DE2760419C2 - - Google Patents

Description

The invention relates to a process for the preparation of 2- (7- Indenyloxymethyl) morpholine according to the claim.

DE-OS 26 01 703 relates to compounds of the general formula

wherein R¹ and R³ each represent a hydrogen atom, a lower alkyl group or represents a phenyl group, R² represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a Phenyl group or a benzyl group; and one of the dashed ones Lines means a single bond and the other means a double bond and its salts with acids Process for the preparation of these compounds and further the Use of these compounds as an active ingredient in the preparation of Medicines for humans and animals as an antidepressant.

Antidepressants with the morpholine ring are already known and Z. B. in US-PS 37 14 167 (GB-PS 11 38 405; BE-PS 7 08 557;  CA-PS 8 60 341; AU-PS 67 30 109; CH-PS 5 04 452 and 5 13 904; FR-PS 15 71 341; FR-PS drug 7 557 etc.) and US-PS 37 12 890 (GB-PS 12 60 886; CA-PS 9 13 090; CH-PS 5 39 068 etc.) described.

As a compound, among the known compounds of this Patents have the highest activity, it will 2- (2-ethoxyphenoxymethyl) morpholine, which is generally considered known as Viloxazine (see "Nature", 238 [1972], pp. 157-158) is. A series of studies has been published by K. B. Mallion, A. H. Todd, R. W. Turner and others performed the inventors of the Viloxazin. It is the relationship between these chemical structures and pharmacological activities of these connections. It follows that the Compound is preferred which has a substituent in the 2-position of a phenoxy group attached to morpholine, having. It is further preferred if the phenoxy group forms a closed ring that z. B. a tetralin-type ring is formed by condensation of a tetramethylene group. But if the condensed ring is an indan type ring through that Condensation of a trimethylene group forms the pharmacological Effect less.

Of particular interest is the salt of 2- (7-indenyloxymethyl) - morpholine with the formula (I)

with acids.

In DE-OS 26 01 703 the compound obtained according to Example 10 is thus 2- (4- or 7-indenyloxymethyl) morpholine and the melting point of the maleate is 135-137 ° C. As a result of further investigation, the inventors found that the compound obtained according to Example 10 actually  a mixture of 2- (7-indenyloxymethyl) morpholine (hereinafter referred to as 7-isomer) and 2- (4-indenyloxymethyl) morpholine (hereinafter referred to as 4-isomer) in the same way as that in Example 16 of DE-OS 26 01 703 represents the compound obtained. Furthermore, the inventors have by separating the product in 2- (7-indenyloxymethyl) morpholine maleate with the melting point at 154-156 ° C and 2- (4-indenyloxymethyl) morpholine maleate the melting point at 167-169 ° C the presence of these compounds ensured. It was also found that the obtained 2- (7-indenyloxymethyl) morpholine salts excellent deliver pharmacological effects compared to the 4-isomers and therefore can be used much cheaper than medication.

The inventors now have a new manufacturing method of the desired products found, which is different from the The process is described in the description of DE-OS 26 01 703 indicated and which is specified in the claim.

In DE-OS 27 07 678 are other manufacturing processes for above compounds and their salts with acids, from which the present subject matter has been divided. In DE-PS 27 07 678 this object is no longer included.

The process is illustrated by the following examples:

example 1 a) Preparation of 2- (1-hydroxy-4-indanyloxymethyl) morpholine

To a mixture of 6 g of 20% sodium hydroxide solution and 38 g 2-aminoethyl hydrogen sulfate was 2.0 g of 1- (1-hydroxy-4-indanyl oxy) -2,3-epoxypropane, dissolved in 10 ml of ethanol. The mixture was stirred at 60 ° C for one hour. To the Solution was added to 2.0 g of 20% sodium hydroxide solution. The mixture was stirred at 60 ° C for 16 hours. After this Cooling, 50 ml of water was added to the mixture, and the reaction mixture was extracted three times with 20 ml of toluene. The extracts were combined, washed with water, dried over anhydrous sodium sulfate, and then was the solvent was distilled off under reduced pressure. Then  the residue was subjected to silica gel column chromatography. A mixture of chloroform / methanol (9: 1 in volume ratio). 900 mg of 2- (1-hydroxy-4- indanyloxymethyl) morpholine with a melting point at 115-117 ° C receive.

Elemental analysis for C₁₄H₁₉NO₃:

Calculated:
C 67.45; H 7.68; N 5.62%.
Found:
C 67.01; H 7.66; N 5.43%.

Nuclear magnetic resonance spectrum: (CDCl₃, ppm):

b) Preparation of 2- (7-indenyloxymethyl) morpholine hydrochloride

50 g were added to 1.0 g of 2- (1-hydroxy-4-indanyloxymethyl) morpholine ml of ethanol and 50 ml of 0.5N hydrochloric acid are added. The mixture was refluxed by heating for 17 hours. After cooling, the reaction mixture was reduced  Pressure is reduced until the total volume is approximately 50 ml was. Then sodium chloride was added for salting out. The reaction mixture was three times with 50 ml Chloroform extracted. The extracts were pooled and over dried anhydrous magnesium sulfate. The solvent was distilled off. The syrupy residue formed was in a small amount of isopropyl alcohol. Was acetone added to the solution. There were 830 mg of a light yellow Powder from 2- (7-indenyloxymethyl) morpholine hydrochloride as Receive precipitation. By recrystallizing the product colorless needle-shaped crystals of the prepared acetone were Obtained compound with a melting point at 155-156 ° C.

Elemental analysis for C₁₄H₁₈NO₂Cl:

Calculated:
C 62.75; H 6.78; N 5.23; Cl 13.24%.
Found:
C 63.43; H 6.72; N 5.43; Cl 12.91%.

Nuclear magnetic resonance spectrum: (CDCl₃ + D₆-DMSO):

Example 2 a) Preparation of 2- (1-oxo-4-indanyloxymethyl) morpholine

To a solution from a mixture of 6 g of 20% sodium hydroxide solution and 3.8 g of 2-aminoethyl hydrogen sulfate became 2.0 g 1- (1-oxo-4-indanyloxy) -2,3-epoxypropane, dissolved in 10 ml of ethanol, added. The mixture was stirred at 60 ° C for one hour. Then 20 g of 20% sodium hydroxide solution was added to the Mixture added. The resulting mixture was 16 hours stirred at 60 ° C. After cooling, 50 ml of water was added given the mixture. Then the reaction mixture with 20 ml Toluene extracted. The extract was washed with water and dried over anhydrous sodium sulfate. Then the solvent distilled off under reduced pressure. The educated The residue was subjected to silica gel column chromatography. The mixture was eluted with a mixture of chloroform / methanol (98: 2 in volume ratio). 110 mg of oily 2- (1-oxo- Obtained 4-indanyloxymethyl) morpholine from the eluate.

Elemental analysis for C₁₄H₁₇NO₃:

Calculated:
C 67.99; H 6.93; N 5.66%.
Found:
C 67.83; H 6.92; N 5.60%.

Nuclear magnetic resonance spectrum: (CDCl₃, ppm):

b) Preparation of 2- (7-indenyloxymethyl) morpholine hydrochloride

The procedure was as in Example 1, Section b), but was the 2- (1-oxo-4-indanyloxymethyl) morpholine obtained above used. It became 2- (7-indenyloxymethyl) morpholine hydrochloride receive.

The elementary analysis and the nuclear magnetic resonance spectrum (CDCl₃) agreed with that obtained in Example 1, Section b) Product match.

Example 3 Preparation of 2- (7-indenyloxymethyl) morpholine hydrochloride

In 500 ml of hydrochloric acid in ethanol (350 ml of 0.5N hydrochloric acid and 150 ml of ethanol) 5.0 g of 4-triphenylmethyl 2- (1-hydroxy-4-indanyloxymethyl) morpholine dissolved. The solution was refluxed with heating for 17 hours. To after cooling the reaction mixture, ethanol was reduced The pressure is reduced until the total volume of the Reaction mixture was about 350 ml. Then sodium chloride added to the reaction mixture for salting out. The  The mixture was extracted three times with 200 ml of chloroform. The Chloroform extracts were combined and over anhydrous magnesium sulfate dried. The solvent was reduced Pressure distilled off. To the syrupy residue obtained acetone was added. 2.0 g of 2- (7-indenyl oxymethyl) morpholine hydrochloride obtained as a precipitate.

Melting point of the hydrochloride: 155-156 ° C.
Melting point of the maleate: 154-156 ° C.

Elemental analysis for C₁₄H₁₈NO₂Cl:

Calculated:
C 62.75; H 6.78; N 5.23; Cl 13.24%.
Found:
C 62.81; H 6.79; N 5.40; Cl 13.11.%

Nuclear magnetic resonance spectrum: (CDCl₃ + D₆-DMSO):

Claims (1)

A process for the preparation of 2- (7-indenyloxymethyl) morpholine, characterized in that 4-triphenylmethyl-2- (1-hydroxy-4-indanyloxymethyl) morpholine or 2- (1-hydroxy-4-indanyloxymethyl) morpholine or Added hydrochloric acid and ethanol to 2- (1-oxo-4-indanyloxymethyl) morpholine and heated under reflux for about 17 hours and the hydrochloride obtained was isolated from the reaction mixture in a conventional manner.