NO753246L - - Google Patents

Description

Procedure for the preparation of N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine.

The present invention relates to a new process for the production of the known N-(2-benzhydry 1-ethyl)-N-(1-phenyl-ethyl)-amine and its salts. The invention further relates to a process for the production of the new (+)- and (-)-N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine and their salts.

N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine is used under the name "Phendilin" for the treatment of patients suffering from angina pectoris or of people who have survived a heart attack, increasingly in practice. The compound is also used preventively to prevent the development of this disease process. The pharmacological effect of "Phendilin" finds its explanation partly in that the heart muscle's metabolism is stimulated, and partly in that there is an improvement in the blood supply to the ischemic area.

A method for the production of "Phendilin" is described in Hungarian patent document 150,534. The compound has an asymmetry center and therefore exists as a racemate consisting of right- and left-rotating optical antipodes. The purification of the anti-pods with regard to their separation from each other is important for biological investigations. The closest and in and of itself known solution to this is racemate cleavage of the racemic base using an optically active acid. The "phendiline" base, however, does not form any salts with carboxylic acid, which make up the - * essential part of the optically active acids.Even if the problem of the racemate cleavage was solved, however, there is no possibility of determining the absolute configuration.

The present invention is based on the basic idea that "Phendilin" is built up by a synthesis which does not rely on the asymmetry center from a possibly optically active α-phenylethylamine with a defined absolute configuration. In carrying out the present invention, only synthesis steps are used which do not involve any risk of racemate formation. According to the above-mentioned earlier patent protected solution according to which one goes. from a-phenyl-ethylamine and forms the Schiff base, is not suitable for this because of the principle possibility of a tautomerism at the Schiff base.

The present invention relates to a method for the production of N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine and its salts and is characterized by the fact that a) a-phenyl-ethylamine is reacted with reactive esters of 3, 3-diphenylpropyl alcohol, or b) the acid amide of a-phenyl-ethylamine and. 3,3-diphenylpropionic acid is reduced, or

c) compounds with the general formula:

where X is halogen, is reduced, or d) the compound with the formula:

w ■

is reduced,

and the compound obtained is optionally transferred to a salt thereof.<0>

The present method not only enables the preparation of the optically active isomers, but is also a new method for the final compound present as a racemate. With the present method, extremely pure products are obtained, and this is of great importance for use in exploring the biological possibilities. Thus, e.g. labeled molecules are produced.

Variant a) of the present method is suitably carried out so that halogenation is carried out with halides or sulphonic acid esters. Particularly suitable are 3,3-diphenyl-propyl bromide or 3,3-diphenyl-propan-1-ol-tosylate. Hydrocarbons, ketones, preferably acetone, or lower alcohols can be used as solvents. If necessary, acid acceptors are also used, e.g. hydrogen carbonates or carbonates. Toluene is preferably used as the reaction medium.

The reduction according to method variant b) is preferably carried out with complex metal hydrides, primarily with lithium aluminum hydride. Dioxane is preferably used as the reaction medium.

As a first step in method variants c) and d) the N-(1-phenyl-ethyl)-(3-alanine ethyl ester) can be prepared by addition

of ethyl acrylate to α-phenyl-ethyl-amine. The addition is carried out at 20 - 140°C without solvent, and the product is separated by distillation.

This (3-amino acid ester) is treated with the Grignard reagent phenyl-magnesium halide, whereby a tertiary alcohol with the formula is formed:

In this reaction, the Grignard reagent is preferably used in excess. From the tertiary alcohol obtained, the desired propylamine derivative can be obtained in two different ways.

First, the alanine derivative of formula II can be formed from the tertiary alcohol (III) by dehydration. The dehydration is preferably carried out with strong concentrated mineral acids in acetic acid as the reaction medium.

Secondly, an amine hydrohalide of the general formula I can be formed from the tertiary alcohol (III) by replacing the hydroxyl group with a halogen atom. This method is preferably carried out with an acetyl halide, preferably the chloride, as halogen-substituting compound. As a solvent, hydrocarbons, e.g. benzene, is used.

The intermediate products obtained in the further reactions of the tertiary alcohol are transferred by reduction to the desired propylamine. The reduction can be carried out as catalytic hydrogenation, primarily with palladium activated carbon as catalyst. For reductive removal of the halogen, metals can also be used, primarily zinc dust.

The compounds produced by the present method

may possibly be transferred to their salts. This applies both to the racemic form and to the optically active forms.

(+)-, respectively The (-)-N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine can be reacted with inorganic or organic acids to acid addition salts. For salt formation there can e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid and organic sulphonic acids are used. The salt formation can be carried out in a manner known per se by reacting the amine with an approximately equimolar amount of the corresponding acid in a suitable organic solvent.

The optically active N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amines and their salts have valuable pharmacodynamic properties and can be used both for the treatment and prophylaxis of angina pectoris and other heart disorders. The aforementioned optically active compounds can be used in pharmacy in the form of preparations containing the active substance and suitable inert solid or liquid carriers. The preparations can be in solid form (e.g. tablets, capsules,

• dragees, suppositories) or in liquid form (e.g. solutions, emulsions, suspensions.). As a carrier can be used e.g. water, polyalkylene glycols, starch, magnesium stearate, calcium carbonate etc. The preparations may also contain excipients

(e.g. dispersants, emulsifiers, buffers, etc.)

and/or other pharmaceutically valuable compounds.

The production of the pharmaceutical preparations takes place by the methods common in the pharmaceutical industry.

Overview of the pharmacological effects of the process compounds.

Overview of the pharmacological effects of the process compounds.

The methods according to the invention will be illustrated by the following examples.

Example 1

2.75 g (0.01 mol) of 3,3-diphenyl-propyl bromide and 1.21 g (0.01 mol) of 1-phenyl-ethyl-amine are dissolved in 50 ml of toluene. The solution is boiled in a round bottom flask under reflux for 5 hours. The solvent is removed and the residue is crystallized. You get 2.5 g

(63.1%) N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine hydrobromide

with melting point 208 - 210°C.

Analysis for C^H^NBr (M = 396.37)

Example 2

4.5 9 (0.118 mol) lithium aluminum hydride is suspended in 200 ml absolute dioxane, and the suspension is added in small portions 6.59 g

(0.02 mol) N-(1-phenyl-ethyl)-3,3-diphenyl-propionic acid amide. The reaction mixture is boiled for 6 hours and then cooled to 15 - 20°C.

At this temperature, first 4.5 ml of water is added drop by drop, then 4.5 ml of 10% caustic soda and finally a further 30 ml of water. The inorganic precipitate is suctioned off, and the solution is evaporated under reduced pressure. The residue is dissolved in 40 ml of ethanol, and the pH of the solution is adjusted to 2 with hydrochloric acid ethyl acetate. 5,89N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amino hydrochloride is obtained, which after recrystallization from absolute alcohol melts at 196 - 197<Q>C.

Analysis for C^H^NCl (M = 531.91)

Example 3

44.26 g (0.2 mol) N-(1-phenyl-ethyl)-(3-alanine-ethyl) are dissolved in 100 ml of anhydrous ether. This solution is added dropwise to the ethereal solution of a Grignard -reagent prepared from 125.6 g (0.8 mol) of bromobenzene and 19.2 g of magnesium shavings. It is cooled during the addition. The mixture is then boiled for 3 hours. Then the mixture is slowly added with 300 ml of 10% ammonium chloride solution, ... and made alkaline with ammonium hydroxide. The ether phase is separated, and the aqueous phase is extracted with 3 x 250 ml of chloroform. The ether phase is combined with the chloroform, and the solution is evaporated. 1,1-diphenyl-3-N-(1-phenylethyl) is obtained )-aminopropan-1-ol. The product shows no carbonyl bands in the IR spectrum. The evaporation residue is suitable for further processing.

Example 4

33.14 g (0.1 mol) of the amino alcohol obtained in Example 3 is boiled in a mixture of 200 ml of glacial acetic acid and 60 ml of concentrated hydrochloric acid for 30 minutes. The solution is evaporated in vacuo, diluted

with water and then made alkaline with ammonium hydroxide solution. Extraction with ether yields 1,1-diphenyl-3-N-(1-phenyl-ethyl)-amino-propane-1. The product is available in the form of an oil which shows no OH band in the IR spectrum.

Example 5

3.13 g (0.01 mol) of the allylamine prepared in Example 4 is hydrogenated in absolute ethyl alcohol containing 0.5 g of HC1 at atmospheric pressure and room temperature in the presence of palladium activated carbon. After absorption of 30 ml (approx. 0.009 mol) of hydrogen, the catalyst is filtered off and the solution is evaporated. The remaining N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine hydrochloride is recrystallized from an alcohol-water mixture.

Example 6

7.33 g (0.02 mol) of 1,1-diphenyl-propan-3-ol-tosylate and 4.859 (0.04 mol) of (-)-1-phenyl-ethylamine are dissolved in 50 ml of absolute alcohol. The solution is boiled for 3 hours. After removal of the solvent, the residue is dissolved in 100 ml of chloroform, and the solution is washed with 300 ml of water. The organic phase is dried over sodium sulphate and evaporated. The residue is dissolved in 40 ml of ethyl acetate and adjusted to pH 2 with hydrochloric acid ethyl acetate. 4.95 g of (-)-N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine hydrochloride are obtained. The product recrystallized from absolute alcohol melts at 196 - 197°C.

Specific rotation: [a]^° -33° (c = 2%, methanol).

Analysis for C H^NCL (M = 351.91)

Example 7

7.33 g (0.02 mol) 1,1-diphenyl-propan-3-ol-tosylate and 4.85 9- ■

(0.04 mol) (+)-1-phenyl-ethylamine is dissolved in 50 ml of absolute alcohol. The solution is boiled for 3 hours. After removal of the solvent, the residue is dissolved in 100 ml of chloroform, and the solution is washed with 300 ml of water. The organic phase is dried over sodium sulfate and evaporated. The residue is dissolved in 40 ml of ethyl acetate and adjusted to pH 2 with hydrochloric ethyl acetate. 4.9 g of ( + )-N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine hydrochloride are obtained. The product melts after recrystallization from absolute alcohol at 196 - 197°C.

Specific rotation: [aj^<0>= +33° (c = 2%, methanol)

Analysis for C^H^NCl (M = 351.91)

Example 8

The procedure is as in example 2 with the difference that 6.59 g (9.02 mol) ( + )-N-(1-phenyl-ethyl)-3,3-diphenyl-propionic acid amide is used as starting material. 5,8 9( + )-N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine hydrochloride is obtained. The product recrystallized from absolute alcohol melts at 196 - 197°C.

Specific rotation: [a]^° = +33° (c = 2%, methanol).

The starting material is produced as follows:

3.63 g (0.03 mol) of (+)-1-phenyl-ethylamine are dissolved in 100 ml of acetone dried over calcium chloride, and 2.52 g (0.03 mol) of sodium bicarbonate are added to the solution. A solution of 2.32 g (0.03 mol) is added to the resulting suspension while stirring. 3,3-diphenylpropionic acid chloride in 25 ml of anhydrous acetone. The reaction mixture is stirred at 28°C for 30 minutes and then poured into 300 ml of water. Within a short time, a crystalline precipitate separates.

This is filtered off, washed with 25 ml of water, dried and recrystallized

from 50 ml of cyclohexane. 6.55 g of (+)-N-(1-phenyl-ethyl)-3,3-diphenyl-propionic acid amide are obtained which, after recrystallization from cyclohexanone, melts at 99 - 103°C.

Specific rotation: [a]^ = +39°

Analysis for C^H NO (M = 329.42)

Example 9

You proceed as described in example 2 with the difference

that 6.59 g (0.02 mol) of (-)-N-(1-phenyl-ethyl)-3,3-diphenyl-propionic acid amide is used as starting material. 5,89(-)-N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine hydrochloride is obtained which, after recrystallization from absolute alcohol, melts at 196 - 197°C. Specific rotation: [a]^° = -33° (c = 2%, methanol).

The starting material is produced as follows:

2.78 g (0.023 mol) (-)-1-phenyl-ethylamine is dissolved in 100 ml of acetone dried over calcium chloride, and 1.93 g (0.023 mol) of sodium bicarbonate is added to the solution. It received a further suspension a solution of 5.6 g (0.023 mol) of 3,3-diphenylpropionic acid chloride in 20 ml of anhydrous acetone is added dropwise while stirring. reaction the mixture is stirred at 28°C for half an hour and then poured into 300 ml of water. A crystalline precipitate is separated and filtered off, washed with 25 ml of water, dried and recrystallized from 40 ml of cyclohexane. 5.00 g of (-)-N^(1-phenyl-ethyl)-3,3-diphenyl-propionic acid amide is obtained which melts at 99 - 103°C.

Analysis: C^<H>^<NO>(M = 329.42)

Specific rotation: [cl]^0<=><->39°.

Claims (2)

1. Process for the preparation of N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine and its salts, characterized by that a) a-phenyl-ethylamine is reacted with a reactive ester of 3,3-diphenylpropyl alcohol, or b) the acid amide of α-phenylethylamine and 3,3-diphenylpropionic acid is reduced, or c) a compound with the general formula: where X is halogen, is reduced,'or d) the compound with the formula: is reduced, and the compound obtained is optionally transferred to a salt thereof. 2. Procedure according to claim lb), characterized in that the reduction is carried out with a complex metal hydride, preferably with lithium aluminum hydride, and that dioxane is used as the reaction medium. 3- Method according to claim 1 in the preparation of (+)-N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine and its salts, characterized in that ( + )-1-phenyl- ethylamine is added with a reactive ester of 3>3-diphenyl-ethylamine, preferably with 1,1-diphenylpropan-3-ol-tosylate, or (+)-N-(1-phenyl-ethyl)-3j3-diphenyl-propionic acid amide is reduced, and that optionally the obtained optically active amine is transferred to an acid addition salt, preferably the hydrogen chloride. 4- Method according to claim 1 in the production of (-)-N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine and its salts, characterized in that (-)-1-phenyl-ethylamine is reacted with a reactive ester of 3,3-diphenyl-propyl alcohol, preferably with 1,1-diphenyl-propan-3-ol-tosylate, or that (-)-N-(1-phenyl-ethyl)-3,3- diphenylpropionic acid amide is reduced, and that the optically active amine obtained is optionally transferred to an acid addition salt, preferably the hydrochloride. 5- Method according to claim 3 or 4, characterized in that the reduction is carried out with a complex metal hydride, preferably with lithium aluminum hydride ... in dioxane.