CS205049B2 - Method of preparing substituted 4-/2-benzofuranyl/-1,2,3,6-tetrahydropyridine - 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 present invention relates to a process for the preparation of a novel substituted 4 (Z-bernzoyl) -1,2,3,6-tetrahydropyridine having valuable pharmacological properties, in particular 4- (7-bromo-5-methoxy-2-benzofuranyl) -1-methyl- 1,2,3,6-tetrafluoro-caprine vision formula I

and the addition salts thereof, especially the pharmaceutically acceptable salts of the compounds of formula I with inorganic and organic acids.

4- (7-bromo-methoxyethoxy-2-eenzofrranyl) -1-ethyl-1,2,3,6-ethyl-4-pyrimidine and its addition salts with inorganic and organic acids have valuable pharmacological properties.

The results of the isotopic assay of enzymatic activity indicate that it inhibits monoamine oxidase in rats and other experimental animals, particularly selectively and reversibly its

A-form after oral or subcutaneous administration of a dose of mg / kg. At the same time, the compound of the formula I also shows, in comparison with a very strong - braking of the A form - monoamloxidases - less pronounced braking - noradrenaline uptake in the heart in rats by oral or subcutaneous administration of 10-100 mg / kg and inhibits the uptake of serotonin into the synaptosomene of the middle brain of rats. Further, intraperitoneal administration of 2 to 40 mg / kg in rats antagonizes the hypothermic effects of reserpine. Together with the favorable therapeutic index, said properties of 4- (7-bromo-5-methoxy-2-benzofuranyl) -11-methyl-6,2,3,6-tetrahedropyridia and their pharmaceutically acceptable salts with inorganic and organic acids characterize and can be administered, for example, orally or parenterally in the treatment of mental depression.

4- (7-Bromo-5-methoxy-2-benzophenyl) -N-methyl-2,3,6,6-tetrahydro-pyridopyrides of formula (I) and its acid addition salts are prepared by reduction with eatrium borohydride in a mixture of methanol or ethanol with ethanol; water of a compound of formula II

wherein a halogen atom having an atomic number of at least 17 and optionally converting a compound of formula I to an inorganic or organic acid addition salt.

The sodium borohydride reduction according to the invention is carried out by slowly adding an aqueous solution of sodium borohydride to the present solution of the starting compound of formula II in methanol or ethanol or in a mixture thereof with water, and allowing the reaction mixture to react for some time while maintaining the reaction. a temperature of 5 to 60 ° C, preferably a room temperature of up to 35 ° C.

The starting materials for the process according to the invention can be prepared in one step from 4- (7-bromo-5-methoxy-2-benzofuranyl) pyridine. 4- (7-bromo-5-methoxy-2-benzofuranyl) pyridine can be prepared, for example, by reacting 3-bromo-5-methoxysallcylaldehyde with 4- (halomethyl) pyridine, in particular 4- (chloromethyl) pyridine or 4- (bromomethyl) pyridine, in the presence of an acid binder such as potassium carbonate, as well as also optionally sodium iodide or potassium iodide with heating in an organic solvent such as dimethylformamide, whereby in addition to the ether bond to 2 - [(4-pyridyl) methoxy] -3-bromo-5-methoxybenzaldehyde as an intermediate, water also forms to form a benzofuran ring.

From 4- (7-bromo-5-methoxy-2-benzofuranyl) pyridine: o ^; in a manner known per se by quaternizing with reactive esters of hydrohalic acid and methanol, for example with the reactive esters mentioned below, a compound of the formula II. 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.

Suitable reactive esters of hydrohalic acid and methanol for the aforementioned quaternization are particularly suitable bromide or iodide.

The compound of the formula I obtained according to the invention can optionally be converted into its addition salts with inorganic or organic acids by methods known per se. For example, a solution thereof in an organic solvent is mixed with an acid providing the desired salt. Preferably, an organic solvent is chosen for the reaction in which the salt formed is poorly soluble so that it can be separated by 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, chloro-4, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, acetic, lactic, succinic, fumaric, maleic, malic, tartaric, citric, benzoic, salicylic, phenyl can be used to form salts with a compound of formula I acetic, almond and embon.

The novel active compounds may be administered orally, rectally or parenterally. The dosage depends on the method of administration, the type, age and individual condition. Daily dosages of free bases or pharmaceutically acceptable salts of free bases are 0.01 mg / kg to 1.0 mg / kg for warm-blooded. Suitable dosage forms such as dragees, 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 scope of the invention. Temperatures are reported in ° C.

Example

To 31.2 g (0.07 mol) of 4- (7-bromo-5-methoxy-2-benzofuranyl) -1-methylpyridinium iodide in 200 ml of methanol was added dropwise a solution of 10.7 g of sodium borohydride in 60 ml with stirring and external cooling. water so that the reaction temperature does not exceed 35 ° C. The solution was then stirred at room temperature for 20 hours. 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 residue was recrystallized from methanol-water to give 4- (7-bromo-5-methoxy-2-benzofuranyl) -1-methyl-1,2,3,6-tetrahydropyridine, m.p. 73-77 ° C. The hydrochloride prepared therefrom by hydrogen chloride solution in ether-tetrahydrofuran has a melting point of 247 to 250 degrees Celsius after recrystallization from ethanol.

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-pyridine hydrochloride, 194 g of potassium carbonate and 15 g of potassium iodide are kept in 320 ml of dimethylformamide under nitrogen for a period of 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 were evaporated in vacuo and the residue was freed from volatiles by keeping 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 mol 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-methoxy-2-benzofuranyl) -1-methylpyridinium iodide thus obtained has a melting point of 260 DEG-265 DEG C. and can be further processed directly.

Claims (1)

I will invent the subject A process for the preparation of a substituted 4- (2-benzofuranyl) -1,2,3,6-tetrahydropyridine of the formula I wherein (I) and its addition salts with inorganic and organic acids, characterized in that it is reduced with sodium borohydride in a mixture of methanol or ethanol with water, a compound of formula II And a halogen atom having an atomic number of at least 17, and optionally converting a compound of formula I to an inorganic or organic acid addition salt.