CS273193B2 - Method of new tetrahydrofuro- and -thienol (2,3-c) pyridine production - Google Patents

Description

The present invention relates to a novel process for the preparation of tetrahydrofuro and thieno [2,3-c] pyridines, as well as their acid addition salts, which have valuable pharmacological properties and can be used as medicaments, in particular as cholinomimetics.

It has been found that the compounds of formula (I)

in which it is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, acetyl, hydroxyethyl, chlorine or bromine;

R ₂ is hydrogen, halogen or straight or branched alkyl having 1 to 4 carbon atoms;

means Líku; atom hydrogen or direct or branched alkyl group with 1 to 4 atoms means Líku; atom hydrogen or direct or branched alkyl group with 1 áž 4 atoms means atom hydrogen or direct or branched alkyl group with 1 to 4 atom

Líku;

R 8 represents a hydrogen atom or a methyl group; and _t

X represents an oxygen atom or a sulfur atom, and optionally their pharmacologically compatible acid addition salts or their quaternary compounds can be used as medicaments with cholinomimetic properties.

For the purposes of the present invention, alkyl, and optionally also as a component of other functional groups, means methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomers thereof.

Preference is given to compounds of the formula I in which R1 represents a straight or branched alkyl group having 1 to 6 carbon atoms, particularly preferably 1 to 4 carbon atoms,

R @ ₂ , R @ 8 and / or R @ 8 are hydrogen, R @ 8 is hydrogen and R @ 6 is a straight or branched C1 -C4 alkyl group.

Preferred alkyl groups, also in the meaning of other substituents, are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

Halogen means one of the atoms from the group consisting of fluorine, chlorine, bromine or iodine.

Particularly preferred are compounds of formula I wherein X is O, ^R 1 ^{and R} 4 ', ^which may be the same or different from each other, are C 1 -C 4 alkyl; R is preferably methyl, ethyl, n-propyl or n-butyl and R is methyl and _R2, Rg, Rg and _Rg are hydrogen.

Preferred bases, their pharmacologically compatible acid addition salts and quaternary compounds are the following:

2,6-dimethyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

2,6-dimethyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

6-methyl-4,5,6,7-tetrahydrofuro [2,3-b] pyridine

2-methyl-4,5,6,7-tetrahydrofuro (2,3-c) pyridine

2-ethyl-6-methyl-4,5,6,7-tetrahydrofuro [2,3-e] pyridine

6-methyl-2-n-propyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

6-methyl-2-n-butyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

6-methyl-2-isobutyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

2-methyl-4,5,6,7-tetrahydrothieno [2,3-c3 pyridine

2,3,6-trimethyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

6-ethyl-2-methyl-4,5,6,7-tetrahydrothieno (2,3-c) pyridine

2-chloro-6-methyl-4,5,6,7-tetrahydrothieno (2,3-c) pyridine

2-methyl-6,6-dimethyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridinium iodide

2-methyl-6,6-dimethyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridinium iodide

2-acetyl-6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

2-bromo-6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

3,6-dimethyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

2-ethyl-6-methyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

2-ethoxycarbonyl-6-methyl-4,5,6,7-tetrahydrofuro (2,3-c) pyridine

2-acetyl-3,6-dimethyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

2-ethyl-3,6-dimethyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

2-bromo-3,6-dimethyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

2-chloro-3,6-dimethyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

2-Cyano-6-methyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine

2-hydroxymethyl-6-methyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine.

The compounds of formula (I) are known in part. Thus, DE-OS 26 28 045 describes tetrahydrothienopyridines which are substituted exclusively at the 6 and 7 positions as compounds having antiinflamatory properties, antiarrhythmic properties as well as the ability to inhibit platelet aggregation.

Unlike the tetrahydrothienopyridines, the corresponding tetrahydrofuropyridines of the formula I have not been known to be used as medicaments.

The compounds of formula I have muscarinic agonist properties and are therefore useful in the treatment of diseases associated with cholinergic system deficiency.

The tertiary amines of formula (I) of the present invention exhibit affinity for muscarinic receptors in the central nervous system and, when tested in animals, exhibit muscarinic agonist properties in the central nervous system.

Thus, for example, 2,6-dimethyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine hydrochloride shows in the waking rabbit electroencephalogram at 3 mg / kg p.o. (1 mg / kg i.v.) a wake-up reaction typical of cholinomimetics.

In monkeys sensitized to haloperidol, compounds of the invention, such as 2,6-dimethyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine hydrochloride (dose ≥1 mg / kg im), potentiate dyskinesia induced haloperidol, optionally at doses lower than the minimum effective dose, release dyskinesia. Furthermore, the compounds of the invention exhibit muscarin binding properties in in vitro experiments, or exhibit GTP (guanosine triphosphate) shifts in agreement with muscarin. Cf. [Birdsall, N.I.M., E.C. Hulme and J.M. Stoecton 1984 in T.I.P.S. Supplement, Proc. Dormitory. Symposium on Subtypes of Muscarinic Receptors, ed. Hirschowitz, Hammer, Giacchetti, Keirn, Levine;

Elsevier pp. 4 - 8 J.

Receptor binding studies in the muscarionic cholinergic system are performed on three receptor subgroups according to the literature cited below:

Watson, H., H.I. Yamamura and W.R. Roeske 1983, Life Sci. 32, 3001-3011;

Hammer, R., C.P. Berrie, N.I.M. Birdsall, A.S.V. Burgen and E.C. Hulme 1980, Nature 283, 90-92;

Hammer, R., E. Giraldo, G.B. Schiavi, E. Monferini and H. Ladinsky 1986, Life Sci. 38, 1653-1662.

The results are summarized in Table I below:

Table I

Results of receptor binding studies

type of receptors ^M 1 ^M 2 ^M 3 organ hippocampus heart tear gland ligand Pirenzepin N-methyls scopolamine custody receptors yumol X ^R 1 · ^R 2 ^R 3 ^R 4 ^R 5 0 CH ₃ H H ch ₃ H 8.3 6.5 24 _r 2 with ch ₃ H H ch ₃ H 7.5 14, - 53.1 with H H H ch ₃ H 36.3 > 100 > 100 with ch ₃ H H H H 39.6 > 100 > 100 with CH ₃ H H ch ₃ ch ₃ 5.8 8.4 34.1 with CH ₃ H H Et H 2.2 4,5 11.4 0 n-Bu H H ch ₃ H 0.5 0.7 0 Et II II ch ₃ H 1.4 1.0 0 iso-Bu II II ch ₃ II 0.8 2.5 2.7 0 ch ₃ CII ₃ H Et H 3.2 3.2

Note:

Rg = hydrogen Cbu = butyl, Et = ethyl]

The compounds produced by the process of the invention suppress muscarinic agonists with high affinity agonists for binding sites. The 3H cis-methyl-dioxolane binding study is performed analogously to A. Closs et al., Naunyn Schmiedebergs Arch. Pharmacol 335, 372-377 (1987). The results are summarized in Table Ia.

Table Ia Ligand L ³ h] cis-methyldioxolane receptor binding [10 ^-9 mol / liter]

X ^R 1 ^R 2 ^R 3 ^R 4 ^R 5 0 n-Bu H H ch ₃ H 39 0 n-Pr H H ch ₃ and 53 0 Et H H ch ₃ H 52 0 ch ₃ H H ch ₃ H 81 0 n-Pr H H H H 160

R 8 = hydrogen; Et = ethyl; Pr = propyl

Based on the pharmacological findings, the compounds of the present invention are useful in the treatment of the following diseases; Alzheimer's disease, senile dementia, impaired memory function and, in addition, the compounds can be used to improve memory.

The quaternary compounds of formula I are particularly suitable for peripheral applications, such as for the treatment of glaucoma.

The compounds of the invention may be prepared according to known analogous procedures.

It is an object of the present invention to provide a process for the preparation of compounds of the formula I as defined above, which comprises reducing the 4-hydroxy-substituted compounds of the formula II

in which

R | to Rg and X are as defined above, for example in a mixture of glacial acetic acid and concentrated hydrochloric acid by treatment with stannous chloride at temperatures from room temperature up to the boiling point of the reaction mixture, optionally followed by a compound of formula I reacting with acetyl chloride in the presence of aluminum chloride in an organic solvent to form a compound of formula I wherein R 1 is acetyl, and optionally reducing this compound with sodium hydride in ethanol to give a compound of formula I wherein R 1 is hydroxyethyl, or, optionally, a compound of formula I wherein H is converted by treatment with sulfuryl chloride in glacial acetic acid to a compound of formula I wherein R ₁ is chlorine, optionally by treatment with potassium bromide and bromine to give a compound of formula I of and then converting the optionally obtained compound into pharmacologically useful acid addition salts or the subsequent treatment with methyl iodide or methyl p-toluenesulfonic acid ester in polar solvents such as nitromethane, acetoCS 273193 B2 nitrile or alcohols to the corresponding quaternary compounds.

The reduction is conveniently carried out in a mixture consisting of glacial acetic acid and concentrated hydrochloric acid with stannous chloride at temperatures between room temperature and the boiling point of the reaction mixture, preferably at temperatures of 50 to 70 ° C.

In one process variant, the reaction of the corresponding alcohol with a mixture consisting of hydroiodic acid and red phosphorus is carried out in glacial acetic acid at boiling point.

Other methods of reduction and reagents are described in the review article Modern Methods for Radical Deoxygenation of Alcohols by W. Hartwig in Tetrahedron 83; St. 39 (16), Vol. 2609 to 2645 and in Tetrahedron Letters £ 2, Vol. 23 (19), 2019.

Quaternary compounds of formula (I) are obtained by conventional procedures from the corresponding tertiary amines by reaction with a suitable quaternizing agent, such as methyl iodide, methyl p-toluenesulfonic acid, in polar solvents such as nitromethane, acetonitrile or alcohols.

The alcohols of formula (II) used as starting materials can also be prepared according to known methods or analogous processes, such as by reduction of the corresponding ketones with complex hydrides such as lithium aluminum hydride, in inert organic solvents such as diethyl ether, tetrahydrofuran and the like.

The tetrahydrofuro- or thieno [3,2-c] pyridines of the formula I according to the invention can be converted into their physiologically tolerable acid addition salts in a customary manner. ,

Suitable salts for forming are, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxalic acid, malonic acid, succinic acid acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid; phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, 8- chlortheophyllin and the like

Preferred acid addition salts are the hydrochlorides as well as the hydrobromides.

For example, the following compounds of formula I can be obtained by the processes described:

T a b u-1 k and II

Compounds of formula (I) wherein R 8 is hydrogen

compound no. X ^R 1 ^R 2 ^R 3 ^R 4 ^R S melting point hydrochloride 1 0 ^CH 3 H H ch ₃ H 256 - 258 (decomposition) 2 WITH ^CH 3 H H CH ₃ H 226 3 WITH ch ₃ H R H H 201–202 4 WITH ^CH 3 H H ch ₃ ch ₃ 200 - 202 5 WITH ch ₃ H H ^C 2 ^K 5 H 210-211 6 WITH Cl H H ch ₃ H 247-248 7 0 H H H ch ₃ H 265-266 8 0 H ch ₃ H ch ₃ H

* 1

iloučenina č. X ^R 1 ^R 2 ^R 3 ^R 4. * 5. melting point of hydrochloride (0 9 0 H H H CH ₃ Η 263 10 0 CH ₃ H H ch ₃ H 256 11 0 ^C 2 ^H 5 H H ch ₃ Η 215 12 0 n-C? H? H H ch ₃ H oil (base) 13 0 n-C-iH? , H H Η Η 174-175 14 ' 0 nC ₄ Hg H H ch ₃ H 116-117 15 Dec 0 nC ₄ H ₉ CH, H H H H 170-172 16 0 > CH-CH, CH H H Η H 198-199 17 0 3 II H H ch ₃ H 129-130 18 0 H ch ₃ H ch ₃ H 260-261 19 Dec 0 ch ₃ · ch ₃ H ch ₃ H 235-236 20 May 0 ch ₃ . ch ₃ H ^C 2 ^H 5 H 184-185 Compounds of general formula I se they can use themselves or together with other effective-

The compounds according to the invention, optionally also in combination with other pharmacologically active substances, for example with other cereactivators.

Suitable dosage forms are, for example, tablets, capsules, lace, solutions, juices, emulsions or dispersible powders. Appropriate tablets may be obtained, for example, by mixing the active ingredient (s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or milk sugar, tablet disintegrating agents such as corn starch or alginic acid, with binders such as starch or gelatin, with lubricants such as magnesium stearate or talc, and / or a depot effecting agent such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also consist of multiple layers.

Correspondingly, dragees can be prepared by coating cores made analogously to tablets by means conventionally used in the coating technique, for example by means of collidone or shellac, gum arabic, talc, titanium dioxide or sugar. In order to achieve a depot effect or to prevent incompatibilities, the dragee core may also consist of multiple layers. Likewise, the dragee coating may also consist of a plurality of layers in order to obtain a depot effect, the excipients mentioned above for tablets being used.

The active ingredient states according to the invention or the active ingredient combination may additionally contain sweetening agents, such as saccharin, cyclamate, glycerin or sugar, as well as flavor enhancers, such as flavorings such as vanillin or orange extract.

In addition, they may contain suspending agents or thickeners, such as sodium carboxymethylcellulose, wetting agents, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives, such as p-hydroxybenzoate.

Injectable solutions are prepared in conventional manner, for example by the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and are filled into injection bottles or ampoules.

Capsules containing one or more active compounds or combinations of active compounds can be prepared, for example, by mixing the active compounds with inert carriers, such as milk sugar or sorbitol, and filling the mixture in gelatin capsules.

Suitable suppositories may be prepared, for example, by mixing with carriers intended for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof.

The following examples illustrate the present invention in more detail without limiting its scope.

Examples of pharmaceutical preparations

A) Tablets per tablet active ingredient 100 mg milk sugar 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg

500 mg

The finely divided active ingredient, lactose and one part of corn starch are mixed together. The mixture is passed through a sieve and then moistened with a solution of polyvinylpyrrolidone in water, sagged, wet granulated and dried. The granulate obtained, the corn starch residue and the magnesium stearate salt are sieved and mixed with one another. The mixture is compressed into tablets of suitable shape and size.

B) Tablets active ingredient 80 mg corn starch 190 mg milk sugar 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium carboxymethyl starch 23 mg magnesium stearate 2 mg

400 mg

The finely divided active ingredient, 1 part maize starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed with one another, sieved through a sieve and processed with the remainder of the maize starch and water to form a granulate. The granulate is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are then added, mixed thoroughly and compressed into tablets of suitable size.

C) Ampoule active ingredient 50 mg sodium chloride 10 mg doubly distilled water to 1.0 ml

Production:

The active substance and sodium chloride are dissolved in redistilled water and the solution obtained is filled into ampoules under sterile conditions.

D) Drops active substance p-hydroxybenzoic acid methyl ester p-hydroxybenzoic acid propyl ester demineralized water

5.0 g 0.1 9 0.1 g to 100.0 ml

Production:

The active ingredient and the preservative are dissolved in demineralised water and the solution obtained is filtered and filled into 100 ml bottles.

Example 1

2,6-dimethyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine g (49 mmol) 2,6-dimethyl-4-hydroxy-4,5,6,7-tetrahydrofuro [2,3] -c] pyridine (produced according to J. Chem. Soc. Perkin Trans I 1986, p. 877 et al., DOS 3315157) is dissolved in a mixture consisting of 120 ml of glacial acetic acid and 60 ml of concentrated hydrochloric acid and the solution obtained. 19.1 g (99 mmol) of oCl chloride are added. The reaction mixture was then stirred at 65 ° C for 2.5 hours. The reaction mixture is then concentrated, the residue is taken up in water, treated with concentrated ammonia under ice-cooling for a basic reaction and then extracted several times with ethyl acetate. After drying and concentration of the solvent, the product is purified by chromatography on silica gel using a mixture of ethyl acetate, methanol and ammonia (Ϊ0: 1: 0.5) as eluent. The purified base is converted to the hydrochloride which is recrystallized from ethanol.

Yield: 2.6 g (28% of the title compound as the hydrochloride salt);

256 DEG-258 DEG C. (decomposition).

Analysis:

calculated: 57.59% C, 7.51% H, 7.46% N, 18.89% Cl; Found: C, 57.31; H, 7.56; N, 7.65; Cl, 18.65.

Example 2

2,6-dimethyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

2.1) 63.5 g (0.45 mol) of 2- (N-methylaminomethyl) -5-methylthiophene together with 47.5 g sodium carbonate, 0.5 g potassium iodide and 76.3 g (0.5 mol) of chloroacetaldehyde diethyl acetal is stirred in 130 ml of anhydrous dimethylformamide for 5.5 hours at 130 DEG C. This suspension is filtered, the filtrate is concentrated and the residue is distilled under reduced pressure.

64.7 g (56% of theory) of 5-methyl-2- (N-methyl-N-2,2-diethoxyethylaminomethyl) thiophene are obtained.

2.2) The amine produced in 2.1) is heated under reflux in 210 ml of 6N hydrochloric acid solution for 3 hours, then the reaction mixture is cooled, then the reaction mixture is poured onto ice, made alkaline by addition of ammonia and extracted several times with ethyl acetate. After the usual working-up and purification, the base thus obtained is converted into the hydrochloride which is recrystallized from isopropyl ether.

22.3 g (49% of theory) of 2,6-dimethyl-4-hydroxy-4,5,6,7-tetrahydrothieno [2,3-c] pyridine hydrochloride, m.p.

2.3) Using 9.4 g (51 mmol) of 2,6-dimethyl-4-hydroxy-4,5,6,7-tetrahydrothieno [2,3-c] pyridine hydrochloride in an analogous manner to that described in Example 1, yields 7.3 g (70% of theory) of the title compound as the hydrochloride, m.p. 226 DEG.

Analysis for:

C.H., NS x HCl (MW 203.73) calculated 53.06% C, 6.93% H, 6.88% N, 17.40% Cl; Found: C, 52.85; H, 6.98; N, 6.81; Cl, 17.21.

Example 3

6-ethyl-2-methyl-4,5,6,7-tetrahydrothieno [2,3-c3 pyridine

2-Methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine hydrochloride, prepared in an analogous manner to that described in Example 2, m.p. 201-202 ° C, is alkylated as follows:

2.5 g (13 mmol) of hydrochloride are dissolved in 100 ml of anhydrous dimethylformamide and 2.8 g (18 mmol) of ethyl iodide, 1.2 g of potassium iodide and 4.2 g of sodium carbonate are added and the reaction mixture is stirred for 3 hours. The reaction mixture is concentrated, the residue is taken up in water and dichloromethane, the aqueous phase is rendered alkaline and further worked up in the usual manner. The residue thus obtained is chromatographed on silica gel, eluting with a dichloromethane / methanol (97: 3) mixture. The isolated base was converted to the hydrochloride, which was recrystallized from ethanol.

Yield: 1.2 g (43% of theory).

Melting point: 210-211 ° C.

Example 4

2-chloro-6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

2.7 g (14 mmol) of 6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine hydrochloride, m.p. 226 DEG-228 DEG C., prepared as described in Example 2, are dissolved in 90 ml of glacial acetic acid at 15 DEG C. were added dropwise to the obtained solution, 2.2 g (16 mmol) of sulfuryl chloride. The reaction mixture was stirred at room temperature, poured onto ice, basified and extracted several times with dichloromethane. The crude product obtained by drying and concentration of the organic phase was chromatographed on silica gel using dichloromethane / methanol as eluent. The uniform fractions were concentrated and the reaction product was converted to the hydrochloride.

Yield: 0.5 g.

Melting point: 247-248 c (from ethanol).

Analysis for:

^C 8 ^H 10 ^{ClNS x HCl} (224.15) calculated: 42.87% C, 4.95% H, 6.25% N, 31.63% Cl, 14.31% S;

Found: C, 42.65; H, 4.95; N, 6.07; Cl, 31.27; 14.38% S.

Example 5

2-methyl-6,6-N, N-dimethyl-4,5,6,7-tetrahydrofuro (2,3-c, 3-pyridinium iodide)

0.5 g (2.7 mmol) of 2,6-dimethyl-4,5,6,7-tetrahydrofuro C2,3-c3 pyridine is dissolved in 10 ml of ethanol and 0.72 g of methyl iodide is added. After stirring at room temperature for 3 hours, the precipitated crystals are filtered off and recrystallized from ethanol.

Yield: 0.52 g.

Melting point: 190-193 ° C.

'* 5

Elementary analysis:

for C ^ gHH gNNO (MW 293.15) calculated C 40.97, H 5.50, N 4.78%, 43.29µ J;

Found: C 41.00, H 5.57, N 4.95, J. 43.04%.

Example 6,

2-methyl-6, G-N, N-dimethyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridinium iodide

In an analogous manner to that described in Example 5, 2.7 mmol of 2,6-dimethyl-4,5,6,7-tetrahydrothieno-2,3-c3 pyridine are dissolved in 10 ml of ethanol and to a zinc solution at 0.8 g. methyl iodide. After the usual work-up, the corresponding quaternary ammonium salt is obtained in the form of white crystals, m.p. 160-161 C.

Example 7

2-acetyl-6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine hydrochloride

3.2 g (21 mmol) of 6-methyl-4,5,6,7-tetrahydrothieno-L2,3-c3 pyridine are dissolved in 10 ml of dichloroethane and 3.3 g of aluminum chloride are added. A solution of 1.7 g of acetyl chloride in 20 ml of dichloroethane was added dropwise to the obtained reaction mixture, and the reaction mixture was stirred for 16 hours. The reaction mixture was then poured onto ice, basified and the base extracted with dichloromethane.

After usual work-up by chromatography, subsequent conversion to the hydrochloride and repeated recrystallization from ethanol, 0.5 g of the title compound is obtained. Mp 256-257 ° C.

Example 8

2- (1-hydroxyethyl) -6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

4.2 g of the acetylderivative (0.018 mol) prepared as described in Example 7 are introduced in 100 ml of ethanol and 30 ml of water and 0.4 g (0.011 mol) of sodium borohydride are added in portions, allowing the temperature of the reaction mixture to rise to 28 ° C. . The reaction mixture was then stirred at 50 ° C for 3 hours and 0.4 g of sodium borohydride was added again. After 2 hours, 50 mL of ice water was added to the reaction mixture, and extraction was performed with dichloromethane. After the usual work-up, the remainder of the organic phase was dissolved in a 2: 1 mixture of ether and ethanol and acidified by the addition of 2N ethanolic hydrogen chloride. 1.7 g (40% of theory) of the title compound are obtained in the form of the hydrochloride, m.p. 131-132 ° C.

Alternatively, the reduction can also be carried out in a mixture of ether and tetrahydrofuran using lithium alanate as the reducing agent.

Example 9

2-bromo-6-methyl-1,4,5,6,7-tetrahydrothieno (2,3-c) pyridine

To a solution of 3.0 g (0.016 mol) of 6-methyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine in 65 ml of water, a solution of 4.6 g (0.038 mol) was added dropwise at 0 ° C. of potassium bromide and 2.4 g (0.017 mol) of bromine in 30 ml of water. The reaction mixture was stirred at 10-15 ° C for 3 hours, the crystals formed were filtered off and washed with ice water. The crystals are then dissolved in dilute ammonium hydroxide solution and then repeatedly extracted several times with dichloromethane. After the usual work-up, the residue of the organic phase is dissolved in ml of methanol. and acidify the methanolic solution with 2N ethanolic hydrogen chloride. 1.7 g (40% of theory) of the title compound are obtained in the form of the hydrochloride. The product is obtained in the form of colorless crystals of m.p. 260 DEG-261 DEG.

Example 10

3-bromo-2,6-dimethyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

In an analogous manner to that described in Example 9, from 2,6-dimethyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine by bromination, the title compound is obtained in the form of a pale yellow crystalline hydrochloride in 49% yield at temperature. mp 300-302 ° C.

Example 11

2,5,6-trimethyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

10.2 g (50 mmol) of 2,5,6-trimethyl-4-hydroxy-4,5,6,7-tetrahydro-thieno [2,3-c3 pyridine is reacted with 18.9 g (100 mmol) of anhydrous chloride of stannous in 60 ml of glacial acetic acid. After 6 hours, the reaction mixture is hydrolytically (NH 4 OH) worked up. 5.6 g (51% of theory) of the title compound of melting point 165 DEG-166 DEG C. are obtained from the organic phase (methylene chloride) after recrystallization from 8: 2 ethyl acetate / ether.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of tetrahydrofuro- and -thieno [2,3-c] pyridines of the general formula I in which? Represents a hydrogen atom, a straight or branched alkyl group having 1 to 6 carbon atoms, an acetyl group, a hydroxyethyl group, a chlorine atom or an atom bromine; R ₂ is hydrogen, halogen or straight-chain or branched alkyl having 1 to 4 carbon atoms; ^R 3 means carbon; atom hydrogen or direct or branched alkyl group with 1 to atoms ^R 4 means carbon; atom hydrogen or direct or branched alkyl group with 1 to 4 atoms ^R 5 means carbon; atom hydrogen or direct or branched alkyl group with 1 to 4 atoms R 8 represents a hydrogen atom or a methyl group and X represents an oxygen atom or a sulfur atom, and optionally their pharmacologically compatible acid addition salts and their quaternary compounds, characterized in that the compound of the formula II in which: X a to R g are as defined above, for example in a mixture of glacial acetic acid and concentrated hydrochloric acid by treatment with stannous chloride at temperatures from room temperature to the boiling point of the reaction mixture, whereupon optionally a compound of formula I wherein R 1 is hydrogen, reacting with acetyl chloride in the presence of aluminum chloride in an organic solvent to form a compound of formula X wherein R 1 is acetyl, and optionally reducing this compound with sodium borohydride in ethanol to give a compound of formula I wherein R 1 is hydroxyethyl, or optionally converting a compound of formula I wherein Rg is hydrogen by treatment with sulfuryl chloride in glacial acetic acid to a compound of formula I wherein Rg is chlorine, optionally by treatment with potassium bromide and bromine to form a compound of formula I wherein Rg is bromine, whereupon the optionally obtained compound is converted to the pharmacologically usable acid addition salts or by subsequent treatment with methyl iodide or methyl p-toluenesulfonic acid ester in polar solvents such as nitromethane, acetonitrile or alcohols to the corresponding quaternary compounds. 2. The process of item 1 for the preparation of compounds of formula I wherein Rg, Rg, Rg, R6, Rg and X are as defined in 1 and Rg is hydrogen as well as their pharmacologically compatible acid addition salts and quaternary compounds thereof, characterized in that the compound of formula II is reduced. in which X and Rj to Rg have the above meanings, for example in a mixture of glacial acetic acid and concentrated hydrochloric acid by treatment with stannous chloride at temperatures from room temperature to the boiling point of the reaction mixture, whereupon optionally a compound of formula I wherein Rg is hydrogen, reacted with acetyl chloride in the presence of aluminum chloride in an organic solvent to form a compound of formula I wherein Rg is acetyl, and optionally reduced with sodium borohydride in ethanol to give a compound of formula I wherein Rg is hydroxyethyl, or optionally converting a compound of formula I wherein Rg is hydrogen by treatment with sulfuryl chloride in glacial acetic acid to a compound of formula I wherein Rg is chlorine, optionally by treatment with potassium bromide and bromine to form a compound of formula I m R @ 1 is bromine, whereupon the optionally obtained compound is converted to the pharmacologically usable acid addition salts or, following treatment with methyl iodide or methyl p-toluenesulfonic acid ester in polar solvents such as nitromethane, acetonitrile or alcohols, to the corresponding quaternary compounds.