NZ621973B2 - Process for the production of estetrol - Google Patents

Abstract

The disclosure relates to a preparation of a compound of formula (I) (estetrol - estra-1,3,5(10)-triene-3,15a,16a, 17B-tetrol), wherein the process involves reacting a starting material with a silylating agent, reacting product in the presence of at least one oxidizing agent selected from permanganate salt, osmium oxide, hydrogen peroxide, or iodine and silver acetate and deprotecting that compound to produce the compound of formula (I). te salt, osmium oxide, hydrogen peroxide, or iodine and silver acetate and deprotecting that compound to produce the compound of formula (I).

Description

PROCESS FOR THE PRODUCTION OF ESTETROL Field of the invention The present invention relates to a new process for the synthesis of Estetrol.

Background of the invention Estrogenic substances are commonly used in methods of Hormone Replacement y (HRT) and methods of female contraception. ol is a biogenic en that is endogenously produced by the fetal liver during human pregnancy. Recently, estetrol has been found effective as an estrogenic substance for use in HRT. Other important applications of estetrol are in the fields of contraception, therapy of auto-immune diseases, prevention and therapy of breast and colon tumors, enhancement of , skin care, and wound healing.

The synthesis of estetrol and derivatives thereof is known in the art. J.FISHMAN and H.GUZ|K ( J.Org.Chem, Vol 33,No 8,3133-3135 ,1968) describe a route to estra- 1,3,5(10)—triene-3,150c,160c,17B-tetrol (estetrol) involving cis hydroxylation of the double bond of an oc—B-unsaturated dioxolane derivative of formula A, wherein Ac is acetyl.

Osmium tetraoxyde was used for the cis hydroxylation of compound (A) and gave the 17,17-ethylenedioxyestra-1,3,5(10)-triene-3,150c,160c—triol 3-acetate as the major product.

However attempts to remove the dioxolane group failed completely.

The carbonyl group at C17 of the oxyestetra-1,3,5(10),15-tetraenone was reduced with LiAlH4 to estra-1,3,5(10),15-tetraene-3,17-diol that was isolated as the diacetate (compound B). Compound B was subjected to cis-hydroxylation of the double bond of D ring by using Osmium tetraoxyde which resulted into the formation of estra- 1,3,5(10)—triene-3,150c,160c,170c—tetraol-3,17-diacetate (compound C) as the major product ated with estra-1,3,5(10)—triene-3,155,165,17B-tetrol-3J7 diacetate. These nds were isolated by thin layer chromatography. Compound C under g with K ZCO gin methanol produces estetrol (compound D) e 1). The overall yield of this three step process was, starting from estrone oxyestetra-1,3,5(10),15-tetraen one, only about 7%.

Ac\ 0.

B 1 /Ac OH MOH ‘— ""OH OH Ac\ Scheme 1 Verhaar M.T; et al () bes a process for the preparation of estetrol by cis ylation of 17-acetyloxybenzyloxy-estra-1,3,5(10),15-tetraene using osmium tetraoxyde and trimethyl-amine N-oxide in THF at 50°C. The resulting 15,16- dihydroxylated crude derivative was ed in 84% yield but several crystallizations were needed in order to purify this intermediate. Finally the yield after these purifications was about 43%.

Bull, James R; et al in Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999),(2), 241-51;1990 described cis hydroxylation using osmium tetraoxyde on a 14, 17-ethano derivative of formula (E) wherein Pa is a methyl group and Pb is an acetyl group. A mixture was obtained consisting of about 56% of the 0c,oc-dihydroxy and 27% of the B,B-dihydroxy derivative.

Beside the poor ivity for osmium-catalyzed dihydroxylation of these 17β-acetyloxy derivatives, exhaustive purifications are needed.

There remain a need for an improved synthesis of estra-1,3,5 (10),15α,16α,17β-tetrol (estetrol).

It is therefore an object of the t ion to provide a process for the preparation of estra-1,3,5(10),-triene 15α,16α,17β-tetrol which overcome at least one of the disadvantages of the prior art, or at the very least, provides the public with a useful choice.

Summary of the invention The t inventors have now found that this object can be obtained by using a s as defined in the appended claims.

According to the present invention, a process for the preparation of a compound of formula (I) (estra-1,3,5(10)-triene-3, 15α,16α,17β-tetrol) is provided: (I) said process comprises the steps of : a) reacting a compound of formula (II), with an acylating or a silylating agent to produce a compound of formula (III), (II) (III) wherein P1 is a protecting group selected from R1CO-, or R2Si(R3)(R4)-, P2 is a protecting group selected from (R6R5R7)C-CO-, or (R3)(R4)-, wherein R1 is a group selected from C1_6alkyl or 03-5cycloalkyl, each group being optionally substituted by one or more tuents independently selected from fluoro or C1-4alkyl; R2, R3 and R4 are each independently a group selected from C1-6alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1_4alkyl; R5 is a group selected from C1-6alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1_4alkyl; R6 and R7 are each independently hydrogen or a group selected from C1-6alkyl or phenyl, each group being optionally substituted by one or more substituents ndently selected from fluoro or kyl; 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 e nd of formula (IV); and (IV) c) deprotecting the compound of formula (IV) to e compound of formula (I).

The invention provides an improved process for producing a compound of formula (I) in significantly higher yield and /or at lower cost than possible by the previous known syntheses. In particular, the present process allows the preparation of estra-1,3,5(10)— -3,150c,16oc,17B-tetrol as the major product with little or no estra-1,3,5(10)—triene- 3,155,165,17B-tetrol .

According to a second , the present invention also encompasses estetrol directly obtained by the s according to the present invention, for use in a method selected from a method of e replacement therapy, a method of treating vaginal dryness, a method of contraception, a method of enhancing libido, of method of treating skin, a method of promoting wound healing, and a method of treating or preventing a disorder selected from the group consisting of autoimmune diseases, breast tumors and colorectal tumors.

The above and other characteristics, features and advantages of the present ion will become apparent from the following detailed description, which illustrate, by way of example, the principles of the invention.

Detailed description of the ion It is also to be understood that the terminology used herein is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

As used herein, the singular forms a , an", and "the" include both singular and plural referents unless the context y dictates othenNise.

The terms "comprising , comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. It will be appreciated that the terms "comprisingII II , comprises" and "comprised of" as used herein se the terms "consisting of", "consists" and "consists of".

The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the d endpoints.

All references cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings of all references herein specifically referred to are incorporated by reference.

Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as ly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

In the ing passages, different aspects of the invention are defined in more detail.

Each aspect so defined may be combined with any other aspect or aspects unless clearly ted to the contrary. In ular, any feature indicated as being preferred or advantageous may be combined with any other feature or features ted as being preferred or advantageous.

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic bed in tion with the embodiment is ed in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places hout this specification are not necessarily all referring to the same ment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more ments. Furthermore, while some embodiments described herein include some but not other features included in other ments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art.

For example, in the appended claims, any of the claimed embodiments can be used in any ation.

The term “alkyl” by itself or as part of another substituent, refers to a straight or branched saturated hydrocarbon group joined by single carbon-carbon bonds having 1 to 6 carbon atoms, for example 1 to 5 carbon atoms, for example 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, C1_6alkyl means an alkyl of one to six carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, 2-methylbutyl, pentyl iso-amyl and its isomers, hexyl and its isomers.

The term “03-5cycloalkyl”, as a group or part of a group, refers to a saturated or partially ted cyclic alkyl l containing from about 3 to about 6 carbon atoms. Examples of monocyclic Cg-scycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, or exyl.

The term lkenyl” by itself or as part of another substituent, refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon- carbon double bonds. Examples of Cz-salkenyl groups are l, 2-propenyl, 2-butenyl, nyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.

The term “Cs_1oaryl”, by itself or as part of another substituent, as a group or part of a group, refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple rings fused together (e.g. alene), or linked covalently, typically containing 6 to 10 atoms; wherein at least one ring is aromatic. Non-limiting examples of Cs-1oaryl include phenyl (Cearyl), naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl.

The term “C1_6alkylcarbonyl”, as a group or part of a group, represents a group of Formula —CO-Ra, n Ra is C1_6alkyl as defined herein.

The term “03-5cycloalkylcarbonyl”, as a group or part of a group, represents a group of Formula —CO-R°, n Ra is cloalkyl as defined herein.

The term kenle1_5alkanoate” refers to a compound having the Formula Rb-O-CO-Ra wherein Ra is C1_6alkyl as defined herein and Rb is 02-6alkenyl as defined herein.

The term “Cz_6alkenylCgecycloalkanoate” refers to a compound having the Formula Rb-O-CO-RC wherein RC is 03-6cycloalkyl as defined herein and Rb is 02-5alkenyl as defined herein.

The term “Cr_6alkylenecarbonate” refers to a compound having the Formula O-O-Ra wherein Ra is C1_6alkyl as defined herein and Rb is 02-6alkenyl as defined herein.

The term “heteroaryl”, by itself or as part of r substituent, refers to an aromatic monocyclic or polycyclic heterocycle having preferably 5 to 7 ring atoms and more preferably 5 to 6 ring atoms, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur. Non-limiting examples of a heteroaryl include: pyridinyl, pyrrolyl, furanyl, thiophenyl, lyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl. Preferably aryl is selected from the group comprising pyridinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, lyl, oxazolyl, thiazolyl, and pyrazinyl. More preferably aryl is pyridinyl.

The present invention relates to a process for preparing nd of formula (I); wherein said process comprises the steps of a) reacting a compound of formula (II), with an acylating or a silylating agent to produce a compound of formula (III), (II) (III) wherein P1 is a protecting group ed from R1CO-, or 3)(R4)-, P2 is a protecting group selected from (R6R5R7)C-CO-, or (R2)Si(R3)(R4)-, R1 is a group ed from C1-6alkyl or 03-5cycloalkyl, each group being optionally substituted by 1, 2 or 3 substituents independently selected from fluoro or kyl; preferably R1 is selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert—butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each group being optionally substituted by 1, 2 or 3 substituents independently selected from fluoro or C1_4alkyl; more preferably R1 is methyl, ethyl, propyl, isopropyl, cyclopentyl, or cyclohexyl, yet more preferably R1 is methyl, or ethyl; R2, R3 and R4 are each independently a group selected from C1-6alkyl or phenyl, each group being optionally substituted by one or more substituents independently ed from fluoro or C1_4alkyl; preferably R2, R3 and R4 are each independently selected from the group comprising methyl, ethyl, , isopropyl, butyl, isobutyl, utyl, and phenyl, each group being optionally substituted with 1, 2 or 3 substituents each independently selected from fluoro or C1-4alkyl; preferably R2, R3 and R4 are each ndently selected from the group comprising methyl, ethyl, propyl, isopropyl, or terf-butyl, and phenyl, each group being optionally substituted with 1, 2 or 3 tuents each independently selected from fluoro or C1_2alkyl; R5 is a group ed from C1-6alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1_4alkyl; preferably R5 is selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, and phenyl, each group being optionally substituted with 1, 2 or 3 substituents each independently selected from fluoro or C1-4alkyl; preferably R5 is selected from the group comprising methyl, ethyl, propyl, isopropyl, or tert—butyl, and phenyl, each group being optionally substituted with 1, 2 or 3 substituents each independently selected from fluoro or kyl; R6 and R7 are each ndently hydrogen or a group selected from C1_6alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4alkyl; ably R6 and R7 are each independently en or are selected from the group comprising , ethyl, propyl, isopropyl, butyl, isobutyl, terf-butyl, and phenyl, each group being optionally substituted with 1, 2 or 3 substituents each independently selected from fluoro or l; preferably R6 and R7 are each independently hydrogen or a group selected from methyl, ethyl, propyl, isopropyl, or tert- butyl, and phenyl, each group being optionally substituted with 1, 2 or 3 substituents each independently selected from fluoro or C1_2alkyl; said process also comprises the steps of: 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 compound of formula (IV); preferably said oxidizing agent is potassium permanganate; and (IV) c) deprotecting the nd of formula (IV) to produce compound of formula (I).

In an embodiment, P1 is 3)(R4)-. Preferably P1 is selected from the group comprising terf-butyI-dimethyl-silyl, diphenyl-methyl-silyl, dimethyl-phenyl-silyl, trimethyl- sinI, triethyI-sinI and triisopropyI-sinI, each group being optionally substituted by one or more substituents independently selected from quoro or C1_4a|kyl; more preferably P1 is terf-butyI-dimethyl-silyl.

According to the invention, step (a) comprises reacting a compound of a (II), with an acyIating or a silylating agent to produce a compound of formula (III), In an embodiment, compound of formula (II) can be reacted with a silylating agent and P2 is RZSi(R3)(R4)-. Preferably P2 is ed from the group comprising terf-butyI-dimethylsilyl , diphenyl-methyl-silyl, dimethyl-phenyl-silyl, trimethyl-silyl, triethyl-silyl and propyI-sinI, each group being optionally substituted by one or more substituents independently selected from quoro or C1_4a|kyl; more preferably P2 is tert—butyI-dimethyl- sinI.

In an embodiment, P1 and P2 are each independently RZSi(R3)(R4)-.

Non-limiting es of suitable silylating agent can be selected from the group comprising C1_5alkylsilylchloride, kylsilyltriflate, Cearylsilylchloride, Cearylsilyltriflate, kleearylsilylchIoride, and C1.6aIkleearylsilyltriflate, each group being ally substituted by one or more substituents ndently selected from quoro or C1_4a|kyl.

For example, ion of protected compound of formula (III) can be performed by reaction of compound of formula (II) with a silylating agent such as terf-butyl dimethylsilylchloride, diphenylmethylsilylchloride, dimethylphenylsilylchloride, trimethylsilylchloride, triethylsilylchloride, or triisopropylsilylchloride, or such as tert—butyl dimethylsilyltriflate, diphenylmethylsilyltriflate, dimethylphenylsilyltriflate, trimethylsilyltriflate, triethylsilyltriflate, or triisopropylsilyltriflate. The reaction can be performed in the presence of a suitable base such as imidazole, 2,6-lutidine, collidine, ylamine, or 1,8—diazabicyclo[5.4.0]undecene (DBU). The on can be performed at room temperature or under reflux. The reaction can be performed in the presence of a suitable solvent such as dimethylformamide, dichloromethane, or toluene, or a mixture thereof.

In an embodiment, compound of formula (II) can be reacted with a silylating agent and P2 is (R6R5R7)C-CO-. Preferably P2 is terbutyl-CO.

In an embodiment, P1 and P2 are each independently (R6R5R7)C-CO-.

Non-limiting examples of le acylating agent can be selected from the group R. c) n5 *0 " o R5 RWQ 5 ,6 ‘ W}Lang sow - , R fir? comprising W R R R , and , preferably R5 a :5. RUM—"7 ‘0 6R3 RT D4, R5_ aficmca ,Kg‘ H and F34 R , wherein R5, R6, R7 have the same meaning as that defined in claim 1, R8 is a group selected from C1-6alkyl, or Cz-ealkenyl, each group being optionally substituted by one or more substituents independently ed from fluoro or C1_4alkyl.

Preferably, the acylating agent can be selected from the group comprising pivaloyl chloride, pivaloyl anhydride and the like.

The ion when performed with acylating agent such as 02-6alkenyl-ter—butyrate, can be performed in the presence of an acid, such as in the presence of sulfuric acid, or in the presence of a Cs-1oarylsulfonic acid, optionally substituted by one or more chloro substituents. Non-limiting examples of a suitable acid e oluene sulfonic acid, and sulfuric acid. 2012/069761 R5 :3 R5, R§%—%_{C} ages-om R if? The acylation when med with H or R R , can be performed in the presence of an organic base, such as imidazole, ylamine and the like.

Step (b) can comprise reacting the compound of formula (III) in the presence of at least one ing agent selected from permanganate salt, osmium oxide, or hydrogen peroxide, or iodine and silver e or ruthenium salt to produce compound of formula (IV).

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

This reaction can be med in the presence of a co-oxidant such as trimethylamine n- oxide, quinuclidine N-oxide, N-methylmorpholine N-oxide, potassium ferricyanide, tert- butylhydroperoxide, or a phase transfer st such as tetralkylammonium salts.

Preferably step (b) is performed in the presence of a permanganate salt, such as ium permanganate. The reaction can be performed in the presence of a suitable acid such as formic acid. The reaction can be performed at low temperature such as temperature below 10°C, preferably below 5°C, preferably around 0°C. The reaction can be performed in the presence of a suitable solvent such as acetone.

According to the invention, step (c) comprises deprotecting the compound of formula (IV) to produce compound of formula (I).

Suitable methods and conditions for deprotecting compound of formula (IV), will be clear to the skilled person and are generally described in the standard handbooks of organic chemistry, such as Greene and Wuts, “Protective groups in organic synthesis”, 3rd Edition, Wiley and Sons, 1999, which is incorporated herein by reference in its entirety.

For example, when P1 and P2 are each independently RZSi(R3)(R4)-, the deprotection can be performed in the presence of a le acid, such as hydrochloric acid, acetic acid and the like, or by employing stoechiometric amount of a tetralkyl ammonium fluoride derivative in a solvent.

For example, when P1 and P2 are each independently (R6R5R7)C-CO-, the deprotection can be performed in the ce of a suitable acid, base or reducing agents. Preferably, the deprotection can be performed using a suitable base such as potassium carbonate, for example in methanol.

The nd of formula (II) can be obtained according to method known to the skilled man in the art.

In an embodiment, compound of formula (II) can be prepared by a process comprising the steps of: i) reacting a compound of formula (V), with an acylating or a silylating agent to produce a compound of formula (VI), (V) (VI) wherein P3 is a protecting group selected from RQCO-, or R1OSi(R11)(R12)-, R9 is a group ed from C1-6alkyl or 03-5cycloalkyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1_4alkyl; ably R9 is a group selected from C1-6alkyl or 03-5cycloalkyl, each group being ally substituted by 1, 2 or 3 substituents independently selected from fluoro or C1.4alkyl; preferably R9 is selected from the group sing methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert—butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each group being optionally substituted by 1, 2 or 3 substituents independently selected from fluoro or C1_4alkyl; more preferably R9 is methyl, ethyl, propyl, pyl, cyclopentyl, or cyclohexyl, yet more preferably R9 is methyl, or ethyl; R10, R11 and R12 are each ndently a group selected from C1-6alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1_4alkyl; preferably R10, R11 and R12 are each independently a group selected from kyl or Csaryl, said kyl or Csaryl, being optionally substituted with 1, 2 or 3 substituents independently selected from fluoro or C1_6alkyl; preferably R10, R11 and R12 are each independently ed from the group comprising methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert—butyl, and phenyl, each group being optionally substituted with 1, 2 or 3 substituents each independently selected from fluoro or C1-4alkyl; preferably R10, R11 and R12 are each independently selected from the group comprising , ethyl, propyl, isopropyl, or terf-butyl, and phenyl, each group being optionally substituted with 1, 2 or 3 substituents each independently selected from fluoro or C1_2alkyl, ii) ng the nd of formula (VI) in the presence of palladium acetate or a derivative thereof, or iodine (V) species, to produce compound of formula (VII); and (Vll) iii) reacting the compound of formula (Vll) with a reducing agent to produce compound of formula (II).

Preferably, nd of formula (II) can be prepared by a process comprising the steps i) reacting a compound of formula (V), with an acylating or a silylating agent to produce a compound of formula (VI), (V) (VI) wherein P3 is a ting group selected from RQCO-, or R1OSi(R11)(R12)-, R9 is a group selected from C1-6alkyl or 03-5cycloalkyl, each group being optionally substituted by one or more substituents ndently selected from fluoro or C1_4alkyl; preferably R9 is a group selected from C1-6alkyl or 03-5cycloalkyl, each group being optionally substituted by 1, 2 or 3 substituents independently selected from fluoro or C1.4alkyl; preferably R9 is selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert—butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each group being optionally substituted by 1, 2 or 3 substituents independently selected from fluoro or C1_4alkyl; more ably R9 is methyl, ethyl, propyl, isopropyl, cyclopentyl, or cyclohexyl, yet more preferably R9 is methyl, or ethyl; R10, R11 and R12 are each independently a group selected from C1-6a|ky| or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1_4alkyl; preferably R10, R11 and R12 are each independently a group selected from C1-6a|ky| or Csaryl, said C1-6a|ky| or Csaryl, being optionally substituted with 1, 2 or 3 tuents independently selected from fluoro or C1_6a|ky|; preferably R10, R11 and R12 are each independently selected from the group comprising methyl, ethyl, , isopropyl, butyl, isobutyl, tert—butyl, and , each group being optionally substituted with 1, 2 or 3 substituents each independently selected from fluoro or C1-4a|ky|; preferably R10, R11 and R12 are each independently selected from the group comprising methyl, ethyl, propyl, isopropyl, or terf-butyl, and phenyl, each group being optionally substituted with 1, 2 or 3 substituents each independently selected from fluoro or kyl, ii) reacting the compound of formula (VI) in the presence of palladium acetate or a derivative thereof to produce compound of a (VII); and (VII) iii) reacting the nd of formula (VII) with a reducing agent to produce compound of formula (II).

In an embodiment, P1 is R1CO-; ably P1 is a group selected from C1-4a|ky|carbony| or C4-6cyc|oa|ky|carbony|, each group being optionally substituted by 1, 2 or 3 substituents independently selected from fluoro or C1-4a|ky|; more preferably P1 is a group selected from C1-2a|kylcarbony or cloalkylcarbonyl, each group being optionally substituted by 1, 2 or 3 substituents independently selected from fluoro or kyl; for example P1 is selected from acetyI, ter—butyI-CO-, or cyclohexylcarbonyl, preferably P1 is acetyI. 2012/069761 In an embodiment, P3 is RQCO-; preferably P3 is a group ed from C1-4alkylcarbonyl or C4.6cycloalkylcarbonyl, each group being optionally substituted by 1, 2 or 3 substituents independently ed from fluoro or C1-4alkyl; more preferably P3 is a group selected from kylcarbony or 05.6cycloalkylcarbonyl, each group being optionally substituted by 1, 2 or 3 substituents independently selected from fluoro or C1_4alkyl; for example P3 is selected from acetyl, or cyclohexylcarbonyl, preferably P3 is acetyl.

In an embodiment, P1 is R1CO- and P3 is RQCO: In an another embodiment, P1 is RZSi(R3)(R4)-. Preferably P1 is selected from the group sing terf-butyl-dimethyl-silyl, diphenyl-methyl-silyl, yl-phenyl-silyl, trimethyl-silyl, triethyl-silyl and triisopropyl-silyl, each group being optionally substituted by one or more substituents independently ed from fluoro or C1-4alkyl; more preferably P1 is tert—butyl-dimethyl-silyl.

In an embodiment, step (i) comprises the steps of (i1) protecting the hydroxyl of compound of formula (V) with a silylating agent to e a compound of formula (Va), wherein P1 has the same meaning as that defined herein above, preferably wherein P1 is RZSi(R3)(R4)-; and (Va) (i2) protecting the ketone of compound of formula (Va) in the presence of an acylating agent to produce compound of formula (VI), preferably wherein P3 is RQCO-.

In an embodiment, P3 is R1°Si(R11)(R12)-; preferably P3 is selected from the group comprising terf-butyl-dimethyl-silyl, diphenyl-methyl-silyl, dimethyl-phenyl-silyl, trimethyl- silyl, triethyl-silyl and triisopropyl-silyl, each group being optionally substituted by one or more tuents ndently selected from fluoro or C1_4alkyl, more preferably P3 is terf-butyl-dimethyl-silyl.

In an embodiment, P1 is RZSi(R3)(R4)- and P3 is R1°Si(R11)(R12)-. in another embodiment, P1 is RZSi(R3)(R4)-; and P3 is R9c0-. Preferably P1 is ed from the group comprising terf-butyl-dimethyl-silyl, diphenyl-methyl-silyl, dimethyl-phenyl- silyl, trimethyl-silyl, triethyl-silyl or triisopropyl-silyl, each group being optionally substituted by one or more substituents independently ed from fluoro or kyl; more preferably P1 is terf-butyl-dimethyl-silyl; and preferably P3 is a group selected from Ci-salkylcarbonyl or 03-6cycloalkylcarbonyl, each group being optionally substituted by 1, 2 or 3 substituents ndently selected from fluoro or Ci-4alkyl; preferably P3 is a group ed from Ci-4alkylcarbonyl or 05.6cycloalkylcarbonyl; each group being optionally substituted by 1, 2 or 3 tuents independently selected from fluoro or C1_2alkyl; more preferably P3 is kylcarbony or 05-6cycloalkylcarbonyl, for example P3 is acetyl or cyclohexylcarbonyl, preferably acetyl.

Suitable silylating agents and conditions are the same as described herein above for step (a) of the process of the invention.

In an ment, wherein P1 is R1CO- and P3 is RQCO-, estrone can be reacted with an acylating agent. Preferably, said acylating agent is 02-6alkenlei.6alkanoate or 02.6alkenles-5cycloalkanoate. Preferably, the acylating agent is selected from the group comprising 02-6alkenylpropanoate, 02-5alkenylbutanoate, 02-6alkenylpentanoate, 02-6alkenylhexanoate, 02-6alkenylcyclopropanoate, 02-6alkenylcyclobutanoate, kenylcyclopentanoate, and 02-6alkenylcyclohexanoate. More preferably, the acylating agent is selected from the group comprising isopropenyl acetate, isopropenyl propionate, isopropenyl butyrate, isopropenyl isobutyrate, vinyl acetate, vinyl propionate, propenyl cyclohexanecarboxylate, l cyclopentanecarboxylate, and vinyl cyclohexanoate. More preferably, the acylating agent is selected from the group comprising isopropenyl acetate, isopropenyl propionate, isopropenyl butyrate, isopropenyl isobutyrate, vinyl e, and vinyl propionate. The acylation can be performed in the presence of an acid, such as in the presence of sulfuric acid, or in the presence of an Cs-1oarylsulfonic acid, optionally substituted by one or more chloro substituents. Non- ng examples of a suitable acid e para-toluene sulfonic acid, and sulfuric acid.

For example, estrone of formula (V) can be was reacted with isopropenyl acetate in the ce of ic acid or para-toluene sulfonic acid to give the estra-1,3,5 (10), 16- tetraene-3,17-diol, 3,17-diacetate. The reaction can be performed under reflux, optionally under inert atmosphere, such as nitrogen atmosphere. The product can be used as such in the next step or further purified by known techniques in the art such as by chromatography, for example on silica with a suitable eluant such as methylene chloride/hexane or ethyl acetate/hexane.

In an embodiment, wherein P1 is RZSi(R3)(R4)- and P3 is R1°Si(R11)(R12)-, estrone of formula (V) can be reacted with a ting agent. The silylating agent can be selected from the group comprising C1_5alkylsilyl triflate, Cearylsilyltriflate, C1.6alkleearylsilyltriflate, each group being optionally substituted by one or more substituents independently selected from fluoro or C1_4alkyl. For example, formation of ted e silyl ether can be performed by reaction of a silylating agent such as tert—butyl dimethylsilyltriflate, diphenylmethylsilyltriflate, dimethylphenylsilyltriflate, trimethylsilyltriflate, triethylsilyltriflate, or triisopropylsilyltriflate. The reaction can be med in the ce of a suitable base such as imidazole, 2,6-lutidine, ine, triethylamine, or 1,8—diazabicyclo[5.4.0]undec ene (DBU). The reaction can be performed at room temperature or under reflux. The reaction can be performed in the presence of a suitable t such as dichloromethane, toluene or dimethylformamide or a mixture thereof.

Step (ii) of the process for ing compound of formula (II) comprises reacting the compound of formula (VI) in the presence of palladium acetate or a derivative thereof such as palladium de to produce a compound of formula (Vll).

In an embodiment, said palladium e can be present in stoichiometric amounts, or sub-stoichiometric catalytic amounts. For example the reaction of step (ii) can be performed using stoichiometric s of palladium acetate, preferably in a suitable solvent such benzonitrile. This reaction can be performed at room temperature.

In another example, said step (ii) can be performed using sub-stoichiometric catalytic amounts of ium acetate in the presence of a C1-6alkylene ate such as allyl carbonate and in the presence of an organotin compound as catalyst. ably, the organotin compound is tri-butyltin methoxide. Preferably the C1_6alkylene carbonate is allyl methyl carbonate. The reaction can be performed under reflux conditions, optionally under inert atmosphere such as nitrogen or argon atmosphere.

In another example, said step (ii) can be performed using sub-stoichiometric catalytic amounts of ium acetate under an oxygen here.

Alternatively, step (ii) of the process for preparing compound of formula (II) comprises reacting the compound of formula (VI) in the presence of iodine (V) species.

Preferably, said iodine (V) species are selected from o—iodobenzoic acid (IBX also known as 1-hydroxy-1,2-benziodoxal-3(1 H)-oneoxide) or IBX complexes, such as lBX'N-oxide complexes. Non-limiting examples of suitable IBX complexes include IBX methoxypyridine-N-oxide complex (IBX'MPO complex), and complexes as described in Nicolaou et al. Angew.Chem.lnt.Ed. 2002, 41, 996-1000 and Angew.Chem.lnt.Ed. 2002, 41, 993-995 hereby orated by reference in their entirety.

In another, more preferred embodiment, the iodine (V) species are selected from HlOs or/and its anhydride l205. These iodine (V) species have the advantage of being mild, safe and chemoselective ts available at reasonable cost for industrial applications.

Preferably, the oxidation with the iodine (V) species is carried out in the presence of a ligand such as tetrahydrofuran (THF), dimethylsulfoxide (DMSO) or N-oxide derivatives such as N-methylmorpholine-N-oxide, 4-methoxypyridine-N-oxide, trimethylamine-N-oxide.

Preferably, the reaction is med in the presence of a solvent, such as DMSO. In an embodiment the reaction is kept at 45-65°C. Preferably the reaction is performed at a temperature ranging from 45 to 65°C in the presence of DMSO.

The next step (iii) in the process comprises the reduction of the compound of formula (IV) with a ng agent to produce nd of a (II). Preferably, said reducing agent is a metal hydride compound. For e, the metal hydride compound can be selected from the group comprising LiAlH4, NaBH4, Ac)3, ZnBH4, and NaBH4/CeCI3. preferably, said reducing agent is NaBH4/CeCI3_ For example said reduction can be performed in a suitable solvent or a mixture thereof, such as in ydrofuran, or a mixture of methanol and tetrahydrofuran. The reaction can be performed at low temperatures such as below 15°C, for example below 10°C.

In an embodiment, compound of formula (Vll) is not isolated but directly d to the alcohol using said reducing agent. In this embodiment, step (ii) and (iii) are performed in one pot. This one-pot/two-step procedure is the shortest chemical pathway bed to obtain compound of a (II).

According to another embodiment, step (i) can be performed in two steps and comprises the steps of (i1) protecting the hydroxyl of compound of formula (V) using a silylating agent to produce a compound of formula (Va), wherein P1 is R28i(R3)(R4)-; and (Va) (i2) converting the ketone of nd of formula (Va) to its enol ether in the presence of an acylating agent to produce a compound of formula (VI).

In this embodiment, wherein P1 independently RZSi(R3)(R4)-, and P3 is RQ-CO-, estrone of formula (V) is reacted with a silylating agent to produce compound of formula (Va). The silylating agent can be selected from the group comprising C1_5alkylsilyl de, Csarylsilyl chloride, C1_6alklesarylsilyl chloride; each group being optionally substituted by one or more substituents independently ed from fluoro or C1_4alkyl. For example, ion of protected estrone silyl ether can be performed by reaction of a silylating agent such as terf—butyl dimethylsilylchloride, diphenylmethylsilylchloride, ylphenylsilylchloride, trimethylsilylchloride, triethylsilylchloride, or triisopropylsilylchloride. The reaction can be performed in the ce of a base such as imidazole, 2,6-lutidine, collidine, triethylamine, or 1,8—diazabicyclo[5.4.0]undecene (DBU).

The next step comprises, converting the ketone of compound of formula (Va) in the ce of an acylating agent to produce a compound of formula (VI) wherein P3 is acyl.

Suitable acylating agents and conditions are as described herein above. The next step can se reacting the formula (VI) wherein P3 is acyl in the presence of palladium acetate or a derivative thereof to produce compound of formula (Vll) wherein P1 is RZSi(R3)(R4)-. This reaction can be performed as described herein above. The next step in the process comprises the reduction of the compound of formula (Vll) with a reducing agent to produce compound of a (II) wherein P1 is RZSi(R3)(R4)-. This reaction can be performed as described herein above.

In another embodiment, compound of a (II) can be ed by a process comprising the steps of: 1) ng a compound of formula (V) with a silylating or an acylating agent to produce compound of formula (Va), wherein P1 has the same meaning as in claim 1; (V) (Va) 2) halogenation or sulfinylation of the nd of formula (Va) to produce a compound of formula (Vb) ; WO 50553 (Vb) wherein X is halo, or R20, and R20 is a group selected from Cs-1oaryl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from chloro or C1_4alkyl; 3) dehalogenation or desulfinylation of the compound of formula (Vb) to produce compound of formula (V); and (VII) 4) reacting the compound of formula (Vll) with a reducing agent to produce compound of formula (II). ing to step (1) of this embodiment, the hydroxyl of estrone of a (V) is protected, to produce compound of formula (Va). In an embodiment, estrone of formula (V) can reacted with a silylating agent. Non-limiting examples of suitable silylating agents and conditions are the same as described herein above for step (a) of the process of the ion. For example, formation of protected estrone silyl ether can be performed by reaction of a silylating agent such as terf-butyl dimethylsilylchloride, ylmethylsilylchloride, dimethylphenylsilylchloride, trimethylsilylchloride, triethylsilylchloride, or triisopropylsilylchloride, or such as terf-butyl dimethylsilyltriflate, diphenylmethylsilyltriflate, dimethylphenylsilyltriflate, hylsilyltriflate, triethylsilyltriflate, or triisopropylsilyltriflate. The reaction can be performed in the presence of a suitable base such as imidazole, 2,6-lutidine, collidine, triethylamine, or azabicyclo[5.4.0]undec ene (DBU). The reaction can be performed at room temperature or under reflux. The reaction can be performed in the presence of a suitable solvent such as dichloromethane, toluene, or dimethylformamide or a e thereof.

In another embodiment, estrone of formula (V) can be reacted with an acylating agent. In an embodiment, said acylating agent can be ed from the group comprising kenyIC1-6alkanoate, 02.6alkeny|03-6cycloalkanoate, acyl chloride, and anhydrides. ably, the acylating agent is selected from the group comprising Cz-ealkenylpropanoate, Cz-salkenylbutanoate, Cz-salkenylpentanoate, Cz-salkenylhexanoate, Cz-salkenylcyclopropanoate, 02-6alkenylcyclobutanoate, Czsalkenylcyclopentanoate, and Cz-salkenylcyclohexanoate, acyl chloride and anhydrides. More preferably, the acylating agent is selected from the group comprising isopropenyl acetate, isopropenyl propionate, isopropenyl butyrate, penyl isobutyrate, vinyl acetate, vinyl propionate, propenyl cyclohexanecarboxylate, ethenyl cyclopentanecarboxylate, vinyl exanoate, acetyl de, propionylchloride, butyrylchloride, acetic anhydride and the like. More preferably, the ing agent is selected from the group comprising isopropenyl acetate, isopropenyl propionate, isopropenyl butyrate, isopropenyl isobutyrate, vinyl acetate, vinyl propionate, acetyl chloride, propionylchloride, butyrylchloride, acetic anhydride and the like. The acylation when performed with Cz_6alkeny|C1_6alkanoate or 02.6alkeny|03-6cycloalkanoate, can be performed in the presence of an acid, such as in the presence of sulfuric acid, or in the ce of a Cs-1oarylsulfonic acid, optionally substituted by one or more chloro substituents. Non-limiting examples of a suitable acid include para-toluene sulfonic acid, and sulfuric acid. The acylation when performed with an acyl chloride or an anhydride, can be performed in the ce of an organic base, such as imidazole, triethylamine and the like.

Step (2) of the process ses halogenation or sulfinylation of the compound of formula (Va) to produce a compound of formula (Vb) ; n X is halo, or -O-SO-R2°, and R20 is a group selected from Cs-1oaryl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from chloro or C1_4alkyl; preferably R20 is phenyl or pyridinyl.

In an embodiment, step (2) is a halogenation and the halogenation is performed by reacting the compound of formula (Va) with a halogenating reagent. Preferably, step 2) is a ation, and X is bromo. In an embodiment, the brominating reagent can be selected from the group comprising copper(l|) bromide, bromine, pyridine e perbromine and the like.

In another embodiment, step (2) is a sulfinylation and the sulfinylation is performed by reacting the nd of formula (Va) with a base and with a sulfinylation reagent. Non- limiting examples of sulfinylation t include methyl 2-pyridinesulfinate, methyl benzenesulfinate, methyl 4-methyl-benzenesufinate, and methyl 4-chloro-benzene sulfinate. The base used in the sulfinylation step can be selected from the group comprising potassium hydride, potassium terbutylate, sodium hydride, sodium terbutylate and a mixture thereof. Non-limiting examples of suitable experimental conditions for the sulfinylation are described in Barry M Trost et al in l of Organic Chemistry, 1993, 58, 1; hereby orated by nce.

The next step (3) comprises the dehalogenation or desulfinylation of the compound of formula (Vb) to produce compound of formula (V).

In an embodiment, step (2) is a halogenation, and step (3) comprises a dehalogenation step which can be performed in the presence of a base. The base can be selected from the group sing imidazole, collidine, 2,6-lutidine, triethylamine, or 1,8- diazabicyc|o[5.4.0]undecene (DBU). The dehalogenation reaction can be performed at a temperature between 30°C and 130°C. Preferably, the dehalogenation reaction is performed in an aprotic solvent.

In another embodiment, step (2) is a ylation, and step (3) comprises a desulfinylation which can be carried out with heat optionally in the ce of cupric sulfate. The temperature of the desulfinylation step can be n 80°C and 130°C, preferably n 90°C and 120°C, preferably between 100°C and 115°C The next step (4) in the process comprises the reduction of the compound of formula (Vb) with a reducing agent to produce compound of formula (II). Preferably, said reducing agent is a metal hydride nd. For example, the metal hydride compound can be selected from the group comprising , NaBH4, NaBH(OAc)3, ZnBH4, and NaBH4/CeCI3. Preferably, said reducing agent is NaBH4/CeC|3_ For example said reduction can be performed in a suitable solvent or a mixture thereof, such as in tetrahydrofuran, or a mixture of methanol and tetrahydrofuran. The reaction can be med at low temperatures such as below 15°C, for example below 10°C.

The present process for preparing compound (I) allows the preparation of estra-1,3,5(10)— triene-3,15oc,160c,17B-tetrol l) as the major product with little or no estra-1,3,5(10)— triene-3,15B,16B,17B-tetrol isomer being formed. As used herein little refers to obtaining more than 90% of estetrol and less than 10% of the 155,165,17B-tetrol isomer, preferably less than 5% of the 15B,16B,17B-tetrol isomer, more ably less than 1% of the 15B,16B,17B-tetrol isomer.

The process ing to the invention has the advantage that estetrol, can be obtained in a reduced number of steps compared to prior art processes, which is more convenient for an economical and industrial synthesis.

The present ion also encompasses the use of estetrol directly ed by the process the invention for the manufacture of a pharmaceutical composition, preferably for use in a method selected from a method of hormone replacement therapy, a method of treating vaginal dryness, a method of contraception, a method of enhancing libido, of method of treating skin, a method of promoting wound healing, and a method of treating or preventing a disorder selected from the group consisting of autoimmune diseases, breast tumors and colorectal tumors.

The invention is illustrated but not limited by the following es.

Examples Example 1: Preparation of a compound of formula (I) using tert-butyl-dimethyl-silyl group as protecting group for P1 and P2 according to an embodiment of the invention.

Step 1: estra-1,3,5(10),15-tetraene-3,17B-diol bis(dimethyl-tert-butylsilyl) ether.

The starting material 3-t-butyldimethylsiloxy-estra-1,3,5 (10)—15-tetraene-17[’>-o| can be prepared as described in Example 3 and 4. To a solution of 3-t-butyldimethylsiloxy-estra- 1,3,5 (10)—15-tetraene-17B-ol (10g, 0.025 mole) in 100 ml of dimethylformamide were added imidazole (4.4g, 0.065 mole) and dimethyl-tert-butylsi|y|-ch|oride (1.5 eq.) and allowed to stand at room ature for 6 hours. The resulting solution was diluted with ethyl acetate, washed with water and ated. The residue was crystallized from methanol to afford (10g) of estra-1,3,5(10),15-tetraene-3,17B-diol bis(dimethyl-tertbutylsilyl ) ether.

NMR (CDCI3): 0.08 17-OSi(CH3)2, 0.18 (6H,3-OSi(CH3)2, 0.81 18—CH3), 0.91 (9H,17-OSi-t-Bu), 0.97 (9H,s,3-OSi-t,Bu), 4.33 (1H, broad s, 17 aH), 5.80 (1H,m,15-H, .95 (1 H,broad,d,16H), 8.45-8.75 (2H,2-and 4H), 7.12 (1 H,d,J=8Hz,1 H). mp :89—91°C Step 2: estra-1,3,5(10), 150c,160c,17B-tetrol : To a stirred solution of 1,3,5(10),15-tetraene-3,17B-diol bis(dimethyl-tert-butylsilyl) ether (10 g, 0.02 mole) and formic acid (0.06 mole, 2.3 ml) in acetone (100ml ) at 0°C was added gradually a solution of potassium permanganate (3.15g, 0.02 mole) in water (20ml) and acetone (100ml). After completion of the reaction, the reaction was quenched with a % aqueous solution of KHSOs. Acetone was partially removed and extracted with ethyl acetate, an washed with water. Ethyl acetate was concentrated under reduced pressure and diluted with heptane. The precipitate was ted by filtration and dissolved in acetone (100ml). To the solution 5N hloric acid (20 ml) was added. After completion of the on the resulting solution was d with water. The solid was collected by filtration, washed with heptane and crystallized from a mixture of methanol and water to afford the title compound.

Example 2: Preparation of a compound of formula (I) using tert-butyl-dimethyl-silyl group as protecting group for P1 and pivaloyl for P2 according to an embodiment of the invention.

The starting material tyldimethylsiloxy-estra-1,3,5 (10)—15-tetraene-17[’>-ol can be prepared as described in Example 3 and 4. To a on of 3-tert-butyldimethylsilyloxy- estra-1, 3, 5(10)—15-tetraeneol (30g, 0.078 mole) in 300ml of romethane and 11 ml of triethylamine were added drop wise 10.36g (0.086 mole) of pivaloyl chloride in 50ml of methylene chloride at 0°C. At the end of the addition the solution was stirred at room temperature for 1 hour. Water was added and the organic layer was washed two time with 100ml of water. Heptane was added and the product was collected by tion and used in the next step without any other purification. 3-terbutyl-dimethylsilyloxy-estra-1,3,5(10)—15-tetraene-17B-pivaloate was converted to its 150c,160c derivative following the procedure described in example 1 step 1.

Then this 3-terbutyl-dimethylsilyloxy-estra-1,3,5(10)—150c,16oc-diol-triene-17B-pivaloate (10g,0.02 mole) and K2C03 ( 2.76g,0.02 mole) was suspended in methanol 200 ml and stirred for 4 hours at room temperature. Water 300ml was added and the mixture was lized with 0.1 N HCI. The product was collected by filtration and dried to afford 7.5g (90% yield ) of 3-terbutyl-dimethylsilyloxy-estra-1 0)—triene-150c,16oc,17B—triol .

Deprotection in acidic medium of the silyl protecting group was performed using the same conditions as described in example 1 step 2, and allowed this compound to be converted to estetrol in 90% yield Example 3: Preparation of a compound of a (II) wherein P1 is t-butyldimethylsilyl according to an ment of the invention.

Step 1: 3,17-di-t-butyldimethylsiloxy-estra-1, 3, 5(10)tetraeneol To a solution of estrone (509, 0.185 mole) and 2,6-lutidine (629, 0.58 mole) in dichloromethane 400ml was added drop wise t-butyl-dimethylsilyl-triflate (102.6g,0.39 mole).The solution was stirred at room temperature for 6 hours. Water (300ml) was added and the organic layer was washed with a d solution of sodium carbonate. The dichloromethane solution was partially evaporated and ethyl acetate was added.

Diisopropyl ether was added to this solution. The mixture was stirred for 2 hours at 0°C.

The precipitate was collected by filtration and dried. 83 9 of the title compound were obtained (90% yield).

Step 2: tyldimethylsiloxy-estra-1, 3, 5 (10)tetraeneone To a solution of 3, 17-di-t-butyldimethylsiloxy-estra-1, 3, 5(10)—16-tetraeneol 83 9 (0.166 mole) in 400ml of acetonitrile was added Pd(OAc)2 3.8 9 (0.017 mole) in an oxygen atmosphere. The mixture was stirred at 40°C for 12 hours then ed through a pad of celite. A diluted solution of sodium carbonate was added and the mixture was extracted with ethyl acetate.

After concentration, diisopropyl ether was added and the mixture was stirred at 0°C for one hour. The product , 86% yield) was collected by tion and used in the next step without further purification.

Step 3: 3 -t-buty|dimethylsiloxy-estra-1, 3, 5 (10)tetraeneol The collected material , 0.143 mole) was dissolved in THF 300ml and a solution of cerium chloride heptahydrate (53.39, 0.143 mole) in methanol (300ml) was added. The mixture was cooled to 0°C sodium borohydride (8.129, 0.213 mole, 1.5eq) was added portion wise keeping the temperature below 9°C. At this end of the addition the mixture was stored for one hour then quenched by addition of a 2N HCl solution (100ml). The on was partly evaporated in situ and water (4L) was added. The precipitate was collected by tion and dried. After crystallization from a mixture of ethanol /diisopropyl ether the product was collected by filtration and dried. lt weighted 46.69 (85% yield).

Example 4: Preparation of a compound of formula (II) wherein P1 is t-butyldimethylsilyl according to an embodiment of the invention.

Step 1: 3 -t-buty|dimethylsiloxy-estra-1, 3, 5(10) -trieneone To a solution of estrone (1009, 0.37 mole) in 400ml of dichloromethane, imidazole (50.369, 0.74 mole) and t-butyl-dimethylsilyl de (61.39,0.41 mole) were added The solution was d at room temperature for 24 hours. Then water (200ml) was added. The c layer was partially evaporated and diisopropyl ether added. The white solid formed was collected by filtration and dried. lt ed 135.29, yield 95%, mp 172°C. 1H NMR (200MHz) :7.12 (d,J=7.9 Hz,1H), 6.61(m,2H),2.84(m,3H), 2.06-1.45 (m,12H), 0.97 (s,9H),0.91 (s,3H),0.18 (s,6H).

Step 2: 3 -t-buty|dimethylsiloxy-estra-1, 3, 5(10) tetraeneacetate 3 -t-butyldimethylsiloxy-estra-1, 3, 5(10) -trieneone 1359 (0.351 mole) were poured in 600ml of isopropenyl acetate and 12 9 of para-toluene-sulfonic acid. The e was refluxed. Acetone and isopropenyl acetate were continuously distilled off until the internal temperature reached 98°C. Then the mixture was cooled to 0°C and potassium carbonate added. After one hour at 0°C the mixture was filtered. The resulting solution was partially concentrated and diisopropyl ether added. The precipitate was collected by filtration and crystallized from a mixture of ethyl e and heptane. The product was collected by filtration and dried. lt weighted 119.59 (yield 80%).

Step 3: 3 -t-buty|dimethylsiloxy-estra-1, 3, 5 (10)tetraeneol To a solution of 3 -t-butyldimethylsiloxy-estra-1, 3, 5(10) traeneacetate 119.59 (0.280 mole) in acetonitrile (1500ml) were added 27.29 (0.085 mole of tributyltin methoxide, 11.2 9 (0.05 mole) of palladium acetate and 64 ml(0.560 mole) of allyl methyl ate. The mixture was refluxed for 2 hours then cooled to room temperature and filtered h a pad of silica gel. The mixture was d with water and extracted with ethyl acetate. After concentration to one third of the initial volume diisopropyl ether was added and the solution cooled at 0°C for one hour.

The product was collected by filtration. lt weighted 919 (85% yield) and was used in the next step without further purification.

Step 4: 3 -t-buty|dimethylsiloxy-estra-1, 3, 5 (10)tetraeneol The reduction step was performed as described in step 3 of example 2: the collected material was ved in THF and a solution of cerium de heptahydrate (1 eq) in methanol was added. The mixture was cooled to 0°C sodium borohydride (1.5eq) was added portion wise keeping the temperature below 9°C. At this end of the addition the mixture was stored for one hour then quenched by addition of a 2N HCI solution. The solution was partly evaporated in situ and water was added. The precipitate was collected by filtration and dried. After crystallization from a mixture of ethanol /diisopropy| ether the product was collected by filtration and dried.

Example 5: ation of a compound of formula (II) wherein P1 is tert- butyldimethylsilyl according to an embodiment of the invention.

Step 1: -butyldimethylsilyloxy-estra-1, 3, 5(10)-trieneone To a solution of 3-hydroxy-estra-1, 3, 5(10)—trieneone (100g, 0.370 mole ) in 500 ml of dichloromethane was added tert—butyldimethylsilyl-chloride , 0.388 mole) and imidazole , 0.388 mole). The mixture was stirred for 24 hours at room ature.

Water (300ml) was added and the organic layer was washed with 200 ml of water. After concentration the product was crystallized from a mixture of l/diisopropyl ether, collected by filtration and dried. lt weighted 145g (95% yield).

Step 2: 3-tert-butyldimethylsilyloxy-estra-1, 3, 5(10)tetraeneone A solution of potassium terbutylate (50g, 0.45 mole ) in 800ml of tetrahydrofuran was treated with 3-ten‘-butyldimethylsilyloxy-estra-1,3,5(10)—trieneone (86.5g, 0.225 mole) under nitrogen and stirred for 1 hour, then methyl benzenesulfinate ( 70.2 g, 0.45 mole ) and triethylamine were added. After ng for 2 hours the solution was poured in 1000 ml of water and 70 ml of hydrochloric acid keeping the temperature below 5°C. 1000m| of toluene was added, phases are separated and the solution was heated to distil off the solvent until the temperature reached 115°C. Reflux was maintained for 5 hours.

Toluene was washed with two time water, and then lly concentrated. Heptane was added. After one hour at 5°C the solid was collected by filtration and used in the reduction step t further cation.

Step 3: 3-tert-butyldimethylsilyloxy-estra-1, 3, 5(10)tetraeneol The material collected in step 2 was dissolved in THF 300ml and a solution of cerium chloride heptahydrate (123g, 0.33 mole) in methanol (300ml) was added. The mixture was cooled to 0°C and sodium borohybride (17.8g, 0.47 mole, 1.5q) was added portionwise keeping the temperature below 9°C. At this end of the addition the mixture was stirred for one hour then quenched by addition of a 2N HCI solution (100ml), extracted with ethyl acetate and washed with water. The organic layer was partly evaporated then ropylether was added. The precipitate was collected by filtration and dried. After llization form a mixture of ethanol propyl ether the title compound was isolated in 90% yield as an off white solid.

Example 6: Preparation of a compound of formula (II) wherein P1 is tert- butyldimethylsilyl according to an ment of the invention.

Step 1: 3-tert-butyldimethylsilyloxy-estra-1, 3, 5(10)-trieneone -butyldimethylsilyloxy-estra-1, 3, 5(10)—trieneone was prepared as described in step 1 of Example 5.

Step 2: 3-tert-butyldimethylsilyloxy-estra-1, 3, 5(10)tetraeneone (via X=Br) Copper(ll) e (1009, 0.45 mole) was added to a warm solution of 3-tert- butyldimethylsilyloxy-estra-1,3,5(10)—trieneone(86.4g, 0.225 mole) in methanol (500ml) and the mixture was heated under reflux for 2 hours. The hot mixture was filtered and was poured in a mixture of dichloromethane (1000 ml) and water (800ml). The organic layer was washed with water.

To this solution imidazole (18.39, 0.27 mole) was added and heated under reflux for 6 hours. After cooling water (500ml) was added and the c layer was concentrated.

The residue was crystallized from a mixture of ethyl acetate and heptane.

Step 3: 3-tert-butyldimethylsilyloxy-estra-1, 3, 5(10)tetraeneol The reduction step was performed as described in step 3 of example 1: The material collected in step 2 of example 2 was dissolved in THF and a solution of cerium chloride heptahydrate (about 1 eq) in ol was added. The e was cooled to 0°C and sodium borohybride (1.5 eq) was added portionwise keeping the temperature below 9°C.

At this end of the addition the mixture was stirred for one hour then quenched by addition of a 2N HCI on, extracted with ethyl acetate and washed with water. The organic layer was partly evaporated then diisopropylether was added. The precipitate was collected by filtration and dried. After crystallization form a mixture of ethanol /diisopropyl ether the title compound was isolated as an off white solid.

Example 7: Preparation of a compound of formula (II) wherein P1 is tert- butyldimethylsilyl according to an embodiment of the invention Step 1: 3-tert-butyldimethylsilyloxy-estra-1, 3, 5(10)-trieneone -butyldimethylsilyloxy-estra-1, 3, 5(10)—trieneone was prepared as described in step 1 of Example 5.

Step 2: 3-tert-butyldimethylsilyloxy-estra-1, 3, 5(10)tetraeneone (via dinesulfinic) 3- terf-butyldimethylsilyloxy-estra-1,3,5(10)-triene 17-one (8.64g, 0.0225 mole) was added to a suspension of potassium hydride (3eq. 35% dispersion in oil) in tetrahydrofuran 100ml. methyl 2-pyridinesulfinate (5.3g, 0.034 mole, 1.5eq) was added. After 30 min at room temperature the reaction was poured into a sulfate buffer. The aqueous phase was neutralized by an aqueous solution of sodium carbonate then extracted with toluene. The solution was heated to 110°C for one hour. After cooling to room temperature the solution was washed with a d solution of sodium hydroxide then with water. The organic layer was partly concentrated following by an addition of e. The 3-ten‘- imethylsilyloxy-estra-1, 3, 5(10)—15-tetraeneone was collected by filtration.

Step 3: 3-tert-butyldimethylsilyloxy-estra-1, 3, 5(10)tetraeneol The ion step was performed as described in step 3 of example 1: The material collected in step 2 of example 3 was ved in THF and a on of cerium chloride heptahydrate in methanol was added. The mixture was cooled to 0°C and sodium borohybride (1.5 eq) was added portionwise keeping the temperature below 9°C. At this end of the addition the mixture was stirred for one hour then quenched by addition of a 2N HCI solution, extracted with ethyl acetate and washed with water. The organic layer was partly evaporated then diisopropylether was added. The precipitate was collected by filtration and dried. After crystallization form a mixture of ethanol /diisopropy| ether the title compound was isolated as an off white solid.

It is to be tood that although preferred embodiments and/or materials have been discussed for providing embodiments according to the present invention, various modifications or changes may be made without departing from the scope and spirit of this invention.

Claims (14)

1. A process for the preparation of a nd of formula (I), hydrates or solvates thereof; said process comprising the steps of a) reacting a nd of formula (II), with a silylating agent to produce a compound of formula (III), (II) (III) wherein P1 is a protecting group selected from R1CO-, or R2Si(R3)(R4)-, and P2 is a protecting group selected from (R3)(R4)-, wherein R1 is a group selected from C1- 6alkyl or C3-6cycloalkyl, each group being optionally substituted by one or more substituents independently ed from fluoro or C1-4alkyl; R2, R3 and R4 are each ndently a group selected from C1-6alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4alkyl; 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 (IV) c) deprotecting the compound of formula (IV) to produce the compound of formula (I).

2. The process according to claim 1, wherein P1 is R2Si(R3)(R4)-, and P2 is (R2)Si(R3)(R4)-

3. The s ing to claim 1 or 2, wherein the silylating agent is selected from the group comprising C1-6alkylsilylchloride, C1-6alkylsilyltriflate, C6arylsilyl chloride, C6arylsilyltriflate, C1-6alkylC6arylsilylchloride, kylC6arylsilyltriflate, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4alkyl.

4. The process according to any of claims 1 to 3, wherein in step (b) said ing 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 any of claims 1 to 5 wherein the compound of formula (II) is ed by a process comprising the steps of: i) reacting a compound of formula (V), with an acylating or a silylating agent to produce a compound of formula (VI), (V) (VI) wherein P3 is a protecting group selected from R9CO-, or R11)(R12)-, wherein R9 is a group selected from kyl or C3-6cycloalkyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4alkyl; R10, R11 and R12 are each independently a group selected from C1-6alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4alkyl; ii) reacting the compound of a (VI) in the presence of palladium acetate or a derivative thereof, or an iodine (V) species, to produce compound of formula (VII); and (VII) iii) reacting the compound of formula (VII) with a reducing agent to produce compound of formula (II).

7. The process according to claim 6, wherein P3 is R9CO-.

8. The process according to claim 7 , wherein step (i) comprises the steps of (i1) protecting the hydroxyl of compound of formula (V) with a silylating agent to produce a compound of formula (Va), wherein P1 has the same meaning as that defined in claim 1; and (Va) (i2) protecting the ketone of compound of formula (Va) in the presence of an ing agent to produce compound of formula (VI).

9. The process according to any of claims 1 to 5, n the compound of formula (II) is obtained by a process comprising the steps of 1) reacting a compound of formula (V) with a silylating or an acylating agent to produce compound of formula (Va), wherein P1 has the same meaning as in claim 1; (V) (Va) 2) halogenation or sulfinylation of the compound of formula (Va) to produce a compound of formula (Vb); (Vb) wherein X is halo, or -SO-R20, and R20 is a group selected from C6-10aryl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from chloro or C1-4alkyl; 3) dehalogenation or desulfinylation of the compound of formula (Vb) to e compound of formula (VII); and (VII) 4) reacting the nd of a (VII) with a reducing agent to produce compound of formula (II).

10. The process according to claim 9, wherein step (2) is a sulfinylation and the sulfinylation is performed by 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 halogenation and the halogenation is performed by reacting the nd of formula (Va) with a halogenating reagent.

12. The process according to any of claims 6 and 9, wherein step (iii) and step (4) are performed using a reducing agent ed from the group of metal hydride compounds.

13. Process ing to any of claims 6 to 12, wherein the silylating agent is selected from the group comprising C1-6alkylsilylchloride, kylsilyltriflate, C6arylsilylchloride, C6arylsilyltriflate, C1-6alkyl C6arylsilylchloride, C1-6alkylC6arylsilyltriflate, each group being optionally tuted by one or more substituents independently selected from fluoro or C1-4alkyl.

14. Process according to any of claims 6 to 12, wherein the acylating agent is selected from the group comprising C2-6alkenylC1-6alkanoates, C2-6alkenylC3-6cycloalkanoate, acyl chlorides and anhydrides.