DK142619B - Substituted 2-benzyl-4-piperidones for use as intermediates in the preparation of benzomorphans, and process for their preparation. - Google Patents

Description

(¾ \ Ra / (11) FRENI DISCLAIMER 142619 DENMARK lm Cl> c 07 D 211/74 § (21) Application No, 1 556/72 (22) Filed on 22 · Π13Γ · 1972 (24) Running Day 5 · jUH · 1 970 (44) The application presented and ian τ

the petition published on 'aec * <y & J

DIRECTORATE OF THE PATENT AND TRADEMARKET (30) Pnontate requested from the

4. Jun. 1969, 69Ο8527, NL

Jun 4 1969 »6908528, NL

Jun 4 1969 * 6908529, NL

(71) ACF CHEMIEFARMA N.V., Wittenkade 78, Amsterdam, NL.

(72) Inventor: Antony Marie Akkerman, 837 Kennedy Avenue, Amster = dam, NL: Paul Adriaan Jah Janssen, 31 Antwerp Sfceenweg, Vosselaar, BE.

(74) Plenipotentiary in the proceedings:

International Patent Bureau (64) Substituted 2-benzyl-4-piperidones for use as intermediates in the preparation of benzomorphans, and process for their preparation

Young.

The present invention relates to novel substituted 2-benzyl-4-piperidones for use as intermediates in the preparation of benzomorphans of general formula II (see formula sheet) wherein each of the substituents R is a methyl or ethyl group, R * is a hydrogen atom, a methyl group, a haloalkyl group of up to 5 carbon atoms, an alkenyl group of up to 5 carbon atoms, a haloalkenyl group of up to 3 carbon atoms, an alkinyl group of up to 3 carbon atoms, an aralkyl group of up to 8 carbon atoms, a cycloalkenyl group having up to 8 carbon atoms, a cycloalkylalkyl group having up to 5 carbon atoms, a cycloalkenyl alkyl group having up to 7 carbon atoms, or a cycloalkylidene group 2 having up to 8 carbon atoms, R is an alkyl group having up to 3 carbon atoms, one, 3 phenyl group or a 2-pyridyl group and R is a hydrogen atom, a hydroxy group, an alkoxy group of up to 2 carbon atoms, a methoxyethoxy group, a nicotinoyl group or an acyloxy group with d up to 7 carbon atoms. Furthermore, the invention relates to a process for producing these 2-benzyl-4-piperidones.

2 U2619

The synthesis of 6,7-benzomorphans is first described by E.L. May and J.G. Murphy, J.Org.Chem. 20, 257 (1955).

Since then, compounds of this type attracted attention because of their interesting pharmacological properties. Notably, 6,7-benzomorphans not only show strong analgesic action, but compounds of this type may further have effects that may be considered antagonistic to the action of morphine, depending on the nature of the substituent at the ring nitrogen atom. Such a combination of properties can lead to analgesic drugs that are practically free from the usual side effects of the classic strong analgesics, such as respiratory depression and induction of tolerance and habituation.

Since the above publication by May et al. several rows of 6,7-benzomorphans have been synthesized and described, cf. U.S. Patent Specifications Nos. 2,924,603, Nos. 3,033,867 and Nos. 3,138,603.

Furthermore, new drugs of this type have emerged, e.g. phenazocin and pentazocin, both introduced into the therapy, and cyclazocin. Alternative pathways for synthesizing 6,7-benzomorphans are described, e.g. in U.S. Patent Specifications Nos. 3,073,837 and Nos. 3,093,650.

An overview of the chemistry and pharmacology of 6,7-benzomorphans is available from N.B. Eddy and E.L. May in International Series of Monographs in Organic Chemistry, Vol. £, Part II (B), Pergamon Press (1966).

As shown in the literature, to show high activity, 6,7-benzomorphan compounds must have a quaternary carbon atom at the 5-position of the ring system, while the carbon atom at the 9-position must preferably be tertiary, at least if the term "quaternary carbon atom "is limited to those bound exclusively to other carbon atoms that do not belong to functional groups. No publications have so far been published regarding 6,7-benzomorphans having a quaternary carbon atom at the 9-position. The methods commonly used for the synthesis of benzomorphans are not suitable for the preparation of this type of compound.

The present novel substituted 2-benzyl-4-piperidones for use as intermediates in the preparation of benzomorphans of formula II are characterized in that they have the formula X (see formula leaf) or salts thereof, wherein each R is a methyl or ethyl group, R is a hydrogen atom, an alkyl group of up to 3 carbon atoms or an aralkyl group of up to 9 cars' carbon atoms, and R is a hydrogen atom or an alkoxy group of up to 3 carbon atoms.

The preparation from these novel substituted 2-benzyl-4-piperidones of the novel 6,7-benzomorphans of formula II is carried out by an analogous procedure. The benzomorphans of formula II have interesting analgesics and / or el.

3 142619 morphine antagonistic effects. Compared to the above-mentioned known compounds having similar pharmacological action, the 6,7-benzomorphans of formula II are distinguished by being active at significantly lower doses than the known compounds, as further illustrated below.

The first step of the aforementioned analogy process for the preparation of benzomorphanes of formula II involves the conversion of the present 2-benzyl-4-piperidone to 2-benzyl-4-piperidinols of formula IV, wherein E, R and 3 '1' R have the above meanings, and R is an alkylgate having up to 3 carbon atoms or an aralkyl group having up to 9 carbon atoms. This conversion can take place by reduction or by reaction with an alkyl metal compound where the alkyl group has up to 3 carbon atoms, a phenyl metal or a 2-pyridyl metal compound.

Reduction can be by catalytic hydrogenation as well as by other methods commonly used to reduce a carbonyl group to a carbinol group, e.g. using complex metal hydrides such as sodium borohydride or especially lithium aluminum hydride.

Preferably, as alkyl, phenyl or 2-pyridyl metal compounds, lithium compounds are used which readily lead to the desired 4-piperidinols. However, with ethyl lithium and more pronounced with propyllithium, the reaction proceeds less fully, and it is advisable to repeat the reaction in order to obtain higher yields.

Furthermore, the 4-ethyl-4-piperidinols of formula IV can be prepared in excellent yields via 4-ethinyl-4-piperidinols, which are products of the reaction of the present 4-piperidones with a monoalkali metal salt of acetylene under suitable conditions. . reaction with ethinyl lithium in liquid ammonia, reaction with ethinyl potassium in tertiary butanol at temperature below 0 ° C or reaction with the complex of ethinyllithium and ethylenediamine in dimethylformamide at temperatures between 0 ° C and room temperature. The 4-ethinyl substituent can be converted to a 4-ethyl group by catalytic hydrogenation. In this way, 4-ethyl-4-piperidinols can be obtained in better yield than in the one-step reaction with ethyl lithiura.

Since in the preparation of 4-piperidinols from 4-piperidones, another asymmetric carbon atom is formed in the piperidine ring, the 4-piperidinols can be formed in two different racemic forms, both of which are equally suitable for the conversion to the same 6,7-benzomorphan derivatives. is therefore not necessary.

The 2-benzyl-4-piperidinols of formula IV obtained in the above first step are then converted to 6,7-benzomorphans of formula II by cyclization below 1 "

action of a highly acidic reagent, followed by a won compound wherein R

31 in 3 jn and / or R has a different meaning from that desired for R and / or R, R and / or 3 '13 clays R by known methods are replaced by R and / or R. A compound thus obtained may then, if desired, be divided into optical enantiomers, this division preferably being carried out on a reaction step where there is a hydrogen atom at R * and, if desired, a compound obtained may be transferred into a salt thereof.

The cyclization of the substituted 2-benzyl-4-piperidinols to the above 6,7-benzomorphans probably extends over a carbonium ion of formula V (see lu 2 3 'formula sheet) wherein R, R, R and R have the above meanings. The cyclization reaction is preferably carried out at elevated temperatures and by a strong inorganic acid, preferably hydrogen bromic acid or phosphoric acid. During the reaction, the alkoxy substituents at the benzene core are converted into hydroxy groups.

Benzomorphans of formula XI, wherein R 2 * H, are recovered from the corresponding benzomorphans where R * = CH 2, by prior art according to von Braun, whereby these 2-methyl derivatives are hydrolyzed and then decarboxylated. Another route to the benzomorphans which are unsubstituted by the nitrogen atom consists in removing the benzyl group from 2-benzyl analogs by catalytic hydrogenolysis.

Subsequently, other substituents may be introduced on the nitrogen atom by methods commonly used in the benzomorphan chemistry, such as reaction with alkyl halides or acyl halides. In the latter case, amides that can be reduced to tertiary amines are formed by lithium aluminum hydride.

Benzomorphans of formula II wherein the two substituents at the 9-position are%, in contrast to the known derivatives with one substituent at said position, two instead of three asymmetric carbon atoms (namely and C

Furthermore, since the piperidine ring in the benzomorphan ring can be present only in cis position relative to the remaining (tetralin) portion of the molecule, the novel 6,7-benzomorphans of formula II can therefore only exist in one racemic form. In order to obtain optically active enantiomers of these novel 6,7-benzomorphans, division as mentioned is preferably carried out with compounds where R * H, after which the optically active compounds obtained can be substituted on the nitrogen atom by the methods described above. The division can advantageously be obtained by (-) - and (+) - 3-bromo-camphor-8-sulfonic acid.

In the present 2-benzyl-4-piperidones, it is preferred according to the invention that each R is a methyl group, these compounds being the most readily available chemically.

The process of the present invention for the preparation of the substituted 2-benzyl-4-piperidones or salts thereof according to the invention is in accordance with the invention.

equal to the conversion of β-keto esters of formula XI (see formula sheet) wherein R and R

have the above meanings, for benzylimino esters of formula XII (see formula sheet), 3 "where R and R have the above meanings, by benzylamine, catalytic hydrogenation of the compounds obtained for benzylamino esters of formula XIII (see 3" formula sheets), wherein R and R has the above meanings, catalytic hydrogenolysis of said benzylamino esters to A-amino esters of formula VII (see formula sheet), wherein R 3 and R have the above meanings, reaction with alkyl acrylates or alkyl 3-halo propionates followed, if desired, of substitution of the nitrogen atom to ten «3« r

3,3-immunodipropionic acid esters of formula VIII (see formula sheet) wherein R, R and R

have the above meanings, ring closure according to Dieckmann for alkyl 4-oxo-3-piperidine-3 'din-carboxylates of formula IX (see formula sheet) wherein R, R and R have the above meanings, and hydrolysis and decarboxylation to 4 the piperidones of formula X followed, if desired, by conversion to salts of said compounds.

The conversion of β -keto esters XI to β-benzyl amino esters XII can be carried out in the usual manner, i. by reaction with benzylamine in the presence of a highly acidic catalyst (e.g., p-toluenesulfonic acid or boron trifluoroethyl diethyl etherate) in a solvent such as toluene which allows removal of the water formed by azeotropic distillation. However, it is more advantageous to use the method of H, Weingarten et al., J. Org.Chem. 32, 3246 (1967), wherein titanium tetrachloride acts as a condensing agent in an inert solvent such as toluene and at room temperature.

The reduction of β-benzylimino esters to β -benzylamino esters XIII takes place by catalytic hydrogenation with platinum oxide as catalyst. The removal of the benzyl group (thereby forming the above β-amino esters of formula VII) is carried out by catalytic hydrogenolysis. Here, palladium is the preferred catalyst, e.g. absorbed on activated charcoal. Said hydrogenation and hydrogenolysis are preferably carried out in an acidic medium. Acetic acid, optionally diluted with alcohol, has been found to be a suitable solvent. These reductions can be carried out at atmospheric pressure and at room temperature.

The conversion of β-amino esters of formula VII to 3,3'-iminodipropionic acid esters of formula VIII is achieved by reaction with β -halo propionic acid esters or, preferably, by reaction with alkyl acrylates at elevated temperature in the presence of acetic acid as a catalyst. The resulting imino esters may be provided 1 "with the above substituents R on the nitrogen atom. The introduction of a methyl group is carried out by the well-known method of Clarke and Eschweiler, heating the iron systems with a mixture of formic acid and aqueous formaldehyde.

The 3,3'-iminodipropionic acid esters may be cyclized under the action of a basic condensing agent such as sodium methoxide or sodium hydride by boiling the reactants suspended or dissolved in an inert solvent such as benzene, toluene or dimethylformamide. The alcohol developed during the reaction is removed by simultaneous distillation of the mixture. The products of this Dieckmann ring are 2-benzyl-4-oxo-5-piperidinecarboxylic acid esters of formula IX.

Hydrolysis and decarboxylation of the keto esters of formula IX to 4-piperidones of formula X are carried out by heating a solution of these compounds in a 1 aqueous strong inorganic acid, thereby limiting the tendency to form neutral material due to decomposition by careful choice of reaction betel - ones that must not be too powerful. In 6N hydrochloric acid, the reaction is completed within 30-50 minutes, in 2N hydrochloric acid over 5 hours, while 1N acid requires a reaction time of 12 hours. The latter approach is the preferred one.

The invention will be described in greater detail by the following Examples, Examples 1-5 illustrating the preparation of the disclosed sun-substituted 2-benzyl-4-piperidones and Examples 6-21 illustrating conversion of the subject substituted 2-benzyl-4-piperidones in part into corresponding 2- benzyl-4-piperidinols, and in part through these 2-benzyl-4-piperidinols to pharmaceutically active benzomorphans.

Example 1 2- (p-Methoxybenzyl) -1,3,3-trimethyl-4-piperidone hydrochloride.

a) Methyl 2,2-dimethyl (p-methoxyphenyl) acetoacetate.

To a gentle refluxing suspension of 227 g of granulated zinc, activated by the addition of 1 g of iodine, in 500 ml of dry tetrahydrofuran, a solution of 700 g of methyl 2-bromoisobutyrate and 540 g of methyl 2-brine was added dropwise. p-methoxy-phenylacetate in 500 ml of tetrahydrofuran.

As soon as the reaction had begun, as evidenced by the formation of a haze and stronger reflux, the addition was continued at such a rate as to maintain gentle reflux with minimal use of exterior heating. After all solution was added, stirring and reflux were continued for 5 hours. The reaction mixture was then cooled with ice, and 1500 ml of 4N sulfuric acid was added dropwise with vigorous stirring. The organic layer was separated after removing any solid material by filtration and the aqueous solution was extracted with ether. The combined organic solutions were washed with an aqueous solution of sodium bicarbonate. Evaporation of the solvent gave as the residue the crude ester which was purified by distillation in vacuo. Yield 60-65%, b.p. 145 ° G / 1 mm, n ^ 1.5140.

b) Methyl 3-benzylamino-2,2-dimethyl-4- (p-methoxyphenyl) butyrate.

Titanium tetrachloride (114 g) was dropped over a period of 2 hours to a mixture of 250 g of methyl 2,2-dimethyl-4- (pyrethoxyphenyl) acetoacetate, obtained under a), 384 g of benzylamine and 1000 ml of dry toluene. . The mixture was kept in an atmosphere of nitrogen, stirred vigorously and cooled with ice to maintain the temperature at 5-10 ° C. Initially, the color of the mixture changed to brown, but after being kept at room temperature for 5 days the mixture assumed a light yellow-brown color.

The resulting Ti (> 2 and benzylamine hydrochloride was removed by filtration and washed thoroughly with toluene).

Evaporation of the combined filtrates gave as evaporation residue 268 g of crude ketimine with a purity of 90%. This corresponds to a yield of approx. 70%. Then the crude Schiff * spoon base (920 g), dissolved in 1.25 l acetic acid, was hydrogenated with 5 g platinum oxide as catalyst and at atmospheric pressure. Hydrogen uptake was quick to begin with, but after absorption of 55 l, it became significantly slower.

At this point, the hydrogenation was quenched, after which the catalyst was removed by filtration, and the solution was concentrated by evaporation of the solvent in vacuo. The residue was taken up in water and the resulting aqueous solution made alkaline with 4N sodium hydroxide solution. The basic material that was excreted was taken up in ether. Removal of the solvent by evaporation gave an oily residue which was dissolved in 700 ml of ethanol. After cooling overnight in the refrigerator, 440 g of coarse crystals were deposited from the solution. Recrystallization of ethanol gave the pure product, m.p. 58-60 ° C.

c) Methyl 3-amino-2,2-dimethyl-4- (p-methoxyphenyl) -bufeyrate.

The benzyl amino acid ester (440 g), obtained under b), could easily be debenzylated by hydrogenation at atmospheric pressure and room temperature. The solvent was 1.25 L of acetic acid and catalyst 20 g of 5¾ palladium on charcoal. After 2 hours, hydrogen uptake ceased, at which time 1 liter of hydrogen was absorbed. By proceeding as under b) a product with m.p. 46-49 ° C in a total yield of 357. based on the starting ketoester.

d) Dimethyl 3- (p-methoxybenzyl) -2,2, N-trimethyl-3,3'-iminodipropienate.

A mixture of 351 g of methyl 3-amino-2,2-dimethyl-4- (p-methoxyphenyl) butyrate, obtained under c), 205 g of methyl acrylate and 3 ral acetic acid, was heated in an autoclave for 18 hours at 130 ° C. G, The contents were removed from the autoclave by ether and the volatiles were evaporated under reduced pressure. To the resulting crude reaction product was added successively 280 ml of formic acid (957.) and 280 ml of aqueous formaldehyde (357.). During this 1.5 hour operation, the mixture was stirred and cooled with water.

It was then heated at 40 ° C for 1 hour, kept at room temperature for 16 hours, and finally heated for another hour at 60 ° C. After removal of low-boiling material by evaporation in vacuo, the oil present as the evaporation residue was treated with chloroform and a concentrated aqueous solution of potassium carbonate. The organic solution was dried over magnesium sulfate and evaporated to give an oily residue. Neither this product nor its unmethylated predecessor could be purified by distillation due to excessive decomposition at elevated temperatures.

The first step of the synthesis described in this step d) could also be carried out at a lower temperature without the use of an autoclave. In this case, a mixture of 450 g of methyl 3-amino-2,2-dimethyl-4- (p toethoxyphenyl) butyrate and 180 ml of methyl acrylate stirred at 50 ° C, adding 45 ml of acetic acid fairly quickly. The temperature of the mixture was raised to 90 ° C using heat and then spontaneously increased to 100 ° C. After 1 hour, the reaction was complete and excess methyl acrylate and acetic acid were removed by evaporation in vacuo at 50 ° C.

e) Methyl 2- (p-methoxybenzyl) -4-oxo-1,3,3-trimethyl-5-piperidine carboxylate hydrochloride.

(i) The crude methyliminodipropionic acid ester prepared under d) was dissolved in dry toluene. Sodium methoxide (157 g) was added and the mixture was stirred and heated in an oil bath at 100-100 ° C. The methanol developed during the reaction was removed by azeotropic distillation. Its formation ceased after 21/2 to 3 hours when only toluene distilled. The mixture was cooled and then water was added. The toluene layer was washed with water and, after drying with magnesium sulfate, was evaporated in vacuo. The residue of crude keto ester was treated with an alcoholic solution of hydrogen chloride. The hydrochloride is separated as a crystalline precipitate. Yield 268 g (54% based on the amount of the starting amino ester described in step c)), m.p. 163-164 ° C (dec.).

(ii) To a solution of 19.0 g of crude methyliminodipropionic acid ester, prepared under d), in 150 ml of dry dimethylformamide was added 4.8 g of sodium hydride (50% dispersion in oil) and the mixture was stirred and gradually heated until , at about. 70 ° C, strong hydrogen evolution took place. The reaction was terminated by heating the mixture at 110-120 ° C for 3 hours. After cooling, a solution of 30 g of ammonium chloride in 300 ml of water was added, after which the solvents were removed by evaporation in vacuo. The residue was shaken with 1N hydrochloric acid and benzene. The acidic aqueous layer was made alkaline with an excess of aqueous ammonia and then extracted with chloroform. The organic solution was worked up as usual and the product was recovered as hydrochloride. The compound was identical to the compound obtained under (i) above. After recrystallization, the yield was 49%.

f) 2- (p-Methoxybenzyl) -1,3,3-trimethyl 4-piperidone hydrochloride.

A solution of the hydrochloride (80 g) of raethyl 2- (p-methoxybenzyl) -4-oxo-1,3,3-trimethyl-5-piperidine carboxylate, obtained under e), was refluxed in 450 ml of 1N hydrochloric acid. 12 hours. After cooling, some resinous material was removed by extraction with ether. Alkalinization of the aqueous solution with ammonia resulted in the excretion of the piperidone, which was extracted with ether. Concentration in vacuo of the extract gave an evaporation residue which was dissolved in ethanolic hydrogen chloride. Evaporation of the ethanol gave a syrupy residue which was dissolved in acetone and the crystalline hydrochloride was separated. Yield 87%, m.p. 168-170 ° C (dec.).

Example 2 2-Benzyl-1,3,3-trimethyl-4-piperidone hydrochloride.

a) Methyl 2,2-dimethyl-4-phenylacetoacetate.

In the same manner as described in Example 1a), but from methylphenyl acetate,

Λ Q

won the title compound. Yield 71%, b.p. 112 C / l mm, ηβ 1.5043.

b) Methyl 3-benzylamino-2,2-dimethyl-4-phenyl-butyrate.

A mixture of 440 g of methyl 2,2-dimethyl-4-phenylacetoacetate, obtained under a), 214 g of benzylamine, 500 ml of toluene and 2 ml of boron trifluoride etherate was refluxed during continuous removal of the water formed by azeotropic distillation. After 9 hours, when only half of the expected water was separated, 90 g of benzylamine and 2 ml of a solution of hydrobromide in acetic acid (45%) were added, and reflux was continued for 25 hours, after which the formation of water was completed. The mixture was shaken with an aqueous solution, of sodium bicarbonate, dried over magnesium sulfate and distilled at reduced pressure. The fraction having the boiling range of 147-170 ° C (0.2 mm) consisted mainly of ketimine (500 g) suitable for hydrogenation without further purification. Fractional distillation gave pure ketimine with a boiling range of 149-152 ° C (0.25mm), n ° 1.5532, Raw ketimine (500g) dissolved in 500ml of acetic acid was subjected to catalytic hydrogenation at atmospheric pressure and room temperature and with platinum dioxide. (2 g) as catalyst. Hydrogen uptake stopped by 24 liters. After removal of the catalyst by filtration, the solvent was evaporated completely in vacuo. The oily residue was dissolved in ca. 250 ml of ethanol. From this solution, the title compound is separated as coarse crystals. Yield 220 g, snap. 92-94 ° G.

c) Methyl 3-amino-2,2-dimethyl-4-phenyl-butyxate.

In a similar manner to that described in Example 1 (c), hydrogenolytic debenzylation of methyl 3-benzylamino-2,2-dimethyl-4-phenyl-butyrate, obtained under b), gave the title compound as an oil which solidified on standing, m.p. . 37-39 ° C. Yield 34% based on the amount of methyl 2,2-dimethyl-4-phenylacetoacetate used.

d) Ethyl 2-benzyl-4-oxo-1,3,3-trimethyl-5-piperidine carboxylate hydrochloride.

A mixture of 240 g of methyl 3-amino-2,2-dimethyl-4-phenyl butyrate, obtained under c), 171 g of ethyl acrylate and 1.5 ml of acetic acid was heated at 130 ° C for 18 hours. The crude addition product (365 g) was methylated by the Clarke-Eschweiler method, as described in Example 1d). As a result, 325 g of a mixed iminodipropionic acid ester was obtained in the form of an oil. This compound (325 g) was subjected to a Dieckmaimering solution by reaction in toluene with 90 g of natritan methoxide under the conditions described in Example 1 e (i).

Upon working up, the reaction mixture was neutralized by addition, under cooling, of acetic acid and then washed with water and worked up in the usual manner. The yield of the hydrochloride was 52%. After recrystallization of ethanol / Acetone, the compound had m.p. 180-182 ° C (dec.).

e) 2-Benzyl-1,3,3-trimethyl-4-piperidone hydrochloride.

A solution of 217 g of the hydrochloride of ethyl 2-benzyl-4-oxo-1,3,3-trimethyl-5-piperidine carboxylate, obtained under d), in 6N hydrochloric acid was refluxed for 40 minutes. The piperidone was collected as hydrophiloride in the same manner as described in Example 1f). Yield 75%, m.p. 177-179 ° C (dec).

Example 3 3,3-Dimethyl-2- (p-methoxybenzyl) -4-piperidone hydrochloride.

a) Ethyl 3,3-dimethyl-2- (p-methoxybenzyl) -4-oxo-5-piperidine carboxylate hydrochloride.

In accordance with Example 1 e (i), but from the addition product of the reaction between ethyl acrylate and methyl 3-amino-2,2-dimethyl-4- (p-methoxy-phenyl) -butyrate, prepared by method (fire described), the title compound was obtained. The yield of the compound was 33%. After recrystallization from ethanol, the compound had m.p. 177-180 ° C. b) 3,3-Dimethyl-2- (p-methoxybenzyl) -4-piperidone hydrochloride, In a similar manner as described in Example 1 f), but from ethyl 2- (p-methoxybenzyl) -3,3- dimethyl 4-oxo-5-piperidine carboxylate, obtained under a), the title compound was obtained in a yield of 75%. After recrystallization from ethanol / ethyl ether, the compound had m.p. 212-213 ° C (dec.).

Example 4 3,3-Dimethyl-2- (p-methoxybenzyl) -4-piperidone hydrochloride.

With 19.1 g of crude 3- (p-methoxybenzyl) -2,2-dimethyl-3,3, -imino-dipropionic acid dimethyl ester (obtained by addition reaction between methyl acrylate and 3-amino-2,2-dimethyl-4- ( p-Methoxyphenyl) -butyric acid methyl ester, prepared according to Example 1 d), dissolved in 150 ml of dry dimethylformamide and in the presence of 7.2 g of sodium hydride (50% dispersion in oil), a Dieckmann cyclization was performed as described in Example 1 e (ii). The crude condensation product was hydrolyzed and decarboxylated as described in Example 1 f) to give the desired piperidone in a total yield of 44%, m.p. 212-213 ° C (dec.).

Example 5 1-Benzyl-3,3-dimethyl-2- (p-methoxybenzyl) -4-piperidone hydrochloride.

A mixture of 24.5 g of crude dimethyl-2,2-dimethyl-3- (p-methoxybenzyl) -3,3, -iminodipropionate, 27 g of benzyl chloride, 23 g of potassium iodide, 40 g of potassium carbonate, and 300 ml of methyl ethyl ketone was refluxed and stirred. for 35 hours. The mixture was cooled and evaporated in vacuo, after which the residue was treated with chloroform. Inorganic material was removed by filtration and the filtrate was concentrated in vacuo to give an evaporation residue which was shaken with 300 ml of 4N hydrochloric acid and 100 ml of petroleum ether to remove neutral products. After basification with aqueous ammonia, N-benzyl-2,2-dimethyl-3- (p-methoxybenzyl) -3,3'-iminodipropionic acid dimethyl ester was extracted from the mixture by shaking with chloroform. It was watered in almost quantitative yield and, without purification, was subjected to a Dieclonann cyclization using 5.2 g of sodium hydride (50% dispersion in oil) and 200 ml of dimethylformamide. Further work-up was carried out according to the guidelines set forth in the previous examples to give the title product which was recrystallized from ethanol / ether. Yield 35%, m.p. 161-162 ° C (dec.).

Example 6 21-Hydroxy-2,5,9,9-tetramethyl-6,7-benzomorphan.

2- (p-Methoxybenzyl) -1,3,3,4-tetramethyl-4-piperidinol.

To a mechanically stirred and nitrogen-flooded ether solution (200 ml) of methyl lithium (prepared in the usual manner from 43 g of methyl iodide and 4.8 g of lithium) was added in small amounts 9 g of 2- (p-methoxybenzyl) -1,3 , 3-trimethyl-4-piperidone hydrochloride. During the addition, which took approx. 1.5 hours, the mixture was cooled with water. It was stirred at room temperature for 16 hours and finally refluxed for 1 hour. Then, the lithium compounds were hydrolyzed by gentle addition of water (cooling with ice) and the basic material extracted from the mixture by 4N hydrochloric acid. Basification of the aqueous solution followed by extraction with ether and reprocessing of the ether solution in the usual manner gave crystals which, after recrystallization from petroleum ether, had m.p. 55-65 ° C. Yield 847. A mixture of epimeric piperidinols was apparently formed.

b. 2'-Hydroxy-2,5,9,9-tetramethyl-6,7-benzomorphan.

A mixture of 7 g of 2- (p-methoxybenzyl) -1,3,3,4-tetramethyl-4-piperidinol, obtained under a), and 70 ml of phosphoric acid (89%) were heated at 180-1B5 ° C for 16 hours. hours. After cooling, the reaction mixture was made alkaline with aqueous ammonia and then extracted with chloroform. The extract was dried over magnesium sulfate and evaporated to give a solid evaporation residue which, after recrystallization from methyl ethyl ketone, m.p. 157-161 ° C, with Sintering at 153 ° G. Yield of the title compound 48%. The hydrochloride had m.p. 180-183 ° C (dec.).

Example 7 2- (p-Methoxybenzyl) -3,3,4-trimethyl-4-piperidinol hydrochloride.

In a similar manner as described in Example 6a), but from the 3,3-dimethyl-2- (p-methoxybenzyl) -4-piperidone hydrochloride, the title compound was obtained. The compound was recovered as hydrochloride which crystallized from a mixture of ethanol and ether, m.p. 211-213 ° C (dec.). Yield 5%.

Example 8 2-Ethyl-2- (p-methoxybenzyl) -1,3,3-trimethyl-4-piperidinol hydrochloride.

Hydrochloride (18g) of 2- (p-methoxybenzyl) -1,3,3-trimethyl-4-piperidone was converted to the free base by shaking with ether and aqueous sodium hydroxide, followed by evaporation of the ether solution. The oily base recovered as evaporation residue was dissolved in 30 ml of absolute ether and then reacted with ethyl lithium (3.6 g in 300 ml of benzene) under the same conditions as described in Example 6 a).

According to gas chromatographic study, the conversion to piperidinol was only graded to 25%. After addition of water, the reaction mixture was worked up as described in Example 6a) and the resulting crude mixture of piperidone and piperidinol was again treated with ethyl lithium (2.7 g in 250 ml benzene). This procedure was repeated again, after which another 20% of the piperidone was found to be present. Work-up as usual yielded 19 g of an oily base which was converted to hydrochloride with ethanolic hydrogen chloride. After addition of acetone and ether, 9 g of the title compound separated as a crystalline product. Yield 45%, m.p. 232-234 ° G (dec.).

Example 9 2'-Hydroxy-5-propyl-2,9,9-trimethyl-6,7-benzomorphan hydrochloride.

a. 2- (p-Methoxybenzyl) -4-propyl-1,3,3-trimethyl-4-piperidinol.

In a similar manner as described in Example 8, but using n-propyllithium instead of ethyl lithium, the title compound was won in a yield of 31%. After recrystallization from petroleum ether, the compound had m.p. 85-102 ° C.

b. 2'-Hydroxy-5-propyl-2,9,9-trimethyl-6,7-benzomorphan hydrochloride.

In a similar manner as described in Example 6b), but using 2- (p-methoxybenzyl) -4-propyl-1,3,3-trimethyl-4-piperidinol, obtained under a), the title compound was obtained. Yield 24%, m.p. 235-245 ° C (dec.).

Example 10 2,5,9,9-Tetramethyl-6,7-benzomorphan hydrochloride.

a. 2-Benzyl-1,3,3,4-tetramethyl-4-piperidinol.

In a similar manner as described in Example 6 a), but from 2-benzyl-1,3,3-trimethyl-4-piperidone hydrochloride, the title compound was obtained. Yield 69%. After recrystallization from light petrol, the compound had m.p. 95-103 ° C.

b. 2,5,9,9-Tetramethyl-6,7-benzomorphan hydrochloride.

In a similar manner as described in Example 6b), but from 2-benzyl-1,3,3,4-tetramethyl-4-piperidinol, obtained under a), the title compound was obtained. Yield 45%, m.p. 222-226 ° C.

Example 11 5- Ethyl 2,9,9-trimethyl-6,7-benzomorphan hydrochloride.

a. 2-Benzyl-4-ethyl-1,3,3-trimethyl-4-piperidino1-hydrochloride d.

In a similar manner as described in Example 8, but from 2-benzyl-1,3,3-trimethyl-4-piperidone hydrochloride, the title compound was obtained as hydrochloride, m.p. 238-240 ° C (dec.). Yield 45%.

b. 5-Ethyl-2,9,9-trimethyl-6,7-benzomorphan hydrochloride.

In a similar manner as described in Example 6 b, but from the 2-benzyl-4-ethyl-1,3,3-trimethyl-4-piperidinol obtained under a), the title compound was obtained. Yield 62%, m.p. 224-226 ° C.

Example 12 5-Ethyl-2,9,9-trimethyl-6,7-benzomorphan hydrochloride. a. 2-Benzyl-4-ethyl-1,3,3-trimethyl-4-piperidinol hydrochloride.

13 142619

A solution of 4.4 g of 2-benzyl-1,3,3-trimethyl-4-piperidone in 30 ml of absolute ether was added at room temperature and over a period of 1 hour to a Grignard reagent prepared from 1.1 g. magnesium, 5.5 g of ethyl bromide and 35 ml of absolute ether.

After the mixture was stirred at room temperature for 2 days, it was cooled with ice and then 25 ml of water was added. The ether solution was dried and acidified with ethanolic hydrogen chloride. The compound crystallized as hydrochloride, mp, 220-230 ° G (dec.). Yield 13%.

b. From the 2-benzyl-4-ethyl-1,3,3-trimethyl-4-piperidinol hydrochloride obtained under (a), 5-ethyl-2.9 was obtained in the same manner as described in Example 11 (b) 9-Triraethyl-6,7-benzomorphan hydrochloride, m.p. 238-240 ° C.

Example 13 2-Benzyl-1,3,3-trimethyl-4-piperidinol hydrochloride.

A solution of 9 g of 2-benzyl-1,3,3-trimethyl-4-piperidone hydrochloride in 50 ml of methanol was subjected to catalytic hydrogenation at room temperature and atmospheric pressure with 0.4 g of platinum oxide zone catalyst. The title compound crystallized from ethanol / ether. Yield 98%, m.p., after recrystallization, 213-222 ° C.

Example 14 4-Ethinyl-2- (p-methoxybenzyl) -1,3,3-trimethyl-4-piperidinol.

A stream of acetylene, after successively being washed with water, cooled to -80 ° C and dried with CaCl 2, was introduced into a mechanically stirred solution of 7 g of lithium in 750 ml of dry liquid ammonia which was cooled to ca. -50 ° C. After approx. 5 hours the blue color disappeared. To the resulting solution of acetylene lithium was added dropwise 60 g of 2- (p-methoxybenzyl) -1,3,3-trimethyl-4-piperidone dissolved in 250 ml of absolute ether. During the addition, a slow stream of acetylene was maintained but then quenched and the reaction mixture stirred for 16 hours during which ammonia was allowed to evaporate gradually. The resulting suspension was diluted by adding 250 ml of absolute ether and stirred for an additional 2 hours at 30 ° C. After cooling, 54 g of ammonium chloride and water were added. The reaction product was recovered from the organic layer in the usual manner. It was recrystallized from a mixture of benzene and petroleum ether. Yield of the title compound 88%, m.p. 103-110 ° C.

Example 15 4-Ethinyl-2- (p-methoxybenzyl) -1,3,3-triethyl-4-piperidinol.

Potassium (23.8 g) was dissolved in 500 ml of dry tertiary butanol, after which 500 ml of absolute ether was added. This solution was cooled with ice and saturated with dry acetylene (cf. Example 14).

Over 45 minutes, a solution of 59.5 g of 2- (p-methoxybenzyl) -1,3,3-trimethyl-4-piperidone in 250 ml of absolute ether was then added dropwise as the mixture was cooled at room temperature. -10 ° C to -15 ° C and stirred mechanically. At the same time, the mixture was flooded with acetylene, which was continued for an additional 3 hours (at -10 ° G).

The reaction mixture was then allowed to reach room temperature over 16 hours. After the addition of 53.5 g of ammonium chloride, stirring was continued for 30 minutes, at which time 500 ml of ice-cold water was added.

The organic solution was separated, dried and evaporated to give the desired product as a crystalline evaporation residue, m.p. 103-110 ° C, yield 98%.

Example 16 5-Ethyl-2 · hydroxy-2,9,9-trimethyl-6,7-benzomorphane. a. 4-Ethyl-2- (p-methoxybenzyl) -1,3,3-trimethyl-4-piperidinol.

A solution of 56 g of 4-ethinyl-2- (p-methoxybenzyl) -1,3,3-trimethyl-4-piperidone in 350 ml of methanol was subjected to hydrogenation at atmospheric pressure and room temperature, the catalyst being 57, palladium on charcoal (5). g).

Absorption of 8.8 liters of hydrogen took place over 2 hours. Removal of the catalyst by filtration and evaporation of the ethanol in vacuo yielded as evaporation residue 55 g of a completely solidified oil. Yield of the title compound 98%, m.p. 90-95 ° C.

b. 5-Ethyl-2'-hydroxy-2,9,9-trimethyl-6,7-benzomorphane, 1) In a similar manner as described in Example 6 b), but using 4-ethyl-2- (p -methoxybenzyl) -1,3,3-trimethyl-4-piperidinol, obtained under a), the title compound was obtained in a yield of 46%. After recrystallization from methyl ethyl ketone, the compound had m.p. 177-181 ° C.

2) A solution of 65 g of 4-ethyl-2- (p-methoxybenzyl) -1,3,3-trimethyl-4-piperidinol, obtained under a), in 700 ml of hydrobromic acid (487) was refluxed for 48 hours. The mixture was diluted with 500 ml of water, filtered and then concentrated in vacuo. The syrupy residue was treated with excess aqueous ammonia. Upon cooling, a precipitate formed which was filtered, washed once with water and three times with cold acetone. Yield of the title compound 40%, m.p. 173-177 ° C.

142619 15

Example 17 2'-Hydroxy-5-phenyl-2,9,9-trimethyl-6,7-benzothorphane.

a. 2- (p-Methoxybenzyl) -4-phenyl-1,3,3-trimethyl-4-piperidinol.

In a similar manner as described in Example 8, but using phenyllithium 1 instead of ethyl lithium, the title compound was won. Yield 887., m.p. 122-124 ° C (after recrystallization from petroleum ether.

b. 2'-Hydroxy-5-phenyl-2,9,9-trimethyl-6,7-benzomorphan.

Similarly scan described in Example 6b), but from the 2- (p-methoxy-benzyl) -4-phenyl-1,3,3-trimethyl-4-piperidinol, the title compound was obtained. Yield 497., m.p. 223-230 ° C.

Example 18 1-Benzyl-2- (p-methoxybenzyl) -3,3,4-trimethyl-4-piperidinole hydrochloride.

In a similar manner as described in Example 6 a), but from 1-benzyl-2- (p-methoxybenzyl) -3,3-dimethyl-4-piperidone hydrochloride, the title compound was obtained. Yield 437., m.p., after recrystallization from ethanol / ether, 213-214 ° C (dec.).

16 U2619

Example 19 9,9-Diethyl-2-methyl-6,7-benzomorphan hydrochloride.

a. 2-Benzyl-3,3-diethyl-1-methyl-4-piperidinol.

To a solution of 6.4 g of 2-benzyl-3,3-diethyl-1-methyl-4-piperidone in 100 ml of ether, 0.9 g of lithium aluminum hydride was added over a few minutes. The mixture was stirred at room temperature for 4 hours. After addition of 5 g of ammonium chloride, stirring was continued for 1/2 hour. The mixture was then washed with 100 ml of water and the ether solution was immersed in vacuo. The residue was chromatographed on alumina using a mixture of benzene-ethanol (98: 2) as eluent. The product, which showed no tendency for crystallization, was a mixture of two stereoisomers. They could easily be separated using the picrates. Fractional crystallization of 6.5 g of a mixture of the picrates gave 2.7 g of a picrate, m.p. 206-208 ° C, which was slightly soluble in ethanol, and 2.7 g of a readily soluble picrate having m.p. 162-164 ° C. From the picrates, the isomeric bases could be obtained as oils.

b. 9,9-Diethyl-2-methyl-6,7-benzomorphan hydrochloride.

In a similar manner as described in Example 6b), but from 2-benzyl-3,3-diethyl-1-methyl-4-piperidinol, obtained under a) (the two isomers give the same final product), the title compound was obtained. Yield 19%, m.p. 237-238 ° C.

Example 20 2'-Hydroxy-5- (2-pyridyl) -2,9,9-trimethyl-6,7-benzomorphan dihydrobromide.

a. 2- (p-Methoxybenzyl) -4- (2-pyridyl) -1,3,3-trimethyl-4-piperidinol dihydrochloride.

In a similar manner as described in Example 8, but using 2-pyridyl-lithium instead of ethyl lithium, the title compound was won. Yield 68% ,. The dihydrochloride was hygroscopic and had m.p. 193-196 ° C (dec.).

b. 2'-Hydroxy-5- (2-pyridyl) -2,9,9-trimethyl-6,7-benzomorphan dihydrobromide.

In a similar manner as described in Example 16b (1), but from 2- (p-methoxy-benzyl) -4- (2-pyridyl) -1,3,3-trimethyl-4-piperidinol dihydrochloride, obtained under a ), the title compound won. It was purified as dihydrobromide, m.p. 230-233 ° C (dec), after recrystallization from isopropanol. Yield 40%.

Example 21 2-Benzyl-9,9-dimethyl-5-ethyl-2 * -hydroxy-6,7-benzomorphan hydrobromide.

a. 1-Benzyl-3,3-dimethyl-4-ethyl-2- (p-methoxybenzyl) -4-piperidinol hydrochloride.

In accordance with Example 14, 5 g of 1-benzyl-3,3-dimethyl-2- (p-methoxybenzyl) -4-piperidone was reacted with acetylene lithium (prepared from 1 g of lithium in 75 ml of liquid ammonia). The crude product of this reaction was catalytically reduced as described above to give the title compound, which was recovered as hydrochloride. Yield 55%, mp, 171-172 ° C (dec).

b. 2-Benzyl-9,9-dimethyl-5-ethyl-2 * -hydroxy-6,7-benzomorphan hydrobromide.

By similar grace as described in Example 6b), but from 1-benzyl-3,3-dimethyl-4-ethyl-2- (p-methoxybenzyl) -4-piperidinol hydrochloride, obtained under a), the title compound was obtained. . The compound could be purified via the O-acetyl derivative, m.p. 232-235 ° C (dec.).

To illustrate the pharmacological action of the 6,7-benzomorphans of formula II, which can be prepared from the present 2-benzyl-4-piperidones, the tests described below were carried out.

(1) Tail withdrawal test in rats.

The analgesic potency of the test compounds was determined by the so-called tail withdrawal test on male rats having a body weight of 250 - 10 g, essentially according to the standard methods described by P.A.J, Janssen, C.J.E.Niemegeers and J.G.H.Dony, Arzneim-Forsch., 13, 502 (1963). The test methods were essentially as described except that measurements were made more frequently, the cut-off time was reduced from 15 seconds to 10 seconds, and the results were assessed according to three different levels of analgesia defined as follows: (a) Moderate analgesia (MA in Table A) below - the reaction time for tail retraction is> 6 and <10 seconds.

(b) Pronounced analgesia (P.A. in Table A) - no withdrawal reaction over a reaction time> 1Q seconds, but small movements of tail in hot water tank.

(c) Surgical analgesia (S.A. in Table A) - no tail retraction reaction over a reaction time of Mo seconds and no tail movement or reaction.

Table A indicates the doses, in mg / kg of body weight, administered subcutaneously, which for each of the compounds listed constitute the ED EDQ values and safety limits for achieving the levels of analgesia defined above (M.A., P.A. and S.A.). For comparison, Table A also indicates the corresponding values for nalorphine, pentazocin, cyclazocin and morphine.

(2) Nalorphine-like effect on rats.

In order to investigate the nalorphine-like effect of the test compounds, i. the strength of such compounds in reversal of respiratory depression, loss of stability reflex, muscle stiffness, surgical analgesia and obstruction of corneal reflex and external ear reflex arising from administration of high doses of fentanyl, male Wistar rats received a subcutaneous injection of 0.63 mg / kg of body weight of fentanyl to induce the phenomena described. Thirty minutes after the fentanyl dose, the same animal received intravenous injections of the test compounds and of nalorphine, pentazocin, cyclazocine and morphine for comparison.

Table A indicates the lowest active dose in mg / kg body weight, showing nalorphine-like properties, ie. were able to immediately reverse the aforementioned phenomena induced by the fentanyl dose.

(3) Twist test on rats.

Female Wistar rats received an injection of 1/2 ml of a 1% acetic acid solution and the number of twists within 60 minutes of the injection was counted. In control animals, the average number of twists was 100 within 60 minutes after the injection of acetic acid solution. The various test compounds listed in Table A and for comparison also nalorphine, pentazocin, cyclazocine and morphine were administered subcutaneously 30 minutes before the standard injection of acetic acid. Table A indicates, for each test compound, the lowest active dose, in mg / kg body weight, which reduced the number of twists by at least half, i. C50 twists within 60 minutes after the acetic acid injection.

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Claims (3)

I. Substituted 2-benzyl-4-piperidones for use as intermediates in the preparation of benzomorphans of general formula II: R 1 R 3 wherein each of the substituents R is a methyl or ethyl group, R 1 is a hydrogen atom, a methyl group, a haloalkyl group of up to 5 carbon atoms, an alkenyl group of up to 5 carbon atoms, a haloalkenyl group of up to 3 carbon atoms, an alkinyl group of up to 3 carbon atoms, an aralkyl group of up to 8 carbon atoms, a cycloalkenyl group of up to 8 carbon atoms, a cycloalkylalkyl group having up to 5 carbon atoms, a cycloalkenylalkyl group having up to 7 carbon atoms or a cycloalkylidene group having up to 8 carbon atoms, R is an alkyl-3 group having up to 3 carbon atoms, a phenyl group or a 2-pyridyl group, and R is a hydrogen atom, a hydroxy group, an alkoxy group of up to 2 carbon atoms, a methoxymethoxy group, a nicotinoyl group or an acyloxy group of up to 7 carbon atoms, wherein R is a methyl or ethyl group, R is a hydrogen atom, an alkyl group of up to 3 carbon atoms or an aralkyl group of up to 3 '* 9 carbon atoms, and R is a hydrogen atom or an alkoxy group of up to 3 carbon atoms. Substituted 2-benzyl-4-piperidones according to claim 1, characterized in that each R is a methyl group. A process for preparing substituted 2-benzyl-4-piperidones according to claim 1 or salts thereof, characterized by the conversion of β-ketoesters of formula XI: OR -CH2 -C "C - C00 Alkyl xi R where R and R have the above meanings, for benzylimino esters of formula XII: Or · NR g3" / ~ \ ___oh2 -2 - c-COM'kyl \ = / I ϊπ R 3 '' wherein R and R have the above meanings, by means of benzylamine, catalytic hydrogenation of the compounds obtained to benzylamino esters of formula XIII: Ot2 p ij · XIII R3 '- i η-CH2 - CH-C-COOAlkyl \ = / IR on wherein R and R have the above meanings, catalytic hydrogenolysis of said benzylamino esters to β-amino esters of formula VII: nh2 R // \ II VII r3 - \ ___ / ~ CH2-CH-j -COO "Alkyl 3" wherein R and R have the above meanings, emission with alkylerylylates or alkyl-halo propionates followed, if desired, by substitution of the nitrogen atom to 3,3'-iminodipropionic acid esters of formula VIII;