CS227328B2 - Method of preparing morpholine derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of morpholine derivatives of the general formula (I) (AND) R is ethyl or phenyl, and salts and N-oxides of these compounds. Process for the production of new compounds reduces the compound of formula of the formula I according to the invention is that ae IV (IV)

Description

(54) A method for producing morpholine derivatives

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

(AND)

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

The process for the preparation of the novel compounds reduces the compound of the general formula (I) according to the invention by ae IV

(IV) in which:

R is as described above and both dashed lines represent one additional bond, whereupon the N-oxide compound is treated with a compound of the formula I if hydrogen peroxide or peracid is treated, or an acid is converted to produce a salt, a base of formula I or an acid. known to the salt.

According to the above procedure, ee reduces the compound of formula IV. If a compound in which the double bond is in the alpha position to the morpholine residue is used as the starting material of the formula IV, the reduction can be carried out catalytically or by treatment with formic acid.

Particularly suitable catalysts are noble metal catalysts, such as platinum, palladium - or possibly coal-embedded -, and Raney nickel. Palladium on carbon is preferred. Solvents suitable for catalytic reduction are hydrocarbons such as benzene, toluene or xylene, as well as alcohols such as methanol or ethanol. Toluene is preferred. The reaction temperatures are preferably selected in the range between 0 and 50 ° C, preferably at room temperature. The reduction of the enamine with formic acid is preferably carried out in the absence of a solvent, and the formic acid, optionally with cooling, is added dropwise to the enamine at 0 to 100 ° C, preferably at 50 to 70 ° C.

By using the starting material in IV, in which the double bond is in the alpha position to the phenyl ring, the reduction can be carried out catalytically. Platinum or palladium is preferably used as the catalyst, water or alcohol being used as the solvent. To avoid possible hydrogenolysis, at least an equivalent of an acid, preferably hydrochloric acid, is added to the reaction mixture.

In order to prepare the N-oxides of the compounds of formula I, the compound of formula I is treated with hydrogen peroxide or peracids. Alcohols such as methanol, ethanol or isopropanol are used as solvents when hydrogen peroxide is used as the oxidizing agent, with the latter isorpopanol being preferred. Preferred reaction temperatures are between 0 and 50 ° C, particularly preferably at 40 ° C. As peracids, for example, peracetic acid, perbenzoic acid, metachloroperbenzoic acid, peradipic acid can be used. Solvents for peracids are preferably halogenated hydrocarbons such as methylene chloride, chloroform or ethylene chloride. Suitable reaction temperatures are those mentioned above for the reaction and 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 include preferably 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. acid, salieylic acid, aorbic 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 IV are known as mixtures / tranes. The cis -containing starting materials of formula IV can be obtained in an analogous manner to that for the preparation of the duty / friction mixtures

The starting materials of the formula IV in which the double bond is in the alpha position to the morpholine moiety can be obtained, for example, by reacting the optionally substituted phenyl-2-ethylpropionaldehyde with cis-2,6-dimethylmorpholine. The hydrogenation of the compounds of the formula IV thus obtained is conveniently carried out in situ.

The starting materials of the formula IV in which the double bond is in the alpha position to the phenyl radical can be obtained, for example, by reaction of a halide which corresponds to the general formula II

ch ₂ - in which

R is as defined above and

Y represents chlorine, bromine or iodine which, however, has a double bond at the alpha-position to the phenyl moiety, with cis-2,6-dimethylmorpholine.

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, L (+) - glutamic acid 4-sulfonate, L (-) malic acid or D (+) - malic acid. This cleavage can be carried out by conventional cleavage methods.

The compounds according to the invention have a fungicidal action and can be used accordingly for combating 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 (Erysiphe cichoracearum), powdery mildew (Fodosphaera leucotricha), powdery mildew (Sphaerotheca pannosa), powdery mildew (Oidium); rust fungi such as Puccinia, Uromyces and Hemileia, in particular Puccinia graminis (grass rust), oat rust (Puccinia coronata), corn rust (Puccinia sorghi), rust rust (Puccinia striiformia), wheat rust (Puccinia recontida) , bean rust (Uromyces fabae) and bean rust (Uromyces appendiculatus), as well as against Hemileia vastatrix and Phragmidium mucronatum.

In addition, the compounds are also active against the following phytopathogenic fungi: Ustilago avenae, Venturia inaequalis, Cercospora arachidicola, Ophiobolus graminis, Septoria nodorum or Marssonia. The individual compounds of this class of compounds also have significant side effects against different species of the following genera: Rhizoctonia, Tilletia, Helminthosporium, as well as partially 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 Erwinia species, for example Erwinia tracheiphila.

In particular, the compounds of 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 mucosa, in particular of the genital tract, for example vaginitis, which is specifically caused by the genus Candida. The selected dosage form is topical so that the active compounds can be used as therapeutically active formulations 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.

Dosage ae is carried out according to individual requirements, but daily administration of 1 to 2 tablets containing 50 to 100 mg of active ingredient over several days is a preferred dosage. The ointments suitably contain 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 efficacy 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 ae achieves an effect of DD 50 trans -4- [3- (p-t-amylphenyl) -2-methylphenyl] -2,6-dimethylmorpholine 0.01 cis -4- / 3- [p- (alpha, alpha-dimethylbenzyl) phenyl] -2-methylpropyl / -2,6-dimethylmorpholine 0.01

He did

To 20.0 g of p- (alpha, alpha-dimethylbenzyl) -alpha-methylcinnaldehyde and 9.6 g of cis-2,6-dimethylmorpholine in 60 ml of methanol was added 1 g of 5% palladium on carbon under argon, and hydrogenation is performed until the hydrogen uptake is complete. The catalyst-free reaction solution was evaporated under reduced pressure, the residue was chromatographed using chloroform on alumina (stage II activity), and the product was then distilled under high vacuum. C18-4- [3- [p- (alpha, alpha-dimethylbenzyl) phenyl] 2-methylpropyl] -2,6-dimethylmorpholine having a boiling point of 162 [deg.] C / 5.33 Pa was obtained.

Example 2

In an analogous manner to that described in Example 1, cis-4- [3- (p-tert-amylphenyl) -2-] is obtained from p- (tert-amylphenyl) -α-methyl-methylnalnaldehyde and cis-2,6-dimethylmorpholine. ⁱ methylpropyl] -2,6-dimethylmorpholine.

Example 3

266 g of eis-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-dimethyl morpholine hydrochloride is obtained as white, slightly hygroscopic crystals, m.p. 204-206 ° C.

Fig. 1 and ú 4

To 21 g of cis-4- [3- (p-t-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine was added dropwise a solution of 60 ml of 30% hydrogen peroxide in 60 ml of acetic anhydride while cooling with a mixture of acetone and solid carbon dioxide. 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 20 hours of further stirring, the reaction mixture is diluted with 500 ml of water and the chloroform is extracted thoroughly. The combined chloroform extracts were washed until neutral, dried and evaporated. Recrystallization of the residue with 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 as usual:

cis-4- [3- (p-t-amylphenyl) -2-methylpropyl] -

-2,6-dimethylmorpholine 50 mg secondary calcium phosphate dihydrate 400 mg directly compressible starch STA-RX1500 261 mg lactose (spray-dried) 100 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:

or S-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 0.7 g polyoxyethylene etherearate 3.3 g stearyl alcohol 8.0 g viscous paraffin oil 10.0 g petrolatum, white 10.0 g carboxyvinylpolymer CARBOPOL 934 Ph 0.3 g sodium hydroxide, pure 0.07 g water, demineralized to 100.0 g

Claims (4)

DILUTE OF THE INVENTION Morpholine of Formula I wherein R represents an ethyl group or a phenyl group, as well as their salts and their N-oxides, characterized in that the compound of the formula IV is reduced CH, (IV) wherein R is as defined above, and the two broken lines represent one additional bond, whereupon the compound of formula I is optionally treated with hydrogen peroxide or peracids for the preparation of the N-oxide, or the base of formula 1 is optionally converted by acid treatment into a salt. 2. The process of claim 1 wherein the compound of formula IV wherein the double bond is in the alpha position to the morpholine moiety is reduced catalytically or by treatment with formic acid. 3. The method according to claim 1, characterized in that: characterized in that the compound of formula IV, in which the double bond is located in the alpha position to the phenyl residue, is catalytically reduced, 4. A process according to claim 1, wherein the racemate obtained is resolved into optical antipodes.