Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-12-20
2003-05-27
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S118000, C536S121000, C536S001110
Reexamination Certificate
active
06570009
ABSTRACT:
The present invention relates to a regioselective method for preparing cyclodextrin derivatives, of beta cyclodextrin in particular, monosulfonylated at C-6.
Monosulfonylated derivatives of cyclodextrins find particular application as starting material for access to monofunctionalized derivatives of cyclodextrins.
Cyclodextrins, or cyclomaltooligosaccharides are natural products obtained by the biotechnological conversion of starch, which is an agricultural resource available in large quantities.
Cyclodextrins, or cyclomaltooligosaccharides are cyclic oligosaccharides which have the property of including within their cavity various molecules whose size is adapted to that of the host structure.
The generally apolar character of these associations leads to the preferential inclusion of structures of hydrophobic type, with which it is possible in particular to achieve solubilization in water of compounds having no or low solubility in these media.
Among the derivatives of cyclodextrins, the cyclodextrin sulfonates, and in particular p-toluenesulfonates, form a class of important derivatives since they can be used to produce nucleophilic substitution reactions on the carbons concerned, and therefore can be used to introduce varied functional groups, azide, amine, halide, thiocyanate, thiol etc., and via such reactive groups, to introduce akyl, alkyl and aryl substituents or further to cause intramolecular reactions (epoxides, 3,6-anhydrides).
These structural changes are widely used to modify the physico-chemical properties of cyclodextrins, in particular their solubility, and their solubilization and inclusion properties.
Hence documents WO-A-95/19994, WO-A-95/21870, EP-A-0403366, PCT/FR97/00447, describe the grafting of glucose, aminoakyl, peptidyl, glycopeptidyl or alkyl substituents by means of oxygen-, sulfur- or thiourea-containing bonds.
In all the cases examined, increases in solubility of the grafted cyclodextrin, and the improvement in solubilization properties are very high and may even reach a factor of 100.
The cytotoxic and especially the haemolytic properties of the grafted cyclodextrins obtained are moreover generally much improved as reported by M. Bost et al. in J. Incl. Phenom. Mol. Recogn., 29 (1997) 57-63.
In more specific manner, among the cyclodextrin sulfonates mentioned above, the monosulfonylated derivatives, and in particular the 6
1
-mono-p-toluenesulfonates form derivatives of choice for access to the monofunctionalized derivatives of cyclodextrins.
The monofunctionalized derivatives of cyclodextrins at the primary alcohol position form a class of cyclodextrin derivatives of particular importance in respect of applications.
Work conducted by V. Lainé et al. in J. Chem. Soc., Perkin Trans.2, 1995, pp 1479-1487 has shown that this type of structure generally has considerably improved inclusion properties compared with the same derivatives involving total substitution of the ring of primary hydroxyls.
This is due to the fact that:
i)The steric hindrance created by persubstitution restricts entry of the included structure if the dynamics of inclusion involve entry through the side of the primary hydroxyls;
ii) The stabilization of the structure included in the cavity frequently uses the formation of hydrogen bonds between one of the primary hydroxyls of cyclodextrin and one of the functional groups of the included structure.
Therefore the monosulfonylated derivatives of cyclodextrins, especially the 6
1
-mono-p-toluene sulfonates, are in particular the compulsory starting material for access to the 6
1
-amino-6
1
-deoxy-cyclodextrins used to prepare mono-thioureidocyclodextrins, solubilisation agents for pharmacologically active ingredients described in international patent application CNRS PCT/FR97/9700447.
The preparation of sulfonylated compounds of cyclodextrins has been the subject of numerous publications.
Hence, the first tosylates of cyclodextrins were described by Von W. Lautsch et al. in Kolloid-Ztg, 135 (1954) 134, by S. Umezawa and K. Tatsuta in Bull. Chem. Soc., Jpn, 41 (1968) 464, and by F. CRAMER et al. in Chem. Ber. 102 (1969) 494.
All these studies concern regioselective pertosylation tests at the primary alcohol position of cyclodextrins.
Ashton et al. in J. Org. Chem., 56 (1991) 7274-7280 report an improvement in these techniques with which it is possible to obtain per-6-0-p-tolysulfonyl-&agr; and &bgr;-cyclodextrins with respective yields of 1% and 5% using an excess of p-toluenesulfonyl chloride reagent in pyridine.
All the above-cited documents therefore concern pertosylation, but as has been seen above, the monosulfonylated derivatives offer particular interest.
It is therefore advantageous to have available a specific synthesis method for said compounds.
The regioselective mono-p-toluenesulfonylation at C-6 of &agr;-cyclodextrin was described for the first time by L. D. Melton and K. L. Slessor in Carbohydr. Res., 18 (1971) 29-37. These authors use p-toluenesulfonyl chloride in pyridine as reagent and purify the mixture of 6-O-p-toluenesulfonylcyclomaltoheptaose obtained by chromatography on an active carbon column.
6
1
-O-p-tolysulfonylcyclomaltohexaose is obtained with a final yield of 46%.
This technique was subsequently extended to &bgr;-cyclodextrin by Y. Matsui et al. in Chem. Lett., (1976) 1037-1040, by I. Tabushi et al., in J. Am. Chem. Soc., 99 (1977) 7100-7102, and by Y. Matsui and A. Okimoto in Bull. Chem. Soc. Jpn., 51 (1978) 3030-3034.
6
1
-O-p-tolysulfonylcyclomaltoheptaose is obtained with an average yield of 30%, but is not completely pure since it is contaminated by di- and tri-tosylates.
J. Defaye et al. [(Carbohydr. Res. 192 (1989), 251-258) described an improvement in this technique with which it is possible to obtain this derivative with improved purity and a yield of 26%.
This improvement essentially consists of modifying the proportions of reagents and the reaction time.
Another approach to obtain 6
1
-O-p-tolysulfonylcyclomaltoheptaose was put forward by K. Takahashi et al. in Tetrahedron Lett. 25 (1984) 3331-3334, then by R. C. Petter et al. in J. Am. Chem. Soc. 112 (1990) 3860-3868.
It uses the same reagent, p-toluenesulfonyl chloride in solution in acetonitrile, which is added to a solution of &bgr;-cyclodextrin in water containing sodium hydroxide.
After 2 h at ambient temperature, a precipitate is obtained which essentially contains 6
1
-O-p-tolysulfonylcyclomaltoheptaose.
After recrystallization, this compound is obtained with a yield of 11% and distinctly improved purity compared with the method which uses pyridine as solvent (m.p. 179° C. compared with 160-162° C. for the method in pyridine).
The results by K. Takahashi et al, published in Tetrahedron Lett., 25 (1984) 3331-3334 indicate that this low yield is probably associated with lack of the reagent's selectivity leading to cyclodextrin derivatives substituted at C-2 and C-3.
The two main techniques for monosulfonylation of cyclodextrins, in particular of &bgr;-cyclodextrin, described above are illustrated in the following diagram:
These two above-mentioned methods in the literature both lead to poor yields which do not exceed 30% for the method which uses pyridine, and 11% for the method conducted in water in the presence of sodium hydroxide.
The 6
1
-O-p-tolysulfonylcyclomaltoheptaose obtained is, however, markedly purer with the second method.
Moreover, the method in water is economically more advantageous for industrial applications than the method which uses pyridine.
The overall yields are however too low in both cases to contemplate industrial application of either of the methods.
A need therefore exists for a selective method to prepare monosulfonylated derivatives of cyclodextrins and in particular of &bgr;-cyclodextrin, with which it is possible to obtain improved selectivity and therefore an increased global yield of 6
1
-sulfonylated derivatives of cyclodextrin, and in particular of 6
1
-sulfonylated derivatives of &bgr;-cyclodextrin.
A further needs exists for a method which, in addition, leads to an end product of high pu
Crouzy Serge
Defaye Jacques
Evrard Nicolas
Law Ho
Centre National de la Recherche Scientifique
White Everett
Wilson James O.
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