DK141508B - Analogous process for the preparation of racemic or optically active 9- (2-hydroxy-3-aminopropyl) -9,10-dihydro-9,10-ethano-anthracenes or their acid addition salts. - Google Patents

Description

(11) SUBMISSION SAFETY SHIFT 1 41 508 DENMARK (FD Int el.3 C 07 C 91/23 '(21) Application No 818/72 (22) Indlsvarat dsn 22 Feb 19 ^ 2 (23) Running day 22 Feb. 1972 (44) The application presented and - the petition published on 8 · Apr. 1 980

Dl THE RECTORATE FOR

PATENT AND TRADE MARKET (30) Priority requested from it

Feb 25 1971, 2578/71, CH

Jan 17 1972, 669/72, CH

71) CIBA-GEIGY AG, 4002 Bagel, CH.

(72) Inventor: Max Wilhelm, Alemannenweg 10, 4125 Allgchwil, CH: Raymond Ber = nasconi, Amselstr. 17a, 4104 Oberwll, CH: Angelo Storni, Lettenweg 8, 4125 Allschwll, CH: Dieter Beck, Froburggtr. 4, 4000 Basel, CH:

Karl Schenker, Rottmannsbodensfr. 99, 4102 Binning, CH, 74) Plenipotentiary:

Dangk Patent Kontor ApS. (64) Analogous procedure for producing racemic or optical acetic acid 9- (2-hydroxy-5-aminopropyl) -9β 10-dl hydro-9,10-ethano-anthracenes or deregylated ethylene bile.

The invention relates to an analogous process for the preparation of novel racemic or optically active 9- (2-hydroxy-3-aminopropyl) -9> 10- dihydro-9,10-ethano-anthracenes of the formula OH p1 / CH0-CH-CHO- N /

l z k * 2 V

Wherein R is hydrogen, methyl or ethyl, R is hydrogen or chlorine and R is methyl or ethyl, or their acid addition salts.

141508 2

The compounds of the invention have valuable pharmacological properties, especially a psychotropic, e.g. antidepressant, activity. Thus, in particular, they inhibit norepinephrine uptake, as shown in animal studies, e.g. on the heart and brain of rats by administration of 0.5-10 mg / kg s.c., 0.2-5 mg / kg i.v. or 5-100 mg p.o. Furthermore, they act antagonistically against reserpine, such as e.g. can be demonstrated in mice in the reserpine antagonism sample by administration of 100-400 mg / kg p.o.

The compounds of the present invention may therefore be used as psychotropic, especially as antidepressant agents.

U.S. Patent No. 3,399 * 201 has known structurally related 9-aminoalkyl-9,10-dihydro-9,10-ethano-anthracenes useful as tranquilizers. As can be seen from the test report below, the compounds prepared according to the process of the invention have a significantly stronger inhibitory effect on the uptake of% noradrenaline in rat hearts than the known compounds, and thus exhibit a surprisingly better psychotropic effect.

Above all, 9- (3-dimethylamino-2-hydroxy-1-propyl) -9,10-dihydro-9,10-ethano-anthracene-methanesulfonate and, in particular, 9- (2-hydroxy-3-methylamino-propyl) - 9,10-dihydro-9,10-ethano-anthracene, e.g. on the heart and brain of rats in subcutaneous administration of 1 mg / kg, intravenous administration of 0.5 mg / kg or oral administration of 10 mg / kg shows a clear inhibition of noradrenaline uptake and shows a clear reserpine antagonism in mice by oral administration of 200 mg / kg.

The present compounds are prepared according to the process according to the invention and this process is characterized by the characterizing part of the claim.

A reactively esterified hydroxyl group Z is by process a) above all a hydroxyl group which is esterified with a strong organic or inorganic acid, such as in particular a hydrogen halide such as hydrogen chloride, bromide or iodide, or an arylsulfonic acid such as one of lower alkyl. or alkoxy groups, or with halogen atoms such as chlorine or bromine atoms, mono-, di- or polysubstituted benzenesulfonic acid, e.g. p-toluenesulfonic acid 3 or p-bromobenzene sulfonic acid, or a low alkanesulfonic acid, e.g.

methanesulfonic acid.

U1508

The reaction is carried out in the usual manner, preferably in the presence of a solvent and optionally in the presence of a condensing agent, e.g. a basic condensing agent, preferably at elevated temperature and optionally in a closed container under pressure. A basic condensing agent is e.g. an alkali metal hydroxide or carbonate, e.g. sodium hydroxide or potassium carbonate, or a tertiary amine, e.g. triethylamine or pyridine. Instead of the secondary amine, an agent which emits such, e.g. a correspondingly symmetrically disubstituted urea. In this case, it is convenient to work during heating and possibly the addition of an inactive diluent, e.g. diphenyl ether or sand.

A reactive ester is by process b) above all an ester derived from a strong organic or inorganic acid, such as in particular one of the above-mentioned acids, or sulfuric acid.

In process c), an azomethine compound obtained as an intermediate is reduced either simultaneously or subsequently to a compound of formula I. The reduction occurs in the usual manner, preferably by a single or complex hydride, e.g. a borane, or a dilet-metal hydride, e.g. an alkali metal base metal hydride such as lithium aluminum, or an alkali metal borohydride such as sodium borohydride, or ethoxy oxyaluminum hydride or alkoxy borohydride, or with formic acid. However, it is also possible to reduce with hydrogen in the presence of a catalyst such as a platinum, palladium or nickel catalyst, or a homogeneous catalyst, e.g. a complex rhodium compound such as a rhodium chloro-triphenylphosphine complex.

In process d) the group Y'f. a silyl group such as a trimethylsilyl group, or above all an acyl group, e.g. an alkanoyl group, above all an optionally halogenated, e.g. fluorinated lower alkanoyl group such as an acetyl group or trifluoroacetyl group, a benzoyl group, phenylalkanoyl group, carbalkoxy group, e.g. and tart. butyloxycarbonyl, carbethoxy or carbomethoxy group, or an aralkoxycarbonyl group, e.g. a carbobenzoxy group.

4 1415 (16)

The hydrolytic cleavage of Y 'or D occurs with hydrolyzing agents, for example in the presence of acidic agents such as e.g. diluted mineral acids, such as sulfuric acid or hydrogen halides, especially hydrochloric acid, or, by acyl groups, preferably in the presence of basic agents, e.g. alkali metal hydroxides such as sodium hydroxide.

Y is In process e) e.g. an α-aralkyl group, such as a benzyl group, or an α-aralkoxycarbonyl group, such as a carbenzoxy group, which may, for example, be decomposed by reduction with catalytically activated hydrogen such as hydrogen in the presence of a hydrogenation catalyst such as a palladium or platinum catalyst.

However, Y may also be a 2-halo-alkoxycarbonyl group such as, for example, a 2,2,2-trichloroethoxycarbonyl group or a 2-iodoethoxycarbonyl group which can be cleaved off by reduction. For the reduction, above all, the metallic reduction (so-called nascent hydrogen) is considered, such as e.g. action of metal or metal alloys, such as also amalgams, preferably in the presence of hydrogen-releasing agents such as carboxylic acids, alcohols or water. Above all, zinc or zinc alloys are used in acetic acid. Furthermore, chromium II compounds such as chromium II chloride or chromium II acetate are also considered. Y may also be an arylsulfonyl group such as a toluene sulfonyl group which can be decomposed into liquid ammonia in the usual manner by reduction with nascent hydrogen, e.g. with an alkali metal such as lithium or sodium. The cleavage of an arylsulfonyl group may also be carried out with a hydride, e.g. one of the above simple or complex hydrides, preferably lithium aluminum hydride, suitably in the presence of an inert solvent such as an ether, e.g. tetrahydro furan.

If compounds of formula VIIb are present, the reduction takes place in the usual manner, e.g. with an amide reducing agent, for example a single or complex hydride, such as a borane, e.g. diborane, or a complex diletal metal hydride, especially an alkali metal aluminum hydride such as lithium or sodium aluminum hydride, or an alkoxy aluminum hydride or borohydride, e.g. sodium dibutoxyaluminum hydride or sodium trimethoxyborohydride, or an alkaline earth metal aluminum hydride such as magnesium aluminum hydride, or sodium borohydride in a tertiary amine such as pyridine or triethylamine, or aluminum hydride aluminum chloride. For example, the reduction can also be electrolytic on high voltage cathodes such as mercury, lead amalgam or lead cathodes. As a catholyte, e.g. a mixture of water, sulfuric acid and a lower alkane carboxylic acid such as acetic or propionic acid.

The anodes may e.g. consist of platinum, coal or lead, and as an anolyte, sulfuric acid is preferably used.

The introduction of the 9,10-ethano group according to process f) takes place in the usual manner. Conveniently, this is done using the method of Diels-Alder, advantageously in a suitable solvent such as an aromatic hydrocarbon, e.g. toluene, and at elevated temperature and / or under pressure.

Depending on the process conditions and the starting materials, the final substances are obtained in free form or in the form of acid addition salts thereof. The acid addition salts of the subject compounds can be transferred to the free compounds in a manner known per se, e.g. with basic agents such as alkalis or ion exchangers.

On the other hand, the obtained free bases can form salts with organic or inorganic acids. For the preparation of acid addition salts, such acids are used which are suitable for forming therapeutically acceptable salts. As such, mention should be made of, for example: hydrogen halides, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic, vinegar, propionic, amber, glycol, milk. -, apple, wine, lemon, ascorbic, maleic, hydroxymaleic or pyruvic acid; phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulfone, ethanesulfone, hydroxyethanesulfonic, ethylene sulfonic acid · halogenobenzene sulfone, toluene sulfone or sulphanilic acid; methionine, tryptophan, lysine or arginine.

Because of the close relationship between the compounds in question in free form and in the form of salts thereof, in the preceding and subsequent compounds, the corresponding salts may also be understood.

U1508 6

Depending on the choice of starting materials and working methods and according to the number of asymmetric carbon atoms, the compounds of the invention may be available as optical antipodes, racemates or as isomer mixtures (eg racemate mixtures).

The obtained isomer mixtures (racemate mixtures) can be divided into the two stereoisomers (diastereomers) pure isomers (e.g. racemates) by known means, for example by chromatography and / or fractional crystallisation, on the basis of the physicochemical differences in the components.

Obtained racemates can be divided by known methods, for example, by recrystallization of an optically active solvent, by microorganisms or by reaction with an optically active acid that forms salts with the racemic compound, and separation of the salts thus obtained, f. eg. on the basis of their various solubilities, in the diastereomers, followed by the release of the antipodes by the action of suitable agents. Particularly used optically active acids are e.g.

The D and L forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphor sulfonic acid or quinic acid. It is advantageous to isolate the most effective of the two antipodes.

Conveniently, in order to carry out the reactions in question, such starting materials are used which lead to the already mentioned or particularly emphasized final substances.

The starting materials, if new, can be obtained by methods known in the art.

The compounds of the invention may e.g. find use in the form of pharmaceutical compositions containing them in free form or, optionally, in the form of therapeutically acceptable salts, in admixture with e.g. suitable pharmaceutical organic or inorganic, solid or liquid carrier suitable for the enteral or parenteral application. To form such substances, such substances do not react with the compounds of the present invention, such as e.g. water, gelatin, lactose, starches, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, propylene glycols, vaseline or other known drug carriers. The pharmaceutical compositions may e.g. available as tablets, dragees, capsules, suppositories or in liquid form as solutions (eg as elixir or syrup), suspensions or emulsions. They are optionally sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolving aids or salts for changing the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

The pharmaceutical compositions are obtained by conventional methods.

The present compounds can also be used in animal medicine, e.g. in any of the above forms or in the form of feed or animal feed additives. For this, e.g. the usual stretching and thinning agents or feed materials.

Test report

To investigate the psychotropic effect of compounds prepared by the process of the invention and to compare it with the action of compounds known from U.S. Patent No. 3,399,201, test animals (rats) were administered the following test compounds: A 9- (3-Methylamino-propyl) - 9,10-dihydro-9,10-ethano-anthracene.

In 9- (2-Hydroxy-3-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene.

XI 9- (2-Hydroxy-3-dimethylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene.

III 2-Chloro-9- (2-hydroxy-3-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene.

Compound A is known from Example 13 of the above-mentioned United States Patent, while Compounds I, II and III are prepared by the process of the invention (Examples 1, 3 and 9, respectively).

The compounds were administered partly intravenously, partly subcutaneously and partly orally. Thirty minutes after the intravenous administration, 100 dCi / kg of DL-3 H-noradrenaline was intravenously injected, while the same dose was only administered 2 hours later by the subcutaneous and oral examination. An hour later the animals were killed. Mean ED ^ Q was determined graphically and is listed in the table below. The above method is described by L.

Maitre, M. Staehelin and H.J. Bein, Biochem. Pharmacol. 20, 2169 (1971) 8 141508

Compound Oral Subcutaneous Intravenous ... A 42 10 4 I 9 1.5 0.5 II 4 4 III 3 _0j3 _-_ The table above shows the inhibitory effect of the test compounds on the uptake of 3 H-noradrenaline in rat hearts, and as As can be seen, compounds I, II and III produced by the process of the invention possess much better properties in this regard than compound A known from US Patent No. 3,399 · 201.

The method according to the invention is described in more detail in the following examples.

Example 1.

3.9 g of 9 - [(3-methyl-5-oxazolidinyl) methyl] -9,10-dihydro-9,10-ethano-anthracene are heated to 90 ° C with 60 ml of 2 M hydrochloric acid for 3 hours. Then 5N sodium hydroxide solution is added until alkaline reaction and extracted with methylene chloride. After separation and evaporation of the solvent, 9- (2-hydroxy-3-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene of the formula

OH

CH2CHCH2HHCH3 remaining. This is dissolved in 10 ml of ethanol, 1 ml of a 10 $ solution of hydrogen chloride in ethanol is added and ether is added. There is thus obtained the crystalline hydrochloride of 9- (2-hydroxy-3-methylamino-propyl) - 9,10-dihydro-9,10-ethano-anthracene, m.p. 237-239 ° C.

'ί · = | κ,. · · '9 1Λ1508

The starting material required for 9 - [(3-methyl-5-oxazolidinyl) methyl] -9,10-dihydro-9,10-ethano-anthracene can be prepared as follows:

To a solution of 46 g of 9- (chlorocarbonylmethyl) -9,10-dihydro-9,10-ethano-anthracene in 200 ml of xylene is added 10 g of 10 $ palladium carbon poisoned with quinoline sulfur and then hydrogen through at 120 ° C. After 7 hours, the catalyst is filtered off and evaporated in vacuo. The residue is dissolved in methylene chloride and shaken with sodium carbonate solution. After separation of the organic phase, it is dried over sodium sulfate and then diluted to a volume of 2 µl ml by the addition of methylene chloride. After adding 1 ml of triethylamine, 20 ml of hydrogen cyanide are added and allowed to stand for 12 hours at room temperature. The mixture is then sprayed with water and the solvent is evaporated. Crystalline 9- (2-hydroxy-2-cyano-ethyl) -9,10-dihydro-9,10-ethano-anthracene, which has m.p. 139-141 ° C after recrystallization from methylene chloride-petroleum ether.

This nitrile (18 g) is dissolved in 150 ml of tetrahydrofuran and dripped to 6 g of lithium aluminum hydride in 100 ml of tetrahydrofuran. After stirring for 8 hours at 60 ° C, cool and add successively 8 ml of water, 8 ml of 15 $ sodium hydroxide solution and 24 ml of water. The precipitated precipitate is filtered off and the filtrate is evaporated in vacuo. Back, 9- (2-hydroxy-3-amino-propyl) -9,10-dihydro-9,10-ethano-anthracene is obtained, m.p. 176-177 ° C.

20 g of this amino alcohol are heated to 95 ° C for 1 hour in 150 ml of formic acid with 10 ml of formalin and then evaporated in vacuo. The residue is made alkaline by the addition of 2N sodium hydroxide solution, extracted with methylene chloride and evaporated the organic phase. 9 - [(3-methyl-5-oxazolidinyl) -methyl] -9,10-dihydro-9,10-ethano-anthracene is obtained, m.p.

106-109 ° C.

Example 2.

A solution of 12 g of N- (p-toluenesulfonyl) -9- (2-hydroxy-3-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene in 100 ml of tetrahydrofuran is slowly added dropwise to 3 g. lithium aluminum hydride in 50 ml of tetrahydro-furan. After the reaction mixture has boiled for 4 hours under reflux, cool to room temperature and gently add 3 ml of water and 10 ml of ± 5% sodium hydroxide solution. The precipitated precipitate is filtered and the filtrate is evaporated. 9- (2-hydroxy-3-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene, identical to the product obtained in Example 1, is obtained in the residue and whose cyclohexyl sulfaminate has m.p. . 143-145 ° C.

The toluene sulfonamide used as a starting material can be prepared as follows:

To a solution of 25 g of 9- (2-hydroxy-3-amino-propyl) -9,10-dihydro-9,10-ethano-anthracene in 200 ml of pyridine is added 25 g of p-toluenesulfochloride. After 12 hours, water is added and after addition of 50 ml of 5 N hydrochloric acid - extracted with methylene chloride. The residual crystalline residue after drying and evaporation of the solvent is dissolved in 150 ml of dimethylformamide and a solution of diazomethane in ether is added. After standing for 12 hours at room temperature, the solution is evaporated in vacuo. There is obtained as the residue the crude N- (p-toluenesulfonyl) -9- (2-hydroxy-5-methylamino-propyl) -9> 10-dihydro-9,10-ethano-anthracene which can be used for the above described turnover without further purification.

Example 3

5 g of 9- (2-p-tosyloxy-3-dimethylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene are refluxed for 2 hours with 2 g of sodium hydroxide - in 50 ml of ethanol and 5 ml of water . Then add 100 ml of water and 50 ml of 2N acetic acid and extract with ether. The aqueous phase is separated and made alkaline by the addition of 10O's sodium hydroxide solution. After extraction with methylene chloride and evaporation of the solvent, 9- (2-hydroxy-3-dimethylamino-propyl) -9,10-dihydro-9,10-ethaho-anthracene of the formula f CH2CHCH2N (CH3) 2 11 141586 remains as a crystalline mass which melts at 118-121 ° C after sublimation. The methanesulfonate melts at 185-86 ° C.

Example 1 ±.

A mixture of 10 g of 9- (2-hydroxy-3-aminopropyl) -9,10-dihydro-9,10-ethano-anthracene, 10 ml of a 35 $ Ts solution of formaldehyde in water and 100 ml of formic acid is heated. hour to 100 ° C. Then, evaporate to dryness in vacuo, dissolve the residue in 100 ml of 2N acetic acid and wash with ether. To the acidic extract is added 10 $ r of sodium hydroxide solution until alkaline reaction and then quenched with methylene chloride.

After drying and evaporation of the solvent, 9- (2-hydroxy-3-dimethylaminopropyl) -9,10-dihydro-9,10-ethano-anthracene remains, which melts at 181-121 ° C after sublimation and is identical to that of the solvent. Example 3 product obtained. The methanesulfonate melts at 185-86 ° C.

Example 5

To a solution of 1.0 g of lithium aluminum hydride in 20 ml of tetrahydrofuran is added a solution of 2.1 g of 5- [9,10-dihydro-9,10-ethano-9-anthryl-methyl] -oxazolidinone- (2 ) in 20 ml of tetrahydrofuran and reflux for hours. Then cool and then add 2 ml of water, 2 ml of 15 $ sodium hydroxide solution and again 6 ml of water. The precipitated precipitate is filtered off, the filtrate is evaporated and the residue is dissolved in 2N acetic acid. The acid solution is washed with ether, After adding 10 $ f sodium hydroxide solution to the acidic extract until the alkaline reaction is shaken with methylene chloride. After evaporation of the solvent, 9- (2-hydroxy-3-methylaminopropyl) -9,10-dihydro-9,10-ethano-anthracene, whose hydrochloride melts at 237-239 ° C, which is identical to that of Example 1 product obtained.

The oxazolidinone used as a starting material can be prepared as follows:

To a solution of 2.8 g of 9- (2-hydroxy-3-amino-propyl) -9,10-dihydro-9,10-ethano-anthracene in 50 ml of benzene, 20 ml of dioxane and 5 ml of 2N sodium hydroxide solution is dropped. stirring at room temperature 20 ml of a 10 $ solution of phosgene in toluene. After 3 hours, the precipitated part is filtered off and the filtrate is evaporated. The residue is dissolved in methylene chloride and extracted with a 3% fs aqueous solution of methanesulfonic acid. After drying and evaporating the solvent, the crude 5- [9,10-dihydro-9,10-ethano-9-anthryl-methyl] -oxazolidinone (2) remains as a solid.

Example 6

16 g of 9- (2,3-epoxy-propyl) ~ 9,10-dihydro-9,10-ethano-anthracene are heated for 4 hours to 90 ° C with 20 g of ethylamine in 150 ml of ethanol and then evaporated in vacuo. The residue is dissolved in ether and extracted with 2N acetic acid. The acidic extract is then made alkaline by addition of 10% sodium hydroxide solution and extracted with ether. After drying and evaporating the ether, 9- (2-hydroxy-3-methylamino-propyl) - 9,10-dihydro-9,10-ethano-anthraene remains, whose hydrochloride melts at 237-239 ° C and is identical to the product obtained in Example 1. The epoxide used as a starting material can be prepared as follows:

To a solution of 46 g of 9- (chlorocarbonylmethyl) -9,10-dihydro-9,10-ethano-anthracene in 200 ml of xylene is added 10 g of $ 10 ps of palladium coal poisoned with quinoline sulfur and then hydrogen to at 120 ° C. After 7 hours, the catalyst is filtered off and evaporated in vacuo.

The residue is dissolved in methylene chloride and extracted with sodium carbonate solution. After separation of the organic phase, it is dried and evaporated. Back it becomes crude 9,10-dihydro-9,10-ethano-9-anthryl-acetaldehyde.

To transfer the aldehyde to the epoxide, 19.6 g of trimethyl oxide sulfonium iodide are added to 2.2 g of sodium hydride in 175 ml of dimethyl sulfoxide. Upon completion of hydrogen evolution, a solution of 21 g of the crude 9,10-di-hydro-9,10-ethano-9-anthryl-acetaldehyde in 35 ml of dimethyl sulfoxide is added dropwise and stirred for 20 minutes at room temperature and then 30 minutes at 55 ° C. 60 ° C. The reaction mixture is now poured into 300 ml of water and extracted with methylene chloride. The methylene chloride. separated and evaporated. Again, the crude 9- (2,3-epoxypropyl) -9,10-dihydro-9,10-ethano-anthracene becomes a cool oil.

Example 7 ·

To a solution of 5.6 g of 9- (2-hydroxy-3-amino-propyl) -9,10-dihydro-9,10-ethano-anthracene in 50 ml of ethanol was added 7.0 g of methyl iodide and 13 U of 1508 heated. two hours to 60 ° C. Then, evaporate in vacuo and dissolve the residue in ether. The ether solution is extracted with 2N acetic acid.

The acidic extract is made alkaline by the addition of 10 $ sodium hydroxide solution. After shaking with methylene chloride and evaporation of the solvent, an oil is left which is dissolved in 5 ml of ethanol. 1.5 g of methanesulfonic acid are added to this solution. Upon addition of ether, crystallization begins. After recrystallization several times from ethanol-ether, the methanesulfonate of 9- (2-hydroxy-3-dimethylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene is obtained, m.p. 185-186 ° C, which is identical to the product obtained in Example 3.

Example 8.

A solution of 11 g of 9- (2-hydroxy-3-dimethylamino-propyl) anthracene in 200 ml of benzene is heated for 6 hours to 70 ° C in autoclave with ethylene under a pressure of 70 ato. Extract with 200 ml of 2N hydrochloric acid. The acidic extract is made alkaline and shaken with methylene chloride. After evaporation of the solvent, an oil remains which slowly crystallizes. By sublimation crystals with m.p. 120-121 ° C. These are dissolved in alcohol, an equivalent of methanesulfonic acid is added and then ether is added until crystallization. There is thus obtained the methanesulfonate of 9- (2-hydroxy-3-dimethylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene of the formula

OH

ch2-gh-ch2-n (CH2) 2, CH3SO3H 1 crystals, m.p. L85-L86 ° C.

Example 9

Similar to Example 2, 12.3 g of N- (p-toluenesulfonyl) -9- (2-hydroxy-3-methyl aminopropyl) -9,10-ethano-9,10-dihydro-2 are obtained. -chloro-anthracene 9- (2-hydroxy-3-methylamino-propyl) -9,10-ethano-9,10-dihydro-2-chloro-anthracene as diastereomeric mixture whose hydrochloride melts at 218-220 ° C.

Claims (2)

Analogy Process for Preparing Racemic or Optically Active 9- (2-Hydroxy-3-Aminopropyl) -9,10-Dihydro-9,10-Ethano-1-Anthracene of the Formula OH, [/ R1 CH2 OH -CH 2 N 2 AAA.- r 2 (° 1. wherein E means hydrogen, methyl or ethyl, R hydrogen or chloro and R 2 methyl or ethyl, or their acid addition salts, characterized in that a) is reacted with a compound of the formula X 1 GH 2 -CH-CHg-Z αΑα, -ε2 \ a) U (1I) wherein X1 means hydroxy and Z is reactively esterified hydroxy, 1. or X and Z together are an epoxy group and R has the meaning given above, with a compound of formula R1 H - (III) \ r3 wherein R 1 and B? has the meaning given above, or b) reacts with a compound of the formula OH CH2-CH-CH2-NH2 ΐΑ / γ ^ -Β2 vvV (IT) p * wherein R has the meaning given above, with a reacton-low esterified compound having Formula 7 R5 - OH (V) wherein Ir is as defined above, or c) in the presence of a reducing agent, a compound of Formula IV undergoes reductive alkylation by means of an oxo compound corresponding to the meaning of Ir or d. ) hydrolyzes a compound of formula C1a-A \ r (VI) wherein A represents a group of the partial formula 0. X2 '1 / Y' - CH - OH2 - (Via) or of the partial formula - CH - CH-, 1 1 3 Ov N-Ir (VIb) b 2 wherein X means hydrogen and Y 'is a group which by hydrolysis o can be replaced by hydrogen, or X is a group which can be replaced by hydrogen by hydrolysis and Y 'has the same meaning as R1, D is an optionally aliphatic groups mono- or disubstituted 2 has the meaning given above, or e) reduces a compound of formula ch2-e kA> U (VII) O wherein R has the meaning given above and E means a group of the partial formula