Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Patent
1985-11-18
1987-02-10
Trousof, Natalie
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
26050118, 562401, 562402, C07C 8300, C07C 8308, C07B 5700
Patent
active
046422056
DESCRIPTION:
BRIEF SUMMARY
SPECIFICATION
TECHNICAL FIELD
The present invention relates to a process for the preparation of the enantiomers of phenylalanine ##STR3## and of the N-acyl derivatives thereof by resolving the corresponding racemic compound. The resolution is carried out by forming new diastereomer salts of the different enantiomers.
Optically active phenylalanine is an amino acid produced on large scale. For example, the L-isomer is used for the synthesis of Aspartam.RTM. (a dipeptide). In the course of the procedures for preparing racemic phenylalanine, the N-formyl or the N-acetyl derivative can be obtained directly in many cases, therefore the economic production of the phenylalanine enentiomers from the free amino acid or from the N-acyl derivatives thereof is of great importance from an industrial point of view.
No procedure is known in the prior art for resolving the racemate of the free acid. The phenylalanine enantiomers are prepared by using a phenylalanine derivative as starting material. It is reported that the phenylalanine alkyl esters can be resolved by an optically active acid (Belgian Patent Specification No. 795,874) and N-formyl-phenylalanine can be resolved by using optically active fenchilamine or by the aid of phenyl ethylamine in water (J. Am. Chem. Soc. 73, (1951)), by brucine in methanol (Liebigs Ann. Chem. 357, 1 (1907)) and by 2-aminobutanol in butanol as solvent (J. Am. Chem. Soc. 76, 2801 (1954)).
N-acetyl-phenylalanine can be resolved by using L-threo-2-amino-1,4-nitrophenyl propanediol in a polar solvent (J. Prakt. Chem. 9, 104 (1959)), by the aid of leucinamide in an alcoholic solvent (Agr. Biol. Chem. 26, 467 (1962)) and by using 2-(2,5-dimethylbenzylamino)-butanol in water as solvent (U.S. Pat. No. 4,151,198).
The above procedures have several disadvantages. They are quite expensive, toxic resolving agents have often to be used and the resolving agents are not always available in sufficient amount for industrial scale production. The yields are rather low and a product of appropriate purity can be obtained only after several recrystallization steps in many cases.
It was found that satisfactory separation can be achieved when compounds of the formula ##STR4## wherein a salt forming group containing a heteroatom, a polar substituent comprising an oxygen atom and an apolar substituent are directly attached to the chirality centre are used as resolving agents.
SUMMARY OF THE INVENTION
The present invention relates to novel diastereomer salts of phenylalanine and N-acyl derivatives thereof of the formula ##STR5## wherein R is hydrogen or acyl, preferably formyl or acetyl, formed with optically active resolving agents of the formula ##STR6## wherein R.sup.1 is carboxy, amino or benzylamino group, benzoyloxy-carboxymethyl, the latter group being optionally substituted by an alkyl group on the benzene ring, optionally substituted by an alkyl group on the benzene ring.
Another object of the present invention is a process for the separation of enantiomers of the compound of the formula I and/or salts thereof.
According to the process of the invention the enantiomers of a racemic compound of the formula I and/or the salts thereof are reacted with an optically active resolving agent of the formula II in a polar solvent and/or a mixture of solvents comprising at least one apolar solvent and optically an achiral acid or base, thereafter
(a) when using the D-isomer of the resolving agent of the formula II, separating the crystalline diastereomer salt formed with the L-isomer of the compound of the formula I, or
(b) when using the L-isomer of the resolving agent of the formula II, separating the crystalline diastereomer salt formed with the D-isomer of the compound of the formula I, and
liberating the enantiomers of the compound of the formula I from the diastereomer salt or the mother liquor by the aid of an achiral acid or base and separating the optically active product in crystalline form.
DETAILED DESCRIPTION OF THE INVENTION
In the formula II the salt-forming group containing a heteroatom
REFERENCES:
patent: 3832388 (1974-08-01), Lorenz
patent: 4151198 (1979-04-01), Halmos
Acs Maria
Faigl Ferenc
Fogassy Elemer
Alkaloida Vegyeszeti Gyar
Clarke Vera C.
Dubno Herbert
Ross Karl F.
Trousof Natalie
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