Process for the preparation of fulvestrant

Abstract

The present invention relates to a new process of preparation of an intermediate compound for the synthesis of Fulvestrant, and its use for the preparation of Fulvestrant.

Description

[0001] PROCESS FOR THE PREPARATION OF FULVESTRANT

[0002] The present invention relates to a new process of preparation of an intermediate compound for the synthesis of Fulvestrant and to a process of preparation of Fulvestrant comprising the preparation of said intermediate compound. BACKGROUND OF THE INVENTION

[0003] Fulvestrant, chemically 7a-[9-[(4, 4,5,5, 5-pentafluoropentyl)-sulfmyl]nonyl]estra-l, 3, 5(10)- triene-3,17P-diol, is a drug used for the treatment of hormone receptor (HR)-positive metastatic breast cancer in post-menopausal women with disease progression following antioestrogen therapy. It is an oestrogen receptor antagonist with no agonist effects, which works both by down-regulating and by degrading the oestrogen receptor.

[0004] Fulvestrant contains a tetracyclic core wherein the carbon atoms are numbered as shown below:

[0005] Approaches towards Fulvestrant of the prior art rely on the preparation of the intermediate compound Hi obtained as a mixture of isomers 7a and 7p by the addition of (9-((4,4,5,5,5- pentafluoropentyl)thio)nonyl)magnesium bromide i to 17P-acetoxyestra-4,6-dien-3-one zz:

[0006]

[0007] The isomer 7a of the intermediate compound Hi is the isomer having a R configuration in position 7 of the tetracyclic core and the isomer 7p of the intermediate compound Hi is the isomer having a S configuration in position 7 of the tetracyclic core:

[0008] Brazier et al. (Org. Process Res. Dev. 2010, 14, 544-552) discloses a synthetic route to Fulvestrant including the preparation of intermediate compound (Hi by adding the dienone compound (if) to a mixture comprising an excess of Grignard compound (i) and CuCl in THF at -34°C over a period of 3 h 30 min. Hogan et al. (Org. Process Res. Dev. 2010, 14, 1188-1193) discloses an optimisation of this process, involving in particular the controlled addition of the dienone compound (zz) to a mixture comprising the Grignard compound (z) and CuCl.

[0009] The same route is used in EP 1 436 256 Bl and in EP 1 328 538 Bl.

[0010] According to this method, the intermediate compound (zzz) is obtained as a mixture of isomers 7a and 7p with an a / p selectivity of 2.5: 1.

[0011] This process therefore requires a purification step using silica chromatography after the conjugated addition reaction and / or a purification step by multiple crystallisations after the final step of the process to obtain Fulvestrant. These purification steps aim to remove the unwanted 7P isomer.

[0012] Therefore, there is still a need for a process of preparation of the intermediate compound Hi for the synthesis of Fulvestrant with high selectivity in 7a isomer during conjugated 1,6- addition and control of impurity formation at this stage in order to guarantee a high yield in Fulvestrant without requiring long and complex purification step after the conjugated 1,6- addition step.

[0013] SUMMARY OF THE INVENTION

[0014] The inventors have now succeeded in developing a novel process for the preparation of Fulvestrant in good yield that does not need a long and complex purification step after the conjugated 1,6-addition step and that is viable at an industrially relevant scale.

[0015] The present invention therefore relates to a process for the preparation of an intermediate compound of formula (I): comprising the following steps in the following order: a) providing a Grignard compound of formula (i): b) reacting said compound of formula (i) with a dienone compound of formula (ii): in the presence of CuCl; wherein step b) comprises a simultaneous and controlled addition of compounds (i) and (ii) with a compound (i) / compound (ii) molar ratio comprised between 0.79 and 0.98.

[0016] The invention also relates to a process for the preparation of Fulvestrant, comprising the following steps in the following order: c) preparing an intermediate compound of formula (I) according to the above process; d) aromatizing the compound obtained in step c); e) deprotecting the compound obtained in step d); f) sulfur oxidizing the compound obtained in step e); and g) purifying the compound obtained in step f) by recrystallization.

[0017] The invention further relates to the use of the compound of formula I, wherein the 7a / 7p ratio is more than 4: 1, as a synthetic intermediate for the preparation of Fulvestrant.

[0018] DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention therefore relates to a process for the preparation of an intermediate compound of formula (I): comprising the following steps in the following order: a) providing a Grignard compound of formula (i): b) reacting said compound of formula (i) with a dienone compound of formula (ii): in the presence of CuCl; wherein step b) comprises a simultaneous and controlled addition of compounds of formula (i) and (ii) with a compound (i) / compound (ii) molar ratio comprised between 0.79 and 0.98, in particular between 0.85 and 0.95, more particularly between 0.86 and 0.92, still more particularly between 0.87 and 0.91, even more particularly between 0.88 and 0.90.

[0020] Unexpectedly, the inventors found that the reaction conditions used, while being compatible with a use at an industrially relevant scale, make it possible to obtain the intermediate compound of formula (I) with a 7a / 7p ratio of more than 4: 1, in particular more than 5: 1, more particularly more than 6:1, still more particularly more than 7:1, still more particularly more than 8: 1, even more particularly more than 9: 1. Said intermediate compound of formula (I) with said 7a / 7p ratio can advantageously be used for the synthesis of Fulvestrant without the need for a complex purification step, in particular by silica chromatography.

[0021] The term “7a / 7p ratio” as used in the context of the present invention refers to the molar ratio between the 7a isomer (or the 1-R isomer) and the 7p isomer (or the 7-5 isomer) of Fulvestrant, or any intermediate compounds of Fulvestrant having an asymmetric carbon, or chiral carbon, in position 7 of the tetracyclic core, including the compound of formula (I). The 7a / 7p ratio of Fulvestrant and its intermediate compound having an asymmetric compound in position 7 of the tetracyclic core may be determined by any technique known by the person skilled in the art, in particular by Ultra High Performance Liquid Chromatography (UPLC) or by High Performance Liquid Chromatography (HPLC).

[0022] In other words, the compound of formula (I) of the process of the invention may be defined as a compound of formula (la): wherein the 7a / 7p ratio is more than 4:1, in particular more than 5: 1, more particularly more than 6: 1, still more particularly more than 7:1, still more particularly more than 8:1, even more particularly more than 9: 1.

[0023] In an embodiment, the 7a / 7p ratio of the compound of formula (la) is comprised between 4: 1 and 20: 1, in particular between 5: 1 and 15: 1, more particularly between 6: 1 and 12: 1, still more particularly between 7: 1 and 11 : 1, still more particularly between 8: 1 and 10: 1, even more particularly between 9: 1 and 10: 1.

[0024] The 7a / 7p ratio of the compound of formula (la) may be determined by any technique known by the person skilled in the art. In particular, the 7a / 7p ratio of the compound of formula (la) may be determined by Ultra High Performance Liquid Chromatography (UPLC), more particularly by reversed UPLC using an Eclipse Plus Cl 8 stationary phase and a CH3CN / H2O mobile phase.

[0025] In one embodiment, the amount of CuCl used in step b) of the process of the invention is comprised between 0.01 equivalents and 0.20 equivalents, in particular between 0.05 equivalents and 0.15 equivalents, more particularly between 0.08 equivalents and 0.12 equivalents, with respect to the amount of dienone compound of formula (ii). Even more particularly, the amount of CuCl used in step b) of the process of the invention is 0.10 equivalents (10 mol%) with respect to the amount of dienone compound of formula (ii). By “simultaneous addition of compounds of formula (i) and (ii)”, it is meant in the context of the present invention that compounds (i) and (ii) are added at the same time in the reaction mixture.

[0026] By “controlled addition of compounds of formula (i) and (ii)”, it is meant in the context of the present invention that compounds (i) and (ii) are added in the reaction mixture at a specific molar rate and during a specific period of time.

[0027] In one embodiment, the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b) of the process of the invention is carried out over a period comprised between 3 h 30 min and 4 h 20 min, in particular between 3 h 36 min and 4 h 24 min, more particularly between 3 h 45 min and 4 h 20 min, still more particularly between 3 h 50 min and 4 h 10 min, even more particularly between 3 h 50 min and 4 h. In a particular example, the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b) of the process of the invention is carried out over 3 h 55 min.

[0028] In one embodiment, the compound of formula (i) is added at a rate comprised between 0.20 and 0.25 equiv. / h, in particular between 0.201 and 0.246 equiv. / h, more particularly between 0.241 and 0.206 equiv. / h, still more particularly between 0.236 and 0.211 equiv. / h, even more particularly between 0.231 and 0.216 equiv. / h, with respect to the total amount of compound of formula (ii), during the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b) of the process of the invention. In a particular example, the compound of formula (i) is added at a rate of about 0.222 equiv. / h, with respect to the total amount of compound of formula (ii), during the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b) of the process of the invention.

[0029] In one embodiment, the compound of formula (ii) is added at a rate comprised between 0.22 and 0.28 equiv. / h, in particular between 0.227 and 0.278 equiv. / h, more particularly between 0.232 and 0.273 equiv. / h, still more particularly between 0.237 and 0.268 equiv. / h, even more particularly between 0.242 and 0.263 equiv. / h, with respect to the total amount of compound of formula (ii), during the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b) of the process of the invention. In a particular example, the compound of formula (ii) is added at a rate of about 0.250 equiv. / h, with respect to the total amount of compound of formula (ii), during the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b) of the process of the invention.

[0030] In one embodiment, the step b) of the process of the invention further comprises the addition of an additional amount of compound of formula (i) after the simultaneous and controlled addition of compounds of formula (i) and (ii).

[0031] Advantageously, the additional amount of compound of formula (i) added after the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b) of the process of the invention is comprised between 0.25 equivalents and 0.70 equivalents, in particular between 0.30 equivalents and 0.65 equivalents, more particularly between 0.35 equivalents and 0.60 equivalents, still more particularly between 0.40 equivalents and 0.55 equivalents, with respect to the amount of compound of formula (ii). In a particular example, the additional of compound of formula (i) added after the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b) of the process of the invention is 0.46 equivalents with respect to the amount of compound of formula (ii).

[0032] In one embodiment, the solvent used in step b) of the process of the invention is an ether solvent. In particular, the solvent used in step b) of the process of the invention is selected from tert-amyl ethyl ether, cyclopentyl methyl ether, di-tert-butyl ether, di(propylene glycol) methyl ether, dibutyl ether, diethyl ether, diisopropyl ether, dimethoxyethane, dimethoxymethane, 1,4-di oxane, ethyl tert-butyl ether, methoxy ethane, 2-(2- methoxyethoxy)ethanol, methyl tert-butyl ether, 2-methyltetrahydrofuran, polyethylene glycol, propylene glycol methyl ether, tetrahydrofuran, tetrahydrofurfuryl alcohol, tetrahydropyran and 2,2,5,5-tetramethyltetrahydrofuran. More particularly, the solvent used in step b) is selected from cyclopentyl methyl ether, diisopropylether, methyl tert-butyl ether, 2-methyl-tetrahydrofuran, 2,2,5,5-tetramethyltetrahydrofuran and tetrahydrofuran. Still more particularly, the solvent used in step b) of the process of the invention is selected from 2-methyltetrahydrofuran, 2, 2, 5, 5 -tetramethyltetrahydrofuran and tetrahydrofuran. Even more particularly, the solvent used in step b) of the process of the invention is tetrahydrofuran. Advantageously, step b) of the process of the invention is run at a temperature of 0°C to - 40°C, in particular -10°C to -30°C, more particularly -17°C to -23°C, still more particularly step b) of the process of the invention is run at -20°C.

[0033] After the reaction of the step b) of the process of the invention is ended, the compound of formula (I) is obtained in a 7a / 7p ratio of more than 4: 1, in particular more than 5:1, more particularly more than 6: 1, still more particularly more than 7: 1, still more particularly more than 8: 1, even more particularly more than 9: 1, and may be used directly for the synthesis of Fulvestrant without any purification step.

[0034] In an embodiment, after the reaction of the step b) of the process of the invention is ended, the compound of formula (I) is obtained in a 7a / 7p ratio comprised between 4:1 and 20: 1, in particular between 5: 1 and 15: 1, more particularly between 6: 1 and 12: 1, still more particularly between 7:1 and 11 : 1, still more particularly between 8:1 and 10: 1, even more particularly between 9: 1 and 10: 1, and may be used directly for the synthesis of Fulvestrant without any purification step.

[0035] The 7a / 7p ratio of the compound of formula (I) may be determined by any technique known by the person skilled in the art. In particular, the 7a / 7p ratio of the compound of formula (I) may be determined by Ultra High Performance Liquid Chromatography (UPLC), more particularly by reversed UPLC using an Eclipse Plus Cl 8 stationary phase and a CH3CN / H2O mobile phase.

[0036] The invention thus also relates to a process for the preparation of Fulvestrant comprising the following steps: c) preparing an intermediate compound of formula (I) according to the above process of preparation of an intermediate compound of formula (I); d) aromatizing the compound obtained in step c); e) deprotecting the compound obtained in step d); f) sulfur oxidizing the compound obtained in step e); and g) purifying the compound obtained in step f) by recrystallization.

[0037] The step d) of aromatizing the compound obtained in step c) may be performed according to any method known by the person skilled in the art. In particular, the step d) of aromatizing the compound obtained in step c) may be performed by treating the compound obtained in step c) with CuBr2, LiBr and AC2O in propionitrile, followed by a treatment with an aqueous solution of ammonia.

[0038] Advantageously, the treatment of the compound obtained in step c) with CuBr2, LiBr and AC2O in propionitrile of step d) of the process of the invention may be performed at temperature comprised between 10°C and 30°C, in particular between 15°C and 25°C, more particularly at a temperature of about 20°C.

[0039] Advantageously, the treatment with an aqueous solution of ammonia of step d) of the process of the invention may be performed at temperature comprised between -10°C and 20°C, in particular between -5°C and 5°C, more particularly at a temperature of about -3°C.

[0040] The aromatized compound obtained at the end of step d) may be used directly in the following e) without any purification step.

[0041] The step e) of deprotecting the compound obtained in step d) may be performed according to any method known by the person skilled in the art. In particular, the step e) aims to remove the acetyl protecting groups from the hydroxyl groups of the compound obtained in step d). In particular, the step of deprotecting the compound obtained in step d) may be performed by treating the compound obtained in step d) with 50% sodium hydroxide in methanol, followed by a treatment with an aqueous solution of acetic acid.

[0042] Advantageously, the treatment of the compound obtained in step d) with 50% sodium hydroxide in methanol of step e) of the process of the invention may be performed at temperature comprised between 15°C and 35°C, in particular between 20°C and 25°C, more particularly at a temperature of about 23°C.

[0043] Advantageously, the treatment with an aqueous solution of acetic acid of step e) of the process of the invention may be performed at temperature comprised between 15°C and 25°C, in particular between 17°C and 23°C, more particularly at a temperature of about 20°C.

[0044] The deprotected compound obtained at the end of step e) may be used directly in the following f) without any purification step.

[0045] The step f) of sulfur oxidizing the compound obtained in step e) may be performed according to any method known by the person skilled in the art. In particular, the step f) of sulfur oxidizing the compound obtained in step e) may be performed by treating the compound obtained in step e) with an aqueous solution hydrogen peroxide and acetic acid in ethyl acetate, followed by a treatment with an aqueous solution of sodium sulfite and an aqueous solution of sodium hydroxide.

[0046] Advantageously, the treatment of the compound obtained in step e) with an aqueous solution of hydrogen peroxide and acetic acid in ethyl acetate of step f) of the process of the invention may be performed at temperature comprised between 12°C and 32°C, in particular between 17°C and 27°C, more particularly at a temperature of about 22°C.

[0047] Advantageously, the treatment with an aqueous solution of sodium sulfite and an aqueous solution of sodium hydroxide of step f) of the process of the invention may be performed at temperature comprised between 15°C and 30°C, in particular between 17°C and 27°C, more particularly at a temperature of about 22°C.

[0048] The crude product obtained after the reaction of sulfur oxidation may then be crystallized. The crystallization may be performed according to any method known by the person skilled in the art. In particular, the crystallization may be performed by maintaining the solution of the crude product in ethyl acetate at a temperature comprised between 45°C and 55°C and then cooling the solution to a temperature comprised between 15°C and 25°C, in particular to a temperature of about 20°C. Advantageously, said step may be repeated once, in particular twice.

[0049] The step f) of the process of the invention makes it possible to obtain crude Fulvestrant with a 7a / 7p ratio of more than 50: 1, in particular more than 60: 1, more particularly more than 80: 1, still more particularly more than 90: 1, even more particularly more than 100:1. In an embodiment, the step f) of the process of the invention makes it possible to obtain crude Fulvestrant with a 7a / 7p ratio comprised between 50: 1 and 200: 1, in particular between 60: 1 and 200: 1, more particularly between 80: 1 and 150: 11, still more particularly between 90: 1 and 130: 1, even more particularly between 100: 1 and 120: 1.

[0050] The 7a / 7p ratio of the crude Fulvestrant may be determined by any technique known by the person skilled in the art. In particular, the 7a / 7p ratio of the compound of formula (I) may be determined by High Performance Liquid Chromatography (HPLC), more particularly by reversed UPLC using an Eclipse Plus Cl 8 stationary phase and a CHjCN / EEO / MeOH mobile phase.

[0051] The step f) of the process of the invention makes it possible to obtain crude Fulvestrant with an overall yield of 35% to 55%, in particular 40% to 50%, more particularly 40% to 45%, with respect to the initial amount of the dienone compound of formula (if).

[0052] The step g) of purifying the compound obtained in step f) by recrystallization may be performed according to any method known by the person skilled in the art. In particular, the step g) of purifying the compound obtained in step f) by recrystallization may be performed by dissolving the compound in step f) of the process of the invention in ethyl acetate and maintaining the resulting solution at a temperature comprised between 45°C and 60°C and then cooling the solution to a temperature comprised between 15°C and 25°C, in particular to a temperature of about 20°C. Advantageously, said step g) may be repeated at least once, in particular once.

[0053] The step g) of the process of the invention makes it possible to obtain pure Fulvestrant with a 7a / 7p ratio of more than 970: 1, in particular more than 1000: 1, more particularly more than 1200: 1, still more particularly more than 1400: 1, even more particularly more than 1600: 1.

[0054] In an embodiment, the step g) of the process of the invention makes it possible to obtain pure Fulvestrant with a 7a / 7p ratio comprised between 970: 1 and 10000: 1, in particular between 1000: 1 and 10000: 1, more particularly between 1200: 1 and 5000: 1, still more particularly between 1400: 1 and 4000: 1, even more particularly between 1600: 1 and 3000: 1. In a particular example, the step g) of the process of the invention makes it possible to obtain pure Fulvestrant with a 7a / 7p ratio comprised between 1900: 1 and 2000: 1.

[0055] The 7a / 7p ratio of the pure Fulvestrant may be determined by any technique known by the person skilled in the art. In particular, the 7a / 7p ratio of the compound of formula (I) may be determined by High Performance Liquid Chromatography (HPLC), more particularly by reversed HPLC using an Eclipse Plus C8 stationary phase and a CH3CN / H2O / MeOH mobile phase.

[0056] The step g) of the process of the invention makes it possible to obtain Fulvestrant with an overall yield of 25% to 40%, in particular 25% to 35%, more particularly 27% to 33%, still more particularly 29% to 31%, with respect to the initial amount of the dienone compound of formula (zz).

[0057] The process of the invention thus makes it possible to obtain Fulvestrant with a 7a / 7p ratio of more than 970: 1 and with an overall yield of 25% to 40%, with respect to the initial amount of the dienone compound of formula (zz), without the need for a complex purification step, in particular by silica chromatography.

[0058] Another aspect of the invention therefore concerns the use of the compound of formula (I): wherein the 7a / 7p ratio is more than 4:1, in particular more than 5: 1, more particularly more than 6: 1, still more particularly more than 7:1, still more particularly more than 8:1, even more particularly more than 9:1, as a synthetic intermediate for the preparation of Fulvestrant.

[0059] In an embodiment, the 7a / 7p ratio of the compound of formula (I) is comprised between 4:1 and 20: 1, in particular between 5:1 and 15:1, more particularly between 6:1 and 12: 1, still more particularly between 7:1 and 11: 1, still more particularly between 8:1 and 10: 1, even more particularly between 9: 1 and 10: 1.

[0060] DEFINITIONS

[0061] The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.

[0062] When describing the process and compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

[0063] The term “7a / 7p ratio” as used herein refers to the molar ratio between the 7a isomer (or the 7-7? isomer) and the 7p isomer (or the 7-5 isomer) of Fulvestrant, or any intermediate compounds of Fulvestrant having an asymmetric carbon, or chiral carbon, in position 7 of the tetracyclic core, including the compound of formula (I) or the compound of formula (la). The 7a / 7p ratio of Fulvestrant and its intermediate compound having an asymmetric compound in position 7 of the tetracyclic core may be determined by any technique known by the person skilled in the art, in particular by Ultra High Performance Liquid Chromatography (UPLC) or by High Performance Liquid Chromatography (HPLC).

[0064] The term “simultaneous addition of compounds of formula (i) and (ii)” as used herein refers to the addition of compounds (i) and (ii) at the same time in the reaction mixture.

[0065] The term “controlled addition of compounds of formula (i) and (ii)” as used herein refers to the addition of compounds (i) and (ii) in the reaction mixture at a specific molar rate and during a specific period of time. In particular, the compound of formula (i) is added at a rate comprised between 0.20 and 0.25 equiv. / h, with respect to the total amount of compound of formula (ii), and the compound of formula (ii) is added at a rate comprised between 0.22 and 0.28 equiv. / h, with respect to the total amount of compound of formula (ii), over a period comprised between 3 h 30 min and 4 h 20 min.

[0066] The term “ether solvent” as used herein refers to a solvent whose chemical structure comprises at least one ether functional group, i.e. a group in which an oxygen atom is bonded to two carbon atoms from alkyl or aryl groups (C-O-C). Examples of ether solvents include but are not limited to tert-amyl ethyl ether, cyclopentyl methyl ether, di-tert-butyl ether, di(propylene glycol) methyl ether, dibutyl ether, diethyl ether, diisopropyl ether, dimethoxy ethane, dimethoxymethane, 1,4-di oxane, ethyl tert-butyl ether, methoxy ethane, 2-(2-methoxyethoxy)ethanol, methyl tert-butyl ether, 2-methyltetrahydrofuran, polyethylene glycol, propylene glycol methyl ether, tetrahydrofuran, tetrahydrofurfuryl alcohol, tetrahydropyran, and 2,2,5,5-tetramethyltetrahydrofuran.

[0067] The term “alkyl” by itself or as part of another substituent refers to a hydrocarbyl radical of Formula CnFhn+i wherein n is an integer greater than or equal to 1.

[0068] The term “aryl” as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (z.e. phenyl) or multiple aromatic rings fused together (e.g. naphthyl), typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. Examples of aryl groups include but are not limited to phenyl, naphthyl and anthracyl.

[0069] The present invention will be better understood with reference to the following examples and figures. These examples are intended to be representative of specific embodiments of the invention and are not intended as limiting the scope of the invention.

[0070] EXAMPLES

[0071] All temperatures are expressed in °C and all reactions were carried out at room temperature (RT) unless otherwise stated.

[0072] The reaction monitoring was performed by reverse phase HPLC.

[0073] NMR spectra were recorded on Bruker Avance DPX300 (operating at 300 MHz for 'H and 75 MHz for13C). Chemical shifts are expressed in ppm relative to tetramethylsilane (TMS) or to residual proton signal in deuterated solvents. Chemical shifts are reported as position (b in ppm), multiplicity (s = singulet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant (Jin Hz) and relative integral.

[0074] The 7a / 7p ratio of the compounds was determined by high performance liquid chromatography (HPLC) or ultra high performance liquid chromatography (UPLC) using Agilent equipment. Solvents, reagents and starting materials were purchased from well-known chemical suppliers (such as for example Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, ABCR, TCI) and the following abbreviations are used: eq. / equiv.: equivalent; HPLC: high performance liquid chromatography;

[0075] PTFE: polytetrafluoroethylene;

[0076] NMR: nuclear magnetic resonance;

[0077] THF : tetrahydrofuran;

[0078] UPLC: ultra high performance liquid chromatography. Synthesis of the intermediate compound of formula (I)

[0079] The intermediate compound of formula (I) (JEN-2) was synthesized according to the synthetic route presented in Scheme 1.

[0080]

[0081] JEN-2 (Intermediate of Formula (I), 7a / 7p > 4:1 ) C34H51 F5O3S Mol Wt: 634,83

[0082] Scheme 1.

[0083] Synthesis of intermediate JEN-1

[0084] To a 1 L three-necked round-bottom flask containing anhydrous THF (126 mL, 8.40 vol.) under a nitrogen atmosphere and equipped with magnetic stirring, an addition funnel and a thermometer were added successively Mg (2.54 g, 2.19 eq.) and then JEN-IN (assumed to be 0.38 M, 6.8 mL, 0.05 eq.), which is a small amount of JEN-1 used an initiator. The medium was heated at 45 ± 5°C, then a first portion of JEN-O-Br was added (3.7 mL, 0.25 eq.) and the reaction mixture was stirred for 30 minutes at 500 rpm. THF (33 mL, 2.20 vol.) and a second portion of JEN-0-Br (6.6 mL, 0.44 eq.) were then added, and the reaction mixture was stirred for 30 minutes. A third portion of JEN-0-Br (6.6 mL, 0.44 eq.) was then added, and the reaction mixture was stirred for 30 minutes. A fourth portion of JEN-0-Br (6.6 mL, 0.44 eq.) was then added, and the reaction mixture was stirred for 30 minutes. A fifth portion of JEN-0-Br (3.2 mL, 0.22 eq.) was then added, and the reaction mixture was stirred for 30 minutes. The addition funnel was rinsed with THF (6.3 mL, 0.42 vol.) and the reaction mixture was stirred for 1 hour at 45 ± 5°C and at 500 rpm.

[0085] Synthesis of the compound of formula (I) (JEN-2)

[0086] To a 500 mL three-necked round-bottom flask containing THF (31.2 mL, 2.10 vol.) under a nitrogen atmosphere was added CuCl (0.47 g, 0.10 eq.), and the medium was then cooled at -20°C under vigorous magnetic stirring. A solution of JEN-0-DE (15.0 g, 1.00 eq.) in THF (64 mL, 4.25 vol.) was loaded in a syringe and added to the CuCl suspension in THF, using a syringe pump, in 4 h ± 12 min, at -20 ± 3°C. Five minutes after starting the addition of the solution of JEN-0-DE, a solution of JEN-1 (109.4 mL, 0.87 eq.) was added simultaneously to the addition of the solution of JEN-0-DE, using a syringe pump, for 3 h 55 min ± 12 min, at -20 ± 3°C. A second portion of JEN-1 (57.9 mL, 0.46 eq.) was then added for 2 h 5 min ± 6 min. The syringes were then rinsed with THF (6.9 mL in total, 0.5 vol.), and the reaction mixture was stirred for 30 minutes. Acetic acid (12.8 g, 4.47 eq.) diluted in THF (15.0 mL, 1.0 vol.) was added to the reaction mixture via a dropping funnel which was then rinsed with THF (10 mL, 0.7 vol.). The reaction mixture was then allowed to warm up to room temperature (20 ± 5°C). Water (105 mL, 7.0 vol.) was then added to the medium at 20 ± 5°C. The resulting mixture was then distilled until obtaining a residual volume of about 217 mL. The medium was cooled to 25°C and isohexane (75 mL, 5.0 vol.) was added. The resulting mixture was then stirred for 1 h. A solution of Na2COs (7.3 g, 1.45 eq.) in water (37.5 mL, 2.5 vol.) was added with a syringe in lh30. The syringe was rinsed with water (7.5 mL, 0.5 vol.) and the resulting mixture was then stirred for 1 h. The mixture was transferred to a 500 mL separating funnel and left to settle for at least 1 h. The organic layer was collected and distilled until obtaining a residual volume of 85 mL. The medium was cooled to about 30°C, isohexane (300 mL, 20.0 vol.) was added, and the resulting mixture was distilled until obtaining a residual volume of 85 mL. The medium was cooled to about 30-50°C, isohexane (300 mL, 20.0 vol.) was added, and the resulting mixture was distilled until obtaining a residual volume of 85 mL. The residue was cooled to 22 ± 3°C and its volume was adjusted to about 93-94 mL by adding isohexane. The compound of formula (I) was then obtained in solution in isohexane (93.8 mL, 6.25 vol.).

[0087] Determination of the 7a / 7p ratio of intermediate JEN-2: The 7a / 7p ratio of the compound JEN-2 was determined by UPLC characterization of a representative batch using the following conditions:

[0088] Column: Zorbax Eclipse Plus C18, 50 * 2.1 mm, 1.8 pm (Agilent: 959757-902);

[0089] Mobile phase: mixture of H2O and CH3CN with the following gradient: 0 min: H2O / CH3CN 35:65, 15 min: H2O / CH3CN 5:95, 20 min: H2O / CH3CN 5:95, 20.5 min: H2O / CH3CN 35:65, 25 min: H2O / CH3CN 35:65;

[0090] Detection: 250 nm; Volume of sample injected: 1.5 pL; Column temperature: 45°C; Sample temperature: 5°C; Flow rate: 0.5 mL / min.

[0091] Ratio JEN-2(7a) / JEN-2(7P) = 7.8.

[0092] NMR characterization of the purified intermediate JEN-2 in CDCI3:

[0093] 'H NMR (CDCI3, 300 MHz): 5 (ppm) 0.85 (s, 3H, C18H3), 0.9-1.4 (m, 2H, C6H2), 0.9-1.4 (m, 1H, C9H), 0.9-1.4 (m, 1H, C10H), 0.9-1.4 (m, 1H, CnH), 0.9-1.4 (m, 2H, C25H2), 0.9-1.4 (m, 2H, C26H2), 0.9-1.4 (m, 2H, C27H2), 0.9-1.4 (m, 2H, C28H2), 0.9-1.4 (m, 2H, C29H2), 0.9- 1.4 (m, 2H, C30H2), 1.4-1.6 (m, 2H, C23H2), 1.4-1.6 (m, 2H, C24H2), 1.4-1.6 (m, 2H, C31H2), 1.4-1.6 (m, 2H, C32H2), 1.4-1.9 (m, 2H, C13H2), 1.4-1.9 (m, 2H, C14H2), 1.4-1.9 (m, 2H, C15H2), 1.4-1.9 (m, 2H, C16H2), 1.7-1.9 (m, 1H, C5H), 2.04 (s, 3H, C36H3), 2.2-2.3 (m, 2H, C1H2), 2.2-2.3 (m, 2H, C7H2), 2.3 (m, 1H, C8H), 2.51 (t,3J = 7.0, 2H, C20H2), 2.59 (t,3J = 7.0, 2H, C22H2), 4.62 (dd,3J = 9.1,3J = 7.8, 1H, C17H), 5.83 (s, 1H, C3H).

[0094] 13C NMR (CDCI3, 75 MHz): 5 (ppm) 12.1 (C18), 20.5 (C31), 21.3 (C36), 22.9 (C15), 25.7 (C14), 27.0 (C6), 27.0 (C32), 27.6 (C16), 27.6 (C29), 28.0 (C24), 29.0 (C25), 29.6 (C26), 29.7 (C27), 29.7 (C28), 30.0 (C23), 32.0 (C20), 32.0 (C22), 32.0 (C30), 36.6 (C13), 36.9 (Cl), 39.8 (C7), 42.8 (C9), 43.1 (C12), 43.2 (CIO), 43.3 (C5), 45.8 (Cl l), 82.7 (C17), 126.7 (C3), 165.3 (C4), 171.4 (C35), 199.9 (C2).

[0095] Synthesis of Fulvestrant Synthesis of intermediate JEN-5

[0096] Intermediate JEN-5 was synthesized according to the synthetic route presented in Scheme 2.

[0097] Scheme 2.

[0098] To a first 250 mL three-necked round-bottom flask containing a solution of JEN-2 in isohexane (94 mL, 30.3 g of active JEN-2, 1.0 eq.) under a nitrogen atmosphere was added isohexane (90.9 mL, 3.0 vol.), and the medium was stirred for 10 min. The medium was then heated and the solvent distilled until obtaining a residual volume of 76 mL in the three- necked round-bottom flask. The medium was cooled to about 45°C and EtCN (90.9 mL, 3.0 vol.) was then added. The solvent was distilled again until obtaining a residual volume of 76 mL and the medium was cooled to 20°C.

[0099] To a second three-necked round-bottom flask containing EtCN (90.9 mL, 3.0 vol.), under magnetic stirring and a nitrogen atmosphere, was added AC2O (5.60 g, 1.15 eq.) and the medium was cooled below 10°C. LiBr (6.88 g, 1.66 eq.) was then added, and the medium was stirred vigorously for 10 min until complete dissolution. CuBr2 (25.25 g, 2.36 eq.) was then added under vigorous stirring. The resulting mixture was warmed to 22 ± 5°C and stirred for 1 h. The temperature was adjusted to 19 ± 3°C and the mixture was stirred for 30 min. The resulting solution was then added to the first three-necked round-bottom flask containing the solution of JEN-2 using a syringe pump in 4 h (25 mL / h) at 20°C. the syringe and the second three-necked round-bottom flask were then rinsed with EtCN (6.1 mL, 0.2 vol.) and the remaining portion of AC2O (4.14 g, 0.85 eq.) was immediately added. The reaction mixture was stirred for 4 h at 20 ± 3 °C under a nitrogen atmosphere. The reaction mixture was then transferred to a 500 mL three-necked round-bottom flask equipped with a dropping funnel and the first flask was rinsed with EtCN (12 mL, 0.4 vol.). The reaction mixture was then cooled to -3°C. A solution of NH3 (25%, 71.6 g, 11.0 eq.) in water (154.0 mL, 5.0 vol.) was added to the reaction mixture using the dropping funnel in about 10 min under vigorous stirring. The reaction mixture was then warmed to 20°C and stirred for 1 h. The mixture was transferred to a 500 mL separating funnel and left to settle for at least 2 h under a nitrogen atmosphere. The organic layer was collected and an aqueous solution of NaCl (mNaCl = 15.44 g / vELO = 73.3 mL, 2.4 vol.) was added, and the resulting mixture was stirred for 45 min. The mixture was transferred again to a separating funnel and left to settle for at least 90 min. The organic layer was collected, MeOH (45.4 mL, 1.5 vol.) was added, and then 50% NaOH (16.41 g, 4.3 eq.) was added to the organic layer in about 5-10 min at 20°C. The flask was rinsed with MeOH (15.1 mL, 0.5 vol.). The resulting mixture was stirred for 3 h at 20 ± 5°C. MeOH (136.3 mL, 4.5 vol.) and isohexane (266.5 mL, 8.8 vol.) were added and the resulting mixture was stirred for 1 h at 20 ± 5°C. The mixture was left to settle for 1 h. The lower layer was collected, isohexane (266.5 mL, 8.8 vol.) was added, and the resulting mixture was stirred for 1 h at 20 ± 5°C. The mixture was left to settle for 30 min. The lower layer was collected, isohexane (266.5 mL, 8.8 vol.) was added, and the resulting mixture was stirred again for 1 h at 20 ± 5°C. The mixture was left to settle again for 30 min. The lower layer was collected and a solution of AcOH (12.32 g, 4.3 eq.) in water (68.1 mL, 2.25 vol.) was added in 20 min. The temperature was adjusted to 20°C and the mixture was stirred for 30 min. The mixture was heated and distilled until obtaining a medium temperature of 100 ± 5°C. The medium was then cooled to 60 ± 5°C and AcOEt (75.7 mL, 2.5 vol.) was added. The medium was cooled to 20 ± 5°C, transferred to a separating funnel and left to settle for at least 30 min. The organic layer was collected, and JEN-5 was obtained as a dark brown-orange solution in AcOEt (99.2 g, 117 mL).

[0100] Determination of the 7a / 7p ratio of intermediate JEN-5:

[0101] The 7a / 7p ratio of the compound JEN-5 was determined by UPLC characterization of a representative batch using the following conditions:

[0102] Column: Zorbax Eclipse Plus C18, 100 x 2.1 mm, 1.8 pm (Agilent: 959759-902);

[0103] Mobile phase: mixture of H2O, CH3CN and MeOH with the following gradient: 0 min: H2O / CH3CN / MeOH 25:60: 15, 10 min: H2O / CH3CN / MeOH 25:60: 15, 30 min:

[0104] H2O / CH3CN / MeOH 5:90:5, 33 min: H2O / CH3CN / MeOH 5:90:5, 34 min:

[0105] H2O / CH3CN / MeOH 0: 100:0, 43 min: H2O / CH3CN / MeOH 0: 100:0, 44 min:

[0106] H2O / CH3CN / MeOH 25:60: 15, 60 min: H2O / CH3CN / MeOH 25:60: 15;

[0107] Detection: 225 nm; Volume of sample injected: 1.0 pL; Column temperature: 45°C; Sample temperature: 5°C; Flow rate: 0.5 mL / min.

[0108] Ratio JEN-5(7a) / JEN-5(7P) = 8.7:1.

[0109] NMR characterization of the purified intermediate JEN-5 in CDCh: 300 MHz): 5 (ppm) 0.78 (s, 3H, C19H3), 0.95-1.09 (m, 1H, CnH), 1.1-1.6 -1.6 (m, 1H, C8H), 1.1-1.6 (m, 2H, C31H2), 1.1-1.6 (m, 2H, C32H2), 1.1-1.6 .1-1.6 (m, 2H, C34H2), 1.1-1.6 (m, 2H, C35H2), 1.1-1.6 (m, 2H, C36H2), 1.1- 1.6 (m, 2H, C37H2), 1.1-1.6 (m, 2H, C38H2), 1.1-1.6 (m, 2H, C39H2), 1.1-1.6 (m, 2H, C40H2), 1.6-2.4 (m, 1H, C10H), 1.6-2.4 (m, 2H, C13H2), 1.6-2.4 (m, 2H, C14H2), 1.6-2.4 (m, 2H, C15H2), 1.6-2.4 (m, 2H, C16H2), 2.49 (t,3J = 7.4, 2H, C21H2), 2.58 (t,3J = 7.0, 2H, C23H2), 2.70-2.85 (dd,3J = 5.3,2J = 17.0, d,2J = 16.8, 2H, C7H2), 3.76 (t,3J = 8.4, 1H, C17H), 5.3- 55 (br s, 1H, O18H), 6.55 (d,4J = 2.6, 1H, C3H), 6.63 (dd,3J = 8.5,4J = 2.7, 1H, CJH), 7.13 (d,3J = 2.6, 1H, C6H).

[0110] 13C NMR (CDCI3, 75 MHz): 5 (ppm) 11.2 (C19), 20.4 (C15), 22.8 (C39), 25.7 (C40), 27.4 (C32), 28.3 (C33), 29.0 (C34), 29.0 (C37), 29.3 (C35), 29.3 (C36), 29.3 (C38), 29.6 (C25), 29.7 (C24), 29.8 (C20), 29.9 (C18), 30.1 (C14), 30.6 (C7), 31.1 (C31), 31.3 (C16), 32.0 (C23), 33.3 (C21), 34.7 (C13), 37.0 (C8), 38.1 (C9), 42.1 (CIO), 43.5 (C12), 46.6 (Cl l) 82.2 (C17), 113.0 (C3), 116.3 (Cl), 127.2 (C6), 131.9 (C5), 137.4 (C4), 153.7 (C2).

[0111] Synthesis of intermediate JEN-6 (Crude Fulvestrant)

[0112] Intermediate JEN-6 was synthesized according to the synthetic route presented in Scheme 3.

[0113] Scheme 3.

[0114] To a 1 L three-necked round-bottom flask, under magnetic stirring and a nitrogen atmosphere, was added a solution of JEN-5 in EtOAc (228 mL, with 60.127 g of active JEN- 5, 1 eq.). The medium was stirred at 22°C. AcOEt (41 mL, 0.7 v / w) and acetic acid (32.3 g, 5.28 eq.) were added and the resulting mixture was stirred at 22°C. A solution of H2O2 (19.5 g, 17.5 mL, 35% wt, 1.97 eq.) in water (18 mL) was added in 120 min at 17 mL / h and at 22°C. Water (12 mL) was then added and the resulting mixture was stirred for at least 240 min at 22°C before analysis of the reaction mixture. When the UPLC level of residual JEN- 5 is > 1.7 % is obtained, a solution of sodium sulfite (17.2 g, 1.34 eq.) in water (159 mL) for 30 min at 22°C. The resulting mixture was stirred for 15 min. AcOEt (106 mL) was then added at 22°C. A solution of NaOH (45.1 g, 29.87 mL, 50% wt, 5.54 eq.) in water (78 mL) was added during 30 min and the resulting mixture was stirred for 15 min at 22°C. The mixture was transferred to a separating funnel and left to settle for at least 30 min. The organic layer was collected and AcOEt (106 mL) and water (106 mL) were added. The mixture was left to settle for 30 min. The organic layer was collected and AcOEt (361 mL) was added. The resulting solution was concentrated until obtaining a residual volume of 162 mL at atmospheric pressure. The medium was then cooled to 67°C and a sample was collected for analysis.

[0115] The medium was cooled to 50°C and stirred for 20 min. A small amount of JEN-7 (123.5 mg, 0.002 eq.) was added as a crystallization initiator and crystallization was performed using the following steps: a. stirring the medium at 50°C for 180 min; b. cooling the medium to 20°C in 450 minutes at a rate of 4°C / h; c. stirring the medium at 20°C for 60 min; d. heating the medium to 45°C; e. stirring the medium at 45°C for 60 min; f. cooling the medium to 20°C in 375 minutes at a rate of 4°C / h; g. repeating the steps c to f; h. stirring the medium at 20°C for 180 min.

[0116] The resulting suspension was filtered, and the obtained cake was washed twice with AcOEt (2 x 61 mL, 1 vol.). The resulting cake was dried for 23 h at 60°C under a pressure of 150 mbar. Intermediate JEN-6 was obtained as crystals (25.3 g) in an overall yield of 41% with respect to the initial amount of dienone JEN-0-DE. HPLC characterization of JEN-6 intermediate for a representative batch:

[0117] Determination of the 7a / 7p ratio of intermediate JEN-6 (Crude Fulvestrant):

[0118] The 7a / 7p ratio of the compound JEN-6 was determined by HPLC characterization of a representative batch using the following conditions: Column: Zorbax Eclipse Plus C8, 4.6 * 150 mm, 3.5 pm (Agilent: 959963-906);

[0119] Mobile phase: mixture of H2O, CH3CN and MeOH with the following gradient: 0 min: H2O / CH3CN / MeOH 41 :30:29, 25 min: H2O / CH3CN / MeOH 41 :30:29, 55 min:

[0120] H2O / CH3CN / MeOH 10:49:41, 65 min: H2O / CH3CN / MeOH 10:49:41, 67 min:

[0121] H2O / CH3CN / MeOH 41 :30:29, 75 min: H2O / CH3CN / MeOH 41 :30:29; Detection: 225 nm; Volume of sample injected: 10.0 pL; Column temperature: 40°C; Sample temperature: 20°C; Flow rate: 2.0 mL / min.

[0122] Ratio JEN-6(7a) / JEN-6(7P) = 111.9: 1.

[0123] Purification of intermediate JEN-6 to obtain JEN-7 (Pure Fulvestrant)

[0124] Intermediate JEN-6 was purified by recrystallization according to the route presented in Scheme d. Scheme 4.

[0125] To a three-necked flask was added JEN-6 (25.0 g, 1 eq.) in AcOEt (225 mL, 9 vol.) under a nitrogen atmosphere. The medium was heated at 70°C and stirred for 60 min. The resulting solution was filtered on 0.22 pm PTFE and the three-necked flask and filter were rinsed with AcOEt (25 mL, 1 vol.). The medium was distilled at atmospheric pressure until obtaining a residual volume of 113 mL (4.5 vol.). The medium was cooled to 67°C and a sample was collected for analysis.

[0126] The medium was maintained a 67°C for 30 min under magnetic stirring and a nitrogen atmosphere, and then cooled to 55°C. A small amount of JEN-7 (50 mg, 0.002 eq.) was added as a crystallization initiator and crystallization was performed using the following steps: a. stirring the medium at 55°C for 180 min; b. cooling the medium to 20°C in 525 minutes at a rate of 4°C / h; c. stirring the medium at 20°C for 60 min; d. heating the medium to 45°C; e. stirring the medium at 45°C for 60 min; f. cooling the medium to 20°C in 375 minutes at a rate of 4°C / h; g. stirring the medium at 20°C for at least 180 min.

[0127] The resulting suspension was filtered, and the obtained cake was washed with AcOEt (25 mL, 1 vol.). The resulting cake was dried for 46 h at 60°C under a pressure of 150 mbar. Compound JEN-7 was obtained as crystals (21.2 g) in a yield of 85% with respect to the JEN-6 amount. This step is repeated once to reach the targeted specification for the JEN-7 pure. The compound JEN-7 is obtained with 30% overall yield with respect to the JEN-0- DE amount.

[0128] Determination of the 7a / 7p ratio of pure compound JEN-7 (Pure Fulvestrant):

[0129] The 7a / 7p ratio of the compound JEN-7 was determined by HPLC characterization of a representative batch using the following conditions:

[0130] Column: Zorbax Eclipse Plus C8, 4.6 * 150 mm, 3.5 pm (Agilent: 959963-906); Mobile phase: mixture of H2O, CH3CN and MeOH with the following gradient: 0 min: H2O / CH3CN / MeOH 41 :30:29, 25 min: H2O / CH3CN / MeOH 41 :30:29, 55 min:

[0131] H2O / CH3CN / MeOH 10:49:41, 65 min: H2O / CH3CN / MeOH 10:49:41, 67 min:

[0132] H2O / CH3CN / MeOH 41 :30:29, 75 min: H2O / CH3CN / MeOH 41 :30:29; Detection: 225 nm; Volume of sample injected: 10.0 pL; Column temperature: 40°C; Sample temperature: 20°C; Flow rate: 2.0 mL / min.

[0133] Ratio JEN-7(7a) / JEN-7(7P) >1950: 1.

[0134] NMR characterization of the JEN-7 pure API (Pure Fulvestrant):

[0135] ^ NMR CDCh, 300 MHz): 5 (ppm) 0.66 (3H), 0.90-1.24 (2H), 1.16-1.37 (12H), 1.16-1.79 (2H), 1.24 (1H), 1.24-1.48 (2H), 1.24-2.25 (2H), 1.37-1.89 (2H), 1.50 (1H), 1.60 (2H), 1.65

[0136] (1H), 1.91 (2H), 2.17 (1H), 2.38 (2H), 2.60-2.73 (2H), 2.66-2.71 (2H), 2.75-2.84 (2H), 3.53 (1H), 4.48 (1H), 6.42 (1H), 6.50 (1H), 7.04 (1H), 8.96 (1H).

[0137] 13C NMR (CDC13, 75 MHz): 5 (ppm) 11.3, 14.0, 22.0, 22.3, 25.0, 27.0, 27.5-29.3, 28.5, 29.8, 32.7, 34.1, 36.7, 37.8, 41.7, 42.9, 46.0, 49.2, 51.0, 80.1, 112.8, 115.7, 115.8, 118.7, 126.6, 129.6, 136.0, 154.9.

Claims

CLAIMS1. A process for the preparation of an intermediate compound of formula (I):comprising the following steps in the following order: a) providing a Grignard compound of formula (i):b) reacting said compound of formula (i) with a dienone compound of formula (ii):in the presence of CuCl; wherein step b) comprises a simultaneous and controlled addition of compounds of formula (i) and (ii) with a compound (i) / compound (ii) molar ratio comprised between 0.79 and 0.98.

2. Process according to claim 1, wherein the amount of CuCl used in step b) is comprised between 0.01 equivalents and 0.20 equivalents, with respect to the amount of compound of formula (ii).

3. The process according to claim 1 or 2, wherein the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b) is carried out over a period comprised between 3 h 30 min and 4 h 20 min, in particular between 3 h 36 min and 4 h 24 min.

4. The process according to any one of claims 1 to 3, wherein the compound of formula(i) is added at a rate comprised between 0.20 and 0.25 equiv. / h with respect to the total amount of compound of formula (ii) during the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b).

5. The process according to any one of claims 1 to 4, wherein the compound of formula(ii) is added at a rate comprised between 0.22 and 0.28 equiv. / h with respect to the total amount of compound of formula (ii) during the simultaneous and controlled addition of compounds of formula (i) and (ii) of step b).

6. The process according to any one of claims 1 to 5, wherein step b) further comprises the addition of an additional amount of compound of formula (i) after the simultaneous and controlled addition of compounds of formula (i) and (ii).

7. The process according to claim 6, wherein the additional of compound of formula (i) is comprised between 0.25 equivalents and 0.70 equivalents with respect to the total amount of compound of formula (ii).

8. The process according to any one of claims 1 to 7, wherein the solvent used in step b) is an ether solvent.

9. Process according to claim 8, wherein the solvent used in step b) is tetrahydrofuran.

10. Process according to any one of claims 1 to 9, wherein step b) is run at a temperature of 0°C to -40°C, in particular -10°C to -30°C, more particularly -17°C to -23°C.

11. Process according to any one of claims 1 to 10, wherein the compound of formula (I) has a 7a / 7p ratio of more than 4: 1, in particular more than 5: 1, more particularly more than 6:1, still more particularly more than 7: 1, still more particularly more than 8: 1, even more particularly more than 9:1.

12. Process for the preparation of Fulvestrant, comprising the following steps in the following order: c) preparing an intermediate compound of formula (I) according to the process according to any one of claims 1 to 11;d) aromatizing the compound obtained in step c); e) deprotecting the compound obtained in step d); f) sulfur oxidizing the compound obtained in step e); and g) purifying the compound obtained in step f) by recrystallization.

13. Use of the compound of formula (I):wherein the 7a / 7p ratio is more than 4: 1, in particular more than 5: 1, more particularly more than 6: 1, still more particularly more than 7:1, still more particularly more than 8: 1, even more particularly more than 9:1, as a synthetic intermediate for the preparation of Fulvestrant.

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