Epimerization of analogs of vitamin D
First Claim
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1. A method of epimerizing a C-24 epimer of a vitamin D analog having a hydroxyl substituent on an asymmetric allylic carbon at the 24 position comprising the steps of:
- a) esterifying the hydroxyl group on the asymetric allylic carbon atom at the 24 position with an esterifying agent, b) contacting>
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a solution of the ester in a solvent with an epimerization-active solid, whereby the ester is epimerized, and c) hydrolyzing the epimerized ester to obtain a mixture of C-24 epimers having a hydroxyl substituent on the asymmetric allylic carbon at position 24
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Abstract
Provided is a method of general applicability of epimerizing a vitamin-D analog having an asymmetric allylic carbon atom at the C-24 position. The method is of particular utility in making calcipotriene.
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Citations
24 Claims
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1. A method of epimerizing a C-24 epimer of a vitamin D analog having a hydroxyl substituent on an asymmetric allylic carbon at the 24 position comprising the steps of:
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a) esterifying the hydroxyl group on the asymetric allylic carbon atom at the 24 position with an esterifying agent, b) contacting>
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a solution of the ester in a solvent with an epimerization-active solid, whereby the ester is epimerized, andc) hydrolyzing the epimerized ester to obtain a mixture of C-24 epimers having a hydroxyl substituent on the asymmetric allylic carbon at position 24 - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
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- 10. A method of decreasing the diastereometric excess of a starting mixture of epimers of a vitamin D analog, which analog is represented by one or the other of structures IV or VII
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18. In a method for making mixed epimers of a vitamin D analog having a hydroxyl substituent on an asymmetric allylic carbon atom at the C-24 position, starting from an individual C-24 OH epimer or a mixture of C-24 OH epimers having an initial diastereometric excess, the steps of:
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a) esterifying the hydroxyl group on the asymetric allylic carbon atom at the 24 position of the epimer or epimers with an esterifying agent, b) contacting a solution of the ester in a solvent with an epimerization-active solid, whereby the ester is epimerized, and. c) hydrolyzing the epimerized ester to obtain a mixture of C-24 epimers having a hydroxyl substituent on the asymmetric allylic carbon at position 24, wherein the diasteromeric excess of the mixture is less than the initial diastereomeric excess. - View Dependent Claims (19, 20, 21, 22, 23)
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24. In a process for making calcipotriene, the steps of:
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a) acetylating an alcohol selected from XI and XII, wherein R1 and R2 are independently H or a silyl hydroxyl protecting group, b) contacting a solution of the acetate in a solvent selected from hexane, heptane, toluene, benzene, dichloromethane, ethyl acetate, and mixtures of these with an epimerization-active solid, c) separating the solution of epimerized ester from the epimerization-active solid, d) washing, at least once, the separated epimerization-active solid with a solvent that can be the same or different from the solvent in which the ester to be epimerized was contacted, e) combining the washings with the separated solution of epimerized ester, and f) removing solvent to obtain the epimerized ester.
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Specification