CS227329B2 - Method for the producing of morpholine derivate - Google Patents

Description

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 (V) is prepared

(VI) (VI)

227329 2 is reacted with a carbonium ion-yielding compound of formula VI h ₃ c-c-ch ₃ in which

R is as defined above, whereupon the compound of formula 1 is optionally treated with hydrogen peroxide or peracids for the preparation of the N-oxide, or optionally converted into a salt in a manner known per se by the acid treatment in a manner known per se.

The alkylation of the compound of formula V is carried out in the presence of a suitable amount of Friedel-Crafts catalyst. Suitable catalysts are the well-known Friedel-Crafts catalysts, such as aluminum chloride, ferric chloride, zinc chloride, boron trifluoride, tin chloride, hydrogen fluoride, sulfuric acid and phosphoric acid. Sulfuric acid is particularly suitable for the purposes of the present invention.

The use of an inert organic solvent is not necessary, but is preferred. Particularly suitable inert organic solvents are alkanes such as hexane, cyclohexane, chlorinated hydrocarbons such as chloroform, ethylene dichloride and methylene chloride, with methylene chloride being particularly preferred. The temperature of the alkylation reaction is not critical, but is generally between 0 and 50 ° C, preferably between 18 and 20 ° C.

Advantageously, and especially when sulfuric acid is used, after the reaction is completed, the product obtained is extracted in the form of a salt with an inert organic solvent such as methylene chloride. If desired, the free amine can be obtained by treating with a suitable base, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or calcium hydroxide.

Preferred compounds which yield carbonate ions of formula VI are the corresponding tert-alcohols, such as 2-methyl-2-butanol or tert-chlorides, such as 2-chloro-2-methylbutane.

In order to prepare the N-oxides of the compounds of formula I, the compound of formula I is treated with peroxide. hydrogen or peracids. 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 preferably 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 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. acid, salicylic acid, sorbic 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.

Compounds of formula (V) may be prepared by treating a compound of formula (VIII)

'3

CHO (VIII) is mixed with a compound of formula III

HN O (III)

and the resulting mixture is catalytically hydrogenated

The solvent used is preferably an organic solvent, for example an alcohol such as methanol. Temperature is not a critical condition, but is typically between 0 and 50 ° C.

Catalytic hydrogenation uses conventional hydrogenation catalysts such as platinum, nickel fianey or palladium, with 5% palladium on carbon being particularly preferred.

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 using 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 fungi such as powdery mildew (Erysiphe gramiňis), cucumber powdery mildew (Erysiphe cichoracearum), powdery mildew (Fodosphaera leucotricha), powdery mildew (Sphaerotheca pannosa), vine mildew (Oidium) ; rust fungi such as Puccinia, Uromyces and Hemileia, in particular Puccinia gramiňis (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, these compounds are also active against the following phytopathogenic fungi: oatmeal oatmeal (Ustilago avenae), scab of apple (Ventura inaequalis), Ceroospora arachidicola, Serum pat (Ophiobolus gramiňis), weedgrass (Septoria nodurum) 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 Pusarium.

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

In particular, however, 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 topical treatment of superficial 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 agents 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 influencing osmotic agents. 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. 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 person skilled in the art with the necessary information for dosing the active substances.

The compounds of the invention were tested for their activity against Candida albicans in the rat by the Veginal-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- [3- (p-t-amylphenyl) -2-methylphenyl] -2,6-dimethylmorpholine 0.01 cS-4- / 3- [p- (alpha, alpha-dimethylbenzyl) phenyl] -2-methylpropyl / -2,6-dimethylmorpholine 0.01

He did

223 1,223 g of cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethylmorpholine in 4 liters of methylene chloride is added dropwise at -5 ° C over 45 minutes to 4,941 g of concentrated sulfuric acid and then over 60 minutes 520 g of 2-methyl-2-butanol. Water was added to the reaction solution under ice-cooling, and the aqueous phase was extracted several times with methylene chloride. The organic extracts were washed with sodium hydroxide and then with water, dried, evaporated and the oily cis-4- [3- (p-t-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine was distilled under vacuum. Boiling point 120 ° C / 13.3 Pa. .

Cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethylmorpholine, which is used as starting material, can be prepared as follows:

000 g of alpha-methylcinnaldehyde, 10 liters of methanol and 789 g of ois-2,6-dimethylmorpholine are mixed under nitrogen atmosphere with the addition of 50 g of 5% palladium on carbon. Hydrogenation is then carried out under cooling with water at 30 DEG C. until the consumption of hydrogen is complete, the catalyst is filtered off, the methanol is distilled off under reduced pressure and the crude cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethylmorpholine is distilled off. distills. 99% pure product boils at 109 ° C / 7.3 Pa.

and

Example 2

In an analogous manner to Example 1, cis-4- / 3- [p- (Elf-slfa óimet ibenzyi _yl) -phenyl ^ -, 2-methylpropyl / -2,6-dimethylmorpholine, b.p. 162 ° C / 5 , 33 Pai

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. This gave eis-4- [3- (p-t-amylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine hydrochloride as white slightly hygroscopic crystals, m.p. 204-206 ° C.

Example 1 a d 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 allowed to react at room temperature for 16 hours. The reaction mixture was then checked by thin layer chromatography (solvent system: hexane / ether 1: 1). In order to destroy the 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 until neutral, dried and evaporated. Recrystallization of the residue with 100 ml of pentane gave pure cis-4- [3- (p-tert-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-teramylphenyl) -2-methylpropyl] -2,6-dimethylmorpholine secondary calcium phosphate dihydrate directly compressible starch STA-RX1500 lactose (spray-dried) polyvinylpyrrolidone citric acid magnesium stearate salt mg

400 mg

26 mg 100 mg 25 mg mg 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 \ cetyl alcohol sheep wool fat white petrolatum paraffin oil

Example 7

A cream having the following composition is prepared:

cis -4- [3- (p-teramylphenyl) -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

^3.8 g 9.0 g

79.3 g 7.4 g 100.0 g

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)

A process for the preparation of morpholine derivatives of the general formula I in which: R represents an ethyl group or a phenyl group, as well as their salts and their N-oxides, characterized in that the compound of formula V (V) is reacted with a compound providing a carbonium ion of formula VI (VI) in which: R is as defined above, whereupon the compound of formula (I) is optionally treated with hydrogen peroxide or peracids to produce the N-oxide, or the base of formula (I) is optionally converted by treatment with an acid into a salt. 2. A process according to claim 1, characterized in that the racemate obtained is resolved into optical antipodes.