DE1593989C - Process for the preparation of the optical antipodes of the alpha methyl beta (3,4 dihydroxyphenyl) alanms - Google Patents

Description

The invention relates to a method of manufacture the optical antipodes of a-methyl- / i- (3,4-dihydroxyphenyl) -alanine by seeding a saturated solution of the racemate of an N-acyl-a-methyl - /? - (3,4-oxysubstituted-phenyl) -alanine with crystals of the corresponding I or D compound, separation of the selectively crystallizing optical antipode and subsequent hydrolysis in the presence of a phenol.

Both the L compound obtainable in this way and the D isomer obtainable in this way are valuable Products, of which the first is known under the name "L-methyldopa".

There are already three known methods with the help of which it is possible to produce "L-methyldopa":

1. The D- and L-salts of DL-N-acetyl-a-methyl-, ö- (3,4-dimethoxyphenyl) -alanine and l - (-) - a-Phenylethylamine are produced and the L-SaIz is made taking advantage of the different solubilities in a given solvent separated from the D salt; the L-salt is called L-N-acetyl-a-methyl - /? - (3,4-dimethoxyphenyl) -alain released and then hydrolyzed, "L-methyldopa" is obtained [cf. "Journal of Organic Chemistry ", 29, 2053 (1964)].

2. dl-α-methyl- β - (3,4-dihydroxyphenyl) -alanine is directly optically broken down to form “L-methyldopa” (cf. US Pat. No. 3,158,648).

3. DL-α-acetamide-α-vanillylpropionitrile is used directly optically broken down to form l - (-) - a-acetamide-a-vanillylpropionitrile, which is hydrolyzed to form "L-methyldopa" (see Japanese patent specification 482 080).

However, these known methods have various disadvantages when they are used for industrial production of "L-methyldopa" can be used. For example, in method 1, the l - (-) - a-Phenylethylamine can be separately synthesized and it is relatively expensive. Also is it is fluid and therefore difficult to separate. In procedure 2, the D-methyldopa should be useful can be reused in a complex process after reduction to DL-methyldopa. at

For method 3, the starting material must be dla-acetamide-a-vanillylpropionitrile can be synthesized from the relatively expensive and difficult to access vanillin. In addition, the last said compound only has a low supersaturation capacity, so that the amount of crystallizing per approach optical isomers extraordinary. is low.

The aim of the invention is now to provide an economical and technically simple method of production the optical antipodes of a-methyl - /? - (3,4-dihydroxyphenyl) -alanine to be indicated by direct optical separation.

It has now been found, surprisingly, that this goal can be achieved by one of a certain DL-N-acyl-a-methyl- / S (3,4-oxysubstituted-phenyl) -alanine goes out and this through selective crystallization in the corresponding optical Antipodes separates.

The process of the type described above which forms the subject of the present invention is characterized in that the racemic mixture DL-N-formyl-α-methyl- / S- (3,4-methyldioxy- C ~ \ phenylalanine or DL-N -Acetyl-a-methyl - /? - (3,4-methylenedioxyphenyl) -alanine, which are hereinafter referred to as "DL-acylalanine".

In the case of the DL-formylalanine used according to the invention or DL-acetyl-alanine are new compounds that are carried out in a manner known per se Formylation or acetylation of DL-alanine can be produced. Then the The resulting racemic mixture produces a supersaturated solution, and this is seeded with crystals one of the two optical isomers (the L- or D-form) is seeded, whereupon the seed crystal corresponding optical isomers selectively crystallized out.

The remaining mother liquor is made by adding another amount of the »DL-acylalanine« again supersaturated and then inoculated with the other optical isomer (the D- or L-form), again, the optically active form corresponding to the seed crystal is selectively obtained.

Be 'as prepared so that eventually the "DL-acylalanine" inserted into the corresponding L- and D-forms is broken - By repeating this process can off r ~ - changing the optical isomers both batch ^. If the L-form (or the D-form) obtained in this way is hydrolyzed in the presence of a phenol with hydrohalic acid in the usual way, the desired "L-methyldopa" is obtained in high yield.

It was now extremely surprising that DL-N-formyl- or DL-N-acetyl-a-methyl - /? - (3,4-methylenedioxyphenyl) -alanine in this simple and effective way by selective crystallization directly can be broken down into the optical antipodes. This was particularly surprising because it was previously not possible to break down compounds into their optical antipodes by selective crystallization, which are structurally very close to the alanine used according to the invention, such as. B. DL-N-Acetyla-methyl- / i (3,4-dimethoxyphenyl) -alanine, Di.-N-Acetyl-ri-methyl- / y- (3-methoxy-4-hydroxyphenyl) -alanine, DL- N-acetyl - «- methyl- / i- (3,4-diacetoxyphenyl) -alanine and -di.-N-acetyl- β - (3,4-methylenedioxyphenyl) -alanine. From the comparison of structurally closely related ones given in the following table

Compounds with the compound used according to the invention (compound no. 9) goes in particular shows that with regard to the decomposability into the optical antipodes by selective crystallization as well if there is a very close structural relationship, there are no 5 fixed rules.

So are z. B. Compounds No. 1, 2, 3 and 9 of the table below by selective crystallization can be dismantled directly in their optical antipodes, while the remaining compounds of the following Table cannot be dismantled despite their close structural relationship. A comparison of the connections No. 1 with No. 10, No. 2 with No. 4, No. 2 with No. 5, No. 2 with No. 11 shows that even compounds that differ only slightly with regard to the position of the substituents or with regard to the substituents themselves differ from each other, in terms of their optical decomposability through selective crystallization are different from each other. This is also shown by the comparison of the compound used according to the invention No. 9 with compounds No. 5, 6, 7 and 8 as well as with compounds No. 13 and 14, which are structurally extremely close and yet with regard to their optical dismantling by selective Crystallization are fundamentally different from one another.

structure

Optical decomposition by
selective crystallization

^H0

CH ₃

CH ₂ CCOOH

NH ₂

Can be dismantled

HO

CH ₂ CCN

NHCOCH,

\ / - CH ₂ CHCOOH · ammonium salt

Can be dismantled

Can be dismantled

H, C

NHCOCH ₃

CH ₃

CH ₂ CCOOH

NHCOCH ₃

CH ₃

CH ₂ CCN

NHCOCH, cannot be dismantled

Cannot be dismantled

Cannot be dismantled

H, C

CH ₇ CHCOOH

NHCOCH ₃ Cannot be dismantled

continuation

Structure Optical decomposition through selective crystallization

H ₇ C

H ₂ C

O O

CH ₃

CH ₂ CCOOH · ammonium salt NHCOCH ₃

CH ₃ CH ₉ CCOOH

OH

NHCOCH,

CH,

CHXCOOH

OH
OCH,

NH ₇

CH ₃

CH ₂ CCN

NHCOCH,

OCH,

H ₂
C.

O O

CH,

\ / = CH ₂ CCOOH · ammonium salt

H ₂

NHCOCH ₃

H ₇ C

H ₇ C

O O

/ N

CH ₃ ^ -CH ₂ CCOOH

NHCOCH ₃

CH ₃ CH ₂ CCOOH

NHCOCH ₂ CH ₃

CH ₃

CH ₂ CCOOH NHCO Cannot be dismantled

Can be dismantled

Cannot be dismantled

Cannot be dismantled

Cannot be dismantled

Cannot be dismantled. Cannot be dismantled. Cannot be dismantled

When carrying out the process according to the invention, the first stage of the process, i. H. the Formylation or acetylation (summarized below under the term "acylation") in an carried out in a known manner. The term "acyl" used here stands for formyl and and acetyl.

When introducing the acetyl group into the dl-alanine, the acetylation can preferably be carried out by Reaction of the DL-alanine with the anhydride or halide, preferably the chloride, of acetic acid in the presence of a basic substance and a suitable inert organic solvent, such as Benzene, toluene, acetic acid and water.

Representative examples of basic substances that can be used for this step are organic basic compounds such as pyridine, pico-Hn and dimethylaniline, as well as inorganic substances, such as sodium and potassium hydroxide. As the organic basic substance both as a solvent as well as acting as an acid-binding agent, such substances can be used in an excess to be used compared to that amount which is required as an acid-binding agent. the additional use of the solvents indicated above is then not necessary.

The reaction temperature in this stage depends mainly on the basic substance used. Generally one can say that the preferred reaction temperature is between about 80 and 13O ⁰ C, when an organic basic substance is applied. In the case of using an inorganic basic substance, the preferred reaction temperature is about 0 to 50 ° C.

The formylation in this stage can be carried out, for example, by using a mixture of formic acid and acetic anhydride as a formylating agent.

After completion of the reaction, the desired product at this stage, i.e. H. "DL-acylalanine", can be obtained from the reaction mixture by methods known per se. For example the solvent is removed by distillation under reduced pressure and the residue becomes treated with a dilute acid to remove excess basic substances, whereby the desired "DL-acylalanine" is obtained.

To carry out the second step, i. H. the decomposition stage, the solvent to be used are those that form supersaturated solutions of "dl-acylalanine". Examples are organic Solvents such as aliphatic alcohols e.g. B. methanol, ethanol and isopropanol; lower alkyl ketones, z. B. acetone and methyl ethyl ketone; aliphatic lower alkyl esters, e.g. B. ethyl acetate and isobutyl acetate, as well as mixtures thereof. Aqueous solutions thereof can also be used. Preferred solvents are aliphatic alcohols, especially methanol, 95% ethanol and isopropanol.

Various methods can be used for supersaturation with "DL-acylalanine". Examples this involves concentrating, cooling and varying the composition of the solvent used, to dissolve the "DL-acylalanine". A preferred method of performing the method According to the invention, a solution of the "DL-acylalanine" is heated or heated is used to make a saturated solution, which is then cooled to form a supersaturated solution will. In order to separate the optical isomer from this supersaturated solution, the above-mentioned can be used Batch processes are used. However, the optical isomer can also be continuous Process can be obtained which is carried out in such a way that the supersaturated solution is passed through a fixed bed, which the

ι ο contains optical isomers, creating a continuous optical decomposition and crystallization is achieved.

The amount of the crystallized optical isomer

varies depending on the degree of supersaturation of the solution. The higher the degree of supersaturation is, the greater the amount of optical isomer crystallized out per batch. The amount of However, optical isomers crystallized per batch has a certain limit, since they are within one such a stable range is limited in which the supersaturated state of one optical isomer, that after the crystallization of the other optical. Isomer remains in solution in sufficient quantity Way can be sustained.

The degree of supersaturation of a supersaturated solution, which is prepared from a saturated solution, which is optimal for the decomposition and crystallization, depends ... on the solubility curve of the saturated solution mentioned. For example, in the case of a solution in an aliphatic alcohol such as methanol, the solubility curve of "DL-acylalanine" is steep. Therefore, the degree of supersaturation is about 2 to 5 g / 100 ml at 3O ⁰ C. In the case of the solution in a lower alkyl ketone, however, the curve is excessively increasing and therefore, the supersaturation degree is about 0.2 to 1.0 g / 100 ml at 30 ⁰ C.

The temperature used in this step to produce a supersaturated solution of "DL-acylalanine" by cooling varies more or less depending on the type of used Solvent. It is usually in the range of about 5 to 40 ° C. The temperature should, however, be more suitable Can be selected in a manner such that a stable supersaturated state can be obtained. in the otherwise, the temperature at the time of decomposition and crystallization is not particularly limited regardless of whether the production is batch or continuous. In however, in practice it is desirable to carry out the crystallization separation operation at or below room temperature to be carried out, with a view to economic efficiency and process implementation, to avoid loss of solvent by filtering the crystals. Incidentally, it is general known fact that the amount of crystallized optical isomer also depends on the size of the seed crystals, the stirring of the solution and the crystallization time is influenced. Even if the selective crystallization under strictly controlled conditions with regard to the degree of supersaturation and Amount of crystallization has been carried out, the obtained crystals are not always optically pure. However, the purpose of the disassembly itself can be sufficiently achieved provided that it is not excessive Crystallization occurs. In practice it is not objectionable if the crystals obtained are visually impure. Such crystals can easily be made optically pure by washing or by recrystallization using a

309 625/214

Solvent in an amount that is sufficient to dissolve the »DL-acylalanine« it contains.

Then the third step, i.e. H. the hydrolysis for deacylation and entälkylation des L-acylalanine thus obtained, by conventional methods accomplished. For example, this can be done according to a method in which the connection is through Treatment with hydrohalic acid in the presence of a phenol or any other Process is deacylated by deacylating the compound with dilute acid or dilute alkali and then dealkylated by treatment with hydrohalic acid in the presence of a phenol will.

So the L-N-acylalanine will either work for you Period of several hours or several tens of hours to complete the hydrolysis with an aqueous hydrochloric acid solution (18 to 22% solution) or with an aqueous solution of hydrobromic acid (18 to 48% solution) in the presence of a phenol, or it is for several hours to several 10 hours together with a dilute mineral acid, such as dilute hydrochloric acid or sulfuric acid (2 to 10% solution), or with a dilute Alkali, such as dilute sodium, potassium or barium hydroxide (2 to 10% solution) under reflux heated. The reaction mixture is then treated with aqueous ammonia or sodium hydroxide, or neutralized with an acid such as hydrochloric or sulfuric acid. Then the neutralized Liquid for several hours to several tens of hours with an aqueous hydrochloric acid solution (18 to 22% solution) or with an aqueous solution of hydrobromic acid (18 to 45% Solution), treated in the presence of a phenol.

The "hydrolysis step described above is carried out in the presence of a phenol, such as phenol or cresol, carried out because the formation of by-products is prevented by such a phenol and that desired "L-methyldopa" or the D-form can be obtained in high yields. The molar The ratio of the L-optical or D-optical isomer to the phenol is usually in the range of not less than 1, and preferably from about 1.5 to 6..

After the hydrolysis has ended, the "L-methyldopa" or the D-isomer formed is removed from the reaction mixture obtained by conventional methods. For example, the reaction mixture is under reduced Pressure distilled to remove excess phenol and hydrochloric acid. The residue is taken up in water and an aliphatic lower alkyl ester such as ethyl acetate or isobutyl acetate, the mixture being stirred to dissolve the residue. Then the aqueous Layer separated and neutralized, whereby L-methyldopa is deposited as a crude product; this will then recrystallized from water to form pure "L-methyldopa". .

As stated above, according to the method of the invention, "L-methyldopa" can be produced by direct optical Decomposition through the advantageous selective crystallization of the »DL-acylalanine« obtained from DL-alanine getting produced. Accordingly, the method of the invention is a remarkably good practice for the technical production of »L-methyldopa«.

The process of the invention is explained in more detail with reference to the following examples.

example 1
a) Production of the starting material

α) 22.3 g of OL- α-methyl- β - (3,4-methyldendioxyphenyl) -alanine were dissolved in 100 ml of glacial acetic acid and 32 g of acetic anhydride. The resulting solution was gradually heated with stirring for 5 hours. After the completion of the reaction, excess acetic acid was removed by distillation under reduced pressure. The residue was treated with 200 ml of water, 25.7 g of crude DL-N-acetyl-a - methyl - β - (3,4 - methylenedioxyphenyl) - were collected alanine. Recrystallization from aqueous methanol gave pure DL-acetylalanine, melting point 160 to 161 ^° C. Elemental analysis gave the following results.

Analysis for C ₁₃ H ₁₅ NO ₅ :

Calculated ... C 58.86, H 5.50, N 5.28%;
found .... C 58.51, H 5.76, N 5.20%.

β) 35.3 g of dl - α - methyl - β - (3,4 - methylenedioxyphenyl) alanine were dissolved in a solution of 7.2 g of sodium hydroxide in 230 ml of water. To the resulting solution, 30 g of acetic anhydride was added dropwise while keeping the temperature below 30 ° C. and the pH in the range of 10 to 11 by adding a 20% aqueous sodium hydroxide solution. After the addition was complete, the resulting mixture was further stirred for 3 hours. After the completion of the reaction, 50 ml of concentrated hydrochloric acid was added to the reaction mixture. The reaction mixture was then left to stand overnight. The crystalline substances which separated out were filtered off, washed with water and dried, 38.6 g of DL-acetylalanine being obtained.

γ) Using the same method as described under ß) , but with the modification that the acetic anhydride was replaced by an equal amount of acetyl chloride, 37.6 g of DL-acetylalanine were obtained. ■ ■

b) Decomposition into the optical antipodes

22 g of the above-prepared DL-N-acetyl-a-methyl- ß - (3,4 - methylene - dioxyphenyl) - alanine (dl - acetylalanine) were stirred at 50 to 6O ⁰ C in 200 ml of methanol to form a clear solution. After cooling to 27 ° C., 1 g of a powder of L-acetylalanine [af = -58 ° (c = 0.5, methanol), melting point 211 to .215 ° C.] was added to the solution. It was gently stirred at this temperature for 10 minutes. The deposited crystals were filtered off, washed with cold methanol and then dried, whereby 1.5 g of crude L-acetylalanine, melting point 210 ° to 215 ° C., r = -56.0 ° (c = 0.5, methanol) were obtained became. Accordingly, the amount of L-acetylalanine crystallized was 0.5 g.

Example 2

20 g of the DL-acetylalanine obtained in Example 1 were dissolved in 200 ml of methanol ^{at 50 to 60 ° C. with stirring, a clear solution being obtained}

would. The solution was then gradually cooled while stirring. When the temperature reached 37 ° C, the solution containing 1 g of powdered D-acetylalanine was [af = + 58.0 ° (c = 1, methanol), mp. 211 to 215 ⁰ C] vaccinated. The solution was cooled to 25 ° C. over a period of 30 minutes and then gently stirred at this temperature for a further period of 60 minutes to cause sufficient crystallization. The crystals obtained were filtered off, washed with 3 ml of cold methanol and then dried, a total of 3.1 g of crude D-acetylalanine, melting point 210 to 215 ° C., ar = + 58.0 ° (c = 0.5 , Methanol), optical purity 99 to 100%. To the-

correspondingly, the amount of crude D-acetylalanine which had crystallized out was 2.1 g.

The mother liquor (together with the washing liquid) was then mixed with 2 g of DL-acetylalanine and, after repeating the procedure described above, inoculated with 1 g of L-acetylalanine, with 2.8 g of crude L-acetylalanine, melting point 210 ° to 215 ° C. al ⁶⁰ = -56.0 ° (c = 0.5, methanol). The amount crystallized out was therefore 1.8 g. The optical purity was 97%.

Then D- and L-acetylalanine were alternately crystallized, with those in the following Results shown in the table were obtained:

Amount of Amount of Seed crystal quantity Crystallized α ο
(c = 0.5, methanol) Fp. No. additional
DL-acetylalanine Mother liquor *) (G) crowd ( ⁰ C) (G) (G) D 1.0 (G) + 55.0 ° 210 to 215 1 3.0 175 L 1.0 2.4 - 54.0 ° 209 to 214 2 3.0 174 D 1.0 2.5 + 55.0 ° 210 to 215 3 3.0 176 L 1.0 3.5 - 55.0 ° 210 to 215 4th 3.0 174 D 1.0 3.5 + 55.2 ° 210 to 215 5 3.0 172 L 1.0 3.0 - 55.0 ° 210 to 215 6th 3.0 173 D 1.0 2.9 + 56.0 ° 210 to 215 7th 3.0 175 L 1.0 2.8 - 56.8 ° 210 to 215 8th 3.0 170 2.9

*) The amount of mother liquor also includes the amount of washing liquid.

6 g of the above-obtained L-acetylalanine was mixed with 54 g of 47% hydrobromic acid and 10.8 g of phenol. The mixture was 3 hours heated under reflux for a long time. After the completion of the reaction, excess hydrobromic acid became and phenol distilled off under reduced pressure. The residue was dissolved in 20 ml of water at 4 ° and 30 ml of ethyl acetate were dissolved, the aqueous layer was separated and collected. After decolorization the aqueous layer was treated with 10% aqueous ammonia containing a small amount of sodium bisulfite contained, neutralized up to pH 5.5.

After the neutralized aqueous layer was allowed to stand at 10 ° C overnight, the precipitated crystals were ge by _filtration: gained and washed with ice-water to give 4.0 g were obtained. The product was pure L-methyldopa-sesquihydrate, aT = - 14.0 ° (c = 1, phosphoric acid buffer solution of pH 6.5). The hydrate obtained in this way was recrystallized from ten times the amount of water containing a small amount of sodium bisulfite, giving pure L-methyldopa-sesquihydrate, af ° = - 14.0 ° (c = 1, phosphoric acid buffer solution of pH 6.5) .

Example 3

Direct optical decomposition was carried out in the same manner as in Example 2, wherein this time 250 ml of isopropanol were used in place of the methanol and 10 g of DL-acetylalanine were dissolved. The results given in the table below were obtained:

No. Amount of
additional
DL-Acety! Alanine Amount of
Mother liquor Seed crystal quantity Crystallized
crowd (c = 0.5, methanol) Fp. (G) (G) (G) (G) ⁰ C 1 202 D 1.0 0.8 + 56.0 210 to 215 2 1.0 196 L 1.0 1.5 - 56.0 210 to 215 3 1.5 203 D 1.0 1.5 + 56.5 210 to 215 4th 1.5 200 L 1.0 1.4 -55.0 210 to 215 5 1.5 198 D 1.0 '1.5 + 56.5 210 to 215 6th 1.5 196 L 1.0 1.5 - 56.3 210 to 215

3 g of the above-obtained L-acetylalanine were subjected to the same operations as in Example 2 with 65

25 ml of 20% hydrochloric acid and 6 g of phenol mixed, carried out, with 2.1 g of the sesquihydrate of

and the mixture was stirred for 15 hours under raw "i.-Methyldopa", ";'i' ° = - 14.1 ° (c = 1, Phos-

Heated to reflux. After completion of the reaction, phosphoric acid buffer solution of pH 6.5) was obtained.

Example 4

11.15 g of a -methyl- β- (3,4-methylenedioxyphenyl) -alanine were dissolved in 12.3 g of acetic anhydride and 46 g of 99% strength formic acid. The resulting solution was stirred at room temperature overnight. After the completion of the reaction, excess formic acid was removed by distillation under reduced pressure. 100 ml of water were added to the residue. The crystallized DL-N-formyla-methyl-ß- (3,4-methylenedioxyphenyl) -alanine was filtered off, washed with water and dried; 10.8 g of crude DL-formylalanine were obtained. Recrystallization from aqueous methanol gave pure DL-formylalanine, melting point 160 to 161 ° C. Elemental analysis gave the following results:

Analysis for C ₁₂ H ₁₃ NO ₅ :

Calculated ... C 57.37, H 5.22, N 5.58%;

found .... C 57.10, H 5.01, N 6.00%.

20 g of DL-N-formyl-a-methyl - /? - (3,4-methylene-dioxyphenyl) alanine (DL-Formylalanin) were dissolved with stirring at 50 to 70 ⁰ C in 200 ml of ethyl acetate to form a clear solution . After cooling to 30 ° C., the solution was inoculated with 1 g of a powder of L-formylalanine [α2Γ = + 38.0 ° (c = 0.5, methanol), melting point 175 to 177 ° C.]. It was then cooled to 10 ° C. over a period of 30 minutes. Stirring was continued for a further 60 minutes, being kept at 2O ⁰ C.

The deposited crystals were filtered, washed with 3 ml of cold ethyl acetate and then dried, whereby a total of 2.5 g of crude L-formylalanine, melting point 174 to 175 ° C., _a f ° = + 37.5 ° (c = 0.5 , Methanol). Accordingly, the amount of L-formylalanine crystallized out was 1.5 g.

·.,. ■: '... B e i s ρ i e 1 5

20 g of DL-Formylalanin were dissolved under stirring at about 50 ⁰ C in 150 ml acetone to form a clear solution. After cooling to 30 ° C., the solution was inoculated with 1 g of a powder of D-formylalanine [al, ⁰⁰ = -37.1 ° (c = 0.5, methanol), melting point 175 to 177 ° C.]. The solution was cooled to 10 ° C. over a period of 30 minutes with gentle stirring. While maintaining at 20 ° C., stirring was continued for an additional 60 minutes. The deposited crystals were filtered, washed with 3 ml of cold acetone and dried, a total of 2.3 coarse D-formylalanine, melting point 171 to 173 ° C, af ° = -37.0 ° (c = 0.5, methanol) , were obtained. Accordingly, the amount of D-formylalanine crystallized out was 1.3 g.

Further DL-formylalanine was found in the remaining mother liquors (including the washing liquid) solved. The resulting solution was treated in the same manner as above, alternately D- and L-formylalanine were obtained. The results obtained are in the following table reproduced:

No. Amount of
additional
DL-formylalanine
(G) Amount of
Mother liquor
(G) Type and amount of
Vaccine formylalanine
(G) Amount of
crystallized
Formylalanine
(G) α?
(c = 0.5, MeOH) Fp.
( ⁰ C) 1
2
3
4th
5
6th 1.5
2.0
2.0
1.8
2.0
1.8 135
140
135
130
135
131 L 1.0
D 1.0
L 1.0
D 1.0
L 1.0
D 1.0 1.2
1.5
1.8
1.8
1.8
1.7 + 37.0
- 36.5
+ 37.0
- 37.5
+ 36.5
-36.5 171 to 173
170 to 173
171 to 173
174 to 176
171 to 174
170 to 173

3 g of the L-formylalanine obtained in Example 4 were mixed with 25 ml of 20% strength hydrochloric acid and 6 g of phenol. The resulting mixture was refluxed for 15 hours. After the reaction had ended, the reaction mixture obtained was worked up in the same way as described in Example 3, with 2.2 g of crude L-methyldopa-sesquihydrate, a ^! g = - 14.0 ° (c = 1, phosphoric acid buffer solution of pH 6.5).

Claims (1)

Claim: Process for the preparation of the optical antipodes of α- methyl - /? - (3,4-dihydroxyphenyl) -alanine by seeding a saturated solution of the racemate of an N-acyl-α-methyl- / 5- (3,4-oxysubstituted-phenyl) ) -alanins' with crystals of the corresponding L or D compound, separation of the selectively crystallizing optical anti- ίο pods and subsequent hydrolysis in the presence of a phenol, characterized in that the racemic mixture DL-N-formyl - α - methyl -β- (3,4 - methylenedioxyphenyl) - alanine or dl - N - acetyl - α - methyl - /? - (3,4-methylenedioxyphenyl) alanine is used.