CS227310B2 - Method of preparing morpholine derivatives - Google Patents

Abstract

Morpholine derivs. (I; R = Et, Ph) and its salt, N-oxide used as fungicides, were prepd. by the reaction of II (Y = c1 Br, I) and III, V and carbonium ion of VI, VII and III. Thus, a solution of 230g 3-(p-tertiaryamyl-phenyl)-2-methylpropion aldehyde and 137g Z-2, 6-dimethyl-Morpholine in 1000ml toluene was refluxed for 16 hr to remove water with N2. At room temp. added to 17.5g 5% pd/c and H2 to give pure Z-4-[3-(p-tertiaryamyl)-2-methylpropyl -2,6-dimethylmorpholine.

Description

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

(I) in which:

R is an ethyl or phenyl group, 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 halide of the formula II in which:

R is as defined above and

Y is chlorine, bromine or iodine, reacted with a compound of formula III

227.3'0

(II)

2273Ю

(III) whereupon, for the preparation of the N-oxide, the compound of formula (I) is optionally treated with hydrogen peroxide or peracids, or, for the production of a salt, a base of formula (I), optionally converted into a salt in a manner known per se

According to the above process, the halide of formula II is reacted with an amine of formula III, suitably in an inert solvent, for example in an ester such as diethyl ether, tetrahydrofuran or dioxane, or in dimethyl sulfoxide, preferably in a high boiling alcohol such as ethylene glycol or glycerin. The mixture is preferably reacted between 50 and 150 ° C. A particularly preferred solvent is ethylene glycol and a temperature of 100 to 110 ° C.

In order to produce the N-oxides of the compounds of the formula I, the compound of the formula I is treated with hydrogen peroxide or peracids. The temperature ranges from 0 to 50 ° C, particularly preferably 40 ° C.

Peracids, for example, peracetic acid, perbenzoic acid, metachloroperbenzoic acid, peradlpic acid may be used as the peracids. Halogenated hydrocarbons such as meetyenchloride, chloroform or ethylene chloride are preferably used as solvents for the peroxygen beads. reaction with hydrogen peroxide ·

The compounds of the 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 carbon thaelines and hydroxycarboxylic acids such as acetic acid, maaic acid, succinic acid, fumaric acid, tartaric acid, citric acid, sallcylic acid, sorbic acid and lactic acid, and finally sulfonic acids such as 1,5-naphthalenedisuioonic acid The production of such salts is carried out in a manner known per se ·

The compounds of the invention contain an asymmetric carbon atom in the propylene chain linking the mooroline moiety to the p-substituted phenyl moiety and may therefore exist as racemates and as optical antipodes. Oppic antipodes may be obtained from the racemates formed by resolution with optically active cyyelin. , for example (+ - camphoric acid, (+) - K-10-β-10-oxoic acid, 0,0'-libososylic acid (L- or D-form), L - (+) - vixic acid, D - (-) - viral acid, 4-sufoonate L (+) - glutamic acid, L (-) - malic acid or D (+) - malic acid · This cleavage ae can be carried out by the usual cleavage methods ·

The compounds according to the invention have a fungicidal action and can be used accordingly for combating fungi in agriculture and in the cultivation of cv0 ^. siphe cichoracearum), powdery mildew (Podoaphaere leucotricha), roses (Sphaerotheca paamooaa), powdery mildew (Oidium tuckeri), rust fungi such as Puuccnia, Hromyses and Hemmiela, in particular Puccinia graminis (rust grass) Puccinia coroicrte), corn rust (Raccinia sorghh), weed rust (Rucinia stfCfoormia), wheat rust (Raccinia recondita), bean rust (Uroaces fabae) and bean rust (Uroarcos apppMicclatus, as well as L against Hernileia vastatrii m a.

In addition, the compounds are also active against the following phytopethogenesis of fungi: Ustilago evenae, apple scab (Venturia Cnaeegills), Cercospora aricodicola, black stalks (Ophiobolus grarnicCs), pseudocerosus pseudorosa pseudorosa pseudoreae. The individual substances from this group of compounds a and j also have significant side effects in different species of the genus: Rhzoctonia, TiHetLa, Hilmintouptfilter, as well as L, also against the genera Peronospora, Coniophora, Lennztes , Corticiua, oleh.oleiCtp8is, and FusafCum.

In addition, the compounds of formula (I) also act against phytopathogenic bacteria such as Xanthorononasiliciltril, Xanthomones oryzee and other xanthomonads, as well as various species of Errin, for example Ephilocyla Ιη ^ βίρ ^ ϋβ.

In particular, the compounds according to the invention are, on the basis of their pharmaceutical and fungicide, due to their age. They are particularly effective against Candida species, such as Canddda albL-caos, and are preferably suitable for use in the treatment of infections caused by fungi and yeasts, e.g. for the treatment of superficial infections of the skin and mucous membranes, especially the genital tract, for example the vaginal cancer, which is specifically caused by the genus Caioidda. The dosage form chosen 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 can be prepared in a manner known per se by admixing the active compounds with customary organic or inorganic inert carriers or / and auxiliaries such as water, gelatin, acetoose, starch. magnesium stearic acid salt, effluent, vegetable oils, polyalkyleoglycols, petrolatum, preservatives, stabilizers, wetting agents or emulators, salts for influencing the axial pressure. or buffers.

The dosing is carried out according to the requirements, but daily administration of 1 to 2 tablets containing 50 to 100 g of the active ingredient for several days represents a preferred dosage. Suitably the MeaM contains 0.3 to 5%, preferably 0.5 to 2%, particularly preferably 0.5 to 1% of active ingredient. ^ watching! the description of the test and the results given in the table provide the skilled person with the necessary information for dosing the active substances.

The compounds of the invention were tested for their efficacy against Candida alb-caos in a rat using the Valisca / CaaCidic18 assay described in Path. Microobol. 23: 62-68 (1960). results: *

Sloúčecioa Concentration in% at which the effect of ED 50 is achieved CDS-4-3- (p-tert. extyl and ^ ^lf) -2-methylbenzenesulfonic ^f ^ en - -2,6-diaethylaofolio 0.01 cds-4- / 3-] p - (*, 4 * - ^ 00 ^ 1 - ^^ 0 ^^ 01 ^ 1 ^ -2-) .alpha.-acetylpiperazin-2-yl 0.01

Example i

To a solution of 22.7 g of 2,6-cis-dimethylmorpholine in 70 ml of ethylene glycol was added dropwise at 125 ° C 44.3 g of 3- (p-t-amylphenyl) -2-methylpropyl bromide and the reaction mixture was stirred at at this temperature. After cooling, 2N hydrochloric acid solution was added and the neutral portions were extracted with ether. The solution containing hydrochloric acid was then basified with 5N sodium hydroxide solution, extracted with ether, washed with water, washed with sodium sulfate and evaporated. Distillation yields pure cis-4- ^g of l- (p-tert-amylphenyl ^{E) -2-methyl-beta-yl p} ro ^{J -2,} 6-dimetylmoo ^{r 0} in the ^{TE p} lota b.p. 120 ° C / 13.3 P ^a .

Example 2

To a solution of 22.7 g of S-cis-dimethylmorpholine in 80 ml of ethylene glycol at 125 ° C was slowly added dropwise 5 ^{1 8} g З-рр-Ь с -dlmetylbenzylHen ^ ^yi] -2-metylpoopylbrom du ⁱ and ^the rea The mixture was stirred at this temperature for 48 hours. Processing was carried out analogously to Example 1. Dee demethylating ^ of ^ ka ^net dimethylbenzyl en ^ ^y i] ^^ ^^ у ру! / ^ Jo-dimethyl-oofolin, b.p. 162 ° C / 5 3 Pa.

Example 3

266 g of cit-4- [3- (p-SyrCa ^and mylfrryl) -2-methylpyrrole-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 solution was heated to dryness on a rotary evaporator and the residue was recrystallized from 100 ml of water, the crystals were washed with water and dried in a vacuum oven at 55 ° C. Cit-4-β (PSb-Caa-ylphenyl) -2-ethylpropyl-2,6-dimethylmorpholine hydrochloride is obtained in the form of white, slightly hyeroscopic crystals, m.p.

206 ° C.

Example 4 ^{To 21 g} -4 - ^ - (^ porceminyl ityl) - ^- - !! Ie 'dtaetylmjrfolinu under cooling with acetone and solid - solution of carbon dioxide 60 ml of 30% hydrogen peroxide in 60 ml of acetic anhydride such that the reaction the temperature did not exceed 50 ° C and then the reaction mixture was allowed to react at 16 ° C for 16 hours. The reaction mixture was then checked by thin layer chromatography (solvent system: hexane / ether 1: 1).

To destroy the excess peroxide, the reaction solution was cooled to -10 ° C and 200 mL of 40% potassium hydroxide was added. After further stirring for 20 hours, the reaction mixture is diluted with 500 ml of water and thoroughly extracted with chlorineoma. The combined chloroform extracts are neutralized, dried and evaporated. Překrystaoováním residue 100 ml of pentene ZIS ^ka pure ^cis-4- [3- ^(p-l Syгc.amy ^phenyl) -2-meth ^{y l p p} lpro J - ^6-yl dims- lmorfolin 4- oxide. .

The following are examples of manufacturing pharmaceuticals:

Example 5

Vaginal tablets of the following composition are prepared as usual:

cit-4- [3- (p-tert-methyl-1-yl) -2-

I-2,6-Dimethylmorpholine mg secondary calcium phosphate dihydrate directly compressed! Starch STA-RX1500

400 mg

261 mg

lactose (spray-dried) 100 mg polyviny lpyrrolidone 25 mg citoonic acid 5 mg magnesium stearic acid salt 6 mg 847 mg

Example 6

An ointment of the following composition is prepared:

cis-4- / 3- [p - ((N, N-dimethylbenzyl) benzyl) -1 H -methyl-propyl] -2,6-dimethylmorpholine0.7 g cetyl alcohol 3.5 g

sheep wool fats9.0 g white petrolatum 79.3 g paraffin oil9.4 g

100.0 g

Example 7 A cream having the following composition is prepared: cis-4- [З- ⁽ p-tert-amylene- ² -O- ⁾ -meatyl-petroleum-dimethylaminopholine 0.9 G polyoзχltylenateθгát 3.3 G stearyl alcohol 8.0 G viscous paraffin oil. 10.0 G white petrolatum 10.0 G carboxyvinylpolymer CARBOPOL 934 Ph 0.3 G Sodium hydroxide, pure 0.09 g water, which has not been purified to 100.0 G

SUBJECT OF THE INVENTION

Claims (2)

A process for the preparation of morpholine derivatives of the general formula I wherein: XI) represents an ethyl group or a phenyl group, as well as their salts and their N-oxides, characterized in that the halide of the general formula II (II) in which: R is as defined above and Y is chlorine, bromine or iodine, reacted with a compound of formula III HN O (III) is then optionally treated with hydrogen peroxide or peracids to produce the N-oxide, or the base of the formula I is converted by treatment with an acid into a salt. Process according to claim 1, characterized in that the racemate obtained is resolved into optical antipodes.