DE2411382B2 - 2-Tetrahydrofurfuryl-6,7-benzomorphane, process for the preparation and their use - Google Patents

Description

The invention relates to new 2-tetrahydrofurfuryl-6,7-benzomorphans the general formula

-N-CH,

(D

HO

underlying norbenzomorphan's formula

-N-H

25th

as well as the acid addition salts of these compounds, their use as medicaments and processes their manufacture.

In the formula I mean

R ¹ methyl, ethyl,

R ² hydrogen, methyl, ethyl,

R ³ hydrogen, methyl,

where R ¹ and R ^{3 must} not be alkyl at the same time when R ^{2 is} hydrogen.

The invention includes compounds of the general formula I in which the radicals R ¹ and R ² are arranged in the cis position with respect to the carbocyclic ring. This means that if the radicals R ¹ and R ^{2 represent} alkyl groups of the type mentioned and R ^{2 is} not equal to R, only compounds of the series with cis-alkyl radicals R ¹ and R ² are included.

2-Tetrahydrofurfuryl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphanes are preferred.

In the definition of the compounds of the formula I given above, the following results with regard to the stereochemistry the following situation: that of the connections

41)

(H)

has 2 centers of asymmetry if R ² = R- 'or 3 centers of asymmetry if R ^{2 is} not identical to R'.

Because of the rigid installation of the asymmetry centers C-I and C-5 in a bridged ring system and because of the definition of the asymmetry center C-9 (restriction to the Λ series), those of the exist Formula I underlying nor compounds of formula II, however, only in a single racemic Form and the associated optical antipodes:

description

Form of II

configuration

(±) -II racemic -

(-) - Il counter-clockwise IR, 5 R, 9 R

(+) -II clockwise IS, 5 S, 9 S

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

Designation configuration
Benzomorphan

N-tetrahydrofurfuryl residue

I, I

1 row, 5 row 9R - (-) D - (-))

I S, 5 S, 9 S- (+) L- (+) f

I R, 5 R, 9R - (-) L- (+)

1 S, 5 P. 9 S- (+) D - (-)

racemic
Diastereomer I

racemic
Diastereomer 2

Which of the optical antipodes belonging to (I, 1) or to (I, 2) is left-rotating and which is clockwise shape cannot be specified based on the configuration alone, but results only from "the measurement in the polarimeter.

For some of the 2-tetrahydrofurfuryl-2'-hydroxy-5,9 \ -dimethyl-6,7-benzomorphanes according to the invention (formula I, R ¹ = R ² = CH ₃ and R ³ = H) it has been shown that the direction of rotation of the main body of the formula II is not changed by the introduction of the D- (-) - or L- (+) -tetrahydrofurfuryl radical. It is likely, but by no means certain, to predict that this connection also applies to compounds of the formula I with other combinations of R — R ³ .

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 1 R, 5 R, 9 R or 1 S, 5 S, 9 S is used, the configuration on the C-9 is clearly defined and the "i" can be omitted in the chemical name. 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 of “diastereomer 1” and “diastereomer 2”, where 1 and 2 denote the sequence of isolation.

The compounds according to the invention can be prepared by various processes known per se of which the following have particularly proven themselves:

A) Alkylation of a norbenzomorphane of the general formula

HO

in which R ¹ -R ^{3 have} the abovementioned conditions, with a compound of the formula

meth)! formamide more appropriate. It can also Mixtures of these solvents can be used. Finally, an excess of alkylating agents, z. B. Excess tetrahydrofurfuryl bromide. as a solution center! to serve. The reaction temperature is within wide limits, the down through / u low Reaction rate and given up by the increased occurrence of side reactions are to be varied. Temperatures are appropriate between 50 and 150 \ preferably around 100 C. If you work with less reactive alkylating agents, z. B. with tetrahydrofurfuryl chloride. can the reaction by adding catalytic or equimolar amounts of potassium or sodium iodide.

B) Reduction of a carbonamide or thioamide of the formula γ

X-CH ₂ O

in which X is a nucleophilically exchangeable group, preferably a halogen atom, especially chlorine, Means bromine or iodine and an arylsulfonyloxy, aralkylsulfonyloxy, alkylsulfonyloxy group.

The calculated amount of the alkylating agent is used of the formula III or, preferably, an excess thereof and is advantageously used in Presence of an acid-binding substance, such as. B. triethylamine, dicyclohexylethylamine, sodium carbonate, Potassium carbonate and calcium oxide or, preferably, sodium hydrogen carbonate. Although you too It is possible to do without solvents in inert solvents, such as, for example Chloroform, toluene, ethanol, nitromethane. Tetrahydrofuran, dimethyl sulphoxide and preferably di-HO

> sj r ~

R- '

R ¹

(IV)

in which R '--- R ³ are as defined above, and Y is an oxygen or sulfur atom.

The reduction of the carbonamides (compounds of the formula IV in which Y is an oxygen atom) can be done by various methods. The reduction with is particularly suitable complex hydrides of high reducing power, especially with lithium aluminum hydride. You set that Hydride in the calculated amount or in an excess, preferably up to twice the calculated amount Crowd, a. The reaction is conveniently carried out in an inert solvent, preferably Diethyl ether, diisopropyl ether and especially tetrahydrofuran made. The reaction temperature is variable within wide limits and is advantageously between OC and the boiling point of the solvent.

The reduction of thioamides (compounds of the formula IV. In which Y is a sulfur atom) takes place much more easily than that of carbonamides. It can be with complex hydrides or with nasal ones 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.

C) Reduction of a compound of the formula

HO

wherein R ¹ - R ³ and Y have the meaning given above, and R ^{4 is} an alkylene radical up to 4 carbon

atoms, preferably a methyl group and A is the anion of an inorganic or organic acid means.

The reduction can be carried out by various methods, and you can, for. B. all those for the reduction -> apply the measures specified for the thiocarbonamides; however, there is one limitation due to the The decomposition of the compounds of the formula V and their tendency to side reactions (e.g. hydrolysis, Aminolysis). It has proven to be advantageous to use the compounds of formula V without Immediately continue to implement insulation. The use of complex metal hydrides with reduced Reducing force, e.g. B. sodium borohydride. It is also possible by nascent hydrogen ι> or by hydrogen in the presence of a hydrogenation catalyst, e.g. B. Raneynickel, the reduction to effect.

D) Ring closure of compounds of the general formula

H ₃ CO

H ₃ CO

(Via)

(VIb)

in which R ¹ -R ^{3 have} the meanings given above, and Zein denotes a halogen atom, a hydroxyl group, w alkoxy, acyloxy, arylsulfonyloxy or alkylsulfonyloxy group.

The ring closure reaction can be carried out by known methods. One works z. B. under the conditions of the Friedel-Crafts reaction with aluminum chloride in carbon disulfide or the ring closure is effected with strong acids, such as. B. phosphoric acid or polyphosphoric acid, preferably at temperatures between 100 and 150 ^° C. When compounds of the formula VI a 5 «are cyclized, compounds of the formula I are obtained in which R ^{3 is} hydrogen. The O-methyl group is cleaved under the reaction conditions of ring closure, giving compounds of formula 1 with free phenolic hydroxyl groups.

E) Tetrahydrofuran ring closure by elimination of water from compounds of the general formula

N-CH ₂

OHH O

65

HO R ¹

wherein R ¹ -R ^{3 are} as defined above.

For the Telrahydrofuran ring connection di various methods for the application of one can, for example, lead to the ring closure ' Elimination of water by the action of acidic catalysts on compounds of the formula VI carry out. Suitable acidic catalysts are ζ. Β inorganic or organic acids or saunas Salts such as sulfuric acid, phosphoric acid, oxalic acid, p-toluenesulfonic acid, sodium hydrogen sulfate, water free zinc chloride. It is preferable to work at an elevated temperature, preferably between 100 unc 200 ° C. It may be advisable to use water-binding agents such as water-binding agents to remove the water. B. excess Sulfuric acid or excess zinc chloride or by azeotropic distillation. It is often also advantageous to substitute one of the two hydroxyl groups as an intermediate with a more reactive one Group to replace. For example, ring closure with toluenesulfonic acid chloride in pyridine can be used cause without the intermediately formed O-toluenesulfonyloxy derivative the compound of formula VIl is isolated.

F) Compounds of the general formula I are also dei by ester cleavage of compounds general formula

R ⁵ O

(VIII)

J5 in which R ¹ -R ^{3 have} the abovementioned meaning and R ^{5 is} an acyl radical derived from an inorganic or organic acid. Of practical importance are, above all, lower aliphatic or simple aromatic and heterocyclic acyl radicals, in particular acetyl, propionyl, benzoyl and tetrahydro-2-furoyl radicals.

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. The reaction temperature, which can be varied within wide limits, is expediently between 20 and 100 ^° C.

The O-acyl group can also be reductive columns. Among the methods that can be used, reduction with complex hydrides is particularly suitable. One works analogously to the procedure described for the reduction of the carboxamides.

A simultaneous reduction of amide and phenol ester grouping is advantageous.

G) Ether cleavage of compounds of the formula

(IX)

wherein R ¹ -R ^{3 are} as defined above, and

R ⁶ denotes an alkyl or aralkyl group.

The ether cleavage of compounds of the formula IX to compounds of the formula 1 can be carried out by a wide variety of methods which ^{vary greatly with the nature of the radical R 6} and which must be chosen so that the telrahydrofuran ring is retained. Suitable is z. B. the selective cleavage of the phenol ether grouping with caustic soda and caustic potash in high-boiling solvents such as diethylene glycol or triethylene glycol. It is advisable to work at temperatures between 150 ° C. and the boiling point of the solvent with excess alkali metal hydroxide. Benzyl ethers can also be split by catalytic hydrogenation. Methoxymethyl ethers are very acid-labile and can be split with dilute mineral acids even under mild conditions.

The reaction products obtained are isolated from the batches using customary methods. Optionally, the crude products obtained using special processes, e.g. B. the Column chromatography, before they are in the form of the bases or suitable acid addition compounds crystallized.

The reaction products obtained depend on the choice of reaction conditions and reactants either sterically uniform compounds or mixtures of racemically or optically active Diastereomers.

Diastereomers can be due to their different chemical and physical properties according to known methods, e.g. B. by fractional crystallization, are separated. Racemic Compounds can with the help of conventional methods for the resolution of the racemate into the corresponding optical Antipodes are separated.

A large part of the starting compounds that are used in the processes described above, are known. So are z. B. the norbenzomorphans of the general formula II in the literature several times described.

The optically active tetrahydrofurfuryl halides of the formula III can optically from the known active alcohols (F.C. Hartmann and R. Barker, J. Org. Chem. 29, 873-877 [1964]) by halogenation, ζ. B. with phosphorus pentachloride or phosphorus pentabromide (Org. Synth. 23, 88) getting produced:

L- (+) -Tetrahydrofurfuryl alcohol:

[, *] «= + L'5.3 ^o (c = 5, nitromethane)

Bp. 76 ° / 16 mm Hg
D- (-) -Tetrahydrofurfuryl alcohol:

O]? = -15.7 ° (c = 5, nitromethane)

Bp. 76716 mm Hg
L- (+) -Tetrahydrofurfuryl bromide:

[ _α ] »= + 3.9 ° (c = 5, nitromethane)

Bp 66-67716 mm Hg
D- (-) -Tetrahydrofurfuryl bromide:

O] J ⁵ = -3.8 (c = 5, nitromethane)

Bp. 67716 mm Hg

By reacting the tetrahydrofurfuryl alcohols with sulfonic acid halides, corresponding sulfonic acid esters are obtained representable.

Carboxamides of the general formula IV are obtained by reacting nor compounds of the Formula II with tetrahydrofuroyl chlorides. From the

Corresponding carbonamides of the formula IV are the corresponding ones by reaction with phosphorus pentasulphide Thiocarbonamides can be produced.

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

Starting compounds of the general formula VIa and VI b are obtained by alkylation of pipcridines of the formula X known from the literature

R ¹

ι
H

R ²

CH

V-OCH.,

and (XI)

(XI)

OCH,

accessible with alkylating agents of the formula III. Starting compounds of the formula VII are thus by reacting nor compounds of the formula II with - / - keto acid esters of the formula

Y-CH ₂ -C-CH ₂ -CH ₂ -COOC ₂ H ₅

(XII)

in which Y denotes a halogen atom, and reduction of the intermediate compounds of the formula obtained thereby
jo C-CH ₇

-N-CH ₂ -C COOC ₂ H ₅

HO

(XIII)

made with complex hydrides.

Starting compounds of the formulas VIII and IX are obtained by alkylating corresponding norbenzomorphanes accessible with alkylating agents of the formula IH.

The compounds of the general formula I according to the invention are bases and can be based on customary Way to be converted into their physiologically acceptable acid addition salts. Suitable for salt formation Acids 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.

The compounds of formula 1 according to the invention and their acid addition salts have a therapeutic effect useful effect on the central nervous system. The analgesic effect is particularly pronounced, the z. B. be demonstrated on the mouse in the writhing test, hot plate test and Haffner test can. The most effective representatives achieve ten to thirty times this amount with subcutaneous injection, depending on the test the strength of morphine. Despite this high level of effectiveness, there are no typical side effects of morphine, e.g. B. the Straub tail phenomenon and the mane gear. The lack of this, in particular Door connections with activity in the Haffner-Tesl typical side effects suggests absence other undesirable properties of morphine, in particular the lack of addictive effects. The relationship between ostrich tail and addiction potential is documented in the literature; see 1. 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 continue to be distinguished by a comparison to morphine a wider therapeutic range. The compounds according to the invention show darübc ■ in addition, no morphine-like effect on the morphine-addicted rat.

A selection of benzomorphans according to the invention was with pentazocine (Merck Index, 8th edition, 1968, Page 794; Red List 1974, Editio Cantor, No. 05.281.5) compared with regard to the analgesic and toxic effects.

The analgesia was determined according to the writhing test (Blumberg, Wolf, Dayton, Proc. Soc. Exp. Bio !. Med. 118, 763-766, 1965).

The studies were carried out on mice of both sexes. Each single dose were 10 animals used. The test compounds were subcutaneously as aqueous solutions of the methanesulfonates or hydrochloride administered.

\ Analgesia CH ₃ R ² R ³ example Writhing as whose LD ₅₀ CH ₃ the Be I connection (as HCI-SaIz) CH ₃ H Scream ED ₅₀ [ Formula I. CH ₃ CH ₃ H exercise (mg / kg) (mg / kg) CH ₃ 3 0.01 94 Ϊ R ¹ CH ₃ CH ₃ CH ₃ 7, m.p. 0.02 268 ! C ₂ H ₅ CH ₃ CH ₃ 166 ° C C ₂ H ₅ C ₂ H ₅ H 6th 0.09 180 CH ₃ CH ₃ H 9 0.02 324 C ₂ H ₅ C ₂ H ₅ H 10 0.45 279 H H 11 0.05 135 H H 12th 0.07 225 Pentazocine 13th 0.4 310 The e 14th 0.05 73 say 1.4 220 : connections according to the invention the general Formula I. Acid addition salts

can be used enterally or parenterally. The dosage for enteral and parenteral Use about 0.5-100 mg, preferably between 1 and 20 mg. The compounds of the formula I or their acid addition salts can be mixed with others pain relievers or other types of active ingredients, e.g. B. Sedatives, tranquilizers, hypnotics be combined. Suitable pharmaceutical dosage forms are, for example, tablets, capsules, Suppositories, solutions, suspensions, powders or emulsions; here can be used for their production commonly used pharmaceutical auxiliaries, carriers, disintegrants or lubricants or substances for Achievement of a depot effect find use. The production of such galenic dosage forms takes place in the usual way according to the known Manufacturing methods.

The following examples explain the invention. The temperature data are "Celsius.

Manufacturing examples

a) Implementation of optically active basic bodies with optically active tetrahydrofurfuryl compounds

example 1
(Method A)

(-) - 2- (D-Tetrahydrofurfuryl) - [(1 R, 5 R, 9R) -

2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] -

methanesulfonate

2.17 g (0.01 mol) (1 R, 5 R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 1.26 g sodium hydrogen carbonate and 1.82 g (0.011 mol) 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. The reaction mixture is then i. V.

evaporated and the residue shaken with 35 ml of chloroform and 35 ml of water. After separating the The chloroform phase in the separating funnel becomes the aqueous Solution extracted twice more with 15 ml of chloroform each time. The combined chloroform solutions are washed with 30 ml of water, dried with sodium sulfate and i. V. evaporated. That as evaporation residue obtained crude reaction product can be carried out directly or better after purification Column chromatography on aluminum oxide are crystallized. Dissolve for column chromatography the crude product in 25 ml of chloroform and the solution is applied to a chromatography column of 50 g Aluminum oxide (activity level III, neutral) in chloroform on. It is eluted with a mixture of 99 parts by volume of chloroform and 1 part by volume of methanol and collects the eluate in fractions of 10-20 ml. After testing by thin-layer chromatography, the fractions are combined with the pure substance and evaporated i.V. 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 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 increases to 201 ° on recrystallization from aqueous methanol increased and did not change when it was recrystallized again. The substance has a specific nature

Rotation of [α] ^? _ο ⁵ = -108.5 ° (c = 1, methanol). To convert to methanesulphonate, 1.55 g (0.005 mol) of crystallized base are dissolved in 8 ml of ethanol with the addition of 0.47 g of methanesulphonic acid and the solution is treated with absolute ether until it becomes cloudy (40 ml). After standing for several days The salt separates out in coarse crystals in a closed vessel at 2 °. The crystals are filtered off with suction, washed with ethanol / ether 1: 1 and then with ether and dried at 50 °. 1.4 g (70.5% of theory) are obtained Th.) Ι ο the title compound with a melting point of 70 ° 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-Telrahydrofurfuryl) - [(l S, 5 S, 9 S) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane]

Starting from 2.17 g (0.01 mol) (IS, 5 S, 9 S) - (+) - 2 '- hydroxy - 5.9 - dimethyl - 6.7 - benzomorphane, 1.26 g sodium hydrogen carbonate and 1, 82 g (0.011 mol) of L- (+) -Tetrahydrofurfurylbromid 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 recrystallizes after recrystallization from aqueous methanol increased to 200 °. The specific rotation of the substance is [ _Λ ] «= +109.3 (c = l, methanol).

20th

35 Example 3

(Method A)

(-) - 2- (L-TetrahydrofurfuryI) - [(1 R, 5 R. 9 R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane]

Starting from 2.17 g (0.0! Mol) (I R. 5 R. 9R) - (-) - 2 '- hydroxy - 5.9 - dimethyl - 6.7 - benzomorphane. 1.26 g sodium hydrogen carbonate and 1.82 g (0.011 mol) L- (+) -Tetrahydrofurfurylbromid is obtained analogously to Example 1 as first crystals from aqueous Methanol 2.3 g (76.5% of theory) of the title compound with a melting point of 133 °, which is at Recrystallization from aqueous methanol increased to 137. The substance has a specific rotation from ["]? = -98.5 ° (c = 1, methanol).

Example 4

(Method A)

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

Starting from 2.17 g (0.01 mol) (IS, 5 S, 9 S) - to (+) - 2 '- Hydroxy - 5.9 - dimethyl - 6.7 - benzomorphan, 1.26 g sodium hydrogen carbonate and 1.82 g (0.011 mol) D - (-) - tetrahydrofurfuryl bromide is 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 becomes clear after recrystallization increased to 137 °. The substance has a specific rotation of [a] 5? = + 98.2 °.

b) Implementation of optically active basic bodies with racemic tetrahydrofurfuryl derivatives

Example 5
(Method A)

(-) - 2- (D-Tetrahydrofurfuryl - [(1 R, 5 R, 9 R) -

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

2'-hydroxy-5,9-dimethyl-6,7-benzomorphane]

21.7 g (0.1 mol) (IR, 5 R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 12.6 g sodium hydrogen carbonate, 18.2 g (0.11 mol) (i) -Tetrahydrofurfurylbromid and 2 g of potassium iodide are heated in 200 ml of dimethylformamide with vigorous stirring at 100 ° for 18 hours. It is then cooled and 400 ml of water are added over the course of 30 minutes while stirring. The precipitated crystals are stirred for a further 2 hours at room temperature. Then it is suctioned off, washed thoroughly with several potions of water and, after the last sharp suction, dried to ^{constant weight at 80 f.} 21.0 g of a mixture of the diastereomeric title compounds are obtained. The mother liquor is saved.

To separate the diastereomers, the crystals are recrystallized from 220 ml of methyl ethyl ketone. After cooling overnight at 2 °, the mixture is filtered off with suction and washed with a little cold methyl ethyl ketone. the Mother liquor is stored, the crystals are dried at 80 °. 11.7 g of crystals are obtained Melting point 197 °, which after recrystallization from 270 ml of methanol and 135 ml of water is 10.6 g of pure (-) - 2- (D-Tetrahydrofurfuryl) - [(IR, 5R, 9R) -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 i. V. evaporated and the residue crystallized from 50 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 ^r gives 4.1 g of the sought-after second diastereomer 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, the methyl ethyl ketone mother liquor 3 and 1.4 g of crystals being obtained. 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 2 and 3 are combined and i. V. evaporated. The evaporation residue, like the secondary crystallizate (4.1 g) isolated from the dimethylformamide mother liquor, consists of the second diastereomer. They are crystallized together from a mixture of toluene and gasoline (60-80 °) in a volume ratio of 70:30. After standing overnight at room temperature, it is filtered off with suction and washed with gasoline. After drying at 80 °, 6.5 g of (-) -2- (L-tetrahydrofurfuryl) - [(l R, 5 R, 9R) -2'-hvdroxv-5.9-di-

methyl-oj-benzomorphan] with the melting point 137. 50 ml are obtained from the evaporation residue of the mother liquor by crystallization Toluene gasoline 2.7 g more substance with the same Melting point. The total yield of the second diastereomer is therefore 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 mol) (±) -2'-hydroxy-5,9,9 - trimethyl - 6.7 - benzomorphane and 0.91 g D- (- (-Tetrahydrofurfuryl bromide), analogously to Example 1, the title compound is obtained with a melting point of 182 ". which does not change after recrystallization from ethanol ether. It is about the one of the two optically 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-benzomorphan
(racemic diastereomers 1 and II)

21.7 g (0.1 mol) (±) -2'-hydroxy-5,9 * -dimethyl-6,7-bcnzomorphan, 13.7 g sodium hydrogen carbonate, 19.9 g (0.12 mol) (±) -telrahydrofurfuryl bromide and 2 g of potassium iodide are heated with vigorous stirring in 200 ml of dimethylformamide for 18 hours at 100 °.

It is then cooled, and 400 ml of water are added over the course of 2 hours, and the mixture is filtered off with suction and removed the residue washed several times with water. After the last sharp suction and drying at 80 ° C., 25.4 g of crystals are obtained which consist of the two racemic diaslereomers I and II. The mother liquor is discarded.

The racemic diastereomers I and II are separated in the form of their hydrochloride. The procedure is as follows: The diastereomer 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 I and the 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 2. Evaporation of the mother liquor 2 to 100 ml leads to 2, 6 g of Naehkristallisat with a melting point of 287 288 and the mother liquor 3. The latter is evaporated together with the mother liquor 1 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 apply. 4 the crystallizates of melting point 287-288 ° WEII ^ n combined (4.1 g) and recrystallized from 40 ml ethanol. this gives again 2.9 g of pure hydrochloride of the diastereomer I with melting point 294 C and ¹ Mother liquor 5. The total.!.: -, 'vutc of pure substance with a melting point of 294' is thus 11.0 g.

The diastereomer JI is isolated from the mother liquors 3, 4 and 5 as follows: The mother liquors are i. V. evaporated and the residue with 75 ml of chloroform, 75 ml of water and 10 ml of conc. Ammonia shaken. After the chloroform phase has been separated off in a separating 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 iV

lü evaporated. The residue consists of the crude base of the second diastereomer. It is crystallized from 100 ml of a mixture of toluene and gasoline (60-80 °) in a volume ratio of 70:30. After standing overnight at room temperature, the product is filtered off with suction and washed with a little cold toluene / gasoline, then with gasoline and dried at 80 °. This gives 10.6 g of pure diastereomer II with melting point 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 thus obtained 11.0 g of (±) -2-hydroxy tetrahydrofurfuryl -T- - 5,9λ - dimethyl - 6,7 - benzomorphan-hydrochlorir ¹ (Diastereomer 1) and 10.6 g of

2) (±) -2-Telrahydrofurfuryl-2'-hydroxy-5,9A-dimethyl-6.7-benzomorphan (Diastereomer II).

By resolution of the racemate, the optical antipodes obtained from the diastereomer I are those in Example 1 and 2, and from the diastereomer 11 that in Example 3

so and 4 described connections.

Example 8
(Method A)

(±) -2-tetrahydrofurfuryl-2'-hydroxy-5,9 \ -dimethyl-

6,7-benzomorphan
(racemic diastereomer I)

2.17 g (0.01 mol) of 2'-hydroxy-5,9 \ -dimethyl-6,7-benzomorphane, 1.26 g of sodium hydrogen carbonate and 2.82 g (0.011 mol) of tetrahydrofurfuryl p-toluenesulfonic acid are in a mixture of 20 ml of dimethylformamide and 25 ml of tetrahydrofuran under Stirring refluxed for 6 hours. Then it is filtered while still warm and the filtrate i. V. at about 50 ° freed from tetrahydrofuran. After the addition of 40 ml of water, that described in Example 7 crystallizes Diastereomer mixture, which is separated in the manner indicated there and 1.0 g of hydrochloride des Diastereomers I with a melting point of 294 ° results. The hydrochloride is used for conversion into the base dissolved in 10 ml of water and the solution ammoniacal by adding dropwise 1 η-ammonia while stirring made. The base precipitates in the process. After standing overnight at room temperature, it is suctioned off, washed with water and after the last sharp suction from 20 ml of methanol and 7 ml Recrystallized water. 0.75 g of substance is obtained with a melting point of 175-176 ', which corresponds to Recrystallization from aqueous methanol does not change.

Example 9

(Method A)

(±) -Telrahydrofurfuryl-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

809 583 / "1"

■ Γ,

(0.0055 moles) (±) -tetrahydrofurfuryl bromide the title compound with a melting point of 207-210 ° after recrystallization is analogous to Example 1 from ethanol / ether increases to 210 °. It is one of the two racemic diastereomers. The second can be isolated from the mother liquors.

Example 10

(Method A)

(± ^ -TetrahydrofurfuryW-hydroxy-S-methyl-9 * -ethyl-6,7-benzomorphane

2.31 g (0.01 mol) (±) -2'-hydroxy-5-methyl-9a-ethyl-6,7-benzomorphane, 1.3 g sodium hydrogen carbonate, 1.97 g (0.012 mol) (±) -tetrahydrofurfuryl bromide and 0.2 g of sodium iodide are added to a mixture of 15 ml of dimethylformamide and 25 ml of tetrahydrofuran Boiled for 60 hours with stirring and reflux. The reaction product is isolated analogously to Example 1, Purified by chromatography on 75 g of aluminum oxide and crystallized from aqueous methanol. Yield 1.2g. The melting point of 171 ° changes after recrystallization from 20 ml of methanol and 5 ml of water does not. The crystallized substance thus obtained is one of the two the reaction resulting racemic diastereomers. The other can be isolated from the mother liquors will.

Example 11
(Method A)

(±) -2-tetrahydrofurfuryl-2'-hydroxy-5-ethyl-9 A _{t-methyl-6,7-benzomorphan}

Starting from 2.31 g (0.01 mol) (±) -2'-hydroxy-5-ethyl-9. \ - methyl-6,7-benzomorphane and 1.97 g (0.012 mol) (±) -tetrahydrofurfuryl bromide are obtained analogously to Example! 10 1.3 g of the title compound with a melting point of 170 °, which when recrystallized from 30 ml of methanol and 10 ml Water doesn't change. The crystallized substance thus obtained 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-5,9 \ -diethyl- ^{> 0} 6,7-benzomorphane hydrochloride

Starting from 2.45 g (0.01 mol) (±) -2'-hydroxy-5,9 * -diethyl-6,7-benzomorphane and 1.97 g (0.012 mol) (±) -Tetrahydrofurfurylbromid a reaction product is obtained which is purified analogously to Example 10 by chromatography on aluminum oxide. The one with it The base obtained is dissolved in 10 ml of absolute ethanol and the solution after acidification with 2-n-ethanolic HCl mixed with absolute ether until turbidity t> o. It crystallizes the hydrochloride, which after Standing overnight, vacuumed and washed with ethanol / ether 1: 1, then washed with ether and dried at 80 " will. 1.0 g of the title compound is obtained with a melting point of 239 °, which crystallizes after recrystallization from ethanol / ether does not change. 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.

Example 13
(Method A)

(±) -2-Tetrahydrofurfuryl-2'-hydroxy-5-methyl-6,7-benzomorphane methanesulfonate

Starting from 2.03 g (0.01 mol) (±) -2'-hydroxy-5-methyl-6,7-benzomorphane and 1.97 g (0.012 mol) of (±) -tetrahydrofurfuryl bromide are obtained analogously to the example 1 2.1 g of the title compound with a melting point of 171-172 °, which crystallizes out after recrystallization from 5 ml of ethanol and diethyl ether does not change. The substance thus obtained is 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-ethyI-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) of (±) -tetrahydrofurfuryl bromide are obtained analogously to the example 10 2.0 g of the title compound with a melting point of 150-151 °, which results in recrystallization from 40 ml of acetone and 30 ml of water does not change. The substance obtained in this way is the one of the two racemic diastereomers formed in the reaction. The other can go isolated from the mother liquors.

Example 15
(Method B)

(±) -2-tetrahydrofurfuryl-2'-hydroxy-

5.9, "» - dimethyl-6,7-benzomorphane
(racemic diastereomers I and II)

21.7 g (0.1 mol) of (±) -2'-hydroxy-5,9A-dimethyl-6,7-benzomorphan are dissolved in 400 ml of methanol with warming and the solution is mixed with 25 g of in 40 ml of water of dissolved potassium carbonate are added. A finely crystalline mixture of part of the base and the carbonate precipitates out. With continued vigorous stirring, 22.2 g (0.165 mol) of tetrahydrofuran-2-carboxylic acid chloride are added dropwise to the suspension in the course of 30 minutes, and stirring is then continued for a further hour. Then i. V. evaporated and the residue shaken with 150 ml of chloroform and 100 ml of water. After the chloroform layer has been separated off, the aqueous phase is extracted once more with 50 ml of chloroform. The combined chloroform extracts are washed successively with 100 ml of 1N HCl and 100 ml of water, dried with sodium sulfate and, after addition of 50 ml of toluene, i. V. evaporated. The residue consists of 2- (tetrahydro- 2- furoyl) - T- hydroxy- 5,9λ -dimethyl -6,7- benzomorphane, which is used for the following reduction:

The evaporation residue is dissolved in 250 ml of absolute tetrahydrofuran and the solution within of 20 minutes with stirring to an ice-cooled suspension of 12 g of lithium aluminum hydride dropped into 150 ml of absolute tetrahydrofuran.

Then the ice bath is removed and still

Stirring for 1 hour at room temperature and then refluxed for 2 hours. On it will cooled and, while stirring and cooling with ice, added dropwise 50 ml of water. Then you give 1200 ml of saturated diammonium tartrate solution to shakes in the separating funnel and separates the (upper) tetrahydrofuran phase from the heavy aqueous layer. The tetrahydrofuran solution is i. V. evaporated, the aqueous solution extracted with 100 ml of chloroform. The evaporation residue is removed from the chloroform extract Tetrahydrofuran solution dissolved: and the solution washed with water, dried with sodium sulfate and

i. V. evaporated. The residue obtained is the crude mixture of diastereomers, which is obtained analogously to Example 6 • using 8 ml conc. HCl and 100 ml of ethanol separate over the hydrochloride. The separation gives 11.3 g of pure hydrochloride of the diastereomer I with a melting point of 294 ° and 9.3 g of the diastereomer

II (base) with a melting point of 166 ".

Example 16
(Method B)

(-) - 2- (D-Tetrahydrofurfuryl) - [(1 R, 5 R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] and
(-) - 2- (L-TetrahydrofurfuryI - [(1 R, 5 R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane]

To a suspension of 8.7 g (0.04 mol) (IR, 5R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphane 87 ml of absolute methylene chloride and 16 ml of triethylamine are added dropwise at room temperature with stirring and with the reflux condenser attached, a solution of 11.9 g within 15 minutes (0.88 mol) of tetrahydrofuran-2-carboxylic acid chloride in 40 ml of absolute methylene chloride. Then will the reaction mixture was refluxed for a further 2 hours. Then it is cooled, twice with each Washed 30 ml of water, dried with sodium sulfate and i. V. evaporated. The residue consists of the crude 2- (tetrahydro-2-furoyl) -2 '- (tetrahydro-2-furoyloxy) -5,9-dimethyl-6,7-benzomarphine, which is used for the following reduction:

The evaporation residue is prepared using 5.0 g of lithium aluminum hydride analogously to Example 15 reduced and the reduction product as described there from the tetrahydrofuran phase and isolated from the chloroform extract of the diammonium tartrate solution. It is obtained from the raw mixture of the title compounds, which are separated from one another analogously to Example 5 and obtained in pure form. 4.8 g of (-) - 2- (D-tetrahydrofurfuryl) - [(1R, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] are obtained. with a melting point of 201 ° and 3.4 g of (-) - 2- (L-tetrahydrofurfuryl) - [(lR, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane ] with a melting point of 137 °.

Example 17
(Method B)

(-) - 2- (D-Tetrahydrofurfuryl) - [(1 R, 5 R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] and
(-) - 2- (L-Tetrahydrofurfuryl) - [(1 R, 5 R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphan] ^b5

4.34 g (0.02 mol) (1 R, 5R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphane are analogous to Example 15 in the corresponding 2- (tetrahydro-2-furoyl) derivative convicted. 8.3 g of crude product are obtained as the evaporation residue, which is as follows the corresponding 2- (tetrahydro-2-thiofuroyl) derivative is thioned:

The residue is dissolved with 100 ml of absolute pyridine and the solution with 2.6 g of phosphorus pentasulfide Boiled under reflux for 3 hours. It is then evaporated down i.V. and the residue with 100 ml Shaken methylene chloride and 100 ml of water. After separation in a separating funnel, the aqueous phase becomes extracted once more with 50 ml of methylene chloride. The combined methylene chloride solutions are sequentially washed in the presence of ice with 30 ml of 2N HCl and 3 times 30 ml of water. After drying with sodium sulfate and evaporation i. V. remains a residue that consists of the crude 2- (tetrahydro-2-thiofuroyl) derivative consists (5.2 g). This is further implemented in the next reaction stage.

The evaporation residue of the methylene chloride solution is reduced analogously to Example 15 using 1.5 g of lithium aluminum hydride. 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 as in Example 5 leads to 0.6 g (-) - 2- (D-tetiahydrofurfuryl) - and 0.5 g (-) - 2- (L-tetrahydrofurfuryl - [(1 R, 5R, 9 R) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphane with melting points 201 ^and 137 ° C.

Example 18
(Method C)

(-) - 2- (D-Tetrahydrofurfuryl) - [(l R, 5R, 9R) -

2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] and

(-) - 2- (L-tetrahydrofurfuryl - [(l R, 5 R, 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 2- (tetrahydro-2-thiofuroyl) derivative analogously to Example 17 convicted. This is boiled in 120 ml of absolute acetone with 6.3 g of methyl iodide for 2 hours with a moisture exclusion and reflux. The reaction product precipitated with 600 ml of absolute ether and the supernatant solution decanted after clarification. Man in this way receives the methoiodide of 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 while stirring within from 5 minutes 2.3 g of finely powdered sodium borohydride in 5 portions. The temperature rises in the first 15 minutes from 23 to 53 °. After a total reaction time of 1 hour, the mixture is cooled and 100 ml of 2N HCl are added dropwise. The mixture is then refluxed for 30 minutes. Afterward is cooled and with conc. Ammonia made ammoniacal and extracted with 100 ml of chloroform. 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 i. V. evaporated. The residue is purified on aluminum oxide as described in Example 1, with the purified but not yet separated mixture of the two title compounds is obtained. The analog

Separation carried out in Example 5 gives 0.4 g (-MD-tetrahydrofurfuryl) - and 0.25 g (-) - (L-tetrahydrofurfuryl) - [(I R, 5 R, 9 R) - 2 '- hydroxy - 5,9 - dimethy | - 6,7-benzomorphane with melting points 2OP and 137 ° C.

Example 19
(Method D)

(±) -2-tetrahydrofurfuryl-2'-hydroxy- ^w

5,9a-dimethyl-6,7-benzomorphan
(racemic diastereomers 1 and IJ)

a) 1-Tetrahycirofurfuryl-2- (p-methoxybenzyl) -3,4-dimethyl-4-hydroxypiperidine (Mixture of isomers)

24.9 g (0.1 mol) 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 24 hours at 100 ° with ICJg (0.12 mol) Tetrahydrofurfuryibromide stirred. Then will the reaction mixture i. V. evaporated and the residue with 150 ml of chloroform and 100 ml of water shaken. After separating in a separator, the aqueous phase is once more with 50 ml of chloroform extracted. The combined chloroform extracts are washed with water and dried with sodium sulfate and i. V. evaporated. The residue is according to the procedure described in Example 1 by column chromatography on aluminum oxide (700 g, activity level III, neutral) using purified from chloroform as a solvent. The pure substance is obtained after evaporation containing eluates a residue of 16 g, which is further reacted in the following reaction stage j5 will.

b) Ring closure to the title compounds

16 g of 1-tetrahydrofurfuryl-2- (p-methoxybenzyl) -3,4-dimethyl -4-hydroxypiperidine (evaporation residue from the previous reaction stage) are stirred with 80 g of crystallized phosphoric acid under a nitrogen atmosphere at 130 for 26 hours. It is then diluted with 85 ml of water and refluxed for 5 hours. After cooling 4> 150 ml of benzene, 150 ml of n-butanol and 165 ml of conc. Add ammonia and shake well. The organic layer is separated off in a separating funnel and the aqueous phase is extracted twice more with benzene / n-butanol. 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 applied to an aluminum oxide column for chromatography. To this end, 200 g of aluminum oxide (activity level III, neutral) are used and the procedure described in Example 1 is followed. The fractions with pure substance determined by thin layer chromatography are combined and i. V. evaporated. In this way 4.0 g of residue are obtained which consist of a mixture of the two stereoisomers I and II and are separated into the pure components according to Example 5. The separation gives ö: 's stereoisomers I as hydrochloric! 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 20
(Method E)

(± j-2-tetrahydrofurluryl-2'-hydrox \ -

5,9n-dimeinyl-6,7-benzomorphan
(racemic diastereomers I and II)

a) (+) -2- (2-Oxo-4-ethoxycarbonyl-butyl) -

2'-hydroxy-5.9 * -dimethyl-6,7-benzomorphane hydrochloride

10.85 g (0.05 mol) (±) -2'-hydroxy-5,9 * -dimeih \ l-6,7-benzomorphan, 4.6 g sodium hydrogen carbonate and 12.3 g (0.055 mol) 5- Ethyl bromolevolate are refluxed for 2 hours with stirring in 50 ml of dimethylformamide and 125 ml of tetrahydrofuran. Then i. V. evaporated and the residue 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 concentrated i. V. evaporated. The residue is dissolved with 75 ml of ethanol and 25 ml of 2N ethanolic HCl and the solution is treated with absolute ether until it starts to become cloudy. The Tilel connection crystallizes. After standing overnight at 2, it is suctioned off and washed with ethanol / ether 1: 1 and then with ether. The crystals are first dried in air, 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) (± l-2- (2.5-dihydroxy-n-pentyl) -2'-hydroxy-

5.9 \ -dimetnyI-6.7-benzomorphane

(Mixture of stereoisomers)

19.8 g (0.05 mol) (±) -2- (2-oxo-4-ethoxycarbon> i-butyl 1-2'- hydroxy- 5,9 \ - dimethyl -6.7- benzomorphane hydrochloride are shaken with 100 ml Chloroform, 100 ml of water and 7 ml of conc. 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 still extracted once with 25 ml of chloroform, combined the chloroform extracts, washed with water, with Sodium sulfate dried and i. V. evaporated. The residue is reduced with lithium aluminum hydride. The solution of the evaporation residue in 100 ml of absolute tetrahydrofuran is added dropwise with stirring and ice-cooling in a suspension of 2.9 g of lithium aluminum hydride within one hour in 250 ml of absolute tetrahydrofuran.

The mixture is then stirred for a further hour at room temperature and finally under reflux for 3 hours cooked. It is then cooled and, with stirring and ice-cooling, dropwise with 10 ml of water and then mixed with 290 ml of saturated diammonium tartrate solution. After shaking well, it becomes separated in the separating funnel. The (upper) tetrahydrofuran phase is i. V. evaporated, the aqueous phase . "" extracted times with 100 ml of chloroform each time. With the combined chloroform extracts are taken from the evaporation residue of the telrahydrofuran phase and wash the solution twice with water. After drying with sodium sulfate and evaporation

i. V. one obtains the raw reduction product in this way (17.5 g). This is purified by chromatography on aluminum oxide. 350 g are used for this Aluminum oxide (activity level III, neutral) and processes in the manner described in Example I. First is chloroform, then a mixture of Chloroform and methanol in a volume ratio of 99: 1 eluted, collecting fractions of 25 ml. After thin-layer chromatographic examination the fractions are combined with the pure main product κ and i. V. evaporated. It stays there Residue of the main product of the reduction, consisting of a mixture of slereoisomers.

c) (±) -2-tetrahydrofurfuryl-2'-hydroxy-

5,9-v-diynyl-6,7-benzomorphane (racemic Diaslereomcre I and II)

The evaporation return of the previous one Reaction stage (17.5 g) is with 17.5 g of p-toluenesulfonic acid in 8 (K) ml xylene under reflux for 45 minutes and: boiled i water separation.

Then i. V. evaporated and the residue with 100 ml of chloroform, 50 ml of water and conc. Ammonia (10 ml) shaken. After separating in the Schcidetrichler, 25 ml of chloro 2 " form extracted. The combined chloroform phases are washed twice with 30 ml of water each time, with Sodium sulfate dried and i. V. evaporated. The evaporation residue is determined by chromatography Purified on 500 g of aluminum oxide (activity level III, neutral) i <, the procedure of Example I being repeated. Man eluted with chloroform / methanol, first at a volume ratio of 99: 1 for the separation of faster running impurities, then with a volume ratio of 95: 5. The factions that the jj containing pure conversion products are combined and evaporated i.V. This leaves 12 g of residue, which is still remnants of solvents contains. With this one carries out the separation of the two Diastercomercn -w described in Example 7 by. The hydrochloride of the diastereomer I (2.4 g) and the diastereomer II are obtained as Base (2.2 g). The melting points of 284 and 161 increase to 294 and 161 respectively after recrystallization. 166 4-,

Example 21 (Method G)

(±) -2-Tctrahydrofurfuryl-2'-hydroxy- -> n

5,9 \ -dimethyl-6.7-benzomorphane (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-6,7-benzomorphan are hydrofurfuryl ester with 2.82 g of tetrahydrofurfuryl ester in the presence of 0.95 g of sodium hydrogen carbonate in dimethylformamide / tetrahydrofuran alkylated analogously to Example 8. Then i. V. evaporated and the residue shaken with 50 ml of chloroform and 50 ml of water. After separation in a separating 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 i. V. evaporated. The residue obtained is a mixture of the two racemic diastereomeric ( t ) -2-Tctrahydro-furfury! -2'-bcnzoyloxy-5,9> -dimethyl-6,7-bcnzomorphane.

, b) (i) -2-telrahydrofurfuryl-2'-hydroxy-

5.9 \ -dimclhyl-6.7-bcnzomorphan
(racemic diastereomers 1 and II)

The evaporation residue from the preceding Synihcscstufe is dissolved in 75 ml of methanol and the

> Solution after adding 20 ml of 2N NaOH for 15 minutes refluxed. It is then acidified with 25 ml of 2N HCl and i. V. evaporated. Of the The residue is mixed with 50 ml of chloroform, 50 ml of water and 2 ml of con /. Ammonia shaken. After separation In the Schcidelrichtcr, the aqueous solution is extraliierl again with 25 ml of chloroform. the combined chloroform extracts are washed with water, dried with sodium sulfate and i. V. evaporated. The residue is obtained from the two racemic diastercomers I and II, which are analogous Example 7 can be separated by crystallization of the hydrochloride. The hydrochloride des is obtained in this way Diastereomers I in a yield of 0.7 g and a melting point of 294 and the Diaslereomcre 11 in a yield of 0.4 g and a melting point of 166.

Example 22
(Method Ci)

(±) -2-tetrahydrofurfuryl-2'-lisdroxv-

5.9 \ -dimethyl-6,7-benzomorphan

(Racemic Diaslcrcomeres 1)

2.0g (0.0062MoI) (±) -tetrahydrofurfur \ l-2'-melhoxy-5,9> -dimethyl-6,7-benzomorphan (() - Methyl derivative of the Tilel compound) are mixed with 2 g of finely powdered potassium hydroxide in 20 ml of diethylene glycol Heated to 210 for 4 hours. The reaction mixture is after cooling with 100 ml of water diluted, with conc. HCl acidified, with conc. ammonia ammoniacal and shaken with 50 ml of chloroform. The one separated in the separating funnel aqueous phase is extracted twice with 25 ml of chloroform each time. Combine the three chloroform extracts, washed with water, dried with sodium sulfate and evaporated i. V. a. The residue gives way Crystallization from aqueous methanol 1.7 g = 89% of theory. Th. The title compound with a melting point from 173-175, which becomes clear after recrystallization aqueous methanol increased to 176.

Example 23
(Method G)

(± -Tetrahydrofurfury l-2'-hydroxy-

5,9 * -dimethyl-6,7-benzomorphane

(racemic diastereomer I)

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

24 Π 382

washed, dried with sodium sulfate and i. V. evaporated. The residue becomes from aqueous Methanol crystallizes. 0.9 g of the Tilel compound is obtained, what a yield of 47% d. Th. Corresponds. The substance melts at 171 174 and after recrystallization from aqueous methanol at.

Formulation examples

Example Λ

Tablets

(-) - 2 - (D-Tetrahydrofurfiryl) - [(I. R, 5R.9R) -2'-hydro \ y-5.9-dimethyl - 6.7 - benzomorphane] - me-

thansulfona!

Lactose

Cornstarch

Colloidal silica

Soluble starch

Magnesium stearate

20.0 mg. 120.0 mn

50.0 mg 2.0 mg 5.0 mg 3.0 mg

200.0 mg which are usually coated with sugar, talc and gum arabic.

Example C suppositories

(-) - 2 - (L - tetrahydrofuran - [(I. R. 5R, 9R) -2'-hydroxy-5,9-di-

methyl-6,7-benzomorphane] 10.0 mg

Milk sugar I 50.0 mg

Suppository mass, q. see ad 1.7 g

Manufacturing

The active ingredient and the milk sugar are mixed together and the mixture in the melted Suppository mass evenly suspended. The suspensions are in chilled forms too Poured out suppositories weighing 1.7 g.

Example D

Manufacturing

The active ingredient comes with part of the excipients mixed and granulated with a solution of the soluble starch in water. After the granulate has dried the rest of the auxiliaries are mixed in and the mixture is compressed.

Example B coated tablets

(-) - 2 - (D-Telrahydrofurfuryl) - [(I R, 5R. 9R) -2'-hydroxy-5,9-dimethyl - 6.7 - benzomorphane] - ine-

thanesulfonate

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 mn

220.0 mg

Manufacturing

The active ingredient and the auxiliary substances are pressed into tablet cores as described in Example Λ.

Ampoules

(L - tetrahydrofurfuryl) - [(1 R, 5 R. 9 R) - 2 '- hydroxy - 5.9 - di-

methyl-6,7-benzomorphane] 1.0 mg

Sodium chloride 10.0 mg

Bidistilled water, q. see ad .... 1.0 ml

Manufacturing

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

Example E.
drops

(±) - 2 - tetrahydrofurfuryl - 2 '- hydroxy - 5.9λ - dimethyl - 6.7 - benzomorphane

(Racemic diastereomeres I) ... 0.70 g of methyl p-hydroxybenzoate 0.07 g propyl p-hydroxybenzoate 0.03 g demineralized water, q.s. ad 100.00 ml

Manufacturing

The active ingredient and the preservatives are dissolved in demineralized water and the solution filtered and filled into bottles of HM) ml each.

Claims (3)

Patent claims: 1. Racemic and optically active 2-tetrahydrofurfury 1-6,7-ber.zomorphane of the general formula I —N— CH ₂ ^ / _R 3
/ R ¹ Methyl, ethyl,
Hydrogen, methyl,
Hydrogen, methyl, Ethyl, /
HO R ¹
R ²
R ³ IO (D wherein mean, where R ¹ and R? may not be alkyl at the same time when R ^{2 is} hydrogen, as well as their acid addition salts. 2. A method for the preparation of compounds according to claim 1, characterized in that one in a manner known per se a) a norbenzomorphan of the general formula II HO (II) in which R ¹ --R ^{3 have} the meanings given above, with a compound of the general formula III X-CH ₂ O (III) in which X is a nucleophilically removable group -> o interprets, implements or b) a carbonamide or thioamide of the general formula IV HO (IV) in which R ¹ R 'have the meaning given above, and Y is an oxygen or sulfur atom, reduced or c) a compound of the general formula V. A.
(V) HO wherein R ¹ —R ¹ and Y have the abovementioned meaning, and R ^{4 is} an alkyl radical of up to 4 carbon atoms, and A is the anion of an inorganic or organic acid, reduced, or d) Compounds of the general formula VIa or VIb -N — CH, - H, C O H ₁ CO (Via) (VIb) in which R '--R ·' have the meanings given above and Z denotes a halogen atom, a hydroxyl group, alkoxy, acyloxy, arylsulfonyloxy or alkylsulfonyloxy group, closes the ring in the presence of acidic catalysts, or
j) from compounds of the general formula VII HO R ²
R ¹ (VIl) wherein R ¹ R ¹ are delineated as indicated above. Splits off water, or
f) compounds of the general formula VIII / ■■ vL / - N-CH, - / R ¹ (VIII) R ⁵ OR ¹ in which R 'R ^{1 has} the meaning given above sit and R ^{5 is} an acyl radical derived from an inorganic or organic acid which is subject to ester cleavage, or g) compounds of the general formula IX R ⁶ O where R ¹ —R- 'are defined as given above and R ^{6 is} an alkyl or aralkyl group which is subject to ether cleavage, and optionally the compounds of the general formula I in their physiologically harmless acid addition 15th salts transferred. 3. Use of compounds according to claim 1 in combating painful conditions.