DE1768417C - Process for the preparation of 2 phenyl 3 acyloxypropionates - Google Patents

Description

CH ₇ CHCOOR

NH ₂

CH ₂ CHCOOR

CHCOOR

CH ₂ OR '

Here, R and R 'have the meaning already mentioned. When the starting compounds (II) in their optically active forms are used in the reaction according to the invention, the corresponding optically active Alkyltropatverbin fertilize (I) formed. Furthermore, according to the Products obtained in the invention are optionally converted into tropic acid by subsequent hydrolysis will. A small amount of by-products, e.g. B.

Esters of icic or Iranian cinnamic acid. Ester of «- or

768 417

,. ■ -hydroxyphene)! Propionic acid, may be present in the product however, these impurities may be from the alkyl tropate compounds (I) in more usual Way, e.g. By chromatographic fractionation, distillation, or a combination of these Methods to be removed.

example 1

11.5 g of ethyl - dl - phenylalaninate hydrochloride were dissolved in 200 ml of glacial acetic acid. 4.2 g of sodium nitrite at 18 to 20 ° C. were gradually added to the solution. The precipitated crystals were filtered off. After condensation of the filtrate there was 300 ml of water added to the condensate, and the mixture was extracted with ether. The ether layer became one by one washed with an aqueous sodium bicarbonate solution, dilute acid and water. The ethereal layer was dried and removed for removal evaporated the solvent. 10.5 g of the residue thus obtained were passed on to a column adsorbed from 400 g of silica gel. The column was eluted with benzene. The eluate was fractionated, with 3500 to 4000 ml were collected. The column was then eluted with chloroform, with the eluate until 1400 ml has been removed. Both fractions were mixed and used to remove the solvents evaporated. The residue was adsorbed onto 350 g of silica gel. 3200 to 4800 ml fractions of the Eluats were collected. After removal of the solvent, the residue became again 130 g gravel gel adsorbed. The column was eluted with benzene. 1,100 to 1,550 ml fraction of Eluats were collected. The fraction was evaporated to remove the solvent. the The residue was distilled under reduced pressure, with 3.0 g of ethyl O-acetyl-DL-tropate from the front Boiling point 125 to 130 ° C / 4 mm Hg were obtained (25% of the theoretical yield).

Example 1 2

10.8 g of methyl L-phenylalaninate hydrochloride were dissolved in 200 ml of acetic acid. After 8.2 g of sodium acetate was added to the solution, 4.2 g of sodium nitrite was added to the mixture while stirring at room temperature. The reaction mixture was evaporated to remove acetic acid. A corresponding amount of water was added to the residue. The mixture was extracted with ether and the ether layer treated in the manner described in Example 1, ethyl-O-acetyl-L-tropate being obtained. Boiling point 110 to 115 C, 2 mm He. Yield 25% of theory.
[u] 'f = + 15.0 to 30.0 (in ethanol).

Example 3

1.93 g of ethyl L-phenylalaninate became one Mixture of 10 ml of acetic acid, 2 ml of acetonitrile and 2 ml of concentrated sulfuric acid added. To the mixture 0.7 g of sodium nitrite was gradually added while stirring at room temperature. The The reaction mixture was poured into ice water, and the mixture was extracted with benzene. The benzene layer was treated in the manner described in Example 1 to obtain ethyl O-acetyl-L-tropate would. Yield 20 to 30% of theory.

Example 4

A solution of 1.93 g of ethyl-L-phenylalanina 'in 12 ml of acetonitrile was added to a mixture of 5 g of a 60% aqueous solution of perchloric acid and added 8 ml of acetonitrile. To the mixture, 0.7 g of sodium nitrite was gradually added. An excess Amount of nitric acid was decomposed with urea and the reaction mixture for removal evaporated the acetonitrile. After adding an appropriate amount of water to the residue, became the mixture extracted with ether. The extract was successively with an aqueous sodium bicarbonate solution, Washed dilute hydrochloric acid and Wasstr. The extract was dried and removed for removal of the ether evaporated. The crude ethyl L-tropate thus obtained was heated in a mixture of glacial acetic acid and pyridine, with crude ethyl-O-acetyl-L-tropate which was further purified in the manner described in Example 1. Yield 20 to 30% the theory.

Example 5

Ethy! - L - phenylalaninate hydrochloride (melting point 153 ° C., [«]” = + 35.1 ° in ethanol) was treated in the manner described in Example 1, ethyl O-acetyl-L-tropate being obtained. Boiling point 130 to 132 ° C / 6 mm Hg. Yield 20 to 30% of theory. [A] l ^J = +2.0 to 5.0 ° (1 = 0.1, no dilution).

Claims (1)

I 768 417 Claim: Process for the preparation of I-phenyl-3-acyloxypropionate compounds cL: r general formula CH - COOR
CHOIR' in which R is an alkyl group having 1 to 3 carbon atoms and R 'is an aliphatic acyl group 1 to 3 carbon atoms mean thereby characterized in that 'one is an alkylphenylalaninate with an alkali metal nitrate, an alkyl titrite with 1 to 6 carbon atoms or nitrogen monoxide in the presence of an acid. The esters of 3-hydroxy-2-phenyl-propionic acid (hereinafter referred to as tropic acid) with different Bases are and are of great importance as antispasmodic remedies (e.g. atropine) essential component of various important alkaloids, such as B. hyoscine and hyoscyamine. In the The synthesis of these therapeutically active substances has the tropic acid as an intermediate product extraordinary Meaning. The previous synthesis of tropic acid was relatively cumbersome. Starting from acetophenone one synthesis started via its cyanohydrin, acrolactic acid, atropic acid, and HCl addition Atropic acid and hydrolysis to tropic acid. A second tropic acid synthesis is based on condensation from phenyl acetic ester with formic acid ester to phenyl formyl acetic ester and reduction to Tropic acid ester (cf. U 11 m a η η, Vol. 13 [1962], P. 83). It has now been found that the production of oxygen acylated tropic acid esters from the Much more accessible alkylphenylalaninate by rearrangement under diazotization conditions is possible. The rearrangement consists in the fact that the phenyl group and the amino or hydroxyl group _{exchange their positions on the C 3} and C ₂ atoms. Phenylalanine can be produced relatively easily as α-amino acid from the acylated aminomalone ester and benzyl chloride with subsequent saponification. Such amino acid syntheses have been known for decades (cf. Ulimann, Vol. 3 [1953], p. 508, V and Iy. 515). According to the process of the invention, it is possible to prepare optically active alkyl tropate compounds from the corresponding more easily accessible optically active enantiomers of alkyl phenylalaninate. The invention accordingly provides a process for the preparation of 2-phenyl-3-acyloxypropionates the general formula ~ CH - COOR CH ₂ O ¹ R '
in which R denotes an alkyl group with 1 to 3 carbon atoms and R 'denotes an aliphatic acyl group with 1 to 3 carbon atoms, characterized in that an alkylphenylalaninate with an alkali metal nitrite, an alkyl nitrite with 1 to 6 carbon atoms or nitrogen monoxide in the presence of an acid implements. It was in no way foreseeable that a rearrangement would take place under diazotization conditions, in which the phenyl group migrates to the carbon atom adjacent to the carboxyl ester group. Rather, it would be it was to be expected that the deamination of alkylphenylalanine to the corresponding hydroxy acid, d. H. leads to fi-hydroxy- / i-phenylpropionic acid. With the new process are esters of tropic acid and their derivatives and, in particular, the optically active Forms of these esters are much easier to prepare than according to the previously known syntheses. That is true especially because optically active α-amino acids and their esters are readily available. The acids used in combination with the nitrous compounds are Usual mineral acids or organic acids, e.g. B. sulfuric acid, hydrochloric acid, perchloric acid, formic acid and acetic acid. The reaction according to the invention is carried out under conditions similar to those of Deamination of the primary amino group of aliphatic compounds carried out. At a preferred embodiment, the reaction is carried out by dissolving the starting compounds (II) in a solution of an acid and gradually adding a nitrous compound to the solution at room temperature accomplished. The preferred solvents for the reaction are water, acetonitrile, Dimethyl sulfoxide, etc. used. When using an organic acid in the above In the reaction, the corresponding O-acyl derivatives are formed by alkyl tropate because the acid acts as an acylating agent is effective. If a mineral acid is used in the reaction, this O-acylation takes place does not take place, and alkyl tropate is formed. The reaction according to the invention can be represented by the following equations: