PROCESS FOR THE PREPARATION OF B-[(7ALPHA,17BETA)-17-HYDROXY-7-[9-[(4,4,5,5,5-PENTAFLUOROPE NTYL)

SULFINYL]NONY] ACID AND INTERMEDIATES OF SAID PROCESS FIELD OF THE INVENTION

The present invention relates to the sector of processes for the synthesis of active ingredients for pharmaceutical use, and in particular to a process for preparing 5~[(7a,17b)~17- hydroxy-7-[9-[(4,4,5,5,5-pentailuoropentyl)sulfmyl]nonyl]est ra-l,3,5(10)-trien-3-yl]-boronic acid, also known as Fulvestrant-3-boronic acid or ZB716, on an industrial scale. The compound is identified by the CAS Number 1853279-29-4.

The invention further relates to an intermediate of said process.

STATE OF THE ART

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

The compound is described and claimed in patent EP 3473630 B1 (Compound 29, claim 1) by Xavier University of Louisiana.

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, reports 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 shown below: The compound KSM can in turn be obtained by following what is reported in the article “Fulvestrant: from the laboratory to commercial-scale manufacture”, E. J. Brazier et a/., Org. Process Res. Dev. 2010, 14, 3, 544-552, which describes the synthesis of another active ingredient, Fulvestrant, also currently used for the treatment of metastatic breast cancer. As can be learned by reading J. Med. Chem. 2016, 59, 8134-8140, compound ZB716 shows apparent clinical advantages over Fulvestrant that shares with it a large portion of the structure.

In the following figure the structural differences between Fulvestrant and ZB716 are highlighted:

The Applicant has been producing Fulvestrant for years but with a different process from that described in Organic Process Research & Development 2010, 14, 544-552.

This process does not involve the use of intermediate 1 by J. Med. Chem. 2016, 59, 8134- 8140, having the following structural formula:

The Applicant has therefore developed a new, industrially applicable, synthetic route for ZB716 which uses as starting material an intermediate of the proprietary synthetic process for Fulvestrant.

SUMMARY OF THE INVENTION

This object is achieved with the present invention, which in a first aspect relates to a process for the synthesis of ZB716 and comprises the following steps: a) reaction of intermediate N-4, (7a, 17b)-7-[9-[(4, 4,5,5, 5-pentafluoropentyl)thio]nonyl]- estra-l,3,5(10)-triene-3,17-diol, with a triflating agent to obtain intermediate N-3, (7a,17β)-7~[9~[(4,4,5,5,5-pentafluoropentyl)thio]nonyl]~est ra-l,3,5(10)-triene-3,17- diol-3-triflate: 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 intermediate N-2, (7a,17b)-7-[9-[(4,4,5,5,5- pentafluoropentyl)thio]nonyl]-3-(4,4,5,5-tetramethyl-l,3,2-d ioxaborolan-2-yl)-estra- 1 ,3,5(10)-tri en- 17-ol : c) oxidation of intermediate N-2 with a peroxycarboxylic acid to obtain intermediate N-

1, (7a,17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl] -3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-estra-l,3,5(10)-trien-17-ol: d) treatment of intermediate N-1 to obtain compound ZB716, 7>-[(7a, 17b)-17-hydroxy- 7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfmyl]nonyl]estra-l,3,5 (10)-trien-3-yl]-boronic acid:

In its second aspect, the invention relates to the compound (7α,17β)-7-[9-[(4,4,5,5,5- pentafluoropentyl)thio]nonyl]-estra-l,3,5(l0)-trien-3, 17-diol~3 -triflate, intermediate N-3 of the process described above, having the formula below:

DETAILED DESCRIPTION OF THE INVENTION

In its first aspect, the invention relates to a process for the synthesis of ZB716 comprising the steps described below.

In the description of the reactions forming the process of the invention, the ratios between reagents are indicated as w/w, i.e. ratios by weight, unless otherwise specified.

Step a) consists in the reaction of intermediate N-4, (7a,17b)-7-[9-[(4,4,5,5,5- pentafluoropentyl)thio]nonl]-estra-l,3,5(10)-triene-3,17-dio l, with a triflating agent to obtain intermediate N-3, (7α, 17β)-7-[9~[(4, 4,5,5, 5-pentafluoropentyi)thio]nonyl]-estra-1, 3, 5(10)- triene-3,17-diol-3 triflate:

The intermediate N-4 is part of the process for the synthesis of Fulvestrant that the Applicant has been using for years to produce this active ingredient. The production of this intermediate is the object of patent EP 2183267 B1 in the name of the Applicant; the process described in EP 2183267 B1 makes intermediate N-4 available with a quality suitable for use also in the process to obtain the new active ingredient ZB716.

Inflation exclusively occurs at the phenolic hydroxy group without having to protect the other hydroxy group present in the molecule, using an aromatic bis(trifluoromethanesulfonimide) of general formula Ar-N(Tf)2 as triflating agent, wherein Ar indicates the aromatic or heterocyclic radical and the N(Tf)2 group is the radical:

For the purposes of the present invention, the preferred triflating agent is the compound 1,1,1 -trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulf onamide (also commonly referred to as N,N-bis (trifluoromethanesulfonyl)aniline) having the formula shown below:

The triflating agent is used in a (w/w) ratio comprised between 0.30 and 1.20 with respect to intermediate N-4, preferably it is used in a (w/w) ratio between 0.6 and 0.9.

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

Step b) consists in the reaction of intermediate N-3 obtained in the previous step with 4,4,4',4',5,5,5',5'-octamethyl-2,-bi-1,3-dioxaborolane to obtain intermediate N-2,

(7 a, 17 )-7-[9~[(4,4,5,5,.5-peniai]uoropentyl)thio]nony]]-3~(4,4,5,5 -tetramethyl~l,3,2- dioxaborolan-2-yl)-estra-l,3,5(10)-trien-17-o1: The compound 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-l,3,2-dioxa borolane is widely commercially available and is also referred to by the common name bis(pinacolato)diboron.

Bis(pinacolato)diboron is used in a (w/w) ratio comprised between 0.11 and 0.45, preferably between 0.25 and 0.40, with respect to intermediate N-3.

The reaction is carried out in acetonitrile operating at a temperature comprised between 70 and 90 °C, preferably between 75 and 85 °C, for a time comprised between 1 and 6 hours, preferably between 2 and 4 hours, in the presence of an organic derivative of palladium(II) such as palladium(II) acetate, a phosphine such as tricyclohexylphosphine, and a base such as sodium or potassium acetate or sodium or potassium methylate; the preferred bases are potassium acetate and potassium methylate.

Step c) consists in the oxidation of the sulfur atom of intermediate N-2 obtained in the previous step with a peroxycarboxylic acid, to obtain intermediate N-l, (7a,17b)-7-[9- [(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-3-(4,4,5,5-tet ramethyl-l,3,2-dioxaborolan-2-yl)- estra- 1 ,3 , 5 (10)-trien- 17-o1 :

Peroxy carboxylic acids are also commonly referred to as peracids. Examples of oxidants useful for the purposes of the invention are peracetic acid, perbenzoic acid and meta- chloroperbenzoic acid; all these compounds are commonly commercially available. The preferred oxidizing agent is 70-80% meta-chloroperbenzoic acid (m-CPBA), preferably used in the form of a solution in water; in this product the compound is generally present in the form of peracid at 70-80%, while the remaining 20-30% is generally formed by the corresponding carboxylic acid (meta-chlorobenzoic acid).

The oxidizing agent is used in a (w/w) ratio between 0.1 and 0.8, preferably between 0.15 and 0.6, and even more preferably between 0.15 and 0.20 with respect to intermediate N-2.

The reaction is carried out in solvents such as dichloromethane (DCM), ethyl acetate or isopropyl acetate, operating at a temperature comprised between -15 and 15 °C for a time comprised between 2 and 8 hours. The preferred conditions are use of DCM as a solvent, operating between -5 and 5 °C for a time comprised between 2.5 and 5 hours.

Finally, in the last step of the process, d), the intermediate N-l is converted into the desired compound, ZB716:

Lithium hydroxide hydrate, potassium hydroxide and sodium hydroxide, or sodium or potassium periodate with ammonium acetate can be used as reagents.

When using a periodate, the reagent is used in a (w/w) ratio comprised between 0.3 and 2.4, preferably between 1.2 and 1.4, with respect to intermediate N-l; the use of sodium periodate is preferred over that of potassium. The required amount of reagent is precisely defined by the reaction control.

Operating with a periodate, the reaction is carried out using as solvent a mixture of water with a water miscible solvent, such as methanol, tetrahydrofuran (THF) or acetone.

Preferred reaction conditions are the use of aqueous acetone in the presence of ammonium acetate, a temperature comprised between 10 and 45 °C, preferably between 20 and 30 °C, and a reaction time comprised between 8 hours and 36 hours, preferably between 16 and 30 hours.

When using hydroxides, it is possible to operate using methanol or tetrahydrofuran (THF) as solvents, optionally in the presence of water.

In its second aspect, the invention relates to compound (7a,17b)-7-[9-[(4,4,5,5,5- pentafluoropentyl)thio]nonyl]-estra- 1 , 3 , 5( 10)-trien-3 , 17-diol-3 triflate, intermediate N-3 of the process described above:

The invention will be further illustrated by the following examples. INSTRUMENTS, METHODS AND EXPERIMENTAL CONDITIONS NMR:

NMR spectrometer JEOL 400 YH (400 MHz); Software JEOL Delta v5.1.1 ;

Spectra recorded in deuterated solvents such as: Chloroform-d, D 99.8%, containing 0.1% (v/v) tetramethylsilane (TMS) as internal standard; and Chloroform-d, “100%”, D 99.96%, containing 0.03% (v/v) TMS, and DMSO-d _6.

MS 1:

Instrument: DSQ-trace Thermofisher

Sample introduction - direct exposure probe (dep)

Chemical ionization (Cl) with methane Methane pressure: 2.2 psi Source Temperature: 200 °C MS 2:

Instrument: Waters Acquity UPLC QDa Detector Electrospray ionization (ESI) with formic acid Source Temperature: 120 °C

UPLC:

Chromatographic System: Waters Acquity UPLC; Detector: Acquity UPLC PDA and l Detector

Chromatographic Conditions:

- Column: Acquity UPLC BEH C18 1.7 pm, 2.1 x 50 mm

- Flow rate: 0.5 mL/min

- Detector: UV 225 nm

- Injection Volume: 1 pL

- Temperature: 35 °C

- Mobile phase A: H2O + 0.01% trifluoroacetic acid (TFA)

- Mobile phase B: Acetonitrile + 0.01% TFA

TLC

MERCK: TLC silica gel 60 F254 Aluminium sheets 20 x 20 cm, cod. 1.0554.0001.

TLC Stains Cerium phosphomolybdate: 25 g of phosphomolybdic acid and 10 g cerium (IV) sulfate are dissolved in 600 mL of H ₂ O. 60 mL of 98% H ₂ SO ₄ are added and brought to 1 L with H ₂ O. The plate is impregnated with the solution and then heated until the products are detected.

NOTES

The water used in the experimental descriptions is to be intended as pure water, unless otherwise indicated.

The organic solvents used in the experimental descriptions are to be intended of “technical” grade, unless otherwise indicated.

The reagents and catalysts used in the experimental descriptions are to be intended of commercial quality, unless otherwise indicated. EXAMPLE 1

This example refers to step a) of the process of the invention, from intermediate N-4 to intermediate N-3 :

N-4 N-3 A flask is charged with 24 g of intermediate N-4, 240 mL of dichloromethane and 17 mL of triethylamine (TEA). It is cooled to 5 °C and a solution of N,N- bis(trifluoromethanesulfonyl)aniline (15.9 g) dissolved in 60 mL of dichloromethane is added dropwise.

The mixture is brought to 25 °C and kept under stirring for 6 hours (TLC monitoring, reaction complete).

The solvent is removed by distilling under reduced pressure at 45 °C until an oil (46.6 g) is obtained, which is reacted as is in the subsequent reaction.

TLC monitoring: silica gel on alumina; starting substrate (intermediate N-4) dissolved in dichloromethane; 100 μL of reaction mixture diluted with 1 mL of water and 1 mL of ethyl acetate; eluent: heptane/EtOAc, 8/2; stain: cerium phosphomolybdate.

A sample of the obtained intermediate N-3, purified exclusively for analytical purposes, is analysed by ¹ H-NMR and mass spectroscopy.

1H-NMR (400MHz, DMSO-d6): 7.41 (d, 1H, J = 8.4 Hz); 7.11 (d, 1H, J = 8.8 Hz); 7.08 (s, 1H); 4.50 (d, 1H, J = 4.8 Hz); 3.52-3.47 (m, 1H); 2.80-0.79 (m, 38H); 0.62 (s, 3H).

The ¹ H-NMR signal at 4.50 ppm disappears after deuteration of the sample with D2O.

Mass (Cl): m/z = 751 [M ⁺ +1+28]; 705 [M ⁺ +1-H ₂ 0]

The compound N-4 (yellow oil) shows the following NMR signals:

¹ H-NMR (400MHz, DMSO-d6): 8.99 (s, 1H); 7.03 (d, 1H, J = 8.8 Hz); 6.49 (d, 1H, J = 8.4 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).

The ¹ H-NMR signals at 8.99 ppm and 4.50 ppm disappear after deuteration of the sample with D2O.

EXAMPLE 2

This example refers to step b) of the process of the invention, from intermediate N-3 to intermediate N-2:

A flask is charged with intermediate N-3, obtained according to the procedure described in the previous example, and 773 mL of acetonitrile. The mixture is kept under stirring at 25 °C for 10 minutes. 15.5 g of bis(pinacolato)diboron, 10.9 g of potassium acetate, 1.22 g of palladium acetate and 2.44 g of tricyclohexylphosphine are added to the solution. It is heated to 80 °C for 2 hours.

The reaction is monitored by ¹ H-NMR analysis.

Once the reaction is complete, it is cooled to 25 °C, carbon is added, and the mixture is filtered.

It is concentrated under reduced pressure at 45 °C until an oil is obtained, which is suspended in 400 mL of isopropyl acetate and stirred with silica gel.

It is filtered, washing the solid on the filter with isopropyl acetate, then it is concentrated under reduced pressure at 45 °C obtaining 54.6 g of intermediate N-2 (oil), which is reacted as such in the subsequent reaction.

A sample of the obtained intermediate N-2, purified exclusively for analytical purposes, is analysed by ¹ H-NMR and mass spectroscopy.

The ¹ H-NMR spectrum of intermediate N-2 in DMSO-d6 has a multiplet of signals between 1.13 and 1.22 ppm, characteristic of the boron pinacolate methyl groups.

Mass (Cl): m/z = 729 [M ⁺ +1+28]; 683 [M ⁺ +1-H ₂ 0]; 601 [M ⁺ +l -(C(CH ) ₂ ) _{2 -} H ₂ 0]; 583 [M ⁺ +l -(C(CH ₃ ) ₂ ) _{2 -} 2H ₂ 0].

EXAMPLE 3

This example refers to implementation of step c) of the process of the invention, from intermediate N-2 to intermediate N-l :

A flask is charged with intermediate N-2 (45.1 g), obtained according to the procedure described in the previous example, and 697 mL of dichloromethane.

The mixture is cooled to 0 °C and 77% meta-chloroperbenzoic acid (9 g) is added.

The mixture is kept under stirring at 0 °C for 2.5 hours (the reaction is monitored by UPLC analysis). Once the reaction is complete, 300 mL of dichloromethane are added while keeping at 0 °C.

A 10% potassium carbonate solution (250 mL) is slowly added dropwise to the reaction mixture.

The mixture is kept under stirring at 25 °C for 30 minutes.

The layers are separated, the organic layer is washed with water and concentrated under reduced pressure at 45 °C until an oil is obtained.

The product is purified by chromatographic column on silica gel, eluting with a 97:3 methylene chloride/methanol mixture.

The solvent is concentrated under reduced pressure at 45 °C obtaining 16 g of intermediate N-1 (off-white solid).

Intermediate N-1 is analysed by ¹ H-NMR and mass spectroscopy.

¹ H-NMR (400MHz, DMSO-de): 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).

The ¹ H-NMR signal at 4.4 ppm disappears after deuteration of the sample with D2O.

Mass (Cl): m/z = 745 [M ⁺ +1+28]; 717 [M ⁺ +l]; 699 [M ⁺ +1-H ₂ 0]; 591 [M ⁺ +l - B(OC(CH ₃ ) ₂ ) ₂ ]; 573 [M ⁺ +l -B(OC(CH ₃ ) ₂ ) ₂ -H ₂ 0]

EXAMPLE 4

This example refers to the implementation of step d) of the process of the invention, from intermediate N-1 to compound ZB716:

A flask is charged with 5 g of intermediate N-1, 55 mL of acetone and 27.5 mL of water. The suspension is kept under stirring at 25 °C for 10 minutes.

5.9 g of sodium periodate and 2.15 g of ammonium acetate are added.

The mixture is kept under stirring at 25 °C for 24 hours (the reaction is monitored by UPLC analysis).

Once the reaction is complete, 75 mL of isopropyl acetate and 65 mL of water are added. The layers are separated, and the aqueous layer is re-extracted with isopropyl acetate.

The organic layer is washed with a saturated sodium chloride aqueous solution and concentrated under reduced pressure at 45 °C until a solid is obtained.

The product is purified by chromatographic column on silica gel, eluting with a 95:5 methylene chloride/methanol mixture.

The solvent is concentrated under reduced pressure at 45 °C obtaining 2.6 g of the desired compound, ZB716, as a white solid whose ¹ H-NMR, ¹³ C-NMR and Ms analytical data coincide with those reported in the literature.

¹ H-NMR (400MHz, DMSO-de): 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).

The 1-H-NMR stlsR 7.68 ppm and 4.36 ppm disappear after deuteration of the sample with D2O.

¹³ C-NMR (400MHZ, DMSO-de): 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.

Mass (ESI): m/z = 657 [M ⁺ +1+22]; 635 [M ⁺ +l]; 617 [M ⁺ +1-H ₂ 0]

EXAMPLE 5

This example refers to the obtaining of the desired product, ZB716, directly from intermediate N-2:

A flask is charged with 1 g of intermediate N-2 (obtained according to the procedure described in Example 2), 11 mL of acetone and 5.5 mL of water. The suspension is kept under stirring at 25 °C for 10 minutes.

2.44 g of sodium periodate and 0.88 g of ammonium acetate are added.

The mixture is kept under stirring at 25 °C for 24 hours.

The reaction is monitored by UPLC analysis. 15 mL of isopropyl acetate and 13 mL of water are added.

The layers are separated, and the aqueous layer is re-extracted with isopropyl acetate.

The organic layer is washed with 8 mL of saturated sodium chloride solution and concentrated under reduced pressure at 45 °C until a brown oil is obtained. After chromatographic purification (95:5 methylene chloride/methanol) on silica gel, 398 mg of ZB716 (white solid) are obtained.

EXAMPLE 6

This example refers to an alternative method for obtaining the desired product ZB716 from intermediate N-l :

A flask is charged with 0.2 g of intermediate N-l and 0.7 mL of methanol. 0.7 mL of tetrahydrofuran are added and the mixture is cooled to 0 °C.

A solution of potassium hydroxide (0.1 g) in methanol (1.3 mL) is added, and the mixture is kept under stirring at 25 °C for 16 hours. The reaction is monitored by UPLC analysis.

Water (1.2 mL) is added, and the solvent is concentrated under reduced pressure at 45 °C.

The residue is taken up with isopropyl acetate (2 mL) and the layers are separated.

The organic layer is washed with water and concentrated under reduced pressure at 45 °C until a brown oil is obtained. After chromatographic purification (95:5 methylene chloride/methanol) on silica gel, 44 mg of ZB716 (white solid) are obtained.

EXAMPLE 7

This example refers to an alternative method for obtaining the desired product ZB716 from intermediate N-l : A flask is charged with 0.2 g of intermediate N-l, 5 mL of tetrahydrofuran and 5 mL of water.

Lithium hydroxide (0.14 g) is added, and the mixture is kept under stirring at 25 °C for 16 hours.

The reaction is monitored by UPLC analysis.

The solvent is concentrated under reduced pressure at 45 °C.

The residue is taken up with isopropyl acetate (5 mL) and washed with water (5 mL). The organic phase is concentrated under reduced pressure at 45 °C until a brown solid is obtained.

After chromatographic purification (95:5 methylene chloride/methanol) on silica gel, 54 mg of ZB716 (white solid) are obtained.

EXAMPLE 8

This example refers to the obtaining of the compound B-[(7a,17β)~17-hydroxy-7-[9- [(4,4,5,5,5-pentafluoropentyl)thio]nonyl]estra-l ,3,5(10)-trien-3-yl]-boronic acid, described in WO 2017/192991 A1, starting from intermediate N-2:

A flask is charged with 0.5 g of intermediate N-2 and 2.5 mL of methanol. 2.5 mL of tetrahydrofuran are added and the mixture is cooled to 0 °C.

A solution of potassium hydroxide (0.6 g) in methanol (3.1 mL) is added, and the mixture is kept under stirring at 25 ° C for 16 hours. The reaction is monitored by UPLC analysis.

Water (3 mL) is added, and the solvent is concentrated under reduced pressure at 45 °C. The residue is taken up with isopropyl acetate (4 mL) and the layers are separated.

The organic layer is washed with water and concentrated under reduced pressure at 45 °C until a brown oil is obtained, which consists of 76% (UPLC analysis) /Mί?a, 17b)· 17-hydroxy- 7-[9-[(4,4,5,5,5~pentaf3uoropentyl)thio]nonyl]estra-l,3,5(10 )-trien~3-yl]-boronic acid, described in WO 2017/192991 A1 as an intermediate useful for the synthesis of ZB716. EXAMPLE 9

This example refers to an alternative method for obtaining the same intermediate of WO

2017/192991 A1 mentioned in Example 8, starting from intermediate N-2: A flask is charged with 0.5 g of intermediate N-2, 12.5 mL of tetrahydrofuran and 12.5 mL of water.

Lithium hydroxide (0.27 g) is added, and the mixture is kept under stirring at 25 °C for 16 hours.

The reaction is monitored by UPLC analysis. The solvent is concentrated under reduced pressure at 45 °C.

The residue is taken up with isopropyl acetate (13 mL) and washed with water.

The organic layer is concentrated under reduced pressure at 45 °C to obtain a brown oil which consists of 70% (UPLC analysis) i?-[(7a,17p)-T7-hydroxy-7-[9-[(4,4,5,5,5- pentafluoropentyl)thio]nonyl]estra-l,3,5(i0)-trien-3-yl]-bor onic acid, described in WO 2017/19299] A1 as an intermediate useful for the synthesis of ZB716.

EXAMPLE 10

This example refers to the obtaining of Fulvestrant triflate, which can be used for an alternative synthesis of ZB716, using the compound Fulvestrant as the starting intermediate.

A flask is charged with 5 g of Fulvestrant, 70 mL of dichloromethane and 3.5 mL of triethylamine (TEA).

The mixture is cooled to 5 °C, and a solution of N,N-bis(trifluoromethanesulfonyl)aniline (4.70 g) dissolved in 12 mL of dichloromethane is added dropwise in about 15 minutes. The mixture is brought to 25 °C and kept under stirring for 6 hours.

Once the reaction is complete (UPLC monitoring) the solvent is removed by distilling under reduced pressure at 45 °C to obtain 11.5 g of Fulvestrant triflate (oil) which is reacted as such in the subsequent reaction.

The Fulvestrant used as the starting reagent of the method, subjected to ¹ H-NMR and Ms analysis, shows the following analytical data:

¹ H-NMR (400MHz, 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).

The ¾-NMK signals at 8.99 ppm and 4.50 ppm (attributable to the mobile protons in position 3 and 17) disappear after deuteration of the sample with D2O.

Mass (ESI): m/z = 629 [M ⁺ +1+22]; 607 [M ⁺ +l]; 589 [M ⁺ +1-H ₂ 0]

The Fulvestrant triflate obtained, subjected to ¹ H-NMR and Ms analysis, shows the following analytical data:

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

Mass (ESI): m/z = 761 [M ⁺ +1+22]; 739 [M ⁺ +l]; 619 [M ⁺ +l - HCF ₂ CF ₃ ].

EXAMPLE 11

This example refers to the synthesis of intermediate N-l of the process of the invention starting from Fulvestrant triflate.

A flask is charged with the intermediate Fulvestrant triflate obtained according to the procedure described in the previous example and 160 mL of acetonitrile. The mixture is kept under stirring at 25 °C for 10 minutes. 3.1 g of bis(pinacolato)diboron, 2.2 g of potassium acetate, 0.25 g of palladium acetate and 0.49 g of tricyclohexylphosphine are added to the solution. The mixture is heated to 80 °C for 2 hours.

The reaction is monitored by UPLC analysis.

Once the reaction is complete, it is cooled to 25 °C, carbon is added (0,2 g) and the mixture is filtered through a layer of dicalite (8 g). It is concentrated under reduced pressure at 45 °C until an oily residue is obtained.

The residue is suspended in 100 mL of isopropyl acetate and silica gel is added.

The suspension is kept under stirring at 25 °C for 1 hour.

The solvent is filtered and concentrated under reduced pressure at 45 °C to obtain 12.8 g of intermediate N-l .