CS205050B2 - Method of preparing 4-/7-brom-5-methoxy-2-benzofuranyl/-1-methylpiperidine - Google Patents

Abstract

The novel 4-(7-bromo-5-methoxy-2-benzofuranyl)piperidine of the formula <IMAGE> is prepared by solvolysis of derivatives thereof which contain on the nitrogen atom an appropriate group which can be replaced by hydrogen. The compound of the formula I can be converted into its acid addition salts. These new substances have pharmacological properties characteristic of antidepressants; the selective, reversible inhibition of the A form of monoamine oxidase should be particularly emphasised.

Description

The invention relates to a process for the preparation of the novel 4- (7-bromo-5-methoxy-2-benzofuran 1) -1-methylpiperidine of the formula I

and its acid addition salts, especially its pharmaceutically acceptable acid addition salts, both inorganic and organic.

The compound of formula I and its addition salts with inorganic and organic acids have valuable pharmaceutical properties.

The isotopic assay results show that monoamine oxidase inhibits monoamine oxidase, particularly selectively and reversibly, its A-form when administered orally or by subcutaneous administration of a dose of 1.0 mg / kg in rats and other experimental animals. At the same time, the compound of formula I also exhibits less pronounced inhibition of nor2 adrenaline uptake in rats by oral or subcutaneous administration of a dose of 10-100 mg / / kg and slows uptake of serotonin into the synaptosomene of the middle brain of rats compared to very strong A-form monoamine oxidase. Further, intraperitoneal administration in rats at a dose of 2 to 40 mg / kg antagonizes the hypothermic action of reserpine. Along with favorable; the therapeutic index is characterized by the properties of the compound of formula I and its pharmaceutically acceptable salts with inorganic and organic acids as antidepressants which can be administered, for example, orally or parenterally in the treatment of mental depression.

The novel 4- (7-bromo-5-methoxy-2-benzofuranyl) -1-methylpiperidine of formula I and its acid addition salts are prepared by the process of the invention by hydrogenating 4- (7-bromo-5-methoxy-2). -benzofuran 1) -1-methyl-1,2,3,6-tetrahydropyridine of formula II

(III in the presence of platinum oxide, palladium, rhodium oxide or Raney nickel catalyst) and the compound of formula I obtained is optionally converted into an inorganic or organic addition salt. with an acid, especially a pharmaceutically acceptable salt.

The catalytic hydrogenation of the compound of formula II can be carried out using the above hydrogenation catalysts, for example in the presence of palladium on, coal or platinum oxide, or. , in the presence of rhodium on carbon or on alumina or may be carried out in the presence of Raney nickel, in an inert organic solvent such as methanol, ethanol or dioxane and optionally with the addition of hydrobromic acid at room temperature and atmospheric at elevated temperatures of up to about 100 ° C and at elevated pressures of up to about 10 MPa, the hydrogenation being interrupted upon receipt of an equimolar amount of hydrogen.

The starting material of the formula II for the process according to the invention can be prepared in two steps from 4- (7-bromo-5-methoxy-2-benzo furanyl) pyridine. 4- (7-Bromo-5-methoxy-2-benzofuranyl] pyridine can be prepared, for example, by reacting 3-bromo-5-methoxysalicylaldehyde with 4- (half-methylmethyl) pyridine, in particular 4- (chloromethyl) pyridine, or with 4- (bromomethyl) pyridine, in the presence of an acid binder such as potassium carbonate, as well as optionally sodium iodide or potassium iodide with heating in an organic solvent such as dimethylformamide, in addition to the formation of an ether next to 2 - [(4-pyridyl) methoxy 3-Bromo-5-methoxybenzaldehyde as an intermediate also forms a benzofuran ring as the water exits.

From 4- (7-bromo-5-methoxy-2-benzofuranyl) pyridine, the corresponding N-methylpyridine compounds are obtained in a manner known per se by quaternization with reactive methanol esters, for example with hydrohalic acid esters, such as bromide or iodide. The quaternization can be carried out in a manner known per se in an inert organic solvent, for example methanol, ethyl methyl ketone, ethyl acetate, tetrahydrofuran or dioxane at room temperature or slightly elevated, up to about 100 ° C.

Starting material of formula I! It is obtained from the aforementioned pyridinium compounds by partial reduction, preferably with sodium borohydride or potassium borohydride in an organic-aqueous medium, for example in the present solution of the pyridinium compound. in an organic, water-miscible solvent such as a lower alkanol such as methanol or ethanol, or in a mixture thereof with water, a slightly aqueous sodium borohydride solution is added and the reaction mixture is allowed to react for some time while maintaining the reaction temperature. about 5 to 60 ° C, preferably room temperature to 35 ° C.

The compound of the formula I obtained by the process according to the invention can be converted into the addition salts by an organic or inorganic acid, if appropriate in a manner known per se. For example, a solution of a compound of Formula I in an organic solvent is mixed with an acid to provide the desired salt. Preferably, an organic solvent is chosen for the reaction in which the resulting salt is poorly soluble so that it can be separated by simple filtration. Such solvents are, for example, ethyl acetate, methanol, ether, acetone, methyl ethyl ketone, acetone-ether, acetone-ethanol, methanol-ether or ethanol-ether.

For example, hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, 2-hydrophthanesulfonic, acetic, lactic, succinic, fumaric, maleic, malic, tartaric, citric, benzoic, salicylic, phenylacetic, mandelic and emonic acids.

The novel active ingredient, i.e. the base of formula I, and its addition salts can be administered orally, rectally or parenterally. The dosage depends on the method of administration, the type, age and individual condition. The daily dose of the free base or the pharmaceutically acceptable salt of the free base is 0.01 mg / kg for warm-blooded. Suitable dosage forms such as dragées, tablets, suppositories or ampoules preferably contain 0.5 to 10 mg of the active ingredient according to the invention.

The following example illustrates the preparation of the novel compound of formula (I) and the intermediates not yet described, but does not limit the process of the invention. Temperatures are reported in ° C.

Example

25.1 g (0.078 mol) of 4- (7-bromo-5-methoxy-2-benzofuranyl) (1-methyl-1,2,3,67-tetrahydropyridine) are dissolved in 970 ml of methanol and hydrogenated in the presence of 1.2 g platinum oxide catalyst and 13.1 g of aqueous 48% hydrobromic acid at 20-25 ° C and at normal pressure until up to about 100 why, theoretically required hydrogen was consumed. The residue is partitioned between ethyl acetate and aqueous 2 N ammonia solution, the ethyl acetate phase is separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. · The residue is distilled under high vacuum ( The fraction passing at 180 to 200 ° C and at a pressure of 13,33 kPa is 4- (7-bromo-5-methoxy-2-benzofuranyl) -1-methylpiptridine From a solution of its base with a solution of · hydrogen chloride in ethyl205050 methyl ketone hydrochloride prepared mp 231-234 ° C.

The starting material can be prepared as follows:

a] 75.5 g · (0., 327 mol) of 3-bromo-5-methoxysalicylaldehyde, 53.6 g (0.327 mol) of 4- (chloromethyl) pyrimidine hydrochloride, 194 g of potassium carbonate and 15 g of potassium iodide are kept in 320 ml of dimethylformamide in a nitrogen atmosphere for 20 hours at 150 ° C with stirring. The reaction mixture was cooled to about 50 ° C and suction filtered at this temperature. The filter residue is heated with 200 ml of dimethylformamide to 100 ° C and filtered off with suction and the new filter residue is washed with dimethylformamide. The combined filtrates are evaporated in vacuo and the residue is freed from volatiles by maintaining it at 80 ° C for two hours under high vacuum. The residue was dissolved in a small amount of methylene chloride and chromatographed on 800 g of alumina (activity · II, neutral). The first fraction eluted with 2 L of chloroform is 4- (7-bromo-5-methoxy-2-benzofuranyl) pyridine, which has a melting point of 149-152 ° C after recrystallization from ethyl acetate.

b) 23.4 g (0.767 mol) of 4- (7-bromo-5-methoxy-2-benzofuranyl) pyridine are dissolved in

470 ml of ethyl methyl ketone and stirred with 11.5 moles of methyl iodide for 15 hours at a temperature of about 50 ° C. The solution is cooled to about -6 ° C and the precipitated salt is filtered off with suction. The filter residue was washed with ether-petroleum ether. The 4- (7-bromo-5-methoxyl-2-mono-1-aminomethyl) -1-methylpyridinium iodide thus obtained has a melting point of 260 DEG-265 DEG C. and can be further processed directly.

(c) To a solution of 31.7 g (0.07 mol) of 4- (7-bromo-5-methyl-4-benzofuranyl) -1-methylpyridine iodide in 200 ml of methanol is added dropwise a solution of 10.7 g with stirring and external cooling. sodium borohydride in 60 mL of water such that the reaction temperature does not exceed 35 ° C. The solution was then stirred at room temperature for 20 hours. The methanol is evaporated off under vacuum, the remaining aqueous phase is extracted twice with 500 ml of chloroform each, the chloroform solution is dried over sodium sulphate, filtered and evaporated. The residue was recrystallized from methanoo-water to give 4- (7-brone-5-ylthio) xy-2-benzofuran-1-ylmethyl-1,2,3,6-tetrahydropyridine, m.p. 73-77 ° C. The hydrochloride prepared therefrom with hydrogen chloride in an ether-tetrahydrofuran system has a melting point of 247 to 250 degrees Celsius after recrystallization from ethanol.

Claims (2)

A process for the preparation of 4- (7-bromo-5-methoxy-2-benzzfuranyl) -1-methylpiperidine of formula I Br (U and its addition salts with inorganic and organic acids, in particular pharmaceutically acceptable salts thereof, characterized in that 4- (7-bromo-5-methoxy-2-benoofuranyl) -1-methyl-1,2,3, 6-tetrahydro-pyridine of formula II CH.O J II ii X “x Br (II) in the presence of a platinum, palladium or rhodium onid or Raney nickel catalyst and optionally the compound of formula I obtained is converted into an addition salt, in particular a pharmaceutically acceptable addition salt with an inorganic or organic acid. 2. A process according to claim 1, wherein 4- (7-bromo-5-methoxy-2-benzofuranyl) -1-methyl-1,2,3,6-tetrahydro-pyridine is hydrogenated in the presence of a platinum onide as · A catalyst and in the presence of hydrobromic acid.