CH473084A - Process for the preparation of acid addition salts of substituted phenylbicyclo- (2,2,2) -octanes - Google Patents

Description

  

  



  Process for the preparation of acid addition salts of substituted Phe nylbicyclo- (2,2,2) -octane
The invention relates to a process for the preparation of acid addition salts of new, optionally substituted 1-amino-4-phenylbicyclo (2, 2, 2, 2) octanes, which have valuable properties as antidepressant agents.



   The products prepared according to the invention represent a new class of compounds which is valuable for pharmaceutical applications. In particular, these compounds are antidepressant agents, recognizable by their ability to counteract the sedation induced by tetrabenazine in mice, to intensify the pressure-increasing effect of norepinephrine in ganglion-blocked, anesthetized dogs and to counteract the pressure-increasing effect of phenylethylamine in ganglion-blocked, anesthetized dogs.



   The compounds obtainable according to the invention have the formula
EMI1.1
 wherein R and R1 are hydrogen or alkyl with 1-4 C
Atoms or allyl, where R and R1 under
Formation of (CH2) n-, where n is an integer from 4 to 6, can be linked together, and X and
Y hydrogen, methyl, ethyl, cyano, chlorine, bromine,
Fluorine, trifluoromethyl, nitro, amino, monoalkylamino, in which the alkyl radical has 1-4 C atoms, dialkylamino, in which each alkyl radical has 1-4 C atoms, hydroxy,
Alkoxy with 1-4 carbon atoms, carboxy or alkoxycarbonyl, in which the alkyl radical contains 1-2 carbon atoms, and A- is an anion.



   Representative salts of the formula (1) are the hydrochloride, sulfates, phosphates, acetates, succinates, adipates, propionates, tartrates, citrates and bicarbonates.



   Anions which are derived from hydrochloric acid, acetic acid, phosphoric acid, succinic acids, carbonic acid and citric acid are preferred.



   The connections where
R and R1 are hydrogen, X is hydrogen and Y is hydrogen or fluorine. Besides hydrogen or fluorine, Y is preferably hydroxy, chlorine, trifluoromethyl or alkoxy.



   The free amines used as starting materials for the process according to the invention are generally colorless, low-melting solids which are soluble in organic solvents. They are moderately basic and in this respect comparable to the alkylamines. You can e.g. B. be prepared as follows: 4-phenylbicyclo (2,2, 2) -octane-1-amine can conveniently be prepared by converting 4-hydroxy-1-phenylbicyclo (2, 2, 2, 2) -octane 2-one goes out, the carbonyl group of this compound is removed with hydrazine by the Wolff-Kishner reaction, then the hydroxyl group is replaced by the acetamido group by the Ritter reaction and then the product is subjected to alkaline hydrolysis.



   Starting compounds in which the substituent X is hydrogen and the substituent Y is not hydrogen can be obtained by nitrating the phenyl ring of a 1-acylamido-4-phenylbicyclo- (2, 2, 2) -octane with subsequent mild reduction to the amino compound, diazotization and conversion of the diazonium salt with various appropriately chosen reagents. The phenol can be formed by simply heating the diazonium salt in an aqueous solution. Reaction with a copper (I) halide leads to the halogen compound, and reaction with copper (I) cyanide gives the nitrile. The phenol can be alkylated with dialkyl sulfate and a base or an alkyl halide and a base to form the alkoxy compound. The nitrile can be hydrolyzed to the carboxylic acid, which by one of the usual methods, e.g.

   With an alcohol and hydrogen chloride, can be converted to the ester, or the carboxyl group can be converted to the trifluromethyl group with sulfur tetrafluoride.



   It can be seen that primarily the p-substituted derivative is obtained by the above nitration, but a certain amount of o and m-substituted products is formed. The separation of the respective o-, m- and p-nitro isomers with subsequent reduction and diazonium salt formation leads to the desired substituted phenyl-1-acylamidobicyclooctane.



   If the amino group is not diazotized, but acylated and reduced with lithium aluminum hydride, it is converted to the alkylamino group. The dialkylamino grouping is formed by repeating these measures.



   After the desired conversion has been made, the 1-acylamido group can be converted to the amino group by hydrolysis, or it can be reduced to the 1-alkylamino group with lithium aluminum hydride and then further acylated and reduced to the 1-dialkylamino group.



   The starting compounds for the process according to the invention can also be prepared by converting 4-phenylbicyclo- (2, 2, 2) -oct-2-en-1-carboxylic acid (for the preparation of 4-phenylbicyclo- (2, 2, 2) -oc- tan-l-amine) or of a 4- (substituted phenyl) bicyclo- (2, 2, 2) -oct-2en-1-carboxylic acid (for the production of 4- (substituted phenyl) -bicyclo- (2, 2, 2) -octan-1amine) starts. The preparation of these compounds, which can be used as starting materials for the preparation of compounds according to the invention, is described in British Patent No. 1,066,005.



   The unsaturated acid can - conveniently with hydrogen-platinum - be reduced, the saturated 4-phenyl- or 4- (substituted phenyl) -bicyclo- (2, 2, 2) -octane-1-carboxylic acid being obtained, and this can can be converted into the 4-phenyl- or 4- (substituted phenyl) -bicyclo- (2, 2, 2) -octan-1-amine by the Hofmann, Curtius, or Schmidt reaction. Schmidt's reaction, in which sodium azide and sulfuric acid are used, is particularly useful.



   The N-alkyl and N, N-dialkyl amines can be prepared by acylation and reduction of the N-acyl compound. Although this can be done in other ways, e.g. B. carried out by catalytic hydrogenation, but Li thiumaluminiumhydrid is excellent for this.



  The acylation can be carried out with a wide variety of reagents, e.g. B. with acyl halides, acid anhydrides, carboxylic acid esters and free carboxylic acids (especially when formic acid is used to prepare the formyl compounds).



  A modification of this method, in which a dicarboxylic acid anhydride is used as acylating agent, can be used to prepare the alkylenimine compounds. It is also possible to alkylate the amino compounds directly with alkyl halides and a base or with dialkyl sulfates and a base, but this is less preferred than acylation and reduction.



   According to a further method, the starting compounds can be prepared by ammonolysis or aminolysis of the methanesulfonic acid esters of 4-hydroxy1-phenyl- (and substituted phenyl) -bicyclo- (2,2,2) octanes, which are obtained by the Wolff-Kish- ner Reaction are obtained. By appropriate choice of the amino reagent, the radicals R and R1 can be varied almost at will. When ammonia is used as the reagent, of course, the primary amine is obtained.



   The process according to the invention is characterized in that the free amines are reacted with acids. The salts obtained are usually colorless, high-melting, crystalline materials which are sparingly soluble in water and insoluble in organic solvents.



   Examples of compounds prepared according to the invention include salts of the following compounds: 4-phenylbicyclo- [2.2.2] octane-1-amine N-methyl-4-phenylbicyclo- [2.2.2] octane-1- amine N, N-Dimethyl-4-phenylbicyclo- 2, 2, 2] -octane-1-amine N-ethyl-4-phenylbicyclo- [2,2,2] -octane-1-amine N-ethyl-N- methyl-4-phenylbicyclo- [2,2,2] -octane-1-amine N, N-Diethyl-4-phenylbicyclo- [2,2,2] -octane-1-amine N-propyl-4-phenylbicyclo- [2 , 2,2] -octane-1-amine N-methyl-N-propyl-4-pheny] bicyco- [2, 2, 2] -octane-1-amine N-methyl-N-isopropyl-4-phenylbicyclo- [2, 2, 2] -octan-1-amine N-isopropyl-4-phenylbicyclo- [2,2,2] -octan-1-amine N-ethyl-N-propyl-4-phenylbicyclo- [2, 2, 2] -octane-1amine N-ethyl-N-isopropyl-4-phenylbicyclo- [2, 2, 2] -octane-1amine N, N-dipropyl-4-phenylbicyclo- [2,

        2, 2] -octane-1-amine N, N-diisopropyl-4-phenylbicyclo [2, 2, 2] -octane-1-amine N-butyl-N-methyl-4-phenylbicyclo [2, 2, 2] -octane-1amine N-isobutyl-N-methyl-4-phenylbicyclo- [2, 2, 2] -octane-1amine N-sec-butyl-N-methyl-4-phenylbicyclo- [2, 2, 2] - octanl-amine N-tert-butyl-N-methyl-4-phenylbicyclo- [2,2,2] -octan-1-amine N-isobutyl-4-phenylbicyclo- [2,2,2] -octan-1-amine N-sec-butyl-4-phenylbicyclo [2, 2, 2] -octan-1-amine N-tert-butyl-4-phenylbicyclo [2, 2, 2] -octan-1-amine N- (4 -Phenylbicyclo- [2, 2, 2] octyl-1) -pyrrolidine N- (4-phenylbicyclo- [2, 2, 2] -octyl-1) -piperidine N- (4-phenylbicyclo- [2, 2, 2 ] -octyl-1) -hexamethyleneimine N- (4-p-chlorophenylbicyclo- [2, 2, 2] -octyl-1) -pyrrolidine N- (4-p-methoxyphenylbicyclo- [2, 2, 2] -octyl- 1)

  - pi pendel N- (4-p-trifluoromethylphenylbicyclo [2, 2, 2] -octyl-1) hexamethyleneimine N- (4-m-fluorophenylbicyclo- [2, 2, 2] -octyl-1) -pyrrolidine N- ( 4-o-Bromophenylbicyclo- [2, 2, 2] -octyl-1) -piperidine N- (4-o-aminophenylbicyclo- [2, 2, 2] -octyl-1) -hexamethyleneimine 4-o-tolylbicyclo- [ 2, 2, 2] -octan-1-amine 4-m-Tolylbicyclo- [2, 2, 2] -octan-1-amine 4-p-Tolylbicyclo- [2, 2, 2] -octan-1-amine 4-p-Ethylphenylbicyclo- [2,2,2] -octan-1-amine 4- (2,4-dimethylphenyl) -bicyclo- [2,2,2] -octan-1-amine 4- (3,5 -Dimethylphenyl) -bicyclo- [2,2,2] -octan-1-amine 4- (2,6-dimethylpenyl) -bicyclo- [2,2,2] -octan-1-amine 4- (4-ethyl -2-methylphenyl) -bicyclo- [2, 2, 2] -octane-1amine 4- (2,4-diethylphenyl) -bicydo- [2, 2, 2] -octane-1 -amine 4-p-fluorophenylbicyclo- [2, 2, 2] -octan-1-amine 4-p-chlorophenyibicyclo [2, 2,

   2] -octan-1-amine 4-p-bromophenylbicyclo- [2, 2, 2] -octan-1-amine 4-o-chlorophenylbicyclo- [2, 2, 2] -octan-1-amine 4-o- Bromophenylbicyclo- [2, 2, 2] -octan-1-amine 4-p-Trifluoromethylphenylbicyclo- [2, 2, 2] -octan-1-amine 4-o-trifluoromethylphenylbicyclo- [2, 2, 2] -octane 1-amine 4-p-nitrophenylbicyclo- [2, 2, 2] -octane-1-amine 4-p-aminophenylbicyclo- [2, 2, 2] -octan-1-amine 4-m-aminophenylbicyclo- [2, 2, 2] -octan-1-amine 4-o-aminophenylbicyclo- [2, 2, 2] -octan-1-amine 4- (p-methylaminophenyl) -bicyclo- [2, 2, 2] -octane-1 -amine 4- (o-butylaminophenyl) -bicyclo- [2, 2, 2] -octane-1-amine 4- (p-dimethylaminophenyl) -bicyclo- [2, 2, 2] -octane-1-amine 4- ( m-Di-sec-butylaminophenyl) -bicyclo- [2, 2, 2] -octane l-amine 4-p-Hydroxyphenylbicyclo- [2, 2, 2] -octan-1-amine 4-p-Methoxyphenylbicyclo- [ 2, 2, 2] -octan-1-amine 4-p-Äthoxyphenylbicyclo- [2, 2,

   2] -octan-1-amine 4-p-isobutoxyphenylbicyclo- [2, 2, 2] -octan-1-amine 4-p-carboxyphenylbicyclo- [2, 2, 2] -octan-1-amine 4-o- Carboxyphenylbicyclo- [2, 2, 2] -octan-1-amine 4-p-Ethoxycarbonylphenylbicyclo- [2, 2, 2] -octan-1-amine 4-p-Methoxycarbonylphenylbicyclo- [2, 2, 2] -octan- 1 amine 4- (2,4-difluorophenyl) -bicyclo- [2, 2, 2] -octane-1-amine 4- (2-chloro-4-fluorophenyl) -bicyclo- [2, 2, 2] -octane -1-amine 4- (4-fluoro-2-trifluoromethylphenyl) -bicyclo- [2, 2, 2] octane-1-amine 4- (2,4-dimethoxyphenyl) -bicyclo- [2, 2, 2] - octan-1-amine 4- (3,4-dimethoxyphenyl) -bicyclo- [2, 2, 2] -octan-1-amine 4- (2,4-dinitrophthenyl) -bicyclo- [2, 2, 2] - octan-1-amine 4- (2,4-dihydroxyphenyl) bicyclo- [2,2,2] -octan-1 -amine
4- (4-Hydroxy-2-methylphenyl) bicyclo- [2,2,2] octane
1-amine
4- (4-carboxy-2-trifluoromethylphenyl) -bicyclo- [2, 2,

   2] octane-1-amine
4-2,3-diaminophenyl) bicyclo- [2,2,2] -octane-1-amine
N-methyl-4-p-chlorophenylbicyclo- [2,2,2] -octan-1-amine N, N-dimethyl-4-p -chlorophenylbicyclo- [2,2,2] -octan-1-amine
N-methyl-4-p-trifluoromethylphenylbicyclo- [2,2,2] octan-1-amine
N, N-Dimethyl-4-p-trifluoromethylphenylbicyclo- [2, 2, 2] -octane-1-amine N-methyl-4-p-methoxyphenylbicyclo- [2, 2, 2] -octane-1amine N, N- Dimethyl-4-p-methoxyphenylbicyclo- [2, 2, 2] -octane-1-amine N-ethyl-4- (p-ethylamino) phenylbicyclo- [2, 2, 2] -octan1-amine Particularly preferred because of its effectiveness and their combination of desirable properties are the salts, especially hydrochlorides, of the following compounds:

   4-Phenylbicyclo- [2,2,2] -octan-1-amine N-methyl-4-phenylbicyclo- [2,2,2] -octan-1-amine N -ethyl-4-phenylbicyclo- [2,2 , 2] -octan-1-amine 4-p-Methoxyphenylbicyclo- [2, 2, 2] -octan-1-amine 4-p-Trifluoromethylphenylbicyclo- [2, 2, 2] -octan-1-amine 4-p -Fluorophenylbicyclo- [2, 2, 2] -octan-1-amine 4-p-hydroxyphenylbicyclo- [2, 2, 2] -octan-1-amine 4-p-nitrophenylbicyclo- [2, 2, 2] -octane -1-amine 4- (2,4-difluorophenyl) -bicyclo- [2, 2, 2] -octane-1-amine 4- (2,6-difluorophenyl) -bicyclo- [2, 2, 2] -octane -1-amine 4 p-Tolylbicydo- [2,2,2] -octane-1-amm 4- (2,4-dimethylphenyl) -bicyclo-2,2,2] -octane-1-amine
The compounds prepared according to the invention can be administered as antidepressant agents in any desired manner.

   For example, the treatment can be parenteral, i. H. subcutaneously, intravenously, intramuscularly, or intraperitoneally. Oral application can take place as an alternative or at the same time.



   The dosage depends on the age, health and weight of the patient, the nature of any concurrent treatment, the frequency of treatment and the type of effect desired. In general, the daily dose of active ingredient is between about 0.005 and 50 mg / kg of body weight, but lower amounts, e.g. B. 0.01 mg / kg, or higher amounts can be used. Usually, amounts of 0.1-20 mg, preferably 0.1-5 mg / kg / day given all at once or over the day will give the desired results.



   The active ingredient prepared according to the invention can be used in preparations such as tablets, capsules, powders or liquid solutions, suspensions or elixirs for oral administration or in liquid solutions for parenteral use and in certain cases in suspensions for parenteral use (except intravenous). These preparations usually always contain the active ingredient in an amount of at least 0.02% by weight and at most 99% by weight, based on the total weight of the preparation.



   In addition to the active ingredients obtainable according to the invention, the preparations can contain solid or liquid non-toxic pharmaceutical carriers or auxiliaries for the active ingredient.



   In the following preparations and examples, the quantities given relate to weight unless otherwise stated.



   example 1
A mixture of 42.5 g (0.197 mol) of 4-hydroxy-1 phenylbicyclo [2, 2, 2] -octan-2-one (J. Colerge and P.



  Vuillement, Bull. Soc. Chim.France, 1961, 2235), 100 cm3 of absolute ethanol and 50 cms-hydrazine hydrate is heated for 4 hours on the steam bath at the reflux condenser and allowed to cool to room temperature. The crystals which separate out are filtered off, washed twice with 50 cm3 of absolute ethanol each time and dried at 60 ° C. under reduced pressure.



  The hydrazone of 4-hydroxy-1-phenylbicyclo [2,2,2] octan-2-one is obtained in a yield of 32.70 g in the form of light yellow crystals with a melting point of 208.4-211.0.degree.



   23.04 g (0.100 mol) of the hydrazone of 4-hydroxy-1-phenylbicyclo [2, 2, 2] octan-2-one, are placed in a 500 cm3 round bottom flask equipped with a stirrer, condenser, thermometer and heating mantle. 2 cm3 hydrazine hydrate, 250 cm3 diethylene glycol and 20 g potassium hydroxide are added. The mixture is stirred at 140 ° C. for 3 hours. The temperature is then increased to the reflux temperature and the mixture is heated on the reflux condenser for 16 hours with stirring. It is cooled to room temperature and poured into 1500 cm3 of water. The precipitate is filtered off, washed with water and dried at 60 ° C. under reduced pressure.

   The product obtained is 16.1 g of 4-phenylbicy clo- [2, 2, 2] -octan-1-ol as a brown solid.



  This product is suitable for the next stage, but can optionally be recrystallized from water, with a purified product in the form of matt, fine, colorless needles with a melting point
122.8-123.8 C is obtained.



   A mixture of 22.7 cm3 of concentrated sulfuric acid, 11.37 g of 4-phenylbicyclo [2, 2, 2] octan-1-ol and 91 cm3 of acetonitrile is refluxed on the steam bath for 1 hour and then poured into 1000 cm3 of water. The precipitate is filtered off, washed with water and dried under reduced pressure at 60 ° C. The product obtained is 8.63 g of 1-acetamido-4-phenylbicyclo- [2, 2, 2] -octane as a light brown solid. This product is suitable for the next stage, but can optionally be recrystallized from a 1: 1 mixture of absolute ethanol and water, a whitish crystalline solid with a melting point of 231.5-233.0 ° C. being obtained.



   A mixture of 7.63 g of 1-acetamido-4-phenylbicyclo [2, 2, 2] octane, 100 cm3 of diethylene glycol and 25 g of sodium hydroxide is placed in a 250 cm3 round-bottomed flask equipped with a stirrer, thermometer and condenser for 48 hours , heated on the reflux condenser. The mixture is cooled to room temperature, diluted with 300 cm3 of water and distilled with steam until the distillate is clear. The distillate is concentrated with
Hydrochloric acid made strongly acidic. A precipitation of 4-phenyibicyclo [2, 2, 2] -octane-1-amine hydrochloride separates out in the form of shiny flakes. The product is filtered off and dried at 60 ° C. under reduced pressure. The yield is 1.85 g. Another amount of 1.06 g can be recovered from the filtrate.

   For cleaning, the raw material is recrystallized from water, whereby colorless platelets are obtained that melt above 300 ° C.



     Analysis: Calculated for C14H2oC1N: 5.89 / o N
Found: 6.02 O / o N
Example 2
In a 250 cm3 flask equipped with a reflux condenser, drying tube and stirrer, 0.10 mol of 1-acetamido-4-phenylbicyclo- [2, 2, 2] coctane (see Example 1), 100 cm3 of diethylene glycol dimethyl ether and 5, 7 g (0.15 mol) of lithium aluminum hydride were added. The mixture is kept at 60 ° C. for 8 hours and at 120 ° C. for 2 hours. After cooling, the reaction mixture is treated with water to decompose the excess lithium aluminum hydride.

   The insoluble aluminum compounds are dissolved by adding a 20% above solution of sodium potassium tartrate. The skeleton is extracted with ether, the ether extract is dried with anhydrous potassium carbonate and concentrated under reduced pressure. The residue is suspended in 50 cm3 of water and brought to pH 2 with concentrated hydrochloric acid. Any traces of unreacted starting material are removed from the resulting solution by extraction with ether. The raffinate is concentrated under reduced pressure to give solid N-ethyl-4-phenylbicyclo [2,2,2] octan-1-amine hydrochloride.



   Example 3
A 1000 cm3 round bottom flask equipped with a stirrer, additional powder funnel, thermometer, condenser with drying tube and heating jacket is carefully dried by applying a flame while passing a stream of dry nitrogen through the apparatus. After cooling, 250 cm3 of diethylene glycol dimethyl ether and 5.00 g (0.13 mol) of lithium aluminum hydride, the latter in small portions, are added. 39.13 g (0.16 mol) of 1-acetamido-4-phenylbicyclo [2,2,2] octane are then added from the powder introduction funnel over a period of about 30 minutes. The temperature after the addition is about 60 ° C. The mixture is heated to the reflux temperature with stirring and kept at this temperature (160 ° C.) for 2 hours.

   After cooling to 15 C, 15 cm3 of water are carefully added dropwise with stirring and then 25 g of sodium potassium tartrate in 100 cm3 of water, the latter at once. The mixture, which contains some solids, is extracted twice with 250 cm3 ether each time and once with 100 cm3 ether. The ether extracts are combined, washed with 300 cm3 of water and dried over potassium hydroxide granules. The ether is evaporated under reduced pressure, 37 g of crude N-ethyl-4-phenylbicyclo [2,2,2] octane-1-amine being obtained as a brown oil.

   This product is taken up in a boiling solution of 200 cm3 of concentrated hydrochloric acid in 4800 cm3 of water, filtered hot to remove a small amount of brown foam from the solution and allowed to cool to room temperature and crystallize. The crystals are filtered off, washed with water and dried. The yield of N-ethyl-4-phenylbicyclo [2, 2, 2] -octane-1-amine hydrochloride is 15.0 g. This compound is recrystallized from 450 cm3 of butyl alcohol, 10.5 g of pure N-ethyl-4-phenylbicyclo [2, 2, 2] octane-1-amine hydrochloride which does not melt below 300 ° C.



  Analysis: C H N Calculated for C16HNCl: 72.29 9.10 5.27 Found: 72.38 9.26 5.36
Preparation 1
A solution of 0.10 mol of 4-phenylbicyclo [2, 2, 2] octane-1-amine (prepared by neutralizing an aqueous solution of the hydrochloride, subsequent extraction with ether and evaporation of the ether) in 46.3 g (1.0 Mol) 98-1000 / o formic acid becomes 18
Left to stand for hours at room temperature. The mixture is concentrated under reduced pressure, l-formamido-4-phenylbicyclo [2, 2, 2] octane being obtained as the residue.



   The product is made with lithium aluminum hydride too
N-methyl-4-phenylbicyclo [2, 2, 2] octane-1-amine reduced by adding 0.10 mol of this compound to the in
Example 2 is used instead of 1 acetamido-4-phenylbicyclo [2, 2, 2] octane.



   Example 4
A mixture of 7.19 g (0.0358 mol) of 4 phenylbicyclo [2, 2, 2] octan-1-amine and is in a 100 cm3 round-bottomed flask equipped with a thermometer, condenser, drying tube and heating mantle 25 cm3 of butyl formate heated under the reflux condenser (110 ° C.) for 16 hours. The mixture is allowed to cool to room temperature, the crystals which form are filtered off, washed with 10 cm3 of 500% ethanol and dried. The yield of 1-formanido-4-phenylbicyclo [2, 2, 2] octane with a melting point of 172.5-173.5 ° C. is 4.45 g (54 oil).



  Analysis: C H N
Calculated for C13H13NO: 78.56 8.35 6.11
Found: 78.92 8.39 6.02
A 100 cm3 round bottom flask fitted with a thermometer,
The condenser is provided with a drying tube, heating mantle and magnetic stirrer, is dried with a flame while dry nitrogen is passed through and then left to cool. Be in the flask
35 cm3 of anhydrous diethylene glycol dimethyl ether, 1.03 g (0.027 mol) of lithium aluminum hydride and 3.10 g (0.0135 mol) of 1-formamido-4-phenylbicyclo [2, 2, 2] octan were added. The reaction mixture is refluxed for 2 hours with stirring (160.degree. C.) and then cooled to 15.degree.

   The excess lithium aluminum hydride is destroyed by carefully adding water dropwise while cooling and stirring. The mixture is with 50 cm3 10 0 / above
Sodium hydroxide transferred into a separating funnel and extracted three times with 50 cm3 ether each time. The ither extracts are combined, washed with 30 cm3 of water and dried over solid potassium hydroxide. The ether is evaporated under reduced pressure to give a liquid residue which is in a hot
Solution of 10 cm3 concentrated hydrochloric acid is taken up in 115 cm3 boiling water.



   The solution is filtered hot and allowed to cool and
Leave to crystallization. The crystals are filtered off and dried. The yield of pure N-methyl-4phenylbicyclo [2,2,2] octan-1-amine hydrochloride, which does not melt below 300 ° C., is 2.45 g.



  Analysis: C H N Calculated for C16H-¯NC1: 71.55 8.81 5.56 Found: 71.70 9.36 5.58
Example 5
A solution of 1.82 is added to a mixture of 3.56 g (0.015 mol) of 4 phenyibicyclo [2, 2, 2] octane-1-amine hydrochloride, 1.2 g (0.03 mol) of sodium hydroxide and 40 cm3 of water G (0.015 mol) of allyl bromide in 2 cm3 of carbon tetrachloride. The mixture is refluxed overnight with vigorous stirring. The cooled mixture is extracted with 20 cm3 carbon tetrachloride. The extract is dried with anhydrous magnesium sulfate, filtered and concentrated, whereby an oily residue is obtained.

   The pure N-allyl-4-phenylbicyclo- [2,2,2] octane-1-amine, which is obtained from the crude oil by preparative gas chromatography, is dissolved in dry ether.



  The ethereal solution is treated with dry hydrogen chloride gas. The N-allyl-4-phenylbicyclo [2, 2, 2] octane-1-amine hydrochloride is filtered off and dried.



  The melting point is 281-284 OC.



  Analysis: C H N Calculated for C17H24ClN: 73.49 8.71 5.04 Found: 73.20 8.88 5.07
Preparation 2
A solution of 0.10 mol of N-methyl-4-phenylbicyclo- [2, 2, 2] -octan-1-amine in 46.3 g (1.0 mol) of 98-1000% formic acid is used for 18 hours at room temperature left to stand and then concentrated under reduced pressure. The residue consists of N-methyiformamido-4-phenylbicyclo [2, 2, 2] octane.



  This compound is converted to N, N-dimethyl-4-phenylbicyclo with lithium aluminum hydride in the manner described in Example 2 in an amount of 0.10 mol instead of the 1-acetamido-4-phenylbicyclo [2, 2, 2] octane used there [2, 2, 2] octan-1-amine reduced.



   Example 6
10.06 g (0.050 mol) of 4-phenylbicyclo [2, 2, 2] octan-1-amine, 11th grade are placed in a 100 cm3 round kettle, which is equipped with a stirrer, thermometer and condenser and can be heated on the steam bath , 8 g (0.25 mol) 98% formic acid and 19.7 g (0.25 mol) 37% formalin are added. The mixture is heated and stirred overnight on the steam bath and then cooled, transferred with 100 cm3 of water to a 500 cm3 Erlenmeyer flask and made strongly basic with 500 cm3 of sodium hydroxide, the flask being cooled in ice.

   The cold solution is transferred to a separating funnel and extracted once with 100 cm3 ether and twice with 50 cm3 ether each time. The ether extracts are combined, washed with 10 cm3 of water and dried over solid potassium hydroxide.



  The ether is evaporated off under reduced pressure.



  Colorless crystals are obtained as residue. These are taken up in a hot solution of 25 cm3 of concentrated hydrochloric acid in 150 cm3 of water. The solution is filtered hot and left to cool and crystallize. The crystals are filtered off and dried, pure N, N-dimethyl-4-phenyl-bicyclo [2, 2, 2] octane-1-amine hydrochloride with a melting point of 239.0-240.5 ° C. being obtained. This material was analyzed to contain 0.5 moles of water per mole of amine hydrochloride.



  Analysis: CH calculated for CjoHs4NCl. 1/2 HsO 69.91 9.17 Found: 69.98 9.26 Non-aqueous titration: Calculated 275, found 274.



  Water (Karl Fischer): Calculated 3.28, found 3.28.



   Example 7
50.25 g (0.25 mol) of 4 phenyibicyclo [2, 2, 2] octan-1-ol and 300 cm3 of pyridine are placed in a 1000 cm3 round-bottomed flask equipped with a stirrer, thermometer and a dropping funnel with pressure compensation . The mixture is stirred until the solids have dissolved, whereupon 57 g (0.50 mol) of methanesulfonyl chloride are added dropwise over the course of 15 minutes.



  The temperature is kept at 30 ° C. or below by cooling slightly with an ice water bath. The mixture is stirred for 4 hours at room temperature and then cooled and stirred in an ice water bath while 50 cm3 of water are added dropwise at such a rate that the temperature does not rise above 40 ° C. The mixture is then poured into a mixture of 1000 cm of water, 1000 g of ice and 454 g of concentrated hydrochloric acid. The crystals which separate out are filtered off, washed well with water and dried at 60 ° C./100 mm Hg. The yield of 1- (methanesulfonyloxy) -4-phenylbicyclo [2,2,2] octane, melting point 132.0-133.0 ° C., is 47 g.

   A small sample that is recrystallized from absolute ethanol has a melting point of 133.0-134.5 ° C.



  Analysis: C H S Calculated for C15H2003S: 64.26 7.19 11.44 Found: 64.58 7.13 11.43
A mixture of 10.0 g of the product and 37 g of butylamine is shaken in a closed reactor (Hastelloy B) for 6 hours at 200 ° C. and then cooled. Volatile material is evaporated under reduced pressure. The residue is suspended in 70 cm3 of the above sodium hydroxide solution.



  The suspension is extracted once with 75 cm3 and twice with 25 cm3 each of ether. The ether extracts are combined, washed with 25 cm3 of water and dried over solid potassium hydroxide. The ether is evaporated in vacuo to give an oil which is taken up in a boiling solution of 10 cm3 of concentrated hydrochloric acid in 1000 cm3. The boiling mixture is filtered to remove a small amount of insoluble oil and allowed to cool and crystallize. The crystals are filtered off, washed with water and dried at 60 ° C. to 1100 mm Hg, 4.55 g of crude N-butyl-4-phenylbicyclo [2,2,2] octane-1-amine hydrochloride being obtained.

   After two recrystallizations from butyl alcohol, the pure amine hydrochloride melts at 245.5-246.5 "C.



  Analysis: C H N Calculated for Cl8H2ACl: 73.57 9.60 4.77 Found: 73.85 9.56 4.82
Preparation 3
A solution of 0.10 mol of N-methyl-4-phenylbicyclo- [2, 2, 2] -octan-1-amine in 75 cm3 of dry pyridine is mixed with 7.85 g (0.10 mol) of acetyl chloride while stirring, which is added at such a rate that the temperature does not exceed 60 ° C. The mixture is then heated on the reflux condenser for 30 minutes, cooled and poured into 500 cm3 of cold water.



  The resulting precipitate is filtered off, washed well with water and dried to give 1-N-methylacetamido4-phenylbicyclo [2, 2, 2] octane. By using 0.10 mol of this compound instead of 1-acetamido-4-phenylbicyclo [2, 2, 2] -octane in the experiment described in Example 2, N-ethyl-N-methyl-4-phenylbicyclo [2, 2, 2] octan-1-amine obtained.



   Example 8
9.62 g (0.0362 mol) of N-ethyl-4-phenylbicyclo [2,2, 2] octane-1-amine hydrochloride, 17, are placed in a 100 cm3 round bottom flask equipped with a condenser, magnetic stirrer and heating jacket 70 g (0.218 mol) 37% formalin, 10.20 g (0.218 mol) 98% formic acid and 2.72 g (0.040 mol) sodium formate were added. The mixture is refluxed with stirring for 4 hours. Gas is evolved during the heating and the solids dissolve. The mixture is cooled, 4 cm3 of concentrated hydrochloric acid are added and the mixture is evaporated to a paste under reduced pressure. The mass is mixed with a solution of 50 cm3 of 50% sodium hydroxide in
Transfer 100 cm3 of water into a separating funnel and extract with 200 cm3 and then with 100 cm3 of ether.



  A small amount of solid remains. The Sither extracts are combined, washed with 50 cm 3 of 5% sodium hydroxide and dried over solid potassium hydroxide. The ether is evaporated off under reduced pressure, 6.92 g of whitish crystals of crude N-ethyl-N-methyl-4-phenylbicyclo [2, 2, 2] octan-1-amine being obtained. This product is taken up in a boiling solution of 25 cm3 of concentrated hydrochloric acid in 500 cm3 of water, filtered hot and left to cool. The solution is evaporated under reduced pressure.

   The residue is triturated in ether and then filtered and dried, 7.25 g of crude N-ethyl-N-methyl-4-phenylbicyclo [2,2,2] octane-1-amine hydrochloride being obtained as a whitish crystalline solid. Recrystallization from 200 cm3 of benzene gives 3.80 g of this compound in pure form. Melting point 217.5-219.0 "C.



  Analysis: C H N Calculated for C17H2GNC1: 72.96 9.36 5.01 Found: 72.79 9.51 4.89
Non-aqueous titration: Calculated 280, found 282.



   Example 9
A solution of 0.1 mol of 4-phenylbicyclo [2, 2, 2] octan-1-amine in 50 cm3 of benzene is slowly added to a solution of 0.1 mol of succinic anhydride in 100 cm3 of benzene. The mixture is heated under the reflux condenser for one hour and the benzene is distilled off.



  Acetyl chloride is added to the residue in an excess of 0.15 mol and the mixture is refluxed on a steam bath for 1 hour. The excess acetyl chloride is distilled off at normal pressure and the acetic acid, which is formed by dehydration of the succinic acid monoamide initially formed, is removed at 100 ° C./15 mm Hg. The residue consists of almost pure N- (4-phenylbicyclo [2, 2, 2] octyl-1) succinimide. After drying in a vacuum desiccator over granular sodium hydroxide, the crude product is dissolved in dry tetrahydrofuran and slowly added to a suspension of lithium aluminum hydride in diethyl ether, used in excess of 0.15 mol.

   After the addition has taken place, the reaction mixture is heated under the reflux condenser for 2 hours, the solvent is distilled off and the amine is isolated by distillation with steam. The distillate is extracted with ether and the solution is dried with sodium hydroxide. Dry hydrogen chloride is passed into the filtered solution until it is no longer absorbed. The hydrochloride of N- (4-phenyibicyclo [2, 2, 2] octyl-p-pyrrolidine is obtained by evaporating off the ether.



   Example 10
A mixture of 10.0 g of 1 1- (methanesulfonyloxy) -4 phenylbicyclo- [2, 2, 2] octane and 40 cm3 of redistilled pyrrolidine is shaken in a closed reactor (Hastelloy B) for 6 hours at 225 ° C. and then cooled. The mixture is diluted with 200 cm3 of water and 75 cm3 of concentrated hydrochloric acid, transferred to a separatory funnel and extracted twice with 100 cm3 of ether each time. The ether extracts are discarded. The aqueous layer is made strongly basic with 50% sodium hydroxide and extracted twice with 100 cm3 of ether each time. The ether extracts are combined and dried with solid potassium hydroxide.

   The ether is removed by concentration under reduced pressure to give 8.08 g of crude N- (4-phenylbicyclo [2,2,2] octyl-1 -) pyrrolidine as a brown oil. The product is suspended in 25 cm3 of water. The mixture is adjusted to pH 3 with about 4 cm3 of concentrated hydrochloric acid. The clear solution is concentrated at 60 ° C. under reduced pressure to a semicrystalline mass, which is dried at 60 ° C. to 1100 mm Hg. The dried solid is extracted with 400 cm3 of boiling benzene.



  The extract is filtered hot, by boiling on
100 cm3 concentrated and left to cool and crystallize. The crystals are filtered off and dried. The yield is 1.67 g. After recrystallization from 200 cm3 of benzene, 0.81 g of pure N (4-phenylbicyclo [2, 2, 2] octyl-1-) pyrrolidine hydrochloride with a melting point of 220-226 ° C. is obtained.



  Analysis: C H N Calculated for C18H26NCl: 74.07 8.98 4.80 Found: 74.07 9.27 4.96
74.09 9.23
Preparation 4
A mixture of 0.10 mol of 1-acetamido-4-phenylbicyclo [2, 2, 2] octane (see Example 1) and 100 cm3 of concentrated sulfuric acid is cooled to -10 C in a mixture of dry ice and acetone and with 9.0 g (0.10 mol) of concentrated nitric acid (70%) are added, which is added dropwise with stirring.



  The temperature is kept between -10 and -15 ° C. during the addition. The cooling bath is then removed and the mixture is allowed to warm to room temperature with further stirring and is stirred for 30 minutes. It is poured into 1000 cm3 of ice and water. The crystals which separate out are filtered off, washed with water and dried at 60 ° C. under reduced pressure. The product consists of 1 acetarido-4-p-nitrophenylbicyclo [2, 2, 2] octane. It is purified by recrystallization from absolute ethanol (whereby it is separated off from the considerably smaller amounts of m-nitrophenyl and m-nitrophenyl isomers formed during the nitration).



   A mixture of 0.10 mol of 1-acetamido-4-p-nitrophenylbicyclo- [2, 2, 2] octane and 200 cm3 of 20% sulfuric acid is refluxed for 8 hours, cooled, diluted with 100 cm3 of water and with 50 of the above Sodium hydroxide neutralized. The mixture is extracted three times with 75 cm3 of ether each time. The ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-p-nitrophenylbicyclo [2,2,2] octan-1-amine.



   Preparation 5
About 50 cm3 of anhydrous hydrogen fluoride are placed in a vessel made of a material that is resistant to attack by hydrogen fluoride (e.g. platinum, Hastelloy steel or polyethylene) and is cooled with solid carbon dioxide and acetone. 10.50 g (0.0432 mol) of 1 acetamido-4-phenylbicyclo [2,2,2] octane are added to the liquid while stirring.



  Then 2 cm3 (3.00 g, 0.043 mol) of fuming nitric acid (90%) are slowly added. The cooling bath is removed and the solution is allowed to stand for 16 hours. After the hydrogen fluoride has evaporated, the residue is dissolved in dichloromethane and washed with 10% sodium carbonate solution. The dichloromethane solution is dried with anhydrous magnesium sulfate and evaporated. The residue is recrystallized from alcohol, 8.73 g of 1-acetamido-4 (p-nitrophenyl) bicyclo [2,2,2] octane with a melting point of 231-233 ° C. being obtained. The structure is confirmed by infrared spectroscopy and elemental analysis.



  Analysis: C H N Calculated for C18H28NO8: 66.64 6.99 9.72 Found: 66.32 7.12 9.63
The compound is hydrolyzed in the manner described in Preparation 4 or in the manner described in Example 11 to give 4- (p-nitrophenyl) bicyclo [2,2,2] octan-1-amine.



   Example 11
A mixture of 2.88 g (0.010 mol) of 1-acetamido4- (p-nitrophenyl) bicyclo [2, 2, 2] octane is refluxed with 50 cm3 of 48% hydrobromic acid for 24 hours. After the mixture has been cooled, the crystals are filtered off, with 4- (p-nitrophenyl) bicyclo [2,2,2] octane-1-amine hydrobromide being obtained.



  The hydrobromide is converted into the hydrochloride by adding the crystals to a mixture of saturated potassium carbonate solution and ether with stirring. The ether extract is dried with anhydrous potassium carbonate and then treated with anhydrous hydrogen chloride, whereupon 4- (p-nitrophenyl) bi cyclo [2,2,2] octane-1-amine hydrochloride with a melting point of 328-330 ° C. (decomposition) is precipitated .



   Preparation 6
A mixture of 0.10 mol of 4-p-nitrophenylbicyc 10 [2, 2, 2] octan-1-amine, 200 cm3 of absolute ethanol and 20 cm3 of separated W-6 Raney nickel catalyst (J. Am. Chem. Soc. 70, 695 (1948)) is hydrogenated at 3.5 kg / cm2 and 50 C until hydrogen is no longer absorbed. The solution is filtered and the filtrate is concentrated under reduced pressure to give 4-p-aminophenylbicyclo [2,2,2] octan-1-amine.



   Preparation 7
A mixture of 0.10 mol of 1-acetamido-4-p-nitrophenylbicyclo- [2, 2, 2] octane, 200 cm of absolute ethanol and 200 cm3 of settled W-6 Raney nickel catalyst is at 3.5 kg / cm2 and Hydrogenated at 50 C until hydrogen is completely absorbed. The solution is filtered and the filtrate is concentrated under reduced pressure to give 1-acetamido-4-p-aminophenylbicyclo [2,2,2] octane. By refluxing this compound in 10% sodium hydroxide for 8 hours, 4-p-aminophenylbicyclo [2,2,2] octan1-amine, the product of preparation 6, is obtained.



   A solution of 0.10 mol of 1-acetamido-4-p-aminophenylbicyclo- [2, 2, 2] octane in 46.3 g (1.0 mol) of 98-100% formic acid will stand for 18 hours at room temperature calmly. The mixture is concentrated under reduced pressure. The residue consists of 1-acetamido-4-p-formamidophenylbicyclo- [2, 2, 2] -octane.



   This compound is obtained using an amount of 0.10 mol in place of 1-acetamido-4-phenylbicyclo- [2, 2, 2] -octane and doubling the amount of lithium aluminum hydride in the manner described in Example 2 to give N-ethyl 4- (p-Methylaminophenyl) bicyclo- [2, 2, 2] -octane-1-amine reduced.



   Example 12
To a solution of 2.88 g (0.010 mol) of 1-acetamido-4- (p-nitrophenyl) bicyclo-2,2,2] -octane and 2 cm3 hydrazine hydrate in 100 cm3 alcohol is added W6-Raney- Given to nickel until gases begin to evolve. The mixture is heated on the reflux condenser and after 10 minutes a further 2 cm3 of hydrazine hydrate are added. The mixture is heated at the reflux condenser for 30 minutes and left to cool. The catalyst is filtered off and the filtrate is evaporated.



  The residue is recrystallized from toluene, with 2.26 g of 1-acetamido-4- (p-aminophenyl) bicyclo [2.2.2] octane with a melting point of 191.5-192.5 ° C. being obtained.



  Analysis: C H N Calculated for C101122N2O: 74.38 8.58 10.84 Found: 74.47 8.74 10.91
A solution of 2.58 g (0.010 mol) of l-acetamido 4- (p-aminophenyl) bicyclo [2.2.2] octane, 3 g (0.10 mol) of sodium hydroxide and 20 cm3 of methanol is 8 in a closed vessel Maintained at 200 ° C. for hours The product is dissolved in a mixture of 150 cm3 of saturated potassium carbonate solution, 50 cm3 of water and 200 cm3 of acetonitrile. The organic layer is separated, dried with anhydrous potassium carbonate and evaporated. The residue is dissolved in 50 cm3 of ln hydrochloric acid and decomposed with concentrated hydrochloric acid, whereby 4- (p-aminophenyl) bicyclo [2,2,2] octane-1-amine dihydrochloride with a melting point of 420 ° C. (decomp.) Is precipitated.



  Analysis: C H N Calculated for C14H20N2 # -2HCl: 58.13 7.67 9.68 Found: 57.92 7.68 9.74
Preparation 8
To a solution of 0.10 mol of N-ethyl-4- (p-methy laminophenyl) bicyclo [2,2, 2] octan-1-amine in 75 cm3 of dry pyridine, 15.70 g (0.20 mol ) Acetyl chloride added dropwise at such a rate that the temperature does not exceed 60 C. The mixture is then heated on the reflux condenser for 30 minutes, cooled and poured into 500 cm3 of cold water. The precipitate formed is filtered off, washed with water and dried, 1-N-ethylacetamido-4-) p-methylacetamidophenyl) bici clo [2, 2, 2] octane being obtained.

   This compound is converted to N, N-diethyl-4- (p-ethylmethyl) aminophenyl) bicyclo [2,2,2] octane in the manner described in Example 2 using an amount of 0.10 mol and twice the amount of lithium aluminum hydride -lamin reduced.



   Preparation 9
A mixture of 19.6 g (0.20 mol) of sulfuric acid, 100 cm3 of water and 0.10 mol of 1-acetamido-4-p-aminophenylbicyclo [2, 2, 2] octane is added to an ice-water bath with stirring Chilled to 5 C. Then a solution of 10.2 g (0.11 mol) of sodium nitrite in 25 cm3 of water is slowly added with stirring while the temperature is kept at 5 ° C. The mixture is stirred for a further 30 minutes at 5 ° C., heated to 50 ° C. on the steam bath and kept at this temperature for half an hour. It is cooled and extracted three times with 50 cm3 ether each time. The ether extracts are combined, washed with 25 cm3 of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, l-acetamido-4-hydroxyphenylbicyclo [2,2,2] octane being obtained as residue.



   A mixture of 0.10 mol of this compound, 100 cm3 of diethylene glycol and 25 g of sodium hydroxide is heated for 48 hours on the reflux condenser, cooled and diluted with 300 cm3 of water. The mixture is adjusted to 8.5 pa with concentrated hydrochloric acid and then extracted three times with 50 cm3 of ether each time. The ether extracts are combined, washed with 25 cm3 of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, 4-p-Hydroxyphenyibi-cyclo- [2, 2, 2] -octan-1-amine being obtained as residue.



   Example 13
A mixture of 5.20 g (0.020 mol) of l-acetamido 4- (p-aminophenyl) bicyclo- [2, 2, 2] -octane and 100 cm3 of ln-HW, SO4 is brought to 5 "C with an ice-water bath while stirring Then a solution of 1.40 g (0.020 mol) of sodium nitrite in 40 cm3 of water is slowly added with stirring so that the temperature does not exceed 5 "C. After adding 200 cm3 of water, the mixture is heated on the reflux condenser for 30 minutes.



  The precipitate is filtered off and washed with water. The solid is kept in an autoclave for 4 hours at 220 ° C. with 200 cm3 of a 100% sodium hydroxide solution. The product is cooled to room temperature and the precipitate is filtered off and washed with water Hydrochloric acid is added, heated to dissolve and left to cool. The crystals of 4- (p-hydroxyphenyl) bicyclo [2, 2, 2] octane-1-amine hydrochloride are filtered off, washed with water and dried. The product decomposes when it is heated.



  Analysis: C H N Calculated for C14H19NO · HCl: 66.26 7.95 5.52 Found: 66.50 8.03 5.57
Preparation 10
A mixture of 0.10 mol of 1-acetamido-4-p-aminophenylbicyclo- [2, 2, 2] -octane, 100 cm3 and 5.0 g of sodium hydroxide is cooled to 5 ° C. with stirring, while 12.6 g (0.10 mol) dimethyl sulfate are added dropwise. The mixture is stirred for 15 minutes at 5 "C and then heated to 75" C on the steam bath for 1 hour. The mixture is cooled and extracted three times with 50 cm3 of ether each time. The ether extracts are combined, washed with 25 cm3 of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, 1 acetamido-4-p-methoxyphenylbicyclo [2, 2, 2] octane being obtained as residue.



   A mixture of 0.10 mol of this compound, 100 cm3 of diethylene glycol and 25 g of sodium hydroxide is refluxed for 48 hours, then cooled and diluted with 300 cm3 of water. The mixture is extracted three times with 50 cm3 of ether each time. The ether extracts are combined, washed with 25 cm3 of water and dried with anhydrous magnesium sulfate. Concentration under reduced pressure gives 4-p-methoxyphenylbicyclo- [2,2,2] -octan-1-amine as residue.



   Preparation 11
A mixture of 19.6 g (0.20 mol) of sulfuric acid, 100 cm3 of water and 0.10 mol of 1-acetamido-4-p-aminophenylbicyclo- [2, 2, 2] -octane is brought to 5 ° with an ice bath while stirring Then a solution of 10.2 g (0.11 mol) of sodium nitrite in 25 cm3 of water is slowly added with stirring so that the temperature remains at 5 C. This solution becomes a cold solution (5 OC) of freshly made copper (I) chloride in 50 cm3 concentrated hydrochloric acid.



  The mixture is stirred well and allowed to warm to room temperature. After the mixture has stood at room temperature for 15 minutes, it is heated to 60 "C for 30 minutes, then cooled to room temperature and extracted three times with 50 cm3 of ether each time. The ether extracts are combined, washed with 25 cm3 of water, dried with anhydrous magnesium sulfate and dried under concentrated under reduced pressure, 1 -acetamido-4-p-chlorophenylbicyclo- [2, 2, 2] -octane being obtained as residue.



   A mixture of 0.10 mol of this compound, 100 cm3 of diethylene glycol and 25 g of sodium hydroxide is refluxed for 48 hours, then cooled and diluted with 300 cm3 of water. It is extracted three times with 50 com ether each time. The ether extracts are combined, washed with 25 cm 3 of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, 4p-chlorophenylbicyclo- [2,2,2] -octan-1-amine being obtained as residue.



   Example 14
A mixture of 12.9 g (0.050 mol) of l-acetamido 4- (p-aminophenyl) bicyclo [2,2,2] octane and 250 cm3 of concentrated hydrochloric acid is cooled to 0 "C. A solution of 3.5 Sodium nitrite in 20 cm3 of water is added dropwise to the mixture, which is stirred for 20 minutes, and then a solution of 5.0 g of cuprous chloride in 250 cm3 of concentrated hydrochloric acid is quickly dripped into the solution after the mixture has reached room temperature it is kept at 55 "C for 16 hours until no further evolution of nitrogen is detected. The mixture is extracted with chloroform. The extract is washed with water, dried with anhydrous magnesium sulfate and evaporated.

   The residue is recrystallized from acetonitrile, l-acetamido-4- (p-chlorophenyl) bicyclo- [2,2,2] octane having a melting point of 230-233 ° C. being obtained. This compound is hydrolyzed and converted into the hydrochloride in the manner described in Example 11, giving 4- (p-chlorophenyl) bicyclo- [2,2,2,2] -octane-1-amine hydrochloride with a melting point of 324-325 ° C (dec .) is obtained.



   Preparation 12
When using 0.10 mol of freshly prepared copper (I) bromide in a mixture of 45 g of concentrated sulfuric acid and 500 cm3 of water instead of the solution of copper (I) chloride in hydrochloric acid used in preparation 11, I-acetamido-4- Obtained p-bromophenylbicyclo- [2,2,2] -octane, which is hydrolyzed with diethylene glycol and sodium hydroxide in the manner described in preparation 11, whereby 4-p bromophenylbicyclo- [2,2,2] -octan-1-amine obtained becomes.



   Example 15 4- (p-Bromophenyl) bicyclo- [2, 2, 2] -octane-1-amine can be conveniently prepared by direct bromination of 1-acetamido-4-phenylbicyclo- [2, 2, 2] -octane will. 8.0 g (0.050 mol) of bromine are added to a solution of 12.2 g (0.050 mol) of 1-acetamido-4-phenylbicyclo- [2, 2, 2] -octane in 50 cm3 of liquid anhydrous hydrogen fluoride. After adding a small amount of iron powder, the mixture is stirred overnight. The hydrogen fluoride is evaporated and the residue is dissolved in chlorine form. The chloroform solution is washed with 1N hydrochloric acid, dried with anhydrous magnesium sulfate and evaporated.



  The residue is recrystallized from alcohol, 8.73 g of 1-acetamido-4- (p-bromophenyl) bicyclo [2,2,2] octane with a melting point of 242-244 ° C. being obtained.



  Analysis: C H N Calculated for Cl6H20BrNO: 59.63 6.26 4.35 Found: 59.57 6.39 4.36
This compound is hydrolyzed with 48% hydrobromic acid and converted to the hydrochloride in the manner described in Example 11.



  The product obtained is 4- (p-bromophenyl) bicyclo [2,2,2] octane-1-amine hydrochloride with a melting point of 325 ° C. (decomp.).



  Analysis: C H N Calculated for C34HleBrN HCl: 53.10 6.05 4.41 Found: 53.08 6.16 4.4'6
Preparation 13
0.10 mol of 1-acetamido-4-p-aminophenylbicyclo- [2, 2, 2] -octane is diazotized in the manner described in Example 14. The cold diazonium salt is slowly added to a solution, kept at 60 ° C., of 0.20 mol of freshly prepared copper (I) cyanide in a mixture of 20 g of sodium cyanide and 75 cm3 of water in a flask which is provided with devices for distillation with steam . The temperature is held at 60 ° C. for half an hour and then increased to the reflux temperature for 1 hour. The mixture is then distilled with steam. The steam distillate is cooled and extracted three times with 50 cm3 of ether each time.

   The ether extracts are combined, washed with 25 cm3 of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, l-acetamido-4-p-cyanophenylbicyclo- [2, 2, 2, 2] octane being obtained as the residue.



   A mixture of 0.10 mol of this compound, 100 cm3 of diethylene glycol and 25 g of sodium hydroxide is refluxed for 48 hours, then cooled, diluted with 300 cm3 of water and adjusted to pH 8.5 with concentrated hydrochloric acid. The mixture is extracted three times with 50 cm3 of ether each time.



  The ether extracts are combined, washed with 25 cm3 of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, 4-p-carboxyphenyl-bicyclo- [2, 2, 2] -octanl-amine being obtained as residue.



   Preparation 14
A suspension of 9.68 g (0.0375 mol) of l-acetamido- (4-aminophenyl) bicyclo- [2, 2, 2] -octane in 50 cm3 of 6N HCl is cooled to 5 ° C., and with 2 , 58 g (0.0374 mol) of sodium nitrite diazotized. Then the solution is made alkaline with potassium carbonate solution. The mixture is poured into 150 cm3 of cold copper (I) cyanide (gelatinized according to the method described in Organic Syntheses, Collective Volume 1, page 514) with stirring.



  After the mixture has been warmed to room temperature, it is stirred for a further 24 hours. The solid is filtered off, washed with water and dried. The product is recrystallized from xylene, whereby 4.66 g of 1 acetamido-4- (p-cyanophenyl) bicyclo- [2,2,2] -octane with a melting point of 267-269 ° C. are obtained.



  Analysis: C H N Calculated for C17H2oN2O: 76.08 7.51 10.44 Found: 76.24 7.85 11.03
Example 16
Hydrogen chloride gas is passed into a solution of 0.10 mol of 4- (p-carboxyphenyl) -bicyclo- [2, 2, 2] -octane in 100 cm3 of absolute ethanol with cooling until the solution is saturated at room temperature. The mixture is left to stand for 48 hours at room temperature and concentrated under reduced pressure, 4-p-Athoxyzarboxylphenylbicyclo- [2,2,2] -octan-1-amine hydrochloride being obtained as a residue.



   Example 17
1-Acetamido-4- (p-cyanophenyl) bicyclo- [2, 2, 2] octane is hydrolyzed in the manner described in Example 11 with 48% hydrobromic acid and converted to the hydrochloride. The product obtained is 4- (p-carboxyphenyl) -bicyclo- [2, 2, 2] -octane-1-amine hydrochloride with a melting point of 350 ° C. (decomp.). The structure of the product is confirmed by its infrared spectrum.



  Analysis: C H N Calculated for C15H10NO · HCl: 63.93 7.15 4.97 Found: 63.46 7.09 5.27
Preparation 15
0.10 mol of 4-p-carboxyphenylbicyclo- [2,2,2] -octan-1-amine, 45 cm3 of nitromethane and 43 g (0.40 mol) of sulfur tetrafluoride are placed in a 145 cm3 bomb made of Hastelloy. The bomb is sealed and kept at 150 ° C. for 8 hours. After cooling and blowing off, the solvent and excess sulfur tetrafluoride are removed by concentration under reduced pressure. The residue is treated with 400 cm3 of ice-cold 20% sodium hydroxide. The mixture is extracted three times with 50 cm3 of ether each time.



  The ether extracts are combined, washed with 25 cm3 of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, 4-p-trifluoromethylphenylbicyclo- [2,2,2] octan-1-amine being obtained as residue.



   Example 18
A suspension of 10.3 g (0.040 mol) of l-acetamido-4- (p-aminophenyl) -bicyclo- [2, 2, 2] -octane in 50 cm3 of 6N hydrochloric acid is cooled to 5 C and treated with 2, 76 g (0.040 mol) of sodium nitrite diazotized. Then 10 cm3 of a 65% hexafluorophosphoric acid solution are added. The precipitate is filtered off, washed with water and dried. The dry precipitation is suspended in 200 cm3 of s-tetrachloroethane. The suspension is heated at the reflux condenser for 2 hours and then left to cool. The solvent is evaporated and the residue is chromatographed on silica with chloroform. 6.14 g of 1-acetamido-4- (p-fluorophenyl) bicyclo- [2,2,2] octane with a melting point of 189-191 ° C. are obtained as the product.



  Analysis: C H N Calculated for C1GHroNOF: 73.53 7.71 5.37 Found: 73.13 7.76 5.39
A mixture of 2.61 g of this compound, 25 cm3 of diethylene glycol, 1 cm3 of water and 2 g of sodium hydroxide is refluxed for 16 hours. The product is poured into ice water and extracted with ether. After evaporation of the ether, a residue is obtained which is soluble in hot 3N hydrochloric acid. Colorless crystals of 4- (p-fluorophenyl) bicyclo [2, 2, 2] -octane-1-amine hydrochloride are obtained in the solution on cooling. These crystals decompose at 335.degree. The structure is confirmed by the infrared analysis.



  Analysis: C H N Calculated for C14H18FN HCl: 65.74 7.49 5.48 Found: 65.50 7.64 5.61
Example 19
15.7 g of acetyl chloride are added to a solution of 24.3 g of 1-acetamido-4-phenylbicyclo- [2, 2, 2] -octane in 100 cm3 of anhydrous liquid hydrogen fluoride. Boron trifluoride is passed into the solution and the mixture is stirred for 16 hours. The boron trifluoride and hydrogen fluoride are evaporated. The residue is dissolved in chloroform and the solution washed with potassium carbonate solution and evaporated. The residue is recrystallized from xylene, 19 g of 1 acetamido-4- (p-accetylphenyl) bicyclo [2,2,2] octane having a melting point of 209-212 ° C. being obtained. The structure is confirmed by the infrared analysis.



   A mixture of 2.85 g of this compound and 1 g
10% palladium carbon in 200 cm3 alcohol is hydrogenated for 16 hours at 3 atmospheres. The catalyst is filtered off and the filtrate is evaporated. The residue is recrystallized from heptane, 2.20 g of 1 acetamido-4- (p-ethylphenyl) bicyclo [2,2,2] octane with a melting point of 156-157 ° C. being obtained. The structure is confirmed by the infrared analysis.



   The compound is hydrolyzed in the manner described in Example 11 to give 4- (p-ethylphenyl) -bicy clo- [2,2,2] -octane-1-amine hydrochloride of melting point 355-359 ° C (decomp.).



  Analysis: C H N C1 Calculated for C1GH23N'HC1 '1/4 H; 30: 71.09 9.13 5.18 13.11 Found: 70.85 9.02 5.22 12.90
Example 20
A solution of 40 g of sithyl-4-phenylbicyclo- [2, 2, 2] -oct-2-en-1-carboxylate (prepared according to the process of US patent application 377 132) in 100 cm3 of ethanol is hydrogenated for 16 hours at normal pressure .



  A solution of 0.2 mol of chloroplatinic acid is first added to the solution until the uptake of hydrogen begins. The catalyst is filtered off and the solvent is evaporated. The residue is recrystallized from methanol, 22.2 g of ethyl 4-phenylbicyclo- [2, 2, 2] octane-1-carboxylate with a melting point of 68-69 ° C. being obtained.



   A mixture of 11 g of this compound and 1000 cm3 of 2N sodium hydroxide solution is heated under a reflux condenser with stirring for 16 hours. After cooling slightly, the mixture is acidified with concentrated HC1 so that the temperature is kept at 80-100 ° C. By cooling the acidified solution, 9.0 g of 4-phenylbicyclo- [2, 2, 2] -octane-1-carboxylic acid are obtained, which can be purified by recrystallization from acetic acid, crystals having a melting point of 277-279 ° C. being obtained. A sample purified for analysis melts at 282-284 OC.



   C H Calculated for C15H1802: 77.23 7.88 molar weight 230 Found: 77.76 7.71 molar weight 226
4-Phenylbicyclo- [2, 2, 2] -octan-1-amine can be prepared in a simple manner from this compound by the known Schmidt reaction. To a mixture of 0.024 mol of the acid, 41 cm3 of concentrated sulfuric acid and 80 cm3 of chloroform, 0.042 mol of sodium azide is added in small portions at 50-55 ° C. while stirring. After all the azide has been added, the mixture is held at 50 ° C. for an additional 30 minutes, diluted with ice and made alkaline. The reaction mixture is steam distilled and the distillate is made strongly acidic with concentrated hydrochloric acid. A precipitation from 4-phenylbicyclo [2, 2, 2] -octan-l-amine hydrochloride separates out.



  The product is identical to the product described in Example 1.



   Example 21
When using ethyl 4-tolyibicyclo [2, 2, 2] oct-2-en-1-carboxylate instead of sithyl-4-phenylbicyclo- [2, 2, 2] -oct-2-en- 1-carboxylate in the experiment described above, 4-tolylbicyclo- [2, 2, 2] octane-1-amine hydrochloride is obtained.



   Example 22
To a mixture of 7.7 g (0.10 mol) of fuming nitric acid and 100 cm3 of concentrated sulfuric acid, which is cooled to 0 C in an ice bath, 0.050 mol of 4-phenylbicyclo- [2, 2, 2] octane-i -carboxylic acid given. The mixture is stirred for 1 hour and then poured into 1 l of ice water. The precipitate is filtered off, washed with water and dried. The precipitate is recrystallized from toluene to give 4- (2,4-dinitrophenyl) bicyclo- [2,2,2] octane-1-carboxylic acid in the form of pale yellow crystals with a melting point of 242.5-245 ° C.



  Analysis: C H N Calculated for Ct5HI6N206: 56.25 5.04 8.75 Found: 56.61 5.09 8.37
To a mixture of 0.24 mol of this acid, 41 cm3 of concentrated sulfuric acid and 80 cm3 of chloroform, 0.042 mol of sodium azide are added in small portions with stirring at 50-55 ° C. After all of the azide has been added, the mixture is held at 50 ° C. for a further 30 minutes, diluted with ice and made alkaline. The organic material is extracted with chloroform. The extract is dried with anhydrous potassium carbonate and evaporated. The residue is extracted with hot In-HCl. The extract is left to cool.

   The precipitate is filtered off, washed with water and dried, with 4- (2,4-dinitrophenyl) bicyclo- [2,2,2] -octane-1-amine hydrochloride being obtained.



   Example 23
1-Acetamido-4- (p-fluorophenyl) bicyclo- [2, 2, 2] -octane is nitrated in the manner described in Example 37. The product is a mixture of isomers and is broken down by chromatography, l-acetamido-4 (4-fluoro-2-nitrophenyl) bicyclo- [2,2,2] octane and 1-acetamido-4- (4-fluoro -3-nitrophenyl) bicyclo 2, 2, 2] octane are obtained. By hydrolysing these compounds with 48% hydrobromic acid and converting them to the hydrochlorides in the manner described in Example 11, 4- (4-fluoro-3-nitrophenyl) bi cyclo- [2,2,2] octane-1-amine hydrochloride and 4- (4 fluoro-3-nitrophenil) byciclo- 2, 2, 2] -octane-1-amine hydrochloride was obtained.



   Example 24
By reducing 1-acetamido-4- (2-nitro-4-fluorophenyl) -bicyclo- [2, 2, 2] -octane and 1-acetamido4- (3-nitro-4-fluorophenyl) -bicyclo- [2, 2, 2] octane in the manner described in Example 10A are l-acetamido-4- (2-amino-4-fluorophenyl) bicyclo- [2, 2, 2] octane and 1-acetamido-4- (3-amino- 4-fluorophenyl) bicyclo- [2, 2, 2] -octane obtained. By hydrolysis in the manner described in Example 11, 4- (2-amino-4-fluorophenyl) bicyclo- [2, 2, 2] -octane-1-amidihydrochloride and 4- (3-amino-4-fluorophenyl) -bicyclo- [ 2, 2, 2] -octanl-amine dihydrochloride.



   Example 25
By diazotization, pyrolysis of the diazonium hexafluorophosphates and hydrolysis of l-acetamido-4- (2 amino-4-fluorophenyl) bicyclo- [2, 2, 2] octane and 4- (3 amino-4-fluorophenyl) bicyclo [2, 2, 2] -octane become 4 (2,4-difluorophenyl) -bicyclo- [2, 2, 2] -octane-1-amine hydrochloride and 4- (3,4-difluorophenyl) -bicyclo- [2, 2, 2 ] octane-1-amine hydrochloride.



   Example 26
The bromination of 1-acetamido-4-tolylbicyclo [2, 2, 2] octane produces a mixture of l-acetamido-4- (2-bromotolyl) bicyclo [2, 2, 2] octane and l-acetamido 4- (3-bromotolyl) -bicyclo- [2, 2, 2] -octane obtained, which can be separated by chromatography. By hydrolyzing each isomer in the manner described in Example 11, 4- (2-bromotolyl) -bicyclo- [2,2,2] -octane-1-amine hydrochloride and 4- (3-bromotolyl) -bi cyclo- [2, 2, 2] -octan-1-amine hydrochloride obtained.



   Example 27
A mixture of 0.1 mol of 1-acetamido-4- (p-hydroxyphenyl) bicyclo- [2, 2, 2] octane, 20 cm3 of benzene, 15 cm3 of H2O and 15 cm8 of concentrated nitric acid is stirred for 1 hour at room temperature . The mixture is diluted and extracted with benzene. The benzene extract is dried with anhydrous magnesium sulfate and evaporated to give 1-acetamido-4- (4-hydroxy-3-nitrophenyl) bicyclo- [2,2,2] octane. By hydrolysis in the manner described in preparation 5, 4- (4-hydroxy-3-nitrophenyl) bicyclo- [2,2,2] -octane-1 amine hydrochloride is obtained.



   Example 28
A mixture of 0.05 mol of 1-acetamido- (4-hydroxy-3-nitrophenyl) bicyclo- [2,2,2] octane, 0.05 mol of methyl sulfate and 0.10 mol of potassium hydroxide as a solution in 50 cm3 of water is gradually heated to 90 C until the color of the solution changes and the product separates. The solution is cooled, diluted and extracted with ether. The ether extract is washed with water, dried with anhydrous magnesium sulfate and evaporated to give 1-acetamido-4- (4-methoxy 3-nitrophenyl) bicyclo- [2, 2, 2] octane.



  By hydrolyzing the product in the manner described in Example 11, 4- (4-methoxy-3-nitrophenyl) bicyclo- [2,2,2] -octane-1-amine hydrochloride is obtained.



   Example 29
By reducing 1-acetamido-4- (4-methoxy-3-nitrophenyl) -bicyclo- [2, 2, 2] -octane with hydrazine hydrate and Raney nickel in the manner described in Example 12, 1-acetamido-4- (3-amino-4-methoxyphenyl) bicyclo- [2, 2, 2] -octane obtained. By hydrolysing the reduction product in the manner described in Example 16, 4- (3-amino-4-methoxyphenyl) bicyclo- [2,2,2] octane-1-amine hydrochloride is obtained.



   Example 30
By hydrolysis of the diazonium compound of 1-acetamido-4- (3-amino-4-methoxyphenyl) -bicyclo- [2, 2, 2] -octane in the manner described in Example 9, 1-acetamido-4- (3-hydroxy- 4-methoxyphenyl) -bicyclo [2, 2, 2] -octane obtained. Purification is done by chromatography. The product comes with
48% hydrobromic acid was hydrolyzed and converted to the hydrochloride in the manner described in Example 11 to give 4- (3-hydroxy-4-methoxyphenyl) bicyclo- [2,2,2] -octane-1-amine hydrochloride.



   Example 31
A mixture of 0.10 moles of 4-phenylbicyclo- [2, 2,
2] Octan-1-amine and 9.87 g (0.10 mol) of 38% strength hydrochloric acid in 100 cm3 of water are concentrated at 60 ° C. under reduced pressure. The obtained salt,
4-Phenylbicyclo- [2, 2, 2] -octan-1-amine hydrochloride, is dried at 60 ° C. under reduced pressure.



   Example 32
A solution of 0.20 mol of 4-phenylbicyclo [2, 2, 2] -octane-1-amine hydrochloride in 200 cm3 of hot water becomes a solution of the disodium salt of 4,4'-methylene-bis- (3-hydroxy-2 -naphthoic acid) in 500 cm3 of water. The precipitate formed is filtered off, washed well with water and dried under reduced pressure at 60 ° C., the pamoate of 4-phenylbicyclo- [2, 2, 21-octan-1-amine being obtained.



   Example 33 Carbon dioxide is dissolved in a solution of 0.10 mol of 4
Phenylbicyclo- [2, 2, 2] -octan-1-amine in 100 cm3 of ether passed until complete precipitation. The precipitate is filtered off and dried under reduced pressure at 60 ° C., 4-phenyibicyclo- [2,2,2] -octane-1 amine bicarbonate being obtained.



   Example 34
Hydrogen chloride (0.10 mol) is dissolved in a solution of 0.1 mol of 4-phenylbicyclo- [2, 2, 2] -octan-1-amine in
100 cm3 of ether. The precipitate is filtered off and dried under reduced pressure at 60 ° C., 4-phenylbicyclo- [2, 2, 2] -octane-1-amine hydrochloride being obtained.



   Example 35
The experiment described in Example 31 is repeated, the compounds mentioned below being used instead of the reagents mentioned there and the products also mentioned being obtained.



   No. Product Acid Product according to
Example preparation a B. 2,850% phosphorus-N-ethyl-4-phenylbicyclo- [2,2,2] - (free acid octane-1-amine phosphate
Base) (0.10 moles) (0.10 moles) b P. 1 sulfuric acid N-methyl-4-phenylbicyclo (0.10 moles) (0.050 moles) [2.2.2] octane-1-amine sulfate c P. 2 Tartaric acid NN, -dimethyl-4-phenylbicyclo- (0.10 mol) (0.10 mol) [2,2,2] -octan-1-amine, bitartrate d B. 7 Tartaric acid N-butyl-4 -phenylbicyclo- 2, 2] - (0.10 mol) (0.050 mol) octan-1-amine, tartrate e P.

   3 Maleic acid N-ethyl-N-methyl-4-phenylbi- (0.10 mol) (0.050 mol) cyclo- [2.2.2] octan-1-amine, maleate f B. 3 Acetic acid N- (4- Phenylbicyclo [2,2,2] octyl (0.10 mol) (0.10 mol) 1) pyrrolidine, acetate g P. 4 succinic acid 4-p-nitrophenylbicyclo- [2, 2, 2] - (0, 10 mol) (0.050 mol) octan-1-amine, succinate h P. 6 mandelic acid 4-p-aminophenylbicyclo- (0.10 mol) (0.10 mol) [octan] -1-amine, mandelate B. 13 lactic acid 4- p-Methoxyphenylbicyclo (0.10 mole) [2.2.2] octane-1-amine, lactate

 

Claims (1)

PATENT CLAIM Process for the preparation of acid addition salts of new optionally substituted 1-amino4-phenylbicyclo- (2, 2, 2) -octanes of the formula (I) EMI14.1 where A- is an anion, R and R1 are hydrogen or alkyl having 1-4 C atoms or allyl, where R and R1 are linked to one another to form - (CH2) n-, where n is an integer from 4 to 6 can be, and X and Y hydrogen, methyl, ethyl, cyano, chlorine, bromine, fluorine, trifluoromethyl, nitro, amino, monoalkylamino, in which the alkyl radical has 1-4 C atoms, dialkylamino, in which each alkyl radical has 1-4 C- Has atoms, are hydroxy, alkoxy with 1-4 C atoms, carboxy or alkoxycarbonyl, in which the alkyl radical contains 1-2 C atoms, characterized in that the free amines are reacted with acids. SUBClaim Process according to patent claim, characterized in that the acid used is hydrochloric, acetic, phosphoric, succinic, carbonic or citric acid.