Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1997-10-22
2001-05-22
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C560S038000, C564S303000, C564S304000, C558S354000, C558S073000, C544S330000, C544S098000, C546S184000
Reexamination Certificate
active
06235927
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a process for the separation of a mixture of enantiomers.
BACKGROUND INFORMATION
Mixtures of enantiomers are obtained, for instance, in reactions that do not, or only to a small extent, proceed stereoselectively and in reactions in which there is no complete inversion or retention. The physical properties of enantiomers, such as boiling point, melting point and the like, are the same, so that a mixture of enantiomers cannot be separated using the customary separation techniques. In one of the methods for the separation of mixtures of enantiomers, for instance racemic mixtures, an optically active resolving agent is used to convert both enantiomers into the corresponding diastereomers. As the physical properties of these diastereomers do differ, the diastereomers can, at any rate in principle, subsequently be separated by, for instance, crystallization or chromatography, both diastereomers being obtained in substantially chemically pure and optically enriched form. The diastereomer can in a third step again be separated into the corresponding, optically enriched enantiomer and the optically active resolving agent. Several processes and optically active resolving agents for the separation of enantiomers are, for instance, extensively described in “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley Interscience, 1994).
However, it is common knowledge that finding the right resolving agent for the separation of mixtures of enantiomers by crystallization of a mixture of diastereomers is in practice a laborious and highly time-consuming process, for a correct choice of the resolving agent cannot in advance be made, not even when applying advanced techniques such as, for instance, computer simulations or X-ray diffraction, and thus has to be found by trial and error for each mixture of enantiomers anew. This implies that for the separation of enantiomers via diastereomers often many experiments have to be conducted, while the individual experiments may take a long time on account of tedious crystallization. Moreover, in not nearly all the cases is a suitable resolving agent found. It will therefore be clear that the search for a good resolving agent for the separation of mixtures of enantiomers of a compound and the conditions under which good results are obtained is a time-consuming matter and the chance of success is unpredictable.
SUMMARY AND OBJECTS OF THE INVENTION
The subject invention therefore aims to provide a process by which a separation of enantiomers can be effected rapidly and with a high chance of success and by which the desired enantiomer is obtained with a high e.e.
According to the invention this is among other things achieved by means of a process for the separation of mixtures of enantiomers in which more than one resolving agent is used, of which at least one resolving agent is optically active, and which yields a diastereomer complex that contains at least two resolving agents in optically active form. It has been found that with the process according to the invention more often than in resolutions with a single resolving agent, directly a crystalline product is obtained instead of an oil, so that immediately the result of the experiment is known. Subsequent experiments can consequently be done in a shorter period of time. Moreover, the process according to the invention allows testing of several resolving agents and/or mixtures of enantiomers in one single experiment, so that the process according to the invention also allows rapid selection of suitable resolving agents. In addition, it has been found that in many cases the enantiomeric excess (e.e.) of the desired resolved enantiomer is higher when more than one resolving agent is used than when use is made of a single resolving agent. Furthermore it has been found that mixtures of enantiomers, which themselves cannot be resolved using a certain resolving agent, could be resolved when they were applied in combination with mixtures of enantiomers of similar structure.
According to the invention it is also possible to separate a mixture of enantiomer mixtures, that is, a mixture of two or more different chemical compounds in which both enantiomers of each compound occur, into substantially optically active enantiomers using one or more resolving agents, of which at least one resolving agent is optically active. This is elucidated with reference to the following example, in which only one resolving agent is used: A mixture of the enantiomers of, for instance, compounds A, B and C (the mixture therefore contains 3 mixtures of enantiomers: 3 pairs of two enantiomers each) is separated into a mixture containing optically enriched enantiomers of compounds A, B and C, use being made of only a single optically active resolving agent. Of this second mixture subsequently the components A, B and C are separated from the resolving agent. After this, the components A, B and C are separated by means of the customary separation techniques. Of course, it is also possible to use a combination of different resolving agents. This way, in a single experiment many combinations can be rapidly tested.
The invention relates among other things to a diastereomer complex, for instance a salt, comprising at least three compounds of which at least one compound is a resolving agent in optically active form and at least one compound is an enantiomer in optically active form.
DETAILED DESCRIPTION OF THE INVENTION
A diastereomer complex of one or more optically active resolving agents and one or more enantiomers is understood to mean complexes in which the resolving agent(s) and the enantiomer(s) are bonded via one or more non-covalent bonds, for instance van der Waals interactions, II—II-interactions, inclusion, ionogenic bonds, coordination bonds, hydrogen bonds and/or a combination of such bonds.
As resolving agent use can be made of any compound that is suitable for converting a mixture of enantiomers via precipitation into a diastereomeric salt containing a mixture of enantiomers with a higher enantiomeric excess. The resolving agent may contain a metal, optionally with the associated ligands. Preferably, as optically active resolving agent use is made of a resolving agent with the highest possible e.e., for instance an e.e. >95%, in particular >98%, more in particular >99%.
The term enantiomer in this context refers to the mixture of enantiomers to be enriched. As mixture of enantiomers in principle all chiral compounds, in practice usually compounds containing at least one asymmetrical carbon atom, can be used. The enantiomers can for instance be compounds that contain at least an acid group, an amino group, a hydroxy group and/or a thiol group.
In principle a chemical compound that can be appropriately used as a mixture of enantiomers to be separated with an appropriate resolving agent, also represents an appropriate resolvent agent to be used in the separation of a mixture of enantiomers.
In the framework of this invention the term mixture of enantiomers means a mixture of the enantiomers of an optically active compound in any ratio.
Naturally, in the framework of this invention the same holds with respect to the separation of a mixture of enantiomers which already has a certain enantiomeric excess as for racemic mixtures.
In a particularly suitable embodiment the mixtures of enantiomers are separated via salt formation. Examples of mixtures of enantiomers that can suitably be separated via salt formation are acids, and bases in particular carboxylic acids, phosphoric acids, sulphonic acids, phosphinic acids, sulphinic acids, amines, acidic alcohols, amino acids, amino alcohols and acidic thiols.
Other examples of ways in which mixtures of enantiomers can suitably be separated according to the invention are separations via inclusion compounds, for which in principle any chiral compound forming an inclusion compound can be used, or separation via metal complexes, for instance as described in J. A. Gladysz & B. J. Boone,
Angew. Chem. Int. Ed. Engl.
36,
Broxterman Quirinus B.
Hulshof Lumbertus A.
Van Echten Erik
Vries Ton R.
Wijnberg Hans
Barts Samuel
DSM N.V.
Pillsbury & Winthrop LLP
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