CH625203A5 - Process for the preparation of enantiomorphs of 2-phenylethylamine derivatives - Google Patents

Description

The invention relates to a process for the preparation of enantiomorphs of 2-phenylethylamine derivatives by homogeneously catalyzed asymmetric hydrogenation.

Homogeneous catalysis, i.e. those catalyzed reactions which, when carried out, both the reactants and the catalysts are soluble in the reaction mass, are known to be particularly valuable in processes in which an asymmetrical result is obtained. For example, it was found that in the homogeneous catalytic hydrogenation of an olefin which is capable of forming a racemic mixture, one of the two possible optically active enantiomorphs in a larger amount and the other optically active enantiomorph in the presence of an optically active catalyst a smaller amount. Furthermore, it was found that certain olefinic substrates of this type, such as, for example, precursors of a-amino acids which contain a-acylamido and carboxyl substituents optionally present as salts, esters or amides, are particularly suitable for hydrogenation under homogeneous catalysis with optically active catalysts are suitable. Such asymmetric catalytic hydrogenations made it possible to produce large amounts of the desired optical enantiomorph. It has also recently been found that certain optically active catalysts which contain optically active bisphosphine ligand-60 den, in the homogeneously catalyzed asymmetric hydrogenation of such “-amino acid precursors, give excellent optical purity levels of 80% and more.

US Pat. No. 3,798,241 discloses certain bidentate 65 ligands which form coordination complexes with transition metals, such as rhodium, which are hydrogenation catalysts for the asymmetric synthesis of optically active amino acids or amines. The ligands can e.g. Bis-phos-

3rd

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be phine, but not the phosphorus atoms themselves, but carbon atoms in the hydrocarbon group connecting the phosphorus atoms are asymmetrical.

US Pat. No. 3,849,480 relates to a general process for the asymmetric hydrogenation of olefins, but neither the hydrogenated olefins of formula B according to the invention nor the catalysts used according to the invention are mentioned.

BE-PS No. 822 848 describes the optically active catalysts used according to the invention, but the olefins of the formula B hydrogenated according to the invention are neither mentioned nor even suggested.

CA-PS No. 937 573 relates to the use of the optically active catalysts described in US Pat. No. 3,849,480 for the hydrogenation of α-acylamidoacrylic acids which are substituted in the β-position to the corresponding ones a-Acylamidocarboxylic acids.

Chemical Abstracts 82, 171 186n reports on DE-OS No. 2 424 543, which relates to the use of trans-1,2-bis (diarylphosphinomethyl) cyclobutanes as catalysts for the asymmetric hydrogenation of acylated, unsaturated amino acids relates.

J. P. Bercz and L. Horner report in Liebigs Ann. Chem. 703, 17-30 (1967) on the preparation of various trans-octahedral complexes of ruthenium with optically active bis-phosphines.

The method according to the invention is defined in claim 1. The compounds of formula A can easily be converted into the corresponding biologically active 2-phenyl-ethylamine derivatives.

It has been found that the constitution (geometry) of the compound of formula B which is hydrogenated affects the results obtained. In general, either the geometric E isomer or the geometric Z isomer can be used to produce the desired optical enantiomorphs. The E / Z system of the nomenclature of geometric isomers (cis-trans nomenclature) is e.g. in "The Journal of Organic Chemistry", Vol. 35, No. 9, September 1970, pages 2849 to 2867. It was introduced by the Chemical Abstracts Service.

R and R1 can mean, for example, methyl, ethyl or propyl. R1 can also mean methoxy, ethoxy, phenyl and phenoxy. Such substituent groups are sometimes precursors of substituents that one actually desires.

If, for example, the desired substituent is amino, the compound of the formula B can contain an acetylamino group as a substituent which, after the catalytic asymmetric hydrogenation, can be converted into the amino group by simple hydrolysis.

The optically active enantiomorphs which can be prepared by the present process are particularly desirable since optical activity is a characteristic property of 2-phenylethylamines which are biologically active; this means that normally only one of the optically active enantiomorphs can be used in the living organism. For example, those optically active enantiomorphs obtainable according to the invention which can be hydrolyzed to 2-amino-3-phenylpropane are particularly valuable. Other such compounds are the homologous butane and pentane derivatives.

The compounds of the formula:

wherein R2 is an alkyl group with 1 to 5 carbon atoms, give excellent results in the process according to the invention and are therefore particularly suitable for the invention.

A particularly preferred embodiment of the process according to the invention is the catalytic asymmetric hydrogenation of one of the geometric isomers of 2-acetami-do-l-phenyl-l-propene; From the enantiomorphs of 2-acetamido-1-phenylpropane obtained in this way, the right-turning enantiomorph of 2-amino-3-phenylpropane can easily be obtained.

The hydrogenation reactions according to the invention are usually carried out in a solvent such as benzene, ethanol, 2-propanol, toluene, cyclohexane or mixtures of these solvents. Almost any aromatic, alkane or cycloalkane solvent which is inert under the conditions of the process according to the invention can be used. The preferred solvents are alcohols, especially methanol, ethanol and 2-propanol.

The optically active catalysts used according to the invention preferably contain at least 0.5 mol of bisphosphine ligands per gram atom of metal. These catalysts are soluble in the reaction mass and are therefore referred to as “homogeneous” catalysts. Preferred bis-phosphine ligands of formula I contain two different aryl groups on each phosphorus atom, with those in which such an aryl group has an alkoxy substituent in ortho division being particularly preferred.

More preferred bis-phosphine ligands correspond to the formula:

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x-p-ch2ch2-p-x y y

(ii)

wherein X represents an optionally substituted phenyl group and Y is an optionally further substituted 2-alkoxy-phenyl group, the alkoxy radical of which has 1 to 6 carbon atoms, the substituents not being allowed to cause any substantial disturbance of the steric conditions around the phosphorus atom and X and Y are different .

Particularly preferred optically active bis-phosphine ligands correspond to the formula:

m-p-ch0ch0-p-m I 2 2 I q Q

so where M is a group of the formula:

(iii)

-er means and Q is a group of the formula:

60

? x

-CH = c

0

ii,

NH-c-r '

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<CH-

means, where R 'and R ", which are the same or different, each represent hydrogen, a halogen atom, an alkyl group with 1

625 203

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to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms and R '"is an n-alkyl group having 1 to 6 carbon atoms, so that M and Q are different.

A particularly preferred optically active bis-phosphine ligand is 1,2-bis (o-anisylphenylphosphino) ethane.

Further examples of suitable optically active bis-phosphine ligands are:

1,2-bis- (o-anisyl-4-methylphenylphosphino) -ethane 1,2-bis- (o-anisyl-4-chlorophenylphosphino) -ethane 1,2-bis- (o-anisyl-3-chlorophenylphosphino) - ethanol l, 2-bis- (o-anisyl-4-bromophenylphosphino) -ethane l, 2-bis - [(2-methoxy-5-chlorophenyl) -phenylphosphino] -ethane l> 2-bis - [(2-methoxy -5-bromophenyl) phenylphosphino]

ethanol l, 2-bis- (2-ethoxyphenylphenylphosphino) -ethane l, 2-bis- [o-anisyl- (p-phenylphenyl) -phosphino] -ethane l, 2-bis - [(2-methoxy-4-methylphenyl ) -phenylphosphino] -ethane 1,2-bis- (2-ethoxyphenyl-4-chlorophenylphosphino) -

1,2-bis- (o-anisyI-2-methylphenylphosphino) -ethane 1,2-bis- (o-anisyl-4-ethylphenylphosphino) -ethane 1,2-bis- (o-anisyl-3-ethylphenylphosphino) - ethane l, 2-bis (o-anisyl-3-phenylphenylphosphino) ethane.

These bis-phosphine ligands, as stated in claim 1, must be optically active and therefore must not be in the meso form.

The optical activity of the catalysts used according to the invention derives from the bis-phosphine ligand and results from the fact that the ethane bridge and two different groups (A and D) are bonded to the phosphorus atoms.

Examples of suitable coordination complexes can be represented by the formula MeTL, in which Me is at least one of the transition metals rhodium, iridium and ruthenium, T is hydrogen, fluorine, bromine, chlorine or iodine and L is the optically active bisphosphine ligand defined above is.

It was found that excellent optical purity levels of the desired optical enantiomorphs can be achieved, not only with the catalysts of the formula MeTL described above, but also when carrying out the hydrogenation in the presence of at least one of the transition metals rhodium, iridium in solution from a solution and ruthenium and at least 0.5 mole of the optically active bis-phosphine ligand per gram atom of metal formed catalyst. For example, such catalysts can be obtained by dissolving a soluble compound of the corresponding metal together with an optically active bis-phosphine ligand of the formula I in a suitable solvent, at least 0.5 mol of ligand per gram atom of metal, preferably 1 mol of ligand per gram atom of metal. It has been found that the catalyst can be formed in situ by adding a soluble metal compound to the reaction mass together with an appropriate amount of the optically active bis-phosphine ligand either before or during the hydrogenation.

The catalyst is preferably a coordination complex of rhodium. Soluble rhodium compounds which can be used to prepare such complexes include a. Rhodium trichloride hydrate, rhodium tribromide hydrate, rhodium sulfate and organic rhodium complexes with ethylene, propylene etc. and dienes such as 1,5-cyclooctadiene, 1,5-hexadiene, bicyclo-2,2,1-hepta-2,5-diene and other dienes that can form bidentate ligands or active forms of metallic rhodium that can be easily solubilized.

In a preferred embodiment of the invention, the ratio of optically active bisphosphine ligand to metal is about 05 to about 2.0 moles, preferably 1.0 mole, per gram atom. In practice it is preferred

that the optically active catalyst is in solid form with regard to its handling and storage. It was found that excellent results can be obtained with fixed, cationic coordination complexes.

Cationic coordination complexes containing one mole of the optically active bis-phosphine ligand per gram atom of metal and a chelating diene are preferred as catalysts. For example, using organic rhodium complexes of the type described above, such cationic coordination complexes of rhodium can be prepared by slurrying the organic rhodium complex in an alcohol such as ethanol, adding one mole of the optically active bis-phosphine ligand per gram atom of rhodium, so that one Solution is formed, and then a suitable anion, for example the tetrafluoroborate, tetraphenylborate or any other anion, is added so that a solid, cationic coordination complex either precipitates directly from the solvent or crystallizes out or precipitates after treatment in a suitable solvent or crystallized out.

Examples of suitable cationic coordination complexes are

Cyclooctadiene-l, 5- [l, 2-bis- (o-anisylphenyl-phosphino) -

ethane] rhodium tetrafluoroborate,

Cyclooctadiene-1,5- [1,2-bis- (o-anisylphenylphosphino) -

äthanj-rhodiumtetraphenylborat and bicyclo-2,2, i-hepta-2,5-dien- [l, 2-bis- (o-anisylphenyl-phosphino) -äthan] -rhodiumtetrafluoroborat.

Without prejudging the present invention, it is believed that the catalyst is actually present as a catalyst precursor and that it is converted to an active form upon contact with hydrogen. This conversion can of course take place either during the actual hydrogenation or can be brought about by bringing the catalyst (or the precursor) into contact with hydrogen before the addition to the reaction mass to be hydrogenated.

As mentioned above, the catalyst can be added to the solvent either as such or in the form of its components which then form the catalyst in situ. If the catalyst is added in the form of its components, it can be added before or after the addition of the olefinic substrate. The components for the preparation of the catalyst in situ are the soluble metal compound and the optically active bis-phosphine ligand. The catalyst can be added in any catalytically effective amount; it is generally used in an amount in the range of 0.001 to 5% by weight of metal contained therein, based on the olefinic substrate to be hydrogenated.

As far as practically possible, it should be avoided that the catalyst or the reaction mass comes into contact with oxidizing materials. In particular, care should be taken to ensure that any contact with oxygen is avoided. Preferably, the preparation of the reaction mass and the actual reaction should be carried out in gases other than hydrogen which are inert with respect to the two reactants and the catalyst, such as nitrogen or argon.

The procedure is preferably as follows: after the addition of the reactants and the catalyst to the solvent, hydrogen is added to the mixture until about 0.5 to 5 moles of hydrogen are present per mole of the olefinic substrate. The pressure in the system depends on s

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the type of reactants, the type of catalyst, the size of the hydrogenation device, the amount of reactants and catalyst and the amount of solvent. Low pressures, including atmospheric and vacuum, as well as higher pressures can be used.

The reaction temperatures can range from about -20 ° C to about 110 ° C. Higher temperatures can be used, but are usually not required and can increase side reactions.

After the end of the reaction, which can be determined using conventional methods, the product can be obtained using conventional methods.

Many naturally occurring substances and medicines exist in optically active forms. In these cases usually only the L or only D form is effective. In the synthetic preparation of these compounds it was previously necessary to split the products into their enantiomorphs in an additional step. This split is expensive and time consuming. The method according to the invention enables the direct formation of the desired optical enantiomorphs with excellent optical purity, which largely eliminates the very time-consuming separation of the optical enantiomorphs. Furthermore, the method according to the invention provides the desired optically active enantiomorph in higher yield, while at the same time the yield of the undesired optically active enantiomorph is reduced.

The process according to the invention is particularly advantageous because it not only provides an unusually high optical purity of the desired optically active enantiomorph, but also results in a high hydrogenation rate at low catalyst concentrations.

In the examples, the percent optical purity (% OR) is determined according to the following equation (the optical activities, expressed as specific rotation, of course, all being determined in the same solvent:

OA of the isomer mixture * -

% OR = x 100

OA of the pure isomer where OA means the observed optical activity.

example 1

A. Preparation of 2-methyl-3-oxo-l-phenyl-l-butene In a 300 ml vessel equipped with a stirrer, the 53 g (0.5 mol) benzaldehyde in 72 g (1.0 mol) methyl ethyl ketone contained and was kept at 0 to 5 ° C, 10.5 g of hydrogen chloride gas were introduced. The red solution obtained was heated to 25 ° C. and stirred for a total of 22 hours. Then the methyl ethyl ketone was driven off on a rotary evaporator at 35 ° C and 20 to 25 Torr. The dark oil obtained was dissolved in 100 ml of chloroform and washed with 50 ml of a 5% sodium hydroxide solution and then with 75 ml of water. The chloroform solution was then dried over anhydrous sodium sulfate. The chloroform was driven off under vacuum and the product (2-methyl-3-oxo-1-phenyl-1-butene) was distilled at 0.6 to 0.8 torr; at this pressure it had a boiling point of 95 to 100 ° C. 60.8 g of this product, which solidified on standing at room temperature, was obtained.

B. Preparation of 2-methyl-3-hydroxyimino-1-phenyl-1-butene To 16 g (0.1 mol) of the 2-methyl-3-oxo-1-phenyl-1-butene obtained under A) in 100 ml of methanol maintained at 0-5 ° C was added a solution of 7.3 g (0.105 mol) of hydroxylamine hydrochloride and 8.82 g (0.105 mol) of sodium bicarbonate in 50 ml of water. The resulting mass was warmed to 25 ° C, stirred for 18 hours and then cooled to 5 ° C. The product was isolated and washed with 25 ml of water to give 14.6 g of crude 2-methyl-3-hydroxyimino-1-phenyl-1-butene (83.5%) of melting point 107 to 109 ° C.

C. Preparation of 2-acetamido-l-phenyl-l-propene To a solution of 7.7 g (0.044 mol) of 2-methyl-3-hydro-xyimino-l-phenyl-l-butene in 100 ml of ether, the was maintained at 0-5 ° C, about 10.1 g (0.048 mol) of phosphorus pentachloride was added in portions. The mixture was stirred for 1 hour and then quenched by pouring it into 400 ml of cold water containing 22 g of sodium bicarbonate. The mass obtained was extracted twice with 100 ml of diethyl ether, the extract was dried and the diethyl ether was stripped off under vacuum. The NMR analysis of the residue showed that it was a mixture of the geometric E and Z isomers of 2-acetamido-1-phenyl-1-propene in a ratio of about 50:50. The residue, a thick oil, was dissolved in 25 ml of hexane / benzene (1: 1); cooling to 0 ° C. gave 1.8 g of a solid which consisted of one of the geometric isomers with a melting point of 97 to 99 ° C. and was obtained by filtration.

The hexane / benzene mother liquor obtained was distilled under vacuum; then 1.5 g of an unknown impurity was removed from the boiling point 60 to 85 ° C at 0.2 torr. The solid residue obtained (2.4 g) was slurried with 25 ml of hexane / benzene (4: 1), 1.7 g of solid were isolated. It was confirmed by NMR analysis that the mixture was a mixture of the two geometric isomers in a ratio of 85:15. This solid was dissolved in 10 ml of diethyl ether and cooled to 0 to 10 ° C; crystals formed which were isolated and washed with 15 ml of hexane / benzene (4: 1). 0.7 g of the other geometric isomer of melting point 81 to 83 ° C. was obtained.

D. Preparation of 2-acetamido-3-phenylpropane 0.2553 g of 2-acetamido-l-phenyl-l-propene (the geometric isomer with melting point 81-83 ° C) were at 3 atmospheres and 50 ° C in a solution of 0.0044 g cyclooctadiene-l, 5- [l, 2-bis- (o-anisylphenylphosphino) -

äthan] -rhodiumtetrafluoroborat hydrogenated in 20 ml of methanol. The hydrogen uptake ceased after about 5 hours. NMR analysis showed that the hydrogenation was only 28% complete. [a] D20 = + 4.1 ° (C = 1.0 in CHC13) (corrected according to NMR analysis). Optical purity = 9.4%.

Example 2

Preparation of 2-acetamido-3-phenylpropane 0.6905 g of 2-acetamido-l-phenyl-l-propene (the geometric isomer with a melting point of 97 to 99 ° C) were at about 27 atmospheres and 50 ° C in a solution of 0.0039 g cyclooctadiene-l, 5- [l, 2-bis- (o-anisylphenylphosphino) -

äthan] -rhodiumtetrafluoroborat hydrogenated in 25 ml of methanol. The hydrogenation was complete after about 35 minutes. The methanol was driven off from the reaction mass on a rotary evaporator, [alo23 = + 21.8 ° (C = 1.0 in CHCI3). Optical purity: 50.1%.

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Claims (6)

625 203 PATENT CLAIMS 1. Process for the preparation of enantiomorphs of compounds of the formula: 0 8 1 nh-c-r OK • nh-c-r (B) r under homogeneous catalysis, asymmetrically hydrogenated in the presence of a coordination complex of rhodium, iridium and / or ruthenium, which has an optically active bisphosphine ligand of the formula: -CT and Q means a group of the formula: (A) in which C * denotes an asymmetric carbon atom, R denotes alkyl with 1 to 5 carbon atoms and R1 denotes alkyl or alkoxy with 1 to 5 carbon atoms, aryl or aryloxy, characterized in that a corresponding compound of the formula: R '"0 10th 15 means, where R 'and R ", which are the same or different, each represent hydrogen, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 20 carbon atoms and R"' is an n-alkyl group having 1 to 6 Carbon atoms means that M and Q are different. 4. The method according to claim 1, characterized in that the bis-phosphine ligand is l, 2-bis (o-anisylphenyl) 25 phosphino) -ethane used. 5. The method according to claim 1, characterized in that rhodium is used as the metal in the catalyst complex. 6. The method according to claim 1 for the hydrogenation of 2-acet-30 amido-l-phenyl-l-propene. a-p-ch-ch -p-a I 2 2 I d d (I) contains, as a catalyst, where A and D, which are different, each represent an optionally substituted alkyl group having 1 to 12 carbon atoms, an optionally substituted cycloalkyl group having 4 to 7 carbon atoms or an optionally substituted aryl group, the substituents being not essential May interfere with the steric conditions around the phosphorus atoms. 2. The method according to claim 1, characterized in that a bis-phosphine ligand of the formula: x-p-ch-ch -p-x I 2 2 I y y (ii) used, wherein X represents an optionally substituted phenyl group and Y represents an optionally further substituted 2-alkoxyphenyl group, the alkoxy group of which contains 1 to 6 carbon atoms, the substituents not being allowed to cause any significant disturbance of the steric conditions around the phosphorus atoms and X and Y are different. 3. The method according to claim 1, characterized in that a bis-phosphine ligand of the formula: m-p-ch ^ ch -p-m l 2 2 I (iii) q q where M is a group of the formula: 35