Salt 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 methyl ester and preparation method thereof

Abstract

Provided herein are novel salts 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, namely, oxalate (I) and dibenzoyltartrate (II).

Description

[0001] Provided herein are novel salts 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.

[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] Provided herein is a novel salt form of compound (2), namely the oxalate salt of said compound:

[0007]

[0008] and dibenzoyl tartrate:

[0009]

[0010] Also provided herein is a method for preparing the salt form of the above compound (2), namely:

[0011] - a method for preparing an oxalate of compound (2), the method comprising the steps of: adding oxalic acid to the compound (2) in a solvent selected from an ester solvent, an ether solvent and toluene; and

[0012] - A process for preparing a dibenzoyl tartaric acid salt of compound (2), said process comprising the step of adding dibenzoyl tartaric acid to said compound in a mixture of toluene and heptane.

[0013] The salts according to the invention are particularly useful in the framework of the preparation of compound (1) as defined above. The advantages of the salts will be apparent from the detailed description of the process.

[0014] The salts according to the present invention can be obtained according to the preparation methods described in detail below.

[0015] WO 2017 / 140669 Route

[0016] In particular, the salts according to the invention can be obtained following the synthetic route as described in patent application WO 2017 / 140669, as shown below in Schemes 3 and 4. The steps prior to obtaining the salts are represented by the scheme below.

[0017]

[0018] Said step may be followed by a salt formation step as described in detail below.

[0019] Example 5 of the present application starts from intermediate (D5) to form compound (2) as defined above via Suzuki coupling, which itself is used to form a salt of compound (2).

[0020] Alternatively, as an improved method described in detail below, the salt according to the present invention can be obtained by a salt-forming step after Suzuki coupling in the framework of the preparation of compound (2).

[0021] Improved methods

[0022] The present invention describes a method for preparing compound (2) (methyl ester of compound (1)) in salt form (achieving the above-mentioned salt form):

[0023]

[0024] The method is characterized in that compound (2) can be obtained by Suzuki coupling of compound (3) (wherein LG represents a leaving group) with an organic boron reagent:

[0025]

[0026] Then the salt-forming reaction is carried out.

[0027] The compound (3) as described above can be obtained by activating the compound (4) with a leaving group LG:

[0028]

[0029] Compound (4) as described above can be obtained by α-arylation of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (hereinafter referred to as compound (5)) using 1-LG'-2,4-dichlorobenzene as defined below:

[0030]

[0031] LG' represents any leaving group.

[0032] LG' can represent

[0033] Formula-O-SO 2 -C n F (2n+1) wherein n=1 to 4, more particularly trifluoromethanesulfonate (where n=1) or nonafluorobutanesulfonate (where n=4), or

[0034] A halogen atom selected from bromine or iodine.

[0035] 1-LG'-2,4-dichlorobenzene may be 1-Hal-2,4-dichlorobenzene, wherein Hal represents a halogen atom selected from bromine or iodine:

[0036] Leaving groups LG and LG' are defined as chemical moieties that exhibit leaving group characteristics and allow for further substitution in subsequent chemical reactions.

[0037] More specifically, the leaving group LG in compound (3) can be 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.

[0038] 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.

[0039] The leaving group LG may be a halogen atom or a mesylate, tosylate, sulfamate, phosphate, triflate or nonafluorobutanesulfonate group.

[0040] The leaving group in compound (3) may be a halogen atom or a mesylate, tosylate, sulfamate, phosphate or triflate group.

[0041] The leaving group LG may be a triflate or nonafluorobutanesulfonate group.

[0042] Advantageously, the leaving group LG is a triflate group (trifluoromethanesulfonyl, corresponding to the formula -OS(O) 2 -CF 3 ).

[0043] In the context of this specification, unless otherwise mentioned throughout the specification, the following terms have the following definitions:

[0044] -Alkyl: an aliphatic radical based on a straight or branched saturated hydrocarbon containing (unless otherwise specified) 1 to 6 carbon atoms (denoted by "(C 1 -C 6 )-alkyl"). As examples, there can be mentioned, but not limited to: methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl, etc. The groups may be partially or completely substituted with fluorine atoms and include, but are not limited to, perfluoromethyl, perfluoroethyl, perfluoropropyl, perfluorobutyl, etc.;

[0045] -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.

[0046] Compound (4) can be activated to compound (3'), wherein compound (3') is defined as compound (3) wherein LG represents a triflate group. Activation of compound (4) to compound (3') is a triflation reaction:

[0047]

[0048] In such reactions, a triflation agent is used, such as N-phenylbistrifluoromethanesulfonimide or trifluoromethanesulfonic anhydride.

[0049] 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).

[0050] Suitable triflation media depend on the triflation reagent used, as known to those skilled in the art.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] The α-arylation of compound (5) to produce compound (4) can be 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.

[0058] 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.

[0059] Advantageously, the α-arylation step can be carried out using palladium(II) acetate (Pd(OAc)) in xylene, toluene, butyl acetate, isopropyl acetate or THF as organic solvent. 2 ) or tris(dibenzylideneacetone)dipalladium(0)(Pd 2 dba 3 ) as catalyst and Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) as ligand. 2 dba 3 When used as a catalyst, DPEPhos (bis[(2-diphenylphosphino)phenyl]ether) can be used as a ligand. Another possible palladium derivative for the α-arylation step is [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (PdCl 2 Advantageously, the α-arylation step can be carried out in toluene as organic solvent and with Pd 2 dba 3 As a catalyst. Under these conditions, heating under reflux can be applied.

[0060] Advantageously, the α-arylation step can be carried out in the presence of a mineral base, such as K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 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 eq.

[0061] The Suzuki reaction applied to compound (3) to produce compound (2) can be defined as a coupling reaction using an organoboron reagent and a transition metal-based catalyst, advantageously a palladium-based catalyst.

[0062] Advantageously, the organoboron reagent used in the Suzuki coupling step of the process described herein may be 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 part of reagent (1), or a salt thereof such as by reacting with potassium dihydrogen fluoride (KHF 2 ) Potassium trifluoroborate salt obtained by salifying the boronic acid or ester portion of reagent (2) or (1) (named reagent (3) as shown below):

[0063]

[0064] 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.

[0065] The organoboron reagent used in the Suzuki coupling step of the methods described herein may advantageously be used in an equimolar amount (ie, about 1 equivalent) relative to compound (3).

[0066] The palladium-based catalyst used in the Suzuki coupling step of the process described herein may advantageously be of the formula PdCl 2 (PPh 3 ) 2 The palladium complex of bis(triphenylphosphine)palladium(II) dichloride.

[0067] It is used in a catalytic amount, for example, in an amount of about 0.05 equivalents.

[0068] Suitable reaction media for use in the Suzuki coupling step of the methods described herein depend on the specific reagents used, as known to those skilled in the art.

[0069] When bis(triphenylphosphine)palladium(II) dichloride is used as a catalyst, the reaction can be advantageously carried out with an inorganic base such as cesium carbonate (Cs 2 CO 3 )) and in an organic solvent such as water / acetonitrile (CH 3 CN) mixture).

[0070] Salt formation step

[0071] The salt formation step as described below can be implemented for two synthetic routes (WO 2017 / 140669 and the improved route).

[0072] Prior to such a salt-forming step, both routes involve a Suzuki coupling step.

[0073] Still within the framework of the preparation of compound (2), the Suzuki coupling step can be followed by a salt-forming reaction in order to obtain compound (2) according to the invention in the form of a salt, advantageously in the form of an oxalate or a dibenzoyltartrate.

[0074] Thus, the Suzuki coupling 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).

[0075] The oxalate of compound (2) provided 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.

[0076] Advantageously, the oxalate salt of compound (2) can be obtained using oxalic acid in isopropyl acetate under heating (eg between 60°C and 80°C, preferably at about 70°C).

[0077] Said method forms part of the present invention.

[0078] Therefore, the present invention further provides a method for preparing an oxalate of compound (2), the method comprising the following steps: adding oxalic acid to compound (2) in a solvent selected from an ester solvent, an ether solvent and toluene.

[0079] In a specific embodiment, the ester solvent is an acetate solvent, in particular ethyl acetate or isopropyl acetate, more in particular isopropyl acetate.

[0080] In another embodiment, the ether solvent is selected from methyl tert-butyl ether and diisopropyl ether.

[0081] In a specific embodiment, the process for preparing the oxalate salt of compound (2) is carried out in isopropyl acetate under heating (particularly between 60°C and 80°C, more particularly at 70°C).

[0082] The dibenzoyl tartrate salt of compound (2) provided herein can be obtained using dibenzoyl tartaric acid (also known as (2R,3R)-2,3-dibenzoyloxysuccinic acid) in a mixture of toluene and heptane.

[0083] Said method forms part of the present invention.

[0084] Therefore, the present invention further provides a process for preparing a dibenzoyl tartaric acid salt of compound (2), said process comprising the step of adding dibenzoyl tartaric acid to compound (2) in a mixture of toluene and heptane.

[0085] The term "salt formation" of the compound (2) as described above means formation of a salt, thereby allowing precipitation of the compound (2).

[0086] 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.

[0087] Such a synthetic route with salt formation is particularly convenient for industrial scale and storage of compound (2).

[0088] Example 6 of the present application illustrates suitable solvents for various methods of obtaining the claimed salts.

[0089] 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%.

[0090] In view of the above description, the method described herein for preparing compound (2) is represented in Scheme 1 below, wherein LG' and LG are as defined above:

[0091] Solution 1 :

[0092]

[0093] The process described herein for preparing compound (2) is also represented in Scheme 2 below, wherein LG' is as defined above:

[0094] Solution 2 :

[0095]

[0096] 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.

[0097] 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.

[0098] Also described herein is a method for preparing compound (1):

[0099]

[0100] The method is carried out by saponification of compound (2):

[0101]

[0102] Wherein compound (2) is obtained by the above method.

[0103] Also disclosed herein are compounds (4), (3) and (3'), wherein LG represents a leaving group as described above:

[0104]

[0105] Compounds (4), (3) and (3') can be used as novel intermediates for preparing compound (2).

[0106] The method for preparing compound (2) described 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.

[0107] 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.

[0108] Solution 3 : Route A

[0109]

[0110] 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 designated as "compound (5)" herein and "intermediate (A5)" in WO 2017 / 140669). Thus, compared to route A, the process for preparing compound (2) described 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.

[0111] 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.

[0112] Solution 4 : Route B

[0113]

[0114] Therefore, it seems that the method for preparing compound (2) in Scheme 4 requires more reaction steps than the method in Scheme 3.

[0115] Therefore, compared to both routes A and B as described in WO 2017 / 140669, the method for synthesizing compound (2) described herein is shorter in terms of the number of steps.

[0116] Described below are examples of protocols for synthesizing salts of compound (2) according to the synthetic methods described herein.

[0117] Example 1: Preparation of organoboron derivative "reagent (1)"

[0118] The preparation of reagent (1) useful in the Suzuki coupling step of the process for synthesizing compound (2) as described herein is illustrated in Scheme 5 below, reproduced from patent application WO 2017 / 140669.

[0119] Solution 5 :

[0120]

[0121] According to Scheme 5, commercially available compound (a) (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol) was condensed on (R)-1-N-Boc-3-hydroxypyrrolidine using N,N,N',N'-tetramethylazodicarbonamide as coupling agent in tetrahydrofuran (THF) at room temperature.

[0122] According to step 2, the compound (c) thus obtained is N-deprotected in methanol (MeOH) at room temperature using an acidic reagent (eg HCl 4N in dioxane).

[0123] Then in step 3, the reaction mixture is reacted with potassium carbonate (K 2 CO 3 ) is reacted with the corresponding 1,1-disubstituted 1-halo-3-fluoropropane (eg 1-iodo-3-fluoropropane) in acetonitrile to effect alkylation of the pyrrolidine nitrogen.

[0124] Steps 1 to 3 of Scheme 5 are illustrated by the following detailed scheme.

[0125] The spectrometer was used to analyze the 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.

[0126] 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 H 2 O + 0.1% HCO 2 H / CH 3 CN + 0.1% HCO 2 H.

[0127] Compound (c). (3S)-3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1-carboxylic acid tert-butyl ester

[0128]

[0129] Under argon, (R)-1-N-Boc-3-hydroxypyrrolidine (b) (84.43 g, 437.41 mmol) was added 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), followed by N,N,N',N'-tetramethyldiazodicarboxamide (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 forming a precipitate of triphenylphosphine oxide (Ph 3 P=O). The reaction mixture was poured into water (1.5 L) and extracted with ethyl acetate (AcOEt) (3 x 1.5 L). The collected organic phase was dried over magnesium sulfate (MgSO 4 )), filtered, and concentrated under reduced pressure. The residue was dissolved in diisopropyl ether (1.5 L), and the solid formed (Ph 3 P=O) was filtered off. 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.

[0130] 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).

[0131] Compound (d). (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine, hydrochloride

[0132]

[0133] 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).

[0134] After 1.5 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in Et 2 O to give a solid, which was then filtered and dried under vacuum to give 61.8 g (95%) of compound (d) as a white powder.

[0135] 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).

[0136] LC / MS (m / z, MH + ):290

[0137] Reagent (1). (3S)-1-(3-Fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine

[0138]

[0139] 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 2 CO 3 To the mixture of 4-(2-(2-iodo-3-fluoropropane)-1-ol (21.22 g, 153.54 mmol) and 1-iodo-3-fluoropropane (12.15 g, 61.42 mmol). 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 formed solid was filtered and washed with DCM. The filtrate was concentrated to give a reagent (1) 21.5 g (100%) in the form of yellow foam.

[0140] 1 H 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).

[0141] LC / MS (m / z, MH + ):350

[0142] Example 2: Synthesis of Compound (2) from Carboxymethoxy-Benzocycloheptanone (5)

[0143] The numbering of the intermediates and final compounds (2), (3'), (4) and (5) refers to Scheme 2 described above.

[0144] 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.

[0145] 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.

[0146] In the third step S3, the cyclic enol triflate (3') is coupled with the chiral borate "reagent (1)" as described earlier by a palladium-catalyzed Suzuki reaction using cesium carbonate as the base in an acetonitrile / water mixture at 40 °C ± 3 °C. After aqueous workup and solvent exchange with isopropyl acetate, residual palladium is removed by sequential treatment with ethylenediamine, charcoal, and silica grafted with dithiocyanuric acid. The oxalate of the crude compound (2) is isolated by crystallization from isopropyl acetate.

[0147] The following detailed protocol illustrates these steps.

[0148] 1H NMR spectra were recorded on a 300 or 400 MHz Bruker Avance 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. Coupling constants (J) are given in Hertz. 1 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 column Acquity UPLC CSH C18 1.7 μm, size 2.1 x 50 mm, mobile phase H

[0149] 2O + 0.1% HCO 2 H / CH 2 CN + 0.1% HCO 3 H. 2

[0150] 2.1: Sequential steps S1 and S2

[0151] 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), bromodichlorobenzene (62.1 g), Xantphos (21.2 g), and Pd2dba3 (8.39 g) in toluene (320 ml) is refluxed under nitrogen and with vigorous stirring until complete.

[0152] ​After cooling to room temperature, the insoluble material was removed by filtration on a silica pad (80 g), and the filter was then washed with toluene (600 ml). Toluene was distilled off from the filtrate and exchanged with Me-THF to give 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 is in the next step.

[0153] A sample of the pure product (4) was isolated by silica gel chromatography (eluent: dichloromethane-heptane) in an aliquot.

[0154] The isolated compound (4) 1 H 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).

[0155] LC / MS ([M+H] + ):363

[0156] 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.

[0157] 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; 3x400ml). 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.

[0158] Yield: 67.4% (in 2 steps S1 and S2).

[0159] 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).

[0160] LC / MS(EI m / z):494 +

[0161] Purity of compound (3'): 99.0% as measured by HPLC:

[0162] .Mobile phase: water / acetonitrile / HCOOH;

[0163] .Stationary phase: XSelect CSH C18-3.5μm (Waters) or equivalent;

[0164] .Column length: 100mm;

[0165] .Column inner diameter: 4.6mm;

[0166] .Flow rate: 1mL / min;

[0167] .Injection volume: 10μL;

[0168] .Detection: 254nm (UV).

[0169] 2.2: Step S3

[0170] Triflate (3') (20 g), borate "reagent (1)" (14.1 g), Cs 2 CO 3 A degassed mixture of (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.

[0171] 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):

[0172]

[0173] 1 H 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).

[0174] LC / MS ([M+H] + ):568

[0175] Purity of compound (2) oxalate: 98.2%, measured by HPLC under the same conditions as described above in step S2.

[0176] Example 3: Alternative to step S1

[0177] 3.1: Alternative 1

[0178] 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 treated with KH 2 PO 4 The molar aqueous solution was quenched.After ethyl acetate extraction, water washing and purification by silica gel chromatography, compound (4) was isolated in 70% yield and 92% purity.

[0179] 1 H 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).

[0180] LC / MS ([M+H] + ):363

[0181] 3.2: Alternative 2

[0182] A mixture containing compound (5) (0.5 g), 1-iodo-2,4-dichlorobenzene (0.76 ml), toluene (9 ml), water (1 ml), Cs 2 CO 3 A degassed mixture of (1.05 g), palladium acetate (50 mg) and Xantphos (250 mg) was heated to reflux for 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.

[0183] 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).

[0184] Example 4: Alternative to step S2

[0185] 3.1: Alternative 1

[0186] 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.

[0187] 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).

[0188] LC / MS ([M+H] + ):494

[0189] 3.2: Alternative 2

[0190] 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.

[0191] 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).

[0192] As shown in the above examples, the synthesis methods of the salts of compound (2) described herein allow for an overall yield of about 33% to 49% from compound (5) to compound (2). This is higher than the yield found in the previously described synthesis method as illustrated 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.

[0193] Furthermore, the synthetic method described herein allows obtaining compound (2) in the form of a novel salt in good yield without the need for column chromatography after the Suzuki coupling step, which is required in previously known synthetic routes involving the base form of compound (2) but is inappropriate when seeking a synthetic route applicable on an industrial level.

[0194] Example 5: Synthesis of Compound (2) in the form of dibenzoyl tartrate

[0195] 8-Bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid methyl ester hydrobromide (25.0 g), 2,4-dichlorophenylboronic acid (9.9 g), K 2 CO 3A degassed mixture of (11.9 g), bis(triphenylphosphine)palladium(II) dichloride (1.4 g), water (75 ml) and 1,4-dioxane (206 ml) is stirred at 60° C. under nitrogen. 2,4-Dichlorophenylboronic acid (9.9 g) is then dissolved in a mixture of water and 1,4-dioxane (25 ml) and added. After complete conversion, the reaction medium is cooled to room temperature and pyrrolidine dithiocarbamate (1.4 g) in water (50 ml) is added. The mixture is stirred at 20° C. and filtered. The filter is washed with toluene and the aqueous phase is separated. The organic phase is washed with a dilute aqueous NaCl solution (2 M, 3×75 ml). Charcoal (2.5 g) and Al are then added at 20° C. 2 O 3 (50.1 g). The mixture was filtered and the filter was washed with toluene (3 x 50 ml). The organic phase was concentrated to 1.8 volumes in order to remove a portion of the 1,4-dioxane.

[0196] (-) dibenzoyltartaric acid (15.4 g) was added to the obtained solution of compound (2) (i.e., 6-(2,4-dichlorophenyl)-5-{4-[1-(3-fluoropropyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-carboxylic acid methyl ester). n-Heptane (300 ml) was added dropwise at 20° C. with stirring. The dibenzoyltartaric acid salt of compound (2) was isolated by filtration with a yield of 85% (43.3 g).

[0197] RMN 1 H(400MHz,DMSO-d 6 , in ppm): 1,82-1,98 (m, 3H); 2,09-2,30 (m, 5H); 2,89-3,22 (m, 7H); 3,39 (m, 1H); 3,86 (s, 3H); 4,39 (td, J = 5,9 and 47,4 Hz, 2H); 4,87 (m, 1H); 5,76 (s, 2H); 6,67 (d, J = 8,9 Hz, 2H); 6,75 (d, J = 8,9 Hz, 2H); 6,90 (d, J = 8,1 Hz, 1H); 7,20 (d , J=8,4Hz,1H); 7,29(dd, J=2,0 and 8,4Hz,1H); 7,54(t, J=7,9Hz,4H); 7,60(d, J=2,0Hz,1H); 7,68(tt, J=1,3 and 7,9Hz,2H); 7,79(dd, J=1,8 and 8,1Hz,1H); 7,96(d, J=1,8Hz,1H); 7,98(t, J=7,9Hz,4H); 10,70(m extended,1H); 13,00(m extended,1H).

[0198] Liquid chromatography / mass spectrometry (LC / MS) data were obtained as follows:

[0199] Mass spectrometry data

[0200] M + =568g.mol-1

[0201] M'(salt)=358g.mol-1

[0202] Mass spectrometer: Waters UPLC-SQD, electrospray ionization (ES+ / -)

[0203] Chromatographic conditions:

[0204] ·Column: ACQUITY UPLC CSH C18-1,7μm-2,1x50mm

[0205] Solvent: A: H2O (+0,1% formic acid) B: CH3CN (+0,1% formic acid)

[0206] Column temperature: 45°C

[0207] Rate: 0,85ml / min

[0208] Gradient (2.5 min): 5% to 100% B in 2.5 min; 100% B in 2.40 min; 100% to 5% B in 0.05 min

[0209] UV: from 190nm to 380nm

[0210] result:

[0211] At 1.12 min (UV purity 31%): ES-(corresponding to [M'-H] - ), m / z=357

[0212] At 1.17 min (UV purity 67%): ES+ (corresponding to [M] + ), m / z=568

[0213] Purity of compound (2) dibenzoyl tartaric acid salt: 93.2% as measured by HPLC.

[0214] Example 6: Salt formation study of compound (2)

[0215] The oxalate and dibenzoyl tartrate salts of compound (2) are particularly advantageous because they precipitate and crystallize from the reaction medium, thereby allowing the salt of compound (2) to be recovered from the reaction medium. Regardless of the solvent and temperature tested, the base form of compound (2) does not allow the product to be separated from the reaction medium. Of the various salts tested with compound (2), the oxalate and dibenzoyl tartrate salts were the only salts that allowed significant precipitation, as shown in Table 1 below.

[0216] Table 1: Salt formation studies for compound (2) on a scale of 0,25 g of base form and used at a temperature of 20°C

[0217]

[0218]

Claims

1. An oxalate of 6-(2,4-dichlorophenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-carboxylic acid methyl ester of the following formula:

2. A dibenzoyl tartrate salt of 6-(2,4-dichlorophenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-carboxylic acid methyl ester of the following formula:

3. A method for preparing the salt according to claim 1, comprising the following steps: Oxalic acid is added to the compound (2) of the following formula in a solvent, The solvent is selected from ethyl acetate, isopropyl acetate, methyl tert-butyl ether or toluene.

4. The method according to claim 3, wherein the solvent is isopropyl acetate.

5. The process according to claim 4, wherein the process is carried out in isopropyl acetate under heating.

6. The process of claim 4, wherein the process is carried out in isopropyl acetate at between 60°C and 80°C.

7. The process according to claim 6, wherein the process is carried out in isopropyl acetate at 70°C.

8. A method for preparing the salt according to claim 2, comprising the following steps: Dibenzoyltartaric acid is added to a toluene solution of the compound (2) of the following formula: Then n-heptane was added dropwise at 20°C with stirring.

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