formula VI & CO.OA.

OH f CH-CH ⁼ N-C-CH ² NH 2.

R ¹ (VI) (in which then the grouping -N = CH- further reduced) and / or formula VII

R ^ OO.OA

? CH = NC-CH ₇ -NHQ

R ¹ (VID (in which the grouping —N = CH— and the ketone bond are further reduced)).

These intermediates of formula (VI) or (VII) (or mixtures thereof) may be prepared and reduced, if desired, in the manner described above. two separate reaction steps.

The starting materials of formula IV can be obtained by oxidation of a compound of formula VIII

R CO. OA as _R-CH3 (VIII) selenium dioxide in an expedient solvent, for example aqueous dioxan, optionally followed by hydrate formation, acetal or hemiacetal, at which the form of the compounds may also be used in the above procedure.

The starting materials of the formula IV can conveniently also be prepared by oxidation of the corresponding phenacyl bromide of the formula IX

dimethylsulfoxide under conventional conditions, for example as described in Example 3 below.

The phenacyl bromides of the formula IX can be obtained by conventional halogenation of the corresponding acetophenone of the formula VIII into the side chain or by transacylation of the di-O-acetylderivative of the formula X,

wherein one of G ¹ and G ² is acetoxy and the other of hydrogen is reacted with the sodium salt of the corresponding acid of formula R ¹ . CO 2 H at 150 to 180 ° C, as exemplified by Example 4 below.

The amino compounds of formula (V) may be obtained by selective acylation of a diamine of formula (XI):

NH2. CR «R ⁷ . CH2. NH ₂ (XI), wherein R ⁶ and R ⁷ are as defined above, an acylating agent structurally derived from an acid of formula Q. OH, wherein Q is as defined above, for example, a halide thereof.

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) can 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 stoichiometric amount of the corresponding hydrogen halide in situ by catalytic hydrogenation of the corresponding benzyl halide, in the presence of an ester of formula I, preferably in an inert solvent or diluent, e.g. in ethanol, at room temperature or at 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.

Proinflammatory properties can be demonstrated by a standard test of inhibition of croton oil-induced inflammation in the ear of 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 marked 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 a manner analogous to the known use of topical anti-inflammatory agents, for example topical steroids.

When used for the topical treatment of the site of inflammation on the skin of warm-blooded animal, for example man, an ester of formula I can be administered topically at a dose of 10 μξ to 15 mg / ^cm, or an equivalent amount, when used pharmaceutically-acceptable acid addition salt of such ester with an acid, and 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-2-12-phenoxyacetamidojethylamino] ethanol to topically treat 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, and if necessary repeated 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 (between 18 and 26 ^° C at atmospheric pressure and all evaporations are carried out on a rotary evaporator under reduced pressure;

(II) optionally present IR spectra values are reported in absorbance values (in _raax ) for the characteristic groups;

(III) NMR spectra, if any, are reported in the form of chemical shifts (Š values) for characteristic protons, relative to tetramethylsilane as a standard, detected using perdeuterodimethylsulfoxide as solvent (unless otherwise specified) at 100 MHz; (IV) the yields indicated are merely illustrative and in no way represent the maximum achievable yields.

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

(V) 'volume / volume' describes 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 part by volume of ethyl acetate together with 19 parts by volume of toluene. Similarly, 70% (v / v) aqueous ethanol contains 70 parts by volume of ethanol in 100 parts by volume of the entire 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.

He did

A solution of 0.68 g (0.002 mol) of 3 ', 4'-bis (pivaloyloxy) phenylglyoxal and 0.41 g (0.002 mol) of N- (2-amino-2-methylpropyl) -2-phenylacetamide in 15 ml After stirring for 18 hours at room temperature, the reaction mixture was cooled to -10 ° C with stirring and 0.23 g (0.003 mol) of sodium borohydride was added portionwise. After the addition was complete, the mixture was stirred at -10 ° C for 45 minutes, then 100 mL of sodium chloride solution was added thereto, and the resulting mixture was extracted three times with 60 mL of ether at room temperature. After washing with 50 ml of sodium chloride solution and drying over magnesium sulfate, the ethereal extracts are evaporated to give 0.64 g of oily 1- [3,4-bis (pivaloyloxy) phenyl] -2- [1,1-dimethyl-2- (2-Phenylacetamido) ethylamino] ethanol A solution of this oily product in 15 ml of ethanol was hydrogenated with 148 µl (0.0012 mol) of benzyl bromide for 2 hours at room temperature under atmospheric pressure in the presence of 0.3 g of 10% palladium on charcoal. the catalyst was filtered off, washed with 5 ml of ethanol and the filtrate together with the ethanol washings were concentrated. Trituration of the residue with 300 ml of ether at 0 ^DEG C. in 48% yield yield l- [3,4-bis (pivaloyloxy Phenyl] -2- [1,1-dimethyl-2- (2-phenylacetamidoethylamino) ethanol hydrobromide An analytically pure sample, obtained by crystallizing this hydrobromide from water, has a melting point of 134-136 ° C.

The starting phenylglyoxal derivative is prepared as follows:

A solution of 2 g of 2-bram-3 ‘, 4‘-bis (pivaloyloxy) acetophenone in 10 ml of dimethyl sulfoxide is allowed to stand at room temperature for 18 hours, poured into ice water and extracted three times with 60 ml of ether each time. The ethereal solution was washed with water (50 ml) and brine (50 ml) and evaporated. 1.8 g of oily 3‘, 4‘-bis (pivaloyloxy) phenylglyoxal are obtained.

IC (max) ^: 1760 cm ^-1 (ester carbonyl),

1690 cm < -1 > CHO 3;

NMR (CDCl3): 8.2-8

7.1 (complex, aromatic hydrogens), 1.35 (18H, singlet, --CH3).

The starting N- (2-amino-2-methylpropyl) -2-phenylacetamide was prepared 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 made alkaline by addition of 50 ml of saturated aqueous sodium carbonate solution and then extracted three times with 250 ml of chloroform each. The extracts were dried over magnesium sulfate and evaporated to an oily residue which crystallized upon addition of a mixture of equal volumes of ether and petroleum ether (b.p. 60 DEG-80 ^and 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.

2-Bromo-3 ‘, 4‘-bis (pivaloyloxy jacetophenone) is obtained as follows:

A suspension of 13.1 g (0.08 mol) of 3,4-dihydroxyacetophenone in 320 ml of chloroform was cooled in ice to 0-5 ° C and a solution of 19.2 ml (0 ml) was added dropwise with stirring over 10 minutes. , 16 mol] of pivaloyl chloride in 80 ml of chloroform, firstly a solution

22.2 ml (0.16 mol) of triethylamine in 80 ml of chloroform. The reaction mixture was stirred at 0-5 ° C for a further 1 hour and then poured into a mixture of 100 ml of 2N hydrochloric acid and 200 g of ice. The resulting mixture was extracted three times with 150 ml of chloroform each, the extracts were 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 sulfate 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 (0.061 mol) of 3 ', 4'-bis (pivaloyloxy) acetophenone and 8.2 ml (0.06 mol) of tert-butyl acetate in 150 ml of chloroform, ob199700 containing a catalytic amount (0.2 g) of anhydrous aluminum chloride, a solution of 3.15 ml (0.061 mol) of bromine in 50 ml of chloroform was added dropwise with stirring at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, then 75 g of silica gel for chromatography were added and the resulting mixture was evaporated in vacuo. The residue was applied to a dry chromatography column of 1 kg of silica gel 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, the fractions collected being monitored by thin layer chromatography on silica gel in a solvent system consisting of equal volumes 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.

Example 2

In an analogous manner to that described in Example 1 for the preparation of 1- [3,4-bis (pivaloyloxy) phenyl] -2- [2- (2-phenylacetamidoethylamino) ethanol, starting from 3'-p'ivaloyloxymethyl-4 ' -pivaloyloxyphenylglyoxal and N- (2-aminoethyl) -2-phenylacetamide prepare 1- (3-pivaloyloxymethyl-4-pivaloyloxyphenyl) -2- [2- (2-phenylacetamido) ethylamino] ethanol ethanol as the methanesulfonic acid salt, m.p. 105-107 ^° C .

The glyoxal derivative used as the starting material is obtained as follows:

The procedure is analogous to that described in Example 1 for the preparation of 3 ', 4'-bls (pivaloyloxy) phenylglyoxal, except starting from 2-bromo-3'-pivaloyloxymethyl-4'-plvaloyloxyacetophenone and substituting 18 It is allowed to react for 6 days at room temperature.

NMR (DMSO-d6):

1.1 (9H, singlet, —C — CH3), 1.3 (9H, singlet, —C — CH3), 6.7 - 8.0 (complex, aromatic hydrogen), 8.3 (singlet, —COCHO) ).

The required N- (2-aminoethyl) -2-phenylacetamide was obtained in an analogous manner to the corresponding amino derivative in Example 1.

Example 3

A solution of 1.45 g of 3'-acetoxymethyl-4'-acetoxyphenylglyoxal hydrate and 1.04 g of N- (2-amino-2-methylpropyl) -2-phenylacetamide in 50 ml of acetonitrile was stirred at room temperature for 30 minutes and then stirred at room temperature. After stirring vigorously with 2 ml of acetic acid and then with 0.64 g of sodium cyanoborohydride, the mixture was stirred at room temperature for 16 hours and then evaporated, and the semi-solid residue was partitioned between 100 ml of ethyl acetate and 100 ml of 10% v / v aqueous acetic acid. The organic phase is separated, dried over magnesium sulphate and evaporated, filtered and the oily residue is purified by chromatography on a 150 g silica gel column using 10% (v / v) ethanol in chloroform as eluant. TLC on silica gel using 10% (v / v) ethanol in chloroform as the solvent system. The appropriate fractions were combined and evaporated to give 0.9 g (36%) of oily oil. [3-acetoxymethyl-4-acetoxyphenyl] -2- [1,1-dimethyl-2- (2-phenylacetamidoethyl) amino] ethanol.

NMR (CDCl3):

7.8 - 6.9 (8H, complex, aromatic protons), 6.3 - 5.8 [2H, broad singlet, CH 2 OH 3 CH 2 and CH 2 NHC (CH 3) 2], 5.0 [3H, broad singlet, COOCH 2 and CH (OH) CH 2], 3.5 (2H, sharp singlet, C 6 H 5 CH 2 CO), 3.35-3.2 [2H, doublet, (CH 3) 2 CCH 2 NH], 3.05-2.8 [2H, complex, CH 2 OH 3 CH 2 NH] 2.25 (3H, sharp singlet, CH 3 CO 6), 2.0 (3H, sharp singlet, CH 3 COOCH 2), 1.2 [6H, doublet,

NHC (CH ₃ ) ₂ CH ₂ ]. _ _ _ ' OF

The product according to thin layer chromatography on silica gel, using 10 ° / ₀ or 20% (v / v) ethanol in chloroform as the solvent system clean.

The starting substituted glyoxal is prepared as follows:

To a mixture of 54 g of anhydrous sodium acetate, 500 ml of glacial acetic acid and 250 ml of acetic anhydride is added 108 g of 3‘-chloromethyl-4‘-hydroxyacetophenone.

The resulting mixture was heated at 95 ° C for 4 hours and then concentrated by distillation under reduced pressure. The resinous residue was dissolved in 500 ml of water, and the aqueous solution was extracted three times with 300 ml of chloroform each. The combined extracts were dried over magnesium sulphate, filtered and evaporated to a yellow oil which was distilled under high vacuum to give 3'-acetoxymethyl-4'-acetoxyacetophenone as a colorless viscous liquid, 108g, boiling at 143-147 °. 40 Pa, which upon cooling crystallizes to a solid, m.p. 47-48 ^° C.

To a solution of 11.0 g of 3'-acetoxymethyl-4'-acetoxyacetophenone in 15p of chloroform, a solution of 7.1g of bromine in 20ml of chloroform was added dropwise with stirring at room temperature. After the addition was complete, the solution was washed twice with 150 ml of water each time and then with 100 ml of sodium chloride solution, the organic phase was dried over magnesium sulphate and evaporated after filtration. To give 3 ^{<-Acetoxymethyl-4-acetoxy-2-bromaoetofenon} in a yield of 10.0 g. The infrared spectra and thin layer chromatography on silica gel eluting with equal volumes of ethyl acetate and petroleum ether (b.p. 60-80 ° C) the product so obtained is sufficiently pure for use without further purification or characterization.

A solution of 10.0 g of 3 ^<: acetoxymethyl-4'-acetoxy-2-bromoacetophenone in 150 ml of dimethyl sulfoxide was stirred for 48 hours at room temperature, then poured into 500 ml of ice water and extracted three times with 200 ml ethyl acetate. Combine the organic layers, dry over magnesium sulfate, and filter. Evaporation of the solvent afforded 6.5 g (81%) of 3'-acetoxymethyl-4'-acetoxyphenylglyoxal hydrate as a yellow oil. Prepared glyo derivative. xalu has a satisfactory spectrum, it is pure by thin layer chromatography on silica gel using ethyl acetate as the solvent system and is therefore used without further characterization or isolation.

Examples 4 and 5

Using a procedure analogous to that of Example 3, the following diesters are obtained in oily form, which is according to thin layer chromatography on silica gel, using 10% or 20% (v / v) ethanol in chloroform as a solvent system in yields of 50 to 70%. , clean:

1- (3 * -Iso valeryloxymethyl-4'-isovaleryloxyphenyl) -2- [1,1-dimethyl-2- (2-phenylacetamidoyl-ethylamino) ethanol (Example 4)

NMR (deuterochloroform, <5):

7.5 - 7.0 (8H, complex, aromatic protons), 6.8 - 6.6 [2H, broad singlet, (CH (OH) CH 2 and CH 2 NHC (CH 3) 2), 5.0 [3H, ' broad singlet, CO2CH2 and CH (OH) CH2], 3.5 (2H, sharp singlet, C6H5CH2CO), 3.4 [2H, broad doublet, (CH3) 2NCH2NH], 3.2 - 2.8 [2H , complex, CH 2 OH 1 CH 2 NH], 2.3 (2H, doublet, CH 2 CO 2), 2.1 (2H, doublet, CH 2 CO 2 CH 2), 1.2 [6H, doublet,

NHC (CH3) 2CH2], 1.1-0.8 [12H, two years ago, (CH3) 2CH];

1- (3‘-Valeryloxymethyl-4'-valeryloxyphenyl) -2- [1,1-dimethyl-2- (2-phenylacetamido) ethylamino] ethanol (Example 5)

NMR (deuterochloroform, δ values):

7.5 to 7.0 (8H, complex, aromatic H); 6.4 to 6.1 [2H, broad singlet, CH (OH) CH2, and CH2 NHC _(CH3) 2], 5.0 [3H, bs singlet, CO2CH2CH (OH) CH2], 3.6 (2H, broad doublet, C6H5GH2CO), 3.4 [2H, broad doublet, C (CH3) 2 CH 2 NH], 3.2 - 2.8 [2H, complex, CH (OH) CH 2 NH], 2.6 [2H, triplet, CH 3 (CH 2) 2 CH 2 CO 2], 2.2 [2H / triplet, ¹⁴

CH3 (CH 2) 2 CH 2 CO 2 OH 2], 1.8 - 1.2 (8H, complex, CH 3 CH 2 CH 2 CH 2 CO 2], 1.2 [6H, doublet, NH - O (CH 3) 2 CH 2], 1.1 - 0.8 [6H, overlapping with triplets, (CH 2 CH 2 O 2 CO 2). _

The starting substituted phenylglyoxal was prepared in an analogous manner to that described for the preparation of the phenylglyoxal derivative in Example 3 using the appropriate 2-bromoacetophenone. Said starting materials are obtained in the form of hydrates and are obtained as oils which, according to thin-layer chromatography (silica gel, ethyl acetate as solvent system) and by IR spectroscopy, are sufficiently pure for use in the reactions described above without further isolation and characterization.

The required 2-bromoacetophenones are prepared as follows:

1. 3‘-Valeryloxymethyl-4‘-valeryloxy-2-bromoacetophenone (for Example 4)

To 150 ml of valeric acid are added with stirring over 15 minutes in portions 2.0 g sodium hydride was added 40 g of 3-acetoxymethyl-4-acetoxyacetophenone, the mixture was heated to 160 ^C and stirred at this temperature for 15 hours. The reaction mixture is concentrated under reduced pressure while maintaining the temperature at 160 ° C, the gummy residue is cooled and dissolved in 500 ml of ether. The solution is washed three times with 250 ml each of a 10% (v / v) sodium carbonate solution, twice with 500 ml each of water and 250 ml of saturated sodium chloride solution, the organic phase is dried over magnesium sulphate and evaporated. The brown oil obtained after distillation under high vacuum afforded 16.0 g (30%) of 3'-valeryloxymethyl-4'-valeryloxyacetophenone as a colorless viscous liquid.

NMR (CDCl3):

7.9 - 7.0 (3H, positions 1, 2, 4 on aromatic ring), 5.0 (2H, sharp singlet, CO2CH2),

2.5 (3H, sharp singlet, COCH3), 2.55-2.15 [4H, complex, CH3 (CH2) 2CH2CO2 and CH5 (CH2) 2CH2CO2CH2), 1.8-1.2 (8H, complex, CH3CH2CH2CH2CO2O) ), 1.1 - 0.8 [6H, overlapping triplets, (CH 2 CH 2 O 2 CO 2).

To a cooled solution of 8.5 g of 3'-valeryloxymethyl-4'-valeryloxyacetophenone in 100 ml of chloroform, a solution of 4.2 g of bromine in 20 ml of chloroform is added dropwise while stirring, maintaining the temperature at 0 to 0 by adding small pieces of solid carbon dioxide. Low: 14 ° C. The solution was washed three times with 100 ml of 1% (w / v) sodium carbonate solution, twice with 100 ml of water and 100 ml of saturated sodium chloride solution each time, the organic phase was dried over magnesium sulphate and evaporated to give 6 g (57%). ) ^3, -valeryloxymethyl-4'-valeryloxy-2-brom199700 1S acetophenone by IR spectroscopy and thin layer chromatography on silica gel eluting with equal volumes of ethyl acetate and petroleum ether (b.p. 60-80 ° C) as the solvent system tion sufficiently pure for use without further purification or characterization.

2. 3‘-Isovaleryloxymethyl-4‘-isovaleryloxy-2-bromoacetophenone (for Example 5)

This compound is prepared in an analogous manner to that described in paragraph 1 except that it is used in the first reaction step instead of va. leric acid Isovaleric acid. The 2-bromoacetophenone derivative is isolated as an oil having a satisfactory IR spectrum and is pure according to thin layer chromatography on silica gel using a mixture of equal volumes of ethyl acetate and petroleum ether (b.p. 60-80 ° C). The intermediate liquid 3‘-isovaleryloxymethyl-4‘-isovaleryloxyacetophenone is also isolated.

NMR (CDCl3):

7.9 - 7.0 (3H, aromatic nucleus positions 1, 2, 4), 5.0 (2H, sharp singlet, CO2CH2), 2.5 (3H, sharp singlet, COCH3),

2.4 (2H, doublet, CH2CO2M), 2.1 (2H, doublet, CH2CO2CH2), 1.1 to 0.8 [12H, complex, (CH3) 2CH] ^_. ..................

Example 6

In an analogous manner to that described in Example 3 for the preparation of 1- [3-acetoxymethyl-4-acetoxyphenyl] -2- [1,1-dimethyl-2- (2-phenylacetamido) ethylamino] ethanol, starting from 3'-acetoxymethyl-4. 1-acetoxyphenylglyoxal and N- (2-amino-2-methylpropyl) -2-phenoxyacetamide in a yield of 42% of 1- [3-acetoxymethyl-4-acetoxyphenyl] -2- [1,1-dimethyl-2- (2 (phenoxyacetamido) ethylamino] ethanol as an oil.

ŇMR (deuterochloroform, hodnoty values):

7.9 - 6.8 (8H, complex, aromatic protons), 6.2 - 5.6 [2H, broad singlet,

CH (OH) CH2 and CH2 NHC (CH3) 2], 5.0 (2H, sharp singlet, CH3CO2CH2], 4.5 (2H, sharp singlet, C6H5OCH2CO), 3.6 - 3.4 [2H, 18-year doublet , C (CH 3) 2 CH 2 NH], 3.3-2.8 [2H, complex, CH (OH) CH 2 NH], 2.25 (3H, sharp singlet, CH 3 CO 2), 2.0 (3H, sharp singlet, CH 3 CO 2 CH 2) 1.3 [6H, doublet, NHC (CH 3) ₂ CH ₂ ].

Thin layer chromatography on silica gel using 20% (v / v) ethanol in chloroform as the solvent system was pure product.

Example 7

To a solution of 10.4 g of 3 ', 4'-bis (pivaloyloxy) phenylglyoxal hydrate in 100 ml of acetonitrile is added with stirring a mixture of 5.56 g of N- (2-amino-2-methylpropyl) -2-phenoxyacetamide and 10 ml of acid. After stirring at room temperature for 30 minutes, 3.15 g of sodium cyanoborohydride was added to the solution while stirring, 500 ml of water were added for 6 hours, and the mixture was extracted with ethyl acetate (3.times.150 ml). The oily residue is suspended in 200 ml of dry ether and ethereal hydrogen bromide is added until the reaction is acidic, after which 10 ml of ethanol slowly begins to crystallize, and 13.7 g of solid material are obtained by filtration and recrystallized. by dissolving in 30 ml of warm ethanol, adding 250 ml of dry ether to the solution and cooling the mixture to 0-5 ° C for 2 hours. 10.1 g of 1- [3,4-bis (p-valoyloxy) phenyl] -2- [1,1-dimethyl-2- (2-phenoxyacetamido) ethylamino] ethanol hydrobromide are obtained, m.p. 154-157 ° C. After two further crystallizations from ethanol-ether, a material melting at 176-178 ° C is obtained.

N- (2-Amino-2-methylpropyl) -2-phenoxyacetamide was prepared in an analogous manner to N- (2-amino-2-methylpropyl) -2-phenylacetamide in Example 1 and, after recrystallization from aqueous ethanol, melted at 55-50 ° C. 56 ^C C.

Example

The following compounds of the formula (XII) in the form of the hydrobromides can also be obtained in a yield of from 30 to 50% in analogy to Example 7:

R ¹ CO.O,

R ¹ CO .0 5

OH

_From CH NHC (R CHjNH CO.RO (XII)

compound C. Rl position of substituents on ring B 1 t-butyl 3.4 2 2,2-dimethylpropyl 3.4 3 ¹ t-butyl 3.5 4 2,2-dimethylpropyl 3.5 5 cyclopentylmethyl 3.5 6 t-butyl 3.4 7 i-propyl '3,4 8 1-ethylpropyl 3.4 9 t-butyl 3.4 10 2,2-dimethylpropyl 3.4 11 1- (2-Methylpropyl) -3- -methylbutyl 3.4 12 1-methyl-2,2-dimethyl- propyl 3.4 13 phenyl 3.4 14 4-methoxyphenyl 3.4 15 Dec i-butyl 3.4 16 t-butyl 3.5 17 1-methyl-2,2-dimethyl- propyl 3.5 18 4-methoxyphenyl 3.5 19 Dec cyclopentylmethyl 3.5 20 May 2,2-dimethylpropyl 3.5 21 i-propyl 3.5 22nd n-propyl 3.4 23 i-propyl 3.4 24 heptyl 3.4 25 i-butyl 3.4 26 i-ethylpropyl 3.4 27 Mar: 1- (2-methylpropyl) -3- -methylbutyl 3.4 28 1-methyl-2,2-dimethyl- propyl 3.4 29 1-ethyl-2,2-dimethylpropyl 3.4 30 1,1-diethylpropyl 3.4 31 phenyl 3.4 32 4-methylphenyl 3.4 33, 4-methoxyphenyl 3.4 34 t-butyl 3.4 35 t-butyl 3.4 36 t-butyl 3.4 37 t-butyl 3.4 38 t-butyl 3.4 39 t-butyl 3.4 40 t-butyl 3.4 41 t-butyl 3.4 42 t-butyl 3.5

R ¹² R ¹¹ Melting point

ΓΟ

H benzyl 110 to 115 H benzyl 141 to 142 (hemihydrate) H benzyl oil ^<a) H benzyl ole] ^(b) H benzyl oil ^(c) H 4-fluorobenzyl 174 to 175. (hemihydrate) CH3 benzyl foam ^(d) CH3 benzyl 70 to 75 CH3 benzyl t 134 to 136 CH3 benzyl 105 to 111 CH3 benzyl 79 to 82 CH3 ¹ benzyl 109 to 110 CH3 benzyl 113 to 117 (• decomposition) CH3 benzyl 168 to 170 CH3 benzyl 80 to 85 - CH3 benzyl 173 to 175 CH3 benzyl 150 to 152 CH3 benzyl 140 to 145 CH3 benzyl 160 to 162 CH3 benzyl 124 to 127 CH3 benzyl 106 to 110 H benzyl 102 to 104 H benzyl 116 to 117 H benzyl oil ^(s) H benzyl 124 to 128 H benzyl 102 to 105 H benzyl 98 to 105 H benzyl 111 to 114 H benzyl oil ^(s) H benzyl foam ^(g) H benzyl oil ^(h) H benzyl foam ^(l) H benzyl oil ^(,) H 4-chlorophenyl 102 to 104 H 4-methoxyphenyl foam ^(k) H 4-methoxybenzyl 105 to 108 H 4-chlorobenzyl 156 to 158 H α-methylbenzyl 79 to 86 H phenoxymethyl 162 to 165 H 3-trifluoromethyl- phenoxymethyl 80 to 81 H phenyl 166 to 169 H 4-methoxybenzyl oil ^(I)

Legend:

^(a) NMR (δ values):

8.17 (1H, —NHCO—),

7.2—67 (8H, complex, aromatic protons),

5.0 (1H, broad singlet, —CHOH—),

3.4-2.6 (complex, —CH2—),

1.1 (18H, singlet, C-CH 3);

^(b) 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, - CH2CO-),

1.06 (18H, singlet, C - CH3);

^(c) NMR (δ values):

8.38 (1H, —NHCO—),

7.4- 6.75 (8H, complex, aromatic protons),

5.0 (1H, broad singlet, —CH.OH—),

3.9-2.7 (complex, —CH2—),

2.5 (4H, complex, —CH2CO—),

2.0-1.0 (—CH2 -, cyclopentyl ring);

^(d) NMR (δ values):

7.4- 7.1 (8H, complex, aromatic protons),

5.0 (1H, complex, CH.OH),

3.6-3.0 (6H, complex, CH 2 N and CH 2 CONH), \

3.0-2.6 (2H, complex, CHCO);

1.26, 1.20 [18H, two singlets, (CH 3) 2 CH and -NHC (CH 3) 2 -];

^(e) NMR (δ values):

9.0-8.5 (2H, broad signal, N ⁺ H2),

8.32 (1H, broad signal, NHCO),

7.5-7.1 (8H, singlet, aromatic protons), 5.0 (1H, doublet, CHOH), 3.6-2.8 (complex, CH2 NH and CH2 CONH),

2.5 [4H, multiplet, CH 3 (CH 2) 5 CH 2 CO],

1.8- 1.0 [20H, complex,

CH3 (CH2) 5CH2CO],

0.88 [6H, wide triplet,

CH3 _(CH2) 5CH2CO];

^<f > NMR (δ values):

9.0-8.5 (2H, broad signal, N ⁺ H2),

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, CH2 NH and CH2 CONH),

2.26 [2H, triplet (J = 7Hz), CH-CO], 1.65 [4H, triplet (I = 7Hz),

CHa — CH — CO],

1.04 [18H, singlet, (CH3) 3C),

0.9 (6H, triplet, CH 3 CH 2);

^(g) NMR (δ values):

8.9-8.5 (2H, complex, N + Hz),

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, (CH3CH2J5CCO),

1.1- 0.5 [18H, complex, (CH2CH2bC.CO);

^(h > NMR (δ values):

9.0-8.6 (2H, broad signal, N + Hz),

8.4 (1H, broad signal, NHCO),

8.1- 7.1 (18H, complex, aromatic protons),

5.1 (1H, doublet, CHOH);

3.6-2.9 (complex, CH 2 NH and CH 2 CONH);

⁽ⁱ⁾ NMR (δ values):

9.0-8.5 (2H, broad signal, N ⁺ H2),

8.38 (1H, broad signal, NHCO),

8.0-7.0 (16H, complex, aromatic protons),

5.06 (1H, doublet, CHOH),

3.6- 2.8 (8H, complex, CH 2 NH and CH 2 CONH),

2.34 (6H, singlet, 4-CH 3 -C 6 H 4);

^(j > NMR (δ 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-CH3O-CeH4),

3.7-2.9 (8H, complex, CH2 NH and CH2 CONH);

^k) NMR (deuterochloroform, δ values):

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-C 6 H 4),

3.8-2.9 (complex, CH2NH), 1.28 [18H, singlet, (CH3) 3C);

⁽¹⁾ NMR (deuterochloroform, δ-values):

9.1- 8.5 (2H, broad signal, N ⁺ Hz),

8.4 (1H, broad singlet, NHCO),

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

3.7 (3H, singlet, 4-CH3O-CeH4),

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

The necessary glyoxal derivatives of formula (IV) may be prepared in an analogous manner to Example 1, by oxidation of the corresponding 2-bromo-3 ', 4' - (or 3 ', 5' -) - bis (acyloxy) acetolenone of formula (IX) with dimethylsulfoxide. The 2-bromoacetophenone derivatives of formula IX can be obtained by acylation of 3 ', 4'- or 3', 5'-dihydroxyacetophenone with the appropriate acyl chloride of formula

RtCO.C1 followed by side chain bromination (analogous to Example 1j or by transacylation from 2-bromo-3 ', 4'- (or 3', 5 '-) - bis (acetoxy) acetophenone (analogous to Example 4J). Most derivatives of formula IX are oily or low-melting solids which are not characterized, but the following characteristics have been found for the following derivatives:

2-bromo-3 ‘, 5‘-bis (cyclopentylacetoxy] acetophenone, oily substance;

NMR (deuterochloroform, values <$):

7,8-r-7,1 (3H, complex, aromatic protons),

4.45 (2H, singlet, -COCHaBr), 2.58 (4H, singlet, CH-CH2-CO),

2.4-2.1 (18H, complex, cyclopentyl ring protons];

2-bromo-3 ‘, 5‘-bis (pivaloyloxy) acetophenone, m.p. 112-114 ° C;

2-bromo-3 ‘, 5‘-bis (3,3-dimethylbutyryloxy) acetophenone, m.p. 37-39 ° C;

2-bromo-3 ‘, 4‘-bis (3,3-dimethylbutyryloxy) acetophenone, oily substance;

NMR (CDCl3): 8.0-7.1 (3H, complex, aromatic protons),

4.42 (2H, singlet, --COCH2 Br),

2.46 (4H, singlet, -C —CH 2 -),

1.15 (18H, singlet, --C - CH3).

The desired starting amines of formula (V) may be obtained by reacting 1,1-dimethylethylenediamine or ethylenediamine with one mole equivalent of the appropriate acid bromide or acid chloride using a procedure analogous to that described in Example 1.

Example 9

The following esters of formula XIII can be prepared in an analogous manner to Example 7:

-ly rIcO.O _of ÍHCH-NHC (CH _{3) from} CHJVH. WHAT. R

Compound No. R ¹ (XIII)

R ¹¹ Melting point (° C) t-butyl isohutyl t-butyl isohutyl

Necessary glyoxal. the derivatives of formula (IV) can be prepared in situ by oxidation of the corresponding 2-bromoacetophenones of formula (IX) with dimethylsulfoxide, analogous to Example 1, and are used without isolation only after characterization by IR spectroscopy.

The desired 2-bromoacetophenone derivatives can be prepared by acylating 2-bromo-3 3, 4‘-dihydroxy-2‘-chloroacetophenone with pivaloyl chloride or isovaleryl chloride. The 2-bromo-3‘, 4‘-dihydroxy-2‘-chloroacetophenone can be obtained by reacting the corresponding 3 lze, 4 reak-dibenzyloxy derivative with hydrogen bromide in acetic acid.

benzyl 139-142 benzyl 128-131 phenoxymethyl 163-164 phenoxymethyl 176-179

The latter dibenzyloxy derivative can be prepared as follows:

An ethereal diazomethane solution was directly distilled into a mixture of 25.0 g of 3,4-bis (benzyloxy) -2-chlorobenzyl chloride and 200 ml of ether, maintained at -25 ° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 4 hours. Saturated ethereal hydrogen bromide solution (ca 15 ml) was then carefully added to the resulting mixture until nitrogen evolution ceased. After the addition of 125 g of silica gel for chromatography, the mixture was evaporated and the residue was dried. ....

a column of 900 g of silica gel for chromatography, previously deactivated with 1 part by weight of water per 10 parts by weight of silica gel and then equilibrated with a mixture of ethyl acetate and toluene (1:19 by volume) in a ratio of 1 part by volume of this mixture to 10 parts by weight of silica gel. The column was fractionally eluted first with 1.1 liters of the above solvent mixture and then with 1.5 liters of ethyl acetate. Evaporation of the appropriate ethyl acetate fractions (monitored by TLC) afforded 28.1 g of 2-bromo-3 ', 4'-bls (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. % ether at a rate such that 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 [deg.] C. 2-Chloro-3,4-bis (benzyloxy) benzoic acid is obtained in 80% yield as a solid, m.p. 159-162 ° C by oxidation of 2-chloro-3,4-bis (benzyloxy) benzaldehyde (which is itself 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).

Claims (9)

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 symbols is a radical of the formula Rh 10 O, where 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 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 -co (!!!) 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; is a carbonyl derivative of the general formula IV in which: R ¹ , R ² , R ³ , A and Z are as defined above, condenses under reducing conditions with an amine of formula V, R ⁶ H ₂ n —C — CH2 — NHQ, R ⁷ (V) wherein R®, R ⁷ and Q are as defined above, whereupon the optionally obtained free base ester of formula (I) is converted by reaction with an acid giving 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 cycloalkylalkyloy group having 3 to 6 carbon atoms in the C 3 -C 6 alkyl group and 1 to 5 carbon atoms in the alkyl portion, one of R ² and R ³ being a hydrogen atom and the other R ¹ CO ² O-, 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 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 or a C 1 -C 3 alkoxy group, and pharmaceutically acceptable salts thereof; that carbonylderivatives of the formula IV wherein R ^1, R ^2, R ^3, a and Z have the · point defined, is condensed under reducing conditions with an amine of the formula V wherein R ^6, R ⁷ and Q are as defined herein, whereupon 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. 3. The process of claim 1 wherein the reducing conditions are formed with an alkali metal borohydride and the reaction is carried out in an inert diluent or solvent at a temperature of from -20 ^° C to 30 ° C. 4. The process of claim 2 wherein the reducing conditions are formed with an alkali metal borohydride and the reaction is carried out in an inert diluent or solvent at a temperature of from -20 ° C to 30 ° C. 5. The process of claim 1 wherein the reducing conditions are formed with an alkali metal cyanoborohydride and the reaction is carried out in an inert diluent or solvent at a temperature of from -20 ° C to 30 ° C. 6. The process of claim 5 wherein the reaction is carried out in the presence of acetic acid. 7. A process according to claim 1 or 3, wherein the starting materials of the above formulas IV and V 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, phenoxyacetyl or benzoyl group and the remaining general symbols are as in point 1. 8. A process according to claim 2 or 3, wherein the starting materials of formulas IV and V are used in which: R ¹ is an isopropyl, tert-butyl, isobutyl or (cyclopentyl) methyl group, R ³ is hydrogen, ₍ R @ ⁷ and R @ ^{7 each} represent either hydrogen atoms or methyl groups, A means a direct bond, Q represents a phenylacetyl or phenoxyacetyl group and the remaining general symbols are as defined in 2. 9. A process according to claim 5 or 6, wherein the starting materials of the above formulas IV and V are used in which: R ¹ is 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 phenylacetyl, phenoxylation. and the remaining general symbols have the meanings given in 1.