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 a C 1 -C 5 alkyl group, preferably a methyl group, or a C 7 -C 12 benzylic group, preferably a benzyl group. This process is particularly suitable to industry.

1 - 31 . (canceled)  
     
     
         32 . A process for the preparation of estra-1,3,5(10)-trien-3,15α,16α,17β-tetraol (1), comprising the steps of: 
 1) converting estrone (7) into 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one (6), wherein A is a protecting group;    2) reduction of the 17-keto group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one (6) to 3-A-oxy-estra-1,3,5(10),15-tetraen-17β-ol (5);    3) protection of the 17-OH group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17β-ol (5) to 3-A-oxy-17-C-oxy-extra-1,3,5(10),15-tetraene (4), wherein C is a protecting group;    4) oxidizing the carbon-carbon double bond of ring D of 3-A-oxy-17-C-oxy-estra-1,3,5(10),15-tetraene (4) to protected estetrol (3); and    5) removing the protecting groups, wherein protecting group A is removed first to form 17-OC protected estetrol (2) and subsequently protecting group C is removed to form estetrol (1);    wherein the protecting group A is selected from the group consisting of a C 1 -C 5  alkyl group and a C 7 -C 12  benzylic group and the protecting group C is selected from monofunctional aliphatic hydroxyl protecting groups.    
     
     
         33 . The process according to  claim 32 , wherein the protecting group is a C 7 -C 12  benzylic group.  
     
     
         34 . The process according to  claim 32 , wherein the protecting group is a benzyl group.  
     
     
         35 . The process according to  claim 32 , wherein the protecting group C is selected from monofunctional aliphatic hydroxyl protecting groups.  
     
     
         36 . The process according to  claim 35 , wherein the monofunctional aliphatic hydroxyl protecting group is acetyl.  
     
     
         37 . The process according to  claim 32 , wherein the reduction of the carbonyl group is carried out using a reducing agent selected from the group of metal hydride compounds.  
     
     
         38 . The process according to  claim 37 , wherein the metal hydride compound is selected from the group consisting of LiAlH 4 , NaBH 4 , NaBH(OAc) 3 , ZnBH 4 , and NaBH 4 /CeCl 3 .  
     
     
         39 . The process according to  claim 38 , wherein the metal hydride compound is NaBH 4  in combination with CeCl 3  hydrate.  
     
     
         40 . The process according to  claim 32 , wherein the oxidation of the carbon-carbon double bond in ring D is carried out with an oxidizing agent comprising osmium tetroxide.  
     
     
         41 . The process according to  claim 40 , wherein the oxidizing agent is osmium tetroxide immobilized on PVP (OsO 4 —PVP).  
     
     
         42 . The process according to  claim 32 , wherein the oxidization of the carbon-carbon double bond in ring D is carried out with a catalytic amount of OsO 4 —PVP.  
     
     
         43 . The process according to  claim 42 , wherein the OsO 4 —PVP is used in combination with a co-oxidant.  
     
     
         44 . The process according to  claim 43 , wherein the co-oxidant is selected from the group consisting of trimethylamine-N-oxide, N-methyl morpholine-N-oxide and hydrogen peroxide.  
     
     
         45 . The process according to  claim 44 , wherein the co-oxidant is trimethylamine-N-oxide.  
     
     
         46 . The process according to  claim 32 , wherein the protective C 7 -C 12  benzylic group is removed by catalytic hydrogenation conditions.  
     
     
         47 . The process according to  claim 46 , wherein the catalytic hydrogenation conditions comprise a hydrogenation reaction using Pd on activated carbon under a hydrogen atmosphere.  
     
     
         48 . The process according to  claim 32 , wherein the protective C 1 -C 5  alkyl group is removed by using BBr 3 .  
     
     
         49 . A process for the preparation of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one (6), comprising the steps of: 
 (a1) converting the 3-OH group of estron (7) into a 3-AO group to form 3-A-oxy-estra-1,3,5(10)-trien-17-one (8);    (b1) converting the 17-keto group of 3-A-oxy-estra-1,3,5(10)-trien-17-one (8) into a protected keto group to form 3-A-oxy-17-D-estra-1,3,5(10)-triene (9);    (c1) halogenating C 16  of 3-A-oxy-17-D-estra-1,3,5(10)-triene (9) to form 3-A-oxy-16-X-17-D-estra-1,3,5(10)-triene (10), wherein X is a halogen atom selected from the group consisting of chloride, bromide and iodide;    (d1) dehalogenating 3-A-oxy-16-X-17-D-estra-1,3,5(10)-triene (10) to 3-A-oxy-17-D-estra-1,3,5(10),15-tetraene (11); and    (e1) deprotecting the protected keto group of 3-A-oxy-17-D-estra-1,3,5(10),15-tetraene (11) to form 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one (6);    wherein A is selected from a C 1 -C 5  alkyl group or a C 7 -C 12  benzylic group and wherein D is ethylene dioxy.    
     
     
         50 . The process according to  claim 49 , wherein the halogen atom is bromide.  
     
     
         51 . The process according to  claim 49 , wherein A is a methyl group.  
     
     
         52 . The process according to  claim 49 , wherein A is a benzyl group.  
     
     
         53 . A process for the preparation of 3-A-oxy-estra-1,3,5(10),15-tetraene-17-one (6), comprising the steps of: 
 (a2) converting the 17-keto group of estron (7) into a protected keto group to form 17-D-estra-1,3,5(10)-trien-3-ol (12);    (b2) converting the 3-OH group of 17-D-estra-1,3,5(10)-trien-3-ol (12) into a 3-AO group to form 3-A-oxy-17-D-estra-1,3,5(10)-trien-17-one (9);    (c2) halogenating C 16  of 3-A-oxy-17-D-estra-1,3,5(10)-triene (9) to form 3-A-oxy-16-X-17-D-estra-1,3,5(10)-triene (10) wherein X is a halogen atom selected from the group consisting of chloride, bromide and iodide;    (d2) dehalogenating 3-A-oxy-16-X-17-D-estra-1,3,5(10)-triene (10) to 3-A-oxy-17-D-estra-1,3,5(10),15-tetraene (11); and    (e2) deprotecting the protected keto group of 3-A-oxy-17-D-estra-1,3,5(10),15-tetraene (11) to form 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one (6);    wherein A is selected from a C 1 -C 5  alkyl group or a C 7 -C 12  benzylic group, and wherein D is ethylene dioxy.    
     
     
         54 . The process according to  claim 53 , wherein the halogen atom is bromide.  
     
     
         55 . The process according to  claim 53 , wherein A is a methyl group.  
     
     
         56 . The process according to  claim 53 , wherein A is a benzyl group.  
     
     
         57 . The process according to  claim 49 , wherein the protected keto group D is formed by converting the 17-keto group with ethylene glycol.  
     
     
         58 . The process according to  claim 53 , wherein the protected keto group D is formed by converting the 17-keto group with ethylene glycol.  
     
     
         59 . The process according to  claim 49 , wherein steps (e1) and (e2) are carried out in the presence of a component selected from the group consisting of p-toluenesulfonic acid, pyridinium p-toluenesulfonate and pyridinium chloride.  
     
     
         60 . The process according to  claim 49 , wherein steps (e1) and (e2) are carried out in the presence of p-toluenesulfonic acid.  
     
     
         61 . The process according to  claim 49 , wherein steps (e1) and (e2) are carried out in the presence of p-toluenesulfonic acid monohydrate using aqueous acetone as solvent.  
     
     
         62 . The process according to  claim 53 , wherein steps (e1) and (e2) are carried out in the presence of a component selected from the group consisting of p-toluenesulfonic acid, pyridinium p-toluenesulfonate and pyridinium chloride.  
     
     
         63 . The process according to  claim 53 , wherein steps (e1) and (e2) are carried out in the present of p-toluenesulfonic acid.  
     
     
         64 . The process according to  claim 53 , wherein steps (e1) and (e2) are carried out in the presence of p-toluenesulfonic acid monohydrate using aqueous acetone as solvent.  
     
     
         65 . A pharmaceutical composition, comprising a carrier and the product obtainable by the method of  claim 32 .  
     
     
         66 . A method of hormone replacement therapy, of treating vaginal dryness, of contraception, of enhancing libido, of treating skin, of promoting wound healing or of treating or preventing an autoimmune disease, breast tumours or colorectal tumours, comprising administering the pharmaceutical composition of  claim 65  to a subject in need thereof.  
     
     
         67 . A cosmetic method of treating skin, comprising adminstering topically the product obtainable by the process of  claim 32 .  
     
     
         68 . A compound according to formula 5, wherein A is a C 7 -C 12  benzylic group.  
     
     
         69 . A compound according to formula 4, wherein A is a C 7 -C 12  benzylic group and C is selected from monofunctional aliphatic hydroxyl protecting groups.  
     
     
         70 . A compound according to formula 3, wherein A is selected from a C 1 -C 5  alkyl group or a C 7 -C 12  benzylic group and C is selected from mono functional aliphatic hydroxyl protecting groups.  
     
     
         71 . A compound according to formula 2, wherein C is selected from monofunctional aliphatic hydroxyl protecting group.  
     
     
         72 . A compound according to formula 10, wherein A is a C 7 -C 12  benzylic group, D is ethylene dioxy and X is halogen.  
     
     
         73 . A compound according to formula 11, wherein A is a C 7 -C 12  benzylic group and D is ethylene dioxy.