Process for preparing B-[(7α,17β)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]oestra-1,3,5(10)-trien-3-yl]-boronic acid and intermediates of said process

Abstract

The present invention relates to a process for preparing B-[(7α,17β)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]oestra-1,3,5(10)-trien-3-yl]-boronic acid, also called fulvestrant-3-boronic acid or ZB716, the structure of which is shown below: .

Description

Title of the invention: Process for the preparation of^-[(7a,17p)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]non yl]oestra-1,3,5(10)-trien-3-yl]-boronic acid and intermediates of said process

[0001] * * * * * * * * * * * * * * * * * * * * Technical field

[0002] The present invention relates to the field of processes for the synthesis of active ingredients for pharmaceutical use, and more particularly to a process for the industrial-scale preparation of B-[(7a,17[3)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]estra-1,3,5(10)-trien-3-yl]-boronic acid, also known as fulvestrant-3-boronic acid or ZB716. The compound is identified by the CAS number 1853279-29-4.

[0003] The invention further relates to an intermediate of said process. State of the prior art

[0004] ZB716 is useful for the treatment of metastatic breast cancer. The structure of the compound is shown below:

[0005] [Chem.l] HQ 26716

[0006] The compound is described and claimed in EP 3473630 B1 (compound 29, Claim 1) of Xavier University of Louisiana.

[0007] The article "Fulvestrant-3 boronic acid (ZB716): an orally bioavailable selective estrogen receptor downregulator (SERD)", J. Liu et al., J. Med. Chem. 2016, 59, 8134-8140, presents an experimental description of the preparation of the compound in question (page 8135, scheme 1); this synthesis starts from the compound KSM, having the formula indicated below:

[0008] [Chem. 2]

[0009]

[0010]

[0011]

[0012]

[0013]

[0014]

[0015] The KSM compound can be obtained as reported in the article "Ful-vestrant: from the laboratory to commercial-scale manufacture", EJ Brazier et al., Org. Process Res. Dev. 2010, 14, 3, 544-552, which describes the synthesis of another active ingredient, fulvestrant, which is currently used for the treatment of metastatic breast cancer. As can be seen from J. Med. Chem. 2016, 59, 8134-8140, compound ZB716 has clear clinical advantages over fulvestrant, with which it shares much of the structure. The following figure highlights the structural differences between fulvestrant and ZB716: [Chem. 3] The Applicant has been producing fulvestrant for years but using a different process than that described in Organic Process Research & Development 2010, 14, 544-552. This process does not consider the use of intermediate 1 from J. Med. Chem. 2016, 59, 8134-8140, having the following structural formula: [Chem. 4]

[0016]

[0017]

[0018]

[0019]

[0020]

[0021]

[0022]

[0023] The Applicant has therefore developed a new industrially applicable synthesis route for ZB716 which uses fulvestrant as the starting material. Summary of the invention This objective is achieved with the present invention, which in its first aspect relates to a method for synthesizing ZB716 and comprises the following steps: a) reaction of fulvestrant, the (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]-estra-1,3,5(10)-triene-3,17 -diol, intermediate N-4 of the process, with a triflating agent to obtain intermediate N-3, (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]-estra-l,3,5(10)-triene-17-ol 3-triflate: [Chem. 5] N-4 N-3 b) reaction of intermediate N-3 with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane to obtain the intermediate N-2, the (7a,17P)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-estra-1,3,5(10)-trien-17-ol: [Chem. 6] N-3 N-2 c) reaction of intermediate N-2 with KHF2 to obtain intermediate Nl, potassium (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]-estra-l,3,5(10)-trien-17-ol-3-trifluoroborate: [Chem. 7] N 2 N-1

[0024]

[0025] d) treatment of intermediate Nl to give compound ZB716, B -[(7a,17[3)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]oestra-l,3,5(10)-trien-3-yl]-boronic acid: [Chem. 8] NEITHER

[0026]

[0027]

[0028] In its second aspect, the invention relates to the compounds: (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5(10)-triene-17 -ol 3-triflate: [Chem.9]

[0029]

[0030]

[0031]

[0032]

[0033] N-3 and potassium (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]-estra-l,3,5(10)-trien-17-ol -3-trifluoroborate: [Chem. 10] OH [ H j (Your TT A . ck T- b '' rim,r Pi i Detailed description of the invention In its first aspect, the invention relates to a method for synthesizing ZB716 which comprises the steps described below. In the description of the reactions which constitute the process of the invention, the ratios between the reactants are indicated in w / w, that is to say ratios by weight, unless otherwise specified. Step a) consists of reacting fulvestrant, (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]-estra-1,3,5(10)-triene-3,17 -diol, intermediate N-4 of the process, with a triflating agent to obtain the N-3 intermediate, the (7a,17P)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]-estra-1,3,5(10)-triene-3,17 -diol 3-triflate:

[0034] [Chem. 11] OH OH

[0035] Fulvestrant, of a quality suitable for use in the process of the present invention, can be obtained either by following the process described in EP 2183267, or by using commercially available fulvestrant.

[0036] Triflatation is carried out exclusively at the phenolic hydroxyl without it being necessary to protect the other hydroxyl present in the molecule, using as triflating agent an aromatic bis(trifluoromethanesulfonimide) of general formula Ar-N(Tf)2, where Ar indicates the aromatic or heteroaromatic radical and the N(Tf) 2 group is the radical:

[0037] [Chem. 12] — SOXF,

[0038] The preferred triflating agent for the purposes of the present invention is the compound 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (also commonly referred to as N,N-bis(trifluoromethanesulfonyl)aniline) having the formula indicated below:

[0039] [Chem. 13]

[0040] The triflating agent is used at a ratio (w / w) of between 0.30 and 1.20 relative to the intermediate N-4, preferably it is used at a ratio (w / w) of between 0.6 and 0.9.

[0041] The reaction is carried out in dichloromethane (DCM), operating at a temperature between -15 and 40 °C, preferably between 0 and 30 °C for a period of between 4 and 12 hours, preferably between 6 and 8 hours, in the presence of an organic base chosen from triethylamine, diisopropylethylamine, pyridine, 4-(dimethylamino)pyridine, 2,6-lutidine. Preferably, triethylamine is used.

[0042] Step b) consists of reacting intermediate N-3 with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane to obtain the intermediate N-2, (7a,17P)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]-3-(4,4,5,5-tetramethyl-l,3, 2-dioxaborolan-2-yl)-estra-l,3,5(10)-trien-17-ol,

[0043] [Chem. 14]

[0044] The compound 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane is commercially available and is also commonly referred to as bis(pinacolato)diboron.

[0045] Bis(pinacolato)diboron is used at a ratio (w / w) of between 0.20 and 0.45, preferably between 0.25 and 0.40, relative to the intermediate N-3.

[0046] The reaction is carried out in acetonitrile, operating at a temperature of between 70 and 90°C, preferably between 35 and 75°C, for a period of between 1 and 6 hours, preferably between 2 and 5 hours, in the presence of an organic palladium (II) derivative such as palladium (II) acetate, a phosphine such as tricyclohexylphosphine and a base such as sodium or potassium acetate or sodium or potassium methoxide; the preferred bases are potassium acetate and potassium methoxide.

[0047] Step c) consists of reacting intermediate N-2 with KHF2 to obtain intermediate Nl, potassium (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]-estra-l,3,5(10)-trien-17-ol-3-trifluoroborate:

[0048] [Chem. 15] NS N-1

[0049] The compound potassium hydrogen difluoride, KHF2, is commercially available and is also commonly referred to as potassium bifluoride.

[0050] Its use is also known as it is presented in Chem. Rev. 2008, 108, pages 288-325 for the preparation of potassium organofluoroborates.

[0051] More particularly, for the conversion of pinacolatoborate to trifluoroborate, see Tetrahedron Letters 2005, vol. 46, pages 7899-7903, which illustrates the reaction on an optionally substituted phenyl, according to the following general scheme (the reaction takes place at room temperature):

[0052] [Chem. 16]

[0053] Potassium bifluoride KHF2 is used at a ratio (w / w) of between 0.45 and 0.75, preferably between 0.55 and 0.70, relative to the intermediate N-2.

[0054] The reaction is carried out in an alcohol such as ethanol, methanol, isopropanol, tert-butanol or in acetone, in THF or in a mixture of acetonitrile and water, operating at a temperature of between 10 and 40°C, preferably between 15 and 35°C, for a time of between 30 minutes and 4 hours, preferably between 45 minutes and 2 hours.

[0055] Finally, in step d) of the process, intermediate N1 is reacted to give compound ZB716, B-[(7a,17[3)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-trien-3-yl]-boronic acid:

[0056] [Chem. 17] NI W1Ê

[0057] As reagents, one can use alkali metal hydroxides, silicon compounds, carbonates (lithium, sodium or potassium carbonate), or bicarbonates (sodium and potassium).

[0058] When hydroxides are used, hydrated lithium hydroxide, potassium hydroxide and sodium hydroxide may be used.

[0059] Preferably, lithium hydroxide monohydrate is used.

[0060] When lithium hydroxide monohydrate is used, the reagent is employed at a ratio (w / w) of between 0.1 and 1.5, preferably between 0.15 and 1.0, relative to the intermediate Nl. The reaction is carried out using as solvent a mixture of water with a water-miscible solvent such as methanol, tetrahydrofuran (THF), acetonitrile or acetone.

[0062] Preferred reaction conditions are the use of aqueous acetonitrile, a temperature between 10 and 45°C, preferably between 20 and 30°C, and a reaction time between 8 hours and 36 hours, preferably between 16 and 30 hours.

[0063] When using silicon compounds, trimethylsilylchloride, triethylsilylchloride, dimethylethylsilylchloride or tert-butyldimethylsilylchloride may be used. Preferably, trimethylsilylchloride is used.

[0064] When trimethylsilylchloride is used, the reagent is employed at a ratio (w / w) of between 0.3 and 0.7, preferably between 0.4 and 0.6 relative to the intermediate N1

[0065] The reaction is carried out using as solvent a mixture of water with a water-miscible solvent such as methanol, tetrahydrofuran (THF), acetonitrile or acetone.

[0066] Preferred reaction conditions are the use of aqueous acetonitrile, a temperature between 10 and 45°C, preferably between 20 and 30°C, and a reaction time between 30 minutes and 3 hours, preferably between 45 minutes and 2 hours.

[0067] In its second aspect, the invention relates to the compounds:

[0068] (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-l,3,5(10)-triene-17 -ol-3-triflate:

[0069] [Chem. 18] [ P > F>c- / I * î * d ~ < H .UA f H-3

[0070] and

[0071] (7a,17P)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-l,3,5(10)-trien-17-ol-3-potassium trifluoroborate:

[0072] [Chem. 19]

[0073] The invention will be illustrated in more detail using the following examples. Materials, methods and experimental conditions

[0074] NMR:

[0075] JEOL 400 YH NMR Spectrometer (400 MHz); JEOL Delta v5.1.1 Software;

[0076] Spectra recorded in deuterated solvents such as chloroform-d, D 99.8%, containing 0.1% (v / v) tetramethylsilane (TMS) as an internal standard; and chloroform-d, "100%", D 99.96%, containing 0.03% (v / v) TMS, and DMSO-d6.

[0077] MS 1:

[0078] Instrument: DSQ-trace Thermofisher

[0079] Sample introduction - direct exposure probe (dep)

[0080] Chemical ionization (CI) methane

[0081] Methane pressure: 2.2 psi

[0082] Source temperature: 200°C

[0083] MS 2:

[0084] Instrument: Waters Acquity UPLC QDa Detector

[0085] Electrospray ionization (ESI) formic acid

[0086] Source temperature: 120°C

[0087] UPLC:

[0088] Chromatographic system: Waters Acquity UPLC; detector: Acquity UPLC PDA and X detector

[0089] Chromatographic conditions:

[0090] - Column: Acquity UPLC BEH Cl8 1.7 pm, 2.1 x 50 mm

[0091] - Flow: 0.5 ml / min

[0092] - Detector: UV 225 nm

[0093] - Injection volume: 1 pl

[0094] - Temperature: 35°C

[0095] - Mobile phase A: H2O + 0.01% formic acid (FA)

[0096] - Mobile phase B: Acetonitrile + 0.01% formic acid (FA) Time (min) Mobile phase A (v / v) Mobile phase B (v / v) 0.00 70 30 0.00-1.00 70 30 1.00-5.00 10 90 5.00-6.00 10 90 6.00-9.50 0 100 9.50-9.60 70 30 9.60-10.50 70 30

[0097] CCM

[0098] MERCK: TLC silica gel 60 F254Aluminium sheets 20 x 20 cm, ref. 1.0554.0001.

[0099] CCM Detectors

[0100] Cerium phosphomolybdate: 25 g of phosphomolybdic acid and 10 g of cerium (IV) sulfate are dissolved in 600 ml of H2O. 60 ml of 98% H2SO4 are added and the volume is made up to 1 liter with H2O. The plate is impregnated with the solution and then heated until the products are detected.

[0101] Remarks

[0102] The water used in the experimental descriptions is pure water, unless otherwise indicated.

[0103] The organic solvents used in the experimental descriptions are of "technical" quality, unless otherwise indicated.

[0104] The reagents and catalysts used in the experimental descriptions are of commercial quality, unless otherwise indicated. Example 1

[0105] [Chem.20]

[0106] 46.8 g of fulvestrant, 468 ml of dichloromethane and 32 ml of triethylamine (TEA) are charged into a flask.

[0107] Cool to 5°C and pour in drop by drop a solution of N,N-bis(trifluoromethanesulfonyl)aniline (41.3 g) dissolved in 164 ml of dichloromethane over the course of about 15 minutes. The mixture is brought to 25°C and stirred for 8 hours.

[0108] Once the reaction is complete (UPLC control), the solvent is removed by distillation under reduced pressure at 45°C until 99 g of fulvestrant triflate (oil) is obtained, which is reacted as such in the following reaction.

[0109] The fulvestrant used as the starting reagent of the method, subjected to analysis by 1H and Ms NMR, presents the following analytical data:

[0110] 'H NMR (400 MHz, DMSO-d6): 8.99 (s, 1H); 7.04 (d, 1H, J = 8.4 Hz); 6.49 (d, 1H, J = 8.0 Hz); 6.41 (s, 1H); 4.50 (s, 1H); 3.54-3.52 (m, 1H); 2.76-0.71 (m, 38H); 0.66 (s, 3H).

[0111] The *H NMR signals at 8.99 ppm and 4.50 ppm (attributable to mobile protons in positions 3 and 17) disappear after deuteration of the sample with D2O.

[0112] Mass (ESI): m / z = 629 [M++1+22]; 607 [M++l]; 589 [M++l-H20].

[0113] The obtained fulvestrant triflate, subjected to analysis by 1H and Ms NMR, shows the following analytical data:

[0114] 'H NMR (400 MHz, DMSO-d6): disappearance of the signal at 8.99 ppm (s, 1H) of fulvestrant but not of the signal at 4.50 ppm (s, 1H) (of fulvestrant).

[0115] Mass (ESP): m / z = 761 [M++1+22]; 739 [M++l]; 619 [M++l - HCF2CF3], Example 2

[0116] [Chem.21]

[0117] The fulvestrant triflate intermediate obtained according to the procedure described in the previous example and 1140 ml of acetonitrile are charged into a flask. Stirring is maintained at 25°C for 10 minutes. 29.3 g of bis(pinacolato)diboron, 20.7 g of potassium acetate, 4.6 g of tricyclohexylphosphine and 2.3 g of palladium acetate are added to the solution. Heating is carried out at 50°C for 4 hours.

[0118] Once the reaction is complete (UPLC control), the solvent is removed by distillation under reduced pressure at 45°C until 99 g of crude fulvestrant 3-pinacolatoborate is obtained.

[0119] The product is purified by chromatography on a silica gel column, eluting with methylene chloride and then with a mixture of methylene chloride / acetonitrile 70:30. The solvent is concentrated under reduced pressure at 45°C to give 40 g of fulvestrant 3-pinacololatoborate (oil).

[0120] The intermediate 3-pinacolatoborate of fulvestrant is analyzed by *H NMR and mass spectrometry.

[0121] 'H NMR (400 MHz, DMSO-d6): 7.40 (d, 1H, J = 7.2 Hz); 7.36 (s, 1H); 7.28 (d, 1H, J = 7.2 Hz); 4.53 (d, 1H, J = 4.4 Hz); 3.56-3.55 (m, 1H); 2.81-0.71 (m, 50H); 0.67 (s, 3H).

[0122] The *H NMR signal at 4.4 ppm disappears after deuteration of the sample with D2 O.

[0123] Mass (CI): m / z = 745 [M++l+28]; 717 [M++l]; 699 [M++l-H20]; 591 [M++l -B(OC(CH3)2)2]; 573 [M++1 -B(OC(CH3)2)2-H2O], Example 3

[0124] [Chem.22]

[0125] Fulvestrant 3-pinacolatoborate (4 g), obtained according to the procedure described in the previous example, and 16 ml of methanol are charged into a flask.

[0126] A solution of potassium bifluoride (2.5 g) dissolved in water (7 ml) is added to the mixture and the mixture is stirred at 25°C for 1 hour (the reaction is monitored by UPLC analysis).

[0127] Once the reaction is complete, the solvent is concentrated under reduced pressure at 45 °C and the residue is taken up with 30 ml of acetone. The inorganic salts present are filtered and the filtration liquid is concentrated under reduced pressure at 45 °C to give 4.5 g of crude potassium fulvestrant 3-trifluoroborate (yellow solid). The solid is taken up with 90 ml of ethyl ether and the suspension is kept stirring at 25 °C for 1 hour. The solid is filtered off, washing with 45 ml of ethyl ether. The solid is resuspended with ethyl ether (90 ml), the suspension is kept stirring at 25 °C for 1 hour and the solid is filtered off, washing with 45 ml of ethyl ether. The solid is dried under reduced pressure at 45 °C to give 3.5 g of white solid. The intermediate fulvestrant potassium 3-trifluroborate is analyzed by 1 H NMR and mass spectrometry.

[0128] 'H NMR (400 MHz, DMSO-d6): 7.03 (d, 1H, J = 8.0 Hz); 6.98 (d, 1H, J = 9.1 Hz); 6.97 (s, 1H); 4.51 (d, 1H, J = 4.8 Hz); 3.55-3.51 (m, 1H); 2.81-0.71 (m, 38H); 0.67 (s, 3H).

[0129] The 'H NMR signal at 4.51 ppm disappears after deuteration of the sample with D2O.

[0130] 19F NMR (400 MHz, DMSO-d6): -84.5 (s, CF3); -117.1 (s, CF2); -138.52 (s, BF3).

[0131] Mass (ESI): m / z = 657. Example 4

[0132] [Chem.23] "a gsm

[0133] 2.5 g of potassium fulvestrant 3-trifluoroborate and 0.53 g of lithium hydroxide monohydrate are charged into a flask. 36 ml of acetonitrile and 18 ml of water are added.

[0134] The suspension is kept stirring at 25°C for 24 hours (the reaction is monitored by *H NMR analysis).

[0135] Once the reaction is complete, a saturated solution of ammonium chloride (30 ml) and 1 M hydrochloric acid (6 ml) is added. Ethyl acetate (30 ml) is added, the phases are separated and the aqueous phase is re-extracted with ethyl acetate.

[0136] The organic phase is washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure at 45°C to give 2.2 g of crude ZB716 (yellow solid).

[0137] The crude product is dissolved with the minimum amount of methanol and crystallized with acetonitrile.

[0138] The solid is dried under reduced pressure at 45°C to give 1.1 g of the desired compound, ZB716, in the form of a white solid whose analytical data for *H NMR, 13C NMR and Ms coincide with those reported in the literature.

[0139] 'H NMR (400 MHz, DMSO-d6): 7.68 (s, 2H); 7.50 (d, 1H, J = 7.6 Hz); 7.43 (s, 1H); 7.23 (d, 1H, J = 7.6 Hz); 4.36 (d, 1H, J = 4.4 Hz); 3.56-3.55 (m, 1H); 2.84-2.60 (m, 6H); 2.45-2.25 (m, 4H); 1.94-1.10 (m, 26H); 0.88 (m, 2H); 0.67 (s, 3H).

[0140] The 'H NMR signals at 7.68 ppm and 4.36 ppm disappear after deuteration of the sample with D2O.

[0141] 13C NMR (400 MHz, DMSO-d6): 141.8; 136.4; 134.2; 131.9; 125.3; 80.6; 51.7; 49.9; 46.7; 43.5; 42.1; 39.1; 37.4; 34.7; 33.3; 30.4; 29.8; 29.5; 29.3; 29.1; 29.0; 28.6; 28.0; 27.3; 25.6; 22.8; 22.5; 14.6; 11.8.

[0142] Mass (ESP): m / z = 657 [M++1+22]; 635 [M++l]; 617 [M++l-H20]. Example 5

[0143] [Chem.24] xjX ...... SH > [ HT \ J Jjp ...................| U h <„> V.. : » ^4 asm

[0144] In a flask, 0.5 g of fulvestrant 3-trifluoroborate potassium, 7.5 ml of acetonitrile and water (0.05 ml) are charged.

[0145] Trimethylchlorosilane (0.3 ml) is added and the mixture is stirred at 25°C for 1 hour (the reaction is monitored by *H NMR analysis).

[0146] Once the reaction is complete, a saturated solution of sodium bicarbonate (1.1 ml) is added and the solution is anhydrized with sodium sulfate. It is filtered and concentrated under reduced pressure at 45 °C to give 0.4 g of crude ZB716 (green solid) whose analytical data *H NMR, 13C NMR and Ms coincide with those indicated in the previous example.

Claims

1. Claims Process for the synthesis of B-acid [(7 a, 17 [3)-17-hydroxy-7 - [9- [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl ] oestra-l,3,5(10)-trien-3-yl]-boronic acid (ZB716), which comprises the following steps: a) reaction of fulvestrant, the (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-œstra-1,3,5(10)-triene-3,17-diol, intermediate N-4 of the process, with a triflating agent to obtain intermediate N-3, (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-œstra-1,3,5(10)-trien-17-ol 3-triflate: N-4 N-3 where, in step a), an aromatic bis(trifluoromethanesulfonimide) of general formula Ar-N(Tf)2 is used as triflating agent, where Ar indicates the aromatic or heteroaromatic radical and the N(Tf)2 group is the radical: SO, THIS, b) reaction of intermediate N-3 with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane to obtain the N-2 intermediate, the (7a,17[3)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-3-(4,4,5,5-te tramethyl-1,3,2-dioxaborolan-2-yl)-estra-l,3,5(10)-trien-17-ol: c) reaction of intermediate N-2 with KHF2 to obtain intermediate Nl, the (7 a, 17 [3)-7- [9- [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl] -estra-1,3,5( 10)-trien-17-ol-3-trifluoroborate of potassium: <_!H hM ) î* 1 > C._1. xJ? ..................................-U? J * •'-ÿÿ v '■ 'y>>i<:sî?fXC^^ r-'S':> ^:CMs>;Sa^.W •• ) H-2 N-1 d) treatment of intermediate Nl to give compound ZB716, B - [(7 a, 17 P)-17-hydroxy-7 - [9- [(4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl ] œ stra-1,3,5(10) -trien-3 - y 1] -boronic acid: X ,-U aïX -. XX X ni ïism

2. A synthesis process according to claim 1, wherein said triflating agent is 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide.

3. A synthesis process according to any one of the preceding claims, wherein step b) is carried out in the presence of palladium (II) acetate, tricyclohexylphosphine and a base chosen from potassium acetate and potassium methoxide.

4. A synthesis process according to any one of the preceding claims, wherein, for the transformation of intermediate N1 into compound ZB716 in step d), a compound selected from an alkali metal hydroxide, a silicon compound, an alkali metal carbonate, sodium bicarbonate and potassium bicarbonate is used.

5. A synthesis method according to claim 4, wherein said alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide, said silicon compound is selected from trimethylsilylchloride, triethylsilylchloride, dimethylethylsilylchloride and tert-butyldimethylsilylchloride, and said alkali metal carbonate is selected from lithium carbonate, sodium carbonate and potassium carbonate.

6.

7.

8. The synthesis process of claim 4, wherein lithium hydroxide monohydrate is used. Synthesis process according to claim 4, in which trimethylsilylchloride is used. Compound (7 a, 17 [3)-7- [9- [(4,4,5,5,5-pentafluoropentyl) sulfmyl] nonyl] -estra-1,3,5( 10)-triene-3,17-diol 3-triflate: No.3