DE4437999A1

DE4437999A1 - N, N-disubstituted arylcycloalkylamines, their salts with physiologically acceptable organic or inorganic acids, process for their preparation and medicaments containing them

Info

Publication number: DE4437999A1
Application number: DE4437999A
Authority: DE
Inventors: Roland Dipl Chem Dr Maier; Peter Dipl Chem Dr Mueller; Eberhard Dipl Chem Dr Woitun; Rudolf Dipl Chem Dr Hurnaus; Michael Dr Mark; Bernhard Dipl Chem Dr Eisele; Ralph-Michael Dipl B Budzinski
Original assignee: Dr Karl Thomae GmbH
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1994-10-25
Filing date: 1994-10-25
Publication date: 1996-05-02

Abstract

Substd. aminocycloalkanes of formula (I), their isomers and, if basic gps. are present, salts with (in)organic acids are new: m = 0 or 1; X = 0, 5 or -MR5; R1 = phenyl with 1-3 substits. (i.e. 1-3 (1-4C alkyl; one phenyl; 1 or 2 OH; halo; benzyloxy; allyloxy or propargyloxy; 1-3 1-4C alkoxy(opt. substd. by NR6R7); one HCO or one up to 4C acetal gp.), or R1 furyl, thienyl or pyrimidinyl (all opt. substd. by 1-3C alkyl and/or alkoxy), or pyridyl or naphthyl; R2a-R2h = H or 1-3C alkyl or alkenyl; R3 = 1-5C alkyl, alkenyl or alkynyl, phenyl, cyclohexyl or cyclohexylmethyl; R4 = 3-19C alkyl or alkenyl (opt. interrupted by O or S, with 1-3 double bonds for alkenyl), phenyl substd. 1-4C alkyl or 2-4C alkenyl (opt. ring substd. by 1-3C alkyl or alkoxy), phenyl (0pt. substd. by 1 or 2 of 1-3C alkyl or alkoxy, or halo); cyclohexyl, cyclohexyl, (1-4C)alkyl or cyclohexyl(2-4C)alkenyl, biphenyl or (opt. substd. by 1-3C alkyl) furyl, thienyl or pyridyl; R5 = phenyl or p-toluenesulphonyl; R6 and R7 = H, phenyl, 1-6C alkyl (opt. substd. by phenyl) or together they complete piperidino, morpholino or pyrrolidino.

Description

Die Erfindung betrifft N.N-disubstituierte Arylcycloalkyl amine, ihre Salze mit physiologisch vertraglichen organi schen oder anorganischen Säuren, Verfahren zur Herstellung dieser Verbindungen und diese enthaltende Arzneimittel.The invention relates to N, N-disubstituted arylcycloalkyl amines, their salts with physiologically contractual organi or inorganic acids, process for the preparation these compounds and medicines containing them.

Die Bedeutung überhöhter Serum-Cholesterin-Spiegel als Haupt risikofaktor für die Entstehung atherosklerotischer Gefäß veränderungen wird allgemein anerkannt. Da der größte Teil des Cholesterins im Organismus selbst synthetisiert und nur ein geringer Teil mit der Nahrung aufgenommen wird, ist die Hemmung der Biosynthese ein besonders attraktiver Weg, er höhte Cholesterinspiegel zu senken. Da die Cholesterinbio synthese über viele Stufen abläuft, sind verschiedene Mög lichkeiten zum Eingriff gegeben.The importance of excessive serum cholesterol levels as the main Risk factor for the emergence of atherosclerotic vessel Changes are generally accepted. Because the biggest part of cholesterol in the organism itself synthesized and only a small part is taken with food is the Inhibition of biosynthesis is a particularly attractive route, he said increased cholesterol levels lower. Since the cholesterol bio Synthesis over many stages is possible possibilities for intervention.

Die größte Bedeutung haben Verbindungen des Mevinolin-Typs erlangt, die bereits in der Therapie Verwendung finden. Es handelt sich dabei um substituierte 3,5-Dihydroxy-carbonsäu ren oder davon abgeleitete δ-Lactone, die kompetitive Hem mer des Enzyms 3-Hydroxy-3-methyl-glutaryl-(HMG-)-CoA-reduk tase darstellen, also in einer frühen Stufe der Cholesterin biosynthese eingreifen. Of greatest importance are compounds of the mevinolin type attained, which are already used in therapy. It this is substituted 3,5-dihydroxycarboxylic acid ren or derived δ-lactones, the competitive Hem of the enzyme 3-hydroxy-3-methyl-glutaryl- (HMG-) - CoA-reduc tase, ie in an early stage of cholesterol intervene in biosynthesis.

Weitere Verbindungsklassen, die auf verschiedenartige Weise zumindest in vitro in die Cholesterinbiosynthese eingreifen, sind z. B. die Oxysteroide, Squalen-Derivate sowie Naphthyl amin-Derivate, wie Naftifine und Terbinafine. Eine Zusammen stellung dieser Verbindungen findet sich in J. Amer. Chem. Soc. 111, 1508-10 (1989). Zu erwähnen sind ferner Isoprenoid- (phosphinylmethyl)phosphonate, die Inhibitoren des Enzyms Squalen-Synthetase darstellen (J. Med. Chem. 31 (10) 1869- 1871 (1988)).Other compound classes in different ways intervene in cholesterol biosynthesis, at least in vitro, are z. As the oxysteroids, squalene derivatives and naphthyl amine derivatives such as naftifine and terbinafine. A collaboration position of these compounds can be found in J. Amer. Chem. Soc. 111, 1508-10 (1989). Also worthy of mention are isoprenoid (phosphinylmethyl) phosphonates, the inhibitors of the enzyme Squalene synthetase (J. Med. Chem. 31 (10) 1869- 1871 (1988)).

Biologisch aktive 5- bis 7gliedrige, N.N-disubstituierte Arylcycloalkylamine, bei denen ein N-Substituent den Acyl-, Thioacyl- oder Imidoylrest darstellt, sind in der Literatur nur vereinzelt beschrieben.Biologically active 5- to 7-membered, N, N-disubstituted Arylcycloalkylamines in which an N-substituent is the acyl, Thioacyl or Imidoylrest are in the literature only sporadically described.

In Il Farmaco. Ed. Sci. 1970, 25, 248-94 (CA 73, 2397r) wer den N.N-disubstituierte Phenyl-cyclohexylamine mit lokal anästhetischer und hypertensiver Wirkung beschrieben.In Il Farmaco. Ed. Sci. 1970, 25, 248-94 (CA 73, 2397r) the N-disubstituted phenyl cyclohexylamine with local anesthetic and hypertensive effects.

4-Tetrazolyl-cyclohexylamine mit analgetischer und entzün dungshemmender Wirkung sind beschrieben in Il Farmaco, Ed. Sci. 1984, 39, 1024-37 (CA 102, 197808y).4-Tetrazolyl-cyclohexylamine with analgesic and inflammatory antiperspirant effect are described in Il Farmaco, Ed. Sci. 1984, 39, 1024-37 (CA 102, 197808y).

4-Phenyl-cyclohexylamine, die ACE-Hemmer darstellen, finden sich in der Europäischen Anmeldung EP-103 927 (CA 101, 91447u), J. Med. Chem. 1983, 26, 1267-77 (CA 99, 88551h) so wie Drug. Dev. Res. 1986, 26, 141-51 (CA 104, 179906r). 5- bis 7gliedrige Arylcycloalkylamine, bei denen ein N-Substituent den Acyl-, Thioacyl- oder Imidoylrest darstellt und die eine cholesterinbiosynthesehemmende Wirkung besitzen sind noch nicht beschrieben worden.4-phenyl-cyclohexylamine, which are ACE inhibitors find in European application EP-103 927 (CA 101, 91447u), J. Med. Chem. 1983, 26, 1267-77 (CA 99, 88551h) like drug. Dev. Res. 1986, 26, 141-51 (CA 104, 179906r). 5- to 7-membered arylcycloalkylamines in which an N-substituent represents the acyl, thioacyl or Imidoylrest and the one possess cholesterol biosynthesis inhibitory effect are still not described.

In der Patentschrift BE 772010-Q (31.8.70) werden substi tuierte 4-Arylcyclohexylamine mit antikonvulsiver, ZNS-sti mulierender und hypotensiver Wirkung mitbeansprucht, die neben anderen Substituenten am Stickstoff durch Alkylreste mit 1 bis 4 Kohlenstoffatomen und Alkanoylreste mit 1 bis 3 Kohlenstoffatomen substituiert sind. In dieser Patentschrift ist jedoch keine einzige Verbindung dieses Strukturtyps be schrieben.In the patent BE 772010-Q (31.8.70) Substi 4-arylcyclohexylamine with anticonvulsant, CNS sti mulatory and hypotensive effect, the in addition to other substituents on the nitrogen by alkyl radicals having 1 to 4 carbon atoms and alkanoyl radicals having 1 to 3 Carbon atoms are substituted. In this patent however, it is not a single compound of this type of structure wrote.

Es wurde überraschenderweise gefunden, daß N.N-disubstitu ierte Arylcycloalkylamine, bei denen ein N-Substituent den Acyl-, Thioacyl- oder Imidoylrest bedeutet, sehr gute Hemmer der Cholesterinbiosynthese darstellen, bei einem von dem der HMG-CoA-Reduktase-Hemmer abweichenden Wirkmechanismus.It was surprisingly found that N, N-disubstitu Arylcycloalkylamine in which an N-substituent is the Acyl, thioacyl or imidoyl means very good inhibitors of cholesterol biosynthesis, in one of which the HMG-CoA reductase inhibitor deviating mode of action.

Die N.N-disubstituierten Arylcycloalkylamine und ihre Salze der vorliegenden Erfindung besitzen die allgemeine Formel IThe N, N-disubstituted arylcycloalkylamines and their salts of the present invention have the general formula I.

In der allgemeinen Formel I bedeuten
n die Zahlen 0 oder 1,
X das Sauerstoff- oder Schwefelatom oder eine Iminogruppe der Formel =NR⁵
R¹ eine mono-, di- oder trisubstituierte Phenylgruppe, die substituiert sein kann durch 1 bis 3 geradkettige oder ver zweigte Alkylgruppen mit 1 bis 4 Kohlenstoffatomen, durch die Phenylgruppe, durch 1 oder 2 Hydroxygruppen, ein Halo genatom, wie z. B. ein Fluor- oder Chloratom, die Benzyl oxy-, Allyloxy- oder Propargyloxygruppe, durch 1 bis 3 Alk oxygruppen mit 1 bis 4 Kohlenstoffatomen im geradkettigen oder verzweigten Alkylrest, wobei der Alkylrest seinerseits substituiert sein kann durch eine Aminogruppe der allgemei nen Formel -NR⁶R⁷, durch eine Formylgruppe oder eine alipha tische Acetalgruppe mit bis zu 4 Kohlenstoffatomen, R¹ be deutet desweiteren die Furyl-, Thienyl- oder Pyrimidinyl gruppe, die gegebenenfalls durch Alkyl- und/oder Alkoxyreste mit 1 bis 3 Kohlenstoffatomen substituiert sein können, die Pyridyl- und die Naphthylgruppe,
R^2a bis R^2h, die gleich oder verschieden sein können, ein Wasserstoffatom, eine Alkyl- oder Alkenylgruppe mit 1 bis 3 Kohlenstoffatomen,
R³ eine geradkettige oder verzweigte Alkyl-, Alkenyl- oder Alkinylgruppe mit 1 bis 5 Kohlenstoffatomen, die Phenylgrup pe, die Cyclohexylgruppe sowie die Cyclohexylmethylgruppe,
R⁴ eine geradkettige oder verzweigte Alkyl- oder Alkenyl gruppe mit 3 bis 19 Kohlenstoffatomen, in der die Kohlen stoffkette durch ein Sauerstoff- oder Schwefelatom unter brochen sein kann und der Alkenylteil 1 bis 3 Doppelbindun gen enthält, eine Phenylalkyl- oder Phenylalkenylgruppe mit 1 bis 4 Kohlenstoffatomen im Alkylenteil oder 2 bis 4 Koh lenstoffatomen im Alkenylenteil, wobei der Phenylteil durch eine Alkyl- oder Alkoxygruppen mit 1 bis 3 Kohlenstoffatomen substituiert sein kann, die Phenylgruppe, die gegebenenfalls durch ein oder zwei Alkyl- oder Alkoxygruppen mit 1 bis 3 Kohlenstoffatomen oder durch 1 oder 2 Halogenatome, wie z. B. Fluor, Chlor- oder Bromatom, substituiert sein kann, die Cyclohexylgruppe oder eine Cyclohexylalkyl- oder Cyclohexyl alkenylgruppe, wobei der Alkylenteil 1 bis 4 Kohlenstoff atome oder der Alkenylenteil 2 bis 4 Kohlenstoffatome auf weist, R⁴ kann aber auch die Biphenylgruppe oder eine ge gebenenfalls durch Alkylgruppen mit 1 bis 3 Kohlenstoffato men substituierte Furyl-, Thienyl- oder Pyridylgruppe bedeu ten,
R⁵ die Phenylgruppe oder die p-Toluolsulfonylgruppe,
R⁶ und R⁷, die gleich oder verschieden sein können, ein Wasserstoffatom, die Phenylgruppe, eine geradkettige oder verzweigte Alkylgruppe mit 1 bis 6 Kohlenstoffatomen, die gegebenenfalls durch einen Phenylrest substituiert sein kann, ferner können
R⁶ und R⁷ zusammen mit dem Stickstoffatom und gegebenen falls einem weiteren Sauerstoffatom die Piperidino-, Morpho lino- oder Pyrrolidinogruppe bilden.In the general formula I mean
n are the numbers 0 or 1,
X is the oxygen or sulfur atom or an imino group of the formula = NR⁵
R¹ is a mono-, di- or trisubstituted phenyl group which may be substituted by 1 to 3 straight or branched chain alkyl groups having 1 to 4 carbon atoms, by the phenyl group, by 1 or 2 hydroxy groups, a halo genatom such. Example, a fluorine or chlorine atom, the benzyl oxy, allyloxy or Propargyloxygruppe, by 1 to 3 alkoxy groups having 1 to 4 carbon atoms in the straight-chain or branched alkyl radical, wherein the alkyl radical may in turn be substituted by an amino group of the general formula - NR⁶R⁷, by a formyl group or an alipha tables acetal group having up to 4 carbon atoms, R¹ be further indicated the furyl, thienyl or pyrimidinyl group, which may optionally be substituted by alkyl and / or alkoxy having 1 to 3 carbon atoms, the pyridyl - and the naphthyl group,
R ^2a to R ^2h , which may be the same or different, represent a hydrogen atom, an alkyl or alkenyl group having 1 to 3 carbon atoms,
R³ is a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 5 carbon atoms, the phenyl group, the cyclohexyl group and the cyclohexylmethyl group,
R⁴ represents a straight-chain or branched alkyl or alkenyl group having 3 to 19 carbon atoms in which the carbon chain can be interrupted by an oxygen or sulfur atom and the alkenyl part contains 1 to 3 double bonds, a phenylalkyl or phenylalkenyl group having 1 to 4 Carbon atoms in the alkylene part or 2 to 4 Koh atoms in the alkenylene part, wherein the phenyl moiety may be substituted by an alkyl or alkoxy groups having 1 to 3 carbon atoms, the phenyl group optionally substituted by one or two alkyl or alkoxy groups having 1 to 3 carbon atoms or by 1 or 2 halogen atoms, such as. As fluorine, chlorine or bromine atom, the cyclohexyl group or a cyclohexylalkyl or cyclohexyl alkenyl group, wherein the alkylene part 1 to 4 carbon atoms or the alkenylene part has 2 to 4 carbon atoms, but R⁴ can also be the biphenyl group or a ge optionally substituted by alkyl groups having 1 to 3 Kohlenstoffato men substituted furyl, thienyl or pyridyl group,
R⁵ represents the phenyl group or the p-toluenesulfonyl group,
R⁶ and R⁷, which may be the same or different, may further include a hydrogen atom, phenyl group, a straight-chain or branched alkyl group having 1 to 6 carbon atoms which may be optionally substituted by a phenyl group
R⁶ and R⁷ together with the nitrogen atom and optionally a further oxygen atom form the piperidino, morpholino or pyrrolidino group.

production methods

Die Verbindungen der allgemeinen Formel I lassen sich nach folgenden Methoden herstellen:The compounds of general formula I can be after create the following methods:

A) Verbindungen, in denen X ein Sauerstoffatom bedeutet und R¹ bis R⁴ und n die vorstehenden Bedeutungen besitzen, lassen sich durch Umsetzung von Aminen der allgemeinen For mel IIA) compounds in which X represents an oxygen atom and R¹ to R⁴ and n have the above meanings, can be prepared by reaction of amines of the general For mel II

in der
R¹, R^2a bis R^2h, R³ und n die vorstehenden Bedeutun gen besitzen, mit einem Säurederivat der allgemeinen Formel IIIin the
R¹, R ^2a to R ^2h , R³ and n have the above meanings gene, with an acid derivative of the general formula III

herstellen, in der
R⁴ die vorstehenden Bedeutungen besitzt und Y eine reak tive austauschbare Gruppe wie z. B. ein Halogenatom, vor zugsweise ein Chloratom oder die Imidazolidgruppe bedeutet.produce in the
R⁴ has the above meanings and Y is a reac tive exchangeable group such. As a halogen atom, preferably before a chlorine atom or the imidazolide group.

Bedeutet Y ein Halogenatom, werden die Umsetzungen in inerten Lösungsmitteln wie Ether, Toluol, Methylenchlorid und der gleichen, vorzugsweise bei Temperaturen zwischen -50°C und 50°C und in Gegenwart eines halogenwasserstoffbindenden Mit tels, wie tertiäre Amine, Natriumcarbonat oder Calciumcar bonat, durchgeführt. Dabei können nicht nur die freien Amine der allgemeinen Formel II eingesetzt werden, sondern auch deren Salze, aus denen in situ die Amine durch geeignete Ba sen, z. B. tertiäre organische Amine, freigesetzt werden können.When Y is a halogen atom, the reactions become inert Solvents such as ethers, toluene, methylene chloride and the same, preferably at temperatures between -50 ° C and 50 ° C and in the presence of a hydrogen halide-binding Mit such as tertiary amines, sodium carbonate or calcium car bonat, performed. Not only the free amines can do this the general formula II, but also their salts, from which the amines are prepared in situ by suitable Ba sen, z. As tertiary organic amines are released can.

Bedeutet Y den Imidazolidrest, werden die Umsetzungen vor zugsweise in einem hochsiedenden Lösungsmittel, wie Xylol, bei Rückflußtemperatur durchgeführt.If Y is the imidazolide radical, the reactions are present preferably in a high boiling solvent such as xylene, carried out at reflux temperature.

Falls im Rest R¹ empfindliche oder die Reaktion störende Substituenten vorhanden sind, wie z. B. die Hydroxygruppe, die primäre oder sekundäre Aminogruppe, oder die Formylgrup pe, empfiehlt es sich, diese vor der Umsetzung in bekannter Weise mit Schutzgruppen zu versehen und diese Schutzgruppen nach beendeter Umsetzung wieder abzuspalten.If in the radical R¹ sensitive or the reaction disturbing Substituents are present, such as. The hydroxy group, the primary or secondary amino group, or the formyl group pe, it is recommended that they are well-known before implementation Ways to provide protective groups and these protecting groups after completion of the implementation split off again.

Als Schutzgruppen eignen sich z. B. für die Hydroxygruppe die Methylgruppe, die durch Bortribromid oder Natriumthio ethanolat abgespalten werden kann, für die Aminogruppe der tert.-Butoxycarbonylrest, der mit Trifluoressigsäure ab spaltbar ist und für den Formylrest eine Acetalgruppe, die sich sauer abspalten läßt.As protective groups are z. B. for the hydroxy group the methyl group, which is boron tribromide or sodium thio ethanolate can be split off, for the amino group of tert-Butoxycarbonylrest, which starts with trifluoroacetic acid is cleavable and for the formyl an acetal group, the can split off sour.

B) Verbindungen der Formel I, in denen X ein Sauerstoffatom bedeutet, n, R^2a bis R^2h, R³ und R⁴ wie eingangs de finiert sind und R¹ eine Phenylgruppe bedeutet, die sub stituiert ist durch die Benzyloxy-, Allyloxy-, Propargyloxy gruppe oder durch eine geradkettige oder verzweigte Alkoxy gruppe mit 1 bis 4 Kohlenstoffatomen, die ihrerseits im Alkylteil substituiert sein kann durch eine Aminogruppe der allgemeinen Formel NR⁶R⁷ mit den oben für R⁶ und R⁷ angegebenen Bedeutungen, durch eine Alkoxygruppe mit 1 bis 3 Kohlenstoffatomen, eine Formyl- oder Acetalgruppe, wobei der Phenylrest gegebenenfalls noch eine oder zwei geradkettige oder verzweigte Alkylgruppen mit 1 bis 4 Kohlenstoffatomen und/oder ein Halogenatom enthalten kann, lassen sich durch Umsetzungen von Verbindungen der allgemeinen Formel I, in de nen X ein Sauerstoffatom ist und n, R^2a bis R^2h, R³ und R⁴ wie oben definiert sind und R¹ einen Monohydroxyphenylrest bedeutet der gegebenenfalls noch eine oder zwei geradkettige oder verzweigte Alkylgruppen mit 1 bis 4 Kohlenstoffatomen und/oder ein Halogenatom enthalten kann, mit Verbindungen der allgemeinen Formel IVB) Compounds of the formula I in which X is an oxygen atom, n, R ^2a to R ^2h , R³ and R⁴ are as defined above and R¹ is a phenyl group which is substituted by the benzyloxy, allyloxy, propargyloxy group or by a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, which in turn may be substituted in the alkyl part by an amino group of the general formula NR⁶R⁷ with the meanings given above for R⁶ and R⁷, by an alkoxy group having 1 to 3 carbon atoms, a formyl or acetal group, where the phenyl radical may optionally also contain one or two straight-chain or branched alkyl groups having 1 to 4 carbon atoms and / or one halogen atom, can be obtained by reactions of compounds of the general formula I in which X is an oxygen atom and n, R ^2a to R ^2h , R³ and R⁴ are as defined above and R¹ is a Monohydroxyphenylrest which may optionally be one or z may contain straight-chain or branched alkyl groups having 1 to 4 carbon atoms and / or a halogen atom, with compounds of general formula IV

R⁸-Z (IV)R⁸Z (IV)

in derin the

R⁸ die Benzyl-, Allyl- oder Propargylgruppe oder eine ge radkettige oder verzweigte Alkylgruppe mit 1 bis 4 Kohlen stoffatomen bedeutet, wobei der Alkylrest seinerseits durch eine Aminogruppe der allgemeinen Formel -NR⁶R⁷ mit den oben angegebenen Bedeutungen für R⁶ und R⁷, durch eine Alkoxygruppe mit 1 bis 3 Kohlenstoffatomen, eine Formyl- oder Acetalgruppe substituiert sein kann und
Z ein Chlor-, Brom- oder Jodatom oder eine Sulfonyloxygruppe wie z. B. die p-Toluolsulfonyloxygruppe darstellt, erhalten.R⁸ is the benzyl, allyl or propargyl group or a GE radkettige or branched alkyl group having 1 to 4 carbon atoms, wherein the alkyl radical in turn by an amino group of the general formula -NR⁶R⁷ with the meanings given above for R⁶ and R⁷, by an alkoxy group 1 to 3 carbon atoms, a formyl or acetal group may be substituted and
Z is a chlorine, bromine or iodine atom or a sulphonyloxy group such as. As the p-toluenesulfonyloxy group is obtained.

Die Umsetzung wird in einem Lösungsmittel wie Ethanol, tert.- Butanol, Tetrahydrofuran oder Dimethylformamid bei Tempera turen zwischen 0°C und 100°C durchgeführt in Gegenwart einer Base wie Kaliumcarbonat, Natriumethanolat, Kalium-tert.-buta nolat oder Natriumhydrid. The reaction is carried out in a solvent such as ethanol, tert. Butanol, tetrahydrofuran or dimethylformamide at tempera temperatures between 0 ° C and 100 ° C in the presence of a Base such as potassium carbonate, sodium ethoxide, potassium tert-buta nolate or sodium hydride.

Falls im Rest R⁸ empfindliche oder die Reaktion störende Substituenten vorhanden sind, wie z. B. die primäre oder se kundäre Aminogruppe oder die Formylgruppe, empfiehlt es sich, diese vor der Umsetzung in bekannter Weise mit Schutz gruppen zu versehen und diese nach beendeter Umsetzung wie der abzuspalten. Geeignete Schutzgruppen wurden bereits wei ter oben beschrieben.If in the radical R⁸ sensitive or the reaction disturbing Substituents are present, such as. B. the primary or se secondary amino group or the formyl group, it recommends itself, this before the implementation in a known manner with protection to provide groups and this after completion as the implementation to split off. Suitable protecting groups have already been white ter described above.

C) Verbindungen der allgemeinen Formel I, in der X ein Sau erstoffatom darstellt, n, R^2a bis R^2h, R³ und R⁴ wie eingangs definiert sind und R eine Phenylgruppe, die in 4-Stellung durch eine Alkoxygruppe mit 1 bis 4 Kohlenstoffatomen, die ihrerseits eine Aminogruppe der Formel -NR⁶R⁷ enthält, substituiert ist, wobei der Phenylrest gegebenenfalls noch eine oder zwei geradkettige oder verzweigte Alkylgruppen mit 1 bis 4 Kohlenstoffatomen und/oder ein Halogenatom enthalten kann, lassen sich dadurch erhalten, daß eine Verbindung der allgemeinen Formel I, in der X, n, R² bis R⁴ wie oben definiert sind und R¹ eine Phenylgruppe, die in 4-Stellung durch eine Alkoxygruppe mit 1 bis 3 Kohlenstoffatomen, die ihrerseits durch eine Formylgruppe substituiert ist, wobei der Phenylrest gegebenenfalls noch eine oder zwei geradket tige oder verzweigte Alkylgruppen mit 1 bis 4 Kohlenstoff atomen und/oder ein Halogenatom enthalten kann, bedeutet, mit einem Amin der allgemeinen Formel VC) Compounds of the general formula I in which X represents an oxygen atom, n, R ^2a to R ^2h , R³ and R⁴ are as defined above and R is a phenyl group which is in the 4-position by an alkoxy group having 1 to 4 carbon atoms, which in turn contains an amino group of the formula -NR⁶R⁷, wherein the phenyl radical may optionally contain one or two straight-chain or branched alkyl groups having 1 to 4 carbon atoms and / or one halogen atom, can be obtained by reacting a compound of the general formula I in which X, n, R² to R⁴ are as defined above and R¹ is a phenyl group which is substituted in the 4-position by an alkoxy group having 1 to 3 carbon atoms, which in turn is substituted by a formyl group, wherein the phenyl radical is optionally one or two more straight atoms containing from 1 to 4 carbon atoms and / or a halogen atom, may mean, with an amine of the general formula V

HNR⁶R⁷ (V)HNR⁶R⁷ (V)

worin R⁶ und R⁷ wie eingangs erwähnt definiert sind, oder mit dessen Salzen mit anorganischen oder organischen Säuren in Gegenwart von Reduktionsmitteln umgesetzt wird. Als Reduktionsmittel eignen sich Natriumcyanborhydrid oder katalytisch erregter Wasserstoff.wherein R⁶ and R⁷ are defined as mentioned above, or with its salts with inorganic or organic Acids is reacted in the presence of reducing agents. Suitable reducing agents are sodium cyanoborohydride or catalytically excited hydrogen.

Diese Umsetzungen werden in Lösungsmittel, wie Alkoholen, Tetrahydrofuran, Dioxan, Wasser oder Gemischen dieser Lö sungsmittel bei Temperaturen zwischen 0 und 100°C, vorzugs weise bei Raumtemperatur, durchgeführt.These reactions are carried out in solvents such as alcohols, Tetrahydrofuran, dioxane, water or mixtures of these Lö at temperatures between 0 and 100 ° C, preferably at room temperature.

In Fällen, in denen der Rest -NR⁶R⁷ eine primäre Amino gruppe darstellt, läßt sich das Verfahren dahingehend abwan deln, daß die intermediär entstehende Schiff′sche Base iso liert wird und anschließend mit Reduktionsmitteln wie Na triumboranat oder katalytisch erregtem Wasserstoff umgesetzt wird.In cases where the residue -NR⁶R⁷ is a primary amino group, the process can be removed that the intermediately formed Schiff base iso and then with reducing agents such as Na triumboranate or catalytically excited hydrogen reacted becomes.

D) Die Verbindungen der allgemeinen Formel I, in der X ein Schwefelatom bedeutet und n sowie R¹ bis R⁴ wie eingangs definiert sind, können durch Umsetzung von Verbindungen der Formel I, in denen n sowie R¹ bis R⁴ wie eingangs defi niert sind und X ein Sauerstoffatom bedeutet, mit Schwefel reagenzien wie Diphosphorpentasulfid oder Lawesson-Reagens erhalten werden.D) The compounds of general formula I in which X is a Sulfur atom and n and R¹ to R⁴ as above can be defined by the implementation of compounds of the Formula I, in which n and R¹ to R⁴ as defi and X is an oxygen atom, with sulfur reagents such as diphosphorus pentasulfide or Lawesson's reagent to be obtained.

Die Umsetzungen lassen sich in inerten Lösungsmitteln wie Acetonitril, Toluol oder Xylol bei Temperaturen zwischen 0 und 150°C durchführen. Eine Übersicht über Umsetzungen mit Lawesson-Reagens findet sich in Tetrahedron Letters 41, 2567 (1985).The reactions can be in inert solvents such as Acetonitrile, toluene or xylene at temperatures between 0 and 150 ° C perform. An overview of conversions with Lawesson's reagent is found in Tetrahedron Letters 41, 2567 (1985).

Befinden sich im Substituenten R¹ empfindliche oder die Reaktion störende Substituenten wie z. B. die Hydroxygruppe, eine primäre oder sekundäre Aminogruppe, oder die Formyl gruppe, empfiehlt es sich, diese vor der Umsetzung in be kannter Weise mit Schutzgruppen zu versehen und diese Schutz gruppen nach beendeter Umsetzung wieder abzuspalten.Are in the substituent R¹ sensitive or the Reaction interfering substituents such. The hydroxy group, a primary or secondary amino group, or the formyl group, it is recommended that these be before implementation in be to be protected with protective groups and this protection to split off groups after completion.

Als Schutzgruppen eignen sich z. B. für die Hydroxygruppe die Methylgruppe, die durch Bortribromid oder Natriumthio ethanolat abgespalten werden kann, für die Aminogruppe der tert.-Butoxycarbonylrest, der mit Trifluoressigsäure ab spaltbar ist und für den Formylrest eine Acetalgruppe, die sich sauer abspalten läßt. As protective groups are z. B. for the hydroxy group the methyl group, which is boron tribromide or sodium thio ethanolate can be split off, for the amino group of tert-Butoxycarbonylrest, which starts with trifluoroacetic acid is cleavable and for the formyl an acetal group, the can split off sour.

E) Verbindungen der allgemeinen Formel I, in der X die Gruppierung =NR⁵ darstellt, in der R⁵ die Phenylgruppe ist und R¹ bis R⁴ und n wie eingangs definiert sind, lassen sich dadurch darstellen, daß Verbindungen der allge meinen Formel I, in der X ein Sauerstoffatom bedeutet und n sowie R¹ bis R⁴ wie eingangs definiert sind, zunächst mit Säurechloriden wie Thionylchlorid, Phosphoroxychlorid, Phosgen oder Oxalylchlorid oder mit Alkylierungsmitteln wie Dimethylsulfat, in reaktionsfähige Derivate umgewandelt wer den, die anschließend mit Anilin zur Reaktion gebracht wer den.E) Compounds of general formula I in which X is the Grouping = NR⁵ represents, in the R⁵ the phenyl group and R¹ to R⁴ and n are as defined above, can be represented by the fact that compounds of the general my formula I, in which X is an oxygen atom and n and R¹ to R⁴ are as defined initially with acid chlorides such as thionyl chloride, phosphorus oxychloride, Phosgene or oxalyl chloride or with alkylating agents such as Dimethyl sulfate, converted into reactive derivatives who those which are subsequently reacted with aniline the.

Die Umsetzungen lassen sich in inerten Lösungsmitteln wie Ether, Methylenchlorid, Chloroform oder Toluol bei Tempera turen zwischen -40°C und der Siedetemperatur des jeweiligen Lösungsmittels durchführen.The reactions can be in inert solvents such as Ether, methylene chloride, chloroform or toluene at Tempera temperatures between -40 ° C and the boiling point of each Perform solvent.

F) Verbindungen der allgemeinen Formel I, in denen X die Gruppe =NR⁵ darstellt, in der R⁵ die p-Toluolsulfonyl gruppe bedeutet und R¹ bis R⁴ sowie n wie eingangs defi niert sind, lassen sich durch Umsetzung von Verbindungen der allgemeinen Formel I, in denen X ein Sauerstoffatom bedeutet und R¹ bis R⁴ sowie n wie eingangs definiert sind, mit p-Toluolsulfonylisocyanat vorzugsweise in siedendem Toluol herstellen.F) Compounds of general formula I in which X is the Group = NR⁵ represents, in the R⁵ the p-toluenesulfonyl group and R¹ to R⁴ and n as initially defi can be achieved by the implementation of compounds of general formula I in which X represents an oxygen atom and R¹ to R⁴ and n are as defined above, with p-toluenesulfonyl isocyanate, preferably in boiling toluene produce.

Befinden sich im Substituenten R¹ empfindliche oder die Reaktion störende Substituenten wie z. B. die Hydroxygruppe, eine primäre oder sekundäre Aminogruppe, oder die Formyl gruppe, empfiehlt es sich, diese vor der Umsetzung in be kannter Weise mit Schutzgruppen zu versehen und diese Schutzgruppen nach beendeter Umsetzung wieder abzuspalten, wie bereits schon weiter oben beschrieben wurde.Are in the substituent R¹ sensitive or the Reaction interfering substituents such. The hydroxy group, a primary or secondary amino group, or the formyl group, it is recommended that these be before implementation in be knowledgeable ways to provide and protections To split off protection groups again after completion of the implementation, as already described above.

Die nach den vorstehenden Verfahren hergestellten Verbindun gen der allgemeinen Formel I lassen sich nach bekannten Methoden, z. B. Kristallisation, Destillation oder Chromato graphie reinigen und isolieren. Sie können gewünschtenfalls, falls basische Reste vorhanden sind, in ihre Salze mit orga nischen oder anorganischen Säuren nach an sich bekannten Methoden überführt werden.The compounds prepared by the above methods gene of the general formula I can be according to known Methods, eg. As crystallization, distillation or chromato clean and insulate graph. If desired, you can if basic radicals are present, in their salts with orga niche or inorganic acids according to known Methods are transferred.

In den erfindungsgemäßen Verbindungen der Formel I können die Reste R¹ und R² sowie das Stickstoffatom entweder die äquatoriale oder die axiale Anordnung einnehmen. Die Er findung umfaßt sowohl die reinen isomeren Formen als auch Gemische der verschiedenen Isomeren.In the compounds of the formula I according to the invention the radicals R¹ and R² and the nitrogen atom either take the equatorial or the axial arrangement. The Er The invention includes both the pure isomeric forms and Mixtures of the different isomers.

raw materials

Die Ausgangsverbindungen der allgemeinen Formel II lassen sich aus Ketonen der allgemeinen Formel VII,Leave the starting compounds of general formula II consisting of ketones of general formula VII,

in der
n, R¹ und R^2a bis R^2h wie eingangs definiert sind, und Aminen der allgemeinen Formel VIIIin the
n, R¹ and R ^2a to R ^{2h are} as defined above, and amines of the general formula VIII

H₂NR³ (VIII)H₂NR³ (VIII)

in der
R³ wie eingangs definiert ist, in Gegenwart von Reduktions mitteln erhalten. Die Reaktion kann dabei so geführt werden, daß entweder das Reaktionsgemisch direkt zu Verbindungen der Formel II umgesetzt wird, z. B. in Gegenwart von Natrium cyanborhydrid oder katalytisch erregtem Wasserstoff, oder daß zunächst die als Zwischenprodukt entstehende Schiff′sche Base der Formel IXin the
R³ as defined above, obtained in the presence of reducing agents. The reaction can be carried out so that either the reaction mixture is reacted directly to compounds of formula II, for. Example, in the presence of sodium cyanborohydride or catalytically excited hydrogen, or that initially formed as an intermediate Schiff's base of the formula IX

isoliert und anschließend reduziert wird, z. B. mit Natrium boranat oder katalytisch erregtem Wasserstoff.isolated and then reduced, for. With sodium borane or catalytically excited hydrogen.

Die Ketone der Formel VII lassen sich nach bekannten Metho den herstellen, z. B. aus Monoethylenketalen der allgemeinen Formel XThe ketones of formula VII can be prepared by known methods produce the, for. B. from monoethylene ketals of the general Formula X

und einer metallorganischen Verbindung R¹-Me, wobei R¹ wie eingangs definiert ist und Me ein Lithiumatom oder die Gruppe Mg Hal bedeutet, in der Hal ein Halogenatom, vorzugs weise ein Chloratom, darstellt, gefolgt von Wasserabspaltung, Hydrierung der entstandenen Doppelbindung und Hydrolyse der Ketalgruppierung. Das Verfahren kann so abgewandelt werden, daß gewünschtenfalls ein oder mehrere Substituenten R² nach beendeter Reaktionsfolge eingeführt werden, z. B. durch Alkylierung des Keton-Enolations.and an organometallic compound R¹-Me, wherein R¹ as defined above and Me is a lithium atom or the Group Mg Hal means, in the Hal, a halogen atom, preferably represents a chlorine atom, followed by dehydration, Hydrogenation of the resulting double bond and hydrolysis of Ketal group. The process can be modified in this way if desired, one or more substituents R² are introduced after completion of the reaction sequence, for. B. by Alkylation of the ketone enolate.

Eine weitere Darstellungsmethode besteht in der Dieckmann- Cyclisierung von Diestern der allgemeinen Formel XIAnother representation method is the Dieckmann Cyclization of diesters of general formula XI

mit anschließender Verseifung und Decarboxylierung nach an sich bekannten Methoden. In der allgemeinen Formel XI ist R ein beliebiger Alkyl-, Aralkyl- oder Arylrest.followed by saponification and decarboxylation after known methods. In general formula XI, R is any alkyl, aralkyl or aryl radical.

Die Verbindungen der allgemeinen Formel I besitzen interes sante biologische Eigenschaften. Sie stellen Inhibitoren der Cholesterinbiosynthese dar.The compounds of general formula I have interes sante biological properties. They are inhibitors of Cholesterol biosynthesis

Aufgrund ihrer biologischen Eigenschaften sind sie besonders geeignet zur Behandlung der Hyperlipidämien, insbesondere der Hypercholesterinämie, Hyperlipoproteinämie, Hypertrigly ceridämie und den daraus resultierenden atherosklerotischen Gefäßveränderungen mit ihren Folgeerkrankungen, wie koronare Herzkrankheit, cerebrale Ischämie, Claudicatio intermittens und andere.Because of their biological properties, they are special suitable for the treatment of hyperlipidemias, in particular hypercholesterolemia, hyperlipoproteinemia, hypertrigly Ceridemia and the resulting atherosclerotic Vascular changes with their sequelae, such as coronary Heart disease, cerebral ischemia, intermittent claudication and other.

Die biologische Wirkung von Verbindungen der Formel I wurde durch Messung der Hemmung des ¹⁴C-Acetat-Einbaus in die mit Digitonin fällbaren Steroide nach der folgenden Methode bestimmt:The biological effect of compounds of the formula I was by measuring the inhibition of ¹⁴C-acetate incorporation into the steroids precipitable with digitonin according to the following method certainly:

method

Humane Hepatoma-Zellen (Hep G2) werden nach 3tägiger An zucht für 16 Stunden in cholesterolfreiem Medium stimuliert. Die zu testenden Substanzen (gelöst in Dimethylsulfoxyd; Endkonzentration 0,1%) werden während dieser Stimulations phase zugesetzt. Anschließend wird nach Zugabe von 200 µMol/l 2-¹⁴C-Acetat für weitere 2 Stunden bei 37°C im Brutschrank weiterinkubiert.Human hepatoma cells (Hep G2) become active after 3 days pork for 16 hours in cholesterol-free medium. The substances to be tested (dissolved in dimethyl sulfoxide; Final concentration 0.1%) during this stimulation added phase. Subsequently, after addition of 200 .mu.mol / l 2-¹⁴C-acetate for another 2 hours at 37 ° C in the incubator continuing incubation.

Nach Ablösen der Zellen und Verseifen des Cholesterolesters wird nach Extraktion Cholesterol mit Digitonin zur Fällung gebracht. Das in Cholesterol eingebaute ¹⁴-C-Acetat wird durch Szintillationsmessung bestimmt.After detachment of the cells and saponification of the cholesterol ester after extraction, cholesterol is precipitated with digitonin brought. The built in cholesterol ¹⁴-C-acetate is determined by scintillation measurement.

Es wurde gefunden, daß beispielsweise die Verbindungen der allgemeinen Formel IIt has been found that, for example, the compounds of general formula I

A = 4-[4-(2-Diethylamino-ethoxy)-3-methylphenyl]-N-hexanoyl- N-methyl-cyclohexylamin
B = N-Hexanoyl-N-methyl-4-[4-(2-pyrrolidinoethoxy)-3-methyl phenyl]-cyclohexylamin
C = 4-[4-(2-Dimethylamino-ethoxy)-3-methylphenyl]-N-hexanoyl- N-methyl-cyclohexylamin
D = 4-[4-(2-Ethylamino-ethoxy)-3-methylphenyl]-N-hexanoyl-N- methyl-cyclohexylamin
E = 4-[4-(2-Diethylamino-ethoxy)-3-methylphenyl]-N-methyl-N- (5-methyl-hex-4-enoyl)-cyclohexylamin
F = 4-[4-(2-Diethylamino-ethoxy)-phenyl]-N-hexanoyl-N-methyl cyclohexylamin
G = 4-[4-(2-Diethylamino-ethoxy)-3-methylphenyl]-N-hexanoyl- N-isopropyl-cyclohexylamin
H = N-Hexanoyl-N-methyl-4-(4-pyridyl)-cyclohexylamin
I = N-Elaidinoyl-N-methyl-4-(4-pyridyl)-cyclohexylamin
K = N-Methyl-N-(4-phenyl-butyryl)-4-(4-pyridyl)-cyclohexyl amin
L = N-Methyl-N-(4-phenyl-3-butenoyl)-4-(4-pyridyl)-cyclo hexylamin
M = N-Methyl-N-(5-methyl-hexanoyl)-4-(4-pyridyl)-cyclohexyl amin
N = N-Methyl-N-stearoyl-4-(4-pyridyl)-cyclohexylamin
O = N-Methyl-N-palmitoyl-4-(4-pyridyl)-cyclohexylamin
P = N-Linolenoyl-N-methyl-4-(4-pyridyl)-cyclohexylamin
Q = 4-[4-(2-Dimethylamino-ethoxy)-phenyl)-N-hexanoyl-N- methyl-cyclohexylaminA = 4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-hexanoyl-N-methylcyclohexylamine
B = N-hexanoyl-N-methyl-4- [4- (2-pyrrolidinoethoxy) -3-methylphenyl] -cyclohexylamine
C = 4- [4- (2-Dimethylamino-ethoxy) -3-methyl-phenyl] -N-hexanoyl-N-methylcyclohexylamine
D = 4- [4- (2-ethylamino-ethoxy) -3-methyl-phenyl] -N-hexanoyl-N-methylcyclohexylamine
E = 4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-methyl-N- (5-methyl-hex-4-enoyl) -cyclohexylamine
F = 4- [4- (2-diethylamino-ethoxy) -phenyl] -N-hexanoyl-N-methylcyclohexylamine
G = 4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-hexanoyl-N-isopropylcyclohexylamine
H = N-hexanoyl-N-methyl-4- (4-pyridyl) -cyclohexylamine
I = N-Elaidinoyl-N-methyl-4- (4-pyridyl) -cyclohexylamine
K = N-methyl-N- (4-phenyl-butyryl) -4- (4-pyridyl) -cyclohexylamine
L = N-methyl-N- (4-phenyl-3-butenoyl) -4- (4-pyridyl) -cyclohexylamine
M = N-methyl-N- (5-methyl-hexanoyl) -4- (4-pyridyl) -cyclohexylamine
N = N-methyl-N-stearoyl-4- (4-pyridyl) -cyclohexylamine
O = N-methyl-N-palmitoyl-4- (4-pyridyl) -cyclohexylamine
P = N-linolenoyl-N-methyl-4- (4-pyridyl) -cyclohexylamine
Q = 4- [4- (2-dimethylamino-ethoxy) -phenyl] -N-hexanoyl-N-methylcyclohexylamine

bei einer Testkonzentration von 10^-6 Mol/l eine Hemmwir kung von mindestens 50% ausüben. at a test concentration of 10 ^-6 mol / l exert an inhibitory effect of at least 50%.

Die Verbindungen A bis Q zeigten sich in der kurativen Do sierung als völlig untoxisch. Beispielsweise zeigte die Ver bindung A nach oraler Applikation von 100 mg/kg an der Maus noch keine toxischen Wirkungen.Compounds A to Q appeared in the curative Do tion as completely non-toxic. For example, Ver binding A after oral administration of 100 mg / kg to the mouse no toxic effects yet.

Zur pharmazeutischen Anwendung lassen sich die Verbindungen der allgemeinen Formel I in an sich bekannter Weise in die üblichen pharmazeutischen Zubereitungsformen, z. B. in Tab letten, Drag´es, Kapseln oder Suppositorien einarbeiten. Die Einzeldosis kann dabei bei oraler Gabe zwischen 0,02 bis 2 mg, vorzugsweise 0,08 bis 1 mg pro kg Körpergewicht va riieren, die Tagesdosis für einen Menschen mit 60 kg Körper gewicht zwischen 1 und 300 mg. Die Tagesdosis wird vorzugs weise in 1 bis 3 Einzelgaben aufgeteilt.For pharmaceutical application, the compounds of the general formula I in a conventional manner in the customary pharmaceutical preparations, for. In tab lettuce, drag'es, capsules or suppositories. The Single dose may be between 0.02 to 2 mg, preferably 0.08 to 1 mg per kg body weight va riieren, the daily dose for a person with 60 kg of body weight between 1 and 300 mg. The daily dose is preferred wise divided into 1 to 3 individual doses.

Die folgenden Beispiele sollen die Erfindung näher er läutern:The following examples are intended to illustrate the invention in more detail purify:

In den nachfolgenden Beispielen wurden die Rf-Werte an Fer tigplatten der Firma E. Merk, Darmstadt bestimmt und zwarIn the following examples, the Rf values on Fer hardboard from E. Merk, Darmstadt

a) Aluminum oxide F-254 (Type E)
b) Silica gel 60 F-254

Beispiele zur Herstellung der Ausgangsmaterialien:Examples for the preparation of the starting materials:

Example A 4- (4-methoxy-3-methylphenyl) cyclohexanone

5 g Lithium-Pulver werden unter Argon in 100 ml Ether vorge legt, ca. 50 ml einer Lösung von 52 g (0,25 Mol) 4-Methoxy- 3-methyl-brom-benzol in 300 ml Ether zugegeben und das Reak tionsgemisch im Ultraschallbad bis zum Anspringen der Reak tion erhitzt (ca. 1 Minute). Anschließend wird die restliche Lösung so zugetropft, daß das Reaktionsgemisch siedet (ca. 1 Stunde). Anschließend wird 1 Stunde nachgerührt, und vom Niederschlag unter Argon abgesaugt. Zum Filtrat werden 36 g (0,23 Mol) Cyclohexan-1,4-dion-monoethylenketal in 250 ml Ether so zugetropft, daß die Lösung siedet und anschließend über Nacht gerührt. Es wird in 400 ml Eiswasser eingerührt, zweimal mit Ether extrahiert, die vereinigten Etherextrakte mit gesättigter Kochsalz-Lösung gewaschen und mit Magnesium sulfat getrocknet. Der nach Verdampfen des Ethers erhaltene Rückstand wird aus Diisopropylether umkristallisiert. Man erhält 45,74 g (65,7% der Theorie) 4-Hydroxy-4-(4-methoxy- 3-methylphenyl)-cyclohexanon-ethylenketal als farblose Kri stalle vom Schmelzpunkt 88°C.5 g of lithium powder are placed under argon in 100 ml of ether 50 ml of a solution of 52 g (0.25 mol) of 4-methoxy Added 3-methyl-bromobenzene in 300 ml of ether and the reaction tion mixture in an ultrasonic bath until the reaction starts heated (about 1 minute). Subsequently, the remaining Dropped solution so that the reaction mixture boils (about 1 Hour). The mixture is then stirred for 1 hour, and from Suction precipitated under argon. The filtrate is 36 g (0.23 mol) cyclohexane-1,4-dione monoethylene ketal in 250 ml Ether added dropwise so that the solution boils and then stirred overnight. It is stirred into 400 ml of ice-water, extracted twice with ether, the combined ether extracts washed with saturated sodium chloride solution and with magnesium dried sulfate. The obtained after evaporation of the ether Residue is recrystallized from diisopropyl ether. you receives 45.74 g (65.7% of theory) of 4-hydroxy-4- (4-methoxy) 3-methylphenyl) cyclohexanone ethylene ketal as a colorless Kri stalls of melting point 88 ° C.

40 g dieses Produkts, 0,8 g p-Toluolsulfonsäure und 41 ml Ethylenglykol werden in 400 ml Toluol am Wasserabscheider gekocht (ca. 2,5 Stunden). Nach Abkühlen werden 200 ml Pe trolether und 250 ml gesättigte Soda-Lösung zugegeben, 20 Minuten gerührt, die organische Phase mit Wasser und gesät tigter Kochsalzlösung gewaschen und mit Magnesiumsulfat ge trocknet. Der nach Verdampfen des Lösungsmittels erhaltene Rückstand ergibt nach Umkristallisation aus Diisopropylether 31,1 g (83% der Theorie) 4-(4-Methoxy-3-methylphenyl) cyclohex-3-enon-ethylenketal als farblose Kristalle vom Schmelzpunkt 69°C.40 g of this product, 0.8 g of p-toluenesulfonic acid and 41 ml Ethylene glycol in 400 ml of toluene on a water cooked (about 2.5 hours). After cooling, 200 ml of Pe trol ether and 250 ml saturated soda solution added, 20 Stirred minutes, the organic phase with water and sown washed brine and ge with magnesium sulfate dries. The product obtained after evaporation of the solvent Residue yields after recrystallization from diisopropyl ether 31.1 g (83% of theory) of 4- (4-methoxy-3-methylphenyl) cyclohex-3-enone ethylene ketal as colorless crystals from Melting point 69 ° C.

30,5 g dieses Produkts werden in 290 ml Essigsäureethylester in Gegenwart von 4,3 g 10%-iger Palladium-Kohle bei Raumtem peratur und einem Druck von 51,4 psi hydriert (ca. 10 Minu ten). Nach Verdampfen des Lösungsmittels erhält man 30,4 g (99% der Theorie) eines gelben Öls, das in 680 ml Aceton und 56 ml Wasser gelöst und nach Zugabe von 2,25 g Pyridi nium-tosylat 72 Stunden zum Rückfluß erhitzt wird. Nach Ver dampfen des Lösungsmittels wird in einem Ether/Essigsäure ethylestergemisch (4 : 1, v:v) gelöst, mit Wasser und gesät tigter Kochsalz-Lösung gewaschen, über Magnesiumsulfat ge trocknet und der nach Verdampfen des Lösungsmittels erhalte ne Rückstand aus Diisopropylether umkristallisiert. Man er hält 22,5 g (89% der Theorie) der Titelverbindung als farb lose Kristalle vom Schmelzpunkt 94°C.30.5 g of this product are dissolved in 290 ml of ethyl acetate in the presence of 4.3 g of 10% palladium-carbon at room temperature hydrogenated at a pressure of 51.4 psi (about 10 minutes) th). After evaporation of the solvent gives 30.4 g (99% of theory) of a yellow oil dissolved in 680 ml of acetone and 56 ml of water are dissolved and after addition of 2.25 g Pyridi Nium-tosylate is heated to reflux for 72 hours. After Ver evaporation of the solvent is carried out in an ether / acetic acid ethyl ester mixture (4: 1, v: v) dissolved, watered and sown washed brine solution, ge over magnesium sulfate ge dries and obtained after evaporation of the solvent The residue was recrystallised from diisopropyl ether. Man he holds 22.5 g (89% of theory) of the title compound as a color loose crystals of melting point 94 ° C.

Auf analoge Weise wurden die folgenden Verbindungen erhal ten, wobei an Stelle von Lithium-Pulver zum Teil n-Butyl lithium eingesetzt wurde.In an analogous manner, the following compounds were obtained in which, instead of lithium powder, some n-butyl lithium was used.

a) 4- (4-ethylphenyl) -cyclohexanone from 4-ethyl-bromobenzene, lithium powder and cyclohexane-1,4-dione monoethyleneketal.
Melting point: 28 ° C
b) 4- (4-tert-butylphenyl) -cyclohexanone from 4-tert-butyl bromobenzene, lithium powder and cyclohexane-1,4-dione mono ethylene ketal.
Melting point: 91-94 ° C
c) 4- (4-methoxyphenyl) cyclohexanone from p-bromoanisole, lithium powder and cyclohexane-1,4-dione monoethylene ketal.
Melting point: 76-78 ° C.
d) 4- (naphthyl-2) cyclohexanone from 2-bromonaphthalene, lithium thium powder and cyclohexane-1,4-dione monoethyleneketal.
Melting point: 56-57 ° C.
e) 4- (3,4-dimethoxyphenyl) -cyclohexanone of 3,4-dimethoxy bromobenzene, n-butyl-lithium and cyclohexane-1,4-dione mono ethylene ketal.
Melting point: 47-48 ° C.
f) 4- (3-methoxyphenyl) cyclohexanone of 3-methoxy-bromobenzene, lithium powder and cyclohexane-1,4-dione monoethyleneketal.
Melting point: 58 ° C.
g) 4- (3,4-dimethylphenyl) -cyclohexanone of 3,4-dimethyl bromobenzene, lithium powder and cyclohexane-1,4-dione monoethylene ketene.
Melting point: 38-40 ° C.
h) 4- (p-biphenyl) -cyclohexanone from 4-bromo-biphenyl, lithium powder and cyclohexane-1,4-dione monoethyleneketal.
Melting point: 130-132 ° C.
i) 4- (3-ethyl-4-methoxyphenyl) cyclohexanone from 3-ethyl-4-methoxy-bromobenzene, n-butyl-lithium and cyclohexane-1,4-dione monoethyleneketal.
Colorless oil of Rf value: 0.51 (silica gel, petroleum ether / ethyl acetate = 4: 1, v: v).
j) 4- (4-methoxy-3-propylphenyl) -cyclohexanone from 4-methoxy-3-propyl-bromobenzene, n-butyl-lithium and cyclohexane-1,4-dione monoethyleneketal.
Colorless oil of Rf value 0.54 (silica gel, petroleum ether / ethyl acetate = 4: 1, v: v).
k) 4- (3-tert-butyl-4-methoxyphenyl) cyclohexanone, of 3-tert-butyl-4-methoxy-bromobenzene, n-butyl-lithium and cyclohexane-1,4-dione monoethylene ketal.
Colorless oil of Rf value: 0.55 (silica gel, petroleum ether / ethyl acetate = 4: 1, v: v).
l) 4- (4-methoxy-2-methylphenyl) -cyclohexanone of 4-methoxy-2-methyl-bromobenzene, n-butyl-lithium and cyclohexane-1,4-dione monoethylene ketal.
Melting point 50-52 ° C.
m) 4- (3-Thienyl) cyclohexanone from 3-bromothiophene, n-butyl lithium and cyclohexane-1,4-dione monoethyleneketal.
Wax, Rf value: 0.54 (silica gel, petroleum ether / ethyl acetate = 7: 3, v: v).
n) 4- (3-Furyl) cyclohexanone from 3-bromofuran, n-butyl-lithium and cyclohexane-1,4-dione monoethyleneketal.
Oil, Rf value: 0.52 (silica gel, petroleum ether / ethyl acetate = 7: 3, v: v).
o) 4- (4-pyridyl) cyclohexanone from 4-bromopyridine, n-butyl lithium and cyclohexane-1,4-dione monoethyleneketal.
Oil, Rf value: 0.31 (silica gel, petroleum ether / ethyl acetate / methanol = 10: 3: 0.3, v: v: v).
p) 4- [5- (2,4-Dimethoxy-6-methylpyrimidinyl)] cyclohexanone from 5-bromo-2,4-dimethoxy-6-methyl-pyrimidine, n-butyl-lithium and cyclohexane-1,4-dione -monoethylenketal.
Melting point: 62-65 ° C.
q) 4- (2.4.5-trimethylphenyl) -cyclohexanone of 2,4,5-tri methyl-bromobenzene, n-butyllithium and cyclohexane-1,4-dione monoethylenketal.
Melting point: 53 ° C.
r) 4- (3,4,5-trimethoxyphenyl) cyclohexanone of 3,4,5-tri methoxy-bromobenzene, n-butyllithium and cyclohexane-1,4-dione monoethylenketal.
Melting point: 113 ° C.
s) 4- (3-Fluoro-4-methoxyphenyl) cyclohexanone from 3-fluoro-4-methoxy-bromobenzene, n-butyllithium and cyclohexane-1,4-dione monoethyleneketal.
Melting point: 74-76 ° C
t) 4- (3-chloro-4-methoxyphenyl) cyclohexanone from 3-chloro-4-methoxy-bromobenzene, lithium and cyclohexane-1,4-dione mono ethylene ketal.
Oil, Rf value: 0.2 (silica gel, petroleum ether / ethyl acetate = 5: 1, v: v).
u) 4- (3-pyridyl) -cyclohexanone from 3-bromopyridine, n-butyl lithium and cyclohexane-1,4-dione monoethyleneketal.
Melting point: 62-63 ° C.
v) 4- (5-Pyrimidinyl) cyclohexanone from 5-bromopyrimidine, n-butyllithium and cyclohexane-1,4-dione monoethylene ketal.
Melting point: 88-90 ° C.

Example B 2-allyl-4- (4-methoxy-3-methylphenyl) cyclohexanone

Zu 4,36 g (0,02 Mol) 4-(4-Methoxy-3-methylphenyl)-cyclohexa non in 30 ml Tetrahydrofuran werden bei -20°C 14 ml (0,021 Mol) einer 1,5molaren Lösung von Lithiumdiisopropylamid in Hexan zugetropft. Nach 30 Minuten Rühren bei -30°C wird die gelbe Lösung bei 0°C zu 4,8 g (0,04 Mol) Allylbromid in 10 ml Tetrahydrofuran innerhalb einer Stunde zugetropft und an schließend über Nacht gerührt. Das Lösungsmittel wird ver dampft, der Rückstand mit 100 ml Wasser verrieben, dreimal mit je 100 ml Ether extrahiert und die Extrakte über Magne siumsulfat getrocknet. Der Ether wird verdampft und der Rückstand durch Chromatographie (Kieselgel, Petrolether/Es sigsäureethylester = 7 : 1, v:v) gereinigt. Man erhält 2 g eines farblosen Öls vom Rf 0,53.To 4.36 g (0.02 mol) of 4- (4-methoxy-3-methylphenyl) cyclohexa non in 30 ml of tetrahydrofuran at -20 ° C 14 ml (0.021 Mol) of a 1.5 molar solution of lithium diisopropylamide in Dropped hexane. After stirring for 30 minutes at -30 ° C is the yellow solution at 0 ° C to 4.8 g (0.04 mol) of allyl bromide in 10 ml of tetrahydrofuran was added dropwise within one hour and at then stirred overnight. The solvent is ver evaporated, the residue triturated with 100 ml of water, three times extracted with 100 ml of ether and the extracts over Magne dried sulfate. The ether is evaporated and the Residue by chromatography (silica gel, petroleum ether / es ethyl acetate = 7: 1, v: v). 2 g are obtained a colorless oil of Rf 0.53.

Auf dieselbe Weise wurde dargestellt:In the same way was shown:

a) 4- (4-Methoxy-3-methylphenyl) -2-methyl-cyclohexanone
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and Methyljo did.
Melting point: 57 ° C.
Isomer A:
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05 (d, 3H), 1.5-2.0 (m, 2H), 2.1-2.3 (s + m, 5H) 2.4-2.7 (m, 3H), 2.95-3.15 (3t, 1H), 3.8 (s, 3H), 6.7-7.1 (m, 3H).
Isomer B:
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.2 (d, 3H), 1.8-2.7 (s + m, 10H), 3.1 (m, 1H), 3.8 (s, 3H), 6.7- 7.1 (m, 3H).

Example C 3- (4-Methoxyphenyl) cyclopentanone

14,9 g (0,082 Mol) Phosphonoessigsäure-trimethylester in 70 ml Tetrahydrofuran werden bei 25-30°C zu 3,4 g (0,078 Mol) entöltem Natriumhydrid (55%ig) zugetropft. Das schwer rühr bare Gemisch wird eine Stunde nachgerührt und anschließend 16,6 g (0,075 Mol) 3-(4-Methoxybenzoyl)-propionsäuremethyl ester in 300 ml Tetrahydrofuran zugetropft. Das Gemisch wird 7 Stunden zum Rückfluß erhitzt, das Lösungsmittel verdampft, der Rückstand mit 250 ml Wasser verrieben, dreimal mit je 250 ml Ether extrahiert, mit Wasser gewaschen, getrocknet und eingedampft. Der ölige Rückstand wird in 150 ml Essig säureethylester gelöst und in Gegenwart von 1,5 g Palladium kohle (10%ig) hydriert (50 psi, 30 Minuten). Das nach Ver dampfen des Lösungsmittels als Öl erhaltene 1,4-Dimethoxy carbonyl-2-(4-methoxyphenyl)-butan wird durch Säulenchroma tographie (Kieselgel, Petrolether/Essigsäureethylester 6 : 1 bis 4 : 1, v:v) gereinigt.14.9 g (0.082 mol) phosphonoacetic acid trimethyl ester in 70 ml of tetrahydrofuran are added at 25-30 ° C to 3.4 g (0.078 mol) de-oiled sodium hydride (55%) was added dropwise. The hard way mixture is stirred for one hour and then 16.6 g (0.075 mol) of methyl 3- (4-methoxybenzoyl) propionate ester in 300 ml of tetrahydrofuran was added dropwise. The mixture is Heated to reflux for 7 hours, the solvent evaporated, The residue triturated with 250 ml of water, three times with each Extracted 250 ml of ether, washed with water, dried and evaporated. The oily residue is dissolved in 150 ml of vinegar acid ethyl ester dissolved and in the presence of 1.5 g of palladium 10% hydrogenated (50 psi, 30 minutes). The after Ver vaporizing the solvent as an oil-derived 1,4-dimethoxy carbonyl-2- (4-methoxyphenyl) -butane is replaced by column chromatography tography (silica gel, petroleum ether / ethyl acetate 6: 1 to 4: 1, v: v).

Das erhaltene Öl wird in einer Suspension von Natriummethy lat in Toluol (hergestellt aus 2,88 g (64,8 mMol) entöltem Natriumhydrid (55%-ig) und 2,08 g (64,8 mMol) Methanol) zu getropft. Das Gemisch wird zwei Stunden auf 85°C erhitzt, in 600 ml verdünnte eiskalte Salzsäure eingerührt und mit Ether extrahiert. Der Extrakt wird mit Wasser, gesättigter Na triumbicarbonat-Lösung, Wasser und gesättigter Kochsalz-Lö sung gewaschen. Nach Trocknen über Magnesiumsulfat wird ein gedampft. Das verbleibende Öl wird mit 7,9 g Kochsalz, 3,95 ml Wasser und 39,5 ml Dimethylsulfoxyd eine Stunde auf 180°C erhitzt. Das Gemisch wird in 40 ml Wasser eingerührt und zweimal mit Petrolether extrahiert. Die organische Phase wird mit Wasser gewaschen, mit Magnesiumsulfat getrocknet und eingedampft. Der Rückstand wird aus wenig Diisopropyl ether umkristallisiert. Man erhält 4,35 g (72% der Theorie) der Titelverbindung vom Schmelzpunkt 47°C. The resulting oil is suspended in a suspension of sodium methy lat in toluene (prepared from 2.88 g (64.8 mmol) of deoiled Sodium hydride (55%) and 2.08 g (64.8 mmol) of methanol) dripped. The mixture is heated at 85 ° C for two hours, in 600 ml of dilute ice cold hydrochloric acid stirred in and with ether extracted. The extract is washed with water, saturated Na triumbicarbonate solution, water and saturated sodium chloride solution washed. After drying over magnesium sulfate becomes steamed. The remaining oil is added with 7.9 g of sodium chloride, 3.95 ml of water and 39.5 ml of dimethyl sulfoxide for one hour at 180 ° C. heated. The mixture is stirred in 40 ml of water and extracted twice with petroleum ether. The organic phase is washed with water, dried with magnesium sulfate and evaporated. The residue is made up of a little diisopropyl recrystallized ether. 4.35 g (72% of theory) are obtained. the title compound of melting point 47 ° C.

Example D trans-4- (4-methoxy-3-methylphenyl) -N-methyl-cyclohexylamine

4,4 g 4-(4-Methoxy-3-methylphenyl)-cyclohexanon werden mit 90 ml einer Methylamin-Lösung in Toluol in Gegenwart von 12 g Molekularsieb 3 A über Nacht gerührt. Vom Molekularsieb wird abgesaugt, das Toluol verdampft und der Rückstand in 80 ml Methanol aufgenommen. Nach portionsweiser Zugabe von 1,5 g Natriumboranat unter Eiskühlung wird 4 Stunden bei Raum temperatur gerührt, das Methanol eingedampft, der Rückstand mit Eiswasser versetzt und mit 2N-Salzsäure angesäuert. Nach 20 Minuten Rühren bei Raumtemperatur wird mit 2N Natronlauge alkalisch gestellt, mit Ether extrahiert, der Extrakt mit Kochsalz-Lösung gewaschen, getrocknet und eingedampft. Der Rückstand (27% cis- und 73% trans-Isomeres) wird in 40 ml Essigsäureethylester gelöst und mit einer Lösung von 3,1 g Benzoesäure in 30 ml Essigsäureethylester versetzt. Der Nie derschlag wird abgesaugt, aus Essigsäureethylester umkri stallisiert, in Wasser suspendiert, mit Ether überschichtet und durch Zugabe von 15 ml 2N-Natronlauge alkalisch ge stellt. Die Etherphase wird abgetrennt, mit Wasser und ge sättigter Kochsalzlösung gewaschen, getrocknet und einge dampft. Man erhält 2,5 g (53,6% der Theorie) der Titelver bindung als farblose Kristalle vom Schmelzpunkt 98°C.
Massenspektrum: M⁺ 233.4.4 g of 4- (4-methoxy-3-methylphenyl) cyclohexanone are stirred overnight with 90 ml of a methylamine solution in toluene in the presence of 12 g of molecular sieve 3A. The molecular sieve is filtered off, the toluene evaporated and the residue taken up in 80 ml of methanol. After portionwise addition of 1.5 g of sodium borohydride with ice cooling is stirred for 4 hours at room temperature, the methanol is evaporated, the residue is mixed with ice water and acidified with 2N hydrochloric acid. After stirring for 20 minutes at room temperature is made alkaline with 2N sodium hydroxide solution, extracted with ether, the extract washed with brine, dried and evaporated. The residue (27% cis and 73% trans isomer) is dissolved in 40 ml of ethyl acetate and treated with a solution of 3.1 g of benzoic acid in 30 ml of ethyl acetate. The Never derschlag is filtered off with suction, recrystallized from ethyl acetate umkri, suspended in water, overlaid with ether and alkaline by the addition of 15 ml of 2N sodium hydroxide solution. The ether phase is separated, washed with water and saturated brine, dried and evaporated. 2.5 g (53.6% of theory) of the title compound are obtained as colorless crystals of melting point 98.degree.
Mass spectrum: M⁺ 233.

Example E cis- and trans-4- (4-methoxyphenyl) -N-methylcyclohexylamine

4,08 g (20 mMol) 4-(4-Methoxyphenyl)-cyclohexanon werden mit 40 ml einer 13%igen Lösung von Methylamin in Toluol in Ge genwart von 6 g Molekularsieb über Nacht gerührt. Vom Mole kularsieb wird abgesaugt, das Toluol verdampft und der Rück stand in 80 ml Methanol gelöst. Unter Eiskühlung werden 1,5 g Natriumborhydrid portionsweise zugegeben und 4 Stunden bei Raumtemperatur gerührt. Das Methanol wird verdampft, der Rückstand mit Eiswasser versetzt und mit 2N-Salzsäure ange säuert. Nach 20 Minuten Rühren bei Raumtemperatur wird mit 2N-Natronlauge alkalisch gestellt, mit Ether extrahiert, mit Kochsalz-Lösung gewaschen, getrocknet und eingedampft. Der Rückstand wird durch Mitteldruckchromatographie gereinigt (Aluminiumoxyd neutral, Aktivitätsstufe III). Elution mit Petrolether/Essigsäureethylester = 1 : 4, v:v) ergab 1,13 g (25,8% der Theorie) cis-4-(4-Methoxyphenyl)-N-methyl-cyclo hexylamin als farbloses Öl.
NMR-Spektrum (200 MHz, CDCl₃); Signale bei ppm: 1,5-1,9 (m, 8H), 2,4-2,6 (m, 4H), 2,75 (m, 1H), 3,75 (s, 3H), 6,8 (dd, 2H), 7,15 (dd, 2H).4.08 g (20 mmol) of 4- (4-methoxyphenyl) cyclohexanone are stirred overnight with 40 ml of a 13% solution of methylamine in toluene in the presence of 6 g of molecular sieve. From Mole kularsieb is filtered off, the toluene evaporated and the back was dissolved in 80 ml of methanol. With ice cooling, 1.5 g of sodium borohydride are added in portions and stirred for 4 hours at room temperature. The methanol is evaporated, the residue is mixed with ice-water and acidified with 2N hydrochloric acid. After stirring for 20 minutes at room temperature is made alkaline with 2N sodium hydroxide solution, extracted with ether, washed with brine, dried and evaporated. The residue is purified by medium pressure chromatography (alumina neutral, activity grade III). Elution with petroleum ether / ethyl acetate = 1: 4, v: v) gave 1.13 g (25.8% of theory) of cis -4- (4-methoxyphenyl) -N-methylcyclohexylamine as a colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.5-1.9 (m, 8H), 2.4-2.6 (m, 4H), 2.75 (m, 1H), 3.75 (s, 3H), 6, 8 (dd, 2H), 7.15 (dd, 2H).

Zugabe von ca. 20% Methanol zum Fließmittel ergab 2,2 g (50,2% der Theorie) trans-4-(4-Methoxyphenyl)-N-methyl cyclohexylamin als farbloses, langsam kristallisierendes Öl.
NMR-Spektrum (200 MHz, CDCl₃+CD₃OD); Signale bei ppm: 1,1-2,1 (m, 8H), 2,4-2,6 (m, 5H), 3,7 (s, 3H), 6,8 (dd, 2H), 7.1 (dd, 2H).Addition of about 20% methanol to the eluant gave 2.2 g (50.2% of theory) of trans-4- (4-methoxyphenyl) -N-methylcyclohexylamine as a colorless, slowly crystallizing oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 1.1-2.1 (m, 8H), 2.4-2.6 (m, 5H), 3.7 (s, 3H), 6.8 (dd, 2H), 7.1 ( dd, 2H).

Auf dieselbe Weise wurden erhalten:In the same way were obtained:

a) 4- (4-ethylphenyl) -N-methyl-cyclohexylamine (cis-trans-mixture)
from 4- (4-ethylphenyl) cyclohexanone and methylamine.
Melting point: 84 ° C.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 1.1-1.7 (m, 7H), 1.85-2.1 (m, 4H), 2.35-2.7 (m, 7H), 7.1 (s, 4H ).
b) 4- (4-tert-butylphenyl) -N-methylcyclohexylamine (cis-trans mixture)
from 4- (4-tert-butylphenyl) cyclohexanone and methylamine.
Melting point: 99 ° C.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 1.1-1.7 (m, 14H), 1.9-2.25 (m, 4H), 2.35-2.7 (m, 5H), 7.1 (dd, 2H ), 7.3 (dd, 2H).
c) N-methyl-4- (naphthyl-2) cyclohexylamine (cis-trans mixture)
from 4- (naphthyl-2) cyclohexanone and methylamine.
Colorless oil.
Rf value: 0.2 (trans) + 0.3 (cis) (silica gel, toluene / ethanol / concentrated NH₃ = 75: 25: 2, v: v).
d) trans-4- (p-biphenyl) -N-methylcyclohexylamine
from 4- (p-biphenyl) cyclohexanone and methylamine.
Melting point: 120-123 ° C.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 1.25-1.7 (m, 4H), 2.4-2.7 (m, 5H), 7.2-7.6 (m, 9H).
e) Nn-Amyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine (cis-trans-mixture)
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and n-amylamine.
Colorless oil, which was further reacted in impure form.
f) trans -N-cyclohexylmethyl-4- (4-methoxy-3-methylphenyl) cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and cyclohexylmethylamine.
Melting point: 71-73 ° C.
g) 4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine (cis-trans mixture)
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and methylamine.
Melting point 98-100 ° C.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 1.1-1.6 (m, 4H), 1.7-2.1 (m, 4H), 2.2 (s, 3H), 2.3-2.5 (m, 5H ), 3.7 (s, 3H), 6.7-7.0 (m, 3H).
h) 4- (3,4-dimethylphenyl) -N-methylcyclohexylamine (cis-trans mixture)
from 4- (3,4-dimethylphenyl) cyclohexanone and methylamine.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 1.1-2.1 (m, 8H), 2.2 (2s, 6H), 2.35-2.7 (m, 5H), 6.9-7.2 (m, 3H ).
i) 4- (3-methoxyphenyl) -N-methylcyclohexylamine (cis-trans mixture)
from 4- (3-methoxyphenyl) cyclohexanone and methylamine.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1-2.8 (m, 14H), 3.8 (s, 3H), 6.6-7.3 (m, 4H).
j) 4- (3,4-Dimethoxyphenyl) -N-methylcyclohexylamine (cis-trans mixture)
from 4- (3,4-dimethoxyphenyl) cyclohexanone and methylamine.
Colorless oil.
Rf value 0.3 (trans) and 0.4 (cis) (silica gel, toluene / ethanol / conc NH₃ = 75: 75: 2, v: v: v).
k) 2-Allyl-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine (isomer mixture)
from 2-allyl-4- (4-methoxy-3-methylphenyl) cyclohexanone and methylamine.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 1.1-2.1 (m, 9H), 2.2 (s, 3H), 2.4-2.5 (m, 4H), 2.65 (m, 1H), 3, 8 (s, 3H), 4.9-5.1 (m, 2H), 5.7-5.9 (m, 1H), 6.7 (m, 1H), 6.9-7.0 ( m, 2H).
l) 3- (4-methoxyphenyl) -N-methyl-cyclopentylamine (cis-trans mixture)
from 3- (4-methoxyphenyl) cyclopentanone and methylamine.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 1.2-2.5 (m + d, 9H), 2.9-3.3 (m, 2H), 3.8 (s, 3H), 6.8-7.2 (m , 4H).
m) cis-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine from 4- (4-methoxy-3-methylphenyl) cyclohexanone and methylamine.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.5-1.9 (m, 8H), 2.2 (s, 3H), 2.4-2.55 (s + m, 4H), 2.75 (m, 1H), 3.7 (s, 3H), 6.7-7.1 (m, 3H).
n) 4- (4-methoxy-3-methylphenyl) -2-methyl-N-methylcyclohexylamine (mixture of isomers A)
from 4- (4-methoxy-3-methylphenyl) -2-methyl-cyclohexanone (Iso mer A) and methylamine.
Colorless oil, which was further reacted as a crude product.
o) 4- (4-methoxy-3-methylphenyl) -2-methyl-N-methylcyclohexylamine (mixture of isomers B)
from 4- (4-methoxy-3-methylphenyl) -2-methylcyclohexanone (isomer B) and methylamine.
Colorless oil, which was further reacted as a crude product.
p) cis- and trans-4- (3-ethyl-4-methoxyphenyl) -N-methylcyclohexylamine
from 4- (3-ethyl-4-methoxyphenyl) cyclohexanone and methylamine.
Separation of the isomers by medium pressure chromatography (aluminum oxide neutral, activity level III).
Elution with petroleum ether / ethyl acetate = 3: 7, v: v, gave the cis-form as a colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 1.2 (t, 3H), 1.5-1.9 (m, 8H), 2.4 (s, 3H), 2.45-2.7 (m, 3H), 2, 75 (m, 1H), 3.8 (s, 3H), 6.8 (m, 1H), 7.05 (m, 2H).
Addition of about 20% methanol to the flux gave the trans form as a colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 1.2 (t, 3H), 1.25-1.6 (m, 5H), 1.85-2.15 (m, 4H), 2.35-2.5 (s + m , 4H); 2.6 (q, 2H), 3.8 (s, 3H), 6.8 (m, 1H), 7.0 (m, 2H).
q) cis- and trans-4- (4-methoxy-3-propylphenyl) -N-methylcyclohexylamine
from 4- (4-methoxy-3-propylphenyl) cyclohexanone and methylamine.
Separation of the isomers by medium pressure chromatography (aluminum oxide neutral, activity level III).
Elution with petroleum ether / ethyl acetate / methanol = 100: 30: 1, v: v: v gave the cis-form as a colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.95 (t, 3H), 1.5-1.9 (m, 10H), 2.45 (s, 3H), 2.45-2.65 (m, 3H), 2, 75 (m, 1H), 3.8 (s, 3H), 6.75 (dd, 1H), 7.02 (m, 2H).
Increasing the polarity of the mobile phase (petroleum ether / ethyl acetate / methanol = 100: 30: 2, v: v: v) gave the trans-form as a colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 0.95 (t, 3H), 1.15-1.7 (m, 7H), 1.85-2.15 (m, 4H), 2.35-2.6 (s + m , 6H), 3.8 (s, 3H), 6.8 (d, 1H), 7.0 (m, 2H).
r) cis and trans-4- (3-tert-butyl-4-methoxyphenyl) -N-methylcyclohexylamine
from 4- (3-tert-butyl-4-methoxyphenyl) cyclohexanone and methylamine.
Separation of the isomers by medium pressure chromatography (aluminum oxide neutral, activity level III).
Elution with petroleum ether / ethyl acetate / methanol = 100: 30: 1, v: v: v gave the cis-form as a colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.4 (s, 9H), 1.45-1.9 (m, 8H), 2.42 (s, 3H), 2.45-2.6 (m, 1H), 2, 75 (m, 1H), 3.8 (s, 3H), 6.8 (d, 1H), 7.0-7.15 (m, 2H).
Increasing the polarity of the mobile phase (petroleum ether / ethyl acetate / methanol = 100: 30: 2) gave the trans-form as a colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05-1.6 (m, 14H), 1.85-2.15 (m, 4H), 2.35-2.5 (s + m, 4H), 3.8 (s , 3H), 6.8 (d, 1H), 7.0 (dd, 1H), 7.1 (dd, 1H).
s) cis- and trans-4- (4-methoxy-2-methylphenyl) -N-methylcyclohexylamine
from 4- (4-methoxy-2-methylphenyl) cyclohexanone and methylamine. Separation of the isomers by medium pressure chromatography (aluminum oxide neutral, activity level III).
Elution with petroleum ether / ethyl acetate / methanol = 100: 30: 1 gave the cis-form as a colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.5-1.8 (m, 6H), 1.8-2.0 (m, 2H), 2.3 (s, 3H), 2.45 (s, 3H), 2, 55-2.75 (m, 1H), 2.8 (m, 1H), 3.75 (s, 3H), 6.7 (m, 2H), 7.15-7.2 (m, 1H) ,
The trans form was also obtained as an oil, which later crystallized.
Melting point: 43-45 ° C
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1-1.6 (m, 4H), 1.75-1.9 (m, 2H), 2.0-2.15 (m, 2H), 2.3 (s, 3H ), 2.35-2.5 (s + m, 4H), 2.55-2.75 (m, 1H), 3.8 (s, 3H), 6.7 (m, 2H), 7, 1 (m, 1H).
t) trans -N-methyl-4- (3-thienyl) cyclohexylamine
from 4- (3-thienyl) cyclohexanone and methylamine.
Isolation by medium-pressure chromatography (aluminum oxide neutral, activity grade III, elution with petroleum ether / ethyl acetate / methanol = 100: 30: 3, v: v: v).
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05-1.6 (m, 3H), 1.6-1.85 (m, 1H), 1.95-2.15 (m, 4H), 2.3-2.5 (s + m, 4H), 2.5-2.75 (m, 1H), 6.9-7.0 (m, 2H), 7.35 (m, 1H).
u) trans-4- (3-furyl) -N-methylcyclohexylamine
from 4- (3-furyl) cyclohexanone and methylamine.
Isolation by medium pressure chromatography (alumina neutral, activity level III, elution with petroleum ether / ethyl acetate / methanol = 100: 30: 3, v: v: v).
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05-1.5 (m, 3H), 1.6-1.8 (m, 1H), 1.95-2.1 (m, 4H), 2.3-2.55 (s + m, 5H), 6.3 (m, 1H), 7.2 (m, 1H), 7.35 (m, 1H).
v) trans -N-ethyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and ethylamine.
Isolation by medium-pressure chromatography (aluminum oxide neutral, activity grade III, elution with petroleum ether / ethyl acetate = 6: 1 to 1: 1, v: v).
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1-1.6 (t + m, 7H), 1.8-2.1 (m, 4H), 2.2 (s, 3H), 2.35-2.6 (m , 2H), 2.65-2.75 (q, 2H), 3.8 (s, 3H), 6.7-7.0 (m, 3H).
w) trans-4- (4-methoxy-3-methylphenyl) -N- (n-propyl) -cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and n-propylamine. Isolation by medium pressure chromatography (alumina neutral, activity level III, elution with petroleum ether / ethyl acetate = 6: 1, v: v).
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.95 (t, 3H), 1.1-1.6 (m, 6H), 1.8-2.15 (m, 4H), 2.2 (s, 3H), 2, 3-2.58 (m, 2H), 2.65 (t, 2H), 3.8 (s, 3H), 6.75 (m, 1H), 7.0 (m, 2H).
x) trans -N- (n-butyl) -4- (4-methoxy-3-methylphenyl) cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and n-butyl amine.
Isolation by medium pressure chromatography (alumina neutral, activity level III, elution with petroleum ether / ethyl acetate = 7: 1, v: v).
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.92 (t, 3H), 1.1-1.6 (m, 10H), 1.8-2.15 (m, 4H), 2.21 (s, 3H), 2, 3-2.6 (m, 2H), 2.65 (t, 2H), 3.8 (s, 3H), 6.75 (m, 1H), 7.0 (m, 2H).
y) trans-4- (4-methoxy-3-methylphenyl) -N- (n-pentyl) -cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and n-pentyl amine.
Isolation by medium pressure chromatography (alumina neutral, activity level III, elution with petroleum ether / ethyl acetate = 13: 1, v: v).
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.1-1.6 (m, 10H), 1.8-2.1 (m, 4H), 2.2 (s, 3H), 2, 3-2.6 (m, 2H), 2.65 (t, 2H), 3.8 (s, 3H), 6.75 (m, 1H), 7.0 (m, 2H).
z) trans-N-isopropyl-4- (4-methoxy-3-methylphenyl) cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and isopropylamine.
Isolation by medium pressure chromatography (alumina neutral, activity level III, elution with petroleum ether / ethyl acetate = 10: 1 to 1: 1, v: v).
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05 (d, 6H), 1.1-1.6 (m, 4H), 1.8-2.1 (m, 4H), 2.2 (s, 3H), 2, 3-2.65 (m, 2H), 2.9-3.1 (m, 1H), 3.8 (s, 3H), 6.7-7.0 (m, 3H).
aa) trans-N-isobutyl-4- (4-methoxy-3-methylphenyl) cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and isobutyl amine.
Isolation by medium pressure chromatography (alumina neutral, activity level III, elution with petroleum ether / ethyl acetate = 6: 1, v: v).
Melting point: 44-46 ° C.
ab) trans -N- (2,2-dimethyl-1-propyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and 2,2-dimethyl-1-propylamine.
Isolation by medium pressure chromatography (alumina neutral, activity level III, elution with petroleum ether / ethyl acetate = 10: 0.25, v: v).
Melting point: 42-44 ° C.
ac) trans-N-allyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and 2-allyl amine.
Isolation by medium pressure chromatography (alumina neutral, activity level III, elution with petroleum ether / ethyl acetate = 15: 1 to 10: 1, v: v).
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1-1.6 (m, 4H), 1.8-2.1 (m, 4H), 2.2 (s, 3H), 2.35-2.65 (m, 2H 3.25-3.6 (m, 2H), 3.8 (s, 3H), 5.1-5.25 (m, 2H), 5.8-6.0 (m, 1H), 6.7-7.0 (m, 3H).
ad) trans-4- (4-methoxy-3-methylphenyl) -N-phenylcyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and aniline.
Isolation by medium pressure chromatography (alumina neutral, activity level III, elution with petroleum ether / ethyl acetate = 30: 1, v: v).
Melting point 99-101 ° C.
ae) trans-N-cyclohexyl-4- (4-methoxy-3-methylphenyl) cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and cyclohexylamine.
Isolation by medium pressure chromatography (alumina neutral, activity level III, elution with petroleum ether / ethyl acetate = 10: 1, v: v).
Melting point: 68-70 ° C.
af) trans -N-methyl-4- (4-pyridyl) -cyclohexylamine
from 4- (4-pyridyl) cyclohexanone and methylamine.
Isolation by medium pressure chromatography (alumina basic, activity level III, elution with petroleum ether / ethyl acetate / methanol = 50: 50: 5, v: v: v).
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1-1.65 (2dq, 4H), 1.85-2.2 (2d, 4H), 1.83-2.6 (s + m, 5H), 7.12 (i.e. , 2H), 8.5 (d, 2H).
ag) 4- [5- (2,4-dimethoxy-6-methylpyrimidinyl)] - N-methylcyclohexylamine (cis-trans-mixture)
from 4- [5- (2,4-dimethoxy-6-methylpyrimidinyl)] cyclohexanone and methylamine.
Yellowish oil, which was further reacted raw. Rf 0.2 (trans) and 0.4 (cis) (petroleum ether / ethyl acetate / methanol = 10: 3: 0.3, v: v) alumina.
ah) N-methyl-4- (2,4,5-trimethylphenyl) -cyclohexylamine (cis-trans-mixture)
from 4- (2.4.5-trimethylphenyl) cyclohexanone and methylamine.
Melting point: 99 ° C.
Colorless oil, which was further reacted as a crude product.
ai) N-methyl-4- (3,4,5-trimethoxyphenyl) -cyclohexylamine (cis-trans mixture)
from 4- (3,4,5-trimethoxyphenyl) cyclohexanone and methylamine.
Melting point: 107-108 ° C.
aj) trans-4- (3-fluoro-4-methoxyphenyl) -N-methylcyclohexylamine
from 4- (3-fluoro-4-methoxyphenyl) cyclohexanone and methylamine.
Oil, Rf value: 0.15 (silica gel, petroleum ether / ethyl acetate / methanol = 10: 1: 0.5, v: v: v).
ak) trans-4- (3-chloro-4-methoxyphenyl) -N-methylcyclohexylamine
from 4- (3-chloro-4-methoxyphenyl) cyclohexanone and methylamine.
Oil, Rf value: 0.1 (silica gel, petroleum ether / ethyl acetate / methanol = 10: 1: 0.5, v: v: v).
al) trans -4- (4-methoxy-3-methylphenyl) -N- (3-methyl-1-butyl) cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and 3-methyl-butylamine.
Colorless oil, Rf value: 0.5 (alumina, petroleum ether / ethyl acetate = 4: 1, v: v).
am) trans -N- (3,3-dimethyl-1-butyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and 3,3-dimethylbutylamine.
Melting point: 36-38 ° C.
an) Trans-4- (4-methoxy-3-methylphenyl) -N- (2-propyn-1-yl) cyclohexylamine
from 4- (4-methoxy-3-methylphenyl) cyclohexanone and propargyl amine.
Colorless oil, Rf value: 0.5 (alumina, petroleum ether / ethyl acetate = 3: 1, v: v).
ao) trans -N-methyl-4- (3-pyridyl) -cyclohexylamine
from 4- (3-pyridyl) cyclohexanone and methylamine.
Yellowish oil, Rf value: 0.26 (alumina, petroleum ether / ethyl acetate = 2: 1, v: v).
po) trans -N-methyl-4- (5-pyrimidinyl) -cyclohexylamine
from 4- (5-pyrimidinyl) cyclohexanone and methylamine.
Colorless oil, Rf value: 0.2 (alumina, petroleum ether / ethyl acetate = 2: 1, v: vv).

Verfahren zur Herstellung der Endprodukte:Process for the preparation of the end products:

example 1 N-hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexyl amine (cis-trans mixture)

650 mg (2,8 mMol) 4-(4-Methoxy-3-methylphenyl)-N-methyl cyclohexylamin (cis-trans-Gemisch) und 300 mg (3 mMol) Tri ethylamin werden in 40 ml Ether und 5 ml Methylenchlorid vorgelegt und unter Eiskühlung 410 mg (3,1 mMol) Hexansäure chlorid in 10 ml Ether zugetropft. Es wird 30 Minuten ohne Kühlung nachgerührt, in 100 ml 1n-Salzsäure eingerührt und mit 100 ml Ether extrahiert. Die organische Phase wird erst mit 50 ml gesättigter Natriumbicarbonatlösung, dann mit Was ser gewaschen, mit Magnesiumsulfat getrocknet und einge dampft. Man erhält 900 mg der Titelverbindung in Form eines leicht gelben Öls.
NMR-Spektrum (200 MHz, CDCl₃); Signale bei ppm: 0,9 (t, 3H), 1,2-2,1 (m, 14H), 2,2 (s, 3H), 2,25-2,5 (m, 3H), 2,85 (2s, 3H), 3,6-3,75 (m, 0,5H), 3,8 (s, 3H), 4,5-4,65 (m, 0,5H), 6,7-7,0 (m, 3H). 650 mg (2.8 mmol) of 4- (4-methoxy-3-methylphenyl) -N-methyl cyclohexylamine (cis-trans mixture) and 300 mg (3 mmol) of triethylamine are introduced into 40 ml of ether and 5 ml of methylene chloride and under ice-cooling 410 mg (3.1 mmol) of hexanoic acid chloride in 10 ml of ether was added dropwise. The mixture is stirred for 30 minutes without cooling, stirred into 100 ml of 1N hydrochloric acid and extracted with 100 ml of ether. The organic phase is washed first with 50 ml of saturated sodium bicarbonate solution, then with water, dried with magnesium sulfate and evaporated. 900 mg of the title compound are obtained in the form of a slightly yellow oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-2.1 (m, 14H), 2.2 (s, 3H), 2.25-2.5 (m, 3H), 2, 85 (2s, 3H), 3.6-3.75 (m, 0.5H), 3.8 (s, 3H), 4.5-4.65 (m, 0.5H), 6.7- 7.0 (m, 3H).

Auf dieselbe Weise wurden dargestellt:In the same way were shown:

a) trans -N-hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl) cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.3-2.1 (m, 14H), 2.2 (s, 3H), 2.25-2.45 (m, 3H), 2, 85 (2s, 3H), 3.6-3.75 and 4.5-4.65 (2m, 1H), 3.8 (s, 3H), 6.7-7.0 (m, 3H).
b) cis-N-hexanoyl-N-methyl-4- (4-methoxyphenyl) -cyclohexylamine
from cis-4- (4-methoxyphenyl) -N-methylcyclohexylamine and hexanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-2.1 (m, 12H), 2.2-2.45 (m, 4H), 2.7 (s, 3H), 3, 02 (m, 1H), 3.6-3.75 and 4.5-4.7 (2m, 1H), 3.8 (s, 3H), 6.88 (m, 2H), 7.3 ( m, 2H).
c) trans -N-hexanoyl-N-methyl-4- (4-methoxyphenyl) cyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.3-2.1 (m, 14H), 2.25-2.55 (m, 3H), 2.85 (2s, 3H), 3, 6-3.75 and 4.5-4.65 (2m, 1H), 3.8 (s, 3H), 6.8 (m, 2H), 7.1 (m, 2H).
d) 4- (4-ethylphenyl) -N-hexanoyl-N-methylcyclohexylamine (cis-trans mixture)
from 4- (4-ethylphenyl) -N-methylcyclohexylamine (cis-trans-mixture) and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2-2.1 (m, 17H), 2.2-2.7 (m, 5H), 2.85 (2s, 3H), 3, 6-3.75 and 4.5-4.65 (2m, 1H), 7.1 (d, 4H).
e) 4- (4-tert-butylphenyl) -N-hexanoyl-N-methylcyclohexylamine (cis-trans mixture)
from 4- (4-tert-butylphenyl) -N-methylcyclohexylamine (cis-trans mixture) and hexanoyl chloride.
Melting point: 72-73 ° C.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.25-2.1 (m, 23H), 2.3-2.55 (m, 3H), 2.8-2.9 (2s, 3H ), 3.6-3.75 and 4.4-4.6 (2m, 1H), 7.1-7.4 (m, 4H).
f) N-hexanoyl-N-methyl-4- (naphthyl-2) cyclohexylamine (cis-trans mixture)
from N-methyl-4- (naphthyl-2) cyclohexylamine (cis-trans-Ge mixed) and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85 (m, 3H), 1.2-2.15 (m, 14H), 2.2-2.7 (m, 3H), 2.85 (2s, 3H), 3, 6-3.8 and 4.55-4.75 (2m, 1H), 7.3-7.9 (m, 7H).
g) trans-4- (p-biphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (p-biphenyl) -N-methylcyclohexylamine and hexanoic acid chloride.
Melting point: 111-113 ° C.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.25-2.1 (m, 14H), 2.25-2.6 (m, 3H), 2.85 (2s, 3H), 3, 6-3.8 and 4.5-4.7 (2m, 1H), 7.2-7.6 (m, 9H).
h) N-hexanoyl-N-methyl-4- (3-methoxyphenyl) -cyclohexylamine (cis-trans mixture)
from 4- (3-methoxyphenyl) -N-methyl-cyclohexylamine (cis-trans-mixture) and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2-2.1 (m, 14H), 2.2-2.6 (m, 3H), 2.85 (25, 3H), 3, 6-3.9 (2s + m, 3.5H), 4.4-4.6 (m, 0.5H), 6.7-7.3 (m, 4H).
i) 4- (3,4-dimethylphenyl) -N-hexanoyl-N-methyl-cyclohexylamine (cis-trans-mixture)
from 4- (3,4-dimethylphenyl) -N-methylcyclohexylamine (cis-trans mixture) and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-2.1 (m, 14H), 2.15-2.5 (m, 9H), 2.85 (d, 3H), 3, 6-3.8 and 4.5-4.65 (2m, 1H), 6.9-7.1 (m, 3H).
j) 4- (3,4-Dimethoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine (cis-trans-mixture)
from 4- (3,4-dimethoxyphenyl) -N-methylcyclohexylamine (cis-trans mixture) and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-2.1 (m, 14H), 2.2-2.5 (m, 3H), 2.45 (d, 3H), 3, 6-3.75 and 4.5-4.65 (2m, 1H), 3.8-3.9 (dd, 6H), 6.7-6.9 (m, 3H).
k) 2-Allyl-4- (4-methoxy-3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine (mixture of isomers)
from 2-allyl-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine (mixture of isomers) and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2-2.7 (m, 18H), 2.8-3.2 (m, 3H), 3.3-3.5 and 4.4 -4.6 (2m, 1H), 3.8 (d, 3H), 4.9-5.1 (m, 2H), 5.6-5.9 (m, 1H), 6.7-7 , 05 (m, 3H).
l) Nn-Amyl-N-hexanoyl-4- (4-methoxy-3-methylphenyl) cyclohexylamine (cis-trans mixture)
from Nn-amyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine (cis-trans mixture) and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8-1.2 (m, 10H), 1.25-2.05 (m, 16H), 2.2 (s, 3H), 2.2-2.5 (m, 3H ), 3.05-3.2 (m, 2H), 3.6-3.75 and 3.9-4.1 (2m, 1H), 3.8 (s, 3H), 6.7-7 , 0 (m, 3H).
m) N-cyclohexylmethyl-N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine (cis-trans mixture)
from N-cyclohexylmethyl-4- (4-methoxy-3-methylphenyl) cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 5H), 1.1-2.05 (m, 24H), 2.15-2.5 (s + m, 6H), 3.0-3.2 (t , 2H), 3.55-3.75 and 3.9-4.1 (2m, 1H), 3.8 (s, 3H), 6.7-7.0 (m, 3H).
n) cis-N-hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from cis -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and hexanoyl chloride.
Colorless oil of R f value 0.3 (pine gel, petroleum ether / ethyl acetate = 3: 1, v: v).
o) N-hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -2-methylcyclohexylamine (I)
from 4- (4-methoxy-3-methylphenyl) -2-methyl-N-methylcyclohexylamine (mixture of isomers A) and hexanoyl chloride.
Isomer A:
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8-1.0 (m, 6H), 1.2-2.1 (m, 13H), 2.2 (s, 3H), 2.25-2.4 (m, 2H ), 2.5-2.7 (m, 1H), 3.15 (2s, 3H), 3.8 (s, 3H), 4.0-4.95 (2m, 1H), 6.7- 7.0 (m, 3H).
Isomer B:
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 6H), 1.2-2.1 (m, 13H), 2.2 (s, 3H), 2.25-3.0 (m, 6H), 3, 2-3.4 (m, 0.5H), 3.8 (s, 3H), 4.3-4.6 (m, 0.5H), 6.7-7.05 (m, 3H).
p) N-hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -2-methylcyclohexylamine (II) (mixture of isomers)
from 4- (4-methoxy-3-methylphenyl) -2-methyl-N-methylcyclohexylamine (mixture of isomers B) and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 6H), 1.2-2.1 (m, 13H), 2.2 (s, 3H), 2.25-2.7 (m, 3H), 2, 8 + 3.15 (2d, 3H), 3.8 (s, 3H), 4.3-4.5, 4.95 (2m, 1H), 6.7-7.05 (m, 3H).
q) cis -4- (3-ethyl-4-methoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine
from cis -4- (3-ethyl-4-methoxyphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.2 (t, 3H), 1.25-2.05 (m, 12H), 2.2-2.45 (m, 4H), 2, 55-2.8 (m, 5H), 3.05 (m, 1H), 3.6-3.75 and 4.45-4.65 (2m, 1H), 3.85 (s, 3H), 6.85 (d, 1H), 7.1-7.2 (m, 2H).
r) trans-4- (3-ethyl-4-methoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (3-ethyl-4-methoxyphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2 (t, 3H), 1.25-1.9 (m, 12H), 1.9-2.1 (m, 2H), 2, 2-2.55 (m, 3H), 2.55-2.7 (q, 2H), 2.9 (2s, 3H), 3.6-3.75 and 4.5-4.7 (2m , 1H), 3.85 (s, 3H), 6.75 (m, 1H), 6.95-7.05 (m, 2H).
s) cis-N-hexanoyl-N-methyl-4- (4-methoxy-3-propylphenyl) -cyclohexylamine
from cis -4- (4-methoxy-3-propylphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8-1.0 (m, 6H), 1.2-2.05 (m, 15H), 2.15-2.45 (3m, 3H), 2.5-2.65 (t, 2H), 2.7 (s, 3H), 3.0 (m, 1H), 3.6-3.75 and 4.5-4.7 (2m, 1H), 3.8 (s , 3H), 6.8 (d, 1H), 7.05-7.2 (m, 2H).
t) trans -N-hexanoyl-N-methyl-4- (4-methoxy-3-propylphenyl) cyclohexylamine
from trans-4- (4-methoxy-3-propylphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-1.0 (m, 6H), 1.25-1.45 (m, 4H), 1.45-1.9 (m, 10H), 1.9-2.1 (m, 2H), 2.25-2.5 (m, 3H), 2.5-2.65 (m, 2H), 2.85 (2s, 3H), 3.6-3.75 and 4 , 5-4.7 (2m, 1H), 3.8 (s, 3H), 6.75 (d, 1H), 6.9-7.05 (m, 2H).
u) cis-4- (3-tert-butyl-4-methoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine
from cis-4- (3-tert-butyl-4-methoxyphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2-2.1 (m, 21H), 2.15-2.45 (m, 4H), 2.75 (s, 3H), 3, 0 (m, 1H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 3.85 (s, 3H), 6.8 (d, 1H), 7.15 ( m, 1H), 7.25 (m, 1H).
v) trans-4- (3-tert-butyl-4-methoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (3-tert-butyl-4-methoxyphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.25-1.45 (m, 13H), 1.5-1.9 (m, 8H), 1.9-2.1 (m, 2H ), 2.25-2.5 (m, 3H), 2.85 (2s, 3H), 3.6-3.75 and 4.5-4.7 (2m, 1H), 3.8 (s , 3H), 6.8 (m, 1H), 7.02 (m, 1H), 7.1 (m, 1H).
w) cis -N-hexanoyl-N-methyl-4- (4-methoxy-2-methylphenyl) -cyclohexylamine
from cis -4- (4-methoxy-2-methylphenyl) -N-methyl-cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.25-2.1 (m, 14H), 2.2-2.4 (s + m, 5H), 2.9 (s, 3H), 3.1 (m, 1H), 3.6-3.75 and 4.5-4.7 (2m, 1H), 3.8 (s, 3H), 6.7 (m, 2H), 7, 3-7.4 (m, 1H).
x) trans -N-hexanoyl-N-methyl-4- (4-methoxy-2-methylphenyl) cyclohexylamine
from trans-4- (4-methoxy-2-methylphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.95 (m, 3H), 1.25-1.45 (m, 4H), 1.5-2.05 (m, 10H), 2.25-2.45 (s + m , 5H), 2.5-2.75 (m, 1H), 2.85 (2s, 3H), 3.6-3.75 and 4.5-4.7 (2m, 1H), 3.8 (s, 3H), 6.7 (m, 2H), 7.12 (d, 1H).
y) trans -N-hexanoyl-N-methyl-4- (3-thienyl) cyclohexylamine
from trans -N-methyl-4- (3-thienyl) cyclohexylamine and Hexansäu chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.1-1.45 (m, 4H), 1.45-1.9 (m, 8H), 2.0-2.25 (m, 2H ), 2.25-2.45 (m, 2H), 2.45-2.75 (m, 1H), 2.85 (2s, 3H), 3.55-3.75 and 4.5-4 , 7 (2m, 1H), 6.95 (m, 2H), 7.25 (m, 1H).
z) trans-4- (3-furyl) -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (3-furyl) -N-methylcyclohexylamine and Hexansäu chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2-1.9 (m, 12H), 1.9-2.2 (m, 2H), 2.2-2.5 (m, 3H ), 2.85 (2s, 3H), 3.55-3.75 and 4.45-4.65 (2m, 1H), 6.3 (s, 1H), 7.2 (m, 1H), 7.35 (m, 1H).
aa) trans-N-ethyl-N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans -N-ethyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-0.95 (m, 3H), 1.1-2.1 (m, 17H), 2.2 (s, 3H), 2.3-2.5 (m, 3H ), 3.2-3.4 (q, 2H), 3.6-3.75 (m, 0.5H), 3.8 (s, 3H), 4.3-4.5 (m, 0 , 5H), 6.7-7.05 (m, 3H).
ab) trans-N-hexanoyl-N- (n-propyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N- (n-propyl) -cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 0.8-1.0 (m, 6H), 1.2-1.45 (m, 4H), 1.45-2.05 (m, 12H), 2.2 (s, 3H ), 2.25-2.55 (m, 3H), 3.05-3.25 (m, 2H), 3.55-3.75 and 4.25-4.45 (2m, 1H), 3 , 8 (s, 3H), 6.8 (d, 1H), 7.0 (m, 2H).
ac) trans -N- (n-butyl) -N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans -N- (n-butyl) -4- (4-methoxy-3-methylphenyl) cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 0.8-1.0 (m, 6H), 1.2-1.45 (m, 6H), 1.45-2.05 (m, 12H), 2.2 (s, 3H ), 2.25-2.55 (m, 3H), 3.1-3.3 (m, 2H), 3.55-3.85 (s + m, 3.5H), 4.25-4 , 45 (m, 0.5H), 6.8 (d, 1H), 7.0 (m, 2H).
ad) trans -N-hexanoyl-N- (n -pentyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N- (n-pentyl) -cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8-1.05 (m, 6H), 1.15-2.05 (m, 20H), 2.22 (s, 3H), 2.25-2.55 (m, 3H ), 3.05-3.3 (m, 2H), 3.55-3.85 (s + m, 3.5H), 4.25-4.5 (m, 0.5H), 6.75 (d, 1H), 7.0 (m, 2H).
ae) trans-N-hexanoyl-N-isopropyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans -N-isopropyl-4- (4-methoxy-3-methylphenyl) cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.95 (t, 3H), 1.15-2.1 (m, 19H), 2.22 (s, 3H), 2.3 (t, 3H), 2.4-2, 75 (m, 2H), 3,4-3,7 and 3,9-4,1 (2m, 1H), 3,8 (s, 3H), 6,75 (d, 1H), 7,0 ( m, 2H).
af) trans -N-hexanoyl-N-isobutyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans -N-isobutyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 0.8-1.0 (m, 9H), 1.2-2.1 (m, 15H), 2.2 (s, 3H), 2.3-2.5 (m, 3H ), 3.05-3.15 (t, 2H), 3.6-3.75 (m, 0.5H), 3.8 (s, 3H), 3.9-4.1 (m, 0 , 5H), 6.7-7.05 (m, 3H).
ag) trans -N- (2,2-dimethyl-1-propyl) -N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans -N- (2,2-dimethyl-1-propyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-1.05 (m, 12H), 1.2-2.1 (m, 13H), 2.2 (s, 3H), 2.25-2.75 (m, 4H ), 2.8-3.0 and 3.5-3.7 (2m, 1H), 3.05-3.2 (m, 2H), 3.8 (s, 3H), 6.7-7 , 0 (m, 3H).
ah) trans -N-allyl-N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-N-allyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.14-2.1 (m, 13H), 2.2 (s, 3H), 2.25-2.5 (m, 3H), 3, 65-3.85 (s + m, 4H), 3.9-4.05 (m, 2H), 4.4-4.6 (m, 1H), 5.05-5.3 (m, 2H ), 5.7-5.95 (m, 1H), 6.75 (d, 1H), 6.95 (m, 2H).
ai) trans -N-hexanoyl-N-phenyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-phenylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8 (t, 3H), 1.05-1.4 (m, 6H), 1.45-1.77 (m, 6H), 1.8-2.05 (m, 6H ), 2.1-2.35 (s + m, 4H), 3.8 (s, 3H), 4.65-4.85 (m, 1H), 6.7 (d, 1H), 6, 9 (m, 2H), 7.1 (m, 2H), 7.4 (m, 3H).
aj) trans -N-cyclohexyl-N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans -N-cyclohexyl-4- (4-methoxy-3-methylphenyl) cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.1-2.1 (m, 23H), 2.2 (s, 3H), 2.25-2.7 (m, 4H), 2, 9-3.3 (m, 1H), 3.4-3.7 (m, 1H), 3.8 (s, 3H), 6.75 (m, 1H), 7.0 (m, 2H) ,
ak) trans-N-butyryl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and butyric acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.0 (m, 3H), 1.6-1.9 (m, 8H), 1.9-2.1 (m, 2H), 2.2 (s, 3H), 2, 25-2.55 (m, 3H), 2.85 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 3.82 (s, 3H), 6.75 (d, 1H), 7.0 (m, 2H).
al) trans-4- (4-methoxy-3-methylphenyl) -N-methyl-N-octanoylcyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and octanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8-1.0 (m, 3H), 1.15-1.45 (m, 8H), 1.45-1.85 (m, 8H), 1.88-2.1 (m, 2H), 2.2 (s, 3H), 2.25-2.5 (m, 3H), 2.85 (2s, 3H), 3.6-3.85 (s + m, 3 , 5H), 4.5-4.7 (m, 0.5H), 6.75 (d, 1H), 7.0 (m, 2H).
am) trans-4- (4-methoxy-3-methylphenyl) -N-methyl-N-nonanoylcyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and nonanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.15-1.5 (m, 10H), 1.5-1.9 (m, 8H), 1.9-2.1 (m, 2H ), 2.2 (s, 3H), 2.3-2.55 (m, 3H), 2.9 (2s, 3H), 3.6-3.8 and 4.4-4.6 (2m , 1H), 3.82 (s, 3H), 6.8 (d, 1H), 7.0 (m, 2H).
an) trans -N- (3,3-dimethyl-butyryl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 3,3-dimethylbutyric acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1 (s, 9H), 1.45-1.85 (m, 6H), 1.85-2.1 (m, 2H), 2.2 (s, 3H), 2, 25-2.5 (m, 3H), 2.85 (2s, 3H), 3.6-3.85 (s + m, 3.5H), 4.5-4.7 (m, 0.5H ), 6.75 (d, 1H), 7.0 (m, 2H).
ao) trans-4- (4-methoxy-3-methylphenyl) -N-methyl-N-pivaloylcyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and pivaloyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 1.3 (s, 9H), 1.4-1.9 (m, 6H), 1.9-2.1 (m, 2H), 2.2 (s, 3H), 2, 35-2.55 (m, 1H), 2.9 (s, 3H), 3.8 (s, 3H), 4.0-4.35 (m, 1H), 6.8 (d, 1H) , 7.0 (m, 2H).
ap) trans-N-cyclohexanecarbonyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and cyclohexanecarboxylic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 1.15-2.1 (m, 18H), 2.2 (2s, 3H), 2.3-2.65 (m, 2H), 2.9 (2s, 3H), 3, 65-3.85 (s + m, 3.5H), 4.4-4.6 (m, 0.5H), 6.8 (dd, 1H), 7.0 (m, 2H).
aq) trans -N-benzoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and benzoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.15-1.5 (m, 1H), 1.5-2.1 (m, 7H), 2.1-2.5 (s + m, 4H), 2.75-3 , 1 (m, 3H), 3.45-3.7 and 4.5-4.75 (2m, 1H), 3.8 (s, 3H), 6.65-6.8 (m, 1H) , 6.8-7.1 (m, 2H), 7.3-7.5 (m, 5H).
ar) trans-4- (4-methoxy-3-methylphenyl) -N-methyl-N-phenylacetylcyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and phenylacetic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.35-1.8 (m, 6H), 1.82-2.05 (m, 2H), 2.2 (s, 3H), 2.25-2.5 (m, 1H ), 2.88 (2s, 3H), 3.65-3.85 (s + m, 3.5H), 4.08 (s, 2H), 4.45-4.65 (m, 0.5H ), 6.8 (d, 1H), 6.98 (m, 2H), 7.2-7.45 (m, 5H).
as) trans-N-butyryl-N-methyl-4- (4-methoxyphenyl) -cyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methyl-cyclohexylamine and butyric acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.0 (m, 3H), 1.45-1.9 (m, 8H), 1.9-2.1 (m, 2H), 2.2-2.55 (m, 3H ), 2.85 (2s, 3H), 3.6-3.85 (s + m, 3.5H), 4.5-4.7 (m, 0.5H), 6.85 (d, 2H ), 7.15 (d, 2H).
at) trans-4- (4-methoxyphenyl) -N-methyl-N-nonanoylcyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methylcyclohexylamine and nonanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.15-1.5 (m, 10H), 1.5-1.9 (m, 8H), 1.9-2.1 (m, 2H ), 2.25-2.55 (m, 3H), 2.85 (2s, 3H), 3.6-3.75 and 4.5-4.7 (2m, 1H), 3.8 (s , 3H), 6.85 (d, 2H), 7.1 (d, 2H).
au) trans -N- (3,3-dimethyl-butyryl) -N-methyl-4- (4-methoxy-phenyl) -cyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methylcyclohexylamine and 3,3-dimethylbutyric acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05 (2s, 9H), 1.45-1.9 (m, 6H), 1.9-2.1 (m, 2H), 2.25-2.6 (m, 3H ), 2.9 (2s, 3H), 3.65-3.9 (s + m, 3.5H) 4.45-4.65 (m, 0.5H), 6.85 (d, 2H) , 7.15 (d, 2H).
av) trans -N-cyclohexanecarbonyl-N-methyl-4- (4-methoxyphenyl) cyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methylcyclohexylamine and cyclohexanecarboxylic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1-2.1 (m, 18H), 2.3-2.6 (m, 2H), 2.9 (2s, 3H), 3.6-3.85 (s + m , 3, 5H), 4.45-4.7 (m, 0.5H), 6.85 (m, 2H), 7.1 (m, 2H).
aw) trans-4- (4-methoxyphenyl) -N-methyl-N-pivaloylcyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methylcyclohexylamine and pivaloyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.3 (s, 9H), 1.45-1.88 (m, 6H), 1.9-2.1 (m, 2H) 2.35-2.6 (m, 1H) , 2.9 (s, 3H), 3.8 (s, 3H), 4.05-4.3 (m, 1H), 6.85 (d, 2H), 7.15 (d, 2H).
ax) trans-4- (4-methoxyphenyl) -N-methyl-N-octanoyl-cyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methylcyclohexylamine and octanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.15-1.45 (m, 8H), 1.45-1.9 (m, 5H), 1.9-2.1 (m, 2H ), 2.25-2.55 (m, 3H), 2.85 (2s, 3H), 3.55-3.85 (s + m, 3.5H), 4.5-4.7 (m , 0.5H), 6.85 (d, 2H), 7.15 (d, 2H).
ay) trans -N-hexanoyl-N-methyl-4- (4-pyridyl) cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) cyclohexylamine and hexanoic acid chloride.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2-1.45 (m, 4H), 1.5-1.9 (m, 8H), 1.9-2.15 (m, 2H ), 2.2-2.6 (m, 3H), 2.85 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 7.1 (m , 2H), 8.5 (m, 2H).
az) trans-N-benzoyl-N-methyl-4- (4-methoxyphenyl) -cyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methylcyclohexylamine and benzoic acid chloride.
Melting point: 155-158 ° C.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1-1.5 (m, 1H), 1.55-2.1 (m, 7H), 2.25-2.6 (m, 1H), 2.75-3.1 (m, 3H), 3.45-3.85 (s, 3H + m, 0.5H), 4.45-4.8 (m, 0.5H), 6.82 (d, 2H), 6 , 94-7.25 (m, 2H), 7.3-7.5 (m, 5H).
ba) trans-4- (4-methoxyphenyl) -N-methyl-N-phenylacetylcyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methylcyclohexylamine and phenylacetyl chloride.
Colorless wax.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.2-1.82 (m, 6H), 1.85-2.0 (m, 2H), 2.3-2.5 (m, 1H), 2.85 (2s, 3H ), 3.6-3.85 (2s + m, 5.5H), 4.5-4.7 (m, 0.5H), 6.85 (d, 2H), 7.0-7.18 (m, 2H), 7.2-7.4 (m, 5H).
bb) 4- [5- (2,4-dimethoxy-6-methylpyrimidinyl)] - N-hexanoyl-N-methylcyclohexylamine (cis-trans mixture)
from 4- [5- (2,4-dimethoxy-6-methylpyrimidinyl)] - N-methylcyclohexylamine (cis-trans mixture) and hexanoyl chloride.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-1.0 (m, 3H), 1.2-1.45 (m, 4H), 1.45-1.85 (m, 8H), 1.85-2.5 (ds + m, 8H), 2.87 + 3.1 (ds + s, 3H), 3.5-3.8 + 4.45-4.8 (2m, 1H), 3.95 (2s, 6H).
bc) N-hexanoyl-N-methyl-4- (3,4,5-trimethoxyphenyl) cyclohexylamine (cis-trans mixture)
from N-methyl-4- (3,4,5-trimethoxyphenyl) -cyclohexylamine (cis-trans mixture) and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2-2.1 (m, 16H), 2.25-2.5 (m, 3H), 2.85 (2s, 3H), 3, 7 + 4.6 (2m, 1H), 3.85 (3s, 9H), 6.4 (s, 2H).
bd) N-hexanoyl-N-methyl-4- (2,4,5-trimethylphenyl) cyclohexylamine (cis-trans mixture)
from N-methyl-4- (2,4,5-trimethylphenyl) -cyclohexylamine and hexanoyl chloride.
Melting point: 65 ° C.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.2-2.0 (m, 16H), 2.15-2.3 (3s, 9H), 2.55-2.7 (m, 1H ), 3.7 + 4.55 (2m, 1H), 6.9-7.0 (s + d, 2H).
be) trans-4- (3-fluoro-4-methoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (3-fluoro-4-methoxyphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃), signals at ppm: 0.93 (t, 3H), 1.23-2.10 (m, 14H), 2.20-2.58 (m, 3H), 2 , 80-2.90 (2s, 3H), 3.67 (m, 0.45H), 3.88 (s, 3H), 4.57 (m, 0.55H), 6.80-7.00 (m, 3H).
bf) trans-4- (3-chloro-4-methoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (3-chloro-4-methoxyphenyl) -N-methylcyclohexylamine and hexanoyl chloride.
Melting point 96-98 ° C.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.92 (t, 3H), 1.18-1.47 (m, 4H), 1.47-2.12 (m, 10H), 2.22-2.56 (m, 3H 2.85-2.89 (2s, 3H), 3.67 (m, 0.4H), 3.90 (s, 3H), 4.57 (m, 0.6H), 6.86 ( d, 1H), 7.06 (d, 1H), 7.21 (m, 1H).
bg) trans-N-methyl-N-pentanoyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and pentanoic acid chloride.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.95 (t, 3H), 1.2-1.5 (m, 2H), 1.5-1.92 (m, 8H), 1.92-2.15 (m, 2H ), 2.2-2.6 (m, 3H), 2.88 (2s, 3H), 3.36-3.8 and 4.48-4.7 (2m, 1H), 7.05-7 , 2 (m, 2H), 8.45-8.6 (m, 2H).
bh) trans-N-heptanoyl-N-methyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and heptanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-1.45 (m, 6H), 1.48-1.9 (m, 8H), 1.92-2.15 (m, 2H ), 2.25-2.6 (m, 3H), 2.9 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 7.08-7 , 18 (m, 2H), 8.45-8.6 (m, 2H).
bi) trans -N-methyl-N-octanoyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and octanoic acid chloride.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-1.46 (m, 8H), 1.49-1.92 (m, 8H), 1.92-2.13 (m, 2H), 2.25-2.6 (m, 3H), 2.88 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 7.08 7.18 (m, 2H), 8.45-8.6 (m, 2H).
bj) trans-N-hexadecanoyl-N-methyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cycloh 86886 00070 552 001000280000000200012000285918677500040 0002004437999 00004 86767exylamine and hexadecanyl chloride.
Yellowish crystals.
Melting point: 52-54 ° C (petroleum ether).
bk) trans-N-methyl-N-octadecanoyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and octadecanoyl chloride.
Colorless crystals.
Melting point: 55-57 ° C (petroleum ether).
bl) trans -N-methyl-N- (trans-9-octadecenoyl) -4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and trans-9-octadecenoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.15-1.48 (m, 20H), 1.5-2.14 (m, 14H), 2.25-2.6 (m, 3H ), 2.88 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 5.32-5.43 (m, 2H), 7.08-7.18 (m, 2H), 8.45-8.59 (m, 2H).
bm) trans -N-methyl-N- (9.12.15-octadecatrienoyl) -4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and 9.12.15-octadecatrienoic acid chloride.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.0 (t, 3H), 1.25-1.49 (m, 8H), 1.5-1.92 (m, 9H), 1.92-2.2 (m, 6H ), 2.22-2.65 (m, 3H), 2.7-2.95 (m, 6H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 5 , 22-5.5 (m, 6H), 7.08-7.2 (m, 2H), 8.45-8.6 (m, 2H).
bn) trans -N-methyl-N-nonanoyl-4- (4-pyridyl) -cyclohexylamine from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and nonanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.15-1.45 (m, 10H), 1.48-1.9 (m, 8H), 1.91-2.13 (m, 2H ), 2.24-2.6 (m, 3H), 2.88 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 7.05-7 , 2 (m, 2H), 8.45-8.6 (m, 2H).
bo) trans -N-methyl-N- (3-methyl-butyryl) -4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and 3-methylbutyric acid chloride.
Colorless crystals.
Melting point: 65-67 ° C (petroleum ether).
bp) trans -N- (3,3-dimethyl-butyryl) -N-methyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and 3,3-di-methylbutyric acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.08 (s, 9H), 1.45-2.15 (m, 8H), 2.29 (d, 2H), 2.33-2.6 (m, 1H), 2, 89 (2s, 3H), 3.65-3.9 and 4.55-4.75 (2m, 1H), 7.08-7.18 (m, 2H), 8.45-8.58 (m , 2H).
bq) trans -N- (4-hexenoyl) -N-methyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and 4-hexenoic acid chloride.
Colorless crystals.
Melting point: 51-53 ° C (petroleum ether).
br) trans -N-methyl-N- (5-methyl-4-hexenoyl) -4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and 5-methyl-4-hexenoic acid chloride.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.45-1.9 (m, 12H), 1.91-2.15 (m, 2H), 2.25-2.63 (m, 5H), 2.88 (2s, 3H ), 3.6-3.82 and 4.5-4.7 (2m, 1H), 5.08-5.25 (m, 1H), 7.05-7.17 (m, 2H), 8 , 42-8.55 (m, 2H).
bs) trans-N-cyclohexanecarbonyl-N-methyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and cyclohexanecarboxylic acid chloride.
Colorless crystals.
Melting point: 119-120 ° C (petroleum ether).
bt) trans-N-benzoyl-N-methyl-4- (4-pyridyl) -cyclohexylamine from trans-N-methyl-4- (4-pyridyl) -cyclohexylamine and benzoyl chloride.
Colorless crystals.
Melting point: 172-173 ° C (petroleum ether).
bu) trans -N-methyl-N-phenylacetyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and phenyl-acetic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.32-2.1 (m, 8H), 2.3-2.58 (m, 1H), 2.88 (s, 3H), 3.6-3.85 (m + d , 2.5H), 4.5-4.72 (m, 0.5H), 7.05-7.18 (m, 2H), 7.2-7.45 (m, 5H), 8.45 -8.6 (m, 2H).
bv) trans -N-methyl-N- (4-phenylbutyryl) -4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and 4-phenylbutyric acid chloride.
Colorless crystals.
Melting point 95-96 ° C (petroleum ether).
bw) trans -N-methyl-N- (4-phenyl-3-butenoyl) -4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and 4-phenyl-3-butenoic acid chloride.
Colorless crystals.
Melting point: 128-130 ° C (acetone).
bx) trans -N-cinnamoyl-N-methyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and cinnamic acid chloride.
Colorless crystals.
Melting point 164-166 ° C (petroleum ether).
by) trans -N-methyl-N- (5-methyl-hexanoyl) -4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and 5-methyl hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (2s, 6H), 1.15-1.35 (m, 1H), 1.4-2.16 (m, 12H), 2.2-2.65 (m, 3H ), 2.88 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 7.05-7.18 (m, 2H), 8.45-8 , 6 (m, 2H).
bz) trans -N-methyl-N- (cis, cis-9,1'-octadecadienoyl) -4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and cis, cis- 9.12-octadecadienoic acid chloride.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-1.5 (m, 12H), 1.5-1.92 (m, 9H), 1.92-2.18 (m, 6H ), 2.2-2.6 (m, 3H), 2.7-2.95 (m, 6H), 3.6-3.8 and 4.5-4.7 (m, 1H), 5 , 25-5.5 (m, 4H), 7.08-7.18 (m, 2H), 8.45-8.6 (m, 2H).
ca) trans-N-decanoyl-N-methyl-4- (4-pyridyl) -cyclohexylamine from trans-N-methyl-4- (4-pyridyl) -cyclohexylamine and decanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.88 (t, 3H), 1.15-1.45 (m, 12H), 1.5-1.9 (m, 8H), 1.9-2.15 (m, 2H ), 2.2-2.65 (m, 3H), 2.9 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 7.05-7 , 19 (m, 2H), 8.45-8.6 (m, 2H).
cb) trans -N-methyl-N-tetradecanoyl-4- (4-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and tetra-decanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.14-1.45 (m, 20H), 1.48-1.9 (m, 8H), 1.9-2.15 (m, 2H), 2.2-2.6 (m, 3H), 2.9 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 7.05- 7.18 (m, 2H), 8.45-8.6 (m, 2H).
cc) traans-N-dodecanoyl-N-ethyl-4- (4-pyridyl) -caclohexa-amine
from trans -N-methyl-4- (4-pyridyl) -cyclohexylamine and Dode cansäurechlorid.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.14-1.45 (m, 16H), 1.48-1.9 (m, 8H), 1.9-2.15 (m, 2H ), 2.2-2.6 (m, 3H), 2.9 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 7.05-7 , 2 (m, 2H), 8.45-8.6 (m, 2H).
cd) trans -N-methyl-N- (cis-9-octadecenoyl) -4- (4-pyridyl) cyclohexylamine
from trans -N-methyl-4- (4-pyridyl) -cyclohexalamine and cis-9-octadecenoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.15-1.5 (m, 20H), 1.5-2.2 (m, 14H), 2.25-2.7 (m, 3H ), 2.89 (25, 3H), 3.6-3.8 and 4.4-4.65 (2m, 1H), 5.25-5.48 (m, 2H), 7.15-7 , 28 (m, 2H), 8.35-8.5 (m, 2H).
ce) trans -N-methyl-N- (5-methyl-hexanoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 5-methylhexanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (d, 6H), 1.15-1.38 (m, 2H), 1.45-2.1 (m, 11H), 2.2 (s, 3H), 2, 25-2.55 (m, 3H), 2.88 (s, 3H), 3.58-3.88 (m + s, 3.5H), 4.45-4.7 (m, 0.5H ), 6.75 (d, 1H), 7.0 (m, 2H).
cf) trans -N- (4-hexenoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methyl-caclohexylamine and 4-hexenoic acid chloride.
Colorless crystals.
Melting point: 82-83 ° C.
cg) trans -N-methyl-N- (4-pentenoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 4-pentenoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.45-2.1 (m, 8H), 2.25 (s, 3H), 2.3-2.55 (m, 5H), 2.88 (2s, 3H), 3, 6-3.88 (m + s, 3.5H), 4.5-4.7 (m, 0.5H), 5.05 (t, 2H), 5.28-6.04 (m, 1H ), 6.75 (d, 1H), 7.0 (m, 2H).
ch) trans -N- (3-hexenoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 3-hexenoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.0 (t, 3H), 1.35-2.15 (m, 9H), 2.25 (s, 3H), 2.28-2.5 (m, 1H), 2, 85 (2s, 3H), 3.0-3.2 (m, 2H), 3.55-3.85 (m + s, 3.5H), 4.42-4.7 (m, 0.5H ), 5.05 (d, 1H), 5.5-5.65 (m, 2H), 6.75 (d, 1H), 6.9 (d, 2H).
ci) trans -N-methyl-N- (trans-9-octadecenoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and trans-9-octadecenoic acid chloride.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.15-1.48 (m, 20H), 1.5-1.88 (m, 8H), 1.9-2.12 (m, 6H ), 2.22 (s, 3H), 2.28-2.5 (m, 3H), 2.9 (2s, 3H), 3.6-3.85 (m + s, 3.5H), 4.4-4.6 (m, 0.5H), 5.3-5.5 (m, 2H), 6.7 (d, 1H), 6.8-6.98 (m, 2H).
cj) trans -N-methyl-N- (cis-9-octadecenoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and cis-9-octadecenoic acid chloride.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.15-1.5 (m, 20H), 1.5-1.9 (m, 8H), 1.88-2.18 (m, 6H ), 2.2 (s, 3H), 2.25-2.55 (m, 3H), 2.85 (2s, 3H), 3.55-3.76 and 4.5-4.7 (2m , 1H), 3.8 (s, 3H), 5.25-5.45 (m, 2H), 6.75 (d, 1H), 6.92-7.05 (m, 2H).
ck) trans -N-methyl-N- (3-methyl-2-butenoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 3-methyl-2-butenoic acid chloride.
Colorless crystals.
Melting point: 75-76 ° C.
c1) trans -N-methyl-N- (4-phenyl-3-butenoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 4-phenyl-3-butenoic acid chloride.
Yellowish crystals.
Melting point: 123-125 ° C.
cm) trans-N-cinnamoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and cinnamic acid chloride.
Yellowish crystals.
Melting point: 165-167 ° C.
cn) trans -N- (3-cyclohexylpropenoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 3-cyclohexylpropenoic acid chloride.
Colorless crystals.
Melting point: 97-99 ° C.
co) trans -N-methyl-N- (3-phenylpropionyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 3-phenylpropionic acid chloride.
Colorless crystals.
Melting point: 123-125 ° C.
cp) trans -N-methyl-N- (4-phenylbutyryl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 4-phenylbutyric acid chloride.
Colorless crystals.
Melting point: 77-79 ° C.
cq) trans -N-methyl-N- (4-phenylbenzoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 4-phenylbenzoic acid chloride.
Yellowish crystals.
Melting point: 177-179 ° C.
cr) trans -N- (4-fluorobenzoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 4-fluorobenzoic acid chloride.
White crystals.
Melting point: 128-130 ° C.
cs) trans -N-methyl-N-nicotinoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and nicotinic acid chloride.
White crystals.
Melting point: 125-127 ° C.
ct) trans -N-methyl-N- (2-pyridinecarbonyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 2-pyridinecarbonyl chloride.
White crystals.
Melting point: 128-130 ° C.
cu) trans -N- (2-furancarbonyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 2-furancarboxylic acid chloride.
White crystals.
Melting point: 158-160 ° C.
cv) trans-N-isonicotinoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and isonicotinic acid chloride.
White crystals.
Melting point: 129-131 ° C.
cw) trans -N- (3-chlorobenzoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 3-chlorobenzoic acid chloride.
White crystals.
Melting point: 126-128 ° C.
cx) trans -N-methyl-N- (3-methylbenzoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 3-methylbenzoic acid chloride.
White crystals.
Melting point: 118-119 ° C.
cy) trans -N-methyl-N- (3-tolylacetyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 3-tolylacetic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.35-1.82 (m, 6H), 1.82-2.0 (m, 2H), 2.2 (s, 3H), 2.25-2.48 (m + s , 4H), 2.85 (s, 3H), 3.65-3.85 (m, d, s, 5.5H), 4.5-4.7 (m, 0.5H), 6.75 (d, 1H), 6.8-7.2 (m, 6H).
cz) trans -N-methyl-N- (2-methylbenzoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 2-methylbenzoic acid chloride.
White crystals.
Melting point: 125-127 ° C.
da) trans -N- (4-methoxyphenylacetyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 4-methoxyphenylacetic acid chloride.
White crystals.
Melting point: 91-93 ° C.
db) trans -N- (4-methoxybenzoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 4-methoxybenzoic acid chloride.
White crystals.
Melting point: 142-143 ° C.
dc) trans -N- (3,4-dimethylbenzoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 3,4-dimethylbenzoic acid chloride.
Melting point: 150-152 ° C.
dd) trans -N- (4,4-dimethoxybenzoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 4,4-dimethoxybenzoic acid chloride.
White crystals.
Melting point: 139-141 ° C.
de) trans -N-methyl-N- (5-methyl-2-thiophenecarbonyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 5-methyl-2-thiophenecarboxylic acid chloride.
White crystals.
Melting point: 133-135 ° C.
df) trans -N- (5-chloro-2-fluorobenzoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and 5-chloro-2-fluorobenzoyl chloride.
White crystals.
Melting point: 63-65 ° C.
dg) trans -N- (ethoxyacetyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methylcyclohexylamine and ethoxyacetic acid chloride.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.35 (t, 3H), 1.4-1.88 (m, 6H), 1.88-2.1 (m, 2H), 2.22 (s, 3H), 2, 3-2.5 (m, 1H), 2.9 (2s, 3H), 3.6 (q, 2H), 3.7-3.9 (m + s, 3.5H), 4.05- 4.25 (m, 2H), 4.4-4.65 (m, 0.5H); 6.75 (d, 1H), 6.92-7.05 (m, 2H).
ie) trans-N-hexanoyl-N-methyl-4- (3-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (3-pyridyl) -cyclohexylamine and hexanoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-1.49 (m, 4H), 1.5-2.16 (m, 10H), 2.22-2.65 (m, 3H ), 2.88 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 7.18-7.3 (m, 1H), 7.48-7 , 6 (m, 1H), 8.4-8.55 (m, 2H).
di) trans -N-benzoyl-N-methyl-4- (3-pyridyl) -cyclohexylamine
from trans -N-methyl-4- (3-pyridyl) -cyclohexylamine and benzoyl chloride.
Colorless crystals.
Melting point 164-166 ° C (petroleum ether).
dj) trans -N-hexanoyl-N-methyl-4- (5-pyrimidinyl) -cyclohexylamine
from trans -N-methyl-4- (5-pyrimidinyl) -cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-1.49 (m, 4H), 1.5-2.2 (m, 10H), 2.22-2.42 (m, 2H ), 2.42-2.68 (m, 1H), 2.9 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 8.53-8 , 7 (m, 2H), 9.05-9.18 (m, 1H).
dk) trans -N-methyl-N- (5-methyl-4-hexenoyl) -4- (5-pyrimidinyl) -cyclohexylamine
from trans -N-methyl-4- (5-pyrimidinyl) -cyclohexylamine and 5-methyl-4-hexenoic acid chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.5-1.95 (m, 12H), 1.95-2.18 (m, 2H), 2.25-2.42 (m, 4H), 2.42-2.69 (m, 1H), 2.9 (2s, 3H), 3.65-3.85 and 4.5-4.7 (2m, 1H), 5.1-5.28 (m, 1H), 8 , 55-8.68 (m, 2H), 9.05-9.15 (m, 1H).
dl) trans -N-methyl-N-phenylacetyl-4- (5-pyrimidinyl) cyclohexylamine
from trans -N-methyl-4- (5-pyrimidinyl) -cyclohexylamine and phenylacetic acid chloride.
Colorless crystals.
Melting point: 71-72 ° C.
dm) trans -N-methyl-N- (4-phenyl-3-butenoyl) -4- (5-pyrimidinyl) cyclohexylamine
from trans -N-methyl-4- (5-pyrimidinyl) -cyclohexylamine and 4-phenylbutanoic acid chloride.
Colorless crystals.
Melting point 122-123 ° C.
dn) trans -N-hexanoyl-N-methyl-4- [5- (2-methoxypyrimidinyl) -cyclohexylamine
from trans -N-methyl-4- [5- (2-methoxypyrimidinyl)] cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.25-1.48 (m, 4H), 1.5-1.9 (m, 8H), 1.92-2.15 (m, 2H ), 2.25-2.6 (m, 3H), 2.88 (2s, 3H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 4.0 (s , 3H), 8.3-8.42 (m, 2H).
do) trans -N-hexanoyl-N- (3-methyl-1-butyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans -N- (3-methyl-1-butyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8-1.1 (m, 9H), 1.2-2.1 (m, 17H), 2.2 (s, 3H), 2.25-2.55 (m, 3H ), 3.14-3.34 (m, 2H), 3.6-3.88 (m + s, 3.5H), 4.25-4.5 (m, 0.5H), 6.78 (d, 1H), 6.92-7.08 (m, 2H).
dp) trans -N- (3,3-dimethyl-1-butyl) -N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans -N- (3,3-dimethyl-1-butyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8-1.1 (m, 12H), 1.2-2.1 (m, 16H), 2.2 (s, 3H), 2.21-2.6 (m, 3H ), 3.1-3.35 (m, 2H), 3.55-3.78 and 4.4-4.55 (2m, 1H), 3.8 (s, 3H), 6.75 (i.e. , 1H), 6.9-7.05 (m, 2H)
dq) trans -N-hexanoyl-N- (2-propyn-1-yl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine
from trans -N- (2-propyn-1-yl) -4- (4-methoxy-3-methylphenyl) cyclohexylamine and hexanoyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-1.46 (m, 4H), 1.5-2.15 (m, 10H), 2.15-2.3 (s + m , 4H), 2.3-2.6 (m, 3H), 3.6-3.88 (m + s, 3.5H), 4.05 (d, 2H), 4.42-4.68 (m, 0.5H), 6.78 (d, 1H), 6.9-7.05 (m, 2H).

Example 2 N-ethoxyacetyl-N-methyl-4- (4-methoxyphenyl) -cyclohexyl amine (cis-trans mixture)

683 mg (2 mMol) Benzoesäure-Salz von 4-(4-Methoxyphenyl)- N-methyl-cyclohexylamin (cis-trans-Gemisch) werden mit 445 mg (4,4 mMol) Triäthylamin in 20 ml Ether gelöst. Zu der auf 0°C gekühlten Lösung werden 270 mg (2,2 mMol) Ethoxyacetyl chlorid in 13 ml Ether in 5 Minuten zugetropft und anschlie ßend eine Stunde bei Raumtemperatur gerührt. Anschließend wird mit Ether verdünnt, mit Wasser, verdünnter Salzsäure, verdünnter Natronlauge und gesättigter Kochsalzlösung gewa schen und mit Magnesiumsulfat getrocknet. Nach Verdampfen des Lösungsmittels erhält man 600 mg (98,2% der Theorie des N-Ethoxyacetyl-N-methyl-4-(4-methoxyphenyl)-cyclohexylamins (cis-trans-Gemisch) als gelbes Öl.
NMR-Spektrum (200 MHz, CDCl₃); Signale bei ppm: 1,15-1,3 (t, 3H), 1,5-2,1 (m, 8H), 2,3-2,5 (m, 1H), 2,85 (d, 3H), 3,5-3,65 (q, 2H), 3,7-3,85 (s+m, 3,5H), 4,1-4,2 (d, 2H), 4,4-4,6 (m, 0,5H), 6,75-6,9 (d, 2H), 7,05-7,15 (d, 2H). 683 mg (2 mmol) of benzoic acid salt of 4- (4-methoxyphenyl) -N-methylcyclohexylamine (cis-trans mixture) are dissolved with 445 mg (4.4 mmol) of triethylamine in 20 ml of ether. 270 mg (2.2 mmol) of ethoxyacetyl chloride in 13 ml of ether are added dropwise in 5 minutes to the solution cooled to 0.degree. C. and then stirred at room temperature for one hour. It is then diluted with ether, washed with water, dilute hydrochloric acid, dilute sodium hydroxide solution and saturated brine and dried with magnesium sulfate. After evaporation of the solvent, 600 mg (98.2% of theory of N-ethoxyacetyl-N-methyl-4- (4-methoxyphenyl) cyclohexylamine (cis-trans mixture) are obtained as a yellow oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.15-1.3 (t, 3H), 1.5-2.1 (m, 8H), 2.3-2.5 (m, 1H), 2.85 (d, 3H ), 3.5-3.65 (q, 2H), 3.7-3.85 (s + m, 3.5H), 4.1-4.2 (d, 2H), 4.4-4 , 6 (m, 0.5H), 6.75-6.9 (d, 2H), 7.05-7.15 (d, 2H).

Example 3 N- (5-methyl-hex-4-enoyl) -N-methyl-4- (4-methoxy-3-methyl phenyl) -cyclohexylamine (cis-trans-mixture)

1,3 g (0,01 Mol) 5-Methyl-hex-4-en-carbonsäure und 1,6 g (0,01 Mol) N.N′-Carbonyldiimidazol werden in 40 ml Xylol 10 Minuten bei Raumtemperatur und 20 Minuten bei 40°C gerührt. Nach Zugabe von 2,3 g (0,01 Mol) 4-(4-Methoxy-3-methyl phenyl)-N-methyl-cyclohexylamin (cis-trans-Gemisch) wird 6 Stunden zum Sieden erhitzt und anschließend über Nacht ste hen gelassen. Vom Imidazol wird abdekantiert, das Xylol ver dampft und der Rückstand in 100 ml Essigsäureethylester auf genommen, mit 15 ml eiskalter 2N-Salzsäure, gesättigter Kochsalzlösung gewaschen, getrocknet und eingedampft. Der Rückstand wird durch Säulenchromatographie (Kieselgel, Es sigsäureethylester/Petrolether = 1 : 3, v:v) gereinigt. Man erhält 2,9 g (84,4% der Theorie) N-(5-Methyl-hex-4-enoyl)- N-methyl-4-(4-methoxy-3-methylphenyl)-cyclohexylamin (cis- trans-Gemisch) als farbloses langsam kristallisierendes Öl.
NMR-Spektrum (200 MHz, CDCl₃); Signale bei ppm: 1,4-2,1 (m, 14H), 2,2 (s, 3H), 2,25-2,5 (m, 5H), 2,85 (s, 3H), 3,7 (m, 0,5H), 3,8 (s, 3H), 4,6 (m, 0,5H), 5,15 (m, 1H), 6,7-7,0 (m, 3H).1.3 g (0.01 mol) of 5-methyl-hex-4-ene-carboxylic acid and 1.6 g (0.01 mol) of NN'-carbonyldiimidazole are dissolved in 40 ml of xylene at room temperature for 10 minutes and at 40 ° for 20 minutes ° C stirred. After addition of 2.3 g (0.01 mol) of 4- (4-methoxy-3-methylphenyl) -N-methyl-cyclohexylamine (cis-trans mixture) is heated to boiling for 6 hours and then hen over night hen calmly. From the imidazole is decanted, the xylene evaporated ver and the residue taken up in 100 ml of ethyl acetate, washed with 15 ml of ice-cold 2N hydrochloric acid, saturated brine, dried and evaporated. The residue is purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1: 3, v: v). This gives 2.9 g (84.4% of theory) of N- (5-methyl-hex-4-enoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine (cis-trans- Mixture) as a colorless slowly crystallizing oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.4-2.1 (m, 14H), 2.2 (s, 3H), 2.25-2.5 (m, 5H), 2.85 (s, 3H), 3, 7 (m, 0.5H), 3.8 (s, 3H), 4.6 (m, 0.5H), 5.15 (m, 1H), 6.7-7.0 (m, 3H) ,

Example 4 N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexyl amine (cis-trans mixture)

430 mg (1,3 mMol) N-Hexanoyl-N-methyl-4-(4-methoxy-3-methyl phenyl)-cyclohexylamin (cis-trans-Gemisch) und 280 mg (3,4 mMol) Natriumthioethanolat werden in 5 ml Dimethylformamid unter Stickstoff 2,5 Stunden zum Rückfluß erhitzt. Anschlie ßend werden 50 ml Wasser zugegeben und dreimal mit je 50 ml Ether extrahiert. Der Extrakt wird mit 10 ml 1N-Salzsäure und anschließend mit Wasser gewaschen, getrocknet, einge dampft, der Rückstand mit Petrolether kristallisiert und nochmals eingedampft. Man erhält 280 mg (67,9% der Theorie) der Titelverbindung als farblose Kristalle vom Schmelzpunkt 116-120°C.
NMR-Spektrum (200 MHz, CDCl₃); Signale bei ppm: 0,9 (t, 3H), 1,2-1,4 (m, 4H), 1,45-2,05 (m, 10H), 2,2-2,4 (s+m, 6H), 2,85 (2s, 3H), 3,6-3,75 (m, 0,5H), 4,5-4,65 (m, 0,5H), 6,7-7,0 (m, 3H).430 mg (1.3 mmol) of N-hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine (cis-trans mixture) and 280 mg (3.4 mmol) of sodium thioethoxide are dissolved in 5 ml of dimethylformamide under nitrogen for 2.5 hours to reflux. Subsequently ßend 50 ml of water are added and extracted three times with 50 ml of ether. The extract is washed with 10 ml of 1N hydrochloric acid and then with water, dried, evaporated, the residue is crystallized with petroleum ether and evaporated again. This gives 280 mg (67.9% of theory) of the title compound as colorless crystals of melting point 116-120 ° C.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.2-1.4 (m, 4H), 1.45-2.05 (m, 10H), 2.2-2.4 (s + m , 6H), 2.85 (2s, 3H), 3.6-3.75 (m, 0.5H), 4.5-4.65 (m, 0.5H), 6.7-7.0 (m, 3H).

Auf dieselbe Weise wurde erhalten:In the same way was obtained:

a) 4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (5-methyl-hex-4-enoyl) -cyclohexylamine (cis-trans-mixture)
from N- (5-methyl-hex-4-enoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine (cis-trans mixture) and sodium thio-ethanolate. Colorless crystals of melting point 139-141 ° C.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.5-2.05 (m, 14H), 2.2-2.4 (m, 8H), 2.35 (2s, 3H), 3.6-3.75 + 4.5 -4.65 (m, 1H), 5.1-5.2 (m, 1H), 6.7-7.0 (m, 3H).
b) trans -N- (4-hexenoyl) -N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N- (4-hexenoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and sodium thioethanolate.
Melting point: 155-157 ° C.
c) trans -N-methyl-N- (trans-9-octadecenoyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (trans-9-octadecenoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and sodium thioethoxide.
Melting point: 80-82 ° C.
d) trans -N-methyl-N- (cis-9-octadecenoyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (cis-9-octadecenoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and sodium thioethanolate.
Melting point: 52-54 ° C.

Example 5 trans-N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) - cyclohexylamine

2,34 g (9,35 mMol) Bortribromid werden unter Eiskühlung zu 1,24 g (3,74 mMol) trans-N-Hexanoyl-N-methyl-4-(4-methoxy-3- methylphenyl)-cyclohexylamin in 25 ml Methylenchlorid zuge tropft. Nach zweistündigem Rühren bei Raumtemperatur wird Eis und 6 ml Methanol zugegeben. Nach weiteren 15 Minuten Rühren wird vorsichtig Natriumbicarbonat zugegeben und nach 30 Minuten mit Methylenchlorid extrahiert. Der Extrakt wird mit Wasser gewaschen, getrocknet und eingedampft. Der Rück stand wird aus Ether bei tiefer Temperatur kristallisiert. Man erhält 0,84 g (70,7% der Theorie) der Titelverbindung vom Schmelzpunkt 126°C.
NMR-Spektrum (200 MHz, CDCl₃); Signale bei ppm: 0,9 (t, 3H), 1,25-2,05 (m, 14H), 2,2-2,4 (s+m, 6H), 2,85 (2s, 3H), 3,6-3,75 und 4,5-4,65 (2m, 1H), 5,3-5,75 (2s, 1H), 6,7-7,0 (m, 3H).Boron tribromide (2.34 g, 9.35 mmol) is added under ice-cooling to 1.24 g (3.74 mmol) of trans -N-hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine in 25 ml of methylene chloride added dropwise. After two hours of stirring at room temperature, ice and 6 ml of methanol are added. After stirring for a further 15 minutes, sodium bicarbonate is carefully added and extracted after 30 minutes with methylene chloride. The extract is washed with water, dried and evaporated. The residue is crystallized from ether at low temperature. This gives 0.84 g (70.7% of theory) of the title compound of melting point 126 ° C.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.25-2.05 (m, 14H), 2.2-2.4 (s + m, 6H), 2.85 (2s, 3H), 3.6-3.75 and 4.5-4.65 (2m, 1H), 5.3-5.75 (2s, 1H), 6.7-7.0 (m, 3H).

Auf dieselbe Weise wurden erhalten:In the same way were obtained:

a) trans-N-hexanoyl-N-methyl-4- (4-hydroxyphenyl) -cyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-methoxyphenyl) -cyclohexylamine and boron tribromide.
Melting point: 115-120 ° C.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.2-1.4 (m, 4H), 1.5-2.1 (m, 10H), 2.3-2.5 (m, 3H ), 2.8-2.95 (d, 3H), 3.6-3.8 and 4.4-4.6 (m, 1H), 6.75 (m, 2H), 7.05 (m , 2H).
b) cis-Nn-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from cis-Nn-hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2-2.0 (m, 12H), 2.15-2.4 (s + m, 7H), 2.7 (s, 3H), 2.95 (s, 1H), 3.6-3.75 (m, 0.5H) 4.5-4.7 (m, 0.5H), 5.15-5.3 (2s, 1H) , 6.7-7.1 (m, 3H).
c) trans-4- (3-ethyl-4-hydroxyphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (3-ethyl-4-methoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine and boron tribromide.
Rf value: 0.62 (silica gel, petroleum ether / ethyl acetate = 1: 1, v: v).
d) trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-propylphenyl) -cyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-methoxy-3-propylphenyl) -cyclohexylamine and boron tribromide.
Rf value: 0.4 (silica gel, petroleum ether / ethyl acetate = 2: 1, v: v).
e) trans-4- (3-tert-butyl-4-hydroxyphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (3-tert-butyl-4-methoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine and boron tribromide.
Rf value: 0.31 (silica gel, petroleum ether / ethyl acetate = 2: 1, v: v).
f) trans-N-hexanoyl-N-methyl-4- (4-hydroxy-2-methylphenyl) cyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-methoxy-2-methylphenyl) -cyclohexylamine and boron tribromide.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2-2.0 (m, 15H), 2.3 (s, 3H), 2.4-2.75 (m, 3H), 2, 95 (s, 3H), 3.6-3.75 and 4.4-4.7 (2m, 1H), 6.65-6.8 (m, 2H), 7.05 (d, 1H).
g) trans-N-ethyl-N-hexanoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-ethyl-N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 137-139 ° C.
h) trans -N-hexanoyl-N- (n-propyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-hexanoyl-N- (n-propyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 113-115 ° C.
i) trans -N- (n-butyl) -N-hexanoyl-4- (4-hydroxy-3-methylphenyl) cyclohexylamine
from trans -N- (n-butyl) -N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 99-101 ° C.
j) trans -N-hexanoyl-N- (n -pentyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
of trans -N-hexanoyl-N- (n -pentyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 122-124 ° C.
k) trans -N-hexanoyl-N-isopropyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-hexanoyl-N-isopropyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 82-84 ° C.
l) trans -N-hexanoyl-N-isobutyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-hexanoyl-N-isobutyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 105-107 ° C.
m) trans -N- (2,2-dimethyl-1-propyl) -N-hexanoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N- (2,2-dimethyl-1-propyl) -N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 121-123 ° C.
n) trans -N-allyl-N-hexanoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-allyl-N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 99-101 ° C.
o) trans-N-hexanoyl-N-phenyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-hexanoyl-N-phenyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 170-172 ° C.
p) trans -N-cyclohexyl-N-hexanoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-cyclohexyl-N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 168-170 ° C.
q) trans -N-butyryl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-butyryl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 159-162 ° C.
r) trans -N-methyl-N-octanoyl-4- (4-hydroxy-3-methylphenyl) cyclohexylamine
from trans -N-methyl-N-octanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 72-75 ° C.
s) trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N-nonanoylcyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methyl-N-nonanoylcyclohexylamine and boron tribromide.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 0.9 (t, 3H), 1.15-1.5 (m, 10H), 1.5-2.1 (m, 10H), 2.23 (2s, 3H), 2, 3-2.5 (m, 3H), 2.9 (2s, 3H), 3.6-3.8 and 4.4-4.6 (2m, 1H), 6.7 (m, 1H), 6.8-7.0 (m, 2H).
t) trans -N- (3,3-dimethyl-butyryl) -N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N- (3,3-dimethyl-butyryl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point 170-173 ° C.
u) trans -N-methyl-N-pivaloyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N-pivaloyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 222-225 ° C.
v) trans -N-cyclohexanecarbonyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-cyclohexanecarbonyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 209-212 ° C.
w) trans -N-benzoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-benzoyl-N-methyl-4- (4-methoxy-3-methylphenyl) cyclohexylamine and boron tribromide.
Melting point: 205-208 ° C.
x) trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (phenylacetyl) -cyclohexylamine
from trans-4- (4-methoxy-3-methylphenyl) -N-methyl-N- (phenylacetyl) -cyclohexylamine and boron tribromide.
Melting point: 65-70 ° C (out of focus).
y) trans-4- (4-hydroxyphenyl) -N-methyl-N-propionylcyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methyl-N-propionylcyclohexylamine and boron tribromide.
Melting point: 196-200 ° C.
z) trans-N-butyryl-N-methyl-4- (4-hydroxyphenyl) -cyclohexylamine
from trans-N-butyryl-N-methyl-4- (4-methoxyphenyl) -cyclohexylamine and boron tribromide.
Melting point: 125-128 ° C.
aa) trans-4- (4-hydroxyphenyl) -N-methyl-N-nonanoylcyclohexylamine.
from trans-4- (4-methoxyphenyl) -N-methyl-N-nonanoylcyclohexylamine and boron tribromide.
Melting point: 74-77 ° C.
ab) trans -N- (3.3-dimethyl-butyryl) -N-methyl-4- (4-hydroxy-phenyl) -cyclohexylamine
from trans -N- (3.3-dimethyl-butyryl) -N-methyl-4- (4-methoxy-phenyl) -cyclohexylamine and boron tribromide.
Melting point: 205-208 ° C.
ac) trans-N-cyclohexanecarbonyl-N-methyl-4- (4-hydroxy-phenyl) -cyclohexylamine
from trans -N-cyclohexanecarbonyl-N-methyl-4- (4-methoxy-phenyl) -cyclohexylamine and boron tribromide.
Melting point: 242-245 ° C.
ad) trans-4- (4-hydroxyphenyl) -N-methyl-N-octanoylcyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methyl-N-octanoylcyclohexylamine and boron tribromide.
Melting point: 120-125 ° C.
ae) trans-4- (4-hydroxyphenyl) -N-methyl-N-pivaloylcyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methyl-N-pivaloylcyclohexylamine and boron tribromide.
Melting point: 205-208 ° C.
af) trans-N-benzoyl-N-methyl-4- (4-hydroxyphenyl) -cyclohexylamine
from trans-N-benzoyl-N-methyl-4- (4-methoxyphenyl) -cyclohexylamine and boron tribromide.
Melting point: 253-255 ° C.
ag) trans-4- (4-hydroxyphenyl) -N-methyl-N-phenylacetylcyclohexylamine
from trans-4- (4-methoxyphenyl) -N-methyl-N-phenylacetylcyclohexylamine and boron tribromide.
Melting point: 218-222 ° C.
ah) trans -N-methyl-N- (5-methyl-hexanoyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (5-methyl-hexanoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 138-140 ° C.
ai) trans -N-methyl-N- (4-pentenoyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (4-pentenoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 124-126 ° C.
aj) trans -N- (3-hexenoyl) -N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N- (3-hexenoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 103-105 ° C.
ak) trans -N-methyl-N- (3-methyl-2-butenoyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (3-methyl-2-butenoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 146-148 ° C.
al) trans -N-methyl-N- (4-phenyl-3-butenoyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (4-phenyl-3-butenoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.4-2.1 (m, 9H), 2.25 (s, 3H), 2.29-2.5 (m, 1H), 2.9 (2s, 3H), 3, 25-3.42 (m, 2H), 3.6-3.85 and 4.45-4.7 (2m, 1H), 6.28-6.6 (m, 2H), 6.72 (i.e. , 1H), 6.35-7.0 (m, 2H), 7.15-7.42 (m, 5H).
am) trans -N-cinnamoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-cinnamoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 220-222 ° C.
an) trans -N- (3-cyclohexylpropenoyl) -N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans- (3-cyclohexylpropenoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 180-182 ° C.
ao) trans -N-methyl-N- (3-phenylpropionyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (3-phenyl-propionyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
NMR spectrum (200 MHz, DMSO); Signals at ppm: 1.35-1.9 (m, 8H), 2.1 (s, 3H), 2.2-2.45 (m, 1H), 2.45-2.9 (m, 7H ), 3.6-3.8 and 4.22-4.5 (2m, 1H), 6.65 (d, 1H), 6.75-6.95 (m, 2H), 7.05-7 , 4 (m, 5H).
ap) trans -N-methyl-N- (4-phenylbutyryl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (4-phenylbutyryl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.3-2.15 (m, 10H), 2.25 (s, 3H), 2.3-2.85 (m, 5H), 2.9 (s, 3H), 3, 6-3.85 and 4.45-4.7 (2m, 1H), 6.7-6.98 (m, 3H), 7.05-7.5 (m, 5H).
aq) trans -N-methyl-N- (4-phenylbenzoyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (4-phenylbenzoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
NMR spectrum (200 MHz, DMSO); Signals at ppm: 1.35-1.95 (m, 8H), 2.08 (s, 3H), 2.2-2.45 (m, 1H), 2.88 (s, 3H), 3, 6-3.85 and 4.25-4.6 (2m, 1H), 6.55-6.95 (m, 3H), 7.35-7.85 (m, 9H).
ar) trans -N- (4-fluorobenzoyl) -N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N- (4-fluorobenzoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 231-233 ° C.
as) trans -N-methyl-N-nicotinoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N-nicotinoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: from 210 ° C decomposition.
at) trans -N-methyl-N- (2-pyridinecarbonyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (2-pyridinecarbonyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point 176-178 ° C.
au) trans -N- (2-furancarbonyl) -N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N- (2-furancarbonyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 226-228 ° C.
av) trans-N-isonicotinoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans-N-isonicotinoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: from 200 ° C decomposition.
aw) trans -N- (3-chlorobenzoyl) -N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N- (3-chlorobenzoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 176-178 ° C.
ax) trans -N-methyl-N- (3-methylbenzoyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (3-methylbenzoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 181-183 ° C.
ay) trans -N-methyl-N- (3-tolylacetyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (3-tolylacetyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1-2.0 (m, 8H), 2.25 (s, 3H), 2.28-3.45 (s + m, 4H), 2.85 (2s, 3H), 3.6-3.8 (d + m, 2.5H), 4.5-4.7 (m, 0.5H), 6.65-6.8 (m, 1H), 7.0-7 , 3 (m, 6H).
az) trans -N-methyl-N- (2-methylbenzoyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (2-methylbenzoyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 221-223 ° C.
ba) trans -N-methyl-N- (5-methyl-2-thiophenecarbonyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-methyl-N- (5-methyl-2-thiophenecarbonyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 224-226 ° C.
bb) trans -N- (5-chloro-2-fluorobenzoyl) -N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N- (5-chloro-2-fluorobenzoyl) -N-methyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 212-214 ° C.
bc) trans -N-hexanoyl-N- (3-methyl-1-butyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N-hexanoyl-N- (3-methyl-1-butyl) -4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 107-110 ° C.
bd) trans -N- (3,3-dimethyl-1-butyl) -N-hexanoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine
from trans -N- (3,3-dimethyl-1-butyl) -N-hexanoyl-4- (4-methoxy-3-methylphenyl) -cyclohexylamine and boron tribromide.
Melting point: 56-58 ° C.

Example 6 trans-4- [4- (4-diethylamino-ethoxy) -3-methylphenyl] -N- hexanoyl-N-methyl-cyclohexylamine

1,5 g (4,7 mMol) trans-N-Hexanoyl-N-methyl-4-(4-hydroxy-3- methylphenyl)-cyclohexylamin und 2,6 g wasserfreies Kalium carbonat werden in 40 ml Dimethylformamid 30 Minuten ge rührt, 1,6 g Diethylamino-ethylchlorid-Hydrochlorid zugege ben, und über Nacht gerührt, in Eiswasser gegossen und mit Ether extrahiert. Der Extrakt wird mit Wasser und gesättig ter Kochsalzlösung gewaschen, getrocknet und eingedampft. Der Rückstand wird durch Chromatographie (Kieselgel, Essig säureethylester/Petrolether = 1 : 2, v:v) gereinigt. Man er hält 1,66 g (85% der Theorie) trans-4-[4-(2-Diethylamino ethoxy)-3-methylphenyl-1-N-hexanoyl-N-methyl-cyclohexylamin als wachsartige Kristalle vom Schmelzpunkt 48-50°C.
NMR-Spektrum (200 MHz, CDCl₃); Signale bei ppm: 0,9 (m, 3H), 1,05 (t, 6H), 1,2-1,4 (m, 4H), 1,5-2,0 (m, 10H), 2,2 (s, 3H), 2,25-2,4 (m, 3H), 2,6-2,7 (q, 4H), 2,8-2,9 (m, 5H), 3,6-4,6 (t+m, 3H), 6,7-7,0 (m, 3H).1.5 g (4.7 mmol) of trans-N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2.6 g of anhydrous potassium carbonate are stirred in 40 ml of dimethylformamide for 30 minutes , 1.6 g of diethylamino-ethyl chloride hydrochloride zugege ben, and stirred overnight, poured into ice-water and extracted with ether. The extract is washed with water and saturated brine, dried and evaporated. The residue is purified by chromatography (silica gel, ethyl acetate / petroleum ether = 1: 2, v: v). Man he holds 1.66 g (85% of theory) of trans-4- [4- (2-diethylamino ethoxy) -3-methylphenyl-1-N-hexanoyl-N-methyl-cyclohexylamine as waxy crystals of melting point 48-50 ° C.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.05 (t, 6H), 1.2-1.4 (m, 4H), 1.5-2.0 (m, 10H), 2, 2 (s, 3H), 2.25-2.4 (m, 3H), 2.6-2.7 (q, 4H), 2.8-2.9 (m, 5H), 3.6- 4.6 (t + m, 3H), 6.7-7.0 (m, 3H).

Die Verbindung wurde mit etherischer Salzsäure in das Hydro chlorid überführt, das nach Umfällen aus Aceton/Ether als klebriges, hygroskopisches Pulver erhalten wurde.
NMR-Spektrum (200 MHz, CDCl₃); Signale bei ppm: 0,9 (m, 3H), 1,3-2,05 (m, 20H), 2,2 (s, 3H), 2,3-2,6 (m, 3H), 2,95 (s, 3H), 3,2-3,4 (m, 4H), 3,4-3,6 (m, 2,5H), 4,3-4,6 (m, 2,5H), 6,7-7,05 (m, 3H).The compound was converted into the hydrochloride with ethereal hydrochloric acid which, after precipitation from acetone / ether, was obtained as a sticky, hygroscopic powder.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.3-2.05 (m, 20H), 2.2 (s, 3H), 2.3-2.6 (m, 3H), 2, 95 (s, 3H), 3.2-3.4 (m, 4H), 3.4-3.6 (m, 2.5H), 4.3-4.6 (m, 2.5H), 6.7-7.05 (m, 3H).

Das IR-Spektrum in Methylenchlorid zeigt eine ausgeprägte breite Salzbande bei 2300 cm^-1, die im IR-Spektrum der freien Base fehlt. The IR spectrum in methylene chloride shows a pronounced broad salt band at 2300 cm ^-1 , which is absent in the IR spectrum of the free base.

Auf dieselbe Weise wurden erhalten:In the same way were obtained:

a) 4- (4-Benzyloxy-3-methylphenyl) -N-methyl-N- (5-methyl-hex-4-enoyl) -cyclohexylamine (cis-trans-mixture)
from 4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (5-methyl-hex-4-enoyl) -cyclohexylamine (cis-trans-mixture) and benzyl bromide.
Colorless crystals of melting point 64-66 ° C.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.4-2.1 (m, 14H), 2.2-2.45 (m, 8H), 3.6-3.8 and 4.5-4.65 (m, 1H) , 5.0 (s, 2H), 5.15 (m, 1H), 6.7-7.0 (m, 3H), 7.2-7.5 (m, 5H).
b) 4- (4-Isopropoxy-3-methylphenyl) -N-methyl-N- (5-methyl-hex-4-enoyl) -cyclohexylamine (cis-trans-mixture)
from 4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (5-methyl-hex-4-enoyl) -cyclohexylamine (cis-trans-mixture) and isopropyl bromide. Gradually solidifying, colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.3 (d, 6H), 1.5-2.0 (m, 14H), 2.2 (s, 3H), 2.3-2.45 (m, 5H), 2, 85 (s, 3H), 3.6-3.7 and 4.35-4.65 (m, 2H), 5.2 (m, 1H), 6.7-7.0 (m, 3H).
c) trans-4- [4- (3-diethylamino-propoxy) -3-methylphenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 3-diethylamino-propyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.05 (t, 6H), 1.2-2.0 (m, 16H), 2.2 (s, 3H), 2.3-2 45 (m, 3H), 2.5-2.7 (m, 6H), 2.7-2.8 (2s, 3H), 3.6-3.75 and 4.4-4.6 (m , 1H), 4.0 (t, 2H), 6.7-7.0 (m, 3H).
d) trans -n-hexanoyl-N-methyl-4- [4- (2-morpholino-ethoxy) -3-methylphenyl] -cyclohexylamine
from trans -n-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-morpholino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.2-1.4 (m, 4H), 1.5-2.05 (m, 10H), 2.2 (s, 3H), 2, 25-2.4 (m, 3H), 2.6 (t, 3H), 2.7-2.9 (m, 5H), 3.55-3.65 and 4.45-4.6 (2m , 1H), 3.7 (t, 4H), 4.1 (t, 2H), 6.7-7.0 (m, 3H).
e) trans-4- (4-allyloxy-3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) cyclohexylamine and allyl bromide.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.2-2.1 (m, 14H), 2.2 (s, 3H), 2.25-2.4 (m, 3H), 2, 8-2.9 (2s, 3H), 3.6-3.7 (m, 0.5H), 4.4-4.6 (m, 2.5H), 5.2-5.4 (m , 2H), 5.95-6.2 (m, 1H), 6.7-7.0 (m, 3H).
f) trans-N-hexanoyl-N-methyl-4- [3-methyl-4- (2-piperidinoethoxy) -phenyl] -cyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-piperidino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.2-2.1 (m, 20H), 2.2 (s, 3H), 2.3-2.6 (m, 7H), 2, 75-2.9 (m, 5H), 3.6-3.75 (m, 0.5H), 4.1 (t, 2H), 4.4-4.6 (m, 0.5H), 6.7-7.0 (m, 3H).
g) trans -N-hexanoyl-N-methyl-4- (3-methyl-4-propargyloxy-phenyl) -cyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) cyclohexylamine and 2-propargyl bromide.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.2-2.1 (m, 14H), 2.2 (s, 3H), 2.3-2.6 (m, 4H), 2, 8-2.9 (2s, 3H), 3.6-3.8 (m, 0.5H), 4.4-4.6 (m, 0.5H), 4.7 (t, 2H), 6.8-7.05 (m, 3H).
h) trans -N-hexanoyl-N-methyl-4- [3-methyl-4- (2-pyrrolidinethoxy) -phenyl] -cyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) cyclohexylamine and 2-pyrrolidinoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.2-2.1 (m, 18H), 2.2 (s, 3H), 2.3-2.45 (m, 4H), 2, 6-2.75 (m, 4H), 2.85-3.0 (m, 4H), 3.6-3.8 (m, 0.5H), 4.0-4.15 (t, 2H ), 4.4-4.6 (m, 0.5H), 6.7-7.0 (m, 3H).
i) trans-4- [4- (2,2-dimethoxy-ethoxy) -phenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans-N-hexanoyl-N-methyl-4- (4-hydroxyphenyl) cyclohexylamine and bromoacetaldehyde dimethyl acetal.
Yellowish oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.2-2.5 (m, 17H), 2.8-2.9 (2s, 3H), 3.45 (s, 6H), 4, 0 (d, 2H), 3.6-3.7 + 4.5-4.65 (2m, 1H), 4.7 (t, 1H), 6.8-7.2 (m, 4H).
Mass spectrum: M⁺ 391.
j) trans-4- [4- (2-dimethylamino-ethoxy) -3-methylphenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) cyclohexylamine and 2-dimethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.25-2.05 (m, 14H), 2.2 (s, 3H), 2.25-2.4 (s + m, 9H), 2.7-2.8 (t, 2H), 2.8-2.9 (2s, 3H), 3.6-3.75 (m, 0.5H), 4.05 (t, 2H), 4.5-4.65 (m, 0.5H), 6.7-7.0 (m, 3H).
k) trans-4- (4-n-butoxy-3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and and n-butylbromide.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 0.8-2.1 (m, 24H), 2.2 (s, 3H), 2.25-2.5 (m, 3H), 2.8-2.9 (d, 3H ), 3.6-3.75 (m, 0.5H), 3.9-4.0 (2s, 2H), 4.4-4.6 (m, 0.5H), 6.7-7 , 0 (m, 3H).
l) cis-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-hexanoyl-N-methylcyclohexylamine
from cis-Nn-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.05 (t, 6H), 1.2-2.0 (m, 12H), 2.2-2.4 (s + m, 7H), 2.6-2.75 (m, 7H), 2.85-3.05 (t + m, 3H), 3.6-3.8 (m, 0.5H), 4.05 (t, 2H ), 4.5-4.7 (m, 0.5H), 6.7-7.2 (m, 3H).
m) 4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-methyl-N- (5-methyl-hex-4-enoyl) -cyclohexylamine (cis-trans-mixture)
from 4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (5-methyl-hex-4-enoyl) -cyclohexylamine (cis-trans mixture) and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1 (t, 6H), 1.5-2.05 (m, 14H), 2.2 s, 3H), 2.25-2.45 (m, 5H), 2.65 -2.9 (m, 7H), 3.0 (t, 2H), 3.6-3.75 and 4.5-4.65 (2m, 1H), 4.1 (t, 2H), 5 , 15 (m, 1H), 6.7-7.0 (m, 3H).
o) trans-4- [3-ethyl-4- (2-diethylamino-ethoxy) -phenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (3-ethyl-4-hydroxyphenyl) -N-hexanoyl-N-methyl-cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.0-1.45 (m, 11H), 1.5-1.9 (m, 10H), 1.9-2.1 (m, 2H ), 2.25-2.5 (m, 3H), 2.55-2.75 (m, 6H), 2.8-2.95 (m, 5H), 3.6-3.8 and 4 , 5-4.7 (2m, 1H), 4.05 (t, 2H), 6.75 (m, 1H), 7.0 (m, 2H).
p) trans-4- [4- (2-diethylaminoethoxy) -3-propylphenyl] -N-hexanoyl-N-methylcyclohexylamine,
from trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-propylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.95 (m, 6H), 1.1 (t, 6H), 1.2-1.45 (m, 4H), 1.5-1.87 (m, 10H), 1, 9-2.1 (m, 2H), 2.2-2.45 (m, 3H), 2.5-2.75 (m, 6H), 2.8-2.95 (m, 5H), 3.55-3.8 and 4.5-4.7 (2m, 1H), 4.05 (t, 2H), 6.78 (m, 1H), 6.95 (m, 2H).
r) trans-4- [3-tert-butyl-4- (2-diethylamino-ethoxy) -phenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (3-tert-butyl-4-hydroxyphenyl) -N-hexanoyl-N-methyl-cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.1 (t, 6H), 1.2-1.5 (m, 11H), 1.5-1.87 (m, 10H), 1, 9-2.1 (m, 2H), 2.25-2.5 (m, 3H), 2.55-2.7 (q, 4H), 2.8-2.98 (m, 5H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 4.05 (t, 2H), 6.8 (dd, 1H), 7.0 (dd, 1H), 7, 1 (ds, 1H).
s) trans-4- [4- (2-diethylamino-ethoxy) -2-methylphenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.1 (t, 6H), 1.2-1.45 (m, 4H), 1.5-2.0 (m, 10H), 2, 2-2.45 (m, 5H), 2.5-2.7 (m, 5H), 2.75-2.95 (m, 5H), 3.6-3.8 and 4.5-4 , 7 (m, 5H), 2.75-2.95 (m, 5H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 4.0 (t, 2H) , 6.7 (m, 2H), 7.1 (m, 1H).
t) trans -N-ethyl-N-hexanoyl-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -cyclohexylamine
from trans -N-ethyl-N-hexanoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-1.0 (m, 3H), 1.05-2.1 (m, 23H), 2.2 (s, 3H), 2.3-2.5 (m, 3H ), 2.6-2.75 (q, 4H), 2.9-3.0 (t, 2H), 3.2-3.4 (m, 2H), 3.6-3.75 (m , 0.5H), 4.0-4.1 (t, 2H), 4.3-4.5 (m, 0.5H), 6.7-7.0 (m, 3H).
u) trans-4- [4- (2-diethylaminoethoxy) -3-methylphenyl] -N-hexanoyl-Nn-propylcyclohexylamine
from trans -N-hexanoyl-N- (n-propyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-0.95 (m, 3H), 1.0-1.1 (t, 6H), 1.2-2.1 (m, 17H), 2.2-2.5 (s + m, 6H), 2.6-2.65 (q, 4H), 2.9 (t, 2H), 3.05-3.35 (m, 2H), 3.55-3.7 and 4.3-4.5 (2m, 1H), 4.0 (t, 2H), 6.7-7.0 (m, 3H).
v) trans -N- (n-butyl) -N-hexanoyl-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -cyclohexylamine
from trans -N- (n-butyl) -N-hexanoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-1.0 (m, 3H), 1.1 (t, 6H), 1.2-2.1 (m, 21H), 2.2 (s, 3H), 2, 3-2.5 (m, 3H), 2.6-2.75 (q, 4H), 2.9-3.0 (t, 2H), 3.1-3.3 (m, 2H), 3.6-3.8 (m, 0.5H), 4.0-4.1 (t, 2H), 4.25-4.4 (m, 0.5H), 6.7-7.0 (m, 3H).
w) trans-4- [4- (4-diethylamino-ethoxy) -3-methylphenyl] -N-hexanoyl-N- (n-pentyl) -cyclohexylamine
from trans -N-hexanoyl-N- (n -pentyl) -4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-0.95 (m, 5H), 1.0-1.15 (t, 6H), 1.2-2.1 (m, 21H), 2.2-2.5 (s + m, 6H), 2.55-2.7 (q, 4H), 2.85-2.95 (t, 2H), 3.05-3.3 (m, 2H), 3.6 -3.65 and 4.3-4.5 (2m, 1H), 4.0 (t, 2H), 6.7-7.0 (m, 3H).
x) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-hexanoyl-N-isopropylcyclohexylamine
from trans -N-hexanoyl-N-isopropyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.1 (t, 6H), 1.15-2.1 (m, 21H), 2.2 (s, 3H), 2.3 (t, 2H), 2.4-2.75 (m, 5H), 2.9 (t, 2H), 3.0-3.3 and 3.35-3.7 (2m, 1H), 4.0 ( t, 2H), 6.75 (d, 1H), 6.95 (m, 2H).
y) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-hexanoyl-N-isobutylcyclohexylamine
from trans -N-hexanoyl-N-isobutyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
Rf value 0.5 (alumina, petroleum ether, ethyl acetate = 4: 1, v: v).
z) trans-4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-hexanoyl-N- (2,2-dimethyl-propyl) -cyclohexylamine
from trans -N- (2,2-dimethyl-propyl) -N-hexanoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-1.1 (m, 18H), 1.2-2.1 (m, 14H), 2.2-2.5 (s + m, 6H), 2.55-2 , 7 (q, 4H), 2.8-2.95 (t, 2H), 3.05-3.2 (m, 2.5H), 3.5-3.65 (m, 0.5H) , 3.95-4.05 (t, 2H), 6.7-7.0 (m, 3H).
aa) trans-N-allyl-N-hexanoyl-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -cyclohexylamine
from trans -N-allyl-N-hexanoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.1 (t, 6H), 1.2-1.45 (m, 4H), 1.48-2.1 (m, 10H), 2, 15-2.5 (s + m, 6H), 2.65 (q, 4H), 2.9 (t, 2H), 3.65-3.8 and 4.45-4.65 (2m, 1H ), 3.85-4.1 (t + m, 4H), 5.05-5.3 (m, 2H), 5.7-5.95 (m, 1H), 6.75 (m, 1H ), 6.95 (m, 2H).
ab) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-hexanoyl-N-phenylcyclohexylamine
from trans -N-hexanoyl-N-phenyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85 (t, 3H), 1.1 (t, 6H), 1.12-1.4 (m, 6H), 1.42-1.8 (m, 4H), 1, 8-2.0 (m, 6H), 2.1-2.3 (s + m, 4H), 2.65 (q, 4H), 2.9 (t, 2H), 4.0 (t, 2H), 4.6-4.85 (m, 1H), 6.7 (m, 1H), 6.9 (m, 2H), 7.1 (m, 2H), 7.4 (m, 3H ).
ac) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-cyclohexyl-N-hexanoyl-cyclohexylamine
from trans -N-cyclohexyl-N-hexanoyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.1 (t, 6H), 1.2-2.0 (m, 25H), 2.05 and 2.2 (ds, 3H), 2, 25-2.4 (m, 2H), 2.4-2.8 (m, 5H), 2.95 (t, 2H), 3.0-3.25 and 3.4-3.75 (2m , 1H), 4.05 (t, 2H), 6.75 (m, 1H), 7.0 (m, 2H).
ad) trans -N-butyryl-N-methyl-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -cyclohexylamine
from trans -N-butyryl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9-1.15 (t + m, 9H), 1.45-2.1 (m, 10H), 2.2 (s, 3H), 2.25-2.5 (m , 3H), 2.65 (q, 4H), 2.8-3.0 (m, 5H), 3.6-3.8 and 4.5-4.7 (2m, 1H), 4.0 (t, 2H), 6.75 (d, 1H), 6.95 (m, 2H).
ae) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N-octanoyl-cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N-octanoylcyclohexylamine and 2-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8-0.9 (m, 3H), 1.05 (t, 6H), 1.2-2.1 (m, 18H), 2.2 (s, 3H), 2, 25-2.4 (m, 3H), 2.55-2.7 (q, 4H), 2.8-2.95 (m, 5H), 3.6-3.75 and 4.5-4 , 65 (2m, 1H), 4.0 (t, 2H), 6.7-7.0 (m, 3H).
af) trans-4- [4- (4-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N-nonanoyl-cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N-nonanoylcyclohexylamine and 2-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.1 (t, 6H), 1.15-1.5 (m, 10H), 1.5-1.88 (m, 8H), 1, 88-2.05 (m, 2H), 2.2 (5, 3H), 2.25-2.5 (m, 3H), 2.65 (q, 4H), 2.8-3.0 ( m, 5H), 3.55-3.8 and 4.5-4.65 (2m, 1H), 4.02 (t, 2H), 6.75 (d, 1H), 6.95 (m, 2H).
ag) trans-4- [4- (4-diethylamino-ethoxy) -3-methylphenyl] -N- (3,3-dimethyl-butyryl) -N-methylcyclohexylamine
from trans -N- (3.3-dimethyl-butyryl) -N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.0-1.15 (m, 15H), 1.45-2.05 (m, 8H), 2.2 (s, 3H), 2.25-2.5 (m, 3H ), 2.7 (q, 4H), 2.8-3.0 (m, 5H), 3.7-3.85 and 4.45-4.65 (2m, 1H), 4.05 (t , 2H), 6.75 (d, 1H), 7.0 (m, 2H).
ah) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N-pivaloylcyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N-pivaloylcyclohexylamine and 2-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05 (t, 6H), 1.3 (s, 9H), 1.4-1.85 (m, 6H), 1.9-2.05 (m, 2H), 2, 2 (s, 3H), 2.3-2.5 (m, 1H), 2.65 (q, 4H), 2.8-2.95 (m, 5H), 3.95-4.3 ( t + m, 3H), 6.75 (d, 1H), 6.9-7.0 (m, 2H).
ai) trans -N-cyclohexanecarbonyl-N-methyl-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -cyclohexylamine
from trans -N-cyclohexanecarbonyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.0 (t, 6H), 1.15-1.4 (m, 3H), 1.4-2.05 (m, 15H), 2.2 (s, 3H), 2, 28-2.6 (m, 2H), 2.65 (q, 4H), 2.78-3.0 (m, 5H), 3.6-3.8 and 4.45-4.65 (2m , 1H), 4.0 (m, 2H), 6.75 (dd, 1H), 7.0 (m, 2H).
aj) trans -N-benzoyl-N-methyl-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -cyclohexylamine
from trans -N-benzoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1 (t, 6H), 1.15-1.45 (m, 1H), 1.5-2.1 (m, 7H), 2-2 (ds, 3H), 2, 25-2.75 (m, 1H), 2.7 (q, 4H), 2.8-3.1 (m, 5H), 3.5-3.75 and 4.5-4.7 (2m , 1H), 4.0 (m, 2H), 6.6-7.1 (m, 3H), 7.3-7.55 (m, 5H).
ak) trans-4- [4- (2-diethylaminoethoxy) -3-methylphenyl] -N-methyl-N-phenylacetylcyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (phenylacetyl) -cyclohexylamine and 2-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1 (t, 6H), 1.3-2.02 (m, 8H), 2.2 (s, 3H), 2.25-2.5 (s, 1H), 2, 7 (q, 4H), 2.8-3.0 (m, 5H), 3.6-3.85 (d + m, 2.5H), 4.05 (t, 2H), 4.4- 4.65 (m, 0.5H), 6.75 (m, 1H), 6.95 (m, 2H), 7.2-7.4 (m, 5H).
al) trans-N-butyryl-N-methyl-4- [4- (2-diethylamino-ethoxy) -phenyl] -cyclohexylamine
from trans-N-butyryl-N-methyl-4- (4-hydroxyphenyl) -cyclohexylamine and 4-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ / CD₃OD); Signals at ppm: 1.05-1.4 (t + m, 9H), 1.5-2.1 (m, 10H), 2.25-2.55 (m, 3H), 2.65 (q , 4H), 2.8-3.0 (m, 5H), 3.6-3.8 and 4.4-4.6 (2m, 1H), 4.05 (t, 2H), 6.85 (d, 2H), 7.1 (d, 2H).
am) trans-4- (4- (4-diethylamino-ethoxy) -phenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-hydroxyphenyl) cyclohexylamine and 2-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.05 (t, 6H), 1.15-1.45 (m, 4H), 1.5-1.9 (m, 8H), 1, 9-2.1 (m, 2H), 2.25-2.5 (m, 3H), 2.65 (q, 4H), 2.8-2.95 (m, 5H), 3.55- 3.7 and 4.5-4.7 (2m, 1H), 4.0 (t, 2H), 6.85 (dd, 2H), 7.1 (dd, 2H).
an) trans-4- [4- (4-diethylamino-ethoxy) -phenyl] -N-methyl-N-nonanoyl-cyclohexylamine
from trans-4- (4-hydroxyphenyl) -N-methyl-N-nonanoylcyclohexylamine and 2-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.05 (t, 6H), 1.15-1.45 (m, 10H), 1.5-2.1 (m, 10H), 2, 2-2.55 (m, 3H), 2.6 (q, 4H), 2.8-2.95 (m, 5H), 3.55-3.8 and 4.45-4.7 (2m , 1H), 4.0 (t, 2H), 6.82 (dd, 2H), 7.1 (dd, 2H).
ao) trans-4- [4- (2-diethylamino-ethoxy) -phenyl] -N- (3,3-di-methyl-butyryl) -N-methylcyclohexylamine
from trans -N- (3.3-dimethyl-butyryl) -N-methyl-4- (4-hydroxy-phenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.0-1.1 (m, 15H), 1.45-1.85 (m, 6H), 1.9-2.1 (m, 2H), 2.3-2.5 (m, 3H), 2.65 (q, 4H), 2.8-2.93 (m, 5H), 3.65-3.85 and 4.5-4.7 (2m, 1H), 4 , 0 (t, 2H), 6.85 (dd, 2H), 7.05-7.15 (m, 2H).
ap) trans-N-cyclohexanecarbonyl-N-methyl-4- [4- (2-diethylamino-ethoxy) -phenyl] -cyclohexylamine
from trans -N-cyclohexanecarbonyl-N-methyl-4- (4-hydroxy-phenyl) -cyclohexylamine and 2-diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05 (t, 6H), 1.15-1.4 (m, 4H), 1.4-2.1 (m, 14H), 2.3-2.55 (m, 2H ), 2.65 (q, 4H), 2.8-2.95 (m, 5H), 3.6-3.8 and 4.45-4.65 (2m, 1H), 4.0 (t , 2H), 6.8-6.9 (m, 2H), 7.05-7.2 (m, 2H).
aq) trans-4- [4- (4-diethylamino-ethoxy) -phenyl] -N-methyl-N-pivaloyl-cyclohexylamine
from trans-4- (4-hydroxyphenyl) -N-methyl-N-pivaloylcyclohexylamine and 4-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05 (t, 6H), 1.3 (s, 9H), 1.45-1.85 (m, 6H), 1.9-2.05 (m, 2H), 2, 35-2.55 (m, 1H), 2.65 (q, 4H), 2.8-2.95 (m, 5H), 4.05 (t, 2H), 4.1-4.35 ( m, 1H), 6.85 (d, 2H), 7.12 (d, 2H).
ar) trans-4- [4- (2,2-dimethoxyethoxy) -3-methylphenyl] -N-hexa-N-methyl-cyclohexylamine
from trans -N-hexanoyl-N-methyl-4- (4-hydroxy-3-methylphenyl) cyclohexylamine and bromoacetaldehyde dimethyl acetal.
Yellowish oil of Rf value 0.4 (silica gel, ethyl acetate / petroleum ether = 2: 5, v: v).
as) trans-4- [4- (4-diethylamino-ethoxy) -phenyl] -N-ethyl-N-octanoyl-cyclohexylamine
from trans-4- (4-hydroxyphenyl) -N-methyl-N-octanoylcyclohexylamine and 4-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8-0.95 (m, 3H), 0.98-1.15 (t, 6H), 1.15-1.45 (m, 8H), 1.45-1.9 (m, 8H), 1.9-2.05 (m, 2H), 2.23-2.5 (m, 3H), 2.55-2.7 (q, 4H), 2.8-2 , 92 (m, 5H), 3.55-3.78 and 4.5-4.68 (2m, 1H), 4.02 (t, 2H), 6.85 (dd, 2H), 7.1 (dd, 2H).
at) trans -N-benzoyl-N-methyl-4- [4- (2-diethylamino-ethoxy) -phenyl] -cyclohexylamine
from trans -N-benzoyl-N-methyl-4- (4-hydroxyphenyl) -cyclohexylamine and 4-diethylamino-ethyl chloride.
Melting point 79-82 ° C.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05 (t, 6H), 1.15-1.45 (m, 1H), 1.5-2.15 (m, 7H), 2.25-2.55 (m, 1H ), 2.63 (q, 4H), 2.75-3.15 (m, 5H), 3.45-3.8 and 4.45-4.8 (2m, 1H), 4.0 (m , 2H), 6.8 (d, 2H), 6.9-7.2 (m, 2H), 7.3-7.5 (m, 5H).
au) trans-4- [4- (2-diethylamino-ethoxy) -phenyl] -N-methyl-N-phenylacetyl-cyclohexylamine
from trans-4- (4-hydroxyphenyl) -N-methyl-N-phenylacetylcyclohexylamine and 2-diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.05 (t, 6H), 1.3-1.8 (m, 6H), 1.8-2.0 (m, 2H), 2.25-2.5 (m, 1H ), 2.65 (q, 4H), 2.75-2.95 (m, 5H), 3.6-3.85 (d + m, 2.5H), 4.05 (t, 2H), 4.5-4.7 (m, 0.5H), 6.82 (d, 2H), 7.0-7.15 (m, 2H), 7.15-7.4 (m, 5H).
av) trans-4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-methyl-N- (5-methyl-hexanoyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (5-methylhexanoyl) -cyclohexylamine and diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (d, 6H), 1.1 (t, 6H), 1.15-1.35 (m, 2H), 1.45-1.9 (m, 9H), 1, 9-2.1 (m, 2H), 2.2 (s, 3H), 2.25-2.5 (m, 3H), 2.65 (q, 4H), 2.8-2.98 ( m, 5H), 3.55-3.78 and 4.45-4.7 (2m, 1H), 4.05 (t, 2H), 6.75 (dd, 1H), 6.9-7, 0 (m, 2H).
aw) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N- (4-hexenoyl) -N-methylcyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N- (4-hexenoyl) -N-methylcyclohexylamine and diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1 (t, 6H), 1.45-1.88 (m, 9H), 1.9-2.1 (m, 2H), 2.2 (s, 3H), 2, 25-2.55 (m, 5H), 2.65 (q, 4H), 2.8-2.98 (m, 5H), 3.58-3.78 and 4.5-4.7 (2m , 1H), 4.03 (t, 2H), 5.42-5.58 (m, 2H), 6.75 (dd, 1H), 6.9-7.02 (m, 2H).
ax) trans-4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-methyl-N- (4-pentenoyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (4-penteneoyl) -cyclohexylamine and diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1 (t, 6H), 1.45-1.88 (m, 6H), 1.89-2.08 (m, 2H), 2.2 (s, 3H), 2, 3-2.5 (m, 5H), 2.65 (q, 4H), 2.82-2.98 (m, 5H), 3.55-3.8 and 4.46-4.7 (2m , 1H), 4.03 (t, 2H), 4.95-5.18 (m, 2H), 5.75-6.02 (m, 1H), 6.75 (dd, 1H), 6, 9-7.02 (m, 2H).
ay) trans-4- [4- (2-diethylaminoethoxy) -3-methylphenyl] -N- (3-hexenoyl) -N-methylcyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N- (3-hexenoyl) -N-methylcyclohexylamine and diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.95-1.2 (2t, 9H), 1.45-1.88 (m, 6H), 1.9-2.18 (m, 4H), 2.2 (s, 3H ), 2.25-2.5 (m, 1H), 2.65 (q, 4H), 2.8-2.98 (m, 5H), 3.05-3.2 (m, 2H), 3.6-3.8 and 4.45-4.7 (2m, 1H), 4.02 (t, 2H), 5.5-5.65 (m, 2H), 6.75 (dd, 1H ), 6.9-7.0 (m, 2H).
az) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (octadecanoyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (octadeoanoyl) cyclohexylamine and diethylaminoethyl chloride.
Colorless crystals.
Melting point: 45-47 ° C.
ba) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (trans-9-octadecenoyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (trans-9-octadecenoyl) -cyclohexylamine and diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.88 (t, 3H), 1.08 (t, 6H), 1.15-1.45 (m, 20H), 1.48-1.88 (m, 8H), 1, 9-2.1 (m, 6H), 2.2 (s, 3H), 2.25-2.5 (m, 3H), 2.65 (q, 4H), 2.8-3.0 ( m, 5H), 3.58-3.75 and 4.5-4.7 (2m, 1H), 4.02 (t, 2H), 5.35-5.45 (m, 2H), 6, 75 (dd, 1H), 6.9-7.05 (m, 2H).
bb) trans-4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-methyl-N- (cis-9-octadecenoyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (cis-9-octadecenoyl) -cyclohexylamine and diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (t, 3H), 1.1 (t, 6H), 1.18-1.5 (m, 20H), 1.5-1.9 (m, 8H), 1, 9-2.15 (m, 6H), 2.2 (s, 3H), 2.25-2.5 (m, 3H), 2.65 (q, 4H), 2.82-3.0 ( m, 5H), 3.55-3.8 and 4.45-4.7 (2m, 1H), 4.02 (t, 2H), 5.25-5.48 (m, 2H), 6, 75 (dd, 1H), 6.9-7.04 (m, 2H).
bc) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (3-methyl-2-butenoyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (3-methyl-2-butenoyl) -cyclohexylamine and diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.08 (t, 6H), 1.45-2.1 (m, 14H), 2.21 (s, 3H), 2.25-2.5 (m, 1H), 2, 65 (q, 4H), 2.85-2.98 (m, 5H), 3.65-3.9 and 4.5-4.7 (2m, 1H), 4.05 (t, 2H), 5.8 (m, 1H), 6.75 (dd, 1H), 6.92-7.03 (m, 2H).
bd) trans-4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-methyl-N- (4-phenyl-3-butenoyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (4-phenyl-3-butenoyl) -cyclohexylamine and diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1 (t, 6H), 1.45-2.1 (m, 8H), 2.2 (s, 3H), 2.25-2.5 (m, 1H), 2, 65 (q, 4H), 2.85-3.0 (m, 5H), 3.25-3.45 (m, 2H), 3.62-3.85 and 4.5-4.7 (2m , 1H), 4.04 (t, 2H), 6.25-6.6 (m, 2H), 6.75 (dd, 1H), 6.9-7.0 (m, 2H), 7, 15-7.45 (m, 5H).
be) trans -N-cinnamoyl-N-methyl-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-cinnainoyl-N-methylcyclohexylamine and diethylaminoethyl chloride.
Colorless crystals.
Melting point: 128-130 ° C.
bf) trans -N-cinnamoyl-N-methyl-4- [4- (2-dimethylamino-ethoxy) -3-methylphenyl] -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-cinnamoyl-N-methylcyclohexylamine and dimethylaminoethyl chloride.
Colorless crystals.
Melting point: 138-140 ° C.
bg) trans -N- (3-cyclohexylpropenoyl) -N-methyl-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N- (3-cyclohexylprope noyl) -N-methylcyclohexylamine and diethylaminoethyl chloride.
Colorless crystals.
Melting point: 58-60 ° C.
bh) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (3-phenylpropionyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl- (3-phenylpropionyl) -cyclohexylamine and diethylaminoethyl chloride.
Colorless crystals.
Melting point: 96-98 ° C.
bi) trans-4- [4- (4-dimethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (3-phenylpropionyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (3-phenylpropionyl) -cyclohexylamine and dimethylaminoethyl chloride.
Colorless crystals.
Melting point: 79-81 ° C.
bk) trans-4- [4- (4-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (4-phenylbutyryl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (3-phenylbutyryl) -cyclohexylamine and diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1 (t, 6H), 1.25-1.82 (m, 6H), 1.82-2.1 (m, 4H), 2.25 (ds, 3H), 2, 3-2.5 (m, 3H), 2.5-2.8 (m, 6H), 2.8-3.0 (m, 5H), 3,4-3,6 and 4,45-4 , 65 (2m, 1H), 3.95-4.1 (m, 2H), 6.75 (dd, 1H), 6.9-7.0 (m, 2H), 7.05-7.4 (m, 5H).
b1) trans-4- [4- (4-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (4-phenylbenzoyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (4-phenylbenzoyl) -cyclohexylamine and diethylaminoethyl chloride.
White crystals.
Melting point: 176-178 ° C.
bm) trans-4- [4- (4-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (4-fluorobenzoyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (4-fluoro-benzoyl) -cyclohexylamine and diethylamino-ethyl chloride.
White crystals.
Melting point: 103-105 ° C.
bm) trans-4- [4- (2-diethylaminoethoxy) -3-methylphenyl] -N-methyl-N-nicotinoylcyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N-nicotinoylcyclohexylamine and diethylaminoethyl chloride.
White crystals.
Melting point: 58-60 ° C.
bp) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (2-pyridinecarbonyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (2-pyridinecarbonyl) -cyclohexylamine and diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.08 (dt, 6H), 1.15-1.5 (m, 1H), 1.6-1.8 (m, 3H), 1.8-2.1 (m, 4H ), 2,2 (ds, 3H), 2,25-2,5 (m, 1H), 2,65 (dq, 4H), 2,8-3,1 (m, 5H), 3,6- 3.8 and 4.55-4.75 (2m, 1H), 4.0 (t, 2H), 6.6-6.8 (m, 1H), 6.85-6.95 (m, 1H 6.95-7.05 (m, 1H), 7.25-7.4 (m, 1H), 7.5-7.65 (m, 1H), 7.8 (t, 1H), 8.6 (d, 1H).
bq) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N- (2-furancarbonyl) -N-methylcyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N- (2-furancarbonyl) -N-methylcyclohexylamine and diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.08 (t, 6H), 1.4-2.1 (m, 9H), 2.2 (s, 3H), 2.25-2.55 (m, 1H), 2, 62 (q, 4H), 2.9 (t, 2H), 3.08 (s, 3H), 4.02 (t, 2H), 4.15-4.7 (m, 1H), 6.5 (d, 1H), 6.75 (d, 1H), 6.9-7.05 (m, 2H), 7.5 (s, 1H).
br) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-isonicotinoyl-N-methylcyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-isonicotinoyl-N-methylcyclohexylamine and diethylaminoethyl chloride.
Yellowish crystals.
Melting point: 63-65 ° C.
bs) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (3-methylbenzoyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (3-methylbenzoyl) -cyclohexylamine and diethylaminoethyl chloride.
White crystals.
Melting point: 50-52 ° C.
bt) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N- (3-tolylacetyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-methyl-N- (3-tolylacetyl) -cyclohexylamine and diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 1.1 (t, 6H), 1.3-2.0 (m, 8H), 2.2 (s, 3H), 2.25-2.45 (m + s, 4H), 2.65 (q, 4H), 2.8-3.0 (m, 5H), 3.6-3.85 (m + d, 2.5H), 4.03 (t, 2H), 4, 5-4.7 (m, 0.5H), 6.75 (d, 1H), 6.85-7.3 (m, 6H).
bu) trans-4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-hexanoyl-N- (3-methyl-1-butyl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-hexanoyl-N- (3-methyl-1-butyl) -cyclohexylamine and diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-1.0 (m, 9H), 1.1 (t, 6H), 1.2-2.1 (m, 17H), 2.2 (s, 3H), 2, 25-2.45 (m, 3H), 2.65 (q, 4H), 2.9 (t, 2H), 3.05-3.25 (m, 2H), 3.5-3.8 and 4.5-4.7 (2m, 1H), 4.05 (t, 2H), 6.75 (d, 1H), 6.9-7.0 (m, 2H).
bv) trans-4- [4- (2-diethylaminoethoxy) -3-methylphenyl] -N-3,3-dimethyl-1-butyl) -N-hexanoylcyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N- (3,3-dimethyl-1-butyl) -N-hexanoylcyclohexylamine and diethylaminoethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-1.15 (m, 18H), 1.15-2.1 (m, 16H), 2.15-2.55 (m + s, 6H), 2.65 (q , 4H), 2.9 (t, 2H), 3.05-3.25 (m, 2H), 3.45-3.7 and 4.5-4.7 (2m, 1H), 4.02 (t, 2H), 6.75 (d, 1H), 6.9-7.05 (m, 2H).
bw) trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-hexanoyl-N- (2-propyn-1-yl) -cyclohexylamine
from trans-4- (4-hydroxy-3-methylphenyl) -N-hexanoyl-N- (2-propyn-1-yl) -cyclohexylamine and diethylamino-ethyl chloride.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.85-1.1 (m, 3H), 1.1 (t, 6H), 1.25-1.45 (m, 4H), 1.5-2.15 (m, 10H , 2.15-2.35 (s + m, 4H), 2.35-2.55 (m, 3H), 2.65 (q, 4H), 2.9 (t, 2H), 3, 65-3.85 and 4.45-4.7 (2m, 1H), 3.9-4.1 (m, 4H), 6.75 (d, 1H), 6.9-7.04 (m , 2H).

Example 7 trans-4- (4-formylmethoxy-3-methylphenyl) -N-hexanoyl-N-methyl cyclohexylamine

4,54 g trans-4-[4-(2,2-Dimethoxy-ethoxy)-phenyl)-N-hexanoyl- N-methyl-cyclohexylamin werden in 45 ml Eisessig und 15 g konzentrierter Salzsäure eine Stunde auf 50°C erwärmt, an schließend zweimal nach Toluolzugabe eingedampft und der Rückstand durch Kieselgelsäulenchromatographie gereinigt (Kieselgel, Methylenchlorid/Methanol = 60 : 1). Man erhält 2,37 g trans-4-(4-Formylmethoxy-3-methylphenyl)-N-hexanoyl- N-methyl-cyclohexylamin als blaßgelbes Harz vom Rf-Wert 0,22 (Kieselgel, Methylenchlorid/Methanol = 60 : 1, v:v).
Massenspektrum: M⁺ 359.4.54 g of trans-4- [4- (2,2-dimethoxy-ethoxy) -phenyl) -N-hexanoyl-N-methyl-cyclohexylamine are heated to 50 ° C. in 45 ml of glacial acetic acid and 15 g of concentrated hydrochloric acid for one hour , then evaporated twice to toluene and the residue purified by silica gel column chromatography (silica gel, methylene chloride / methanol = 60: 1). This gives 2.37 g of trans-4- (4-formylmethoxy-3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine as a pale yellow resin of Rf value 0.22 (silica gel, methylene chloride / methanol = 60: 1, v: v).
Mass spectrum: M⁺ 359.

Auf dieselbe Weise wurde erhalten:In the same way was obtained:

a) Trans-4- (4-formylmethoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans-4- [4- (2,2-dimethoxy-ethoxy) -phenyl] -N-hexanoyl-N-methylcyclohexylamine.
Colorless resin of Rf value 0.33 (silica gel, methylene chloride / methanol = 60: 1, v: v).

Example 8 trans-4- [4- (2-isopropylamino-ethoxy) -phenyl] -N-hexanoyl- N-methyl-cyclohexylamine

48 mg trans-4-(4-Formylmethoxyphenyl)-N-hexanoyl-N-methyl- cyclohexylamin, 145 mg Isopropylamin und 0,615 ml 2N-ethano lische Salzsäure werden in 2 ml Methanol 30 Minuten bei Raumtemperatur gerührt, 28,3 mg Natriumcyanborhydrid fest zugegeben und 75 Minuten bei Raumtemperatur gerührt. Das Lösungsmittel wird verdampft, 1 ml 15%ige Natronlauge zu gegeben und viermal mit Ether extrahiert. Der Extrakt wird getrocknet, eingedampft und der Rückstand durch Kieselgel chromatographie gereinigt. Man erhält 41 mg (43% der Theo rie trans-4-[4-(2-Isopropylamino-ethoxy)-phenyl]-N-hexanoyl- N-methyl-cyclohexylamin als farbloses Harz vom Rf-Wert 0,35 (Kieselgel, Toluol/Ethanol/konz. Ammoniak = 75 : 25 : 2, v:v:v).
Massenspektrum: M⁺ 388. 48 mg of trans-4- (4-formylmethoxyphenyl) -N-hexanoyl-N-methylcyclohexylamine, 145 mg of isopropylamine and 0.615 ml of 2N-ethano lische hydrochloric acid are stirred in 2 ml of methanol for 30 minutes at room temperature, 28.3 mg Natriumcyanborhydrid added and stirred for 75 minutes at room temperature. The solvent is evaporated, added to 1 ml of 15% sodium hydroxide solution and extracted four times with ether. The extract is dried, evaporated and the residue purified by silica gel chromatography. This gives 41 mg (43% of theory trans-4- [4- (2-isopropylamino-ethoxy) -phenyl] -N-hexanoyl-N-methyl-cyclohexylamine as a colorless resin of Rf value 0.35 (silica gel, Toluene / ethanol / concentrated ammonia = 75: 25: 2, v: v: v).
Mass spectrum: M⁺ 388.

Auf dieselbe Weise wurden erhalten:In the same way were obtained:

a) Trans-4- [4- (2-anilinoethoxy) -3-methylphenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (4-formylmethoxy-3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine and aniline.
Colorless resin of Rf value 0.16 (silica gel, ethyl acetate / petroleum ether = 2: 5, v: v).
Mass spectrum: M⁺ 436.
b) Trans-4- [4- (2-N-methylanilinoethoxy) -3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (4-formylmethoxy-3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine and N-methylaniline.
Colorless resin of Rf value 0.26 (silica gel, ethyl acetate / petroleum ether = 2: 5, v: v).
Mass spectrum: M⁺ 450.
c) trans-4- [4- (2-ethylamino-ethoxy-3-methylphenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (4-formylmethoxy-3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine and ethylamine.
Colorless resin of Rf value 0.2 (silica gel, methylene chloride / methanol = 8: 1, v: v).
Mass spectrum: M⁺ 388.
d) trans-4- [4- (2-benzylamino-ethoxy) -3-methylphenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (4-formylmethoxy-3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine and benzylamine.
Colorless resin of Rf value 0.24 (silica gel, methylene chloride / methanol = 30: 1, v: v).
e) trans-4- [4- (2-aminoethoxy) -3-methylphenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (4-formylmethoxy-3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine and ammonia.
Colorless resin of Rf value 0.28 (silica gel, methylene chloride / methanol = 6.5: 1, v: v).
Mass spectrum: M⁺ 360.
f) trans-4- [4- (2-methylamino-ethoxy) -3-methylphenyl] -N-hexanoyl-N-methylcyclohexylamine
from trans-4- (4-formylmethoxy) -3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine and methylamine.
Colorless oil.
NMR spectrum (200 MHz, CDCl₃ + CD₃OD); Signals at ppm: 0.9 (m, 3H), 1.3-2.1 (m, 14H), 2.2 (s, 3H), 2.25-2.4 (m, 3H), 2, 6 (s, 3H), 2.8-2.9 (2s, 3H), 3.15 (m, 2H), 3.7 (m, 0.5H), 4.15 (m, 2H), 4 , 5 (m, 0.5H), 6.7-7.05 (m, 3H).

Example 9 trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl- N-cyclohexylamine thiohexanoyl

133 mg trans-4-[4-(2-Diethylamino-ethoxy)-3-methylphenyl]-N- hexanoyl-N-methyl-cyclohexylamin und 92 mg Phosphorpentasul fid in 1,5 ml Tetrahydrofuran werden 23 Minuten im Ultra schallbad gehalten, nochmals 147 mg Phosphorpentasulfid und 1 ml Tetrahydrofuran zugegeben und weitere 20 Minuten im Ul traschallbad bei 30-38°C gehalten. Die klare Lösung wird ab pipettiert und der weiße Feststoff dreimal mit Methylenchlo rid extrahiert. Der konzentrierte organische Extrakt wird an Kieselgel chromatographiert (Essigsäureethylester/Petrol ether = 1 : 2, v:v). Man erhält 80 mg (58% der Theorie) trans- 4-[4-(2-Diethylamino-ethoxy)-3-methylphenyl]-N-methyl-N-thio hexanoyl-cyclohexylamin als farblose, wachsartige Substanz vom Rf-Wert 0,42 (Kieselgel, Essigsäureethylester/Petrolether = 1 : 2, v:v).
Massenspektrum: M⁺ 439.133 mg of trans-4- [4- (2-diethylaminoethoxy) -3-methylphenyl] -N-hexanoyl-N-methylcyclohexylamine and 92 mg of phosphorus pentasulfide in 1.5 ml of tetrahydrofuran are kept in the ultrasonic bath for 23 minutes, again added 147 mg of phosphorus pentasulfide and 1 ml of tetrahydrofuran and held for another 20 minutes in Ul traschallbad at 30-38 ° C. The clear solution is pipetted off and the white solid is extracted three times with methylene chloride. The concentrated organic extract is chromatographed on silica gel (ethyl acetate / petroleum ether = 1: 2, v: v). This gives 80 mg (58% of theory) of trans-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -N-methyl-N-thio-hexanoyl-cyclohexylamine as a colorless, waxy substance of Rf value 0 , 42 (silica gel, ethyl acetate / petroleum ether = 1: 2, v: v).
Mass spectrum: M⁺ 439.

Example 10 trans-N¹1-4- (4-methoxyphenyl) -cyclohexyl-N¹-methyl-N²- phenyl-hexanamidin

Zu 635 mg (2 mMol) trans-N-Hexanoyl-N-methyl-4-(4-methoxy phenyl)-cyclohexylamin in 2 ml Toluol werden 307 mg (2 mMol) Phosphoroxychlorid zugetropft. Nach Zugabe von 186 mg (2 mMol) Anilin wird über Nacht bei Raumtemperatur gerührt, in Ether eingerührt, mit Wasser versetzt, mit 2n-Natronlauge alkalisch gestellt und die organische Phase abgetrennt. Die Etherphase wird mit Wasser und gesättigter Kochsalzlösung gewaschen, getrocknet und eingedampft. Der Rückstand wird durch Säulenchromatographie an Aluminiumoxyd gereinigt. Man erhält 502 mg (66% der Theorie trans-N¹-[4-(4-Methoxy phenyl)-cyclohexyl]-N¹-methyl-N²-phenyl-hexanamidin als farbloses Öl vom Rf-Wert 0,37 (Aluminiumoxyd, Essigsäuree thylester/Petrolether = 1 : 10, v:v).
Massenspektrum: M⁺ 392.To 635 mg (2 mmol) of trans -N-hexanoyl-N-methyl-4- (4-methoxy-phenyl) -cyclohexylamine in 2 ml of toluene are added dropwise 307 mg (2 mmol) of phosphorus oxychloride. After addition of 186 mg (2 mmol) of aniline is stirred overnight at room temperature, stirred into ether, mixed with water, made alkaline with 2N sodium hydroxide solution and the organic phase was separated. The ether phase is washed with water and saturated brine, dried and evaporated. The residue is purified by column chromatography on alumina. This gives 502 mg (66% of theory trans-N¹- [4- (4-methoxy-phenyl) -cyclohexyl] -N¹-methyl-N²-phenyl-hexanamidine as a colorless oil of Rf 0.37 (alumina, ethyl acetate Petroleum ether = 1:10, v: v).
Mass spectrum: M⁺ 392.

Example 11 N-hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -2-n-propyl cyclohexylamine (isomer mixture)

100 mg (0,27 mMol) 4-Allyl-4-(4-methoxy-3-methylphenyl)-N- hexanoyl-N-methyl-cyclohexylamin (Isomerengemisch) werden in 10 ml Essigsäureethylester in Gegenwart von 100 mg 10%iger Palladiumkohle 30 Minuten bei Raumtemperatur und 50 psi hydriert. Nach Entfernen des Katalysators und Verdampfen des Lösungsmittels erhält man 100 mg N-Hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl)-2-n-propyl-cyclohexylamin (Isome ren-Gemisch) als farbloses Öl.
NMR-Spektrum (200 MHz, CDCl₃); Signale bei ppm: 0,8-1,0 (m, 6H), 1,05-2,1 (m, 17H), 2,2 (s, 3H), 2,25-2,6 (m, 3H), 2,75-3,0 (d+s, 3H), 3,25-3,4 (m, 0,5H), 3,8 (s, 3H), 4,3-4,55 (m, 0,5H), 6,7-8,0 (m, 3H).100 mg (0.27 mmol) of 4-allyl-4- (4-methoxy-3-methylphenyl) -N-hexanoyl-N-methylcyclohexylamine (mixture of isomers) are dissolved in 10 ml of ethyl acetate in the presence of 100 mg of 10% palladium carbon Hydrogenated at room temperature and 50 psi for 30 minutes. After removal of the catalyst and evaporation of the solvent, 100 mg of N-hexanoyl-N-methyl-4- (4-methoxy-3-methylphenyl) -2-n-propyl-cyclohexylamine (Isome ren mixture) is obtained as a colorless oil.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.8-1.0 (m, 6H), 1.05-2.1 (m, 17H), 2.2 (s, 3H), 2.25-2.6 (m, 3H ), 2.75-3.0 (d + s, 3H), 3.25-3.4 (m, 0.5H), 3.8 (s, 3H), 4.3-4.55 (m , 0.5H), 6.7-8.0 (m, 3H).

Example 12 trans-N¹-4- [4- (4-diethylamino-ethoxy) -3-methylphenyl] - cyclohexyl-N¹-methyl-N²-p-toluenesulfonyl-hexanamidin

416 mg (1 mMol) trans-4-[4-(2-Diethylamino-ethoxy)-3-methyl phenyl]-N-n-hexanoyl-N-methyl-cyclohexylamin werden mit 600 mg (3 mMol) p-Toluolsulfonylisocyanat in 5 ml Toluol zwei Stunden zum Rückfluß erhitzt. Nach Kühlen wird mit etwas Eis zersetzt, mit Ether und Essigsäureethylester verdünnt und mit 2N-Natronlauge ausgeschüttelt, die organische Phase mit Wasser gewaschen, getrocknet und eingedampft. Der Rückstand wird durch Chromatographie an Aluminiumoxyd gereinigt (Essig säureethylester/Petrolether = 1 : 1, v:v). Man erhält 281 mg (49,3% der Theorie) trans-N¹-4-[4-(2-Diethylamino-ethoxy)- 3-methylphenyl]-cyclohexyl-N¹-methyl-N²-p-toluolsulfonyl hexanamidin vom Schmelzpunkt 112-114°C.
NMR-Spektrum (200 MHz, CDCl₃); Signale bei ppm: 0,9 (m, 3H), 1,05 (t, 6H), 1,2-2,1 (m, 14H). 2,2 (5, 3H), 2,4 (s, 3H), 2,65 (q, 4H), 2,8-3,0 (m, 8H), 3,6-3,8 (m, 0,5H), 4,0 (t, 2H), 4,6-4,75 (m, 0,5H), 6,7-7,9 (m, 7H). 416 mg (1 mmol) of trans-4- [4- (2-diethylaminoethoxy) -3-methylphenyl] -Nn-hexanoyl-N-methyl-cyclohexylamine are treated with 600 mg (3 mmol) of p-toluenesulfonyl isocyanate in 5 ml Toluene heated for two hours to reflux. After cooling, it is decomposed with a little ice, diluted with ether and ethyl acetate and shaken out with 2N sodium hydroxide solution, the organic phase is washed with water, dried and evaporated. The residue is purified by chromatography on aluminum oxide (ethyl acetate / petroleum ether = 1: 1, v: v). This gives 281 mg (49.3% of theory) of trans -N¹-4- [4- (2-diethylamino-ethoxy) -3-methylphenyl] -cyclohexyl-N¹-methyl-N²-p-toluenesulfonyl hexanamidine of melting point 112- 114 ° C.
NMR spectrum (200 MHz, CDCl₃); Signals at ppm: 0.9 (m, 3H), 1.05 (t, 6H), 1.2-2.1 (m, 14H). 2,2 (5,3H), 2,4 (s, 3H), 2,65 (q, 4H), 2,8-3,0 (m, 8H), 3,6-3,8 (m, 0.5H), 4.0 (t, 2H), 4.6-4.75 (m, 0.5H), 6.7-7.9 (m, 7H).

Im folgenden wird die Herstellung pharmazeutischer Anwen dungsformen anhand einiger Beispiele beschrieben:In the following, the preparation of pharmaceutical Applic described using some examples:

Example I Tablets containing 5 mg of 4- [4- (4-diethylamino-ethoxy) -3-methyl phenyl] -N-hexanoyl-N-methyl-cyclohexylamine composition

1 Tablette enthält:1 tablet contains:

Wirkstoff|5,0 mgActive ingredient | 5.0 mg Milchzuckerlactose 148,0 mg148.0 mg Kartoffelstärkepotato starch 65,0 mg65.0 mg Magnesiumstearatmagnesium stearate 2,0 mg 2.0 mg 220,0 mg220.0 mg

production method

Aus Kartoffelstärke wird durch Erwärmen ein 10%iger Schleim hergestellt. Die Wirksubstanz, Milchzucker und die restliche Kartoffelstärke werden gemischt und mit obigem Schleim durch ein Sieb der Maschenweite 1,5 mm granuliert. Das Granulat wird bei 45°C getrocknet, nochmals durch obiges Sieb gerie ben, mit Magnesiumstearat vermischt und zu Tabletten ver preßt.Potato starch becomes a 10% mucus by heating manufactured. The active substance, lactose and the rest Potato starch is mixed with the above mucus through Granulated a sieve of mesh size 1.5 mm. The granules is dried at 45 ° C, again by the above sieve ben, mixed with magnesium stearate and ver to tablets ver presses.

Tablettengewicht: 220 mg
Stempel: 9 mm Tablet weight: 220 mg
Stamp: 9 mm

Example II Drag'es with 5 mg of 4- [4- (2-diethylamino-ethoxy) -3-methyl phenyl] -N-hexanoyl-N-methyl-cyclohexylamine

Die nach Beispiel I hergestellten Tabletten werden nach be kanntem Verfahren mit einer Hülle überzogen, die im wesent lichen aus Zucker und Talkum besteht. Die fertigen Drag´es werden mit Hilfe von Bienenwachs poliert.
Drag´egewicht: 300 mgThe tablets prepared according to Example I are coated according to any known method with a shell which consists in wesent union of sugar and talc. The finished Drag'es are polished using beeswax.
Drag'e weight: 300 mg

Example III Suppositories containing 5 mg of 4- [4- (2-diethylaminoethoxy) -3- methylphenyl] -N-hexanoyl-N-methyl-cyclohexylamine composition

1 Zäpfchen enthält:1 suppository contains:

Wirkstoff|5,0 mgActive ingredient | 5.0 mg Zäpfchenmasse (z. B. Witepsol W 45®)Suppository mass (eg Witepsol W 45®) 1695,0 mg1695.0 mg 1700,0 mg1700.0 mg

production method

Die feinpulverisierte Wirksubstanz wird in der geschmolzenen und auf 40°C abgekühlten Zäpfchenmasse suspendiert. Man gießt die Masse bei 37°C in leicht vorgekühlte Zäpfchenformen aus.
Zäpfchengewicht 1,7 g. The finely pulverized active substance is suspended in the molten suppository mass which has been cooled to 40.degree. Pour the mass at 37 ° C in slightly pre-cooled suppository forms.
Suppository weight 1.7 g.

Example IV Capsules containing 5 mg of 4- [4- (2-ethylamino-ethoxy) -3-methylphenyl] - N-hexanoyl-N-methyl-cyclohexylamine composition

1 Kapsel enthält:1 capsule contains:

Wirkstoff|5,0 mgActive ingredient | 5.0 mg Lactoselactose 82,0 mg82.0 mg StärkeStrength 82,0 mg82.0 mg Magnesiumstearatmagnesium stearate 1,0 mg 1.0 mg 170,0 mg170.0 mg

production method

Die Pulvermischung wird intensiv gemischt und auf einer Kap selabfüllmaschine in Hartgelatine-Steckkapseln der Größe 3 abgefüllt, wobei das Endgewicht laufend überprüft wird.The powder mixture is mixed thoroughly and on a cape Self-filling machine in size 3 hard gelatin capsule filled, with the final weight is checked continuously.

Example V Capsules containing 5 mg of N-methyl-N- (4-phenyl-3-butenoyl) -4- (4-pyridyl) cyclohexylamine composition

1 Kapsel enthält:1 capsule contains:

Wirksubstanz|5,0 mgActive substance | 5.0 mg Lactoselactose 82,0 mg82.0 mg StärkeStrength 82,0 mg82.0 mg Magnesiumstearatmagnesium stearate 1,0 mg 1.0 mg 170,0 mg170.0 mg

production method

Claims

1. N, N-disubstituted arylcycloalkylamines of the general formula I. in the
n, X and R¹ to R⁴ represent the following meanings:
n are the numbers 0 or 1,
X is the oxygen or sulfur atom or an imino group of the formula = NR⁵
R¹ is a mono-, di- or trisubstituted phenyl group which may be substituted by 1 to 3 straight or branched chain alkyl groups having 1 to 4 carbon atoms, by the phenyl group, by 1 or 2 hydroxy groups, a halo genatom such. Example, a fluorine or chlorine atom, the benzyl oxy, allyloxy or Propargyloxygruppe, by 1 to 3 alkoxy groups having 1 to 4 carbon atoms in the straight-chain or branched alkyl radical, wherein the alkyl radical may in turn be substituted by an amino group of the general formula - NR⁶R⁷, by a formyl group or an alipha tables acetal group having up to 4 carbon atoms, R be further indicates the furyl, thienyl or pyrimidinyl group, which may optionally be substituted by alkyl and / or alkoxy having 1 to 3 carbon atoms, the pyridyl - and the naphthyl group,
R ^2a to R ^2h , which may be the same or different, represent a hydrogen atom, an alkyl or alkenyl group having 1 to 3 carbon atoms,
R³ is a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 5 carbon atoms, the phenyl group, the cyclohexyl group and the cyclohexylmethyl group,
R⁴ represents a straight-chain or branched alkyl or alkenyl group having 3 to 19 carbon atoms in which the carbon chain can be interrupted by an oxygen or sulfur atom and the alkenyl part contains 1 to 3 double bonds, a phenylalkyl or phenylalkenyl group having 1 to 4 Carbon atoms in the alkylene part or 2 to 4 Koh atoms in the alkenylene part, wherein the phenyl moiety may be substituted by an alkyl or alkoxy groups having 1 to 3 carbon atoms, the phenyl group optionally substituted by one or two alkyl or alkoxy groups having 1 to 3 carbon atoms or by 1 or 2 halogen atoms, such as. As fluorine, chlorine or bromine atom, the cyclohexyl group or a cyclohexylalkyl or cyclohexyl alkenyl group, wherein the alkylene part 1 to 4 carbon atoms or the alkenylene part has 2 to 4 carbon atoms, but R⁴ can also be the biphenyl group or a ge optionally substituted by alkyl groups having 1 to 3 Kohlenstoffato men substituted furyl, thienyl or pyridyl group,
R⁵ represents the phenyl group or the p-toluene fulyl group,
R⁶ and R⁷, which may be identical or different, a hydrogen atom, the phenyl group, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which may optionally be substituted by a phenyl radical, further R⁶ and R⁷ may together with the nitrogen atom and optionally a further oxygen atom form the piperidino, morpholino or pyrrolidino group,
their isomers and, if basic groups are present, their physiologically acceptable salts with inorganic or organic acids.

2. N, N-Disubstituted Arylcycloalkylamine of the general formula I according to claim 1, in which n, X and R¹ to R⁴ represent the following meanings:
n is the number 1;
X is an oxygen atom;
R¹ is a mono-, di- or trisubstituted phenyl group which may be substituted by 1 to 3 straight or branched chain alkyl groups having 1 to 4 carbon atoms, by the phenyl group, by 1 or 2 hydroxy groups, a halo genatom such. Example, a fluorine or chlorine atom, the benzyl oxy, allyloxy or Propargyloxygruppe, by 1 to 3 alkoxy groups having 1 to 4 carbon atoms in the straight-chain or branched alkyl radical, wherein the alkyl radical may in turn be substituted by an amino group of the general formula - NR⁶R⁷, by a formyl group or an alipha tables acetal group having up to 4 carbon atoms, R¹ be further indicated the furyl, thienyl or Pyrimidinylgrup pe, which may optionally be substituted by alkyl and / or alkoxy having 1 to 3 carbon atoms, the pyri dyl and naphthyl group,
R ^2a to R ^2h each represent a hydrogen atom;
R³ is a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 5 carbon atoms, the phenyl group, the cyclohexyl group and the cyclohexylmethyl group,
R⁴ represents a straight-chain or branched alkyl or alkenyl group having 3 to 19 carbon atoms in which the carbon chain can be interrupted by an oxygen or sulfur atom and the alkenyl part contains 1 to 3 double bonds, a phenylalkyl or phenylalkenyl group having 1 to 4 Carbon atoms in the alkylene part or 2 to 4 Koh atoms in the alkenylene part, wherein the phenyl moiety may be substituted by an alkyl or alkoxy groups having 1 to 3 carbon atoms, the phenyl group optionally substituted by one or two alkyl or alkoxy groups having 1 to 3 carbon atoms or by 1 or 2 halogen atoms, such as. As fluorine, chlorine or bromine atom, the cyclohexyl group or a cyclohexylalkyl or cyclohexyl alkenyl group, wherein the alkylene part 1 to 4 carbon atoms or the alkenylene part has 2 to 4 carbon atoms, but R⁴ can also be the biphenyl group or a ge optionally substituted by alkyl groups having 1 to 3 Kohlenstoffato men substituted furyl, thienyl or pyridyl group,
R⁶ and R⁷, which may be identical or different, a hydrogen atom, the phenyl group, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which may optionally be substituted by a phenyl radical, further R⁶ and R⁷ may together with the nitrogen atom and optionally a further oxygen atom form the piperidino, morpholino or pyrrolidino group;
their isomers and, if basic groups are present, their physiologically acceptable salts with inorganic or organic acids.

3. As NN-disubstituted arylcycloalkylamines of the general mean of my formula I according to claim 1, the compounds:
4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-hexanoyl-N-methylcyclohexylamine
N-hexanoyl-N-methyl-4- [4- (2-pyrrolidino-ethoxy) -3-methyl-phenyl] -cyclohexylamine
4- [4- (2-Dimethylamino-ethoxy) -3-methyl-phenyl] -N-hexanoyl-N-methylcyclohexylamine
4- [4- (2-ethylamino-ethoxy) -3-methyl-phenyl] -N-hexanoyl-N-methylcyclohexylamine
4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl) -N-methyl-N- (5-methyl-hex-4-enoyl) -cyclohexylamine
4- [4- (2-diethylamino-ethoxy) -phenyl] -N-hexanoyl-N-methylcyclohexylamine
4- [4- (2-diethylamino-ethoxy) -3-methyl-phenyl] -N-hexanoyl-N-isopropylcyclohexylamine
N-hexanoyl-N-methyl-4- (4-pyridyl) cyclohexylamine
N-Elaidinoyl-N-methyl-4- (4-pyridyl) cyclohexylamine
N-methyl-N- (4-phenyl-butyryl) -4- (4-pyridyl) cyclohexylamine
N-methyl-N- (4-phenyl-3-butenoyl) -4- (4-pyridyl) cyclohexylamine
N-Methyl-N- (5-methyl-hexanoyl) -4- (4-pyridyl) cyclohexylamine
N-methyl-N-stearoyl-4- (4-pyridyl) cyclohexylamine
N-methyl-N-palmitoyl-4- (4-pyridyl) cyclohexylamine
N-linolenoyl-N-methyl-4- (4-pyridyl) cyclohexylamine
4- [4- (2-Dimethylamino-ethoxy) -phenyl] -N-hexanoyl-N-methylcyclohexylamine
their isomers and, if basic groups are present, their physiologically acceptable salts with inorganic or organic acids.

4. Medicaments containing one or more compounds the general formula I according to claims 1 to 3 in addition the usual carriers and / or excipients.

5. Use of the compounds of claims 1 to 3 for Production of drugs for the inhibition of cholesterol biosynthesis or for the treatment of hyperlipidemia and the Atherosclerosis.

6. A process for the preparation of NN-disubstituted aryl cycloalkylamines of the general formula I. in the
n, X and R¹ to R⁴ represent the following meanings:
n are the numbers 0 or 1,
X is the oxygen or sulfur atom or an imino group of the formula = NR⁵
R¹ is a mono-, di- or trisubstituted phenyl group which may be substituted by 1 to 3 straight or branched chain alkyl groups having 1 to 4 carbon atoms, by the phenyl group, by 1 or 2 hydroxy groups, a halo genatom such. Example, a fluorine or chlorine atom, the benzyl oxy, allyloxy or Propargyloxygruppe, by 1 to 3 alkoxy groups having 1 to 4 carbon atoms in the straight-chain or branched alkyl radical, wherein the alkyl radical may in turn be substituted by an amino group of the general formula - NR⁶ R⁷, by a formyl group or an alipha tables acetal group having up to 4 carbon atoms, R¹ be further indicated the furyl, thienyl or Pyrimidinylgrup pe, which may optionally be substituted by alkyl and / or alkoxy having 1 to 3 carbon atoms, which Pyridyl and the naphthyl group,
R ^2a to R ^2h , which may be the same or different, represent a hydrogen atom, an alkyl or alkenyl group having 1 to 3 carbon atoms,
R³ is a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 5 carbon atoms, the phenyl group, the cyclohexyl group and the cyclohexylmethyl group,
R⁴ represents a straight-chain or branched alkyl or alkenyl group having 3 to 19 carbon atoms in which the carbon chain can be interrupted by an oxygen or sulfur atom and the alkenyl part contains 1 to 3 double bonds, a phenylalkyl or phenylalkenyl group having 1 to 4 Carbon atoms in the alkylene part or 2 to 4 Koh atoms in the alkenylene part, wherein the phenyl moiety may be substituted by an alkyl or alkoxy groups having 1 to 3 carbon atoms, the phenyl group optionally substituted by one or two alkyl or alkoxy groups having 1 to 3 carbon atoms or by 1 or 2 halogen atoms, such as. As fluorine, chlorine or bromine atom, the cyclohexyl group or a cyclohexylalkyl or cyclohexyl alkenyl group, wherein the alkylene part 1 to 4 carbon atoms or the alkenylene part has 2 to 4 carbon atoms, but R⁴ can also be the biphenyl group or a ge optionally substituted by alkyl groups having 1 to 3 Kohlenstoffato men substituted furyl, thienyl or pyridyl group,
R⁵ represents the phenyl group or the p-toluenesulfonyl group,
R⁶ and R⁷, which may be identical or different, a hydrogen atom, the phenyl group, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which may optionally be substituted by a phenyl radical, further R⁶ and R⁷ may together with the nitrogen atom and optionally a further oxygen atom form the piperidino, morpholino or pyrrolidino group,
and of their isomers and, if basic groups are present, of their salts with inorganic or organic acids, characterized in that

a) for the preparation of compounds of the general formula I in which X represents an oxygen atom, R¹ to R⁴ and n have the meanings given above, an amine of the general formula II me in the
R¹, R ^2a to R ^2h , R³ and n are as defined above, with an acid derivative of the general formula III in the
R⁴ is as defined above and Y represents an exchangeable group, in an inert solvent at temperatures from -50 ° C to the boiling point of the reaction mixture is set, or
b) for the preparation of compounds of the general formula I, wherein X is an oxygen atom, n, R²a to R²h, R³ and R⁴ are as defined above and R¹ represents a phenyl group which is substituted by the benzyloxy, allyloxy, Pro pargyloxygruppe or by a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, which in turn may be substituted in the alkyl moiety by an amino group of the general formula NR⁶R⁷ with the meanings given above for R⁶ and R⁷, by an alkoxy group having 1 to 3 carbon atoms, a formyl or acetal group, where the phenyl radical may optionally also contain one or two straight-chain or branched alkyl groups having 1 to 4 carbon atoms and / or one halogen atom, a compound of the general formula I in which X is an oxygen atom and n, R ^2a to R ^2h , R³ and R⁴ are as defined above and R¹ is a monohydroxyphenyl radical, which may optionally have one or two straight-chain or chain branched alkyl groups having 1 to 4 carbon atoms and / or may contain a halogen atom, meaning tet, with a compound of general formula IV R⁸-Z (IV) in the
R⁸ is the benzyl, allyl or propargyl group or a GE radkettige or branched alkyl group having 1 to 4 carbon atoms, wherein the alkyl radical in turn by an amino group of the general formula -NR⁶R⁷ with the meanings given above for R⁶ and R⁷, by an alkoxy group 1 to 3 carbon atoms, a formyl or acetal group may be substituted and
Z represents a chlorine, bromine or iodine atom or a sulphonyloxy group,
is reacted in a solvent at temperatures between 0 ° C and 100 ° C in the presence of a base, or,
c) for the preparation of compounds of general formula I in which X represents an oxygen atom, n, R ^2a to R ^2h , R³ and R⁴ are as defined above and R¹ is a phenyl group which is in the 4-position by an alkoxy group having 1 to 4 carbon atoms, which in turn contains an amino group of For -NR⁶R⁷ contains, wherein the phenyl radical may optionally contain one or two straight-chain or branched alkyl groups having 1 to 4 carbon atoms and / or a halogen atom, a compound of general formula I, in which X, n, R² to R⁴ are as de fi ned above and R¹ is a phenyl group in the 4-position by an alkoxy group having 1 to 3 carbon atoms, which in turn is substituted by a formyl group, wherein the phenyl radical optionally one or two geradket atoms containing from 1 to 4 carbon atoms and / or a halogen atom, means, with an amine of the general formula V HNR⁶R⁷ (V), in the
R⁶ and R⁷ are as defined above, or reacted with the salts of salts with inorganic or organic acids in the presence of reducing agents Ge in a solvent at temperatures between 0 and 100 ° C, or
d) for the preparation of a compound of general formula I in which X represents a sulfur atom and n and R¹ to R⁴ are as defined above, a compound of the general formula I, in which n and R¹ to R⁴ as defined above defi ned and X represents an oxygen atom, is reacted with sulfur reagents in an inert solvent at temperatures between 0 and 150 ° C, or
e) for the preparation of compounds of general formula I in which X represents the grouping = NR⁵ in which R⁵ is the phenyl group and R¹ to R⁴ and n are as defined above, a compound of general formula I in which X represents an oxygen atom and n and R¹ to R⁴ are as defined above, first treated with acid chlorides or Alky lierungsmitteln and then the resulting reactive derivative with aniline in inert solvents at temperatures between -40 ° C and the boiling temperature of the reaction mixture is reacted, or
f) for the preparation of compounds of general formula I in which X represents the group = NR⁵ in which R⁵ is p-toluenesulfonyl group, and R¹ to R⁴ and n are as defined above, a compound of general formula I in which X represents an oxygen atom and R¹ to R⁴ and n are as defined above, is reacted with p-toluenesulfonyl isocyanate in a solvent at temperatures up to the boiling point of the reaction mixture,

optionally in the above-mentioned processes, the substituents which disturb the reactions in the starting materials are provided with protective groups before the reaction, which are removed again after the reaction, and
the compounds obtained are optionally separated into their isomers and / or, if appropriate, the compounds thus obtained, if they contain basic radicals, are converted into their acid addition salts with inorganic or organic acids.

7. The method according to claim 6a, characterized in that an acid derivative of the general formula III is used, in which Y represents a halogen atom or the imidazolide group and, optionally, the reaction with a salt of the amine of the general formula II is added of bases.

8. The method according to claim 6c, characterized in that as reducing agent sodium cyanoborohydride or catalytically excited hydrogen is used and, optionally, if in the general formula V the radical -NR⁶R⁷ is a represents primary amino group, one in the reaction inter isolated Schiff'sche base isolated, and then ßend is used with said reducing agents.

9. The method according to claim 6d, characterized in that as sulfur reagents diphosphorus pentasulfide or Lawesson's Reagent can be used.

10. The method according to claim 6f, characterized that the reaction is carried out in boiling toluene.