DK149102B - ANALOGY PROCEDURE FOR PREPARING A HIGH-RANGE BASIC DERIVATIVE OF THE 9,10 ETHANOANTHRAC OR ACID ADDITION SALTS THEREOF - Google Patents

Abstract

For all designated states : BE, CH, DE, FR, GB, IT, LU, NL, SE 1. S-(+)-alpha-[methylamino)methyl]-9-10-ethano anthracene-9(10H)-ethanol of the formula I see diagramm : EP0014434,P11,F1 or an acid addition salt thereof. For the contracting state : AT 1. A process for the production of S-(+)-alpha-([methylamino)methyl]-9-10-ethano anthracene-9(10H)-ethanol of the formula I ad indicated in claim 1, or of an acid addition salt thereof, which process comprises a) resolving the racemic alpha-[(methylamino)-methyl]-9-10-ethanoanthracene- 9(10H)-ethanol and isolating S-(+)-alpha-[(methylamino)-methyl]-9-10-ethano anthracene-9(10H)-ethanol, if desired in the form of an acid addition salt, or b) reacting a compound of the formula II see diagramm : EP0014434,P12,F1 with a compound of the formula III X2 -CH3 wherein one of X1 and X2 is the amino group and the other is a reactive esterified hydroxyl group, and Y1 is a free hydroxyl group, and X1 together with Y1 can also be an epoxy group, and A is the 9,10-ethanoanthracen-9(10H)-yl radical, or c) in a compound of the formula IV see diagramm : EP0014434,P12,F2 in which at least one of Z1 and Z2 is a removable radical and the other may be hydrogen, or Z1 and Z2 together are a divalent removable radical, and A is the 9,10-ethanoanthracen-9(10H)-yl radical, removing Z1 and/or Z2 , d) reducing a compound which differs from the compound of the formula I only in that, in said compound, a carbon atom adjacent to the nitrogen atom is attached to this latter through a double bond or is substituted by a hydroxyl group or an oxo radical, optionally together with lower alkoxy, or e) adding ethylene to S-alpha-[(methylamino)-methyl]-9(10H)-anthracene, or hydrolyzing the intermediate obtained, and, if desired, converting the resultant S-(+)-alpha-[(methylamino)methyl]-9,10-ethanoanthracen- e-9(10H)-ethanol into an acid addition salt and/or liberating the base from a resultant acid addition salt.

Description

149102 i

The present invention relates to an analogous process for the preparation of a novel right-turning basic derivative of 9,10-ethanoanthracene, S - (+) - α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol with the formula

OH

? CH _--- C --- CH0 - NH -CH- 2 A 2 3 (I) 5! ch9 or acid addition salts thereof, (+) - the antipode of the racemic α - [(methylamino) methyl] -9,10-ethano disclosed in U.S. Patent No. 4,017,542 and similar patents in other Swiss priority countries of February 23, 1971 -10 anthracene-9 (10H) -ethanol. Acid addition salts of the compound of formula I are in particular pharmaceutically acceptable salts such as the hydrobromide, phosphate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, acetate, lactate, malonate, succinate, fumarate, maleinate, malate, tartrate, citrate, benzoate, the phenylacetate, the mandelate or the embonate and, above all, the hydrochloride, and generally light crystallizing salts with optically active acids, in addition to the aforementioned e.g. also the (1: 1) salt with bis-0.0 '- (p-toluoyl) -D-tartaric acid. Due to the close connection between the free base and its acid addition salts, the free base and its acid addition salts are optionally also understood as the acid addition salts and the free base, respectively.

S - (+) - a - [(methylamino) methyl] -9,10-ethanoanthracen-. 9 (10H) -ethanol and its acid addition salts have valuable pharmacological properties. Above all, they show particularly strong effects in trials characteristic of antidepressants. A clear antagonization of that of 2 mg / kg sc. reserpine induced hypothermia in male mice [Askew, Life Sci. 10, 725 (1963), and Benz and Waser, Dissertation 1971, Pharmacologist. Institute of Universitat Ziirich] can already be ascertained at doses of 0.3 mg / kg of the hydrochloride of the compound of formula I and is stronger than the effect of multiple doses of the corresponding racemate. That of 2 mg / kg sc. reserpine induced ptosis in male rats [Rubin et al, J. Pharmacol.

Exp. Therap. 120, 125 (1957)] is already clearly diminished by 0.1 mg / kg p.o. of the hydrochloride of the compound of formula I and is abolished by 0.3 mg / kg p.o., while the corresponding, in itself also highly effective racemate first abolishes ptosis completely at a substantially higher dosage.

Neurobiochemically, the hydrochloride of the compound of formula I shows a strong inhibition of noradrenaline uptake in rat heart by the method of L. Maitre, M. Staehelin and H. Bein, Biochem. Pharmacol. 20, 2169 (1971) with a 20 EDj 0.3 mg / kg po, while the ED 2 q for the corresponding racemate is at 1.5 mg / kg po, as well as a strong inhibition of the noradrenaline-depleting effect of H 77/77 (3-hydroxy-4, ) in the rat brain as an indirect indication of the noradrenaline uptake inhibition [A. Carlsson, H. Corrodi, K. Fuxe, and T. Hoefkelt, Europ. J. Pharmacol. J5, 367 (1969)] with an ED 50 of ca. 2 mg / kg p.o., compared to an ED 10 mg / kg p.o. of the corresponding racemate. The endogenous concentrations of norepinephrine and dopamine 30 in rat brain, as measured by P. Waldmeier, de Herdt, and L. Maitre [Chir. Chem. 20, 81, (1974)] are neither affected by the hydrochloride of the compound of formula I in doses of up to 100 mg / kg and 30 mg / kg po, respectively, or of the corresponding racemate in doses of up to 10 mg / kg 35 and up to 100 mg, respectively. / kg.

3 169102

The results of the noradrenaline uptake make it obvious that the strong reserpine antagonistic effects of the compound of formula I or its acid addition salts also depend on a corresponding influence on noradrenaline transport and metabolism. The increase in the effect to much more than twice that in this trial can at least not be explained by the fact that only the (+) antipode present in the known racemate is effective, and must therefore be regarded as surprising.

In a number of further experiments, the compound of formula I, tested as hydrochloride, has about the same to at most twice the potency of the corresponding racemate.

Equal doses of the two substances produce approximately the same effects, e.g. by antagonizing the histamine toxicity in guinea pigs, by testing the exploratory activity in mice [A. Delini-Stula and R. Meier, Neuro-. Pharmacology, 3J>, 383-388 (1976)], and in the foot-induced combat response in mice [Tedeschi et al., J. Pharmacol. Exp. Therap. 125, 28-34 (1959)], while the hydrochloride of the compound of formula I has half the dosage is as effective as the corresponding racemate in antagonizing rat catalepsy induced by rat after oral administration and by potentiating that of G 29 505 [2- (4-allyl-2-methoxyphenoxy) -25 Ν, Ν diethyl acetamide] induced anesthesia in mice [W. Theobald and R. Domenjoz, Arzneimittelforsch. 9, 285-286 (1959)] after intraperitoneal administration.

The acute toxicities of the compound of formula I and the corresponding racemate by oral and intravenous administration are approximately the same. The same negative inotropic effects on isolated left anterior chamber from reserpine, viz. guinea pigs pretreated with reserpine were elicited by the compound of formula I at ca. half the concentrations of the racemate, while the negative chronotropic effect of the compound of formula I on the isocentric right anterior chamber was weaker than that of the racemate, and the comparison of the effect of 1 mg / kg of each of the racemates. two substances on the isolated front compartments from unreserved guinea pigs and from reserpined guinea pigs show that they have approximately the same cardiostimulatory effect.

From the aforementioned and further experiments, it appears that the substantial increase in the reserpine antagonistic effect and the noradrenaline uptake inhibition as well as the approximately double tetrabenazine antagonist effect of the compound of formula I and its acid addition salts, which for antidepressants, is particularly pronounced. characteristic qualities of action, in comparison with the racemate and its acid addition salts, are in no way accompanied by a similar increase in toxicity and / or 15 of the side effects. S - (+) - α - [(Methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol of formula I and its pharmaceutically acceptable salts may find use as antidepressants, especially for the treatment of mental depressions.

The process of the invention is characterized in that a) divides racemic α - [(methylamino) methyl] -9,10-ethano-anthracene-9 (10H) -ethanol and isolates S - (+) - α - [(methylamino) ) -methyl] -9,10-ethanoanthracene-9 (10H) -ethanol, optionally in the form of an acid addition salt, or b) in a compound of the formula 0-Z1 Z2

T I

CH0 --- C --- CH -N-CH_ (II) I A 2 3

AH

1 2 wherein at least one of the symbols Z and Z represents a leaving group and the other optionally hydrogen, or 1 2

Z and Z together form a divalent leaving group, and A

Represents a 9,10-ethanoanthracene-9 (10H) -yl group, from -12 cleaves the group Z and / or Z, or c) reduces a compound which differs only from the compound of formula I by a carbon atom adjacent to the nitrogen 5 therein is bonded thereto with a double bond or is substituted with a hydroxyl group or with an oxo group, optionally together with lower alkoxy, or d) ethylene is added to S-α - [(methylamino) methyl] - 9 (10H) -10 anthracene ethanol, or e) reacting a compound of the general formula H CO-R1

? IN

CH + --- C --- CHO-N-CH_ (III) \. k Z å

A OH

wherein R · means an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and A is a 9,10-ethanoanthracene-9 (10H) -yl group having a strong oxygen-containing inorganic or organic acid or a halide of such and hydrolyzing the intermediate formed and, if desired, transferring the thus obtained S - (+) - α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -20 ethanol to an acid addition salt and / or releasing the base from a obtained acid addition salt.

The division and isolation according to method a) is carried out in a manner known per se. For example, the racemate can be transferred to acid addition salts with salt-forming optically active acids such as organic carboxylic or sulfonic acids, e.g. The (D) and (L) forms of tartaric acid, bis-0,0 '- (p-toluoyl) tartaric acid, malic acid, mandelic acid, campersulfonic acid, quinic acid, lactic acid, glutamic acid or aspartic acid. The obtained mixtures of the corresponding 30 salts can be based on physicochemical differences, e.g. in solubility or crystallization ability, is divided into the 6 149102 diastereoisomeric salts and the optically active (+) form may optionally be released from the salt.

From the racemate, by fractional crystallization from a suitable solvent, optionally also from an optically active solvent, or by chromatography, especially thin layer chromatography on an optically active carrier, the (+) form can be separated.

In the starting materials of the general formula II to process b), leaving groups Z and Z as well as 12 and Z and Z together form divalent leaving groups, for example by solvolysis, especially hydrolysis, or by reduction, e.g. hydrogenolysis, leaving groups.

Considering that with solvolysis, especially hydrolysis, cleavable groups Z and Z, e.g. acyl groups such as alkanoyl groups, especially halogenated ones, e.g. fluorinated lower alkanoyl groups such as the acetyl group or the trifluoroacetyl group; aroyl and aryl avalkanoyl groups, such as the benzoyl or phenylacetyl group, or acyl residues of carbonic acid esters, e.g. lower alkoxycarbonyl groups such as the methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group or aralkoxycarbonyl groups such as the benzyloxycarbonyl group and e.g. also silyl groups, such as the trimethyl-silyl group. 1 2

A divalent group formed by Z and Z is, for example, a geminal divalent hydrocarbon group, especially a lower alkylidene group such as a methylene, ethylidene or 1-methylethylidene group (isopropylidene group), or an aralkylidene group such as a benzylidene group. eg. a phosphorylidene group, especially a lower alkoxy-phosphorylidene group, such as a methoxy or ethoxy, phosphorylidene group.

149102 7 1 9

The hydrolytic cleavage of Z and / or Z occurs with hydrolyzing agents, for example in the presence of acidic agents such as dilute 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, in suitable organic or organic aqueous solvents, e.g. in optionally water-diluted low alkanols, at a lower temperature, e.g.

At room temperature, or preferably under heating.

1 2

The hydrolytic cleavage of a divalent group formed by Z and Z can be done by analogy.

1 2

For reduction, cleavable groups Z and Z are, for example, 1-aryl arylalkyl groups, such as the benzyl group, or 1-aryl aalkylalkoxycarbonyl groups, such as the benzyloxycarbonyl group, which can be, for example, split off by hydrogenolysis, e.g. by reduction with catalytically activated hydrogen such as hydrogen in the presence of a hydrogenation catalyst such as a palladium or platinum catalyst. The aralkylidene groups formed from Z and Z together, such as the benzylidene group, can also be cleaved by hydrogenolysis. However, Z or Z may also be a 2-halo-alkoxycarbonyl group such as the 2,2,2-trichloroethoxycarbonyl group or the 2-iodoethoxycarbonyl group which can be cleaved off by reduction. In view of reduction, above all, the metallic reduction (so-called nascent hydrogen), such as the effect of metal or metal alloys, as well as amalgams, preferably occurs in the presence of hydrogen emitter. agents such as carboxylic acids, alcohols or water. Above all, zinc or zinc alloys are used in acetic acid.

Also considered are chromium (II) compounds such as chromium (II) chloride or chromium (II) acetate. Z may also be an arylsulfonyl group such as a toluene sulfonyl group which may be cleaved in the usual manner by reduction with nascent hydrogen, e.g. with an alkali metal, such as lithium or sodium, in liquid ammonia. The cleavage of an arylsulfonyl group may also be carried out with a hydride, e.g. one of the simple or complex hydrides mentioned below in connection with process c), preferably lithium aluminum hydride, suitably in the presence of an inert solvent such as an ethereal organic solvent, e.g. tetrahydrofuran.

Starting materials for process c) with a double bond between nitrogen atoms and a neighboring carbon atom are S-α - [(methylenamino) methyl] -9, 10-ethanoanthracene-9 (10H) -ethanol and S-α - [(methylimino) - methyl] -9,10-ethanoanthracene-9 (10H) -ethanol. In the proximity to the nitrogen atom 15 with hydroxy substituted compounds, these are Sa - [(hydroxymethylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol and S1- (methylamino) -9,10-ethanoanthracene 9 (10H) -propane-l, 2-diol. The reduction of the above four compounds may be effected in the usual manner, preferably 20 by a simple or complex hydride, e.g. a borane, or a dile metal hydride, e.g. an alkali metal alkaline earth metal hydride such as sodium borohydride or lithium aluminum hydride, or an alkoxy aluminum or alkoxy borohydride, e.g. one of the below.

However, it is also possible to complete the reduction as hydrogenation 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.

If a carbon atom adjacent to the nitrogen atom is substituted with an oxo group, the corresponding starting materials on the one hand are SN-methyl-9,10-ethanoanthracene-9 (10H) -lactamide and on the other hand N- [3 - (9,10-Ethanoanthracene-9 (10H) -yl) -2 (S) -hydroxy-propyl) -formamide and on the nitrogen atom with the same group of substituted carbamic acid low alkyl esters such as the methyl and ethyl ester. Their reduction may be effected by the usual methods of amide reduction, for example by means of a simple or complex hydride such as a borane, e.g. diborane, or a complex dile metal hydride, especially an alkali metal aluminum hydride such as lithium-10 or sodium aluminum hydride, in an ethereal solvent such as diethyl ether or tetrahydrofuran, or by means of an alkali metal alkoxy aluminum hydride or borohydride, e.g. sodium dibutoxyaluminum hydride or sodium trimethoxyborohydride, or an alkaline earth aluminum hydride such as magnesium aluminum hydride, or by sodium borohydride in a tertiary amine such as pyridine or triethylamine, or by an aluminum hydride aluminum chloride.

The introduction of the 9,10-ethano group according to d) may take place in the usual manner, e.g. by reacting the corresponding anthracene derivative with ethylene by the method of Diels-Alder, advantageously in a suitable solvent such as an aromatic hydrocarbon, e.g. toluene, and at elevated temperature such as from 50 to 250 ° C, and / or under pressure, for example, at 25 to 150 atm.

10 149102

The corresponding starting materials of formula 111 can be prepared from, e.g. by dividing racemic α - [(methylamino) methylJ-9,10-ethanoanthracene-9 (10H) -ethanol as a by-product formed free R - (-) - α - [(methylamino) methyl] -9.10-5 ethanoanthracene-9 (10H) -ethanol by conventional acylation methods, especially using carboxylic acid halides or lower alkyl esters or, in particular, to prepare the starting compound particularly suitable with methyl as R 1 of anhydrides such as acetic anhydride.

As strong, oxygen-containing inorganic or organic acids in process e), concentrated sulfuric acid or phosphoric acid is used, in addition, e.g. strong organic sulfonic acids, such as aliphatic sulfonic acids, e.g. methane sulfonic acid, or aromatic sulfonic acids such as an optionally substituted phenylsulfonic acid such as 4-methyl, 4-bromo, 4-nitro or 2,4-dinitrophenylsulfonic acid or naphthalene sulfonic acids, e.g. 1-naphthalene sulfonic acid; and, as their halides, primarily the chlorides or bromides, such as above all thionyl chloride, furthermore e.g. thionyl bromide, sulfuryl chloride, chlorosulfonic acid, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or methanesulfonyl chloride. Furthermore, the said halides of polyhydric acids similar to mixed ester halides such as low alkoxysulfonyl halide, e.g. methoxy or ethoxysulfonyl chloride or phosphoric acid low alkyl ester halides, e.g. phosphoric acid dimethyl ester chloride.

The reactions with strong acids, especially concentrated sulfuric acid or phosphoric acid, are carried out in the presence or absence of solvents or diluents, such as acetic anhydride, at temperatures ranging from approx. -50 to 200 ° C, and the reactions with acid halides, such as thionyl chloride, also in the presence or absence of solvents or diluents, e.g. hydrocarbons or in particular 35 hydrocarbons, such as methylene chloride, in a temperature range of 14? -10 to + 70 ° C, preferably from ca. +10 to + 50 ° C. As reaction products from these reactions can be obtained 2- [5- (9,10-ethanoanthracen-9 (10H) -yl) -4,5-dihydro-3-methyl-oxazolium salts whose anion corresponds to that of the reaction acid used or in the case of reactions with acid halides is the corresponding halogen ion.

The hydrolysis of the intermediates is carried out in acidic or basic medium. Suitable acidic agents are e.g. aqueous acids such as aqueous mineral acids, e.g. aqueous hydrochloric acid, sulfuric acid or phosphoric acid. The acidic hydrolysis is carried out in a temperature range from 0 to + 120 ° C, conveniently at +10 to + 50 ° C. Suitable as basic media are e.g. aqueous hydroxide solutions, e.g. of alkali or alkaline earth metals, such as sodium hydroxide, or potassium hydroxide, or the hydroxides of calcium or magnesium, said reagents being advantageously used at elevated temperature, e.g. in a range of from 50 to 150 ° C.

The hydrolysis can also be carried out stepwise, hydrolyzing an intermediate optionally over the corresponding free base as an intermediate step, in aqueous medium to the corresponding N-acyl compound of the general formula III, with the reverse steric configuration of the starting material of the formula III used and then hydrolyzes this compound to a compound of formula I.

The process according to (e) can advantageously also be carried out by reacting the starting material of the general formula V immediately without isolating it in pure form, in the same reaction charge with a suitable acid or halide thereof and subjecting it to it obtained 30 intermediate hydrolysis, also without further purification.

The optically active starting materials necessary for processes b) to d) can be prepared either by dividing known racemic, especially basic starting materials in a manner known per se, or by analogy with the racemic starting materials necessary for the preparation of the known racemate. of optically active rather than racemic 5 starting compounds.

Acid addition salts, especially pharmaceutically acceptable acid addition salts, of the compound of formula I, e.g. the above may be prepared in the usual manner. For example, a solution of the base in an organic solvent such as methylene chloride, ethyl acetate, ethanol or 2-propanol is added to the acid desired salt component or a solution thereof in the same or other organic solvents such as ethyl acetate or diethyl ether, and if necessary, after cooling or evaporation, or after adding a solvent of poorer solubility to salts, such as diethyl ether, the precipitated salt is filtered off.

The following examples illustrate the preparation of the compound of formula I according to the process of the invention.

Example 1.

184.8 g (0.63 mol) of racemic α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) ethanol and 127.5 g (0.315 mol) (-) - bis-0.0r - (p-toluoyl) -L-tartaric acid is dissolved in 2500 ml of methanol at 40 ° C and then left for 24 hours at room temperature. The precipitated crystallate of R - (-) - α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10) -ethanol - (-) - bis-0,0 '- (p-toluoyl) L-tartrate (1: 1) is extracted and washed twice with 50 ml of ice-cold methanol per ml. walk.

The filtrate is evaporated in aqueous air pump vacuum. The residue 30 is dissolved in 500 ml of methylene chloride and this solution is shaken three times with 100 ml of 2 N sodium hydroxide solution per ml. once and then twice more with 100 ml of water per ml. walk. After evaporation of the methylene chloride, 132.5 g are obtained partially with S - (+) - α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol-enriched base. This base (0.452 mol) and 91.4 g (0.226 mol) (+) - bis-0.0 '- (p-toluoyl) -D-tartaric acid are dissolved in 1800 ml of methanol at 40 ° C and recommended 24 hours at room temperature. The precipitated crystal lysate is aspirated and dissolved in methanol and the resulting solution is evaporated to a third volume and left to stand for 24 hours at room temperature. The separated crystals are suctioned off and washed with slightly cold methanol to give S - (+) - α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol - (+) - bis 0.0 '- (p-toluoyl) -D-tartrate (1: 1) melting at 178 ° C under decomposition; [α] D = + 63 ° (c = 0.774 in methanol).

To recover the free base, dissolve 4.9 g (0.01 15 mol) of the above salt in 50 ml of methylene chloride, extract the solution twice with 15 ml of 1 N sodium hydroxide solution per ml. once, it was washed twice with 15 ml of water. and evaporate it at approx. 14 mbar. The residual crystallized S - (+) - α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol melts at 106-107 ° C, [a] + = +9.5 ( c = 1.06 in methanol). If desired, the base can also be recrystallized from ether.

To prepare the hydrochloride, 88.4 g (0.18 mol) of S - (+) - α - [(methylamino) methyl] -9,10-ethanoanthracene-25 (10H) -ethanol - (+) - bis 0.0 '- (p-toluoyl) -tartrate (1: 1) in 300 ml of methylene chloride and, with stirring at room temperature, an ethereal hydrogen chloride solution is added until the superimposed vapor stains congop paper persistently blue. Thereby, S - (+) - α - [(methylamino) methyl] -30 9,10-ethanoanthracene-9 (10H) -ethanol hydrochloride crystallizes. After the addition of 450 ml of ether, the crystallization is suctioned off and then recrystallized once from ethanol-methanol.

The hydrochloride thus obtained melts at 231-232 ° C; = + 9 ° (c = 2.1 in methanol).

14 149102

Example 2.

a) To a solution of 2.93 g (0.010 mol) of R - (-) - α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol in 8 ml of dimethylformamide is dropped at 5 -10 ° C 1.9 ml of acetanhydride.

The solution is stirred for 4 hours at room temperature, then poured into 60 ml of water and extracted with 100 ml of ethyl acetate. The ethyl acetate solution is washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated in vacuo. The residual crude R - (-) - α-10 [(N-methylacetamido) -methyl] -9,10-ethanoanthracene-9 (10H) -ethanol can be processed directly.

b) The crude product from a) (2.5 g) is dissolved in 6 ml of methylene chloride. With stirring, at 5-10 ° C, a solution of 0.77 ml of thionyl chloride in 4 ml of 15 methylene chloride is added over 15 minutes. The reaction solution is stirred for 2 hours at 20 ° C and then for 1 hour at 35 ° C and then evaporated at ca. 14 mbar (water air pump vacuum) to dryness.

c) The evaporation residue from b) is dissolved in 10 ml of ethanol and 2.5 ml of water and 1.6 g of sodium hydroxide are added and boiled under reflux for 3 hours. The reaction mixture is then evaporated at ca. 14 mbar, 50 ml of ice water is added and then extracted with 100 ml of ethyl acetate. The ethyl acetate solution is washed neutral with water, dried over sodium sulfate and evaporated at ca. 14 mbar, leaving 25 the raw inverted base.

The residue is dissolved in 10 ml of methylene chloride and ethereal hydrogen chloride solution is added to crystallize S - (+) - 1 - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol hydrochloride. The crystals are aspirated and recrystallized from 2-propanol. Mp. 229-231 ° C, [α] D = + 9 ° -1 ° (c = 1.6 in methanol).

149102 15

The starting material for step a) is obtained as follows: 60 g of the R (-) - α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol - (-) first formed in Example 1 bis-0.0 '- (p-toluoyl) -L-tartrate- (1: 1) [m.p. Dissolve 180 ° C under 5 decomposition, [α] D = -64 ° (c = 1.135 in methanol)] in 500 ml of methylene chloride and this solution is shaken three times with 100 ml of 2 N sodium hydroxide solution per ml. once and then twice more with 100 ml of water per ml. walk. The residue of 10 R - (-) - α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol (mp 107-108 ° C) evaporating directly after the acetylation of a ).

Example 3

2.93 g (0.010 mol) of R - (-) - α - [(methylamino) methyl] -9,10-15 ethanoanthracene-9 (10H) -ethanol are dissolved portionwise in 14 ml of acetanhydride. To this solution is added, with stirring, a solution of 1.75 g of 96% sulfuric acid in 6 ml of acetanhydride and then the mixture is refluxed for 3 hours. Then the obtained solution is evaporated at approx. 14 mbar and the residual reaction product formed by N-acetylation and cyclization is taken up in 30 ml of 1 N-sulfuric acid and refluxed for 2 hours. 50 g of ice is then added and the resulting mixture is adjusted with aqueous ammonia solution 25 to pH 9 and extracted twice with 50 ml of ethyl acetate per ml. walk. The combined organic phases are dried over sodium sulfate and evaporated to dryness. The residual crude base is dissolved in 10 ml of methylene chloride and ethereal hydrogen chloride solution is added to give S - (+) - α - [(methyl-30-amino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol-hydrochloride. chloride crystallizes. It is extracted and recrystallized from 2-propanol; mp. 228-230 ° C.

16 149102

Example 4

3.9 g of crude 5 (S) - [(9,10-ethano-anthracen-9 (10H) -yl) methyl] -3-methyl-oxazolidine obtained according to a) are heated with 60 ml of 2N hydrochloric acid. 3 hours to 90 ° C. Then, 5N sodium hydroxide solution is added to the alkaline reaction, extracted with methylene chloride and evaporated the organic phase. The residual crude S-α - (+) - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol is dissolved in 10 ml of ethanol and 1 ml of a 10% ethanolic hydrogen chloride solution is added. Upon addition of ether, the hydrochloride of the above base is crystallized. The crystallized hydrochloride is aspirated and further purified, if desired, by analogy to Example 1 or Example 2.

The starting material may be prepared as follows: a) 20.0 g of S-α- (aminomethyl) -9,10-ethanoanthracene-9 (10H) -ethanol (obtainable from the corresponding, in U.S. Patent No. 4,017,542, Example 1, racemic compound described with m.p. 76-177 ° C, for example, similar to the present Example 1), a mixture of 10 ml of 35% aqueous formaldehyde solution and 150 ml of formic acid is heated for 1 hour to 95 ° C. The reaction mixture is evaporated in vacuo and the residue is made alkaline by the addition of 2N sodium hydroxide solution and extracted with methylene chloride. The organic phase is evaporated to leave 5 (S) - [(9,10-ethano-anthracen-9 (10H) -yl) methyl] -3-methyl-oxazolidine.

Example 5

To a suspension of 0.7 g of lithium aluminum hydride in 20 ml of tetrahydrofuran is added a solution of 1.5 g of N- [3- (9,10-ethanoanthracen-9 (10H) -yl) -2 (S) -hydroxy propyl] -formamide in 20 ml of tetrahydrofuran and boil the mixture for 4 hours under reflux. Then it is cooled and 1.4 ml of water is added, then 1.4 ml of 15% sodium hydroxide solution and again 5 ml of water. The precipitated precipitate is filtered off, the filtrate is evaporated and the residue is dissolved in 2N acetic acid. The acidic solution is washed with ether and then 10% sodium hydroxide solution is added to the alkaline reaction and extracted with methylene chloride. The solvent is evaporated and the residual crude S - (+) - o - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol is transferred analogously to Example 1 or 2 to the hydrochloride with m.p. 231-232 ° C.

The substituted formamide used as the starting material can be prepared as follows: a) 5 g (S) -a- (aminomethyl) -9,10-ethanoanthracene-9 (10H) -ethanol [cf. Example 4a)] is boiled in 75 ml of formic acid ethyl ester for 2 hours under reflux. The cooled solution is evaporated at ca. 14 mbar to dryness. The residue is dissolved in 75 ml of methylene chloride and this solution is washed with 40 ml of 1N hydrochloric acid, dried over sodium sulfate and evaporated again at ca. 14 mbar to dryness. The residual N- [3- (9,10-ethanoanthracene-9 (10H) -yl) -2 (S) -hydroxy-propyl] -formamide can be used directly for the reduction.

Example 6

A solution of 10 g of S-α - [(methylamino) methyl] -anthracene-25 (10H) -ethanol in 200 ml of benzene is heated in autoclave with ethylene under a pressure of 70 atm. for 6 hours to 70 ° C. Extract with 200 ml of 2N hydrochloric acid. The acidic extract is alkaline and extracted with methylene chloride.

The organic phase is evaporated and the residual crude 30 s-a - (+) - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol is transferred analogously to Example 1 to its hydrochloride.

Claims (3)

149102 An analogous process for preparing a right-turning basic derivative of 9,10-ethanoanthracene, S - (+) - α - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) -ethanol 5 of the formula OH? CH 2 --- J --- ch 2 -NH-CH 3 III (I) I CH 2 IS / Pv or acid addition salts thereof, characterized in that a) dividing racemic ot- [(methylamino) methyl] -9,10-ethano - 10 anthracene-9 (10H) ethanol and isolates s - (+) - <x - [(methylamino) methyl] -9,10-ethanoanthracene-9 (10H) ethanol, optionally in the form of an acid addition salt, or b) in a compound of the formula 1. O-Z Z T I. CH 2 --- C --- CH-N-CH (II) \ ik Δ in AH 1 2 15 wherein at least one of the symbols Z and Z represents a leaving group and the other optionally hydrogen, or Z and Z together a divalent leaving group, and A represents a 9,10-ethanoanthracene-9 (10H) -yl group, from -12 cleavage group Z and / or Z, or c) reducing a compound which differs only from the compound of formula I, wherein a carbon atom adjacent to the nitrogen therein is bonded thereto with a