CS239418B1 - Preparation method of 1-/2,6-dimethylfenoxy/-2-propylamine - Google Patents

Abstract

The invention is within the scope of the synthetic lieSlv. His predaeto · is a kind of preparation 1- (2,6-paletyl-phenoxy) -2-propyleaine was added I ^ CH3 Z * - O CHj CH CHj (i) ch3 MH2 and a salt thereof pharmaceutically acceptable inorganic salt or organic! acid · !. The Compound of the Surrender I Reports to the Pr! reacts with i- (2,6-diaethylphenoxy) - -aeetone with excess · aaoniak and hydrogen with the addition of borld to the cobalt to the appropriate inorganic · noeiSi. Compound Sore I and her sol! sd antiarytalkd. Their use is in the treatment of heart rhythm disorders. -

Description

The present invention relates to the preparation of 1- (2,6-diaethylphenoxy) -2-propylsain of formula I

CH ₃ -O-CH ₂ -CH-CH ₃ as well as its aols and pharmaceutically acceptable inorganic or organic acids. The compound of formula I in the form of suitable salts aa is used in medicine as antiarrhythmic drugs.

Until now, this compound has been prepared from oxiau or hydrasone of 1- (2,6-diethylphenoxy) acetone or 1- (2,6-dimethylphenoxy) -2-ialnopropane by hydrogenation with hydrogen under Raney nickel catalysis or reduction with a complex metal hydride ( H. Koppe, K. Zeile, W. Kumaer,

H. Stihle, P. Danneberg, Cel. U.S. Pat. No. 166,236; U.S. Pat. 3954872; Pr. pat. 1551055 »South African pat. 6903 * 772).

The method described for the preparation of the compound is to remove the bensyl group from 1- (2,6-paletylphenoxy) -2-phtheliaidopropane, the toluane sulfonyl group from 1- (2,6-diaethylphenoxy) -2-toluenesulfonaaldopropane, or the forayl group from 1- (2,6) -dimethylphenoxy) -2-formamidopropane by catalytic hydrogenation or hydrolysis (H. Koppe, K. Zeile,

V. Kuamer, H. Stihle, P. Danneberg, MS. pat. 166234).

The violet is a process for the preparation of compound I by reacting 2,6-diaethylphenol or its salts with alkali metal with propylanllamine or 1-chloro, optionally bromo-2-aa-propropane (H. Koppe, K. Zeile, V. Kuamer, H. Stihle, P. Danneberg, No. 166,235). A known known method for the preparation of compound I is ammonolysis of 1- (2,6-diaethylphanoxy) -2-alkanesulfoxy-, respectively. of aranneulfoxypropane with ammonia in proetredl lower aliphatic alcohols (Karima, K. Ruohonen, J., Fin. pat. 54292).

The salt is tolerated by a method for the preparation of compound I is the reduction of 1- (2,6-dimethylphenoxy-2-propyleside) with boron-sodium hydride, lithium aluminum-lithium hydride, bls- (2-methoxyethoxy) aluminum sodium hydride, hydrogen sulfide, sodium hydrogen sulfide, propane 3-ditlol, aluminum, sun, sodium, hydrogen in the presence of hydrogenation catalysts or hydrohydrate, and hydrogenated hydrogenation catalysts The present invention is based on the reaction of 1- (2,6-diethylphenoxy) -2-propylaside to form triphenylphosphine. of the corresponding P-yllde which decomposes with water and water into triphenylphosphine oxide and compound I.

The process for the preparation of the compound (I) according to the invention is based on the reaction. 1- (2,6-Diaethylphenoxy) acetone vs. II

CH ₃

The -ji _-CH2 - CH ₃ in H ₃ o (II) E 2 to 12 molar prebytkoa ammonia and hydrogen in an aliphatic alcohol of carbon number e C, to C ^, or supine saeeiach water or in the presence of water seaotnej 0.2 to 4 wt. of cobalt to the weight of the compound II as a catalyst either alone or on an inorganic carrier such as alica gel, alumina, barium sulfate, calcium carbonate, activated carbon or creamer at a hydrogen pressure of 0.1-10 MPa and a temperature of 20-120 ° C and the base obtained for converting to faxaacologlocs the appropriate salt by treatment with acid.

The process according to the invention is carried out by treating the compound II with excess ammonia in an environment of aliphatic alcohols, in an environment of water or in a mixture of said alcohols and water, preferably in methanol, e.g. ethanol in the pressure vessel, the pressure vessel e is sealed, and after addition of excess hydrogen under hydrogenation, the elevated temperature and boiling point are hydrogenated. excess

2394.8 ammonia ranges from 2 to 12 mol, preferably 3 to 6 mol, per 1 mol of the compound of the formula II, depending on the reaction medium in which the reaction is carried out and, if appropriate, the amount of catalyst used. The excess hydrogen is realized as its excess pressure. The pressure is operated at a pressure of from 0.1 to 0.1

KPa, preferably 1.5 to 3.0 MPa of hydrogen.

The elevated temperature at which the reaction proceeds is in the range of 20 to 120 ° C. and preferably 70 to 95 ° C. As a catalyst in the reaction! cobalt catalysts are used which coat a primary amine of formula 1 from compound II, substantially free of the corresponding secondary amine.

Preferably, the cobalt boride may be used alone or on a suitable carrier in an amount of 0.2 to 4% cobalt by weight of compound II. The concentration of cobalt boride on a suitable carrier aa is from 2 to 40% by weight. cobalt. Silica gel, alumina, barium sulphate, calcium carbonate, preferably actively charcoal grade or diatomaceous earth are used as suitable carriers.

The cobalt boride aa is suitably activated by the addition of chromium, iron, molybdenum, nickel, and preferably platinum. The activating additive can be used for 1 a and uses cobalt boride alone or on a carrier. In both cases, the cobalt boride activator 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 as a base, respectively. after dilution of the base with a suitable solvent, treatment with hydrogen chloride gas such as the hydrochloride. The amine hydrochloride of formula II can also be prepared from the undistilled crude base.

Suction, filtration on a pressure filter, centrifugation or other suitable methods can be used to separate the catalyst. As a pressure vessel, a conventional autoclave can be used and with sufficient agitation, rotary or bisected, tower pressure reactors and the like.

The main advantage of the process according to the invention over the hitherto described hydrogenation processes for the preparation of the amine of formula 1 is the formation of a pure primary amine free of extraneous secondary amine which has to be removed by demanding separation methods, which adversely affects yields.

A salerary advantage is to obtain the amine of formula (1) or its hydrochloride in higher yields than in previous alarm procedures.

The invention is further described in the examples without being limited thereto.

Example 1 g (0.2 mol) of 1- (2,6-dimethylphenoxy) acetone in 90 ml of 23% strength ammonia matanollckého was hydrogenated over 1.2 g of activated Co ₂ B (Pt) catalyst (15% Co, and 0, 1% Pt) on activated carbon at 85 to 92 ° C and a hydrogen pressure of 1.5 to 3 KPa until an apparent hydrogen consumption (about 2 h). After separation of the catalyst, the methanol is evaporated, the dark crude base is diluted with 140 ml of toluene-isopropanol (9: 1) and hydrogen chloride gas is introduced into the solution to acidify the mixture, crystallizing 1- (2,6-dimethylphenoxy) -2- aminopropane.

After standing for 2-3 hours at 2-5 ° C, the product is filtered off with suction. The yield of white fine crystalline amine hydrochloride of formula I is 36.4 g (84%). MP: Mp 200-202.5 ° C.

EXAMPLES 1 and 4 2 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 Co ₂ B (Pt) catalyst ( 33% Co and 0.1% Pt) on activated carbon at 92-93 ° C and a hydrogen pressure of 1.8-3 MPa until apparent hydrogen consumption (oca 1 h).

The reaction mixture is then stirred with 60 ml of toluene and the catalyst is filtered off with suction. The product was extracted into toluene. The red-brown crude product obtained after evaporation of toluene was quenched with 140 mL of toluene-isopropanol (9: 1) and hydrogen chloride was introduced into the solution to acidify, crystallizing the product. After standing for 2-3 hours at 2-5 ° C, the product is filtered off with suction. The yield of the white fine-crystalline amine hydrocyl chloride of formula 1 is 34 g (79%).

MP: Mp 201-203 ° C.

Example 3 g (0.1 mol) of 1- (2,6-dimethylphenoxy) acetone in 60 ml of a 28% aqueous ethanol solution (50% ethanol) of ammonia ea is hydrogenated in the presence of 0.6 g of activated CojB (Pt) ( 33% Co and 0.1% Pt) catalyst on activated carbon at 88-92 ° C and a hydrogen pressure of 1.8-3 MPa until evident hydrogen consumption (25 minutes). After the catalyst has been separated, most of the filtrate is evaporated from the filtrate and the product is extracted into bonsan. The base and evaporator were evaporated and the crude base was converted to the hydrochloride by treatment with gaseous hydrogen chloride according to Example 1. 16.5 g (77%) of the amine hydrochloride of formula I were obtained. Mp 201-202.5 ° C.

Example 4 g (0.2 mol) of 1- (2,6-dimethylphenoxy) acetone in 80 ml of 34% aqueous ammonia is hydrogenated with the presence of 1.2 g of activated Co ₂ B (Cr) catalyst (33% Co and 1). % Cr) on Carborafine at 90 to 92 ° C and a hydrogen pressure of 2 to 3 MPa until evidently hydrogen consumption (about 4 h). The product is isolated according to Example 1. The yield of pinkish amine 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 are 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 the end of hydrogen consumption (about 2 h). After separation of the catalyst, the product was isolated as the hydrochloride by the procedure described in Example 1. Yield of amine hydrochloride of formula 1 is 35.7 g (83%). Mp 201-202 ° C.

Example 6 g (0.2 mol) of 1- (2,6-dimethylphenoxy) acetone in 75 ml of 17% ethanol ethanol are hydrogenated in the presence of 2.7 g of activated Co ₂ B (Bt) catalyst (10% Co and O). , 1% Pt) on silica gel at 90 ° C and a hydrogen pressure of 1.5 to 3 MPa until the end of hydrogen consumption (eea 80 min). After separation of the catalyst, the solvent was evaporated and the hydrochloride was prepared as a brownish crude base as described in Example 1 to yield 36.5 g (85%) of white crystalline amine hydrochloride hydrochloride of formula 1. Mp 201-202 ° C.

EXAMPLE 7 g (0.2 mol) of 1- (2,6-dimethyl-phenoxy) aeetónu in 40 ml of 25% ethanolic ammonia was hydrogenated with 2.6 g of activated Co ₂ B (Pt) catalyst (9% Co, and 0 1% Pt) on diatomaceous earth at 60 to 85 ° C and a hydrogen pressure of 2 to 3 MPa until the consumption of hydrogen ceased (about 100 minutes). After separation of the catalyst, the hydrochloride of Example 1 is prepared.

The yield of white crystalline amine hydrochloride of formula I is 33.2 g (77%).

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 to 3 MPa until the end of hydrogen consumption (about 55 minutes). After separation of the catalyst, the solvent was evaporated and the product was isolated as in Example 1. The yield of the amine hydrochloride of formula I is 13.9 g (65%). MP: Mp 201-202 ° C.

Claims (8)

OBJECT OF THE INVENTION Process for the preparation of 1- (2,6-dimethylphenoxy) -2-propylamine of the formula I O ₂ -ch-ch ₃ nh ₂ (I) as well as pharmaceutically acceptable acid addition salts thereof, characterized in that 1- (2,6-dimethylphenoxy) acetone of formula II CH, 0CH, CH, -cII o CH, (II) undergoes a reaction! % with a 2 to 12 molar excess of ammonia and hydrogen in the environment of aliphatic alcohols having a carbon number of C 1 to C 4, or mixtures thereof with water or water alone in the presence of 0.2 to 4 wt. of cobalt on the weight of compound II either alone or on an inorganic carrier such as silica gel, alumina, barium sulfate, calcium carbonate, activated carbon or diatomaceous earth at a hydrogen pressure of 1 to 10 MPa and at a temperature of 20 to 120 ° C and the base obtained is optionally converted into a pharmacologically acceptable salt by treatment with an acid. 2. The method of claim 1 and ethanol. 3. The method of claim 1, wherein ammonia is used per mole of compound II. 4. Method according to claim 1, characterized in that from 1.5 to 3 MPa. that the reaction is carried out in methanol medium, that the reaction is carried out with an excess of 3 to 6 moles Λ that the reaction is carried out. at hydrogen pressure 5. The process of claim 1 wherein the reaction is carried out at 80-95 ° C. 6. The process of claim 1, wherein the catalyst used is borld cobalt with a content of 2 to 40% by weight. % cobalt preferably 5 to 15 wt. on activated carbon or on kremlinna. 7. The method of claim 6, wherein the catalyst is activated with chromium, iron, molybdate, nickel, and preferably platinum. 8. The method of claim 7, wherein the activator additive is added in an amount of 0.03 to 1% by weight. by weight of catalyst and carrier.