DE2537837A1 - TETRAHYDROPYRIDINE AND PIPERIDINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

CiSA-GEIGYAG, CIi-4002 Case!

4-9368 / +

Germany

^ 5 ρ * ^J '"i'i

Te tv et h _f 7 fly gpy £ j; Q ^ - ⁿ _ ~ and pipe rl di ηde r iya te and procedure

for yr ^ r production:

The present invention relates to new tetrahydropyridine and piperidine derivatives with valuable pharmacological properties, processes y.va: production of these new compounds and therapeutic preparations containing them.

The invention new tetra hydropyridine and piperidine derivatives correspond to the general formula I.

NO-,

(D

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in whichever

Hydrogen, an aliphatic hydrocarbon radical with 1 - 12 or a cycloaliphatic hydrocarbon radical with 3 - 12. "Carbon atoms, which radicals can be substituted by hydroxyl groups or an oxo radical and / or interrupted by oxygen, or a phenyl (lower alkyl) radical, in the benzene ring of which a maximum of three hydrogen atoms can be replaced by substituents from the group consisting of halogen up to atomic number 35 _: lower alkyl and lower alkoxy groups, methylenedioxy and trifluoromethyl group and its lower alkyl chain on one of its carbon atoms not directly connected to the ring nitrogen atom by an oxo radical or a hydroxyl group can be substituted, or denotes a cinnamyl radical optionally substituted accordingly in the benzene ring, hydrogen or a lower alkyl group,

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R ~ and R / independently of one another hydrogen, lower alkyl or lower alkoxy groups, halogen atoms up to atomic number 35, benzyloxy or hydroxyl groups, and Ro also a trifluoromethy! Group, a lower one 1- hydroxyalkyl or lower alk-1-eiiy! Group, a 1-hydroxycycloalkyl, cycloalk-1-enyl or cycloalkyl group each with 5-8 carbon atoms, or R ,. and R, together the trimethylene or tetramethylene radical or, corresponding to a fused-on benzene ring j, the 1,3-butadienylene radical,

R ₁ - hydrogen or an alkyl group with a maximum of 4 carbon atoms, and

A and B divalent saturated aliphatic hydrocarbon radicals mean and one of these symbols can also mean the direct bond, where A and B together always have 3 chain links and together with Rr a maximum of 9 carbon atoms,

X and Y each represent a hydrogen atom or together an additional one Bond mean.

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The invention also relates to addition salts, in particular pharmaceutically acceptable ones Addition salts of the compounds of the general formula I with inorganic and organic acids, as well as the preparation of these addition salts.

In the compounds of general formula I, R-i is an aliphatic or cycloaliphatic one, if appropriate Hydrocarbon radical substituted by definition or interrupted by oxygen, for example a methyl, Äe thy 1-, propyl, isopropyl, butyl, isobutyl, Pentyl, isopentyl, neopentyl, hexyl, heptyl, 1-methylhexyl, Octyl, nonyl, decyl, dodecyl, allyl, Crotyl, 2-methylallyl, 2-propynyl, cyclopropyl, cyclopropy, methyl, Cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclopentylethyl, cyclohexylmethyl, 2-nor ~ bornany! methyl, bicyclo [2.2.2] oct-2-ylmethyl, 1-adamantylmethyl, 3-cyclohexen-l-ylmethyl, 2-norbornen-5-y! Methyl-, 2-hydroxyethyl-, 2-hydroxypropyl-, 3-hydroxy-.propyl-, 3-hydroxybutyl, 2,3-dihydroxypropyl, acetonyl, 3-oxobutyl, 2-hydroxycyclohexyl, 2-oxocyclohexyl, 2-methoxyethyl, 2-ethoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 2-butoxymethyl, 2,3-dimethoxypropyl, 3,3-diethoxybutyl, 2- (2-ethoxyethoxy) ethyl, 2-cyclohexyloxyethyl, 2- (l-adamantyloxy) ethyl, furfuryl, tetra

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hydro-furfuryl, (2,2-dimethyl-1,3-dioxolan-4-yl) methyl or 2- (2-methyl-1,3-dioxolan-2-yl) ethyl group. As an optionally substituted phenyl (lower alkyl) group according to the definition, R is preferably one with 1-3 carbon atoms in the lower alkyl chain. Lower alkyl and alkoxy groups as substituents on the phenyl radicals contain 1-7, preferably 1-4 carbon atoms and are primarily methyl or methoxy groups. Examples of phenyl (lower alkyl) and cinnamyl radicals which may be substituted according to the definition are the benzyl group, the p-fluorine, o-, m- or p-chlorine, p-bromine, 3,4-dichloro, p -Methyl ~, p-isopropyl-, o- or p-methoxy-, p-ethoxy-, p-isopropoxy-, 3,4-dimethoxy-, 3,4,5-trimethoxy- 3,4-methylenedioxy- and p -Trifluoromethylbenzyl and the phenethyl, α-methylphenethyl, 2-phenylpropyl, ß- hydroxyphenethyl, S-hydroxy-S-phenylpropyl, phenacyl, 2-benzoylethyl or cinnamyl groups, for example, may be substituted analogously to the aforementioned benzyl groups can, called "

As a lower alkyl group, Ry is in particular one with 1-4 carbon atoms and especially the methyl group.

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Dei: Subsfeituent R ₃ as halogen is fluorine, bromine and in particular chlorine, as lower alkyl or lower alkoxy group is one with 1-7, preferably 1-4 carbon atoms, for example an ethyl, isopropyl, tert.butyl $ ethoxy -, propoxy, isopropoxy, butoxy or isobutoxy group, but above all a methyl or methoxy group is, for example, the hydroxymethyl, 1-hydroxy ~ ethyl, 1-hydroxypropyl, 1-hydroxy-1-methylethyl, 1-hydroxybutyl, 1-hydroxy-1-methylpropyl or 1-hydroxy-1-ethylbutyl group or the Vinyl, prop-1-enyl, isopropenyl, but-1-enyl, 1-methylprop-1-enyl or 1-ethylprop-1-enyl group, as 1-hydroxycycloalkyl, cycloalk-1-enyl or cycloalkyl group with 5-8 carbon atoms, R ^ is, for example, the 1-hydroxycycloheptyl, 1-hydroxycyclooctyl, cyclohept-1-enyl, cyclooct-1-enyl, cycloheptyl or cyclooctyl group, preferably however, the 1-hydroxycyclopentyl, cyclopent-1-enyl or cyclopentyl group and especially the 3-hydroxycyclohexyl, cyclohex-1-enyl or cyclohexyl group.

As halogen atoms or lower alkyl or alkoxy groups For example, the radicals mentioned above as corresponding substituents R "come into consideration.

A methylenedioxy group R "+ R" is preferably in the 5,6-position, the same also applies to trimethylene and trimethylene

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-T

and tetramethylene radicals, while a fused-on benzene nucleus Ε- + R / themselves in 5,6- or 6,7-, but in particular can be in the 4.5 position.

As a lower alkyl group, Rc is, for example Ethyl, propyl or n-butyl group or, in particular, a methyl group.

Divalent saturated aliphatic hydrocarbon radicals A and B are methylene, ethylene and trimettrylene radicals and corresponding lower alkylated radicals which, together and with R ₁ . or, since one of the symbols A and B is the direct bond and R ₁ . Can mean hydrogen, also individually have a maximum of 9 carbon atoms, such as ethylidene, propylidene, dimethyl, propylene, 1-ethyl-ethylene, 1,1-dimethylethylene, 1-methyltrimethylene, 2-methyltrimethylene -, 1-ethyltrimethylene, 1,1-dimethyltreline ethylene or 2,2-dimethyltriniethylene radicals. If A represents a direct bond or a radical with one or three chain links, such as the methylene or trimethylene group, and B correspondingly represents a radical with three or two chain links or the direct bond, the symbols X and Y preferably denote hydrogen atoms but also mean an additional bond.

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The compounds of general formula I and their addition salts with inorganic and organic acids have valuable pharmacological properties. They effect the rat moderate inhibition of monoamine oxidase after oral administration, as can be seen from the results of the isotopic determination of the enzyme activity. Particularly noteworthy is that Inhibition of the uptake of serotonin in the midbrain synaptosomes of rats after oral administration of a dose of 100 mg / kg per os. Certain compounds of the general formula I, such as 4- (3-benzofuranyl) piperidine and its pharmaceutically acceptable salts, e.g., the hydrochloride, also act in the same dosage an inhibition of the uptake of norepinephrine into the heart and into the midbrain synaptosomes of rats. When administered intraperitoneally to the mouse in doses of 3 mg / kg or more, the compounds potentiate of the general formula I by 5-hydroxy-tryptophan caused arousal. Together with a favorable therapeutic index, the above properties characterize the compounds of the general formula I and their pharmaceutically acceptable salts with inorganic and organic acids as antidepressants, those e.g. orally or parenterally for the treatment of Gemlitsdepressionen can be administered.

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The present invention relates in particular to compounds of the general formula I in which R ~ is a methyl group or preferably hydrogen, R ~ is hydrogen, halogen up to atomic number 35, a lower alkyl or lower alkoxy group, the hydroxy group, the trifluoromethyl group or a 1-hydroxycycloalkyl, Cycloalk-1-enyl or Cj ^ cloalkyl group each with 5 to 8 carbon atoms, preferably in the 5-position, and R ^ hydrogen, halogen up to atomic number 35, a lower alkyl or lower alkoxy group or the hydroxyl group, preferably in 6 Position, or R ~ + R, a fused-on benzene ring in 4,5-Starte or a trimethylene radical in 5, 6- position, and R _{5 is} hydrogen or a methyl group, while R.,, A, B, X and Y are the have the meaning given under the formula I, but preferably methylene, ethylidane, ethylene, propylene or trimethylene radicals and the direct bond, taking into account the sum of the chain links set at 3, as A and B lie. Particularly important are compounds of the general formula I in which hydrogen as R ₂ and hydrogen, halogen up to atomic number 35, lower alkyl or lower alkoxy groups or hydroxyl groups as R ₃ , preferably in the 5-position, and as R, preferably in the 6-position , R _{5 is} hydrogen, A is the methylene group and B is the ethylene group, or A is the direct bond and B is the tr! methylene group, or preferably A is the ethylene group and B is the methylene group,

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while R,, X and Y have the meaning given under the formula I. In particular, the invention relates to compounds of the general formula I which contain as R., hydrogen or an alkyl group with a maximum of 4 carbon atoms, especially the methyl group, also the 2-propynyl, cyclopropylmethyl or benzyl group, while X and Y contain the under Formula I indicated and R ^ »Rq> R /, 'A- ^and B have the above restricted meanings, where Ro especially hydrogen or chlorine, the methyl, methoxy or hydroxyl group, preferably in the 5-position, and R, especially hydrogen or chlorine, the methyl, methoxy or hydroxyl group, preferably in the 6-position, and the pharmaceutically acceptable acid addition ™ salts of these compounds. The invention primarily relates to compounds of the general formula I in which R ₁ is primarily hydrogen or the methyl group, also the ethyl, 2-propynyl, cyclopropylmethyl or benzyl group, Rr, hydrogen, R "is hydrogen or a methyl group or chlorine each in the 5-position, R, hydrogen or, together with hydrogen or a methyl group R-> a methyl group in the 6-position, R ₁ - hydrogen, A is the ethylene group and B is the methylene group and X and Y are those given under the formula I. Have meaning, such as the l-methyl-4- (3-benzofuranyl) -1,2,3,6 ~ tetrahydropyridine, the l-methyl-4- (3-benzofuranyl) piperidine and the 4- (3-benzofuranyl) -piperidine, and the pharmaceutically acceptable acid addition salts of these compounds, such as the hydrochlorides.

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The new tetrahydropyridine and piperidine derivatives of the general formula I and their acid addition salts are produced according to the invention by using a " way

a) in a compound of the general formula II,

N - Ac

in which

Ac denotes a residue that can be split off and It}, R3. R ^ and R ^ are given under the formula I. Have meaning the rest: Ac splits off, and

b) if desired, a compound of the general formula I obtained in accordance with a) or in some other way comprised general formula Ia

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in which R ", R, R, and R ₁ . have the meaning given under the general formula I, with a reactive ester of a hydroxy compound dez "general formula III

HO - R _L ^a - (III)

in which R, indicated under the formula I for R- Has meaning with the exception of hydrogen, or under reducing conditions with an oxo compound of the general formula IHa

0 = R _t ^b ■ (HIa)

in which

R ₁ corresponds to a residue R ^ ^{a which} satisfies e inv /,

geminal divalent radical means, converts, · or

c) in a compound of the general formula IV

.A-

in which

R ^ a radical reduced by one methylene group

according to the definition for R, or a

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means lower alkoxycarbonyl group, the carbonyl group or alkoxycarbonyl group is reduced, or

d) a compound of the general formula V.

Z © (V)

in which
7.Θ

a monovalent anion or the corral equivalent: of a polyvalent anion means

and R _{7 is} hydrogen or alkyl radicals with together at most

-i »

6 carbon atoms, RC ₅ ^unc * Ra have the meaning given under the formulas III and I, partially reduced to the corresponding compound of the general formula I, in which X and Y represent an additional bond, or

e) a compound of the general formula VI

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(VI)

in which R ^, R ^, R, R ^ and R are as defined under of formula I or of the formula V indicated _7, or a compound falling under the general formula I formula Ib

(Ib)

in which R ,, R ₃₅ R ₃₅ R ^, R ₅₃ A and B have the meaning given under formula I, catalytically hydrogenated to the corresponding piperidine compound, or

f) a compound of the general formula I in which R-. one denotes optionally substituted benzyl group according to the definition, and / or R- and / or R, optionally inertly substituted Benzyloxy groups mean, and X and Y always mean hydrogen, while R ^, R ^ j A and B and optionally R, and / or R ~ have the meaning given under the formula I, subjected to hydrogenolysis, or

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g) from a compound of the general formula VII

in which A ^c and B ^{c have} the meaning given under the formula I for A or B with the exception of the direct bond as A ^a and a radical with 3 chain links as B ^a and R, which is under the formula III and R ^, R . ,, R / and R ₁ - have the meaning given under the formula Ϊ.

or from a connection of the

general formula I, in which R ~ is a lower 1-hydroxyalkyl group or is a 1-hydroxycycloalkyl group with 5-8 carbon atoms, while R-, the meaning given under the formula I.

with the exception of hydrogen and R_, R,, R ₁ ^, A, B, X and Y have the meaning given under formula I, splits off water, or

h ") a compound of the general formula I ₅ in which R., has the meaning given under formula I with the exception of hydrogen and oxo and hydroxy-substituted radicals and halogen-substituted phenyl (lower alkyl) radicals, R" ChI ο ίο the bromine and R, hydrogen or a lower alkyl group

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and R ₂ , R ₅ , A, B _5, X and Y have the meaning given under the formula I, converted into the corresponding compound with a metal radical in the place of R-, and the latter compound with a lower oxoalkane or a cycloalkanol! with 5-8 carbon atoms, or

i) a compound of the general formula VIII,

(VIII)

, R3 and

in what R? have the meaning given under the formula III and the meaning given under the formula I, or the crude reaction product of a compound of the general formula IX,
R.

(IX)

the double molar amount of formaldehyde and a compound

of the general formula X,

(X)

in which R has the meaning given under the formula I.

- »

and which is used as an addition salt of a strong acid or together with such, with a treated with strong acid

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if desired, one of the trades specified under a) to i) Process obtained compound of general formula I in an addition salt with an inorganic or organic acid.

The Acyl radical which can be split off is in particular an acyl radical. Its splitting takes place, for example, through Hydrolysis or solvolysis, hydrolysis or reduction. In the starting materials of the general formula II, Ac can, for example, be any organic acyl group, for example a lower alkanoyl group such as the acetyl group, an arene carbonyl group such as the benzoyl group, an alkanesulfonyl or arenesulfonyl group like the methanesulfonyl or p-toluenesulfonyl group or an inorganic acyl group such as the nitroso group MO. Meanwhile, acyl groups are preferred which are one good accessibility of the compounds containing them in general Ensure formula II and / or can be split off relatively easily are. According to this point of view, the acyl groups Ac on the one hand are mainly acyl groups from carbonic acid

and thiocarbonic acid half-esters, in particular by hydrolysis cleavable groups, e.g. lower alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl groups, furthermore the phenoxycarbonyl and the benzyloxycarbonyl group as well as the methoxythiocarbonyl and the methylthio-thiocarbonyl group, and on the other hand acyl groups of other derivatives of carbonic acid, such as the chlorocarbonyl group and especially the Cyano group into consideration.

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The hydrolysis of compounds of the general new formula II according to process a) can be carried out in alkaline or acidic medium. For example, by heating it for a long time with a

Alkali hydroxide, in particular sodium or potassium hydroxide in a hydroxy compound in the presence of a little water at temperatures between about 80 ° and 200 ⁰ C completed. A suitable reaction medium is, for example, ethylene glycol or a lower monoalkyl ether thereof, and furthermore, if the hydrolysis is carried out in a closed vessel, a lower alkanol such as methanol, ethanol or butanol is also suitable. In addition, compounds of the general formula II in which Ac is a cyano group, ie the acyl radical of cyanic acid, or a chlorocarbonyl group, can also be prepared by heating with a mineral acid in an organically aqueous or aqueous medium, for example by boiling for several hours in a mixture of 85% -iger phosphoric acid and formic acid, or by heating for several hours in 48% hydrobromic acid or in a hydrobromic acid-acetic acid mixture to about 60-10O ⁰ C, preferably 60-7O ⁰ C hydrolyze.

Further cleavable groups Ac are those by addition of a methyl group present instead of Ac to azodicarboxylic acid di-lower alkyl esters groups formed, preferably by hydrolysis in an acidic medium, especially cooking in dilute, e.g. 1-n. Hydrochloric acid, with the release of Hydrazodicarboxylic acid di-lower alkyl ester, are split off.

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A residue that can be split off by solvolysis is e.g. the tert-butoxycarbonyl residue, which under anhydrous conditions by treating with a suitable acid, such as trifluoroacetic acid, can be split off.

Residues Ac which can be split off by reduction are, for example, ot-aralkoxycarbonyl radicals, such as benzyloxycarbonyl radicals, which can be split off in the usual way by hydrogenolysis, in particular by catalytically activated ones Hydrogen, such as by hydrogen in the presence of a hydrogenation catalyst, for example platinum, palladium or Raney nickel. Further radicals which can be split off by reduction are, for example, 2-haloalkoxycarbonyl radicals, such as 2,2,2-Trichloräthoxycarbonylrest or the 2-Jodäthoxy- or 2,2,2-Tribromäthoxycarbonylrest, which in the usual way, in particular can be split off by metallic reduction (so-called nascent hydrogen). Nascent hydrogen can be caused by the action of metal or metal alloys, such as amalgams, on hydrogen-supplying agents, such as carboxylic acids, alcohols or water, in particular zinc or zinc alloys together with acetic acid be considered. The reduction of 2-halo-alkoxycarbony residues can also be done by chromium (II) compounds such as chromium (II) chloride or chromium (II) acetate.

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A radical Ac which can be split off by reduction can also be a sulfonyl group, such as a lower alkanesulfonyl group or arylsulfonyl group, e.g. methanesulfonyl or p-toluenesulfonyl, be, which in the usual way by reduction with nascent hydrogen, e.g. by an alkali metal, such as Lithium or sodium in liquid ammonia, or electrolytically can be split off.

The preparation of the starting materials of the general formula II is explained below.

As reactive esters of compounds of the general formula III for the reaction with compounds of the General formula Ia according to process b) are suitable, for example Hydrohalic acid esters, in particular chlorides, bromides and iodides, further lower alkanesulphonic acid esters and arenesulfonic acid esters such as the methanesulfonic acid esters, or the 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 with compounds of the general formula Ia are preferably carried out in the presence an acid-binding agent carried out in an organic solvent which is inert under the reaction conditions. Tertiary organic bases such as triethylamine, pyridine, sym. Collidine and especially ethyldiisopropylamine, or inorganic "basic substances, such as sodium or potassium

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carbonate, and as solvents, for example, lower alkanols such as methanol, ethanol, isopropanol or butanol, ethereal 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 N, N, N ', N', N ", N ^u -Hexamethylphosphorsäure triamide. The reaction temperature is between about 0 ° and 200 ° C, preferably between room temperature and about 120 ⁰ C. The reaction temperature at necessary for reactions with reactive esters of primary hydroxy compounds are usually at the lower limit of the specified ranges, while reactions with reactive esters of non-primary hydroxy compounds are usually carried out at higher temperatures and accordingly if necessary in closed reaction vessels, the use of a particularly effective acid-binding agent such as ethyldiisopropylamine being advantageous.

Reactions of compounds of the general formula Ia with oxo compounds of the general formula. III a can for example in formic acid at temperatures between about 70 and 100 ⁰ C, or optionally with the action of hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel, platinum oxide or palladium-carbon, at normal or moderately elevated pressures and temperatures in a suitable organic solvent such as ethanol or dioxane. As an oxover

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bonds come, for example, aliphatic aldehydes with at least 2 carbon atoms, aliphatic and cycloaliphatic Ketones, benzaldehyde and, by definition, substituted benzaldehydes are possible. Above all, however, is suitable formaldehyde, which is preferably used with formic acid as a reducing agent.

Reactive esters of hydroxy compounds of the general formula III and oxo compounds of the general A considerable number of formulas IHa are known and can be prepared analogously to the known compounds. The starting materials of the general formula Ia can generally be prepared by the process mentioned under a) produce. Another advantageous production method for those compounds in which X and Y are hydrogen atoms is the hydrogenation of, if appropriate, mentioned under e) and explained in more detail below according to the definition for R «, Rq, Ra, Rg and R ^ substituted 2-, 3- or 4- (3-benzofuranyl) pyridines.

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The amide group of compounds of general formula IV according to c) is reduced, for example, 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 between about 20 and 100 ⁰ C or the boiling point of the reaction medium used if this is below 100 ° C. The diborane can either be prepared and introduced separately or formed in situ from sodium borohydride and boron trifluoride etherate. The preparation of the starting materials of the general formula IV is explained below.

The partial reduction of compounds of the general Formula V according to d) is preferably obtained with the aid of sodium or potassium borohydride in organic-aqueous Medium carried out by, for example, the initial solution of the starting material of the general formula V in an organic, water-miscible solvent, e.g. in a lower alkanol such as methanol or ethanol or their mixtures with water gradually add an aqueous solution of sodium borohydride and the reaction mixture then wait a while longer.

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leaves, wherein a reaction ^{temperature between about 5 and 6O c} Cj, preferably room temperature to 35 ⁰ C, is maintained. The preparation of the starting materials of the general formula V is explained below.

The catalytic hydrogenation of compounds of general formulas VI and Ib 'may _f using conventional hydrogenation catalysts, such as noble metal catalysts such as palladium on carbon or platinum oxide, rhodium catalysts such as rhodium on carbon or alumina, or alloy skeleton catalysts, such as Raney nickel, dioxane, be carried out bar at room temperature and normal pressure or moderately elevated temperatures up to about IQO ⁰ C and elevated pressures to about lOO in an inert organic solvent such as methanol, Aethanöl odex *. the hydrogenation of the tetrahydropyridine derivatives of the general formula Ib is the generally under milder conditions

before itself than the hydrogenation of compounds of the general formula VI. Hydrogenations of compounds of the general formula Ib ₅ which contain an optionally substituted benzyl group as R, the splitting off of which is to be avoided, are advantageously carried out in the presence of an equivalent of hydrogen chloride and, after the equimolar amount of water has been taken up,

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fabric broken off. The production of the starting materials of the general Formula VI is explained below. The starting materials of the general formula Ib are for example according to one of the aforementioned processes for the preparation of compounds of the general formula I, preferably by the under d) called partial reduction of corresponding pyridinium salts.

The hydrogenolytiscbe cleavage of a possibly substituted benzyl group R ^ according to f) takes place essentially under the reaction conditions given for the abovementioned process e) and using those given there Catalysts. Therefore, this hydrogenolysis can also take place in the same process as the itydration according to e), but on the other hand, as already mentioned, in particular the selective hydrogenation of the cyclic double bond of compounds of the general formula Ib while retaining a benzyl group R ^ j can also be carried out easily. The hydrogenolysis can also be carried out under the same reaction conditions as process e) Cleavage of optionally inertly substituted benzyloxy groups R ~ and / or R, take place. Under inert substituents are understood to mean those that are neither changed nor delayed during hydrogenolysis «As such substituents are mainly lower alkyl and lower alkoxy groups, such as methyl or methoxy groups, into consideration.

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The water splitting according to method g) is in a manner known per se by heating the compounds of the general formula VII or those suitable for splitting off water Compounds of the general formula I, advantageously with separation of the water formed and preferably in the presence of a strong acid, e.g. of conc. Hydrochloric acid in glacial acetic acid or of sulfuric acid, which is concentrated but in low levels Amounts used, or of p-toluenesulfonic acid carried out. The elimination of water can also be carried out by heating in an inert organic solvent, see B. in a water-immiscible solvent, such as benzene, toluene or xylene, and advantageously with separation of water.

In the compounds of the general formula I which are suitable as starting materials for the process according to h) the chlorine or bromine atom R ~ is preferably activated by means of Magnesium into a chloromagnesium or bromomagnesium residue converted or by means of an alkali metal compound, such as butyllithium, replaced by an alkali metal radical, in particular the lithium radical, with, for example, as a solvent an ether or an ethereal solvent such as diethyl ether or tetrahydrofuran is used. in the the same medium or, if appropriate, with the addition of an inert solvent such as benzene, the subsequent Implementation with the lower oxoalkane or the definition

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mass cycloalkanones, for example, at temperatures between -10 ° C and boiling point of the reaction medium are carried out.

In process i), the strong acid is preferred a mineral acid such as hydrochloric acid, especially concentrated hydrochloric acid, or sulfuric acid, especially moderately dilute 66% sulfuric acid is used. the The reaction temperature is, after initial cooling to control the exothermic reaction, between 60 and 110 ° C, preferably at 90-100 °, maintaining a reaction time of about 1 to 10 hours, preferably 5-6 hours.

The starting materials of the general formula VIII are formed together with! -Substituted 4- (3-benzofuranyl) -4-piperidinols, which fall under the general formula VH, in the implementation of the compounds of the general formula IX with twice the molar amount of formaldehyde, for example as approx. 35% aqueous solution, and the equimolar amount of a mineral acid salt, in particular des Hydroclilorids, a compound of the general formula X and are therefore also in the place of the connections of the general Formula VIII contain usable crude reaction products. The latter is essentially made under the same reaction conditions as the subsequent process i), but one is used to combine the general

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Formula X is just an equinormal amount of a strong acid, such as conc. Hydrochloric acid, if one does not prefer, uses the compound of the general formula X as an acid addition salt, preferably to be used as hydrochloride. To then the rearrangement of the resulting compound of the general formula VHI and at the same time the dehydration of the resulting compound To effect piperidinols, one then only needs to gradually add more mineral acid while cooling, e.g. at 50-70 ° C, like conc. Sulfuric acid, and bring the reaction to an end by heating to e.g. 90-95 C. After a usually less advantageous process variant, one can see the formation of the crude reaction product and the rearrangement or Carry out dehydration of the same at the same time by starting from the beginning an excess of a strong acid, in particular sulfuric acid or hydrochloric acid.

Of the starting materials not already falling under the general formula I and not already specifically mentioned For the abovementioned processes, some can be prepared in one or more stages from compounds of the abovementioned produce general formula VI. Of the latter compounds, the unsubstituted 4- (3-benzofuranyl) pyridine and were Hydrochloride already described in US Pat. No. 3,678,062. According to what is stated in this patent specification Manufacturing process is initially using 3 (2H) -benzofuranone

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4-Pyridyllithium reacted in diethyl ether at -30 ° C and that 2,3-dihydro-3- (4-pyridyl) -3-benzofuranol obtained by heating with potassium bisulfate to 190 ° C. to give the desired 4- (3-benzofuranyl) pyridine dehydrated. Further compounds of the general formula VI can be prepared analogously, with the substituted 3 (2H) -benzofuranones required as precursors, e.g. by cyclizing appropriately substituted

(Phenoxy) acetic acids or other 2- (phenoxy) lower alkanoic acids can get.

Another process for the preparation of compounds of the general formula VI consists in that first an optionally corresponding to the definition for R ~ and R, substituted 4-, 3- or 2- (o-hydroxybenzoyl) pyridine in the presence of an acid binding agent such as potassium carbonate, and optionally a small amount of potassium iodide with a chloroacetic acid or bromoacetic acid lower alkyl ester, in particular the methyl ester, in an organic solvent such as dimethylformamide, converts in the heat, whereby through Etherification and subsequent cyclization in the same operation of the corresponding 3- (4-pyridyl) -, 3- (3-pyridyl) - or 3- (2-pyridyl) -2-benzofurancarboxylic acid lower alkyl ester obtained will. From this one obtains by hydrolysis, e.g. in Usually with a lower alkanolic alkali hydroxide solution, the corresponding free carboxylic acid, which in a manner known per se, e.g. by heating with copper powder, in Quinoline at its boiling point, for the corresponding

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bond of the general formula VI is decarboxylated. Of those required as starting materials for this reaction sequence (o-Hydroxybenzoyl) -pyridines 4- (o-Hydroxybenzoyl) -pyridine is described in British patent 1,231,783. Isomers of this and substituted analogs can, for example, by reacting optionally substituted o-Methoxyphenyl magnesium bromide in diethyl ether or a other ethereal solvents with nicotinonitrile, picolinonitrile or isonicotinonitrile can be obtained.

The compounds of the general formula VI are obtained by quaternizing with reactive esters of Hydroxy compounds of the general formula III, the compounds of the general formula V, of which the l-methyl-4- (3-benzofuranyl) pyridinium iodide in U.S. Patent 3,678,062. The quaternization can be carried out in the usual way an inert organic solvent, e.g. in the lower alkanol on which the reactive ester is based, further e.g. in ethyl acetate, tetrahydrofuran or dioxane Room temperature or moderately elevated temperatures up to approx.

Starting materials of the general formula II. In which Ac is the acyl radical of a carbonic acid or thiocarbonic acid -ha! best s © a cyano residue or a chlorocarbonyl residue is »let us look, for example, from

80B8T2 / 0967

Speaking compounds of the general formula I in which R-. an easily removable group, such as the allyl or benzyl group and especially the methyl group, by reaction with chloroformic acid esters or thioesters .. especially with chloroformic acid ethy ester, -tert.butyl ester, -benzyl ester, -phenyl ester or chlorothioformic acid-S-methyl ester, or with cyanogen bromide or phosgene in an inert organic solvent in the UHrme, e.g. in Produce toluene at its boiling point.

Instead of the aforementioned

Carbonic acid derivatives can also be used, for example, carboxylic acid halides such as acetyl bromide or benzoyl chloride, but requires the appropriate reaction to split off the Group R - mostly more energetic conditions and is less complete than e.g. when using ethyl chloroformate and especially cyanogen bromide. Of importance is that from the implementation of suitable compounds in general Formula I with chloroformic acid esters, Brcmcyan or similar reagents and the subsequent hydrolysis according to a) existing reaction sequence especially for the preparation of end products of the general formula I, in where R-, a hydrogen atom and X and Y together are one mean additional bond. Thus, in the production

609812/0967

Such starting materials of the general formula II, in particular, start from compounds of the narrower general formula Ib in which R 1 is a methyl, allyl or benzyl group. Also starting from compounds of the general formula Ib ₉ in which R _{1 is} a methyl group, the corresponding adducts are prepared by reaction with azodicarboxylic acid di-lower alkyl esters, such as azodicarboxylic acid diethyl ester, for example in methanol or preferably by boiling for several hours in cyclohexane, cf. Ann. Chem. 590, 37-54 (1954) and J.prakt. Chern (4) 26., 218-224 (1964).

Of the starting materials of the general formula II with a -NO group as the radical Ac, there are above all those of interest which is a methyl or other lower carbon atom on the carbon atom adjacent to the acylated nitrogen atom Carry alkyl group, which in corresponding compounds without this group by metalation and subsequent reaction with a lower alkyl halide was introduced.

Starting materials of the general formula IV for the reduction according to c), in particular those with a Additional bonding at the point of X and Y can be carried out in accordance with or analogously to the aforementioned preparation

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of starting materials of the general formula II using suitable carboxylic acid halides from corresponding compounds of the general formula I, especially those of the narrower formula Ib with a methyl group as R, but it is particularly suitable for the preparation of compounds of the general formula IV with hydrogen Atoms than X and Y are more advantageous to start from compounds of the general formula Ia, especially from the compounds of this formula with hydrogen atoms as X and Y which are readily accessible by hydrogenation according to the process, and to start their imino group in the usual way, for example by reaction with suitable, i.e. ,H. with the definition of R ₁ matching carboxylic acid halides in the presence of sMurebinding agents such as potassium carbonate, in an inert organic solvent such as dioxane, or in pyridine or its mixture with inert organic solvents at room temperature or moderately elevated temperatures.

Starting materials of the general formula VlI are obtained in particular by reacting corresponding, in 3-position by halogen, especially bromine-substituted benzofurans with magnesium or especially alkali metal compounds, such as butyllithium, and immediately following conversion of the resulting organometallic compounds

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with according to the definition for R, and optionally according to the definitions for R ₁ -. A and B substituted 4-piperidones and 3-piperidones, some of which are known and others can be prepared analogously to the known compounds.

The present invention also relates to such modifications of those mentioned under a) to i) Processes and their preliminary stages, in which a process is terminated at any stage or in which one of one occurring at some stage as an intermediate Compound runs out and carries out the missing steps: or a starting material under the reaction conditions forms or optionally used in the> form of a salt. If the required starting materials are optically active, both the racemates and the isolated antipodes, or in the presence of diastereomerism either Mixtures of racemates or certain racemates or likewise isolated antipodes can be used. Also such Starting materials can optionally be used in the form of salts. Preferably one uses for the Carrying out the reactions according to the invention are those starting materials which are specific to those mentioned at the beginning Lead groups of end products.

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Depending on the process conditions and starting materials, the end products are obtained in free form or in the form of their acid addition salts likewise included in the invention, or optionally also than hydrates of the latter. The acid addition salts of the new compounds of general formula I can be used in can be converted into the free bases in a manner known per se, e.g. with basic agents such as alkalis or ion exchangers. On the other hand, the compounds of the general formula I obtained by the process according to the invention can, if desired in the usual way into their addition salts with inorganic ones or organic acids are converted. For example, one adds a solution of a compound of the general Formula I in an organic solvent with the acid desired as the salt component. Preferably one chooses for the implementation of organic solvents, in which the resulting salt is sparingly soluble, so that it through Filtration can be separated. Such solvents are e.g. ethyl acetate, methanol, ether, acetone, methyl ethyl ketone, Acetone-ether, acetone-ethanol, methanol-ether or ethanol-ether.

For use as medicinal substances, pharmaceutically acceptable acid addition salts can be used instead of free bases

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are used, i.e. salts with acids whose No anions at the dosages in question are toxic. It is also advantageous if the salts to be used as medicinal substances can be readily crystallized and are not or only slightly hygroscopic. For salt formation

with compounds of the general formula I, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 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, mandelic acid and emboxylic acid are used will.

The new compounds can act as optical antipodes, depending on the variety of starting materials and working methods or racemates or, if they contain at least two asymmetric carbon atoms, also as mixtures of isomers (Mixtures of racemates) are present. Isomer mixtures (racemic mixtures) obtained can be due to the physico-chemical Differences between the components in a known manner in the two stereoisomeric (diastereomeric) pure racemates be separated, for example by chromatography and / or fractional crystallization.

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2 b 3 7 8 3

Preserved racemates can be laughably known Methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reaction with an optically active acid which forms salts with the racemic compound and separation of the salts thus obtained, for example on the basis of their different solubilities, into the Disassemble diastereomers from which the antipodes can be released by the action of suitable means. Optically active acids that are particularly common are e.g. the D- and L-forms of tartaric acid, di-o-toluyltartaric acid, Malic acid, mandelic acid, camphorsulfonic acid or quinic acid. It is advantageous to isolate the more effective of the two antipodes. ..

The new active ingredients are administered orally, rectally or parenterally. The dosage depends on the mode of administration, the species, the age and the individual condition. The daily doses of the free bases or of pharmaceutically acceptable salts of the free bases range between Öjl ^ s / ^ S ^and 10 mg / kg for warm-blooded animals. Suitable unit dosage forms, such as dragees, tablets ,. Suppositories or ampoules preferably contain 5-100 mg of an active ingredient according to the invention.

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2B37837 -iff-

Unit dosage forms for oral use contain preferably between 5-90% of an active ingredient Compound of the general formula I or a pharmaceutical acceptable salt of such. To produce them, the active ingredient is combined, for example, with solid, powdery ones. Carriers such as lactose, sucrose, sorbitol, mannitol; Starches, such as potato starch, shark starch or amylopectin, also laminaria powder or citrus pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants, such as magnesium or calcium tear at or polyethylene glycols, to tablets or dragee cores. The dragee cores are coated with concentrated, for example Sugar solutions, which e.g. still contain Arabic gum, talc and / or titanium dioxide, or with a varnish that is in volatile organic solvents or solvent mixtures is resolved. Dyes can be added to these coatings, e.g. to identify various active substances cans.

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Other oral unit forms are suitable Push-fit capsules made of gelatine and soft, closed capsules made of gelatine and a plasticizer such as glycerine. The push-fit capsules contain the active ingredient preferably as granules, e.g. mixed with fillers such as corn starch, and / or Lubricants such as talc or magnesium stearate, and optionally Stabilizers, such as Katriunmetabisulfit (Ka ^ S ^ O, -) or Ascorbic acid. In soft capsules, the active ingredient is preferably in suitable liquids, such as liquid polyethylene glycols, dissolved or suspended, it also being possible for stabilizers to be added.

As unit dosage forms for rectal use For example, suppositories come into consideration, which consist of a combination of an active ingredient with a suppository base exist. Natural or synthetic triglycerides, paraffin hydrocarbons, Polyethylene glycols or higher alkanols. Gelatin rectal capsules made from a combination are also suitable of the active ingredient with a base material. As a base Liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons are suitable.

Ampoules for parenteral, especially intramuscular Administration preferably contain a water-soluble salt of an active ingredient in a concentration of preferably

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0.5 - 5%, if necessary together with suitable stabilizing agents and buffer substances, in aqueous solution.

The following rules are intended to explain the manufacture of tablets and capsules in more detail.

a) 250 g of 1-methyl-4- (3-benzofuranyl) -1, 2,3,6-tetrahydropyridine hydrochloride are mixed with 175.80 g of lactose and 169.70 g of potato starch, the mixture with an alcoholic Solution of 10 g of stearic acid moistened and granulated through a sieve. After drying, mix 160 g of potato starch, Add 200 g talc, 2.50 g magnesium tear at and 32 g colloidal silicon dioxide and press the mixture into 10,000 tablets each 100 mg weight and 25 mg active ingredient content, if desired can be provided with partial notches for finer adjustment of the dosage.

b) To produce 1000 capsules, each with 10 mg active ingredient content, mix 10 g of 4- (3-benzofuranyl) piperidine hydrochloride with 248 g of lactose, moisten the mixture evenly with an aqueous solution of 2 g of gelatin and granulate them through a suitable sieve (e.g. Sieve III according to Ph.HeIv. V). The granulate is mixed with 10.0 g of dried material Corn starch and 15.0 g talc and fill it evenly into 1000 hard gelatine capsules of size 1.

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The following examples illustrate the preparation of the new compounds of the general formula I and of hitherto Zx ^ ischenprodukte not described in more detail, but should the Do not limit the scope of the invention in any way. The temperatures are given in degrees Celsius.

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example 1

7.5 g of 1-methyl-4- (3-benzofuranyl) -4-piperidinol are in 180 ml of glacial acetic acid and 60 ml of 12-n. Hydrochloric acid refluxed for 7 hours. The solution is brought to room temperature cooled and evaporated in vacuo, the evaporation remains in Dissolved 250 ml of water and extracted the aqueous phase twice with 100 ml of ethyl acetate. Then the aqueous solution adjusted to pH 12 by adding 10% sodium hydroxide solution and extracted with 500 ml of chloroform. The chloroforral solution is dried with sodium sulfate, suction filtered and evaporated. The crude product is dissolved in 100 ml of chloroform and chromatographed on 500 g of aluminum oxide (neutral, activity III). The first fractions eluted with a total of 1 liter of chloroform yield pure 1-methyl-4- (3-benzofuranyl) -l, 2,3,6-tetrahydropyridine after evaporation. Its hydrochloride is made with hydrogen chloride in ethyl acetate and from Acetone recrystallizes, whereupon it melts at 248-250 <■

The raw material is produced as follows:

a) 100 ml 2-n. Solution of butyllithiuni in hexane (Fluka) are pre-cooled to -70 to -80. To this solution a solution of 39.4 g (0.2 mol) of 3-bromobenzofuran in 150 ml of abs is at a temperature of -70 °. Diethyl ether inside -

6 09812/0967

added dropwise half past 30 minutes. The solution is then stirred at -70 for a further 2 hours. Then there is a solution of 23.0 g (0.203 mol) of 1-methyl-4-piperidone in 70 ml of abs. Diethyl ether was added dropwise within 30 minutes, the reaction temperature being reduced to -70 hours by external cooling. Then the reaction solution is stirred for a further 2 hours at -70 °.

The reaction solution is then warmed to -5 and poured onto 300 g of ice. The organic phase is separated off and the aqueous phase two more times with 250 ml each Ethyl acetate extracted. The organic phases are combined, dried over sodium sulfate, suction filtered and evaporated. The residue is in 300 ml of 2-n. Dissolved hydrochloric acid and washed the acidic solution with ether. Then the sour aqueous solution by adding 10% sodium hydroxide solution adjusted to pH 12 and extracted with one liter of chloroform. The chloroform solution is made with sodium sulfate dried, suction filtered and evaporated, the crude 1-methyl-4- (3-benzofuranyl) -4-piperidinol is obtained. The evaporation residue is dissolved in chloroform and over 500 g of aluminum oxide (neutral, activity III) chromatographed. The first fractions eluted with 7 liters of chloroform yield after evaporation pure 1-methyl-4- (3-benzofuranyl) -4-piperidinol. the After recrystallization from ethyl acetate-hexane, the free base melts at 149-151 °.

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Example 2

Analogously to example 1 one obtains

from 7.5 g of l-benzyl-4- (3-benzofuranyl) -4-piperidinol the 1-Benzyl ~ 4- (3-benzofuranyl) -1,2,3,6-tetrahydrofuran and its hydrochloride,

from 7.5 g of l-methyl-4- (5-chloro-3-benzofuranyl) -4-piperidinol das 1-methyl-4- (5-chloro-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

from 7.5 g of 1-methyl-4- (6-chloro-3-benzofuranyl) -4-piperidinol the 1-methyl-4- (6-chloro-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

from 7.5 g of l-methyl-4- (5-methyl-3-benzofuranyl) -4-piperidinol das 1-methyl-4- (5-methyl-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

from 7.5 g of l-methyl-4- (6-methyl-3-benzofuranyl) -4-piperidinol das l-methyl-4- (6-methyl-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

from 7.5 g of 1-methyl-4- (5-methoxy-3-benzofuranyl) -4-piperidinol the 1-methyl-4- (5-methoxy-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

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-HS '

from 7.5 g of 1-methyl-4- (6-methoxy-3-benzofuranyl) -4-piperidinol the 1-methyl-4- (6-methoxy-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

from 7.5 g of l-methyl-4- (5, o-dichloro-S-benzofuranyl) -4-piperidinol the 1-methyl-4- (5,6-dichloro-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

from 7.5 g of 1-methyl-4- (5,6-dimethyl-3-benzofuranyl) -4-piperidinol l-methyl-4- (5,6 ~ dimethyl-3-benzofuranyl) -l, 2,3,6-tetrahydropyridine and its hydrochloride,

from 7.5 g of 1-methyl-4- (5,6-dimethoxy-3-benzofuranyl) -4-piperidinol the 1-methyl-4- (5.6-dmethoxy-3-benzofuranyl) -l, 2,3,6-tetratrydropyridine and its hydrochloride.

a) The first-mentioned starting material is analogous

Example 1 a) using 37.9 g (0.203 mol) of 1-benzyl-4-piperidone obtain.

The other starting materials are analogous to Example 1 a) using 0.2 mol each of the correspondingly substituted 3-bromobenzofurans, which, for example, are analogous to those described in Chem.Ber. 35 , 1636 (1902) and in US Pat. No. 3,010,971, Example 11, for the preparation process for the 3-bromobenzofuran which can be obtained from the correspondingly substituted benzofurans by bromine addition and elimination of hydrogen bromide.

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To a solution of 9.5 g (0.03 mol) of 1-methyl-4- (3-benzofuranyl) pyridinium iodide a solution of 9.5 g of sodium borohydride is made in 160 ml of methanol with stirring and external cooling added dropwise in 26 ml of water so that the reaction temperature does not rise above 38 °. Then the Solution stirred at room temperature for 20 hours. The methanol is then evaporated off in vacuo, and the remaining aqueous phase extracted three times with 300 ml of ethyl acetate each time. The combined organic phases are washed twice with 500 ml of water each time, dried over sodium sulfate and filtered and evaporated. The obtained 1-methyl-4- (3-benzofuranyl) -1,2,3,6-tetrahydropyridine is fractionated in a high vacuum, the desired base distilling at 109-111 0.04 torr.

The starting material is prepared as follows: a) 12 g of 4- (o-hydroxybenzoyl) pyridine (cf. British Patent 1,231,783); 11 g of methyl bromoacetate, 70 g of potassium carbonate and 0.5 g of potassium iodide are poured into 250 ml Dimethylformamide heated to 100-110 ° for 4 hours with stirring. The warm solution and the filter residue are then sucked in washed with 150 ml of warm dimethylformamide. The combined filtrates are evaporated in vacuo and the Residue dissolved in one liter of ethyl acetate. The organic phase is washed three times with one liter of water each time, dried over sodium sulfate, suction filtered and evaporated.

609812/0967

The remaining oil is dissolved in a little methylene chloride dissolved and chromatographed over 300 g of aluminum oxide (activity II, neutral). The first, with 2 liters Methylene chloride eluted fraction is the 3- (4-pyridyl) -2-benzo · furancarboxylic acid methyl ester, which after recrystallization from diisopropyl ether melts at 117-119 °.

b) To a solution of 15 g of 3- (4-pyridyl) -2-benzofurancarbons acid methyl ester in 260 ml of ethanol are 20 g Sodium hydroxide was added and the solution was refluxed under nitrogen for one hour. Then that will Ethanol evaporated in vacuo, the residue dissolved in 300 ml of water, suction filtered and the clear filtrate by addition from 2-n. Hydrochloric acid adjusted to pH 5.5. The 3- (4-pyridyl) -2-benzofurancarboxylic acid precipitates out; the crystals are suction filtered and washed with 100 ml of water in portions. After recrystallization from Methanol melts the carboxylic acid obtained at 259-260 °.

c) The solution of 6.0 g of 3- (4-pyridyl) -2-benzofurancarboxylic acid in 45 ml of quinoline is refluxed with 0.7 g of copper powder with stirring and under nitrogen for 30 minutes cooked. The solvent is then evaporated off in vacuo. The residue is fractionated in a high vacuum. The 4- (3-benzofuranyl) pyridine distilled at 129-130 ° / O, 06 torr.

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d) To a solution of 5.5 g of 4- (3-benzofuranyl) pyridine 3 ml of methyl iodide are added in 200 ml of methanol. the The solution is stirred for 15 hours at a temperature of 50 °. The solution is then cooled to -20 ° and the crystallized Iodide sucked off. The l-methyl-4- (3-benzofuranyl) pyridinium iodide melts after recrystallization from methanol at 242-245 °.

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Example 4

To a solution of 1.0 g of 1-methyl-4- (5-chloro-3-benzofuranyl) pyridinium iodide a solution of 1.0 g of sodium borohydride is made in 10 ml of methanol with stirring and external cooling in 3 ml of water added dropwise so that the reaction temperature does not over 35 rises. The solution is then stirred for 20 hours at room temperature. Then the methanol is in vacuo evaporated, the remaining aqueous phase extracted twice with 7 ml of chloroform each time, the chloroform solution over sodium sulfate dried, filtered and evaporated. The obtained 1-methyl-4- (5-chloro-3-benzofuranyl) -1, 2,3,6-tetrahydropyridine is recrystallized from hexane and then converted into its hydrochloride with a solution of hydrogen chloride in ethyl acetate .

Analogously one obtains

from 1.0 g of l-methyl-4- (6-chloro-3-benzofuran3 ^ 1) -pyridinium iodide l-methyl-4- (6-chloro-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

from 1.0 g of 1-methyl-4- (5-methyl-3-benzofuranyl) pyridinium iodide l-methyl-4- (5-methyl-3-benzofuranyl) -l, 2,3,6-tetrahydropyridine and its hydrochloride,

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from 1.0 g of 1-methyl-4- (6-methyl-3-benzofuranyl) pyridinium iodide the 1-methyl-4- (6-methyl-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

from 1.0 g of 1-methyl-4- (5-methoxy-3-benzofuranyl) pyridinium iodide 1-methyl-4- (5'-methoxy-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

from 1.0 g. 1-methyl-4- (6-ynethoxy-3-benzofuranyl) pyridinium iodide 1-methyl-4- (6-methoxy-3-benzofuranyl) -1,2,3,6-tetrahydropy ~ ridin and its hydrochloride,

from 1.0 g of 1-methyl-4- (5,6-dimethyl-3-benzofuranyl) pyridinium iodide the 1-methyl-4- (5,6-dimethyl-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride,

from 1.0 g of 1-methyl-4- (5,6-diinethoxy-3-benzofuranyl) pyridinium iodide the 1-methyl-4- (5,6-dimethoxy-3-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride.

The first-mentioned starting material can be produced as follows:

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- 5t-

a) 17.4 g (0.11 mol) of 4-bromopyridine in 50 ml of abs. Dissolved diethyl ether and the solution cooled to -80 °. To this solution at a temperature of -70 285 ml of a 0.56-n. Solution of butyllithium in abs. Diethyl ether was added dropwise over the course of 20 minutes and the solution was stirred at -70 for a further 2 hours. Then the solution of 18.6 g (0.11 mol) 5-chloro-3 (2H) -benzofuranone in 600 ml abs. Diethyl ether was added dropwise within an hour. The reaction temperature increases from -80 to -60 and the solution is stirred for a further 8 hours at this temperature. The reactant solution is thereupon warmed up to 0 and poured onto 500 g of ice. The organic phase is separated off and the aqueous phase still extracted twice with 300 ml of ethyl acetate each time. The organic phases are combined, dried over sodium sulfate and suction filtered and evaporated. The residue is dissolved in 300 ml of a 10% solution of methanesulfonic acid in water and the acidic solution extracted with 150 ml of ether. The aqueous phase is then made up by adding 10% sodium hydroxide solution adjusted to pH 12 and extracted with 500 ml of chloroform. The chloroform solution is dried with sodium sulfate and suction filtered and evaporated. The crude 2,3-dihydro-3- (4-pyridyl) -5-chloro-3-benzofuranol is dissolved in 50 ml of chloroform and chromatographed on 600 g of aluminum oxide (neutral, activity III),

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The first fraction eluted with 2 liters of chloroform will not further edited. The second fraction eluted with 2 liters of chloroform gives pure 2,3-dihydro-3- (4-pyridyl) -5-chloro-3-benzofuranol, which after recrystallization from ethyl acetate-hexane melts at 161-163.

b) 2.5 g of 2,3 ~ dihydro-3- (4-pyridyl) -5-chloro-3-benzofuranol and 0.6 g of potassium bisulfate are heated to 190 for 15 minutes. After cooling, the melt is in excess, aqueous sodium hydroxide solution and extracted with chloroform. The chloroform solution is dried with sodium sulfate, sucked and evaporated, leaving the crude 4- (5-chloro-3-benzofuranyl) pyridine remains behind.

c) 1.4 g of 4- (S-chloro-S-benzofuranyl) pyridine become dissolved in 5 ml of methanol and stirred with 3 ml of methyl iodide for 15 hours at 40-45 °. The solution is then cooled to 0 ° and that excreted salt sucked off. The filter material is washed with a little isopropanol and then recrystallized from isopropanol, the l-methyl-4- (5-chloro-3-benzofuranyl) pyridinium iodide is obtained.

The other starting materials are obtained by reacting 0.11 mol each of the appropriately substituted, known 3 (2H) -benzofuranones with 0.11 mol of 4-bromopyridine analogous to Example 4 a),

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Dehydration of the substituted 2,3-dihydro-3- (4-pyridyl) -3-benzofuranols obtained analogously to Example 4 b),

and quaternization of the substituted 4- (3-benzofuranyl) pyridines obtained with methyl iodide analogously to Example 4 c) manufactured.

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5.33 g (0.025 mol) of l-methyl-4- (3-benzofuranyl) -1,2,3,6-tetrahydropyridine are dissolved in 200 ml of ethanol and dried in the presence of 0.6 g of palladium-carbon catalyst (5 / 0 hydrogenated at a temperature between 20 ° and 25 ° under normal pressure * After the theoretical amount of hydrogen has been absorbed, the hydrogenation is interrupted, the catalyst is filtered off and the filtrate is evaporated dissolved in 100 ml of toluene and the solution was extracted twice with 100 ml of 10% aqueous methanesulfonic acid. the combined acidic aqueous extracts _o sodium hydroxide solution to pH 12 are adjusted by adding 407 and extracted three times with 300 ml of chloroform The organic phases are combined, dried with sodium sulfate, suction filtered and evaporated * The remaining 1-methyl-4- (3-benzofuranyl) piperidine is converted into its hydrochloride with a solution of hydrogen chloride in ethyl acetate, which melts after Umkrista llization from methyl ethyl ketone at 205 °.

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Using 0.1 g of catalyst is obtained analogously in 20 ml of ethanol

from 0.45 g of 1-methyl-4- (5-methyl-3-benzofuranyl) -1, 2,3,6-tetrahydropyridine 1-methyl-4- (5-methyl-3-benzofuranyl) piperidine and its hydrochloride,

from 0.45 g of 1-methyl-4- (6-methyl-3-benzofuranyl) -1,2,3,6-tetrahydropyridine 1-methyl-4- (6-methyl-3-benzofuranyl) piperidine and its hydrochloride, and

from 0.48 g of 1-methyl-4- (5,6-dimethyl-3-benzofuranyl) -1, 2,3,6-tetrahydropyridine 1-methyl-4- (5,6-dimethyl-3-benzofuranyl) piperidine and its hydrochloride.

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253783?

Example 6 - 56 "

5.33 g (0.025 mol) of the l-methyl-3- (3-benzofuranyl) tetrahydropyridine obtained in g) (see below) are hydrogenated analogously to Example 5 to the l-methyl-3- (3-benzofuranyl) piperidine and leads the latter with hydrogen chloride in Ethyl acetate in its hydrochloride.

The starting material is prepared as follows: a) To a solution of o-methoxyphenyl magnesium bromide (prepared as usual from 45 g of o-bromoanisole, 5.8 g of magnesium turnings, 0.1 g of iodine in 400 ml of diethyl ether) is a Solution of 20.8 g (0.20 mol) of nicotinonitrile in 200 ml of abs. Diethyl ether was added dropwise. The reaction solution is then refluxed for a further hour with stirring and then cooled to 5 °. Now 25 ml of water and then 300 ml of a saturated aqueous ammonium chloride solution are slowly added dropwise. The aqueous phase is then separated off and extracted with 500 ml of diethyl ether. The combined organic phases are washed twice with 300 ml of water each time and extracted four times with 150 ml of a 10% aqueous methanesulfonic acid solution each time. The combined acidic phases are by adding 2-n. Ammonium hydroxide solution adjusted to pH 10 and extracted three times with 500 ml of diethyl ether each time.

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The ether phases are washed with 500 ml of water, with Sodium sulfate dried, suction filtered and evaporated. The residue is fractionated in a high vacuum. The received 3_ (o-Methoxybenzoyl) pyridine distilled at 140 ° / O, O5 Torr.

b) In a solution of 13 g of 3- (o-methoxybenzoyl) pyridine hydrogen chloride is passed in 60 ml of pyridine until the strongly exothermic reaction subsides. Then will the solution was refluxed for one hour, cooled to 140 ° and poured onto 500 ml of an ice-water mixture while stirring poured. By adding 2-n. aqueous ammonium hydroxide solution, the aqueous phase is adjusted to pH 9 and extracted three times with 500 ml of diethyl ether each time. The organic phases are washed five times with 500 ml of water each time and then three times with 300 ml 2-n. Sodium hydroxide solution extracted. The alkaline solution is made by adding from 2-n. Hydrochloric acid adjusted to pH 6 and extracted three times with 500 ml of chloroform each time. The organic Phases are washed once with one liter of water, dried with sodium sulfate, suction filtered and evaporated. The pure 3- (o-Hydroxybenzoyl) pyridine melts after recrystallization from cyclohexane at 72-74 °.

609812/0967

c) 14.5 g of 3- (o-hydroxybenzoyl) pyridine, 13.4 g of methyl bromoacetate, 82.5 g of potassium carbonate and 0.5 g of potassium iodide are dissolved in 250 ml of dimethylformamide with stirring Heated for 1 1/2 hours to 105-110 °. Then the warm solution is sucked and the filter residue with 200 ml warm Washed dimethylformamide. The combined filtrates are evaporated in vacuo and the residue in a Liters of ethyl acetate dissolved. The resulting solution is used three times washed with one liter of water, dried over sodium sulfate, suction filtered and evaporated. The methyl 3- (3-pyridyl) -2-benzofurancarboxylic acid obtained after recrystallization from cyclohexane melts at 117-119 °.

d) To a solution of 7.5 g of 3- (3-pyridyl) -2-benzofurancarbon- · methyl acid ester in 130 ml of methanol, 9 g of sodium hydroxide are added and the solution is stirred and under nitrogen refluxed for an hour. The ethanol is then evaporated in vacuo, the residue is dissolved in 300 ml of water, sucked and the filtrate by adding 2-n. Hydrochloric acid adjusted to pH 5.5. The excreted crystal Ie of the 3- (3-pyridyl) -2-benzofurancarboxylic acid are suction filtered. After recrystallization from tetrahydrofuran, the substance melts at 251-252 °.

609812/0967

e) A solution of 3.7 g of 3- (3-pyridyl) -2-benzofurancarboxylic acid in 35 ml of quinoline is mixed with 0.7 g of copper powder while stirring and refluxed under nitrogen for 35 minutes. The solution is cooled to 20 °, suction filtered and the filtrate im Evaporated in vacuo. The residue is dissolved in a little methylene chloride and over 150 g of aluminum oxide (activity II, neutral) chromatographed. The first fractions eluted with a total of 2 liters of methylene chloride give after evaporation of the solvent in vacuo, pure 3- (3-benzofuranyl) pyridine. Its hydrochloride is treated with hydrogen chloride in ethyl acetate and recrystallized from methyl acetate, whereupon it melts at 272-275 °.

f) Analogously to Example 3 d), starting from 5.5 g of 3- (3-benzofuranyl) pyridine, 1-methyl-3- (3-benzofuranyl) pyridinium iodide is obtained.

g) Analogously to Example 3, using 9.5 g (0.03 mol) of 1-methyl-3- (3-benzofuranyl) pyridinium iodide is obtained a crude l-methyl-3- (3-benzofuranyl) tetrahydropyridine that can be distilled in a high vacuum.

609812/0967

Example 7 fJQ - 253/8

5.33 g (0.025 mol) of the l-methyl-2- (3-benzofuranyl) tetrahydropyridine obtained in g) (see below) are hydrogenated analogously to Example 5 to the l-methyl-2- (3-benzofuranyl) piperidine and leads the latter with hydrogen chloride in ethyl acetate into its hydrochloride.

The starting material is prepared as follows: a) To a solution of o-methoxyphenyl magnesium bromide, prepared from 45 g (0.24 mol) of o-bromoanisole, 5.8 g of magnesium turnings, 0.1 g of iodine in 150 ml of absolute diethyl ether within one hour a solution of 20.8 g (0.20 mol) of picolinonitrile in 200 ml of abs. Diethyl ether was added dropwise. The reaction solution is then boiled for a further hour with stirring and reflux. Then will after cooling the solution to 5 ° slowly 25 ml of water and then 300 ml of a saturated aqueous. Ammonium chloride solution was added dropwise. The aqueous phase is then separated off and washed with 500 ml of diethyl ether extracted. The combined organic phases are washed twice with 300 ml of water each time and four times with each 150 ml of a 10% aqueous methanesulfonic acid solution extracted. The combined acidic phases are by adding 2-n. Ammonium hydroxide solution to pH set of 10 and three times with 500 ml each

609812/0967

Diethyl ether extracted. The organic phases are washed with 500 ml of water, dried with sodium sulfate, sucked and evaporated. The residue is fractionated in a high vacuum. The 2- (o-methoxybenzoyl) pyridine distilled at 140 ° / 0.06 Torr and melts after recrystallization from hexane at 68-70 °.

b) In a solution of 21 g of 2- (o-methoxybenzoyl) pyridine in 90 ml of pyridine is hydrogen chloride as long initiated until the exothermic reaction (temperature increase up to 125 °) subsides again. Then will the solution at reflux temperature for 75 minutes with stirring heated from about 2.10-220 °, then cooled to 180 ° and poured into 500 ml of an ice-water mixture while stirring. By adding 2-n. aqueous ammonium hydroxide solution, the aqueous phase is adjusted to pH 9 and extracted three times with 500 ml of diethyl ether each time. The organic phases are five times with each 500 ml of water and then washed three times with 300 ml of 2-n. extracted aqueous sodium hydroxide solution. The alkaline extracts are made by adding 2-n. Hydrochloric acid adjusted to pH 6 and three times with 500 ml of diethyl ether extracted each time. Vjcrden the organic phases washed once with a liter of water, with sodium sulfate

60981 2/0967

fat dried, sucked and evaporated. The received 2- (o-Hydroxybenzoyl) pyridine melts after recrystallization from cyclohexane at 54-55 °.

c) 10.7 g of 2- (o-hydroxybenzoyl) pyridine, 9.8 g of methyl bromoacetate, 60 g of potassium carbonate (anhydrous) and 0.5 g of potassium iodide are dissolved in 175 ml of dimethylformamide dissolved or suspended and stirred at 130-135 ° for 1 1/2 hours. The warm reaction mixture is then suction filtered and the filter material is washed with 100 ml of warm dimethylformamide. The combined filtrates are evaporated in vacuo, the residue is dissolved in 500 ml of methyl acetate and the resulting The solution was washed three times with 500 ml of water each time, dried with sodium sulfate, suction filtered and evaporated, the methyl 3- (2-pyridyl) -2-benzofurancarboxylate being obtained is obtained; M.p. 98 ° after recrystallization from diethyl ether.

d) Analogously to Example 6 d), the hydrolysis of 7.5 g of methyl 3- (2-pyridyl) -2-benzofurancarboxylate is obtained 3- (2-pyridyl) -2-benzofurancarboxylic acid.

e) Analogously to example 6 e) is obtained by decarboxylation from 3.4 g of 3- (2-pyridyl) -2-benzofurancarboxylic acid, 2- (3-benzofuranyl) pyridine.

609812/096 7

f) Analogously to Example 3 d), starting from 5.5 g of 2- (3-benzofuranyl) pyridine, 1-methyl-2- (3-benzofuranyl) pyridinium iodide is obtained.

g) Analogously to Example 3, using 9.5 g (0.03 mol) of 1-methyl-2- (3-benzofuranyl) pyridinium iodide a crude 1-methyl-2- (3-benzofuranyl) -tetrahydropyridine which can be distilled in a high vacuum.

609812/0967

- 6V-

Example 8

0.50 g (0.002 mol) l-methyl-4- (5-chloro-3-benzofuranyl) 1,2,3,6-tetrahydropyridine are dissolved in 15 ml of methanol and in the presence of 0.10 g of platinum oxide at a temperature between 20-30 and hydrogenated under normal pressure. After the theoretical, i.e. equimolar, amount of hydrogen has been absorbed, the hydrogenation takes place interrupted, the catalyst filtered off and the filtrate evaporated in vacuo. The residue is dissolved in a little chloroform dissolved and chromatographed on 3 g of aluminum oxide (activity II, neutral) and the main product eluted with chloroform l-Methyl-4- (5-chloro-3-benzofuranyl) piperidine purified by recrystallization from hexane and treated with a solution of hydrogen chloride converted into its hydrochloride in ethyl acetate.

Analogously one obtains

starting from 0.50 g of 1-methyl-4- (δ-chloro-S-benzofuranyl) -1,2,3,6-tetrahydropyridine l-methyl-4- (6-chloro-3-benzofuranyl) piperidine and its hydrochloride, and

starting from 0.57 g of 1-methyl-4- (5, δ-dichloro-S-benzofuranyl) -1,2,3,6-tetrahydropyridine the 1-methyl-4- (5,6-dichloro-3-benzofuranyl) piperidine and its hydrochloride.

609812/0967

Example 9

0.49 g (approx. 0.002 mol) 1-methyl-4- (5-methoxy-3-

benzofuranyl) -1,2,3,6-tetrahydropyridine are dissolved in 10 ml of methanol and hydrogenated in the presence of 0.1 g of palladium-carbon catalyst (57o Pd) at a temperature of 40-50 and under normal pressure. After the equimolar amount of hydrogen has been absorbed, the hydrogenation is interrupted, the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is dissolved in a little chloroform and chromatographed on 10 g of aluminum oxide (activity II, neutral). 1-Methyl-4- (5-methoxy-3-benzofuranyl) piperidine is eluted as the main product with chloroform. It is purified by recrystallization from hexane and converted into its hydrochloride with a solution of hydrogen chloride in ethyl acetate.

In an analogous way one obtains

by hydrogenation of 0.49 g of 1-methyl-4- (6 ~ methoxy-3-benzofuranyl) 1,2,3,6-tetrahydropyridine, 1-methyl-4- (6-methoxy-3-benzofuranyl) piperidine and its hydrochloride, and

by hydrogenation of 0.55 g of 1-methyl-4- (5,6-dimethoxy-3-benzofuranyl) -1,2,3,6-tetrahydropyridine the 1-methyl-4- (5,6-dimethoxy-3-benzofuranyl) piperidine and its hydrochloride. ·

609812/0967

Example 10

-64-

0.59 g (0.002 moles) of 1-benzyl-4- (3-benzofuranyl) -1,2,3,6-tetrahydropyridine are dissolved in 5 ml of methanol and after adding 3.2 ml of 2.28% (w / v) methanol it is more likely to be hydrogen chloride solution (corresponding to one equivalent of HCl) and 0.1 g of palladium-carbon (5%) at a temperature between 20 to 30 and hydrogenated under normal pressure. After the equimolar amount of hydrogen has been absorbed, the hydrogenation is interrupted, the catalyst is filtered off and the filtrate is evaporated in vacuo, the l-benzyl-4- (3-benzofuranyl) piperidine remains behind. This is purified by recrystallization from hexane and treated with a solution of hydrogen chloride in Ethyl acetate converted into its hydrochloride.

6098 12/096 7

4.26 g (0.02 mol) of 1-methyl-4- (3-benzofuranyl) piperidine are dissolved in 85 ml of toluene and 3.9 g (0.04 mol) of ethyl chloroformate are added. The solution is stirred at 50 ° for 15 hours. A further 3.9 g of ethyl chloroformate are then added and the mixture is stirred at 50 ° for a further two hours. For working up, the excess ethyl chloroformate is distilled off under normal pressure, a small portion of the toluene being distilled off to completely remove it. The solution is then cooled to 70 °, then suction filtered and the filter residue is washed with 50 ml of toluene. The combined filtrates are in turn
after with 100 ml of water, 100 ml of a 10% aqueous methanesulfonic acid solution, 100 ml of water, 100 ml of 2-n. Washed sodium hydroxide solution and 100 ml of water, dried over sodium sulfate, filtered and evaporated. The remaining, crude 4- (3-benzofuranyl) -1-piperidinecarboxylic acid ethyl ester is uniform according to thin-layer chromatography and is processed further without purification.

3.0 g of the above 4- (3-benzofuranyl) -1-piperidinecarboxylic acid ethyl ester are dissolved in 35 ml of ethylene glycol solved. After adding 6.5 g of solid sodium hydroxide, the resulting cloudy solution becomes cloudy with vigorous stirring heated to 100 ° under nitrogen for 15 hours. The reaction solution is then cooled to 20 ° and twice

609812/0967

extracted with 150 ml of toluene each time. The combined organic phases are three times with 150 ml of a 10% aqueous Methanesulfonic acid solution extracted. Then the watery Solution through. Addition of 40% sodium hydroxide solution to the pH value 12 and extracted with 500 ml of chloroform. The chloroform solution is dried with sodium sulfate and filtered and evaporated. The evaporation residue is distilled in a high vacuum (short-path distillation), whereby the 4- (3-benzofuranyl) piperidine distilled at 140 ° below 0.4 torr. The hydrochloride is converted from the base with hydrogen chloride in ethyl acetate prepared and recrystallized from ethyl methyl ketone.

Analogously one obtains

using 4.26 g (0.02 mol) of 1-methyl-3- (3-benzofuranyl) piperidine the 3- (3-benzofuranyl) piperidine, and

using 4.26 g (0.02 mol) of l-methyl-2- (3-benzofuranyl) piperidine the 2- (3-benzofuranyl) -piperidine.

Similarly, but using 1.0 g of chloroformate in 25 ml of toluene in the first Stage and of 20 g of sodium hydroxide in 15 ml of ethylene glycol in the second stage carried out with the entire crude product and recrystallization of the crude base from hexane instead of high vacuum distillation, one obtains

609812/0967

from 1.24 g of l-methyl-4- (5-chloro-3-benzofuranyl) piperidine 4- (5-chloro-3-benzofuranyl) piperidine and its hydrochloride,

from 1.24 g of l-methyl-4- (6-chloro-3-benzofuranyl) piperidine 4- (6-chloro-3-benzo £ uranyl) piperidine and its hydrochloride,

from 1.41 g of methyl-4- (5, o-dichloro-S-benzofuranyl) piperidine 4- (5,6-dichloro-3-benzofuranyl) piperidine and its hydrochloride,

from 1.15 g of l-methyl-4- (5-methyl-3-benzofuranyl) piperidine 4- (5-methyl-3-benzofuranyl) piperidine and its hydrochloride,

from 1.15 g of l-methyl-4- (6-methyl-3-benzofuranyl) piperidine 4- (6-methyl-3-benzofuranyl) piperidine and its hydrochloride,

from 1.22 g of 1-methyl-4- (5,6-dimethyl-3-benzofuranyl) piperidine 4- (5,6-dimethyl-3-benzofuranyl) piperidine and its hydrochloride,

from 1.23 g of l-methyl-4- (5-methoxy-3-benzofuranyl) piperidine 4- (5-methoxy-3-benzofuranyl) piperidine and its hydrochloride,

from 1.23 g of l-methyl-4- (6-methoxy-3-benzofuranyl) piperidine 4- (6-methoxy-3-benzofuranyl) piperidine and its hydrochloride,

from 1.38 g of 1-methyl-4- (5,6-dimethoxy-3-benzofuranyl) piperidine 4- (5,6-Dijnethoxy-3-benzofuranyl) piperidine and its hydrochloride.

609812/0967

Example 12.

2.0 g of 4- (3-benzofuranyl) piperidine and 1.2 g of 3-bromopropine are dissolved in 50 ml of methanol and, after adding 10 g of potassium carbonate, stirred for 30 hours at room temperature. Then the reaction mixture is suction filtered, the suction filter is washed with 100 ml of chloroform and the combined filtrates evaporated in vacuo. The residue is dissolved in a little methylene chloride and 60 g of aluminum oxide (activity II, neutral) chromatographed. The first fractions, eluted with a total of 250 ml of methylene chloride, contain the 1- (2-propynyl) -4- (3-benzofuranyl) piperidine. The base can be recrystallized from hexane and, if desired, with a solution of hydrogen chloride in ethyl acetate in its hydrochloride be transferred, which recrystallized from the same solvent will.

Analogously one obtains

using 7.8 g of ethyl iodide, 1-ethyl-4- (3-benzofuranyl) piperidine and its hydrochloride;

using 6.8 g of cyclopropyl methyl bromide 1- (cyclopropylmethyl) -4- (3-benzofuranyl) piperidine and its hydrochloride, and

1-benzyl-4- (3-benzofuranyl) piperidine using 8.6 g of benzyl bromide and its hydrochloride.

609812/0967

Example 13 7i

2.5 g of 4- (3-benzofuranyl) piperidine are dissolved in 15 ml of formic acid solved. 1.5 ml of a 40% strength aqueous formaldehyde solution are added dropwise to this solution with stirring. That The reaction mixture is heated for 5 hours at 95-100 ° and then stirred for 15 hours at room temperature. This is followed by adding 2.5ml of conc. Hydrochloric acid made the solution strongly acidic and the solvent under Vacuum evaporated. The evaporation residue is dissolved in 2.5 ml of water, the non-basic substances with Toluene extracted, the aqueous phase by adding 10% aqueous sodium hydroxide solution to pH 12 and extracted three times with 75 ml of chloroform each time. The organic phases are combined over sodium sulfate dried, filtered and evaporated. The remaining crude 1-methyl-4- (3-benzofuranyl) piperidine is dissolved in ethyl acetate and with a solution of hydrogen chloride converted into its hydrochloride in ethyl acetate and the latter by recrystallization from methyl ethyl ketone cleaned.

609812/0967

Example 14 _

To a refluxing solution of 2.7 g of lithium aluminum hydride in 50 ml of tetrahydrofuran a solution of 2.9 g of 1- (cyclopropylcarbonyl) -4- (3-benzofuranyl) piperidine in 25 ml of tetrahydrofuran is added dropwise. To Boiling under reflux for 15 hours, the reaction mixture is cooled and the excess lithium aluminum hydride is added -10 ° by means of 5 ml of water, 3 ml of 10% sodium hydroxide solution and 10 ml of water decomposes. The reaction solution is suction filtered, the filter material is washed with one liter of chloroform and the combined filtrates evaporated in vacuo. The residue is in 100 ml of 2-n. Dissolved hydrochloric acid and the acidic Solution washed with ether. The aqueous solution is then brought to pH 12 by adding 10% sodium hydroxide solution placed and extracted with one liter of chloroform. The chloroform solution is dried with sodium sulfate and suction filtered and evaporated to give the crude 1- (Cyclopropy! methyl) -4- (2-benzofuranyl) piperidine is obtained. It is purified by recrystallization from hexane. The hydrochloride this base is prepared with hydrogen chloride in ethyl acetate and recrystallized from ethyl acetate.

The 1- (cyclopropylcarbonyl) -4- (3-benzofuranyl) piperidine used as starting material can be based on the following Way to be made:

609812/0967

253783?

2.42 g of 4- (3-benzofuranyl) piperidine are dissolved in 50 ml of dioxane and the solution is 1.47 g of cyclopropanecarbonyl chloride and 10 g of potassium carbonate are added. The reaction solution is stirred for 15 hours at room temperature. Thereupon the reaction solution sucked, the filter residue washed with 200 ml of chloroform and the combined filtrates evaporated in vacuo. The residue is dissolved in 50 ml of ethyl acetate and the solution in turn with 2-n. Hydrochloric acid, water, 2-n. Ammonium hydroxide and water, dried over sodium sulfate, filtered and evaporated. The raw material is obtained as the evaporation residue 1- (Cyclopropylcarbonyl) -4- (3-benzofuranyl) -piperidine, which is used directly for reduction with lithium aluminum hydride can be.

609812/0967

Claims (1)

253783? Claims Tetrahydropyridine and piperidine derivatives of the general formula I, (D in which R ' Hydrogen, an aliphatic hydrocarbon residue with 1-12 or an eyeloaliphatic Hydrocarbon residue with 3 - 12. *. · .--- carbon atoms, which residues by hydroxyl groups or an oxo radical can be substituted and / or interrupted by oxygen, or one Phenyl (lower alkyl) radical means in the benzene ring of which there are at most three hydrogen atoms Substituents selected from halogen up to atomic number 35, lower alkyl and lower alkoxy groups, the 'Methylenedioxy and the trifluorinethyl group Group can be replaced and its lower. alkyl chain on one of its not directly with the Po.ng- 609812/0967 253783? nitrogen atom connected by carbon atoms an oxo radical or a hydroxyl group can be substituted, or one optionally in the benzene ring appropriately substituted cinnamyl radical, R. denotes hydrogen or a "lower alkyl group, R "and R, independently of one another, hydrogen, lower alkyl or lower alkoxy groups, halogen atoms up to atomic number 35, benzyloxy or hydroxyl groups, and R "also a trifluoromethyl group, a lower one 1- hydroxyalkyl or lower AIk-1-e'ny! Group,. one 1-hydroxycycloalkyl, cycloalk-1-enyl or cycloalkyl group with 5-8 carbon atoms each, or R ₀ and R- together denote the trimethylene or tetra-3 4 · ^J methylene radical or, corresponding to a fused-on benzene ring, the 1,3-butadienylene radical, Rc is hydrogen or an alkyl group with at most 4 carbon atoms, and A and B divalent saturated aliphatic ^ hydrocarbon radicals mean and one of these symbols can also mean the direct bond, where A and B together always have 3 chain links and together with Rc a maximum of 9 carbon atoms, X and Y each represent a hydrogen atom or together an additional bond, and your. Addition salts with inorganic and organic acids. 609812/0967 2. Compounds according to claim 1, in.welchen R ^ Hydrogen, an alkyl group with a maximum of 4 carbon atoms, the 2-propynyl, the cyclopropylmethyl or the Benzyl group, R ^ hydrogen, R, and.R, hydrogen, halogen up to atom number 35, lower alkyl or lower alkoxy groups or hydroxyl groups, R, - hydrogen, A the methylene group and B the ethylene group or A the direct bond and B the trimethylene group or A the ethylene group and B the methylene group and X and Y have the meaning given in claim 1 to have. 3. Compounds according to claim 1, in which R, hydrogen, the methyl, the ethyl, the 2-propynyl, the cyclopropylmethyl or the benzyl group, R ^ hydrogen, Ro and R, hydrogen, chlorine, methyl, methoxy or hydroxyl groups, Rc hydrogen, A the methylene group and B the ethylene group, or A the direct bond and B the trimethylene group or A is the ethylene group and B is the methylene group and X and Y are as defined in claim 1. 4 · - Compounds according to claim 1, in which R, hydrogen, the methyl, ethyl, 2-propynyl, cyclopropylmethyl or benzyl group, Rw hydrogen, R ~ hydrogen or a methyl group or chlorine each in the 5-position, R, hydrogen or, together with hydrogen or a methyl group R ^, a methyl group, A denotes the ethylene group and B denotes the methylene group and X and Y have the meaning given in claim 1. 609812/0 & 67 5. Compounds according to claims 1-4, in which R,, I ^ ^R V ^ L ' ^R S' ^ ^unt * ^B ^ ^e ^ ^ort have the meaning given and X and Y together represent a direct bond. 6. Compounds according to claims 1-4, in which R-j »Ro» Ro »Ra> Rc »A and B have the meaning given there and X and Y each represent hydrogen. 7. The l-methyl-4- (3-benzofuranyl) -1,2,3,6-tetrahydro · pyridine The 1-methyl-4- (3-benzofuranyl) piperidine 9. The 4- (3-benzofuranyl) piperidine. 10. The addition salts of the compounds of claims 1 to 9 with inorganic and organic acids. 11. The pharmaceutically acceptable addition salts of the compounds of claims 1 to 9 with inorganic and organic acids. 12. Process for the production of new tetrahydro- pyridine and piperidine derivatives !! stated in claim 1 general formula 1, in which R ₁ , RRR ρ δ _R 1 2 '3' L ' ^κ ς' ^A » ^ß ' en X 609812/0967 253783? and Y have the meaning defined there, and their addition salts with inorganic and organic Acids, characterized in that one a) in a compound of the general formula II, N-Ac in which Ac denotes a residue that can be split off and R2, Rß, R. and R- are those given under the formula I. Have meaning, the remainder Ac splits off, and b) if desired one according to a) or in another way obtained compound of general formula Ia encompassed by general formula I 609812/0967 in which R ₀ , R_, R. and R _c the under the general . λ 5 i \ D. . - ° Formula I have given meaning with a reactive Ester one. Hydr oxy connection in connection with the generalities Formula III HO-R ₁ ⁰ - (III) • left in which R, ^{a has} the meaning given under the formula I for R, with the exception of hydrogen, or under reducing conditions with an oxo compound of the general formula IHa in which Q. the one corresponding to a monovalent radical R ^, geminal divalent residue means, converts, or .... · c) in a compound of the general formula IV -A- in which c a radical reduced by one methylene group according to the definition for R ^ or a 609812/0967 y. . ■ means lower alkoxycarbonyl group, the carbonyl group or alkoxycarbonyl group is reduced, or d) a compound of the general formula V. (V) in which means a monovalent anion or the normal equivalent of a polyvalent anion, R, and R _{7 are} hydrogen or alkyl radicals with together at most 6 carbon atoms mean and R-, ^a , Ro, Ro ^and R, which have the meanings given under the formulas III and I, are partially reduced to the corresponding compound of the general formula I in which X and Y mean an additional bond, or e) a compound of the general formula VI 609812/0967 2b3783? (VI) ** ^ In which R ₀ , R ₀ , R., R, - and R-, the meaning given under the formula I or the formula V, or a compound of the general formula Ib falling under the general formula I (Ib) in which R ₁ , Rp, R ₃ , R ^, R ₅₅ A and B have the meaning given under the formula I, catalytically hydrogenated to the corresponding piperidine compound, or f) means a compound of the general formula I in which R, is an optionally definition, substituted benzyl group, and / or R ^ and / or R, optionally inert mean substituted benzyloxy groups, and X and Y always are hydrogen _s while R _2, Rc, A and B and optionally R and / or R _{3 have} the meaning given under the formula I, are subjected to hydrogenolysis, or 609812/0967 g) from a compound of the general formula VII R, in which A ^a and B ^{a have} the meaning given under the formula I for A b? w, B with the exception of the direct bond as A ^a and a radical with 3 chain links as B ^a and R ^a that under the formula III and R ₂ , R ₃ , R and R _{5 have} the meaning given under formula I _? or from a connection of the general formula I in which R ^ is a lower 1-hydroxyalkyl group or a 1-Hydroxycycloalkylgruppe with 5-8 carbon atoms, while R, the meaning given under the formula I. with the exception of hydrogen and R_, R ,, R _1. , A, B, X and Y have the meaning given under the formula I, splits off water, or h) a compound of the general formula I, in which R, has the meaning given under formula I with the exception of hydrogen and oxo- and hydroxy-substituted radicals and halogen-substituted phenyl (lower alkyl) radicals, R is chlorine or bromine, and R, Hydrogen or a lower alkyl group 609812/0967 and R ^, R ^, A, B, X and Y have the meaning given under the formula I, converted into the corresponding compound with a metal radical in the place of R ₃ and the latter compound with a lower oxoalkane or a cycloalkanone with 5 -8 carbon atoms, or i) a compound of the general formula VIII, (VIII) in what R? those under the formula III and R ₃ , R ₃ and R _{4 have} the meaning given under the formula I, or the crude reaction product from a compound of the general formula IX, R, (IX) the double molar amount of formaldehyde and a compound of the general formula X, H ₂ N - (X) in which R has the meanings given under formula I and which is used as addition salt with a strong acid or together with such treated with a strong acid ,. 609812/0967 2537 * 3? and, if desired, one according to one of a) to i) specified Process obtained compound of general formula I in an addition salt with an inorganic or organic acid. • 13. Process according to claim 12, characterized in that compounds of the general formula I given in claim 1, in which R ^ is hydrogen, an alkyl group with at most 4 carbon atoms, the 2-propynyl, the cyclopropylmethy1 or the eenzyl group, IL, hydrogen, Rg and R, hydrogen, halogen up to atomic number 35, lower alkyl or lower alkoxy groups or hydroxy groups, R ₅ hydrogen, A the methylene group and B the ethylene group, or A the direct bond and B the tr! Methylene group or A the ethylene group and B the Is methylene group and X and Y have the meaning given in claim 1, and their acid addition salts are prepared. 14. The method according to claim 12, characterized in that one Compounds of the general formula I given in claim 1, in which R, hydrogen, an alkyl group with a maximum of 4 carbon atoms, the 2-propynyl, the cyclopropylmethyl or the Benzyl group, R2 hydrogen, Ro and R, hydrogen, chlorine, methyl, Methoxy or hydroxyl groups, Rr hydrogen, A the methylene group and B the ethylene group, or A the direct bond and B the 609812/0967. the trimethylene group or A the ethylene group and B the Is methylene group and X and Y have the meaning given in claim 1, and their pharmaceutically acceptable acid addition salts manufactures. 15. The method according to claim 12, characterized in that compounds of the general formula I given in claim 1, in which R, hydrogen, the methyl, ethyl, 2-propynyl, cyclopropylmethyl or benzyl group, IU hydrogen, R.- hydrogen or a Methyl group or chlorine each in the 5-position, R, hydrogen or, together with hydrogen or a methyl group Ro, a methyl group, A denotes the ethylene group and B denotes the methylene group and X and Y have the meaning given in claim 1, produces. 16. The method according to claim 12, characterized in that that you get the l-methyl-4- (3-benzofuranyl) -l, 2,3,6-tetrahydropyridine and its pharmaceutically acceptable acid addition salts, particularly its hydrochloride. 17. The method according to claim 12, characterized in that that l-methyl-4- (3-benzofuranyl) piperidine and its pharmaceutically acceptable acid addition salts, in particular its hydrochloride. 609812/0967 18. The method according to claim 12, characterized in that that you have the 4- (3-Benzofüranyl) piperidine and its pharmaceutical produces acceptable S-Mure addition salts, especially its hydrochloride » 19. Modification of the method according to claim 12 and their preliminary stages, characterized in that a process is terminated at any stage or from one to any Stage occurring as an intermediate compound goes out and carries out the missing steps or a starting material forms under the reaction conditions or optionally used in the form of a salt. 20. Pharmaceutical preparations for the treatment of mood depression, Containing at least one of the compounds of claims 1 to 6 and 11 together with a pharmaceutical Carrier material. 21. Pharmaceutical preparations according to claim 20, containing at least one of the compounds of claims 7 to 9, or a pharmaceutically acceptable addition salt thereof with an inorganic or organic acid, together with a pharmaceutical carrier material. 609812/0 967