CA1110271A - Process for the manufacturing of optically active amino acids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:
The present invention relates to a process for the manufacture of optically active amino acids, wherein a diastere-omer mixture, obtained by asymmetric induction, of a chirally substituted 2-imidazolin-5-one is hydrolyzed in a solvent or solvent mixture in the presence of acid or alkali. L-.alpha.-methyl-.beta.-(3,4-dihydroxy-phenyl)-alanine (or .alpha.-methyl-DOPA) which may be obtained from the above process is a powerful human anti-hypertensive agent.

Description

- This application is a division of Canadian patent application No. 293,445 filed on December 20, 1977.
The original application relates to chirally substituted

2-imidazolin-5-ones and their use as intermediates for the pre-paration of optically active aminoacids, especially of optically ; active ~-substituted aminoacids.
An optically active compound is as a rule prepared from the racemic compound which is obtained when the asymmetric ~; molecule is synthesized from symmetrical components. The re-solution of a racemate into the optically active components is as a rule achieved in either of two ways, namely by spon-taneous resolving crystallization or by utilizing an optically active auxiliary.
Both methods have been described for, for example, the synthesis of optically active aminoacids, e.g. ~-methyl-DOPA. Resolution by crystallization can be carried out at the stage of the aminoacid or at an intermediate stage; resolution by means of an auxiliary compound, e.g. an optically active amine or an acid, is normally carried out at an intermediate stage (German Published Application DAS 1,593,989).
The unmistakable disadvantage of these processes is that at most half the racemate employed can be obtained in the form of the desired enantiomer, whilst the second half, which is accounted for by the undesired enantiomer, is either lost or must be racemized by an involved method, so that it can be re-used in the resolution stage. This also applies for bio-chemical methods of resolving racemates, in which, in many casesr one of the enantiomers, namely the one which is not required, is destroyed by degradation.
Optically active compounds can also be prepared by synthesis from a symmetrical compound in the presence of an optically active :

'4'Z~1 auxiliary compound. In such an as~mmetric synthesis, the optically active auxiliary compound must form a bond, whieh may be covalent or eomplex, with the symmetrieal compound.
Consequently, the synthesis results in the formation of two diastereomers, which, beeause of their different energy content, may be formed in unequal amounts. A measure of the sueeess of the asymmetrie synthesis is the asymmetric induetion AA+B 100 (%), whieh indieates the percentage excess of the preferentially formed diastereomer. A over the diastereomer B. After removing the optically aetive auxiliary eompound, a mixture of the two enantiomers is obtained, in whieh one enantiomer now predominates and, under advantageous eonditions, may even be virtually the sole produet. The loss of the undesired enantiomer, whieh is a disadvantage in the case of racemate resolution, is thus reduced or even avoided.
An example of the above is the synthesis of optieally aetive aminoacids which still have a hydrogen in the ~-position, by hydrogenating ~-aminoaerylic acid derivatives in the presence of optically active catalysts, whieh hydrogenation takes plaee with a high asymmetric induetion (J.D. Morrisen et al., Asymmetrie Organie Reaetions, New Jersey, 1971).
However, this method is not applieable to aminoacids which are completely substituted in the ~-position, e.g. the pharmaeologieally important eompounds ~-methyl-DOPA and ~-methyl-tyrosine. An attempt to obtain eompounds of this type by asymmetrie alkylation of ~-isoeyanoearboxylie aeid menthyl esters followed by hydrolysis gives the aminoaeid with an unsatisfactory asymmetric induction of at most 15 (M. Susuki et al., Chem. and Ind., (1972), 687).
We have found that 2-imidazolin-5-ones of the formula I R ~

N ~ -~2 where Rl is L-~-phenylethyl, (+)-3-pinyl-methyl, (-)-nopinyl, or L-~-carbo-tert.-butoxy-ethyl, R2 is hydrogen, methyl, benzyl or phenyl, R3 and R4 are different from one another and R3 is alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms substituted by methoxy, methylthio, dimethylamino, cyano and carbethoxy, benzyl or benzyl which is mono- or disubstituted by alkoxy containing 1 to 4 carbon atoms, acyloxy and mono-substituted by chloro, bromo, nitro or methylenedioxy, or phenyl, and R4 is alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms substituted by methoxy, methylthio, dimethylamino, cyano and carbethoxy, benzyl or benzyl which is mono- or disubstituted by alkoxy containing 1 to 4 carbon atoms, acyloxy, and mono-substituted by chloro, bromo, nitro or methylenedioxy, or allyl, or R4 is additionally a radical selected from the group consisting ; of naphthyl-methyl, thienyl-methyl, benzothienyl-methyl and i bromo-benzofuranyl-methyl, are exceptionally suitable as in-termediates for the synthesis of asymetric compounds.
Amongst the possible meanings of R3 and R4, the fol-lowing should be singled out:
R3: alkyl of 1 to 4 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, substituted alkyl of l to 4 carbon atoms, e.g. methoxymethyl, ~-methyl-thioethyl, benzyloxymethyl, carbethoxymethyl and carbethoxy-- ethyl, benzyl, which may be unsubstituted, or monosubstituted or disubstituted by alkoxy containing 1 to 4 carbon atoms, acyloxy, or by benzyloxy, or monosubstituted by methylenedioxy, e.g. 3,4-dimethoxybenzyl, p-methoxybenzyl and 3,4-methylene, dioxybenzyl, and phenyl.
R4: alkyl of 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl and butyl and substituted alkyl of 1 to 4 carbon atoms, e.g. methoxymethyl, ~-methylthioethyl, benzyloxymethyl, cyanomethyl, carbomethoxymethyl, carbethoxymethyl, p-bromo-27:1 benzoylmethyl, benzyl and substituted benzyl, as specified for R3, e.g. 3,4-dimethoxybenzyl, p-methoxybenzyl, p-nitrobenzyl, o- and p-chlorobenzyl, p-bromobenzyl, 3,4-methylenedioxybenzyl, and 3,4-dibenzyloxybenzyl, and allyl. R4 may additionally ; represent a radical selected from the group consisting of naphthyl-methyl, thienyl-methyl, benzothienyl-methyl, and bromo-benzofuranyl-methyl.
The following meanings are particularly preferred:
R : L-~-phenylethyl, R2: hydrogen, R3: methyl, or benzyl in which the phenyl part is unsubstituted or monosubstituted or disubstituted by alkoxy containing 1 to 4 carbon atoms,acyloxy (in each case of 1 to 4 carbon atoms) or benzyloxy or monosubstituted by methylenedioxy, e.g. 4-methoxy-, 3,4-dimethoxy- and 3,4-methylenedioxy-benzyl, i and R4: methyl, or benzyl in which the phenyl part is unsubstituted or monosubstituted or disubstituted by alkoxy containing 1 to 4 carbon atoms, acyloxy, or benzyloxy or mono-substituted by methylenedioxy, e.g. 4-methoxy-, 3,4-dimethoxy-- and 3,4-methylenedioxy-benzyl.
The compounds according to the original application, of the formula I, can be prepared by reacting a 2-imidazolin-5-one of the formula II
J H
R3 ¦ O

-R
. 12 -I where Rl to R3 have the above meanings, in a solvent or a solvent mixture, and in the presence of a base which converts a compound of the formula II to its anion, with an alkylating agent of the formula R4-X, where R4 has the above meanings and X is a radical l~r~z :
: which is easily removed in alkylation reactions.
The reaction can be illustrated by the following equation:

R~p ( ) R~,D

Base ~ ~N-R ~ N N-R

~ R4 R -X ~ ~N_Rl N N-IA IB
Which of the two diastereomers, namely IA or IB, is ¦ formed preferentially by the asymmetric induction, depends on the radical Rl. The process according to the invention provides the possibility of starting from a 2-imidazolin-5-one of the formula II which contains a radical Rl which has the S- or R-configuration and obtaining the desired diastereomer . IA or IB, that is to say of determining the steric position of the radical R4 to be introduced.
Suitable solvents for the formation of the anion of the compound /
/

-4a-of the formula II and for the subsequent alkylation are those which are inert toward the base used and toward the alkylating agent used. Advantageous solvents are cyclic ethers, e.g. dioxane and tetrahydrofuran, dialkyl ethers, e.g. diethyl ether, aliphatic halohydrocarbons, e.g. methylene chloride, chloroform and carbon tetrachloride, carboxylic acid esters, e.g. ethyl acetate, benzene, alkylbenzenes and halobenzenes, e.g. toluene, xylene and chlorobenzene, ~dimethylformamide, dimethylsulfoxide, hexamethylphospho-triamide and mixtures of the above solvents.
Solvents to be singled out particularly are cyclicethers, e.g. tetrahydrofuran, and halohydrocarbon, e.g.
methylene chloride.
Bases to be used to convert a starting compound of the formula II into the anion are, advantageously, alkali metal or alkaline earth metal compounds, especially of lithium, sodium, potassium, magnesium and calcium,in which the metal is bonded to an aliphatic or aromatic hydrocarbon radical or to an acetylide group, or to the N atom of a primary or secondary amine or of ammonia, or in which the metal is in the form of the hydride, an alcoholate or the hydroxide.
Further suitable bases are Grignard compounds and quaternary ammonium hydroxides.
Specific examples are butyl-lithium, phenyl-lithium, phenyl-sodium, sodium methanolate, sodium ethanolate, potassium tert.-butanolate, potassium amide, lithium diiso-propylamide, sodium acetylide, phenyl-magnesium bromide, methyl-magnesium chloride, sodium hydride, calcium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylbenzylammonium hydroxide, tetrabutylammonium hydroxide and dimethyldibenzylammonium hydroxide.

Preferred bases to be used from amongst the above 2'~1 are alkali metal compounds of lithium, sodium and potassium, for example metal alkyls, e.g. butyllithium, alcoholates, e.g. sodium methanolate, sodium ethanolate and potassium tert.-butanolate, metal amides, e.g. lithium diisopropylamide, alkali metal hydroxides, e.g. sodium hydroxide and potassium hydroxide, and quaternary ammonium compounds, e.g. triethyl-benzylammonium hydroxide, tetrabutylammonium hydroxide and dimethyldibenzylammonium hydroxide.
Alkylating agents for the purposes of the invention means compounds by means of which the radical R4 can be introduced into metallized or anionized compounds of the formula II. In the alkylating agents R4-X, where R4 has the above meanings and especially the meanings singled out or particularly preferred, X as a rule is halogen, especially chlorine, bromine or iodine, or the radical of an appropriate organic sulfuric acid derivative, especially of a tosylate, benzenesulfonate or methanesulfonate.
Examples of advantageous and particularly preferred alkylating agents are methyl chloride, bromide, iodide and tosylate, benzyl chloride, bromide and tosylate, 4-methoxy-benzyl chloride and bromide, 3,4-dimethoxybenzyl chloride, bromide and tosylate, 3,4-methylenedioxybenzyl chloride, bromide and tosylate, allyl chloride, bromide, iodide and tosylate, chloroacetonitrile, bromoacetonitrile, and methyl and ethyl chloroacetate and bromoacetate.
As a rule, the alkylation is carried out by employing the base and the alkylating agent advantageously in stoichiometric amounts or excess, in the solvent or solvent mixture employed. It is possible first to produce the anion and then to add the alkylating agent. However, it can also be advantageous to add the mixture of the starting compound and the alkylating agent to the base or to add the base to a ;Z7:~

mixture of the starting compound and alkylating agent.
The metallization and alkylation reactions are ad~-antageously carried out at from -80 to +80C, preferably at from -40 to +50C.
It may be advantageous to carry out the reaction in the absence of atmospheric oxygen, for example under nitrogen.
In an advantageous embodiment of the alkylation, two-phase solvent mixtures, especially mixtures of water with a chlorohydrocarbon, e.g. methylene chloride, or a benzene hydrocarbon, e.g. benzene or toluene, or ethyl acetate, are used and the conventional methods of phase transfer catalysis, as described, for example, by M. Makosza /
' /

: /
. ,, /

- 6a -in Pure Appl. Chem., 43 (1975), 439-462, are employed. The preferred bases are mixtures of an alkali metal hydroxide, especially sodium hydroxide, with a quaternary ammonium base or a phosphonium base, which is used, in the form of its halide, in catalytic amounts; examples of the second component are triethylbenzylammonium chloride,tetrabutylammonium bromide, dimethyldibenzylammonium chloride and tributylhexadecylphos-phonium bromide.
Surprisingly, the alkylation of an anion of a 2-imidazolin-5-one of the formula II, which carries an optically active radical in the l-position, leads, with a high degree of asymmetric induction, in some cases amounting to almost 100%, to the 2-imidazolin-5-ones, disubstituted in the 4-position, of the formula I. Furthermore, it was not foreseeable that the alkylation would take place virtually entirely at the carbon atom 4 and that no alkylation at the oxygen, such as might have been expected ! iS observed, particularly since the 2-imidazolin-5-ones of the formula II can, depending on the nature of the substituents, be entirely or partially in the enol form.
l 20 The particular importance of the compounds according to the original application is that aminoacids can be obtained . by hydrolysis.

IA,B ~ / C - CO2H + `C - CO2H

IIIA IIIB
This provides a novel, advantageous and economical method of pre-paring optically active ~-substituted aminoacids by asymmetric synthesis of a 2-imidazolin-5-one of the formula I followed by its hydrolysis, especially if an asymmetric induction of at least 20% has taken place during the preparation.
In addition to the compounds mentioned in the Z7~1 Examples, the following may be given as examples of compounds according to the original application,of the formula I: l-L-~-phenylpropyl-2-isobutyl-4-ethyl-.,, /

., /

(m-methoxybenzyl)-2-imidazolin-5-one, l-a-norbonylethyl-4-methyl-4-benzyl-2-imidazolin-5-one, l-(L-a-phenyl-a-hydroxy-isopropyl)-4-methyl-4-(3', 4'-dimethoxybenzyl)-2-imidazolin-5-one, 1-(a-phenyl-~-methoxyethyl)-2,4-dibenzyl-. 4-isopropyl-2-imidazolin-5-one, 1-(a-hydroxy-sec.-butyl)-4-: methyl-4-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one, l-(L-~-: carbo-tert.-butoxy-~-phenylethyl)-4-methyl-4-benzyl-2-imida-zolin-5-one, 1-(L-a-3',4'-dimethoxybenzyl-~-carboethoxyiso-propyl)-4-methyl-4-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one, 1-(L-a-phenylethyl)-4-benzyl-4-methoxymethyl-2-imidazolin-. 5-one, 1-(L-a-phenylethyl)-4-benzyl-4-~-methylthioethyl-2-imidazolin-5-one, 1-(L-a-phenylethyl)-4-methyl-4-(3',4'-diacetoxybenzyl)-2-imidazolin-5-one, 1-(L-a-phenylpropyl)-4-methyl-4-p-acetoxybenzyl-2-imidazolin-5-one, l-(a-phenyl-~-methoxyethyl)-4-benzyl-4-~-dimethylaminoethyl-2-imidazolin-5-one and 1-(L-a-phenylpropyl)-4-methyl-4-(3'-methoxy-4'-acetoxybenzyl)-2-imidazolin-5-one.
The 2-imidazolin-5-ones of the formula II, possessing an optically active substituent on the nitrogen atom 1, have not been disclosed per se. However, they can readily be prepared in accordance with conventional methods described in the literature, as shown below:
1. By cyclizing a DL-a-aminoacid amide of the formula IV

H

IV
where Rl and R3 have the above meanings, with an orthocarboxy-lic acid ester of the general formula R2C(OR")3, where R2 hasthe above meanings and R" is methyl or ethyl, at from 100 to 130C, with elimination of alcohol, to give a 2-imidazolin-~ - 8 -5-one of the general formula II. This process is described in the literature, for example by J. Brunken and G. Bach, Chem. Ber., 89 (1956), 1363 et seq. or by S. Ginsburg, J.
org. Chem., 27 (1962), 4062 et seq.
The DL-~-aminoacid amide of the formula IV which is used can be obtained by reacting a DL-~-aminoacid ester of the general formula V

R - C - COOR' ,. 1~ V

where R3 has the above meaning and R' is methyl or ethyl, with an optically active amine of the formula Rl-NH2, where Rl has the above meanings, by a conventional process, as described, for example, by J. Brunken and B. Bach in Chem.
Ber. 89 (1956), 1363 et seq.
2. It has been disclosed, for example in Ber. dt.
Chem. Ges. 47 (1914), 2545 et seq., that imido-acid esters of the general formula OR' R - C ~
NH
where R2 has the above meanings and R' is methyl or ethyl, can be reacted with an ~-aminoacid ester to give a condensation product of the general formula VI, where R2 and R3 have the above meanings and R' is methyl or ethyl OR' R2 _ C ~ H

VI

and this compound, in turn, can be cyclized with an amine of the general formula Rl-NH2 to give a 2-imidazolin-5-one _ g _ .''Z~

of the formula II, as described, for example, in J. Chem. Soe., 1959, 1648 et seq.

3. 2-Imidazolin-5-ones of the formula II whieh are - unsubstituted in the 2-position, i.e., where R2 is H, may be obtained by reaeting an ~-substituted isoeyanoaeetie aeid ester of the formula VII

R - C - COOR' NC
, 10 - VII
where R has the above meaning and R' is methyl or ethyl, with an optieally active amine Rl-NH2, where Rl has the above meaning, to give an isocyanoacetic acid amide of the general formula VIII

R - C - CONHR

C
VIII

where Rl and R3 have the above meanings, which, on conversion to the anion by treatment with a base, eyelizes spontaneously to a 2-imidazolin-5-one of the formula II, where R2 is hydrogen.
For this purpose, a eompound of the formula VIII is reaeted with a base under the eonditions described above for the production of the anion of a compound of the formula II, and an equimolar amount of an aeid is then added.
The compounds of the formula VIII can also be obtained by reacting an N-formylaminoacid with an optically active amine of the formula Rl-NH2, where Rl has the above meanings, in the presenee of triphenylphosphine and carbon tetrachloride.

4. 2-Imidazolin-5-ones of the formula II, l~lS~z~, :
especially those where R3 is benzyl or substituted benzyl and which carry phenyl or benzyl radicals in the 2-position, can be prepared in accordance with conventional methods from the corresponding oxazol~ones of the formula IX, where R2 is phenyl or benzyl and Ar is phenyl or substituted - phenyl ArC ~ ~ O ArCH\ ~ O

N o N N-R

~' 10 R2 R2 IX X

by reaction with an optically active amine Rl-NH2, where has the above meaning.
This method is described, for example, in publications in Indian J. Chem. 9 (1975), 789 et seq. and Aust. J. Chem. 26 (1973), 827 et seq. and 1701 et seq. After hydrogenating the intermediate X by conventional methods, for example in the presence of catalytic amounts of platinum or palladium, as described, for example, in J. Org. Chem. 27 20 (I962), 4527 et seq., the corresponding 2-imidazolin-5-ones II are obtained.
An advantageous variant of the method of preparation of the compounds according to the invention, of the formula ; I, is to cyclize an ~-substituted isocyanoacetic acid amide of the formula VIII directly with a base under the above conditions to give the anion of a 2-imidazolin-5-one of the formula II, where R2 is hydrogen, and then to react the anion obtained with an alkylating agent in the manner described above.
- 30 We have established that the asymmetric induction found is independent of whether a previously prepared and isolated 2-imidazolin-5-one of the formula II or a correspond-ing a-substituted isocyanoacetic acid amide of the formula VIII is used as the starting material.
~ n anionized 2-imidazolin-5-one of the formula II
can also be obtained by converting an unsubstituted isocyano-aceticacid amide of the formula XI

H C - CONHR (-) O (-) 2, ~ 1 N _ ~ C N - CH - C - N - R

XI
where Rl has the above meaning, lnto the dianion by reaction with 2 equivalents of a base, especially of an organo-metallic compound or of a dialkylamide, and monoalkylating the dianion : stepwise with one equivalent of an alkylating agent of the formula R3-X, where R3 and X have the above meanings, whereupon spontaneous cyclization occurs and an anion of the formula II
is obtained. Thereafter, alkylation is carried out with an alkylating agent of the formula /
- lla -R4-X, using the method described above, to give a compound of the formula I.
The advantage of this method is that both substituents, R3 and R4, are introduced by means of an alkylating reaction which takes place readily, so that the process can be varied very easily.
The preferred use of the compound according to the invention, of the formula I, is for the preparation of optical-ly active aminoacids. Accordingly, the subject divisional application relates to a process for the preparation of op-tically active aminoacids, wherein a diastereomer mixture, obtained by asymmetric induction, of a chirally substituted - 2-imidazolin-5-one of the formula I is hydrolyzed in the con-ventional manner in a solvent or solvent mixture in the presence of an acid or alkali.
~i The preferred embodiment of the divisional application is a process for the preparation of optically active ~-methyl-aryl-alanines, wherein a diastereomer mixture, obtained by asymmetric induction, of a chirally substituted 2-imidazolin-

5-one of the formula I
.' 3 R

: R ~
~ Rl .' ~1/

where Rl and R2 have the meanings given above, R3 and R4 are different from one another and ` R3 is methyl, or benzyl which is mono or disubstituted by alkoxy containing 1 to 4 carbon atoms or acyloxy, and monosubstituted by methylenedioxy and R4 iS methyl, benzyl or benzyl which is mono- or disubstituted by alkoxy containing 1 to 4 carbon atoms or acyloxy and monosubstituted by methyl-enedioxy, ; -12-' . ' Z ~.
;'`' ' is hydrolyzed in a solvent or solvent mixture in the presence of an acid or alkali.
Amongst the above meanings of Rl and R2, the case where Rl is L-~-phenylethyl and R2 is hydrogen is particularly preferred.
Examples of substituted benzyl radicals R3 and R4 are 4-methoxybenzyl, 4-ethoxybenzyl, 4-acetoxybenzyl, 4-butyroxy-benzyl, 3,4-dimethoxybenzyl, 3,4-methylenedioxybenzyl, 3,4-dibenzyloxybenzyl, 3,4-diacetoxybenzyl, 3-methoxy-4-acetoxy-benzyl and 3-acetoxy-4-methoxybenzyl, amongst which 4-methoxy-benzyl, 3,4-dimethoxybenzyl and 3,4-methylenedioxybenzyl are preferred.
Advantageous solvents to use for the hydrolysis are water, lower monohydric or dihydric alcohols of 1 to 4 carbon atoms, e.g. methanol, ethanol, n-butanol, ethylene glycol or ethylene glycol monoethers, e.g. 2-ethoxyethanol, or aprotic solvents, for example cyclic saturated ethers, e.g. tetrahy-drofuran or dioxane, or dimethylsulfoxide, or mixtures of these solvents, especially mixtures with water.
Preferred solvents are water, lower monohydric alcohols, especially methanol and ethanol, ethylene glycol and cyclic saturated ethers, especially tetrahydrofuran and dioxane.
Preferred solvent mixtures are aqueous-alcoholic mixtures, especially water/methanol and water/ethanol.
' The acids used for the hydrolysis are strong monobasicor polybasic inorganic hydro-acids such as hydrohalic acids, e.g. hydrogen chloride or hydrogen bromide, sulfuric acid or phosphoric acid. The bases used are, in particular, alkali metal hydroxides, e.g. sodium hydroxide or potassium hydroxide.
For alkaline hydrolysis, ethanol/water and glycol/water have proved particularly expedient as solvent mixtures.
The hydrolysis is advantageously carried out at elevated tem-$~'~2t71 peratures, i.e. at from 50 to 150C. As a rule, it is carried out at the boiling point of the particular solvent or solvent mixture; however, it can also be carried out by heating the mixture at from 50 to 150C in an autoclave.
In some cases lt may prove advantageous first to prepare the aminoacid ester by treatment with an anhydrous acid, for example a hydrohalic acid, e.g. hydrogen chloride or hydrogen bromide, or with sulfuric acid, in an alcohol;
the ester can then, if required, be hydrolyzed in the con-ventional manner. The hydrolysis may also give the aminoacidamide, which is then hydrolyzed to the desired acid.
The course of the hydrolysis can readily be followed, and its end determined, by thin layer chromatography.
During the hydrolysis, the optically active amine used for the synthesis of the compound I is recovered and can be reused. This is a particular advantage of the process according to the invention for asymmetric syntheses.
If the preparation of the starting compounds of the formula I takes place with quantitative or almost quantitative asymmetric induction, the aminoacid obtained after hydrolysis is virtually optically pure. In other cases, purification may be necessary. This purification or resolution may already be carried out on the diastereomer mixture of - the intermediates of the formula I. In general, resolution can be effected by recrystallization, alcohol and ether being advantageous solvents; alternatively, the resolution is - carried out in the conventional manner, for example by selective crystallization, on the enantiomer mixture of the ` aminoacids obtained by hydrolysis.
Particular examples of optically active aminoacids which can be prepared from the compounds according to the invention, of the formula I, are L-~-methyl-~-(3,4-dihydroxy-;~ - 14 -Z'~l phenyl)-alanine, L-a-methylphenylalanine and L-a-methyl-~-(p-hydroxyphenyl)-alanine.
a-Methyl-~-(3,4-dihydroxyphenyl)-alanine, referred to as _ . .
- 14a -~-methyl-DOPA, has proved a powerful anti-hypertensive agent in humans. ~-Methyl-~-p-hydroxyphenyl-alanine, referred to as ~-methyltyrosine, is a promising tranquilizer. With these compounds, as with most aminoacids which have an asymmetric carbon atom, it is the L-form which is active. The D-form is inactive as an anti-hypertensive agent or tranquilizer, but is as toxic as the L-form.
The inventions of the original and divisional applications will be further understood by reference to the following non restrictive Examples.
EXAMPLES
In the Examples in which the asymmetric induction is stated, the latter is calculated from the ratio of the diastereomers IA and IB, which is easily determined by NMR
spectroscopy, since the diastereomers, being physically dif-ferent species, exhibit different chemical shifts for certain protons. The correctness of the allocation can be proved by converting the diastereomer mixture of the imidazolinone I
by hydrolysis into the enantiomer mixture of the aminoacid, determining the optical rotation of this mixture and com-paring it with that of the pure, preferentially formed, enan-tiomer.
A. Preparation of starting compounds 1. ~-Isocyanopropionic acid L-~-phenylethylamide . .
a) from methyl ~-isocyanopropionate:
11.3 g (0.1 mole) of methyl ~-isocyanopropionate, 12.1 g (0.1 mole) of L-a-phenylethylamine and 0.1 g of p-toluenesulfonic acid are stirred for 12 hours at room temper-ature. The mixture is then heated at 100C for 30 minutes and the amide obtained is purified by recrystallization from methanol.

16.4 g (81~) of ~-isocyanopropionic acid L-~-phenylethylamide of melting point 89C are obtained.

7~

IR spectrum (KBr): 3,300 (N-H), 2,140 (N=C) and 1,665 cm 1 (C=O) C12H14N2(22) calculated C 71.3 H 7.0 found C 71.1 H 6.9 b) from N-formyl-~-alanine 1.17 g (10 mmoles) of N-formyl-~-alanine, 1.33 g (11 mmoles) of L-~-phenylethylamine and 3.15 g (12 mmoles) of triphenylphosphine are dissolved in 20 ml of acetonitrile.
2.0 g (20 mmoles) of triethylamine and 1.54 g (10 mmoles) of carbon tetrachloride are added there-' /

~. ~

-15a-327~1 to, whilst stirring. The mixture is stirred for 5 hours at ~ room temperature, a solution of 3.15 g (12mmoles) of triphenyl-- phosphine in 5 ml of acetonitrile is added and a mixture of 1.54 g (10 mmoles) of carbon tetrachloride and 1.0 g (10 mmoles) of triethylamine is then introduced dropwise. After 12 hours, the triethylamine hydrochloride which has precipitated is filtered off and the solvent is distilled off. The residue is purified by column chromatography over silica gel, using ether. After recrystallization from methanol, 1.2 g (60%) of ~-isocyanopropionic acid ~-phenylethylamide of melting point 89C are obtained.
2. ~-Alanine-L-~-phenylethylamide 42.0 g (0.3 mole) of DL-alanine methyl ester hydrochloride are introduced into 108.0 g (0.9 mole) of L-~-phenylethylamine at room temperature and the mixture is heated for 3 hours at 95 - 100C whilst stirring. It is cooled, 250 ml of absolute ethanol are added, 27.0 g (0.33 mole) of sodium acetate are then introduced and the mixture is stirred for 45 minutes at room temperature. The ethanol is then stripped off and the residue is taken up in methylene chloride and rendered alkaline with a solution of 13.2 g (0.33 mole) of sodium hydroxide in 90 ml of water. After .
repeated extraction by shaking with methylene chloride, the combined organic phases are dried over anhydrous sodium sulfate, the solvent is distilled off and the excess L-~-phenethylamine is distillèd off under 15 mm Hg. The fraction (90.2 g) which passes over at 78 - 85C is pure L-~-phenyl-ethylamine, which can be re-used for further reactions. The semi-crystalline distillation residue (28.2 g = 49.0% of theory) is pure according to NMR spectroscopy.
H-NMR (CDC13) : ~ = 2.33 (broad, CONH), 2.85 (Ph-H), (9, J = 7.0 Hz, CH), 6.62 (9, J = 7.0 Hz, CH), . ~ , ~ - 16 -~ `

27~

8-37 (NH2), 8.56 (d, J = 7.0 Hz, CH3), 8.75 (d, J = 7.0 Hz, CH3).
3. ~-Isocyanopropionic acid (+)-3-pinylmethylamide A mixture of 5.7 g (50 mmoles) of methyl ~-isocyanopropionate and 8.3 g (50 mmoles) of (+)-3-aminomethyl-pinane is stirred for 15 hours at room temperature, initially with slight cooling. After distilling off the resulting methanol in a high vacuum at 80C, 11.6 g of crystalline ~-isocyanopropionic acid (+)-3-pinylmethylamide of melting point 58 - 59C remain. IR spectrum (KBr): 3,230 (N-H), 2,130 (N_C), 1,670 cm 1 (C=O).
4. DL-Alanine-(+)-3-pinylmethylamide 1.40 g (0.1 mole) of ~-alanine methyl ester hydro-chloride are introduced into 50.2 g (0.3 mole) of (+)-3-aminomethyl-pinane and the mixture is heated for 3 hours at 95 - 100C. When it has cooled, 100 ml of absolute ethanol are added, 9.0 g (0.11 mole) of sodium acetate are introduced and the batch is stirred for 45 minutes at room temperature.
The ethanol is then distilled off and the residue is taken up in methylene chloride and rendered alkaline with a solution of 4.4 g (0.11 mole) of sodium hydroxide in 30 ml of water. The mixture is repeatedly extracted with methylene chloride, the extract is dried over anhydrous sodium sulfate and the solvent is distilled off. The excess (+)-3-aminomethyl-pinane is distilled from the residue at 110C under 15 mm Hg. 28.6 g are recovered. The crude product which remains, in a yield of 70~, can be employed, without addikional purification, for the cyclization reactions which follow. lHNMR (CDC13) 1 = 2.41 (broad, CONH) 5. ~-Isocyanopropionic acid (-)-nopinylamide A mixture of 5.7 g (50 mmoles) of methyl ~-isocya-nopropionate and 7.0 g (50 mmoles) of (-)-nopinylamine is P2~7i stirred for 15 hours at room temperature, initially employing slight cooling. After removing the resulting methanol in a high vacuum at 80C, 9.8 g of crystalline ~-isocyanopropionic acid (-)-nopinylamide remain. Melting point 114 - 115C
(after recrystallization from isopropanol).
IR spectrum (KBr): 3,310 (N-H), 2,130 (N-C), 1,655 cm 1 lC=O) C13H20N20 (220) calculated C 70.8 H 9.1 N 12.7 found 70.8 9.2 12.7

6. ~-Isocyano-~-phenyl-propionic acid L-~-phenylethylamide 18.9 g (0.1 mole) of methyl ~-isocyano-~-phenylpropionate and 12.1 g (0.1 mole) of L-~-phenylethylamine are heated for 12 hours at 60C. After removing the resulting methanol in a high vacuum at 60C, 26.5 g of amide remain.
Melting point 135 - 136C (after recrystallization from isopropanol).
IR-spectrum (KBr): 3,290 (N-H), 2,150 (C_N?, 1,665 cm 1 (C=0) C18H18N20 (278) calculated C 77.7 H 6.5 N 10.1 found 77.5 6.6 10.3

- 7. Isocyanoacetic acid L-~-phenylethylamide 9.9 g (0.1 mole) of methyl isocyanoacetate are slowly added dropwise, at +lO~C, to 12.1 g (0.1 mole) of L-~-phenylethylamine. When the slightly exothermic reaction has ended, the mixture is heated for 2 hours at 30 - 35C and the resulting methanol is then removed in a high vacuum at 60C. Recrystallization from ethyl acetate gives 15.0 g of isocyanoacetic acid L-~-phenylethylamide of melting point 122 - 123C.
CllH12N20 (188) calculated C 70.2 H 6.4 N 14.9 found 70.0 6.2 15.2

8. N-(~-Isocyano-propionyl)-L-alanine tert.-butyl ester 1.13 g (10 mmoles) of methyl ~-isocyanopropionate are stirred with 1.45 g (10 mmoles) of L-alanine tert.-butyl -~ ~
~ - 18 -ester and a pinch of p-toluenesulfonic acid at 50C overnight.
The mixture is then chromatographed over 100 g of alumina of activity level II, using ether.1.4 g (60%) of product are obtained.

H-NMR (60 MHz, CDCl ): ~ = 8.5 (s, tert.-butyl, 5.53) (mc, both CH), 2.7 (mc, NH).
IR (film): ~ = 1,680 (amide C=O), 1,735 (ester C=O), 2,140 (N=C), 3,305 cm (N-H).
C11lll8N203 (226.3) calculated C 58.39 H 8.02 found 58.5 8.0 B. Preparation of compounds of the formula II
1. 1-L-~-Phenylethyl-4-methyl-2-imidazolin-5-one

9.4 ml of a 1.6 N solution of n-butyl-lithium (15 mmoles) in hexane are added dropwise to a solution of 3.1 g (15 mmoles) of ~-isocyanopropionic acid L-~-phenyl-ethylamide in 20 ml of tetrahydrofuran at -60C. The mixture - is allowed to rise to -20C and is neutralized, at this temperature, by adding 0.9 g (15 mmoles) of glacial acetic ` acid in 5 ml of tetrahydrofuran. The solvent is distilled off on a rotary evaporator and the residue is partitioned between methylene chloride and water. The organic phase is concentrated. After distilling the residue, 2.05 g (65%) of l-L-~-phenylethyl-4-methyl-2-imidazolin-5-one of boiling point 105C/10 mm Hg are obtained.
IR spectrum (film): 1,610 (C=N), 1,715 cm 1 (C=O) C13H14N20 (202) calculated C 71.3 H 7.0 found 71.1 6.9 2. 1-L-~-Phenylethyl-4-methyl-2-imidazolin-5-one 63.6 g (0.6 mole) of trimethyl orthoformate are added to 26.2 g (0.135 mole) of ~-alanine-L-~-phenylethylamide and the mixture is heated for 2 hours at 85C and then for 1 hour at 120C, the methanol thus formed being distilled off.

, -- 19 --The reaction product is freed from excess trimethyl ortho-formate on a rotary evaporator and the residue is distilled under reduced pressure. 10.5 g (38.5% of theory) of l-L-~-phenylethyl-4-methyl-2-imidazolin-5-one of boiling point 129 - 133C/0.1 mm Hg and melting point 43 - 44C are obtained.
C12H14NO2 (202.3) calculated N 13-85 ` found 13.9 According to the IR and NMR spectra the compound is identical with the product obtained as described in Example B. 1.
3. 2,4-Dimethyl-l-L-~-phenylethyl-2-imidazolin-5-one 120 g (1 mole) of trimethyl orthoacetate are added to 56.4 g (0.293 mole) of ~-alanine-L-a-phenylethylamide, ` the mixture is heated for 4 hours at 85C and then for 1 hour at 120C and the methanol which is eliminated is distilled off. After cooling, the excess trimethyl orthoacetate is distilled off on a rotary evaporator and the residue is distilled under reduced pressure. 37.25 g, i.e. 58.7%
of theory, of a product of boiling point 139 - 141C/0.4 mm Hg are obtained.
IR (film): 1,720 cm 1 (C=O), 1,630 cm 1 (C=N) H-NMR (COC13): 1 = 2.90 (Ph-H), 4.78 (q, J = z,O Hz, CH), 6.13 (q, J = 7.5 Hz, CH), 8.19 (d, J = 2.0 Hz, CH3?, 8.33 (d, J = 7.0 Hz, CH3), 8.67 (dd, J = 2.0 and 7.5 Hz, CH3).
4. 2-Methyl-4-benzyl-1-L-~-phenylethyl-2-imidazolin-5-one a) DL-Phenylalanine-L-~-phenylethylamide 64.7 g (0.3 mole) of DL-phenylalanine methyl ester hydrochloride and 108.0 g (0.9 mole) of L-~-phenyletilylamine are reacted, and worked up, as described in Example A. 2.
42.7 g (53.4~ of theory) of DL-phenylalanine-L-~- phenyl-ethylamide are obtained, and are directly reacted further.

b) 2-Methyl-4-benzyl-1-~ ~phenylethyl-2-imidazolin-5-one 21.3 g (80 mmoles) of DL-phenylalanine-L-~-phenylethylamide and 30.0 g (0.25 mole) of trimethyl ortho-acetate are reacted, and worked up, as described in Example B. 3. 7.9 g (33.8% of theory) of the desired product of - boiling point 160 - 170C/0.2 mm Hg are obtained.
IR (film): 1,725 cm 1 (C=O), 1,635 cm (C=N).
-NMR: T = 2.63 and 2.70 (Ph-H), 4.72 (q, J = 7.0 Hz, CH), 5.62 (dt, J = 2.0 Hz and 5.0 Hz, CH), 6.70 (t, J = 5.0 Hz, CH2), 8,28 (dd, J = 5.0 and 2.0 Hz, CH3), 8.40 (d, I = 7.0 Hz, CH3)-5. 4-Methyl-1-~(+)-3'-pinylmethyl~-2-imidazolin-5-one 16.6 g (70 mmoles) of ~-alanine-(+)-3-pinylmethylamide and 21.2 g (0.2 mole) of trimethyl orthoformate are reacted, and worked up, as described in Example B. 2. After distillation ~` under reduced pressure, 9.0 g (50.8% of theory) of the desired product, of boiling point 144 - 148C/0.1 mm Hg, are obtained.
6. 1-L-~-Phenylethyl-4-isobutyl-2-imidazolin-5-one 15.5 g (0.1 mole) of methyl 2-isocyano-4-methyl-valerate (boiling point 56 - 58C/0.3 mm Hg) and 12.1 g (0.1 mole) of L-~-phenylethylamine are heated to 80C in the course of 1 hour and stirred for 5 hours at this temperature.
Methanol and unconverted starting compounds are then distilled off by heating to 100C under reduced pressure (0.1 mm Hg).
12.4 g of 1-L-~-phenylethyl-4-isobutyl-2-imidazolin-5-one remain; according to the NMR and IR spectra, this product is a keto-enol mixture.
C. Preparation of compounds of the formula I
1. 1-L-~-phenylethyl-4-methyl-4-benzyl-2-imidazolin-5-one 62.5 ml of a 1.6 N solution of n-butyl-lithium (0.1 mole) in hexane are added dropwise to a solution of - 20.2 g (0.1 mole) of ~-isocyanopropionic acid L-~-phenyl-ethylamide in 125 ml of tetrahydrofuran at -60C. At the ~ - 21 -same temperature, 17.1 g (0.1 mole) of benzyl bromide dissolved in 50 ml of tetrahydrofuran are added dropwise to the pale yellow solution and the mixture is allowed to come to room temperature, whilst stirring. The solvent is distilled off, the residue is taken up in 150 ml of methylene chloride and the solution is washed with twice 100 ml of water. After distilling off the solvent, 27.5 g of crystalline l-L-a-phenylethyl-4-methyl-4-benzyl-2-imidazolin-5-one remain.
Analysis of the NMR spectrum (220 MHz, CDC13) shows that the product contains at least 95~ of pure diastereomer. Melting point (after recrystallization from methylene chloride/ether) 110C.
IR spectrum (KBr): 1,610 (C=N), 1,715 cm (C=O) C19H20N20 (292) Calculated C 78.1 H 6.9 found 78.1 6.9 2. 1-L-a-Phenylethyl-4-methyl-4-benzyl-2-imidazolin-5-one In an experiment similar to that in Example C. 1., potassium tert.-butanolate is employed instead of n-butyl-lithium. According to analysis of the NMR spectrum (220 MHz, CDC13), the crude 1-L-a-phenyl-ethyl-4-methyl-4-benzyl-2-imidazolin-5-one obtained consists of a mixture of the diastereomers in the ratio of 95 : 5, which corresponds to an - asymmetric induction of 90%.

3. 1-L-a-Phenylethyl-4-methyl-4-benzyl-2-imidazolin-5-one In an experiment similar to that in Example C. 1., sodium methanolate is employed instead of butyl-lithium.
The benzyl bromide is added dropwise at +50~C. According to analysis of the NMR spectrum (220 MHz, CDC13) the crude 30 1-L-a-phenylethyl-4-methyl-4-benzyl-2-imidazolin-5-one obtained consists of a mixture of the diastereomers in the ratio of 76 : 24, corresponding to an asymmetric induction of 52%.
4. 1-L-~-Phenylethyl-4-methyl-4-benzyl-2-imidazolin-5-one A solution of 2.05 g (10 mmoles) of l-L-~-phenylethyl-4-methyl-2-imidazolin-5-one and 1.3 g ( 10 mmoles) of benzyl chloride in lO'ml of methylene chloride is added dropwise in the course of 30 minutes, at from 10 to 20C, to a vigorously stirred mixture of 20 g of 50% strength sodium hydroxide solution and 10 ml of methylene chloride, to which lO0 mg of triethylbenzylammonium chloride are added as a phase transfer catalyst. The mixture is stirred for a further 2 hours at room temperature, the two phases are separated and the methylene chloride solution is washed with water and dried by means of sodium sulfate. After distilling off the solvent, 2.8 g of 1-L-~-phenylethyl-4-methyl-4-benzyl-2-imidazolin-5-one remain. Analysis of the NMR spectrum (220 MHz, CDCl3) shows a ratio of the diastereomers of 84 : 16 (asymmetric induction 68~), 5. 1-L-~-Phenylethyl-2,4-dimethyl-4-benzyl-2-imidazolin-5-one A solution of 4.4 g (20 mmoles) of l-L-~-phenyl-20 ethyl-2,4-dimethyl-2-imidazolin-5-one in 30 ml of tetra-hydrofuran is metallated with butyl-lithium by the method described in Example C. l. and is then reacted with benzyl bromide. After working up as described, 5.9. g of crude l-L-~-phenylethyl-2,4-dimethyl-4-benzyl-2-imidazolin-5-one remain. Analysis of the NMR spectrum (220 Mllz, CDCl3) shows a ratio of the diastereomers of 73 : 27 (asymmetric induction 46~).
'l'hc diastereomer which is formed in excess is separated off by column chromatography (silica gel, methylene chloride, ethyl acetate) and recrystallized from petroleum ether.

Melting point 108 - 109C.

IR spectrum (KBr): 1,710 (C=?, 1, 635 cm 1 (C=N) C20H22N2O (306) calculated C 78.5 H 7.2 N 9.2 found 78.5 7.2 9.4 6. 1-L-~-Phenylethyl-2,4-dimethyl-4-benzyl-2-imidazolin-5-one Potassium tert.-butanolate or sodium methanolate is employed in place of n-butyl-lithium in experiments similar to those described in Example C. 5. The following results are obtained:

Base ReactionDiastereomerAsymmetric temperature ratio induction ' 10 KOC4Hg -40C 70 : 30 40%
NaOCH3 -40C 65 : 35 30%
7. 1-L-~-Phenylethyl-2,4-dimethyl-4-benzyl-2-imidazolin-5-one 2.6 g (22 mmoles) of 95~ strength potassium tert.-butanolate are introduced into a solution of 5.8 g (20 mmoles) of l-L-~-phenylethyl-2-methyl-4-benzyl-2-imidazolin-5-one in 40 ml of tetrahydrofuran at -30C. The mixture is stirred ; for 10 minutes at OC and cooled to -65C, and a solution of 1.9 g (20 mmoles) of methyl bromide in 8 ml of tetrahydrofuran - is added dropwise. The mixture is worked up as described in Example C. 1. and 5.4 g of crude 1-L-~-phenylethyl-2,4-dimethyl-4-benzyl-2-imidazolin-5-one are obtained.
Analysis of the NMR spectrum (220 MHz, CDC13) shows a ratio of the diastereomers of 42 : 58, the diastereomer - formed preferentially in the present case corresponding to the diastereomer formed in the minor proportion in Examples C. 5. and C 6. The reversal of the reaction sequence ( in C. 5. and C. 6. the 4-methyl substituent was present first and benzyl was introduced whilst in the present Example the 4-methyl substituent is present first and methyl is introduced) also results in an inversion of the diastereomer ratio.
8. 1-(+)-3'-Pinylmethyl-4-methyl-4-benzyl-2-imidazolin-5-one :~"

~3~

1.3 g (11 mmoles) of 95~ strength potassium tert.-butanolate are introduced into a solution of 2.5 g (10 mmoles) of ~-isocyanopropionic acid (+)-3-pinylmethylamide in 20 ml of tetrahydrofuran at -30C. The mixture is stirred for 10 minutes at 0C and is cooled to -65C, and 1.75 g (10 mmoles) of benzyl bromide are added dropwise.
The batch is worked up as described in Example C. 1. and 3.3 g of crude 1-(+)-3'-pinylmethyl-4-methyl-4-benzyl-2-imidazolin-5-one, melting point 96 - 98C, are obtained.
Analysis of the NMR spectrum (220 MHz, CDC13) shows a ratio of the diastereomers of 57 : 43.
IR spectrum (KBr): 1,710 (C=O), 1,610 cm l(C=N) C22H30N20 (338) calculated C 78.1 H 8.9 N 8.3 found 78.1 8.9 8.5 9. 1-(-)-Nopinyl-4-methyl-4-benzyl-2-imidazolin-5-one 6.5 g (55 mmoles) of 95% strength potassium tert.-butanolate are introduced into a solution of 11.0 g (50 mmoles) of ~-isocyanopropionic acid (-)-nopinylamide in 100 ml of tetrahydrofuran at -30C. The mixture is stirred for 10 minutes at 0C and is cooled to -65C, and 8.8 g (50 mmoles) of benzyl bromide are added dropwise. The batch is worked up as described in Example C 1. and 15.5 g of crude crystalline l-(-)-nopinyl-4-methyl-4-benzyl-2-imidazolin-5-one are obtained.
~- - Analysis of the NMR spectrum (220 Mllz, CDC13) shows a ratio of the diastereomers of 75 to 25.
` The diastereomer which is formed in excess is isolated by recrystallization from isopropanol, melting point 150C.
IR spectrum (KBr): 1.705 (C=O), 1,600 cm 1 (C=N) C20H26N20 (310~ calculated C 77.4 H 8.4 N 9.0 found 77.1 8.2 8.9 .

. .

10. 1-L-a-Phenylethyl-4-methyl-4-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one - 6.2 ml (10 mmoles) of a 1.64 N solution of butyl-lithium in hexane are added dropwise to a solution of 2.05 g (10 mmoles) of a-isocyanopropionic acid L-a-phenylethylamide in 2.0 ml of tetrahydrofuran at -65C. 1.9 g (10 mmoles) of 3,4-dimethoxybenzyl chloride are then added and the mixture is stirred for 3 hours at +40C.
The solvent is distilled off. The residue is partitioned between methylene chloride and water and the methylene chloride solution is evaporated to dryness. 3.6 g of crude l-L-a-phenylethyl-4-methyl-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one, which crystallize on scratching, remain.
Analysis of the NMR spectrum (220 MHz, CDC13) shows a ratio of the diastereomers of 80 : 20, which corresponds to an asymmetric induction of 60%.
The diastereomer formed in excess is isolated by suspension in ether and is recrystallized from isopropanol;
melting point 99 - 100 C.
IR spectrum: 1,603 (C=N), 1,705 cm 1 (C=O) C21H24N203 (352) calculated C 71.6% H 6.8% N 8.0%
found 71.5 6.8 8.0

11. 1-L-a-Phenylethyl-4-methyl-4-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one In a experiment similar to that described in Example C. 10., 1-L-a-phenylethyl-4-methyl-2-imidazolin-5-one is employed instead of a-isocyanopropionic acid L-a-phenyl-ethylamide. The diastereomer mixture obtained shows the same composition (ratio 80 : 20 = 60% asymmetric induction).

12. 1-L-a-Phenylethyl-4-methyl-4-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one In an experiment similar to that described in ~L~7~L

Example C. 10., 3,4-dimethoxybenzyl bromide is employed instead of 3,4-dimethoxybenzyl chloride. Analysis of the NMR spectrum (220 M~lz, CDC13) shows that the diastereomer ratio in the imidazolinone obtained is 90 : lO (asymmetric induction 80%).

13. 1-L-a-Phenylethyl-4-methyl-4-(3',4'-dimethoxybenzyl?-2-imidazolin-5-one 1.3 g (11 mmoles) of potassium tert.-butanolate are added to a solution of 2.05 g (lO mmoles) of a-isocya-nopropionic acid L-~-phenylethylamide in 20 ml of tetra-hydrofuran at -25C. The mixture is stirred for 10 minutes at 0C, 1.9 g (10 mmoles) of 3,4-dimethoxybenzyl chloride are added and stirring is continued for one hour at 20C.
The mixture is worked up as described in Example C. lO. and 3.6 g of l-L-a-phenylethyl-4-methyl-4-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one are obtained. Analysis of the NMR spectrum (220 MHz, CDC13) shows a ratio of the diastereomers of 78 : 22 (asymmetric induction 56%).

14. 1-L-a-Phenylethyl-4-methyl-4-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one A solution of 2.05 g ( 10 mmolesJ of a-isocyano-propionic acid L-~-phenylethylamide and l.9 g (lO mmoles) of 3,4-dimethoxybenzyl chloride in lO ml of methylene chloride is added dropwise in the course of 30 minutes, at 25C, to a vigorously stirred mixture of 20 g 50% strength sodium hydroxide solution and 10 ml of methylene chloride, to which lO0 mg of triethylbenzylammonium chloride have been added as a phase transfer catalyst. When the exothermic reaction has subsided, the mixture is heated for 3 hours at 40C. The phases are separated. The methylene chloride phase is washed with water, dried and concentrated to dryness. 3.6 g of l-L-a-phenylethyl-4-methyl-4-(3',4'-~ - 27 -7 ~

dimethoxybenzyl)-2-imidazolin-5-one remain; the NMR
spectrum (220 MHz, CDC13) of this material shows a ratio of the diastereomers of 83 : 17 (asymmetric induction 66~).
Similar reaction mixtures using the catalysts shown below give the following results:
Tetrabutylammonium bromide in methylene chloride:
diastereomer ratio 80 : 20.
Dimethyldibenzylammonium chloride in methylene chloride: diastereomer ratio 80 : 20.
Triethylbenzylammonium chloride in toluene : dias-tereomer ratio 70 : 30.

15. 1-L-~-Phenylethyl-2,4-dimethyl-4-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one In an experiment similar to that described in Example C. 10., 1-L-a-phenylethyl-2,4-dimethyl-2-imidazolin-5-one is employed instead of a-isocyanopropionic acid L-a-phenylethylamide. The resulting crude product, consisting of 3.7 g of 1-L-a-phenylethyl-2,4-dimethyl-4-(3',4'-dimethoxy-benzyl)-2-imidazolin-5-one, contains, according to NMR analysis (220 MHz, CDC13), the diastereomers in a ratio of 71 : 29.
After purification by filtration over a silica gel column (me-thylene chloride, ethyl acetate) the diastere-omer formed in the minor proportion is obtained in a crystal-line form by suspension in ether; melting point 123 - 124C.
IR spectrum (Ksr): 1,720 (C=O), 1,635 cm 1 (C=N) C22H26N23 (366) calculated C 72.1 H 7.1 N 7.7 found 71.9 7.2 7.8

16. 1-L-~-Phenylethyl-2,4-dimethyl-4-(3',4'-dimethoxy-benzyl-2-imidazolin-5-one 1.3 g (11 mmoles) of potasium tert.-butanolate are added to a solution of 2.2 g (10 mmoles) of l-L-a-pnenyl-ethyl-2,4-dimethyl-2-imidazolin-5-one in 20 ml of tetrahy-~ - 28 -`i271 drofuran at -25C. The mixture is stirred for 10 minutes at 0C, 1.9 g (10 mmoles) of 3,4 dimethoxybenzyl chloride are added and the batch is stirred for 12 hours at room temperature.
Working up is carried out as described in Example C. 10. and 3.7 g of 1-L-~-phenylethyl-2,4-dimethyl-4-(3', ; 4'-dimethoxybenzyl)-2-imidazolin-5-one (C. 15.) are obtained.
Analysis of the NMR spec-trum (220 MHz, CDC13) shows a ratio of the dlastereomers of 60 : 40 (asymmetric induction 20~).

17. 1-(-)-Nopinyl-4-methyl-4-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one In an experiment similar to that described in Example C. 9., 9.5 g (50 mmoles) of 3,4-dimethoxybenzyl chloride are employed instead of benzyl bromide. The resulting oily product, consisting of 19.2 g of 1-(-)-nopinyl-4-methyl-4-(3',4'-dimethoxybenzyl)-2- imidazolin-5-one, contains, according to NMR analysis (220 MHz, CDC13), the diastereomers in a ratio of 69 : 31 (asymmetric induction 38~). Purification is effected by filtration over silica gel (methylene chloride; ethyl acetate).
IR spectrum (film): 1,720 (C=O), 1,600 cm 1 (C=N) C22H30N2O3 (370) calculated N 7-6 found 7.5

18. 1-L-~-Phenylethyl-4-methyl-4-p-methoxy-benzyl-2-, imidazolin-5-one 1.3 g (11 mmoles) of potassium tert.-butanolate are added to a solution of 2.0 g (10 mmoles) of isocya-nopropionlc acid L-~-phenylethylamide in 20 ml of tetra-hydrofuran at -25C. The mixture is stirred for 10 minutes at 0C and is cooled to -65C, and 1.6 g (10 mmoles) of p-methoxybenzyl chloride are added at this temperature.

When the mixture has returned to room temperature, it is worked up as described in Example C. 10. 3.3 g of crude l-L-~-phenylethyl-4-methyl-4-p-methoxybenzyl-2-imidazolin-5-one are isolated. According to NMR analysis (220 MHz, CDC13), this product contains the diastereomers in a ratio of 86 : 14 (asymmetric induction 72%).
In order to isolate the diastereomer formed in excess, the crude product is extracted with cyclohexane, the solvent is distilled from the extract and the residue is recrystallized from ether; melting poing 72 - 73C.
IR spectrum (KBr): 1,710 (C=0), 1,610 cm 1 (C=N) C20H22N2o2 (322) calculated N 8.7 found 8.7

19. 1-L-~-Phenylethyl-2,4-dimethyl-4-p-methoxybenzyl-2-imidazolin-5-one 1.3 g (11 mmoles) of potassium tert.-butanolate are added to a solution of 2.2 g (10 mmoles) of l-L-~-phenyl-ethyl-2,4-dimethyl-2-imidazolin-5-one in 20 ml of tetra-hydrofuran at -25C. The mixture is stirred for 10 minutes

- 20 at 0C and is then cooled to -65C, and at this temperature 1.6 g (10 mmoles) of p-methoxybenzyl chloride are added.
When the mixture has returned to room temperature, it is worked up as described in C. 10. 3.3 g of crude l-L-~-phenylethyl-2,4-dimethyl-4-p-methoxybenzyl-2-imidazolin-5-one are isolated. Analysis of the NMR spectrum(220 MHz, CDC13) shows a ratio of the diastereomers of 64 : 36 (asymmetric induction 28~). Purification is carried out by filtration over silica gel (methylene chloride, ethyl acetate).
IR spectrum (film): 1,725 (C=O), 1.635 cm ((C=N) C21H24N202 (336) calculated C 75.0 H 7.2 N 8.3 found 74.5 7.2 8.2 111~;~271 20. l~L-~-Phenylethyl-4-methyl-4-p-nitrobenzyl-2-imidazOlin-5-one In an experiment similar to that described in Example C. 18., 1.7 g (10 mmoles) of p-nitrobenzyl chloride are employed instead of methoxybenzyl chloride. 3.3 g of crystalline l-L-~-phenylethyl-4-p-nitrobenzyl-2-imidazolin-5-one are isolated; according to the NMR spectrum (220 MHz, CDC13), this product contains the diastereomers in the ratio of 70 : 30 (asymmetric induction 40%). Purification is effected by recrystallization from ethyl acetate; melting point 138 - 139C.
IR spectrum (Ksr): 1,710 (C=O), 1,600 cm (C=N) ClgHlgN303 (337) calculated C 67. 6 H 5.7 N 12.5 found 67.5 5.6 12.4

21. 1-L-~-Phenylethyl-2,4-dimethyl-4-p-nitrobenzyl-2-imidazolin-5-one In an experiment similar to that described in C. 19., 1.7 g (10 mmoles) of p-nitrobenzyl chloride are employed instead of p-methoxybenzyl chloride. 3.3 g of oily 20 1-L-~-phenylethyl-2,4-dimethyl-4-p-nitrobenzyl-2-imidazolin-5-one are isolated; according to the NMR spectrum (220 MHz, CDC13), this product contains the diastereomers in the ratio - of 62 : 38 (asymmetric induction 24%). Purification is - effected by filtration o~er silica gel (methylene chloride, ethyl acetate).
IR spectrum (film: 1,725 (C=O), 1,630 cm (C=N) C20H21N3O3 (351) calculate C 68.3 H 6.0 H 11.9 found 68.1 6.1 11.8

22. 1-L-~-Pnenyl-ethyl-2,4-dimethyl-4-o-chlorobenzyl-2-imidazolin-5-one In an experiment similar to that described in C. 19., 1.6 g (10 mmoles) of o-chlorobenzyl chloride are employed :

instead of p-methoxybenzyl chloride. 3.5 g of oily l-L-a-- phenylethyl-2,4-dimethyl-4-o-chlorobenzyl-2-imidazolin-5-one are isolated; according to the NMR spectrum (220 MHz, CDC13), this product contains the diastereomers in the ratio of 70 : 30 (asymmetric induction 40%).
The diastereomers are separated by column chromato-graphy over silica gel (methylene chloride, ethyl acetate).
The diastereomer formed in excess is characterized as follows:
Melting point 92 - 93C (after recrystallization from petroleum ether) IR spectrum (film): 1,720 (C=O), 1,630 cm l (C=N) C20H21ClN2O (340.5) calculated C 70.4 H 6.2 N 8.2 found 70.7 6.3 8.2

23. 1-L-~-Phenylethyl-2,4-dimethyl-4-p-chlorobenzyl-2-imidazolin-5-one In an experiment similar to that described in Example C. 19., 1.6 g (10 mmoles) of p-chlorobenzyl chloride are employed in place of p-methoxybenzyl chloride. 3.5 g of oily l-L-~-phenylethyl-2,4-dimethyl-4-p-chlorobenzyl-2-imidazolin-5-one are isolated; according to the NMR spectrum (220 MHz, CDC13), this product contains the diastereomers in the ratio of 72 : 28 (asymmetric induction 44%). Purification is effected by filtration over silica gel (methylene chloride, ethyl acetate).
IR spectrum (film): 1,725 (C=O), 1,635 cm (C=N) C20H21ClN2O (340.5) calculated C 70.4 H 6.2 N 8.2 found 70.2 6.4 8.1

24. 1-L-~-Phenylethyl-4-methyl-4-cyanomethyl-2-imidazolin-5-one In an experiment similar to -that described in Example C. 18, 0.8 g (10 mmoles) of chloroacetonitrile is ll~r~z7,~

employed in place of p-methoxybenzyl chloride. 2.5 g of oily l-L-~-phenylethyl-4-methyl-4-cyanomethyl-2-imidazolin-5-one are isolated; according to the NMR spectrum (220 MHz, CDC13), this product contains the diastereomers in the ratio of 67 : 33 (asymmetric induction 35%). Purification is effected by filtration over silica gel (methylene chloride, ethyl acetate).
IR spectrum (film): 2,250 (C=N), 1,730 (C=O), 1,620 cm 1 (C=N) C14H15N3O (241) calculated N 17.4 found 17.3

25. 1-L-~-Phenylethyl-2,4-dimethyl-4-cyanomethyl-2-imidazolin-5-one In an experiment similar to that described in Example C. 19, 0.8 g ( 10 mmoles) of chloroacetonitrile is employed in place of p-methoxybenzyl chloride. 2.4 g of oily l-L-~-phenylethyl-2,4-dimethyl-4-cyanomethyl-2-imidazolin-5-one are isolated; according to the NMR spectrum (220 MHz, CDC13), this product contains the diastereomèrs in the ratio of 62 : 38 (asymmetric induction 24%). Purification is effected by filtration over silica gel (methylene chloride, ethyl acetate).
IR spectrum (film): 1,730 (C=O), 1,630 cm 1 (C=N) C15H17N3O (255) calculated C 70.5 H 6.7 N 16.5 found 70.5 6.9 16.1

26. 1-L-~-Phenylethyl-2,4-dimethyl-4-allyl-2-imidazolin-5-. , one 12.5 ml of 1.6 N solution of n-butyl-lithium (20 mmoles) ln hexanc are added dropwisc to a solution o~ 4.4 g (20 mmoles) of 1-L-~-phenylethyl-2,4-dimethyl-2-imidazolin-5-one in 30 ml of tetrahydrofuran at -60C. 2.4 g (20 mmoles) of allyl bromide are then added dropwise at the same temper-ature. After the mixture has returned to room temperature, it is worked up as described in Example C. 10. After distillation (boiling point 135 - 140C/0.3 mm Hg), 4.2 g of l-L-a-phenylethyl-2,4-dimethyl-4-allyl-2-imidazolin-5-one are obtained; according to the NMR spectrum (220 MHz, CDC13) this product contains the diastereomers in the ratio of 78 : 22 (asymmetric induction 56%).
IR spectrum (film): 1,720 (C=O), 1,630 cm 1 (C=N) C16H20N20 (256) calculated C 75.0 H 7.8 N 10.9 found 74.7 7.9 11.0

27 to 40.
General procedure: 10 mmoles of the stated base (butyl-lithium at -70C; potassium tert.-butanolate or sodium hydride at -25C) are added to a solution of 2.8 g (10 mmoles) of ~-isocyano-~-phenyl-propionic acid L-~-phenylethylamide in 45 ml of dry solvent. The mixture is stirred for 10 minutes at room temperature and is then cooled to -70C, and the alkylating agent is added. When the mixture has returned to room temperature, the solvent is distilled off, the residue is taken up in 45 ml of methylene chloride and the solution is washed with twice 25 ml of water.
The crude product which remains after concentrating the methylene chloride solution is purified by filtration over alumina (activity level II, ether/petroleum ether) and is - characterized by the IR and NMR spectra and by elementary analysis.
The results are sur arized in Table 1.

. /~

~//

27i Rl = L-~-phenylethyl, R2 = H, R3 = benzyl Alkylating agent Base/Solvent Yield, Asymmetric R4X %induction, %

27 CH3I C4HgLi - THF 90 20

28 CH3I KO-t-C4Hg - THF90 20

29 CH3I NaH - DMSO/ether 90 11

30 C2H5I C4HgLi - THF 65 23

31 C2115I KO-t-C4H9 - THF85 25

32 n-C4HgI C4HgLi - THF 72 55

33 n-C4HgI KO-t-C4H9 - THF70 50

34 i-C3H7I KO t C4 9 62 65

35 CH2=CH-CH2I C4HgLi - THF 90 36

36 CH2=CH-CH2Br C4HgLi - THF 90 43

37 CH2=CH-CH2Cl C4HgLi - THF 85 39

38 CH2=CH-CH2OTos C4HgLi - THF 90 23

39 p-Br-C6H4-CH2Br C4HgLi - THF 90 ~95

40 BrCH2 2 2 5 C4HgLi - THF 75 31 :

41. to 49.
Compounds of formula I from isocyanoacetid acid L-~-phenylethylamide General procedure: 20 mmoles of n-butyl-lithium solution (13 ml of a 1.55 N solution in hexane) are added - dropwise to a solution of 1.9 g (10 mmoles) of isocyanoacetic acid L-~-phenylethylamide in 25 ml of dry tetrahydrofuran at -70C. After 10 minutes, 10 mmoles of the first alkylating agent, dissolved in 10 ml of tetrahydrofuran, are added at the same temperature.
The mixture is allowed to warm up and at +10C

; ~
,~1 Z7~

the second alkylating agent, dissolved in 10 ml of tetra-hydrofuran, is added. Af-ter stirring for 2 hours, the mixture is worked up as described for C. 27. The products obtained are characterized by the IR and NMR spectra and by elementary analysis.
The results are summarized in Table 2.

Rl = L-a-phenylethyl, R = ll ~ 1st Alkylating agent 2nd Alkylating Yield, Asymmetric ; 10 R X agent Induction, R %
. .
41 CH3I C6H5CH2Br 90 95 43 CH2=CH-CH2Br 6 5 2 6 5 2 r CH =CH-CH Br 69 45 45 P-Br-c6H4-cH2Br C6H5CH2Br 72 95 46 C2H5I C6H5CH2Br 85 95 47 n-C4HgI C6H5CH2Br 58 95 48 i-C3H7I C6H5CH2Br 78 95 49 3'4~(CH3)2- CH3I 60 20 C6H3CH2Cl -, 50 n-C3H7I 6 5 2 90 51. 1-L-~-Carbo-tert.-butoxy-ethyl-4-benzyl-4-methyl-2-imidazolin-5-one 1.13 g of N-(a-isocyano-propionyl)-L-alanine tert.--- butyl ester and 0.85 g of benzyl bromide are reacted by the method described in Example C. 1. 1.4 g (89%) of l-L-a-carbo-tert.-butoxy-ethyl-4-benzyl-4-methyl-2-imidazolin-5-one are obtained and are purified by chromatography (with ether over alumina of activity level II). 0.7 g (45%) of pure compound of melting point 97C (CH2C12: ether : petroleum ether = 1:10:10) remain. The diastereomer ratio is 6:1, corresponding to an asymmetric induction of 72%.
H-NMR (100 MHz, CSC13): 1 = 9.12 (d,CH3, J = 8 Hz?, 8-62 (s, tert.-butyl), 8.56 (s, 4-CH3), 5.64 (q, C-H, J = 8 Hz), 2.86 (s, phenyl), for the LL diastereomer: 6.96 (s, CH2?, 2.42 (s, 2-CH), for the DL diastereomer: 6.99 (s, CH2), 2.38 (s, 2-CH).
IR (KBr): v = 1,615 (N=C), 1,735 cm 1 (C=O).
52. 1-L-~-Carbo-tert.-butoxy-ethyl-4-allyl-4-methyl-2-imidazolin-5-one 1.13 g of N-(~-isocyano-propionyl)-L-alanine tert.-butyl ester and 0.6 g of allyl bromide are reacted by the method described in Example 50. 1.1 g (85%) of l-L-~-carbo-tert.-butoxy-ethyl-4-allyl-4-methyl-2-imidazolin-5-one are obtained. Distillation gives 1.0 g (75%) of pure compound of boiling point 95 - 100C/0.01 mm Hg. The diastereomer ratio is 2 : 1, corresponding to an asymmetric induction of 33%.
H-NMR (100 MHz, CDC13): ~ = 8.56 (s, tert.-butyl), 7.53 (d, CH2, J = 7 Hz), 2.18 (s, 2-CH).
IR (film): v = 1,615 (N=C), 1,725 cm 1 (C=O) (Separation by adding the paramagnetic reagent Eu (tfc)3.).
53. 1-L-Q-Phenylethyl-4-isobytyl-4-benzyl-2-imidazolin-5-one 1.3 (11 mmoles) of 95% strength potassium tert.-bu-tanolate are introduced into a solution Or 2.5 g ( 10 mmolcs) of l-L-~-phenyle-thyl-4-isobutyl-2-imidazolin-5-one in 20 ml of TIIF at -30C. TI~e mixturc is stirred for 10 minutes at 0C and is then cooled to -65C, and a solution of 1.75 g - (10 mmoles) of benzyl bromide is added dropwise. The batch is worked up as described in Example B. 1. and the product is purified by filtration over silica gel (methylene chloride, ethyl acetate). 1.1 g of 1-L-~-phenylethyl-4-isobutyl-4-i27~

benzyl-2-imidazolin-5-one are obtained, melting point 116C.
Analysis of the NMR spectrum (220 MHz, CDC13) shows that the product contains at least 95% of pure diaste-reomer.
Melting point ( af-ter recrystallization from isopropanol) 128C.
IR spectrum (KBr): 1,700 (C=O), 1,600 cm 1 (C=N) C22H26N20 (334) calculated C 79.0 H 7.8 N 8.4 found 79.1 7.6 8.4 54. 1-L-~-Phenylethyl-4-methyl-4-(3',4'-methylenedioxy-benzyl)-2-imidazolin-5-one 4.05 y (20 mmoles) of ~-isocyanopropionic acid L-~-phenylethylamide, 3.4 g (20 mmoles) of 3,4-methylenedioxy-benzyl chloride and 200 mg of triethylbenzylammonium chloride are dissolved in 40 ml of methylene chloride. After adding 3.2 ml of water, the mixture is heated to the boil, 3.2 g of 50% strength sodium hydroxide solution (40 mmoles) are added dropwise, with vigorous stirring, in the course of 15 minutes, stirring is continued for 30 minutes, the mixture is cooled and the phases are separated. The methylene chloride phase is washed with water and concentrated to dryness.
3.8 g of oily 1-L-~-phenylethyl-4-methyl-4-(3',4'-methyl-enedioxybenzyl)-2-imidazolin-5-one remain; the NMR spectrum (220 MHz, CDC13) of this product indicates a ratio of the diastereomers of 70 : 30 (asymmetric induction 40%).
The product is obtained in a pure form by filtration over silica gel (methylene chloride, ethyl acetate).
IR spectrum (film): 1,710 (C=O), 1,600 cm (C=N).
C20H20N2O3 (336) calculated C 71.5% H 5.9% N 8.3%
found 71.4% 5.9% 8.4%
D. Hydrolysis to the optically active aminoacids 1. L-~-Methylphenylalanine . ~ .
,~ - 38 -~lr~z7l.

A solution of 4.2 g of crude l-L`~-phenylethyl-4-methyl-4-benzyl-2-imidazolin-5-one obtained as described in Example C. 1., in 20 ml of methanol and 5 ml of water, is saturated with hydrogen chloride gas and boiled for 24 hours ~- under reflux. The solvent is distilled off, the residue istaken up in 20 ml of half-concentrated hydrochloric acid and the solution is boiled under reflux for 24 hours. It is then allowed to cool and is extracted with twice 20 ml of methylene chloride, and the extract is concentrated to dry-ness. The residue is dissolved in a little absolute ethanol and propylene oxide is added. Hereupon 1.8 g of L-~-methyl-; phenylalanine precipitate, and are filtered off and dried (67~ yield).
Melting point 290C, with decomposition (the literature gives a melting point of 316C).
[ ~ ~D = ~4 7 (C= 1.025 in 1 N HCl) The literature gives ~ ~ ~20 = _4 5o (C= 1 in 1 N
HCl) Hydrochloride:
Melting point 249C, with decomposition.
r ~20 = 8 55 (C= 1.03 in H2 The literature gives ~ ~ ~D = -8.6 (C= 1 in H2O).
Comparison of the measured values with the data from the literature shows that the ~-methylphenylalanine obtained is optically pure and hence also confirms the result of the NMR analysis, namely that at the intermediate stage ` the imidazolinone contains at least 95% of pure diastereomer.
The literature data are given in the article by K.
Weinges et al., Chem. Ber. 104 (1971), 3594.
2. L-(-)-N-Acetyl-~-methyl-~-(3,4-dimethoxyphenyl)-alanine 7.0 g of the diastereomer mixture of l-L-~-phenyl-ethyl-4-methyl-4-(3',4'-dimethoxybenzyl)-2-imidazolin-5-one ' obtained as described in Example C. 10., are hydrolyzed to the aminoacid by heating with aqueous-ethanolic potassium hydroxide (6 g in 40 ml of ethanol and 20 ml of water). After distilling off the solvent, the residue is taken up in water.
The aqueous phase is extracted wi-th methylene chloride and is concentrated under reduced pressure. The dry residue is heated in dimethylformamide, in the presence of 6 g of acetic anhydride, for one hour at 90. Undissolved salt is filtered off, the filtrate is concentrated under reduced pressure and the residue is takèn up in 50 ml of water. The solution is acidified to pH 1 with hydrochloric acid. The precipitate of N-acetyl-~-methyl-~-(3,4-dimethoxyphenyl)-alanine, which crystallizes on rubbing is filtered off, washed with a little cold water and dried. Melting point 189 - 191C; ~ ~ ~D
-28.8 (C= 2; CH30H).
The conversion of the imidazolinone into the N-acetylaminoacid, described above, is advantageous because the ; product has a relatively high optical rotation, so that the asymmetric induction can be determined accurately.
The literature gives the following values for the pure enantiomer: Tristram et al., J. Org. Chem 29 (1964), 2053: melting point 192-194C, ~ ~ ~D5 = ~55 (C= 1,CH30H);
Slater et al., L. Org. Chem. 29 11964), 1424: melting point 186 - 187C, ~ ~ ~D =-21 (acetone).
The N-acetyl compound obtained from optically pure L-(+)-N-formyl-a-methyl-~-(3,4-dimethoxyphenyl)-alanine (cf. German Laid-Open Application DOS 2,406,898) by hydrolysis and subsequent acetylation gives thc following values after recrystallization from acetone: melting point 186 - 187C, L ~ ~D = -52 (C = 2, CH30H). From this the asymmetric induction is calculated to be 55~, in good agreement with the result of 60~ obtained by NMR analysis of the diastereomer -~r` - 39a -27~

mixture at the imidazolinone stage.
3. L-~-Methyl-DOPA
A solution of 14.1 g (40 mmoles) of the diastereomer mixture of l-L-~-phenylethyl-4-methyl-4-(3',4'-dimethoxy-benzyl)-2-imidazolin-5-one, obtained as described in Example C. 14., in aqueous-ethanolic potassium hydroxide (18 g in 80 ml of ethanol and 40 ml of water) is refluxed for 20 hours. After distilling off the ethanol and adding water, the aqueous phase is extracted with methylene chloride. The methylene chloride solution contains the L-a-phenylethylamine formed on hydrolysis, and some residual ~-methyl-~-(3,4-dimethoxyphenyl)-alanine L-~-phenyiethylamide, the primary product of the hydrolytic ring scission of the imidazolinone employed. The aqueous phase is brought to pH 6 - 6.5 by adding hydrochloric acid. The precipitate is filtered off and dried in a high vacuum at 80C. 7.7 g of a-methyl-~-- (3,4-dimethoxyphenyl)-alanine are obtained as the enantiomer ` mixture, melting point 244 - 246C.
7.2 g ~30 mmoles) of this enantiomer mixture are refluxed with 60 ml of 48% strength hydrobromic acid for 12 hours. The hydrobromic acid is then distilled off under reduced pressure at 70C. The residue is digested in 10 ml of water, the water is distilled off, the residue now obtained is taken up in 20 ml of water, a little sodium pyrosulfite and active charcoal are added and the solution is filtered.
The filtrate is brought to pH 6.3 by adding about 3 ml of concentrated ammonia solution. The precipitate is filtered off, rinscd with a little water and with acetone and dried at 60C under 3 mm Hg. 4.2 g of L-~-methyl-DOPA (containing about 11~ of water as determined by the Karl Fischer method) are obtained, melting point 289 - 291C, r ~ ~D0 = 4 7O

~C = 2 in 0.1 N HC1).

- 39b -7~1 In the same way, 8.1 g of optically pure L-~-methyl-~-(3,4-dimethoxyphenyl)-alanine, melting point 259C
(after recrystallization from water), are obtained from pure imidazolinone diastereomer prepared as described in Example C 10.
7.2 g of this aminoacid give 6.1 g of L-~-methyl-DOPA, having the stated properties.
4. L-~-Methyl-DOPA
l-L-~-Phenylethyl-4-methyl-4-(3',4'-methylenedioxy-benzyl)-2-imidazolin-5-one, obtained as described in Example C. 54., is hydrolyzed as described in D. 3. to give ~-methyl-~-(3,4-methylenedioxypenyl)-alanin-e. The asymmetric induction calculated from the optical rotation of the hydrochloride, ~ ~ ~D = +3 0 (C = 1, CH30H) in comparison with the optical rotation of the optically pure compound, ~ ~ ~D0 = +8.1 (C = 1, CH30II) is 37%, in good agreement with the value obtained in Example C. 54. (Suzuki et al., Chem. and Ind., 1972, 687).
The hydrolysis to give ~-methyl-DOPA is carried out in accordance with conventional methods, for example with 20%
strength hydrochloric acid in the presence of phenol, as described in German Published Application DAS 2,302,937 (Example 1.5).
5. L-~-Methyl-~-p-methoxyphenyl-alanine A mixture of 6.45 g (20 mmoles) of l-L-~-phenylethyl-4-p-methoxyphenyl-4-methyl-2-imidazolin-5-one and 5.4 g (80 mmoles) of 85~ strength potassium hydroxide in 20 ml of ethylene glycol is heated for 5 hours at 150C. Ethylene glycol, and L-~-phenylethylamine formed, are distilled off under reduced pressure on a rotary evaporator. The residue is partitioned between water and methylene chloride. The aqueous phase is neutralized with dilute hydrochloric acid `~1 ~ - 39c -and concentrated by evaporation under reduced pressure.
Extraction of the residue with ethanol gives 4.2 g of crude ~-methyl-~-p-methoxyphenyl-alanine, melting point 243 - 244C, JD5 = -3.1 (C = 1, l N HCl).
Recrystallization from water gives the optically pure aminoacid, melting point 265 - 266C. ~ ~ JD = ~4 4 (C = 1, 1 N HCl).
CllH15NO3 (209 calculated C 63.2 H 7.2 found63.0 7.3 NMR spectrum (60 MHz, D2O): ~ = 1.47 (s); 2.8 and 3.2 (AB, J = 15 Hz); 3.7 (s); 6.95 ppm (AA'BB', JAB = 8.6 Hz).
The optical rotations confirm the asymmetric induction determined by NMR spectroscopy in Example C. 18.
The hydrolysis to L-~-methyl-tyrosine can be carried out with hydrobromic acid under the conditions described in D. 3.
Table 3 gives further examples of the hydrolysis of formula I compounds to form optically active amino acids.
Rl always denotes L-~-phenylethyl and the amino acids are characterized as N-acetyl derivatives. The 2-imidazolin-5-ones a to e are prepared from l-L-~-phenylethyl-4-methyl-2-imidazolin-5-one by reaction in tetrahydrofuran in the presence of one equivalent of butyllithium as the base with a bromide corresponding to the radical R4 indicated.
Compounds f to i are prepared from isocyanoacetic acid L-~-phenylethylamide by reaction in tetrahydrofuran in the presence of 2 equivalents of butyllithium, initially with R3 iodide and then with benzyl bromide.
:

- 39d -z~7 ~

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CO ~ O O O ~ O O O~
IV ~1 1~~\ L~L^~ W O CO ':~
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r-l ~ I rl I L~ L~ Ir~
I I ~J SO ~ -- X X
(1) S " I
S: ~ O O C~
O S S ;) N ;-~ I
J ~~d S ~ II --r~
N C) ll ~ ~ ~_ ,, r1 ~) S
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~ ~ ~ C) ~ ~ ~ 5~ S r~

` -- 40 --

Claims (3)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for the manufacture of optically active amino acids, wherein a diastereomer mixture, obtained by asymmetric induction, of a chirally substituted 2-imidazolin-5-one of the formula I

(I) where R1 is L-.alpha.-phenylethyl, (+)-3-pinyl-methyl, (-)-nopinyl, or L-.alpha.-carbo-tert.-butoxy-ethyl, R2 is hydrogen, methyl, benzyl or phenyl, R3 and R4 are different from one another and R3 is alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms substituted by methoxy, methylthio, dimethylamino, cyano and carbethoxy, benzyl or benzyl which is mono- or disubstituted by alkoxy containing 1 to 4 carbon atoms, acyloxy and mono-substituted by chloro, bromo, nitro or methylenedioxy, or phenyl, and R4 is alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms substituted by methoxy, methylthio, dime-thylamino, cyano and carbethoxy, benzyl or benzyl which is mono- or disubstituted by alkoxy containing 1 to 4 carbon atoms, acyloxy and monosubstituted by chloro, bromo, nitro or methylene-dioxy, or allyl, or R4 is additionally a radical selected from the group consisting of naphthyl-methyl, thienylmethyl, benzo-thienyl-methyl and bromo-benzofuranyl-methyl, is hydrolyzed in a solvent or solvent mixture in the presence of acid or alkali.

2. Process for preparation of an optically active .alpha.-methyl-aryl-alanine as claimed in claim 1, wherein a diastere-omer mixture, obtained by asymmetric induction, of a chirally substituted 2-imidazolin-5-one of the formula I where R1 and R2 have the meanings given in claim 1, R3 and R4 are different from one another and R3 is methyl, or benzyl which is mono-or disubstituted by alkoxy containing 1 to 4 carbon atoms or acyloxy and monosubstituted by methylenedioxy and R4 is methyl, benzyl or benzyl which is mono- or disubstituted by alkoxy containing 1 to 4 carbon atoms or acyloxy and monosubstituted by methylenedioxy, is hydrolyzed in a solvent or solvent mix-ture in the presence of acid or alkali.

3. Process as claimed in claim 2 for the preparation of L-.alpha.-methyl-.beta.-(3,4-dihydroxyphenyl)-alanine, wherein a com-pound of the formula I in which R3 is methyl and R4 is 3,4-disubstituted benzyl is hydrolyzed.