CH513809A - 1 3-amino alcohols c n s stimulants intermediates - stimulants and intermediates - Google Patents

Abstract

(A) Cmpds. (I) and (II):- R = H, (1-6C) alkyl, or (2-12C) acyl; n = 1-4; R' = H, (1-6C) alkyl, (5-8C) cycloalkyl, (2-6C) alkoxyalkyl, hydroxyalkyl, opt. subst. Ph, or PhCH2. R2 = H, (1-6C) alkyl, PhCH2, or (2-12C) acyl; R3 = H and R4 = (1-6C) alkyl opt. subst. by OH, (2-6C) alkoxyalkyl, (5-8C) cycloalkyl, or opt. subst. Ph or R3=R4 = (1-6C) alkyl, or R3=PhCH2 and R4 = (1-6C) alkyl R5,R6 and R7 = H, halogen, (1-6C) alkyl, (1-6C) Alkyl, or CF3 (III) Acid addn. and quat. ammonium salts of (I) and (II). (IV) N-oxides of (I) and (II). (V) Stereoisomers of (I)-(IV). (I) (a) C.N.S. stimulants. Dose 0.1-10 mg./kg./day. (b) Diuretics, herbicide, mothproofing and corrosion inhibitor intermediates. (II) Intermediates for (I).

Description

  

  
 



  Process for the preparation of substituted 1,3-amino alcohols
The present invention relates to a process for the preparation of new, substituted 1,3-amino alcohols and also their acid addition salts. The new 1,3-amino alcohols can be used to convert them into the corresponding ethers. The compounds which can be prepared according to the invention have a stimulating effect on the central nervous system.



   The new compounds are stimulants to the central nervous system of mammals and birds and can be used as intermediates in the manufacture of diuretics.



   The compounds that can be prepared according to the invention have the following formula:
EMI1.1
 where n is an integer of 14, the moiety
EMI1.2
 in one of the forms
EMI1.3
 or
EMI1.4
 is present, in which forms each alkyl radical has 1-6 carbon atoms, each hydroxyalkyl and alkoxyalkyl radical contains 2-6 carbon atoms, each cycloalkyl radical has 5-8 carbon atoms and the phenyl radical is optionally substituted, R ', R "and R "'Denotes hydrogen, halogen, an alkyl or alkoxy radical each having 1-6 carbon atoms or the group -CF3.



   The process according to the invention is characterized in that a diketo compound of the formula
EMI1.5
 with an amine of the formula
EMI1.6
 heated in the presence of an acidic catalyst to form the corresponding unsaturated ketone II of the following formula:
EMI1.7
  and hydrogenating the compound II obtained with at least 2 parts by mole of hydrogen per part by mole of the unsaturated ketone II in the presence of a noble metal catalyst.



   Compounds of the formula III obtained in which Rs or R4 are benzyl can additionally be hydrogenated with one molar part of hydrogen per molar part of compound III to split off the benzyl group and form primary or secondary amines. But it is also possible to carry out the hydrogenation of compounds of the formula II in which R3 or R is benzyl immediately with 3 parts by mole of hydrogen per part by mole of the ketone II in order to reduce the benzyl group from the ketone II in addition to the hydrogenation and reduction.



   The cycloalkyl radicals listed above are represented by the following formula:
EMI2.1
 and they are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl radicals.



   Alkyl groups with 1-6 carbon atoms are z. B.



   Methyl, sithyl, propyl,
Isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-methylbutyl,
Neopentyl, hexyl,
2-methylpentyl, 3-methylpentyl and the like.



   The halogen substituents of R ', R "or R"' are understood to mean fluorine, chlorine, bromine or iodine.



   Examples of hydroxyalkyl groups are
2-hydroxyethyl, 3-hydroxypropyl,
4-hydroxybutyl, 5-hydroxypentyl,
6-hydroxyhexyl, 2-hydroxypropyl,
2-hydroxybutyl, 3-hydroxypentyl and the like.



   Examples of alkoxyalkyl groups are
Methoxymethyl, 2-methoxyethyl,
3-methoxypropyl-, 4-methoxybutyl-,
5-methoxypentyl-, 3-methoxypentyl-,
2,2-diethoxyethyl radicals and the like.



   The optionally substituted phenyl radical is represented by the following formula:
EMI2.2
 wherein R "" represents halogen, an alkyl or alkoxy radical having 1-6 carbon atoms or -CF3, e.g. o-, m- or p-chlorophenyl, o-, m- or p-fluorophenyl, o-, m- or p-tolyl, o-, m- or p-butylphenyl, o-, mp-anisyl, o-, m- or p-butoxyphenyl, o-, m- or p-ethylphenyl, o-, m- or p-bromophenyl, o-, m- or p-trifluoromethylphenyl or similar radicals.



   The process according to the invention comprises the following steps: heating a diketo compound of the formula (I), in which one of the radicals on the central carbonyl group is a 2-oxocycloalkyl group with 5-8 carbon atoms and the other radical is a substituted or unsubstituted phenyl group, with an amine the following formula
EMI2.3
 where R3 and R4 have the meaning given above, in the presence of an acidic catalyst, e.g. B.



   Benzenesulfonic acid, p-chlorobenzenesulfonic acid or p-toluenesulfonic acid to form the unsaturated keto compound of the formula (II), hydrogenation of the compound (II) obtained in this way in the presence of a noble metal catalyst, preferably platinum oxide, rhodium, palladium or the like, and addition of at least 2 molar equivalents of hydrogen to form the corresponding compounds of Formula III.



   The compounds of the formula (III) obtainable according to the invention can be used to convert them into the corresponding ethers of the formula
EMI2.4
 convict. In this formula, n, R ', R "and R"' have the meaning given above, R is an alkyl radical with 1-6 carbon atoms and R3, and R4 'are the same as R3 and R1 and can also be hydrogen at the same time. The new ethers are preferably prepared by reacting 1,3-amino alcohols with an alkanol with 1-6 C atoms in the presence of hydrogen chloride and treating the ether chloride formed with a base.



   Compounds of the formula (III) and (IVa) can by neutralization with inorganic or organic acids in acid addition salts such as
Hydrochloride, hydrobromide,
Hydroiodide, sulfate,
Phosphate, perchlorate,
Pamoate, cyclohexanesulfamate,
Methanesulfonate, ethanesulfonate, p-toluenesulfonate, benzenesulfonate,
Tartrate, citrate, lactate and the like can be converted.



   The compounds of formulas (III) and (IVa) including the acid addition salts are useful stimulant agents which have an effect on the central nervous system. They can be used to stimulate the respiratory, brain, vagic and vasomotor centers of mammals and birds.



   They can be administered orally and parenterally to mammals and birds for pharmacological effects, e.g. a stimulating effect. For oral administration, the new compounds of the formulas (III) and (IVa) can be used just as well as the acid addition salts in solid and liquid dosage forms such as tablets, capsules, powders, granules, syrups, elixirs and similar forms, which have the appropriate amount for a treatment contained, administered to. For tablets, the generally acceptable pharmaceutical carriers such as starch, lactose, kaolin, dicalcium phosphate and the like are used. The compounds (III) and (IVa) can also be used as a powder, in particular in gelatin capsules with or without carriers such as methyl cellulose, magnesium stearate, potassium stearate, talc and the like.

  For liquid preparations, these compounds can be dissolved or suspended in aqueous alcoholic vehicles with or without buffering agents and flavor mixtures.



   The pharmaceutical preparations obtained in this way are used in animals for the treatment of conditions associated with breathing difficulties, such as e.g. B.



  Pneumonia, bronchitis, asthma, or those related to heart failure. In particular, these compounds are useful geriatric stimulants for potters. Dosages of 0.1 to 10 mg / kg body weight per day cause noticeable stimulation.



   The compounds of formula (IVa), in which R3 'and R4 represent hydrogen, are also useful intermediates for the preparation of highly active diuretics, especially when reacted with 1,5-dibrinm- or 1,5-diiodopentane these give 2- Aminocycloalkanes
Piperidinocycloalkane compounds.



  Thus the ether of cis-B- 1 [2- (a, p-dimethoxybenzyl) cyclohexyl] - piperidine with a melting point of 82 to 840 C, obtained from cis-B-2- (a, p-dimethoxybenzyl) - cyclohexylamine, at a dose of 5 mg / kg body weight in rats an increase in diuresis by 73%, as by the method of Lipschitz et al., J. Pharmacol. Exp.



  Therap. 79, 97, 1943.



   As noted above, the new compounds of formula (III) as well as the amino compounds of formula (IVa) can be used in the form of their acid addition salts with inorganic or organic acids, e.g. Hydrochlorides, lactates, sulfates, tartrates, hydroiodides, hydrobromides and others.



  In addition, the fluosilicates of these compounds are particularly useful moth repellants (according to U.S. Pat. Nos. 1,915,334 and 2,075,359). The thiocyanic acid addition salts of the same compounds can be condensed with formaldehyde to give resinous polymers, which according to US Pat. Nos.



     2425 320 and 2606 155 are useful pickling inhibitors. The trichloroacetic acid addition salts of the same compounds are useful as herbicides, e.g. against johnson grass, yellow and green foxtail, Bermuda grass and couch grass.



   The starting materials for formula (I) are, for. B. by Campbell et al., J. Am. Chem. Soc. 82: 2389 (1960); Linn et al., J. Am. Chem. Soc. 78: 6066 (1956); Eistert et al., Ann. 650, 133 (1961) is known. An elegant method for preparing the 1,3-diones of the formula (I) is based in particular on the reduction of a specific cycloalkanone with pyrrolidine or piperidine to the corresponding enamine and the reaction of the enamine with a specific substituted or unsubstituted benzoyl chloride [Campbell et al., J. Org. Chem. 28, 379 (1963)]. This particular method is shown repeatedly in the preparations to produce the heretofore unknown 1,3-diones of the type of formula (I).



   When carrying out the process according to the invention, a 1,3-diketo compound (I) is allowed to react with an amine (V) in the presence of an acidic catalyst, preferably with separation of the water formed during the condensation from the reaction mixture by using an azeotropic separator in conjunction with a Reflux condenser. The solvents used are mainly anhydrous organic solvents such as benzene, toluene, xylene or the like.

  The following amines in particular are used as amines:
N-methylbenzylamine, N-ethylbenzylamine,
N-propylbenzylamine, N-butylbenzylamine,
Ethylamine, isopropylamine,
Butylamine, pentylamine,
Hexylamine, dimethylamine,
Diethylamine, dipropylamine,
N-methylpentylamine, dibutylamine,
Dihexylamine, benzylamine,
Aniline, o-, m- or p-toluidine, p-butylaniline, o-, m- or p-anisidine, o-, m- or p-chloroaniline, o-, m- or p-trifluoromethylaniline,
2-hydroxyethylamine, 3-hydroxypropylamine,
2-hydroxypropylamine, 3-hydroxypentylamine,
4-hydroxybutylamine, 6-hydroxyhexylamine,
2-hydroxyhexylamine, 2-ethoxyethylamine, 4-ethoxybutylamine, 5-methoxypentylamine,
3-propoxypropylamine, cyclopentylamine,
Cyclohexylamine, cyclooctylamine and the like.



   The reaction is generally carried out at a temperature of 30 to 1500 ° C., but lower or higher temperatures can also be used. The reaction is preferably carried out at the boiling point of the reaction mixture. It generally takes up to 48 hours to complete the reaction, but longer reaction times are necessary when working at lower temperatures. After the reaction has ended, the reaction product can be isolated in a customary manner, such as evaporating the reaction mixture.



   The keto compound of formula (II) is then hydrogenated in the presence of a catalyst, e.g. Platinum oxide, rhodium and the like, palladium on a carrier, e.g. B. clay or charcoal, preferably at a hydrogen pressure of 2.8 to 4.2 kg / cm9. Higher or lower pressures can be used, but a hydrogen pressure between 0.35 and 4.2 kg / cm2 at the start of the reaction is particularly favorable. The reaction can be followed by hydrogen absorption. To form the alcohol of the formula (III), 2 molar parts of hydrogen are added. After the hydrogenation has ended, the product can be isolated by filtering the reaction mixture to remove the catalyst and by evaporating the solvent, and the alcohol of the formula (III) is obtained.

  The product isolated in this way is usually purified by known methods such as crystallization and recrystallization, chromatography or similar methods.



   The compounds of the formula (II) with an N benzyl group (RQ or R4 is a benzyl radical) can be hydrogenated and cleaved hydrogenatively at the same time, or the hydrogenative cleavage can take place after the hydrogenation to form these compounds which have at least one hydrogen atom on Have nitrogen atom. If R = H and R4 = benzyl in the compounds of the formula (II), the free primary amino alcohol can be obtained by hydrogenation and hydrogenative cleavage.



   The conversion of 1,3-amino alcohols into ether (IVa) is generally achieved by two methods: conversion of the alcohol in liquid ammonia, which contains sodium amide or potassium amide, at low temperatures with a certain alkyl halide, or 2. preferably the conversion of the alcohol with a lower alkanol in the presence of hydrogen chloride. The starting temperature of the first method is usually the temperature of the dry ice-acetone bath, about -700 C, and the reaction is terminated at about room temperature. In a preferred embodiment, the alcohol can be dissolved in ether and added to the liquid ammonia, which contains sodium amide, with constant stirring.

  When the mixture cools to the dry ice acetone bath temperature, a solution of the alkyl halide, particularly an alkyl iodide, is usually added over a period of a few minutes while maintaining the lower temperature. When the calculated amount of the alkyl halide has been consumed, the reaction mixture in the flask can be removed from the dry ice acetone bath and generally allowed to warm to room temperature with continued stirring. Instead of sodium amide or other strongly basic compounds, potassium, lithium amide and the like can also be used. Instead of liquid ammonia and alkali amides, other reaction systems can also be used, e.g. B.

  Butyllithium in the presence of tetrahydrofuran at a temperature of -70 to +250 C. After the reaction has ended, the ether (IVa) produced in this way can be isolated by known methods, such as extraction, evaporation of the solvent, formation of amine addition salts such as hydrochloride, Application of the characteristic water solubility of the hydrochloride and the like. Recrystallization and chromatography are generally used for purification.



   In the second preferred method, the alcohol is stirred with a solution of hydrogen chloride gas in a lower alcohol such as methanol, ethanol, propanol, 1-butanol, 2-butanol and the like, generally at room temperature. However, it is possible to work at lower or higher temperatures. The product is preferably obtained as an amino ether hydrochloride. The free base can be obtained by reacting the hydrochloride with a base, e.g. B. with 20% sodium hydroxide solution, the free base extracted with a solvent which is immiscible with water, z. B.



  Ether, methylene chloride, chloroform and the like, and then the solvent is evaporated.



   Acid addition salts of the amino alcohols (II) and amino ethers (IVa) can be prepared in a known manner; H. by direct reaction of the acid with the free amine, preferably in an aqueous or anhydrous solvent such as water, ether, methanol, ethanol, ethyl acetate and the like. Evaporation of the solvent usually gives the desired acid addition salt.



   The configuration of the compounds (III) and (IVa) shows that they can occur in more than one isomeric structure, since they have at least three asymmetric centers. The present inventive method for the preparation of these compounds favors the preparation of the cis compounds.



   Preferred embodiments of the invention are described in the following examples.



  Preparation 1 2- (3,4,5-trimethoxybenzoyl) cyclohexanone
A mixture of 147 g (1.5 mol) of cyclohexanone and 213.3 g (3 mol) of pyrrolidine was refluxed in 2250 ml of benzene in a vessel which was provided with an azeotrope separator. After the water formed during the reaction had been removed, the solution was evaporated to dryness in vacuo, and the crude oil obtained, which consisted of 1-pyrrolidine-1-cyclohexene, was used for the next steps in the process.



   A solution of 3,4,5-trimethoxybenzoyl chloride (138.3 g; 0.6 mole) in 240 ml of chloroform was added to a solution of crude 1-pyrrolidine-1-cyclohexene in 630 ml of chloroform in a nitrogen atmosphere with constant stirring for two Hours given; the temperature was 5 to 100 C. After the solution was stirred overnight (about 18 hours) at room temperature (about 22-250 C), 900 ml of 1OX aqueous hydrochloric acid was added, and the resulting mixture was stirred at room temperature for two hours . The aqueous layer was extracted with two 150 ml portions of chloroform and the chloroform extracts combined, the chloroform layer on top.

  The combined extracts were washed with water, further with saturated aqueous sodium bicarbonate solution, water and saturated saline solution. The chloroform solution thus obtained was dried by being passed through anhydrous sodium sulfate, and the dry solution was evaporated to give a residue, which was recrystallized from methanol. 100 g of long, colorless needles of 2- (3,4,5-trimethoxybenzoyl) cyclohexanone, which had a melting point of 141-1420 ° C., were obtained.

 

   Analysis:
For C16H20O5: C, 65.74; H 6.90 Found: C 65.48; H 6.84 Preparation 2 2- (3,4,5-trimethoxybenzoyl) cyclopentanone
A mixture of 126 g (1.5 mol) of cyclopentanone and 213.3 g (3 mol) of pyrrolidine was refluxed in 2250 ml of benzene in a reaction vessel which was provided with an azeotrope separator. After the calculated amount of water formed during the condensation was collected, the reaction mixture was evaporated to give an oil, 1-pyrrolidino-1-cyclopentene.



   A solution of 3,4,5-trimethoxybenzoyl chloride (138.3 g; 0.6 mol) in chloroform was added to a chloroform solution of oily 1-pyrrolidino-1-cyclopentene over one hour. The reaction mixture was processed as in Preparation 1, and a brown oil which weighed 190 g was obtained.



  This oil was dissolved in 500 ml of ethanol, and then the ethanol solution was added to a solution of 172 g of copper acetate monohydrate in 2600 ml of water. The mixture was cooled for 1/2 hour and filtered. The crude copper complex of 2- (3,4,5-trimethoxybenzoyl) cyclopentanone was obtained.



  This compound was recrystallized from methylene chloride and obtained 70 g of the pure copper complex with a melting point of 206-2080 C.



   analysis
Calculated for C30H34CU010:
C 58.29; H 5.54; Cu 10.28.



   Found:
C 58.58; H 5.81; Cu 9.49.



  The copper complex (70 g) thus obtained was dissolved in 350 ml of chloroform and decomposed with 670 ml of 10% aqueous hydrochloric acid to obtain 60 g (yield 36%)
2- (3,4,5-Trimethoxybenzoyl) -cyclopentanone with a melting point of 81-860 C. A sample of this compound was recrystallized from Skellysolve B (hexanes) to obtain
2- (3,4,5-trimethoxybenzoyl) -cyclopentanone with a melting point of 92-950 C.



   Analysis:
Calculated for C15H18O5: C 64.73 H 6.52.



   Found: C 64.95; H 6.52.



   If twice the amount of the starting materials is used in this synthesis, the yield is 47%.



  Preparation 3 2- (3,4,5-trimethoxybenzoyl) cycloheptanone
A mixture of 500 g of cycloheptanone (4.5 mol), 785 g of morpholine (9 mol), 900 ml of toluene and 5 g of p-toluenesulfonic acid was refluxed for 23 hours. The water of reaction was collected with an azeotropic separator. 98 ml of a lower phase were obtained, which was collected and discarded. The remaining mixture was then evaporated in vacuo to give an oil which was distilled. The faction with a Kp.



  between 119-1250 C consisted mainly of 262.7 g of 1-morpholino-1-cycloheptene (32% yield).



   In the same way as in Preparation 1, 3,4,5-trimethoxybenzoyl chloride (92.5 g; 0.4 mol) was allowed to react with 181.37 g (1 mol) of 1-morpholino-1-cycloheptene. The crude product was recrystallized from 500 ml of methanol, and a first precipitate of crystals, 26 g of 2- (3, 4,5-trimethoxybenzoyl) cycloheptanone with a melting point of 99-1000 ° C., was obtained. After two further recrystallizations from methanol, the product had a melting point of 107-1080 C.



   Analysis:
Calculated for C17H2205: C, 66.65; H 7.24.



   Found: C, 66.16; H 7.48.



   A further 48.3 g of 2- (3, 4,5-trimethoxybenzoyl) cycloheptanone were obtained from the methanol-containing filtrate as a second connection. The total yield was 61%.



  Preparation 4 2- (p-methoxybenzoyl) cyclohexanone
A solution of 167 g (0.98 mol) of p-anisoyl chloride in 480 ml of chloroform became a solution of 371.7 g (2.46 mol) of distilled 1-pyrrolidino-1-cyclohexene in 1260 ml of chloroform over a period of 1.5 hours given. The temperature was kept between 5-100 ° C. by cooling with ice. After stirring for 20 hours at room temperature, the mixture was decomposed by adding 1800 ml of 10% strength aqueous hydrochloric acid over 20 minutes. The mixture was then stirred for 2 hours, allowed to stand, the organic layer was separated and the aqueous layer was extracted twice with 250 ml portions of chloroform.

  The original organic layer and the chloroform extracts were combined, washed with water and saturated saline, and then dried by passage through anhydrous sodium sulfate and evaporated.



  The residue obtained after evaporation was a brown oil which was dissolved in 1 liter of ethanol and added to a solution of 344 g of copper acetate monohydrate in 5200 ml of water which had been preheated to 650.degree. The mixture was stirred for 1/2 hour, cooled to room temperature and filtered.



  The resulting precipitate was washed first with water and then with ether. It was dissolved in 800 ml of chloroform and added to a solution of 300 ml of concentrated hydrochloric acid in 1100 ml of water.



  The mixture was stirred for one hour.



   The organic layer was separated and the aqueous layer was extracted once with chloroform.



  The original chloroform layer and the extract were combined, washed with water and saturated saline, dried by passing through anhydrous sodium sulfate and evaporated. A solid material was obtained which was recrystallized from 7 l of methanol. The amount was 136.5 g
2- (p-Methoxybenzoyl) -cyclohexanone with a melting point of 115-1280 C. A second batch of 26 g with a melting point of 116-1270 C was obtained from the mother liquor; the overall yield was 71%. A sample of
2- (p-Methoxybenzoyl) -cyclohexanone had a melting point of 117-1220 C.

 

   Analysis:
For C14H16O2: C, 72.39; H 6.94.



   Found: C, 72.30; H 7.05.



  Preparation 5 2- (p-Methoxybenzoyl) cyclopentanone
In the same way as in Preparation 2, 204 g (1.2 mol) of p-anisoyl chloride were allowed to react with 1-pyrrolidino-cyclopentene, which was prepared from 252 g (3 mol) of cyclopentanone. The crude product was converted to the copper complex as in Preparation 4, the complex was recrystallized from chloroform-ether, and 80 g of the copper complex of 2- (p-methoxybenzoyl) cyclopentanone with a melting point of 2520 ° C. (decomposition) were obtained. The copper complex was decomposed with hydrochloric acid, and 67 g of an oil were obtained, which was recrystallized from methanol to give 13.9 g of 2- (p-methoxybenzoyl) cyclopentanone with a melting point of 82-830.degree.

  The filtrate from the first crystallization was evaporated to dryness, and the crystals obtained were recrystallized from lither-Skellysolve B (hexanes), and 30.1 g of a second batch of 2- (p-methoxybenzoyl) -cyclopentanone with a melting point were obtained of 76-770 C (total yield 17 S). A second recrystallization from methanol gave 2- (p-methoxybenzoyl) -cyclopentanone with a melting point of 83-870 C.



   Analysis:
Calculated for C13H1403: C, 71.54; H 6.47.



   Found: C, 71.83; H 6.48.



  Preparation 6 2- (p-Ethoxybenzoyl) cyclohexanone
In the same manner as in Preparation 2, 1-piperidino-1-cyclohexene was reacted with p-ethoxybenzoyl chloride in chloroform solution, and after purification by the copper complex (Preparation 2), 2- (o-sithoxybenzoyl) cyclohexanone was obtained.



     Preparation 7 2- (o-Methoxybenzoyl) -cyclohexanone
In the manner indicated in preparation 2, l-piperidino-l-cyclohexene was allowed to react with o-methoxybenzoyl chloride in chloroform. After purification via the copper complex (preparation 2), 2- (o-methoxybenzoyl) -cyclohexanone with a melting point of 65-68 ° C. was obtained.



  Preparation 8 2- (2-methoxy-4-methylbenzoyl) -cyclohexanone
In the same way as in preparation 2, l-piperidino-1-cydohexene was reacted with 2-methoxy-4-methylbenzoyl chloride in chloroform solution and, after purification by the copper complex (preparation 2), 2- (2-methoxy-4- methylbenzoyl) cyclohexanone.



  Preparation 9 2- (3,5-Dimethyl-4-methoxybenzoyl) -cyclohexanone
In the same way as in preparation 2, 1-pyrrolidino-1-cyclohexene was reacted with 3,5-dimethyl-4-methoxybeuzoyl chloride in chloroform solution and, after purification by the copper complex (preparation 2), 2- (3,5-dimethyl- 4-methoxybenzoyl) cyclohexanone with a melting point of 125-126 C.



  Preparation 10 2- (p-Trifluoromethylbenzoyl) -cyclohexanone
In the same way as in preparation 2, 1-pipendino-1-cyclohexene was reacted with p-trifluoromethylbenzoyl chloride in chloroform solution and, after purification via the copper complex (preparation 2), 2- (p-trifluoromethylbenzoyl) -cyclohexanone was obtained.



  Preparation 11 2- (p-chlorobenzoyl) cyclohexanone
As in preparation 2, 1-piperidino-1-cyclohexene was reacted with p-chlorobenzoyl chloride in chloroform solution and, after purification by the copper complex (preparation 2), 2- (p-chlorobenzoyl) cyclohexanone was obtained.



  Preparation 12 2- (o-methylbenzoyl) cyclohexanone
In the same way as in preparation 2, 1-piperidino-1-cyclohexene was reacted with o-methylbenzoyl chloride in chloroform solution and, after purification by the copper complex (preparation 2), 2- (o-methylbenzoyl) -cyclohexanone was obtained.



  Preparation 13 2- (p-Methylbenzoyl) -cyclohexanone
As in preparation 2, 1-pyrrolidino-1-cyclohexene was reacted with p-methylbenzoyl chloride in chloroform solution and, after purification by the copper complex (preparation 2), 2- (p-methylbenzoyl) cyclohexanone with a melting point of 108-110 ° C. was obtained .



  Preparation 14 2- (2,4-Dimethylbenzoyl) -cyclohexanone
In the manner indicated in preparation 2, 1-pyrrolidino-1-cyclohexene was reacted with 2,4-dimethylbenzoyl chloride in chloroform solution and, after purification by the copper complex (preparation 2), 2- (2,4-dimethylbenzoyl) -cyclohexanone was obtained with a melting point of 51-51.50 C.



  Preparation 15 2- (2-methoxy-4-methylbenzoyl) -cyclohexanone
In the same way as in preparation 2, 1-piperidine-1-cyclohexene was reacted with 2-methoxy-4-methylbenzoyl chloride in chloroform solution and, after purification by the copper complex (preparation 2), 2- (2-methoxy-4- methylbenzoyl) cyclohexanone.



  Preparation 16 2- (p-Ethoxybenzoyl) cyclooctanone
In the same way as in preparation 2, 1-morpholino-1-cyclooctene was reacted with p-ethoxybenzoyl chloride in chloroform and, after purification by the copper complex (preparation 2), 2- (p ethoxybenzoyl) -cyclooctanone was obtained.



  Preparation 17 2- (2,3,4-trimethoxybenzoyl) cyclooctanone
In the same way as in preparation 2, 1-piperidino-1-cyclooctene was reacted with 2,3,4-trimethoxybenzoyl chloride in chloroform and, after purification by the copper complex (preparation 2), 2- (2,3,4- Trimethoxybenzoyl) cyclooctanone.



  Preparation 18 2- (p-bromobenzoyl) cyclooctanone
In the same way as in preparation 2, 1-piperidino-1-cyclooctene was reacted with p-bromobenzoyl chloride in chloroform solution and, after purification by the copper complex (preparation 2), 2- (p bromobenzoyl) cyclooctanone was obtained.



  Preparation 19 2- (m-Methylbenzoyl) -cyclooctanone
In the same way as in preparation 2, 1-piperidino-1-cyclooctene was reacted with m-methylbenzoyl chloride in chloroform solution. After purification by the copper complex (preparation 2), 2- (m-methylbenzoyl) -cyclooctanone was obtained.



   In the same way as in the previous ones
Other 2-benzoylcycloalkanones of the formula (I) (starting compounds) are prepared by reacting a l-cycloamino-l-cycloalkene, in which the cycloalkene part has 5 to 8 carbon atoms in the nucleus, the cyclic amino part has 5 to 10 nucleus atoms, such as. B. morpholino, pyrrolidino, piperidino and other similar compounds made with a benzoyl chloride ago.

  Examples of starting materials produced in this way are:
2- (3,5-Diiodobenzoyl) -cyclopentanone,
2- (p-fluorobenzoyl) -cyclohexanone,
2- (2-methoxy-4-chlorobenzoyl) -cyclohexanone,
2- (2-methoxy-3-methylbenzoyl) -cyclohexanone, 2- (2-methyl-4-trifluoromethylbenzoyl) -cyclohexanone,
2- (3,4-Dipropylbenzoyl) -cycloheptanone,
2- (2,5-dichlorobenzoyl) -cycloheptanone,
2- (3,4-dichlorobenzoyl) cyclooctanone,
2- (p-propoxybenzoyl) cyclooctanone,
2- (2,5-diiodobenzoyl) cycloheptanone,
2- (m-fluorobenzoyl) -cyclopentanone,
2- (p-bromobenzoyl) -cyclopentanone,
2- (p-hexylbenzoyl) -cyclopentanone,
2- (m-pentylbenzoyl) -cyclohexanone,
2- (o-butylbenzoyl) -cyclohexanone,
2- (o-Propylbenzoyl) -cycloheptanone, 2- (m-Ethylbenzoyl) -cyclooctanone,
2- (2-methoxy-5-bromobenzoyl) -cyclopentanone,
2-benzoylcyclooctanone,
2-benzoylcycloheptanone and the like.



   Example 1 cis-A-a- (p-Methoxyphenyl) -2- (methylamino) cyclohexanemethanol
A solution of 58 g (0.25 mol) of 2- (p-methoxybenzoyl) cyclohexanone, 91 g (0.75 mol) of N-methylbenzylamine and 1.6 g of p-toluenesulfonic acid monohydrate in 2 l of toluene was refluxed during Heated for 20 hours. During the reaction, 4 ml of water was collected in a Dean-Stark device. The mixture was then concentrated in vacuo to give a residue which was taken up in 400 ml of ethanol. In the presence of a platinum oxide catalyst, hydrogenation was carried out for 18 hours at a hydrogen pressure of 0.35 to 2.1 kg / cm 2, after which the reaction mixture was filtered to remove the catalyst, and the yellowish filtrate became in the presence of 4.0 g of a 10% palladium-on-carbon cata- lyst hydrogenated for 20 hours.

  The mixture was filtered again to remove the catalyst and evaporated in vacuo to leave a residue. This residue was dissolved in 600 ml of ether and 500 ml of 10% strength aqueous acetic acid. The mixture was stirred for one hour, the acetic acid layer was separated off, made alkaline with 20% strength sodium hydroxide solution and the separated oil was extracted with methylene chloride. The methylene chloride layer was washed with water and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and after concentrating in vacuo, a residue was obtained.

  This residue was recrystallized from a mixture of ether-pentane, and 31.85 g (from two connections, 51%) of cis-A-a- (p-methoxyphenyl) -2- (methylamino) -cyclohexanemethanol were obtained. After recrystallization from Skellysolve B, the compound had a melting point of 8S-900C. Ultraviolet: man 225 (11,250); 276 (1,550); 282 (1,350).



   Analysis:
Calculated for ClsH23NO2:
C 72.25; H 9.30; D 5.62.



   Found:
C 72.17; H 9.45; N 5.55.



   Example 2 cis-B -a- (p-methoxyphenyl) -2- (methylamino) cyclohexanemethanol
To 80 ml of trifluoroacetic acid at a temperature of 0-100 ° C., 10 g of cis-Aa- (p-methoxyphenyl) -2- (methylamino) -cyclohexanemethanol were added and the resulting mixture at 10-250 ° C. for 45 minutes touched. The reaction mixture was cooled in an ice bath and 60 g of ice, 200 ml of water and 200 ml of 20% aqueous sodium hydroxide were added. The mixture was stirred for 45 minutes and then extracted with methylene chloride. The methylene chloride extracts were washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. Then the dried solution was evaporated and 9.45 g of a rubbery precipitate was obtained.

  Four components of this gummy precipitate were found by gas chromatography. 77.3% represented the desired B-isomer, 14.2% was the A-isomer, and 8.5% was foreign matter. The rubbery body was dissolved in 100 ml of pentane and inoculated with a sample of the desired product from a previous experiment (the salt crystals were obtained by dipping a sample of the rubbery substance from a previous experiment into the oxalate of cis-Ba- (p-methoxyphenyl ) -2- (methylamino) cyclohexanemethanol, which after recrystallization from methanol ether had a melting point of 227-228 C and then converted the salt into the free base by adding aqueous sodium hydroxide).

  After inoculation, 7.16 g (71.6%) of the crude cis-B-a- (p-methoxyphenyl) -2- (methylamino) cyclohexanemethanol were obtained in two batches. The pure product, recrystallized from ether-Skellysolve B (hexane), had a melting point of 92-93 C. Ultraviolet: max. 225 (11,200); 275 (1,550); 282 (1,300).

 

   Analysis:
Calculated for C15H23N02:
C 72.25; H 9.30; N 5.62.



   Found:
C 72.61; H 9.45; N 5.89.



   Example 3 cis-A-a- (p-Methoxyphenyl) -2- (benzylamino) -cyclohexanemethanol and its hydrochloride
A solution of 23.0 g (0.099 mol) of 2- (p-methoxybenzoyl) cyclohexanone and 11.0 g (0.103 mol) of benzylamine in 150 ml of benzene was heated under reflux for 1.5 hours. The water of reaction, 2.2 ml, was collected. The reaction mixture was concentrated in vacuo to give a residue which was taken up in 150 ml of ethanol. This solution was hydrogenated in the presence of 1.5 g of platinum oxide catalyst for 18 hours. The reaction mixture was then filtered, the filtrate was concentrated in vacuo and the residue was taken up in 200 ml of 10% strength aqueous acetic acid and 300 ml of ether.

  The mixture was stirred for 1.5 hours, the acidic layer was separated, made alkaline with 20% aqueous sodium hydroxide solution, and an oily matter was obtained, which separated. This oil was extracted with methylene chloride, the methylene chloride extracts were washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After the reaction mixture had evaporated, 22.8 g of an oil remained which, when combined with hydrogen chloride in ether, gave a hydrochloride.



  This was recrystallized from ethanol-ether, and 18.35 g of cis-Aa- (p-methoxyphenyl) -2- (benzylamino) cyclohexanemethanol hydrochloride with a melting point of 210.5-211 C were obtained after additional recrystallization from methanol Ether. A sample of this hydrochloride was treated with aqueous sodium hydroxide solution, and cis-A-ss- (p-methoxyphenyl) -2- (benzylamino) cyclohexanemethanol was obtained as the free base with a melting point of 86-87 C.



   Analysis of the C21H27NO2 - HC1:
C 69.69; H 7.80; N, 3.87; C1 9.80.



   Found:
C 68.18; H 7.86; N, 3.87; C1 9.80.



   Example 4 cis-a- (3,4,5-trimethoxyphenyl) -2- (benzylamino) cyclohexanemethanol and its hydrochloride
A mixture of 83 g (0.287 mol) of 2- (3,4,5-trimethoxybenzoyl) cyclohexanone and 31 g (0.29 mol) of benzylamine in 500 ml of benzene was refluxed for 1.5 hours. A total of 7.5 ml of water was collected in a special device. The reaction mixture was then concentrated in vacuo and a residue was obtained which was dissolved in 500 ml of ethanol and hydrogenated in the presence of 3.0 g of a platinum oxide catalyst at a hydrogen pressure of 1.05 to 2.1 kg / cm 2 for 20 hours.

  The reaction mixture was then filtered to remove the catalyst, and 3.0 g of a 10% palladium catalyst on charcoal was added to the filtrate and hydrogenated for a further 24 hours at a pressure of 1.4 to 2, 1 kg / cm2. The reaction mixture was filtered, concentrated in vacuo and the residue obtained was taken up in 750 ml of ether and 600 ml of 10% aqueous hydrochloric acid. The mixture was then stirred for one hour, after which the acidic layer was separated. The acidic layer was filtered and made alkaline with 20% aqueous sodium hydroxide solution to give an oil which separated from the mixture. The oil was extracted with methylene chloride, washed with water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate.

  The dried solution was evaporated, and a rubbery substance was obtained which, with ethereal hydrogen chloride, formed a white solid hydrochloride. This acid addition salt was recrystallized from methanol-ether and yielded 63 g of impure cis-α- (3,4,5-trimethoxyphenyl) 2- (benzylamino) -cyclohexane-methanol hydrochloride with a melting point of 192-1950 ° C. (sintering occurs first one). After further recrystallization of a sample of 20 g from methanol-ether, the melting point rose to 197-1990 C (sintering occurs first).



   The latter compound was treated with aqueous sodium hydroxide to provide the free base, which was extracted with methylene chloride.



  After evaporation of the extract, 13.75 g of a rubbery substance were obtained. An oxalate of this material was prepared and recrystallized from isopropanol.



  12.3 g with a melting point of 208 to 2090 ° C. were obtained. The oxalate (12 g) was treated with aqueous sodium hydroxide solution, and 9.92 g of a rubber-like material were obtained, which partially solidified on standing. Crystallization from Skellysolve B gave 3.1 g of cis-a- (3,4,5-trimethoxyphenyl) -2- (benzylamino) cyclohexanemethanol with a melting point of 113-1150 ° C. and a second portion of 1.33 g of the same substance. Recrystallization of this compound gave the pure cis-a- (3,4,5-trimethoxyphenyl) -2- (benzylamino) - cyclohexanemethanol with a melting point of 114-1150 C.



   Analysis:
Calculated for C2H11NO4:
C 71.66; H 8.11; N 3.63.



   Found:
C 71.60; H 8.19; N 3.95.



   Ultraviolet: m 235 (7270); 258 (667); 267 (810);
279 (459).



   Example 5 cis-a- (p-Methoxyphenyl) -2- (2-hydroxyethylamino) cyclohexanemethanol
A solution of 23.0 g (0.1 mol) of 2- (p-methoxybenzoyl) cyclohexanone and 6.37 g (0.105 mol) of 2 aminoethanol in 150 ml of benzene was heated under reflux for 2.25 hours, and in a Separator (Dean-Stark) was collected 1.8 ml of water. The reaction mixture was then concentrated in vacuo and a yellow, gummy substance was obtained, which was dissolved in 200 ml of ethanol.



  It was hydrogenated for 20 hours in the presence of 1.5 g of a platinum oxide catalyst. The catalyst was then removed by filtration, the filtrate was concentrated in vacuo, the residue obtained was dissolved in 200 ml of a mixture of 10% strength acetic acid and 300 ml of ether and stirred for 30 minutes. The acidic layer was then separated, made alkaline with 20% sodium hydroxide solution, and the mixture was extracted with methylene chloride. The methylene chloride extracts were combined, washed with water and saturated sodium chloride solution and finally dried over anhydrous magnesium sulfate.

 

  After evaporation of the solution, 25.61 g of a white, solid substance were obtained which, after having been recrystallized a few times from benzene-Skellysolve B, contained cis-a- (p-methoxyphenyl) -2- (2-hydroxyethylamino) cyclohexanemethanol a melting point of 111 to 1120 C (solidification of the remelted compound at about 119-121 C).



   Analysis:
Calculated for C16H21NOa:
C 68.78; H 9.02; N 5.01.



   Found:
C 68.47; H 8.73; N 5.24.



   Ultraviolet: imax 226 (11,900); weak shoulder
268 (1200); 275 (1600); 282 (1300).



   Example 6 a- (3, 4,5-Trimethoxyphenyl) -2- (butylamino) -cyclopentanemethanol
In the same manner as in Example 5, 2- (3, 4,5-trimethoxybenzoyl) -cyclopentanone was refluxed with butylamine in benzene; the product obtained was hydrogenated with a platinum oxide catalyst to give α- (3,4,5-trimethoxyphenyl) -2- (butylamino) cyclopentanemethanol.



   Example 7 a- (3,4,5-Trimethoxyphenyl) -2- (hexylamino) -cycloheptane-methanol
In the same manner as in Example 5, 2- (3, 4,5-trimethoxybenzoyl) cycloheptanone was refluxed with hexylamine in benzene; the obtained product was hydrogenated in the presence of a platinum oxide catalyst to give α- (3,4,5-trimethoxyphenyl) 2- (hexylamino) cycloheptanemethanol.



   Example 8 a- (p-Methoxyphenyl) -2- (6-hydroxyhexylamino) cyclopentanemethanol
In the same manner as in Example 5, 2- (p-methoxybenzoyl) cyclopentanone was refluxed with 6-aminohexanol in benzene, and the product obtained was hydrogenated in the presence of a platinum oxide catalyst. A- (p-Methoxyphenyl) 2- (6-hydroxyhexylamino) -cyclopentanemethanol was obtained.



   Example 9 a- (p-Ethoxyphenyl) -2- (ethylamino) -cyclohexane-methanol
As in Example 1, 2- (p-ethoxybenzoyl) cyclohexanone was allowed to react with N-sithylbenzylamine in benzene under reflux. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then subsequently in the presence of a palladium catalyst with a carbon support, and a- (p-ethoxyphenyl) -2- (äthylamino) -cyclohexane-methanol was obtained.



   Example 10 a- (o-Methoxyphenyl) -2- (3-methoxypropylamino) cyclohexanemethanol
As in Example 5, 2- (o methoxybenzoyl) -cyclohexanone was reacted with 3-methoxypropylamine in benzene under reflux. The product obtained was hydrogenated in the presence of a platinum oxide catalyst, and a- (o-methoxyphenyl) -2 (3-methoxypropylamino) cyclohexanemethanol was obtained.



   Example 11 a- (2-Methoxy-4-methylphenyl) -2-anilinocyclohexanemethanol
In the same way as in Example 1, 2- (2-methoxy-4-methylbenzoyl) -cyclohexanone was allowed to react with N-benzylaniline in benzene under reflux. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium catalyst supported on a carbon support, to give α- (2-methoxy-4-methylphenyl) -2-anilinocyclohexanemethanol.



   Example 12 a- (3, 5-Dimethyl-4-methoxyphenyl) -2- (propylamino) -cyclohexanemethanol
As in Example 1, 2- (3,5-dimethyl4-methoxybenzoyl) -cyclohexanone was refluxed with N-propylbenzylamine in benzene. The reaction product was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium catalyst which was on a carbon support, and a- (3,5-dimethyl-4-methoxyphenyl) -2- (propylamino) -cyclohexanemethanol was obtained.



   Example 13 a- (p-Trifluoromethylphenyl) -2- (pentylamino) -cyclohexanemethanol
As in Example 5, 2- (p-trifluoromethylbenzoyl) -cyclohexanone was allowed to react with pentylamine in benzene under reflux. The reaction product obtained was hydrogenated in the presence of a platinum oxide catalyst to give α- (p-trifluoromethylphenyl) -2 (pentylamino) cyclohexanemethanol.



   Example 14 a- (p-Chlorophenyl) -2- (isopropylamino) -cyclohexanemethanol
In the same way as in Example 1, one set
2- (p-Chlorobenzoyl) cyclohexanone with N-isopropylbenzylamine in benzene. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give a- (p-chlorophenyl) -2- (isopropylamino) cyclohexane methanol.



   Example 15 a- (o-Methylphenyl) -2-aminocyclohexanemethanol
As in Example 1, 2- (o-methylbenzoyl) cyclohexanone was reacted with benzylamine in benzene under reflux. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give α- (o-methylphenyl) -2-aminocyclohexanemethanol.



   Example 16 a- (p-Methylphenyl) -2- (ethylamino) -cyclohexane-methanol
In the same manner as in Example 1, reflux was carried out
2- (p-Methylbenzoyl) -cyclohexanone with N-ethylbenzylamine in benzene. The product obtained was then hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give α- (p-methylphenyl) -2- (ethylamino) cyclohexane methanol.



   Example 17 a- (2,4-Dimethylphenyl) -2- (p-toluidino) -cyclohexanemethanol
In the same way as in Example 5, reflux was carried out
2- (2,4-Dimethylbenzoyl) cyclohexanone with p-toluidine in benzene. The product obtained was hydrogenated in the presence of a platinum oxide catalyst to give a- (2,4-dimethylphenyl) -2- (p-toluidino) cyclohexanemethanol.



   Example 18 a- (2-Methoxy-4-methylphenyl) -2- (2-ethoxyethyl-amino) -cyclohexanemethanol
In the same way as in Example 5, one brought
2- (2-Methoxy-4-methylbenzoyl) -cyclohexanone under reflux with 2-ethoxyethylamine in benzene in reaction. The reaction product obtained was hydrogenated in the presence of a platinum oxide catalyst to give a- (2-methoxy-4-methylphenyl) -2- (2-ethoxy-ethylamino) -cyclohexanemethanol.



   Example 19 a- (p-Ethoxyphenyl) -2- (methylamino) -cyclooctanemethanol
In the same way as in Example 1, 2- (p-ethoxybenzoyl) -cyclooctanone was reacted under reflux with N-methylbenzylamine in benzene.



  The reaction product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give α- (p-athoxyphenyl) -2- (methylamino) -cyclooctanemethanol.



   Example 20 a- (2,3,4-Trimethoxyphenyl) -2- (4-hydroxybutyl-amino) -cyclooctanemethanol
In the same manner as in Example 5, a- (2,3,4-trimethoxybenzoyl) cyclooctanone was reacted with 4-hydroxybutylamine in benzene under reflux, and the product obtained was converted into a- (2 , 3, 4-trimethoxyphenyl) -2- (4-hydroxy-butylamino) -cyclooctanemethanol hydrogenated.



   Example 21 a- (p-Bromophenyl) -2- (isobutylamino) -cyclooctanemethanol
In the same way as in Example 5, one set
2- (p-bromobenzoyl) -cyclooctanone with isobutylamine in benzene, and the product obtained was hydrogenated in the presence of a platinum oxide catalyst to give a- (p-bromophenyl) -2- (isobutylamino) -cyclo octanemethanol.



   Example 22 a- (m-Methylphenyl) -2- (o-toluidino) -cyclooctane-methanol
In the manner indicated in Example 5 one continued
2- (m-Methylbenzoyl) -cyclooctanone with o-toluidine in benzene. The product obtained was hydrogenated to a- (methylphenyl) -2- (o-toluidino) cyclooctane methanol in the presence of a platinum oxide catalyst.



   Example 23 a- (p-Fluorophenyl) -2-aminocyclohexanemethanol
In the same way as in Example 1 was
2- (p-Fluorobenzoyl) -cyclohexanone refluxed with benzylamine in benzene. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium catalyst which was on a carbon support to give a- (p-fluorophenyl) -2-aminocyclohexanemethanol.



   Example 24 a- (2,5-Diiodophenyl) -2- (methylamino) -cycloheptane methanol
In the same way as in Example 1 was
2- (2,5-Diiodobenzoyl) cycloheptanone reacted with N-methylamine in benzene under reflux. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium catalyst which was on a carbon support, and a- (2,5-diiodophenyl) -2- (methylamino) -cycloheptane-methanol was obtained.



   Example 25 a- (p-Bromophenyl) -2- (ethylamino) -cyclopentane-methanol
In the same way as in Example 1, one brought
2- (p-Bromobenzoyl) -cyclopentanone in reaction with N-ethylbenzylamine in benzene. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium catalyst which was on a carbon support, and a- (p-bromophenyl) -2- (ethylamino) cyclopentane methanol was obtained.



   Example 26 a- (p-Hexylphenyl) -2- (4-ethoxybutylamino) -cyclopentane methanol
In the same way as in Example 5, one brought
2- (p-Hexylbenzoyl) -cyclopentanone under reflux with 4-ethoxybutylamine in benzene in reaction. The product obtained was hydrogenated in the presence of a platinum oxide catalyst and obtained a- (p-hexylphenyl) -2- (4-ethoxybutylamino) -cydo pentanemethanol.



   Example 27 a- (3,4-Dipropylphenyl) -2- (3-hydroxypropyl-amino) -cycloheptanemethanol
In the same way as in Example 5, it was left
React 2- (3,4-Dipropylbenzoyl) -cycloheptanone with 3-hydroxypropylamine in benzene under reflux. The product obtained was hydrogenated in the presence of a platinum oxide catalyst, and a- (3,4-Dipropylphenyl) -2- (3-hydroxypropylamino) cycloheptane methanol was obtained.

 

   Example 28 a- (2,4-Diiodophenyl) -2- (ethylamino) -cycloheptanmethanol
In the same way as in Example 1, one brought
2- (2,4-Diiodobenzoyl) cycloheptanone reacts with N-ethylbenzylamine in benzene under reflux. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium catalyst which was on a carbon support, and a- (2,4-diiodophenyl) -2- (ethylamino) cycloheptane methanol was obtained.



   In the manner indicated in Examples 1 and 5, other 1,3-amino alcohols of the formula (III) are obtained by reacting 1,3-diketo compound (I) with a primary or secondary amine (V) and hydrogen. Representatives of the 1,3-amino alcohols obtained in this way are the following: a- (p-Butoxyphenyl) -2- (methylamino) -cyclopentane methanol, a- (p-Isopropylphenyl) -2- (ethylamino) -cyclopentane methanol, a- (m-Trifluoromethylphenyl) -2- (butylamino) -cyclopentanemethanol, a- (2,4-Diiodophenyl) -2- (3-ethoxypropylamino) -cyclo- pentanemethanol, a- (p-Fluorophenyl) -2- (m-toluidino) -cyclopentane methanol, a- (p-isopropoxyphenyl) -2-anilinocyclohexane-methanol, a- (p-pentylphenyl) -2- (hexylamino) -cyclohexane methanol,

   a- (o-Bromophenyl) -2- (5-hydroxypentylamino) -cyclohexanemethanol, a- (2,3 -Diethylphenyl) -2- (2methoxyäthylamino) - cyclohexanemethanol, a- (2,4-diethoxyphenyl) -2-aminocyclohexane methanol, u- (3,4,5 -Triäthoxyphenyl) -2- (äthylaminio) -cyclo- heptanmethanol, a- (2-chlorophenyl) -2- (o-toluidino) -cycloheptanmethanol, a- (2,4- Dichlorophenyl) -2- (4-ethoxybutylamino) - cycloheptanmethanol, a- (p-trifluoromethylphenyl) -2- (propylamino) cycloheptanemethanol, a- (p-iodophenyl) -2- (diethylamino) -cycloheptane methanol, a- (2, 4-diethoxyphenyl) -2- (isobutylamino) -cyclo octane methanol, a- (o-fluorophenyl) -2- (hexylamino) -cydooctane methanol, a- (p-methoxyphenyl) -2-aminocyclooctane methanol,

   a- (p-Butoxyphenyl) -2-anilinocyclooctane methanol, α- (3,5-dipropylphenyl) -2- (4-hydroxybutylamino) cyclooctane methanol, and the like.



   Example 29 cis-A- <i- (p-Methoxyphenyl) -2-aminocyclohexane-methanol and its hydrochloride
1. A suspension of 8.0 g (0.0221 mol) of cis-Aa- (p-methoxyphenyl) -2- (benzylamino) -cyclo hexanemethanol hydrochloride in 150 ml of ethanol was in the presence of 1 g of a 10% Palladium-carbon catalyst hydrogenated for 25 hours at a hydrogen pressure of 1.96-3.64 kg / cm2. The mixture was then filtered to remove the catalyst, the filtrate was evaporated in vacuo and the residue was recrystallized from isopropanol-ether. 4.32 g (72%) of cis-A-a- (p-methoxyphenyl) -2-aminocyclohexane methanol hydrochloride with a melting point of 202-203 ° C. were obtained.



   The hydrochloride was treated with aqueous sodium hydroxide and the mixture extracted with methylene chloride. The methylene chloride extracts were washed with aqueous sodium chloride and then evaporated to obtain the free base of cis-A-a- (p-methoxyphenyl) -2-aminocyclohexane methanol with a melting point of 86-870 ° C.



   In the same way, a suspension of 20 g of the free base cis-Aa- (p-methoxyphenyl) -2- (benzylamino) -cyclohexanemethanol was hydrogenated in 1 l of ethanol in the presence of 3 g of a 10% palladium-carbon catalyst for 32 hours long at a hydrogen pressure of 1.75-2.1 kg / cm at room temperature. The reaction mixture was then filtered and the filtrate evaporated in vacuo to give a residue which was taken up in ether. The ether extract was evaporated, and the residue obtained was recrystallized from Skellysolve B several times to obtain cis-A-a- (p-methoxyphenyl) -2-aminocyclohexane methanol with a melting point of 86-88 C.



   Analysis:
Calculated for C14H21NG2:
C 71.45; H 9.00; N 5.95.



   Found:
C 71.10; H 9.00; N 5.88.



   The preparation of cis-A-a- (p-methoxyphenyl) -2-aminocyclohexane methanol can also be carried out without isolation of the benzylamino derivative in the following way:
2. 23 g of 2- (p-methoxybenzoyl) -cyclohexanone were allowed to react with 11 g of benzylamine in 150 ml of benzene, and the reaction was then carried out in the presence of a platinum oxide catalyst in ethanol (150 ml).



  The mixture was then filtered and 2 g of a 1% palladium-carbon catalyst were added to the filtrate, and the mixture was hydrogenated for 24 hours at a hydrogen pressure of 2.45-3.5 kg / cm 2. The mixture was then filtered again, the filtrate was evaporated in vacuo and the residue was taken up in 200 ml of 10% strength acetic acid and 250 ml of ether.



  The acetic acid layer was separated off and combined with 50 ml of a water extract of the ether layer. The combined acetic acid layer and the water extract were made alkaline with 20% aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extracts were washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. A residue was obtained which was recrystallized from Skellysolve B ether; 15.8 (67%) cis-A-a- (p-methoxyphenyl) -2-aminocyclohexane methanol with a melting point of 85-870 C.



   Example 30 cis-B-a- (p-Methoxyphenyl) -2-aminocyclohexane methanol and the oxalate
20 ml of trifluoroacetic acid were cooled to 0-5 ° C. 2.35 g (0.01 mol) of cis-A-a- (p-methoxyphenyl) -2-aminocyclohexane-methanol were added all at once. The ice bath used for cooling was removed and the greenish solution was stirred for 40 minutes. The reaction mixture was then cooled in an ice bath; 20 g of ice, 50 ml of water and 50 ml of a 20% aqueous sodium hydroxide solution were added and the mixture was stirred for 45 minutes. The mixture was then extracted with methylene chloride, the extract was washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The dried solution was evaporated to give 2.45 g of a rubber-like material.

  It was shown by gas chromatography that this material contained six components of 1.25-42.77%.



   The rubber-like material was reacted with oxalic acid in ether, the ether was evaporated and the salt was suspended in 200 ml of methyl ethyl ketone. The methyl ethyl ketone suspension was heated on a steam bath for 5 minutes and filtered. 1.5 g of a white, solid substance were obtained, which was recrystallized from methanol-ether. 1.424 g (44%) of cis-B-a- (p-methoxyphenyl) -2-aminocyclohexane-methanol-oxalate with a melting point of 178-179 ° C. were obtained.



   The oxalate (1.3 g) was converted to the free base by dissolving the salt in methanol and adding an excess of sodium methoxide in methanol. The mixture was diluted with water and extracted several times with methylene chloride. The methylene chloride extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. 1.03 g of an oil were obtained which, after trituration with pentane, gave a solid. Recrystallization of this substance from Skellysolve B gave 0.43 g of cls-B -a- (p-methoxyphenyl) -2-aminocyclohexane-methanol with a melting point of 86-87 C.



   Analysis:
Calculated for C14H21N02:
C 71.45; H 9.00; N 5.95.



   Found:
C 71.90; H 8.93 N 5.89.



   Ultraviolet: imwl, x 225 (11,600); 274 (1150); 281 (13001).



   Example 31 cis-A-a- (o-Methoxyphenyl) -2-aminocyclohexanemethanol
A mixture of 23 g (0.099 mol) of 2- (o-methoxybenzoyl) cyclohexanone and 11 g (0.103 mol) of benzylamine in 150 ml of benzene was refluxed for 1.5 hours. A water separator (Dean-Stark) was used. A total of 1.5 ml of water was separated. The mixture was then evaporated in vacuo and the residue obtained was dissolved in 150 ml of ethanol. It was hydrogenated in the presence of 1.5 g of a platinum oxide catalyst for 24 hours at a hydrogen pressure of 1.4-3.5 kg / 'cm2. During this time, approximately 1.6 molar equivalents of hydrogen were absorbed. The reaction mixture was then filtered to remove the catalyst.

  1.5 g of a 10% palladium-carbon catalyst were added to the filtrate and the mixture was hydrogenated for 24 hours at a hydrogen pressure of 2.8-3.5 kg / cm2. The resulting reaction mixture was then filtered and the filtrate was evaporated. One he thought was an oily substance in a mixture of
400 ml of aqueous 10% acetic acid and 500 ml of ether methylene chloride (1: 1) was added. The
The acetic acid layer was separated and made alkaline with 20% aqueous sodium hydroxide solution. The oil separated and was extracted with methylene chloride. The methylene chloride extracts were washed with water and an aqueous saturated sodium chloride solution and finally dried over anhydrous magnesium sulfate.

  After evaporation of the solution, a solid material was obtained, which was recrystallized several times from Skellysolve B ether. Cis-A-a- (o-methoxyphenyl) -2-aminocyclohexane methanol with a melting point of 122-123 ° C. was obtained.



   Analysis:
Calculated for C14H2lNO2:
C 71.45; H 9.00; N 5.95.



   Found:
C 71.59; H 9.15; N 6.31.



   Ultraviolet: amine 216 (8450); 272 (2150);
278 (2000).



   Example 32 cis-a- (3,4,5-trimethoxyphenyl) -2-aminocyclohexanemethanol hydrochloride
3 g of cis-a- (3,4,5-trimethoxyphenyl) -2- (benzyl amino) -cyclohexanemethanol in 150 ml of ethanol were in the presence of 1 g of a 10% palladium-carbon catalyst for 6.5 hours at a hydrogen pressure of 3.22-3.43 kg / cm2 hydrogenated. The reaction mixture was then filtered, the filtrate was evaporated in vacuo, the residue was dissolved in ether, filtered again and the filtrate was mixed with an ethereal solution of hydrogen chloride. The hydrochloride precipitate was collected on a filter and recrystallized from methanol-ether. 1.47 g of cis-a- (3,4,5-trimethoxyphenyl) -2-aminocyclohexanemethanol hydrochloride with a melting point of 2340 ° C. were obtained.



   Analysis:
Calculated for C16H3jN04'HC1:
C 57.91; H 7.90; N 4.22; C1 10.69.



   Found:
C 58.11; H 8.24; N 4.24; Cl 10.76.

 

   Ultraviolet: amine shoulder 232 (7250); 268 (790);
278 (604).



   Example 33 a- (p-Ethoxyphenyl) -2-aminocyclohexanemethanol
In the same manner as in Example 29 (Part 2), 2- (p-ethoxybenzoyl) cyclohexanone was treated with benzylamine. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst. A- (p-ethoxyphenyl) -2-aminocyclohexane-methanol was obtained.



   Example 34 a- (3,4,5-Trimethoxyphenyl) -2-aminocyclopentane-methanol
In the same manner as in Example 29 (Part 2), 2- (3, 4,5-trimethoxybenzoyl) cyclopentanone was treated with benzylamine. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give α- (3,4,5-trimethoxyphenyl) -2-aminocyclopentane methanol.



   Example 35 a- (3,4,5-Trimethoxyphenyl) -2-aminocycloheptane-methanol
In the same manner as in Example 29 (Part 2) 2- (3, 4,5-trimethoxybenzoyl) -cycloheptanone was treated with benzylamine. The product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give α- (3,4,5-trimethoxyphenyl) -2-aminocycloheptane methanol.



   Example 36 a- (p-Methoxyphenyl) -2-aminocyclopentanemethanol
In the same manner as in Example 29 (Part 2)
Treated 2- (p-methoxybenzoyl) cyclopentanone with benzylamine. The reaction product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give a- (p-methoxyphenyl) -2-aminocyclopentane methanol.



   Example 37 a- (2-Methoxy-4-methylphenyl) -2-aminocyclohexane-methanol
In the same manner as in Example 29 (Part 2)
Treated 2- (2-methoxy-4-methylbenzoyl) -cyclohexanone with benzylamine. The reaction product was hydrogenated to α- (2-methoxy-4-methylphenyl) -2-aminocyclohexane methanol in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst.



   Example 38 a- (3,5-Dimethyl-4-methoxyphenyl) -2-aminocyclohexanemethanol
In the same manner as in Example 29 (Part 2)
2- (3,5-Dimethyl-4-methoxybenzoyl) -cyclohexanone treated with benzylamine. The reaction product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give α- (3,5-dimethyl-4-methoxyphenyl) -2-aminocyclohexanemethanol.



   Example 39 a- (p-Trifluoromethylphenyl) -2-aminocyclohexanemethanol
In the same manner as in Example 29 (Part 2)
2- (p-Trifluoromethylbenzoyl) -cyclohexanone treated with benzylamine. The reaction product was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give α- (p-trifluoromethylphenyl) -2-aminocyclohexane methanol.



   Example 40 a- (p-Chlorophenyl) -2-aminocyclohexanemethanol
In the same manner as in Example 29 (Part 2)
Treated 2- (p-chlorobenzoyl) cyclohexanone with benzylamine. The reaction product was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to obtain a- (p-chlorophenyl) -2-aminocyclohexanemethanol.



   Example 41 a- (p-Ethoxyphenyl) -2-aminocyclooctanemethanol
As in Example 29 (Part 2), 2- (p-Ethoxybenzoyl) -cyclooctanone was treated with benzylamine. The reaction product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give α- (p-9ithoxyphenyl) -2-aminocyclooctanemethanol.



   Example 42 a- (2,3,4-Trimethoxyphenyl) -2-aminocyclooctane-methanol
In the same manner as in Example 29 (Part 2)
Treated 2- (2,3,4-trimethoxybenzoyl) cyclooctanone with benzylamine. The reaction product obtained was hydrogenated first in the presence of a platinum oxide catalyst and then in the presence of a palladium-carbon catalyst to give α- (2,3,4-trimethoxyphenyl) -2-aminocyclooctane methanol.



   In the manner indicated in Example 29 (Part 2), namely the condensation of a diketo compound (I) with benzylamine and the hydrogenation in the presence of a platinum oxide catalyst, followed by hydrogenation with a palladium-carbon catalyst, gives a-phenyl-2-aminocycloalkanemethanols when R3 = R4 = hydrogen.

  Representatives of a-phenyl-2-aminocycloalkanemethanols obtained in this way are: a- (2,4-dimethylphenyl) -2-aminocyclohexanemethanol, a- (p-bromophenyl) -2-aminocyclohexanethanol, a- (p-iodophenyl ) -2-aminocyclohexanemethanol, a- (p-fluorophenyl) -2-aminocyclohexanemethanol, a- (2,5-diiodophenyl) -2-aminocyclohexanemethanol, a- (p-isopropoxyphenyl) -2-aminocyclohexanemethanol, a- (p -Pentylphenyl) -2-aminocyclohexanemethanol, a- (2,4-diethoxyphenyl) -2-aminocyclohexanemethanol, a- (o-bromophenyl) -2-aminocyclohexanemethanol, a- (p-butoxyphenyl) -2-aminocyclopentanemethanol, a- (p -Isopropylphenyl) -2-aminocyclopentanemethanol, a- (m-trifluoromethylphenyl) -2-aminocyclopentanemethanol, a- (2,4-diiodophenyl) -2-aminocyclopentanemethanol, a- (p-fluorophenyl) -2-aminocyclopentanemethanol,

   a- (p-Bromophenyl) -2-aminocyclopentanemethanol, a- (2,5-Diiodophenyl) -2-aminocycloheptamethanol, a- (3,4-Dipropylphenyl) -2aminocycloheptanemethanol, a- (3,4,5-Triethoxyphenyl ) -2-aminocycloheptane methanol, a- (2-chlorophenyl) -2-aminocycloheptane methanol, a- (2,4-dichlorophenyl) aminocycloheptane methanol, a- (p-trifluoromethylphenyl) -2-aminocycloheptane methanol, a- (p-iodophenyl) -2-aminocycloheptanemethanol, a- (m-methylphenyl) -2-aminocyclooctanemethanol, a- (p-ethoxyphenyl) -2-aminocyclooctanemethanol, a- (p-bromophenyl) -2-aminocyclooctanemethanol, a- (2,4-diethoxyphenyl) -2-aminocyclooctanemethanol, a- (o-fluorophenyl) -2-aminocyclooctanemethanol, a- (p-methoxyphenyl) -2-aminocyclooctanemethanol,

   a- (p-Butoxyphenyl) -2-aminocyclooctane methanol, a- (3, 5-dipropylphenyl) -2-aminocyclooctane methanol, and the like
Example 43 cis -2- (a, p-Dimethoxybenzyl) -N-methylcyclohexylamine hydrogen oxalates and methanesulfonates
1. A solution of 5 g (0.02 mol) of cis-A-a- (p-methoxyphenyl) -2-methylamino) -cyclohexanemethanol in 400 ml of methanol, which contained 10 g of hydrogen chloride, was left to stand for 17 hours at room temperature. The reaction mixture was evaporated in vacuo, at a temperature below 450 ° C., to give a residue which was diluted with ice water, made alkaline with 20% aqueous sodium hydroxide solution and then extracted with methylene chloride. The methylene chloride extracts were combined, washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated.

  5 g of an oil were obtained. The oil was chromatographed on 300 g of neutral clay. The column was filled with 1 liter of a mixture of 10% ether-90% Skellysolve B, 1 liter of a mixture of 20% ether-80% Skellysolve B, 1 liter of a mixture of 50% ether-SO% Skellysolve B, 11 ether, 1 1 of a mixture of 5% methanol-95% ether, 1 1 of a mixture of 10% methanol-90% ether and 0.5 1 of methanol eluted. The ether-Skellysolve B fractions contained no product. 2 l of the ether fractions were evaporated, and 1.85 g of an oil were obtained.



  The fraction 5% methanol-95% ether contained 1.8 g of an oil, and the fraction 10% methanol-90% ether contained 0.38 g of an oil. The 1.85 g of the oil obtained from the ether fractions were triturated with Skellysolve B, and a rubbery solid was obtained which was not further characterized. The mother liquors from the trituration and the oil from the ether-methanol fractions were combined, evaporated in vacuo, the residue was dissolved in ether, an oxalate was prepared and ether was recrystallized from methanol. The total amount was 3.68 g (52%) of the compound cis-2- (a, p-dimethoxybenzyl) -N-methylcyclohexylamine hydrogenoxalate, which had a melting point of 223-224 ° C. after additional recrystallization from methanol-ether.



   Analysis:
Ultraviolet: Amax 227 (12350); 275 (1500);
282 (1350).



   Analysis:
Calculated for C16H25NO C2HO4:
C 61.17; H 7.70; N 3.96.



   Found:
C 61.49; H 8.07; N 4.06.



   A sample of the oxalate was converted to the free base with aqueous sodium hydroxide, the free base extracted with ether and treated with methanesulfonic acid. The corresponding methanesulfonate of cis-2- (a, p-dimethoxybenzyl) -N-methylcyclohexylamine with a melting point of 150-155 ° C. was obtained.



   Analysis:
Calculated for Cl6H20NO2 - CH3SO3H:
C 56.81; H 8.13; N 3.90.



   Found:
C 56.47; H 7.93; N 3.98.



   Example 44 cis -2- (a, p-Dimethoxybenzyl) -cyclohexylamine and its maleate
A solution of 1.18 g (0.005 mol) of cis-A- (p-methoxyphenyl) -2-aminocyclohexane methanol in 100 ml of methanol, which contained 25 g of anhydrous hydrogen chloride, was left to stand at room temperature for 20 hours. The mixture was then evaporated in vacuo to give a residue which was diluted with ice water, made alkaline with 20% aqueous sodium hydroxide solution and extracted with methylene chloride. It was washed with water and saturated sodium chloride solution and then concentrated. 1.48 g of a yellowish oil were obtained, which in ether gave the maleate. The white salt was recrystallized from methyl ethyl ketone ether, and 0.585 g of cis-2- (a, p-dimethoxybenzyl) cyclohexylamine maleate were obtained.



  After additional recrystallization from methyl ethyl ketone ether, the compound had a melting point of 142-145 C.

 

   Analysis:
Calculated for Cl5H23N02 - C4H204:
C 62.45; H 7.45; N 3.83.



   Found:
C 62.50; H 7.37; N 3.82.



   A sample of the maleate was treated with aqueous sodium hydroxide and the mixture extracted with ether. The ether fractions were concentrated and a residue was obtained, which was recrystallized a few times from pentane. The free cis-2- (a, p-dimethoxybenzyl) -cyclohexylamine with a melting point of 52-540 ° C. was obtained.



   Example 45 2- (a, 3,4,5-Tetramethoxybenzyl) -N-methylcyclohexylamine and its hydrochloride
A solution of 0.01 mol of α- (3, 4,5-trimethoxyphenyl) -2- (methylamino) -cyclohexanemethanol hydrochloride in 160 ml of water was made alkaline by adding a sufficient amount of a 10% aqueous sodium hydroxide solution . This solution was extracted three times with 100 ml of methylene chloride. The methyl euchloride solution was evaporated, and the free base α- (3, 4,5-trimethoxyphenyl) -2- (methylamino) -cyclohexanemethanol remains in oily form.



   A solution of the free base α- (3, 4,5-trimethoxyphenyl) -2- (methylamino) -cyclohexanemethanol in 25 ml of ether was added to 100 ml of liquid ammonia containing 0.01 mol of sodium amide. While cooling in dry ice acetone, the mixture was stirred for 50 minutes. A solution of 0.01 mol of methyl iodide in 5 mol of ether was added over 5 minutes; the dry ice bath was removed and the mixture was stirred at room temperature for a further 7 hours. It was left to evaporate overnight, approximately 20 hours. 50 ml of water were added to this reaction mixture, and the mixture was extracted with 3 portions of 50 ml each of methylene chloride.



  The combined methylene chloride extracts were washed with water and saturated sodium chloride solution, dried by passage through anhydrous sodium sulfate and evaporated. An oily product was obtained which was dissolved in methylene chloride and then chromatographed on 100 g of Florisil (anhydrous magnesium silicate). The Florisil® column was eluted with 4 portions of 200 ml each of a mixture of 3 S acetone-97% Skellysolve B, and an oil was obtained after evaporation of the solvents. The oil was dissolved in ether and treated with essential hydrogen chloride. The compound 2- (a-3,4,5-tetramethoxybenzyl) -N-methylcyclohexylamine hydrochloride was obtained.



  A portion of this hydrochloride was treated with aqueous sodium hydroxide solution, the reaction mixture was extracted with methylene chloride, the extracts were evaporated and the residue was recrystallized from methanol. 2- (a, 3, 4,5-tetramethoxybenzyl) -N-methylcyclohexylamine was obtained.



   Example 46 2- (a, 3, 4,5-tetramethoxybenzyl) -N-butylcyclopentylamine and its hydrochloride
A solution of a- (3,4,5-trimethoxyphenyl) -2- (butylamino) -cyclopentanemethanol (0.01 mol) in 50 ml of methanol was treated with a solution of 5 g of hydrogen chloride in 50 ml of methanol, and additionally set 100 ml of methanol are added. The solution was left to stand at 250 ° C. for 18 hours and then evaporated to dryness at 450 ° C. in vacuo. 2- (a, 3, 4,5-tetramethoxybenzyl) -N-butylcyclopentylamine hydrochloride was obtained as a residue. This residue was dissolved in 50 ml of water, the solution was made alkaline with aqueous sodium hydroxide solution and extracted with ether.

  The extract was washed with water and then with saturated sodium chloride solution, dried by passing through anhydrous sodium sulfate and evaporated to dryness. 2- (a, 3, 4,5-tetramethoxybenzyl) -N-butylcyclopentylamine was obtained.



   Example 47 2 - (- Ethoxy-3, 4,5-trimethoxybenzyl) -N-hexyl-cycloheptylamine and its hydrochloride
In the same way as in Example 46, a- (3, 4,5-trimethoxyphenyl) -2- (hexylamino) -cyclo- heptanemethanol in ethanol solution containing hydrogen chloride was allowed to react for 20 hours at room temperature, and 2- (α-Ethoxy-3, 4,5-trimethoxybenzyl) -N-hexylcycloheptylamine hydrochloride.



   Treatment of the hydrochloride with aqueous sodium hydroxide solution gave the free base 2- (a-rithoxy-3,4,5-trimethoxybenzyl) -N-hexyl-cycloheptylamine.



   Example 48 2- (a-Propoxy-p-methoxybenzyl) -N- (6-hydroxyhexyl) -cyclopentylamine and its hydrochloride
In the same manner as in Example 46, a- (p-Methoxyphenyl) -2- (6-hydroxyhexylamino) cyclopentanemethanol in propanol containing hydrogen chloride was allowed to react for 20 hours at room temperature, and 2- (a-propoxy- p-methoxybenzyl) -N- (6-hydroxy hexyl) -cyclopentylamine hydrochloride.



   Treatment of this hydrochloride with aqueous potassium hydroxide gave the free base 2- (a-propoxy-p-methoxybenzyl) -N- (6-hydroxyhexyl) -cyclopentylamine.



   Example 49 2- (a-Butoxy-p-trifluoromethylbenzyl) -N -pentylcyclohexylamine and its hydrochloride
In the same manner as in Example 46, a- (p-Trifluoromethylphenyl) -2- (pentylamino) -cyclohexanemethanol in n-butanol containing hydrogen chloride was allowed to react for 20 hours at room temperature, and 2- (a- Butoxy-p-trifluoromethylbenzyl) -N-pentylcyclohexylamine hydrochloride.



   Treatment of this hydrochloride with aqueous sodium hydroxide solution gave the free base 2- (a-butoxy-p-trifluoromethylbenzyl) -N-pentylcyclohexylamine.



   Example 50 2- (a, p-Diethoxybenzyl) -N-methylcyclooctylamine and its hydrochloride
In the same manner as in Example 46, a- (p-Ethoxyphenyl) -2- (methylamino) -cyclooctane-methanol in ethanol containing hydrogen chloride was allowed to react for 20 hours at room temperature. The reaction product was 2- (a, p-diethoxybenzyl) -N-methylcyclooctylamine hydrochloride.



   Treatment of this hydrochloride with dilute aqueous sodium hydroxide solution gave the free base 2- (a, p-diethoxybenzyl) -N-methylcyclooctylamine.



   Example 51 2- (α-Isopropoxy-2,3,4-trimethoxybenzyl) -N- (4 hydroxybutyl) -cyclooctylamine and its hydrochloride
In the same manner as in Example 46, a- (2,3,4-trimethoxyphenyl) -2- (4-hydroxybutyl amino) -cyclooctanemethanol in isopropyl alcohol containing hydrogen chloride reacted to give 2- (a-isopropoxy for 20 hours at room temperature 2,3,4-trimethoxybenzyl) -N- (4-hydroxybutyl) -cyclooctylamine hydrochloride.



   Treatment of this hydrochloride with dilute aqueous sodium hydroxide solution gave the free base 2- (a-isopropoxy-2,3,4-trimethoxybenzyl) -N- (4-hydroxybutyl) cyclooctylamine.



   Example 52 2- (α-Hexyloxy-2,5-diiodobenzyl) -N-methylcycloheptylamine and its hydrochloride
In the same manner as in Example 45, a- (2,5-Diiodophenyl) -2- (methylamino) -cycloheptane-methanol in ether was added to a solution of sodium amide in liquid ammonia at about -700 ° C. Thereupon an ethereal solution of Hexyl iodide was added, and 2- (a-hexyloxy-2,5-diiodobenzyl) -N-methylcycloheptylamine was obtained.



  Treatment of the free base with ethereal hydrogen chloride gave the hydrochloride of 2- (a-hexyloxy-2,5-diiodobenzyl) -N-methylcyclo heptylamine.



   In the same manner as in Example 46, other ethers of formula (IVa) are prepared by adding a lower alkanol, e.g. B. methanol, ethanol, propanol, 2-propanol, butanol or the like, with a 1,3-amino alcohol in the presence of acidic reagents, such as. B. gaseous hydrogen chloride or hydrogen bromide can react.

  Examples of ethers produced in this way are: 2- (a, p-Dimethoxybenzyl) -N- (6-hydroxyhexyl) cyclopentylamine, 2- (a-butoxy-p-bromophenyl) -N-ethylcyclopentylamine,
2- (a-Isobutoxy-p-hexylbenzyl) -N- (4-ethoxybutyl) cyclopentylamine, 2- (a-methoxy-p-butoxybenzyl) -N-methylcyclopentylamine, 2- (a-ethoxy-p-isopropylbenzyl) -N-ethylcyclopentylamine,
2- (a-Ethoxy-m-trifluoromethylbenzyl) -N-butylcyclo pentylamine, 2- (a, 4-dimethoxy-3, 5-dimethylbenzyl) -N-propyl cyclohexylamine,
2- (a-pentyloxy-p-chlorobenzyl) -N-isopropylcyclohexylamine, 2- (a-propoxy-2,5-diiodobenzyl) -N-methylcyclohexylamine, 2- (a-ethoxy-pp entylbenzyl) -N -hexylcyclo- hexylamine,
2- (a-Methoxy-2,3-diethylbenzyl) -N- (2-methoxy

   ethyl) -cyclohexylamine, 2- (a-propoxy-o-bromobenzyl) -N-5-hydroxypentyi) cyclohexylamine, 2- (a-butoxy-2,4-diiodobenzyl) -N-methylcycloheptylamine, 2- (a, 3, 4,5-tetraethoxybenzyl) cycloheptylamine,
2- (a-propoxy-o-chlorobenzyl) -N- (o-tolyl) -cycloheptylamine, 2- (a-methoxy-2,4-dichlorobenzyl) -N- (4-ethoxy-butyl) -cycloheptylamine, 2 - (a-Ethoxy-p-trifluoromethylbenzyl) -N-propyl-cycloheptylamine, 2- (a-Ethoxy-o-chlorobenzyl) -N- (o4olyl) -cycloheptylamine, 2- (a, 2,4-triethoxybenzyl) - N-isobutylcyclooctylamine,
2- (a-Methoxy-o-fluorobenzyl) -N-hexylcyclooctylamine, 2- (a-ethoxy-3, 5-dipropoxybenzyl) -N- (4-hydroxy butyl) -cyclooctylamine,

   
2- (a-Ethoxybenzyl) -N-methylcyclooctylamine, 2- (a-butoxy-p-bromobenzyl) -N-isobutylcyclooctylamine, 2- (a-hexyloxy-p-butoxybenzyl) -N-phenylcyclooctylamine and the like.



   Acid addition salts of compounds (III) and (IVa) are prepared by e.g. the free bases (III) and (IVa) treated with the stoichiometrically calculated amount of the acids, usually in alcoholic or ethereal solution, and then the solution evaporated. In this way pharmaceutically active salts were prepared, such as e.g. B. hydrochlorides, hydrobromides, sulfates, tartrates, lactates, malates, maleates, acetates, citrates, salts of succinic acid, laurates and similar salts of the compounds (III) and (IVa).



   Example 53 cis-a- (3,4,5-Trimethoxyphenyl) -2- (dimethylamino) -cyclohexanemethanol hydrochloride
In the same manner as in Example 4, but replacing the benzylamine with 0.9 mol of dimethylamine, cis-a- (3,4,5-trimethoxyphenyl) -2- (dimethylamino) cyclohexanemethano-hydrochloride was obtained, which after recrystallization from methanol-ether had a melting point of 221-222 C.



   Analysis:
Calculated for C18H29NO4 HC1
C 60.07; H 8.40; C1 9.85; N 3.89.



   Found:
C 59.84 H 8.56; C1 9.82; N 3.80.



   Example 54 cis-a- (p-Methoxyphenyl) -2- (cyclohexylamino) cyclohexanemethanol hydrochloride
In the same way as in Example 3, but replacing benzylamine with cyclohexylamine, cis-a- (p-methoxyphenyl) -2- (cyclohexylamino) -cyclohexanemethanol hydrochloride was obtained, which after recrystallization from ethanol-ether had a melting point of 234-2350 C.

 

   Analysis:
Calculated for C20H31NO2 HC1:
C 67.87; H 9.11; C1 10.02; N 3.96.



   Found:
C 67.57; H 9.28; C1 10.34; N 4.02.



   The same way was done using
Cyclopentylamine, Cycloheptylamine and
Cyclooctylamine instead of the
Cyclohexylamines the corresponding
2- (cyclopentylamino) -,
2- (cycloheptylamino) - and
2- (Cyclooctylamino) compounds produced.



   Example 55 cis-a- (p-Methoxyphenyl) -2-anilinocyclohexanemethanol
As in Example 3, but replacing benzylamine with aniline, cis-a- (p-methoxyphenyl) -2-anilinocyclohexane methanol was obtained.



  After recrystallization from methanol, the compound had a melting point of 107-108.degree.



   Analysis:
Calculated for C20H2sNO2:
C 77.13; H 8.09; N 4.50.



   Found:
C 77.12; H 7.88; N 4.52.



   Example 56 cis-a- (p-Methoxyphenyl) -2- (p-methoxyanilino) cyclohexanemethanol and its hydrochloride
As in Example 3, here the benzylamine was replaced by p-anisidine, cis-a- (p-methoxyphenyl) -2- (p-methoxyanilino) cyclohexanemethanol was obtained.



  After recrystallization from benzene petroleum ether, the compound had a melting point of 125 to 1260 C.



   Analysis:
Calculated for C2lH2lNO3:
C 73.87; H 7.97; N 4.10.



   Found:
C 73.55; H 7.98; N 4.18.



   cis-a- (p-Methoxyphenyl) -2- (p-methoxyanilino) cyclohexanemethanol hydrochloride was prepared by mixing an ethereal solution of the free base prepared above with a solution of hydrogen chloride in ether.



  After recrystallization from methanol, the hydrochloride had a melting point of 184.5-185.5 C.



   Analysis:
Calculated for C21HnN03 - HCl:
C 66.74; H 7.47; Cl 9.38; N 3.70.



   Found:
C 66.57; H 7.57; Cl 9.38; N 3.95.



   PATENT CLAIM I
Process for the preparation of substituted 1,3 amino alcohols of the formula
EMI17.1
 and the corresponding acid addition salts, in which formula n is an integer of 14, the moiety
EMI17.2
 in one of the forms
EMI17.3
 in which forms each alkyl radical has 1-6 carbon atoms, each hydroxyalkyl and alkoxyalkyl radical contains 2-6 carbon atoms, each cycloalkyl radical has 5-8 carbon atoms and the phenyl radical is optionally substituted, R ', R "and R"' Denotes hydrogen, halogen, an alkyl or alkoxy radical each having 1-6 C atoms or the group -CF3, characterized in that

   that you have a diketo compound of the formula
EMI17.4
 with an amine of the formula
EMI17.5
 heated in the presence of an acidic catalyst to form the corresponding unsaturated ketone II of the following formula
EMI17.6
 and the compound II obtained is hydrogenated with at least 2 parts by mole of hydrogen per part by mole of the unsaturated ketone II in the presence of a noble metal catalyst.



   SUBCLAIMS
1. The method according to claim I, characterized in that from
2- (p-methoxybenzoyl) -cyclohexanone and 2-aminoethanol produce the alcohol cis-a- (p-methoxyphenyl) -2- (2-hydroxyethylamino) - cyclohexanemethanol.



   2. The method according to claim I, characterized in that from
2- (p-methoxybenzoyl) -cyclohexanone and benzylamine the alcohol

** WARNING ** End of DESC field could overlap beginning of CLMS **.



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. Example 55 cis-a- (p-Methoxyphenyl) -2-anilinocyclohexanemethanol As in Example 3, but replacing benzylamine with aniline, cis-a- (p-methoxyphenyl) -2-anilinocyclohexane methanol was obtained. After recrystallization from methanol, the compound had a melting point of 107-108.degree. Analysis: Calculated for C20H2sNO2: C 77.13; H 8.09; N 4.50. Found: C 77.12; H 7.88; N 4.52. Example 56 cis-a- (p-Methoxyphenyl) -2- (p-methoxyanilino) cyclohexanemethanol and its hydrochloride As in Example 3, here the benzylamine was replaced by p-anisidine, cis-a- (p-methoxyphenyl) -2- (p-methoxyanilino) cyclohexanemethanol was obtained. After recrystallization from benzene petroleum ether, the compound had a melting point of 125 to 1260 C. Analysis: Calculated for C2lH2lNO3: C 73.87; H 7.97; N 4.10. Found: C 73.55; H 7.98; N 4.18. cis-a- (p-Methoxyphenyl) -2- (p-methoxyanilino) cyclohexanemethanol hydrochloride was prepared by mixing an ethereal solution of the free base prepared above with a solution of hydrogen chloride in ether. After recrystallization from methanol, the hydrochloride had a melting point of 184.5-185.5 C. Analysis: Calculated for C21HnN03 - HCl: C 66.74; H 7.47; Cl 9.38; N 3.70. Found: C 66.57; H 7.57; Cl 9.38; N 3.95. PATENT CLAIM I Process for the preparation of substituted 1,3 amino alcohols of the formula EMI17.1 and the corresponding acid addition salts, in which formula n is an integer of 14, the moiety EMI17.2 in one of the forms EMI17.3 in which forms each alkyl radical has 1-6 carbon atoms, each hydroxyalkyl and alkoxyalkyl radical contains 2-6 carbon atoms, each cycloalkyl radical has 5-8 carbon atoms and the phenyl radical is optionally substituted, R ', R "and R"' Denotes hydrogen, halogen, an alkyl or alkoxy radical each having 1-6 C atoms or the group -CF3, characterized in that that you have a diketo compound of the formula EMI17.4 with an amine of the formula EMI17.5 heated in the presence of an acidic catalyst to form the corresponding unsaturated ketone II of the following formula EMI17.6 and the compound II obtained is hydrogenated with at least 2 parts by mole of hydrogen per part by mole of the unsaturated ketone II in the presence of a noble metal catalyst. SUBCLAIMS 1. The method according to claim I, characterized in that from 2- (p-methoxybenzoyl) -cyclohexanone and 2-aminoethanol produce the alcohol cis-a- (p-methoxyphenyl) -2- (2-hydroxyethylamino) - cyclohexanemethanol. 2. The method according to claim I, characterized in that from 2- (p-methoxybenzoyl) -cyclohexanone and benzylamine the alcohol cis-A-a- (p-methoxyphenyl) -2- (benzylamino) cyclohexanemethanol. 3. The method according to claim I, characterized in that from 2- (3,4,5-trimethoxybenzoyl) -cyclohexanone and benzylamine produces the alcohol cis-a- (3,4,5-trimethoxyphenyl) -2- (benzylamino) -cyclohexanemethanol. 4. The method according to claim I, characterized in that one obtained compounds of formula (III), in which R3 or R4 are benzyl, additionally with one molar part of hydrogen per molar part of the compound of formula (III) to split off the benzyl group and form primary or secondary amines hydrogenated. 5. The method according to claim I, characterized in that the hydrogenation of compounds of the formula (II) in which RQ or R4 are benzyl, with 3 molar parts of hydrogen per molar part of the ketone (II) is carried out in addition to the hydrogenation and reduction To split off the benzyl group reductively from the ketone (II). 6. The method according to dependent claim 4 or dependent claim 5, characterized in that cis-A-a- (p-methoxyphenyl) -2- (methylamino) - cyclohexanemethanol is prepared. 7. The method according to dependent claim 4 or dependent claim 5, characterized in that cis-A-a- (p-methoxyphenyl) -2-aminocyclohexane methanol is prepared. 8. The method according to claim I, characterized in that the compounds of the formula (II) obtained are converted into the corresponding acid addition salts by reaction with organic or inorganic acids. PATENT CLAIM II Use of the compounds obtained by the process according to patent claim I or dependent claim 4 for the preparation of 1 ethers of the formula EMI18.1 and the corresponding acid addition salts, in which formula R ', R ", R"' and n have the meaning given in claim I, R is an alkyl radical having 1-6 carbon atoms and R3 'and R4 are the same as R8 and R4 and can additionally be hydrogen at the same time, characterized in that 1,3-amino alcohols are reacted with an alkanol having 1-6 C atoms in the presence of hydrogen chloride and the ether chloride formed is treated with a base. SUBCLAIMS 9. Use according to claim II, characterized in that cis-Aa- (p-methoxyphenyl) -2- (methylamino) cyclohexanemethanol is reacted with methanol and hydrogen chloride to form cis-2- (a, p-dimethoxybenzyl) -N-methylcyclohexylamine hydrochloride . 10. Use according to claim II, characterized in that cis-A-a- (p-methoxyphenyl) -2-aminocyclo hexanemethanol with methanol and hydrogen chloride 2- (a, p-Dimethoxybenzyl) -cyclohexylamine hydrochloride is reacted and that the free ether is prepared by treatment with a base. 11. Use according to claim II, characterized in that the ethers of the formula (IVa) obtained are converted into the corresponding acid addition salts by reaction with organic or inorganic acids.