NO801556L - ANTIMYCOTIC AGENT. - Google Patents

Description

From DE OS 2,752,135 it is known that 3-(4'-tert-butyl-cyclohexyl-1')-2-methyl-1-(3'-methyl-1'-piperidino)-propane, 3_ (4 - -tert-butyl-cyclohexyl-1*)-2-methyl-1-(3' ,5'-dimethyl-1'-piperidino)-propane and 3-(4'-tert-butyl-cyclohexyl -1')-2-methyl-1-(2',6'-cis-dimethyl-morpholino)-propane and their salts can be used to combat plant pathogenic fungi and also human pathogenic fungi and yeasts, such as Candida albicans , Trichophyton mentagrophytes and Histoplasma capsulatum.

The aforementioned compounds exist in consideration of the two substituents in the 1,4 position on the cyclohexane ring as cis-trans isomer mixtures.

The present invention relates to a method for producing the pure trans compounds

trans-3-(4'-tert-butyl-cyclohexyl-1')-2-methyl-1-(3'methyl-1'-piperidino)-propane, (1),

trans-3-(4'-tert-butyl-cyclohexyl-1')-2-methyl-1-(3',5'-dimethyl-1'-piperidino)-propane (2)

and trans-3-(4'-tert-butyl-cyclohexyl-1')-2-methyl-1-(2',6'-cis-dimethylmorpholino)-propane (3),

from the cis/trans isomer mixts.

Due to the surprising finding that the pure trans-compounds act 10 times or more more strongly against human pathogenic fungi and yeasts from the dermatophyte genus than the cis-compounds, it is a task of the invention to develop a method for producing the pure the trans compounds 1) to 3) .

It is known to the person skilled in the art that in the case of catalytic hydrogenation of para-substituted aromatics, isomer mixtures of the most diverse compositions are formed. For example, predominantly cis-1,4-disubstituted cyclohexane compounds frequently occur in hydrogenations carried out with platinum catalysts. Hydrogenations with nickel, cobalt or palladium catalysts also lead to predominantly cis-disubstituted cyclohexane compounds (cf. Houben-Weyl, volume 11/1, page 680, Georg Thieme-Verlag, Stuttgart 1957). Similar results are obtained with ruthenium catalysts, but proportions of the corresponding trans compounds are also obtained.

When reducing para-substituted aromatics with sodium in • alcohol, clearly more trans-proportions are usually obtained, however, the selectivity of this reaction is not satisfactory and the costs are significantly higher.

Furthermore, it is known, for example, from Houben-Weyl, volume 5/1a, page 553, Georg Thieme Verlag, Stuttgart 1970, that splitting a mixture of cis/trans-1,4-di-substituted cyclohexanfur compounds requires very highly effective columns. Separation aggregates with over 100 theoretical bottoms are mostly used and a backflow ratio as high as 1:200 is chosen. The major difficulties in the separation of cis-trans mixtures of disubstituted cyclohexane compounds can be seen, for example, from the fact that for the separation of 1,4-diisopropylcyclohexane into the cis and trans isomers, a column with 100 theoretical separation steps is needed, and where a reflux ratio of 1:200 is used. The pure cis-isomer boils at 14 Torr at 96.9°C and the trans-isomer at 96.1°C. If the fractionation is carried out at a pressure of 7.5 Torr, the cis-isomer boils lower and then at 78.9°C, and the trans-isomer at 84.4°C. These changes in the boiling points show very clearly the difficulties of such fractionation.

The separation of 1,4-di-tert-butyl-cyclohexane into the corresponding pure cis- and trans-isomers requires approximately the same separation conditions. Several days are required, as the experimental conditions show, to isolate small quantities of the pure compounds (Houben-Weyl, vol. 5/la, page 558). It is also shown that the separation of mixtures of the isomeric forms obtained by hydrogenation of 1-methyl-4-tert-butyl-benzene also requires very large expenses.

These examples show that a division of 1,4-disubstituted cyclohexane compounds is very expensive and difficult, and that it is no longer conceivable technically to carry out a division into the pure cis-isomer and trans-compound by fractional distillation with a corresponding increase in the amount of one of the substituents, as they occur in connection with the above-mentioned compounds.

It was now found that the pure trans-3-(4'-tert-butyl-cyclohexyl-1')-2-methyl-1-(3'-methyl-piperidino, 3',5'-dimethyl- piperidino and 2<1>6'-cis-dimethyl-morpholino)-propanes, when the cis-trans mixture obtained by hydrogenating the corresponding 1,4-disubstituted phenyl compound in a manner known per se to a cyclohexane compound is enriched for distilling off the solvent used for the hydrogenation by fractional distillation at a pressure at the top of the column of from 0.05 to 50 Torr in a 10- to 100-bottom column under a reflux ratio of from 1:1 to 1:100 and at the temperature that sets during the distillation, to a trans proportion of over 85% and the pure trans isomer can be crystallized after conversion to an acid addition salt with hydrohalic acid and crystallization in an organic solvent.

The temperatures which are measured at the top of the column in the fractional distillation and which are set on the basis of the reflux conditions and the number of bottoms, are usually at 160 to 240°C.

Surprisingly, the above-mentioned trans-cyclohexane compounds 1), 2) and 3), compared to the described difficult separations of 1,4-dialkyl-cyclohexane, are divided into fractions enriched with low-boiling cis-compound and higher-boiling trans-compound with significantly less expensive distillation technique, even if the molecule exhibits a tertiary amino group.

As a rule, isomer mixtures obtained by hydrogenation in a known manner with a ruthenium, palladium, platinum, nickel or cobalt catalyst are fractionally distilled.

Glass sieve bottom columns or columns filled with silver or stainless steel wire are used as columns.

web spins.

The preferred conditions for the fractional distillation of 1) are a column with 20 to 40 bottoms at 2 to 20 Torr and a reflux ratio of from 1:3 to 1:10, setting temperatures from 183 to 186°C;

the conditions for 2) are a 20- to 40-bottom column at 2 to 20 Torr and a reflux ratio of 1:3 to 1:10, whereby a temperature of 193 to 200°C is set and

the conditions for 3) are a 20- to 40-bottom column at 2 to 20 torr and a reflux ratio of 1:3 to 1:10, setting temperatures from 203 to 208°C.

Thereby, a distillation residue of 5 to 10% may remain after the end of the distillation, which, under the above conditions, is subjected to a short-path distillation which gives a degree of purity of the trans compound of 92 to 98%.

The fractions which are enriched to over 85% of trans-compounds are transferred in a suitable solvent and transferred after conversion to an acid addition salt of a hydrohalic acid by crystallization in the pure trans-compound.

Suitable solvents for the crystallization are especially monovalent, lower alcohols with 1-4 C atoms, such as methanol and ethanol, esters of lower aliphatic carboxylic acids with 1-4 C atoms in the ester alcohol, especially acetic acid esters, such as ethyl acetic acid ester, lower ketones , such as acetone, methyl ethyl ketone and methyl isopropyl ketone, or dialkyl ethers with 1-4 C atoms in the alkyl part or saturated, cyclic ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane. Optionally, the crystallization is carried out in the presence of excess amounts of hydrohalic acids. The preferred acid addition salt is the hydrochloride.

Preferred crystallization conditions are approx. 20% by weight, methanolic or ethanolic solutions, which are prepared at approx. 80°C and which cools to approx. 25°C, possibly during grafting.

The final separation of the pure trans compounds by crystallization from an isomer mixture with at least 85% trans content has the particular advantage that the prior fractional crystallization can be carried out at lower costs. This leads to a smaller thermal load on the isomers to be separated, so that cleavage products, which can occur under certain circumstances, are avoided. By the combination of fractional distillation and crystallization, more than 99% pure trans-compounds and also the pure cis-compounds are obtained in a technically surprisingly simple way, as the design examples show.

After liberation of the bases, the mother liquors can be subjected to a

renewed fractional distillation.

It should also be noted that the cis-compound in its mixtures or after separation of the trans-compound according to the invention can be transferred into the trans-compound by a palladium- or nickel-catalyzed isomerization.

The separation and production of the pure trans compounds according to the invention gives as a further important advantage the assumption that the existing configurational isomers, due to the chirality centers present, can be separated in the optical antipodes.

Surprisingly, the pure trans compounds are almost exclusively carriers of the good antifungal effect. Compared to the existing cis-compound and on the basis of the heme interaction against microorganisms, the trans-compounds 1), 2) and 3) are 10 times and more as strongly active. This means, for example, that with roughly the same toxicity values, they have a significantly improved therapeutic range.

It is therefore also possible to obtain an antifungal agent for local and systemic use, which has a content of a pure trans compound or their physiologically compatible syread-dis ion salts as an active ingredient next to normal carriers and diluents that can be used in combating dermatomycoses.

For salt formation with an in and of itself usual physiologically compatible acid, organic or inorganic acids, such as nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid or nicotinic acid are taken into account . However, the inorganic acids mentioned, especially hydrochloric acid, are preferred.

The pure trans compounds and their salts to be used exhibit strong antifungal effects. They have a broad spectrum of antifungal activity, particularly against dermatophytes, for example epidermophyton species, such as Epidermophyton floccosum, trichophyton species, such as Trichophyton mentagrophytes, microsphoron species, such as Microsphoron ferugineum. The enumeration of these micro-organisms shall not constitute any limitation of the micro-organisms that can be combated, but only serve as an explanation.

The effect on microorganisms can be demonstrated according to methods described, for example, in P. Klein, Bakteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlag Berlin, 1957.

For example, it was investigated which minimal inhibitory concentrations (MHK values) could be achieved in the agar dilution test against pathogenic fungi.

In the following table 1, the results are summarized:

Table 1 shows that the trans-compounds are significantly stronger than the cis-compounds and thus in practice are carriers of the business. Furthermore, it is shown that the trans-compounds show clearly lower MHK values compared to the known antifungal agents "Clotrimazole", "Miconazole" and especially to "Tolnaftate", one of the currently most used agents for dermatomycoses.

LD,. Q-value one, determined by addition to mice per os, amounts for 1)-trans to 305 mg/kg, for 2)-trans as hydrochloride to 335 mgAg and for 3)-trans to 2250 mgAg- From these LD^^ values it follows that a sufficient therapeutic width is achieved for local and systemic application after oral administration.

Correspondingly, dermatomycoses in humans and animals, especially caused by species of the genera epidermophyton, microsporum and trichophyton, come into consideration as an indication area.

Agents or preparations for oral and local use can also be prepared by mixing in the usual way with usual carriers or diluents and the usually used pharmaceutical-technical auxiliaries with a dosage suitable for internal or external use.

As a rule, both in human and veterinary medicine it has proven advantageous to use the active substance or substances externally in amounts of approx. 0.07 to 0.1 g/. cm 2 body surface, possibly in the form of several single doses. However, there may also be deviations from the dosages mentioned, depending on the nature and severity of the disease. The determination of the actual necessary dosage and its frequency can be varied by the attending physician on the basis of his experience.

As a rule, the single doses are given 1 to 2 times per day. For external, local application, the preparations contain 0.5 to 5, preferably 1 to 2% by weight of active substance. In the case of oral dosing, single doses in amounts of 50 to 1000 mg, preferably 500 to 800 mg are taken into consideration, which are given, for example, 1 to 2 times per day. day.

Preparations for oral application are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders or suspensions.

Corresponding tablets can, for example, be obtained by mixing with known excipients, for example inert diluents, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbonate, calcium phosphate or milk sugar, explosives such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents for obtaining depot effect such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can consist of several layers.

Similarly, coatings can be produced by coating cores produced analogously to the tablets with agents used in coating coatings, for example collidon or shellac, gum arabic, talc, titanium dioxide or sugar. Thereby, the coating covering can also consist of several layers, whereby the excipients mentioned above in connection with the tablets can be used.

Suspensions with the active substances produced according to the invention can also contain flavor enhancers, such as saccharin, cyclamate or sugar, as well as, for example, flavoring substances such as vanillin or orange extract. They can also contain suspending aids such as sodium carboxymethyl cellulose, or protective substances such as p- hydroxybenzoate. Capsules containing active substances can, for example, be prepared by mixing the active substance with an inert carrier, such as milk sugar or sorbitol, and encapsulating it in gelatin capsules.

For external application, pastes, ointments, gels, creams, lotions, powders, solutions or emulsions and sprays in particular come into consideration.

Ointments, pastes, creams and gels may contain, in addition to the active substances, the usual carrier substances, for example animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and sprays can, in addition to the active substance, contain common carrier substances, for example milk sugar, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may also contain common propellants, for example chlorofluorohydrocarbons.

Solutions and emulsions can, in addition to the active substances, contain usual carrier substances, such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide , oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

EXAMPLES

1. cis- and trans-3-(4-tert.-Butyl-cyclohexyl-1)-2-methyl-1-(3'-methyl-1-piperidino)-propane.

a) Synthesis of the aromatic amine:

306 g of 3-(p-tert-butyl-phenyl)-2-methyl-propanal are placed in a 2 liter three-necked flask, and 72>5 g of 98% formic acid are added drop by drop. Then, over the course of three hours, 149 g of 3-methyl-piperidine are added dropwise. The temperature thereby rises from 25 to over 50°C. The reaction mixture is then further heated for 24 hours under reflux, whereby CG^ evolution occurs.

After completion of the conversion, it is fractionally distilled under reduced pressure. After a course of 47 g, passing up to a temperature of 130°C at >0.2 torr, 3-(p-tert-butyl-phenyl)-2-methyl-1-(3<1- >methyl-1'-piperidino)-propane between 130 and 133°C at a pressure of 0.2 torr. 355 g is obtained, which corresponds to a yield, calculated on the aldehyde used, of 82.4%.

b) Hydrogenation to the cyclohexane derivative:

In a 3 liter roller autoclave, 309 g of 3-(p-tert-butyl-phenyl)-2-methyl-1-(3' methylr-1'-piperidino)-propane are hydrogenated in 1000 ml of dioxane with the aid of 0.5 g Ru20^ hydrate. At a hydrogen pressure of 100 bar and a temperature of 120°C, no more hydrogen is absorbed after 3 hours. Then, at 140°C and 120 bar I^ pressure, a pressure drop of 35 bar is determined within 12 hours and after resetting the hydrogen pressure to 160 bar, a pressure drop of 10 is recorded at one temperature of 160°C within 10 hours. By further raising the hydrogen pressure to 160 bar and the temperature to 180°C, no further hydrogen uptake occurs.

c) Fractional distillation:

The reaction mixture, -1310 g, is fractionally distilled over

a sieve bed column with 10 sieve beds at a pressure of 10 torr.

After distilling off the dioxane, the following fractions are obtained at a reflux ratio of 1:5: 1. at 185°C 27 g containing 85% cis- and 10% trans-compound (the remainder of 5% is run-off) 2. at 185°C 114 g containing 75% cis and 25% trans compound 3. to 186°C 60 g containing 40% cis and 60% trans compound 4. to 187°C 55 g containing 30% cis and 70% trans connection

The distillation residue of 40 g is subjected to a short-path distillation at 10 torr and 197°C. 38 g are obtained with the composition 92% trans and only 8% cis. This leaves 2 g of distillation residue.

The cis-trans ratio is determined by gas chromatography. 504 g according to the method described above produced 3-(4'-tert-butyl-cyclohexyl-1')-2-methyl-1-(3<1->methyl-1'-piperidino)-propane, which contains 54 % cis- and 46% trans-cyclohexane derivative (total 425 g) is fractionated on a column with 20 sieve bases. A backflow ratio of 1:3 is set.

Up to a transition temperature of 192°C, more than 70 g progress. The following fractions are then obtained: 1. to 197°C/28T13 g containing: 85% cis and 3% trans

(Remainder of 12% is progress)

2. to 198°C/2 6T 52 g containing: 93% cis and 7% trans

3. to 197°C/25T87 g containing: 90% cis and 10% trans 4. to 192°C/22T82 g containing: 85% cis and 15% trans 5. to 196°C/22T81 g containing: 80% cis and 20% trans 6. to 202°C/28T87 g containing: 30% cis and 70% trans 7. to 196°C/22T73 g containing: 97% trans and 3% cis The distillation residue of 27 g is subjected to a short path distillation. 24 g are obtained with a trans compound content of over 98%.

d) Preparation of the HBr salt of the pure cis form:

The further purification of the start and/or end fractions to

the pure cis form is made by recrystallization of the hydrobromide in acetic acid/water and in the case of the trans compound by means of hydrogen chloride in methanol:

25 g of the first fraction obtained above is added

20 g aqueous, 48% hydrobromic acid. Then 50 g of acetic acid is added and the total crystallisate is brought into solution by heating. On cooling, the hydrobromide crystallizes out in the cis form. NMR analysis confirms the presence of the pure cis form. 28 g with a melting point of 210°C are obtained.

C ber.: 64.15% found: 64.5%; H ber.: 10.77%,

found: 10.3%

N beg.: 3.74% found: 3.60%; Br ber.: 20.34%,

found: 20.6%

e) Preparation of the HCl salt in the pure trans form:

60 g of hydrogen chloride are added to 35 g of the fraction 5 obtained above in methanol. On cooling, 28 g of hydrochloride crystallizes out with a melting point of 168°C. NMR analysis confirms the presence of the trans form. 2. cis- and trans-3-(4'-tert-butyl-cyclohexyl-1')-2-methyl-1-(3<1>,5'-dimethyl-1-piperidino)-propane.

a) 361 g of 3-(p-tert-butylphenyl)-2-methyl-propanal are reacted as described under example 1, with 200 g of 3,5-dimethyl-piperidine

and 86 g of 98% formic acid. Purification of the amine is achieved by fractional distillation at a pressure of 0.2 Torr over a 10-bottom column. At 136 °C, 406 g of pure amine is converted.

b) Hydrogenation to the cyclohexane compound:

In a shaking autoclave with a reaction volume of 250 ml, 80 g of dioxane are added to 70 g of 3-(p-tert-butylphenyl)-2-methyl-1-(3',51-dimethyl-1'-piperidino)-propane. , 0.5 g of ruthenium oxide hydrate is added as a hydrogenation catalyst. At 100 bar hydrogen and 120°C after press during 37 hours 358 bar.

The fractional distillation of the reaction extract (139 g) gives 64 g of the cyclohexane derivative, which distills above between 136 to 146°C at a pressure of 3 Torr. Gas chromatographic analysis shows that it is an isomer mixture of both cis-

and the trans form of the cyclohexane derivative.

c) Fractional distillation:

562 g of the aromatic amine, which is hydrated in 1000 g of dioxane using RU2O.J • hydrate at 140 bar hydrogen pressure and at 120°C, is separated by fractionation over a column with 10 sieve bottoms at a reflux ratio of 1:5, as described under example 1.

The more than 90% cis-cyclohexane derivative converts at a pressure of 0.1 Torr between 124-125°C The trans-cyclohexane derivative enriched to more than 90% converts between 129-131°C.

A repetition of the fractional distillation over an 80 cm long column equipped with silver wire mesh spins at a pressure of 12-13 Torr enables recovery of 154 g of over 90% enriched cis compound. An intermediate of 136 g consisted of a mixture of 1:1 cis-trans-cyclohexane derivative. 98 g of trans-enriched cyclohexane derivative (enrichment to over 90%) is recovered.

The intermediate flow is subjected to new fractionation. A residual formation occurred only to a very small extent. In the fractional distillation of the cis-trans isomer mixture, only 2 g of higher-boiling fractions are formed from 390 g. At a pressure of 12 Torr, the cis derivative transitions between 193 to 195°C and the enriched trans product between 199-200°C. d) Crystallization of the pure cis compound over the HCl salt: 20 g of the more than 90% enriched cis product is taken up in 25 g of methanolic hydrogen chloride solution, whereby the solution is heated almost to boiling. On cooling, 12 g of hydrochloride crystallises. The melting point of the recrystallized cis-cyclohexane derivative is at 240°C. A sample of the salt, which is decomposed with KOH, showed by gas chromatographic analysis that it is a trans-free cis compound. e) Crystallization of the pure trans-compound over the HCl salt: 20 g of the trans-compound enriched to over 90% is taken up in 30 g of ethanolic hydrogen chloride solution. On cooling, the hydrochloride crystallises of the pure trans compound with m.p. 202°C. 13 g are obtained. The free base, which is obtained by splitting a salt sample, shows by gas chromatological examination that it is a cis-—free trans compound. NMR analyzes confirm the statements already obtained with GC analysis. 3. cis- and trans-3-(4<1->tert.-Butyl-cyclohexyl-1<1>)-2-methyl-1-(2<1>,6'-cis-dimethyl-morpholyl)- propane.

a) The production of 3-(p-tert-butylphenyl)-2-methyl-1-(2',6<1->cis-dimethyl-morpholyl)-propane takes place according to the below

example 1 described working method by reaction of 3-(p-tert-butylphenyl)-2-methyl-propahal with 2,6-cis-dimethyl-morpholine and formic acid. The purification of the aromatic amine takes place by des-

authorization. The amine goes over at 3.0 Torr between 170-175°C.

b) Hydrogenation to the cyclohexane compound:

720 g of the morpholine derivative described above are added

500 g of dioxane. 0.5 g of ruthenium oxide hydrate is added as a hydrogenation catalyst. The hydrogenation is carried out at a temperature of 140°C and a hydrogen pressure of 120 bar. In the course of 24 hours, a total of 130 bar of hydrogen is pressurized in the 2.6 liter roller autoclave during the completed hydrogenation.

c) Fractional distillation:

623 g of the obtained cis-trans isomer mixture, which consists of 60% cis and 40% trans compound, is fractionated in an 80 cm column filled with silver wire mesh spins at a pressure of 3.0 Torr. The return ratio is set to 1:5. The cis compound transitions between 144 and 145°C at 3.0 Torr. The enrichment of cis- ■ the compound in the first three fractions of approx. 70 g amounts to over 90%. The last three fractions contain the enriched trans compound. 71 g, 54 g and 38 g. The trans proportion is over 85%. d) Crystallization of the pure cis- and trans-HCl salts: According to the method described under examples 1 and 2, it can

pure hydrochloride of the cis compound is obtained with ethanolic hydrogen chloride solution. Temp. 161°C.

The pure trans compound forms a hydrochloride with a

melting point of 199°C.

Gas chromatographic analysis of the free bases of both salts obtained by reaction with KOH confirms the purity of the bases. The prepurified cis-cyclohexane derivative contains less than 0.5% trans product; the trans product contains less than 1% cis compound. NMR analysis confirms the findings of the GC analysis.

Examples of pharmaceutical preparations:

1. Example of tablets.

The active substance is moistened with polyvinylpyrrolidone in a 10% aqueous solution, passed through a sieve with an internal mesh size of 1.0 mm and dried at 50°C. This granule is mixed with polyethylene glycol (average molecular weight 4000), hydroxypropylmethyl cellulose,

talc and magnesium stearate and pressed into tablets of 280 g.

2. Example of drags

The mixture of the active substance and lactose and corn starch is granulated with an 8% aqueous solution of polyvinylpyrrolidone through a 1.5 mm sieve, dried at 50°C and grated once more through a 1.0 mm sieve. The granules thus obtained are mixed with magnesium stearate and pressed into coating cores. The resulting coating cores are coated in the usual way with a coating which essentially consists of sugar and talc.

3. Example of cream with 2% active ingredient

The finely powdered active ingredient is suspended in the propylene glycol and the suspension is stirred into the 65°C heated melt of glycerol monostearate, cetyl alcohol, polyethylene glycol 400 stearate and polyethylene glycol sorbitan monostearate. In this mixture, the 70°C warm solution of p-hydroxybenzoic acid methyl ester in water is emulsified. After cooling, the cream is homogenized in a colloid mill and filled into tubes.

4. Example of powder with 2% active substance

The active substance is micronised in an air jet mill and mixed

homogeneous with the other components.

The mixture is passed through sieve no. 7 and filled into polyethylene containers with a litter insert.

Claims (1)

Process for the preparation of pure trans-3-(4 <1-> tert-butyl-cyclohexyl-1 <1> )-2-methyl-1-(3'-methyl-piperidino, 31,51-dimethyl-piperidino and 2 ',6'-cis-dimethylmorpholino)-propanes from the cis-trans mixtures obtained by hydrogenation of the corresponding 1,4-disubstituted phenyl compound, characterized in that the isomer mixture after distillation of the solvent used in the hydrogenation is enriched by a fractional distillation at a pressure at the top of the column of from 0.05 to 50 torr in a 10- to 100-bottom column under a reflux ratio of 1:1 to 1:100 at the temperatures established during the distillation, to a trans fraction of more than 85% and the pure trans isomer is crystallized after conversion to an acid addition salt of a hydrohalic acid by crystallization in an organic solvent.