Process for the preparation of estetrol

• US 10,844,088 B2
• Filed: 02/07/2017
• Issued: 11/24/2020
• Est. Priority Date: 07/19/2011
• Status: Active Grant

• Current Assignee: Mithra Recherche et Developpement SA (Mithra Pharmaceuticals S.A.)
• Original Assignee: Estetra SPRL
• Inventors: Platteeuw, Johannes Jan, Coelingh Bennink, Herman Jan Tijmen, Damen, Franciscus Wilhelmus Petrus, Van Vliet, Michiel Christian Alexander
• Primary Examiner(s): Zucker, Paul A
• Application Number:
  US15/426,209
• Publication Number:
  US 20170369521A1
• Time in Patent Office: 1,386 Days
• CPC Class Codes: C07J 1/0059 substituted in position 17 by a keto group
• CPC Class Codes: C07J 1/007 the substituent being an OH group free esterified or etherified
• CPC Class Codes: C07J 13/005 with double bond in position 16 (17)
• CPC Class Codes: C07J 75/00 Processes for the preparation of steroids in general
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a process for the preparation of estra-1,3,5(10)-trien-3, 15a, 16a, 17β-tetraol (estetr-01), via a silyl enol ether derivative 17-B-oxy-3-A-oxy-estra-1,3,5(10), 16-tetraene, wherein A is a protecting group and B is —Si(R²)₃. The invention further relates to a process for the synthesis of 3-A-oxy-estra-1,3,5(10), 15-tetraen-17-one, in which A is a protecting group, via silyl enol ether derivative 17-B-oxy-3-A-oxy-estra-1,3,5(10),16-tetraene, and B is —Si(R²)₃.

Claims

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;

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 (O₂), 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.

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.

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: