FIELD OF THE INVENTION

The present disclosure is directed to the synthesis of an intermediate in the production of the estrogen steroidal hormone, estetrol (estra-1 ,3,5(10)-triene-3, 15a, 16a, 17p-tetrol).

BACKGROUND TO THE INVENTION

The use of oral estrogen - most commonly estrone (Ei ), estradiol (E2) and estriol (E3) - for menopausal hormone therapy (MHT) and oral contraception (OC) is long established. However, the use or oral estrogen is not without risk. For example, the current versus non-current use of oral contraceptives is associated with a statistically significant increase in certain cardiovascular diseases, in particular venous thromboembolism (VTE) and ischemic stroke. In addition, whilst it has been suggested that long term use of oral contraception may reduce the lifetime risk of contracting endometrial cancer, ovarian cancer and colorectal cancer, several studies have linked the use of exogenous estrogen preparations to an increase in the lifetime risk of initiating breast cancer.

As recognized by inter alia Gerard et al. Journal of Endocrinology (2015) 224, 85-95, the use of estetrol (E4) as an estrogen can present a safer pharmacological profile which may serve to improve women’s health during and after their fertile lifetime. Estetrol (E4) is a human-specific natural estrogen produced only during pregnancy by the fetal liver. Given that E4 maternal plasma levels may reach 1 ng/ml (3 nM) and that from 0.5 to 3.8 mg/day of E4 have been measured in urine at the end of pregnancy, it is suggested exposure to high concentrations of E4 is not toxic. E4 binds to both estrogen receptors, with a higher affinity for estrogen receptor alpha (ERa-ESR1). In contrast to estradiol (E2), estetrol (E4) exhibits a high oral bioavailability with an elimination half-life of 28 hours in humans. Estetrol (E4) neither binds to nor stimulates the production of the sex hormone-binding globulin and it has no or only a minimal impact on liver function. Further, when used at 5-20 mg in a Phase 2 clinical trial - as reported by Gerard et al. - E4 induces minimal changes compared with ethinyl estradiol (EE) in binding cortisol globulin, angiotensinogen, triglycerides, or estrogensensitive coagulation proteins.

A number of authors have addressed the synthesis of either estetrol (estra-1 ,3,5(10)-triene-3, 15a, 16a, 17|3-tetrol) itself or of intermediates which can be transformed to estetrol. W02004/041839 A (Pantarhei Bioscience B.V.) discloses a process for the preparation of estra-1 , 3,5(10)-trien- 3,15a,16o,17p-tetrol, said process comprising the steps of: i) converting estrone into 3-A-oxy-estra-1 ,3,5(10), 15- tetraen-17-one, wherein A is a C1-C5 alkyl or C7 - C12 benzyl protecting group; ii) reduction of the 17-keto group of 3-A-oxy-estra-1 ,3,5(10),15-tetraen-17-one to yield 3-A-oxy-estra-l,3,5(10),15-tetraen-17p-ol; ill) protection of the 17-OH group of 3-A-oxy-estra-1 ,3,5(10),15-tetraen-17p-ol to yield 3-A-oxy-17-C-oxy-estra-1 ,3,5(10), 15- tetraene, wherein C is a monofunctional, aliphatic hydroxyl protecting group; iv) oxidizing the carbon-carbon double bond of ring D of 3-A-oxy-17-C-oxy-estra-1 ,3,5(10),15-tetraene to from protected estetrol; and, v) removing the protecting groups.

WO2013/012328 A1 (Pantarhei Bioscience B.V.) discloses a process for the preparation of estra-1 , 3,5(10)-trien- 3, 15a,16a,17p-tetrol (I), which process is depicted below.

More particularly, given A and C denote protecting groups, the disclosed process comprises the steps of: (i) conversion of estrone (II) into 17-B-oxy-3-A-oxy-estra-1 ,3,5(10),16-tetraene (III), wherein B is -Si(R ² )s in which R ² is independently selected from Ci-Ce alkyl or C6-C12 aryl groups; (II) conversion of compound (III) into 3-A- oxy-estra-1 ,3,5(10),15-tetraen-17-one (IV); (ill) reduction of the 17-keto group of compound (IV) to form 3-A-oxy- estra-1 ,3,5(10), 15-tetraen-17-ol (V); (iv) protection of the 17-OH group of compound (V) to form 3-A-oxy-17-C- oxy-estra-l,3,5(10),15-tetraene (VI); (v) oxidation of the carbon-carbon double bond of ring D of compound (VI) to form protected estetrol (VII); and, (vi) removal of protecting groups A and C to form estetrol (I). The protecting group A is selected from C1-C5 alkyl, C7-C12 benzyl and -Si(R ¹ )s in which each R ¹ is independently selected from Ci-Ce alkyl and C6-C12 aryl.

SUBSTITUTE SHEET (RULE 26) WO2012/164095 A1 (Estetra S.A.) discloses a process for the preparation of a compound of Formula (I), which process is depicted below:

More particularly, the process of this reference comprises the steps of: a) reacting a compound of formula (II) with an acylating or silylating agent to produce a compound of formula (III) wherein:

P ¹ is protecting group selected from R ² Si-R ³ R ⁴ or R ¹ CO-;

R ¹ is selected from Ci-Cs alkyl or C3-C6 cycloalkyl, each group being optionally substituted by one or more F or C1-C4 alkyl;

R ² , R ³ and R ⁴ are each independently selected from Ci-Ce alkyl or phenyl, each group being optionally substituted by one or more F or C1-C4 alkyl; b) halogenation or sulfinylation of the compound of formula (III) to produce a compound of formula (IV), in which formula (IV) X is halo or -O-SO-R ⁵ , wherein R ⁵ is Ce-Cio aryl or heteroaryl, each group being optionally substituted by one or more Cl or C1-C4 alkyl; c) dehalogenation or desulfinylation of the compound of formula (IV) to produce compound of formula (V); and, d) reacting the compound of formula (V) with a reducing agent to produce compound of formula (I).

This process is considered to be characterized by formation of a significant number of impurities which renders it impractical for manufacturing compound (I) at an industrial scale. It was found by the present inventors that, when the compound of formula (III) is sulfinylated according to the process described in WO 2012/164095, protecting group P ¹ of compound of formula (III) (in particular, when P ¹ is a silyl protecting group) is prone to degradation due to the harsh basic conditions used. For example, when P ¹ was a TBDMS protecting group, significant cleavage of the protecting group was observed. This is detrimental to the yield of the overall process described in WO 2012/164095.

WO2012/164096 A1 (Estetra S.A.) discloses a process for the preparation of a compound of Formula (I), which process is depicted below:

3

SUBSTITUTE SHEET (RULE 26)

More particularly, the process of this reference 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) wherein:

P ¹ and P ² are protecting groups independently selected from R ² Si-R ³ R ⁴ or R ¹ CO-;

R ¹ is selected from Ci-Ce alkyl or C3-C6 cycloalkyl, each group being optionally substituted by one or more F or C1-C4 alkyl;

R ² , R ³ and R ⁴ are each independently selected from Ci-Ce alkyl or phenyl, each group being optionally substituted by one or more F or C1-C4 alkyl; b) reacting the compound of formula (III) in the presence of palladium acetate or a derivative thereof to produce the compound of formula (IV); and c) reacting the compound of formula (IV) with a reducing agent to produce the compound of formula (I).

W02013/050553 A1 (Estetra S.P.R.L) discloses a process for the preparation of a compound of formula (I), hydrates or solvates thereof, which process is depicted below:

II III IV I

More particularly, the process of this reference 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), wherein:

P ¹ is a protecting group selected from R ¹ CO- or R ² Si(R ³ )(R ⁴ )-;

P ² is a protecting group selected from (R ⁶ R ⁵ R ⁷ )C-CO- or (R ² )Si(R ³ )(R ⁴ )-, wherein:

R ¹ is a group selected from Ci-C ₆ alkyl or C ₃ -C ₆ cycloalkyl, each group being optionally substituted by one or more F or C1-C4 alkyl;

SUBSTITUTE SHEET (RULE 26) R ² , R ³ and R ⁴ are each independently a group selected from Ci-ealkyl or phenyl, each group being optionally substituted by one or more F or C1-C4 alkyl;

R ⁵ is a group selected from Ci-Ce alkyl or phenyl, each group being optionally substituted by one or more F or C1-C4 alkyl;

R ⁶ and R ⁷ are each independently hydrogen or a group selected from Ci-Ce alkyl or phenyl, each group being optionally substituted by one or more F or C1-C4 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 compound of formula (IV); and c) deprotecting the compound of formula (IV) to produce compound of formula (I).

W02013/034780 A2 (Crystal Pharma S.A.U) discloses a process for the preparation of a compound of formula (I) or a salt or solvate thereof, the process comprising reacting a compound of formula (II) with an oxidizing agent wherein R represents H or an hydroxyl protecting group.

WO2015/040051 A1 (Crystal Pharma S.A.U) discloses a process for the preparation of estetrol or a salt or solvate thereof, the process comprising: a) reacting a compound of formula (IV) or a salt or solvate thereof with an oxidizing agent selected from OsO4 or a source of osmium tetroxide to produce Estetrol or a compound of formula (II) or a salt or solvate thereof

SUBSTITUTE SHEET (RULE 26) wherein: R ¹ is a hydroxyl protecting group selected from a silyl ether, an ether, an ester, a carbamate and a carbonate, and

R ² is a hydroxyl protecting group selected from an ether; and, b) deprotecting said compound to produce Estetrol.

US 2014/0107358 describes a process for the preparation of a compound of formula (I) said process comprising the steps of: a) reacting a compound of formula (II), with an acylating or a silylating agent to produce a compound of formula (III), where P ¹ and P ² are each independently a protecting group selected from R2-SI-R3R4, or R1CO-, wherein R ¹ is a group selected from C1-6 alkyl or C3-6 cycloalkyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4 alkyl; R ² , R ³ and R ⁴ are each independently a group selected from Ci. ₆ alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4 alkyl; b) reacting the compound of formula (III) in the presence of palladium acetate or a derivative thereof to produce compound of formula (IV); and c) reacting the compound of formula (IV) with a reducing agent to produce compound of formula (I).

The process is depicted below:

(II) (HI) (IV) (I)

The present disclosure is directed to the synthesis of alternative intermediate compounds which can be facilely converted to: estetrol (estra-1 ,3,5(10)-triene-3,15a, 16a, 17p-tetrol) and to salts, hydrates and solvates thereof; or, to 1 -, 2- or 4-alkyl estetrol compounds and the salts, hydrates and solvates thereof. The synthesis steps of the present disclosure are not associated with a high level of impurities and thus the synthetic pathway may be scaled up to facilitate industrial scale production of estetrol and derivatives thereof.

STATEMENT OF THE INVENTION

In accordance with a first aspect of the invention, there is provided a method of preparation of a compound of Formula (VI)

6

SUBSTITUTE SHEET (RULE 26)

wherein: R ¹ , R ² and R ³ are independently selected from H, halogen or methyl; and,

Pr ² is -Q ² , -C(O)Q ² or — S i (Q ² ) ₃ wherein each Q ² is independently selected from

Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C8 heterocycloalkyl, Ce-Cw aryl, C7-C18 alkylaryl or C7-C18 aralkyl; and, said method comprising the steps of: a) reacting a compound of Formula (I) with a compound of Formula (II) to form a product of Formula wherein: Z is OR ⁴ or SR ⁵ ;

R ⁴ is C1-C4 alkyl or Ce-Cw aryl;

R ⁵ is C1-C4 alkyl or Ce-Cw aryl;

T ¹ is Ci-Ce alkyl or a 5- or 6-membered aromatic ring having 0, 1 or 2 heteroatoms, said aromatic ring being substituted with n substituents X; each X is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or

C(O)R ⁶ ;

R ⁶ is C1-C4 alkyl; and, n Is O, 1 or 2;

SUBSTITUTE SHEET (RULE 26) b) reacting said compound of Formula (III) with a compound Pr ² -A to yield a compound of Formula (IV):

(III) (IV) wherein: Pr ² is -Q ² , -C(O)Q ² or — Si(Q ² )3 wherein each Q ² is independently selected from Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C8 heterocycloalkyl, Ce-Cio aryl, C7-C18 alkylaryl or C7-C18 aralkyl; and,

A is halogen or -OSO2CF3; c) eliminating the sulfoxide group of said Compound of Formula (IV) to form a compound of Formula (V), wherein said elimination is performed under heating in the presence of a non-polar aprotic solvent and at least one of a base and a trialkylphosphite of formula P(OR ⁷ )3, wherein each R ⁷ is independently selected from C1-C2 alkyl; and, d) subjecting the compound of Formula (V) to a reduction to form said compound of Formula (VI), wherein said reduction comprises treating said compound of Formula (V) in the presence of a solvent with at least one hydride donor selected from the group consisting of borohydrides and aluminium hydride compounds.

For illustration, this aspect of the invention is depicted in the reaction scheme of Figure 1 appended hereto.

The present invention disclosure relates in particular to a compound of Formula (VI) wherein: each of R ¹ , R ² and R ³ is H; and, Pr ² is - Si(Q ² )s in which each Q ² is independently selected from C1-C4 alkyl or Ce-Cw aryl. In an important embodiment Pr ² is selected from the group consisting of: t-butyldimethylsilyl (TBDMS); t- butyldiphenylsilyl; diphenylmethylsilyl; and, tri(isopropyl)silyl.

8

SUBSTITUTE SHEET (RULE 26) In accordance with an important embodiment of this aspect of the invention, the method of preparation of a compound of Formula (VI) comprises the steps of: a) reacting a compound of Formula (I) with a compound of Formula (IIA) to form a product of Formula wherein: Z is OR ⁴ or SR ⁵ ;

R ⁴ is C1-C4 alkyl or Ce-Cw aryl;

R ⁵ is C1-C4 alkyl or C ₆ -Ci ₀ aryl; each X is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or C(O)R ⁶ ;

R ⁶ is C1-C4 alkyl; and, n Is O, 1 or 2; b) reacting said compound of Formula (II IA) with a compound Pr ² -A to yield a compound of Formula (IVA): wherein : Pr ² is -Q ² , -C(O)Q ² or - S I (Q ² )s wherein each Q ² is independently selected from

Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C8 heterocycloalkyl, Ce-Cio aryl, C7-C18 alkylaryl or C7-C18 aralkyl; and, A is halogen or -OSO2CF3; c) eliminating the sulfoxide group of compound of Formula (IVA) to form a compound of Formula (V), wherein said elimination is performed under heating in the presence of a non-polar aprotic solvent and at least one of a base and a trialkylphosphite of formula P(OR ⁷ )3, wherein each R ⁷ is independently selected from C1-C2 alkyl; and,

SUBSTITUTE SHEET (RULE 26)

d) subjecting the compound of Formula (V) to a reduction to form said compound of Formula (VI), wherein said reduction comprises treating said compound of Formula (V) in the presence of a solvent with at least one hydride donor selected from the group consisting of borohydrides and aluminium hydride compounds.

At least one of the following sets of conditions should be applied in the constituent reaction steps: i) said reaction of step a) is performed in the presence of an aliphatic (Ci-C ₄ )alkoxide of sodium, potassium or lithium and a polar aprotic solvent; ii) reactant Pr ² -A is A-Si(Q ² )s and said reaction of step b) is performed in the presence of a basic tertiary amine catalyst and a polar aprotic solvent; and, iii) in step c) , said base is selected from the group consisting of potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, calcium carbonate, caesium carbonate and mixtures thereof.

These conditions i) to iii) are not mutually exclusive and indeed one, two or preferably three of these conditions are applied.

As regards step b) of the process defined in accordance with condition ii) above, it is preferred that the basic tertiary amine catalyst is selected from imidazole or N-methylimidazole. Independently of or supplementary to this statement of preference, the molar ratio of the basic tertiary amine catalyst to the reactant Pr ² -A in step b) should be in the range from 1 :2 to 4:1 , preferably from 1 :1 to 3:1 and more preferably from 2:1 to 3:1 .

In an embodiment, the hydride donor of step d) is a borohydride or aluminium hydride compound selected from the group consisting of: potassium borohydride (KBF ); sodium borohydride (NaBF ); sodium triacetoxyborohydride (NaBH(OAc)3); diborane (B2H6); sodium cyanoborohydride (NaBHsCN); zinc borohydride (ZnBH ₄ ); aluminium hydride (AIH3); and, lithium aluminium hydride (LiAIH ₄ ).

10

SUBSTITUTE SHEET (RULE 26) In an independent embodiment, the reduction of step d) is performed in the presence of a Ci-Cs alkanol as solvent with a lanthanide chloride and at least one hydride donor selected from the group consisting of potassium borohydride (KBH4), sodium borohydride (NaBFL), sodium triacetoxyborohydride (NaBH(OAc)3), diborane (B ₂ He), sodium cyanoborohydride (NaBFLCN), zinc borohydride (ZnBFL), aluminium hydride (AIH3) and lithium aluminium hydride (Li Al H4) . Said lanthanide chloride of this embodiment of step d) should preferably be selected from cerium

(III) chloride, samarium (III) chloride or samarium (III) iodide. It is particularly preferred that, in this embodiment of step d), said lanthanide chloride comprises or consists of cerium (III) chloride.

The present invention further relates to a method for the preparation of a compound of Formula (VIB): wherein each Q ² is independently selected from C1-C4 alkyl or Ce-Cio aryl, said method comprising the steps of: a) reacting a compound of Formula (IB) with a compound of Formula (I I B) in the presence of an aliphatic (C1-C4) alkoxide of sodium, potassium or lithium and a polar aprotic solvent to form a product of Formula (IIIB); wherein: R ⁴ is C1-C2 alkyl;

X is halogen, C1-C2 alkyl or C1-C2 alkoxy; and, n Is O, 1 or 2; b) reacting a compound of Formula (IIIB) with CI-Si(Q ² )3 in the presence of a basic tertiary amine catalyst and a polar aprotic solvent to form a product of Formula (IVB);

SUBSTITUTE SHEET (RULE 26)

Sulfoxide Estrone c) eliminating the sulfoxide group of the compound of Formula (IVB) to form a compound of Formula (VB), wherein said elimination is performed under heating in the presence of: a non-polar aprotic solvent; a trialkylphosphite of formula P(OR ⁷ )s wherein each R ⁷ is independently selected from C1-C2 alkyl; and, a base selected from the group consisting of potassium carbonate, sodium carbonate, calcium carbonate and mixtures thereof; and, d) subjecting the compound of Formula (VB) to a reduction to form said compound of Formula (VIB), wherein said reduction comprises treating said compound of Formula (VB) in the presence of a Ci-Cs alkanol as solvent with: i) a lanthanide chloride selected from cerium (III) chloride, samarium (Illi) chloride or samarium (III) iodide; and, II) a hydride donor selected from sodium borohydride (NaBFL) or zinc borohydride (ZnBFL).

For illustration, this aspect of the invention is depicted in the reaction scheme of Figure 3 appended hereto. In an important embodiment of this aspect of the invention, said reactant CI-Si(Q ² )3 in step b) is t-butyldimethylsilyl chloride (TBDMS-CI).

In accordance with a still further aspect of the present invention, there is provided a method for the preparation of estra-1 ,3,5(10)-tri ene-3 , 15a, 16a, 17p-tetrol (VI I B)

12

SUBSTITUTE SHEET (RULE 26)

said method comprising: i) providing a compound of Formula (VIB) by performing the method as defined immediately hereinabove and in appended claim 19 or claim 20; ii) treating the pendent hydroxyl group (C17) of the compound of Formula (VIB) with a protecting group (Pr ³ ); iii) syn dihydroxylation of the pendent C=C bond (C15, C16) of the compound obtained in step ii) in the presence of at least one oxidizing agent; and, iv) deprotecting the compound (C3, C17) obtained in step iii) to produce estra-1 ,3,5(10)-triene- 3,15a,16o,17p-tetrol (VIIB).

DEFINITIONS

As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

The terms “comprising, “comprises" and “comprised of as used herein are synonymous with “including", “includes", “containing" or “contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps.

13

SUBSTITUTE SHEET (RULE 26) As used herein, the term “consisting of excludes any element, ingredient, member or method step not specified.

When amounts, concentrations, dimensions and other parameters are expressed in the form of a range, a preferable range, an upper limit value, a lower limit value or preferable upper and limit values, it should be understood that any ranges obtainable by combining any upper limit or preferable value with any lower limit or preferable value are also specifically disclosed, irrespective of whether the obtained ranges are clearly mentioned in the context.

Further, in accordance with standard understanding, a range represented as being “from 0 to )C specifically includes 0%: for example, where a weight range is expressed in the form “from 0 to x wt.%”, the ingredient defined by said range may be absent from the composition or may be present in the composition in an amount up to x wt.%.

The words "preferred', "preferably, “desirably and “particularly are used frequently herein to refer to embodiments of the disclosure that may afford particular benefits, under certain circumstances. However, the recitation of one or more preferable, preferred, desirable or particular embodiments does not imply that other embodiments are not useful and is not intended to exclude those other embodiments from the scope of the disclosure.

As used throughout this application, the word “may is used in a permissive sense - that is meaning to have the potential to - rather than in the mandatory sense.

As used herein, room temperature is 23°C plus or minus 2°C.

The molecular weights referred to in this specification - to describe to macromolecular, oligomeric and polymeric components of the curable compositions - can be measured with gel permeation chromatography (GPC) using polystyrene calibration standards, such as is done according to ASTM 3536.

The term “molar equivalents" is used in accordance with its standard meaning: it thus refers to the number of moles of specified compound A in relation to the number of moles of specified compound B.

The term “solvate" represents an aggregate that comprises one or more molecules of the solute and one or more molecules of solvent. The term "hydrate" refers to a solvate wherein the solvent is water. The term “estrogen" used in this disclosure encompasses steroidal compounds having estrogenic activity.

The term “aprotic solvents" as used herein refers to solvents that do not yield or accept a proton. Conversely “protic solvents" are those solvents capable of yielding or accepting a proton. The “polar solvent’ as used herein refers to a solvent having a dielectric constant (s) of more than 5 as measured at 25°C: the term encompasses both aprotic and protic solvents. The determination of dielectric constant (s) is well known in the art and is within the knowledge of the skilled person: the use of measured voltages across parallel plate capacitors in such determinations may be mentioned.

The term “base" as used herein refers to a species capable of abstracting a proton in either a polar or non-polar solvent.

As used herein, "Ci-C _n alkyt' group refers to a monovalent group that contains 1 to n carbons atoms, that is a radical of an alkane and includes straight-chain and branched organic groups. As such, a "Ci-Cs alkyt' group refers to a monovalent group that contains from 1 to 8 carbons atoms, that is a radical of an alkane and includes straight-chain and branched organic groups. Examples of alkyl groups include but are not limited to: methyl; ethyl; propyl; isopropyl; n-butyl; isobutyl; sec-butyl; tert-butyl; n-pentyl; n-hexyl; n-heptyl; and, 2-ethylhexyl. In the present invention, such alkyl groups may be unsubstituted or may be substituted with one or more fluorine (F). Where applicable for a given moiety (R), a tolerance for one or more non-halogen substituents within an alkyl group will be noted in the specification.

The term “Ci-Cis hydroxyalkyf’ as used herein refers to a HO-(alkyl) group having from 1 to 18 carbon atoms, where the point of attachment of the substituent is through the oxygen-atom and the alkyl group is as defined above.

The term “C1-C4 alkox refers to a mono-valent group represented by -OA where A is a C1-C4 alkyl group as defined above. Non-limiting examples thereof are a methoxy group, an ethoxy group and an iso-propyloxy group.

The term “C2-C4 alkylene" as used herein, is defined as saturated, divalent hydrocarbon radical having from 2 to 4 carbon atoms. The term “C3 -C18 cycloalkyl’ is understood to mean a saturated, mono- or polycyclic hydrocarbon group having from 3 to 18 carbon atoms. In the present invention, such cycloalkyl groups may be unsubstituted or may be substituted with one or more halogen. Where applicable for a given moiety (R), a tolerance for one or more nonhalogen substituents within a cycloalkyl group will be noted in the specification. Examples of cycloalkyl groups include: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl; cyclooctyl; adamantane; and norbornane.

As used herein, an “Ce-Cio aryl’ group used alone or as part of a larger moiety - as in “aralkyl group" - refers to monocyclic, bicyclic and tricyclic ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. The bicyclic and tricyclic ring systems can include benzofused 2-3 membered carbocyclic rings. In the present invention, such aryl groups may be unsubstituted or may be substituted with one or more halogen. Where applicable for a given moiety (R), a tolerance for one or more non-halogen substituents within an aryl group will be noted in the specification. Exemplary Ce-Cw aryl groups include: phenyl; indenyl; naphthalenyl; tetrahydronaphthyl; and, tetrahydroindenyl. And a preference for phenyl groups may be noted.

As used herein, the term “Ci-Cs alkanol’ refers to compounds of the general formula ROH, where R is a linear or branched alkyl group having from 1 to 8 carbon atoms. As regards the reduction step d) of the claimed method, a preference for a C1-C4 alkanol and more particularly a C1-C2 alkanol should be noted.

As used herein, "alkylaryl" refers to alkyl-substituted aryl groups, with alkyl and aryl radicals being defined as above. Further, as used herein "aralkyl' means an alkyl group substituted with an aryl radical as defined above.

The term "hetero" as used herein refers to hydrocarbyl groups or moieties containing one or more heteroatoms. Thus, for example "heterocyclic" refers to cyclic hydrocarbyl groups having one or more heteroatoms as part of the ring structure.

For completeness, "heteroalkyl' and "heterocycloalkyl' moieties are “alkyl’ and “cycloalkyf’ groups as defined hereinabove, respectively, containing at least one heteroatom as part of their structure. Specifically, the term “C1- Ce heteroalkyl’ refers to a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms and having at least one heteroatom in the backbone of the chain. And the term “C3 -Cs heterocycloalkyf’ is understood to mean a saturated, mono- or polycyclic hydrocarbon group having from 3 to 8 carbon atoms and having at least one heteroatom in the backbone of the chain. In the present invention, such heteroalkyl or heterocycloalkyl groups may be unsubstituted or may be substituted with one or more fluorine (F). Where applicable for a given moiety (R), a tolerance for one or more non-halogen substituents within a hetero(cyclo)alkyl group will be noted in the specification.

The term “heteroatom" as used herein refers to oxygen, nitrogen or sulphur atoms. Where two heteroatoms are present in a moiety, each heteroatom may be independently selected from 0, N or S.

As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). In the present disclosure, it is conventional for a halogen substituent to be selected from F, Cl or Br.

As used herein, “cyano" means a -CN group.

The present method steps may be defined herein as being “substantially free" of certain compounds, elements, ions or other like components. The term “substantially free" is intended to mean that the compound, element, ion or other like component is not deliberately added to the reaction mixture and is present, at most, in only trace amounts which will have no (adverse) effect on the progress of the reaction. An exemplary trace amount is less than 500 ppm by weight of the reaction mixture. The term “substantially free" expressly encompasses those embodiments where the specified compound, element, ion, or other like component is completely absent from the reaction mixture or is not present in any amount measurable by techniques generally used in the art.

The reaction conditions of a given step are described below with reference to compounds defined by a generic formula, such as Formula (I) or Formula (II). This stated reaction conditions are applicable to all sub-generic formulae - such as Formula (IB), Formula (HA) and Formula (I I B) - encompassed within the generic formula.

BRIEF DESCRIPTION OF THE DRAWINGS

With respect to the appended drawings:

Figure 1 illustrates the reaction scheme for the synthesis of a compound of Formula (VI) in accordance with one embodiment of the present invention.

Figure 2 illustrates the reaction scheme for the synthesis of a compound of Formula (VI) in accordance with a further embodiment of the present invention.

Figure 3 illustrates the reaction scheme for the synthesis of a compound of Formula (VIB) - of which 3- TBDMS-estra-1,3,5(10),15-tetraen-17-ol is an important example - in accordance with yet another embodiment of the invention. DETAILED DESCRIPTION OF THE INVENTION

The individual steps of the process as defined above will be discussed in more detail herein below. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates.

Step a)

This step of the process of this disclosure entails the conversion of a compound of formula (I) into a sulfoxideestrone compound of formula (III) herein below.

In the compound of Formula (I), R ¹ , R ² and R ³ are independently selected from H, halogen or methyl, which selection may be subject to the proviso that at most two of R ¹ , R ² and R ³ are methyl. Preferably R ¹ , R ² and R ³ are independently selected from H or methyl, subject to the proviso that at most one of R ¹ , R ² and R ³ is methyl. More preferably compound (I) is estrone (IB) wherein each of R ¹ , R ² and R ³ is H.

As is known in the art, estrone is one of the major mammalian estrogens and is an aromatized Cis steroid with a 3-hydroxyl group and a 17-ketone. It is produced in vivo from androstenedione or from testosterone via estradiol. Estrone has, of course, been synthesized in vitro and instructive background references to such synthetic routes is provided by Yeung et al. Journal of the American Chemical Society, 129(34): 10346-7 (2007) and, Prevost et al. in Angewandte Chemie, Volume 53: 33, 8770-8773 (2014).

In the sulfinate ester compound of Formula (II):

Z is OR ⁴ or SR ⁵ ;

R ⁴ is C1-C4 alkyl or Ce-Cio aryl;

R ⁵ is C1-C4 alkyl or Ce-Cio aryl;

T ¹ is Ci-Ce alkyl or a 5- or 6-membered aromatic ring having 0, 1 or 2 heteroatoms, said aromatic ring being substituted with n substituents X;

18

SUBSTITUTE SHEET (RULE 26) each X is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or C(O)R ⁶ ;

R ⁶ is C1-C4 alkyl; and, n Is O, 1 or 2.

In one illustrative embodiment, Z is SR ⁵ , wherein R ⁵ is phenyl. It is preferred however that: Z is OR ⁴ ; R ⁴ is C1-C2 alkyl; T ¹ is Ci-Ce alkyl or a 6-membered aromatic ring having 0, 1 or 2 heteroatoms, said aromatic ring being substituted with n substituents X; each X is independently selected from halogen, C1-C2 alkyl or C1-C2 alkoxy; and, n Is O, 1 or 2.

In an important embodiment: Z is OR ⁴ ; R ⁴ is methyl; T ¹ is a 6-membered aromatic ring having 0, 1 or 2 heteroatoms, said aromatic ring being substituted with n substituents X; each X is independently selected from F, Cl, methyl or methoxy; and n is 0, 1 or 2, preferably 1 .

The following reaction scheme represents an important example of step a) wherein T ¹ is an optionally substituted phenyl ring: wherein R ¹ , R ² , R ³ , Z, X and n are as defined above, including the statements of preference therefor. In Formula (IIA), a substituent X should preferably be in the para-position. Where n is 2, the substituents X should desirably be in the ortho- and para- positions of the aromatic ring.

Sulfinate esters and sulfinate thioesters of Formula (II) and Formula (IIA) are commercially available. For instance, methyl 4-chlorobenzene sulfinate, which is a preferred reactant in this step, is available from SynQuest Laboratories. That aside, instructive references on the formation of sulfinate (thio)esters include: Kaboudin et al. American Chemical Society 5:29, 17947-17954 (2020); Huang et al. Green Chemistry 18: 1874-1879 (2016); Lujan-Montelongo et al, European Journal of Organic Chemistry, 7, 1602-1605 (2015); and Shyam et al. Advanced Synthetic Catalysis 56: 358 (2016).

19

SUBSTITUTE SHEET (RULE 26) It is preferred that the compound of Formula (II) is in molar excess to the compound of Formula (I) in the reaction of this step. Preferably, from 1.1 to 1.8, for example from 1.3 to 1.6 moles of the compound of Formula (II) will be added to the reaction mixture per mole of said compound of Formula (I).

The reaction of step a) is performed in the presence of at least one alkali metal alkoxide selected from aliphatic, aromatic or araliphatic alkoxides of lithium, sodium or potassium. Non-limiting examples thereof are lithium, sodium or potassium methoxide, ethoxide, n-propoxide, isopropoxide, n-butoxide, sec-butoxide, tert-butoxide, n- pentoxide, isopentoxide, hexoxide, amyl alkoxide, 3,7-dimethyl-3-octoxide, phenoxide, 2,4-di-tert-butylphenoxide, 2,6-di-tert-butylphenoxide, 3,5-di-tert-butylphenoxide, 2,4-di-tert-butyl-4-methylphenoxide and trimethylsilanoate. Preference is given to using the aliphatic (C1-C4) alkoxides, in particular methoxides, ethoxides, n-propoxides, isopropoxides, n-butoxides, sec-butoxides and tert-butoxides of sodium, potassium or lithium. A particular preference is given to the use of potassium tert-butoxide.

There is no particular limitation on the amount of said at least one metal alkoxide employed in the reaction but it will typically be from 1 to 4 moles and preferably from 2 to 4 moles, based on 1 mole of said compound of Formula (I)-

The described reaction of step a) should also be carried out in the presence of a polar aprotic solvent. Examples of such polar aprotic solvents, which may be used alone or in combination, include but are not limited to: acetonitrile; N,N-di(Ci-C4)alkylacylamides, such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMAc); hexamethylphosphoramide; N-methylpyrrolidone; pyridine; esters, such as (Ci-Cs)alkyl acetates, ethoxydiglycol acetate, dimethyl glutarate, dimethyl maleate, dipropyl oxalate, ethyl lactate, benzyl benzoate, butyloctyl benzoate and ethylhexyl benzoate; ketones, such as acetone, ethyl ketone, methyl ethyl ketone (2- butanone) and methyl isobutyl ketone; ethers, such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF) and 1,2-dimethoxyethane; 1,3-dioxolane; dimethylsulfoxide (DMSO); and, dichloromethane (DCM).

In accordance with a preferred embodiment of this step, the polar aprotic solvent employed should have a boiling point of at least 20°C, desirably at least 30°C and more desirably at least 40°C, as measured at 1 atmosphere pressure (1.01325 Bar). A suitable polar aprotic solvent of this embodiment includes one or more compounds selected from the group consisting of: ethyl acetate; acetonitrile; N,N-dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetone; and, hexamethylphosphoramide. A solvent comprising or consisting of both dimethylsulfoxide (DMSO) and tetrahydrofuran may have particular utility in step a). Whilst it is not critical, it is preferred that the reaction of this step be performed under anhydrous conditions. Water can, for example, react with certain alkali metal alkoxides and, at low levels of that alkoxide, deleteriously impede the desired reaction. Where necessary, exposure to atmospheric moisture may be avoided by providing the reaction vessel with an inert, dry gaseous blanket. Whilst dry nitrogen, helium and argon may be used as blanket gases, precaution should be used when common nitrogen gases are used as a blanket, because such nitrogen may not be dry enough on account of its susceptibility to moisture entrainment; the nitrogen may require an additional drying step before use herein.

The reaction may or may not be performed under reflux conditions. Further, the performance of the reaction at room temperature is not precluded but, equally, the use of slightly elevated temperatures can drive the reaction. For an exothermic reaction, some cooling might however be required as the reaction progresses.

The process pressure is not critical: as such, the reaction can be run at sub-atmospheric, atmospheric, or super- atmospheric pressures but pressures at or slightly above atmospheric pressure are preferred. Mention in this regard may be made of pressures of from 100 to 500 MPa or from 100 to 200 MPa.

The progress of the above reaction can be monitored by known techniques of which mention may be made of ¹ H NMR, Fourier Transform Infrared Spectroscopy, Ultra Performance Liquid Chromatography (UPLC) or thin layer chromatography (TLC). At an appropriate time, the reaction may be quenched through the addition of a quenching reagent: examples thereof include potassium hydrogen sulfate (KHSO^aq)), sulfuric acid (FfeSO^aq)) and acetic acid (CH3COOH (aq)), which compounds are preferably added in aqueous solution.

The reaction product is a mixture of four diastereoisomers of Formula (III). The crude product may be used in the subsequent step of the process or, alternatively, the compound of Formula (III) may be purified using methods known in the art, including but not limited to solvent extraction, filtration and chromatography. The separation of the four diastereoisomers need not be performed in the present process.

It follows from the above that provided herein is a compound of Formula (III) or a salt, hydrate or solvate thereof:

21

SUBSTITUTE SHEET (RULE 26) wherein: R ¹ , R ² and R ³ are independently selected from H, halogen or methyl;

T ¹ is Ci-C ₆ alkyl or a 5- or 6-membered aromatic ring having 0, 1 or 2 heteroatoms, said aromatic ring being substituted with n substituents X; each X is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or C(O)R ⁶ ;

R ⁶ is C1-C4 alkyl; and n is 0, 1 or 2, preferably 1 or 2, more preferably 1 .

In a preferred embodiment, the compound of Formula (III) is a compound of Formula (IIIA) or a salt, hydrate or solvate thereof: wherein: R ¹ , R ² and R ³ are independently selected from H, halogen or methyl; each X is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or C(O)R ⁶ ;

R ⁶ is C1-C4 alkyl; n is 0, 1 or 2, preferably 1 or 2, more preferably 1 .

In a more preferred embodiment, the compound is a compound of Formula (IIIA), wherein: each of R ¹ , R ² and R ³ is H; each X is independently selected from halogen, C1-C2 alkyl or C1-C2 alkoxy, preferably halogen, more preferably F, Cl or Br; n is 0, 1 or 2, preferably 1 or 2, more preferably 1 .

Step b)

Step (b) of the defined process comprises treating the compound of Formula (III) with a hydroxyl protecting group. More specifically, the compound of Formula (III) is reacted with a compound Pr ² -A to yield a compound of Formula

22

SUBSTITUTE SHEET (RULE 26)

wherein: T ¹ is as defined hereinabove;

Pr ² is -Q ² , -C(O)Q ² or - Si (Q ² )s wherein each Q ² is independently selected from Ci-Ce alkyl, Ci-Ce heteroalkyl, C3-C8 heterocycloalkyl, Ce-Cw aryl, C7-C18 alkylaryl or C7-C18 aralkyl; and,

A is halogen or -OSO2CF3

As regards the protecting group (Pr ² ), it is evident that the moiety Q ² may be bound to the phenyl moiety of Formula (IV) by an ether, ester or silyloxy linkage. For each of these alternatives, it is preferred that each Q ² is independently selected from C1-C4 alkyl or Ce-Cw aryl.

The following reaction scheme represents that important example of step b) wherein T ¹ is an optionally substituted phenyl ring: wherein: X is as defined hereinabove; n is as defined hereinabove;

Pr ² is -Q ² , -C(0)Q ² or - Si(Q ² )s wherein each Q ² is independently selected from Ci-Ce alkyl, C1-

C ₆ heteroalkyl, C ₃ -C ₈ heterocycloalkyl, C ₆ -Ci ₀ aryl, C7-C18 alkylaryl or C7-C18 aralkyl; and,

A is halogen or -OSO ₂ CF ₃

As regards the protecting group (Pr ² ), it is again evident that the moiety Q ² may be bound to the phenyl moiety of Formula (IVA) by an ether, ester or silyloxy linkage.

For ether (Pr ² = Q ² ) protecting groups, exemplary groups Q ² include but are not limited to tert-butyl (t-Bu), methoxypropyl, ethoxyethyl, tetrahydropyranyl and benzyl. For ester (Pr ² = -C(0)Q ² ) protecting groups, exemplary groups Q ² include but are not limited to methyl (Me) and tert-butyl (t-Bu).

23

SUBSTITUTE SHEET (RULE 26) The above aside, a preference for Pr ² being — Si(Q ² )s may be mentioned, wherein it is further preferred that each Q ² be independently selected from C1-C4 alkyl or Ce-C aryl. As regards the reactant Pr ² A, a preference may also be noted for A being a halogen and more particularly Cl. And thus, exemplary compounds Pr ² A include: t-butyldimethylsilyl chloride (TBDMS-CI); t-butyldiphenylsilyl chloride; diphenylmethylsilyl chloride; and, tri(isopropyl)silyl chloride. The use of t-butyldimethylsilyl chloride (TBDMS-CI) is particularly preferred.

Step b) should desirably be performed using a stoichiometric excess of Pr ² A relative to the compound of Formula (III). The molar ratio of Pr ² A to the compound of Formula (III) may, for instance, be in the range from 1.1 :1 to 1.5:1 or from 1.2:1 to 1.3:1.

Whilst not strictly required, the reaction of step b) may be carried out in the presence of a catalyst. For ether (Pr ² = Q ² ) and ester (Pr ² = -C(O)Q ² ) protecting groups, acid catalysts may be suitable. However, where Pr ² -A is A- S i (Q ² )3, the reaction of step b) should desirably be carried out in the presence of a basic catalyst. More preferably, where Pr ² -A is A— Si(Q ² )3, a basic catalyst is employed such that the molar ratio of basic catalyst to the reactant Pr ² -A is in range from 1 :2 to 4: 1 , for example in the range of 1 : 1 to 3: 1 or from 2: 1 to 3: 1 .

Without intention to limit the present invention, said basic catalyst should be selected from the group consisting of: tertiary amines; alkali metal hydrides; alkali metal sulfides; and, mixtures thereof. A preference for the use of basic tertiary amine catalysts is noted and as suitable basic tertiary amine catalysts, mention may be made of: tri(Ci-C4 alkyl amines) such as trimethylamine, triethylamine and tributylamine; N, N-dimethylaniline; 2-, 3- or 4- picoline; 2,6-lutidine; pyridine, N-(Ci-C4)alkylpiperidines, such as N-methyl piperidine or N-ethyl piperidine; N-(Ci- C4)alkyl morpholines such as N-methyl morpholine or N-ethyl morpholine; imidazole; N-(Ci-C4)alkylimidazoles, such as N-methylimidazole or N-ethylimidazole; diazabicyclononene (DBN); and, diazabicycloundecene (DBU). The use of imidazole or N-methylimidazole as the tertiary amine catalyst is particularly preferred.

The described reaction of step b) should also be carried out in the presence of a polar aprotic solvent. Examples of such polar aprotic solvents, which may be used alone or in combination, include but are not limited to: acetonitrile; N,N-di(Ci-C4)alkylacylamides, such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMAc); hexamethylphosphoramide; N-methylpyrrolidone; pyridine; esters, such as (Ci-Cs)alkyl acetates, ethoxydiglycol acetate, dimethyl glutarate, dimethyl maleate, dipropyl oxalate, ethyl lactate, benzyl benzoate, butyloctyl benzoate and ethylhexyl benzoate; ketones, such as acetone, ethyl ketone, methyl ethyl ketone (2- butanone) and methyl isobutyl ketone; ethers, such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF) and 1,2-dimethoxyethane; 1,3-dioxolane; dimethylsulfoxide (DMSO); and, dichloromethane (DCM). The use of N,N-dimethylformamide (DMF) and dichloromethane (DCM) as the solvent is particularly preferred.

Whilst it is not critical, it is preferred that the reaction of this step be performed under anhydrous conditions. Water can, for example, react with certain compounds Pr ² A and, at low levels of said Pr ² A, deleteriously impede the desired reaction. Where necessary, exposure to atmospheric moisture may be avoided by providing the reaction vessel with an inert, dry gaseous blanket. Whilst dry nitrogen, helium and argon may be used as blanket gases, precaution should be used when common nitrogen gases are used as a blanket, because such nitrogen may not be dry enough on account of its susceptibility to moisture entrainment; the nitrogen may require an additional drying step before use herein.

The reaction may or may not be performed under reflux conditions. Importantly, the performance of the reaction at a temperature of from -10 to +25°C has been found to promote the silylation reaction over other competitive reactions. A preferred temperature range is from -5 to +10°C. For an exothermic reaction, some cooling might however be required to maintain these temperatures as the reaction progresses.

The process pressure is not critical: as such, the reaction can be run at sub-atmospheric, atmospheric, or super- atmospheric pressures but pressures at or slightly above atmospheric pressure are preferred. Mention in this regard may be made of pressures of from 100 to 500 MPa or from 100 to 200 MPa.

The progress of the above reaction can be monitored by known techniques of which mention may be made of ¹ H NMR, Fourier Transform Infrared Spectroscopy, Ultra Performance Liquid Chromatography (UPLC) or thin layer chromatography (TLC). At an appropriate conversion, a C1-C4 alkanol may be added to quench the reaction.

The reaction product of this step is a mixture of four diastereoisomers of Formula (IV). This product may be isolated and may be used in step c) in crude form. Alternatively, the compound of Formula (IV) may be purified using methods known in the art including, but not limited to, solvent extraction, filtration, evaporation and chromatography. The separation of the four diastereoisomers is not necessary.

It follows from the above that provided herein is a compound of Formula (IV) or a salt, hydrate or solvate thereof:

wherein: R ¹ , R ² and R ³ are independently selected from H, halogen or methyl;

T ¹ is Ci-Ce alkyl or a 5- or 6-membered aromatic ring having 0, 1 or 2 heteroatoms, said aromatic ring being substituted with n substituents X; each X is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or C(O)R ⁶ , preferably halogen, more preferably F, Cl, or Br;

R ⁶ is C1-C4 alkyl; n is 1 or 2, preferably 1 ; and,

Pr ² is -Q ² , -C(O)Q ² or - Si(Q ² ) ₃ wherein each Q ² is independently selected from Ci-C ₈ alkyl, Ci-C ₆ heteroalkyl, C ₃ -C ₈ heterocycloalkyl, C ₆ -Ci ₀ aryl, C ₇ -Ci ₈ alkylaryl or C ₇ -Ci ₈ aralkyl.

In a preferred embodiment, the compound of Formula (IV) is a compound of Formula (IVA) or a salt, hydrate or solvate thereof: wherein: R ¹ , R ² and R ³ are independently selected from H, halogen or methyl; each X is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy or C(O)R ⁶ ;

R ⁶ is C1-C4 alkyl, preferably halogen, more preferably F, Cl, or Br; n is 1 or 2, preferably 1 ; and,

Pr ² is -Q ² , -C(O)Q ² or — Si(Q ² ) ₃ wherein each Q ² is independently selected from Ci-C ₈ alkyl, C1- C ₈ heteroalkyl, C ₃ -C ₈ heterocycloalkyl, Cs-Cw aryl, C ₇ -Ci ₈ alkylaryl or C ₇ -Ci ₈ aralkyl.

26

SUBSTITUTE SHEET (RULE 26) In a more preferred embodiment, the compound is a compound of Formula (IVA), wherein: each of R ¹ , R ² and R ³ is H; each X is independently selected from halogen, C1-C2 alkyl or C1-C2 alkoxy, preferably halogen, more preferably F, Cl or Br; n is 1 or 2;

Pr ² is — Si(Q ² )3 in which each Q ² is independently selected from C1-C4 alkyl or Ce-Cw aryl, preferably C1-C4 alkyl.

In an even more preferred embodiment, the compound is a compound of Formula (IVA), wherein: each of R ¹ , R ² and R ³ is H; each X is independently selected from halogen, preferably F, Cl or Br; n is 1 or 2;

Pr ² is — Si(Q ² )3 in which each Q ² is independently selected from C1-C4 alkyl or Ce-Cw aryl, preferably C1-C4 alkyl.

It has been found that elimination of the sulfinyl group from a compound of Formula (IVA) in step c) described below was surprisingly faster when the compound of Formula (IVA) was a compound wherein n is 1 or 2 and X is halogen than when the compound of Formula (IVA) was a compound wherein n is 0.

Step c)

This step entails the p-elimination of the sulfoxide group from compound (IV), thereby introducing unsaturation into the five membered ring.

The following reaction scheme represents that important example of step c) wherein T ¹ is an optionally substituted phenyl ring:

27

SUBSTITUTE SHEET (RULE 26)

As depicted, the elimination reaction is performed under heating in the presence of a non-polar aprotic solvent and at least one of a base and a trialkylphosphite of formula P(OR ⁷ )3, wherein each R ⁷ is independently selected from C1-C2 alkyl. Acceptable yields for this step can be attained in using a base alone and the use of a trialkylphosphite alone is also envisaged. However, a preference for the use of a trialkylphosphite in combination with a base is noted. And in an important embodiment, the elimination reaction is performed in the presence of trimethylphosphite in combination with a base. The presence of a base, a trialkylphosphite, or a combination thereof in the elimination step is beneficial to suppress the formation of by-products. When the elimination step is carried out in the absence of a base and a trialkylphoshite, only a limited amount of desired reaction product is formed.

When included, the tri(Ci-C2)alkyphosphite should be present in the reaction mixture in an amount of from 0.1 to 1.5 molar equivalents relative to the amount of compound (IV). At such levels, the tri(Ci-C2)alkyphosphite is considered to be an effective trap for the eliminated moiety.

When included, the base should present in the reaction mixture in an amount of from 1 to 5 molar equivalents to the amount of compound (IV). It is preferred that the base is present in an amount of from 1.5 to 3 molar equivalents or from 2 to 3 molar equivalents to the amount of compound (IV).

Without intention to limit the present invention, the base should desirably consist of at least one compound selected from alkali metal (Ci-C4)alkoxides, alkali metal carbonates, alkaline earth metal carbonates or alkali metal hydroxides. A preference for the use of at least one of potassium carbonate, sodium carbonate and calcium carbonate is noted.

This step is still further performed in the presence of non-polar aprotic solvent. Examples of suitable non-polar aprotic solvents, which may be used alone or in combination, include but are not limited to: pentane; hexane; heptane; cyclopentane; cyclohexane; cycloheptane; dimethylether; chloroform; dimethyl carbonate; ethylmethyl carbonate; diethyl carbonate; toluene; o-xylene; m-xylene; p-xylene; chlorobenzene; ethylbenzene; 2-

28

SUBSTITUTE SHEET (RULE 26) propylbenzene (cumene); 2-isopropyltoluene (o-cymol); 3-isopropyltoluene (m-cymol); 4-isopropyltoluene (p- cymol); 1 ;3;5-trimethylbenzene (mesitylene); and the like. Preference is given to the use of: toluene; o-xylene; m- xylene; p-xylene; ethylbenzene; 1 ,3,5-trimethylbenzene (mesitylene); and, any mixture thereof.

In one embodiment, step c) is performed under reflux conditions. As would be understood by the skilled artisan, the reflux temperature is dependent upon the reactants and the solvent present. That acknowledged it will be typical for the reflux temperature of this step - at atmospheric pressure - to be from 75 to 250 °C, for example from 100 to 225 °C or from 125 to 210 °C.

$

In an alternative embodiment, step c) is carried out in a sealed autoclave in which an autogenous pressure is generated in dependence upon the temperature at which the reaction is carried out. A temperature of from 75 to 250 °C, for example from 100 to 225 °C may be established, such reaction temperatures generating autogenous pressures in the region of from 0.5 to 40 bar.

The progress of the above reaction can be monitored by known techniques of which mention may be made of ¹ H NMR, Fourier Transform Infrared Spectroscopy, Ultra Performance Liquid Chromatography (UPLC) or thin layer chromatography (TLC). At an appropriate level conversion, the reaction mixture may first be cooled to room temperature. The compound of Formula (V) is then subsequently isolated and may either be used in the subsequent synthesis step in crude form or further purified. Effective isolation and purification methods have included extraction of the obtained product mixture with water, stabilization and trituration of the obtained organic phase and crystallization of the compound therefrom by solvent evaporation.

Step d)

In accordance with this step of the disclosed process, Compound (V) is subjected to a reduction by which the o,p-unsaturated ketone is selectively converted to a cycloallylic p-alcohol.

SUBSTITUTE SHEET (RULE 26) The reduction is performed by treating said compound of Formula (V) in the presence of a solvent with at least one hydride donor selected from borohydrides and aluminium hydride compounds.

In an embodiment, said at least one hydride donor is selected from the group consisting of: potassium borohydride (KBH4); sodium borohydride (NaBF ); sodium triacetoxyborohydride (NaBH(OAc)3); diborane (B2H6); sodium cyanoborohydride (NaBHsCN); zinc borohydride (ZnBF ); aluminium hydride (AIH3); and, lithium aluminium hydride (IJAIH4).

The hydride donor may be added in amount of from 0.5 to 2 molar equivalents to the amount of Compound (V). As would be recognized by the skilled artisan, the latter equivalence range for sodium borohydride (NaBF ) would equate to a 2- to 8-fold excess of hydride (H) and serves to ensure complete reduction.

The selection of hydride donor(s) and / or the desired selectivity of the reaction are determinative of the solvent in which this reduction step should take place. Exemplary solvents for step d) are polar aprotic solvents including but not limited to: water; Ci-Cs alkanols; acetonitrile; N,N-di(Ci-C4)alkylacylamides, such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMAc); hexamethylphosphoramide; N-methylpyrrolidone; pyridine; esters, such as (Ci-Cs)alkyl acetates, ethoxydiglycol acetate, dimethyl glutarate, dimethyl maleate, dipropyl oxalate, ethyl lactate, benzyl benzoate, butyloctyl benzoate and ethylhexyl benzoate; ketones, such as acetone, ethyl ketone, methyl ethyl ketone (2-butanone) and methyl isobutyl ketone; ethers, such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF) and 1,2-dimethoxyethane; 1,3-dioxolane; dimethylsulfoxide (DMSO); and, dichloromethane (DCM).

The reduction of step d) is preferably performed in the presence of lanthanide chloride. Thus, in an important embodiment, the reduction comprises treating said compound of Formula (V) in the presence of a Ci-Cs alkanol as solvent with: i) a lanthanide chloride; and, ii) at least one hydride donor selected from the group consisting of potassium borohydride (KBH4), sodium borohydride (NaBF ), sodium triacetoxyborohydride (NaBH(OAc)3), diborane (B2H6), sodium cyanoborohydride (NaBHsCN), zinc borohydride (ZnBF ), aluminium hydride (AIH3) and lithium aluminium hydride (IJAIH4).

The reduction may, in particular, comprise treating said compound of Formula (V) in the presence of a Ci-Cs alkanol with: a lanthanum chloride selected from cerium (III) chloride, samarium (III) chloride or samarium (III) iodide; and, a hydride donor selected from sodium borohydride (NaBF ) or zinc borohydride (ZnBF ). A particular preference for performing the reduction with NaBF and cerium (III) chloride is noted. It has been noted that, when a lanthanide chloride is present, the reduction of step d) should be performed in the presence of a Ci-Cs alkanol as solvent: of particular preference is the use of ethanol or methanol in this regard. The presence in the reaction mixture of supplementary polar aprotic solvents - selected, by way of example, from the aforementioned list - is not however precluded and can indeed be beneficial. Good results have, for instance, been obtained where tetrahydrofuran (THF) has been added to the reaction mixture in addition to Ci-Cs alkanol.

When present, it is preferred that the lanthanide chloride is added in amount of at least 0.25 molar equivalents to the amount of compound (V): for example, lanthanide chloride may be added in an amount of from 0.5 to 2 molar equivalents to the amount of compound (V).

The reaction of this step does not require specialized equipment to exclude either water or air. Further, the reduction may be performed at a temperature of from -20 to 40°C, which range includes room temperature.

The progress of the above reaction can be monitored by known techniques of which mention may again be made of ¹ H NMR, Fourier Transform Infrared Spectroscopy, Ultra Performance Liquid Chromatography (UPLC) or thin layer chromatography (TLC). At the end of the reaction the compound of Formula (VI) may be isolated and purified using methods known in the art. Mention in this regard may be made of solvent extraction, filtration, evaporation and chromatography.

Exemplary Compounds of Formula (IV)

Table 1 herein below illustrates certain exemplary compounds according to Formula (IV) of the present disclosure.

Table 1

SUBSTITUTE SHEET (RULE 26)

SUBSTITUTE SHEET (RULE 26)

34

SUBSTITUTE SHEET (RULE 26)

35

SUBSTITUTE SHEET (RULE 26)

36

SUBSTITUTE SHEET (RULE 26) Exemplary Synthesis

The following describes an exemplary synthetic route in accordance with the present disclosure. Having regard to Formulae (IB) to (I IIB) and Pr ² -A above: R ¹ , R ² and R ³ are each H; Z is OR ⁴ ; R ⁴ is C1-C2 alkyl; X is halogen, Ci- 02 alkyl or C1-C2 alkoxy; n is 1 or 2 subject to the proviso that one X is disposed in the para position of the phenyl ring; Pr ² is t-butyldimethylsilyl; and, A is Cl. t-butyldimethylsilylchloride Imidazole

DCM

As noted above, the present disclosure also provides for the use of the compound of Formula VIB - of which 3- TBDMS-estra-1 ,3,5(10),15-tetraen-17-ol derived in this exemplary synthetic route in an important example - as an intermediate for the synthesis of estetrol. Broadly, the synthesis of estetrol from the compound of Formula VIB will include the following steps: i) treating the hydroxyl group (C17) with a protecting group (Pr ³ ); ii) syn dihydroxylation of the pendent C=C bond (C15, C16) of the compound obtained in step i) in the presence of at least one oxidizing agent; and, iii) deprotecting the compound (C3, C17) obtained in step ii) to produce estetrol. For completeness, the numeric applied to the carbon at (C) denotes the ring number. Without intention to limit the present invention, it is preferred that said at least one oxidizing agent is selected from: permanganate salts; osmium oxide; hydrogen peroxide; or, iodine and silver acetate.

The following example is illustrative of the present invention and is not intended to limit the scope of the invention in any way.

37

SUBSTITUTE SHEET (RULE 26) EXAMPLES

The following abbreviations are employed in the Example: DMSO: dimethyl sulfoxide; THF: tetrahydrofuran; KOtBu: potassium tert-butyloxide; TBDMS-CI: t-butyldimethylsilyl chloride; TBDMS: t-butyldimethylsilyl; DCM: dichloromethane; OMe: methoxide; NH4CI: ammonium chloride; Na2COs: sodium carbonate; TMP: trimethylphosphite; NaBFU: sodium borohydride; MeOH: methanol; UPLC: Ultra performance liquid chromatography; TLC: thin layer chromatography; eq.: molar equivalent.

Example 1

Step a):

The performed sulfinylation step a) is summarized as follows:

Estrone, E1 16-(4-chlorobenzenesulfinyl)-estrone

A mixture of estrone (E1 , 9.5 g, 35.3 mmol), methyl 4-chlorobenzenesulfinate (9.4 g, 49.4 mmol), THF (38 ml and DMSO (57 ml) was prepared and cooled to 5 °C. Whilst maintaining a temperature of 5 +/- 5 °C, a solution of KOfBu (10.5 g, 93.5 mmol) in THF (38 ml) was dosed to the prepared mixture over a period of 15 minutes. The reaction was quenched after a reaction time of 60 minutes by the addition of a 30% aqueous solution of acetic acid (39 ml), followed by the addition of water (116 ml). The product was isolated by filtration and washed with water and by a mixture of methanol and water. The product was dried under vacuum to yield a white-to-cream colored solid (14.9 g, 99%). The product was obtained as a mixture of 4 stereoisomers; a mixture of 16a/16p and sulfoxide isomers.

Step b):

The performed TBDMS protection step b) is summarized as follows:

SUBSTITUTE SHEET (RULE 26)

16-(4-chlorobenzenesulfinyl)-estrone 3-TBDMS-16-(4-chlorobenzenesulfinyl)-estrone

To a cooled mixture (-5 °C) of 16-(4-chlorobenzenesulfinyl)-estrone (6.4 g, 14.9 mmol) and imidazole (2.5 g, 37.2 mmol) in DCM (55 ml) was added a solution of TBDMS-CI (2.7 g, 17.9 mmol) in DCM (9 ml) over a period of 1 hour, keeping the temperature at -5 °C. Over a period of 3 hours, the reaction was gradually allowed to warm-up to 5 °C and subsequently an additional portion of TBDMS-CI (0.3 g, 1.8 mmol) in DCM (1 ml) was added. The reaction was quenched after a total reaction time of 6 hours, by the addition of methanol (0.5 ml). The organic phase was washed twice with a 10% aqueous solution of NH ₄ CI (22 and 12 ml), followed by a wash with water (18 ml). The combined aqueous phases were extracted with DCM (10 ml) and the combined organic phases were concentrated. After evaporation, 3-TBDMS-16-(4-chlorobenzenesulfinyl)-estrone was isolated in a 99% yield (8.0 g), again as a mixture of 4 stereoisomers, identified by ¹ H NMR. The crude product can be reacted in the elimination step (Step c) as such.

Step c):

The performed elimination reaction (desulfinylation) of step c) is summarized as follows:

3-TBDMS-16-(4-chlorobenzenesulfinyl)-estrone 3-TBDMS-A15-16-estrone

The crude 3-TBDMS-16-(4-chlorobenzenesulfinyl)-estrone (5.0 g, 9.2 mmol) obtained in step b) was stirred in o-xylene at a temperature of 140°C in the presence of trimethyl phosphite (0.5 ml, 4.6 mmol) and Na2COs (2.2 g, 20.7 mmol). The reaction mixture was stirred at this temperature for 10 hours at which point a full conversion (>99%) of the starting material was obtained (determined by UPLC analysis).

The product mixture was cooled to 40°C and extracted with water (25 ml). The organic phase was removed under vacuum to yield the crude product. Trituration of the crude product with 1 -butanol initiated the crystallization of the product. The obtained suspension was cooled to 0°C and the product was collected by filtration, washed with

39

SUBSTITUTE SHEET (RULE 26) chilled 1 -butanol and with heptane and then dried under vacuum. 3-TBDMS-A15-16-estrone was obtained with a yield of 2.3 g (65%).

The identity of the product of this step was confirmed by ¹ H NMR (500 MHz, CDCI3): 5 (ppm) 7.61 (d, 1 H, H15), 7.11 (dd, 1 H, H1), 6.64 (dd, 1 H, H2), 6.58 (d, 1 H, H4), 6.08 (dd, 1 H, H16), 2.90 (m, 2H, H6o/p), 2.51 (m, 1 H, H- 14a), 2.44 (m, 1 H, H-11 a), 2.36 (m, 1 H, H-9a), 2.16 (m, 1 H, H-7p), 2.01 (m, 1 H, H-12 ), 1.80 (m, 1 H, H-8p), 1.73 (m, 1 H, H-12a), 1.70 (m, 1 H, H11 p), 1.56 (m, 1 H, H-7a), 1.11 (s, 3H, H18p), 0.99 (s, 9H, TBDMS), 0.19 (s, 6H, TBDMS).

The performed reduction of step d) is summarized as follows:

3-TBDMS-A15-16-estrone 3-TBDMS-A15-16-estradiol

3-TBDMS-A15-16-estrone (5.0 g, 13.1 mmol) was treated with CeC T^O (5.8 g, 15.7 mmol) and NaBH4 (0.54 g, 14.4 mmol) in a mixture of methanol (30 ml) and THF (80 ml) at 0 °C. Upon full conversion (>99%) of the starting material (monitored by TLC), the reaction was quenched by the addition of 2N aqueous hydrochloric acid (6.6 ml). The organic solvents were removed by distillation while water was added to the mixture. The suspension was stirred 20 °C, the precipitate was isolated by filtration and washed with water. The 17-p alcohol - identified herein as 3-TBDMS-A-15, 16-estradiol or 3-TBDMS-estra-1 ,3,5(10), 15-tetraen-17-ol - was isolated after drying as an off-white solid with a yield of 98%. ¹ H NMR spectrum of the product was in accordance with the data reported in WO2012/164096 A1.

Examples 2 to 6

Additional examples of the sulfinylation/desulfinylation strategy on estrone were performed using methyl benzenesulfinate, methyl 4-methylbenzenesulfinate, methyl 4-methoxybenzensulfinate, methyl 4- fluorobenzenesulfinate and methyl 2,4-dichlorobenzenesulfinate as starting materials. These sulfinates were reacted with estrone according to the method described in Step a) of Example 1 , yielding the 16-(benzenesulfi nyl)- estrone derivatives again as a mixture of 4 stereoisomers. Further following the procedures of steps b) and c) of

40

SUBSTITUTE SHEET (RULE 26) Example 1, the crude products were reacted with TBDMS-CI followed by the desulfinylation reaction. The reduction step d) of Example 1 was not repeated for these Examples.

Example 2: Reaction sequence using methyl benzenesulfinate

To a mixture of estrone (24.0 g, 88.8 mmol), methyl benzenesulfinate (16.3 ml, 0.12 mol) and DMSO (300 ml) was added KOfBu (25.00 g, 0.22 mol) at a temperature of 20 - 25°C. After a reaction time of 1 hour, the reaction was poured into a mixture of sulfuric acid (9.5 ml) and water (450 ml). The product was isolated by filtration and washed with water and with a mixture of methanol and water. The product was dried under vacuum to yield a white-to-cream colored solid (28.8 g, 96%).

To a cooled mixture (-5°C) of 16-(benzenesulfinyl)-estrone (20.0 g, 50.7 mmol) and imidazole (10.4 g, 0.15 mol) in DCM (190 ml) was added a solution of TBDMS-CI (10.3 g, 68.4 mmol) in DCM (15 ml) over a period of 1 hour. The reaction was stirred at 0°C until full conversion (>99%) of the starting material was reached (monitored by UPLC or TLC). The organic phase was washed with aqueous solutions of NH4CI and NaCI and concentrated. After evaporation, 3-TBDMS-16-(benzenesulfinyl)-estrone was isolated in a quantitative yield (26 g). The crude product can be reacted in the elimination step (Step c) as such.

The desulfinylation reaction was performed according to the procedure applied for 3-TBDMS-16-(4- chlorobenzenesulfinyl)-estrone. A mixture of 3-TBDMS-16-(benzenesulfinyl)-estrone (25.5 g, 50.1 mmol), sodium hydrogen carbonate (18.9 g, 0.22 mol), trimethyl phosphite (17.7 ml, 0.15 mol) in o-xylene (510 ml) was stirred at 134°C for 17 hours. The mixture was cooled to room temperature, washed with water (2 x 130 ml) and dried over sodium sulphate. Triethylamine (1.4 ml) was added to the organic phase and the solvent was removed under vacuum. The residue was triturated with methanol and the suspension was cooled to 0°C. The solid was isolated by filtration, washed with cold methanol and dried, yielding 13.3 g (69%) 3-TBDMS-A15-16-estrone as an off- white solid with a purity of 89% (by ¹ H NMR).

Example 3: Reaction sequence using methyl 4-methylbenzenesulfinate

16-(4-methylbenzenesulfinyl)-estrone was prepared according to the procedure applied for 16-(benzenesulfinyl)- estrone, using estrone (3.0 g, 11.1 mmol), methyl (4-methylbenzene)-sulfinate (2.8 g, 16.7 mmol), DMSO (38 ml) and KOtBu (3.4 g, 30.6 mmol). The product was isolated as an off-white solid in a quantitative yield.

3-TBDMS-16-(4-methylbenzenesulfinyl)-estrone was prepared according to the procedure applied for 3-TBDMS- 16-(benzenesulfinyl)-estrone using 16-(4-methylbenzenesulfinyl)-estrone (4.0 g, 9.9 mmol), imidazole (2.5 g, 36.7 mmol), TBDMS-CI (2.2 g, 14.7 mmol) and DCM (50 ml). The product was isolated in a 61% yield (3.2 g) after purification by flash chromatography.

The desulfinylation reaction was performed according to the procedure applied for 3-TBDMS-16-(4- chlorobenzenesulfinyl)-estrone. A mixture of 3-TBDMS-16-(4-methylbenzenesulfinyl)-estrone (98 mg, 0.19 mmol), Na2CC>3 (75 mg, 0.71 mmol), trimethyl phosphite (70 pl, 0.60 mmol) in o-xylene (1.6 ml) was stirred at 140°C for 11 hours. TLC confirmed full conversion of the starting material. 65% of the starting material was converted into 3-TBDMS-A15-16-estrone, as determined by UPLC on the crude reaction mixture. No work-up of the reaction mixture was performed.

Example 4: Reaction sequence using methyl 4-methoxybenzenesulfinate

16-(4-methoxybenzenesulfinyl)-estrone was prepared according to the procedure applied for 16- (benzenesulfinyl)-estrone, using estrone (6.2 g, 23.6 mmol), methyl (4-methoxy)-benzenesulfinate (5.2 g, 32.9 mmol), DMSO (78 ml) and KOtBu (7.0 g, 61.9 mmol). The product was isolated as an off-white solid in a quantitative yield.

3-TBDMS-16-(4-methoxybenzenesulfinyl)-estrone was prepared according to the procedure applied for 3- TBDMS-16-(benzenesulfinyl)-estrone using 16-(4-methoxybenzenesulfinyl)-estrone (8.9 g, 20.9 mmol), imidazole (4.8 g, 70.8 mmol), TBDMS-CI (4.3 g, 28.5 mmol) and DCM (111 ml). The product was isolated in a 43% yield (4.9 g) after purification by flash chromatography.

The desulfinylation reaction was performed according to the procedure applied for 3-TBDMS-16-(4- chlorobenzenesulfinyl)-estrone. A mixture of 3-TBDMS-16-(4-methoxybenzenesulfinyl)-estrone (95 mg, 0.18 mmol), Na2CO3 (75 mg, 0.71 mmol), trimethyl phosphite (70 pl, 0.60 mmol) in o-xylene (1.6 ml) was stirred at 140°C for 7 hours. TLC confirmed full conversion of the starting material. Approximately 57% of the starting material was converted into 3-TBDMS-A15-16-estrone, as determined by UPLC on the crude reaction mixture. No work-up of the reaction mixture was performed.

Example 5: Reaction sequence using methyl 4-fluorobenzenesulfinate

16-(4-fluorobenzenesulfinyl)-estrone was prepared according to the procedure applied for 16-(benzenesulfinyl)- estrone, using estrone (10.0 g, 37.0 mmol), methyl (4-fluoro)-benzenesulfinate (9.0 g, 51.8 mmol), DMSO (100 ml) and KOtBu (11.4 g, 0.10 mol, added as solution in 40 ml THF). The product was isolated as an off-white solid in a quantitative yield. 3-TBDMS-16-(4-fluorobenzenesulfinyl)-estrone was prepared according to the procedure applied for 3-TBDMS- 16-(4-chlorobenzenesulfinyl)-estrone using 16-(4-fluorobenzenesulfinyl)-estrone (15.0 g, 36.4 mmol), imidazole (6.2 g, 91.0 mmol), TBDMS-CI (7.1 g, 47.2 mmol) and DCM (68 ml). The product was isolated in a 96% yield (17.2 g)-

The desulfinylation reaction was performed according to the procedure applied for 3-TBDMS-16-(4- chlorobenzenesulfinyl)-estrone. A mixture of 3-TBDMS-16-(4-fluorobenzenesulfinyl)-estrone (100 mg, 0.19 mmol), Na2CC>3 (45 mg, 0.43 mmol), trimethyl phosphite (11 pl, 0.10 mmol) in o-xylene (2 ml) was stirred at 140°C for 10 hours. UPLC confirmed full conversion of the starting material. 89% of the starting material was converted into 3-TBDMS-A15-16-estrone, as determined by ¹ H NMR on the crude reaction mixture. No work-up of the reaction mixture was performed.

Example 6: Reaction sequence using methyl 2,4-dichlorobenzenesulfinate

16-(2,4-dichlorobenzenesulfinyl)-estrone was prepared according to the procedure applied for 16- (benzenesulfinyl)-estrone, using estrone (1.0 g, 3.7 mmol), methyl (2,4-dichlorobenzene)-sulfinate (1.17 g, 5.2 mmol), DMSO (10 ml) and KOtBu (1.1 g, 10.2 mmol, added as solution in 4 ml THF). The product was isolated as a yellowish solid in a yield of 68% (1 .2 g).

3-TBDMS-16-(2,4-dichlorobenzenesulfinyl)-estrone was prepared according to the procedure applied for 3- TBDMS-16-(4-chlorobenzenesulfinyl)-estrone using 16-(2,4-dichlorobenzenesulfinyl)-estrone (1.0 g, 2.2 mmol), imidazole (0.37 g, 5.4 mmol), TBDMS-CI (0.42 g, 2.8 mmol) and DCM (11 ml). The product was isolated as an off-white solid in a 75% yield (0.93 g) after purification by flash chromatography.

The desulfinylation reaction was performed according to the procedure applied for 3-TBDMS-16-(4- chlorobenzenesulfinyl)-estrone. A mixture of 3-TBDMS-16-(2,4-dichlorobenzenesulfinyl)-estrone (100 mg, 0.17 mmol), Na2CC>3 (41 mg, 0.39 mmol), trimethyl phosphite (10 pl, 0.09 mmol) in o-xylene (2 ml) was stirred at 140°C for 10 hours. UPLC confirmed full conversion of the starting material. 88% of the starting material was converted into 3-TBDMS-A15-16-estrone, as determined by ¹ H NMR on the crude reaction mixture. No work-up of the reaction mixture was performed.

In view of the foregoing description and examples, it will be apparent to those skilled in the art that equivalent modifications thereof can be made without departing from the scope of the claims. Examples 7 to 10

Additional examples (Examples 7 to 9) of the sulfinylation/desulfinylation strategy on estrone were performed using 3-OH protecting groups such as: tert-butyldiphenylsilyl chloride (TBDPS-CI), benzyl bromide (BnBr) and pivaloyl chloride (PivCI). Methyl 4-chlorobenzenesulfinate was reacted with estrone according to the method described in Step a) of Example 1, yielding the 16-(4-chlorobenzenesulfinyl)-estrone derivatives as a mixture of four stereoisomers. Further, following adapted procedures of steps b) and c) of Example 1, the crude products were reacted with either tert-butyldiphenylsilyl chloride or benzyl bromide or pivaloyl chloride followed by the desulfinylation reaction.

Additionally, in Example 10, the sulfinylation/desulfinylation strategy on estrone was performed using

2-pyridinesulfinic acid methyl ester yielding 16-(2-pyridylsulfinyl)-estrone. Further, following the procedures of steps b) and c) of Example 1, the crude products were reacted with TBDMS-CI followed by the desulfinylation reaction.

Example 7: Reaction sequence using tert-butyldiphenylsilylchloride

3-OTBDPS-16-(4-chlorobenzenesulfinyl)-estrone was prepared according to the procedure of step b) of Example 1 using 16-(4-chlorobenzenesulfinyl)-estrone (2.0 g, 4.7 mmol), imidazole (0.8 g, 11.7 mmol), TBDPS-CI (1.5 g, 5.6 mmol) and DCM (20 ml). TLC confirmed full conversion of the starting material. The crude product (4.0 g) was isolated after extraction and evaporation of DCM.

The desulfinylation reaction was performed according to the procedure applied in step c) of Example 1. A mixture of the crude 3-OTBDPS-16-(4-chlorobenzenesulfinyl)-estrone (4.0 g), Na2CO3 (1.1 g, 10.4 mmol), in o-xylene (62 ml) was stirred at 140°C for 16 hours. TLC confirmed full conversion of the starting material. The mixture was cooled to room temperature, washed with water (2 x 16 ml) and the solvent was removed under vacuum. 47% of 3-OTBDPS-A15-16-estrone was detected by ¹ H-NMR analysis of the crude reaction mixture. Yield: 1.15 g (58%) of 3-OTBDPS-A15-16-estrone over two steps (by ¹ H NMR analysis of the crude mixture).

Example 8: Reaction sequence using benzylbromide

To a mixture of 16-(4-chlorobenzenesulfinyl)-estrone (2.0 g, 4.7 mmol) and K2CO3 (1.4 g, 10.3 mmol) in MeOH (20 mL) was added BnBr (1.7 g, 9.8 mmol) over a period of 20 minutes. The reaction was stirred under reflux. Conversion of the starting material reached 80% based on TLC monitoring. Extraction was performed with dichloromethane; the organic phase was washed with water and concentrated. After evaporation, the crude product (2.6 g) was reacted in the elimination step (step c) as such. The desulfinylation reaction was performed as follows. A mixture of the crude 3-OBn-16-(4- chlorobenzenesulfinyl)-estrone (2.5 g), Na2CC>3 (1.2 g, 2.3 mmol) in o-xylene (50 ml) was stirred at 140°C for 16 hours. TLC confirmed full conversion of the starting material. The mixture was cooled to room temperature, washed with water (2 x 13 ml) and the solvent was removed under vacuum. 61% of 3-OBn-A15-16-estrone was detected by ¹ H-NMR analysis of the crude reaction mixture. Yield: 1.5 g (75%) of 3-Bn-A15-16-estrone over two steps (by ¹ H NMR analysis of the crude mixture).

Example 9: Reaction sequence using pivaloylchloride

3-OPiv-16-(4-chlorobenzenesulfinyl)-estrone was prepared according to adapted procedure of step b) of Example 1 using 16-(4-chlorobenzenesulfinyl)-estrone (1.0 g, 2.3 mmol), imidazole (0.4 g, 5.8 mmol), EtsN (0.4 mL, 2.84 mmol), PivCI (0.53 g, 4.4 mmol) and DCM (12 ml). TLC confirmed full conversion of the starting material. The crude product (1 .2 g) was isolated after extraction and evaporation of DCM.

The desulfinylation reaction was performed according to adapted procedure of step c) of Example 1. A mixture of the crude 3-OPiv-16-(4-chlorobenzenesulfinyl)-estrone (1.2 g), Na2CO3 (0.6 g, 5.3 mmol), in o-xylene (24 ml) was stirred at 140°C for 16 hours. TLC confirmed full conversion of the starting material. The mixture was cooled to room temperature, washed with water (2 x 6 ml) and the solvent was removed under vacuum. 67% of 3-OPiv- A15-16-estrone was detected by ¹ H-NMR analysis of the crude reaction mixture. Yield: 0.7 g (70%) of 3-OPiv- A15-16-estrone over two steps (by ¹ H NMR analysis of the crude mixture).

Example 10: Reaction sequence using 2-pyridinesulfinic acid methyl ester

16-(2-pyridylsulfinyl)-estrone was prepared according to the procedure of step a) of Example 1, using estrone (0.8 g, 2.96 mmol), 2-pyridinesulfinic acid methyl ester (0.65 g, 4.14 mmol), DMSO (4.8 ml) and THF (3.2 ml). KOtBu (0.88 g, 7.84 mmol, added as solution in 3.2 ml THF). The product was isolated as a pink solid (0.9 g, 77%).

3-TBDMS-16-(2-pyridylsulfinyl)-estrone was prepared according to the procedure of step b) of Example 1 using 16-(2-pyridylsulfinyl)-estrone (0.5 g, 1.26 mmol), imidazole (0.22 g, 3.16 mmol), TBDMS-CI (0.38 g, 2.53 mmol) and DCM (5 ml). The product was isolated as an off-white solid after crystallization.

The desulfinylation reaction was performed according to the adapted procedure applied in step c) of Example 1 . A mixture of 3-TBDMS-16-(2-pyridylsulfinyl)-estrone (50 mg, 0.10 mmol), Na2CO3 (20 mg, 0.22 mmol) in o-xylene (1 ml) was stirred at 140°C for 13 hours. TLC confirmed full conversion of the starting material. 64% of 3-TBDMS- A15-16-estrone was present in the crude isolated product as determined by UPLC. The impurities profile of the final product obtained after desulfinylation is in accordance with the results obtained in the other examples. Example 11 : Use of additives in the elimination step

The desulfiny lation reaction was performed according to an adapted procedure from step c) of Example 1 . A mixture of the crude 3-OTBDPS-16-(4-chlorobenzenesulfinyl)-estrone (0.1 g) was added to a 10 mL test tube along with o-xylene (2 ml). Three different conditions were tested: 1) Trimethyl phosphite (0.5 eq.) without Na2CC>3

2) Without trimethyl phosphite and without Na2CC>3

3) Na2CC>3 (2.25 eq.) without trimethyl phosphite

The reaction mixtures were stirred at 140°C for 16 hours. TLC confirmed full conversion of the starting material in all three conditions. The presence of an alkyl phosphite (condition 1) or a base (condition 3) was, surprisingly, found to increase yield. Only a relatively small amount of desired product formed in the absence of both a phosphite and a base (condition 2). The presence of a base in the elimination step (as in condition 3) was found to be particularly beneficial to suppress the formation of by-products. Trimethyl phosphite (condition 1) also limited by-product formation, but to a smaller extent than the base used in condition 3.