CS227330B2 - Method of preparing morpholine derivatives - Google Patents

Description

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

(I) in which:

R is ethyl or phenyl, and the salts and N-oxides of these compounds.

The process for the preparation of the novel compounds of the formula I according to the invention is characterized in that the compound of the formula VII is prepared

R.

h ₃ c

Crlo

XX ’

CHO (VII) in which

R is as defined above, reacted under hydrogenation conditions with a compound of formula 111

(III), where appropriate, for the preparation of the N-oxide, the compound of the formula I is optionally treated with hydrogen peroxide or peroxyacids, or, for the production of a salt of the base of the formula 1, optionally converted into a salt by a known method.

The reaction of the substituted cinnamic aldehyde VII with cis-2,6-dimethylmorpholine III is carried out under hydrogenation conditions, for example using a palladium catalyst, for example methanol.

In order to prepare the N-oxides of the compounds of formula I, the compound of formula I is treated with hydrogen peroxide or peroxy acids. Alcohols such as methanol, ethanol or isopropanol are used as solvents when hydrogen peroxide is used as the oxidizing agent, the latter isopropanol being preferred. Preferred reaction temperatures are between 0 and 50 ° C, particularly preferred 40 ° C. As peracids, for example, peracetic acid, perbenzoic acid, metachlorobenzoic acid, peradipic acid can be used. Preferred solvents for peracids are halogenated hydrocarbons such as methylene chloride, chloroform or ethylene chloride. Suitable reaction temperatures are those mentioned above for the reaction with hydrogen peroxide.

The compounds of formula I form salts with organic and inorganic acids. Suitable salts for the compounds of the formula I are, in particular, salts with physiologically acceptable acids. These preferably include hydrohalic acids such as hydrochloric acid and hydrobromic acid, phosphoric acid, nitric acid, monohydric and dibasic carboxylic acids and hydroxycarboxylic acids such as acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid. and lactic acid, and finally sulfonic acids, such as 1,5-naphthalenedisulfonic acid. The preparation of such salts is carried out in a manner known per se.

The starting materials of formula VII are known compounds. The starting material of formula III is known as a cis / trans mixture. Out! the compound of formula III with a cis configuration can be obtained in an analogous manner to that for producing a cis / trans mixture.

The compounds of the invention contain an asymmetric carbon atom in the propylene chain linking the morpholine moiety to the p-substituted phenyl moiety and may therefore exist in the form of racemates and in the form of optical antipodes. Optical antipodes can be obtained from the racemates formed by resolution with optically active acids, for example (+) - camphoric acid, (+) - camphor-10-sulfonic acid, O, O'-dibenzoyltartaric acid (L- or D-form), L - (+) - tartaric acid, D - (-) - tartaric acid, 4-sulfonate of L (+) - glutamic acid, L (-) - malic acid or D ( ⁺ ) - malic acid. This cleavage can be carried out by conventional cleavage methods.

The compounds of the invention have fungicidal activity and can be used accordingly to combat fungi in agriculture and horticulture. The compounds are particularly suitable for combating powdery mildew fungi such as grass powdery mildew (Erysiphe graminis), cucumber powdery mildew (Sryaiphe cichoraeearum), powdery mildew (Podosphaera leucotrleha), powdery mildew (Sphaerotheca pannosa), vine padli (Oid); longer rust-like fungi such as Puceinia, Uromyces and Hemilela, in particular Puccinla graminis (grass rust), oat rust (Puccinla coronata), corn rust (Puceinia sorghi), rust rust (Puccinla etrliformla), common rust rust (Puccinla) , bean rust (Uromyces fabae) and bean rust (Uromyces appendiculatue), as well as against Hemilela vastatrix and Phragmidium mucronatum.

In addition, the compounds are also active against the following phytopathogenic fungi: roasted oat anemones (Uetilago avenae), apple flesh (Venturia inaequalis), Cereospora arachidlcola, blackening of the stalks (Ophiobolua graminis), weevils (Septoria nodorosa) or Marseonia. The individual compounds of this class of compounds also have significant side effects against different species of the following genera: Hizoctonia, Tilletia, Helminthosporlum, as well as partial against the genera Peronospora, Coniophora, Lenzites, Corticium, Thielaviopsis and Fusarium.

In addition, the compounds of formula I also act against phytopathogenic bacteria, such as Xanthomonas vesicatoria, Xanthomonas oryzae and other xanthomonads, as well as against various Erwinla species, for example Erwinla tracheiphila.

In particular, however, the compounds according to the invention are suitable for combating infections caused by fungi and yeasts, for example of the genera Candida, Trichophytes or Histoplasma, because of their fungistatic and fungicidal activity. They are particularly effective against Candida species such as Candida albicans and are advantageously suitable for the topical treatment of topical infections of the skin and mucous membranes, in particular of the genital tract, e.g. The selected dosage form is topical so that the active compounds can be used as therapeutically active preparations in the form of ointments, suppositories, globules or other suitable forms.

The pharmaceutical preparations may be prepared in a manner known per se by mixing the active compounds with customary organic or inorganic inert carriers and / or excipients such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, preservatives, stabilizers, wetting or emulsifying agents, salts for affecting the osmotic pressure or buffers.

Dosing is carried out according to individual requirements, but daily dosing of 1 to 2 tablets containing 50 to 100 mg of active ingredient over several days is the preferred dosage. Suitably, the hasti contains 0.3 to 5%, preferably 0.5 to 2%, particularly preferably 0.5 to 1% of active ingredient. The following test description and the results shown in the table also provide the skilled person with the necessary information for dosing the active ingredients.

The compounds of the invention were tested for their potency against Candida albicans in the rat by the Vaginal-Candidiasis assay described in Path. Microbiol. 23: 62-68 (1960) with the following results:

Compound Concentration in% at which the effect of ED 50 is achieved cis -4- [1-] 3- (p-tert-amylphenyl) -2-methylphenyl] -2,6-dimethylmorpholine 0.01 or S-4- / 3- [p- (alpha, alpha-dimethylbenzyl) phenyl] -2-methylpropyl / -2,6-dimethylmorpholine 0.01

Example 1

230 g of 3- (p-tertamylphenyl) -2-methylpropionaldehyde and 137 g of cis-2,6-dimethylmorpholine were heated in 1000 ml of toluene using a water separator and under a nitrogen atmosphere for 16 hours until the water was removed under reflux. . At room temperature, 17.5 g of 5% palladium on carbon are added under nitrogen, and then hydrogenation is carried out until the consumption of hydrogen is complete, the catalyst is filtered off and the toluene is evaporated off under vacuum. Distillation of the residue gave pure cis-4- [3- (p-t-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine, b.p. 120 ° C / 13.3 Pa.

Example 2

In an analogous manner to that described in Example 1, reaction of 3- [p- (alpha, alpha-dimethylbenzyl) phenyl] -2-methylpropionaldehyde with cis-2,6-dimethylmorpholine and hydrogenation affords cis-4- / 3- [ p- (alpha, alpha-dimethylbenzyl) phenyl] -2-methylpropyl / -2,6-dimethylmorpholine, boiling point 162 ° C / 5.3 Pa.

Example 3

266 g of cis-4- [3- (p-t-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine are dissolved in 500 ml of absolute ethanol and 500 ml of a 28% solution of hydrogen chloride in ethanol are added dropwise at room temperature. The homogeneous solution is concentrated to dryness on a rotary evaporator and the residue is recrystallized from 100 ml of water. The crystallizate is washed with water and dried in a vacuum oven at 55 ° C. Cis-4- [3- (p-t-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine hydrochloride is obtained in the form of white, slightly hygroscopic crystals, m.p. 204-206 ° C.

Example 4

A solution of 60 ml of 30% hydrogen peroxide in 60 ml of acetic anhydride is added dropwise to 21 g of cis-4- [3- (p-t-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine while cooling with a mixture of acetone and solid carbon dioxide. The reaction mixture was allowed to react for a further 16 hours at room temperature. The reaction mixture was then checked by thin layer chromatography (solvent system; hexane / ether 1: 1). To destroy excess peroxide, the reaction solution was cooled to -10 ° C and 200 mL of 40% potassium hydroxide was added. After stirring for 20 hours, the reaction mixture is diluted with 500 ml of water and thoroughly extracted with chloroform. The combined chloroform extracts were washed neutral, dried and evaporated. Recrystallization of the residue from 100 mL of pentane gave pure cis-4- [3- (p-t-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine-4-oxide.

The following examples describe the manufacture of pharmaceutical preparations:

Example 5

Vaginal tablets of the following composition are prepared in a conventional manner: cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine 50 mg secondary calcium phosphate dihydrate directly compressible starch STA-RX1500

400 mg 261 mg

lactose (spray-dried) 100 ALIGN! mg polyvinylpyrrolidone 25 mg citric acid 5 mg magnesium salt of stearic acid 6 mg 847 mg

Example 6

An ointment of the following composition is prepared:

Cis-4- / 3- p- (alpha, alpha-dimethylbenzyl) phenyl -2-methylpropyl / -2,6-dimethylmorpholine 0.7 g cetyl alcohol 3.6 g sheep wool fat 9.0 g white petrolatum 79.3 g paraffin oil 7.4 g

100.0 g

Example 7

A cream having the following composition is prepared:

cis-4- [3- (p-t-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine polyoxyethylene stearate stearyl alcohol viscous paraffin oil petrolatum, white carboxyvinylpolymer CARBOPOL 934 Ph sodium hydroxide, pure water, demineralized

0.7 g

3.3 g

8,0 g

10.0 g 10.0 g

0.3 g

0.07 g to 100.0 g

Claims (2)

Object of the invention A process for the preparation of morpholine derivatives of the general formula I wherein: R is ethyl or phenyl, (I) έ as well as their salts and their N-oxides, characterized in that the compound of the general formula VXI (VII) CHO in which R is as defined above, reacted under hydrogenation conditions with a compound of formula III (III) and optionally treated with hydrogen peroxide or peracids to produce the N-oxide of the compound of formula I, or optionally converting a base of formula I with an acid into a salt. 2. A process according to claim 1, characterized in that the racemate obtained is resolved into optical antipodes.