Compositions and methods for selectively binding amines or...

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C549S348000, C210S749000, C210S767000

Reexamination Certificate

active

06686479

ABSTRACT:

FIELD OF THE INVENTION
The present invention is drawn toward compositions and methods for separating an amine or amino acid enantiomer from its counter-enantiomer in order to obtain a high degree of chiral purity.
BACKGROUND OF THE INVENTION
Effective methods for the separation and recovery of particular enantiomers of biochemicals such as amines and amino acids as well as other types of biochemicals is of great importance in modern technology. This importance is exemplified by the growing need and desire to produce and use optically pure pharmaceuticals and other biochemicals for human and other use. For example, often only one enantiomer of a chemical compound is biologically active or produces a desired effect. Thus, in order for a recipient of a pharmaceutical to receive enough of the biologically active enantiomer, twice the amount of pharmaceutical is generally given (assuming that the enantiomers are represented at about a 50:50 ratio). In other cases, the undesired enantiomer may be toxic or produce side effects. For example, the undesired enantiomer of thalidomide[4] has been known to cause severe malformation in children born to pregnant women who took the drug by prescription for the benefits of the desired enantiomer. Therefore, much research has been conducted in order to produce optically or enantiomerically pure pharmaceuticals such that the biologically active or desired enantiomer may be used in essentially pure forms in order to eliminate the drawbacks discussed above.
There are essentially three theoretical methods that may be used to obtain optically pure compounds for pharmaceutical or other use. First, the desired enantiomer may be synthesized in the desired enantiomeric or optically pure form. Unfortunately this method is often impractical because, in many cases, these types of synthesis methods have not been discovered, or alternatively for those which have been discovered, the production cost of making the pure enantiomer has been prohibitive.
The second method involves separating the desired enantiomer from a mixture containing both enantiomers. However, because the enantiomers differ only in chirality, such processes have proven very difficult to carry out. In some instances, these separations have been accomplished by means of crystallization. For example, tartaric acid as a crystallization platform has been used for such a separation. Though this is a somewhat cost effective method, it is useful in only a minority of cases. In most instances, such separations must be performed using a chromatographic stationary phase and a chromatographic method of separation. However, these type of chromatographic separations have low throughputs and high operating costs.
The third method for chiral separation involves a combination of the two methods described above. In this combination method, an initial chiral intermediate is separated at a relatively high purity followed by additional synthesis steps that further purify the chiral intermediate to a final product without introducing additional chiral impurity. However, with this method, a cost effective chiral separation approach is still needed.
In general, what is often needed to overcome the high cost of performing a chiral separations is to provide a method that allows for high selectivity of the desired enantiomer. As such, in accordance with the present invention, nonchromatographic or equilibrium bind/release separation modes using solid resin phases have been formed to accomplish this result. Before now, solid resin phases of sufficient selectivity and/or stability have not been available to accomplish such an enantiomeric separation function to a degree of purity that is both practical to use and cost effective. This is significant because it is the separation itself that accounts for a large portion of the total cost of making a pure enantiomer product. Thus, by reducing the separation costs, the final selling price of the pure enantiomer may be reduced.
As stated, some research has been done in producing chiral ligands capable of some selectivity between chiral enantiomers of the same compound. Additionally, electrophoresis has been used as well for such chiral separations. However, both of these methods, i.e., chromatography and electrophoresis, provide only low throughputs, and therefore, are not as desired as that described by the present invention. Some articles have described electrophoresis as a separation method and several other articles have discussed the use of such ligands in chromatographic resin phases. Such patents and articles include: U.S. Pat. Nos. 4,001,279 and 4,043,979 issuing to Cram, D. J.; Dotsevi, G., et al.,
Chromatographic Optical Resolution through Chiral Complexation of Amino ester Salts by a Host Covalently Bound to Silica Gel, J. Amer. Chem. Soc.,
97:5, pp 1259-61 (1974); Bradshaw, J. S., et al.,
Enantiomeric Recognition of Organic Ammonium Salts by Chiral Dialkyl
-,
Dialkenyl
-,
and Tetramethyl
-
Substituted Pyridino
-18-
crown
-6
and Tetramethyl
-
Substituted Bis
-
pyridino
-18-
crown
-6
Ligands: comparison of Temperature
-
Dependent H NMR and Empirical Force field techniques, J. Org. Chem
., Volume 55, pp. 3129-37 (1990); Zhang, et al.,
Enantiomeric Recoqnition of Amine Compounds by Chiral Macrocyclic Receptors, Chem. Rev
., Volume 97, pp. 3313-61 (1997); Pirkle, W. H. et al.,
Chiral Stationary Phases for the Direct LC Separation of Enantiomers, Adv. Chromatography
, Volume 27, pp. 73-127 (1987); Armstrong, D. W., et al.,
Macrocyclic Antibiotics as a New Class of Chiral Selectors for Liquid Chromatoqraphy, Anal. Chem
., Volume 66, pp. 1473-1484 (1994); Armstrong, D. W., et al.,
Optical Isomer Separation by Liquid Chromatoqraphy, Anal. Chem
., Volume 59, pp. 84A-91A (1987); Huszthy, P., et al.,
Entiomeric Separation of Chiral [&agr;
-(1-
Naphth
)
Ethyl]Ammonium Perchlorate by Silica Gel
-
Bound Chiral Pyridino
-18-
Crown
-6
Liqands, Acta Chim Hung
, Volume 131, pp. 445-54 (1994); Pirkle, W. H., et al.,
Chem. Rev
., Volume 89, pp. 347-362 (1989), all of which are incorporated herein by reference.
Specifically, Cram has worked with the naphthyl crown compounds including some attachments to solid supports. However, Cram has only been able to show chromatographic separations with ligand bound solid supports, or alternatively, with coated solid supports. Work to accomplish the high selectivity nonchromatographic separation of amines and amino acids via highly stable covalently attached naphthyl crown ether compounds in three separation stages or less has not been previously demonstrated.
The other references cited above disclose procedures for synthesizing either chromatographic resin materials for chiral separations or for synthesizing unbound ligands with chiral selectivity in single phases. Further, none of the references cited above describe any separations other than chromatographic separations. Therefore, it would be desirable to provide compositions and methods of separating enantiomers using nonchromatographic separation techniques that allow for much faster separations at much higher quantities while maintaining lower cost basis for the separation.
SUMMARY OF THE INVENTION
The present invention is drawn to compositions and methods, the compositions comprising naphthyl crown ether ligand molecules containing at least two naphthyl groups that are covalently bonded to suitable solid supports and coated by hydrophobic organic solvents. These compositions exhibit selectivity of desired amine or amino acid enantiomers over their counter-enantiomers and derivatives. The composition preferably has an &agr;-value greater than or equal to 4 such that one enantiomer is selected over its counter-enantiomer by a factor of 4 or greater. This allows for the separation of such enantiomers with nonchromatographic resin bed separations of three separation stages or less.
Additionally, a nonchromatographic method of separating an enantomeric molecule from its counter-enantiomer is disclosed comprising (a) flowing a feed solution containing a desired

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