Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-02-23
2002-11-26
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S807000, C568S878000
Reexamination Certificate
active
06486355
ABSTRACT:
BACKGROUND OF INVENTION
The present invention relates to molecular clusters. In particular, the invention relates to compositions, methods of making and methods of using molecular clusters of solvent mixtures in supercritical fluid.
Supercritical fluids are unique states of matter existing above certain temperatures and pressures. As such, these fluids exhibit a high level of functionality and controllability that can influence not only the macrophysical properties of the fluid, but also influence nano-structures of molecules dissolved in them.
Solvent mixtures in supercritical fluids and pressurized liquids are known to form molecular clusters about dilute solute molecules. These molecular clusters can be described as transient molecular cages and can behave as microscopic reactors. Molecular clusters can confine the space through which trapped molecules can diffuse which can increase the odds that trapped molecules might encounter a reactive collision. Organic solvents have the ability to cluster about dilute solute molecules in mixtures of supercritical fluids and pressurized fluids, and confine the space through which these “caged” molecules can diffuse. Under these circumstances, it can be possible to maintain high reaction efficiency with minute, and possibly stoichiometric amounts of reactants.
The degree to which certain organic solvents cluster in supercritical and pressurized fluids has been studied. For example, acetonitrile has been investigated for its potential to cluster in CO
2
above and below the critical point for the mixture. The use of solvents in supercritical fluids to affect the reaction kinetics and the yield of products produced from dilute solute reactant molecules has also been studied. For example, the use of acetonitrile in supercritical carbon dioxide has been investigated for its use as a solvent, as it applies to producing useful quantities of radioactive biomolecules for use in Positron Emission Tomography (PET) in connection with the alkylation reaction between methyiodide and L-&agr;-methyl-N-2-propynyl phenylethylamine (nordeprenyl) to yield L-deprenyl.
In WO 92/20812, certain enzymes were used to selectively catalyze the reaction of only one enantiomer of a chiral compound in supercritical carbon dioxide. Specifically, a racemic mixture of a chiral compound was brought into contact with the enzyme that was only capable of reacting with one enantiomer of the mixture. The chiral product that was obtained was enantiomerically pure and easily separated from the reaction mixture by conventional methods such as extraction, crystallization or evaporation.
U.S. Pat. No. 5,403,703 discloses an enzymatic esterification reaction involving a primary terpene secondary alcohol with a higher fatty acid in a reaction medium of supercritical carbon dioxide in the presence of a lipase. Racemic resolution of the primary terpene secondary alcohol having chirality was achieved by first producing a fatty acid ester of the alcohol having an optical purity of almost 100% and then hydrolyzing the fatty acid ester to convert it back to an alcohol having high optical purity. Furthermore, the reaction velocity of the esterification reaction was found to have increased more than six times when the reaction medium was in supercritical carbon dioxide.
None of the technologies mentioned above disclose the use of fluids as a reaction medium under conditions that cause the reactants to form optically active chiral centers which would not form under ordinary reaction conditions. The technologies mentioned above also do not mention controlling chemical reactions by directing the position of bonding between ligands and molecules. Furthermore, the use of critical clusters for drug synthesis formed by directing the position of bonding between ligands and molecules wherein new chiral centers are formed have not been addressed. Finally, the use of critical clusters for racemic resolution reactions without the use of enzymes has not been addressed.
Thus, there is a need for new compositions which can be used to create optically active chiral centers with the advantages of using supercritical fluids. In addition, there is a need to be able to direct the position where ligands bond to molecules in a chemical reaction. Finally, there is a need to be able to make pharmaceutical compounds and perform racemic resolution reactions using critical clusters.
SUMMARY OF THE INVENTION
According to the present invention, it has now been found that molecular clusters formed by the aggregation of substantially optically-pure chiral solvent molecules dissolved in a supercritical fluid and maintained at or close to its critical density can exert certain spatial constraints on encaged solute molecules that allow for the creation of optically active chiral centers as a result of their undergoing a chemical reaction. In addition, certain kinetic control can be exerted over these molecular clusters and encaged reactant solute molecules that allow for control over the position where ligands bond on molecules. It has been found that these qualities can be tuned by adjusting the pressure and/or temperature of the supercritical fluid medium. Finally, pharmaceutical drug synthesis and racemic resolution reactions without the use of enzymes can be accomplished using critical clusters.
One aspect of the invention is directed to a critical cluster for asymmetric synthesis in which the critical cluster contains substantially optically-pure chiral solvent molecules in a supercritical fluid. The solvent molecules are capable of multipoint hydrogen bonding and encaging at least one solute molecule capable of reacting within the cluster to form an optically active chiral center.
Another aspect of the invention is directed to a method of making critical clusters for asymmetric synthesis which includes encaging at least one solute molecule, which is capable of reacting within the critical cluster to form an optically active chiral center, with substantially optically-pure chiral solvent molecules in a supercritical fluid under conditions of temperature and pressure sufficient to form critical clusters. The substantially optically-pure chiral solvent molecules are capable of multipoint hydrogen bonding with the encaged solute molecules.
In yet another aspect, the invention is directed to a method for asymmetric synthesis using critical clusters. This method involves encaging at least one solute molecule with substantially optically-pure chiral solvent molecules in a supercritical fluid under conditions of temperature and pressure sufficient to form critical clusters. The solvent molecules are capable of multipoint hydrogen bonding with the solute molecules. The encaged solute molecules are then reacted within the cluster whereby an optically active chiral center is formed in a product of the reaction.
In a preferred embodiment, the substantially optically-pure chiral solvent molecules of the present invention are secondary alcohol molecules, preferably having from four to about nine carbon atoms. More preferably, the secondary alcohol molecules are selected from the group consisting of S(+)-2-butanol and R(−)-2-butanol. In another embodiment, the solute molecule is benzaldehyde.
In a preferred embodiment, the supercritical fluid that is employed in the present invention is carbon dioxide. The supercritical carbon dioxide is preferably maintained at a pressure from about 71 bar to about 275 bar, more preferably from about 100 bar to about 150 bar, and at a temperature from about 31° C. to about 125° C., more preferably from about 50° C. to about 70° C.
In another embodiment, the conditions of temperature and pressure of the supercritical fluid are sufficient to change the electric charge distribution of the solute molecule(s). The weight percentage of cosolvent and solute in the supercritical fluid is preferably from about 1% to about 20%, more preferably from about 5% to about 15%.
In a further embodiment, the solute molecule employed is benzaldehyde and the product formed which has an optically active ch
Barts Samuel
Bogosian Margaret C.
Brookhaven Science Associates LLC
Price Elvis O.
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