DE3819438A1 - Process for the preparation of optically active 1-arylethylamines - Google Patents

Abstract

Preparation of optically active 1-arylethylamines I <IMAGE> *centre of chirality (Ar = Aryl NOTEQUAL unsubstituted phenyl) by hydrogenating cleavage of optically active N-(phenylethyl-1-arylethylamines)II <IMAGE> (Ph = unsubstituted phenyl) at 0-50@C and 1-300 bar using hydrogen and a noble metal of group VIII of the Periodic System.

Description

The present invention relates to a new process for the production of optically active 1-arylethylamines of the general formula I

* Chirality center

in which Ar denotes an aromatic radical with the exception of the phenyl group.

Nuclear substituted 1-phenylethylamines of type I deserve special interest, since they are known to be important building blocks for physiological synthesis effective compounds such as pesticides and pharmaceuticals are. For example, the structural element is 1- (2-methoxy) phenylethylamine in the natural product quinocarcinol, which is an important is an anti-tumor agent.

While the unsubstituted optically active 1-phenylethylamine

by conventional racemate resolution of your racemate with mandelic acid accessible, this applies to the other optically active 1-arylethylamines I, e.g. B. core-substituted 1-phenylethylamine, not too, so that the synthesis of compounds based thereon set economic limits are.

The invention was therefore based on the object, the optically active 1-arylethylamines (I) make it easier to access than before.

Accordingly, a method for manufacturing optically active 1-arylethylamines of the general formula I

* Chirality center

in which Ar denotes an aromatic radical with the exception of the phenyl group, found, which is characterized in that one is an optically active N- (1-phenylethyl) -1-arylethylamine of the general formula II

in the Ph means the phenyl group, at 0-50 ° C and 1-300 bar Hydrogen and a noble metal of group VIII of the periodic table of the subject to hydrating cleavage.

In this process, it is noteworthy that predominantly the Compounds I and phenylethane and not what you would expect an approximately equal mixture of I and phenylethane on the one hand and the optically active 1-phenylethylamine and the arylethane Ar-CH₂-CH₃ on the other hand.

The starting compounds II are in themselves in the following reaction sequence known way available:

a) reaction of an aryl methyl ketone (III) with an optically active 1-phenylethylamine (IV) to the corresponding Schiff base V

For example, this reaction can be carried out according to the regulation of N. Schamp et al, Synthesis 1986, page 192, by III and IV in a methylene chloride solution at 0 to 30 ° C in the presence of Triethylamine and titanium tetrachloride reacted with each other, or by III with IV in toluene solution in the presence of p-toluenesulfonic acid and with continuous removal of the water of reaction by distillation can react. When the Schiff base V is formed, the Chirality of the part of the molecule derived from IV is obtained.

b) Hydrogenation of the Schiff base V under relatively mild conditions II, e.g. B. with Raney nickel at 20 to 60 ° C and 1 to 200 bar

Here the chiral center of V exerts an asymmetric induction off, so that when II is formed in high optical yield second chirality center emerges.  

The reaction mixture obtained in process step (a) can in this Be subjected to the form of hydrogenation (b), d. H. the Schiff bases V do not need to be isolated for further implementation. If the optical induction in the hydrogenation with regard to the invention Implementation is not sufficient, you can use the predominantly formed diastereomer clean in a known manner by recrystallization.

If one considers the method according to the invention together with those described Preliminary stages, so ultimately the chirality of the easily accessible optically active 1-phenylethylamine IV to another 1-arylethylamine transferred, the optically pure form in other ways, for. B. that of the classic racemate separation via diastereomeric salt pairs, only with would be available at much greater expense. Which isomer is used in the Hydrogenation according to the invention receives, so whether the S or R form can do not predict and must be determined by a preliminary test. Arises however, in a particular case from S-IV the R-I, it means that one must start from R-IV to produce S-I.

The hydrogenating cleavage according to the invention is preferably taken at 20 up to 50 ° C and 1 to 200 bar hydrogen pressure. Among those as hydrogenation catalysts The platinum metals used are particularly suitable. It is advantageously used in the form of commercially available supported activated carbon catalysts with Pd contents of 2 to 20, preferably 5 to 15 % By weight.

The hydrogenation of II works best if, apart from the catalyst, in homogeneous liquid phase of II, which is why in all As a rule, the use of a solvent is recommended.

Polar water-soluble liquids are particularly suitable as solvents such as water itself, C₁-C₄ alkanols, dimethylformamide and acids such as Acetic acid or mixtures of these solvents.

For the rest, the methodology for hydrogenated cleavage of amines is general is known and does not offer any process engineering in the present case either Particularities.

In the case of strongly polar solvents, this also arises Ethylbenzene and only needs to be decanted after the reaction has ended to become. What remains is the phase containing I, which is carried out as usual can work on I by z this phase. B. alkaline with sodium hydroxide solution and then the amine therefrom with a water-insoluble extractant  extracted like ether and then optionally in salt form, e.g. B. transferred the hydrochloride.

In principle, the process according to the invention can be applied to any starting compounds II apply. These output connections as well as them underlying aryl methyl ketones III are either known or in available in a known manner.

The Ar radicals are by definition substituted Phenyl groups, because in the case of the phenyl group itself, the process would bring no advantage, because only the starting compound IV regressed would be.

As Ar, for example, come optionally substituted polynuclear aromatic radicals, such as the α - and β-naphthyl be considered, but particularly substituted phenyl groups having 1 to 5, preferably 1 to 3 substituents.

The substituents increase the electron density in the aromatic nucleus the preferential formation of I is particularly pronounced, whereas substituents without this effect the selectivity of the cleavage from II to I Reduce.

Accordingly, the method is particularly suitable for the production of such compounds I, in which Ar represents a phenyl group, one or carries several of the following substituents:

• - fluorine and chlorine;
• - the hydroxyl group;
• - Alkoxy groups, especially C₁-C₄ alkoxy groups such as the ethoxy, propoxy, Isopropoxy and especially the methoxy group;
• - Carbalkoxy groups, especially those with 2 to 4 carbon atoms, e.g. B. the Acetoxy group;
• - Alkoxycarbonyl groups, especially those with 2 to 4 carbon atoms, such as the methoxycarbonyl group;
• - The amino group and alkyl and dialkyl and acylamino groups with preferably up to 4 carbon atoms;
• - Alkyl groups, preferably with up to 4 carbon atoms;
• - Aralkyl groups and the benzyl group and
• - The sulfur analogues of the aforementioned oxygen-containing groups.

The substituents can also be linked together, e.g. B. via a fused (-O-CH₂-O -) grouping. For the principle of the invention The procedure does not matter whether the substituents are under the conditions  the hydrating cleavage itself can be changed by hydrogenation. This effect may even be desirable if, for example on a 1-hydroxyalkyl group or an aminomethyl group as Is interested in substituents. In this case one starts from the corresponding one Acyl group or the cyano group.

The optically active obtainable by the process according to the invention 1-arylethylamines are valuable intermediates for the production physiologically active substances and enrich the synthesis possibilities in this area.

Examples 1 to 11

1 mmol each of an optically pure starting compound II

by reacting a ketone Ar-CO-CH₃ (III) with R-1-phenylethylamine (IV) to the corresponding Schiff base (V) and subsequent hydrogenation V had been produced were at 25 ° C and 180 bar Hydrogen pressure in a solution of 25 ml acetic acid and 75 ml methanol in the presence of 0.05 g of a supported palladium / activated carbon catalyst (10th % By weight of Pd) are subjected to the hydrogenative cleavage. Here it fell visually active process product I

after usual isolation in a yield of y %.

Details of these experiments can be found in the following table.

Claims (2)

1. Process for the preparation of optically active 1-arylethylamines of the general formula I * Chirality center of Ar means an aromatic radical with the exception of the phenyl group, characterized in that an optically active N- (1-phenylethyl) -1-arylethylamine of the general formula II in the Ph is the phenyl group, at 0-50 ° C and 1-300 bar using hydrogen and a noble metal of the VIII. Group of the periodic table of the hydrogenative cleavage. 2. The method according to claim 1, characterized in that the rest Ar is a phenyl group which has 1 to 3 of the following substituents: Fluorine, chlorine, the hydroxyl group, C₁-C₄-alkyl groups, C₁-C₄-alkoxy groups, C₂-C₄-alkoxycarbonyl groups, C₂-C₄-carbalkoxy groups, the Amino group, alkyl, dialkyl and acylamino groups with up to 4 carbon atoms as well as the sulfur analogues of the aforementioned oxygen-containing Leftovers.