Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-08-25
2003-03-04
Richter, Johann (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S124000
Reexamination Certificate
active
06528642
ABSTRACT:
The invention relates to a method comprising synthesis and purification of mono- and di-derivatives of cyclodextrins (abbreviated to CD), also the synthesis of supports from these cyclodextrin derivatives. These novel supports comprise one or two spacer arms regioselectively bonded to the 2, 3 or 6 position of a glucoside unit of the cyclodextrin.
The invention also relates to the use of these supports for the preparation or separation of enantiomers, for asymmetric synthesis, for catalysis, for the preparation or separation of geometrical isomers or positional isomers or for the preparation or separation of organic molecules with a hydrophobic nature.
The invention also relates to a method comprising synthesis of polymers obtained from mono- and di-derivatives of cyclodextrins, also to the synthesis of supports from these cyclodextrin polymers.
The invention also relates to the use of the supports for the preparation or separation of enantiomers, for asymmetric synthesis, for catalysis, for the preparation or separation of geometrical isomers, or for the preparation or separation of organic molecules with a hydrophobic nature.
Separating organic molecules using the encapsulation properties of cyclodextrins has been carried out for a large number of years. See in particular M. L. Bender: “Cyclodextrin Chemistry”—Springer Verlag—New York, 1978; R. J. Clarke: “Advanced Carbohydrates Chemistry and Biochemistry”, 1988, 46, 205; W. Saenger: ANGEW CHEM.—Int. Edit., 1980, 19, 344; G. Wenz: ANGEW CHEM.—Int. Edit., 1996, 33, 803. These properties are currently widely exploited on an industrial scale in the perfume and flavouring industries and in the pharmaceutical industry. See in particular J. Szejtli: MED. CHEM. REV. 1994, 14, 353, and D. Duchene: J. COORD. CHEM., 1992, 21, 223.
The use of cyclodextrins bonded to supports has demonstrated their ability to separate and prepare organic molecules and positional isomers (see in particular Y. Kawaguchi: ANAL. CHEM. 1983, 55, 1852-1857, and K. Fujimura: ANAL. CHEM. 1983, 55, 446-450) or geometrical isomers (E/Z isomerism)—(see in particular Y. Inoue: J. AM. CHEM. SOC. 1995, 117, 11033-11034).
More recently, the same supports have been used to separate or prepare enantiomers (see in particular K. Takahaschi: J. INCL. PHENOM., 1994, 17, 1) or a variety of molecules by catalysis (see in particular G. Wenz: ANGEW. CHEM.—Int. Edit., 1996, 33, 803). This field has been expanding for about twenty years, both on the analytical and on a preparative level. This is particularly true in the pharmaceutical industry, where the health authorities of industrialised countries require the separate study of optical isomers of any chiral compound used in a medicament composition.
Native or derivative cyclodextrins have been the subject of a number of studies and cyclodextrins, bonded or otherwise to supports, are commercially available.
Supports based on cyclodextrin derivatives or based on polymers from these derivatives have not been chemically defined and are in the form of mixtures of mono- and poly-derivatives. Cyclodextrins contain a large number of hydroxyl functions of almost equivalent reactivity and up until now, chemically and regioselectively defined CD derivatives produced on an industrial scale have not existed.
The present invention provides access to mono- and di-derivatives of pure and regioselectively defined cyclodextrins as regards the position of the derivative on the glucoside unit: the 2, 3 or 6 position.
The derivatives can be grafted onto a mineral or organic matrix via a covalent hydrocarbon bond carrying a thioether function. The ensemble constitutes a support with increased selectivity over known supports for the following applications:
separation or preparation of organic molecules with a hydrophobic nature;
separation or preparation of positional isomers or geometrical isomers;
separation or preparation of enantiomers; or
asymmetric synthesis of chiral molecules.
The increased selectivity of these supports is an important factor for enabling them to be used on a laboratory, pilot or industrial scale, as it can reduce production costs.
The supports of the invention, which are completely original, can produce chromatographic performances which are hitherto unknown, in particular in the field of separation of enantiomers by liquid chromatography: the selectivities obtained prove to be higher than those currently obtained with commercially available cyclodextrin-based chiral columns.
A number of parameters combine to produce this unexpected result:
The regioselectivity of the bond between the glucoside unit of the cyclodextrin and the spacer arm connecting it to the organic or mineral support. The synthesis technique and purification of the cyclodextrin mono-derivative can produce practically pure derivatives bonded in the 2, 3 or 6 position of the glucoside unit of the cyclodextrin.
Synthesis of a support using a single spacer arm between the very high purity cyclodextrin mono-derivative and the functionalised silica gel.
The presence of a supplemental interaction side constituted by the thioether, sulphoxide or sulphone function on the spacer arm, enabling the creation of Van Der Waals type bonds with the solute, with the latter being engaged in other reactions with the cyclodextrin.
The combination of these interactions leads to the supports of the invention, which have a higher discriminating power over those described in the prior art.
The state of the art is represented by European patent application EP-A-0 608 703 and United States patent U.S. Pat. No. 4,539,399, which describes chromatographic supports based on cyclodextrins. Those supports are not chemically defined as their method of synthesis leads to undifferentiated mixtures of compounds mono- and poly-substituted in the three positions (2, 3 and 6) of the glucoside unit. Chromatographic supports using a spacer arm containing a thioether function have been widely used to separate enantiomers. As an example, Rosini et al. described the immobilisation of cinchona bark alkaloids with that type of arm in TETRAHEDRON LETT. 26, 3361-3364, 1985. More recently, Tambute et al. described the immobilisation of tyrosine derivatives using the same technique in NEW J. CHEM. 13, 625-637, 1989. More recently still, Caude et al. disclosed the results of their studies and have demonstrated the advantage of the thioether arm in terms of chemical stability in J. CHROMATOGR. 550, 357-382, 1991.
Salvadori et al. have shown the efficacy of quinine derivatives in the form of osmium tetraoxide adducts for the oxidation of asymmetric olefins in homogeneous and heterogeneous phases, in CHIRALITY 4, 43-49, 1992. Such derivatives were present in the form of copolymers of acrylonitrile and quinine derivatives carrying a sulphoxide spacer arm. The efficacy of the presence of the sulphoxide function was not discussed in that type of support used for asymmetrical synthesis.
Further, a route to mono-alkenylcyclodextrins has been described by Hanssian et al. in J. ORG. CHEM. 1995, 60, 4786-4797. They described the synthesis of mono-2-allyl-&agr;-cyclodextrin by the action of allyl bromide and lithium hydride in the presence of dimethylsulphoxide. The reaction medium was then purified with acetone, then chromatographic purification was carried out on virgin silica gel in a 90/10 v/v, then in a 40/10 v/v, acetonitrile/water mixture to obtain a monoallyl-&agr;-cyclodextrin. However, the authors admit, the data obtained from proton nuclear magnetic resonance showed the presence of 20% of mono-6-allyl-&agr;-cyclodextrin.
Schürig et al (J. HIGH RESOLUT. CHROMATOGR. 13, 713-717, 1990) have described the synthesis of allyl, pentenyl and octenyl derivatives of &bgr;-CD which were then grafted onto hydrogenopolysiloxanes (methylhydrogenopolysiloxane+dimethylpolysiloxane=copolymer) by hydrosilylation in toluene in the presence of dihydrogenoplatinum hexachloride. No structural study on the chemical purity and regioselectivity of the CD derivatives could confirm the 6 position as the attachment point fo
Duval Raphaël
Lévêque Hubert
Crane L E
Institut Francais du Pe'trole
Millen White Zelano & Branigan P.C.
Richter Johann
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