Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1994-12-20
1996-10-08
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536123130, 540 17, 540 19, 540 20, C07G 1700, C07J 7100
Patent
active
055632599
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to a process for the synthesis of steroidal glycosides, and particularly to the preparation of diosgenyl, tigogenyl, 11-ketotigogenyl and hecogenyl .beta.-O-cellobioside heptaalkanoates 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 metal salts 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 trichloroacetimidate analog reportedly yield 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.
SUMMARY OF THE INVENTION
This invention is directed to a process for the synthesis of peracyl-1-O-steroidal-.beta.-cellobiosides that provides excellent .beta.-anomeric selectivity without the use of a metal salt promoter. The process comprises reacting heptaacyl-.beta.-D-cellobiosyl-1-fluoride and a trisubstituted silyl-3-O-steroid, wherein the steroid is tigogenin, hecogenin, 11-ketotigogenin or diosgenin in the absence of a metal salt under suitable conditions. Typically 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 particularly efficient, preferable process, the glycosyl compounds and steroids are reacted neat.
Another aspect of this invention are the compounds trimethylsilyl-3-O-hecogenin, trimethylsilyl-11-keto-3-O-tigogenin and trimethylsilyl-3-O-tigogenin. These compounds are useful intermediates to the above steroidal glycosides.
Other features and advantages will be apparent from the specification and claims.
DETAILED DESCRIPTION OF THE INVENTION
Preferably the peracyl-D-saccharidyl-1-halide used to couple with the steroid is heptaacyl-D-cellobiosyl-1-halide. As used herein the term peracyl refers to the substitution by an acyl group on each of the available hydroxy positions of the saccharidyl moiety. Preferably, the peracyl-D-saccharidyl-1-halides are the beta anomer. In addition, it is preferred that the halide is fluoride. It is also preferred that the acyl is alkanoyl(C.sub.1 -C.sub.6), benzoyl or
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Goggin Kathleen D.
Lambert John F.
Walinsky Stanley W.
Benson Gregg C.
Crane L. Eric
Kight John
Olson A. Dean
Pfizer Inc.
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