HK1003111B - Benzomorphanes and their use as pharmaceuticals - Google Patents

Description

The invention relates to new benzomorphans, their manufacturing process and their use as medicinal products. Other In which XO or sulphur;R1C1-C8 alkyl, C3-C6-alkenyl, C3-C6-alkynyl, an aromatic residue containing 6 to 10 carbon atoms, whether or not in compounds, where the aromatic residue may be substituted by one or more niederalkyl groups (n), alkoxy groups (n), nitrogroups (n), amines (n) and/or one or more halogen atoms (s) equal to or different from each other;R2hydrogen, C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, an aromatic residue with 6 to 10 carbon atoms, whether or not in compounds, where the aromatic residue may be substituted by one or more niederalkyl groups (n), alkoxy groups (n), nitrogroups (n), amines (n) and/or one or more halogen atoms (s), whether or not identical with each other; a length of not more than 30 mm,the aromatic compound may be substituted with one or more niederalkyl groups (n), alkoxy groups (n), nitrogroups (n), aminogroups (n) and/or one or more halogen atoms (n) which are the same or different from each other;R3Hydrogen, C1-C6-alkyl;R4C1-C8-alkyl;R5C1-C8-alkyl;R6C1-C8-alkyl, an aromatic residue containing 6 to 10 carbon atoms, whether or not in compounds where the aromatic compound may be substituted with one or more niederalkyl groups (n), alkoxy groups (n), nitrogroups (n), aminogroups (n) and/or one or more halogen atoms (n) which are the same or different from each other;R7and R8 Hydrogen, C1-C8-alkyl, halogens, and their halogens -OH, C1-C8-Alkoxy, an O-benzoyl or O-alkylcarbonyl residue with a straight-chain or branched-chain niederalkyl residue of 1 to 6 carbon atoms, where the alkyl residue may be replaced by one or more halogen atoms, which may be the same or different, as appropriate,Other -CN, -NO2, a thickness of not more than 0,05 mm, -N (C1-C8-alkyl) 2, wherein the Alkyl residues may be the same or different, -NH acyl or -N acyl-C1-C8-alkyl, where acyl is used for benzoyl or for an alkyl carbonyl residue with a straight chain or branched n-alkyl residue of 1 to 6 carbon atoms, where the alkyl residue may be substituted, where appropriate, by one or more halogen atoms, which may be the same or different, their stereoisomers and their acid addition salts, provided that - in the case of XOxygen;R1C1-C3-alkyl, C3-alkenyl, and other C3 alkynyl;R2 hydrogen, C1 to C4 alkyl, C3 and C4-alkenyl;R3Hydrogen, C1-C3-alkyl;R4Methyl;R5Methyl;R6C1-C4-alkyl or phenyl and one of the two substituents R7 or R8 means hydrogen - the remaining substituent R7 or R8 in the 2' position shall not have the meaning of hydrogen, hydroxy, C1-C3-alkoxy or O-acyl.

The preference shall be given to compounds of general formula I. In which XOxygen or sulphur;R1Methyl, ethyl, propyl, isopropyl, phenyl;R2Methyl, ethyl, propyl, isopropyl, allyl, propargyl, phenyl, benzyl;R3Hydrogen, C1-C4-alkyl;R4Methyl, ethyl, propyl, isopropyl;R5Methyl, ethyl, propyl, isopropyl;R6Methyl, ethyl, propyl, isopropyl, phenyl;R7Fluor, chlorine, hydroxy, niederalkyl, C1-C3-alkoxy, an O-benzoyl or O-alkylcarbonyl residue with a straight chain or branched niederalkyl residue containing 1 to 6 carbon atoms, where the alkyl residue may be replaced by one or more halogen atoms, if applicable, which may be the same or different;R8 may mean hydrogen, niederalkyl, hydroxy or C1-C8-alkoxy, their stereoisomers and their acid addition salts.

The use of compounds of general formula I is particularly favoured. In which XOxygen,R1Methyl,ethyl;R2Methyl;Ethyl;R3Hydrogen;R4Methyl,ethyl;R5Methyl,ethyl;R6Methyl,ethyl;R7Hydroxy,methyl,methoxy, an O-benzoyl or O-alkylcarbonyl residue with a straight chain or branched niederalkyl residue containing 1 to 6 carbon atoms, where the alkyl residue may be replaced by one or more halogen atoms, if applicable, which may be the same or different;R8 may mean hydrogen, methyl, ethyl, hydroxy or C1-C3-alkoxy, their stereoisomers and their acid addition salts.

The most commonly used compounds are formula I compounds, In which X may mean oxygen;R1Methyl;R2Methyl;R3Hydrogen;R4Methyl;R5Methyl;R6Methyl;R7Hydroxy, Methyl, Methoxy, Acetoxy;R8Hydrogen, Methyl, Hydroxy, Methoxy or Ethoxy and the substituent R7 is in the 3' position and the substituent R8 is in the 2' position and the 2' carbon atom has an R configuration and their acid addition salt. Other The invention relates to the individual isomers, their mixtures and the corresponding physiologically suitable acid addition salts with inorganic or organic acids. For example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulphonic acid, ethanol sulphonic acid, toluene sulphonic acid, benzene sulphonic acid, lactic acid, malonic acid, amber acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid or benzoic acid are preferred.

Unless specifically different information is given, the general definitions shall be used in the following sense: C1-C6-alkyl or C1-C8-alkyl generally means a branched or unbranched hydrocarbon residue with 1 to 6 or 8 carbon atoms, respectively, which may be replaced by one or more halogen atoms, preferably fluorine, which may be the same or different from each other. The substance is to be classified in the immediate vicinity of the place of manufacture, in accordance with the provisions of the relevant provisions of the relevant Union legislation, and in the immediate vicinity of the place of destination.

Alkenyl is generally a straight chain or branched hydrocarbon residue with 3 to 6 carbon atoms and one or more, preferably with a double bond, which may be replaced by one or more halogen atoms, preferably fluorine, which may be the same or different.

Examples are: The following substances are to be classified in the same heading as the product: 2-propenyl (allyl), 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-hexenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-2-butenyl-2-butenyl, 2-methyl-2-butenyl-2-butenyl, 2-methyl-2-buten-2-buten, 2-methyl-2-buten-2-buten, 2-methyl-2-buten-2-buten, 2-methyl-2-buten-2-buten, 2-methyl-2-buten-2-buten, 2-methyl-2-buten-1-buten, 2-methyl-2-buten, 2-methyl-2-buten-2-buten, 2-methyl-2-buten, 2-methyl-2-buten-2-buten, 2-methyl-2-buten, 2-methyl-2-buten-1-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-buten-1-buten, 2-methyl-2-buten, 2-methyl-2-buten, 2-buten-1-buten, 2-methyl-2-buten, 2-buten-1-buten, 2-methyl-2-buten, 2-buten-1-buten, 2-methyl-2-buten, 2-buten, 2-buten-1-buten, 2-butyl-2-buten, 2-buten, 2-butyl-2-buten, 2-buten, 2-butyl-2-buten, 2-butyl-buten, 2-butyl-butyl-butyl-butyl, 2-butyl-butyl, 2-but

The allyl residue is preferred.

Alkynyl is generally a straight chain or branched hydrocarbon residue with 3 to 6 carbon atoms and one or more triple bonds.

Preferably a low alkyl residue (propargyl) with 3 carbon atoms and a triple bond, which may be replaced by one halogen atom, preferably fluorine, or by several halogen atoms, which may be the same or different.

Acyl is generally a synonym for benzoyl or alkylcarbonyl residues, such as straight-chain or branched niederalkyl with 1 to about 6 carbon atoms, which are bound by a carbonyl group, whereby the alkyl residue may be substituted, where appropriate, by one or more halogen atoms, which may be the same or different from each other.

Acyloxy stands for an acyl group bound by an oxygen, where acyl has the following meanings.

Aryl generally represents an aromatic residue with 6 to 10 carbon atoms, even in compounds where the aromatic residue can be substituted with one or more niederalkyl groups, alkoxy groups, nitrogroups, amines and/or one or more halogen atoms, whether or not the same.

An aryl is generally an aryl residue with 7 to 14 carbon atoms bound by an alkyl chain, whereby the aromatic compound may be substituted with one or more niederalkyl groups (n), alkoxy groups (n), nitrogroups (n), amines (n) and/or one or more halogen atoms (s) which are the same or different from each other. Aryl residues with 1 to 6 carbon atoms (n) in the aliphatic part and 6 carbon atoms (n) in the aromatic part are preferred. The preferred aryl residues are, unless otherwise stated, benzyl, ethyl and phenylpropyl.

Alkoxy generally refers to a straight chain or branched hydrocarbon residue with 1 to 8 carbon atoms bound to an oxygen atom.

Amino means, unless otherwise specified, an NH2 function, which may be substituted by one or two C1-C8 alkyl, aryl or aryl residues, whether or not the same.

Alkylamine is an acronym for methylamine, ethylamine, propylamine, 1-methylethylamine, butylamine, 1-methylpropylamine, 2-methylpropylamine or 1,1-dimethylethylamine.

Dialkylamine is an acronym for dimethylamine, diethylamine, dipropylamine, dibutylamine, di- ((1-methylethyl) amine, di- ((1-methylpropyl) amine, di-2-methylpropylamine, ethylmethylamine, methylpropylamine.

Halogen, unless otherwise stated, is the primary representation of fluorine, chlorine and bromine and the secondary representation of iodine.

Some of the benzomorph derivatives of generic formula I are known from European patent application No 0 004 960.

The pharmacological characterisation of the product

It is known that after systemic application of glutamate, neurons in the brain of mice are destroyed [S.M. Rothman and T.W. Olney, Trends in Neurosciences 10 (1987) 299] This finding leads, among other things, to the conclusion that glutamate plays a role in neurodegenerative diseases [R. Schwarcz and B. Meldrum, The Lancet 11 (1985) 140].

Substances such as quisqualinic acid, caicic acid, ibotic acid, glutamic acid and N-methyl-D-aspartic acid (NMDA) are also known as exogenous and endogenous neurotoxins. These substances are selective in their neurotoxicity to individual cell types, so that in animals specific brain lesions can induce malfunctions comparable to those associated with epilepsy and other neurodegenerative diseases such as Huntington's disease and Alzheimer's disease.

In addition, in vivo and in vitro studies have shown that the cell damage and dysfunction in the brain due to hypoglycaemia, hypoxia, anoxia and ischemia are partly due to increased synaptic activity, with the glutamate synapse being of particular importance. Substances and ions that inhibit the activity of the glutamate receptor and the ion channel associated with this receptor, such as competitive and noncompetitive antagonists of excitatory amino acids and magnesium ions (Mg2+) protect brain cells from hypoxic and ischemic damage, respectively. These findings indicate that the important glutamate receptor plays an important role in the mediation of ischemic injury.

Biochemical and electrophysiological studies show that the receptor ion channel is highly sensitive to fluctuations in magnesium concentration, and that a drop in magnesium concentration leads to spontaneous epileptic discharges in the hippocampus which can be inhibited by excitatory amino acid antagonists.

Surprisingly, it has now been found that generic formula I benzomorphans block the NMDA channel and have neuroprotective effects.

The production of these benzomorph derivatives is known from DE-PS 21 05 743 and DE-OS 28 28 039 and from the literature (H. Merz and K. Stockhaus, J. Med. Chem. 22 (1979) 1475); it is also known that such compounds have analgesic properties and can be used therapeutically as non-addictive analgesics and antitussives (DE-PS 21 05 743).

The hippocampal section is used as a test system for the detection of the NMDA antagonistic effect of benzomorphanderivatives, by means of microelectrodes, the shaper collaterals of the hippocampal section in a perfusion chamber are stimulated and the resulting sum potentials extracellularly derived at the pyramidal cells of the CAI region (H.L. Haas, B. Schaerer and M. Vosmansky, J. Neuroscience Meth. 1 (1979) 323).

The neuroprotective effect of benzomorphanderivatives, which are included in the generic formula I, has also been demonstrated in relation to protein synthesis and neurotransmitter release in the hippocampal tract.

Receptor binding tests further indicate that the benzomorphanderivatives disclosed are non-competitive glutamate receptor antagonists.

Furthermore, the neuroprotective effect of benzomorph derivatives of generic formula I in mice has been demonstrated in vivo by inhibition of N-methyl-D-aspartic acid induced lethality (J.D. Leander et al., Brain Research 448 (1988) 115) and by inhibition of ischaemic neuronal cell death in mice and desert sprint mice (gerbil).

These results provide evidence that the benzomorph derivatives of the general formula I can be used in neurodegenerative diseases and in various genetic brain chemistry. The following conditions are considered to be associated with the treatment of patients with epilepsy, hypoglycaemia, hypoxia, anoxia, brain injury, brain oedema, amyotrophic lateral sclerosis, Huntington' s disease, Alzheimer' s disease, hypotension, heart attack, stroke and perinatal asphyxia.

The Commission has

The benzomorph derivatives of generic formula I and their acid addition salts with pharmacologically harmless acids are known to be capable of being transferred to the usual formulations, such as tablets, dressing, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inert pharmaceutically suitable carriers or solvents, where the proportion of pharmaceutically active compounds should be in the range of 0,5 to 90% by weight of the total composition, i.e. in amounts sufficient to achieve the dosage range indicated below.

For example, the formulations are prepared by spreading the active substances with solvents and/or carriers, using emulsifiers and/or dispersants where appropriate, where, for example, when using water as a diluent, organic solvents may be used as solvent intermediates or auxiliary solvents where appropriate.

The excipients are water, pharmaceutically safe organic solvents such as paraffins (e.g. petroleum fractions), oils of vegetable origin (e.g. peanut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerin), carrier substances such as natural rock flour (e.g. kaolin, clay, talcum, chalk), synthetic rock flour (e.g. highly dispersible silica and silicates), sugars (e.g. cane, milk and sugar), emulsifiers (e.g. lignin, suflavins, polyethyl ethanol, polyethyl nitrate and starch) and methylamine (e.g. sodium, methylamic acid and sodium) and methylamic acid (e.g. sodium, methylamic acid and sodium).

The tablets are normally administered intravenously, preferably by parental injection, especially by infusion. In the case of oral administration, the tablets may naturally contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate, in addition to the substances mentioned above, together with various additives, such as starch, preferably potato starch, gelatine and the like. Lubricants, such as magnesium stearate, sodium lauryl sulphate and talcum powder, may also be used. In the case of aqueous suspensions, the active substances in addition to the excipients mentioned above may be replaced by various flavourings or colouring agents.

For parenteral use, solutions of the active substances may be used using suitable liquid carriers.

The dosage for oral administration is 1 to 300 mg, preferably 5 to 150 mg.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the route of administration, the individual's behaviour towards the medicinal product, the formulation and the time or interval at which it is administered.

In addition, the compounds of generic formula I or their acid additive salts may be combined with other active substances.

Examples of wording Tablets The tablet contains the following ingredients:

Wirkstoff gemäß Formel I	0,020 Teile
Stearinsäure	0,010 Teile
Dextrose	1,890 Teile
gesamt	1,920 Teile

Manufacture

The substances are mixed in a known way and the mixture is sold in tablets, each weighing 1.92 g and containing 20 mg of the active substance.

Ampulla solution Composition of the

Wirkstoff gemäß Formel I	1,0 mg
Natriumchlorid	45,0 mg
Aqua pro inj.	ad   5,0 ml

Manufacture:

The active substance is dissolved in water at its own pH or, where appropriate, at pH 5,5 to 6,5 and mixed with sodium chloride as an isotonic agent. The resulting solution is filtered without pyrogen and the filtrate is filled under aseptic conditions in ampoules which are then sterilised and melted down.

Other, of circular cross-section

Each of the cones contains: Other

Wirkstoff gemäß Formel I	1,0 Teile
Kakaobutter (Schmp.: 36-37°C)	1200,0 Teile
Carnaubawachs	5,0 Teile

Manufacture

Cocoa butter and carnauba wax are melted together, the active substance is added at 45°C and stirred until the mixture is completely dispersed, the mixture is poured into a suitable size and the suppositories are packaged appropriately.

The synthesis process

The production of the bezomorph derivatives of type 2 used as starting materials for the various synthesis processes is either known from the state of the art (DE-A 20 27 077, CA 74 (1971) 125482x; EP-B 4960, CA 93 (1980) 4941 f) or described in the following examples. The substituents R9 and R10 are either identical to the desired substituents R7 and R8 or are transferred to them at a later stage of synthesis.

Other

The introduction of a desired substituent to the amino function of the benzomorphan nitrogen can be achieved by acylation with an appropriate activated carbonic acid derivative, and corresponding type 4 carbonic acid derivatives are known from the state of the art or are readily available by common synthesis methods.

The acylation itself is a variety of selection methods (C. Ferri, Reactions of organic synthesis, Georg Thieme Verlag Stuttgart, 1978, pp. 222 et seq. and cit.

Err1:Expecting ',' delimiter: line 1 column 275 (char 274)

The production of the desired hydrocarbons is known from the state of the art (Houben-Weyl, Methods of Organic Chemistry, Volumes VIII and E5, Georg Thieme Verlag, Stuttgart, 1952 and 1985 respectively) insofar as they are not commercially available. The type 2 benzomorph derivative is preferably produced in halogenated hydrocarbons, particularly dichloromethane, and in the presence of tertiary amines, such as triethylamine, with the desired hydrocarbons, particularly the heavily weighted varicoyl chloride, but it is also possible to introduce the product into water or into an alcohol containing hydrocarbons, particularly in the presence of alkali, in the presence of tertiary amines, such as triethylamine, with the desired hydrocarbons, particularly the heavily weighted varicoyl chloride, but it is also possible to introduce the product into water, particularly in the presence of the highly reactive agent, the so-called Schumann-Varicoyl chloride, in the presence of alkali, and in the presence of alkali, especially in the presence of the reactive agent, the Alkalic acid, which is known as the Varicoyl chloride, and the hydrocarbons, which are produced by the German chemical agent, Varicoyl chloride, and the hydrocarbons, which are known as the alkali, are produced by the Alkalic acid, and the hydrocarbons, but not by the hydrocarbons, but by the hydrocarbons, which are produced by the hydrocarbons.

Err1:Expecting ',' delimiter: line 1 column 192 (char 191)

The reaction temperature can be varied to a great extent by the use of carbonic acid halogenides, particularly carbonic acid chlorides, which are lowered by too low a reaction rate and increased by the predominance of undesirable side reactions. The reaction temperatures have been shown to be in the range of -50°C to 150°C, preferably 0°C to 75°C. It is advisable to use a small excess of the acylation agent in the presence of an acid-binding agent in a slightly larger excess to ensure the most complete implementation of the method.

Other

To obtain the desired type 6 amine, the next reaction step requires the reduction of the acid amide 3.

Such reductions of acid amides are known from the state of the art and can be achieved by electrolytic reduction, by reduction with alkali metals and by catalytic reduction (R. Schröter in Houben-Weyl, Methods of Organic Chemistry, Volume XI/1, Georg Thieme Verlag, Stuttgart 1957, p. 574) or by diboran or boron hydrogen derivatives (J. Fuhrhop and G. Penzlin, Organic Synthesis - Concepts - Methods - Starting Materials, VCH-Verlagsgesellschaft, Weinheim 1986, p. 90).

The preferred method is to reduce with complex hydrides, such as alkali boron or alkali aluminium hydrides or with their suitable derivatives, where appropriate in the presence of a catalyst (N.G. Gaylord, Reduction with Complex Metal Hydrides, Wiley New York 1965; A. Hàjos, Complex Hydrides, Elsevier New York 1979; V. Baant, M. apka, M. erny, V. Chvalovsky, K. Kochloefl, M. Kraus and J. Màlek, Tetrahedron, 9 - (((1968) 3303), with particular preference for luminium hydridinium.

The reaction media are all inert organic solvents which do not change under the given reaction conditions, preferably ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, di-n-butyl ether, glycol dimethyl ether (glyme), diglycol dimethyl ether (diglyme), cyclic ether such as dioxane and particularly tetrahydrofuran, the choice of solvent being determined, inter alia, by the type of reducing agent used.

It is generally advantageous to allow such reductions to be carried out in the presence of an excess of the reducing agent, preferably one of the above complex hydrides, in particular lithium alanate, which is in the range of 5 to 100%, preferably in the range of 10 to 50%.

The reaction partners are usually put together under freezing or at room temperature and then heated to temperatures in the range of 150°C to 75°C, depending on the reactivity of the conduits.

3.2 Other

Another way to produce benzomorph derivatives of type 6 is to implement the benzomorph derivative 2 with suitable alkylators of type 5, where in the formula 5Z is a leafing group. Preferred leafing groups are halogens such as Cl, Br, I or O-SO2-aryl such as tosylate or an alkyl sulfonate such as O-SO2-alkyl or methan sulfonate or sulfate.

All inert solvents which do not change substantially under the given reaction conditions and which cannot themselves adversely affect the reaction process as reactive components are suitable as solvents. These 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 (Glyme), diethyl glycol dimethyl ether (Diglyme), diethyl ether (Diglyme), diethyl or ketone such as methylen or tetrahydrofuran or aceton or acid amides such as hexanethylphosphorethyl or dimethyl methylamide.

In addition, mixtures of the above solvents may be used, with particular preference being given to tetrahydrofuran or dimethylformamide or mixtures of these two solvents.

The reaction temperature can vary widely in the reaction line, which is pushed downwards for practical purposes by too low a reaction rate and upwards by taking over by-products.

3.3 Other

The conversion of R9 and/or R10 to R7 and/or R8 as necessary, if necessary, is a series of reactions which cannot be summarised in a uniform scheme.

4. Examples

Note:Ether is defined as diethyl ether, unless otherwise specified.

4.1 Compounds of type (1) - produced by the 3.1 process The test chemical is a chemical which is used to determine the concentration of a substance in a solution. (a) Acceleration

27.8 g (0.12 mol) (±)-2'-hydroxy-5,9.9-trimethyl-6,7-benzomorphan [DOS 20 27 077; CA 74, 125482x (1971) ] are mixed in 278 ml of absolute dichloromethane in the presence of 27.9 g (0.275 mol) triethylamine, stirred for about 30 minutes with 19.2 g (0.156 mol) (R) 2-methoxypropionic acid chloride. The reaction temperature is maintained in the range 30-35 °C. The reaction is then boiled for one hour in the return stream. Then cooled and washed successively with 175 ml of water, 175 ml of 2 N saline acid and 175 ml of water twice. After drying with the sulphur dioxide and draining the solution, the solution is injected into a vacuum, and the final solution is obtained at 80 °C and a volume of 42 g/cm3 (a) at a temperature of 80 °C. The product is then washed twice with 175 ml of water.

(b) Reduction

The acylation product obtained by the above procedure is dissolved in 425 ml of absolute tetrahydrofuran, stirred and chilled for one hour at 10-15°C, then dripped into a suspension of 9.1 g (0.24 mol) of lithium aluminium hydride (lithium tetrahydridoalanate) in 300 ml of tetrahydrofuran, then stirred and boiled for two hours, then dripped in 25 ml of water in an ice bath and stirred, and finally, after adding another 70 ml of water and saturated dihydromethane tetrahydrofuran (890 ml) in a separator, the separated water is diluted in a thin phase of i.V. This phase of i.V. is then dissolved in a dihydromethane hydrochloride solution containing 0.7 g/ ml of water and 100 ml of ammonium chloride (350 ml/ ml) of water, with a second phase of dihydromethane tetrahydrofuran (D.C.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H.H

The diastereomers can be separated by crystallization of the hydrochloride. The base mixture is dissolved in 120 ml of absolute ethanol and acidified with hydrochloric acid (12 ml of 32 % hydrochloric acid). The solution immediately crystallizes the title compound (Rf = 0.42), which is sucked after cooling (ice bath), washed in portions with ice-cold ethanol (40 ml) and finally dried at 80 °C to weight consistency. The yield is 15.0 g (73.5% of the theoretically maximum amount available). $\frac{\text{25}}{\text{D\hspace{1em}}}$ A sample crystallized from a mixture of methanol and diethyl ether melts unchanged at 264°C (zero) and has a specific rotation of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -118.6° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

The mother sludge produced in the process described in example 1 contains predominantly the diastereomer with a Rf value of 0.51. It is steamed and the residue (25 g) is heated for one hour with 40 ml of isopropanol by stirring to return temperature. The resulting crystalline suspension is left at room temperature for about 12 hours, then vacuumed and washed in portions with a little cold isopropanol. The crystalline solution consists mainly of the title compound next to residues of the diastereomer (example 1). The title compound is transferred to the free forms and basaltatographically cleaned.After the phases have been separated, the aqueous layer is extracted once more with 25 ml dichloromethane. The combined dichloromethane extracts are washed twice with 25 ml of water each, then dried with sodium sulphate after filtration of the drying agent and evaporated, last at 80°C and in a full water jet vacuum. The residue (15.4 g) is polychromatographed to 2 kg of silica gel (MN K 60, 230-400 mesh ASTM, by Macherey and Nagel) using dichloromethane methanol concentrate ammonia 95:5:0.1 as an elution agent. The fractions with the pure substance are finally obtained and give a residue (6.8) called gamp. The residue is dissolved in 14 ml of ethanol and the solution is dissolved in 10 ml of ethanol.After leaving the product for about 12 hours in the refrigerator, it is sucked out and first washed with a methanol-ether mixture of 1:2, then with ether. After drying, last at 80°C, 6.4 g of the product (31.4% of the theoretically maximum quantity available) with a melting point of 236° (Zers. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a chemical compound with a specific gravity of 10 μm.

The test chemical is used to determine the concentration of the active substance in the test chemical.

Based on 9,25 g (0,040 mol) (±)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 6,37 g (0,052 mol) (S)-2-methoxypropionic acid chloride, the title compound is obtained by analogy in Example 1 at a yield of 5,1 g (75,0 % d. Th) with an Rf value of 0,42, a melting point of 270 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +117° (c = 1, CH3OH).

The test chemical is a chemical which is used to determine the concentration of a substance in a solution.

The parent sludge in example 3 gives the title compound in an analogue to example 2 at a yield of 3.2 g (47.1% d.j.) with a melting point of 235 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -89.9° (c = 1, CH3OH).

The test chemical is a chemical which is used to determine the concentration of a substance in a solution.

By analogy, if the racemic parent compound 2,31 g (0,010 mol) of enantiomeric pure (-)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan is replaced by 1,60 g (0,013 mol) (R) -methoxypropionic acid chloride, the sterically pure base of the parent compound is obtained from example 1 and from this base the hydrochloride is obtained at a yield of 3,0 g (88,4% d. Th.) at a melting point of 264 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -117.5° (c = 1, CH3OH).

The test chemical is a chemical which is used to determine the concentration of a substance in a solution.

If the synthesis with (S) -2-methoxypropionic acid described in example 5 is performed, the title compound is obtained at a yield of 2,9 g (85,3% by weight) with a melting point of 235 °C (zers.) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -89.7° (c = 1, CH3OH).

The test chemical is a chemical which is used to determine the concentration of a substance in a solution.

Starting from 4,62 g (0.020 mol) (-)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 3,20 g (0.026 mol) (R/S)-2-methoxypropionic acid chloride, a mixture of the expected diastereomeric bases is obtained in analogy in example 1, separated by analogy in example 2 by column chromatography. The slower-moving substance (Rf = 0,42) is crystallized as hydrochloride as described there. The title compound is obtained at a yield of 2.1 g (61.8% d. Th.) with a melting point of 264 °C (Zers.) and a specific rotational value of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -117.9° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in Annex I to Regulation (EC) No 1907/2006'

From the fast-acting substance (Rf = 0,51) separated in example 7, the title compound is obtained after transfer to the analogue hydrochloride in example 2 at a yield of 2,2 g (64.7% by weight) with a melting point of 235 °C (zers.) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -88,6° (c = 1, CH3OH).

The test chemical is a chemical which is used to determine the concentration of a substance in a solution.

2,60 g (0.025 mol) (S) -2-methoxypropionic acid chloride is stirred in 100 ml of absolute tetrahydrofuran with 4,04 g (0.025 mol) 1,1'-carbonyldiimidazole for two hours at room temperature. After adding 4,62 g (0.020 mol) (+)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan, stir for two days at room temperature. Then evaporated, the residue is then absorbed with 75 ml of dichloromethane and washed successively with 2 N HCl and twice with water. After separation, the organic phase is dried with sodium sulphate and, after filtration of the dry point, finally reduced to a vacuum at 80 °C and water, the resulting vacuum is specified. The resulting product is described in an example as a reduction product of Lithium hydride (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) (Lithium) ( $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +117,4° (c = 1, CH3OH).

The test chemical is a chemical which is used to determine the concentration of a substance in a solution.

Starting from 1,69 g (0.006 mol) (±) -9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphan hydrochloride [DOS 20 27 077; CA 74, 125482x (1971) ], 1,82 g (0.018 mol) triethylamine and 0,96 g (0.0078 mol) (R) -methoxypropionic acid chloride, analogue example 1 gives a mixture of the expected diastereomeric bases (1,7 g) separated by analogy in example 2 by column chromatography. The slower-moving substance (0,6 g, Rf = 0,40) is classified as an analogue hydrochloride. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -100,5° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

The fast-acting diastereomer (0,7 g, Rf = 0,45) separated by column chromatography in example 10 is crystallized as hydrochloride in analogy to example 2 to obtain the title compound at a yield of 0,23 g (21,7% d. th.) with a melting point of 216 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +62,4° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

Starting from 1,69 g (0.006 mol) (±) -9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphan hydrochloride, 1,82 g (0.018 mol) triethylamine and 0,96 g (0.0078 mol) (S) -2-methoxypropionic acid chloride, analogue example 1 gives a mixture of the expected diastereomeric bases (1,7 g) which are separated by column chromatography in analogue example 2. The slower-moving substance (0.6 g, Rf = 0,40) is crystallized as hydrochloride in analogue example 2. The title compound is obtained in a yield of 0,6 g (56.6 d. %) with a melting point of 275 °C (zero and a specific gravity of [α]). $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +102,5° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

The fast-acting diastereomer (0,6 g, Rf = 0,45) separated by column chromatography in Example 12 is crystallized as hydrochloride in the same way as in Example 2 and the title compound is obtained at a yield of 0,65 g (61,2% d. th.) with a melting point of 219 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -67.6° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

Starting from 1,76 g (6 mMol) (±) -9,9-dimethyl-2'-hydroxy-5-phenyl-6,7-benzomorphan [EP-B-4960; CA 93, 4941f (1980) ] and 0,96 g (7,8 mMol) (R) -2-methoxypropionic acid chloride, analogue example 1 produces a mixture of the expected diastereomeric bases (2,1 g) with Rf values of 0,50 and 0,55 (see example 2). The mixture is crystallized in analogue example 2 as the hydrochlorides (2,4 g) and transferred back to the corresponding free bases (final vapour return 1,8 g). This base residue is obtained by crystallizing 6 ml of acetic acid and 18 ml of petroleum cysteine (80 °C). The result is a specific titration of 0,50 g of ethyl alcohol with a titration of 0,50 g (65,5 °C) and a specificity of 202 g (65,5 °C). $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately -24.4° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

The parent spirit (acetic acid/petroleum ether) obtained by crystallization in accordance with example 13 is evaporated. The residue (1.2 g) is dissolved in 5 ml of ethanol and the solution is acidified with 2.5 N of ethanolic hydrochloric acid. After addition of diethyl ether to the point of turbidity, hydrochloride (0.4 g) crystallizes as an impure raw product. The parent spirit contains the pure title compound which is isolated as a residue after its final evaporation: yield 0.75 g (62.0 % d. Th.), melting point 168°C (zero), Rf = 0.55 specific turnover [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +11° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive: (a) Outgoing connection

The (±) 3'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan required in this and other examples is not yet known from the state of the art. For example, it can be produced by the synthesis route specified for the known 2'-hydroxy isomer (DOS 20 27 077, CA 74 (1971), 125482x) by using m-methoxybenzyl lithium instead of p-methoxybenzyl lithium. The latter, when connected to the benzene system, contains two isomeric compounds which are further used as a mixture. The last obtained mixture of 1'-hydroxy and 3'-hydroxybenzomorphan (DOS 20 27 077, CA 74 (1971), 125482x) is obtained by flash-mapping the mixture in a mixture of the above mentioned substances in a ratio of 0.0 to 0.0 (± 0,9-methoxybenzyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl

(b) Transposition to the title page

Starting from 2,31 g (0.010 mol) (±)-3'-hydroxy-5,9.9-trimethyl-6,7-benzomorphan and 1,6 g (0.013 mol) (R)-2-methoxypropionic acid chloride, a mixture of the expected diasteromeric bases is obtained by analogy in Example 1 separated by column chromatography at 100 times the amount of silica gel in Example 2. The slow-acting substance (Rf = 0,65) is crystallized as hydrochloride as described there. The title compound is obtained in a yield of 0,86 g (50,6%) with a melting point of 240-242 °C (c.v.) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -90.9° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in the Annex to Regulation (EC) No 1907/2006'

The fast-acting substance (Rf = 0,74) separated in example 16 is crystallized as hydrochloride in analogy to example 2 to obtain the title compound at a yield of 1,28 g (75.3% d.T.) with a melting point of 250-251 °C and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is +57,1° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in Annex I to Regulation (EC) No 1907/2006':

Starting from 2,31 g (0.010 mol) (±)-3'-hydroxy-5,9.9-trimethyl-6,7-benzomorphan (see example 16) and 1,60 g (0.013 mol) (S) -methoxypropionic acid chloride, analogue example 1 gives a mixture of the expected diastereomeric bases separated by chromatography - analogue example 2 - at 100 times the amount of silica gel. The slower-moving substance (Rf = 0,65) is crystallized as hydrochloride, as described there. The title compound is obtained at a yield of 0,57 g (33.4% d. Th.) with a melting point of 239-240 °C (Zers.) and a specific spin of [α]. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a chemical compound with a specific gravity of 10 μm.

The following is the list of active substances in the active substance:

The fast-acting substance (Rf = 0,74) separated in example 18 is crystallized as hydrochloride in analogy to example 2 to obtain the title compound at a yield of 0,67 g (39.2% d.T.) with a melting point of 250-251 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -56.5° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

Starting from 2,31 g (0.010 mol) (±)-1'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan (see example 16) and 1,60 g (R)-2-methoxypropionic acid chloride, analogue example 1 produces a mixture of the expected diastereomeric bases separated analogue example 2 at 100 times the amount of silica gel. The slower-moving substance (Rf = 0,52) is crystallized analogue example 2 as hydrochloride. The title compound is obtained at a yield of 0.70 g (41.2 % d. Th.) with a melting point of 128-135 °C (Zers.) and a specific rotation of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -100,5° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in Annex I to Regulation (EC) No 1907/2006':

The fast-acting substance (Rf = 0,56) separated in example 20 is crystallized as hydrochloride in analogy to example 2 to obtain the title compound at a yield of 0,40 g (23,6% d. th.) with a melting point of 88-89 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately 50 °C.

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in the Annex to Regulation (EC) No 1907/2006'

Starting from 2,31 g (0.010 mol) (±)-1'-hydroxy-5,9.9-trimethyl-6,7-benzomorphan (see example 16) and 1,60 g (0.013 mol) (S)-2-methoxypropionic acid chloride, analogue example 1 produces a mixture of the expected diastereomeric bases separated analogue example 2 at 100 times the amount of silica gel. The slower-acting substance (Rf = 0.52) is crystallized analogue example 2 as hydrochloride. The title compound is obtained at a yield of 0.63 g (36.8% d. Th.) with a melting point of 85-90 °C and a specific rotation value of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +96.2° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

The fast-acting substance (Rf = 0,56) separated in example 22 is crystallized as hydrochloride in analogy to example 2 to obtain the title compound at a yield of 0,50 g (29,4% d. th.) with a melting point of 90-91 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -64.0° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive: (a) Manufacture of the starting connection

The production of the (±)-4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan required in this and other examples is not yet known from the state of the art. It can be produced, for example, by the state of the art synthesis route for the known 2'-hydroxy isomer [DOS 20 27 077, CA 74, 125482x (1971) ] by substituting o-methxybenzyllithium for p-methxybenzyllithium. The compound sought is crystallized as a base from isopropanol petroleum ether with a melting point of 227 °C. In the thin layer chromatogram (tickle 60:35:3) a 0.20-W of this ammonium can be assigned to a 65-C.

(b) Transposition to the title page

Based on 2,31 g (0.010 mol) (±)-4'-hydroxy-5,9.9-trimethyl-6,7-benzomorphan and 1,60 g (0.01 mol) (R)-2-methoxypropionic acid chloride, a mixture of the expected bases (3,0 g) is obtained by analogy with example 1 and separated by column chromatography at 450 g of silica gel by analogy with example 2. This results in 0,9 g of the slower-moving compound (Rf = 0,34) and 1,3 g of the faster-moving compound (Rf = 0,43). The former is crystallized as hydrochloride, resulting in the title compound at a yield of 0,95 g (55.9 g/d) with a melting point of 263 °C (Zh) and a specific gravity of [α]. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -86.9° (c = CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in the Annex to Regulation (EC) No 1907/2006'

The rapidly moving compound (Rf = 0,43) separated in example 24 is crystallized as hydrochloride in analogy to example 2. The title compound is obtained at a yield of 1.23 g (72.4% d.T.) with a melting point of 258 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +51,7°, (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in the Annex to Regulation (EC) No 1907/2006'

From 2,31 g (0.010 mol) (±)-4'-hydroxy-5,9.9-trimethyl-6,7-benzomorphan (see example 24) and 1,60 g (0.013 mol) (S) -methoxypropionic acid chloride, analogue example 1 produces a mixture of the expected diastereomeric bases (3,1 g) separated by analogue example 2 by column chromatography at 450 g of silica gel, yielding 1,0 g of the slow-acting compound (Rf = 0,34) and 1,2 g of the fast-acting compound. The first example 2 is crystallized in the form of the hydrochloride and gives the title compound in an output of 1,15 g (67,7 g) with a melting point of 260 °C (zero and a specific spin value of %α). $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -51,2° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

The fast-acting substance (Rf = 0,43) separated in Example 26 is crystallized as hydrochloride in analogy to Example 2 and gives the title compound at a yield of 0,95 g (55,9% by weight) with a melting point of 261 °C (zers.) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The following table shows the results of the analysis:

The following is the list of active substances which are to be classified in the additive:

The sterically uniform titration compound in the form of the free base (2,3 g) is obtained by analogy with Example 1 from 2,45 g (0,010 mol) (-)-2'-methoxy-5,9,9-trimethyl-6,7-benzomorphan [DOS 20 27 077; CA 125482x (1971) ] and 1,35 g (0,011 mol) (R)-2-methoxypropionic acid chloride. It is dissolved in 5 ml of absolute ethanol. The resulting solution is acidified with methanosulfonic acid with diethyl ether until turbidity. While the methanosulfonate crystallizes, the same amount of ether is added after stirring. The reaction mixture is cooled for 4 hours with an ice bath, then washed, then first with a specific titration of 1:2, then with a specific titration of 1,2% (D.C. 79,8 to 3,3 g) of etheric acid, and finally in a dry solution at a temperature of 16 °C. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -92.4° (c = 1, CH3OH).

The test chemical is used to determine the concentration of methanol in the test medium.

From 2,45 g (0,010 mol) (+) -2-methoxy-5,9,9-trimethyl-6,7-benzomorphan [DOS 20 27 077; CA 74, 125482x (1971) ] and 1,35 g (0,011 mol) (S) -2-methoxypropionic acid chloride, the title compound is obtained by analogy in Example 28 at a yield of 3,1 g (75,0% d.j.) with a melting point of 165°C to 167°C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +92,3° (c = 1, CH3OH).

The following is the list of active substances which are to be used in the preparation of the product: (a) Manufacture of the starting connection

The production of the (±) 5,9,9-trimethyl-6,7-benzomorphan required in this and other examples is not yet known from the state of the art. It can be produced, for example, by the synthesis route specified for the known 2'-hydroxy derivative [DOS 20 27 077; CA 74 (1971) 125482x], using benzyllithium instead of p-methoxybenzyllithium. The desired compound is crystallized as hydrobromide from an isopropanol ether melting point of 259 °C (zero).

(b) Transposition to the title page

Based on 2.96 g (0.010 mol) (±) -5.9.9-trimethyl-6,7-benzomorphan and 1.35 g (0.011 mol) (R) -2-methoxypropionic acid chloride, a mixture of the expected diastereomeric bases is obtained in analogy to example 1. These are separated by column chromatography at 150 times the amount of silica gel in analogy to example 2. The slower-moving substance (Rf = 0.63) is crystallized as hydrochloride, as described there. The title compound is obtained at a yield of 1.3 g (76.5% d. Th.) with a melting point of 225 °C (Zers.) and a specific rotation rate of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -101.7° (c = 1, CH3OH).

The following is the list of active substances which are to be used in the preparation of the product:

The fast-acting substance (Rf = 0.67) separated in example 30 is dissolved in 5 ml of ethanol. After acidification with oxalic acid, the solution is mixed with diethyl ether until it becomes cloudy. During the subsequent crystallization, half of the original ether is added gradually and left in the refrigerator for about 12 hours. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +60,2° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive: (a) Manufacture of the starting connection

The (±)-2',5,9,9-tetramethyl-6,7-benzomorphan required in this and other examples is not yet known from the state of the art. It can be produced, for example, by the synthesis route specified for the known 2'-hydroxy analogue by substituting p-methoxybenzyllithium for p-methylbenzyllithium. The intermediate thus obtained is crystallized from an isopropanol-diethyl ether mixture as hydrobromide, which melts at 227 °C under decomposition.

(b) Transposition to the title page

Starting from 1,51 g (5 mMol) (±) -2,5,9,9-tetramethyl-6,7-benzomorphan and 0,68 g (5,5 mMol) -2-methoxypropionic acid chloride, a mixture of the expected diastereomeric bases is obtained, as described in Example 1, which is crystallized and separated as hydrochloride, resulting in the title compound at a yield of 0,7 g (after recrystallization 0,4 g = 47,3% d. Th.) with a melting point of 212 °C (Zers.) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -110,0° (c = 1, CH3OH).

The following is the list of active substances which are to be used in the preparation of the product:

From 1,51 g (5 mMol) (±) -2,5,9,9-tetramethyl-6,7-benzomorphan and 0,68 g (5,5 mMol) (S) -2-methoxypropionic acid chloride, the title compound is obtained by analogy, Example 32, at a yield of 0,4 g (47,3% d. th.) with a melting point of 212 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +111,8° (c = 1, CH3OH).

The following is the list of active substances in the active substance: (a) Manufacture of the starting connection

The (±)-2'-nitro-5,9,9-trimethyl-6,7-benzomorphan required in this and other examples is not yet known from the state of the art. It can be produced, for example, by nitrating (±)-5,9,9-trimethyl-6,7-benzomorphan (Example 30) in analogy to a rule by E.L. May and E.M. Fry [J. Org. Chem. 22 (1957) 1366].

(b) Acceleration

2.97 g (0.01 mol) (±)-2'-nitro-5,9.9-trimethyl-6,7-benzomorphan hydrochloride is acylated with 1.35 g (0.011 mol) (R)-2-methoxypropionic acid chloride in the presence of 3.04 g (0.03 mol) of triethylamine analogue Example 1 and after treatment is obtained 3.5 g (approximately 100% by weight) of the intermediate of type (3).

(c) Catalytic hydration of the 2'-nitro to the 2'-amino group

3,5 g of the intermediate product obtained in step (b) are dissolved in 70 ml of methanol and hydrated at 20 °C at a hydrogen pressure of 5 bar in the presence of 0,4 g of palladium on charcoal (Pd content: 5 %). The hydrogen uptake stops after 4 hours after the calculated amount has been consumed. After the catalyst has been filtered, the reaction mixture is evaporated, last at 80 °C and under full water jet vacuum. Residue: 3.1 g (approximately 100 % d.T.).

(d) Reduction with lithium aluminium hydride

The evaporation residue (3.1 g) obtained above is reduced by 1.3 g of lithium aluminiumum hydride (lithium tetrahydridoalanate) in analogue example 1. The resulting mixture of the two diastereomeric bases (2.7 g) is separated by column chromatography in analogue example 2 to 500 g of silica gel. The slower-moving substance (0.7 g, Rf = 0.65) is crystallized as dihydrochloride in analogue example 2 (but with two salt equivalents). The title compound is obtained in a yield of 0.95 g (50.6% d. Th.) and with a melting point of 260 °C (C) and a specific rotation of [α]. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -93.4° (c = 1, CH3OH).

The following is the list of active substances which are to be used in the preparation of the active substance:

0.9 g of the fast-acting substance (Rf = 0.70) separated in example 34 is crystallized from a methanol-diethyl ether mixture analogous to example 28 (but with 2 equivalents of methanesulfonic acid) to obtain the title compound at a yield of 0.48 g (19.4% d.j.) with a melting point of 189 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is +55,6° (c = 1, CH3OH).

The following is the list of active substances in the active substance:

Starting from 2,97 g (0.01 mol) (±)-2'-nitro-5,9.9-trimethyl-6,7-benzomorphan hydrochloride, 3,04 g (0.03 mol) triethylamine and 1,35 g (0.011 mol) (S)-2-methoxypropionic acid chloride, 3,5 g (approximately 100% d. Th.) of the acylation product is obtained, which is catalytically hydrated as described therein (resulting in 3.2 g of hydration product) and then curdled with lithium aluminium dihydride (lithium tetrahydride) (LH) The reduction product, consisting of a miscellaneous reducing base of the expected diasteric point, is heated in 10 g of propanol. The resulting crystalline solution is obtained by heating it for a period of 12 hours at a temperature of approximately 12,37 g (0.75 °C) with a crystalline titration of 0,75 g of isocyanide (R) and a crystalline titration of approximately 26 °C (R) (R) = 42,6 g. The total amount of the crystalline is obtained by mixing it with a crystalline titration of approximately 0,75 g of isocyanide (R) and a crystalline titration of approximately 0,75 g (0.75 °C) at a temperature of approximately 26 °C (R) = 42,6 °C) with a crystalline titration of approximately 0,75 g of isocyanide (R) = 0,75 g. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a chemical compound with a specific gravity of 10 μm.

The following is the list of active substances in the active substance:

The isopropanol mother liquor of example 34 is evaporated and the residue (2.0 g) of 300 g of silica gel is chromatographed in analogy to example 2 and the further 0.3 g of the slower-acting substance (Rf = 0.65, example 34) and the faster-acting diastereomer (1.2 g, Rf = 0.70) are crystallized in analogy to example 32 as dihydrochloride, resulting in the title compound at a yield of 1.48 g (78.8% d. Th.) with a melting point of 259 °C (zers.) and a specific rotational value of [α]. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -68.4° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

Starting from 1,16 g (0.005 mol) (±)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 0,75 g (0.055 mol) 2-methoxybutyric acid chloride, the basic form of the title compound (1,1 g) is obtained by analogy with Example 1. It is dissolved in 5 ml of methanol and, after acidification with HBr (62 g/l) with diethyl, the solution is made to a powdered state. When left in the refrigerator for about 12 h, the title compound crystallizes, is vacuumed, washed with an ethanol ether mixture and dried at 80 °C. Yield is 1,1 g (55.2 g/l), melting point 232 °C (zero). A methanol ether crystallization is obtained at 240 °C (milligram).

The following is the list of active substances which are to be classified in the additive: (a) Manufacture of the starting connection

The (R) 2-methoxybutyric acid chloride required in this and other examples can be prepared, for example, from the known (R) 2-methoxybutyric acid (N.K. Kochetkov, A.M. Likhosherstov and V.N. Kulakov, Tetrahedron 25 (1969) 2313] and thionyl chloride at room temperature.

(b) Transposition to the title page

Based on 3,47 g (0,015 mol) (±)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 2,46 g (0,018 mol) (R)-2-methoxybutyric acid chloride, the title compound is obtained by analogy in Example 1 at a yield of 1,8 g (67,8% d. th.) with a melting point of 246 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -118.4° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in the Annex to Regulation (EC) No 1907/2006'

The parent sludge produced in example 39 is evaporated and the residue is extracted from the residue in analogy to example 2 to produce the title compound at a yield of 1.3 g (48.9% d. th.) with a melting point of 228 °C (zers.) and a specific rotational speed of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +79.9° (c = 1, CH3OH).

The following is the list of active substances in the active substance: (a) Manufacture of the starting connection

The (S) 2-methoxybutyric acid chloride required in this and other examples can be prepared, for example, from the known (S) 2-methoxybutyric acid (Tetrahedron 25 (1969) 2322) analogue in example 39.

(b) Transposition to the title page

From 3,47 g (0,015 mol) (±)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 2,46 g (0,018 mol) (S)-2-methoxybutyric acid chloride, the title compound is obtained by analogy in Example 1 at a yield of 1,6 g (60,3% d. Th.) with a melting point of 246 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The following table shows the results of the analysis:

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as the active substances:

The parent sludge in example 41 is evaporated and the residue is extracted from the residue in analogy to example 2 to produce the title compound at a yield of 0.6 g (22.6% d. th.) with a melting point of 228 °C (zero) and a specific rotational speed of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -71.7° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive: (a) Manufacture of the starting connection

The (R) - 2 benzyloxypropionic acid chloride used in this and other examples can be prepared, for example, as follows: The commercial (R) -(+) lactic acid isobutyl ester is benzyled with benzyl bromide O in the presence of silver oxide, followed by sodium saline soaking to yield (R) -2-benzyloxypropionic acid with a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +79.5° (c = 1, CH3OH). This gives the corresponding acid chloride analogue Example 39.

(b) Transposition to the title page

Based on 3,47 g (0.015 mol) (±)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 3,3 g (0.0165 mol) (R)-2-benzyloxypropionic acid chloride, a mixture of the expected diastereomers is obtained, as described in example 1, by crystallization of the corresponding hydrochloride, and the title compound is obtained at a yield of 2,39 g (76.6% d. Th.) with a melting point of 250 °C (Zers.) and a specific rotation rate of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately -119.3° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive: (a) Manufacture of the starting connection

The (S) - 2 benzyloxypropionic acid chloride used in this and other examples can be e.g. analogous to Example 43 from (S) - 2 benzyloxypropionic acid (specific rpm: [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The resulting product is a solution of -78,5° (c = 1, CH3OH).

(b) Transposition to the title page

Based on 3,47 g (0,015 mol) (±)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 3,3 g (0,0165 mol) (S)-2-benzyloxypropionic acid chloride, the title compound is obtained by analogy in Example 43 at a yield of 2,56 g (82,1% by weight) with a melting point of 250 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a chemical compound with a specific gravity of 10 μm.

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in Annex I to Regulation (EC) No 1907/2006': (a) Manufacture of the starting connection

The (R) 2-methylthiopropionic acid chloride required in this and other examples can be prepared, for example, by analogy with example 39 from the known (R) 2-methylthiopropionic acid (L.N. Owen and M.B. Rahman J. Chem. Soc. [c] 1971, 2432).

(b) Transposition to the title page

1,62 g (0.007 mol) (±)-2'-hydroxy-5,9.9-trimethyl-6,7-benzomorphan are analogously converted to Example 1 with 1,07 g (7,7 mMol) (R)-2-methylthiopropionic acid chloride. After reducing the resulting reaction product with lithium aluminium hydride (LiAlH4), a mixture of the expected diastereomers is obtained, which are separated by crystallization of their nitrates. The substance which finally crystallizes from ethanol after acidification with 65 % hydrochloric acid and dissolving with diethyl base to turbidity is placed in a refrigerator at a drying point of about 12 h, then washed with ether at 80 °C (0.5 g/mL) and then crystallized at a specific temperature. The sample is then released from a nitrous oxide (Ethanol) analogue and settled in a crystallized solution at 26 °C (0.52 g/mL) and the resulting substance is called ethanol (Nitrate) nitrate. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -135.1° (c = 0.5 CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in Annex I to Regulation (EC) No 1907/2006':

The parent sludge of the first nitrate crystallization obtained in accordance with example 45 is evaporated and the nitrate residue is transferred to the free base. This (1 g) is filtered by analogy with example 55 over 20 g of aluminium oxide and then crystallized as hydrochloride (ethanol ether). This (0,29 g) is recrystallized from a mixture of 2 ml of methanol and diethyl ether. The title compound is obtained at a yield of 0,21 g (16,8% d. th.) with a melting point of 238 °C (Zers.) and a specific rotation rate of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a chemical compound with a specific gravity of 10 μm.

The following is the list of active substances which are to be classified in the additive: (a) Manufacture of the starting connection

The (S) 2-methylthiopropionic acid chloride required in this and other examples can be prepared, for example, from the known (S) 2-methylthiopropionic acid (J. Chem. Soc. 1971, 2437) by analogy with example 39.

(b) Transposition to the title page

From 1,62 g (0,007 mol) (±)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan, the analogue example 45 gives the title compound at a yield of 0,42 g (33,6% by weight) with a melting point of 265 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a chemical compound with a specific chemical structure.

The following is the list of active substances which are to be classified in the additive:

From the nitrate parent sludge in Example 47 the titration compound is obtained in an analogue to Example 46 at a yield of 0,34 g (27,2% d. th.) with a melting point of 238 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -73.9° (c = 0.5, CH3OH).

The following is the list of active substances which are to be classified in the additive: (a) Manufacture of the starting connection

The (S) - ((-) 2) allyloxypropionic acid chloride used herein can be prepared, for example, by allyling the commercial (S) - ((-) lactic acid ethyl ester with allyl bromide O in the presence of silver oxide, and subsequently by soaking with baking soda to give (S) - (2) allyloxypropionic acid with a boiling point of 110 to 112 °C at a pressure of 15 mbar and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ This gives the corresponding acid chloride analogue Example 39.

(b) Transposition to the title page

Based on 3,47 g (0.015 mol) (±)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 3,3 g (0.0165 mol) (S)-2-allyloxypropionic acid chloride, a mixture of the two expected diastereomers is obtained, as described in Example 1, by crystallization of the corresponding hydrochlorides, resulting in the title compound at a yield of 1,4 g (51,0% d. Th.) with a melting point of 245 °C (zero) and a specific rotation rate of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is not equal to + 120° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

The parent algae in Example 49 are evaporated, and the residue is used to produce the title compound in an analogous way to Example 2 at a yield of 0.62 g (22.6% d. th.) with a melting point of 213 °C and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately -38° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as the active substances:

2,31 g (0.010 mol) (±)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and 2,03 g (0.011 mol) (R)-2-phenoxypropionic acid chloride (produced - analogue example 39 - from the known acid [CA 72, 12917d] are implemented analogue example 1. A mixture of the two diastereomers to be expected is obtained, which are separated by crystallization of the corresponding hydrochlorides as described therein. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -142.9° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in the Annex to Regulation (EC) No 1907/2006'

If we work analogously with example 51 with (S) -2-phenoxypropionic acid chloride, we obtain the title compound at a yield of 1,6 g and a specific rotational speed of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is +143,3°C (c = CH3OH).

The following is the list of active substances which are to be classified in the additive: (a) Outgoing connection

The (+/-) 3'-hydroxy-5,9,9,2'-tetramethyl-6,7-benzomorphan required in this and other examples is not yet known from the state of the art. It can be produced, for example, by the synthesis route specified for the known 2'-hydroxy derivative (DOS 20 27 077; CA 74 (1971), 125482x) by substituting p-methoxybenzyllithium with 3-methoxy-4-methylbenzyllithium. The 3'-hydroxy-5,9,9,2'-tetramethyl-6,7-benzomorphan predominantly obtained at the ring closure to the benzomorphan system is purified by flash-season chromatography (see Figure 16).

(b) Transposition to the title page

Starting from 2,44 g (0.010 mol) (+/-) 3'-hydroxy-5,9,9,2'-tetramethyl-6,7-benzomorphan and 1,6 g (0.013 mol) (R)-2-methoxypropionic acid chloride, a mixture of the expected diasteriomeric bases is obtained by analogy in example 1, separated by column chromatography at 100 times the amount of silica gel in analogy in example 2. The slower-acting substance (Rf = 0,25) is crystallized as hydrochloride. The title compound is obtained at a yield of 1,06 g (59.9%) with a melting point of 181-182 °C and a specific rotation point of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The following table shows the results of the analysis:

The following is the list of active substances which are to be classified in the additive:

The fast-acting substance (Rf = 0,34) separated in example 53 is cut as in example 2 as hydrochloride, and the title compound is obtained at a yield of 1,24 g (70,1%) as an amorphous powder with a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +55,9° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances of very high concern':

Starting from 2,44 g (0.010 mol) (+/-) 3'-hydroxy-5,9,9,2'-tetramethyl-6,7-benzomorphan (see example 53) and 1,6 g (0.013 mol) (S) -2-methoxypropionic acid chloride, analogue example 1 gives a mixture of the expected diasteriomeric bases separated by column chromatography at 100 times the amount of silica gel analogue example 2. The slower-acting substance (Rf = 0,25) is crystallized as hydrochloride. The title compound is obtained at a yield of 1.48 g (83.6%) with a melting point of 186-188 °C and a specific spin of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +88,2° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

The fast-acting substance (Rf = 0,34) separated in example 55 is cut as in example 2 as hydrochloride, and the title compound is obtained at a yield of 1.40 g (79.1%) as an amorphous powder with a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -56.8° (c = 1, CH3OH).

The following is a list of the active substances which may be used in the preparation of the active substance: (a) Outgoing connection

The (+/-) 2'-hydroxy-5,9,9,3'-tetramethyl-6,7-benzomorphan required in this and other examples is not yet known from the state of the art. It can be produced, for example, by the synthesis route specified for the known 2'-hydroxy derivative (DOS 20 27 077; CA 74 (1971), 125482x) by substituting p-methoxybenzyllithium with 4-methoxy-3-methylbenzyllithium. The 2'-hydroxy-5,9,9,3'-tetramethyl-6,7-benzomorphan predominantly obtained at the end of the ring to the benzomorphan system is purified by flash-season chromatography (see Figure 16).

(b) Transposition to the title page

Starting from 2,44 g (0.010 mol) (+/-)-2'-hydroxy-5,9,9,3'-tetramethyl-6,7-benzomorphan and 1,6 g (0.013 mol) (R)-2-methoxypropionic acid chloride, a mixture of the expected diasteriomeric bases is obtained by analogy in example 1, separated by column chromatography at 100 times the amount of silica gel in analogy in example 2. The slower-acting substance (Rf = 0,26) is crystallized as methanosulfonate. The title compound is obtained at a yield of 1,64 g (79.3%) with a melting point of 266-268 °C and a specific rotation point of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -95.4° (c=1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in the Annex to Regulation (EC) No 1907/2006'

The fast-acting substance (Rf = 0,29) separated in example 57 is cut as in example 2 as hydrochloride, and the title compound is obtained at a yield of 1.60 g (90.4%) as an amorphous powder with a specific spin of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +73,4° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

Starting from 2,44 g (0.010 mol) (+/-)-2'-hydroxy-5,9,9,3'-tetramethyl-6,7-benzomorphan (see example 57) and 1,6 g (0.013 mol) (S) -2-methoxypropionic acid chloride, analogue example 1 gives a mixture of the expected diasteriomeric bases separated by column chromatography at 100 times the amount of silica analogue example 2. The slower-acting substance (Rf = 0,26) is crystallized as methane sulfonate. The title compound is obtained at a yield of 1,56 (88,1%) with a melting point of 265-267 °C and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a chemical compound with a specific gravity of 10 μm.

The following is the list of active substances which are to be classified in the additive:

The fast-acting substance (Rf = 0,29) separated in example 59 is cut as in example 2 as hydrochloride, and the title compound is obtained at a yield of 1.36 g (76.8%) as an amorphous powder with a specific spin of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -74.9° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive: (a) Outgoing connection

The (+/-) 2''-dihydroxy-5,9,9-trimethyl-6,7-benzomorphan required in this and in another example is not yet known from the state of the art. It can be produced, for example, by the synthesis route specified for the known 2'-hydroxy derivative [DOS 20 27 077; CA 74 (1971), 125482x] by substituting 3,4-dimethoxybenzyllithium for p-methoxybenzyllithium. The ring link to the benzomorphan system, predominantly obtained 2''-dihydroxy-5,9,9-trimethyl-6,7-benzomorphan, is cleaned by column flash chromatography (cf. e.g. 16).

(b) Transposition to the title page

Starting from 8,51 g (0.03 mol) (+/-)-2',3'-dihydroxy-5,9,9-trimethyl-6,7-benzomorphan hydrochloride and 4,1 g (0.033 mol) (R)-2-methoxypropionic acid chloride, a mixture of the expected diasteriomeric bases is obtained by analogy with example 1 separated by column chromatography at 100 times the amount of silica gel in analogy with example 2.

The title compound is obtained at a yield of 2,54 g (47,6%) with a melting point of 167 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -98.6° (c = 0.5; CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in Annex I to Regulation (EC) No 1907/2006':

The fast-acting substance (Rf = 0,29) separated in example 61 is cut as in example 2 as hydrochloride, resulting in the title compound with a yield of 2.28 g (42.7%) at a melting point of 251 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is +64.3° (c = 0.5; CH3OH).

Compounds (1) according to procedure 3.2 The following is the list of active substances in the active substance:

Stir 0,6 g (0.003 mol) (±)-2'-hydroxy-5,9.9-trimethyl-6,7-benzomorphan, 0,72 g (0.0075 mol) 2-methoxyethyl chloride, 0,11 g (0.0075 mol) sodium iodide and 0,95 g (0.0113 mol) sodium hydrocarbonate in 10 ml of absolute dimethylformamide for 23 hours at 95°C. Then evaporate the reaction mixture in the rotary evaporator, last at 95°C and in a full vacuum. The residue is shaken with 25 ml and 25 ml of dihydromethane and the water-separated aqueous phase is extracted again with 10 ml of dihydromethane. The combined extracts are washed with water, dried with sodium tri sulphate and dried after extraction of the liquid. The remaining solution is described as a free-standing solution of 0.48 g of e-thromate (e.g. e-thromate) at a temperature of 24°C. The resulting solution is described as a solution of 0.7 mg of e-thromate.

The test chemical is used to determine the concentration of the active substance in the test chemical. (a) Manufacture of the alkylating agent

The technique of reducing the known (+) - ((R) -2) -methoxypropionic acid with lithium aluminium hydride (LiAlH4) produces (-) - ((R) -2-methoxypropanol with a boiling point of 70 °C at a pressure of 76 mbar and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The corresponding (+) - ((S) -methoxypropanol is obtained from the similarly known (-) - (c) -) -2-methoxypropionic acid, with a boiling point of 70 °C at a pressure of 76 mbar and a rotational speed of [α]. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The maximum value of the product obtained shall be the value of the product obtained from the product.

The conversion of (-) - ((R) -2) -methoxypropanol with p-toluol sulphonic acid chloride into pyridine analogue R.S. Tipson (J. Org. Chem. 9 (1944) 235)) gives the (+) - ((R) -2) -methoxypropyl p-toluol sulphonate in the form of a yellowish oil with a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ + 3,7° (C = 100) and by analogy from (+) - ((S) -2) -methoxypropanol the corresponding (-) - ((S) -2) -methoxypropyl-p-toluol sulphonate with a rotational speed of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The value of the product is calculated as follows:

(b) Transposition to the title page

1,16 g (5 mMol) (±)-2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan (Example 1) is heated with 1,83 g (7,5 mMol) (R)-2-methoxypropyl-p-toluol sulphonate, 1,26 g (0,015 mol) sodium hydrocarbonate and 1,12 g (7,5 mMol) sodium iodide in a mixture of 15 ml of absolute dimethylformamide and 25 ml of absolute tetrahydrofuran for 60 hours under stirring at return temperature. Analogue treatment is then carried out on Example 63. A mixture of the two expected diastereomeric bases (2 g) is obtained, which can also be produced by other means according to Example 1. The hydrochloride compound is separated in the manner described therein by the method described in the title and obtained in a specific crystalline solution of 0,4 g/oz (64,55 °C) and 26 g/oz (64,7 °C) [T]. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The diastereomer can be obtained from the mother's saliva by analogy with example 2.

The test chemical is to be used in the manufacture of the test chemical.

2,97 g (0.010 mol) (±)-2'-nitro-5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 34) is first isolated as described in the reaction product, a mixture of the two expected diastereomers (3.2 g) to be separated. To separate the by-products, this is dissolved in 64 ml of dichloromethane and filtered through a titration of 64 g of aluminium sulphate (activity point III - neutral according to Dr. Trimmann) for three days. It is then further combined with 128 g of specific chloromethane (4:1 C.E.T.E.T.E.) and dissolved in a solution of 80 g of ethanol (E.T.E.T.E.) at a temperature of 80 °C. The final solution is dissolved in a vacuum with a crystalline solution of ethylene and ethanol at a temperature of 0.6 °C. The solution is then dissolved in water and dissolved in a solution of Nitrogen and Nitrogen at a temperature of 0.6 °C. The final solution is obtained by dissolving the ethanol at a temperature of 0.6 °C. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The stereoisomeric compound (+) - ((1S,5R,2'R) can be obtained from the mother larva if desired.

The test chemical is to be used in the manufacture of the test chemical.

Based on 2,97 g (0,010 mol) (±)-2'-nitro-5,9,9-trimethyl-6,7-benzomorphan hydrochloride and 2,68 g (0,011 mol) (S)-2-methoxypropyl-p-toluol sulphonate, the title compound is obtained by analogy Example 65 at a yield of 0,96 g (52,0% by weight) with a melting point of 226 °C (zers.) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The stereoisomeric (-) - (((1R,5S,2'S) form can be obtained from the mother's saliva, as in example 2.

The test chemical is used to determine the concentration of the active substance in the test chemical. (a) Manufacture of the starting connection

The (±) 3'-nitro-5,9,9-trimethyl-6,7-benzomorphan required in this and other examples is produced alongside the (±) 2'-nitro isomer by the nitration of 5,9,9-trimethyl-6,7-benzomorphan (example 34) in a ratio of approximately 1 : 3. It is obtained from the parent sludge of the 2'-nitro isomer crystallized as a hydrochloride via the base initially produced. It is crystallized as an oxalate (melting point 158°C, (zero) from ten times the amount of methanol. The oxalate is transferred back to the base (uncrystallized) which is used for the implementation described below. A sample of the base crystallized as methanol isotope at 24°C (zero) isotope.

(b) Transposition to the title page

5,2 g (0.02 mol) (±)-3'-nitro-5,9,9-trimethyl-6,7-benzomorphan are analogously converted to example 65 with 5,36 g (0.022 mol) (R)-2-methoxypropyl-p-toluol sulphonate. The reaction product is a mixture of the two expected stereoisomeric bases (8 g) which is cleaned by filtering over aluminium oxide (4,7 g of purified base mixture) as described in example 65. In the thin-layer chromatogram (silica gel 60, toluol ester 85:15, 3 times developed), the Rf diastereomers show respectively 0,81 and 0,85 washes. A separation of 1 g of diastero-gel equals 300 g of silica gel (100 mg) on the Rf titer is obtained by a highly uncrystalline solution of 0,81 mg of the non-crystalline oil.

The test chemical is used to determine the concentration of the active substance in the test chemical.

In addition to the (-) - ((1R,5S,2'R) form (Rf = 0,81) isolated therein, 100 mg of the (+) - ((1S,5R,2'S) form (Rf = 0,85) were obtained from the column chromatography of the diasteromeric mixture described in Example 67 as a brownish, highly viscous oil which does not crystallize.

The test chemical is used to determine the concentration of the active substance in the test chemical. (a) Manufacture of the starting connection

The (±) 2'-Chlor-5,9,9-trimethyl-6,7-benzomorphan required in this and other examples can be prepared, for example, from the 2'-nitro analogue (Example 34) by hydrating the latter to the 2'-amino compound (dihydrochloride: melting point 283°C, (zero.)), and transferring it to the desired 2'-Chlor compound (hydrobromide: melting point > 310°C, (zero.)) by Sandmeyer reaction.

(b) Transposition to the title page

3,3 g (0.010 mol) (±)-2'-Chlor-5,9,9-trimethyl-6,7-benzomorphan hydrobromide and 2,68 g (0.011 mol) (R)-2-Methoxypropyl-p-toluolsulfonate are converted analogously to Example 65 to a mixture of the two diastereomeric bases to be expected and, as described therein, filtered through aluminium oxide. The purified diastereomeric analogue mixture is separated by crystallization of the hydrochlorides in Example 1. The title compound is obtained at a yield of 0,27 g (15.1% d. th.) at a melting point of 287 °C (Zers.) and a turning point of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -102.6° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

The parent sludge of example 69 is evaporated and the residue dissolved with the required amount of boiling methanol. After addition of diethyl ether to the point of initial turbidity and simultaneous crystallization, the title compound is obtained, which, after standing for about 12 hours at room temperature, is sucked out, washed with ethanol ether 1:1, then with ether and dried at 80 °C. Yield 0,56 g (31,3% d. th.), melting point: 289 °C, specific rotation: [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature is +67.9°.

The test chemical is used to determine the concentration of the active substance in the test chemical.

Based on 3,3 g (0,010 mol) (±)-2'-Chlor-5,9,9-trimethyl-6,7-benzomorphan and 2,68 g (0,011 mol) (S)-2-Methoxypropyl-p-toluolsulfonate, the title compound is obtained by analogy in Example 69 at a yield of 0,41 g (22,9% d.j.) with a melting point of 288 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +101.7° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

From the parent liquor of example 71 the title compound is obtained by analogy with example 70 at a yield of 0,75 g (41,9% d. th.) with a melting point of 288 °C and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -68,6° (c = 1, CH3OH).

Compounds (1) according to procedure 3.3 The following is the list of active substances which are to be used in the preparation of the active substance:

After 30 minutes of stirring, 0,31 g (2,2 mMol) of 2-hydroxy-2- ((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((( $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -68,7° (c = 1, CH3OH).

The test chemical is used to determine the concentration of methanol in the test medium.

Starting from 0,68 g (2 mMol) (+) - ((1S,5R,2'R) -2-hydroxy-2- ((2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 2) the analogue to Example 73 is obtained, the title compound, at a yield of 0,38 g (46,0 % d.j.) with a melting point of 150-152 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is + 67,2° (c = 1,CH3OH).

The following is the list of active substances which are to be used in the preparation of the test chemical:

Based on 0,34 g (1 mMol) (-)-((1R,5S,2'R)-2'-hydroxy-2-(2-methoxypropyl)-5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 1) and 0,17 g (0,0011 mol) ethyliodide, the analogue example 73 is obtained, the title compound, at a yield of 0,30 g (70,2% by weight), with a melting point of 146 to 148 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -93.4° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

After adding 0,51 g (5 mMol) triethylamine, stir the solution at room temperature for approximately 10 minutes with 0,19 g (2,4 mMol) acetyl chloride dissolved in 5 ml of dichloromethane, stir it for another 2 hours at room temperature, then wash it with 10 ml of water, dry with sodium sulphate and after drying the solution with a dry-point of evaporation (rotation, lastly at 80 °C (0.6 to 0.7 °C) and dissolve it in water. The solution is dissolved in a vacuum containing a mixture of methanol and ethanol, the titrate of which is equal to 0,6 g/mol (e.g. ethanol) and the base is dissolved in a crystalline solution of ethanol, the titrate of which is equal to 0,74 g/mol (e.g. ethanol) and the titrate of evaporation is equal to 12 g/mol (e.g. ethanol) (e.g. ethanol) (e.g. ethanol) at a temperature of 0.6 to 80 °C (0.6 to 0.7 to 0.7 °C). The solution is dissolved in a vacuum containing a mixture of ethanol, the titrate of which is equal to 0.6 g/mol (e.g/mol) and the titrate of ethanol is equal to 0.6 to 0.7 to 0.7 g/o. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -83.9° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

Based on 0,68 g (0,002 mol) (+) - ((1S,5R,2'S) - 2'-hydroxy-2- ((2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 3) the title compound is obtained by analogy, for example 76, at a yield of 0,6 g (68,0 % d.j.) with a melting point of 183-184 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +82,8° (c = 1, CH3OH).

The following is a list of the active substances which may be used in the preparation of the test chemical:

Based on 0,68 g (0,002 mol) (-) - (((1R,5S,2'S)-2'-hydroxy-2-(2-methoxypropyl)-5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 4) the analogue to Example 76 is obtained, the title compound, at a yield of 0,58 g (65,7% by weight), with a melting point of 183 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -57,1° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

Starting from 0,68 g (2 mMol) (+) - ((1S,5R,2'R) -2-hydroxy-2- ((2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 2) the analogue to Example 76 is obtained the title compound at a yield of 0,67 g (75,9% d. th.) with a melting point of 183 °C and a specific rotational speed [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +58,2° (c = 1, CH3OH).

The test chemical is used to determine the concentration of the active substance in the test chemical.

Based on 0,34 g (1 mMol) (-) - (((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) propionic anhydride, the analogue example 76 gives the title compound at a yield of 0,21 g (46,1% by weight) with a melting point of 145 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -78.3° (c = 1, CH3OH).

The following is the list of active substances which are to be used in the preparation of the active substance: (a) (-) - 1R,5S,2'R) - 2 - 2-methypropyl-2'- 1-phenyl-5-tetrazolyloxy-5,9,9-trimethyl-6,7-benzomorphan hydrochloride

1,36 g (4 mMol) (-) - (((1R,5S,2'R)-2'-hydroxy-2-(2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 1) is heated with 0,79 g (4,4 mMol) 5-chlorophenyltetrazol and 1,36 g (0,01 mol) of dry, fine powdered potassium carbonate in 78 ml of absolute acetone for 6 days under stirring at room temperature. The solution is then evaporated and the residue is diluted with 50 ml. Extract twice with 25 ml of dichlorothiazide and wash the combined extracts with 15 ml of water. After drying dry with 24 g of sulphur dioxide and drying the mixture, the reaction product is sampled for the period of time required. The product is then dissolved in water, dissolved in a crystalline solution of ethanol and ethanol at approximately 80 °C (16,1 g/mL), and then injected into a vacuum with a solution of ethanol and ethanol (11,67 g/mL) at a temperature of approximately 80 °C. The product is then dissolved in water with a crystalline solution of ethanol and ethanol at a temperature of approximately 12 °C (11,3 °C).

(b) Hydration of the intermediate to the title link

The intermediate product (1,67 g, 3,5 mMol) is hydrated in the presence of 0,7 g of 10% palladium carbon in 70 ml of ice vinegar at a hydrogen pressure of 5 bar and at room temperature until complete transformation (6-10 hours). Then the catalyst is sucked out, the filtrate is evaporated and the residue is extracted with dichloromethane (2 times each 25 ml) after addition of 50 ml of water and excess ammonia. The combined extracts are washed with water, dried with sodium sulphate and, after filtration of the drying agent, immersed in the rotary vaporizer, last at 80 °C and full water vacuum. The residue is obtained as an analogue of hydrochloride. The resulting crystal is obtained as an example 2. The compound is obtained in a specific solution of 0,5 g (38,5 °C) of a specific substance with a specific gravity of 225 °C (38,5 °C) and a specific gravity of 0,5 g (α) (T). $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -101,5° (c = 1 CH3OH).

The following is the list of active substances which are to be used in the preparation of the product:

Starting from 1,36 g (0,004 mol) (+) - (((1S,5R,2'S) -2-hydroxy-2- ((2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 3) we obtain by analogy Example 81 on the corresponding intermediate product (1,65 g, 85,1% of the dry weight, melting point 241° (zero)) the title compound in a total yield of 0,64 g (49,4% of the dry weight) with a melting point of 225°C (zero) and a specific rotation rate of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +106.9° (c = 1, CH3OH).

The following is a list of the active substances which may be used in the preparation of the product:

Starting from 1,36 g (4 mMol) (-)-((1R,5S,2'S)-2'-Hydroxy-2-(2-methoxypropyl)-5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 4) an analogue Example 81 is obtained on the corresponding intermediate product (1,73 g, 89,4% by weight, melting point 218,5°C (zero)). the free base-like title compound (0,7 g). This is dissolved with 2 ml of isopropanol and mixed with the corresponding molten acid (0,22 g). It crystallizes the title compound while adding 50 ml of diethyl oxalate after stirring. The final storage point is reached over a period of approximately 12 hours, then with Isopropanol-E, with a specific value of 0,8 g/L. The title compound is kept in a refrigerator at a temperature of 80°C (53,0 g/L) and a specific value of 0,8 g/L. The title compound is kept in a freezer at a temperature of 80°C (zero). $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -60,0° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

Starting from 1,36 g (4 mMol) (+) - ((1S,5R,2'R) -2-hydroxy-2- ((2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 2) we obtain by analogy Example 81 over the corresponding intermediate product (1,65 g, 85,1% by weight, melting point 217°C (zero)). $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is measured at the temperature of the water.

The following is the list of active substances which are to be classified in the additive:

0,70 g (1,87 mMol) (-) - (((1R,5S,2'R)-2'-amino-2-(2-methoxypropyl)-5,9,9-trimethyl-6,7-benzomorphan dihydrochloride (Example 34) is dissolved in 20 ml of absolute dichloromethane, 0,76 g (7,4 mMol) triethylamine and then dripped at room temperature with 0,17 g (2,1 mMol) acetyl chloride dissolved in 5 ml of dichloromethane, then heated at a feed-back temperature for 1 hour, then cooled, washed three times with 10 ml of water, dried with sodium sulphate and drained to the crystal thickness of the dry solution in a rotary dryer, finally at 80 °C and 80 °C. The water is then dissolved in a vacuum after a specific period of time. The residue is dissolved in a solution of ethylene oxide and dissolved in a steam bath containing a solution of ethylene oxide and ethylene oxide at a temperature of 12 °C. The titrated water is then dissolved in a vacuum chamber with a specific concentration of 0,8 g (1,8 °C) and a specific pressure of 12 °C. The residue is then dissolved in a solution of ethylene oxide and dissolved in a solution of ethylene oxide with a specific strength of 2,5 g (t) of ethylene oxide. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -108.2° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

Based on 1,07 g (2,58 mMol) (+) - 1S,5R,2'S) -2-amino-2- ((2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 36) the analogue to Example 85 is obtained, the title compound, at a yield of 0,73 g (74,3% d.j.t.) with a melting point of 249 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a chemical compound with a specific gravity of 10 to 150.

The following is the list of active substances which are to be used in the preparation of the active substance:

1,0 g (0.0026 mol) (-) - ((1R,5S,2'S)-2'-Amino-2-(2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan dihydrochloride is carried out in analogy with example 85. The reaction product is isolated and crystallized from 0,5 ml of isopropanol and 5 ml of petrolether as described therein. The title compound is obtained at a yield of 0,7 g (76,4% d. Th.) with a melting point of 128 °C and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The following table shows the results of the analysis:

The following is the list of active substances which are to be used in the preparation of the active substance:

Based on 1,11 g (2,5 mMol) (+) - ((1S,5R,2'R) -2-Amino-2- ((2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan dimethane sulphonate (Example 35) the analogue to Example 87 is the title compound at a yield of 0,37 g (47,7% by weight) with a melting point of 129 °C and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The following formulae are used:

The following is the list of active substances in the active substance:

After stirring for 2 hours, the residue is placed in the rotary evaporator, lastly at 80°C and full water jet. The residue is placed in a vacuum using a solution similar to that of nitrocellulose (Hydrochlorothiazide) and a solution of 0.8 g of nitrocellulose (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hydrochlorothiazide) (Hothiazide) (Hydrochlorothiazide) (Hothiazide) (Hothiazide) (Hothiazide) (Hothiazide) (Hothiazide) (Hothiazide) (Hothiazide) (Hothiazide) (Hothiazide) (Hothiazide) (Hothiazide) (Hothiazide) (Hothia $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -82,5° (c = 1, CH3OH).

The following is the list of active substances in the active substance:

0,85 g (2,5 mMol) (-)-(1R,5S,,2'R)-2'-hydroxy-2-(2-methoxypropyl)-5,9,9-trimethyl-6,7-benzomorphan hydrochloride is suspended at 20 °C in 30 ml of ice vinegar and stirred with 0,18 ml (0,25 g) of 65% hydrochloric acid (2,6 mMol HNO3). Within about 10 minutes a clear yellow solution is formed, which turns brown after another 5 minutes and begins to cloudy with crystalline secretion. After a reaction time of one hour, the solution is sucked and dried with a diethyl etheric mixture (1:1), then washed with etheric drying and soaked at 80 °C. The gels are washed at 24 °C (0,35 g) in water-soluble methanol (33,5 °C) in a special solution of methanol (33,5 ml) and dried with a diethyl etheric solution (≥ 80 °C) and cooled in a special bath with a diethyl etheric solution (≥ 0,75 ml) and dried at 80 °C. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a chemical compound with a specific gravity of 10 μm.

The following is the list of active substances which are to be classified in the additive:

In the nitration described in example 90, the 1'-nitro derivative (Rf = 0,45), the isomeric 3'-nitro derivative (Rf = 0,72) and the 1',3'-dinitro derivative (Rf = 0,10) (DC: silica gel 60, chloroform methanol concentrates, ammonia 90:10:0,5) are formed from the parent compound (Rf = 0,57) after the 1'-nitro compound has been removed, the remaining parent sludge (Example 90) is evaporated and the residual juice is transferred to the free bases. These are diluted in 10 ml of dichloromethane solution and the yellow solution is filtered over 25 g of dry aluminium oxide (active III, neutral). The residual solution is then diluted with electrolytic chloride (Elucyl ethanol) for a period of time not exceeding 80 g. The residual is then dissolved in a solution of ethylene oxide and ethanol at a temperature of 12 °C. The residual is then cooled to a temperature of 12 °C. The solution is then cooled to a temperature of 12 °C. The residual is then dissolved in a solution of ethylene oxide and ethanol with a specific strength of 0,6 g. The residual is then cooled to a temperature of 12 °C. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -110,1° (c = 1, CH3OH).

The following is the list of active substances in the active substance:

1,52 g (5 mMol) (-)-(1R,5S,2'R)-2'-hydroxy-2-(2-methoxypropyl)-5,9,9-trimethyl-6,7-benzomorphan (Example 1) are dissolved in 3 ml of ice vinegar and stirred at 3-4°C for 1,5 hours with a mixture of 3,4 ml of ice vinegar and 5,42 ml of 100% nitric acid. Stir for another 3 hours at room temperature. Then the yellow reaction mixture is poured into 50 g of ice water, the solution is ammoniated and extracted three times with 20 ml of natrium chloride each. After measuring the combined extraction with water and dry washing and cooling the dry washing, the reaction mixture is finally determined by a specific pressure of 0,05 g/cm3 (± 0,05 °C) in a vacuum containing a volume of water and a volume of 0,05 g/cm3 of ethanol. The resulting solution is then stored in a vacuum with a density of > 300 g/cm3 (± 0,05 °C). $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +27,9° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in the Annex to Regulation (EC) No 1907/2006'

Hydrate 0,35 g (1,0 mMol) (+) - (((1R,5R,2'R)-2'-hydroxy-2-(2-methoxypropyl)-1'-nitro-6,7-benzomorphan hydrochloride (Example 90) in 40 ml of methanol in the presence of 0,1 g of palladium carbon (5 % Pd) for 4 hours at a hydrogen pressure of 5 bar at room temperature. After filtration of the catalyst, the reaction mixture is crystallized in the rotary evaporator, last at 80 °C and full water jet vacuum, with steam and the residue of 10 ml of ethanol. After cooling in the backwash, the crystals are sucked away, washed with an ether-oil rock mixture and titrated at 80 °C. The titration is obtained in a specific solution of 0,17 g (52,7 °C) of ethanol with a specific dilution of 250 °C and a specific dilution of 28 °C (52,7 °C). $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -128.3° (c = 1, CH3OH).

The following is a list of the active substances which may be used in the preparation of the product:

Based on 0,39 g (1,0 mMol) (-)-(1R,5S,2'R)-2'-hydroxy-2-(2-methoxypropyl)-3'-nitro-5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 91) the title compound is obtained by analogy with Example 93 at a yield of 0,27 g (76,1% by weight) with a melting point of 268 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a chemical compound with a specific chemical structure.

The following is a list of the active substances which may be used in the preparation of the product:

Based on 0,70 g (1,63 mMol) (+) - ((1R,5R,2'R) - 1',3'-dinitro-2'-hydroxy-2- ((2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 92) the title compound is obtained by analogy with Example 93 at a yield of 0,20 g (33,2% d.j.) with a melting point of 228 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -111.7° (c = 0.5 CH3OH).

The following table shows the results of the analysis of the use of the test chemical in the manufacture of the test chemical:

The diastereomeric mixture of (-) - ((1R,5S,2'R) and (+) - ((1S,5R,2'R) - ((2-Methoxypropyl) -3-nitro-5,9,9-trimethyl-6,7-benzomorphan (3,7 g) obtained in accordance with example 67 is dissolved in 75 ml of methanol and hydrated in the presence of 0,8 g of palladium carbon (5 % Pd) at a hydrogen pressure of 5 bar and a temperature of 20 °C until the hydrogen uptake is stopped (approximately 3 hours). In the seed chromatogram (Kiesel 60, Chloroform methanol concentrates, Ammonium metal 90:10:0,5) the complete translocation of the 3'-nitro compounds (Rf = 0,73) to the corresponding 3'-nitro compounds (Ammonium nitrate 3,6 g) is followed by a specific dialysis of the three-nitro compounds (Rf = 0,6 g. The resulting dialysis is obtained in the case of the last example of the methanol, which is 0,6 g/m3′, and the resulting dialysis is obtained in the case of the second sample of the methanol, with a vacuum of 0,6 mmol/m2′, and a response of 0,6 mmol/m3′. The resulting dialysis is obtained in the case of the last example of the methanol, which is 0,6 g/m/m3′, and a reaction of 0,6 mmol (Ammonium metal 0,6 g/m) at a vacuum of 0,6 g/m2′, where the diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diisolated diiso diisolated diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso diiso di $\frac{\text{25}}{\text{D\hspace{1em}}}$ The resulting crystalline solution is a solution of −39.8° (c = 1, CH3OH), which has withstood all previous crystallization attempts.

The following is a list of the active substances which may be used in the preparation of the test chemical:

The above described diastereomer separation by column chromatography (Example 96) results in the title compound as the evaporation residue of the relevant eluates (1,0 g, specific rotational speed) as the substance with the higher Rf value of 0,69: [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The resulting crystalline solution is a solution of the formula C.

The following is a list of the active substances which may be used in the preparation of the active substance: (a) 3'-nitro precursor (diastereomeric mixture)

From 5,2 g (0,02 mol) (±) 3'-nitro-5,9,9-trimethyl-6,7-benzomorphan and 5,36 g (0,022 mol) (S) 2-methoxypropyl-p-toluol sulphonate, a mixture of the two expected diastereomeric bases is obtained by analogy, for example 67, which is purified by filtration over aluminium oxide, resulting in 4,7 g of purified base mixture.

(b) 3'-amino compounds (diastereomeric mixtures)

The 3'-nitro precursor (4,7 g of purified diastereomeric enzyme) is hydrated to the corresponding 3'-amino compounds (3,7 g of diastereomeric enzyme) in the same way as in example 96.

(c) Column chromatographic separation of the title link

The mixture of diastereomeric 3'-amino compounds (3,7 g) is separated by column chromatography on silica gel in analogy to example 96 and the title compound with the lower Rf value of 0,63 is obtained at a yield of 1,0 g as evaporation residue of the relevant eluates with a specific spin of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The resulting crystalline solution is a solution of the formula C.

The following is a list of the active substances which may be used in the preparation of the active substance:

In the column chromatography described above (Example 98), the title compound is obtained as the second substance with the higher Rf value of 0,69 as evaporation residue of the eluate concerned 1,1 g, specific rotational speed: [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The resulting crystalline state is -105° (c = 1, CH3OH).

The following is the list of active substances which are to be used in the preparation of the active substance:

0,95 g (3.14 mMol) (-) - ((1R,5S,2'R)-3'-amino-2-(2-methoxypropyl)-5,9,9-trimethyl-6,7-benzomorphan (Example 96) are acetylated analogously to Example 85. The acetylation product is purified by filtration over aluminium oxide analogously to Example 65. In the thin-film chromatogram (silica gel 60, chloroform methanol-concentrate ammonia 90:10:0.5) the starting compound has an Rf value of 0,64 and the acetylation product has an Rf value of 0.57. The evaporation residue (0.69), which resisted all crystallization attempts, has a specific spin of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -53.6° (c = 1, CH3OH).

The following is the list of active substances which are to be used in the preparation of the product:

The titration residue of the substance purified by aluminium oxide (0.5 g) is crystallized in the form of oxalate in analogy to example 83. The titration residue is obtained at a yield of 0.4 g (27.8% d. Th.) with a melting point of 148 °C (zero) and a specific rotation rate of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +39,3° (c = 1, CH3OH).

The following table shows the results of the analysis of the data collected for the determination of the concentration of acetaminophen in the feed additive:

The titration compound is obtained by analogy with Example 100 as a non-crystallising evaporation residue (0,6 g, 41,7% by weight) with an Rf value of 0,57 and a rotational speed of [α] from 1,0 g (3,31 mMol) (+) - 1S,5R,2'S) - 3'-amino-2- ((2-methoxypropyl) -5,9,9-trimethyl-6,7-benzomorphan (Example 98) $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +52,8° (c = 1, CH3OH).

The following is a list of the active substances which are to be used in the preparation of the product:

Based on 0,95 g (3,14 mMol) (-)-(1R,5S,2'S)-3'-Amino-2-(2-methoxypropyl)-5,9,9-trimethyl-6,7-benzomorphan (Example 99), the analogue to Example 101 is the title compound at a yield of 0,7 g (51,1 %) with a melting point of 148 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately -39° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances of very high concern':

Based on 0,71 g (2 mMol) (-)-(1R,5S,2'R)-3'-hydroxy-2-(2-methoxypropyl)-5,9,9,2'-tetramethyl-6,7-benzomorphan hydrochloride (Example 53), the analogue Example 73 is obtained, the title compound, at a yield of 0,38 g (52,0 %), with a melting point of 221-224 °C and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -82.6° (c = 1, CH3OH).

The following is the list of active substances in the active substance:

Based on 0,71 g (2 mMol) (+) - ((1S,5R,2'R) -3-hydroxy-2- ((2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7-benzomorphan hydrochloride (Epipel 54), the title compound is obtained by analogy in Example 73 as an amorphous powder with a yield of 0,44 g (59,8 %) and a specific spin of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +42,2° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

Based on 0,71 g (2 mMol) (+) - 1S,5R,2'S) - 3'-hydroxy-2- ((2-methoxypropyl) -5,9,9,2'-tetramethyl-6,7-benzomorphan hydrochloride (Example 55), the title compound is obtained by analogy with Example 73 at a yield of 0,40 g (54,7 %) with a melting point of 221-224 °C and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +81,7° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances of very high concern':

Based on 0,71 g (2 mMol) (-)-(1R,5S,2'S)-3'-Hydroxy-2-(2-Methoxypropyl)-5,9,9,2'-tetramethyl-6,7-benzomorphan hydrochloride (Example 56), the analogue Example 73 is obtained, the title compound in an yield of 0,42 g (56,1 %) as an amorphous powder and a specific spin of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -41,0° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'methoxypropyl' and 'methoxypropyl'

Based on 0,71 g (2 mMol) (-)-(1R,5S,2'R)-2'-hydroxy-2-(2-methoxypropyl)-5,9,9,3'-tetramethyl-6,7-benzomorphan hydrochloride (Example 57) the analogue to Example 73 is obtained, the title compound, at a yield of 0,36 g (49,3 %) with a melting point of 224-226 °C and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -112.2° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

Based on 0,71 g (2 mMol) (+) -(1S,5R,2'R)-2'-hydroxy-2-(2-methoxypropyl)-5,9,9,3'-tetramethyl-6,7-benzomorphan hydrochloride (Example 58) the analogue to Example 73 is obtained the title compound at a yield of 0,39 g (53,0 %) as an amorphous powder and a specific spin of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +72,4° (c =1, CH3OH).

The following is the list of active substances in the active substance:

Starting from 0,64 g (2 mMol) (+) - ((1S,5R,2'S) -2-hydroxy-2- ((2-methoxypropyl) -5,9,9,3'-tetramethyl-6,7-benzomorphan (Example 59) the analogue Example 73 is obtained, the title compound in a yield of 0,45 g (61,5 %) with a melting point of 228-229 °C and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +111,5° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the additive:

Based on 0,71 g (2 mMol) (-)-(1R,5S,2'S)-2'-hydroxy-2-(2-methoxypropyl)-5,9,9,3'-tetramethyl-6,7-benzomorphan hydrochloride (Example 60), the analogue Example 73 is obtained, the title compound in an yield of 0,40 g (53,4 %) as an amorphous powder and a specific spin of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -71.8° (c = 1, CH3OH).

The following is a list of the active substances which may be used in the preparation of the product:

Starting from 3,56 g (10 mMol) (-)-(1R,5S,2'R)-2',3'-dihydroxy-2-(2-methoxypropyl)-5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 61) the analogue example 73 is obtained, but with two sodium hydride equivalents a mixture of the two isomeric monomethoxy derivatives and the dimoxy derivative separated by column chromatography at 100 times the amount of silica gel analogue example 2 [Current: dichloromethane isopropanol cons. Ammonium ammonium 97:303]. The intermediate compound (Rf = 0,73) is crystallized as a hydromide. The title compound is obtained at a melting point of 0,62 g (15,0 C) with a specific melting point of 212 g (α) and a melting point of 0.62 g (α) [0 C]. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -78.4° (c = 0.5; CH3OH).

The following is a list of the active substances which may be used in the preparation of the product:

The slower-acting substance (Rf = 0,68) separated in example 112 is cut as hydrobromide, resulting in the title compound with a yield of 0,88 g (21.2%) at a melting point of 235 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -93,1° (c = 0,5; CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances of very high concern':

The fast-acting substance (Rf = 0,86) separated in example 112 is cut as hydrochloride, resulting in the title compound with a yield of 0,87 g (22,7%) at a melting point of 193 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -93,2° (c = 0,5; CH3OH).

4.4 Compounds (1) by special processes The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in Annex I to Regulation (EC) No 1907/2006'

Err1:Expecting ',' delimiter: line 1 column 273 (char 272) $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -127.4° (c = 1, CH3OH).

The test chemical is a chemical which is used to determine the concentration of a substance in a solution.

Starting from 1,5 g (3,6 mMol) (+) - 1S,5R,2'S) -2- ((2-benzyloxypropyl) -2-hydroxy-5,9,9-trimethyl-6,7-benzomorphan hydrochloride (Example 44) the analogue to Example 115 is obtained the title compound at a yield of 1,0 g (85,5% d.j.) with a melting point of 276 °C (zero) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is +126.8° (c = 1, CH3OH).

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as 'substances which are to be classified in the Annex to Regulation (EC) No 1907/2006'

The diastereme remaining in the mother's milk (3.17 g evaporation residue) is hydrated in the same way as in example 115, to obtain the title compound at a yield of 1.5 g (56.2% d.T.) with a melting point of 247 °C (zero) and a specific rotational speed of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is -86.8° (c = 1, CH3OH).

The test chemical is a chemical which is used to determine the concentration of a substance in a solution.

The diastereomer remaining in the mother's milk (3.17 g evaporation residue) is hydrated in the same way as in example 115 to obtain the title compound at a yield of 1.5 g (56.2% d.T.) with a melting point of 247 °C (zero) and a specific rotational speed of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The temperature of the water is approximately +86.4° (c = 1, CH3OH).

The test chemical is a mixture of two or more of the following: (a) Compound: (1R/S,5S/R,2'S)-2'-fluor-2- ((2-methoxypropionyl) 5,9,9-trimethyl-6,7-benzomorphan (diastereomeric mixed) and isomers of other metals

The resulting acylation product (7,0 g) is hydrated to the corresponding 2'-amino analogue as described therein, the latter being hydrated to the corresponding 2'-fluorodeviate by a method known to the state of the art (T.L. Fletcher and M.J. Namkung, Chem. and Ind., 1961, 179) to the corresponding 2'-fluorodeviate by (5,7 g), resulting in a mixture of the expected diasteres which cannot be separated in the thin-film chromatogram (Rf = 0,73, Kiesel, Chlorophenol-methanol-concentrate: 90:100,105).

(b) Transposition to the title page

1.58 g (5 mMol) of the precursor is reduced to the title compound by analogy with example 32 with lithium aluminium hydride (LiAlH4) and purified by column chromatography on silica gel as described therein. The evaporation residue of the eluates with the purified substance (0.4 g, Rf = 0.78) is crystallized as oxalate by analogy with example 83. The title compound is obtained at a yield of 0.35 g (17.7% d. Th.) with a melting point of 165 °C (Zers.) and a rotational rate of [α]. $\frac{\text{25}}{\text{D\hspace{1em}}}$ The substance consists of a mixture of the expected diastereomers ((1R,5S,2'S) and (1S,5R2'S) compound) in a ratio of approximately 1:1 (determined by H-NMR spectroscopy).

The test chemical is used to determine the concentration of the active substance in the test chemical. (a) Compound: (1R/S,5S/R,2'R)-2'-fluor-2- ((2-methoxypropionyl) 5,9,9-trimethyl-6,7-benzomorphan (diastereomerised mixed with other compounds)

Based on 2,97 g (0,01 mol) (±)-2'-nitro-5,9,9-trimethyl-6,7-benzomorphan hydrochloride, a mixture of the expected diastereomers 2'-fluor-2- (r) 2-methoxypropionyl)-5,9,9-trimethyl-6,7-benzomorphane (reaction sequence analogous to example 119) which cannot be separated by thin film chromatography (Rf = 0,73, silica gel, chloroform methanol concentrates Amak 90:10:0,5) is obtained by using 1,34 g (0,011 mol) (R)-2-methoxypropionic acid chloride. Yield: 2,9 g.

(b) Transposition to the title page

The evaporation residue of the pure fractions (0.9 g) is crystallized as oxalate in analogue to example 98. The title compound is obtained at a yield of 0.88 g (22.3% d. th.) with a melting point of 169 °C (Zers.) and a specific gravity of [α] $\frac{\text{25}}{\text{D\hspace{1em}}}$ The test chemical is a mixture of the expected diastereomers (a 1R,5S,2'R) and a 1S,5R,2'R) compound.

Claims (10)

1. Benzomorphans of general formula I wherein

   X   denotes oxygen or sulphur;

   R¹   denotes C₁₋₈-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, an aromatic group having 6 to 10 carbon atoms, also in combinations- it being possible for the aromatic moeity to be substituted by one or more lower alkyl group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s) which may be identical to or different from one another;

   R²   denotes hydrogen, C₁₋₈-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, an aromatic group having 6 to 10 carbon atoms, also in combinations, it being possible for the aromatic moeity to be substituted with one or more lower alkyl group(s), alkoxy group(s), nitro group(s), amino group(s), and/or one or more halogen atom(s), which may be identical to or different from one another; an aryl group bound to an alkylene chain and having 7 to 14 carbon atoms, whilst the aromatic moeity may be substituted with one or more lower alkyl group(s), alkoxy group(s), nitro group(s), amino group(s) and/or one or more halogen atom(s), which may be identical to or different from one another;

   R³   denotes hydrogen, C₁₋₆-alkyl;

   R⁴   denotes C₁₋₈-alkyl;

   R⁵   denotes C₁₋₈-alkyl;

   R⁶   denotes C₁₋₈-alkyl, an aromatic group having 6 to 10 carbon atoms, also in combinations, it being possible for the aromatic moeity to be substituted with one or more lower alkyl group(s), alkoxy group(s), nitro group(s), amino group(s), and/or one or more halogen atom(s), which may be identical to or different from one another;

   R⁷   and R⁸ independently of each other represent hydrogen, C₁₋₈-alkyl, halogen, -OH, C₁₋₈-alkoxy, an O-benzoyl or O-alkyl carbonyl group with one straight-chained or branched lower alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may optionally be substituted with one or more halogen atom(s) which may be identical to or different from one another, -CN, -NO₂, NH₂, -NH(C₁₋₈-alkyl), -N(C₁₋₈-alkyl)₂, wherein the alkyl groups may be identical or different, -NH-acyl or -N-acyl-(C₁₋₈-alkyl), wherein acyl represents benzoyl or an alkyl carbonyl group with a straight-chained or branched lower alkyl group having 1 to 6 carbon atoms, whilst the alkyl group may optionally be substituted with one or more halogen atom(s) which may be identical to or different from one another,

   the stereoisomeres thereof as well as the acid addition salts thereof, with the proviso that if

   X   denotes oxygen;

   R¹   denotes C₁₋₃-alkyl, C₃-alkenyl, C₃-alkynyl;

   R²   denotes hydrogen, C₁₋₄-alkyl, C₃- and C₄-alkenyl;

   R³   denotes hydrogen, C₁₋₃-alkyl;

   R⁴   denotes methyl;

   R⁵   denotes methyl;

   R⁶   denotes C₁₋₄-alkyl or phenyl

   and one of the two substituents R⁷ or R⁸ denotes hydrogen, the remaining substituent R⁷ or R⁸ in the 2'-position must not denote hydrogen, hydroxy, C₁₋₃-alkoxy O-acyl.
2. Benzomorphans of general formula I wherein

   X   denotes oxygen or sulphur;

   R¹   denotes methyl, ethyl, propyl, isopropyl, phenyl;

   R²   denotes methyl, ethyl, propyl, isopropyl, allyl, propargyl, phenyl, benzyl;

   R³   denotes hydrogen, C₁₋₄-alkyl;

   R⁴   denotes methyl, ethyl, propyl, isopropyl;

   R⁵   denotes methyl, ethyl, propyl, isopropyl;

   R⁶   denotes methyl, ethyl, propyl, isopropyl, phenyl;

   R⁷   denotes fluorine, chlorine, hydroxy, lower alkyl, C₁₋₃-alkoxy, an O-benzoyl or O-alkyl carbonyl group with one straight-chained or branched lower alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may optionally be substituted with one or more halogen atom(s) which may be identical to or different from one another;

   R⁸   denotes hydrogen, lower alkyl, hydroxy or C₁₋₈-alkoxy

   the stereoisomers and acid addition salts thereof.
3. Benzomorphans according to claim 1 wherein

   X   denotes oxygen;

   R¹   denotes methyl, ethyl;

   R²   denotes methyl, ethyl;

   R³   denotes hydrogen;

   R⁴   denotes methyl, ethyl;

   R⁵   denotes methyl, ethyl;

   R⁶   denotes methyl, ethyl;

   R⁷   denotes hydroxy, methyl, methoxy, an O-benzoyl or O-alkyl carbonyl group with one straight-chained or branched lower alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may optionally be substituted with one or more halogen atom(s) which may be identical to or different from one another;

   R⁸   denotes hydrogen, methyl, ethyl, hydroxy or C₁₋₃-alkoxy

   the stereoisomers and acid addition salts thereof.
4. Benzomorphans according to claim 1 wherein

   X   denotes oxygen;

   R¹   denotes methyl;

   R²   denotes methyl;

   R³   denotes hydrogen;

   R⁴   denotes methyl;

   R⁵   denotes methyl;

   R⁶   denotes methyl;

   R⁷   denotes hydroxy, methyl, methoxy, acetoxy;

   R₈   denotes hydrogen, methyl, hydroxy or C₁₋₃-alkoxy

   the stereoisomers and acid addition salts thereof.
5. Benzomorphans according to claim 1 wherein

   X   denotes oxygen;

   R¹   denotes methyl;

   R²   denotes methyl;

   R³   denotes hydrogen;

   R⁴   denotes methyl;

   R⁵   denotes methyl;

   R⁶   denotes methyl;

   R⁷   denotes hydroxy, methyl, methoxy, acetoxy;

   R⁸   denotes hydrogen, methyl, hydroxy, methoxy or ethoxy,

   whilst R⁷ is in the 3'-position and R⁸ is in the 2'-position and the 2''-carbon atom has the R-configuration, as well as the acid addition salts thereof.
6. (-)-(1R,5S,2''R)-3'-hydroxy-2-(2-methoxypropyl)-5,9,9-trimethyl-6,7-benzomorphan and the acid addition salts thereof.
7. Pharmaceutical preparations, characterised in that they contain a compound according to one of claims 1 to 6 or an acid addition salt thereof together with conventional excipients and carriers.
8. Use of compounds according to one of claims 1 to 6 in pharmaceutical compositions.
9. Use of compounds of general formula I wherein

   X   denotes oxygen or sulphur;

   R¹   denotes C₁₋₈-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, an aromatic group having 6 to 10 carbon atoms, also in combinations, it being possible for the aromatic moeity to be substituted with one or more lower alkyl group(s), alkoxy group(s), nitro group(s), amino group(s), and/or one or more halogen atom(s), which may be identical to or different from one another;

   R²   denotes hydrogen, C₁₋₈-alkyl, C₃₋₆-alkenyl, C₃₋₆-alkynyl, an aromatic group having 6 to 10 carbon atoms, also in combinations, it being possible for the aromatic moeity to be substituted with one or more lower alkyl group(s), alkoxy group(s), nitro group(s), amino group(s), and/or one or more halogen atom(s), which may be identical to or different from one another; an aryl group bound to an alkylene chain and having 7 to 14 carbon atoms, wherein the aromatic moeity may be substituted with one or more lower alkyl group(s), alkoxy group(s), nitro group(s), amino group(s), and/or one or more halogen atom(s), which may be identical to or different from one another.

   R³   denotes hydrogen, C₁₋₆-alkyl;

   R⁴   denotes C₁₋₈-alkyl;

   R⁵   denotes C₁₋₈-alkyl;

   R⁶   denotes C₁₋₈-alkyl, an aromatic group having 6 to 10 carbon atoms, also in combinations, it being possible for the aromatic moeity to be substituted with one or more lower alkyl group(s), alkoxy group(s), nitro group(s), amino group(s), and/or one or more halogen atom(s), which may be identical to or different from one another;

   R⁷ and R⁸   independently of each other represent hydrogen, C₁₋₈-alkyl, halogen, -OH, C₁₋₈-alkoxy, an O-benzoyl or O-alkylcarbonyl group with one straight-chained or branched lower alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may optionally be substituted with one halogen atom(s) which may be identical to or different from one another, -CN, -NO₂, NH₂, -NH(C₁₋₈-alkyl), -N(C₁₋₈-alkyl)₂ whilst the alkyl groups may be identical to or different, -NH-acyl or -N-acyl-(C₁-C₈-alkyl), wherein acyl is benzoyl or an alkyl carbonyl group with a straight-chained or branched lower alkyl group having 1 to 6 carbon atoms, whilst the alkyl group may optionally be substituted with one or more halogen atom(s) which may be identical to or different from one another,

   the stereoisomers and the acid addition salts thereof for preparing a medicament for the therapeutic treatment of cerebral ischaemia of various origins, epilepsy and neurodegenerative diseases.
10. Process for preparing compounds of general formula I wherein the substituents R¹ to R⁸ have the meanings given in claim 1, characterised in that either

    a) the benzomorphans of general formula II (wherein R⁴, R⁵ and R⁶ are as hereinbefore defined and R⁹ and R¹⁰ either have the same meaning as R⁷ and R⁸ or represent substituents which can be converted into the latter in known manner, in inert solvents in known manner, optionally in the presence of an acid binding agent) are reacted with carboxylic acid derivatives of general formula 4 wherein Y represents a leaving group capable of being substituted by a secondary amino group, selected from the group comprising halogen, hydroxy, OC(O)alkyl, O-acyl, OSO₂alkyl and OSO₂aryl and R¹, R² and R³ and X are as hereinbefore defined, and the resulting acid amide 3 is subsequently reduced in an inert solvent, in known manner, to obtain the amine of general formula 6 and optionally the substituents R⁹ and R¹⁰ are converted into R⁷ and R⁸ and the product (1) is isolated from the reaction mixture or

    b) benzomorphans of general formula 2 wherein R⁴, R⁵ and R⁶ are as hereinbefore defined and R⁹ and R¹⁰ either have the same meanings as R⁷ and R⁸ or represent substituents which can be converted into the latter in known manner, in inert solvents in known manner, optionally in the presence of an acid binding agent, are reacted with an alkylating agent of general formula 5 wherein Z represents a leaving group, which can be substituted by a secondary amino group, selected from the group comprising halogen, such as Cl, Br and I, or arylsulphonates OSO₂aryl, such as tosylate or alkylsulphonates, e.g. methanesulphonate or halomethanesulphonate or a sulphate group, to obtain the tertiary amine of type 6 and optionally the substituents R⁹ and R¹⁰ are converted into R⁷ and R⁸ and the reaction product is isolated.