DE2026952C3 - Process for the preparation of L-3,4-dihydroxyphenylalanine - Google Patents

Description

CH-NH-COR ₁

CH ₂

OH

wherein Ri is a hydrogen atom, a methyl, trifluoromethyl, phenyl, methoxy, ethoxy, isopropyloxy, sec. Butyloxy, terL butyloxy or benzyloxy and R _{2 is} a lower alkyl or benzyl radical, converted in a manner known per se with acyl peroxides into the monoacyl derivative of L-3,4-dihydroxyphenylalanine, then acylated in a manner known per se to the diacyl compound which Purified diacyl compound by recrystallization and then hydrolyzed in the usual way to the free L-3,4, -dihydroxyphenylalanine.

2. The method according to claim 1, characterized in that the acyl peroxide is benzoyl peroxide and benzoyl chloride is used to produce the diacyl compound.

The invention relates to a new process for the production of L-3,4-DihydroxyphenylaIanin from tyrosine.

The known processes for the production of L-dihydroxyphenylalanine (L-Dopa) go into the most cases of dihydroxybenzaldehyde or its derivatives. After building the amino acid side chain mixtures of the optical isomers are formed, which are separated by complex operations have to.

There are also already known methods according to which the tyiosin is used as a starting material. So will the inconvenient chemical introduction of a second hydroxy group into L-tyrosine via the 3-nitro- and 3-aminotyrosine described (HeIv. Chimica Acta, vol. 4.1921, pages 657 to 666).

All known methods have the disadvantage that they are very expensive and the desired highly purified Only deliver L-Dopa in poor yields. However, there is still a great deal of interest in procedures which make the therapeutically valuable L-Dopa available in good yields and in great purity.

In DE-PS 20 23 461 L- and DL-dopa derivatives from 3-alkanoyl-tyrosine derivatives were proposed or from 4-alkanoyl-m-tyrosine derivatives by oxidative To produce rearrangement with hydrogen peroxide.

It has now been found that the reaction of N-acylated tyrosine esters with acyl peroxides, in particular Benzoyl peroxide, in excellent yields to the 3-acylates, especially 3-monobenzoates, the N-acyHerten tyrosine ester leads. The monoacylates are acylated, in particular benzoylated, for purification. The diacylates, which crystallize well, can and can be easily purified by recrystallization then easily hydrolyzed to the free L-3,4-dihydroxyphenylalanine.

The reactions should be based on the following formula scheme are explained in more detail:

COOR ₂

CH-NH-COR ₁

CH ₁

1. (Q ₁ H ₅ COO) ₂

2. CH ₅ COCI

H ⁺ / H ₂ 0

OH

OH

R ₁ = H, CH. ,, CF ₁ , Q ₁ H ₅ , OCH ₃ , OC ₂ H ₅ ,

OCH (CH,) ,, OCH (CH ₃ ) C ₂ H ₅ , OC (CH,) ₃ , OCH ₂ QH ₅

R ₂ = lower alkyl or benzyl

The invention accordingly relates to a new process for the preparation of L-3,4-dihydroxyphenylalanine from Tyroüin, which is characterized by the fact that one L-N-acylated tyrosine ester of the general formula

COOR ₂

CH- NH- COR,

I Oj

OH
where Ri is a hydrogen atom, a methyl, trifluoro

methyl-. Phenyl, methoxy, ethoxy, isopropyloxy, sec. Butyloxy, tert-butyloxy or benzyloxy radical and R2 mean a lower alkyl or benzyl radical, in on known way with acyl peroxides in the Moaoacylderivat of L-3,4-dihydroxyphenylalanine transferred, then in a known manner to Diacyl compound acylated, the diacyl compound purified by recrystallization and then in the usual way hydrolyzed to the free L-3,4-dihydroxyphenylalanine

The reaction with benzoyl peroxide is preferably carried out in the presence of organic solvents, such as chloroform, benzene or acetonitrile, at 0 to 100 ° C., especially at the boiling point of the solvent perform. It is therefore advisable to slowly add a solution of the acyl peroxide to a solution or suspension of the N-acyl-L-tyrosine ester and, at the same time, to continuously distill off the added solvent. The addition of complexes and salts such as Cr (III) - or Fe (IH) acetylacetonate, or a mixture of CuCl and CuCl ₂ can favorably influence the reaction. When the reaction is carried out in the presence of copper chlorides, the reaction temperature can be reduced to 0 to 30.degree. The yields are around 50 to 70% of theory.

It is already known that p-cresol with Reacting benzoyl peroxide to 4-methylpyrocatechol (J. Chem. Soc. 1949, pages 3189 to 3194). Man but could not expect the sensitive derivatives of L-tyrosine to react just as smoothly would like the permanent p-cresol, especially not because the analogous phenylalanine derivative with Benzoyl peroxide makes up a whole range of products

Representation of the N-acylated tyrosine esters

92.4 g of L-tyrosine methyl ester hydrochloride, 21.4 g of anhydrous sodium carbonate, 100 ml of water and 800 ml of chloroform are rapidly cooled to 0 ° C. with vigorous stirring. 64 ml of carbobenzoxychloride and a solution of 31.8 g of anhydrous sodium carbonate in 50 ml of water are then simultaneously added dropwise with vigorous stirring so that the internal temperature does not rise above + 3 ° C. When the dropwise addition has ended, the cooling is removed and the mixture is stirred for a further 2 hours at room temperature. 100 ml of water are added and the organic phase is separated off, washed with 50 ml of water, dried, filtered and concentrated in vacuo. The remaining oil is then dried to constant weight using the oil pump. The crystalline residue is recrystallized from chloroform-hexane to give 109 g = 82.5% of N-carbobenzoxy-tyrosine-methylester of melting point: 88 ⁰ C; [<%] _D = 33.4 ° (c = 1 in dimethylformamide).

92.4 g (0.4 mol) of L-tyrosine methyl ester hydrochloride, 21.4 g of anhydrous sodium carbonate, 100 ml of water and 800 ml of chloroform are rapidly cooled to 0 ° C and immediately, with vigorous stirring, 52.2 ml (0, 45 mol) of benzoyl chloride and 31.8 g of anhydrous sodium carbonate (0.3 mol) in 50 ml of water were ^{added dropwise at the same time at an internal temperature of 0 to +5 0} C within 30 minutes. The colorless N-benzoyl-L-tyrosine methyl ester precipitates out. Then 90 minutes at +24 ⁰ C is stirred to be evaporated 200 π 11 chloroform in vacuo. The precipitated colorless substance is filtered off and carefully with a lot Washed with water and dried in vacuo. Approx. 115 to 116 g of N-benzoyl-L-tyrosine methyl ester with a melting point of 151 to 153 ° C. are obtained Recrystallize well from methanol or ethanol.

In the representation of the other N-acyl derivatives you can also use the suspended L-tyrosine methyl ester hydrochloride with one equivalent of triethvlamin in Convert methylene chloride in the cold into the free amino ester and then with the acid anhydride or in the case of the formyl compound with the mixed anhydride of formic and acetic acid in convert the cold, the N-acyl-L-tyrosine methyl ester formed in yields between 80 and 90% will.

example 1

3.29 g (0.01 mol) of N-carbobenzoxy-L-tyrosine methyl ester and 10 mg of Cr (IJI) acetylacetonate in 6 ml of abs. Chloroform was added with 2.42 g (0.01 mol) of benzoyl per oxide (recrystallized from methanol-chloroform) 24 Stirred for hours at 70 ° C., then 2 g calcium carbonate (finely powdered) was added and the mixture was stirred at 70 ° C. for a further 24 hours. After filtration and evaporation, the mixture was stirred the residue (4.039 g) in 100 ml of abs. Pyridine dissolved, with Cooled ice and 1.24 ml (lOmMol) of benzoyl chloride were added dropwise within 20 minutes, stirred for 36 hours at 24 ⁰ C and evaporated several times the pyridine with xylene at 30 to 40 ° C / 10 mm Hg The residue was dissolved in chloroform washed successively with Natriumhydrogencar-

jo bonate solution and ice, 2 N sulfuric acid and saturated Washed sodium chloride solution, dried over magnesium sulfate and evaporated. The residue (5.095 g) became from abs. Ether recrystallized by cooling to -20 ° C and gave 3.02 g of L-N-carbobenz

j5 oxy-S ^ -dibenzoyloxy-phenylalanine methyl ester of melting point 109 to 111 ° C. The mother liquor was chromatographed in toluene on 60 g SiO _2. Elution with toluene / ethyl acetate (9: 1) (600 ml) yielded 300 mg of substance, and a further 300 mg of N-Carbo from methanol benzoxydibenzoate resulted. Total yield = 332 g. For analysis, it was recrystallized from ether. Melting point: 109 to Hl ⁰ C; [<%] _D = + 33.8 ° (c = \ in chloroform)

Example 2

29.92 g (0.1 Mo!) Of N-benzoyl-L-tyrosine methyl ester were in 20 ml of abs. Suspended chloroform and at 85 ° C bath temperature with stirring 24.2 g (0.1 mol) Benzoyl peroxide (recrystallized from methanol-chloroform siert) in 75 ml of chloroform within 6.5 hours with simultaneous distilling off of the added solvent was added dropwise Stirred for hours at a bath temperature of 70 ° C., a clear brown solution being formed. The thin layer chroma togram (SiO ₂ , upper phase from toluene to acetic acid: H ₂ O = 5: 5: 1) then showed only traces of starting material.

The reaction mixture was diluted with 300 ml of chloroform and treated with 300 ml of ice-cold sodium hydrogen car-

bo bonat solution washed. The chloroform solution (about 500ml) was then nac ¹ Schotten-Baumann with 40 ml of water and 6.24 g (0.06 mmol) of anhydrous sodium carbonate are added, cooled with ice and 11.62 ml (0.1 mmol) of benzoyl chloride in 50 ml of chloroform under

μ vigorous stirring within 30 minutes at 0 to 5 ° C Internal temperature added dropwise. The mixture was then stirred at 24 ° C. for 20 hours, and the aqueous phase was separated off and washed twice with 100 ml of chloroform each time.

The combined chloroform phases were again with 300 ml of ice-cold sodium hydrogen carbonate solution washed, dried over sodium sulfate and gave, after evaporation, 56.1 g of a brown, viscous oil, which was removed 300 ml of methanol 23.6 g of pure L-N-benzoyl-3,4-dibenzoyloxy-phenylalanine methyl ester with a melting point 163-165 ° C. The brown mother liquor was evaporated with benzene and dissolved in methylene chloride over 600 g AI2O3 (A III, Woelm neutral) filtered to the polar To remove impurities.

The 2 l eluate were evaporated and the residue was recrystallized from methanol to give a further 5.2 g. For analysis, it was recrystallized from methanol. Melting point :! 63 to 165 ° C; [<k] d = +102 " (c = 1 in chloroform).

You can also extract the crude product hot with isopropanol before the Schotten-Baumann reaction, to remove polar products. After the isopropanol filtrate has evaporated, it is taken up in chloroform and benzoylated as described by Schotten-Baumann and continued working in this way the filtration of the mother liquor over aluminum oxide is superfluous.

535 g (0.01 mol) of N-benzyl-LO ^ -dibenzoyloxy-phenylalanine methyl ester in 150 ml of methanol, 150 ml of conc. Hydrochloric acid and 25 ml of water were refluxed for 32 hours and the solvents were evaporated. The residue was suspended in 40 ml of water, extracted 3 times with 20 ml of chloroform each time, the aqueous phase was cooled to 0 ° C. and treated dropwise with 10% under nitrogen and with vigorous stirring. mixed with pure NH4OH. At pH = 2.7, colorless L-dopa begins to precipitate. Further ammonia was added until pH = 3.5. The crystals were filtered off, washed with a little cold water, ethanol and ether and _{dried in vacuo (0.01 mm) over P 2} O _5. 1.79 g of colorless L-Dopa vom Melting point 278 ° C. (with decomposition) [ä] d = 10.1 ° (c = 1 in 1 nHCl).

The hydrolysis of the N-carbobenzoxydibenzoyl compound according to Example 1 was carried out analogously with the same yields

Claims (1)

Patent claims: 1. Process for the preparation of L-3,4-dihydroxyphenylalanine from tyrosine, characterized in that an L-N-acylated tyrosine ester the general formula COOR ₁