Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1994-12-20
1997-02-25
Hollinden, Gary E.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 5, 536 6, 536 61, 536 186, C07G 300, C07H 1500, C07J 900
Patent
active
056060416
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to processes for the synthesis of steroidal glycosides, and particularly to the preparation of steroidal peracyl glycosides used as intermediates therein.
Tigogenin beta-O-cellobioside is a known compound having utility in the treatment of hypercholesterolemia and atherosclerosis (Malinow, U.S. Pat. Nos. 4,602,003 and 4,602,005; Malinow et al., Steroids, vol. 48, pp. 197-211, 1986). Each patent discloses a different synthesis of this compound from alpha-D-cellobiose octaacetate; the first via the glycosyl bromide heptaacetate which is coupled with tigogenin in the presence of silver carbonate, and finally hydrolyzed; and the second via direct stannic chloride catalyzed coupling of the cellobiose octaacetate with tigogenin in methylene chloride, again followed by hydrolysis. In Malinow et al., reaction of cellobiose octaacetate with titanium tetrabromide gave the cellobiosyl bromide heptaacetate, which was coupled with tigogenin by means of mercuric cyanide, and then hydrolyzed. All of these methods have serious drawbacks for producing bulk material to be used as a pharmaceutical drug. A desirable goal, met by the present invention, has been to devise synthetic methods which avoid toxic and/or expensive reagents, and which cleanly produce the desired tigogenin beta-O-cellobioside, avoiding tedious and expensive purification steps.
Schmidt, Angew. Chem. Int. Ed. Engl., vol. 25, pp. 212-235 (1986) has reviewed the synthesis and reactions of O-glycosyl trichloroacetimidates formed by the reaction of sugars possessing a 1-hydroxy group (but with other hydroxy groups protected, e.g., by benzyl or acetyl) with trichloroacetonitrile in the presence of a base. There is preferential formation of the alpha-anomer when sodium hydride is used as base, and preferential formation of the beta-anomer when the base is potassium carbonate. The alpha anomer of tetrabenzylglucosyl trichloroacetimidate when coupled with cholesterol gave anomeric mixtures which varied with catalyst (p-toluenesulfonic acid or boron trifluoride etherate) and temperature (-40.degree. to +20.degree. C.). On the other hand, both the alpha and beta anomers of tetraacetylglucosyl analog reportedly yielded exclusively beta-anomeric products.
Thus, there has been a continuing search in this field of art for improved methods of stereocontrolled syntheses of steroidal glycosides. For example, Gilbert Stork, J. Am. Chem. Soc. 1992, 114, 1087 and the authors cited therein support the need for better stereoselective glycoside syntheses.
SUMMARY OF THE INVENTION
This invention is directed to a process for the synthesis of 1-O-steroidal-peracyl-.beta.-glycosides that provides greater .beta.-anomeric selectivity with reduced by-products and side reactions. The process comprises reacting heptaacyl-D-cellobiosyl-1-halide, tetraacyl-D-glucosyl-1-halide or tetraacyl-D-galactosyl-1-halide and a trisubstituted silyl-3-O-steroid, wherein the steroid is tigogenin, hecogenin, 11-ketotigogenin, diosgenin, or cholesterol, in the presence of zinc fluoride under suitable conditions. Typically, the halide is bromide, chloride or fluoride, the acyl is alkanoyl(C.sub.1 -C.sub.6), benzoyl or toluoyl and the silyl substitution is alkyl(C.sub.1 -C.sub.6), phenyl or phenyl alkyl(C.sub.1 -C.sub.6).
In a preferred aspect of this invention the metal salt is zinc fluoride, the acyl is acetate, the silyl substitution is methyl and the peracyl glycosyl halide is the .alpha.-anomer. In a particularly efficient, especially preferred process, substantially stoichiometric amounts of the glycosyl compounds and trimethylsilyl ethers of the steroids are reacted together. This is a significant advantage over earlier processes which used excess glycosyl halide.
Other features and advantages will be apparent from the specification and claims.
DETAILED DESCRIPTION OF THE INVENTION
The metal salt used in the stereospecific coupling of the silyl sterol ether and glycosyl compounds may be zinc fluoride, zinc bromide or zinc cyanide. It i
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Busch Frank R.
Goggin Kathleen D.
Lambert John F.
Shine Russell J.
Walinsky Stanley W.
Benson Gregg C.
Hollinden Gary E.
Lee Howard C.
Olson A. Dean
Pfizer Inc.
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