NO141800B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZOMORPHANES - Google Patents

Description

The invention relates to an analogous process for the production of new 2-tetra-hydrofurfuryl-6,7-benzoarophanes with the general formula

and acid addition salts thereof.

In formula I means

R^" methyl, ethyl or propyl,

R 2 means hydrogen, methyl or ethyl,

R 3 means hydrogen or methyl, and

R 4 means hydrogen, alkyl with 1-4 carbon atoms or acyl with 2-5 carbon atoms.

The invention includes compounds of formula I where R^<* >and R are in the cis position with respect to the carbocyclic ring. 12 2 This means that the formula, when the residues R and R are alkyl groups and R is different from R 3, only includes compounds a a series with alkyl residues 1 2

R and R in the cis position.

Compounds of formula I where R 4 means hydrogen and the other residues are as indicated above are preferred. Particularly preferred are compounds of formula I where R means methyl and R and R 4 mean hydrogen (2-tetrahydrofurfuryl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan).

With the above definition of the compounds of formula I, the following situation is obtained with regard to stereochemistry: The norbenzomorphan which forms the basis of the compounds, and which has the following formula

has 2 asymmetry centers when R 2 = R 3, resp. 3 asymmetry centers when

2 3

R is not identical to R.

Due to the rigid incorporation of the asymmetry centers

C-1 and C-5 in a ring system with a bridge, and due to the determination of the asymmetry center C-9 (restriction to the a-row), however, the norcombindelscn with formula II, which is the basis of formula I, exists only in a single racemic form and the associated optical antipodes.

With the N-tetrahydrofurfuryl substitution, a further center of asymmetry appears in the molecule (at C-2" in the tetrahydrofuran ring). It is therefore to be expected that in the formula I defined above, two rows (1,1) and (1 ,2) of racemic diastereomers and the associated optical antipodes, which exist due to the following combination possibilities:

Which of the optical antipodes belonging to (1,1) and (1,2) respectively, which are left-rotating and which are right-rotating, cannot in principle be determined only because of the configuration, but only by measurement in a polarimeter.

For some of the more closely examined 2-tetrahydrofurfuryl-21-hydroxy-5,9a-dimethyl-6,7-benzomorphans according to the invention (formula I, R<1> = R<2> = CH3 and R<3> = R4 = H) it has been shown that the direction of rotation of the basic compound of formula II is not changed by introducing D-(-)- or L-(+)-tetrahydrofurfuryl residues. It is likely, but can by no means be predicted with certainty, that this relationship also applies to compounds of formula I with other combi-1 4

nations of R - R .

With regard to the nomenclature of the compounds of formula I, there are no difficulties with the optically active representatives, as can be seen in the above table. If one uses the characteristics IR, 5R, 9R, respectively IS, 5S, 9S, then the configuration at C-9 is thus unambiguously determined, and in the chemical designation "a" can be omitted. With the racemic compounds, on the other hand, it is not possible to say in advance which of the two possible diastereomers are present. In the description of the invention, both racemic diastereomers are marked with (+) and are distinguished from each other with the addition "diastereomer 1" or "diastereomer 2", where 1 and 2 mean the order of isolation.

The compounds are produced according to the invention

following different methods:

A) by alkylation of a norbenzomorphan with the formula 1 4 where R - R have the meanings given above, with a connection of the formula

where X means a nucleophilic removable group, preferably a halogen atom, especially chlorine, bromine or iodine, or an arylsulfonyloxy, aralkylsulfonyloxy or alkylsulfonyloxy group.

A calculated amount of the alkylating agent is used

with formula III, or preferably an excess thereof, and works appropriately in the presence of an acid-binding substance, such as e.g. triethylamine, dicyclohexylethylamine, sodium carbonate, potassium carbonate and calcium oxide, or preferably sodium bicarbonate. Although solvents can also be dispensed with, it is appropriate to carry out the reaction in inert solvents, such as, for example, chloroform, toluene, ethanol, nitromethane, tetrahydrofuran, dimethylsulfoxide and preferably dimethylformamide. Mixtures of these solvents can also be used. Finally, an excess of the alkylating agent can also be used as a solvent, e.g. excess of tetrahydrofurfuryl bromide. The reaction temperature can be varied within wide limits, the lower of which is determined by a low reaction rate and the upper by the occurrence of side reactions. Appropriately, the temperature is between 50 and 150°C. If one

working with less reactive alkylating agents, e.g. tetrahydro-furfuryl chloride, the reaction can be accelerated by the addition of catalytic or equimolar amounts of potassium or sodium iodide.

B) When reducing a carboxyl amide resp. thioamide with the formula

1 4

where R - R have the meanings given above, and Y means an oxygen or sulfur atom.

The reduction of the carboxyl amide (compounds of formula

IV where Y means an oxygen atom) can be carried out by different methods. Particularly suitable is the reduction with complex hydrides with high reducing power, especially with lithium aluminum hydride. The hydride is added in the calculated amount or in excess, preferably in an inert solvent, preferably diethyl ether, diisopropyl ether and especially tetrahydrofuran. The reaction temperature can be varied within wide limits and is preferably between 0°C and the boiling point of the solvent.

In the reduction of O-acyl derivatives of formula IV, where Y means an oxygen atom, with complex metal hydrides, e.g. by reduction with lithium aluminum hydride, in addition to the reduction of the carbonyl group, the O-acyl residue is simultaneously also reductively cleaved, and

4

in this case compounds of formula I are obtained where R means a hydrogen atom.

The reduction of the thioamide (compounds of formula IV where

Y means a sulfur atom) takes place significantly more easily than the reduction

of the carboxyl amide. It can be carried out with complex hydrides or with nascent hydrogen (eg Zn/hydrochloric acid, Zn/acetic acid or aluminum amalgam/water). It is also possible to remove sulfur with Raney nickel or to carry out the reduction electrochemically. When using reducing agents with stronger reducing power, O-acyl groups can be reductively split off. This case results in pre-

4

compounds of formula I where R means a hydrogen atom.

C) When reducing a compound with the formula

14 5

where R - R and Y have the meanings given above, and R means an alkyl residue with up to 4 carbon atoms, preferably a methyl group, and A^~) means the anion of an inorganic or organic acid.

The reduction can take place according to different methods,

and you can e.g. apply all the precautions indicated for the reduction of the thiocarboxyamide. However, there is a limitation due to the cleavability of the compounds of formula V and their propensity for side reactions (eg hydrolysis and aminolysis). It has proven advantageous that the compounds of formula V are immediately reacted further without isolation. Use of complex metal hydrides with reduced reducing power, e.g. sodium borohydride, is advantageous. It is further possible to carry out the reduction with nascent hydrogen and/or hydrogen in the presence of a hydrogenation catalyst, e.g. Raney nickel. during the reduction, the O-acyl groups can be cleaved, depending on the reaction conditions.

D) Compounds of formula I where R 4 represents a hydrogen atom are produced by ring closure of compounds with the general formulas

1 4

where R - R have the meanings given above, and Z means a halogen atom, a hydroxy group, alkoxy, acyloxy or arylsulfonyloxy or alkylsulfonyloxy group.

The cyclization reaction can be carried out according to known methods. One can e.g. work under the conditions for Friedel-Crafts reactions with aluminum chloride in carbon disulfide, or one can effect ring closure with strong acids, such as e.g. phosphoric acid or polyphosphoric acid, and preferably at temperatures between 100 and 150°C. By cyclization of compounds of formula VII a, compounds of formula I are obtained where R means hydrogen. Under the reaction conditions for the ring closure, O-acyl or O-alkyl groups can in certain cases be cleaved, whereby compounds of formula I with a free phenolic hydroxy group (R 4 = hydrogen) are obtained.

E) by tetrahydrofuran ring closure of compounds with the formula

1 4

Where R - R is as above indicated.

A wide variety of methods can be used for the tetrahydrofuran ring closure. One can, for example, carry out the splitting off of water which leads to the ring closure, by the action of acid catalysts on compounds of formula VIII. Suitable acid catalysts are e.g. inorganic or organic acids or acid salts, such as sulfuric acid, phosphoric acid, oxalic acid, p-toluenesulfonic acid, sodium hydrogen sulfate and anhydrous zinc chloride. One preferably works at elevated temperatures and best between 100 and 200°C. It may be appropriate to remove the separated water with a water-binding agent, such as e.g. excess sulfuric acid or excess zinc chloride, or by azeotropic distillation. Often it is also advantageous to temporarily replace one of both hydroxy groups with a more reactive group. Thus, for example, ring closure can be effected with toluenesulfonic acid chloride in pyridine without the temporarily formed O-toluenesulfonyloxy derivative of the compound of formula VIII being isolated. Depending on the relatively drastic reaction conditions, O-acyl and O-alkyl groups can be cleaved to free phenolic hydroxy groups.

4

F) Compounds with the general formula I where R means a hydrogen atom are produced by ester cleavage of compounds with the formula

13 7

where R - R have the meanings given above, and R means an acyl residue derived from an inorganic or organic acid. Of practical importance above all are lower aliphatic or simple aromatic and heterocyclic acyl residues, especially acetyl, propionyl, benzoyl and tetrahydro-2-furoyl.

The splitting can be carried out according to different procedures. The simplest is acid or alkaline hydrolysis, which is preferably carried out in an aqueous, alcoholic or aqueous-alcoholic solution. The reaction temperature, which can be varied within wide limits, is suitably between 20 and 100°C.

One can also cleave the O-acyl grouping reductively. Reduction with complex hydrides is particularly suitable among the applicable methods. One thereby works with the method described for the reduction of carboxylic acid amides. A simultaneous reduction of amide and phenolic ester grouping is advantageous.

G) For the preparation of compounds of formula i where R 4 means a hydrogen atom, compounds of the formula are submitted

13 8

where R - R is as indicated above, and R means an alkyl or aralkyl group, ether cleavage.

The ether cleavage of compounds of formula X to compounds of formula I can be carried out by the various methods, which vary greatly with the nature of the residue R Q , and which must be chosen so that the tetrahydrofuran ring is maintained. The selective cleavage of the phenol ether grouping with caustic soda and caustic alkali in high-boiling solvents, such as diethylene glycol or triethylene glycol, is e.g. suitable. Herein, one works expediently at temperatures between 150°C and the boiling point of the solvent, with excess alkali hydroxide. Benzyl ethers can also be split by catalytic hydrogenation. Methoxymethyl ether is very acid-labile and can already be decomposed under mild conditions with dilute mineral acids.

4 H) For the preparation of compounds of formula I where R means an acyl group, compounds of formula I where R 4 means hydrogen are acylated with an acylating agent containing 2-5 carbon atoms in the acyl part.

The acylation can take place according to a variety of methods. It is most advantageous to work with corresponding carboxylic acid chlorides or carboxylic acid anhydrides. You can work in an inert solvent with the calculated amount or with a small excess of the acylating agent. But it is also possible to use excess acylating agent, which also serves as a solvent. It can be recommended to add an acid-binding agent to the reaction mixture. Particularly suitable for this purpose is pyridine, which can be added in catalytic amounts, equimolar amounts or in excess and also as a solvent. A further base suitable for this purpose is triethylamine. As a reaction temperature, the range 20-150°C, preferably 50-100°C, has particularly stood out.

I) For the preparation of compounds of formula I where R 4 means a lower alkyl residue, compounds of formula I where R<4> means H are alkylated with an alkylating agent containing 1-4 C atoms in the alkyl part.

Alkylation can be carried out using a variety of methods. Preferred are alkylating agents and reaction conditions which enable a selective O-alkylation, without any quaternization of the nitrogen occurring. For this purpose, it is particularly suitable to add diazoalkanes or phenyltrialkylammonium hydroxides as alkylating agents. Diazoalkanes are used in suitable inert solvents, e.g. in diethyl ether or tetrahydrofuran, and preferably at room temperature. When trialkylammonium hydroxide is used, the starting compound is heated with the alkylating agent in suitable inert solvents, preferably in dimethylformamide.

The reaction products obtained are isolated from the mixture using standard methods. The raw products obtained can optionally be purified using special methods, e.g. column chromatography, before crystallizing them in the form of bases or suitable acid addition compounds.

Depending on the choice of reaction conditions and reaction participants, the recovered reaction products are either sterically uniform compounds or mixtures of racemic or optically active diastereomers.

Diastereomers can be separated according to known methods on the basis of their different chemical and physical properties,

e.g. by fractional crystallization. Racemic compounds can be split into the corresponding optical anitpods using common methods for racemate resolution.

A large part of the output compounds that can be added by

the methods described above are known. Thus, e.g. nor benzomorphans with the general formula II several times described in the literature.

The optically active tetrahydrofurfuryl halides of formula

III can be prepared from the known optically active alcohols (F.C. Hartmann and R. Barker, J. Org. Chem. 29, 873-877 (1964) by halogenation, e.g. with forforpentaclpride or phosphorus pentabromide (Org. Synth. 23 ^, 88) :

Corresponding sulphonic acid esters can be prepared by reacting tetrahydrofurfuryl alcohols with sulphonic acid halides.

Carboxylic acid amides of the general formula IV are obtained by reacting nor compounds of formula II with tetrahydro-furoyl chlorides. From the corresponding carboxylamides of formula IV, the corresponding thiocarboxylamides can be prepared by reaction with phosphorus pentasulphide.

Compounds of formula v are recovered by reacting compounds of formula IV with alkylating agents.

The preparation of compounds of formula VI appears by reaction of nor compounds of formula II with R-phenylethyl chloride, naphthylethyl chloride or 1,2-diphenylethyl chloride and subsequent quaternization of the tertiary amines with compounds of formula III.

Output compounds with the general formulas VII a and

Vllb can be obtained by alkylation of piperidines of formula XI known from the literature

Z </><3>

H CH 2 -Q> -OR^

with alkylating agents of formula ill.

Starting compounds of formula VIII are prepared by reacting nor compounds of formula II with f-keto acid esters of the formula

where Y has the meaning given above, and reduction of the thereby obtained intermediate compounds with the formula

with complex hydrides.

Starting compounds with formulas IX and X can be obtained by alkylation of corresponding norbenzomorphans with alkylating agents with

the formula ill.

The compounds of the general formula I, prepared according to the invention, are bases and can be converted in the usual way into their physiologically compatible acid addition salts. Acids that are suitable for salt formation are, for example, mineral acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid and nitric acid, or organic acids, such as acetic acid, propionic acid, butyric acid, valerian acid, pivalic acid, caproic acid, oxalic acid, malonic acid , succinic acid, maleic acid, fumaric acid, lactic acid, grape acid, tartaric acid, citric acid, benzoic acid, p-hydroxybenzoic acid, salicylic acid, p-amino-benzoic acid, phthalic acid, cinnamic acid, ascorbic acid, 8-chloro-theophylline, methanesulfonic acid, ethanephosphonic acid and such.

The compounds of formula I and their acid addition salts, prepared according to the invention, exert a therapeutically useful effect on the central nervous system. The analgesic effect is particularly pronounced, and it can e.g. demonstrated in mice by the twisting test, the hot-plate test and the Haffner test. The most effective compounds achieve, by subcutaneous injection, according to the test, a potency that is ten to thirty times that of morphine. Despite this strong effect, the typical side effects of morphine are missing, e.g. the rough-tail phenomenon and the maneat behavior. The lack of these side effects, which are particularly typical of the connection with activity in the Haffner test, can be inferred from the absence of other undesirable properties of morphine, especially the lack of demand effect. Correlation between rough-tail and need potential is documented in the literature, compare with I. Shemano and H. Wendel: A Rapid Screening Test for Potential Addiction Liability of New Analgesic Agents, Toxicol. Appl. Pharmacol. 6_, 334-339 (1964). The new compounds are further distinguished by a greater therapeutic breadth compared to morphine. The compounds produced according to the invention also show no morphine-like effect in morphine-starved rats.

The compounds of the general formula I and acid addition salts thereof, produced according to the invention, can be used enterally or also parenterally. The dosage for enteral or par-enteral use is around 0.5-100 mg, preferably between 1 and 20 mg. The compounds with formula in resp. acid addition salts thereof can be combined with other painkillers or with other types of active substances, e.g. with sedatives, tranquilizers and hypnotics. Suitable forms of administration are, for example, tablets, capsules, suppositories, solutions, suspensions, powders or emulsions. For the production of these, commonly used galenic aids, carriers, explosives or lubricants or substances can be used to achieve a depot effect. The production of such galenic administration forms takes place in the usual way according to the known preparation methods.

In particular, from the descriptions of US patent 3,499,906 and Norwegian patent 134,054, 5,9-dialkylbenzomorphans with analgesic effect are known, which are closely related to the compounds produced according to the invention, and with such known compounds a comparative investigation of the analgesic effect has been carried out on mice (NMRI strain, both sexes, 19-24 g weight, 10 animals per dose, subcutaneous administration of test compound Isen).

The analgesic effect was investigated by the hot plate test (G. Woolfe and A.D. MacDonald, J. Pharmacol. Ex. Ther. 80,

300 (194 4) and the torsion test (H. Blumberg, P.S. Wolf and H.B. Dayton, Proe. Soc, Exp. Biol. Med. 118, 763 (1965)).

The results listed in the table below show

that the tetrahydrofurfurylbenzomorphans produced by the method according to the invention generally have a better analgesic effect than the known furfuryl or thenyl benzomorphans or the known 5,9-diethyl-substituted tetrahydrofurfurylbenzomorphans.

Pharmacological comparison trials

The following examples shall illustrate the invention.

i «* 1 ouu Preparation examples a) Reaction of optically active basic bodies with optically active teti raliydrof urf urylf orcompounds.

Example 1 (method A)

(-)-2-(D-tetrahydrofurfuryl)-[(IR, 5R, 9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan]-methanesulfonate

2.17 g (0.01 mol) (IR,5R,9R)-(-)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 1.26 g sodium bicarbonate and 1.82 g ( 0.011 mol) of D-(-)-tetrahydrofurfuryl bromide is boiled with stirring under reflux in a mixture of 15 ml of dimethyl furoamide and 25 ml of tetrahydrofuran, for 75 hours. The reaction mixture is then evaporated in vacuo and the residue is shaken with 35 ml of chloroform and 35 ml of water. After separation of the chloroform phase in a separatory funnel, the aqueous solution is extracted twice more with 15 ml of chloroform each time. The combined chlorform solutions are washed with 30

ml of water, is dried with sodium sulfate and evaporated in vacuo. The crude reaction product obtained as evaporation residue can be crystallized directly, or better after purification by column chromatography on aluminum oxide. For column chromatography, the crude product is dissolved

in 25 ml of chloroform and put the solution on a chromatography column with 50 g of alumina (activity level III, neutral) in chloroform. One elutes with a mixture of 99 parts by volume chloroform and 1 part by volume methanol and collects the eluate in fractions of 10-20 ml. After thin-layer chromatographic testing, the fractions with the pure substance are combined and evaporated in a vacuum. The evaporation residue is crystallized from a mixture of 10 ml of methanol and 6 ml of water. After standing overnight at 2°, the crystals are suctioned off and washed with a little aqueous methanol. After drying at 80°, 2.3 g (76.5% of theory) of crystallized base with a melting point of 197° is obtained, which is raised to 201° by recrystallization from aqueous methanol and which does not change after several times of recrystallization. The substance has a specific rotation of [ a] = - 108.5

(c = 1, methanol).

For conversion to the methanesulfonate, 1.55 g (0.005 mol) of crystallized base is dissolved in 8 ml of ethanol with the addition of 0.47 g of methanesulfonic acid, and ether (40 ml) is added to the solution until just clouding. After resting for several days in a closed vessel at 2°, the salt separates in coarse crystals. The crystals are suctioned off, washed with 1:1 ethanol/ether and then with ether and are dried at 50°. 1.4 g (70.5% of theoretical) of the title compound with a melting point of 70° are obtained during cleavage. The hygroscopic substance does not change its melting point after recrystallization from ethanol/ether and drying at 50° in high vacuum.

Example 2 (method A)

(+)-2-(L-tetrahydrofurfuryl)-[IS,5S,9S)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan].

Starting from 2.17 g (0.01 mol) (IS, 5S, 9S)-(+)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 1.26 g of sodium bicarbonate and 1.82 g (0.011 mol) of L-(+)-tetrahydrofurfuryl bromide is obtained, analogously to example 1, 2.2 g (72.5% of theory) of the title compound with a melting point of 199° as the first crystallisate from an aqueous medium, which melting point increases to 200° after recrystallization from aqueous methanol. The specific rotation of the substance lies at [a]_ 2 5 = + 109.3 (c = 1, methanol).

Example 3 (method A)

(-)-2-(L-tetrahydrofurfuryl)-[(IR, 5R, 9R)-2<1->hydroxy-5,9-dimethyl-6,7-benzomorphan].

Starting from 2.17 g (0.01 mol) (IR, 5R, 9R)-(-)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 1.26 g of sodium bicarbonate and 1.82 g (0.011 mol) of L-(+)-tetrahydrofurfuryl bromide is obtained, analogously to example 1, 2.3 g (76.5% of theory) of the title compound with a melting point of 133° as the first crystallisate from aqueous methanol, which melting point is raised to 137° by recrystallization from aqueous methanol. The substance has a specific spin of [«]D 2 5 =

- 98.5° (c = 1, methanol).

Example 4 (method A)

(+)-2-(D-tetrahydrofurfuryl)-[(IS, 5S, 9S)-2<1->hydroxy-5,9-dimethyl-6,7-benzomorphan].

Starting from 2.17 g (0.01 mol) (IS, 5S, 9S)-(+)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 1.26 g of sodium bicarbonate and 1.82 g (0.011 mol) D-(-)-tetrahydrofurfuryl bromide is obtained, analogously to example 1, 2.1 g = 69.5% of the title compound with a melting point of 13 3° as the first crystallisate from aqueous methanol, which melting point is elevated to 137° after recrystallization. The substance has a specific rotation of [a]<25> = + 98.2°. b) Reaction of optically active basic bodies with racemic tetrahydrofurfuryl derivatives.

Example 5 (method A)

(-)-2-(D-tetrahydrofurfuryl)-[(IR, 5R, 9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] and (-)-2-(L-tetrahydrofurfuryl) -[(IR, 5R, 9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan].

21.7 g (0.1 mol) (1R, 5R, 9R)-(-)-2'-hydroxy-5,9-dimethyl-benzomorphan, 12.6 g sodium bicarbonate, 18.2 g (0.11 mol ) (-.)-tetrahydrofurfuryl bromide and 2 g of potassium iodide are heated to 100° with vigorous stirring for 18 hours in 200 ml of dimethylformamide. The mixture is then cooled and 400 ml of water is added over the course of 30 minutes while stirring. The thus precipitated crystallisate is stirred for a further two hours at room temperature. Then you vacuum, wash thoroughly with several portions of water and dry, after the last vigorous suction, at 80°, until constant weight. 21.0 g of a mixture of the diastereomeric title compounds is obtained. The mother liquor is kept.

To separate the diastereomers, the crystallisate is recrystallized from 220 ml of methyl ethyl ketone. After cooling overnight at 2°, it is suctioned off and washed with a little cold methyl ethyl ketone. The mother liquor is kept and the crystals are dried at 80°. 11.7 g of crystals with a melting point of 197° are obtained, which after recrystallization from 270 ml of methanol and 135 ml of water give 10.6 g of pure (-)-2-(D-tetrahydrofurfuryl)-[(IR, 5R, 9R )-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] with a melting point of 201°.

The other diastereomer is recovered from dimethylformamide-

and the methyl ethyl ketone mother liquor: The dimethylformamide mother liquor is evaporated in vacuo and the residue is crystallized from 50 ml of dimethylformamide and 200 ml of water. After standing for 2 days at room temperature, suction, washing with water and drying at 80°, 4.1 g of the desired second diastereomer is obtained in fairly pure form. Additional substance is isolated from the methyl ethyl ketone mother liquor. This is evaporated and the residue is crystallized from 30 ml of methyl ethyl ketone. After standing overnight at room temperature, it is filtered off, thereby obtaining methyl ethyl ketone mother liquor 2 and 4.4 g of crystallisate, dried at 80°. The crystallisate is recrystallised from 35 ml of methyl ethyl ketone, thereby obtaining methyl ethyl ketone mother liquor 3_ and 1.4 g of crystallisate. The latter consists of a mixture of both diastereomers in a ratio

of about 1:1 and can again be subjected to the described separation. The mother liquors 2 and 3 are mixed together and evaporated in vacuo, the evaporation residue consists, like the post-crystallisate (4.1 g) isolated from the dimethylformamide mother liquor, of the second diastereomer.

They are crystallized together from a mixture of toluene and petrol (60-80°) in the volume ratio 70 : 30. After standing overnight at room temperature, suction is applied and washed with petrol. After drying at 80°, 6.5 g of (-)-2-(L-tetrahydrofurfuryl)-[(IR, 5R, 9R)-2<1->hydroxy-5,9-dimethyl-6,7-benzomorphan is obtained ] with a melting point of 137°. From the evaporation residue of the mother liquor, 2.7 g of additional substance with the same melting point is recovered by crystallization from 50 ml of toluene/gasoline. The yield of the second diastereomer thus amounts to a total of 9.2 g.

Example 6 (method A) (-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane-methanesulfonate.

Starting from 1.16 g (0.005) {-)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 0.91 g D-(-)-tetrahydrofurfuryl bromide, one obtains, analogously with Example 1, the title compound with a melting point of 182°, which does not change after recrystallization from ethanol/ether. It concerns one of the two optically active diastereomers. The other can be isolated from the mother liquor.

c) Conversion of racemic basic bodies with

racemic tetrahydrofurfuryl derivatives

Example 7 (method A) (-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomers I and II).

21.7 g (0.1 mol) (<±>)-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan, 13.7 g sodium bicarbonate, 19.9 g (0.12 mol) ( -)-tetrahydrofurfuryl bromide and 2 g of potassium iodide are heated to 100° for 18 hours with vigorous stirring in 200 ml of diethylformamide. It is then cooled and 400 ml of water is added within 2 hours. It is then suctioned off and the residue is washed several times with water. After the last extraction and drying at 80°, 25.4 g of a crystallisate consisting of both racemic diastereomers I and II are obtained. The mother lute is discarded.

The racemic diastereomers I and II are separated in the form of their hydrochlorides. This is done as follows: The diastereomer mixture is dissolved in 100 ml of ethanol with the addition of 7.3 ml of concentrated hydrochloric acid. Crystallization then immediately occurs. After standing overnight, it is suctioned off, washed with 1:1 ethanol/ether and then with ether and then dried in air and finally at 80°. 13.5 g of the still not quite pure hydrochloride of diastereomer I and mother liquor 1_ are obtained. Recrystallization from 350 ml of ethanol yields 8.1 g of pure substance with melting point 294° and mother liquor 2_. Evaporation of mother liquor 2_ to 100 ml leads to 2.6 g of post-crystallize with a melting point of 287-288° and mother liquor 3_. The latter is evaporated in vacuum together with mother liquor 1 and the residue is crystallized from 50 ml of ethanol, whereby 1.5 g of substance with melting point 287-288° and mother liquor 4 is further precipitated. The crystallisates with melting point 287-288° are barked together (4, 1 g) and recrystallized from 40 ml of ethanol. 2.9 g of pure hydrochloride of diastereomer I with melting point 294°C and mother liquor 5_ is thereby obtained once more. The total yield of pure substance with a melting point of 294° is therefore 11.0 g.

Diastereomer II is isolated from the mother liquors 3_, 4 and 5 in the following way: The mother liquors are evaporated in vacuo and the residue is shaken with 75 ml of chloroform, 75 ml of water and 10 ml of concentrated ammonia. After separation of the chloroform phase in a separatory funnel, the aqueous phase is extracted once more with 25 ml of chloroform. The combined chloroform extracts are washed with water, dried with sodium sulfate and evaporated in vacuo. The remainder consists of the crude base of the other diastereomer. It is crystallized from 100 ml of a mixture of toluene and petrol (60-80°) in the volume ratio 70:30. After standing overnight at room temperature, it is suctioned off and then washed with a little cold toluene/petrol and then with petrol and dried at 80°. 10.6 g of pure diastereomer II with melting point 166° is obtained. The evaporated mother liquor gives a residue of 3.5 g consisting of a mixture of both diastereomers, which can again be subjected to the described separation.

According to example 7, 11.0 g (<±>)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan hydrochloride (diastereomer I) and 10.6 g (<* >)-2-tetrahydrofurfuryl-2'-hydroxy-5,9cr-dimethyl-6,7-benzomorphan (diastereomer II).

In case of racemate cleavage, optical antipodes are obtained

from diastereomer I the compounds described in examples 1 and 2 and from diastereomer II the compounds described in examples 3 and 4.

Example 8 (method A)

(-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomer I). 2.17 g (0.01 mol) of 2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan, 1.26 g of sodium bicarbonate and 2.82 g (0.011 mol) of p-toluenesulfonic acid tetrahydrofurfuryl ester are refluxed -ling for 6 hours with stirring in a mixture of 20 ml of dimethylformamide and 25 ml of tetrahydrofuran. Then hot-filtering is carried out and the filtrate is left in a vacuum at approx. 50° freed from the tetrahydrofuran. After the addition of 40 ml of water, the diastereomer mixture described in Example 7 crystallizes, which is separated in the manner indicated there and yields 1.0 g of the hydrochloride of diastereomer I with a melting point of 294°. To convert to the base, the hydrochloride is dissolved in 10 ml of water and the solution is made alkaline while stirring by the dropwise addition of ln ammonia. This precipitates the base. After standing overnight at room temperature, it is filtered off with suction, washed with water and, after the last vigorous suction, is recrystallized from 20 ml of methanol and 7 ml of water. 0.75 g of substance with a melting point of 175-176° is obtained, which does not change after recrystallization from aqueous methanol. Example 9 (method A) (-)-tetrahydrofurfuryl-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane-methanesulfonate (racemic diastereomer I).

Starting from 1.16 g (0.005 mol (<±>)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 0.91 g (0.0055 mol) {-) -tetrahydrofurfuryl bromide gives, analogously to example 1, the title compound with a melting point of 207-210°, which after recrystallization from ethanol rises to 210°. It concerns one of the two racemic diastereomers. The other can be isolated from the mother liquor.

Example 10 (method A)

{-)-2-tetrahydrofurfuryl-2'-hydroxy-5-methyl-9a-ethyl-6,7-benzomorphan.

2.31 g (0.01 mol) (-)-2'-hydroxy-5-methyl-9a-ethyl-benzomorphan, 1.3 g sodium bicarbonate, 1.97 g (0.012 mol) (-)-tetrahydrof uryl bromide and 0.2 g of sodium iodide are refluxed for 60 hours with stirring in a mixture of 15 ml of dimethylformamide and 25 ml of tetrahydrofuran. The reaction product is isolated analogously to in example 1, is purified by chromatography on 75 g of aluminum oxide and crystallized from aqueous methanol. The dividend is on

1.2 g. The melting point of 171° does not change after recrystallization from 20 ml of methanol and 5 ml of water. The crystallized substance thus obtained is one of the two racemic diastereomers formed by the reaction. The other can be isolated from the mother liquor.

Example 11 (method A) (-)-2-tetrahydrofurfuryl-2<1->hydroxy-5-ethyl-9a-methyl-6,7-benzomorphan.

Starting from 2.31 g (0.01 mol) (-)-2'-hydroxy-5-ethyl-9a-methyl-6,7-benzomorphan and 1.97 g (0.012 mol) (-)- tetrahydrofurfuryl bromide gives, analogously to example 10, 1.3 g of the title compound with a melting point of 170°, which does not change upon recrystallization from 30 ml of methanol and 10 ml of water. The crystallized substance thus obtained is one of the two racemic diastereomers formed by the reaction. The andro Van is isolated from the mother liquor.

Example 12 (method A) (-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9cr-diethyl 1-6,7-benzomorphan hydrochloride.

Starting from 2.45 g (0.01 mol) (-)-2•-hydroxy-5,9a-diethyl-6,7-benzomorphan and 1.97 g (0.012 mol) (-)-tetrahydrofurfuryl bromide yields a reaction product which, analogously to example 10, is purified by chromatography on aluminum oxide. The base thus obtained is dissolved in 10 ml of absolute ethanol and, after acidification with 2N ethanolic HCl, absolute ether is added to the solution until it darkens. The hydrochloride is crystallized out, filtered off after standing overnight, washed with 1:1 ethanol/ether and then with ether and dried at 80°. 1.0 g of the title compound is obtained with a melting point of 239°, which does not change after recrystallization from ethanol/ether. The substance thus obtained is the hydrochloride of one of the two racemic diastereomers formed by the reaction. The other can be isolated from the mother liquor.

Example 13 (method A)

{-)-2-tetrahydrofurfuryl-2<1->hydroxy-5-methyl-6,7-benzomorphane-methane-sulfonate.

Starting from 2.03 g (0.01 mol) (<±>)-2'-hydroxy-5-methyl-6,7-benzomorphan and 1.97 g (0.012 mol) (-)-tetrahydrofurfuryl bromide yields man, analogously to example 1, 2.1 g of the title compound with a melting point of 171-172°, which does not change after recrystallization from 5 ml of ethanol and diethyl ether. The substance obtained is one of the two racemic diastereomers formed by the reaction. The other can be isolated from the mother liquor.

Example 14 (method A)

(-)-2-tetrahydrofurfuryl-2'-hydroxy-5-ethyl-6,7-benzomorphan.

Starting from 2.17 g (0.01 mol) (-)-2<1->hydroxy-5-ethyl-6,7-benzomorphan and 1.97 g (0.012 mol) {-)-tetrahydrofurfuryl bromide yields man, analogously to example 10, 2.0 g of the title compound with a melting point of 150-151°, which does not change upon recrystallization from 40 ml of acetone and 30 ml of water. The substance thus obtained is one of the two racemic diastereomers formed by the reaction. The other can be isolated from the mother liquor.

Example 15 (method A)

(-)-2-tetrahydrofurfuryl-2<1->hydroxy-5-n-propyl-6,7-benzomorphan.

Starting from 2.31 g (0.01 mol) (-)-hydroxy-5-n-propyl-6,7 benzomorphan and 1.97 g (0.012 mol) (-)-tetrahydrofurfuryl bromide, one obtains, analogously to example 10, 2.1 g of the title compound with a melting point of 152°, which does not change on recrystallization from 30 ml of methanol and 40 ml of water. The substance thus obtained is one of the two racemic diastereomers formed by the reaction. The other can be isolated from the mother liquor.

Example 16 (method B) (-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomers I and II).

21.7 g (0.1 mol) (-)-2<1->hydroxy-5,9a-dimethyl-6,7-benzomorphan is dissolved in 400 ml of methanol during heating and the solution becomes, by vigorous stirring at room temperature added 25 g of potassium carbonate dissolved in 40 ml of water. Thereby, a finely crystalline mixture of part of the base and the carbonate is precipitated. During further vigorous stirring, 22.2 g (0.165 mol) of tetrahydrofuran-2-carboxylic acid chloride are added dropwise to the suspension over the course of 30 minutes and then stirred for another hour. It is then evaporated in vacuo and the residue is shaken with 150 ml of chloroform and 100 ml of water. The aqueous phase is, after separation of the chloroform layer in a separatory funnel, extracted once more with 50 ml of chloroform. The combined chloroform extracts are washed successively with 100 ml of 1 N HCl and 100 ml of water, are dried with sodium sulfate and evaporated in vacuo after adding

addition of 50 ml of toluene. The residue consists of 2-(tetrahydro-2-furoyl)-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan, which is used in the following reduction: the evaporation residue is dissolved in 250 ml of absolute tetrahydrofuran and the solution is in in the course of 20 minutes with stirring was added dropwise to an ice-cooled suspension of 12 g of lithium aluminum hydride in 150 ml of absolute tetrahydrofuran. The ice bath is then removed and it is stirred for another hour at room temperature and then it is boiled under reflux for 2 hours. It is then cooled and, while stirring and ice-cooling, 50 ml of water is added dropwise. Then 1200 ml of saturated diammonium tartrate solution is added, shaken in a separatory funnel and, after settling, the tetrahydrofuran phase (at the top) is separated from the heavy aqueous layer. The tetrahydrofuran solution is evaporated in vacuo and the aqueous solution is extracted with 100 ml of chloroform. The evaporation residue of the tetrahydrofuran solution is dissolved with the chloroform extract and the solution is washed with water, dried with sodium sulphate and evaporated in vacuo. As a residue, the crude diastereomer mixture is obtained, which is separated, analogously to example 6, as hydrochlorides using 8 ml of concentrated HCl and 100 ml of ethanol. The separation gives 11.3 g of pure hydrochloride of diastereomer I with a melting point of 294° and 9.3 g of diastereomer II (base) with a melting point of 166°.

Example 17 (method B)

(-)-2-(D-tetrahydrofurfuryl)-[(IR, 5R, 9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] and (-)-2-(L-tetrahydrofurfuryl- [(IR,5R,9R)-2'-hydroxy-5,'9-dimethyl 1-6,7-benzomorphan].

To a suspension of 8.7 g (0.04 mol) (IR, 5R, 9R)-(-)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan in 87 ml of methylene chloride and 16 ml of triethylamine a solution of 11.9 g (0.88 mol) tetrahydrofuran-2-carboxylic acid chloride in 40 ml of absolute methylene chloride is added dropwise at room temperature with stirring and with a reflux condenser installed over the course of 15 minutes. The reaction mixture is then boiled under reflux for a further 2 hours. It is then cooled, washed twice with 30 ml of water each time, dried with sodium sulphate and evaporated in vacuo. The residue consists of crude 2-(tetrahydro-2-furoyl)-2'-(tetra-hydro-2-furoyloxy)-5,9-dimethyl-6,7-benzomorphan, which is used in the following reduction: The evaporation residue is reduced , analogous to example 16, using 5.0 g of lithium aluminum hydride, and the reaction product is isolated as described from the tetrahydrofuran phase and the chloroform extract of the diammonium tartrate solution. It consists of the crude mixture of the title compounds, which, analogously to example 5, are separated from each other and extracted in pure form. 4.8 g of (-)-2-(D-tetrahydrofurfuryl)-[(IR, 5R, 9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] with a melting point of 201 ° and 3.4 g (-)-2-(L-tetrahydrofurfuryl)-[(IR, 5R, 9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] with a melting point of 137° .

Example 18 (method B)

(-)-2-(D-tetrahydrofurfuryl).-[(IR,5R,9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] and (-)-2-(L-tetrahydrofurfuryl )-[(IR, 5R, 9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan]. 4.34 g (0.02 mol) (IR, 5R, 9R)-(-)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan is, analogously to example 16, transferred to the corresponding 2 -(tetrahydro-2-furoyl) deriv. As evaporation residue, 8.3 g of crude product is obtained, which is thiolated to the corresponding 2-(tetrahydro-2-thiofuroyl) derivative in the following way: The residue is dissolved with 100 ml of absolute pyridine and the solution is boiled together with 2.6 g of phosphorus pentasulfide for 3 hours under reflux. The mixture is then evaporated in vacuo and the residue is shaken with 100 ml of methylene chloride and 100 ml of water. After separation in a separatory funnel, the aqueous phase is extracted once more with 50 ml of methylene chloride. The combined methylene chloride solutions are washed in the presence of ice first with 30 ml of 2n HCl and then 3 times with 30 ml of water. After drying with sodium sulfate and evaporation in vacuo, a residue remains which consists of the crude 2-(tetrahydro-2-thiofuroyl) derivative (5.2 g). This is further converted in the next reaction step.

the evaporation residue of the methylene chloride solution is, analogously to example 16, reduced using 1.5 g of lithium aluminum hydride. As described in example 1, the reduction product is purified by column chromatography on aluminum oxide. The purified but not separated mixture of both title compounds is obtained. The separation analogous to example 5 leads to 0.6 g (-)-2-(D-tetrahydrofurfuryl)- and 0.5 g (-)-2-(L-tetrahydrofurfuryl-[(IR, 5R, 9R)-2' -hydroxy-5,9-dimethyl-6,7-benzomorphan with melting points of 201° and 137°.

Example 19 (method C)

(-)-2-(D-tetrahydrofurfuryl)-[(IR, 5R, 9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] and (-)-2-(L-tetrahydrofurfuryl- [(IR, 5R, 9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan].

4.34 g (0.02 mol) (IR, 5R, 9R)-(-)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan is, analogously to example 18, transferred to 2-( tetrahydro-2-thiofuroyl) deriv. This is refluxed with 1120 ml of absolute acetone together with 6.3 g of methyl iodide for 2 hours while excluding moisture. The reaction product is precipitated with 600 ml of absolute ether, and the supernatant solution is decanted after clarification. In this way, the methoiodide of the 2-(tetrahydro-2-thiofuroyl) compound is obtained, which is reduced with sodium borohydride.

For this purpose, 40 ml of absolute ethanol are added to the precipitation product and, with stirring, 2.3 g of finely pulverized sodium borohydride in 5 portions during 5 minutes. The temperature rises in the first 15 minutes from 23 to 53°. After a reaction time of a total of 1 hour, cool and add; dropwise lOO ml of 2 n HCl.

It is then heated for 30 minutes under reflux cooling. The mixture is then cooled and made alkaline with concentrated ammonia and extracted with 100 ml of chloroform. After separation in a separatory funnel, it is shaken out once more with 50 ml of chloroform, and the combined chloroform extracts are washed twice with water, dried with sodium sulfate and evaporated in vacuo. The residue is purified, as described in example 1, with aluminum oxide, whereby the purified but not separated mixture of both title compounds is obtained. The separation carried out analogously to example 5 yields 0.4 g (-)-(D-tetrahydrofurfuryl)- and 0.25 g (-)-(L-tetrahydrofurfuryl)-[(IR, 5R, 9R)-2'-hydroxy -5,9-dimethyl-6,7-benzomorphan with melting points 201 and 137°.

Example 20 (method D)

(+)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomers I and II). a) 1-tetrahydrofurfuryl-2-(p-methoxybenzyl)-3,4-dimethyl-4-hydroxy-piperidine (isomer mixture).

24.9 g (0.1 mol) of 2-(p-methoxybenzyl)-3,4-dimethyl-4-hydroxy-piperidine are stirred in 200 ml of dimethylformamide in the presence of 12.6 g

sodium bicarbonate for 24 hours at 100° together with 19.7 g

(0.12 mole) of tetrahydrofurfuryl bromide. The reaction mixture is then evaporated in vacuo and the residue is shaken with 150 ml of chloroform and 100 ml of water. After separation in a separatory funnel, the aqueous phase is extracted once more with 50 ml of chloroform. The combined chloroform extracts are washed with water, dried with sodium sulfate and evaporated in vacuo. The residue is purified in a similar manner as in example 1 by column chromatography on aluminum oxide (700 g, activity stage III, neutral) using chloroform as eluent. After evaporation of the eluate containing the pure substance, a residue of 16 g is obtained, which is further reacted in the following reaction step.

b) Circularization to the title compounds

16 g of 1-tetrahydrofurfuryl-2-(p-methoxybenzyl)-3,4-dimethyl-4-hydroxy-piperidine (evaporation residue from the previous reaction step) is stirred for 26 hours at 130° together with 80 g of crystallized phosphoric acid under a nitrogen atmosphere. Then dilute with 85 ml of water and boil for 5 hours under reflux. After cooling, 150 ml of benzene, 150 ml of n-butanol and 165 ml of concentrated ammonia are added and shaken well. The organic layer is separated in a separatory funnel and the aqueous phase. is shaken out twice more with benzene/n-butanol. The combined organic phases are washed 3 times with water, dried with sodium sulfate and evaporated in vacuo. The residue (10 g) is dissolved in 50 ml of chloroform and the solution is added to an alumina column to be chromatographed. For this, 200 g of aluminum oxide (activity level III, neutral) is used and the procedure is as described in example 3. The fractions with pure substance obtained by thin-layer chromatography are mixed together and evaporated in a vacuum. In this way, 4.0 g of a residue is obtained which consists of a mixture of both stereoisomers I and II and which is separated into the pure components in accordance with example 5. The separation gives stereoisomer I as hydrochloride with a melting point of 294 ° with a yield of 1.9 g and stereoisomer II as base with a melting point of 166° with a yield of

1.3g.

Example 21 (method E)

(-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomers I and II). a) (-)-2-(2-oxo-4-ethoxycarbonyl-butyl)-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan hydrochloride. 10.85 g (0.05 mol) (-)-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan, 4.6 g sodium bicarbonate and 12.3 g (0.055 mol) 5-bromo-levulinic acid -ethyl ester is boiled with stirring and reflux for 2 hours in 50 ml of dimethylformamide and 125 ml of tetrahydrofuran. It is then evaporated in vacuo and the residue is shaken with 250 ml of chloroform and 100 ml of water. The aqueous phase separated in a separatory funnel is extracted once more with 50 ml of chloroform, the combined chloroform solutions are washed with water, dried with sodium sulfate and evaporated in vacuo. The residue is dissolved with 75 ml of ethanol and 25 ml of 2N ethanolic HCl and absolute ether is added to the solution just until it begins to darken. The title compound crystallizes out. After standing overnight at 2°, it is filtered off and washed with first 1:1 ethanol/ether and then with ether. The crystallisate is dried, first in air and then at 80°. 18.2 g (92% of theoretical) of the title compound with a melting point of 212-215° are obtained. A sample recrystallized from ethanol/ether melts at 214-216°. The melting point does not change with further recrystallizations. b) (-)-2-(2,5-dihydroxy-n-pentyl)-2'-hydroxy-5,9o-dimethyl-6,7-benzomorphan (stereoisomer mixture).

19.8 g (0.05 mol) (-)-2-(2-oxo-4-ethoxycarbonyl-0-butyl)-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan hydrochloride is converted to the corresponding base by shaking with 100 ml of chloroform, 100 ml of water and 7 ml of concentrated ammonia, and the base is then found dissolved in the chloroform phase. After separation of the chloroform phase, the aqueous phase is extracted once more with 25 ml of chloroform, the chloroform extracts are collected, washed with water, dried with sodium sulfate and evaporated in vacuo. The remainder is reduced with lithium aluminum hydride. At the same time, a solution of the evaporation residue is dripped

in 100 ml of absolute tetrahydrofuran with stirring and ice-cooling during half an hour into a suspension of 2.9 g of lithium aluminum hydride in 250 ml of absolute tetrahydrofuran. It is then stirred for a further hour at room temperature and boiled for a further 3 hours under reflux cooling. It is then cooled and, with stirring and ice-cooling, 10 ml of water and then 290 ml of saturated diammonium tartrate solution are added dropwise. After thorough shaking, separate in a separatory funnel. The tetrahydrofuran phase (top) is evaporated in vacuo

and the aqueous phase is extracted 2 times with 100 ml each time

chloroform. The evaporation residue of the tetrahydrofuran phase is taken up

in the combined chloroform extracts and wash the solution twice with water. After drying with sodium sulfate and evaporation in vacuo, the crude reduction product (17.5 g) is obtained. This is purified by chromatography on aluminum oxide. For this, 350 g of aluminum oxide (activity level III, neutral) is used and the procedure is as described in example 1. First, it is eluted with chloroform and then with a mixture of chloroform and methanol in the volume ratio 99:1, whereby fractions of 25 ml. After a thin layer chromatographic sample, the fractions with the pure main product are collected and evaporated in vacuum. There is then a residue consisting of a stereoisomer mixture of the main product of the reduction.

c) (-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomers I and II). The evaporation residue from the preceding reaction step (17.5 g) is boiled under reflux and water separation for 45 minutes together with 17.5 g of p-toluenesulfonic acid in 800 ml of xyiol. It is then evaporated in vacuo and the residue is shaken with 100 ml of chloroform, 50 ml of water and concentrated ammonia (10 ml). After separation in a separatory funnel, it is extracted once more with 25 ml of chloroform. The combined chloroform phases are washed twice with 30 ml of water each time, dried with sodium sulfate and evaporated in vacuo. The evaporation residue is purified by chromatography on 500 g of aluminum oxide (activity level III, neutral), during which the procedure is analogous to example 1. One elutes with chloroform/methanol, first at a volume ratio of 99:5. The fractions containing the pure reaction products are collected and evaporated in vacuo. There is then a residue of 12 g, which still contains residues of solvent. With this residue, the separation of both diastereomers described in example 7 is carried out. The hydrochloride of diastereomer I (2.4 g) and diastereomer II as base (2.2 g) is thereby obtained. Melting points of 284 resp. 161°, which after recrystallization rises to 294 resp. 166°. Example 22 (method F) (-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomers I and II). a) (-)-2-tetrahydrofurfuryl-2'-benzoyloxy-5,9a-dimethyl-6,7-benzomorphan (diastereomer mixture). 3.21 g (0.01 mol) of 2'-benzoyloxy-5,9a-dimethyl-6,7-benzomorphan is alkylated, analogously to example 8, in the presence of 0.95 g of sodium bicarbonate in dimethylformamide/tetrahydrofuran together with 2, 82 g of p-toluenesulfonic acid tetrahydrofurfuryl ester. It is then evaporated in vacuo and the residue is shaken with 50 ml of chloroform and 50 ml of water. After separation in a separatory funnel, the aqueous phase is extracted once more with 25 ml of chloroform. The combined chloroform extracts are, after washing with water, dried with sodium sulphate and evaporated in vacuo. As a residue, a mixture of both racemic diastereomers is obtained (-)-2-tetrahydro-furfuryl-2'-benzoyloxy-5,9a-dimethyl-6,7-benzomorphan. b) (-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomers I and II). the evaporation residue from the previous synthesis step is dissolved in 75 ml of methanol and the solution is, after adding 20 ml of 2N NaOH, boiled under reflux for 15 minutes. It is then acidified with 25 ml of 2n HCl and evaporated in vacuo. The residue is shaken with 50 ml of chloroform, 50 ml of water and 2 ml of concentrated ammonia. After separation in a separatory funnel, the aqueous solution is extracted once more with 25 ml of chloroform. The combined chloroform extracts are washed with water, dried with sodium sulfate and evaporated in vacuo. The remainder consists of both the racemic diastereomers I and II, which, analogously to example 7, are separated by crystallization of the hydrochloride. The hydrochloride of diastereomer I is thus obtained with a yield of 0.7 g and with a melting point of 294° and diastereomer II with a yield of 0.4 and with a melting point of 166°. Example 23 (method G) (-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomer I).

2.0 g (0.0062 mol) of (i)-tetrahydrofurfuryl-2-'-methoxy-5,9a-dimethyl-6,7-benzomorphan (O-methyl derivative of the title compound) is heated to 210° for 4 hours together with 2 g of finely powdered potassium hydroxide in 20 ml of diethylene glycol. The reaction mixture is, after cooling with 100 ml of water, diluted, acidified with concentrated HCl, made ammoniacal with concentrated ammonia and shaken with 50 ml of chloroform. The aqueous phase separated in a separatory funnel is extracted twice more with 25 ml of chloroform each time. The three chloroform extracts are combined, washed with water, dried with

sodium sulfate and evaporate in vacuo. After crystallization from aqueous methanol, the residue gives 1.7 g = 89% of the theoretical of the title compound with a melting point of 173-175°, which increases to 176° after recrystallization from aqueous methanol.

Example 24 (method G)

{-)-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomer I).

2.0 g (0.0062 mol) {-)-2-tetrahydrofurfuryl-2'-methoxy-5,9a-dimethyl-6,7-benzomorphan (O-methyl derivative of the title compound) is heated to 190° for 30 minutes together with 20 g of anhydrous pyridine hydrochloride. After cooling, 20 ml of water and 12.5 g of sodium carbonate are added to the mixture and the pyridine is distilled off with steam. The residue is shaken with 50 ml of chloroform and the aqueous phase separated in a separatory funnel is extracted once more with 25 ml of chloroform. The combined chloroform extracts are washed with water, dried with sodium sulphate and evaporated in vacuo. The residue is crystallized from aqueous methanol. 0.9 g of the title compound is obtained, which corresponds to a yield of 47% of theoretical. The substance melts at 171-174° and after recrystallization from aqueous methanol at 176°.

Example 25 (method H)

(-)-2-(D-tetrahydrofurfuryl-[(IR, 5R, 9R)-2'-acetoxy-5,9-dimethyl-6,7-benzomorphan]. 3.0 g (0.01 mol) (- )-2-(D-tetrahydrofurfuryl-[(IR, 5R, 9R)-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] is heated on a boiling water bath for 30 minutes together with 25 ml of acetic anhydride. Then is evaporated in vacuo and the residue is stirred for a few minutes together with 100 g of ice and 100 ml of water. After adding 100 ml of ether, it is made just ammoniacal with further stirring with 2n ammonia. The ether phase is separated and the aqueous solution is extracted once more with 50 ml of ether. The combined extracts are washed with water, dried well with sodium sulfate and evaporated in vacuo. The title compound remains in the form of a yellowish syrup. The substance is thin-layer chromatographically pure and has an Rf value of 0.5 against a Rf value of 0.25 for the starting substance (DC silica gel, chloroform/methanol/concentrated ammonia 90:10:0.5). Example 26 (method I) (i)-2-tetrahydrofurfuryl-2'-methoxy-5, 9a-dim ethyl 1-6,7-benzomorphan (O-methyl derivative of diastereomer I from Example 7). 3.37 g (0.01 mol) {-)-2-tetrahydrofurfuryl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan hydrochloride (diastereomer I from Example 7) and 1.9 g (0.011 mol) of phenyl-trimethyl-ammonium chloride is dissolved together in 100 ml of methanol and 1.08 g (0.02 mol) of sodium methylate is added to the solution while stirring. As a result, sodium chloride is precipitated and this is extracted after stirring for 2 hours. The filtrate is evaporated, the residue is dissolved with dimethylformamide and the solution is again evaporated. Fresh dimethylformamide (30 ml) is then added and the reaction mixture is boiled for 2 hours under reflux. After cooling, evaporate the roan and shake the residue in a separatory funnel with 50 ml of 2N NaOH and 50 ml of chloroform. After separation of the phases, the aqueous solution is extracted twice more with 50 ml of chloroform each time. The combined extracts are washed with water, dried with sodium sulfate and evaporated in vacuo. The residue is purified by chromatography on 200 g of silica gel using chloroform/methanol/concentrated ammonia in the volume ratio 90:10:0.5 as eluent. To this end, the evaporation residue is dissolved in 20 ml of the eluent and the solution is added to a silica gel column, which was prepared using the aforementioned eluent, to be chromatographed. One elutes and collects the eluate

in fractions of 25 ml. After testing with thin-layer chromatography, the fractions are combined with the pure substance and evaporated in a vacuum. The residue is dissolved with a little ethanol and the solution is acidified with ethanolic HCl and ether is added just until it begins to darken. The hydrochloride crystallizes out and it is filtered off after standing overnight at 2° and is washed first with ethanol/ether 1:1 and then with ether and is dried at 80°. One obtains 1.5 g of

the title compound with a melting point of 207-208°, which does not change after recrystallization from ethanol/ether.

Claims (1)

Analogous process for the preparation of therapeutically active 2-tetrahydrofurfuryl-6,7-benzomorphans of the general formula where R means methyl, ethyl or propyl, R 2 means hydrogen, methyl or ethyl, 3 R means hydrogen or methyl, and ' 4 R means hydrogen, alkyl with 1-4 carbon atoms or acyl with 2-5 carbon atoms, and acid addition salts thereof, characterized in that a) a norbenzomorphan with the formula where R''" - R<4> have the meanings indicated above, is reacted with a compound of the formula where X means a nucleophilic removable group, preferably a halogen atom, especially chlorine, bromine or iodine, or an arylsulfonyloxy, aralkylsulfonyloxy or alkylsulfonyloxy group; or b) a carboxylamide resp. thioamide with the formula 1 4 where R - R have the meanings given above, and Y means an oxygen, or sulfur atom, is reduced; or c) a compound of the formula 14 5 where R - R and Y have the meanings given above, and R means an alkyl residue with up to 4 carbon atoms, preferably a methyl group, and a' ^ means the anion of an inorganic or organic acid, is reduced; or d) for the preparation of compounds of formula I where R 4 means a hydrogen atom, compounds are ring-closed with the general ones formulas 1 4 where R - R have the meanings given above, and Z means a halogen atom, a hydroxy group, alkoxy, acyloxy or aryl sulfonyloxy or alkylsulfonyloxy group, in the presence of acid catalysts; or e) from compounds with the formula CH I ^ Z ^OH HO N R3 VI11 W v R 0 1 4 where R - R is as stated above, water is split off; or f) for the preparation of compounds of formula I where R 4 means a hydrogen atom, compounds of the formula are submitted CH-L N RO Hf 13 7 where R - R have the meanings given above, and R means an acyl residue derived from an inorganic or organic acid, ester cleavage; or g) for the preparation of compounds of formula I where R 4 means a hydrogen atom, subject to compounds of formula 13 8 where R - R is as above, and R represents an alkyl or aralkyl group, ether cleavage; or h) for the preparation of compounds of formula I where R^ denotes an acyl group, compounds of formula I where R<4 > denotes a hydrogen atom are acylated with an acylating agent containing 2-5 carbon atoms in the acyl part, or i) for the preparation of compounds with formula I where R<4> means a lower alkyl residue, compounds with formula I where R 4 means hydrogen are alkylated with an alkylating agent containing 1-4 carbon atoms in the alkyl part, and optionally the compounds of formula I are transferred to the physiologically compatible acid addition salts.