DE1543774A1 - Process for the preparation of optical isomers of phenyl-substituted alpha-methyl-alpha-cyanopropionic acid and their esters - Google Patents

Description

The invention relates to a new method of manufacture optical isomer of a pheny! -substituted a-methyl-a-oyanopropionic acid and its isomers, the important Intermediate products for the preparation of certain optically active α-methylphenyl-alanines. In particular The invention relates to a process for the preparation of the above-specified cyanoeater, in which the Raoenate sur recovery of the desired inantionorphs are separated in practically pure form and the undesired inantio- «Orph sur! ^ Cyclization is realized.

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BATHROOM OBlGiNAL

a-methyl-ß - (; 5,4-dihydroxyphenyl) -alanine or α-methyl-DOPA, as this connection is generally called " has proven to be an effective antihypertensive agent People proved. The 4-hydroxy analogue, which in general α-Methyltyrosine is called »is a very promising one Tranquillizer. The activity of these compounds lies in the L-Fore. The D forms are considered antihypertensive or tranquilizers completely inactive, but just as toxic as the L-form. Bs 1st therefore important for use in medicine L-Pora can be produced free of the D-Fonn.

Exemplary for the method according to which L-hydroxyphenyla-alkyl-alanine currently being produced is the production of α-methyl-DOPA. The synthesis of this compound generally takes place on the basis of methylvenillyl- or veratryl ketone in one or two ways. Either the ketone is reacted with ammonium carbonate and a cyanide salt to form a hydantoin, which after the corresponding a-ketbylitethoxyhydroxy- (or -dimethoxy) -phenylalanine delivers, or it will Xetone with ammonium cyanide to form an a-atoino-avanlllyl (or -veratryl) -propionitrile brought to implementation, which gradually to the corresponding AnId

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hydrolyzed and then at the same time with formation des Dihydroxyphenylalanine demethylated and hydrolyzed will. In these previously known processes, the optical isomers are generally released at the end of the synthesis or at an intermediate stage in the construction of the molecule separated.

However, such procedures olne accumulation have the unusable D ~ Fonn result _f which can only with difficulty CDER racemlsiert economically catfish degraded to give an intermediate which can be verwondet again, or they are connected with difficulties in an intermediate stage of performing the method, In which case expensive intermediate products are lost through the usual separation and dissolution losses. Consequently, there is a continuing need for a more economical synthesis to be carried out on an industrial scale.

The main object of the present invention is that Creation of an optically active intermediate product that can be converted into the desired in a simple and economical manner optically active o-methylphenyl-alanine are converted can. Another goal is to develop an excellent method for synthesis and separation

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such intermediates. Further, the invention has to provide a method for synthesis of the cyanoester intermediates according to the invention for Aim set for which reagents are used, which are produced in simple and cheap catfish from readily available raw materials. These and other goals of the present invention will become more apparent from the description below.

According to the invention, the ct-methyl-a-cyanophenyl-alanines and hangovers in the desired optically active form a process produced »which 1.) in the contacting a compound of the formula

-CH ₂ X

where R ₁ and R ₂ can be equally different and hydrogen or lower-alkyl, η 0 or 1 and X mean halogen or di-lower-alkylaraino «with a lower allyl ester of α-cyanopropionic acid and in the simultaneous removal of hydrogen halide ( for example by using a suitable amount of a base) to dissolve a compound of the formula

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- ^C ° 2 ^R 3

wherein R., Rp and η have the meaning given above and R, is lower alkyl «(2.) in the hydrolysis this low-alkyl ester for obtaining a compound the formula

- C - COOH

where R ,, Rp and η have the meaning given above own, in the form of a raoemisehen mixture of D- and

L-Ieomers, 3 » ) in the separation of this racemic mixture

>
and separate recovery of the separated D- and L-lees obtained as nledrlg-alkyl esters, 4.) in the contacting of the D-isomers obtained with an aqueous solution of a strong 3 mure to obtain an aeido meter of the Forael

f3

in the D configuration, in which R ₁ , R _g , R, and η have the meaning given above, 5.) in the Raceei

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sization of this DoAmidooatera for the recovery of oiner racemic Mixture of D- and L-Iscraeren of the named Amidoesters and 6.) in contacting the racemic Mixture with a dehydrating agent to obtain the corresponding compound in which the aod d function converted again into the original nitrile function is, exists. The production of an α-methyl-α «cyano« ß- (3,4-di »lower alkoxyphenyl) propionic acid ester, those in the contacting of a 3,4-dialkoxybenzyl halide with a lower ~ alkyl ester of a-cyano-propionic acid for Obtaining a lower alkyl ester of α «cyano-α-methyl-ß- (3,4-dialko ^ yphenyl) propionic acid, in contacting the ester with an aqueous solution of a strong acid for hydrolyzing the ester and for obtaining the corresponding free acid as a racemic mixture of D- and L-isomers, in the separation of the racemic mixture and recovery of the L-isomer and in the re-evaluation of the D-isomer by a process which 1.) results from the hydrolysis of the cyano group to a carbaraoyl group, 2 «) Racemization of the amide obtained by contacting with a small amount of a base (generally a strong base) and 3.) dehydration of the resulting racemate for obtaining the lower alkyl ester of a-cyano-amethyl «ß- (3,4-dialkoxyphenyl) propionic acid as racemic

90988 7/1728 BAD original

Mixture composed, is one is preferred Embodiment of the present invention. Sine others The preferred embodiment is that described above Procedure execution j. at which one 4-Aikoxybenzylhalagenid to obtain the corresponding Cyanoester, i.e. the lower alkyl ester of a-cyano-araethyl " fl- (4-alkoxyphenyl) propionic acid is used.

The following examples illustrate the invention without it to restrict.

example 1

A) 2,4-diraethoxybenzyl chloride

To a solution of 138 g (1.0 mol) veratrol in 500 ml Benzene, which is saturated with hydrogen chloride at 10 * C * 37.6 g (0.42 mol) of faraformaldehyde C (HCHO),] are added. The slurry is then stirred at 10 ° C, whereby the temperature is raised to 40 ° C. while bubbling through hydrogen chloride for 90 minutes. the Solution is filtered and concentrated under reduced pressure to a residual oil, which is 115-118Vl mm is fractionated to obtain a distillate, which turns into a white solid, 3 * 4-Dimethoxybenzylehlorid, solidified.

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B) 4-methoxybenzyl chloride

37.6 g (0.42 hol) paraformaldehyde [(HCHO),] are added to a solution of 108 ε (1.0 mol) methoxybenzene in 300 ml benzene which ^{is saturated with hydrogen chloride at 10 9 C.} The AufGC-iläiaraung is then stirred at 10 ⁰ C, the temperature is increased to 4G ⁰ C during a 90 minute long by bubbling hydrogen chloride. The solution is filtered and concentrated under reduced pressure to a residual oil which is fractionated to give a distillate which solidifies to a white solid, 4-methoxybenzyl chloride.

Example 2 A) Preparation of the methyl ester of a-methyl-cc-cyano-ß-

(3 # 4-dimethoxyphenyl) propionic acid

Ski of a solution of sodium ethoxide, which consists of 11.5 β (0.5 mol) Sodium is produced in 400 al of dry methanol, a solution of 56.5 g (0.5 mol) of the methyl ester is vcn α-Cyanoproplonic acid in 60 ml of methanol for a period of time of one hour at 25 ° C. was added. A solution of 93.3 g (0.5 mol) is added to this solution of the cyano ester enolate 3,4-Dimethoxybenzy1-chloride in 100 ml of methanol during a Time span of 30 minutes given »whereupon the received The mixture is refluxed for 4 hours. The mixture

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is cooled and the salt is removed by filtration, whereupon the PiItrat under reduced pressure to a Oil residue is concentrated after the addition of 200 ml of hexane crystallized on cooling and was in good condition Yield the product, namely the methyl ester of α-methyla-oyano-e> (3 «4 <» dimethoxyph «nyl) propionic acid supplies.

B) Preparation of the methyl ester of a-methyl-oc-cyano-B- (4-methoxyphenyl) »propionic acid

The procedure described in Example 2 (B) is repeated Procedure, with the exception that 0.5 mol of 4 <methoxybenzyl chloride instead of 0.5 mol of 5,4-dimthoxybenzyl chloride for the preparation of the corresponding methyl ester of a-Methyla-oyano-8- (4-iDethoxyphenyl) «propionic acid be used.

The work described in example 2 is again * gets «where dl · ethoxy-, n-propoxy-, iaopropoxy-, n-butoxy-, tert-butoxy and similar alkoxy analogs of 4-methoxybenxyl chloride in equivalent molar amounts for the preparation of the methyl ester of a-methyl-a-cyano-ß-O-ethoxyphenyl) propionic acid, a-Mothyl-a-oyano-fl- (4-n-propoxyphenyl) -proplonsMure, a-methyl-a-oyano-fl- (4-iao-propoxyphenyl) propionic acid, a-methyl-a-cyano-S- {4-n-butoxyphenyl) -propion-

acid or a-methyl-a-cyano-Q-i ^ -tert.-tiitooyphenyD-pro-

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pionsSure can be used. Similarly, you can different hydrooarbyl esters using the in example 2 procedures described are produced, indea instead of the methyl cc-cyanopropionate used dio corresponding ethyl, isopropyl, η-butyl, hexyl, Octyl- or similar ot-cyanopropionates for the production the corresponding alkyl ester derivatives are used.

The preparation of the α-lower alkyl-α-cyano-O-Cp-alkoxylated phenyl) propionic acid esters includes a nucleophilic replacement which can be carried out by using another labile leaving group instead of the halide. For example, the tosyl or mesyl derivatives of the corresponding benzyl alcohol can be used instead of the p-alkoxybenzyl halide. The production of the corresponding p-hydroxy compounds, however, takes place via HiiJination addition reactions (on the chloronomethide occurring as an intermediate), and only all of the above-mentioned leaving groups can be used, but also the N-di-lower alkyl derivative, - for example N-dimethylvanlllylamine. Furthermore, other alkali metals and alkenols can be used in place of sodium and methanol in Example 2 "and" ar Depending on which nledrlg-alkyl ester is desired. Examples of alkali metals are potassium, lithium, rubidium and cesium,

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while as alcohols, for example, ethanol, propanols Butanol or the like. can be used.

In carrying out these nucleophilic replacement reactions is there because the response is on a stoichiometric The basis is, in general preferable, stoichiometric Use quantities of all raw materials. However, the p-hydroxybenzylamine compounds react on an auto « catalytic base, so in the latter case it is preferable is to use about 5 to about 10 $ of the alkali metal alcoholate (i.e. the ratio of alcoholate: the above-mentioned di alkyl a mi η is 0.05 to 0.1U).

It should be pointed out that in addition to the alkali metal alcoholates other polishing agents can be used, for example alkali hydrides, e.g. Sodium hydride, potassium hydride and lithium hydride; Alkali metal powders or dispersions, such as potassium or Lithlum grit dispersions as well as other conventional enolizing agents can also be used.

In general, the temperature appears to be inappropriate Level of the nuoleophilic substitution is not critical be; this step can be carried out at one temperature

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which is sufficient to initiate the reaction, but which is below the decomposition temperature of the external substances and products. In most cases, this temperature is within dos range of from about 25 ^e C to about 100 C. Any inert solvent ^e, ^ edes solvent which does not interfere with the desired reaction in interaction that is, can be used, benzene or can beispieJ.aweise other inert aromatic hydrocarbon solvents, hexane and similar inert aliphatic hydrocarbon solvents, inert ethers such as tetrahydrofuran or similar inert solvents are used *

Example 3

Separation of the * Cyanoeeters

To a solution of 87.7 g (0 * 33 mol) of the methyl ester from DL-a-M * thyl-a-cy * no-3 - (; 5,4-dieethoxypbenyl) -proplonetfure in 300 ml of 5 * strength aqueous acetone is added with stirring given 1.0 ml of concentrated sulfuric acid at 25 ° C. After one hour, the solution is applied to a column containing 230 g (0.63 mol) of brucine, which intimately is mixed with 250 g of Supercel. The filled column will to adjust the equilibrium left to itself for two hours and then with 400 ml of acetone / petroleum

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other (1: 3) ^{eluted at a rate of 2} JO ml / hour. The fraction containing the soluble brucine salt of L-CyanosHure is concentrated and dissolved in slightly acidic methanol; After the concentration obtained, a precipitate is obtained from the methyl ester of L ~ a-methy1-a-cyano-β- (3, ^ - dimethoxyphenyl) propionic acid.

When the column is leached with hot acetone, this occurs less soluble brucine salt obtained, which in a similar work-up process the D-cyanoester * i.e. the methyl ester of D-ot-methyl-a «cyano ~ 9- (3 * 4-dimethoxyphenyl) propionic acid, supplies.

The separation of the methyl ester of DL-α-methyl »α-cyano-0- {4-methoxyphenyl) propionic acid can be carried out in a similar manner be carried out »by instead of this racemisohen Compound the dirnethoxy derivative used in Example 3 is used.

That shown by the examples described above Separation can be carried out using other optically active bases as separation agents, for example using cinchonine, clnchonldine, quinine, quinidine,

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Strychnine, morphine, 1-methylamine, d- and 1-a-phenylethylainine, d "2 ~ Amino-1" hydroxyhydrinden, L-arginine and α-methyl benzylanine. Although in the examples described above, the separation by the preparation of a salt the free acid is carried out, the separation also take place via a free phenolic function using the above-mentioned separation agents. Example catfish can use the 4 ~ hydroxyphenyl analogues be disconnected this way.

In addition to the separation method described in Example 3, which includes the recovery of the less soluble salt after the elution of the other salts, The more usual batch-wise can be selective Krlstalllsationsnetnode, which is the less soluble salt directly supplies can also be used.

Example 4 Preparation of the amido ester

1 mol (263 g) of the methyl ester of Da-methyl-a-oyano-fl-0,4-din »tho * yphenyl) propionic acid is dissolved in 2 kg of 85% sulfur! Eure 'and stirred for 12 to 15 hours 'heated to 100 to HO ^{0 C for a long time.} The solution is cooled, slowly poured into crushed ice with stirring and

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BATHROOM 0RM3MWA:

then extracted three times with 533 ml of methylene chloride combined extracts are diluted with »bio carbonate washed, dried and concentrated in vacuo, whereby a yellowish gourmand substance accrues »the residue is digested with three times 500 ml of methanol and then again concentrated in vacuo to a small volume (300 ml), a heavy slurry is obtained which, on cooling over ice, contains 259 g (0.92 mol) of the methyl ester of D-α-methyla-carbamoyl-fl-0,4-diroethoxyphenyl) propionic acid supplies.

Example 4 described above is used of the 4-methoxy homologue is repeated, then becomes the corresponding methyl ester of D-α-methyl-α-carbarooylß- (4-methoxyphenyl) propionic acid obtain.

Hydrolysis de "Cyanoestera described above to the Aeldoestftr (dl · expressly ·" Aeido "and" carbamoyl ^r In the present case interchangeable) may be implemented using other HydroIysemethoden be performed. For example, can be used to that described in the above example sulfuric other mineral acids in addition In another procedure for converting the cyanoester into the corresponding amide, sulfuric acid monohydrate is used.

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9370

see conditions used. Another method is to use the CyanGoater with PolyphosphorsHure Heat ζμ. The origin of the nitrile function of the cyanoester in the Amidoeator Scann also using of methanolic hydrogen chloride to obtain the corresponding imino ether, which is followed by pyrolysis into the desired amido ester.

Example 5 Racemization of the D-amidoester

For 1 liter of xylene in an autoclave equipped with a stirrer, “which contains 1.0 g (0.1184 mol) of KatrluoMthylat, are 10 ml of methanol containing 0.16 g (0.0092 mol) of ammonia, and 259 grams (0.092 moles) of the methyl meter of D-α-methyl-aaarbaaoyl-fi (3,4-dimathoxyphenyl) propionic acid given. The mixture is heated to 170 ° C. for 4 hours with stirring heated, cooled and washed old cold Ο, Ιη-SalxsKure. The xylene layer is then reduced to a small size in a vacuum. Volume concentrated, diluted with 1 1 of methanol and concentrated again in vacuo to approximately 300 ml, with a thick camouflage on the soles, which occurs when cooling over Ils In good yields <* en methyl ester of DL-a-methyl-a-ß « (3,4-dimethoxyphenyl) propionic acid provides.

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The other optically active amidoalkyl esters can be racemized in a similar manner, for example the ethyl, propyl and butyesters and their branched-chain derivatives, as well as the mono »and dialkoxy analogs of the D-amido ester starting material used in Example 5» for example the 3,4-Diethoicy ", j5, *" Diprop "· oxy-, 3 $ 4-dibutoxy-, 4-methoxy-, 4-ethoxy-, 4-propoxy-, 4-butoxyderivate or the like., Whereby the corresponding be obtained alkyl ester of an a ^ methyl-a-carbarooyl ^'a fl "(Alkox ^ profiled-phenyl)» propionic acid.

The example described above shows the racemization of the undesired optically active isomer, which is fed back into the process according to the invention. It should be pointed out that in this racemization a new trace equilibrium setting principle for Conversion of the asymmetric carbon of the D-amldoester into its optically inactive or racemized form a traces-> 01elchsgewlchts »production with the non-» asymmetrical diamide is applied. This principle is therefore a preferred embodiment of the present invention Invention, since it is an extremely simple, direct and economical method of racemization which is based on a A large number of other optically active systems in which there are comparable imbalances, such as for example

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the reversible hydrolysis-dehydration of an asymmetrical double cyanamide into the symmetrical diamide in counter was a large volume of phosphoric acid, widely applicable "

Example 6 Production of the DL-cyanoester from the corresponding DL amido ester

300 g of Supercel and 173 g (1.22 mol) of phosphorus pentoxide are added to 228 g (0.81 mol) of the DL amldoester, dissolved in 500 ml of sym.-tetraohlorethane. The mixture is refluxed for 5 hours while stirring. cooled and poured into 1.5 liters of water. The super oil is removed by filtration, whereupon the filtrate layers are separated. The organic layer is concentrated in vacuo to a small volume, extracted with three times 500 ml of hexane in vacuo and finally again to a residue. volume of 350 concentrated al After a two-hour cooling to 0-5 C ^e are l68,5 g {0.64 Hol) of Methylesters of DL ~ a-methyl-a-cyano-3 '{3 "4-diroethoxyphenyl). - propionic acid obtained.

The procedure described in Example 6 can also be used

to convert the methyl ester of DL-a-Hethyl-a-carbaraoyl-

S- (4- »ethoxyphenyl) propiolic acid in the corresponding

909887/1728 -18- bad original

1s

Cyanoester can be applied.

The DL-Cyanoeeter described above is repeated Return to the separation stage · such as in Example 3 is suitable. The invention therefore provides an excellent method of using the undesired optisohen isomer in the preparation of the economically important enantlonorph. In the preceding series of examples, for example the L-form of the methyl ester of o-methyl-o-oyano-fl-O »4-diMthoxyphenyl) propionic acid for conversion into the therapeutically important hypotensive agent, L-a-methyl-DOPA, suitable because the L-form of the cyanoester intermediate is freed from the D-shape without it at the same time an enrichment of the unusable D-form takes place.

In addition to the dehydration described in Example 6 sewing methods using phosphorus pentoxide, other procedures can be used, for example dehydration using Halides or anhydrides of organic or inorganic acids are carried out with the application of heat; aside from that can use catalytic methods (see Chemical Review, 42, 189) come into use. Example of inorganic halide are phosphorus pentachloride, phosphorus oxychloride and thionyl '

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Chloride. Examples of acid anhydrides that are used are acidic anhydride, succinic anhydride or the like ..

By using the above dehydrating agents can convert a large number of the optically active arcidoesters according to the invention into the corresponding raoeoic Cyanoesters are converted. For example, the ethyl, propyl and butyl esters of a-methyl-a-carbaiaoyl α- (I, 4-diroethoxyphenyl) propionic acid or such esters of α-methyl-α-aarbamoyl-Ö- (4- «ethoxyphenyl) propionic acid converted to the corresponding cyanoesters using the dehydrating agents described above will. Similarly, other alkoxy11ers Phenyl analogs are converted »for example the Ethoxy, propoxy or butoxy derivatives as well as the mono- and substituted analogs of such α-methyl-α-aeldo- (alkoxyl ter-phsnyl) propionate esters.

Examples 3 and 6 are made using the same Amounts of other optically active amidoesters instead of the methyl ester of a-methyl «a *> carbamoyl-8- (3« 4-> dimethoxyphenyl) propionic acid repeated then similar yields of the desired racemate are obtained. For example supplies the methyl ester of D-a-methyl-a-carbamoyl-ß-

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(4-methoxyphenyl) propionic acid, the methyl ester of DL-α-methyl-α-oyano-β- (4-methoxyphenyl) propionic acid; the ethyl ester of D-a-Methvl-a-carbamoyl-B-O. ^ - diethoxyphenyl) propionic acid gives the ethyl ether of DL-a-Methyla-oyano-Q- (3,4-diethoxyphenyl ^ propionic acid ;, the propyl ester of D-a-methyl-a-carbaraoyl-ßM; 5,4-di-n-butoxyphenyl) proponic acid provides the isopropyl ester of DL ~ a-Methyla-oyajio-fl - (;% 4-di-n-butoxyphenyl) propionic acid; the sec-butyl ester of D-a-methyl "a-oarbaooyl" S- (3,4-di-n-butoxyphenyl) propionic acid supplies the aek-butyl ester of DL-a-methyl-a-oyano-0 - (?, 4-di-n-butoxyphenyl) propionic acid; In a similar way, other alkyl esters give an optional one active a-methyl-a-oarbanoyl-e- (alkoxylated-phenyl) -proplonalure the corresponding liters of a DL-a-methyla-oyano «i- (alkoxyIiorten-phenyl)» proplonic acid. Is general becomes the D-Inantiooorph for the production of the Raoeaat "venteivSet" da ea the L-For · 1st, which · dl · desired Has ind use properties as above has already been discussed. Ss is therefore the D pore, which is responsible for racemization and for recirculation to the invention Procedure is available.

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Claims (9)

■ t 9370 ^l8 October 1966 Claims 1 · Process for the production of optical isomers of a phenyl-substituted a-methyl-a-cyanopropionic acid and of their prayers, characterized in that a connection the Fonwl R ₂ OL where R ₁ and Rg can be the same or different and are hydrogen or lower-alkyl, η 0 or 1 and X are halogen, bit of a low-alkyl ether of a-CyanoproplonsXure with simultaneous removal of hydrogen halide to obtain a compound of the formula wherein R ₁ , R ₂ and η are as defined above and R _{5 is} lower alkyl, the nledrlg alkyl ester is contacted to obtain a compound of the Forael - 22 909887/1728 BATH ORIGINAL j
C - COOH vjorin R ,, R ₂ and η have the meaning given above, hydrolyzed in the form of a racemic mixture of D and L isomers, the racemic mixture is separated and the separated D and L isomers obtained are obtained separately as lower alkyl esters «The D-isomer obtained with an aqueous solution of a strong S acid to obtain an amidoester in the D-configuration of the formula (JH,
CONH ₂ in which R, «Rp, R, and η have the meaning given above own "contacted" the D-amidoester for extraction a racemic mixture of D and! "" Isomers of Amidoesters is racemized and the racemic mixture with a dehydrating agent to obtain the corresponding Connection in which the Araid function is replaced by a Nitri! Function «is contacted · 23 ~ 2. Process for the preparation of the L-isomer of a phenyl substituted α-methyl-a-cyanopropionic acid, characterized that a compound of the formula where R, and R _{g are the} same or different and hydrogen or lower-alkyl «η 0 or 1 and X is halogen, with a lower-alkyl ester of a-cyanopropionic acid to obtain a racemic mixture of D- and L-isomers of a Cyanoesters of the formula wherein R ₁ * R ₂ and η have the meaning given above and R- is lower-alkyl, the cyanoes ^ er is hydrolyzed to produce a ct-cy anopropionic acid as a racemic mixture of D and L isomers; then the racemic mixture is separated and the L-isomer obtained is recovered. 909887/1728 BATH ORIGINAL as 3 · Process for the preparation of a compound of the formula C - CQ, CN in which R ₁ , R ₂ and η have the meaning given above and R, denotes lower-alkyl »characterized in that a mixture of D- and L-Iaoeeren of a compound of the formula in which R 1 and R _{2 are} identical or different and are hydrogen or lower-alkyl and η O or 1 is separated, the separated D-isoere is obtained as a lower-alkyl ester , which is obtained as a D ~ Xstmere is hydrolyzed by KoAtaktierfn AdLt a solution of a strong acid to obtain the corresponding α-amido-α-methylpropionate ester, the α-aciido-α-methylpropionate ester is contacted with a small amount of a base to carry out the racemization and the racemate obtained is dehydrated. - 25th ας 9370 4. Process for the preparation of the lower alkyl ester of a «Methyl-a-eyano ~ 8 ~ (3» 4-dialkoxyphenyl) -propionic acid In Form of a raceric mixture characterized in that it is a 3,4-dialkoxybenzyl halide with a lower alkyl ester of a-cyanopropionic acid to obtain a low- Alley! Esters of a-cyano-a-nethyl "3- (3,4 ~ dialkoxyphenyl) -> propionic acid is contacted, this ester with a aqueous solution of a strong acid for hydrolysis of the ester and contacted to obtain the corresponding free acid as a Raoeml mixture of D and L isomers is, the raoemisohe mixture is separated, the L-isomer is separated therefrom and the D-isomer is recycled according to a process, which 1.) from the hydrolysis of the cyano group to a carbamoy group, 2.) the racemization of the amide obtained by contact with a small amount of a base and 3.) from the dehydration of the racenate obtained. 5. Process for the preparation of the lower alkyl ester of See α-methyl-a ~ cyano ~ Q- (4-alkoxyphenyl) propanol acid as racemic acid Mixture, characterized in that 4-alkoxy benzyl halide ait a nledrig-alkyl ester of α-cyano-propion-8Hure for the production of a low-alkyl ester from a-cyano-a-it »thyl-Ä- (4-alkoxypfcenyl) propionic acid This ester is contacted with an aqueous solution of a strong acid 903887/1728 " ²⁶ " BATH ORIGINAL for hydrolysing the ester and for obtaining the corresponding free acid is contacted as a racemic mixture of D- and L-isoners, the racemic mixture separated and the!. "isomers are separated from it as well as the D-Xsoraere is recycled according to a process, which 1.) in the hydrolysis of the cyano group to one Amido group, 2.) in the racemization of the amide obtained by contact with a small amount of a base and 3.) in the dehydration of the racemate obtained . 6 «Process for the preparation of the L-isomer of a« cyano ~ a «methyl-fl- (3,4-dialkoxyphenyl ^ propionic acid, characterized in that 3,4-dialkoxybenzyl halide with a 'lower-alkyl ester of a- Cyano-proplonic acid is contacted to obtain a racemic mixture of D- and L-isomers of the lower-alkyl ester of α-methyl-a ~ cyano-β- (3 _i .4-dialkoxyphenyl) -propionic acid, the lower alkyl ester with a aqueous solution of a strong acid is contacted to produce the corresponding α-cyanopropionic acid as a racemic mixture of D and L isomers, the racemic mixture is separated into the corresponding D and L isomers and the L isomer is obtained. - 27 909887/1728 7 · Process for the preparation of the L-isomerone of α-cyanoa-ynethyl ~ ß- (4 «alkoxyphenyl) propionic acid, characterized by "that 4-alkoxybenzy!" halide with a lower alkyl ether of a-cyano-propionic acid to obtain a racemic mixture of D and L isomers of the lower alkyl ester of a-Methyi-a-cyano-ß-C ^ -alkoxyphenyl) - propionic acid * this lower alkyl ester is contacted with an aqueous solution of a strong acid for production the corresponding a-cyanopropionic acid as racetnic Mixture of D and L isomers is contacted, the racemic Mix into the corresponding D- and L-isomers is separated and the L-isomer is recovered. 8 * Method of performing a racemization over a trace balance setting, characterized in that that an optically active isomer of an amidoester the formula CONH ₂ wherein R ₁ , Rg and R, can be identical or different and are lower-alkyl and η is 0 or 1, with a small amount of ammonia and a considerable amount of excess 909887/1728 '" ²⁸ " BAD ORIQiNAt R, OH is contacted, the stated amounts being added sufficient «to cause racemization. 9. Process for the preparation of the lower alkyl ester of a-cyano-a-ynethyl-e- (3,4-dialkoxyphenyl) propionic acid, characterized in that the D-isomer of α-methyl-acarbamoyl-β- (3,4-dlalkoxyphenyl) propionic acid with a small amount of a strong base to carry out the racemization and to obtain a raoemisehen mixture contacted by D- and L-isoroerenes of the propionic acid ester and said compound is dehydrated. 10. Process for the preparation of the lower alkyl ester of a-cyano-a-methyl-B- (4-alkoxyphenyl) propionic acid, characterized in that the D-isomer of a-methyl-otcarbamoyl-fl- (4 »alkoxyphenyl) propionic acid with a small amount of a strong base to carry out the racemization and to prepare a racemisehen- mixture of D- and L-isomers of the corresponding lower alkyl propionic acid ester is contacted and said compound is dehydrated. 11. Method for the resolution of a racemic mixture of D- and L-isomers of a-cyano-a-raethyl-fl- (3,4 «> dialkoxyphenyl) propionic acid, characterized by the one 909887/1728 " ²⁹ " BATH Solution of the CyanosHure with at least one equimolar Amount of brucine is contacted to form a diastereoisomeric pair of bruoine salts of the D- and L-cyano acids * separated the brucine salt of L-cyano acid as a solution and the solution with an acidified lower alkenol for the preparation of the isomer of a lower alkyl ester of α-cyano-α-methyl-8- (3,4-dialkoxyphenyl) propionic acid is contacted. 12. Process for the preparation of a lower alkyl ester of a-cyano-a-methyl-3- (3,4-dialkoxyphenyl) propionic acid, characterized in that the brucine salt of the D isomer of a-cyano-a-methyl-fl - ^, 4-dialkoxyphenyi) -propionic acid with a solution of an acidified lower alkanol to form the lower alkyl ester of D-a-cyano-a-methyl-B » (3,4-dialkaxyphenyl) propionic acid is contacted, the Isomer in the presence of a strong mineral acid for the production of a low ° alkyl ester of D-α-Methy1-a-carbamoyΙΟ- (3, 4-dialkoxy phenyl) propionic acid is heated, the Propienoic acid ester with a small amount of a base Conversion of the D-isosera into a racemic mixture of D- and L-isomers of said propionic acid ester contacted and the racemic mixture obtained is dehydrated will. - 30 909887/1728 BAD original 9370 . Process for the preparation of a racemization mixture a phenyl-substituted α-methyl-α-cyano-proplonic acid esters, characterized in that a connection of the formula -CH ₂ X wherein R _{1 and R 2 can be} identical or different and represent hydrogen or lower alkyl, η stands for 0 or 1 and X stands for halogen, di-lower alkylamino tosyl or mesyl, with a lower alkyl ester of α-cyanopropionic acid for the recovery a compound of the Fornel 3H ₂ -C- wherein R ₁ , R ₂ and η have the meanings given above and R, lower-alkyl 1, is contacted, the lower-alkyl ester to produce a compound of the formula 809887/17 28 BAD ORlG ¹ NAL CH, () <^ \ - _CH2 -C- CQOH I] CN I] wherein Η., R ₉ and η have the meaning given above, is hydrolyzed in the form of a racemic mixture of D and L isomers, the racemic? Mixture is separated, the obtained D- and .L- 1 some re η are obtained as low-A? KyIester getx ^ rint, the separated D ~ l3omers with an aqueous reading; A strong acid for the production of an amido star in the P-configuration of the formula -CIU -C- CO ₂ R, ONH ₂ i ( wherein R ,, R ₂ * R ^ and η have the meaning given above, is contacted, the D «amldoester to obtain a chemical mixture of D- and L-isomers of the Amidcestera raceraisf.ert and the racetnisohe mixture with a tte}. is acted upon. ORIGINAL 9 i '"S ■ · ■ R 7 / " -. · A