Process for the production of estetrol intermediates

Abstract

The present invention relates to a process for the preparation of a compound of formula (I), a stereoisomer, a salt, a hydrate or a solvate thereof, (II) comprising the step of sulfinylation of a compound of formula (IV) to produce compound of formula (II); (IV) wherein: R1 and R2 are as defined in the claims, wherein said sulfinylation step is performed in the presence of a solvent selected from the group comprising benzene, toluene, ethylbenzene, xylene, chlorobenzene, bromobenzene, fluorobenzene, anisole, nitrobenzene, tetralin, dichlorobenzene, trimethylbenzene, ethylacetate, propylacetate, butylacetate, propanol, butanol, 2- methyltetrahydrofuran, diethylether, methyltertbutylether, cyclopentyl methyl ether, dichloromethane, tetrachloromethane, pentane, hexane, heptane, cyclohexane, decaline and mixtures thereof.

Description

[0001] PROCESS FOR THE PRODUCTION OF ESTETROL INTERMEDIATES

[0002] Field of the invention

[0003] The present invention relates to a new process for the synthesis of a key intermediate in the synthesis of estetrol.

[0004] BACKGROUND OF THE INVENTION

[0005] Estrogenic substances are commonly used in methods of Hormone Replacement Therapy (HRT) and methods of female contraception. Estetrol is a biogenic oestrogen that is endogeneously produced by the foetal 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 tumours, enhancement of libido, skin care, and wound healing.

[0006] The synthesis of estetrol and derivatives thereof is known in the art. Verhaar M.T; et al (WO 2004 / 041839) describes a process for the preparation of estetrol starting from a 3-A- oxy-estra 1 ,3, 5(10),15-tetraen-17-one, wherein A is a C1-C5 alkyl group, or a C7 - C12 benzylic group. In this document, 3-A-oxy-estra 1 ,3, 5(10), 15-tetraen-17-ol is prepared in 6 steps from estrone where A is a benzyl group, the steps comprising protection of the 3-OH group by a benzyl group, then transformation of the 17-keto-group to a 17,17- ethylenedioxy derivative which is halogenated at the C16 position using pyridinium bromide perbromide. Dehydrohalogenation is carried out by using potassium tert-butoxide in dimethylsulfoxide. Deprotection of the 17-keto-group is conducted using p-toluenesulfonic acid monohydrate in aqueous acetone. Reduction of 17-keto-group affords the 17-ol derivative.

[0007] One of the disadvantages of the process described in WO 2004 / 041839 is the protection of 3-OH function with a benzyl group which is removed by hydrogenation using Pd / C as catalyst in the last steps of the estetrol synthesis. Furthermore, the level of this catalyst in the final drug substance must be determined and must comply with the ICH guidelines.

[0008] Another disadvantage of the synthesis described in WO 2004 / 041839 is the two-step protection / deprotection of the 17-keto function in order to generate the 15-16 double bond with a low yield.

[0009] WO 2012 / 164095 discloses a process for the preparation of a compound of Formula (I), which process is depicted below:

[0010] (II) (III) (IV) (V) (I)

[0011] 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:

[0012] P1is protecting group selected from R2Si-R3R4or R1C(O)-;

[0013] R1is selected from Ci-Cealkyl or Cs-Cecycloalkyl, each group being optionally substituted by one or more F or Ci-C4alkyl;

[0014] R2, R3and R4are each independently selected from Ci-Cealkyl or phenyl, each group being optionally substituted by one or more F or Ci-C4alkyl; b) halogenation or sulfinylation of the compound of formula (III) to produce a compound of formula (IV) wherein:

[0015] X is a halogen or a sulfoxide (-S(O)-R5)

[0016] R5is selected from Ce-C aryl or heteroaryl, each group being optionally substituted by one or more Cl or Ci-C4alkyl; 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).

[0017] 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 has been reported that when the compound of formula (III) is sulfinylated according to the process described in WO 2012 / 164095, protecting group P1of compound of formula (III) (in particular, when P1is a base sensitive silyl protecting group) is prone to degradation due to the harsh basic conditions used. For example, when P1was a TBDMS protecting group, significant cleavage of the protecting group has been reported. This is detrimental to the yield of the overall process described in WO 2012 / 164095.

[0018] WO 2023 / 021026 therefore suggests sulfinylating first and then protecting in order to avoid the disadvantages described above. However, the present inventors have found that disadvantages from the original process from WO 2012 / 164095 described above can be circumvented by careful optimization of the reaction solvent. Moreover, the invention described in this document proved to be more efficient in term of reaction time since total conversion for the sulfinylation step was reached in only 15 minutes. Moreover, the workup requires additional steps such as filtration and drying of the intermediates in order to proceed with further reaction steps. These additional operations are time consuming and require the use of large quantities of organic solvent. Additionally, it was found by the present inventors that the control of the water content is a critical factor for the TBDPS protection step in the process from WO 2023 / 021026. Therefore, long drying time are needed to obtain a low water content. All these drawbacks make the process described in WO 2023 / 021026 not optimal for industrial applications.

[0019] There remains a need for an improved synthesis of 3-protected-oxy-estra-1 ,3,5(10),15- tetraene-17-ol. It is therefore an object of the present invention to provide a process for the preparation of 3-protected-oxy-estra-1 ,3,5(10),15-tetraene-17-ol which overcomes at least one of the disadvantages of the prior art.

[0020] Summary of the invention

[0021] The present inventors have now found that this object can be obtained by using a process as defined in the appended claims. The present inventors have surprisingly found that by modifying the reaction conditions, for instance by using a specific solvent, 3-protected- oxy-estra-1 ,3,5(10),15-tetraene-17-ol can be obtained in excellent yield and with a very high degree of purity. In addition, the present process was developed to facilitate the industrial production by reducing the amount of solvent and the reaction time, which minimizes costs and improves the environmental footprint of the present process.

[0022] According to a first aspect of the present invention, a process is provided for the preparation of a compound of formula (II), a stereoisomer, a salt, a hydrate or a solvate thereof, comprising the step of sulfi nylation of a compound of formula (IV) to produce compound of formula (II); wherein:

[0023] R1is selected from the group comprising, R3Si(R4)(R5)-, Ci-ealkyl, Ce- aryl, Ce-warylCi- ealkyl, -CH2-CH=CRaRb, Ci-ealkoxy, and Cs-ecycloalkyl; each of said Ci-ealkyl, Ce- aryl, Ce- warylCiwalkyl, and Cs-ecycloalkyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, Ce- aryl, heterocyclyl, and nitro;

[0024] R2is Ce-waryl, or heteroaryl; wherein each Ce-waryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, C2-ealkenyl, C2- ealkynyl, Ce-waryl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, -SR8, -NR9R10, cyano and nitro;

[0025] R3, R4and R5are each independently Ci-ealkyl or Ce-waryl, wherein each Ci-ealkyl or Ce- waryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi- ealkoxy; preferably fluoro, chloro or Ci-4alkyl;

[0026] R6, R7and R8are each independently selected from the group consisting of Ci-ealkyl, Ce- waryl, and Cs-ecycloalkyl, wherein each Ci-ealkyl, Ce-waryl, or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy;

[0027] R9and R10are each independently selected from the group consisting of hydrogen, Ci- ealkyl, Ce-waryl, Cs-ecycloalkyl, wherein each Ci-ealkyl, Ce-waryl, or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy;

[0028] Raand Rbare each independently hydrogen, Ci-ealkyl or Ce-waryl; wherein said sulfinylation step is performed in the presence of a solvent selected from the group comprising benzene, toluene, ethylbenzene, xylene, chlorobenzene, bromobenzene, fluorobenzene, anisole, nitrobenzene, tetralin, dichlorobenzene, trimethylbenzene, ethylacetate, propylacetate, butylacetate, propanol, butanol, 2- methyltetrahydrofuran, diethylether, methyltertbutylether, cyclopentyl methyl ether, dichloromethane, tetrachloromethane, pentane, hexane, heptane, cyclohexane, decaline and mixtures thereof.

[0029] According to a second aspect, the present invention also encompasses a process for the preparation of estra-1, 3, 5(10), -triene 3,15a,16a,17p-tetrol of formula (E), also named Estetrol, a stereoisomer, a salt, a hydrate, an ester, an ether or a solvate thereof, said process comprising the step of preparing a compound of formula (I) by a process as described herein, and further reacting compound of formula (I) to produce estetrol of formula (E), a stereoisomer, a salt, a hydrate, an ester, an ether or a solvate thereof,

[0030] The above and other characteristics, features and advantages of the present invention will become apparent from the following detailed description, which illustrate, by way of example, the principles of the invention.

[0031] Detailed description of the invention

[0032] When describing the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.

[0033] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly 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.

[0034] In the following passages, various aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0035] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment, 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 embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, 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.

[0036] 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 "comprising", "comprises" and "comprised of" as used herein comprise the terms "consisting of', "consists" and "consists of".

[0037] As used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise. By way of example, "a step" means one step or more than one step.

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art.

[0039] The recitation of numerical ranges by endpoints includes all integer numbers and, where appropriate, fractions subsumed within that range (e.g., 1 to 5 can include 1 , 2, 3, 4 when referring to, for example, a number of elements, and can also include 1.5, 2, 2.75 and 3.80, when referring to, for example, measurements). The recitation of endpoints also includes the end point values themselves (e.g., from 1.0 to 5.0 includes both 1.0 and 5.0). Any numerical range recited herein is intended to include all sub-ranges subsumed therein.

[0040] The term "about" as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of + / -10% or less, preferably + / -5% or less, more preferably + / -1% or less, of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier "about" refers is itself also specifically, and preferably, disclosed.

[0041] When describing the present invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise. HPLC as used herein is high performance liquid chromatography utilizing UV absorption detection with the method described in the Example section.

[0042] "Reaction impurities" are process related impurities (by-products) including all residual starting materials, residual intermediates, and other reaction products other than compound of formula (II) detected by HPLC.

[0043] Whenever the term “substituted” is used herein, it is meant to indicate that one or more hydrogen atoms on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom’s normal valence is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently robust to survive isolation from a reaction mixture. Where groups can be substituted, such groups may be substituted with one or more, and preferably one, two or three substituents.

[0044] The term “halo” or “halogen” as a group or part of a group is generic for fluoro, chloro, bromo, iodo.

[0045] The term “nitro” as used herein refers to the group -NO2.

[0046] The term “amino” refers to the group -NH2.

[0047] The term “cyano” as used herein refers to the group -CN.

[0048] The term “thiol” or “sulfhydryl” refers to the group -SH.

[0049] The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl group of formula CnH2n+i wherein n is a number greater than or equal to 1. Alkyl groups may be linear or branched and may be substituted as indicated herein. Generally, alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 5 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 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. For example, the term "Ci-ealkyl", as a group or part of a group, refers to a hydrocarbyl group of formula CnH2n+i wherein n is a number ranging from 1 to 6. Thus, for example, “Ci- ealkyl” includes all linear or branched alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, / -propyl, butyl and its isomers (e.g., n-butyl, / - butyl and f-butyl); pentyl and its isomers, hexyl and its isomers. For example, “Ci-salkyl” includes all linear or branched alkyl groups with between 1 and 5 carbon atoms, and thus includes methyl, ethyl, n-propyl, / -propyl, butyl and its isomers (e.g., n-butyl, / -butyl and t- butyl); pentyl and its isomers. For example, “Ci-4alkyl” includes all linear or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes methyl, ethyl, n-propyl, / - propyl, butyl and its isomers (e.g., n-butyl, / -butyl and t-butyl). For example, “Ci-3alkyl” includes all linear or branched alkyl groups with between 1 and 3 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl. A “substituted Ci-ealkyl" refers to a Ci-ealkyl group substituted with one or more substituent(s) (for example 1 to 3 substituent(s), for example 1 , 2, or 3 substituent(s)) at any available point of attachment.

[0050] The term "haloCi-ealkyl" as a group or part of a group, refers to a Ci-ealkyl group having the meaning as defined above wherein one, two, or three hydrogen atoms are each replaced with a halogen as defined herein. Non-limiting examples of such haloCi-ealkyl groups include chloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1 -trifluoroethyl, trichloromethyl, tribromomethyl, and the like.

[0051] The term “Ci-ealkoxy" or “Ci-ealkyloxy”, as a group or part of a group, refers to a group having the formula -ORbwherein Rbis Ci-ealkyl as defined herein above. Non-limiting examples of suitable Ci-ealkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- butoxy, pentyloxy and hexyloxy.

[0052] The term “Ci-ealkylthio", as a group or part of a group, refers to a group having the formula -S-Rbwherein Rbis Ci-ealkyl as defined herein above. Non-limiting examples of Ci- ealkylthio groups include methylthio (-SCH3), ethylthio (-SCH2CH3), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.

[0053] The term “haloCi-ealkoxy”, as a group or part of a group, refers to a group of formula -O-Rewherein Reis haloCi-ealkyl as defined herein. Non-limiting examples of suitable haloCi-ealkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2- trifluoroethoxy, 1 ,1 ,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2- difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy.

[0054] The term “cycloalkyl”, as a group or part of a group, refers to a cyclic alkyl group, that is a monovalent, saturated, hydrocarbyl group having 1 or more cyclic structure, and comprising from 3 to 12 carbon atoms, more preferably from 3 to 9 carbon atoms, more preferably from 3 to 7 carbon atoms; more preferably from 3 to 6 carbon atoms. Cycloalkyl includes all saturated hydrocarbon groups containing 1 or more rings, including monocyclic or bicyclic groups. The further rings of multi-ring cycloalkyls may be either fused, bridged and / or joined through one or more spiro 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. For example, the term “Cs-ecycloalkyl”, a cyclic alkyl group comprising from 3 to 6 carbon atoms. Examples of C3-i2cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycle[2.2.1]heptan-2yl, (1 S,4F?)-norbornan-2-yl, (1F?,4F?)-norbornan-2-yl, (1 S,4S)- norbornan-2-yl, (1 ?,4S)-norbornan-2-yl.

[0055] As used herein, the term “spiro atom” refers to the atom that connects two cyclic structures in a spiro compound. Non limiting examples of spiro atoms include quaternary carbon atoms. As used herein, the term “spiro compound” refers to a bicyclic compound wherein the two rings are connected through one atom.

[0056] The term “alkenyl” as a group or part of a group, refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon-carbon double bonds. 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. For example, the term “C2-6alkenyl” refers to an unsaturated hydrocarbyl group, which may be linear, or branched comprising one or more carbon-carbon double bonds and comprising from 2 to 6 carbon atoms. For example, C2-4alkenyl includes all linear, or branched alkenyl groups having 2 to 4 carbon atoms. Examples of C2-ealkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3- butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, and the like.

[0057] The term “alkynyl” by itself or as part of another substituent, refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carboncarbon triple bonds. 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. For example, the term “C2-6alkynyl” refers to an unsaturated hydrocarbyl group, which may be linear, or branched comprising one or more carbon-carbon triple bonds and comprising from 2 to 6 carbon atoms. For example, C2-4alkynyl includes all linear, or branched alkynyl groups having 2 to 4 carbon atoms. Non limiting examples of C2-ealkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its chain isomers, 2-hexynyl and its chain isomers, and the like.

[0058] The term “Ce-waryl”, as a group or part of a group, refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl), or linked covalently, typically containing 6 to 10 atoms, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Examples of suitable aryl include Ce- aryl, more preferably Ce-saryl. Non-limiting examples of Ce-waryl comprise phenyl, biphenylyl, biphenylenyl, or 1-or 2-naphthanelyl; 1-, 2-, 3-, 4-, 5- or 6- tetralinyl (also known as “1 ,2,3,4-tetrahydronaphtalene); 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- azulenyl, 4-, 5-, 6 or 7-indenyl; 4- or 5-indanyl; 5-, 6-, 7- or 8-tetrahydronaphthyl; 1 ,2, 3, 4- tetrahydronaphthyl; and 1 ,4-dihydronaphthyl; 1-, 2-, 3-, 4- or 5-pyrenyl. A “substituted Ce- waryl” refers to a Ce-waryl group having one or more substituent(s) (for example 1 , 2 or 3 substituent(s), or 1 to 2 substituent(s)), at any available point of attachment.

[0059] The term "Ce-warylCi-ealkyl", as a group or part of a group, means a Ci-ealkyl as defined herein, wherein at least one hydrogen atom is replaced by at least one Ce- aryl as defined herein. Non-limiting examples of Ce-warylCi-ealkyl group include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3-(2-naphthyl)-butyl, and the like.

[0060] The term “Ce- arylthioCi-ealkyl", as a group or part of a group, refers to a Ci-ealkyl, wherein at least one hydrogen atom is replaced by at least one group having the formula -S-Rfwherein Rfis Ce-waryl as defined herein above.

[0061] The term "heterocyclyl", as a group or part of a group, refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or comprising a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring; wherein said ring may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Each ring of the heterocyclyl group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from N, O and / or S, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and wherein at least one carbon atom of heterocyclyl can be oxidized to form at least one C=O. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocyclyl may be fused, bridged and / or joined through one or more spiro atoms.

[0062] Non limiting exemplary heterocyclyl groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, oxetanyl, pyrrolidinyl, thietanyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, chromanyl (also known as 3,4- dihydrobenzo[b]pyranyl), isoindolinyl, 2H-pyrrolyl, 1 -pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3- pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3- dioxolanyl, 1 ,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4- ylsulfone, 1 ,3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, 1 H-pyrrolizinyl, tetrahydro-1 ,1 -dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl. The term “aziridinyl” as used herein includes aziridin-1-yl and aziridin-2-yl. The term “oxyranyl” as used herein includes oxyranyl-2-yl. The term “thiiranyl” as used herein includes thiiran-2- yl. The term “azetidinyl” as used herein includes azetidin-1-yl, azetidin-2-yl and azetidin-3- yl. The term “oxetanyl” as used herein includes oxetan-2-yl and oxetan-3-yl. The term “thietanyl” as used herein includes thietan-2-yl and thietan-3-yl. The term “pyrrolidinyl” as used herein includes pyrrolidin-1 -yl, pyrrolidin-2-yl and pyrrolidin-3-yl. The term “tetrahydrofuranyl” as used herein includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. The term “tetrahydrothiophenyl” as used herein includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. The term “succinimidyl” as used herein includes succinimid-1-yl and succininmid-3-yl. The term “dihydropyrrolyl” as used herein includes 2,3- dihydropyrrol-1 -yl, 2,3-dihydro-1 H-pyrrol-2-yl, 2,3-dihydro-1 H-pyrrol-3-yl, 2,5- dihydropyrrol-1 -yl, 2,5-dihydro-1 H-pyrrol-3-yl and 2,5-dihydropyrrol-5-yl. The term “2H- pyrrolyl” as used herein includes 2H-pyrrol-2-yl, 2H-pyrrol-3-yl, 2H-pyrrol-4-yl and 2H- pyrrol-5-yl. The term “3H-pyrrolyl” as used herein includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl and 3H-pyrrol-5-yl. The term “dihydrofuranyl” as used herein includes 2,3- dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5- dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5-dihydrofuran-4-yl and 2,5-dihydrofuran-5-yl. The term “dihydrothiophenyl” as used herein includes 2,3-dihydrothiophen-2-yl, 2,3- dihydrothiophen-3-yl, 2,3-dihydrothiophen-4-yl, 2,3-dihydrothiophen-5-yl, 2,5- dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4-yl and 2,5- dihydrothiophen-5-yl. The term “imidazolidinyl” as used herein includes imidazolidin-1 -yl, imidazolidin-2-yl and imidazolidin-4-yl. The term “pyrazolidinyl” as used herein includes pyrazolidin-1 -yl, pyrazolidin-3-yl and pyrazolidin-4-yl. The term “imidazolinyl” as used herein includes imidazolin-1 -yl, imidazolin-2-yl, imidazolin-4-yl and imidazolin-5-yl. The term “pyrazolinyl” as used herein includes 1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 2-pyrazolin-1- yl, 2-pyrazolin-3-yl, 2-pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3-pyrazolin-2-yl, 3- pyrazolin-3-yl, 3-pyrazolin-4-yl and 3-pyrazolin-5-yl. The term “dioxolanyl” also known as “1 ,3-dioxolanyl” as used herein includes dioxolan-2-yl, dioxolan-4-yl and dioxolan-5-yl. The term “dioxolyl” also known as “1,3-dioxolyl” as used herein includes dioxol-2-yl, dioxol-4-yl and dioxol-5-yl. The term “oxazolidinyl” as used herein includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl and oxazolidin-5-yl. The term “isoxazolidinyl” as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl and isoxazolidin-5-yl. The term “oxazolinyl” as used herein includes 2-oxazolinyl-2-yl, 2-oxazolinyl-4-yl, 2- oxazolinyl-5-yl, 3-oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4-oxazolinyl-2-yl, 4- oxazolinyl-3-yl, 4-oxazolinyl-4-yl and 4-oxazolinyl-5-yl. The term “isoxazolinyl” as used herein includes 2-isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl-3- yl, 3-isoxazolinyl-4-yl, 3-isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4- isoxazolinyl-4-yl and 4-isoxazolinyl-5-yl. The term “thiazolidinyl” as used herein includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl and thiazolidin-5-yl. The term “isothiazolidinyl” as used herein includes isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl and isothiazolidin-5-yl. The term “chromanyl” as used herein includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl and chroman-8-yl. The term “thiazolinyl” as used herein includes 2-thiazolinyl-2-yl, 2- thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3-thiazolinyl-2-yl, 3-thiazolinyl-4-yl, 3-thiazolinyl-5-yl, 4- thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4-thiazolinyl-4-yl and 4-thiazolinyl-5-yl. The term “isothiazolinyl” as used herein includes 2-isothiazolinyl-3-yl, 2-isothiazolinyl-4-yl, 2- isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl-4-yl, 3-isothiazolinyl-5-yl, 4- isothiazolinyl-2-yl, 4-isothiazolinyl-3-yl, 4-isothiazolinyl-4-yl and 4-isothiazolinyl-5-yl. The term “piperidyl” also known as “piperidinyl” as used herein includes piperid-1-yl, piperid-2- yl, piperid-3-yl and piperid-4-yl. The term “dihydropyridinyl” as used herein includes 1 ,2- dihydropyridin-1-yl, 1 ,2-dihydropyridin-2-yl, 1 ,2-dihydropyridin-3-yl, 1 ,2-dihydropyridin-4-yl, 1 ,2-dihydropyridin-5-yl, 1 ,2-dihydropyridin-6-yl, 1 ,4-dihydropyridin-1 -yl, 1 ,4-dihydropyridin- 2-yl, 1 ,4-dihydropyridin-3-yl, 1 ,4-dihydropyridin-4-yl, 2,3-dihydropyridin-2-yl, 2,3- dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl,

[0063] 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin- 5-yl, 2,5-dihydropyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4- dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl and 3,4-dihydropyridin-6-yl. The term “tetrahydropyridinyl” as used herein includes 1 ,2,3,4-tetrahydropyridin-1 -yl, 1 , 2,3,4- tetrahydropyridin-2-yl, 1 ,2,3,4-tetrahydropyridin-3-yl, 1 ,2,3,4-tetrahydropyridin-4-yl,

[0064] 1 .2.3.4-tetrahydropyridin-5-yl, 1 ,2,3,4-tetrahydropyridin-6-yl, 1 ,2, 3,6-tetrahydropyridin- 1 -yl,

[0065] 1 .2.3.6-tetrahydropyridin-2-yl, 1 ,2,3,6-tetrahydropyridin-3-yl, 1 ,2,3,6-tetrahydropyridin-4-yl,

[0066] 1 .2.3.6-tetrahydropyridin-5-yl, 1 ,2,3,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl,

[0067] 2.3.4.5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl,

[0068] 2.3.4.5-tetrahydropyridin-5-yl and 2,3,4,5-tetrahydropyridin-6-yl. The term

[0069] “tetrahydropyranyl” also known as “oxanyl” or “tetrahydro-2H-pyranyl”, as used herein includes tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl. The term “2H-pyranyl” as used herein includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H- pyran-5-yl and 2H-pyran-6-yl. The term “4H-pyranyl” as used herein includes 4H-pyran-2- yl, 4H-pyran-3-yl and 4H-pyran-4-yl. The term “3,4-dihydro-2H-pyranyl” as used herein includes 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3.4-dihydro-2H-pyran-5-yl and 3,4-dihydro-2H-pyran-6-yl. The term “3,6-dihydro-2H- pyranyl” as used herein includes 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl,

[0070] 3.6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-5-yl and 3,6-dihydro-2H-pyran-6-yl. The term “tetrahydrothiophenyl”, as used herein includes tetrahydrothiophen-2-yl, tetrahydrothiophenyl -3-yl and tetrahydrothiophenyl -4-yl. The term “2H-thiopyranyl” as used herein includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H- thiopyran-5-yl and 2H-thiopyran-6-yl. The term “4H-thiopyranyl” as used herein includes 4H-thiopyran-2-yl, 4H-thiopyran-3-yl and 4H-thiopyran-4-yl. The term “3,4-dihydro-2H- thiopyranyl” as used herein includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H- thiopyran-3-yl, 3,4-dihydro-2H-thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl and 3,4- dihydro-2H-thiopyran-6-yl. The term “3,6-dihydro-2H-thiopyranyl” as used herein includes

[0071] 3.6-dihydro-2H-thiopyran-2-yl, 3,6-dihydro-2H-thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4- yl, 3,6-dihydro-2H-thiopyran-5-yl and 3,6-dihydro-2H-thiopyran-6-yl. The term “piperazinyl” also known as “piperazidinyl” as used herein includes piperazin-1 -yl and piperazin-2-yl. The term “morpholinyl” as used herein includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. The term “thiomorpholinyl” as used herein includes thiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl. The term “dioxanyl” as used herein includes

[0072] 1.2-dioxan-3-yl, 1 ,2-dioxan-4-yl, 1 ,3-dioxan-2-yl, 1 ,3-dioxan-4-yl, 1 ,3-dioxan-5-yl and 1,4- dioxan-2-yl. The term “dithianyl” as used herein includes 1 ,2-dithian-3-yl, 1 ,2-dithian-4-yl,

[0073] 1.3-dithian-2-yl, 1 ,3-dithian-4-yl, 1 ,3-dithian-5-yl and 1 ,4-dithian-2-yl. The term “oxathianyl” as used herein includes oxathian-2-yl and oxathian-3-yl. The term “trioxanyl” as used herein includes 1,2,3-trioxan-4-yl, 1 ,2,3-trioxay-5-yl, 1,2,4-trioxay-3-yl, 1 ,2,4-trioxay-5-yl,

[0074] 1.2.4-trioxay-6-yl and 1 ,3,4-trioxay-2-yl. The term “azepanyl” as used herein includes azepan-1-yl, azepan-2-yl, azepan-1-yl, azepan-3-yl and azepan-4-yl. The term “homopiperazinyl” as used herein includes homopiperazin-1 -yl, homopiperazin-2-yl, homopiperazin-3-yl and homopiperazin-4-yl. The term “indolinyl” as used herein includes indolin-1 -yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “isoindolinyl” as used herein includes isoindolin-1 -yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6-yl, and isoindolin-7-yl. The term “3H-indolyl” as used herein includes 3H-indol-2-yl, 3H-indol- 3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol-6-yl, and 3H-indol-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “quinolizinyl” as used herein includes quinolizidin-1 -yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “tetrahydroquinolinyl” as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3- yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl and tetrahydroquinolin-8-yl. The term “tetrahydroisoquinolinyl” as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl and tetrahydroisoquinolin-8-yl. The term “1 H-pyrrolizine” as used herein includes 1 H-pyrrolizin-1 -yl, 1 H-pyrrolizin-2-yl, 1 H- pyrrolizin-3-yl, 1 H-pyrrolizin-5-yl, 1 H-pyrrolizin-6-yl and 1 H-pyrrolizin-7-yl. The term “3H- pyrrolizine” as used herein includes 3H-pyrrolizin-1 -yl, 3H-pyrrolizin-2-yl, 3H-pyrrolizin-3- yl, 3H-pyrrolizin-5-yl, 3H-pyrrolizin-6-yl and 3H-pyrrolizin-7-yl.

[0075] The term “heteroaryl” as a group or part of a group, refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 or 2 rings which can be fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by N, O and / or S atoms where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and wherein at least one carbon atom of said heteroaryl can be oxidized to form at least one C=O. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, benzothiazolyl, imidazo[2, 1 -b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1- benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin- 1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl; preferably said heteroaryl group is selected from the group consisting of pyridyl, tetrazolyl, benzothiazolyl, 1,3-benzodioxolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, pyrazinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, benzimidazolyl, pyrimidinyl, triazolyl and thiazolyl. The term “pyrrolyl” (also called azolyl) as used herein includes pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl. The term “furanyl” (also called "furyl") as used herein includes furan-2-yl and furan-3-yl (also called furan-2-yl and furan-3-yl). The term “thiophenyl” (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term “pyrazolyl” (also called 1 H-pyrazolyl and 1 ,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl. The term “imidazolyl” as used herein includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl. The term “oxazolyl” (also called 1 ,3-oxazolyl) as used herein includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl. The term “isoxazolyl” (also called 1,2-oxazolyl) as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term “thiazolyl” (also called 1 ,3-thiazolyl) as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4-thiazolyl and 5-thiazolyl). The term “isothiazolyl” (also called 1 ,2- thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. The term “triazolyl” as used herein includes 1 H-triazolyl and 4H-1 ,2,4-triazolyl, “1 H-triazolyl” includes 1 H-1 ,2,3-triazol-1 -yl, 1 H-1 ,2,3-triazol-4-yl, 1 H-1 ,2,3-triazol-5-yl, 1 H-1 ,2,4-triazol- 1-yl, 1 H-1 ,2,4-triazol-3-yl and 1 H-1 ,2,4-triazol-5-yl. “4H-1 ,2,4-triazolyl” includes 4H-1.2.4- triazol-4-yl, and 4H-1 ,2,4-triazol-3-yl. The term “oxadiazolyl” as used herein includes

[0076] 1.2.3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1 ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,5- oxadiazol-3-yl and 1 ,3,4-oxadiazol-2-yl. The term “thiadiazolyl” as used herein includes

[0077] 1.2.3-thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1 ,2,5- thiadiazol-3-yl (also called furazan-3-yl) and 1 ,3,4-thiadiazol-2-yl. The term “tetrazolyl” as used herein includes 1 H-tetrazol-1-yl, 1 H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5- yl. The term “oxatriazolyl” as used herein includes 1 ,2,3,4-oxatriazol-5-yl and 1 , 2,3,5- oxatriazol-4-yl. The term “thiatriazolyl” as used herein includes 1 ,2,3,4-thiatriazol-5-yl and 1 ,2,3,5-thiatriazol-4-yl. The term “pyridinyl” (also called "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2-pyridyl, 3-pyridyl and 4-pyridyl). The term “pyrimidyl” as used herein includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl and pyrimid-6-yl. The term “pyrazinyl” as used herein includes pyrazin-2-yl and pyrazin-3-yl. The term “pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl. The term “oxazinyl” (also called "1,4-oxazinyl") as used herein includes 1,4-oxazin-4-yl and 1,4- oxazin-5-yl. The term “dioxinyl” (also called "1 ,4-dioxinyl”) as used herein includes 1 ,4- dioxin-2-yl and 1 ,4-dioxin-3-yl. The term “thiazinyl” (also called "1,4-thiazinyl”) as used herein includes 1 ,4-thiazin-2-yl, 1 ,4-thiazin-3-yl, 1 ,4-thiazin-4-yl, 1 ,4-thiazin-5-yl and 1 ,4- thiazin-6-yl. The term “triazinyl” as used herein includes 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3- yl, 1 ,2,4-triazin-5-yl, 1 ,2,4-triazin-6-yl, 1 ,2,3-triazin-4-yl and 1 ,2,3-triazin-5-yl. The term “imidazo[2, 1 -b][1 ,3]thiazolyl” as used herein includes imidazo[2, 1 -b][1 ,3]thiazoi-2-yl, imidazo[2, 1 -b][1 ,3]thiazol-3-yl, imidazo[2,1-b][1 ,3]thiazol-5-yl and imidazo[2,1- b][1 ,3]thiazol-6-yl. The term “thieno[3,2-b]furanyl” as used herein includes thieno[3,2- b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl. The term “thieno[3,2-b]thiophenyl” as used herein includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2-b]thien-6-yl. The term “thieno[2,3-d][1 ,3]thiazolyl” as used herein includes thieno[2,3-d][1 ,3]thiazol-2-yl, thieno[2,3-d][1 ,3]thiazol-5-yl and thieno[2,3-d][1 ,3]thiazol-6-yl. The term “thieno[2,3- d]imidazolyl” as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl and thieno[2,3-d]imidazol-5-yl. The term “tetrazolo[1 ,5-a]pyridinyl” as used herein includes tetrazolo[1 , 5-a]pyridine-5-yl , tetrazolo[1 , 5-a]pyridine-6-yl , tetrazolo[1 , 5-a]pyridine-7-yl , and tetrazolo[1 ,5-a]pyridine-8-yl. The term “indolyl” as used herein includes indol-1-yl, indol-2- yl, indol-3-yl,-indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl. The term “indolizinyl” as used herein includes indolizin-1 -yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. The term “isoindolyl” as used herein includes isoindol-1 -yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl and isoindol-7-yl. The term “benzofuranyl” (also called benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl. The term “isobenzofuranyl” (also called benzo[c]furanyl) as used herein includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl and isobenzofuran-7-yl. The term “benzothiophenyl” (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4- benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7-benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl). The term “isobenzothiophenyl” (also called benzo[c]thienyl) as used herein includes isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl and isobenzothien-7-yl. The term “indazolyl” (also called 1 H-indazolyl or 2-azaindolyl) as used herein includes 1 H- indazol-1 -yl, 1 H-indazol-3-yl, 1 H-indazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol- 7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H-indazol-7-yl. The term “benzimidazolyl” as used herein includes benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term “1 ,3-benzoxazolyl” as used herein includes 1 ,3-benzoxazol-2- yl, 1 ,3-benzoxazol-4-yl, 1 ,3-benzoxazol-5-yl, 1 ,3-benzoxazol-6-yl and 1 ,3-benzoxazol-7-yl. The term “1 ,2-benzisoxazolyl” as used herein includes 1 ,2-benzisoxazol-3-yl, 1 ,2- benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1 ,2-benzisoxazol-6-yl and 1,2-benzisoxazol-7-yl. The term “2,1-benzisoxazolyl” as used herein includes 2,1-benzisoxazol-3-yl, 2,1- benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl, 2,1-benzisoxazol-6-yl and 2,1-benzisoxazol-7-yl. The term “1,3-benzothiazolyl” as used herein includes 1,3-benzothiazol-2-yl, 1,3- benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1 ,3-benzothiazol-6-yl and 1,3-benzothiazol-7-yl. The term “1,2-benzoisothiazolyl” as used herein includes 1,2-benzisothiazol-3-yl, 1,2- benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl and 1,2- benzisothiazol-7-yl. The term “2,1 -benzoisothiazolyl” as used herein includes 2,1- benzisothiazol-3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6- yl and 2,1-benzisothiazol-7-yl. The term “benzotriazolyl” as used herein includes benzotriazol- 1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7- yl. The term “1,2,3-benzoxadiazolyl” as used herein includes 1,2,3-benzoxadiazol-4-yl,

[0078] 1.2.3-benzoxadiazol-5-yl, 1 ,2,3-benzoxadiazol-6-yl and 1,2,3-benzoxadiazol-7-yl. The term “2,1,3-benzoxadiazolyl” as used herein includes 2,1 ,3-benzoxadiazol-4-yl, 2,1,3- benzoxadiazol-5-yl, 2,1,3-benzoxadiazol-6-yl and 2,1 ,3-benzoxadiazol-7-yl. The term “1 ,2,3-benzothiadiazolyl” as used herein includes 1,2,3-benzothiadiazol-4-yl, 1,2,3- benzothiadiazol-5-yl, 1,2,3-benzothiadiazol-6-yl and 1,2,3-benzothiadiazol-7-yl. The term “2,1,3-benzothiadiazolyl” as used herein includes 2,1,3-benzothiadiazol-4-yl, 2,1,3- benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-6-yl and 2,1,3-benzothiadiazol-7-yl. The term “thienopyridinyl” as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl. The term “purinyl” as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term “imidazo[1 ,2-a]pyridinyl”, as used herein includes imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2- a]pyridin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl and imidazo[1,2- a]pyridin-7-yl. The term “1,3-benzodioxolyl”, as used herein includes 1,3-benzodioxol-4-yl,

[0079] 1.3-benzodioxol-5-yl, 1 ,3-benzodioxol-6-yl, and 1,3-benzodioxol-7-yl. The term “quinolinyl” as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6- yl, quinolin-7-yl and quinolin-8-yl. The term “isoquinolinyl” as used herein includes isoquinolin-1 -yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The term “cinnolinyl” as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term “quinazolinyl” as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5- yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term “quinoxalinyl” as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl. Heteroaryl and heterocyclyl as used herein includes by way of example the groups described in Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C.W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.

[0080] Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected.

[0081] The term « xylene » as used herein refers to dimethylbenzene ; in particular this term refers to 1 ,2-dimethylbenzene (o-xylene), 1 ,3-dimethylbenzene (m-xylene) and 1 ,4- dimethylbenzene (p-xylene).

[0082] The term « dichlorobenzene » as used herein refers to all dichlorobenzene isomers. In particular this term refers to 1 ,2-dichlorobenzene (o-dichlorobenzene), 1 ,3- dichlorobenzene (m-dichlorobenzene) and 1,4-dichlorobenzene (p- dichlorobenzene).

[0083] The term « trimethylbenzene » as used herein refers to all trimethylbenzene isomers. In particular this term refers to 1 ,2,3-trimethylbenzene (hemimellitene), 1 ,2,4- trimethylbenzene (pseudocumene), and 1,3,5-trimethylbenzene (mesitylene).

[0084] The term « propanol » as used herein refers to all propanol isomers. In particular this term refers to 1 -propanol and 2-propanol.

[0085] The term « butanol » as used herein refers to all butanol isomers. In particular this term refers to 1 -butanol, 2- butanol, tert-butanol and / so-butanol.

[0086] The term « propylacetate » as used herein refers to all propylacetate isomers. In particular this term refers to n-propylacetate and / so-propylacetate.

[0087] The term « butylacetate » as used herein refers to all butylacetate isomers. In particular this term refers to n-butylacetate, / so-butylacetate , tert-butylacetate and secbutylacetate .

[0088] As used herein, the term “salt” refers to a chemical compound consisting of an ionic assembly of positively charged cations and negatively charged anions. Preferably, the anion or cation is an organic molecule. In another preferred embodiment, the anion or cation is an organic molecule. Some preferred, but non-limiting examples of suitable organic and / or inorganic acids or bases are sodium hydroxide, potassium hydroxide, ammonium hydroxide, tetrabutylammonium hydroxide, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid. When the compounds contain an acidic group as well as a basic group the compounds may also form internal salts, and such compounds are within the scope of the invention. When the compounds contain a hydrogen-donating heteroatom, the invention also covers salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

[0089] Salts of compounds of formula (II) may be prepared by one or more of these methods:

[0090] (i) by reacting the compound of formula (II) with the desired acid;

[0091] (ii) by reacting the compound of formula (II) with the desired base;

[0092] (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (II) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or

[0093] (iv) by converting one salt of the compound of formula (II) to another by reaction with an appropriate acid or by means of a suitable ion exchange, preferably by using an ion exchange column.

[0094] All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost nonionized.

[0095] Salts of the compounds of formula (II) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include ammonium, aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. The term “continuous flow conditions” encompasses processes developed in continuous flow micro- and / or macro / mesofluidic reactors. These continuous flow processes may encompass one or several chemical steps or downstream processing steps in a fluidic module or a combination of fluidic modules fluidically connected in series or in parallel. A microfluidic reactor is a type of continuous flow reactor encompassing a reaction channel with an internal dimension ranging from 1 to 800 micrometers, but preferably between 100-800 micrometers and more specifically between 500 and 750 micrometers and with an internal volume ranging from 0.1 to 20 mL, but preferably between 0.5 and 15 mL and more specifically between 0.75 and 10 mL. A microfluidic reactor can be constructed from various materials, including, but not restricted to, stainless steel, copper, alloys, glass, ceramics and polymer materials. A macro / mesofluidic reactor is a type of continuous flow reactor encompassing a reaction channel with internal dimension ranging from 800 to 50000 micrometers, preferably ranging from 800 and 20000 micrometers, preferably ranging from 800 and 15000 micrometers, for example ranging from 800 to 5000 micrometers, for example ranging from between 800 and 2000 micrometers and for example ranging from 800 and 1500 micrometers; and with an internal volume ranging from 1 to 20000 mL, preferably ranging from 1 to 18000, preferably ranging from 1 to 15000 mL, preferably ranging from 1 to 12000 mL, preferably ranging from 1 to 10000, preferably ranging from 1 to 6000 mL, preferably ranging from 2.5 and 500 mL and preferably ranging from 5 and 200 mL. A macro / mesofluidic reactor can be constructed from various materials, including, but not restricted to, stainless steel, copper, alloys, glass, ceramics and polymer materials. Downstream processing steps are defined as post-reactional treatment, including, but not restricted to, extractions, separation, adding a solvent or an additive, precipitating, filtrating, drying and in-line analysing. A fluidic module can be composed either of a microfluidic or a macro / mesofluidic reactor. Fluidic modules can be fluidically connected in series or in parallel. Fluidic modules can be integrated with static mixers, heat exchangers, injection points, sampling valves, pressure regulators and in-line analytics.

[0096] Preferred statements (features) and embodiments and uses of this invention are set herein below. Each statement and embodiment of the invention so defined may be combined with any other statement and / or embodiment unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features or statements indicated as being preferred or advantageous. Hereto, the present invention is in particular captured by any one or any combination of one or more of the below numbered statements and embodiments, with any other aspect and / or embodiment.

[0097] 1. A process for the preparation of a compound of formula (II), a stereoisomer, a salt, a hydrate or a solvate thereof, comprising the step of sulfinylation of a compound of formula (IV) to produce compound of formula (II); wherein:

[0098] R1is selected from the group comprising, R3Si(R4)(R5)-, Ci-ealkyl, Ce- aryl, Ce-warylCi- ealkyl, -CH2-CH=CRaRb, Ci-ealkoxy, and Cs-ecycloalkyl; each of said Ci-ealkyl, Ce- aryl, Ce- arylCiwalkyl, and Cs-ecycloalkyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, Ce- aryl, heterocyclyl, and nitro;

[0099] R2is Ce-waryl, or heteroaryl; wherein each Ce-waryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, C2-ealkenyl, C2- ealkynyl, Ce-waryl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, -SR8, NR9R10, cyano and nitro;

[0100] R3, R4and R5are each independently Ci-ealkyl or Ce-waryl, wherein each Ci-ealkyl or Ce-waryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci- ealkoxy, and haloCi-ealkoxy; preferably fluoro, chloro or Ci-4alkyl; R6, R8and R8are each independently selected from the group consisting of Ci-ealkyl, Ce- aryl, and Cs-ecycloalkyl, wherein each Ci-ealkyl, Ce-waryl, or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; R9and R10are each independently selected from the group consisting of hydrogen, Ci- ealkyl, Ce-i2aryl, Cs-ecycloalkyl, wherein each Ci-ealkyl, Ce- aryl, or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy;

[0101] Raand Rbare each independently hydrogen, Ci-ealkyl or Ce- aryl; wherein said sulfinylation step is performed in the presence of a solvent selected from the group comprising benzene, toluene, ethylbenzene, xylene, chlorobenzene, bromobenzene, fluorobenzene, anisole, nitrobenzene, tetralin, dichlorobenzene, trimethylbenzene, ethylacetate, propylacetate, butylacetate, propanol, butanol, 2- methyltetrahydrofuran, diethylether, methyltertbutylether, cyclopentyl methyl ether, dichloromethane, tetrachloromethane, pentane, hexane, heptane, cyclohexane, decaline and mixtures thereof. The process according to statement 1 , wherein said sulfinylation step is performed by reaction of compound of formula (IV) with at least one sulfinylation reagent, preferably in the presence of at least one base.

[0102] The process according to statement 1 or 2, wherein said sulfinylation step is performed by reaction of compound of formula (IV) with at least one sulfinylation reagent selected from the group comprising methyl benzenesulfinate, methyl 2- pyridinesulfinate, methyl 4-chloro-benzene sulfinate, methyl 4-bromo-benzene sulfinate, methyl 4-nitro-benzenesufinate, methyl 4-methyl-benzenesufinate, methyl 4- methoxy-benzene sulfinate, methyl 2,3,4,5,6-pentafluorobenzenesulfinate, methyl 2,3,4,5,6-pentachlorobenzenesulfinate, methyl-4-(trifluoromethylsulfonyl)- benzenesulfinate, 1 -(4-methylsulfnylphenyl)ethanone, methyl-4-cyano- benzenesulfinate, methyl-4-(dimethylamino)-benzenesulfinate, and methyl 4-(2- benzothiazolyl)-benzenesulfinate; preferably selected from methyl benzenesulfinate, methyl 2-pyridinesulfinate, methyl 4-chloro-benzene sulfinate, methyl 4-bromo- benzene sulfinate, methyl 4-nitro-benzenesufinate, methyl 4-methyl-benzenesufinate, methyl 4-methoxy-benzene sulfinate, methyl 2,3,4,5,6-pentafluorobenzenesulfinate, methyl 2,3,4,5,6-pentachlorobenzenesulfinate and methyl-4-(dimethylamino)- benzenesulfinate; preferably selected from methyl benzenesulfinate, methyl 2- pyridinesulfinate, methyl 4-chloro-benzene sulfinate, methyl 4-bromo-benzene sulfinate, methyl 4-nitro-benzenesufinate, methyl 4-methyl-benzenesufinate and methyl 4-methoxy-benzene sulfinate. The process according to any one of statements 1 to 3, wherein said sulfinylation step is performed by reaction of compound of formula (IV) with at least one sulfinylation reagent, and wherein the at least one sulfinylation reagent is present in an amount of at least 1.0 to at most 10.0 equivalents; preferably at least 1.0 to at most 8.0 equivalents; preferably at least 1.0 to at most 7.0 equivalents; preferably at least 1.1 to at most 6.0 equivalents; preferably at least 1.2 to at most 5.5 equivalents; preferably at least 1.3 to at most 5.0 equivalents; preferably at least 1.5 to at most 5.5 equivalents; preferably at least 1.7 to at most 5.0 equivalents; preferably at least 2.0 to at most 8.0 equivalents; preferably at least 2.0 to at most 7.0 equivalents; preferably at least 2.0 to at most 5.0 equivalents. The process according to any one of statements 1 to 4, wherein the sulfinylation reaction is performed in the presence of at least one base selected from the group comprising potassium hydride, potassium tert-butylate, sodium hydride, sodium tert- butylate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and a mixture thereof. The process according to any one of statements 1 to 5, wherein: R1is R3Si(R4)(R5)-;

[0103] R2is Ce-waryl, or heteroaryl; wherein each Ce-waryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, C2-ealkenyl, C2- ealkynyl, Ce- aryl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, -SR8, NR9R10, cyano and nitro; preferably from the group consisting of fluoro, chloro, bromo, nitro, Ci-4alkyl, Ci-4alkyloxy, haloCi-4alkyloxy, C2-4alkenyl, C2-4alkynyl, phenyl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, Ci-ealkylthio, amino, mono-Ci-4alkylamino, di-Ci-4alkylamino, cyano; preferably, R2is Ce-waryl, or 5-6 membered heteroaryl containing at least one N and / or S; wherein each Ce-waryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, C2-ealkenyl, C2-ealkynyl, Ce-waryl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, -SR8, -NR9R10, cyano and nitro; preferably from the group consisting of fluoro, chloro, bromo, nitro, Chalky I, Ci-4alkyloxy, haloCi- 4alkyloxy, C2-4alkenyl, C2-4alkynyl, phenyl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7Ci-ealkylthio, - amino, mono-Ci-4alkylamino, di-Ci-4alkylamino, cyano; preferably, R2is Ce-waryl, or 5-6 membered heteroaryl containing at least one N; wherein each Ce-waryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci- ealkoxy, haloCi-ealkoxy, C2-ealkenyl, C2-ealkynyl, Ce-waryl, heterocyclyl, heteroaryl, - S(O)2R6, -S(O)R7, -SR8, -NR9R10, cyano and nitro; preferably from the group consisting of fluoro, chloro, bromo, nitro, Ci-4alkyl, Ci-4alkyloxy, haloCi-4alkyloxy, C2-4alkenyl, C2- 4alkynyl, phenyl, heterocyclyl, heteroaryl, -S(O)2R7, -S(O)R7, Ci-ealkylthio, amino, mono-Ci-4alkylamino, di-Ci-4alkylamino, cyano; preferably R2is phenyl, or pyridinyl; wherein each phenyl or pyridinyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, C2-ealkenyl, C2-ealkynyl, Ce-waryl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, -SR8, -NR9R10, cyano and nitro; preferably from the group consisting of fluoro, chloro, bromo, nitro, Chalky I, Ci-4alkyloxy, haloCi- 4alkyloxy, C2-4alkenyl, C2-4alkynyl, phenyl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, Ci-ealkylthio, amino, mono-Ci-4alkylamino, di-Ci-4alkylamino, cyano;

[0104] R3, R4and R5are each independently Ci-ealkyl or Ce-waryl, wherein each Ci-ealkyl or Ce-waryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci- ealkoxy, and haloCi-ealkoxy; preferably fluoro, chloro or Ci-4alkyl; preferably R3, R4and R5are each independently Ci-ealkyl or phenyl, wherein each Ci-ealkyl or phenyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi- ealkoxy; preferably fluoro, chloro or Ci-4alkyl; and

[0105] R6, R7and R8are each independently selected from the group consisting of Ci-ealkyl, Ce- aryl, and Cs-ecycloalkyl, wherein each Ci-ealkyl, Ce- aryl, or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; preferably R6, R7and R8are each independently Ci-4alkyl, phenyl, and Cs-ecycloalkyl wherein each Ci-4alkyl, phenyl or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci- ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; preferably from the group consisting of fluoro, chloro, bromo, Ci-4alkyl, Ci-4alkyloxy, and haloCi-4alkyloxy;

[0106] R9and R10are each independently selected from the group consisting of Ci-ealkyl, Ce- aryl, Cawcycloalkyl; wherein each Ci-ealkyl, Ce- aryl, or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; preferably R11and R12are each independently Ci-4alkyl, phenyl, and Cs-ecycloalkyl wherein each Ci-4alkyl, phenyl or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; preferably from the group consisting of fluoro, chloro, bromo, Ci-4alkyl, Ci-4alkyloxy, and haloCi-4alkyloxy. The process according to any one of statements 1 to 6, wherein the sulfinylation step is performed in the presence of a solvent selected from the group comprising benzene, toluene, ethylbenzene, xylene, chlorobenzene, bromobenzene, fluorobenzene, anisole, tetralin, dichlorobenzene, trimethylbenzene, ethylacetate, propylacetate, butylacetate, propanol, butanol, 2-methyltetrahydrofuran, methyltertbutylether, cyclopentyl methyl ether, dichloromethane, tetrachloromethane, pentane, hexane, heptane, cyclohexane, decaline and mixtures thereof; preferably selected from the group comprising benzene, toluene, ethylbenzene, xylene, chlorobenzene, bromobenzene, fluorobenzene, anisole, tetralin, dichlorobenzene, trimethylbenzene, butylacetate, propanol, 2-methyltetrahydrofuran, methyltertbutylether, cyclopentyl methyl ether, dichloromethane, hexane, cyclohexane, decaline and mixtures thereof; preferably selected from the group comprising benzene, toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, fluorobenzene, anisole, dichlorobenzene, trimethylbenzene, iso-propylacetate, tert-butylacetate , secbutylacetate, 2-propanol, 2-methyltetrahydrofuran, methyltertbutylether, cyclopentyl methyl ether, cyclohexane and mixtures thereof.

[0107] 8. The process according to any one of statements 1 to 7, wherein compound of formula (II) is a compound of formula (II’) and compound of formula (IV) is a compound of formula (IV’)

[0108] 9. The process according to any one of statements 1 to 8, wherein compound of formula (IV) is obtained by a process comprising the step of protecting the hydroxyl of a compound of formula (III) to produce a compound of formula (IV)

[0109] 10. The process according to any one of statements 1 to 9, further comprising the step of desulfynilating a compound of formula (II) to produce a compound of formula (I),

[0110] (I).

[0111] 11. The process according to statement 10, wherein the desulfinylation step is performed by thermolysis.

[0112] 12. The process according to any one of statements 10 or 11 , wherein said desulfinylation step is performed by a continuous flow process.

[0113] 13. The process according to any one of statements 10 to 12, wherein said desulfinylation step is performed by thermolysis, at a thermolysis temperature, T, of at least 100°C; preferably at a temperature of at least 110°C, preferably at a temperature of at least 120°C; preferably at a temperature of at least 130°C; preferably at a temperature of at least 140°C; preferably at a temperature of at least 150°C; preferably at a temperature of at least 160°C; preferably at a temperature of at least 170°C; preferably at a temperature of at least 175°C; preferably at a temperature of at least 180°C. The process according to any one of statements 10 to 14, wherein said desulfinylation step is performed by thermolysis, at a thermolysis temperature, T, of at least 100°C to at most 300°C; preferably at a temperature of at least 120°C to at most 300°C; preferably at a temperature of at least 140°C to at most 300°C; preferably at a temperature of at least 160°C to at most 300°C; preferably at a temperature of at least 170°C to at most 290°C; preferably at a temperature of at least 175°C to at most 280°C; preferably at a temperature of at least 175°C to at most 270°C; preferably at a temperature of at least 175°C to at most 260°C; preferably at a temperature of at least 175°C to at most 250°C; preferably at a temperature of at least 175°C to at most 240°C; preferably at a temperature of at least 175°C to at most 230°C; preferably at a temperature of at least 180°C to at most 230°C; preferably at a temperature of at least 180° to at most 220°C; preferably at a temperature of at least 190° to at most 220°C; preferably at a temperature of at least 200° to at most 220°C; preferably at a temperature of at least 190°C to at most 215°C; preferably at a temperature of at least 205°C to at most 215°C. The process according to any one of statements 10 to 15, wherein said desulfinylation step is performed by thermolysis, wherein said thermolysis is performed at a pressure, P, of at least 1 bar, preferably at a pressure of at least 2.0 bar; preferably at a pressure of at least 3.0 bar; preferably at a pressure of at least 4.0 bar; preferably at a pressure of at least 5.0 bar. The process according to any one of statements 10 to 15, wherein said desulfinylation step is performed by thermolysis, wherein said thermolysis is performed at a pressure, P, of at least 1.0 bar to at most 60.0 bar; preferably at least 3.0 bar to at most 60.0 bar; preferably at a pressure of at least 5.0 bar to at most 60.0 bar; preferably at a pressure of at least 10.0 to at most 55.0 bar; preferably at a pressure of at least 12.0 to at most 50.0 bar; preferably at a pressure of at least 20.0 to at most 50.0 bar; preferably at a pressure of at least 25.0 to at most 45.0; preferably at a pressure of at least 30.0 to at most 40.0 bar; preferably at a pressure of at least 12.0 to at most 40.0 bar; preferably at a pressure of at least 12.5 to at most 35.0 bar; preferably at a pressure of at least 15.0 to at most 35.0 bar. The process according to any one of statements 10 to 16, wherein said desulfinylation step is performed by thermolysis, for a thermolysis time, t, of at most 60 min; preferably of at most 40 min, preferably of at most 30 min; preferably at most 25 min; preferably at most 20 min; preferably at most 18 min. The process according to any one of statements 10 to 17, wherein said desulfinylation step is performed by thermolysis, for a thermolysis time, t, of at least 0.1 min, preferably of at least 0.3 min; preferably at least 0.5 min; preferably at least 0.7 min; preferably at least 0.9 min; preferably at least 1.0 min. The process according to any one of statements 10 to 18, wherein said desulfinylation step is performed by thermolysis, for a thermolysis time, t, of at least 0.1 min to at most 30 min; preferably at least 0.5 min to at most 30 min; preferably at least 1.0 min to at most 25 min; preferably at least 1.0 min to at most 20 min, preferably at least 1.0 min to at most 15 min; preferably at least 2 min to at most 10 min, preferably at least 2 min to at most 8 min; preferably at least 3 min to at most 8 min; preferably at least 3 min to at most 6 min; preferably at least 3 min to at most 10 min, preferably at least 4 min to at most 8 min; preferably at least 5 min to at most 8 min. The process according to any one of statements 10 to 19, wherein the desulfinylation step is performed in at least one diluent; preferably performed in solution; preferably performed using at least one solution. The process according to any one of statements 10 to 20, wherein the desulfinylation step is performed in at least one diluent and compound of formula (II) is present in the at least one diluent in an amount of at least 0.01 mole / L of diluent; preferably of at least 0.02 mole / L; preferably of at least 0.05 mole / L; preferably of at least 0.10 mole / L of diluent. The process according to any one of statements 10 to 21, wherein the desulfinylation step is performed in at least one diluent and compound of formula (II) is present in the at least one diluent in an amount of at most 5.0 mole / L of diluent; preferably of at most 4.0 mole / L; preferably of at most 3.0 mole / L; preferably of at most 2.0 mole / L; preferably of at most 1.0 mole / L of diluent. The process according to any one of statements 10 to 22, wherein the desulfinylation step is performed in at least one diluent and compound of formula (II) is present in the at least one diluent in an amount of at least 0.01 mole / L to at most 5.0 mole / L of diluent; preferably of at least 0.01 mole / L to at most 3.0 mole / L; preferably of at least 0.01 mole / L to at most 1.0 mole / L; preferably of at least 0.01 mole / L to at most 0.80 mole / L; preferably at least 0.02 mole / L to at most 0.70 mole / L; preferably at least 0.05 mole / L to at most 0.60 mole / L; preferably at least 0.06 mole / L to at most 0.56 mole / L; preferably at least 0.10 mole / L to at most 0.55 mole / L; preferably at least 0.15 mole / L to at most 0.50 mole / L; preferably at least 0.15 mole / L to at most 0.45 mole / L; preferably at least 0.15 mole / L to at most 0.40 mole / L; preferably at least 0.15 mole / L to at most 0.35 mole / L; preferably at least 0.15 mole / L to at most 0.30 mole / L; preferably at least 0.15 mole / L to at most 0.25 mole / L of diluent. The process according to any one of statements 10 to 23, wherein the desulfinylation step is performed in at least one diluent and compound of formula (II) is present in the at least one diluent in an amount of at least 0.01 mole / L to at most 5.0 mole / L; preferably of at least 0.01 mole / L to at most 4.0 mole / L; preferably of at least 0.01 mole / L to at most 2.0 mole / L; preferably of at least 0.01 mole / L to at most 0.90 mole / L; preferably at least 0.02 mole / L to at most 0.80 mole / L; preferably at least 0.05 mole / L to at most 0.70 mole / L; preferably at least 0.06 mole / L to at most 0.56 mole / L; preferably at least 0.06 mole / L to at most 0.40 mole / L; preferably at least 0.06 mole / L to at most 0.30 mole / L; preferably at least 0.06 mole / L to at most 0.25 mole / L of diluent The process according to any one of statements 10 to 24, wherein the desulfinylation step is performed in at least one diluent and compound of formula (II) is present in the at least one diluent in the form of a solution of the said at least one diluent. The process according to any one of statements 10 to 25, comprising the following steps:

[0114] (a) forming a mixture by contacting a compound of formula (II) with: at least one diluent; optionally at least one scavenger; and optionally at least one base (organic or inorganic), preferably at least one organic base; or optionally no base is used;

[0115] (b) feeding the mixture to an inlet of a channel of a reaction zone, (c) driving a flow of the mixture along the channel from the inlet to an outlet, to form reaction products including at least compound of formula (I);

[0116] (d) recovering the reaction products at the outlet and

[0117] (e) optionally separating the at least one compound of formula (I) from the other reaction products or keeping the compound of formula (I) in the reaction products.

[0118] 27. The process according to any one of statements 10 to 26, comprising the following steps:

[0119] (a) forming a solution by contacting a compound of formula (II) with: at least one solvent; optionally at least one scavenger; and optionally at least one base (organic or inorganic), preferably at least one organic base, or optionally no base is used;

[0120] (b) feeding the solution to an inlet of a channel of a reaction zone,

[0121] (c) driving a flow of the solution along the channel from the inlet to an outlet, to form reaction products including at least compound of formula (I);

[0122] (d) recovering the reaction products at the outlet and

[0123] (e) optionally separating the at least one compound of formula (I) from the other reaction products or keeping the compound of formula (I) in the reaction products.

[0124] 28. The process according to statements 26 or 27, further comprising the steps of

[0125] (d1) feeding the reaction products from step (d) to an inlet of a channel of a cooling zone,

[0126] (d2) exposing the reaction products from step (d) to cooling by driving a flow of the reaction products along the channel from the inlet to an outlet, for a cooling time, tc, and at a cooling temperature, Tc; and

[0127] (d3) recovering the cooled reaction products at the outlet of the cooling zone.

[0128] 29. The process according to any one of statements 26 to 28, wherein the reaction zone is a thermolysis reaction zone and step (c) comprises exposing the mixture to thermolysis by driving a flow of the mixture along the channel from the inlet to the outlet, for a thermolysis time, t, at a pressure, P, and at a thermolysis temperature, T, to form thermolysis reaction products including at least compound of formula (I). The process according to anyone of statements 26 to 29, wherein the reaction of step (c) is carried out at a pressure, P, of at least 1.0 bar, preferably at least 2.0 bar; preferably at least 3.0 bar; preferably at least 4.0 bar; preferably at least 5.0 bar; preferably said reaction of step (c) is a thermolysis reaction carried out at a pressure, P, as described herein above. The process according to any one of statements 26 to 30, wherein the reaction of step (c) is carried out at a pressure, P, of at least 1.0 bar to at most 60.0 bar; preferably at least 3.0 bar to at most 60.0 bar; preferably at least 5.0 bar to at most 60.0 bar; preferably at a pressure of at least 10.0 to at most 55.0 bar; preferably at a pressure of at least 20.0 to at most 50.0 bar; preferably at a pressure of at least 30.0 to at most 40.0, preferably at a pressure of at least 10.0 to at most 40.0 bar, preferably a ta pressure of at least 10 to at most 30.0 bar, preferably at a pressure of at least 12.0 to at most 50.0 bar; preferably at a pressure of at least 12.0 to at most 40.0 bar; preferably at a pressure of at least 11.0 to at most 35.0 bar; preferably said reaction of step (c) is a thermolysis reaction carried out at a pressure, P, as described herein above. The process according to any one of statements 26 to 31, wherein the reaction of step (c) is carried for a reaction time, t, of at most 60 min; preferably of at most 40 min, preferably of at most 30 min; preferably at most 25 min; preferably at most 20 min; preferably at most 18 min; preferably said reaction of step (c) is a thermolysis reaction carried out for a thermolysis time, t, as described herein above. The process according to any one of statements 26 to 32, wherein the reaction of step (c) is carried for a reaction time, t, of at least 0.1 min; preferably at least 0.3 min; preferably at least 0.5 min; preferably at least 0.7 min; preferably at least 0.9 min; preferably at least 1.0 min; preferably said reaction of step (c) is a thermolysis reaction carried out for a thermolysis time, t, as described herein above The process according to any one of statements 26 to 33, wherein the reaction of step (c) is carried for a reaction time, t, of at least 0.1 min to at most 30 min; preferably at least 0.3 min to at most 30 min; preferably at least 0.5 min to at most 30 min; preferably at least 1.0 min to at most 25 min; preferably at least 1.0 min to at most 20 min, preferably at least 1.0 min to at most 15 min; preferably at least 1.5 min to at most 10 min, preferably at least 1.5 min to at most 8 min; preferably at least 2.5 min to at most 8 min; preferably at least 2.0 min to at most 6 min; preferably at least 2.5 min to at most 10 min, preferably at least 4.0 min to at most 8.0 min, preferably at least 5.0 min to at most 8.0 min, preferably said reaction of step (c) is a thermolysis reaction carried out for a thermolysis time, t, as described herein above.

[0129] 35. The process according to any one of statements 26 to 34, wherein the reaction of step (c) is carried at a reaction temperature, T, of at least 100°C; preferably at a temperature of at least 110°C, preferably at a temperature of at least 120°C; preferably at a temperature of at least 130°C; preferably at a temperature of at least 140°C; preferably at a temperature of at least 150°C; preferably at a temperature of at least 160°C; preferably at a temperature of at least 170°C; preferably at a temperature of at least 175°C; preferably at a temperature of at least 180°C; preferably said reaction of step (c) is a thermolysis reaction carried out at a thermolysis temperature, T, as described herein above.

[0130] 36. The process according to any one of statements 26 to 35, wherein the reaction of step (c) is carried at a reaction temperature, T, of at least 100°C to at most 300°C; preferably at a temperature of at least 120°C to at most 300°C; preferably at a temperature of at least 140°C to at most 300°C; preferably at a temperature of at least 160°C to at most 300°C; preferably at a temperature of at least 170°C to at most 290°C; preferably at a temperature of at least 175°C to at most 280°C; preferably at a temperature of at least 175°C to at most 270°C; preferably at a temperature of at least 175°C to at most 260°C; preferably at a temperature of at least 175°C to at most 250°C; preferably at a temperature of at least 175°C to at most 240°C; preferably at a temperature of at least 175°C to at most 230°C; preferably at a temperature of at least 180°C to at most 230°C; preferably at a temperature of at least 180° to at most 220 °C; preferably at a temperature of at least 190° to at most 220°C; preferably at a temperature of at least 200° to at most 220°C; preferably at a temperature of at least 190°C to at most 215°C; preferably at a temperature of at least 205°C to at most 215°C; preferably said reaction of step (c) is a thermolysis reaction carried out at a thermolysis temperature, T, as described herein above.

[0131] 37. The process according to any one of statements 26 to 36, wherein the cooling temperature, Tc, of step (d2) is of at least -10.0°C to at most 20.0°C, preferably of at least -5.0°C to at most 20.0°C, preferably of at least -5.0°C to at most 15.0°C, preferably of at least -5.0°C to at most 10.0°C; preferably at a temperature of at least - 4.0°C to at most 8.0°C; preferably at a temperature of at least -3.0°C to at most 7.0°C; preferably at a temperature of at least -2.0 °C to at most 6.0°C; preferably at a temperature of at least -1 ,0°C to at most 5.0°C.

[0132] 38. The process according to any one of statements 26 to 37, wherein the cooling is carried out at the same pressure as reaction step (c).

[0133] 39. The process according to any one of statements 26 to 38, wherein the cooling is carried out at atmospheric pressure.

[0134] 40. The process according to any one of statements 26 to 39, wherein the cooling time, tc, of step (d2) is of at most 120 min; preferably of at most 60 min, preferably at most 30 min, preferably at most 25 min; preferably at most 15 min, preferably at most 10 min; preferably at most 5 min; preferably at most 3 min; preferably at most 1 min.

[0135] 41. The process according to any one of statements 26 to 40, wherein the cooling time, tc, of step (d2) is of at least 0.08 min to at most 20 min; preferably at least 0.08 min to at most 15 min; preferably at least 0.08 min to at most 10 min; preferably at least 0.08 min to at most 5 min; preferably at least 0.1 min to at most 4 min; preferably at least 0.1 min to at most 3 min; preferably at least 0.4 min to at most 3 min; preferably at least 0.4 min to at most 2 min; preferably at least 0.4 min to at most 1.5 min; preferably at least 0.4 min to at most 1.2 min; preferably at least 0.5 min to at most 1.2 min.

[0136] 42. The process according to any one of statements 26 to 41 , wherein compound of formula (II) is present in the mixture of step (a) in an amount of at least 0.01 mole / L of diluent; preferably of at least 0.02 mole / L; preferably of at least 0.05 mole / L; preferably of at least 0.10 mole / L; preferably of at most 5.0 mole / L; preferably of at most 4.0 mole / L; preferably of at most 3.0 mole / L; preferably of at most 2.0 mole / L; preferably of at most 1.0 mole / L of diluent.

[0137] 43. The process according to any one of statements 26 to 42, wherein compound of formula (II) is present in the mixture of step (a) in an amount of at least 0.01 mole / L to at most 5.0 mole / L of diluent; preferably of at least 0.01 mole / L to at most 3.0 mole / L; preferably of at least 0.01 mole / L to at most 1.0 mole / L; preferably of at least 0.01 mole / L to at most 0.80 mole / L; preferably at least 0.02 mole / L to at most 0.70 mole / L; preferably at least 0.05 mole / L to at most 0.60 mole / L; preferably at least 0.06 mole / L to at most 0.56 mole / L; preferably at least 0.10 mole / L to at most 0.55 mole / L; preferably at least 0.15 mole / L to at most 0.50 mole / L; preferably at least 0.15 mole / L to at most 0.45 mole / L; preferably at least 0.15 mole / L to at most 0.40 mole / L; preferably at least 0.15 mole / L to at most 0.35 mole / L; preferably at least 0.15 mole / L to at most 0.30 mole / L; preferably at least 0.15 mole / L to at most 0.25 mole / L of diluent. The process according to any one of statements 26 to 43, wherein compound of formula (II) is present in the mixture of step (a) in an amount of at least 0.01 mole / L to at most 5.0 mole / L of diluent; preferably of at least 0.01 mole / L to at most 4.0 mole / L; preferably of at least 0.01 mole / L to at most 2.0 mole / L; preferably of at least 0.01 mole / L to at most 0.90 mole / L; preferably at least 0.02 mole / L to at most 0.60 mole / L; preferably at least 0.06 mole / L to at most 0.50 mole / L; preferably at least 0.06 mole / L to at most 0.40 mole / L; preferably at least 0.06 mole / L to at most 0.30 mole / L; preferably at least 0.06 mole / L to at most 0.25 mole / L of diluent. The process according to any one of statements 26 to 44, wherein compound of formula (II) is present in the solution of step (a) in an amount of at least 0.01 mole / L of solution; preferably of at least 0.02 mole / L; preferably of at least 0.05 mole / L; preferably of at least 0.10 mole / L; preferably of at most 5.0 mole / L; preferably of at most 4.0 mole / L; preferably of at most 3.0 mole / L; preferably of at most 2.0 mole / L; preferably of at most 1 .0 mole / L of solution. The process according to any one of statements 10 to 45, wherein the desulfinylation step is carried out in the presence of at least one scavenger. The process according to any one of statements 10 to 46, wherein the desulfinylation step is carried out in the presence of at least one scavenger, wherein the at least one scavenger is selected from the group comprising dialkyl acetylenedicarboxylate (such as dimethyl acetylenedicarboxylate (DMAD) or diethyl acetylenedicarboxylate (DEtAD)), triethylamine, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), 2,6-lutidine, diethyl fumarate (DEF), 2-mercaptobenzothiazole (MBT), 1 ,4-dimethoxybenzene, crotonaldehyde, cyclohexenone, 1 ,4-diazabicyclo[2.2.2]octane (DABCO), diisopropyl azodicarboxylate (DIAD), methyl propiolate, phenylacetylene, / V, / V- diisopropylethylamine (DIPEA), trimethyl phosphite (TMP), methanol, dimethylsulfoxide, p-benzoquinone; NaHCOs, K2CO3, Na2COs, CaCOs, CS2CO3; and a combination thereof; preferably the at least one scavenger is dialkyl acetylenedicarboxylate; preferably the at least one scavenger is DMAD; preferably the at least one scavenger is TEMPO; preferably the at least one scavenger is DABCO. The process according to any one of statements 10 to 47, wherein the desulfinylation step is carried out in the presence of at least one scavenger, and wherein the at least one scavenger is present in an amount of at least 0.1 to at most 10.0 equivalents; preferably in an amount of at least 0.2 to at most 9.0 equivalents; preferably in an amount of at least 0.3 to at most 8.5 equivalents; preferably in an amount of at least 0.2 to at most 8.0 equivalents; preferably in an amount of at least 0.5 to at most 7.0 equivalents; preferably in an amount of at least 0.5 to at most 5.0 equivalents; preferably 0.5 to at most 4.0 equivalents; preferably in an amount of at least 1.0 to at most 3.0 equivalents; preferably in an amount of at least 1.0 to at most 2.0 equivalents.

[0138] 49. The process according to any one of statements 10 to 48, wherein the desulfinylation step is carried out in the presence of two or more scavengers, and wherein the scavengers are present in an amount of at least 0.1 to at most 10.0 equivalents; preferably in an amount of at least 0.2 to at most 9.0 equivalents; preferably in an amount of at least 0.3 to at most 8.5 equivalents; preferably in an amount of at least 0.2 to at most 8.0 equivalents; preferably in an amount of at least 0.5 to at most 7.0 equivalents; preferably in an amount of at least 0.5 to at most 5.0 equivalents; preferably 0.5 to at most 4.0 equivalents; preferably in an amount of at least 1.0 to at most 3.0 equivalents; preferably in an amount of at least 1.0 to at most 2.0 equivalents.

[0139] 50. The process according to any one of statements 10 to 49, wherein the desulfinylation step is carried out in the absence of a base.

[0140] 51. The process according to any one of statements 10 to 49, wherein the desulfinylation step is carried out in the presence of at least one base; preferably at least one organic base.

[0141] 52. The process according to any one of statements 10 to 49, 51, wherein the desulfinylation step is carried out in the presence of at least one organic base, and wherein the at least one organic base is selected from the group comprising triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4- diazabicyclo[2.2.2]octane (DABCO), / V, / V-diisopropylethylamine (DI PEA), (2, 2,6,6- tetramethylpiperidin-1-yl)oxyl (TEMPO), imidazole, 2,6-lutidine, and a combination thereof; preferably the at least one organic base is triethylamine.

[0142] 53. The process according to any one of statements 10 to 49, 51 , 52, wherein the desulfinylation step is carried out in the presence of at least one organic base, and wherein the at least one organic base is present in an amount of at least 0.01 to at most 10.0 equivalents; preferably at least 0.01 to at most 5.0 equivalents; preferably 0.01 to at most 1.0 equivalents; preferably at least 0.01 to at most 0.9 equivalents; preferably at least 0.05 to at most 0.8 equivalents; preferably at least 0.05 to at most 0.5 equivalents, preferably 0.05 to at most 0.3 equivalents; preferably at least 0.05 to 0.2 equivalents.

[0143] 54. The process according to any one of statements 10 to 49, 51 to 53, wherein the desulfinylation step is carried out in the presence of two or more organic bases, and wherein the organic bases are present in combined amount of at least 0.01 to at most 10.0 equivalents; preferably at least 0.01 to at most 5.0 equivalents; preferably 0.01 to at most 1.0 equivalents; preferably at least 0.01 to at most 0.9 equivalents; preferably at least 0.05 to at most 0.8 equivalents; preferably at least 0.05 to at most 0.5 equivalents, preferably 0.05 to at most 0.3 equivalents; preferably at least 0.05 to 0.2 equivalents.

[0144] 55. The process according to any one of statements 10 to 54, wherein the desulfinylation step is carried out in the presence of at least one scavenger and at least one organic base.

[0145] 56. The process according to any one of statements 10 to 55, wherein the desulfinylation step is carried out in the presence of at least one diluent, preferably at least one solvent, preferably wherein the at least one solvent is selected from the group comprising toluene, o-xylene, m-xylene, p-xylene, 1,2-dichloroethane, chloroform, tetrachloromethane, tetra hydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methyl acetate, ethyl acetate, butyl acetate, iso-butyl acetate, n-butyl acetate, anisole, chlorobenzene, tetrahydrofuran, propan-2-one, butan-2-one, pentan- 2-one, 4-methylpentan-2-one, dichlorobenzene, dimethylformamide, dimethylacetamide, / V-methyl-2-pyrrolidone, dimethyl sulfoxide, / V, / V'- dimethylpropyleneurea, sulfolane, and a combination thereof.

[0146] 57. The process according to any one of statements 10 to 56, wherein the desulfinylation step is carried out in the presence of at least one diluent, preferably at least one solvent, preferably wherein the at least one solvent is selected from the group comprising toluene, o-xylene, 1,2-dichloroethane, chloroform, 2-methyltetrahydrofuran, ethyl acetate, anisole, chlorobenzene, tetrahydrofuran, acetone, dichlorobenzene, and a combination thereof.

[0147] The process according to statement 1 , wherein desulfinylation step is performed using a reducing agent; preferably the reducing agent is selected from the group of metal hydride compounds. The process according to statement 12, wherein the reducing agent is selected from the group comprising NaBH^CeCh, UAIH4, NaBH4, NaBH(OAc)3, and ZnBH4.

[0148] 58. Process for the preparation of estra-1 , 3, 5(10), -triene 3,15a,16a,17p-tetrol of formula (E), a stereoisomer, a salt, a hydrate, an ester, an ether or a solvate thereof, said process comprising the step of preparing a compound of formula (II) by a process according to any of statements 1 to 57, and further reacting compound of formula (II) to produce estra-1 ,3, 5(10), -triene 3,15a,16a,17p-tetrol of formula (E), a stereoisomer, a salt, a hydrate, an ester, an ether or a solvate thereof,

[0149] 59. Process according to statement 58, wherein estra-1 , 3, 5(10), -triene 3,15a,16a,17p- tetrol of formula (E) is estetrol of formula (E’),

[0150] Any reference to a “compound” also includes isomers such as stereoisomers and tautomers, salts such as pharmaceutically and / or physiologically acceptable salts, hydrates, ethers, esters, polymorphs and solvates of such compounds unless expressly indicated otherwise.

[0151] The term "isomers" as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formulae herein may possess, but not including position isomers. Typically, the structures shown herein exemplify one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well.

[0152] The compounds of the invention may exist in solvated and not solvated forms. The term “solvates” refers to crystals formed by an active compound and a second component (solvent) which, in isolated form, is liquid at room temperature. Alternatively, a solvate can be an amorphous solid. Such solvates may be formed with common organic solvents, e.g., hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol, or isopropanol; ethereal solvents such as diethyl ether or tetra hydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds herein may be formed with water, in which case they will be hydrates.

[0153] A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Britain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0154] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0155] Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug- host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see Chem. Commun., 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a general review of multi-component complexes, see J. Pharm. Sc / ., 64 (8), 1269-1288, by Haleblian (August 1975), incorporated herein by reference.

[0156] The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COO'Na+, -COO'K+, or -SC>3'Na+) or non-ionic (such as -N' N+(CHS)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970), incorporated herein by reference.

[0157] In the reactions described herein, it can be necessary to protect reactive functional groups, for example hydroxy, amino, or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1999.

[0158] The present inventors have surprisingly found that the choice of solvent in the sulfinylation reaction according to the present invention has an important impact on the reactivity of the compound of formula (IV), which has therefore an effect on the yield of this reaction. Indeed, the present inventors have found than when using solvents according to the present invention, the compound of formula (IV) undergoes very little deprotection (less than 5%) or no deprotection which allows that the yield of the reaction according to the present invention to be in the range of 95 to 100%.

[0159] In addition, the process according to the present invention allows to shorten the reaction time of the sulfinylation reaction. Under optimal reaction conditions, the reaction time can even be reduced to 15 minutes.

[0160] Furthermore, the compounds produced according to the present invention can be easily converted to: estetrol (estra-1 ,3,5(10)-triene-3, 15a, 16a, 17p-tetrol) and to salts, hydrates or solvates thereof; as well as to 1-, 2- or 4-alkyl estetrol compounds and salts, hydrates and solvates thereof.

[0161] The synthesis according to the present invention allows to produce estetrol intermediates in a high yield and with a very low level of impurities. This is advantageous, the process according to the present invention may be scaled up to facilitate industrial scale production of estetrol and derivatives thereof.

[0162] The present invention provides a process for the preparation of a compound of formula (II), a stereoisomer, a salt, a hydrate or a solvate thereof, comprising the step of sulfi nylation of a compound of formula (IV) to produce compound of formula (II); wherein:

[0163] R1is selected from the group comprising R3Si(R4)(R5)-, Ci-ealkyl, Ce- aryl, Ce-warylCi- ealkyl, -CH2-CH=CRaRb, Ci-ealkoxy, and Cs-ecycloalkyl each of said Ci-ealkyl, Ce- aryl, Ce- arylCiwalkyl, Cs-ecycloalkyl, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, Ce- aryl, heterocyclyl, and nitro; preferably R1is selected from the group comprising R3Si(R4)(R5)-, Ci-4alkyl, phenyl, Ce-warylCi^alkyl, - CH2-CH=CRaRb, Ci-4alkoxy, and Cs-ecycloalkyl ; each of said Ci-4alkyl, phenyl, Ce-warylCi- 4alkyl, or Cs-ecycloalkyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci- ealkoxy, haloCi-ealkoxy, and nitro; preferably R1is selected from the group comprising R3Si(R4)(R5)-, Ci-4alkyl, phenyl, Ce-warylCi^alkyl, -CH2-CH=CRaRb, Ci-4alkoxy, and C3- ecycloalkyl; each of said Ci-4alkyl, phenyl, Ce-warylCi^alkyl, or Cs-ecycloalkyl may be optionally substituted with one or more substituents each independently selected from the group consisting of fluoro, chloro, bromo, Ci-4alkyl, haloCi-4alkyl, Ci-4alkoxy, haloCi- 4alkoxy, and nitro; preferably R1is selected from the group comprising R3Si(R4)(R5)-, Ci- ealkyl, Ce-waryl, and Ce-warylCi-ealkyl ; each of said Ci-ealkyl, Ce-waryl, and Ce-warylCi- ealkyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi- ealkoxy, and nitro; preferably R1is selected from the group comprising R3Si(R4)(R5)-, Ci- ealkyl, Ce-waryl, and Ce-warylCi-ealkyl; preferably R1is R3Si(R4)(R5)-; preferably R1is selected from the group comprising R3Si(R4)(R5)-, Ci-4alkyl, Ce-waryl, and Ce-warylCi- 4alkyl; preferably R1is R3Si(R4)(R5)-;

[0164] R2is Ce-waryl, or heteroaryl; wherein each Ce-waryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, C2-ealkenyl, C2- ealkynyl, Ce-waryl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, -SR8, -NR9R10, cyano and nitro; preferably fluoro, chloro, bromo, nitro, Ci-4alkyl, Ci-4alkyloxy, haloCi-4alkyloxy Ce- waryl, heteroaryl, -S(O)2R6, -NR9R10or cyano; preferably, R2is Ce-waryl, or 5-6 membered heteroaryl containing at least one N and / or S; wherein each Ce- aryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, C2-ealkenyl, C2-ealkynyl, Ce-waryl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, -NR9R10, cyano and nitro; preferably fluoro, chloro, bromo, nitro, Ci-4alkyl, Ci-4alkyloxy, haloCi-4alkyloxy, C2- ealkenyl, C2-ealkynyl, Ce-waryl, heteroaryl, -S(O)2R6, -NR9R10or cyano; preferably, R2is Ce- waryl, or 5-6 membered heteroaryl containing at least one N; wherein each Ce-waryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi- ealkoxy, C2-ealkenyl, C2-ealkynyl, Ce-waryl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, - SR8, -NR9R10, cyano and nitro; preferably fluoro, chloro, bromo, nitro, Ci-4alkyl, C1- 4alkyloxy, haloCi-4alkyloxy, C2-ealkenyl, C2-ealkynyl, Ce-waryl, heteroaryl, -S(O)2R6, - S(O)R7, -NR9R10, or cyano;

[0165] R3, R4and R5are each independently Ci-ealkyl or Ce-waryl, wherein each Ci-ealkyl or Ce- waryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi- ealkoxy; preferably fluoro, chloro or Ci-4alkyl;

[0166] R6, R7, and R8are each independently selected from the group consisting of Ci-ealkyl, Ce- waryl, and Cs-ecycloalkyl, wherein each Ci-ealkyl, Ce-waryl, or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; preferably R6, R7, and R8are each independently selected from the group consisting of Ci-4alkyl, phenyl, and Cs-ecycloalkyl, wherein each Ci-4alkyl, phenyl, or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; preferably fluoro, chloro, bromo, iodo, Ci-4alkyl, haloCi-4alkyl, Ci-4alkoxy, and haloCi-4alkoxy; preferably R6, R7, and R8are each independently selected from the group consisting of Ci-4alkyl and phenyl, wherein each Ci-4alkyl, or phenyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi- ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; preferably fluoro, chloro, bromo, iodo, Ci-4alkyl, haloCi-4alkyl, Ci-4alkoxy, and haloCi-4alkoxy; R9and R10are each independently selected from the group consisting of hydrogen, Ci- ealkyl, Ce-waryl, Cs-ecycloalkyl; wherein each Ci-ealkyl, Ce- aryl, or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; preferably R9and R10are each independently selected from the group consisting of hydrogen, Ci-4alkyl, phenyl, Cs-ecycloalkyl, wherein each Ci-4alkyl, phenyl, or Cs-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; preferably fluoro, chloro, bromo, iodo, Ci-4alkyl, haloCi-4alkyl, Ci-4alkoxy, and haloCi-4alkoxy; preferably R9and R10are each independently selected from the group consisting of Ci-4alkyl and phenyl, wherein each Ci-4alkyl, or phenyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi- ealkyl, Ci-ealkoxy, and haloCi-ealkoxy; preferably fluoro, chloro, bromo, iodo, Ci-4alkyl, haloCi-4alkyl, Ci-4alkoxy, and haloCi-4alkoxy;

[0167] Raand Rbare each independently hydrogen, Ci-ealkyl or Ce- aryl; wherein said sulfinylation step is performed in the presence of a solvent selected from the group comprising benzene, toluene, ethylbenzene, xylene, chlorobenzene, bromobenzene, fluorobenzene, anisole, nitrobenzene, tetralin, dichlorobenzene, trimethylbenzene, ethylacetate, propylacetate, butylacetate, propanol, butanol, 2- methyltetrahydrofuran, diethylether, methyltertbutylether, cyclopentyl methyl ether, dichloromethane, tetrachloromethane, pentane, hexane, heptane, cyclohexane, decaline and mixtures thereof; preferably a solvent selected from benzene, toluene, ethylbenzene, xylene, chlorobenzene, bromobenzene, fluorobenzene, anisole, nitrobenzene, tetralin, dichlorobenzene, trimethylbenzene, ethylacetate, propylacetate, butylacetate, propanol, butanol, 2-methyltetrahydrofuran, methyltertbutylether, cyclopentyl methyl ether, pentane, hexane, heptane, cyclohexane, decaline and mixtures thereof; preferably a solvent selected from benzene, toluene, , xylene, chlorobenzene, bromobenzene, fluorobenzene, anisole, tetralin, dichlorobenzene, trimethylbenzene, ethylacetate, propylacetate, butylacetate, propanol, butanol, 2-methyltetrahydrofuran, methyltertbutylether, cyclopentyl methyl ether, cyclohexane, decaline and mixtures thereof.

[0168] In some embodiments R3, R4and R5are each independently 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 Ci-4alkyl; preferably R3, R4and R5are each independently selected from the group comprising methyl, ethyl, isopropyl, or tert-butyl, and phenyl, each group being optionally substituted with 1 , 2 or 3 substituents each independently selected from fluoro or Ci-2alkyl; more preferably R3, R4and R5are each independently selected from the group comprising methyl, isopropyl tert-butyl, and phenyl.

[0169] In some embodiments R1is R3Si(R4)(R5)-. In some embodiments R1is selected from the group comprising tert-butyl-dimethyl-silyl, diphenyl-methyl-silyl, dimethyl-phenyl-silyl, triethyl-silyl and triisopropyl-silyl, each group being optionally substituted by one or more substituents independently selected from fluoro or Ci-4alkyl; preferably R1is tert-butyl- dimethyl-silyl.

[0170] In some embodiments, R1is selected from the group comprising R3Si(R4)(R5)-, Ci-ealkyl, - CH2-CH=CRaRb, Ci-ealkoxy, Cs-ecycloalkyl; each of said Ci-ealkyl, Ce-waryl, Ce-warylCi- ealkyl, and Cs-ecycloalkyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci- ealkoxy, haloCi-ealkoxy, Ce- aryl, heterocyclyl, and nitro; preferably R1is a group selected from Ci-ealkyl or Ci-ealkoxy, each group being optionally substituted by 1 , 2 or 3 substituents independently selected from fluoro or Ci-4alkyl; more preferably R1is a group selected from Ci-2alkyl or Cs-ecycloalkyl, each group being optionally substituted by 1 , 2 or 3 substituents independently selected from Ci-2alkyl or Ce-waryl; for example R1is selected from benzyl, methyl or methoxym ethyl; preferably R1is benzyl.

[0171] In some embodiments, the compound of formula (IV) is obtained by a process comprising the step of protecting the hydroxyl of a compound of formula (III) to produce a compound of formula (IV)

[0172] In some embodiments the step of protecting the hydroxyl of a compound of formula (III) is performed in the presence of a reagent selected from the group consisting of silylating agent, alkylating agent and arylating agent. In some embodiments, the step of protecting the hydroxyl of a compound of formula (III) is performed in the presence of a silylating agent selected from the group comprising Ci-ealkylsilylchloride, Ciwalkylsilyltriflate, phenylsilylchloride, phenylsilyltriflate, Ci-ealkyl phenylsilylchloride and Ciwalkylphenylsilyltriflate, each of said groups being optionally substituted by one or more substituents independently selected from fluoro or Ci-4alkyl.

[0173] For example, formation of protected estrone silyl ether can be performed by reaction of a silylating agent such as tert-butyl dimethylsilylchloride, diphenylmethylsilylchloride, dimethylphenylsilylchloride, triethylsilylchloride, or triisopropylsilylchloride, or such as tert- butyl dimethylsilyltriflate, diphenylmethylsilyltriflate, dimethylphenylsilyltriflate, triethylsilyltriflate, or triisopropylsilyltriflate. The reaction can be performed in the presence of a suitable base such as imidazole, 2,6-lutidine, collidine, triethylamine, or 1 ,8- diazabicyclo[5.4.0]undec-7-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 mixture thereof.

[0174] In some embodiments the step of protecting the hydroxyl of a compound of formula (III) is performed in the presence of an alkylating agent. In an embodiment, said alkylating agent is Ci-ealkyl, wherein said Ci-ealkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCiwalkyl, Ci- ealkoxy, haloCiwalkoxy, Ce-waryl, heterocyclyl, and nitro.

[0175] In some embodiments, the alkylating agent is Ciwalkyl; wherein said Cioalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ciwalkyl, haloCi-salkyl, Ci-3alkoxy, haloCi-salkoxy, Ce- aryl, heterocyclyl, and nitro preferably, the alkylating agent is selected from the group comprising benzyl bromide, benzyl chloride, methoxymethyl bromide, dihydropyrane; preferably the akylating agent is selected from the group comprising benzyl bromide, methoxymethyl bromide and dihydropyrane.

[0176] In some embodiments the process according to the present invention further comprises the step of desulfynilating a compound of formula (II) to produce a compound of formula (I), wherein R1is as defined herein.

[0177] In some embodiments, the desulfinylation step is carried out with heat optionally in the presence of cupric sulfate. The temperature of the desulfinylation step can be between 80°C and 130°C, preferably between 90°C and 120°C, preferably between 100°C and 115°C.

[0178] In some embodiments the desulfinylation step is performed by a continuous flow process as described herein.

[0179] The invention is illustrated but not limited by the following examples.

[0180] EXAMPLES

[0181] General information

[0182] All reactions were carried out in oven-dried glassware under a dry nitrogen atmosphere using standard techniques for handling air-sensitive materials unless otherwise stated.

[0183] All solvents used were purchased from Fisher Scientific and dried over activated 4 molecular sieves.

[0184] All reagents were used as supplied. Air-sensitive reagents were stocked under argon in a desiccator.

[0185] Reactions were monitored by HPLC and / or by TLC.

[0186] Yields refer to chromatographically and spectroscopically pure compounds unless otherwise stated.

[0187] HPLC method:

[0188] Eluent: A: Water; B: Acetonitrile

[0189] Gradient of the eluents are indicated in Error! Reference source not found..

[0190] Table 1

[0191] Flow rate: 2 mL / min-1 Column: C18, 100 x 4.6 mm, 3 pm

[0192] Oven Temperature: 40 °C

[0193] Diode Array Detector: 180-800 nm

[0194] Wavelength for analysis: 190nm

[0195] Example 1 : Representative synthesis of 3-tert-butyldimethylsilyloxy-16- (phenylsulfinyl)-estrone

[0196] Compound 1 was prepared as schematically illustrated in scheme 1 .

[0197] Scheme 1

[0198] Step 1 : 3-tert-butyldimethylsilyloxy-estrone

[0199] To a suspension of estrone (50.00g, 185 mmol) in CH2CI2 (175 mL) at room temperature imidazole (13.85 g, 203 mmol) was added. The reaction mixture was warmed to 35 °C and TBSCI (30.66 g, 203 mmol) in CH2CI2 (23 mL) was then slowly added. After stirring for 1 h at 35 °C the conversion was controlled by TLC (PE / EtOAC [6:4]). Water (100 mL) was loaded on the reaction mixture (solubilization of the suspension) and the mixture was stirred for 5 min at rt. The aqueous phase was separated and extracted with CH2CI2 (100 mL). The organic phases were combined, dried with MgSCL and the volatiles evaporated under reduced pressure.

[0200] The product was isolated as a white solid (quantitative yield).

[0201] 1H-NMR (CDCI3): 6 0.20 (s, 6H, (CH3)2-Si-), 0.90 (s, 3H, CH3at C-18), 1.00 (s, 9H, (CH3)3-C-Si), 1.20-2.60 (m, 13H), 2.75-2.95 (m, 2H), 5.65-5.75 (m, 1 H), 6.58 (broad s, 1 H, H4), 6.63 (dd, 1 H, H2), 7.12 (d, 1 H, H1).

[0202] 13C-NMR (CDCI3): 5 -4.3, 13.9, 21.6, 25.8 (2C), 25.9, 26.6, 29.5, 31.7, 35.9, 38.4, 44.1 , 48.1 , 50.5, 117.4, 120.0, 126.2, 132.5, 137.6, 153.5. Carbon of the C=O not observed due to high relaxation time.

[0203] Step 2: 3-te / Y-butyldimethylsilyloxy-16-(phenylsulfinyl)-estrone A solution of 3-TBS-estrone (5.00g, 13.0 mmol) in toluene (36 mL) was added to a suspension of tBuOK (2.92g, 26.0 mmol) in toluene (50 mL) at room temperature under N2 atmosphere. The mixture was stirred for 15 minutes at room temperature, cooled down to 0°C and methyl benzenesulfinate (4.2 mL, 32.5 mmol) was added at once. The reaction was stirred at 0°C for 20 minutes and then warmed to room temperature. The conversion of the starting material was followed by TLC analysis [PE / EtOAc (7:3)]. After between 15- 30 minutes, the reaction was quenched by addition of a 5% aqueous NH4CI solution (30 mL) and diluted with CH2CI2 (35 mL). The layers were separated and the organic layer washed with a saturated NaHCCh aqueous solution (25 mL). Drying over MgSCL and evaporation of the volatiles under reduced pressure afforded the crude product as a lightyellow solid (98%HPLC). Purification of the crude product by chromatography over silica gel (DCM / EtOAc [100 / 0 to 9 / 1]) gave 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estrone as a light-yellow solid (6.41g, 97%).

[0204] 1H-NMR (CDCh): 5 0.17 (s, 6H, (CH3)2-Si-), 0.91 (s, 3H, CH3at C-18), 0.97 (s, 9H, (CH3)3-C-Si), 1.08-2.92 (m, 12H), 3.25-3.73 (m, 1 H, H16), 6.53-6.58 (m, 1 H, H4), 6.62 (d, 1 H, H2), 7.04-7.14 (m, 1 H, H1), 7.47-7.58 (m, 3H, PhS(O)-), 7.59-7.68 (m, 2H, PhS(O)-).

[0205] 13C-NMR (CDCh): 5 -4.3, 11.1 , 14.6, 17.9, 18.2, 20.6, 25.7, 26.3, 26.7, 29.4, 31.3, 32.0, 37.7, 38.4, 43.5, 44.0, 47.8, 48.6, 48.9, 49.1 , 69.4, 72.1 , 117.4, 117.5, 120.0, 123.9, 124.2, 126.1 , 129.3, 131.0, 131.5, 132.0, 132.3, 137.4, 137.6, 142.6, 143.1 , 153.6, 211.9, 212.1. A mixture of diastereomers was isolated. Therefore, the number of signals exceeds the number of carbon atoms of the compound.

[0206] Example 2: Synthesis of 3-tert-butyldimethylsilyloxy-estrone in toluene

[0207] To a suspension of estrone (1.50 g, 5.55 mmol) in toluene (11 mL) at room temperature imidazole was added (416 mg, 6.10 mmol). The reaction mixture was warmed to 35 °C and a solution of tert-butyldimethylsilyl chloride (TBSCI) (920 mg, 6.10 mmol) in toluene (1.1 mL) was then slowly added. After stirring for 17h at 35 °C the conversion was followed by TLC (PE / EtOAC [6:4]). The reaction mixture was cooled down to room temperature and water (5 mL) was loaded (solubilization of the suspension) and the mixture was stirred for 15-30 min at room temperature. The aqueous phase was separated and extracted with toluene (5 mL). The organic phases were combined, dried with MgSCh and the volatiles evaporated under reduced pressure to afford the crude product as a white solid (1.94g, 91 %).

[0208] Example 3: Synthesis of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estrone in different solvents Procedure A

[0209] A solution of 3-TBS-estrone (250 mg, 0.65 mmol) in solvent (1.8 mL) was added to a suspension of fBuOK (146 mg, 1.30 mmol) in solvent (2.5 mL) at room temperature under N2 atmosphere. The mixture was stirred for 15 minutes at room temperature, cooled down to 0°C and methyl benzenesulfinate (0.21 mL, 1.62 mmol) was added at once. The reaction was stirred at 0°C for 20 minutes and then warmed to room temperature. The conversion of the starting material was followed by TLC analysis [PE / EtOAc (7:3)]. The reaction was quenched by addition of a 5% aqueous NH4CI (1.5 mL) solution and CH2CI2 (2.0 mL). The layers were separated and the organic layer washed with a saturated NaHCOs aqueous solution (25 mL). Drying over MgSCL and evaporation of the volatiles under reduced pressure afforded the crude product as a light-yellow solid.

[0210] Procedure B

[0211] To a suspension of fBuOK (146 mg, 1.30 mmol) in solvent (6.5 mL) at room temperature under N2 atmosphere is added 3-TBS-estrone (250 mg, 0.65 mmol) in one portion. The mixture was stirred for 30 minutes at room temperature, cooled down to 0°C and methyl benzenesulfinate (0.21 mL, 1.62 mmol) was added at once. The reaction was stirred at 0°C for 20 minutes and then warmed to room temperature. The conversion of the starting material was followed by TLC analysis [PE / EtOAc (7:3)]. The reaction was quenched by addition of a 5% aqueous NH4CI solution (1.5 mL). The organic layer was diluted with CH2CI2 (10 mL), washed with a saturated NaHCCh aqueous solution, dried over MgSCL and the volatiles evaporated under reduced pressure.

[0212] Error! Reference source not found, shows the yield of the sulfinylation reaction using different solvents. The yields are given in % area as determined by HPLC.

[0213] Table 2

[0214] Example 4: Synthesis of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estrone in different bases

[0215] A solution of 3-TBS-estrone (250 mg, 0.65 mmol) in toluene (1.8 mL) was added to a suspension of base (1.30 mmol) in toluene (2.5 mL) at room temperature under N2 atmosphere. The mixture was stirred for 15 minutes at room temperature, cooled down to 0°C and methyl benzenesulfinate (0.21 mL, 1.62 mmol) was added at once. The reaction was stirred at 0°C for 20 minutes then warmed to room temperature and stirred for 40 minutes. The conversion of the starting material was followed by TLC analysis [PE / EtOAc (7:3)]. The reaction was quenched by addition of a 5% aqueous NH4CI (1.5 mL) solution and CH2CI2 (2.0 mL). The layers were separated and the organic layer washed with a saturated NaHCCh aqueous solution (25 mL). Drying over MgSCL and evaporation of the volatiles under reduced pressure afforded the crude product as a light-yellow solid.

[0216] Error! Reference source not found, shows the yield of the sulfinylation reaction using different bases. The yields are given in % area as determined by HPLC.

[0217] Table 3 Example 5: Synthesis of 3-tert-butyldimethylsilyloxy-16-(2-pyridinesulfinyl)-estrone

[0218] Scheme 2

[0219] Step 1 : 3-tert-butyldimethylsilyloxy-estrone

[0220] 3-tert-Butyldimethylsilyloxy-estrone was prepared as described in step 1 of Example 1. Step 2: 3-tert-butyldimethylsilyloxy-16-(2-pyridinesulfinyl)-estrone A solution of 3-TBS-estrone (250 mg, 0.65 mmol) in toluene (1.8 mL) was added to a suspension of fBuOK (146 mg, 1.30 mmol) in toluene (2.5 mL) at room temperature under N2 atmosphere. The mixture was stirred for 15 minutes at 28°C, cooled down to 0°C and methyl 2-pyridinesulfinate (254.6 mg, 1.62 mmol) was added at once. The reaction is stirred at 0°C for 20 minutes then warmed to 28°C. The conversion of the starting material was followed by TLC analysis [PE / EtOAc (7:3)]. The reaction was quenched by addition of a 5% aqueous NH4CI solution (5 mL) and diluted with CH2CI2 (5 mL). The layers were separated and the organic layer washed with a saturated NaHCCh aqueous solution (5 mL). Drying over MgSCL and evaporation of the volatiles under reduced pressure afforded the crude product as a light-yellow solid. Purification of the crude product by chromatography over silica gel (ChhCh / EtOAc [95:5 to 90:10]) afforded 3-tert- butyldimethylsilyloxy-16-(2-pyridinesulfinyl)-estrone as a light-yellow solid (301.5 mg, 91%).

[0221] 1H-NMR (CDCh): 6 0.16-0.21 (6H, m), 0.95-0.98 (9H, m), 1.10-2.66 (14 H, m), 2.72-2.93 (2H, m), 3.89-4.18 (1 H, m), 6.50-6.65 (2H, m), 7.05-7.13 (1 H, m), 7.34-7.43 (1 H, m), 7.91- 8.05 (2H, m), 8.59-8.66 (1 H, m). A mixture of diastereomers was isolated, the multiplicity is therefore difficult to assess.

[0222] 13C-NMR (CDCh): 5 -4.4, 14.4, 17.8, 20.7, 25.7, 29.3, 31.2, 37.7, 38.4, 43.5, 44.0, 47.8, 48.2, 49.1, 66.0, 66.8, 69.5, 117.3, 117.4, 119.0, 119.9, 120.0, 120.5, 120.6, 121.1 , 124.5, 125.7, 126.1 , 132.2, 137.5, 137.6, 137.9 (2C), 149.2, 149.5, 149.7, 153.5, 153.6, 163.1, 163.4, 163.7, 212.2. A mixture of diastereomers was isolated. Therefore, the number of signals exceeds the number of carbon atoms of the compound.

[0223] Example 6: Synthesis of 3-tert-butyldimethylsilyloxy-16-(4-chlorophenylsulfinyl)- estrone ne

[0224] Scheme 3

[0225] Step 1 : 3-tert-butyldimethylsilyloxy-estrone

[0226] 3-tert-Butyldimethylsilyloxy-estrone was prepared as described in step 1 of Example 1.

[0227] Step 2: 3-tert-butyldimethylsilyloxy-16-(4-chlorophenylsulfinyl)-estrone A solution of 3-TBS-estrone (250 mg, 0.65 mmol) in toluene (1.8 mL) was added to a suspension of fBuOK (146 mg, 1.30 mmol) in toluene (2.5 mL) at room temperature under N2 atmosphere. The mixture was stirred for 15 minutes at 28°C, cooled down to 0°C and methyl 4-chlorobenzenesulfinate (309 mg, 1.62 mmol) was added at once. The reaction was stirred at 0°C for 20 minutes then warmed to 28°C. The conversion of the starting material was followed by TLC analysis [PE / EtOAc (7:3)]. The reaction was quenched by addition of a 5% aqueous NH4CI solution (5 mL) and diluted with CH2CI2 (5 mL). The layers were separated and the organic layer washed with a saturated NaHCCh aqueous solution (5 mL). Drying over MgSCL and evaporation of the volatiles under reduced pressure afforded the crude product as a light-yellow solid. Purification of the crude product by chromatography over silica gel (CH2CI2 / PE [50:50 to 100:0] then ChLCh / EtOAc [100:0 to 80:20]) afforded 3-tert-butyldimethylsilyloxy-16-(4-chlorophenylsulfinyl)-estrone as a light-yellow solid (271.1 mg, 77%).

[0228] 1H-NMR (CDCh): 6 0.15-0.21 (6H, m), 0.96-0.98 (9H, m), 1.01-2.58 (14H, m), 2.72-2.92 (2H, m), 3.23-3.67 (1 H, m), 6.52-6.59 (1 H, m), 6.59-6.67 (1 H, m), 6.99-7.13 (1 H, m), 7.48- 7.64 (2H, m). A mixture of diastereomers was isolated, the multiplicity is therefore difficult to assess.

[0229] 13C-NMR (CDCI3): 5 -4.4, 11.0, 14.5, 17.9, 18.1 , 20.6, 25.7, 26.2, 26.6, 29.3, 31.2, 31.8, 37.6, 38.3, 43.3, 43.9, 47.7, 48.5, 48.9, 49.0, 68.6, 69.4, 72.0, 117.3, 117.4, 119.9, 120.0, 125.3, 125.6, 126.0 (2C), 126.2, 129.1 , 129.3, 131.9, 132.1 , 137.2, 137.3, 137.4, 141.0, 153.5 (2C), 211.5, 211.7. A mixture of diastereomers was isolated. Therefore, the number of signals exceeds the number of carbon atoms of the compound.

[0230] Example 7: Synthesis of 3-triisopropyl-16-(phenylsulfinyl)-estrone

[0231] Scheme 4

[0232] Step 1 : 3-triisopropylsilyloxy-estrone

[0233] To a solution of estrone (10.00 g, 36.99 mmol) and imidazole (7.55 g, 110.97 mmol) in dimethylformamide (148 ml) triisopropylsilyl chloride (8.56 g, 44.39 mmol) was added. The solution was stirred for 17 hours at room temperature. The reaction mixture was diluted with diethyl ether (200 mL) and water (150 mL) was added. The aqueous layer was extracted twice with diethyl ether (2x100 mL). The combined organic layers were washed respectively with brine (150 mL) and dried over MgSCL. Filtration and evaporation of the volatiles afforded 3-triisopropylsilyloxy-estra-1 ,3,5(10)-triene-17-one as a white solid (13.30 g, 84%).

[0234] 1H-NMR (CDCI3): 5 0.91 (3H, s, CH3at C-18), 1.05-1.11 (21H, m), 1.18-1.32 (3H, m), 1.36-1.69 (4H, m), 1.90-2.28 (4H, m), 2.34-2.41 (1 H, m), 2.50 (1 H, dd), 2.82-2.88 (2H, m), 6.61 (1 H, d), 6.66 (1 H, dd), 7.10 (1 H, d).

[0235] 13C-NMR (CDCI3): 5 12.7, 13.9, 17.7, 18.0, 21.6, 25.8, 26.6, 29.5, 31.6, 35.9, 38.2, 38.3 (2C), 44.0 (2C), 48.0, 50.4, 117.0, 119.7, 126.0, 132.1, 137.5, 153.8. A mixture of diastereomers was isolated. Therefore, the number of signals exceeds the number of carbon atoms of the compound. Carbon of the C=O not observed due to high relaxation time.

[0236] Step 2: 3-triisopropyl-16-(phenylsulfinyl)-estrone

[0237] A solution of 3-triisopropylsilyloxy-estrone (277 mg, 0.65 mmol) in toluene (1.8 mL) was added to a suspension of fBuOK (146 mg, 1.30 mmol) in toluene (2.5 mL) at room temperature under N2 atmosphere. The mixture was stirred for 15 minutes at room temperature, cooled down to 0°C and methyl benzenesulfinate (0.26 mL, 1.95 mmol) was added at once. The reaction was stirred at 0°C for 20 minutes then warmed to room temperature. The conversion of the starting material was followed by TLC analysis [PE / EtOAc (7:3)]. The reaction was quenched by addition of a 5% aqueous NH4CI solution. The organic layer was diluted with CH2CI2 (5 mL), washed with a saturated NaHCO3aqueous solution (5 mL), dried over MgSCL and the volatiles evaporated under reduced pressure. HPLC analysis of the crude product showed total conversion of the starting material after 2h of reaction. Purification by chromatography over silica gel (PE:EtOAc [9:1 to 7:3]) afforded the sulfoxide as an off-white solid (262 mg, 73%).

[0238] 1H-NMR (CDCI3): 6 0.99 (3H, s, CH3at C-18), 1.06-1.14 (21H, m), 1.18-1.29 (4H, m), 1.41-2.55 (7H, m), 2.72-2.91 (2H, m), 3.27-3.74 (1 H, m), 6.59 (1H, d), 6.64 (1H, dd), 7.09 (1 H, d), 7.48-7.59 (3H, m), 7.65 (2H, t). A mixture of diastereomers was isolated, the multiplicity is therefore difficult to assess.

[0239] 13C-NMR (CDCI3): 5 12.7, 18.0, 20.6, 25.6, 26.3, 26.6, 29.3, 31.2, 31.9, 37.7, 38.4, 43.4, 44.0, 47.8, 48.6, 48.9, 49.0, 69.0, 69.3, 72.0, 117.1, 119.7, 123.9, 124.2, 125.0, 126.0, 129.1, 129.3, 131.0, 131.6, 131.9, 137.3, 137.4, 143.1, 153.9, 154.0, 212.1. A mixture of diastereomers was isolated. Therefore, the number of signals exceeds the number of carbon atoms of the compound. Example 8: Synthesis of 3-benzyl-16-(phenylsulfinyl)-estrone

[0240] Scheme 5

[0241] Step 1 : 3-benzyl-estrone

[0242] To a solution of estrone (50.00 g, 18.49 mmol) at room temperature in acetonitrile (74 mL) was added successively potassium carbonate (6.39 g, 46.23 mmol) and benzyl bromide (2.4 mL, 20.34 mmol). The mixture was stirred at reflux for 48 hours. The reaction mixture was cooled down and quenched with an aqueous 10% NH4CI solution (75 mL). The organic layer was washed with an aqueous 10% NaHCCh solution (75 mL), brine (75 mL) and the volatiles were removed under reduced pressure to afford 3-benzyloxy-estra- 1 ,3,5(10)-triene-17-one as a white solid (2.8581 g, 43%).

[0243] 1H-NMR (CDCI3): 5 0.91 (3H, s, CH3 at C-18), 1.38-1.72 (6H, m), 1.91-2.21 (3H, m), 2.21- 2.32 (1 H, m), 2.36-2.46 (1 H, m), 2.46-2.57 (1 H, m), 2.70 (1 H, dd), 2.85-2.94 (2H, m), 5.04 (2H, s), 6.74 (1 H, s), 6.80 (1 H, dd), 7.21 (1 H, d), 7.31-7.45 (5H, m).

[0244] 13C-NMR (CDCI3): 5 13.9, 21.6, 26.0, 26.6, 29.7, 31.6, 35.9, 38.4, 44.0, 48.1 , 50.5, 70.0, 112.4, 114.9, 126.4, 127.5, 127.9, 128.6, 132.4, 137.3, 137.8, 156.9. Carbon of the C=O not observed due to high relaxation time.

[0245] Step 2: 3-benzyl-16-(phenylsulfinyl)-estrone

[0246] A solution of 3-benzyl-estrone (234 mg, 0.65 mmol) in toluene (1.8 mL) was added to a suspension of fBuOK (146 mg, 1.30 mmol) in toluene (2.5 mL) at room temperature under N2 atmosphere. The mixture was stirred for 15 minutes at room temperature, cooled down to 0°C and methyl benzenesulfinate (0.26 mg, 1.95 mL) was added at once. The reaction was stirred at 0°C for 20 minutes then warmed to room temperature. The conversion of the starting material was followed by TLC analysis [PE / EtOAc (7:3)]. After 2 hours the reaction was quenched by addition of a 5% aqueous NH4CI solution. The organic layer was diluted with CH2CI2 (5 mL), washed with a saturated NaHCCh aqueous solution (5 mL), dried over MgSCL and the volatiles evaporated under reduced pressure. Purification by chromatography over silica gel (PE:EtOAc [9:1 to 7:3]) afforded the sulfoxide as an off- white solid (284 mg, 90%).1H-NMR (CDCh): 6 0.99 (3H, d, CH3 at C-18), 1.46-2.55 (11H, m), 2.76-2.96 (2H, m), 3.27-3.72 (2H, m), 5.03 (2H, s), 6.70-6.75 (1H, m), 6.78 (1H, d), 7.19 (1H, d), 7.28-7.48 (5H, m), 7.48-7.60 (3H, m), 7.60-7.69 (2H, m). A mixture of diastereomers was isolated, the multiplicity is therefore difficult to assess.

[0247] 13C-NMR (CDCh): 6 11.0, 14.6, 17.9, 20.7, 23.4, 25.8, 26.3, 26.6, 29.6, 31.3, 32.0, 37.7, 38.4, 43.5, 44.0, 47.7, 48.1 , 48.6, 48.9, 49.1 , 69.4, 70.0, 72.1 , 112.4, 114.9, 123.9, 124.2, 125.0, 126.3 (2C), 127.5, 127.9, 128.6, 129.1 , 129.3, 131.0, 132.1 , 137.7, 143.1, 156.9, 212.1. A mixture of diastereomers was isolated. Therefore, the number of signals exceeds the number of carbon atoms of the compound.

[0248] Example 9: Synthesis of 3-tert-butyldiphenylsilyloxy-16-(phenylsulfinyl)-estrone

[0249] Scheme 6

[0250] Step 1: Synthesis of 3-tert-butyldiphenylsilyloxy-estrone

[0251] To a solution of estrone (10.00 g, 36.98 mmol) and imidazole (5.04 g, 73.97 mmol) in dimethylformamide (74 ml) was added tert-butyl(chloro)diphenylsilane (11.18 g, 40.68 mmol). The mixture was stirred for 24 hours at room temperature. The reaction mixture was diluted with dichloromethane (200 mL) and water (200 mL) was added. The organic layer was washed respectively with an aqueous 10% NH4CI solution (100 mL), an aqueous 10% NaHCCh solution (100 mL) and brine (100 mL). Evaporation of the volatiles afforded 3-tert-butyldiphenylsilyloxy-estra-1,3,5(10)-triene-17-one as an off-white solid (13.33 g, 84%).

[0252] 1H-NMR (CDCh): 5 0.89 (3H, s, CH3 at C-18), 1.08 (9H, s, (CH3)3-Si-), 1.34-1.62 (6H, m), 1.86-1.97 (2H, m), 1.97-2.04 (1 H, m), 2.06-2.38 (3H, m), 2.48 (1 H, dd), 2.65-2.82 (2H, m), 6.49 (1 H, dd), 6.58 (1 H, d), 6.96 (1 H, d), 7.34-7.44 (6H, m), 7.70-7.75 (4H, m).

[0253] 13C-NMR (CDCh): 5 13.9, 19.5, 21.6, 25.8, 26.6, 26.7, 29.4, 31.6, 35.9, 38.3, 44.0, 48.1 , 50.5, 117.0, 119.7, 126.0, 127.8, 129.8, 132.2, 133.2, 135.6, 137.5, 153.5. Carbon of the C=O not observed due to high relaxation time.

[0254] Step 2: Synthesis of 3-tert-butyldiphenylsilyloxy-16-(phenylsulfinyl)-estrone A solution of 3-tert-butyldiphenylsilyloxy-estrone (331 mg, 0.65 mmol) in toluene (1.8 mL) was added to a solution of fBuOK (146 mg, 1.30 mmol) in toluene (2.5mL) at room temperature under N2 atmosphere. The mixture was stirred for 15 minutes at room temperature, cooled down to 0°C and methyl benzenesulfinate (0.26 mg, 1.95 mmol) was added at once. The reaction is stirred at 0°C for 20 minutes then warmed to room temperature. The conversion of the starting material was followed by TLC analysis [PE / EtOAc (7:3)]. After 2 hours the reaction was quenched by addition of a 5% aqueous NH4CI solution (5 mL). The organic layer was diluted with CH2CI2 (5 mL), washed with a saturated NaHCCh aqueous solution, dried over MgSCL and the volatiles evaporated under reduced pressure. Purification by chromatography over silica gel (PE:EtOAc [9:1 to 7:3]) afforded the sulfoxide as an off-white solid (297 mg, 72%).

[0255] 1H-NMR (CDCI3): 6 0.96 (3H, s, CH3 at C-18), 1.09 (9H, s, (CH3)3-Si-), 1.16-2.38 (14H, m), 2.42-2.54 (1 H, m), 2.65-2.76 (2H, m), 3.24-3.72 (1 H, m), 6.49 (1 H, d), 6.52-6.58 (1 H, m), 6.95 (1 H, d), 7.31-7.48 (6H, m), 7.47-7.59 (3H, m), 7.59-7.67 (2H, m), 7.67-7.78 (4H, m). A mixture of diastereomers was isolated, the multiplicity is therefore difficult to assess.

[0256] 13C-NMR (CDCh): 6 11.0, 14.6, 17.8, 19.4, 20.6, 25.5, 26.2, 26.5, 29.2, 31.2, 37.6, 38.3, 43.4, 43.9, 47.7, 49.0, 69.0, 69.3, 72.0, 116.9, 117.0, 119.6 (2C), 123.8, 124.2, 124.9, 125.8, 127.7, 129.0, 129.2, 129.8, 130.9, 132.0, 133.1 (2C), 135.5, 137.3, 143.0, 153.4, 212.0. A mixture of diastereomers was isolated. Therefore, the number of signals exceeds the number of carbon atoms of the compound.

[0257] Example 10: Synthesis of 3-tetrahydropyranyl-16-(phenylsulfinyl)-estrone

[0258] Scheme 7

[0259] Step 1: Synthesis of 3-tetrahvdropyranyl-estrone

[0260] To a suspension of estrone (2.00 g, 7.40 mmol) in CH2CI2 (30 mL) at room temperature (~25°C) under nitrogen atmosphere were added pyridinium p-toluenesulfonate (186 mg, 0.74 mmol) and 3,4-dihydropyran (2.0 mL, 22.19 mmol). After stirring at room temperature for 17h the reaction was quenched by addition of water (10 mL). The reaction mixture was diluted with dichloromethane (10 mL) and the organic layer was washed with an aqueous 5% NaHCOs solution (10 mL). The layers were separated, and the organic layer was dried over MgSC>4 and concentrated under vacuum to afford the crude product as a white solid (2.35 g, 89%).

[0261] 1H-NMR (CDCI3): 5 0.94 (3H, s, CH3 at C-18), 1.38-1.73 (10H, m), 1.80-1.89 (2H, m), 1.93-2.05 (3H, m), 2.07-2.19 (1 H, m), 2.20-2.31 (1 H, m), 2.36-2.45 (1 H, m), 2.50 (1 H, dd, J = 19.0 and 8.6 Hz), 2.82-2.97 (2H, m), 3.90 (1 H, t, J = 10.4 Hz), 5.40 (1 H, t, J = 3.6 Hz), 6.77-6.83 (1 H, m), 6.83-6.90 (1 H, m), 7.19 (1 H, d, J = 8.6 Hz). A mixture of diastereomers was isolated, the multiplicity is therefore difficult to assess.

[0262] 13C-NMR (CDCI3): 5 13.8, 18.7, 21.6, 25.2, 25.8, 26.5, 29.6, 30.4, 31.6, 35.8, 38.3, 44.0, 48.0, 50.4, 61.9 (2C), 96.3 (2C), 114.0, 116.5, 116.6, 126.2, 132.9, 137.6, 155.0 (2C). A mixture of diastereomers was isolated. Therefore, the number of signals exceeds the number of carbon atoms of the compound. Carbon of the C=O not observed due to high relaxation time.

[0263] Step 2: Synthesis of 3-tetrahydropyranyl-16-(phenylsulfinyl)-estrone

[0264] A solution of 3-tetrahydropyranyl-estrone (230 mg, 0.65 mmol) in toluene (1.8 mL) was added to a solution of fBuOK (146 mg, 1.30 mmol) in toluene (2.5mL) at room temperature under N2 atmosphere. The mixture was stirred for 15 minutes at room temperature, cooled down to 0°C and methyl benzenesulfinate (0.26 mg, 1.95 mmol) was added at once. The reaction was stirred at 0°C for 20 minutes then warmed to room temperature. The conversion of the starting material was followed by TLC analysis [PE / EtOAc (7:3)]. After 2 hours the reaction was quenched by addition of a 5% aqueous NH4CI solution (5 mL). The organic layer was diluted with CH2CI2 (5 mL), washed with a saturated NaHCCh aqueous solution, dried over MgSCL and the volatiles evaporated under reduced pressure. Purification by chromatography over silica gel (PE:EtOAc [9:1 to 7:3]) afforded the sulfoxide as an off-white solid.

[0265] 1H-NMR (CDCI3): 6 1.29-1.75 (11H, m), 1.78-1.92 (3H, m), 1.92-2.05 (3H, m), 2.10-2.57 (3H, m), 2.75-2.96 (2H, m), 3.27-3.75 (2H, m), 3.91 (1H, t, J = 10.2 Hz), 5.35-5.42 (1H, m), 6.75-6.82 (1 H, m), 6.85 (1 H, dd, J = 8.9 and 2.6 Hz), 7.16 (1 H, d, J = 8.9 Hz), 7.47- 7.59 (3H, m), 7.63 (2H, t, J = 6.5 Hz). A mixture of diastereomers was isolated. Therefore, the number of signals exceeds the number of carbon atoms of the compound.

[0266] 13C-NMR (CDCI3): 6 11.0, 14.5, 17.8, 18.7, 20.6, 23.3, 23.8, 25.1, 25.6, 25.7, 26.2, 26.5, 29.4, 30.4, 31.2, 31.9, 37.5, 37.6, 38.3, 43.4, 44.0, 47.7, 48.0, 48.5, 48.8, 49.0, 61.9, 69.0, 69.3, 72.0, 96.2, 96.3 (2C), 114.0, 114.1, 116.4, 116.5, 116.6, 123.8, 124.2, 124.9, 126.1 (3C), 129.0, 129.2 (2C), 130.9, 131.5, 132.7, 137.4, 137.5, 142.5, 142.9, 155.0, 155.1 (2C), 211.8, 212.0. A mixture of diastereomers was isolated. Therefore, the number of signals exceeds the number of carbon atoms of the compound.

[0267] Example 11 : Synthesis of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraene-17- one

[0268] Scheme 8

[0269] A solution of compound (IV) (975 g, 1.96 mol) and Et3N (26.1 mL, 0.20 mol) in toluene (8.0 L) was pumped with “pump A” with a flow rate of 41.68 mL / min. A solution of DMAD (288 mL, 2.46 mol) in toluene (298 mL) was pumped with “pump B” with a flow rate of 3.05 mL / min. Flow A and Flow B were mixed and the combined flows were injected in a SS flow reactor (Vint = 134 mL) heated at 210°C with a global flow rate of 44.73 mL / min for a residence time of 3 minutes. The feed was maintained liquid with a back-pressure regulator of 15 bar (220 psi). The flow was then cooled to 15 °C and the crude reaction mixture was retrieved in a flask. The organic layer was washed with a 1M aqueous solution of NaOH (8.0 L). The volatiles were removed under reduced pressure to give a brown crude solution containing an 88 / 5 / 3 / 3 % area by HPLC of 3-tert- butyldimethylsilyloxy-estra-1 ,3,5(10)-15-tetraene-17-one / 3-tert-butyldimethylsilyloxy-estra- 1 ,3,5(10)-triene-17-one / 3-tert-butyldimethylsilyloxy-estra-1 ,3,5(10)-14-tetraene-17-one / 3- tert-butyldimethylsilyloxy-16-phenylthio-estra-1,3,5(10)-15-tetraene-17-one.

Claims

CLAIMS1. A process for the preparation of a compound of formula (II), a stereoisomer, a salt, a hydrate or a solvate thereof,comprising the step of sulfinylation of a compound of formula (IV) to produce compound of formula (II);wherein:R1is selected from the group comprising, R3Si(R4)(R5)-, Ci-ealkyl, Ce- aryl, Ce-warylCi- ealkyl, -CH2-CH=CRaRb, Ci-ealkoxy, and Cs-ecycloalkyl; each of said Ci-ealkyl, Ce- aryl, Ce- arylCiwalkyl, and Cs-ecycloalkyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, Ce- aryl, heterocyclyl, and nitro;R2is Ce-waryl, or heteroaryl; wherein each Ce-waryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, haloCi-ealkoxy, C2-ealkenyl, C2- ealkynyl, Ce-waryl, heterocyclyl, heteroaryl, -S(O)2R6, -S(O)R7, -SR8, -NR9R10, cyano and nitro;R3, R4and R5are each independently Ci-ealkyl or Ce-waryl, wherein each Ci-ealkyl or Ce-waryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci- ealkoxy, and haloCi-ealkoxy; preferably fluoro, chloro or Ci-4alkyl;R6, R7and R8are each independently selected from the group consisting of Ci-ealkyl, Ce-waryl, and Cs-ecycloalkyl, wherein each Ci-ealkyl, Ce-waryl, or Cs-ecycloalkyl may beoptionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy;R9and R10are each independently selected from the group consisting of hydrogen, Ci- ealkyl, Ce-waryl, Cs-ecycloalkyl, wherein each Ci-ealkyl, Ce- aryl, or Ce-ecycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of halo, Ci-ealkyl, haloCi-ealkyl, Ci-ealkoxy, and haloCi-ealkoxy;Raand Rbare each independently hydrogen, Ci-ealkyl or Ce- aryl; wherein said sulfinylation step is performed in the presence of a solvent selected from the group comprising benzene, toluene, ethylbenzene, xylene, chlorobenzene, bromobenzene, fluorobenzene, anisole, nitrobenzene, tetralin, dichlorobenzene, trimethylbenzene, ethylacetate, propylacetate, butylacetate, propanol, butanol, 2- methyltetrahydrofuran, diethylether, methyltertbutylether, cyclopentyl methyl ether, dichloromethane, tetrachloromethane, pentane, hexane, heptane, cyclohexane, decaline and mixtures thereof.

2. The process according to claim 1 , wherein said sulfinylation step is performed by reaction of compound of formula (IV) with at least one sulfinylation reagent, preferably in the presence of at least one base.

3. The process according to claim 1 or 2, wherein said sulfinylation step is performed by reaction of compound of formula (IV) with at least one sulfinylation reagent selected from the group comprising methyl benzenesulfinate, methyl 2-pyridinesulfinate, methyl 4-chloro-benzene sulfinate, methyl 4-bromo-benzene sulfinate, methyl 4-nitro- benzenesufinate, methyl 4-methyl-benzenesufinate, methyl 4-methoxy-benzene sulfinate, methyl 2,3,4,5,6-pentafluorobenzenesulfinate, methyl 2, 3, 4,5,6- pentachlorobenzenesulfinate, methyl-4-(trifluoromethylsulfonyl)-benzenesulfinate, 1 - (4-methylsulfnylphenyl)ethanone, methyl-4-cyano-benzenesulfinate, methyl-4- (dimethylamino)-benzenesulfinate, methyl 4-(methylsulfinate)-benzoate, and methyl 4- (2-benzothiazolyl)-benzenesulfinate.

4. The process according to any one of claims 1 to 3, wherein said sulfynilation step is performed by reaction of compound of formula (IV) with at least one sulfinylation reagent, and wherein the at least one sulfinylation reagent is present in an amount of at least 1.0 to at most 10.0 equivalents.

5. The process according to any one of claims 1 to 4, wherein the sulfinylation reaction is performed in the presence of at least one base selected from the group comprisingpotassium hydride, potassium tert-butylate, sodium hydride, sodium tert-butylate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and a mixture thereof.

6. The process according to any one of claims 1 to 5, wherein compound of formula (IV) is obtained by a process comprising the step of protecting the hydroxyl of a compound of formula (III) to produce a compound of formula (IV)7. The process according to any one of claims 1 to 6, further comprising the step of desulfynilating a compound of formula (II) to produce a compound of formula (I),(I).

8. The process according to claim 7, wherein the desulfinylation step is performed by thermolysis.

9. The process according to any one of claims 7 or 8, wherein said desulfinylation step is performed by a continuous flow process.

10. The process according to any one of claims 7 to 9, wherein the desulfinylation step is carried out in the presence of at least one scavenger.

11. The process according to any one of claims 7 to 10, wherein the desulfinylation step is carried out in the presence of at least one base.

12. Process for the preparation of estra-1 , 3, 5(10), -triene 3,15a,16a,17p-tetrol of formula (E), a stereoisomer, a salt, a hydrate, an ester, an ether or a solvate thereof, said process comprising the step of preparing a compound of formula (II) by a process according to any of claims 1 to 11 , and further reacting compound of formula (II) to produce estra-1 ,3, 5(10), -triene 3,15a,16a,17p-tetrol of formula (E), a stereoisomer, a salt, a hydrate, an ester, an ether or a solvate thereof,

Images