SU539522A3 - Method for preparing hydrazine-α-phenylpropionic acid - Google Patents

Description

(54) METHOD OF OBTAINING L-a-HYDRAZINE-p-PHENYLPROPIC ACID

.one

The invention relates to a method for producing novel, α-hydrazine-3-phenyl-propionic acid derivatives not described in the literature, which have biological activity and can be used in medicine.

The literature describes a method for the preparation of the derivatives of 3- (3,4-dioxyphenyl) -2-methylamine of the general formula

SP,

CH-C-COOH N

.

where Rb Ra and Kz are hydrogen or an acyl group, consisting in the diazotization of 4-aminoveratol, followed by sequential reaction with methyl methacrylate, hydrolysis and amination I.

However, in the literature there is no information about the method of obtaining L-a-hydrazine-p-phenylpropionic acid of formula I

where RI and R2 are hydrogen, hydroxy or alkoxy, containing not more than 6 carbon atoms, phenyloxy or benzyloxy,

RS and R4 are hydrogen or an alkyl group containing not more than 7 carbon atoms,

RS is a hydrogen, metal atom or alkyl group containing not more than 6 carbon atoms with high biological activity.

The proposed method for the preparation of L-a-hydrazine-p-phenylpropionic acid of general formula I consists in the fact that L is an isomer of a compound of general formula II

15

where RI, R2, RS, and R4 are as defined,

R is cyano- or carboxigrunna, which is alkylated or aminated. Re - group

Кз R СН-С-СООТГд

HN-NH2

R

1 -N-f, ll-B,

1 / С

H

3) -NH-NHa, 4) hydrazone group, or 5) -NRs-NRgRio, where Rg, Rg and Rio are hydrogen or acyl, or Rg and Rio together with the nitrogen atom form an imidogroup of an aromatic diacid, or Re and R together form groups :

6) NH-CHg-NC1-C-7) -NH-C-NH-O-C-

ABOUT

NH

about

9

R-CH-H, O

C-NH-O-CIII

-N-C-t-N-COO l I I NHjO HjNHj

7 / j0

-NH-NH-C; ;

X

X

II

-JMH-NH-C-NH-e1) X X

fi ii

-N-C-N-CI1

NH NHj

where X is oxygen or sulfur, is subjected to hydrolysis, for example with an aqueous solution of an acid or base. The process is carried out at a temperature of from -50 to - | -200 ° C, preferably at 90-165 ° C, and the target product is isolated by known methods.

Example 1. A. Obtaining and separation of diastereomers a (1-methoxy-acetylhydrazo) a-methyl - p- (3.4 - dimethoxyphenyl) propioic acid.

To an ice-cooled solution of the racemate a-hydrazine a-methyl-p - (3,4 - dimethoxyphenyl) propionic acid (10 mmol) in 2% sodium bicarbonate solution (50 ml) was added 12 mmol of 1-methoxychloroformate and the mixture was stirred for 3 hours. The mixture is acidified to pH 3 and the product is filtered off. The resulting product is a mixture of D and Z a- (1-methoxy-acetylhydrazo) a-methyl-p- (3,4-dimethoxyphenyl) propionic acid.

The sodium salt of a mixture of D and Z is obtained by dissolving the mixture in ethanol, followed by processing it with 1 equivalent of sodium hydroxide. The sodium salt precipitates from the solution and is dissolved in a mixture of methanol and water. Hexane is then added until the solution becomes cloudy. The precipitated Z-isomer is separated by filtration and is hydrolyzed by boiling the acidic solution. After recrystallization from a mixture of methanol and water, the pure Z-a-hydrazine-a-methyl-p - (3,4-dioxyphenyl) propionic acid has a melting point of 200 g 202-205 ° C (decomposition),

, 3 ° (с 2, СНзОН). Found,%: C 49.13, H 6.74, N 11.19.

CioHi4N204H20.

Calculated,%: C 49.17, H 6.60, N 11.47. Example 2. A. Preparation and separation of diastereoisomers of a-a-O-acetylacetate-hydrazo-p-methyl phenylpropionic acid methyl ester.

90.11 g (0.5 mol) of racemic a-hydrazine-p-phenylpropionic acid is dissolved in 200 ml of methanol. The solution is saturated with gaseous hydrogen chloride at room temperature (25 ° C) and the mixture is left to stand for 40 hours. The racemic solution is concentrated to dryness in vacuo, washed once with methanol and again dissolved in 200 ml of methanol. Di5 ethylamine is added to the solution to pH 8. The mixture is cooled to 0 ° C, maintained for 1 hour, filtered and a precipitate is formed to obtain the a-hydrazine-p-phenylpropionic racemic methyl ester.

0 To 83.09 g (0.5 mol) of a-0-acetylatrolactonic acid, 119.0 g (1.0 mol) of cooled thionyl chloride was added. The mixture was heated at reflux and held for 2 hours. The mixture was concentrated in vacuo at 50 ° C to remove excess thionyl chloride and dissolved gases.

To 97.12 g (0.5 mol) of a-hydrazine-p-phenylpropionic acid methyl ester, 300 ml of pyridine are added with cooling, and the a-O- obtained in the previous step is added to the mixture to be moved and cooled to 20-25 ° C. acetyltrolactyl chloride. The mixture was incubated overnight at 25 ° C, concentrated in vacuo, and the residue was recrystallized from methanol / water to obtain the a-enriched form of a- (a-O-acetyltrolactylhydrazo) methyl ester of p-phenylpropionic acid.

0 V. Preparation of L-a-hydrazine-p-phenylpropionic acid.

38.44 g (0.1 mol) of the L-enriched methyl ester obtained in Example 1A is hydrolyzed with 150 ml of 5N. hydrochloric acid for 2 hours at reflux. The mixture is cooled to room temperature and extracted with ether.

After drying over MgSO4, the ethereal solution is concentrated to remove a-atrolactonic acid. The aqueous phase is concentrated to dryness, placed in methanol and diethyl amine is added to a pH of 6.0. After one hour at room temperature, L-a-hydrazine-p-phenylpropionic acid is separated

5 by filtration and recrystallized from

water containing 0.5 g sodium bisulfite.

Example 3. Preparation of L-p- (3,4-dioxyphenyl) -a-hydrazinpropionic acid.

K 7.50 g (0.05 mol) of L-tartaric acid in

0 50 ml of methanol was added at 50 ° C to 21.22 g in 100 ml of methanol. L-p- (3,4-dioxyphenyl) -agidrazinpropionic acid. The mixture is allowed to cool. The mixture is concentrated, removed part of it, diluted with ether, heated and cooled, rubbed with a glass rod until the embryos of crystals are in place. These embryos are used to seed the mixture, which is kept for 18 hours at 25 ° C. The mixture is cooled to 0 ° C, filtered, washed and dried to obtain the L-tartaric salt of Lp-5 (3,4-dioxyphenyl) -a-hydrazine-propionic qiK 212.21 g (1.0 mol) B, L-p- ( 3,4-dioxyphenyl) -a-hydrazinpropioic acid was added 200 ml of 2.5N. hydrochloric acid and mixture o are concentrated to dryness in vacuo. The residue is placed in 1.4 L of methanol at 60 ° C, 37.5 g (0.25 mol) of L-tartaric acid is added and dissolved, and the mixture is allowed to cool to 25 ° C. The mixture was seeded with the previously obtained salt of tartaric acid 15 and left overnight at 25 ° C. The mixture is cooled to O-5 ° C, filtered, washed and the precipitate is dried. The residue is recrystallized twice from water to obtain the L- (3,4-dioxyphenyl) -a-hydrazine-20-nopionic acid L-vinyl salt. 57.44 g (0.1 mol) of tartrate obtained in the previous step are triturated with 250 ml of water and 10 m and with stirring and cooling. sodium hydroxide to pH 6.4. 25 The mixture is filtered, washed and the precipitate is dried to obtain L-a-hydrazine- (3,4-dioxyphenyl) propionic acid with m.p. 197 ° C (darkens with decomposition). Found,%: C 47.08; H 5.84; N 12.29. CgHisNaOi-HgO. Calculated,%: C 46,95; H 6.13; N 12.17. 280 mla log / 3.44 (, 0.1N HCl). Example 4. Preparation of D, L-p- (3,4-dioxyphenyl) -a-hydrazine propionic acid methyl ester. In 212.21 g (1.0 mol) O, L-p (3,4-dioxypha-40-nyl) -a-hydrazin-propionic acid in 1 liter of methanol, gaseous hydrogen chloride is introduced at O-5 ° C until until the mixture becomes a mixture. After keeping the mixture for 24 hours at 20-25 ° C, it is evaporated to dryness 45 under vacuum. The residue is placed in 2 liters of methanol, 27.01 g (0.5 mol) of sodium methoxide is added, the mixture is filtered, washed and the filtrate is concentrated to 2 liters. To the concentrate was added 100.1 g (0.50 mol) a-camoric acid. The single amount is removed, ether is added, the mixture is heated, cooled, rubbed against the walls with a glass rod to cause crystallization. The remaining solution is concentrated to half the volume of 55 and seeded. The mixture is left for 18 hours. The irs are 25 ° C, cooled to 0-5 ° C, filtered and the precipitate is washed with cold methanol. After drying, the precipitate is recrystallized from isopropyl alcohol to obtain 60 a-camphor salt of L- | 3- (3,4-dioxyphenyl) -a-hydrazinpropionic acid methyl ester. 63.94 g (0.15 mol) of the ethereal salt, obtained in the previous step, are boiled under nitrogen over a period of 2 hours with 100 ml of 2 p hydrochloric acid. The mixture is cooled to 10-15 ° C, iodine, acidified to pH 6.4 and 10. sodium hydroxide, filtered, the precipitate washed with water and dried. The residue is recrystallized from ode to give L-p- (3,4-dnoxyfenpl) -cc-gdrazipropionovuyu acid, so pl. 197 ° C. Example 5. A. 45 g of B, b (a) - (3,4-dioxybenzyl) -a-hydrazinpropioic acid is dissolved in 115 ml of 1N. hydrochloric acid at 45 ° C. The mixture is filtered and the saturated solution is seeded at 45 ° C with 5 g of L-a- (3,4-dioxybenzyl) -a-hydrazinpropioic acid. Then, the organic solution is cooled to 25 ° C for 35 minutes and held for 1 hour at 25 ° C. The precipitated product is separated by filtration, washed with two portions of 15 ml each of water (25 ° C) and dried in vacuo to obtain L-a- (3,4-dioxybenzyl) -a-hydrazinepropionic acid, m.p. 208 ° C (decomposition). B. The mother liquor of stage A is combined with 5 g of 0, L-a- (3,4-d yuxibepzil) -a-hydrazin-propionic acid and heated to 45 ° C. The mixture is heated to 45 ° C and filtered. This valuable solution is treated with 4 g of D-a- (3,4-dioxybenzyl) -a-hydrazinpropionic acid and cooled to 25 ° C in half an hour. The crystallized material is then recovered as described previously. B. The mother liquor from step B is recycled with 5 g of B, L-a- (3,4-dioxybenzyl) -a-hydrazine-pro-ionic acid, as in stage A to obtain L-a- (3,4-dioxybenzyl) - a-hydrazinpropionic acid. Example 6. In the vessel And load 195 ml of 0.1 n. hydrochloric acid and 19 g of 0, L-a- (3,4-dioxybenzyl) -a-hydrazinpropionic acid. The resulting pasty paste is heated to 45 ° C in a water bath and kept at this temperature for the duration of the operation. The pipeline from vessel A goes through the filter and is divided into two pipelines that go to vessels B and C. In vessels B and C, 12 g of O, L-a- (3,4-dioxybenzyl) -a-hydrazinpropionic acid are loaded, dissolved 230 ml 0.1 n. hydrochloric acid at 25 ° C. The solution is filtered and poured into vessel B, and the remaining amount into vessel C. Throughout the entire operation, vessels B and C are kept at 25 ° C. 1.35 g of L-a- (3,4-dioxybeisyl) -a-hydrazinpropionic acid is introduced into vessel B, and 1.35 g of B-a- (3,4-dioxybenzyl) -a hydrazinpropionic acid. The solution from vessel A is pumped at a rate of 2 ml / min to vessels B and C. From vessels B and C, flow pipelines are connected to the overflows from vessels B and C and returned to vessel A. Through regular time intervals into vessel A Additional quantities of 0, b-racemic mixture are introduced to maintain the saturation of the solution. D and L-isomers are removed at regular intervals. and when necessary, additional

seed crystals. In this way, a continuous separation of the racemate is carried out to isolate the D and L-isomers.

Example 7. A. Preparation of L-a-methyl-aureido- | 3- (3,4-demitoxynphenyl) propionic acid.

A solution of 44 g (0.16 mol) of the hydrochloric acid salt of L-a-methyl-a-amino-p- (3,4 - dimethoxyphenyl) propionic acid is prepared by dissolving it in 440 ml of water and gently heating. The solution is then rapidly cooled to 5 ° C and 77.6 g (0.96 mol) of potassium dianate are added in small portions. The resulting dough paste is heated to 60 ° C for 4 hours and filtered. The filtrate is cooled and acidified to pH 1 with concentrated hydrochloric acid. The crystalline precipitate is filtered off, washed with water and dried at 50 ° C, to obtain 34.5 g of L-a-methyl-a-ureido-P (3,4-dimethoxyphenyl) pro -ionic acid. By recrystallization from ethanol: water, a product is obtained having a mp. 205-207 ° C.

Paideno,%: C 55.56; H 6.52; N 9.99.

CigHisNaOs.

Calculated,%; C 55.31; H 6.43; N 9.92.

B. Preparation of L-a-methyl-a-hydrazin-p (3,4-dimethoxyphenyl) propionic acid.

To an ice-cooled solution of 2.2 g (7.8 mol) of L-a-methyl-a-ureido-p- (3,4-dimethoxyphenyl) propionic acid obtained in stage A in 15.6 ml of 2.5 n . Potassium hydroxide added 13.6 ml of a 0.71 M solution of sodium hyiochlorite (9.75 mmol). 5 minutes after the addition is complete, the solution is heated to 80 ° C for 1.5 hours. Then 45 ml of toluene and 0.8 ml of hydrazine hydrate are added and the mixture is stirred vigorously with 8 ml of concentrated hydrochloric acid. The mixture was stirred at 80 ° C for 30 minutes, after which the phases were separated and the aqueous layer was extracted with 25 ml of toluene. The aqueous solution is evaporated to dryness and the mixture of salts is poured into ethanol. The alcohol solution is neutralized with diethylamine to pH 6.4. The precipitated product is filtered off, washed with ethanol and dried to obtain 1.25 g of L-a-methyl-a-hydrazine-p- (3,4-dimethoxyphenyl) propionic acid in 60% yield. By recrystallization from water, a product is obtained with t. Il. 222-224 ° C (decomposition).

, 6 °.

Found,%: C 53.01; H 7.46; N 10.28.

Ci2Hi804N2.

Calculated,%: C 52.93; H 7.40; N 10.29.

Example 8. A. Preparation of L-a-ethyl-aureido-p- (3,4 - dimethoxyphenyl) propionic acid.

To a solution of 0.47 mol of La-ethyl-a-amino-p (3,4-dioxyphenyl) propionic acid and 600 mg of sodium bisulfite in 500 ml of water was added 57.6 g of potassium cyanate and the solution was heated to 60 ° C in an atmosphere nitrogen for 1 hour. Then add another portion (57.6 g) of potassium dianate and continue heating

2 hours. The resulting reaction product is methylated without being isolated as follows: water is distilled from the reaction zone until ammonia is completely absent. The residue is diluted to the original volume, 20 ml of 8 N are added. potassium hydroxide solution and cooled to 15 ° C. With vigorous stirring, 566 ml 8 n are added. solution of potassium hydroxide and at the same time 376 ml (3.6 mol) of dimethyl sulfate at such a rate that the temperature was not higher than 20 ° C. The addition is continued for about 1 hour.

The solution is acidified to pH 2 with hydrochloric acid and the precipitated product is filtered off.

After washing with water and drying, L-a-ethyl-a-ureido - | 3- (3,4 - dimethoxyphenyl) propionic acid is obtained with a yield of 70%. After recrystallization from ethanol: water, m.p. 218-220 ° C.

Found,%: C 56.71; H 6.88; N 9.53. CuH oNsOs.

Calculated,%: C 56.74; H 6.80; N 9.45. B. Preparation of L-a-ethyl-a-hydrazin-p (3,4-dimethoxyphenyl) propionic acid.

To an ice-cooled solution of 7.8 mmol of L-a-ethyl-a-ureido-p - (3,4 - dimethoxyphenyl) proiionic acid, obtained in step A, in 15.6 ml of 2.5 n. potassium hydroxide added 13.7 ml 0.71 n. sodium hypochlorite solution (9.75 mmol). 5 minutes after the end of the addition, the solution is heated to 80 ° C for 1.5 hours. Then 45 ml of toluene and 0.8 ml of hydrazine hydrate are added and the mixture is vigorously stirred while adding 8 ml

condensed hydrochloric acid. The mixture was stirred at 80 ° C for 30 minutes, then the phases were separated and the aqueous layer was extracted with 25 ml of toluene. The aqueous layer is evaporated to dryness and the mixture of salts is dissolved.

in ethanol. The alcohol solution obtained is neutralized to pH 6.4 with diethylamine and the precipitated precipitate is filtered off, washed with ethanol and dried to obtain L-a-ethyl-a-hydrazine-3,4-dimethoxyphenyl) propionic acid

with a yield of 53%. After recrystallization from water, a product with m.p. 215-220 ° C. Found,%: C 53.16; H 7.60; N 10.40.

Cl3H2oO4N2.

Calculated,%; C 58.19; H 7.51; N 10.44.

Example 9. L-a-hydrazine-a-methyl-p- (3,4-dioxyphenyl) propionic acid.

119.1 g (0.5 mol) of L-a-methyl-p- (3,4-dioxyphenyl) alanine sesquihydrate and toluene are placed in a flask and heated to boiling. With the aid of an aqueous separator, water is distilled off as an azeotrope and toluene is returned to the flask. When the theoretically calculated amount of water is distilled off, the mixture is concentrated in vacuo to dryness. The residue is poured

500 ml of methanol at 0-5 ° C are saturated with gaseous hydrogen chloride and left to stand for 42 hours.

The mixture is then evaporated to dryness and methyl methyl α-methyl-3,4-dioxyphenyl alanium is obtained. 67.58 g (0.3 mol) of ether obtained in the previous step are triturated with 1 l of tetrahydrofuran, and phosgene is passed through the mixture at 55-70 ° C at a rate of 0.5 mol / h. Then pass nitrogen. After 2 hours from the start of nitrogen flow, the mixture is cooled to room temperature. The solution is evaporated in vacuo to obtain methyl, L-a-chlorocarbonyl-a-methyl-p- (3.4carbonyldioxyphenpl) alanine ester. 500 ml of dimethoxyethane and 19.5 g (0.3 mol) of powdered sodium azide are added to the ether obtained in the previous step and boiled for 3 hours as it moves. The mixture is filtered, the filtrate is evaporated to dryness in vacuum, and the residue is crystallized from acetone: hexane to obtain LaN-azidocarbonyl-a-methyl-p (3,4-carbonyldioxyphenyl) alanine methyl ester. 32.03 g (0.1 mol) of the ether thus obtained are transferred for 18 hours at 25 ° C. with 100 ml of 1N. hydrochloric acid. The mixture was concentrated in vacuo to dryness to obtain L-a-N-azidocarbonyl-a-methyl-p- (3,4-dioxyphenyl) alanine. 300 ml of water are added to the residue and the mixture is first heated to 80 ° C with stirring, then cooled to 0 ° C and subjected to photolysis at the temperature of light of a mercury lamp. The mixture is then diluted to 1 liter with water heated to 90 ° C, filtered and the filtrate is treated with Amberlite III-120 ion exchange resin in hydrogen form, eluted with 1N. ammonium hydroxide and the eluate is evaporated to dryness in a vacuum. A crude product is obtained, after recrystallization of which L-a-hydrazine-a-methyl-p- (3,4-dioxyphenyl) propionic acid is obtained with m.p. 222-224 ° C. Example 10. L-a-ethyl-a-hydrazine-p- (3,4-dioxyphenyl) propionic acid. 112.6 g (0.5 mol) of L-a-ethyl-3,4-dioxyphenylalanine are displaced with 500 ml of methanol and the mixture is saturated at 0-5 ° C with gaseous hydrogen chloride. The resulting mixture was allowed to stand for 42 hours and then evaporated to dryness to obtain Lb-a-ethyl-3,4-dioxyphenylalanine methyl ester. 71.8 g (0.3 mol) of ether obtained in the previous step are triturated with 1 liter of tetrahydrofuran and phosgea is passed at 55-70 ° C at a rate of 0.5 mol / h and then nitrogen. After 2 hours from the start of nitrogen flow, the mixture was allowed to cool to room temperature. The solution is concentrated in vacuo to obtain β-chloro-carboxy-α-ethyl- (5- (3,4-carbonyldioxyphenyl)) alanine methyl ester. The ether obtained in the previous step is mixed with 500 ml of dimethoxyethane, 19.5 g (0.3 mol) of powdered sodium azide is added and the mixture is stirred at reflux for 3 hours. The mixture is filtered, the filtrate is concentrated in vacuo to dryness and the residue is crystallized from acetone: hexane mixtures to obtain LaN-azido methyl ester 5 10 15 20 25 30 35 40 45 50 55 60 carbonyl-a-ethyl - p- (3,4 - carbonyldioxyphenyl) alanine. 33.43 g (0.1 mol) of the ether thus obtained are stirred for 18 hours at 25 ° C. with 100 ml of 1N. hydrochloric acid. The mixture was concentrated in vacuo to dryness to obtain L-a-N-azidocarbonyl-a-ethyl-p- (3,4-dioxyphenyl) alanine. 300 ml of water are added to the residue and the resulting mixture is first heated to 80 ° C with stirring and then cooled to 0 ° C. The mixture is diluted to 1 L with water heated to 90 ° C, filtered, and the filtrate is cooled to room temperature. The cooled filtrate is treated with Amberlite IR-120 ion exchange resin in the hydrogen form, eluted with I n. ammonium hydroxide and evaporate the eluate to dryness in a vacuum. Get the crude product, the recrystallization of which receive L-a-ethyl-hydrazine- | 3 - (3,4-dioxyphenyl) propionic acid, so pl. 215-220 ° C. Example 11. A. L-a- (1-Acetylhydrazine) -methyl-p- (3,4-dimethoxyphenyl) propionitrile. 250 mg (5.2 mmol) of a 55% sodium hydride solution in mineral oil are washed with hexane and suspended in 6 ml of dimethyl sulfoxide (DMSO). To this mixture is added a solution of 1.05 g of L-a-acetamino-a-methyl-p (3,4-dimethoxyphenyl) propionitrile (4 mmol) in 10 ml of DMSO, and gases begin to form. 15 minutes after the gassing decay, the solution is cooled to 15 ° C and 4.5 mmol of chloramine is added as a solution in 12 ml of dry ether over 2 minutes. After stirring for 12 hours at room temperature, a few drops of acetic acid are added and the mixture is concentrated in vacuo. The resulting syrup is treated with water and chloroform. The organic layer is dried, the solvent is removed and the residue is crystallized from ethyl acetate and ether. After recrystallization from methanol, m.p. 121-123 ° C. Found,%: C 60.82; P 7,10; N 15.21. SMNShMZOz. Calculated,%: C 60.63; H 6.91; N 15.15. B. L-a-Hydrazine-a - methyl-p- (3,4-dioxyphenyl) propionic acid. 150 mg of the product obtained in the previous step are dissolved in 2.5 ml of concentrated hydrochloric acid and heated in a sealed tube at 120 ° C for 0.5-1 h. The mixture is evaporated to dryness in vacuo and the product is washed with ethanol. Upon addition of the diethylampic acid to pH 6.4, the acid precipitates, which is filtered off, washed with ethanol, and dried to obtain L-a-gndrazine-a-methyl - p - (3,4-dioxyphenyl) propionic acid. By recrystallization from water containing a small amount of sodium bisulfite, a product with m.p. 208 ° C (decomposition). -17.0 ° (c 2, СНзОН) Example 12. A. L-a- (1-benzoylhydrazine) -methyl - p- (3,4 - dibenzyloxyphenyl) propionamide.

AND

250 ml (5.2 mmol) of sodium hydride as a 55% solution in mineral oil are washed with hexane and suspended in 6 ml of DMSO. To this mixture is added a solution of 4 mmol of L-a-benzamido-a-methyl-p- (3,4-dibenzoyloxyphenyl) propionamnd in 10 ml of DMSO. 15 minutes after the gas evolution becomes insignificant, the solution is cooled to 15 ° C and a solution of 4.5 mmol of chloramine in 12 ml of dry ether is added within 2 minutes. After stirring for 12 hours at room temperature, a few drops of acetic acid are added and the mixture is concentrated in vacuo. The resulting syrup is treated with water and chloroform. The organic layer is dried, the solvent is removed, and the residue is crystallized from ethyl acetate and ether.

B. L-a-Hydraznp-a-methyl-p - (3,4-dioxyphenyl) propionic acid.

A solution of the product obtained in the previous step in 2.5 ml of concentrated hydrochloric acid is heated in a sealed tube at 100 ° C for 0.5–1 h. The final product is obtained as in Example 1.

Example 13. A. Preparation of L-p- (3,4-dimethoxybenzyl) -a-hydrazinpropionic acid.

To an ice-cooled solution of hydrochloric L-a-amino-p- (3,4-dimethoxybenzyl) proPIONIC acid (Ri H,)

2.2 g (8 mmol) in 2.5 n. Sodium hydroxide added 1.8 g (16 mmol) of hydroxylamine O-sulfonic acid. After 20 minutes, the mixture is heated at 90 ° C for 1 hour. The solution is acidified with hydrochloric acid and evaporated to dryness in vacuo. The residue is dissolved in ethanol and the crude product is precipitated by adding diethylamine to pH 6.4. The mixture is purified by chromatography on silica gel. After recrystallization from water, L-p- (3,4-dimethoxybenzyl) -a-hydrazinpropionic acid is obtained, m.p. 222-224 ° C (decomposition).

Found,%: C 53.01; H 7.46; N 10.28.

CisHigNaOi-HaO.

Calculated,%: C 52.93; H 7.40; N 10.29.

B. Hydrolysis of L-P- (3,4-dimethoxybenzyl) -. Agidrazinpropionic acid into L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid.

A mixture of 10.0 g (32.3 mmol) of Lp- (3,4-dimethoxybenzyl) -a-hydrazine propionic acid and 150 ml of concentrated hydrochloric acid is heated in a sealed tube at 120 ° C for 2 h. The resulting mixture is evaporated to dryness. under vacuum and the product is leached with ethanol. Hydrazinic acid precipitates upon addition of diethylamine to pH 6.4, the mixture is filtered and the precipitate is washed with ethanol and dried to obtain 6.5 g of L-p- (3,4-dioxybenzyl) a-hydrazinpropionic acid (73%). By recrystallization from water containing a small amount of sodium bisulfite, a product is obtained with a mp. 208 ° C (decomposition).

 17.3 ° (с 2, СНЗОП)

12

Found,%: C 49.13; H 6.74; N 11.19. ClOniN204-H90.

Calculated,%: C 49.17; H 6.60; N 11.47. Example 14. A. Preparation of L-a-N-acetylhydrazine-p - (3,4-dimethoxybenzyl) propionitrile.

250 mg (5.2 mmol) of sodium hydride in the form of its 55% solution in mineral oil are washed with hexane and suspended in 6 ml (DMSO). To this mixture is added a solution of 1.05 g (4 mmol) of L-a-acetamido-p- (3,4-dimethoxybenzyl) propionitrile in 10 ml of DMSO. After a drop in gas evolution (15 minutes), the solution is cooled to 15 ° C and a solution of 4.5 mmol of chloramine in 12 ml of dry ether is added over 2 minutes. After stirring for 12 hours at room temperature, a few drops of acetic acid are added and the mixture is concentrated in vacuo.

0 The resulting syrup is treated with water and chloroform. The organic layer is dissolved, the solvent is removed and the residue is crystallized from ethyl acetate and ether; According to NMR spectroscopy, a mixture of the product and the starting material is obtained in the ratio 6: 4. Chromatographic using 30 g of silica gel (elution with chloroform and 3% ethanol) yields 570 mg (52%) of L-a-N-acetylhydrazino-p- (3,4-dimethoxybenzyl) propionitrile and g) 320 mg of the starting material. This corresponds to 56% of the theoretical yield, or 80%, calculated on the unconverted starting material. Upon recrystallization from methanol, a product with m.p. 121-123 ° C. Found,%: C 60.82; H 7.10; N 15.21.

CuHigNsOs.

Calculated,%: C 60.63; H 6.91; N 15.15.

B. Hydrolysis of L-a-M-acetylhydrazino-p- (3,4 dimethoxybenzyl) propionitrile to L-p- (3,4 Dioxybenzyl) -a-hydrazine propionic acid.

A solution of 150 mg of the product obtained in the previous step in 2.5 ml of concentrated hydrochloric acid is heated in a sealed tube at 120 ° C for one and a half hours.

After isolating in the usual manner, 50 mg of hydrazinic acid are obtained with a m.p. 208 ° C (decomposition).

 -17.3 ° (c 2, SNZON)

Example 15. A. Preparation of L-a-N-acetylhydrazino - p- (3,4-dimethoxybenzyl) propionic acid. To the porridge from 100 ml of water, 200 ml of ether,

36 ml of concentrated hydrochloric acid and 70.3 g (0.25 mol) of LN-acetyl-a- (3,4-dimethoxybenzyl) alanine at O-10 ° C are added dropwise with vigorous movement of 18 g (0, 26 mole) of sodium nitrate in 36 ml of water.

The temperature is maintained at -10 ° C during the addition and stirring for 1 hour. The ether layer is separated, the aqueous layer is extracted in portions with 100 ml of ether, the ether extracts are combined, washed with brine and dried over MgSO4.

The mixture was concentrated in vacuo to give L-N-acetyl-N-nitroso-p- (3,4-dimethoxybenzyl) alanine.

A mixture of 65.5 g (1.0 mol) of zinc powder and 100 ml of water is cooled to 10 ° C. 75 g (0.24 mol) of the nitroso compound in 150 ml of glacial acetic acid are added at 10-15 ° C under stirring. After that, the mixture is allowed to warm to room temperature for about 1 hour, then it is heated to 80 ° C in a water bath. The mixture is filtered to remove unreacted zinc and the precipitate is washed with three portions of 25 ml of warm 2N. hydrochloric acid. The combined filtrate is cooled to room temperature and alkalized to a pH of 6.5. The precipitate is filtered and dried. The residue is extracted with three portions of 200 ml of chloroform. The extract, dried over MgSO4, is concentrated in vacuo, the residue is converted from methanol and L-a-N-acetylhydrazine-a (3,4-dimethoxybenzyl) propionic acid is obtained.

B. Hydrolysis of L-a-L-acetylhydrazine-a- (3,4-dimethoxybenzyl) propionic acid into L-a (3,4-dioxybenzyl) -a -hydrazin-propionic acid.

This compound is hydrolyzed to b-a- (3,4-dioxybenzyl) -a-hydrazinpropionic acid according to the procedure described in example 14.

Example 16. Preparation of L-3-chloro-5 (3,4-dimethoxybenzyl) -5-methyl-4-imidazolinone.

LaN-acetylamino-p- (3,4-dimethoxybenzyl) propionic acid in the amount of 56.2 g (0.20 mol) and 19.0 g (0.25 mol) of ammonium rodanic are suspended in 100 ml of acetic anhydride and 1.0 ml of acetic acid. The mixture is heated in a water bath, cooled and poured into water at 10 ° C. Then it is filtered off, the precipitate is washed and dried. The crude product is recrystallized from methanol-water to obtain a-1-acetyl-5- (3,4-dimethoxybenzyl) -5-methyl-2-thiogidantoin.

Acetylthiohydantoin is dissolved in 6N. hydrochloric acid when heated in a water bath. Upon evaporation, L-5- (3,4-dimethoxybenzyl) -5-methyl-2-tpohydantoin is obtained, which is recrystallized from water.

L-5- (3,4-dimethoxy) -5-methyl-2-thiogidantoin in the amount of 28.0 g (0.1 mol) is dissolved in 600 ml of boiling amyl alcohol and 23.0 g are added with vigorous stirring. sodium nitrate. When sodium nitrate is dissolved, the mixture is neutralized to pH 6.0 with 6 n. hydrochloric acid and the mixture is extracted with chloroform.

The chloroform extract is dried over sodium sulfate and concentrated to give crude L-5- (3,4-dimethoxybenzyl) -5-methyl-4-imidazolinone. The crude product is recrystallized from acetone-hexane. 12.5 g (0.05 mol) of imidazolinone are dissolved in 300 ml of 50% aqueous methanol and 1.25 equivalents of sodium hypochlorite are added at about 0 ° C.

The mixture is then heated under reflux for 1 hour and concentrated to remove the methanol.

The residue is L-3-chloro-55 (3,4-dimethoxybenzyl) -5-methyl-4-imidazolinone.

B. Hydrolysis of L-3-chloro-5- (3,4-dimethoxybenzyl) -5-methyl-4-imidazolinone to L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid.

The residue is alkalinized with 50% sodium hydroxide and boiled under nitrogen for 30 minutes. After cooling the mixture to room temperature, it is acidified with concentrated hydrochloric acid to obtain

5 L-p- (3,4 - dimethoxybenzyl) -a - hydrazinpropionic acid. This compound can be hydrolyzed, as previously described, to produce L-p- (3,4-dioxybenzene) -a-hydrazine propionic acid.

0

Example 17. A. Preparation of L-p- (3,4-dimethoxybenzyl) -a - diaziridonylpropionic acid. To a solution of 100 g (0.47 moles) of La-methyl 5 (3,4-dioxyphenyl) alanine and 600 mg of sodium bisulfite in 500 ml of water, 57.6 g of potassium cyanate are added and the solution is heated to 60 ° C under a nitrogen atmosphere in for 1 hour. Then another portion of 56.7 g of potassium silicate is added and

The Q mixture is heated for another 2 hours. According to NMR spectroscopy, during this time about 90% of the amino acid is converted to L-4- (3,4-dnoxybeisyl) 4-methylhydantoic acid.

28.2 g (0.1 mol) of the obtained acid and

g 69.5 g of hydroxylamine hydrochloride in 100 ml of water are heated under nitrogen for 18 hours. During cooling, L-p (3,4-dimethoxybenzyl) -a-oxybenzyl-a-oxyureido-propionic acid crystallizes. The product is recrystallized from methanol-water.

40

An equivalent amount of dicyclohexylcarbodiimide in 50 ml of dimethoxyethane is added to 14.9 g (0.05 mol) of oxyureido acid in 50 ml of dimethoxyethane. The mixture was stirred at room temperature for 2 hours, filtered and the filtrate was concentrated in vacuo to give L-5- (3,4-dimethoxybenzyl) -5-methyl-1,2,4-oxydiazine (4H, 5H) -3,6-dione, Oxydiazine is dissolved in 100 ml of 50% aqueous methanol at -5 ° C and 0.062 equivalents of sodium hypochlorite are added. The mixture is then boiled for 1 hour and concentrated to remove the methanol. The residue is alkalinized with 50% sodium hydroxide and heated under reflux for 2 hours. The intermediate L-p- (3,4-dimethoxybenzyl) -a-diaziridonylpropionic acid is not isolated.

B. Hydrolysis of L-p- (3,4-dimethoxybenzyl) -agidrazinpropionic acid in L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid.

Upon acidification, crude L-p- (3,4-dimethoxybenzyl) -a-hydrazinpropionic acid

extracted with chloroform, the extract is dried and

chromatographic on silica gel. 15 The purified product is treated as described in Example 13 to obtain L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid. Example 18. A. Preparation of L-5- (3,4 dimethoxybenzyl) -5-methyl-1,2,4-oxadiazine (4H, 5H) -3,6-dione. L-a-N-acetylamino - p- (3,4 - dimethoxybenzyl) propionitrile in the amount of 52.4 g (0.2 mol) is stirred with 500 ml of tetrahydrofuran. Heated to 45-50 ° C. Phosgene is passed through the mixture until its excess is not reached. The excess phosgene is removed with a stream of nitrogen, after which the mixture is concentrated in vacuo to half the volume. At the room temperature, 8.25 g (0.25 mol) of hydroxylamine and 11.2 g (0.2 mol) of potassium hydroxide in 70 ml of methanol are added to the residue in order to avoid the loss of hydroxylamine as a hydrochloric acid salt. After the addition is complete, the mixture is heated to boiling for 30 minutes and maintained at reflux for 30 minutes. The mixture is concentrated in vacuo to dryness and the residue is crystallized from acetone-hexane. N-Acetyliminooxadiazinone is heated with 100 ml 2 n. hydrochloric acid for 1 h at 100 ° C. The mixture is cooled to room temperature, the oxadiazinedione is extracted with chloroform, the extract is dried and evaporated in vacuo. L-5- (3,4-dimethoxybenzyl) -5-methyl1, 2,4-oxadiazine- (4H, 5H) -3,6-dione is recrystallized from acetone-hexane. B. Hydrolysis of L-5- (3,4-dimethoxybenzyl) -5methyl-1, 2,4-oxadiazine- (4H, 5H) -3,6-dione in L-p- (3,4-dioxybenzyl) -a - hydrazinpropionic acid. L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid is prepared as described in Example 13. Example 19. A. Preparation of L-1,4-diamino-3, 6-bis (3,4-dimethoxybenzyl) -3,6 - dimethylpiperazin-2, 5-dione. A mixture of 23.0 g (0.1 mol) of L-a-amino-a- (3.4 dimethoxybenzyl) propionic acid in 23 ml 4 n. NaOH (0.1 mol) is cooled to 5 ° C and 30 ml of 4 N are added. NaOH (0.12 mol) and 18.7 g (0.11 mol) of carbobenzoxychloride alternately in 5 equal portions for 30 minutes with vigorous shaking and cooling in an ice bath. The reaction mixture should be slightly alkaline the whole time. After completion of the reaction, the solution is extracted with ether to remove excess acid chloride, the aqueous fraction is acidified over Congo red 5N. HC1 and cooled in an ice bath. After cooling for 15 minutes to 0 ° C, crystalline M-carbobenzoxy-L-a-amino p (3,4-dimethoxybenzyl) propionic acid is filtered off and dried. This intermediate is combined with the following intermediate as described below. Hydrogen chloride gas is passed through a solution of 23.9 g (0.1 mol) of L-a-amino (3,4-dimethoxybenzyl) propionic acid into 500 ml of methanol until it is completely saturated. The mixture is stirred at room temperature for 24 hours, then evaporated to dryness in vacuo. The residue is crystallized from methanol-ethyl acetate. L-a-amino-p- (3,4-dioxybenzyl) propionic acid methyl sulfate is used in the next step. To a mixture of 37.3 g M-carbobenzoxy-L-a-amino | 3- (3,4-dimethoxybenzyl) propionic acid, 25.3 g of methyl ester b-a-amino-p- (3,4-dimethoxybenzyl) propionate and 14 ml of triethylamine in 600 ml of methylene chloride added 21.8 g of M, N-dicyclohexylcarbodiimide. After keeping the mixture for 18 hours at room temperature, 1.0 ml of glacial acetic acid is added. The precipitated dicyclohexyl urea is removed by filtration, and the filtrate is successively washed with water, dilute hydrochloric acid, water, half-saturated sodium bicarbonate solution, saturated aqueous salt solution, and dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is dried in vacuo over phosphoric anhydride and recrystallized from acetone / hexane. 6.1 g (0.01 mol) of dicarbobenzoxydipeptide methyl ester in 150 ml of methanol containing 0.35 g of 10% palladium on carbon and 5 drops of acetic acid are hydrolyzed at room temperature and atmospheric pressure until about 0.01 mol of carbon dioxide. The mixture is concentrated to dryness, and the residue is recrystallized from acetone-hexane to obtain b-3,6-bis (3,4-dimethyl-piperazine) 2, 5-dione. To a mixture of 100 ml of water, 200 ml of ether, 28.8 ml of concentrated hydrochloric acid and 44.25 g (0.1 mol) of piperazin-2, 5-dione obtained earlier at O-10 ° C are added dropwise 14.5 g of sodium nitrite (0.21 mol) in 30 ml of water at O-10 ° C and stirred for 1 hour. The ether layer is separated, the aqueous layer is extracted with two 100 ml ether portions, and the combined ether extract is washed with a saturated salt solution and the ether extract is dried over MgSO4. The ether solution is concentrated under vacuum to obtain 1,4-dinitrosopiperazin-2,5-dpona. A mixture of 26.1 g (0.40 mol) of zinc powder and 100 ml of water is cooled to 10 ° C. With stirring, 25.0 g (0.05 mol) of 1,4-dinitrosopiperazin-2,5-dione in 150 ml of glacial acetic acid at 10-15 ° C is added. The mixture was allowed to warm to room temperature over 1 h, then it was heated to 80 ° C in a water bath. The mixture is filtered to remove zinc, the precipitate is washed 3 times with warm 2N. hydrochloric acid in 25 ml portions. The combined filtrate is cooled to room temperature and, upon cooling, alkalinized to pH 6.5. Filter the mixture and dry the precipitate. Sediment extracted three

17

200 ml portions of chloroform. The extract, dried over MgSO4, is concentrated in vacuo, the residue is recrystallized from methanol to obtain L-1,4-diamino-3,6-bis- (3,4-dimethoxybenzyl) -3,6-dimethylpiperazine - 2.5 dione.

B. Hydrolysis of L-1,4-diamino-3,6-bis- (3,4-dimethoxybenzyl) -3,6-dimethylpitserazine - 2,5-diocetes in L-p- (3,4-dioxybenzyl) -a -hydrazinpropionic acid.

9.45 g (0.02 mol) of diaminopiperazinedione are hydrolyzed to give L-a- (3,4-dioxybenzyl) a-hydrazinpropionic acid, as described in Example 13.

Example 20. A. Preparation of b-1,4-diamino-3, 6-bis (3,6-dimethoxybenzyl) -3,6-dimethylpiperazin-2, 5-dione.

44.25 g (0.1 mol) of piperazin-2,5-dione from example 19 is dissolved in 500 ml of dry dimethoxyethane and 0.2 mol of sodium hydride (previously freed from mineral oil by washing with hexane and suspended in 120 ml of dimethoxyethane). After the end of gas evolution (15 min), the mixture is cooled to 50 ° C and a solution of 0.23 moles of chloramine in 600 ml of dimethoxyethane is added. The mixture is stirred for 2 hours at room temperature and for another 2 hours at 50 ° C. After cooling to room temperature, the mixture is made slightly acidic by the addition of glacial acetic acid, and the mixture is concentrated to a syrup under vacuum. The residue is treated with chloroform and water. The chloroform layer is separated, washed, dried over magnesium sulfate and evaporated in vacuo. The resulting residue is recrystallized from methanol as in Example 19, and L-1,4-diamino-3,6-bis (3,4-dimethoxybenzyl) -3,6-dimethylpiperazium-2,5-dione is obtained.

B. Hydrolysis of L-1,4-diamino-3,6-bis- (3,4-dimethoxybenzyl) -3,6-dimethylpiperazine - 2,5-dione to L-p- (3,4-dioxybenzyl) -a -hydrazinpropionic acid.

The diaminopiperazinedione is hydrolyzed as described in Example 1 to obtain L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid, m.p. 208 ° C (decomposition).

Example 21 A. A. Preparation of L-p- (3,4-dimethoxybenzyl) -a (3-feiyl1-diaziridinyl) propionic acid methyl ester.

28.96 g (0.1 mol) of Lp- (3,4-dimethoxybenzyl) propionic acid hydrochloride methyl ester is stirred with 300 ml of benzene and 10.1 g (0) are added dropwise with cooling to 10-15 ° C. , 1 mole) of triethylamine. After adding 10.6 g of benzaldehyde, 20.6 g (0.1 mol) of dicyclohexylcarbodiimide was added to 25 ml of benzene and the mixture was stirred for 18 hours at room temperature without access of moisture. The mixture is filtered, washed and the filtrate is concentrated in vacuo.

To the resulting Schiff base, 100 ml of ether, saturated with 0.1 mol of ammonia, are added and 0.1 mol of (35N) chloramine is added. After a short time18

ammonium chloride begins to precipitate. The mixture is left for 18 hours, filtered and the precipitate is washed with ether. The ether solution is partially concentrated in vacuo, extracted with water, the ether extract is dried over CsSO3, filtered and concentrated in vacuo.

B. Hydrolysis of L-p- (3,4-dimethoxybenzyl) -a- (3-phenyl-1-diaziridinyl) methyl ester

propionic acid in L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid.

L-p- (3,4-dimethoxybenzyl) a- (3-phenyl-1-diaziridinyl) methyl a-propionic acid methyl ester is crystallized from acetone-hexane. Then it is hydrolyzed by the method of example 13 and get to L-p- (3,4-dioxybenzyl) a-hydrazinpropionic acid with so pl. 208 ° C (decomposition). Example 22. A. Preparation of L-3-amino 4- (3,4-dimethoxybenzyl) -4-methyl -2-trifluoromethyloxazolidone-5.

To a solution of 23.0 g (0.1 mol) of L-a-amino- (3.4 dimethoxybenzyl) propionic acid in 100 ml of dimethoxyethane while cooling to

21 g (0.1 mol) of trifluoroacetic anhydride is added dropwise to 15-20 ° C. The mixture is heated under reflux for 30 minutes with stirring and then cooled to room temperature. 23.8 g added

(0.2 mol) of thionyl chloride and the mixture is refluxed for 2 hours. The mixture is evaporated in vacuo to give 2-trifluoromethyl - 4- (3,4-dimethoxybenzyl) - 4-methyloxazolone-5, which is crystallized from toluene .

To a solution of 30.33 g (0.1 mol) of oxazolone and 10.69 g (0.11 mol) of potassium rhodium in 150 ml of acetic acid and mushroom 17.86 g (0.11 mol) of iodine monochloride with stirring. The mixture is hydrogenated under stirring and heated to 85-90 ° C for 2 hours at a hydrogen pressure of 1-3 atm in the presence of platinum oxide as a catalyst in 1 liter of pyridine. The mixture is filtered, washed with 100 ml of pyridine and evaporated to dryness in vacuo. L-3-amino-4- (3,4-dimethoxybenzyl-4-methyl-2-trifluoromethyloxazolidone-5 is obtained.

B. Hydrolysis of L-3-amino-4- (3,4-dimethoxybepzil) -4-methyl-2-trifluoromethyloxazolidone-5 into L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid.

To the resulting product was added 150 ml. 6 n. hydrochloric acid and the mixture is heated in an autoclave to 150 ° C for 2 hours. The autoclave is cooled, blown and the mixture is evaporated in

vacuum to dryness. The residue is crystallized from

water containing 1% sodium bisulfite, and

a pure L-p- (3,4-dioxybenzyl) -agidrazinpropionic acid is obtained.

Example 23. A. Preparation of L-a- (1-Mentoxyacetylhydrazo) -: p- (4-oxides-3-methoxybenzyl) propionitrile.

To a mixture of 92.3 g (0.435 moles) O, L-a-hydrazin-a-vanillylpropionitrile in 2 liters of dioxane and 0.5 liters of tetrahydrofurap, 100 g (0.430 moles) of 1-mentoxyacetate are added simultaneously.

tilchloride and 58 ml (0,415 moles) of triethylamine. The mixture is stirred at room temperature for 18 hours. The precipitated salts and solvents are removed to give an oily mixture. The residue was crystallized from ethyl acetate and hexane, to give 66 g of product for the most part of the L-a diastereoisomer.

The recrystallized product is recrystallized 3 times more from ethyl acetate: hexai and 12 g of pure L-a (1-methoxy-acetylhydrazo) -p- (4-hydroxy-3-methoxybenzyl) propionitrile are obtained, mp. 126-126.5 ° C.

Found,%: C 66.21; H 8.68; M 10.23.

С2зНз5МзО4.

Calculated 7o: C 66.16; H 8.45; N 10.06.

B. Hydrolysis of L-a- (1-methoxyacetylhydrazo) P- (4-hydroxy-3-methoxybenzyl) propioiitrile into L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid.

25 ml of metaiol and 30 ml of concentrated hydrochloric acid are saturated with gaseous hydrogen chloride at a temperature from 0 to minus 10 ° C. With stirring, 3.0 g (0.0072 mol) of La (1-methoxy-acetylhydrazo) -p - (4-hydroxy-3-methoxybenzyl) propionitrile was added to the mixture at 0 ° C and the mixture was stirred to warm to room temperature over a period of 18 h. The solution is evaporated to dryness, and the residue is dissolved in a mixture of 45 ml of concentrated hydrochloric acid and 5 ml of acetic acid. This solution is heated in a sealed tube at 120 ° C for 90 minutes. The resulting dark solution is evaporated to dryness. 25 ml of ethanol is removed from the residue. After the addition of 5 ml of benzene, the hydrazine acid precipitates with diethlamine at pH 6.5. The crude product 1.1 g (56%) is treated with activated charcoal, filtered and crystallized from 50 ml of boiling water to give L- | 3- (3,4-dioxybenzyl) -a-hydrazinpropionic acid, m.p. 208 ° C.

, 5 -17.3 ° (c 2, SNZON).

Example 24. Hydrolysis of methyl ester of L-p- (3,4-dibenzyloxybenzyl) - a-hydrazinpropionic acid into L-p- (3,4-dibenzoyloxybenzoyl) -a-hydrazinpropionic acid.

9.6 g (0.04 mol) of L-p (3,4-dibenzyloxybenzyl) -a-hydrazinpropionic acid methyl ester is dissolved in 1N. hydrochloric acid and boiled for 3 hours. The mixture was evaporated to dryness in vacuo and L-p- (3,4-dibenzyloxybenzyl) -a-hydrazinpropionic acid was obtained in the form of its hydrochloric acid salt. The compound was isolated from the salt using an ion exchange resin.

A. Preparation of L-1-S Mentoxyacetylhydrazino-p- (4-hydroxy-3-methoxybenzyl) propionitrile.

A mixture of 228.3 g (1.0 mol) of 1-methoxyacetic acid methyl ester in 300 ml of methanol and 120 ml of 85% hydrazine hydrate is boiled for 4 hours. The mixture is concentrated under vacuum to dryness, and the residue is recrystallized from

20

methanol-water mixtures to obtain methyloxyacetylhydrazine.

To 90.1 g (0.5 mol) of 4-hydroxy-3-methoxyphenylacetone in 1 l of a 1: 1 mixture of methanol and water were added 171.3 g (0.75 mol) of 1-menthoxyacetylhydrazine and 32 g (0.54 mole) sodium cyanide. The mixture was vigorously stirred for 18 hours at room temperature, then evaporated in vacuo to half volume and left to crystallize at 0-5 ° C for 48 hours. The product was filtered, dried and recrystallized from ethyl acetate, the solution at 30 ° C and the mixture was minus 20 ° C. The product is L-l-N-mentoxyacetylhydrazino-p-4-hydroxy-3-methoxybenzylpropionitrile, m.p. 126-126.5 ° C.

B. Hydrolysis of L-N-mentoxyacetylhydrazino-4-hydroxy-3-methoxybenzylpropionitrile.

The product is hydrolyzed as described in Example 13, thereby obtaining L-a- (3,4-dioxybenzyl) -a-hydrazine propionic acid.

Example 26. A. Preparation of methyl ester of L-a-M-acetyl-L-phthaloyl hydrazio-4methoxy-3-hydroxybenzoyl propionic acid. 97.6 g (0.5 mol) of La-methyltyrosine, 153.1 g (1.5 mol) of acetic anhydride and 200 ml of pyridine are heated in a water bath at 90-95 ° C for 3 hours. The mixture is cooled to room temperature. temperature, poured into 500 g of ice and extracted with ether. The ether extract is washed with water, dilute acid and brine. After the mixture was concentrated in vacuo, the residue was recrystallized from acetone-hexane.

111.7 g (0.4 mol) of L-O, M-diacetyl-a-methyl-tyrosine are heated under reflux with 1 liter of 1N. hydrochloric acid for 2 hours. The mixture was concentrated in vacuo to dryness. The residue is stirred into a mixture of chloroform-water. Vacuum drying. The residue L-N-acetyl-a-methyltnrosine is recrystallized from methanol-water.

71.19 g (0.3 mol) of L-N-acetyl-a-methyl-tyrosine are nitrosated and reduced by zinc in Example 15, to obtain L-a-N-acetylhydrazino-p-4-oxybenzylpropionic acid.

To 50.45 g (0.2 mol) of the N-acetyl compound obtained in the previous step, in 25 ml of a 1: 1 mixture of methanol-water, 25.47 g (0.2 ml) were added under reflux in a nitrogen atmosphere. mole) benzaldehyde in 50 ml of methanol. The mixture was boiled for 2 hours, concentrated to dryness in vacuo, and the residue was crystallized from acetone-hexane to give L-a-L-acetyl-M-benzylidene hydrazino-p-4-hydroxybenzylpropionic acid.

To 50.05 g (0.15 mol) of the above hydrazone in 150 ml of methanol and 50 ml of triethylamine were added 33.3 g (0.17 mol) of tetranitromethane in 50 ml of methanol. The mixture is stirred for 18 hours at room temperature, evaporated in vacuo to dryness, treated with chloroform and extracted with dilute acetic acid. The extract, dried over sodium sulfate, is evaporated to dryness in vacuo and the residue is recrystallized from methanol. L-a-N-acethyl-N-benzylidene hydrazino-p-4-hydroxy-3-nitrobenzylpropionic acid is obtained. To 38.44 g (0.1 mol) of the obtained compound in 100 ml of dimethoxyethane, an ethereal solution of 0.22 mol of dasomethane is added dropwise with stirring at-5 ° C. The mixture was allowed to warm to room temperature and left for 18 hours. The mixture is concentrated to dryness and the residue is recrystallized from acetone-hexane to obtain b-a-M-acetyl-M-bisylenidenehydrazino-4-methoxy-3-nitrobenzylpropionic acid methyl ester. 20.62 g (0.05 mol) of the ether obtained at the previous stage are reduced to 200 ml of methanol over platinum (starting from 0.100 g of oxide) at room temperature and 3 atm to absorb 5 moles of hydrogen per 1 mole of the starting product. The catalyst is filtered off, the filtrate is concentrated and the residue is recrystallized from methanol-water to obtain L-a-N-acetylp1drazino-p-3-amino-4-methoxybenzylpropionic acid methyl ester. To a mixture of 28.13 g (0.1 mol) of the above ester in 300 ml of dimethoxyethane was added at room temperature 14.81 g (0.1 mol) of phthalic anhydride in 100 ml of dimethoxyethane. After adding 1 g of 2,4-dinitrobenzenesulfonic acid, the mixture is boiled under reflux for 5 hours. The mixture is cooled, concentrated in vacuo to dryness. The residue is taken up in ice-cooled chloroform and water, and the aqueous layer is made alkaline with sodium bicarbonate. The chloroform layer is washed with water, dried over magnesium sulfate and concentrated. The residue is crystallized from methanol-water to obtain methyl B-a-M-acetyl-S-phthaloyl-hydrazino-4-methoxy-3-aminobenzyl-propionic acid methyl ester. To 20.57 g (0.05 mol) of the ester from the preceding stage, in 22 ml of 50% sulfuric acid t O-5 ° C, add 3.8 g (0.055 mol) of sodium nitrite in 15 ml of water. The mixture was stirred for 1 hour in an ice bath, allowed to warm to room temperature and then heated in a water bath until the evolution of nitrogen was complete. The mixture is cooled, extracted with ethyl acetate, the extract is dried over sodium sulfate and concentrated to dryness in vacuo. The residue is L-a-L-acetyl-L-phthaloyl hydrazino-4methoxy-3-hydroxybenzoyl propionic acid methyl ester. B. Hydrolysis of b-a- methyl ester: M-acetyl-phthaloyl-hydrazino-4-methoxy-3-hydroxybenzoyl-propionic acid to b- | 3- (3,4-dioxybenzyl) -a-hydrazin-propionic acid. The residue is hydrolyzed, as previously described in Example 13, to obtain L-p- (3,4-dioxybenzyl) -a-hydraziiiropionic acid with m.p. 208 ° C (decomposition). Example 27. A. Preparation of L-4- (3,4 dimethoxybenzyl) -4-methyldiazetidinone-3. To 20.63 g (0.01 mol) of L-a-amino-p- (4-hydroxy-3methoxybenzyl) yropionitrile in 100 ml of dimethoxyethane was added 0.15 mol of diazomethia as an ether solution at 5-10 ° C. The mixture is stirred for 2 hours while maintaining this temperature, then it is allowed to warm to room temperature. The mixture is concentrated in vacuo to remove traces of diazomethane and then diluted with dimethoxyethane to its original volume. A half volume of treg.butyl alcohol is added, and at 0-5 ° C with vigorous stirring, 130 ml of 2.5N is added. sodium hypochlorite. With vigorous stirring, the mixture is allowed to warm to room temperature and stirred for an additional 1 hour. The mixture is concentrated in vacuo at room temperature and the concentrate is extracted with ether, dried over sodium sulfate and concentrated to dryness in vacuo at 10-20 ° C. The residue is heated for 1 hour at 80-85 ° C in pyridine (100 ml), cooled and concentrated in vacuo. The solid consists of diazethidinone and pyridine hydrochloride, it is distributed between water and chloroform, washed with diluted 1N. hydrochloric acid, 5% aqueous sodium bicarbonate and brine. The chloroform layer was dried over sodium sulfate and concentrated in vacuo to give L-4- (3,4-dimethoxybenzyl) -4-methyldiazetidinone-3. An analytical product is obtained by recrystallization from a mixture of benzene: nhexane. B. Hydrolysis of L-4- (3,4-dimethoxybenzyl) -4 methyldiazetidinone-3 into L-p- (3,4-dioxybenzyl) -a-hydrazinepropionic acid. 7.09 g of the said azetidinone (0.03 mol) is hydrolyzed with 25 ml of constantly boiling hydrobromic acid, first by moving for 1 hour at room temperature, then for 1 hour by heating under reflux. L-p- (3,4-dioxybenzyl) -agidrazinpropionic acid is obtained from the hydrolyzed mixture with m.p. 208 ° C (decomposition). Example 28. A. Preparation of L-1,3-diamino-5- (3,4-dimethoxybenzyl) - 5-methylgndantoin. 28.23 g (0.1 mol) of L-p- (3,4-dimethoxybenzyl) -a-ureidopropionic acid are boiled for 3 hours with 150 ml of a mixture of 1: 1 ethanol and water, acidified to pH 2 with concentrated hydrochloric acid. . The mixture is concentrated in vacuo, to remove ethanol, to approximately / volume and allow to cool. After keeping at 0 ° -5 ° C for 1 h, the mixture is filtered, and the precipitate is washed and existing to give 0, L-5- (3,4-dimethyl-oxybenzyl) -5-methylhydantoin. Hydantoin is recrystallized from methanol-water. To 13.21 g (0.05 mol) of hydantoin in 100 ml of dimethyl sulfoxide were added 2.3 g (0.1 mol) of sodium hydride in mineral oil. The mixture is heated at 50 ° C. Irn stirring until sodium hydride reacts. The mixture is cooled to room temperature and 0.1 mol of chloroamine in ether is added to it. After one hour at room temperature, the mixture is heated to 80 ° C with stirring and maintained for 1 hour at 75-80 ° C. The mixture is concentrated in vacuo to about D volume, diluted with an equal volume of water and filtered. After drying in air at 50 ° C, the precipitate is recrystallized from methanol with water to obtain L-1,3-diamino-5- (3.4 dimethoxybenzyl) -5-methylp1-dantone. B. Hydrolysis of L-1,3-diamino-5- (3,4-dimethoxybenzyl) -5-methylhydanotoin. This hydantoin is boiled with constantly boiling hydrobromic acid for 3 hours to obtain crude L-p-3,4-dioxybenzyl-agidrazin-propionic acid, which is purified as described in Example 27. Example 29. A. Preparation L -1- (Nphthalimido) -2- (3,4-dimethoxybenzyl) -2-methylhydantoin. 131.15 g (0.5 mol) of D-a-N-acetylamino-a (3,4-dimethoxybenzene) propionitrile is stirred at 0-5 ° C with 1 liter of 45% hydrochloric acid. The mixture was allowed to warm to room temperature with stirring and then boiled for 2 hours. The mixture was concentrated in vacuo to about 100 ml, filtered and the precipitate was washed with ice water and dried. The hydrochloric acid salt of the amino acid is mixed with 200 ml of water and diethylamine pH 6.0 is added. After stirring for one hour at room temperature, the mixture is filtered, washed and dried, yielding B-a-amio-p- (3.4 dimethoxybenzyl) propionic acid. To a mixture of 23.9 g (0.1 mol) of 0-amino-p- (3.4 dimethoxybenzyl) propionic acid in 200 ml of acetic acid containing 10% by weight of hydrogen bromide was added 10.35 g (0.15 mol ) sodium nitrite in 20 ml of water at 5-10 ° C. The mixture is stirred for 2 hours at 5-15 ° C, then gently heated to 50 ° C with stirring. The mixture was filtered through a glass melted filter, and the filtrate was concentrated in vacuo. The residue was taken up in chloroform, washed with water, dried over magnesium sulfate, and concentrated. The residue is crystallized from methanol-water to give D-a-bromo- (3,4-dimethoxybenzyl) propionic acid. Into a solution of 30.3 g (0.1 mol) of O-a-bromo-p (3,4-dimethoxybenzyl) propionic acid in 200 ml of methanol, a cooled gaseous hydrogen chloride is added. The mixture is left to stand at room temperature for 42 hours. After concentrating to dryness in vacuo, the residue is stirred into a water-ether mixture, extracted with sodium bicarbonate 5%, water and brine and the ether extract is dried (magnesium sulfate. Evaporated in vacuo to dryness Da-bromo-p- (3,4-dimethoxybenzyl) propionic acid methyl ester is obtained. 12.1 g (0.09 mol) of aminoisoindoline, this ester and 200 ml of benzene are boiled for 3 hours under nitrogen atmosphere. The mixture is cooled by adding 2.07 g (0.09 mol) of sodium hydride with stirring and the mixture is again boiled in an atmosphere The mixture is cooled for 3 hours, the water is added dropwise, the aqueous layer is neutralized with glacial acetic acid. The layers are separated and the benzene layer is washed with water, brine and dried over magnesium sulfate. benzene-hexane to obtain L-1- (N-phthalimido-2 - (3,4-dimethoxybenzyl) -2-methylaziridinone. B. Hydrolysis of L-1- (L-phthalimido-2- (3,4-dimethoxybenzyl) - 2-methylisaridinone in Lp (3,4-dioxybenzyl) -a-hydrazine propionic acid. The product obtained in the previous stage is treated with constantly boiling hydrobromic acid, as described previously in Example 27, to obtain L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid. Example 30. A. Preparation of L-6- (3,4 dimethoxybenzyl) -6-methyl-1,2,4-triazinedione-5, 6. To 97.12 g (0.5 mol) of 3,4-dimethoxyphenylacetone in 1 liter of a 1: 1 mixture of methanol: water, 83.0 g (0.75 mol) of semicarbazide hydrochloride and 32 g (0.54 mol) were added. sodium cyanide. The mixture is vigorously stirred for 18 hours at room temperature and concentrated in vacuo to half volume. Crystallization begins, which lasts for 24 hours at about -5 ° C. D, L-a- (3,4-dimethoxybenzyl) - a - semcarbazinpropionic acid in the amount of 83.49 g (0.3 mol) is dissolved in 1 liter of 45% hydrochloric acid at ~ -5 ° C. The mixture is concentrated in vacuo to near dryness, diluted with 800 ml 1.5 and. hydrochloric acid is refluxed for 2 hours to obtain 0, L-a-semicarbazinpropionic acid. 74.33 g (0.25 mol) of semicarbazinic acid in 150 ml of methanol are mixed at 60 ° C with 18.55 g (0.15 mol) of L-phenethylamine in 100 ml of methanol. The mixture is concentrated in vacuo to half the volume and allowed to crystallize. The 0, b-salt is filtered off, washed with 1: 1 methanol: ether and dried. To paste b, b-salt in 500 ml of water add 50 ml of 2.5 n. hydrochloric acid and the mixture is unmixed for 1 hour at 0-5 ° C. Introduce an additional 65 ml of 2N. hydrochloric acid and the mixture is stirred at-5 ° C for another 1 h. The mixture is filtered and the precipitate is washed. L-phenethylamine can be collected from the filtrate when it is strongly alkalized and the organic solvent is extracted with a water-immiscible HiiH solvent.

25

29.73 g (0.1 mol) of L-a- (3,4-dimethoxybeisyl) -a-semicarbazinpropionic acid are mixed with 200 ml of benzene and distilled from a mixture of 20 ml. This mixture is cooled to 25 ° C and 20.63 g (0.1 mol) of dicyclohexylcarbodiimide in 100 ml of benzene is added to it. The resulting mixture was stirred at 25 ° C for 18 h, filtered, the precipitate was washed with benzene, and the benzene solution was successively extracted with a 5% bicarbonate solution, water, and brine. The benzene solution is dried over sodium sulfate.

After concentration, the residue is obtained in L-6- (3,4-dimethoxybenzpl) -6-methyl-1,2,4-triazinon-3, 5, which is crystallized from methanol-water.

B. Hydrolysis of L-6- (3,4-dimethoxybenzyl) -6methyl-1, 2,4-triazinone-3,5 to L- | 3- (3,4-dioxnbenzyl) -a-hydrazinpropionic acid.

Hydrolysis of constantly quitting hydrobromic acid for 3 hours at reflux leads to L- | 3- (3,4-dioxybenzyl) -a-hydrazine propionic acid.

Example 31. A. Preparation of L-a- (N-auetil-M-Phthaloyl hydrazine) - - (3,4-dimethoxybenzyl) nopionic acid.

90.79 g (0.5 mol) of N-chlorophthalimide was added to 101.6 g (0.3 mol) of LON-diacetyl-a-methyl methyl serine and 500 ml of pyridine and the mixture was stirred for 5 hours. The mixture was concentrated to dryness in vacuo In addition, chloroform-water is added to the mixture and washed with dilute hydrochloric acid, water and oil, and brine. The chloroform phase is dried over sodium sulfate, concentrated to dryness in vacuo, and the residue is recrystallized from methanol-water to obtain L-a-N-acetyl-M-phthaloyl-hydrazine-a-methyl-O-acetoxypropionic acid.

139.3 g (0.4 mol) of the acid obtained in the previous stage are boiled with 100 ml of acetic acid and 900 ml of 1N. hydrochloric acid for 3 hours. The mixture is cooled to room temperature, washed and dried at 50 ° C in vacuo to give L-a-B-acetyl-B phthaloyl hydrazine-a-methyl hydracrylic acid.

92.0 g (0.3 mol) of the acid obtained in the pure air, its stages, and 66.0 g (0.32 mol) of dicyclohexylcarbodiimide in 500 ml of benzene are stirred for 24 hours at room temperature. The mixture is filtered, water is added to the filtrate, and the benzene phase is successively washed with 5% sodium bicarbonate, water, and brine. The benzene phase is dried over magnesium sulfate and concentrated in vacuo, and the residue is recrystallized from ethyl acetate-hexane to obtain L-a-A-acetyl-N-phthaloyl hydrazine-amethylpropiolactone.

To immediately 57.65 g (0.2 mol) of the lactone obtained at the previous stage and 182.3 g (1.32 mol) of veratrol were added 100 g (0.75 mol) of aluminum chloride. The mixture is heated at

26

80 ° C for 4 h, poured on ice and extracted with ether. The ether solution is extracted 3 times with chlorine 1N. sodium hydroxide. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The ether extract is washed with water, dried over sodium sulfate and concentrated in vacuo.

The residue is crystallized from methanol:

water, thus obtaining L-a- (L-acetyl-L phthaloyl hydrazine) -p - (3,4 - dimethoxybenzyl) propionic acid.

B. Hydrolysis of L-a- (M-acetyl-L-phthaloyl-hydrazine) -p- (3,4-dimethoxybenzyl) propionic acid to L-p- (3,4-dioxybenzyl) -a-hydrazinpropionic acid.

The acid obtained above is hydrolyzed, as previously described in Example 13, in order to obtain L-p- (3,4-dioxbenzyl) -a-hydrazinopionic acid, m.p. 208 ° C (decomposition).

Example 32. 10.75 g (0.03 mol) of L-p- (3.4 dimethoxybenzyl) -a-N-bisylhydrazin-propionic acid is refluxed for 2 hours with 50 ml of hydrocybromide hydrochloric acid. The mixture is concentrated to dryness in vacuo, washed with vigorous shaking with treg.butanol, and dried to obtain the crude hydrobromic salt of L-p- (3,4-dioxybenzene 1) -a-L - benzyl hydrazine propionic acid.

This salt is dissolved in 200 ml of acetic acid and reduced over 1.0 g of 5% palladium on carbon at room temperature and a pressure of 3 atm. Relieve pressure

the mixture is filtered, the precipitate is washed and the combined filtrates are evaporated to dryness in vacuo. The residue is dissolved in methanol and the mixture is adjusted to pH 6.5 by addition of diethylamine.

L-a- (3,4-dioxybenzyl) -a-hydrazinpropionic acid is separated by filtration and recrystallized from water containing 0.5% sodium bisulfite, i.e. 208 ° C (decomposition).

Example 33. To 50.06 g (0.15 mol) of La-N-acetyl-N - benzylidene hydrazine-a-methyl-p-4oxyphenylpropionic acid in 150 ml of methanol and 50 ml of triethylamine add 33.3 g (0.17 mol) tetranitromethane in 50 ml

methanol. The mixture is stirred at room temperature for 18 hours. After evaporation in vacuo to dryness, chloroform was poured into the mixture and extracted with dilute acetic acid. The extract, dried over sodium sulfate, is concentrated to dryness in vacuo and non-recrystallized from methanol to give L-a-N-acetyl-N-benzylidene hydrazine-a-methyl-p- (4-hydroxy-3-nitrophenyl) propionic acid.

To 38.44 g (0.1 mol) of the above acid in 100 ml of dimethoxyethane, an ethereal solution of diazomethane (0.22 mol) was added dropwise with stirring at 0-5 ° C. The mixture is allowed to warm to room temperature and

leave it for 18 h. The mixture is concentrated

27

dry under vacuum and the residue is crystallized from acetone: hexane to give L-a-N-acetylN-benzylidene hydrazine-a-methyl - p- (4-methoxy-3-nitrophenyl) propanoic acid.

20.62 g (0.05 mol) of the ether obtained in the previous step in 200 ml of methanol is reduced over 0.100 g of platinum oxide at room temperature and a pressure of 3 atm until 5 moles of hydrogen are absorbed per 1 mole of the starting material. The catalyst is filtered off, the filtrate is concentrated and the residue is recrystallized from methanol-water.

To a mixture obtained from 28.13 g (0.1 mol) of LaN-acetylhydrazine-a-methyl-p- (3-amino-4-methoxyphenyl) propionic acid methyl ester in 300 ml of dimethoxyethane was added to a room temperature of 14.81. g (0.1 mol) of phthalic anhydride in 100 ml of dimethoxyethane. After adding 1 g of 2,4-dinitrobenzenesulfonic acid, the mixture is heated to boiling point for 5 hours. The mixture is cooled, concentrated in vacuo to dryness. The residue is placed in a mixture of chloroform cooled with ice and water, the aqueous layer is made alkaline with sodium bicarbonate. The chloroform layer is washed with water, dissolved over magnesium sulfate and concentrated. The residue is crystallized from methanol-water to give L-a-L-acetyl-N-phthaloyl-hydrazine-a-methyl-p- (4-methoxy-3-aminophenyl) propionic acid methyl ester.

3.8 g (0.55 mol) of sodium nitrite in 15 ml are added to 20.57 g (0.05 mol) of the ester obtained in the previous step in 22 ml of 50% sulfuric acid at -5 ° C. water.

The mixture was moved on an ice bath for 1 hour, allowed to warm to room temperature, then heated on a water bath until the evolution of nitrogen was complete. The mixture is cooled, extracted with ethyl acetate, the extract is dissolved over sodium sulfate and concentrated to dryness in vacuo. The residue is hydrolyzed, as previously described, to obtain L-a-hydrazine-a-methyl-3-(3,4-dioxyphenyl) propionic acid, m.p. 208 ° C (decomposition).

Example 34. 50 g of the enzyme nitrilase are extracted from barley with 100 ml of 0.1 M phosphate buffer at pH 7.5.

To this substrate of the enzyme is added L- | 3 (3,4-dioxnbenzyl) -a-hydrazine acetonitrile, dissolved in an amount of methanol so that the final concentration is 2%. The hydrolysis is carried out at 25-37 ° C for I-6 hours. The pH is maintained at 7.0-8.0 by the addition of dilute alkali. At the end of this time, the mixture is acidified to pH 1-2 with dilute hydrochloric acid and extracted with chloroform. The aqueous extracts are washed with chloroform and concentrated to dryness in vacuo, after which the residue is non-recrystallized from water to give hydrochloric acid (3,4-dioxyphenyl) - a - hydrazinpropionic acid, m.p. 208 ° C (decomposition).

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Example 35. A. Preparation of L-p- (3,4-dimethoxybeisyl) -a-M-sulfamylalanine methyl ester.

Hydrogen chloride gas is introduced into a solution of 239 g (0.10 mol) of L- | 3- (3,4-dimethoxybenzyl) alanine in 500 ml of methanol until the saturation point is reached at 20 ° C. The mixture was stirred at room temperature for 42 hours, then concentrated to dryness in vacuo. TO

dissolved in methanol, the residue is added while cooling 101 g (1.0 mol) of triethylamine and 96.1 g (1.0 mol) of sulfamide. The mixture while moving slowly heated under reflux, incubated for 18 h and

concentrated to dryness in vacuo. The residue was recrystallized from methanol-water, to give L-ip (3,4-dnmethoxybenzyl) -a-N-sulfamyl-alanine methyl ester.

B. Preparation of L-p- (3,4-dimethoxybenzyl) -a-hydrazinepropnonic acid.

To an ice-cooled mixture of 160.2 g (0.5 mol) of ether obtained in the previous step in 600 ml of 2.5 n. potassium hydroxide added 892 ml (0.625 mol) 0.71 n. gppochlorite sodium. After 5 minutes at ~ 5 ° C, the mixture is heated to 80 ° C and transferred to this temperature for 1.5 hours. After that, the mixture is cooled to 35 ° C.

2 liters of toluene and acidify the mixture with concentrated hydrochloric acid to RP 2.

The mixture was not stirred for another 0.5 h, the phases were separated and the aqueous phase was washed with 0.5 l of toluene. The aqueous phase is concentrated to dryness in vacuo and the residue is treated with ethanol and the residue is obtained to obtain L. 3- (3,4-dimethoxybenzyl) -agidrazinpropionic acid.

B. Preparation of L-p- (3,4-dioxybenzyl) -agidrazinpropionic acid.

L-p- (3,4-dimethoxybenzyl) - a - hydrazinopropionic acid is dissolved in 150 ml of concentrated hydrochloric acid and heated in a sealed tube at 120 ° C for 2 hours. The mixture is evaporated to dryness in vacuo and the product is leached with ethanol. . Hydrazinic acid is precipitated by the addition of diethlamine to rP 6.4, the mixture is filtered, the precipitate is liquefied with ethanol, and substantial. Recrystallization from water containing

a small amount of sodium bisulfite, get the final product.

Claims (2)

Invention Formula The method obtained L-a-hydrazine-p-phenylpropionic acid of General formula I KG years Sn-s-sootg E HN-NH. where RI and R: 2 are hydrogen, hydroxy or alkoxy, containing not more than 6 carbon atoms, phenyloxy-yl benzyloxy, and R4 is hydrogen, HvTH alkyl, containing not more than 7 carbon atoms, Rs is hydrogen, metal, or alkyl group a pas containing not more than 6 carbon atoms characterized in that the L-isomer of a compound of the general formula II where RI, R2, Rs and R4 are as defined above, RT is an iono or carboxy group which can be alkylated or aminated Re is group 2) , I) -: 4-NH 4) hydrazone group, or 3) -NH-NH2, where Rs, Rs and Rio are hydrogen 5) -NRs-NRsRio, or acyl, or Rg and RIO together with a the volume of nitrogen forms an imido group of aromatic dioxides, or Re and Ry together form the groups Sj-MH-tHj-JJCl-e-7) -NH- (i-NH-0-66OH 8), - JvIIl-0-C5; E-CH-I, 0 1 I 11 -N-C-t-N-C00 l I I KH, OE, NH, J} - 5 io) -ji - №-o4-NH-NH-C / 5; f 12) -N-li-ilH-NH-C-NH.-CNRjBio No.} X X II II -N-C-N-CNH, NHj where X is oxygen or sulfur, is subjected to hydrolysis, for example, with an aqueous solution of an acid or base, followed by isolation of the desired product. Priority signs: 05.02.70. 1. Target products with Ri and R2 are hydrogen, hydroxy or alkoxy group containing not more than 6 carbon atoms, benzyloxy group, Ra is hydrogen, R4 is hydrogen or alkyl group containing not more than 7 carbon atoms, Rs is hydrogen, metal atom or alkyl group containing not more than 6 carbon atoms. 2. Starting materials with R - cyano or carboxy group, which can be alkylated or aminated. Re is group 5), where Rs and Rg are hydrogen and Rio is acyl, or Rg and RIO together with the nitrogen atom form an imido group of an aromatic diacid. 02.24.70. 1. Target products with RI and R2 are phenyloxy. 2. Starting products with Re are group 3) or 5), where Rs and Rg and Rio are hydrogen. 03.25.70. 1. Target products with Rs are an alkyl group containing not more than 7 carbon atoms. 2. Initial products at Re and Ry - together form groups 1), 2), 4), 6), 14). The source of information taken into account in the examination: 1. GDR patent number 36929, cl. 12q, 16/01, 1965 (prototype).