SI7410523A8 - Process for preparing new tetrahydropyridine and piperidine derivatives - Google Patents

Description

The present invention relates to a process for the preparation of novel tetrahydropyridine and piperidine derivatives with valuable pharmacological properties.

According to the invention, the new tetrahydropyridine and piperidine derivatives of the invention are prepared according to the general formula I

in which they mean

R3 and R5 independently of one another are hydrogen, methyl, methoxy or halogen atoms up to an atomic number of 35 and R3 also a cyclohexyl group, or R3 and R4 together are a trimethylene residue or, correspondingly to a fused benzene ring, a 1,3-butadienylene residue,

A is an ethylene residue and at the same time B is a methylene residue, or A is a methylene residue and B is an ethylene residue, and

X and Y are each hydrogen atom or together an additional bond.

It is also an object of the invention to provide physiologically acceptable addition salts of compounds of general formula I with inorganic and organic acids.

In the compounds of general formula I, the substituents R1 and R4 are halogen fluorine, bromine and in particular chlorine.

Trimethylene group R3 + R (preferably in position 5,6, while the condensed benzene core R3 + Ra may be in position 5,6 or 6,7, and in particular in position 4,5.

If A represents a methylene group and B a corresponding ethylene group, the symbols X and Y are preferably hydrogen atoms, but may also represent an additional bond.

The compounds of general formula I and their addition salts with inorganic and organic acids have valuable pharmacological properties. In rats and in other experimental animals, monoamine oxidase, especially selective form A, is inhibited after oral and subcutaneous administration in the dosage range of 2 to 100 mg / kg, as is clear from the results of isotopic determination of enzyme activity. Concurrent inhibition of noradrenaline uptake in the heart by oral and subcutaneous administration of 2 to 100 mg / kg is also inhibited in rats and also inhibition of serotonin uptake by rat midbrain synaptosomes. In addition, they inhibit serotonin uptake in human blood cells in vitro. Furthermore, intraperitoneal administration in the rat at doses of 2 to 40 mg / kg antagonizes the effect of tetrabenazine. Together with the favorable therapeutic index, the abovementioned properties of the compound of general formula I and their pharmaceutically acceptable salts with inorganic and organic acids are indicated as antidepressants which can be administered e.g. orally or parenterally for the treatment of mental depression.

Of particular interest are compounds of general formula I in which R3 is of formula I having the above meaning and preferably is in position 5, R4 is hydrogen or a methyl group, the latter preferably in addition to the lower alkyl group R3 in position 6, or R3 + Pu is in position 4,5 Condensed benzene ring or trimethylene residue in position 5,6.

A and B have the meanings given in Formula I and mean X Jin Y is an additional bond or preferably, especially if A is a methylene group, hydrogen. Particularly important are compounds with hydrogen, chlorine, bromine, methyl or methoxy group such as R3, preferably in position 5, hydrogen or, in particular in addition to the methyl group R3, a methyl group as R4, a methylene group as A and an ethylene group as B or preferably an ethylene group as A and methylene group as B, and hydrogen as X and Y. Particularly important compounds are e.g. 4- (2-benzofuranyl) -piperidine, 4- (5.6-dimethyl-2-benzofuranyl) -piperidine, and 3- (2-benzofuranyl) -piperidine and their pharmaceutically acceptable acid addition salts, such as e.g. hydrochlorides.

New tetrahydropyridine and piperidine derivatives of the general formula I and their physiologically acceptable acid addition salts are obtained according to the invention, such that in a compound of the general formula II

in which

Ac denotes ethoxycarbonyl or cyano residue, and having R3 and R4 of the formula I have the meaning indicated, cleave the residue of Ac by treatment with alkali hydroxide in ethylene glycol at temperatures between 160 and 180 ° C, or, if Ac means cyano residue, also with hydrochloric acid at the boiling point of the reaction mixture, and optionally the resulting compound of general formula I is converted into a physiologically acceptable addition salt with inorganic or organic acid.

Hydrolysis of compounds of the general formula 11 is carried out e.g. by prolonged heating with sodium or potassium hydroxide, in ethylene glycol, in the presence of water in the form of water at the indicated temperatures. Compounds of general formula II in which Ac is a cyan group can also be hydrolyzed by heating with dilute, e.g. 0.2 to / 2.5 n hydrochloric acid at boiling point, e.g. by boiling for 0,5 n hydrochloric acid overnight, into compounds of general formula I.

The starting materials for the process described above can be prepared in several steps from compounds of general formula

Of the latter compounds, the unsubstituted 4- (2-benzofuranyl) -pyridine and the further methylsubstituted or benzene-substituted chlorine or methyl-substituted analogs in the pyridine ring and their hydrochlorides have already been described in Swiss Patent File Nos. 451 963 (cf. also French Patent File No. 5337 M. U.S. Patent File No. 3 470 192). In the Swiss patent, said preparation process proceeds from the case in question (substituted salicylaldehyde, which is first condensed to acetic acid ester by 4-picolin in acetanhydride, in accordance with a method known previously [J. Org. Chem. 21, 1039 to 1041 (1956)] optionally substituted o- [2- (4-pyridyl) -vinyl] -phenol. With the addition of bromine, the corresponding o- [1,2-dibromo-2- (4-pyridyl) -ethyl] compound is obtained which they are either cyclized directly to the corresponding compounds of general formula III with the aid of alkali hydroxide or alcoholate in an alcoholic solution or first converted with the corresponding o- (2-bromo-2- (4-pyridyl) -vinyl] compounds with sodium acetate in acetic acid, which can be purely analogously glided into the compounds of general formula III.

In the sense of the second, in Swiss patent file no. 501610 of the described reaction sequence of the optionally substituted salicylaldehyde is first converted to its methyl ether, which is reduced to the corresponding alcohol, the latter converted to the optionally substituted (o-methoxyphenyl) -acetonitrile, and condensed with the corresponding C-acylated ethyl ester of isonicotinic acid. -methoxyphenyl) -acetonitrile, and the final compound of this nitrile with an alkali metal, by the action of concentrated hydrobromic acid, is slid into the desired, optionally substituted 4- (2-benzofuranyl) -pyridine. Lower nicotinic acid alkyl esters may also be used in this reaction sequence. In the latter case, 3- (2-benzofuranyl) -pyridine is obtained.

We have now invented a further reaction sequence leading to those compounds of the general Formula III in which the 2-benzofuran residue is fused to the 4-position of the pyridine ring, which in most important cases also originates from the optionally substituted salicylaldehyde but is easier to carry out and is shorter than the known Reaction sequence above. The new process is characterized in that it is a compound of the general formula lilac

in which Ih -in E4 under formula I have the meanings indicated, in the presence of an acid-binding agent with 4- (halogenmethyl) -pyridine, in particular 4- (chloromethyl) -pyridine or 4- (bromomethyl) -pyridine, by heating in the presence of or in the absence of a condensing agent, is converted to ether by the general formula Illb

in which R3 and Rt are as defined in Formula I, and this ether is cyclized by heating in the presence or absence of a condensing agent. The compounds of general formula III thus obtained are, with the exception of the agents of the new substance described in the Swiss patent documents mentioned above.

The metabolism of compounds of the general formula lyl with 4- (chloromethyl) - or, 4- (bromomethyl) -pyridine can be carried out e.g. in an inert organic solvent, such as e.g. dimethylformamide, in the presence of an acid-binding agent, such as e.g. sodium or potassium carbonate, at temperatures between about 50 and 150, preferably at about 70 to 100 ° C, and optionally accelerated by the addition of a small amount of potassium aii or sodium iodide. The following ring assembly is carried out e.g. by heating isolated but not necessarily purified compounds of the general Illb formula to temperatures between about 240 and 320'C. Alternatively, ring engagement may be carried out at the same working stage as the formation of ether and subjected to the required reaction conditions or, if necessary, by prolonged heating and / or heating to higher temperatures within said range, wherein the excess acid binding agent may serve as a condensing agent.

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From the compounds of general formula III, methyl halides, in particular methyl bromide or iodide, of the general formula III of the compound of general formula IV are obtained by quaternation of the reaction esters of hydroxyl compounds

in which R3 and Ra have the meanings given by formula I. Quaternation can be carried out in the usual way in an inert organic solvent, e.g. in lower alcohol, which is also the basis for the ester-capable reactions, e.g. in ethyl acetate, tetrahydrofuran or dioxane at room temperature or at moderately elevated temperatures up to about 100 ° C.

Compounds of general formula IV are then partially reduced to compounds of general formula V

wherein R3 and Ra are as defined in Formula I.

The primary reduction of compounds of the general formula IV is preferably accomplished by means of sodium or potassium borohydride in an organic-aqueous medium such that e.g. to a presented solution of a starting material of general formula IV in an organic water miscible solvent, e.g. in lower alkanol, such as methanol or ethanol, or mixtures thereof with water, an aqueous solution of sodium borohydride is gradually added and the reaction mixture is then further reacted while maintaining the reaction temperature between about 5 and 60 ° C, preferably between room temperature. and 35 ° C.

Catalytic hydrogenation of compounds of general formula V yields compounds of general formula VI

Hydrogenation can be carried out using conventional hydration catalysts, e.g. catalysts of precious metals such as palladium on charcoal or platinum oxide, rhodium catalysts as rhodium on charcoal or aluminum oxide, or catalysts from a framework of alloys such as Raney nickel, in an inert organic solvent such as methanol, ethanol or dioxane, at room temperature normal pressure or moderately elevated temperatures from about 100'C and increased pressures up to about 100 bar.

The starting materials of general formula II can be prepared from the corresponding compounds of general formula V or VI by metabolism with hydrochloric acid ethyl ester, or with bromcyan in an organic organic solvent in warm, e.g. in toluene at its boiling point.

According to the process of the invention, the compounds of the general formula I obtained can be optionally converted into their addition salts with inorganic or organic acids, as desired. To a solution of a compound of general formula X in an organic solvent e.g. add the acid that is desired as the com- ponent of the salt. Preferably, the organic solvents in which the resulting salt is difficult to solubilize are selected for metabolism to be extracted by filtration. Such solvents are e.g. ethyl acetate, methanol, ether, acetone, methylethylketone, acetone / ether, acetone / ethanol, methanol / ether or ethanol / ether.

For use as medicines, pharmaceutically acceptable acid addition salts may be used instead of free bases, i.e. salts with such acids whose anions are not toxic at the dosages to be used, It is further advantageous if the salts used as medicaments crystallize well and are not or slightly hydroscopic. For the formation of salts with compounds of general formula I, e.g. 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, maleic acid. tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, almond acid and embonic acid.

k

New compounds can be obtained by selecting starting materials and modes of operation as optical antipodes or racemates, or to the extent that they contain at least two asymmetric carbon atoms, including isomeric mixtures (racemic mixtures). The resulting isomeric mixtures (racemic mixtures) can, however, be separated into the two stereoisomeric (diasteromem) pure racemates based on physicochemical differences of the constituent parts, e.g. by chromatography and / or fractional crystallization.

The obtained racemates can be used by known methods, e.g. by recrystallization from an optically active solvent, by micro-organisms or by metabolism with an optically active acid which forms the salts with the racemic compound, and the separation of salts thus obtained, e.g. on the basis of their different solubilities, it separates S7 1C mo into diastereomers from which antipodes can be released by the action of suitable agents. Particularly useful optically active acids are e.g. D- and L-forms of tartaric acid, di-otoluylic acid, malic acid, almond acid, camphrasulfonic acid or kinaic acid. Preferably, the more effective the two antipodes are isolated.

The new active substances are administered orally, rectally or parenterally. The dosage depends on the type of application, type, age and individual status. Daily bases of free bases or pharmaceutically acceptable salts of free bases for warm-blooded animals range from 0.1 to 10 mg / kg. Suitable dosage unit forms, such as dragees, tablets, suppositories or ampoules, preferably contain 5 to 100 mg of the active substance of the invention .

The dosage unit forms for oral administration contain preferably between 5 and 90% of a compound of general formula I or a pharmaceutically acceptable salt thereof as an active substance. For its preparation, an effective substance is combined, e.g. with solid, dusty carriers such as lactose, sucrose. sorbitol, mannitol, starches, such as potato starch, corn starch or amylopectin, further laminar powder or citrus pulp powder. cellulose or gelatin derivatives, optionally with the addition of glidants such as magnesium or calcium stearate or polyethylene glycols, in tablets or in dragee cores. Dragee cores are coated e.g. with concentrated sugar solutions, which can e.g. Containing arabic gum, talc and / or titanium dioxide, or varnish dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, e.g. to indicate different doses of the active substance.

Gelatin plug capsules as well as soft, closed gelatin and plasticizer capsules such as glycerin are suitable as further dosage unit forms. The plug capsules contain the active substance preferably as a granulate, e.g. mixed with fillers. cornstarch and / or glidants such as talc or magnesium stearate, and optionally stabilizers such as sodium metabisulphite or ascorbic acid. In the soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, and stabilizers may also be added.

As dosage unit forms for rectal use, e.g. suppositories consisting of a combination of an effective substance with a suppository base mass. Suitable suppository base masses are e.g. natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules consisting of a combination of an active substance with a basic weight are also suitable. As a base mass, e.g. liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

Ampoules for parenteral, especially intramuscular administration, contain preferably a water-soluble salt of the active substance in a concentration of preferably 0.5 to 5%: optionally, together with suitable stabilizing agents and buffering agents, in an aqueous solution.

The preparation of tablets, dragees, capsules, suppositories and ampoules should be explained in greater detail in the following regulations.

a) 250 g of 4- (2-benzofuranyl) -piperidine hydrochloride are mixed with 175.80 g of lactose and 169.70 g of potato starch, the mixture is moistened with an alcoholic solution of 10 g of stearic acid and granulated through a sieve. After drying, 160 g of potato starch, 200 g of talc, 2.50 g of magnesium stearate and 32 g of colloidal silicon dioxide are mixed and the mixture is pressed into 10000 tablets of 100 mg / kg by weight and 25 mg of the active substance, which may be optionally equipped with dividing notches for more accurate dosing adjustment.

b) From 250 g of 4- (5,6-dimethyl-2-benzofuranyl) -piperidine hydrochloride. 175.90 g of lactose and alcohol solution 10 g of stearic acid are prepared granulate. which is mixed after drying .'s 56.60 g of colloidal silica, 165 g of talc, 20 g of potato starch and 2.50 g of magnesium stearate and pressed into 10,000 Dragee nuclei. They are then coated with concentrated syrup of 502.28 g of crystalline sucrose, 6 g of shellac, 10 g of Arabic gum. 0.22 g of dye and 1.5 g of titanium dioxide and dried. The resulting dragees weigh 120 mg each and contain 25 mg of the active substance.

c) To prepare 1000 capsules containing 10 mg of active substance content, mix 10 g of 4- (5-methoxy-2-benzofuramyl) -piperidine hydrochloride with 248 g of lactose, moisten the mixture evenly with an aqueous solution of 2 g of gelatin and granulate through a mixture. sieve (e.g., sieve III by Ph. Helv. V). The granulate is mixed with 10.0 g of dried corn starch and 15.0 g of talc and filled evenly into 1000 hard gelatin capsules of mercury; 1.

d) The suppository base is prepared from 2.5 g of 4- (5-chloro-2-benzofuranyl) -piperidine hydrochloridine 167.5 g of Adeps solidus, and 100 suppositories of 25 mg of active substance content are poured from it.

e) A solution of 10.0 g of 3- (2-benzofuranyl) -piperidine hydrochloride in 1 liter of water is filled into 1000 ampoules (and sterilized. Each ampoule contains a 1% solution of 10 mg of the active substance.

The preparation of novel compounds of the general formula I and the intermediates so far not described are explained by the following examples, and the scope of the invention should not be construed in any way. Temperatures are given in degrees Celsius.

c

163

Example 1

15.0 g of 1-methyl-4- (5-chloro-2-benzofuranyl) -piperidine were dissolved in 150 ml of toluene and 40.0 g of hydrochloric acid ethyl ester were added. After stirring for 15 hours, the solution was heated to boiling point, / during which a small portion of toluene was distilled off during the first hour to remove the released methyl chloride and then a complete reflux of toluene was maintained. The solution was then cooled to 20 ° C, filtered off with suction and the filter cake washed with 800 ml of toluene. The combined filtrates were washed in turn with 500 ml of water, 1 1 10% methanesulfonic acid solution in water, 1 1 water, 500 ml 2 n sodium hydroxide solution and 500 ml water, dried over sodium sulfate, filtered and evaporated. The remaining crude ethyl ester of 4- (5-chloro-2-benzofuranyl) -1-piperidinecarboxylic acid is further processed without further purification.

a) 11.5 g of 4- (5-chloro-2-benzofuranyl) -1-piperidinecarboxylic acid ethyl ester are dissolved in 75 ml of ethylene glycol. After the addition of 50 ml of a 50% aqueous potassium hydroxide solution, the turbid solution formed is stirred for 15 hours. 160 °. The reaction solution was then cooled to 20 'and extracted twice with 500 ml of ethyl acetate each. The organic phases are washed five times with 1 l of water each, dried over sodium sulfate, filtered and evaporated. The residue was dissolved in 300 ml of 10% methanesulfonic acid solution in water and the acidic solution was extracted with ether. The aqueous solution was then adjusted to pH 12 with the addition of 10% sodium hydroxide and extracted with 1 L of chloroform. The chloroform solution was dried over sodium sulfate, filtered and evaporated to give crude 4- (5-chloro-2-benzofuranyl) -piperidine. After recrystallization from hexane, the free base melts at 77 to 78 ° C. The hydrochloride was prepared with hydrogen chloride in ethyl acetate and recrystallized from ethyl acetate, then melted at 252 to 254 ° C.

In an analogous manner, from 17.7 g of 1-methyl-4- (5-bromo-2-benzofuranyl) -piperidine via the crude ethyl ester of 4- (5-bromo-2-benzofuranyl) -1-piperidinecarboxylic acid, 4- (5- bromo-2-benzofuranyl) -piperidine and its hydrochloride m.p. 268 ° C.

The starting materials can be prepared as follows:

a) 210 g of 5-chlorosalicylaldehyde, 220 g of 4- (chloromethyl) -pyridine hydrochloride, 750 g of potassium carbonate and 3.3 g of potassium iodide in 2 L of dimethylformamide are heated to 80 'under stirring for 20 hours. The solution is then sucked off and the filter residue is washed with 1 L of chloroform. The combined filtrates were evaporated in vacuo and the residue was dissolved in chloroform after evaporation. The organic phase was washed twice with 1 l of 2 n sodium hydroxide each and then with 1 l of water, dried over sodium sulfate, filtered and evaporated. The remaining crude 2 - [(4-pyridyl) -methyl] -5-chlorobenzaldehyde is further processed without further purification.

b) 272 g of 2 - [(4-pyridyl) -methoxy] -5-chlorobenzaldehyde under nitrogen were heated to 300 ° C for 30 minutes. After cooling, the residue was dissolved in a little of methylene chloride and chromatographed on 2 kg of alumina (activity II, neutral). The first fraction eluted with 5 L of methylene chloride is 4- (5-chloro-2-benzofuranyl) -pyridine. After recrystallization from ethanol, the compound melts at 132 to 133'C. The hydrochloride hydrochloride solution prepared from it with a solution of hydrogen chloride in ethyl acetate melts at 285 'after recrystallization from ethyl acetate.

c) 142 g of 4- (5-chloro-2-benzofuranyl) -pyridine are dissolved in 450 ml of methanol and stirred at 40-45 ° for 15 hours with 300 ml of methyl iodide. The solution was then cooled to 0 ° and the precipitated salt was filtered off with suction. The filter residue was washed with 500 ml of isopropanol. After recrystallization from isopropanol, 1-methyl-4- (5-chloro-2-benzofuranyl) -pyridinium iodide melts at 258 to 280 °.

Analogous a) crude 2 - [(4-pyridyl) -methoxy] -5-bromosalicylaldehyde is obtained using 269 g of 5-bromosalicylaldehyde, further using 320 g of this crude product analogous to b) 4- (5-bromo-2-benzofuranyl- pyridine of m.p. 156 to 158'C, and the Final Analog c) of 168 g of 4- (5-bromo-2-benzofuranyl) -pyridine 1-methyl-4- (5-bromo-2-benzofuranyl) -pyridinium iodide with m.p. 266 to 270 °.

d) A solution of 70 g of sodium borohydride in 150 ml of water is added dropwise to a solution of 70 g of 1-methyl-4- (5-chloro-2-benzofuranyl) -pyridinium iodide in 500 ml of methanol in such a way that the reaction temperature does not grow to d 35 °. The solution was then stirred at room temperature for 20 hours. The methanol was then evaporated in vacuo, the remaining aqueous phase was extracted twice with 500 ml of chloroform each, the chloroform solution was dried over sodium sulfate, filtered and evaporated. The resulting 1-methyl-4- (5-chloro-2-benzfuranyl) -1,2,3,6-tetrahydropyridine was recrystallized from hexane and then melted at 108 to 118 °. The hydrochloride hydrochloride solution prepared from it with a solution of hydrogen chloride in ethyl acetate is melted at 266 ° after recrystallization from ethyl acetate.

In an analogous manner, using 78.2 g of 1-methyl-4- (5-bromo-2-benzofuranyl) -pyridinium iodide yields 1-methyl-4- (5-bromo-2-benziofuranyl) -1,2,3, 6- tetrahydricpyridine from m.p. 129 °.

e) 112 g of 1-methyl-4- (5-chloro-2-benzofuranyl) -1,2,3,6-tetrahydropyridine are dissolved in 2,3 l of methanol and hydrated in the presence of 11 g of platinum oxide at a temperature between 20 and 30 ° and under normal pressure. After 9 hours, 9.87 l of hydrogen is defaulted, which corresponds exactly to the default of the theoretical amount of hydrogen. Hydration was discontinued, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in a little chloroform and chromatographed on 600 g of alumina (activity II, neutral). The first fraction alloyed with 2 L of chloroform is 1-methyl-4- (5-chloro-2-benzofuranyl) -piperidine. After recrystallization from hexane, this melts at 107 °. The hydrochloride prepared from the hydrochloric acid solution in ethyl acetate was melted at 260 °.

Analogous was obtained using 132 g of 1-methyl-4- (5-bromo-2-benzofuranyl) -1,2,3-G-tetrahydropyridine (cf. Example 12) 1-methyl-4- (5-bromo-2- benzofuranyl) -piperidine m.p. 116 to 119 ° and its hydrochloride from the ground. 272 to 275 °.

Example 2

12.0 g of 1-methyl-4- (naphtho [2, 1b] furan-2-yl) -piperidine (cf. example 23) was dissolved in 150 ml of toluene and 40.0 g of ethyl chloroformic acid were slowly added dropwise under a strong stream of nitrogen , for faster removal of the released methyl chloride. The solution was then refluxed for 20 hours, cooled, sucked off and the filter residue was washed with 500 ml of toluene. The combined filtrates were washed in a garden with 500 ml water, 1 10% methanesulfonic acid solution in water, 500 ml water, 500 ml 2 n sodium hydroxide and 500 ml water, dried over sodium sulfate, filtered and evaporated. The remaining 4- (naphtho [2, 1-b] furan-2-yl) -1-piperidyl carboxylic acid ethyl ester was melted at 89-92 ° C after recrystallization from pentane.

a) 7.8 g of 4- (naphtho [2, 1b] furan-2-yl) -1-piperinecarboxylic acid ethyl ester was dissolved in 60 ml of ethylene glycol. After the addition of 40 ml of a 50% aqueous potassium hydroxide solution, the cloudy solution was heated to 160 ° with vigorous stirring for 15 hours. The reaction solution was then cooled to 20 ° and extracted twice with 500 m each! ethyl acetate. The organic phases are washed five times with 1 l of water each, dried over sodium sulfate, filtered and evaporated. The residue was dissolved in 400 ml of 2 n hydrochloric acid and the acidic solution was extracted with toluene. The aqueous solution was then adjusted to pH, 12 with the addition of 10% sodium hydroxide and extracted with the evil chloroform. The chloroform solution was dried with sodium sulfate, filtered and evaporated to give crude 4- (naphtho [2, 1b] furan-2-yl) -piperidine. Hydrochloride those most ¹ call with hydrogen chloride in ethyl acetate and recrystallised from ethyl acetate, and then melted at 225 °.

In an analogous manner, 15.8 g of 1-methyl-4- (naphtho [2, 1b] furan-2-yl) -1,2,3,6-tetrahydropyridine (see under d) are obtained crude ethyl 4- (naphtho) [2, 1b] furan-2-yl) 3, G-dihydro-1 (2H) -pyridinecarboxylic acid and from this 4- (naphtho [2, 1b] furan-2-yl) -1,2,3,6 -tetrahydropyridine.

The starting materials can be prepared as follows:

a) 83.4 g of 2-hydroxy-naphthaldehyde, 79.3 g of 4- (chloromethyl) -pyridine hydrochloride, 300 g of potassium carbonate and 2.5 g of potassium iodide in 800 ml of dimethylformamide are heated under stirring for 20 hours.

100 °. The solution was then sucked off and the filter residue was washed with 1 L of chloroform. The combined filtrates were evaporated in vacuo and the residue was dissolved in 1 L of chloroform after evaporation. The organic phase was first washed twice with 1 l of 2 n sodium hydroxide each and then the evil water, dried over sodium sulfate, filtered and evaporated. The remaining crude 2 - [(4-pyridyl) -methoxy] -1-naphthaldehyde is further processed without purification.

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

c) 51.0 g of 4- (naphtho [2,1-b] furan-2-yl) -pyridine are dissolved in 570 ml of methanol and stirred at 40: 45 ° for 20 hours with 100 ml of methyl iodide. The solution was then cooled to 0 °, the precipitated salt was filtered off and washed with 150 ml of isopropanol. After recrystallization from isopropanol, 1-methyl-4- (naphtho [2, 1-b] furan-2-yl) -pyridinium iodide melts at 310 to 315 ° (dec.).

d) A solution of 27.0 g of sodium borohydride in 110 ml is added dropwise to a solution of 65.5 g of 1-methyl-4- (naphtho [2, 1-bifuran-2-yl) -pyridinium iodide in 900 ml of methanol. of water in such a way that the reaction temperature does not rise above 30 °. The solution was then stirred at room temperature for 15 hours. Then the methanol was evaporated in vacuo, the remaining aqueous phase was extracted twice with 500 ml of chloroform each, the chloroform solution was dried over sodium sulfate, filtered and evaporated. The oil thus obtained is dissolved in 150 ml of methylene chloride and chromatographed on 1 kg of alumina (activity H, neutral), the first fractions eluted with 2 l of methylene chloride containing l-methyl-4- (naphtho- [2, 1b] furan-2- orI) -1,2,3,6-tetrahydropyridine. The free base was recrystallized from hexane and melted at 120 to 122 °. The hydrochloride hydrochloride solution prepared from it with hydrochloric acid solution in ethyl acetate is melted at 277 ° after recrystallization from ethyl acetate.

c) Dissolve 26,0 g of 1-methyl-4- (naphtho [2, 1b] furan-2-yl) -1,2,3,6-tetrahydropyridine in 300 ml of methanol and hydrate in the presence of 3 g of 5%; palladium on charcoal at a temperature between 40 and 50 ° and under normal pressure. After 2 hours, 2.27 l of hydrogen is assumed, which corresponds exactly to the theoretical hydrogen consumption. Hydration was discontinued, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue is 1-m; tyl-4- (naphtho [2,1-b] furan-2-yl) -piperidine. After recrystallization from pentane, this melts at 83 to 85 °. The hydrochloride solution prepared from the hydrochloric acid solution in ethyl acetate was melted at 243 °.

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Example 3 G of 1-methyl-4- (5, S-dimethyl-2-benzofuranyl) -piperidine (see Example 32) was dissolved in 800 ml of thioul and 80 g of hydrochloric acid ethyl ester were added. After stirring for 15 hours, the solution was heated to boiling, whereby during the first hour a smaller portion of the toiuol was distilled off for the faster removal of the released methyl chloride and then a complete reflux of the toiuol was maintained. The solution was then cooled to 20 °, filtered off with suction and the filter residue was washed with 100 mI of tocol. The combined filtrates were washed in turn with 500 water, 1000 and 10 ^{fl /} ml of aqueous methanesulfonic acid, 1003 ml of water, 500 ml of 2 n aqueous sodium hydroxide and 500 ml of water, dried over sodium sulfate, filtered and evaporated. The remaining, crude ethyl ester of 4- (5,6-dimethyl-2-benzofuranyl) -1-piperidinecarboxylic acid is melted at 83 to 97 ° C after recrystallization and from pentene.

a) 33.5 g of 4- (5S-dimethyl-2-benzofuranyl) -1-piperidinecarboxylic acid ethyl ester is dissolved in 130 ml of ethylene glycol. After the addition of 70 g of solid sodium hydroxide, the cloudy solution was heated to 130 ° with vigorous stirring for 15 hours. The reaction solution was then cooled to 20 'and extracted twice with 509 ml ethyl acetate each. The organic phases are washed five times with 1> 1 water each, dried over sodium sulfate, filtered and evaporated. The residue was dissolved in 300 ml of 10% aqueous methanesulfonic acid and the acidic solution was extracted with track. Then, the aqueous solution was adjusted to the value at 12 with the addition of 10% sodium hydroxide, extracted with 1 L of chloroform, the ifioroform solution was dried with sodium sulfate, filtered and evaporated to give crude 4- (5,6-dimethyl-2-benzoiurans). ) -piperidine. The hydrochloride is prepared with hydrogen chloride in ethyl acetate and recrystallized from methanol / ethyl acetate, then obtained as a hydrate melting at 230 to 2337

Analogous was obtained using 43 g of 1-methyl-4- (4,7-d ^; methyl-2-benzoofuranyl) -piperidine (see below 32) crude ethyl ester 4- (4,7-dimethyl-2-benzofuranyl) - Incarboxylic acid 1-pyrid and 4- (4,7-dimethyl-2-henzofuranyl) -piperidine and its hydrochloride from the ground. 26S, using 43 g of 1-methyl-4- (5,7-dimeth; 1-2-benzofuran]) - piperidine (see below 32) crude ethyl ester 4- (5,7-dimethyl-2-benzofuranyl) - 1-piperidinecarboxylic acid and 4- (5,7-dimethyl-2-benzofuranyl) -piperidine and its hydrochloride from the m.p. 215 to 218 ° and using 43 g-methyl-4- [5,6- (trimethylene) -2-benzofuranyl] -pipericillin (see below 32) crude ethyl [4- [5,6- (trimethylene) -2- benzofuranyl] -1-piperidinecarboxylic acid and 4- [5,6- (irimethylene) -2-benzofuranyl] -pipericillin and its hydrochloride from m.p. 229 to 230 °.

The starting materials can be prepared as follows:

a) 53.5 g of 4,5-dimethylsalicyldehyde, 64,0 g of 4- (chloromethyl) -pyridine hydrochloride, 240 g of potassium carbonate and 2.0 g of potassium iodide in 500 ml of dimethyloromide are stirred for 130 hours at 130 to I73. ^e . The reaction mixture was then filtered off with suction and the filtrate washed with chloroform. The combined filtrates were evaporated in vacuo, the residue was evaporated after evaporation in 150 ml of methylene chloride and chromiographed on 2000 g of alumina (activity II, neutral). The first fraction, eluent: 2.S and methylene chloride, is 4- (3, G-dimethyl) -2-J, m. . oiritiin. The compound was recrystallized from hexane at 168 to 170 °. From it with a solution of hydrochloride in mc-thi? Cetate, the hydrochloride prepared sr after melting from ethyl acetate melts at 278 to 280 °.

In an analogous manner, 58.5 g of 4- (4,7-dimethyl-2-pyrrouranyl) -pyridine from 3.3-dimethylsalicylaldehyde are obtained from m.p. 78 to 80 °, hydrochloride hydrate m.p. 266 to 269 °.

from 33.5 g of 3,5 quimethylsalicylaldohide 4- (5,7-dimethyl-2-benzo-urea) -pyridine m.p. 107 to 109 °, hydrocycld m.p. 233 °, and from 62.8 g of 4.5- (trim.ei: len) -saI; siluide (6-hydroxy-5-yl) benzoic acid, cf. 1. Amer. Chem. Soz. 77 , 54C2 to 2475) · 1- [5,6- (ιΓίι 'iefilcn) -2-benzofurantyl-pirldm. m.p. 99 to 82 °.

h) 79.0 g of 4- (5, S-dimethyl-2-benzc'uranyl) -pyridine were dissolved in 750 ml of methanol and stirred at 40-45 ° for 20 hours with 190 ml of methyl iodide. The solution was then cooled to -20 °, the precipitated salt was sucked off and washed with 159 ml of isopropanol. After recrystallization from isopropanol, the obtained 1-methyl-4- (5,6-dimethyl-p-benzofuranium-pyridinium iodide was melted at 219 to 221 °.

In an analogous manner, it is obtained by use

79.0 g of 4- (4,7-dimethyl-2-benzyuranyl) -pyridine 1-rneyl-4- (5,7-dirnethyl-2-benzofuryl) -pyridinium iodide m.p. 238 to 270 ° in

83.4 g 4- [5.3- (trimethylene) -2-benzofuranyl] -pyridinium 1-methyl 4- [5,0- (trimethylene) -2-benzofuranyl-pyridinium iodide from m.p. 194 to 197 '.

c) A solution of 45.0 g of sodium borohydride in ISO ml is added dropwise to a solution of 99 g of 1-methyl-4- (ii, S-dimethyl-2-benzofur. nyl) -pyridinium iodide in 1500 ml of methanol. conducts in such a way that the reaction temperature does not rise above 35 °. The solution was then stirred at room temperature for 15 hours. Then the methanol was evaporated in vacuo, the remaining aqueous phase was extracted twice with 750 ml of chloroform each, the chloroform solution was dried over sodium sulfate, filtered and evaporated. The oily residue was recrystallized from eichlohexane to give 1-m-t :: 11-4- (5,1-dimethyl-2-benzofuranyl) -1,2,3,6-tetra-37 163 -hydropyridine from m.p. 124 to 126 °. The hydrochloride hydrochloride solution prepared from it with a solution of hydrogen chloride in ethyl acetate is melted at 231 to 233 ° after recrystallization from acetone.

Analogous was obtained from 99 g of 1-methyl-4- (4,7-dimethyl-2-benzofuranyl) -pyridinium iodine 1-methyl-4- (4,7-dimethyl-2-benzofuranyl) -1,2,3 , 6-tetrahydropyridine m.p. 69 to 7Γ, hydrochloride m.p. 281 to 283 °, from 99 g of 1-methyl-4- (5,7-dimethyl-2-benzofuranyl) -pyridinium iodide 1-methyl-4- (5,7-dimethyl-2-benzofuranyl) -1,2, 3,6-tetrahydropyridine m.p. 99 to 102 °, hydrochloride m.p. 250 to 252 °, and from 102 g of 1-methyl-4- [5,6-trimethylene) -2-benzofuranyl] -pyridinium iodide 1-methyl-4- [5,6- (trimethylene) -2-benzofuranyl] - 1,2,3,6-tetrahydropyridine and its hydrochloride.

d) 139 g of 1-methyl-4- (5,6-dimethyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine (see Example 31) were dissolved in 1500 ml of methanol and hydrated in the presence of 14 g of 5-th palladium on charcoal at a temperature between 20 and 25 ° and under normal pressure. After 8 hours, the theoretical required amount of 13 1 hydrogen is the default. Hydration was discontinued, the catalyst was filtered off and the filtrate was evaporated in vacuo. The remaining crude 1-methyl-4- (5,8-dimethyl-2-benzofuranyl) -piperidine was recrystallized from cyclohexane and then melted at 122 to 124 °. The hydrochloride prepared from the hydrochloric acid solution in ethyl acetate was melted at 205 to 207 °.

In an analogous manner, 1-methyl-4- (4,7-dimethyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine 1-methyl-4- (4,7-dimethyl-2-benzofuranyl) is obtained in equal quantities ) -piperidine, whose hydrochloride melts at 242 °, and 1-methyl-4- (5,7-dimethyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine 1-methyl-4- (5,7 -dimethyl-2-benzofuranyl) -piperidine and its hydrochloride melt. 210 to 212 °.

It is also obtained by hydrogenation in the presence of 8 g of catalyst in 800 ml of methanol to yield 5 l of hydrogen, and otherwise analogously from 5 fr, 0 g of l-methyl-4- [5,6- (trimethylene) -2-benzofuranyl] -1 , 2,3,6-Tetrahydropyridine 1-methyl-4- [5,6-trimethylene) -2-benzofuranyl] -piperidine and its hydrochloride.

Example 4

11.2 g of 1-methyl-3- (2-benzofuranyl) -piperidine (see Example 40) were dissolved in 100 ml of toluene and 22.5 g of hydrochloric acid ethyl ester were added. After stirring for 15 hours, the solution was heated to boiling, whereby during the first hour a smaller portion of toluene was distilled off to remove the released methyl chloride and then refluxed. The solution was then cooled to 70 °, aspirated and the filter residue was washed with 500 ml of toluene. The combined filtrates were washed in turn with 500 ml of water, 1 1 10% aqueous methanesulfonic acid, 1 l of water, 500 ml of 2 n sodium hydroxide and 500 ml of water, dried over sodium sulfate, filtered and evaporated. The remaining, crude ethyl ester of 3- (2-benzofuranyl) -1-piperidinecarboxylic acid is further processed without purification.

Dissolve 12.2 g of 3- (2-benzofuranyl) -1-piperidinecarboxylic acid ethyl ester in 150 ml of ethylene glycol. After the addition of 50 g of solid sodium hydroxide, the resulting cloudy solution, with vigorous stirring, was heated to 160 ° for 15 hours. The reaction solution was then cooled to 20 ° and extracted twice with 500 ml of toluene each. The organic phases are washed five times with 1 l of water each, dried over sodium sulfate. filtered and evaporated. The residue was dissolved in 300 ml of 10% aqueous methanesulfonic acid and the acidic solution was extracted with ether. The aqueous solution was then adjusted to pH 12 with the addition of 10% sodium hydroxide and extracted with 1 L of chloroform. The chloroform solution was dried with sodium sulfate, filtered and evaporated. After evaporation, the residue is distilled off under high vacuum (short-path distillation), passing 3- (2-benzofuranyl-piperidine) from 0.26 mbar at 160 to 166 ° C. Hydrochloride is prepared from this base with hydrogen chloride in ethyl acetate and recrystallized from ethyl acetate and then melts at 216 to 218 °.

The starting material can be prepared as follows:

a) 40 g of 3- (2-benzofuranyl) -pyridine [Chim. Ther. 6, 159 to 166 (1971)] was dissolved in 300 ml of methanol and stirred at 40 to 45 ° with 100 ml of methyl iodide for 15 hours. The solution was then cooled to 0 to -5 ° and the precipitated salt was filtered off with suction. The filter residue was washed with 300 ml of isopropanol. After recrystallization from isopropanol, 1-methyl-3- (2-benzofuranyl) -pyridinium iodide melts at 222 °.

b) A solution of 50 g of sodium borohydride in 100 ml of water is added dropwise to a solution of 56.0 g of 1-methyl-3- (2-benzofuranyl) -pyridinium iodide in 600 ml of methanol in such a way that the reaction temperature does not increase above 35 °. The solution was then stirred for 15 hours and the solution of 50 g of sodium borohydride in 100 ml of water was added dropwise again so that the reaction temperature did not rise above 35 °. Then the methanol was evaporated, in vacuo, the remaining aqueous phase was extracted twice with 300 ml of chloroform each, the chloroform solution was dried over sodium sulfate, filtered and evaporated. The resulting 1-methyl-3- (2-benzofuranyl) -1,2,5,6-tetrahydropyridine was recrystallized from diisopropyl ether and melted at 63 °. The hydrochloride hydrochloride solution prepared from it with a solution of hydrogen chloride in ethyl acetate is melted at 244 to 246 ° after recrystallization from ethyl acetate.

'9

- 37 163 -

c) 29.2 g of i-methyl-3- (2-benzofuramyl) -1,2,5,6-tetrahydroplridine (see example 39) are dissolved in 300 ml of methanol and in the presence of 6 g of 5% palladium on charcoal at 40 to 50 'and under normal pressure. After 44 hours, the default is 2.1 1 hydrogen, which corresponds exactly to the theoretical hydrogen consumption. Hydration was discontinued, the catalyst was filtered off and the filtrate was evaporated in vacuo. After evaporation, the residue was fractionally distilled off under high vacuum. The fraction distilled at 108-110 ° and 0/2 rnbar is 1-methyl-3- (2-benzofuranyl) -piperidine. Hydrochloride prepared from hydrochloride hydrochloride solution in c1 in acetate melts at 193 to 195 °.

Example 5

Analogues of Example 1 are obtained.

from 14.6 g-methyl-4- (5-methoxy-2-benzofuranyl) piperidine [see paragraph a) and d) to f) below]. 4- (5-Methoxy-2-benzofuranyl) -1-piperidinecarboxylic acid crude ethyl ester 4- (5-methoxy-2-benzofuranyl-piperidine), which distils below 0,13 rnbar at 120 to 128® and from it hydrochloride from m.p. 220 to 222 ° (from acetone) and from 16.4 g of 1-methyl-4- (5,6-dimethoxy-2-benzofuran; 1) -piperidine [see paragraphs b) and c) to f) below] over crude 4- (5,6-Dimethoxy-2-benzofuran ^: 1L) -1-piperidinecarboxylic acid ethyl ester 4- (5,6-dimethoxy-2-benzofuranyl) -piperidine m.p. 95 to 98 ° and its hydrochloride from the ground. 227 to 229 °.

The starting materials are prepared as follows:

a) 65.6 g of 5-methoxysalicylaldehyde, 74 g of 4- (chloromethyl pyridine hydrochloride, 280 g of potassium carbonate and 2 g of potassium iodide in 809 ml of dimethylformamide are heated to 100 ° for 20 hours, then the solution is sucked off and the filter residue is washed with 1 1 chloroform The combined filtrates were evaporated in vacuo and the residue dissolved in 1 l chloroform The organic phase was washed first with 500 ml of 2 n sodium hydroxide and then with 1 l of water, dried over sodium sulfate, filtered and evaporated The remaining 4- (5-methoxy) After recrystallization from ethyl acetate, -2-benzofuranyl) pyridine melts at 123 DEG C. The hydrochloride solution in ethyl acetate is recrystallized from ethyl acetate and then melted at 228 DEG.

b) 127.5 g of 4,5-dimethoxy-salicylaldehyde, 116 g of 4- (chloromethyl) -pyridine hydrochloride, 420 g of sodium carbonate and 2 g of sodium iodide in 1000 ml of dimethyliormamide are heated to 90 to 95 ° for 15 hours. The mixture was then sucked off and the filter residue was washed with 1 L of chloroform. The combined filtrates were evaporated in vacuo and the residue dissolved in 1 L of chloroform. The organic phase is washed first with 500 ml of 2 n sodium hydroxide solution and then with 1 l of water. dried over sodium sulfate, filtered and evaporated. After evaporation, the residue is a mixture of 4- (5,6-dimxy-2-benzofuranyl) -pyridine and 2 - [(4-pyridyl) -methoxy] -4,5-dimethoxybenzaldehyde and is further processed without purification.

c); 'In the sense of b) the resulting mixture under nitrogen is heated to 250 ° for 4 minutes. After cooling, the residue was dissolved in a little of methylene chloride and chromatographed over 2000 g of alumina (activity It, neutral). First fraction, eluted with 4 l of methylene chloride. is 4- (5,6-dimethoxy-2-benzofuranyl) -pyridine. After recrystallization from ether, the compound was melted at 129 to 133 °. Hydrochloride solution in ethylacetafc prepared hydrochloride melts at 241 to 242 °.

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

.Allogically obtained using 33.3 g of 4- (5,6-dimethoxy-2-benzofuranyl) -pyridine [cf. c) i-Methyl-4- (5.3-dimethoxy-2-benzofuranyl) -pyridinium iodide, m.p. 258 to 270 °.

e) A solution of 49 g of sodium borohydride in 100 ml of water is added dropwise to a solution of 44.3 g of 1-methyl-4-; T-methoxy-2-benzofuranyl) -pyridinium iodide in 350 ml of methanol in such a way that the reaction temperature does not scatter beyond 35 °. The solutions were then stirred at room temperature for 20 hours. Then the methanol was evaporated in vacuo, the remaining aqueous phase was extracted twice with 500 ml of chloroform each, the chloroform solution was dried over sodium sulfate, filtered and evaporated. The resulting 1-methyl-4- (5-methoxy-2-benzofuranyl) -1,2,3,6-tetrahydropyridine was recrystallized from cyclohexane and then melted at 99 to 101 °.

The hydrochloride hydrochloride solution prepared from it with a solution of hydrogen chloride in ethyl acetate is melted at 238 ° C after recrystallization from ethyl acetate.

Analogous was obtained using 47.9 g of 1-methyl-4-1,5, C-dimethoxy-2-benzofuranyl) -pyridinium iodide 1-methyl-4- (5,6-dimethoxy-2-benzofuranyl) -1,2, 3,6-ietrahydropyridine m.p. 139 to 141 ° and its hydrochloride from the ground. 234 to 236 °.

f) 22.0 g of 1-methyl-4- (5-methoxy-2-benzofuranyl) -1,2,3,6-tetrahydropyridine are dissolved in 220 ml of methanol and hydrated in the presence of 4 g of 5% palladium on carbon at temperatures of 40 to 50 ° and under normal pressure. After 11 hours of hydrogenation, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in a little chloroform and chromatographed on 400 g of alumina (activity II, neutral). The first fraction - 37 163 - cation eluted with 2 L chloroform is 1-methyl-4- (5-methoxy-2-benzofuranyl) -piperidine. After recrystallization from hexane, this melts at 68 °. The hydrochloride solution prepared from the hydrochloric acid solution in ethyl acetate was melted at 282 to 284 °.

24.7 g of 1-methyl-4- (5,6-dimethoxy-2-benzofuranyl) -1,2,3,6-tetrahydropyridine 1-methyl-4- (5,6-dimethoxy- 2-Benzofuranyl) -piperidine m.p. 73 to 75 ° and from it hydrochloride from the ground. 228 to 231 °.

Example 6

Analogous to Example 1, 13.6 g of 1-methyl-4- (5-methyl-2-benzofuranyl) -piperidine [see sections a), d), e) and h) below are obtained over crude ethyl 4- (5- methyl-2-benzofuranyl) -1-piperidinecarboxylic acid 4- (5-methyl-2-benzofuranyl) -piperridine m.p. 51 to 53 ° (from pentane) and from it its hydrochloride from the ground. 158 to 161 °, from 13.6 g of 1-methyl-4- (6-methyl-2-benzofuranyl) -piperidine [see sections a), f) and h) below] over 4- (6-methyl- 2-Benzofuranyl) -1-piperidinecarboxylic acid 4- (6-methyl-2-benzofuranyl) -piperidine m.p. 123 to 125 ° and from it its hydrochloride from the ground. 220 to 221 ° and from 12.8 g of 1-methyl-4- (2-benzofuranyl) -piperidine [see sections b), c), g) and h) below] through the crude ethyl ester 4- (2-benzofuranyl) -1-piperidinecarboxylic acid 4- (2-benzofuranyl) -piperidine by boiling. 122 to 129 ° below 0.13 mbar and from it hydrochloride from the ground. 228 to 230 °.

The starting materials are prepared as follows:

a) 173.8 g of 5-methylsalicalaldehyde, 210 g of 4- (chloromethyl) -pyridine hydrochloride, 620 g of potassium carbonate and 7 g of potassium iodide in 1000 ml of dimethylformamide were heated to 80-90 ° with stirring for 20 hours. The solution was then sucked off, the filter residue with 500 ml of dimethylformamide was evaporated in vacuo and the residue was dissolved with chloroform fork after evaporation. The organic phase is washed first with evil 1N sodium hydroxide and then with evil water, dried over sodium sulfate, filtered off with suction and evaporated. The remaining oil is a mixture of 2 - [(4-pyridyl) -methoxy] -5-methyl, benzaldehyde and 4- (5-methyl-2-benzofuranyl) -pyridine and distilled under high vacuum. The fraction distilled at 170-190 ° and 0.13 mbar was dissolved for further purification into a little methylene chloride and chromatographed over 3 kg of alumina (activity II, neutral). The first fraction eluted with 4 L of methylene chloride is 4- (5-methyl-2-benzofuranyl) -pyridine. After recrystallization from pentane, the compound melts at 160-162 °.

In an analogous manner, 4- (6-methyl-2-benzofuranyl) -pyridine is obtained using the same amount of 4-methyl-salicylaldehyde.

b) 146.4 g of salicylaldehyde, 196.8 g of 4- (chloromethyl) -pyridine hydrochloride, 750 g of potassium carbonate and 2 g of potassium iodide in 3 L of dimethylformamide are heated to 80 to 90 ° with stirring for 15 hours. The solution was then sucked off and the filtered residue was washed with evil chloroform. The combined filtrates were evaporated in vacuo and the residue was dissolved after evaporation of chloroform forks. The organic phase was washed first with evil 2 n sodium hydroxide and then with 11 water, dried over sodium sulfate, filtered off with suction and evaporated. The remaining crude o - [(4-pyridyl) -methoxy] benzaldehyde is further processed without purification.

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

d) 80 g of 4- (5-methyl-2-benzofuranyl) -pyridine are dissolved in 150 ml of methanol and 450 ml of methyl iodide are stirred at 40 to 45 ° for 15 hours. The solution was then cooled to 0 ° and the precipitated salt was filtered off with suction. The filter residue was washed with 500 ml of ethanol. After recrystallization from methanol, 1-methyl-4- (5-methyl-2-benzofuranyl-pyridinium iodide melts at 198 to 200 °.

e) A solution of 60 g of sodium borohydride in 150 ml of water is added dropwise to a solution of 125 g of 1-methyl-4- (5-methyl-2-benzofuranyl pyridinium iodide in 750 ml of methanol in such a way that the reaction temperature does not exceed The solution was then stirred at room temperature for 20 hours, then the methanol was evaporated in vacuo, the remaining aqueous phase was extracted twice with 500 ml of chloroform, the chloroform solution was dried over sodium sulfate, filtered and evaporated. methyl-2-benzofuranyl) -1,2,3,6-tetrabidropyridine was recrystallized from diisopropylether and melted at 102 ° C. The hydrochloride solution prepared with hydrogen chloride in ethyl acetate was melted at 243 ° C after recrystallization from ethyl acetate.

f) Analog d) 80 g of 4- (6-methyl-2-benzofuranyl) -pyridine crude 1-methyl-4- (6-methyl-2-benzofuranyl) -pyridinium iodide are obtained and 125 g of the last analog e) 1 -methyl-4- (6-methyl-2-benzofuranyl) -1,2,3,6-tetrahydropyridine and its hydrochloride m.p. 264 °.

g) Analogous d) from 74 g of 4- (2-benzofuranyl) -pyridine crude 1-methyl-4- (2-benzofuranyl) -pyridinium iodide are obtained and

-t Π

- 37 163 from 120 g of the last analogous to e) 1-methyl-4- (2-benzofuranyl) -1,2,3,6-tetrahydropyridine m.p. 74 to 75 ° dissolved hydrochloride from m.p. 234 to 236.

Example 7

Analogous to Example 3 from 32.8 g of 1-methyl-4- (5-cyclohexyl-2-benzoiuranyl) -piperidine via the crude ethyl ester of 4- (5-cyclohexyl-2-benzofuranyl) -1-piperidinecarboxylic acid, 4- (5- cyclohexyl-2-benzofuranyl) -piperidine and its hydrochloride from ground 223.

The starting material 1-methyl-4- (5-cyclohexyl-2-benzofuranyl) -piperidine is prepared as follows:

a) To a solution of 60 g of 1-methyl-4- (5-bromo-2-benzouranyl) -piperidine (cf. Example 19), dropwise at -5 ° C, dropwise at -5 ° C for 30 minutes 480 ml of 1.35 n solution. n-butyllithium in absolute diethyl ether. During the drop-off, the reaction temperature is maintained by external cooling between -5 and 0. The solution is then stirred at 5 to 10 ° for 90 minutes. A solution of 85 ml of cyclohexanone in 100 ml of absolute diethyl ether is then added dropwise over 30 minutes. maintaining the reaction temperature by external cooling at 0 to 5 °. The reaction solution was then stirred at room temperature for 15 hours, poured onto 300 g of ice with stirring, and each phase extracted three times with 500 ml of ethyl acetate each time. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The residue was dissolved in 300 ml of 2 n hydrochloric acid and the acidic solution was washed with ether. The aqueous solution was then adjusted to pH 12 with the addition of 10% sodium hydroxide and extracted with 1000 ml of chloroform. The chloroforne solution was dried with sodium sulfate, filtered off and evaporated to give crude 1-methyl-4- [5- (1-hydroxycyclohexyl) -2-benzofuranyl] piperidine. After recrystallization from cyclohexane, the free base was melted at 155 to 1577 The hydrochloride was prepared with hydrogen chloride in ethyl acetate and recrystallized from acetone and then melted at 226 to 229 °.

b) 20 g of 1-methyl-4- [5- (1-hydroxycyclohexyl) -2-benzoiuranyl] piperidine in 60 ml of glacial and 15 ml of hydrochloric acid are boiled under reflux for 48 hours. The reaction solution was cooled to room temperature and evaporated in vacuo. After evaporation, the residue was suspended in 1000 ml of chloroform and washed with 2 n sodium hydroxide solution. The organic phase was dried over sodium sulfate, filtered and chromatographed on 700 g of alumina (activity II, neutral). The first fractions, eluted with 3000 ml of chloroform, were added by evaporation of crude 1-methyl-4- [5- (1-cyclohexenyl) -2-benzofuranyl] -piperidine. After recrystallization from hexane, the compound melts at Sl to 85 °. The hydrochloride solution in ethyl acetate hydrochloride prepared after melting from ethyl acetate melts at 227 to 229 °.

c) Dissolve 2.0 g of 1-methyl-4- [5- (1-cyclohexenyl) -2-benzofuranyl-piperidine in 30 ml of methanol and in the presence of 0.2 g of 5% palladium on carbon. up to 25 ”and under normal pressure. After 3 hours, the hydrogenation was stopped at 100% hydrogen uptake, the catalyst was filtered off and the filtrate was evaporated in vacuo. The remaining I-methyl-4- (5-cyclohexyl-2-benzofuranyl) -piperidine was melted at 89-90 ° C after recrystallization from hexane. The hydrochloride solution in ethyl acetate hydrochloride prepared after melting from ethyl acetate melts at 238 to 240 °.

Example 8

Analogous to Example 1 of 15.0 g of 1-methyl-4- (6-chloro-2-benzofuranyl) -piperidine via the crude ethyl ester of 4- (6-chloro-2-'-oenzofuranyl) -1-piperidinecarboxylic acid, 4- (6 -Cylor-2-benzofuranyl) -piperidine and from it hydrochloride from the ground. 237 °.

As the starting material, the required 1-methyl-4- (6-chloro-2-benzofuranyl) -piperidine was prepared analogously to examples 1a) to e) of 4-chlorocycloaldehyde.

Example 9

Analogous to Example 5, from 14.6 g of 1-methyl-4- (6-methoxy-2-benzofuranyl) -piperidine over 4- (6-methoxy-2-benzofuranyl) -1-piperidinecarboxylic acid crude ethyl ester, 4- (6 -methoxy-2-benzofuranyl) -piperidine and from it hydrochloride from the ground. 208 °.

As the starting material, the required 1-methyl-4- (6-methoxy-2-benzofuranyl) -piperidine, whose hydrochloride melts at 205 °, is prepared from 4-methoxy-salicylaldehyde analogous to Example 5a) to f).

Example 10

Analogous to Example 1, 15.8 g of 1-methyl-4- (5-chloro-6-methyl-2-benzofuranyl) -piperidine (m.p. 227 °) was obtained over crude ethyl 4- (5-chloro-6-methyl -2-Benzofuranyl) -1-piperidinecarboxylic acid 4- (5-chloro-6-methyl-2-benzofuranyl) -piperidine and from it hydrochloride from m.p. 190 ° (from ethyl acetate) and from 14.6 g of 1-methyl- (5-fluoro-2-benzofuranyl) -piperidine (m.p. 227 to 228 °) over crude ethyl 4- (5-fluoro-2-benzofuranyl) -1-piperidinecarboxylic acid 4- (5-fluoro-2-benzofuranyl) -piperidine and from it its hydrochloride from m.p. 235 °.

The starting materials were prepared analogously to Example 1 a) to e) from 4-methyl-5-chlorosalicylaldehyde or. 5-fluorsalicylaldehyde.

- 37 133

Example 11

47.8 g (0.20 mol) of 4- (5,6-dimethyl-2-benzofuranyl) -1-piperidinecarbonitrile in 400 ml of 0.5 n hydrochloric acid for 5 hours (boiled under reflux. The clear reaction solution was adjusted alkaline with concentrated The aqueous ammonia solution was extracted with ether. From the hydrochloride base in ethyl acetate, the prepared hydrochloride was crystallized from methanol / ethyl acetate to give the hydrate from mp 230 to 233 °.

The starting material can be prepared as follows:

To a solution of 62.2 g (0.272 mol) of 4- (5,6-dimethyl-2-benzofuranyl) -1-methylpiperidine in 1000 ml of benzene, a solution of 31.6 <g (0.299 mol) of bromcine was added dropwise over 15 minutes at room temperature. in 500 benzene. The reaction mixture was then refluxed for 1 hour. The reaction mixture was washed thoroughly with water and then extracted with 2N hydrochloric acid in ice-cold water. The remaining benzene solution was dried over sodium sulfate and evaporated completely in vacuo. The remaining 4- (5,6-dimethyl-2-benzofuranyl) -1-piperidine-carbonitrile can be used without further purification.

Example 12

13.7 g of 4- (5,6-dimethyl-2-benzofuranyl) -1-piperidine-carboxylic acid ethyl ester (compare Example 3,

(1) dissolve in 60 ml of ethylene glycol and add 20 g of solid sodium hydroxide. The resulting cloudy solution was heated to 180 ° with stirring for 6 hours. The reaction solution was then cooled to 20 ° and further processed in analogy to Example 3, paragraph 2, to give crude 4- (5,6-dimethyl-2-benzofuranyl) -piperidine and from it hydrochloride as a hydrate from the ground. 230 to 233 °.

Claims (3)

A process for the preparation of novel tetrahydropyridine and piperidine derivatives of the general formula I in which Publisher: Save the Bureau of R3 and R4 independently of one another are hydrogen, methyl, methoxy, halogen atoms up to an atomic number of 35, and R3 is also a cyclohexyl group, or R3 and R4 together are a trimethylene residue or, respectively, a fused benzene ring, a 1,3-butadienylene residue, and A is an ethylene residue and at the same time B is a methylene residue or A is a methylene residue and B is an ethylene residue and X and Y in each case a hydrogen atom or together an additional bond, and their physiologically acceptable addition salts with inorganic and organic acids, characterized in that in a compound of general formula II with which Ac stands for ethcksicarbonyl residue or cyano residue and they have R3, R4, A, B, X and Y are as defined in Formula I, the Ac residue is cleaved by treatment with alkali hydroxide in ethylene glycol at temperatures between 160 and 180 ° C, or, if Ac is a cyano residue, also by dilute salt. of the acid at boiling point, and optionally the resulting compound of general formula I is converted into a physiologically acceptable addition salt with inorganic or organic acid. Process according to claim 1, characterized in that the compound of claim 1 states the general formula I in which Ac represents an ethoxycarbonyl group and R 3, R 4, X,; Y, A and B have the meaning indicated in claim 1, the residue Ac is cleaved by treatment with sodium or potassium hydroxide in ethylene glycol at a temperature between 160 and 180 ° C. Process according to claim 1, characterized in that the compound of claim 1 states the general formula I, in which Ac represents a cyano group and R ₃ , R 4, X, Y, A and B have the meaning indicated in claim 1, the residue Ac is cleaved using dilute hydrochloric acid at boiling point. e, Belgrade, bzun Mirkova 1 Printed by: IPP »BANAT« OOUR »Graphics« Kikinda, B. Kidrica 54