Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1987-02-27
1990-10-02
Griffin, Ronald W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 58, 514 2, 536125, 536127, 536112, 536 56, 560 78, 210639, 210656, 210659, C07B 5700
Patent
active
049607626
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a system and a method for chiral resolution of racemic mixtures and for separation of diastereomers.
The pharmaceutical industry generally makes great demands on the optical purity of the pharmaceutical preparations. However, the synthesis of the drug frequently results in a relatively low optical purity, and the resulting product must be enriched by the right enantiomer by some method of separation.
An attractive method in the context is the direct chiral resolution based on HPLC technique (see for example reference 1). However, because of the low capacity of these systems, the use is restricted to the analytical scale, and therefore there is need in the art for a system which is suitable for upscaling and can be used for preparative purposes.
The invention aims at providing a chiral two-phase system for resolution of racemic mixtures, or for separation of diastereomers, said system being characterised in that it comprises two immiscible liquid phases and one or more enantioselectively binding chiral components, each of which is substantially in one of said phases.
Furthermore, the invention aims at providing a method for chiral resolution of racemic mixtures, or for separation of diastereomers, said method being characterised in that the different enantiomers or diastereomers are partitioned differently between the phases of a chiral two-phase system comprising two immiscible liquid phases and one or more enantioselectively binding chiral components, each of which is substantially in one of said phases, by selectively binding one of said enantiomers or diastereomers to one of the chiral components.
The two-phase system according to the invention thus is a liquid/liquid/two-phase system for direct chiral resolution. The phase system consists of two immiscible liquid phases which may consist either of two immiscible solvents or of two different polymers mixed with water. Examples of immiscible solvents are water and butanol. Examples of different polymers which in mixture with water provide two immiscible phases are a polysaccharide (such as dextran, Aquaphase) and a polyalcohol (polyethylene glycol=PEG).
Phase systems of this type are capable of resolving chiral components, such as proteins, carbohydrates, crownethers and amino acids, or derivatives thereof. By selecting suitable conditions in the two-phase system, such a chiral component can be placed to almost 100% in one phase, whereas other components partition themselves more equally between the two phases.
By selecting the chiral component such that it selectively binds one enantiomer in a racemic mixture or one component in a mixture of diastereomers, this enantiomer will lie substantially within one phase.
After that, the two phases may be separated either by extraction or by means of a multistage process, such as countercurrent distribution.
Examples of carbohydrates that may be used as chiral components in the system according to the invention are cyclodextrin and cellulose. As chiral amino acids, use may be made of D- and/or L-proline, and in that case one phase may contain a D-proline derivative and the other phase a L-proline derivative.
The invention will now be described in more detail, reference being had to the following nonrestrictive Examples.
EXAMPLE 1
The protein BSA (bovine serum albumin) is used as chiral component for separation of D,L-tryptophan. The protein was located in the bottom phase of a PEG/dextran system.
Chemicals and phase system
Dextran 40 was obtained from Pharmacia (Uppsala, Sweden), and polyethylene glycol PEG 6000 (now renamed PEG 8000) from Union Carbide (N.Y., USA). The composition of the phase system was: 10% (w/w) Dextran 40, 7% (w/w) PEG 6000, 0.1 M sodium chloride and 50 mM sodium carbonate buffer (pH 9.2). Bovine serum albumin (6.5 g) (Sigma, No. A-3912, fraction V) was added per 100 g phase system. The albumin-containing phase system was shaken carefully and then left overnight in cold store (4.degree. C.). D- and L-tryptophan had been obtained from Sigma and L-(side chain-2,3
REFERENCES:
Title Page of Journal of Chromatography, vol. 333, Pub. Date-9/27/85.
P.-A. Ablertsson, "Partition of Cell Particles and Macromolecules", Wiley, New York, 1971.
Backman, L., "Protein-Protein Interactions Studied by Counter-Current Distribution", J. Chrom., vol. 196 (1980), pp. 207-216.
Albertsson, P.-A. et al., "Phase Partition--A Method for Purification and Analysis of Cell Organelles and Membrane Vesicles", Methods of Biochemical Analysis, vol. 28 (1982), pp. 115-150.
Takeuchi, T. et al., "Enantioselective Solvent Extraction of Neutral DL-Amino Acids in Two-Phase Systems Containing N-n-Alkyl-L-proline Derivatives and Copper(II) Ions", Anal. Chem., vol. 56 (1984), pp. 1152-1155.
Allenmark, S., "Recent Advances in Methods of Direct Optical Resolution", J. Biochem. Biophys. Meth., vol. 9 (1984), pp. 1-25.
Ekberg, B. et al., "Direct Chiral Resolution in an Aqueous Two-Phase system Using the Counter-Current Distribution Principle", J. Chrom., vol. 333 (1985), pp. 211-214.
Albertsson Per-Ake
Ekberg Bjorn A.
Mosbach Klaus
Sellergren Borje
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