CS207697B2 - Method of makingthe substituted propanolamine and morpholine derivatives - Google Patents

Description

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

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

R and Η ¹ , 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 with at least one substituent selected from the group consisting of hydroxy, alkoxy x ^R 5 of 1 to 6 carbon atoms, -N 6 and -CO-N, wherein ^R 6 and ^R 6 are each ^R 6 ^R 6 hydrogen or alkyl; 1-6 carbon atoms, aryl- (C, -Cg) alkyl, optionally at least one substituent selected from hydroxy, alkoxy / ^R 5 / ^R 5 group having 1 to 6 carbon atoms, -N. and -CO-NF, wherein Rc and Rg, ^{R @} 6 ^{R @} 6 as hereinbefore defined, aryl- (CI-Cg) alkoxy, optionally substituted with at least one

207697 2 is a substituent selected from the group consisting of hydroxy, C 1 -C 6 alkoxy, -N, and -CO-N 6, wherein R 6 and R 6 are as defined above, ^Xr 6 ^r 6 / ^r 5 nitro, general - ^R 6 or two adjacent R groups, or two adjacent R groups, together form the radical -O-CH ₂ -O-,

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

-N f or -CO-N, wherein R5 and Rg is as defined above, or aryl (Cj-Cg) alkyl, ^R 6 ^R 6 group being, and

R 3 and R 4, 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 -N-R ₅ ^Xr 6 group or CO-N

wherein Rj and Rg

Shora is as defined above, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl- (C 1 -C 4) alkyl optionally substituted in aryl with at least one C 1 -C 6 alkyl, (C 1 -C 6) haloalkyl, hydroxy, (C 1 -C 6) alkoxy or ^R 5 and ^R 6 are as defined above, C 3 -cycloalkyl having at least one C 1 -C 6 alkyl, up to 6 carbon atoms, hydroxy, C1-C7alkoxy, optionally halogen, C1-C6haloalkyl or C1-C6alkoxy;

Wherein R 5 and R 8 are as defined above, or both ^R 6 and ^R 6 together with ^R 6 together with the nitrogen atom to which they are attached form a 5- or 6-membered, saturated or unsaturated heteromonocyclic radical optionally containing additional heteroatoms from the group consisting of oxygen, sulfur and nitrogen and which is optionally substituted by alkyl having 1 to 6 carbon atoms or aryl, or R ₂ and R 4 together form a radical of formula -CH ₂ -CH ₂ the invention also encompasses pharmaceutically acceptable salts of compounds of formula I, and also all their possible isomers and mixtures of these isomers, and their metability, provided that they possess pharmacological, e.g. antidepressant, and metabolic precursors of the compounds of formula I.

In the compounds of formula I, 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 alkyl having 1 to 6 carbon atoms, it is preferably an alkyl group substituted by a hydroxyl group, x ^ ^r 5 / ^r 5 alkoxy having 1-6 carbon atoms or radicals of the formulas - N. or -CON. ^Xr 6 ^Xr 6 wherein R 5 and R 8 are as defined above.

The aryl group is preferably a phenyl group.

In the event that one or more of the groups R3 and R4 are alkyl having 1-6 carbon atoms, it is preferably an alkyl group substituted with one or more substituents selected from halogeno, hydroxy, alkoxy ^.tau.kr 5 x ^R 5 a group having 1 to 6 carbon atoms or a group of formulas -N. and -CON in which R and R ^R 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, aryl-C 1 -C 6 alkyl, and aryl- (C 1 -C 6) alkoxy groups are preferably those whose aryl radical is substituted with one or more alkyl groups of 1 to 6 carbon atoms, halogen atoms, haloalkyl groups having 1 to 6 carbon atoms, hydroxy groups, alkoxy groups having 1 to 6 carbon atoms or groups of the formula -N. ^R 6 wherein R 8 and R 8 are as defined above.

carbon and a group of formula -N ^

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 group, a C 1 -C 6 ^R 5, wherein Rg and Rg are as defined above.

^r 6

C1-C6alkyl is preferably methyl, ethyl or isopropyl.

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

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

C 2 -C 4 alkynyl is preferably propargyl.

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- (C1-C6) alkyl or aryl- (C1-C6) alkyl is preferably benzyl or phenethyl.

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

In the group -NI, R8, R8 and R8 are each independently hydrogen or ^{R6 is} C1 -C3 alkyl, in particular methyl, ethyl or isopropyl.

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

When R 8 and R 8 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.

Due to the presence of at least two asymmetric carbon atoms in the compounds of Formula 1, 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 dia207697 stereoisomers and mixtures thereof, as well as said individual enantiomers, are included within the scope of the invention.

Examples of 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, preferred are the radicals of the formula -N.

^R 4 with hydrochloric acid.

salts of such salts of the compounds of formula (I) in which they form a salt with one of the abovementioned acids, preferably

Preferred compounds of the invention are those compounds of formula (I) wherein, independently of each other, 1 or 2, each R and R is independently hydrogen, methoxy, ethoxy, chloro, or trifluoromethyl. or two adjacent R groups form -O-CH ₂ -O-, R ₂ represents a hydrogen atom or a methyl group, and one of R 1 and R 4 represents a hydrogen atom and the other represents a methyl group, as well as pharmaceutically acceptable salts thereof.

••and

Particularly preferred compounds of the invention are those compounds of formula I wherein aan is, independently of each other, the number 1 or 2, each R and H independently of one another being hydrogen, methoxy, ethoxy, chlorine or chlorine; a trifluoromethyl group, or two adjacent R groups form an -O-CH ₂ -O- radical, R 8 and R 6 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.

Examples of preferred compounds of the invention include:

2- (alpha-phenoxybenzyl) morpholine;

2- (alpha / 2-methoxyphenoxy) benzyl) morpholine;

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

2- (alpha- (4-methoxyphenoxy) benzyl) morpholine j

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N-methyl-2-hydroxy-3- (3,4-methylenedioxyphenoxy) -3-phenylpropylamine;

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- (2-methoxyphenoxy) -3- (3-chlorophenyl) propylamine;

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

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

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

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

N-methyl-2-methoxy-3- (2-ethoxyphenoxy) -3-phenylpropylamine;

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

N-methyl-2-methoxy-3- (3,4-methylenedioxyphenoxy) -3-phenylpropylamine;

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

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

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

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

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

N-methyl-2-methoxy-3- (2-methoxyphenoxy) -3- (4-trifluoromethylphenyl) 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, as well as pharmaceutically acceptable salts thereof.

The principle of the preparation of the compounds of the formula I according to the process of the invention is that the compound of the formula VI

(VI)

II

O

6 207 697 in which n, n ,, R, R, and R are as defined above, and Z represents a group]> CH ₂ or-C = 0 is reduced to a compound of formula I in which R ₂ and R 4 together form a group -CH ₂ -CH ₂ , an, n 1, R 1, R 1, R 1 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.

Reduction of the compounds of formula VI can be carried out, for example, using the procedure described in J. Med. Chem. 19, 41 (1976), especially when Z in the compound of formula VI is / C = O.

When, in the compounds of the above formula (VI), one or more substituents R 1, R 1, R 1 and R 4 represent reducible groups and in order to keep these groups unchanged in the final compounds of formula I, the reduction should preferably be carried out the use of selective reaction conditions.

For example, the reduction of a compound of formula (VI) containing halogen or nitro groups in the molecule can be carried out selectively with respect to these groups by, for example, borane in tetrahydrofuran or an aliphatic ether such as diethyl ether under nitrogen. 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 VI in which R1 and R4 are C2 -C4 alkenyl or C2 -C4 alkynyl can be carried out selectively with respect to these groups using, for example, lithium aluminum hydride as the reducing agent, with the reaction of 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 I in which one or more R and R substituents are both nitro or halogen and at the same time cannot be prepared by this reduction. R 1 represents a C 2 -C 4 alkenyl group or a C 2 -C 4 alkynyl group. Said compounds can be prepared, for example, by converting a suitable compound of formula I into the desired other compound of formula I.

The same considerations apply to the other reduction processes described by the present invention as regards the preparation of final compounds or the preparation of intermediates.

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

Thus, for example, can be a compound of formula I wherein R3 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, aryl- (C 1 -C 4) alkyl or C 3 -C 7 cycloalkyl, by conventional alkylation methods amines, for example by reductive amination or 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 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 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 to up to about 50 ° C, as described, for example, in Org. Reactions £ 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 Leukart-Wallac reaction, preferably formic acid is used in excess and the reaction mixture is heated for two to twelve hours as described in Org. Reactions 2,301 (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 a 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, 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 in J. Org. Chem. 2, 139 (1938); Org. Synth., Vol. II, p. 183 (1943), J. Am. Chem. Soc. 21, 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. Copper. Chem. JJ (1), 654 (1974).

A compound of formula (I) wherein one of R ^ and R ^ is hydrogen can be converted to the corresponding compound of formula (I) wherein one of R ^ and R ₄ is methyl, preferably also by starting the amino compound is reacted with ethyl chloroformate in chloroform, in the presence of excess potassium hydroxide, at a temperature in the range of about 0 to 5 ° C, and the obtained carbamic acid ester is reduced with excess lithium aluminum hydride or borane in diethyl ether at boiling point. .

Compounds of formula I wherein one of R 1 and R 4 is C 1 -C 6 alkyl and the other is hydrogen may alternatively be prepared by the following process: a ') a compound of formula I wherein R 1 and R 2 are both substituents. is hydrogen, 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 with mixed hydrides, for example lithium aluminum hydride or sodium borohydride, as described, for example, in Houben-Weyla, Vol. XI, Part 1, p. 341 (1957); c ') the benzylamine obtained is alkylated with a suitable alkyl halide using the alkylation procedures described above; ad ') from the alkylated benzylamine obtained, the benzyl group is removed, 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 ₃ 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 3 and R 6 are hydrogen can be converted to the corresponding compound of formula I wherein one of the substituents

R1 and R2 are 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, for example lithium aluminum hydride or borane, in tetrahydrofuran or diethyl ether, at the boiling point of the reaction mixture.

Compounds of formula I wherein R ₂ represents hydrogen can be converted into compounds of formula 1 wherein R ₂ represents alkyl having 1 to 12 carbon atoms or aryl (Cj-Cg) alkyl, commonly used methods for etherification of alcohols, for example by reacting an alkali metal salt of an alcohol, for example a lithium or sodium salt, with a corresponding 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 alcohol salt may be obtained by reacting the corresponding alcohol with an alkyl lithium such as butyl lithium in an inert anhydrous solvent such as tetrahydrofuran. The sodium salt 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 1 in which one of R and R represents a hydroxyl group can be converted into the corresponding compounds of formula 1 in which one of R and R represents an alkoxy group having 1 to 6 carbon atoms or aryl- ( C 1 -C 8 alkoxy.

Compounds of formula I in which R ₂ represents an alkoxy group having 1 to 6 carbon atoms or ary1- (C, -Cg) alkoxy, may be converted to corresponding compounds of formula 1 in which R ₂ represents a hydroxy group by conventional methods deéterifikace. Thus for example a compound of formula 1 wherein R ₂ represents methoxy, can deéterifikovat treatment with pyridine hydrochloride or boron tribromide, or by treatment with potassium etanthiolátu in dimethylformamide at 100 to 130 ° C, such as described in J. Med. Chem.

(1), 165 (1977). When the de-etherifications are carried out with pyridine hydrochloride, the reaction is preferably carried out under a nitrogen atmosphere at a temperature of about 150 ° C. The de-etherification with boron tribromide is preferably carried out by adding a solution of boron tribromide in chloroform to a solution of the compound of formula 1, cooled to -70 to -80 ° C under nitrogen, and quenching the reaction 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 1 in which one of R 1 and R 4 is methyl and the other is hydrogen, for example by reacting 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 (1) in which one of R and R is n-4 can be converted to the corresponding compounds of formula (I) in which one of R and R) is amino by methods commonly used to reduce aromatic nitro compounds, for example by catalytic hydrogenation, using for example platinum, palladium or Raney nickel as a catalyst, by known organic chemistry techniques.

Compounds of formula (I) in which one of R and R 1 represents an aminoacin can be converted to the corresponding compounds of formula (I) in which one of R and R 1 is substituted by aminoacetin. denotes a hydroxyl group, i.e. by converting the amine to the corresponding diazonium salt and then hydrolyzing it, for example, as described in Org. Synth.

22, 11 (1943), or in J. Org. Chem. 42, 2053 (1977).

Compounds of formula I wherein one of R and R is amino may be converted to the corresponding compounds of formula I wherein one of R and R is mono- or dialkylamino of 1 to 6 carbon atoms by reductive amination or by alkylation as described above.

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

For example, a hydrochloric acid salt of a compound of formula (X) 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 hydrochloric acid and isolating the resulting hydrochloride.

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 separated high pressure liquid chromatography.

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

Compounds of formula VI in which Z is a group can be prepared, for example, by cyclization of compounds of formula XVI

wherein R, R ,, n, _t n, R and X are as defined above. The cyclization is carried out by boiling with a solvent capable of forming an azeotropic mixture with water, for example with toluene, in the presence of an acid catalyst, for example p-toluenesulfonic acid or boron trifluoride, and / or in the presence of a dehydrating agent, for example anhydrous copper sulfate. Alternatively, the cyclization is carried out by treatment with a base, for example with tertiary butyl alcohol, or with sodium hydride in dimethylformamide, dimethylsulfoxide or dimethylacetamide, or with butyllithium or diisopropylamine-lithium or similar agents in tetrahydrofuran or aliphatic ether such as sodium ether or amide Potassium in liquid ammonia, using known organic chemistry techniques.

When one or more R and R in the compound of formula XVI are hydroxyl groups, in order to avoid the presence of these aromatic hydroxyl groups in the cyclization reaction, it is appropriate to use a base in an amount sufficient to convert all hydroxyl groups present to the corresponding hydroxyl groups. salts: the reactivity of the alcoholic hydroxyl groups in the form of salts is higher than the reactivity of the phenolic hydroxyl groups converted to salts and therefore the phenolic groups in this form cannot subsequently interfere in the reaction.

Compounds of formula (VI) wherein Z is Z; ^! C = O, can be obtained, for example, by the compound of formula XVII

wherein R, R ,, n and n ₁ are as defined above and each group R _a, which may be the same or different, represents alkyl having 1 to 6 carbon atoms, preferably methyl or ethyl radical, is reacted with an amine of formula R 1 -NHg, wherein R 1 is as defined above. The reaction is preferably carried out under pressure in a suitable solvent such as a C 1 -C 6 aliphatic alcohol, for example ethyl alcohol, at a temperature in the range of about 50 to about 150 ° C. By carrying out the reaction at a controlled temperature, reaction time and stoichiometry conditions then provides a compound of formula XVII, in which one of the groups _{-COOR, and} is replaced by -CONHR 3, from which it can be prepared a compound of formula VI by boiling the cells for the acetic acid, or by treatment with a strong base, for example sodium hydride, in a suitable solvent, for example dimethylforraamide or dimethylsulfoxide.

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

The antidepressant activity of the compounds was tested in mice by monitoring the effect of eyelid contractions and reserpine-induced hypothermia.

Reserpine was administered andoperitoneally at a dose of 2.4 mg / kg and the test compounds of Formula I were administered orally 30 minutes prior to administration of reserpine. One hour or four hours after the administration of reserpine, wolf contractions were recorded (the number of contractions was measured by the technique described by B. Rubin and co-workers in J. Pharmacol. 120. 125 (1957)) and body temperature was measured (using a rectal thermoelectric cell) ).

The following table shows the antidepressant activity of the two compounds produced by the method of the invention in comparison to amitriptyline as a known antidepressant drug.

Antidepressant efficacy was evaluated by preventing reserpine-induced blepharospasm and hypothermia. φ

Table

Antireserpine effect in mice (SCF / 4 tests) EDgQ mg / kg / pers

Compound Blefar0spasmus 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 adults, a suitable dose of a compound of Formula I 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 cellulose; glidants such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; binders such as starches, gelatin, methylcellulose, acacia, tragacanth or polyvinylpyrrolidone; raising agents, for example 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 manufactured by methods known per se, for example by mixing, granulating, tabletting and coating with a sugar layer or a film of another suitable fly.

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

The following abbreviations are used in the following examples:

THF = tetrahydrofuran,

DMF = dimethylformamide,

DMA = dimethylacetamide,

MCPBA = n-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 5 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 oily liquid; yield 94.8%.

The crude oil 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 at room temperature for 20 hours then cooled. The 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-phenylpropylemine;

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

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

N-Methyl-2-hydroxy-3- (4-trifluoromethylphenoxy) -3- (4-methoxyphenyl) propylamine;

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

N-Methyl-2-hydroxy-3- (2-methoxyphenoxy) -3- (2-chlorophenyl) propylemine 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. 128-145 ° C;

N-methyl-2-hydroxy-3- (2-ethoxyphenoxy) -3- (3-chlorophenyl) propylamine hydrochloride, m.p. 110-127 ° 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-methoxyphenoxy) -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-methoxyphenoxy) -3- (4-trifluoromethylphenyl) propylamine;

N-methyl-2-hydroxy-3- (4-methoxyphenoxy) -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-methoxyphenoxy) -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-phenylpropyl-13 amine 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 is refluxed for a further 20 hours, then the solvent is distilled off, the residue is taken up in water and the product is 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-methylindioxyphenoxy) -3-phenylpropylamine are obtained as an oil; yield 8.3%. 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-methoxyphenoxy) -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-methoxyphenoxy) -3- (2-methoxyphenyl) propylamine;

N-Methyl-2-methoxy-3-phenoxy-3- (4-methoxyphenyl) propylamine;

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-methoxyphenoxy) -3- (4-methoxyphenyl) propylamine;

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

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

N-Methyl-2-methoxy-3- (4-trifluoromethylphenoxy) -3- (4-methoxyphenyl) propylamine;

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

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 DEG -40 DEG C .;

N-methyl-2-methoxy-3- (2-ethoxyphenoxy) -3- (3-chlorophenyl) propylamine hydrochloride, m.p. 108-135 ° 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-methoxyphenoxy) -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 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. No. (CHC1 ₃₎ in N-CH, 2805 cm ^-1, in aroma. ethers 1,255 cm -1, in 1.2 aubstit. phenyl

750 cm -1; *

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

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

I, NO. (CHC1 ₃₎ in N-CH 2805 cm '' in aroma. ethers 1250 cm -1, in monosubstit. phenyl

695 cm -1;

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-ethoxybenzyl) morpholine;

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

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

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

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

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

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

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

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

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

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

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

I. No. (CHCl ₃ ) in O-CH ₃ 2840 cm -1, in N-CH ₃ 2 805 cm -1, _in aromatics. ethers 1 245 cm -1, in 1,2 substit. phenyl 750 cm -1;

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

I. No. (CHCl3) in N-CH3, 2 810 cm @ -1, in aromatics. ethers 1,255 cm -1, _at 1.2 substit. phenyl

745 cm -1;

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

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

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

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

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 4

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 to 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). The mixture was stirred at room temperature for 20 hours, then 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 oily liquid.

All 4-methylmorpholine derivatives listed in Example 3 were prepared in an analogous manner.

Example 5

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. water (8 mL) and then sodium borohydride (6.024 g) over 1 hour. 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 (82.3% yield) of 4-isopropyl-2- (alpha / 2-methoxyphenoxy) -2-chlorobenzyl) morpholine are obtained, the hydrochloride having 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-methoxyphenoxy) -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-methoxyphenoxy) -2-chlorobenzyl) morpholine;

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

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-methoxyphenoxy) -4-chlorobenzyl) morpholine;

4-Isopropyl-2- (alpha- (4-methoxyphenoxy) -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-methoxyphenoxy) -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 6

To a solution of 12.3 g of 2- (alpha- (2-nitrophenoxy) benzyl) -4-methylmorpholin-5-one in 350 ml of anhydrous THF was slowly added dropwise a 77 ml molar solution of borane in THF. The deer was heated under reflux for 6 hours, then excess borane was decomposed by dropwise addition of methanol at room temperature, 50 ml of 23% hydrochloric acid was slowly added to the reaction mixture, and the mixture was stirred at 60 ° C for 1 hour. The solution was concentrated to a small volume, the residue was diluted with water, basified with sodium hydroxide and the product was taken up in methylene chloride. The usual work-up and recrystallization of the crude product from isopropyl ether gave 8.1 g (68% yield) of 2- (alpha / 2-nitrophenoxy / benzyl) -4-methylmorpholine, m.p. 78-81 ° C.

IR spectrum ^{max (chloroform):} 1525 om '' (NOG).

Nuclear Magnetic Resonance Spectrum, ppm (in deuterochloroform): 5.3 (d, H benzyl), 7.4 to 6.8 (s, 9H, aromatic), 2.27 (s, GH 3).

In a similar manner, starting from the corresponding morpholin-5-one derivatives, the compounds of Examples 3 and 5 as well as the following compounds were prepared:

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, n _D = 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 ° C;

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 _E = 1, 5672;

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

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

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

2-Thalpha-phenoxy-2-chlorobenzyl) morpholine;

2- (allyl- [2-methoxyoxyphenoxy] -2-chlorobenzyl) morpholine, mp 80-102 ° C; 2- (alpha- (2-ethoxyphenoxy) -2-chlorobenzyl) morpholine;

2- (alpha-phenoxy-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;

f 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.

Example 7

To a solution of 24.7 g of N-chloroacetyl-K-methyl-2-hydroxy-3-phenyl-3- (2-nitrophenoxy) propylamine in 300 ml of anhydrous DUP is added 3.5 g of a 50% dispersion of sodium hydride in mineral oil. The reaction mixture was heated, with stirring, to 50 ° C for 3 hours, then allowed to stand for 16 hours and poured into 2 L of water. The precipitated brown solid was filtered off and purified by boiling with 95% ethanol. 18 g (80% yield) of 2- (alpha- (2-nitrophenoxy) benzyl) -4-methylmorpholin-5-one are obtained, m.p. 192-195 ° C.

IR spectrum ^max (nujol): 1660 cm ^- '(CON) 1525 cm "' (NO2) ·

Morpholin-5-one derivatives corresponding to the compounds of Examples 17, 19 and 20 were prepared in a similar manner.

Example 8

To a solution of 55 g of N-methyl-2-hydroxy-3-phenyl-3- (2-nitrophenoxy) propylamine hydrochloride in 770 ml of distilled water is added 185 ml of 2 N sodium hydroxide solution and 200 ml of methylene chloride at room temperature. A solution of 16.7 ml of chloroacetyl chloride in 350 ml of anhydrous methylene chloride is slowly added dropwise to 0 ° C. The reaction mixture was stirred at room temperature for 3 hours, then the organic layer was separated, washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried and the solvent was distilled off. 60 g (97% yield) of N-chloroacetyl-N-methyl-3-phenyl-2-hydroxy-3- (2-nitrophenoxy) propyl amine are obtained.

Infrared spectrum, _max (in chloroform): 3500 cm ^-1 (OH, Wide band),

640 cm '(CON) 1525 cm "' (NO _2).

Similarly, other analogous intermediates required for the preparation of the morpholin-5-one derivatives shown in Example 34 were prepared.

Example 9

To a solution of 7 g of 2- (alpha- (2-nitrophenoxy) benzyl) -4-methylmorpholin-5-one in 200 ml of DMF was added 5% palladium on charcoal (0.7 g) and the mixture was hydrogenated for 0.5 hour at a pressure of 350 kPa. The catalyst was filtered off, the filtrate was poured into water and the product was taken up in ethyl acetate. After drying and distilling off the solvent, the crude product is recrystallized from ethyl ether. 5.3 g (75.2% yield) of 2- (alpha / 2-aminophenoxy) benzyl) -4-methylmorpholin-5-one of melting point 167 DEG-170 DEG C. are obtained.

IR spectrum ^max (nujol): 3300 cm _'(NH2), 1660 cm "' (CON). ΐ

Example 10

10 g of 2- (alpha / 2-aminophenoxy / benzyl) -4-methylmorpholin-5-one are dissolved in 32 ml of 35% sulfuric acid at 0 DEG C. and a solution of 2.76 g of sodium nitrite is slowly added at this temperature. in 40 ml of water. The mixture was stirred under cooling for 20 minutes and then a solution of 120 g of cupric nitrate in 1000 ml of water and 4.2 g of cuprous oxide was added at 0 ° C. After 5 minutes, the product was extracted into ethyl acetate in the cold, the combined organics washed with saturated aqueous sodium chloride until neutral, dried over anhydrous sodium sulfate, and the solvent was distilled off. The oil was purified by column chromatography on silica gel using ethyl acetate / cyclohexane (2: 1) as eluent to give 6 g (60% yield) of 2- (alpha / 2-hydroxyphenoxy / benzyl) -4 -me tylmorpholin-5-one.

Infrared spectrum, ⁱⁿ max (chloroform): 3500 cm -1 (OH), 1660 cm -1 (CON).

Example 11

To a solution of 10 g of 2- (alpha- (2-hydroxyphenoxy) benzyl) -4-methylmorpholin-5-one in 150 ml of anhydrous DMF is added 4.8 g of anhydrous potassium carbonate and then, dropwise, a solution of 2.6 is added dropwise. ml of bromoethane in 20 ml of DMF. The mixture was heated to 60 ° C with stirring for 4 hours, then poured into 1.5 liters of water and the product was taken up in ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. 8.49 g (78% yield) of 2- (alpha / 2-ethoxyphenoxy) benzyl) -4-methylmorpholin-5-one are obtained.

IR spectrum ^max (nujol): 16660 cm '(CON).

Example 12

A solution of 6.8 g of 2- (alpha / 2-methoxyphenoxy / benzyl) -4-methylmorpholine-3,5-dione in 40 ml of anhydrous tetrahydrofuran was added dropwise to a suspension of lithium aluminum hydride (1.9 g) with stirring. in 35 ml THF and the mixture is heated under reflux for 6 hours. The reaction mixture was cooled at 0-5 ° C and 4.1 ml of 23% hydrochloric acid was added dropwise and the mixture was stirred at room temperature for 2 hours. The suspended solid was filtered off, washed several times with THF and the solvent was distilled off under reduced pressure. The residue is taken up in ethyl ether and 4 ml of 1% methanolic hydrogen chloride are added to the ether solution. The precipitated amorphous hydrochloride is washed several times with fresh ethyl ether and then filtered off. 5.8 g (84% yield) of 2- (alpha- (2-methoxyphenoxy) benzyl) -4-methylmorpholine hydrochloride, m.p. 67-90 ° C, are obtained.

IR spectrum ^max (KBr disc): 2700 cm ^- '(NH +), 2815 cm ^-' (OCH).

All of the compounds listed in Examples 3, 5 and 6 were prepared in an analogous manner except those containing a chlorine atom in the molecule.

Example 13

To a solution of 4 g of ethyl 2-ethoxycarbonylmethyloxy-3-phenyl-3- (2-methoxyphenoxy) propionate in 30 ml of ethanol is added 20 ml of 10% ethanolic methylamine solution and the mixture is heated in an autoclave at 150 ° C for 20 hours. The reaction mixture was cooled, the solvents were distilled off under reduced pressure, and the residue was recrystallized from ethanol. 2.26 g of 2- (alpha / 2-methoxyphenoxy) benzyl) -4-methylmorpholine-3,5-dione are obtained; 64% yield.

Infrared spectrum ⁱⁿ chloroform max): 1680 cm ^- '(CONC), 1625 cm ^-' (conc)

Other morpholine-3,5-dione derivatives required as starting materials for the preparation of the compounds of Example 12 were prepared in an analogous manner.

Example 14

To a solution of 3.85 g of ethyl 2-hydroxy-3-phenyl-3- (2-methoxyphenoxy) propionate in 35 ml of DMF is added 5.34 ml of ethyl bromoacetate and 3.32 g of anhydrous potassium carbonate, and the mixture is heated, stirring, 60 hours at 60 ° C. The reaction mixture is then poured into water, the product is taken up in ethyl acetate, the combined organic extracts are washed neutral with water, dried and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate / cyclohexane 1: 1 as eluent to give 3.35 g (67% yield) of ethyl 2- (ethoxycarbonylmethyloxy) -3-phenyl-3- (2-methoxyphenoxy) propionate.

IR ^{spectrum? Max} cm ^- '(^ O), 1740 cm ^-'

In a similar manner, analogous intermediates required for the synthesis of the compounds of Example 13 were prepared.

> Example 15

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%.

IR ⁽ max chloroform): 2700 cm @ -1 (NH @ +).

Example 16

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%.

IR spectrum _max (KBr disc): 3400 cm ^- _'(NH2), 2700 cm ^-' (NH +).

Example 17

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. 4 g (76% yield) of 2- (alpha / 2-methoxyphenoxy / benzyl) -4-methylmorpholine hydrochloride having a melting point of 67-90 [deg.] C. (from decomposition) are obtained after adding 18% strength alcoholic hydrogen chloride solution to the concentrated solution.

Infrared spectrum v (KBr): 2820 cm ^- '(O-i), 2700 cm "' (NH +).

'Max J'

Example 18

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 with 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. Dilution with a small amount of ethyl ether gave 4.65 g (31% yield) of 2- (alpha / 2-hydroxyphenoxy) benzyl) -4-methylmorpholine hydrochloride.

Infrared ^spectrum, m _ax (KBr disc): 3500 cm ^- '(OH), 2700 cm "' (NH +).

/

Example 19

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 ether extracts were washed with saturated brine, 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%.

IR spectrum, _'m x ² cm (^ if' 525 cm '(N0 _2).

The compounds of Example 6 were prepared in a similar manner.

Example 20

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 charcoal for 4 hours at room temperature. 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-like liquid; hydrochloride has a melting point of 140-170 ° C.

The morpholine derivatives of Example 6, except those containing a chlorine atom or a noro group, are prepared in an analogous manner.

Example 21

A solution of 4-benzyl-2- (alpha / 2-methoxyphenoxy / benzyl) morpholine (5 g) in benzene (70 mL) was heated to reflux with ethyl chloroformate (1.23 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 6 were prepared in a similar manner.

Example 22

To a solution of 1.23 g of lithium aluminum hydride in 50 ml of diethyl ether is added dropwise a solution of 6.8 g of 4-benzyl- (alpha / 2-methoxyphenoxy / benzyl) morpholin-5-one in a mixture of 100 ml of anhydrous ethyl ether and 30 ml of anhydrous. tetrahydrofuran. The reaction mixture is stirred for two days at room temperature, then the excess reducing agent is quenched carefully with a small amount of water, sodium hydroxide solution and additional water are added, and the solid is filtered off. The filter was washed with tetrahydrofuran, the combined organic filtrates were dried over anhydrous sodium sulfate, and the solvents were distilled off under reduced pressure. 4.9 g (78% yield) of 4-benzyl-2- (alpha / 2-methoxyphenoxy / benzyl) morpholine are obtained as a clear oil.

4-Benzyl-2- (alpha / 2-ethoxyphenoxy / benzyl) morpholine as well as the compounds of Examples 3, 5 and 6 are prepared in an analogous manner except those containing a chlorine atom in the molecule.

Example 23

To a solution of N-benzylamino-2-hydroxy-3- (2-methoxyphenoxy) -3-phenylpropylamine (3.5 g) in methylene chloride (60 mL) at 0 ° C was added sodium hydroxide (0.6 g) and water ( A solution of chloroacetyl chloride (1.1 mL) in methylene chloride (10 mL) was added dropwise with cooling to -50 ° C and stirring. The organic portion was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. 4.0 g (yield

%) N-benzyl-N-chloroacetyl-2-hydroxy-3- (2-methoxyphenoxy) -3-phenylpropylamine, which is chromatographically pure and can be used directly as such for the next steps.

To a solution of 2.5 g of the latter product in dimethylsulfoxide (10 ml) was added 55% sodium hydride (0.275 g), the mixture was stirred at room temperature for 1.5 hours and then poured into water. The product is taken up in ethyl acetate, the combined organic extracts are washed several times with water, dried over anhydrous sodium sulfate and the solvent is distilled off. 2.2 g (94% yield) of 4-benzyl-2- (alpha / 2-methoxyphenoxy) benzyl) morpholin-5-one are obtained.

In a similar manner, 4-benzyl-2- (alpha- (2-ethoxyphenoxy) benzyl) morpholin-5-one was prepared as well as other 4-benzyl derivatives required for the preparation of the compounds of Example 6 by the procedure of Examples 20 and 21.

Example 24

(a) To a solution of 2-hydroxy-3- (2-methoxyphenoxy) -3-phenylpropylamine (6 g) in methyl chloride (70 ml) is added a solution of sodium hydroxide (1.3 g) in water (40 ml) and stirring and cooling to 0 ° C a solution of benzoyl chloride (3.6 mL) and methylene chloride (20 mL) was added dropwise. The mixture was stirred for an additional 30 minutes, then the organic layer was separated and the aqueous portion was shaken with methylene chloride. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was evaporated to dryness. 8.1 g (98% yield) of N-benzoylamino-2-hydroxy-3- (2-methoxyphenoxy) -3-phenylpropylamine are obtained as an oil-yellow liquid.

(b) To a solution of lithium aluminum hydride (16.3 g) in anhydrous ethyl ether (1000 ml) is added dropwise a solution of the oily product obtained in a) (8.1 g) in anhydrous ether (1500 ml) and a mixture of The mixture was heated at reflux for 12 hours. After the usual working-up of the reaction mixture and purification of the base by shaking it in aqueous acid, liberating it by alkalization and removing it in ether, 3.5 g (yield 45%) of N-benzyl-2-hydroxy-3- (2-methoxyphenoxy) are obtained after distilling off the solvent. -3-phenylpropylamine as a mixture of diastereoisomers (colorless oil).

N-benzyl-2-hydroxy-3- (2-ethoxyphenoxy) -3-phenylpropylamine as well as other N-benzylamino derivatives required for the preparation of the compounds of Example 23 are prepared in an analogous manner.

Example 25

To a solution of 2- (alpha- / 2-ethoxyphenoxy / benzyl) morpholine (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) morpholine methanesulfonate, mp 144-146 ° C, ultraviolet spectrum (MeOH): _{ma 3 C} -275 nm; e} = 50.

Example 26

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 lactose maize starch talc (spread) magnesium stearate

250 g

1,230 g

450 g 20 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 resulting mass is compressed into tablets using an 8 mm diameter butcher.

Example 27

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

Composition (for iO 000 Lcblet):

N-methyl-2-methoxy-3- (2-ethoxyphenoxy) -3-phenylpropylpylamine. 250 g lactose 1, 230 g corn starch 450 g tfilek (spread) 50 g magnesium stearate 20 g

Tablets were prepared as described in Example 26.

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of substituted propanolamine and morpholine derivatives of the general formula I Vn, (I) in which n and n, respectively denote the number 1, 2 or 3, R and R ', 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 Nou substituted by at least one substituent selected from hydroxy, alkoxy / ^R 5 / ^R 5 dialkylamino having 1 to 6 carbon atoms, -N and -CO-N. wherein R e and R g are each ^Xr 6 ^Xr 6 notably hydrogen or C 1 -C 6 alkyl, aryl- (C 1 -C 6) alkyl, optionally substituted with at least one substituent selected from the group consisting of R 1 -hydroxy, alkoxy having 1-6 C atoms, and the group -N ^y / ^R 5 ^R 6 -CO-N, wherein Rg and Rg are as defined above, aryl (C ^ -Cg) alkoxy, optionally substituted with ^R 6 at least one substituent selected from the group consisting of hydroxy, C 1 -C 6 alkoxy, -N ^ and -CO-N ^ are as defined above, nitro, -Nl wherein R 8 and R 8 wherein R 8 and R 8 are as defined above , or two adjacent groups R 1, or two adjacent groups R 1, together form the radical -O-CH 2 -O-, R2 represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, optionally substituted by a halogen atom, a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, a group / ^r5 -Nf ³ or -GO-N; ^R 6 ^R 6 group being, and wherein Rg and Rg are as defined above, or aryl LCJ-CgjalkyloR-j and R, which may be identical or different, represent, individually, hydrogen, alkyl having 1-6 carbon optionally substituted by halogen, hydroxy, C1-C6alkoxy, -N ^ or -CO-N ^ in which R8 and R8 are as defined above, C2-4 alkenyl, C2-4 alkynyl C 2 -C 4 aryl, C 1 -C 6 alkyl optionally substituted in aryl with at least one C 1 -C 6 alkyl, halogen, C 1 -C 6 haloalkyl, hydroxy, C 1 -C 6 alkoxy, or a group -Ν / ζ ^R 5 wherein R 8 and R 8 are as defined above, a C 3 -C 7 cycloalkyl group; optionally substituted with at least one C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, hydroxy, C 1 -C 6 alkoxy, or -N R g ^r 6 wherein R g and R g are as defined above, or both substituents 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 radical optionally containing additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with C 1-6 alkyl or R 2 and R 4 together form a radical of formula -CH 2 -CH 2 -, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula VI wherein n, n, R, R 1 and R 3 have the above and Z represents CH 2 or C = O, reduced to a compound of formula I wherein T 2 ^{and R} 4 together form -CH 2 -CH 2 and n, n, R, R, and R 1 are as defined above, and optionally obtaining a compound of formula I is converted to another compound of formula I, and / or optionally the compound of formula I is converted to a salt, or a free compound of formula I # is prepared from a salt thereof, and or the optionally obtained mixture of isomers of the formula I is separated into the individual isomers. 2. The process according to item 1, for the preparation of substituted propanolamine and morpholine derivatives of the general formula Ia (Ia) in which nano ₁ is individually the numbers 1, 2 or 3, R and R 1, which may be the same or different, each represent a hydrogen atom, a halogen atom, an alkyl of 1 to 6 carbon atoms, an aryl- (C 1 -C 6) alkyl, a hydroxy group, an alkoxy group of 1 to 6 carbon atoms, an aryl- (C 1 -C 8) alkoxy, or two R groups or two R groups, together form the radical -O-CHg-O-, R ₃ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-4 carbon atoms, alkynyl of 2-4 carbon atoms, aryl-alkyl or cycloalkyl of 3 to 7 carbon atoms and pharmaceutically acceptable salts thereof, wherein by reducing a compound of formula (VIa) wherein n, n ₁ , E, R 18, R 8 are as defined above, and the compound of formula (Ia) obtained is optionally converted to another compound of formula (Ia) and / or the mixture of isomers is resolved to the individual isomers and / or the compound of formula (Ia) is converted into a salt thereof by the action of a pharmaceutically acceptable acid. 3. The process according to item 1, for the preparation of substituted propanolamine and morpholine derivatives of the general formula Ia. In which n and n, respectively represent the number 1 or 2, R represents a hydrogen atom, a chlorine atom, or an alkoxy group having 1 or 2 carbon atoms, or two R groups together form a 3,4-methylenedioxy group, R 1 represents a hydrogen atom, a chlorine atom or a methoxy group; R ^ represents a hydrogen atom or a methyl or isopropyl group, and pharmaceutically acceptable salts thereof, characterized in that a compound of the formula (VIa) in which n, rij, R, R, and Rj are as defined above, and the compound of formula (Ia) is optionally converted to another compound of formula (Ia) and / or the mixture of isomers is resolved into the individual isomers and / or the compound of formula (Ia) is converted into a salt thereof by treatment with a pharmaceutically acceptable acid.