Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-03-02
1989-02-28
Springer, David B.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548497, C07D20918
Patent
active
048087289
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The present invention relates to a process for synthetically producing alpha-ketoacids from their respective alpha-aminoacids.
This invention is particularly useful for the production of 3-indolepyruvic acid and the derivatives thereof, from tryptophan.
Various methods for the synthesis of 3-indolepyruvic acid have been described in the literature.
Ellinger and Matsouka (Hoppe-Seylers z.109, 259 (1920)) obtained the ketoacid by condensation of indole-3-aldehyde and benzoyl-glycine, followed by hydrolysis of the reaction product (2-phenyl-4-indolyl-methylene-5-oxazolone).
Bentley et al (Biochem. J. 64, 44 (1956)) had instead condensed indole-3-aldehyde with hydantoin, followed by acidification with sulphuric acid.
Kaper et al (Arch. Bioch, Biophys. 103, 469 (1963)), after the condensation reaction of indole-3-aldehyde with hydantoin, reacted the compound thus obtained with barium hydroxide, followed by acidification with hydrochloric acid.
Sakurai (J. Biochem. 44, 47 (1957)) used methyl-indoleacetate as a starting material in a reaction with diethyloxalate.
In U.S. Pat. No. 4,551,471 a synthesis of 3-indole-pyruvic acid is described starting from L-tryptophan, under the action of the enzyme aspartate-aminotrans-ferase, obtained from mitochondria of animal organs.
It has now been found, and this is the object of the present invention, that tryptophan, both in the form of the individual L- and D-isomers, and the D,L-mixture, can be used as a starting compound for a chemical synthesis of 3-indolepyruvic acid with high yields.
The process according to the invention, however, can be used in a general way to obtain indole-alpha-ketoacids from their respective D,L-alpha-aminoacids and an aromatic aldehyde.
Object of the present invention is thus a process for the production of indole-alpha-ketoacids through a coupling reaction of an indole-alpha-aminoacid or an ester thereof, and an aromatic aldehyde, wherein said reaction is carried out in the presence of a basic dehydrating proton acceptor agent in a solvent which can be anhydrous.
Consequently the invention is characterized by the use of an agent having a high dehydrating power with respect to a coupling reaction, which reaction is assumed to lead to a Schiff base.
According to the invention, particularly preferred as a dehydrating agent are 1,8-diazabicyclo(5.4.0)-undec-7-ene, hereafter indicated by the abbreviation DBU, and also a salt containing a metal which can form a stable bond with the reaction intermediates. Particularly preferred among said salts is zinc chloride which is assumed to form a complex with the intermediate of synthesis. DBU is a reactant which has been used so far for completely different processes, such as the insertion of silane groups into organic compounds (Tetrahedron Lett. 26, 475, 1985), the esterification of carboxylic acids (Bull. Chem. Soc. Jap. 51, 2401, 1978) or the preparation of peptides (Tetrahedron 40, 4237, 1984). There is no indication in the literature of a use of DBU as provided in the present invention.
As aldehydes to be reacted with the alpha-amino-acid, aromatic aldehydes are preferred.
Representatives of said aldehydes are isonicotinaldehyde and hydroxy derivatives of benzaldehyde, which are particularly preferred.
The solvent used in the reaction can be an anhydrous solvent. Representatives thereof are dimethylformamide (DMF) and acetonitrile. A aqueous solvent can also be used. Representatives of this are DMF and methanol.
The reaction can be carried out at room temperature with good results, depending anyway on the particular species of aminoacids to be reacted.
The process of the present invention has shown itself particularly effective for the production of 3-indolepyruvic acid, in that the reaction runs with very high yields (higher than 50%) with respect to the tryptophan or its ester. However, as stated above, the process is of more general validity, as tryptophan which is substituted in 5-position has also shown to react under the same conditions.
Examples of preparation of the process accord
REFERENCES:
patent: 4551471 (1985-11-01), De Luca
Sidgwick, The Org. Chem. of Nitrogen (1937) Clarendon Press Oxford (p. 104).
Chem. Abstracts, vol. 73, No. 17, 26 Oct. 1970 (Columbus, OH), T.-T. Kuo et al: "Role of Aminotransferase and Indole-3-Pyruvic Acid in the Synthesis of Indole-3-Acetic Acid in Pseudomonas Savas-Tanoi", pp. 36-37.
Chem. Abstracts, vol. 69, No. 21, 18 Nov. 1968 (Columbus, OH), T. C. Moore et al.: "Synthesis of Indoleacetic Acid from Trypotophan via Indolepyruvic Acid in Cell-Free Extracts of Pea Seedlings", p. 7860.
De Luca Giovanna
Di Stazio Giovanni
Margonelli Andrea
Materazzi Mario
Politi Vincenzo
Polifarma S.p.A.
Springer David B.
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