Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfate esters
Patent
1996-07-10
1997-12-30
Conrad, Joseph
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfate esters
C07C30500
Patent
active
057032610
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for the production of sulfuric acid semi-esters of general formula I II
Many such processes that are referred to as sulfation are already known (Rompp Chemie Lexikon 8th Ed., 1979, p. 4045--Frankch Publishing House, DE Stuttgart--and 9th Ed. 1992, p. 4376--Georg Thieme Verlag, Stuttgart and New York). In this known process, sulfuric acid, oleum, chlorosulfonic acid, amidosulfonic acid or sulfur trioxide are used as sulfation reagents. The sulfating reagent that is probably used most often in the case of complex hydroxy compounds is the pyridine-sulfur trioxide complex (Luis Fieser and Mary Fieser; Reagents for Organic Synthesis, John Wiley and Sons Inc., New York et al. Vol. 1, 1967, p. 127, Vol. 2, 1969, p. 393, Vol. 3, 1972, p. 275, Vol. 4, 1974, p. 473 and Vol. 9, 1981, p. 396), with whose aid, i.a., sulfuric acid semi-esters have been produced from aliphatic alcohols, from phenols, from hydroxy steroids, from carbohydrates, or from heterocyclene that contains hydroxyl groups.
This reagent, however, has not only the drawback that when it is used, considerable amounts of undesirable by-products are often formed. Even more serious is the fact that the production of the pyridine-sulfur trioxide complex itself takes place in an unusually strong exothermic reaction, which requires extremely intense and thus expensive cooling, which is quite problematic and also dangerous, especially in the case of reactions on an industrial scale. In addition, an environmentally acceptable process for disposal of the sulfuric acid that accumulates in the working-up of the reaction and waste water that contains pyridine can be implemented only at considerable expense.
It has now been found that it is possible, surprisingly enough, to produce the sulfuric acid semi-esters of general formula I from the hydroxy compounds of general formula II, by reacting the latter in an inert solvent with a disulfuric acid salt of general formula III
X symbolizes an alkali metal atom.
This reaction should very probably be just as universally applicable as the sulfation of hydroxy compounds with the pyridine-sulfur trioxide complex, but to date only those hydroxy compounds of general formula II, in which radical R represents a steroid radical, have been reacted within the scope of these studies.
From the standpoint of industrial applicability, interest is focused mainly on the production of those sulfuric acid semi-esters that are referred to as conjugated estrogens (conjugated estrogens are contained, for example, in the Premarin.sup.(R) tablets of the Ayerst Labs. company, New York; detailed data on the subject of conjugated estrogens are found in, for example, the publications Pharmacopeial Forum, May, June 1991, pp. 1951-1962 and Journal of Chromatography 224, 1981, 355-370 as well as 234, 1982, 234-239).
These pharmacologically effective conjugated estrogens that include a few intermediate products for their production are characterized by general formula Ia ##STR1## in which
the three bonds characterized by . . . . . . symbolize three single bonds, two single bonds and a double bond, or two conjugated double bonds, and
Y represents a carbonyl group, a hydroxymethylene group, an acyloxymethylene group with up to 8 carbon atoms in the acyl radical, or a benzyloxymethylene group.
The conjugated estrogens of general formula Ia can be produced using the process according to the invention from the corresponding hydroxy compounds of general formula IIa ##STR2## in which
bonds . . . . . . . and Y have the same meanings as in formula Ia.
Only in the case of the compounds of formula IIa with Y meaning a hydroxymethylene group are just quite small yields of desired process product generally obtained, since this hydroxymethylene group is preferably converted to the sulfate ester.
For the production of conjugated estrogens of general formula Ia with a free 17.alpha.- or 17.beta.-hydroxy group, in most cases the first step in achieving good yields is to take hydroxy compounds of formula IIa; their 17-hydroxy groups ar
Conrad Joseph
Schering Aktiengesellschaft
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