DK149105B - PROCEDURE FOR PREPARING 2-ARYLOXYALKYL MORPHOLINE DERIVATIVES - Google Patents

Description

in 149105

The invention relates to a particular process for the preparation of 5-aryloxyalkylmorpholine derivatives which possess valuable therapeutic properties, e.g. central nerve suppressive and thymoleptic properties.

British Patent Nos. 1,138,405, 1,260,886 and 10,295,447 disclose certain novel aryloxyalkylmorpholine derivatives which possess the above-mentioned valuable therapeutic properties and also describe chemical processes for their preparation. aryloxyal-kylmorpholinderivater. These known methods provide a process for preparing aryloxyalkylmorpholine derivatives wherein the nitrogen atom of the morpholine ring is unsubstituted by removing a protecting group from the nitrogen atom during the final step of the synthesis. It has now been found that such N-substituted aryloxyalkylmorpholine derivatives 20 can be prepared by reacting the appropriate aryl alcohol with a preformed morpholine derivative. One would expect that such a reaction would lead to polymerization of the morpholine derivative by self-condensation. However, it has surprisingly been found that an acceptable yield of the desired 2-aryloxyalkylmorpholine derivative can be obtained.

According to the invention, there is provided a process for the preparation of 2-aryloxyalkylmorpholine derivatives of the general formula:

x-o-cr4r5v ^ ^ 0 ^^ · r6 X

R2 H

Wherein R 2, R 3, R 4, R 5 and R 6, which may be the same or different, represent hydrogen or alkyl groups of up to 3 carbon atoms and wherein X represents a phenyl or naphthyl group which is unsubstituted or substituted by one or two substituents selected from halogen atoms, alkyl, alkoxy and alkylthio groups, each having up to 10 carbon atoms, haloalkyl and halogen alkoxy groups, each having up to 5 carbon atoms and having up to 4 halogen atoms, alkenyl, alkenyloxy, alkynyloxy, cycloalkyl and cycloalkyloxy groups, each having up to 6 carbon atoms, aryl, aryloxy, alkylaryloxy, aralkyl and aralkoxy groups, each having up to 10 carbon atoms, alkyl groups having up to 5 carbon atoms substituted with alkoxy groups of up to 5 carbon atoms, alkanoyl groups of up to 6 carbon atoms, hydroxy and methylenedioxy groups, and alkylene groups of 3 or 4 carbon atoms which together with the phenyl or naphthyl group form an indanyl or tetrahydric group dronaphthyl group, or acid addition salts thereof. The process is characterized in that an aryl alcohol of formula X-OH, wherein X is as defined above, is reacted with a morpholine derivative of formula: R3 2 - CR4 R5v ^ 11 R 2 H 30 wherein R 2, R 3, R 4, R 1 and R 6 have the meanings given above, X represents a halogen atom or a methanesulfonyloxy or toluene-p-sulfonyloxy group, and if desired, an obtained aryloxyalkylmorpholine derivative in the form of the free base is reacted with an acid to form an acid addition salt thereof.

It is to be understood that the above definition of morpholine derivatives includes all possible stereoisomers thereof and mixtures thereof.

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A suitable meaning of R 2, R 3, R 4, R 5 or R 6 when they denote an alkyl group is e.g. methyl group.

A suitable meaning of z when halogen is a chlorine, bromine or iodine atom.

A suitable meaning of X is e.g. a phenyl or naphthyl group or a phenyl or naphthyl group substituted with one or two substituents selected from fluoro, chloro and bromo atoms, methyl, ethyl, isopropyl, n-butyl, t-butyl -, t-amyl, methoxy, ethoxy, n-propoxy and isopropoxy groups.

Suitable acid addition salts of the aryloxyalkylmorpholine derivatives which can be prepared by the process of the invention are e.g. the acid addition salts derived from inorganic or organic acids, e.g. hydrochlorides, hydrobromides, phosphates, sulfates, oxalates, lactates, tartrates, acetates, gluconates, salicylates, citrates, ascorbates, benzoates, β-naphthoates, adipates or 1,1-methylene bis- (2-hydroxy-3-naphthoates) or acid addition salts derived from acidic synthetic resins, e.g. sulfonated polystyrene resins, e.g. "Zeo-Karb" 225 ("Zeo-Karb" is a trademark).

Specific aryloxyalkylmorpholine derivatives which can be prepared by the process of the invention are those described in particular in British Patent Nos. 1,138,405, 1,260,886 and 1,295,447.

Of these, particularly valuable compounds are 2- (o-ethoxyphenoxy-methyl) morpholine and 2- (m-methoxyphenoxymethyl) morpholine and its acid addition salts.

The process for preparing aryloxyalkylmorpholine derivatives can e.g. carried out in a diluent or solvent, e.g. dimethylformamide, dimethylsulfoxide, dioxane or dimethoxyethane. It can e.g. carried out at an elevated temperature, e.g. at a temperature of up to 4 149105 150 ° C and can be carried out in the presence of a strong base, e.g. an alkali metal or an amide or hydride thereof, e.g. sodium hydride.

The invention is illustrated by the following examples.

Example 1 1 ^

A solution of potassium hydroxide (1.12 g) and 2-ethoxyphenol (2.0 10 g) in water (50 ml) is added to 2- (toluene-p-sulfonyloxymethyl). morpholine (0.5 g) in a nitrogen atom sphere. The resulting mixture is heated to 95 ° C under nitrogen for 2 hours, cooled and extracted with toluene (50 ml). The toluene solution is again extracted with a solution of 36% w / w hydrochloric acid (0.1 ml) in 15 water (30 ml), and this acidic extract is basified to pH 10 with sodium hydroxide solution and extracted with toluene (50 ml). The toluene solution is evaporated at a pressure of 18 mm Hg and a temperature of 45 ° C to give an oil which is distilled at a pressure of 0.03 mm Hg. The fraction boiling at 135-20 145 ° C is collected and dissolved in chloroform (2 ml), then 1.0 ml of 3 M HCl in isopropanol is added to this solution. The solvent is removed from the solution at a pressure of 0.1 mm Hg and a temperature of 22 ° C until solid. fabric. This solid is filtered off and dried to give 2- (2-ethoxyphenoxymethyl) morpholine hydrochloride, mp 185.7-186 ° C.

2- (toluene-p.sulfonyloxymethyl) morpholine used as starting material can be prepared as follows: 30. A solution of 3- (2-hydroxyethylamino) -1,2-propanediol (13.3 g) and toluene-β-sulphonic acid monohydrate (42 g) in xylene (250 ml) is heated to 140 ° C for 19 hours with azeotropic water removal. The aqueous layer is separated and extracted with ethyl acetate (250 mL), then sodium hydroxide is added to the aqueous layer at a temperature below 20 ° C until its pH is 7. The neutralized mixture is extracted three times with ethyl acetate (100 mL, 100 ml and 50 ml) and the combined extracts are dried (MgSO 2) and the solvent is evaporated at 45 ° C and a pressure of 18 mm Hg to give 2- (toluene-p-sulfonyloxymethyl) morpholine as an oil . The acetate salts, mp 131.5-132 ° C, can be formed by adding acetic acid to a solution of the 5 free base in ether.

Example 2

The procedure described in Example 1 is repeated using an equivalent amount of the appropriate phenol instead of 2-ethoxyphenol as the starting material and oxalic acid to isolate the free base. In this way, the following compounds are obtained:

H

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Melting point Recrystallization R Salt (eC) 5 H hydrogen oxalate 132-134 methanol / ethyl acetate 10 2-Me hydrogen oxalate 117-120 methanol / ethyl acetate 2-MeS hydrogen oxalate 136-137 methanol / ether 2-CH 3 CH = CH oxalate 198-199 methanol / ethyl acetate 20 2- Ph hydrogen oxalate | 95-96 methanol / ethyl! ; acetate | in 3- MOe hydrogen oxalate 159-161 methanol / ethyl acetate

E

in

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Claims (2)

149105 Patent Claims. Process for the preparation of a 2-aryloxyalkylmorpholine derivative of the general formula R 3 X-O-CR 4 R 3 x, one Wherein R 2, R 3, R 4, R 5 and R 6, which may be the same or different, represent hydrogen or alkyl groups of up to 3 carbon atoms and wherein X represents a phenyl or naphthyl group which is unsubstituted or substituted with one or two substituents selected from halogen atoms, alkyl, alkoxy and alkylthio groups, each with up to 10 carbon atoms, haloalkyl and halogenoalkoxy groups, each with up to 5 carbon atoms and with up to 4 halogen atoms, alkenyl, alkenyloxy -, alkynyloxy, cycloalkyl and cycloalkyloxy groups, each having up to 6 carbon atoms, 25 aryl, aryloxy, alkylaryloxy, aralkyl and aralkoxy groups, each having up to 10 carbon atoms, alkyl groups having up to 5 carbon atoms substituted by alkoxy groups of up to 5 carbon atoms, alkanoyl groups of up to 6 carbon atoms, hydroxy and methylenedioxy groups, and alkylene groups of 3 or 4 carbon atoms which together with the phenyl or naphthyl group form an indanyl or tet rahydronaphthyl group, or acid addition salts thereof, characterized in that an aryl alcohol of formula X-OH, wherein X has the meaning given above, is reacted with a morpholine derivative of formula: