Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-23
2004-01-06
Shah, Mukund J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C562S553000, C562S559000, C562S557000, C562S561000, C562S570000, C562S573000, C560S022000
Reexamination Certificate
active
06673942
ABSTRACT:
This Application was filed under 35 U.S.C. 371, and is the U.S. national state PCT/EP00/01112, filed Feb. 11, 2000.
FIELD OF THE INVENTION
The present invention relates to a process for the resolution DL-racemic mixtures of chiral compounds which crystallize in the form of any conglomerate and some DL-racemic systems which exhibit various kinds of crystal twinning, such as microtwinning, lamellar macrotwinning as well as DL-racemic mixtures having different crystalline polymorphs, enabling the recovery of both the D and the L enantiomers. The invention farther provides an industrially feasible process for the optical resolution of such DL-racemates for continuously isolating both the D and L enantiomers.
BACKGROUND OF THE INVENTION
Among the large variety of existing methods for the resolution of enantiomers, only a few are suitable for a large scale industrial application. The classical method of spontaneous resolution, i.e. fractional crystallization of one enantiomer from a racemic supersaturated solution, usually by seeding the solution with seed crystals of the desired enantiomer, are still the most used, particularly for the resolution of DL-racemic mixtures which crystallize as conglomerates. These methods are, however, quite limited to systems which have no tendency for crystal twinning or in which there is a low barrier to spontaneous nucleation. In such cases the two enantiomers crystallize together spontaneously even in the presence of seeds of only one enantiomer. In accordance with many other known methods of resolution, a DL-racemic compound is reacted with an optically active reagent (resolving agent) to form a mixture of diastereoisomeric derivatives, e.g. by salt formation, which can be separated e.g. by fractional crystallization. Each of the thus isolated diastereoisomeric derivatives can then be decomposed to obtain the desired enantiomer of the initial DL-racemic compound. One of the drawbacks of these methods resides in the comparative large number of operational steps they involve.
The same applies to the traditional methods for resolving DL-racemates by selective enzymatic decomposition of a suitable derivative. For example the L-enantiomer of most of the amino acids can be isolated from their racemic N-acetyl-DL-ammo acid racemic mixtures by enantioselective hydrolysis of the N-acetyl-L-enantiomer using acylase I enzyme to afford the optically pure L-enantiomer.
Our U.S. Pat. No. 4,864,031 (the disclosure of which is incorporated herein by reference) describes a process for the kinetic resolution of DL-racemic mixtures crystallizing in the form of conglomerates from a supersaturated solution thereof by preferential crystallization in the presence of chiral crystal growth inhibitors that preclude or delay the nucleation of one enantiomorph, while leaving the opposite one unaffected, resulting in the preferential crystallization of the desired enantiomer. These chiral crystal growth inhibitors are carefully designed polymers consisting of a polymer backbone to which there is bound either the D or the L form of the compound to be resolved or of a modified derivative thereof. These polymeric inhibitors are effective in very small concentrations of up to about 3% by weight of the racemic mixture to be resolved.
Among the chiral polymeric crystal growth inhibitors disclosed in
U.S. Pat. No. 4,864,031 and are also employed in the process according to the present invention are those listed below together with their abbreviations which would be used herein.
L- or D- PAL
Poly-(N -acryloyl- L- or D-lysine)
L- or D- PMAL
Poly-(N -methacryloyl- L- or D-lysine)
L- or D- PGAH
Poly-[L- or D- -glutamyl (N-acryloyl hydra-
zide)]
L- or D- PA-Phe
Poly-(p-acrylamido L-or D-phenyl-alanine)
L- or D- PA-PAB-PHA
Poly-[N-acryloyl-(p-amiobenzoyl)-L- or
D-sec-phenethylamide]
The L- or D-enantiomer of the amino acid bound to the polymer will be chosen according to the L- or D-enantiomer, respectively, the crystallization of which is to be inhibited.
In the batchwise resolution, process according to the above-mentioned U.S. Pat. No. 4,864,031, by preferential crystallization of one enantiomer in the presence of an enantioselective polymer which inhibits the crystallization of the opposite enantiomer, there is left, after the separation of the crystallized enantiomer a mother liquor containing both the D and L enantiomers, the uncrystallized enantiomer being in excess, and the entire initial amount of the polymeric crystal growth inhibitor. In order to recover the opposite enantiomer which is present in the mother liquor in excess, the polymeric crystal growth inhibitor must be removed from the mother liquor. However, attempts to remove it by ultrafiltration were in most cases unsatisfactory for the following reasons: i) it is impossible to completely trap the polymer which owing to its random coil configuration penetrates through the ultrafiltration membrane under the pressure employed; ii) layers of the polymer accumulate on the surface of the ultrafiltration membrane, thereby decreasing its porosity and effectiveness; and iii) the ultrafiltration membrane is insufficiently stable during a prolonged filtration process, especially when the solution is highly acidic, such as an aqueous hydrochloric acid solution.
U.S. Pat. No. 4,864,031 also discloses a resolution method for the simultaneous recovery of both the D and L enantiomers where the DL-racemate is provided in two adjacent compartments of a resolution cell, separated by a suitable membrane which is permeable to the D- and L-enantiomers, but impermeable to the chiral polymeric inhibitor. To one compartment there is added an inhibitor of the D-enantiomer crystallization and to the other compartment—an inhibitor of the L-enantiomer crystallization. The result is that in the first compartment an essentially pure L-enantiomer is crystallized and in the other—an essentially pure D-enantiomer. This process was found to be too time consuming for industrial application, because of the low rates of passage of the solutions between the compartments, through the membrane due to the considerably small concentration differentials between the enantiomers in each compartment.
OBJECTS OF THE INVENTION
It is the object of the present invention to provide a process for the resolution of DL-racemic mixtures crystallizing as conglomerates, so as to recover each of the D and L-enantiomers in a substantially pure optical form, which process is adapted for large scale industrial application.
It is a further object of the invention to provide a process for the continuous resolution of DL-racemic mixtures crystallizing as conglomerates through repeated cycles of the above-mentioned resolution process by the addition of fresh amounts of the DL-racemic mixture in each cycle so as to recover increasing amounts of each of the D- and L-enantiomers.
SUMMARY OF THE INVENTION
The invention, in a first aspect thereof, provides a process for the resolution of a DL-racemic mixture of a compound crystallizing in the form of a conglomerate from a supersaturated solution thereof, to recover both the D and the L enantiomers, which process comprises the steps of:
a) effecting a preferential crystallization of one of said enantiomers from said supersaturated solution in the presence of an effective amount of a chiral enantioselective polymer which inhibits the crystallization of the opposite enantiomer;
b) physically separating the thus crystallized said one enantiomer to obtain a mother liquor comprising an excess of said opposite enantiomer;
c) adding to said mother liquor solid DL-racemic mixture of said compound in about twice the amount of said one enantiomer separated in step (b) and stirring the resulting suspension at a suitable temperature until substantially the entire suspended solid phase consists of said opposite enantiomer, and
d) physically separating said solid opposite enantiomer, to obtain a solution having substantially the same composition as the initial solution used in step (a).
In a second aspect thereof the invention prov
Drauz Karlheinz
Knaup Guenter
Kottenhahn Matthias
Lahav Meir
Zbaida David
Degussa - AG
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Shah Mukund J.
Tucker Zachary C.
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