FI105913B - Process for the preparation of pharmaceutically valuable benzomorphans - Google Patents

Abstract

Benzomorphane derivs. of formula (I) are new. In (I), X = O or S; R1 = 1-8C alkyl, 3-6C alkenyl, 3-6C alkynyl or aryl; R2 = H, 1-8C alkyl, 3-6C alkenyl, 3-6C alkynyl, aryl or aralkyl; R3 = H or 1-6C alkyl; R4 and R5 = each 1-8C alkyl; R6 = 1-8C alkyl or aryl; R7 and R8 = each H, 1-8C alkyl, halogen, OH, 1-8C alkoxy, O-Acyl, CN, NO2, NH2, NH(1-8C alkyl), N(1-8C alkyl)2 (n which the alkyl gps. are opt. different), NH-acyl or N-acyl-(1-8C alkyl).

Description

105913

Process for the Preparation of Pharmaceutically Valid Benzomorphans Benzo Morphaner Förfarande för framställning av farmaceutiskt

The invention relates to a process for the preparation of new benzomorphans. The benzomorphans of the invention are those of general formula I: wherein: R 1 is -NH-CH-C-X - R 2 / R 4 1n m 10 R 7 wherein X is oxygen or sulfur; R 1 is C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkyl, an aromatic group having 15 to 10 carbon atoms, also in combination, which aromatic group may be substituted by one or more of lower alkyl, alkoxy, nitro, amino, halogen, wherein the substituents may be the same or different; R 2 is hydrogen, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, an aromatic group having 6 to 10 carbon atoms, also in combination, which aromatic group may be substituted by one or more of lower alkyl, alkoxy, nitro, amino, halogen, wherein the substituents may be the same or different, an alkylene chain-linked aryl group having 7-14 carbon atoms, which aroma may be substituted by one or more of the following: lower alkyl, alkoxy, nitro, amino, halogen, which substituents may be the same or different; R 3 is hydrogen, C 1 -C 6 alkyl; R 4 is C 1 -C 6 alkyl; r 'R 5 is C 1 -C 6 alkyl; R 6 is C 1 -C 6 alkyl, an aromatic group having 6 to 10 carbon atoms, also in combination, which aromatic group may be substituted by one or more of lower alkyl, alkoxy, nitro, amino, halogen, the substituents may be the same or different; 2 105913 R 7 and R 8 are independently hydrogen, C 1 -C 6 alkyl, halogen, -OH, C 1 -C 8 alkoxy, O-benzoyl or O-alkylcarbonyl, the alkyl group of which may be straight or branched lower alkyl of 1 to 6 carbon atoms and which alkyl group may be substituted by one or more halogen atoms, which may be the same or different, -CN, -NO 2, NH 2, -NH (C 1 -C 6 alkyl), -C 1-6 alkyl) 2, wherein the alkyl groups may be identical or different, -NH-acyl or -N-acyl-(C1-C8-alkyl), wherein the acyl is a benzoyl or alkylcarbonyl group, the alkyl group of which may be straight or branched lower alkyl of 1 to 6 carbon atoms and the alkyl group may be substituted with one or more 10 halogen atoms, which may be the same or different, as well as their stereoisomers and acid addition salts, provided that when X is oxygen R 1 is C 1 -C 3 alkyl, C 3 alkenyl, C 3 alkynyl; R 2 is hydrogen, C 1 -C 4 alkyl, C 3 and C 4 alkenyl; R 3 is hydrogen, C 1 -C 3 alkyl; R 4 is methyl; R5 is methyl; R 6 is C 1 -C 4 alkyl or phenyl, and one of the substituents R 7 and R 8 is hydrogen, so the remaining substituent R 7 or R 8 at the 2-position is not hydrogen, hydroxy, C 1 -C 3 alkoxy or o-acyl.

«

Preferred are compounds of general formula I wherein X is oxygen, 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 -C 4 alkyl; R 4 is methyl, ethyl, propyl, isopropyl; R5 is methyl, ethyl, propyl, isopropyl; R 6 is methyl, ethyl, propyl, isopropyl, phenyl; R 7 is fluoro, chloro, hydroxy, lower alkyl, lower alkoxy, acyloxy; R 8 is hydrogen, lower alkyl, hydroxy or alkoxy.

105913 3

Particularly preferred are compounds of general formula I wherein X is oxygen; 'R 1 is methyl, ethyl; R 2 is methyl, ethyl; R3 is hydrogen; R 4 is methyl, ethyl; R5 is methyl, ethyl; R 6 is methyl, ethyl; R 7 is hydroxy, methyl, methoxy, acyloxy; R8 is hydrogen, methyl, ethyl, hydroxy or lower alkoxy.

Particularly preferred are compounds of general formula I wherein X is oxygen; R 1 is methyl; R2 is methyl; R 3 is hydrogen; R 4 is methyl; R5 is methyl; R 6 is methyl; R7 is hydroxy, methyl, methoxy, acetoxy; R 8 is hydrogen, methyl, hydroxy, methoxy or ethoxy, with the substituents R 7 and R 8 at the 2 'and 3' positions, and the 2 "carbon atom having the R configuration.

25 / Ri

2 "/, rN - CH - C - X - R

J XR3 '* / äo y = * Rt r7 /

The definition of the compounds of the formula I to be prepared according to the present invention also includes the individual isomers, mixtures thereof as well as the corresponding physiologically acceptable acid addition salts with inorganic or organic acids. For example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, malonic acid, maleic acid, fumaric acid, fumaric acid, are preferred.

Unless stated otherwise in individual cases, the general definitions used are as follows: (C 1 -C 8 alkyl or C 1 -C 8 alkyl is a branched or unbranched hydrocarbon group having from 1 to 6 or 8 carbon atoms. Examples include the following hydrocarbon groups: methyl, ethyl, propyl, -methylethyl (isopropyl), butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methyl-butyl, 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-trimethylpropyl, 1- ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl groups wherein n 1-3 carbon atoms such as methyl, ethyl, propyl, isopropyl.

t

Alkenyl is a straight-chain or branched hydrocarbon group having from 3 to 6 carbon atoms and 1 or more, preferably 1 double bond. 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, 5-hexenyl, 1-methyl-2-pentenyl , 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenes 105913yl, 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-di-5-methyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-bu tenyl), 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, -ethyl 1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl.

An allyl group is preferred.

Alkynyl is a straight or branched hydrocarbon group having from 3 to 6 carbon atoms and having 1 or more triple bonds. A lower alkynyl group (propargyl) having 3 carbon atoms and one triple bond is preferred.

15

Acyl is generally a benzoyl or alkylcarbonyl group, such as a straight or branched lower alkyl having from 1 to about 6 carbon atoms attached to a carbonyl group, the alkyl group being optionally substituted by 1 or more halogen atoms, which may be the same or different. Preferred are alkyl groups having up to 4 carbon atoms. Examples include: acetyl, trifluoroacetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, as well as isobutylcarbonyl. Particularly preferred is the acetyl group.

Acyloxy is an oxygen-attached acyl group, whereby acyl has the meaning given above.

*. Aryl is an aromatic group having 6 to 10 carbon atoms - also in compositions wherein the aromatic may be substituted with 1 or more lower alkyl groups, 30 alkoxy groups, nitro groups, amino groups and / or 1 or more halogen atoms - the same or different. A preferred aryl group is phenyl.

6, 105913

Aralkyl is an alkylene chain-linked aryl group having 7 to 14 carbon atoms, wherein the aromatic may be substituted with 1 or more lower alkyl groups, alkoxy groups, nitro groups, amino groups and / or 1 or more halogen atoms - the same or different. Aralkyl groups having 5 to 1 carbon atoms in the aliphatic moiety and 6 carbon atoms in the aromatic moiety are preferred. Unless otherwise stated, benzyl, phenethyl and phenylpropyl are preferred aralkyl groups.

Alkoxy is a straight or branched hydrocarbon group having from 1 to 8 carbon atoms attached to an oxygen atom. A lower alkoxy group having 1 to 3 carbon atoms is preferred. Especially preferred is the methoxy group.

Amino is, unless otherwise stated, a NH 2 function which may be optionally substituted with 1 or 2 C 1 -C 6 alkyl, aryl or aralkyl groups which are the same or different.

Alkylamino is, for example, methylamino, ethylamino, propylamino, 1-methyl-ethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino.

20

For example, dialkylamino is dimethylamino, diethylamino, dipropylamino, dibutylamino, di- (1-methylethyl) amino, di- (1-methylpropyl) amino, di-2-methylpropylamino, ethylmethylamino, methylpropylamino.

Halogen is, unless otherwise stated, primarily fluorine, chlorine and bromine, and secondarily iodine.

1. Pharmacological Characterization It is known that neurons are destroyed in the brain of mice following systemic administration of glutamate [S.M. Rothman and T.W. Olney, Trends in Neurosciences 10: 299 (1987)]. From this result, it can be concluded, inter alia, that * 7 105913 glutamate is important in neurodegenerative diseases [R. Schwarcz and B. Meldrum, The Lancet 11, 140 (1985)].

In addition, agents such as quisqualic acid (Quisqualinsäure), Kainic acid-5 po, ibotenic acid, glutamic acid and N-methyl-D-aspartic acid (NMDA) are known as exogenous or endogenous neurotoxins. In terms of neurotoxicity, these agents selectively affect individual cell types such that animals can be induced to deactivate by specific brain damage. These are comparable to those associated with epilepsy and other neurodegenerative diseases such as Huntington's Dance and Alzheimer's.

In addition, in vivo and in vitro experiments have shown that cellular damage and loss of function in the brain as a result of hypoglycemia, oxygen deficiency, oxygen deficiency and anemia are partly due to increased synaptic activity, with glutamatergic synapse playing a special role. Substances and ions that inhibit the activity of the glutamate receptor and the ion channel associated with this receptor, such as competitive and non-competitive antagonists of excitatory amino acids as well as magnesium ions (Mg2 *), protect brain cells from damage by oxygen deficiency or anemia. These results indicate that the glutamate receptor plays an important role in mediating hypertension.

Biochemical and electrophysiological studies teach that the receptor-ion channel is highly sensitive to variations in magnesium concentration. As the magnesium concentration decreases, spontaneous epileptic ruptures occur in the cerebellum, which can be prevented by antagonizing excitatory amino acids.

•

It has now surprisingly been discovered that benzomor 30 fans of general formula I block the NMDA channel and have a neuroprotective effect.

105913 8 The preparation of such benzomorphan derivatives is known from F1 patents 67372, 68227 and 68228, DE patent application 2105743 and DE application 2828039, as well as from the literature [H. Merz and K. Stockhaus, J. Med. Chem. 22: 1475 (1979). It is also known that compounds of this type have analgesic and morphine antagonistic activity and can be used therapeutically as non-anesthetic analgesics and as cough medications (DE-A-2105743).

As a test system for detecting the NMDA-antagonistic activity of benzomorphan derivatives, the brainstem is used. Schäffer collaterals of the cerebellar cortex in the perfusion chamber are stimulated with microelectrodes, and the summed potentials generated are delivered extracellularly to CA1 pyramidal cells [H. L. Haas, B. Schaerer, and M. Vosmansky, J. Neuroscience Meth. 1, 323 (1979)].

15

In addition, the neuroprotective effect of the benzomorphan derivatives of general formula I was demonstrated also taking into account protein synthesis and neurotransmitter release in the cerebellar section.

Receptor binding assays further demonstrate that the reported benzomorphan derivatives are non-competitive glutamate receptor antagonists.

Further, the neuroprotective effect of the benzomorphan derivatives of general formula I was demonstrated in mice by inhibiting N-methyl-D-aspartic acid-induced lethality in vivo [J.D. Leander et al., Brain Research 448 (1988) 115] and preventing nerve death from hypertension in the mouse and the desert hippopotamus (Gerbil).

These results demonstrate that the benzomorphan derivative of general formula I can be used in neurodegenerative diseases as well as in cerebral hypertension. This includes, for example: epilepsy, hypoglycemia, hypoxia, anoxia, brain injury, brain; edema, amyotrophic lateral sclerosis, Huntington's Korea, Alzheimer's »9. 105913 rhin disease, hypertension, myocardial infarction, stroke and postnatal oxygen deficiency.

2. Formulation 5

Benzomorphan derivatives of the general formula I as well as their acid addition salts with pharmacologically acceptable acids can be formulated in known manner into standard formulations such as tablets, granules, pills, granules, sprays, syrups, emulsions, suspensions and solutions using inert pharmaceutically acceptable media. In this case, the proportion of the pharmaceutically active compound (s) must in each case be in the range of 0.5 to 90% by weight of the total composition, i.e. in amounts sufficient to achieve the stated dosage range.

Formulations are prepared, for example, by diluting the active compounds with solvents and / or vehicles, optionally using emulsifiers and / or dispersing agents, for example, when using water as a diluent, it may be possible to use organic solvents as a vehicle or cosolvent.

Examples of adjuvants include water, pharmaceutically acceptable organic solvents such as paraffin (e.g. petroleum fractions), vegetable oils (e.g. peanut or sesame oil), mono- or poly-functional

V

alcohols (e.g. ethanol or glycerin), media such as natural stone powders (e.g. kaolins, alumina, talc, chalk), synthetic stone powders (e.g., highly dispersed silica and silicates), sugar (e.g., cane, milk, and grape sugar) , emulsifiers (e.g., lignin, sulfite waste, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

30

Administration is carried out in the usual manner, especially parenterally, especially by infusion, intravenously. In the case of oral use, the tablets may, of course, contain, in addition to the said media, additives such as sodium citrate, calcium and dicalcium phosphate, together with various excipients such as starch, in particular potato starch, gelatin and the like.

Further, a lubricant such as magnesium stearate, sodium lauryl sulfate and talc may be used for tabletting purposes. In the case of aqueous suspensions, the active ingredients may additionally be mixed with the aforementioned excipients and various flavoring and coloring agents.

In the case of parenteral administration, solutions of the active ingredients may be added using suitable liquid carrier materials.

10

The dosage for oral administration is 1 to 300 mg, particularly between 5 and 150 mg.

Nevertheless, it may be necessary to deviate from these amounts, and depending on body weight or type of route of administration, individual attitudes to the drug, the type of formulation and the time or interval at which the administration occurs. Thus, in some cases, a lower amount than the above-mentioned minimum may be sufficient, while in other cases it will be necessary to exceed this ceiling. For larger amounts, it may be advisable to divide this into several single doses over the course of the day.

In addition, the compounds of general formula I or their acid addition salts can also be combined with other types of active ingredients.

25 Formulation Examples

Tablets *% • 1. The tablet contains the following ingredients: 30 active ingredients of formula I 0.020 parts stearic acid 0.010 parts dextrose 1.890 parts; 1,920 parts of “105913

Preparation * The substances are mixed in a known manner and the mixture is compressed into tablets each weighing 1.92 g and containing 20 mg of the active ingredient.

5

Ampoule solution

Composition The active ingredient of the formula I is 1.0 mg of sodium chloride 45.0 mg

Water for injections to 5.0 ml

Preparation: The active ingredient is dissolved in water at a specific pH or possibly pH 5.5 to 6.5 and is made isotonic with sodium chloride. The resulting solution is pyrogen-free filtered and the filtrate is filled under aseptic conditions into ampoules, which are then sterilized and thawed. The ampoules contain 1 mg, 5 mg and 10 mg of active ingredient.

20

suppositories

Each drum contains: Active ingredient of formula I 1.0 part 25 cocoa butter (m.p. 36-37 ° C) 1200.0 parts carnauba wax 5.0 parts · Preparation 30 Cocoa butter and carnauba wax are melted together. The active ingredient is added at 45 ° C and mixed until a complete dispersion is formed. The mixture is poured into a mold of a similar size and packed appropriately.

3. Synthesis Method 12 105913

The preparation of benzo-morphane derivatives of type 2 which serve as starting materials for various synthetic processes is either known in the art [DE-A-570777, CA 74, 125482x (1971); European Patent Publication B4960, CA 93: 4941-480 (1980)] or described in the following examples.

oh J! R1 p2 R1 "N pN-CH2-yLx / R2

1 ° Rio - AV

O r3 ^ = / ^ r6 RJX = y (4) R3 y / Reducers 15 ΓΝ-Η \ ΓΗ Rl »2 I R- X ΓΝςΗ! ^ · Χ-Κ R \ X == J ^ R6 (2) R '. The substituents R 9 and R 10 are then either identical to the desired substituents R 7 and R 8, or are converted to these at a later stage of the synthesis.

The addition of the desired substituent to the amino function of the benzomorphan nitrogen may be accomplished by acylation with a suitably activated carboxylic acid derivative. The corresponding type 4 carboxylic acid derivatives are known in the art or can be readily obtained by a rapid synthesis process.

In turn, a large number of methods are available for acylation itself [C. Ferri, Reactionen der organizchen Synthese, Georg Thieme Verlag Stuttgart, 1978, p. 222 ff. and the literature cited therein; J. March, Advanced Organic Chemistry, 3rd Edition, John Wiley and Sons, New York 1985, p. 370 ff and references cited therein, 3 105913; R.C. Larock, Comprehensive Organic Transformations A Guide to Functional Group Preparations, VCH Verlagsgesellschaft, D-6940 Weinheim 1989, pp. 963 ff. and the literature cited therein, whereby reactions with carboxylic acid halides [A.L.J. Beckwith in J. Zabicki, 'The Chemistry of 5 Amides', Interscience, New York 1970, p. 73], under the reaction conditions under substantially inert solvents, in the presence of possible acid-binding reagents, organic solvents are generally used which do not change. under reaction conditions such as hydrocarbons such as benzene, toluene, xylene or petroleum fractions or ether - such as diethyl ether, glycol dimethyl ether (glymi), diglycol dimethyl ether - or cyclic ethers such as tetrahydrofuran or dioxan , chloroform or dichloromethane.

The preparation of the desired carboxylic acid halides is known in the art (Houben-Weyl, Methoden derorganchen Chemie, Volume V and Volume E5, Georg Thieme Verlag, Stuttgart, 1952 or 1985) unless otherwise commercially available. Suitably, the benzomorphan derivative of type 2 is then reacted preferably with halogenated hydrocarbons 20 - particularly preferably dichloromethane - and tertiary amines such as triethylamine in the desired acid halide, particularly preferably the desired acid chloride. However, it is also possible to carry out the reaction in water or aqueous alcohol in the presence of alkali hydroxides or alkaline carbonates - according to the so-called Schotten-Baumann variant [see, e.g., Organikum, Autorenkollektiv, VEB Deutscher Verlag der Wissenschaften, 17th ed., Berlin 1988, p. 407]. Depending on the precursors used, it may be more particularly advantageous to carry out the acylation with the ·· Einhorn variant using pyridine as well as the acid-binding agent as well as the reaction medium.

In addition, there is the possibility of carrying out the acylation reaction with the respective free carboxylic acid [see, e.g., A.L.J. Beckwith in J. Zabicki, The Chemistry of Amides, Interscience, New York 1970, p. 105 ff .; 30 105913 14 JA Mitchell and EE Reid, J. Am. Chem. Soc. 53 (1931) 1879]. it may be convenient to use mixed anhydride instead of the free carboxylic acid - for example with carbonic ester (C. Ferri, J. Thrisse Verlag, Georg Thieme Verlag, 1978, p. 222 and 5); of Amides, Interscience, New York 1970, p. 86; J. March, Advanced Organic Chemistry, 3rd Edition, John Wiley and Sons, New York 1985, p. 371 and the literature cited therein; R.C. Larock, Comprehensive Organic Transformations, VCH Publishers, D-6940 Weinheim 1989, p. 981 and the glory referred thereto], 10

In a preferred acylation with carboxylic acid halides, particularly carboxylic acid chlorides, the reaction temperature may vary within wide limits, limited to too slow reaction rates down and overcoming of unwanted side reactions. Reaction temperatures in the range -50 to 150 ° C, preferably 0 to 75 ° C, have proven to be good. In this case, a slight excess of the acylating reagent in the presence of a slightly larger excess of the acid-binding agent is conveniently employed to effect complete reaction of the promoters.

20 3.1b

Reduction of the acid amide 3 is required in the next reaction step to obtain the desired amine of type 6.

Such acid amide reductions are known in the art and can be accomplished by electrolytic reduction, alkali metal reduction, as well as catalytic reduction [R. Schröter in Houben-Weyl, Methden der Organchen Chemie, Volume XI / 1, Georg Thieme Verlag, Stuttgart 1957,. 574] or diborane or boron hydrogen derivatives [J. Fuhrhop and G. Penzlin, acting as Agents,

Organic Synthesis Concepts Methods for Starting Materials, VCH-Verlagsgesell-30 Schaft, Weinheim 1986, p. 90].

Preferably, the reduction is carried out with complex hydrides, such as alkali boron or alkaline aluminum hydrides or their appropriate derivatives - optionally in the presence of 1S 105913 catalyst [N.G. Gaylord, Reduction with Complex Metal Hydrides, Wiley New York 1965; A. Häjos, Complex Hydrides, Elsevier New * York 1979; V. Bazant, M. Capka, M. Cerny, V. Chvalovsky, K. Kochloefl, M.

Kraus and J. Malek, Tetrahedron Lett. 9, 3303 (1968)], with lithium aluminum hydride being particularly preferred.

The reaction media are all inert organic solvents which do not change under the reaction conditions. These preferably include an ether such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, di-n-butyl ether, glycol dimethyl ether (glyme), diglycol dimethyl ether (diglyme), cyclic ethers such as, for example, dioxane, wherein the choice of solvent is carried out e.g. the type of reducing agent used.

In such cases, it is usually advantageous to allow such reactions to proceed in the presence of an excess of the reducing reagent, which is concretized in particular in the complex hydrides mentioned above, in particular in the range of 5-100% lithium aluminate, particularly in the range of 10-50%.

20

The reaction partners are usually added together under ice-cooling or at room temperature, and subsequently heated to reactivity of the prodrugs to temperatures of from 150 ° C to 75 ° C, in particular.

25 3.2

A further possibility for the preparation of benzomorphane derivatives of type 6 consists in the reaction of the benzomorphan derivative 2 with suitable type 5 alkylation reagents wherein in the formula 5 Z is a leaving group of the alkylation group. Preferred leaving groups are halogen such as Cl, Br, I, or O-SO 2 aryl such as tosylate or alkylsulfonate O-SO 2 alkyl such as methanesulfonate or halomethanesulfonate or sulfate. Corresponding alkylation reagents are either commercially available or are well known in the art.

16 105913

Suitable solvents are all inert solvents which do not substantially change under the prevailing reaction conditions and which cannot themselves adversely affect the reaction mixture as reactive components. These preferably include, for example, alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, di-n-butyl ether, tert-butyl methyl ether, glycol dimethyl ether (glymi), diethylene glycol dimethyl ether, diglyme, ketones such as methyl ethyl ketone or acetone or acid amides such as hexane-methyl-phosphoric acid triamide or dimethylformamide.

10

Furthermore, it is possible to use mixtures of said solvents. Tetrahydrofuran or dimethylformamide or mixtures of both solvents are particularly preferred. In particular, the reaction is carried out in the presence of acid-binding reagents such as alkali or alkaline earth carbonates or hydrogen carbonates.

The reaction temperature can be varied in reaction performance over a wide range, from low reaction rates too low for practical execution and upward gains in unwanted side reactions. Suitable reaction-temperatures are in the range of 0 ° C to 150 ° C and preferably between 50 ° C and 100 ° C.

3.3

The possible conversion of R9 and / or R10 to R7 or R8 involves a number of different types of reactions which cannot be summarized below. Such conversion reactions are illustrated by the corresponding examples.

• 4. Examples 30 Note: Ether means - unless otherwise stated - diethyl ether. The preparation of the title compounds of Examples 1-15, 28, 29, 38-42, 4, 50, 63, 64, 73-84 and 115-118 is not within the scope of the present invention.

105913 17 4.1 Compounds Type (1) - Prepared by Method 3.1 4.1.1 Example 1 5 M-nR.SS ^ - ^ - - Hydroxy -? - methoxypropyl-SQQ-trimethyl-eZ-benzomorphane hydrochloride a) Acylation 10 27, To 8 g (0.12 mol) of (±) -2,5-hydroxy-519,9-trimethyl-6,7-benzomorphane [DOS 20 27 077; CA74, 125482x (1971)] is added in 278 ml of absolute dichloromethane in the presence of 27.9 g (0.275 mol) of triethylamine over a period of about 30 minutes, 19.2 g (0.156 mol) of (R) -2-methoxypropionic acid chloride. The reaction temperature is then maintained between 30 and 35 ° C. It is then boiled under reflux for one hour. It is then cooled and washed successively with 175 ml of water, 175 ml of 2N hydrochloric acid and a further 2x175 ml of water. After drying over sodium sulfate and after filtering off the solid, the solution is evaporated in vacuo, finally at 80 ° C and under a full water jet vacuum. An acylation product of type (3) is obtained as an evaporation residue in a yield of 42.3 g (about 100% of theory-20).

b) Reduction n

The acylation product prepared by the above procedure is dissolved in 425 ml of 25 absolute tetrahydrofuran. The solution is added dropwise with stirring and ice-cooling over a period of 1 hour to 10-15 ° C, to a suspension of 9.1 g (0.24 mol) of lithium aluminum hydride (lithium tetrahydridealanoate) in 300 ml of tetrahydrofur. raania. The reaction mixture is then refluxed for two hours with stirring. Then, while cooling in an ice bath and stirring, 30 25 ml of water are added dropwise and finally 70 ml of water and after addition of saturated diammonium tartrate solution (890 ml) are shaken in a separatory funnel. The separated tetrahydrofuran phase is evaporated in vacuo and the aqueous phase is extracted with 3 x 175 ml of dichloromethane. The evaporation residue of the tetrahydrofuran phase is dissolved in dichloromethane extract and the solution is washed twice with 100 ml of water. After drying over sodium sulfate and after filtering off the solid, the solution is evaporated, finally at 80 ° C and under a full water jet vacuum. A residue (37 g, about 100% of theory) is obtained which is a mixture of the two desired diastereomeric compounds. In a thin-layer chromatogram (DC), these diasteroemers show an Rf of 0.42 or 0.51 (silica gel 60, chloroform-methanol-conc. Ammonia 95: 5: 0.1).

The diastereomers can be separated by crystallization with hydrochloride. The 10 base mixture is then dissolved in 120 ml of absolute ethanol and acidified with hydrochloric acid (12 ml of 32% hydrochloric acid). The title compound crystallizes immediately (Rf = 0.42), which after suction cooling, is filtered off with suction, washed portionwise with ice-cold ethanol (40 ml) and finally dried at 80 ° C to constant weight. The yield is 15.0 g (73.5% of the theoretical maximum yield). The material melts at 264 ° C with decomposition and has a specific rotation [? 0d5 = -116.9 ° (c = 1, CH3OH)]. The recrystallized sample from a mixture of methanol and diethyl ether melts unchanged at 264 ° C (dec) and has a specific rotation value of [α] 25 D = -118.6 ° (c = 1, CH 3 OH).

4.1.2 Example 2 (+ 1- (1S, 5R, 2R) -2'-Hydroxy-2- (2-methoxypropyl) -5.9.9-thymyl-6.7-benzomorphane hydrochloride The mother liquor obtained in the method of Example 1). mainly contains the diastereomer of Rf 0.51, evaporate to dryness and heat the residue (25 g) with 40 ml of isopropanol with stirring at reflux for 1 hour, leave the crystal suspension thus formed to stand for about 12 hours at room temperature, then separate by suction and wash with a small amount of 30 cold isopropanol in portions. The crystals consist mainly of the title compound and additionally residues of the diastereomer (Example 1) .The title compound is converted into the free base form and purified by column chromatography. Additionally, the crystals are shaken with water (75 mL) of ammonia (6 ml, 25%), and after phase separation, the aqueous layer is extracted once more with 25 ml of dichloromethane. The dichloromethane extracts are washed with 2 x 25 ml water, then dried over sodium sulfate, after filtration of the solid, evaporated, finally at 80 ° C and under a full water jet vacuum. The residue (15.4 g) is purified by column chromatography over 2 kg of silica gel (MN K 60, 230-400 mesh ASTM, Macherey and Nagel) using dichloromethane-methanol concentrate. ammonia 95: 5: 0.1 as eluent. Fractions of pure material after evaporation give a residue (6.8 g) consisting of the base of the title compound.

The residue is dissolved in 14 ml of absolute ethanol and the solution is acidified with 10 ml of 2.5 N ethanolic hydrochloric acid. After addition of diethyl ether until uniform turbidity begins, the title compound crystallizes. After about 12 hours in the refrigerator, suction is removed and washed first with methanol-ether 1: 2, then with ether. After drying, finally at 80 ° C, 6.4 g of the title compound (31.4% of theory) are obtained, having a melting point of 236 ° C (dec.) And a specific rotation value of [α] 25 D = + 88.0 ° (c = 1, CH 3 OH).

4.1.3 Example 3 f + W 1 S 5 R 2. 2S-2,1-Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride From 9.25 g (0.040 mol). ) (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 6.37 g (0.052 mol) of (S) -2-methoxypropionic acid chloride is obtained as in Example 1 in 5 yield. , 1 g (75.0% of theory) with an Rf of 0.42, a melting point of 270 [deg.] C. (dec.) And a specific rotation value of [.alpha.] D @ 20 = + 117 DEG (c = 1, CH3OH).

Example 4 (-V (1R, 5S, 2S) -2, -Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-e.7-benzomorphane hydrochloride. from the mother liquor, the title compound is obtained as in Example 2 in a yield of 3.2 g (47.1% of theory) having a melting point of 235 ° C (dec) and a specific rotation value of [α] 20 = -89.9 ° (c = 1, CH 3 OH).

4.1.5 Example 5 (-V (1R, 5S, 2'R) -2, -Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride If racemic in place of the starting compound, 2.31 g (0.010 mol) of enantiomerically pure (- ^ '- hydroxy-S, 3'-trimethyl-β-benzomorphan) are reacted with 1.60 g (0.013 mol) of (R) -2-methoxypropionic acid chloride, an almost sterically pure base of the title compound is obtained in place of a mixture of diastereomeric base and hydrochloride 20 in a yield of 3.0 g (88.4% of theory) having a melting point of 264 ° C (dec) and a specific rotation value of [α] = -117.5 ° (c = 1, CH 3 OH).

4.1.6 Example 6 25 (-VMR.5S.2 ', SV2, -Hydroxy-2 - (, 2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride • If the synthesis described in Example 5 is performed (S) -2-methoxypropionic acid to give the title compound in a yield of 2.9 g (85.3% of theory) having a melting point of 235 ° C (dec) and a specific rotation value of [α] D = -89.7 ° (c = 1, CH 3 OH).

9 21 105913 4.1.7 Example 7 (-) - (1R) -S - (-) - - - - - - - - - - - - - - - - hydroxy-4-t-methoxypropyl-SQQ-trimethyl-6-benzo-morphane hydrochloride. ) (-) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 3.20 g (0.026 mol) of (R / S) -2-methoxypropionic acid chloride are obtained as described in Example 1. a mixture of diastereomeric bases which is separated by column chromatography as in Example 2. Slow fluid 10 (Rf = 0.42) is crystallized as described above as the hydrochloride to give the title compound in a yield of 2.1 g (61.8% of theory), m.p. 264 ° C (dec.) And the specific rotation value is [α] D = -117.9 ° (c = 1, CH 3 OH).

4.1.8 Example 8 (-) - (1R, 2S, 2S) -2, -Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride Starting from the separation in Example 7, after conversion to a liquid (Rf = 0.51), the title compound is obtained after conversion to the hydrochloride as in Example 2 in a yield of 2.2 g (64.7% of theory) with a melting point of 23 [deg.] C. (dec.) and [α] 25 = -88.6 ° (c = 1, CH 3 OH).

4.1.9 Example 9 25 (+) - (1S, 5R, 2S) -2'-Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride 2.60 g. 0.025 mol) of (S) -2-methoxypropionic acid chloride is stirred in 100 ml of 30 absolute tetrahydrofuran with 4.04 g (0.025 mol) of 1,1'-carbonyl di-imidazole for two hours at room temperature 4.62 g (0.020 mol) ( After addition of +) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane, stirring is continued for two days, then evaporated to dryness, the residue is then dissolved in 22 105913 75 ml of dichloromethane and washed successively with 2 N HCl and twice with water After separation the organic phase is dried over sodium sulphate and after filtration of the solid, evaporated in vacuo, finally at 80 ° C and in a full water jet vacuum. in Example 2 The title compound is obtained in a yield of 6.9 g (81.3% of theory) with a melting point of 264 ° C (dec) and a specific rotation of [α] D = + 117.4 ° (c = 1, CH 3 OH). .

4.1.10 Example 10 (-W1R5S.2 "R1-9.9-Dimethyl-5-ethyl-2,1-hydroxy-2-f2-methoxypropyl) -6.7-benzomorphane hydrochloride From 1.69 g (0.006 mol) ) (+) - 9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphane hydrochloride [DOS 20 27 077; CA74: 125482x (1971)], from 1.82 g (0.018 mol) ) triethylamine and 0.96 g (0.0078 mol) of (R) -2-methoxypropionic acid chloride are obtained as a mixture of the desired diastereomeric bases (1.7 g) in Example 1, which are separated as in Example 2 by column chromatography. the liquid (0.6 g, Rf = 0.40) is crystallized as the hydrochloride as in Example 2. This gives the title compound in a yield of 0.6 g (56.6% of theory) having a melting point of 275 [deg.] C. (dec.) and [ [α] D = -100.5 ° (c = 1, CH 3 OH).

4.1.11 Example 11 f + VMS.5R.2 "R 9, 9 -Dimethyl-5-ethyl-2, -hydroxy-2- (2-methoxypropyl) -6.7- · 'benzomorphane hydrochloride In Example 10, separated by column chromatography the flowable diastereomer (0.7 g, Rf = 0.45) is crystallized as the hydrochloride as in Example 2. The title compound is obtained in a yield of 0.23 g (21.7% of theory) with a melting point of 216 ° C (dec.). and the specific rotation value is [α] D 25 = + 62.4 ° (c = 1, CH 3 OH).

23 105913 4.1.12 Example 12 5 (+ H 1 S 5 R 2. 5 S-9.9-Dimethyl-5-ethyl-2'-hydroxy-2- (2-methoxypropyl-1.6-benzomorphane hydrochloride) Starting from 1.69 g ( 0.006 mol) of (±) -9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphane hydrochloride, 1.82 g (0.018 mol) of triethylamine and 0.96 g (0). (0078 mol) of (S) -2-methoxypropionic acid chloride is obtained as a mixture of the desired diastereomeric bases (1.7 g) in Example 1, which - as in Example 10 - is separated by column chromatography Slow fluid (0.6 g, Rf = 0) , 40) is crystallized as the hydrochloride as in Example 2. The title compound is obtained in a yield of 0.6 g (56.6% of theory) having a melting point of 275 ° C (dec) and a specific rotation value of [α] 25 = + 102.5 ° (c). = 1, CH 3 OH).

4.1.13 Example 13 M-MR.5S.2 "S1-9.9-Dimethyl-5-ethyl-2'-hydroxy-2- (2-methoxypropyl) -6.7-benzomorphane hydrochloride 20 According to Example 12, a faster-running diastereomer separated by column chromatography. (0.6 g, Rf = 0.45) is crystallized as the hydrochloride as in Example 2. The title compound is obtained in a yield of 0.65 g (61.2% of theory) having a melting point of 219 ° C (dec.) And a specific rotation of [αβ5]. = -67.6 ° (c = 1, CH 3 OH).

4.1.14 Example 14 (-1-9.9-Dimethyl-2'-hydroxy-2 - ((R1-2-methoxypropyl) -5-phenyl-6.7-benzomorphane) From 1.76 g (6 mmol) ) (+) - 9,9-dimethyl-2'-hydroxy-5-phenyl-6,7-benzomorphane (EP-B-4960; CA 93.4941f (1980)) and 0.96 g ( 7.8 mmol) of (R) -2- * methoxypropionic acid chloride is obtained as a mixture of the desired diastereoisomeric bases (2.1 g) in Example 1 (2.1 g) with Rf values of 0.50 and 0.55 (compare Example 2). as in Example 2 in the form of the hydrochloride (2.4 g) and further converted to the corresponding free base (evaporation residue 1.8 g) This base residue is recrystallized from 6 ml of acetic acid 5-ethyl ester and 18 ml of petroleum ether (80 ° C). Thereafter, the title compound is obtained in a yield of 0.72 g (65.5% of theory), having a melting point of 202 ° C, a Rf value of 0.50 and a specific rotation value of [α] 25 D = -24.4 ° (c = 1, CH 3 OH).

4.1.15 Example 15 10 (+ 9, 9-Dimethyl-2, -hydroxy-2- (N, R-2-methoxypropwin-5-phenyl-6.7-benzomorphane hydrochloride)

According to Example 13, the mother liquor obtained by crystallization (acetic ester / petroleum ether) 15 is evaporated to dryness. The residue (1.2 g) is dissolved in 5 ml of ethanol and the solution is acidified with 2.5 N ethanolic hydrochloric acid. After addition of diethyl ether, the hydrochloride (0.4 g) crystallizes as a crude product from clear turbidity. The mother liquor contains the pure title compound which, after evaporation, is isolated as a residue: Yield 0.75 g (62.0% of theory), melting point 208 ° C (dec), Rf = 0.55 Specific rotation value [α] 25 D = + 11.6 ° (c = 1, CH 3 OH).

4.1.16 Example 16 * (-H1R5S.2 "R) -3'-Hydroxy-2- (2-methoxypropyl-5.9.9-trimethyl-6.7-benzo-25-morphane hydrochloride a) Starting compound ±) -3'-hydroxy-5,9,9-trimethyl-6,7-30 benzomorphan is not yet known in the art, for example it can be prepared for the known 2'-hydroxy isomer [DOS 20 27 077, CA 74 ( 1971), 125482x] using m-methoxybenzyl-lithium instead of p-methoxybenzyl-lithium. - The mixture of 'hydroxy and 3'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan is separated by flash column chromatography on 100 times silica gel (MN K 60, 230-400 5 mesh ASTM, Macherey and Nagel). acetic acid ethyl ester-methanol-concentrated ammonia 80: 20: 5 as eluent. Subsequently, (+) - 1'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (R f = 0.20) and (±) -3'-hydroxy-5,9,9-trimethyl- are obtained. 6,7-Benzomorphane (R f = 0.14) in a 1: 2 ratio in the form of a viscous oil (R: DC, silica gel 60, using the above eluent).

10 b) Reaction to the title compound From 2.31 g (0.010 mol) of (+) - 3'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 1.6 g (0.013 mol) ) (R) -2-Methoxypropionic acid chloride is obtained as in Example 1 from a mixture of the desired diasteromeric bases which are separated by column chromatography on 100 times silica gel as in Example 2. The slower fluid (Rf = 0.65) - as described above - crystallizes as the hydrochloride. The title compound is obtained in a yield of 0.86 g (50.6%) having a melting point of 240-242 ° C (dec) and a specific rotation value of [α] 25 D = -90.9 ° C (c = 1, CH 3 OH).

4.1.17 Example 17 (+) - (1S, 5R, 2R) -3'-Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzo-25-morphane hydrochloride

In Example 16, the isolated, faster-flowing material (Rf = 0.74) is crystallized as in Example 2 as the hydrochloride. The title compound is obtained in a yield of 1.28 g (75.3% of theory) having a melting point of 250-251 ° C and a specific rotation value of 30 [α] 25 = +57.10 (c = 1, CH 3 OH).

4.1.18 Example 18 26 105913 (+ W 1 S 5 R 2,1S) -3 11 -Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride 5 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 (S) -2-methoxypropionic acid chloride is obtained as a mixture of the desired diastereomeric bases in Example 1, which is chromatographed - as in Example 2 - with 100 times the amount of silica gel. Slower fluid (Rf = 0.65) - as described above, is crystallized as the hydrochloride. The title compound is obtained in a yield of 0.57 g (33.4% of theory) having a melting point of 239-240 ° C (dec) and a specific rotation value of [α] D = + 90.7 ° (c = 1, CH 3 OH).

4.1.19 Example 19 M-MR.5S.2 "S) -3'-Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride 20 Rf = 0.74) is crystallized as the hydrochloride as in Example 2. The title compound is obtained in a yield of 0.67 g (39.2% of theory) having a melting point of 250-251 ° C (dec.) And a specific rotation value of [αβ5 = -56]. 5 ° (c = 1, CH 3 OH).

4.1.20 Example 20 (-V (1R, 5R, 2R) -1, -Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzo-1H-morphane hydrochloride From 2.31 g (0.010 mol) of (±) -1'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (see Example 16) and 1.60 g of (R) -2-methoxypropionic acid chloride is obtained as in Example 1 a mixture of the desired diastereomeric bases which are separated by 100 times on silica gel as in Example 2. Hi 105913 27 The further flowable material (R 1 = 0.52) is crystallized as in Example 2 to give the title compound in a yield of 0.70 g. 41.2% of theory) having a melting point of 128-135 ° C (dec) and a specific rotation value of [α] 25 D = -100.5 ° (c = 1, CH 3 OH).

4.1.21 Example 21 (+ H1S.5S.2 "RH'-Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride.

In Example 20, the isolated, faster-flowing material (Rf = 0.56) is crystallized as in Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.40 g (23.6% of theory) having a melting point of 88-89 ° C (dec) and a specific rotation value of [α] 25 = 50.4 ° (c = 1, CH 3 OH).

4.1.22 Example 22 (+ W 1 S, 5 S, 2 S 5 S) -1, -Hydroxy-2- (2-methoxypropyl-5.9.9-trimethyl-6.7-benzomorphane hydrochloride 20 Starting from 2.31 g (0.010 mol). (+) - 1'-hydroxy-5,9,9-methyl-6,7-benzomorphane (see Example 16) and 1.60 g (0.013 mol) of (S) -2-methoxypropionic acid.

'9 I

·· Acid chloride is obtained as a mixture of the desired diastereomeric bases in Example 1, which, as in Example 2, is separated by 100 times the amount of 25 g of silica gel. The slower fluid (Rf = 0.52) is crystallized as in Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.63 g (36.8% of theory) having a melting point of 85-90 ° C and a specific rotation value of [α] D = + 96.2 ° ·; (C = 1, CH 3 OH).

28 105913 4.1.23 Example 23 (-VMR.5R.211S11-111-Hydroxy-2- (2-methoxy-Dro-Dimethyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride

In Example 22, the isolated, faster-flowing material (Rf = 0.56) is crystallized as in Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.50 g (29.4% of theory) having a melting point of 90-91 ° C (dec) and a specific rotation value of [α] D = -64.0 ° (c = 1, CH 3 OH).

4.1.24 Example 24 (-H1R5S.2 "R) -4H-Hydroxy-2- (2-methoxyDropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride 15 a) Preparation of the starting compound The preparation of (+) - 4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane is not yet known in the art, for example, it can be prepared by the prior art 2'-hydroxy isomer [DOS 20 27 077, CA 74, 125482x (1971)] using o-methoxybenzyl lithium instead of p-methoxy-benzyl lithium The desired compound crystallizes as the base from isopropanol-petroleum ether, m.p. 227 ° C. ammonia-25 ki 65: 35: 3) this can be given an R f value of 0.20.

b) Reaction to the title compound • Starting from 2.31 g (0.010 mol) of (+) - 4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 1.60 g (0). (01 mol) (R) -2-methoxypropionic acid chloride is obtained as in Example 1 a mixture of the desired bases (3.0 g) which is separated by column chromatography on 450 g of silica gel as in Example 2. This gives 0.9 g of a slower fluid (R 1 = 0.34) and 1.3 g of a faster fluid 29 105913 (R 1 = 0.43). The former is crystallized as in Example 2 as the hydrochloride. This gives the title compound in a yield of 0.95 g (55.9% of theory), m.p. 263 ° C (dec) and a specific rotation value of [α] 20 = -86.9 ° (c = CH 3 OH).

4.1.25 Example 25 t +) - 1S, 5R, 2 "RM, -Hydroxy-2-β-methoxypropyl-5.9.9-trimethyl-6.7-benzomorphane hydrochloride.

In Example 24, the isolated, faster-flowing compound (Rf = 0.43) is crystallized as in Example 2 as the hydrochloride. The title compound is obtained in a yield of 1.23 g (72.4% of theory) having a melting point of 258 ° C (dec) and a specific rotation value of [α] 25 D = + 51.7 ° (c = 1, CH 3 OH).

4.1.26 Example 26 (+ W1S.5R.2 "S1-4. -Hydroxy-2- (2-methoxypropyl-5.9.9-trimethyl-6.7-benzomorphane hydrochloride) Starting from 2.31 g (0.010 mol) ) (+) - 4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (see Example 24) and 1.60 g (0.013 mol) of (S) -2-methoxypropionic acid chloride is obtained as in Example 1 a mixture of the desired diastereomeric bases (3.1 g) which is separated by column chromatography on 25 450 g of silica gel as in Example 2. This yields 1.0 g of a slower flowable compound (Rf = 0.34) and 1.2 g faster The former is crystallized as in Example 2 in the form of the hydrochloride to give the title compound in a yield of 1.15 g (67.7%) having a melting point of 260 ° C (dec.) and a specific rotation value of [α] ρ5 = -51.2 ° ( c = 1, CH 3 OH).

30 30 4.1.27 Example 27 105913 (-W 1 R 5 S 2 "SM-Hydroxy-2-f 2 -methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphanehydrochloride

The faster-flowing material isolated in Example 26 (Rf = 0.43) is crystallized as in Example 2 as the hydrochloride to give the title compound in a yield of 0.95 g (55.9% of theory) having a melting point of 261 [deg.] C. (dec.) And [α] [Α] 20 D = + 86.1 °, (c = 1, CH 3 OH).

4.1.28 Example 28 (-W1R5S.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-5,9,9-trimethyl-6,7-benzomorphane [DOS 20 27 077; CA 125482x (1971)] and 1.35 g (0.011 mol) (R) -2-Methoxypropionic acid chloride is obtained as in Example 1 in the form of the sterically uniform title compound in the form of the free base (2.3 g), dissolved in 5 ml of 20 absolute ethanol, and after the acidification with methanesulfonic acid, diethyl ether is added. After crystallization, the same amount of ether is added gradually with stirring, then the reaction mixture is cooled for 4 hours on an ice bath, then filtered off with suction, then washed with ethanol-ether 1: 2, then with ether only 25 ° C. yields the title compound in a yield of 3.3 g (79.8% of theory), m.p. the seat is 165-166 ° C (dec.) and the specific rotation is [α] D = -92.4 ° (c = 1, CH 3 OH).

• 31 4.1.29 Example 29 105913 (+) - MS.5R.2 "S1-2, -Methoxy-2- (2-methoxypropyl) -5.9.9-trimethyl-n-7-benzomorphane methanesulfonate 5 Starting from 2.45 g (0.010 mol) of (+) - 2'-methoxy-5,9,9-trimethyl-6,7-benzomorphane [DOS 20 27 077; CA74: 125482x (1971)] and 1.35 g (0.011) mol) (S) -2-methoxypropionic acid chloride is obtained as in Example 28 in a yield of 3.1 g (75.0% of theory) having a melting point of 165-167 ° C (dec.) 10 and a specific rotation value of [a] = +92 , 3 ° (c = 1, CH 3 OH).

4.1.30 Example 30 (-H 1 R 5. 5S.2llR) -2- (2-Methoxypropyl) -5.9.9-trimethyll-7-benzomorphanihvd-15 hydrochloride a) Preparation of the starting compound The (±) - required for this and the following examples. The preparation of 5,9,9-trimethyl-6,7-benzo-20 morphane is not yet known in the art. For example, it may be prepared by the known synthesis of a 2'-hydroxy derivative [DOS 20 27 077; CA 74, 125482x (1971)], wherein benzyl lithium is used instead of p-methoxybenzyl lithium. The desired compound crystallizes as a hydrobromide from a mixture of isopropanol / ether, m.p. 259 ° C (dec).

25 b) Reaction 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-Methoxy-propionic acid chloride is obtained, as in Example 1, from a mixture of the expected diastereomeric bases. These are separated, as in Example 2, by column chromatography on 150 times silica gel. The slower fluid (Rf = 0.63) - as described above - is crystallized as the hydrochloride. The title compound is obtained in a yield of 1.3 g (76.5% of 32 105913 theoretical) having a melting point of 225 ° C (dec) and a specific rotation value of [α] 25 = -101.7 ° (c = 1, CH 3 OH).

4.1.31 Example 31 5 (+) - (1S, 5R, 2R, -2- (2-Methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane oxalate

In Example 30, the isolated, faster-flowing substance (Rf = 0.67) is dissolved in 105 ml of ethanol. After acidification with oxalic acid, diethyl ether is added to the solution until cloudy. During the subsequent crystallization, a further half of the initial amount of ether is gradually added and allowed to stand for about 12 hours in the refrigerator. After suction separation, washing with ethanol-ether and drying at 80 ° C, the title compound is obtained in a yield of 1.1 g (60.4% of theory) with a melting point of 135 ° C (dec.) And a [α] ] = + 60.2 ° (c = 1, CH 3 OH).

4.1.32 Example 32 20 (-) - (1R.5S.2 "R) -2- (2-Methoxypropyl) -2,5,5,9,9-tetramethyl-6,7-benzomorphane hydrochloride a) Preparation of the starting compound the (±) -2'-5,9,9-tetramethyl-6,7-benz-somorphane required in the examples is not yet known in the art, for example, it can be prepared by synthesis of the known 2'-hydroxy analogue, wherein p-methoxybenzyl. The intermediate thus obtained is crystallized from a mixture of isopropanol-diethyl ether as the hydrobromide, which melts at 227 ° C.

b) Reaction to the title compound 105913 33 Starting from 1.51 g (5 mmol) of (+) - 2, -5,9,9-tetramethyl-6,7-benzomorphan and 0.68 g (5.5 mmol) (R) -2-Methoxypropionic acid chloride is obtained as in a mixture of the desired diastereomeric bases in Example 5, which, as described above, is crystallized and separated as the hydrochloride. This gives the title compound in a yield of 0.7 g (after recrystallization 0.4 g = 47.3% of theory) having a melting point of 212 ° C (dec) and a specific rotation value of [α] 25 D = -110.0 ° ( c = 1, CH 3 OH).

4.1.33 Example 33 (+) - 1S, 5R, 2S-2 - [(2-Methoxypropyl) -2,5,5,9,9-tetramethyl-6,7-benzomorphane hydrochloride Starting from 1.51 g (5 mmol) ) (+) -2,5,9,9-tetramethyl-6,7-benzomorphane and 0.68 g (5.5 mmol) of (S) -2-methoxypropionic acid chloride are obtained as in Example 32 in a yield of 0.4 g (47.3% of theory) with a melting point of 212 ° C (dec) and a specific rotation value of [α] 25 D = + 111.8 ° (c = 1, 20 CH 3 OH).

4.1.:34 Example 34 m (-M 1 R 5 S 2,, R) -2, -Amino-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomor-25-phane dihydrochloride a) Preparation of the starting compound and the (+) - 2'-nitro-5,9,9-trimethyl-6,17-30 benzomorphane required in the following examples is not yet known in the art. It can be prepared, for example, by nitrating (+) - 5,9,9-trimethyl-6,7-benzomorphane (Example 30) in analogy to E.L. May and E.M. Fry'n [J. Org. Chem. 22 (1957) 1: 366]. The resulting intermediate is crystallized from ethanol-ether as the hydrochloride melting at 289 ° C (dec).

b) Acylation 2 2.97 g (0.01 mol) of (+) - 2'-nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride are acylated in the presence of 3.04 g (0.03 mol) of triethylamine as in Example 1 with 1.35 g (0.011 mol) of (R) -2-methoxypropionic acid chloride. After work up, 3.5 g (about 100% of theory) of intermediate type (3) is obtained.

C) Catalytic hydrogenation of the 2'-nitro group to the 2'-amino group 3.5 g of the intermediate obtained in process step b) are dissolved in 70 ml of methanol and 0.4 g of palladium on carbon (Pd content: 5%). hydrogenated at 15 ° C under a hydrogen pressure of 5 bar. Hydrogen consumption stops after 4 hours of calculated amount. After filtering off the catalyst, the reaction mixture is evaporated, finally at 80 ° C and under a full water jet vacuum. Residue: 3.1 g (about 100% of theory).

D) Reduction with lithium aluminum hydride

The evaporation residue (3.1 g) obtained above is reduced as in Example 1 to 1.3 g. Ha lithium aluminum hydride (lithium tetrahydroalanoate). The resulting mixture of the two expected diastereomeric bases (2.7 g) is separated as in Example 2 by column chromatography on 500 g silica gel. The slower fluid (0.7 g, Rf = 0.65) is crystallized as in Example 2 (but with two equivalents of hydrochloric acid) as the dihydrochloride. The title compound is obtained. zero 0.95 g (50.6% of theory) with a melting point of 260 ° C (dec) and a specific rotation of [α] 25 D = -93.4 ° (c = 1, CH 3 OH).

30 35 35.3.35 Example 35 105913 f + W 1 S 5 R 2 "R 2'-Amino-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphanedimethanesulfonate 0.9 g, isolated from Example 34, the faster liquid (Rf = 0.70) is crystallized from methanol-diethyl ether mixture as in Example 43 (but with 2 equivalents of methanesulfonic acid) to give the title compound in a yield of 0.48 g (19.4% of theory) with a melting point of 189 ° C (dec. ) and the specific rotation value 10 is [α] 15 D = + 55.6 ° (c = 1, CH 3 OH).

4.1.36 Example 36 (+ H1S.5R.2 "SV2'-Amino-2- (2-methoxypropyl-5.9.9-trimethyl-6.7-benzomor-15) -hane hydrochloride Starting from 2.97 g (0.01 mol) (+) - 2'-Nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride, 3.04 g (0.03 mol) triethylamine and 1.35 g (0.011 mol) ( S) -2-methoxypropionic acid chloride gives 3.5 g (about 100% of theory) of the 20 desired acylation products which, as described above, are catalytically hydrogenated from Gö, 3.2 g of the hydrogenation product are obtained, followed by lithium aluminum hydride (lithium tetrahydridoalate). The reduction product (2.8 g), consisting of a mixture of the desired diasteromeric bases, is dissolved in 10 ml of isopropanol with warming, and the liquid (Rf = 0.65) is crystallized more slowly as a base while standing in the refrigerator for about 12 hours. 75 g = 49.0% of theory) having a melting point of 142 [deg.] C. 0.3 g of this is crystallized as in Example 32 as the dihydrochloride to give the title compound (0.37 g) having a melting point is 265 ° C (dec.) and the specific rotation is [0] 2 D 5 = + 92.5 ° (c = 1, CH 3 OH).

36 105913 4.1.37 Example 37 ιο f - ') - (1R.5S.2 ") $ 1-2, -Amino-2- (2-methoxypropyl-5.9.9-trimethyl-6.7-benzomorphane dihydrochloride 5

The isopropanol mother liquor from Example 34 is evaporated to dryness and the residue (2.0 g) is chromatographed on 300 g of silica gel as in Example 2. In this case, another 0.3 g of the slower fluid (Rf = 0.65, Example 34) is the faster-flowing diastereomer (1). , 2 g, Rf = 0.70) is crystallized as in Example 32 as di-10 hydrochloride. There is thus obtained the title compound in a yield of 1.48 g (78.8% of theory) having a melting point of 259 ° C (dec) and a specific rotation value of [α] 25 D = -68.4 ° (c = 1, CH 3 OH).

4.1.38 Example 38 15 (N, N-Hydroxy-N-methoxy-isobutyl-Sgg-trimethyl-N, N-benzomorphane / N-bromobromide Starting from 1.16 g (0.005 mol) of (+) - 2'-hydroxy-5), 9,9-Trimethyl-6,7-benzomor-20cane and 0.75 g (0.055 mol) of 2-methoxyisobutyric acid chloride are obtained first as in Example 1, in the form of the base compound (1.1 g), which is dissolved in 5 ml methanol and acidified with HBr (62% ig) to the solution.

• I

followed by diethyl ether until cloudy. After allowing to stand for about 12 h in the refrigerator, the title compound crystallizes out, which is filtered off with suction, washed with ethanol-ether and dried at 80 ° C. Yield 1.1 g (55.2% of theory), m.p. 232 ° C (dec). A sample recrystallized from a methanol-ether mixture melts at 240 ° C (dec).

4.1.39 Example 39 30 (-) - (1R.5S.2 "R1-2'-Hydroxy-2- (2-methoxybutyvin-5.9.9-trimethyl-6.7-benzomorphane hydrochloride) a) Preparation of the starting compound 105913 37 In this and the following examples, the required (R) -2-methoxy-butyric acid chloride can be prepared, e.g., from the known (R) -2-methoxy-butyric acid [NK Kochetkov, 5 AM Likhosherstov and VN Kulakov, Tetrahedron 25 (1969) 2313] and thionyl chloride After removal of the excess thionyl chloride, the remaining acid chloride is used without further purification in the next reaction step.

10 b) Reaction to the title compound From 3.47 g (0.015 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 2.46 g (0.018 mol). ) (R) -2-methoxybutyric acid chloride is obtained as in Example 1 in a yield of 1.8 g (67.8% of theory) having a melting point of 246 ° C (dec) and a specific rotation value of [α] 25 D = -118.4 ° (c = 1, CH 3 OH).

4.1.40 Example 40 20 (+ W 1 S, 5 R 21, R 1 -2'-Hydroxy-2- (2-methoxybutyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride

The mother liquor obtained in Example 39 is evaporated to dryness. The residue is obtained as in Example 2 in a yield of 1.3 g (48.9% of theory) having a melting point of 228 ° C (dec) and a specific rotation value of [α] 25 = + 79.9 ° (c = 1, CH 3 OH). ).

* 4.1.41 Example 41 30 M-MR.SS. ^ S 1 '- H 2 -hydroxy 4 - (4-methoxybutyl) -SgO-trimethyl-1J-benzomorphanhydrochloride 38 105913 a) Preparation of starting compound The (S) - 2-Methoxy-butyric acid chloride can be prepared, e.g., from the known (S) -2-methoxy-butyric acid [Tetrahedron 25 5, 2322 (1969)] as in Example 39.

b) Reaction to the title compound From 3.47 g (0.015 mol) of (+) - 2'-hydroxy-5,9,9-trimethyl-6,7-benzomor-10-phane and 2.46 g (0.018 mol). ) (S) -2-methoxybutyric acid chloride is obtained as in Example 1 in a yield of 1.6 g (60.3% of theory) having a melting point of 246 ° C (dec) and a specific rotation value of [αβ5 = + 119.2 ° (c = 1, CH 3 OH).

4.1.42 Example 42 (+) - (1S, 5R, 2S) -2H-hydroxy-2- (2-methoxybutyl) -5.9.9-trimethyl-6,7-benzomorphane hydrochloride The mother liquor obtained in Example 41. The residue is obtained as in Example 2 in a yield of 0.6 g (22.6% of theory) having a melting point of 228 ° C (dec) and a specific rotation value of [α] 25 = -71.7 ° (c = 1). ,: CH 3 OH).

4.1.43 Example 43 (-) - (1R, 5S, 2R) -2- (2-Benzyloxypropyl) -2,1-hydroxy-5.9.9-trimethyl-6-7'-benzomorphane hydrochloride 30 a) Preparation of the starting compound and (R) -2-benzyloxypropionic acid chloride for use in the following examples may be prepared, for example, by the following route: 39 105913

Commercial (R) - (+) - lactic acid isobutyl ester is O-benzylated in the presence of silver oxide with benzyl bromide. Sodium hydroxide saponification gives (R) -2-benzyloxy-propionic acid having a specific rotation value of [α] 25 = + 79.5 ° (c = 1, CH 3 OH). This gives the corresponding acid chloride as in Example 39.

5 b) Reaction to the title compound From 3.47 g (0.015 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 3.3 g (0, (0165 mol) (R) -2-benzyloxypropionic acid chloride is obtained as in Example 1 in a mixture of the desired diastereomers which, as described above, are separated by crystallization from the corresponding hydrochloride. The title compound is obtained in a yield of 2.39 g (76.6% of theory) having a melting point of 250 ° C (dec) and a specific rotation value of [α] 25 D = -119.3 ° (c = 1, CH 3 OH).

4.1.44 Example 44 (+) - (1S, 5R, 2S) -2- (2-Benzyloxypropyl) -2, -hydroxy-5.9.9-trimethyl-6.7-benzomorphane hydrochloride 20 a) Preparation of the starting compound the (S) -2-benzyloxypropionic acid chloride used in the following examples may be prepared, e.g., as in Example 43 from (S) -2-benzyloxypropionic acid (specific rotation: [α] 25 D = -78.5 ° (c = 1, CH 3 OH)). .

B) Reaction to the title compound From 3.47 g (0.015 mol) of (+) - 2,2-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 3.3 g (0 (0165 mol) of (S) -2-benzyloxypropionic acid chloride is obtained as in Example 43 in a yield of 2.56 g (82.1% of theory) having a melting point of 250 [deg.] C. (dec.) And a specific rotation value of [α] + 119.5 ° (c = 1, CH 3 OH).

4.1.45 Example 45 105913 4 ° (-) - (1R.S.S.Z'R 1 '' - Hydroxy - (-) - methylthiopropyl) -SQQ-trimethyl-eZ-benzomorphane hydrochloride 5 (a) Preparation of the starting compound In this and the following examples: (R) -2-Methylthio-propionic acid chloride may be prepared, e.g., from 10 (R) -2-methylthio-propionic acid known in Example 39 (LN Owen and MB Rahman J. Chem. Soc. [C] 1971, 2432).

b) Reaction to the title compound 1.62 g (0.007 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane are reacted as in Example 1 with 1.07 g (7.7 g). mmol) of (R) -2-methylthiopropionic acid chloride. After reduction of the reaction product thus obtained with lithium aluminum hydride (LiAlH4), a mixture of the desired diastereomers is obtained, which is separated by crystallization with its nitrate.

After acidification with ethanol at 65% ethanol and addition to diethyl ether, the crystallizing agent is suctioned off in a refrigerator after storage for about 12 h, then washed with ethanol / ether and then with ether and dried at 80 ° C. The nitrate (0.67 g) is crystallized from boiling ethanol (0.52 g), then converted to the free base and finally, as in Example 2, crystallized as the hydrochloride. The title compound is obtained in a yield of 0.43 g (34.4% of theory) having a melting point of 265 ° C (dec) and a specific rotation value of [α] D = -135.10 (c = 0.5 CH 3 OH).

4.1.46 Example 46 105913 (+ VnS.5R.2 "R) -2, -Hydroxy-2- (2-methylthiopropyl-5.9.9-trimethyl-6.7-benzomorphane hydrochloride 5

The mother liquor of the first nitrate crystallization obtained according to Example 45 is evaporated to dryness and the nitrate residue is converted to the free base. This (1 g) is filtered as in Example 53 with 20 g of alumina and then crystallized as the hydrochloride (ethanol-ether). This (0.29 g) is recrystallized from 10 2 ml of a mixture of methanol and diethyl ether. The title compound is obtained in a yield of 0.21 g (16.8% of theory) having a melting point of 238 ° C (dec) and a specific rotation value of [α] D = + 73.0 ° (c = 0.5, CH 3 OH).

4.1.47 Example 47 15 M-MR.SS, 1S, 2S, 3-hydroxy, 6-t-methylthiopropyl-Sgg-trimethyl-eT-benzomorphane hydrochloride a) Preparation of the starting compound In this and the following examples, the required (S) -2-methylthiopropionic acid chloride e.g. from the known (S) -2-methylthio-propionic acid [J. Chem. Soc. 1971. 2437] as in Example 39.

B) Reaction to the title compound From 1.62 g (0.007 mol) of (±) -2'-hydroxy-5,9,9-trimethyl-6,7-. Benzomorphan is obtained as in Example 45 in a yield of 0.42 g (33.6% of theory) having a melting point of 265 ° C (dec) and a specific rotation of [α] 15 D + 135.1 ° (c = 0.5, CH 3 OH).

4.1.48 Example 48 105913 M- (1R.5S.2 "S1-2, -Hydroxy-2-f2-methylthiopropyl-5.9.9-trimethyl-6.7-benzomorphane hydrochloride 5 Starting from the nitrate mother liquor in Example 47 is obtained as in Example 46, the title compound is obtained. in a yield of 0.34 g (27.2% of theory) with a melting point of 238 ° C (dec) and a specific rotation of [α] D = -73.9 ° (c = 0.5, CH 3 OH).

4.1.49 Example 49 (+) - (1S, 5R, 2S, 2S) -2- (2-Allloxypropyl-1,2'-hydroxy-5.9.9-trimethyl-6.7-benzomorphane hydrochloride 15 a) Preparation of the starting compound S) - (-) - 2-Allyloxypropionic acid chloride can be prepared, for example, by the following route: Commercial (S) - (-) - lactic acid ethyl ester is o-allylated with allyl bromide in the presence of silver oxide. Subsequent saponification with 20% sodium hydroxide gives (S) -2-allyloxy-propionic acid having a boiling point of 110-112 ° C at 15 mbar and a specific rotation value of [α] 25 D = 78.4 ° (c = 1, CH 3 OH). This gives the corresponding acid chloride as in Example 39.

«Fb) Reaction to the title compound 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-allyloxy-propionic acid chloride is obtained. as in Example 1, a mixture of the two desired diastereomers which, as described above, is separated by crystallization of the corresponding hydrochlorides. The title compound is obtained in a yield of 1.4 g (51.0% of theory) with a melting point of 245 ° C (dec) and a specific rotation value of [α] 25 D = + 120 ° (c = 1, CH 3 OH).

43 4.1.50 Example 50 105913 (-) - (1S, 5R, 2S) -2- (2-Alloxypropyl) -2'-hydroxy-5.9.9-trimethyl-6.7-benzomorphane hydrochloride 5

The mother liquor obtained in Example 49 is evaporated. The residue is obtained, as in Example 2, in a yield of 0.62 g (22.6% of theory) with a melting point of 213 ° C and a specific rotation value of [α] 25 = -38.6 ° (c = 1, CH 3 OH).

4.1.51 Example 51 (-) - (1R, 5S, 2R) -2'-Hydroxy-2- (2-phenoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride 2.31 g (0.010 mol) ( +) -2,2-hydroxy-5,9,9-trimethyl-6,7-benzomorphane and 2.03 g (0.011 mol) of (R) -2-phenoxypropionic acid chloride (prepared as in Example 39) from a known acid [CA 72, 12917d]) is reacted as in Example 1. A mixture of both desired diastereomers is obtained which, as described above, is separated by crystallization of the corresponding hydrochlorides. This gives the title compound in a yield of 1.6 g (79.6% of theory) with a melting point of 279 ° C (dec) and a specific rotation of [α] 25 D = -142.9 ° (c = 1, CH 3 OH).

4.1.52 Example 52 25 (+) - (1S, 5R, 2R, 5S) -2'-Hydroxy-2- (2-phenoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride

Working as in Example 51 with (S) -2-phenoxy-propionic acid chloride-30, the title compound is obtained in a yield of 1.6 g with a specific rotation value of [α] D = + 143.3 ° C (c = CH 3 OH).

4.1.53 Example 53 105913 44 (-W1R.5S.2 "RV3, -Hydroxy-2- (2-methoxypropyl-dimethyl-5.7,9, -tetramethyl-6.7-benzomorphane hydrochloride 5a) Starting compound Necessary in this and the following examples (+/- ) -3'-hydroxy-5,9,9,2'-tetramethyl-6,7-benzomorphane is not yet known in the art, for example it can be prepared for the known 2'-hydroxy derivative [DOS 20 27 077; CA 74 (1971), 125482x] using 3-methoxy-4-methylbenzyl lithium instead of p-methoxybenzyl lithium. 3'-hydroxy-5'-2'-tetramethyl obtained mainly in the ring closure reaction leading to the benzomorphan system The N-benzomorphane is purified by flash-15 column chromatography (compare, e.g., 16).

b) Reaction to the title compound From 2.44 g (0.010 mol) of (+/-) - 3'-Hydroxy-5,9,9,2'-tetramethyl-6,7-20 benzomorphan and 1.6 g. (0.013 mol) of (R) -2-methoxypropionic acid chloride is obtained as a mixture of the desired diastereomeric bases in Example 1, which is separated by column chromatography on 100 times silica gel as in Example 2. The slower fluid (Rf = 0.25) is crystallized as the hydrochloride. The title compound is obtained in a yield of 1.06 g (59.9%) having a melting point of 181-182 ° C and a specific rotation value of [α] 25 D = -89.5 (c = 1, CH 3 OH).

. 4.1.54 Example 54 30 (+ H 1 S 5 R 2 "R 3'H -hydroxy-2- (2-methoxypropyl) -59.9.2'-tetramethyl-6.7-benzomorphanehydrochloride 105913

In Example 53, the isolated, faster-flowing substance (R 1 = 0.34) is mixed as in Example 2 as the hydrochloride. The title compound is obtained in a yield of 1.24 g (70.1%) as an amorphous powder having a specific rotation value of [α] 25 D = + 55.9 ° (c = 1, CH 3 OH).

4.1.55 Example 55 f +) - nS.5R.2 "S1-3, -Hydroxy-2- (2-methoxy-Dro-D'Vl1-5.9.9.21-tetramethyl-6.7-benzomorphane hydrochloride) Starting from 2.44 g (0.010 mol) ) (+/-) - 3'-hydroxy-5,9,9,2'-tetramethyl-6,7-benz somorphane (see Example 53) and 1.6 g (0.013 mol) of (S) - 2-Methoxypropionic acid chloride is obtained as in Example 1, a mixture of the desired diastereomeric bases which is separated by column chromatography on 100 times 15 silica gels as in Example 2. The slower fluid (Rf = 0.25) is crystallized as the hydrochloride to yield the title compound (83). , 6%) having a melting point of 186-188 ° C and a specific rotation value of [α] 25 D = + 88.2 ° (c = 1, CH 3 OH).

4.1.56 Example 56 M-MR.5S.2 "S1-3'-Hydroxy-2- (2-methoxypropyl) -5.9.9.2, -tetramethyl-6.7-benzomorphane hydrochloride 25 Example 55 isolated, faster fluid (R, = 0.34) is crystallized as in Example 2 as the hydrochloride to give the title compound in a yield of 1.40 g (79.1%) as an amorphous powder having a [α] 25 D = -56.8 ° (c = 1, CH 3 OH).

4.1.57 Example 57 (-) - (1R, 5S.2 "R '- 2'-Hydroxy-2- (2-methoxypropyl) -5.9-9.3, -tetranethyl-6.7-benzomorphane methanesulfonate 46 105913 a) Starting compound and the (+/-) - 2'-hydroxy-5,9,9,3'-tetra-5-methyl-6,7-benzomorphane required in the following examples is not yet known in the art, for example it may be prepared for the known 2'-hydroxy (DOS 20 27 077; CA 74 (1971), 125482x) using 4-methoxy-3-methylbenzyl lithium in place of p-methoxybenzyl lithium. The 2'-hydroxy obtained mainly in the ring closure reaction leading to the benzomorphan system The 5,9,9,3'-tetramethyl-6,7-benzomorphane is purified by flash column chromatography (cf. e.g. 16).

b) Reaction to the title compound 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 (R) -2-methoxypropionic acid chloride is obtained as a mixture of the desired diastereomeric bases in Example 1, which is separated by column chromatography on 100 times silica gel as in Example 2. The slower fluid (Rf = 0.26) is crystallized as methane-20 sulfonate. The title compound is obtained in a yield of 1.64 g (79.3%) having a melting point of 266-268 ° C and a specific rotation of [α] 25 D = -95.4 ° (c = 1, CH 3 OH).

«4.1.58 Example 58 25 (+) - (1S, 5R, 2R) -2'-Hydroxy-2- ('2-methoxypropyl) -5.9.9.3'-tetramethyl-6.7-benzomorphane hydrochloride

• I

•

In Example 57, the isolated, faster-flowing material (Rf = 0.29) is crystallized as in Example 2 as the hydrochloride. The title compound is obtained in a yield of 1.60 g (90.4%) as an amorphous powder having a specific rotation of [α] 25 D = + 73.4 ° (c = 1, CH 3 OH).

47 INROLI 4.1.59 Example 59 IUJ7 1 ° (• «• W1S.5R.2" S2 -2, -Hydroxy-2- (2-methoxypropyl) methyl 5.9.9.3, -tetramethyl-6,7-benzomorphane methanesulfonate 5 From 2 , 44 g (0.010 mol) of (+/-) - 2'-hydroxy-5,9,9,3'-tetramethyl-6,7-benz somorphan (see Example 57) and 1.6 g (0.013 mol) of (S) -2-methoxypropionic acid chloride is obtained as in Example 1, a mixture of the desired diastereomeric bases which is separated by column chromatography on 100 times 10 silica gel as in Example 2. The slower fluid (Rf = 0.26) is crystallized from methane sulfate. in 1.56 g (88.1%) with a melting point of 265-267 ° C and a specific rotation value of [α] 25 D = + 96.9 ° (c = 1, CH 3 OH).

4.1.60 Example 60 (-) - (1R, 5S.2 "SV2'-Hydroxy-2-i2-methoxypropyl) -5.9.9.3, -tetramethyl-6.7-benzomorphane hydrochloride

In Example 59, the isolated, faster-flowing material (Rf = 0.29) is crystallized as in Example 2 as the hydrochloride. The title compound is obtained in a yield of 1.36 g (76.8%) as an amorphous powder having a specific rotation value of [α] 25 D = -74.9 ° (c = 1, CH 3 OH).

25 4.1.61 Example 61. (-) - (1R, 5S.2 "R) -2'.3'-Dihydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride 30 a) Starting compound 105913 48 Hereinafter, the (+/-) - 2,13'-dihydroxy-51919-trimethyl-6,7-benzomorphane required in the examples is not yet known in the art, for example it may be prepared for the known 2'-hydroxy derivative [DOS 20 27 077; CA 74 (1971), 125482x] employing 3,4-dimethoxybenzyl lithium instead of p-methoxybenzyl lithium-5 min The 2 ', 3'-dihydroxy-5,9,9-trimethyl mainly obtained in the ring closure reaction leading to the benzomorphan system The -6,7-benzomorphane is purified by flash column chromatography (cf. e.g. 16).

10 b) Reaction to the title compound Starting from 8.51 g (0.03 mol) of (+/-) -2,3,3'-dihydroxy-5,9,9-trimethyl-6,7-benzomorphane hydrochloride and 4.1 g (0.033 mol) of (R) -2-methoxypropionic acid chloride is obtained as a mixture of the desired 15 diastereomeric bases in Example 1, which is separated by column chromatography on 100 times silica gel as in Example 2. The slower fluid (R 1 = 0.21) is crystallized as the hydrochloride.

The title compound is obtained in a yield of 2.54 g (47.6%) having a melting point of 20,167 ° C (dec) and a specific rotation value of [α] D = -98.6 ° (c = 0.5; CH 3 OH).

4.1.62 Example 62 v (+) - (1S, 5R, 2R) -2,3'-Dihydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-25 Benzomorphane hydrochloride

In Example 61, the isolated, faster-flowing substance (Rf = 0.29) is crystallized. as in Example 2 as the hydrochloride. The title compound is obtained in a yield of 2.28 g (42.7%) having a melting point of 251 ° C (dec) and a specific rotation value of [α] D = 30 + 64.3 ° (c = 0.5; CH 3 OH).

49 105913 4.2. Compounds (mukaan according to Method 3.2 4.2.1 Example 63 5 (+/- ') - 2'-Hydroxy-2 - (, 2-methoxyethyl) -5.9.9-trimethyl-6.7-benzomorphane hydrobromide 0.6 g (0.003 mol) (+) -2,2-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 hydrogencarbonate are stirred in 10 ml of absolute dimethylformamide for 23 hours at 95 [deg.] C. The reaction mixture is then evaporated in a vortex evaporator, finally at 95 [deg.] C. and in a full water jet vacuum. 25 ml of dichloromethane and the separated aqueous phase is extracted once more with 10 ml of 15 dichloromethane The combined extracts are washed with water, dried over sodium sulphate and after filtration of the solid as described above, the product is evaporated in vacuo. Let's get the headline in a yield of 0.48 g (43.5% of theory), m.p. 247 ° C (dec).

4.2.2 Example 64 (-) - (1R, 5S.2 "R) -2'-Hydroxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6,7-25 Benzomorphane Hydrochloride a) Preparation of the alkylating agent.

Reduction of the (+) - (R) -2-methoxypropionic acid known in the art with lithium aluminum hydride (UAIH4) provides (-) - (R) -2-methoxypropanol with a boiling point of 76 mbar and a specific rotation of [ [α] 25 D = -15.8 ° (c = 100). Analogously, (+) - (S) -2-methoxypropanol corresponding to the known (-) - (S) -2-methoxypropyl 105913 50 boiling acid having a boiling point of 76 mbar and a rotation value of [a] is obtained. = + 16.5 ° (c = 100).

By reacting (-) - (R) -2-methoxypropanol with p-toluenesulfonic acid chloride in pyridine, R.S. Tipson [J. Org. Chem. 9 (2344) (1944)] gives (+) - (R) -2-methoxypropyl-p-toluenesulfonate in the form of a yellowish oil having a specific rotation [α] = + 3.7 ° (c = 100) and the like ( +) - (S) -2-methoxypropanol (-) - (S) -2-methoxypropyl p-toluenesulfonate corresponding to a [α] D = -3.7 ° (c = 100).

B) Reaction to the title compound 1.16 g (5 mmol) of (a) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane (Example 1) is heated with 1.83 g (7.5 mmol) (R) -2-methoxypropyl-p-toluenesulfonate 15, 1.26 g (0.015 mol) of sodium hydrogen carbonate and 1.12 g (7.5 mmol) of sodium iodide in a mixture of 15 ml of absolute dimethylformamide and 25 ml absolute tetrahydrofuran for 60 hours with stirring at reflux temperature. It is then treated as in Example 63. A mixture of both desired diastereomeric bases (2 g) is obtained which, according to Example 20, may also be prepared by a different route. The hydrochloride is isolated by crystallization as described therein, and the title compound is obtained in a yield of 0.55 g (64.7% of theory) having a melting point of 264 ° C (dec) and a specific rotation value of [α] D = -118.2 ° (c = 1). , CH 3 OH).

As in Example 2, the (+) - (1S, 5R, 2 "R) diastereomer 25 can be separated from the mother liquor.

4.2.3 Example 65 M-nR.5S.2 (R) -2- (2-Methoxy-Dimethyl) -2, -nitro-5.9.9-trimethyl-6.7-30 Benzomorphane hydrochloride 2.97 g (0.010 mol) (+) - 2'-Nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 34) is reacted as in Example 54 with 2.68 g (0.011 mol) of 51,105,913 (R) -2-methoxypropyl-p-toluenesulfonate, 65 g (0.011 mol) of sodium iodide and 2.1 g (0.025 mol) of sodium hydrogen carbonate The reaction product is isolated as described above with a mixture of bases of both desired diastereomers (3.2 g) and dissolved in 64 ml of 5 dichloromethane to separate the by-products. and the solution is filtered through a column of 64 g of alumina (activity grade III - neutral according to Brockmann) After elution with 128 ml of additional dichloromethane, the combined eluates are evaporated in a vortex evaporator - finally at 80 [deg.] C. and a full water jet vacuum. Dissolve in 10 ml of methanol and add to the solution 10 acid after stirring with 2.5 N ethanolic hydrochloric acid until diethylether begins to cloud. The title compound crystallizes, which after standing for 3 days at room temperature is filtered off with suction, 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) having a melting point of 15226 ° C (dec) and a specific rotation value of [α] 25 D = -120 ° (c = 1, CH 3 OH).

If desired, a stereoisomeric (+) - (1S, 5R, 2 "R) compound can be obtained from the mother liquor.

4.2.4 Example 66 20 f + 1- (1S.5R.2 "SV2- (2-Methoxypropro-DwiV2, -nitro-5.9.9-trimethyl-6.7-benzomorphane hydrochloride) Starting from 2.97 g (0.010 mol) ( +) -2,5-Nitro-5,9,9-trimethyl-6,7-25 benzomorphane hydrochloride and 2.68 g (0.011 mol) of (S) -2-methoxypropyl-p-toluenesulfonate are obtained as in Example 65 in the yield 0.96 g (52.0% of theory) with a melting point of 226 ° C (dec) and a specific rotation value of [α] 25 D = +121 ° (c = CH 3 OH).

The mother liquor can give the stereoisomeric (-) - 30 (1R, 5S, 2S) form as in Example 2.

4.2.5 Example 67 105913 52 (-1- (1R, 5S.2 "R1-2- (2-Methoxypropyl) -3'-nitro-5,9,9-trimethyl-6.7-benzomorphan a) Preparation of the starting compound In this and the following examples, the required (+) - 3'-nitro-5,9,9-trimethyl-6,7-benzomorphan is formed in addition to the (±) -2'-nitro isomer by nitration of 5,9,9-tri-methyl- 6,7-Benzomorphane (Example 34) in a ratio of about 1: 3. It is obtained via the 10 bases prepared from the mother liquor of the 2'-nitro isomer which crystallizes as a hydrochloride, which is crystallized from ten times the amount of methanol as the oxalate (melting point 158 ° C (dec.)). is converted back to base (not crystallized) which is used in the reaction described below: A sample of the base crystallized as methanesulfonate melts at 242 ° C (dec).

B) Reaction to the title compound 5.2 g (0.02 mol) of (+) - 3'-nitro-5,9,9-trimethyl-6,7-benzomorphane is reacted as in Example 65 to 5.36 g (0.022 mol). (R) -2-methoxypropyl-p-toluenesulfonate. The reaction product gives a mixture of the two desired isomeric bases (8 g) which - as described in Example 65 - is purified by filtration over alumina (4.7 g of purified base mixture). The Rf values for the diastereomers are 0.81 and 0.85 in the thin layer chromatogram (silica gel 60, toluene-ethyl acetate 85:15, 3 times). The separation of 1 g of the diasteroomer mixture in 300 g of silica gel by column chromatography gives the title compound (100 mg), which has an R 1 value of 0.81 as a brownish, highly viscous, non-crystallizing oil.

4.2.6 Example 68 30 (+ 1- (1S, 5R, 21'R1-2- (2-Methoxypropyl) -3, -nitro-5.9.9-trimethyl-6.7-benzomorphan 105913)

Column chromatography of the diastereomeric mixture described in Example 67 gives, in addition to the isolated (-) - (1R, 5S, 2 "R) form (R 1 = 0.81), 100 mg of (+) - (1S, 5R, 2" S). form (Rf = 0.85) as a brownish, very viscous, non-crystallizing oil.

4.2.7 Example 69 M- (1R, 5S, 2'-R) -2'-Chloro-2-f2-methoxy-Dro-DWiV5.9.9-trimethyl-6.7-benzomorphane hydrochloride 10 a) Preparation of the starting compound The (+) -2'-Chloro-5,9,9-trimethyl-6,7-benzomorphane may be prepared, for example, from the 2'-nitro analog (Example 34), whereby the latter is hydrogenated to the 2'-amino compound (dihydrochloride: mp 283). ° C (dec), and this is converted by the Sandmeyer reaction to the desired 2'-chloro compound (hydrobromide: melting point> 310 ° C, (dec)).

b) Reaction to the title compound 3.3 g (0.010 mol) of (+) - 2'-chloro-5,9,9-trimethyl-6,7-benzomorphana anhydrobromide and 2.68 g (0.011 mol) of (R) - 2-methoxypropyl-p- • ·? toluene sulfonate is reacted as in Example 65 to form a mixture of the desired diastereomeric bases and, as described above, -25 is purified by filtration with alumina. The purified diastereomeric mixture is separated as in Example 1 by crystallization with hydrochloride. The title compound is obtained in a yield of 0.27 g (15.1% of theory) having a melting point of 287 ° C (dec) and a rotation value of [α] D = -102.6 ° (c = 1, CH 3 OH).

4.2.8 Example 70 (+ W1S.5R.2 "R1-2'-Chloro-2- (2-methoxypropyl-5.9.9-trimethyl-6.7-benzomorphane hydrochloride) 54 105913

The mother liquor from Example 69 is evaporated and the residue is dissolved in the required amount of boiling methanol. Until diethylether is added to turbidity and co-crystallization, the title compound is obtained which, after about 12 hours of storage at room temperature, is filtered off with suction, washed with ethanol-ether 1: 1, then with ether and dried at 80 ° C. Yield 0.56 g (31.3% of theory), melting point: 289 ° C, specific rotation: [αββ = + 67.9 ° C 4.2.9 Example 71 (+ H 1 S.SR methoxypropyl10-SQQ-trimethyl-S, 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 is obtained as in Example 69 in a yield of 0.41 g (22.9% of theory) having a melting point of 288 ° C (dec.) and a [α] ] = + 101.7 ° (c = 1, CH 3 OH).

4.2.10 Example 72 '(-W 1 R 5 S 2,, S) -2, -Chloro-2-t 2 -methoxypropyl-5.9.9-trimethyl-6.7-benzomorphane hydrochloride

From the mother liquor in Example 61, the title compound is obtained as in Example 70 in a yield of 0.75 g (41.9% of theory) having a melting point of 288 ° C and a specific rotation value of [α] D = -68.6 ° (c = 1, CH 3 OH).

30 4.3. Compounds (1) according to Method 3.3 4.3.1 Example 73 105913 55 (-1- (1R, 5S, 2S) -2,2-Methoxy-2- (2-methoxypropyl) -59.9-trimethyl-6.7-benzomorphane methanesulfonate , 68 g (2 mmol) of (-) - (1R, 5S, 2S) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-tri-5-methyl-6,7- Benzomorphan hydrochloride (Example 4) in 20 ml of absolute dimethylformamide is added, with stirring and ice-cooling, 0.13 g of a 77% sodium hydride suspension in paraffin (4.2 mmol) .After stirring for 30 minutes, 0.31 g (2.2 mmol) is added dropwise. ) methyl iodide dissolved in 5 ml of dimethylformamide over 5 minutes, then stirred for a further 3 hours at room temperature and then evaporated in a vortex evaporator, finally at 95 ° C and in a full water jet vacuum, the residue is shaken with 25 ml of dichloromethane and 25 ml of water. Extract once more with 15 ml of dichloromethane.

15

After washing with 15 ml of water, the combined extracts are evaporated and the residue is crystallized as in Example 28 as methanesulfonate. The title compound is obtained in a yield of 0.38 g) (46.0%) having a melting point of 150-152 ° C (dec.) And a specific rotation value of [α] 25 = -68.7 ° (c = 1, CH 3 OH).

4.3.2 Example 74: (+ 1- (1S, 5R, 2'R1-2'-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-benzomorphane hydrochloride (Example 2) is obtained. as in Example 73, in a yield of 0.38 g (46.0% of theory) having a melting point of 150-152 ° C (dec) and a specific rotation of [α] 25 D = + 67.2 ° (c = 1.30 CH 3 OH). ).

4.3.3 Example 75 105913 56 M-nR, 5S.2 "R 2'-Ethoxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane methanesulfonate Starting from 0.34 g (1 mmol) (- ) - (1R, 5S, 2 "R) -2'-Hydroxy-2- (2-methoxypropyl) -5,5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 1) and 0.17 g: (0.0011 mol) of ethyl iodide is obtained as in Example 63 in a yield of 0.30 g (70.2% of theory) having a melting point of 146-148 ° C (dec) and a specific rotation value of [α] D = -93.4 ° (c = 1, CH 3 OH).

4.3.4 Example 76 (-1- (1R, 5S.2 "R1-2'-Acetoxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane methanesulfonate) 0.68 g (2 mmol) (-) - (1R, 5S, 2 "R) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 1) is dissolved in 15 ml After addition of 0.51 g (5 mmol) of triethylamine, 0.19 g (2.4 mmol) of acetyl chloride dissolved in 5 ml of dichloromethane are added to the solution at room temperature with stirring for about 10 minutes. 2 hours at room temperature.

It is then washed three times with 10 ml of ice water each time, dried over sodium sulphate and, after removal of the solid by filtration, evaporated (vortex evaporator, finally at 80 ° C and in a full water jet vacuum).

The residue consisting of the free base of the title compound (0.6 g, 1.74 mmol) is dissolved in 3 mL of ethanol and acidified to pH by addition of methanesulfonic acid (0.16 g, (1.74 mmol) in 3 mL of ethanol). 4.

• After the addition of diethyl ether, the clouding begins to crystallize out which, after storage in a refrigerator for about 12 h, is suctioned off, washed with ethanol-ether 1: 2 and dried at 80 ° C. Yield 0.7 g (79.3% of theory), melting point: 183-184 ° C (dec), [α] D = -83.9 ° (c = 1, CH 3 OH).

57 105913 4.3.5 Example 77 (+ H 1 S 5 R 2 "S) -2'-Acetoxy-2- (2-methoxypropyl] -5.9.9-trimethyl-6.7-benzomorphane methanesulfonate 5 Starting from 0.68 g ( 0.002 mol) (+) - (1S, 5R, 2S) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 3) is obtained as in Example 76 in a yield of 0.6 g (68.0% of theory) having a melting point of 183-184 ° C (dec) and a specific rotation value of [α] 25 = + 82.8 ° C (c = 1, CH 3 OH).

4.3.6 Example 78 M-nR.5S.2 "S1-2'-Acetoxy-2 - (, 2-methoxypropyl) -5.9.9-trimethyl-6.7-benzo-15-morphane methanesulfonate Starting from 0.68 g (0.002 mol). ) (-) - (1R, 5S, 2nS) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 4) is obtained as in Example 76 the title compound in a yield of 0.58 g (65.7% of theory) having a melting point of 183 ° C (dec) and a specific rotation of [α] 25 = -57.1 ° (c = 1, CH 3 OH).

4.3.7 Example 79 25 (+ H 1 S 5 R 2 "R 2, -acetoxy-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane methanesulfonate Starting from 0.68 g (2 mmol) (+) - (1S, 5R, 2 "R) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 2) in Example 76, the title compound was obtained in a yield of 0.67 g (75.9% of theory) having a melting point of 183 ° C and a specific rotation value of [α] 25 D = + 58.2 ° (c = 1, CH 3 OH).

58 105913 4.3.8 Example 80 (-1- (1R, 5S, 2R) -2- (2-Methoxypropyl-2,2, -propionyloxy-5.9.9-trimethyl-6.7-benz somorphane methanesulfonate) From 0.34 g (1 mmol) of (-) - (1R, 5S, 2 "R) -2, -hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 1) and 0.15 g (1.1 mmol) of propionic anhydride are obtained as in Example 76 in a yield of 0.21 g (46.1% of theory) having a melting point of 145 [deg.] C. (dec.) And [α] 25 D = -78.3 ° (c = 1, CH 3 OH).

4.3.9 Example 81 (-1- (1R, 5S, 2R) -2- (2-Methoxypropyl-5-5.9.9-trimethyl-6.7-benzomorphane, dihydrochloride a) (-) - (1R, 5S) , 2 "R) -2- (2-Methoxypropyl) -2 '- (1-phenyl-5-tetrazolyloxy) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride 1.36 g (4 mmol) (- ) - (1R, 5S, 2 "R) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 1) is heated to 0.79 g: of 5-chloro-1-phenyl-tetrazole and 1.36 g (0.01 mol) of dry, finely divided potassium carbonate in 78 ml of absolute acetone for 6 days with stirring at reflux temperature. Evaporate and add 50 ml of water to the residue, extract twice with 25 ml of dichloromethane twice and wash the combined extracts with 15 ml of 25. After drying over sodium sulphate and after filtration of the solid, the reaction mixture is evaporated in a rotary evaporator and finally at 80 ° C. Dissolve in 5 m 1 ethanol and after acidification with ethanolic hydrochloric acid, diethyl ether is added to the onset clouding. The intermediate crystallizes, which - after about 12 hours in the refrigerator - is filtered off with suction, washed with ethanol-ether (1: 1), then with ether and dried at 80 ° C. Yield 1.67 g (86.3% of theory), m.p. 241 ° C (dec).

105913 b) Hydrogenate the intermediate to the title compound The intermediate (1.67 g, 3.5 mmol) is hydrogenated in 0.7 g of 10% palladium on carbon in 70 mL of glacial acetic acid at 5 bar and room temperature 5 until complete reaction is achieved. (6-10 hours). The catalyst is then removed by suction, the filtrate is evaporated and the residue - after addition of 50 ml of water and excess ammonia - is evaporated with dichloromethane (2 x 25 ml). The combined extracts are washed with water, dried over sodium sulfate and, after filtration of the solid, evaporated in a vortex evaporator, finally at 80 ° C and under a full water jet vacuum. The residue is crystallized as in Example 2 as the hydrochloride. The title compound is obtained in a total yield of 0.5 g (38.5% of theory) having a melting point of 225 ° C (dec) and a specific rotation of [α] 25 = -101.5 ° (c = 1, CH 3 OH).

4.3.10 Example 82 (+) - (1S, 5R, 2S) -2- (2-Methoxy-propyl) -5.9.9-trimethyl-6.7-benzomorphane / hydrochloride 20 From 1.36 g (0.004) mol) (+) - (1S, 5R, 2 "S) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 3) as in Example 81 via the corresponding intermediate (1.65 g, 85.1% of theory, m.p. 241 ° C (dec.)), the title compound in a total yield of 0.64 g (49.4% of theory) having a melting point is 225 ° C (dec) and the specific rotation is [α] 25 = 106.9 ° (c = 1, CH 3 OH).

4.3.11 Example 83 «(-) - (1R, 5S.2" S) -2- (2-Methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphaneoxa-30 Starting from 1.36 g (4 mmol) (-) - (1R, 5S, 2 "S) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 4) 105913 in Example 81 via the corresponding intermediate (1.73 g, 89.4% of theory, m.p. 218.5 ° C (dec.)), The title compound in the form of the free base (0.7 g). This is dissolved in 2 ml of isopropanol and the corresponding molar amount of oxalic acid (0.22 g). The title compound crystallizes as 50 ml of diethyl ether are gradually added with stirring. After about 12 h of storage in the refrigerator, suction is removed, washed with isopropanol-ether, then with ether and dried at 80 ° C. The title compound is obtained in a total yield of 0.8 g (53.0% of theory) having a melting point of 135 ° C (dec) and a specific rotation value of [α] D = -60.0 ° (c = 1, CH 3 OH).

4.3.12 Example 84 (+ 1- (1 S. 5 R 2. 1 R 2 - (2-Methoxypropyl) -5.9.9-trimethyl-6.7-benzormorphane oxalate) Starting from 1.36 g (4 mmol) (+) - (1S, 5R, 2 "R) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 2) is obtained as in Example 81. via the intermediate (1.65 g, 85.1% of theory, m.p. 217 ° C (dec.)), the base of the title compound which is crystallized as oxalate as in Example 83 Total yield 0.6 g (39.7% of theory), melting point: 135 ° C (dec), specific rotation: [α] 25 = + 60.2 ° (c = 1, CH 3 OH).

·: 4.3.13 Example 85 25 (-1- (1R, 5S, 2R) -2, -Aetamido-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride 1 0.70 g ( 1.87 mmol) of (-) - (1R, 5S, 2R) -2'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane dihydrochloride (Example 34) Dissolve in 20 ml of 30 absolute dichloromethane, add 0.76 g (7.4 mmol) of triethylamine and then, while stirring at room temperature, add 0.17 g (2.1 mmol) of acetyl chloride dissolved in 5 ml of dichloromethane. It is then heated for 1 hour at reflux temperature, then cooled, washed three times 105913 times with 10 ml of water each time, dried over sodium sulfate and, after filtering off the solid, evaporated in a vortex evaporator, finally at 80 ° C and in a full water jet vacuum.

The residue is dissolved in 2 ml of methanol and after acidification with diethyl ether, 2.5 N ethanolic hydrochloric acid is added to the onset cloud. The precipitating crystals - after about 12 hours storage in a refrigerator - are suctioned off, 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) with a melting point of 252 ° C (dec) and a specific rotation value of [α] ρ5 = -108.2 ° (c = 1, CH 3 OH).

4.3.14 Example 86 15 (+ 1- (1S, 5R, 2S) -2'-Acetamido-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride Starting from 1.07 g (2.58 mmol) of (+) - (1S, 5R, 2S) -2-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 36) as in Example 20, the title compound is obtained in a yield of 0.73 g (74.3% of d. theory) having a melting point of 249 ° C (dec.) and a specific rotation of [α] 25 D = + 109.5 ° (c = 1, CH 3 OH).

4.3.15 Example 87 25 (-W 1 R 5 S 2 S) -2-Acetamido-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphan 1.0 g (0.0026 mol). ) (-) - (1R, 5S, 2 "S) -2'-Amino-2- (2-methoxypropyl) -5,9,9-tri-30-methyl-6,7-benzomorphane dihydrochloride is reacted as in Example 85 The reaction product - as described above - is separated and crystallized from 0.5 ml of isopropanol and 5 ml of petroleum ether to give the title compound 105913 62 in a yield of 0.7 g (76.4% of theory) having a melting point of 128 ° C and an intrinsic value. [α] 20 D = -89.3 ° (c = 1, CH 3 OH - 1 N HCl 1).

4.3.16 Example 88 5 (+ W 1 S 5 R 2 "R 2, -Acetamido-2- (2-methoxypropyl-5.9.9-trimethyl-6.7-benzomorphan) Starting from 1.11 g (2.5 mmol) (+) - (1S, 5R, 2 "R) -2'-Amino-2- (2-methoxypropyl) -10,5,9,9-trimethyl-6,7-benzomorphane dimethanesulfonate (Example 35) is obtained as in Example 87 the title compound in a yield of 0.37 g (47.7% of theory) having a melting point of 129 ° C and a specific rotation value of [α] 25 D = + 89.9 ° (c = 1, CH 3 OH-1 N HCl 1: 1).

4.3.17 Example 89 M-MR.SS ^ H 1 -Bromo-4-hydroxy-N-4-methoxypropyl-Sgg-trimethyl-ej-benzomorphane hydrochloride 20 0.85 g (2.5 mmol) (-) - (1 R) , 5S, 2 "R) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 1) is suspended in 30 ml of glacial acetic acid. The suspension is added with stirring at room temperature. 0.15 ml (0.47 g, 2.9 mmol) of bromine, After stirring for 2 hours, evaporate in a vortex evaporator, finally at 80 ° C and in a full water-jet vacuum. Add 25 ml of water and 25 ml with shaking. The separated aqueous phase is extracted once with 15 ml of dichloromethane, the combined extracts are washed with 15 ml of water, dried over sodium sulphate and, after filtering off the solid, as described above, are evaporated. The residue (1 g) is purified by column 250 g. silica gel-30 gel - as in Example 2 - using dichloromethane 90: 10: 0.5 Toluene-Concentrated Ammonia. The pure eluate eluate is evaporated as above and the residue is crystallized as in Example 2 as the hydrochloride. The title compound is obtained in a yield of 0.75 g (65.8% of theory), having a 10591363 melting point of 245 ° C (dec) and a specific rotation value of [α] 25 D = -82.5 ° (c = 1, CH 3 OH).

4.3.18 Example 90 5 (+ H 1 R 5 R 2 "R 2, -Hydroxy-11-nitro-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride 0.85 g (2.5 mmol) (-) - (1R, 5S, 2''R) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9-tri-10-methyl-6,7-benzomorphane hydrochloride is suspended at 20 ° C. of glacial acetic acid and add 0.18 ml (0.25 g) of 65% nitric acid (2.6 mmol HNO3) with stirring to a clear yellow solution which after 10 additional minutes turns brown and begins to After a total reaction time of 1 h, the mixture is filtered off with suction and washed with glacial acetic acid / diethyl ether (1: 1), then washed with ether and dried at 80 [deg.] C. The crystals (0.35 g) are dissolved in hot methanol-water (17.5 ml + 1.75 ml) and diethyl ether (40 ml) is added to the solution. After cooling, the crystallized material is filtered off with suction, washed with ether and dried at 80 ° C to give the title compound in a yield of 0.32 g (33.3). % of theory) with a melting point> 245 ° C (gradually turning brown and decomposing); specific rotation [α] D 25 = + 87.0 ° (c = 1, CH 3 OH).

4.3.19 Example 91 25 N-MR.SS ^ R 1 R 3 -Hydroxy 4 R 4 -methoxypropyl-S 4 -Nitro-Sgg 3-trimethyl-1-j-benzomorphan hydrochloride *, The nitration described in Example 90 consists of the starting compound (R f = 0.57). T-nitro derivative (Rf = 0.45), isomeric 3'-nitro-derivative (Rf = 0.72) and 1 ', 3'-dinitro-derivative (Rf = 0.10) (DC: silica gel 60, chloroform-methanol-concentrated ammonia 90: 10: 0.5). After suction separation of the 1'-nitro compound, the mother liquor formed (Example 90) is evaporated to dryness and the residue is converted to the free base. This is dissolved in 10 ml of dichloro- 105913 64 methane and the yellowish solution is filtered with 25 g of alumina (activity III, neutral). Elute with dichloromethane until the eluate is no longer bright yellow and then evaporate the eluate to dryness. The residue (0.35 g) is dissolved in 2.5 ml of ethanol and, after acidification, 5 ml of ethanolic hydrochloric acid are added to the mixture to begin the clouding of diethyl ether. After about 12 h of storage in the refrigerator, suction is removed, 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. .

4.3.20 Example 92 (+ W 1 R 5 R 2 "R 1-1, 3,3 -Dinitro-2'-hydroxy-2- (2-methoxypropyl-5.9.9-trimethyl-6.7-benzomorphane hydrochloride) 1.52 g (5 mmol) (-) - (1R, 5S, 2R) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan (Example 1) ) is dissolved in 3 ml of glacial acetic acid and a solution of 3.4 ml of glacial acetic acid and 5.42 ml of 100% nitric acid is added with stirring at 3-4 ° C for 1.5 hours, followed by stirring for a further 3 hours. The yellow reaction mixture is then poured into 50 g of ice-water, the solution is made alkaline and extracted with 3 x 20 ml of dichloromethane.When the combined extracts are washed with water and dried over sodium sulfate *, and after filtration of the solid, the reaction mixture is evaporated , finally at 80 ° C and in a full water jet vacuum.

The residue is crystallized from ethanol-ether. The title compound is obtained in a yield of 1.0 g (46.5% of theory) with a melting point> 300 ° C (dec) and a specific rotation [α] D = + 27.9 ° (c = 1, CH 3 OH).

65 105913 4.3.21 Example 93 M- (1R, 5R, 2R) -1'-Amino-hydroxy-4- (4-methoxy) -dimethyl-dimethyl-trimethyl-benzomorphane hydrochloride 5 0.35 g (1.0) mmol) (+) - (1R, 5R, 2 "R) -2, -hydroxy-2- (2-methoxypropyl) -1'-nitro-6,7-benzomorphane 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 hydrogen pressure at 5 bar room temperature. After filtering off the catalyst, the reaction mixture is evaporated in a vortex evaporator, finally at 80 ° C and under a full water-jet vacuum, and the residue is crystallized from 10 ml of ethanol. After cooling in an ice bath, the crystals are suctioned off, 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) having a melting point of 282 ° C (after slow decomposition starting at 15 250 ° C) and a specific rotation value of [α] 25 D = -128.3 ° (c = 1, CH 3 OH).

4.3.22 Example 94 (-VMR.5S.2,, R 3'-Amino-2'-hydroxy-2- (2-methoxyDroDwiV5.9.9-trimethyl-6.7-20) benzomorphane hydrochloride Starting from 0.39 g (1.0 mmol) (-) - (1R, 5S, 2 "R) -2'-Hydroxy-2- (2-methoxypropyl) -3'-nitro-5,9,9-methylmethyl-6,7-benzomorphane hydrochloride (Example 91) is obtained as in Example 93 in a yield of 0.27 g (76.1% of Theo-25), having a melting point of 268 ° C (dec.) and a specific rotation of [αβ5 = -99.7 ° (c = 0). , 5, CH 3 OH).

66 105913 4.3.23 Example 95 (-W 1 R 5 R 2 "R 1 ', 3'-Diamino-2'-hydroxy-2- (2-methoxyDroDvinyl-5.9.9-trimethyl-6.7-benzomorphane hydrochloride) From 0.70 g (1.63 mmol) of (+) - (1R, 5R, 2 "R) -1 ', 3'-dinitro-2'-hydroxy-2- (2-methoxypropyl) -5,9,9 trimethyl-6,7-benzomorphane hydrochloride (Example 93) is obtained as in Example 93 in a yield of 0.20 g (33.2% of theory) having a melting point of 228 ° C (dec) and a specific rotation value of 10 [α] = - 111.7 ° (c = 0.5, CH 3 OH).

4.3.24 Example 96 f-UIR.SS ^ R 4 -Amino-4-t-methoxypropyl-S.g.g-trimethyl-eT-benzomor-15 fan

The diastereomeric mixture obtained according to Example 67 is (-) - (1R, 5S, 2R) and (+) - (1S, 5R, 2R) -2- (2-methoxypropyl) -3, -nitro-5, Of 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-carbon 20 (5% Pd) at a hydrogen pressure of 5 bar and a temperature of 20 ° C, until hydrogen consumption has ceased (about 3 hours). The thin-layer chromatogram (silica gel 60, chloroform-methanol-concentrated ammonia 90: 10: 0.5) shows the complete reaction of the 3'-nitro compound (Rf = 0.73) to the corresponding 3'-amino compound (Rf = 0.61). ).

25

After filtering off the catalyst, the reaction mixture is evaporated in a vortex evaporator, finally at 80 ° C and under a full water jet vacuum. The residue (3.1 g) is subjected, as in Example 2, to column chromatography on 600 g of silica gel. The diastereomeric 3'-amino compounds are separated by thin-layer chromatography (silica gel 60, chloroform-methanol-conc. Ammonia 95: 5: 0.1.2 x realization). The title compound is obtained which has a lower Rf value of 0.63 in 0.95 g of the evaporation residue of the eluate in question and has a specific rotation value of 10591367 of [α] 25 = -39.8 ° (c = 1, CH 3 OH) so far opposed to all attempts at crystallization. .

4.3.25 Example 97 5 (+ H 1 S 5 R 2 "R) -3'-Amino-2-f 2 -methoxypropyl-5.9.9-trimethyl-6.7-benzomorphan

In the diastereomer separation described above, column chromatography (Example 10 96) gives the title compound as a higher residue with an Rf of 0.69 (1.0 g, specific rotation: [α] 25 D = + 104 ° (c = 1, CH 3 OH)), which has so far opposed all attempts at crystallization.

4.3.26 Example 98 15 (+ H 1 S 5 R 2 ', S) -3'-Amino-2- (2-methoxypropyl-5,9,9-trimethyl-6,7-benzomorphan a) 3'-Nitro precursor ( diastereomeric mixture) Starting from 5.2 g (0.02 mol) of (±) -3'-nitro-5,9,9-trimethyl-6,7-benzomorphan and 5.36 g (0.022 mol) ( S) -2-methoxypropyl-p-toluene sulfonate is obtained as in Example 67, both of the desired diastereomeric bases which are purified by filtration over alumina to give 4.7 g of pure 25 base mixture.

b) 3'-Amino Compounds (Mixture of Diastereomers) • R '* 3'-Nitro Precursor (4.7 g of purified diastereomeric mixture) is hydrogenated as in Example 96 to the corresponding 3'-amino compound (3.7 g of diastereomeric mixture).

68 105913 (c) Column chromatography separation of the title compound

The mixture of diastereomeric 3'-amino compounds (3.7 g) is separated as in Example 96 by column chromatography on silica gel.

5

The title compound with a lower FV value of 0.63 is obtained in a yield of 1.0 g of the eluate as an evaporation residue having a specific rotation value of [α] 25 D = + 40.5 ° (c = 1, CH 3 OH), which has so far resisted any attempt at crystallization.

4.3.27 Example 99 (-H1R5S.2 "S) -3'-Amino-2- (2-methoxypropyl] -5.9.9-trimethyl-6.7-benzomorphan 15 The above column chromatography (Example 98) gives with a higher Rf of 0.69, the title compound as a evaporation residue of 1.1 g of the eluate, specific rotation: [α] D = -105 ° (c = 1, CH3OH), which so far has not crystallized.

4.3.28 Example 100 f -) - (, 1 R 5 S 2 "R) -3'-Acetamido-2-f 2 -methoxypropyl) -5.9.9-trimethyl-6.7-benzomorphane 0.95 g (3.14 mmol) of (-) - (1R, 5S, 2R) -3'-amino-2- (2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphane (Example 96) is acylated as in Example 85. The acetylation product is purified by filtration over alumina as in Example 65. In a thin-layer chromatogram (silica gel 60, chloroform-methanol-ammonia 90: 10: 0.5), the starting compound has an R f of 0.64 and 57. The evaporation residue (0.69 g), which so far has resisted all attempts at crystallization, has a specific rotation value of [α] 25 = -53.6 ° (c = 1, CH 3 OH).

69 105913 4.3.29 Example 101 f + MIS.SR.ZRVffAcetamido [beta] -methoxypropyl-SQQ-trimethyl-ej-benzomorphane oxalate 5 From 1.0 g (3.31 mmol) (+) - (1 , 5R, 2 "R) -3'-Amino-2- (2-methoxypropyl) -5.9.9-trimethyl-6,7-benzomorphane (Example 97) is obtained as in Example 90. The title compound is purified by alumina (0.5 g). ), the evaporation residue is crystallized as in Example 83. In the form of the oxalate, the title compound is obtained in a yield of 0.4 g (27.8% of theory) having a melting point of 148 [deg.] C. (dec.) and [α] 25 , 3 ° (c = 1, CH 3 OH).

4.3.30 Example 102 15 (+ W 1 S 5 R 2 'S) -3, -Aetamido-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) is obtained as in Example 20 100 of the title compound as a non-crystalline evaporation residue (0.6 g, 41.7% of theory) with an Rt of 0.57 and a rotation of [α] D = + 52.8 ° (c = 1, CH 3 OH).

V

v '4.3.31 Example 103 25 (-1- (1R, 5S, 2S, 11'-Acetamido-2- (2-methoxypropyl-5.9.9-trimethyl-6.7-benzomorphane oxalate) Starting from 0.95 g ( 3.14 mmol) of (-) - (1R, 5S, 2S) -3'-amino-2- (2-methoxypropyl) -5.9.9-trimethyl-6,7-benzomorphane (Example 99) is obtained as in Example 30, the title compound in a yield of 0.7 g (51.1%) having a melting point of 148 ° C (dec) and a specific rotation value of [α] 25 D = -39.2 ° (c = 1, CH 3 OH).

70 4.3.32 Example 104 105913 (-) - (1R, 5S, 2'-3-Methoxy-, 6-methoxypropyl-5,9,9,2'-tetramethyl-6,7-benzomorphane hydrochloride 5 From 0.71 g: (2 mmol) of (-) - (1 R, 5 S, 2 "R) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7-benzomorphane hydrochloride (Example 53 ) is obtained as in Example 73 in a yield of 0.38 g (52.0%) having a melting point of 221-224 ° C and a specific rotation value of [α] 25 = -82.6 ° (c = 1, CH 3 OH).

4.3.33 Example 105 (+) - (1S, 5R, 2R) -3'-Methoxy-2- (2-methoxy-propyl) -5.9.9.2'-tetramethyl-6.7-benzomorphane hydrochloride From 0, From 71 g (2 mmol) of (+) - (1S, 5R, 2R) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7 Benzomorphan hydrochloride (Example 54) is obtained as in Example 73 in a yield of 0.44 g (59.8%) as an amorphous powder with a specific rotation of [α] 25 D = + 42.2 ° (c = 1, CH 3 OH).

4.3.34 Example 106 m "(+) - (1S, 5R, 2S) -3'-Methoxy-2- (2-methoxypropyl) -5.9.9.2, -tetramethyl-6.7-benzomorphane hydrochloride From 0, From 71 g (2 mmol) of (+) - (1S, 5R, 2S) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7 benzomorphane hydrochloride (Example 55) is obtained. as in Example 73, the title compound in a yield of 0.40 g (54.7%) having a melting point of 221-224 ° C and a specific rotation value of [α] D = + 81.7 ° (c = 1, CH 3 OH).

30 71 4.3.35 Example 107 105913 (-) - (1R, 5S.2 "S) -3'-Methoxy-2- (2-methoxypropyl) -5.9.9.2'-tetramethyl-6.7-benzomorphanohydrochloride 0.71 g (2 mmol) of (-) - (1R, 5S, 2S) -3'-hydroxy-2- (2-methoxypropyl) -5,9,9,2'-tetramethyl-6, 7-Benzomorphane hydrochloride (Example 56) is obtained as in Example 73 in a yield of 0.42 g (56.1%) as an amorphous powder with a specific rotation of [α] D = -41.0 ° (c = 1, CH 3 OH).

4.3.36 Example 108 M- (1R, 5S.2 "R ') -2,2-Methoxy-2- (2-methoxypropyl) -5,9,9,3,3-tetramethyl-6.7-benzomorphane hydrochloride Starting from 0.71 g (2 mmol) of (-) - (1R, 5S, 2 "R) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7- Benzomorphan hydrochloride (Example 57) is obtained as in Example 73 in a yield of 0.36 g (49.3%), m.p. 224-226 ° C and a specific rotation value of [α] 25 D = -112.2 ° (c = 1, CH 3 OH). ).

4.3.37 Example 109 * (+) - (1 S) SR 1 H 2 R 2 -Methoxy 4-methoxypropyl-SQQS 4-tetramethyl 3-ej-benzomorphane hydrochloride From 0.71 g (2 mmol) (+ ) - (1S, 5R, 2 "R) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphane hydrochloride (Example 58) is obtained as in Example 73 in a yield of 0.39 g (53.0%) as an amorphous powder and a specific rotation value of [α] 25 = + 72.4 ° (c = 1, CH 3 OH).

30 72 105913 4.3.38 Example 110 (+ W 1 S 5 R 2 "SV 2, -Methoxy-2- (2-methoxypropyl-5.9.9.3'-tetramethyl) -6,7-benzomorphane hydrochloride 5 Starting from 0.64 g (2 mmol) (+) - (1S, 5R, 2 "S) -2'-Hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphane (Example 59) is obtained as in Example 73 in a yield of 0.45 g (61.5%) having a melting point of 228-229 ° C and a specific rotation value of [α] D = + 111.5 ° (c = 1, CH 3 OH).

4.3.39 Example 111 M- (1R, 5S.2, 5S-2'-Methoxy-2- (2-methoxypropyl) -5.9.9.3'-tetramethyl-6.7-benzomorphane hydrochloride From 0.71 g (2 mmol) of (-) - (1R, 5S, 2S) -2'-hydroxy-2- (2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphane hydrochloride (Example 60) is obtained as in Example 73 in a yield of 0.40 g (53.4%) as an amorphous powder and having a specific rotation value of [α] 25 D = -71.8 ° (c = 1, CH 3 OH).

4.3.40 Example 112 t M-MR.5S.2 "R1-3'-Hydroxy-2l-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- Benzomorphane hydrochloride (Example 61) is obtained as in Example 73, but with two equivalents of sodium hydride, a mixture of both isomeric monomethoxy derivatives and dimethoxy derivative, which is separated by column chromatography on 100 times silica gel as in Example 2 [eluent: dichloromethane. ammonia 97: 3: 03]. As a middle substance, the flowable compound (Rf = 0.73) is crystallized as: hydrobromide. The title compound is obtained in a yield of 0.62 g (15.0%) having a 73 105913 melting point of 212 ° C (dec) and a specific rotation value of [α] 25 D = -78.4 ° (c = 0.5; CH 3 OH).

4.3.41 Example 113 5 M-MR.5S.211RV21H-hydroxy-3'-methoxy-2- (2-methoxy-dipro-yl) -5.9.9-trimethyl-6.7-benzomorphane hydrobromide

In Example 112, the separated, slow-flowing material (Rf = 0.68) is precipitated as hydro-10 bromide. The title compound is obtained in a yield of 0.88 g (21.2%) having a melting point of 235 ° C (dec) and a specific rotation value of [α] 25 D = -93.1 ° (c = 0.5; CH 3 OH).

4.3.42 Example 114 15 (-1- (1R, 5S.2 "R1-2,3,3-Dimethoxy-2-f2-methoxy-dimethyl-5,9,9-trimethyl-6,7-benzomorphan hydrochloride)

In Example 112, the separated, faster-flowing substance (Rf = 0.86) is precipitated as the hydrochloride. The title compound is obtained in a yield of 0.87 g (22.7%) having a melting point of 193 ° C (dec) and a specific rotation value of [α] 25 = -93.2 ° (c = 0.5; CH 3 OH).

4.4 Compounds (11 According to Special Methods 4.4.1 Example 115 25 (-1- (1R, 5S.2 "R1-2, -Hydroxy-2- (2-hydroxyDropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride) · 1.5 g (3.60 mmol) of (-) - (1R, 5S, 2R) -2- (2-benzyloxypropyl) -2'-hydroxy-5,9,9-30 trimethyl-6,7 Benzomorphan hydrochloride (Example 43) is dissolved in 75 ml of methanol and in the presence of palladium hydroxide on activated carbon (0.6 g of moist "Pearlman catalyst") at a hydrogen pressure of 5 bar and hydrogenated completely to about 6.2 hours. The residue is dissolved in 10 ml of methanol and 30 ml of diethyl ether are added to the solution, after which the separated crystals are separated for about 12 hours. at 5 with suction, washed 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) having a melting point of 276 [deg.] C. (dec.) and a specific rotation value of [α] 25 = -127.4 ° (c = 1). , CH 3 OH).

4.4.2 Example 116 (+ H1S.5R.2 "S1-2, -Hydroxy-2- (2-hydroxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride 15 Starting from 1.5 g (3 , 6 mmol) (+) - (1S, 5R, 2S) -2- (2-Benzyloxypropyl) -2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane hydrochloride (Example 44 ) is obtained as in Example 115 in a yield of 1.0 g (85.5% of theory) having a melting point of 276 ° C (dec) and a specific rotation of [α] D = + 126.8 ° (c = 1, CH 3 OH).

4.4.3 Example 117 (-) - (1R, 5S, 2S, 2S) -2H-Hydroxy-2- (2-hydroxypropyl) -5.9,9-trimethyl-6.7-benzomorphane hydrochloride

According to Example 44, the diastereomer remaining in the mother liquor (3.17 g evaporation residue) is hydrogenated as in Example 115. The title compound is obtained in a yield of 1.5 g (56.2% of theory) having a melting point of 247 [deg.] C. (dec.) [Α] 25 D = -86.8 ° (c = 1, CH 3 OH).

A

t 30 75 105913 4.4.4 Example 118 (+ 1- (1 S. 5 R 2 "R 1-2'-hydroxy-2-f 2 -hydroxypropyl) -5.9.9-trimethyl-6.7-benzomorphane hydrochloride?

According to Example 43, the diastereomer remaining in the mother liquor (3.17 g evaporation residue) is hydrogenated as in Example 115. The title compound is obtained in a yield of 1.5 g (56.2% of theory) having a melting point of 247 [deg.] C. (dec.) [.Alpha.] D @ 20 = + 86.4 DEG (c = 1, CH3 OH).

4.4.5 Example 119 (+ 1- (1R / 5S / 5R, 2S) -2'-Fluoro-2- (2-methoxypropyl) -5.9,9-trimethyl-6.7-benzomorphane oxalate a) Starting compound: (1R / S, 5S / R, 2 "S) -2'-Fluoro-2- (2-methoxypropionyl) -5,9,19-trimethyl-6,7-benzomorphane (diastereomeric mixture) 5, 94 g (0.02 mol) of (+) - 2, -nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride 20 are acylated as in Example 32 with 2.68 g (0.22 mol) (S) -2-metoksipropioni-acid chloride. The acylation product thus obtained (7.0 g) is hydrogenated as described above to the corresponding 2'-amino analog. The latter is hydrogenated by methods known in the art [T.L. Fletcher and M.J. Namkung, Chem. and Ind. 1961. 179] - the corresponding 2'-fluoro derivative (5.7 g). This gives a mixture of the expected diastereomers which do not show separation in TLC (Rf = 0.73, silica gel, chloroform-methanol-concentrated ammonia 90: 10: 0.5).

(B) Reaction to the title compound 1.58 g (5 mmol) of the precursor is reduced as in Example 32 with lithium aluminum hydride (LiAlH4) to the title compound and, as described above, purified by: column chromatography on silica gel. The evaporation residue of the eluate is purified by crystallization of purified re 105913 (0.4 g, Rf = 0.78) as in Example 83 as the oxalate. The title compound is obtained in a yield of 0.35 g (17.7% of theory) having a melting point of 165 ° C (dec) and a rotation of [α] 25 D = + 9.7 ° (c = 1, CH 3 OH). The material is formed by a mixture of the expected diastereomers ((1R, 5S, 2 "S) and (1S, 5R2" S)) in a ratio of about 1: 1 (obtained by 1 H-NMR spectroscopy).

4.4.6 Example 120 (-W1R / S. 5S / R. 2nR) -2'-Fluoro-2- (2-methoxypropyl) -5.9.9-trimethyl-6.7-benzo-10-morphane oxalate (a) Starting compound: (1) R / S, 5S / R, 2 "R) -2, -Fluoro-2- (2-methoxypropionyl) -5,9,9-trimethyl-6,7-benzomorphane (diastereomeric mixture) From 2.97 g (0.01 mol) of (+) - 2'-nitro-5,9,9-trimethyl-6,7-benzomorphane hydrochloride is obtained using 1.34 g (0.011 mol) of (R) -2-methoxypropionic acid. acid chloride, a mixture of the expected diastereomers of 2'-fluoro-2- (2-methoxypropionyl) -5,9,9-trimethyl-6,7-benzomorphans (reaction flow as in Example 119), which does not show separation by thin layer chromatography (Rf = 0.73, silica gel) , Chloroform-methanol-concentrated ammonia 90: 10: 0.5), yield: 2.9 g.

b) Reaction to the title compound 2.9 g (9.2 mmol) of the above precursor is reduced as in Example 119 with lithium aluminum hydride to the title compound. The reaction product is purified as described above. The evaporation residue (0.9 g) of the pure fractions is crystallized as in Example 98 as oxalate. The title compound is obtained in a yield of 0.88 g (22.3% of theory) having a melting point of 169 ° C (dec) and a specific rotation value of [α] ρ5 = -9.5 ° (c = 1, CH 3 OH) of the expected diastereomers ((1R) , 5S, 2 "(R) - and 30 (1S, 5R, 2" (R))).

«

Claims (2)

A process for the preparation of pharmaceutically valuable benzomorphans of the general formula I 1 R 1 -N-CH-C-X - R 2 10 R 7 where X is oxygen or sulfur; R 1 is C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkinyl, an aromatic group of 6-10 carbon atoms, also as a combination, which aromatic group may be substituted by one or more of the following: lower alkyl , alkoxy, nitro, amino, halogen, wherein the substituents may be the same or different; R 2 is hydrogen, Ο, -CV alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkinyl, an aromatic group of 6-10 carbon atoms, also as a combination, which aromatic group may be substituted by one or more of the following: lower alkyl, alkoxy, nitro, amino, halogen, wherein the substituents may be the same or different, an aryl group bonded by an alkylene of 7-14 carbon atoms, which aromat may be substituted by one or more of the following: lower alkyl, alkoxy, nitro, amino, halogen, which substituents may be the same or different; R 3 is hydrogen, C 1 -C 6 alkyl; R 4 is C 1 -C 8 alkyl; R5 is C1-C8 alkyl; R 6 is C 1 -C 6 alkyl, an aromatic group of 6-10 carbon atoms, also as a combination which aromatic group may be substituted by one or more of the following: lower alkyl, alkoxy, nitro, amino, halogen, the substituents may be the same or different; R 7 and R B are independently hydrogen, C alkyl group may be substituted with one or more halogen atoms which may be the same or different, -CN, -NO 2 NH 2 -NH 1 C 1 -C 6 alkyl, -N 2 -C 8 alkyl), the alkyl groups being the same or different, -NH -acyl or -N-acyHC ^-Cg alkyl), wherein acyl is a benzyl or alkylcarbonyl group, the alkyl group of which may be a straight or branched lower alkyl of 1-6 carbon atoms and which alkyl group may be substituted by one or several halogen atoms, which may be the same or different, as well as their stereoisomers and acid addition salts, provided that X is oxygen R 1 is C 1 -C 3 alkyl, C 3 alkenyl, C 3 alkinyl; R 2 is hydrogen, C 1 -C 4 alkyl, C 3 and C 4 alkenyl; R 3 is hydrogen, C 1 -C 3 alkyl; R 4 is methyl; R 5 is methyl; R 6 is C 1 -C 4 alkyl or phenyl, and one of the substituents R 7 and R 8 is hydrogen, so the residual substituent R 7 and R 8 in the 2 'position does not refer to hydrogen, hydroxy, C either a) benzomorphans of the general formula 2, wherein R4, R5 and R6 are the same as above and R9 and R10 are either the same as R7 and R8 or are substituents substitutable in per se known manner and known per se in an inert solvent - optionally in the presence of an acid-binding medium - is reacted with a carboxylic acid derivative of the general formula 4 · JfT R, Y-2- £ x- * 2 Jff 30 - * TVCR5 R & X = J XR '(2) (3)' 84 where Y is a substituent leaving a substituted amino group selected from the group of halogen, hydroxy, OC (O) alkyl, O-acyl, OSO2 alkyl and OSO2aryl and R1, R2 and R3 and X refers to the above, and the resulting acid amide 3 is then reduced in an inert solution medium. part in a manner known per se to an amine of the general formula 6 J R3 / R4 R 6 = R 2 (6) and if necessary substituents R 9 and R 10 are converted to substituents R 7 and R 8 and reaction mixture separates r f 2 T 2 R 2 (6) <1) Ψ or b) benzomorphans of general formula 2; fN-Π R '•: · r \ r “ζ ~ 0Ηά * ^ * 2 cf rr / ^ r6 (2) (β) 105913 - where R4, R5 and R6 refer to the same as above and R9 and R10 either refer to the groups R7 and R8 or thereto transferable substances individually known in the art - known per se in an inert solvent - optionally in the presence of an acid binding agent - are reacted with an alkylating agent of the general formula 5, wherein Z is a substituent leaving group substituted with a secondary amino group selected from the group of halogen - such as C1, Br and I - or arylsulfonated OSO2aryl - such as e.g. tosylate or alkyl sulfonate - such as e.g. methanesulfonate or halogenomethanesulfonate or a sulfate group, to a tertiary amine of type 6 R> K == γ R6 (6) and, when required, substituents R9 and R10 are converted to groups R7 and R8 We ds (R R r 2 L L / / \ rzV - / R6 (6) (1) and the reaction product is separated into sinus optical isomers. 2. A process according to claim 1 for the preparation of (-) - (1R, 5S, 2 "R) -3'-wt hydroxy-2- (2-methoxypropyl) -5,9> 9-trimethyl-6,7- benzomorphan and its acid addition salt, characterized in that corresponding starting materials are used.