Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1994-05-23
1996-06-25
Rollins, John W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 41, C07J 5300, C07H 100
Patent
active
055301070
DESCRIPTION:
BRIEF SUMMARY
This application was filed under 35 U.S.C. .sctn.371 based on PCT/US92/08638, which was filed on Oct. 15, 1992 which is a continuation of U.S. application Ser. No. 07/797,574 which was filed on Nov. 25, 1991 and is now abandoned.
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 disc;loses 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 anomerio 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 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 tigogenin .beta.-O, 11-ketotigogenin .beta.-O, hecogenin .beta.-O, or diosgenin .beta.-O cellobioside heptaalkanoate that provides greater .beta.-anomeric selectivity and increased yields. The process is particularly useful for preparing tigogenin .beta.-O-cellobioside heptaalkanoate, which is an intermediate for the known hypocholesterolemic agent tigogenin .beta.-O-cellobioside. The process comprises reacting .alpha.-cellobiosyl bromide heptaalkanoate and .beta.-tigogenin, 11-.beta.-ketotigogenin, .beta.-hecogenin or .beta.-diosgenin in the presence of zinc fluoride or zinc cyanide under conditions suitable for forming the tigogenin .beta.-O-, 11-ketotigogenin .beta.-O, hecogenin .beta.-O-, or diosgenin .beta.-O-cellobioside heptaalkanoate.
Other features and advantages will be apparent from the specification and claims.
DETAILED DESCRIPTION OF THE INVENTION
Preferably the metal salt used in the stereospecific reaction of .alpha.-cellobiosyl bromide heptaalkanoate and .beta.-tigogenin, 11-keto-.beta.-tigogenin, .beta.-hecogenin or .beta.-diosgenin is zinc fluoride or zinc cyanide. It is especially preferred that the metal salt is zinc fluoride. It is preferred that about 0.5 equivalents to about 4 equivalents and especially preferred that about 1.5 equivalents to about 2.25 equivalents metal salt is used.
REFERENCES:
patent: 2991282 (1961-04-01), Rubin
patent: 3303187 (1967-02-01), Rubin
patent: 3935194 (1976-01-01), Loken
patent: 4260603 (1981-04-01), Pegel et al.
patent: 4602003 (1986-07-01), Malinow
patent: 4602005 (1986-07-01), Malinow
patent: 5010185 (1991-04-01), Urban
Urban et al., Synthesis of Tigogenyl .beta.-O-Cellobioside Heptaacetate and Glycoside Tetraacetate via Schmidt's Trichloroacetimidate Method; Some New Observations, Tetrahedron Letters, vol. 31, No. 31, pp. 4421-4424, 1990.
Agnew. Chem., vol. 86, No. 5, 1974, Gunter Wulff et al.: "Ergebnisse und Probleme der O-Glykosidsynthese", pp. 173-208.
Caglioti et al., Tetrahedron 19,1127 (1963)--discloses .beta.-togogenin and its preparation.
K. Freudenberg and W. Nagari, Ann., 494,63 (1932)--discloses the synthesis of cellulose derivatives.
T. Kawasaki et al., Chem. Pahrm. Bull., Japan 10,698 (1962)--duscoses .beta.-diosgenin and its preparation.
Malinow et al., Steroids, vol. 48, pp. 197-211, 1986--discloses the synthesis of togogenin beta-O-cellobioside.
Marker et al., J. Amer. Chem. Soc., 69, 2167-2211 (1947)--discloses .beta.-hecogenin and its preparation.
Schmidt, Angew. Chem. Int. Ed. Engl., vol. 25, pp. 212-235 (1986)--discloses the synthesis and reactions of O-glycosyl trichloroacetimidates.
Allan Douglas J. M.
Busch Frank R.
Lambert John F.
Shine Russell J.
Walinsky Stanley W.
Benson Gregg C.
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
Rollins John W.
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