Process for the preparation of estetrol

1. A process for the preparation of estra-1,3,5(10)-trien-3,15α,16α,16α,17β-tetraol I, which comprises the steps of:

(1) conversion of estrone II into 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene III, wherein A is a protecting group and B is —Si(R 2 ) 3 ;

(2) conversion of 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene III into 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one IV, wherein A is a protecting group;

(3) reduction of the 17-keto group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one IV to form 3-A-oxy-estra-1,3,5(10),15-tetraen-17β-ol V, wherein A is a protecting group;

(4) protection of the 17-OH group of 3-A-oxy-estra-1,3,5(10),15-tetraen-17β-ol V to form 3-A-oxy-17-C-oxy-estra-1,3,5(10),15-tetraene VI, wherein A and C are protecting groups;

(5) oxidation of the carbon-carbon double bond of ring D of 3-A-oxy-17-C-oxy-estra-1,3,5(10),15-tetraene VI to form protected estetrol VII, wherein A and C are protecting groups; and

(6) removal of protecting groups A and C to form estetrol I;

wherein:

A is a protecting group selected from the group consisting of a C7-C12 benzylic group and a —Si(R 1 )3 group, wherein R 1 is independently selected from the group consisting of a C 1 -C 6 alkyl group and a C 6 -C 12 aryl group;

B is —Si(R 2 )3, wherein R 2 is independently selected from the group consisting of a C 1 -C 6 alkyl group and a C 6 -C 12 aryl group; and

C is a protecting group selected from the group consisting of monofunctional aliphatic hydroxyl group protecting groups;

and wherein step (2) of the process is performed in the presence of an iodine (V) species, wherein the iodine(V) species is present in an amount of 0.1 mol % or more with respect to compound III, and wherein the iodine(V) species comprises 2-iodoxybenzoic acid (IBX), stabilised 2-iodoxybenzoic acid (SIBX), 2-iodoxybenzenesulphonic acid (IBS), and/or a derivative thereof selected from the group consisting of 2,3,4,5-tetrafluoro-6-iodoxybenzoic acid (FIBX), 5-methoxy-3-methyl-2-iodoxybenzoic acid, and 5-methyl-2-iodoxybenezensulphonic acid (5-Me-IBS).

2. The process according to claim 1 , wherein the iodine(V) species comprises a species formed by complexation of IBX, IBS and/or a derivative thereof selected from the group consisting of stabilized 2-iodoxybenzoic acid (SIBX), 2,3,4,5-tetrafluoro-6-iodoxybenzoic acid (FIBX), 5-methoxy-3-methyl-2-iodoxybenzoic acid, and 5-methyl-2-iodoxybenzenesulphonic acid (5-Me-IBS) with a ligand.

3. The process according to claim 1 , wherein the iodine(V) species comprises 2-iodoxybenzenesulphonic acid (IBS) and/or a 5-methyl-2-iodoxybenzenesulphonic acid (5-Me-IBS), and wherein the IBS and/or 5-methyl-2-iodoxybenzenesulphonic acid (5-Me-IBS) is present in an amount of 0.1 mol % to 50 mol % with respect to compound III.

4. The process according to claim 1 , wherein the solvent in step (2) is selected from the group consisting of DMSO, DMF, DMA, NMP, a combination thereof, and a combination of DMSO, DMF, DMA and/or NMP with one or more organic solvents.

5. The process according to claim 1 , wherein step (2) of the process is performed in the presence of a transition metal compound, and wherein the transition metal compound is present in an amount of 0.1 mol % to 30 mol % with respect to compound III.

6. The process according to claim 1 , wherein step (2) of the process is performed in the presence of a transition metal compound, and wherein the transition metal compound is present in an amount of 0.1 mol % to 50 mol % with respect to compound III, and wherein an oxidant is further present.

7. The process according to claim 1 , wherein the oxidant is molecular oxygen (O 2 ), allyl methyl carbonate and/or copper(II) acetate.

8. The process according to claim 1 , wherein the solvent in step (2) is selected from the group consisting of DMSO, or a combination of DMSO with one or more organic solvents.

9. The process according to claim 1 , wherein B is a trimethylsilyl or a triethylsilyl group.

10. The process for the synthesis of 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one IV, wherein A is a protecting group, which comprises the steps of:

(1) conversion of estrone II into 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene III, wherein A is a protecting group and B is —Si(R 2 ) 3 ; and

(2) conversion of 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene III into 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one IV, wherein A is a protecting group, wherein said conversion of III into IV is performed in the presence of an iodine(V) species, and wherein the iodine(V) species is present in an amount of 0.1 mol % or more with respect to compound III;

wherein:

A is a protecting group selected from the group consisting of a C 7 -C 12 benzylic group and a —Si(R 1 ) 3 group, wherein R 1 is independently selected from the group consisting of a C 1 -C 6 alkyl group and a C 6 -C 12 aryl group; and

B is —Si(R 2 ) 3 , wherein R 2 is independently selected from the group consisting of a C 1 -C 6 alkyl group and a C 6 -C 12 aryl group, and wherein the iodine(V) species comprises 2-iodoxybenzoic acid (IBX), 2-iodoxybenzenesulphonic acid (IBS), stabilised 2-iodoxybenzoic acid (SIBX), and/or a derivative thereof selected from the group consisting of 2,3,4,5-tetrafluoro-6-iodoxybenzoic acid (FIBX), 5-methoxy-3-methyl-2-iodoxybenzoic acid, and 5-methyl-2-iodoxybenzenesulphonic acid (5-Me-IBS).

11. The process according to claim 2 , wherein the ligand is DMSO or an N-oxide.

12. The process according to claim 6 , wherein the oxidant is present in an amount of from about 1 to about 3 equivalents, relative to the amount of III.