Process for the production of estetrol

1. A process for the preparation of a compound of formula (I), or a hydrate or solvate thereof;

said process comprising the steps of

a) reacting a compound of formula (II), with a silylating agent to produce a compound of formula (III),

wherein P 1 is a protecting group selected from R 1 CO—, or R 2 Si(R 3 )(R 4 )—, and P 2 is (R 2 )Si(R 3 )(R 4 )—, wherein R 1 is a group selected from C 1-6 alkyl or C 3-6 cycloalkyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl; R 2 , R 3 and R 4 are each independently a group selected from C 1-6 alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl;

b) reacting the compound of formula (III) in the presence of at least one oxidizing agent selected from permanganate salt, osmium oxide, hydrogen peroxide, or iodine and silver acetate to produce a compound of formula (IV); and

c) deprotecting the compound of formula (IV) to produce the compound of formula (I).

2. The process according to claim 1 , wherein P 1 is R 2 Si(R 3 )(R 4 )—, and P 2 is (R 2 )Si(R 3 )(R 4 )—.

3. The process according to claim 1 or 2 , wherein the silylating agent is selected from C 1-6 alkylsilylchloride, C 1-6 alkylsilyltriflate, C 6 arylsilyl chloride, C 6 arylsilyltriflate, C 1-6 alkylC 6 arylsilylchloride, or C 1-6 alkylC 6 arylsilyltriflate, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl.

4. The process according to claim 1 , wherein in step (b) said oxidizing agent is potassium permanganate.

5. The process according to claim 4 , wherein step (b) is performed in the presence of an acid.

6. The process according to claim 1 , further comprising preparing the compound of formula (II) by a process comprising the steps of:

i) reacting a compound of formula (V), with an acylating agent and/or a silylating agent to produce a compound of formula (VI),

wherein P 3 is a protecting group selected from R 9 CO—, or R 10 Si(R 11 )(R 12 )—, wherein R 9 is a group selected from C 1-6 alkyl or C 3-6 cycloalkyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl; R 10 , R 11 and R 12 are each independently a group selected from C 1-6 alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl;

ii) reacting the compound of formula (VI) in the presence of palladium acetate or a derivative thereof, or an iodine (V) species, to produce a compound of formula (VII); and

iii) reacting the compound of formula (VII) with a reducing agent to produce the compound of formula (II).

7. The process according to claim 6 , wherein P 3 is R 9 CO—.

8. The process according to claim 6 , wherein step (i) comprises the steps of

(i1) protecting the hydroxyl of the compound of formula (V) with a silylating agent or an acylating agent to produce a compound of formula (Va), wherein P 1 has the same meaning as that defined in claim 1 ; and

(i2) protecting the ketone of the compound of formula (Va) in the presence of an acylating agent to produce compound of formula (VI).

9. The process according to claim 1 , further comprising preparing the compound of formula (II) by a process comprising the steps of

1) reacting a compound of formula (V) with a silylating agent or an acylating agent to produce a compound of formula (Va), wherein P 1 has the same meaning as in claim 1 ;

2) performing halogenation or sulfinylation of the compound of formula (Va) to produce a compound of formula (Vb);

wherein X is halo, or —SO—R 20 , and R 20 is a group selected from C 6-10 aryl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from chloro or C 1-4 alkyl;

3) performing dehalogenation or desulfinylation of the compound of formula (Vb) to produce the compound of formula (VII); and

4) reacting the compound of formula (VII) with a reducing agent to produce the compound of formula (II).

10. The process according to claim 9 , wherein step (2) is performing a sulfinylation, comprising reacting the compound of formula (Va) with a base and with a sulfinylation reagent.

11. The process according to claim 9 , wherein step (2) is a performing a halogenation, comprising reacting the compound of formula (Va) with a halogenating reagent.

12. The process according to claim 6 or claim 10 , wherein the reducing agent is selected from metal hydride compounds.

13. The process according to claim 6 or claim 10 , wherein the silylating agent is selected from C 1-6 alkylsilylchloride, C 1-6 alkylsilyltriflate, C 6 arylsilylchloride, C 6 arylsilyltriflate, C 1-6 alkylC 6 arylsilylchloride, and C 1-6 alkylC 6 arylsilyltriflate, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl.

14. The process according to claim 6 or claim 10 , wherein the acylating agent is selected from C 2-6 alkenylC 1-6 alkanoates, C 2-6 alkenylC 3-6 cycloalkanoate, acyl chlorides and anhydrides.

15. The process according to claim 1 , wherein in step (b) said oxidizing agent is osmium tetroxide.