DE2411382A1 - NEW 2-TETRAHYDROFURFURYL-6,7-BENZOMORPHANES, THEIR ACID ADDITIONAL SALTS, THEIR USE AS A MEDICINAL PRODUCTS AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

Case 1/506 Dr.Cr/A

C. H. BOEHRINGER SOHN, Ingelheim / Rhine

New Z-tetrahydrofurfuryl-b ^ -benzomorphans, their acid addition salts, their use as medicaments and processes

for their production

The invention relates to new 2-tetrahydrofurfuryl-ö, '/ - benzomorphane the general formula

and the acid addition salts of these compounds, their use as drugs and processes for their manufacture.

In the formula I mean
R ¹ methyl, ethyl, propyl,

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R hydrogen, methyl, ethyl,
R- ⁵ hydrogen, methyl,

R is hydrogen, lower alkyl of 1 to 4 carbon atoms or lower acyl of 2 to 5 carbon atoms.

The invention includes compounds of formula I in which the

1 2
R and R radicals are arranged cis with respect to the carbocyclic ring. That means if the leftovers

12 2 3

R and R represent alkyl groups, and R is not equal to R, only compounds of the α series with cis alkyl radicals

1 ?
R and R are included.

Preference is given to compounds of the formula I in which R is hydrogen and the other radicals are as defined above. Particular preference is given to compounds of the formula I in which R ¹ and R ^{2 are} methyl, R 1 and R 2 are hydrogen (2-tetrahydrofurfuryl-2, ^1- hydroxy-5,9-dimethyl-6,7-benzomorphane).

With the definition of the compounds of the formula I given above, the following situation arises with regard to the stereochemistry: The norbenzomorphane on which the compounds are based formula

II

2 3 has 2 centers of asymmetry if R = R or 3 asymmetry centers

2 3

Centers if R is not the same as R ^. / 3

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Because of the rigid installation of the asymmetry centers C-I and C-5 exist in a bridged ring system and because of the definition of the asymmetry center C-9 (restriction to the α series) the nor compounds of the formula II on which the formula I is based, however, only in a single racemic form and the associated optical antipodes

description Form of II configuration (+) - II
(-) - II
(+) - II racemic
counterclockwise
clockwise IR, 5R, 9R
IS, 5 S, 9 S

An additional one occurs with the N-tetrahydrofurfuryl substitution Center of asymmetry in the molecule (at C-2 "in the tetrahydrofuran ring ). It is therefore to be expected that under the formula I defined above, two series (1,1) and (1,2) of racemic Diastereomers and the associated optical antipodes hide the possible combinations following their existence owe:

description I.
configuration Benzomorphan N-tetrahydro
furfuryl residue " (racemic
) Diastereomer
^J 1
7racemic
\ iJiastereomeres
^J 2. 1 row, 5 row, 9 row - (-)
1 S, 5 S, 9 S - (+)
1 row, 5 row, 9 row - (-)
1 S, 5 S, 9 S - (+) D - (-)
D - (-) 1.1
1.2

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to

Which of the / {1,1) ln: w. : ~ u (I ,. ') belonging optical antipodes the counter-clockwise and which is the clockwise form cannot be determined solely on the basis of the configuration but only results from the measurement in the polarimeter.

It has been shown for some of the 2r-tetrahydrofurfury1-2-hydroxy-5,9a-dimethyl-6,7-benzomorphanes according to the invention (formula I, R ¹ = R ² = CH ₃ and R ³ = R ⁴ = H) that were examined in more detail that the direction of rotation of the base body of the formula II is not changed by the introduction of the D - (-) - or L - (+) - tetrahydrofurfuryl radical. It is probable, but by no means certain, to predict that this connection will also apply to connections
is applicable.

compounds of formula I with other combinations of R-R

With regard to the nomenclature of the compounds of the formula I, there is no problem with the optically active representatives, as can be seen from the table above. If the designation IR, 5R, 9R or 12, 5S, 9S is used, the configuration on the C-9 is clearly defined and the "α" can be omitted in the chemical designation. In the case of the racemic compounds, on the other hand, it is impossible to predict which of the two possible diastereomers is present. In the description of the invention, both racemic diastereomers are identified by (+) and are distinguished from one another by the addition "Diastereomer 1" and "Diastereomer 2", where 1 and 2 denote the sequence of isolation.

The compounds of the present invention can be prepared by various processes including the following have particularly proven:

A) Alkylation of a norbenzomorphane of the formula

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II

1 4
in the RR have the meanings given above with a compound of the formula

X-CH

in which X is a nucleophilically exchangeable group, preferably a halogen atom, especially chlorine, bromine or iodine and also one Arylsulfonyloxy, aralkylsulfonyloxy, alkylsulfonyloxy means »

The calculated amount of the alkylating agent of the formula III or, preferably, an excess thereof is used works best in the presence of an acid-binding substance such as triethylamine, dicyclohexylethylamine, sodium carbonate, Potassium carbonate and calcium oxide or, preferably, sodium hydrogen carbonate. Although you can also do without solvents can be carried out in inert solvents such as chloroform, toluene, ethanol, nitromethane,

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Tetrahydrofuran, dimethyl sulfoxide and preferably dimethyl forraamide more expedient. Mixtures can also be used

these solvents can be used. Finally, an excess of alkylating agents, e.g. B. excess Tetrahydrofurfuryl bromide, serve as a solvent. The reaction temperature is within wide limits, downwards are given by too low a reaction rate and upwards by the increased occurrence of side reactions, varies will. Temperatures between 50 and 150 °, preferably around 100 ° C., are expedient. If you work with less reactive Alkylating agents, e.g. B. with tetrahydrofurfuryl chloride, the reaction can by adding catalytic or equimolar Amounts of potassium or sodium iodide can be accelerated.

B) Reduction of a carbonamide or thioamide of the formula

IV

1 4
in the RR have the meaning given above, and Y denotes an oxygen or sulfur atom.

The reduction of the carbonamides (compounds of the formula IV in which Y is an oxygen atom) can be carried out in various ways Methods are carried out. Reduction with complex hydrides with high reducing power is particularly suitable, / 7

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especially with lithium aluminum hydride. The hydride is used in the calculated amount or in an excess, preferably up to double the calculated amount. The reaction is conveniently carried out in an inert solvent, preferably Diethyl ether, diisopropyl ether and especially tetrahydrofuran made. The reaction temperature is in wide limits and is advantageously between 0 C and the boiling point of the solvent.

In the reduction of O-acyl derivatives of the formula IV in which

Y means an oxygen atom, with complex metal hydrides, e.g. in the reduction with lithium aluminum hydride, is next to the reduction of the carbonyl group simultaneously also the O-acyl radical reductively cleaved and in this case compounds of the formula I in which R is a hydrogen atom are obtained.

The reduction of thioamides (compounds of the formula IV in which

Y means a sulfur atom) is much easier than that of the carbonamides. It can be used with complex hydrides or with nasal hydrogen (e.g. Zn / hydrochloric acid, Zn / acetic acid or aluminum amalgam / water); it is also possible to desulfurize with Raney nickel or to carry out the reduction electrochemically to undertake. When using reducing agents with a stronger reducing power, O-acyl groups can be reductive be split off. This results in compounds of the formula I in which R represents a hydrogen atom.

C) Reduction of a compound of the formula

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Y-R '

A ¹

1 4
where R - R and Y are as defined above, and R is an alkyl radical of up to 4 carbon atoms, preferably a methyl group, and A ^ "'is the anion of an inorganic or organic acid.

The 'reduction can be done by various methods and For example, all of the measures indicated for the reduction of thiocarbonamides can be used; however, there is one limitation due to the decomposition of the compounds of formula V and their tendency to side reactions (e.g. hydrolysis, aminolysis) given. It has been found to be advantageous to continue the compounds of the formula V without isolation to implement. It is advantageous to use complex metal hydrides with reduced reducing power, e.g. sodium hydride. It is also possible by nascent hydrogen

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or by means of hydrogen in the presence of a hydrogenation catalyst, for example Raneynic.kei, to effect the reduction. Depending on the reaction conditions, O-acyl groups can be used in the course of
Reduction to be split.

D) Hofmann's degradation of a quaternary ammonium compound of formula

VI

1 k (-)
where RR and A ^v 'have the meaning given above, and R is a group which can be removed by Hofmann elimination, for example β-phenylethyl, naphthylethyl or 1,2-diphenylethyl
represents.

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The reaction takes place through the action of bases on the uraternary salts and can be carried out in a wide variety of ways. Under the conditions of the Hofmann elimination you can O-acyl groups are cleaved, with corresponding

4 compounds of the general formula I are obtained in which R is a hydrogen atom.

E) ring closure of compounds of the general formula

R ⁴ O

VII a

Z R

-0

VII b

/ i:

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1 4
in which R - R have the meanings given above, and Z denotes a halogen atom, a hydroxyl group, alkoxy, acyloxy or arylsulfonyloxy or alkylsulfonyloxy groups.

The ring closure reaction can be carried out by known methods. For example, one works under the conditions the Friedel-Crafts reaction with aluminum chloride in carbon disulfide or the ring closure is effected with strong acids, such as phosphoric acid or polyphosphoric acid, preferably at temperatures between 100 and 150 ° C. When compounds of the formula VII a are cyclized, compounds of the Formula I in which R is hydrogen. Under the reaction conditions of the ring closure, O-acyl- or 0-alkyl groups are cleaved, whereby compounds of formula I with free phenolic hydroxyl group (R = hydrogen) is obtained.

F) Tetrahydrofuran ring closure of compounds of the formula

/ VA /

CH.

X) HHO ^

VIII

1 4
where RR are as defined above.

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- 19 -

-J- C

A wide variety of methods can be used for the tetrahydrofuran ring closure. One can for example the elimination of water through action leading to ring closure of acidic catalysts to carry out compounds of formula VIII. Suitable acidic catalysts are, for example, inorganic ones or organic acids or acid salts, such as sulfuric acid, phosphoric acid, oxalic acid, p-toluenesulfoiic acid, Sodium hydrogen sulfate, anhydrous zinc chloride. It is preferable to work at an elevated temperature, preferably between 100 and 200 ° C. It can be useful to use water-binding agents such as excess water to remove the water Sulfuric acid or excess zinc chloride or by azeotropic distillation. Often it is also beneficial to replace one of the two hydroxyl groups with a more reactive group as an intermediate. So you can, for example cause the ring closure with toluenesulfonic acid chloride in pyridine without the O-toluenesulfonyloxy derivative formed as an intermediate the compound of formula VIII is isolated. Depending on the relatively drastic reaction conditions can convert O-acyl and O-alkyl groups to free phenolic Hydroxy groups are cleaved.

G) Compounds of the general formula I in which R is a hydrogen atom are obtained by ester cleavage of compounds the general formula

IX

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in which R-R have the abovementioned meaning and R represents an acyl radical derived from an inorganic or organic acid. Are of practical importance especially low aliphatic ^ or simple aromatic and heterocyclic acyl radicals, especially acetyl, propionyl, Benzoyl and tetrahydro-2-furoyl.

The cleavage can be carried out by various methods. The simplest is acidic or alkaline hydrolysis, which is preferably carried out in an aqueous, alcoholic or aqueous-alcoholic solution. That within wide limits The variable reaction temperature is expediently between 20 and 100 ° C.

The O-acyl group can also be split reductively. Under Reduction with complex hydrides is particularly suitable for the processes that can be used. You work in the same way as for them Reduction of the carboxamides described procedure. A simultaneous reduction of amide is advantageous and phenol ester moiety.

H) Ether cleavage of compounds of the formula

CH.

^ R

«0 ·

wherein R-R are as given above, defined and

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R is an alkyl or aralkyl group, compounds of formula I, in which R represents a hydrogen atom.

The ether cleavage of compounds of the formula X to give compounds of the formula I can be carried out by a wide variety of methods, which vary greatly with the nature of the radical R, and which must be chosen so that the tetrahydrofuran ring preserved. For example, the selective splitting of the phenol ether group with caustic soda and caustic potash is suitable high-boiling solvents such as diethylene glycol or triethylene glycol. It is expedient to work at temperatures between 150 ° C. and the boiling points of the solvents excess alkali hydroxide. Benzyl ethers can also be split by catalytic hydrogenation. Methoxymethyl ether are very acid-labile and can be split with dilute mineral acids under mild conditions.

I) Acylation of compounds of the formula I in which R is hydrogen is, to compounds of the formula I in which R is an acyl group.

The acylation can be carried out by a wide variety of methods. It is most advantageous to work with corresponding carboxylic acid chlorides or carboxylic acid anhydrides. The calculated amount or a slight excess of the acylating agent can be used in an inert solvent. However, it is also possible to use excess acylation squeegee, which also serves as a solvent. It is advisable to add an acid-binding agent to the reaction mixture. Particularly suitable for this purpose is pyridine, which can be used in catalytic amounts, equimolar amounts or in excess and as a solvent. Another base that is well suited for this purpose is triethylamine. As a reaction temperature to the range of 20 - 15Ü ^W C, preferably 50 - 100 ° proven particularly.

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K) alkylation of compounds of the formula I in which R is hydrogen to give compounds of the formula I in which

4th
R denotes a lower alkyl radical.

The alkylation can be carried out by a wide variety of methods. Alkylating agents and reaction conditions which allow selective O-alkylation are preferred, without quaternization of the nitrogen occurring. The use of diazoalkanes is particularly suitable for this purpose. or phenyltrialkylammonium hydroxides as alkylating agents. With diazoalkanes one works in suitable inert Solvents, e.g. in diethyl ether or tetrahydrofuran, preferably at room temperature. When using trialkyl aramonium hydroxide the starting compound is heated with the alkylating agent in suitable inert solvents, preferably in dimethylformamide.

The reaction products obtained are isolated from the batches using customary methods. If necessary, can the raw products obtained using special processes, e.g. column chromatography, before they can be purified in the form of bases or suitable acid addition compounds crystallized.

Depending on the choice of reaction conditions and reactants, the reaction products obtained are either sterically uniform compounds or mixtures of racemically or optically active diastereomers.

Diastereomers can be known due to their different chemical and physical properties Process, e.g. by fractional crystallization, can be separated. Racemic compounds can help with customary methods for the resolution of racemates are separated into the corresponding optical antipodes.

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A large part of the starting compounds which are used in the processes described above are known. For example, the norbenzomorphans of the general formula II are described many times in the literature.

The optically active tetrahydrofurfuryl halides of the formula III can be obtained from the known optically active alcohols (F.C. Hartmann and R.Barker, J. Org. Chem. 29, 873-877 (1964)) Halogenation, e.g. with phosphorus pentachloride or phosphorus pentabromide (Org. Synth. 2_3, 88) can be produced:

L - (+) - tetrahydrofurfuryl alcohol: [ <x7q ⁵ = + 15.3 ° Cc = 5,

Nitromethane) bp 76 ° / lb mm Hg

D - (-) - Tetrahydrofurfuryl alcohol: [OJ ²⁵ = - 15.7 ° (c = 5,

D. Nitromethane)

Kp 76 ° / 16 mm Hg

L - (+) - tetrhydrofurfuryl bromide: - [oJ-q = + 3.9 ° (c = 5, nitromethane)

Kp 66 - 67 ° / 16 mm Hg

D - (-) - Tetrahydrof ur fur ury bromide: / α 7 • ^p = _3.8 (c = 5, nitromethane)

"D

Bp 67 ° / 16 mm Hg

By reacting the tetrahydrofurfuryl alcohols with sulfonic acid halides Corresponding sulfonic acid esters can be prepared.

Carboxamides of the general formula IV are obtained by reacting nor compounds of the formula II with tetrahydrofuroyl chlorides. The corresponding carbonamides of the formula IV are reacted with phosphorus pentasulfide corresponding thiocarbonamides can be produced.

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^"17 - 2A11 382

Compounds of the formula V are obtained by reacting compounds of the formula IV with alkylating agents.

Compounds of the formula VI are prepared by reacting nor compounds of the formula II with β-phenylethyl chloride, naphthylethyl chloride or 1,2-diphenylethyl chloride and subsequent quaternization of the tertiary
Amines with compounds of the formula III.

Starting compounds of the general formulas VII a and VII b are obtained by alkylating piperidines known from the literature
of formula XI

R ¹

XI

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and XII

XII

accessible with alkylating agents of the formula III.

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

Y - CH ₀ - C - CH ₀ - CH ₀ - COOC ₀ H. 2 j, 2 2 2 5

XIII

in which Y has the abovementioned meaning, and reduction of the intermediate compounds of the formula obtained thereby

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R ⁴ O

ζ C COOC ₀ H, -CH ₂ ^ ₀

• CH.

XIV

made with complex hydrides.

Starting compounds of the formulas IX and X are obtained by alkylating corresponding norbenzomorphanes with alkylating agents Formula III accessible.

The compounds of the general formula I according to the invention are bases and can be physiologically converted into theirs in a customary manner compatible acid addition salts are transferred. Acids suitable for salt formation are, for example, mineral acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, Hydrofluoric acid, sulfuric acid, phosphoric acid, Nitric acid or organic acids such as acetic acid, propionic acid, butyric acid, valeric acid, pivalic acid, caproic acid, Oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, pyruvic acid, tartaric acid, citric acid, malic acid, Benzoic acid, p-hydroxybenzoic acid, salicylic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, ascorbic acid, 8-chlorotheophylline, Methanesulfonic acid, ethanephosphonic acid and the like.

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The compounds of the formula I according to the invention and their acid addition salts have a therapeutically useful effect on the central nervous system. The analgesic effect is particularly pronounced, e.g. on mice in the V / rithing test, Hot plate test and Haffner test can be demonstrated. The most effective representatives reach ten to thirty times the strength of morphine when injected subcutaneously, depending on the test. Despite this high effectiveness, the typical side effects of morphine, e.g. the Straub tail phenomenon, are missing and the maneuvering. The lack of this, especially for compounds with activity in the Haffner test, typical Side effects suggests the absence of other undesirable properties of morphine, especially the lack of Close addictive effect. The relationship between ostrich tail and addiction potential is documented in the literature; see I. Shemano and H. Wendel: A Rapid Screening Test for Potential Addiction Liability of New Analgesic Agents, Toxicol. Appl. Pharmacol. έ>, 334 (1964). The new compounds are also characterized by a greater therapeutic breadth compared to morphine the end. In addition, the compounds according to the invention show no morphine-like action on the morphine-addicted rat.

The compounds of general formula I according to the invention and their acid addition salts can be used enterally or parenterally. The dosage for enteral and parenteral use reads at about 0.5-100 mg _f, preferably between 1 and 20 mg. The compounds of the formula I or their acid addition salts can be combined with other analgesic agents or with other types of active ingredients, for example sedatives, tranquilizers, hypnotics. Suitable galenic dosage forms are, for example, tablets, capsules, suppositories, solutions, suspensions, powders or emulsions; the pharmaceutical auxiliaries, carriers, disintegrants or lubricants usually used or substances for achieving a depot effect can be used for their production. The production of such. ^ Galenic *

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- 21 - 2AΊ1382

Dosage forms are carried out in the usual way according to the known manufacturing methods.

The tablets can consist of several layers. Corresponding can coated tablets by coating cores produced analogously to the tablets with usually coated tablets Agents used, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar getting produced.

To achieve a depot effect or to avoid incompatibilities the core can also consist of several layers. The coated tablet shell can also be used to achieve this a depot effect can be built up from several layers, the auxiliaries mentioned above for the tablets being used can be.

Juices of the active ingredients or combinations of active ingredients according to the invention You can also use a sweetener such as saccharin, cyclamate, glycerin or sugar and a taste-enhancing one Means, e.g. B. contain flavorings such as vanillin or orange extract. You can also use suspension aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene dioxide or contain protective substances such as p-hydroxybenzoates.

Injection solutions are used in the usual way, e.g. with the addition of preservatives such as p-hydroxybenzoates or stabilizers, manufactured like complexones and in injection bottles or filled into ampoules.

The capsules containing active ingredients or combinations of active ingredients can be produced, for example, by adding the active ingredients mixes with inert carriers such as lactose or sorbitol and encapsulates gelatin capsules.

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Suitable suppositories can be combined, for example, by mixing the intended active ingredients or active ingredient combinations with conventional carriers such as neutral fats or polyethylene glycol or its derivatives.

The following examples illustrate the invention in a non-limiting manner Way.

Manufacturing examples

a) Implementation of optically active basic bodies with optically active Tetrahydrofurfury! compounds

Example 1 (method A)

(_) _ 2- (D-Tetrahydrofurfuryl) - [(1R, 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-benzomorphane, 1.2b g of sodium hydrogen carbonate and 1.82 g (0.011 mol) of D - (-) - tetrahydrofurfuryl bromide are in a Mixture of 15 ml of dimethylformamide and 25 ml of tetrahydrofuran boiled for 75 hours with stirring and reflux. Then will the reaction mixture i'.V. evaporated and the residue shaken with 35 ml of chloroform and 35 ml of water. After detaching the chloroform phase in the separating funnel, the aqueous solution is extracted twice with 15 ml of chloroform each time. The combined Chloroform solutions are washed with 30 ml of water, dried with sodium sulfate and evaporated down i.V. That as evaporation residue obtained crude reaction product can be obtained directly or better after purification by column chromatography be crystallized on aluminum oxide. For column chromatography, the crude product is dissolved in 25 ml of chloroform and applies the solution to a chromatography column with 50 g of aluminum oxide (activity level III, neutral) in chloroform. It is eluted with a mixture of 99 parts by volume of chloroform and 1 part by volume of methanol and the eluate is collected in fractions from 10 - 20 ml. After thin non-chromatographic testing, the fractions are combined with the pure substance

/ 23 509838/0931

and evaporated iV. The EindampfüngsrUckstand is crystallized from a mixture of IO ml of methanol ^unc ^ ^ ^bm water. After standing overnight at 2 °, the crystals are filtered off with suction * and washed with a little aqueous methanol. After drying at 80 °. 2.3 g (76.5 % of theory) of crystallized base are obtained with a melting point of 197 °, which increased to 201 ° on recrystallization from aqueous methanol and no longer changed when recrystallized again. The substance has a specific rotation of [α] _D = - 108.5 (c = 1, methanol).

To convert to the methanesulfonate, 1.55 g (0.005 mol) of crystallized base are dissolved in 8 ml of ethanol with the addition of 0.47 g of methanesulfonic acid and the solution is treated with absolute ether until it becomes cloudy (40 ml). After standing in a closed vessel at 2 ° for several days, the salt separates out in coarse crystals. The crystals are filtered off with suction, with ethanol / ether 1 ; 1 and then washed with ether and dried at 50 °. 1.4 g (70.5% of theory) of the title compound with a melting point of 70 ° are obtained with decomposition. The hygroscopic substance does not change its melting point after recrystallization from ethanol / ether and drying at 50 ° in a high vacuum.

Example 2 (method A)

(+) - 2- (L-tetrahydrofurfuryl) - [lS, 5S, 9S) -2'-hydroxy-5,9-dimethyl- 6,7-benzomorphane ]

Starting from 2.17 g (0.01 mol) (IS, 5S, 9 S) - (+) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 1.26 g sodium hydrogen carbonate and 1, 82 g (0.011 mol) of L - (+) - tetrahydrofurfuryl bromide are obtained analogously to Example 1 as first crystals from aqueous methanol, 2.2 g (72.5 % of theory) of the title compound with a melting point of 199 °, which is after Recrystallization from aqueous methanol increased to 200 °. The specific rotation of the substance is [oc] ^ ⁵ = + 109.3 (c = 1, methanol).

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50983 870931

Example 3 (method A)

(_) _ 2- (L-Tetrahydrofurfury] J - [(IR, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane)

Starting from 2.17 g (0.01 mol) (IR, 5R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 1.26 g sodium hydrogen carbonate and 1.82 g (0.011 mol) of L - (+) - tetrahydrofurfuryl bromide are obtained analogously to Example 1 as first crystals from aqueous methanol, 2.3 g (76.5 / o of theory) of the title compound with a melting point of 133 °, which crystallizes on recrystallization from aqueous methanol increased to 137 °. The substance has a specific rotation of [a] _D = -98.5 ° (c = 1, methanol).

Example 4 (method A)

( ₊ ) _2- (D-tetrahydrofurfuryl) - [(lS, 5S, 9S) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane]

Starting from 2.17 g (0.01 mol) (IS, 5S, 9S) - (+) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 1.26 g sodium hydrogen carbonate and 1.82 g (0.011 mol) of D - (-) - tetrahydrofurfuryl bromide are obtained analogously to Example 1 as first crystals from aqueous methanol, 2.1 g = 69.5 % of the title compound with a melting point of 133 °, which increases to 137 ° after recrystallization. The substance has a specific rotation of [cc] ^ ^{= +} 98.2

b) Implementation of optically active basic bodies with

Racemic Tetrahydrofurfuryl Derivatives Example 5 (Method A)

(-) - 2- (D-Tetrahydrofurfuryl - [(lR, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] and

(-) - 2- (L-tetrahydrofurfuryl) - [(lR, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane]

21.7 g (0.1 mol) (lR, 5R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-b, 7-benzomorphane, 12, b g sodium hydrogen carbonate, 18.2 g (0.11 mol) (+) - tetrahydrofurfuryl bromide and 2 g potassium iodide are in 200 ml Dimethylformamide with vigorous stirring for 18 hours

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heated to 100 °. It is then cooled down and within 400 ml of water are added for 30 minutes while stirring. The precipitated crystals are stored for a further 2 hours at room temperature stirred further. Then it is suctioned off, washed thoroughly with several portions of water and after the last sharp suction dried at 80 to constant weight. 21.0 g of a mixture of the diastereomeric title compounds are obtained. The mother liquor is kept.

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

The second diastereomer is obtained from the dimethylformamide and the methyl ethyl ketone mother liquor: The dimethylformamide mother liquor is evaporated in vacuo ^{and the residue is crystallized from c} j0 ml of dimethylformamide and 200 ml of water. After standing for two days at room temperature, filtering off with suction, washing with water and drying at 80 °, 4.1 g of the desired second diastereomer are obtained in fairly pure form. Further 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, the mixture is filtered off with suction, giving the methyl ethyl ketone mother liquor 2 and 4.4 g of crystals dried at 80 °. The crystals are recrystallized from 35 ml of methyl ethyl ketone, giving the methyl ethyl ketone mother liquor 3 and 1.4 g of crystals. The latter consists of a mixture of the two diastereomers in a ratio of about 1: 1 and can be subjected to the separation described again. The mother liquors Z and 3 are collected together

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and evaporated i.V. The evaporation residue consists of the residual crystals isolated from the dimethylformamide mother liquor (4.1 g) from the second diastereomer. They are made up of a mixture of toluene and gasoline (60-80) in volume ratio 70:30 crystallized. After standing overnight at room temperature, it is filtered off with suction and washed with gasoline. To Drying at 80 ° gives 6.5 g of (-) - 2- (L-tetrahydrofurfuryl) - [(1R, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] with the Melting point 137 °. 2.7 g are obtained from the evaporation residue of the mother liquor by crystallization from 50 ml of toluene / gasoline another substance with the same melting point. The total yield of the second diastereomer is therefore 9.2 g.

Example b (method A)

(-) - 2-Tetrahydrofurfuryl-2'-hydroxy-5,9,9-trimethyl-o, 7-benzomorphane methane sulfonate

Starting from 1.16 g (0.005 mol) (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 0.91 g of D - (-) - tetrahydrofurfuryl bromide is obtained analogously to Example 1, the title compound with a melting point of 182, which does not change after recrystallization from ethanol / ether. It is one of the two visually active diastereomers. The other can be isolated from the mother liquors.

c) Implementation of racemic basic elements with racemic tetrahydrofurfuryl derivatives

Example 7 (method A)

(+) -2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomo rphane (racemic diastereomers I and II)

21.7 g (0.1 mol) (+) - 2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane, 13.7 g sodium hydrogen carbonate, 19.9 g (0.12 mol) (+) - tetrahydrofurfuryl bromide and 2 g of potassium iodide are heated in 200 ml of dimethylformamide for 18 hours at 10 ° C. while stirring vigorously.

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It is then cooled and used within 2 hours 400 ml of water sucked and washed several times with water. After the last sharp suction and drying at 80 °, one obtains 25.4 g of crystals consisting of the two racemic diastereomers I and II. The mother liquor is discarded.

The racemic diasteremers I and II are separated in the form of their hydrochlorides. The procedure is as follows: The diasteremoric mixture is concentrated with the addition of 7.3 ml. Hydrochloric acid dissolved in 100 ml of ethanol. Immediately crystallization occurs. After standing overnight it is suctioned off, washed with ethanol / ether 1: 1 then with ether and dried in the air and finally at 80. 13.5 g of not yet completely pure hydrochloride of diastereomer 1 and mother liquor 1 are obtained. Recrystallization from 350 ml of ethanol gives 8.1 g of pure substance with a melting point of 294 ° and the mother liquor Z. Evaporation of mother liquor 2 to 100 ml leads to 2 , 6 g of recrystallized material with a melting point of 287-288 ° and the mother liquor 35. The latter is evaporated together with the mother liquor IL iV and the residue is crystallized from 50 ml of ethanol, a further 1.5 g of substance with a melting point of 287-288 ° and the Mother liquor 4 incurred. The crystals with a melting point of 287-288 ° are combined (4.1 g) and recrystallized from 40 ml of ethanol. This gives another 2.9 g of pure hydrochloride of Diatermeren I with a melting point of 294 ° and the mother liquor 5_. The total yield of pure substance with a melting point of 294 ° is thus 11.0 g.

The diastereomer II is obtained from the mother liquors 3, 4 and f? Isolated as follows: The mother liquors are evaporated down by evaporation and the residue with 75 ml of chloroform and 75 ml of water ■ and 10 ml conc. Ammonia shaken. After the chloroform phase has been separated off in a separating funnel, the aqueous phase becomes extracted once more with 25 ml of chloroform «. The combined Chloroform extracts are washed with water, dried with sodium sulfate and evaporated down i.V. The residue

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consists of the crude base of the second diastereomer. He will from 100 ml of a mixture of toluene and gasoline (öO - 80 °) im Volume ratio 70:30 crystallized. After standing overnight at room temperature, it is suctioned off and with a little cold Toluene / gasoline, then washed with gasoline and dried at 80 °. 10.6 g of pure diastereomer II with the melting point are obtained 166 °. The evaporated mother liquor gives a residue of 3.5 g, which consists of a mixture of the two diastereomers, which can be used again for the separation described.

According to Example 7, 11.0 (+) - 2-tetrahydrofurfuryl-2'-hydroxy-5,9cc-dimethyl-6,7-benzomorphane hydrochloride is obtained (Diastereomer I) and 10.6 g (+) - 2-tetrahydrofurfuryl-2'-hydroxy-5,9adimethyl-6,7-benzomorphan (Diastereomer II).

By resolution of the racemate, the optical antipodes obtained from the diastereomer I are those in Examples 1 and 2, and from the diastereomer II the compounds described in Examples 3 and 4.

Example 8 (method A)

(+) -2-Tetrahydrofuran uryl-2'-hydroxy-5,9 <x -dimethyl6,7-benzomorphane (racemic diastereomer I)

2.17 g (0.01 mol) of 2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane, 1.26 g sodium hydrogen carbonate and 2.82 g (0.011 mol) tetrahydrofurfuryl p-toluenesulfonic acid ester are in a mixture of 20 ml of dimethylformamide and 25 ml of tetrahydrofuran under Stir refluxed for hours. Then it is filtered while still warm and the filtrate is removed from the tetrahydrofuran at about 50 ° freed. After adding 40 ml of water, the mixture of diastereomers described in Example 7 crystallizes the manner indicated there is separated and 1.0 g of the hydrochloride of the diastereomer I with the melting point 294 results. For · overpass the hydrochloride is dissolved in 10 ml of water in the base and the solution is stirred by adding dropwise 1 η ammonia made ammoniacal. The base precipitates in the process.

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After standing overnight at room temperature, it is filtered off with suction, washed with water and, after the last sharp suction, is removed 20 ml of methanol and 7 ml of v / water recrystallized. 0.75 g of substance with a melting point of 175-176 are obtained 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-benzomorphane and 0.91 g (0.0055 moles) of (+) tetrahydrofurfuryl bromide the title compound is obtained analogously to Example 1 with a melting point of 207-210 °, which is after recrystallization from ethanol / ether increases to 210 °. It is one of the two racemic diastereomers. The second can can be isolated from the mother liquors.

Example 10 (method A)

(+) - 2-Tetrahydrofurfuryl-2'-hydroxy-5-methyl-9a-ethyl-6,7-benzomorphan

2.31 g (0.01 mol) (j -) - 2 '' - hydroxy-5-methyl-9a-ethyl-b, 7-benzomorphane, 1.3 g sodium hydrogen carbonate, 1.97 g (0.012 mol) (+) - tetrahydrofurfuryl bromide and 0.2 g of sodium iodide are in a mixture of 15 ml of dimethylformamide and 25 ml of tetrahydrofuran Boiled for 60 hours, stirring and refluxing. The reaction product is isolated analogously to Example 1, by chromatography Purified on 75 g of aluminum oxide and crystallized from aqueous methanol. Yield 1.2g. The melting point of 171 ° does not change after recrystallization from 20 ml of methanol and 5 ml of water. In the thus obtained crystallized Substance is one of the two racemic diastereomers formed in the reaction. The other

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can be isolated from the mother liquors.

Example 11 (method A)

(+) - 2-Tetrahydrofurfuryl-2'-hydroxy - ^ - ethyl-ga-methyl-6, 7-benzomorphane

Starting from 2.31 g (0.01 mol) (+) - 2'-hydroxy-5-ethyl-9ocmethyl-6,7-benzomorphane and 1.97 g (0.012 mol) (+) - tetrahydrofurfuryl bromide analogously to Example 10, 1.3 g of the title compound with a melting point of 170 °, which is at Recrystallization from 30 ml of methanol and 10 ml of water does not change. The crystallized substance thus obtained acts it is one of the two racemic diastereomers formed in the reaction. The other can come from the mother liquor to be isolated.

Example 12 (method A)

(+) -2-Tetrahydrofurfuryl-2'-hydroxy-5,9a-diethyl -6,7-benzomorphane hydrochloride

Starting from 2, h ^c j g (0.01 mol) (+) - <- '-hydroxy-5> 9 "-diethyl- 6,7-benzomorphan and 1.97 g (0.012 mol) (+) - tetrahydrofurfuryl bromide a reaction product is obtained which is purified analogously to Example 10 by chromatography on aluminum oxide. The base obtained in this way is dissolved in 10 ml of absolute ethanol and, after acidification with 2 η ethanolic HCl, the solution is treated with absolute ether until it becomes cloudy. The hydrochloride crystallizes and is filtered off with suction after standing over night and washed with ethanol / ether 1: 1, 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 obtained in this way is the hydrochloride of one of the two racemic diastereomers formed in the reaction. The other can be isolated from the mother liquors.

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Example 13 (method A)

(+) - 2-Tetrahydrofurfuryl-2'-hydroxy-5-methyl-o, 7-benzomorphanraethanesulfonate

Starting from 2.03 g (0.01 mol) (+) - 2 ^f -hydroxy-5-methyl-6,7-benzomorphan and 1.97 g (0.012 Hol) (+) - tetrahydrofurfuryl bromide, analogous to Example 1 2 is obtained , 1g 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 in this way is one of the two racemic diastereomers formed in the reaction. The other can be isolated from the mother liquors.

Example 14 (method A)

(+) - 2-Tetrahydrofurfuryl-2'-hydroxy-5-ethyl-6,7-benzomorphane

Starting from 2.17 g (0.01 mol) (+) - 2'-hydroxy-5-ethyl-6,7-benzomorphane and 1.97 g (0.012 mol) (+) - tetrahydrofurfury1-bromide analogously to Example 10, 2.0 g of the title compound with a melting point of 150-151, which crystallizes on recrystallization, are obtained from 40 ml of acetone and 30 ml of water does not change. The substance obtained in this way is one of the two racemic diastereomers formed in the reaction. The other can be isolated from the mother liquors.

Example 15 (method A)

(+) - 2-Tetrahydrofurfuryl-2'-hydroxy-5-n-propyl-6,7-benzomorphane

Starting from 2.31 g (0.01 mol) (+) - 2'-hydroxy-5-n-propyl-b, 7-benzomorphane and 1.97 g (0.012 moles) (+) - tetrahydrofurfuryl bromide analogously to Example 10, 2.1 g of the title compound with a melting point of 152 °, which crystallizes out after recrystallization, are obtained from 30 ml of methanol and 40 ml of water does not change. / 32

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The substance obtained in this way is one of the two racemic diastereomers formed in the reaction. The other can be isolated from the mother liquors.

Example 16 (method B)

(+) - 2-Tetrahydrofurfuryl-2'-hydroxy-5,9cc-dimethyl-6,7-benzomorphane (racemic diastereomers I and II)

21.7 g (0.1 mole) of (+) - 2'-hydroxy-5,9a-dimethyl-6,7-benzamorphan are dissolved with warming in 400 ml of methanol and the solution at room temperature and vigorous stirring with 25 g in A-O ml of water dissolved potassium carbonate added. A finely crystalline mixture of part of the base and the carbonate precipitates out. Under Further vigorous stirring is added dropwise to the suspension within 30 minutes, 22.2 g (0.165 mol) of tetrahydrofuran-2-carboxylic acid chloride and then stir for a further 1 hour. It is then evaporated down i.V. and the residue with 150 ml of chloroform and 100 ml of water shaken. After the chloroform layer has been separated off, the aqueous phase becomes in a separating funnel extracted once more with 50 ml of chloroform «· The combined chloroform extracts are successively with 100 ml of 1 η HCl and Washed 100 ml of water, dried with sodium sulphate and, after adding 50 ml of toluene, evaporated in vacuo. The residue is there from 2- (tetrahydro-2-furoyl) -2 '-hydroxy-5, 9 <x-dimethyl-6,7-benzomorphan, which is used for the following reduction:

The evaporation residue is dissolved in 250 ml of absolute tetrahydrofuran and the solution is added dropwise within 20 minutes with stirring 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 the mixture is stirred for a further 1 hour at room temperature and then refluxed for 2 hours. The mixture is then cooled and 50 ml of water are added dropwise while stirring and cooling with ice. Then add 1200 ml of saturated diammonium tartrate solution, shake in the / ■ *, - *

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Separating funnel and, after it has settled well, separates the (upper) tetrahydrofuran phase 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 sulfate and evaporated in vacuo. The residue obtained is the crude diastereomer mixture, which is obtained analogously to Example 6 using 8 ml of conc. HCl and 100 ml of ethanol separate over the hydrochloride. 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 IbG ⁰ .

Example 17 (method B)

(_) _ 2- (D-Tetrahydrofurfuryl) - [(lR, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] and

(-) - 2- (L-Tetrahydrofurfuryl - [(lR, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane]

To a suspension of 0.7 g (0.04 mol) of (IR, 5R, 9R) - (-) - 2 ^f -hydroxy-5,9-dimethyl-G, 7-benzomorphan in 87 ml of absolute methylene chloride and 16 ml Triethylamine is added dropwise at room temperature with stirring and with the reflux condenser attached, a solution of 11.9 g (0.88 mol) of tetrahydrofuran-2-carboxylic acid chloride in 40 ml of absolute methylene chloride in the course of 15 minutes. The reaction mixture is then refluxed for a further 2 hours. It is then cooled, washed twice with 30 ml of water each time, dried with sodium sulfate and evaporated in vacuo. The residue consists of the crude 2- (tetrahydro-2-furoyl) -2 '- (tetrahydro-2-furoyloxy) -5,9-dimethyl-b, 7-benzomorphane, which is used for the following reduction:

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The evaporation residue is reduced using 5.0 g of lithium aluminum hydride analogously to Example Ib and the reduction product is isolated as described there from the tetrahydrofuran phase and the chloroform extract of the diammonium tartrate solution. It consists of the crude mixture of the title compounds, which are separated from one another as in Example 5 and obtained in pure form. 4.8 g of (-) - 2- (D-tetrahydrοfurfuryl) - [(1R, 5R, 9R) -2 ^! -hydroxy-5,9-dimethyl-6,7-benzomorphane] with a melting point of 201 ° and 3.4 g (-) - 2- (L-tetrahydrofurfuryl) [(1R, 5R, 9R) -2 ^l - hydroxy-5,9-dimethyl-6,7-benzomorphane] with a melting point of 137 °.

Example 18 (method B)

(-) - 2- (D-tetrahydrofurfuryl) - [(lR, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6, / - benzomorphane] and

(-) - 2- (L-Tetrahydrofurfuryl) - [(IR, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane]

4.34 g (0.02 mol) of (IR, 5R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphane are converted into the corresponding 2- (tetrahydro-2-furoyl) derivative analogously to Example Ib. One receives as evaporation residue 8.3 g of crude product which thionates to the corresponding 2- (tetrahydro-2-thiofuroyl) derivative as follows will:

The residue is dissolved with 100 ml of absolute pyridine and the solution with 2.6 g of phosphorus pentasulfide for 3 hours under reflux cooked. It is then evaporated down in vacuo and the residue is shaken with 100 ml of methylene chloride and 100 ml of water. To Separation in a separating funnel, the aqueous phase is extracted once more with 50 ml of methylene chloride. The combined methylene chloride solutions are washed successively in the presence of ice with 30 ml of 2 η HCl and 3 times 30 ml of water. After drying with sodium sulphate and evaporation i.V., a residue remains which is obtained from the crude 2- (tetrahydro-2-thiofuroyl) derivative j

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consists (Ο ,: ¹ ρ :). This is further implemented in the next reaction stage.

The residue from evaporation of the methylene chloride solution becomes analogous to Example 16 using 1.5 g of lithium aluminum hydride reduced. The reduction product is purified as described in Example 1 by column chromatography on aluminum oxide. The purified but not yet separated mixture of the two title compounds is obtained. The separation is analogous Example 5 leads to 0, u (-) - 2- (D-tetrahydrofurfuryl) - and 0.5 »g (-) - 2- (L-Tetrahydrofurfuryl - [(IR, 5R, 9R) -2-'-hydroxy-5,9-dimethylö / Z-benzornorphane with melting points 201 ° and 137 °.

Example 19 (method C)

(-) - 2- (D-Tetrahydrofurfuryl) - [(IR, 5R, 9R) -2'-hydroxy ^^ - dimethyl-ö ^ -benzomorphane] and

(-) - 2- (L-Tetrahydrofurfuryl - [(lR, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane]

4.34 g (0.02 mol (IR, 5R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan are converted into the 2- (tetrahydro-2-thiofuroy]) derivative analogously to Example 18 convicted. This is in 120 ml of absolute acetone with 6.3 g of methyl iodide for 2 hours with a moisture exclusion and refluxed. The reaction product precipitated with 600 ml of absolute ether and the supernatant solution after Clarification decanted. The methoiodide is obtained in this way the 2- (tetrahydro-2-thiofuroyl) compound, which is reduced with sodium borohydride.

For this purpose, 40 ml of absolute ethanol are added to the precipitate, and 2.3 g of fine ethanol are added over the course of 5 minutes, while stirring powdered sodium borohydride in 5 servings. The temperature rises from 23 to 53 ° in the first 15 minutes. After a The reaction time of a total of 1 hour is cooled and 100 ml of 2η HCl are added dropwise. Then it is heated for 30 minutes under reflux. It is then cooled and treated with conc.

/ 36 509 8 3 8/0931

Ammonia made ammoniacal and with 100 ml of chloroform extracted. After separation in a separating funnel, it is extracted once more with 50 ml of chloroform and the combined chloroform extracts Washed twice with water, dried with sodium sulfate and evaporated down i.V. The residue is as in Example! Described cleaned on aluminum oxide, whereby one the purified but not yet separated mixture of the two title compounds is obtained. The analogous to Example 5 carried out Separation gives 0.4 g (-) - (D-tetrahydrofurfuryl) - and 0.25 g (-) - (L-tetrahydrofurfuryl) - [(1R, 5R, 9R) -2'-hydroxy-5,9-dimethyl6 , 7-benzomorphan with melting points 201 ° and 137 °.

Example 20 (method E)

(+) - 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 (Mixture of isomers)

24.9 g (0.1 mole of 2- (p-methoxybenzyl) -3,4-dimethyl-4-hydroxypiperidine are'in 200 ml of dimethylformamide in the presence of 12.6 g of sodium hydrogen carbonate for 24 hours at 100 ° with 19.7 g (0.12 mol) tetrahydrofurfuryl bromide. The reaction mixture is then evaporated in vacuo and the residue with 150 ml of chloroform and 100 ml of water are shaken. After separating in a separating funnel, the aqueous phase is once more with 50 ml of chloroform extracted. The combined chloroform extracts are washed with water, dried with sodium sulfate and evaporated in vacuo. The residue is according to the procedure described in Example 1 by column chromatography Aluminum oxide (700 g, activity level III, neutral) was purified using chloroform as a mobile phase. You get after evaporation of the eluates containing the pure substance a residue of 16 g, which continues in the following reaction stage is implemented. / 37

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b) Ring closure to the title compounds

Io g of 1-tetrahydrofurfuryl-2- (p-methoxybenzyl) -3,4-dimethyl-4-hydroxypiperidine (Evaporation residue from the previous reaction stage) with 80 g of crystallized phosphoric acid stirred under a nitrogen atmosphere for 26 hours at 130 °. It is then diluted with 85 ml of water and refluxed for 5 hours. After cooling, 150 ml of benzene and 150 ml n-butanol and 165 ml of conc. Add ammonia and shake well. The organic layer is separated off in a separating funnel, the aqueous phase twice with benzene / n-butanol shaken out. The combined organic phases are washed 3 times with water, dried with sodium sulfate and i.V. evaporated. The residue (10 g) is dissolved in 50 ml of chloroform and the solution is chromatographed on an aluminum oxide column applied. To this end, 200 g of aluminum oxide (activity level III, neutral) are used and the procedure described in Example is used 1 described way. The fractions with pure substance determined by thin-layer chromatography are combined and evaporated i.V. In this way 4.0 g of residue are obtained, which consists of a mixture of the two stereoisomers I. and II and is separated into the pure components according to Example 5. The separation yields the stereoisomer I as a hydrochloride with a melting point of 294 in a yield of 1.9 g and the stereoisomer II as a base with a melting point of 166 ° in a yield of 1.3 g.

Example 21 (method F)

(+) - 2-Tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-u, 7-benzomorphane (racemic diastereomers I and II)

a) (+) -Z- (2-0xo-4-ethoxycarbonyl-butyl) -2'-hydroxy-5,9o-dimethyl-6,7-benzomorphane hydrochloride

10.85 g (0.05 mol) (+) -2 ^l -hydroxy-5,9oc-dimethyl-6,7-denzomorphan, 4.6 g sodium hydrogen carbonate and 12.3 g (0.055 mol) 5-bromo

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Ethyl levulinate is refluxed for 2 hours with stirring 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 off in the separating 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 2 η ethanolic HCl and the solution is treated with absolute ether until it starts to become cloudy. The title compound crystallizes. After standing overnight at 2 °, it is suctioned off and washed with ethanol / zither 1: 1 and then with ether. The crystals are first dried in air and then at 80 °. 18.2 g (92 % of theory) of the title compound with a melting point of 212 ° -215 ° are obtained. A sample recrystallized from ethanol / ether melts at 214 216. It no longer changes the melting point with further recrystallization.

b) (+) - 2- (2,5-dihydroxy-n -pentyl) -2'-hydroxy-5,9 "-dimethyl-6,7-benzomorphane (Mixture of stereoisomers)

19.8 g (0.05 mol) (+) - 2- (2-0xo-4-ethoxycarbonyl-butyl) -2'-hydroxy-5,9 "-dimethyl-b, 7-benzomorphane hydrochloride are concentrated by shaking with 100 ml of chloroform, 100 ml of water and 7 ml. Ammonia converted into the corresponding base, which can be found in the Finds dissolved chloroform phase. After the chloroform phase has been separated off, the aqueous phase is once again mixed with 25 ml of chloroform extracted, the chloroform extracts combined, washed with water, dried with sodium sulfate and evaporated i.V. The residue is reduced with lithium aluminum hydride. The solution of the evaporation residue is added dropwise to 100 ml absolute tetrahydrofuran with stirring and ice cooling in a suspension of 2.9 g lithium aluminum hydride within one hour in 250 ml of absolute tetrahydrofuran.

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- Γ> 9 -

The mixture is then stirred for a further hour at room temperature and finally refluxed for 3 hours. Then will cooled and, with stirring and ice-cooling, dropwise with 10 ml of water and then with 290 ml of saturated diammonium tartrate solution offset. After shaking well, it is separated in a separating funnel. The (upper) tetrahydrofuran phase is i.V. evaporated, the aqueous phase extracted 2 times with 100 ml of chloroform. Take with the combined chloroform extracts the residue from evaporation of the tetrahydrofuran phase and the solution was washed twice with water / water. After drying with sodium sulfate and evaporation i.V., the crude reduction product (17.5 g) is obtained. This is done by chromatography on aluminum oxide cleaned. 350 g of aluminum oxide (activity level III, neutral) and proceed in the manner described in Example 1. First it is with chloroform, then a mixture eluted by chloroform and methanol in a volume ratio of 99: 1, collecting fractions of 25 ml. To Thin-layer chromatographic testing, the fractions ■ are combined with the pure main product and evaporated down in vacuo. It what remains is a residue of the main reduction product, which consists of a mixture of stereoisomers.

c) (+) - 2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethylox 7-benzomorphane (racemic diastereomers I and II)

The evaporation residue from the previous reaction stage (17.5 g) is mixed with 17.5 g of p-toluenesulfonic acid in 800 ml Xylene was refluxed for 45 minutes with separation of water.

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It is then evaporated in vacuo and the residue with 100 ml of chloroform, 50 ml of water and conc. Ammonia (10 ml) shaken. After separation in a separating funnel, extraction is carried out 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), the procedure of Example 1 being repeated. It is eluted with chloroform / methanol, first with a volume ratio of 99 '· 1 to remove impurities that run faster, then with a volume ratio of 95: 5. The fractions which contain the pure urase products are combined and evaporated in vacuo. This leaves 12 g of residue which still contains residues of solvents. This is used to carry out the separation of the two diastereomers described in Example 7. The hydrochloride of diastereomer I (2.4 g) and diastereomer II are obtained as base (2.2 g). The melting points of 284 ° and IbI ⁰ increase to 294 and 166 ° after recrystallization.

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Example 22 (method G)

(+) - 2-Tetrahydrofurfuryl-2 · -hydroxy-5,9a-diinethyl-6,7'-benzomorphan (racemic diastereomers I and II)

a) (+) - 2-Tetrahydrofurfuryl-2 '-benzoyloxy-5, 9 "- dimethyl-6,7-benzomorphane (Mixture of diastereomers)

3.21 g (0.01 mol) of 2'-benzoyloxy-5,9a-dimethyl-c, 7-benzomorphane are in the presence of 0.95 g of sodium hydrogen carbonate in dimethylforraamide / tetrahydrofuran with 2.82 g of tetrahydrofurfuryl p-toluenesulfonate alkylated analogously to Example 8. It is then evaporated down i.V. and the residue with 50 ml of chloroform and shaken 50 ml of water. After separation in a separating funnel, the aqueous phase is once again mixed with 25 ml of chloroform extracted. The combined chloroform extracts are washed with water, dried with sodium sulfate and i.V. evaporated. The residue obtained is a mixture of the two racemic diastereomeric (+) - 2-tetrahydrofurfuryl-2'-benzoyloxy-5 , 9a-dimethyl-6,7-benzomorphane.

b) (+) - 2-Tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomers I and II)

The evaporation residue from the previous synthesis stage is dissolved in 75 ml of methanol and, after adding 20 ml of 2η NaOH, the solution is refluxed for 15 minutes. Afterward is acidified with 25 ml of 2 η HCl and evaporated down i.V. The residue is mixed with 50 ml of chloroform, 50 ml of water and 2 ml conc. Ammonia shaken. After separation in a separating funnel, the aqueous solution is extracted once more with 25 ml of chloroform. The combined chloroform extracts are washed with water washed, dried with sodium sulfate and evaporated i.V. The residue consists of the two racemic diastereomers I and II, analogous to Example 7 by crystallization the hydrochloride are separated. The hydrochloride of diastereomer I is thus obtained in a yield of 0.7 g

42 509838/0931

and a melting point of .294 ° and the diastereomer II in a yield of 0.4 g and a melting point of Ibυ.

Example 23 (method H)

(+) - 2-Tetrahydrofurfuryl-2 '-hydroxy-5, 9cc-dimethyl-b, 7-benzomorphane (racemic diastereomer I)

2.0 g (0.0062 mol) of (+) - tetrahydrofurfuryl-2'-methoxy-5,9a-dimethyl-6,7-benzomorphan (O-methyl derivative of the title compound) are mixed with 2 g of finely powdered potassium hydroxide in 20 ml of diethylene glycol heated to 210 ° for 4 hours. After cooling, the reaction mixture is diluted with 100 ml of water, with conc. HCl acidified, with conc. Ammonia made ammoniacal and shaken with 50 ml of chloroform. The aqueous phase separated off in the separating 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 evaporated in vacuo. After crystallization from aqueous methanol, the residue gives 1.7 g = 89 % of theory. of the title compound with a melting point of 173-175 °, which increases to 176 ° after recrystallization from aqueous methanol.

Example 24 (method H)

(+) -Tetrahydro! "Uryl-2 '-hydroxy-5,9 <x -dimethyl-6,7-benzomorphane (racemic diastereomer I)

2.0 g (0.0062 moles) of (+) - 2-tetrahydrofurfuryl-2'-methoxy-5,9adimethyl-6,7-benzomorphane (O-methyl derivative of the title compound) are treated with 20 g of anhydrous pyridine hydrochloride for 30 minutes heated to 190 °. After cooling, the melt is mixed with 20 ml of water and 12.5 g of sodium carbonate and the pyridine distilled off with steam. The residue is shaken with 50 ml of chloroform and the separated in a separating funnel aqueous phase extracted once more with 25 ml of chloroform. the

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combined chloroform extracts are washed with water, dried with sodium sulfate 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 theory. is equivalent to. The substance melts at 171-174 ° and after recrystallization from aqueous methanol at 176

Example 23 (method I)

. (-) - 2- (D-Tetrahydrofurfüryl - [(IR, 5R, 9R) -2'-acetoxy-5,9-dimethyl-6,7-benzomorphane]

3.0 g (0.01 mol) of (-) - 2- (D-tetrahydrofurfuryl - [(lR, 5R, 9R) -2 · - hydroxy-5,9-dimethyl-6,7-benzomorphan] are mixed with 25 ml acetic anhydride Heated for 30 minutes on a boiling water bath. It is then evaporated in vacuo and the residue a few Stirred for minutes with 100 g of ice and 100 ml of water. After adding 100 ml of ether, 2 η ammonia is added while stirring just made ammoniacal. The ether phase is separated and the aqueous solution extracted once more with 50 ml of ether. The combined extracts are washed with water, well dried with sodium sulphate and evaporated i.V. The title compound remains in the form of a yellowish one Syrups. The substance is pure according to thin-layer chromatography and has an Rf value of 0.5 compared to the Rf value of 0.25 of the starting substance (TLC silica gel, chloroform / methanol / conc. Ammonia 90: 10: 0.5).

Example 26 (method K)

(+) - 2-Tetrahydrofurfuryl-2'-methoxy-5,9a-dimethyl-6,7-benzomorphane (O-methyl derivative of the diastereomer I from Example 7)

3.37 g (0.01 mol) (+) - 2-tetrahydrofurfuryl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane hydrochloride (Diastereomer I from Example 7) and 1.9 g (0.011 mol) of phenyl trimethyl ammonium chloride are dissolved together in 100 ml of methanol and the

509838/0 931

_ 44 -

1.08 g (0.02 mol) sodium methylate are added to the solution while stirring. Sodium chloride precipitates out and is filtered off with suction after stirring for 2 hours. The filtrate is evaporated, the The residue was dissolved in dimethylformamide and the solution was evaporated again. Fresh dimethylformamide (30 ml) is then added and the reaction mixture was refluxed for 2 hours. After cooling, it is evaporated and the residue is shaken in a separating funnel with 50 ml of 2 η NaOH and 50 ml of chloroform. After the phases have separated, the aqueous solution is still extracted twice with 50 ml of chloroform each time. The United Extracts are washed with water, dried with sodium sulfate and evaporated down i.V. The residue is determined by chromatography on 200 g of silica gel using the mobile phase chloroform / methanol / conc. Ammonia in volume ratio 90: 10: 0.5 cleaned. For this purpose, the evaporation residue is dissolved in 20 ml of the solvent and the solution on a Silica gel column, which was prepared using the said solvent, applied for chromatography. One elutes and collects the eluate in fractions of 25 ml. After checking by thin layer chromatography, the fractions are combined with the pure substance and evaporates it i.V. The residue is dissolved with a little ethanol and the solution with ethanolic HCl acidified and mixed with ether until the beginning of the cloudiness. The hydrochloride crystallizes after standing Sucked off overnight at 2 ° and washed with ethanol / ether 1: 1, then ether and dried at 80 °. 1.5 g are obtained the title compound with a melting point of 207-208 °, which does not change after recrystallization from ethanol / ether.

509838/0931

Formulation Examples Example A; Tablets

(-) - 2- (D-Tetrahydrofuran) - [(1R, 5R, 9R) -2'-hydroxy-5,9-dimethyl-b, 7-benzomorphane] -raethanesulfonate

Lactose corn starch

colloidal silica soluble starch magnesium stearate

20.0 mg 120.0 mg 50.0 mg 2.0 mg 5.0 mg 3.0 ^m £ 200.0 mg

Manufacturing:

The active ingredient is mixed with some of the excipients and granulated with a solution of the soluble starch in water. After the granules have dried, the rest of the Additives are mixed in and the mixture is compressed into tablets.

Example B: coated tablets

(-) - 2- (D-Tetrahydrofurfuryl) - [(1R, 5R, 9 R) -2 • -hydroxy-5,9-dimethyl-6,7-benzomorphan] methanesulfonate

Lactose Cornstarch

colloidal silica soluble starch magnesium stearate

15.0 mg 100.0 mg 95.0 mg 2.0 mg 5.0 mg 3.0 mg 220.0 mg

/ 46

509838/0931

Manufacturing:

The active ingredient and the excipients are as in Example A described, pressed into tablet cores, which are usually coated with sugar, talc and gum arabic.

Example C: suppositories

(-) - 2- (L-tetrahydrofurfuryl) - [(lR, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] '

Milk sugar 150.0 mg

Suppository mass q.s. ad 1.7 g

Manufacturing:

The active ingredient and the lactose are mixed together and the mixture in the melted Suppository mass evenly suspended. The suspensions are made into suppositories in refrigerated molds poured out of 1.7 g weight.

Example D: ampoules

(_) _ 2- (L-tetrahydrofurfuryl) - [(lR, 5R, 9R) -2'-hydroxy-5,9-

dimethyl-6,7-benzomorphane]., _

1.0 mg

Sodium chloride 10.0 mg

double distilled water q.s. ad. 1.0 ml

Manufacture!

The active ingredient and the sodium chloride are dissolved in double-distilled water and the solution is sterile filled into ampoules.

509838/0931

Example E: drops

(+) - 2-Tetrahydrofurfuryl-2 '-hydroxy -!;, 9o-

dimethyl-b, 7-benzomorphane

(Raceraisches Diastereomores 1) 0.70 g

methyl p-hydroxybenzoate 0.07 g

Propyl p-hydroxybenzoate 0.03 g

demineralized water q.s. ad 100.00 ml

Manufacture;

The active ingredient and preservatives are demineralized Dissolved water and the solution filtered and filled into bottles of 100 ml each.

- patent claims -

509838/0931

Claims (5)

Claims Z-Tetrahydrofurfuryl-6,7-benzomorphane of the general formula worm R ¹ methyl, ethyl, propyl, R ² hydrogen, methyl, ethyl, B? Hydrogen, methyl, R is hydrogen, lower alkyl having 1 to 4 carbon atoms or mean lower acyl with 2 to 5 carbon atoms and their acid addition salts 2.Racemates or racemic mixtures and optically active forms of the compounds of the formula I according to claim 1 and their acid addition salts. 509838/0931 - -49 - 3. 2-Tetrahydrof uryl-υ, 7-benzoinorphane according to claim 1 of formula I in which R ¹ and R ² methyl, R- ^ and R denote hydrogen and their acid addition salts. 4. (-> - 2- (D-Tetrahydrofurfuryl) - [(1R, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzoraorphan] methanesulfonate 5. (+) - 2-Tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomer I) 6. (+) - 2-Tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan (racemic diastereomer II) 7. (-) - 2- (L-Tetrahydrofurfuryl) - [(lR, 5R,? R) -2'-hydroxy-5,9-dimethyl-6,7-t> enzomorphan] 8. Process for the preparation of 2-tetrahydrofurfuryl-6,7-benzomorphans of the general formula I and their acid addition salts, characterized in that one a) a norbenzomorphan of the formula ■ Μ ' R ¹ II 509838/0931 1 4
in the RR have the meanings given above with a compound of the formula OH III in which X is a nucleophilically removable group, preferably a halogen atom, especially chlorine, bromine or iodine, and also one Arylsulfonyloxy, aralkylsulfonyloxy, or represents an alkylsulfonyloxy group; or b) a carbonamide or thioamide of the formula IV R ^J 1 4
in the RR have the meaning given above and Y denotes an oxygen or sulfur atom, reduced; or c) a compound of the formula 509838/0931 Y-R ' A ⁽ 1 4
where RR and Y are as defined above, and R is an alkyl radical of up to 4 carbon atoms, preferably a methyl group, and A ^ ~ 'is the anion of an inorganic or organic acid, reduced; or d) a quaternary ammonium compound of the formula r'o 509838/0931 VI 1 4 C-)
where RR and A ^v 'have the meaning given above and R is a group which can be removed by Hofmann elimination, for example β-phenylethyl, naphthylethyl or 1,2-diphenylethyl, with strong bases according to Hofmann; or e) compounds of the general formulas VII a VII b 509838/0931 1 4
in which R - R have the meanings given above and Z denotes a halogen atom, a hydroxyl group, alkoxy, acyioxy or arylsulfonyloxy or alkylsulfonyloxy groups, closes the ring in the presence of acidic catalysts; or f) from compounds of the formula CH., HHO ' VIII 1 4
in which R - R are defined as indicated above, splits off water or g) for the preparation of compounds of the formula I, in which 4th
R denotes a hydrogen atom, compounds of the formula R ⁷ O N ' R- : x 509838/0931 in row from row have the above mentioned Bedeatang and 7th
R represents an acyl radical derived from an inorganic or organic acid which is subject to ester cleavage; or h) for the preparation of compounds of the formula I, in which R denotes a hydrogen atom, compounds of the formula X 11) Method according to one of claims ti - IC, characterized in that that the reactions are carried out in the presence of an organic solvent or solvent mixture performs. 12) Method according to one of the preceding claims 8-11, characterized in that the reaction "at a Performs a temperature of -10 ° C to the boiling point of the solvent or solvent mixture. 13) Process according to any one of the preceding claims 8-12, characterized in that the N- or O-acylation or N-alkylation in the presence of an acid-binding agent Carries out means. 14) Method according to claim 13, characterized in that the acid-binding agent amines, metal carbonates, Metal hydrogen carbonates, metal hydroxides or oxides used. 15) Pharmaceutical preparations, characterized in that they contain one or more compounds as the active ingredient of the general formula I or their physiologically acceptable acid addition salts. 16) Process for the preparation of medicaments according to claim 15, characterized in that one or more Compounds of the formula I or their acid addition salts with customary pharmaceutical auxiliaries, carriers, disintegrants or Lubricants or substances to achieve a depot effect for tablets, capsules, suppositories, coated tablets, powders, Processed solutions or emulsions. 5 0 9838/0931