CS207696B2 - Process for preparing substituted propanolamine and morpholine derivatives - Google Patents

Abstract

The invention relates to a process for the production of substituted propanolamine and morpholine derivatives of the general formula I * in which n and n, individually denote the number 1, 2 or 3, * RaKj, which may be the same or different, individually denote a hydrogen atom, a halogen atom, a haloalkyl group with 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group with 1 to 6 carbon atoms, an alkyl group with 1 to 6 carbon atoms, optionally substituted by at least one hydroxyl group, an alkoxy group with 1 to 6 carbon atoms, a group -N. or the group -CO-N(T , in which Rj and Rg individually represent a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, an aryl(C,-Cg)alkyl group, optionally substituted with at least one hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a -Nζ group

Description

(54) Process for the production of substituted propanolamine and morpholine derivatives

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

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

RaKj, which may be the same or different, individually represent a hydrogen atom, a halogen atom, a haloalkyl group with 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group with 1 to 6 carbon atoms, an alkyl group with 1 to 6 carbon atoms, optionally substituted with at least one hydroxyl group, an alkoxy group with 1 to 6 carbon atoms, a group

-N. or a group -CO-N(T , in which Rj and Rg individually denote a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, an aryl(C,-Cg)alkyl group, optionally substituted by at least one hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a group -Νζ «6 / ^r 5 or a group -CO-N^ , in which Rg and Kg have the above-mentioned meaning, an aryl(C|-Cg)alkoxy% group, optionally substituted by at least one hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a group -N[ or -CO-N , in which Rg and Rg have the above-mentioned ^meaning , a nitro group of the formula -N , in which Rg and Rg have the above-mentioned meaning, or two ^Xr 6 adjacent R groups, or two adjacent R groups, together form the residue -O-CHg-O-,

R ₂ represents a hydrogen atom, an alkyl group with 1 to 12 carbon atoms, optionally substituted by a halogen atom, a hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a group / ^r 5 ^/- ^r 5

-N or -CO-N, in which Rg and Rg have the above meaning, or ^an aryl(C,-Cg) ^alkyl group, and

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

X- ^R 5

-N or ^6

in which

Rg and Rg have the above meaning, an alkenyl group with 2 to 4 carbon atoms, an alkynyl group with 2 to 4 carbon atoms, an aryl(C1-C6)alkyl group, optionally substituted in the aryl by at least one alkyl with 1 to 6 carbon atoms, a halogen atom, a haloalkyl with 1 to 6 carbon atoms, a hydroxy group, an alkoxy group with 1 to 6 carbon atoms or a group

^-NR 5 , in which Rg and Rg have the above meaning, a cycloalkyl group with 3 to 7 carbon atoms, optionally substituted with at least one alkyl with 1 to 6 carbon atoms, a halogen atom, a haloalkyl with 1 to 6 carbon atoms, a hydroxy group, an alkoxy group with 1 to 6 carbon atoms

X ^r 5 carbon or the group -N *6 in which Rg and Rg have the above meaning, or both substituents Rg and R^ together with the nitrogen atom to which they are attached form a five- or six-membered, saturated or unsaturated heteromonocyclic radical, which optionally contains further heteroatoms from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted by alkyl with 1 to 6 carbon atoms or aryl, or

R1 and R4 together form a residue of the formula -CH6-CH6-.

The invention also includes pharmaceutically acceptable salts of the compounds of general formula 1, as well as all their possible isomers and mixtures of these isomers, and their metabolites provided that they have pharmacological, for example antidepressant, activity, and metabolic precursors of the compounds of general formula I.

2-phenoxymethylmorpholine and propanolamine and their production processes are described in numerous patent documents, for example, U.S. Pat. Nos. 3,774,61 and 3,712,890 and French Pat. No. 2,248,049. However, the compounds mentioned do not have a phenyl substituent on the methyl residue, which is, on the contrary, characteristic of the compounds produced by the process according to the present invention.

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

In the case where one or more of the groups R and Rf represent a substituted alkyl group of up to 6 carbon atoms, it is preferably an alkyl group substituted by a hydroxyl group, an r ₅ r ₅ alkoxy group of 1 to 6 carbon atoms or groups of the general formula -N or -CON.

R ₆ r ₆ in which R j and R g have the above meaning.

The aryl group preferably represents a phenyl group.

In the case where one or more of R1 and R2 represent a substituted alkyl group having 1 to 6 carbon atoms, it is preferably an alkyl group substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, an alkoxy group, or a alkoxy group.

X ^r 5 / ^r 5 represents a group of from 1 to 6 carbon atoms or groups of the formulae -N and -CON, in which R 6 and ^R 6 have the meanings given above. The above-mentioned alkyl group of from 1 to 12 carbon atoms may also be substituted in the same way.

Substituted aryl(C1-C6)alkyl, aryl(C1-C6)alkyl and aryl(C1-C6)alkoxy groups are preferably those groups whose aryl residue is substituted by one or more alkyl groups with 1 to 6 carbon atoms, halogen atoms, haloalkyl groups with 1 to 6 carbon atoms, hydroxy groups, alkoxy groups with 1 to 6 carbon atoms or ^R5 groups of the general formula -N, in which R6 and R7 have the meanings given above.

^X- R6

Substituted cycloalkyl groups with 3 to 7 carbon atoms are such cycloalkyl groups which are substituted by one or more substituents, preferably selected from the group comprising an alkyl group with 1 to 6 carbon atoms, a halogen atom, a halogenated alkyl group with 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group with 1 to 6 carbon atoms

Λ carbon and a group of the general formula -N, in which R^ and Rg have the meanings given above.

⁶

An alkyl group having 1 to 6 carbon atoms preferably denotes a methyl, ethyl or isopropyl group.

An alkyl group with 1 to 12 carbon atoms preferably denotes a methyl, ethyl, isopropyl or octyl group.

The alkenyl group having 2 to 4 carbon atoms is preferably a vinyl or allyl group.

An alkynyl group with up to 4 carbon atoms preferably denotes a propargyl group.

The 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.

Alkoxy with 1 to 6 carbon atoms preferably denotes a methoxy or ethoxy group.

Aryl(C1-C8)alkyl or aryl(C1-C6)alkyl group preferably denotes a benzyl or phenethyl group.

Aryl(C1-C8)alkoxy preferably denotes a benzyloxy group.

207596

In the group of the general formula -N, Rg and Rg independently of one another represent a hydrogen atom or a C1-6 alkyl group having 1 to 3 carbon atoms, in particular a methyl, ethyl or isopropyl group.

A cycloalkyl group with 3 to 7 carbon atoms preferably denotes a cyclopropyl, cyclopentyl or cyclohexyl group.

In the case where the groups R1 and R4 together with the nitrogen atom to which they are attached form a substituted heteromonocyclic radical, the preferred substituents are an alkyl group with 1 to 6 carbon atoms or an aryl group, and particularly preferred are a methyl or phenyl group; the preferred heteromonocyclic radical is a morpholine, piperidine, N-pyrrolidinyl, N-methylpiperazinyl or N-phenylpiperazinyl residue.

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

Due to the presence of at least two asymmetric carbon atoms in the compounds of formula I, each of these compounds can exist in the form of at least two different diastereoisomers, from which at least four different enantiomers can be obtained; both the individual diastereoisomers and their mixtures, as well as said individual enantiomers, are included within the scope of the present invention.

As pharmaceutically acceptable salts of the compounds of general formula I, both salts with inorganic acids, for example with hydrochloric, hydrobromic or sulfuric acid, and salts with organic acids, for example with citric acid, tartaric acid, methanesulfonic acid, fumaric acid, malic acid, maleic acid or mandelic acid, can be used.

According to the invention ^, preferred salts are those salts of compounds of general formula I in which the group of general formula -N forms a salt with one of the above-mentioned acids, preferably ^Xr 4 with hydrochloric acid.

Preferred compounds according to the invention are those compounds of the general formula I, in which nan, independently represents the number 1 or 2, each individual group R and R, independently represents a hydrogen atom, a methoxy group, an ethoxy group, a chlorine atom or a trifluoromethyl group, or two adjacent groups R form the residue -O-CH ₂ -O-, R ₂ represents a hydrogen atom or a methyl group, and one of the substituents R 3 and R 4 represents a hydrogen atom and the other represents a methyl group, as well as pharmaceutically acceptable salts thereof.

Particularly preferred compounds according to the invention are those compounds of the general formula I in which nan, independently of one another, represents the number 1 or 2, each individual group R and R, independently of one another represents a hydrogen atom, a methoxy group, an ethoxy group, a chlorine atom or a trifluoromethyl group, or two adjacent groups R form the radical -O-CH ₂ -O-, R ₂ and R4 together form the radical -CH ₂ -CH ₂ - and Rj represents a hydrogen atom, a methyl group or an isopropyl group, as well as pharmaceutically acceptable salts thereof.

The essence of the production of compounds of general formula I by the method according to the invention is that the compound of general formula III is reduced

in which n, n,, R, R, R ₂ , Rj and R^ have the meanings given above, and the obtained compound of general formula I is optionally converted into another compound of general formula I, and/or the compound of general formula I is optionally converted into a salt, or the free compound of general formula I is prepared from its salt, and/or the obtained mixture of isomers of general formula I is optionally separated into the individual isomers.

_The reduction of the compound of general formula III can generally be carried out by methods usually used for the reduction of nitriles and amides, for example by the action of lithium aluminum hydride or borane in an anhydrous inert solvent, preferably in an aliphatic ether, for example in diethyl ether, or in tetrahydrofuran, or in a mixture of these solvents, at a temperature in the range from about f 0 ° C to the boiling point of the solvent used, or by the action of an alkali metal borohydride, for example sodium borohydride, in the presence of alkali metals, as described for example in the journal Tetr. Lett. 1969, p. 4 555.

In the case where in the compounds of the above formula III one or more of the substituents R, Ej, S^ and R^ represent reducible groups and it is desired to retain these groups unchanged in the final compounds of the formula 1, then the reduction should preferably be carried out using selective reduction conditions.

For example, the reduction of compounds of general formula III containing halogen atoms 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, for example diethyl ether, in a nitrogen atmosphere, by the method described, for example, in the journal J. Am. Chem. Soc. 86. 3 566 (1964), or by reducing with zinc in ethanol, by the method described in the journal Experientia 33 (1), 101-102 (1977).

The reduction of compounds of the general formula III, in which Rj and R4 denote an alkenyl group with 2 to 4 carbon atoms or an alkynyl group with 2 to 4 carbon atoms, can be carried out selectively with respect to these groups using, for example, lithium aluminum hydride as a reducing agent, under the reaction conditions described above. However, under these conditions, nitro groups and halogen atoms are also reduced, if present in the molecule of the substances, and therefore compounds of the general formula X, in which one or more substituents R and R^ denote a nitro group or a halogen atom and at the same time R^ represents an alkenyl group with 2 to 4 carbon atoms or an alkynyl group with 2 to 4 carbon atoms, cannot be prepared by this reduction method. The said compounds can be prepared by converting a suitable compound of the general formula I into the desired other compound of the general formula I.

*

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

For example, a compound of the general formula I in which Rj represents a hydrogen atom and R4 has the above meaning or together with _R2 forms a group of the formula _-CH2 - _CH2- , can be converted into the corresponding compound of the general formula I in which Rj represents an alkyl group with 1 to 6 carbon atoms, an alkenyl group with 2 to 4 carbon atoms, an alkynyl group with 2 to 4 carbon atoms, an arylH^-C^alkyl group or a cycloalkyl group with 3 to 7 carbon atoms, by conventional methods of alkylation of amines, for example by reductive amination or direct alkylation.

Reductive alkylation consists in the reaction of a compound of general formula I, in which R3 and/or R4 represent a hydrogen atom, with a suitable carbonyl compound, i.e. with an aldehyde or a ketone, in the presence of a reducing agent, which may be hydrogen gas or preferably mixed hydrides, such as 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, for example 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 to about 50°C, as described, for example, in Org. Reactions 4, 174 (1948). When a mixed hydride, for example sodium cyanoborohydride or sodium borohydride, is used as the reducing agent, the reductive amination can be carried out in the presence of an excess of the 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 the reductive amination is carried out using formic acid under Leukert-Wallac reaction conditions, formic acid is preferably used in excess and the reaction mixture is heated for two to twelve hours as described in the monograph Org. Reactions 5, 301 (1949).

Alkylation can further be carried out by reacting a primary amine of formula I, for example, with a suitable alkyl or aralkyl halide, or with a reactive ester, for example, a tosylate or mesylate, of a suitable alcohol. 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 the above solvents, in the presence of an acid acceptor, such as triethylamine, 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 the journals J. Org. Chem. 2, 139 (1938), Org. Synth., Vol. II, p. 183 (1943), J. Am. Chem. Soc. 54. 4,457 (1932).

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

Org. Chem. 40, 23, 3453 (1975), J. Chem. Soc. 2223 (1969), J. Med. Chem. U (1), 654 (1974).

A compound of general formula 1, in which one of the substituents R3 and R4 represents a hydrogen atom, can be converted into the corresponding compound of general formula I, in which one of the substituents R1 and R4 represents a methyl group, preferably also by reacting the starting amino substance with ethyl chloroformate in chloroform, in the presence of excess potassium hydroxide, at a temperature in the range 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 general formula 1, in which one of the substituents R3 and R4 represents an alkyl group with 1 to 6 carbon atoms and the other represents a hydrogen atom, can alternatively be prepared by the following procedure: a') a compound of general formula I, in which both substituents R3 and R4 represent hydrogen atoms, is 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 and in the presence of Raney nickel or palladium on activated carbon, or by means of mixed hydrides, for example lithium aluminum hydride or sodium borohydride, as described, for example, in the Houben-Weyl monograph, volume XI, part 1, page 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 the journal J. Am. Chem. Soc. 63. 1964 (1941), or preferably, by treatment with ethyl chloroformate at the boiling temperature of the reaction mixture, as described in J. Med. Chem. 18 (6), 576 (1975). In an analogous manner, a compound of the general formula I in which one of the substituents R1 and R4 represents a benzyl group can be converted into the corresponding compound of the general formula I in which one of the substituents R1 and R4 represents a hydrogen atom.

A compound of general formula I in which both substituents Rj and R4 represent hydrogen atoms can be converted into the corresponding compound of general formula I in which one of the substituents Rj and R4 represents a hydrogen atom and the other represents a benzyl group, also by reacting it with benzyl chloride in the presence of aqueous sodium hydroxide, in an organic solvent, such as dichloromethane, preferably at a temperature in the range from 0 °C to room temperature, and the benzoylamino derivative obtained is reduced with a mixed hydride, for example lithium aluminum hydride or borane, in a tetrahydrofuran or diethyl ether environment, at the boiling point of the reaction mixture.

, Compounds of general formula I, in which Rg represents a hydrogen atom, can be converted into compounds of general formula I, in which Rg represents an alkyl group with 1 to 12 carbon atoms or an aryl(C1-C8)alkyl group, by methods usually used for the etherification of alcohols, for example by reacting an alkali metal salt of the alcohol, for example the lithium or sodium salt, with the appropriate alkyl or aralkyl halide. The said reaction can be carried out at a temperature ranging from room temperature to the boiling point of the reaction mixture, in an organic solvent, which can be, for example, the same solvent in which the alkali metal salt of the alcohol is prepared.

The lithium salt of an alcohol can be obtained by reacting the corresponding alcohol with an alkyl lithium, for example butyl lithium, in an inert anhydrous solvent such as tetrahydrofuran. The sodium salt can be prepared by reacting the corresponding alcohol with metallic sodium or sodium hydride in an inert solvent such as benzene, toluene or dimethylformamide. In an analogous manner, compounds of the general formula I in which one of the substituents R and R is a hydroxyl group can be converted into the corresponding compounds of the general formula I in which one of the substituents R and R is an alkoxy group with 1 to 6 carbon atoms or an aryl(C1-C6)alkoxy group.

Compounds of the general formula I in which R2 represents an alkoxy group with 1 to 6 carbon atoms or an aryl(C1-C6)alkoxy group can be converted into the corresponding compounds of the general formula I in which _R2 represents a hydroxyl group by conventional methods of deetherification. For example, a compound of the general formula I in which Rg represents a methoxy group can be deetherified by the action of pyridine hydrochloride or boron tribromide, or by the action of potassium ethanethiolate in dimethylformamide at 100 to 130 °C, as described, for example, in the Journal J. Med. Chem. 20 (1), 165 (1977). If the deetherification is carried out by the action of pyridine hydrochloride, it is preferably carried out in a nitrogen atmosphere at a temperature of about 150 °C. Deetherification using boron tribromide ⁽⁾ is preferably carried out by adding a solution of boron tribromide in chloroform to a solution of the compound of general formula I, cooled to -70 to -80 °C, under a nitrogen atmosphere, and terminating the reaction by dropwise addition of methanol at 0 °C.

Compounds of general formula I, in which both substituents R1 and R4 represent methyl groups, can be converted into the corresponding compounds of general formula I, in which one of the substituents R1 and R4 represents a methyl group and the other represents a hydrogen atom, for example by reacting them with ethyl chloroformate in benzene or toluene at the boiling point of the solvent used, and the product obtained is decomposed by the action of an alcoholic solution of potassium hydroxide at the boiling point of the reaction mixture.

Compounds of general formula I, in which one of the substituents R and R, represents a nitro group, can be converted into the corresponding compounds of general formula I, in which one of the substituents R and Rj represents an amino group, by methods usually used for the reduction of aromatic nitro compounds, for example by catalytic hydrogenation, using for example platinum, palladium or Raney nickel as a catalyst, by known methods of organic chemistry.

Compounds of general formula 1, in which one of the substituents R and R represents an amino group, can be converted into the corresponding compounds of general formula 1, in which one of the substituents R and R represents a hydroxyl group, by converting the amine to the corresponding diazonium salt and then hydrolyzing it, for example by the method described in the journal Org.

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

Compounds of formula I in which one of the substituents R and R represents an amino group can be converted into the corresponding compounds of formula I in which one of the substituents R and R represents a mono- or dialkylamino group with 1 to 6 carbon atoms by reductive amination or alkylation by the methods described above.

As already mentioned above, the conversion of compounds of general formula I into salts, as well as the preparation of the free compound from its salt and the separation of isomers from their mixture, can also be carried out by conventional methods. ₍

For example, the hydrochloric acid salt of a compound of formula I can 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 hydrogen chloride, and isolating the resulting hydrochloride by either filtering or evaporating the solvent.

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

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

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

Compounds of formula III, in which Rg, Rj and R^ are as defined above except that Rg and R^ do not together form a group -CHg-CHg-, can be prepared by conventional methods for preparing amides, for example by reacting an amine of formula HNR3R4, in which Rj and R4 are as defined above, with an acid of formula XII.

in which R, R, n, n ₁ and Rg have the above-mentioned meaning, or with a reactive derivative thereof, for example with an acid halide, or with an alkyl ester with 1 to 6 carbon atoms, preferably 3 ethyl acid ester. The reaction can be carried out either in the absence of a solvent, or in the presence of a suitable solvent, such as an aliphatic alcohol with 1 to 6 carbon atoms, for example ethyl alcohol, optionally in the presence of a condensing agent, for example dicyclohexylcarbodiimide, or in the presence of an acid acceptor, for example an alkali metal carbonate or bicarbonate or a tertiary amine, for example triethylamine, or an excess of the starting amine of the general formula HNR3R4.

Compounds of general formula III, in which _R2 and R4 together form a group -CH2-CH2-, can be prepared, for example, by cyclization of a compound of general formula XIII

< ^R l'n.

jy-r, (XIII) in which R, R ₁ , n, n, and R j have the above-mentioned meaning and X represents a hydroxyl group or a halogen atom, or preferably a residue of a reactive alcohol ester, for example a tosyloxy or mesyloxy group, using the reaction conditions described for example above, preferably in the case where X represents a halogen atom or a residue of a reactive alcohol ester, in the presence of at least an equimolar amount of a base preferably selected from the group comprising alkali metal carbonates and bicarbonates, for example potassium carbonate, in a suitable solvent, for example dimethylformamide, dimethylsulfoxide and the like.

Compounds of general formula III, in which _R2 and R3 together form the group _-CH2 - _CH2- , can alternatively also be prepared by reacting a compound of general formula XIV

in which R, R1, n, and R3 have the meanings given above, is heated in a suitable solvent, for example in phosphoric acid hexamethyltriamide, to a temperature in the range of from 120 to 160°C, as described, for example, in the journal Can. J. Chem. 49, 914 (1971).

The compounds of general formula I according to the invention have an effect on the central nervous system and are important antidepressant-active substances.

The antidepressant efficacy of the substances was tested in mice by monitoring the effect on eyelid twitching and hypothermia induced by reserpine.

Reserpine was administered endoperitoneally at a dose of 2.4 mg/kg and the tested compounds of general formula I were administered orally 30 minutes before the administration of reserpine. One hour or four hours after the administration of reserpine, eyelid twitching was recorded (the number of twitches was assessed using the technique described by B. Rubín and co-workers in the journal J. Pharmacol.

120. 125 /1957/) and body temperature was measured (using a rectal thermocouple).

The following table shows the antidepressant efficacy of two compounds produced by the method of the invention in comparison with antitriptyline, a known antidepressant drug. The antidepressant efficacy was evaluated based on the prevention of reserpine-induced blepharospasm and hypothermia.

207696 10

Antireserpine effect in mice (SCF/4 tests) ED^q mg/kg/person

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 general formula X have been administered primarily orally, although they can also be administered by other conventional routes, for example by injection or rectally.

For oral administration to adults, a suitable dose of the compound of general formula 1 is preferably 5 to 30 mg for a dose of 2 to 4 times daily.

Pharmaceutical preparations containing compounds of general formula I as active ingredient can be produced by conventional methods, using conventional excipients.

For example, for oral administration, pharmaceutical preparations containing compounds of the general formula I can be produced, preferably in the form of tablets, pills or capsules, which contain the active ingredient together with suitable excipients, such as diluents, for example lactose, glucose, sucrose, mannitol, sorbitol or cellulose; lubricants, for example silicon dioxide, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binders, for example starches, gelatin, methylcellulose, gum arabic, tragacanth or polyvinylpyrrolidone; leavening agents, for example starches, alginic acid or alginates; effervescent mixtures; colorants; sweeteners; wetting agents, for example lecithin, polysorbates or lauryl sulfates; and generally non-toxic and pharmacologically inactive substances used in the manufacture of pharmaceutical preparations. The pharmaceutical preparations mentioned can be manufactured by methods known per se, for example by mixing, granulating, tabletting and coating with a layer of sugar or a film of another suitable substance.

Other pharmaceutical preparations containing a compound of general formula I as an active ingredient, for example syrups or drops for oral administration, sterile solutions for injection or suppositories, can also be produced by known methods.

In the following examples, the following abbreviations are used: 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 relate to mixtures of diastereoisomers.

The method according to the invention is explained in more detail in the following examples, which, however, do not limit the scope of the invention in any way.

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 at this temperature 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 another 15 minutes, then the organic layer was separated and the aqueous portion was shaken with chloroform. The combined organic portions were washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. N-ethoxycarbonyl-2-hydroxy-3-(3,4-methylenedioxyphenoxy)-3-phenylpropylamine was obtained in the form of an oily liquid; yield 94.8%.

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

The following compounds are prepared by an analogous procedure:

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

N-methyl-2-hydroxy-3-(2-methoxyphenoxy)-3-phenylpropylamine, hydrochloride, mp 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, mp 125-145°C; N-methyl-2-hydroxy-3-(4-ethoxyphenoxy)-3-phenylpropylamine;

N-methyl-2-hydroxy-3-(2-chlorophenoxy)-3-phenylpropylamine, hydrochloride, mp 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-ethoxyphenoxy)-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 mp 126-145°C;

N-methyl-2-hydroxy-3-(2-ethoxyphenoxy)-3-(3-chlorophenyl)propylamine, hydrochloride, mp 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) is added methyl iodide (6.23 ml) and 55% sodium hydride (4.36 g) is added while stirring and cooling to 0 to 5 °C. The reaction mixture is stirred with constant cooling for 1 hour 30 minutes, then the excess hydride is carefully decomposed with water, excess water is added and the product is taken up in ethyl acetate. The organic extract is washed with water, dried with anhydrous sodium sulfate and the solvent is distilled off. The residue is purified by dissolving in methanol and filtering off the insoluble portion. After distilling off the solvent from the filtrate, 3.1 g of N-methyl-N-ethoxycarbonyl-2-methoxy-3-(3,4-methylenedioxyphenoxy)-3-phenylpropylamine was obtained as an oily liquid; yield 80.2%.

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

The following compounds are prepared in an analogous manner:

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

N-methyl-2-methoxy-3-(2-methoxyphenoxy)-3-phenylpropylamine, hydrochloride, mp 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, mp 123-137°C; N-methyl-2-methoxy-3-(4-ethoxyphenoxy)-3-phenylpropylamine;

N-methyl-2-methoxy-3-(2-chlorophenoxy)-3-phenylpropylamine, hydrochloride, mp 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-ethoxyphenyl)pro pylamin;

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)pro pylamin;

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-c-chlorophenyl)propylamine;

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

N-methyl-2-methoxy-3-(2-ethoxyphenoxy)-3-(3-chlorophenyl)propylamine, hydrochloride, mp 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-ethoxyphenoxy)-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 a temperature of 8 °C, 340 ml of a molar solution of diborane in THF is slowly added.

The mixture is heated to reflux for 4 hours, then cooled to room temperature, the excess diborane is decomposed carefully by dropwise addition of methanol and the mixture is acidified, again at room temperature, by adding 400 ml of ethereal hydrogen chloride solution. The mixture is left to stand for 16 hours, then the volatiles are distilled off under reduced pressure, the residue is taken up in methylene chloride and the solution is washed once with an aqueous solution of sodium hydrogen carbonate. The organic portion is washed several times with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and the solvent is distilled off. The dark oily residue is dissolved in 800 ml of ethyl ether and an alcoholic solution of hydrogen chloride (18% solution) is added to the solution; 50.9 g of N-methyl-2-hydroxy-3-(2-nitrophenoxy)-3-phenylpropylamine hydrochloride are obtained, melting point 197-203°C; yield 94%.

Infrared spectrum, v _max (KBr): 1,525 cm-' (N0 ₂ ), 2,700 cm-' (NH ₂ ).

All compounds mentioned in Examples 1 and 2 are prepared in an analogous manner.

Example 4

To a solution of 40 g of ethyl 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 for 24 hours at 40 to 50 °C in a closed autoclave. The volatile components are distilled off under reduced pressure, the residue is dissolved in 200 ml of absolute ethyl alcohol, the solution is evaporated to dryness again and the residue is recrystallized from isopropyl alcohol. 36 g (94.2%) of N-methyl-2-hydroxy-3-phenyl-3-(2-nitrophenoxy)propionamide with a melting point of 162 to 163 °C are obtained.

Infrared spectrum, ^v max (nujol): 1,640 om ^- ' (CON), 3,300 cm"' (OH, broad band),

400 cm ^- ' (narrow, intense band).

In an analogous manner, the propionamides required for the preparation of propylamines are prepared by the method described in Example 3. Example 5

To a solution of 66 g of trans ethyl glycidate (i.e. ethyl ester of trans-2,3-epoxypropionic acid) 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, with stirring, to reflux for 48 hours. Then another 24 g of o-nitrophenol is added and the mixture is refluxed for a further 36 hours. The solvent is distilled off under reduced pressure, the residue is dissolved in water and the product is taken up in ethyl acetate. The ethyl acetate extract is shaken with 2 N sodium hydroxide solution until the excess phenol is completely removed, then washed with water until neutral, dried over anhydrous sodium sulfate and the solvent is distilled off. After recrystallization of the residue from diethyl ether, g (60%) of ethyl 2-hydroxy-3-phenyl-3-(2-nitrophenoxy)propionic acid ester with a melting point of 129-131 °C is obtained.

Infrared spectrum, v (nujol): 1525 cm"' (N0 _P ), 3300 cm"' (OH, Broadband), 1740 cm"' ( ^c C ₀ /·

In an analogous manner, all 2-hydroxypropionates required for the synthesis of 2-hydroxypropionamides are prepared as described in Example 4 (including the respective 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 at 3 °C is added methyl iodide (0.78 ml) and then, at the same temperature, in two portions, a total of 0.3 g of 50% sodium hydride. The mixture is stirred for one hour at 3 °C and one hour at room temperature, then the solution is poured into 300 ml of water and the product is taken up in ethyl ether. The ethereal solution is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent is 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 ).

NMR spectrum, ppm (CDCl 3 ): 3.24 (3H).

In an analogous manner, all 2-methoxypropionates required for the preparation of 2-methoxypropionamides are prepared according to the procedure of Example 4.

Example 7

A solution of 6.9 g of ethyl 3-phenyl-3-(2-nitrophenoxy)-2-methoxypropionate in 150 ml of absolute ethanol is hydrogenated in the presence of 5% palladium on activated carbon at atmospheric pressure at room temperature. The reduction is complete within 30 minutes. The catalyst is filtered off and the solvent is 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, in (KBr); 2,850 cm' (ArNH1), 1,740 cm' (c^ ), max J \

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

Infrared spectrum,

740 cm ^- '

^v max ( ⁱⁿ chloroform): 3,500 cm ^-1 (OH dimer - broad 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 was added 4.8 ml of anhydrous potassium carbonate and then a solution of 2.2 ml of methyl iodide in 15 ml of dimethylformamide was added dropwise with stirring. 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. After purification of the crude product by column chromatography on silica gel, 8.6 g of ethyl 3-phenyl-3-(2-methoxyphenoxy)-2-methoxypropionate were obtained in a yield of 86.8%.

Infrared spectrum, ^v max (film): 2,815 cm ^- ' (OCHj), 1,738 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 a solution of methyl iodide (5.5 g) in benzene (20 ml) was added dropwise at room temperature over 1 hour. The reaction mixture was stirred at room temperature for 20 hours, then the solid was filtered off and the solvent was distilled off from the filtrate. The oily product gave 7 g (57% yield) of 4-methyl-2-(alpha-(2-methoxyphenoxy)-4-chlorobenzyl)morpholine after column chromatography on silica gel.

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, mp 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 ) vN-CH ₃ 2 805 cm ^- ', in arom. ethers 1 255 cm ^- ', in 1.2 subst. phenyl 750 cm'; 4-methyl-2-(alpha-/4-ethoxyphenoxy/benzyl)morpholine, | I. δ. (CHCl^) in N-CH ₃ 2 805 cm ^- ', in arom. ethers 1 250 cm ^- ', in monosubstit. 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-ε-toxyphenoxy]-2-methoxybenzyl)morpholine;

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

4-methyl-2-(alpha-[4-ethoxyphenoxy]-4-ethoxybenzyl)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-methyloxyphenoxy]-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,

IC (CHClj) in O-CH-j 2840 cm ^- ' , in N-CH^ 2805 cm ^- ' , in arom. ethers 1 245 cm ^- ', in 1,2 substt. phenyl 750 cm ^-1 ;

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

IC (CHClj) in N-CH^ 2,810 cm ^- ', _in arom. ethers 1 255 cm ^- ', in 1,2 substit. 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-ε-toxyphenoxy]-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 2N sodium hydroxide (18.2 ml) and then ethyl chloroformate (3.5 ml) was added dropwise over 30 minutes while cooling to 0 °C. The reaction mixture was stirred while cooling to 0 °C for another 1 hour, then the organic layer was separated, washed with water and dried over anhydrous calcium chloride. The solvent was distilled off, the colorless oily product obtained 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). The mixture was stirred for 20 hours at room temperature, then the excess hydride was carefully decomposed 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 fraction was extracted with diethyl ether. The combined organic fractions were washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. 6.25 g (yield 82%) of 4-methyl-2-(alpha-(2-methoxyphenoxy)-4-chlorobenzyl)morpholine was obtained as an oily liquid.

All 4-methylmorpholine derivatives listed in Example 10 are 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) and water (8 ml) and then, over 1 hour, sodium borohydride (6.024 g) with good stirring at a temperature of about 0 °C. Then, more acetone (12 ml) and sodium borohydride (3 g) were added, the temperature of the reaction mixture was allowed to rise to room temperature and the mixture was stirred for 30 hours. The reaction mixture was poured into an aqueous solution of sodium bicarbonate and the product was taken up in diethyl ether. The ether extracts were combined, washed with water, dried with 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 was obtained; the hydrochloride has a melting point of 200 to 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, mp 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-chlo-rbenzy-Dmorpholine;

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

Infrared spectrum, ^v max (in chloroform): 3,320 cm ^-1 (NH), 1,525 cm- ¹ (NO ₂ ).

The following compounds are prepared in an analogous manner:

2-(alpha-phenoxybenzyl)morpholine, hydrochloride, mp 199-202°C;

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

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

2-(alpha-/4-methoxyphenoxy/benzyl)morpholine, hydrochloride, m.p. 50-57 °C; 2-(alpha-/2-ethoxyphenoxy/benzyl)morpholine, one diastereoisomer has 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 to 97°C;

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

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

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

2-(alpha-/2-ε toxyphenoxy/-2-methoxybenzyl)morpholine;

2-(alpha-phenoxy-4-e toxybenzyl)morpholine;

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

2-(alpha-[4-e toxyphenoxy]-4-ethoxybenzyl)morpholine;

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

2-(alpha-[4-chlorophenoxy]-4-e toxybenzyl)morpholine;

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

2-(alpha-[4-methoxyphenoxy]-4-e toxybenzyl)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, mp 155-160°C; 2-(alpha-/2-ethoxyphenoxy/-3-chlorobenzyl)morpholine, hydrochloride, mp 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, mp 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-e toxyphenoxy]-3,4-dichlorobenzyl)morpholine;

2-(alpha-/2-methoxyphenoxy/benzyl)-4-methylmorpholine, hydrochloride, mp 67 to 90 °C, Infrared spectrum, v _max (KBr): 2,700 cm ^- ', (NI?); 2815 cm'(OCH^); 2-(alpha-/2-nitrophenoxy/benzyl)-4-methylmorpholine, mp 78 to 81 °C,

Infrared spectrum, v _max (in chloroform): 1,525 cm ^-1 (NOg),

NMR spectrum, ppm (in deuterochloroform): 5.3 (d, H benzylic), 7.4-6.8 (s, 9H, thioic aroma), 2.27 (s, CH^), and also all compounds mentioned 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 is added 1.38 g of potassium carbonate. The mixture is heated with stirring for 5 hours at 50 °C, then poured into water and the product is taken up in ethyl acetate. The combined organic extracts are dried and the solvent is distilled off. The residue gives, after chromatography on a silica gel column, 1.27 g (yield 38.6%) of 2-(alpha-/2-nitrophenoxy/benzyl)morpholin-3-one.

Infrared spectrum, in (nujol): 3,450 cm ^-1 (NH), 1,670 cm ^- ' (CONH),

IΠ&Χ

525 cm ¹ (NO ₂ ).

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

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, while stirring and cooling to -10 °C, a solution of 1.83 g of methyl chloride in 30 ml of THF is slowly added dropwise. The reaction mixture is stirred for 45 minutes at -10 °C, then the temperature is allowed to rise to room temperature and the solution is 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 with water until neutral and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from 95% ethanol. 4.86 g (yield 76.5%) of N-(2-methyloxyethyl)-3-phenyl-2-hydroxy-3-(2-nitrophenoxy)propionamide with a melting point of 122-125°C are obtained.

Infrared spectrum, v _max (KBr): 3,500 cm ^-1 (OH, broad band), 3,450 cm ^-1 (NH),

650 cm ¹ (CONH), 1,525 cm- ¹ (NO2), 1,350 cm“ ¹ (SO 2 ), 1,180 cm ¹ (S0 ₂ ).

The other N-(2-methyloxyethyl)propionamides required for the preparation of the compounds listed in Example 14 are 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 Ø 50 ml of anhydrous ethanol is heated to reflux for 20 hours. The solvent is distilled off under reduced pressure, the residue is stirred with water and the solid product is filtered off. After recrystallization from ethyl acetate, 1.8 g of N-(2-hydroxyethyl)-3-phenyl-2-hydroxy-3-(2-nitrophenoxy)propionamide is obtained with a melting point of 166-188 °C; yield 58%.

Infrared spectrum, v _max (nujol): 3,400 cm ^-1 (OH, NH, broad band),

650 cm ¹ (CONH), 1,525 cm ¹ (NO ₂ ).

In an analogous manner, other N-(2-hydroxyethyl)propionamides required for the preparation of the compounds mentioned in Example 15 are prepared.

Example 17

A solution of 0.9 g of 2-(alpha-phenoxycarbonyloxybenzyl)morpholin-3-one in 2.5 ml of phosphoric acid hexamethyltriamide is heated to 140 °C; after 1 hour the reaction is complete. The mixture is diluted with water, the product is taken up in ethyl acetate, the combined organic extracts are washed with water, dried over anhydrous sodium sulfate, filtered and the solvent is 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 listed in Example 13 are 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, 0.5 g of phenyl chloroformate was added dropwise. The mixture was stirred for 12 hours at room temperature, then 30 ml of methylene chloride was added and the solution was 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 was obtained in a yield of 95%.

In a similar manner, all analogous intermediates required as starting materials for the preparation of the compounds given in Example 17 are prepared.

Example 19

Under a nitrogen atmosphere and with the exclusion of atmospheric moisture, 26.7 ml of a 15% solution of butyllithium in hexane was 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 for 2.5 hours at room temperature, 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 for 3 hours at -62 °C, then the temperature was allowed to rise to room temperature and stirred at this temperature for a further 16 hours. The excess butyllithium was decomposed by adding a little water, the solvents were distilled off and the residue was taken up in a dilute sodium bicarbonate solution. The product is extracted with ethyl acetate, the organic portions are combined, washed with water, dried over anhydrous sodium sulfate, filtered and the solvent is 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 130-140 ° C. Yield 58%.

Infrared spectrum, v _max (in chloroform): 3,400 cm ^-1 (OH, broad band), 3,300 to 3,200 cm“ ¹ (NH), 1,660 cm ¹ (CO).

In an analogous manner, all intermediates required as starting materials for the preparation of the compounds listed in Example 18 are prepared.

Example 20

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

.Infrared spectrum, v _max (in chloroform): 2,700 cm' (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 activated carbon 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. After recrystallization from a mixture of ethyl acetate and ethanol, 5.1 g of 2-(alpha-(2-aminophenoxy)benzyl)-4-methylmorpholine monohydrochloride is obtained; yield 76%.

Infrared spectrum, v _max (KBr): 3,400 cm -1 (NH ₂ ), 2,700 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, 2.2 g of anhydrous potassium carbonate were added with stirring at room temperature, and then 1 ml of methyl iodide was slowly added dropwise. The mixture was stirred for 5 hours at 55 °C, then poured into 700 ml of cold water and the product was taken up in ethyl ether. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to a small volume. After adding 18% alcoholic hydrogen chloride solution to the concentrated solution, 4 g (yield 76%) of 2-(alpha-/2-methoxyphenoxy/benzyl)-4-methylmorpholine was precipitated as the hydrochloride with a melting point of 67-90 °C (with decomposition).

Infrared spectrum, v _max (KBr): 2,820 cm' (OCH3), 2,700 cm' (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, the mixture is cooled to 0 °C and at the indicated temperature a solution of 3.45 g of sodium nitrite in 20 ml of water is slowly added dropwise with stirring. The mixture is stirred with cooling for 20 minutes, then the temperature is allowed to rise to room temperature and finally the solution is heated on a water bath at 40 °C until the evolution of nitrogen ceases. 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 to the solution. After dilution with a small amount of ethyl ether, 4.65 g (31% yield) of 2-(alpha-/2-hydroxyphenoxy/benzyl)-4-methylmorpholine hydrochloride is separated.

Infrared spectrum, ^v _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, 3 ml of ethyl chloroformate are added and the mixture is heated to reflux for 24 hours. The solvent is distilled off, the oily residue obtained (5.9 g) is dissolved in 15 ml of 8% aqueous-alcoholic hydrochloric acid and the solution is heated to reflux for 4 hours. The solvents are evaporated to dryness, the residue is dissolved in 50 ml of water and the product is shaken into ethyl ether. The combined ether extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to a small volume. After addition of an 18% solution of hydrogen chloride in absolute ethanol, 3.5 g of 2-(alpha-(2-nitrophenoxy)benzyl)morpholine hydrochloride precipitated; yield 68%.

Infrared spectrum, v _max ^; 2,800 cm' (NH), 1,525 cm' (N0 ₂ ).

The compounds shown in Example 13 are 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) and hydrochloric acid (6 ml) was hydrogenated in the presence of palladium on activated carbon for 4 hours at room temperature. The catalyst was filtered off, the solvents were distilled off under reduced pressure and the residue was chromatographed on a silica gel column, using a mixture of chloroform with methanol and concentrated ammonia in a ratio of 170:30:2 as eluent. 2.1 g (yield 54.7%) of 2-(alpha-(2-methoxyphenoxy/benzyl)morpholine was obtained as a clear oily liquid; the hydrochloride had a melting point of 140-170 °C.

The morpholine derivatives given in Example 13 are prepared in an analogous manner, except for 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 with ethyl chloroformate (1.2 ml) at reflux for 5 hours. The solvent was distilled off and the residue was heated with 10% methanolic potassium hydroxide solution (70 ml) at reflux for 2 days. The solvent was evaporated to dryness and the residue was partitioned between ethyl ether and water. The aqueous portion was extracted with fresh ether and the combined ethereal extracts were worked up by shaking the base into the acid, releasing it from the acidic solution by alkalization and taking it up into ethyl ether. After drying over anhydrous sodium sulfate, filtering off the drying agent 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; the hydrochloride has a melting point of 140-170 °C.

All compounds listed in Example 13 are prepared in a similar manner.

Example 27 j

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

i oL Π18Χ

Example 28

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

Composition (for 10,000 tablets):

2-(alpha-/2-methoxyphenoxy/benzyl)morpholine 250 g lactose 1 ,230 g cornstarch 450 g talc (ground) 50 g magnesium stearate 20 g

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

Example 29

Tablets, each weighing 200 mg and containing 25 mg of active ingredient, are prepared as follows.

Claims (4)

SUBJECT OF THE INVENTION 1. A process for the production of substituted propanolamine and morpholine derivatives of the general formula I in which n and nj individually represent the number 1, 2 or 3, ΠβΗρ which may be the same or different, individually represent a hydrogen atom, a halogen atom, a haloalkyl group with 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group with 1 to 6 carbon atoms, an alkyl group with 1 to 6 carbon atoms, optionally substituted by at least one hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a group -N^ ^R 5 or x^ ^r 5 by a group -CO-N , in which Re and R _fi individually represent a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, an aryl(C,-Cg)alkyl group, optionally substituted by at least one hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a group -N or a group ^R ₅ ^XR 6 -CO-N, in which Rg and Rg have the above meaning, an aryl(C,-Cg)alkoxy group, optionally substituted by at least one hydroxy ^group , an alkoxy group with 1 to 6 carbon atoms, a -Rc/Rg group with -N or a -CO-N group, in which Rg and Rg have the above meaning, a nitro group with ^R5 , a group of the formula -N, in which Rg and Rg have the above meaning, or two adjacent ^ ^r 6 R groups or two adjacent R groups together form the residue -O-CHg-O, R ₂ represents a hydrogen atom, an alkyl group with 1 to 12 carbon atoms, optionally substituted by a halogen atom, a hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a group ^Rg -^Rg -N or -CO-N, in which Re and R< have the above meaning, or an aryl(C,-Cg) _alkyl ^group , and Rj and R^, which may be the same or different, each represent a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, optionally substituted by a halogen atom, a hydroxy group, x-Rg /Rg an alkoxy group with 1 to 6 carbon atoms, a -N or -CO-N group, in which Re and Rz- have the above-mentioned meaning, an alkenyl group with 2 to 4 carbon atoms, an alkynyl group with 2 to 4 carbon atoms, an aryl(C,-Cg)alkyl group, optionally substituted in the aryl by at least one alkyl with 1 to 6 carbon atoms, a halogen atom, a haloalkyl with 1 to 6 carbon atoms/Rg ku, a hydroxy group, an alkoxy group with 1 to 6 carbon atoms or a -N group, in which Re ^XR 6 and Rg have the above-mentioned meaning, a cycloalkyl group with 3 to 7 carbon atoms carbon, optionally substituted by at least one alkyl with 1 to 6 carbon atoms, a halogen atom, a haloalkyl with 1 to 6 carbon atoms, a hydroxy group, an alkoxy group with 1 to 6 carbon atoms or a group/R5 pina -N, in which Re and R _ò have the above-mentioned meaning, or both substituents Ri and R. together with the nitrogen atom to which they are bound, form a five-membered or six-membered, saturated or unsaturated heteromonocyclic radical, which optionally contains further heteroatoms from the group comprising an oxygen, sulfur and nitrogen atom and which is optionally substituted by alkyl with 1 to 6 carbon atoms or aryl, or Rg and R^ together form a radical of the formula -CHg-CHg-, and their pharmaceutically acceptable salts, characterized in that the compound of the general formula III (III) is reduced 3) in which n, , R, Rp R ₂ , R3 and R4 have the above-mentioned meaning, and the obtained compound of general formula I is optionally converted into another compound of general formula I, and/or the compound of general formula I is optionally converted into a salt, or the free compound of general formula I is prepared from its salt, and/or the obtained mixture of isomers of general formula I is optionally separated into individual isomers. 2. The process according to item 1, for the production of substituted propanolamine and morpholine derivatives of the general formula Ia in which n and n^ individually represent the number 1, 2 or 3, R and R, which may be the same or different, individually represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group with 1 to 6 carbon atoms, an alkyl group with 1 to 6 carbon atoms, optionally substituted as mentioned above, an aryl(C,-C)alkyl group, an aryl(C,-C)alkoxy group, or two adjacent R groups or two adjacent R groups together form the radical -C-CH ₂ -O-, _R2 represents a hydrogen atom, an alkyl group with 1 to 2 carbon atoms, optionally substituted as mentioned above, or an aryl(C1-C8)alkyl group and R ₃ and R^, which may be the same or different, individually denote a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an alkenyl group with 2 to 4 carbon atoms, an alkynyl group with 2 to 4 carbon atoms, an aryl(C,-Cg)alkyl group, or both substituents Rj and R4 together with the nitrogen atom to which they are attached form a five- or six-membered, saturated or unsaturated heteromonocyclic radical, which optionally contains another heteroatom from the group comprising an oxygen, sulfur and nitrogen atom, and their pharmaceutically acceptable salts, characterized in that a compound of the general formula IIIa in which n, n^, R, Rj, Rj and R4 have the above-mentioned meaning is reduced, and the obtained compound of the general formula Ia is optionally converted into another compound of the general formula Ia, and/or the compound of the general formula Ia is optionally converted into a salt, or the free compound of the general formula Ia is prepared from its salt, and/or the mixture of isomers of the general formula Ia obtained is optionally separated into the individual isomers. 3. The process according to point 1, of derivatives of the general formula Ib for the production of substituted propanolamine and morpholine derivatives in which n and n, individually represent the number 1, 2 or 3, RaRp which may be the same or different, gene, hydroxyl group, alkoxy group with 1 to 6 carbon atoms, individually represent a hydrogen atom, a halo atom, an alkyl group with 1 to 207696 26 6 carbon atoms, optionally substituted as above, an aryl(C1-C8)alkyl group, /R5 an aryl(C1-C8)alkoxy group, a nitro group, a group of the formula -N, in which R= and Rg ^xr 6 individually represent a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, or two adjacent groups Rj together form the residue -O-CHg-O-, Rg represents a hydrogen atom, an alkyl group with 1 to 12 carbon atoms, optionally substituted as mentioned above, or an aryl(C1-C8)alkyl group, and Rj and R4, which may be the same or different, each represent a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, optionally substituted as mentioned above, an alkenyl group with 2 to 4 carbon atoms, an aryl(Cj- _C4 )alkyl group, a cycloalkyl group with 3 to 7 carbon atoms, optionally substituted as mentioned above, or both substituents Rj and R^ together with the nitrogen atom to which they are attached form a five- or six-membered, saturated or unsaturated heteromonocyclic radical, which optionally contains further heteroatoms. from the group consisting of oxygen, sulfur and nitrogen, or Rj and R4 together form a residue of the formula -CHg-CHg-, and their pharmaceutically acceptable salts, characterized in that the compound of the general formula IIIb is reduced ^with (R) _n ^R 2° C-Ny 3 (IIIb) in which n, n,, R, R,, Rg, Rj and R ₄ have the above-mentioned meaning, and the obtained compound of the general formula Ib is optionally converted into another compound of the general formula Ib, and/or the compound of the general formula Ib is optionally converted into a salt, or the free compound of the general formula Ib is prepared from its salt, and/or the obtained mixture of isomers of the general formula Ib is optionally separated into individual isomers.