SK280776B6 - Benzomorphanes, method of their preparation, pharmaceutical agents containing them, and their use - Google Patents

Abstract

Benzomorphan derivatives of the general formula (I) wherein R1 is C1-8alkyl, C3-6alkenyl, C3-6alkinyl, C6-10aryl; R2 is H, C1-8alkyl, C3-6alkenyl, C3-6alkinyl, C6-10aryl, C7-14aralkyl; R3 is H, C1-6alkyl; R4 is C1-8alkyl; R5 is C1-8alkyl; R6 is C1-8alkyl, C6-10aryl, and R7 and R8 independently represent for instance H, C1-8alkyl, halo, -OH, -CN, -NH2 and others; X is O or S.

Description

Technical field

The invention relates to novel benzomorphans, to a process for their preparation and to their use as medicaments.

BACKGROUND OF THE INVENTION

The preparation of benzomorphane derivatives is known from DE-PS 2105743 and DE-OS 28 28 039, as well as from the literature (H. Merz and K. Stockhaus, J. Med. Chem. 22 (1979) 1475). the compounds have analgesic activity and can be used as non-addictive analgesics and antitussives (DE-PS 21 05 743).

The hippocampus section serves as a test system to demonstrate the NMDA-antagonistic activity of the benzomorphane derivatives. Electrodes stimulate the sheep collateral in the perfusion chamber of the hippocampus cut and remove the total potential generated by the extracellular on CAI-region pyramid cells (H.L. Haas, B. Schaerer, and M. Vosmansky, J. Neuroscience Meth. 1 (1979) 323).

Furthermore, the neuroprotective efficacy of benzomorphan derivatives in mice has been demonstrated in vivo by suppressing N-methyl-D-aspartic acid-induced lethality (J. D. Leander et al., Brain Research 448 (1988) 115) and suppressing ischemia-induced cell death in mice and gerbils.

SUMMARY OF THE INVENTION

The benzomorphans according to the invention correspond to the general formula (I)

where

X represents an oxygen atom or a sulfur atom,

R ¹ represents C _1-8 alkyl, C ₃ . ₆ alkenyl, C _{3. 6} alkynyl, C ₆ . ₁₀ aryl,

R ² is H, C ^ alkyl, C _{3. 6} alkenyl, C _{3. 6} alkynyl, C ₆ . ₁₀ aryl, C _{7-10 4} aralkyl,

R ³ is hydrogen, _C-alkyl,

R ⁴ is C 1-6 alkyl,

R ⁵ is C 1. ₈ alkyl,

R ⁶ can be C 1-6 alkyl, C ₆ . ₁₀ aryl,

R ⁷ and R ⁸ independently represent a hydrogen atom, C 1-6 alkyl; ₈ alkyl, halogen, OH, C _b8 alkoxy, -O-acyl, -CN, _{-NO2, NH2,} -NH _(BS alkyl), -N (C !. ₈ alkyl) _2, the alkyl the radicals may be the same or different, -NH-acyl or -N-acyl- (C _1-8 alkyl), wherein acyl is R-CO-, wherein R is phenyl or C 1-6. _{e is} alkyl, alkoxy is C 1-6. _The alkoxy group and the acyloxy group is R-CO-O-, wherein R is phenyl or C 1-4 alkyl.

Preferred are compounds of formula (1) wherein

X is an oxygen or sulfur atom,

R ¹ is methyl, ethyl, propyl, isopropyl, phenyl,

R ² is methyl, ethyl, propyl, isopropyl, allyl, propargyl, phenyl, benzyl,

R ³ represents a hydrogen atom, C 1-4 alkyl,

R ⁴ is methyl, ethyl, propyl, isopropyl,

R ⁵ is methyl, ethyl, propyl, isopropyl,

R ⁶ is methyl, ethyl, propyl, isopropyl, phenyl,

R ⁷ is fluorine, chlorine, hydroxy, C ₃ . ₆ alkyl, C ₃ .6. alkoxy, acyloxy,

R ⁸ represents a hydrogen atom, C ₃ . ₆ alkyl, hydroxy or alkoxy.

Particularly preferred are compounds of formula (1) wherein

X is an oxygen atom,

R ¹ is methyl or ethyl,

R ² is methyl or ethyl,

R ³ represents a hydrogen atom,

R ⁴ is methyl or ethyl,

R ⁵ is methyl or ethyl,

R ⁶ is methyl or ethyl,

R ⁷ is hydroxy, methyl, methoxy, acyloxy,

R ⁸ represents a hydrogen atom, methyl, ethyl, hydroxy or C ₃ . ₆ . alkoxy.

Most preferred are compounds of formula (I) wherein

X is an oxygen atom,

R ¹ is methyl,

R ² is methyl,

R ³ represents a hydrogen atom,

R ⁴ is methyl,

R ⁵ is methyl,

R ⁶ is methyl],

R ⁷ is hydroxy, methyl, methoxy or acetoxy,

R ⁸ is hydrogen, methyl, hydroxy, methoxy or ethoxy, wherein the substituents R ⁷ and R ⁸ are in the 2'- and 3'-positions and the carbon atom in the 2-position has the R-configuration.

The present invention relates to the individual isomers, their mixtures, and the corresponding physiologically acceptable acid addition salts with both inorganic and organic acids. Preferred are, for example, salts with hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, lactic, butyric, maleic, filmaric, malic, tartaric, citric or benzoic acids.

If the in each case indicated otherwise, the generally used definition as defined below: C ^ alkyl, optionally a C _alkyl generally represents a straight or branched hydrocarbon radical having 1 to 6 or 8 carbon atoms, which may optionally be substituted by one or more halogen halogen, preferably fluorine, which may be the same or different. Examples which may be mentioned are the following hydrocarbon radicals: methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3- methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,

1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2- trimethylpropyl, 1,2,2-trimethylpro2

Pollen, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl radicals having 1 to 3 carbon atoms, such as methyl, ethyl, propyl and isopropyl, are preferred.

Alkenyl generally represents a hydrocarbon radical having 3 to 6 carbon atoms which is straight or branched and contains one or more, preferably one double bond, and which may be optionally substituted by one or more halogen atoms, preferably fluorine, which may be the same or different.

Examples include:

2-propenyl (allyl), 2-butenyl, 3-butenyl,

1-Methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl,

3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl,

2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,

3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,

1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 6-hexenyl,

-methyl-2-penteneyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,

1-methyl-3-pentenyl, 2-methyl-3-pentenyl

3-Methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl,

4-Methyl-4-pentenyl, 1,1-dimethyl-2-butenyl

1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl,

1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl,

1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl,

2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-1-3-butenyl,

2-ethyl-1-butenyl, 2-ethyl-2-butenyl,

2-ethyl-1-3-butyl-1,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl.

An allyl residue is preferred.

Alkynyl generally means a straight or branched chain hydrocarbon having from 3 to 6 carbon atoms and having one or more triple bonds.

Preferably, it is a lower alkynyl (propargyl) radical having 3 carbon atoms and a triple bond, which may be optionally substituted by one halogen atom, preferably fluorine, or by multiple halogen atoms, which may be the same or different.

Acyl is generally a benzoyl or alkylcarbonyl radical having both straight and branched lower alkyl having 1 to about 6 carbon atoms attached through a carbonyl group, wherein the alkyl radical may be optionally substituted by one or more halogen atoms which may be the same or different . Preferably, the alkyl radicals contain up to 4 carbon atoms. Examples are acetyl, trifluoroacetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, as well as isobutylcarbonyl. An acetyl residue is particularly preferred.

Acyloxy represents an acyl group attached through oxygen, wherein acyl is as defined above.

Aryl generally represents an aromatic radical having 6 to 10 carbon atoms, also in composite form, wherein the aroma may be substituted by one or more lower alkyl, alkoxy, nitro, amino and / or one or more halogen atoms, which may be the same or different. A preferred aryl moiety is phenyl.

Aralkyl is generally an aryl radical of 7 to 14 carbon atoms attached via an alkylene radical, wherein the aromatic may be substituted by one or more lower alkyl, alkoxy, nitro, amino and / or one or more halogen atoms, which may be the same or different. Aralkyl radicals having 1 to 6 carbon atoms in the aliphatic moiety and 6 carbon atoms in the aromatic moiety are preferred. Unless otherwise indicated, preferred aralkyl radicals are benzyl, phenethyl and phenylpropyl.

Alkoxy generally represents a straight or branched hydrocarbon radical having 1 to 8 carbon atoms attached through an oxygen atom. Preferred is a lower alkoxy radical having 1 to 3 carbon atoms. Methoxy is particularly preferred.

Amino represents, unless otherwise indicated, an NH ₂ group which may be optionally substituted by one or two C 1-6 groups. ₈ alkyl, aryl or aralkyl radicals which may be the same or different.

Alkylamino represents, for example, methylamino, ethylamino, propylamino, 1-methylethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino.

Dialkylamino represents, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, di- (1-methylethyl) amino, di- (1-methylpropyl) amino, di-2-methylpropylamino, ethylmethylamino, methylpropylamino.

Halogen means, unless otherwise indicated, in particular fluorine, chlorine and bromine.

Pharmacological characteristics

Systemic administration of glutamate is known to destroy neurons in the brain in mice (S. M. Rotham and T. W. Olney, Trends in Neurosciences 10 (1987) 299). This finding concludes, inter alia, that glutamate plays a role in neurodegenerative diseases (R. Schwarcz and B. Yeldrun, The Lancent 11 (1985) 140).

Furthermore, substances such as quisqualic acid, kaic acid, ibotic acid, glutamic acid and N-methyl-D-aspartic acid (NMDA) are known as exogenous or endogenous neurotoxins. Because of their neurotoxicity, these substances act selectively on individual cells so that functional disorders can be induced in animals by specific brain lesions. These are comparable to disorders arising from epilepsy and other neurodegenerative diseases such as Huntington's and Alzheimer's disease.

In vivo and in vitro experiments have shown that brain damage involves hypoglycemia, hypoxia, anoxia and ischemia, and functional disorders partly based on increased synaptic activity, with glutamatergic synapsia being of particular importance. Substances and ions that suppress the activity of glutamate receptors and receptor-associated ion channels, such as competitive and non-competitive excitatory amino acid antagonists, as well as magnesium ions, protect brain cells from hypoxic and ischemic damage. These findings indicate that glutamate receptor plays an important role in mediating ischemic damage.

Biochemical and electrophysiological studies show that the receptor-ion channel is highly sensitive to fluctuations in magnesium concentration. As the magnesium concentration decreases, spontaneous epileptic manifestations in the hippocampus can be suppressed by excitatory amino acid antagonists.

Surprisingly, it has now been found that the benzomorphans of formula (I) block the NMDA channel and have neuroprotective activity.

The preparation of such benzomorphane derivatives is known from DE-PS 2105743 and DE-OS 28 28 039 as well as from the literature (H. Merz and K. Stockhaus, J. Med. Chem. 22 (1979)).

It is also known that such compounds have analgesic activity and can be used as non-addictive analgesics and antitussives (DE-PS 21 05 743).

The hippocampus section serves as a test system to demonstrate the NMDA-antagonistic activity of the benzomorphane derivatives. Electrodes stimulate the sheep collateral in the perfusion chamber of the hippocampus cut and remove the total potential generated by the extracellular on CAI-region pyramid cells (H.L. Haas, B. Schaerer, and M. Vosmansky, J. Neuroscience Meth. 1 (1979) 323).

In addition, the neuroprotective activity of the benzomorphane derivatives belonging to the general formula (I) has also been demonstrated in relation to protein synthesis and the release of neurotransmitters in the cross section of the hippocampus.

Receptor binding assays further show that the benzomorphane derivatives of the invention are non-competitive glutamate receptor antagonists.

Furthermore, the neuroprotective efficacy of the benzomorphan derivatives of formula (I) in mice has been demonstrated in vivo by suppressing N-methyl-D-aspartic acid-induced lethality (JD Leander et al., Brain Research 448 (1988) 115) and suppressing ischemia-induced cell death in mice and gerbils.

These results provide a basis for considering that the benzomorphane derivatives of formula (I) may be used in neurodegenerative diseases as well as cerebral ischemia of various origins. These include, for example, epilepsy, hypoglycemia, hypoxia, anoxia, cerebral trauma, brain edema, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotonia, heart attack, stroke and perinatal asphyxia.

Pharmaceutical compositions

The benzomorphane derivatives of formula (I), as well as their addition salts with pharmaceutically acceptable acids, can be converted by conventional methods into conventional compositions such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inert pharmaceutically acceptable carriers or solvents. The proportion of the pharmaceutical active compound (a) is usually in the range of 0.5 to 90% by weight of the total composition, i.e. in amounts which make it possible to achieve the desired dose range.

The compositions may be prepared, for example, by treating the active ingredient with a solvent and / or carrier, optionally using emulsifying agents and / or dispersing agents, whereby, for example, using water as a diluent, optionally organic solvents may be used as solubilizers or solubilizers.

For example, excipients include water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), vegetable origin (e.g., peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerin), carriers such as for example natural mineral meal (for example kaolin, diatomaceous earth, talc, chalk), synthetic mineral meal (for example highly dispersed silicic acid and silicates), sugar (for example cane, milk and grape sugar), emulsifying agents (for example lignin, kraft liquor, methylcellulose) , starches and polyvinylpyrrolidone) and glidants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

Administration is carried out in a conventional manner, preferably parenterally, in particular by intravenous infusion. For oral use, tablets may of course also contain excipients such as sodium citrate, calcium citrate and dicalcium phosphate together with various disintegrants, such as starches, especially potato starch, gelatin and the like. Additionally, glidants such as magnesium stearate, lauryl sulfate and talc may be used. In the case of aqueous suspensions, in addition to the excipients mentioned above, the active ingredients may be mixed with various flavoring agents which improve the taste of the composition or with coloring agents.

For parenteral use, the active ingredient solutions may contain suitable liquid carrier materials.

The dosage for oral use is in the range of 1 to 300 mg, preferably 5 to 150 mg.

Nevertheless, it may be appropriate to vary the amount, depending on the body weight or the type of administration, the individual relationship with the drug, the type of formulation and the time or interval in which it is administered. In some cases it may also be appropriate to start with smaller doses than indicated, while in other cases the limits mentioned must be exceeded. If larger amounts are applied, it is recommended to divide them into smaller doses throughout the day.

Furthermore, the compounds of the formula I or their acid addition salts can also be combined with other active substances.

Examples of pharmaceutical compositions

tablets

The tablet contains the following ingredients:

active ingredient of the formula (I) stearic acid dextrose together 0.020 parts 0.010 parts 1,890 parts 1,920 parts Production

The substances are mixed together in the indicated amounts and the mixture is compressed into tablets having a weight of 1.92 g each and an active compound content of 20 mg.

Ampoule solution

Ingredients:

active ingredient of formula (I) 1.0 mg sodium chloride 45.0 mg water for injections to 5.0 ml

Production

The active ingredient is dissolved in water at its own pH or, if appropriate, at a pH of 5.5 to 6.5 and mixed with sodium chloride as an isotonic agent. The resulting solution is pyrogen-filtered and the filtrate is filled under aseptic conditions into ampoules which are finally sterilized and sealed. The ampoules contain 1 mg, 5 mg and 10 mg of active ingredient.

suppository

One suppository contains: active ingredient of the formula (I) cocoa butter (m.p. 36-37 ° C) kamauba wax

Production

Cocoa butter and Kamauba wax will melt together.

The active ingredient is added at 45 ° C and mixed until a complete dispersion is obtained. The mixture is poured into a mold of appropriate size and the suppositories are suitably packed.

1.0 part

1200.0 parts

5.0 parts

Synthesis method

The preparation of benzomorphane derivatives which serve as starting material in various synthesis processes of type 2 are known in the art (DE-A 20 27 077, CA 74 (1971) 125482x, EP-B 4960, CA 93 (1980)) 4941 f) or as described in the following examples.

The substituents R ⁹ and R ¹⁰ are either identical to the desired substituents R ⁷ and R ⁸ , or can later be converted to these substituents.

Method A

The introduction of any of the desired substituents on the amino function of the benzomorphane nitrogen may be accomplished by acylation with a suitable activated carboxylic acid derivative. Corresponding carboxylic acid derivatives of type 4 are known in the art or are readily accessible to our synthesis process.

For the acylation itself, there are many ways to choose again (C. Ferri, Reaktionen der organischen Synthese, Georg Thiem Verlag Stuttgart, 1978, p. 222 et seq. And references J. March, Advanced Organic Chemistry, 3rd edition, John Wiley and Sons, New York 1985, p. 370 et seq., RC Larock, Comprehensive Organic Transformation - A Guide to Functional Group Preparations, VCH Verlagsgesellschaft, D-6940 Weinheim 1989, p. 963 et seq. reactions with carboxylic acid halides (ALJ Beckwith in J. Zabicki, "The Chemistry of Amides", Interscience, New York 1970 page 73) are preferred in a solvent which is substantially inert under the reaction conditions, optionally in the presence of acid binding agents Inert solvents which are generally used are organic solvents which do not change under the reaction conditions, such as hydrocarbons such as benzene, toluene, xylene and the like. or petroleum fractions or an ether such as diethyl ether, glycol dimethyl ether (glyme), diglycol dimethyl ether or cyclic ethers such as tetrahydrofuran or dioxane, or halogenated hydrocarbons such as carbon tetrachloride, chloroform or dichloromethane.

The production of the desired carboxylic acid halides is known in the art (Houben-Weyl, Methoden der organischen Chemie, Vol. VIII and Vol. E5, Georg

Thieme Verlag (Stuttgart, 1952 and 1985), if not commercially available. Preferably, the benzomorphane derivative of type 2 is preferably reacted in halogenated hydrocarbons, in particular dichloromethane and in the presence of a tertiary amine such as triethylamine, with the desired acid halide, particularly preferably with acid chloride. However, it is also possible to carry out the reaction with respect to the Schotten-Baumann variants in water or aqueous alcohol in the presence of an alkali metal hydroxide or an alkali metal carbonate (see, for example, Organikum, et al., VEB Deutscher Verlag der Wissenschaften, 17th edition, Berlin 1988, p. 407). Depending on the adducts used, it may furthermore be particularly advantageous to show acylation by the Einhom variant, where pyridine is used as both an acid binding agent and a reaction medium.

In addition, it is possible to carry out acylation with a free carboxylic acid (see, for example, ALJ Beckwith in J. Zabicki, "The Chemistry of Amides", Interscience, New York 1970, p. 105 et seq .; JA Mitchell and EE Reid, J. Am. Chem. Soc., 53 (1931) 1879). Furthermore, it may be advantageous to use a mixed anhydride instead of the free acid, for example with a carbonic acid ester (C. Ferri, Reaktionen der organischen Synthese, Georg Thieme Verlag, Stuttgart 1978, p. 222 and references cited; Interscience, New York, 1970, p. 86, J. March, Advanced Organic Chemistry, 3rd Edition, John Wiley and Sons, New York, 1985, p. 371 and references, RC Larock, Comprehensive Organic Transformations, VCH Publishers, D-6940 Weiheim 1989, p. 981 and references cited.

In the preferred acylation with carboxylic acid halides, in particular carboxylic acid chlorides, the reaction temperature can be varied within a wide range, limited at the bottom by a low reaction rate and at the top by undesired side reactions. In an embodiment, the temperatures are in the range of -50 ° C to 150 ° C, preferably 0 to 75 ° C. It is expediently carried out in the presence of a small excess of the acylating agent, in the presence in the excess of an acid-binding agent, in order to prevent possible side reactions of the adduct.

Method B

The following reaction step of reducing the acid amide 3 is required to obtain the amine type 6.

Such acid amide reductions are known in the art and can be carried out by electrolytic reduction, alkali metal reduction as well as catalytic reduction (R. Schroter in Houben-Weyl, Methoden der Organischen Chemie, Vol. XI / 1, Georg Thieme Verlag, Stuttgart 1957, p. 574) or with boron or possibly boron derivatives (J. Fuhrhop and G. Penzlin, Organic Synthesis - Concepts - Methods - Starting Materials, VCH-Verlagsgesellschaft, Weinheim 1986, p. 90).

Preferably, the reduction is carried out with complex hydrides such as alkali metal boron or aluminum hydrides, or suitable derivatives thereof, optionally with the presence of a catalyst (NG Gaylord, Complex Metal Hydrides, Wiley New York 1965; A. Hajos, Complex Hydrides, Elsevier New York 1979, V. Bazant, M. Capka, M. Cemy, V. Chvalovsky, K. Kochloefl, M. Kraus and J. Malek, Tetrahedron Lett. 9 (1968) 3303), lithium aluminum hydride being particularly suitable.

Suitable reaction media are all inert organic solvents which do not change under the reaction conditions used. These include, in particular, an ether such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, di-n-butyl5 ether, glycol dimethyl ether (glyme), diglycol dimethyl ether (diglyme), cyclic ethers such as dioxane and particularly preferably tetrahydrofuran, the solvent choice being controls, inter alia, the reducing agents used.

It is generally advantageous to carry out these reductions in the presence of reducing agents which are said complex hydrides, in particular lithium analate, which are used in the range from 5 to 100%, preferably in the range from 10 to 50%.

The reactants are generally mixed under ice-cooling or at room temperature and finally, depending on the reactivity of the adduct, heated to a temperature in the range of 150 ° C, preferably up to 75 ° C.

Method C

Another possibility for the production of the type 6 benzomorphane derivatives is by reacting the benzomorphane derivative 2 with a suitable type 5 alkylating agent, wherein in formula 5 Z represents an leaving group. Z represents a secondary amino group replaceable leaving halogen group such as chlorine, bromine or iodine, or OSO ₂ -aryl arylsulfonate such as tosylate, or an alkyl sulfonate such as methanesulfonate or halomethanesulfonate, or a sulfate group. The corresponding alkylating agents are either commercially available or are known in the art.

Suitable solvents are all inert solvents which do not substantially change under the reaction conditions and do not themselves affect the reactants as reaction components. These include, in particular, alcohols such as methanol, ethanol, propano! or isopropanol, or an ether, such as diethyl ether, di-n-butyl ether, tert-butyl methyl ether, glycol dimethyl ether (glyme), diethylene glycol methyl ether (diglyme), tetrahydrophirane and dioxane or ketone, for example ethyl ketone or acetone, or acid amides such as hexamethylphosphoramide dimethylformamide.

In addition, mixtures of the solvents mentioned may be used. Tetrahydrofuran or dimethylformamide or mixtures thereof are particularly preferred. The reaction is preferably carried out in the presence of an acid binding agent, for example an alkali metal or alkaline earth metal carbonate or a bicarbonate thereof.

The reaction temperature can be varied within a wide range when carrying out the reaction, which is limited at the bottom by a very slow reaction rate and at the top by the course of side reactions. Suitable reaction temperatures are in the range of 0 to 150 ° C, preferably between 50 to 100 ° C.

The possible conversion of R ⁹ and / or R ¹⁰ to R ⁷ or R ⁸ , if necessary, involves many different reactions which cannot be summarized in a single reaction scheme. Such reactions will be exemplified in the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Note: Unless otherwise indicated, the term ether means diethyl ether.

Compounds of type 1 - produced according to method A

Example 1 (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

a) Acylation

27.8 g (0.12 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (DOS 20 27 077; CA 74, 125482x (1971)) are mixed in 278 ml of absolute dichloromethane in the presence of 27.9 g (0.275 mol) of triethylamine with stirring for about 30 minutes with 19.2 g (0.156 mol) of (R) -2-methoxypropionic acid chloride. The reaction temperature is maintained in the range of 30 to 35 ° C. Then reflux for one hour. It is cooled and washed successively with 175 ml of water, 175 ml of 2N hydrochloric acid and twice more with 175 ml of water. After drying with sodium sulfate and subsequent filtration, the solution is evaporated in vacuo, finally at 80 ° C and under full vacuum of the water pump. An acylation product of type 1 is obtained as a residue after evaporation in a yield of 42.3 g of approximately 100% of theory.

b) Reduction

The acylation product obtained is dissolved in 425 ml of absolute tetrahydrofuran. The solution was added dropwise to a suspension of 9.1 g (0.24 mol) of lithium aluminum hydride (lithium tetrahydridoanalate) in 300 ml of tetrahydrofuran under stirring and ice-cooling at 10-15 ° C for one hour. The reaction mixture was then refluxed under stirring for two hours. It is then treated dropwise with 25 ml of water while cooling in an ice bath and stirred, and then, after addition of another 70 ml of water and saturated ammonium tartrate solution (890 ml), are shaken in a separatory funnel. The separated tetrahydrofuran phase is evaporated in vacuo and the aqueous phase is extracted three times with 175 ml of dichloromethane each time. The evaporation residue of the tetrahydrofuran phase is dissolved by extraction in dichloromethane and the solution is washed twice with 100 ml of water each time. After drying with sodium sulfate and subsequent filtration, the solution is evaporated, finally at 80 ° C and complete vacuum of the water pump. There remains a residue (37 g, about 100% of theory) which is a mixture of the two expected diastereomeric compounds. The chromatography by thin layer (TLC) shows the values of the diastereomers of _Rf = 0.42, or 0.52 (silica gel 60, chloroform-methanol-concentrated ammonia 95: 5: 0.1).

The diastereomers may be separated by crystallization of the hydrochlorides. Therefore, the basic mixture is dissolved in 120 ml of absolute ethanol and acidified with a solution of hydrochloric acid (12 ml of 32% hydrochloric acid). Awarded the title compound crystallizes _(Rf = 0.42) which was filtered off after cooling (ice bath), was washed in portions with ice-cold ethanol (40 ml) and finally dried to constant weight at 80 ° C. Yield: 15.0 g (73.5% of theory). The substance melts at 264 ° C with decomposition and has a specific optical rotation [α] _D ²⁵ = -116.9 ° (c = 1, CH ₃ OH). A sample recrystallized from a mixture of methanol and diethyl ether melts also at 264 ° C (decomposition) and has a specific rotation of [α] _D ²⁵ = -118.6 ° (c = 1, CH 3 OH).

Example 2 (+) - [1S, 5R, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

The mother liquors obtained in the process of Example I, include in particular the diastereoisomer having a _Rf = 0.51. It is evaporated and the residue (25 g) is heated to reflux with 40 ml of isopropanol for one hour. The resulting crystalline suspension is allowed to stand at room temperature for about 12 hours, then suctioned off and washed in portions with a small amount of cold isopropanol. The crystallizate is mainly composed of the title compound according to the residues

Diastereomers (Example 1). The title compound was converted to the free base form and purified by column chromatography. To this end, the crystallizate was shaken with water (75 mL), dichloromethane (75 mL) and excess concentrated ammonia (6 mL, 25%). After phase separation, the aqueous layer is extracted once more with 25 ml of dichloromethane. The combined dichloromethane extracts are washed twice with 25 ml of water each, then dried over sodium sulphate, filtered and evaporated, finally at 80 ° C and complete vacuum of the water pump. The residue (15.4 g) was purified by column chromatography on 2 kg silica gel (MN K 60, 230-400 mesh ASTM), from Macherey and Nagel) using dichloromethane-methanol-concentrated ammonia 95: 5: 0.1 as eluent. . Fractions with a purity of the substances gave, after evaporation, a residue (6.8 g), which is the base of the title compound. The residue was dissolved in 14 ml of absolute ethanol and acidified with 2.5N ethanolic hydrochloric acid. Upon addition of diethyl ether, the title compound crystallizes to a permanent turbidity. It is allowed to stand for about 12 hours in a refrigerator, then suctioned off and washed first with a 1: 2 mixture of methanol-ether, then with ether. After drying, finally at 80 ° C, 6.4 g of the title compound is obtained (31.4% of the theoretical maximum) with a melting point of 236 ° C (with decomposition) and a specific rotation of [α] _D ²⁵ = + 88.0 ° (c = 1, CH ₃ OH).

Example 3 (+) - [1S, 5R, 2'S] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from 9.25 g (0.040 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 6.37 g (0.52 mol) of (S) - Of 2-methoxypropionic acid, analogous to Example 1, to give the title compound in a yield of 5.1 g (75% of theory) with an Rf value of 0.42, a melting point of 270 DEG C. (with decomposition) and a specific rotation of [a] _D ²⁵ = + 117 ° (c = 1, CH ₃ OH).

Example 4 (-) - [1R, 5S, 2'S] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

The mother liquors obtained from Example 3, which were treated analogously to Example 2, gave the title compound in a yield of 3.2 g (47.1% of theory), m.p. 235 DEG C. (dec.) And specific rotation [.alpha.] _D ²⁵ = -89.9 ° (c = 1, CH ₃ OH).

Example 5 (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

The procedure is analogous to Example 1, but 2.31 g (0.010 ml) of the enantiomeric (-) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane with 1.60 g is used instead of the racemic starting compound. g (0.013 mol) of (R) -2-methoxypropionic acid chloride is obtained, instead of a mixture of diastereomeric bases, of the sterically pure base of the title compound first and of this hydrochloride in a yield of 3.0 g (88.4% of theory); (dec.) and specific rotation [α] _D ²⁵ = -117.5 ° (c = 1, CH ₃ OH).

Example 6 (-) - [1R, 5S, 2'S] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

The synthesis of (S) -2-methoxypropionic acid as described in Example 5 was performed to give the title compound in a yield of 2.9 g (85.3% of theory), m.p. rotation [a] _D ^{@ 25} = -89.7 DEG (c = 1, CH ₃ OH).

Example 7 (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from 4.62 g (0.020 ml) of (-) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 3.20 g (0.026 mol) of acid chloride (R / S) - 2-methoxypropionic, and in analogy to Example 1 a mixture of the expected base diastereomers is obtained, which is separated by column chromatography in analogy to Example 2. The slower moving substance (Rf = 0.42) is then crystallized as described above as hydrochloride. To give the title compound in a yield of 2.1 g (61.8% of theory) of melting point 264 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = -117.9 ° (c = 1, CH ₃ OH) .

Example 8 (-) - [1R, 5S, 2'S] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

Starting from the faster moving substance _(Rf = 0.51) separated in Example 7, and following conversion into the hydrochloride analogously to Example 2 gives the title compound in a yield of 2.2 g (64.7% of theory), mp 235 ° C (dec.) And specific rotation [α] _D ²⁵ = -88.6 ° (c = 1, CH ₃ OH).

Example 9 (+) - [1S, 5R, 2'S] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

2.60 g (0.025 mol) of (S) -2-methoxypropionic acid chloride are stirred in 100 ml of absolute tetrahydrofuran with 4.04 g (0.025 mol) of 1,1'-carbonyldiimidazole for two hours at room temperature. After addition of 4.62 g (0.020 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane, it was further stirred at room temperature for two days. It is then evaporated, the residue is taken up in 79 ml of dichloromethane and washed successively with 2N HCl and twice with water. After separation, the organic phase is dried over sodium sulphate and filtered off by evaporation in vacuo, finally at 80 ° C under complete vacuum of the water pump. The evaporation residue as described in Example 1 is reduced with lithium aluminum hydride (lithium tetrahydridoanalate) and the reduction product crystallizes in analogy to Example 2 as the hydrochloride. To give the title compound in a yield of 6.9 g (81.3% of theory) and a melting point of 264 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = + 117.4 ° (c = 1, CH ₃ OH) .

Example 10 (-) - [1R, 5S, 2'R] -9,9-dimethyl-5-ethyl-2'-hydroxy-2- (2-methoxypropyl) -6,7-benzomorphane hydrochloride

Starting from 1.69 g (0.006 mol) of (±) -9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphan hydrochloride (DOS 20 27 077, CA 74, 125482x (1971)) 1.82 g (0.018 mol) of triethylamine and 0.96 g (0.0078 mol) of (R) -2-methoxypropionic acid chloride, analogously to Example 1, a mixture of the expected diastereomeric bases (1.7 g) is obtained, The slow-moving substance (0.6 g, R f = 0.40) was crystallized in analogy to Example 2 as the hydrochloride. Yield: 0.6 g (56.6% of theory), m.p. 27 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -100.5 DEG (c = 1, CH3 OH).

Example 11 (+) - [1S, 5R, 2'R] -9,9-dimethyl-5-ethyl-2'-hydroxy-2- (2-methoxypropyl) -6,7-benzomorphane hydrochloride

In Example 10, the faster moving diastereomer (0.7 g, Rf = 0.45) separated by column chromatography was crystallized in analogy to Example 2 as the hydrochloride. To give the title compound in a yield of 0.23 g (21.7% of theory) of melting point 216 DEG C. (with decomposition) and a specific rotation [<x] _D ²⁵ = + 62.4 ° (c = 1, CH ₃ OH ).

Example 12 (+) - [1S, 5R, 2'S] -9,9-dimethyl-5-ethyl-2'-hydroxy-2- (2-inethoxypropyl) -6,7-benzomorphane hydrochloride

Starting from 1.69 g (0.006 mol) of (±) -9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphan hydrochloride, 1.82 g (0.018 mol) of triethylamine and 0, 96 g (0.0078 mol) of (S) -2- (methoxypropionic acid chloride), analogously to Example 1, gave a mixture of the expected diastereomeric bases (1.7 g) which were separated by column chromatography in analogy to Example 2. Slower addition moving substance (0.6 g, _Rf = 0.40) is crystallized in analogy to Example 2 as the hydrochloride. obtained the title compound in a yield of 0.6 g (56.6% of theory), mp 275 DEG C. (dec ) and specific rotation [α] _D ²⁵ = + 102.5 ° (c = 1, CH ₃ OH).

Example 13 (-) - [1R, 5S, 2'S] -9,9-dimethyl-5-ethyl-2'-hydroxy-2- (2-methoxypropyl) -6,7-benzomorphane hydrochloride

According to Example 12, the separated, faster moving diastereomer (0.6 g, R _f = 0.45) was crystallized as the hydrochloride analogously to Example 2. To give the title compound in a yield of 0.65 g (61.2% of theory) of melting point 219 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = -67.6 "(c = 1, CH ₃ OH) .

Example 14 (-) - 9,9-Dimethyl-2'-hydroxy-2 - ((R) -2-methoxypropyl) -5-phenyl-6,7-benzomorphane

Starting from 1.76 g (6 mmol) of (+) - 9,9-dimethyl-2'-hydroxy-5-phenyl-6,7-benzomorphane (EP-B-4960, CA 93, 4941 f (1980)) and 0.96 g (7.8 mmol) of (R) -2-methoxypropionic acid chloride and analogously to Example 1 a mixture of the expected diastereomeric bases (2.1 g) is obtained with Rf values of 0.50 and 0.55 ( Comparative Example 2) The mixture was crystallized in analogy to Example 2 as hydrochlorides (2.4 g) and again converted to the corresponding free base (1.8 g evaporation residue), which was crystallized from 6 ml of ethyl acetate. and 18 ml petroleum ether (80 ° C) to give the title compound in a yield of 0.72 g (65.5% of theory), m.p. 202 ° C, Rf = 0.50, and specific rotation [α] _D ²⁵ = -24.4 ° (c = 1, CH ₃ OH).

Example 15 (+) - 9,9-Dimethyl-2'-hydroxy-2 - ((R) -2-methoxypropyl) -5-phenyl-6,7-benzomorphane hydrochloride

The mother liquors obtained in the crystallization of Example 13 (acetic acid ester / petroleum ether) were evaporated. The residue (1.2 g) was dissolved in 5 ml of ethanol and the solution was acidified with 2.5N ethanolic hydrochloric acid. After addition of diethyl ether until turbidity, the hydrochloride crystallizes (0.4 g) as an impure crude product. The mother liquor contains pure title compound which is isolated after evaporation as a residue: yield 0.75 g (62.0% of theory), melting point 168 ° C (dec.), Rf = 0.55, specific rotation [a] c ^{[Α] 25} = + 11.6 ° (c = 1, CH ₃ OH).

Example 16 (-) - [1R, 5S, 2'R] -3'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

a) Starting compound

The (±) -3'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane necessary in this and other examples is not known in the art. For example, it can be made from the known 2'-hydroxy-isomer (DOS 20 27 077, CA 74 (1971), 125482x) by the above procedure using m-methoxybenzyllithium instead of p-methoxybenzyllithium. The ring closure of the benzomorphane system in the latter case results in two isomeric compounds which are further used as a mixture. The resulting mixture of 1'-hydroxy and 3'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane was separated by flash column chromatography on 100-fold silica gel (MN K 60, 230-400 mesh ASTM, from Macherey and Nagel) using ethyl acetate-methanol-concentrated ammonia 80: 20: 5 as eluent. There was thus obtained (±) -1'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (Rf = 0.20) and (±) -3'-hydroxy-5,9,9-trimethyl-6. , 7-benzomorphan _(Rf = 0.14) 1: 2 as a thick liquid oils _(Rf = DC, silica gel 60, under conditions uvedcných clučných agents).

b) Conversion to the title compound

Starting from 2.31 g (0.010 mol) and (±) -3'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 1.6 g (0.013 mol) of (R) -2 acid chloride of methoxypropionic acid, and analogously to Example 1, a mixture of the expected diastereomeric bases is obtained, which is separated analogously to Example 1 by column chromatography over 100-fold silica gel. Faster moving substance _(Rf = 0.65) as described crystallized as the hydrochloride. The title compound was obtained in a yield of 0.86 g (50.6%), mp 240-242 ° C (dec.) And specific rotation [α] _D ²⁵ = -90.9 ° (c = 1, CH ₃ OH) ).

Example 17 (+) - [1S, 5R, 2'R] -3'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

In Example 16, the separated, faster moving substance (Rf = 0.74) is crystallized analogously to Example 2 as the hydrochloride. To give the title compound in a yield of 1.28 g (75.3% of theory) with a melting point of 250-252 DEG C. and a specific rotation [a] _D ²⁵ = + 57.1 ° (c = 1, CH ₃ OH).

Example 18 (+) - [1S, 5R, 2'S] -3'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

Starting from 2.31 g (0.010 mol) of (±) -3'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (see Example 16) and 1.60 g (0.013 mol) of the acid chloride ( S) -2-methoxypropionic a

In analogy to Example 1, the expected diastereomeric bases are obtained which are separated by chromatography, analogously to Example 2, on a 100-fold amount of silica gel. Faster moving substance _(Rf = 0.65) is, as described above, crystallized as the hydrochloride. The title compound is obtained in a yield of 0.57 g (33.4% of theory), m.p. 239 DEG-240 DEG C. (with decomposition) and specific rotation [.alpha.] _D @ ²⁵ = + 90.7 DEG (c = 1, CH3 _). OH).

Example 19 (-) - [1R, 5S, 2'S] -3'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

In Example 18, the separated, faster moving substance (Rf = 0.74) is crystallized analogously to Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.67 g (39.2% of theory), m.p. 250 DEG-251 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -56.5 DEG (c = 1, CH3 OH). .

Example 20 (-) - [1R, 5R, 2'RJ-1'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from 2.31 g (0.10 mol) of (±) -1'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (see Example 16) and 1.60 g of acid chloride (R) - 2-methoxy propionic acid. Analogously to Example 1, a mixture of the expected diastereomeric bases is obtained, which, in analogy to Example 2, is separated on a 100-fold amount of silica gel. Faster moving substance _(Rf = 0.52) was crystallized analogously to Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.60 g (41.2% of theory), m.p. 128-135 ° C (dec.) And specific rotation [α] _D ²⁵ = -100.5 ° (c = 1, CH). ₃ OH).

Example 21 (+) - [1S, 5S, 2'R] -1'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

In Example 20, the separated, faster moving substance (Rf = 0.56) is crystallized as the hydrochloride analogously to Example 2. The title compound is obtained in a yield of 0.40 g (23.6% of theory), m.p. 88 DEG-89 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -50.4 DEG (c = 1, CH3 _). OH).

Example 22 (+) - [1S, 5S, 2'S] -1'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

Starting from 2.31 g (0.010 mol) of (±) -1'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (see Example 16) and 1.60 g (0.013 mol) of chloride (S) -2-methoxypropionic acid. Analogously to Example 1, a mixture of the expected diastereomeric bases is obtained, which is analogously to Example 2 separated on a 100-fold amount of silica gel. The slower moving substance (Rf = 0.52) is crystallized analogously to Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.63 g (36.8% of theory) with a melting point of 85-90 ° C and a specific rotation of [α] _D ²⁵ = + 96.2 ° (c = 1, CH ₃ OH).

Example 23 (-) - [1R, 5R, 2'S] -1'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

In Example 22, the separated, faster moving substance (Rf = 0.56) is crystallized as the hydrochloride analogously to Example 2. The title compound is obtained in a yield of 0.50 g (29.4% of theory), m.p. 90 DEG-91 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -64.0 DEG (c = 1, CH3 _). OH).

Example 24 (-) - [1R, 5S, 2'S] -4'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

(a) Production of the starting compound

The preparation of (±) -4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane required in this and other examples is not yet known in the art. However, it can be prepared, for example, by the known synthesis for the known 2'-hydroxy-isomer (DOS 20 27 077, CA 74, 125482x (1971)), in which o-methoxybenzyllithium is used instead of p-methoxybenzyllithium. The title compound crystallizes as a base from isopropanol-petroleum ether, m.p. 227 ° C. The thin layer chromatogram (silica gel 60, chloroform-methanol-concentrated ammonia (65: 35: 3) as follows: _Rf = 0.20.

b) Conversion to the title compound

Starting from 2.31 g (0.10 mol) of (±) -4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 1.60 g (0.01 mol) of acid chloride (R) Of 2-methoxypropionic acid, analogously to Example 1, a mixture of the expected bases (3.0 g) is obtained, which is separated, analogously to Example 2, by column chromatography over 450 g of silica gel. 0.9 g of a slower moving compound (Rf = 0.34) and 1.3 g of a faster moving compound are obtained.

The first is crystallized analogously to Example 2 as the hydrochloride. Thereby give the title compound in a yield of 0.95 g (55.9% of theory) of melting point 263 DEG C. (with decomposition) and a specific rotation [a] ^_D25 - -86.9 ° (c = 1, CH ₃ OH ).

Example 25 (+) - [1S, 5R, 2'R] -4'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

In Example 24, the separated, faster moving compound (Rf = 0.43) was crystallized in an analogous manner to Example 2 in a yield of 1.23 g (72.4% of theory) with a melting point of 258 ° C (with decomposition) and a specific rotation of [ [.alpha.] _D @ ²⁵ = + 51.7 DEG (c = 1, CH3 OH).

Example 26 (+) - [S, 5 R, 2 'S] ^{-4'-hydroxy-2-} (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

Starting from 2.31 g (0.10 mol) of (±) -4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (see Example 24) and 1.60 g (0.013 mol) of chloride (S) -2-methoxy-propionic acid. Analogous to Example 1, a mixture of the expected diastereomeric bases (3.1 g) is obtained, which is analogously to Example 2 separated by silica gel column chromatography. 1.0 g of a slower moving compound (Rf = 0.34) and 1.2 g of a faster moving compound are obtained. The first was crystallized as the hydrochloride in analogy to Example 2 to give the title compound in a yield of 1.15 g (67.7%) with a melting point of 260 ° C (dec.) And a specific rotation of [α] _D ²⁵ = -51.2 ° (c = 1, CH 3 OH).

Example 27 (-) - [1R, 5S, 2'S] -4'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

In Example 26, the separated, faster moving substance (Rf = 0.43) was crystallized in analogy to Example 2 as the hydrochloride to give the title compound in a yield of 0.95 g (55.9% of theory), m.p. decomposition) and specific rotation [α] _D ²⁵ = +86.1 (c = 1, CH ³ OH).

Example 28 (-) - [1R, 5S, 2'R] -2'-Methoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 2.45 g (0.010 mol) of (-) - 2'-methoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane (DOS 20 27 077, CA 125482x ( (1971)) and 1.35 g (0.011 mol) of (R) -2-methoxypropionic acid chloride. Analogously to Example 1, a sterically uniform title compound was obtained as the free base (2.3 g). This was dissolved in 5 ml of absolute ethanol. After acidification with methanesulfonic acid, the resulting solution was mixed with diethyl ether until turbidity. While the methanesulfonate crystallizes, the same amount of ether is added once again with stirring. The reaction mixture was then cooled in an ice bath for 4 hours. It is then filtered off with suction, ethanol-ether 1: 2 is added first, then washed with ether, after drying at 80 [deg.] C. the title compound is obtained in a yield of 3.3 g (79.8% of theory), m.p. ° C (dec.) And specific rotation [α] _D ²⁵ = -92.4 ° (c = 1, CH 2 OH).

Example 29 (+) - [1S, 5R, 2'S] -2'-Methoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 2.45 g (0.010 mol) of (+) - 2'-methoxy-5,9,9-trimethyl-6,7-benzomorphane (DOS 20 27 077, CA 74, 125482x (1971)) and 1, 35 g (0.011 mol) of (S) -2-methoxypropionic acid chloride. Analogously to Example 28, the title compound is obtained in a yield of 3.1 g (75.0% of theory), m.p. 165-167 ° C (dec.) And specific rotation [.alpha.] _D @ ²⁵ = + 92.3 DEG (c). = 1, CH ₃ OH).

Example 30 (-) - [1R, 5S, 2'R] -2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

(a) Production of the starting compound

The production of the (+) - 5,9,9-trimethyl-6,7-benzomorphane required here and in other examples is not yet known in the art. It can be produced, for example, by the synthesis used for the known 2'-hydroxy derivative (DOS 20 27 077, CA 74 (1971) 125482x) using benzyllithium instead of p-methoxybenzyllithium. The title compound crystallizes as the hydrobromide from isopropanol-ether, mp 259 ° C (dec.).

b) Conversion to the title compound

Starting from 2.96 g (0.010 mol) of (±) -5,9,9-trimethyl-6,7-benzomorphane and 1.35 g (0.011 mol) of (R) -2-methoxypropionic acid chloride. Analogously to Example 1, a mixture of the desired diastereomeric bases is obtained. These were separated, as in Example 2, by column chromatography over 100-fold silica gel. The slower substance _(Rf = 0.63) is, as described above, and a co hydrochloride crystallized. To give the title compound in a yield of 1.3 g (76.5% of theory) of melting point 225 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = -101.7 ° (c = 1, CH ₃ OH) .

Example 31 (+) - [1S, 5R, 2'R] -2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane oxalate

In Example 30 separate, faster moving substance _(Rf = 0.67) was dissolved in 5 ml of ethanol. After acidification with oxalic acid, the solution is mixed with diethyl ether until turbid. While crystallization is in progress, half the original amount of ether is added once more and left in the refrigerator for about 12 hours. After aspiration, washing with ethanol-ether and drying at 80 ° C, the title compound is obtained in a yield of 1.1 g (60% of theory), m.p. 135 ° C (dec.) And specific rotation [α] _D ²⁵ = +60 2 ° (c = 1, CH ₃ OH).

Example 32 (-) - [1R, 5S, 2'R] -2- (2-methoxypropyl) -2,5,5,9,9-tetramethyl-6,7-benzoformian hydrochloride

(a) Production of the starting compound

The (±) -2 ‘, 5,9,9-tetramethyl-6,7-benzomorphane required in this and other examples is not known in the art. However, it can be produced, for example, by the synthesis known for the 2‘-hydroxy analogue, in which p-methylbenzyllithium is used instead of p-methoxybenzyllithium. The intermediate thus obtained is crystallized from isopropanol / diethyl ether as the hydrobromide, which melts at 227 ° C with decomposition.

b) Conversion to the title compound

Starting from 1.51 g (5 mmol) of (±) -2 ', 5,9,9-tetramethyl-6,7-benzomorphane and 0.68 g (5.5 mmol) of (R) -2- propionic acid ethyl ester. Analogously to Example 1, a mixture of the expected diastereomeric bases is obtained, which, as described above, crystallizes as the hydrochloride and separates. Thus, the title compound is obtained in a yield of 0.7 g (after recrystallization of 0.4 g = 47.3% of theory), m.p. 212 DEG C. (dec.) And specific rotation [.alpha.] _D @ ^{25 =} -110.0 DEG ( c = 1, CH ₃ OH).

Example 33 (+) - [1S, 5R, 2'S] -2- (2-methoxypropyl) -2,5,5,9,9-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 1.51 g (5 mmol) of (S) -2-methoxypropionic acid chloride. Analogously to Example 32, the title compound is obtained in a yield of 0.4 g (47.3% of theory), m.p. 212 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = + 111.8 DEG (c = 1). CH ₃ OH).

Example 34 (-) - [1R, 5S, 2'R] -2'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane dihydrochloride

(a) Production of the starting compound

The (±) -2‘-nitro-5,9,9-trimethyl-6,7-benzomorphane required in this and other examples is not known in the art. For example, it can be produced by nitration of (±) -5,9,9-trimethyl-6,7-benzo-nifane (Example 30) analogously to the procedure described by EL May and EM Fry (J. Org. Chem. 22 (1957) 1366 ). The resulting intermediate was crystallized10

It is a hydrochloride from ethanol-ether melting at 289 ° C (dec.).

b) Acylation

2.97 g (0.01 mol) of (±) -2'-nitro-5,9,9-trimethyl-6,7-benzomorphan hydrochloride are acylated in the presence of 3.04 g (0.03 mol) of triethylamine analogously as in Example 1 1.35 g (0.011 mol) of (R) -2-methoxypropionic acid chloride. After working up, 3.5 g (almost 100% of theory) of the intermediate type 3 are obtained.

c) Catalytic hydrogenation of 2‘-nitro and 2‘-amino

3.5 g of intermediate from preparation b) are dissolved in 70 ml of methanol and hydrogenated in the presence of 0.4 g of palladium on carbon (Pd content: 5%) at 20 DEG C. under a hydrogen pressure of 0.5 MPa. Hydrogen uptake is stopped 4 hours after the calculated amount is consumed. After filtering off the catalyst, the reaction mixture was evaporated, finally at 80 ° C and under full vacuum of the water pump. The residue 3.1 g (almost 100% of theory).

d) Reduction with lithium aluminum hydride

The residue obtained (3.1 g) was reduced in analogy to Example 1 by 1.3 g of lithium aluminum hydride (lithium tetrahydroanalate). The mixture of the two expected diastereomers (2.7 g) was separated in a manner analogous to Example 2 by column chromatography over 500 g of silica gel. The slower moving substance (0.7 g, R _f = 0.65) was crystallized as the dihydrochloride analogously to Example 2 (but with two equivalents of hydrochloric acid). To give the title compound in a yield of 0.95 (50.6% of theory) of melting point 260 DEG C. (with decomposition) and a specific rotation [a] _D ^{@ 25} = -93.4 DEG (c = l, _CH3 OH) .

Example 35 (+) - [1S, 5R, 2'R] -2'-Amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane dimethanesulfonate

0.9 g of Example 34 separate, faster moving substance _(Rf = 0.70) analogously to Example 43 (but with 2 equivalents of methanesulfonic acid) crystallized from metanoldietyléter. The title compound is obtained in a yield of 0.48 g (19.4% of theory), m.p. 189 DEG C. (dec.) And specific rotation [.alpha.] _D @ ^{25 =} + 55.6 DEG (c = 1, CH3 OH).

Example 36 (+) - [1S, 5R, 2'S] -2‘-Amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

Starting from 2.97 g (0.01 mol) of (±) -2'-nitro-5,9,9-trimethyl-6,7-benzomorphan hydrochloride, 3.04 g (0.03 mol) of triethylamine and 1.35 g (0.011 mol) of (S) -2-methoxypropionic acid chloride gave 3.5 g (almost 100% of theory) of the desired acylation product which, as described above, was catalytically hydrogenated (3.2 g) hydrogenation product) and finally reduced with lithium aluminum hydride (lithium tetrahydridoanalate). The reducing product (2.8 g), which is a mixture of the expected diastereomeric bases, is dissolved in 10 ml of isopropanol during heating. After about 12 hours of crystallization on standing in the refrigerator is eliminated by chromatography slower moving substance _(Rf = 0.65) as the base (0.75 g = 49.0% of theory), mp 142 ° C. 0.3 g of the dihydrochloride is crystallized from this as in Example 32. The title compound (0.37 g) is obtained, m.p. 265 DEG C. (with decomposition) and specific rotation [.alpha.] _D @ ²⁵ = + 92.5 DEG (c = 1, CH3 OH).

Example 37 (-) - [1R, 5S, 2'S] -2‘-Amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane dihydrochloride

The isopropanol mother liquors from Example 4 was concentrated and the residue (2.0 g) was chromatographed on 300 g of silica gel analogously to Example 2. The addition of another 0.3 g of the slower moving substance _(Rf = 0.65, Example 34) was the faster moving substance (1.2 g, Rf = 0.70) of the diastereomer is crystallized in analogy to Example 32 as the dihydrochloride. Yield: 1.48 g (78.8% of theory), m.p. 269 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -68.4 DEG (c = 1, CH3 _). OH).

Example 38 (±) -2‘-Hydroxy-2- (2-methoxyisobutyl) -5,9,9-trimethyl-6,7-benzomorphane hydrobromide

Starting from 1.16 g (0.005 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 0.75 g (0.055 mol) of 2-methoxyisobutyric acid chloride are obtained. in analogy to Example 1, the basic form of the title compound (1.1 g) was first used. This was dissolved in 5 ml of methanol and, after acidification with HBr (62%), the solution was mixed with diethyl ether until turbid. By standing in a refrigerator for about 12 hours, the title compound crystallized, filtered off with suction, washed with ethanol-ether and dried at 80 ° C. Yield 1.1 g (55.2% of theory), mp 232 DEG C. (dec.). The sample is recrystallized from methanol-ether and melted at 240 ° C (dec.).

Example 39 (-) - [1R, 5S, 2'R] -2‘-Hydroxy-2- (2-methoxybutyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

(a) Production of the starting compound

In this and other examples, the (R) -2-methoxybutyric acid chloride required may be prepared, for example, from the known (R) -2-methoxybutyric acid (NK Kochetkov, AM Likhosherst and VN Kulakov, tetrahedron 25 (1969) 2313) and thionyl chloride at temperature. rooms. The acid chloride remaining after removal of excess thionyl chloride is used without purification in the next step.

b) Conversion to the title compound

Starting from 3.47 g (0.015 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 2.46 g (0.018 mol) of (R) -2- The title compound was obtained in analogy to Example 1 in a yield of 1.8 g (67.8% of theory), m.p. 246 DEG C. (dec.) and specific rotation [.alpha.] _D @ ²⁵ = -118.4 DEG (c). = 1, CH ₃ OH).

Example 40 (+) - [1S, 5R, 2'R] -2'-Hydroxy-2- (2-methoxybutyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

The mother liquor of Example 39 was evaporated. Analogously to Example 2, the title compound is obtained in a yield of 1.3 g (48.9% of theory), melting point 228 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = + 79.9 DEG (c). = 1,

CH ₃ OH).

SK 280776-6

Example 41 (-) - [1R, 5S, 2'S] -2‘-hydroxy-2- (2-methoxybutyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

(a) Production of the title compound

In this example and in other examples, the (S) -2-methoxybutyric acid chloride required may be prepared, for example, from the known (S) -2-methoxybutyric acid (Tetrahedron 25 (1969) 2322) analogously to Example 39.

b) Conversion to the title compound

Starting from 3.47 g (0.015 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 2.46 g (0.018 mol) of (S) -2- The title compound is obtained in analogy to Example 1 in a yield of 1.6 g (60.3% of theory), m.p. 246 DEG C. (dec.) and specific rotation [.alpha.] _D @ ²⁵ = + 119.2 DEG (c). = 1, CH 3 OH).

Example 42 (+) - [1S, 5R, 2'S] -2‘-Hydroxy-2- (2-methoxybutyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

The mother liquor of Example 41 was evaporated. Analogously to Example 2, the title compound is obtained in a yield of 0.6 g (22.6% of theory), m.p. 228 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -71.7 DEG (c). = 1, CH 3 OH).

Example 43 (-) - [1R, 5S, 2'R] -2- (2-Benzyloxypropyl) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane hydrochloride

(a) Production of the starting compound

The (R) -2-benzyloxypropionic acid chloride used in this and other examples can be produced, for example, as follows:

Commercially available (R) - (+) - lactic acid isobutyl ester in the presence of silver oxide with O-benzyl with benzyl bromide. Subsequent saponification with sodium hydroxide gives (R) -2-benzyloxypropionic acid having a specific rotation value [α] _D ²⁵ = + 79.5 ° (c = 1, CH ₃ OH). Analogous to Example 39, the corresponding acid chloride is obtained.

b) Conversion to the title compound

Starting from 3,47 g (0,015 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 3,3 g (0,0165 mol) of (R) -acid chloride 2-benzyloxypropionic acid, a mixture of the expected diastereomers is obtained analogously to Example 1, which, as described above, is separated by crystallization of the corresponding hydrochlorides. To give the title compound in a yield of 2.39 g (76.6% of theory) of melting point 250 DEG C. (with decomposition) and a specific rotation [a] _D ^{@ 25} = -119.3 DEG (c = 1, CH ₃ OH ).

Example 44 (+) - [1S, 5R, 2'S] -2- (2-Benzyloxypropyl) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane hydrochloride

(a) Production of the starting compound

For example, the (S) -2-benzyloxypropionic acid chloride used in this and other examples can be prepared analogously to Example 43 from (S) -2-benzyloxypropionic acid (specific rotation [α] _D ²⁵ = -78.5 ° (c) = 1, CH ₃ OH).

b) Conversion to the title compound

Starting from 3,47 g (0,015 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 3,3 g (0,0165 mol) of (S) - Of 2-benzyloxypropionic acid is obtained analogously to Example 43 in a yield of 2.56 g (82.1% of theory), m.p. 250 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = + 119.5 DEG ( c = 1, CH ₃ OH).

Example 45 (-) - [1R, 5S, 2'R] -2‘-Hydroxy-2- (2-methylthiopropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

(a) Production of the starting compound

In this and other examples, the (R) -2-methylthiopropionic acid chloride required may be prepared analogously to Example 39 from the known (R) -2-methylthiopropionic acid (LN Owen and MB Rahman, J. Chem. Soc. (C) 1971 , 2432).

b) Conversion to the title compound

1.62 (0.007 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane were reacted in analogy to Example 1 and 1.07 g (7.7 mmol) of the acid chloride was added. (R) -2-methylthiopropionic. Reduction of the resulting reaction product with lithium aluminum hydride (LiAlH 4) yields a mixture of the expected diastereomers which are separated by crystallization of their nitrates. The substance which crystallizes from ethanol after acidification with 65% nitric acid and after mixing with diethyl ether until turbidity is obtained is sucked off in a refrigerator for about 12 hours, washed with ethanol-ether and then with ether and dried at 80 ° C. The nitrate (0.67 g) is recrystallized from boiling ethanol (0.52 g), converted to the free base and finally crystallized as the hydrochloride analogously to Example 2. To give the title compound in a yield of 0.43 g (34.4% of theory), mp 265 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = -135.1 ° (c = 1, CH ₃ OH) .

Example 46 (+) - [1S, 5R, 2'R] -2'-Hydroxy-2- (2-methylthiopropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

The mother liquors of Example 45 after the first crystallization of the nitrate were evaporated and the nitrate residue was converted to the free base. This (1 g) was filtered through 20 g of alumina analogously to Example 53 and then crystallized as the hydrochloride (ethanol-ether). This (0.29 g) was recrystallized from a mixture of 2 ml of methanol and diethyl ether. The title compound is obtained in a yield of 0.21 g (16.8% of theory), m.p. 238 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = + 73.0 DEG (c = 0.5, CH3 OH). .

Example 47 (-) - [1R, 5S, 2'S] -2‘-Hydroxy-2- (2-methylthiopropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

(a) Production of the starting compound

The (S) -2-methylthiopropionic acid chloride required in this and the other examples can be produced, for example,

From the known (S) -2-methylthiopropionic acid (J. Chem. Soc. 1971, 2437) analogously to Example 39.

b) Conversion to the title compound

Starting from 1.62 g (0.007 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and analogously to Example 45, the title compound is obtained in a yield of 0.42 g ( 33.6% of theory), m.p. 265 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = + 135.1 DEG (c = 0.5, CH3 OH).

Example 48 (-) - [1R, 5S, 2'S] -2‘-Hydroxy-2- (2-methylthiopropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

Starting from the nitrate mother liquors of Example 47, and analogously to Example 46, the title compound was obtained in a yield of 0.34 g (27.2% of theory), mp 238 ° C (dec.) And specific rotation [α] _D ²⁵ = -73.9 ° (c = 0.5, CH 3 OH).

Example 49 (+) - [1S, 5R, 2'S] -2- (2-Allyloxypropyl) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane hydrochloride

(a) Production of the starting compound

The (S) - (-) - 2-allyloxypropionic acid chloride used can be prepared, for example, as follows: commercially available (S) - (-) - lactic acid ethyl ester in the presence of silver oxide is O-allylated with allyl bromide. Subsequent saponification with sodium hydroxide affords (S) -2-allyloxypropionic acid having a boiling point of 110-112 ° C at a pressure of 0.0015 MPa and a specific rotation [α] _D ^{25 =} 78.4 ° (c = 1, CH ₃ OH) ). Analogous to Example 39, the corresponding acid chloride is obtained.

b) Conversion to the title compound

Starting from 3,47 g (0,015 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 3,3 g (0,0165 mol) of (S) - 2-allyloxypropionic and analogously to Example 1, a mixture of the two expected diastereomers is obtained, which, as described above, is separated by crystallization of the corresponding hydrochlorides. To give the title compound in a yield of 1.4 g (51% of theory) of melting point 245 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = + 120 ° (c = 1, CH ₃ OH).

Example 50 (-) - [1S, 5R, 2'S] -2- (2-Allyloxypropyl) -2H-hydroxy-5,9,9-trimethyl-6,7-benzomorphane hydrochloride

The mother liquors of Example 49 were evaporated. Analogously to Example 2, the title compound is obtained in a yield of 0.62 g (22.6% of theory) with a melting point of 213 ° C and a specific rotation of [α] _D ²⁵ = -38.6 ° (c = 1, CH ₃ OH).

Example 51 (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-phenoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

2.31 g (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 2.03 g (0.011 mol) of (R) -2-phenoxypropionic acid chloride (produced by analogously to Example 39 from the corresponding acid (CA 72, 12917d)) was reacted analogously to Example 1. A mixture of the two expected diastereomers is obtained, which, as described above, is separated by crystallization of the corresponding hydrochlorides. In this way the title compound is obtained in a yield

1.6 g (79.6% of theory), m.p. 279 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -142.9 DEG (c = 1, CH3 OH).

Example 52 (+) - [1S, 5R, 2'S] -2‘-Hydroxy-2- (2-phenoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

Proceeding analogously to Example 51 with (S) -2-phenoxypropionic acid chloride to give the title compound in a yield of 1.6 g with a specific rotation [α] _D ²⁵ = + 143.3 ° (c = 1, CH ₃₎ OH).

Example 53 (-) - [1R, 5S, 2'R] -3'-Hydroxy-2- (2-methoxypropyl) -5,9,9,2‘-tetramethyl-6,7-benzomorphane hydrochloride

a) Starting compound

The (±) -3‘-hydroxy-5,9,9,2‘-tetramethyl-6,7-benzomorphane required in this and other examples is not yet known in the art. It can be prepared, for example, by the method known for the 2‘-hydroxy derivative (DOS 20 27 077, CA 74 (1971), 125482x) in which 3-methoxy-4-methylbenzyllithium is used instead of p-methoxybenzyllithium. Ring closure on the benzomorphane system yields mainly 3‘-hydroxy-5,9,9,2‘-tetramethyl-6,7-benzomorphane, which is purified by flash column chromatography (Comparative Example 16).

b) Conversion to the title compound

Starting from 2,44 g (0,010 mol) of (±) -3'-hydroxy-5,9,9,2'-tetramethyl-6,7-benzomorphane and 1,6 g of (R) -2-methoxypropionic acid chloride (0.013 mol) and obtained analogously to Example 1 a mixture of the expected diastereomeric bases which were separated by column chromatography on a 100-fold amount of silica gel analogously to Example 2. The slower moving substance (Rf = 0.25) was crystallized as the hydrochloride. The title compound was obtained in a yield of 1.06 g (59.9%) with a melting point of 181-182 ° C and a specific rotation of [α] _D ²⁵ = -89.5 ° (c = 1, CH ₃ OH).

Example 54 (+) - [1S, 5R, 2'R] -3‘-Hydroxy-2- (2-methoxypropyl) -5,9,9,2‘-tetramethyl-6,7-benzomorphane hydrochloride

In Example 53, a separate, faster moving substance (Rf = 0.34) is eliminated analogously to Example 2 as the hydrochloride. To give the title compound in a yield of 1.24 g (70.1%) as an amorphous powder with a specific rotation [a] _D ²⁵ = + 55.9 ° (c = 1, CH ₃ OH).

Example 55 (+) - [1S, 5R, 2'S] -3‘-Hydroxy-2- (2-methoxypropyl) -5,9,9,2‘-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 2.44 g (0.010 mol) of (±) -3‘-hydroxy-5,9,9,2‘-tetramethyl-6,7-benzomorphane (see Example 53), and

1.6 g (0.013 mol) of (S) -2-methoxypropionic acid chloride. Analogously to Example 1, a mixture of the expected diastereomeric bases is obtained, which is separated by column chromatography on a 100-fold amount of silica gel. Faster moving substance (R _r = 0.25) was

It crystallizes as the hydrochloride. The title compound is obtained in a yield of 1.48 (83.6%) with a melting point of 186-188 ° C and a specific rotation of [α] _D ²⁵ = + 88.2 ° (c = 1, CH ₃ OH).

Example 56 (-) - [1R, 5S, 2'S] -3‘-Hydroxy-2- (2-methoxypropyl) -5,9,9,2‘-tetramethyl-6,7-benzomorphane hydrochloride

In Example 55, a separate, slower moving substance (Rf = 0.34) is eliminated analogously to Example 2 as the hydrochloride. The title compound was obtained in a yield of 1.40 g (79.1%) as an amorphous powder with a specific rotation of [α] _D ²⁵ = -56.8 ° (c = 1, CH ₃ OH).

Example 57 (-) - [1R, 5S, 2'R] -2‘-Hydroxy-2- (2-methoxypropyl) -5,9,9,3‘-tetramethyl-6,7-benzomorphane hydrochloride

a) Starting compound

The (±) -2‘-hydroxy-5,9,9,3‘-tetramethyl-6,7-benzomorphane required in this and other examples is not yet known in the art. It can be prepared, for example, by the method known for the 2‘-hydroxy derivative (DOS 20 27 077, CA 74 (1971), 125482x) in which 4-methoxy-3-benzyllithium is used instead of p-methoxybenzyllithium. Ring closure on the benzomorphane system predominantly yields 2‘-hydroxy-5,9,9,3‘-tetramethyl-6,7-benzomorphane, which is purified by flash column chromatography (Comparative Example 16).

b) Conversion to the title compound

Starting from 2,44 g (0,010 mol) of (±) -2'-hydroxy-5,9,9,3'-tetramethyl-6,7-benzomorphane and 1,6 g (0,013 mol) of acid chloride (R) -2-methoxy analogously to Example 1 to give a mixture of the expected diastereomeric bases which are separated by column chromatography on 100-fold amount of silica gel of Example 2. the faster moving substance _(Rf = 0.26) is crystallized as the methanesulphonate. The title compound is obtained in a yield of 1.64 g (79.3%) with a melting point of 266-268 ° C and a specific rotation [α] D ²⁵ = -95.4 ° (c = 1, CH ₃ OH).

Example 58 (+) - [1S, 5R, 2'R] -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9,3‘-tetramethyl-6,7-benzomorphane hydrochloride

Example 57 In a separate, faster moving substance _(Rf = 0.29) analogously to Example 2 as the hydrochloride salt precipitated. The title compound was obtained in a yield of 1.60 g (90.4%) as an amorphous powder with a specific rotation of [α] _D ²⁵ = + 73.4 ° (c = 1, CH ₃ OH).

Example 59 (+) - [1S, 5R, 2'S] -2‘-Hydroxy-2- (2-methoxypropyl) -5,9,9,3‘-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 2.44 g (0.010 mol) of (±) -2‘-hydroxy-5,9,9,3'-tetramethyl-6,7-benzomorphane (see Example 57), and

1.6 g (0.013 mol) of (S) -2-methoxypropionic acid chloride) is obtained, analogously to Example 1, of a mixture of the expected diastereomeric bases which are separated by column chromatography on a 100-fold amount of silica gel analogously to Example 2. moving substance _(Rf = 0.26) is crystallized as the methanesulphonate. To give the title compound in a yield of 1.56 g (88.1%), mp 265-267 DEG C. and a specific rotation [a] _D ²⁵ = + 96.9 ° (c = 1, CH ₃ OH).

Example 60 (-) - [1R, 5S, 2'S] -2‘-Hydroxy-2- (2-methoxypropyl) -5,9,9,3‘-tetramethyl-6,7-benzomorphane hydrochloride

In Example 59 separate, faster moving substance _(Rf = 0.29) is precipitated analogously to Example 2 as the hydrochloride. The title compound was obtained in a yield of 1.36 g (76.8%) as an amorphous powder with a specific rotation of [α] _D ²⁵ = -74.9 ° (c = 1, CH 3 OH).

Example 61 (-) - [1R, 5S, 2'R] -2 ', 3'-dihydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

a) Starting compound

The (+) - 2 ‘, 3-dihydroxy-5,9,9-trimethyl-6,7-benzomorphane required in this and other examples is not yet known in the art. For example, it can be prepared by a method known for a 2'-hydroxy derivative (DOS 20 27 077, CA 74 (1971) 125482x) in which 3,4-dimethoxybenzyllithium is used instead of p-methoxybenzyllithium. Ring closure on the benzomorphane system predominantly yields 2 ', 3'-dihydroxy-5,9,9-trimethyl-6,7-benzomorphane, which is purified by flash column chromatography (Comparative Example 16).

b) Conversion to the title compound

Starting from 8.51 g (0.03 mol) of (±) -2 ', 3'-dihydroxy-5,9,9-trimethyl-6,7-benzomorphan hydrochloride and 4.1 g (0.033 mol) of chloride of (R) -2-methoxypropionic acid. Is obtained analogously to Example 1 a mixture of the expected diastereomeric bases which are separated by flash column chromatography on a 100-fold amount of silica gel analogously to Example 2. The slower moving substance _(Rf = 0.21) is crystallized as the hydrochloride.

The title compound was obtained in a yield of 2.54 g (47.6%) with a melting point of 167 ° C (dec.) And a specific rotation of [α] _D ²⁵ = -98.6 ° (c = 0.5, CH ₃ OH). ).

Example 62 (+) - [1S, 5R, 2'R] -2 ', 3'-dihydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

In Example 61, a separate, faster moving substance (Rf = 0.29) is eliminated as the hydrochloride analogously to Example 2. The title compound is obtained in a yield of 2.28 g (42.7%) with a melting point of 251 ° C (dec.) And a specific rotation of [α] _D ²⁵ = + 64.3 ° (c = 0.5, CH ₃ OH). ).

Type 1 compounds - prepared according to Method B

Example 63 (±) -2‘-Hydroxy-2- (2-methoxyethyl) -5,9,9-trimethyl-6,7-benzomorphane hydrobromide

0.6 g (0.003 mol) of (±) -2‘-hydroxy-5,9,9-trimethyl-6,7-benzomorphane, 0.72 g (0.0075 mol) of 2-methoxyethyl chloride,

0.11 g (0.0075 mol) of sodium iodide and 0.95 g (0.0113 mol) of sodium bicarbonate in 10 ml of absolute dimethylformamide were stirred at 95 ° C for 23 hours. Then the reaction mixture was evaporated on a rotary evaporator, finally at 95 ° C and under full vacuum of the water pump. The residue is shaken with 25 ml of water

The reaction mixture was extracted with 10 ml of dichloromethane and the separated aqueous phase was further extracted with 10 ml of dichloromethane. The combined extracts were washed with water, dried over sodium sulphate and filtered, as described above, and evaporated in vacuo. The free base residue of the title compound is crystallized analogously to Example 38 as the hydrobromide. Yield: 0.48 g (43.5% of theory), m.p. 247 DEG C. (dec.).

Example 64 (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

a) Production of an alkylating agent

Reduction of the known (+) - (R) -2-methoxypropionic acid with lithium aluminum hydride (LiAlH ₄ ) affords (-) - (R) -2-methoxypropanol with a boiling point of 70 ° C at a pressure of 0.0076 MPa and a specific rotation [α] _D ²⁵ = 15.8 ° (c = 100). Similarly, it is obtained from the known (-) - (S) -2-methoxypropionic acid corresponding to (+) - (S) -2-methoxypropanol having a boiling point of 70 ° C at a pressure of 0,0076 MPa and a specific rotation [α] of ^2S = +16.5 ° (c = 100).

Reaction of (-) - (R) -2-methoxypropanol with p-toluenesulfonic acid chloride in pyridine analogously to the method of RS Tipson (J. Org. Chem. 9 (1944) 235)) affords (+) - (R) - 2-methoxypropyl p-toluenesulfonate in the form of a yellowish oil with a specific rotation of [α] _D ²⁵ = + 3.7 ° (c = 100) and analogously from (+) - (S) -2-methoxypropanol corresponding to (-) - (S) -2-methoxypropyl p-toluenesulfonate having a specific rotation [α] _D ²⁵ = -3.7 ° (c = 100).

b) Conversion to the title compound

1.16 g (5 mmol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (Example 1) was heated with 1.83 g (7.5 mmol) of (R). Of 2-methoxypropyl p-toluenesulfonate, 1.26 g (0.015 mol) of sodium bicarbonate and 1.12 g (7.5 mmol) of sodium go in a mixture of 15 ml of absolute dimethylformamide and 25 ml of absolute tetrahydrofuran for 60 hours with stirring for the reflux temperature. Finally, it is worked up analogously to Example 63. A mixture of the two expected diastereomeric bases (2 g) is obtained, which can be prepared according to Example 1 in another manner. Separation by crystallization of the hydrochlorides as described above gives the title compound in a yield of 0.55 g (64.7% of theory), m.p. 264 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -118.2 DEG (c). = 1, CH ₃ OH). The (+) - (1S, 5R, 2'R) -diastereomer can be obtained from the mother liquors analogously to Example 2.

Example 65 (-) - [1R, 5S, 2'R] -2- (2-methoxypropyl) -2'-nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride

2.97 g (0.010 mol) of (+) - 2'-nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 34) was reacted in analogy to Example 54 with 2.68 g ( 0.011 mol) of (R) -2-methoxypropyl p-toluenesulfonate, 1.65 g (0.011 mol) of sodium iodide and 2.1 g (0.025 mol) of sodium bicarbonate.

As a reaction product, a mixture of both expected diastereomeric bases (3.2 g) was first isolated as described above. To separate the by-products, this is dissolved in 64 ml of dichloromethane and the solution is filtered through a column of 64 g of alumina (activity III - neutral - according to Brockmann). After elution with an additional 128 ml of dichloromethane, the combined eluate was evaporated on a rotary evaporator, finally at 80 ° C and under full vacuum of the water pump. The residue (2.4 g) was dissolved in 10 ml of methanol and, after acidification with 2.5N ethanolic hydrochloric acid, diethyl ether was added until turbidity started. The title compound crystallized, which was aspirated after 3 days at room temperature, washed with ethanol-ether (1: 1), then with ether, and dried at 80 ° C. The title compound is obtained in a yield of 0.84 g (45.5% of theory), m.p. 226 [deg.] C. (dec.), Specific [α] _D ²⁵ = -120 ° (c = 1, CH ₃ OH). The stereoisomeric (+) - (1S, 5R, 2'R) -compound can be obtained from the mother liquors as desired.

Example 66 (+) - [1S, 5R, 2'S] -2- (2-methoxypropyl) -2'-nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride

2.97 g (0.010 mol) of (±) -2'-nitro-5,9,9-trimethyl-6,7-benzomorphan hydrochloride and 2.68 g (0.011 mol) of (S) -2-methoxy are obtained. p-toluenesulfonate, analogously to Example 65, afforded the title compound in a yield of 0.96 g (52.0% of theory), mp 226 ° C (dec.) and specific rotation [α] _D ²⁵ = + 121 ° ( c = 1, CH ₃ OH). From the mother liquors, the stereoisomeric (-) - (1R, 5S, 2'S)-compound can be obtained analogously to Example 2.

Example 67 (-) - [1R, 5S, 2'R] -2- (2-methoxypropyl) -3'-nitro-5,9,9-trimethyl-6,7-benzomorphane

(a) Production of the starting compound

In this and other examples, the (±) -3'-nitro5,9,9-trimethyl-6,7-benzomorphane required is formed next to the (±) -2'-nitro isomers upon nitration of 5,9,9-trimethyl-6,7- benzomorphane (Example 34) in a ratio of about 1: 3. It is obtained from the mother liquors, 2'-nitro isomers crystallizing as the hydrochloride, via a base prepared above. Crystallized as oxalate (m.p. 158 ° C, dec.) From a ten-fold amount of methanol. The oxalate is converted back to the base (not crystallized), which is used for the reaction described below. A sample of the base crystallized as the methanesulfonate melted at 242 ° C (with decomposition).

b) Conversion to the title compound

5.2 g (0.02 mol) of (±) -3'-nitro-5,9,9-trimethyl-6,7-benzomorphane were reacted in analogy to Example 65 and 5.36 g (0.022 mol) ( R) -2-methoxypropyl-p-toluenesulphonate. As a reaction product, a mixture of the two expected stereoisomeric bases (8 g) is obtained, which, as described in Example 65, is purified by filtration through alumina (4.7 g of purified base). The thin layer chromatogram (silica gel 60, toluénetylester acetate 85: 15, developed 3 times) the diastereomers have _Rf value of 0.81 and 0.85. Separation of diastereomers 1 g per 300 g of silica gel column chromatography eluted the title compound (100 mg) having a _Rf = 0.81 as a brownish very viscous oil which does not crystallize.

Example 68 (+) - [1S, 5R, 2'R] -2- (2-methoxypropyl) -3'-nitro-5,9,9-trimethyl-6,7-benzomorphane

In the column chromatography described in Example 67, in addition to (-) 15, it is also isolated from the mixture of diastereomers.

SK 280776-6

- (1R, 5S, 2 "R) -forms (R _f = 0.81) and 100 mg of (+) - (1S, 5R, 2" S) -form (R _f = 0.85) as brownish very viscous oil which does not crystallize.

Example 69 (-) - [1R, 5S, 2'R] -2'-Chloro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

(a) Production of the starting compound

The (±) -2'-chloro-5,9,9-trimethyl-6,7-benzomorphane required in this and other examples can be prepared, for example, from a 2'-nitro analogue (Example 34), where the latter is hydrogenated to 2'-nitro The di-hydrochloride (dihydrochloride, m.p. 283 DEG C. with decomposition) and this was converted by the Sandmeyer reaction to the desired 2 ' -chloro compound (hydrobromide: mp > 310 DEG C. with decomposition).

b) Conversion to the title compound

3.3 g (0.010 mol) of (±) -2'-chloro-5,9,9-trimethyl-6,7-benzomorphane hydrobromide and 2.68 g (0.011 mol) of (R) -2-methoxypropyl The p-toluenesulfonate is reacted analogously to Example 65 to a mixture of both desired diastereomeric bases and purified as described above by filtration through alumina. The purified mixture of diastereomers was separated, as in Example 1, by crystallization of the hydrochlorides. To give the title compound in a yield of 0.27 g (15.1% of theory) of melting point 287 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = -102 ° (c = 1, CH ₃ OH).

Example 70 (+) - [1S, 5R, 2'R] -2'-Chloro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

The mother liquors of Example 69 were evaporated and the residue dissolved in boiling methanol. After addition of diethyl ether just to the beginning of turbidity and crystallization, the title compound is obtained, which is sucked off after about 12 hours at room temperature, washed with ethanol-ether 1: 1, then with ether and dried at 80 ° C. Yield 0.56 g (31.3% of theory), m.p. 289 DEG C. and specific rotation [.alpha.] _D @ ²⁵ = + 67.9 DEG.

Example 71 (+) - [1S, 5R, 2'S] -2'-Chloro-2- (2-methoxy-propyl) -5,9,9-trimelyl-6,7-benzomorphane hydrochloride

Starting from 3.3 g (0.010 mol) of (±) -2'-chloro-5,9,9-trimethyl-6,7-benzomorphane and 2.68 g (0.011 mol) of (S) -2-methoxypropyl- p-toluenesulfonate, and the title compound is obtained in analogy to Example 69 in a yield of 0.41 g (22.9% of theory), m.p. 288 DEG C. (dec.) and specific rotation [.alpha.] _D @ ²⁵ = + 101.7 DEG (c = 1, C I ₃ OH).

Example 72 (-) - [1R, 5S, 2'S] -2'-Chloro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

From the mother liquors of Example 61, the title compound is obtained analogously to Example 70 in a yield of 0.75 g (41.9% of theory), m.p. 288 DEG C. and specific rotation [.alpha.] _D @ ²⁵ = -68.6 DEG (c). = 1, CH ₃ OH).

Type 1 compounds - produced by Method C

Example 73 (-) - [1R, 5S, 2'S] -2'-Methoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

0.68 g (2 mmol) of (-) - [1R, 5S, 2'S] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 4) was mixed in 20 ml of absolute dimethylformamide with stirring and ice cooling with 0.13 g of a 77% suspension of sodium hydride in paraffin (4.2 mmol). After stirring for 30 minutes, 0.31 g (2.2 mmol) of methyl iodide dissolved in 5 ml of dimethylformamide is added dropwise over 5 minutes. It is then further stirred for 3 hours at room temperature and then evaporated on a rotary evaporator, finally at 95 ° C and under full vacuum of the water pump. The residue was shaken with 25 mL of dichloromethane and 25 mL of water. The separated aqueous phases are extracted once more with 15 ml of dichloromethane. After washing with 15 ml of water, the combined extracts are evaporated and the residue is crystallized in analogy to Example 28 as the methanesulfonate. The title compound is obtained in a yield of 0.38 g (47.0%), m.p. 150-152 ° C (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -68.7 DEG (c = 1, CH3 _). OH).

Example 74 (+) - [1S, 5R, 2'R] -2'-Methoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 0.68 g (2 mmol) of (+) - [1S, 5R, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- benzomorphan hydrochloride (Example 2), the title compound was obtained in analogy to Example 73 in a yield of 0.38 g (46.0% of theory), m.p. 150-152 ° C (dec.) and specific rotation [α] _D ²⁵ = + 67.2 ° (c = 1, CH ₃ OH).

Example 75 (-) - [1R, 5S, 2'R] -2'-Ethoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 0.34 g (1 mmol) of (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6 Of 7-benzomorphan hydrochloride (Example 1) and 0.17 g (0.0011 mol) of ethyl iodide are obtained analogously to Example 63 in a yield of 0.30 g (70.2% of theory), m.p. 146-148. [Deg.] C. (with decomposition) and specific rotation [[alpha]] _D <^25> = -93.4 [deg.] (C = 1, CH3OH).

Example 76 (-) - [1R, 5S, 2'R] -2'-Acetoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

0.68 g (2 mmol) of (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 1) was dissolved in 15 mL of absolute dichloromethane. After the addition of 0.51 g (5 mmol) of triethylamine, 0.19 g (2.4 mmol) of acetyl chloride dissolved in 5 ml of dichloromethane is stirred at room temperature with stirring for about 10 minutes. It is then stirred at room temperature for a further 2 hours. It is then washed three times with 10 ml of ice-water, dried over sodium sulphate and then filtered off (rotary evaporator, finally at 80 [deg.] C. and full vacuum of the water pump). The free base residue (0.6 g, 1.74 mmol) was dissolved in 3 mL of ethanol and acidified by addition of methanesulfonic acid (0.16 g, 1.74 mmol) in 3 mL of ethanol to pH 4 After addition of diethyl ether until turbidity, the title compound crystallizes and, after standing for about 12 hours in a refrigerator, is sucked off, washed

Ethanol-ether 1: 2 and dried at 80 ° C. Yield 0.7 g (79.3% of theory), m.p. 183 DEG-184 DEG C. (dec.), [.Alpha.] _D @ ²⁵ = -83.9 DEG (c = 1, CH3 OH).

Example 77 (+) - [1S, 5R, 2'S] -2'-Acetoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 0.68 g (0.002 mol) of (+) - [1S, 5R, 2'S] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- benzomorphan hydrochloride (Example 3) and analogously to Example 76, the title compound is obtained in a yield of 0.6 g (68.0% of theory), m.p. 183-184 ° C (dec.) and specific rotation [.alpha.] _D ²⁵ = + 82.8 ° (c = 1, CH 3 OH).

Example 78 (-) - [1R, 5S, 2'S] -2'-Acetoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 0.68 g (0.002 mol) of (-) - [1R, 5S, 2'S] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- benzomorphan hydrochloride (Example 4) and the title compound is obtained in an analogous manner to Example 76 in a yield of 0.58 g (65.7% of theory), m.p. 183 DEG C. (dec.) and specific rotation [.alpha.] _D @ ²⁵ = - 57.1 ° (c = 1, CH ₃ OH).

Example 79 (+) - [1S, 5R, 2'R] -2'-Acetoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 0.68 g (0.002 mol) of (+) - [1S, 5R, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- benzomorphan hydrochloride (Example 2) and the title compound is obtained in analogy to Example 76 in a yield of 0.67 g (75.9% of theory) with a melting point of 183 ° C (dec.) and a specific rotation of [α] _D ²⁵ = + 58.2 ° (c = 1, CH ₃ OH).

Example 80 (-) - [1R, 5S, 2'R] -2- (2-methoxypropyl) -2'-propionoxy-5,9,9-trimethyl-6,7-benzomorphane methanesulfonate

Starting from 0.34 g (1 mmol) of (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- of benzomorphan hydrochloride (Example 1) and 0.15 g (1.1 mmol) of propionic anhydride, analogously to Example 76, yielding the title compound in a yield of 0.21 g (46.1% of theory), m.p. 145 ° C. (dec.) and specific rotation [α] _D ²⁵ = -78.3 ° (c = 1, CH ₃ OH).

Example 81 (-) - [1R, 5S, 2'R] -2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

a) (-) - [1R, 5S, 2'R] -2- (2-methoxypropyl) -2 '- (1-phenyl-5-tetrazolyloxy) -5,9,9-trimethyl-6,7- benzomorphan hydrochloride

1.36 g (4 mmol) of (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 1) was heated with 0.79 g (4.4 mmol) of 5-chloro-1-phenyl tetrazole and 1.36 g (0.01 mol) of dry, finely powdered potassium carbonate in 78 ml of absolute acetone for 6 days with stirring to reflux temperature. The solution was evaporated and the residue was mixed with 50 ml of water. It is extracted twice with 25 ml of dichloromethane and the combined extracts are washed with 15 ml of water. After drying with sodium sulfate and subsequent filtration, the reaction mixture is evaporated in a rotary evaporator, finally at 80 ° C under full vacuum of the water pump. The residue is dissolved in 5 ml of ethanol and, after acidification with ethanolic hydrochloric acid, mixed with diethyl ether until turbid. The intermediate crystallizes and, after standing for about 12 hours in a refrigerator, is suctioned off, then washed with ethanol-ether (1: 1), then with ether and dried at 80 ° C. Yield 1.67 g (86.3% of theory), mp 241 DEG C. (dec.).

b) Hydrogenation of the intermediate to the title compound

The intermediate (1.67 g, 3.5 mmol) was hydrogenated in the presence of 0.7 g of 10% palladium on carbon in 70 ml of glacial acetic acid at 50 psi of hydrogen at ambient temperature to complete the reaction (6-10 hours). ). The catalyst was filtered off with suction, the filtrate was evaporated and the residue was mixed with 50 ml of water and excess ammonia and extracted with dichloromethane (2 x 25 ml). The combined extracts were washed with water, dried over sodium sulphate and filtered to evaporate, finally at 80 ° C and under full vacuum of the water pump. The residue is crystallized in analogy to Example 2 as the hydrochloride. Gave the title compound in a total yield of 0.5 g (38.5% of theory) of melting point 225 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = -101.5 ° (c = 1, CH ₃ OH ).

Example 82 (+) - [1S, 5R, 2'S] -2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from 1.36 g (0.004 mol) of (+) - [1S, 5R, 2'S] -2-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 3), analogously to Example 81, via the corresponding intermediate (1.65 g, 85.1% of theory, melting point 241 ° C (dec.)), the title compound is obtained in a total yield of 0.64 g (49%). , 4% yield), mp 225 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = + 106.9 ° (c = 1, CH ₃ OH).

Example 83 (-) - [1R, 5S, 2'S] -2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan oxalate

1.36 g (4 mmol) of (-) - [1R, 5S, 2'S] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane are obtained. hydrochloride (Example 4) and analogously to Example 81 was obtained via the corresponding intermediate (1.73 g, 89.4% of theory, m.p. 218 DEG C. (dec.)) of the title compound as the free base (0.7 g). ). This was dissolved in 2 ml of isopropanol and treated with the corresponding molar amount of oxalic acid (0.22 g). The title compound crystallizes with the addition of 50 ml and stirring. After storage for about 12 hours in a refrigerator, it is aspirated, washed with isopropanol-ether, then with ether and dried at 80 ° C. To give the title compound in a total yield of 0.8 g (53.0% of theory) of melting point 145 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = -60.0 ° (c = 1, CH ₃ OH ).

Example 84 (+) - [1S, 5R, 2'R] -2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane oxalate

1.36 g (4 mmol) of (+) - [1S, 5R, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane are obtained. hydrochloride (Example 2) and obtained analogously to Example 81 via the corresponding intermediate (1.65 g, 85.1% of theory, melting point 217 ° C (dec.)) of the title compound, which crystallizes in analogy to Example 83. as oxalate. The total yield of 0.6 g (39.7% of theory), m.p. 135 DEG C. (decomposition) Specific rotation [a] _D ^{@ 25} = + 60.2 ° (c = 1, CH ₃ OH).

Example 85 (-) - [1R, 5S, 2'R] -2'-Acetamido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

0.70 g (1.87 mmol) of (-) - [1R, 5S, 2'R] -2'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane of the dihydrochloride (Example 34) is dissolved in 20 ml of absolute dichloromethane, mixed with 0.76 g (7.4 mmol) of triethylamine and then dropwise with stirring at room temperature with 0.17 g (2.1 mmol). of acetyl chloride dissolved in 5 ml of dichloromethane. It is then heated to the boiling point for one hour, cooled, washed three times with 10 ml of water each time, dried over sodium sulphate and, after filtration, evaporated on a rotary evaporator, finally at 80 ° C and under full vacuum. The residue was dissolved in 2 ml of methanol and, after acidification with 2.5N ethanolic hydrochloric acid, treated with diethyl ether until turbidity started. The precipitated crystallizate is suctioned off after about 12 hours in the refrigerator, washed with ethanol-ether (1: 1), then with ether and dried at 80 ° C. The title compound is obtained in a yield of 0.49 g (68.8% of theory), m.p. 252 DEG C. (with decomposition) and specific rotation [.alpha.] _D @ ²⁵ = -108.2 DEG (c = 1, CH3 OH).

Example 86 (+) - [1S, 5R, 2'S] -2'-Acetamido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

Starting from 1.07 g (2.58 mmol) of (+) - [1S, 5R, 2'S] -2'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6 , 7-benzomorphan hydrochloride (Example 36) to yield analogously to Example 85, the title compound in a yield of 0.73 g (74.3% of theory) of melting point 249 DEG C. (with decomposition) and a specific rotation [a] _D ^[ Α] ²⁵ = + 109.5 ° (c = 1, CH ₃ OH).

Example 87 (-) - [1R, 5S, 2'S] -2'-Acetamido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

1.0 g (0.0026 mol) of (-) - [1R, 5S, 2'S] -2'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane The dihydrochloride is worked up analogously to Example 85. The reaction product is isolated as described therein and crystallized from 5 ml of petroleum ether and 0.5 ml of isopropanol. To give the title compound in a yield of 0.7 g (76.4% of theory), m.p. 128 DEG C. and a specific angle of rotation [a] _D ²⁵ = -89.3 ° (c = l, CH ₃ OH 1NHC1 1: 1).

Example 88 (+) - [1S, 5R, 2'R] -2'-Acetamido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

Starting from 1.11 g (2.5 mmol) of (+) - [1S, 5R, 2'R] -2'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6, Of 7-benzomorphane dimethylsulfonate (Example 35) and the title compound is obtained in an analogous manner to Example 87 in a yield of 0.37 g (47.7% of theory) with a melting point of 129 ° C and a specific rotation of [α] _D ²⁵ = +89, 9 ° (c = 1, CH ₃ OH - in HC11: 1).

Example 89 (-) - [1R, 5S, 2'R] -3'-Bromo-2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

0.85 g (2.5 mmol) of (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane of the hydrochloride (Example 1) is suspended in 30 ml of glacial acetic acid. The suspension was treated with 0.15 mL (0.47 g, 2.9 mmol) of bromine at room temperature with stirring. After two hours of stirring, evaporate on a rotary evaporator, finally at 80 ° C and under full vacuum of the water pump. 25 ml of water and 25 ml of dichloromethane with excess ammonia are added to the residue with shaking. The separated aqueous phase is extracted once more with 15 ml of dichloromethane, the combined extracts are washed with 15 ml of water, dried over sodium sulphate and, after filtration, evaporated as indicated. The residue (1 g) was purified over a 250 g silica gel column (analogous to Example 2) using dichloromethane-methanol-concentrated ammonia 90: 10: 0.5. The eluate with the pure substance was evaporated as above and the residue crystallized analogously to Example 2 as the hydrochloride. To give the title compound in a yield of 0.75 g (65.8% of theory) of melting point 245 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = -82.5 ° (c = 1, CH ₃ OH) .

Example 90 (+) - [1R, 5R, 2'R] -2'-hydroxy-1'-nitro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

0.85 g (2.5 mmol) of (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane The hydrochloride was suspended at 20 ° C in 30 ml of glacial acetic acid and 0.18 ml (0.25 g) of 65% nitric acid (2.6 mmol of HNO ₃ ) was added with stirring. Within about 10 minutes, a clear, yellow solution was formed, which turned brown after a further 5 minutes and was quenched by precipitation of the crystalline compound. After about one hour, it is filtered off with suction and washed with a mixture of glacial acetic acid and diethyl ether (1: 1), then with ether, and dried at 80 ° C. The crystals (0.35 g) were dissolved in hot methanol-water (17.5 mL + 1.75 mL) and treated with diethyl ether (40 mL). The crystallized substance is suctioned off after cooling in an ice bath, washed with ether and dried at 80 ° C. The title compound is obtained in a yield of 0.32 g (33.3% of theory), m.p. &gt; 245 DEG C. (with gradual brown color and decomposition), specific rotation [.alpha.] _D @ ²⁵ = + 87.0 DEG (c). = 1, CH ₃ OH).

Example 91 (-) - [1R, 5S, 2'R] -2'-hydroxy-3'-nitro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

In Example 90 described the nitration is formed from the starting compound (Rf = 0.57) indicated L-nitro derivative _(Rf = 0.45), the isomeric 3'-nitroferivát _(Rf = 0.72) and ', 3'-dinitro (Rf = 0.10) (DC: Kieselgel 60, chloroform-methanol-concentrated ammonia 90: 10: 0.5). The mother liquor remaining after aspiration of the 1'-nitro compound (Example 90) is evaporated and the residue is converted to the free base. These were dissolved in 10 ml of dichloromethane and the yellow solution was filtered through 25 g of alumina (activity III, neutral). Elute with dichloromethane until the eluate is no longer yellow and the eluate is evaporated. The residue (0.35 g) was dissolved in 2.5 ml of ethanol and, after acidification with ethanolic hydrochloric acid, mixed with the starting haze with diethyl ether. After standing in the refrigerator for about 12 hours, it is filtered off with suction, washed with ethanol-ether (1: 1) and dried at 80 ° C. The title compound is obtained in a yield of 0.40 g (41.6% of theory), m.p. 229 DEG-230 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -110.1 DEG (c = 1, CH3 OH). ).

Example 92 (+) - [1R, 5R, 2'R] -1 ', 3'-Dinitro-2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

1.52 g (5 mmol) of (-) - [? R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane (Example 1) was dissolved in 3 ml glacial acetic acid and the solution was mixed with stirring at 3-4 ° C for 1.5 hours

3.4 ml glacial acetic acid and 5.42 ml 100% nitric acid. Stirring is continued for 3 hours at room temperature. The yellow reaction mixture was poured into 50 g of ice water, the solution basified with ammonia and extracted three times with 20 ml of dichloromethane each time. After washing the combined extracts with water and drying over sodium sulfate as well as filtering off, the reaction mixture is evaporated on a rotary evaporator, finally at 80 ° C and under full vacuum of the water pump. The residue was crystallized from ethanol-ether. The title compound was obtained in a yield of 1.0 g (46.5% of theory), m.p. 300 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = + 27.9 DEG (c = 1, CH3 OH).

Example 93 (-) - [1R, 5R, 2'RJ-1'-amino-2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

0.35 g (1.0 mmol) of (+) - [1R, 5R, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -1'-nitro-5'-trimethyl-6 '- of benzomorphan hydrochloride (Example 90) is hydrogenated in 40 ml of methanol in the presence of 0.1 g of palladium on carbon (5% Pd) for 4 hours under a hydrogen pressure of 0.5 MPa at room temperature. After filtering off the catalyst, the reaction mixture is evaporated in a rotary evaporator, finally at 80 ° C and under full vacuum of the water pump, and the residue is crystallized from 10 ml of ethanol. After cooling, the crystals are filtered off with suction, washed with ethanol-ether and dried at 80 ° C. The title compound is obtained in a yield of 0.17 g (52.7% of theory) with a melting point of 282 DEG C. (slow decomposition at 250 DEG C.) and a specific rotation of [.alpha.] _D @ ²⁵ = -128.3 DEG (c = 1, CH 3 OH).

Example 94 (-) - [1R, 5S, 2'R] -3'-Amino-2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

Starting from 0.39 g (1.0 mmol) of (-) - [1R, 5S, 2'R] -2'-hydroxy-2- (2-methoxypropyl) -3'-nitro-5,9,9 -trimethyl-6,7-benzomorphane hydrochloride (Example 91), and analogously to Example 93 the title compound is obtained in a yield of 0.27 g (76.1% of theory), m.p. 268 DEG C. (dec.) and specific rotation. [α] _D ²⁵ = -99.7 ° (c = 0.5, CH ₃ OH).

Example 95 (-) - [1R, 5R, 2'R] -1 ', 3'-diamino-2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7- benzomorphan hydrochloride

Starting from 0.70 g (1.63 mmol) of (+) - [1R, 5R, 2'RJ-1 ', 3'-dinitro-2'-hydroxy-2- (2-methoxypropyl) -5,9, Of 9-trimethyl-6,7-benzomorphane hydrochloride (Example 93) and the title compound is obtained in an analogous manner to Example 93 in a yield of 0.20 g (33.2% of theory), m.p. 228 DEG C. (dec.) And specific [α] _D ²⁵ = -111.7 ° (c = 0.5, CH 3 OH).

Example 96 (-) - [1R, 5S, 2'R] -3'-Amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

According to Example 67 the diastereomeric mixture obtained (-) - [1R, 5S, 2'RJ- and (+) - (1S, 5R, 2'R) -2- (2-methoxypropyl) -3'-nitro-5, 9,9-trimethyl-6,7-benzomorphane (3.7 g) is dissolved in 75 ml of methanol and hydrogenated in the presence of 0.8 g of palladium on carbon (5% Pd) under a hydrogen pressure of 0.5 MPa and a temperature of 20 g. ° C until hydrogen consumption is complete (about 3 hours). Thin layer chromatography (Kieselgel 60, Chloroform-methanol-concentrated ammonia 90: 10: 0.5) shows the complete conversion of the 3'-nitro compound (R _f = 0.73) to the corresponding 3'-amino compound (R _f = 0). , 61). After filtering off the catalyst, the reaction mixture was evaporated on a rotary evaporator, finally at 80 ° C and under complete vacuum of the water pump. The residue (3.1 g) was subjected to column chromatography on 600 g of silica gel in analogy to Example 2. Separation of diastereomeric 3'-amino compounds was monitored by thin layer chromatography (Kieselgel 60, chloroform-methanol-concentrated ammonia 95: 5: 0.1, developed twice). Gave the title compound with the smaller _Rf value of 0.63 in a yield of 0.95 g as a residue of the eluate, which has a specific rotation [a] _D = -39.8 ° ^{2 S} (C = 1, CH ₃ OH), which is resistant to all by attempting to crystallize.

Example 97 (+) - [1S, 5R, 2'R] -3'-Amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

In the above separation of the diastereomers by column chromatography (example 96) was obtained as a substance with a higher R _f value of 0.69, the title compound as a residue of the eluent (1.0 g), specific rotation [a] _D ²⁵ = + 104 ° (c = 1 , CH ₃ OH), which resists all crystallization attempts.

Example 98 (+) - [1S, 5R, 2'S] -3'-Amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

a) 3'-nitro-step (diastereomeric mixture)

Starting from 5.2 g (0.02 mol) of (±) -3'-nitro-5,9,9-trimethyl-6,7-benzomorphane and 5.36 g (0.022 mol) of (S) -2- of methoxypropyl p-toluenesulfonate and analogously to Example 67, a mixture of both expected diastereomeric bases is obtained, which is purified by filtration through alumina to give 4.7 g of purified base mixture.

b) 3'-amino compounds (diastereomeric mixture)

The 3'-nitro compound (4.7 g of the purified diastereomeric mixture) was hydrogenated analogously to Example 86 to the corresponding 3'-amino compound (3.7 g of the diastereomeric mixture).

Separation of the title compound by column chromatography

The mixture of diastereomeric 3'-amino compounds (3.7 g) was separated analogously to Example 96 by silica gel column chromatography. The title compound is obtained with less

R _f value of 0.63 in a yield of 1.0 g as a residue of the eluate has a specific rotation [a] _D ²⁵ = + 40.5 ° (c = 1, CH ₃ OH), which resists all attempts to crystallize.

Example 99 (-) - (1R, 5S, 2S) -3'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

The described column chromatography (example 98) was obtained as the second substance with the higher Rf of title compound _{(R f} = 0.69) as eluent of the residue in an amount of 1.1 g with a specific rotation [a] _D ²⁵ = -105 ° ( c = 1, CH ₃ OH), which does not crystallize.

Example 100 (-) - (1R, 5S, 2'R) -3'-Acetamido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

0.95 g (3.14 mmol) of (-) - (1R, 5S, 2'R) -3'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane (Example 96) was acetylated analogously to Example 85. The acetylation product was purified by filtration through alumina analogously to Example 65. In a thin layer chromatography (Kieselgel 60, chloroform-methanol-concentrated ammonia 90: 10:: 0.5) the starting compound R _f is 0.64 and the acetylation product R _f is 0.57. The residue (0.69 g), which resists all crystallization attempts, has a specific rotation [α] _D ²⁵ = -53.6 ° (c = 1, CH ₃ OH).

Example 101 (+) - (1S, 5R, 2'R) -3'-Acetamido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane oxalate

Starting from 1.0 g (3.31 mmol) of (+) - (1S, 5R, 2'R) -3'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6 7-benzomorphane (Example 97) and the title compound is obtained analogously to Example 90. The residue of the substance purified through alumina (0.5 g of substance) is crystallized in analogy to Example 83 as oxalate to give the title compound in a yield of 0. 4 g (27.8% of theory) of melting point 148 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = + 39.3 ° (c = 1, CH ₃ OH).

Example 102 (+) - (1S, 5R, 2S) -3'-Acetamido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane

Starting from 1.0 g (3.31 mmol) of (+) - (1S, 5R, 2'S) -3'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6 7-benzomorphane (Example 98) and analogously to Example 100, the title compound is obtained as a non-crystallizing residue (0.6 g, 41.7% of theory) with an Rf value of 0.57 and a specific rotation [α] _D ²⁵ = +52 8 ° (c = 1, CH 3 OH).

Example 103 (-) - (1R, 5S, 2'S) -3'-Acetamido-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane oxalate

Starting from 0.95 g (3.14 mmol) of (-) - (1R, 5S, 2'S) -3'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6, Of 7-benzomorphane (Example 99) and analogously to Example 101, the title compound is obtained in a yield of 0.7 g (51.1%) with a melting point of 148 ° C (dec.) And a specific rotation of [α] _D ²⁵ = -39 2 ° (c = 1, CH ₃ OH).

Example 104 (-) - (1R, 5S, 2'R) -3'-Methoxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (-) - (1R, 5S, 2'R) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6 7-benzomorphan hydrochloride (Example 53) and analogously to Example 73 gave the title compound in a yield of 0.38 g (52.0%) with a melting point of 221 ° C to 224 ° C and a specific rotation of [α] _D ²⁵ = -82.6 ° (c = 1, CH ₃ OH).

Example 105 (+) - (1S, 5R, 2'R) -3'-Methoxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (+) - (1S, 5R, 2'R) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl- Of 6,7-benzomorphan hydrochloride (Example 54) and analogously to Example 73, the title compound is obtained in a yield of 0.44 g (59.8%) as an amorphous powder with a specific rotation [<x] d ²⁵ = +42.2 ° (c = 1, CH ₃ OH).

Example 106 (+) - (1S, 5R, 2'S) -3'-Methoxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (+) - (1S, 5R, 2'S) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6 7-benzomorphan hydrochloride (Example 55) and analogously to Example 73 gave the title compound in a yield of 0.40 g (54.7%), mp 221-224 ° C and specific rotation [α] _D ²⁵ = + 81.7 ° (c = 1, CH 3 OH).

Example 107 (-) - (1R, 5S, 2'S) -3'-Methoxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (-) - (1R, 5S, 2'S) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6 7-benzomorphan hydrochloride (Example 56) and analogously to Example 73 gave the title compound in a yield of 0.42 g (56.1%) as an amorphous powder with a specific rotation [α] _D ²⁵ = -41.0 ° ( c = 1, CH 3 OH).

Example 108 (-) - (1R, 5S, 2'R) -3'-Methoxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (-) - (1R, 5S, 2'R) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6 7-benzomorphan hydrochloride (Example 57) and analogously to Example 73 gave the title compound in a yield of 0.36 g (49.3%) with a melting point of 224-226 ° C and a specific rotation of [α] _D ^{2 S} = - 112.2 ° (c = 1, CH ₃ OH).

Example 109 (+) - (1S, 5R, 2'R) -2'-Methoxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (+) - (1S, 5R, 2'R) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl- Of 6,7-benzomorphan hydrochloride (Example 58) and analogously to Example 73, the title compound is obtained in a yield of 0.39 g (53.0%) as an amorphous powder with a specific rotation [<x] _D ²⁵ = +72.4 ° (c = 1, CH ₃ OH).

Example 110 (+) - (1S, 5R, 2'S) -2'-Methoxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphane hydrochloride

SK 280776-6

Starting from 0.64 g (2 mmol) of (+) - (1S, 5R, 2'S) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl- Of 6,7-benzomorphan hydrochloride (Example 59) and analogously to Example 73, the title compound is obtained in a yield of 0.45 g (61.5%) with a melting point of 228-229 ° C and a specific rotation [α] _D ²⁵ = + 111.5 ° (c = 1, CH ₃ OH).

Example 111 (-) - (1R, 5S, 2'S) -2'-Methoxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphane hydrochloride

Starting from 0.71 g (2 mmol) of (-) - (1R, 5S, 2'S) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6 , 7-benzomorphan hydrochloride (Example 60) and analogously to Example 73, the title compound was obtained in a yield of 0.40 g (53.4%) as an amorphous powder with a specific rotation [α] _D ²⁵ = -71.8 ° ( c = 1, CH ₃ OH).

Example 112 (-) - (1R, 5S, 2'R) -3'-hydroxy-2'-methoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrobromide

Starting from 3.56 g (10 mmol) of (-) - (1R, 5S, 2'R) -2 ', 3'-dihydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6 7-benzomorphan hydrochloride (Example 61) and analogously to Example 73 gave (with two equivalents of sodium hydride) a mixture of both isomeric monomethoxy derivatives and dimethoxy derivatives which was separated by column chromatography on 100 times silica gel analogously to Example 2 (eluent). dichloromethane-isopropanol-concentrated ammonia 97: 3: 0.3). the compound of movement as the mean substance _(Rf = 0.73) is crystallized as the hydrobromide. provide the title compound in a yield of 0.62 g (15.0%) mp 212 ° C (dec.) and specific rotation [α] _D ²⁵ = -78.4 ° (c = 0.5, CH ₃ OH).

Example 113 (-) - (1R, 5S, 2'R) -2'-hydroxy-3'-methoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrobromide

In Example 112, a separate, slower moving substance (Rf = 0.68) is eliminated as the hydrobromide. The title compound is obtained in a yield of 0.88 g (21.2%) with a melting point of 235 ° C (dec.) And a specific rotation of [α] _D ²⁵ = -93.1 ⁰ (c = 0.5, CH ₃ OH). ).

Example 114 (-) - (1R, 5S, 2'R) -2 ', 3'-Dimethoxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

In Example 112, a separate, slower moving substance (Rf = 0.86) is eliminated as the hydrochloride. The title compound is obtained in a yield of 0.87 g (22.7%), mp 193 ° C (dec.) And specific rotation [α] _D ²⁵ = -93.2 ° (c = 0.5, CH ₃ OH) ).

Type 1 compounds - produced by special methods

Example 115 (-) - (1R, 5S, 2'R) -2'-hydroxy-2- (2-hydroxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride

1.5 g (3.60 mmol) of (-) - (1R, 5S, 2'R) -2- (2-benzyloxypropyl) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane of the hydrochloride (Example 43) is dissolved in 75 ml of methanol and hydrogenated under 0.5 MPa of hydrogen at 70 ° C in the presence of palladium hydroxide on activated carbon (0.6 g of wet Pearlman catalyst) until complete conversion. The catalyst is filtered off and the filtrate is evaporated on a rotary evaporator, finally at 80 ° C and under full vacuum of the water pump, the residue is dissolved in 10 ml of methanol and the solution is mixed with 30 ml of diethyl ether. After standing for 12 hours at room temperature, suction is washed first with ethanol-ether (1: 1), then with ether and dried at 80 DEG C. The title compound is obtained in a yield of 1.0 g (85.5% of theory). mp 276 ° C (dec.) and specific rotation [α] _D ²⁵ = -127.4 ° (c = 1, CH ₃ OH).

Example 116 (+) - (1S, 5R, 2S) -2'-hydroxy-2- (2-hydroxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

Starting from 1.5 g (3.6 mmol) of (+) - (1S, 5R, 2'S) -2- (2-benzyloxypropyl) -2'-hydroxy-5,9,9-trimethyl-6 Of 7-benzomorphan hydrochloride (Example 44), analogously to Example 115, yielding the compound in a yield of 1.0 g (85.5% of theory) with a melting point of 276 ° C (dec.) And a specific rotation of [α] _D ²⁵ = + 126.8 ° (c = 1, CH ₃ OH).

Example 117 (-) - (1R, 5S, 2'S) -2'-Hydroxy-2- (2-hydroxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

The diastereomer remaining in Example 44 in the mother liquors (3.17 g of residue) was hydrogenated analogously to Example 115. The title compound was obtained in a yield.

1.5 g (56.2% of theory) of melting point 247 DEG C. (with decomposition) and a specific rotation [a] _D ²⁵ = -86.8 ° (c = 1, CH ₃ OH).

Example 118 (+) - (1S, 5R, 2'R) -2'-Hydroxy-2- (2-hydroxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride

The diastereomer remaining in Example 43 in the mother liquors (3.17 g of residue) was hydrogenated analogously to Example 115. The title compound was obtained in a yield.

1.5 g (56.2% of theory), m.p. 247 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = + 86.4 DEG (c = 1, CH3 OH).

Example 119 (+) - (1R / S, 5S / R, 2 'S] ^-2, fluoro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan oxalate

a) Starting compound: (1R / 5S / R, 2'S) -2'-fluoro-2- (2-methoxypropionyl) -5,9,9-trimethyl-6,7-benzomorphane (diastereomeric mixture)

5.94 g (0.02 mol) of (+) - 2'-nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride were acylated analogously to Example 32, 2.68 g (0.22 mol) (S) -2-methoxypropionic acid chloride. The resulting acylation product (7.0 g) was hydrogenated as described to the corresponding 2'-amino analog. This was converted to the corresponding 2'-fluoro derivative (5.7 g) by a method known in the art (TL Fletcher and MJ Namkung, Chem. And Ind. 1961, 179). This creates a mixture of the expected diastereomers, which can not be resolved in thin layer chromatography _(Rf = 0.73, silica gel, chloroform-methanol-concentrated ammonia 90: 10: 0.5).

b) Conversion to the title compound

The intermediate (1.58 g, 5 mmol) was reduced in analogy to Example 32 with lithium aluminum hydride (LiAlH ₄ ) to the title compound and purified as described by column chromatography on silica gel. The residue of the eluate with the purified substance (0.4 g, _Rf = 0.78) was crystallized analogously to Example 83 as the oxalate. The title compound is obtained in a yield of 90.35 g (17.7% of theory) with a melting point of 165 (with decomposition) and a specific rotation of [α] _D ²⁵ = + 9.7 ° (c = 1, CH ₃ OH). The substance consists of a mixture of the expected diastereomers ((1R, 5S, 2'S) - and (1S, 5R, 2'S) compound in a ratio of about 1; 1 (by 1 H NMR spectroscopy).

Example 120 (-) - (1R / 5S / R, 2'R) -2'-Fluoro-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane oxalate

a) Starting compound (1R / S, 5S / R, 2'R) -2'-fluoro-2- (2-methoxypropionyl) -5,9,9-trimethyl-6,7-benzomorphane (mixture of diastereomers)

Starting from 2.97 g (0.01 mol) of (±) -2'-nitro-5,9,9-trimethyl-6,7-benzomorphan hydrochloride, obtained using 1.34 g (0.011 mol) (R) -2-methoxypropionic acid chloride a mixture of the expected diastereomeric 2'-fluoro-2- (2-methoxypropionyl) -5,9,9-trimethyl-6,7-benzomorphane (reaction procedure according to Example 119), but not It can be separated by thin layer chromatography (Rf = 0.73, silica gel, chloroform-methanol-concentrated ammonia 90: 10: 0.5), yield 2.9 g.

b) Conversion to the title compound

2.9 g (9.2 mmol) of the above intermediate were reduced in analogy to Example 119 with lithium aluminum hydride. The reaction product is purified as described therein. The residue of the pure fractions (0.9 g) was crystallized in analogy to Example 98 as the oxalate. The title compound is obtained in a yield of 0.88 g (22.3% of theory), m.p. 169 DEG C. (dec.) And specific rotation [.alpha.] _D @ ²⁵ = -9.5 DEG (c = 1, CH3 OH) as a mixture of the expected diastereomers ((1R, 5S, 2'R) - and (1S, 5R, 2'R) compound.

Claims (9)

PATENT Claims where X represents an oxygen atom or a sulfur atom, R ¹ is C alkyl, C _3-6 alkenyl, C ^ alkynyl, C ₆ - | Oaryl, R ² is H, C ^ alkyl, C _{3. 6} alkenyl, C _{3. 6-} alkynyl, C ₆ . ₁₀ aryl, C ₇ . _{] 4} aralkyl, R ³ is hydrogen, C 1-6. ₆ alkyl, R ⁴ is C 1. ₈ alkyl, R ⁵ is C 1. ₈ alkyl, R ⁶ may be C _1-8 alkyl, C _6-10 aryl, R ⁷ and R ⁸ independently of one another represent a hydrogen atom, C 1-6. _with alkyl, halogen, -OH, C 1-6 alkyl. ₈ alkoxy, -O-acyl, -CN, -NO ₂ , NH ₂ , -NH (C _1-8 alkyl), -N- (C _1-8 alkyl) ₂ , wherein the alkyl radicals may be the same or different, -NH -acyl or -N-acyl- (C _1-8 alkyl), wherein acyl is R-CO-, wherein R is phenyl or C 1-8. ₆ alkyl, alkoxy is C | _ ₈ acyloxy and alkoxy, R-CO-O-, wherein R is phenyl or C. ₆ alkyl. 2. Benzomorphans of formula (I) wherein X is oxygen or sulfur; R ¹ is methyl, ethyl, propyl, isopropyl, phenyl, R ² is methyl, ethyl, propyl, isopropyl, allyl, propargyl, phenyl, benzyl, R ³ is hydrogen, C ^1-4 alkyl, R ⁴ is methyl, ethyl, propyl, isopropyl R ⁵ is methyl, ethyl, propyl, isopropyl, R ⁶ is methyl, ethyl, propyl, isopropyl, phenyl, R ⁷ is fluorine, chlorine, hydroxy, C 1-4 alkyl, C 1-6 alkoxy, C 1-6 acyloxy, R ⁸ is hydrogen atom; ₃ alkyl, hydroxy or alkoxy, wherein alkoxy and acyloxy are as defined in claim 1. 3. A compound of formula (I) wherein X is O, R ¹ is methyl or ethyl, R ² is methyl or ethyl, R ³ is hydrogen, R ⁴ is methyl or ethyl, R ⁵ is methyl or ethyl, R ⁶ is methyl or ethyl, R ⁷ is hydroxy, methyl, methoxy, acyloxy, R ⁸ is H, methyl, ethyl, hydroxy or C ^ alkoxy, wherein alkoxy and acyloxy are as defined in claim 1. 4. A compound of formula (I) wherein X is O; R ¹ is methyl, R ² is methyl, R ³ is hydrogen, R ⁴ is methyl, R ⁵ is methyl, R ⁶ is methyl, R ⁷ is hydroxy, methyl, methoxy or acetoxy, R ⁸ is hydrogen, methyl, hydroxy or C 1. ₃ alkopričom alkoxy and acyloxy are as defined in claim 1. 5. A compound of formula (I) wherein X is O, R ¹ is methyl, R ² is methyl, R ³ is hydrogen, R ⁴ is methyl, R ⁵ is methyl, R ⁶ is methyl, R ⁷ is hydroxy, methyl, methoxy or acetoxy, R ⁸ is hydrogen, methyl, hydroxy, methoxy or ethoxy, wherein the substituents R ⁷ and R ⁸ are in the 2'- and 3'-positions and the carbon atom in the 2-position has the R-configuration. 6. A process for the preparation of the benzomorphane compounds of formula (I) SK 280776 Β6 characterized in that: (a) a benzomorphane of formula (2) wherein R ⁴ , R ⁵ and R ⁶ are as defined above and R ⁹ and R ¹⁰ are either as defined for R ⁷ and R ⁸ as set forth in claim 1 or are convertible substituents to said substituents in a known manner, reacted in a known manner in inert solvents, in the presence of an acid binding agent with a carboxylic acid derivative of formula (4), wherein Y is a leaving group, a secondary amino group replaceable group selected from halogen, hydroxy, OC (O) -alkyl, O-acyl, OSO ₂ -alkyl and OSO ₂ -aryl, R ¹ , R ² , R ³ and X are as defined above, and the resulting acid amide of formula (3) is then reduced in a known manner in an inert solvent to the amine of formula (6) and optionally the substituents R ⁹ and R ¹⁰ are converted to R ⁷ and R ⁸ and the benzomorphane compound of formula (1) or benzomorphane in general is isolated from the reaction mixture of formula (2) wherein R ⁴ , R ⁵ and R ⁶ are as defined above and R ⁹ and R ¹⁰ are either R ⁷ and R ⁸ as defined in claim 1 or can be converted to these by known methods in inert solvents, in a known manner in inert solvents optionally in the presence of an acid binding agent, an alkylating agent of formula (5), wherein Z is a secondary amino-replaceable leaving group from the group consisting of halogen, such as chlorine, bromine or iodine or an OSO ₂ -aryl arylsulfonate, such as tosylate, or an alkylsulfonate, such as methanesulfonate or halomethanesulfonate, or a sulfate group, to form a tertiary amine of type (6) and optionally convert R ⁹ and R ¹⁰ to R ⁷ and R ⁸ and isolating the benzomorphane compound of formula 7. A pharmaceutical composition comprising the benzomorphane compound of claim 1 Any one of claims 1 to 6 or an acid addition salt thereof together with excipients and carriers. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament. Use of a compound according to any one of claims 1 to 6 and acid addition salts thereof for the manufacture of a medicament for the therapeutic treatment of cerebral ischemia of various origins, epilepsy and neurodegenerative diseases.