Method for preparing methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidine-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annuren-2-carboxylate

Abstract

Provided herein is a novel method for preparing 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 Suzuki coupling of compound (3), wherein LG represents a leaving group, with an organoboron reagent: (3). Compound (3) is obtained by activating compound (4) with a leaving group LG, and compound (4) is obtained by α-arylating 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: (4).

Description

[0001] Provided herein is a novel method for preparing methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate, and novel compounds that can be used in this method.

[0002] 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid methyl ester, also known as 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid methyl ester and hereinafter referred to as "Compound (2)", is the N-1 intermediate in the synthesis of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (hereinafter referred to as "Compound (1)"). Actually, compound (1) can be obtained by saponification of compound (2).

[0003] The compound (1) shown below is a selective estrogen receptor degrader (SERD) that has estrogen receptor antagonist properties and accelerates the proteasomal degradation of estrogen receptors. It can be used in particular as an anticancer agent. This compound is disclosed in patent application WO 2017 / 140669.

[0004]

[0005] For active ingredients in pharmaceutical products and their synthetic intermediates, there is always a need to find new synthetic routes that are more suitable for industrial implementation.

[0006] A novel process for preparing compound (2) (methyl ester of compound (1)) in base form or in salt form is described herein:

[0007]

[0008] The method is characterized in that compound (2) is obtained by reacting compound (3) (wherein LG represents a leaving group) with an organic boron reagent:

[0009]

[0010] A Suzuki coupling is performed, optionally followed by a salt formation reaction.

[0011] Also described herein is a method for preparing compound (2) in base form or in salt form:

[0012]

[0013] The method is characterized in that compound (2) is obtained by: compound (3)

[0014]

[0015] Where LG represents a leaving group,

[0016] 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 formula:

[0017]

[0018] A Suzuki coupling is performed, optionally followed by a salt formation reaction.

[0019] In one embodiment of the methods provided herein, compound (3) as described above is obtained by activating compound (4) with a leaving group LG:

[0020]

[0021] In another embodiment of the methods provided herein, compound (4) as described above is obtained by α-arylating 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylic acid methyl ester (represented as compound (5) below) with 1-LG'-2,4-dichlorobenzene as defined below:

[0022]

[0023] According to the present invention, LG' represents any leaving group.

[0024] In one embodiment, LG' represents

[0025] Formula -O-SO2-C n F (2n+1) wherein n=1 to 4, more particularly trifluoromethanesulfonate (where n=1) or nonafluorobutanesulfonate (where n=4), or

[0026] A halogen atom selected from bromine or iodine.

[0027] In a specific embodiment, 1-LG'-2,4-dichlorobenzene is 1-Hal-2,4-dichlorobenzene, wherein Hal represents a halogen atom selected from bromine or iodine.

[0028] In the methods provided herein, leaving groups LG and LG' are defined as chemical moieties that exhibit leaving group characteristics and allow for further substitution in subsequent chemical reactions.

[0029] More specifically, the leaving group LG in compound (3) is obtained by activating the carbonyl functional group in compound (4). As known to those skilled in the art, conventional activation reactions of the carbonyl functional group in compound (4) can be used.

[0030] For example, the leaving group LG in compound (3) may be a halogen atom, or an alkyl or aryl sulfamate, an alkyl or aryl phosphate, or an alkyl or aryl sulfonate, particularly a halogen atom or an alkyl or aryl sulfonate.

[0031] In one embodiment, the leaving group in compound (3) may be a halogen atom or a mesylate, tosylate, sulfamate, phosphate or triflate group.

[0032] In another embodiment of the invention, the leaving group LG is a halogen atom or a mesylate, tosylate, sulfamate, phosphate, triflate or nonafluorobutanesulfonate group.

[0033] In a particular embodiment of the invention, the leaving group LG is a triflate or nonafluorobutanesulfonate group.

[0034] Advantageously, the leaving group LG is a triflate group (trifluoromethanesulfonyl, corresponding to the formula -OS(O)2-CF3).

[0035] In the context of the present invention, unless otherwise mentioned throughout the specification, the following terms have the following definitions:

[0036] -Alkyl: an aliphatic group based on a straight or branched saturated hydrocarbon containing (unless otherwise mentioned) 1 to 6 carbon atoms (denoted as "(C1-C6)-alkyl"). By way of example, but not limited to: methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl, etc. The group may be partially or completely substituted by fluorine atoms and includes, but is not limited to, perfluoromethyl, perfluoroethyl, perfluoropropyl, perfluorobutyl, etc.;

[0037] -Aryl: phenyl, naphthyl or substituted phenyl, wherein substituted phenyl is defined as a phenyl in which one or more hydrogens are replaced by the same or different substituents, the substituents including but not limited to halogen atoms, alkyl, nitro, cyano, alkoxy, aryl, heteroaryl and trifluoromethyl.

[0038] Thus, in one embodiment of the methods provided herein, compound (4) is activated to compound (3'), wherein compound (3') is defined as compound (3) wherein LG represents a triflate group. Activating compound (4) to compound (3') is a triflation reaction:

[0039]

[0040] In such reactions, a triflation agent is used, such as N-phenylbistrifluoromethanesulfonimide or trifluoromethanesulfonic anhydride.

[0041] Advantageously, N-phenylbistrifluoromethanesulfonimide, also known as N,N-bis(trifluoromethylsulfonyl)aniline, is used as the trifluoromethanesulfonylating agent. This agent is advantageously used in a slight excess amount relative to compound (4), such as about 1.3 eq. (equivalent).

[0042] Suitable triflation media depend on the triflation reagent used, as known to those skilled in the art.

[0043] The trifluoromethanesulfonylation reaction is carried out in a suitable organic solvent (for example, THF (tetrahydrofuran), Me-THF (methyl-tetrahydrofuran), acetonitrile, dioxane, or a mixture of toluene and Me-THF). Advantageously, Me-THF is used as the organic solvent.

[0044] The triflation reaction is advantageously carried out using N-phenylbistriflation as the triflation agent in Me-THF as the organic solvent. The temperature of the triflation reaction is advantageously selected between 0°C and room temperature.

[0045] The triflation reaction is carried out with a strong base, for example sodium hydride (NaH), potassium bis(trimethylsilyl)amide (KHMDS) or a phosphazene base such as BEMP (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphabenzene) or BTPP (tert-butylimino-tris(pyrrolidinyl)phosphane). Advantageously, sodium hydride is used as a strong base.

[0046] When NaH is used as a strong base, the triflation reaction is carried out with a catalyst such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or DBN (1,5-diazabicyclo(4.3.0)non-5-ene). Advantageously, DBU is used as a catalyst.

[0047] Advantageously, the trifluoromethanesulfonylation reaction is carried out with sodium hydride as a strong base and DBU as a catalyst. Advantageously, a catalytic amount of DBU (such as about 0.2 equivalent) and a stoichiometric amount of NaH (such as about 1.0-1.1 equivalent) or a substoichiometric amount of NaH (about 0.7-0.8 equivalent) and a stoichiometric amount of DBU (about 1.0-1.2 equivalent) are used in the trifluoromethanesulfonylation reaction.

[0048] Advantageously after the triflation reaction, the product obtained is crystallized according to crystallization techniques known to those skilled in the art, so as to obtain compound (3) of high purity (such as a purity equal to or greater than 99%), before subjecting it to the next step of the process. Such a crystallization step can be carried out, for example, in acetonitrile, tert-amyl alcohol, heptane or diisopropyl ether. Advantageously, the crystallization is carried out in acetonitrile. The crystallization in acetonitrile is advantageously carried out at 0° C. and can then be dried at about 45° C.

[0049] In one embodiment of the methods provided herein, the α-arylation of compound (5) to produce compound (4) is carried out with 1-iodo-2,4-dichlorobenzene or 1-bromo-2,4-dichlorobenzene, both of which are commercially available reactants. Advantageously, 1-bromo-2,4-dichlorobenzene is used as the α-arylation reactant.

[0050] This α-arylation step can be carried out in an organic solvent in the presence of a palladium derivative as a catalyst, a suitable ligand for α-arylation reaction, and a mineral base.

[0051] Advantageously, the α-arylation step is carried out in xylene, toluene, butyl acetate, isopropyl acetate or THF as organic solvent using palladium(II) acetate (Pd(OAc)2) or tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) as catalyst and Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) as ligand. Alternatively, when Pd2dba3 is used as catalyst, DPEpHos (bis[(2-diphenylphosphino)phenyl]ether) can be used as ligand. Another possible palladium derivative for the α-arylation step is [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dtbpf)). Advantageously, the α-arylation step is carried out in toluene as organic solvent and using Pd2dba3 as catalyst. Under these conditions, heating under reflux can be applied.

[0052] Advantageously, the α-arylation step is carried out in the presence of a mineral base, such as K2CO3, K3PO4, Cs2CO3 and tBuONa. The mineral base is advantageously present in excess relative to compound (5), such as 1.5 to 4 equivalents (eq), more particularly 2.5 to 4 equivalents.

[0053] In the methods provided herein, the Suzuki reaction applied to compound (3) to produce compound (2) is defined as a coupling reaction using an organoboron reagent and a transition metal-based catalyst, advantageously a palladium-based catalyst.

[0054] Advantageously, the organoboron reagent used in the Suzuki coupling step of the methods provided herein is reagent (1), i.e., (3S)-1-(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (which is described in patent application WO 2017 / 140669), or the corresponding acid (named reagent (2) as shown below obtained by hydrolysis of the ester portion of reagent (1)), or a salt thereof such as the potassium trifluoroborate salt obtained by salifying the boronic acid or ester portion of reagent (2) or (1) with potassium difluoride (KHF2) (named reagent (3) as shown below):

[0055]

[0056] The contents of patent application WO 2017 / 140669 regarding the preparation of (3S)-1-(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (reagent (1)) are incorporated herein by reference.

[0057] The organoboron reagent used in the Suzuki coupling step of the methods provided herein is advantageously used in an equimolar amount (ie, about 1 equivalent) relative to compound (3).

[0058] The palladium-based catalyst used in the Suzuki coupling step of the methods provided herein is advantageously the palladium complex bis(triphenylphosphine)palladium(II) dichloride of the formula PdCl2(PPh3)2.

[0059] It is used in a catalytic amount, for example, in an amount of about 0.05 equivalents.

[0060] Suitable reaction media for the Suzuki coupling step of the methods provided herein depend on the specific reagents used, as known to those skilled in the art.

[0061] When bis(triphenylphosphine)palladium(II) dichloride is used as a catalyst, the reaction is advantageously carried out with an inorganic base such as cesium carbonate (Cs2CO3) and in an organic solvent such as a water / acetonitrile (CH3CN) mixture.

[0062] In one embodiment of the methods provided herein, a salt-forming reaction can be performed after the Suzuki coupling step to obtain compound (2) in the form of a salt, advantageously in the form of an oxalate.

[0063] Thus, the Suzuki coupling step may be followed by a salt-forming reaction, for example to obtain the oxalate salt of compound (2) or the dibenzoyl tartaric acid salt of compound (2).

[0064] The oxalate of compound (2) herein can be obtained using oxalic acid in a solvent selected from an ester solvent (such as an acetate solvent, for example, ethyl acetate or isopropyl acetate), an ether solvent (such as MTBE (methyl tert-butyl ether) or diisopropyl ether), and toluene.

[0065] Advantageously, the oxalate salt of compound (2) is obtained using oxalic acid in isopropyl acetate under heating (eg at about 70°C).

[0066] The dibenzoyl tartaric acid salt of compound (2) can be obtained using dibenzoyl tartaric acid (also known as (2R,3R)-2,3-dibenzoyloxysuccinic acid) in toluene and heptane.

[0067] The term "salt formation" of the compound (2) as described above means formation of a salt, thereby allowing precipitation of the compound (2).

[0068] In particular for the oxalate salt, such a salt-forming step allows compound (2) to be recovered from the reaction mixture in high purity. It also allows the avoidance of the use of column chromatography for the recovery of compound (2) in high purity from the reaction mixture.

[0069] Such a synthetic route with salt formation is particularly convenient for industrial scale and storage of compound (2).

[0070] The dibenzoyl tartrate salt of compound (2) precipitated at a purity of about 93%, and the oxalate salt of compound (2) precipitated at a purity equal to or greater than 98%.

[0071] The present text also describes compound (2) in the form of an oxalate salt:

[0072]

[0073] The present text also describes compound (2) in the form of a dibenzoyltartrate salt:

[0074]

[0075] In view of the above description, an embodiment of the method provided herein for preparing compound (2) is represented in Scheme 1 below, wherein LG' and LG are as defined above:

[0076] Solution 1 :

[0077]

[0078] Another embodiment of the method provided herein for preparing compound (2) is represented in Scheme 2 below, wherein LG' is as defined above:

[0079] Solution 2 :

[0080]

[0081] Compound (2) can be subjected to a saponification reaction, whereby hydrolysis of the ester functional group will produce a compound (1) having a corresponding acidic functional group. Such saponification reactions can be carried out under conditions known to those skilled in the art, i.e. in an alkaline medium, advantageously using sodium hydroxide as a base, and in an organic solvent, advantageously an alcohol solvent, such as methanol. Heating is applied during the saponification reaction to accelerate the hydrolysis of the ester moiety (e.g., at about 60° C.). Such saponification reactions are described in patent application WO2017 / 140669.

[0082] When a salt form of the compound (2) is used, the free base of the compound (2) is prepared, for example, using an aqueous potassium carbonate solution, before conducting the saponification reaction.

[0083] The present invention also provides a method for preparing compound (1) or a pharmaceutically acceptable salt thereof:

[0084]

[0085] The method is carried out by saponification of compound (2):

[0086]

[0087] Wherein compound (2) is obtained by the above method.

[0088] Also provided herein are compounds (4), (3) and (3'), wherein LG represents a leaving group as described above:

[0089]

[0090] Compounds (4), (3) and (3') can be used as novel intermediates for preparing compound (2).

[0091] The method for preparing compound (2) provided herein is particularly advantageous for industrial implementation because it comprises fewer reaction steps than other methods for synthesizing compound (2) known to date (which are described in patent application WO 2017 / 140669).

[0092] Scheme 3 below illustrates the shortest method for synthesizing compound (2) described in WO 2017 / 140669. In Scheme 3, each intermediate is designated by the same name as provided in the international patent application. This method starting from the commercially available intermediate 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one as illustrated in Scheme 3 is designated as "Route A" hereinafter.

[0093] Solution 3 : Route A

[0094]

[0095] In route A illustrated in Scheme 3, compound (2) is obtained in 4 steps starting from 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylic acid methyl ester (the same compound as designated by "compound (5)" herein and "intermediate (A5)" in WO 2017 / 140669). Thus, compared to route A, the method for preparing compound (2) provided herein allows obtaining this compound in only 3 steps starting from 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylic acid methyl ester.

[0096] A second method for synthesizing compound (2) is described in WO 2017 / 140669, starting from the same intermediate 2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one and intermediate (A2) as in Scheme 3 above. This second method for synthesizing compound (2) is illustrated in Scheme 4 below, where each intermediate is designated by the same name as provided in patent application WO 2017 / 140669. This method in Scheme 4 is designated as "Route B" hereinafter.

[0097] Option 4: Route B

[0098]

[0099] Therefore, it seems that the method for preparing compound (2) in Scheme 4 requires more reaction steps than the method in Scheme 3.

[0100] Therefore, compared to both routes A and B as described in WO 2017 / 140669, the novel method for synthesizing compound (2) provided herein is shorter in terms of the number of steps.

[0101] Described below are examples of schemes for synthesizing compound (2) according to the novel synthetic methods provided herein.

[0102] Example 1: Preparation of organoboron derivative "reagent (1)"

[0103] The preparation of reagent (1), which is useful in the Suzuki coupling step of the method for synthesizing compound (2) as provided herein, is illustrated in Scheme 5 below, reproduced from patent application WO 2017 / 140669.

[0104] Solution 5 :

[0105]

[0106] According to Scheme 5, the commercially available compound (a) (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol) was condensed onto (R)-1-N-Boc-3-hydroxypyrrolidine using N,N,N',N'-tetramethyldiazodicarboxamide as a coupling agent in tetrahydrofuran (THF) at room temperature.

[0107] According to Step 2, the resulting compound (c) was N-deprotected in methanol (MeOH) at room temperature using an acidic reagent (e.g., a solution of HCl 4N in dioxane).

[0108] Then in Step 3, alkylation of the pyrrolidine nitrogen was carried out by reacting compound (d) with the corresponding 1,1-disubstituted 1-halo-3-fluoropropane (e.g., 1-iodo-3-fluoropropane) in acetonitrile in the presence of potassium carbonate (K2CO3) at about 40 °C.

[0109] Steps 1 to 3 of Scheme 5 are illustrated by the following detailed scheme.

[0110] 1H NMR spectra were recorded on a Bruker Avance DRX-400 spectrometer, where the chemical shift (δ, in ppm) in the reference solvent dimethyl sulfoxide-d6 (dDMSO-d6) at a temperature of 303 K was 2.50 ppm. The coupling constant (J) is given in Hertz. 1 Liquid chromatography / mass spectrometry (LC / MS) data were obtained on a UPLC Acquity Waters instrument, a Sedere light scattering detector, and an SQD Waters mass spectrometer using UV detection DAD 210 < l < 400 nm and a column Acquity UPLC CSH C18 1.7 μm, size 2.1 x 30 mm, with a mobile phase of H2O + 0.1% HCO2H / CH3CN + 0.1% HCO2H.

[0111] Compound (c). (3S)-3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1-carboxylic acid tert-butyl ester

[0112]

[0113] ​

[0114] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (82.7 g, 364.51 mmol) in THF (2 L) under argon was added (R)-1-N-Boc-3-hydroxypyrrolidine (b) (84.43 g, 437.41 mmol), followed by N,N,N',N'-tetramethylazodicarbonamide (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, while a triphenylphosphine oxide precipitate (Ph3P=O) was formed. The reaction mixture was poured into water (1.5 L) and extracted with ethyl acetate (AcOEt) (3x1.5 L). The collected organic phase was dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in diisopropyl ether (1.5 L) and the solid formed (Ph3P=O) was filtered. The solvent was concentrated under reduced pressure and the residue was purified by column chromatography eluting with a mixture of heptane and AcOEt (90 / 10; v / v) to give 145 g (100%) of (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1-carboxylic acid tert-butyl ester (c) as a colorless oil.

[0115] 1 H NMR (400MHz, DMSO-d6, δppm): 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 = 8.4Hz, 2H); 7.61 (d, J = 8.4Hz, 2H).

[0116] Compound (d). (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine, hydrochloride

[0117]

[0118] 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 slowly added HCl 4N in dioxane (250 ml).

[0119] After 1.5 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in Et2O with stirring to give a solid, which was then filtered and dried under vacuum to give Compound (d) 61.8 g (95%) as a white powder.

[0120] 1 H NMR (400MHz, DMSO-d6, δppm): 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 = 8.4Hz: 2H); 7.63 (d, J = 8.4Hz: 2H); 9.48 (s: 1H); 9.71 (s: 1H).

[0121] LC / MS (m / z, MH + ):290

[0122] Reagent (1). (3S)-1-(3-Fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine

[0123]

[0124] 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 KCO (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 dissolved 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.

[0125] 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).

[0126] LC / MS (m / z, MH + ):350

[0127] Example 2: Synthesis of Compound (2) from Carboxymethoxy-Benzocycloheptanone (5)

[0128] The numbering of the intermediates and final compounds (2), (3'), (4) and (5) refers to Scheme 2 described above.

[0129] 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 by palladium-catalyzed coupling of 1-bromo-2,4-dichloro-benzene in refluxing toluene and in the presence of potassium carbonate to give the 2,4-dichlorophenyl precursor (4) which is isolated as a Me-THF solution after silica gel filtration.

[0130] In the second step S2, a Me-THF solution of crude compound (4) is reacted with N-phenyl-bis-trifluoromethanesulfonimide in the presence of catalytic DBU and excess sodium hydride. After water washing and solvent exchange to acetonitrile, the desired trifluoromethanesulfonylated compound (3') is isolated by crystallization as a white solid.

[0131] In the third step S3, the cyclic enol triflate (3') is coupled with the chiral boronate "reagent (1)" as described earlier by a palladium-catalyzed Suzuki reaction in an acetonitrile / water mixture using cesium carbonate as a base at 40°C ± 3°C. After aqueous workup and solvent exchange with isopropyl acetate, residual palladium is removed by sequential ethylenediamine, charcoal, and dimercaptotriazine-grafted silica treatments. The crude oxalate salt of compound (2) is isolated by crystallization in isopropyl acetate.

[0132] The following detailed protocol illustrates these steps.

[0133] Performed on a 300 or 400 MHz Bruker Avance spectrometer 11H NMR spectrum, where the chemical shift (δ, in ppm) in the reference solvent dimethyl sulfoxide-d6 (dDMSO-d6) at a temperature of 303 K is 2.50 ppm. The coupling constant (J) is given in Hertz.

[0134] Liquid chromatography / mass spectrometry (LC / MS) data were obtained on a UPLC-SQD Waters instrument, an evaporative light scattering detector Sedere, and a SQD Waters mass spectrometer using UV detection DAD 210 < l < 400 nm and a column Acquity UPLC CSH C18 1.7 μm, size 2.1 x 50 mm, with the mobile phase H2O + 0.1% HCO2H / CH3CN + 0.1% HCO2H.

[0135] 2.1: Steps S1 and S2 in series

[0136] A degassed mixture of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (5) (40 g), potassium carbonate (K2CO3, 40 to 101 g, i.e., 1.5 to 4 equivalents), bromo-dichlorobenzene (62.1 g), Xantphos (21.2 g), and Pd2dba3 (8.39 g) in toluene (320 ml) was refluxed under nitrogen and with vigorous stirring until completion.

[0137] After cooling to room temperature, the insoluble material was removed by filtration over a silica pad (80 g), and then the filter was washed with toluene (600 ml). Toluene was distilled off from the filtrate and exchanged with Me-THF to obtain a solution of the α-arylated product (4) (methyl 6-(2,4-dichlorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo[7]annulene-2-carboxylate) in MeTHF (400 ml), which was used as such in the next step.

[0138] Samples of the pure product (4) were separated by preparative silica gel chromatography (eluent: dichloromethane - heptane).

[0139] For the separated compound (4) 1 1H NMR (400 MHz, DMSO-d6, in ppm): 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).

[0140] LC / MS ([M+H] + ):363

[0141] N,N-bis(trifluoromethylsulfonyl)aniline (80 g) was added to the Me-THF solution of compound (4) obtained in step S1 (scale: 40 g of compound (4)). The resulting solution was added dropwise to a suspension of NaH (10 g - 60% dispersion in oil) in Me-THF (200 ml) containing DBU (5 ml) at 0°C under stirring. The reaction mixture was stirred at room temperature until completion.

[0142] After being cooled to 0 ℃, acetic acid (4ml) is added dropwise, and then water (400ml) is added dropwise. The aqueous phase is separated at room temperature, and the organic phase is washed with a diluted sodium chloride aqueous solution (NaCl, 0.6M; 3x 400ml). Me-THF is distilled off and exchanged with acetonitrile. After filtering and removing insoluble matter in hot acetonitrile, compound (3') (6-(2,4-dichlorophenyl)-5-(trifluoromethylsulfonyloxy)-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid methyl ester) is crystallized in 250ml acetonitrile, separated by filtration and washed with cold acetonitrile and heptane to obtain 61.2g of pure trifluoromethanesulfonate as a white solid.

[0143] Yield: 67.4% (in 2 steps S1 and S2).

[0144] 1 H 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).

[0145] LC / MS(EI m / z):494 +

[0146] Purity of compound (3'): 99.0% as measured by HPLC:

[0147] .Mobile phase: water / acetonitrile / HCOOH;

[0148] .Stationary phase: XSelect CSH C18-3.5μm (Waters) or equivalent;

[0149] .Column length: 100mm;

[0150] .Column inner diameter: 4.6mm;

[0151] .Flow rate: 1mL / min;

[0152] .Injection volume: 10μL;

[0153] .Detection: 254nm (UV).

[0154] 2.2: Step S3

[0155] A degassed mixture of trifluoromethanesulfonate (3') (20 g), boronate "reagent (1)" (14.1 g), Cs2CO3 (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, isopropyl acetate (100 ml) is added and the aqueous phase is separated. The organic phase is washed with a dilute aqueous NaCl solution (0.3 M; 2×200 ml), dried by azeotropic distillation of isopropyl acetate and subsequently treated with ethylenediamine, charcoal and dithiothiotriazine-grafted silica to remove residual palladium.

[0156] A solution of the obtained compound (2) (i.e., 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 isopropyl acetate (adjusted to 200 ml) was heated to 70° C., and a solution of oxalic acid (3.6 g) in isopropyl acetate (43 ml) was added dropwise with stirring. After seeding (using seed crystals previously prepared in another batch by conventional crystallization techniques) and cooling to 0° C., the oxalate of the desired compound (2) depicted below was crystallized and isolated by filtration in a yield of 70% (18.6 g, white powder):

[0157]

[0158] 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).

[0159] LC / MS ([M+H] + ):568

[0160] Purity of compound (2) oxalate: 98.2%, measured by HPLC under the same conditions as described above in step S2.

[0161] Example 3: Alternative to step S1

[0162] 3.1: Alternative 1

[0163] A 2M THF solution of sodium tert-butoxide (19.48 ml) was 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 was heated at 60° C. until completion, cooled to room temperature and quenched with a molar aqueous solution of KH2PO4. After extraction with ethyl acetate, washing with water and purification by silica gel chromatography, compound (4) was isolated with a yield of 70% and a purity of 92%.

[0164] 1H NMR (400MHz, 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 (d d,J=11.3,3.6Hz,1H); 7.47(m,2H); 7.61(d,J=1.8Hz,1H); 7.65(d,J=7.9Hz,1H); 7.92(d,J=7.7Hz,1H); 7.95(s,1H).

[0165] LC / MS ([M+H] + ):363

[0166] 3.2: Alternative 2

[0167] A degassed mixture containing compound (5) (0.5 g), 1-iodo-2,4-dichlorobenzene (0.76 ml), toluene (9 ml), water (1 ml), Cs2CO3 (1.05 g), palladium acetate (50 mg) and Xantphos (250 mg) was heated to reflux over about 22 hours. After cooling to room temperature, the organic phase was diluted with dichloromethane, washed with water and purified by silica gel chromatography to give 730 mg (87%) of a white solid.

[0168] 1 H 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).

[0169] Example 4: Alternative to step S2

[0170] 3.1: Alternative 1

[0171] A 0.5 M THF solution of potassium bis-trimethylsilylamide (7.70 ml) was added dropwise to a mixture of compound (4) (1 g) and N-phenylbis-trifluoromethanesulfonimide (1.22 g) in THF (18 ml) at -50° C. After warming to room temperature, the reaction medium was quenched with water at 0° C.-5° C., extracted with dichloromethane and then with ethyl acetate, and purified by silica gel chromatography (eluent: dichloromethane-heptane) to give the desired compound (3′) in a yield of 80% and a purity of 90% as measured by LC / MS.

[0172] 1 H 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).

[0173] LC / MS ([M+H] + ):494

[0174] 3.2: Alternative 2

[0175] DBU (247 μl) was added dropwise at 0°C-5°C to a suspension containing compound (4) (500 mg) and N,N-bis(trifluoromethylsulfonyl)aniline (639 mg) in acetonitrile (2 ml). After stirring at room temperature for 22 hours, the conversion was about 80%. The reaction mixture was cooled to 0°C-5°C and sodium hydride (27.5 mg, 60% dispersion in oil) was added. After stirring at room temperature for 1.5 hours, the conversion was about 100%. The resulting suspension was cooled to 0°C-5°C, filtered and washed with pre-cooled acetonitrile (0.5 ml), then washed with water (2 ml) to obtain 460 mg of compound (3') as a white powder (yield: 67.5%), with a purity of 98% measured by LC / MS.

[0176] 1 H 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).

[0177] As shown in the above examples, the novel synthesis method of compound (2) provided herein allows for an overall yield of about 33%-49% from compound (5) to compound (2). This is higher than the yield found in the previously described synthesis method as described in Scheme 3, in which the yield of compound (2) was about 26% when starting from the same compound 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylic acid methyl ester.

[0178] Furthermore, the novel synthetic method provided herein allows obtaining compound (2) in good yields without the need for column chromatography after the Suzuki coupling step, which is required in previously known synthetic routes but is inappropriate when seeking synthetic routes applicable on an industrial level.

Claims

1. A method for preparing compound (2) in base form or in salt form: Features Compound (2) is obtained by Suzuki coupling of compound (3) with an organoboron reagent, optionally followed by a salt-forming reaction. wherein LG represents a leaving group, which is a triflate group, The organic boron reagent is (3S)-1-(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine, a corresponding acid or a salt thereof.

2. The method according to claim 1, wherein the organoboron reagent is selected from reagent (2) and reagent (3):

3. The method according to claim 1 or 2, wherein the Suzuki coupling is performed in the presence of a palladium complex.

4. The method of claim 3, wherein the palladium complex is bis(triphenylphosphine)palladium(II) dichloride.

5. The method according to claim 1 or 2, wherein the Suzuki coupling is carried out in an organic solvent in the presence of bis(triphenylphosphine)palladium(II) dichloride and cesium carbonate.

6. The method according to claim 1 or 2, wherein the compound (2) is prepared in the form of oxalate by performing a salt-forming reaction after the Suzuki coupling.

7. The process according to claim 6, wherein the oxalate of the compound (2) is obtained using oxalic acid in isopropyl acetate.

8. The method according to claim 1, wherein compound (3) is obtained by activating compound (4) with a leaving group LG:

9. The method according to claim 8, wherein compound (4) is activated to compound (3') using a trifluoromethanesulfonylating agent:

10. The process according to claim 9, wherein sodium hydride is used as a strong base and DBU is used as a catalyst.

11. The process according to claim 9 or 10, wherein N-phenylbistrifluoromethanesulfonimide is used as triflating agent in Me-THF as organic solvent.

12. The process according to any one of claims 8 to 10, wherein compound (4) is obtained by α-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.

13. The method according to claim 12, wherein the leaving group LG' is a halogen atom selected from bromine or iodine.

14. The method according to claim 12, wherein the α-arylation is carried out in an organic solvent in the presence of a palladium derivative as a catalyst, a ligand and a mineral base.

15. The method of claim 14, wherein the palladium derivative is Pd(OAc)2 or Pd2dba3.

16. The method of claim 14, wherein the mineral base is K2CO3, K3PO4, Cs2CO3 or tBuONa.

17. The process according to claim 14, wherein the α-arylation is carried out in toluene in the presence of Pd2dba3 as catalyst and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene as ligand.

18. A method for preparing compound (1) or a pharmaceutically acceptable salt thereof: The method is carried out by saponification of compound (2): Features Compound (2) is obtained by the method according to any one of claims 1 to 17.

19. Compounds (4) and (3), wherein LG represents a leaving group which is a triflate group:

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