DE1468377C - Process for the preparation of 4,4 diphenylcyclohexylamene - Google Patents

Description

It has been found that 4,4-diphenylcyclohexylamine of the general formula I, which may be unsaturated in the 2,3-position, and those in the 4-position Phenyl radicals can be substituted by a p-alkyl group with 1 to 4 carbon atoms development of the cyclohexane ring may have a double bond),

R ¹ -

wherein X = H, -NO ₂ ; = NOH; = NR ³ ; H, -N = R '; H, -NR ² acyl;

25th

and where R ¹ = H, alkyl or alkenyl each with up to 4 carbon atoms, R ² = H or alkyl with 1 to 4 carbon atoms and R ³ = H, alkyl or alkenyl each with up to 8 carbon atoms, Cycloalkyl with 3 to 8 carbon atoms or aralkyl whose aliphatic part contains 1 to 4 carbon atoms and whose aromatic part can be substituted by a methylenedioxy group or one or more times by alkyl with 1 to 4 carbon atoms, methoxy or hydroxyl, means and in which the radicals R ² and R ^{3 can} also form a pyrrolidine ring together with the nitrogen atom, and their acid addition salts and quaternary ammonium salts have valuable pharmacological properties. In particular, there are spasmolytic, cholinolytic and coronary flow-increasing effects. In addition, blood pressure-increasing effects were also bepb-; respect. For example, l-isopropylamino-4,4-diphenylcyclohexane and l- (N-methyl-N-isopropylamino) -4,4-diphenylcyclohexane (on the isolated rat intestine) showed about 9 to 10 times the spasmolytic effectiveness of eupaverine, while they were about had the same cholinolytic potency and duration as atropine sulfate (on isolated guinea pig intestines). This combination of a strong and long-lasting cholinolytic effect with a strong spasmolytic effect component, which is only weakly pronounced or not present in most known cholinolytics, is considered to be a particular advantage of some. considered the novel compounds obtainable according to the invention. Furthermore, in contrast to cholinolytics with quaternary nitrogen and eupaverine, the substances are well absorbed from the gastrointestinal tract.

The invention relates to a process for the preparation of the 4,4-diphenylcyclohexylamines of the general formula I and their acid addition salts and quaternary ammonium salts, which is characterized in that a compound of the general formula II (in the formulas II to VI have R ¹ to R ³ the meaning given above, the phenyl groups in the 4-position can be substituted as indicated above, and in 2,3-position

or another radical which can be reductively converted into the group N (R ² ) R ^S and R '= an ^{alkylidene or aralkylidene radical corresponding to R 3} or an enamine of the general formula III

HT

(the dotted line means that there is a double bond in one of the positions indicated) in a manner known per se, especially catalytically, in the presence of noble metal catalysts, copper-chromium oxide, nickel or cobalt catalysts at normal pressure and room temperature or elevated pressure up to about 200 at and / or elevated temperature up to about 200 ⁰ C in the presence of a solvent, hydrogenated with nascent hydrogen, cathodically or by means of complex metal hydrides, or that one compound of the general formula IV

IV

wherein Y = H, OH; H, lower alkoxy; H, Hal or = O and Hai = CI, Br or J means in an

in a known manner with a base of the general formula V

R ² -NH-R ³ V

or with agents that donate such a base, optionally under reducing conditions, advantageously in the presence of platinum or Raney nickel, or in a compound with the basic structure of the general formula I which contains one or more hydroxyl groups in functionally modified form and / or the amino group present in functionally modified form, the hydroxyl and / or amino group or groups in the usual manner by catalytic hydrogenation, hydrolysis, or aminolysis alcoholic sets in freedom * ^r t "of that an organometallic compound of general formula VI,

where M = Li or Mg-Hal. means in a manner known per se with a hydroxylamine derivative of the general formula _;

H ₈ NZ

in which Z = lower alkoxy or Hai, and that a obtained primary or secondary amine of the general formula I (R ² = H) is optionally treated in a manner known per se with alkylating agents and optionally this and the alkylation products with an acid or an alkylating agent converted into their physiologically harmless acid addition salts or quaternary ammonium salts.

In addition to hydrogen, the radical R ¹ preferably denotes methyl or ethyl; but it can also mean, for example, propyl, isopropyl, butyl, isobutyl, secondary butyl tertiary butyl or allyl. The radicals R ² and R ^{3 are} preferably hydrogen, methyl, ethyl, propyl, isopropyl, η-butyl, secondary "butyl, tertiary butyl; R ³ furthermore n-amyl, isoamyl, 2-methylbutyl- (l), pentyl- ( 2), pentyl- (3), 3-methylbutyl- (2), neopentyl, tertiary amyl, n-hexyl, isohexyl, n-heptyl, n-octyl, allyl, butene- (l) -yl- (3), Butene- (2) -yl- (l), butene- (3) -yl- (l), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl, ο-, m- or p-methylbenzyl, 1- or 2-phenylethyl, 3-phenylpropyl- (1), 4-phenylbutyl- (1), 4-phenylbutyl- (2), p-methoxybenzyl.

r- As. Substituted phenyl radicals in the aromatic part of the radical R ³ are preferably mentioned: 3,4-methylenedioxyphenyl, o-, m- and p-tolyl, o-, m- and p-ethylphenyl, o-, m- and p-methoxyphenyl, 2 , 3- and .3,4-dimethoxyphenyl, o-, m- and p-hydroxyphenyl and 3-methoxy-4-hydroxyphenyl.
. Possible acyl groups in the radical X are in principle all acyl groups which can be converted into the radical R ³ reductively, primarily formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, capronyl, enanthoyl, caprylyl, acryloyl, benzoyl, p -Methoxybenzoyl, phenylacetyl, 2-phenylpropionyl, 3-phenylbutyryl.

R 'preferably denotes methylene, ethylidene, propylidene, isopropylidene, butylidene- (1), butylidene- (2), Benzylidene, 2-phenylethylidene, 4-phenyl-butylidene- (2).

The remainder X can in principle also be another

radical which can be converted reductively into the group NR ² R ³ , for example = NCl, NR ² R ³ -> ■ O, a

ίο. Azo group, N ₃ , NCO, NCS.

In the substituents Y and Z, the lower alkoxy groups are preferably methoxy and ethoxy, also occur mainly propoxy, isopropoxy, n-butoxy and isobutoxy.

¹ S The amines of the general formula I can be prepared by reducing the compounds of the general formulas II or III.

Particularly suitable compounds of the general formula II are the corresponding nitroso cyclohexanes such as 1-nitro-4,4-diphenylcyclohexane; Cyclohexanone oximes such as 4,4-diphenyl-, 2-methyl-4,4-diphenyl-, 2-ethyl-4,4-diphenyl-, 2-isopropyl-4,4-diphenyl-, 4,4TBis-p-tolyl-cyclohexanone oxime; Imine like 1-methylimino, 1-ethylimino, 1-propylimino, 1-iso

«5 propylimino, 1-n-butylimino, 1-isobutylimino, · 1-secondary butylimino, 1-n-amylimino, 1-isoamylimino, 1-n-hexylimino, 1-n-heptylimino, 1-n-octylimino, 1-allylimino, l-cyclohexylimino, 1 -benzylimino-1-4 diphenylcyclohexane; 1- methylene

amino-, 1-ethylideneamino-, 1-propylideneamino-, 1-isopropylideneamino-, l-butylidene- (l) -amino-, 1-butylidene- (2) -amino-, 1-isobutylideneamino-, 1-benzylideneamino-, 1- (2-Phenylethylideneamino) -, 1- (4-Phenylbutylidene- (2) -amino) -4,4 ^ diphenylcyclohexane; Hydrazones such as 4,4-diphenylcyclohexanone-p-sulfophenylhydrazone; Azines such as 4,4-diphenylcyclohexanone azine; Acyl derivatives such as 1-formamido, 1-acetamido, 1-pror pionamido, 1-butyramido, 1-isobutyrarnido, 1-valeramido, 1-isovaleramido, 1-capronamido, 1-enanthamido, 1-caprylamido, 1-acrylamido, 1-benzamido, 1-p-methoxybenzamido-, 1-phenylacetamido-. l- (2-phenylpropionamido) -j. l- (3-phenylbutyramido) -, 1 - N - methylacetamido, 1 - N - ethyl - propionamido-4,4-diphenylcyclohexane.

_; Also suitable are the 2,3-dehydro derivatives of the above compounds such as 4,4-diphenylcyclohexen- (2) -one oxime, 4,4-diphenyl-6-n-butylcyclohexen- (2) -one oxime, l-isopropyl- imino-4,4-diphenyl-cyclohexene (2), 1-secondary butylimino-4,4-diphenylcyclohexene (2), l-benzylideneamino ^^ - diphenylcyclohexene (2), l-acetamido-4,4-diphenylcyclohexene - (2), 1-Cyclohexylimino-4,4-diphenylcyclohexene-(2).

The following can preferably be used as enamines of the general formula III: 1-dimethylamino-, 1-diethylamino, 1-methylethylamino, 1-methyl-isopropylamino, 2-methyl-secondary butylamino-,

l-pyrrolidino-4,4-diphenylcyclohexene (l). . '

A compound of the general formula II or III

can. for example by catalytic hydrogenation

In this way, they can be converted into a compound of the general formula I. They come as catalysts customary, preferably noble metal catalysts, but also copper-chromium-oxide and nickel and cobalt catalysts are possible. The noble metal catalysts can be used, for example, as supported catalysts (e.g. palladium on carbon), as oxide catalysts (e.g. Platinum oxide) or as finely divided metal catalysts a (e.g. Platin-Mohr) are present. Nickel and cobalt

5 6

Catalysts are useful as Raney metals, as sodium dithionite in alkaline or ammonia nickel also on kieselguhr or pumice stone as a carrier of potash solution; iron (II) hydroxide; tin (II) chloride; used. Depending on the constitution of the starting hydrogen sulfide, hydrogen sulfide, sulfide and Compounds will hydrogenate with normal polysulfides; Hydrazine.

Pressure and room temperature or under increased ti Basically, the reduction methods

Pressure (up to about 200 at) and / or increased temperature - depending on which of the starting materials mentioned

rature (up to about 200 ⁰ C) carried out. The hydrogenation alien chosen is all the usual in question like them

takes place in the presence of a solvent, preferred examples are described in H ο u b e n — We y 1,

Weise methanol, ethanol, isopropanol, from tertiary methods of organic chemistry, 4th edition, 1957

Butanol, ethyl acetate, dioxane, tetrahydrofuran, ίο (hereinafter referred to as »Η ο u b e n — We y 1«),

Water, acetic acid, an aqueous mineral acid or Bd, 11/1, nitrogen compounds II, pp. 341 to 731.

Alkali lye or mixtures of the solutions mentioned It is of course possible that in the reduction

medium, but the constitution of the other groups that may be present in the molecule

must take into account inbound connections. You can also reduce pen. This is how both-

therefore basically in acidic, neutral or 15 for example lightly in the starting compounds

work in the basic area. Any double bonds in 2,3-

of the general formula II, which hydrogenate a C = N double position at the same time. Will an equal

contain a bond, one draws a reaction in early reduction of such double bonds or

neutral or basic medium. _ Groups not desired, so either

Chemical reducing agents such as lithium aluminum and reaction with nascent hydrogen can generally be used as the reduction method. hydride or nascent hydrogen, their speci-these can be used, for example, by treating fish mode of action is known, of metals with acids or bases. Either way, partial catalytic hydrogenations are carried out you can z. B. a mixture of zinc with acid under the conditions known from the literature or alkali, of iron with hydrochloric acid or 25 through.

Use acetic acid or tin with hydrochloric acid. It is also possible to connect the general

The use of sodium my formula IV by treatment with a base is also suitable

or another alkali metal in ethanol, iso- of the general formula V or with agents that

propanol or butanol; in particular amines of such a base under the reaction conditions

give general formula I with a double bond in 30, in a compound of general formula I.

2,3-St; llung can advantageously be produced in this way. to convict. As starting compounds of the general

An aluminum-nickel alloy can also be used for this embodiment of Formula IV

in alkaline-aqueous solution, optionally under the invention, are preferably suitable: 4,4-diphenyl-

Addition of alcohol, use. Also sodium or cyclohexanol, 4,4-diphenylcyclohexyl chloride and

Aluminum amalgam in aqueous-alcoholic or 35 -bromide, 4,4-diphenylcyclohexanone and 4,4-di-

aqueous solution are to generate the nascent phenylcyclohexen- (2) -ol, 4,4-diphenylcyclohexen- (2) -

Suitable for hydrogen. The reaction can also be carried out in yl chloride and bromide and 4,4-diphenylcyclo-

heterogeneous phase are carried out, where one hexen- (2) -one. ;

An aqueous and a benzene base or base of the general formula V are expedient in the first place

Toluene phase used. The applied reaction line is suitable: ammonia, methyl, ethyl, propyl,

temperatures are between room temperature and isopropyl, butyl, isobutyl, secondary butyl,

the boiling point of the solvent used. tertiary butyl, amyl, isoamyl, hexyl, isohexyl,

The reaction is advantageously terminated by boiling heptyl, octyl, allyl, cyclopropyl, cyclobutyl,

of the reaction mixture. Cyclopentyl, cyclohexyl, benzyl, 2-phenylethyl,

Starting compounds of the general formula II 45 1-phenylethyl, dimethyl, methylethyl, diethyl,

can also by cathodic reduction in amines methylpropyl-, methylisopropyl-, methyl-n-butyl-,

of the general formula I can be converted. Instead, methyl isobutyl, methyl secondary butylamine and

an aqueous acidic reaction solution, pyrrolidine, is used. *

the optionally also a further solvent. The base releasing agents are mainly the

such as glacial acetic acid or alcohol, contains and reduced to 50 corresponding salts, e.g. B. the carbonates, bicarbonates

a lead, copper, nickel or carbon electrode. or carbaminates in question. The implementation can be done in

The reducing agent can also be complex in the presence or absence of a solvent

Metal hydrides, especially lithium aluminum hydride, take place. You can z. B. lower aliphatic alcohol

also sodium borohydride in the presence of aluminum, such as methanol, ethanol or isopropanol, or

minium chloride or lithium bromide, to 55 lower aliphatic ketones, such as acetone or butanone,

turn come. As a starting material for this or benzene, toluene, acetonitrile or mixtures of the

Reduction methods are in particular to use Schiff's same as solvent. In selecting

Bases (general formula II, X = = N - R ^s or the solvent one must of course have the structure

H, N = R ') and acylamines are suitable. Take into account the response of the output connections; exemplary

tion conditions are the usual; one works 60 is wise for the implementation of the compounds

expediently in the presence of an inert solution of general formula IV (Y = H, OH or O) the

by means of, e.g. B. ether, tetrahydrofuran, ethylene glycol use of alcohols or ketones as Lö-

dimethyl ether. The implementation is advantageous by solvents because of the possibility of side reactions

Cooking of the reaction mixture led to the end. nen less cheap. Depending on the constitution of the

The decomposition of the formed metal complexes can take place in various starting compounds

in the usual way, e.g. B. work with an aqueous ammonium temperature ranges, e.g. B. at room temperature

chloride solution. temperature or at the boiling point of the one used

Other suitable reducing agents are, for example, solvents. It is possible to also see the reaction in

to make an excess of the base of the general formula V as a solvent. One can go to faster execution of the implementation work under pressure and / or at elevated temperature, whereby one advantageously uses the base of the general formula V in excess. This way of working is special recommended when using alcohols of the general formula IV (Y = H, OH) as starting compounds used; here it is advantageous to use hydrogenation catalysts, such as Raney nickel, platinum or palladium and heated in a pressure vessel to preferably 130 to 220 ° C. For the reaction come general those in Houben-Weyl, Vol. 11/1, p. 24 to 189, specified methods in question.

It is also possible to carry out the amination under reducing conditions. For example you can 4,4-diphenylcyclohexanones or their 2,3-dehydro derivatives in the presence of a base of Hydrogenate general formula V, the preferred catalysts being platinum or Raney nickel used and among the in H ο u b e η— W e y 1, Vol. 11/1, pp. 611 to 618 and 627 to 632, described conditions works.

A conversion of the ketones (general formula IV, Y = O) to the amines of the general formula I succeeds furthermore with amines and formic acid or corresponding ammonium formates or formamides under the conditions of the Leuckart-Wallach reaction (see for example Organic Reactions, Vol. V, 1949, pp. 301 to 330).

Furthermore, compounds of the general formula I can be prepared by adding one (or more) functionally modified hydroxyl group (or groups) ^{in the radical R 3 and / or their amino group in a compound with the basic structure of the general formula I} functionally modified form is present, the hydroxyl and / or the amino group or groups in the usual way by catalytic hydrogenation, hydrolytic, alcoholytic or aminolytic sets free.

Functionally modified hydroxyl groups are to be understood as meaning, for example: acyl oxy or other ester groups, such as chlorine or bromine, alkoxy or benzyloxy groups. The functionally modified Amino groups can e.g. B. acylated or as N-arylsulfonyl, N-benzal, N-benzyl, N-carbobenzoxy or N-nitroso derivatives are present. In particular, the following starting compounds can preferably be used insert: 1-acetamido-, 1-benzenesulfonamido-, 1-benzylideneamino, 1-benzylamino, 1 - carbobenzoxyamino, 1-nitrosamino, 1-phthalimido-4,4-diphenylcyclohexane. The amino group can also be modified in the form of an isocyanate group, the 4,4-diphenylcyclohexyl isocyanate as well intermediate in a Hofmann, Curtius, Lossen or Schmidt degradation of 4,4-diphenylcyclohexanecarboxamides can arise.

Hydrogenation takes place with catalytically excited hydrogen under the conditions given above. Furthermore, the starting compounds can be subjected to hydrolysis, whereby the hydroxyl and / or amino group (s) are set free. The hydrolysis can take place in an acidic or alkaline medium be performed. It is expedient to work in an aqueous alkaline medium at the boiling point Reaction solution. Suitable acids are preferably hydrochloric acid or sulfuric acid, and suitable bases are especially sodium or potassium hydroxide. The hydrolysis conditions have to be considerably more drastic if you want to achieve a hydrolytic cleavage of ether groups. In this case it works it is advantageous to use a concentrated aqueous hydrohalic acid solution and the reaction is carried out at an elevated temperature. Furthermore, you can for ether cleavage or aluminum chloride -bromide, boron tribromide, diphenylphosphine in the presence of butyllithium or sodium amide in liquid

ίο use ammonia. An acylated amino group an amine of the general formula I can also be set free alcoholytically by one treated such compound with a lower aliphatic alcohol in the presence of hydrogen chloride, or aminolytic, by treating the starting compounds in the autoclave with ammonia or an amine, for example methyl or ethylamine treated. The amine used or the one used Ammonia also serve as a solvent and are used in large excess Applied. One works at reaction temperatures of up to about 250.degree. To split from Acylamines can be used, for example, in H ο uben — Weyl, Vol. 11/1, pp. 926 to 936, 939 to to 948, use the methods described.

It is also possible to convert organometallic compounds of the general formula VI with hydroxylamine derivatives of the general formula H ₂ N - Z to give compounds of the general formula I. The organometallic compounds used are preferably 4,4-diphenylcyclohexyl lithium or 4,4-diphenylcyclohexylmagnesium chloride or bromide, which can be obtained in the customary manner from the corresponding 4,4-diphenylcyclohexyl halides. As a hydroxyl

amine derivatives include O-methyl- and O-ethylhydroxylamine or chloramine. These reactions can take place under conditions as described in Houben-Weyl, loc. Cit., Pp. 807/808 are.

It is also possible to treat any primary or secondary amines of the general formula I (R ³ = H) obtained with alkylating agents.

Alkylating agents are preferably to be understood as being alkyl, alkenyl, cycloalkyl or aralkyl esters of inorganic acids, such as hydrohalic acids, sulfuric acid, phosphoric acid, or organic sulfonic acids, such as p-toluenesulfonic acid. It is also possible to condense with aldehydes or ketones to form aldehyde * ammonia compounds or Schiff bases and then either hydrogenate them as indicated above or treat them with an alkylating agent and hydrolyze them. The alkylation of the amino group can, for. B. by condensation with benzaldehyde to give the Schiff base and treatment of the condensation product with alkyl halides _; such as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, isopropyl bromide or with dimethyl sulfate, can be achieved. This initially creates the quaternary salt of Schiff's base, which subsequently, e.g. B.

is converted into the secondary amine by treatment with aqueous ethanol or with acids such as hydrochloric acid. The new compounds of general formula I are also obtained if an amine of general formula I (R ³ = H) is reacted with an aldehyde in the presence of formic acid. The reaction of an amine of the general formula I (R ³ = H) with an alcohol in the presence of Raney nickel and its acylation

009 524/270

9 10

and subsequent reduction, for example with: with hydroxylamine the oximes (general

Lithium aluminum hydride, formula II, X = NOH), with amines the Schiffschen can with good success

be performed. Bases (general formula II, X = NR ³ ) or the

In general, the enamines of the general formula III mentioned in H ο u b e n — with hydrazines

W e y 1, Vol. 11/1, for the alkylation of primary or 5 the corresponding hydrazones and azines. The Cyclo

secondary amines work specified methods. Hexanols can be converted into ethers by etherification

The compounds of general formula I can (general formula IV, Y = H, lower alkoxy),

through treatment with acids in physiological terms through reaction with hydrogen chloride or hydrogen bromide,

compatible acid addition salts are converted. Phosphorus tribromide, thionyl chloride or other other

For this purpose, inorganic or organic, z. B. «> organic acid halides into the cyclohexyl

aliphatic, alicyclic, araliphatic, aromatic halides (general formula IV, Y = H, Hai)

or heterocyclic monobasic or polybasic carbon are converted. From the cyclohexyl halides

or sulfonic acids in question. In detail, two can be produced: with magnesium or lithium

for example the following are mentioned: Mineral acids, such as the corresponding organometallic compounds

Hydrochloric acid, hydrobromic acid, iodine 15 of the general formula VI, with silver nitrite the nitro

hydrofluoric acid, sulfuric acid, nitric acid, or compounds (general formula II, X = H, NO ₂ ),

Phosphoric acids, such as orthophosphoric acid, sulfamine with phthalimide potassium, the l-phthalimido-4,4-diphenyl

acid, or organic acids such as formic acid, cyclohexane. The 2,3-dehydro derivatives are analogous

Acetic acid, propionic acid, butyric acid, pivalic acid, accessible to these compounds; the cyclohexene (2) -

Diethyl acetic acid, oxalic acid, malonic acid, succinic 2 ° oils (general formula IV, Y = Η, ΟΗ; double bond

acid, pimelic acid, fumaric acid, maleic acid, ci- dung in the 2,3-position) can be obtained from the cyclohexene (2>

tronic acid, gluconic acid, lactic acid, tartaric acid, ions by reaction with lithium aluminum hydride

Malic acid, benzoic acid, salicylic acid, phenylpropionic acid.

acid, ascorbic acid, isonicotinic acid, nicotinic acid, It is also possible to use these starting materials only in situ

Methanesulfonic acid, ethanedisulfonic acid, / S-hydroxy-25 to generate. This can be done by heating ketones

Ethanesulfonic acid, p-toluenesulfonic acid, naphthalene (general formula IV, Y = O) with primary amines

mono- or -disulfonic acids. in the autoclave to preferably 150 to 250 ⁰ C die

By treating with alkylating agents such as Schiff's bases (general formula II, X = NR ³ )

Prepare methyl iodide, dimethyl sulfate or ethyl halides, which are then placed in the same vessel

can amines of the general formula I also in their 30 addition of a catalyst to the amines of the general

physiologically compatible quaternary ammonium my formula I are hydrogenated,

salts are converted. Ketones of the general formula IV (Y = O), in

The free bases of the general formula I can, where R ¹ Φ H, can by alkylation of

if desired, from their salts by treatment with enamines of the general formula III (R ¹ = H, R ²

strong bases such as sodium or potassium hydroxide 35 and R ³ 4 = H) are produced. You can also do it

or sodium or potassium carbonate. obtained by implementing the ketones of the general

Those compounds of the general formula I, formula IV (Y = O, R = H) with primary amines, in which R ^{1 is} not H, have two asymmetric carbon atoms, for example with cyclohexylamine, see Schiffsche. They are therefore obtained in their bases and implementation of these Schiff bases with synthesis in two racemic forms (cis and trans 4 ° of a Grignard compound, for example the ethyl form). Depending on the manufacturing magnesium bromide used; one or the other of these hydrocarbon (for example ethane) forms predominates under the splitting process. In many cases, it is expedient to use only N-metalated enamines which, with alkylating agents, are used to isolate the predominantly obtained form. In others (e.g. alkyl halides or sulfates) in those cases in which both forms are obtained, 45 2-position alkylated Schiff bases can be converted; their separation take place in the usual way, for. B. these are lysed with acid to give the desired ketones by distillation, crystallization of the free bases of the general formula IV (Y = O, R ¹ = H) hydro- or suitable salts, chromatography or by.

combined application of these separation methods. The new compounds can be mixed with Each of these racemates can be 50 conventional drug carriers in human or known manner by treatment with optically active acids, e.g. B. Veterinary medicine can be used. As a carrier tartaric acid, Camphorsulfonic acid, mandelic acid, apple substances come those organic or acidic acids, Lactic acid, in its optically active compo- organic substances in question, for the parenteral nent columns. Such a cleavage can be suitable for general or enteral application and those with mine according to the new compounds in Houben - Weyl, Vol. 4/2, 55 do not react, 4th edition, 1955, pp. 513 to 519, indicated metho-, for example, water, vegetable oils, polyethylene ends respectively. glycols, gelatin, lactose, starch, magnesium

The starting compounds of the general forest stearate, talc, petrolatum or cholesterol. To the parent

Meln II to VI are partly known, partly real application can serve in particular solutions,

they are preferably oily or aqueous solutions according to the methods described in the literature 60, as well as

produce. Suspensions, emulsions or implants. For the

Condensation of diphenylacetaldehydes with meenteral application can also be tablets or

ethyl vinyl ketone leads to 4,4-diphenylcyclohexene (2) - coated tablets, which may be sterilized or with auxiliary

ons. These can be added to the corresponding cyclo- substances, such as preservatives, stabilizers or

hexanones (general formula IV, Y = O) or 65 wetting agents or salts, to influence the osmo-

Cyclohexanols (general formula IV, Y = H, OH) under pressure or mixed with buffer substances

are reduced, preferably by catalytic are, can be applied.

Hydrogenation. The new compounds are preferably obtained from the cyclohexanones

Dosages between 2 and 100 mg administered per dosage unit.

The table below shows the spasmolytic (based on eupaverine = 100, determined on the isolated Rat intestine) and the cholinolytic effects (based on atropine sulfate = 100, determined on isolated guinea pig small intestine) of process products produced according to the invention are listed.

example 1

effect cholino 4,4-diphenylcyclohexanes spasmo- lytic (Hydrochloride, lytic ι on unless otherwise noted related Atropine Eupaverine sulfate = 100 = 100 l- (N-methyl-N-secondary- 25th Butylamino) - 1130 l- (N-methyl-N-isopropyl- 16 amino) -, chloromethylate 850 l- (N-methyl-N-secondary Butylamino) -, 20th Bromomethylate 600 1-n-hexylamino 530 18th 1-secondary-butylamino- 430 1 - [2 - (3,4 - methylenedioxy- phenyl) propylamino] - .. 350 25th 1-pyrrolidino 290 l-pyrrolidino-2-allyl- 290 l-amino-2-n-butyl- 280 1-n-butylamino 270 l-cyclohexylamino- 260 l-dimethylamino-2-n-butyl- 250 50 1-ethylamino 240 l- (N-methyl-N-isopropyl- amino) -2-dehydro- .... 240 l-isopropylamino-2-methyl- 240 l- (N-methyl-N-cyclohexyl- amino) - 230 1-n-octylamino 230 10 1-n-propylamino 230 1 - [2 - (3 - hydroxy - 4 - meth- oxyphenyl) ethylamino] -, Ethanesulfonate 230 l-dimethylamino-2-methyl- ("A-isomer") 230 l- (2-p-toluylethylamino), Methanesulfonate 210 1-dimethylamino 2-n-propyl 210 12th 1-amino 190 l-dimethylamino-2-methyl- (»/ J-isomer«) 180 l- [2-phenylbutyl- (l)] - amino- 170 l-amino-2-ethyl- ("A-isomer") 170 l-isopropylamino-2-allyl- 170 1-isobutylamino 160 l-allylamino-2-dehydro- .. 150 l-amino-2-n-propyl- 150 18th 1-dimethylamino 140 4,4 - bis - ρ - tolylcyclohexane (Hydrochloride) 1-isopropylamino 2-methyl- 170 1-isopropylamino 120 l- (N-methyl-N-iso- propylamino) - 120

2 g of potassium hydroxide and 7.5 g of 4,4-DiphenylcycIohexen- (2) -one oxime (F. 142 ⁰ C) are dissolved in 200 ml of methanol and after adding 2 g of Raney nickel at 50 ⁰ C and 6 at hydrogenated. After the 3 mol corresponding amount of hydrogen has been taken up, the catalyst is filtered off, the mixture is acidified with dilute hydrochloric acid, evaporated and crystallized

ίο the residue from ethanol to. 6.2 g of 4,4-diphenylcyclohexylamine hydrochloride with a melting point of 260 ^° C. are obtained.

The starting material is obtained as follows: 12.4 g of 4,4-diphenylcyclohexen- (2) -one and 5 g of potassium

hydroxide are dissolved in 50 ml of ethanol. One gives

Add 5 g of hydroxylamine hydrochloride and the mixture boils

6 hours, sucks off and evaporates. The residue is taken up in water and extracted with ether. The ether solution is dried with magnesium sulfate, evaporated and the remaining crystallized Oxime from ethanol.

Example 2

43.4 g of 4,4-Diphenylcyclohexanon oxime (F. 160 ⁰ C) are dissolved in 500 ml of methanol and, after addition of 11.5 g of potassium hydroxide and 10 g of Raney nickel at 10 and hydrogenated at 50 to 6O ⁰ C. After about 6 hours, the amount of hydrogen corresponding to 2 moles has been absorbed. The catalyst is filtered off with suction, the methanol is distilled off and the residue is taken up in dilute hydrochloric acid. The acidic solution is washed with ether, made alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform solution is dried over magnesium sulfate, filtered and evaporated. The residual 4,4-Diphenylcyclohexylamin boils at 160 to 165 ° C / 0.05 mm Hg and melts to give 33 g of pure base at 100 ⁰ C..

Are 49 g of 4,4-Diphenylcyclohexen- (2) -one are dissolved in 500 ml of methanol and shaken ig ^em after addition of 5 g of 5% palladium-carbon catalyst at room temperature and normal pressure under hydrogen: The starting material is obtained as follows. After the calculated amount of hydrogen has been taken up, the hydrogenation is terminated and the catalyst is filtered off while hot. After the methanol has been distilled off to about 100 ml, the mixture is cooled and, after standing for a short time, suctioned off. 48 g of 4,4-diphenylcyclohexanone are obtained

F. 100 ° C, which one with 100 ml of ethanol, 100 ml of pyridine and mix 36 g of hydroxylamine hydrochloride and cook for 5 hours. The mixture is then evaporated in vacuo and the residue is taken up in chloroform. The chloroform solution is washed with water, dry it over magnesium sulfate, filter and evaporate. The remaining oxime crystallizes to convert from ethanol.

B e i s ρ i el 3

3 g 4,4-Diphenylcyclohexylamin hydrochloride, ormiat 5 ml of formic acid, 0.7 g Natriumf and 4 ml 40volumprozentige formaldehyde solution are mixed and heated for 3 hours at 6O ⁰ C and after 12 hours 100 ⁰ C. Then it is mixed with water, mixed alkaline with sodium hydroxide solution and extracted with ether. After the ether has dried, the l-dimethylamino-4,4-diphenylcyclohexane hydro-

chloride with ethereal hydrochloric acid and recrystallized it from ethanol; 2.6 g of F. 248 ^° C. are obtained.

Example 4

A solution of 5 g of 4,4-diphenylcyclohexylamine in 50 ml of benzene is boiled with 3 g of benzaldehyde on a water separator until no more water passes over (about 2 hours). The resulting benzene solution of the Schiff base is shaken together with 10 g of methyl iodide for 12 hours at 150 ⁰ C in a sealed tube and then distilled off the benzene and the excess methyl iodide. The residue is boiled 10 minutes in 90% strength ^em ethanol, the alcohol is distilled off, taken up in dilute hydrochloric acid and extracted with ether to split benzaldehyde. The acidic aqueous solution is made alkaline with sodium hydroxide solution and extracted with chloroform. After the chloroform solution has been dried and evaporated, the remaining 1-methylamino-4,4-diphenylcyclohexane is distilled at 151 to 152 ° C./0.04 mm. Yield 3.5 g hydrochloride, mp 266-268 ° C.

Example 5

5 g of 4,4-diphenylcyclohexylamine are dissolved together with 2.2 g of triethylamine in 50 ml of absolute benzene. 1.6 g of acetyl chloride in 20 ml of absolute benzene are added dropwise to the solution while stirring. The temperature of the reaction mixture rises from 20 to 4O ⁰ C on. The mixture is stirred for a further 2 hours at room temperature and extracted with dilute hydrochloric acid. The benzene solution is dried and evaporated. The residue is dissolved in 50 ml of absolute tetrahydrofuran and the solution is added dropwise with stirring to 1 g of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran. The mixture is boiled for a further 2 hours, then dilute hydrochloric acid is slowly added while cooling and stirring, and the tetrahydrofuran is distilled off. The acidic aqueous solution that remains is washed with ether, made alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform extract is dried and evaporated, the remaining 1-ethylamino-4,4-diphenyl-cyclohexane is distilled at 160 to 162 ° C / 0.05 mm Hg; Yield 4 g of hydrochloride, melting point 237 to 238 ^° C. (from alcohol-ether).

The following are also available:

1-propylamino-4,4-diphenylcyclohexane, b.p. 162 to 164 ° C / 0.05 mm Hg; Hydrochloride, m.p. 210 ^° C

(from ethanol);
In-butylamino-4,4-diphenylcyclohexane, b.p. 168 to 170 ° C / 0.05 mm Hg; Hydrochloride hemi-

hydrate, m.p. 110 ° C (from ethanol);
ln-hexylamino ^^ - diphenylcyclohexane, b.p. 178 to 179 ° C / 0.05 mm Hg; Hydrochloride, m.p. 120 °

(from ethanol);
ln-octylamino ^^ - diphenylcyclohexane, b.p. 190 to 193 ° C / 0.05 mm Hg; Hydrochloride, F. 128

to 13O ⁰ C (from ethanol).

Example 6

5 g of 4,4-diphenylcyclohexylamine are boiled together with 7 g of isobutyraldehyde in 100 ml of benzene for 5 hours with separation of water. The benzene is then distilled off. The remaining Schiff base is shaken under hydrogen at room temperature and normal pressure in 150 ml of methanol after adding 0.5 g of platinum oxide. After the amount of hydrogen corresponding to one mol has been absorbed, the catalyst is filtered off, the mixture is acidified with dilute hydrochloric acid and the methanol is removed in vacuo. The remaining aqueous solution is made alkaline with sodium hydroxide solution and extracted with ether. After the ether extract has been dried and concentrated, the l-isobutylamino-4,4-diphenylcyclohexane is distilled at from 171 to 175 ° C./0.03 mm Hg; Hydrochloride, m.p. 208 to 209 ⁰ C (from ethanol-ether), ίο Yield: 3.9 g.

Example 7

20 g of 4,4-diphenylcyclohexan (2) -one, 10 g of isopropylamine and 50 ml of tetrahydrofuran are shaken in a sealed tube at 200 ° C. for 10 hours. The mixture is then cooled and the tetrahydrofuran and the excess isopropylamine are distilled off. The remaining Schiff base is dissolved in methanol and, after the addition of 2 g of platinum oxide, is hydrogenated at normal pressure and room temperature until the 2 mol corresponding amount of hydrogen has been absorbed. Work up as in Example 6. This gives 17 g C l-isopropylamino-4,4-diphenylcyclohexane, bp. 164-165 ° C / 0.05 mm Hg. Hydrochloride, m.p. 23O ⁰ C

(from ethanol).

The following are also available:

l-secondary-butylamino ^^ - diphenylcyclohexane, b.p. 166 to 167 ° C / 0.05 mm Hg; Hydrochloride, m.p. 17O ⁰ C;

l-cyclohexylamino-4,4-diphenylcycIohexan, hydrochloride, m.p. 264-265 ⁰ C (the preparation of the Schiff base was carried out by boiling the components in Toluo} on a water separator).

Example 8

Dissolve 10 g of 4,4-diphenylcyclohexanol (F. 138 ⁰ C) in 40 ml of isopropylamine and shaking the solution after addition of 2 g of Raney nickel for 15 hours at 16O ⁰ C in a sealed tube. After filtering off the catalyst, distilling the excess isopropylamine, worked up, the reaction mixture as in Example 6, and receives l-isopropylamino ^^ -.. 165 diphenylcyclo- L of boiling hexane to 175 ° C / 0.05 mm Hg hydrochloride salt, m.p. 230 ° C (from ethanol). Yield: 4.1 g.

The starting material is obtained by hydrogenating 4,4-diphenylcyclohexen- (2) -one on platinum oxide in methanol until an amount of hydrogen corresponding to 2 moles is absorbed. Yield practically quantitatively.

Example 9

84 g of 4,4-diphenylcyclohexen- (2) -one and 35 g of isopropylamine are heated ^{to 200 ° C. in 700 ml of methanol in an autoclave for 5 hours.} The mixture is then allowed to cool, after opening the autoclave, 20 g of Raney nickel moist with methanol are added and the mixture is then hydrogenated at 100 atmospheres and 79 ° C. After about an hour, the amount of hydrogen corresponding to 2 moles has been absorbed. The procedure is as in Example 6 and obtained 67 g of l-isopropylamino ^^ - diphenylcyclohexane hydrochloride, F. 23O ⁰ C (from ethanol). 4.6 g of 4,4-diphenylcyclohexanol are obtained as a by-product.

Example 10

7 g of l-isopropylamino-4,4-diphenylcyclohexane are dissolved in 40 ml of formic acid. Give 6 g

40volumprozentige formaldehyde solution added and the mixture heated for 3 hours at 60 ° C and 12 hours at 100 ⁰ C. It is then evaporated in vacuo, taken up in water, makes with sodium hydroxide solution and extracted with ether from alkaline. After drying and evaporation of the ethereal solution, 5.5 g are obtained

1 - (N - methyl - N -isopropylamino) - 4,4-diphenylcyclohexane of bp 164 to 165 ° C / 0.05 mm Hg; Hydrochloride, Mp 214-215 ° C (from ethanol).

2.5 g of 1- (N-methyl-N-isopropylamino) -4,4-diphenylcyclohexane are dissolved in 50 ml of benzene and 9 g of methyl iodide are added to the solution. After 3 hours of boiling, 3 g of quaternary iodide are obtained. The salt is suspended in 150 ml of water, freshly prepared silver chloride from 17 g of silver nitrate is added and the mixture is heated on the steam bath for 1 hour. Then it is suctioned off, the water is distilled off in vacuo and the residue is recrystallized from ethanol-ether. This gives 1.9 g of N- (4,4-diphenylcyclohexyl) - N, N-dimethyl -N-isopropyl- Ammoni monium chloride, melting at 245 ⁰ C (decomposition).

The following are also available:

1 - (N- methyl - N - secondary butylamino) - 4,4 - diphenylcyclohexane, Bp 165-167 ° C / 0.05mm Hg; Hydrochloride, mp 188-190 ° C;

Brommethylat by 12stündiges heating of the free base with methyl bromide in benzene at 100 ⁰ C in a bomb tube, F. 208 to 21O ⁰ C (from ethanol);

1 - (N-Methyl -N- cyclohexylamine) - 4,4 - diphenylcyclohexane, Hydrochloride, mp 234 to 235 ° C (from ethanol-ether);

Bromomethylate, m.p. 215-216 ° C (from ethanol).

Example 11

Dissolve 8.5 g4,4-diphenyl-6-methylcyclohexen- (2) -one oxime (F. 144-145 ⁰ C) in 150 ml methanol and hydrogenated after addition of 1 g of potassium hydroxide and

2 g of Raney nickel at 6 at and 6O ⁰ C, until the 3 mol corresponding amount of hydrogen has been taken up. After 2 hours, the catalyst is filtered off with suction, the filtrate is acidified with dilute hydrochloric acid and the methanol is distilled off. The hydrochloric acid solution is then washed with ether, made alkaline with sodium hydroxide solution and the base extracted with ether. After drying and evaporation of the ether solution, 7.5 g of base remain, which are carefully dissolved in 10 ml of 5N hydrochloric acid. After cooling and standing for several hours to obtain 3.1 g of a hydrochloride of the stereoisomers ( "α-isomer") of the 2-methyl-4,4-dipheny! Cyclohexylamine, melting at 255-256 ⁰ C (from ethanol).

The mother liquor of the hydrochloride is mixed with sodium hydroxide solution and extracted with ether. the Base is chromatographed on a silica gel column with 98% benzene and 2% triethylamine as solvent. First of all, 0.9 g of the isomer described above is obtained. The second parliamentary group will ^ Isomers obtained. The / S base is dissolved in ether and precipitated as the hydrochloride with ethereal hydrochloric acid; Mp 214-215 ° C (from ethanol). Yield 3.5g.

The starting material is obtained as follows: 24 g of l-cyclohexylimino-4,4-diphenylcyclohexene (2) are dissolved (obtained by boiling 4,4-diphenylcyclohexen (2) -one and cyclohexylamine in toluene until the dehydration has ended) in 100 ml of absolute tetrahydrofuran and adds this solution to an ethyl magnesium bromide solution prepared from 3 g of magnesium and 13.5 g of ethyl bromide in 100 ml of absolute tetrahydrofuran. The mixture is boiled for 18 hours, then mixed with 25 g of methyl iodide and boiled again for 18 hours. Thereafter, the mixture is cooled, added dropwise 150 ml 10% hydrochloric acid to ^e, boils more

2 hours and the tetrahydrofuran is distilled off. The remaining acidic aqueous phase is washed with ether extracted. From the ethereal solution one obtains

ίο after drying and evaporation 13 g of 4,4-diphenyl-6-methylcyclohexen- (2) -one with a melting point of 94 ° C (from ethanol); Bp 162 to 165 ° C / 0.05 mm Hg.

10 g of 4,4-diphenyl-6-methylcyclohexen- (2) -one are added together with 8.5 g of hydroxylamine hydrochloride

and 60 ml of pyridine in 200 ml of ethanol boiled for 5 hours. The solvents are then distilled off and takes up the residue in water and ether. From the dried ethereal solution one obtains after evaporation 8.5 g of oxime.

Example 12

31 g of 4,4-diphenyl-6-methylcyclohexen- (2) -one are dissolved in 400 ml of methanol in the presence of 5 g 5% palladium-carbon catalyst hydrogenated at normal pressure and room temperature. After admission the 1 mol corresponding amount of hydrogen is sucked hot from the catalyst. After distilling off the Methanol is obtained 30 g of 2-methyl-4,4-diphenylcyclohexanone with a melting point of 99 to 100 ° C., which is obtained according to the Method described in example 12 into the oxime (26.5 g; mp 154 to 155 ° C) and further as in example 12 into the stereoisomeric 2-methyl-4,4-diphenylcyclohexylamine hydrochloride (α-isomer 11.5 g; ^ -isomer 9.8 g) transferred.

The starting product is also available as follows: 20 g of 4,4-diphenylcyclohexanone and 20 g of cyclohexylamine are boiled in 100 ml of toluene on a water separator until the water splits off is finished. Thereafter, toluene and excess cyclohexylamine are removed in vacuo and the obtained Schiff base methylated according to the method described in Example 11.

Example 13

3 g of 2-methyl-4,4-diphenylcyclohexylamine hydrochloride (α-Isomeres) are dissolved in 50 ml of formic acid. After adding 0.7 g of sodium formate and

3 ml of 40 percent by volume formaldehyde solution are heated to 60 ° C. for 1 hour and then for 5 hours to 100 ° C. Work-up is carried out as in Example 3.

2.8 g of 1-dimethylamino-2-methyl-4,4-diphenylcyclohexane hydrochloride are obtained (α-isomer) of

F. 230 to 231 ° C (from ethanol).

Are obtained analogously from 3 g of the /? - isomer of 2 - methyl - 4,4 - diphenylcyclohexylamin - hydrochloride 2.7 g of l-dimethylamino ^ -methyl ^^ - diphenylcyclohexane hydrochloride (SS isomer), mp 26O ⁰ C .

Example 14

9.5 g of 2-methyl-4,4-diphenylcyclohexanon, 15 g of isopropylamine and 50 ml of toluene are agitated for 10 hours at 18O ⁰ C in a sealed tube. Thereafter, toluene and excess isopropylamine are distilled off in vacuo. The Schiff base is dissolved in 200 ml of methanol and, after the addition of 0.5 g of platinum oxide, is hydrogenated at room temperature and normal pressure. The calculated amount of hydrogen has been absorbed after about 50 minutes. Work as in example 6

009 524/270

on, but converts the crude base into the hydrochloride without distilling. After recrystallizing twice 4.7 g of 1-isopropylamino-2, which is uniform according to thin-layer chromatography, are obtained from ethanol - methyl - 4,4 - diphenylcyclohexane hydrochloride vom 198 to 200 ° C.

Example 15

Analogously to Example 11, from 12 g of 4,4-diphenyl-6-ethylcyclohexen- (2) -one-oxime [F. 168 to 170 ⁰ C; obtained by reacting 1-cyclohexylimino-4,4-diphenylcyclohexen- (2) with ethylmagnesium bromide and ethyl iodide and oximation of the 4,4-diphenyl-6-ethylcyclohexen- (2) -one (bp. 165 to 170 ° C / 0.05 mm) analogous to Example 11] 9.5 g of 2-ethyl-4,4-diphenylcyclohexylamine (mixture of the «- and the / S isomers) with a boiling point of 164 to 166 ° C. / 0.03 mm Hg: hydrochloride F. 245 ⁰ C (consists of approximately equal parts of the two isomers).

If the hydrochloride mixture is recrystallized from 60 ml of water, 4 g of hydrochloride of the α-isomer with a melting point of 275 ° C. are obtained. Chromatography of the mother liquor residue on silicic acid gel with benzene-triethylamine (95.5) gives 3 g of the ε base receive; Pikrat, F. 216 to 218 ⁰ C (decomposition; from ethanol).

The following can be prepared analogously: 4,4-Diphenyl-6-isopropylcyclohexen- (2) -one (boiling point 165 to 170 ° C./0.05 mm Hg) and from this via the oxime 2-isopropyl-4,4-diphenylcyclohexylamine; Hydrochloride mp 300 C (from ethanol; sterically uniform); 4,4-diphenyl-6-propylcyclohexen- (2) -one (boiling point 180 to 185 ° C./0.5 mm Hg) and, therefrom, 2-propyl-4,4-diphenylcyclohexylamine; Hydrochloride; F. 264 to 265 ⁰ C (from ethanol; sterically uniform); 4,4-diphenyl-6-n-butylcyclohexen- (2) -one (b.p. 185 to 188 ° C / 0.05 mm Hg) and therefrom 2-n-butyl-4-4-diphenylcyclohexylamine; Hydrochloride, mp 217 to 218 ° C (from ethanol, sterically uniform).

Example 16

4 g of 2-ethyl-4,4-diphenylcyclohexylamine hydrochloride (α-isomer) are methylated twice on nitrogen by the method described in Example 13. This gives 3.5 g of l-dimethylamino-2-ethyl-4,4-diphenylcyclohexane-hydrochloride (α-isomer), mp 244-245 ⁰ C.

The following can be prepared analogously from the corresponding cyclohexylamines:

l-dimethylamino-2-ethyl-4,4-diphenylcyclohexane (/? - isomer), hydrochloride, m.p. 235 ⁰ C;

1 - Dimethy lamino - 2 - η - propyl 4,4-diphenylcyclohexane hydrochloride, mp 243 ⁰ C;

1 - Dimethylamino - 2 - η - butyl - 4,4 - diphenylcyclohexane hydrochloride, F. 23O ⁰ C.

Example 17

Dissolve 18.3 g of l-isopropylimino ^^ - diphenylcyclohexen- (2) (Bp. 156 to 158 ° C / 0.05 mm Hg; obtained as in Example 7) in 100 ml of absolute ether and the solution is added dropwise to 4 g of lithium aluminum hydride in 50 ml of absolute ether. Then you cook them Mix for 5 hours and carefully add water. Extracted after adding sodium hydroxide solution one with ether, dries the ethereal solution with magnesium sulphate and evaporates it. The residue is in transferred the hydrochloride and recrystallized from ethanol. 15.3 g of 1-isopropylamino-4,4-diphenylcyclohexene (2) hydrochloride are obtained from 258 to 259 ° C.

B e i s ρ i e 1 18

3.5 g of 1-isopropylamino-4,4-diphenylcyclohexene (2) hydrochloride, 20 ml of formic acid, 1.3 g of sodium formate and 5 ml of 40 percent by volume formaldehyde solution are reacted as described in Example 13 and worked up. 3.2 g of 1- (N-methyl-N-isopropylamino) -4,4-diphenylcyclohexene (2) -hydro- chloride with a temperature of 244 to 245 ° C (from ethanol).

Example 19

10 g of 4,4-diphenylcyclohexen- (2) -one, 5.6 g of pyrrolidine and 50 ml of tetrahydrofuran are shaken in a sealed tube ^{at 160 ° C. for 12 hours.} After cooling, the mixture is evaporated, the residue is dissolved in 200 ml methanol and hydrogenated after addition of 4 g of Raney nickel at 6 and at 6O ⁰ C. After aspiration of the catalyst is acidified with hydrochloric acid and methanol was distilled off. The remaining 1-pyrrolidino-4,4-diphenylcyclohexane hydrochloride is recrystallized twice from ethanol-ether. F. 244 ^° C. Yield: 6.3 g.

B e i s ρ i e 1 20

a) Analogously to Example 1, 7 g of 4,4-bis-p-tolyl-cyclo- (2) -one-oxime are obtained (M.p. 140 ° C) at 60 ° C the 4,4-bis-p-tolyl-cyclohexylamine hydrochloride from

Mp 240 ° C (from ethanol). Yield: 5.7 g.
The starting material can be obtained by reacting bis-p-tolyl-acetaldehyde with methyl vinyl ketone and subsequent oximation of the 4,4-bis-p-tolylcyclohexen (2) -one (boiling point 173 ° to 175 ° C./0.05 mm Hg) .

b) Analogously to Example 3, 3 g of 4,4-bis-p-tolyl-cyclohexylamine hydrochloride are obtained 1-dimethylamino-4,4-bis-ρ-tolyl-cyclohexane-hydrochloride with a temperature of 232 ° C. Yield: 2.3 g.

Example 21

a) Analogously to Example 7, 11 g of 4,4-bis-p-tolylcyclohexen- (2) -one are reacted with isopropylamine to give the Schiff base and then hydrogenated to 1-isopropylamino-4,4-bis-ρ-tolyl-cyclohexane. Hydrochloride, m.p. 261 ^° C. Yield: 8.9 g.

b) Analogously to Example 10, 4 g of 1-isopropylamino-4,4-bis-p-tolyl-cyclohexane are converted into 1- (N-methyl-N-isopropylamino) -4,4-bis-p-tolyl-cyclohexane. Hydrochloride, m.p. 245 ^° C. Yield: 3.3 g.

B e i s ρ i e 1 22

Analogously to Example 1, from 21 g of 4,4-bis-p-isopropylphenylcyclohexen - (2) - on - oxime at 60 ⁰ C, the 4,4 - bis - ρ - isopropylphenyl - cyclohexylamine. Hydrochloride, mp 240 ° C. Yield: 12.2 g.

The starting material is obtained by reacting bis - ρ - isopropylphenyl -. Acetaldehyde (F. 55 ⁰ C) with methyl vinyl ketone, followed by oximation of the obtained 4,4-bis-p-isopropylphenylcyclohexen- (2) -one (bp 210-215 ° C / 0.05 mm Hg).

Example 23

a) Analogously to Example 7, 1-isopropylamino-4,4-bis-ρ-isopropylphenylcyclohexane is obtained from 10 g of 4,4-bisp-isopropylphenylcyclohexen (2) -one. Hydrochloride, m.p. 280 ^° C. Yield: 8.2 g.

b) Analogously to Example 10, l- (N-methyl-N-isopropylamino) -4,4-bis-p-isopropylphenylcyclohexane is obtained from 2 g of 1-isopropylamino - ^ - bis-p-isopropylphenylcyclohexane. Hydrochloric !, F. 26O ⁰ C, yield: 1.8 g.

Example 24

a) Analogously to Example 11, 8.5 g of 4,4-bisp - tolyl - 6 - methyl - cyclohexene - (2) - one - oxime are obtained from 8.5 g 2-Methyl-4,4-bis-p-tolyl-cyclohexylamine in the form of an isomer mixture. Hydrochloride, m.p. 85 ° C (Mixture). Yield: 6 g.

The starting material is obtained analogously to Example 11 by reacting 4,4-bis-p-tolyl-cyclohexen (2) -one with cyclohexylamine, subsequent reaction with methyl magnesium iodide and hydrolysis as well Oximation of the 4,4-bis-p-tolyl-6-methyl-cyclohexen (2) -one obtained (Kp. 185 to 186 ° / 0.05 mmHg).

b) Analogously to Example 13, 1-dimethylamino-2-methyl-4,4-bis-p-tolyl-cyclohexane is obtained by methylating 2 g of the isomer mixture obtained as above. Hydrochloride, m.p. 233 to 235 ⁰ C (mixture). Yield: 1.5 g.

Example 25

Analogously to Example 7, 1-isopropylamino-2-methyl-4,4-bis is obtained from 8 g of 4,4-bis-p-tolyl-6-methyl-cyclohexen-2-one by reaction with isopropylamine and subsequent hydrogenation -p-tolyl-cyclohexane as a mixture of isomers. The free bases are separated by column chromatography and converted into the hydrochloride. F. 242 to 243 ⁰ C (α-isomer) or up to 256 ⁰ C (/ 9-isomer). Yields: 1.7 and 2.6 g, respectively.

Example 26

a) 36 g of 4,4-diphenylcyclohexanone, 150 ml of toluene and 40 ml of pyrrolidine are boiled for 6 hours. The water formed is then removed azeotropically. Another 40 ml of pyrrolidine are added, the mixture is boiled for a further 12 hours, distilled and the residue is dissolved in 200 ml of acetonitrile. After adding dropwise 24 g of allyl bromide, the mixture is boiled again for 15 hours, the distillation is carried out, the 1-pyrrolidino-2-allyl-4,4-diphenylcyclohexene obtained is taken up in 200 ml of absolute tetrahydrofuran and 7.6 g of lithium aluminum hydride in 200 ml are slowly added with stirring Tetrahydrofuran too. After boiling for an hour, the mixture is acidified with dilute hydrochloric acid, the tetrahydrofuran is distilled off and the hydrochloric acid aqueous solution is washed with ether, dried over sodium sulfate and ethereal hydrochloric acid is added. 21.3 g of 1 - pyrrolidino - 2 - allyl - 4,4 - diphenylcyclohexane hydrochloride with a melting point of 234 to 235 ^° C. (from ethanol) are obtained.

b) In an analogous manner, by reacting 23 g of 2-allyl-4,4-diphenylcyclohexanone (boiling point 171 ° to 172 ° C./0.05 mm Hg) with isopropylamine in toluene, an ether solution of the product obtained is then added dropwise to give lithium aluminum hydride in absolute ether and cooking overnight, the l-isopropylamino-2-allyl-4,4-diphenylcyclohexane hydrochloride, mp 238 ⁰ C (one isomer). Yield: 8.3 g.

Example 27

Analogously to Example 7, 10 g of 4,4-diphenylcyclohexen- (2) -one are made in each case with 2-p-tolylethylamine, 2- (3-hydroxy-4-methoxyphenyl) ethylamine, 2- (3,4-methylenedioxyphenyl) propylamine or 2-phenyl-butylamine and subsequent hydrogenation the following 4,4-Diphenylcyclohexane are obtained:

1- (2-p-tolyl-ethylamino) -, methanesulphate, m.p. 282 ⁰ C; Yield: 11.4 g;

l- [2- (3-Hydroxy-4-methoxyphenyl) ethylamino] -,

Ethanesulphonate, F. 255 ⁰ C; Yield: 15.4 g; 1 - [2 - (3,4 - methylenedioxyphenyl) propylamino] -,

Hydrochloride, mp 214 ° C; Yield: 12.2 g; ίο 1- (2-phenylbutylamino) -, hydrochloride, m.p. 171 ⁰ C; Yield: 12.9 g.

Example 28

58.5 g of 1 - isopropylamino - 4,4 - diphenylcyclohexane and 30 g of triethylamine are dissolved in 200 ml of benzene. A solution of 33 g of benzoyl chloride in 100 ml of benzene is slowly added dropwise with stirring, then boiled for ¹ l for ₂ hours, cooled and washed with dilute hydrochloric acid. The benzene phase is evaporated and the obtained l- (N-Isopropylbenzamido) -4,4-diphenylcyclohexane recrystallized from ethanol (mp 188 ⁰ C). 70 g of the benzoyl compound are dissolved in 800 ml of absolute tetrahydrofuran, the solution is added dropwise to 8 g of lithium aluminum hydride in 200 ml of tetrahydrofuran, cooked for 5 hours and decomposed with dilute hydrochloric acid. The solvent is distilled off, the residue is treated with tartaric acid, made alkaline with sodium hydroxide solution and extracted with chloroform. After evaporation and recrystallization from ethanol, 58 g of 1- (N-isopropyl-N-benzylamino) -4,4-diphenylcyclohexane with a melting point of 110 ° C. Hydrochloride, melting point 155 ° C. are obtained.

Example 29

Analogously to Example 7, 10 g of 4,4-diphenylcyclohexen- (2) -one are used with allylamine to the Schiff base and then reduced with lithium aluminum hydride to l-allylamino-4,4-diphenylcyclohexene (2). Hydrochloride, mp 213 ° C. Yield: 7.1 g.

B e i s ρ i e 1 30

A solution of 5.2 g of 4,4-diphenylcyclohexen- (2) -one oxime in 50 ml of acetic acid is added with stirring 3 g of zinc dust. The mixture is stirred for a further 4 hours, filtered, diluted with water and made with ammonia alkaline and extracted with chloroform. After the solvent has been distilled off, 1.8 g are obtained 1-Amino-4,4-diphenylcyclohexene (2) with a boiling point of 158 to 160 ° C / 0.05 mmHg.

Example 31

A solution of 5.6 g of l-nitro-4,4-diphenylcyclohexane (obtained from 4,4-diphenylcyclohexyl iodide and

Silver nitrite) in 100 ml of hot ethanol is mixed with a solution of 15 g of sodium dithionite in 60 ml of water. The mixture is boiled for 1 hour, filtered and diluted with water. After the alcohol has been distilled off, the mixture is extracted with chloroform, dried and evaporated, and the 4,4-diphenylcyclohexylamine obtained is recrystallized from ethanol. M.p. 100 ^° C. Yield: 3.2 g.

Example 32

A solution of 8.1 g of 4,4-diphenylcyclohexyl chloride and 3.6 g of isopropylamine in 50 ml of toluene is boiled until no further precipitation of Isopropylamine hydrochloride precipitates more. Man cool

off, filtered, the filtrate extracted with dilute hydrochloric acid and worked up as in Example 6. You get 2.3 g of l-isopropylamino - ^ - diphenylcyclohexane vom Bp. 164 to 165 / 0.05 mm Hg.

Example 33

a) Analogously to Example 7, 2.48 g of 4,4-diphenylcyclohexen- (2) -one are obtained reacted with benzylamine to give Schiff's base and then hydrogenated on platinum oxide to l-benzylamino-4,4-diphenylcyclohexane. Yield: 2.0 g.

b) 2 g of crude l-benzylamino-4,4-diphenylcyclohexane are dissolved in 50 ml of methanol and strength after the addition of 200 mg of 5% palladium-carbon ^it is hydrogenated at room temperature and normal pressure to stop. The procedure is as in Example 6 and 1.3 g of 4,4-diphenylcyclohexylamine hydrochloride with a melting point of 260 ^° C. are obtained.

20th

Example 34

g of l-phthalimido-2-allyl-4,4-diphenylcyclohexane is boiled with 10 ml of concentrated hydrochloric acid for 6 hours. Most of the hydrochloric acid is distilled off, made alkaline with sodium hydroxide solution and the base extracted with ether. After the ethereal solution has dried, ethereal hydrochloric acid is added, the product is filtered off and the 2-allyl-4,4-diphenylcyclohexylamine hydrochloride obtained is recrystallized from ethanol. F. about 220 ⁰ C (decomposition). Yield: 0.3 g.

The starting material is obtained from 2-allyl-4,4-diphenylcyclohexanone via 2-allyl-4,4-diphenylcyclohexanol and 2-allyl-4,4-diphenylcyclohexyl bromide.

35

Claims (1)

Claim: Process for the preparation of 4,4-diphenylcyclohexylamines of the general formula I, which may be unsaturated in the 2,3-position and whose in Phenyl radicals located in the 4-position are substituted by a p-position alkyl group with 1 to 4 carbon atoms could be 45 and
R ¹ : R ² : R ³ = R ² -N-R ³ wherein = H, alkyl or alkenyl each with up to 4 carbon atoms, = H or alkyl with 1 to 4 carbon atoms and = H ₅ alkyl or alkenyl each with up to 8 carbon atoms, cycloalkyl with 3 to 8 carbon atoms or aralkyl, the aliphatic part of which contains 1 to 4 carbon atoms and the aromatic part of which is represented by a methylenedioxy group or one or more times by alkyl can be substituted with 1 to 4 carbon atoms, methoxy or hydroxyl, 55 60 65 means, and in which the radicals R ² and R ^{3 can} also form a pyrrolidine ring together with the nitrogen atom, as well as their acid addition salts and quaternary ammonium salts, characterized in that a compound of the general formula II (in the formulas II to VI have R ¹ to R ^{3 have} the meaning given above, the phenyl groups in the 4-position can be substituted as stated above, and a double bond can be present in the 2,3-position of the cyclohexane ring), II wherein X = H, NO ₂ ; = NOH; = NR ³ ; H ₅ N = R '; H ₁ NR ² acyl; SO ₃ H; = N-NH = N - N = <H or another radical which can be converted reductively into the group NR ² R ^{3 and} R '= an alkylidene or aralkylidene radical corresponding to ^{R 3} or an enamine of the general formula III y \ / III R ² -N-R ³ (the dotted line means that there is a double bond in one of the positions indicated) in a manner known per se, in particular catalytically in the presence of noble metal catalysts, copper-chromium oxide, nickel or cobalt catalysts at normal pressure and room temperature or elevated pressure up to about 200 at and / or elevated temperature up to about 200 ⁰ C in the presence of a solvent, or reduced with nascent hydrogen, cathodically or by means of complex metal hydrides that a compound of the general formula IV IV worm Y = H, OH; H, lower alkoxy, H ₅ Hal or = O and HaI = Cl, Br or J means in a manner known per se with a base of the general formula V R ² - NH - R ³ V or with agents that donate such a base, optionally under reducing conditions, advantageously treated in the presence of platinum or Raney nickel, or that one in a compound with the basic structure of the general formula I, which has one or more hydroxyl groups contains in functionally modified form and / or their amino groups in functionally modified form Form is present, the hydroxyl and / or amino group or groups in the usual way by catalytic hydrogenation, hydrolytic, alcoholytic or aminolytically set free or that an organometallic compound of general formula VI VI where M = Li or MgHaI, in a manner known per se with a hydroxylamine derivative the general formula H ₂ N - Z, in which Z = lower alkoxy or Hai, and that a obtained primary or secondary amine of the general formula I (R ² = H) is optionally treated in a manner known per se with alkylating agents and optionally this, as well as the alkylation products, in the customary manner an acid or an alkylating agent in their physiologically harmless acid addition salts or quaternary ammonium salts 009 524/270