Process for the Preparation of Methyl 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-Fluoropropyl)Pyrrolidin-3-yl]Oxyphenyl]-8,9-Dihydro-7H-Benzo[7]Annulene-2-Carboxylate

Abstract

Herein is provided a novel process for the preparation of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate by a Suzuki coupling of compound (3), wherein LG represents a leaving group, with an organoboron reagent:

##STR00001##

Compound (3) is obtained by activation of compound (4) with a leaving group LG, and compound (4) is obtained by alpha-arylation of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate with 1-LG′-2,4-dichlorobenzene, wherein LG′ represents a leaving group:

##STR00002##

Claims

1. A process for the preparation of compound (2): ##STR00027## in the base form or in a salt form, characterized in that compound (2) is obtained by a Suzuki coupling of compound (3), ##STR00028## wherein LG represents a leaving group, with an organoboron reagent OrganoB-X wherein OrganoB is a boron derivative and X is a (3S)-1-(3-fluoropropyl)-3-phenoxypyrrolidine moiety of the following formula: ##STR00029## optionally followed by a salification reaction.

2. The process according to claim 1, wherein said organoboron reagent is (3S)-1-(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine, the corresponding acid or a salt thereof.

3. The process according to claim 2, wherein said organoboron reagent is selected from reagents (1), (2) and (3): ##STR00030##

4. The process according to any of claims 1 to 3, wherein the Suzuki coupling is carried out in the presence of a palladium complex.

5. The process according to claim 4, wherein said palladium complex is bis(triphenylphosphine)palladium(II) dichloride.

6. The process according to any of claims 1 to 5, wherein the Suzuki coupling is carried out in the presence of bis(triphenylphosphine)palladium(II) dichloride and of cesium carbonate, in an organic solvent.

7. The process according to any of claims 1 to 6, wherein the leaving group LG in compound (3) represents a triflate group.

8. The process according to any of claims 1 to 7, wherein compound (2) is prepared in the form of an oxalate salt, by a salification reaction performed after the Suzuki coupling.

9. The process according to claim 8, wherein the oxalate salt of compound (2) is obtained using oxalic acid in isopropylacetate.

10. The process according to any of claims 1 to 9, wherein compound (3) is obtained by activation of compound (4) with a leaving group LG: ##STR00031##

11. The process according to claim 10, wherein compound (4) is activated into compound (3′) with a triflation reagent: ##STR00032##

12. The process according to claim 11, wherein sodium hydride is used as strong base and DBU as catalyst.

13. The process according to claim 11 or 12, wherein N-phenylbistriflimide is used as triflation reagent, in Me-THF as organic solvent.

14. The process according to any of claims 10 to 13, wherein compound (4) is obtained by alpha-arylation of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate with 1-LG′-2,4-dichlorobenzene, wherein LG′ represents a leaving group.

15. The process according to claim 14, wherein said leaving group LG′ is a halogen atom selected from bromine or iodine.

16. The process according to claim 14 or 15, wherein the alpha-arylation is carried out in an organic solvent, in presence of a palladium derivative as catalyst, of a ligand, and of a mineral base.

17. The process according to claim 16, wherein the palladium derivative is Pd(OAc).sub.2 or Pd.sub.2dba.sub.3.

18. The process according to claim 16 or 17, wherein the mineral base is K.sub.2CO.sub.3, K.sub.3PO.sub.4, Cs.sub.2CO.sub.3 or tBuONa.

19. The process according to any of claims 16 to 18, wherein the alpha-arylation is carried out in toluene, in the presence of Pd.sub.2dba.sub.3 as catalyst and of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene as ligand.

20. A process for the preparation of compound (1) or a pharmaceutically acceptable salt thereof: ##STR00033## by saponification of compound (2): ##STR00034## characterized in that compound (2) is obtained by the process according to any of claims 1 to 19.

21. Compounds (4), (3) and (3′), wherein LG represents a leaving group: ##STR00035##

Description

EXAMPLE 1: PREPARATION OF THE ORGANOBORON DERIVATIVE “REAGENT (1)”

[0072] The preparation of reagent (1), useful in the Suzuki coupling step of the process for synthesis of compound (2) as provided herein, is illustrated in scheme 5 below, reproduced from the patent application WO 2017/140669.

##STR00022##

[0073] According to scheme 5, the commercially available compound (a) (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol) is condensed in tetrahydrofuran (THF) at room temperature on (R)-1-N-Boc-3-hydroxypyrrolidine, using N,N,N′,N′-tetramethylazodicarboxamide as coupling agent.

[0074] According to step 2, the compound (c) thus obtained is N-deprotected in methanol (MeOH) at room temperature using an acidic agent, for example a solution of HCl 4N in dioxane.

[0075] Alkylation of the pyrrolidine nitrogen is then performed under step 3 by reacting compound (d) with the corresponding 1,1-disubstituted 1-halogeno-3-fluoro propane, for example 1-iodo-3-fluoropropane, in acetonitrile in presence of potassium carbonate (K.sub.2CO.sub.3) at about 40° C.

[0076] Steps 1 to 3 of scheme 5 are illustrated by the detailed protocols below.

[0077] The .sup.1H NMR spectra were performed on a BrukerAvance DRX-400 spectrometer, with the chemical shifts (δ in ppm) in the solvent dimethyl sulfoxide-d6 (dDMSO-d6) referenced at 2.50 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0078] The liquid chromatography/mass spectrography (LC/MS) data were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210<l<400 nm and column Acquity UPLC CSH C18 1.7 μm, dimension 2.1×30 mm, mobile phase H.sub.2O+0.1% HCO.sub.2H/CH.sub.3CN+0.1% HCO.sub.2H.

Compound (c). Tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine-1-carboxylate

[0079] ##STR00023##

[0080] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (a) (82.7 g, 364.51 mmol) in THF (2 L) was added under argon (R)-1-N-Boc-3-hydroxypyrrolidine (b) (84.43 g, 437.41 mmol) followed by N,N,N′,N′-tetramethylazodicarboxamide (99.1 g, 546.77 mmol). The clear reaction mixture turned orange and triphenylphosphine (143.41 g, 546.77 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, meanwhile a precipitate of triphenylphosphine oxide formed (Ph.sub.3P═O). The reaction mixture was poured in water (1.5 L) and extracted with ethyl acetate (AcOEt) (3×1.5 L). Gathered organic phases were dried over magnesium sulfate (MgSO.sub.4), filtered and concentrated under reduced pressure. The residue was taken up into diisopropylether (1.5 L) and the solid formed (Ph.sub.3P═O) was filtered. The solvent was concentrated under reduced pressure and the residue purified by column chromatography eluting with a mixture of heptane with AcOEt (90/10; v/v) to give 145 g (100%) of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1-carboxylate (c) as a colorless oil.

[0081] .sup.1H NMR (400 MHz, DMSO-d6, δ ppm): 1.27 (s, 12H); 1.39 (s, 9H); 2.05 (m, 1H); 2.14 (m, 1H); 3.37 (3H); 3.55 (m, 1H); 5.05 (s, 1H); 6.94 (d, J=8.4 Hz, 2H); 7.61 (d, J=8.4 Hz, 2H).

Compound (d). (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride

[0082] ##STR00024##

[0083] To a solution of (S)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate (c) (80 g, 195.23 mmol) in MeOH (450 ml) was added slowly HCl 4N in dioxane (250 ml).

[0084] After 1.5 hours, the reaction mixture was concentrated under reduced pressure and the residue was taken up into Et.sub.2O with stirring to give a solid which then was filtered and dried under vacuum to give compound (d) 61.8 g (95%) as a white powder.

[0085] .sup.1H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (s: 12H); 2.10 (m: 1H); 2.21 (m: 1H); 3.31 (3H); 3.48 (m: 1H); 5.19 (m: 1H); 6.97 (d, J=8.4 Hz: 2H); 7.63 (d, J=8.4 Hz: 2H); 9.48 (s: 1H); 9.71 (s: 1H).

[0086] LC/MS (m/z, MH.sup.+): 290

Reagent (1). (3S)-1-(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine

[0087] ##STR00025##

[0088] To a suspension of (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine hydrochloride (d) (20 g, 61.42 mmol) in acetonitrile (100 ml), was added K.sub.2CO.sub.3 (21.22 g, 153.54 mmol) and 1-iodo-3-fluoropropane (12.15 g, 61.42 mmol), under argon. The reaction mixture was stirred at 40° C. for 24 hours. After cooling to room temperature, the reaction mixture was filtered and washed with acetonitrile. The filtrate was concentrated under reduced pressure and the residue was taken up in DCM and the solid formed was filtered and washed with DCM. The filtrate was concentrated to give reagent (1) 21.5 g (100%) as a yellow foam.

[0089] .sup.1H NMR (400 MHz, DMSO-d6, δ ppm): 1.27 (s, 12H); 1.77 (m, 2H); 1.84 (m, 1H); 2.27 (m, 1H); 2.41 (m, 1H); 2.49 (2H); 2.62 (dd, J=2.6 and 10.4 Hz, 1H); 2.69 (m, 1H); 2.83 (dd, J=6.2 and 1.4 Hz, 1H); 4.47 (td, J=6.2 and 47 Hz, 2H); 4.99 (m, 1H); 6.77 (d, J=8.4 Hz, 2H); 7.58 (d, J=8.4 Hz, 2H).

[0090] LC/MS (m/z, MH.sup.+): 350

EXAMPLE 2: SYNTHESIS OF COMPOUND (2) FROM CARBOXYMETHOXYBENZOSUBERONE (5)

[0091] The numbering of the intermediate and final compounds (2), (3′), (4) and (5) refer to scheme 2 described before.

[0092] In the first step S1, the 5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene core of compound (5) (carboxymethoxybenzosuberone) is arylated at the 6-position via a palladium catalyzed coupling of 1-bromo-2,4-dichloro-benzene in refluxing toluene and in the presence of potassium carbonate, to yield the 2,4-dichlorophenyl precursor (4) isolated as a Me-THF solution after silica gel filtration.

[0093] In the second step S2, the crude Me-THF solution of compound (4) is reacted with N-phenyl-bis-triflimide in the presence of catalytic DBU and an excess of sodium hydride. After water washing and solvent exchange to acetonitrile, the desired triflated compound (3′) is isolated by crystallization as a white solid.

[0094] In a third step S3, the cyclic enol triflate (3′) is coupled to the chiral boronic ester “reagent (1)” as described earlier via a palladium catalyzed Suzuki reaction performed in an acetonitrile/water mixture at 40±3° C., using cesium carbonate as a base. After aqueous work-up and solvent exchange with isopropylacetate, residual palladium is eliminated by sequential ethylenediamine, charcoal and dimercaptotriazine grafted silica treatments. The crude oxalate salt of compound (2) is isolated by crystallization in isopropylacetate.

[0095] These steps are illustrated by the detailed protocols below.

[0096] The .sup.1H NMR spectra were performed on a 300 or 400 MHz Bruker Avance spectrometer, with the chemical shifts (δ in ppm) in the solvent dimethyl sulfoxide-d6 (dDMSO-d6) referenced at 2.50 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0097] The liquid chromatography/mass spectrography (LC/MS) data were obtained on a UPLC-SQD Waters instrument, evaporating light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210<<400 nm and column Acquity UPLC CSH C18 1.7 μm, dimension 2.1×50 mm, mobile phase H.sub.2O+0.1% HCO.sub.2H/CH.sub.3CN+0.1% HCO.sub.2H.

[0098] 2.1: Steps S1 and S2 Concatenated

[0099] A degassed mixture of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (5) (40 g), potassium carbonate (K.sub.2CO.sub.3, 40 to 101 g i.e. 1.5 to 4 eq.), bromo-dichlorobenzene (62.1 g), Xantphos (21.2 g) and Pd.sub.2dba.sub.3 (8.39 g) is refluxed in toluene (320 ml) under nitrogen and vigorous stirring until completion.

[0100] After cooling to room temperature, insoluble material is eliminated by filtration on a pad of silica (80 g), followed by washings of the filter with toluene (600 ml). Toluene is distilled off from the filtrate and exchanged with Me-THF to yield a solution of the α-arylation product (4) (methyl 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene-2-carboxylate) in MeTHF (400 ml), used as is in the next step.

[0101] A sample of pure product (4) has been isolated by silica gel chromatography of an aliquot (eluent: dichloromethane-heptane).

[0102] .sup.1H NMR (400 MHz, DMSO-d6 in ppm) of the isolated compound (4): 1.77 (m, 1H) 2.00 (m, 1H); 2.18 (m, 2H); 3.08 (m, 1H); 3.20 (m, 1H); 3.89 (s, 3H); 4.46 (dd, J=11.3, 3.7 Hz, 1H); 7.46 (m, 2H); 7.59 (d, J=2.0 Hz, 1H); 7.64 (d, J=7.9 Hz, 1H); 7.91 (dd, J=8.0, 1.4 Hz, 1H); 7.94 (s, 1H).

[0103] LC/MS ([M+H].sup.+): 363

[0104] To the Me-THF solution of compound (4) obtained in step S1 (scale: 40 g of compound (4)) is added N,N-bis(trifluoromethylsulfonyl)aniline (80 g). The resulting solution is added dropwise at 0° C., under stirring, to a Me-THF (200 ml) suspension of NaH (10 g-60% dispersion in oil) containing DBU (5 ml). The reaction mixture is stirred at room temperature until completion.

[0105] After cooling to 0° C., acetic acid (4 ml), followed by water (400 ml), are added dropwise. The aqueous phase is separated at room temperature and the organic phase is washed with diluted aqueous sodium chloride (NaCl, 0.6 M; 3×400 ml). Me-THF is distilled off and exchanged with acetonitrile. After elimination of insoluble material by filtration in hot acetonitrile, compound (3′) (methyl 6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate) is crystallized in 250 ml of acetonitrile, isolated by filtration and washings with cold acetonitrile and heptane, to yield 61.2 g of pure triflate as a white solid.

[0106] Yield: 67.4% (in 2 steps S1 and S2).

[0107] .sup.1H NMR (400 MHz, DMSO-d6 in ppm): 2.18 (m, 2H); 2.41 (m, 2H); 2.95 (m, 2H); 3.90 (s, 3H); 7.55 (m, 2H); 7.68 (d, J=8 Hz, 1H); 7.80 (d, J=1.8 Hz, 1H) 8.01 (m, 2H).

[0108] LC/MS (EI m/z): 494.sup.+

[0109] Purity of compound (3′): 99.0%, measured by HPLC:

[0110] Mobile phase: water/acetonitrile/HCOOH;

[0111] Stationary phase: XSelect CSH C18—3.5 μm (Waters) or equivalent;

[0112] Column length: 100 mm;

[0113] Column internal diameter: 4.6 mm;

[0114] Flow rate: 1 mL/minute;

[0115] Injection volume: 10 μL;

[0116] Detection: 254 nm (UV).

[0117] 2.2: Step S3

[0118] A degassed mixture of the triflate (3′) (20 g), the boronic ester “reagent (1)” (14.1 g), Cs.sub.2CO.sub.3 (19.7 g), bis(triphenylphosphine) palladium(II)dichloride (1.4 g), water (100 ml) and acetonitrile (260 ml), is stirred at 40° C. under nitrogen. After complete conversion, the reaction medium is cooled to room temperature, isopropylacetate (100 ml) is added and the aqueous phase is separated. The organic phase is washed with diluted aqueous NaCl (0.3 M; 2×200 ml), dried by azeotropic distillation of isopropylacetate and treated subsequently with ethylenediamine, charcoal and dimercaptotriazine grafted silica, to remove residual palladium.

[0119] The resulting solution of compound (2), namely 6-(2,4-dichlorophenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-carboxylic acid methyl ester, in isopropylacetate, adjusted at 200 ml, is heated to 70° C. and an oxalic acid (3.6 g) solution in isopropylacetate (43 ml) is added dropwise under stirring. After seeding (using seeds previously prepared on another batch of product by conventional crystallisation techniques) and cooling to 0° C., the desired oxalate salt of compound (2), depicted below, crystallizes and is isolated by filtration in a 70% yield (18.6 g, white powder):

##STR00026##

[0120] .sup.1H NMR (400 MHz, DMSO-d6 in ppm): 7.92 (d, J=2.0 Hz, 1H); 7.78 (dd, J=8.0 and 2.0 Hz, 1H); 7.59 (d, J=2.2 Hz, 1H); 7.29 (dd, J=8.3 and 2.2 Hz, 1H); 7.22 (d, J=8.3 Hz, 1H); 6.90 (d, J=8.0 Hz, 1H); 6.78 (d, J=9.0 Hz, 2H); 6.73 (d, J=9.0 Hz, 2H); 4.98 (m, 1H); 4.50 (dt, J=47.2 and 5.7 Hz, 2H); 3.86 (s, 3H); 3.49 (dd, J=12.8 and 5.8 Hz, 1H); from 3.38 to 3.08 (m, 5H); 2.94 (t, J=5.0 Hz, 2H); 2.34 (m, 1H); from 2.23 to 2.11 (m, 3H); from 2.07 to 1.93 (m, 2H).

[0121] LC/MS ([M+H].sup.+): 568

[0122] Purity of compound (2), oxalate salt: 98.2%, measured by HPLC under the same conditions as described in step S2 above.

EXAMPLE 3: ALTERNATIVE PROTOCOLS FOR STEP S1

[0123] 3.1: Alternative 1

[0124] A 2 M THF solution of sodium tert-butoxide (19.48 ml) is added dropwise at 60° C. to a degassed mixture containing compound (5) (5 g), 1-bromo-2,4-dichlorobenzene (7.76 g), palladium acetate (257 mg), Xantphos (660 mg) and THF (20 ml). The reaction is heated at 60° C. until completion, cooled to room temperature, quenched with molar aqueous KH.sub.2PO.sub.4. After ethyl acetate extraction, water washings and purification by silica gel chromatography, compound (4) is isolated in a 70% yield and 92% purity.

[0125] .sup.1H NMR (400 MHz, DMSO-d6 in ppm): 1.78 (m, 1H); 2.01 (m, 1H); 2.19 (m, 2H); 3.10 (m, 1H); 3.22 (m, 1H); 3.89 (s, 3H); 4.47 (dd, J=11.3, 3.6 Hz, 1H); 7.47 (m, 2H); 7.61 (d, J=1.8 Hz, 1H); 7.65 (d, J=7.9 Hz, 1H); 7.92 (d, J=7.7 Hz, 1H); 7.95 (s, 1H).

[0126] LC/MS ([M+H].sup.+): 363

[0127] 3.2: Alternative 2

[0128] A degassed mixture containing compound (5) (0.5 g), 1-iodo-2,4-dichlorobenzene (0.76 ml), toluene (9 ml), water (1 ml), Cs.sub.2CO.sub.3 (1.05 g), palladium acetate (50 mg) and Xantphos (250 mg) is heated to reflux during about 22 hours. After cooling to room temperature, the organic phase is diluted with dichloromethane, washed with water and purified by chromatography on silica gel to yield 730 mg (87%) of a white solid.

[0129] .sup.1H NMR (400 MHz, DMSO-d6 in ppm): 1.78 (m, 1H); 2.01 (m, 1H); 2.19 (m, 2H); 3.09 (m, 1H); 3.21 (m, 1H); 3.89 (s, 3H); 4.47 (dd, J=11.3, 3.7 Hz, 1H); 7.47 (m, 2H); 7.60 (d, J=2.0 Hz, 1H); 7.64 (d, J=8.1 Hz, 1H); 7.92 (dd, J=7.9, 1.5 Hz, 1H); 7.95 (s, 1H).

EXAMPLE 4: ALTERNATIVE PROTOCOLS FOR STEP S2

[0130] 3.1: Alternative 1

[0131] A 0.5 M THF solution of potassium bis-trimethylsilylamide (7.70 ml) is added dropwise at −50° C. to a mixture of compound (4) (1 g) and N-phenylbis-triflimide (1.22 g) in THF (18 ml). After warming up to room temperature, the reaction medium is quenched with water at 0-5° C., extracted with dichloromethane followed by ethyl acetate, and purified by silica gel chromatography (eluent: dichloromethane-heptane) to afford the desired compound (3′) in an 80% yield and 90% purity measured by LC/MS.

[0132] .sup.1H NMR (400 MHz, DMSO-d6 in ppm): 2.18 (m, 2H); 2.41 (m, 2H); 2.95 (m, 2H); 3.89 (s, 3H); 7.55 (m, 2H); 7.68 (d, J=8.1 Hz, 1H); 7.80 (d, J=1.7 Hz, 1H); 8.01 (m, 2H).

[0133] LC/MS ([M+H].sup.+): 494

[0134] 3.2: Alternative 2

[0135] DBU (247 μl) is added dropwise at 0-5° C. to a suspension containing compound (4) (500 mg), and N,N-bis(trifluoromethylsulfonyl)aniline (639 mg) in acetonitrile (2 ml). The conversion rate is about 80% after stirring 22 hours at room temperature. The reaction mixture is cooled down to 0-5° C. and sodium hydride (27.5 mg of a 60% dispersion in oil) is added. After 1.5 hours stirring at room temperature, the conversion rate is about 100%. The resulting suspension is cooled down to 0-5° C., filtrated and washed with pre-cooled acetonitrile (0.5 ml) followed by water (2 ml) to yield 460 mg of compound (3′) as a white powder (yield: 67.5%) with a purity of 98% measured by LC/MS.

[0136] .sup.1H NMR (400 MHz, DMSO-d6 in ppm): 2.18 (m, 2H); 2.42 (m, 2H); 2.95 (m, 2H); 3.90 (s, 3H); 7.55 (m, 2H); 7.68 (d, J=7.9 Hz, 1H); 7.82 (s, 1H); 8.02 (m, 2H).

[0137] As shown in the above examples, the new process of synthesis for compound (2) provided herein allows a global yield, from compound (5) to compound (2), of about 33 to 49%. This is a greater yield than the one found in the previously described process of synthesis as set forth in scheme 3, wherein the yield for obtaining compound (2) is about 26% when starting from the same compound methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.

[0138] Also, the new process of synthesis provided herein allows to obtain compound (2) in a good yield without the need to perform column chromatographies after the Suzuki coupling step, which was needed in the syntheses routes previously known, but which is not appropriate when seeking a synthesis route applicable at the industrial level.