FI69455C - FREQUENCY FARING FOR CIS-2,6-DIMETHYLMORPHOLINDERIVAT WITH FUNGICID NETWORK - Google Patents

Description

luMrTI rB1 ANNOUNCEMENT 694 5 5

We l "J UTLÄGGNINGSSKRIFT

C (45) Patent granted

Pnt: nt co ’10 00 10 PC

(51) Kv.lk.Vlnt.CI. * c 07 D 265/30 FINLAND — FINLAND (21) Patent application - Patentansökning 802 ^ + 18 (22) Filing date - Ans & kningsdag 01 .08.80 (Fl) (23) Starting date - Giltighetsdag 01 .08.80 (41) Has become public - Blivit offentlig 1 8.02.81

Patent · and National Board of Registration Date of display and publication—

Patent · och registerstyrelsen '' Ansökan utlagd och utl.skriften publicerad 31.10.85 (32) (33) (31) Privilege requested - Begärd priority 17.08.79 29.05.80 Switzerland (CH) 7560/79, 4187/80 (71) F. Hoffmann-La Roche & Co. Akt i engesel 1 Schaf t, Grenzacherstrasse 124-181 *, Basel, Switzerland-Switzerland (CH) (72) Albert Pfiffner, Bulach, Switzerland-Switzerland (CH) (74) Oy Koister Ab (54) Method for fungis 2,6-dimethylmorpholine derivatives for the preparation of 2,6-dimethylmorpholine derivatives with fungicides

The invention relates to a process for the preparation of fungicidally active cis-2,6-dimethylmorpholine derivatives of the formula CH0 R CH3 # 3

H3c>] ^ jl SH3 [° W \ T

I 1 / N 9 x CH 3 wherein R is ethyl or phenyl and n is O or 1, and for the preparation of salts of compounds of formula I wherein n is O.

2 69455 DE-A-27 52 096 describes e.g. both compounds 4- [3- (p-tert-amyl-phenyl) -2-methylpropyl] -2,6-dimethyl-morpholine and 4- [3- (p-(O, N) -dimethylbenzyl) - phenyl / -2-metyylipropyyli7-2,6-dimethyl-morfoliin.i. However, these compounds are in the form of cis / trans mixtures, while the compounds of the present invention are c.is compounds.

The process for the preparation of the compounds according to the invention is characterized in that a) a halide of the formula R 1 .Ch 3 r μ

9H3 II

C H 2-Y

wherein R is as defined above and Y is chlorine, bromine or iodine, is reacted with cis-2,6-dimethylmorpholine of the formula CHo

HN O TTT

W

b) a derivative of the formula 3 69455 R CH3 CH3 "3CUX-^» ch3 wherein R has the meaning given above and one of the dotted lines corresponds to an additional bond, or c) cis- A 2,6-diraethylmorpholine derivative of the general formula ch3 Γ /> CH3 is reacted with a compound which forms a carbonium ion of the general formula R ®

C Ho VI

h3c ^ 3

R OH

preferably with a tertiary alcohol of the formula H 2 CC-CH 2 or R t a tertiary chloride of the formula H 3c ch 3 in which R has the meaning given above, or d) a compound of the formula 69455 4 fl, ch 3 H 3 C> ii] Γ 3 VI1 wherein R is as defined above, is reacted under hydrogenating conditions with a base of cis-2,6-dimethylmorpholine of formula III, or to prepare an N-oxide, a compound of formula I is treated with hydrogen peroxide or peracids, or to form a salt, a compound of formula I the base is converted into a salt in a known manner by treatment with an acid.

According to process variant a), the halide of formula II is reacted with an amine of formula III, suitably in a neutral solvent, for example an ether such as diethyl ether, tetrahydrofuran or dioxane, or a dimethyl sulfoxide or an excess of glycol, preferably in the presence of an amine of formula III to be used. The mixture is preferably reacted at a temperature between 50 and 150 ° C. Ethylene glycol is a particularly preferred solvent, and a temperature in the range of 100 to 110 ° C is particularly preferred.

Following the process variant b), the compound of formula IV is reduced. If a compound of formula IV is used as the starting material in which the double bond is in the CX position relative to the morpholine residue, the reduction can take place catalytically or with formic acid.

Particularly suitable catalysts are precious metal catalysts such as platinum, palladium - possibly precipitated on carbon - and Raney nickel. Palladium on carbon is most preferred. Suitable solvents for the catalytic reduction include hydrocarbons such as benzene, toluene or xylene, as well as alcohols such as methanol or ethanol. Toluene is preferred. The reaction temperature is preferably 0 to 50 ° C.

li 5 69455, primarily room temperature. The reduction of the enamine with formic acid is preferably carried out without solvent, the formic acid being added dropwise to the enamine at a temperature of 0 to 100 ° C, preferably 50 to 70 ° C, if necessary with cooling.

When using a starting material of formula IV in which the double bond is in the d. Position relative to the phenyl residue, the reduction can take place catalytically. Platinum or palladium is preferably used as the catalyst, in which case water or alcohol is used as the solvent. In order to avoid possible hydrogenolysis, at least an equivalent amount of acid, preferably hydrochloric acid, is added to the reaction mixture.

The alkylation of the compound of general formula V according to process variant c) takes place in the presence of a suitable amount of Friedel-Crafts catalyst. Suitable catalysts are known Friedel-Crafts catalysts such as, for example, aluminum chloride, ferric chloride, zinc chloride, boron trifluoride, tin chloride, hydrofluoric acid, sulfuric acid and phosphoric acid. For the purposes of this invention, sulfuric acid is particularly preferred.

The use of a neutral organic solvent is then not necessary, although it is preferred. Suitable neutral organic solvents are, in particular, 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, although it is generally in the range of 0 to 50 ° C, preferably in the range of 18 to 20 ° C.

Preferably, and especially when sulfuric acid is used, the product obtained after completion of the reaction is extracted in the form of a salt with a neutral organic solvent such as, for example, methylene chloride. If desired, the free amine can be obtained by treatment with a suitable base such as NaOH, KOH, Na 2 CO 3, KaCO 3 or calcium hydroxide.

Preferred compounds for producing carbonium ions of general formula VI are the corresponding tert-alcohols, such as 2-methyl-2-butanol, or tert-chlorides, such as 2-chloro-2-methyl-butane.

6 69455

The reaction of a substituted cinnamic aldehyde of formula VII with cis-2,6-dimethylforfoline of formula III is carried out under hydrogenating conditions, for example using a palladium catalyst, e.g. in methanol.

To prepare the N-oxides of the compounds of formula I, the compound of formula I is treated with hydrogen peroxide or peracid. The solvents used, when hydrogen peroxide is used as the oxidant, are alcohols such as methanol, ethanol or isopropanol, the latter being preferred. The preferred reaction temperatures are in the range 0 to 50 ° C, particularly preferably 40 ° C. As the peracids, for example, peracetic acid, perbenzoic acid, metachloroperbenzoic acid, peradipic acid can be used. Halogenated hydrocarbons such as methylene chloride, chloroform or ethylene chloride are mainly used as peracid solvents. Suitable reaction temperatures are the same as those described above for the reaction with hydrogen peroxide.

The compounds of formula I form salts with organic and inorganic acids. Suitable salts of the compounds of the formula I are, in particular, salts with physiologically acceptable acids. These are mainly hydrohalic acids, such as hydrochloric acid and hydrobromic acid, further phosphoric acid, nitric acid, in addition to mono- and difunctional carboxylic acids and hydroxycarboxylic acids, such as, for example, acetic acid, maleic acid, succinic acid, succinic acid, fumaric acid, , sorbic acid and lactic acid and finally sulfonic acids such as 1,5-naphthalene disulfonic acid. The salts are prepared in a known manner.

The starting materials of the formulas II and VI are known compounds. Starting materials III and IV are known as cis / trans mixtures. The cis starting materials III and IV are obtained in a similar manner to the preparation of cis / trans mixtures.

The starting materials of the formula IV in which the double bond is in the λ position relative to the morpholine residue can be obtained, for example, by reacting the correspondingly substituted phenyl-2-methylpropionaldehyde with cis-2,6-dimethylmorpholine. The hydrogenation of the compounds of formula IV thus obtained takes place expediently in situ.

Il 7 69455

The starting materials of the formula IV in which the double bond is in the phenyl position can be obtained, for example, by reacting a halide of the formula II which, however, has a double bond in the β-position with respect to the phenyl residue with cis-2,6-dimethylmorpholine. .

Compounds of general formula V can be prepared by mixing general formula ^ ch3

. VIII

^ CHO

with a compound of general formula III and by catalytic hydrogenation.

The solvent used is preferably an organic solvent, e.g. an alcohol such as methanol. Temperature is not critical, but is usually in the range of 0-50 ° C.

In the catalytic hydrogenation, conventional hydrogenation catalysts are used, such as, for example, platinum, Raney nickel or palladium, with a catalyst containing 5% palladium on carbon being particularly preferred.

The propylene chain linking the morpholine residue of the compounds of the invention to the p-substituted phenyl residue has an asymmetric C atom and can therefore exist as racemates and optical antipodes. The latter can be obtained from the resulting racemates by cleavage with optically active acids, e.g. (+) - camphoric acid, (+) - camphor-10-sulfonic acid, 0,0'-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 take place by conventional cleavage methods.

8 69455

The active compounds according to the invention are suitable for controlling infections caused by fungi and yeasts, for example Candida, trichophyte and Histoplasma species, due to their antifungal and antifungal activity. They are particularly effective against Cand.ida and, like Candida albicans, and are mainly suitable for the topical treatment of superficial infections of the skin and mucous membranes, in particular the genital area, for example for the treatment of vaginitis caused in particular by Candida yeasts. The form of application chosen is topical, so that the active ingredients can be used as therapeutically active preparations in the form of ointments, suppositories, suppositories, Ovula injection or other suitable preparations.

The pharmaceutical preparations can be prepared in a manner known per se by mixing the active ingredients with customary organic or inorganic neutral carriers and / or excipients, such as water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, vaseline - or with emulsifiers, salts or buffers for breaking the osmotic pressure.

The dosage is according to individual needs, however, the primary dosage for a few days should correspond to the administration of 1 to 2 tablets per day containing 50 to 100 mg of active ingredient. The ointments suitably contain 0.3-5%, mainly 0.5-2%, preferably preferably 0.5-1% of active ingredient. The following experimental report and the results reported in the table also provide the person skilled in the art with the necessary information for the dosing of the active ingredients.

The efficacy of a mixture of the c.is compounds according to the invention and the corresponding cis / trans compounds known from DE-A-27 52 096 was tested against Candida albicans in Path. Microbiol. 23: 62-68 (1960) according to the Vaginal-Candidia-sis test using rats, the results being as follows:

II

9 69455

Concentration (%),

The compound which showed an "ED 50" effect of cis-4- [3- (p-tert-amylphenyl) -2-methylpropyl] -2,6-dimethylimorpholine 0.01 cis-4- / 3 - β- (Cl, O 1 -dimethylbenzyl) -phenyl] -2-methylpropyl] -2,6-dimethylmorpholine 0.01 cis / trans mixture of the corresponding compounds 0.1

The results of the table show that the compounds of the present invention surprisingly have a substantially higher antifungal activity than the c.is/trans mixtures known from DE-A-27 52 096.

Example 1

A mixture of 230 g of 3- (p-tert-amyl-phenyl) -2-methyl-propionaldehyde and 137 g of cis-2,6-dimethylmorpholine in 100 ml of toluene in a water separator is heated under reflux under nitrogen for 16 hours until the water decomposes. has ended. At room temperature, 17.5 g of 5% palladium-on-carbon are added under nitrogen and then hydrogenated until hydrogen bonding is complete, the catalyst is filtered off and the toluene is evaporated off under vacuum. Distillation of the residue gives pure cis-4- [3- (p-tert-amyl-phenyl) -2-methyl-propyl] -2,6-dimethyl-morpholine, boiling at 120 ° C / 0.1 torr (13, 3 Pa).

Example 2

In the same manner as in Example 1, 3 - [(N- (dimethylbenzyl) phenyl] -2-methylpropionaldehyde is reacted with cis-2,6-dimethylmorpholine and hydrogenated with cis-4- (3-dimethylbenzyl). -phenyl-2-methyl-propyl--2,6-dimethyl-morpholine having a boiling point of 162 ° C / 0.04 torr (5.3 Pa).

10 6 9 4 5 5

Example 3

To a mixture of 1223 g of cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethylmorpholine in 4 liters of methylene chloride is added 4941 g of concentrated sulfuric acid at -5 ° C over 45 minutes, followed by dropwise addition. Within 60 minutes 520 g of 2-methyl-2-butanol. Water is added to the reaction solution under ice-cooling, and the aqueous phase is extracted several times with methylene chloride. The organic extracts are washed with NaOH and then with water, dried, evaporated to dryness and the oily cis-4- [3- (p-tert-amyl-phenyl) -2-methylpropyl] -2,6-dimethylmorpholine is distilled off in vacuo; boiling point 120 ° C / 0.1 torr (13.3 Pa). In this case, the starting cis-4- (2-methyl-3-phenylpropyl) -2,6-dimethylmorpholine can be obtained as follows:

To a mixture of 1000 g of Oc-methyl-chelaldehyde, 10 l of methanol and 789 g of cis-2,6-dimethyl-morpholine are added 50 g of 5% palladium on carbon under a nitrogen atmosphere. It is then hydrogenated with water under cooling at 30 [deg.] C. until hydrogen bonding is complete, the catalyst is filtered off, the methanol is distilled off in vacuo and then the crude cis-4- (2-methyl-3-phenylpropyl) -2.6 is distilled off. dimethyl-morpholine. The 99% pure product boils at 109 ° C under a vacuum of 0.055 torr (7.3 Pa).

Example 4

To a mixture of 20.0 g of p- (Cl, Ck-dimethyl-benzyl) -N, N'-methylcinnamic aldehyde and 9.6 g of cis-2,6-dimethylmorpholine in 60 ml of methanol under argon is added 1 g of 5% palladium on carbon and then hydrogenation until hydrogen bonding is complete. The deactivated reaction solution is evaporated to dryness in vacuo, chromatographed on chloroform with alumina (activity grade II) and then distilled under high vacuum. Cis-4- {3- [β- (β, β-dimethylbenzyl) phenyl] -2-methylpropyl] -2,6-dimethylmorpholine having a boiling point of 162 ° C / 0.04 torr (5 , 3 Pa).

Example 5

According to the instructions of Example 4, starting from p- (tert-amyl-phenyl) -d'-methyl-cinnamic aldehyde and cis-2,6-dimethylmorpholine, cis-4- [3- (p-tert-amyl-phenyl)] is obtained. -2-methyl-propyl / -2,6-dimethyl-morpholine.

11 69455

Example 6

To a solution of 22.7 g of 2,6-cis-dimethylmorpholine in 70 ml of ethylene glycol is slowly added dropwise at 125 ° C 44.3 g of 3- (p-tert-amyl-phenyl) -2- methyl propyl bromide and further stirred at this temperature for 48 hours. After cooling, 2-hydrochloric acid is added and the neutral portions are extracted with ether. The hydrochloric acid solution is then made alkaline with 5N NaOH solution, extracted with ether, the ether extract is washed with water, dried over sodium sulfate and evaporated to dryness. Distillation gives pure cis-4- [3- (p-tert-amyl-phenyl) -2-methyl-propyl] -2,6-dimethyl-morpholine, boiling point 120 ° C / 0.1 torr (13.3 Pa ).

Example 7

To a solution of 22.7 g of 2,6-cis-dimethylmorpholine in 80 ml of ethylene glycol is slowly added dropwise at 125 ° C 51.8 g of 3 -? - (1R, N-dimethylbenzyl) - phenyl / -2-methylpropyl bromide and further stirred at this temperature for 48 hours. Further processing is carried out according to Example 6. Distillation gives pure cis-4- [3-, p- (M, A-dimethyl-benzyl) -phenyl] -2-methyl-propyl] -2,6-dimethyl-morpholine, boiling point 162 ° C / 0.04 torr ( 5.3 Pa).

Example 8 266 g of cis-4- [3- (p-tert-amyl-phenyl) -2-methyl-propyl] -2,6-dimethyl-morpholine are dissolved in 500 ml of absolute ethanol and 500 ml of 28 ml are added dropwise at room temperature. -% hydrogen chloride-ethanol solution. The homogeneous solution is evaporated to dryness on a rotary evaporator and the residue is recrystallized from 100 ml of water. The crystallization is washed with water and dried in a vacuum oven at 55 ° C. Cis-4- [3- (p-tert-amyl-phenyl) -2-methyl-propyl] -2,6-dimethyl-morpholine hydrochloride is obtained as white, slightly hygroscopic crystals with a melting point of 204-206 ° C.

69455

Example 9 To 21 g of cis-4- [3- (p-tert-amyl-phenyl) -2-methyl-propyl] -2,6-dimethyl-morpholine is added dropwise a solution of acetone-dry ice while cooling the solution, with 60 ml of 30% hydrogen peroxide in 60 ml of acetic anhydride so that the reaction temperature does not rise above 50 ° C and then the mixture is allowed to react for a further 16 hours at room temperature. The batch is examined using thin layer chromatography (hexane: ether = 1: 1). To remove excess peroxide, the reaction solution is cooled to -10 ° C and 200 ml of 40% KOH solution are added.

After stirring for 20 hours, the mixture is diluted with 500 ml of water and extracted thoroughly with chloroform. The combined chloroform extracts are washed neutral, dried and evaporated to dryness. Recrystallization of the residue from 100 ml of pentane gives pure cis-4- [3- (p-tert-amyl-phenyl) -2-methyl-propyl] -2,6-dimethyl-morpholine-4-oxide.

Il

Claims (5)

13 6 9 4 5 5 A process for the preparation of fungicidally active cis-2,6-dimethylmorpholine derivatives of the formula CH3 [0] H yc (1 CH3 / J '1 L m P ch3 wherein R is ethyl or phenyl and n is 0 or 1 , and for the preparation of salts of compounds of formula I in which n is 0, characterized in that a) a halide of the formula FL reacting with c.is-2,6-dimethylmorpholine of formula III, CH 3 Ht / b H. 14 694 5 5 or b) reducing the cis-2,6-dimethylmorpholine derivative of formula IV Ch 3 R 2 / CH 3 - / CH 3 / \ IV Il? wherein R has the meaning given above and one of the two dotted lines corresponds to an additional bond, or c) the cis-2,6-dimethylmorpholine derivative of formula V sh3 f \ Γ / Λ - is reacted with a compound which forms a carbonium ion of the general formula is R ®> C-CH 3 VI h3c ^ R OH \ / preferably a tertiary alcohol of the formula H ^ CC-CH ^ or R, C1 with a tertiary chloride of the formula C, h3o vch3 wherein R has the meaning given above, or d) a compound of formula n is 69455 r ^ / CH3 h3c> S ^ <(H3 l .L VII Lc ^ / ~ ^ <y ^ -cho in which R is as defined above is reacted under hydrogenating conditions to give a compound of formula III. with .is-2,6-dimethylnorpholine, or that, in order to prepare the N-oxide, the compound of the formula I is treated with hydrogen peroxide or peracids, or that, in order to prepare the salt, the base of the formula I is converted into a salt by treatment with an acid. Process according to Claim 1, characterized in that the process catalytically reduces a compound of the formula IV in which the double bond is in the ok position relative to the morpholine residue. Process according to Claim 1, characterized in that the process catalytically reduces a compound of the formula IV in which the double bond is in the 06 'position relative to the phenyl residue. 16 69455 A process for the preparation of cis-2,6-dimethylmorpholinders with a fungicidal effect, preferably in the form of CH3 ° n _- / H3c 7 ^ || CH3 / \, II JH P ch3 color R betyder ethyl or phenyl and n 0 or 1, the same as in the case of formula I, a is O, kännetecknat därav, att man (a) the halogen content of formula CH3 ix color R in the form of anhydrous and Y starch chlorine, Bromine or iodine, with cis-2,6-dimethylmorpholine with the formula CH3 ^ - H. 69455 or, b) reducing with cis-2,6-dimethylmorpholine derivative with the formula ch3 r ^ / CH3 The h3c ^> <^ Y ^ | Ί 9H3 / \ IV I, Α. V 9 ch3 color R is an anhydrous and anhydrous bond of the same type of bond, or (c) a cis-2,6-dimethylmorpholine derivative with the form of ch3 n rk * n— (ch3 with enrichment, a single picture of carbonium in the form of form ®> -CH3 VI h3c ^ R OH \ / företrädesvis med en tertiary alcohol of form H ^ CC-CH ^ eller R Cl \ / en tertiary chlorides of form C, h3c ch3 color R har ovan angivna betydelse, eller d) omsätter en förening med formeln