FI63571B - FOERFARANDE FOER FRAMSTAELLNING AV ANALGETISKT VERKANDE RACEMISKA ELLER DIASTEREOMERA OCH OPTISKT AKTIVA 2-TETRAHYDROFURFURYL- (1R / S 5R / S 9R / S) -2'-HYDROXI-5,9-DIMETHYL-6,7-DIMETHYL-6,7 - Google Patents

Description

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PatMtfe- och registarstyrelMn Aiwektn utltgd oeh uti ^ krNUn puMk ^ nd J '(32) (33) (31) Prr * «xy ueielkuu * —Begird prlorkuc 09.03.71+

Federal Republic of Germany-Förbundsrepubliken lyskland (DE) P 21 + 11382.1 + (71) C.H. Boehringer Sohn, Ingelheim am Rhein, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Herbert Merz, Ingelheim / Rhein, Adolf Langbein, Ingelheim / Rhein,

Gerhard Walther, Bingen / Rhein, Klaus Stockhaus, Bingen / Rhein,

Federal Republic of Germany-Förbundsrepubliken lyskland (DE) (7I +) Leitzinger Oy (5I +) Method for analgesically active, racemic or diastereomeric and optically active 2-tetrahydrofurfuryl- [1R / S, 5R / S, 9R / s7-2] -hydroxy For the preparation of 5,9-dimethyl-6,7-benzomorphans and their acid addition salts - For the preparation of an analogous network, racemic or diastereomeric and optically active 2-tetrahydrofurfuryl- [1R / S, 5R / S, 9R / S7-2, 'hydroxy -5,9-dimethyl-6,7-benzomorphaner and the desired addition salt

The invention relates to a process for the treatment of analgesically active, racemic or diastereomeric and optically active 2-tetrahydrofurfuryl-fR / S, 5R / S, 9R / SJ-2'-hydroxy-5,9-dimethyl-6,7-benzomorphans and for the preparation of acid addition salts of compounds of general formula I (R-form) or a mirror image thereof (S-form)

-N - CH, -1 $ "J

2 _r (I) xCH 3 HC> 263571

In the above definition of compounds of formula I, the situation with regard to stereochemistry is as follows:

With the underlying norbenzomorphane of formula II

B

r - * / S (II) y —- X ^ ch3 '(ΓΗ-, HO ^ 3 is the 3-asymmetric center.

Because the structure of the asymmetry centers C1 and C-5 is rigid in a bridged ring system, and because the asymmetry center C-9 is locked (limited to the <* series), the nitro compounds of formula II underlying Formula I exist in only a single racemic form and associated optical antipodes. .

Marking Form II Racemic of Configuration (±) - II

(-) - II to the left 1 R, 5 R, 9 R

k circulating

(+) - II to the right IS, 5 S, 9 S

in the case of a circulating 3 63571 N-tetrahydrofurfuryl substitution, the molecule has another center of asymmetry (in the C-2 "tetrahydrofuran ring). Thus, it is expected that two sets of (1,1) and (1,2) racemic diastereomers and their optical antipodes that exist due to the following combination possibilities: _Configuration_ N-tetrahydrofur-

Labeling Benzomorphan furyl group 1.1 1.1 R, 5 R, 9 R - (-) D - (-) racemic IS, 5 S, 9 S - (+) L - (+) diastereomer 1.2 1 R, 5 R, 9 R - (-) L - (+) racemic 1 S, 5 S, 9 S - (+) D - (-) diastereomer _2_

Which of the optical antipodes in series (1,1) and (1,2) has a left-rotating and which a right-rotating shape cannot, in principle, be deduced from the configuration alone, but only from polarimeter measurements.

2-Tetrahydrofurfuryl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphans of formula I have been shown to add a D - (-) or L - (+) - tetrahydrofurfuryl group to a compound of formula II. the direction of rotation of the parent compound.

There are no difficulties with the designation of the compounds of the formula I in optically active cases, as can be seen from the table above. If the notation 1R, 5R, 9R or IS, 5S, 9S is used, then the C-9 configuration is unambiguously given and "<*" may be omitted in the chemical notations. With racemic compounds, on the other hand, it is not possible to predict which of the two possible diastereomers is involved. In the description of the invention, both racemic diastereomers are denoted by (±) and separated by the addition of "diastereomer 1" or diastereomer 2, where 1 and 2 denote the order of isolation.

4,63571

The compounds of the formula I can be prepared by various methods, of which the following have proved to be particularly advantageous: a) Alkylation of the norbenzomorphan H0 ch3

With a compound of formula III

JQ

x-ch2 wherein X is a nucleophilically exchangeable group, preferably a halogen atom, especially chlorine, bromine or iodine, and an arylsulfonyloxy, aralkylsulfonyloxy, alkylsulfonyloxy group.

The alkylating agent of formula III is used in a calculated amount or preferably in excess and is conveniently carried out in the presence of an acid scavenger such as triethylamine, dicyclohexylethylamine, sodium carbonate, potassium carbonate and calcium oxide or preferably sodium hydrogen carbonate. Although the solvent may be omitted, the reaction is more conveniently carried out in an inert solvent such as chloroform, toluene, ethanol, nitromethane, tetrahydrofuran, dimethyl sulfoxide and most preferably dimethylformamide. Mixtures of these solvents can also be used. Finally, an excess of alkylating agents, for example an excess of tetrahydrofurfuryl bromide, can also act as a solvent. The reaction temperature can be varied within wide limits, which is limited from below by too low a reaction rate and by an increasing incidence of side reactions from above. Temperatures are suitably between 50 and 150 ° C, preferably about 100 ° C.

If less reactive alkylating agents are used, for example tetrahydrofurfuryl chloride, the reaction can be accelerated by the addition of a catalytic or equirolar amount of potassium or sodium iodide.

5 63571 b) Reduction of a carbonamide or thioamide of formula IV

MJ

p — w IV

Z8® 'ch3

HO

where Y is an oxygen or sulfur bond.4.

The reduction of the carbonamide (compounds of formula IV in which Y represents an oxygen atom) can be carried out by various methods. Reduction with reducing complex complex hydrides, especially lithium aluminum hydride, is particularly suitable. The calculated amount or excess of hydride is added, preferably up to twice the calculated amount. The reaction is conveniently carried out in an inert solvent, preferably diethyl ether, diisopropyl ether and especially tetrahydrofuran. The reaction temperature can be varied within wide limits and is preferably between 0 ° C and the boiling point of the solvent.

Reduction of O-acyl derivatives of the formula IV in which Y represents an oxygen atom with complex metal hydrides, for example reduction with lithium aluminum hydride, simultaneously reductively cleaves the O-acyl group in parallel with the reduction of the carbonyl group, in which case compounds of the formula I are obtained.

The reduction of thioamide (compounds of formula IV in which Y represents a sulfur atom) is substantially easier than that of carbonamide. It can occur with complex hydrides or evolving hydrogen (e.g. zinc / hydrochloric acid, zinc / acetic acid or aluminum amalgam / water); it is also possible to remove sulfur with Raney nickel or to carry out the reduction electrochemically. When more reducing agents are used, the O-acyl groups can be reductively cleaved. In this case, compounds of formula I are obtained in which 6 63571 c) Reduction of a compound of formula V Y-R5-1 ‘(+)

• C_I J

-N * / - (#, 3 j / == S: J CH,

HO J

wherein Y is as defined above, and R 5 is an alkyl group having 1 to 4 carbon atoms, preferably a methyl group, and represents an anion of an inorganic or organic acid.

The reduction can take place by various methods and, for example, all the measures given for the reduction of thiocarbonamide can be used; however, a limitation is caused by the degradability of the compounds of formula V and their tendency to side reactions (e.g. hydrolysis, aminolysis). It has proved advantageous to further react the compounds of formula V without isolating them. The use of a complex metal hydride having a lower reducing power, for example sodium boride, is preferred. It is further possible to carry out the reduction with evolving hydrogen or hydrogen in the presence of a hydrogenation catalyst such as Raney nickel. Depending on the reaction conditions, the O-acyl groups may cleave during the reduction.

d) Ring closure in compounds of general formula Vila and VIIIb

^ CH2- ^ 0 J

/ \ / H Vila ^ / CH3 HO ^ 3 '_ 63571 7

CH2-L J

> / 2

_ N

VIIb f ~% sr * -,

/ == ^ / CHj HO

wherein Z is a halogen atom, a hydroxy group, an alkoxy, acyloxy or arylsulfonyloxy or alkylsulfonyloxy group.

Ring closure can be performed by known methods. Using, for example, under the conditions of the Friedel-Grafts reaction, aluminum chloride on carbon disulphide or ring closure is performed with strong acids such as phosphoric acid or polyphosphoric acid, preferably at temperatures between 100 and 150 ° C. Ring closure in compounds of formula VIIa gives compounds of formula I wherein R 3 is hydrogen. Under ring closure conditions, O-acyl or O-alkyl groups can be cleaved in some cases to give compounds of formula I, e) Closing the tetrahydrofuran ring in compounds of formula VIII CH_T] / 2 - ^ ΟΗΗΘΓ _w ^ CH3 VI11 hox

Various methods can be used to seal the tetrahydrofuran ring. For example, cleavage of water leading to ring closure can be performed by allowing acid catalysts to act on compounds of formula VIII. Suitable acid catalysts are, for example, inorganic or organic acids or acid salts such as sulfuric acid, phosphoric acid, oxalic acid, p-toluenesulfonic acid, sodium hydrogen sulfate, anhydrous zinc chloride. Operates best at elevated temperatures, best between 100 and 200 ° C. It may be appropriate to remove the diluted water with a water-binding agent, for example with excess sulfuric acid or excess zinc chloride, or by azeotropic distillation. It is also often preferred to replace one of the hydroxy groups with a reactive group in between. Thus, for example, ring closure can be accomplished with toluenesulfonic acid chloride in pyridine without isolating the intermediate O-toluenesulfonyloxy derivative of the compound of formula VIII. Depending on the relatively stringent reaction conditions, the O-acyl and O-alkyl groups can be cleaved to free phenolic hydroxy groups.

f) Compounds of general formula I, which are obtained by ester cleavage in compounds of general formula IX

-OF

r ~ \ / Η ιχ ΜΛλ-3 JS “3 • 7] In part, r denotes an acyl group derived from an inorganic or organic acid. In particular, lower aliphatic or simple aromatic and heterocyclic acyl groups, in particular acetyl, propionyl, benzoyl and tetrahydro-2-furoyl, are of practical importance.

Cleavage can be performed by various methods. The simplest is to use acidic or alkaline hydrolysis, which is best carried out in aqueous, alcoholic or aqueous-alcoholic solution. The reaction temperature, which can be varied within wide limits, is conveniently in the range of 20 to 100 ° C.

9,63571 The O-acyl moiety can also be cleaved by reduction. Of the useful methods, reduction with complex hydrides is particularly suitable. In this case, the procedure is the same as described for the reduction of the carboxylic acid amide. The amide and phenol ester moieties are preferably reduced simultaneously.

g) Ether cleavage is carried out on compounds of formula X -N Ä r 80 3 g wherein R represents an alkyl or aralkyl group.

The ether cleavage of the compounds of formula X to the compounds of formula I can be carried out by various methods which vary depending on the nature of the group R and which must therefore be chosen so as to preserve the tetrahydrofuran ring. A suitable method is, for example, the selective cleavage of the phenol-ether group with sodium hydroxide or potassium hydroxide in a high-boiling solvent such as diethylene glycol or thienylene glycol. In this case, it is expedient to operate at temperatures between 150 ° C and the boiling point of the solvent and by using additional alkali hydroxide. The benzyl ether can be cleaved catalytically by hydrogenation. Methoxymethyl ethers are highly acid-labile and can be cleaved under mild conditions with dilute mineral acids.

Depending on the choice of reaction conditions and reaction component, the reaction products obtained are either sterically homogeneous compounds or mixtures of racemic or optically active diastereomers.

Diastereomers can be separated on the basis of various chemical and physical properties by known methods, for example by fractional crystallization. Racemic compounds can be separated into the corresponding optical antipodes by conventional methods of racemate cleavage.

Many of the starting compounds used in the methods described above are known. Thus, for example, norbenzomorphans of general formula II have been described many times in the literature.

1Ό 63571

The optically active tetrahydrofurfuryl halides of the formula III can be prepared from known optically active alcohols (FC Hartmann and R. Barker, J. Org. Chem. 29, 873-877 (1964)) by halogenation with, for example, phosphorus pentachloride or phosphorus pentabromide (Org. Synth. Z3). , 88): L - (+) - tetrahydrofurfuryl alcohol: [α] 25 D = + 15.3 ° (c = 5, nitromethane) bp 76 ° / 16 mmHg D - (-) - tetrahydrofurfuryl alcohol: = "15.7 ° (c = 5, nitromethane) b.p. 76 ° / 16 mmHg L - (+) - tetrahydrofurfuryl bromide: [α] 25 D = + 3.9 ° (c = 5,.

nitromethane) b.p. 66-67 ° / 16 mmHg D - (-) - tetrahydrofurfuryl bromide: / α = -3.8 (c = 5, nitromethane) b.p. 67 ° / 16 mmHg

The corresponding sulfonic acid esters can be prepared by reacting tetrahydrofurfuryl alcohols with sulfonic acid halides.

The carboxylic acid amides of the general formula IV are obtained by reacting the nor compounds of the formula II with tetrahydrofuroyl chlorides. The corresponding thiocarbonamides of the corresponding carbonamides of formula IV can be prepared by reacting them with phosphorus pentasulfide.

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

The compounds of formula VI are prepared by reacting the nor compounds of formula II with β-phenylethyl chloride, naphthylethyl chloride or 1,2-diphenylethyl chloride and then quaternizing the tertiary amine with the compounds of formula III.

The starting compounds of the general formulas VIIa and VIIIb are obtained by alkylation of piperidines of the formula XI and of the formula XII 11 63571 CH3 (V-

CH2 -O OH XI

\ / CH3 fV-i

^ ^ ^ _OH XII

by an alkylation wave of formula III.

The parent compounds of formula VIII are obtained by reacting the nor compounds of formula II with γ-keto acid esters of formula XIII

Y - CH2 - c - ch2 - CH2 - COOC2H5 XIII

o in which formula Y is as defined above and the intermediates of formula XIV thus obtained by reduction with complex hydrides.

C - ch2 COOC, Hc / V 25

CH0 O

/ 2

- N XIV

/ j ^ —X ^ CH3 HO ^

The starting compounds of formulas IX and X can be obtained by alkylation of the corresponding norbenzomorphans with alkylating agents of formula III.

63571 12

The compounds of the general formula I are bases and can be converted into their physiologically acceptable acid addition salts in the customary manner. Suitable acids for salt formation include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, or organic acids such as acetic acid, propionic acid, butyric acid, capric acid, valeric acid, pivalic acid, pivalic acid, , fumaric acid, lactic acid, pyruvic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxy-benzoic acid, salicylic acid, p-aminobenzoic acid, phthalic acid, Kane-acid, ethanesulfonic acid, 8-ascorbic acid, 8-chloroic acid

The compounds of formula I and their acid addition salts have a therapeutically beneficial effect on the central nervous system. Particularly clear is the analgesic effect that can be demonstrated in mice in the Writhing test, the Hot-Plate test, and the Haffner test. The most effective compounds achieve 10-30 times the potency of morphine when injected subcutaneously, depending on the test. Despite this high potency, they do not have the typical side effects of morphine, such as Straub’s tail effect and peripheral running. The absence of these side effects, especially those active in the Haffner test, suggests the absence of other non-smoky morphine properties, in particular the absence of a craving effect. The relationship between the Straub tail and the lust-causing potential is presented in the literature: vert. I. Shemano and H. Wendel: A Rapid Screening Test for Potential Addiction Liability of New Analgesic Agents, Toxicol. Appl. Pharmacol. 6, 334-339 (1964). In addition, the new compounds have a greater therapeutic breadth compared to morphine. Moreover, the compounds of the invention do not have any morphine-like effect in morphine-craving rats.

The compounds of the general formula I and their acid addition salts can be used enterally or also parenterally. The dose for enteral and parenteral use is about 0.5-100 mg, preferably 1-20 mg. The compounds of the formula I or their acid addition salts can also be combined with other analgesics or other active ingredients, such as sedatives, sedatives and hypnotics.

13 63571

In the following, the analgesic properties of the compounds prepared according to the invention and of the compounds known from Finnish patent applications 327/72 and 1142/73 have been studied. The hot plate test (G.Woolfe and ADMacDonald, J. Pharmacol. Ex. Ther. 80, 300 (1944)) and the Writhing test (H.Blumberg, PS Wolf and HBDayton, Proc. Soc., Exp. Biol. Med. 118, 763 (1965).

The following table shows the results of experiments showing that the compounds according to the invention have a better analgesic effect than known furfuryl or phenylbenzomorphans or 5,9-diethyl-substituted tetrahydrofurfuryl benzomorphans.

Table

Hot-plate test Writhing test

Compound ed50 m9 / k9 ED50 m9 / k9 _s.c. hiiri_s.c. Mouse (i) -2-Tetrahydrofurfuryl-2'-hydroxy-5,9'-dimethyl-6,7-benzomorphane hydrochloride (racemic diastereomer I) 5.0 10.0 (±) -2- Tetrahydrofurfuryl-2 '-5,9-α-dimethyl-6,7-benzomorphane hydrochloride (racemic diastereomer II) 0.01 0.02 (-) - 2- (D-tetrahydrofurfuryl-C (1R, 5R (9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] hydrochloride 3,0 3,0 (-) - 2- (L-tetrahydrofurfuryl - [(1R, 5R, 9R) - 2'-Hydroxy-5,9-dimethyl-6,7-benzomorphane] hydrochloride 0.01 0.01 (i) -N-Furfuryl-2'-hydroxy-5,90i-diethyl-6,7-benzomorphane hydrochloride (FI 327/72) inactive 18 (-) - N-urfuryl-2'-hydrochloride-5,90f-dimethyl-6,7-benzomorphane hydrochloride (FI 327/72) inactive inactive (i) -N-phenyl-2 '-hydroxy-5,90 (-dimethyl-6,7-benzomorphane hydrochloride (FI 1142/73) inactive inactive 63571 14

The following examples further illustrate the invention.

Preparation Examples a) Reaction of optically active basic compounds with optically active tetrahydrofurfuryl compounds.

Example 1 (Method a) (-) - 2- (D-Tetrahydrofurfuryl) - / (1R, 5R, 9R) -2, -hydroxy-5'9-dimethyl-6,7-benzomorphane-2-methanesulfonate 2.17 g ( 0.01 mol) of (1R, 5R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphane, 1.26 g of sodium hydrogen carbonate and 1.82 g (0.011 mol) of D- (-) - Tetrahydrofurfuryl bromide is refluxed with stirring for 75 hours in a mixture of 15 ml of dimethylformamide and 25 ml of tetrahydrofuran. The reaction mixture is then evaporated in vacuo and the residue, 35 ml of chloroform and 35 ml of water are shaken together. The chloroform phase is separated on a separatory funnel and the aqueous solution is extracted twice more with 15 ml of chloroform. The combined chloroform solutions are washed with 30 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude reaction product obtained as an evaporation residue can be crystallized directly or, preferably, after column chromatography on alumina. For column chromatography, the crude product is dissolved in 25 ml of chloroform and the solution is applied to a chromatography column containing 50 g of alumina (activity step III, neutral) in chloroform. Elute with a mixture of 99 parts by volume of chloroform and 1 part by volume of methanol and collect the eluate in 10 to 20 ml fractions. After checking by thin-layer chromatography, the fractions containing the pure substance are combined and evaporated in vacuo. The evaporation residue is crystallized from a mixture of 10 ml of methanol and 6 ml of water. Allow to stand overnight at 2 ° C, after which the crystals are filtered off with suction and washed with a small amount of aqueous methanol. After drying at 80 [deg.] C., 2.3 g (76.5% of theory) of a crystallized base with a melting point of 197 [deg.] C. are obtained, which on recrystallization from aqueous methanol rose to 201 [deg.] C. and no longer changed on recrystallization. The specific rotation of the compound was = -108.5 ° (c = 1, methanol).

15 63571

To convert to the methanesulfonate, 1.55 g (0.005 moles) of crystallized base are dissolved in 8 ml of ethanol while adding 0.47 g of methanesulfonic acid. Absolute ether (40 ml) is added to the solution until slightly cloudy. The salt separates as coarse crystals after standing for several days in a closed vessel at 2 ° C. The crystals are filtered off with suction, washed with ethanol / ether 1: 1 and then with ether and dried at 50 ° C. 1.4 g (70.5% of theory) of the title compound with a melting point of 70 [deg.] C. (decomposition) are obtained. The melting point of the hygroscopic substance does not change when recrystallized from ethanol / ether and dried at 50 ° C under high vacuum.

Example 2 (Method a) (+) - 2- (L-tetrahydrofurfuryl) - (5S, 9S) -2'-hydroxy-5,9-dimethyl-6H-benzomorphane, / Using 2.17 g (0.01 mol) of (1S, 5S, 9S) - (+) - 21-hydroxy-5,9-dimethyl-6,7-benzomorphane, 1.26 g of sodium hydrogen carbonate and 1.82 g (0.011 mol) of L - (+ ) -tetrahydrofurfuryl bromide is obtained pre-; 2.2 g (72.5% of theory) of the title compound as an initial crystallization from aqueous methanol according to label 1, melting point 199 ° C. The melting point rises to 200 ° C upon recrystallization from aqueous methanol. The specific inversion of the compound is / ά7ρ5 = + 109.3 (c = 1, methanol).

Example 3 (Method a) (-) - 2- (L-tetrahydrofurfuryl) - / (1R, 5R, 9R) -2 * -hydroxy-5,9-dimethyl-6,7-benzomorphane Using 2.17 g (0.01 mol) of (1R, 5R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphane, 1.26 g of sodium hydrogen carbonate and 1.82 g (0.011 mol) of L- ( +) - Tetrahydrofurfuryl bromide is obtained according to Example 1 as a first crystallization from aqueous methanol, 2.3 g (76.5% of theory) of the title compound with a melting point of 133 ° C. The melting point rises to 137 ° C upon recrystallization from aqueous methanol. The specific inversion of the compound is = -98.5 ° (c = 1, methanol).

63571 16

Example 4 (Method a) (+) - 2- (D-Tetrahydrofurfuryl) - [(1S / 5Sy 9S) -2, -hydroxy-5,9-dimethyl-6,7-benzomorphane] Using 2f17 g (0 (01, moles) (1S, 5S, 9S) - (+) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphane, 1.26 g of sodium hydrogen carbonate and 1.82 g (0.011 moles) of D- ( -) - Tetrahydrofurfuryl bromide is obtained according to Example 1 as the first crystallization from aqueous methanol 2.1 g = 69.5% of the title compound with a melting point of 133 ° C. After recrystallization, the melting point rises to 137 ° C. The specific inversion of the compound is / c = + 98.2 °.

b) Reaction of optically active basic compounds with racemic tetrahydrofurfuryl derivatives.

Example 5 (Method a) (-) - 2- (D-tetrahydrofurfuryl - / (1R, 5R, 9R) -21-hydroxy-5,9-dimethyl-6,7-benzomorphane / and (-) - 2 - (L-tetrahydrofurfuryl) - (1R, 5R, 9R) -21-hydroxy-5,9-dimethyl-6,7-benzomorphane / 21.7 g (0.1 mol) (1R, 5R, 9R) ) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphane, 12.6 g of sodium hydrogen carbonate, 18.2 g (0.11 mol) of (+) - tetrahydrofurfuryl bromide and 2 g of potassium iodide are heated to 18 ° C. hours at 100 ° C with vigorous stirring in 200 ml of dimethylformamide. It is then cooled and 400 ml of water are added with stirring over 30 minutes. In this case, the precipitated crystals are stirred for a further 2 hours at room temperature. It is then separated by suction, washed thoroughly with several portions of water and, after the last brief separation, dried at 80 [deg.] C. to constant weight. 21.0 g of a mixture of diastereomeric title compounds are obtained. The mother liquor is stored.

To separate the diastereomers, the crystals are recrystallized from 220 ml of methyl ethyl ketone. Cool overnight at 2 ° C, separate by suction and wash with a small amount of cold methyl ethyl ketone. The mother liquor is stored, the crystals are dried at 80 ° C. II, 7 g of crystals with a melting point of 197 ° C are obtained. Recrystallization from a mixture of 270 ml of methanol and 135 ml of water gives 10.6 g of pure (-) - 2- (D-tetrahydrofurfuryl) - [(1R, 5R, 9R) -21-hydroxy-5,9-dimethyl -6,7-benzomorphane7 with a melting point of 201 ° C.

17 63571

The second diastereomer is obtained from the mother liquor solutions of dimethylformamide and methyl ethyl ketone as follows: The dimethylformamide mother liquor is evaporated in vacuo and the residue is crystallized from a mixture of 50 ml of dimethylformamide and 200 ml of water. Allow to stand for 2 days at room temperature, separate by suction, wash with water and dry at 80 ° C to give 4.1 g of the desired second diastereomer in approximately pure form. The compound is further isolated from the methyl ethyl ketone mother liquor. This is evaporated and the residue is crystallized from 30 ml of methyl ethyl ketone. Allow to stand overnight at room temperature and separate by suction to give a methyl ethyl ketone mother liquor 2 and 4.4 g of crystalline precipitate dried at 80 ° C. The crystals are recrystallized from 35 ml of methyl ethyl ketone to give methyl ethyl ketone mother liquor 2 and 1.4 g of crystal precipitate. The latter consists of a mixture of both diastereomers in a ratio of about 1: 1 and can be separated as described again. Stock solutions 2 and 2 are combined and evaporated in vacuo. The evaporation residue consists of two diastereomers as well as a crystal precipitate (4.1 g) isolated from dimethylformamide mother liquor. They are crystallized together from a mixture of toluene and petrol (60-80 ° C) in a volume ratio of 70:30. Allow to stand overnight at room temperature, separate by suction and wash with petrol. After drying at 80 ° C, 6.5 g of (-) - 2- (L-tetrahydrofurfuryl) .- [T (1R, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7 -benzomorphane7 with a melting point of 137 ° C. From the evaporation residue of the mother liquor, a further 2.7 g of compound having the same melting point are obtained by crystallization from 50 ml of toluene / petrol. The yield of both diastereomers is thus a total of 9.2 g.

Example 6 (Method a) (-) - 2-Tetrahydrofurfuryl-2 * -hydroxy-5,9,9-trimethyl-6,7-benzomorphan methanesulfonate Using 1.16 g (0.005 mol) of (+) - 2 ' -hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 0.91 g of D - (-) - tetrahydrofurfuryl bromide are obtained according to Example 1 to give the title compound having a melting point of 182 ° C. The melting point does not change upon recrystallization from ethanol / ether. This is another optical active diastereomer. The other can be isolated from mother liquors.

18 63571 c) Reaction of racemic basic compounds with racemic tetrahydrofurfuryl derivatives.

Example 7 (Method a) (±) -2-Tetrahydrofurfuryl-21-hydroxy-5,9a-dimethyl-6,7-benzomorphane (racemic diastereomers I and II) 21.7 g (0.1 mol) ( +) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphane, 13.7 g of sodium hydrogen carbonate, 19.9 g (0.12 mol) of (+) - tetrahydrofurfuryl bromide and 2 g of potassium iodide are heated with vigorous stirring 18 hours at 100 ° C in 200 ml of dimethylformamide. It is then cooled and 400 ml of water are added over 2 hours, the mixture is filtered off with suction and the residue is washed several times with water. After a final short separation and drying at 80 [deg.] C., 25.4 g of crystalline precipitate are obtained, consisting of both racemic diastereomers I and II. The mother liquor is discarded.

The racemic diastereomers I and II are separated as the hydrochlorides. In this case, proceed as follows: The mixture of diastereomers is dissolved in 100 ml of ethanol with the addition of 7.3 ml of concentrated hydrochloric acid. Crystallization occurs immediately. Allow to stand overnight, separate by suction, wash with ethanol / ether 1: 1 and then with ether and dry in air and lastly at 80 ° C. 13.5 g of not pure diastereomer I hydrochloride and mother liquor are obtained. Recrystallization from 350 ml of ethanol gives 8.1 g of pure compound with a melting point of 294 ° C and mother liquor 2. Evaporation of mother liquor 2 to 100 ml gives 2.6 g of crystalline precipitate having a melting point of 287-288 ° C, and mother liquor 3_. The latter is co-evaporated with mother liquor 1 in vacuo and the residue is crystallized from 50 ml of ethanol, precipitating a further 1.5 g of compound with a melting point of 287-288 [deg.] C., to give mother liquor 4. The crystalline precipitates, m.p. 287-288 ° C, are combined (4.1 g) and recrystallized from 40 ml of ethanol. This gives a further 2.9 g of pure hydrochloride of diastereomer I, having a melting point of 294 ° C and a mother liquor. The total yield of pure compound with a melting point of 294 ° C is thus 11.0 g.

Diastereomer II is isolated from mother liquors 3, 4 and 5 as follows: The mother liquors are evaporated in vacuo and shaken together with the residue, 75 ml of chloroform, 75 ml of water and 10 ml of concentrated ammonia. After separating the chloroform phase in a separatory funnel, the aqueous phase 19 63571 is extracted once more with 25 ml of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated. The residue consists of the crude base of both diastereomers. It is crystallized from 100 ml of a mixture of toluene and petrol (60-80 ° C) in a volume ratio of 70:30. Allow to stand overnight at room temperature, separate by suction and wash with a small amount of cold toluene / petrol and then with petrol and dry at 80 ° C. 10.6 g of pure diastereomer II with a melting point of 166 ° C are obtained. 3.5 g of the evaporated mother liquor are obtained as a residue, consisting of a mixture of both diastereomers, which can be separated as described again.

According to Example 7, 11.0 g of (+) - 2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzoraorphane hydrochloride (diastereomer I) and 10.6 g of (+ ) -2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane (diastereomer II).

Racemic cleavage affords the compounds described in Examples 1 and 2 as diastereomer I as optical antipodes and the compounds described in Examples 3 and 4 for diastereomer II.

Example 8 (Method a) (+) - 2-Tetrahydrofurfuryl-21-hydroxy-5,9a-dimethyl-6,7-benzomorphane (racemic diastereomer I) 2.17 g (0.01 mol) of 2'-hydroxy -5,9a-Dimethyl-6,7-benzomorphane, 1.26 g of sodium hydrogen carbonate and 2.82 g (0.011 mol) of p-toluenesulphonic acid tetrahydrofurfuryl ester are refluxed for 6 hours with stirring in a mixture of 20 ml of dimethylformamide and 25 ml of tetrahydrofuran. It is then filtered while still warm and the filtrate is removed in vacuo at about 50 [deg.] C. tetrahydrofuran. 40 ml of water are added to crystallize the mixture of diastereomers described in Example 7, which is separated as given in this example to give 1.0 g of diastereomer I hydrochloride, m.p. 294 ° C. For the conversion into a base, the hydrochloride is dissolved in 10 ml of water and the solution is made ammonia-containing by dropwise addition and stirring with 1N ammonia. The base precipitates. Allow to stand overnight at room temperature, separate by suction, wash with water and, after the last brief separation, recrystallize from a mixture of 20 ml of methanol and 7 ml of water. 0.75 g of 63571 compound with a melting point of 175-176 ° C is obtained. The melting point does not change upon recrystallization from aqueous methanol.

Example 9 (Method a) (+) - Tetrahydrofurfuryl-21-hydroxy-5,9,9-trimethyl-6,7-benzomorphane methanesulfonate (racemic diastereomer I) Using 1.16 g (0.005 mol) (+) 2'-Hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 0.91 g (0.0055 mol) of (+) - tetrahydrofurfuryl bromide are obtained according to Example 1 to give the title compound, m.p. 207-210 ° C. After recrystallization from ethanol / ether, the melting point rises to 210 ° C. This is the second racemic diastereomer. The other can be isolated from the mother liquor.

Example 10 (Method a) (±) -2-Tetrahydrofurfuryl-2'-hydroxy-5-methyl-9a-ethyl-6,7-benzomorphane 2.31 g (0.01 mol) of (+) - 2'-hydroxy -5-methyl-9a-ethyl-6,7-benzomorphane, 1.3 g of sodium hydrogen carbonate, 1.97 g (0.012 mol) of (+) - tetrahydrofurfuryl bromide and 0.2 g of sodium iodide are refluxed with stirring for 60 hours. time in a mixture of 15 ml of dimethylformamide and 25 ml of tetrahydrofuran. The reaction product is isolated according to Example 1, purified by chromatography on 5 g of alumina and crystallized from aqueous methanol. The yield is 1.2 g. Melting point 171 ° C, unchanged on recrystallization from a mixture of 20 ml of methanol and 5 ml of water. The crystallized compound thus obtained is one of the racemic diastereomers formed in the reaction. The other can be isolated from mother liquors.

Example 11 (Method a) (±) -2-Tetrahydrofurfuryl-2'-hydroxy-5-ethyl-9a-methyl-6,7-benzomorphane Using 2.31 g (0.01 mol) of (+) - 2'- hydroxy-5-ethyl-9a-methyl-6,7-benzomorphane and 1.97 g (0.012 mol) of (+) - tetrahydrofurfuryl bromide are obtained according to Example 10 to give 1.3 g of the title compound having a melting point of 170 ° C. The melting point does not change when recrystallized from a mixture of 30 ml of methanol and 10 ml of water. The obtained 21,63571 crystallized compound is one of the racemic diastereomers formed in the reaction. The other can be isolated from the mother liquor.

Example 12 (Method a) (±) -2-Tetrahydrofurfuryl-21-hydroxy-5,9a-diethyl-6,7-benzomorphanane hydrochloride Using 2.45 g (0.01 mol) of (+) -2 1'-Hydroxy-5,9-diethyl-6,7-benzomorphane and 1.97 g (0.012 mol) of (+) - tetrahydrofurfuryl bromide give the reaction product, which is purified according to Example 10 by chromatography on alumina. The base thus obtained is dissolved in 10 ml of absolute ethanol and the solution is acidified with 2N ethanolic hydrochloric acid, after which absolute ether is added until it is cloudy. The hydrochloride crystallizes and is filtered off with suction after standing overnight. Wash with ethanol / ether 1: 1, then ether and dry at 80 ° C. 1.0 g of the title compound with a melting point of 239 ° C is obtained, which does not change on recrystallization from ethanol / ether. The substance obtained is the hydrochloride of the second racemic diastereomer formed in the reaction. The other can be isolated from the mother liquor.

Example 13 (Method a) (±) -2-Tetrahydrofurfuryl-21-hydroxy-5-methyl-6,7-benzomorphane methanesulfonate Using 2.03 g (0.01 mol) of (+) - 2'-hydroxy-5 -methyl-6,7-benzomorphane and 1.97 g (0.012 mol) of (+) - tetrahydrofurfuryl bromide give 2.1 g of the title compound having a melting point of 171-172 ° C according to Example 1. The melting point does not change on recrystallization from a mixture of 5 ml of ethanol and diethyl ether. The compound obtained is one of the racemic diastereomers formed in the reaction. The other can be isolated from mother liquors.

Example 14 (Method a) (±) -2-Tetrahydrofuryl-2 1-hydroxy-5-ethyl-6,7-benzomorphane Using 2.17 g (0.01 mol) of (+) - 2'-hydroxy-5 -ethyl 6,7-benzomorphane and 1.97 g (0.012 mol) of (+) - tetrahydrofurfuryl bromide give 2.0 g of the title compound having a melting point of 150-151 ° C according to Example 10. The melting point is not changed by recrystallization from a mixture of 40 ml of acetone and 30 ml of water. The compound thus obtained is one of the racemic diastereomers formed in the reaction. The other can be isolated from mother liquors.

Example 15 (Method a) (±) -2-Tetrahydrofurfuryl-2 * -hydroxy-5-n-propyl-6,7-benzomorphane Using 2.31 g (0.01 mol) of (+) - 2'-hydroxy 5-n-Propyl-6,7-benzomorphane and 1.97 g (0.012 mol) of (+) - tetrahydrofurfuryl bromide are obtained according to Example 10 to give 2.1 g of the title compound having a melting point of 152 ° C. The melting point does not change on recrystallization from a mixture of 30 ml of methanol and 40 ml of water. The compound thus obtained is one of the racemic diastereomers formed in the reaction. The other can be isolated from mother liquors.

Example 16 (Method a) (±) -2-Tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane (racemic diastereomers I and II) 21.7 g (0.1 mol) ( +) - 2'-Hydroxy-5,9a-dimethyl-6,7-benzomorphane is dissolved with heating in 400 ml of methanol and 25 g of potassium carbonate dissolved in 40 ml of water are added to the solution at room temperature with vigorous stirring. A fine crystalline mixture of a portion of a base and a carbonate then precipitates. With further vigorous stirring, 22.2 g (0.165 mol) of tetrahydrofuran-2-carboxylic acid chloride are added dropwise to the suspension within 30 minutes, followed by stirring for a further 1 hour. It is then evaporated in vacuo and the residue, 150 ml of chloroform and 100 ml of water are shaken together. The chloroform layer is separated in a separatory funnel and the aqueous phase is extracted once more with 50 ml of chloroform. The combined chloroform extracts are washed successively with 100 ml of 1N hydrochloric acid and 100 ml of water, dried over sodium sulphate, 50 ml of toluene are added and evaporated in vacuo. The residue is 2- (tetrahydro-2-furoyl) -2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane, which is used in the following reduction:

The evaporation residue is dissolved in 250 ml of absolute tetrahydrofuran and the solution is added dropwise over 20 minutes with stirring to an ice-cooled suspension containing 12 g of lithium aluminum hydride 23 63571 in 150 ml of absolute tetrahydrofuran. The ice bath is then removed and stirred for an additional 1 hour at room temperature and then refluxed for 2 hours. Cool and add dropwise, with stirring and ice-cooling, 50 ml of water.

Then 1200 ml of saturated diammonium tartrate solution are added, shaken in a separatory funnel after good separation of the tetrahydrofuran phase (upper) 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 in chloroform extract and the solution is washed with water, dried over sodium sulfate and evaporated in vacuo. As a residue, a crude mixture of diastereomers is obtained, which is separated according to Example 6 via the hydrochlorides using 8 ml of concentrated hydrochloric acid and 100 ml of ethanol. Separation gives 11.3 g of pure hydrochloride of diastereomer I, m.p. 294 ° C, and 9.3 g of diastereomer II (base), m.p. 166 ° C.

Example 17 (Method b) (-) - 2- (D-Tetrahydrofurfuryl) -1H, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane / and (-) - 2- (L-tetrahydrofurfuryl - * (1R, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane47

To a suspension of 8.7 g (0.04 mol) of (1R, 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 under a condenser over 15 minutes a solution of 11.9 g (0.88 mol) of tetrahydrofuran-2-carboxylic acid chloride in 40 ml of absolute methylene chloride. The reaction mixture is then refluxed for a further 2 hours. Cool, wash twice with 30 ml of water, dry over sodium sulfate and evaporate in vacuo. The residue is crude 2- (tetrahydro-2-furoyl) -2 '- (tetrahydro-2-furoyloxy) -5,9-dimethyl-6,7-benzomorphane, which is used in the following reduction:

The evaporation residue is reduced according to Example 16 using 5.0 g of lithium aluminum hydride, and the reduction product is isolated from the tetrahydrofuran phase and the chloroform extract of the diammonium tartrate solution as described in said example. A crude mixture of the title compounds is obtained, which is separated according to Example 5 and is obtained in pure form. 4.8 g of (-) - 2- (D-tetrahydrofurfuryl) - ((1R, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane) are obtained, m.p. 201 ° C, and 3.4 g of (-) - 2- (L-tetrahydrofurfuryl) - [(1R, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane], m.p. 137 ° C.

Example 18 (Method bj (-) - 2- (D-tetrahydrofurfuryl) - / (1R, 5R, 9R) -2'-hydroxy>> 5,9-dimethyl-6,7-benzomorphane] and (-) - 2 - (L-tetrahydrofurfuryl) - [N- [1R, 5R, 9R) -2'-hydroxy-5,9-dimethyl-6,7-benzomorphane] 4.34 g (0.02 moles) (1R, 5R, 9R) - (-) - 2'-Hydroxy-S, 9-dimethyl-6,7-benzomorphane is converted according to Example 16 to the corresponding 2- (tetrahydro-2-furoyl) derivative. 8.3 g of crude product are obtained as an evaporation residue, which is thionated in the following manner to give the corresponding 2- (tetrahydro-2-thiofuroyl) derivative: . The residue is then evaporated off and the residue is shaken together, 100 ml of methylene chloride and 100 ml of water. After separation in a separatory funnel, the aqueous phase is extracted once more with 50 ml of methylene chloride. The combined methylene chloride solutions are washed successively in the presence of ice with 30 ml of 2N hydrochloric acid and three times with 30 ml of water. Dry over sodium sulfate, evaporate in vacuo to leave a residue of the crude 2- (tetrahydro-2-thiofuroyl) derivative (5.2 g). This is further reacted in the next reaction step.

The evaporation residue of the methylene chloride solution is reduced according to Example 16 using 1.5 g of lithium aluminum hydride. The reduction product is purified by column chromatography on alumina as described in Example 1. This gives a purified but not yet separated mixture of the two title compounds. Separation is carried out according to Example 5 to give 0.6 g of (-) - 2- (D-tetrahydrofurfuryl) and 0.5 g of (-) - 2- (L-tetrahydrofurfuryl) -1H, 5R, 9R) -2 1'-hydroxy-5,9-dimethyl-6,7-benzomorphane with melting points of 201 ° and 137 ° C.

63571 25

Example 19 (Method c) (-) - 2- (D-Tetrahydrofurfuryl) - / * (1R, 5R, 9R) -2 * -hydroxy-5,9-dim-tZY.11-6-7. -benzomorphane / and (-) - 2- (L-tetrahydrofurfuryl) -N- (1R, 5R, 9R) -21-hydroxy-5,9-dimethyl-6,7-benzomorphane: L7 4.34 g (0.02 moles) of (1R, 5R, 9R) - (-) - 2'-hydroxy-5,9-dimethyl-6,7-benzomorphane is converted to the 2- (tetrahydro-2-thiofuroyl) derivative according to Example 18. This is boiled in 120 ml of absolute acetone together with 6.3 g of methyl iodide for 2 hours at reflux and preventing the ingress of moisture. The reaction product is precipitated with 600 ml of absolute ether and the supernatant is decanted after clarification. In this way, the methiodide of 2- (tetrahydro-2-thiofuroyl) is obtained, which is reduced with sodium borohydride.

For this purpose, 40 ml of absolute ethanol are added to the precipitated product and, with stirring over 5 minutes, 2.3 g of finely ground sodium borohydride in 5 parts. The temperature rises in the first 15 minutes from 23 ° to 53 ° C. After a total of about one hour, cool and add dropwise 100 ml of 2N hydrochloric acid. It is then heated at reflux for 30 minutes. It is then cooled and adjusted to ammonia with concentrated ammonia and extracted with 100 ml of chloroform. Separate on a separatory funnel and shake once more with 50 ml of chloroform. The combined chloroform extracts are washed twice with water, dried over sodium sulfate and evaporated in vacuo. The residue is purified according to Example 1 with alumina, the purified but not yet separated mixture containing both title compounds. The separation is carried out according to Example 5 to give 0.4 g of (-) - (D-tetrahydrofurfuryl) - and 0.25 g of (-) - (L-tetrahydrofurfuryl) - / * (1R, 5R, 9R) -2'- hydroxy-5,9-dimethyl-6,7-benzomorphane with melting points of 201 ° and 137 ° C.

Example 20 (Method d) (±) -2-Tetrahydrofurfuryl-21-hydroxy-5,9a-dimethyl-6,7-benzomorphane (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 mol) of 2- (p-methoxybenzyl) -3,4-dimethyl-4-hydroxy- · 63571 26 piperidine 200 ml in dimethylformamide and 12.6 g of sodium hydrogen carbonate and 19.7 g (0.12 mol) of tetrahydrofurfuryl bromide are stirred for 24 hours at 100 ° C. The reaction mixture is then evaporated in vacuo and the residue, 150 ml of chloroform and 100 ml of water are shaken together. After separation in a separatory funnel, the aqueous phase is extracted once more with 50 ml of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is purified according to Example 1 by column chromatography on alumina (700 g, activity step III, neutral) using chloroform as eluent. After evaporation of the eluate containing pure substance, 16 g of residue are obtained, which is further reacted in the next reaction step.

b) Ring closure 16 g of 1-tetrahydrofurfuryl-2- (p-methoxybenzyl) -3,4-dimethyl-4-hydroxypiperidine (evaporation residue from the previous reaction step) and 80 g of crystallized phosphoric acid are stirred under nitrogen for 26 hours at 130 ° C. It is then diluted with 85 ml of water and refluxed for 5 hours. After cooling, add 150 ml of benzene, 150 ml of n-butanol and 165 ml of concentrated ammonia and shake well. The organic layer is separated in a separatory funnel and the aqueous phase is shaken twice more with benzene / n-butanol. The combined organic phases are washed three times with water, dried over sodium sulfate and evaporated in vacuo. The residue (10 g) is dissolved in 50 ml of chloroform and the solution is applied to an alumina column for chromatography. To this is added 200 g of alumina (activity stage III, neutral) and continued as described in Example 1. The fractions obtained by thin layer chromatography, which contain the pure substance, are combined and evaporated in vacuo. In this way, 4.0 g of residue are obtained, which consists of a mixture of both stereoisomers I and II and is separated according to Example 5 into pure components. Separation gives stereoisomer I as the hydrochloride, melting point 294 ° C and a yield of 1.9 g, and stereoisomer II as a base, melting point 166 ° C and a yield of 1.3 g.

Example 21 (Method e) (+) - 2-Tetrahydrofurfuryl-2'-hydroxy-5,9g-dimethyl-6,7-benzomorphane (racemically diastereomers I and II) 63571 27 a) (±) -2- ( 2-Oxo-4-ethoxycarbonyl-butyl) -2 * -hydroxy-5,9-dimethyl-6,7-benzomorphane hydrochloride 10.85 g (0.05 mol) of (+) - 2'-hydroxy- 5,9a-Dimethyl-6,7-benzomorphane, 4.6 g of sodium hydrogen carbonate and 12.3 g (0.055 mol) of 5-bromo-levulinic acid ethyl ester are refluxed for 2 hours in a mixture of 50 ml of dimethylformamide and 125 ml of ml of tetrahydrofuran. It is then evaporated in vacuo and the residue, 250 ml of chloroform and 100 ml of water are shaken together. The aqueous phase separated in a separatory funnel is extracted once more with 50 ml of chloroform, the combined chloroform solutions are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in a mixture of 75 ml of ethanol and 25 ml of 2N ethanolic hydrochloric acid, and absolute ether is added to the solution until it just begins to cloud. The title compound crystallizes. Allow to stand overnight at 2 ° C, separate by suction and wash with ethanol / ether 1: 1 and then with ether. The crystal precipitate is dried first in air and then at a temperature of 80 ° C. 18.2 g (92% of theory) of the title compound are obtained, m.p. 212-215 ° C. The ethanol / ether recrystallized sample melts at 214-216 ° C. The melting point no longer changes upon recrystallization.

b) (±) -2- (2,5-dihydroxy-n-pentyl) -2'-hydroxy-5,9a-dimethyl-6,7-benzomorphane (mixture of stereoisomers) 19.8 g (0.05 mol) (+) - 2- (2-oxo-4-ethoxycarbonyl-butyl) -2 * -hydroxy-5,9a-dimethyl-6,7-benzomorphane hydrochloride is converted into the corresponding base by shaking with a mixture of 100 ml of chloroform, 100 ml of water and 7 ml of concentrated ammonia, the base being dissolved in the chloroform phase. After separation of the chloroform phase, the aqueous phase is extracted once more with 25 ml of chloroform, the chloroform extracts are combined, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is reduced with lithium aluminum hydride. To this end, the evaporation residue are added dropwise to a solution of 100 ml of absolute tetrahydrofuran under ice-cooling with stirring and within a half hour, a suspension containing 2.9 g of lithium aluminum hydride in 250 ml of absolute tetrahydrofuran.

It is then stirred for a further hour at room temperature and finally refluxed for 3 hours. It is then cooled and 10 ml of water and then 290 ml of saturated diammonium tartrate solution are added dropwise with stirring and cooling. Shake well and separate the phases in a separatory funnel. The tetrahydrofuran phase (upper) is evaporated in vacuo and the aqueous phase is extracted twice with 100 ml of silica chloride. The evaporation residue of the tetrahydrofuran phase is taken up in the combined chloroform extracts and the solution is washed twice with water. Dry over sodium sulfate and evaporate in vacuo to give the crude reduction product (17.5 g). This is purified by chromatography on alumina. In this case, 350 g of alumina (activity stage III, neutral) are used and the procedure described in Example 1 is followed. Elute first with chloroform, then with a mixture of chloroform and methanol (99: 1 by volume), collecting in 25 ml fractions. After thin layer chromatography, the fractions containing the pure main product are combined and evaporated in vacuo. This gives a reduction residue which is the main product of the stereoisomeric mixture.

c) (±) -2-Tetrahydrofurfuryl-21-hydroxy-5,9a-dimethyl-6,7-benzomorphane (racemic diastereomers I and II)

The evaporation residue from the previous reaction step (17.5 g) and 17.5 g of p-toluenesulfonic acid are refluxed in 800 ml of xylene for 45 minutes using a water separator. It is then evaporated in vacuo and the residue, 100 ml of chloroform, 50 ml of water and concentrated ammonia, (10 ml) are shaken together. After separation in a separatory funnel, extract once more with 25 ml of chloroform. The combined chloroform phases are washed twice with 30 ml of water, dried over sodium sulfate and evaporated in vacuo. The evaporation residue is purified by chromatography on 500 g of alumina (activity stage III, neutral), proceeding as in Example 1. Elute first with chloroform / methanol (99: 1 by volume) to separate the faster impurities and then using a 95: 5 by volume ratio. The fractions containing pure reaction product are combined and evaporated in vacuo. This leaves 12 g of residue which still contains some solvent. This residue is subjected to the separation of the two diastereomers described in Example 7. This gives the hydrochloride of diastereomer I (2.4 g) and diastereomer II as a base (2.2 g). Melting points of 284 ° C and 161 ° C increase after recrystallization to 294 ° C and 166 ° C.

29

Example 22 (Method f) 6 35 71 (±) -2-Tetrahydrofurfuryl-21-hydroxy-5,9a-dimethyl-6,7-benzomorphane (racemic diastereomers I and II) a) (±) -2- tetrahydrofurfuryl-21-benzoyloxy-5,9a-dimethyl-6,7-benzomorphane (mixture of diastereomers) 3.21 g (0.01 mol) of 2'-benzoyloxy-5,9a-dimethyl-6,7-benzomorphane are alkylated in Example 8. in the presence of 0.95 g of sodium hydrogen carbonate in dimethylformamide / tetrahydrofuran, 2.82 g of p-toluenesulfonic acid tetrahydrofurfuryl ester. It is then evaporated in vacuo and the residue, 50 ml of chloroform and 50 ml of water are shaken together. After separation in a separatory funnel, the aqueous phase is extracted once more with 25 ml of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated in vacuo. A mixture of both racemic diastereomers (+) - 2-tetrahydrofurfuryl-21-benzoyloxy-5,9a-dimethyl-6,7-benzomorphans is obtained as a residue.

b) (±) -2-Tetrahydrofurfuryl-2 * -hydroxy-5,9a-dimethyl-6,7-benzomorphane (racemic diastereomers I and II)

The evaporation residue from the previous synthesis step is dissolved in 75 ml of methanol and 20 ml of 2N sodium hydroxide are added to the solution, followed by refluxing for 15 minutes. It is then acidified with 25 ml of 2N hydrochloric acid and evaporated in vacuo. Shake together the residue, 50 ml of chloroform, 50 ml of water and 2 ml of concentrated ammonia. After separation in a separatory funnel, the aqueous solution is extracted once more with 25 ml of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue consists of both racemic diastereomers I and II, which are separated according to Example 7 by crystallization of the hydrochloride. Thus, the hydrochloride of diastereomer I is obtained in a yield of 0.7 g, melting point 294 ° C, and diastereomer II in a yield of 0.4 g, melting point 166 ° C.

63571 30

Example 23 (Method g) (±) -2-Tetrahydrofurfuryl-21-hydroxy-5,9a-dimethyl-6,7-benzomorphane (racemic dlastereomer I) 2.0 g (0.0062 mol) of (+) - tetrahydrofurfuryl 21-Methoxy-5,9a-dimethyl-6,7-benzomorphane (O-methyl derivative of the title compound) and 2 g of finely ground potassium hydroxide are heated for 4 hours at 210 ° C in 20 ml of diethylene glycol. The reaction mixture is cooled and diluted with 100 ml of water, acidified with concentrated hydrochloric acid, adjusted to ammonia with concentrated ammonia and shaken with 50 ml of chloroform. The aqueous phase separated in a separatory funnel is extracted twice more with 25 ml of chloroform. The three chloroform extracts are combined, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from aqueous methanol to give the title compound 1.7 g = 89% of theory, m.p. 173-175 ° C. The melting point rises to 176 ° C after recrystallization from aqueous methanol.

Example 24 (Method g) (±) -Tetrahydrofurfuryl-21-hydroxy-5,9-dimethyl-6,7-benzomorphane (racemic diastereomer I) 2.0 g (0.0062 mol) of (+) - 2-tetrahydrofurfuryl 2'-Methoxy-5,9-dimethyl-6,7-benzomorphane (O-methyl derivative of the title compound) and 20 g of anhydrous pyridine hydrochloride are heated at 190 ° C for 30 minutes. After cooling, 20 ml of water and 12.5 g of sodium carbonate are added to the melt and the pyridine is distilled off with steam. The residue is shaken with 50 ml of chloroform and the aqueous phase separated in a separatory funnel is extracted once more with 25 ml of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from aqueous methanol. 0.9 g of the title compound is obtained, corresponding to a yield of 47% of theory. The compound has a melting point of 171-174 ° C, which rises to 176 ° C after crystallization from aqueous methanol.

Claims (1)

Process for the treatment of analgesically active, racemic or diastereomeric and optically active 2-tetrahydrofurfuryl-1R / S, 5R / S, 9R / SJ-2, hydroxy-5,9-dimethyl-6,7-benzomorphans and their acid addition salts for the preparation of compounds of general formula I (R-form) or a mirror image thereof (S-form) —TH CH2-12 "y> = / V HO J characterized in that a) norbenzomorphane of formula II --N / HCT J is reacted with a compound of formula III wherein X is a nucleophilically removable group, preferably a halogen atom, especially chlorine, bromine or iodine, and arylsulfonyloxy, aralkylsulfonyloxy. , or an alkylsulfonyloxy group, or 32 6 3 5 71 b) reducing a carbonamide or thioamide of formula IV AU -N_ / IV <QX '' ch3 HO 3 wherein Y is an oxygen or sulfur atom, or c) reducing a compound of formula V γΙγί] «*», _ ^ 0 'V, __ S * A <“> __H0 ^' CH3 _ where Y has the same meaning as above, and R 1 * is an alkyl group having 1 to 4 carbon atoms, preferably a methyl group, and is an anion of an inorganic or organic acid; or d) in the presence of acid catalysts in the compounds of the general formulas VIIa and VIIIb, the ring J7 \ 's / - CH3 HO ^ 33 63571 / CH2-to j —Nr \, H VIIb / 3 / C'cH3 2 ®3 in which Z is a halogen atom is closed , a hydroxy group, an alkoxy, acyloxy or arylsulfonyl or alkylsulfonyloxy group; or e) cleaving water from compounds of formula VIII -N VIII C 1-3 HO 'CH 3 or f) performing ester cleavage in compounds of formula IX / CH 2 -O 0 -N ft ch 3 R 70 ^ CH 3 having an acyl group derived from an inorganic or organic acid; or g) performing ether cleavage on compounds of formula X 34 6 3 5 71 CH 2 -L0 / r-N 'X' 'CH 3 o s> =' VCH r 80 3 p 3 in which R is an alkyl or aralkyl group; and optionally converting the compounds of general formula I into their physiologically acceptable acid addition salts. 35 6 3 5 71 For the preparation of an analgesic network, racemic or diastereomeric and optically active 2-tetrahydrofurfuryl-tlR / S, 5R / S, 9R / SJ-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane and a compound of the form of a salt of formula I (R-form) and a mirror image of the form (S-form) -Tl · * —ch2— [2 ^ h3 1 For the purposes of this invention, a) norbensomorph of form II - / rL XH-CH11 is a nucleophilic moiety, a halogen atom, a brominated chlorine, bromine or iodine, as well as an arylsulfonyloxy, aralkylsulfonyloxyl or alkylsulfonyl sulfone group. en carbonamide or thioamide with formula IV 36 63571 JO -N _TIV <ryvN ch3 ^ = /% ch- HO * där Y är en syre- eller svavelatom, reducer, eller c) en förening med formulaeln V / -g I «—N v / a (_) ^ y -— * K ^ CH3 HO CH3 d Y Y is selected from the group consisting of 1-4 carbon atoms, a methyl group having 1 to 4 carbon atoms, and an organic group r is an organic anion, a reducing agent or d) a compound having all the forms Vila and Vllb «/ CH2-0 ^ N / Vila V \ \ = J \ CH3 H0 / 3 63571 37 / ch2 — L0 J —N _ / H VII b OXS ΗοΛ-7 ^ CH3 is a halogen atom, a hydroxy group, an alkoxy, an acyloxy or an arylsulfonyloxy or an alkylsulfonyloxy group, a ring in the nerve of the catalyst, or e) ur for a compound of formula VIII and CH2 Ldhfk -N / \ ^ H VIII <fVVcH3 HO S— * 'CH3 spjälks vatten, eller f) i föreningar med formiel IX / «2— ^ L0J -N fW. Λ 7 'CH3 for R7 is an organic or organic acrylic group which is ether-treated, or (g) which is derived from formula X