FI62296B - NYTT FOERFARANDE FOER FRAMSTAELLNING AV THERAPEUTISKT ANVAENDBARA 2-ARYLOXIMETYLMORFOLINER - Google Patents

Description

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England-England (GB) 31255/69 (71) Imperial Chemical Industries Limited, Imperial Chemical House, Millbank,

London SW1, England-England (GB) (72) Stanley Arnold Lee, Macclesfield, Cheshire, England-England (GB) (7M 0y Kolster Ah (5M) A new process for the preparation of therapeutically useful 2-aryloxymethylmorpholines The present invention relates to a new process for the preparation of therapeutically useful 2-aryloxymethylmorpholines, which have the following characteristics: (2) Separated from application 1718/70 (Publication 61890)

X-O-CH, -r NH

wherein X is unsubstituted phenyl, 1-naphthyl or 5,6,7,8-tetrahydro-1-naphthyl, or phenyl substituted by a chlorine atom or a methoxy, ethoxy, methylthio, phenyl, phenoxy or benzyloxy group or up to two methyl groups.

The process according to the invention is characterized in that the compound of the formula: «296 2 / ° \

X0CH2CH- <1- CH2 II

wherein X is as defined above, is reacted with a compound of formula:

h2nch2ch2z III

wherein Z is a halogen atom or a sulfonyloxy group, in the presence of a strong base.

A suitable meaning for Z is a chlorine or bromine atom or a sulfonyloxy group of the formula -SOSO 2 R, wherein R is hydrogen or lower alkyl. As a suitable base, an alkali metal hydroxide or an alkaline earth metal hydroxide can be mentioned, for example, sodium hydroxide, potassium hydroxide or barium hydroxide.

The process according to the invention is carried out in a diluent or solvent, for example water or an alcohol, for example methanol, ethanol, isopropanol, n-butanol, t-butanol or ethylene glycol, or an ether, for example diethyl ether, tetrahydrofuran or dioxane, or an aromatic hydrocarbon, for example or in toluene, or in a mixture of some of the above solvents. The process can be carried out at ambient temperature or at an elevated temperature, for example at a temperature up to the boiling point of the diluent or solvent, for example between 0-100 ° C, and in particular between 40-60 ° C.

Particularly preferred compounds which can be prepared by the process of the invention are 2- (o-ethoxyphenoxymethyl) -morpholine and 2- (m-methoxyphenoxymethyl) morpholine.

It is known that the 2-aryloxymethylmorpholines prepared by the process of the invention have valuable therapeutic properties, for example central nervous system sedative and thymoleptic properties (British Patent Publication No. 1,130,405). Thus, a new, special method for the preparation of these valuable compounds has now been invented.

It is known that phytohydride diethylamine derivatives can be cyclized to morpholine derivatives under the action of acids 3,629,296 (German Patent Publication No. 973,048, especially Examples 1 and 3 and the corresponding U.S. Patent Publication No. 2,835,669, and Finnish Patent Application 668/68).

U.S. Patent No. 2,835,669 (as well as German Patent No. 973,048) relates to a process for the preparation of morpholine derivatives by reacting diethanolamine of the formula ^ 4 ^ 3 ^ 2? 1

HO-CH-CH-NH-CH-CH-OH VII

wherein R 1 is phenyl, R 2 and R 3 are hydrogen, phenyl or alkyl, and R 4 is hydrogen or phenyl, to react with a concentrated acid at room temperature or with an acid diluted with water or alcohol - at elevated temperature. This method is an example of the well-known acid-catalyzed cyclization of 1,5-diol to a 6-membered oxygen heterocyclic compound, and the reaction apparently proceeds through a reaction between a primary hydroxy group and a positive benzylcarbonium ion: H

t \ · ©

VIII

2 H J

A similar situation exists in the process according to the above-mentioned Finnish patent application 668/68, item e), which uses a starting material of the formula (OH OH.

Instead, the process of the invention proceeds via an anion of formula 4,629,26 X-O-CH-.

T

B

that is, a nucleophinic reaction occurs at the carbon atom bearing the group Z. Thus, the known methods differ from the process according to the invention in the following respects: 1) according to known methods, diethanolamine having an activated (benzylic) secondary hydroxy group attached to the aromatic ring of the group -CHC reacts. instead, according to the process of the invention the secondary hydroxy group is not activated in this way but is attached to the aromatic ring via the chain -OC 2 -CH 2, 2) the known processes are carried out in the presence of an acid, either dilute or concentrated acid; the process is carried out in the presence of a base; In fact, the compounds prepared by the process of the invention cannot be prepared according to known methods, but thus a completely new synthesis is required to prepare the desired compound.

Cyclic ethers can be prepared by the known Williamson reaction (see "Named Organic Reactions", 1969, page 240). In the synthesis of ether by the Williamson reaction, there is a step in which the alkoxide ion displaces the leaving group, usually the halogen atom, so that no compounds other than the ether can be formed. Instead, other reactions may occur in the intramolecular Williamson reaction; indeed, it has been stated in the above-mentioned reference publication that numerous by-products are formed.

It should also be noted that the Williamson reaction occurs only under the influence of a strong anhydrous base (e.g., Na t r lumme ta Uin), 62296 because otherwise no alkoxide anion is formed (except in the special case that the starting material is phenol, i.e. the hydroxy group is relatively acidic). If a base diluted with water were used in a normal Williams reaction, the alcohol would not form an anion but only the hydrolysis of the alkyl halide would occur.

For the above reasons, the process according to the invention is new, and also very surprising, given the numerous reaction options, namely 1) nucleophilic hydrolysis to give a substituted diethanolamine of general formula VII above, 2) cleavage of HX to give --- olefin according to NCH = CH2, „3) formation of aziridine; as known nitrogen is more nucleophilic than oxygen, so when treating the above compound of formula II (wherein the side nitrogen atom has a hydrogen atom) with a base diluted with water, aziridines are expected to form (cf. the well-known ethyleneimine synthesis from 2-aminoethyl , performed in the presence of sodium hydroxide - see Organic Syntheses, Collected Volume IV, page 433), and 4) dimerization; there is a single case in the literature where a compound having the side chain structure of a compound of formula II is treated with a base, namely an article by Crane and Rydon (see J. Chem. Soc. 1947, 527-530); this article describes (page 529, line 6 from below) the reaction of a compound of formula XII with sodium ethoxide to form a compound of formula XIII: HO Cl (CH 2 CH 2 OH) 2 n e '»0 J ->

kN S

CH2CH2OH (CH2CH2OH) 2

XII XIII

6 62296

Thus, it is expected that the compounds of formula II and III will react in an analogous manner.

However, the compounds of formula II and III do not react as would be expected. Quite surprisingly, a 2- (aryloxymethyl) morpholine derivative is formed, in good yield. This is a completely new reaction, given the state of the art. On the contrary, a completely different behavior can be expected from each prior art publication.

The invention is illustrated by the following examples:

Example 1

A mixture of crude (83%) 1,2-epoxy-3- (o-ethoxyphenoxy) propane (19.4 g), 2-aminoethyl hydrogen sulphate (70.5 g), sodium hydroxide (40, 0 g), ethanol (400 ml) and water (200 ml) are stirred at 60 ° C for 18 hours, after which it is evaporated to dryness. The residue is dissolved in water (200 ml) and the mixture is extracted three times with diethyl ether (3 x 150 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness. The crude product (21.5 g) is dissolved in isopropanol (20 ml) and concentrated hydrochloric acid (10.5 ml) and ethyl acetate are added, followed by cooling. The mixture is filtered to give 2- (o-ethoxy-phenoxymethyl) -morpholine hydrochloride as a solid, m.p. 179-182 ° C. (8.6 g, 38%, yield calculated on the total amount of epoxide used).

Example 2

Mixture of crude (83%) 1,2-epoxy-3- (o-ethoxyphenoxy) propane (10 g), 2-chloroethylamine hydrochloride (23.2 g), sodium hydroxide (20 g), ethanol (200 ml) and water (100 ml) are maintained at 60-65 ° C for 24 hours. The reaction mixture is acidified with concentrated hydrochloric acid, the ethanol is removed by distillation and the remaining aqueous solution is extracted with ethyl acetate (100 ml) and the extract is removed. The aqueous phase is basified with sodium hydroxide solution and extracted twice with ether (2 x 200 ml). The combined extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. This gives a crude base (6.0 g), of which 2.0 g are chromatographed on silica gel (100 g) using first chloroform and then 10% (w / w) methanol in chloroform as eluent. The elution step is followed by thin layer chromatography. The appropriate fractions of the eluent are combined and evaporated to dryness and the residue is dissolved in ethyl acetate (15 ml). 10% (w / v) hydrogen chloride in isopropanol is added dropwise until the solution is acidic, after which the solution is cooled and filtered. In this case, 62296 gives 2- (o-ethoxyphenoxymethyl) -morpholine hydrochloride, m.p. 179-183 ° C (0.35 g).

Example 3

A solution of crude (86.1%), 1,2-epoxy-3- (m-methoxy-phenoxy) -propane (52.3 g) in methanol (250 ml) is added to a solution of 2-aminoethyl hydrogen sulphate ( 352.5 g) in 70% (w / v) sodium hydroxide solution (141 ml), and the mixture is stirred vigorously at 55 ° C for one hour. An additional 70% (w / v) sodium hydroxide solution (141 ml) is added and the mixture is stirred vigorously at 55 ° C for 12 hours. Toluene (500 ml) and water (1 liter) are added and the mixture is stirred vigorously, after which the toluene layer is isolated and extracted with aqueous 2-n-sulfuric acid (500 ml). The acidic extract is basified with sodium hydroxide solution and the mixture is extracted twice with toluene (2 x 300 ml). The combined toluene extracts are washed with water and evaporated to dryness under reduced pressure, and the residue (50.3 g) is distilled to give 2- (m-methoxyphenoxymethyl) morpholine (41.3 g, yield 74% based on the total amount of epoxide used), b.p. 114 ° C / 0.02 mm.

Example 4

A solution of 1,2-epoxy-3- (o-tolyloxy) propane (1 equivalent), 2-aminoethyl hydrogen sulphate (3 equivalents) and sodium hydroxide (3 equivalents) in water (5 ml each g of sodium hydroxide per mixture) and dioxane (8 ml for each g of sodium hydroxide) are heated under reflux for 90 minutes. Sodium hydroxide solution (10 equivalents as 70% (w / v) aqueous solution) is added and the mixture is heated under reflux conditions for 6 hours. The mixture is cooled and extracted twice with toluene, and the combined toluene extracts are extracted twice with 2N sulfuric acid.

The combined acidic extracts are basified with sodium hydroxide solution and the mixture is extracted twice with toluene. The combined toluene extracts are washed with water and the toluene is removed by evaporation under reduced pressure. The residue is dissolved in ethyl acetate and the solution is chromatographed on a silica column, using first ethyl acetate and then a mixture of ethyl acetate and ethanol (4: 1 v / v) as eluent. Elution is followed by thin layer chromatography and the eluate-containing fractions containing 2- (o-to-yloxymethyl) -morpholine are combined and evaporated to dryness. The residue is dissolved in methanol and the solution is added to a methanolic solution of oxalic acid 62296. Ethyl acetate is added and the mixture is cooled until crystallization is complete. The mixture is filtered and the precipitate is washed with ethyl acetate and dried; the pure 2- (o-tolyloxymethyl) morpholine hydrogen oxalate obtained has a melting point of 119 ° C; yield 9.7%.

The 1,2-epoxy-2- (appropriately substituted-phenoxy) -propane used as starting material of the formula:

A solution of o-cresol (1 equivalent), epichlorohydrin (1.5 equivalents) and sodium hydroxide (1.2 equivalents) in water (10 ml for each g of sodium hydroxide) is stirred at 20 ° C for 16 hours. The mixture is extracted twice with ethylene dichloride and the combined extracts are dried and evaporated to dryness, the crude epoxide obtained as an oily residue being used as such without further purification. The epoxide content of the raw material can be calculated by adding a certain amount of a solution of aqueous hydrochloric acid in dioxane to an equal portion of the crude epoxide and estimating the amount of hydrochloric acid used by titrating the excess hydrochloric acid with methanolic sodium hydroxide solution.

Example 5

Proceed as in Example 4, but starting from 1,2-epoxy-3-O- (chlorophenoxy) propane. The resulting 2- (o-chlorophenoxymethyl) morpholine hydrogen oxalate has a melting point of 143 ° C; yield 18%.

Example 6

Proceed as in Example 4, but starting from 1,2-epoxy-3- (p-chlorophenoxypropane), the resulting 2- (p-chlorophenoxymethyl) -morpholine hydrogen oxalate melts at 164 ° C, yield 22%.

Example 7

Proceed as in Example 4, but starting from 1,2-epoxy-3-naphth-1-yl-oxypropane. The resulting 2- (naphth-1-yloxymethyl) -morpholine hydrogen oxalate melts at 161 ° C; yield 4%.

Example 8

Proceed as in Example 5, but starting from 1,2-epoxy-3- (o-methylthiophenoxy) propane. The resulting 2- (o-methylthiophenoxymethyl) morpholine hydrogen oxalate melts at 174-177 ° C; yield 16%.

62296

Example 9

Proceed as in Example 4, but starting from 1,2-epoxy-3- (o-benzyloxyphenoxy) propane. The resulting 2- (o-benzyloxy-phenoxymethyl) morpholine hydrogen oxalate melts at 164-167 ° C; yield 17%.

Example 10

Proceed as in Example 4, but starting from 1,2-epoxy- (3-o-phenylphenoxy) propane. The 2- (o-phenylphenoxymethyl) morpholine formed is converted to the hydrochloride, m.p. 159-163 ° C (recrystallized from methanol / ethyl acetate); yield 5%.

"Example 11

Proceed as in Example 4, but starting from 1,2-epoxy-3-m-tolyloxypropane. The resulting 2- (m-tolyloxymethyl) -morpholine hydrogen oxalate melts at 157-160 ° C (recrystallized from methanol / ethyl acetate); 15% yield.

Example 12

Proceed as in Example 4, but starting from 1,2-epoxy-3- (m-chlorophenoxy) propane. The formed 2- (m-chlorophenoxymethyl) morpholine hydrogen oxalate melts at 144-147 ° C (recrystallized from methanol / ethyl acetate); yield 21%.

Example 13

Proceed as in Example 4, but starting from 1,2-epoxy-3- (m-ethoxyphenoxy) propane. The 2- (m-ethoxyphenoxymethyl) morpholine hydrogen oxalate formed melts at 155-157 ° C (recrystallized from methanol / ethyl acetate); yield 9%.

Example 14

Proceed as in Example 4, but starting from 1,2-epoxy-3- (m-phenoxyphenoxy) propane. The 2- (m-phenoxyphenoxymethyl) morpholine hydrogen oxalate formed melts at 132-134 ° C (recrystallized from ethanol); yield 25%.

Example 15

Proceed as in Example 4, but starting from 1,2-epoxy-3- (5,6,7,8-tetrahydronaphth-1-yloxy) propane. The formed 2- (5,6,7,8-tetrahydronaphth-1-yloxymethyl) morpholine hydrogen oxalate melts at 186-189 ° C (recrystallized from methanol / ethyl acetate); yield 19%.

Claims (1)

Example 16 Proceed as in Example 4, but starting from 1,2-epoxy-3- (2,5-dimethylphenoxypropane) The 2- (2,5-dimethylphenoxymethyl) morpholine hydrogen oxalate formed melts at 118-119 ° C (recrystallized from methanol / ethyl acetate), yield 12% Example 17 The procedure is as in Example 4, but starting from 1,2-epoxy-3- (3,5-dimethylphenoxy) propane. -phenoxymethyl) morpholine is converted to the hydrochloride melting at 156-158 ° C (recrystallized from methanol / ethyl acetate), yield 7% A new process for the preparation of therapeutically useful 2-aryloxymethyl-morpholines of the formula: I wherein X is unsubstituted phenyl, 1-naphthyl or 5,6,7,8-tetrahydro-1-naphthyl, or phenyl substituted by a chlorine atom or methoxy, ethoxy, methylthio, phenyl, phenoxy or with a benzyloxy group or up to two methyl groups, characterized in that a compound of the formula: wherein X is the same as above, is reacted with a compound of the formula: wherein Z is a halogen atom or a sulfonyloxy group in the presence of a strong base.