Method for making hydroxy-25-ene-vitamin D compounds

Abstract

The present invention provides a method for preparing a novel class of vitamin D compounds in which the C-25 or equivalent position has a double bond. In addition, the side chain is optionally extended by one or two methylene or methyne groups. The compounds prepared by the method of the present invention are of value as prodrugs for active 1α, 24-dihydroxylated vitamin D compounds.

What is claimed is:  
     
         1 . A method of making 25-ene-vitamin D compounds comprising the steps of reacting a 2,3-dimethyl-3-butene phenyl sulfone with a hydroxyl-protected C-22 aldehyde of a vitamin D, the vitamin D being hydroxyl-protected at C-3 or at C-3 and C-1.  
     
     
         2 . The method of  claim 1  wherein the 2,3-dimethyl-3-butene phenyl sulfone is prepared by: 
 methylating, isomerizing and hydrolyzing ethyl dimethylacrylate to yield a dimethyl-3-ene-butanoic acid;  
 amidating the dimethyl-3-ene-butanoic acid with oxazolidone to form oxazolidinones;  
 separating the oxazolidinones to the desired isomer;  
 oxidizing and reducing the desired isomer to yield a methyl-3-ene-butanol;  
 reacting the methyl-3-ene-butane with methane sulfonyl chloride to form a mesylate; and  
 substituting a phenyl sulfone group for the mesylate group to yield the 2,3-dimethyl-3-butene phenyl sulfone.  
 
     
     
         3 . The method of  claim 1  wherein the hydroxyl-protected C-22 aldehyde of vitamin D is prepared by: 
 hydroxyl protecting the C-3 position of vitamin D 2  to yield a C-3 hydroxyl-protected vitamin D 2 ;  
 sulfonating the C-3 hydroxyl-protected vitamin D 2  to yield a SO 2  adduct;  
 subject the adduct to SO 2  extrusion to yield the trans-C-3 hydroxyl-protected vitamin D 2 ;  
 hydrolyzing the trans-C-3 hydroxyl-protected vitamin D2 at the C-1 position;  
 hydroxyl-protecting the C-1 position;  
 forming a SO 2  adduct;  
 truncating the C-17 sidechain to form a C-22 alcohol; and  
 subjecting the C-22 alcohol to SO 2  extrusion and Swem oxidation to form the C-22 aldehyde.  
 
     
     
         4 . The method of  claim 1  wherein the C-22 aldehyde-phenyl sulfone reaction yields a hydroxyl-protected-25-ene-vitamin D; and further comprises reducing, isomerizing, deprotecting and irradiating the hydroyxl-protected-25-ene-vitamin D to yield a hydroxy-25-ene-vitamin D 2 .  
     
     
         5 . The method of  claim 1  wherein the hydroxyl-protected C-22 aldehyde of vitamin D is prepared by: 
 hydroxyl protecting the C-3 position of vitamin D 2  to yield a C-3 hydroxyl-protected vitamin D 2 ;  
 sulfonating the C-3 hydroxyl-protected vitamin D 2  to yield a SO 2  adduct;  
 truncating the C-17 sidechain of the adduct to form a C-22 alcohol;  
 subjecting the C-22 alcohol to SO 2  extrusion and Swern oxidation to form the C-22 aldehyde.  
 
     
     
         6 . The method of  claim 1  wherein the C-22 aldehyde-phenyl sulfone reaction yields a hydroxyl-protected-25-ene-vitamin D; and further comprising reducing, isomerizing, and deprotecting the hydroyxl-protected-25-ene-vitamin D to yield a 25-ene-vitamin D 2 .  
     
     
         7 . The method of  claim 6  further comprising incubation of the 25-ene-vitamin D 2  with hepatoma cells to yield the 24(S)-hydroxy-25-ene-vitamin D 2 .  
     
     
         8 . The method of  claim 1  wherein the vitamin D is a previtamin D.  
     
     
         9 . The method of  claim 1  wherein the vitamin D is a cholesterol or an ergosterol.