DE1493484C3 - Process for the preparation of L - (-) - aIpha-methyl-beta- (3,4-dihydroxyphenyl) -alanine - Google Patents

Description

20th

The subject of patent 1,235,946 is a process for the preparation of l - (-) - a-methyl-ß- (3,4-dihydroxyphenyl) alanine, which is characterized in that 3,4-dimethoxyphenylacetone with an alkali metal cyanide and Reacts benzylamine in a manner known per se, the resulting a-benzylamino-a- (3,4-dimethoxybenzyl) propionitrile a resolution with V ₂ moles of d - (+) - camphorsulfonic acid per mole of racemate in aqueous suspension in the presence of one with water not miscible organic solvent is carried out at room temperature or at 10 to 15 ° C and the precipitated d - (+) - camphorsulphonic acid salt of L - (+) - benzylaminonitrile is converted into the free L - (+) - by adding a base in a conventional manner. Benzylaminonitrile, the L-isomer is separated off and the D-isomer remaining in the mother liquor is racemized in an alkaline medium in a manner known per se to give D, L-benzylaminonitrile, whereupon the L - (+) - a - benzylamino - a - (3 , 4 - dimethoxybenzyl) propionitrile gradually through acidic or Alkaline saponification and catalytic hydrogenation are converted into l - (-) - a-methyl- / S- (3,4-dihydroxyphenyl) alanine in a manner known per se. .

According to a particular embodiment of the process according to patent 1,235,946, the L - (+) - a-benzylamino is used - α - (3,4 - dimethoxybenzyl) - propionitrile by treatment with concentrated sulfuric acid, catalytic hydrogenation, alkaline saponification and treatment with concentrated hydrohalic acids in a manner known per se into l - (-) - a-methyl- / S- (3,4-dihydroxyphenyl) alanine convicted.

It has now been found that by using optically active d - {-) - a-methylbenzylamine instead of benzylamine, the process according to patent 1,235,946 can be considerably simplified.

The invention therefore relates to the further development of the process for the preparation of L - (-) - α - methyl- β- (3,4 - dihydroxyphenyl) - alanine according to Patent 1,235,946, which is characterized in that instead of Benzylamine optically active d - (-) - (z-methyl-benzylamine used and the l- (-) - «- (3,4-dimethoxybenzyl) -Na-methyl-benzylamino-propionitrile obtained in this way directly stepwise through acidic or alkaline Saponification and catalytic hydrogenation are converted into L - (-) - a - methyl - β - (3,4 - dihydroxyphenyl) - alanine in a manner known per se.

This synthesis is all previously known methods for the preparation of l - (-) - a-methyl - /? - (3,4-dihydroxyphenyl) -alanine superior due to their simple and economical feasibility. Especially advantageous is the fact that the separation of the optical isomers in the course of the process an intermediate product or at the final stage. Rather, it is made by using an optically active amine as a starting material, the synthesis exclusively in the desired optically active direction directed. Although optically active syntheses in organic chemistry have already been carried out in isolated cases could be, it is surprising that in the present case by using the optically active D- (-) -a-methylbenzylamine exclusively the desired optically active form of the methylbenzylcyanamine configuration is obtained - which is not optically active on the residue used, but on the one newly emerging optical center. The method according to the invention is also extraordinary economical, since the optically active amine used as the starting material is very easy to manufacture.

The first step of the process of the invention is that 3,4-dimethoxyphenylacetone with an alkali cyanide and D - (-) - a-methyl-benzylamine implemented using the reaction conditions described in patent 1,235,946. To this L - (-) - α - (3,4 - Dimethoxybenzyl) - N - α - methylbenzylaminopropionitrile is obtained in excellent yield (I) in crystalline form, which is used in the next stage without further purification can be.

^CH3 ° CH ₃ (I)

L - (-) CH ₃ O- / "^ CH ₂ -C-CN

NH-CH-CH ₃
C ₆ H ₅

In the second stage, the L - (-) - a- (3,4-dimethoxybenzyl) - N - α - methylbenzylamino - propionitrile (I) is converted into the L - (- ) by stepwise acidic or alkaline saponification and catalytic hydrogenation -a- methyl - β - (3,4 - dihydroxyphenyl) - alanine transferred.

If the compound I is treated in a manner analogous to that described in Patent 1,235,946, with concentrated Sulfuric acid in the cold, partial hydrolysis to the amide of formula II takes place.

CH ₃ (II)

S ^ CH ₂ -C-CO-NH ₂

NH-CH-CH ₃
C ₆ H ₅

SO ₃ H

From this compound II can then by catalytic hydrogenation in a conventional manner a-methyl-benzyl group are split off, wherein the reaction conditions described in Patent 1,235,946 are used. The debenzylated compound can then be carried out according to the patent 1 235 946

described methods - if desired in stages - hydrolyze. But you can also make the connection II first hydrolyze and remove the debenzyla-

H ₂ / cat.

OH

CH, - C - CO - NH

Interposition at any stage. The following have so far been found to be particularly advantageous Proven ways:

CH ₃

CH ₂ -C-COOH (V) 1- (+) NH-CH-CH ₃ QH ₅

HO

Although it is already known that alanine by means of an optically active synthesis using a-methylbenzylamine can produce (H a r a d a and Fox, Naturwissenschaften Vol. 51, 1964, p. 106). In this process, however, is used as the starting substance the corresponding cyanohydrin compound is used. If you try to use this method l- (-) -a-methyl- (3- (3,4-dihydroxyphenyl) -alanine to obtain only very poor yields. It is therefore surprising that this connection produce sterically uniform in excellent yields by the process according to the invention leaves, and compared to the method of H a r ad a and Fox saved one reaction stage will.

B e i s ρ i e 1 1

Preparation of 1- (-) -a- (3,4-dimethoxybenzyl) -Ν-α-methyl-benzylamino-propionitrile (I)

A solution of 108 g of 3,4-dimethoxyphenylacetone (0.55 mol), 400 ml of methanol, 69 g of D - (-) - a-methylbenzylamine (0.55 mol) and 36 g of sodium cyanide (0.73 mol) is added with stirring 48 ml of glacial acetic acid (0.8 mol) are added, the internal temperature rising to about 50.degree. The mixture is stirred at room temperature for a few hours and then the crystal slurry formed is filtered off with suction. In this manner there is obtained 137 g (76.2% of theory) of l- (-) -a- (3,4-dimethoxybenzyl) -Na-methylbenzylamino-propionitrile (I), mp 107 to 109 ⁰ C. [α]? = -82 ° (c = 1, in methanol).

A further 8 g (4.5% of theory) of this compound can be obtained from the mother liquor by concentration will. Total yield: 145 g (80.7% of theory).

Conversion of the L - (-) - a- (3,4-Dimethoxybenzyl) -

Ν-α-methylbenzylamino-propionitrile in the l - (-) - a-methyl - /? - (3 ^ -dihydroxyphenylalanine (IV)

a) A solution of 60 g of l - (-) - a- (3,4-dimethoxybenzyl) - N - α - methylbenzylamino - propionitrile (0.184 mol) in 100 ml of methylene chloride is concentrated in 200 ml. Sulfuric acid added dropwise at -8 to -5 ° C. The reaction mixture is kept for several hours with stirring at -8 to -5 ° C, then at Γ C and then poured into about 1000 ml of ice water. The resulting crystal slurry is filtered off and dissolved in 400 ml of water with the addition of conc. Dissolved ammonia solution. By adjusting the pH of the solution to 6.8 to 7.8 and adding 200 ml of chloroform, the monohydrate of the ammonium salt of L - (+) - a-methyl - /? - (3,4-dimethoxyphenylsulfonic acid-6) -Na-methylbenzyl-alanine amide (II) precipitated. Yield 84.4 g (98% of theory); Mp. 105 to 107 ⁰ C.

This salt can be used directly in the following stage.

To obtain the free acid, the ammonium salt is dissolved in ammoniacal water and the The pH of the solution was brought to 5.5. In this way the L - (+) - a-methyl- / if- (3,4-dimethoxyphenylsulfonic acid-6) -N-a-methylbenzylalanine amide is obtained (II) from m.p. 275 to 277 ° C; [α] ?? = + 35.6 ° (c = 1, in Methanol).

b) 50 g of the monohydrate of the ammonium salt of compound II (0.109 mol) are dissolved in 400 ml of methanol dissolved and with 10 ml of 12.5N ammonia in the presence hydrogenated by 4 g of 10% Pd-carbon at room temperature. The filtered reaction solution is mixed with 20 ml conc. Hydrochloric acid and evaporates in a vacuum

Dry one. The residue is heated with 80 ml of water and filtered off with suction after leaving to stand at room temperature. In this way, 29 g of monohydrate of L - (-) - a-methyl- / i- (3,4-dimethoxyphenylsulfonic acid-6) -alanine amide (III) with a melting point of 328 to 333 ⁰ QIa] S ⁵ = -48 are obtained ° (c = 1, in methanol).

Another 1.9 g of material of mp be after evaporation from the mother liquor ⁰ C to 33O 328th; [α]? = -47.4 ° (c = 1, in methanol). Overall yield: 30.9 g (84.2% of theory).

c) 20 g of the monohydrate of compound III (0.059 mol) are dissolved in 100 ml of 48% hydrobromic acid, refluxed for 2 hours on a water bath and boiled for 3 hours under reflux cooling and with the exclusion of air. The reaction solution is then concentrated to dryness in vacuo. The reaction product is largely freed from free hydrobromic acid by adding water and renewed distillation. The distillation residue is dissolved in 50 ml of water, the solution is clarified with activated charcoal and, while cooling, is brought to a pH of 2.5 with 80% hydrazine hydrate solution. After standing at -I ⁰ C, the L - (-) - o-methyl- / i- (3,4-dihydroxyphenyl) alanine (IV) is filtered off with suction and washed with a little water; it crystallizes with 1.5 mol of water of crystallization. Yield: 13.1 g (93% of theory); Mp 305-308 ° C, [α] f = -14.1 ° (c = 1, in water).

Claims (1)

Claim: Further development of the process for the preparation of l - (-) - a-methyl - /? - (3,4-dihydroxyphenyl) alanine according to Patent 1,235,946, characterized in that optically active D - (- ) -a-methylbenzylamine used and the resulting L - (-) - α - (3,4 - dimethoxybenzyl) - N - a - methylbenzylamino-propionitrile directly in stages by acidic or alkaline saponification and catalytic hydrogenation in per se known Way converted into the L - (-) - α - methyl - β - (3,4 - dihydroxyphenylalanine. 15th