Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-04
2003-11-25
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06653482
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
None.
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to multistep synthesis of a 1,5-dideoxy-1,5-imino hexitol from a ketoaldonic acid methyl ester of a hexose sugar with protected hydroxyl groups and to novel intermediates. In particular the present invention relates to processes which enable the production of novel intermediates to the hexitol and in particular, a ketoaldonic acid methyl ester oxime or alkylimine, which forms the ring structure of the hexitol by alternate routes.
(2) Description of Related Art
Over the last three decades there has been a continued interest in natural and synthetic imino-sugars because of their high potency as glycosidase inhibitors ((a) Grabner, R. W., et al., U.S. Pat. No. 5,695,969; (b) Boshagen, H., et al., U.S. Pat. No. 4,940,705; (c) Shilvock, J. P., et al., Tetrahedron Lett., 37 8569-8572 (1996); (d) Rajanikanth, D. B., et al., J. Chem. Soc. Perkin Trans. I 2151-2152 (1992); (e) Hussain, A., et al., Tetrahedron, 49 2123-2130 (1993); (f) Defoin, A., et al., Tetrahedron Lett. 34 4327-4330) (1997); (g) Defoin, A., et al., Tetrahedron 53 13769-13782 (1997); (h) Defoin, A., et al., Tetrahedron Lett. 35 5653-5656 (1994); (i) Fleet, G. W. J., et al., Tetrahedron lett. 29 2871-2874 (1988); (j) Fleet, G. W. J., et al., Tetrahedron 45 327-336 (1989); (k) Takahashi, S., et al. Chem. Lett. 21-24 (1992); (1) Takahashi, S., et al., J. Chem. Soc., Perkin Trans. I, 607-612 (1997); (m) Hendry, D., et al., Tetrahedron Lett. 28 4597-4600 (1987); (n) Hendry, D., et al., Tetrahedron Lett. 28 4601-4604 (1987); (o) Straub, A., et al., J. Org. Chem. 55 3926-3932 (1990); Delinck, D.L., et al., Tetrahedron Lett. 31 3093-3096 (1990); (r) Look, G. C., et al., Acc. Chem. Res. 26 182-190 (1993); (s) Kajimoto, T., et al., J. Am. Chem. Soc. 113 6678-6680 (1991)) Glycosidases catalyze the hydrolysis of glycosidic linkages and are the key enzymes in the degradation of complex carbohydrates. One of their main metabolic roles is the conversion of complex non-absorbable carbohydrates into absorbable mono- or oligosaccharides (Truscheit, E., et al., Angew. Chem. Int. Ed. Engl. 20 744-761 (1981)). The rapid action of these enzymes can lead, however, to undesirable elevations in blood glucose in diabetes. Iminosugars have been shown to act as glycosidase inhibitors and to retard and regulate the intestinal carbohydrate digestion. They are therefore excellent drug candidates for diabetes therapy (Liu, P.S., U.S. Pat. No. 4,634,765 (1987)). An even more exciting potential use of iminosugars is in the treatment of cancer and viral diseases (Rohrschneider, L. R., et al., U.S. Pat. No. 4,837,237 (1989)). It has been shown that modification of oligosaccharide structures may alter metastatic capacity of cancer cells and 1,5-diimino-1,5-dideoxyglucitol (deoxynojirimycin) (1) (Tsuruoka, T., et al., U.S. Pat. No. 5,250,545 (1993)) swainsonine (2) (Dennis, J. W., Cancer Res. 46 5131-5136 (1986)) and castanospermine (3) (Humphries, M. J., et al., Cancer Res. 46 5215-5222 (1986)) (
FIG. 1.
) can markedly inhibit metastasis of cancer cells. They might, therefore, be used for the effective treatment of cancer.
N-Butyl-deoxynojirimyciin shows excellent activity against herpes virus (Jacob, G. S., et al., U.S. Pat. No. 4,957,926 (1990)) whilst having low cyto-toxicity and no inhibitory effect on the growth of normal cells. The greatest prospect for the use of iminosugars as drugs is probably for the treatment of AIDS. Glycosidase inhibitors prevent the processing of N-linked complex oligosaccharides. This results in the disruption of the synthesis of viral coat glycoproteins such as the critical one called gp120. This supposedly leads to the loss of recognition by the CD-4 receptor of the target cell with concomitant reduction of syncytia formation resulting in the reduction of virus infectivity and the inhibition of viral replication (Walker, B. D., et al., Proc. Natl. Acad. Sci. USA 84 8120-8124 (1987); Karpas, A., et al., Proc. Natl. Acad. Sci. USA 85 9229-9233 (1988); Fleet, G. W. J., et al., FEBS Lett. 237 128-132 (1988)). Clinical trials have been launched for N-Butyl-deoxynojirimycin (Rohrschneider, L. R., U.S. Pat. No. 5,643,888 (1997)). The iminosugars that have been the most investigated are deoxynojirimycin ((a) Schroder, T., et al., U.S. Pat. No. 4,806,650 (1989); (b) Koebernick, W., U.S. Pat. No. 4,611,058 (1986); (c) Anzeveno, P.B., et al. U.S. Pat. No. 5,227,479 (1993); (d) Anzeveno, U.S. Pat. No. 4,908,439 (1990); (e) Tsuda, Y., et al., Heterocycles, 27 63-66 (1988); (f) Inouye, S., et al., Tetrahedron 23 2125-2144 (1968); (g) Vasella, A., et al., Helv. Chim. Acta 65 1134-1144 (1982); Ikota, N., et al., Heterocycles 46 637-643 (1997); (i) Paulsen, H., et al., Chem. Ber 100 802-815 (1967); (j) Rudge, A. J., et al., Angew. Chem. Int. Ed. Engl. 33 2320-2322 (1994); (k) Behling, J., et al., Synth. Commun. 21 1383-1386 (1991); (1) Kinast, G., et al., Angew. Chem. Int. Ed. Engl. 20 805-806 (1981); (m) Pederson, R. L., et al., Tetrahedron Lett. 29 4645-4648 (1988); (n) Osten, C.H., et al., J. Am. Chem. Soc. 111 3924-3927 (1989)) and its N-alkyl analogues (Grabner, R. W., et al., U.S. Pat. No. 5,610,039 (1997); U.S. Pat. No. 4,806,650; U.S. Pat. No. 4,611,058; U.S. Pat. No. 4,940,705).
The chemical synthesis of nojirimycin derivatives are generally too involved and not suitable for commercial applications. The chemo-microbiological method patented by Grabner (U.S. Pat. Nos. 5,695,969; 5,610,039)) provides an elegant method for transforming a sugar into its imino-derivative by reductive animation of a 5-keto aldose obtained by bacterial oxidation of glucose. The method is in particular however, not applicable to the D-galacto derivatives of the present invention.
Other related patents are: U.S. Pat. Nos. 5,227,479, 5,250,545, 5,695,969, 4,957,926, 4,908,439 and 4,634,765.
SUMMARY OF INVENTION
The present invention relates to a process for the preparation of an aldonic-5-oxime methyl ester of a hexose sugar which has protected hydroxyl groups which comprises:
(a) reacting a ketoaldonic acid methyl ester of the sugar with the protected hydroxyl groups with a an alkylamine or hydroxylamine acid salt in an organic solvent with a tertiary amine to react with an acid generated in the reaction at a temperature of about 60° C. or less to produce the oxime methyl ester in a reaction mixture; and
(b) separating the oxime methyl ester from the reaction mixture.
The present invention also relates to a a process for the preparation of methyl 2,3,4,6-tetra-O-acetyl-5-hexulosonic acid oxime which comprises:
(a) reacting methyl 2,3,4,6 tetra-O-acetyl-5-hexulosonic acid methyl ester with hydroxylamine hydrochloride in a first organic solvent with a tertiary amine to react with an acid generated in the reaction mixture at a temperature of between about −10 and 60° C.;
(b) introducing the reaction mixture into water containing ice;
(c) extracting the oxime from the reaction mixture with a second organic solvent for the oxime; and
(d) separating the oxime from the second solvent.
Further, the present invention relates to a process for the preparation of an aldonic acid hydrazide oxime of a hexose sugar with protected hydroxyl groups which comprises:
(a) reacting an aldonic acid-5-oxime or alkylimine methyl ester of the sugar with the protected hydroxyl groups with anhydrous hydrazine in an organic solvent at less than about 30° C. to produce the hydrazide oxime; and
(b) separating the hydrazide oxime of the sugar from the reaction mixture.
The present invention also relates to a process for the preparation of the 5-lactam of a hexose sugar which has hydroxyl groups which comprises:
(a) reacting an aldonic acid methyl ester oxime or alkylimine of the sugar with the protected hydroxyl groups with hydrogen and a hydrogenation catalyst in an acidic solvent at a temperature between about 20 and 80° C. and at a pressure between about 200 and 400 psi of the hydrogen to produce the acid lactam of the sug
Hollingsworth Rawle I.
Pistia-Brueggeman Gabriela
Board of Trustees of Michigan State University
McLeod Ian C.
Rotman Alan L.
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