Synthesis of estetrol via estrone derived steroids

Abstract

A process is provided for the making of estetrol starting from a 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one, wherein A is an C1-C5 alkyl group, preferably a methyl group, or a C7-C12 benzylic group, preferably a benzyl group. This process is particularly suitable to industry.

1 . A process the preparation of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one, comprising:
 (a) converting the 17-keto group of estrone into a protected keto group to form 17-D-estra-1,3,5(10)-trien-3-ol;   (b) converting the 3-OH group of 17-D-estra-1,3,5(10)-trien-3-ol into a 3-AO group to form 3-A-oxy-17-D-estra-1,3,5(10)-trien-17-one;   (c) halogenating C 16  of 3-A-oxy-17-D-estra-1,3,5(10)-triene to form 3-A-oxy-16-X-17-D-estra-1,3,5(10)-triene wherein X is a halogen atom selected from the group chloride, bromide and iodide;   (d) dehalogenating 3-A-oxy-16-X-17-D-estra-1,3,5(10)-triene to 3-A-oxy-17-D-estra-1,3,5(10),15-tetraene; and   (e) deprotecting the protected keto group of 3-A-oxy-17-D-estra-1,3,5(10),15-tetraene to form 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one;   wherein A is selected from an C 1 -C 5  alkyl group or a C 7 -C 12  benzylic group, and wherein D is ethylene dioxy.   
     
     
         2 . The process according to  claim 1 , wherein the protected keto group D is formed by converting the 17-keto group with ethylene glycol. 
     
     
         3 . The process according to  claim 1 , wherein step (e) is carried out in the presence of a component selected from the group consisting of p-toluenesulfonic acid, pyridinium p-toluenesulfonate, and pyridinium chloride. 
     
     
         4 . The process according to  claim 1 , wherein step (e) is carried out in the presence of p-toluenesulfonic acid. 
     
     
         5 . A method of hormone replacement therapy, treating vaginal dryness, contraception, enhancing libido, treating skin, promoting wound healing or of treating or preventing an autoimmune disease, breast tumours and colorectal tumours, comprising administering to a subject in need thereof the pharmaceutical composition comprising a carrier and estra-1,3,5(10)-trien-3,15α,16α,17β-tetraol, wherein the estra-1,3,5(10)-trien-3,15α,16α,17β-tetraol is prepared in a process comprising:
 (a) converting estrone into 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one, wherein A is a protecting group; 
 (b) reducing the 17-keto group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one to 3-A-oxy-estra-1,3,5(10),15-tetraen-17β-ol; 
 (c) protecting the 17-OH group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17β-ol to 3-A-oxy-17-Cp-oxy-estra-1,3,5(10),15-tetraene, wherein Cp is a protecting group; 
 (d) oxidizing the carbon-carbon double bond of ring D of 3-A-oxy-17-Cp-oxy-estra-1,3,5(10),15-tetraene to protected estetrol; and 
 (e) removing the protecting groups; 
 wherein the protecting group A is selected from an C 1 -C 5  alkyl group or a C 7 -C 12  benzylic group and the protecting group Cp is selected from monofunctional aliphatic hydroxyl protecting groups.