CS207696B2 - Method of making the substituted propanolamine and morpholine derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of substituted propanolamine and morpholine derivatives of formula (I) * in which n and n, respectively, denote 1, 2 or 3, * RaKj, which may be the same or different, is individually hydrogen, halo a gene, a haloalkyl group having 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group C 1 -C 6 alkyl, C 1 -C 6 alkyl optionally substituted at least one hydroxy group, an alkoxy group having 1 to 6 carbon atoms, a group -N. or -CO-N (T, in which R 1 and R 8 are each hydrogen or alkyl) "(C 1 -C 6) alkyl group, aryl (C 1 -C 8) alkyl group optionally substituted at least one hydroxy group, an alkoxy group having from 1 to 6 carbon atoms, a group -Νζ «

Description

(54) A method for producing substituted propanolamine and morpholine derivatives

The invention relates to a process for the preparation of substituted propanolamine and morpholine derivatives of the general formula I

in which n and n, respectively, denote the number 1, 2 or 3,

R a R c, which may be the same or different, each represent a hydrogen atom, a halogen atom, a haloalkyl group having 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms optionally substituted by at least one hydroxy, (C1-C6) alkoxy;

-N. or -CO-N (T) in which R 1 and R 8 are each hydrogen or C 1 -C 6 alkyl, aryl (C 1 -C 6) alkyl optionally substituted by at least one hydroxy, C 1 -C 6 alkoxy alkoxy, -Νζ «6 / ^R 5 or -CO-N-in which Rg and K₂ are as defined above, aryl (C | -Cg) alkoxy% group optionally substituted by at least one hydroxy, C 1 -C C6 alkyl, -N [or -CO-N, wherein Rg and Rg are as defined above ^R 5 known nitro formula -N wherein Rg and Rg are as defined above, ^Xr or two adjacent R groups 6, or two adjacent R 1 groups, taken together, are -O-CH 3 -O-,

R ₂ is hydrogen, alkyl having 1 to 12 carbon atoms optionally substituted by halogen, hydroxy, C 1-6 alkoxy, / ^r ^ 5 / - ^R 5

Or -CO-N-N in which Rg and Rg are as defined above, or aryl (C, -Cg) alkyl ^Xr ^ 6 ^R 6 group, or a

R g and R p, which may be the same or different, each represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, optionally substituted by a halogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, a group

X- ^R 5

-N or ^ 6

in which

R8 and R8 are as defined above, C2 -C4 alkenyl, C2 -C4 alkynyl, aryl (C1 -C6 alkyl optionally substituted in aryl with at least one C1 -C6 alkyl, halogen atom) , (C1-C6) -haloalkyl, hydroxy, C1-C6alkoxy or C1-C6alkoxy;

^-NR 5, wherein R 8 and R 8 are as hereinbefore defined, C 3 -C 7 cycloalkyl optionally substituted with at least one C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, hydroxy, alkoxy having 1 to 6 atoms

X ^R5 atoms or -N * 6 wherein Rg and Rg are as defined above, or both the proviso that both R and Rg together with the nitrogen atom to which they are bonded form a five or six membered, saturated or unsaturated heteromonocyclic radical optionally contains additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted with C1-6 alkyl or aryl, or

R 1 and R 4 together form a radical of formula -CHg-CHg-.

The invention also encompasses pharmaceutically acceptable salts of the compounds of Formula I, as well as all possible isomers and mixtures thereof, and metabolites thereof, provided they have pharmacological, e.g., antidepressant, and metabolic precursors of the compounds of Formula I.

2-phenoxymethylmorpholines and propanolamines and methods for their preparation are discussed in numerous patents, for example, US Pat. Nos. 3, 7,4, 61 and 3,712,890 and French Pat. However, said compounds do not have a phenyl substituent on the methyl radical, which in turn is characteristic of the compounds produced by the process of the invention.

In the compounds of the above formula (1) produced by the process of the invention, the alkyl, alkenyl, alkynyl and alkoxy groups may have straight or branched carbon chains.

In the event that one or more of R and R represents a substituted alkyl group to 6 carbon atoms, it is preferably an alkyl group substituted by a hydroxy group, R ₅ R ₅ alkoxy having 1-6 carbon atoms or radicals of the formulas -CON or -N-.

R ₆ r ₆ wherein R 1 and R 8 are as defined above.

The aryl group is preferably a phenyl group.

When one or more of R 1 and R 2 represents a substituted alkyl group having 1 to 6 carbon atoms, it is preferably an alkyl group substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy

X ^R 5 / ^R 5 groups st to 6 carbon atoms or a group of formula -N -CON in which R and R G «6 ^R 6 are as defined above. The above-mentioned alkyl group having 1 to 12 carbon atoms can also be substituted.

Substituted aryl (C 1 -C 6) alkyl, arylC 1 -C 6 alkyl and aryl (C 1 -C 6) alkoxy groups are preferably those whose aryl radical is substituted by one or more C 1 -C 6 alkyl groups, halogen atoms , C1-C6-haloalkyl, hydroxy, C1-C6-alkoxy or / ^{R5 of the} formula -N, in which Rg is as defined above.

^X R6

Substituted C 3 -C 7 cycloalkyl groups are those cycloalkyl groups which are substituted by one or more substituents selected preferably from the group consisting of C 1 -C 6 alkyl, halogen, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkoxy

Λ carbon and a group of the formula -N wherein R R and Rg are as defined above.

^r 6

A (C 1 -C 6) alkyl group is preferably a methyl, ethyl or isopropyl group.

C1-C12alkyl is preferably methyl, ethyl, isopropyl or octyl.

The C 2 -C 4 alkenyl group is preferably a vinyl or allyl group.

An alkynyl group having up to 4 carbon atoms is preferably a propargyl group.

A halogenated alkyl group having 1 to 6 carbon atoms is preferably a trihalogenated alkyl group having 1 to 6 carbon atoms, in particular a trifluoromethyl group.

C 1 -C 6 alkoxy is preferably methoxy or ethoxy.

Aryl (C 1 -C 8) alkyl or aryl (C 1 -C 4) alkyl is preferably benzyl or phenethyl.

Aryl (C 1 -C 8) alkoxy is preferably benzyloxy.

207596

In the group of formula -N. R 6 and R 8 are each independently hydrogen or C 1 -C 3 alkyl, in particular methyl, ethyl or isopropyl.

The C 3 -C 7 cycloalkyl group is preferably a cyclopropyl, cyclopentyl or cyclohexyl group.

When R 1 and R 4 together with the nitrogen atom to which they are attached form a substituted heteromonocyclic radical, preferred substituents are C 1 -C 6 alkyl or aryl, and methyl or phenyl are particularly preferred; a preferred heteromonocyclic radical is a morpholine, piperidine, N-pyrrolidinyl, N-methylpiperazinyl or N-phenylpiperazinyl radical.

When two adjacent R groups or two adjacent R 1 groups form -O-CH ₂ -O-, it is preferably 3,4-methylenedioxy. ¹

Because of the presence of at least two asymmetric carbon atoms in the compounds of Formula I, each compound may exist in the form of at least two different diastereoisomers from which at least four different enantiomers may be obtained; both individual diastereoisomers and mixtures thereof, as well as said individual enantiomers, are included within the scope of the invention.

Pharmaceutically acceptable salts of the compounds of formula I include both salts with inorganic acids such as hydrochloric, hydrobromic or sulfuric acid and salts with organic acids such as citric acid, tartaric acid, methanesulfonic acid, fumaric acid, malic acid, maleic acid or mandelic acid.

According to the invention the preferred salts are those salts of the compounds of formula I, who / ^r 3 REM group of formula -N forms a salt with one of the aforementioned acids, preferably ^Xr 4 with hydrochloric acid.

Preferred compounds of the invention are those compounds of formula I wherein n, n, independently or independently of each other is the number 1 or 2, each of R and R, independently of one another, is hydrogen, methoxy, ethoxy, chloro, or trifluoromethyl. or two adjacent R groups are -O-CH ₂ -O-, R ₂ is hydrogen or methyl, and one of R 3 and R 4 is hydrogen and the other is methyl, and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of the invention are those compounds of formula (I) wherein n, n, independently, is 1 or 2, each R and R, independently, is hydrogen, methoxy, ethoxy, chloro, or the like. trifluoromethyl, or two adjacent R groups form the radical -O-CH ₂ -O-, R ₂ and R 4 together form the radical -CH ₂ -CH ₂ - and R 1 represents a hydrogen atom, a methyl group or an isopropyl group, as well as their pharmaceutically acceptable salts.

The essence of the preparation of the compounds of the formula I by the process according to the invention is that the compound of the formula III is reduced

wherein n, n ,, R, R ,, R _2, R and R are as defined above, and the obtained compound of formula I is optionally converted into another compound of formula I, and / or optionally a compound of formula I is converted to a salt, or to prepare a free compound of formula I from a salt thereof, and / or to separate the optionally obtained mixture of isomers of formula I into the individual isomers.

_{with the} reduction of the compound of formula (III) can generally be carried out by methods conventionally used to reduce nitriles and amides, for example by treatment with lithium aluminum hydride or borane in an anhydrous inert solvent, preferably an aliphatic ether such as diethyl ether or tetrahydrofuran; at a temperature in the range of from about 0 ° C to the boiling point of the solvent used, or by treatment with an alkali metal borohydride such as sodium borohydride in the presence of an alkali metal as described, for example, in Tetr. Lett. 1969, page 4,555.

When, in the compounds of the above formula (III), one or more substituents R 1, E 1, R 8 and R 4 represent reducible groups, and if we wish to keep these groups unchanged in the final compounds of formula 1, use of selective reducing conditions.

For example, the reduction of compounds of the formula III containing halogen or nitro groups in the molecule can be carried out selectively with respect to these groups by using borane in tetrahydrofuran or an aliphatic ether such as diethyl ether under nitrogen, as described, for example, in J. Am. Chem. Soc. 86, 3566 (1964), or that the reduction is performed with zinc in ethanol, as described in Experientia 33 (1), 101-102 (1977).

The reduction of compounds of formula III in which R1 and R4 are C2 -C4 alkenyl or C2 -C4 alkynyl can be performed selectively with respect to these groups using, for example, lithium aluminum hydride as the reducing agent, reaction conditions described above. However, under these conditions, nitro and halogen atoms are also reduced, if present in the substance molecule, and therefore, compounds of formula X in which one; or more R @ 1 and R @ 2 are nitro or halogen and R @ 1 is C2 -C4 alkenyl or C2 -C4 alkynyl. Said compounds can be prepared by converting a suitable compound of formula I to the desired other compound of formula I.

*

Both the eventual conversion of a compound of formula I into another compound of formula I, and optionally the preparation of salts or the preparation of free compounds of formula I from the corresponding salts, as well as the optional separation of a mixture of isomers into individual isomers, can be carried out by conventional methods.

Thus, for example, can be a compound of formula I wherein R is hydrogen and R4 has the above meanings, or together with R ₂ -CH ₂ -CH ₂ -, converted to the corresponding compound of formula I in which R denotes C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, arylC 1 -C 6 alkyl or C 3 -C 7 cycloalkyl, by conventional methods of alkylation of amines, e.g. by reductive amination or by direct alkylation.

Reductive alkylation consists in reacting a compound of formula I wherein R 3 and / or R 4 is hydrogen with a suitable carbonyl compound, i.e., an aldehyde or a b-ketone, in the presence of a reducing agent which may be hydrogen gas or preferably mixed hydrides such as for example sodium cyanoborohydride or sodium borohydride, or formic acid under the conditions of the Leukart-Wallach reaction.

When hydrogen is used as the reducing agent, the reductive amination is preferably carried out in an alcoholic solvent such as methanol or ethanol in the presence of a catalyst such as Raney nickel or palladium on activated carbon at atmospheric pressure and at a temperature ranging from room temperature. up to about 50 ° C, as described, for example, in Org. Reactions 4, 174 (1948). When a mixed hydride such as sodium cyanoborohydride or sodium borohydride is used as the reducing agent, the reductive amination can be carried out in the presence of excess hydride, preferably at room temperature, using the procedure described in Tetr. Lett. J, 261 (1963); J. Org. Chem. 37, 1673 (1972) or Synthesis J, 140 (1975). When reductive amination is carried out using formic acid under the conditions of the Leukert-Wallac reaction, formic acid is preferably used in excess and the reaction mixture is heated for two to twelve hours as described in Org. Reactions 5: 301 (1949).

The alkylation can further be carried out by reacting a primary amine of the formula I with, for example, a suitable alkyl or aralkyl halide, or a reactive ester, for example, tosylate or mesylate, of a suitable alcohol. The alkylation can be carried out either without a solvent or in a suitable solvent, such as water, an aliphatic alcohol, for example ethyl or methyl alcohol, a glycol, for example ethylene or propylene glycol, benzene or dimethylformamide, or mixtures of said solvents, in the presence of an acid acceptor such as triethylamine, an alkali metal carbonate or bicarbonate, or an excess of the starting amine, at a temperature in the range of about 60 ° C to the boiling point of the solvent used, as described, for example, in J. Org. Chem. 2, 139 (1938); Org. Synth., Vol. II, p. 183 (1943), J. Am. Chem. Soc. 54, 4,457 (1932).

Alternatively, the monoalkylation may be carried out, for example, by the methods described in J.

Org. Chem. 40, 23, 3,453 (1975), J. Chem. Soc. 2,223 (1969), J. Med. Chem. U (1), 654 (1974).

A compound of formula I wherein one of R3 and R4 is hydrogen may be converted to the corresponding compound of formula I wherein one of R1 and R4 is methyl, preferably also by reacting the starting amino compound with ethyl chloroformate in chloroform, in the presence of excess potassium hydroxide, at a temperature ranging from 0 to 5 ° C, and the obtained carbamic acid ester is reduced with excess lithium aluminum hydride or borane in diethyl ether at the boiling point of the reaction mixture.

Compounds of formula I wherein one of R 3 and R 4 is C 1 -C 6 alkyl and the other is hydrogen may alternatively be prepared by the following procedure: a ') a compound of formula I wherein R 3 and R 4 are both hydrogen atoms, are reacted with benzaldehyde in a suitable solvent such as benzene or toluene at the boiling point of the reaction mixture; b ') the Schiff base obtained is reduced, for example by catalytic hydrogenation in an alcoholic solvent medium and in the presence of Raney nickel or palladium on activated carbon, or by mixed hydrides, for example lithium aluminum hydride or sodium borohydride, as described, for example, in Houben-Weyl Vol. XI, Part 1, p. 341 (1957); c ') the benzylamine obtained is alkylated with a suitable alkyl halide using the alkylation procedures described above; and d) the benzyl group is removed from the alkylated benzylamine obtained, for example by catalytic hydrogenation, as described in J. Am. Chem. Soc. 63, 1964 (1941), or preferably, by treatment with ethyl chloroformate at the boiling point of the reaction mixture, as described in J. Med. Chem. 18 (6), 576 (1975). Analogously, a compound of formula I wherein one of R 1 and R 4 is benzyl can be converted to a corresponding compound of formula I wherein one of R 1 and R 4 is hydrogen.

A compound of formula I wherein both R 1 and R 4 are hydrogen may be converted to the corresponding compound of formula I wherein one of R 1 and R 2 is hydrogen and the other is benzyl, also by reaction with benzyl chloride in the presence of aqueous sodium hydroxide, in an organic solvent such as dichloromethane, preferably at a temperature ranging from 0 ° C to room temperature, and the obtained benzoylamino derivative is reduced with a mixed hydride such as lithium aluminum hydride or borane in tetrahydrofuran or diethyl ether, at the boiling point of the reaction mixture.

Compounds of formula (I) in which R8 is hydrogen may be converted to compounds of formula (I) in which R8 is C1 -C12 alkyl or aryl (C1 -C6) alkyl, by methods commonly used to etherify alcohols. for example, by reacting an alkali metal salt of an alcohol, such as a lithium or sodium salt, with an appropriate alkyl or aralkyl halide. Said reaction may be carried out at a temperature ranging from room temperature to the boiling point of the reaction mixture, in an organic solvent medium, which may be, for example, the same solvent in which the alkali metal salt is prepared.

The lithium salt of the alcohol may be obtained by reacting the corresponding alcohol with an alkyl lithium such as butyl lithium in an inert anhydrous solvent such as tetrahydrofuran. Sodium (III) may be prepared by reacting the corresponding alcohol with sodium metal or sodium hydride in an inert solvent such as benzene, toluene or dimethylformamide. Analogously, compounds of formula I in which one of R and R represents a hydroxyl group can be converted to the corresponding compounds of formula I in which one of R and R represents an alkoxy group having 1 to 6 carbon atoms or aryl (C , -Cg) alkoxy.

Compounds of formula I wherein R 2 is C 1 -C 6 alkoxy or aryl (C 1 -C 6) alkoxy can be converted to the corresponding compounds of formula I wherein R ₂ is hydroxyl by conventional methods of de-etherification. For example, a compound of formula I in which Rg is methoxy may be de-etherified by treatment with pyridine hydrochloride or boron tribromide, or by treatment with potassium ethanethiolate in dimethylformamide at 100 to 130 ° C, as described, for example, in J. Med. Chem. 20 (1), 165 (1977). When the de-etherification is carried out with pyridine hydrochloride, it is preferably carried out under a nitrogen atmosphere at a temperature of about 150 ° C. Deéterifikace using boron ^tribromide) is preferably carried out so that a solution of a compound of formula I, cooled to -70 to -80 ° C under nitrogen was added a solution of boron tribromide in chloroform and quenched by dropwise addition of methanol at 0 ° C.

Compounds of formula I in which both R 1 and R 4 are methyl can be converted to the corresponding compounds of formula I wherein one of R 1 and R 4 is methyl and the other is hydrogen, e.g. The reaction mixture is treated with ethyl chloroformate in benzene or toluene at the boiling point of the solvent used, and the product obtained is decomposed by treatment with an alcoholic potassium hydroxide solution at the boiling point of the reaction mixture.

Compounds of formula I in which one of R and R is nitro may be converted to the corresponding compounds of formula I in which one of R and Rj is amino, by methods commonly used to reduce aromatic nitro compounds, for example by catalytic hydrogenation, with using, for example, platinum, palladium or Raney nickel as a catalyst, by known organic chemistry techniques.

Compounds of formula (1) in which one of the substituents R and R, which represents an amino group, can be converted to the corresponding amino acids can be of a compound of formula 1 wherein one of R and R is a hydroxyl group by converting the amine to the corresponding diazonium salt and then hydrolyzing it, for example, as described in Org.

Synth. 2J, 11 (1943), or in J. Org. Chem. 42, 2053 (1977).

Compounds of formula (I) in which one of R and R is an amino group may be converted to the corresponding compounds of formula (1) in which one of R and R 1 is substituted by an amino group. represents a mono- or dialkylamino group having 1 to 6 carbon atoms, by reductive amination or alkylation as described above.

As mentioned above, you can. also converting the compounds of formula I to a salt, as well as preparing the free compound from its salt and separating the isomers from their mixture by conventional methods. ₍

For example, a hydrochloric acid salt of a compound of formula (I) may be prepared by treating a solution of the compound in a suitable anhydrous solvent such as diethyl ether, benzene or ethyl alcohol with anhydrous hydrogen chloride gas or an anhydrous alcoholic solution of hydrochloric acid and isolating the hydrochloride formed by filtering or evaporating the solvent.

A mixture of isomers, for example a mixture of diastereoisomers, can be separated into the individual isomers, for example, by fractional crystallization from a suitable solvent or by chromatography.

Chromatographic separation of the mixture of isomers may be carried out both by preparative thin layer chromatography and by column chromatography using silica gel or magnesium silicate as the carrier and, for example, benzene, ethyl acetate, cyclohexane, chloroform, methylene chloride, ethyl ether or mixtures thereof as eluents, or may be separated by high pressure. liquid chromatography.

The possible conversion of the compounds of the formula I to other compounds of the formula I as described above, as well as the separation of the isomers, for example the diastereoisomers, from their mixture can also be carried out, if necessary, already at the starting materials or the corresponding intermediates.

Compounds of formula III in which R8, R8 and R8 are as defined above except that R8 and R8 do not together form a -CHg-CHg- group can be prepared by conventional methods of amide preparation, for example by reaction of an amine of the formula HNR3R4 in which R1 and R4 are as defined above, with an acid of formula XII

in which R, R, n, n ₁ and R 8 are as defined above, or with a reactive derivative thereof, for example with an acid halide, or with an alkyl ester of 1 to 6 carbon atoms, preferably 3 ethyl ester of the acid. The reaction may be carried out either in the absence of a solvent, or in a suitable solvent such as a C 1 -C 6 aliphatic alcohol such as ethanol, optionally in the presence of a condensing agent such as dicyclohexylcarbodiimide, or in the presence of an acid acceptor such as an alkali metal carbonate or bicarbonate; a tertiary amine, such as triethylamine, or an excess of the starting amine of formula HNR 3 R 4.

Compounds of formula III in which R ₂ and R 4 together form a -CH 2 -CH 2 - group can be prepared, for example, by cyclization of a compound of formula XIII

< ^R l'n.

jy-r, (XIII) in which R, R ₁ , n, n, and R 1 are as defined above and X represents a hydroxyl group or a halogen atom, or preferably a residue of a reactive alcohol ester, for example tosyloxy or mesyloxy, using reaction conditions as described above, preferably when X is a halogen atom or a reactive alcohol ester residue, in the presence of at least an equimolar amount of a base selected preferably from the group consisting of alkali metal carbonates and bicarbonates, e.g. potassium carbonate, in a suitable solvent such as dimethylformamide, dimethylsulfoxide; similar.

Alternatively, compounds of formula III wherein R ₂ and R 2 together form -CH ₂ -CH ₂ - may also be prepared by reacting a compound of formula XIV

wherein R, R 1, n, and R 3 are as defined above, heated in a suitable solvent, for example hexamethylphosphoric triamide, to a temperature in the range of 120 to 160 ° C, as described, for example, in Can. J. Chem. 49, 914 (1971).

The compounds of the formula I according to the invention have central nervous system activity and are important antidepressant active substances.

Antidepressant efficacy of the compounds was tested in mice by monitoring the effect of eyelid contractions and reserpine-induced hypothermia.

Reserpine was administered endoperitoneally at a dose of 2.4 mg / kg and test compounds of Formula I were administered orally 30 minutes prior to administration of reserpine. Eyelid contractions were recorded at one hour or four hours after the administration of reserpine (the number of contractions was evaluated using the technique described by B. Rubin and co-workers in J. Pharmacol.

120, 125 (1957)) and measured body temperature (using a rectal thermoelectric cell).

The following table shows the antidepressant activity of the two compounds produced by the method of the invention compared to antitriptyline as a known antidepressant drug. Antidepressant efficacy was evaluated by preventing reserpine-induced blepharospasm and hypothermia.

207696 10

Antireserpine Effect on Mice (SCF / 4 Assays) ED? Q mg / kg / os

Compound Blepharospasm Hypothermia N-methyl-2-hydroxy-3- (2-methoxyphenoxy) -3-phenylpropylamine hydrochloride 10.94 3.68 2- (alpha / 2-methoxyphenoxy) benzyl) morpholine hydrochloride 0.53 0.48 amitriptyline 10.95 19.68

The compounds of formula (X) have been administered primarily orally, although they can also be administered by other conventional routes, for example by injection or rectal administration.

For oral administration to adult humans, a suitable dose of a compound of Formula 1 is preferably 5 to 30 mg for a dose of 2 to 4 times daily.

Pharmaceutical compositions containing the compounds of formula I as active ingredient can be prepared by conventional methods using conventional excipients.

For example, for oral administration, pharmaceutical compositions containing the compounds of formula (I) may be prepared preferably in the form of tablets, pills or capsules containing the active ingredient together with suitable excipients such as diluents, for example lactose, glucose, sucrose, mannitol, sorbitol or the like. cellulose; glidants such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; binding agents, for example starches, gelatin, methylcellulose, acacia, tragacanth or polyvinylpyrrolidone; leavening agents such as starches, alginic acid or alginates; effervescent mixtures; dyes; sweeteners; wetting agents such as lecithin, polysorbates or lauryl sulfates; and generally non-toxic and pharmacologically inactive substances used in the manufacture of pharmaceutical preparations. Said pharmaceutical preparations may be prepared by methods known per se, for example by mixing, granulating, tabletting and coating with a sugar layer or a film of another suitable substance.

Other pharmaceutical preparations containing as active ingredient a compound of the formula I, for example syrups or drops for oral administration, sterile injectable solutions or suppositories, can be prepared by known methods.

The following abbreviations are used in the following examples: THF = tetrahydrofuran, D1IF = dimethylformamide, DMA = dimethylacetamide, MCPBA = m-chloroperbenzoic acid, and diglyme = diethylene glycol dimethyl ether.

Melting points, which are given in a wide range, usually refer to mixtures of diastereoisomers.

The process according to the invention is illustrated in more detail by the following non-limiting examples.

Example 1

To a solution of 2-hydroxy-3- (3,4-methylenedioxyphenoxy) -3-phenylpropylamine (2.87 g) in chloroform (28 mL) was added 2 N sodium hydroxide solution (8.3 mL) with vigorous stirring. The mixture was cooled to 0 ° C and a solution of ethyl chloroformate (1.58 mL) in chloroform (2 mL) was added dropwise over about 30 minutes. The reaction mixture was stirred for an additional 15 minutes, then the organic layer was separated and the aqueous portion was shaken with chloroform. The combined organics were washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. There was thus obtained N-ethoxycarbonyl-2-hydroxy-3- (3,4-methylenedioxyphenoxy) -3-phenylpropylamine as an oil; yield 94.8%.

The crude oily product was dissolved in anhydrous diethyl ether (100 mL) and the solution was added dropwise with stirring to a suspension of lithium aluminum hydride (1.02 g) in anhydrous diethyl ether (25 mL). The reaction mixture was stirred at room temperature for 20 hours, then cooled, excess hydride was carefully quenched with water (1 mL) and 20% sodium hydroxide solution (0.75 mL) and water (3 mL) were added. The insoluble material is filtered off, washed with diethyl ether, the combined filtrates are dried over anhydrous sodium sulfate and the ether is distilled off. 2.35 g (85% yield) of N-methyl-2-hydroxy-3- (3,4-methylenedioxyphenoxy) -3-phenylpropylamine are obtained, m.p. 100-122 ° C.

The following compounds were prepared in an analogous manner:

N-methyl-2-hydroxy-3-phenoxy-3-phenylpropylamine;

N-methyl-2-hydroxy-3- (2-methoxyphenoxy) -3-phenylpropylamine hydrochloride, m.p. 94-112 ° C;

N-methyl-2-hydroxy-3- (3-methoxyphenoxy) -3-phenylpropylamine;

N-methyl-2-hydroxy-3- (4-methoxyphenoxy) -3-phenylpropylamine;

N-methyl-2-hydroxy-3- (2-ethoxyphenoxy) -3-phenylpropylamine hydrochloride, m.p. 125-145 ° C; N-methyl-2-hydroxy-3- (4-ethoxyphenoxy) -3-phenylpropylamine;

N-methyl-2-hydroxy-3- (2-chlorophenoxy) -3-phenylpropylamine hydrochloride, m.p. 129-147 ° C; N-methyl-2-hydroxy-3- (4-chlorophenoxy) -3-phenylpropylamine;

N-methyl-2-hydroxy-3- (4-trifluoromethylphenoxy) -3-phenylpropylamine;

N-methyl-2-hydroxy-3-phenoxy-3- (2-methoxyphenyl) propylamine;

N-methyl-2-hydroxy-3- (2-methoxyphenoxy) -3- (2-methoxyphenyl) propylamine;

N-methyl-2-hydroxy-3- (2-ethoxyphenoxy) -3- (2-methoxyphenyl) propylamine;

N-methyl-2-hydroxy-3-phenoxy-3- (4-ethoxyphenyl) propylamine;

N-methyl-2-hydroxy-3- (2-methoxyphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-hydroxy-3- (4-methoxyphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-hydroxy-3- (2-ethoxyphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-hydroxy-3- (4-ethoxyphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-hydroxy-3- (2-trifluoromethylphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-hydroxy-3- (4-trifluoromethylphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-hydroxy-3-phenoxy-3- (2-chlorophenyl) propylamine;

N-methyl-2-hydroxy-3- (2-methoxyphenoxy) -3- (2-chlorophenyl) propylamine;

N-methyl-2-hydroxy-3- (2-methoxyphenoxy) -3- (2-chlorophenyl) propylamine;

N-methyl-2-hydroxy-3-phenoxy-3- (3-chlorophenyl) propylamine;

N-methyl-2-hydroxy-3- (2-methoxyphenoxy) -3- (3-chlorophenyl) propylamine hydrochloride, m.p. 126-145 ° C;

N-methyl-2-hydroxy-3- (2-ethoxyphenoxy) -3- (3-chlorophenyl) propylamine hydrochloride, m.p. 190-127 ° C;

N-methyl-2-hydroxy-3-phenoxy-3- (4-chlorophenyl) propylamine;

N-methyl-2-hydroxy-3- (2-methoxyphenoxy) -3- (4-chlorophenyl) propylamine;

N-methyl-2-hydroxy-3- (2-ethoxyphenoxy) -3- (4-chlorophenyl) propylamine;

N-methyl-2-hydroxy-3-phenoxy-3- (4-trifluoromethylphenyl) propylamine;

N-methyl-2-hydroxy-3- (2-methoxyphenoxy) -3- (4-trifluoromethylphenyl) propylamine;

N-methyl-2-hydroxy-3- (4-methoxyphenoxy) -3- (4-trifluoromethylphenyl) propylamine;

N-methyl-2-hydroxy-3- (2-ethoxyphenoxy-3- (4-trifluoromethylphenyl) propylamine);

N-methyl-2-hydroxy-3- (4-ethoxyphenoxy) -3- (4-trifluoromethylphenyl) propylamine;

N-methyl-2-hydroxy-3-phenoxy-3- (3,4-dichlorophenyl) propylamine;

N-methyl-2-hydroxy-3- (2-methoxyphenoxy) -3- (3,4-dichlorophenyl) propylamine;

N-methyl-2-hydroxy-3- (2-ethoxyphenoxy) -3- (3,4-dichlorophenyl) propylamine.

Example 2

To a solution of N-ethoxycarbonyl-2-hydroxy-3- (3,4-methylenedioxyphenoxy) -3-phenylpropylamine (3.59 g) in anhydrous dimethylformamide (30 mL) was added methyl iodide (6.23 mL) with stirring and cooling. 55% sodium hydride (4.36 g) was added to 0-5 ° C. The reaction mixture is stirred under cooling for 1 hour 30 minutes, then excess hydride is carefully quenched with water, excess water is added and the product is taken up in ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is purified by dissolving in methanol and filtering off the insoluble material. After distilling off the solvent from the filtrate, 3.1 g of N-methyl-N-ethoxycarbonyl-2-methoxy-3- (3,4-methylenedioxyphenoxy) -3-phenylpropylamine is obtained as an oil; yield 80.2%.

The resulting oily product was dissolved in 10% methanolic potassium hydroxide (44.8 mL) and the mixture was heated to reflux for 48 hours with stirring. The solvent was distilled off and n-propyl alcohol was added to the residue to the original volume. The solution was heated at reflux for 20 hours, then the solvent was distilled off, the residue was taken up in water and the product was taken up in diethyl ether. The ethereal solution is extracted with 3% hydrochloric acid, the acidic aqueous extracts are combined, basified with 20% sodium hydroxide and the product is taken up in diethyl ether. The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. 2.05 g of N-methyl-2-methoxy-3- (3,4-methylenedioxyphenoxy) -3-phenylpropylamine are obtained as an oil; yield 81.3%. The base hydrochloride had a melting point of 142-145 ° C.

The following compounds were prepared in an analogous manner:

N-methyl-2-methoxy-3-phenoxy-3-phenylpropylamine;

N-methyl-2-methoxy-3- (2-methoxyphenoxy) -3-phenylpropylamine hydrochloride, m.p. 115-120 ° C; N-methyl-2-methoxy-3- (3-methoxyphenoxy) -3-phenylpropylamine;

N-methyl-2-methoxy-3- (4-methoxyphenoxy) -3-phenylpropylamine;

N-methyl-2-methoxy-3- (2-ethoxyphenoxy) -3-phenylpropylamine hydrochloride, m.p. 123-137 ° C; N-methyl-2-methoxy-3- (4-ethoxyphenoxy) -3-phenylpropylamine;

N-methyl-2-methoxy-3- (2-chlorophenoxy) -3-phenylpropylamine hydrochloride, m.p. 138-155 ° C; N-methyl-2-methoxy-3- (4-chlorophenoxy) -3-phenylpropylamine;

N-methyl-2-methoxy-3- (4-trifluoromethylphenoxy) -3-phenylpropylamine;

N-methyl-2-methoxy-3-phenoxy-3- (2-methoxyphenyl) propylamine;

N-methyl-2-methoxy-3- (2-methoxyphenoxy) -3- (2-methoxyphenyl) propylamine;

N-methyl-2-methoxy-3- (2-ethoxyphenoxy) -3- (2-methoxyphenyl) propylamine;

N-methyl-2-methoxy-3-phenoxy-3- (4-methoxyphenyl) for pylamine;

N-methyl-2-methoxy-3- (2-methoxyphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-methoxy-3- (4-methoxyphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-methoxy-3- (2-ethoxyphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-methoxy-3- (4-ethoxyphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-methoxy-3- (2-trifluoromethylphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-methoxy-3- (4-trifluoromethylphenoxy) -3- (4-ethoxyphenyl) propylamine;

N-methyl-2-methoxy-3-phenoxy-3- (2-chlorophenyl) for pylamine;

N-methyl-2-methoxy-3- (2-methoxyphenoxy) -3- (2-chlorophenyl) propylamine;

N-methyl-2-methoxy-3- (2-ethoxyphenoxy) -3- (2-chlorophenyl) propylamine;

N-methyl-2-methoxy-3-phenoxy-3- (3-chlorophenyl) propylamine;

N-methyl-2-methoxy-3- (2-methoxyphenoxy) -3- (3-chlorophenyl) propylamine hydrochloride, m.p. 115-140 ° C;

N-methyl-2-methoxy-3- (2-ethoxyphenoxy) -3- (3-chlorophenyl) propylamine hydrochloride, m.p. 128-135 ° C;

N-methyl-2-methoxy-3-phenoxy-3- (4-chlorophenyl) propylamine;

N-methyl-2-methoxy-3- (2-methoxyphenoxy) -3- (4-chlorophenyl) propylamine;

N-methyl-2-methoxy-3- (2-methoxyphenoxy) -3- (4-chlorophenyl) propylamine;

N-methyl-2-methoxy-3-phenoxy-3- (4-trifluoromethylphenyl) propylamine;

N-methyl-2-methoxy-3- (2-methoxyphenoxy) -3- (4-trifluoromethylphenyl) propylamine; N-methyl-2-methoxy-3- (4-methoxyphenoxy) -3- (4-trifluoromethylphenyl) propylamine; N-methyl-2-methoxy-3- (2-ethoxyphenoxy) -3- (4-trifluoromethylphenyl) propylamine; N-methyl-2-methoxy-3- (4-ethoxyphenoxy) -3- (4-trifluoromethylphenyl) propylamine; N-methyl-2-methoxy-3-phenoxy-3- (3,4-dichlorophenyl) propylamine;

N-methyl-2-methoxy-3- (2-methoxyphenoxy) -3- (3,4-dichlorophenyl) propylamine;

N-methyl-2-methoxy-3- (2-ethoxyphenoxy) -3- (3,4-dichlorophenyl) propylamine.

Example 3

To a solution of 50.3 g of N-methyl-2-hydroxy-3-phenyl-3- (2-nitrophenoxy) propionamide in 1000 mL of anhydrous THF at 8 ° C was slowly added 340 mL of a molar solution of diborane in THF.

The mixture was heated at reflux for 4 hours, then cooled to room temperature, excess diborane was carefully decomposed by dropwise addition of methanol, and the mixture was acidified again at room temperature by addition of 400 ml of ethereal hydrogen chloride solution. The mixture was not allowed to stand for 16 hours, then the volatiles were distilled off under reduced pressure, the residue was taken up in methylene chloride and the solution was washed once with aqueous sodium bicarbonate solution. The organic portion was washed several times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. The dark oily residue was dissolved in 800 mL of ethyl ether and treated with an alcoholic solution of hydrogen chloride (18%); 50.9 g of N-methyl-2-hydroxy-3- (2-nitrophenoxy) -3-phenylpropylamine hydrochloride, m.p. 197-203 ° C; yield 94%.

Infrared Spectrum, ν _max (KBr): 1525 cm -1 (NO ₂ ), 2700 cm -1 (NH ₂ ).

All of the compounds of Examples 1 and 2 were prepared in an analogous manner.

Example 4

To a solution of 40 g of 2-hydroxy-3-phenyl-3- (2-nitrophenoxy) propionate in one liter of 95% ethyl alcohol is added 250 ml of 35% methylamine and the mixture is heated at 40-50 ° C in a closed autoclave for 24 hours. The volatiles were distilled off under reduced pressure, the residue was dissolved in 200 ml of absolute ethyl alcohol, the solution was again evaporated to dryness and the residue was recrystallized from isopropyl alcohol. There was obtained 36 g (94.2%) of N-methyl-2-hydroxy-3-phenyl-3- (2-nitrophenoxy) propionamide, m.p. 162-163 ° C.

Infrared spectrum, ^v max (nujol): 1640 µm ^- (CON), 3300 cm -1 (OH, wide band),

400 cm ^- (narrow, intense band).

The propionamides required for the preparation of propylamines are prepared in an analogous manner as described in Example 3.

To a solution of 66 g of trans ethyl glycidate (ie, trans-2,3-epoxypropionic acid ethyl ester) and 48 g of o-nitrophenol in 1 liter of anhydrous ethyl alcohol is added 36 g of anhydrous sodium carbonate and the mixture is heated under stirring for 48 hours. reflux. An additional 24 g of o-nitrophenol was then added and the mixture was refluxed for an additional 36 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in water and the product was taken up in ethyl acetate. The ethyl acetate extract was shaken with 2 N sodium hydroxide solution until the excess phenol was completely removed, then washed with water until neutral, dried over anhydrous sodium sulfate, and the solvent was distilled off. Recrystallization of the residue from diethyl ether gave g (60%) of 2-hydroxy-3-phenyl-3- (2-nitrophenoxy) propionic acid ethyl ester, m.p. 129-131 ° C.

Infrared spectrum, v (nujol): 1525 cm @ -1 (NO _P ), 3,300 cm @ -1 (OH, Wide band), 1,740 cm @ -1 ( ^c C ₀ / ·

In an analogous manner, all the 2-hydroxypropionates required for the synthesis of the 2-hydroxypropionamides were prepared as described in Example 4 (including the corresponding diastereoisomers prepared using the corresponding cis-glycidates).

Example 6

To a solution of 2 g of ethyl 2-hydroxy-3-phenyl-3- (2-nitrophenoxy) propionate in 30 ml of anhydrous dimethylformamide is added methyl iodide (0.78 ml) at 3 ° C and then, at the same temperature, in two portions. total 0.3 g of 50% sodium hydride. The mixture is stirred at 3 ° C for one hour and at room temperature for one hour, then the solution is poured into 300 ml of water and the product is taken up in ethyl ether. The ethereal solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 2 g (96%) of ethyl 2-methoxy-3-phenyl-3- (2-nitrophenoxy) propionate are obtained in the form of an oily liquid.

Infrared spectrum, ^at max 1,740 cm ”'

525 cm "(N0 _2).

Nuclear Magnetic Resonance Spectrum, ppm (CDCl 3): 3.24 (3H).

In an analogous manner, all the 2-methoxypropionates required for the preparation of the 2-methoxypropionamides were prepared as described in Example 4.

Example 7

A solution of 6.9 g of ethyl 3-phenyl-3- (2-nitrophenoxy) -2-methoxyproponate in 150 ml of absolute ethanol was hydrogenated in the presence of 5% palladium on activated carbon at atmospheric pressure at room temperature. The reduction is completed within 30 minutes. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The oily residue is taken up in a small amount of ethanol, 4 ml of 18% ethanolic hydrogen chloride are added to the solution, and the mixture is diluted with ethyl ether; ethyl 3-phenyl-3- (2-aminophenoxy) -2-methoxypropionate hydrochloride is obtained.

Infrared spectrum, v (KBr); 2,850 cm -1 (ArNHI), 1,740 cm -1 (c ^), max J \

NMR ppm (DMSO-d _6): 3.24 (s, 3H), 4.05 (q, 2H), 1.21 (t, 3H).

Example 8 To a solution of 8 g of ethyl 3- (2-aminophenoxy) -3-phenyl-2-methoxypropionate in 23% hydrochloric acid (11.6 mL) at 4-5 ° C was added water (30 mL) and then a solution of sodium nitrite (1.73 g) in water (30 ml) was slowly added dropwise while cooling. The reaction mixture was stirred at room temperature for 30 minutes and then heated to 50 ° C for 15 minutes; the evolution of nitrogen can be observed. The solution was extracted with methylene chloride, the organic portion was washed with water and the solvent was distilled off. An oily residue is obtained which is purified by column chromatography; 4.0 g (50% yield) of ethyl 3- (2-hydroxyphenoxy) -3-phenyl-2-methoxypropionate are obtained.

Infrared spectrum,

740 cm ^- '

^v max ( ⁱⁿ chloroform): 3 500 cm ^-1 (OH dimer - wide band),

Example 9

To a solution of 9.5 g of ethyl 3- (2-hydroxyphenoxy) -3-phenyl-2-methoxypropionate in 130 ml of anhydrous dimethylformamide is added 4.8 ml of anhydrous potassium carbonate, and then a solution of 2.2 ml of methyl iodide in 15 ml of dimethylformamide. The mixture was stirred for four and a half hours, then poured into 1 liter of water and the product was taken up in ethyl acetate. The combined organic extracts were washed with water, dried and the solvent was distilled off under reduced pressure. Purification of the crude product by silica gel column chromatography gave 8.6 g of ethyl 3-phenyl-3- (2-methoxyphenoxy) -2-methoxypropionate in 86.8% yield.

IR spectrum ^max (film): 2815 cm ^- '(OCH), 1738 cm ^-'

Example 10

To a solution of 2- (alpha- (2-methoxyphenoxy) -4-chlorobenzyl) morpholine (11.6 g) in benzene (100 mL) was added triethylamine (3.5 g) and then at room temperature for 1 hour. , a solution of methyl iodide (5.5 g) in benzene (20 mL) was added dropwise. The reaction mixture is stirred at room temperature for 20 hours, then the solid is filtered off and the solvent is distilled off from the filtrate. The oily product gave 7 g (57% yield) of 4-methyl-2- (alpha / 2-methoxyphenoxy) -4-chlorobenzyl) morpholine after silica gel column chromatography.

The following 4-methylmorpholine derivatives are prepared in an analogous manner:

4-methyl-2- (alpha-phenoxybenzyl) morpholine;

4-methyl-2- (alpha- (2-methoxyphenoxy) benzyl) morpholine hydrochloride, m.p. 67-90 ° C;

4-methyl-2- (alpha- (3-methoxyphenoxy) benzyl) morpholine;

4-methyl-2- (alpha- (4-methoxyphenoxy) benzyl) morpholine;

4-methyl-2- (alpha / 2-ethoxyphenoxy) benzyl) morpholine,

I. 5. (CHC1 ₃₎ in _N-CH3 2805 cm ^- 'in aroma. ethers, 1255 cm ^- ', 1,2 subst. phenyl 750 cm -1; 4-methyl-2- (alpha- (4-ethoxyphenoxy) benzyl) morpholine; I. δ. (CHCl?) In N-CH ₃ 2805 cm ^- 'in aroma. ethers, 1250 cm ^- ', in monosubstituted. phenyl 695 cm ^- '

4-methyl-2- (alpha- (2-chlorophenoxy) benzyl) morpholine;

4-methyl-2- (alpha- (4-chlorophenoxy) benzyl) morpholine;

4-methyl-2- (alpha / 4-trifluoromethylphenoxy) benzyl) morpholine;

4-methyl-2- (alpha- (3,4-methylenedioxyphenoxy) benzyl) morpholine;

4-methyl-2- (alpha-phenoxy-2-methoxybenzyl) morpholine;

4-methyl-2- (alpha- (2-methoxyphenoxy) -2-methoxybenzyl) morpholine;

4-Methyl-2- (alpha- (2-methoxyphenoxy) -2-methoxybenzyl) morpholine;

4-methyl-2- (alpha-phenoxy-4-methoxybenzyl) morpholine; 4-methyl-2- (alpha- (2-ethoxyphenoxy) -4-ethoxybenzyl) morpholine;

4-methyl-2- (alpha- (4-ethoxyphenoxy) -4-methoxybenzyl) morpholine;

4-methyl-2- (alpha- (4-trifluoromethylphenoxy) -4-ethoxybenzyl) morpholine;

4-methyl-2- (alpha- (4-chlorophenoxy) -4-ethoxybenzyl) morpholine;

4-methyl-2- (alpha- (2-methoxyphenoxy) -4-ethoxybenzyl) morpholine;

4-methyl-2- (alpha- (4-methoxyphenoxy) -4-ethoxybenzyl) morpholine;

4-methyl-2- (alpha-phenoxy-2-chlorobenzyl) morpholine;

4-methyl-2- (alpha- (2-methoxyphenoxy) -2-chlorobenzyl) morpholine;

4-methyl-2- (alpha- (2-ethoxyphenoxy) -2-chlorobenzyl) morpholine;

4-methyl-2- (alpha-phenoxy-3-chlorobenzyl) morpholine;

4-methyl-2- (alpha- (2-methoxyphenoxy) -3-chlorobenzyl) morpholine,

IR (CHCl₃) in O-CH-J 2840 cm ^- ', N-CH ^ 2805 cm ^-' in aroma. ethers, 1245 cm ^- ', 1,2 of substitution. phenyl 750 cm ^-1 ;

4-methyl-2- (alpha- (2-ethoxyphenoxy) -3-chlorobenzyl) morpholine,

IR (CHCl₃) N-CH ^ 2810 cm ^- _'in aroma. ethers, 1255 cm ^- ', 1,2 of substitution. phenyl 745 cm ''

4-methyl-2- (alpha-phenoxy-4-chlorobenzyl) morpholine;

4-methyl-2- (alpha- (2-ethoxyphenoxy) -4-chlorobenzyl) morpholine;

4-methyl-2- (alpha- (4-ethoxyphenoxy) -4-chlorobenzyl) morpholine;

4-methyl-2- (alpha- (4-methoxyphenoxy) -4-chlorobenzyl) morpholine;

4-methyl-2- (alpha- (4-chlorophenoxy) -4-chlorobenzyl) morpholine;

4-methyl-2- (alpha-phenoxy-4-trifluoromethylbenzyl) morpholine;

4-methyl-2- (alpha- (2-methoxyphenoxy) -4-trifluoromethylbenzyl) morpholine;

4-methyl-2- (alpha- (4-methoxyphenoxy) -4-trifluoromethylbenzyl) morpholine;

4-methyl-2- (alpha- (2-ethoxyphenoxy) -4-trifluoromethylbenzyl) morpholine;

4-methyl-2- (alpha- (4-methoxyphenoxy) -4-trifluoromethylbenzyl) morpholine;

4-methyl-2- (alpha- (4-chlorophenoxy) -4-trifluoromethylbenzyl) morpholine;

4-methyl-2- (alpha-phenoxy-3,4-dichlorobenzyl) morpholine;

4-methyl-2- (alpha- (2-methoxyphenoxy) -3,4-dichlorobenzyl) morpholine;

4-methyl-2- (alpha- (2-ethoxyphenoxy) -3,4-dichlorobenzyl) morpholine.

Example 11

To a solution of 2- (alpha- (2-methoxyphenoxy) -4-chlorobenzyl) morpholine (7.35 g) in chloroform (50 mL) was added 2 N sodium hydroxide (18.2 mL) and then cooled to 0 ° with cooling. C, ethyl chloroformate (3.5 mL) was added dropwise over 30 minutes. The reaction mixture was stirred with cooling at 0 ° C for an additional 1 hour, then the organic layer was separated, washed with water and dried over anhydrous calcium chloride. The solvent was distilled off, the obtained colorless oily product was dissolved in diethyl ether (100 mL) and the solution was added dropwise at room temperature to a suspension of lithium aluminum hydride (2.5 g) in anhydrous diethyl ether (200 mL). After stirring at room temperature for 20 hours, the excess hydride was carefully quenched with water (2.5 mL) and 15% sodium hydroxide solution (2.5 mL) and water (7.5 mL) were added. The inorganic fraction was filtered off, the ether layer was separated from the filtrate and the aqueous portion was extracted with diethyl ether. The combined organics were washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. 6.25 g (82% yield) of 4-methyl-2- (alpha / 2-methoxyphenoxy) -4-chlorobenzyl) morpholine are obtained as an oil.

All 4-methylmorpholine derivatives listed in Example 10 were prepared in an analogous manner.

Example 12

To a solution of 2- (alpha- (2-methoxyphenoxy) -2-chlorobenzyl) morpholine (2 g) in glacial acetic acid (5.2 mL) was added acetone (12 mL) with good stirring, at about 0 ° C. and water (8 mL) and then, over 1 hour, sodium borohydride (6.044 g). Additional acetone (12 mL) and sodium borohydride (3 g) were then added, the temperature of the reaction mixture was allowed to reach room temperature, and the mixture was stirred for 30 hours. The reaction mixture was poured into aqueous sodium bicarbonate solution and the product was taken up in diethyl ether. The ethereal extracts were combined, washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. 1.85 g (yield 82.3%) of 4-isopropyl-2- (alpha / 2-methoxyphenoxy) -2-chlorobenzyl) morpholine are obtained; hydrochloride has a melting point of 200-240 ° C.

The following 4-isopropylmorpholine derivatives are prepared in an analogous manner:

4-isopropyl-2- (alpha-phenoxybenzyl) morpholine;

4-isopropyl-2- (alpha / 2-methoxyphenoxy) benzyl) morpholine hydrochloride, m.p. 196-203 ° C; 4-Isopropyl-2- (alpha / 3-methoxyphenoxy) benzyl) morpholine;

4-isopropyl-2- (alpha- (4-methoxyphenoxy) benzyl) morpholine;

4-Isopropyl-2- (alpha- (2-ethoxyphenoxy) benzyl) morpholine; 4-isopropyl-2- (alpha / 4-ethoxyphenoxy) benzyl) morpholine; 4-isopropyl-2- (alpha / 2-chlorophenoxy) benzyl) morpholine; 4-isopropyl-2- (alpha- (4-chlorophenoxy) benzyl) morpholine;

4-isopropyl-2- (alpha- (4-trifluoromethylphenoxy) benzyl) morpholine;

4-Isopropyl-2- (alpha- (3,4-methylenedioxyphenoxy) benzyl) morpholine;

4-isopropyl-2- (alpha- (2-methoxyphenoxy) -2-methoxybenzyl) morpholine;

4-isopropyl-2- (alpha- (2-ethoxyphenoxy) -2-methoxybenzyl) morpholine;

4-isopropyl-2- (alpha-phenoxy-4-ethoxybenzyl) morpholine;

4-isopropyl-2- (alpha- (2-ethoxyphenoxy) -4-ethoxybenzyl) morpholine; 4-isopropyl-2- (alpha- (4-ethoxyphenoxy) -4-ethoxybenzyl) morpholine;

4-isopropyl-2- (alpha- (4-trifluoromethylphenoxy) -4-ethoxybenzyl) morpholine;

4-isopropyl-2- (alpha- (4-chlorophenoxy) -4-ethoxybenzyl) morpholine;

4-isopropyl-2- (alpha- (2-methoxyphenoxy) -4-ethoxybenzyl) morpholine;

4-isopropyl-2- (alpha- (4-methoxyphenoxy) -4-ethoxybenzyl) morpholine;

4-Isopropyl-2- (alpha-phenoxy-2-chlorobenzyl) morpholine;

4-isopropyl-2- (alpha- (2-ethoxyphenoxy) -2-chlorobenzyl) morpholine;

4-isopropyl-2- (alpha- phenoxy-3-chlorobenzylmorpholine);

4-Isopropyl-2- (alpha- (2-methoxyphenoxy) -3-chlorobenzyl) morpholine;

4-isopropyl-2- (alpha- (2-ethoxyphenoxy) -3-chlorobenzyl) morpholine;

4-isopropyl-2- (alpha-phenoxy-4-chlorobenzyl) morpholine;

4-isopropyl-2- (alpha- (2-ethoxyphenoxy) -4-chlorobenzyl) morpholine;

4-isopropyl-2- (alpha- (4-ethoxyphenoxy) -4-chlorobenzyl) morpholine;

4-isopropyl-2- (alpha-2-methoxyphenoxy / -4-chlorobenzyl) morpholine;

4-isopropyl-2- (alpha- (4-methoxyphenoxy) -4-chlorobenzyl) morpholine;

4-isopropyl-2- (alpha- (4-chlorophenoxy) -4-chlorobenzyl) morpholine;

4-Isopropyl-2- (alpha-phenoxy-4-trifluoromethylbenzyl) morpholine;

4-isopropyl-2- (alpha- (2-methoxyphenoxy) -4-trifluoromethylbenzyl) morpholine;

4-isopropyl-2- (alpha- (4-methoxyphenoxy) -4-trifluoromethylbenzyl) morpholine;

4-isopropyl-2- (alpha- (2-ethoxyphenoxy) -4-trifluoromethylbenzyl) morpholine;

4-isopropyl-2- (alpha- (4-ethoxyphenoxy) -4-trifluoromethylbenzyl) morpholine; 4-isopropyl-2- (alpha- (4-chlorophenoxy) -4-trifluoromethylbenzyl) morpholine;

4-Isopropyl-2- (alpha-phenoxy-3,4-dichlorobenzyl) morpholine;

4-isopropyl-2- (alpha- (2-methoxyphenoxy) -3,4-dichlorobenzyl) morpholine; 4-Isopropyl-2- (alpha- (2-ethoxyphenoxy) -3,4-dichlorobenzyl) morpholine.

Example 13

To a solution of 33 g of 2- (alpha- (2-nitrophenoxy) benzyl) morpholin-3-one in 60 ml of anhydrous THF was added dropwise with stirring 16.7 ml of a 0.9 M solution of borane in THF. The reaction mixture was heated to boiling for 3 hours, then cooled, and 3 ml of methanol and then 3 ml of 23% hydrochloric acid were added under cooling to 0-5 ° C. The solvents are distilled off under reduced pressure, the residue is taken up in water, the solution is rendered alkaline and the product is taken up in chloroform. The organic extracts were combined, washed neutral, dried and the solvent was distilled off. 28.6 g (94% yield) of 2- (alpha / 2-nitrophenoxy) benzyl) morpholine are obtained.

IR spectrum ^max (chloroform): 3320 cm ^-1 (NH), 1525 cm ^-1 (NO _2).

The following compounds were prepared in an analogous manner:

2- (alpha-phenoxybenzyl) morpholine hydrochloride, m.p. 199-202 ° C;

2- (alpha / 2-methoxyphenoxy) benzyl) morpholine hydrochloride, m.p. 140-170 ° C;

2- (alpha / 3-methoxyphenoxy) benzyl) morpholine, 1.5762, hydrochloride, mp 58-64 ° C;

2- (alpha / 4-methoxyphenoxy) benzyl) morpholine hydrochloride, m.p. 50-57 ° C; 2- (alpha / 2-ethoxyphenoxy) benzyl) morpholine, one diastereoisomer having a melting point of 170-171.

degrees Celsius (as hydrochloride);

2- (alpha / 4-ethoxyphenoxy) benzyl) morpholine;

2- (alpha / 4-chlorophenoxy) benzyl) morpholine hydrochloride, m.p. 75-97 ° C;

2- (alpha / 4-trifluoromethylphenoxy) benzyl) morpholine hydrochloride, m.p. 188-195 ° C; 2- (alpha- (3,4-methylenedioxyphenoxy) benzyl) morpholine hydrochloride, m.p. 82-130 ° C;

2- (alpha-phenoxy-2-methoxybenzyl) morpholine;

2- (alpha- (2-methoxyphenoxy) -2-methoxybenzyl) morpholine, n _D 1.5672;

2- (alpha- (2-methoxyphenoxy) -2-methoxybenzyl) morpholine;

2- (alpha-phenoxy-4-methoxybenzyl) morpholine;

2- (alpha- (2-ethoxyphenoxy) -4-ethoxybenzyl) morpholine;

2- (alpha- (4-ethoxyphenoxy) -4-ethoxybenzyl) morpholine;

2- (alpha- (4-trifluoromethylphenoxy) -4-ethoxybenzyl) morpholine;

2- (alpha- (4-chlorophenoxy) -4-methoxybenzyl) morpholine;

2- (alpha- (2-methoxyphenoxy) -4-ethoxybenzyl) morpholine;

2- (alpha- (4-methoxyphenoxy) -4-methoxybenzyl) morpholine;

2- (alpha-phenoxy-2-chlorobenzyl) morpholine;

2- (alpha- (2-methoxyphenoxy) -2-chlorobenzyl) morpholine, m.p. 80-102 ° C;

2- (alpha- (2-ethoxyphenoxy) -2-chlorobenzyl) morpholine;

2- (alpha-phenoxy-3-chlorobenzyl) morpholine;

2- (alpha- (2-methoxyphenoxy) -3-chlorobenzyl) morpholine hydrochloride, m.p. 155-160 ° C; 2- (alpha- (2-ethoxyphenoxy) -3-chlorobenzyl) morpholine hydrochloride, m.p. 147-158 ° C;

2- (alpha-phenoxy-4-chlorobenzyl) morpholine;

2- (alpha- (2-ethoxyphenoxy) -4-chlorobenzyl) morpholine;

2- (alpha- (4-ethoxyphenoxy) -4-chlorobenzyl) morpholine;

2- (alpha- (2-methoxyphenoxy) -4-chlorobenzyl) morpholine hydrochloride, m.p. 175-200 ° C; 2- (alpha- (4-methoxyphenoxy) -4-chlorobenzyl) morpholine;

2- (alpha / 4-chlorophenoxy) -4-chlorobenzyl) morpholine; 2- (alpha-phenoxy-4-trifluoromethylbenzyl) morpholine;

2- (alpha- (2-methoxyphenoxy) -4-trifluoromethylbenzyl) morpholine;

2- (alpha- (4-methoxyphenoxy) -4-trifluoromethylbenzyl) morpholine;

2- (alpha- (2-ethoxyphenoxy) -4-trifluoromethylbenzyl) morpholine;

2- (alpha- [4-ethoxyphenoxy] -4-trifluoromethylbenzyl) morpholine; 2- (alpha- (4-chlorophenoxy) -4-trifluoromethylbenzyl) morpholine;

2- (alpha-phenoxy-3,4-dichlorobenzyl) morpholine;

2- (alpha- (2-methoxyphenoxy) -3,4-dichlorobenzyl) morpholine;

2- (alpha- (2-ethoxyphenoxy) -3,4-dichlorobenzyl) morpholine;

2- (alpha / 2-phenoxy / benzyl) -4-methylmorpholine hydrochloride, mp 67-90 ° C IR spectrum _max (KBr): 2700 cm ^- '(NI?); 2815 cm @ -1 (OCH3); 2- (alpha / 2-nitrophenoxy) benzyl) -4-methylmorpholine, mp 78-81 ° C,

Infrared spectrum, in _max (in chloroform): 1525 cm ^-1 (NOg),

Nuclear Magnetic Resonance Spectrum, ppm (in deuterochloroform): 5.3 (d, H benzyl), 7.4 to 6.8 (s, 9H, thio aroma), 2.27 (s, CH 2), as well as all compounds listed in Examples 10 and 12.

Example 14

To a solution of 4.24 g of N- (2-methyloxyethyl) -3-phenyl-2-hydroxy-3- (2-nitrophenoxy) propionamide in 150 mL of DMF was added 1.38 g of potassium carbonate. The mixture was heated to 50 ° C with stirring for 5 hours, then poured into water and the product was taken up in ethyl acetate. The combined organic extracts were dried and the solvent was distilled off. The residue was purified by silica gel column chromatography to give 1.27 g (38.6% yield) of 2- (alpha / 2-nitrophenoxy / benzyl) morpholin-3-one.

Infrared spectrum v (nujol) 3450 cm ^-1 (NH), 1670 cm ^- '(CONH)

ΙΠ & Χ

525 cm ^-1 (NO ₂ ).

The morpholin-3-one derivatives required for the preparation of the compounds of Examples 10, 12, 13 are prepared in an analogous manner.

Example 15 <

To a solution of 5.2 g of N- (2-hydroxyethyl) -3-phenyl-2-hydroxy-3- (2-nitrophenoxy) propionamide in 200 ml of anhydrous THF is added 2.4 ml of triethylamine and then, with stirring and cooling A solution of 1.83 g of methyl chloride in 30 ml of THF is slowly added dropwise to -10 ° C. The reaction mixture was stirred at -10 ° C for 45 minutes, then allowed to warm to room temperature and the solution was concentrated to a small volume under reduced pressure. The solution is poured into water, the product is taken up in chloroform, the combined extracts are washed neutral with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized from 95% ethanol. There was obtained 4.86 g (yield 76.5%) of N- (2-methyloxyethyl) -3-phenyl-2-hydroxy-3- (2-nitrophenoxy) propionamide, m.p. 122-125 ° C.

Infrared spectrum, v _max (KBr): 3500 cm ^-1 (OH, broad band), 3450 cm ^-1 (NH),

650 cm ^-1 (CONH), 1525 cm @ ^-1 (NO2), 1350 cm ^"1 (S02), 1180 cm ^-1 (S0 _2).

Other N- (2-methyloxyethyl) propionamides required for the preparation of the compounds of Example 14 were prepared in an analogous manner.

Example 16

A mixture of 3 g of ethyl 3-phenyl-2-hydroxy-3- (2-nitrophenoxy) propionate, 5.4 ml of ethanolamine and 50 ml of anhydrous ethanol is heated to reflux for 20 hours. The solvent was distilled off under reduced pressure, the residue was stirred with water and the solid product was filtered off. Recrystallization from ethyl acetate gave 1.8 g of N- (2-hydroxyethyl) -3-phenyl-2-hydroxy-3- (2-nitrophenoxy) propionamide, m.p. 166-188 ° C; 58% yield.

Infrared spectrum, in _max (nujol): 3400 cm ^-1 (OH, NH, wide band),

650 cm ^-1 (CONH), 1525 cm ^-1 (NO _2).

Other N- (2-hydroxyethyl) propionamides necessary for the preparation of the compounds of Example 15 are prepared in an analogous manner.

Example 17

A solution of 0.9 g of 2- (alpha-phenoxycarbonyloxybenzyl) morpholin-3-one in 2.5 ml of hexamethylphosphoric triamide is heated to 140 ° C; after 1 hour the reaction was complete. The mixture was diluted with water, the product was taken up in ethyl acetate, the combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the solvent was distilled off; 2- (alpha-phenoxybenzyl) morpholin-3-one is obtained.

In a similar manner, all morpholin-3-one derivatives required for the preparation of the compounds of Example 13 were prepared.

Example, 8

To a solution of 0.6 g of 2- (alpha-hydroxybenzyl) morpholin-3-one in 5 ml of anhydrous pyridine at 0 ° C was added dropwise 0.5 g of chloroformic acid phenyl ester. The mixture is stirred at room temperature for 12 hours, then 30 ml of methylene chloride are added and the solution is washed with 5% hydrochloric acid, 5% sodium hydroxide solution and then with water. The organic portion was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. 2- (alpha-phenoxycarbonyloxybenzyl) morpholin-3-one is obtained in a yield of 95%.

In a similar manner, all analogous intermediates needed as starting materials for the preparation of the compounds of Example 17 were prepared.

Example 19

Under a nitrogen atmosphere and excluding air humidity, 26.7 ml of a 15% solution of butyllithium in hexane are added dropwise over 45 minutes to a solution of 2.02 g of morpholin-3-one in 60 ml of anhydrous THP at room temperature, with stirring. The mixture was stirred at room temperature for 2.5 hours, then cooled to -62 ° C and a solution of 2.02 ml of freshly distilled benzaldehyde in 10 ml of anhydrous THF was added dropwise over 45 minutes. The reaction mixture was stirred at -62 ° C for 3 hours, then allowed to warm to room temperature and stirred at this temperature for an additional 16 hours. Excess butyllithium is quenched by the addition of a little water, the solvents are distilled off and the residue is taken up in dilute sodium bicarbonate solution. The product was extracted with ethyl acetate, the organics were combined, washed with water, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated to dryness. The solid residue is triturated with 40 ml of ethyl ether and the product is filtered off. 2.4 g of 2- (alpha-hydroxybenzyl) morpholin-3-one are obtained, which, after recrystallization from ethyl acetate, has a melting point of 130 DEG-140 DEG. Yield 58%.

Infrared spectrum, in _max (in chloroform): 3400 cm ^-1 (OH, broad band), 3300-3200 cm ^-1 (NH), 1660 cm ^-1 (CO).

All intermediates needed as starting materials for the preparation of the compounds of Example 18 were prepared in an analogous manner.

Example 20

To a solution of 3 g of 2- (alpha / 2-aminophenoxy) benzyl) -4-methylmorpholine in 30 ml of acetonitrile was added 4 ml of a 37% aqueous formaldehyde solution followed by 1 g of sodium cyanoborohydride. The mixture was stirred at room temperature for 30 minutes, then acetic acid was added until neutral and stirring was continued at room temperature for a further 3 hours. The solvent was distilled off under reduced pressure, the residue was basified and the product was taken up in chloroform. The combined organic extracts were washed with water until neutral, dried and the solvent was evaporated under reduced pressure. The oily residue was dissolved in ethanol and treated with 2 ml of 18% strength alcoholic HCl solution. Dilution of the solution with ethyl ether gave 2.67 g of 2- (alpha- / 2-N, N-dimethylaminophenoxy / benzyl) -4-methylmorpholine monohydrochloride; yield 74%.

Infrared spectrum, _max (in chloroform): 2700 cm @ -1 (NH @ +).

Example 21

To a solution of 6.5 g of 2- (alpha / 2-nitrophenoxy / benzyl) -4-methylmorpholine in 200 ml of absolute ethanol is added 0.7 g of 5% palladium on charcoal and the mixture is hydrogenated for 0.5 hour at 0, 25 MPa. The catalyst is filtered off, the solvent is distilled off and the oily residue obtained is converted into the hydrochloride with an alcoholic solution of hydrogen chloride. Recrystallization from ethyl acetate-ethanol yielded 5.1 g of 2- (alpha- (2-aminophenoxy) benzyl) -4-methylmorpholine monohydrochloride; yield 76%.

Infrared spectrum, ν _max (KBr): 3400 cm -1 (NH ₂ ), 2700 cm ^-1 (NH ⁺ ).

>

Example 22

To a solution of 4.5 g of 2- (alpha- / 2-hydroxyphenoxy / benzyl) -4-methylmorpholine in 70 ml of anhydrous DMF was added 2.2 g of anhydrous potassium carbonate while stirring at room temperature and then slowly added dropwise 1 ml. methyl iodide. The mixture is stirred at 55 ° C for 5 hours, then poured into 700 ml of cold water and the product is taken up in ethyl ether. The combined organic extracts were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to a small volume. After addition of 18% strength alcoholic hydrogen chloride solution to the concentrated solution, 4 g (76% yield) of 2- (alpha / 2-methoxyphenoxy / benzyl) -4-methylmorpholine hydrochloride precipitated, m.p. 67 DEG-90 DEG C. (dec.).

Infrared Spectrum, ν _max (KBr): 2820 cm -1 (OCH 3), 2700 cm -1 (NH ⁺ ).

Example 23

To a solution of 15 g of 2- (alpha / 2-aminophenoxy / benzyl) -4-methylmorpholine hydrochloride in 50 ml of water is added 18.5 ml of 23% hydrochloric acid, cooled to 0 ° C and stirred at that temperature with stirring a solution of 3.45 g of sodium nitrite in 20 ml of water is slowly added dropwise. The mixture was stirred under cooling for 20 minutes, then the temperature was allowed to rise to room temperature and finally the solution was heated in a water bath at 40 ° C until nitrogen evolution ceased. The reaction mixture is basified to pH 9, the product is taken up in chloroform, the combined organic extracts are dried and the solvent is distilled off. The residue is dissolved in 5 ml of anhydrous ethanol and 9 ml of a 20% solution of hydrogen chloride in ethanol are added. After dilution with a small amount of ethyl ether, 4.65 g (yield 31%) of 2- (alpha- / 2-hydroxyphenoxy) benzyl) -4-methylmorpholine hydrochloride precipitated.

IR spectrum _^max (KBr): 3500 cm (OH) 2700 cm '(ΙΟΓ * ·).

Example 24

To a solution of 5.1 g of 2- (alpha / 2-nitrophenoxy / benzyl) -4-methylmorpholine in 70 ml of anhydrous toluene was added 3 ml of ethyl chloroformate and the mixture was heated under reflux for 24 hours. The solvent was distilled off, the obtained oily residue (5.9 g) was dissolved in 15 ml of 8% aqueous-alcoholic hydrochloric acid, and the solution was heated under reflux for 4 hours. The solvents are evaporated to dryness, the residue is dissolved in 50 ml of water and the product is taken up in ethyl ether. The combined ethereal extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to a small volume. 3.5 g of 2- (alpha- / 2-nitrophenoxy / benzyl) morpholine hydrochloride precipitated after 207696 g of an 18% solution of hydrogen chloride in absolute ethanol; yield 68%.

Infrared spectrum, v _max ^; 2,800 cm -1 (NH), 1525 cm -1 (NO ₂ ).

The compounds of Example 13 were prepared in a similar manner.

Example 25

A solution of 4-benzyl-2- (alpha / 2-methoxyphenoxy / benzyl) morpholine (5 g) in a mixture of 99% ethanol (150 mL) with hydrochloric acid (6 mL) was hydrogenated in the presence of palladium on charcoal for 4 hours at rooms. The catalyst is filtered off, the solvents are distilled off under reduced pressure and the residue is chromatographed on a silica gel column, eluting with a chloroform / methanol / conc. Ammonia (170: 30: 2) mixture. 2.1 g (yield 54.7%) of 2- (alpha / 2-methoxyphenoxy / benzyl) morpholine are obtained in the form of a clear oil; hydrochloride, m.p. 140-170 ° C.

The morpholine derivatives of Example 13 are prepared in an analogous manner except those containing a chlorine atom or a nitro group in the molecule.

Example 26

A solution of 4-benzyl-2- (alpha / 2-methoxyphenoxy / benzyl) morpholine (5 g) in benzene (70 mL) was heated to reflux with ethyl chloroformate (1.2 mL) for 5 hours. The solvent was distilled off and the residue was heated to reflux with 10% methanolic potassium hydroxide solution (70 ml) for 2 days. The solvent was evaporated to dryness and the residue was partitioned between ethyl ether and water. The aqueous portion is extracted with fresh ether and the combined ether extracts are treated by shaking the base into the acid, liberating it from the acidic solution by alkalizing and removing it into ethyl ether. After drying over anhydrous sodium sulfate, filtering off the desiccant and distilling off the solvent under reduced pressure, 2.4 g (yield 60%) of 2- (alpha / 2-methoxyphenoxy / benzyl) morpholine is obtained in the form of a mixture of two diastereoisomers; m.p. 140-170 ° C.

All of the compounds of Example 13 were prepared in a similar manner.

Example 27 j

To a solution of the 2- (alpha / 2-ethoxyphenoxy / benzyl) morpholine diastereoisomer (1.6 g) in anhydrous ethanol was added methanesulfonic acid (0.33 mL). Dilution with diethyl ether (200 mL) precipitated a solid which was collected by filtration to give 2- (alpha / 2-ethoxyphenoxy / benzyl) -4-morpholine methanesulfonate, mp 144-146 ° C, ultraviolet spectrum (CH-iOH) Λ: 275 nm;

iL Π18Χ

Example 28

Tablets of 200 mg each containing 25 mg of active ingredient are prepared as follows:

Ingredients (for 10,000 tablets):

2- (alpha- (2-methoxyphenoxy) benzyl) morpholine 250 G lactose 1, 230 G cornstarch 450 G talc (spread) 50 G magnesium stearate 20 May G

The 2- (alpha / 2-methoxyphenoxy / benzyl) morpholine, lactose and half of said corn starch are mixed and passed through a 0.55 mm sieve. 30 g of corn starch are dispersed in 300 ml of hot water and the above powdery mixture is granulated with the obtained grease starch. The granules are dried, sieved through a 1.4 mm sieve and the starch, talc and magnesium stearate are added to the sieved material. The mixture is mixed thoroughly and the obtained mass is compressed into tablets using a punch having a diameter of 8 mm.

Example 29

Tablets of 200 mg each containing 25 mg of the active ingredient are prepared as follows.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of substituted propanolamine and morpholine derivatives of the general formula I in which n and nj are respectively 1, 2 or 3, ΠβΗρ, which may be the same or different, each represent a hydrogen atom, a halogen atom, a haloalkyl group having 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, optionally substituted by at least one hydroxy group , C 1-6 alkyl, ^-N-R 5 or 5 x ^ ^r -CO-N in which R e and R _fi denote individually a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, aryl (C -Cg) alkyl ekupinu optionally substituted with at least jed207696 Nou hydroxyl, alkoxy having 1 to 6 carbon atoms, or a group --N @ ₅ R 6 ^XR -CO-N in which R8 and R8 are as defined above, aryl (C1-C6) alkoxy, optionally ^Vr6 substituted by at least one hydroxy, C1-C6 alkoxy, -N-Rc / Rg or -N-group; -CO-N, wherein Rg and Rg are as defined above, ^R 5 nitroskuX pin, --N wherein Rg and Rg are as defined above, or two adjacent ^R @ 6 R groups or two adjacent groups R form a together the remainder -O-CHg-O, R ₂ is hydrogen, alkyl having 1 to 12 carbon atoms optionally substituted by halogen, hydroxy, alkoxy having 1 to 6 carbon atoms, · a group Rg ^ - ^ Rg Or -CO-N-N in which R e and R <are as defined above, or aryl (C, -Cg) alkyloXR _O \ Vou Rg ⁵ group, and R 1 and R 2, which may be the same or different, each represent a hydrogen atom, a C 1 -C 6 alkyl group optionally substituted by a halogen atom, a hydroxy group, a C 1 -C 6 alkoxy group, an N or -CO-N, in which Re and R2 are as defined above, C2-C4 alkenyl, C2-C4 alkynyl, aryl (C1-C6) alkyl optionally substituted in aryl by at least one alkyl of 1 to 6 carbon atoms, halogen, haloalkyl having 1-6 carbon atoms / Rg ku, hydroxy, alkoxy having 1-6 carbon atoms or N, in which R 6 ^XR and Rg are as defined above, a cycloalkyl group C 3 -C 7 alkyl optionally substituted with at least one C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, hydroxy, C 1 -C 6 alkoxy, or a group R 5 -N in which R e is and R _ň have from above and the aforementioned meaning, or both R1 and R. together with the nitrogen atom to which they are attached, form a 5- or 6-membered, saturated or unsaturated heteromonocyclic radical optionally containing another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with (C 1 -C 6) alkyl or aryl, or R 8 and R 8 together form a radical of the formula -CHg-CHg-, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula III (III) is reduced 3) wherein n,, R, R p R ₂ , R 3 and R 4 are as defined above, and the compound of formula I obtained is optionally converted into another compound of formula I, and / or optionally the compound of formula I is converted into a salt, or a free compound of formula I is prepared from a salt thereof, and / or the optionally obtained mixture of isomers of formula I is separated into its individual isomers. 2. A process according to item 1, for the preparation of substituted propanolamine and morpholine derivatives of the general formula Ia in which n and n are each 1, 2 or 3, R @ 1 and R @ 2, which may be the same or different, each represent a hydrogen atom, a halogen atom, a hydroxyl group, a C1 -C6 alkoxy group, a C1 -C6 alkyl group, optionally substituted as mentioned above, aryl C1-6 - C 1-6 alkyl, aryl (C 1 -C 8) alkoxy, or two adjacent R groups or two adjacent R 1 groups together form the radical -C-CH ₂ -O-, R ₂ is hydrogen, alkyl having 1 to 2 carbon atoms, optionally substituted Nou as above, or aryl (C] -Cg) alkyl and R ₃ and R 4, which may be the same or different, each represent a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 4 alkenyl group, a C 2 -C 4 alkynyl group, aryl (C 1 -C 4 alkyl) (Cg) an alkyl group, or both R 1 and R 4 together with the nitrogen atom to which they are attached, form a 5- or 6-membered, saturated or unsaturated heteromonocyclic moiety optionally containing an additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and pharmaceutically acceptable a compound of formula (IIIa) wherein n, n1, R1, R1, R1 and R4 are as defined above, and the compound of formula (Ia) obtained is optionally converted to another compound of formula (Ia), and / or optionally converting a compound of formula Ia into a salt, or preparing a free compound of formula Ia from a salt thereof, and / or optionally obtained the mixture of isomers of formula (Ia) is separated into its individual isomers. 3. A process according to item 1, derivatives of the general formula Ib for the production of substituted propanolamine and morpholine in which n and n, respectively, denote the number 1, 2 or 3, RaR p, which may be the same or different, of a gene, a hydroxyl group, an alkoxy group of 1 to 6 individually denotes a hydrogen atom, a halo-carbon atom, an alkyl group of 1 to 6 207696 26 6 carbon atoms optionally substituted as above, an aryl (C 1 -C 8) alkyl group, a R 5 aryl (C 1 -C 8) alkoxy group, a nitro group, a group of the formula -N wherein R = and R 8 are each ^xr 6 individually hydrogen or (C 1 -C 6) alkyl or two adjacent R 1 groups taken together are -O-CHg-O-, R 8 represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, optionally substituted as above, or an aryl (C 1 -C 8) alkyl group, and R 1 and R 4, which may be the same or different, each represent a hydrogen atom, a C 1 -C 6 alkyl group optionally substituted as described above, a C 2 -C 4 alkenyl group, an aryl (C 1 -C ₄ ) alkyl group, C 3 -C 7 cycloalkyl optionally substituted as above, or both R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- or 6-membered, saturated or unsaturated heteromonocyclic moiety optionally containing other heteroatoms. from the group consisting of oxygen, sulfur and nitrogen, or R and R4 together form a radical the patterns' ce-CH₂-CHg-, and pharmaceutically acceptable salts thereof, characterized by reducing a compound ^of formula IIIb (R) _n ^R 2 ° C-N 3 (IIIb) wherein n, n, R, R, R 8, R 8 and R ₄ are as defined above, and the compound of formula Ib obtained is optionally converted to another compound of formula Ib, and / or or optionally converting a compound of formula Ib into a salt, or preparing a free compound of formula Ib from a salt thereof, and / or separating the optionally obtained mixture of isomers of formula Ib into individual isomers.