DE2002864A1 - 2,3,5,9-tetrasubstit.-2'-hydroxy-6,7-benzomorphane and process for their preparation - Google Patents

Description

The present invention relates to new benzomorphan derivatives, the processes for their preparation and their use as medicaments. The disclosed class of compounds of the invention has pronounced analgesic activity, that is, is effective in relieving pain.

The most widely used medicine for pain relief is still morphine. However, this drug shows violent effects because the prolonged use of morphine generally leads to physiological and psychological dependence on the drug. It also has a depressing effect on breathing. The search has been tirelessly and at great expense for an analgesic that should be as effective as morphine but free from its harmful effects. Many analgesics related to the morphine model have been synthesized and disclosed; the best known of them is pethidine. Originally it was believed that

Pethidine was a non-addictive drug, but it was soon found to be dangerously addictive. Other synthetic analgesics include a group of substances called benzomorphans. The best-known member of this group is phenazocin, which, like morphine, is also dangerously addictive.

The present invention relates to a new group of chemical compounds which are 2,3,5-trisubstituted-2'-hydroxy-6,7-benzomorphans and further the nontoxic, pharmaceutically acceptable salts thereof. The present invention also relates to the novel processes for the preparation of the 2,3,5-trisubstit.-2'-hydroxy-6,7-benzomorphanes according to the invention.

The compounds of the invention can be represented by the following structural formula:

Here R [deep] 2 are hydrogen, -CN,

CH [deep] 2R, where R stands for hydrogen, alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, etc.), alkenyl (preferably lower alkenyl, such as vinyl, isopropenyl, allyl, methallyl, 3-butenyl, etc.), cycloalkyl (preferably Cyclone lower alkyl, such as cyclopropyl, cyclobutyl, etc.), cycloalkylalkyl (preferably cyclone lower alkyl lower alkyl, such as cyclopropylmethyl, cyclopropylethyl, etc.), cycloalkenyl (preferably cyclone lower alkenyl, such as 1-cyclobutenyl, 2-cyclobutenyl, 3-cyclopentenyl etc.), cycloalkenylalkyl (preferably cyclone-lower alkenyl-lower alkyl, such as 1-cyclobutenylmethyl, 2-cyclobutenylmethyl, etc.), alkylcycloalkyl (preferably lower alkylcyclo-lower alkyl, such as methylcyclopropyl, ethylcyclopropyl, etc.), alkenylcyclopentylene-cycloalkyl, such as methylcyclopropyl, etc.), alkenylcyclopentylene-cyclocyclocycloxycycloxyalkylene, methylcyclopentylcyclocyclokenyl-3-alkyl, such as methylpropylene-cycloalcylcyclocycloxy-3-methylcyclocycloxyalkylene, such as methylpropylene-cycloalcylcycloxy-3-alkyl, such as (preferably lower alkylcyclo-lower alkenyl, such as 2,2,3-trimethylcyclopropenyl, 2-methylcyclopentyl, etc.) or spiroalkyl (preferably spiron-lower alkyl, such as spiropentyl, 5-spiropentyl, 5-spiro- (3,2) -hexyl);

R [deep] 3 alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, etc.), cycloalkyl (preferably cyclone-lower alkyl, such as cyclopropyl, cyclobutyl, etc.), aryl (preferably phenyl or a substituted phenyl capable of forming an aryllithium reactant such as p-methoxyphenyl) or aralkyl (preferably ar-lower alkyl such as benzyl, phenylethyl, etc.); and

R [deep] 5 hydrogen, alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.) aryl (preferably phenyl) or substituted aryl (preferably substituted phenyl provided that the substituent does not react with a lithium reactant such as p-methoxyphenyl). R [deep] 9 has the meaning described above for R [deep] 5, with the exception that it cannot stand for hydrogen.

The present invention also encompasses the geometric isomers which result from the various possible cis or trans relationships between the groups R [deep] 3, R [deep] 5 and R [deep] 9, and also the optical isomers , into which each of these geometric isomers can be split.

The following compounds fall within the scope of the present invention: 3,5,9-trisubstit.-2'-hydroxy-6,7-benzomorphane and 2,3,5,9-tetrasubstit.-2'-hydroxy-6,7 -benzomorphans.

The more preferred aspects of the present invention relate to the benzomorphans and their salts having the following formula:

Here R [deep] 2 is hydrogen or -CH [deep] 2R, where R is hydrogen, lower alkyl, lower alkenyl, cyclone-lower alkyl or lower alkenyl-cyclone-lower alkyl;

R [deep] 3 lower alkyl (such as methyl or ethyl); and

R [deep] 5 and R [deep] 9 lower alkyl (such as methyl, ethyl, propyl or butyl).

Representative compounds of the invention are the following:

3,5,9-trimethyl-2'-hydroxy-6,7-benzomorphane,

2,3,5,9-tetramethyl-2'-hydroxy-6,7-benzomorphane,

2,5,9-trimethyl-3-ethyl-2'-hydroxy-6,7-benzomorphane,

2,5,9-trimethyl-3-n-propyl-2'-hydroxy-6,7-benzomorphane,

2,5,9-trimethyl-3-i-propyl-2'-hydroxy-6,7-benzomorphane,

2-cyclopropylmethyl-3,5-dimethyl-9-n-butyl-2'-hydroxy-6,7-benzomorphane,

2-cyclopropylmethyl-3-methyl-5,9-di-n-butyl-2'-hydroxy-6,7-benzomorphane,

2-cyclopropylmethyl-3-methyl-5,9-diphenyl-2'-hydroxy-6,7-benzomorphane,

2- (2-methallyl) -3-methyl-5,9-di-n-butyl-2'-hydroxy-6,7-benzomorphane,

2-cyclopropylmethyl-3-benzyl-5,9-diethyl-2'-hydroxy-6,7-benzomorphane,

3,9-dimethyl-5-n-butyl-2'-hydroxy-6,7-benzomorphane,

3-i-propyl-5-n-butyl-9-methyl-2'-hydroxy-6,7-benzomorphane,

3,5-di-n-butyl-9-methyl-2'-hydroxy-6,7-benzomorphan,

3-methyl-5,9-di-n-butyl-2'-hydroxy-6,7-benzomorphane,

3,9-diethyl-5-n-butyl-2'-hydroxy-6,7-benzomorphane,

3-n-propyl-5,9-diethyl-2'-hydroxy-6,7-benzomorphane, and

3,9-dimethyl-5-phenylethyl-2'-hydroxy-6,7-benzomorphane.

Another aspect of the present invention relates to a method of treatment for relieving pain by administering compounds of the structural formula in which: R [deep] 2 hydrogen, -CN, and -CH [deep] 2R, where R stands for hydrogen, alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, etc.), alkenyl (preferably lower alkenyl, such as vinyl, isopropenyl, allyl, methallyl, 3-butenyl, etc.), cycloalkyl (preferably cyclone-lower alkyl, such as cyclopropyl, cyclobutyl, etc.), cycloalkylalkyl (preferably cyclone-lower alkyl-lower alkyl, such as cyclopropylmethyl, cyclopropylethyl, etc.), cycloalkenyl (preferably cyclone-lower alkenyl, such as 1-cyclobutenyl, 2-cyclobkenyl-lower alkyl, preferably , such as 1-cyclobutenylmethyl, 2-cyclobutenylmethyl, etc.), alkylcycloalkyl (preferably lower alkyl-cyclone-lower alkyl, such as methylcyclopropyl, ethylcyclopropyl, etc.),

Alkenylcycloalkyl (preferably lower alkenyl cyclone lower alkyl, such as methylenecyclopropyl, methylenecyclobutyl, 3-vinylcyclopentyl, etc.), alkylcycloalkenyl (preferably lower alkyl cyclone lower alkenyl, such as 2,2,3-trimethylcyclopropenyl, 2-methylcyclopentyl or spiro-lower alkyl, such as 5-spiro-lower alkyl, preferably 5-spiro-pentyl, etc.) Spiro- (3,2) -hexyl);

R [deep] 3 alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, etc.), aryl (preferably phenyl or a substituted phenyl which has an aryl lithium reactant such as p-methoxyphenyl, is able to form), aralkyl (preferably Ar-lower alkyl, such as benzyl, phenylethyl, etc.); and

R [deep] 5 hydrogen, alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, etc.), aryl (preferably phenyl) or substituted aryl (preferably substituted phenyl, provided that the substituent does not react with a lithium reactant such as p-methoxyphenyl); and

R [deep] 9 has the meaning described above for R [deep] 5, with the exception that it cannot stand for hydrogen.

The present invention encompasses the method of treatment for relieving pain by administering compounds of the above structure and their optical isomers.

The more preferred aspects of the present invention relate to a method of treatment for relieving pain by administering compounds of the structural formula

in which: R [deep] 2 is hydrogen or -CH [deep] 2R, where R is hydrogen, lower alkyl, lower alkenyl, cyclone-lower alkyl or lower alkenyl-cyclone-lower alkyl;

R [deep] 3 lower alkyl (such as methyl or ethyl); and

R [deep] 5 and R [deep] 9 lower alkyl (such as methyl, ethyl, propyl or butyl).

The benzomorphan derivatives according to the invention show good effectiveness in a modified Randall Selitto test. Good effectiveness in this test indicates useful analgesic activity.

The benzomorphan derivatives according to the invention generally show little or no narcotic antagonist activity. The lack of narcotic antagonist activity may be beneficial because of the observation that high antagonist activity is generally accompanied by undesirable side effects.

Another feature of the present invention is the fact that the compounds of the invention can be more conveniently prepared by synthetic methods than members of the morphine family from naturally occurring alkaloid analgesics.

The compounds according to the invention are administered orally or subcutaneously, preferably as an aqueous solution of the hydrochloride salt in the range from about 0.001 mg / kg to about 18 mg / kg per day.

Various animal experiments were carried out in order to demonstrate that the compounds according to the invention are able to show reactions which can be correlated with activity in humans. One of these tests, that of

Charles A. Winter and Lars Flataker in The Journal of Pharmacology and Experimental Therapeutics, Volume 150, No. 1, Pages 165-171, shows the ability of the compounds of the invention to exhibit analgesic activity. The threshold of reaction to pressure in the hind paws of rats injected with a phlogistic agent is measured. These measurements are compared with those of known analgesic drugs and the effects are found to be significantly increased. Drug dosages up to 18 mg / kg are administered subcutaneously. The experiments are carried out on female Sprague-Dawley rats weighing 60 to 80 g. The reaction threshold is determined by applying pressure to the paws and reading the pressure on a manometer at which an audible "squeak" is induced. Groups of 6 rats are used for each test and the mean pressure gauge is recorded.

The activity of the compounds according to the invention, tested according to the procedure outlined above by Winter et al, indicates that they are to be regarded as compounds with analgesic activity.

The benzomorphane compounds of the present invention are conveniently prepared by the following processes.

If 2,4,5-trisubstituted-1-methyl-1,2,3,6-tetrahydropyridines VI are reacted with p-methoxybenzyl halide, the quaternary p-methoxybenzyl halide Va is formed. The quaternary compound Va then becomes rearranged with phenyllithium in the Stephens rearrangement in an inert solvent (such as ether) to 6-p-methoxybenzyl-1-methyl-2,4,5-trisubstit.-1,2,3,6-tetrahydropyridine IVa, which is then rearranged with 48 % hydrobromic acid is treated to produce the desired 2-methyl-3,5,9-trisubstituted-2'-hydroxy-6,7-benzomorphan (IIIa). The following equations explain this manufacturing method: (VI) (Va) (IVa) (IIIa)

Here R [deep] 3, R [deep] 5 and R [deep] 9 have the meanings described above and X denotes halide.

If the other benzomorphane isomer, i.e. the one with R [deep] 3 in the epimeric position, is desired, it is necessary that the p-methoxy-benzyl group is already linked to the pyridine nitrogen atom at the beginning of the synthesis, so that when the quaternary connection is made it is formed from the opposite side. 2,4,5-trisubstituted-1-benzyl-1,2,3,6-tetrahydropyridines (VII) are used for this isomer. If these compounds are treated with a methyl halide (preferably methyl bromide or methyl iodide) in a preferably polar solvent, the quaternary compound Vb is formed. This is then also rearranged with phenyllithium in the Stephens rearrangement to the isomeric 6-p-methoxybenzyl-1-methyl-2,4,5-trisubstitute-1,2,3,6-tetrahydropyridine IVb. Treatment with 48% hydrobromic acid provides the desired epimeric 2-methyl-3,5,9-trisubstituted-2'-hydroxy-6,7-benzomorphan (IIIb). The following equations illustrate this manufacturing method.

(VII) (Vb) (IVb) (IIIb)

Here, R [deep] 3, R [deep] 5 and R [deep] 9 have the meanings described above, and X denotes halide.

The production of the 3,5,9-trisubstituted-2'-hydroxy-6,7-benzomorphane II is preferably carried out by adding the corresponding tetrasubstituted-2'-hydroxy-2-methyl-6,7-benzomorphane III with acetic anhydride acylated in the 2'-position, the acylated compound is heated to elevated temperature with cyanogen bromide in an organic solvent, preferably a halogenated hydrocarbon such as chloroform, whereby the 2-methyl group is replaced by a cyano group and then the cyano and acetyl group by Hydrolysis can be removed in a dilute acid solution. The acetyl group can be hydrolyzed to the desired 2-cyano compounds (Id) by known methods. This is shown in the sequence of reactions below.

(III)

(Id) (II)

Here, R [deep] 3, R [deep] 5 and R [deep] 9 have the meanings described above, and R 'denotes alkyl.

The 2,3,5,9-tetrasubstit.-2'-hydroxy-6,7-benzomorphane I according to the invention can be prepared by the following general process:

(III) (II) (I)

Here, R [deep] 2, R [deep] 3, R [deep] 5 and R [deep] 9 have the meanings described above.

The reaction of the trisubstituted-2'-hydroxy-6,7-benzomorphane with two equivalents of an acid halide of the formula RCOX (where X is chloride or bromide, and R has the meaning given above, in an inert solvent (such as chloroform or benzene) preferably in the presence of a tertiary amine base (such as pyridine or triethylamine) leads to the formation of the corresponding tetrasubstit.-2'-acyloxy-2-acyl-6,7-benzomorphane derivative

where R has the meaning given above]. The reduction of these derivatives, for example with lithium aluminum hydride in diethyl ether or tetrahydrofuran, gives tetrasubstituted-2'-hydroxy-6,7-benzomorphane compounds (Ia) according to the invention. The 2'-acyl group can be hydrolyzed by known methods to produce the corresponding 2-amide compounds (Ic). The following equations illustrate this manufacturing method: (II) (Ic) (Ia)

Here R, R [deep] 3, R [deep] 5 and R [deep] 9 have the meanings described above.

In the process described above, the desired end products are isolated from their special reaction solutions or mixtures by methods belonging to the known prior art.

The 2,3,5,9-tetrasubstituted-2'-hydroxy-6,7-benzomorphans according to the invention can be used as such or in the form of their non-toxic, pharmaceutically acceptable acid addition salts. Such salts are prepared from suitable acids (e.g. inorganic acids such as hydrochloric or sulfuric acid, or organic acids such as acetic or maleic acid and the like). The acid addition salts are prepared by reacting the appropriate benzomorphane base with about 1 equivalent of the appropriate acid in an organic solvent (such as diethyl ether or alcohol) or aqueous solution.

The starting materials for the preparation of the novel compounds according to the invention, namely the trisubstituted-1-methyl- and -1-benzyl-1,2,3,6-tetrahydropyridines VI and VII, can be prepared by the following reactions.

When known 2,5-disubstituted pyridines are treated with a methyl halide or a benzyl halide (preferably bromide or iodide) in a solvent (preferably a polar solvent such as acetone, ether, ethyl alcohol, etc.), quaternary 2,5-disubstituted is formed. 1-methyl- or -1-benzyl-pyridinium halide. Reduction of these quaternary compounds with sodium borohydride yields disubstituted tetrahydropyridines (b).

If the 2,5-disubstit.-1-methyl- or -1-benzyl-1,2,3,6-tetrahydropyridines (b) are subjected to a hydroboration reaction and then a peroxide oxidation, 2,5-disubstit.-1- is formed Methyl or -1-benzyl-4-piperidinol (c). This can then be further oxidized to the 4-piperidone (d) compounds by a pyridine-sulfur trioxide reaction. This reaction is carried out in a tertiary amine (preferably trialkylamine) in the presence of dimethyl sulfoxide.

The piperidones are then reacted with a lithium or Grignard reactant which has the desired R [deep] 5 group. The tertiary alcohol (e) occurring as an intermediate can then be dehydrated by known methods to give the desired 2,4,5-trisubstituted-1-methyl- or -1-benzyl-1,2,3,6-tetrahydropyridine (f). The following equations illustrate the process for producing the starting materials for the process according to the invention:

Here R [deep] 3, R [deep] 5, R [deep] 9 and X have the meanings described above, and Y denotes methyl or benzyl.

The isomeric forms of 3,5,9-trisubstituted-2'-hydroxy-6,7-benzomorphans II can also be used for the preparation of compounds of structure I. These isomeric compounds can be prepared by known methods using a cleaving agent such as camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid and the like to form the (-) - lävo and (+) - dextro isomers. Each optical isomer can then be used as starting material in the various examples leading to (+) - dextro- or (-) - lävo-2,3,5,9-tetrasubstit.-2'-hydroxy-6,7-benzomorphanes to lead. On the other hand, the racemic tetrasubstit.-2'-hydroxy-6,7-benzomorphane end products can be resolved even by a procedure similar to that described above to produce the dextrorotatory (+) and levorotatory (-) isomers of tetrasubstit.- To prepare 2'-hydroxy-6,7-benzomorphanes.

The following examples illustrate the various methods which have been described above for the preparation of the novel benzomorphans according to the invention.

It is intended that the examples be construed as illustrating, but not limiting, the invention.

example 1

1,2,5-trimethylpyridinium iodide

107 g of 2,5-dimethylpyridine and 168 g of methyl iodide are dissolved in 500 ml of acetone. This solution is left to stand for 12 hours at room temperature, filtered, washed with acetone and sucks dry. 224 g of 1,2,5-trimethylpyridinium iodide (melting point 180-181 ° C.) are obtained.

Example 1a

1,2-dimethyl-5-ethylpyridinium iodide

121 g (1 mol) of 2-methyl-5-ethylpyridine and 156 g (1.1 mol) of methyl iodide are dissolved in 700 ml of acetone. This solution is left in an ice bath for several hours. The crystalline mass obtained is collected by suction filtration and washed with acetone. 244.6 g of 1,2-dimethyl-5-ethylpyridinium iodide (melting point 156.5-157.5 ° C.) are obtained.

Example 2

By following the procedure of Example 1 but using any of the 2,5-disubstituted pyridines listed in Table I below in place of 2,5-dimethylpyridine, the corresponding in the table below is obtained in place of 1,2,5-trimethylpyridinium iodide the halide salt listed in Table II.

Table I Table II

Starting material product

2-n-propyl-5-methylpyridine 1,5-dimethyl-2-n-propyl-pyridinium iodide

2-i-propyl-5-methylpyridine 1,5-dimethyl-2-i-propyl-pyridinium iodide

2-n-Butyl-5-methylpyridine 1,5-dimethyl-2-n-butyl-pyridinium iodide

2-methyl-5-n-propylpyridine 1,2-dimethyl-5-n-propyl-pyridinium iodide

2-methyl-5-n-butylpyridine 1,2-dimethyl-5-n-butyl-pyridinium iodide

2-n-propyl-5-ethylpyridine 1-methyl-2-n-propyl-5-ethyl-pyridinium iodide

2-n-butyl-5-ethylpyridine 1-methyl-2-n-butyl-5-ethylpyridinium iodide

2,5-diethylpyridine 1-methyl-2,5-diethylpyridinium iodide

2-methyl-5-phenylpyridine 1,2-dimethyl-5-phenyl-pyridinium iodide

2,5-diphenylpyridine 1-methyl-2,5-diphenyl-pyridinium iodide

2-methyl-5- (p-methoxyphenyl) - 1,2-dimethyl-5- (p-methoxyphenyl) -

pyridine pyridinium iodide

2-methyl-5-benzylpyridine 1,2-dimethyl-5-benzyl-pyridinium iodide

2-Benzyl-5-ethylpyridine 1-methyl-2-benzyl-5-ethylpyridinium iodide

Example 3

1,2,5-trimethyl-1,2,3,6-tetrahydropyridine

To 222 g of 1,2,5-trimethylpyridinium iodide, which have been dissolved in 550 ml of water and 100 ml of methanol, 41.6 g of sodium borohydride, dissolved in 200 ml of water, are added. The temperature is kept below 35 ° C during the dropwise addition. The reaction mixture is stirred for 2 hours and the solution is saturated with potassium carbonate and then extracted with ether. The combined ether extracts are evaporated and the residue is dissolved in 200 ml of 6N hydrochloric acid. The acid solution is washed with ether and then made basic with ammonia. The basic solution is saturated with potassium carbonate and extracted with ether. The combined ether extracts are dried over magnesium sulfate, filtered and evaporated to dryness. The concentrate is distilled. 59 g of 1,2,5-trimethyl-1,2,3,6-tetrahydropyridine (melting point 103 ° C./80 mm) are obtained.

Example 3a

1,2-dimethyl-5-ethyl-1,2,3,6-tetrahydropyridine

To a stirred, ice-cold solution of 240 g (0.91 mol) of 1,2-dimethyl-5-ethylpyridinium iodide in 1 l of 50% strength aqueous methanol, a solution of 37.8 g (1 mol) of sodium borohydride in 200 ml of 0.01 molar aqueous sodium hydroxide are added. This mixture is stirred for 2 1/2 hours and then the methanol is removed under reduced pressure. The residue is treated with 200 ml of 20% strength aqueous potassium carbonate and extracted four times with 200 ml portions of ether. The combined extracts are dried over magnesium sulfate. The drying agent is removed by filtration and the filtrate is concentrated under reduced pressure. Distillation of the concentrate gives 77 g of 1,2-dimethyl-5-ethyl-1,2,3,6-tetrahydropyridine (boiling point 105-106 ° C./76 mm).

Example 4

By following the procedure of Example 3, but using the halide salts of Table II, Example 2 instead of 1,2,5-trimethylpyridinium iodide, instead of 1,2,5-trimethyl-1,2,3, 6-tetrahydropyridine the corresponding 1,2,5-trisubstituted-1,2,3,6-tetrahydropyridine in Table I below.

Table I.

1,5-dimethyl-2-n-propyl-1,2,3,6-tetrahydropyridine,

1,5-dimethyl-2-i-propyl-1,2,3,6-tetrahydropyridine,

1,5-dimethyl-2-n-butyl-1,2,3,6-tetrahydropyridine,

1,2-dimethyl-5-n-propyl-1,2,3,6-tetrahydropyridine,

1,2-dimethyl-5-n-butyl-1,2,3,6-tetrahydropyridine,

1-methyl-2-n-propyl-5-ethyl-1,2,3,6-tetrahydropyridine,

1-methyl-2-n-butyl-5-ethyl-1,2,3,6-tetrahydropyridine,

1-methyl-2,5-diethyl-1,2,3,6-tetrahydropyridine,

1,2-dimethyl-5-phenyl-1,2,3,6-tetrahydropyridine,

1-methyl-2,5-diphenyl-1,2,3,6-tetrahydropyridine,

1,2-dimethyl-5- (p-methoxyphenyl) -1,2,3,6-tetrahydropyridine,

1,2-dimethyl-5-benzyl-1,2,3,6-tetrahydropyridine,

1-methyl-2-benzyl-5-ethyl-1,2,3,6-tetrahydropyridine.

Example 5

1,2,5-trimethyl-4-piperidinol

500 ml of 1N diborane in tetrahydrofuran are added to a stirred solution of 29 g of 1,2,5-trimethyl-1,2,3,6-tetrahydropyridine which have been dissolved in 100 ml of tetrahydrofuran. This mixture is then stirred for 15 hours at room temperature and then water is added dropwise to decompose any excess diborane and then the mixture is made slightly acidic with 5N aqueous hydrochloric acid and stirred for 1 hour. The mixture is made slightly basic with 2.5N sodium hydroxide and then 30 ml of 2.5N sodium hydroxide followed by dropwise addition of 30 ml of 30% hydrogen peroxide while maintaining the temperature at 35 ° C. The mixture is now saturated with potassium carbonate, the tetrahydrofuran is decanted and the mixture is washed with ether. The organic solutions are combined and dried over potassium carbonate, filtered and evaporated to dryness and the residue is distilled. 23 g of 1,2,5-trimethyl-4-piperidinol (boiling point 68 ° C./13 mm) are obtained.

Example 5a

1,2-dimethyl-5-ethyl-4-piperidinol

946 ml of 1.0 molar diborane in tetrahydrofuran are added dropwise under nitrogen to a stirred, ice-cold solution of 63.6 g of 1,2-dimethyl-5-ethyl-1,2,3,6-tetrahydropyridine in 200 ml of tetrahydrofuran given. The reaction mixture is stirred for 3 hours at room temperature and then excess diborane is destroyed by careful addition of water. To this stirred solution, 66 ml of 2.5 N aqueous sodium hydroxide and then 66 ml of 30% strength hydrogen peroxide are added dropwise at 30.degree. This mixture is heated and stirred at 35 to 40 ° C. for 1 hour, and then potassium carbonate is added to saturation. The tetrahydrofuran solution is decanted and concentrated under reduced pressure. 150 ml of 6N hydrochloric acid are added to the concentrate with stirring. After stirring for 15 minutes, the solution is made basic with concentrated aqueous ammonia and extracted four times with several portions of ether. The combined extracts are dried over magnesium sulfate, filtered and evaporated to a liquid residue. The distillation gives 43.8 g of piperidinol (boiling point 111-113 ° C / 13 mm).

Example 6

1,2,5-trimethyl-4-piperidone

To a rapidly stirred mixture of 1 mol of 1,2,5-trimethyl-4-piperidinol and 100 ml of dimethyl sulfoxide are added dropwise over 1 hour 47.7 g (0.3 mol) of pyridine-sulfur trioxide complex in 250 ml of dimethyl sulfoxide solved, given. The reaction mixture is stirred for 15 hours at room temperature and then extracted with ether. The solvents are removed under reduced pressure and the residue is diluted with 250 ml of water and then extracted with petroleum ether. The combined organic solution is washed with a saturated solution of aqueous sodium chloride, then dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is distilled. 6.5 g of 1,2,5-trimethyl-4-piperidone (boiling point 87-89 ° C./20 mm) are obtained.

Example 6a

1,2-dimethyl-5-ethyl-4-piperidone

A solution of 50 g of sulfur trioxide-pyridine complex in 265 ml of dimethyl sulfoxide dissolved, given. The reaction mixture is stirred for 5 hours and then extracted seven times with 100 ml portions of ether. The combined extracts are concentrated under reduced pressure to remove ether and the residue is diluted with 250 ml of ice water and extracted five times with 100 ml portions of pentane. The combined extracts are washed twice with 100 ml portions of a saturated aqueous saline solution and then dried over anhydrous magnesium sulfate. The drying agent is removed by filtration and the filtrate is concentrated under reduced pressure. Distillation of the concentrate gives 10.6 g of 1,2-dimethyl-5-ethyl-4-piperidone (boiling point 100-102 ° C./20 mm).

Example 7

1,2,5-trimethyl-4-n-butyl-4-piperidinol

To 25 g of 1,2,5-trimethyl-4-piperidone, which have been dissolved in 150 ml of hexane and 150 ml of ether, 100 ml of 21.8 percent by weight ethereal butyllithium are added. This mixture is then stirred for 15 hours at room temperature. The reaction mixture is poured onto ice and the organic layer separated. The aqueous layer is extracted with ether which is then combined with the organic solutions, dried over magnesium sulfate, filtered, evaporated in vacuo to a yellow residue and distilled. 23.5 g of 1,2,5-trimethyl-4-n-butyl-4-piperidinol (boiling point 120-130 ° C./9 mm) are obtained. This product is further purified by recrystallization from petroleum ether. A crystalline product is obtained (melting point 64 ° -65 ° C.).

Example 7a

1,2-dimethyl-4,5-diethyl-4-piperidinol

200 ml of 1.3 molar ethereal ethyl lithium are added to a stirred solution of 23 g (0.15 mol) of 1,2-dimethyl-5-ethyl-4-piperidone in 250 ml of ether. The reaction mixture is stirred under reflux for 8 hours and then poured onto ice and the organic layer is separated. The organic solution is dried over anhydrous magnesium sulfate, filtered and evaporated. Distillation of the concentrate gives 21.1 g of 1,2-dimethyl-4,5-diethyl-4-piperidinol (boiling point 130 ° C./20 mm).

Example 7b

1,2-dimethyl-4-n-propyl-5-ethyl-4-piperidinol

By following the procedure of Example 7a, but using 1.3 molar ethereal n-propyllithium instead of ethyl lithium, the product obtained is 1,2-dimethyl-4-n-propyl-5-ethyl-4-piperidinol (boiling point 106- 108 ° C / 3.7 mm).

Example 8

1,2,5-trimethyl-4-n-butyl-1,2,3,6-tetrahydropyridine

To 135 ml of 6N aqueous hydrochloric acid is added 21 g of 1,2,5-trimethyl-4-n-butyl-4-piperidinol, and the solution is refluxed for 9 hours. After cooling, the reaction mixture is washed with ether, made basic with concentrated ammonia and then extracted with ether (three times 130 ml). The combined extracts are dried over magnesium sulfate, filtered, evaporated and distilled. 16.4 g of 1,2,5-trimethyl-4-n-butyl-1,2,3,6-tetrahydropyridine (melting point 125 ° -127 ° C./25 mm) are obtained.

Example 8a

1,2-dimethyl-4,5-diethyl-1,2,3,6-tetrahydropyridine

A solution of 21.1 g (0.126 mol) of 1,2-dimethyl-4,5-diethyl-4-piperidinol in 150 ml of 6N hydrochloric acid is heated to reflux temperature for 10 hours and stirred. The cooled reaction mixture is made basic with ammonia and extracted four times with 150 ml portions of ether. The combined extracts are dried over anhydrous magnesium sulfate and filtered, and the filtrate is removed under reduced pressure constricted. The concentrate is distilled. 12.1 g of 1,2-dimethyl-4,5-diethyl-1,2,3,6-tetrahydropyridine (melting point 102 ° C./27 mm) are obtained.

Example 8b

1,2-Dimethyl-4-n-propyl-5-ethyl-1,2,3,6-tetrahydropyridine

By following the procedure of Example 8a, but using 1,2-dimethyl-4-n-propyl-5-ethyl-4-piperidinol in place of 1,2-dimethyl-4,5-diethyl-4-piperidinol, one obtains as product 1,2-dimethyl-4-n-propyl-5-ethyl-1,2,3,6-tetrahydropyridine (melting point 121 ° C./18 mm).

Example 9

By following the procedures of Examples 3 to 8 but using any of the tetrahydropyridines in Table I, Example 4 in place of 1,2,5-trimethyl-1,2,3,6-tetrahydropyridine, 1,2 are obtained in place of 1,2 , 5-Trimethyl-4-n-butyl-1,2,3,6-tetrahydropyridine the corresponding 4-n-butyl-tetrahydropyridine from Table I below.

Table I.

1,5-dimethyl-2-n-propyl-4-n-butyl-1,2,3,6-tetrahydropyridine,

1,5-dimethyl-2-i-propyl-4-n-butyl-1,2,3,6-tetrahydropyridine,

1,5-dimethyl-2,4-di-n-butyl-1,2,3,6-tetrahydropyridine,

1,2-dimethyl-4-n-butyl-5-n-propyl-1,2,3,6-tetrahydropyridine,

1,2-dimethyl-4,5-di-n-butyl-1,2,3,6-tetrahydropyridine,

1-methyl-2-n-propyl-4-n-butyl-5-ethyl-1,2,3,6-tetrahydropyridine,

1-methyl-2,4-di-n-butyl-5-ethyl-1,2,3,6-tetrahydropyridine,

1-methyl-2,5-diethyl-4-n-butyl-1,2,3,6-tetrahydropyridine,

1,2-dimethyl-4-n-butyl-5-phenyl-1,2,3,6-tetrahydropyridine,

1-methyl-2,5-diphenyl-4-n-butyl-1,2,3,6-tetrahydropyridine,

1,2-dimethyl-4-n-butyl-5- (p-methoxyphenyl) -1,2,3,6-tetrahydropyridine,

1,2-dimethyl-5-benzyl-4-n-butyl-1,2,3,6-tetrahydropyridine,

1-methyl-2-benzyl-5-ethyl-4-n-butyl-1,2,3,6-tetrahydropyridine.

Example 10

By following the procedure of Example 9 but using each of the reactants listed in Table I below in place of butyllithium, the various corresponding 4-substituted tetrahydropyridine compounds are obtained in place of the 4-n-butyl-tetrahydropyridine compounds. Some of these compounds are shown in Table II below.

Table I.

Methyllithium phenylethylmagnesium chloride

Ethyllithium p-methoxybenzyl magnesium chloride

Propyllithium i-propylmagnesium chloride

Phenyllithium Benzyllithium

Table II

1,2,4-trimethyl-5-n-butyl-1,2,3,6-tetrahydropyridine,

1,2,4-trimethyl-5-n-propyl-1,2,3,6-tetrahydropyridine,

1-methyl-2,4,5-triethyl-1,2,3,6-tetrahydropyridine,

1-methyl-2-n-propyl-4,5-diethyl-1,2,3,6-tetrahydropyridine,

1-methyl-2-n-butyl-4,5-diethyl-1,2,3,6-tetrahydroypridine,

1,2-dimethyl-4,5-diphenyl-1,2,3,6-tetrahydropyridine,

1,2-dimethyl-4,5-di-n-propyl-1,2,3,6-tetrahydropyridine,

1,2,5-trimethyl-4-phenylethyl-1,2,3,6-tetrahydropyridine,

1-methyl-2,5-diethyl-4- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine,

1,5-dimethyl-2,4-di-i-propyl-1,2,3,6-tetrahydropyridine,

1,2-dimethyl-4,5-dibenzyl-1,2,3,6-tetrahydropyridine,

1-methyl-2-benzyl-4,5-diethyl-1,2,3,6-tetrahydropyridine.

Example 11

1,2,5-Trimethyl-4-n-propyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine chloride

16 g of p-methoxybenzyl chloride are added to 16 g of 1,2,5-trimethyl-4-n-propyl-1,2,3,6-tetrahydropyridine which have been dissolved in 200 ml of acetone. This solution is refluxed for 3 1/2 hours and then evaporated to dryness under reduced pressure. 32 g of 1,2,5-trimethyl-4-n-propyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride remain.

Example 12

By following the procedure of Example 11 but using any of the tetrahydropyridines of Example 9 in place of 1,2,5-trimethyl-4-n-propyl-1,2,3,6-tetrahydropyridine, 1,2 were obtained in place of 1,2 , 5-Trimethyl-4-n-propyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride the corresponding tetrahydropyridinium halide from Table I below.

1,2,4-trimethyl-5-n-butyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride,

1,2,4-trimethyl-5-n-propyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride,

1-methyl-2,4,5-triethyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride,

1-methyl-2-n-propyl-4,5-diethyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride,

1-methyl-2-n-butyl-4,5-diethyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride,

1,2-dimethyl-4,5-diphenyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride,

1,2,5-trimethyl-4-phenylethyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride,

1-methyl-2,5-diethyl-4- (p-methoxybenzyl) -1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride,

1,5-dimethyl-2,4, di-i-propyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride,

1,2-dimethyl-4,5-dibenzyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride,

1-methyl-2-benzyl-4,5-diethyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride.

Example 13

1,2,5-trimethyl-4-n-propyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine

A mixture of 32 g of 1,2,5-trimethyl-4-n-propyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyrdinium chloride and 500 ml of ether is slurried. 200 ml of 2.18 N phenyllithium solution are added as quickly as possible under N [deep] 2. The resulting mixture is stirred at room temperature for 30 minutes and then under reflux for 5 hours. The cooled reaction mixture is poured onto ice and the organic layer is separated and extracted with 25% hydrochloric acid. The combined acidic extracts are made basic with ammonia and extracted with ether. The combined ether extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oily product. The distillation of the concentrate gives 24 g of 1,2,5-trimethyl-4-n-propyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine (boiling point 153-160 ° C / 0.07 mm ).

Example 13a

1,2-Dimethyl-4,5-diethyl-6-p-methoxybenzyl-1,2,3,6-tetrahydropyridine

A solution of 10.13 g (0.066 mol) of 1,2-dimethyl-4,5-diethyl-1,2,3,6-tetrahydropyridine and 8.1 g of p-methoxybenzyl chloride in 100 ml of acetone is refluxed for 3 hours heated, cooled and evaporated to dryness. The residue is slurried with 350 ml of dry ether and treated with 153 ml of 1.9 molar phenyllithium (70:30 benzene ether), which are added dropwise with stirring. This mixture is heated and stirred at reflux temperature for 3 hours, then poured onto ice and the organic layer is separated. The organic solution is extracted with aqueous hydrochloric acid. The acid extract is made basic with ammonia and extracted with ether. The ether extract is dried over anhydrous magnesium sulfate and then filtered. The filtrate is concentrated and the concentrate is distilled. 13.4 g of 1,2-dimethyl-4,5-diethyl-6-p-methoxybenzyl-1,2,3,6-tetrahydropyridine (boiling point 142-148 ° C./0.5 mm) are obtained.

Example 13b

1,2-Dimethyl-4-n-propyl-5-ethyl-6-p-methoxybenzyl-1,2,3,6-tetrahydropyridine

By following the procedure of Example 13a, but using 1,2-dimethyl-4-n-propyl-5-ethyl-1,2,3,6-tetrahydropyridine instead of 1,2-dimethyl-4,5-diethyl-1 , 2,3,6-tetrahydropyridine is used, the product obtained is 1,2-dimethyl-4-n-propyl-5-ethyl-6-p-methoxybenzyl-1,2,3,6-tetrahydropyridine (col. 149- 153 ° C / 0.3 mm).

Example 14

By following the procedure of Example 13, but instead of 1,2,5-trimethyl-4-n-propyl-1- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium chloride the corresponding 1- ( p-Methoxybenzyl) -1,2,3,6-pyridinium halides of Table I, Example 12, are used instead of 1,2,5-trimethyl-4-n-propyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine the corresponding 1,2,4,5-tetrasubstitute-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridinium compounds of Table I below.

1,2,4-trimethyl-5-n-butyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine,

1,2,4-trimethyl-5-n-propyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine,

1-methyl-2,4,5-triethyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine,

1-methyl-2-n-propyl-4,5-diethyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine,

1-methyl-2-n-butyl-4,5-diethyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine,

1,2-dimethyl-4,5-diphenyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine,

1,2,5-trimethyl-4-phenylethyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine,

1-methyl-2,5-diethyl-4- (p-methoxybenzyl) -6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine,

1,5-dimethyl-2,4-di-i-propyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine,

1,2-dimethyl-4,5-dibenzyl-6- (p-methoxybenzyl) -1,2,3,6-terrahydropyridine,

1-methyl-2-benzyl-4,5-diethyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine.

Example 15

2,3,9-trimethyl-2'-hydroxy-5-n-propyl-6,7-benzomorphane

25 g of 1,2,5-trimethyl-4-n-propyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine are dissolved in 210 ml of 48% strength hydrobromic acid and kept at 145 ° C. for 24 hours heated. This solution is then poured onto a mixture of ice and 250 ml of concentrated aqueous ammonia and extracted twice with 300 ml of chloroform. The chloroform solution is dried over magnesium sulfate, filtered and evaporated to a brown residue. The residue is triturated with acetone. 6.5 g of a crystalline compound are obtained, which is recrystallized from hot ethanol to give pure 2,3,9-trimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane (melting point 237-242 ° C) to obtain.

Example 15a

2,3-dimethyl-5,9-diethyl-2'-hydroxy-6,7-benzomorphane

A solution of 13.41 g (0.0467 mol) of 1,2-dimethyl-4,5-diethyl-6-p-methoxybenzyl-1,2,3,6-tetrahydropyridine in 150 ml of 48% hydrobromic acid is 24 Heated to 140 ° C for hours. This solution is then poured onto a mixture of aqueous ammonia and ice and extracted with chloroform as in Example 15. Recrystallization from methanol-acetone gives 1.4 g of 2,3-dimethyl-5,9-diethyl-2'-hydroxy-6,7-benzomorphane (melting point 261-263 ° C.).

Example 15b

2,3-Dimethyl-5-n-propyl-9-ethyl-2'-hydroxy-6,7-benzomorphane

By following the procedure of Example 15a, but

1,2-Dimethyl-4-n-propyl-5-ethyl-6-p-methoxybenzyl-1,2,3,6-tetrahydropyridine instead of 1,2-dimethyl-4,5-diethyl-6-p-methoxybenzyl When -1,2,3,6-tetrahydropyridine is used, the product obtained is 2,3-dimethyl-5-n-propyl-9-ethyl-2'-hydroxy-6,7-benzomorphane (melting point 232-234 ° C ).

Example 16

By following the procedure of Example 15 but instead of 1,2,5-trimethyl-5-n-propyl-6- (p-methoxybenzyl) -1,2,3,6-tetrahydropyridine the compounds of Table I, Example 14, used, the corresponding benzomorphans in Table I below are obtained instead of 2,3,9-trimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane:

Table I.

2,3,5-trimethyl-9-n-butyl-2'-hydroxy-6,7-benzomorphane,

2,3,5-trimethyl-9-n-propyl-2'-hydroxy-6,7-benzomorphane,

2-methyl-3,5,9-triethyl-2'-hydroxy-6,7-benzomorphane,

2-methyl-3-n-propyl-5,9-diethyl-2'-hydroxy-6,7-benzomorphane,

2-methyl-3-n-butyl-6,9-diethyl-2'-hydroxy-6,7-benzomorphane,

2,3-dimethyl-5,9-diphenyl) -2'-hydroxy-6,7-benzomorphane,

2,3,9-trimethyl-5-phenylethyl-2'-hydroxy-6,7-benzomorphane,

2-methyl-3,9-diethyl-5- (p-methoxybenzyl) -2'-hydroxy-6,7-benzomorphane,

2,9-dimethyl-3,5-di-i-propyl-2'-hydroxy-6,7-benzomorphane,

2,3-dimethyl-6,9-dibenzyl-2'-hydroxy-6,7-benzomorphan,

2-methyl-3-benzyl-5,9-diethyl-2'-hydroxy-6,7-benzomorphane.

Example 17

3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane

A solution of 7 g of 2,3,9-trimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane

Heat in 7 ml of acetic anhydride on a steam bath for 40 minutes. The cooled solution is poured onto ice, left to stand for 5 minutes and then basified with 50% aqueous potassium hydroxide (ice cold) and extracted quickly with ether. The combined extracts are dried over magnesium sulfate, filtered and concentrated. The residue is taken up in 50 ml of chloroform and added dropwise over the course of one hour with stirring to a solution of 3.2 g of cyanogen bromide in 30 ml of chloroform. The solution is then stirred under reflux for 3 hours and then evaporated to dryness. The residue is dissolved in 150 ml of 6% hydrochloric acid and refluxed for 8 hours. The solution is made basic with concentrated ammonia and extracted with chloroform. The combined extracts are dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in acetone, filtered and cooled for several hours. 3,9-Dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane separates out of the filtrate.

Example 18

By following the procedure of Example 17, but instead of 2,3,9-trimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane, the corresponding benzomorphans of Table I, Example 16, or their optical isomers used, instead of 3,9-dimethyl-5-propyl-2'-hydroxy-6,7-benzomorphane, the corresponding norbenzomorphanes in Table I below or their optical isomers are obtained.

Table I.

3,5-dimethyl-9-n-butyl-2'-hydroxy-6,7-benzomorphane,

3,5-dimethyl-9-n-propyl-2'-hydroxy-6,7-benzomorphane,

3,5,9-triethyl-2'-hydroxy-6,7-benzomorphane,

3-n-propyl-5,9-diethyl-2'-hydroxy-6,7-benzomorphane,

3-n-butyl-5,9-diethyl-2'-hydroxy-6,7-benzomorphane,

3-methyl-5,9-diphenyl-2'-hydroxy-6,7-benzomorphan,

3,9-dimethyl-5-phenylethyl-2'-hydroxy-6,7-benzomorphane,

3,9-diethyl-5- (p-methoxybenzyl) -2'-hydroxy-6,7-benzomorphane,

3,5-di-i-propyl-9-methyl-2'-hydroxy-6,7-benzomorphan,

3-methyl-5,9-dibenzyl-2'-hydroxy-6,7-benzomorphan,

3-Benzyl-5,9-diethyl-2'-hydroxy-6,7-benzomorphane.

Example 19

2-Cyclopropylmethyl-3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane

The following reactants are combined: 1.5 g of 3-methyl-5-n-butyl-2'-hydroxy-6,7-benzomorphane, 1.67 g of cyclopropyl carbonyl chloride, 1.62 g of triethylamine and 65 ml of methylene chloride . The mixture is stirred under reflux for 5 hours. The solvent is evaporated and the residue taken up in 250 ml of ether and washed with 5% aqueous sodium bicarbonate and water (50 ml of each). The organic solution is dried over magnesium sulfate, filtered and evaporated. The residue, dissolved in 50 ml of ether, is added dropwise to a stirred slurry of 1.5 g of lithium aluminum hydride in 150 ml of ether, and the organic slurry is heated and stirred at reflux temperature for 5 hours, cooled, then 3 ml of water are added dropwise, and the mixture is filtered and the residue thoroughly washed with fresh ether. The combined filtrates are evaporated and the residue is dissolved in 25 ml of acetone and the solution is filtered. The filtrate is cooled. 510 mg of product are deposited. Recrystallization from methanol / acetone (1: 1) gives pure 2-cyclopropylmethyl-3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane.

Example 20

By following the procedure of Example 19, but using any of the acid chlorides in Table I below in place of the cyclopropylcarbonyl chloride, each of the corresponding 2-substit.-3,9-dimethyl-5 listed in Table II below is obtained -n-propyl-2'-hydroxy-6,7-benzomorphane.

Table I.

Acetyl chloride,

Propionyl chloride,

Vinyl acetyl chloride,

Methacryloyl chloride,

Allylacetyl chloride,

Cyclobutyl carbonyl chloride,

Cyclopropylacetyl chloride,

3-cyclopentenylcarbonyl chloride,

(1-cyclobutenyl) acetyl chloride,

2-methylcyclopropylcarbonyl chloride,

2-methylenecyclopropylcarbonyl chloride,

3-vinylcyclopentylcarbonyl chloride,

2,3,3-trimethylcyclopropenylcarbonyl chloride,

2-methylcyclopentylcarbonyl chloride,

Spiropentyl carbonyl chloride,

Spiro (3,2) hexane-5-carbonyl chloride

Table II

2-ethyl-3-9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2-propyl-3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2- (3-butenyl) -3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2- (2-methallyl) -3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2- (4-pentenyl) -3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2-cyclobutylmethyl-3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2-cyclopropylethyl-3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2- (3-cyclopentenylmethyl) -3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2- (1-cyclobutenylethyl) -3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2- (2-methylcyclopropylmethyl) -3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2- (3-vinylcyclopentylmethyl) -3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2- (2,2,3-trimethylcyclopropenylmethyl) -3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2- (2-methylcyclopentenylmethyl) -3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2-spiropentylmethyl-3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane,

2- [Spiro- (3,2) -5-hexylmethyl] -3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane.

Example 21

Following the procedure of Example 19 but using the acid chlorides of Table I, Example 20 and each of the nor-3,5,9-trisubstituted-2'-hydroxy-6,7-benzomorphanes of Table I, Example 18 , or their optical isomers to the

Instead of 3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane, the corresponding 2,3,5,9-tetrasubstit.-2 'shown in Table I below are used -hydroxy-6,7-benzomorphane or their optical isomers synthesized.

Table I.

2-cyclopropylmethyl-3,5-dimethyl-9-n-butyl-2'-hydroxy-6,7-benzomorphane,

2-cyclopropylmethyl-3-methyl-5,9-di-n-butyl-2'-hydroxy-6,7-benzomorphane,

2-cyclopropylmethyl-3-methyl-5,9-diphenyl-2'-hydroxy-6,7-benzomorphane,

2- (2-methallyl) -3-methyl-5,9-di-n-butyl-2'-hydroxy-6,7-benzomorphane,

2-Cyclopropylmethyl-3-benzyl-5,9-diethyl-2'-hydroxy-6,7-benzomorphane.

Example 22

If you use p-methoxybenzyl chloride instead of methyl iodide in Examples 1 to 10 and then methyl iodide instead of p-methoxybenzoyl chloride in Examples 11 and 12, in Examples 13 to 21 the corresponding, on the remainder R [deep] 3 epimeric product synthesized.

Claims (40)

1. Process for preparing compounds of the formula in which: R [deep] 3 is alkyl, aryl, or a substituted aryl capable of forming an aryl lithium reactant; R [deep] 5 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant; and R [deep] 9 alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant, characterized in that one is in a combination of stages (1) a 1,2,3,6-tetrahydropyridine compound of the formula in which R [deep] 3, R [deep] 5 and R [deep] 9 have the meanings described above, treated with a p-methoxybenzyl halide; (2) rearranges the quaternary compound formed with a lithium reactant; and (3) treated with hydrobromic acid to produce the desired product. 2. The method according to claim 1, characterized in that all radicals R [deep] 3, R [deep] 5 and R [deep] 9 mean lower alkyl. 3. The method according to claim 1, characterized in that R [deep] 3 is methyl, R [deep] 5 is n-propyl and R [deep] 9 is methyl. 4. The method according to claim 1, characterized in that R [deep] 3 is methyl, R [deep] 5 is n-butyl and R [deep] 9 is methyl. 5. A process for preparing the dextrorotatory (+), optically isomeric form of compounds according to Claim 1. 6. A process for producing the levorotatory (-), optically isomeric form of compounds according to Claim 1. 7. Process for preparing compounds of the formula in which: R [deep] 3 is alkyl, aryl, or a substituted aryl capable of forming an aryl lithium reactant; R [deep] 5 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant; and R [deep] 9 alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant, characterized in that one is in a combination of stages (1) a compound of the formula in which R [deep] 3, R [deep] 5 and R [deep] 9 have the meanings given above, acylated, then (2) heated to an elevated temperature with cyanogen bromide and then (3) hydrolyzes the cyano and acetyl groups. 8. The method according to claim 7, characterized in that all radicals R [deep] 3, R [deep] 5 and R [deep] 9 mean lower alkyl. 9. The method according to claim 7, characterized in that R [deep] 3 is methyl, R [deep] 5 is n-propyl and R [deep] 9 is methyl. 10. The method according to claim 7, characterized in that R [deep] 3 is methyl, R [deep] 5 is n-butyl and R [deep] 9 is methyl. 11. A method for producing the dextrorotatory (+), optically isomeric form of compounds according to claim 7. 12. A method for producing the levorotatory (-), optically isomeric form of compounds according to claim 7. 13. Process for preparing compounds of the formula in which: R alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, alkylcycloalkyl, alkenyl cycloalkyl, alkylcycloalkenyl or spiroalkyl; R [deep] 3 is alkyl, aryl, or a substituted aryl capable of forming an aryl lithium reactant; R [deep] 5 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant; and R [deep] 9 alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant, characterized in that one is in a combination of stages (1) a compound of the formula in which the radicals R [deep] 3, R [deep] 5 and R [deep] 9 have the meanings given above, with a compound of the formula in which X is an active halogen group and R has the meaning given above, brings into intimate contact; and (2) the 2-acyl-2'-acyloxy derivative formed is reduced. 14. The method according to claim 13, characterized in that all radicals R [deep] 3, R [deep] 5 and R [deep] 9 are lower alkyl and R is cyclone-lower alkyl or lower alkenyl-cyclone-lower alkyl. 15. The method according to claim 13, characterized in that R [deep] 3 is methyl, R [deep] 5 is n-propyl, R [deep] 9 is methyl and R is cyclopropyl. 16. The method according to claim 13, characterized in that R [deep] 3 is methyl, R [deep] 5 is n-butyl, R [deep] 9 is methyl and R is cyclopropyl. 17. The method according to claim 13, characterized in that R [deep] 3 is methyl, R [deep] 5 is n-propyl, R [deep] 9 is methyl and R is methylenecyclopropyl. 18. The method according to claim 13, characterized in that R [deep] 3 is methyl, R [deep] 5 is n-butyl, R [deep] 9 is methyl and R is methylenecyclopropyl. 19. A method for producing the dextrorotatory (+), optically isomeric form of compounds according to claim 13. 20. A method for producing the levorotatory (-) optically isomeric form of compounds according to claim 13. 21. Compounds of the formula in which: R [deep] 2 hydrogen, -CN, or -CH [deep] 2R, where R stands for alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl or spiroalkyl; R [deep] 3 is alkyl, aryl, or a substituted aryl capable of forming an aryl lithium reactant; R [deep] 5 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant; and R [deep] 9 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant. 22. Compounds according to claim 21, characterized in that all radicals R [deep] 3, R [deep] 5 and R [deep] 9 are lower alkyl and R [deep] 2 are hydrogen or -CH [deep] 2R, where R is Lower alkyl, lower alkenyl, cyclone lower alkyl or lower alkenyl-cyclone lower alkyl. 23. Compounds according to claim 21, characterized in that all radicals R [deep] 3, R [deep] 5 and R [deep] 9 are lower alkyl and R [deep] 2 are hydrogen. 24. Compounds according to claim 21, characterized in that all radicals R [deep] 2, R [deep] 3, R [deep] 5 and R [deep] 9 are lower alkyl. 25. The dextrorotatory (+), optically isomeric form of the compounds according to claim 21. 26. The levorotatory (-), optically isomeric form of the compounds according to claim 21. 27. 3,9-Dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphan. 28. 3,9-Dimethyl-5-n-butyl-2'-hydroxy-6,7-benzomorphan. 29. 2,3,9-Trimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphan. 30. 2,3,9-Trimethyl-5-n-butyl-2'-hydroxy-6,7-benzomorphan. 31. 2-Cyclopropylmethyl-3,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphane. 32. 2-Cyclopropylmethyl-3,9-dimethyl-5-n-butyl-2'-hydroxy-6,7-benzomorphane. 33. Compounds of Formula in which: R alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl or spiroalkyl; R [deep] 3 is alkyl, aryl, or a substituted aryl capable of forming an aryl lithium reactant; R [deep] 5 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant; and R [deep] 9 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant. 34. Compounds of Formula in which: R [deep] 3 alkyl, aryl, a substituted aryl capable of forming an aryl lithium reactant, or aralkyl; R [deep] 5 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant; and R [deep] 9 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant. 35. Method of treatment for relieving pain, characterized in that one uses a compound of the formula administered, in which mean: R [deep] 2 hydrogen, -CN, or -CH [deep] 2R, where R stands for alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl or spiroalkyl; R [deep] 3 alkyl, aryl, or substituted aryl capable of forming an aryl lithium reactant; R [deep] 5 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant; and R [deep] 9 is alkyl, aryl, or substituted aryl, provided that the substituent does not react with a lithium reactant. 36. Treatment method according to claim 35, characterized in that all radicals R [deep] 3, R [deep] 5 and R [deep] 9 are lower alkyl and R [deep] 2 are hydrogen or -CH [deep] 2R, where R is Lower alkyl, lower alkenyl, cyclone lower alkyl or lower alkenyl-cyclone lower alkyl. 37. Treatment method according to claim 35, characterized in that all radicals R [deep] 3, R [deep] 5 and R [deep] 9 are lower alkyl and R [deep] 2 are hydrogen. 38. Treatment method according to claim 35, characterized in that all radicals R [deep] 2, R [deep] 3, R [deep] 5 and R [deep] 9 mean lower alkyl. 39. Treatment method according to claim 35, characterized in that the dextrorotatory (+), optically isomeric form of the compound is administered. 40. Treatment method according to claim 35, characterized in that the levorotatory (-), optically isomeric form of the compound is administered.