CS214831B2 - Method of making the trans-3-+l4-terc.butylcyclohexyl-1-1+p-2-methyl-1-+l3-methylpiperidineopropane,3,5-dimethylpiperidineopropane and 2,6-dimmorpholino+p-propane - Google Patents

Abstract

The compounds are prepared pure from mixtures of cis and trans isomers and are used in antimycotic agents for topical and systemic administration for controlling dermatomycoses.

Description

Process for preparing pure trans-3- (4'-tert-butyl-1'-cyclohexyl) -2-methyl-1- (3'-methylpiperidino) propane, - (3 ', 5'-dimethylpiperidino) propane and - (2 6'-cis-dimethylmorpholino) propane from mixtures of cis-trans isomers obtained by liydrogenation of the corresponding 1,4-disubstituted phenyl derivative, characterized in that, after distilling off the solvent used for hydrogenation, the mixture of isomers is enriched by fractional distillation at column head pressure 6.5 to 6560 Pa in a 10 to 100 tray column at a reflux ratio of 1: 1 to 1: 100 and at temperatures of 160 to 240 ° C to a trans-isomer content greater than 85% and the pure trans isomer after conversion to addition the hydrochloric acid salt and crystallize from the organic solvent.

4

The present invention relates to a process for the production of trans-3- (4‘-tert-butylcyclohexyl-1-2-methyl-1- (3‘-methylpiperidinopropane), 3‘, 5‘-dimethylpiperidinopropane and 2‘, 6‘-dimethylmorpholinopropane.

It is known from DOS 27 52 135 that 3- (4'-tert-butylcyclohexyl-1 ') -2-methyl-1- (3'-methyl-1'-piperidino) propane, 3- [4'-tert-butyl] Butylcyclohexyl-η 2 -2-methyl-1- (3 ', 5'-dimethyl-1'-piperidinol) propane and 3- (4'-tert-butylcyclohexyl-1'-2-methyl-1- [2] ^The 6'-cis-dimethylmorpholino] propane and salts thereof can be used to combat fungi that are pathogenic to plants and fungi and yeasts that are pathogenic to humans, such as Candida albicans, Trichophyton mentagrophytes and Histoplasma capsulatum.

The aforementioned compounds usually occur due to the position of the two substituents on. cyclohexane ring at position 1,4 as a mixture of cis and trans isomers.

The present invention relates to a process for the preparation of pure trans isomers of formulas 1, 2, 3

trans-3- (4'-tert-butylcyclohexyl-11 ') -2-methyl-1- (3'-methyl-11'-piperidino) propane (1), trans-3- (4'-tert-butylcyclohexyl-1') - 2-methyl-1- (3 ', 5'-dimethyl-11'-piperidino] propane (2), and trans-3- [4'-tert-butylcyclohexyl]' -2-methyl-1- (2 ', 6' -cis-dimethylmorpholino] propane (3), from a mixture of cis and trans isomers, as well as antimycotic agents containing these compounds.

Based on the surprising finding that pure trans-isomers are 10 or more times more potent against fungi, both human and plant pathogenic than cis-isomers, it has been the task of designing a process for producing the pure trans-isomers of the above formulas.

It is known that when. catalytic hydrogenation of para-substituted aromatic compounds results in mixtures of isomers of different compositions. For example, predominantly cis-1,4-disubstituted cyclohexane compounds are formed by using platinum-based catalysts, but also by nickel, cobalt or palladium are formed predominantly by hydrogenation. cis-substituted cyclohexane compounds [Houben-Weyl, Vol. 11/1, p. 680 ff, Georg Thieme-Verlag, Stuttgart 1957]. Similar results are obtained with ruthenium, but there is an increased proportion of the trans-isomer.

The reduction of the sodium-substituted aromatic compounds in the alcohol typically results in predominantly trans-isomers, but the selectivity of this reaction is not sufficient, and the technical implementation of this reaction imposes high time and equipment requirements.

It is further known, in particular from Houben-Weyl, vol. 5 (1a), p. 553 ff, Georg Thieme-Verlag, Stuttgart 1970], that in the separation of the cis / trans-1,4-disubstituted cyclohexane mixture. especially effective columns are needed. In most cases, separating aggregates with 100 times the theoretical efficiency and sometimes with an efficiency of 1: 200 are used. The great difficulties that arise in the separation of mixtures of cis and trans isomers in the case of disubstituted cyclohexane derivatives arise from the fact that the abovementioned columns are required for the separation of 1,4-diisopropylcyclohexane into these isomers. The pure cis isomer has a boiling point of 96.9 ° C at 0.1 Pa and the trans-isomers at 96.1 ° C. When the fractionation is carried out at a pressure of 0.05 Pa, the boiling point of the cis-isomer is lower than 78.9 ° C, the trans-isomer temperature being 84.4 ° C. These changes in the boiling point are effective. other difficulties in dividing.

The separation of 1,4-di-tert-butylcyclohexane into the corresponding pure cis and trans isomers encounters similar difficulties and requires similar separation conditions. It takes several days to isolate a small amount of pure compound as described in Houben-Weyl vol. It is also known that the separation of a mixture of isomeric forms resulting from the hydrogenation of 1-methyl-4-tert-butylbenzol also requires a long time and expensive technical equipment.

These examples show that the resolution of the 1,4-disubstituted cyclohexane derivatives is exceptionally difficult, and that, with adequate extension of the substituents, the separation of the above isomers into pure cis and trans isomeric fractions is technically and practically impossible.

Accordingly, the present invention provides a process for the preparation of pure trans-3- (4'-tert-butyl-1'-cyclohexyl) -2-methyl-1- (3'-methylpiperidino) propane, - (3 ', 5'-dimethylpiperidino) propane and - (2 ', 6'-cis-dimethylmorpholino) propane from mixtures of cis-trans isomers obtained in the hydrogenation of the corresponding 1,4-disubstituted phenyl derivative, characterized in that, after distilling off the solvent used, the isomer mixture is enriched by fractional distillation. at a head pressure of 6.5 to 6560 Pa in a 10 to 100 tray column at a reflux ratio of 1: 1 to 1: 100 and at temperatures of 160 to 240 ^° C to a trans isomer content greater than 85% and a pure trans isomer After crystallization into the hydrochloride acid addition salt and crystallization, it is crystallized from an organic solvent.

The temperatures measured during fractional distillation at the top of the column are in the range of 160 to 240 ^° C, depending on the reflux ratio and the number of trays.

Surprisingly, the above-mentioned trans-isomers of the cyclohexane compounds of formulas 1, 3 and 2 can be separated against the heavy resolution of the 1,4-dialkycyclohexane compounds with considerably less strain by the distillation technique if the molecule contains a tertiary amino group. to the low-boiling cis-isomer and to the high-boiling isomer.

As a rule, they are subjected to fractional distillation of a mixture of isomers obtained by hydrogenation in a conventional manner using ruthenium, palladium, platinum, nickel or cobalt catalysts.

Of the columns used, it is expedient to use columns, the bottom of which is provided with a glass screen or columns which are provided with a precious metal silver grid.

Preferred conditions for the fractional distillation of the compound of Formula 1 are: a column of 20 to 40 °, a pressure of 1.3 to 0.13 Pa and a feedstock ratio of 1: 3 to 1:10 at 183 to 186 ° C.

Suitable conditions for compound 2 are: a column of 20 to 40 °, a pressure of 1.3 to 0.13 Pa, a 1: 3 to 1:10 ratio of feed back material at a temperature of 193 to 200 ° C.

Suitable conditions for obtaining the compound of formula 3 are: column 20 to 40 °, pressure

1.3 to 0.13 Pa, the proportion of feed back of 1: 3 to 1:10 and the temperature ^from 203 to 208 C,

In this distillation, the distillation residue is 5-10%, relatively short distillation times can be used and the trans-isomer is obtained with a purity of 92-98%.

Fractions enriched in the trans-isomer to greater than 85% / q can be crystallized from a suitable solvent and converted to the hydrochloride acid addition salt to give the pure trans-isomer.

Suitable solvents for this crystallization are, in particular, monohydric alcohols having from 1 to 4 carbon atoms, for example methanol and ethanol, esters of aliphatic carboxylic acids having from 1 to 4 carbon atoms in alcohol and acids, in particular ethyl acetate, ketones such as acetone, methyl ethyl ketone and methylisopropyl ketone; dialkyl ethers having 1 to 4 carbon atoms in the alkyl moiety, and optionally saturated cyclic ethers, for example diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane. The crystallization is optionally carried out in the presence of an excess of hydrohalic acid. The most preferred addition salt is the hydrochloride.

The crystallization is preferably carried out using a 20% methanol or ethanol solution prepared at 80 ° C after cooling to 25 ° C and optionally after seeding.

Final separation of the pure trans-isomer by crystallization from a mixture of isomers containing at least 85% of the trans-isomer has the advantage that less expensive equipment is required for fractional distillation. This leads to a lower energy cost for the separation of the isomers and also requires less heating of the mixture, so that no decomposition products are formed which would be formed under other conditions. By combining fractional distillation and crystallization, a trans-compound with a purity greater than 99% and a pure trans-isomer is obtained in a relatively simple manner, as will be apparent from the following examples.

The mother liquor may be subjected to fractional distillation once the base has been released.

It should also be noted that the cis-isomer can be converted into the trans-isomer by catalytic isomerization using palladium or nickel as a catalyst in the mixture or after separation of the trans-isomer.

The separation of the mixture of isomers and the preparation of the pure t-ransisomer by the process according to the invention also has the advantage that it is also possible at the same time to separate the isomers formed as optical antipodes by virtue of the center of chirality.

It is surprising that trans-isomers are the sole carriers of antifungal activity. When the activity of the trans isomer is compared to that of the cis isomer over the various microorganisms for the compounds of formulas 1 and 3, the trans isomers are ten or more times more potent. This means a substantial improvement in the therapeutic range of the compounds at approximately the same toxicity.

Accordingly, the present invention also provides an antifungal composition for topical or systemic use, comprising a trans-isomer of the compounds of formulas (I) to (1) or one of the physiologically acceptable acid addition salts of said compounds and, in addition, a suitable carrier or diluent.

The salt can be prepared using conventional organic and inorganic acids such as nitric, hydrochloric, sulfuric, phosphoric, acetic, propionic, lactic, succinic, tartaric, citric, benzoic, salicylic or nicotinic acids. Most preferred are inorganic salts, especially hydrochlorides.

The trans-isomers of the above compounds and their salts have potent antifungal activity. They also have a broad antifungal spectrum, particularly against dermatocytes of, for example, the Epidermophyton type, such as Epider214831 mophytom floccosum, Trichophyton, such as Trichophyton mentagrophytes, and Microsporon, such as Microsporon ferrugieeum. These microorganisms have been exemplified only to illustrate the effect of the compounds of the invention, but they are also effective against other microorganisms.

The activity of these compounds against microorganisms can be demonstrated, for example, as described by P. Klein.

Bacterlologic Grundlagen der Chemotherapeutischen Laboratoriumspraxis, Springer-Verlag Berlin, 1957.

For example, it has been shown which minimum effective concentrations (MHK) can be achieved against pathogenic fungi by dilution on agar.

The results are shown in Table 1 below.

TABLE 1

Comparative MHK values (µg / ml) for dermatophytes of cyclohexylpropylamine derivatives. Clotrimazole, Miconazole. and Tolnaphthate

Family Strain [2] cis (2) trans ^{+ +} ) [3] cis Compound [3] trans [1] cis (1) trans Microsporumferrugineum Microsporum no. 5 / M +) 0,0625 <0.0078 0.0312 <0.0078 0.0312 0.0078 .gypseum ... , No. 156 / M 0.125 0.0312 0.125 0.0156 0.25 0.0156 Microsporum cannis No. 155 / M 0.125 0.0312 0.5 0.0312 0.125 0.0156 Microsporum. cannis No. 167 / M 0.125 0.0156 0,0625 0.0312 0.25 0.0312 Microsporum cannis No. 168 / M 0.0312 <0.0078 0,0625 0.0156 0,0625 0.0156 Microsporum .. cannis No. 169 / M 0.125 0.0312 0.125 0.0312 0.5 0,0625 Trichophyton ' ¹ sčhóenleinil''Trlchopbyton ::: no. 9 / M 0,0625 0.0156 0.125 0.0156 0.125 0,0625 violaceum No. 10 / M 0,0625 <0.0078 0.125 0.0156 0,0625 0.0156 Tгichóphytón. rubrum Trichophyton No. 158 / M 0.125 0.0312 > 1 0,0625 0.25 0.0312 mentagrophytes Trichophyton No. 19 / M 0.25 0,0625 1 0.0312 0.5 0.0312 mentagrophytes T ^^ 'chophyton No 21 / M 0.125 0.0312 1 0,0625 0.25 0.0312 mentagrophytes Trichophyton No. 159 / M 0.0156 <0.0078 0,0625 <0.0078 0.0312 0.0078 mentagrophytes Trichóphytón No. 160 / M 0.125 0,0625 0.0312 0.125 0,0625 0.25 0.0312 mentagrophytes Trlchóphytón No. 170 / M <0.0078 0,0625 0.0156 0.125 0.0156 mentagrophytes Trichophyton No. 171 / M 0,0625 <0.0078 0,0625 0.0156 0.125 0.0156 mentagrophytes Trichophyton No. 172 / M 0.125 0.0312 0.25 0,0625 0.5 0,0625 mentagrophytes Trichophyton No. 173 / M 0.25 0.0312 0.25 0,0625 0.25 0.0312 mentagrophytes Epidermophyton No. 174 / M 0.125 0.0156 0.125 0.0156 0.125 0.0312 floccosum No. 157 / M 0.125 0.0156 0.25 0.0312 0.25 0.0312

+) No 5 / M = strain 5 Nordmark-Werke GmbH ^{+ +} ) (2) as hydrochloride, other compounds as free base

Family

Microsporum ferrugineum

Microsporum gypseum

Microsporum Canis Microsporum Canis Microsporum Canis

Trichophyton mentagrophytes Trichophyton mentagrophytes Trichophyton mentagrophytes Trichophyton mentagrophytes Trichophyton mentagrophytes Trichophyton mentagrophytes

Table 1 - continued

Clotrimazole strain

Miconazole Tolnaftate

No. 5 / M +) No. 156 / M No. 155 / M No. 167 / M No. 168 / M No. 169 / M No. 9 / M

No 10 / M No 158 / M

No. 19 / M No. 21 / M No. 15 9 / M No. 160 / M No. 170 / M

No. 171 / M

No. 172 / M

No 173 / M No 174 / M No 157 / M

0.16

0.64

0.32

0.64

0.16

0.64

0.64

0.16

1,28

1,28

1,28

0.32

0.64

0.32

0.32

0.64

0.64

1,28

0.32

> 1,28 0.16 > 1,28 0.16 > 1,28 0.32 > 1,28 0.16 > 1,28 0.04 > 1,28 0.32 > 1,28 0.04 0.64 <0.01 > 1,28 0.08 > 1,28 0.04 > 1,28 0.32 0.32 0.08 > 1,28 0.32 1,28 0.08 0.64 0.16 0.32 0.64 0.32 0.32 > 1,28 0.08 > 1,28 0.32

+) No. 5 / M = strain 5, Nordmark-Werke GmbH

It can be seen from Table 1 that the trans isomers have a significantly higher effect than the cis isomers and thus carry efficacy. Furthermore, it is clear that the trans-isomers produced by the process according to the invention have a significantly higher effect than the known antifungal agents Clotrimazole Miconazole and in particular against Tolnaftate, as is evident from the lower MHK value.

The LD50 in the oral mouse is 1305 mg / kg for the trans-isomer of the formula, 335 mg / kg for the trans-isomer of the formula 2, and 2250 mg / kg for the trans-isomer of the formula 3. From these LD 50 values, it is apparent that the therapeutic breadth is sufficient for both local and systemic administration by the oral route.

The compounds according to the invention can be used in humans and animals in the case of dermatomycoses, in particular caused by the families Epidermophyton, Microsporum and Trichophyton.

Compositions containing the above compounds suitable for oral or topical administration may be prepared in conventional manner using conventional carriers and diluents and other excipients, for example by mixing.

In both human and veterinary medicine, it is generally preferred that the active ingredient be administered in an amount of 0.07 to 0.1 g / cm 2 body area per 24 hours, or in several divided doses, externally. However, different doses may be used depending on the type and severity of the disease. · The physician will determine the optimal dose and interval between doses.

As a rule, a single dose is applied 1 to 2 times a day. For topical administration, the compositions contain 0.5 to 5, preferably 1 to 2% by weight of the active ingredient. For oral administration, 50 to 50 are used as a single dose

1000 mg, preferably 500 to 800 mg of active ingredient 1 to 2 times a day.

For oral administration, for example, tablets, coated tablets, dragees, capsules, pills, powders or suspensions are used.

Tablets may be prepared, for example, by mixing the active ingredient with known excipients such as inert diluents, for example dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbonate, calcium phosphate or milk sugar, fillers, for example corn starch or alginic acid, binders , such as starch or gelatin, glidants, for example magnesium stearate or talc, and / or delayed absorption means, for example carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of several layers.

Dragees can be obtained by coating cores whose composition is similar to tablets as coating materials are used, for example, collidone, shellac, gum arabic, talc, silica or sugar. The dragee coatings may also consist of several layers, the excipients mentioned for tablets being used.

Active ingredient suspensions may be prepared using flavor enhancers such as saccharin, cyclamate or sugar and flavorings such as vanillin or orange extract. Such suspending agents, for example sodium carboxymethylcellulose or preservatives, for example p-hydroxybenzoate. Capsules containing the active ingredient can be obtained, for example, by mixing the active ingredient with an inert carrier, for example milk sugar

No. 4,831 or sorbitol and the resulting mixture is filled into gelatin capsules.

Pastes, ointments, jellies, creams, lotions, powders, solutions, emulsions and sprays are particularly suitable for external administration.

Ointments, pastes, creams and jellies may contain, in addition to the active ingredients, conventional carriers, for example animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonlt, silicic acid, talc and zinc oxide or mixtures thereof.

The powders and sprays may contain, in addition to the active ingredient, conventional carriers, for example, milk sugar, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or a mixture thereof. Sprays may additionally contain one of the conventional propellants, for example a chlorinated and fluorinated hydrocarbon.

The solutions and emulsions may contain, in addition to the active ingredients, conventional carriers, for example solvents, co-solvents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil, in particular cottonseed oil. seeds, peanut oil, maize germ oil, olive oil, castor oil and sesame oil and in addition glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol aliphatic acid esters or mixtures of the foregoing.

The invention will be illustrated by the following examples.

Example 1

Cis- and trans-3- (4-tert-butylcyclohexyl-1) -2-methyl-1- (3‘-methyl-1-piperidino) propane and synthesis of an aromatic amine

In a 2-liter three-necked flask, 306 g of 3- (p-tert-butylphenyl) -2-phenylpropanol are mixed with 72.5 g of 98% formic acid, which is added dropwise and then added over 3 hours. 149 g of 3-methylpiperidine are added dropwise during which time the temperature is raised from 25 to 50 ° C and above, and the reaction mixture is refluxed for a further 12 hours, releasing carbon dioxide. Fractional distillation under reduced pressure A 47 g pre-fraction is collected, boiling at 130 ° C at 26.6 Pa, then distilling 3- (p-tert-butylphenyl) -2-methyl-1- (3). 1'-methyl-1'-piperidinium propane at a temperature range of 130 to 133 ° C under the same pressure to give 355 g of this compound, which represents a yield of 82.4% based on the starting aldehyde.

b) Hydrogenation of the cyclohexane derivative

309 g of 3- (p-tert-butylphenyl) -2-methyl-1- (3'-methyl-1'-piperidino) propane are hydrogenated in 1000 g dioxane in the presence of 0.5 g oxide hydrate in a 3-liter rotary autoclave. No hydrogen is bound after 3 hours at a pressure of 100 x χ 10 ⁵ Pa and at a temperature of 120 ° C. Finally, at a temperature of 140 ° C and an initial pressure of 120 x χ vod ³ Pa of hydrogen, a pressure drop of 12 35 χ 10 ⁵ Pa and after the hydrogen pressure has been restored to 160 χ 10 ⁵ Pa at 160 ^° C, a further 10 hours pressure drop of 10 χ 10 ⁵ Pa is observed over the next 10 hours. When the hydrogen pressure is adjusted again to 160 χ 10 ⁵ Pa and the temperature at 180 ° C no longer absorbs hydrogen.

(c) Fractional distillation

1310 g of the reaction mixture were subjected to fractional distillation in a 10 ° column at a pressure of 1330 Pa. After dioxane is distilled off, the following fractions are obtained when the original material is returned in a ratio of 1: 5:

1. at a temperature of up to 185 ° C, 27 g of material is obtained, consisting of 85% of the cis isomer and 10% of the trans isomer, the remainder 5% being a pre-fraction.

2. At 185 ° C, 114 g of a material consisting of 75% of the cis-isomer and 25% of the trans-isomer are obtained.

3. At 186 ° C, 60 g of material is obtained which consists of 40% of the cis -isomer and 60% of the trans -isomer.

4. At 187 ° C, 55 g of material is obtained which contains 30% of the cis -isomer and 70% of the trans -isomer.

The distillation residue (40 g) is distilled at a pressure of 1330 Pa at 187 ° C. 38 g of a material which includes about _92/0 trans isomer and only 8% of cis isomer. The distillation residue weighed 2 g.

The ratio of cis and trans isomers is determined in each case by gas chromatography.

504 g of the obtained 3- (4'-tert-butylcyclohexyl-1 ') -2-methyl-1- (3'-methyl-1'-piperidino) propane, which contains 54% of the cis-isomer and 46% of the trans-isomer ( a total of 425 g) was subjected to fractionation on a column of 20 degrees and the material was returned 1: 3.

70 g of pre-fraction were collected at a temperature of 192 ° C. The following fractions are then obtained:

1. At a temperature of 197 ° C / 28 _T , 13 g of material are obtained which contains 85% of the cis-isomer and 3% of the trans-isomer, 12% of the residue being a pre-fraction.

2. At a temperature of 198 ° C / 26 _T , 52 g of mate214831 material are obtained which contains 93% cis-isomer and 7% trans-isomer.

3. 87 g of material containing 90% of the cis-isomer and 10% of the trans-isomer are obtained at a temperature of 197 ° C / 25 _T.

4. At a temperature of 192 ° C / 22 _T , 82 g of material is obtained which contains 85% of the cis -isomer and 15% of the trans -isomer.

5. To a temperature of 196 ° C / 22 _T , 82 g of material is obtained which contains 80% of the cis-isomer and 20% of the trans-isomer.

6. 87 g of material containing 30% of the cis-isomer and 70% of the trans-isomer are obtained at a temperature of 202 ^° C / 28 _T.

7. At a temperature of 196 ° C / 22 _T , 73 g of a material containing 97% of the trans-isomer and 3% of the cis-isomer are obtained.

g of the distillation residue is subjected to a further distillation to obtain 24 g of a material containing more than 98% of the trans-isomer.

d) Production of the pure cis-isomer hydrobromide

Further purification of the initial and / or final fraction to the pure cis-isomer is accomplished by recrystallization of the hydrobromide from a mixture of acetic acid and water, and in the case of the trans-isomer, hydrochloric acid in methanol is used.

g of the above first fraction were mixed with 20 g of a 48% aqueous hydrobromic acid solution. 50 g of acetic acid are then added and the crystalline material obtained is dissolved by heating. Upon cooling, the cis-isomer hydrobromide crystallizes. NMR showed pure cis-isomer. In this way, 28 g of pure cis -isomer, m.p. 210 DEG C., are obtained.

Analysis:

calculated:

H, 10.77; N, 3.75; Br, 20.34. Found:

64.50 o / o C, 10.30% H, 3.60% N, 20.60% Br.

e) Preparation of the pure trans-isomer hydrochloride g of fraction 5 obtained above is mixed in methanol with 60 g of hydrochloric acid. After cooling, 28 g of hydrochloride crystallize, m.p. 168 ° C. The NMR spectrum showed the presence of pure trans-isomer.

Example 2

Cis- and trans-3- (4‘-tert-butylcyclohexyl-1‘-2-methyl-1- (3‘, 5‘-dimethyl-1‘-piperidino) propane

a) 361 g of 3- (p-tert-butylphenyl) -2-methylpropanol were reacted as described in Example 1 with 200 g of 3,5-dimethylpiperidine and 86 g of 98% formic acid. The amine is purified by traction distillation at pressure

26.6 Pa in a column of 10 degrees. 406 g of pure amine are obtained at 136 ° C.

b) Hydrogenation to a cyclohexane compound

In a 250 ml shake autoclave, 70 g of 3- (p-tert-butylphenyl) -2-methyl-1- (3 ', 5'-dimethyl-1'-piperidino) propane are reacted with 80 g of dioxane. 0.5 g of ruthenium oxide hydrate is used as the hydrogenation catalyst. At a pressure of 100 x x 10 ⁵ Pa of hydrogen at a temperature of 120 ° C, the pressure should be increased by 358 xx 10 ⁵ Pa within 37 hours.

Fractional distillation 139 g of the reaction product gives 64 g of cyclohexane derivative which is distilled at a temperature of 136 to 146 ° C at a pressure of 40 Pa. Analysis by gas chromatography showed a mixture of cis and trans cyclohexane derivative isomers.

(c) Fractional distillation

562 g of an aromatic amine which has been hydrogenated in 1000 g of dioxane in the presence of ruthenium oxide hydrate at a pressure of 140 x 10 ⁵ Pa of hydrogen and at 120 ° C for 20 hours is subjected to fractionation using a 10-degree column. in a ratio of 1: 5 as described in Example 1.

% Of the cis-cyclohexane derivative passes through the column in the temperature range from 124 to 125 ^C under a pressure of 13.3 Pa. The trans-isomer with a purity of over 90% passes at a temperature of 129 to 131 ° C.

The fractional distillation was repeated in a column equipped with silver wire in the form of a 80 cm sieve at a pressure of 1 to 5 mm Hg, yielding 154 g of the cis-isomer with a purity of more than 90%. In addition, 136 g of an intermediate fraction consisting of the cis-isomer and the trans-isomer of the cyclohexane derivative in a ratio of 1: 1 are obtained. In addition, 98 g of the trans-isomer of the cyclohexane derivative with a purity greater than 90% are obtained.

The intermediate fraction is subjected to further fractionation. After this fractionation, only a very small residue of 390 g of the mixture of the cis-isomer and the trans-isomer is left with only 2 g of the high-boiling fraction. At a pressure of 15 mbar, the cis-isomer distills in the temperature range of 193-195 ° C and the trans-isomer at 199-200 ° C.

d) Crystallization of the pure cis-isomer via hydrochloride g of the cis-isomer with a purity of more than 90% is dissolved in 25 g of methanolic hydrochloric acid solution and the solution is heated to near boiling point. After cooling, 12 g of the hydrochloride crystallized. The melting point of the recrystallized cis-isomer of the cyclohexane derivative is about 240 ^° C. A sample of the salt is taken and decomposed by treatment with potassium hydroxide, after which it can be shown, by gas chromatography, that it is a cis-isomer substantially free of the trans-isomer.

e) Crystallization of the pure trans-isomer before the hydrochloride g of the trans-isomer with a purity of more than 90 percent is dissolved in 30 g of ethanolic hydrochloric acid solution. Upon cooling, the pure trans-isomer hydrochloride crystallizes, m.p. 202 ° C. 13 g of this product are obtained. The free base obtained by decomposition of the salt is subjected to gas chromatography to show that it is a cis-isomer-free trans-isomer. The NMR spectrum of both crystalline materials confirms the above results.

Example 3

Cis- and trans-3- (4'-tert-butylcyclohexyl-1 ') - 2-methyl-1- (2', 6'-cis-dimethylmorpholyl) propane

a) The preparation of 3- (p-tert-butylphenyl) -2-methyl-1- (2 ', 6'-cis-dimethylmorpholyl) propane is carried out by the method of Example 1 by reacting it in the reaction of 3- (p-tert-butyl) Butylphenyl} -2-methylpropanol with 2,6-cis-dimethylmorpholine and formic acid The aromatic amine is purified by distillation and the amine is distilled at 40 Pa at 170 to 175 ° C.

b] Hydrogenation to cyclohexane derivative

720 g of the morpholine derivative described above are mixed with 500 g of dioxane. 0.5 g of ruthenium oxide hydrate are added as hydrogenation catalyst. Hydrogenation is carried out at a hydrogen pressure of 120 x 10 ⁵ Pa and at a temperature of 140 ° C. Within 24 hours of use

The 2.6 liter rotating autoclave gradually increases the hydrogenation pressure to a total of 130 x x 10 ⁵ Pa.

(c) Fractional distillation

623 g of the thus obtained mixture of cis-isomer and trans-isomer containing 60% cis-isomer and 40% trans-isomer are subjected to fractional distillation in an 80 cm column filled with a silver wire mesh at 40 Pa. The starting material is returned 1: 5. Cis isomer distills at temperatures from 144 to 145 ^c C at a pressure of 40 Pa. In this way, 70 g of the cis -isomer with a purity of more than 90% are obtained in the first three fractions. In the last three fractions, 71 g, 54 gag of the trans-isomer is obtained, the purity of which is greater than 85%.

d) Crystallization of the hydrochloride of the pure cis-isomer and the trans-isomer

The methods of Examples 1 and 2 provide pure cis-isomer hydrochloride using ethanolic hydrochloric acid solution. Melting point: 161 ° C.

The pure trans-isomer forms the hydrochloride, m.p. 199 ° C.

Both salts can be treated with potassium hydroxide to give the free base which is analyzed by gas chromatography. In this way, it can be shown that the purified cis-isomer of the cyclohexane derivative contains less than 0.5% of the trans-isomer and the purified trans-isomer contains less than 1% of the cis-isomer. The NMR spectrum confirms these results.

Example 4

Tablets

Ingredients active substance200 average molecular weight polyvinylpyrrolidone 25 00020 polyethylene glycol average molecular weight 400014 hydroxypropylmethylcellulose40 talc4 magnesium stearate2

280 mg

The active ingredient is moistened with a 10% aqueous solution of polyvinylpyrrolidone and the material is passed through a 1.0 mm sieve and then dried at 50 ° C. The granules so obtained are compressed after the addition of 4000 MW polyethylene glycol, hydroxypropyl methylcellulose, talc and magnesium stearate into 280 mg tablets.

Example 5

Dragee

Ingredient mg

active substance 150 laktčza 60 cornstarch 30 polyvinylpyrrolidone 4 magnesium stearate 1

245 mg

The active ingredient is mixed with lactose and corn starch and this mixture is moistened after wetting

8% aqueous solution of polyvinylpyrrolidone ingredient is sieved through sieve 1.5 mm, the granules are dried at 50 ° C, ^G and again forced through a sieve of mesh size 1.0 mm. The granulate so obtained is mixed with magnesium stearate and pressed into dragee cores. The cores thus obtained are coated in a known manner, consisting essentially of sugar and talc.

Example 6

A cream containing 2 o / ₀ effective can be made from the following mixture:

Ingredient Active ingredient glycerol monostearate cetyl alcohol polyethylene glycol-400 stearate polyethylene glycol sorbitan monostearate polyethylene glycol p-hydroxybenzoic acid methyl ester demineralized water

Finely powdered active substance g

2,0 10,0

5.0

10.0

10.0

6.0

0.2 100.0 is suspended in propylene glycol and the suspension is heated to 65 ° C and mixed in a heated mixture of glycerol monostearate, cetyl alcohol, polyethylene glycol 400-stearate and polyethylene glycol sorbitan monostearate. In the mixture obtained, a solution of p-hydroxybenzoic acid methyl ester in water at 70 ° C is emulsified. After cooling, the cream is homogenized in a colloid mill and filled into tubes.

Example 7

Powder containing 2% active ingredient

Ingredient g Active ingredient2,0 Zinc oxide10,0 Magnesium oxide10,0 Highly dispersed silica2,5 Magnesium stearate1,0 Talc75,5

The active ingredient is micronized and then mixed homogeneously with the other ingredients.

The mixture is passed through a No. 7 sieve and filled into a polyethylene spout.

Claims (1)

Process for the preparation of pure trans-3- (4'-tert-butyl-1'-cyclohexyl) -2-methyl-1- (3'-methylpiperidino) propane, - (3 ', 5'-dimethylpiperidino) propane and - (2', 6) cis-dimethyl morpholino) propane from mixtures of cis-trans isomers obtained in the hydrogenation of the corresponding 1,4-disubstituted phenyl derivative, characterized in that after distilling off the solvent used for the hydrogenation, the isomer mixture is enriched by fractional distillation at a head pressure of 6.5 to 6.5. 6560 Pa in a 10 to 100 tray column at a reflux ratio of 1: 1 to 1: 100 and at temperatures of 160 to 240 ° C to a trans-isomer content greater than 85 percent and the pure trans-isomer after conversion to the hydrochloric acid addition salt and crystallizing from an organic solvent by crystallization.