DE1543775A1 - Process for the production of optically active alpha-methylphenylalanines - Google Patents

Description

NBRCK 4 CO. » INC. 126 East Lincoln Avenue "Rahway" N.J. 07065, V.St.A.

Process for the preparation of optically active α-methylphenylalanines

The invention relates to a new / cija ^ i '? · Aur production optically active α-methylphenylaiaiiiae. In particular, relates the invention relates to the preparation of these alanines from optically active cyanoesters.

<x-methyl- (j5,4-dihydroxyphenyl) -alanine or a-methyl-DOPA, as this compound is commonly called, has become Proven to be a potent antihypertensive agent in humans. The 4-hydroxy analogue is generally a-methyltyrosine is a promising tranquillizer, the activity of these compounds is in the L-porm. The D-form is completely inactive as an antihypertensive or tranquilizing agent, but is exactly the same toxic like the L-Porra. It is therefore with regard to the

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Wounding of importance in medicine, the L-shape free to win from the D-Forra.

Exemplary of the manner in which L-hydroxyphenylalanines are currently manufactured »is the manufacture of α-methyl-DOPA. The synthesis of this compound usually takes place starting from methylv * nlllyl ~ or Veratryl ketone in one or two ways. Either will taking the ketone with ammonium carbonate and a cyanide salt Formation of a hydantoin converted, which during hydrolysis produces the corresponding α-methylmethoxyhydroxy (or -dimethoxy) -phenylalanine delivers, or the ketone becomes brewed with ammonium cyanide to form an a-araino-avanillyl (or -veratryl) propionitrile for reaction, which gradually leads to the corresponding amide hydrolyzed and then simultaneously with the formation of the di » hydroxyphenylalanine is demethylated and hydrolyzed. In these known methods, the optical isomers are in general at the end of the synthesis or separated less often at an intermediate stage in the construction of the molecule.

Such previously known methods result in an "accumulation of the unusable D-shape" which neither simple way racemlsiert still economically

BAD ORIGINAL 909 ^ 8 ² I? 1513

can be broken down into an intermediate product that again may be used, or are having difficulty with the implementation of Irs process tainted with some intermediate stages, - in which by the separation and racemization expensive intermediate products are consumed. Consequently, there is a continuing need for a more economical, Synthesis to be carried out on a technical scale.

The main aim of the present invention lies in Providing such a synthesis. Another one The aim is the division of optically active α-methylphenylalanine from cheap, optically active cyanoester intermediates. Another aim is to provide a method in which the optical activity of the starting material is maintained throughout the synthesis. Another goal is the production of a-methylphenylalanines, using simple and economical process equipment and technology.

These and other objects of the present invention are made more optically active by a method of making a-methylphenylalane: lne achieved which in the hydrolysis an optically active cyanoester of the formula

- 5 - BAD ORlO ¹ HAL

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.CO ₂ R ₃

where R- and R ~ can be the same or different and Hydrogen or n: Ledrig-alkyl, η is 0 or 1 and R., means lower alkyl, to obtain an optical active araidoesters of the Ponnel

- C - CC CONH ₂

wherein R., R «, R, and η have the meaning given above, and in the conversion of the araidoester about a Hofmann degradation and subsequent acidic or alkaline hydrolysis to the corresponding optically active α-methylphenylalanine of the formula

-C- COgH

where η has the meaning given above,

ORIQiNAL

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stands. (It should be pointed out that the terms "amido" and "Cnrbamoyl" is synonymous in the present application be used}

When carrying out the Hofmann degradation stage of the invention Procedure can be used in two ways. One is to implement the above specified amidoestera with halide (usually chlorine or bromine, preferably in the form of a hypohalogenite, where however, free halogen can also be used) and a strong base, being an optically active isonitrile the formula

wherein R ₁ , R 0, R _x and η have the meanings given above, is obtained.

The other method is to implement the optically active Araidoesters with halide (again chlorine or Bromine in the form of hypohalite is preferred; becomes, though free Halogen can also be used) UTid an appropriate one Metal alcoholates being an optically active compound of the formal

. BATH

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C - CO

wherein R ,, Rp, R, and η have the meanings given above, is obtained. The latter method will preferred because of the very desirable stability of the N-carboalkoxy derivative in the alkanol solution, either the isonitrile or the N-carboalkoxy compound can then

by acidic or alkaline hydrolysis into the desired optically active o-methylphenylalanine can be converted.

The hydrolysis of the cyanoester defined above can be carried out using sulfuric acid, generally 80 to 906, and using Warne. In addition, other mineral acids, such as for example, dilute hydrochloric acid can be used. Another method of working consists in converting the cyanoester into the corresponding amide by using Sulfuric acid donohydr & t hydrogen peroxide can also be used under alkaline conditions. Another method is to heat the cyanoester vLt polyphosphorous acid. The nitrile function of the cyanoester can also be converted into the amidoester by using ffiethanoli3chera hydrogen chloride with recovery of the

- β - BAD ORIGINAL

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speaking iminoether, which is subsequently produced by pyrolysis Converted into the desired amidoester is »converted will.

The following examples illustrate the invention without it to restrict.

example 1

1 mol (26> g) of the methyl ester of L-α-methyl-α-cyano-β- (3,4-dimethoxyphenyl) propionic acid is dissolved in 2 kg of 85 # sulfuric acid and stirred for about 15 hours heated to 100 to 10 ° C for a long time. The solution is cooled, slowly poured into crushed ice with stirring and then extracted with three times 333 ml of methylene chloride. The combined extracts are washed with dilute bicarbonate, dried and concentrated in vacuo to a yellow gum. The residue is washed three times with 50O ml of methanol digested and then concentrated again in vacuo to a low volume (approximately 300 ml), with a thick slurry is obtained which, on cooling over ice, contains the methyl ester of L-α-methyl-α-carbamoyl-δ- (3,4-diroethoxyphenyl) propionic acid supplies.

BATH 909881/1513

Example 2

The procedure described in Example 1 is followed * with the exception that proportions of the 3,4-diraethoxyphenyl derivative of the cyanoester of the methyl ester of L-α-methyl-α-cyano-ß- (4-methoxyphenyl) propionic acid in one equivalent amount to obtain the methyl ester of L-α-methyl-α-carbamoyl-ß- (4-methoxyphenyl) propionic acid is used.

The preceding examples show the production of an optically active amidoester, while the following examples show the rearrangement of such an optically active amidoester via Hofmann degradation in an alkanol solution demonstrate the corresponding carbaroate (i.e., carboxylate).

Example ?

To 42.4 g (1.84 g-Atoa) dissolved in 1 1 of methanol, 259 g (0.92 mol) of the methyl ester of La-methyl-acarbaraoyl-ß-0,4-diroethoxyphertfl) propionic acid are added at O ^- C given. To this solution are added 65.3 g (O.92 mol) of chlorine over a period of two hours with stirring at 0 to 5 C ^e. The mixture is then heated to 40 ° C., kept at this temperature for 15 minutes, ^{cooled to 10 3} ° C. and slowly poured into 2 l of ice water. The precipitated carbamate, the methyl ester of La-methyl-fl

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(3,4-dimethoxyphenyl) -N-carbomethoxyalanine, is filtered and washed with concentrated hydrochloric acid; a wet cake is obtained which is suitable for use in the following described cleavage stage is suitable.

Example 4-

The method described in Example 3 is used, with the exception that instead of the methyl ester of La-methyl-a-carbamoyl-Q- (3,4-dimethoxyphenyl} propionic acid, 0.93 mol of the methyl ester of a-methyl-a -carbamoyl-ö- (4-methoxyphenyl) -propionic acid can be used to obtain the methyl ester of La-methyl-ö- (4-roethoxyphenyl) -N-carbomethoxyalanine.

The cleavage of those prepared in Examples 3 and 4 N-carbomethoxy compounds are used in the following examples shown:

Example 5

A wet cake made from the methyl ester of L-a-methyl according to the procedure described in Example 3 ß- (3,4-dieethoxyphenyl) -N-carbomethoxyalanine is used in 1 1 on-SaI zs acid and placed in an autoclave for 8 hours • Heated to 170 * C. The solution is cooled and in vacuo

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focused on the minimum volume. Da3 remaining water and the acid are then mixed with 2 χ 750 ml of seic.-Butanoi rinsed in vacuo, whereupon the residue is dissolved in 750 el of the same solvent. The solution will then diluted with 100 ml of propylene oxide and stirred at 25 ° C. for 5 hours. This solution is then with 75 ml Diluted water and stirred for an additional two hours. The precipitated L-a-methyl-S- (3, ^ - dihydroxyphenyl) -alanine is filtered, washed with cold water and dried. When recrystallizing from aqueous sulfuric acid and treatment with carbon drops L-a-methyl-S- (3, * - dihydroxyphenyl) alanine-8esquihydrate.

Example 6

The procedure described in Example 5 is repeated « wherein an equivalent amount of the methyl ester of L-α-methyl-3- (4-methoxyphenyl} -N-carboroethoxyalanine is used to obtain L-α-methyl-tyrosine as salt hydrate.

The inventive method is in the same way the preparation of the corresponding racenic amldoic acid from the racemate of the inventive cyanoester starting material, materials applicable. Therefore also falls in the orbits of the Br the production of racemic or DL-a-methylphenyl-

* ¹⁰ - BATHROOM

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alanine and in particular of DL-α-methyl-DOPA and DL-α-methyltyrosine from the corresponding DL cyanoester.

The Hofmann degradation stage according to the invention can be achieved by dissolving of the amidoester in a slight excess of an aqueous hypchalogenite solution and then rapid Heating can be carried out. The stage is preferably carried out in an alcoholic, preferably methanolic, solution carried out with subsequent hydrolysis of the urethane obtained.

Although, as already explained above, in general any alkali hypohalogenite can be used in the process according to the invention, sodium hypochlorite is preferred since this compound leads to faster rearrangement and in many cases to higher yields. Therefore, the most frequently used method of carrying out this stage is the preparation of a sodium hypochlorite solution by reacting concentrated hydrochloric acid with potassium permanganate in a weight ratio of acid: alkali permanganate of 10 to 15: 1 and then collecting the chlorite produced on this catfish in cooled alkali, for example sodium hydroxide.

- 11 - ■
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In general, the degradation with approximately equimolar amounts of halide and alkali to produce the corresponding Isocyanate, which is hydrolyzed to the amine in the presence of water and an excess of alkali, carried out. If an alcoholic solution is used, then the corresponding urethane is produced, which supplies the desired amine in the subsequent hydrolysis. In the latter case, the halide will generally be quickly and with intimate mixing of an alcoholic, generally methanolic, solution of an approximately equimolar amount of the amidoester, which is an excess Amount of alkali metal alcoholate is added. Sin heating the solution completes the implementation; in some Minutes, the urethane is isolated in a simple manner from the 'reaction mixture, the desired amine in good yield by saponification with alkali, in general Sodium, potassium or Celciumhydroxyd, is obtained. Usually the alkali metal alcoholate is used in about a two-fold molar excess.

The temperatures used in the process according to the invention are generally only influenced by the decomposition temperatures of the starting materials and the desired products Limits set; they are of course at or above the temperature required to initiate the desired

■ - 9098 ^ / 1513. BADOR.Q.NAL

/ «9

Response is required. For the purposes of the invention, such temperatures vary from about 25 ° C. to 200 ° C. Usually the hydrolyses are carried out at a temperature which is -not higher than about 115 ° C., while the Hofmann ¹ see degradation reactions take place at temperatures between about 0 ^e C and about 75 * C. in addition, the cleavage of the carbamates is the desired alanine generally at temperatures no defense than about 200 ^e C and. in most cases from about l4o carried out to about 170 ⁰ C.

From the above it can be seen that the "process according to the invention is a cheap, technically feasible synthesis of such important optically active α-methylphenylalanines, such as α-methyl-DOPA and α-methyl-tyrosine, easily available These intermediates, ie the racemic lower alkyl esters of α-cyano-α-methyl-B- (alkoxylated phenyl) propionic acid, can be obtained by contacting an alkoxylated benzyl halide with a lower alkyl ester of a -Cyano-propionic acid © The cyanoester racemate is then treated with an aqueous solution of a strong

- 13 909881/1513 BAD

Acid brought into contact with hydrolysis of the ester to form the corresponding free acid racemate. After that, will the racemate separated again, whereupon the L-isomer is separated off. The D-isomer is used to convert again and recycled racemization to the starting lower alkyl cyanoester.

To further illustrate the preparation of the cyanoesters according to the invention by way of example. is the synthesis of the low-alkyl ester of a-methyl-a-cyano-ss - (> _Jt 4-dialkoxyphenyl) propionic acid, which is a 3,4-DAFL Dialkoxybenzylhalogenid with a low-alkyl ester of an a-Cyanopropionsaure to obtain a lower-alkyl ester of a-cyano-a-methyl-ß - (; 5,4-dialkoxyphenyl) propionic acid is contacted. This ester is then contacted with an aqueous solution of a strong acid to hydrolyze the isomer and to obtain the corresponding free acid as a chemical mixture of D and L isomers. These isomers are then separated again, after which the L-isomer is separated off and the D-isomer is recycled by a process which 1.) results from hydrolysis of the cyano group to a carbamoyl group, 2.) racemization of the resulting amide by contact with a small amount of a Base and j5.) Dehydration of the racemate obtained to obtain the lower alkyl ester of

- 14 909881/15 13 BAD ORIGINAL

α-Mefchyl-α-cyano-8 - (>, 4-dialkoxyphenyl) propionic acid as racemic «? Mixture consists.

Examples' for other optically active cyanoesters that are used in the process according to the invention can be used as starting materials are the methyl, ethyl, propyl or butyl (including branched chain derivatives) esters of the following acids!

La - ?. tliyl-a-cyano-ß- (3,4-dimethoxyphenyl) -propionic acid, D ~ a-propyl-a-cyano-ß- (3,4-diSthoxyphenyl) -propionic acid, La-butyl-a- cyano-SO, 4-dibutoxyphenyl! -propionic acid, La-ter.-Butyl-a ~ eyano-ß- (4rbutoxyphenyl) -propionic acid, Lai-Propyl-a-cyano-ß- (4-ßek.-butylphenyl) propionic acid . _#, etc. When using the above-mentioned cyano · esters as Ausganganaaterialien for erfindunt .. ^ enäße method are obtained · dl corresponding optically active α-Μβthy -phenylalanine, nfimlich: La-ethyl-.beta.

phenyl) -alanine «La-Buty 1-fl- Kj>, 4-dihydroxyphftny 1) -alanine, La-tert-butyl-f- (4-hydroxyphenyl) -alanine, L-gt-i-Propyi« β- (^ -hydroxyphenyl) -alanine and the like.

90361 ^ / 1513.

Claims (1)

1643775 l8. October 1966 claims 1. Process for the production of optically active a-methylphenylalanines * characterized in that an optically active cyanoester of the formula CN in which R, and Rp _t, which can be identical or different, are hydrogen or lower-alkyl, η 0 or 1 and R, are lower-alkyl, for obtaining an optically active amidoester of the formula wherein R, R * Ti _t and η are as defined above possess, is hydrolyzed and the amido a Hofmann'sehen degradation and subsequent acidic or alkaline hydrolysis to the corresponding optically active ct-methylphenyl! alanine For the? nel - 16 - BATHROOM ψ 909881/1513 - CO ₂ H ^NH a wherein η has the meaning given above will. 2. The method according to claim 1, characterized in that the Hofmann ¹ degradation stage see the contacting of the aroidoester with chlorine or bromine and an alkali metal low alcoholate to obtain an optically active carboxylate of the formula f » wherein R ₁ , R 2 * R * and η have the meaning given above. 5. The method according to claim 1, characterized in that the Hofmann's degradation stage involves contacting the amido ester with chlorine or bromine and a strong base to obtain an optically active isonitrile of the formula - 17 »09 * 81 / 1513- _BATH CH, < ^R i °> n-rf γ® ¹ : · - f wherein R ,, Rg, R, and η have the meaning given above own * includes. 4. A process for the preparation of optically active a-methylphenylalanlne, characterized in that an optically active low-alkyl ester of a-methyl-a-cyano-ß ~ "(alkoxylated phenyl) propionic acid for obtaining an optically active low-alkyl ester of a-methyl -a-carbamoyl-.beta. (alkoxylated-phenyl) -propionic acid is hydrolyzed "hedgehog this is seen by Hofmann degradation ¹ to the corresponding optically active _N Carbaraat converted and hydrolyzing the carbamate to the corresponding optically active amino acid. 5 · The method according to claim 4, characterized in »that as a lower alkyl ester of a-methyl-oc-cyano-ß- (alkoxylated phenyl) propionic acid the lower alkyl ester of a-Methyla-cyano-ß- (3 » 4-di-lower-alkoxyphenyl) propionic acid is used will. 6. The method according to claim 4, characterized in that DAFL as lower alkyl ester of a-methyl-a-cyano-.beta. (alkoxylated-phenyl) -propionic acid alkyl esters of the low- - 18 - 909081/1513 bad original α-methyl-a-cyano-ß- (4-lower-alkoxyphenyl) propionic acid is used. 7. The method according to claim 4, characterized in that that the Hofmann * see degradation stage the contacting of the amidoester with chlorine or bromine and an alkali metal lower alcoholate to obtain the corresponding optically active Carbamate. 8. The method according to claim 7. » characterized, that the lower-alkyl ester of α-methyl-acarbamoyl-ß- (3 "4-di-lower-alkoxyphenyl) propionic acid is used as the amido ester is used. 9. The method according to claim 7 *, characterized in that as amido ester, the lower alkyl ester of α-methyl-α-carbamoyl-β ~ (4-lower-alkoxypheny1) propionic acid is used. 10. Process for the preparation of L-tx-methyl-ß- (3,4-dihydroxyphenyl) -alanine, which is essentially free of the D-enantlomorph, characterized in that the Methyl ester of L-a ~ methyl-a-eyano ~ ß ° (3 * 4-diraethoxyphenyl) propionic acid is hydrolyzed to the corresponding L-amidoester, the L-amidoester with a chlorine or bromine solution and methanolic sodium solution to obtain the corresponding * - 19 - ' _BAD ORIGINAL. 909881/1513 ZO the carbamate is contacted and the carbamate too L-α-methyl-β- (3,4-dihydroxyphenyl) alanine is hydrolyzed. 11. Process for the production of L-a-methyltyrosine, characterized in that the methyl ester of L-cc-methyla-cyano-ß- (4-methoxyphenyl) propionic acid is hydrolyzed to the corresponding L-amido ester, the L-amido ester with a solution of sodium in methanol and chlorine or bromine contacted for the extraction of the corresponding carbamate and the carbamate is hydrolyzed to L-a-methyltyrosine. 12. A process for the preparation of L-a-methyl-ß- (3,4-dihydroxyphenyl) alanine, characterized in that the Methyl ester of L-a-methyl-a-cyano-ß- (3,4-dimethoxyphenyl) propionic acid is hydrolyzed with 80 to 90 ^ -lger sulfuric acid to obtain the corresponding L-amidoester, approximately equimolar amounts of the L-amidoester and chlorine or bromine in a solution of sodium, which is dissolved in methanol, to obtain the corresponding L-carbamate are implemented and then the L-carbamate is hydrolyzed with a strong mineral acid to obtain L-a-methyl-ß- (3,4-dihydroxyphenyl) -alanine. 13. The method according to claim 12, characterized in that about 6N hydrochloric acid is used as the strong mineral acid will. - 20 909881/1513 BAD ORIGINAL 14. Process for the production of L-a-methyltyrosine, characterized in that the methyl ester of L-a-methyla-cyano-ß- (4-methoxyphenyl) propionic acid with 80 to 90 # - iger sulfuric acid is hydrolyzed to obtain the corresponding amidoester, approximately equimolar amounts of L-amidoester and chlorine or bromine in a solution of sodium, which is dissolved in methanol, for recovery of the corresponding L-carbamate are implemented and then the L ^ carbamate is hydrolyzed with a strong mineral acid to obtain L-a-methyltyrosine. 15. The method according to claim 14, characterized in that that about 6N hydrochloric acid is used as a strong mineral acid. - 21 - 909881 / 1513- _B AD