DK147051B - METHOD OF ANALOGUE FOR PREPARING RACEMIC OR OPTICALLY ACTIVE 4- (2-BENZOFURANYL) -TETRAHYDROPYRIDINES OR PIPERIDINES OR ACID ADDITION SALTS THEREOF - Google Patents

Description

147051 i

The present invention relates to an analogous process for the preparation of novel racemic or optically active 4- (2-benzofuranyl) -tetrahydropyridines or -piperidines of the general formula 5 * 3- [jJLX "2-CV1 -" V'Nr xx : h -chox R 1 in 1 γ wherein R 1 is an alkyl group of 1-4 carbon atoms, 2-propynyl, 3 4 3-oxobutyl or cyclopropylmethyl, R and R are independently hydrogen, alkyl or alkoxy groups of not more than 4 carbon atoms . group, chloro, fluorine or bromine, wherein R can also be a cycloalk-1-enyl or cycloalkyl group 34 of 5-8 carbon atoms, or R and R together are a trimethylene or 1,3-butadienylene group, X and Y is individually a hydrogen atom or together an additional bond, however, R1 may not be methyl if R and R are hydrogen, or the acid addition salts thereof with inorganic or organic acids.

In the compounds of general formula I, R 1 is as an alkyl group of 1-4 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group.

3

The substituent R is as an alkyl or alkoxy group e.g. an ethyl, isopropyl, tert-butyl, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy group, most importantly, however, a methyl or methoxy group. As the cycloalk-1-enyl or 3 cycloalkyl group of 5-8 carbon atoms, R is e.g. a cyclohept-1-enyl, cyclooct-1-enyl, cycloheptyl or cyclooctyl group, preferably, however, a cyclopent-1-enyl or cyclopentyl group and, above all, a cyclohex-1-enyl or cyclohexyl group.

As alkyl or alkoxy groups R, e.g. the groups mentioned above as corresponding substituents R are considered.

3 4

A trimethylene group R + R is preferably in the 5,6-position, while a 1,3-butadienyl group R + R can be found in 5,6- or 6,7-, especially in 4, 5-position.

The compounds of general formula I and their addition salts with inorganic and organic acids have valuable pharmacological properties. They inhibit in rats and other test animals after oral and subcutaneous administration in the dose range 10 of from 2 to 100 mg / kg monoamine oxidase, especially selectively its A form, as shown by the results of the isotopic determination of enzyme activity. Also, in rats, by oral and subcutaneous administration of 2 to 100 mg / kg, they inhibit the uptake of norepinephrine into the heart and also inhibit the uptake of serotonin into rat midbrain synaptosomes. In addition, they inhibit the uptake of serotonin into human platelets in vitro depending on the concentration. Furthermore, by intraperitoneal administration to rats, they antagonize at doses of 2 to 40 mg / kg the effect of tetrabenazine.

Along with a favorable therapeutic index, the above properties characterize the compounds of general formula I and their pharmaceutically acceptable salts with inorganic and organic acids as antidepressants, e.g. can be administered orally or parenterally to treat depressive disorders.

The pharmacological effects of the compounds of the invention are illustrated in the following.

Determination of the monoamine oxidase inhibition;

The test compound is administered to rats at doses of 100 mg / kg per os and after 2 hours the rats are sacrificed. Liver homogenates and brain homogenates are prepared and determination of the oxidation inhibitory activity on isotopically labeled 5-hydroxytryptamine as substrate (monoamine).

3 U7051

The numerical values given in the table below indicate how many percent of the organ homogenates from rats which have been administered the test compound, ie. diminished oxidation constitutes the oxidation of the substrate 5-hydroxytryptamine caused by organ homogenizer 5 from untreated rats, cf. the method of R. J. Wurtman and J. Axelrod, Biochemical Pharmacology 12, 1439 (1963).

3

Determination of the uptake of H-serotonin (5-HT or 5-hydroxytryptamine) in rat midbrain synaptosomes.

10 a) In vitro experiments: Male rats mesencephalon and diencephalon (Tif: RAIf + (SPF), animal farm Sisseln, Switzerland) with a body weight of 200 g are homogenized in ice-cold, 0.32 molar sucrose solution (tissue: sucrose = 1: 10 ) in a teflon mill using the method of Whittacker 15 [Handbook of Neurochemistry, Vol. 2, pages 327-364, publisher A.Lajtha, Plenum Press, London 1969]. The homogenate is centrifuged twice at 1000 G for 10 minutes. To 0.1 ml aliquots of the above suspension is added 1 ml of Cancer Solution [according to Besson et al., Proc.Natl.Acad.Sci., 62, 20741-748, 1969, composition in mmol / 1: NaCl 126, KCl 2.4,

MgCl2 0.8, Na2SO4 0.5, CaCl2 1.1, KH2PO4 0.5, D-glucose 5.9,

NaHCO, 27.4, ascorbic acid 0.6, EDTA 0.07, pargylin 0.08, J 3 equilibrated with 5% CO 2 in O 2]. H-Serotonin with a specific activity of 30.1 Ci / mmol, Radiochemical Center, Amersham, England, is added to the final concentration of -9 2.5 moles of serotonin in a total volume of 1.3 ml required. The incubation tubes are filled with carbon monoxide, closed and incubated for 6 minutes at 37 ° C. Incubation is interrupted upon cooling to 0 ° C. The synaptosomes are separated by millipore filter (0.5 µm), the filter dried and counted in 15 ml of toluene containing 0.6%.

By adding different appropriate amounts of the test compound during the incubation, the amount of -6 in micromoles (10 moles) per micron is determined. sample which reduces the uptake of 4-HT by 5% by 50% compared to control samples.

b) In the ex-vivo experiments, brains from rats (n = 6) were used, which 1 hour before was administered the desired dose of the test compound (100 mg / kg per os). Determination of the uptake of 5-HT by the test compound decreased as a percentage of the uptake of midbrain synaptomas from untreated control animals.

Potentiation of L-5-hydroxytryptophan (L-5-HTP)

The potentiation of L-5-HTP is determined by the main shake induced by this substance in mice. Male mice (TiVa: MAGf, weight 18-22 g) in groups of 20 animals per day. dose of each test compound and as control animal is first administered sub-cutant 25 mg / kg pargyline and 2 hours later intraperitoneally 15 mg / kg L-5-HTP. In between, administration of the test compound is done and per 1 hour before L-5-HTP. The control animals are injected with a sodium chloride solution.

Thirty minutes after the injection of L-5-HTP, in each group, the number of mice exhibiting head shaking over 2 minutes is determined. The statistical determination is made by means of the quadruplicate test, n- ^ = n2 = 20, as DEmin is indicated ^ a lowest dose with significant effect (p <0.01), dose levels 1, 3, 10, 30, 100 mg / kg, cf.

S.J.Corne, R.W.Pickering, B.I.Warner, Br.J.Pharmacol. 20, 106-120 (1963).

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conclusion

The compounds of the invention have a mostly potent, at least pronounced monoamine oxidase inhibitory effect. This is accompanied by a serotonin uptake inhibitory effect, which is particularly pronounced in compounds II and XIV, which have less potent MAO inhibitory activity, while compound VIII is characterized by uniformly high efficacy levels in all three test types.

H.J.Ziegler et al. in Chimie Thérapeutique (Chimi-10ca Therapeutica) 1971 (3), pages 159-166, describes the preparation and pharmacological study of 4- (2-benzofuranyl) and 2- (2-benzofuranyl) pyridines. As hydrogenated derivatives, 1-methyl-4- (2-benzofuranyl) -1,2,3,6-tetrahydropyridine (compound 9n) and 1-methyl-4- (2-benzofuranyl) -piperidine (compound 9o). Table IV on page 161 of this article shows that some of the studied 4- and 2- (2-benzofuranyl) pyridines and the compound 9 n have some neuro-depressant effect (seen by the decrease in motor activity in mice and the potentiation of barbiturate anesthesia on 20 mice). For the compound 9 o no pharmacological data are given.

On the basis of the information in Table IV and the results of a large number of further tests with 4- (2-benzofuranyl) -pyridine (pyridarone, compound 9h), it was surprising that the compounds prepared according to the invention general formula I showed the above pharmacological properties corresponding to a pronounced anti-depressant effect.

Of particular importance are compounds of general formula I, wherein R is hydrogen, fluoro, chloro or bromo, an alkyl or alkoxy group having no more than 4 carbon atoms or a cycloalk-1-enyl or cycloalkyl group having 5 to 8 carbon atoms. 4 atoms, preferably in the 5-position, and R is hydrogen or an alkyl group having a maximum of 4 carbon atoms, the latter 3

tea preferably next to a winner the definition of R

3 4 -alkyl group at the 6-position or where R + R means a 1,3-butadienyl group at the 4,5-position or a 5-trimethylene group at the 5,6-position and X and Y together represent an additional bond or preferably hydrogen. Particularly important are compounds of formula I wherein R is hydrogen, chlorine, bromine or a methyl or methoxy group, 4 preferably in the 5-position, R is hydrogen or, more preferably, next to a methyl group R , a methyl group, and X and Y represent an additional bond or preferably hydrogen. Particularly important compounds of the general formula I are those wherein R 1 represents a methyl group or 34 a 2-propynyl group, while R, R, X and Y have the above-mentioned restricted or, above all, the above-specified meanings, whereby the conditions specified for the presence of a methyl group R1 must be observed.

The process of the invention for the preparation of the 4- (2-benzofuranyl) -tetrahydropyridines or 20-piperidines of the general formula I or their acid addition salts is characterized by a) reacting a compound of the general formula E3_f || - j] / H2-CH2n l X 11-C NH (II) 4 X / CH CH2

R Y

Wherein R, R, X and Y are as defined in the general formula I, with a reactive ester of a hydroxy compound of the general formula HO - R1 (III) wherein R with a methyl group, if R and R in formula II are hydrogen, or under reducing conditions with an oxo-alkane having not more than 4 carbon atoms or adding a compound of general formula II to methyl vinyl ketone or 5 b) in a compound of the general formula r- £ U <2 ™ 04 X CH-CH 2 R / 2

Y

lb 1

wherein R is a group corresponding to the definition of R

except for a primary methylene group and furthermore with the exception of an acetonyl group, or also, if at least one of the symbols R and R is not hydrogen, means an alkoxy group having a maximum of 4 carbon atoms, and R, R, X and Y has the meanings of formula I, reduces the carbonyl group or the akoxycarbonyl group or c) reduces a compound of the general formula cf \ - Θ 15 r3-- new - v (v) wo R4 Θ wherein Z is a monovalent anion or norma lascivent one of lc a polyvalent anion, R is a group corresponding to dif 1 3 4

the addition of R with the exception of 3-oxobutyl, and R and R

has the meaning given under formula I, in part, to the corresponding compound of general formula I wherein X and Y represent an additional bond, or 1 hydrogenates a compound of the above general formula V or a compound of the general formula 147051 10 formula I belongs to the general formula

3 fil 11 CH, -CH

~ T! Wherein R has the meaning given by formula V and R 4 and R have the meaning given by formula I catalytically to the corresponding pyridine compound or ) splits water from a compound of the general formula R3® ^ Π-fT CH0-CHo LJJ-c 'VRla (VI) SCH-CH / R4 / 2

V

"in.

3 s wherein R is a 1-hydroxycycloalkyl group having 5-8 Carla 4 bon atoms and R, R, X and Y have the meaning given by Formula I, using the racemate or an isolated antipode of an optically active starting substance or in the presence of diastereomeric, a racemate mixture, a particular racemate or optionally an isolated antipode, optionally in the form of a salt, optionally splits an isomeric mixture obtained as isomeric mixture (racemate mixture) in a manner known per se in the two stereoisomeric racemates and / or cleave an obtained racemate in a manner known per se in the antipodes and, if desired, converting a compound of the general formula I into an acid addition salt by an inorganic salt by one of the methods set out in (a) to (e) or organic acid, or converting an obtained acid addition salt into the free base.

147051 11

As reactive esters of compounds of general formula III for the reaction with compounds of general formula II according to process a) are suitable e.g. the hydrogen halide esters, especially the chlorides> bromides and iodides, further lower alkanesulfonic acid esters and arylsulfonic acid esters such as methanesulfonic acid esters or benzenesulfonic acid and p-toluenesulfonic acid esters, as well as esters of other strong acids, e.g. sulfuric acid esters such as dimethyl sulfate and diethyl sulfate. The reactions of compounds of the general formula II are preferably carried out in the presence of an acid-binding agent in an inert organic solvent under the reaction conditions. Suitable as acid-binding agents are tertiary organic bases such as triethylamine, pyridine, symcollidine and, above all, ethyl diisopropylamine, or unusual alkaline substances such as sodium or potassium carbonate. lower alkanols such as methanol, ethanol, isopropanol or butanol, ether-like compounds such as dioxane, tetrahydrofuran or 2-methoxyethanol, lower aliphatic ketones such as methyl ethyl ketone, and N-substituted acid amides such as dimethylformamide or Ν, Ν, Ν ', N 1, N ', N "-hexamethylphosphorsyre triamide. The reaction temperature is between ca. 0 to 200 ° C, preferably between room temperature and approx. 120 ° C. The reaction temperatures required for reactive esters of primary hydroxy compounds are most often at the lower limit of the indicated ranges, while reactions with reactive esters of non-primary hydroxy compounds must most often be carried out at higher temperatures and, if necessary, in closed reaction vessels, whereby use of a particularly effective acid binding agent such as ethyl diisopropylamine is advantageous.

Reactions of compounds of the general formula II with oxoalkanes having a maximum of 4 carbon atoms can e.g. is carried out in formic acid at temperatures of between approx. 70 and 100 ° C, or optionally also under the influence of hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum oxide or palladium coal, at normal or moderate elevated pressures and temperatures in an organic solvent, such as ethanol or dioxane. As oxoalkanes, aliphatic aldehydes or ketones having 1-4 and 3-4 carbon atoms are used, respectively. Above all, however, if, in the compound of formula II used as the reaction component, at least one of the groups R and R is different from hydrogen, formaldehyde, which is preferably used with formic acid as a reducing agent.

The addition of compounds of general formula II to methyl vinyl ketone is carried out e.g. in an inert organic solvent, such as benzene, at room temperature or, if necessary, under heating.

Reactive esters of hydroxy compounds of the general formula III as well as the corresponding oxoalkanes are known in large numbers, and several can be prepared analogously to the known compounds. The preparation of the starting materials of general formula II is explained below.

The reduction of the amide group in compounds of the general formula IV according to b) occurs e.g. by means of lithium aluminum hydride or diborane in an ethereal solvent, such as diethyl ether, tetrahydrofuran, dibutyl ether or diethylene glycol diethyl ether or mixtures thereof, at temperatures of between ca. 20 and 100 ° C or the boiling temperature 25 of the reaction medium used if it is below 100 ° C. Diborane can either be prepared separately and fed or formed from sodium borohydride and boron trifluoride etherate. The preparation of starting materials of general formula IV is explained below.

The partial reduction of compounds of the general formula V according to c) is preferably carried out by means of sodium or potassium borohydride in organic aqueous medium, e.g. to the proposed solution of the starting compound of the general formula V in an organic water-miscible solvent, e.g. a lower alkanol, such as methanol or ethanol or mixtures thereof with water, gradually adds an aqueous solution of sodium borohydride and then allows the reaction mixture to continue for some time, maintaining a reaction temperature of between ca. 5 and 60 ° C, preferably from room temperature up to 35 ° C. The preparation of the starting materials of general formula V is explained below.

The catalytic hydrogenation of compounds of general formulas V and Ia can be carried out using the usual hydrogenation catalysts, e.g. precious metal catalysts such as palladium on carbon or platinum oxide, rhodium catalysts such as rhodium on coal or on alumina, or alloy skeletal catalysts such as Raney nickel in an inert organic solvent such as methanol, ethanol or dioxane at room temperature and normal pressure or moderately elevated temperatures up to approx. 100 ° C and elevated pressure until approx. 100 bar. The hydrogenation of the tetrahydropyridine derivatives of the general formula Ia is generally carried out under substantially milder conditions than the hydrogenation of compounds of the general formula V. For the hydrogenation of the latter compounds, in particular, rhodium-alumina catalysts are considered. The starting materials of the general formula Ia are prepared e.g. according to one of the aforementioned processes for the preparation of compounds of general formula I, preferably by the partial reduction of corresponding pyridinium salts mentioned in (c).

The water cleavages according to process e) are carried out in a manner known per se by heating the compounds of general formula VI with advantage in separating the formed water and preferably in the presence of a strong acid, e.g. sulfuric acid used in concentrated but low amounts, or p-toluenesulfonic acid. The water cleavage 5 can also be carried out by heating in an inert organic solvent, e.g. in a water immiscible solvent such as benzene, toluene or xylene, and advantageously under water separation.

The starting materials of formula VI for process e) 10 are prepared from compounds of general formula I, 3 wherein R is a chlorine or bromine atom. This is first converted, preferably by means of activated magnesium, to a chloro-magnesium or bromine magnesium group or replaced by an alkali metal compound such as butyl lithium with an alkali metal ·, especially a lithium atom, whereby as a solvent e.g. an ether such as diethyl ether or tetrahydrofuran is used. The metal compound formed is then reacted in the same medium or optionally with the addition of an inactive solvent such as benzene with a cycloalkanone having 5-7 carbon atoms, e.g. at temperatures between -10 ° C and the boiling temperature of the reaction medium.

The starting materials not included in the general formula I and not already mentioned above for the above-mentioned processes can be prepared in several steps from compounds of the general formula 'IOU-o · R4 3 4 wherein R and R have the meaning given in formula I . Of the latter compounds, unsubstituted 4- (2-benzofuranyl) -pyridine and in the benzene ring with chlorine or methyl-substituted analogs and their hydrochlorides are already described in Swiss Patent No. 451,963 (cf. also French Patent No. 5337 M and U.S. Patent No. 3,470,192).

The method of manufacture disclosed in the Swiss patent is based on optionally substituted salicylaldehyde, first corresponding to an already known method (J.Org.

Chem. 21, 1039-1041 (1956)) are condensed with 4-picoline in acetic anhydride to the acetic ester of optionally similarly substituted o- [2- (4-pyridyl) vinyl] phenol. By bromine addition, the corresponding o- [1,2-dibromo-2- (4-10 pyridyl) ethyl] compounds are obtained, either cyclized directly by an alkali metal hydroxide or alcoholate in alcoholic solution to similar compounds with the general Formula VII or first with sodium acetate in acetic acid is converted to the corresponding o- [2-bromo-2- (4-pyridyl) vinyl] -15 compounds which can be cyclized quite analogously to compounds of the general formula VII.

According to another reaction series described in Swiss Patent No. 501,610, optionally substituted salicylic aldehyde is transferred to its methyl ether, this reduced to the corresponding alcohol, the latter converted over the chloride to optionally substituted (o-methoxyphenyl) acetonitrile, this being condensed with optionally methyl substituted iso nicotinic acid ethyl ester to corresponding C-acylated (o-methoxyphenyl) -acetonitrile, and finally, an alkali metal compound of this nitrile is cyclized by the action of concentrated hydrogen bromide to the desired, optionally substituted 4- (2-benzofuranyl) pyridine.

A further series of reactions have now been found, leading to the starting materials of the general formula VII wherein the 2-benzofuranyl group is linked to the 4-position of the pyridine group, and which is also based on optionally substituted salicylic aldehyde, but which is simpler to conduct and shorter than the above known reaction sequences. The novel method consists in reacting a compound of the general formula — c = 0 R-Η Π (Vlla) 4XXoh

R

Wherein R and R are as defined in Formula I in the presence of an acid-binding agent with a 4- (halo-methyl) -pyridine, especially with 4- (chloromethyl) -pyridine or 4- (bromomethyl) -pyridine. , to an ether of the general formula

F

R 3 is C = ° (V11b) -O R4 34 wherein R and R are as defined in Formula I and cyclize this ether by heating in the presence or absence of a condensing agent. The compounds of formula VII thus obtained are, with the exception of the agents described in the aforementioned Swiss patents, novel substances.

The reaction of compounds of the general formula VIIa with 4- (chloromethyl) - or 4- (bromomethyl) pyridine can e.g.

15 is carried out in an inert organic solvent such as dimethyl fomamide in the presence of an acid-binding agent such as sodium or potassium carbonate at temperatures between about 50 and 150 ° C, preferably at approx. 70-100 ° C and, if desired, can be accelerated by the addition of a small amount of potassium or sodium iodide. The subsequent ring closure is carried out e.g. by heating the isolated but not necessarily purified compounds of the general formula VIIb to temperatures between ca. 240 and 320 ° C. However, the ring closure may also be carried out in the same operation 25 as the ether formation and under the reaction conditions necessary for this, or if necessary by heating for a longer period of time and / or to higher temperatures within the specified range, whereby an excess of acid binding agent can act as condensing.

From the compounds of the general formula VII, by quaternization with reactive esters of hydroxy compounds of the general formula III, the compounds of the general formula V. are obtained. The quaternization can be carried out in the usual manner in an inert organic solvent, e.g. the alkanol which also forms the reactive ester, e.g. ethyl acetate, tetrahydrofuran or dioxane at room temperature or moderately elevated temperature up to approx. 100 ° €.

Starting materials of the general formula II can e.g. is prepared from similar compounds of the general formula I in which R 1 is a methyl group, or from analogous compounds with other readily leaving groups, such as an allyl or benzyl group, by reaction with chloroformic acid esters or thioesters, above all with chloroformic acid ethyl ester, tert-butyl ester, benzyl ester, phenyl ester 20 or chlorothiomyric acid S-methyl ester, or with bromocyan or phosgene in an inert organic solvent in the heat, e.g. in toluene at its boiling temperature and subsequently alkaline or acidic hydrolysis. Instead of compounds of the general formula I, 1-methyl-4- (2-benzofuranyl) -1,2,3,6-tetrahydropyridine and 1-methyl-4- (2- benzofuranyl) -piperidine. Instead of the aforementioned carbonic acid derivatives, e.g. also use carboxylic acid halides, such as acetyl bromide or benzoyl chloride, however, the corresponding reaction 30 for cleavage of the methyl group usually requires more energetic conditions and it is less complete than e.g. using chloroformic acid ethyl ester and especially bromocyan.

The hydrolysis for compounds of the general formula II is carried out e.g. by prolonged heating with an alkali metal hydroxide, especially sodium or potassium hydroxide, in a hydroxy compound in the presence of a little water at temperatures of between ca. 80 and 200 ° C. As a reaction medium, e.g. ethylene glycol or a lower monoalkyl ether thereof, further by carrying out the hydrolysis in a sealed container also a lower alkanol such as methanol, ethanol or butanol. Furthermore, in particular, such compounds which are similar to those of the general formula I but which have been replaced by a cyano group can also be hydrolyzed by heating with a mineral acid in an organic aqueous or aqueous medium, e.g. by boiling for several hours in a mixture of 85% phosphoric acid and formic acid, or by several hours heating in 48% hydrogen bromide solution or in a hydrogen bromide-acetic acid mixture to ca. 60-100 ° C, preferably 60-70 ° C.

Starting materials of the general formula IV for the reduction according to b), especially those where X and Y together are an extra bond, can be prepared according to or analogous to the first step of the aforementioned preparation of starting materials of the general formula II using corresponding carboxylic acid halides from similar compounds of general formula I, above all those with a methyl group such as R 1, or from 1-methyl-4- (2-benzofuranyl) -1,2,3,6-tetrahydropyridine. However, it is more advantageous, in particular, to prepare compounds of general formula IV having hydrogen atoms such as X and Y starting from compounds of general formula II and acylating their imino group in the usual manner, e.g. by trading with similar, ie. with the definition of Rx conforming carboxylic acid halides in the presence of acid binding agents such as potassium carbonate, in an inert organic solvent such as dioxane, or in pyridine or mixtures thereof with inert organic solvents at room temperature or moderately elevated temperatures.

Starting materials of the general formula VI are furthermore obtained 3e e.g. optionally corresponding to the definition of R and 4 R substituted benzofurans, of which various are known, by reaction with alkali metal compounds such as butyl lithium, in situ and reaction of the obtained 2-alkali metal derivative of the benzofuran used with corresponding to the definition of R-substituted 4-piperidones, some of which are known and the others can be prepared analogously to the known compounds.

The present invention also relates to such modifications to the processes mentioned in a) to d) using the starting material in the form of a salt. If the necessary starting materials are optically active, then both racemates and the isolated antipodes may be used, or in case 10 of diastereomerism either racemate mixtures or certain racemates or similarly isolated antipodes. Such starting materials may also be used in the form of salts. Preferably, for starting the reactions in question, such starting materials are used which lead to the previously mentioned groups of end products.

Depending on process conditions and starting materials, the final products are obtained in free form or in the form of their acid addition salts. The acid addition salts of the compounds of the general formula I can be transferred in a manner known per se to the free bases, e.g. with basic agents, such as bases or ion exchangers. On the other hand, the compounds of the general formula I obtained according to the processes according to the invention may, in the usual manner, be transferred to their addition salts with inorganic or organic acids.

For example. to a solution of a compound of general formula I in an organic solvent is added the acid desired as a salt component. Preferably, for the reaction, organic solvents are selected in which the salt formed is heavily soluble so that it can be separated by filtration. Such solvents are e.g. ethyl acetate, methanol, ether, acetone, methyl ethyl ketone, acetone ether, acetone ethanol, methanol ether or ethanol ether.

147051 20

For use as pharmaceuticals, pharmaceutically acceptable acid addition salts can be used instead of free bases, i.e. salts with such acids, if the anions at the doses available are not toxic. Furthermore, it is an advantage if the salts to be used as drugs are well crystallizable and not or only slightly hygroscopic. For salt formation with compounds of general formula I, e.g. hydrogen chloride, bromide, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 10 2-hydroxyethanesulfonic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, phenylacetic acid,

The compounds of the present invention may, depending on the choice of starting materials and working methods, be available as optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, also as isomer mixtures (racemate mixtures). The obtained isomer mixtures (racemate mixtures) can be divided into the two stereoisomeric (diastereomeric) pure racemates on the basis of the physico-chemical differences between the constituents, in known manner. by chromatography and / or fractional crystallization.

Obtained racemates can be divided by known methods, e.g. by recrystallizing an optically active solvent, by microorganisms or by reacting with an optically active acid which forms salts with the racemic compound, and separating the salts thus obtained, e.g. on the basis of their various solubilities, in the diastereomers from which the antipodes can be released by the action of suitable agents. Particularly useful optically active acids are e.g. The D and L forms of tartaric acid, di-o-toluyl-tartaric acid, malic acid, almond acid, camphor sulfonic acid or quina acid. Advantageously, one isolates the most effective of the two antipodes.

147051 21

The active substances in question are administered orally, rectally or parenterally. The dosage depends on the mode of application, the species, the age and the individual condition. The daily doses of the free bases or pharmaceutically acceptable salts of the free bases are between 0.1 mg / kg and 10 mg / kg for warm blooded animals. Suitable dosage unit forms, such as dragees, tablets, suppositories or ampoules, preferably contain 5-100 mg of active ingredient.

The following examples further illustrate the present methods 10 of the invention.

Example 1.

10.0 g of 4- (2-benzofuranyl) -piperidine and 6.0 g of 3-bromopropylene are dissolved in 200 ml of methanol and after the addition of 50 g of potassium carbonate is stirred for 30 hours at room temperature. The reaction mixture is then filtered, the filter cake washed with 500 ml of chloroform and the combined filtrates evaporated in vacuo. The residue is dissolved in a little methylene chloride and chromatographed on 300 g of alumina (Activity II, neutral). The first fractions, eluted with a total of one liter of methylene chloride, contain 1- (2-propynyl) -4- (2-benzofuranyl) -piperidine. The base is recrystallized from hexane and then melted at 75-77 ° C. The hydrochloride prepared with a solution of hydrogen chloride in ethyl acetate is recrystallized from ethyl acetate and then melts at 203-205 ° C.

The starting 4- (2-benzofuranyl) -piperidine used can be prepared as follows: a) 146.4 g of salicylaldehyde, 196.8 g of 4- (chloromethyl) pyridine hydrochloride, 750 g of potassium carbonate and 2 g of potassium iodide are heated. in 3 liters of dimethylformamide with stirring for 15 hours 30 to 80-90 ° C. The solution is then suction filtered and the filter cake washed afterwards with 1 liter of chloroform. The combined filtrates are evaporated in vacuo and the residue is dissolved in 1 liter of chloroform. The organic phase is first washed with 1 liter of 2 N sodium hydroxide solution and then with 1 liter of water, dried over sodium sulfate, filtered and evaporated.

The remaining crude o - [(4-pyridyl) -methoxy] -benzaldehyde 5 is further processed without purification.

b) 290 g of o - [(4-pyridyl) methoxy)] benzaldehyde are heated for 30 minutes at 300 ° C under nitrogen. After cooling, the residue is dissolved in a little methylene chloride and chromatographed over 3 kg of alumina (Activity II, neutral). The first fraction, eluted with 4 liters of methylene chloride, is 4- (2-benzofuranyl) pyridine. The compound melts after recrystallization of ethanol at 132-133 ° C.

c) 81.0 g of 4- (2-benzofuranyl) -pyridine are dissolved in 1.5 liters of ethanol and hydrogenated in the presence of 10.0 g of palladium carbon (5%) at a temperature between 70 and 80 ° C and an initial pressure of 80 bar. After 15 hours, 25.8 liters of hydrogen are absorbed. The hydrogenation is quenched, the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is fractionally distilled in high vacuum. The distillation fraction at 20 122 to 129 ° C and 0.10 mm Hg is 4- (2-benzofuranyl) -piperidine. The hydrochloride prepared with a solution of hydrogen chloride in ethyl acetate melts after recrystallization of acetone at 228-230 ° C.

Example 2.

In the same manner as in Example 1, 11.4 g of 4- (5,6-dimethyl-2-benzofuranyl) -piperidine 1- (2-propynyl) -4- (5,6-dimethyl-2-benzofuranyl) are obtained. ) -piperidine with m.p. 104-106 ° C and its hydrochloride, m.p. 231-233 ° C.

The starting material can be prepared as follows: Dissolve 43 g of 1-methyl-4- (5,6-dimethyl-2-benzofuranyl) -piperidine (see Example 18) in 800 ml of toluene and 80 g of chloromyric acid ethyl ester are added. The solution is heated for 15 hours with stirring to a boil, whereby a smaller portion of the toluene is distilled off in the first hour for faster removal of the released methyl chloride and then the reflux of the toluene is completely refilled. The solution is then cooled to 20 ° C, filtered and the residue is washed with 100 ml of toluene. The combined filtrates are washed successively with 500 ml of water, 1000 ml of a 10% solution of methanesulfonic acid in water, 1000 ml of water, 500 ml of 2 N aqueous sodium 10 hydroxide solution and 500 ml of water, dried over sodium sulfate, filtered and evaporated. The residual crude 4- (5,6-dimethyl-2-benzofuranyl) -1-piperidinecarboxylic acid ethyl ester melts after recrystallization of pentane at 96-97 ° C.

36.5 g of 4- (5,6-dimethyl-2-benzofuranyl) -1-piperidinecarboxylic acid ethyl ester are dissolved in 150 ml of ethylene glycol. After the addition of 70 g of solid sodium hydroxide, the cloudy solution is heated under vigorous stirring for 15 hours to 160 ° C. The reaction solution is then cooled to 20 ° C and extracted twice, each time with 500 ml of ethyl acetate. The organic phases 20 are washed five times, each time with one liter of water, dried over sodium sulfate, filtered and evaporated. The residue is dissolved in 300 ml of a 10% solution of methanesulfonic acid in water and the acid solution is extracted with ether. The aqueous solution is then adjusted by adding 10% sodium hydroxide solution to pH 12 and extracted with one liter of chloroform. The chloroform solution is dried over sodium sulfate, filtered and evaporated to give the crude 4- (5,6-dimethyl-2-benzofuranyl) -piperidine. The hydrochloride is prepared with hydrogen chloride in ethyl acetate and recrystallized from methanol-ethyl acetate, which is obtained as hydrate, melting at 230-233 ° C.

Example 3

5.8 g of 4- (2-benzofuranyl) -piperidine (see Example 1c)), 27 ml of Ν, Ν-diisopropyl-ethylamine and 27 g of isopropyl bromide are refluxed in 100 ml of isopropanol for 15 hours. The solution is then evaporated in vacuo, the residue is dissolved in 500 ml of chloroform, and the organic phase is washed first with 500 ml of 1 N sodium hydroxide solution and then with 500 ml of water, dried over sodium sulfate, filtered and evaporated. The residual crude base with a solution of hydrogen chloride in ethyl acetate l -isopropyl-4- (2-benzofuranyl) -piperidine hydrochloride melts after recrystallization from ethyl acetate at 186-188 ° C.

Example 4.

A solution of 6.0 g of 4- (2-benzofuranyl) -piperidine (cf. Example 1c)) and 6.0 g of methyl vinyl ketone in 100 ml of benzene is stirred for 24 hours at room temperature. The solvent is then evaporated in vacuo (bath temperature maximum 45 ° C). To the residue is added a solution of hydrogen chloride in ethyl acetate and the resulting 1- (3-oxobutyl) -4- (2-benzofuranyl) -piperidine hydrochloride ([2- [4- (2-benzofuranyl) -piperidino] -ethyl ] methyl ketone hydrochloride) is filtered off.

It melts at 184-186 ° C.

Example 5.

To a refluxing solution of 13.5 g of lithium aluminum hydride in 200 ml of tetrahydrofuran is added a solution of 14.5 g of 1- (cyclopropylcarbonyl) -4- (2-benzofuranyl) -piperidine in 100 ml of tetrahydrofuran. After refluxing for 15 hours, the reaction mixture is cooled and the excess lithium aluminum hydride is decomposed at -10 ° C by means of 15 ml of water, 15 ml of 10% sodium hydroxide solution and 45 ml of water. The reaction solution is filtered, the filter cake is washed with 1 liter of chloroform and the combined filtrates are evaporated in vacuo. The residue is dissolved in 500 ml of 2N hydrochloric acid and the acid solution is washed with ether.

The aqueous solution is then adjusted by adding 10% sodium hydroxide solution to pH 12 and extracted with 1 liter of chloroform. The chlorophom solution is dried over sodium sulfate, filtered and evaporated to give the crude 1- (cyclopropylmethyl) -4- (2-benzofuranyl) -piperidine. After recrystallization of hexane, the free base melts at 68 ° C.

The hydrochloride is prepared with hydrogen chloride in ethyl acetate and recrystallized from ethyl acetate, whereupon it melts at 223-225 ° C.

Analogously, by reducing 16.0 g of 1- (cyclopropylcarbonyl) -4- (5,6-dimethyl-2-benzofuranyl) -piperidine 1- (cyclopropylmethyl) -4- (5,6-dimethyl) -2-benzofuranyl) -piperidine, m.p. 80-83 ° C and its hydrochloride, m.p. 184-186 ° C.

The 1- (cyclopropylcarbonyl) -4- (2-benzofuranyl) -piperidine used as a starting material can be prepared as follows: 12.1 g of 4- (2-benzofuranyl) -piperidine is dissolved in 250 ml of dioxane, and added to the solution 7 , 35 g of cyclopropane carbonyl chloride and 50 g of potassium carbonate. The reaction solution is stirred for 15 hours at room temperature. The reaction solution is then filtered, the filter residue is washed with 1 liter of chloroform and the combined filtrates are evaporated in vacuo. The residue is dissolved in 250 ml of ethyl acetate and the solution is washed successively with 2N hydrochloric acid, water, 2N ammonium hydroxide and water, dried over sodium sulfate, filtered and evaporated. The oily evaporation residue is, according to chromatographic analysis, uniform 1- (cyclopropylcarbonyl) -4- (2-benzofuranyl) -piperidine, which can be used for reduction with lithium aluminum hydride.

Analogously obtained from 13.7 g of 4- (5,6-dimethyl-2-benzofuranyl) -piperidine (cf. Example 2) 1- (cyclopropylcarbonyl) -4- (5,6-dimethyl-2-benzofuranyl) -piperidine .

Example 6

Analogously to Example 5, 8.0 g of 1-acetyl-4- (2-benzofuranyl) -piperidine in 100 ml of tetrahydrofuran is reduced by 12.0 g of lithium aluminum hydride in 150 ml of tetrahydrofuran, boiling the reaction mixture for 15 hours under reflux. . The crude 1-ethyl-4- (2-benzofuranyl) -piperidine obtained is transferred to the hydrochloride which after crystallization of ethyl acetate 5 melts at 198 ° 0.

The starting material is prepared as follows:

To a solution of 7.0 g of 4- (2-benzofuranyl) -piperidine (see Example 1c) in 100 ml of pyridine is added 150 ml of acetic anhydride, and first stirred for 15 hours at room temperature and then for 2 hours. hours at 45 ° C. The reaction mixture is then evaporated in vacuo, the residue is dissolved in ethyl acetate and this solution is washed successively twice with 2N hydrochloric acid, twice with 2N aqueous ammonia solution and twice with water, dried over sodium sulfate and evaporated. The remaining crude l-acetyl-4- (2-benzofuranyl) -piperidine can be processed directly. A pentane recrystallized sample of samples melts at 95-97 ° C.

Example 7

To a solution of 70 g of 1-methyl-4- (5-chloro-2-benzofuranyl) -20 pyridinium iodide in 500 ml of methanol is added dropwise with stirring and external cooling a solution of 70 g of sodium borohydride in 150 ml of water so that the reaction temperature does not rise above 35 ° C. The solution is then stirred for 20 hours at room temperature. The methanol is then evaporated in vacuo, the residual aqueous phase is extracted twice, each time with 500 ml of chloroform. The chloroform solution is dried over sodium sulfate, filtered and evaporated. The obtained 1-methyl-4- (5-chloro-2-benzofuranyl) -1,2,3,6-tetrahydropyridine is recrystallized from hexane and then melts at 108-118 ° C. The hydrochloride prepared from it with a solution of hydrogen chloride in ethyl acetate melts after recrystallization from ethyl acetate at 266 ° C.

Analogously, 78.2 g of 1-methyl-4- (5-bromo-2-benzofuranyl) -pyridinium iodide 1-methyl-4- (5-bromo-2-benzofuranyl) -1,2 are obtained. , 3,6-tetrahydropyridine, m.p.

129 ° C.

The starting materials can be prepared as follows: a) 210 g of 5-chlorosalicylaldehyde, 220 g of 4- (chloromethyl) pyridine hydrochloride, 750 g of potassium carbonate and 3.3 g of potassium iodide are heated in 2 liters of dimethylformamide with stirring for 20 hours to 80 ° C. The solution is then filtered and the filter residue is washed with 1 liter of chloroform. The combined filtrates are evaporated in vacuo and the residue is dissolved in 1 liter of chloroform. The organic phase is first washed twice, each time with 1 liter of 2N sodium hydroxide solution and then with 1 liter of water, dried over sodium sulfate, filtered and evaporated. The remaining crude 2 - [(4-pyridyl) -methoxy] -5-chlorobenzaldehyde is further processed without purification.

b) 272 g of 2 - [(4-pyridyl) methoxy] -5-chlorobenzaldehyde are heated for 30 minutes under nitrogen to 300 ° C. After cooling, the residue is dissolved in a little methylene chloride and chromatographed on 2 kg of alumina (Activity II, neutral). The first fraction eluting with 5 liters of methylene chloride is 4- (5-chloro-2-benzofuranyl) pyridine. The compound melts after recrystallization of ethanol at 132-133 ° C. The hydrochloride prepared with a solution of hydrogen chloride in ethyl acetate melts after recrystallization of ethyl acetate at 265 ° C.

c) Dissolve 142 g of 4- (5-chloro-2-benzofuranyl) -pyridine in 450 ml of methanol and stir with 300 ml of methyl iodide for 15 hours at 40-45 ° C. The solution is then cooled to 0 ° C and the separated salt is filtered off. The filter cake is washed afterwards with 500 ml of isopropanol. After recrystallization from isopropanol, 1-methyl-4- (5-chloro-2-benzofuranyl) -pyridinium iodide melts at 258-260 ° C.

147051 28

Analogously to a), the crude 2 - [(4-pyridyl) methoxy] -5-bromosalicyl aldehyde is obtained using 269 g of 5-bromo-salicylaldehyde and from 320 g of this crude product analogous to b) 4- ( 5-bromo-2-benzofuranyl) -pyridine, m.p. 156-158 ° C, and finally analogous to c) from 168 g of 4- (5-bromo-2-benzofuranyl) -pyridine 1-methyl-4- (5-bromo-2-benzofuranyl) -pyridine nium iodide with m.p. 266-270 ° C.

Example 8.

To a solution of 44.3 g of 1-methyl-4- (5-methoxy-2-benzo-furanyl) -pyridinium iodide in 350 ml of methanol is added dropwise with stirring and external cooling a solution of 40 g of sodium borohydride in 100 ml. ml of water so that the reaction temperature does not rise above 35 ° C. The solution is then stirred for 20 hours at room temperature. The methanol is then evaporated in vacuo, the remaining aqueous phase is extracted twice, each time with 500 ml of chloroform. The chlorophom solution is dried over sodium sulfate, filtered and evaporated. The 1-methyl-4- (5-methoxy-2-benzofuranyl) -1,2,3,6-tetrahydropyridine obtained is recrystallized from cyclohexane and then melts at 99-101 ° C.

The hydrochloride prepared from a solution of hydrogen chloride in ethyl acetate melts after recrystallization of ethyl acetate at 238 ° C.

The starting material can be prepared as follows: a) 65.6 g of 5-methoxysalicylaldehyde, 74 g of 4- (chloromethyl) -25 pyridine hydrochloride, 280 g of potassium carbonate and 2 g of potassium iodide are heated in 800 ml of dimethylformamide for 20 hours to 100 ° C. The solution is then filtered and the filter cake washed afterwards with 1 liter of chloroform. The combined filtrates are evaporated in vacuo and the residue is dissolved in 1 liter of chloroform.

The organic phase is first washed with 500 ml of 2 N sodium hydroxide solution and then with 1 liter of water, dried over sodium sulfate, filtered and evaporated. The remaining 4- (5-methoxy-2-benzofuranyl) -pyridine melts after recrystallization from ethyl acetate at 123 ° C. The hydrochloride prepared with a solution of hydrogen chloride in ethyl acetate is recrystallized from ethyl acetate and then melts at 228 ° C.

b) 29.4 g of 4- (5-methoxy-2-benzofuranyl) -pyridine are dissolved in 250 ml of methanol and stirred with 100 ml of methyl iodide for 15 hours at 40-45 ° C. The solution is then cooled to 20 ° C, stirred with activated charcoal and filtered over purified diatomaceous earth. The filtrate is evaporated in vacuo and the residue is recrystallized from isopropanol. The obtained 1-methyl-10 4- (5-methoxy-2-benzofuranyl) -pyridinium iodide melts at 210-212 ° C.

Example 9

To a solution of 91.0 g of 1-methyl-4- (7-methoxy-2-benzo-furanyl) -pyridinium iodide in 1500 ml of methanol is added dropwise with stirring and external cooling a solution of 40.0 g of sodium borohydride in 160 ml of water so that the reaction temperature does not rise above 35 ° C. The solution is then stirred for 20 hours at room temperature. The methanol is then evaporated in vacuo, the remaining aqueous phase is extracted twice, each time with 500 ml of methylene chloride. The methylene chloride solution is dried over sodium sulfate, filtered and evaporated. The residue is dissolved in a little methylene chloride and chromatographed on 900 g of alumina (Activity II, neutral). The first fraction eluted with 3 L of methylene chloride is 1-methyl-4-25 (7-methoxy-2-benzofuranyl) -1,2,3,6-tetrahydropyridine. The free base melts after recrystallization of pentane at 89-92 ° C. The hydrochloride prepared with a solution of hydrogen chloride in ethyl acetate melts after recrystallization from ethyl acetate at 246-248 ° C.

Similarly, 98.8 g of 1-methyl-4- (5,6-dimethoxy-2-benzofuranyl) -pyridinium iodide (cf. d)) are obtained 1-methyl-4- (5,6-dimethoxy) -2-benzofuranyl) -1,2,3,6-tetrahydro-pyridine, m.p. 139-141 ° C and its hydrochloride, m.p. 234-236 ° C.

147051 30

The starting materials can be prepared as follows: a) 106.5 g of ortho-vanillin, 116 g of 4- (chloromethyl) pyridine hydrochloride, 420 g of sodium carbonate and 2 g of sodium iodide are heated in 1000 ml of dimethylformamide for 15 hours to 90-95 ° C. .

The mixture is then filtered and the filter cake washed afterwards with 1 liter of chloroform. The combined filtrates are evaporated in vacuo and the residue is dissolved in 1 liter of chloroform. The organic phase is washed first with 500 ml of 2N sodium hydroxide solution and then with 1 liter of water, dried over sodium sulfate, filtered and evaporated. The residue is a mixture of 4- (7-methoxy-2-benzofuranyl) -pyridine and 2 - [(4-pyridyl) -methoxy] -3-methoxybenzaldehyde and is further processed without purification.

b) 140 g of the mixture obtained in (a) are heated under nitrogen for 4 minutes to 250 ° C. After cooling, the residue is dissolved in a little methylene chloride and chromatographed over 2000 g of alumina (Activity II, neutral). The first fraction eluted with 4 liters of methylene chloride is 4- (7-methoxy-2-benzofuranyl) -pyridine. The compound melts after recrystallization of ether at 138-141 ° C. The hydrochloride prepared with a solution of hydrogen chloride in ethyl acetate melts at 240-242 ° C.

Analogously to a), a crude mixture of 2 - [(4-pyridyl) methoxy] -4,5-dimethoxybenzaldehyde and its cyclization product is obtained from 127.5 4,5-dimethoxysalicyl aldehyde.

This mixture is transferred analogously to b) completely to 4- (5,6-dimethoxy-2-benzofuranyl) pyridine with m.p. 129-133 ° C, hydrochloride m.p. 241-242 ° C.

c) 60 g of 4- (7-methoxy-2-benzofuranyl) -pyridine are dissolved in 750 ml of methanol and stirred with 150 ml of methyl iodide for 15 hours at 40-45 ° c.

147051 31

The solution is then cooled to 0 ° C and the crystals are filtered off. The 1-methyl-4- (7-methoxy-2-benzofuranyl) pyridinium iodide thus obtained melts after recrystallization of ethanol at 219 ° C.

D) Similar to Example 8, 33.3 g of 4- (5,6-dimethoxy-2-benzofuranyl) -pyridine 1-methyl-4- (5,6-dimethoxy-2-benzofuranyl) are obtained. ) -pyridinium iodide with m.p. 268-270 ° C.

Example 10.

To a solution of 125 g of 1-methyl-4- (5-methyl-2-benzo-furanyl) -pyridinium iodide in 750 ml of methanol is added dropwise with stirring and external cooling a solution of 60 g of sodium borohydride in 150 ml of water. so that the reaction temperature does not rise above 35 ° C. The solution is then stirred for 20 hours at room temperature. The methanol is then evaporated in vacuo, the residual aqueous phase is extracted twice, each time with 500 ml of chloroform. The chloroform solution is dried over sodium sulfate, filtered and evaporated. The 1-methyl-4- (5-methyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine obtained is recrystallized from diisopropyl ether and melted at 102 ° C. The hydrochloride prepared with a solution of hydrogen chloride in ethyl acetate melts after recrystallization of ethyl acetate at 243 ° C.

The starting material can be prepared as follows: a) 173.8 g of 5-methylsalicylic aldehyde, 210 g of 4- (chloromethyl) pyridine hydrochloride, 620 g of potassium carbonate and 7 g of potassium iodide are heated in 1000 ml of dimethylformamide with stirring for 20 hours until 80-90 ° C. The solution is then filtered and the filter cake is evaporated with 500 ml of dimethylformamide in vacuo and the residue is dissolved in 1 liter of chloroform.

The organic phase is first washed with 1 liter of 1 N sodium hydroxide solution and then with 1 liter of water, dried over sodium sulfate, filtered and evaporated. The residual oil is a mixture of 2 - [(4-pyridyl) -methoxy] -5-methyl-benzaldehyde and 4- (5-methyl-2-benzofuranyl) -pyridine and distilled in high vacuum. The distillation fraction at 170-190 ° C and 0.1 mm Hg is dissolved for further purification in a little methylene chloride and chromatographed over 3 kg of alumina (Activity II, neutral). The first fraction eluted with 4 liters of methylene chloride is 4- (5-methyl-2-benzofuranyl) -pyridine. The compound melts after recrystallization of 10 pentane at 160-162 ° C.

b) Dissolve 80 g of 4- (5-methyl-2-benzofuranyl) -pyridine in 150 ml of methanol and stir with 150 ml of methyl iodide for 15 hours at 40-45 ° C. The solution is then cooled to 0 ° C and the separated salt is filtered off. The filter cake is washed with 500 ml of ethanol.

After recrystallization from methanol, 1-methyl-4- (5-methyl-2-benzofuranyl) -pyridinium iodide melts at 198-200 ° C.

Example 11.

To a solution of 65.5 g of 1-methyl-4- (naphtho [2,1-b] furan-2-yl) -pyridinium iodide in 900 ml of methanol is added dropwise with stirring and external cooling a solution of 27 0 g of sodium borohydride in 110 ml of water so that the reaction temperature does not rise above 30 ° C. The solution is then stirred for another 15 hours at room temperature. The methanol is then evaporated in vacuo, the residual aqueous phase is extracted twice, each 25 times with 500 ml of chloroform. The chloroform solution is dried over sodium sulfate, filtered and evaporated. The oil thus obtained is dissolved in 150 ml of methylene chloride and chromatographed on 1 kg of alumina (Activity II, neutral). The first fractions eluted with 2 liters of methylene chloride contain 1-methyl-4- (naphtho [2,1-b] furan-2-yl) -1,2,3,6-tetrahydropyridine. The free base is recrystallized from hexane and melts at 120-122 ° C. The hydrochloride prepared from it with a solution of hydrogen chloride in ethyl acetate melts after recrystallization of ethyl acetate at 277 ° C.

U7051 33

The starting material can be prepared as follows: a) 83.4 g of 2-hydroxy-naphthaldehyde, 79.3 g of 4- (chloromethyl) pyridine hydrochloride, 300 g of potassium carbonate and 2.5 g of potassium iodide are heated in 800 ml of dimethylformamide under stirring for 20 hours to 100 ° C. The solution is then filtered and the filter residue washed afterwards with 1 liter of chloroform.

The combined filtrates are evaporated in vacuo and the residue is dissolved in 1 liter of chloroform. The organic phase is first washed twice, each time with 1 liter of 2 N sodium hydroxide solution and then with 1 liter of water, dried over sodium sulfate, filtered and evaporated. The remaining crude 2- [(4-pyridyl) -methoxy] -1-naphthaldehyde is re-processed without purification.

b) 93.0 g of 2 - [(4-pyridyl) methoxy] -1-naphthaldehyde is heated for 30 minutes under nitrogen to 300 ° C. After cooling, the residue is dissolved in a little methylene chloride and chromatographed on 2 kg of alumina (Activity II, neutral). The first fraction eluted with 3 liters of methylene chloride is 4- (naphtho [2,1-b] furan-2-yl) -pyridine. The compound melts after recrystallization of ethyl acetate at 137-139 ° C. The hydrochloride prepared from it with a solution of hydrogen chloride in ethyl acetate melts after recrystallization of ethyl acetate at 295-300 ° C.

c) Dissolve 51.0 g of 4- (naphtho [2,1-b] furan-2-yl) -pyridine in 750 ml of methanol and stir with 100 ml of methyl iodide for 20 hours at 40-45 ° C. The solution is then cooled to 0 ° C and the separated salt is filtered off and washed with 150 ml of isopropanol.

After recrystallization from isopropanol, the obtained 1-methyl-4- (naphtho [2,1-b] furan-2-yl) -pyridinium iodide melts at 310-315 ° C (with decomposition).

Example 12.

112 g of 1-methyl-4- (5-chloro-2-benzofuranyl) -1,2,3,6-tetrahydro-pyridine (cf. Example 7) is dissolved in 2.3 liters of methanol and hydrogenated in the presence of 11 g of platinum oxide at a temperature of 20-30 ° C and under normal pressure. After 9 hours, 9.87 liters of hydrogen is absorbed, which is exactly 5 of the absorption of the theoretical amount of hydrogen. The hydrogenation is quenched, the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is dissolved in a little chloroform and chromatographed on 600 g of alumina (Activity II, neutral). The first fraction eluting with 2 liters of chloroform is 1-methyl-4- (5-chloro-2-benzofuranyl) -piperidine.

This melts after recrystallization of hexane at 107 ° C.

The hydrochloride prepared from a solution of the base with a solution of hydrogen chloride in ethyl acetate melts at 260 ° C.

Analogously, 132 g of 1-methyl-4- (5-bromo-2-benzo-furanyl) -1,2,3,6-tetrahydropyridine (cf. Example 7) is obtained. bromo-2-benzofuranyl) -piperidine, m.p.

116-119 ° C and its hydrochloride, m.p. 272-275 ° C.

Example 13

20.0 g of 1-methyl-4- (5-methoxy-2-benzofuranyl) -1,2,3,6-tetrahydropyridine (cf. Example 8) are dissolved in 220 ml of methanol and hydrogenated in the presence of 4 g. palladium carbon catalyst (5% Pd) at a temperature of 40-50 ° C and under normal pressure. After 11 hours, the hydrogenation is quenched, the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is dissolved in a little chloroform, chromatographed on 400 g of alumina (Activity II, neutral). The first 2-liter chloroform-eluted fraction is 1-methyl-4- (5-methoxy-2-benzofuranyl) -piperidine. This melts after recrystallization of hexane at 68 ° C. The hydrochloride prepared from a solution of the base with a solution of hydrogen chloride in ethyl acetate melts at 282-284 ° C.

Analogously, hydrogenation of 24.7 g of 1-methyl-4- (5,6-dimethoxy-2-benzofuranyl) -1,2,3,6-tetrahydropyridine-1-methyl-4- (5) is obtained. 6-dimethoxy-2-benzofuranyl) -piperidine, m.p. 73-75 ° C and hence the hydrochloride with m.p. 228-231 ° C.

Example 14.

24.2 g of 1-methyl-4- (7-methoxy-2-benzofuranyl) -1,2,3,6-tetrahydropyridine (cf. Example 9) are dissolved in 200 ml of methanol and hydrogenated in the presence of 4 g of palladium. carbon catalyst (5¾ Pd) at a temperature of 40-50 ° C and under normal pressure. After 15 hours, the hydrogenation is quenched, the catalyst is filtered off and the filtrate is evaporated in vacuo. 1-Methyl-yl-4- (7-methoxy-2-benzofuranyl) -piperidine melts after recrystallization of pentane at 76-78 ° C. The hydrochloride 15 prepared from a solution of hydrogen chloride in ethyl acetate melts at 172-173 ° C.

Example 15

28.5 g of 1-methyl-4- (5-methyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine (cf. Example 10) are dissolved in 150 ml of methanol and hydrogenated in the presence of 60 g of Raney nickel at a temperature of between 90 and 95 ° C and an initial pressure of 100 bar. After 15 hours, exactly the theoretical amount of hydrogen is absorbed. The hydrogenation is quenched, the catalyst is filtered off and the filtrate is evaporated. 1-Methyl-4- (5-methyl-2-benzofuranyl) -piperidine melts after recrystallization of hexane at 88-90 ° C. The hydrochloride prepared from a solution of the base with a solution of hydrogen chloride in ethyl acetate melts at 186-189 ° C.

Example 16.

26.0 g of 1-methyl-4- (naphtho [2,1b] furan-2-yl) -1,2,3,6-tetrahydropyridine are dissolved in 300 ml of methanol and hydrogenated in the presence of 3 g of palladium. carbon catalyst (5% Pd) at a temperature of between 40 and 50 ° C and under normal pressure. After 2 hours, 2.27 liters of hydrogen is absorbed, which is exactly the same as the theoretical hydrogen consumption. The hydrogenation is quenched, the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is 1-methyl-4- (naphtho [2,1-b] furan-2-yl) -piperidine. This melts after recrystallization of pentane at 83-85 ° C. The hydrochloride prepared from a solution of the base with a solution of hydrogen chloride in ethyl acetate melts at 243 ° C.

The starting material is prepared according to Example 11.

Example 17

To a solution of 99 g of 1-methyl-4- (5,6-dimethyl-2-benzo-furanyl) -pyridinium iodide in 1500 ml of methanol is added dropwise with stirring and external cooling a solution of 45.0 g of sodium borohydride in 190 ml of water so that the reaction temperature does not rise above 35 ° C. The solution is then stirred for another 15 hours at room temperature. The methanol is then evaporated in vacuo, the remaining aqueous phase is extracted twice, each time with 750 ml of chloroform. The chloroform solution is dried over sodium sulfate, filtered and evaporated. The oily residue is recrystallized from cyclohexane to give 1-methyl-4- (5,6-dimethyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine, m.p. 124-126 ° C. The hydrochloride prepared with a solution of hydrogen chloride in ethyl acetate 25 melts after recrystallization of acetone at 231-233 ° C.

Analogously, 99 g of 1-methyl-4- (4,7-dimethyl-2-benzofuranyl) -pyridinium iodide 1-methyl-4- (4,7-dimethyl-2-benzofuranyl) -1,2 is obtained. 3,6-tetrahydropyridine, m.p. 69-71 ° C, hydrochloride m.p. 281-283 ° C and from 99 g of 1-methyl-4- (5,7-30 dimethyl-2-benzofuranyl) -pyridinium iodide 1-methyl-4- (5,7-dimethyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine, m.p. 99-102 ° C, hydrochloride m.p. 250-252 ° C, and from 102 g of 1-methyl-4- [5,6- (trimethylene) -2-benzofuranyl] -pyridinium iodide 1-methyl-4- [5,6- (trimethylene) -2 -benzofuranyl] -35 1,2,3,6-tetrahydropyridine and its hydrochloride.

37 14705 1

The starting materials can be prepared as follows: a) 58.5 g of 4,5-dimethylsalicylaldehyde, 64.0 g of 4- (chloromethyl) pyridine hydrochloride, 240 g of potassium carbonate and 2.0 g of potassium iodide are heated in 500 ml of dimethylformamide under stirring for 20 hours to 150-170 ° C. The reaction mixture is then filtered and the filter residue washed afterwards with 1 liter of chloroform. The combined filtrates are evaporated in vacuo and the residue is dissolved in 150 ml of methylene chloride and chromatographed on 2000 g of alumina (active II, neutral). The first fraction eluting with 2.8 liters of methylene chloride is 4- (5,6-dimethyl-2-benzofuranyl) pyridine. The compound melts after recrystallization of hexane at 168-170 ° C. The hydrochloride prepared from a solution of hydrogen chloride in methyl acetate 15 melts after recrystallization from ethyl acetate at 278-280 ° C.

Analogously, 58.5 g of 3,6-dimethylsalicylaldehyde 4- (4,7-dimethyl-2-benzofuranyl) -pyridine are obtained, m.p.

78-80 ° C, hydrochloride hydrate m.p. 266-269 ° C, from 58.5 g of 3,5-dimethylsalicylaldehyde 4- (5,7-dimethyl-2-benzofuranyl) pyridine, m.p. 107-109 ° C, hydrochloride m.p. 285 ° C, and from 62.8 g of 4,5- (trimethylene) -salicylaldehyde (6-hydroxy-5-indanecarboxaldehyde, cf. J. Ammer.Chem.Soc. 77, 2466-75) 4- [ 5,6- (trimethylene) -2-benzofuranyl] -pyridine, m.p. 90-92 ° C.

B) 79.0 g of 4- (5,6-dimethyl-2-benzofuranyl) -pyridine are dissolved in 750 ml of methanol and stirred with 100 ml of methyl iodide for 20 hours at 40-45 ° C. The solution is then cooled to -20 ° C and the separated salt is filtered off and washed with 150 ml of isopropanol. After recrystallization from isopropanol, the obtained 1-methyl-4- (5,6-dimethyl-2-benzofuranyl) -pyridinium iodide melts at 219-221 ° C.

Analogously, 79.0 g of 4- (4,7-dimethyl-2-benzofuranyl) -pyridine 1-methyl-4- (4,7-dimethyl-2-benzofuranyl) -pyridinium iodide are obtained. with m.p. 316-320 ° C, of 79.0 g of 4- (5,7-dimethyl-2-benzofuranyl) -pyridine 1-methyl-4- (5,7-dimethyl-2-benzofuranyl) -pyridinium iodide, m.p.

268-270 ° C and of 83.4 g of 4- [5,6- (trimethylene) -2-benzofuranyl] pyridine 1-methyl-4- [5,6- (trimethylene) -2-benzofuranyl] pyridinium iodide with m.p. 194-197 ° C.

Example 18.

139 g of 1-methyl-4- (5,6-dimethyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine (see Example 17) are dissolved in 1500 ml of methanol and hydrogenated in the presence of 14 g of palladium carbon catalyst (5% Pd) at a temperature of 20-25 ° C and under normal pressure. After 8 hours, the theoretically necessary amount of 13 liters of hydrogen is absorbed. The hydrogenation is quenched, the catalyst is filtered off and the filtrate is evaporated in vacuo. The remaining crude 1-methyl-4- (5,6-dimethyl-2-benzo-furanyl) -piperidine is recrystallized from cyclohexane and then melts at 122-124 ° C. The hydrochloride prepared from a solution of the base with a solution of hydrogen chloride in ethyl acetate melts at 205-207 ° C.

Analogously, from the same amounts of 1-methyl-4- (4,7-dimethyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine (see Example 17), 1-methyl-4- ( 4,7-dimethyl-2-benzofuranyl) -piperidine, whose hydrochloride melts at 242 ° C, and of 1-methyl-4- (5,7-dimethyl-2-benzofuranyl) -1,2,3,6-tetrahydro -25 pyridine (see Example 17) 1-methyl-4- (5,7-dimethyl-2-benzo-furanyl) -piperidine and its hydrochloride, m.p. 210-212 ° C.

Similarly, hydrogenation is obtained in the presence of 8 g of catalyst in 800 ml of methanol until up to 5 liters of hydrogen and otherwise analogous to 56.0 g of 1-methyl-4- [5,6-30 (trimethylene) -2-benzofuranyl ] -1,2,3,6-tetrahydropyridine (see Example 17) 1-methyl-4- [5,6- (trimethylene) -2-benzo-furanyl] -piperidine and its hydrochloride.

147051 39

Example 19.

100 g of 4- (5,6-dimethyl-2-benzofuranyl) -piperidine (see Example 2a)) are dissolved in 50 ml of formic acid. To this solution, 6 ml of a 40% aqueous formaldehyde solution is added dropwise with stirring. The reaction mixture is heated for 5 hours at 95-100 ° C and stirred for 15 hours at room temperature. The solution is then adjusted by adding 10 ml of concentrated hydrochloric acid to highly acidic reaction and the solvent is evaporated under vacuum. The residue is dissolved in 100 ml of water, the non-10 basic substances are extracted with toluene, the aqueous phase is adjusted by adding 10% aqueous sodium hydroxide solution to pH 12 and extracted three times, each time with 300 ml of chloroform. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed over 500 g of alumina (Activity II, neutral). The first fraction, eluted with 500 ml of methylene chloride, according to thin-layer analysis is not uniform and is not further processed. The second fraction eluted with 500 ml of methylene chloride is pure 1-methyl-4- (5,6-dimethyl-2-benzofuranyl) -piperidine. The compound melts after recrystallization of cyclohexane at 122-124 ° C and is identical to the compound prepared according to Example 18.

Example 20

20 g of 1-methyl-4- [5- (1-hydroxycyclohexyl) -2-benzofuranyl] -25 piperidine are boiled in 60 ml glacial acetic acid and 15 ml of hydrochloric acid for 48 hours at reflux. The reaction solution is cooled to room temperature and evaporated in vacuo. The residue is suspended in 1000 ml of chloroform and washed with 2N sodium hydroxide solution. The organic phase is dried over sodium sulfate, filtered and chromatographed on 700 g of alumina (Activity II, neutral). The first fractions eluted with 3000 ml of chloroform after evaporation give the crude 1-methyl-4- [5- (1-cyclohexenyl) -2-benzofuranyl] -piperidine. The compound melts after recrystallization of hexane at 81-85 ° C.

The hydrochloride prepared with a solution of hydrogen chloride in ethyl acetate melts after recrystallization from ethyl acetate at 227-229 ° C.

The starting material is prepared as follows:

To a solution of 60 g of 1-methyl-4- (5-bromo-2-benzofuranyl) -piperidine (cf. Example 12) in 300 ml of diethyl ether, drop at 480 ° C 480 ml of a 1.35 N solution of n -butyllithium in absolute diethyl ether over 30 minutes. During the drip, the reaction temperature is maintained by an external cooling between -5 and 0 ° C. The solution is then stirred for another 90 minutes at 5-10 ° C. Then, a solution of 85 ml of cyclohexanone in 100 ml of absolute diethyl ether is added dropwise over 30 minutes, maintaining the reaction temperature with external cooling at 0 to 5 ° C. The reaction solution is then stirred for 15 hours at room temperature and then poured with stirring on 300 g of ice, and the aqueous phase is extracted three times, each time with 500 ml of ethyl acetate. The combined organic extracts are dried over sodium sulfate, filtered and evaporated. The residue is dissolved in 300 ml of 2N hydrochloric acid and the acid solution is washed with ether. The aqueous solution is then adjusted by adding 10% sodium hydroxide solution to pH 12 and extracted with 1000 ml of chloroform. The chloroform solution is dried over sodium sulfate, filtered and evaporated to give the crude 1-methyl-4- [5- (1-hydroxycyclohexyl) -2-benzofuranyl] -piperidine. After recrystallization from cyclohexane, the dpn free base melts at 155-157 ° C. The hydrochloride is prepared with hydrogen chloride in ethyl acetate and recrystallized from acetone and it melts at 226-229 ° C.

Example 21.

To a solution of 24.8 g (0.07 mol) of 1-methyl-4- (5-fluoro-2-benzofuranyl) -pyridinium iodide in 200 ml of methanol is added dropwise with stirring and external cooling a solution of 23.2 g sodium borohydride in 60 ml of water so that the reaction temperature does not exceed 35 ° C. Then, the solution is stirred for 2 hours at room temperature. The methanol is then evaporated in vacuo, the residual aqueous phase is extracted twice 5 with 500 ml of chloroform per ml. and the chloroform solution is dried over sodium sulfate, filtered and evaporated. The residue is short-distilled under high vacuum. The fraction which passes at 170 ° C and 0.1 mm Hg is 1-methyl-4- (5-fluoro-2-benzofuranyl) -1,2,3,6-tetrahydropyridine, which after recrystallization from hexane melts at 117-119 ° C. The hydrochloride produced by a solution of hydrogen chloride in ethyl acetate melts after recrystallization from methyl ethyl ketone at 252 ° C.

Similarly, 15 of 26.0 g of 1-methyl-4- (6-chloro-2-benzofuranyl) -pyridinium iodide 1-methyl-4- (6-chloro-2-benzofuranyl) -1,2 are obtained. 3,6-tetrahydropyridine and hence its hydrochloride, m.p. 281 ° C, of 24.6 g of 1-methyl-4- (6-methyl-2-benzofuranyl) -pyridinium iodide 1-methyl-4- (6-methyl-2-benzofuranyl) -1,2,3, 6-tetrahydropyridine and hence its hydrochloride, m.p. 264 ° C, of 25.7 g of 1-methyl-4- (6-methoxy-2-benzofuranyl) -pyridinium iodide 1-methyl-4- (6-methoxy-2-benzofuranyl) -1,2,3, 6-tetrahydropyridine, and hence its hydrochloride, m.p. 279 ° C, of 28.4 g of 1-methyl-4- (5,7-dichloro-2-benzofuranyl) -pyridinium-iodide 1-methyl-4- (5,7-dichloro-2-benzofuranyl) -1,2,3,6-tetrahydropyridine and hence its hydrochloride with m.p. 286 ° C, of 27.0 g of 1-methyl-4- (5-chloro-6-methyl-2-benzofuranyl) pyridinium iodide 1-methyl-4- (5-chloro-6-methyl-2-benzofuranyl) ) - 1,2,3,6-tetrahydropyridine and hence its hydrochloride with 30 m.p. 262-263 ° C.

The starting material can be prepared as follows: a) 16.8 g (0.12 mole) of 5-fluorosalicylic aldehyde, 27.8 g (0.17 mole) of 4- (chloromethyl) pyridine hydrochloride, 105 g of potassium carbonate 35 and 3, 0 g of potassium iodide is heated in 160 ml of dimethylformamide under nitrogen for 20 hours to 150 ° C with stirring. The reaction mixture is then cooled to 120 ° C and suction filtered at this temperature. The filter residue is heated with 200 ml of dimethylformamide to 100 ° C and washed with dimethylformamide. The combined filtrates are evaporated under vacuum and the residue is then freed by heating for 2 hours under high vacuum to 80 ° C for volatiles. The residue is dissolved in a little methylene chloride and chromatographed on 800 g of alumina (Activity II, neutral). The first fraction eluted with 10 2 liters of methylene chloride is 4- (5-fluoro-2-benzofuranyl) -pyridine, which after recrystallization from 2-propanol melts at 100-102 ° C.

Similarly, using 18 µg of 4-chloro-salicylaldehyde 4- (6-chloro-2-benzofuranyl) -pyridine, whose hydrochloride melts at 225-230 °, of 16.3 g of 4-methylsalicylic acid is obtained. aldehyde 4- (6-methyl-2-benzofuranyl) -pyridine, m.p. 143-144 ° C (from cyclohexane), of 18.2 g of 4-methoxysalicylaldehyde 4- (6-methoxy-2-benzofuranyl) pyridine, whose hydrochloride melts at 240 ° C, of 22.9 g of 3,5-dichlorosalicylaldehyde 4- (5,7-dichloro-2-benzofuranyl) -pyridine, whose hydrochloride melts at 255 ° C, of 20.5 g of 4-methyl-5-chlorosalicylaldehyde 4- (5-chloro-6-methyl-2 benzofuranyl) pyridine (crude product).

b) 18.5 g (0.087 mol) of 4- (5-fluoro-2-benzofuranyl) -pyridine are dissolved in 170 ml of methanol and stirred with 57 ml of methyl iodide for 15 hours at 40-45 ° C. The solution is then cooled to -10 ° C and the separated salt is filtered off with suction. Wash the filter cake with 100 ml of cold 2-propanol. The 1-methyl-4- (5-fluoro-2-benzofuranyl) -pyridinium iodide thus obtained can be directly processed further.

Similarly, 20.0 g of 4- (6-chloro-2-benzofuranyl) -pyridine 1-methyl-4- (6-chloro-2-benzofuranyl) -pyridinium iodide of 18.2 g of 4 - (6-methyl-2-benzofuranyl) -pyridine 1-methyl-4- (6-methyl-2-benzofuranyl) -pyridinium iodide, of 19.6 g of 4- (6-methoxy-2-benzofuranyl) -pyridine 1-methyl-4- (6-methoxy-2-benzofuranyl) -pyridinium iodide, of 23.0 g of 4- (5,7-dichloro-2-benzofuranyl) -pyridine 1-methyl-4- (5) 7-Dichloro-2-benzo-furanyl) -pyridinium iodide, of 21.3 g of 4- (5-chloro-6-methyl-2-benzofuranyl) -pyridine 1-methyl-4- (5-chloro-6 -methyl-2-5 benzofuranyl) -pyridinium iodide.

Example 22.

13.9 g (0.06 mol) of 1-methyl-4- (5-fluoro-2-benzofuranyl) - 1.2.3.6-tetrahydropyridine is dissolved in 250 ml of methanol and hydrogenated in the presence of 0.7 g of palladium carbon catalyst. tor (5% Pd) at a temperature between 15 and 20 ° C and under normal pressure. After 17 hours, 1,376 liters of hydrogen is absorbed, which corresponds exactly to the theoretical hydrogen consumption. The hydrogenation is quenched, the catalyst is filtered off and the filtrate is evaporated under vacuum. The residue is short-15 distilled under high vacuum. The fraction passing at 150 ° C and 0.1 mm Hg is 1-methyl-4- (5-fluoro-2-benzofuranyl) -piperidine, which after recrystallization from pentane melts at 75-76 ° C. The hydrochloride prepared from a solution of the base with a solution of hydrogen chloride in ethyl acetate melts after recrystallization from ethyl methyl ketone at 228 ° C.

Similarly, 14.9 g of 1-methyl-4- (6-chloro-2-benzofuranyl) -1,2,3,6-tetrahydropyridine 1-methyl-4- (6-chloro-2-benzofuranyl) are obtained. -piperidine and hence its hydrochloride 25, m.p. 295 ° C, of 13.6 g of 1-methyl-4- (6-methyl-2-benzo-furanyl) -1,2,3,6-tetrahydropyridine 1-methyl-4- (6-methyl-2-benzofuranyl) ) -piperidine and hence its hydrochloride, m.p. 222 ° C, of 14.6 g of 1-methyl-4- (6-methoxy-2-benzofuranyl) -1,2,3,6-tetrahydropyridine 1-methyl-4- (6-methoxy-2-benzofuranyl) -piperidine and hence its hydrochloride, m.p. 205 ° C, of 16.9 g of 1-methyl-4- (5,7-dichloro-2-benzofuranyl) -1,2,3,6-tetrahydropyridine 1-methyl-4- (5,7-dichloro-2-benzofuranyl) ) -piperidine and hence its hydrochloride, m.p. 258-260 ° C, of 15.7 g of 1-methyl-4- (5-chloro-6-methyl-2-benzofuranyl) -35 1,2,3,6-tetrahydropyridine 1-methyl- (4,5- chloro-6-methyl-2- (benzofuranyl) -piperidine, and hence its hydrochloride, mp.224 ° C.

Example 23

To a solution of 9.8 g of 1- (2-propynyl) -4- (5,6-dimethyl-2-benzofuranyl) -pyridinium bromide in 150 ml of methanol is added dropwise with stirring and external cooling a solution of 10 g. g of sodium borohydride in 25 ml of water so that the reaction temperature does not exceed 30 ° C. Then the solution is stirred for 15 hours at room temperature. Then the methanol is evaporated under vacuum, the residual aqueous phase extracted twice with 250 ml of chloroform per ml. and the chloroform solution is dried over sodium sulfate, filtered and evaporated. The residue is dissolved in 200 ml of 10% aqueous methanesulfonic acid and the acid solution is washed with ether.

Then the acidic aqueous phase is adjusted to pH 12 by the addition of 30% sodium hydroxide solution and extracted with 1000 ml of chloroform. The chloroform solution is dried over sodium sulfate, filtered and evaporated. The residue is dissolved in a little methylene chloride and chromatographed on 50 g of alumina (Activity II, neutral). The first 1000 ml of methylene chloride eluted fraction is 1- (2-propynyl) -4- (5,6-dimethyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine. The hydrochloride thereof is prepared by means of hydrogen chloride in ethyl acetate and recrystallized from ethyl methyl ketone, then it melts at 260 ° C.

The starting material can be prepared as follows: a) 8.5 g of 4- (5,6-dimethyl-2-benzofuranyl) pyridine (see Example 17a)) are dissolved in 150 ml of methanol and stirred with 6.0 g of 3-bromopropin for 4 hours under reflux.

The solution is then cooled to 20 ° C, stirred with activated charcoal and filtered through purified diatomaceous earth. The filtrate is evaporated in vacuo and the evaporation residue is recrystallized from acetone. The obtained 1- (2-propynyl) -4- (5,6-dimethyl-2-benzofuranyl) -pyridinium bromide melts at 240-242 ° C.

147051 45

Example 24.

14.2 g of 4- (5-cyclohexyl-2-benzofuranyl) -piperidine and 6.0 g of 3-bromopropylene are dissolved in 300 ml of methanol and stirred after addition of 50 g of potassium carbonate for 30 hours at room temperature. Then, the reaction mixture is suction filtered, the filter cake washed with 500 ml of chloroform and the combined filtrates evaporated under vacuum. The residue is dissolved in a little methylene chloride and chromatographed on 300 g of alumina (Activity II, neutral). The first eluted fraction containing a total of 1000 ml of methylene chloride contains 1- (2-propynyl) -4- (5-cyclohexyl-2-benzofuranyl) -piperidine. The crude base is converted to the hydrochloride by a solution of hydrogen chloride in ethyl acetate. This is recrystallized from ethyl acetate and then melts at 248 ° C.

The starting material is prepared as follows: a) 2.0 g of 1-methyl-4- [5- (1-cyclohexenyl) -2-kenzofuranyl] piperidine are dissolved in 30 ml of methanol and hydrogenated in the presence of 0.2 g of palladium carbonate. catalyst (5% Pd) at a temperature of 20-25 ° C and under normal pressure. After 3 hours, hydrogenation is interrupted by 100% hydrogen uptake. The catalyst is filtered off and the filtrate is evaporated in vacuo. The remaining 1-methyl-4- (5-cyclohexyl-2-benzofuranyl) -piperidine melts after recrystallization of hexane at 89-90 ° C. The hydrochloride prepared with a solution of hydrogen chloride in ethyl acetate melts after recrystallization from ethyl acetate at 238-240 ° C.

b) In a manner similar to Example 2., 52.7 g of 1-methyl-4- (5-cyclohexyl-2-benzofuranyl) -piperidine 4- (5-cyclohexyl-2-benzofuranyl) -piperidine are obtained and thereof its hydrochloride with m.p. 223 ° C.

147051 46

Example 25

To a refluxing solution of 13.5 g of lithium aluminum hydride in 200 ml of tetrahydrofuran is added a solution of 19.0 g of 1- (cyclopropylcarbonyl) -4- (5-cyclohexyl-2-benzofuranyl) -piperidine in 150 ml of tetrahydrofuran .

Then, the reaction mixture is refluxed for another 15 hours, cooled, and decomposes excess lithium aluminum hydride at -10 ° C using 15 ml of water, 15 ml of 10% sodium hydroxide solution and 45 ml of water.

Then the reaction solution is suction filtered, the filter cake is re-washed with 1000 ml of chloroform; and the combined filtrates are evaporated under vacuum. The residue is dissolved in 500 ml of 2N hydrochloric acid and the acid solution is washed with ether. Then the aqueous solution is adjusted to pH 12 by the addition of 10% sodium hydroxide solution and extracted with 1 liter of chloroform. The chloroform solution is dried over sodium sulfate, suction filtered and evaporated to give crude 1- (cyclopropylmethyl) -4- (5-cyclohexyl-2-benzofuranyl) -piperidine. This is converted by hydrogen chloride in 20 ethyl acetate to the hydrochloride which is recrystallized from ethyl acetate, after which it melts at 220 ° C.

The starting material is prepared in a similar manner to Example 5 using 17.1 g of 4- (5-cyclohexyl-2-benzofuranyl) -piperidine (cf. Example 24b)) and can be reused as a crude product.

Example 26

Analogous to the procedure described in Example 19, using 14.2 g of 4- (5-cyclohexyl-2-benzo-furanyl) -piperidine (cf. Example 24b)), 30 ml of formic acid and 30 ml of 40% aqueous are prepared. formaldehyde solution 1-methyl-4- (5-cyclohexyl-2-benzofuranyl) -piperidine, m.p. 89-90 ° C (from hexane).

Claims (2)

This compound is also prepared in Example 24a) from the final product of Example 20. By treating the compound with a solution of hydrogen chloride in ethyl acetate, the hydrochloride is obtained which after crystallization from ethyl acetate 5 melts at 238-240 ° C. Analogous Process for Preparing Racemic or Optically Active 4- (2-Benzofuranyl) -tetrahydropyridines or Piperidines of the General Formula R3- [/ CH2_CH2v. A) -> C N-R1 (1) R4 x ^ CH-CH2 ^ wherein R1 is an alkyl group of 1-4 carbon atoms, 2-propynyl, 344 "" 3-oxobutyl or cyclopropylmethyl, R and R are independently hydrogen, alkyl or alkoxy groups having a maximum of 4 carbon atoms per group may also be a cycloalk-1-enyl or cycloalkyl group 34 having 5-8 carbon atoms, or R and R together are a trimethylene or 1,3-butadienylene group, X and Y are individually a hydrogen atom or together an additional bond, however, R 2 34 may not be methyl if R and R are hydrogen, or 20 acid addition salts thereof with inorganic or organic acids, characterized in that a) reacting a compound of the general formula R 3 -ril IRY 147051 3 4 wherein R, R, X and Y are as defined in the general formula I, with a reactive ester of a hydroxy compound of the general formula HO - R1 (III 5 wherein R 2 - has the meaning given by formula I with the exception of. 3, if R and R in formula II are hydrogen, or under reducing conditions with an oxo-alkane of not more than 4 carbon atoms, or add a compound of the general formula II to methyl vinyl ketone or 10 b) in a compound with the general formula R3_jfV-jj / CHj-CH U> Jl J] -NN-C0-Rlb (IV) RY wherein R represents a group corresponding to the definition of R1 other than a primary methylene group and furthermore with the exception of an acetonyl group, or also if at least 15 of the symbols R 1 and R 2 are not hydrogen, means a 3 4 alkoxy group having a maximum of 4 carbon atoms and R, R, x and Y have the meanings given in the formula I, reducing the carbonyl group or alkoxycarbonyl group or c ) reduces a compound of the general formula 3 // where R @ 2 wherein Z is a monovalent anion or the normal equivalent of le a polyhydric anion, R is a group corresponding to the definition of R with the exception of 3-oxobutyl, R and R have it