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

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

Description Title of the invention: Process for preparing B-acid - [(7β,17B)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]non yl|estra-1,3,5(10)-trien-3-yl]-boronic technical field

[0001] = The present invention relates to the field of processes for synthesizing active ingredients for pharmaceutical use, and more specifically for a preparation process the industrial scale of B- acid [(7a,17P)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5(1 0)-trien-3-y1]-boronic, also called fulvestrant-3-boronic acid or ZB716. The compound is identified by CAS number 1853279-29-4, Prior art

[0002] = ZB716 is useful for the treatment of metastatic breast cancer. The structure of The compound is indicated below:

[0003] [Chem.1] HAS US (A NS HO \ À A , B a mcna-nai"ane OH

[0004] The compound is described and claimed in patent EP 3473630 B1 (compound 29, re- demand 1) from Xavier University of Louisiana.

[0005] The article "fulvestrant-3 boronic acid (ZB716): an orally bioavailable selective estrogen receptor downregulator (SERD)", J. Liu et al., J. Med. Chem. 2016, 59, Pages 8134-8140 present an experimental description of the preparation of the compound in question (page 8135, diagram 1); this synthesis starts from the compound KSM, having the formula indicated below:

[0006] [Chem.2] To ad A. A TO THE AN br pu tp A ES The KSM compound, for its part, can be obtained as reported in the article "Fulvestrant: 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, the compound ZB716 offers clear clinical advantages over fulvestrant, with which it shares much of its structure. The following figure highlights the structural differences between fulvestrant and ZB716: [Chem.3] H cH —yÙ sd _ Pa el Pan ea LOT + ca LA $ PA Map SGH) 0P0F, ROC PopHaa- S-—{OHa)—OF,0F2 0H to Li Ai mme SPRAY 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 involve the use of intermediate 1 from J. Med. Chem. 2016, 59, 8134-8140, which has the following structural formula: [Chem.4] THIS - NF og 30h" 0RES The present invention aims to provide a process for the production of compound ZB716. Summary of the invention This objective is achieved with the present invention, which relates to a process for the synthesis of ZB716 comprising the following steps: a) reaction of the N-3 intermediate, the (70,17B)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-oestra-1,3,5(10)-tien-3,17-diol (Fulvestrant), with a triflatant agent to obtain the N-2 intermediate, (70,17B)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-oestra-1,3,5(10)-tien-3,17- diol-3-triflate: [Chem.5] — f ç FA AANISOASF SN 5 ——— - &ç of À & no No SOICHIROFOP de RO SOICHR CF20F4 w3 Rnz b) reaction of the N-2 intermediate with 4,4,4,4,5,5,5',5-octamethyl-2,2"-bi-1,3,2-dioxaborolane to obtain the N-1 intermediate, the (70,176)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-estra-1,3,5(10)-trien-17-ol: [Chem.6] D nas Ï AT à $ na” a NEHEOTHSCFICFS os: { to this - $ RCHNSOCHENCTIOF f #2 N4 c) treatment of intermediate N-1 to give compound ZB716, B-[(7a,17B)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]oestra-1,3,5(10 )-trien-3-y1]-boronic acid: [Chem.7] CS Se HH 1 nf 47 AR f ka Ë "On floor f “4h OS pre > ë VOHROSO(CHACCFROFS BP SH BO CHA CFIOES A sù + 18716 The reagent used in step c) for the conversion of intermediate N-1 to compound ZB716 can be a periodate of an alkali metal. Detailed description of the invention In its first aspect, the invention relates to a method for synthesizing ZB716 which includes the steps described below. In the description of the reactions that constitute the process of the invention, the ratios between the reactants are indicated in w / w, that is to say, ratios by weight, except contrary specification. Step a) consists of reacting the N-3 intermediate, the (7a,17G)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-oestra-1,3,5(10)-triene-3,17-diol, with a triflatant agent to obtain the N-2 intermediate, the (7a,17G)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17 -diol-3 triflate: [Chem.8] 2222220000 L M4 ui AeNiSOZCE NE \ { LA À ref; He Note) “ CH BOCCHARCF20FS go HCH)9SO(CHO OP ZUES N-3 N-2 The N-3 intermediate is the Fulvestrant compound produced by the Applicant according to the process described in patent EP 2183267 B1; the process described in EP 2183267 B1 makes available the N-3 intermediate, Fulvestrant, of a quality suitable for use also in the process of obtaining the new active ingredient ZB716. The triflatation is carried out exclusively with the phenolic hydroxyl group without it being necessary to protect the other hydroxyl group present in the molecule, using as the triflating agent an aromatic bis(trifluoromethanesulfonimide) of the general formula Ar-N(Tf), where Ar denotes the aromatic or heterocyclic radical and the N(Tf) group is the radical. [Chem.9] ,SO,GF, y"2WEWT 3 —N, SO,CF, The preferred triflatant agent for the purposes of the present invention is the compound 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (commonly also referred to as N,N-bis(trifluoromethanesulfonyl)aniline) having the formula reproduced below: [Chem.10] sas 3, 06 fu +h LS The triflatant agent is used at a ratio (w / w) between 0.30 and 1.20 relative to the N-3 intermediate, preferably it is used at a ratio (w / w) between 0.6 and 1.0. 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 duration 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. Step b) consists of reacting the N-2 intermediate obtained in the previous step with 4,4,4',4',5,5,5',5'-octamethyl-1-2,2"-bi-1,3,2-dioxaborolane to obtain the N-1 intermediate, the (7a,17G)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-estra-1,3,5(10)-trien-17-ol: [Chem.11] { Te ve nm CH gReci mod LES 4 RCHRSORH NC FACE 2 4 ñ - * > 0? Peisai SOCCHEN ECS = ; Na N.4 The compound 4,4,4,4',5,5,5',5'-octamethyl-2,2"-bi-1,3,2-dioxaborolane is widely available commercially and is also commonly referred to as bis(pinacolato)dibore. Bis(pinacolato)dibore is used at a ratio (w / w) between 0.11 and 0.45, preferably between 0.25 and 0.40, relative to the N-2 intermediate. The reaction is carried out in acetonitrile by operating at a temperature between 70 and 90 °C, preferably between 75 and 85 °C, for a time between 1 and 6 hours, preferably between 2 and 4 hours, in the presence of an organic palladium derivative (ID) such as palladium acetate (II), 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. Finally, in the last step of the process, c), the intermediate N-1 is converted into the desired compound, ZB716: [Chem.12] Leconte ce HH a+ Hi, l Î OR —— HIV Dur PnPn HO A 7 ë > SCHEISSOCHACFICTS ki DES A SO(CHICEICES Vi NA ZB718 As reagents, one can use hydrated lithium hydroxide, hydroxide of potassium and sodium hydroxide or sodium or potassium periodate with ammonium acetate. When using a periodate, the reagent is used at a ratio (w / w) between 0.3 and 2.4, preferably between 1.1 and 1.4, relative to the N-1 intermediate; the use of sodium periodate is preferred to that of potassium periodate. The amount of reagent required is precisely determined by monitoring the reaction. When operating with a periodate, the reaction is carried out using as a solvent a mixture of water with a water-miscible solvent such as methanol, tetrahydrofuran (THF) or acetone. The preferred reaction conditions are the use of aqueous acetone in the presence of ammonium acetate, 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. When using hydroxides, one can operate using methanol or tetrahydrofuran (THF) as solvents, optionally in the presence of water. The invention will be illustrated in more detail using the following examples. Materials, methods and experimental conditions NMR: JEOL 400 YH (400 MHz) NMR Spectrometer; JEOL Delta v5.1.1 Software; 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-ds. MS1: Instrument: DSQ-trace Thermofisher Sample introduction: direct exposure probe (dep) Chemical ionization (CI): methane Methane pressure: 2.2 psi Source temperature: 200°C MS 2: Instrument: Waters Acquity UPLC QDa detector Electrospray ionization (EST) of formic acid Source temperature: 120 °C UPLC: Chromatographic system: Waters Acquity UPLC; detector: Acquity UPLC PDA and detector A Chromatographic conditions: - Column: Acquity UPLC BEH CI18 1.7 um, 2.1 x 50 mm - Flow rate: 0.5 ml / min - Detector: UV 225 nm - Injection volume: 1 µl - Temperature: 35°C - Mobile phase A: H,0 + 0.01% trifluoroacetic acid (TFA) - Mobile phase B: Acetonitrile + 0.01% TFA |Mobile phase A (v / v) |Mobile phase B (v / v) CCM MERCK: CCM 60 F silica gel,s4 Aluminum sheets 20 x 20 cm, ref. 1.0554.0001. CCM Detectors Cerium phosphomolybdate: Dissolve 25 g of phosphomolybdic acid and 10 g of cerium sulfate (TV) in 600 ml of H₂O. Add 60 ml of 98% H₂SO₄ and make up to 1 ml with H₂O. Impregnate the plate with the solution and then heat it until the products are detected. Remarks The water used in the experimental descriptions is pure water unless otherwise stated. The organic solvents used in the experimental descriptions are of technical grade unless otherwise stated. The reagents and catalysts used in the experimental descriptions are commercial grade unless otherwise stated. Example 1 This example relates to step a) of the process of the invention, from the N-3 intermediate, Fulvestrant, to the N-2 intermediate, fulvestrant triflate. [Chem.13] pen An go: 59 pe at FRA PRE 250 LS bi md ti 7 ef EE Put “ SOGC FO GFa or tt rt — FOR to HOT SP Se BOLOHER OF SCES Fuivestrant Faibveetrant triflato Fulvestrant Triflate In a balloon, 5 g of N-3 fulvestrant, 70 ml of dichloromethane and 3.5 ml of triethylamine (TEA) are loaded. 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 in approximately 15 minutes. The solution was brought to 25 °C and kept under stirring for 6 hours. Once the reaction is complete (UPLC control), the solvent is removed by distillation under reduced pressure at 45 °C until 11.5 g of N-2 fulvestrant triflate (oil) is obtained, which is then reacted as is in the following reaction. The fulvestrant used as the starting reagent for the method, subjected to ¹H and Ms NMR analysis, presents the following analytical data: '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). 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 D,0. Mass (ESI): m / z = 629 [M++1+22]; 607 [M++1]; 589 [M++1-H,0]. The fulvestrant triflate obtained, subjected to ¹H and Ms NMR analysis, presents the following analytical data: '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). Mass (ESI): m / z = 761 [M++1+22]; 739 [M++1]; 619 [M++1 — HCF,CF3]. Example 2 This example relates to step b) of the process of the invention, the synthesis of the intermediate N-1 of the process of the invention from ful- vestrant triflate (intermediate N-2). [Chem.14] PdtdAcle, KORC CHEN 5 N1 6 5) OH H »-e 41 es ne Hi > g Étienne AN p Po $ 7 PatoArk, > D. CI BC T6 SA T; phosphine CRT CH) SO / CH2CF CF Z 3e, OH SOLCHANCF2F2 Hrieycahessiphosphine, 754 NEHzke 2HCFoCF3 Fuivestrant frifiate Ces N4 a Trifiate de fuivestrant 80'C.2h In a round-bottom flask, the triflate intermediate of N-2 fulvestrant obtained according to the procedure described in the previous example is loaded, along with 160 mL of acetonitrile. The mixture is stirred at 25 °C for 10 minutes. Then, 3.1 g of bis(pinacolato)diborine, 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 at 80 °C for 2 hours. The reaction is monitored by UPLC analysis. Once the reaction is complete, the mixture is cooled to 25 °C, carbon (0.2 g) is added, and the mixture is filtered through a layer of dicalite (8 g). It is then 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 agitation at 25°C for 1 hour. The solvent is filtered and concentrated under reduced pressure and at 45 °C to give 12.8 g of N-1 intermediate. Example 3 This example relates to the implementation of step c) of the process of the invention, from intermediate N-1 to compound ZB716: [Chem.15] Acetane'M2G 25°C. 24h Hi 41 ” Ï FX pts mu ae” f L > rss NaiDs NHsOAG kidneys | QAR EM CUT media Te DS peHauSO CHSjeCFoGHS | AcetanaiH2O HO ELA, “ ô: 25°0, 94h a ​​(CHAsSO{CHeJeGFLCFS NT 28718 In a round-bottom flask, 5 g of intermediate N-1, 55 mL of acetone, and 27.5 mL of water are loaded. The suspension is stirred at 25 °C for 10 minutes. 5.9 g of sodium periodate and 2.15 g of ammonium acetate are added. The mixture is stirred 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 phases are separated, and the aqueous phase is re-extracted with isopropyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure at 45 °C until a solid is obtained. The product is purified by silica gel column chromatography by eluating with a 95:5 methylene chloride / methanol mixture. The solvent is concentrated under reduced pressure at 45 °C to give 2.6 g of the desired compound, ZB716, in the form of a white solid whose analytical data ''H NMR, 'C NMR and Ms coincide with those reported in the literature. 'H NMR (400 MHz, DMSO-d4): 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 'H' NMR signals at 7.68 ppm and 4.36 ppm disappear after deuteration of the sample with DO. NMR “C (400 MHz, 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; 29.3; 29.0; 28.0: 22.8; Mass (EST): m / z = 657 [M++1+22] ; 635 [M++1] ; 617 [M++1-H20]

Claims

Demands

1. Process for the synthesis of B- acid [(70,17P)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl ]œstra-1,3,5(10)-trién-3-y1]-boronique (ZB716), which includes the Next steps: a) reaction of the N-3 intermediate, the (70,17B)-7-[9-[(4,4,5,5, 5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17-diol (Fulvestrant), with a triflatant agent to obtain the N-2 intermediate, the (7a,17P)-7-[9-[(4,4,5,5,5-pentafluoropentyl) sulfinyl]nonyl]-estra-1,3,5(10)-trien-3,17-diol-3-triflate: — Da "' ARNSOS ER # 7 15; 1 FE CL HE ae YCHAASO(CHGACE2CFS #w 4 CH JS OICHNOELES Na N2 b) reaction of the N-2 intermediate with 4,4,4',4',5,5,5',5'-octamethyl-2,2"-bi-1,3,2-dioxaborolane to obtain the intermediary N-1, (7a,17B)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-3-(4,4,5,5-te tramethyl-1,3,2-dioxaborolan-2-yl)-estra-1,3,5(10)-trien-17-ol: as: nf ë go D AS EE Rec y 03Œ 55 OECD 2 + c) treatment of intermediate N-1 to give compound ZB716, acid B- [(7œ,176)-17-hydroxy-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl |estra-1,3,5(10)-trien-3-y1]-boronic: guy SR 4 CB TOR)SSO(CHEICFICFS "H af roses" mr Frtre [T8 to Bag > 7 CH SSO CHHSCRICES > N+ 28718

2. A method according to claim 1, wherein, in step a), one uses as a triflating agent an aromatic bis(trifluoromethanesulfonimide) of the general formula Ar-N(Tf),, where Ar denotes the aromatic radical or heterocyclic and the group N(Tf); is the radical: ,SQ,GF, CGI READ EL IE SIT NL EI 2 CS AC SAMU = 114340 = —N \ SO,CF,

3. Method according to claim 2, wherein said triflatant agent is the 1,1,1-trifluoro-N-phenyl-N-[(tifluoromethyl)sullonylmethanesulfonami] of.

4. A method according to any one of the preceding claims, in which reagent is used in step c) for the conversion of The N-1 intermediate in compound ZB716 is a periodate of a metal alkaline.

5. A method according to claim 4, wherein said reagent is the periodatc of sodium.