Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Patent
1983-07-05
1985-03-26
Phillips, Delbert R.
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
C07C10352
Patent
active
045072310
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of .alpha.-aspartyl phenylalanine methyl ester.
.alpha.-aspartyl phenylalanine methyl ester (or aspartam) is in great demand as an anti-caloric artificial sweetening agent. Its pharmacological and toxicological properties are now well known and its use does not involve any of the risks ascribed to the use of products such as saccharine and cyclohexylsulfamate.
It is also known that said aspartam should be used in its isomer form, because its .beta.-isomer has no sweetening power and is on the contrary bitter in flavor.
It is therefore desirable to find a simple process for the synthesis of said aspartam, such process permitting to minimize the production of undesirable by-products (such as said .beta.-isomer) and comprising a valorizing technique by conversion of said .beta.-isomer into an .alpha.-isomer.
SUMMARY OF THE INVENTION
The process comprises condensing in known manner in an aqueous base medium, phenylalaline methyl ester with the anhydride of N-formyl L-aspartic acid and then treating the product from said condensation reaction in at least one ion-exchanging resin column, in which acidification of said product takes place and after recovery of the N-formyl isomer, on the one hand, and of a mixture of N-formyl .alpha.- and .beta.-isomers, on the other hand, treating the mixture of .alpha.- and .beta.-isomers with acetic anhydride in order to obtain the corresponding aspartimide. The resulting product is then treated with an acid so as to convert into .alpha.-isomer the largest part of the .beta.-isomer contained in said mixture and to ensure deformylation of said products.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
As already indicated, the condensation reaction of phenylalanine methyl ester with anhydride of N-formyl L-aspartic acid is known. It is known, on the one hand, because it is but a novel use of the general condensation process of two aminoacids, and on the other hand, because it has been described in a number of documents, including French Pat. Nos. 2 040 473, 2 078 640 and 2 160 471.
But the techniques wherein, at the end of the condensation reaction described hereinabove, the products which have formed are recovered with a view to preparing the pure .alpha.-isomer of aspartam, are of major importance in making said process commercially viable and in giving a final product which is as pure as possible.
In the present invention, the reaction product is therefore subjected to an acidification by being directed through an ion-exchanging column containing a resin of the sulfonic polystyrene type. This results, on the one hand, in the conversion of the sodium salts formed during the condensation reaction into corresponding acids, and on the other hand, in the demineralization of the medium. There is thus obtained a product (aspartam comprising a formyl blockage) containing more than about 80% of .alpha.-isomer of N-formyl aspartam; the .alpha.-isomer content of the eluate is such that it is possible, after concentration, to precipitate a solid crystalline product by simple seeding of the concentrated eluate with crystals of N-formyl aspartam .alpha.-isomer.
The advantage of such a treatment is obvious.
The N-formyl aspartam of .alpha.-form thus obtained can be deformylated by known techniques, such as by treatment with hydrochloric acid diluted at temperatures of between 30.degree. and 75.degree. C., in order to obtain aspartam.
But, on the other hand, the condensation process produces N-formyl aspartam of .beta.-form which is recovered as such or which is mostly in the form of mixtures with N-formyl aspartam of .alpha.-form. It is therefore desirable to have a process permitting to convert said .beta.-isomer into .alpha.-isomer.
According to the present invention, isomerization of the .beta.-isomer into .alpha.-isomer and deformylation of the starting mixture are simultaneously carried out by the conversion described hereinafter.
Said conversion comprises: .alpha.- and .beta.-isomers with a
REFERENCES:
patent: 3833554 (1974-09-01), Ariyoshi et al.
patent: 3879372 (1975-04-01), Boesten
patent: 4017472 (1977-04-01), Farkas et al.
patent: 4309341 (1982-01-01), Kubo et al.
Chemical Abstracts, 86, 505 (1977); Abs. No. 155982w.
Battersby et al., J. of the Chem. Soc., 259-269 (1955).
Laboratoires Fournier S.A.
Moezie F. T.
Phillips Delbert R.
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