CA1146551A - Trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2- methyl-1-(3'-methylpiperidino,3',5'- dimethylpiperidino and 2',6'-dimethylmorpholino)- propane, their preparation in a pure form, anti-mycoti c agents containing these compounds, and their use - Google Patents
Trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2- methyl-1-(3'-methylpiperidino,3',5'- dimethylpiperidino and 2',6'-dimethylmorpholino)- propane, their preparation in a pure form, anti-mycoti c agents containing these compounds, and their useInfo
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- CA1146551A CA1146551A CA000351285A CA351285A CA1146551A CA 1146551 A CA1146551 A CA 1146551A CA 000351285 A CA000351285 A CA 000351285A CA 351285 A CA351285 A CA 351285A CA 1146551 A CA1146551 A CA 1146551A
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- methyl
- tert
- propane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Abstract of the Disclosure: Pure trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3'-methyl-1'-piper-dino)-propane, trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3',5'-dimethyl-1'-piperdino)-propane and trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(2',6'-cis-dimethylmorpholino)-propane, their prepara-tion in a pure form from cis/trans-isomer mixtures, anti-mycotic agents, containing these, for topical and systemic application, and their use in combating dermatomycoses.
Description
11~6551 O.Z. 0050/033879 Trans-3-(4'-tert,-butyl-cyclohex-1'-yl)-2-methyl-1-(3'-methylpiperidino, 3',5l-dimethylpiperidino and
2',6'-dimethylmorpholino)-propane, their preparation in a pure form, anti-mycotic agents containing these com-pounds, and their use , GermanLaid-Open ApplicationDOS 2,752,135 discloses that 3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3'-methyl-1'-piperidino)-propane, 3-(4'-tert.-butyl-cyclohex-l'-yl)-2-methyl-1-(3',5'-dimethyl-1'-piperid-ino)-propane and 3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(2',6'-cis-dimethyl-morpholino)-propane and their salts may be used to combat phytopathogenic fungi and also human-pathogenic fungi and yeasts, ~or example Candida ~1bicans, Trichophyton mentagrophytes and Histoplasma capsulatum, The above compounds are in the form of cis-trans-isomer mixtures in respect of the two substituents in the 1,4-position of the cyclohexane ring, m e present in~ention relates to the pure trans-compounds (O
H
(2) ,J~
~1~6551 - 2 - O.Z. oo50/o33879 ~ N ~ (3) trans-~-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3~-methyl-1~-piperidino)-propane (1), trans-3-(4'-tert.-butyl-cyclohex-l'-yl)-2-methyl-1-(3',5l-dimethyl-l'-piperidino)-propane (2) and trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(2',6'-cis-dimethylmorpho-lino)-propane (3) respectively, their preparation in a pure form from cis/trans-isomer mixtures, and their use in antimycotic agents.
In view of the surprising discovery that the pure trans-compounds are 10 or more times as active against human-pathogenic fungi and yeasts from the fam-ily of the dermatophytes than are the cis-compounds, it is an obJect of the present invention to provide pro-ces~e~ for preparing the pure trans-compounds (1), (2) and (3).
It is known to tho~e skilled in the art that the catalytic hydrogenation of para-substituted aromatics results in isomer mixtures, the compositions of which may differ greatly, For example, if the hydrogenation is carried out over platinum catalysts, it is often the cis-1,4-disubstituted cyclohexane compounds which are formed predominantly, and this is also true when using nickel, cobalt or palladium catalysts (cf. Houben-Weyl, Volume 11/1, page 680 et seq., Georg Thieme-Verlag, Stuttgart 1957) With rutherium catalysts, similar ~ 114655~
_ 3 - O.Z. oo50/o33879 results are obtained, but certain proportions of the corresponding trans-compounds are also formed.
On reducing para-substituted aromatics with sodium in alcohol, a substantially greater proportion of trans-compounds is generally obtained, but the selectiv-ity of this reaction is unsatisfactory and the technical effort required to carry out the reaction is substanti-~ly greater.
Further, it is known, for example from Houben-lo Weyl, Volume 5/la, page 553 et seq., Georg Thieme-Verlag, Stuttgart (1970), that the separation of a mix-ture of cis- and trans-1,4-disubstituted cyclohexane compounds requires extremely efficient columns. In most cases, separating units with more than 100 theo-retical plates are employed, and a very high reflux ratio, of 1 : 200, is chosen. m e great difficulties of separating cis-trans-mixtures of disubstituted cyclo-hexane derivatives may be seen, for example, from the fact that to separate 1,4-d~s ~ ~yl-cyclohexane into the 20 Ci3- and trans-isomer a column of 100 theoretical plates i-s required~ and i8 operated w-ith a re n ux ratio of 1 : 200. At 14 mm Hg, the pure cis-isomer boils at 96.9C and the trans-isomer at 96 1C
If the fractionation is carried out under a pressure of 7,5 mm Hg, it is the cis-isomer which boils at a lower temperature, namely 78 9C, whilst the trans-isomer boils at 84.4C. This inversion of the boiling points very clearly indicates the difficulties of such a separation ~ 1~46551 . .
- 4 - O.Z. 0050/033879 The separation of 1,4-di-tert.-butyl-cyclohexane into the corresponding pure cis- and trans-isomers requires similar separation conditions. As shown by the description of the experiments, several days are required in order to isolate small amounts of the pure compounds (Houben-Weyl, Volume 5/la, page 558). It has also been shown that the separation of the mixture of isomeric forms obtained by hydrogenation of l-methyl-4-tert.-butyl-benzene requires very much effort.
The above examples show that separation of the cis- and trans-isomers of 1,4-disubstituted cyclo-hexane derivatives is extremely expensive and difficult and that if one substituent is made larger, as is the case with the compounds referred to above, separation into the pure cis- and trans-isomer by fractional dis-tillation is technically no longer feasible.
We have found that the pure trans-3-(4'-tert.-butyl-cyclohex-l'-yl)-2-methyl-1-(3'-methyl-piperidino,
H
(2) ,J~
~1~6551 - 2 - O.Z. oo50/o33879 ~ N ~ (3) trans-~-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3~-methyl-1~-piperidino)-propane (1), trans-3-(4'-tert.-butyl-cyclohex-l'-yl)-2-methyl-1-(3',5l-dimethyl-l'-piperidino)-propane (2) and trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(2',6'-cis-dimethylmorpho-lino)-propane (3) respectively, their preparation in a pure form from cis/trans-isomer mixtures, and their use in antimycotic agents.
In view of the surprising discovery that the pure trans-compounds are 10 or more times as active against human-pathogenic fungi and yeasts from the fam-ily of the dermatophytes than are the cis-compounds, it is an obJect of the present invention to provide pro-ces~e~ for preparing the pure trans-compounds (1), (2) and (3).
It is known to tho~e skilled in the art that the catalytic hydrogenation of para-substituted aromatics results in isomer mixtures, the compositions of which may differ greatly, For example, if the hydrogenation is carried out over platinum catalysts, it is often the cis-1,4-disubstituted cyclohexane compounds which are formed predominantly, and this is also true when using nickel, cobalt or palladium catalysts (cf. Houben-Weyl, Volume 11/1, page 680 et seq., Georg Thieme-Verlag, Stuttgart 1957) With rutherium catalysts, similar ~ 114655~
_ 3 - O.Z. oo50/o33879 results are obtained, but certain proportions of the corresponding trans-compounds are also formed.
On reducing para-substituted aromatics with sodium in alcohol, a substantially greater proportion of trans-compounds is generally obtained, but the selectiv-ity of this reaction is unsatisfactory and the technical effort required to carry out the reaction is substanti-~ly greater.
Further, it is known, for example from Houben-lo Weyl, Volume 5/la, page 553 et seq., Georg Thieme-Verlag, Stuttgart (1970), that the separation of a mix-ture of cis- and trans-1,4-disubstituted cyclohexane compounds requires extremely efficient columns. In most cases, separating units with more than 100 theo-retical plates are employed, and a very high reflux ratio, of 1 : 200, is chosen. m e great difficulties of separating cis-trans-mixtures of disubstituted cyclo-hexane derivatives may be seen, for example, from the fact that to separate 1,4-d~s ~ ~yl-cyclohexane into the 20 Ci3- and trans-isomer a column of 100 theoretical plates i-s required~ and i8 operated w-ith a re n ux ratio of 1 : 200. At 14 mm Hg, the pure cis-isomer boils at 96.9C and the trans-isomer at 96 1C
If the fractionation is carried out under a pressure of 7,5 mm Hg, it is the cis-isomer which boils at a lower temperature, namely 78 9C, whilst the trans-isomer boils at 84.4C. This inversion of the boiling points very clearly indicates the difficulties of such a separation ~ 1~46551 . .
- 4 - O.Z. 0050/033879 The separation of 1,4-di-tert.-butyl-cyclohexane into the corresponding pure cis- and trans-isomers requires similar separation conditions. As shown by the description of the experiments, several days are required in order to isolate small amounts of the pure compounds (Houben-Weyl, Volume 5/la, page 558). It has also been shown that the separation of the mixture of isomeric forms obtained by hydrogenation of l-methyl-4-tert.-butyl-benzene requires very much effort.
The above examples show that separation of the cis- and trans-isomers of 1,4-disubstituted cyclo-hexane derivatives is extremely expensive and difficult and that if one substituent is made larger, as is the case with the compounds referred to above, separation into the pure cis- and trans-isomer by fractional dis-tillation is technically no longer feasible.
We have found that the pure trans-3-(4'-tert.-butyl-cyclohex-l'-yl)-2-methyl-1-(3'-methyl-piperidino,
3',5'-dimethylpiperidino and 2i,6l-cis-dimethylmorpho-lino)-propanes are obtained if the cis-trans-mixtures obtained on hydrogenating the corresponding 1,4-disub-stituted phenyl compound in a conventional manner to give the cyclohexane compound are freed from the hydro-genation solvent by distilling off the latter and the trans-isomer is then enriched to a content of more than 85% by fractional distillation in a column with fromlO to 100 theoretical plates, under a reflux ratio of from 1 : 1 to 1 : 100, a pressure at the column top of 0.05 -50 mm Hg, at the temperatures which result from these _ 5 _ o.Z. 0050/03387g conditions during the distillation, the enriched product is converted to an addition salt with a hydrohalic acid, and the salt of the pure trans-isomer is allowed to crystallize out from an organic solvent.
The temperatures which are measured at the column top during the fractional distillation and which result from the particular reflux conditions and number of theoretical plates are as a rule from 160 to 240C.
Surprisingly, the above cyclohexane compounds (1), (2) and (3) are separated into low-boiling ~rac-t~ons enriched in cis-compound and higher-boiling fractions enriched in trans-compound by a substantially less expensive distillation technique than that des-cribed for the difficult separations of 1,4-dialkyl-cyclohexane isomer mixtures, notwithstanding the fact that in the present instance the molecule contains a tertiary amino group.
As a rule, the isomer mixtures sub~ected to frac-tional distillation have been obtained by hydrogenation in a conventional manner over a ruthenium, palladium, platinum, nickel or cobalt catalyst Advantageous columns to use are glass screen plate columns or columns packed with silver gauze spirals or stainless steel gauze spirals.
The preferred conditions ~or the fractional dis-tillation of (1) are to use a 20-40-plate column under from 2 to 20 mm Hg, with a reflux ratio of from 1 : 3 to 1 : 10, these conditions resulting in temperatures of ~4~'5S~
- 6 o. z. oo50/o33879 183 - 186C; for (2) and (3), similar conditions are preferred and result in temperatures of 193 - 200G and 203 - 208C respectively.
After completion of the distillation, a distil-lation residue of from 5 to 10~ may remain and if this is subjected to distillation under the con-ditions described above, gives~-directly-~ aStrans-compound which is from 92 to 98~ pure.
The fractions which have been enriched to more ~han 85~ of trans-compound are converted to an addition salt with a hydrohalic acid, from which the pure trans-compound is obtained by crystallization in a suitable solvent Suitable sol~ents for the crystallization are, in particular, monohydric lower alcohols of 1 to 4 carbon atoms, eg, methanol and ethanol, esters of lower ali-phatic carboxylic acids, in which both the alcohol and the acid are of 1 to 4 carbon atoms, especially esters of acetic acid, eg. ethyl acetate, lower ketones, eg acet-one, methyl ethyl ketone and methyl isopropyl ketone, anddialkyl ethers, where alkyl is of 1 to 4 carbon atoms, and saturated cyclic ethers, eg. diethyl ether, diiso-propyl ether, tetrahydrofuran and dioxane. The crystallization may or may not be carried out in the pre-sence of an excess of the hydrohalic acid. The preferred addition salt is the hydrochloride The preferred crystallization conditions are to ~465Sl - 7 - o. z . oo50/0~3879 use solutions of about 20 percent strength by weight in methanol or ethanol, the solutions being prepared at about 80C and being allowed to cool to about 25C, with or without seeding.
The final isolation o~ the pure trans-compound by crystallization from an isomer mixture containing at least 85% of trans-compound has the particular advantage that ~he preceding fractional distillation can be oper-ated under less difficult conditions. This leads to less severe heat exposure of the isomers to be separ-ated, so that decomposition products, which under certain circumstances can form, are avoided. The com-bination of fractional distillation and crystallization gives, in a technically surprisingly simple manner, trans-compounds which are more than 9g% pure, as well as -- the pure cis-compounds, as is shown in the Examples.
After liberating the base from the mother liquors, the latter can - again be subjected to fractional dis-tillation.
It is to be noted that the cis-compound can be converted in - its mixtures or can, after removal of the trans-compound in accordance with the invention, be con-verted to the trans-compound-by a palladium-catalyzed or nickel-catalyzed isomerization, ~146551 - 8 - o. z. oo50/033879 A ~urther advantage of the novel method of sepa-ration, and of preparation of the pure trans-isomers, is that it creates the preconditions for a separation of the configurational isomers, existing as a result of the chirality centers present, into the optical antipodes.
Surprisingly, it is the trans-compounds which are almost exclusively responsible ~or the good anti-mycotic action.
Compared to the corresponding cis-compound, the inhibit-ing effects,on micro-organisms,of the trans-compounds (1), (2) and (3) are 10 or more times as great. This means, for example, that if the toxicities are similar, the therapeutic range is substantially greater for the trans-compound.
Hence, the present invention also relates to an anti-mycotic agent for topical and systemic use, which contains a pure trans-compound as claimed in claim 1 or 2 or 3, or a physiologically tolerated acid addition salt thereof, as the active ingredient, together with con-~entional carriers and diluents, and to the use of thepure trans-compound in combating dermatomycoses.
Suitable conventional physiologically tolerated acids for forming the salts include organic and inorganic acids, eg. nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and nicotinic acid. However, the inor-ganic acids mentioned, especially hydrochloric acid, are ~ 1146551 .
- 9 - o. z. ooso/03387s - preferred.
The pure trans-compounds, and their salts, to be used according to the invention possess powerful anti-mycotic effects. They have a broad anti-mycotic spectrum of action, especially against dermatophytes, for example species of Epidermophyton, eg. Epidermophyton n occosum, species of Trichophyton, eg. Trichophyton mentagrophytes, and species of Mlcrosphoron, eg.
Microsphoron ferrugineum, This list of micro-organisms is purely illustrative and in no way intended to be exhaustive.
The effect on micro-organisms can be demonstrated by such methods as those described in P. N ein, Bakteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlag Berlin, 1957.
For example, the minimum inhibitory concentra-tions (MIC values) achievable against pathogenic fungi in the agar dilution test were determined.
The results are summarized in Table 1 which follows:
~ ~46SS~
- 10 - o. Z . 0050/033879 _~ C~ L~ ~D N N ~ 1 ~1 O o ~ I~ L~ _ U~ ~ ~ U~ _ Lr~ ~ ~ ~ _ _ 8 -- o o o o c c o o o o c o c o c tu U~ U~ ~
O ~1 Ir N N ~a In m ~ Ln N N 1~ N L--O ~ N O 1~ -- O ~ 'J O ~'J '~ '^ 'r ~ ~ ~J
~_ O O O O O O O O C~ O O O O O C 0 0-0 O
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1~6551 0. Z . 0050/033879 V ~D ~0 N ~.0 -- ~J = _I CO = ~ = ~1 ~ ~0 = t~ ~0 ~U
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-~ 114655~ .
-.12 - O.Z. 0050/033879 It may be seen from Table l that the trans-compounds are substantially stronger than the cis-compounds and thus virtually constitute the activity carriers, Further, it will be seen that the trans-compounds have substantially lower MIC values than the conventional anti-mycotic agents Clotrimazol and Miconazol, and, especially, Tolnaftat, one of the cur-rently most extensively used agents against dermatomycoses.
The LD50 value, determined for oral administra-tion to mice, is 305 mg/kg for trans-(l), ~35 mg/kg for trans-(2) hydrochloride and 2,250 mg/kg $or trans-(3), m ese LD50 values show a sufficient therapeutic range for -~ay~temi-c. .~ ~ ~ use after oral administratior.
and-~or .topical admini~tra~io~
Accordingly, fields of indication in man and ---animals are dermatomycoses, especially those caused by 5pecies of the genera Epidermophyton, Microsporum and Trlchophyton, The present invention also includes the prepara-tion of agents or formulatlons for oral and topical use by compounding, especially by mixing, with conventional carriers or diluents and conventional pharmaceutical auxiliaries, the active compound being present in a dos-age suitable for internal or external use.
As a rule it has proved advantageous, both in - . 1146551 - 13 - o.Z~ 0050J033879 human and in veterinary medicine, to apply the acti~e compound or compounds externally in amounts of from about 0,07 to 0.1 g/cm2 of body surface per 24 hours, if appropriate in the form of several individual applica-tions. However, it is also possible to deviate from the above dosages, depending on the nature and severity of the disorder. m e required optimum dose and its i'requency can be decided by the responsible physician, on the basis of his expert knowledge.
As a rule, 1 or 2 doses are applied per day, In the case of external, local application the formula-tions contain from 0 5 to 5, preferably from 1 to 2, %
by weight of active compound. In the case of oral administration, suitable individual doses are from 50 to 1,000 mg, preferably from 500 to 800 mg, which may, for example, be administered once or twice daily.
Examples of formulations for oral administration are tablets, film tablets, dragees, capsules, pills, pow-ders and suspensions Appropriate tablets can be obtained, for example, by mixing the active compound with conventional auxilia-ries, for example inert diluents, eg, dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbon-ate, calcium phosphate or lactose, disintegrating agents, eg, corn starch or alginic acid, binders, eg. starch or gelatin, lubricants, eg, magnesium stearate or talc, and/
or agents for achieving a depot effect, eg. carboxypoly-methylene, carboxymethylcellulose, cellulose acetate-phthalate or polyvinyl acetate. The tablets can also 11465~1 i _ 14 - O.Z. 0050/033879 consist of a plurality of layers.
Correspondingly, dragees can be prepared by coating c~res, prepared similarly to the tablets, with agents conventionally used in dragee coatings, eg. col-lidone or shellac, gum arabic, talc, titanium dioxide or sugar, The dragee coatings can also consist of a plurality of layers, and the auxiliaries mentioned in connection with tablets may be used.
Suspensions containing the active compounds to iO be used according to the in~ention may in addition con-tain flavoring agents, eg. saccharin, cyclamate or sugar, and, for example, aroma substances, eg. vanillin or orange extract. They may in addition contain sus-pending agents, eg, sodium carboxymethylcellulose, or protective agents, e;g. p-hydroxy~
benzoates. Capsules containing the active compounds may be prepared, for example, by mixing the active com-pound with an inert carrier, such as lactose or sorbitol, and enclosing the mixture in gelatin capsules.
For external application, pastes, ointments, gels, creams, lotions, powders, solutions, emulsions and sprays are particularly suitable.
In ointments, pastes, creams and gels, the act-ive compound or compounds may be accompanied by the conventional carriers, for example animal and vegetable fats, waxesS paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc or zinc oxide, or mixtures of these materials ~4.~ 551 - 15 - o. z . oo50/033879 - In powders and sprays, the act~ve compounds may be accompanied by the conventional carriers, eg, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powders, or mixtures of these materials.
Sprays may in addition contain the conventional propel-lants, eg. chlorofluorohydrocarbons.
In solutions and emulsions, the acti~e compound or compounds may be accompanied by the conventional car-riers, such as solvents, solubilizing agents and e~ulsi-fiers, eg, water, ethyl - alcohol ,.isopropy1 alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, l,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol-formal, tetrahydrofurfuryl aloohol, polyethylene glycols or fatty acid esters of sorbitan, or mixtures of these materials.
l, Cis- and trans-3-(4-tert -butyl-cyclohex-l-yl)-2-methyl-l-(3~-methyl-l-piperidino~-propane a) Synthesis of the aromatic amine-306 g of 3-(p-tert,-butyl-phenyl)-2-methyl-propanal are introduced into a 2 liter three-neck flask and 72,5 g of 98Yo strength formic acid are added dropwise, 149 g of ~-methylpiperidine are then introduced dropwise over three hours, during which the temperature rises from 25C to above 50C, The reaction mixture is then refluxed for 12 hours, during which C02 is evolved.
- ~146S51 - 16 - o.Z. 0050/033879 After completion of the reaction, the mixture is sub~ected to fractional distillation under reduced pressure. After first runnings of 47 g, passing over at up to 130C under 0.2 mm Hg, 3-(p-tert.-butyl-phenyl)-2-methyl-1-(3'-methyl-1~-piperidino)-propane distils at 130 - 1~3C under a pressure o~ 0.2 mm Mg.
355 g are obtained, corresponding to a yield of 82,4%, based on aldehyde employed.
b) Hydrogenation to the cyclohexane derivative:
309 g of 3-(p-tert.-butylphenyl)-2-methyl-1-~3'-methyl-1'-piperidino)-propane in 1,000 g of dioxane are hydrogenated in the presence of 0.5 g of Ru203-hydrate in a 3 liter rolling autocla~e. Using a hydrogen pressure of 100 bar, at 120C, no further hydro-gen is absorbed after 3 hours. The temperature is then raised to 140C and the H2 pressure to 120 bar, whereupon a pressure drop of 35 bar is found over 12 hours; after resetting the hydrogen pressure to 160 bar and the temperature to 160C, a further pressure drop of ; bar is recorded over a further 10 hours.
On raising the hydrogen pressure to 160 bar and the temperature to 180C, there is no further hydro-gen absorption.
c) Fractional distillation:
m e reaction mixture, amounting to 1,310 g, is sub~ected to ~ractional distillation through a perfor-ated tray column with 10 trays, under a pressure of 10 mm Hg After distilling off the dioxane.the follow-ing fractions are obtained, using a reflux ratio of . - 17 - o.Z. 0050/033879 - 1 : 5:
1. up to 185C - 27 g, containing 85% of cis-compound and 10~ of trans-compound (the remaining 5% constitutes first runnings) 2. at 185C - 114 g, containing 75% of cis-compound and 25% of trans-compound 3, up to 186C - 60 g, containing 40~ of cis-compound and 60% of trans-compound
The temperatures which are measured at the column top during the fractional distillation and which result from the particular reflux conditions and number of theoretical plates are as a rule from 160 to 240C.
Surprisingly, the above cyclohexane compounds (1), (2) and (3) are separated into low-boiling ~rac-t~ons enriched in cis-compound and higher-boiling fractions enriched in trans-compound by a substantially less expensive distillation technique than that des-cribed for the difficult separations of 1,4-dialkyl-cyclohexane isomer mixtures, notwithstanding the fact that in the present instance the molecule contains a tertiary amino group.
As a rule, the isomer mixtures sub~ected to frac-tional distillation have been obtained by hydrogenation in a conventional manner over a ruthenium, palladium, platinum, nickel or cobalt catalyst Advantageous columns to use are glass screen plate columns or columns packed with silver gauze spirals or stainless steel gauze spirals.
The preferred conditions ~or the fractional dis-tillation of (1) are to use a 20-40-plate column under from 2 to 20 mm Hg, with a reflux ratio of from 1 : 3 to 1 : 10, these conditions resulting in temperatures of ~4~'5S~
- 6 o. z. oo50/o33879 183 - 186C; for (2) and (3), similar conditions are preferred and result in temperatures of 193 - 200G and 203 - 208C respectively.
After completion of the distillation, a distil-lation residue of from 5 to 10~ may remain and if this is subjected to distillation under the con-ditions described above, gives~-directly-~ aStrans-compound which is from 92 to 98~ pure.
The fractions which have been enriched to more ~han 85~ of trans-compound are converted to an addition salt with a hydrohalic acid, from which the pure trans-compound is obtained by crystallization in a suitable solvent Suitable sol~ents for the crystallization are, in particular, monohydric lower alcohols of 1 to 4 carbon atoms, eg, methanol and ethanol, esters of lower ali-phatic carboxylic acids, in which both the alcohol and the acid are of 1 to 4 carbon atoms, especially esters of acetic acid, eg. ethyl acetate, lower ketones, eg acet-one, methyl ethyl ketone and methyl isopropyl ketone, anddialkyl ethers, where alkyl is of 1 to 4 carbon atoms, and saturated cyclic ethers, eg. diethyl ether, diiso-propyl ether, tetrahydrofuran and dioxane. The crystallization may or may not be carried out in the pre-sence of an excess of the hydrohalic acid. The preferred addition salt is the hydrochloride The preferred crystallization conditions are to ~465Sl - 7 - o. z . oo50/0~3879 use solutions of about 20 percent strength by weight in methanol or ethanol, the solutions being prepared at about 80C and being allowed to cool to about 25C, with or without seeding.
The final isolation o~ the pure trans-compound by crystallization from an isomer mixture containing at least 85% of trans-compound has the particular advantage that ~he preceding fractional distillation can be oper-ated under less difficult conditions. This leads to less severe heat exposure of the isomers to be separ-ated, so that decomposition products, which under certain circumstances can form, are avoided. The com-bination of fractional distillation and crystallization gives, in a technically surprisingly simple manner, trans-compounds which are more than 9g% pure, as well as -- the pure cis-compounds, as is shown in the Examples.
After liberating the base from the mother liquors, the latter can - again be subjected to fractional dis-tillation.
It is to be noted that the cis-compound can be converted in - its mixtures or can, after removal of the trans-compound in accordance with the invention, be con-verted to the trans-compound-by a palladium-catalyzed or nickel-catalyzed isomerization, ~146551 - 8 - o. z. oo50/033879 A ~urther advantage of the novel method of sepa-ration, and of preparation of the pure trans-isomers, is that it creates the preconditions for a separation of the configurational isomers, existing as a result of the chirality centers present, into the optical antipodes.
Surprisingly, it is the trans-compounds which are almost exclusively responsible ~or the good anti-mycotic action.
Compared to the corresponding cis-compound, the inhibit-ing effects,on micro-organisms,of the trans-compounds (1), (2) and (3) are 10 or more times as great. This means, for example, that if the toxicities are similar, the therapeutic range is substantially greater for the trans-compound.
Hence, the present invention also relates to an anti-mycotic agent for topical and systemic use, which contains a pure trans-compound as claimed in claim 1 or 2 or 3, or a physiologically tolerated acid addition salt thereof, as the active ingredient, together with con-~entional carriers and diluents, and to the use of thepure trans-compound in combating dermatomycoses.
Suitable conventional physiologically tolerated acids for forming the salts include organic and inorganic acids, eg. nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and nicotinic acid. However, the inor-ganic acids mentioned, especially hydrochloric acid, are ~ 1146551 .
- 9 - o. z. ooso/03387s - preferred.
The pure trans-compounds, and their salts, to be used according to the invention possess powerful anti-mycotic effects. They have a broad anti-mycotic spectrum of action, especially against dermatophytes, for example species of Epidermophyton, eg. Epidermophyton n occosum, species of Trichophyton, eg. Trichophyton mentagrophytes, and species of Mlcrosphoron, eg.
Microsphoron ferrugineum, This list of micro-organisms is purely illustrative and in no way intended to be exhaustive.
The effect on micro-organisms can be demonstrated by such methods as those described in P. N ein, Bakteriologische Grundlagen der chemotherapeutischen Laboratoriumspraxis, Springer-Verlag Berlin, 1957.
For example, the minimum inhibitory concentra-tions (MIC values) achievable against pathogenic fungi in the agar dilution test were determined.
The results are summarized in Table 1 which follows:
~ ~46SS~
- 10 - o. Z . 0050/033879 _~ C~ L~ ~D N N ~ 1 ~1 O o ~ I~ L~ _ U~ ~ ~ U~ _ Lr~ ~ ~ ~ _ _ 8 -- o o o o c c o o o o c o c o c tu U~ U~ ~
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1~6551 0. Z . 0050/033879 V ~D ~0 N ~.0 -- ~J = _I CO = ~ = ~1 ~ ~0 = t~ ~0 ~U
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-~ 114655~ .
-.12 - O.Z. 0050/033879 It may be seen from Table l that the trans-compounds are substantially stronger than the cis-compounds and thus virtually constitute the activity carriers, Further, it will be seen that the trans-compounds have substantially lower MIC values than the conventional anti-mycotic agents Clotrimazol and Miconazol, and, especially, Tolnaftat, one of the cur-rently most extensively used agents against dermatomycoses.
The LD50 value, determined for oral administra-tion to mice, is 305 mg/kg for trans-(l), ~35 mg/kg for trans-(2) hydrochloride and 2,250 mg/kg $or trans-(3), m ese LD50 values show a sufficient therapeutic range for -~ay~temi-c. .~ ~ ~ use after oral administratior.
and-~or .topical admini~tra~io~
Accordingly, fields of indication in man and ---animals are dermatomycoses, especially those caused by 5pecies of the genera Epidermophyton, Microsporum and Trlchophyton, The present invention also includes the prepara-tion of agents or formulatlons for oral and topical use by compounding, especially by mixing, with conventional carriers or diluents and conventional pharmaceutical auxiliaries, the active compound being present in a dos-age suitable for internal or external use.
As a rule it has proved advantageous, both in - . 1146551 - 13 - o.Z~ 0050J033879 human and in veterinary medicine, to apply the acti~e compound or compounds externally in amounts of from about 0,07 to 0.1 g/cm2 of body surface per 24 hours, if appropriate in the form of several individual applica-tions. However, it is also possible to deviate from the above dosages, depending on the nature and severity of the disorder. m e required optimum dose and its i'requency can be decided by the responsible physician, on the basis of his expert knowledge.
As a rule, 1 or 2 doses are applied per day, In the case of external, local application the formula-tions contain from 0 5 to 5, preferably from 1 to 2, %
by weight of active compound. In the case of oral administration, suitable individual doses are from 50 to 1,000 mg, preferably from 500 to 800 mg, which may, for example, be administered once or twice daily.
Examples of formulations for oral administration are tablets, film tablets, dragees, capsules, pills, pow-ders and suspensions Appropriate tablets can be obtained, for example, by mixing the active compound with conventional auxilia-ries, for example inert diluents, eg, dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbon-ate, calcium phosphate or lactose, disintegrating agents, eg, corn starch or alginic acid, binders, eg. starch or gelatin, lubricants, eg, magnesium stearate or talc, and/
or agents for achieving a depot effect, eg. carboxypoly-methylene, carboxymethylcellulose, cellulose acetate-phthalate or polyvinyl acetate. The tablets can also 11465~1 i _ 14 - O.Z. 0050/033879 consist of a plurality of layers.
Correspondingly, dragees can be prepared by coating c~res, prepared similarly to the tablets, with agents conventionally used in dragee coatings, eg. col-lidone or shellac, gum arabic, talc, titanium dioxide or sugar, The dragee coatings can also consist of a plurality of layers, and the auxiliaries mentioned in connection with tablets may be used.
Suspensions containing the active compounds to iO be used according to the in~ention may in addition con-tain flavoring agents, eg. saccharin, cyclamate or sugar, and, for example, aroma substances, eg. vanillin or orange extract. They may in addition contain sus-pending agents, eg, sodium carboxymethylcellulose, or protective agents, e;g. p-hydroxy~
benzoates. Capsules containing the active compounds may be prepared, for example, by mixing the active com-pound with an inert carrier, such as lactose or sorbitol, and enclosing the mixture in gelatin capsules.
For external application, pastes, ointments, gels, creams, lotions, powders, solutions, emulsions and sprays are particularly suitable.
In ointments, pastes, creams and gels, the act-ive compound or compounds may be accompanied by the conventional carriers, for example animal and vegetable fats, waxesS paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc or zinc oxide, or mixtures of these materials ~4.~ 551 - 15 - o. z . oo50/033879 - In powders and sprays, the act~ve compounds may be accompanied by the conventional carriers, eg, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powders, or mixtures of these materials.
Sprays may in addition contain the conventional propel-lants, eg. chlorofluorohydrocarbons.
In solutions and emulsions, the acti~e compound or compounds may be accompanied by the conventional car-riers, such as solvents, solubilizing agents and e~ulsi-fiers, eg, water, ethyl - alcohol ,.isopropy1 alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, l,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol-formal, tetrahydrofurfuryl aloohol, polyethylene glycols or fatty acid esters of sorbitan, or mixtures of these materials.
l, Cis- and trans-3-(4-tert -butyl-cyclohex-l-yl)-2-methyl-l-(3~-methyl-l-piperidino~-propane a) Synthesis of the aromatic amine-306 g of 3-(p-tert,-butyl-phenyl)-2-methyl-propanal are introduced into a 2 liter three-neck flask and 72,5 g of 98Yo strength formic acid are added dropwise, 149 g of ~-methylpiperidine are then introduced dropwise over three hours, during which the temperature rises from 25C to above 50C, The reaction mixture is then refluxed for 12 hours, during which C02 is evolved.
- ~146S51 - 16 - o.Z. 0050/033879 After completion of the reaction, the mixture is sub~ected to fractional distillation under reduced pressure. After first runnings of 47 g, passing over at up to 130C under 0.2 mm Hg, 3-(p-tert.-butyl-phenyl)-2-methyl-1-(3'-methyl-1~-piperidino)-propane distils at 130 - 1~3C under a pressure o~ 0.2 mm Mg.
355 g are obtained, corresponding to a yield of 82,4%, based on aldehyde employed.
b) Hydrogenation to the cyclohexane derivative:
309 g of 3-(p-tert.-butylphenyl)-2-methyl-1-~3'-methyl-1'-piperidino)-propane in 1,000 g of dioxane are hydrogenated in the presence of 0.5 g of Ru203-hydrate in a 3 liter rolling autocla~e. Using a hydrogen pressure of 100 bar, at 120C, no further hydro-gen is absorbed after 3 hours. The temperature is then raised to 140C and the H2 pressure to 120 bar, whereupon a pressure drop of 35 bar is found over 12 hours; after resetting the hydrogen pressure to 160 bar and the temperature to 160C, a further pressure drop of ; bar is recorded over a further 10 hours.
On raising the hydrogen pressure to 160 bar and the temperature to 180C, there is no further hydro-gen absorption.
c) Fractional distillation:
m e reaction mixture, amounting to 1,310 g, is sub~ected to ~ractional distillation through a perfor-ated tray column with 10 trays, under a pressure of 10 mm Hg After distilling off the dioxane.the follow-ing fractions are obtained, using a reflux ratio of . - 17 - o.Z. 0050/033879 - 1 : 5:
1. up to 185C - 27 g, containing 85% of cis-compound and 10~ of trans-compound (the remaining 5% constitutes first runnings) 2. at 185C - 114 g, containing 75% of cis-compound and 25% of trans-compound 3, up to 186C - 60 g, containing 40~ of cis-compound and 60% of trans-compound
4. up to 187C - 55 g, containing 30% of cis-compound and 70~ of trans-compound, me distillation residue of 40 g is subjected to molecular dist~llation at 10 mm Hg and 187C, 38 g ..
of a product containing 92% of trans-compound and only 8~ of cis-compound are obtained. 2 g of distilla-tlon residue remain, The cis-trans ratio is in each case determined by ga.q chromatography, 504 g of the 3-(4'-tert,-butyl-cyclohex-1l-yl)-2-methyl-1-(3'-methyl-1'-piperidino)-propane prepared by the method described above and containing 54% of cis- and 46% of trans-cyclohexane derivative, -- - -are -- - fractionated using a column with 20 perfor-ated trays, The re'flux ratio is set to 1 : 3.
70 g of first runnings pass over at temperatures up to 192C, Thereafter, the following fractions are 1~655~.
~ 18 - O.Z. 0050/033879 obtained:
1, up to 197C/28 mm Hg - 13 g, containing 85% of cis-compound and 3% of trans-compound (the remaining 12% is first runnings) 2. up to 198C/26 mm Hg - 52 g, containing 93~ of cis-compound and 7% of trans-compound 3. up to 197C/25 mm Hg - 87 g - containing 90% of cis-compound and 10% of trans-compound 4. up to 192C/22 mm Hg - 82 g, containing 85~ of cis-compound and 15~ of trans-compound
of a product containing 92% of trans-compound and only 8~ of cis-compound are obtained. 2 g of distilla-tlon residue remain, The cis-trans ratio is in each case determined by ga.q chromatography, 504 g of the 3-(4'-tert,-butyl-cyclohex-1l-yl)-2-methyl-1-(3'-methyl-1'-piperidino)-propane prepared by the method described above and containing 54% of cis- and 46% of trans-cyclohexane derivative, -- - -are -- - fractionated using a column with 20 perfor-ated trays, The re'flux ratio is set to 1 : 3.
70 g of first runnings pass over at temperatures up to 192C, Thereafter, the following fractions are 1~655~.
~ 18 - O.Z. 0050/033879 obtained:
1, up to 197C/28 mm Hg - 13 g, containing 85% of cis-compound and 3% of trans-compound (the remaining 12% is first runnings) 2. up to 198C/26 mm Hg - 52 g, containing 93~ of cis-compound and 7% of trans-compound 3. up to 197C/25 mm Hg - 87 g - containing 90% of cis-compound and 10% of trans-compound 4. up to 192C/22 mm Hg - 82 g, containing 85~ of cis-compound and 15~ of trans-compound
5, up to 196C/22 mm Hg - 81 g, containing 80% of cis-compound and 20% of trans-compound
6. up to 202C/28 mm Hg - 87 g, containing 30% of cis-compound and 70% of trans-compound
7. up to 196C/22 mm Hg - 73 g, containing 97% of trans-compound and 3~ of cis-compound.
The distillation residue, amounting to 27 ~, is sub~ected to - -- _- distillation. 24 g of a pro-duct containing more than 98~ of trans-compound are obtained, m e further purification of the first fraction and/or last fraction to give the pure cis-form or trans-form is effected, in the case of the cis-compound, by recrystallizing the hydrobromide from acetic acid/water, and,in the case of the trans-compound,with the aid of hydrogen chloride in methanol.
- 19 - O. Z . ooso/033s7s d) Preparation of the HBr salt of the pure cis-form:
25 g of the first fraction, obtained above, and 20 g of aqueous 48~o strength hydrobromic acid are mixed.
50 g of acetic acid are then added and the entire crystalline product is dissolved by heating. On cooling, the hydrobromide of the cis-form crystallizes out. ~he NMR analysis confirms that the product is the pure cis-form. 28 g, of melting point 210C, are obtained.
Calc.: 64 15%, found: 64.50/o;- H calc.: 10.77%, - found: 10,3h; N calc.: 3 74%, found: 3.60h;
Br calc.: 20.34~, found: 20. 6h.
e) Preparation of the HCl salt o~ the pure trans-form:
60 g of hydrogen chloride are added to 35 g o~
the above fraction 7 in methanol On cooling, 28 g of hydrochloride, melting at 168C, crystallize out.
me NMR analysi~ confirms that the compound is the trans-form, 2) Ci8- and trans-3-(4'-tert,-butyl-cyclohex-1'-yl)-2-methyl-1-(3',5' -dimethyl-1'-piperidino)-propane a) 361 g of 3-(p-tert -butylphenyl)-2-methyl-propanal are reacted with 200 g of 3,5-dimethyl-piperi-dine and 86 g of 98h strength formic acid, by the method de~cribed in Example 1, The amine is purified by fractional distillation through a 10-tray ~!
column ~-- under a pressure of 0 2 mm Hg. 406 g of pure amine pass over at 136C.
b) Hydrogenation to the cyclohexane compound:
70 g of 3-(p-tert -butylphenyl)-2-methyl-- 114655:1 - 20 - O.Z. oo501033879 1-(3l,5 t -dimethyl-l~-piperidino)-propane and 80 g of d~oxaneare mixed in a shaken autoclave, having .
a~ ~se~ul volume of 250 ml. - 0.~
g of ruthenium oxide hydrate is added as the hydrogena-tion catalyst. The reaction is carried out under 100 bar of hydrogen at 120C, and over 37 hours an amount o~ hydrogen equivalent to 358 bar has to be forced in to maintain the pressure at 100 bar. ~
Fractional distillation of the 139 g o~ reac-t~on product gives 64 g o~ the cyclohexane derivative,~hich distils at 136 - 146C under a pressure of 3 mm Hg. Analysis by gas chromatography shows that the product is a mixture of the cis- and trans-isomers of the cyclohexane derivative, c) Fractional distillation:
562 g of the aromatic amine, which has been hydrogenated in 1,000 g of dioxane,with the aid of Ru203.hydrate, at 140 bar hydrogen pressure and 120C
over 20 hours are sepa~rated ~ fractionation.t~rough a column with 10 perforated trays, using a re~lux ratio o~ 1 : 5, as described in Example 1.
The cis-cyclohexane derivative, in more than 90% purity, passes over at 124 - 125C under a pressure of 0.1 mm Hg. The trans-cyclohexane derivative, in - 1~465s~
- 21 _ o. z . oo50/033879 more than 90% purity, passes over at 129 - 131C
under the same pressure , Repetition of the fractional distillation through an 80 cm long column packed with silver gauze spirals, under a pressure of 12 - 13 mm Hg, gives 154 g of ~ore than 90% pure cis-compound. Intermediate runnings of 136 g consist of a 1 : 1 mix*ure of the cis-and trans-cyclohexane derivative. 98 g of more than 90% pure trans-cyclohexane derivative are then obtained.
The intermediate runnings are re-fractionated.
Only a very small amount of residue is obtained; thus, only 2 g of higher-boiling constituents are formed on fractional distillation of 390 g of the Ci5- and trans-isomer mixture. Under a pressure of 12 mm Hg, the cis-derivative passes over at 193 - 195C and the en~iched trans-product at 199 - 200C.
d) Crystallization o~ the HCl salt of the pure cis-compound:
20 g of the more than 90~ pure cis-product are taken up in 25 g of a solution of hydrogen chloride in methanol, causing the temperature to rise almost to the boil On cooling~ 12 g of hydrochloride crystallize - 22 - O.Z. 0050/033879 out, The melting point of the recrystallized cis-cyclohexane derivative (? hydrochloride) is 240C, A
sample of the salt is decomposed with KOH and gas chromatography of the product shows that it consists of trans-free cis-compound.
e) Crystallization of the HCl-salt of the pure-t-rans-c~mp~und: -20 g of the more than 90% pure trans-compound are taken up in 30 g of a solution of hydrogen chloride in ethanol, On cooling, the hydrochloride of the pure trans-compound, melting point 202C, crystallizes out, 13 g are obtained. The free base, which is obtained by decomposing a sample of the salt,is examined by gas chromatography and found to be cis-free trans-compound, The NMR analyses of the two crystalline products confirm the results of the gas-chromatographic analysis, 3) Cis- and trans-3-(4~-tert,-butyl-cyclohex-1~-yl)-2-methyl-1-(2',6'-cis-dimethyl-morpholyl)-propane a) 3-(p-tert,-Butylphenyl)-2-methyl-1-(2',6'-cis-dimethyl-morpholyl)-propane is prepared, using the method described in Example 1, by reaction of 3-(p-tert,-butyl-phenyl)-2-methyl-propanal with 2,6-cis-dimethyl-morpholine and formic acid, The aromatic amine is purified by distillation, It passes over at 170 -175~C/3,0 mm Hg, b) Hydrogenation to the cyclohexane compound:
720 g of the morpholine derivative described above are mixed with 500 g of dioxane,and 0.5 g of 114655i - 23 - o.z 0050/033879 - ruthenium oxide hydrate is added as a hydrogenation catalyst. The hydrogenation is carried out under a hydrogen pressure of 120 bar, at 140C, in a 2.6 liter rolling autoclave Over 24 hours, a total of 130 bar of hydrogen is additionally forced in ~o maintai~ the- -pressure~at 120 ~ar.
c) Fract~onal distillation:
623 g of the resulting cis- and trans-isomer mixture, containing 60% of cis- and 40% of trans-compound, are fractionated in an 80 cm column, packedwith silver gauze spirals, under a pressure of 3.0 mm Hg, with a reflux ratio set to 1 : 5. ~ The cis-compound passes over at 144 - 145C/3.0 mm Hg. In~
the first three fractions, each of about 70 g, the con-centration of cis-compound is more than 90%. The la-~t three fractions, of 71 g, 54 g and 38 g, contain the enriched trans-compound, at a concentration of more than 85%, d) Crystallization of the HCl salts of..t~e:.-pure cis- and trans-compounds :
Using the method described in Examples 1 and 2, the pure hydrochloride of the cis-compound can be obtained by employing a solution of hydrogen chloride in ethanol Melting point 161C
m e pure trans-compound forms a hydrochloride o~ melting point 199C
Gas-chromatographic analysis of the free bases 1~46551 - 24 - O.Z. 0050/033879 prepared from each of the salts by reaction with KOH
confirms the purity of the bases. The cis-cyclohex-ane derivative -- purified -~ in this way contains less than 0.5~ of trans-product; the trans-product con-tains less than 1% of cis-compound. NMR analysis confirms the findings of gas-chromatographic analysis.
Examples of pharmaceutical formulations:
1. Example of tablets 1, Active compound 200 mg - 10 2. Polyvinylpyrrolidone (mean molecular weight 25,000) 20 mg 3. Polyethylene glycol (mean mo~ecular weight 4,000) 14 mg 4, Hydroxypropylmethylcellulose 40 mg 5, Talc 4 mg 6, Magnesium stearate 2 m~
280 mg The active compound is moistened with a l~/o strength aqueous solution of polyvinylpyrrolidone and the mixture is forced through a sieve of l.O mm mesh size and dried at 50C. The resulting granules are mixed with polyethylene glycol (mean molecular weight 4,000), hydroxypropylmethylcellulose, talc and magnesium stearate and the mixture is pressed to give tablets each weighing 280 mg.
~146551 - 25 - O.Z. 0050/033~79 - 2, Example of dragees 1, Active compound 150 mg 2, Lactose 60 mg 3, Corn starch 30 mg 4, Polyvinylpyrrolidone 4 mg 5, Magnesium stearate 1 m~
245 mg T,he mixture of the active compound, lactose and corn starch is moistened with an 8% strength aqueous solution of the polyvinylpyrrolidone, granulated by forcing it through a 1.5 mm sieve, dried at 50C and forced through a 1.0 mm sieYe. The resulting gran-ules are mixed with magnesium stearate and the mixture is pressed to form dragee cores, These cores are provided, in a conventional manner, with a coating essentially consisting of sugar and talc, 3. Example of a cream containing 2yo of active compound:
1, Active compound 2,0 g 2. ~lycerol monostearate 10.0 g 3. Ce.tyl alcohol 5.0 g '' 4. Polyethylene glycol 400 stearate 10.0 g 5, Polyethylene glycol-sorbitan monostearate 10.0 g 6, Propylene glycol 6,0 g 7. Methyl p-hydroxybenzoate 0.2 g
The distillation residue, amounting to 27 ~, is sub~ected to - -- _- distillation. 24 g of a pro-duct containing more than 98~ of trans-compound are obtained, m e further purification of the first fraction and/or last fraction to give the pure cis-form or trans-form is effected, in the case of the cis-compound, by recrystallizing the hydrobromide from acetic acid/water, and,in the case of the trans-compound,with the aid of hydrogen chloride in methanol.
- 19 - O. Z . ooso/033s7s d) Preparation of the HBr salt of the pure cis-form:
25 g of the first fraction, obtained above, and 20 g of aqueous 48~o strength hydrobromic acid are mixed.
50 g of acetic acid are then added and the entire crystalline product is dissolved by heating. On cooling, the hydrobromide of the cis-form crystallizes out. ~he NMR analysis confirms that the product is the pure cis-form. 28 g, of melting point 210C, are obtained.
Calc.: 64 15%, found: 64.50/o;- H calc.: 10.77%, - found: 10,3h; N calc.: 3 74%, found: 3.60h;
Br calc.: 20.34~, found: 20. 6h.
e) Preparation of the HCl salt o~ the pure trans-form:
60 g of hydrogen chloride are added to 35 g o~
the above fraction 7 in methanol On cooling, 28 g of hydrochloride, melting at 168C, crystallize out.
me NMR analysi~ confirms that the compound is the trans-form, 2) Ci8- and trans-3-(4'-tert,-butyl-cyclohex-1'-yl)-2-methyl-1-(3',5' -dimethyl-1'-piperidino)-propane a) 361 g of 3-(p-tert -butylphenyl)-2-methyl-propanal are reacted with 200 g of 3,5-dimethyl-piperi-dine and 86 g of 98h strength formic acid, by the method de~cribed in Example 1, The amine is purified by fractional distillation through a 10-tray ~!
column ~-- under a pressure of 0 2 mm Hg. 406 g of pure amine pass over at 136C.
b) Hydrogenation to the cyclohexane compound:
70 g of 3-(p-tert -butylphenyl)-2-methyl-- 114655:1 - 20 - O.Z. oo501033879 1-(3l,5 t -dimethyl-l~-piperidino)-propane and 80 g of d~oxaneare mixed in a shaken autoclave, having .
a~ ~se~ul volume of 250 ml. - 0.~
g of ruthenium oxide hydrate is added as the hydrogena-tion catalyst. The reaction is carried out under 100 bar of hydrogen at 120C, and over 37 hours an amount o~ hydrogen equivalent to 358 bar has to be forced in to maintain the pressure at 100 bar. ~
Fractional distillation of the 139 g o~ reac-t~on product gives 64 g o~ the cyclohexane derivative,~hich distils at 136 - 146C under a pressure of 3 mm Hg. Analysis by gas chromatography shows that the product is a mixture of the cis- and trans-isomers of the cyclohexane derivative, c) Fractional distillation:
562 g of the aromatic amine, which has been hydrogenated in 1,000 g of dioxane,with the aid of Ru203.hydrate, at 140 bar hydrogen pressure and 120C
over 20 hours are sepa~rated ~ fractionation.t~rough a column with 10 perforated trays, using a re~lux ratio o~ 1 : 5, as described in Example 1.
The cis-cyclohexane derivative, in more than 90% purity, passes over at 124 - 125C under a pressure of 0.1 mm Hg. The trans-cyclohexane derivative, in - 1~465s~
- 21 _ o. z . oo50/033879 more than 90% purity, passes over at 129 - 131C
under the same pressure , Repetition of the fractional distillation through an 80 cm long column packed with silver gauze spirals, under a pressure of 12 - 13 mm Hg, gives 154 g of ~ore than 90% pure cis-compound. Intermediate runnings of 136 g consist of a 1 : 1 mix*ure of the cis-and trans-cyclohexane derivative. 98 g of more than 90% pure trans-cyclohexane derivative are then obtained.
The intermediate runnings are re-fractionated.
Only a very small amount of residue is obtained; thus, only 2 g of higher-boiling constituents are formed on fractional distillation of 390 g of the Ci5- and trans-isomer mixture. Under a pressure of 12 mm Hg, the cis-derivative passes over at 193 - 195C and the en~iched trans-product at 199 - 200C.
d) Crystallization o~ the HCl salt of the pure cis-compound:
20 g of the more than 90~ pure cis-product are taken up in 25 g of a solution of hydrogen chloride in methanol, causing the temperature to rise almost to the boil On cooling~ 12 g of hydrochloride crystallize - 22 - O.Z. 0050/033879 out, The melting point of the recrystallized cis-cyclohexane derivative (? hydrochloride) is 240C, A
sample of the salt is decomposed with KOH and gas chromatography of the product shows that it consists of trans-free cis-compound.
e) Crystallization of the HCl-salt of the pure-t-rans-c~mp~und: -20 g of the more than 90% pure trans-compound are taken up in 30 g of a solution of hydrogen chloride in ethanol, On cooling, the hydrochloride of the pure trans-compound, melting point 202C, crystallizes out, 13 g are obtained. The free base, which is obtained by decomposing a sample of the salt,is examined by gas chromatography and found to be cis-free trans-compound, The NMR analyses of the two crystalline products confirm the results of the gas-chromatographic analysis, 3) Cis- and trans-3-(4~-tert,-butyl-cyclohex-1~-yl)-2-methyl-1-(2',6'-cis-dimethyl-morpholyl)-propane a) 3-(p-tert,-Butylphenyl)-2-methyl-1-(2',6'-cis-dimethyl-morpholyl)-propane is prepared, using the method described in Example 1, by reaction of 3-(p-tert,-butyl-phenyl)-2-methyl-propanal with 2,6-cis-dimethyl-morpholine and formic acid, The aromatic amine is purified by distillation, It passes over at 170 -175~C/3,0 mm Hg, b) Hydrogenation to the cyclohexane compound:
720 g of the morpholine derivative described above are mixed with 500 g of dioxane,and 0.5 g of 114655i - 23 - o.z 0050/033879 - ruthenium oxide hydrate is added as a hydrogenation catalyst. The hydrogenation is carried out under a hydrogen pressure of 120 bar, at 140C, in a 2.6 liter rolling autoclave Over 24 hours, a total of 130 bar of hydrogen is additionally forced in ~o maintai~ the- -pressure~at 120 ~ar.
c) Fract~onal distillation:
623 g of the resulting cis- and trans-isomer mixture, containing 60% of cis- and 40% of trans-compound, are fractionated in an 80 cm column, packedwith silver gauze spirals, under a pressure of 3.0 mm Hg, with a reflux ratio set to 1 : 5. ~ The cis-compound passes over at 144 - 145C/3.0 mm Hg. In~
the first three fractions, each of about 70 g, the con-centration of cis-compound is more than 90%. The la-~t three fractions, of 71 g, 54 g and 38 g, contain the enriched trans-compound, at a concentration of more than 85%, d) Crystallization of the HCl salts of..t~e:.-pure cis- and trans-compounds :
Using the method described in Examples 1 and 2, the pure hydrochloride of the cis-compound can be obtained by employing a solution of hydrogen chloride in ethanol Melting point 161C
m e pure trans-compound forms a hydrochloride o~ melting point 199C
Gas-chromatographic analysis of the free bases 1~46551 - 24 - O.Z. 0050/033879 prepared from each of the salts by reaction with KOH
confirms the purity of the bases. The cis-cyclohex-ane derivative -- purified -~ in this way contains less than 0.5~ of trans-product; the trans-product con-tains less than 1% of cis-compound. NMR analysis confirms the findings of gas-chromatographic analysis.
Examples of pharmaceutical formulations:
1. Example of tablets 1, Active compound 200 mg - 10 2. Polyvinylpyrrolidone (mean molecular weight 25,000) 20 mg 3. Polyethylene glycol (mean mo~ecular weight 4,000) 14 mg 4, Hydroxypropylmethylcellulose 40 mg 5, Talc 4 mg 6, Magnesium stearate 2 m~
280 mg The active compound is moistened with a l~/o strength aqueous solution of polyvinylpyrrolidone and the mixture is forced through a sieve of l.O mm mesh size and dried at 50C. The resulting granules are mixed with polyethylene glycol (mean molecular weight 4,000), hydroxypropylmethylcellulose, talc and magnesium stearate and the mixture is pressed to give tablets each weighing 280 mg.
~146551 - 25 - O.Z. 0050/033~79 - 2, Example of dragees 1, Active compound 150 mg 2, Lactose 60 mg 3, Corn starch 30 mg 4, Polyvinylpyrrolidone 4 mg 5, Magnesium stearate 1 m~
245 mg T,he mixture of the active compound, lactose and corn starch is moistened with an 8% strength aqueous solution of the polyvinylpyrrolidone, granulated by forcing it through a 1.5 mm sieve, dried at 50C and forced through a 1.0 mm sieYe. The resulting gran-ules are mixed with magnesium stearate and the mixture is pressed to form dragee cores, These cores are provided, in a conventional manner, with a coating essentially consisting of sugar and talc, 3. Example of a cream containing 2yo of active compound:
1, Active compound 2,0 g 2. ~lycerol monostearate 10.0 g 3. Ce.tyl alcohol 5.0 g '' 4. Polyethylene glycol 400 stearate 10.0 g 5, Polyethylene glycol-sorbitan monostearate 10.0 g 6, Propylene glycol 6,0 g 7. Methyl p-hydroxybenzoate 0.2 g
8, Demineralized water to 100,0 g The very finely powdered active compound is sus-pended in the propylene glycol and the suspension is stirred into a melt, at 65C, of the glycerol 11~6551 - 26 _ O.Z. 0050/033879 monostearate, cetyl alcohol, polyethylene glycol 400 stearate and polyethylene glycol sorbitan monostearate.
A solution of the methyl p-hydroxybenzoate in water, at 70C, is emulsified in this mixture. When the cream has cooled, it is homogenized in a colloid mill, and packed in tubes.
4. Example of a powder containing 2~ of active compound 1, Active compound 2.0 g 2, Zinc oxide 10.0 g 3, Magnesium oxide 10.0 g 4. Highly disperse silicon oxide2.5 g 5, Magnesium stearate 1,0 g 6, Talc 75.5 g The active compound is micronized on an air-jet mill and homogeneously mixed with the other constituents.
The mixture is forced through a No. 7 sieve and i8 packed in polyethylene containers having a sprinkler top.
A solution of the methyl p-hydroxybenzoate in water, at 70C, is emulsified in this mixture. When the cream has cooled, it is homogenized in a colloid mill, and packed in tubes.
4. Example of a powder containing 2~ of active compound 1, Active compound 2.0 g 2, Zinc oxide 10.0 g 3, Magnesium oxide 10.0 g 4. Highly disperse silicon oxide2.5 g 5, Magnesium stearate 1,0 g 6, Talc 75.5 g The active compound is micronized on an air-jet mill and homogeneously mixed with the other constituents.
The mixture is forced through a No. 7 sieve and i8 packed in polyethylene containers having a sprinkler top.
Claims (11)
1. A process for the preparation of pure trans-isomers of 1,4-disubstituted cyclohexane derivatives selected from the group consisting of: -trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3'-methyl-1'-piperidino)-propane;
trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3',5'-dimethyl-1'-peperidino)-propane and trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(2',6'-cis-dimethylmorpholino)-propane, from the cis-trans mixtures obtained by hydrogenating the corresponding 1,4-disubstituted phenyl compound in the presence of a catalytic solvent, wherein, after distilling off the solvent used for the hydrogenation, the isomer mixture is enriched to a content, of trans-compound, of more than 85% by fractional distillation in a column with from 10 to 100 theoretical plates, under a reflux ratio of from 1 : 1 to 1 : 100, a pressure at the column top of 0.05 - 50 mm Hg, at the temperatures which result from these conditions during the distillation, the enriched product is converted to an addition salt with a hydrohalic acid, and the salt of the pure trans-isomer is allowed to crystallize out from an organic solvent.
trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3',5'-dimethyl-1'-peperidino)-propane and trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(2',6'-cis-dimethylmorpholino)-propane, from the cis-trans mixtures obtained by hydrogenating the corresponding 1,4-disubstituted phenyl compound in the presence of a catalytic solvent, wherein, after distilling off the solvent used for the hydrogenation, the isomer mixture is enriched to a content, of trans-compound, of more than 85% by fractional distillation in a column with from 10 to 100 theoretical plates, under a reflux ratio of from 1 : 1 to 1 : 100, a pressure at the column top of 0.05 - 50 mm Hg, at the temperatures which result from these conditions during the distillation, the enriched product is converted to an addition salt with a hydrohalic acid, and the salt of the pure trans-isomer is allowed to crystallize out from an organic solvent.
2. Process for the preparation of pure trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3'-methyl-1'-piperidino)-propane, from the cis-trans mixture obtained by hydrogenating 3-(p-tert.-butylphenyl)-2-methyl-1-(3'-methyl-1'-piperidino)-propane in the presence of a catalytic solvent, wherein after distilling off the solvent, the isomer mixture is enriched to a content, of trans-compound, of more than 85% by fractional distillation in a column with from 10 to 100 theoretical plates, under a reflux ratio of from 1 : 1 to 1 : 100, a pressure at the column top of 0.05-50 mm Hg, at the temperatures which result form these conditions during the distillation, the enriched product is converted to an addition salt with a hydrohalic acid, and the salt of the pure trans-isomer is allowed to crystallize out from an organic solvent.
3. Process for the preparation of pure trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3',5'-dimethyl-1'-piperidino)-propane, from the cis-trans mixture obtained by hydrogenating 3-(p-tert.-butylphenyl)-2-methyl-1-(3',5'-dimethyl-1'-piperidino)-propane in the presence of a catalytic solvent, the isomer mixture is enriched to a content, of trans-compound, of more than 85% by fractional distillation in a column with from 10 to 100 theoretical plates, under a reflux ratio of from 1 : 1 to 1 : 100, a pressure at the column top of 0.05-50 mm Hg, at the temperatures which result from these conditions during the distillation, the enriched product is converted to an addition salt with a hydrohalic acid, and the salt of the pure trans-isomer is allowed to crystallize out from an organic solvent.
4. Process for the preparation of pure trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(2',6'-cis-dimethyl-morpholino)-propane, from the cis-trans mixture obtained by hydrogenating 3-(p-tert.-butylphenyl)-2-methyl-1-(2',6'-cis-dimethyl-morpholino)-propane in the presence of a catalytic solvent, the isomer mixture is enriched to a content, of trans-compound, of more than 85% by fractional distillation in a column with from 10 to 100 theoretical plates, under a reflux ratio of from 1 : 1 to 1 : 100, a pressure at the column top of 0.05-50 mm Hg, at the temperatures which result from these conditions during the distillation, the enriched product is converted to an addition salt with a hydrohalic acid, and the salt of the pure trans-isomer is allowed to crystallize out from an organic solvent.
5. A process for the production of the pure trans-compound as claimed in claim 2, wherein the fractional distil-lation is carried out in a column with 20 to 40 theoretical plates under from 2 to 20 mm Hg, with a reflux ratio of from 1 : 3 to 1 : 10, these conditions resulting in temperatures of from 183 to 186° C.
6. A process for the production of the pure trans-compound as claimed in claim 3, wherein the fractional distillation is carried out in a column with 20 to 40 theoretical plates under from 2 to 20 mm Hg, with a reflux ratio of from 1 : 3 to 1 : 10, these conditions resulting in temperatures of from 193 to 200° C.
7. A process for the production of the pure trans-compound as claimed in claim 4, wherein the fractional distillation is carried out in a column with 20 to 40 theoretical plates under from 2 to 20 mm Hg, with a reflux ratio of from 1 : 3 to 1 : 10, these conditions resulting in temperatures of from 203 to 208° C.
8. Pure trans-isomers of 1,4-disubstituted cyclohexane derivatives selected from the group consisting of: -trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3'-methyl-1'-piperidino)-propane; trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3',5'-dimethyl-1'-piperidino)-propane and trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(2',6'-cis-dimethylmorpholino)-propane, whenever obtained by a process as claimed in claim 1 or its obvious chemical equivalents.
9. Pure trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3'-methyl-1'-piperidino)-propane whenever obtained by a process as claimed in claim 2 or its obvious chemical equivalents.
10. Pure trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(3',5'-dimethyl-1'-piperidino)-propane, whenever obtained by a process as claimed in claim 3 or its obvious chemical equivalents.
11. Pure trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2-methyl-1-(2',6'-cis-dimethylmorpholino)-propane, whenever obtained by a process as claimed in claim 4 or its obvious chemical equivalents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2921221.3 | 1979-05-25 | ||
| DE19792921221 DE2921221A1 (en) | 1979-05-25 | 1979-05-25 | TRANS-3- (4'-TERT.-BUTYL-CYCLOHEXYL-1 ') - 2-METHYL-1- (3'-METHYLPIPERIDINO, 3', 5'-DIMETHYLPIPERIDINO AND 2 ', 6'-DIMETHYLMORPHOLINO) -PROPAN, METHOD FOR THEIR PREPARATION AND ANTIMYCOTIC AGENTS CONTAINING THEM |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1146551A true CA1146551A (en) | 1983-05-17 |
Family
ID=6071686
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000351285A Expired CA1146551A (en) | 1979-05-25 | 1980-05-05 | Trans-3-(4'-tert.-butyl-cyclohex-1'-yl)-2- methyl-1-(3'-methylpiperidino,3',5'- dimethylpiperidino and 2',6'-dimethylmorpholino)- propane, their preparation in a pure form, anti-mycoti c agents containing these compounds, and their use |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0019764A1 (en) |
| JP (1) | JPS55157567A (en) |
| AU (1) | AU5871080A (en) |
| CA (1) | CA1146551A (en) |
| CS (1) | CS214831B2 (en) |
| DD (1) | DD150893A5 (en) |
| DE (1) | DE2921221A1 (en) |
| DK (1) | DK226080A (en) |
| ES (1) | ES491793A0 (en) |
| FI (1) | FI801364A (en) |
| HU (1) | HU179864B (en) |
| IL (1) | IL59956A0 (en) |
| NO (1) | NO801556L (en) |
| ZA (1) | ZA803108B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3001581A1 (en) * | 1980-01-17 | 1981-07-23 | Basf Ag, 6700 Ludwigshafen | SUBSTITUTED N- (3 (4'-TERT-BUTYL-CYCLOHEX-1'-EN1'YL) -2-METHYL-PROPYL-1) -CYCLOALKALAMINE, THEIR PRODUCTION AND THEIR USE AS FUNGICIDES |
| DE3225879A1 (en) * | 1982-07-10 | 1984-01-12 | Basf Ag, 6700 Ludwigshafen | TRANS-3- (4'-TERT.-BUTYLCYCLOHEXYL-1 ') - 2-METHYL-1-DIALKYL-AMINOPROPANE, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCT |
| DE3321712A1 (en) * | 1983-06-16 | 1984-12-20 | Basf Ag, 6700 Ludwigshafen | 2,6-TRANS-DIMETHYLMORPHOLINE DERIVATIVES AND FUNGICIDES CONTAINING THEM AND METHOD FOR CONTROLLING FUNGI |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE614214A (en) * | 1961-02-22 | |||
| DE1214471B (en) * | 1965-01-16 | 1966-04-14 | Basf Ag | Fungicide for crop protection |
| AT354187B (en) * | 1976-11-22 | 1979-12-27 | Hoffmann La Roche | FUNGICIDE AGENT |
| DE2657476A1 (en) * | 1976-12-18 | 1978-06-22 | Basf Ag | MORPHOLINE DERIVATIVES |
| DE2830127A1 (en) * | 1978-07-08 | 1980-01-17 | Basf Ag | N-ARYL PROPYL SUBSTITUTED CYCLIC AMINES |
| DE2965247D1 (en) * | 1978-08-08 | 1983-05-26 | Hoffmann La Roche | Synthesis of phenyl-propyl morpholine and piperidine derivatives |
-
1979
- 1979-05-25 DE DE19792921221 patent/DE2921221A1/en not_active Withdrawn
-
1980
- 1980-04-28 FI FI801364A patent/FI801364A/en not_active Application Discontinuation
- 1980-04-30 IL IL59956A patent/IL59956A0/en unknown
- 1980-05-05 CA CA000351285A patent/CA1146551A/en not_active Expired
- 1980-05-08 EP EP80102509A patent/EP0019764A1/en not_active Withdrawn
- 1980-05-22 JP JP6721680A patent/JPS55157567A/en active Pending
- 1980-05-22 DD DD80221320A patent/DD150893A5/en unknown
- 1980-05-23 HU HU80801307A patent/HU179864B/en unknown
- 1980-05-23 DK DK226080A patent/DK226080A/en unknown
- 1980-05-23 NO NO801556A patent/NO801556L/en unknown
- 1980-05-23 ZA ZA00803108A patent/ZA803108B/en unknown
- 1980-05-23 AU AU58710/80A patent/AU5871080A/en not_active Abandoned
- 1980-05-23 CS CS803655A patent/CS214831B2/en unknown
- 1980-05-23 ES ES491793A patent/ES491793A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| ES8102095A1 (en) | 1980-12-16 |
| CS214831B2 (en) | 1982-06-25 |
| DD150893A5 (en) | 1981-09-23 |
| DE2921221A1 (en) | 1980-12-11 |
| AU5871080A (en) | 1980-11-27 |
| IL59956A0 (en) | 1980-06-30 |
| DK226080A (en) | 1980-11-26 |
| ES491793A0 (en) | 1980-12-16 |
| FI801364A (en) | 1980-11-26 |
| ZA803108B (en) | 1981-06-24 |
| NO801556L (en) | 1980-11-26 |
| EP0019764A1 (en) | 1980-12-10 |
| HU179864B (en) | 1982-12-28 |
| JPS55157567A (en) | 1980-12-08 |
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