CS239418B1

CS239418B1 - Preparation of 172,6-dimethylphenoxy / 2-propylamine

Info

Publication number: CS239418B1
Application number: CS842196A
Authority: CS
Inventors: Fridrich Szemes; Alfonz Rybar; Dusan Hesek; Marian Tegza; Rudolf Kosalko
Original assignee: Fridrich Szemes; Alfonz Rybar; Dusan Hesek; Marian Tegza; Rudolf Kosalko
Priority date: 1984-03-27
Filing date: 1984-03-27
Publication date: 1986-01-16
Also published as: CS219684A1

Abstract

Vynále* sapadá do odboru syntetických lieSlv. Jeho predaeto· je spdsob přípravy I-(2,6-dlaetylfenoxy)-2-propyleaínu vsorea I ^ch3 \ Z*— O CHj CH CHj (i) ch3 MH2 a jeho solí e farmaceuticky vhodnýai anorganlokýai alebo organický·! kyselina·!. ZlúSenina vsorea I sa podlá vyndlesu pr! pravuje reakciou s i-(2,6-diaetylfenoxy)- -aeetonu s prebytko· aaoniaku a vodíka sa prítoanosti borldu kobaltu na vhodnoe anorganicko· noeiSi. ZlúSenina vsorea I a jej sol! sd antiarytalkd. Ich použitie je v terapii porúch srdcového rytau. -The invention belongs to the field of synthetic drugs. Its subject is a method for preparing I-(2,6-diethylphenoxy)-2-propylene acetate I ^ch3 \ Z*— O CHj CH CHj (i) ch3 MH2 and its salts with a pharmaceutically acceptable inorganic or organic acid. The acetate compound I is prepared according to the invention by reacting with I-(2,6-diethylphenoxy)- -acetone with an excess of ammonia and hydrogen in the presence of cobalt boride on a suitable inorganic base. The acetate compound I and its salts are antiarrhythmics. Their use is in the therapy of cardiac rhythm disorders. -

Description

239418 2

The invention relates to a process for preparing 1- (2,6-diaethylphenoxy) -2-propylic amine (I).

Ch 3 -O-CH 2 -CH-CH 3 as its pharmaceutically acceptable inorganic or organic acids. Suitable salts and suitable for use in medicine as antiarrhythmic agents.

At this point, this compound was prepared with either 1- (2,6-dimethylphenoxy) -acetone or 1- (2,6-dimethylphenoxy) -2-lane-propane hydrogenation and hydrogenation with Raney-nickel and / or with reductive metal complex hydride (U. Koppe, K. Zeile, W. Kummer, H. Stihla, P. Danneberg, Cell Pat., 166, 236, U.S. Pat. the violet alarm method for the preparation of the alkali is the deoxygenation of the benzyl group of the 1- (2,6-dimethylphenoxy) -2-thiimidimidone, the tolundenesulfonyl group, and the 1- (2,6-dimethylphenoxy) -2-tolinosulfonamido-propane and / or formyl group; 6-dimethylphenoxy) -2-formamidopropdane by catalytic hydrogenation and / or hydrolysis (H. Koppe, K. Zeile, V. Kummer, H. Stihla, P. Danneberg, Sa. Pat. 166234). Fialdia andma Method for the Preparation of Alloy I is a reaction of 2,6-dimethylphenol or pyrolysis with alkaline metal and propyldimethyl and 1-chloro, optionally with 1-bromo-2-amino propane (H. Koppe, K. Zeile, V. Kummer, H. Stihla, P. Danneberg, U.S. Pat. The well-known method for the preparation of alkanes 1 is the ammonium and 1- (2,6-dimethylphenoxy) -2-alkane sulfoxy, reactive sulfosypropane and ammonia in the aliphatic alcohols (Karina, K. Ruo-honen. J., Pl. Pat. 54292). .

Baldia andma Method for the Preparation of Alloy I is reduction with 1- (2,6-dimethylphenoxy-2-propyl-aaide with boronodium hydride, aluminum-aluminum hydride, bia- (2-methoxyethoxy) hydride, sodium hydrogen sulphide, alkali metal hydride, propylene hydride, hydrogen sulphide, hydrogen sulphide, hydrogen sulphide, hydrogen sulphide, hydrogen sulphide, hydrogen sulphide, hydrogen sulphide, hydrogen sulphide; 1,3-dithiol, hydrocarbon, sun, hydrogen, hydrogen, hydrogenation of catalysts, or hydroperhydroxide and the presence of hydrogenation catalysts, and the last method for the preparation of compounds for the reaction of 1- (2,6-dimethylphenoxy) -2-propylaside from triphenylphosphine to form the corresponding P-yllde, which was precipitated with water and treated with triphenylphosphine oxide and alumina.

The method of preparing the aliquots according to the invention is based on the reaction! 1- (2,6-dimethylphenoxy) -aeetone, II

CH 3 O — CH 3 —CH 3 vH 3 o (II) and 2 ad 12-excess excess ammonia and hydrogen in the aliphatic alcohols and C, C, or light mixtures and water or water alone in the presence of 0.2 and 4% wt. cobalt to the weight of the alkanol II as catalyst either alone or on an inorganic support such as slaggel, alumina, barium sulphate, calcium carbonate, activated carbon or silica at a hydrogen pressure of 0.1 and 10 MPa and at a temperature of 20 and 120 ° C; aa translates the appropriate aor reakeiou and acid to faxmakologleky.

Thus, the process according to the invention results in a mixture of sulfur and excess ammonia in the environment of aliphatic alcohols, in water or in a mixture of said alcohols and water in methanol. ethanol in a pressurized vessel, pressurized and sealed, and after the addition of excess hydrogen and hydrogenated, and at elevated temperature and agitation. An excess of 3 239418 ammonia ranges from 2 to 12 moles, preferably 3 to 6 moles, per mole of the compound of the formula II, according to which reaction takes place in the reaction medium, or any amount of catalyst is used. Excess hydrogen is exerted as its excess pressure. Working is carried out at a pressure of 0.1 to 10 VPa, preferably 1.5 to 3.0 MPa of water.

The elevated temperature at which the reaction takes place is from 20 to 120 ° C, preferably from 70 to 95 ° C. As a catalyst, it is possible to react! cobalt catalysts are used to provide! from Compound II, the primary amine of Formula I, substantially free of the corresponding secondary amine. Preferably, cobalt boride can be used either alone or on a suitable carrier in an amount of 0.2 to 4% cobalt per weight of Compound II. The concentration of cobalt boride to suitably ranges from 2 to 40% by weight. cobalt. Suitable carriers include silica gel, alumina, barium sulfate, calcium carbonate, and preferably activated carbon or diatomaceous earth.

The cobalt boride is suitable to be activated by the addition of chromium, iron, molybdenum, nickel, with preference, the active ingredient may be used when cobalt boride alone or nanosiSi is used. In both cases, the cobalt boride active ingredient is used in an amount of 0.03 to 1% by weight of catalyst and carrier.

The amine of formula II can be isolated by vacuum distillation after separation of the catalyst and the base, respectively. after diluting the base with a suitable solvent, gaseous hydrochloric acid as hydrochloride. The amine hydrochloride of formula II can also be prepared from a non-distilled crude base.

Suction, pressure filter filtration, centrifugation, or other suitable methods may be used to separate the catalyst. As a pressure vessel, it is possible to use a conventional autoclave with sufficient agitating or halving, tower pressure reactors and the like.

The main advantage of the process according to the invention over the described hydrogenation process for the preparation of the amine of formula I is the formation of a primary amine slurry without an appropriate secondary amine, which has to be removed by demanding separation methods.

Another advantage is that the amine of the formula I or its hydrochloride is recovered in higher yields than in the described hydrogenation processes. In the following, the invention is described in the examples without limitation. Example 1 36 g (0.2 mol) of 1- (2,6-dimethylphenoxy) acetone in 90 ml of 23 SS ammonia ammonia were hydrogenated to 1.2 g of activated CogB (Pt) catalyst (15% Co and 0.1%). Pt) to charcoal at 85 to 92 ° C and a hydrogen pressure of 1.5 to 3 MPa to apparent water consumption (about 2 h). After separation of the catalyst, the methanol was evaporated, the dark crude base was diluted with 140 mL of toluene-isopropanol (9: 1) and hydrogen chloride gas was introduced into the acidic reaction mixture to crystallize 1- (2,6-dimethylphenoxy) -2-aminopropane hydrochloride.

After 2-3 hours at 2 to 5 ° C, the product is filtered off with suction. The white fine-crystalline amine hydrochloride of the formula (I) yields 36.4 g (84%). Mp 200-202.5 ° C. 239418 4 EXAMPLE 4 36 g (0.2 mol) of 1- (2,6-dimethylphenoxy) acetone in 100 ml of 35% aqueous ammonia and hydrogenated to 1.2 g of activated Co2B (Pt) catalyst ( 33% Co and 0.1% Ft) on activated carbon at 92 to 93 ° C and a hydrogen pressure of 1.8 to 3 MPa to apparent hydrogen consumption (about 1 h).

The reaction mixture is then stirred with 60 ml of toluene and the catalyst is filtered off with suction. The product is extracted into toluene. The brown-brown crude product obtained after evaporation of toluene was treated with 140 mL of toluene-1-propanol (9: 1) and hydrogen chloride was added to the solution to acidify the product. After 2-3 hours of standing at 2 to 5 ° C, the product was collected. The yield of the white fine crystalline hydrocyclide of the amine of formula I is 34 g (79%). Mp 20-203 ° C. EXAMPLE 3 18 g (0.1 mol) of 1- (2,6-dimethylphenoxy) acetone in 60 ml of a 28% aqueous-ethanolic solution (50% ethanol) of ammonia are hydrogenated in the presence of 0.6 g of activated CojB (Ft) (33% Co and 0.1% Pt) catalyst on activated carbon at 88-92 ° C and hydrogen pressure of 1.8-3 MPa to apparent hydrogen consumption (25 minutes). The separated catalyst is evaporated from the filtrate-free ethanol and the product is extracted into benzene. The solvent was evaporated and the crude base was converted into the hydrochloride salt by the addition of hydrogen chloride gas (Example 1) to give 16.5 g (77%) of the amine hydrochloride of formula (I) 20-202.5 ° C. Example 4 36 g (0.2 mol) of 1- (2,6-dimethylphenoxy) acetone in 80 ml of 34% aqueous ammonia are hydrogenated in the presence of 1.2 g of activated Co2B (Cr) catalyst (33% Co and 1% Cr) ) at Carborafine at 90 to 92 ° C and a hydrogen pressure of 2 to 3 MPa to apparent hydrogen consumption (about 4 h). The product is isolated according to Example 1. The yield of pinkish hydrochloride of Formula I is 29.1 g (68%). Mp 198-202 ° C. Example 5 36.2 g (0.2 mol) of 1- (2,6-dimethylphenoxy) acetone in 100 ml of 17% ethanolic ammonia were hydrogenated in the presence of 2 g of activated CojB (Pt) catalyst (5% Co and 0.1%). % Pt) on activated carbon, at 90 ° C and a hydrogen pressure of 1.8 to 3 MPa until hydrogen uptake is complete (ca. 2 h). After separation of the catalyst, the product was isolated as the hydrochloride as described in Example 1. The yield of the amine hydrochloride of Formula 1 was 35.7 g (83%). Mp 201-202 ° C. EXAMPLE 6 36 g (0.2 mol) of 1- (2,6-diaethylphenoxy) acetone in 75 ml of 56% ethanolic ammonia were hydrogenated in the presence of 2.7 g of activated CogB (Pt) catalyst (10% Co and 0, 1% Pt) on a silica at 90 ° C and a hydrogen pressure of 1.5 to 3 MPa until the consumption of hydrogen (eca 80 min) is complete. After the catalyst has been separated off, the solvent is evaporated and the hydrochloride salt is prepared from the brown-red crude base. hydrochloride of formula 1 is 36.5 g (85 V). Mp 201-202 ° C.

Claims

EXAMPLE 7 36 g (0.2 mol) of 1- (2,6-dimethylphenoxy) acetone in 40 ml of 25% ethanolic ammonia are hydrogenated in the presence of 2.6 g of activated Co2B (Pt) catalyst (9% Co and 0%). , 1% Pt) on silica at 60 to 85 ° C and a hydrogen pressure of 2-3 MPa until hydrogen uptake is complete (about 100 minutes). After separation of the catalyst, the hydrochloride of Example 1 was prepared. The yield of white crystalline amine hydrochloride of formula I was 33.2 g (77.96). Example • 8 g (0.1 mol) of 1- (2,6-dimethylphenoxy) -2-propanone in 28 ml of 25% ethanolic ammonia are hydrogenated in the presence of 1.8 g of activated (0.1% Pt) CogB catalyst (10% Co) on calcium carbonate at 90 ° C and a hydrogen pressure of 2-3 MPa until hydrogen uptake is complete (about 55 minutes). After separation of the catalyst, the solvent is evaporated and the product is isolated as described in Example 1. The yield of the amine hydrochloride of formula I is 13.9 g (65%). M.p. Mp 201-202 ° C. OF THE INVENTION

A process for preparing 1- (2,6-dimethylphenoxy) -2-propylamine of formula (I)

CH 2 CH 3 CH 2 (I) as well as its pharmaceutically acceptable salts with acids, characterized in that 1- (2,6-dimethylphenoxy) acetone of formula II is CH 2 O-CH, CH 2 -c- II o CH 2 (II) ) undergoes a reaction! with a 2 to 12 molar excess of ammonia and hydrogen in the aliphatic alcohols having a carbon number of C to C alebo or in mixtures thereof with water or in the presence of 0.2 to 4 wt. cobalt to the weight of compound II as a cell catalyst alone or on an inorganic support such as silica gel, alumina, barium sulfate, calcium carbonate, activated carbon or diatomaceous earth at a hydrogen pressure of 0.1 to 10 MPa and at 20 to 120 ° C and the resulting base is optionally converted into a pharmacologically acceptable salt with an acid.

2. A method according to claim 1, wherein the ethanol is present.

3. Process according to claim 1, characterized in that ammonia per mole of compound II.

4. Process according to claim 1, characterized by 1.5 to 3 MPa. that the reaction is carried out in methanol, that the reaction is carried out with an excess of 3 to 6 moles, such that the reaction is carried out under a hydrogen pressure of 2394.

5. Process according to claim 1, characterized in that the reaction is carried out at 80 to 95 ° C.

6. Process according to claim 1, characterized in that cobalt is used as a catalyst with a content of 2 to 40% by weight. % cobalt preferably 5 to 15 wt. on activated carbon or nakremellne.

7. Process according to claim 6, characterized in that the catalyst is activated by chromium, iron, molybdate, carbon, and preferably platinum.

8. Process according to claim 7, characterized in that the admixture additive is added in an amount of 0.03 to 15.5% by weight. the weight of the catalyst and the support.