DE1274586B - Process for the preparation of L- (í¬) -ª ‡ -Methyl-ª ‰ - (3, 4-dihydroxyphenyl) -alanine - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

German KL:

Number:
File number:
Registration date:
Display day:

C07c

A61k

12q-34
30 h-2/36

P 12 74 586.7-42 (B 72780)

July 20, 1963

August 8, 1968

The a-methyl - /? - (3,4-dihydroxyphenyl) -alanine, the also known as "a-methyl-DOPA" has recently gained special importance as an antihypertensive agent, but only the l - (-) - connection is blood pressure active.

The present invention relates to a new process for the preparation of l - (-) - a-methyl- / S- (3,4-dihydroxyphenyl) alanine, which due to its simple and economic feasibility ■ - especially with regard to the extraction on a technical scale - is superior to the known display methods. It is special to emphasize that the entire process of the method according to the invention practically in one Corridor, d. H. can be carried out without purifying the intermediate products, and that nevertheless the process product is obtained in excellent yields and a high degree of purity.

The first step in the process of the present invention is that of 3,4-dimethoxyphenylacetone allowed to react with an alkali metal cyanide in the presence of an ammonium salt, wherein one the reaction is carried out according to the invention at 37 to 42 ° C. in concentrated aqueous ammonia. as Alkali cyanide can be used with potassium cyanide, but the cheaper sodium cyanide is preferable. Ammonium chloride and ammonium acetate are suitable as ammonium salts; in the latter case it is sufficient adding an appropriate amount of glacial acetic acid to the concentrated ammonia solution. Instead of the free 3,4-Dimethoxyphenylacetons can also be used its BisuIfit adduct, whereby the use the ammonium salts become superfluous; d. That is, the reaction can then be carried out with the alkali metal cyanide in concentrated ammonium solution alone. This way you get in handy quantitative yield of the D, L-a-amino - <% - (3,4-dimethoxybenzyl) propionitrile in crystalline form, which can be subjected to the subsequent racemate resolution without further purification.

The subject of the earlier patent application F 38564 IVb / 12q (German Auslegeschrift 1183 912) is a Process for the production of a-amino-a-methyl - /? - (3,4-dimethoxyphenyl) -propionitrile, which is characterized in that equimolar amounts of 3,4-dimethoxyphenylacetone, potassium cyanide and ammonium chloride are used at 55 to 60 ° C in the presence of ammonia. In contrast, the first stage of the process according to the invention is carried out at temperatures carried out from 37 to 42 ° C.

The second stage of the process according to the invention consists in that the racemic amino

Process for the preparation of l - (-) - <x -methyl- / J- (3,4-dihydroxyphenyl) alanine

Applicant:

CF Boehringer & Soehne G. mb H.,
6800 Mannheim-Waldhof, Sandhofer Strasse

Named as inventor:

Dr. phil. Adolf Hagedorn,

6800 Mannheim-Waldhof;

Dr. rer. nat. Franz Braun, 6401 Rimbach;

Dr. rer. nat. Werner Güthlein,

6800 Mannheim-Neckarau

nitrile in aqueous suspension with D-tartaric acid and the excreted bitartrate of the D-a-amino- <x- (3,4-dimethoxybenzyl) propionitrile is separated off, whereupon the filtrate is neutralized beforehand extracted with an inert organic solvent and the extract with hydrohalic acid a5 treated. This way you get in handy quantitative yield of the crystalline hydrogen chloride or hydrogen bromide of L-a-aminoa- (3,4-dimethoxybenzyl) propionitrile, that by boiling with aqueous hydrohalic acids to the desired l - (-) - a-methyl - /? - (3,4-dihydroxyphenyl) -alanine can be hydrolyzed. The racemate separation is carried out at temperatures from 0 to 20 ° C carried out, it is expedient to work in the presence of dilute acetic acid or hydrochloric acid. This addition of acid to the aqueous suspension of the racemic aminonitrile enables a particular smooth, abundant, and rapidly separable optical isomers; furthermore it becomes a Saving in volume is achieved, since the addition of acid does not result in such large amounts of water for the optical Cleavage needed. The filtrate obtained after separating off the D-aminonitrile bitartrate is preferred neutralized with concentrated ammonia; for the following extraction with an inert organic Solvent is z. B. ethylene chloride well suited. That from the extract using hydrohalic acid L-aminonitrile hydrogen halide precipitated then with aqueous hydrohalic acids at normal or positive pressure in practical quantitative yield to l - (-) - <x-methyl-DOPA hydrolyze, both hydrochloric acid and hydrobromic acid being useful.

809 589/470

In the third stage of the process according to the invention, that which occurs during the optical splitting is used Bitartrate of D-α-amino-α- (3,4-dimethoxybenzyl) propionitrile racemized in a neutral or alkaline medium to D, L-aminonitrile, which can then be used again in the resolution according to stage 2. Racemization is preferred effected by treatment with aqueous ammonia; it is advisable to work at a slightly higher level Temperature (e.g. 50 ° C) or not at room temperature with the addition of one with water miscible organic solvent, e.g. B. ethylene chloride. This smooth, simple and practical quantitative racemization of the unusable D-aminonitrile is an essential one Factor for the productivity and economy of the new process for the production of L - (-) - «- methyl-DOPA.

The process according to the invention for the preparation of l - (-) - «- methyl - /? - (3,4-dihydroxyphenyl) alanine from 3,4-dimethoxyphenylacetone and alkali cyanide and an ammonium salt is characterized by that the implementation of the three components mentioned at 37 to 42 ° C in concentrated aqueous ammonia, whereupon the obtained D, L - «- Amino -« - (3,4-dimethoxybenzyl) propionitrile reacted in aqueous suspension with D-tartaric acid and the excreted bitartrate des D-aminonitrile is separated off while the filtrate, after previous neutralization with an inert extracted organic solvent, treated the extract with hydrohalic acid and the obtained L-aminonitrile hydrogen halide by boiling hydrolysed with aqueous hydrohalic acids to l - (-) - a-methyl- / 3- (3,4-dihydroxyphenyl) -alanm, whereupon the bitartrate of D-aminonitrile obtained in the optical cleavage in the neutral or alkaline medium racemized to D, L-aminonitrile.

In the publication by Stein et al., J. Am. Chem. Soc, 77 (1955), pp. 700 to 703, and in the USA patent 2868 818 is the reaction of 3,4-dimethoxyphenylacetone with potassium cyanide in aqueous solution in the presence of ammonium chloride described. The stated yield of 77% D, L - <% - amino-a- (3,4-dimethoxybenzyl) propionitrile hydrogen chloride however, it is not reproducible; As experiments have shown, the hydrogen chloride des is not obtained by this process D, L-aminonitrile, but a mixture of about 50% of the D, L-aminonitrile base and about 40% of non-basic by-products. In contrast, one obtains according to the process of the invention, in which the reaction of the 3,4-dimethoxyphenylacetone with the Alkali cyanide is carried out in concentrated aqueous ammonia, the pure D, L-aminonitrile in practically quantitative yield (cf. also the corresponding melting point information from Stein et al. as well as in Example 1 of the present invention).

Following the method of Stein et al. the D, L-aminonitrile obtained is boiled for 18 hours by means of concentrated hydrochloric acid and subsequent treatment of the reaction product with concentrated hydrochloric acid hydrolyzed at 150 ° C under pressure to D, L-a-methyl-yS- (3,4-dihydroxyphenyl) -alanine, only a yield of 34% of theory (based on the D, L-aminonitrile) obtained will. In contrast, the hydrolysis carried out by the process according to the invention succeeds of L-aminonitrile in practically quantitative yield. This result can be described as surprising, since the optically active forms are known easily racemize from aminonitriles.

The main advantage of the new process for the preparation of l - (-) - a-methyl- _/ 5- (3,4-dihydroxyphenyl) alanine is that the racemate separation is already carried out at the aminonitrile stage

ίο, being as a result of the feasible according to the invention subsequent racemization of the unusable D-aminonitrile is practically quantitative Conversion of the entire aminonitrile into l - (-) - «- methyl-DOPA is possible. In contrast is used in the previously known processes for the production of optically active "-Methyl - /? - (3,4-dihydroxyphenyl) -alanine the racemate separation is always carried out at the amino acid level (cf. on this the Belgian patents 604 858 and

ao 620113). In the first-mentioned Belgian patent it is mentioned that in principle there is also the possibility of racemate separation any other stage of the process, e.g. B. the aminonitrile stage to perform; it will however no further details or examples have been given. The same goes for the statement in that Belgian patent mentioned that the unusable D-aminonitrile can be converted into 3,4-dimethoxyphenylacetone can regenerate; the possibility of racemization of D-aminonitrile to D, L-aminonitrile is not considered at all. This now found, surprisingly easy to carry out Racemization, which proceeds in practically quantitative yield, is a decisive factor for the economy of the entire process according to the invention. Otherwise it was for the person skilled in the art cannot foresee that the optical cleavage of the D, L-a-amino-a- (3,4-dimethoxybenzyl) propionitrile would proceed so smoothly and with such excellent yields; the corresponding According to the findings, 3-methoxy-4-hydroxybenzyl compound can namely under Do not separate the same or similar reaction conditions into the optical isomers.

Also in comparison to the one described by Stein et al. revealed »Hydantoin process« [production of a-methyl-DOPA via 4-methyl-4- (3,4-dimethoxybenzyl) hydantoin] the process according to the invention is much simpler and more economical. To According to the authors mentioned, the hydantoin process is via the route described there the aminonitriles to be preferred. The method of the present invention thus enables for the first time an industrially useful synthesis of l - (-) - a-methyl-DOPA via aminonitrile, this new process all in terms of its economic viability previously known method is superior.

Examples

1.Preparation of DL-a-amino-a- (3,4-dimethoxybenzyl) propionitrile (DL-aminonitrile)

Method I.

In 2640 ml (32.2 mol) of concentrated ammonia (12.2 N) there are 154.5 g (3.15 mol) of sodium cyanide (96 to 98%) and 160.5 g (3 mol) of ammonium chloride dissolved at room temperature. Then warmed up the solution to 37 ° C, gives under vigorous

Stir 582.6 g (3 mol) of 3,4-dimethoxyphenylacetone rapidly and stir for 1 hour. Then in

Cooled for 1 to 1.5 hours to 20 to 25 ° C, the then already fine-grained product was stirred for several hours, filtered off with suction at 0 ° C, washed well with 800 ml of ice-cold water and dried in a desiccator. Yield: 615.24 g (93.1% of theory); Melting point 85 to 87 ° C. The DL-aminonitrile can be used for the resolution of racemates without further purification. C ₁₂ H ₁₆ N ₂ O ₂ (220.3):

Calculated N 12.72, found N 12.98.

Method II

To 194 g of 3,4-dimethoxyphenylacetone are added

II ammonia solution (14 to 16 n), 66 ml of glacial acetic acid and 62 g finely powdered sodium cyanide (92%). The reaction mixture is stirred well and steadily warmed to 42 ° C, at the same time ammonia is introduced into the cloudy reaction solution. To Stirring at 40 to 42 ° C for 30 to 35 minutes, white settles on the walls of the reaction flask Crystals, whereupon the ammonia supply is interrupted. The mixture is stirred in the cooling water bath 16 hours further, then sucks off the aminonitrile and washes out with 100 to 150 ml of water. Yield: 207 g (94% of theory) DL-aminonitrile; F. = 88 to 92 ° C. The hydrogen chloride produced in the usual way melts at 159 to 162 ° C (decomposition).

Method III

320 g bisulfite adduct of 3,4-dimethoxyphenylacetone (corresponding to 186 g = 0.96 mol of the ketone) are poured into 900 ml (10.98 mol) with vigorous stirring concentrated ammonia (12.2 n) entered. The emulsion obtained is heated to 37 ° C. and added rapidly adding 51.5 g (1.03 mol) of sodium cyanide (96 to 98%). After stirring at 37 ° C. for one hour, the mixture is left in Cool to 20 ° C. for 1.5 hours and stir at 20 ° C. for 16 hours. The fine-grained crystalline material is suctioned off at 0 ° C, washed with 500 ml of ice-cold water and dried in a desiccator. Yield: 222 g (105% of theory; the compound still contains inorganic material); F. = 85 to 88 ° C. The DL-aminonitrile obtained in this way can be used for racemate separation without further purification be used.

If desired, the crude product can be purified as follows: The DL-aminonitrile is dissolved in methylene chloride, adds 2N hydrochloric acid and separates the aqueous phase, which is then washed with 2N ammonia and methylene chloride is added. From the methylene chloride extract obtained in this way after drying and evaporation in 94% yield, the pure DL-aminonitrile from F. = 87 to 88 ° C isolated.

2. Resolution of DL-α-amino-α- (3,4-dimethoxybenzyl) propionitrile (DL-aminonitrile)

Method I.

330 g (2.2 mol) of D-tartaric acid are dissolved in 400 ml of water and the resulting solution (580 ml) halved. The first half of the solution is mixed with 250 ml (0.5 mol) of 2N hydrochloric acid and in about one Minute at 15 ° C with stirring to the slurry of 440 g (2 mol) of fine-grained raw DL-aminonitrile in 3.9 l of water at 15 ° C.

60 After a few minutes, the DL-aminonitrile almost completely dissolved and the slow continued stirring the D-aminonitrile-bitartrate at about 15 ⁰ C begins after 2 to 3 minutes to crystallize. The second half of the tartaric acid solution is then added dropwise over about 30 minutes while cooling with ice, and stirring is continued for another 45 minutes. The crystal slurry obtained is sharply suctioned off at 0 ° C. and washed twice with 100 ml of ice-cold water. Yield: about 667 g of colorless, moist D-aminonitrile bitartrate, which is racemized (see Example 3).

The ice-cold filtrate is mixed with 800 ml of ethylene chloride, with vigorous stirring at 0 to 5 ° C about 480 ml of 6N ammonia are added dropwise in 30 to 40 minutes, adjusted to pH 6.7, the ethylene chloride is separated off and the aqueous phase with 200 ml of ethylene chloride shaken. The ice-cold, combined ethylene chloride solution is then added dropwise with ice-cooling and vigorous stirring to 480 ml of 6N hydrochloric acid at 0 to 5 ° C. Washed out hydrochloric acid and 200 ml of ethylene chloride and dried in vacuo. Yield: 233.31 g (42.5% of theory) of colorless L - (+) - aminonitrile hydrochloride monohydrate, melting point = 153 to 155 ° C (decomposition, sintering from 105 ⁰ C); [<x] f = +10.2 ± 0.2 ° (c = 2 in methanol).

C ₁₂ H ₁₇ N ₂ O ₂ Cl · IH ₂ O (274.7):
Calculated .. C 52.46, H 6.97, N 10.20, α 12.90; found .. C 52.64, H 7.02, N 10.23, Cl 12.91.

Water according to Karl Fischer:
Calculated 6.56%, found 6.9 ± 0.3%.

Method II

A mixture of 105 g (0.47 mol) of DL-aminonitrile, 850 ml of water and 30 ml of glacial acetic acid at + 1O ⁰ C internal temperature with half of a solution of 75 g of D-tartaric acid (0.5 mole) in 150 ml of water offset. After vigorous crystallization of D-aminonitrile bitartrate has set in, the remainder of the tartaric acid solution is dripped into the solution within 20 minutes while stirring. The mixture is stirred for IV2 hours at + 10 ° C., the crystalline D-aminonitrile bitartrate is filtered off with suction and washed with 50 ml of ice-cold water (see Example 3 for further details).

The mother liquor is brought under cooling at an internal temperature of +5 ⁰ C with 13-η ammonia to pH 6.8 to 7.0 (about 77 ml) and twice with 100 ml of ethylene chloride is extracted. The ethylene chloride extract is stirred into a mixture of 50 ml of water and 100 ml of concentrated hydrochloric acid with cooling (internal temperature + 5 ° C.). The crystal suspension obtained is allowed to crystallize at 0 ° C., then filtered off with suction and washed with 50 ml of ethylene chloride and 50 ml of ice-cold 3η hydrochloric acid. Yield: 53.7 g (41% of theory) of L-aminonitrile hydrogen chloride monohydrate with a melting point of 153 to 156 ° C .; [«]» = + 10.0 ° (2%, methanol).

Method III

A mixture of 105 g of DL-aminonitrile (0.47 mole), 850 ml of water and 50 ml of 2N hydrochloric acid with stirring at an inner temperature of +5 ⁰ C with half of a solution of 65 g D-tartaric acid (0.43 Mol) in 130 ml of water. After that

D-aminonitrile bitartrate has crystallized out (about 10 minutes), the remainder of the tartaric acid solution is added dropwise to the mixture over a period of 20 minutes while stirring. After 40 minutes of stirring at ⁰ +8 C, the D-aminonitrile-bitartrate is suction filtered and washed with 50 ml of ice-water 5 (continued s. Example 3).

The mother liquor is worked up as described above under II. Yield of L-aminonitrile hydrogen chloride monohydrate: 55.5 g (42.6% of theory); [«] Ff = +10.1 ± 0.3 ° (2o / o, methanol).

3. Racemization of the D - «- amino-a- (3,4-dimethoxy-

benzyl) propionitrile (D-aminonitrile)

Method I.

For racemization, the moist D-aminonitrile bitartrate (667 g) obtained according to Example 2 is introduced with vigorous stirring into a 50 ° C. mixture of 456 ml of concentrated ammonia (about 12N) and 180 ml of water and the oily aminonitrile separated out for 30 minutes stirred at 50 ° C further _a o. The mixture is then cooled to about 35 ° C., the DL-aminonitrile crystallizing out with vigorous stirring. It is suctioned off at 0 ° C., washed twice with 100 ml of ice-cold water and dried in a vacuum desiccator. Yield: 211.64 g _ag (48.1% of theory, based on the DL-aminonitrile used for the racemate separation) of colorless DL-aminonitrile with a melting point of 84 to 87 ° C .; [x] f = ± 0 ° (c = 2 in methanol).

C ₁₂ H ₁₆ N ₂ O ₂ (220.3)

Calculated C 65.43, H 7.32, N 12.72;

Found C 65.34, H 7.11, N 13.00.

The substance can be used again in the racemate separation without further purification.

Method II

170 g of filter-moist D-aminonitrile bitartrate (contains 0.25 mol of pure substance) are stirred with 250 ml of ethylene chloride and 250 ml of concentrated ammonia solution (12.5 N) for 6 hours at room temperature. The aqueous layer is then separated off and extracted with 100 ml of ethylene chloride. The combined ethylene chloride extracts are washed with 100 ml of water, then dried with sodium sulfate and distilled in vacuo. Yield: 53.5 g of DL-aminonitrile with a melting point of 86 to 88 ° C .; [α] f = ± 0 ° (2%, methanol), that is 96.4% of theory (based on the D-aminonitrile bitartrate used).

4. Hydrolysis of the L - (+) - a-amino - «- (3,4-dimethoxybenzyty-propionitrile hydrogen chloride (L-amino

nitrile hydrochloride) to l - (-) - a-methyl - /? - (3,4-dihydroxyphenyl) -alanine [l - (-) - «- methyl-DOPA]

Method I.

412 g (1.5 mol) of L-aminonitrile hydrogen chloride monohydrate are stirred with 2.5 liters of 48% hydrobromic acid for 2 hours at 60 to 70 ° C., then heated to 120 ° C. in 1.5 hours and with stirring for 1.5 hours held at this temperature. Then distilled under vacuum at 40 to 5O ⁰ C water bath temperature about 21 from hydrobromic acid, removed by filtration the precipitated ammonium bromide and then distilled in vacuo at 70 to 80 ° C, the remaining amounts of hydrogen bromide acid from. The distillation residue is taken up in about 200 ml of water, cooled to 0 ° C. and about 1 g of sodium bisulfite is added. Cold 6 η aqueous ammonia containing 1 g of sodium bisulfite is then added to the contents of the flask, while stirring, until the pH is 4.5, and stirring is continued at 0 ° C. for 1 hour. The precipitated crystal pulp is filtered off with suction, washed with water and methylene chloride and redissolved from about 2 liters of water with the addition of a little aqueous sulfur dioxide solution. After drying to constant weight, 310 g of analytically and paper chromatographically pure l - (-) - a-methyl - ^ - (3,4-dihydroxyphenyl) alanine, which contains 1.5 mol of water of crystallization, are obtained; Yield: 86.8% of theory; M.p. = 310 to 311 ° C (decomposition).

A further 25.74 g (7.2% of the Theory) of this pure substance. Total yield: 335.74 g (94.0% of theory); [«] £ = -13.3 + 0.3 ° (c = 1 in water).

C ₁₀ H ₁₃ O ₄ N-1.5 H ₂ O (238.2):

Calculated C 50.41, H 6.77, N 5.88;

found C 50.40, H 6.78, N 5.87.

Water according to Karl Fischer:

Calculated 11.34%, found 11.7 ± 0.2%.
Potentiometric titration:

Calculated Equivalent Weight 238.2;

equivalent weight found 236, 239.

Method Π

20.60 g (0.075 mol) of L-aminonitrile hydrogen chloride monohydrate was added in a sealed tube of about 340 ml with 75 ml of concentrated hydrochloric acid and is introduced into the crystal suspension at 2O ⁰ C until saturated hydrogen chloride. The then clear, practically colorless solution is heated to 60 to 70 ° C. for 2 hours and to 140 ° C. for 7 hours in the closed bomb. After similar work-up as described above under I, 15.83 g (88.62%) of colorless 1- (-) - «- methyl-DOPA (1.5 mol of water of crystallization) with a melting point of 310 to 311 ° C. are obtained (Decomposition); [«] * = -13.4 ± 0.3 ° (c = 1 in water). Working up the mother liquor yields a further 1.10 g (6.16%) of this pure substance with a melting point of 310 to 311 ° C. (decomposition); Mf = -13.1 + 0.3 ° (c = 1 in water). Overall yield: 16.93 g (94.78%).

Claims (2)

Patent claims: 1. A process for the preparation of l - (-) - α - methyl - β - (3,4 - dihydroxyphenyl) - alanine from 3,4-dimethoxyphenylacetone and alkali metal cyanide and an ammonium salt, characterized in that the reaction of the three components mentioned is carried out carried out at 37 to 42 ° C in concentrated aqueous ammonia, whereupon the D, La-aminoa- (3,4-dimethoxybenzyl) propionitrile obtained is reacted in aqueous suspension with D-tartaric acid and the precipitated bitartrate of D-aminonitrile is separated off while the filtrate is extracted after previous neutralization with an inert organic solvent, the extract is treated with hydrohalic acid and the L-aminonitrile hydrogen halide obtained is boiled with aqueous hydrohalic acids to give l - (-) - a-methyl-y5- (3,4-dihydroxyphenyl) ) -alanine hydrolyzed, whereupon the bitartrate of the D-amino- nitrile in neutral or alkaline medium alkali metal cyanide in concentrated ammonia solution racemized to the D, L-aminonitrile. without using the ammonium salts 2. The method according to claim 1, characterized in that
indicates that one takes the place of the free 3,4-dimethoxyphenylacetone its bisulfite 5 Older patents considered: Adduct uses and the implementation with German Patent No. 1183 912. 809 589/470 7.68 © Bundesdruckerei Berlin