DE2406898C2 - Process for the recovery of L-α-methyl-DOPA - Google Patents

Description

The invention relates to a process for the production of L-öc-methyl-DOPA, in which the racemate separation with quinine at the level of D, L-N-formyl - «- methyl-j3- (3,4-dimethoxyphenyl) -alanine is carried out.

Racemate separations of intermediates for the production of α-methyl-DOPA are known and are used in the production of a-methyl-DOPA on various Synthesis stages have been carried out. For example, Tristram et al., J. org. Chem. 29, 2053 (1964), the resolution of N-acetyl-oc-methyl-j? - (3,4-dimethoxyphenyl) -alanine with (-) - 1-phenylethylamine or Reinhold et al., J. org. Chem. 33, 1209 (1968), the resolution of the racemate at the stage of the -aminonitrile compound with champhersulfonic acid. In all cases must, however, in order to obtain products with high optical purity, repeated recrystallization, what so results in a sharp decrease in the yield.

The subject matter of the invention is defined in the claims.

D, L-N-Formyl- <x-methyl-ß- (3,4-dimethoxyphenyI) -alanine, which has not yet been described is surprisingly extremely suitable for a technical one Process for resolution with quinine. The diastereomeric salt of L (+) -N-formyl- <x-methyl-j9- (3,4-dimethoxyphenyl) -alanine and quinine is obtained in pure form in an almost quantitative yield, without it being caused by & o needs further recrystallization to be purified. From this the L (+) -N-formyl-iX-methyl-j9- (3,4-dimethoxyphenyl) -alanine can be obtained can be obtained with a yield of over 90% in high optical purity, which is then without difficulty to L - «- methyl-DOPA = 5 can hydrolyze.

D, L-N-Formyl-a-methyl - /? - (3,4-dimethoxyphenyl) -alanine is an easily accessible connection. You can, for example, under the DE-OS 20 28 015 or DE-OS 20 63 502 specified conditions can be obtained.

The resolution of the racemate according to the invention is carried out in lower alcohols, e.g. B. methanol, ethanol or Isopropanol, or ketones, ζ. Β. Acetone

It is advantageous to use solutions that are not too dilute if possible. For example, are expedient 10 to 25 percent by weight solutions of D, L-N-Formyl-a-methyl - /? - (3,4-dimethoxyphenyl) -alanine and 20 to 50 weight percent solutions of quinine. If necessary, a concentrated as possible Solution of D, L-N-Formyl - «- methy '-) 5- (3,4-dimethoxyphenyl) -alanine be prepared at higher temperatures up to the boiling point of the solvent used.

The particularly preferred solvent! is methanol, when using quinine as the cleavage reagent, a surprisingly large difference in the Solubilities of the diastereomeric quinine salts. While the L-SaIz is less than 1 percent by weight is soluble in methanol in the cold, the D-salt mixes with the in practically every proportion Solvent. Even with other optically active bases, such as brucine, cinchonidine, 1-phenylethylamine, they can be used In no case similarly good racemate separations in methanol or in the other solvents mentioned reach. Another advantage of the N-formyl-a-methyl - /? - (3,4-dimethoxyphenyl) -alanine used is that there is practically no loss due to premature hydrolysis during work-up develop.

As a rule, one proceeds in such a way that one adds to the solution of D, L-N-formyl - «- methyl-j? - (3,4-dimethoxyphenyl) -alanine, optionally at the boiling point, the solution of quinine, usually in the same solvent, is added dropwise and with stirring and standing for several hours, optionally with ice-cooling, the diastereomeric Salt of L (+) -N-formyl - «- methyl - /} - (3,4-cJimethoxyphenyl) -alanine and quinine crystallizes out.

The quinine is expediently used in an equivalent amount or in an excess of up to 10%.

In a particularly noteworthy embodiment, you can resolve the racemate with a half Perform equivalent quinine, approximately in the ratio 1: 0.5 up to 0.6. The poorly soluble crystallizes in the process diastereomeric salt is made up of the L-form and quinine and the D-alanine compound remains in solution.

In this procedure, the addition of a tertiary amine, such as triethylamine, proves to be advantageous as an auxiliary base, which serves to neutralize the remaining alanine and is useful in the calculated equivalent amount is added.

The crystallized diastereomer salt is in the Usually vacuumed with the solvent used! washed and used for the cleavage and recovery of the Quinine dissolved in water and made alkaline with aqueous alkali, especially sodium hydroxide. Afterward the separated quinine is advantageous with an organic solvent, preferably chloroform, severed. It is advantageous to use the crystalline diastereomer salt initially in a dilute 0.5 to Dissolve in hydrochloric acid and only then to make it alkaline. This addition of acid can cause a partial hydrolysis of L-N-formyl-a-methyl - /? - (3,4-dimethoxyphenyl) -alanine effectively prevented.

After the quinine has been extracted, strong mineral acids, especially concentrated hydrochloric acid, are

re, acidified, and the L (+) -N-formyl-Ä-methyl-j? - (3,4-dimethoxyphenyi) alanine is advantageously left with cooling in an ice bath crystallize.

The optically pure L (+) -N-Formy! -A-methyl-ß- (3,4-dimethoxyphenyl) -alanine obtained then becomes Λ-methyl-DOPA in the usual manner hydrolyzed. Appropriate process conditions are 8 to 15 hours of heating in a boiling 40 to 48 percent by weight hydrobromic acid, which, after hydrolysis is complete, then under reduced m Pressure is distilled off. After recrystallization, z. B. from water, pure α-methyl-DOPA won.

B e i s ρ i e 1 1 r>

N-formyl - «- methyl-j3- (3,4-dimethoxyphenyl) alanine

a) 166 g of veratrumaldehyde are at room temperature In portions into the solution of 127 g -> o a-Isocyanpropionäureäthylester and 2.7 g of sodium methylate registered in 800 ml of dichloromethane. After 1.5 hours of stirring, the organic Phase washed with water. After the solvent has been removed, 287 g remain (97.5% yield): "> 4-methyl-5- (3 ', 4'-dimethoxyphenyl) -2-oxazoline-4-carboxylic acid ethyl ester. The NMR spectrum shows a mixture of the cis-trans isomers, from which the cis isomer has a melting point of 94 ° C by crystallization can be separated from benzene petroleum ether j <>.

CH.N determination Ci ₅ Hi ₉ NO ₅ (293.3)
Ber. C 61.4, H 6.5, N 4.8
Found C 61.2, H 6.4, N 4.5. _j?

b) 147 g of 4-methyl-5- (3 ', 4'-dimethoxyphenyl) -2-oxazoline - ^ -. aibonic acid ethyl ester (cis-trans mixture) "/ earth in 1 l of ethanol with 15 g of palladium (5% on charcoal) hydrogenated for 20 hours at 102 bar hydrogen pressure and 100 ^° C. After suctioning off the contact, the filtrate is treated with a solution of 40 g of potassium hydroxide (85%) in 120 ml of water and left to stand for 15 hours at room temperature The solvent is distilled under reduced pressure, the residue is taken up in 1 l of water and the solution is extracted with chloroform and the aqueous phase is acidified with 70 ml of concentrated hydrochloric acid.After 5 hours of cooling in an ice bath, the crystals are filtered off with suction, washed with a little cold water as and in the High vacuum at 1.3 mbar and 60 ⁰ C dried.

HOg (82% yield) of N-formyl-amethyl-jS- (3,4-dimethoxyphenyl) -alanine is obtained from the

Melting point 169 to 171 ° C. After recrystallization from methanol, melting point 172 to 173 ° C.

C, H, N determination _{Ci 3} H, 7NO5 (267.3)
Ber. C 58.5, H 6.4, N 5.2,
Found C 58.6, H 6.7, N 5.4.

Example 2

N-formyl - «- methyl-j3- (3,4-dimethoxyphenyl) alanine

0.6 1 dry dichloromethane and stir for 1.5 hours at room temperature. The solvent is distilled off and the residue - as described in Example Ib) - saponified. This gives 219 g (82% yield) of N-Formy] - * - methyl - /? - (3,4-dimethoxyphenyl) alanine, melting point 168-170 ⁰ C, according to mixed melting point and comparison of spectra with the product from Ib) are identical.

Example 3

L (+) - N -formyl - «- methyl-j3- (3,4-dimethoxyphenyl) alanine

The solution of 325 g of quinine in 600 ml of methanol is added to the boiling solution of 267 g of D, LN-formyl-a-methyl - /? - (3,4-dimethoxyphenyl) -alanine in 1400 ml of methanol. The mixture is stirred for several hours at room temperature, then for 2 hours in an ice bath, the precipitate is filtered off with suction and washed with cold methanol. After drying at 100 ° C (1.3 mbar) melting point 228 to 229 ^c C.

C, H, N determination _{C33H4iN 3} O ₇ (591.7)

a)

b)

c)

oU Ber.
Found

C 67.0
C 66.9

H 7.0
H 6.8

N 7.1, N 7.5.

The quinine salt is cleaved by introducing it into 800 ml of 0.75 η hydrochloric acid. After adding 300 ml of 4 η sodium hydroxide solution, the quinine is extracted with chloroform. When the aqueous phase is acidified with about 70 ml of concentrated hydrochloric acid, L (+) -N-formyl - «- methyl-jS- (3,4-dimethoxypheny!) - alanine crystallizes out. The mixture is stirred for 2 hours in an ice bath, filtered off with suction, washed with cold water and the crystals are dried at 110 ^° C. (20.0 mbar). One receives 120 g (90% yield), melting point 17Ί to 172 ° C, [<x] ί ° + 34 ° (c = 1 in methanol).
(Values of the product obtained by repeated salt formation and cleavage: melting point 172 to 173 ° C, [a] ² _D ⁰ = + 34.4 °.)

C, H, N determination C ₃ H ₁₇ NO ₅ (267.3) '
Ber. C 58.5, H 6.4, N 5.2,
Found C 58.6, H 6.6, N 5.3.

The quinine used is obtained from the chloroform extract and from the methanolic mother liquor approx. 97% recovered.

8.2 g of quinine (half equivalent), dissolved in 30 ml of methanol, are added to the boiling solution of 13.4 g of D, LN-formyl-ix-methyI-j8- (3,4-dimethoxyphenyl) alanine and 2.5 added g of triethylamine in 70 ml of methanol. The precipitated quinine salt is cleaved as described under a): 5.5 g (82% yield) of LN-formyl - «- methyl-J3 (3,4-dimethoxyphenyl) alanine, melting point 172-173 ⁰ C, [λ] %> + 34.2 ° (c = 1 in methanol).
The same approach as b), but without the addition of triethylamine, gives 5.4 g (80.5% yield)

L-N-FormyI - «- methyl - /? - (3,4-dimethoxy phenylalanine, melting point 172 to 173 ° C, [λ] ^ ⁰ + 34.1 ° (c = 1 in methanol).

Example 4
L (-) -E-methyl - /? - (3,4-dihydroxyphenyl) -alanine

g of sodium methylate are dry in 1 1

Dichloromethane suspended. After adding 127 g The mixture of 267 g L (+) -N-Formyl - «- methyl - /? -

Ethyl isocyanopropionate is added dropwise at +10 ⁰ C (3,4-dimethoxyphenyl) alanine in 2 1 of 48% strength bromine

the solution of 207 g of 3,4-dimethoxybenzyl chloride in hydrogen acid is heated to the boil for 12 hours. the

Hydrobromic acid is then distilled off at 70 ° C. under reduced pressure. The residue is digested in 300 ml of water, the water is distilled off, taken up in 600 ml of water, 0.5 g of sodium pyrosulfite and activated charcoal are added and the solution is filtered. The filtrate is adjusted to pH 6.3 by adding approx. 105 ml of concentrated ammonia solution. It is allowed to crystallize out in an ice bath, the precipitate is filtered off with suction, washed three times with 100 ml of water each time, then with acetone and dried at 60 ° C. (4.0 mbar). This gives 202 g La-methyl-DOPA, melting point 288 to 29o ⁰ C (water content by Karl Fisher 11.1%). Another 10 g are obtained by concentrating the mother liquor. Melting point 288 to 290 ° C. Yield 89.5% of theory. Th.

A sample recrystallized from water melts at 293 ° C., [a] £ "-4.8 ° (c = 2 in 0.1 η HCl).

Claims (4)

Patent claims: 1. Method of Obtaining L-a-Methyl-DOPA by resolution, characterized in that one A) D, LN formyl-a-methyl - /? - (3,4-dimethoxyphenyl) alanine is reacted in lower alcohols or ketones with quinine, the crystalline diastereomers _re L - (+) - N-formyl-ix-rnethyl- 0- (3,4-dimethoxyphenyl) -alanine-quininsaiz separates and in each case in a manner known per se B) the diastereomeric salt obtained in process step A) is broken down into the components and from that obtained in crystalline form L- (+) -N-Formy! - «- methyl- / 3- (3,4-dimethoxyphenyl) -alanine C) splitting off the phenol ether groups and the formyl group in one process stage. 20th 2. The method according to claim 1, characterized in that that one carries out the resolution in methanol. 3. The method according to claim 1, characterized in that the resolution with quinine carries out in a molar ratio of 1 to 0.5 to 0.6. 4. The method according to claim 1, characterized in that the resolution with a half equivalent of quinine in the presence of half an equivalent of triethylamine.