Estetrol intermediate manufacturing process

Abstract

The present invention relates to a process for the preparation of a compound of formula (I), its stereoisomer, salt, hydrate or solvate, which comprises the step of desulfinylating a compound of formula (II) to produce a compound of formula (I), wherein R 1 and R 2 is as defined in the claims, wherein the desulfinylation step is carried out by a continuous flow process. TIFF2025513928000072.tif62170

Description

[Technical field]

[0001] The present invention relates to a new process for the synthesis of a key intermediate in the synthesis of estetrol. [Background technology]

[0002] Estrogen mimetics are commonly used in methods of hormone replacement therapy (HRT) and female contraception. Estetrol is a biological estrogen that is endogenously produced in the fetal liver during human pregnancy. Recently, estetrol has been found to be effective as an estrogen mimetic for use in HRT. Other important applications of estetrol are in the fields of contraception, treatment of autoimmune diseases, prevention and treatment of breast and colon tumors, enhancement of libido, skin care, and wound healing.

[0003] The synthesis of estetrol and its derivatives is known in the art. Verhaar MT; et al. (Patent Document 1) describes a process for the preparation of estetrol starting from 3-A-oxy-estra-1,3,5(10),15-tetraen-17-one, where A is a C1-C5 alkyl group or a C7-C 12 In this document, 3-A-oxy-estra-1,3,5(10),15-tetraen-17-ol is prepared in six steps from estrone, where A is a benzyl group, by protecting the 3-OH group with a benzyl group, then converting the 17-keto group to the 17,17-ethylenedioxy derivative, which is then converted to C 16 This involves halogenation at position 17 using pyridinium bromide perbromide. Dehydrohalogenation is accomplished using potassium tert-butylate in dimethylsulfoxide. Deprotection of the 17-keto group is carried out using p-toluenesulfonic acid monohydrate in aqueous acetone. Reduction of the 17-keto group gives the 17-ol derivative.

[0004] One of the drawbacks of the process described in WO 2005 / 023363 is the protection of the 3-OH function with a benzyl group that can only be removed by hydrogenation using Pd / C as catalyst in the final step of the estetrol synthesis. Furthermore, the level of this catalyst in the final drug substance must be determined and must comply with ICH guidelines.

[0005] Another drawback of the synthesis described in WO 02 / 04331 is the two-step protection / deprotection of the 17-keto function to generate the 15-16 double bond in low yield.

[0006] There remains a need for an improved synthesis of 3-protected-oxy-estra-1,3,5(10),15-tetraen-17-one. Therefore, it is an object of the present invention to provide a process for the preparation of 3-protected-oxy-estra-1,3,5(10),15-tetraen-17-one that overcomes at least one of the shortcomings of the prior art. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2004 / 041839 Summary of the Invention

[0008] The inventors have now found that this object can be achieved by using a process as defined in the appended claims, in which one of the reaction steps is carried out by a continuous flow process. The inventors have surprisingly found that 3-protected-oxy-estra-1,3,5(10),15-tetraen-17-one can be obtained in good yield and excellent purity when at least one of the synthesis steps is carried out under continuous flow conditions.

[0009] According to a first aspect of the present invention, there is provided a compound of formula (I): [ka] A process for the preparation of a compound of formula (II): [ka] to produce a compound of formula (I), During the ceremony, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , C 1~6 Alkoxy, C 3~6 Cycloalkyl and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, and C 3~6 Each cycloalkyl may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R8 , -CO2R 9 , -C(O)R 10 , -SR 13 , -C(O)SR 14 , N.R. 11 R 12 , optionally substituted with one or more substituents each independently selected from the group consisting of cyano and nitro; R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; R 6 is C 1~6 Alkyl, C 6~10 Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, hydroxyl, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 11 and R 12 are each independently hydrogen, C 1~6 Alkyl, C 6~10 Aryl, C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 13 and R 14 are each independently hydrogen, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 is aryl, Here, a process is provided, wherein the above-mentioned desulfinylation step is carried out by a continuous flow process.

[0010] According to a second aspect, the present invention also relates to a compound of formula (E): [ka] The present invention also encompasses a process for the preparation of estetrol of formula (E), its stereoisomers, salts, hydrates, esters, ethers or solvates, which comprises preparing a compound of formula (I) by a process described herein and further reacting the compound of formula (I) to produce estetrol of formula (E), its stereoisomers, salts, hydrates, esters, ethers or solvates.

[0011] According to a third aspect, the present invention also encompasses a composition obtainable by the process according to the first aspect, wherein said composition comprises a compound of formula (I) and a compound of formula (IIa): [ka] Including, In the formula, R 1 and R 2 is as defined herein above.

[0012] These and other characteristics, features and advantages of the present invention will become apparent from the following detailed description, which illustrates, by way of example, the principles of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description of the Invention In describing the present invention, the terms used shall be construed in accordance with the following definitions, unless the context indicates otherwise.

[0014] Unless otherwise defined, all terms, including technical and scientific terms, used in the disclosure of the invention have the meanings commonly understood by those of ordinary skill in the art to which this invention belongs. For further guidance, definitions of terms are included to enable a better understanding of the teachings of the present invention.

[0015] In the following text, the various aspects of the invention are defined in more detail. Each aspect thus defined can be combined with any other aspect or aspects, unless expressly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous can be combined with any other feature or features indicated as being preferred or advantageous.

[0016] Throughout this specification, references to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment, although they may. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments, as would be apparent to one of ordinary skill in the art from this disclosure. Furthermore, some embodiments described herein include some features but not other features included in other embodiments, and combinations of features of different embodiments are meant to be within the scope of the present invention and form different embodiments that may be understood by one of ordinary skill in the art.

[0017] 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, unrecited members, elements, or method steps. The terms "comprising," "comprises," and "comprised of," as used herein, should be understood to include the terms "consisting of, consists, and consists of."

[0018] As used in this 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.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0020] The recitation of numerical ranges by endpoints includes all integers and, where appropriate, fractions subsumed within the range (e.g., 1 to 5 can include 1, 2, 3, 4, e.g., when referring to a multiple element, and can also include 1.5, 2, 2.75, and 3.80, e.g., when referring to a measurement). The recitation of endpoints also includes the endpoint values ​​themselves (e.g., 1.0 to 5.0 includes both 1.0 and 5.0). Any numerical range recited herein is intended to include all subranges subsumed therein.

[0021] The term "about" as used herein when referring to a measurable value such as a parameter, amount, duration, etc., is meant to encompass a variation within ±10%, preferably within ±5%, and more preferably within ±1% of the specified value, to the extent that such variation is consistent with the practice of the disclosed invention. It should be understood that the value to which the modifier "about" refers refers specifically, and preferably to the value itself that is disclosed.

[0022] The terms "wt. %, "vol. %, "or "mole %" refer to the weight percentage of a component, the volume percentage of a component, or the mole percentage of a component, based on the total weight, volume, or moles of a material, respectively, that includes the component.

[0023] As used herein, HPLC refers to high performance liquid chromatography utilizing UV absorbance detection by the methods described in the Examples section.

[0024] "Area percent of compound X" or "area % of compound X" refers to the area percentage obtained by dividing the HPLC peak area of ​​compound X by the sum of all HPLC peak areas of compound X and each reaction product / impurity and multiplying by 100.

[0025] "Reaction impurities" refers to process related impurities (by-products) including all residual starting materials, residual intermediates, and other reaction products other than the compound of formula (I) as detected by HPLC.

[0026] In describing the present invention, unless otherwise indicated, the terms used shall be construed in accordance with the following definitions.

[0027] Whenever the term "substituted" is used herein, it is meant to indicate that one or more hydrogen atoms on the atom designated with "substituted" are replaced by a selection from the designated group, provided that the replacement does not exceed the normal valence of the designated atom and that the replacement results in a chemically stable compound, i.e., a compound that is sufficiently robust to survive isolation from a reaction mixture. When a group can be substituted, such a group may be substituted with one or more, preferably one, two or three, substituents.

[0028] The terms "halo" or "halogen" as a group or part of a group are generic to fluoro, chloro, bromo, and iodo.

[0029] The term "nitro" as used herein refers to a -NO2 group.

[0030] The term "amino" refers to the group --NH.

[0031] As used herein, the term "cyano" refers to a -CN group.

[0032] The term "thiol" or "sulfhydryl" refers to a --SH group.

[0033] The term “alkyl” by itself or as part of another substituent refers to a group of the formula C n H 2n+1 where n is a number equal to or greater than 1. The alkyl groups may be linear or branched and may be substituted as provided herein. Generally, the alkyl groups of the present invention contain 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, and even more preferably 1 or 2 carbon atoms. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, "C 1~6 The term "alkyl" as a group or part of a group refers to a group of the formula C n H 2n+1 In the formula, n is a number ranging from 1 to 6. Thus, for example, "C 1~6 "Alkyl" includes all straight or branched alkyl groups having 1 to 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers. For example, "C 1~5 "Alkyl" includes all straight or branched alkyl groups having 1 to 5 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl and t-butyl); pentyl and its isomers. For example, "C 1~4 "Alkyl" includes all straight or branched alkyl groups having 1 to 4 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl, and their isomers (e.g., n-butyl, i-butyl, and t-butyl). For example, "C 1~3 "Alkyl" includes all straight or branched alkyl groups having 1 to 3 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl. "Substituted C 1~6 "Alkyl" refers to a C alkyl group substituted with one or more substituents (e.g., 1 to 3 substituents, e.g., 1, 2, or 3 substituents) at any available point of attachment.1~6 Refers to an alkyl group.

[0034] "Haro C 1~6 The term "alkyl", as a group or part of a group, refers to a C alkyl group having the meaning as defined above, in which one, two or three hydrogen atoms are each replaced by a halogen as defined herein. 1~6 Refers to an alkyl group such as haloC 1~6 Non-limiting examples of alkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, trichloromethyl, tribromomethyl, and the like.

[0035] "C 1~6 Alkoxy" or "C 1~6 The term "alkyloxy" as a group or part of a group refers to a group of the formula -OR b In the formula, R b is C as defined herein above 1~6 Alkyl. Preferred C 1~6 Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

[0036] "C 1~6 The term "alkylthio" as a group or part of a group refers to a group of the formula -SR b In the formula, R b is C as defined herein above 1~6 It is an alkyl group. 1~6 Non-limiting examples of alkylthio groups include methylthio (-SCH3), ethylthio (-SCH2CH3), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like.

[0037] "Haro C 1~6 The term "alkoxy" as a group or part of a group refers to a group of the formula -OR cIn the formula, R c is haloC as defined herein 1~6 Alkyl. Suitable haloC 1~6 Non-limiting examples of alkoxy 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.

[0038] The term "cycloalkyl" as a group or part of a group refers to a cyclic alkyl group, i.e., a monovalent saturated hydrocarbyl group having one or more ring structures and containing 3 to 12 carbon atoms, more preferably 3 to 9 carbon atoms, more preferably 3 to 7 carbon atoms, more preferably 3 to 6 carbon atoms. Cycloalkyl includes all saturated hydrocarbon groups, including monocyclic or bicyclic groups, containing one or more rings. The further rings of polycyclic cycloalkyls may be either fused, bridged and / or joined through one or more spiro atoms. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, "C 3~6 The term "cycloalkyl" refers to a cyclic alkyl group containing 3 to 6 carbon atoms. 3~12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptan-2-yl, (1S,4R)-norbornan-2-yl, (1R,4R)-norbornan-2-yl, (1S,4S)-norbornan-2-yl, (1R,4S)-norbornan-2-yl.

[0039] As used herein, the term "spiro atom" refers to an atom that connects two ring 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 in which two rings are connected through one atom.

[0040] The term "alkenyl," as a group or part of a group, refers to an unsaturated hydrocarbyl group, which may be linear or branched, and which contains one or more carbon-carbon double bonds. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, "C 2~6 The term "alkenyl" refers to an unsaturated hydrocarbyl group, which may be linear or branched, containing one or more carbon-carbon double bonds and containing from 2 to 6 carbon atoms. For example, "C 2~4 "Alkenyl" includes all straight or branched alkenyl groups having 2 to 4 carbon atoms. 2~6 Examples of alkenyl groups include ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, and the like.

[0041] The term "alkynyl" by itself or as part of another substituent refers to an unsaturated hydrocarbyl group that may be straight or branched and that contains one or more carbon-carbon triple bonds. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, C 2~6 The term alkynyl refers to an unsaturated hydrocarbyl group, which may be linear or branched, containing one or more carbon-carbon triple bonds and containing from 2 to 6 carbon atoms. For example, C 2~4 Alkynyl includes all straight or branched alkynyl groups containing 2 to 4 carbon atoms. 2~6Non-limiting examples of alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and chain isomers thereof, 2-hexynyl and chain isomers thereof, and the like.

[0042] "C 6~10 The term "aryl", 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 covalently bonded (typically containing 6 to 10 atoms), where at least one ring is an aromatic ring. The aromatic ring may optionally contain one or two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Examples of suitable aryls include C 6~10 Aryl, more preferably C 6~8 Aryl is an example. 6~10 Non-limiting examples of aryl include phenyl, biphenylyl, biphenylene, or 1- or 2-naphthanelyl; 1-, 2-, 3-, 4-, 5-, or 6-tetralinyl (also known as 1,2,3,4-tetrahydronaphthalene); 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. "Substituted C 6~10 "Aryl" refers to a C alkyl group having one or more substituents (e.g., 1, 2, or 3, or 1 or 2 substituents) at any available point of attachment. 6~10 Refers to an aryl group.

[0043] "C 6~10 Aryl C 1~6 The term "alkyl," as a group or part of a group, refers to a C 1~6 alkyl, wherein at least one hydrogen atom is selected from the group consisting of at least one C6~10 It is replaced by aryl. 6~10 Aryl C 1~6 Non-limiting examples of alkyl groups include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3-(2-naphthyl)-butyl, and the like.

[0044] "C 6~10 Arylthio C 1~6 The term "alkyl" as a group or part of a group refers to 1~6 refers to an alkyl group in which at least one hydrogen atom is a group of the formula -SR g wherein R g is C as defined herein above 6~10 It is aryl.

[0045] The term "heterocyclyl" as a group or part of a group refers to a non-aromatic fully saturated or partially unsaturated cyclic group (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) having at least one heteroatom in at least one carbon atom-containing ring, where said ring may be fused to an aryl ring, a cycloalkyl ring, a heteroaryl ring, or a heterocyclyl ring. Each ring of a heteroatom-containing heterocyclyl group may have 1, 2, 3, or 4 heteroatoms selected from N, O, and / or S, where the N heteroatoms and S heteroatoms may be optionally oxidized and the N heteroatoms may be optionally quaternized, where at least one carbon atom of the heterocyclyl may be oxidized to form at least one C=O. The heterocyclyl group may be attached to any heteroatom or carbon atom of the ring or ring system, as valence permits. The rings of polycyclic heterocyclyls can be fused, bridged and / or joined through one or more spiro atoms.

[0046] 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, isoaryl, aryl, aryl- ... Indolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl), isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolidinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2 H-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-yl sulfoxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolidinyl, 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 "oxiranyl" as used herein includes oxiranyl-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 succinimid-3-yl. The term "dihydropyrrolyl" as used herein includes 2,3-dihydropyrrol-1-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydropyrrol-1-yl, 2,5-dihydro-1H-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" as used herein, also known as "1,3-dioxolanyl", includes dioxolan-2-yl, dioxolan-4-yl and dioxolan-5-yl. The term "dioxolyl" as used herein, also known as "1,3-dioxolyl", 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" as used herein, also known as "piperidinyl", includes piperid-1-yl, piperid-2-yl, piperid-3-yl and piperid-4-yl.As used herein, the term "dihydropyridinyl" 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, yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl, 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. As used herein, the term "tetrahydropyridinyl" 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, 1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-2 ... 1,2,3,6-tetrahydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl and 2,3,4,5-tetrahydropyridin-6-yl.The term "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. As used herein, the term "3,6-dihydro-2H-pyranyl" includes 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-5-yl and 3,6-dihydro-2H-pyran-6-yl. As used herein, the term "tetrahydrothiophenyl" 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 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 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, 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-trioxan-5-yl, 1,2,4-trioxan-3-yl, 1,2,4-trioxan-5-yl, 1,2,4-trioxan-6-yl, and 1,3,4-trioxan-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 "1H-pyrrolidine" as used herein includes 1H-pyrrolidin-1-yl, 1H-pyrrolidin-2-yl, 1H-pyrrolidin-3-yl, 1H-pyrrolidin-5-yl, 1H-pyrrolidin-6-yl, and 1H-pyrrolidin-7-yl. The term "3H-pyrrolidine" as used herein includes 3H-pyrrolidin-1-yl, 3H-pyrrolidin-2-yl, 3H-pyrrolidin-3-yl, 3H-pyrrolidin-5-yl, 3H-pyrrolidin-6-yl, and 3H-pyrrolidin-7-yl.

[0047] The term "heteroaryl" refers, as a group or part of a group, to, but is not limited to, an aromatic ring or ring system containing 5 to 12 carbon atoms, typically 5 or 6 atoms, containing one or two rings that can be fused or covalently bonded together, at least one of which is aromatic, and one or more carbon atoms in one or more of these rings can be replaced with N, O and / or S atoms, where the N and S heteroatoms can be optionally oxidized, the N heteroatoms can be optionally quaternized, and at least one carbon atom of said heteroaryl can be oxidized to form at least one C=O. Such rings can be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.Non-limiting examples of such heteroaryls 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, thiazolyl, pyridyl ... eno[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-benzisothiazolyl, 2,1-benzoi Sothiazolyl, 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-dihydrobenzofuranyl, 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 yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, and preferably, the heteroaryl group is selected from the group consisting of pyridyl, tetrazolyl, benzothiazolyl, 1,3-benzodioxolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydrobenzofuranyl, pyrazinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, benzimidazolyl, pyrimidinyl, triazolyl, and thiazolyl.

[0048] 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 1H-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 1H-triazolyl and 4H-1,2,4-triazolyl, where "1H-triazolyl" includes 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl and 1H-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 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 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 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term "oxatriazolyl" as used herein includes 1,2,3,4-oxatriazolyl-5-yl and 1,2,3,5-oxatriazolyl-4-yl. The term "thiatriazolyl" as used herein includes 1,2,3,4-thiatriazolyl-5-yl and 1,2,3,5-thiatriazolyl-4-yl. The term "pyridinyl" as used herein (also called "pyridyl") 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 referred to as "1,4-oxazinyl") as used herein includes 1,4-oxazin-4-yl and 1,4-oxazin-5-yl. The term "dioxinyl" (also referred to as "1,4-dioxinyl") as used herein includes 1,4-dioxin-2-yl and 1,4-dioxin-3-yl. The term "thiazinyl" (also referred to as "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]thiazol-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. As used herein, the term "thieno[3,2-b]thiophenyl" 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.As used herein, the term "thieno[2,3-d][1,3]thiazolyl" 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. As used herein, the term "thieno[2,3-d]imidazolyl" 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]pyridin-5-yl, tetrazolo[1,5-a]pyridin-6-yl, tetrazolo[1,5-a]pyridin-7-yl, and tetrazolo[1,5-a]pyridin-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 1H-indazolyl or 2-azaindolyl) as used herein includes 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-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. As used herein, the term "1,3-benzothiazolyl" 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. As used herein, the term "1,2-benzisothiazolyl" 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-benzisothiazolyl" 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, 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, 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.

[0049] Heteroaryl and heterocyclyl as used herein include, by way of example, those groups described in Paquette, Leo A. "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), especially 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), especially Volumes 13, 14, 16, 19 and 28; Katritzky, Alan R., Rees, CW and Scriven, E. "Comprehensive Heterocyclic Chemistry" (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.

[0050] Any substituent designation found at more than one site in a compound of the invention is intended to be independently selected.

[0051] As used herein, the term "salt" refers to a chemical compound consisting of an ionic assembly of positively charged cations and negatively charged anions. Some preferred, but non-limiting examples of suitable organic and / or inorganic acids or bases include sodium hydroxide, potassium hydroxide, ammonium hydroxide, tetrabutylammonium hydroxide, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, and citric acid.

[0052] When a compound contains both acidic and basic groups, the compound may also form internal salts, and such compounds are within the scope of the present invention. When a compound contains a hydrogen-donating heteroatom, the present invention also covers salts and / or isomers formed by the transfer of said hydrogen atom to a basic group or atom within the molecule.

[0053] Salts of compounds of formula (I) can be prepared by one or more of these methods, i.e. (i) by reacting a compound of formula (I) with a desired acid, (ii) by reacting a compound of formula (I) with a desired base, (iii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I) or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid, or (iv) by converting one salt of a compound of formula (I) into another salt by reaction with a suitable acid or by using a suitable ion exchange column, can be prepared.

[0054] All of these reactions are typically carried out in solution. The salts precipitate from the solution and can be recovered by filtration or by evaporation of the solvent. The degree of ionization in the salts can vary from completely ionized to almost non-ionized.

[0055] Salts of the compound of formula (I) include its acid addition salts and base salts.Suitable acid addition salts are formed from acids that form non-toxic salts.Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, etc. Salts include, for example, salts of acid, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, olamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.

[0056] 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 or downstream processing steps in fluidic modules or combinations of fluidic modules fluidly connected in series or parallel. Microfluidic reactors are a type of continuous flow reactor that encompass reaction channels with internal dimensions ranging from 1 micrometer to 800 micrometers, preferably 100 micrometers to 800 micrometers, more specifically 500 micrometers to 750 micrometers, and internal volumes ranging from 0.1 mL to 20 mL, but preferably 0.5 mL to 15 mL, more specifically 0.75 mL to 10 mL. Microfluidic reactors can be constructed from a variety of materials, including but not limited to stainless steel, copper, alloys, glass, ceramic and polymeric materials. A macro / mesofluidic reactor is a type of continuous flow reactor that includes a reaction channel with internal dimensions in the range of 800 micrometers to 50000 micrometers, preferably in the range of 800 micrometers to 20000 micrometers, preferably in the range of 800 micrometers to 15000 micrometers, for example in the range of 800 micrometers to 5000 micrometers, for example in the range of 800 micrometers to 2000 micrometers, for example in the range of 800 micrometers to 1500 micrometers, and an internal volume in the range of 1 mL to 20000 mL, preferably in the range of 1 mL to 18000 mL, preferably in the range of 1 mL to 15000 mL, preferably in the range of 1 mL to 10000 mL, preferably in the range of 1 mL to 12000 mL, preferably in the range of 1 mL to 6000 mL, preferably in the range of 2.5 mL to 500 mL, preferably in the range of 5 mL to 200 mL. Macro / mesofluidic reactors can be constructed from a variety of materials, including but not limited to stainless steel, copper, alloys, glass, ceramic and polymeric materials. Downstream processing steps are defined as procedures following a reaction including, but not limited to, extraction, separation, addition of solvents or additives, precipitation, filtration, drying, and on-line analysis.Fluidic modules can consist of microfluidic or macro / mesofluidic reactors. Fluidic modules can be fluidly connected in series or parallel. Fluidic modules can be integrated with static mixers, heat exchangers, injection points, sampling valves, pressure regulators, and in-line analytics.

[0057] Preferred items (features) and embodiments and applications of the present invention are set out below. Each item and embodiment of the present invention thus defined may be combined with any other item and / or embodiment, unless expressly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features or items indicated as being preferred or advantageous. In this regard, the present invention is particularly intended to be combined with any other aspect and / or embodiment by any combination of any one or more of the following numbered items and embodiments:

[0058] 1. Formula (I): [ka] A process for the preparation of a compound of the formula (I) or a stereoisomer, salt, hydrate or solvate thereof, comprising the steps of: Formula (II): [ka] to produce a compound of formula (I), During the ceremony, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , C 1~6 Alkoxy, C 3~6 Cycloalkyl and R 6CO-, 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, and C 3~6 Each cycloalkyl may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , -SR 13 , -C(O)SR 14 , N.R. 11 R 12 From the group consisting of fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy and haloC 1~4 optionally substituted with one or more substituents each independently selected from the group consisting of alkyloxy; R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 6 is C 1~6 Alkyl, C 6~10 Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents independently selected from alkyl, R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, hydroxyl, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 11 and R 12 are each independently hydrogen, C 1~6 Alkyl, C 6~10 Aryl, C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 13 and R 14 are each independently hydrogen, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 is aryl, A process wherein the above-mentioned desulfinylation step is carried out by a continuous flow process.

[0059] 2. Formula (I): [ka] A process for the preparation of a compound of the formula (I), its stereoisomers, hydrates or solvates, comprising the steps of: Formula (II): [ka] to produce a compound of formula (I), During the ceremony, R 1 is hydrogen, R 3 Si(R 4 )(R5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , C 1~6 Alkoxy, C 3~6 Cycloalkyl and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, and C 3~6 Each cycloalkyl may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , -SR 13 , -C(O)SR 14 , N.R. 11 R 12 From the group consisting of fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy and haloC 1~4optionally substituted with one or more substituents each independently selected from the group consisting of alkyloxy; R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 6 is C 1~6 Alkyl, C 6~10 Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents independently selected from alkyl, R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, hydroxyl, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 11 and R 12 are each independently hydrogen, C 1~6 Alkyl, C 6~10 Aryl, C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 13 and R 14 are each independently hydrogen, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 is aryl, A process wherein the above-mentioned desulfinylation step is carried out by a continuous flow process.

[0060] 3. Formula (I): [ka] A process for the preparation of a compound of the formula (I), its stereoisomers, hydrates or solvates, comprising the steps of: Formula (II): [ka] to produce a compound of formula (I), During the ceremony, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl and C 6~10 Aryl C 1~6 Each of the alkyl groups may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy, and nitro; R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 6 is C 1~6 Alkyl, C 6~10 Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 is aryl, A process wherein the above-mentioned desulfinylation step is carried out by a continuous flow process.

[0061] 4. The process according to items 1 to 3, wherein the desulfinylation step is carried out by pyrolysis.

[0062] 5. The process according to any one of items 1 to 4, wherein said desulfinylation step is carried out by pyrolysis at a pyrolysis 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.

[0063] 6. The above-mentioned desulfinylation step is carried out by pyrolysis at a pyrolysis 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 least 175°C The process according to any one of items 1 to 5, wherein the process is carried out 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°C to at most 220°C, preferably at a temperature of at least 190°C to at most 220°C, preferably at a temperature of at least 200°C 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.

[0064] 7. The process according to any one of items 1 to 6, wherein said desulfinylation step is carried out by pyrolysis, wherein said pyrolysis is carried out 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.

[0065] 8. The process according to any one of items 1 to 7, wherein said desulfinylation step is carried out by pyrolysis, wherein said pyrolysis 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 least 10.0 bar to at most 55.0 bar, preferably at least 12.0 bar to at most 50.0 bar, preferably at least 20.0 bar to at most 50.0 bar, preferably at least 25.0 bar to at most 45.0 bar, preferably at least 30.0 bar to at most 40.0 bar, preferably at least 12.0 bar to at most 40.0 bar, preferably at least 12.5 bar to at most 35.0 bar, preferably at least 15.0 bar to at most 35.0 bar.

[0066] 9. The process according to any one of items 1 to 8, wherein said desulfinylation step is carried out by pyrolysis for a pyrolysis time t of at most 60 min, preferably at most 40 min, preferably at most 30 min, preferably at most 25 min, preferably at most 20 min, preferably at most 18 min.

[0067] 10. The process according to any one of items 1 to 9, wherein said desulfinylation step is carried out by pyrolysis for a pyrolysis 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.

[0068] 11. The process according to any one of items 1 to 10, wherein said desulfinylation step is carried out by pyrolysis for a pyrolysis time t of at least 0.1 min at most 30 min, preferably at least 0.5 min at most 30 min, preferably at least 1.0 min at most 25 min, preferably at least 1.0 min at most 20 min, preferably at least 1.0 min at most 15 min, preferably at least 2 min at most 10 min, preferably at least 2 min at most 8 min, preferably at least 3 min at most 8 min, preferably at least 3 min at most 6 min, preferably at least 3 min at most 10 min, preferably at least 4 min at most 8 min, preferably at least 5 min at most 8 min.

[0069] 12. The process according to any one of items 1 to 11, wherein the desulfinylation step is carried out in at least one diluent, preferably in solution, preferably using at least one solution.

[0070] 13. The process according to any one of items 1 to 12, wherein the desulfinylation step is carried out in at least one diluent and the compound of formula (II) is present in the at least one diluent in an amount of at least 0.01 mol per liter of diluent, preferably at least 0.02 mol per liter of diluent, preferably at least 0.05 mol per liter of diluent, preferably at least 0.10 mol per liter of diluent.

[0071] 14. The process according to any one of items 1 to 13, wherein the desulfinylation step is carried out in at least one diluent and the compound of formula (II) is present in the at least one diluent in an amount of at most 5.0 mol per liter of diluent, preferably at most 4.0 mol per liter of diluent, preferably at most 3.0 mol per liter of diluent, preferably at most 2.0 mol per liter of diluent, preferably at most 1.0 mol per liter of diluent.

[0072] 15. The desulfinylation step is carried out in at least one diluent, and the compound of formula (II) is present in the at least one diluent in an amount of from at least 0.01 mol per liter of diluent to at most 5.0 mol per liter of diluent, preferably from at least 0.01 mol per liter of diluent to at most 3.0 mol per liter of diluent, preferably from at least 0.01 mol per liter of diluent to at most 1.0 mol per liter of diluent, preferably from at least 0.01 mol per liter of diluent to at most 0.80 mol per liter of diluent, preferably from at least 0.02 mol per liter of diluent to at most 0.70 mol per liter of diluent, preferably from at least 0.05 mol per liter of diluent to at most 0.60 mol per liter of diluent, preferably from at least 0.06 mol per liter of diluent to at most 0.08 mol per liter of diluent. 15. The process according to any one of items 1 to 14, wherein the diluent is present in an amount of at most 0.56 moles, preferably at least 0.10 moles per liter diluent to at most 0.55 moles per liter diluent, preferably at least 0.15 moles per liter diluent to at most 0.50 moles per liter diluent, preferably at least 0.15 moles per liter diluent to at most 0.45 moles per liter diluent, preferably at least 0.15 moles per liter diluent to at most 0.40 moles per liter diluent, preferably at least 0.15 moles per liter diluent to at most 0.35 moles per liter diluent, preferably at least 0.15 moles per liter diluent to at most 0.30 moles per liter diluent, preferably at least 0.15 moles per liter diluent to at most 0.25 moles per liter diluent.

[0073] 16. The desulfinylation step is carried out in at least one diluent, and the compound of formula (II) is present in the at least one diluent in an amount of from at least 0.01 mol per liter of diluent to at most 5.0 mol per liter of diluent, preferably from at least 0.01 mol per liter of diluent to at most 4.0 mol per liter of diluent, preferably from at least 0.01 mol per liter of diluent to at most 2.0 mol per liter of diluent, preferably from at least 0.01 mol per liter of diluent to at most 0.90 mol per liter of diluent, preferably from at least 0.02 mol per liter of diluent to at most 5.0 mol per liter of diluent, more preferably from at least 0.01 .... 16. The process according to any one of items 1 to 15, wherein the diluent is present in an amount of at most 0.80 moles, preferably at least 0.05 moles per liter diluent to at most 0.70 moles per liter diluent, preferably at least 0.06 moles per liter diluent to at most 0.56 moles per liter diluent, preferably at least 0.06 moles per liter diluent to at most 0.40 moles per liter diluent, preferably at least 0.06 moles per liter diluent to at most 0.30 moles per liter diluent, preferably at least 0.06 moles per liter diluent to at most 0.25 moles per liter diluent.

[0074] 17. The process according to any one of items 1 to 16, wherein the desulfinylation step is carried out in at least one diluent and the compound of formula (II) is present in the at least one diluent in the form of a solution in said at least one diluent.

[0075] 18.R 1 But R 3 Si(R 4 )(R 5 )-and R 2 But, C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 From the group consisting of alkoxy and nitro, preferred are fluoro, chloro, bromo, nitro, C1~4 Alkyl, C 1~4 Alkyloxy and haloC 1~4 and optionally substituted with one or more substituents each independently selected from the group consisting of alkyloxy, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N and / or S, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 From the group consisting of alkoxy and nitro, preferred are fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy and haloC 1~4 and optionally substituted with one or more substituents each independently selected from the group consisting of alkyloxy, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 From the group consisting of alkoxy and nitro, preferred are fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy and haloC 1~4 and optionally substituted with one or more substituents each independently selected from the group consisting of alkyloxy, preferably R 2 is phenyl, or pyridinyl, where each phenyl or pyridinyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 From the group consisting of alkoxy and nitro, preferred are fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C1~4 Alkyloxy and haloC 1~4 optionally substituted with one or more substituents each independently selected from the group consisting of alkyloxy; R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, preferably R 3 , R 4 , and R 5 are each independently 1~6 alkyl or phenyl, where each C 1~6 Alkyl or phenyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 18. The process according to any one of items 1 to 17, optionally substituted with one or more substituents each independently selected from alkyl.

[0076] 19.R 1 But R 3 Si(R 4 )(R 5 )-and R 2 But, C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , -SR 13 , -C(O)SR 14 , N.R. 11 R 12 , cyano and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy, C 2~4 Alkenyl, C 2~4 Alkynyl, phenyl, heterocyclyl, heteroaryl, -S(O)2R 7 , -CO2R 9 , -C(O)R 10 , thiol, C 1~6 Alkylthio, -C(O)SR 14 , Amino, Mono-C 1~4 Alkylamino, Di-C 1~4 and optionally substituted with one or more substituents each independently selected from the group consisting of alkylamino, alkylamino, and cyano, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N and / or S, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , -SR 13 , -C(O)SR14 , N.R. 11 R 12 , cyano and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy, C 2~4 Alkenyl, C 2~4 Alkynyl, phenyl, heterocyclyl, heteroaryl, -S(O)2R 7 , -CO2R 9 , -C(O)R 10 , thiol, C 1~6 Alkylthio, -C(O)SR 14 , Amino, Mono-C 1~4 Alkylamino, Di-C 1~4 and optionally substituted with one or more substituents each independently selected from the group consisting of alkylamino, alkylamino, and cyano, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , -SR 13 , -C(O)SR 14 , N.R. 11 R 12 , cyano and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy, C 2~4 Alkenyl, C 2~4Alkynyl, phenyl, heterocyclyl, heteroaryl, -S(O)2R 7 , -CO2R 9 , -C(O)R 10 , thiol, C 1~6 Alkylthio, -C(O)SR 14 , Amino, Mono-C 1~4 Alkylamino, Di-C 1~4 and optionally substituted with one or more substituents each independently selected from the group consisting of alkylamino, alkylamino, and cyano, preferably R 2 is phenyl, or pyridinyl, where each phenyl or pyridinyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , -SR 13 , -C(O)SR 14 , N.R. 11 R 12 , cyano and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy, C 2~4 Alkenyl, C 2~4 Alkynyl, phenyl, heterocyclyl, heteroaryl, -S(O)2R 7 , -CO2R 9 , -C(O)R 10 , thiol, C 1~6 Alkylthio, -C(O)SR 14 , Amino, Mono-C 1~4 Alkylamino, Di-C 1~4 optionally substituted with one or more substituents each independently selected from the group consisting of alkylamino, cyano, R 3, R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, preferably R 3 , R 4 , and R 5 are each independently 1~6 alkyl or phenyl, where each C 1~6 Alkyl or phenyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, hydroxyl, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, preferably R 7 , R 8 , R 9 , and R10 are each independently hydrogen, C 1~4 Alkyl, phenyl, and C 3~6 cycloalkyl, where each C 1~4 Alkyl, phenyl, or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 The group consisting of alkoxy, preferably fluoro, chloro, bromo, C 1~4 Alkyl, C 1~4 Alkyloxy and haloC 1~4 and optionally substituted with one or more substituents independently selected from the group consisting of alkyloxy; R 11 and R 12 are each independently hydrogen, C 1~6 Alkyl, C 6~10 Aryl, C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, preferably R 11 and R 12 are each independently hydrogen, C 1~4 Alkyl, phenyl, and C 3~6 cycloalkyl, where each C 1~4 Alkyl, phenyl, or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 The group consisting of alkoxy, preferably fluoro, chloro, bromo, C 1~4 Alkyl, C 1~4 Alkyloxy and haloC 1~4and optionally substituted with one or more substituents independently selected from the group consisting of alkyloxy; R 13 and R 14 are each independently hydrogen, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, preferably R 13 and R 14 are each independently hydrogen, C 1~4 Alkyl, phenyl, and C 3~6 cycloalkyl, where each C 1~4 Alkyl, phenyl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 The group consisting of alkoxy, preferably fluoro, chloro, bromo, C 1~4 Alkyl, C 1~4 Alkyloxy and haloC 1~4 18. The process according to any one of items 1 to 17, wherein the alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of alkyloxy.

[0077] 20. The following process: (a) reacting a compound of formula (II) at least one diluent; Optionally, at least one capture agent; Optionally with at least one base (organic or inorganic), preferably at least one organic base, or Optionally, without the use of a base, contacting to form a mixture; (b) feeding the mixture into an inlet of a channel of a reaction zone; (c) conveying a flow of the mixture along a channel from an inlet to an outlet to form a reaction product comprising at least a compound of formula (I); (d) recovering the reaction product at an outlet; (e) optionally separating at least one compound of formula (I) from other reaction products or retaining the compound of formula (I) in the reaction products; 20. The process according to any one of items 1 to 19, comprising:

[0078] 21. The following process: (a) reacting a compound of formula (II) At least one solvent; Optionally, at least one capture agent; Optionally with at least one base (organic or inorganic), preferably at least one organic base, or Optionally, without the use of a base, contacting to form a solution; (b) providing a solution to an inlet of a channel of a reaction zone; (c) conveying a flow of the solution along the channel from the inlet to the outlet to form a reaction product comprising at least a compound of formula (I); (d) recovering the reaction product at an outlet; (e) optionally separating at least one compound of formula (I) from other reaction products or retaining the compound of formula (I) in the reaction products; 21. The process according to any one of items 1 to 20, comprising:

[0079] twenty two. (d1) feeding the reaction product from step (d) to an inlet of a channel of a cooling zone; (d2) exposing the reaction product from step (d) to cooling by conveying a flow of the reaction product along a channel from the inlet to the outlet at a cooling temperature Tc for a cooling time tc; (d3) recovering the cooled reaction product at an outlet of the cooling zone; 22. The process according to item 20 or 21, further comprising:

[0080] 23. The process according to any one of items 20 to 22, wherein the reaction zone is a pyrolysis reaction zone and step (c) comprises subjecting the mixture to pyrolysis by conveying a flow of the mixture along a channel from an inlet to an outlet at a pressure P, and a pyrolysis temperature T, for a pyrolysis time t, to form a pyrolysis reaction product comprising at least the compound of formula (I).

[0081] 24. The process according to any one of items 20 to 23, 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 pyrolysis reaction carried out at a pressure P as described herein above.

[0082] 25. The process according to any one of items 20 to 24, 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 least 10.0 bar to at most 55.0 bar, preferably at least 20.0 bar to at most 50.0 bar, preferably at least 30.0 bar to at most 40.0 bar, preferably at least 10.0 bar to at most 40.0 bar, preferably at least 10 bar to at most 30.0 bar, preferably at least 12.0 bar to at most 50.0 bar, preferably at least 12.0 bar to at most 40.0 bar, preferably at least 11.0 bar to at most 35.0 bar, preferably said reaction of step (c) is a pyrolysis reaction carried out at a pressure P as described herein above.

[0083] 26. The process according to any one of items 20 to 25, wherein the reaction of step (c) is carried out for a reaction time t of at most 60 minutes, preferably at most 40 minutes, preferably at most 30 minutes, preferably at most 25 minutes, preferably at most 20 minutes, preferably at most 18 minutes, preferably said reaction of step (c) is a pyrolysis reaction carried out for a pyrolysis time t as described herein above.

[0084] 27. The process according to any one of items 20 to 26, wherein the reaction of step (c) is carried out 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 pyrolysis reaction carried out for a pyrolysis time t as described herein above.

[0085] 28. The process according to any one of items 20 to 27, wherein the reaction of step (c) is carried out 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 pyrolysis reaction carried out for a pyrolysis time t as described herein above.

[0086] 29. The process according to any one of items 20 to 28, wherein the reaction of step (c) is carried out 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 least 180°C, preferably said reaction of step (c) is a pyrolysis reaction carried out at a pyrolysis temperature T as described herein above.

[0087] 30. The reaction of step (c) is carried out 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 least 175°C to at most 240°C. 30. The process according to any one of items 20 to 29, wherein the reaction of step (c) is carried out at a pyrolysis temperature T as described herein above, 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°C to at most 220°C, preferably at a temperature of at least 190°C to at most 220°C, preferably at a temperature of at least 200°C 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 wherein the above-mentioned reaction of step (c) is a pyrolysis reaction carried out at a pyrolysis temperature T as described herein above.

[0088] 31. The process according to any one of items 20 to 30, wherein the cooling temperature Tc in step (d2) is at least -10.0°C to at most 20.0°C, preferably at least -5.0°C to at most 20.0°C, preferably at least -5.0°C to at most 15.0°C, preferably at least -5.0°C to at most 10.0°C, preferably at least -4.0°C to at most 8.0°C, preferably at least -3.0°C to at most 7.0°C, preferably at least -2.0°C to at most 6.0°C, preferably at least -1.0°C to at most 5.0°C.

[0089] 32. The process according to any one of items 20 to 31, wherein the cooling is carried out at the same pressure as in the reaction step (c).

[0090] 33. The process according to any one of items 20 to 32, wherein the cooling is carried out at atmospheric pressure.

[0091] 34. The process according to any one of items 20 to 33, wherein the cooling time tc of step (d2) is at most 120 min, preferably 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.

[0092] 35. The process according to any one of items 20 to 34, wherein the cooling time tc in step (d2) is 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.

[0093] 36. The process according to any one of items 20 to 35, wherein the compound of formula (II) is present during the mixing in step (a) in an amount of at least 0.01 mol per liter of diluent, preferably at least 0.02 mol per liter of diluent, preferably at least 0.05 mol per liter of diluent, preferably at least 0.10 mol per liter of diluent, preferably at most 5.0 mol per liter of diluent, preferably at most 4.0 mol per liter of diluent, preferably at most 3.0 mol per liter of diluent, preferably at most 2.0 mol per liter of diluent, preferably at most 1.0 mol per liter of diluent.

[0094] 37. The compound of formula (II) is present during the mixing in step (a) in an amount of at least 0.01 moles per liter of diluent to at most 5.0 moles per liter of diluent, preferably at least 0.01 moles per liter of diluent to at most 3.0 moles per liter of diluent, preferably at least 0.01 moles per liter of diluent to at most 1.0 moles per liter of diluent, preferably at least 0.01 moles per liter of diluent to at most 0.80 moles per liter of diluent, preferably at least 0.02 moles per liter of diluent to at most 0.70 moles per liter of diluent, preferably at least 0.05 moles per liter of diluent to at most 0.60 moles per liter of diluent, preferably at least 0.06 moles per liter of diluent to at most 0.56 ... 37. The process according to any one of items 20 to 36, wherein the diluent is present in an amount of at least 0.10 moles per liter of diluent to at most 0.55 moles per liter of diluent, preferably at least 0.15 moles per liter of diluent to at most 0.50 moles per liter of diluent, preferably at least 0.15 moles per liter of diluent to at most 0.45 moles per liter of diluent, preferably at least 0.15 moles per liter of diluent to at most 0.40 moles per liter of diluent, preferably at least 0.15 moles per liter of diluent to at most 0.35 moles per liter of diluent, preferably at least 0.15 moles per liter of diluent to at most 0.30 moles per liter of diluent, preferably at least 0.15 moles per liter of diluent to at most 0.25 moles per liter of diluent.

[0095] 38. The compound of formula (II) is present during the mixing in step (a) in an amount of from at least 0.01 moles per liter of diluent to at most 5.0 moles per liter of diluent, preferably from at least 0.01 moles per liter of diluent to at most 4.0 moles per liter of diluent, preferably from at least 0.01 moles per liter of diluent to at most 2.0 moles per liter of diluent, preferably from at least 0.01 moles per liter of diluent to at most 0.90 moles per liter of diluent, preferably from at least 0.02 moles per liter of diluent to at most 1.0 moles per liter of diluent. 38. The process according to any one of items 20 to 37, wherein the diluent is present in an amount of at most 0.60 moles per litre, preferably at least 0.06 moles per litre diluent to at most 0.50 moles per litre diluent, preferably at least 0.06 moles per litre diluent to at most 0.40 moles per litre diluent, preferably at least 0.06 moles per litre diluent to at most 0.30 moles per litre diluent, preferably at least 0.06 moles per litre diluent to at most 0.25 moles per litre diluent.

[0096] 39. The process according to any one of items 21 to 38, wherein the compound of formula (II) is present in the solution of step (a) in an amount of at least 0.01 mol per liter of solution, preferably at least 0.02 mol per liter of solution, preferably at least 0.05 mol per liter of solution, preferably at least 0.10 mol per liter of solution, preferably at most 5.0 mol per liter of solution, preferably at most 4.0 mol per liter of solution, preferably at most 3.0 mol per liter of solution, preferably at most 2.0 mol per liter of solution, preferably at most 1.0 mol per liter of solution.

[0097] 40. The compound of formula (II) is present in the solution of step (a) in an amount of at least 0.01 moles per liter of solution to at most 5.0 moles per liter of solution, preferably at least 0.01 moles per liter of solution to at most 3.0 moles per liter of solution, preferably at least 0.01 moles per liter of solution to at most 1.0 moles per liter of solution, preferably at least 0.01 moles per liter of solution to at most 0.80 moles per liter of solution, preferably at least 0.02 moles per liter of solution to at most 0.70 moles per liter of solution, preferably at least 0.05 moles per liter of solution to at most 0.60 moles per liter of solution, preferably at least 0.06 moles per liter of solution to at most 0.56 moles per liter of solution, preferably at least 1.0 moles per liter of solution, more preferably at least 0.01 moles per liter of solution to at most 0.80 moles per liter of solution, more preferably at least 0.02 moles per liter of solution to at most 0.70 moles per liter of solution, more preferably at least 0.05 moles per liter of solution to at most 0.60 moles per liter of solution, more preferably at least 0.06 moles per liter of solution to at most 0.56 moles per liter of solution, more preferably at least 1.0 moles per liter of solution, 40. The process according to any one of items 21 to 36, 39, wherein the compound is present in an amount of at least 0.10 moles per liter to at most 0.55 moles per liter of solution, preferably at least 0.15 moles per liter of solution to at most 0.50 moles per liter of solution, preferably at least 0.15 moles per liter of solution to at most 0.45 moles per liter of solution, preferably at least 0.15 moles per liter of solution to at most 0.40 moles per liter of solution, preferably at least 0.15 moles per liter of solution to at most 0.35 moles per liter of solution, preferably at least 0.15 moles per liter of solution to at most 0.30 moles per liter of solution, preferably at least 0.15 moles per liter of solution to at most 0.25 moles per liter of solution.

[0098] 41. The compound of formula (II) is present in the solution of step (a) in an amount of from at least 0.01 mol per L of solution to at most 5.0 mol per L of solution, preferably from at least 0.01 mol per L of solution to at most 4.0 mol per L of solution, preferably from at least 0.01 mol per L of solution to at most 2.0 mol per L of solution, preferably from at least 0.01 mol per L of solution to at most 0.90 mol per L of solution, preferably from at least 0.02 mol per L of solution to at most 1.0 mol per L of solution. 41. The process according to any one of items 21 to 36, 39 or 40, wherein the cation is present in an amount of at most 0.60 moles, preferably at least 0.06 moles per litre of solution to at most 0.50 moles per litre of solution, preferably at least 0.06 moles per litre of solution to at most 0.40 moles per litre of solution, preferably at least 0.06 moles per litre of solution to at most 0.30 moles per litre of solution, preferably at least 0.06 moles per litre of solution to at most 0.25 moles per litre of solution.

[0099] 42. The process according to any one of items 1 to 41, wherein the desulfinylation step is carried out in the presence of at least one scavenger.

[0100] 43. The desulfinylation step is carried out in the presence of at least one scavenger, where the at least one scavenger is selected from the group consisting of dialkyl acetylenedicarboxylate (e.g., 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, and the like. 43. The process according to any one of items 1 to 42, wherein the at least one scavenger is selected from the group comprising dialkyl acetylenedicarboxylate (DIAD), methyl propiolate, phenylacetylene, N,N-diisopropylethylamine (DIPEA), trimethyl phosphite (TMP), methanol, dimethylsulfoxide, p-benzoquinone; NaHCO3, K2CO3, Na2CO3, CaCO3, Cs2CO3; and combinations thereof, preferably, the at least one scavenger is a 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.

[0101] 44. The process according to any one of items 1 to 43, wherein the desulfinylation step is carried out in the presence of at least one scavenger, wherein the at least one scavenger is present in an amount of at least 0.1 equivalents to at most 10.0 equivalents, preferably in an amount of at least 0.2 equivalents to at most 9.0 equivalents, preferably in an amount of at least 0.3 equivalents to at most 8.5 equivalents, preferably in an amount of at least 0.2 equivalents to at most 8.0 equivalents, preferably in an amount of at least 0.5 equivalents to at most 7.0 equivalents, preferably in an amount of at least 0.5 equivalents to at most 5.0 equivalents, preferably in an amount of 0.5 equivalents to at most 4.0 equivalents, preferably in an amount of at least 1.0 equivalents to at most 3.0 equivalents, preferably in an amount of at least 1.0 equivalents to at most 2.0 equivalents.

[0102] 45. The process according to any one of items 1 to 44, wherein the desulfinylation step is carried out in the presence of two or more scavengers, wherein the scavengers are present in an amount of at least 0.1 equivalents to at most 10.0 equivalents, preferably in an amount of at least 0.2 equivalents to at most 9.0 equivalents, preferably in an amount of at least 0.3 equivalents to at most 8.5 equivalents, preferably in an amount of at least 0.2 equivalents to at most 8.0 equivalents, preferably in an amount of at least 0.5 equivalents to at most 7.0 equivalents, preferably in an amount of at least 0.5 equivalents to at most 5.0 equivalents, preferably in an amount of 0.5 equivalents to at most 4.0 equivalents, preferably in an amount of at least 1.0 equivalents to at most 3.0 equivalents, preferably in an amount of at least 1.0 equivalents to at most 2.0 equivalents.

[0103] 46. ​​The process according to any one of items 1 to 45, wherein the desulfinylation step is carried out in the absence of a base.

[0104] 47. The process according to any one of items 1 to 45, wherein the desulfinylation step is carried out in the presence of at least one base, preferably at least one organic base.

[0105] 48. The process according to any one of items 1 to 45, 47, wherein the desulfinylation step is carried out in the presence of at least one organic base, 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), N,N-diisopropylethylamine (DIPEA), (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), imidazole, 2,6-lutidine, and combinations thereof, preferably the at least one organic base is triethylamine.

[0106] 49. The process according to any one of items 1 to 45, 47 and 48, wherein the desulfinylation step is carried out in the presence of at least one organic base, wherein the at least one organic base is present in an amount of at least 0.01 equivalents to at most 10.0 equivalents, preferably at least 0.01 equivalents to at most 5.0 equivalents, preferably 0.01 equivalents to at most 1.0 equivalents, preferably at least 0.01 equivalents to at most 0.9 equivalents, preferably at least 0.05 equivalents to at most 0.8 equivalents, preferably at least 0.05 equivalents to at most 0.5 equivalents, preferably 0.05 equivalents to at most 0.3 equivalents, preferably at least 0.05 equivalents to 0.2 equivalents.

[0107] 50. The process according to any one of items 1 to 45, 47 to 49, wherein the desulfinylation step is carried out in the presence of two or more organic bases, wherein the organic bases are present in a total amount of at least 0.01 equivalents to at most 10.0 equivalents, preferably at least 0.01 equivalents to at most 5.0 equivalents, preferably 0.01 equivalents to at most 1.0 equivalents, preferably at least 0.01 equivalents to at most 0.9 equivalents, preferably at least 0.05 equivalents to at most 0.8 equivalents, preferably at least 0.05 equivalents to at most 0.5 equivalents, preferably 0.05 equivalents to at most 0.3 equivalents, preferably at least 0.05 equivalents to 0.2 equivalents.

[0108] 51. The process according to any one of items 1 to 50, wherein the desulfinylation step is carried out in the presence of at least one scavenger and at least one organic base.

[0109] 52. The process according to any one of items 1 to 51, 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, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, n-butyl acetate, anisole, chlorobenzene, tetrahydrofuran, propan-2-one, butan-2-one, pentan-2-one, 4-methylpentan-2-one, dichlorobenzene, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, N,N'-dimethylpropyleneurea, sulfolane, and combinations thereof.

[0110] 53. The process according to any one of items 1 to 52, 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 combinations thereof.

[0111] 54. The process according to any one of items 1 to 53, wherein the compound of formula (II) is a compound of formula (II') and the compound of formula (I) is a compound of formula (I'): [ka]

[0112] 55. A compound of formula (II): a) protecting the hydroxyl of a compound of formula (III) to form a compound of formula (IV), 1 has the same meaning as in items 1 to 3: [ka] b) sulfinylating a compound of formula (IV) to form a compound of formula (II); 55. The process according to any one of items 1 to 54, which is obtained by a process comprising:

[0113] 56. The process according to item 55, wherein the sulfinylation is carried out by reacting the compound of formula (IV) with at least one sulfinylating reagent, preferably in the presence of at least one suitable base.

[0114] 57. The sulfinylation is carried out by reacting the compound of formula (IV) with at least one sulfinylating reagent, preferably the at least one sulfinylating reagent is selected from the group consisting of methyl benzenesulfinate, methyl pyridine-2-sulfinate, methyl 4-methylbenzenesulfinate, methyl 4-chlorobenzenesulfinate, methyl 4-bromobenzenesulfinate, methyl 4-fluorobenzenesulfinate, methyl 4-methoxybenzenesulfinate, methyl 4-nitrobenzenesulfinate, methyl 2,3,4,5,6 57. The process according to item 55 or 56, wherein the methyl 4-(trifluoromethylsulfonyl)-benzenesulfinate, 1-(4-methylsulfinylphenyl)ethanone, methyl 4-cyano-benzenesulfinate, methyl 4-(dimethylamino)-benzenesulfinate, methyl 4-(methylsulfinic acid)-benzoate, and methyl 4-(2-benzothiazolyl)-benzenesulfinate are selected from the group comprising methyl 4-(methylsulfinic acid)-benzoate, methyl 4-(methylsulfinic acid)-benzoate, and methyl 4-(2-benzothiazolyl)-benzenesulfinate.

[0115] 58. The process according to any one of items 55 to 57, wherein the sulfinylation reaction is carried out in the presence of at least one suitable base, wherein the at least one base is selected from sodium hydride, sodium tert-butylate, potassium hydride, potassium tert-butylate, or a mixture thereof.

[0116] 59. The composition described above comprises a compound of formula (I) and a compound of formula (IIa): [ka] Including, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , C 1~6 Alkoxy, C 3~6 Cycloalkyl and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, and C 3~6 Each cycloalkyl may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , -SR 13, -C(O)SR 14 , N.R. 11 R 12 optionally substituted with one or more substituents each independently selected from the group consisting of , cyano and nitro; R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 6 is C 1~6 Alkyl, C 6~10 Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 7 , R 8 , R 9 , and R 10 is hydrogen, hydroxyl, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 11 and R 12 is hydrogen, C 1~6 Alkyl, C 6~10 Aryl, C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 13 and R 14 is hydrogen, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 59. The composition obtainable by the process according to any one of items 1 to 58, wherein the compound is aryl.

[0117] 60. The composition described above comprises a compound of formula (I) and a compound of formula (IIa): [ka] Including, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl and C 6~10 Aryl C 1~6 Each of the alkyl groups may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy, and nitro; R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4and optionally substituted with one or more substituents each independently selected from alkyl, R 6 is C 1~6 Alkyl, C 6~10 Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 59. The composition obtainable by the process according to any one of items 1 to 58, wherein the compound is aryl.

[0118] 61. A composition, comprising a compound of formula (I) and a compound of formula (IIa): [ka] Including, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , C 1~6 Alkoxy, C 3~6 Cycloalkyl and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, and C 3~6 Each cycloalkyl may be halo, C1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , -SR 13 , -C(O)SR 14 , N.R. 11 R 12 optionally substituted with one or more substituents each independently selected from the group consisting of , cyano and nitro; R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 6 is C 1~6 Alkyl, C 6~10Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, hydroxyl, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 11 and R 12 are each independently hydrogen, C 1~6 Alkyl, C 6~12 Aryl, C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 13 and R 14 are each independently hydrogen, C 1~6 Alkyl, C 6~10Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 The composition, wherein:

[0119] 62. The composition comprises a compound of formula (IIb): [ka] Also includes In the formula, R 1 The composition according to items 59 to 61, wherein said composition is as defined in any one of items 59 to 61.

[0120] 63. The composition comprises a compound of formula (IIc): [ka] Also includes In the formula, R 1 The composition according to items 59 to 62, wherein the composition is as defined in any one of items 59 to 61.

[0121] 64. The composition comprises a compound of formula (IId): [ka] Also includes In the formula, R 1 and R 2 The composition according to items 59 to 63, wherein said composition is as defined in any one of items 59 to 61.

[0122] 65. The composition according to any one of items 59 to 64, wherein the composition comprises compound (IIa) in an amount of at least 0.01 area % by HPLC, preferably at least 0.1 area % by HPLC, preferably at least 0.5 area % by HPLC, preferably at least 1.0 area % by HPLC of compound (IIa), based on the total area of ​​the composition determined by HPLC, wherein the HPLC method is as described in the Examples section of the present application.

[0123] 66. The composition according to any one of items 59 to 65, wherein the composition comprises at most 25.0 area % of compound (IIa) by HPLC, preferably at most 20.0% of compound (IIa), preferably at most 15.0 area % of compound (IIa) by HPLC, preferably at most 10.0 area % of compound (IIa) by HPLC, preferably at most 10.5 area % of compound (IIa) by HPLC, preferably at most 5.0 area % of compound (IIa) by HPLC, based on the total area of ​​the composition determined by HPLC, wherein the HPLC method is as described in the Examples section of the present application.

[0124] 67. The composition according to any one of items 59 to 66, wherein the composition comprises compound (IIb) in an amount of at most 16.0 area % by HPLC, preferably compound (IIb) in an amount of at most 10.0 area % by HPLC, preferably compound (IIb) in an amount of at most 5.0 area % by HPLC, based on the total area of ​​the composition determined by HPLC, wherein the HPLC method is as described in the Examples section of the present application.

[0125] 68. The composition according to any one of items 59 to 67, wherein the composition comprises compound (IIc) in an amount of at most 10.0 area % by HPLC, preferably at most 8.0 area % by HPLC of compound (IIc), preferably at most 5.0 area % by HPLC of compound (IIc), preferably at most 2.0 area % by HPLC of compound (IIc), based on the total area of ​​the composition determined by HPLC, wherein the HPLC method is as described in the Examples section of the present application.

[0126] 69. The composition according to any one of items 59 to 68, wherein the composition comprises compound (IId) in an amount of at most 3.0 area % by HPLC, preferably at most 2.0 area % by HPLC, preferably at most 1.0 area % by HPLC, preferably at most 0.5 area % by HPLC of compound (IId), based on the total area of ​​the composition determined by HPLC, wherein the HPLC method is as described in the Examples section of the present application.

[0127] 70.Formula (E): [ka] A process for preparing estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol of formula (E), its stereoisomer, salt, hydrate, or solvate, comprising the steps of preparing a compound of formula (I) by a process according to any one of items 1 to 58, and further reacting the compound of formula (I) to produce estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol of formula (E), its stereoisomer, salt, hydrate, ester, ether, or solvate.

[0128] 71. The estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol of formula (E) is reacted with the compound of formula (E'): [ka] 71. The process according to item 70, wherein the estetrol is of formula (I).

[0129] 72.Formula (E): [ka] A process for the preparation of estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol, its stereoisomers, salts, hydrates, esters, ethers or solvates, comprising The above process is a1) using a process according to any one of items 1 to 58, the formula (I): [ka] A process for preparing a compound of the formula: In the formula, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , C 1~6 Alkoxy, C 3~6 Cycloalkyl and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, and C 3~6 Each cycloalkyl may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 6 is C 1~6 Alkyl, C 6~10 Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 aryl; b1) contacting a compound of formula (I) with a reducing agent to produce a compound of formula (A): [ka] and producing a compound of the formula: c1) contacting the compound of formula (A) with an acylating agent or a silylating agent to obtain a compound of formula (B): [ka] A process for producing a compound of the formula: In the formula, R 2a is (R 7 R 8 R 9 )C-CO-, or (R 10 )Si(R 11 )(R12 )-, R 7 , R 8 , and R 9 are each independently hydrogen, C 1~6 Alkyl or C 6~10 aryl, as described above. 1~6 Alkyl or C 6~10 Each of the aryl groups may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy; R 10 , R 11 , and R 12 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 optionally substituted with one or more substituents each independently selected from alkyl; d1) contacting the compound of formula (B) with at least one oxidizing agent to produce a compound of formula (C): [ka] and producing a compound of the formula: e1) deprotecting the compound of formula (C) to form a compound of formula (E); The process includes:

[0130] 73.R 1 But R 3 Si(R 4 )(R 5 )- and R 2a But R 10 Si(R 11 )(R12 73. The process according to item 72, wherein

[0131] 74.Formula (E): [ka] A process for the preparation of estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol, its stereoisomers, salts, hydrates, esters, ethers or solvates, comprising The above process is a2) using a process according to any one of items 1 to 58, the formula (I): [ka] A process for preparing a compound of the formula: During the ceremony, R 1 is benzyl; and b2) contacting the compound of formula (I) with a reducing agent to produce a compound of formula (A): [ka] and producing a compound of the formula: c2) contacting the compound of formula (A) with at least one oxidizing agent to form a compound of formula (K): [ka] and producing a compound of the formula: d2) contacting the compound of formula (K) with an acylating agent to obtain a compound of formula (L): [ka] A process for producing a compound of the formula: During the ceremony, R 20 is selected from hydrogen or methyl; e2) removing the benzyl protecting group at position 3 by transfer hydrogenation or catalytic hydrogenation to obtain a compound of general formula (M): [ka] and obtaining a compound of formula (I) f2) deprotecting the compound of formula (M) using an alkali metal carbonate, alkali metal bicarbonate or alkali metal hydroxide in a suitable solvent to form compound (E); The process includes:

[0132] 75. The process according to item 74, wherein the acylating agent in step d2) is selected from the group consisting of acetic anhydride, acetyl chloride, acetic-formic mixed anhydride and acetyl bromide.

[0133] 76. The process according to item 74 or 75, wherein step d2) is carried out in the presence of a tertiary amine base.

[0134] 77.Formula (E): [ka] A process for the preparation of estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol, its stereoisomers, salts, hydrates or solvates, comprising The above process is a3) using a process according to any one of items 1 to 58, the formula (I): [ka] A process for preparing a compound of the formula: During the ceremony, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , C 1~6 Alkoxy, C 3~6 Cycloalkyl and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C1~6 Alkyl, and C 3~6 Each cycloalkyl may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 6 is C 1~6 Alkyl, C 6~10 Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 aryl; b3) contacting the compound of formula (I) with a reducing agent to obtain a compound of formula (A): [ka] and producing a compound of the formula: c3) Removal of the protecting group R from the compound of formula (A) 1 to produce a diol; d3) Protecting the hydroxyl group at C3 of the diol obtained in step c) to give the diol of formula (G) [ka] A process for producing a compound of the formula: During the ceremony, R 1b is R 13 -CO-, R 14 Si(R 15 )(R 16 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, C 3~6 Cycloalkyl, heterocyclyl, heteroaryl, R 17 R 18 N-CO- or R 19 -OCO-, preferably R 13 -CO-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Arylthio C 1~6 alkyl, heterocyclyl, or heteroaryl, preferably R 13 -CO-, C 1~4 Alkyl, C 6~10 Aryl, C 6~10 Arylthio C 1~6 is a protecting group selected from alkyl, heterocyclyl, or heteroaryl, 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, C 3~6 Cycloalkyl, heterocyclyl or heteroaryl can be selected from halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylthio and haloC 1~6alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, preferably R 1b is R 13 -CO-, 1-butoxyethyl, tetrahydropyranyl, phenylthiomethyl, and methyloxymethyl; R 13 is C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, C 3~6 cycloalkyl, heterocyclyl, or heteroaryl, wherein each C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, C 3~6 Cycloalkyl, heterocyclyl or heteroaryl can be selected from halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylthio and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 14 , R 15 , and R 16 are each independently 1~6 Alkyl, C 3~6 Cycloalkyl, or C 6~10 aryl, where each C 1~6 Alkyl, C 3~6 Cycloalkyl, or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4and optionally substituted with one or more substituents each independently selected from alkyl, R 17 and R 18 are each independently 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 19 is C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, C 3~6 cycloalkyl, heterocyclyl, and heteroaryl, wherein each C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, C 3~6 Cycloalkyl, heterocyclyl, or heteroaryl can be selected from halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 optionally substituted with one or more substituents each independently selected from alkyl; e3) optionally protecting the hydroxyl group at C17 of the compound of formula (G) to give a compound of formula (H): [ka] A process for producing a compound of the formula: During the ceremony, R 2b is C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Arylthio C 1~6 The group consisting of alkyl, heterocyclyl, and heteroaryl, preferably C 1~4 Alkyl, C 6~10 is a protecting group selected from aryl, heterocyclyl, or heteroaryl, 1~6 Alkyl, C 6~10 Each of the aryl, heterocyclyl, or heteroaryl is selected from halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylthio and haloC 1~6 The group consisting of alkoxy, preferably fluoro, chloro, C 1~4 Alkoxy or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, preferably R 2b is selected from the group consisting of 1-butoxyethyl, tetrahydropyranyl, phenylthiomethyl, and methyloxymethyl; f3) contacting the compound of formula (G) or the compound of formula (H) with at least one oxidizing agent selected from the group consisting of permanganate, osmium oxide, potassium osmate, hydrogen peroxide, iodine, and silver acetate to produce a compound of formula (E) or a compound of formula (J): [ka] and producing a compound of the formula: g3) if a compound of formula (J) is obtained in step f3), deprotecting the compound of formula (J) to give a compound of formula (E); The process includes:

[0135] 78. The process according to any one of items 72 to 77, wherein the at least one oxidizing agent is selected from the group consisting of permanganate, osmium oxide, potassium osmate, hydrogen peroxide, iodine, and silver acetate.

[0136] 79. The process according to any one of items 72 to 78, wherein the at least one oxidizing agent is supported osmium oxide.

[0137] 80. The process according to any one of items 72 to 79, wherein the at least one oxidizing agent is osmium oxide immobilized on poly(4-vinyl-pyridine) (PVP).

[0138] 81. The process according to any one of items 72 to 80, wherein the at least one oxidizing agent is used in combination with a co-oxidizing agent.

[0139] 82. The process according to any one of items 72 to 81, wherein said at least one oxidizing agent is used in combination with a co-oxidizing agent selected from the group consisting of trialkylamine-N-oxide, N-methylmorpholine-N-oxide and hydrogen peroxide, preferably trimethylamine-N-oxide, triethylamine-N-oxide, N-methylmorpholine-N-oxide or hydrogen peroxide.

[0140] 83. The process according to any one of items 72 to 82, wherein the at least one oxidizing agent is osmium oxide immobilized on PVP in combination with a co-oxidizing agent.

[0141] 84. The process according to any one of items 72 to 83, wherein said at least one oxidizing agent is osmium oxide fixed on PVP in combination with a co-oxidizing agent selected from the group consisting of trialkylamine-N-oxide, N-methylmorpholine-N-oxide and hydrogen peroxide, preferably trimethylamine-N-oxide, triethylamine-N-oxide, N-methylmorpholine-N-oxide or hydrogen peroxide.

[0142] 85.R1b and R 2b The process according to any one of items 72 to 84, wherein are the same protecting group.

[0143] 86. The compound of formula (E) is represented by the formula (E'): [ka] 86. The process according to any one of items 72 to 85, wherein the estetrol is of the formula:

[0144] 87. A manufacturing line for preparing a compound of formula (I) by a continuous flow process, comprising: (a) Below: A source of a compound of formula (II), A source of diluent, and optionally a source of at least one scavenger and optionally a source of at least one base, preferably at least one organic base; a source of reactants comprising (b) a diluent tank (preferably a solution tank) in fluid communication with the source of reactant; (c) at least one pump that fluidly connects a diluent tank (preferably a solution tank) with the reaction zone; Where: (d) The reaction zone is a channel extending from an inlet to an outlet located downstream of the inlet, where at least one pump is located directly upstream of the inlet; a heating module arranged to heat the channel at a reaction temperature; Optionally, a cooling zone for cooling the mixture exiting the channel, said cooling zone being located downstream of the outlet; Including, (e) optionally a separation zone for separating at least one compound of formula (I) from other reaction products; A production line comprising:

[0145] 88. The production line according to item 87, wherein the diluent is a solvent.

[0146] 89. The production line according to item 87 or 88, wherein the reaction zone is a pyrolysis reaction zone.

[0147] 90. A production line for preparing a compound of formula (I) by pyrolysis, comprising: (a) Below: A source of a compound of formula (II), A source of solvent; and optionally a source of at least one scavenger and optionally a source of at least one base, preferably at least one organic base; a source of reactants comprising (b) a solution tank in fluid communication with a source of reactant; (c) at least one pump fluidly connecting the solution tank with the pyrolysis reaction zone; (d) The pyrolysis reaction zone is a channel extending from an inlet to an outlet located downstream of the inlet, where at least one pump is located directly upstream of the inlet; a heating module arranged to heat the channel at a pyrolysis temperature; Optionally, a cooling zone for cooling the solution exiting the channel, said cooling zone being located downstream of the outlet; Including, (e) optionally a separation zone for separating the at least one compound of formula (I) from other pyrolysis products; A production line comprising:

[0148] 91. The process according to any one of items 1 to 86, comprising contacting, after the reaction, the reaction mixture comprising the compound of formula (I) and other reaction products with an aqueous solution.

[0149] 92. The process according to item 91, wherein the aqueous solution comprises an inorganic base.

[0150] 93. The process according to item 91 or 92, wherein the aqueous solution comprises an inorganic base selected from the group comprising NaOH, KOH, NaHCO3, K2CO3, NH4Cl, Na2S2O3 and mixtures thereof, preferably said aqueous solution comprises NaOH.

[0151] 94. The process according to any one of items 91 to 93, wherein the aqueous solution is a 0.5 mol / L to 2 mol / L NaOH solution, preferably a 1 mol / L NaOH solution.

[0152] 95. The process according to any one of items 91 to 94, wherein the reaction mixture is contacted with the aqueous solution and stirred for at least 15 minutes to at most 10 hours, preferably for at least 15 minutes to at most 5 hours, preferably for at least 30 minutes to at most 2 hours.

[0153] 96. The process according to any one of items 91 to 95, wherein the reaction mixture is a cooled reaction mixture.

[0154] Any reference to a "compound" also includes, unless otherwise specified, isomers, e.g., stereoisomers and tautomers, salts, e.g., pharma- ceutically and / or physiologically acceptable salts, hydrates, ethers, esters, and solvates of such compound.

[0155] The term "isomer" as used herein refers to all possible isomeric forms, including tautomers and stereochemical forms that the compounds of each formula herein may have, but does not include positional isomers. Typically, the structures shown herein illustrate one tautomer or resonance form of the compound, but the corresponding alternative configurations are also contemplated.

[0156] The compounds of the present invention may exist in solvated and non-solvated forms. The term "solvate" refers to the crystal formed by an active compound and a second component (solvent) that is liquid at room temperature in isolated form. Such solvates can be formed with common organic solvents, for example, hydrocarbon solvents such as benzene or toluene, chlorinated solvents such as chloroform or dichloromethane, alcoholic solvents such as methanol, ethanol or isopropanol, ether solvents such as diethyl ether or tetrahydrofuran, or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds herein can be formed with water, in which case they become hydrates.

[0157] A currently accepted classification system for organic hydrates defines isolated site hydrates, channel hydrates, or metal ion coordinated hydrates; see KR Morris, Polymorphism in Pharmaceutical Solids, Ed. HG Britain, Marcel Dekker, 1995, incorporated herein by reference. Isolated site hydrates are those in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules are in lattice channels where they are next to other water molecules. In metal ion coordinated hydrates, the water molecules are bound to the metal ion.

[0158] If the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. However, if the solvent or water is weakly bound, such as in channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0159] Also included within the scope of the present invention are multicomponent complexes (excluding salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes clathrates (drug-host inclusion complexes) and cocrystals. The latter are usually defined as crystalline complexes of neutral molecular components bound together through non-covalent interactions, but can also be complexes of neutral molecules with salts. Cocrystals can be prepared by melt crystallization, recrystallization from solvents, or by physically grinding the components together. See O. Almarsson and MJ Zaworotko, Chem. Commun., 17, 1889-1896 (2004), which is incorporated herein by reference. For a review of multicomponent complexes, see Haleblian, J. Pharm. Sci., 64 (8), 1269-1288 (August 1975), which is incorporated herein by reference.

[0160] The compounds of the invention can also exist in a mesophase (mesophase or liquid crystal) when subjected to appropriate conditions. A mesophase is intermediate between a true crystalline state and a true liquid state (either melt or solution). Mesophases that result as a result of a change in temperature are described as "thermotropic" and those that result as a result of the addition of a second component, such as water or another solvent, are described as "lyotropic". Compounds that can form lyotropic mesophases are described as "amphiphilic" and may be ionic (-COO - Na + , -COO - K + , or -SO3 - Na + etc.) or non-ionic (-N - N + For more information, see NH Hartshorne and A. Stuart, "Crystals and the Polarizing Microscope," 4th edition, which is incorporated herein by reference. th See the American Journal of Physics, Vol. 13, No. 1, 1970 (Edward Arnold).

[0161] The present invention relates to a compound of formula (I): [ka] A continuous flow process for preparing a compound of the formula (I), a stereoisomer, salt, hydrate or solvate thereof, comprising: Formula (II): [ka] to produce a compound of formula (I), During the ceremony, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , C 1~6 Alkoxy, C 3~6 Cycloalkyl and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, C 3~6 Each cycloalkyl may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 Optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro, preferably R 1 is R 3 Si(R 4 )(R 5 )-, C 1~4 Alkyl, Phenyl, C 6~10 Aryl C 1~4 Alkyl, -CH2-CH=CR a R b , C1~4 Alkoxy, C 3~6 Cycloalkyl and R 6 CO-, 1~4 Alkyl, Phenyl, C 6~10 Aryl C 1~4 Alkyl or C 3~6 Each cycloalkyl may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy, and nitro, preferably R 1 is R 3 Si(R 4 )(R 5 )-, C 1~4 Alkyl, Phenyl, C 6~10 Aryl C 1~4 Alkyl, -CH2-CH=CR a R b , C 1~4 Alkoxy, C 3~6 Cycloalkyl and R 6 CO-, 1~4 Alkyl, Phenyl, C 6~10 Aryl C 1~4 Alkyl or C 3~6 Each cycloalkyl is fluoro, chloro, bromo, C 1~4 Alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy, HaloC 1~4 Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy, and nitro, preferably R 1 is R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl and C6~10 Aryl C 1~6 Each of the alkyl groups may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy, and nitro, preferably R 1 is R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl and C 6~10 Aryl C 1~6 alkyl, preferably R 1 is R 3 Si(R 4 )(R 5 )-, preferably R 1 is R 3 Si(R 4 )(R 5 )-, C 1~4 Alkyl, C 6~10 Aryl and C 6~10 Aryl C 1~4 alkyl, preferably R 1 is R 3 Si(R 4 )(R 5 )-and R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , -SR 13, -C(O)SR 14 , N.R. 11 R 12 , cyano and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy C 6~10 Aryl, heteroaryl, -S(O)R 7 , -CO2R 9 , -C(O)R 10 , N.R. 11 R 12 or cyano, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N and / or S, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , N.R. 11 R 12 , cyano and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heteroaryl, -S(O)R 7 , -CO2R 9 , -C(O)R 10 , N.R. 11 R 12or cyano, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , -SR 13 , -C(O)SR 14 , N.R. 11 R 12 , cyano and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heteroaryl, -S(O)R 7 , -S(O)R 8 , -CO2R 9 , -C(O)R 10 , N.R. 11 R 12 or cyano, R 3 , R 4 , and R 5 are each independently 1~6 Alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 6 is C 1~6 Alkyl or C 3~6 cycloalkyl, where each C 1~6 Alkyl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents independently selected from alkyl, R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, hydroxyl, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, preferably R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, hydroxyl, C 1~4 Alkyl, phenyl, and C 3~6 cycloalkyl, wherein each C 1~4 Alkyl, phenyl, or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6Alkyl, C 1~6 Alkoxy and haloC 1~6 The group consisting of alkoxy, preferably fluoro, chloro, bromo, iodo, C 1~4 Alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy and haloC 1~4 Optionally substituted with one or more substituents independently selected from alkoxy, preferably R 7 , R 8 , R 9 , and R 10 are each independently 1~4 alkyl and phenyl, wherein each C 1~4 Alkyl or phenyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 The group consisting of alkoxy, preferably fluoro, chloro, bromo, iodo, C 1~4 Alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy and haloC 1~4 optionally substituted with one or more substituents independently selected from alkoxy; R 11 and R 12 are each independently hydrogen, C 1~6 Alkyl, C 6~12 Aryl, C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, preferably R 11 and R 12 are each independently hydrogen, C 1~4 Alkyl, Phenyl, C 3~6cycloalkyl, wherein each C 1~4 Alkyl, phenyl, or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 The group consisting of alkoxy, preferably fluoro, chloro, bromo, iodo, C 1~4 Alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy and haloC 1~4 Optionally substituted with one or more substituents independently selected from alkoxy, preferably R 11 and R 12 are each independently 1~4 alkyl and phenyl, wherein each C 1~4 Alkyl or phenyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 The group consisting of alkoxy, preferably fluoro, chloro, bromo, iodo, C 1~4 Alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy and haloC 1~4 optionally substituted with one or more substituents independently selected from alkoxy; R 13 and R 14 are each independently hydrogen, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, preferably R 13and R 14 are each independently hydrogen, C 1~4 Alkyl, Phenyl, C 3~6 cycloalkyl, wherein each C 1~4 Alkyl, phenyl, or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 The group consisting of alkoxy, preferably fluoro, chloro, bromo, iodo, C 1~4 Alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy and haloC 1~4 Optionally substituted with one or more substituents independently selected from alkoxy, preferably R 13 and R 14 are each independently 1~4 alkyl and phenyl, wherein each C 1~4 Alkyl or phenyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 The group consisting of alkoxy, preferably fluoro, chloro, bromo, iodo, C 1~4 Alkyl, haloC 1~4 Alkyl, C 1~4 Alkoxy and haloC 1~4 optionally substituted with one or more substituents independently selected from alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 is aryl, Preferably, the above mentioned desulfinylation step is carried out by pyrolysis, providing a continuous flow process.

[0162] The present invention also relates to a compound of formula (I): [ka] A continuous flow process for preparing a compound of the formula (I), a stereoisomer, salt, hydrate or solvate thereof, comprising: Formula (II): [ka] to produce a compound of formula (I), During the ceremony, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl and C 6~10 Aryl C 1~6 Each of the alkyl groups may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 Optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro, preferably R 1 is R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl and C 6~10 Aryl C 1~6 Each of the alkyl groups may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6Optionally substituted with one or more substituents each independently selected from the group consisting of alkoxy, and nitro, preferably R 1 is R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl and C 6~10 Aryl C 1~6 alkyl, preferably R 1 is R 3 Si(R 4 )(R 5 )-, preferably R 1 is R 3 Si(R 4 )(R 5 )-, C 1~4 Alkyl, C 6~10 Aryl and C 6~10 Aryl C 1~4 alkyl, preferably R 1 is R 3 Si(R 4 )(R 5 )-and R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 The group consisting of alkoxy and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy or haloC 1~4 and optionally substituted with one or more substituents each independently selected from alkyloxy, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N and / or S, where each C 6~10 Aryl or heteroaryl is halo, C1-6 alkyl, haloC1-6 alkyl, C 1~6Alkoxy, HaloC 1~6 The group consisting of alkoxy and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy or haloC 1~4 and optionally substituted with one or more substituents each independently selected from alkyloxy, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 The group consisting of alkoxy and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy or haloC 1~4 optionally substituted with one or more substituents each independently selected from alkyloxy; R 3 , R 4 , and R 5 are each independently C1-6 alkyl or C 6~10 aryl, where each C 1~6 Alkyl or C 6~10 Aryl is halo, C1-6 alkyl, haloC1-6 alkyl, C 1~6 Alkoxy and haloC 1~6 alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents each independently selected from alkyl, R 6 is C 1~6 Alkyl or C 3~6 cycloalkyl, where each C 1~6 Alkyl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6alkoxy, preferably fluoro, chloro or C 1~4 and optionally substituted with one or more substituents independently selected from alkyl, Preferably, the above mentioned desulfinylation step is carried out by pyrolysis, providing a continuous flow process.

[0163] In some embodiments, R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 The aryl or heteroaryl may be optionally substituted with 1, 2, 3, 4 or 5 substituents, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N and / or S, where each C 6~10 The aryl or heteroaryl may be optionally substituted with 1, 2, 3, 4 or 5 substituents, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N, where each C 6~10 The aryl or heteroaryl may be optionally substituted with 1, 2, 3, 4 or 5 substituents, preferably R 2 is phenyl, or pyridinyl, where each phenyl or pyridinyl is optionally substituted with 1, 2, 3, 4, or 5 substituents.

[0164] In some embodiments, R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy, phenyl, heterocyclyl, heteroaryl, -S(O)2C 1~4 Alkyl, -S(O)2, C 1~4 Haloalkyl, CO2C1~4 Alkyl, CO2C 1~4 Haloalkyl, C(O)C 1~4 Alkyl, C(O)C 1~4 Haloalkyl, Amino, Mono-C 1~4 Alkylamino, Di-C 1~4 and optionally substituted with one or more substituents each independently selected from the group consisting of alkylamino, cyano, and preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N and / or S, where each C 6~10 Aryl or heteroaryl is fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy, phenyl, heterocyclyl, heteroaryl, -S(O)2C 1~4 Alkyl, -S(O)2, C 1~4 Haloalkyl, CO2C 1~4 Alkyl, CO2C 1~4 Haloalkyl, C(O)C 1~4 Alkyl, C(O)C 1~4 Haloalkyl, Amino, Mono-C 1~4 Alkylamino, Di-C 1~4 and optionally substituted with one or more substituents each independently selected from the group consisting of alkylamino, alkylamino, and cyano, preferably R 2 is C 6~10 aryl, or 5- or 6-membered heteroaryl containing at least one N, where each C 6~10 Aryl or heteroaryl is fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy, phenyl, heterocyclyl, heteroaryl, -S(O)2C 1~4 Alkyl, -S(O)2, C 1~4 Haloalkyl, CO2C 1~4 Alkyl, CO2C 1~4 Haloalkyl, C(O)C 1~4 Alkyl, C(O)C1~4 Haloalkyl, Amino, Mono-C 1~4 Alkylamino, Di-C 1~4 and optionally substituted with one or more substituents each independently selected from the group consisting of alkylamino, alkylamino, and cyano, preferably R 2 is phenyl or pyridinyl, where each phenyl or pyridinyl is fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy, HaloC 1~4 Alkyloxy, phenyl, heterocyclyl, heteroaryl, -S(O)2C 1~4 Alkyl, -S(O)2, C 1~4 Haloalkyl, CO2C 1~4 Alkyl, CO2C 1~4 Haloalkyl, C(O)C 1~4 Alkyl, C(O)C 1~4 Haloalkyl, Amino, Mono-C 1~4 Alkylamino, Di-C 1~4 It may be optionally substituted with one or more substituents each independently selected from the group consisting of alkylamino and cyano.

[0165] The present invention also encompasses a production line for the preparation of a compound of formula (I), preferably by desulfinylation, preferably by pyrolysis, of a compound of formula (II), said production line comprising: (a) Below: A source of a compound of formula (II), A source of diluent, and optionally a source of at least one scavenger and optionally a source of at least one base, preferably at least one organic base; a source of reactants comprising (b) a solution tank in fluid communication with a source of reactant; (c) at least one pump fluidly connecting the solution tank with a reaction zone, preferably a pyrolysis reaction zone; (d) The pyrolysis reaction zone is a channel extending from an inlet to an outlet located downstream of the inlet, where at least one pump is located directly upstream of the inlet; a heating module arranged to heat the channel at a pyrolysis temperature; Optionally, a cooling zone for cooling the solution exiting the channel, said cooling zone being located downstream of the outlet; Including, (e) optionally a separation zone for separating the at least one compound of formula (I) from other pyrolysis products; Equipped with.

[0166] The various sources can be provided with valves or volumetric pumps to control the flow rate of the various components from the corresponding sources to the solution tanks. For example, piston pumps (or syringes) can be used to precisely control the flow of each reactant to the solution tanks. The valves or volumetric pumps can be controlled by a control unit.

[0167] A reactive solution (reaction mixture) is formed in a solution tank comprised of reactants provided by a reactant source. Preferably, the reactive solution comprises a compound of formula (II), a solvent, at least one scavenger, and optionally at least one organic base. In some embodiments, the reactive solution does not comprise a base. Optionally, the solution tank can be provided with an agitator to increase the homogeneity of the reactive solution. Heating means can also be provided to heat the reactive solution, for example, to reduce the viscosity of the reactive solution or to increase the solubility of a reagent.

[0168] Preferably, the solution tank is in fluid communication with at least one pump for injecting the reactive solution under pressure into an inlet of a channel extending from the inlet to an outlet located downstream of the inlet.

[0169] Pressures up to 60.0 bar can be used for pyrolysis of the reactive solution, however lower pressures such as 5.0 bar to 50.0 bar, preferably 5.0 bar to 40.0 bar, preferably 5.0 bar to 30.0 bar, preferably 10.0 bar to 45.0 bar, preferably 10.0 bar to 30.0 bar, preferably 10.0 bar to 25.0 bar, preferably 12.0 bar to 40.0 bar, preferably 12.0 bar to 35.0 bar are preferred.

[0170] The channel preferably forms a capillary defined by a closed perimeter Pe and may be formed by a recess in a tube or plate. The channel may be equipped with a back pressure regulator, which may be inserted downstream to allow pressurized operation. Depending on the pyrolysis temperature and the type of heating module used, the channel may be made of stainless steel, preferably passivated stainless steel, aluminum, copper, PEEK, PEKK, PTFE, ceramics such as silicon carbide, etc.

[0171] The channel may include a central portion contained between the inlet and the outlet. If the channel is formed by a tube, the central portion may preferably form one or more coils. If it is formed by a recess in a plate, the recess may snake over the surface of the plate to form a serpentine path. The inner wall of the channel may, for example, include a specific structure to achieve high mixing. These configurations allow a large linear length of the channel to be accommodated in a small volume, thus saving space. The central portion of the channel may be part of a pyrolysis microreactor module, which may include a heating module arranged to heat the channel at a pyrolysis temperature of at least 100°C. The heating module may be any type of furnace known in the art that allows heating of the channel at the aforementioned temperatures and enclosure of the central portion of the channel. For example, the heating module may be a conventional electric or gas furnace, or may heat the channel by radiation such as IR, induction, Joule effect, etc. The heating module must be suitable for heating the interior of the channel to a temperature of at least 100°C, preferably between 150°C and 300°C, more preferably between 200°C and 275°C. If the reaction channel is formed by a recess in the plate, the heating module can also be integrated in the plate as a second recess independent of the channel, in which the thermal fluid is circulated. The heating module can also be a heating cartridge housed in the plate. Any heating means known in the art that allows heating of the reaction mixture in the channel can be applied without affecting the present invention.

[0172] The pressure (and back pressure) in the channel can be controlled to control the pyrolysis time t according to the inner water pressure diameter D of the channel. The pyrolysis time t can be comprised between 0.1 and 30 minutes, preferably between 0.5 and 25 minutes, preferably between 0.5 and 20 minutes, preferably between 1.0 and 15 minutes, preferably between 2 and 10 minutes, and preferably between 2.5 and 8 minutes.

[0173] A back pressure regulator BPR can be placed downstream of the channel to control and increase the pressure inside the channel. The BPR can be a variable or non-variable channel cross-section restriction, or can actively generate back pressure.

[0174] The production line may further comprise a cooling module located directly downstream of the channel outlet to cool the reaction products of the pyrolysis reaction. Any cooling means known in the art that allows the reaction products to be cooled in a short time may be applied without affecting the present invention. Although a cooling module is not essential, it is advantageous if an in-line analytical module, such as an IR spectrometer, is provided to identify the components exiting the channel. Such an in-line analytical module may require cooling, since it may not be heat-resistant enough to accommodate the flow of reactants.

[0175] Optionally, a separation module for separating the compound of formula (I) from other pyrolysis products can be placed downstream of the outlet.

[0176] The separation module can be in-line or off-line to the channel. Separation steps can include neutralization, liquid-liquid extraction, liquid-liquid separation, gas-liquid separation, filtration over silica gel, in-line distillation, etc. In some embodiments, liquid-liquid extraction requires the injection of a second phase, such as an aqueous phase. The aqueous phase can contain an inorganic base. Alternatively, liquid-liquid or gas-liquid separation can be performed in-line using membranes or settling tanks.

[0177] The above-mentioned production line for the compound of formula (I) can be used to carry out the continuous flow process according to the present invention for the preparation of the compound of formula (I) by desulfinylation of the compound of formula (II).

[0178] Preferably, the above-mentioned continuous flow process comprises the following steps: (a) contacting a compound of formula (II) with at least one solvent, optionally at least one scavenger, and optionally at least one organic base to form a mixture; (b) feeding the mixture into an inlet of a channel of a pyrolysis zone; (c) subjecting the mixture to pyrolysis by conveying a flow of the mixture along a channel from an inlet to an outlet at a pressure P and a pyrolysis temperature T greater than 100° C. for a pyrolysis time t to form a pyrolysis reaction product comprising at least a compound of formula (I); (d) recovering the pyrolysis reaction product at an outlet; (e) optionally separating at least one compound of formula (I) from other pyrolysis reaction products or retaining the compound of formula (I) in the reaction products; Includes.

[0179] As described herein above, the pressure P in the channel can be controlled by the pressure generated by at least one pump and the back pressure generated by a back pressure regulator (BPR), if present. The pressure P can be in the range of preferably 5 bar to 60 bar, preferably in the range of 5 bar to 50 bar, preferably in the range of 5 bar to 40 bar, preferably in the range of 8 bar to 60 bar, preferably in the range of 8 bar to 50 bar, preferably in the range of 8 bar to 40 bar, preferably in the range of 10 bar to 60 bar, preferably in the range of 10 bar to 50 bar, preferably in the range of 10 bar to 40 bar, preferably in the range of 12 bar to 50 bar, more preferably in the range of 12 bar to 40 bar, preferably in the range of 13 bar to 35 bar, preferably in the range of 20 bar to 60 bar, preferably in the range of 20 bar to 50 bar, preferably in the range of 20 bar to 40 bar. The pyrolysis time t may be in the range of preferably 0.5 to 45 minutes, preferably 0.5 to 15 minutes, preferably 0.5 to 10 minutes, preferably 0.5 to 8.0 minutes, preferably 1.0 to 30 minutes, preferably 1.0 to 15 minutes, preferably 1.0 to 8.0 minutes, preferably 1.5 to 20 minutes, preferably 2.0 to 15 minutes, preferably 2.0 to 8.0 minutes, preferably 2.5 to 6 minutes. The pyrolysis temperature T may be in the range of preferably 150°C to 270°C, more preferably 180°C to 225°C.

[0180] This process further includes: (d1) feeding the reaction product from step (d) to an inlet of a channel of a cooling zone; (d2) exposing the reaction product from step (d) to cooling by conveying a flow of the reaction product along a channel from the inlet to the outlet at a cooling temperature Tc for a cooling time tc; (d3) recovering the cooled reaction product at an outlet of the cooling zone and optionally separating the compound of formula (I) from other pyrolysis reaction products; Includes.

[0181] The process may further comprise recovering the reaction products at the outlet of the reaction zone and contacting the reaction mixture comprising the compound of formula (I) and other reaction products with an aqueous solution. Preferably, the aqueous solution comprises an inorganic base. More preferably, the aqueous solution comprises an inorganic base selected from the group comprising NaOH, NaHCO3, K2CO3, NH4Cl, Na2S2O3, and mixtures thereof, preferably said aqueous solution comprises NaOH. The aqueous solution is preferably a 0.5 mol / L to 2 mol / L NaOH solution, preferably a 1 mol / L NaOH solution.

[0182] The reaction mixture described above may be contacted with the aqueous solution described above and stirred for at least 15 minutes, preferably at least 30 minutes to a maximum of 2 hours.

[0183] In a preferred embodiment, the process includes (d3) recovering the cooled reaction product at the outlet of the cooling zone and contacting the cooled reaction mixture comprising the compound of formula (I) and other reaction products with an aqueous solution, wherein the aqueous solution comprises at least one inorganic base. More preferably, the aqueous solution comprises an inorganic base selected from the group comprising NaOH, NaHCO3, K2CO3, NH4Cl, Na2S2O3 and mixtures thereof, preferably said aqueous solution comprises NaOH. The aqueous solution is preferably a 0.5 mol / L to 2 mol / L NaOH solution, preferably a 1 mol / L NaOH solution.

[0184] Those skilled in the art know how to translate the disclosed parameters and conditions from small scale conditions (research and development laboratory) to industrial scale conditions.

[0185] The process may further include removing the organic layer from the mixture containing the aqueous solution and evaporating the organic layer, preferably under reduced pressure, to recover the reaction product.

[0186] The present invention also includes compositions comprising the reaction products described above.

[0187] Preferably, the above-mentioned composition comprises a compound of formula (I) and at least one additional by-product selected from the group comprising compounds of formula (IIa), formula (IIb), formula (IIc) and formula (IId) and mixtures thereof, [ka] During the ceremony, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl, -CH2-CH=CR a R b , C 1~6 Alkoxy, C 3~6 Cycloalkyl and R 6 CO-, 6~10 Aryl, C 6~10 Aryl C 1~6 Alkyl and C 3~6 Each cycloalkyl may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 2~6 Alkenyl, C 2~6 Alkynyl, C 6~10 Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O)R 7 , -S(O)R 8 , -CO2R9 , -C(O)R 10 , -SR 13 , -C(O)SR 14 , N.R. 11 R 12 , cyano and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy or haloC 1~4 optionally substituted with one or more substituents each independently selected from alkyloxy; R 6 is C 1~6 Alkyl, C 6~10 Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, hydroxyl, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C1-6 alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 11 and R 12 are each independently hydrogen, C 1~6 Alkyl, C 6~12 Aryl, C 3~6cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R 13 and R 14 are each independently hydrogen, C 1~6 Alkyl, C 6~10 Aryl and C 3~6 cycloalkyl, wherein each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6 Alkyl or C 6~10 It is aryl.

[0188] Preferably, the above-mentioned composition comprises a compound of formula (I) and at least one additional by-product selected from the group comprising compounds of formula (IIa), formula (IIb), formula (IIc) and formula (IId) and mixtures thereof, [ka] During the ceremony, R 1 is hydrogen, R 3 Si(R 4 )(R 5 )-, C 1~6 Alkyl, C 6~10 Aryl, C 6~10 Aryl C 1~6Alkyl, -CH2-CH=CR a R b , and R 6 CO-, 1~6 Alkyl, C 6~10 Aryl and C 6~10 Aryl C 1~6 Each of the alkyl groups may be halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, C 6~10 optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R 2 is C 6~10 aryl, or heteroaryl, where each C 6~10 Aryl or heteroaryl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 The group consisting of alkoxy and nitro, preferably fluoro, chloro, bromo, nitro, C 1~4 Alkyl, C 1~4 Alkyloxy or haloC 1~4 optionally substituted with one or more substituents each independently selected from alkyloxy; R 6 is C 1~6 Alkyl, C 6~10 Aryl or C 3~6 cycloalkyl, where each C 1~6 Alkyl, C 6~10 Aryl or C 3~6 Cycloalkyl is halo, C 1~6 Alkyl, haloC 1~6 Alkyl, C 1~6 Alkoxy and haloC 1~6 and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R a and R b are each independently hydrogen, C 1~6Alkyl or C 6~10 It is aryl.

[0189] The present invention also includes compositions comprising a compound of formula (I) as defined herein and a compound of formula (IIa).

[0190] In some embodiments, the composition comprises a compound of Formula (I), a compound of Formula (IIa), and optionally any one of the compounds of Formula (IIb), Formula (IIc), Formula (IId), or a mixture thereof.

[0191] In some embodiments, the composition comprises a compound of Formula (I), a compound of Formula (IIb), and optionally any one of the compounds of Formula (IIa), Formula (IIc), Formula (IId), or a mixture thereof.

[0192] In some embodiments, the composition comprises a compound of Formula (I), a compound of Formula (IIc), and optionally any one of the compounds of Formula (IIa), Formula (IIb), Formula (IId), or a mixture thereof.

[0193] In some embodiments, the composition comprises compound (IIa) in an amount of at least 0.01 area % by HPLC, preferably at least 0.1 area % by HPLC, preferably at least 0.5 area % by HPLC, and preferably at least 1.0 area % by HPLC of compound (IIa), based on the total area of ​​the composition as determined by HPLC.

[0194] In some embodiments, the composition comprises compound (IIa) in an amount of at most 25.0 area % by HPLC, preferably at most 20.0% by HPLC, preferably at most 15.0 area % by HPLC, preferably at most 10.5 area % by HPLC, preferably at most 5.0 area % by HPLC of compound (IIa), based on the total area of ​​the composition as determined by HPLC.

[0195] In some embodiments, the composition comprises Compound (IIb) in an amount of at most 16.0 area % by HPLC, preferably at most 10.0 area % by HPLC, preferably at most 5.0 area % by HPLC of Compound (IIb), based on the total area of ​​the composition as determined by HPLC.

[0196] In some embodiments, the composition comprises compound (IIc) in an amount of at most 10.0 area % by HPLC, preferably at most 8.0 area % by HPLC, preferably at most 5.0 area % by HPLC of compound (IIc), based on the total area of ​​the composition as determined by HPLC.

[0197] In some embodiments, the composition comprises Compound (IIb) in an amount of at most 3.0 area % by HPLC, preferably at most 2.0 area % by HPLC, preferably at most 1.0 area % by HPLC of Compound (IIb), based on the total area of ​​the composition as determined by HPLC.

[0198] The following examples are provided for the purpose of illustrating the present invention and should not be construed as limiting the scope of the present invention in any way. EXAMPLES

[0199] The following equipment and reactants were used in the continuous flow process used in the examples.

[0200] pump Liquid delivery was handled using a Knauer AZURA P 4.1S HPLC pump or a Chemyx Fusion 6000 High Force syringe pump equipped with stainless steel syringes (20 mL) with Dupont Kalrez Spectrum AS-568 O-rings (0.549 x 0.103 inches).

[0201] Stainless Steel (SS) Coil Reactor SS coil reactors were constructed from deburred, steam cleaned and acid passivated 316SS tubing ([1.59 mm OD, 0.76 mm ID] or [3.17 mm OD, 2.10 mm ID]) of the specified internal volume.

[0202] PFA tubing and coils A perfluoroalkoxy (PFA) coil reactor and collection lines were constructed with PFA tubing (high purity PFA; 1.58 mm OD, 750 μm ID).

[0203] Connectors, Ferrules and Mixers The section of the reactor not subjected to high temperature was equipped with a conical poly-ether-etherketone (PEEK) fitting and a micromixer. The section of the reactor subjected to high temperature was equipped with Valco SS fittings, ferrules and unions. Connectors, ferrules and unions were purchased from IDEX / Upchurch.

[0204] Check valve Check valves inserted between the pump and the reactor were purchased from IDEX / Upchurch Scientific (PEEK or SS check valve holders).

[0205] Back Pressure Regulator Spring-loaded BPRs were purchased from IDEX / Upchurch Scientific (PEEK or SS check valve holders).

[0206] Temperature Control Device The 1 / 16" SS coil was thermostated in a ThalesNano Phoenix Flow Reactor™. The 1 / 8" SS coil was thermostated in a modified GC oven.

[0207] Chemicals and Solvents All solvents used were purchased from Fisher Scientific.

[0208] NaHCO3, NaOH and HCl were purchased from VWR.

[0209] Imidazole, tert-butyldimethylsilyl chloride and methyl benzenesulfinate were purchased from TCI Corp. NaH, sodium borohydride, cerium chloride heptahydrate and triethylamine were purchased from Sigma Aldrich.

[0210] Et3N was distilled before use and stored at room temperature.

[0211] Dimethyl acetylenedicarboxylate (DMAD) was distilled before use and stored at 4 °C.

[0212] CH2Cl2, DMSO and MeOH were dried over molecular sieves (3 Å for MeOH, 4 Å for CH2Cl2 and DMSO).

[0213] All other reagents and solvents were purchased from Sigma Aldrich and used as supplied.

[0214] HPLC method: Eluent A: water; B: acetonitrile The eluent gradient is shown in Table 1.

[0215] [Table 1]

[0216] Flow rate: 2mL / min Column: C18, 100 x 4.6 mm, 3 μm Oven temperature: 40℃ Diode array detector: 180nm~800nm Analysis wavelength: 190nm

[0217] Example 1: Synthesis of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one (Compound 1) Compound 1 was prepared as shown generally in Scheme 1. [ka]

[0218] To a solution of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (2) (9.71 g, 19.08 mmol) in toluene (83 mL) at room temperature, EtN (0.3 mL, 1.90 mmol) and dimethyl acetylenedicarboxylate (DMAD) (3.5 mL, 28.52 mmol) were added sequentially. The solution was pumped at a flow rate of 0.833 mL / min (over a pyrolysis time of 6 min) into a stainless steel tube heated to 210° C. The feed was kept liquid with a back pressure regulator at 34 bar (500 psi) and then cooled to 0° C. with a PFA coil. The entire crude product was collected in a round bottom flask and stirred with 1 M aqueous NaOH (80 mL) for 30 min. The organic layer was separated and evaporated under reduced pressure to give compound (1) as a solid.

[0219] 1 H-NMR (CDCl3): δ 0.20 (s, 6H, (CH3)2-Si-), 1.00 (s, 9H, (CH3)3-C-Si-), 1.13 (s, 3H, CH3 at C-18), 1.20-2.70 (m, 11 H), 2.80-3.00 (m, 2H), 6.10 (dd, 1 H, H15), 6.58 (broad s, 1 H, H4), 6.62 (dd, 1H, H2), 7.11 (d, 1H, H1), 7.63 (dd, 1H, H16).

[0220] Example 2: Synthesis of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one (Compound 1) in different solvents and at different pyrolysis temperatures 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one (1) was prepared from a 0.06 M solution of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (2) using dimethyl acetylenedicarboxylate (1.0 equivalent) and trimethyl phosphite (1.0 equivalent) according to the procedure and settings described in Example 1 in different solvents and pyrolysis temperatures listed in Table 2.

[0221] Table 2 shows the yields of the desulfinylation reaction using different pyrolysis temperatures and solvents, given as area % as determined by HPLC.

[0222] [Table 2]

[0223] Example 3: Synthesis of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one (Compound 1) using different pyrolysis times and different pyrolysis temperatures 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one (compound 1) was prepared from a 0.06 M solution of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (2) in o-xylene using trimethyl phosphite (3.0 equivalents) at different pyrolysis temperatures and pyrolysis times listed in Table 3 according to the procedure and settings described in Example 1.

[0224] Table 3 shows the yield of the desulfinylation reaction when the pyrolysis temperature and pyrolysis time were changed. The yield is shown as an area % measured by HPLC.

[0225] [Table 3]

[0226] Example 4: Synthesis of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one (Compound 1) using different scavengers The 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one compound of formula (I) (Compound 1) was prepared from a 0.06 M solution of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (2) in toluene in the presence of different scavengers as listed in Table 4 according to the procedure described in Example 1.

[0227] Table 4 shows the yields of the desulfinylation reaction in the presence of different scavengers, given as area % as determined by HPLC.

[0228] [Table 4]

[0229] Example 5: Synthesis of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one (Compound 1) using different bases at different concentrations 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one (compound 1) was prepared from a 0.22 M solution of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (2) in toluene in the presence of dimethyl acetylenedicarboxylate (1.5 equivalents) and different bases listed in Table 5, according to the procedure and settings described in Example 1.

[0230] Table 5 shows the yields of the desulfinylation reaction in the presence of different bases, given as area % as determined by HPLC.

[0231] [Table 5]

[0232] Example 6: Synthesis of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one (Compound 1), identification and quantification of by-products 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one (compound 1) was prepared from 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (2) according to the procedure and settings described in Example 1, applying the conditions listed in Table 6. The reaction products were analyzed using HPLC, NMR, IR spectroscopy and mass spectrometry. The following impurities were identified: [ka]

[0233] Table 6 shows the area percentages by HPLC of compound (1) and by-products (2a), (2b), (2c), and (2d) obtained depending on the experimental conditions used.

[0234] [Table 6] TIFF2025513928000054.tif254170TIFF2025513928000055.tif254170

[0235] Example 7: Preparation of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol (Compound 3) 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol (compound 3) was prepared as shown generally in Scheme 2. [ka]

[0236] Step 1: 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one To a solution of 3-hydroxy-estra-1,3,5(10)-trien-17-one (100 g, 0.370 mol) in dichloromethane (500 mL) was added tert-butyldimethylsilyl chloride (58.3 g, 0.388 mol) and imidazole (26.4 g, 0.388 mol). The mixture was stirred at room temperature for 24 hours. Water (300 mL) was added and the organic layer was washed with 200 mL of water. After concentration, the product was crystallized from a mixture of ethanol / diisopropyl ether, collected by filtration and dried. The product was isolated as a white solid (145 g, 95%).

[0237] 1 H-NMR (CDCl3): δ 0.20 (s, 6H, (CH3)2-Si-), 0.90 (s, 3H, CH3 at 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, 1H), 6.58 (broad s, 1H, H4), 6.63 (dd, 1H, H2), 7.12 (d, 1H, H1).

[0238] Step 2: 3-tert-Butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one (250 mg, 0.650 mmol) was added to a suspension of sodium hydride (78.0 mg, 1.950 mmol, 60% in parafilm) in THF (7.1 mL) at room temperature under N2 atmosphere. Then methyl benzenesulfinate (152.3 mg, 0.975 mmol) was added and the white mixture was stirred at room temperature for 60 min. The conversion of the starting material was controlled by TLC analysis [PE / EtOAc (8:2)]. The reaction was quenched by addition of a 5% aqueous solution of NaHCO3 (15 mL) and extracted with toluene (2 x 15 mL). The organic layer was evaporated under reduced pressure and the crude product was purified by chromatography on silica gel (petroleum ether / EtOAc [8 / 2]) to give the product as a white solid (139.5 mg, 42% yield).

[0239] 1 H-NMR (CDCl3): δ 0.17 (s, 6H, (CH3)2-Si-), 0.91 (s, 3H, CH3 at C-18), 0.97 (s, 9H, (CH3)3-C-Si), 1.08-2.92 (m, 12H), 3.25-3.73 (m, 1H, H16), 6.53-6.58 (m, 1H, H4), 6.62 (d, 1H, H2), 7.04-7.14 (m, 1H, H1), 7.47-7.58 (m, 3H, PhS(O)-), 7.59-7.68 (m, 2H, PhS(O)-).

[0240] Step 3: 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one To a solution of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (2.89 g, 5.70 mmol) in toluene (24 mL) was added dimethyl acetylenedicarboxylate (1.02 mL, 14.20 mmol) and triethylamine (0.08 mL, 0.57 mmol) in succession. The solution was placed in a tube (V) heated to 210 °C. int= 5 mL) at a flow rate of 0.833 mL / min. The feed was kept liquid with a back pressure regulator (BPR) at 34 bar (500 psi). The flow was then cooled to 0 °C and the crude reaction mixture was collected in a flask. The organic layer was washed with 0.5 M aqueous NaOH (45 mL) and the organic layer was dried over MgSO4. The volatiles were removed under reduced pressure and the crude product was purified by chromatography on silica gel (petroleum ether / EtOAc [8 / 2]) to give the product as an off-white solid (2.43 g, 71% yield).

[0241] 1 H-NMR (CDCl3): δ 0.20 (s, 6H, (CH3)2-Si-), 1.00 (s, 9H, (CH3)3-C-Si-), 1.13 (s, 3H, CH3 at C-18), 1.20-2.70 (m, 11 H), 2.80-3.00 (m, 2H), 6.10 (dd, 1 H, H15), 6.58 (broad s, 1 H, H4), 6.62 (dd, 1H, H2), 7.11 (d, 1H, H1), 7.63 (dd, 1H, H16).

[0242] Step 4: 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol The material collected in step 3 was dissolved in THF (7.6 mL) and a solution of cerium chloride heptahydrate (3.19 g, 8.55 mmol) in methanol (8.0 mL) was added. The mixture was cooled to 0° C. and sodium borohydride (0.45 g, 11.97 mmol) was added in small portions while keeping the temperature below 9° C. After the addition was complete, the mixture was stirred for 1 h and then quenched by the addition of 2N HCl solution (2.5 mL), extracted with ethyl acetate and washed with water. The organic layer was partially evaporated and then diisopropyl ether was added. The precipitate was collected by filtration and dried. After crystallization from a mixture of ethanol / diisopropyl ether, the title compound was isolated as an off-white solid in 90% yield. The yield over two steps is 63%.

[0243] 1 H-NMR (CDCl3): δ 0.20 (s, 6H, (CH3)2-Si-), 0.89 (s, 3H, CH3 at C-18), 1.00 (s, 9H, (CH3)3-C-Si-), 1.20-2.40 (m, 10H), 2.75-2.95 (m, 2H), 4.40 (broad s, 1 H, H17), 5.65-5.75 (m, 1 H), 5.95-6.10 (m, 1H), 6.57 (broad s, 1H, H4), 6.60 (dd, 1H, H2), 7.13 (d, 1H, H1).

[0244] Alternatively, the procedure of steps 3 and 4 as described herein above can be combined with purification only in the last step.

[0245] Step 3 + Step 4: 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol To a solution of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (10.0 g, 19.08 mmol) in toluene (84 mL), dimethyl acetylenedicarboxylate (3.5 mL, 28.52 mmol) and triethylamine (0.3 mL, 1.90 mmol) are added sequentially. The solution is then placed in a tube (V) heated to 210 °C. int= 5 mL) at a flow rate of 0.833 mL / min. The feed was kept liquid with a back pressure regulator (BPR) at 34 bar (500 psi). The flow was then cooled to 0°C and the crude reaction mixture was collected in a flask. The organic layer was washed with a 1 M aqueous solution of NaOH (85 mL) and the organic layer was dried over MgSO4. The volatiles were removed under reduced pressure, the residue was dissolved in THF (25 mL) and a solution of cerium chloride heptahydrate (10.66 g, 28.62 mmol) in methanol (29 mL) was added. The mixture was cooled to 0°C and sodium borohydride (1.50 g, 40.07 mmol) was added in small portions while keeping the temperature below 9°C. After the addition was complete the mixture was stirred for 1 h and then quenched by the addition of 2N HCl solution (8.0 mL), extracted with ethyl acetate and washed with water. The organic layer was partially evaporated and then diisopropyl ether was added. The precipitate was collected by filtration and dried. The title compound was isolated as a beige solid after crystallization from a mixture of ethanol / diisopropyl ether (5.07 g, 69% over two steps).

[0246] 1 H-NMR (CDCl3): δ 0.20 (s, 6H, (CH3)2-Si-), 0.89 (s, 3H, CH3 at C-18), 1.00 (s, 9H, (CH3)3-C-Si-), 1.20-2.40 (m, 10H), 2.75-2.95 (m, 2H), 4.40 (broad s, 1 H, H17), 5.65-5.75 (m, 1 H), 5.95-6.10 (m, 1H), 6.57 (broad s, 1H, H4), 6.60 (dd, 1H, H2), 7.13 (d, 1H, H1).

[0247] Example 8: Preparation of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol (Compound 3) As shown generally in Scheme 3, 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol (compound 3) was prepared. [ka]

[0248] Step 1: 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one was prepared as described in step 1 of Example 7.

[0249] Step 2: 3-tert-butyldimethylsilyloxy-16-(4-chloro-phenylsulfinyl)-estra-1,3,5(10)-trien-17-one 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one (250 mg, 0.650 mmol) was added to a suspension of sodium hydride (78.0 mg, 1.950 mmol, 60% in parafilm) in THF (7.1 mL) at room temperature under N2 atmosphere. Then methyl 4-chlorobenzenesulfinate (185.9 mg, 0.975 mmol) was added and the white mixture was stirred at room temperature for 60 min. The conversion of the starting material was controlled by TLC analysis [PE / EtOAc (8:2)]. The reaction was quenched by the addition of a 5% aqueous solution of NaHCO3 (15 mL) and extracted with toluene (2 x 15 mL). The organic layer was evaporated under reduced pressure and the crude product was purified by chromatography on silica gel (petroleum ether / EtOAc [8 / 2]) to give the product as a white solid.

[0250] 1 H-NMR (CDCl3): δ 0.17 (s, 6H, (CH3)2-Si-), 0.97 (s, 9H, (CH3)3-C-Si), 1.07-2.58 (m, 13H), 2.73-2.89 (m, 2H, H6), 3.23-3.63 (m, 1H, H16), 6.52-6.59 (m, 1H, H4), 6.59-6.65 (m, 1H, H2), 7.09 (d, 1H, H1), 7.49-7.55 (m, 2H), 7.59-7.68 (m, 2H).

[0251] Step 3: 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one To a solution of 3-tert-butyldimethylsilyloxy-16-(4-chlorophenylsulfinyl)-estra-1,3,5(10)-trien-17-one (1.19 g, 2.20 mmol) in toluene (9.6 mL), dimethyl acetylenedicarboxylate (0.4 mL, 3.30 mmol) and triethylamine (0.03 mL, 0.22 mmol) are added sequentially. The solution is then placed in a tube (V) heated to 210 °C. int = 5 mL) at a flow rate of 0.833 mL / min. The feed was kept liquid with a back pressure regulator (BPR) at 500 psi (34 bar). The flow was then cooled to 0°C and the crude reaction mixture was collected in a flask. The organic layer was washed with 1 M aqueous NaOH (10 mL) and the organic layer was dried over MgSO4. The volatiles were removed under reduced pressure to give a crude brown mixture containing 91 / 6 / 2 / 1 area % by HPLC of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one / 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-14-tetraen-17-one / 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one / 3-tert-butyldimethylsilyloxy-16-phenylthio-estra-1,3,5(10)-15-tetraen-17-one.

[0252] 1 H-NMR (CDCl3): δ 0.20 (s, 6H, (CH3)2-Si-), 1.00 (s, 9H, (CH3)3-C-Si-), 1.13 (s, 3H, CH3 at C-18), 1.20-2.70 (m, 11 H), 2.80-3.00 (m, 2H), 6.10 (dd, 1 H, H15), 6.58 (broad s, 1 H, H4), 6.62 (dd, 1H, H2), 7.11 (d, 1H, H1), 7.63 (dd, 1H, H16).

[0253] Step 4: 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-tetraen-17-ol was prepared from 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-tetraen-17-one as described in Example 7, step 4.

[0254] Example 9: Preparation of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol (Compound 3) 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol (compound 3) was prepared as shown generally in Scheme 4. [ka]

[0255] Step 1: 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one was prepared as described in step 1 of Example 7.

[0256] Step 2: 3-tert-butyldimethylsilyloxy-16-(2-pyridinesulfinyl)-estra-1,3,5(10)-trien-17-one 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one (250 mg, 0.650 mmol) was added to a suspension of sodium hydride (78.0 mg, 1.950 mmol, 60% in parafilm) in THF (7.1 mL) at room temperature under N2 atmosphere. Methyl pyridine-2-sulfinate (153.3 mg, 0.975 mmol) was then added and the white mixture was stirred at room temperature for 60 min. The conversion of the starting material was controlled by TLC analysis [PE / EtOAc (8:2)]. The reaction was quenched by the addition of 5% aqueous NaHCO3 (15 mL) and extracted with toluene (2 x 15 mL). The organic layer was evaporated under reduced pressure and the crude product was purified by chromatography on silica gel (petroleum ether / EtOAc [8 / 2]) to give the product as a white solid.

[0257] Step 3: 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one To a solution of 3-tert-butyldimethylsilyloxy-16-(2-pyridinesulfinyl)-estra-1,3,5(10)-trien-17-one (1.12 g, 2.20 mmol) in toluene (9.6 mL), dimethyl acetylenedicarboxylate (0.4 mL, 3.30 mmol) and triethylamine (0.03 mL, 0.22 mmol) are added sequentially. The solution is then placed in a tube (V) heated to 210 °C. int= 5 mL) at a flow rate of 0.833 mL / min. The feed was kept liquid with a back pressure regulator (BPR) at 34 bar (500 psi). The flow was then cooled to 0°C and the crude reaction mixture was collected in a flask. The organic layer was washed with 1 M aqueous NaOH (10 mL) and the organic layer was dried over MgSO4. The volatiles were removed under reduced pressure to give a brown crude mixture containing 86 / 13 / 1 area % 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one / 3-tert-butyldimethylsilyloxy-16-(2-pyridinesulfinyl)-estra-1,3,5(10)-trien-17-one / 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one by HPLC.

[0258] 1 H-NMR (CDCl3): δ 0.20 (s, 6H, (CH3)2-Si-), 1.00 (s, 9H, (CH3)3-C-Si-), 1.13 (s, 3H, CH3 at C-18), 1.20-2.70 (m, 11 H), 2.80-3.00 (m, 2H), 6.10 (dd, 1 H, H15), 6.58 (broad s, 1 H, H4), 6.62 (dd, 1H, H2), 7.11 (d, 1H, H1), 7.63 (dd, 1H, H16).

[0259] Step 4: 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-tetraen-17-ol was prepared from 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-tetraen-17-one as described in Example 7, step 4.

[0260] Example 10: Preparation of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol (Compound 3) 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol (compound 3) was prepared as shown generally in Scheme 5. [ka]

[0261] Step 1: 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one was prepared as described in step 1 of Example 7.

[0262] Step 2: 3-tert-butyldimethylsilyloxy-16-(p-toluenesulfinyl)-estra-1,3,5(10)-trien-17-one 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one (250 mg, 0.650 mmol) was added to a suspension of sodium hydride (78.0 mg, 1.950 mmol, 60% in parafilm) in THF (7.1 mL) at room temperature under N2 atmosphere. Methyl p-toluenesulfinate (166.0 mg, 0.975 mmol) was then added and the white mixture was stirred at room temperature for 60 min. The conversion of the starting material was controlled by TLC analysis [PE / EtOAc (8:2)]. The reaction was quenched by addition of 5% aqueous NaHCO3 (15 mL) and extracted with toluene (2 x 15 mL). The organic layer was evaporated under reduced pressure and the crude product was purified by chromatography on silica gel (petroleum ether / EtOAc [8 / 2]) to give the product as a white solid.

[0263] 1H-NMR (CDCl3): δ 0.17 (s, 6H, (CH3)2-Si-), 0.97 (s, 9H, (CH3)3-C-Si), 1.09-2.56 (m, 13H), 2.73-2.89 (m, 2H, H6), 3.24-3.69 (m, 1H, H16), 6.52-6.59 (m, 1H, H4), 6.59-6.64 (m, 1H, H2), 7.09 (d, 1H, H1), 7.29-7.37 (m, 2H), 7.47-7.56 (m, 2H).

[0264] Step 3: 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one To a solution of 3-tert-butyldimethylsilyloxy-16-(p-toluenesulfinyl)-estra-1,3,5(10)-trien-17-one (1.15 g, 2.20 mmol) in toluene (9.6 mL) was added dimethyl acetylenedicarboxylate (0.4 mL, 3.30 mmol) and triethylamine (0.03 mL, 0.22 mmol) in succession. The solution was placed in a tube (V) heated to 210 °C. int = 5 mL) at a flow rate of 0.833 mL / min. The feed is kept liquid with a back pressure regulator (BPR) at 34 bar (500 psi). The flow is then cooled to 0°C and the crude reaction mixture is collected in a flask. The organic layer is washed with 1 M aqueous NaOH (10 mL) and the organic layer is dried over MgSO4. The volatiles are removed under reduced pressure to give a brown crude mixture containing 59 / 41 area % 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one / 3-tert-butyldimethylsilyloxy-16-(p-toluenesulfinyl)-estra-1,3,5(10)-trien-17-one by HPLC.

[0265] 1H-NMR (CDCl3): δ 0.20 (s, 6H, (CH3)2-Si-), 1.00 (s, 9H, (CH3)3-C-Si-), 1.13 (s, 3H, CH3 at C-18), 1.20-2.70 (m, 11 H), 2.80-3.00 (m, 2H), 6.10 (dd, 1 H, H15), 6.58 (broad s, 1 H, H4), 6.62 (dd, 1H, H2), 7.11 (d, 1H, H1), 7.63 (dd, 1H, H16).

[0266] Step 4: 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-tetraen-17-ol was prepared from 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-tetraen-17-one as described in Example 7, step 4.

[0267] Example 11: Preparation of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol (compound 3, see Scheme 2) using two pump settings Step 1: 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one was prepared as described in step 1 of Example 7.

[0268] Step 2: 3-tert-Butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one 3-tert-Butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one was prepared as described in step 2 of Example 7.

[0269] Step 3: 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one A solution of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (4.00 g, 7.19 mmol) and EtN (0.1 mL, 0.72 mmol) in toluene (31.2 mL) was pumped with "Pump A" (see Scheme 6) at a flow rate of 2.440 mL / min. A solution of DMAD (1.3 mL, 10.79 mmol) in toluene (2.7 mL) was pumped with "Pump B" at a flow rate of 0.220 mL / min. Flows A and B were mixed in a "T-mixer" and the combined flows were transferred to a tube (V) heated to 210 °C. int = 16 mL) at a total flow rate of 2.660 mL / min. The feed was kept liquid with a back pressure regulator at 34 bar (500 psi). The flow was then cooled to 0°C and the crude reaction mixture was collected in a flask. The organic layer was washed with 1 M aqueous NaOH (30 mL) and dried over MgSO4. The volatiles were removed under reduced pressure to give a crude brown mixture containing 80 / 13 / 2 / 5 area % by HPLC of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one / 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one / 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-14-tetraen-17-one / 3-tert-butyldimethylsilyloxy-16-phenylthio-estra-1,3,5(10)-15-tetraen-17-one. [ka]

[0270] 1H-NMR (CDCl3): δ 0.20 (s, 6H, (CH3)2-Si-), 1.00 (s, 9H, (CH3)3-C-Si-), 1.13 (s, 3H, CH3 at C-18), 1.20-2.70 (m, 11 H), 2.80-3.00 (m, 2H), 6.10 (dd, 1 H, H15), 6.58 (broad s, 1 H, H4), 6.62 (dd, 1H, H2), 7.11 (d, 1H, H1), 7.63 (dd, 1H, H16).

[0271] Step 4: 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol was prepared as described in step 4 of Example 7.

[0272] Example 12: Preparation of 3-tert-butyldiphenylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol Step 1: 3-tert-butyldiphenylsilyloxy-estra-1,3,5(10)-trien-17-one To a solution of 3-hydroxy-estra-1,3,5(10)-trien-17-one (10.00 g, 36.98 mmol) and imidazole (5.04 g, 73.97 mmol) in dimethylformamide (74 ml) is added tert-butyl(chloro)diphenylsilane (11.18 g, 40.68 mmol). The mixture is stirred at room temperature for 24 h. The reaction mixture is diluted with dichloromethane (200 mL) and water (200 mL) is added. The organic layer is washed with 10% aqueous NH4Cl (100 mL), 10% aqueous NaHCO3 (100 mL) and brine (100 mL), respectively. The volatiles are evaporated to give 3-tert-butyldiphenylsilyloxy-estra-1,3,5(10)-trien-17-one as an off-white solid (13.33 g, 84%).

[0273] 1H-NMR (CDCl3): δ 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 (1H, m), 2.06-2.38 (3H, m), 2.48 (1H, dd), 2.65-2.82 (2H, m), 6.49 (1H, dd), 6.58 (1H, d), 6.96 (1H, d), 7.34-7.44 (6H, m), 7.70-7.75 (4H, m).

[0274] Step 2: 3-tert-butyldiphenylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one 3-tert-Butyldiphenylsilyloxy-estra-1,3,5(10)-trien-17-one (6.34 g, 12.47 mmol) is added to a suspension of sodium hydride (1.50 g, 37.40 mmol, 60% in parafilm) in THF (55 mL) at room temperature under N2 atmosphere. Methyl benzenesulfinate (2.92 g, 18.70 mmol) is then added to the reaction mixture and the white mixture is stirred at room temperature for 1 h 0 min. The conversion of the starting material is controlled by TLC analysis [PE / EtOAc (8:2)]. The reaction is quenched by the addition of a 5% aqueous solution of NaHCO3 (215 mL) and extracted with toluene (2 x 215 mL). The organic layer is evaporated under reduced pressure and the crude product is purified by chromatography on silica gel to give 3-tert-butyldiphenylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one as a white solid (4.67 g, 59%).

[0275] 1H-NMR (CDCl3): δ 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 (1H, m), 2.65-2.76 (2H, m), 3.24-3.72 (1H, m), 6.49 (1H, d), 6.52-6.58 (1H, m), 6.95 (1H, 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).

[0276] Step 3: 3-tert-butyldiphenylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one To a solution of 3-tert-butyldiphenylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (2.59 g, 4.10 mmol) in toluene (17.8 mL) was added dimethyl acetylenedicarboxylate (0.8 mL, 6.16 mmol) and triethylamine (0.06 mL, 0.41 mmol) in succession. The solution was placed in a tube (V) heated to 210 °C. int = 5 mL) at a flow rate of 0.833 mL / min. The feed was kept liquid with a back pressure regulator at 34 bar (500 psi). The flow was then cooled to 0 °C and the crude reaction mixture was collected in a flask. The organic layer was washed with 1 M aqueous NaOH (20 mL) and the organic layer was dried over MgSO4. The volatiles were removed under reduced pressure and the crude product was purified by chromatography on silica gel (petroleum ether / EtOAc [8 / 2]) to give the product as an off-white solid (1.78 g, 86%).

[0277] 1H-NMR (CDCl3): δ 1.09 (9H, s, (CH3)3-Si-), 1.38-1.87 (7H, m), 1.97 (1H, d), 2.06-2.16 (1H, m), 2.21-2.39 (2H, m), 2.46 (1H, d), 2.71-2.84 (2H, m), 6.07 (1H, dd), 6.51 (1H, dd), 6.56 (1H, dd), 6.96 (1H, d), 7.34-7.46 (6H, m), 7.60 (1H, d), 7.68-7.78 (4H, m).

[0278] Step 4: 3-tert-butyldiphenylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol 3-tert-Butyldiphenylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol is prepared as described in step 4 of Example 7.

[0279] The product is an off-white solid (362 mg, 68%).

[0280] 1 H-NMR (CDCl3): δ 0.87 (3H, s), 1.13 (9H, s, (CH3)3-Si-), 1.52-1.71 (3H, m), 1.84 (1H, bs), 1.95-2.10 (3H, m), 2.17-2.31 (2H, m), 2.66-2.85 (2H, m), 4.41 (1H, s), 5.71-5.76 (1H, m), 6.03 (1H, d), 6.54 (1H dd), 6.60 (1H, d), 7.00 (1H, d), 7.36-7.48 (6H, m), 7.73-7.82 (4H, m).

[0281] Example 13: Preparation of 3-benzyloxy-estra-1,3,5(10)-15-tetraen-17-ol Step 1: 3-Benzyloxy-estra-1,3,5(10)-trien-17-one To a solution of 3-hydroxy-estra-1,3,5(10)-trien-17-one (10.00 g, 36.97 mmol) in acetonitrile (148 mL) at room temperature, potassium carbonate (12.78 g, 92.47 mmol) and benzyl bromide (4.8 mL, 40.69 mmol) are added successively. The mixture is stirred under reflux for 24 h. The reaction mixture is cooled and quenched with 10% aqueous NH4Cl (150 mL). The organic layer is washed with 10% aqueous NaHCO3 (150 mL), brine (150 mL) and the volatiles are removed under reduced pressure to give 3-benzyloxy-estra-1,3,5(10)-trien-17-one as a white solid (4.36 g, 33%).

[0282] 1 H-NMR (CDCl3): δ 0.91 (3H, s, CH3 at C-18), 1.38-1.72 (6H, m), 1.91-2.21 (3H, m), 2.21-2.32 (1H, m), 2.36-2.46 (1H, m), 2.46-2.57 (1H, m), 2.70 (1H, dd), 2.85-2.94 (2H, m), 5.04 (2H, s), 6.74 (1H, s), 6.80 (1H, dd), 7.21 (1H, d), 7.31-7.45 (5H, m).

[0283] Step 2: 3-Benzyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one To a suspension of potassium tert-butoxide (1.01 g, 9.00 mmol) in tetrahydrofuran (13.3 mL) is added 3-benzyloxy-estra-1,3,5(10)-trien-17-one (1.08 g, 3.00 mmol) at room temperature under N2 atmosphere. The mixture is stirred at room temperature for 1 h, then methyl benzenesulfinate (0.70 g, 4.50 mmol) is added in one portion. After stirring for 72 h, the reaction mixture is poured into 1 M aqueous HCl (25 mL). The organic layer is washed with 5% aqueous NaHCO3 (25 mL) and brine (25 mL). The volatiles are removed under reduced pressure to give 3-benzyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one as an off-white solid (1.23 g, 85%).

[0284] 1 H-NMR (CDCl3): δ 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).

[0285] Step 3: 3-Benzyloxy-estra-1,3,5(10)-15-tetraen-17-one To a solution of 3-benzyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (626 mg, 1.29 mmol) in toluene (10.0 mL), dimethyl acetylenedicarboxylate (0.4 mL, 3.30 mmol) and triethylamine (0.03 mL, 0.22 mmol) are added sequentially. The solution is then placed in a tube (V) heated to 210 °C. int= 5 mL) at a flow rate of 0.833 mL / min. The feed is kept liquid with a back pressure regulator at 34 bar (500 psi). The flow is then cooled to 0 °C and the crude reaction mixture is collected in a flask. The organic layer is washed with 1 M aqueous NaOH (10 mL) and dried over MgSO4. The volatiles are removed under reduced pressure and the crude product is purified by chromatography on silica gel (petroleum ether / EtOAc [8 / 2]) to give the product as an off-white solid (327 mg, 71%).

[0286] 1 H-NMR (CDCl3): δ 1.11 (3H, s, CH3 at C-18), 1.53-1.84 (4H, m), 1.96-2.08 (1H, m), 2.15-2.25 (1H, m), 2.31-2.40 (1H, m), 2.40-2.48 (1H, m), 2.53 (1H, d), 2.89-3.03 (2H, m), 5.04 (2H, s), 6.03-6.15 (1H, dd), 6.74 (1H, bs), 6.81 (1H, d), 7.21 (1H, d), 7.28-7.47 (5H, m), 7.62 (1H, d).

[0287] Step 4: 3-Benzyloxy-estra-1,3,5(10)-15-tetraen-17-ol 3-Benzyloxy-estra-1,3,5(10)-15-tetraen-17-ol is prepared as described in step 4 of Example 7.

[0288] The product is an off-white solid (229 mg, 70%).

[0289] 1H-NMR (CDCl3): δ 0.86 (3H, s, CH3 at C-18), 1.37-1.52 (1H, m), 1.56-1.73 (4H, m), 2.00-2.12 (2H, m), 2.22-2.42 (2H, m), 2.83-3.00 (2H, m), 4.42 (1H, s), 5.05 (2H, s), 5.66-5.78 (1H, m), 6.03 (1H, d), 6.73 (1H, dd), 6.82 (1H, dd), 7.20 (1H, d), 7.30-7.46 (4H, m).

[0290] Example 14: Preparation of 3-triisopropylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol Step 1: 3-Triisopropylsilyloxy-estra-1,3,5(10)-trien-17-one To a solution of 3-hydroxy-estra-1,3,5(10)-trien-17-one (10.00 g, 36.99 mmol) and imidazole (7.55 g, 110.97 mmol) in dimethylformamide (148 ml) is added triisopropylsilyl chloride (8.56 g, 44.39 mmol). The solution is stirred at room temperature for 17 h. The reaction mixture is diluted with diethyl ether (200 mL) and water (150 mL) is added. The aqueous layer is extracted twice with diethyl ether (2 x 100 mL). The combined organic layers are washed with brine (150 mL each) and dried over MgSO4. Filtration and evaporation of volatiles give 3-triisopropylsilyloxy-estra-1,3,5(10)-trien-17-one as a white solid (13.30 g, 84%).

[0291] 1H-NMR (CDCl3): δ 0.91 (3H, s, CH3 at 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 (1H, m), 2.50 (1H, dd), 2.82-2.88 (2H, m), 6.61 (1H, d), 6.66 (1H, dd), 7.10 (1H, d).

[0292] Step 2: 3-Triisopropylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one 3-Triisopropylsilyloxy-estra-1,3,5(10)-trien-17-one (5.00 g, 11.72 mmol) is added to a suspension of sodium hydride (1.18 g, 35.15 mmol, 60% in parafilm) in THF (44 mL) at room temperature under N2 atmosphere. Methyl benzenesulfinate (2.75 g, 17.58 mmol) is then added to the reaction mixture and the white mixture is stirred at room temperature for 1 h 0 min. The conversion of the starting material is controlled by TLC analysis [PE / EtOAc (8:2)]. The reaction is quenched by the addition of a 5% aqueous solution of NaHCO3 (50 mL) and extracted with toluene (2 x 50 mL). The organic layer is evaporated under reduced pressure and the crude product is purified by chromatography on silica gel (petroleum ether / EtOAc [7 / 3]) to give 3-triisopropylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one as a white solid (4.76 g, 74%).

[0293] 1H-NMR (CDCl3): δ 0.99 (3H, s, CH3 at 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 (1H, m), 6.59 (1H, d), 6.64 (1H, dd), 7.09 (1H, d), 7.48-7.59 (3H, m), 7.65 (2H, t).

[0294] Step 3: 3-Triisopropylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one To a solution of 3-triisopropylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (1.21 g, 2.20 mmol) in toluene (9.6 mL) was added dimethyl acetylenedicarboxylate (0.4 mL, 3.30 mmol) and triethylamine (0.03 mL, 0.22 mmol) in succession. The solution was placed in a tube (V) heated to 210 °C. int = 5 mL) at a flow rate of 0.833 mL / min. The feed was kept liquid with a back pressure regulator at 34 bar (500 psi). The flow was then cooled to 0 °C and the crude reaction mixture was collected in a flask. The organic layer was washed with 1 M aqueous NaOH (10 mL) and dried over MgSO4. The volatiles were removed under reduced pressure and the crude product was purified by chromatography on silica gel (petroleum ether / EtOAc [8 / 2]) to give the product as an off-white solid (414 mg, 44%).

[0295] 1H-NMR (CDCl3): δ 1.06-1.15 (21H, m), 1.19-1.30 (4H, m), 1.47-1.89 (5H, m), 1.98-2.06 (1H, m), 2.13-2.22 (1H, m), 2.28-2.38 (1H, m), 2.38-2.46 (1H, m), 2.46-2.56 (1H, m), 2.80-3.00 (1H, m), 6.09 (1H, dd), 6.63 (1H, d), 6.68 (1H, dd), 7.11 (1H, d), 7.62 (1H, d).

[0296] Step 4: 3-Triisopropylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol 3-Triisopropylsilyloxy-estra-1,3,5(10)-15-tetraen-17-ol was prepared as described in step 4 of Example 7.

[0297] The product is an off-white solid (310 mg, 75%).

[0298] 1 H-NMR (CDCl3): δ 0.86 (3H, s, CH3 at C-18), 1.04-1.30 (21H, m), 1.35-1.51 (1H, m), 1.57-1.73 (3H, m), 1.97-2.03 (2H, m), 2.05-2.10 (2H, m), 2.19-2.38 (2H, m), 2.77-2.94 (2H, m), 4.33-4.50 (1H, m), 5.71 (1H, m), 6.02 (1H, d), 6.60 (1H, d), 6.66 (1H, dd), 7.08 (1H, d).

[0299] Example 15: R 1 and R 2a Preparation of estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol of formula (E) via compound (B) using tert-butyldimethylsilyl group as a protecting group of [ka]

[0300] Step 1: Estra-1,3,5(10),15-tetraene-3,17β-diol bis(tert-butyldimethylsilyl) ether The starting material 3-tert-butyldimethylsiloxy-estra-1,3,5(10)-15-tetraen-17β-ol can be prepared as described in Examples 7 to 11. To a solution of 3-tert-butyldimethylsiloxy-estra-1,3,5(10)-15-tetraen-17β-ol (10.00 g, 25.0 mmol) in 100 ml of dimethylformamide, imidazole (4.40 g, 65.0 mmol) and tert-butyldimethylsilyl chloride (14.70 g, 97.5 mmol) were added and left at room temperature for 6 hours. The resulting solution was diluted with ethyl acetate, washed with water and evaporated. The residue was crystallized from methanol to give estra-1,3,5(10),15-tetraene-3,17β-diol bis(dimethyl-tert-butylsilyl) ether (10.00 g, 80%).

[0301] 1 H-NMR (CDCl3): δ 0.08 (s, 6H, 17-OSi(CH3)2, 0.18 (s, 6H, 3-OSi(CH3)2, 0.81 (s, 3H, 18-CH3), 0.91 (s, 9H, 17-OSi-t-Bu), 0.97 (s, 9H, 3-OSi-t-Bu), 4.33 (broad s, 1H, H17), 5.60 (m, 1H,H-15), 5.95 (d, 1H, H16), 6.45-6.75 (m, 2H, H2 and H4), 7.12 (d, 1H, H1) mp:89℃~91℃.

[0302] Step 2: Estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol To a stirred solution of estra-1,3,5(10),15-tetraene-3,17β-diol bis(dimethyl-tert-butylsilyl) ether (10.00 g, 20.0 mmol) and formic acid (2.3 mL, 60.0 mmol) in acetone (100 mL) at 0° C., a solution of potassium permanganate (3.15 g, 20.0 mmol) in water (20 mL) and acetone (100 mL) was slowly added. After the reaction was completed, the reaction was quenched with 10% aqueous KHSO3. The acetone was partially removed, extracted with ethyl acetate, and washed with water. The ethyl acetate was concentrated under reduced pressure and diluted with heptane. The precipitate was collected by filtration and dissolved in acetone (100 mL). 5N hydrochloric acid (20 mL) was added to the solution. After the reaction was completed, the resulting solution was diluted with water. The solid was collected by filtration, washed with heptane, and crystallized from a mixture of methanol and water to give the title compound.

[0303] Example 16: R 1 The protecting group of is tert-butyldimethylsilyl group and R 2a Preparation of estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol of formula (E) via compound (B) using pivaloyl as the protecting group [ka]

[0304] The starting material 3-tert-butyldimethylsiloxy-estra-1,3,5(10)-15-tetraen-17β-ol can be prepared as described in Examples 7 to 11. To a solution of 3-tert-butyldimethylsiloxy-estra-1,3,5(10)-15-tetraen-17-ol (30.00 g, 78.0 mmol) in 300 mL of dichloromethane and 11 mL of triethylamine, pivaloyl chloride (10.36 g, 86.0 mmol) in 50 mL of methylene chloride was added dropwise at 0° C. After the addition was complete, the solution was stirred at room temperature for 1 hour. Water was added and the organic layer was washed twice with 100 ml of water. Heptane was added and the product was collected by filtration and used in the next step without any other purification.

[0305] 3-tert-Butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraene-17β-pivaloate was converted to its 15α,16α derivative following the procedure described in step 2 of Example 15.

[0306] The 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15α,16α-diol-triene-17β-pivaloate (10.00 g, 20.0 mmol) and K2CO3 (2.76 g, 20.0 mmol) were then suspended in methanol (200 mL) and stirred at room temperature for 4 hours. Water (300 mL) was added and the mixture was neutralized with 0.1 N HCl. The product was collected by filtration and dried to give 7.50 g (90% yield) of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-triene-15α,16α,17β-triol.

[0307] Deprotection of the silyl protecting group in acidic medium was carried out using the same conditions as described in step 2 of Example 15, converting this compound to estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol in 90% yield.

[0308] Example 17: Calculation of the effect of different substituents on the activation energy of the compounds of formula (II) according to the invention, more specifically in the desulfinylation process according to the invention An in silico approach was used to calculate the transition state (TS) and activation energy in the desulfinylation reaction of the compound of formula (W) (see Table 7 for the definition of R). Accordingly, the constant rate was determined using the appropriate rate law in order to evaluate the reaction time required to reach a certain conversion at a given temperature. In this case, the thermolysis phenomenon depends on first-order kinetics. This method allowed us to evaluate the modulation effect of various substituents (R) on the activation barrier and thus on the reaction time. [ka]

[0309] The unsubstituted derivative (compound Y, R=H) was used as a reference compound to calibrate the model. [ka]

[0310] The calculations were performed using commercially available software (Gaussian 16 package) employing implicit solvation (SMD, solvent = toluene). Density functional theory (DFT)-based kinetic data for the thermal decomposition of different R substituents of compound (W) are shown in Table 7.

[0311] [Table 7]

[0312] Example 18: Comparative example of sulfinylation carried out in a batch synthesis and using a continuous flow process according to the invention [ka]

[0313] To a solution of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (L, 1.12 g, 2.20 mmol) in o-xylene (10.0 mL, 0.22 M) was added DMAD (0.8 mL, 6.60 mmol). The reaction mixture was stirred at 135° C. for 17 h and quenched by addition of water (15 mL). The phases were separated and the organic layer was dried over Na2SO4. After drying, 1 mL of Et3N was added and the volatiles were removed under reduced pressure. Compound (M) was detected in the crude product in 28% yield by HPLC.

[0314] Following the procedure described in Example 1, a feed solution containing 0.22 M of compound (L) in toluene in the presence of 1.5 equivalents of DMAD and 0.1 equivalents of triethylamine was subjected to pyrolysis at 210° C. for a residence time of 6 minutes. 91% of compound (M) was detected in the crude product by HPLC.

[0315] Example 19: Pilot scale setup A solution of 3-tert-butyldimethylsilyloxy-16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (975 g, 1.96 mol) and EtN (26.1 mL, 0.20 mol) in toluene (8.0 L) was pumped with "Pump A" (see Scheme 6) at 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" at a flow rate of 3.05 mL / min. Flows A and B were mixed and the combined flows were transferred to a SS flow reactor (V) heated to 210 °C. int= 134 mL) at a total flow rate of 44.73 mL / min over a residence time of 3 minutes. The feed was kept liquid with a back pressure regulator at 15 bar (220 psi). The flow was then cooled to 15°C and the crude reaction mixture was collected in a flask. The organic layer was washed with 1 M aqueous NaOH (8.0 L). The volatiles were removed under reduced pressure to give a crude brown solution containing 88 / 5 / 3 / 3 area % by HPLC of 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one / 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-trien-17-one / 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-14-tetraen-17-one / 3-tert-butyldimethylsilyloxy-16-phenylthio-estra-1,3,5(10)-15-tetraen-17-one. Purification of the crude product by recrystallization in MTBE gave 3-tert-butyldimethylsilyloxy-estra-1,3,5(10)-15-tetraen-17-one as an off-white solid (78%, 96.9% pure by HPLC).

[0316] Example 20: Preparation of estra-1,3,5(10)-15-tetraen-17-one Step 1: 16-(Phenylsulfinyl)-estra-1,3,5(10)-trien-17-one 16-(Phenylsulfinyl)-estra-1,3,5(10)-trien-17-one was prepared as described in step 2 of Example 7.

[0317] Step 2: Estra-1,3,5(10)-15-tetraen-17-one To a solution of 16-(phenylsulfinyl)-estra-1,3,5(10)-trien-17-one (500 mg, 1.27 mmol) in N-methyl-2-pyrrolidone (12.6 mL) was added (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (396 mg, 2.53 mmol). The solution was heated to 210 °C in a tube (V int= 5 mL) at a flow rate of 0.833 mL / min. The feed was kept liquid with a back pressure regulator (BPR) at 34 bar (500 psi). The flow was then cooled to 0°C and the crude reaction mixture was collected in a flask. The product was obtained in 69% yield (determined by HPLC).

[0318] 1 H-NMR (CDCl3): δ 1.11 (3H, s, CH3 at C-18), 1,57-1,87 (4H, m), 1.98-2.07 (1H, m), 2.13-2.25 (1H, m), 2.39-2.47 (1H, m), 2.51 (1H, d), 2.87-3.02 (2H, m), 4.66 (1H, s), 6.09 (1H, dd), 6.60 (1H, d), 6.65 (1H, dd), 7.15 (1H, d), 7.63 (1H, d).

Claims

1. Formula (I): 【Chemistry 1】 A process for the preparation of a compound of the formula (I) or a stereoisomer, salt, hydrate or solvate thereof, comprising the steps of: Formula (II): 【Chemistry 2】 to produce a compound of formula (I), During the ceremony, R １ is hydrogen, R ３ Si(R ４ ) (R ５ ) -, C １～６ Alkyl, C ６～１０ Aryl, C ６～１０ Aryl C １～６ Alkyl, -CH ２ -CH=CR ａ R ｂ , C １～６ Alkoxy, C ３～６ Cycloalkyl, and R ６ CO-, １～６ Alkyl, C ６～１０ Aryl, C ６～１０ Aryl C １～６ Alkyl, and C ３～６ Each cycloalkyl can be selected from halo, C １～６ Alkyl, haloC １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C ６～１０ optionally substituted with one or more substituents each independently selected from the group consisting of aryl, heterocyclyl, and nitro; R ２ is C ６～１０ aryl, or heteroaryl, where each C ６～１０ Aryl or heteroaryl is halo, C １～６ Alkyl, haloC １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkoxy, C ２～６ Alkenyl, C ２～６ Alkynyl, C ６～１０ Aryl, heterocyclyl, heteroaryl, hydroxyl, -S(O) ２ R ７ , -S(O)R ８ , -CO ２ R ９ , -C(O)R １０ , -SR １３ , -C(O)SR １４ , N.R. １１ R １２ optionally substituted with one or more substituents each independently selected from the group consisting of , cyano and nitro; R ３ , R ４ , and R ５ are each independently １～６ Alkyl or C ６～１０ aryl, where each C １～６ Alkyl or C ６～１０ Aryl is halo, C １～６ Alkyl, haloC １～６ Alkyl, C １～６ Alkoxy and haloC １～６ The group consisting of alkoxy, preferably fluoro, chloro or C １～４ optionally substituted with one or more substituents each independently selected from alkyl, R ６ is C １～６ Alkyl, C ６～１０ Aryl, or C ３～６ cycloalkyl, where each C １～６ Alkyl, C ６～１０ Aryl, or C ３～６ Cycloalkyl is halo, C １～６ Alkyl, haloC １～６ Alkyl, C １～６ Alkoxy and haloC １～６ and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R ７ , R ８ , R ９ , and R １０ are each independently hydrogen, hydroxyl, C １～６ Alkyl, C ６～１０ Aryl, and C ３～６ cycloalkyl, wherein each C １～６ Alkyl, C ６～１０ Aryl, or C ３～６ Cycloalkyl is halo, C １～６ Alkyl, haloC １～６ Alkyl, C １～６ Alkoxy and haloC １～６ and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R １１ and R １２ are each independently hydrogen, C １～６ Alkyl, C ６～１２ Aryl, C ３～６ cycloalkyl, wherein each C １～６ Alkyl, C ６～１０ Aryl, or C ３～６ Cycloalkyl is halo, C １～６ Alkyl, haloC １～６ Alkyl, C １～６ Alkoxy and haloC １～６ and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R １３ and R １４ are each independently hydrogen, C １～６ Alkyl, C ６～１０ Aryl, and C ３～６ cycloalkyl, wherein each C １～６ Alkyl, C ６～１０ Aryl, or C ３～６ Cycloalkyl is halo, C １～６ Alkyl, haloC １～６ Alkyl, C １～６ Alkoxy and haloC １～６ and optionally substituted with one or more substituents independently selected from the group consisting of alkoxy; R ａ and R ｂ are each independently hydrogen, C １～６ Alkyl or C ６～１０ is aryl, The process wherein the desulfinylation step is carried out by a continuous flow process.

2. The process of claim 1 , wherein the desulfinylation step is carried out by pyrolysis.

3. 3. The process according to claim 1 or 2, wherein the desulfinylation step is carried out by pyrolysis, at a pyrolysis temperature T of at least 100° C.

4. 4. The process according to any one of claims 1 to 3, wherein the desulfinylation step is carried out by pyrolysis, the pyrolysis being carried out at a pressure P of at least 1 bar.

5. 5. The process according to any one of claims 1 to 4, wherein the desulfinylation step is carried out by pyrolysis for a pyrolysis time t of at most 60 minutes.

6. The process according to any one of claims 1 to 5, wherein the desulfinylation step is carried out in at least one diluent.

7. The following steps: (a) reacting a compound of formula (II) At least one diluent; optionally at least one scavenger, and optionally at least one base; contacting to form a mixture; (b) feeding said mixture into an inlet of a channel of a reaction zone; (c) conveying a flow of solution along said channel from said inlet to said outlet to form a reaction product comprising at least a compound of formula (I); (d) recovering said reaction products at said outlet; and (e) optionally separating said at least one compound of formula (I) from other reaction products or retaining said compound of formula (I) in said reaction products. The process according to any one of claims 1 to 6, comprising:

8. 8. The process of claim 7, wherein the reaction zone is a pyrolysis reaction zone and step (c) comprises subjecting the mixture to pyrolysis by conveying a flow of the mixture along the channel from the inlet to the outlet at a pressure P, and a pyrolysis temperature T, for a pyrolysis time t, to form a pyrolysis reaction product comprising at least the compound of formula (I).

9. 9. The process of claim 7 or 8, wherein the compound of formula (II) is present in the mixture of step (a) in an amount of at least 0.01 moles per liter of diluent.

10. The process according to any one of claims 1 to 9, wherein the desulfinylation step is carried out in the presence of at least one scavenger.

11. 11. The process of any one of claims 1 to 10, wherein the desulfinylation step is carried out in the presence of at least one scavenger, and the at least one scavenger is present in an amount of at least 0.1 equivalents to at most 10.0 equivalents.

12. The process according to any one of claims 1 to 11, wherein the desulfinylation step is carried out in the presence of at least one base.

13. The compound of formula (II) a) protecting the hydroxyl of a compound of formula (III) to form a compound of formula (IV), １ has the same meaning as in claim 1: 【Chemistry 3】 b) sulfinylating a compound of formula (IV) to give a compound of formula (II); The process according to any one of claims 1 to 12, which is obtained by a process comprising:

14. Formula (Estetrol E): 【Chemistry 4】 14. A process for the preparation of an estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol of formula (E), its stereoisomer, salt, hydrate, ester, ether or solvate, said process comprising the steps of preparing a compound of formula (I) by the process of any one of claims 1 to 13 and further reacting the compound of formula (I) to produce an estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol of formula (E), its stereoisomer, salt, hydrate, ester, ether or solvate.

15. Compounds of formula (I) and compounds of formula (IIa): 【Chemistry 5】 Including, In the formula, R １ and R ２ A composition as defined in claim 1.

Images