NO764008L - - Google Patents

Description

Process for the preparation of benzazocine derivatives. ■

The present invention relates to a new method for producing compounds with the general formula

in which

R^, , R 3 and R 4 independently of each other are hydrogen or lower alkyl and R^ lower alkyl, and where if <R> 4 and R 5 are different from each other and/or R 2 and R 3 are different alkyl residues, the compounds may

exist as racemates or as optical antipodes, and for acid addition salts of these compounds. This method is characterized by allowing a connection with the formula

where X and Y are cyan or aminomethyl and lower alkyl

and R^ and Rj. has the above' meaning,

at a temperature between approx. 100 and 250°Cj under a pressure between approx. 10 and 100 bar hydrogen, in the presence of a nickel-o,g/or cobalt catalyst react with an alcohol of the formula

where

R 2 and R 3 have the above meaning,

and that in the event that a compound of formula I is to be obtained in which R^ is hydrogen, the obtained compound or an acid addition salt thereof is O-dealkylated in the desired order,

and optionally cleaves an obtained racemate in the optical antipodes and optionally converts an obtained base into an acid addition salt.

The term "lower alkyl" alone or in compositions refers to straight or branched hydrocarbon groups with 1-6, preferably 1-4 carbon atoms such as e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl > t-butyl, pentyl, hexyl or the like.

The compounds of formula I form acid addition salts with organic or inorganic acids, such as e.g. hydrochloric or hydrobromic acid, phosphoric acid, citric acid, sulfuric acid, succinic acid, maleic acid, p-toluenesulfonic acid, tartaric acid, perchloric acid and the like.

As representative examples of compounds that can be prepared according to the present invention are mentioned: rac.-6-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-3,6-dimethyl-3-benzazocine, rac. 3,6-diethyl-1,2,3,4,5,6-hexahydro-8-methoxy-6-methyl-3-benzazocine,

rac. 6-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-6-methyl-3-propyl-3-banzazocine,

rac. 6-ethyl-1,2,3,4,5,6-hexahydro-3-isopropyl-8-methoxy-6-methyl-3-benzazocine,

rac. 6-ethyl-1,2,3,4,5,6-hexahydro-3-butyl-8-methoxy-6-methyl-3-benzazocine,

rac. 6-ethyl-1,2,3,4,5,6-hexahydro-3-isobutyl-8-methoxy-6-methyl-3-benzazocine,

rac. 6-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-6-methyl-3-(1-methylpropyl)-3-benzazocine,

rac. 6'-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-6-methyl-3-pentyl-3-benzazocine,

rac. 6-ethyl-1,2,3,4,5,6-hexahydro-8-hydroxy-3,6-dimethyl-3-benzazocine,

(+)-6-ethyl-1,2,3,4,5,6-hexahydro-8-hydroxy-3,6-dimethyl-3-. benzazocine,

1, 2, 3, 4, 5, 6-hexahydrc-8-hydroxy-3, 6, 6-trimethyl-3-benz.azocine,

and such.

Until now, N-substituted benzazocines could only be prepared in a complicated manner and with poor yields. Thus, from Belgian patent no. 806 387, a method for the preparation of compounds of formula I is previously known. In this known method, an amino acid is first cyclized, namely 1-(2-carboxymethyl-5-lower alkoxyphenyl)-1,1-di -lower alkyl-3-propylamine derivative of a lactan, namely a 6,6-di-lower alkyl- 8-lower alkoxy-1,4,5,6-tetrahydro-3-benzazocin-2-(3H)-one -derivative and the latter then reduced to the corresponding N-unsubstituted 1,2,3,4,5,6-hexahydro-8-lower alkoxy-6,6-di-lower alkyl-3-benzazocine, which is then N-alkylated to corresponding to 1,2,3,4,5,6-hexa-hydro-8-lower alkoxy-3,6,6-tri-lower alkyl-3-benzazocine.

In this known method, the total yield of the latter product is very low. In contrast to this known method, a dinitrile, a diamine or an aminonitrile of formula II is transferred in a very simple manner and with high yield in one step to the desired 1,2,3,4,5,6-hexahydro-8-lower Alkoxy-3,6,6-tri-lower alkyl-3-benzazocine of formula I.

The release materials with formula II are known or can be prepared in a manner known per se from known compounds. Thus, for example, one can convert an acid halide, e.g. the acid chloride of an acid with the formula

in which

R^, R,_ and Rg have the above meaning,

with a reducing agent, e.g. with sodium borohydride in a solvent, e.g. diethylene glycol dimethyl ether to an alcohol with the formula

replace the hydroxymethyl residue present in the latter

by means of a halogen hydrogen acid in a solvent, e.g. hydrochloric acid in benzene, at a halomethyl residue and treating the halide obtained with an alkali metal cyanide in a solvent, e.g. sodium cyanide in dimethyl sulfoxide, in the corresponding dinitrile of formula II, wherein X and Y are cyan. The dinitrile can be hydrogenated with a catalyst, e.g. Raney nickel, in an ammoniacal environment, e.g. in ammoniacal methanol to the corresponding compound of formula I, in which X is cyan and Y aminomethyl, e.g. to the corresponding diamine of formula II, wherein X and Y

is aminomethyl.

As examples of starting materials with the formula II, 3r-(2-cyanomethyl-5-methoxyphenyl)-3-methyl-pentanonitrile and 2-(2-cyanomethyl-5-methoxyphenyl)-2-methyl-butanonitrile can be mentioned.

Examples of alcohols of formula III include methanol, ethanol, propanol, isopropanol, n-butanol, 1- or 3-methyl-propanol.

As examples of the nickel and/or cobalt catalysts used according to the method of the invention, Raney nickel, Raney cobalt and the nickel precipitation catalysts can be mentioned. The best yields are obtained with Raney nickel.

The quantity ratios between the starting material of formula II, the alkanol of formula III and the catalysts are not critical. Appropriately, however, approx. 1 - 50, preferably 5-20 parts by weight of the compound with the formula II to 100 parts by weight of the reaction mixture and from approx. 1 - 10, preferably approx. 5 parts by weight of the catalyst for 100 parts by weight of the compound of formula II.

The reaction of a compound of formula II with a compound of formula III can therefore be carried out continuously or discontinuously, preferably continuously.

In a preferred embodiment of the method according to the invention, a compound of formula II is treated at a temperature between approx. 140 and 235°C, preferably at a temperature between approx. 180 and 220°C, under a pressure between approx. 15 and 50 bar hydrogen, preferably under a pressure of approx. 30 bar hydrogen with Raney nickel. To obtain optimal yields, the used auto-

the clave over the course of 15 minutes, preferably between 4 and 8

minutes is brought to the required reaction temperature.

The starting material with formula II is preferably one in which X and Y are cyan, especially 3-(2-cyanomethyl-5-methoxyphenyl)-3-methylpentahonitrile. In a particularly preferred embodiment of the method according to the invention, the latter dinitrile is reacted with methanol at approx. 220°C under a hydrogen pressure of approx. 30 bar in. presence of Raney nickel.

The O-dealkylation of a compound of formula 1, in which R is lower alkyl or an acid addition salt thereof can be carried out with an ether-cleaving agent such as an aqueous acid, e.g. hydrobromic acid, a Lewis acid, e.g. boron tribromide or pyridine hydrochloride. The turnover is preferably carried out by higher temperature up to the reflux temperature of the reaction mixture, except when boron tribromide is used, whereby lower temperatures e.g. -20°C is used.

A compound of formula I obtained by the method according to the invention can, for example, be purified by filtration over neutral aluminum oxide using toluene or benzene as solvent.

The compounds of formula I, in which R 4 and R 1 - are different from each other and/or R 2 and R 1 are alkyl residues different from each other, can exist as racemates or as optical antipodes. If an optical antipode is required instead of a racemate, some can

of the intermediate products, e.g. the compounds with the formula II or IV, or the products with the formula I are cleaved in a manner known per se, e.g. by formation of diastereomeric fractions. Thus, for example, the cleavage when treating the racemic mixture of a compound of formula I or II can take place with an optically active acid. For the resolution of the optical isomers suitable

acids are, for example, tartaric acid, camphorsulfonic acid, di-(p-tolyl)-tartaric acid, (-)-di-O-isopropylidene-2-keto-L-gulonic acid, [(-)-DAG] and the like. The reaction between the racemic mixture and the optically active acid is preferably carried out in the presence of a solvent such as, for example, methanol, ethanol, pyropanol, acetone, acetonitrile, ethyl acetate and the like. The diastereomeric salts thus obtained can be separated from each other as a result of different solubility, crystal formation etc. The separation is carried out using usual methods, e.g. fractional crystallization and the like. After cleavage, the obtained diastereomeric salts can be transferred by treatment with base in the corresponding optically active bases. Suitable bases for this are e.g. alkali metal hydroxides, such as sodium hydroxide, calcium hydroxide and ammonium hydroxide.

The compounds of formula I obtained according to the invention and the acid addition salts thereof are pharmacologically active. As particularly valuable with regard to their high analgesic activity, the compound of formula I in which R is hydrogen, e.g. rac. 6-ethyl-1,2,3,4,5,6-hexahydro-8-hydroxy-3,6-dimethyl-3-benzazocine and its (+)-antipode were demonstrated.

Example 1

Production of rac. 6-Ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-3,6-dimethyl-,3-benzazocine.

242 g of 3-(2-cyanomethyl-5-methoxyphenyl)-3-methyl-pentanonitrile are dissolved in 3500 ml of methanol, mixed with 25 g of methanol-moistened Raney nickel and heated in a rapidly heatable stirring autoclave (compare e.g. Chemie- Ing. Techn, Heft 22, 1974, page 963) under a pressure of 30 bar hydrogen for approx. 8 minutes at 220°C and allowed to stand at this temperature. After 2 1/2 hours, the reaction solution is cooled to room temperature and filtered from the catalyst and the clear, colorless filtrate is evaporated to dryness, whereby the desired benzazocine is obtained in the form of an oil with a yield of 92%...

For further purification, the oil obtained is taken up in toluene and filtered over aluminum oxide. You get 213.5 g of the above-mentioned benzazocine with 98% purity, which corresponds to a total yield of 84.6%.

2.5 g of this benzazocine (dissolved at room temperature in 25 ml of absolute ethanol) is mixed with 3 ml of an ethanolic hydrochloric acid solution. The resulting solution is evaporated to dryness. The residue is dissolved in 5 ml of acetone and the solution is allowed to crystallize in a freezer. The crystals are filtered, washed with 2 ml of acetone and 4 ml of n-hexane

and dried under reduced pressure at 60°C. The benzazocine hydrochloride obtained melts at 194-195°C.

The 3^-(2-cyanomethyl-5-methoxy phenyl)-3-methyl-pentanonitrile used in the above preparation can be prepared as follows:

'in

A reading of 100 g of sodium hydroxide in 900 ml of water is added with stirring over the course of 1 hour to a mixture of 1361 g of p-anisaldehyde, 1000 g of 3-methyl-2-pentanone, 3000 ml of ethanol and 1300 ml of water and the reaction mixture is stirred further overnight at room temperature. The mixture is poured into 7 liters of ice water 6g is treated 3 times with 3 liters of toluene. The organic phases are washed one after the other with water, saturated sodium bicarbonate solution and saturated sodium chloride solution until the reaction is neutral and dried over magnesium sulfate. The solvent is distilled off under reduced pressure. The oil obtained is distilled under high vacuum and 1484 g of 1-(4-methoxyphenyl)-4-methyl-1-hexen-3-one are obtained in the form of a yellowish oil.

A mixture of this oil and 8 liters of ethanol is hydrated with stirring in the presence of 150 g of Raney nickel. In the course of 2 hours, 175 ml of hydrogen is absorbed. The mixture is filtered from the catalyst and mixed and rehydrated with 150 g of water-wet Raney nickel and 125 g of anhydrous sodium carbonate. In the course of 24 hours, 175 liters of hydrogen are absorbed. After separation of the catalyst, the solvent is distilled off under reduced pressure and the oil obtained is then distilled, whereby 1434 g of 1-(4-methoxy-phenyl)-4-methyl-3-hexanol are obtained.

This substance is mixed with 2870 ml of 85% phosphoric acid and kept for 8 hours at reflux temperature. After cooling, the reaction mixture is poured into 10 liters of ice water and treated 3 times with 4 liters of ethyl acetate.

The organic phase is washed neutrally with saturated sodium chloride solution and dried over magnesium sulfate. After distilling off the solvent, the obtained oily residue is distilled, whereby 1-ethyl-7-methoxy-1-methyl-1,2,3,4,5,6-tetrahydro-naphthalene is obtained.

A mixture of 600 g of this substance and 3.8 liters of ethyl acetate is brought to 0°C with stirring. It is then infused. a mixture of 906 g of chromic anhydride, 495 ml of water and 1330 ml of ethyl acetate in the course of approx. 2 hours so that the reaction temperature does not exceed 25°C. After completion, the addition is stirred for 2 hours at room temperature and the reaction mixture is poured on

5 liters of ice water. The mixture is taken up 3 times in 5 liters of methylene chloride, the organic phase is washed in sequence with 7 liters of 3N sodium hydroxide solution, 5 liters of saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off at 40°C under reduced pressure. The oily residue is distilled under high vacuum, whereby 4-ethyl-6-methoxy-4-methyl-3,4-dihydro-1(2H)-naphthalinone is obtained. 1 2.5 litres, absolute ethanol is preceded by 14.0 g of hydrochloric acid gas. While stirring, 531 g of 4-ethyl-6-methoxy-4-methyl-3,4-dihydro-1(2H)-naphthalenone are introduced. During ice/water cooling, a solution of 342 g of isoamyl nitrite in 530 ml of absolute ethanol is added dropwise in a stream of approx. 2 hours, so that the temperature is 2 - 5°C. Then stir for 2 hours. The precipitate that precipitates is filtered off and washed successively with a little cold diethyl ether and n-hexane and dried at room temperature under reduced pressure. You get: 4-ethyl-6-methoxy-4-methyl-3,4-dihydro-1,2-naphthoquinone-2-oxime. Temp. 162°C.

500 g of this substance is dissolved in a solution of 280 g of sodium hydroxy in 2.5 liters of water. A solution of 587 g of p-toluene sulphochloride in 2 liters of toluene is added dropwise over the course of 50 - 60 minutes so that the reaction temperature does not exceed 15°C. Then continue stirring for 4 hours at room temperature. The organic phase is separated, the aqueous phase is shaken again with 500 ml of toluene, the organic phases are combined and shaken out with 300 ml of water. The combined aqueous phases are stirred slowly with 1.2 liters of 6N hydrochloric acid at pH 3.0. The formed crystalline precipitate is filtered off after 1 hour and washed with water until the reaction is neutral. The product obtained is dried, whereby 2-[(2-cyano-1-ethyl-1-methyl)-ethyl]-4-methoxybenzoic acid is obtained in the form of white crystals. Temp. 105 - 106°C.

A mixture of 500 g of this substance in 1.5 liters of absolute benzene is added dropwise to 360 g of thionyl chloride. The mixture is kept for 1 hour at reflux temperature. The solvent and the excess thionyl chloride are distilled off under reduced pressure, the oily residue is mixed again 2 times with 200 ml of absolute benzene and the solvent is distilled off under reduced pressure, whereby 575 g of oily acid chloride are obtained. A mixture of this substance in 2 liters of diethylene glycol dimethyl ether is added dropwise with stirring to a suspension of 190 g of sodium borohydride in 2500 ml of diethylene glycol dimethyl ether over the course of 1 hour under ice cooling so that the temperature is 30 - 35°C. Then stir for another 2 hours at room temperature. After mixing with 70 ml of acetone and stirring for 15 minutes, the mixture is poured into 7 liters of ice water and mixed while stirring slowly with a solution of 300 ml of concentrated hydrochloric acid in 300 ml of water so that the pH is between 4 and 5. The aqueous phase is treated 2 times with 4 liter of ethyl acetate. The two ethyl acetate flasks are washed with 1 liter of water, 500 ml of 1N sodium hydroxide solution and then several times with 1 liter of neutral water, the solvent is dried over magnesium sulphate and first distilled off under reduced pressure and then in high vacuum, whereby 402 g of 3-(2-hydroxymethyl) is obtained -5-methoxyphenyl)-3-methylpentanonitrile in the form of a yellow oil.

A solution of this substance is dripped in 1.8 liters of benzene over the course of 15 minutes to .7.35 liters of concentrated hydrochloric acid. It is stirred further for 15 minutes in The mixture is treated with 2.5 liters of benzene, the organic phase is separated and washed neutrally with water. The mixture is dried over magnesium sulphate and the solvent is distilled off at 40°C under reduced pressure. 366 g of 3-(2-chloromethyl-5-methoxyphenyl)-3-methylpentanonitrile are obtained in the form of a yellow oil.

Over the course of 30 minutes, a solution of this substance in 1000 ml of dimethyl sulphoxide is added dropwise to a solution of 102.3 g of sodium cyanide and 1800 ml of dimethyl sulphoxide, so that the temperature does not exceed 35°C. The mixture is then stirred at room temperature, poured into 5 liters of ice water and treated 3 times with .3 liters of toluene. The individual toluene phases are washed 3 times with 1 liter of water, combined and dried over 100 g of magnesium sulphate, filtered and the solvent is first distilled off under reduced pressure and then under high vacuum. You get 92 g of a light orange oil. "For purification, this is purified using 3,000 g of aluminum oxide and 20 liters of toluene, whereby 235 g of a pale yellow oil is obtained. The oil obtained is mixed with .250 ml of isopropyl ether and stirred overnight at room temperature. The obtained crystalline precipitate is filtered off, washed with 50 ml of n-hexane and dried, thereby obtaining 230 g of 3-(2-cyanomethyl-5-methoxyphenyl)-3-methylpentanonitrile in the form of colorless crystals.

Temp. 47-48°C. ,

Example 2

Variant for the production of rac. 6-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-3,6-dimethyl-3-benzazocine.

2.5 g of 3-[2-(2-ethylamino)-5-methylpentyl]-3-methyl-pentylamine is dissolved in 250 ml of methanol, mixed with 5 g of methanol-moistened Råney nickel and allowed to react in a stirring autoclave under a pressure of 50 bare hydrogen at 220°C. After cooling, the catalyst is filtered off and the processing takes place as described in the example

1. You get 2.0 g of it. the above benzazocine.

The starting amine used further above can be prepared as follows:

24 g of 3-(2-cyanomethyl-5-methoxyphenyl)-3-methyl-pentanonitrile with

5 g of Raney nickel are placed in a stirred autoclave and the resulting mixture is fed with 2 liters of liquid ammonia. It is then allowed to react for 15 hours under pressure of 20 bar hydrogen, at 50°C. After the reaction has finished, the ammonia is evaporated, the residue is taken up in 500 ml of dioxane and the catalyst is filtered off. The residue evaporated to dryness (22.8 g dark yellow viscous oil) is distilled for further purification. 19.2 g of diamine is obtained.

E xample 3-

In an analogous way to example 1, the following reactions are carried out:

a) 7.26 g of 3-(2-cyanomethyl-5-methoxyphenyl)-3-methyl-pentano-nitrile (hereinafter called "dinitrile") is reacted with 800 ml of ethanol in

presence of 5 g of ethanol-moistened Raney nickel, under ^.30 bar hydrogen at 180°C. After 2 1/2 hours you get 6.4 g of pure rac. 3,6-diethyl-1,2,3,4,5,6-hexahydro-8-methoxy-6-methyl-3-benzazocine, whose hydrochloride melts at 174-176°C

B) 7.26 g of dinitrile is reacted with 800 ml of n-propanol, in the presence of 5 g of propanol-moistened Raney nickel under 30 bar of hydrogen at 150°C. After 4 1/2 hours you get 6.6 g of pure rac. 6-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-6-methyl-3-propyl-benzazocine, if

hydrochloride melts at 183 - 185°C.

c) 7.26 g dinitrile is reacted with 800 ml isopropanol in the presence of 5.g isopropanol-moistened Raney nickel under 30 bar

hydrogen at 190°C. After 6 hours you get 3.7 g of pure rac. 6-ethyl-1,2,3,4,5,6-hexahydro-3-isopropyl-8-methoxy-6-methyl-3-benzazocine, the hydrochloride of which melts at 145<->146°C.

d) 7.26 g of dinitrile is reacted with 800 ml of n-butanol, in the presence of 5 g of n-butanol-moistened Raney nickel under 30 bar. hydrogen

at 140°C. After 3 1/3 hours you get 7.8 g of pure rac. 6-ethyl-1,2,3,4,5,6-hexahydro -3-butyl-8-methoxy-6-methyl-3-benzazocine, the hydrochloride of which melts at 184'-185°C.

e) 7.26 g dinitrile is reacted with 800 ml isobutanol i

presence of 5 gisobutanol-moistened Raney nickel under 30 stretchers

hydrogen at 180°C. After 10 hours you get 5.5 g of pure rac. 6-Ethyl-1,2,3,4,5,6-hexahydro-3-isobutyl-8-methoxy-6-methyl-3-benzazocine, whose hydrochloride . melts at 156-157°C..;

f) 7.26 g of dinitrile is reacted with 800 ml of 2-butanol in the presence of 5 g of 2-butanol-moistened Raney nickel under 30 bar of hydrogen

at 180°C. After 6 1/2 hours you get 2.6 g of pure rac. 6-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-6-methyl-3-(1-methylpropyl)-3-benzazocine, whose hydrochloride melts at 163 - 164°C.

g) 7.26 g of dinitrile is reacted with 800 ml of n-pentanol in the presence of 5 g of n-pentanol-moistened Raney nickel under 30 bar

hydrogen at 180°C. After 14 hours, 8.3 g of pure rac.. 6-ethyl-1, 2, 3, 4, 5v.6-hexahydro-8-methoxy-6-methyl-3-pentyl-3-benzazocine are obtained, the hydrochloride of which melts at 174 - i75°C.

Example 4

In an analogous manner to example 2, 2.5 g of rac are reacted. 3-[2-(-2-ethyl amino)-5-methoxyphenyl]-3-methyl-pentylamine with 250 ml of ethanol in the presence of 5 g of ethanol-moistened Raney nickel, under 30 bar of hydrogen at 200°C. After 1 1/2 hours, 2.1 g of pure product is obtained which is identical to the benzazocine produced in example 3a).

Example 5

In an analogous manner to example 1, 5 g of 3-(2-cyanomethyl-5-methoxymethyl)-3-methyl-pentanonitrile is allowed to react with 800 ml of methanol

in the presence of 5 g of methanol-moistened Raney nickel, under 30 bar of hydrogen at 220°C. After 30 minutes, make the yield of raw rac. 6-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-3,6-dimethyl-3-benza-

zocin 92%.

Used instead of Raney nickel Raney cobalt as a catalyst,

is the yield of crude benzazocine 50% after 3 hours of reaction, a nickel precipitation catalyst is used, a yield of 80% is obtained after 1 hour of reaction.

Example 6

The rac produced according to example 1. 6-Ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-3,6-dimethyl-3-benzazocine hydrochloride is O-demethylated using aqueous hydrobromic acid to non-crystallizable rac. 6-ethyl-1,2,3,4,5,6-hexahydro-8-hydroxy-3,6-dimethyl-3-benzazocine hydrochloride;

. Melting point of the perchlorate 174-175°C.

Example 7

The rac.-6-ethyl-1,2,3,4,5,6-hexa-hydro-8-methoxy-3,6-dimethyl-3-benzazocine prepared according to example 1 is cleaved using ( + )-di -(p-tolyl)-tartaric acid as a resolving agent in the optical antipodes, which saw in the form of its di-(p-tolyl)-tartrate, namely ( + )-6-ethyl-l, 2,3,4,5, 6-Hexahydro-8-methoxy-3", 6-dimethyl-3-benzazocine-(+)-di-(p-tolyl)-tartrate [m.p. 144-146°C (decomposition); [a]^3 of the free base +23.1° (c = 4.02%)] and (-)-6-ethyl-1,2,3,4,5,6-hexahydro-8-methoxy-3,6-dimethyl-3-benzazocine -(-)-di-(p-tolyl)-tartrate [aJD of the free base -23.2

(c = 3.86%)] is isolated.

in

By O-demethylation of the bases corresponding to these di-(p-tolyl)-tartrates with the aid of aqueous hydrobromic acid, (+)-6-ethyl-1,2,3,4,5,6-hexahydro-8- hydroxy-3,6-dimethyl-3-benzazocine, whose hydrochloride melts at 171-172°C1 and has an optical calculation [oc]^° of +26.0° (c 1 in methanol).

Example 8

In an analogous manner to example 1, 1, 2, 3, 4, 5, 6«-hexahydro-8-methoxy-3,6,6-trimethyl-3-benzazocine is prepared, the hydrochloride of which melts

at 185-186.5°C, by reacting 2-(2-cyanomethyl-5-methoxyphenyl)-2-methyl-butanonitrile with methanol. The benzazocine obtained is then O-demethylated in a manner analogous to example 6 to 1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,6-trimethyl-3-benzazocine perchlorate with melting point 238-240 °C.

Claims (10)

1. Procedure for the preparation of compounds of the general formula In which R1' R2' R3° and R4 independently of each other are hydrogen or lower alkyl and R1 is lower alkyl, and where, if R4 and R1- are different from each other pg/or and R1 are alkyl residues different from each other, there is the compounds as racemates or optical antipodes and of acid addition salts of these compounds, characterized by allowing a compound of the formula in which X and Y are cyan or aminomethyl and R, lower alkyl andR^ and. R,_ has the above meaning, react at a temperature between approx. 100 and 250°C under a pressure between approx. 10 and 100 bar hydrogen in the presence of a nickel and/or cobalt catalyst with an alcohol of the formula in which R2 and R^ have the above meaning, and that in the case that a compound of the formula I is to be prepared where R^ means hydrogen, the compound obtained or an acid addition salt thereof is O-dealkylated and, in any order, if desired, a racemate obtained is split into the optical antipodes and, if desired, converts a base obtained into an acid addition salt. 2. Method, according to claim 1, characterized in that the necessary reaction temperature is reached within 15 minutes. 3. Method according to claim 1 or 2, characterized in that the required reaction temperature is reached within 4-8 minutes. 4. Method according to one of claims 1-3, characterized in that the turnover is carried out at a temperature between approx. 140 and 235°C, preferably at a temperature between approx. 180 and 220°C. 5. Method according to one of claims 1-4, characterized in that the reaction is carried out under a pressure between approx. 15 and 50 bar hydrogen., preferably under a pressure of approx. 30 bar hydrogen. 6. Method according to one of claims .1 - 5, characterized in that Raney nickel is used as catalyst. 7. Method according to one of claims 1-6, characterized in that a compound of formula II is used, in which X and Y are cyan as starting material. 8. Method according to one of claims 1-7, characterized in that 3-(2-cyanomethyl-5-methoxyphenyl)-3-methyl-pentanonitrile is used as starting material with formula II and methanol as starting material with formula IH and carries out the turnover of these compounds at approx. ,220°C under a pressure of approx. 30 bar hydrogen in the presence of Raney nickel. 9. Procedure according to claims 1 and 8, character- terized by O-demethylating the product obtained. 10. Method according to claim 9, characterized in that the O-demethylation is carried out with aqueous hydrobromic acid.