New synthesis method of piperazinyl-ethoxy-bromophenyl derivatives and their use in producing compounds containing them

Abstract

A process for the industrial synthesis of compounds of formula (I).

Description

[0001] The present invention relates to a novel process for preparing piperazinyl-ethoxybromophenyl and piperazinyl-ethoxyphenylboronic acid derivatives and their use in producing compounds containing them.

[0002] More specifically, the present invention relates to a novel process for preparing 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine and 1-{2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl}-4-methylpiperazine and their use in producing compounds containing them.

[0003] Even more specifically, the present invention relates to a novel process for preparing 1-{2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl}-4-methylpiperazine and its application in the production of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]methoxy}phenyl) The invention relates to the use of propionic acid (referred to herein as 'Compound 1') and 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid (referred to herein as 'Compound 2').

[0004] In particular, the present invention relates to a process for preparing piperazinyl-ethoxybromophenyl compounds of formula (I):

[0005]

[0006] in:

[0007] ◆R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group,

[0008] ◆R3 represents a linear or branched (C1-C6) alkyl group.

[0009] In particular, the present invention relates to a process for preparing a compound of formula (I), wherein:

[0010] ◆ R1 and R2 independently represent a halogen atom or a linear or branched (C1-C6) alkyl group,

[0011] ◆R3 represents a linear or branched (C1-C6) alkyl group.

[0012] The present invention also relates to a method for preparing a piperazinyl-ethoxyphenylboronic acid compound of formula (II):

[0013]

[0014] in:

[0015] ◆R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group,

[0016] ◆R3 represents a straight chain or branched (C1-C6) alkyl group,

[0017] ◆R4 and R5 represent hydrogen, a linear or branched (C1-C6) alkyl group, or R4 and R5 together with the oxygen atom carrying them form a ring which may be substituted by one to four linear or branched (C1-C6) alkyl groups.

[0018] In particular, the present invention relates to a process for preparing a compound of formula (II), wherein:

[0019] ◆ R1 and R2 independently represent a halogen atom or a linear or branched (C1-C6) alkyl group,

[0020] ◆R3 represents a straight chain or branched (C1-C6) alkyl group,

[0021] ◆R4 and R5 represent hydrogen, a linear or branched (C1-C6) alkyl group, or R4 and R5 together with the oxygen atom carrying them form a ring which may be substituted by one to four linear or branched (C1-C6) alkyl groups.

[0022] More particularly, the present invention relates to a process for preparing 1-{2-[2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl}-4-methylpiperazine of formula (III):

[0023]

[0024] The compounds of formula (I), (II) and (III) obtained according to the method of the present invention can be used to synthesize compound 1 or compound 2 and their analogs with similar structures.

[0025] Specifically, compounds 1 and 2 have pro-apoptotic properties, notably, they are able to inhibit Mcl-1 protein (Mcl-1 protein is an anti-apoptotic Bcl-2 family member overexpressed in various types of cancer), making it possible to use compounds 1 and 2 in pathological conditions involving apoptotic defects, such as in the treatment of cancer and in the treatment of immune and autoimmune diseases.

[0026] Considering the pharmaceutical value of these compounds, it is important to be able to obtain them by an efficient synthetic method that can be easily converted to industrial scale and produces compound 1 or compound 2 in high yield and excellent purity starting from economical and readily available starting materials.

[0027] The preparation of compound 1 and its pharmacological effects on various cancer models are described in the literature (Kotschy et al., Nature 2016, 538, 477-482 and corresponding supplementary information, which are incorporated herein by reference). Moreover, WO 2015 / 097123 describes compound 1, compound 2 and structurally similar analogs thereof, their preparation, their use as Mcl-1 inhibitors for treating cancer and their pharmaceutical preparations. In particular, the preparation 5b of WO 2015 / 097123 specifically discloses a method for synthesizing a compound of formula (III), wherein the compound of formula (III) is obtained from 4-bromo-2-chloro-phenol in five steps. Recently, CN 107573360 also discloses an alternative method for preparing a compound of formula (III) in five steps from 4-bromo-2-chlorophenol. In addition, the compound of formula (III) and its preparation are also specifically disclosed in WO 2016 / 207226, WO 2016 / 207217, WO 2016 / 207216 and WO 2017 / 125224. However, when transferred to industrial scale, the difficulties of implementing the method soon became apparent: in particular, the risk of using highly flammable and potentially explosive reagents in the protection step, the lack of selectivity during the methylation reaction, the low yield and the large number of by-products in the borylation and Mitsunobu reactions.

[0028] In addition, WO 2015 / 097123 specifically discloses an alternative method for synthesizing a compound of formula (II), wherein the compound of formula (II) is obtained in three steps starting from 2,3-disubstituted phenol. However, when transferred to an industrial scale, the difficulties in implementing the method are also quickly exposed: specifically, the yield is low in the bromination step, the yield is low and there are many by-products in the Mitsunobu reaction, and the yield is low in the boration step.

[0029] Therefore, still in the ongoing search for new efficient synthetic routes, the applicant has continued its research to develop a new synthesis which produces compounds of formula (I), (II) or (III) in a reproducible manner in excellent yields and without cumbersome purification, in a purity suitable for their use as pharmaceutically acceptable intermediates.

[0030] More particularly, the applicant has now developed a new synthesis method that enables the use of 1,2-disubstituted-3-bromophenyl derivatives as starting materials, without cumbersome purification, in a reproducible manner to obtain compounds of formula (I) and (II). The advantage of this new starting material is that it is simple and can be easily obtained in large quantities at a relatively low cost. In particular, the applicant has developed a new industrial synthesis method that enables the use of 3-bromo-2-chlorotoluene as starting material, without cumbersome purification, in a reproducible manner to obtain compounds of formula (III). 3-bromo-2-chlorotoluene also has the advantage of having a methyl group in its structure, which avoids the inclusion of a non-selective methylation step in the synthesis, which creates problems when transferred to an industrial scale.

[0031] The advantages of the novel method of the present invention are the use of effective regioselective monobromination reaction, outstanding ring-opening reaction of 1-alkyl-1-azonium bicyclo [2.2.2] octane compounds and effective borylation reaction. WO 2015 / 162515 has disclosed the bromination reaction of formula (VI) compounds, particularly 2- fluoro-3-methyl-phenol using N-bromosuccinimide (NBS) as reagent. However, it has been found that the use of NBS reagent provides undesirable dibromination by-products and lower yields. The ring-opening reaction of 1-alkyl-1-azonium bicyclo [2.2.2] octane compounds has been described in the literature (Maras et al., Organic and Biomolecular Chemistry 2012, 10, 1300-1310, which is incorporated by reference). However, the applicant has found unexpected experimental conditions, which are reversely taught by Maras publications.

[0032] Scheme 1 shows an overview of the process of the present invention, see below.

[0033]

[0034] Process 1

[0035] Ring-opening reaction of 1-alkyl-1-azonia bicyclo[2.2.2]octane derivatives: (IV)+(V)→(I)

[0036] A particular embodiment of the present invention relates to a process for preparing a compound of formula (I):

[0037]

[0038] in:

[0039] ◆R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group,

[0040] ◆R3 represents a straight chain or branched (C1-C6) alkyl group,

[0041] The method comprises treating a compound of formula (IV):

[0042]

[0043] wherein R1 and R2 are as defined above,

[0044] reacting with a compound of formula (V) in a solvent at high temperature in the presence of a base,

[0045]

[0046] Wherein R3 is as defined above, and X - represents a monovalent anionic counter ion.

[0047] In one embodiment, the solvent that can be used to carry out the transformation of the compound of formula (IV) to form the compound of formula (I) is preferably a polar aprotic solvent. Among the polar aprotic solvents that can be used to carry out the transformation of the compound of formula (IV) to form the compound of formula (I), there can be mentioned without any limitation anisole, pyridine, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, diethylene glycol dimethyl ether, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, polyethylene glycol, sulfolane...

[0048] The solvents which can be used to carry out the conversion of the compound of formula (IV) to form the compound of formula (I) may also consist of a mixture of two or more solvents from the abovementioned solvents.

[0049] A preferred solvent for carrying out the conversion of the compound of formula (IV) to form the compound of formula (I) is anisole.

[0050] Preferably, the reaction of converting the compound of formula (IV) into the compound of formula (I) is carried out at a temperature above 135° C., more preferably between 140° C. and 150° C. An advantageous embodiment for converting the compound of formula (IV) into the compound of formula (I) is to carry out the reaction between 135° C. and 145° C. Another advantageous embodiment for converting the compound of formula (IV) into the compound of formula (I) is to carry out the reaction at 140° C.

[0051] Among the bases that can be used to carry out the conversion of the compound of formula (IV) to form the compound of formula (I), there may be mentioned without any limitation potassium tert-butoxide, lithium tert-butoxide, potassium acetate, lithium ethoxide, carbonates such as cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate ...

[0052] Preferred bases for carrying out the conversion of the compound of formula (IV) to form the compound of formula (I) are carbonates, more preferably cesium carbonate.

[0053] The compound of formula (I) can be isolated as a free base, a monohalide salt or a dihalide salt. Preferably, the compound of formula (I) can be isolated as a monohalide salt or a dihalide salt. More preferably, the compound of formula (I) is isolated as a dihalide salt, even more preferably as a dihydrochloride salt.

[0054] The isolation of the compound of formula (I) as a monohalogen acid salt is preferably carried out in tert-butyl methyl ether, dioxane, toluene, cyclohexane, cyclopentyl methyl ether or ethyl acetate, more preferably in tert-butyl methyl ether.

[0055] The isolation of the compound of formula (I) as dihalide salt is preferably carried out in water.

[0056] The compound of formula (V) is obtained from 1,4-diazabicyclo[2.2.2]octane (also known as DABCO; CAS No.: 280-57-9). The compound of formula (V) can be synthesized by reacting 1,4-diazabicyclo[2.2.2]octane with an alkylating agent selected from alkyl halides, alkyl toluene sulfonates, alkyl sulfonates or alkyl methane sulfonates. In particular, the compound of formula (V) is defined as follows:

[0057]

[0058] wherein R3 is as defined above, and X - represents a monovalent anionic counterion selected from a halide, tosylate, sulfonate or mesylate.

[0059] Advantageously, the compound of formula (V) is defined as follows:

[0060]

[0061] Where R3 represents a methyl group and X - represents the tosylate counter ion.

[0062] Preferably, the compound of formula (V) can be synthesized with a methylating agent selected from methyl halide, methyl tosylate (also known as 4-methylbenzene-1-sulfonate), methyl sulfonate or methyl methanesulfonate, more preferably methyl tosylate.

[0063] The compounds of formula (V) can be synthesized separately or in situ, preferably in situ.

[0064] In a particular embodiment, the compound of formula (I) is obtained by using 1,4-diazabicyclo[2.2.2]octane.

[0065] Regioselective monobromination reaction: (VI) → (IV)

[0066] A particular embodiment of the present invention relates to such a method, wherein: the compound of formula (IV)

[0067]

[0068] wherein R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group,

[0069] The product is obtained by regioselective monobromination of a compound of formula (VI) in a solvent in the presence of a brominating agent:

[0070]

[0071] wherein R1 and R2 are as defined above.

[0072] In the process of the present invention, the reaction of converting the compound of formula (VI) into the compound of formula (IV) is carried out in the presence of 1 equivalent of a brominating agent.

[0073] Among the brominating agents that can be used to carry out the conversion of the compound of formula (VI) to form the compound of formula (IV), there may be mentioned without any limitation N-bromosuccinimide, bromine, sodium bromide / trichloroisocyanuric acid, bromine / sodium acetate, bromotrichloromethane, 1,2-dibromo-1,1,2,2-tetrachloroethane, tetrabromomethane, carbon tetrabromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, pyridinium tribromide perbromide), 4-dimethylaminopyridinium tribromide, 1-butyl-3-methylimidazolium tribromide, 1,8-diazabicyclo[5.4.0]-7-undecene hydrogen tribromide, N-bromophthalimide, N-bromosaccharin, N-bromoacetamide, 2-bromo-2-cyano-N,N-dimethylacetamide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, monosodium bromoisocyanurate hydrate, boron tribromide (17% solution in dichloromethane, about 1 mol / L), boron tribromide (29% solution in heptane, about 1 mol / L), phosphorus tribromide, dimethylsulfonium bromide, 5,5-dibromomeldrum's acid, 2,4,4,6-Tetrabromo-2,5-cyclohexadienone, bis(2,4,6-trimethylpyridinium)-bromonium hexafluorophosphate...

[0074] Preferred brominating agents for carrying out the conversion of the compound of formula (VI) to form the compound of formula (IV) are N-bromosuccinimide, bromine, sodium bromide / trichloroisocyanuric acid, or bromine / sodium acetate, more preferably bromine, sodium bromide / trichloroisocyanuric acid, or bromine / sodium acetate, even more preferably bromine.

[0075] Among the solvents that can be used to carry out the conversion of the compound of formula (VI) to form the compound of formula (IV), there may be mentioned without any limitation dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, acetone, dimethylformamide, water, methanol, acetic acid, sulfuric acid, hydrobromic acid ...

[0076] The solvent used to carry out the conversion of the compound of formula (VI) to form the compound of formula (IV) may also consist of a mixture of two or more solvents from the group of organic solvents mentioned above.

[0077] The solvent that is preferably used for carrying out the conversion of the compound of formula (VI) to form the compound of formula (IV) is a mixture of acetic acid, methylene dichloride, methanol and sulfuric acid or a mixture of acetic acid and methylene dichloride. In a preferred embodiment, the solvent that is used for carrying out the conversion of the compound of formula (VI) to form the compound of formula (IV) is a mixture of acetic acid and methylene dichloride, more preferably a mixture of 10%v / v to 100%v / v acetic acid in methylene dichloride, even more preferably a mixture of 15%v / v to 30%v / v acetic acid in methylene dichloride. Advantageously, the solvent that is used for carrying out the conversion of the compound of formula (VI) to form the compound of formula (IV) is a mixture of 25%v / v acetic acid and methylene dichloride.

[0078] Preferably, the reaction of converting the compound of formula (VI) into the compound of formula (IV) is carried out between -20°C and 30°C, more preferably between -15°C and 5°C, even more preferably between -15°C and -5°C. In other preferred embodiments, the reaction of converting the compound of formula (VI) into the compound of formula (IV) is carried out between -5°C and 5°C.

[0079] Preferably, the bromination reaction can be carried out by diluting the compound of formula (VI) with about 10 to about 20, more preferably about 10 to about 15, even more preferably about 10 volumes of an organic solvent or mixture of organic solvents.

[0080] Hydroxylation reaction: (VII) → (VI)

[0081] A particular embodiment of the present invention relates to such a method, wherein: the compound of formula (VI)

[0082]

[0083] wherein R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group,

[0084] The method is obtained by hydroxylating a compound of formula (VII) in a solvent in the presence of a metal transition complex and a base:

[0085]

[0086] wherein R1 and R2 are as defined above.

[0087] In the method of the present invention, the reaction of converting the compound of formula (VII) into the compound of formula (VI) can be carried out by various metal-catalyzed hydroxylation reactions (Maleczka et al., J. Am. Chem. Soc. 2003, 125, 7792-7793; Willis, Angew. Chem. Int. Ed. 2007, 46, 3402-3404; Alonso et al., Chem. Eur. J. 2010, 16, 5274-5284; Enthaler et al., Chem. Soc. Rev. 2011, 40, 4912-4924; Xia et al., J. Am. Chem. Soc. 2016, 138, 13493-13496, incorporated by reference). Advantageously, in the process of the present invention, the reaction of converting the compound of formula (VII) into the compound of formula (VI) can be carried out in the presence of a metal transition complex, which is a palladium complex comprising a palladium catalyst and a ligand.

[0088] Among the palladium catalysts that can be used to carry out the conversion of the compound of formula (VII) to form the compound of formula (VI), there can be mentioned without any limitation tris(bisbenzylideneacetone)dipalladium Pd2(dba)3, palladium(II) acetate Pd(OAc)2, palladium on carbon Pd / C, tetrakis(triphenylphosphino)palladium Pd(PPh3)4.....

[0089] A preferred palladium catalyst for use in carrying out the conversion of the compound of formula (VII) to form the compound of formula (VI) is Pd2(dba)3.

[0090] Among the ligands that can be used to carry out the transformation of the compound of formula (VII) to form the compound of formula (VI), there may be mentioned without any limitation 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhos, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl t-BuXPhos.....

[0091] A preferred ligand for effecting the conversion of the compound of formula (VII) to form the compound of formula (VI) is t-BuXPhos.

[0092] In the method of the present invention, the reaction of converting the compound of formula (VII) into the compound of formula (VI) is carried out in the presence of at least 0.01 equivalent, more preferably at least 0.0075 equivalent of a palladium catalyst. The reaction of converting the compound of formula (VII) into the compound of formula (VI) is carried out in the presence of at least 0.03 equivalent, more preferably at least 0.02 equivalent of a ligand. Advantageously, the reaction of converting the compound of formula (VII) into the compound of formula (VI) is carried out in the presence of at least 0.01 equivalent of a palladium catalyst and at least 0.03 equivalent of a ligand. More advantageously, the reaction of converting the compound of formula (VII) into the compound of formula (VI) is carried out in the presence of 0.01 equivalent of a palladium catalyst and 0.04 equivalent of a ligand.

[0093] Among the bases that can be used to carry out the conversion of the compound of formula (VII) to form the compound of formula (VI), there may be mentioned without any limitation potassium acetate, sodium tert-butoxide, sodium bicarbonate, potassium carbonate, hydroxide salts such as potassium hydroxide, sodium hydroxide, cesium hydroxide, lithium hydroxide, ...

[0094] Preferred bases for carrying out the conversion of the compound of formula (VII) to form the compound of formula (VI) are hydroxide salts, more preferably potassium hydroxide, sodium hydroxide, cesium hydroxide, lithium hydroxide, even more preferably potassium hydroxide.

[0095] Among the solvents that can be used to carry out the conversion of the compound of formula (VII) to form the compound of formula (VI), there may be mentioned without any limitation 1,4-dioxane, cyclopentyl methyl ether, toluene, heptane, water, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether ...

[0096] The solvent used to carry out the conversion of the compound of formula (VII) to form the compound of formula (VI) may also consist of a mixture of two or more solvents from the abovementioned organic solvents or a mixture of water and a solvent from the abovementioned organic solvents.

[0097] Preferred solvents for carrying out the conversion of the compound of formula (VII) to form the compound of formula (VI) are 1,4-dioxane or a mixture of water and 1,4-dioxane, more preferably a mixture of water and 1,4-dioxane. Advantageously, the proportion of 1,4-dioxane in water is at least 5%, more preferably at least 15%, even more preferably at least 25%.

[0098] Advantageous embodiments relate to a sequence of hydroxylation and regioselective monobromination reactions to convert the compound of formula (VII) to the compound of formula (IV) without isolating the compound of formula (VI). In such advantageous embodiments, the organic solvent used to convert the unisolated compound of formula (VI) to the compound of formula (IV) consists of a solvent mixture, preferably a mixture of 1,4-dioxane, acetic acid and dichloromethane, wherein 1,4-dioxane is a residual solvent from the hydroxylation step (i.e., the step of converting the compound of formula (VII) to the compound of formula (VI)).

[0099] Boration reaction: (I) → (II)

[0100] A particular embodiment of the present invention relates to a process for preparing a compound of formula (II):

[0101]

[0102] in:

[0103] ◆R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group,

[0104] ◆R3 represents a straight chain or branched (C1-C6) alkyl group,

[0105] ◆R4 and R5 represent hydrogen, a straight or branched (C1-C6) alkyl group, or R4 and R5 together with the oxygen atom carrying them form a ring which can be substituted by one to four straight or branched (C1-C6) alkyl groups, the method comprising the steps of: making a compound of formula (I)

[0106]

[0107] wherein R1, R2 and R3 are as defined above,

[0108] Reaction with boric acid ester of formula (VIII):

[0109]

[0110] wherein R4 and R5 are as defined above, and R represents a hydrogen atom, a hydroxyl group, a linear or branched (C1-C6) alkoxy group, or a (C0-C6) alkyl-B(OR4)(OR5) group.

[0111] In the method of the present invention, the conversion of the compound of formula (I) to the compound of formula (II) comprises the action of the compound (VIII) in an organic solvent or an organic solvent mixture in the presence of a base, wherein R represents a hydrogen atom, a hydroxyl group or a straight or branched (C1-C6) alkoxy group. Advantageously, the reaction of converting the compound of formula (I) to the compound of formula (II) is carried out in tetrahydrofuran or 2-methyltetrahydrofuran, more preferably 2-methyltetrahydrofuran. Preferably, the reaction of converting the compound of formula (I) to the compound of formula (II) is carried out in the presence of n-butyllithium.

[0112] Alternatively, in the process of the present invention, the conversion of the compound of formula (I) to the compound of formula (II) comprises the action (Miyaura boronization) of a compound of formula (VIII) in an organic solvent or an organic solvent mixture in the presence of a base and a palladium complex, wherein R represents a (C0-C6) alkyl-B(OR4)(OR5) group. Advantageously, the palladium complex is bis(triphenylphosphine)palladium(II) chloride Pd(PPh3)2Cl2.

[0113] The compound of formula (I) is preferably used as a free base for its conversion into the compound of formula (II). When the compound of formula (I) is a dihydrohalide salt, two additional equivalents of said base are advantageously added to the reaction mixture to effect the conversion of the compound of formula (I) to form the compound of formula (II).

[0114] To convert the compound of formula (I) to form the compound of formula (II), the compound of formula (I) is advantageously obtained by reacting a compound of formula (IV) with a compound of formula (V).

[0115] Advantageously, the present invention relates to a process for preparing a compound of formula (II):

[0116]

[0117] in:

[0118] ◆R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group,

[0119] ◆R3 represents a straight chain or branched (C1-C6) alkyl group,

[0120] ◆R4 and R5 represent hydrogen, a linear or branched (C1-C6) alkyl group, or R4 and R5 together with the oxygen atom carrying them form a ring which may be substituted by one to four linear or branched (C1-C6) alkyl groups, characterized in that the compound of formula (VII) in which R1 and R2 are as defined above

[0121]

[0122] The hydroxylation reaction is carried out in a solvent in the presence of a metal transition complex and a base.

[0123] Producing a compound of formula (VI) wherein R1 and R2 are as defined above,

[0124]

[0125] The compound of formula (VI) is subjected to a regioselective monobromination reaction in the presence of a brominating agent in a solvent to obtain a compound of formula (IV) wherein R1 and R2 are as defined above:

[0126]

[0127] The compound of formula (IV) is reacted in a solvent at high temperature in the presence of a base and a compound of formula (V),

[0128]

[0129] Wherein R3 is as defined above, and X - represents a monovalent anionic counterion,

[0130] Producing a compound of formula (I) wherein R1, R2 and R3 are as defined above:

[0131]

[0132] The compound of formula (I) undergoes a borylation reaction in the presence of a boric acid ester of formula (VIII),

[0133]

[0134] wherein R4 and R5 are as defined in formula (II), and R represents a hydrogen atom, a hydroxyl group, a linear or branched (C1-C6) alkoxy group, or a (C0-C6) alkyl-B(OR4)(OR5) group,

[0135] This produces a compound of formula (II).

[0136] In a particular embodiment, R1 preferably represents a halogen atom or a straight or branched (C1-C6) alkyl group, more preferably a fluorine atom, a chlorine atom, an ethyl group or a methyl group, even more preferably a methyl group. R2 advantageously represents a halogen atom or a straight or branched (C1-C6) alkyl group, more advantageously represents a chlorine atom or a methyl group, even more advantageously represents a chlorine atom. In particular, R3 represents a methyl group. More particularly, R1 represents a straight or branched (C1-C6) alkyl group, R2 represents a halogen atom, and R3 represents a methyl group. Even more particularly, R1 and R3 represent a methyl group and R2 represent a chlorine atom. Preferably, R4 and R5 form a ring together with the oxygen atom carrying them, and the ring can be dioxaborolan, dioxaborolan, dioxaborohexane or dioxaboroheptane, more preferably a dioxaborolan ring. Advantageously, R4 and R5 together with the oxygen atom carrying them form a ring which may be substituted by one to four linear or branched (C1-C6) alkyl groups. More advantageously, R4 and R5 together with the oxygen atom carrying them form a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ring.

[0137] Advantageously, the present invention relates to a process for preparing compounds of formula (III):

[0138]

[0139] It is characterized in that the compound of formula (VII)

[0140]

[0141] wherein R1 represents a methyl group, and R2 represents a chlorine atom,

[0142] The hydroxylation reaction is carried out in the presence of a metal transition complex and a base in a solvent to produce a compound of formula (VI):

[0143]

[0144] wherein R1 and R2 are as defined above,

[0145] The compound of formula (VI) undergoes a regioselective monobromination reaction in the presence of a brominating agent in a solvent to produce a compound of formula (IV):

[0146]

[0147] Where R1 and R2 are as defined above,

[0148] The compound of formula (IV) is reacted in a solvent at high temperature in the presence of a base and a compound of formula (V):

[0149]

[0150] Wherein R3 represents a methyl group and X - represents a monovalent anionic counterion,

[0151] Producing compounds of formula (I):

[0152]

[0153] wherein R1, R2 and R3 are as defined above,

[0154] The compound of formula (I) undergoes a borylation reaction in the presence of a boric acid ester of formula (VIII):

[0155]

[0156] wherein R4 and R5 together with the oxygen atom carrying them form a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ring and R represents a hydrogen atom, a hydroxyl group, a linear or branched (C1-C6) alkoxy group, or a (C0-C6) alkyl-B(OR4)(OR5) group,

[0157] This produces compound (III).

[0158] The compounds of formula (V), (VII) and (VIII) are commercially available or can be readily prepared by a person skilled in the art using conventional or literature described chemical reactions.

[0159] The method of the present invention is particularly advantageous for the following reasons:

[0160] - it enables the compounds of formula (I) to be obtained in good yields on an industrial scale starting from simple and low-cost starting materials and without the need for cumbersome purification;

[0161] - it enables compounds of the formula (II), more particularly compounds of the formula (III), to be obtained in good yields on an industrial scale starting from simple and low-cost starting materials and without the need for cumbersome purification;

[0162] - It enables the avoidance of volatile intermediates and the use of highly flammable and potentially explosive reagents;

[0163] - It enables high levels of purity to be obtained using standard crystallization techniques.

[0164] The present invention also relates to the use of the compound of formula (VII) for synthesizing the compound of formula (I) or the compound of formula (II). Alternatively, the present invention also relates to the use of the compound of formula (VII) wherein R1 represents a methyl group and R2 represents a chlorine atom for synthesizing compound 1 or compound 2.

[0165] The present invention also relates to the use of the compound of formula (V) for synthesizing the compound of formula (I) or the compound of formula (II). Alternatively, the present invention also relates to the use of the compound of formula (V) wherein R3 represents a methyl group for synthesizing compound 1 or compound 2.

[0166] The compound of formula (II) or the compound of formula (III) thus obtained is then subjected to a series of conventional chemical reactions, such as those described in WO 2015 / 097123, to produce compound 1 or compound 2 and their structurally close analogs. Advantageously, the compound of formula (III) obtained according to the invention can be used in a cross-coupling reaction, such as a Suzuki-type cross-coupling reaction, for the preparation of compound 1 or compound 2.

[0167] Advantageously, compound 1 or compound 2 is obtained by employing 1,4-diazabicyclo[2.2.2]octane during the process of preparing the compound of formula (II) or the compound of formula (III).

[0168] In order to properly confirm that the reaction pathway is valid, the synthetic intermediates are systematically isolated and characterized. However, it is possible that the operation can be optimized considerably by limiting the number of isolated intermediates.

[0169] Preferably, the reactants are stirred during the reaction time using a suitable mechanical oscillator or stirrer. The reaction may be carried out for about 2 to about 24 hours or longer, depending on the temperature, dilution volume, catalyst, concentration and / or nature of the materials in the reaction mixture. As used herein, the term 'about' means + / -5%, particularly + / -2%, more particularly + / -1%.

[0170] The structures of the compounds were confirmed by conventional spectroscopic techniques. For example, 1 H NMR data are in the form of δ values, expressed in parts per million (ppm), using the residual peak of the solvent (7.26 ppm, CDCl3) as an internal standard. The splitting pattern is designated as follows: s (singlet), d (doublet), t (triplet), m (multiplet), br or brs (broad singlet).

[0171] The following examples illustrate the invention but do not limit it in any way.

[0172] Example 1 :Preparation of 2-chloro-3-methylphenol (hydroxylation reaction)

[0173] A solution of 1-bromo-2-chloro-3-methylbenzene (5.00 g; 24.33 mmol) in dioxane (12.5 mL) and a solution of potassium hydroxide (2.25 g; 40.14 mmol) in water (12.5 mL) were degassed with nitrogen for 15 minutes. The solutions were combined. t-BuXPhos (827 mg; 1.95 mmol) and Pd2(dba3) (446 mg; 0.48 mmol) were added and the reaction mixture was heated at 100°C in a sealed test tube for 35 minutes. The reaction mixture was cooled to 20°C and washed with tert-butyl methyl ether. The aqueous phase was back-extracted with 1N NaOH solution, acidified to pH 4 with 3N hydrochloric acid solution and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated to give the title compound as a light yellow solid (2.8 g, 80% yield).

[0174] 1 H NMR (400MHz, CDCl3): δppm 6.97-7.11(m,1H); 6.73-6.90(m,2H); 5.88(brs,1H); 2.37(s,3H)

[0175] Example 2 : Preparation of 4-bromo-2-chloro-3-methylphenol (regioselective monobromination reaction)

[0176] A solution of bromine (1089 g; 6.82 mol) in dichloromethane (1.94 L; 2 vol.) was added to a solution of 2-chloro-3-methylphenol (972 g; 6.82 mol, obtained as described in Example 1 above) in a mixture of dichloromethane (5.35 L; 5.5 vol.) and acetic acid (2.43 L; 2.5 vol.) at 0°C. After stirring at 0°C for 15 minutes, the reaction mixture was warmed to room temperature, washed with water and 5% KHCO3 solution, and then dried over sodium sulfate. After filtration, the product was obtained by concentration to dryness and was carried on to the next step as is (1.44 kg; 95%).

[0177] 1 H NMR (400MHz, CDCl3): δppm 7.35 (d, J=8.8Hz, 1H); 6.78 (d, J=8.6Hz, 1H); 5.64 (brs, 1H); 2.49 (s, 3H)

[0178] 13 C NMR (101MHz, CDCl3): δppm 150.7,135.9,131.2,121.1,115.3,114.5,20.8LC-MS[ESI - ]m / z:219.0,219.8[M+H] +

[0179] Example 3 :Preparation of 4-bromo-2-chloro-3-methylphenol (regioselective monobromination – other conditions)

[0180] A solution of a brominating agent (1 eq.) in a solvent is added to a solution of 2-chloro-3-methylphenol (100 mg) in a solvent at 0°C. After stirring at 0°C for 15 minutes, the reaction mixture is washed with water and with a 5% KHCO3 solution, and then dried over sodium sulfate. After filtration, the product is obtained by concentration to dryness and used as it is in the next step. 1 H NMR confirmed the structure of the expected product, and the δ value was consistent with the value measured in Example 2 above.

[0181] Table 1. Experimental conditions for the preparation of 4-bromo-2-chloro-3-methylphenol

[0182]

[0183]

[0184] Example 4 :Preparation of 4-bromo-2-chloro-3-methylphenol (One-pot hydroxylation and regioselective monobromination)

[0185] A solution of 1-bromo-2-chloro-3-methylbenzene (354 g; 1.72 mol) and potassium hydroxide (242 g; 4.30 mol) in 1,4-dioxane (710 mL; 2.0 vol.) and water (2150 mL; 6.0 vol.) was degassed with nitrogen for 15 minutes under stirring. t-BuXphos (29.2 g; 0.069 mol) and Pd2(dba)3 (15.8 g; 0.017 mol) were added and the suspension was heated to reflux (90-95°C) for 60 minutes. Completion of the reaction was determined by HPLC. The resulting suspension was cooled to 20-25°C. Tert-butyl methyl ether (800 mL) was added and the two-phase mixture was stirred for 10-15 minutes. The crystalline residue was removed by filtration through a pad of celite and the filter cake was washed with tert-butyl methyl ether and 1N potassium hydroxide solution. The aqueous phase was washed three times with tert-butyl methyl ether and then acidified to pH 1-2 with 12N hydrochloric acid solution. The solution was extracted three times with dichloromethane and then the solution volume (1153 mL; 5.0 vol, relative to phenol) was adjusted with dichloromethane to reduce to the appropriate concentration in the next step. The concentration of 2-chloro-3-methylphenol in the solution was determined by quantitative GC-FID analysis (128.1 mg / mL; 230.6 g; 1.617 mol.).

[0186] The 2-chloro-3-methylphenol solution was charged to a 5.0 L reactor and acetic acid (584 mL; 2.5 vol. relative to phenol) was added. The solution was then cooled to -10°C / -15°C under nitrogen and a solution of bromine (258.5 g; 1.617 mol) in dichloromethane (477 mL; 2.1 vol. relative to phenol) was added between -13°C and -7°C over 70 minutes. Additional bromine (3.5 g; 0.022 mol) in dichloromethane (20 mL; 0.06 vol.) was added. Water (1.4 L) was added between -11°C and 2°C over 10 minutes. The solution was warmed to 20-25°C and sodium bisulfite (50 g; 0.48 mol) was added. The solution was stirred for 15-20 minutes. The phases were separated and the aqueous phase was extracted with dichloromethane. The pooled organic phases were washed twice with water, twice with 10% potassium bicarbonate solution and brine. The solution was dried over magnesium sulfate. The filter cake was washed with dichloromethane. The solvent was evaporated under vacuum and the residual 1,4-dioxane was azeotroped with heptane to give the title product as a light brown solid (353 g, crude yield: 92.6%).

[0187] 1 H NMR (400MHz, CDCl3): δppm 7.35 (d, J = 8.8Hz, 1H); 6.78 (d, J = 8.6Hz, 1H); 5.64 (brs, 1H); 2.49 (s, 3H)

[0188] 13 C NMR (101MHz, CDCl3): δppm 150.7,135.9,131.2,121.1,115.3,114.5,20.8LC-MS[ESI - ]m / z:219.0,219.8[M+H] +

[0189] Example 5 : Preparation of 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine (Ring opening of 1-alkyl-1-azoniabicyclo[2.2.2]octane)

[0190] A solution of methyl 4-methylbenzene-1-sulfonate (592 g; 3.18 mol) in anisole (320 mL) was added to a solution of 1,4-diazabicyclo[2.2.2]octane (389 g; 3.47 mol) in anisole (6.4 L) over 15 minutes. After stirring at 70°C for 1 hour with vigorous stirring, Cs2CO3 (1130 g; 3.466 mol) was added portionwise over 5 minutes. A solution of 4-bromo-2-chloro-3-methylphenol (640 g; 2.89 mol) obtained as described in Example 2 or 3 above in anisole (0.64 L) was added over 10 minutes. The reaction mixture was stirred at 140°C for 6 hours. After cooling to room temperature, tert-butyl methyl ether and ethyl acetate were added, the mixture was washed with water and brine, dried over sodium sulfate, and the resulting product solution was used in the next step.

[0191] A mixture of tert-butyl methyl ether (1.28 L) and ethanol (219 mL; 3.75 mol) was added to a solution of acetyl chloride (272 g; 3.46 mol) over 30 minutes, keeping the mixture temperature below 25°C. After stirring for 30 minutes, the resulting solution was added to the organic phase obtained above at room temperature over 1 hour. After stirring the resulting suspension for 1 hour, the product was collected by filtration and washed with tert-butyl methyl ether. The solid was dissolved in dichloromethane and 1N aqueous NaOH solution was added until alkaline. After separation, the aqueous layer was washed with dichloromethane and the combined organic layers were dried over sodium sulfate and evaporated. After addition of 2-methyltetrahydrofuran and filtration through a pad of celite, the filter cake was washed with 2-methyltetrahydrofuran and the solvent was evaporated to give an amber oil (894 g; 89%).

[0192] 1 H NMR (400MHz, CDCl3): δppm 7.33 (d, J=8.8Hz, 1H); 6.63 (d, J=8.8Hz, 1H); 4.09 (t, J=5.8Hz, 2H); 2.83 (t, J=5.8Hz, 3H); 2.63 (brs, 4H); 2.47 (s, 4H); 2.37-2.45(m,2H);2.25(s,3H)

[0193] Example 6 : Preparation of 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine monohydrochloride (Ring opening of 1-alkyl-1-azoniabicyclo[2.2.2]octane)

[0194] A solution of methyl 4-methylbenzene-1-sulfonate (435 g; 2.34 mol) in anisole (235 mL) was added over 15 minutes to a solution of 1,4-diazabicyclo[2.2.2]octane (286 g; 2.55 mol) in anisole (4.7 L). The thick white suspension was heated to 70°C for 60 minutes. Cesium carbonate (831 g; 2.55 mol) was added in one portion, followed by a solution of 4-bromo-2-chloro-3-methylphenol (470 g; 2.12 mol) in anisole (470 mL) obtained as described above in Example 2 or 3 at 70°C over 12 minutes. The brown suspension was heated to 140°C for 6 hours and the reaction was determined to be complete by HPLC. Water, tert-butyl methyl ether and ethyl acetate were added and the two-phase mixture was stirred for 10 minutes. The layers were separated and the aqueous phase was then extracted with a 1:1 mixture of tert-butyl methyl ether and ethyl acetate. The pooled organic phases were washed with brine and then dried over sodium sulfate for about 30 minutes. The suspension was filtered through a Buchner filter and the filter cake was then washed with tert-butyl methyl ether. The free base solution was set aside.

[0195] Acetyl chloride (200 g; 2.55 mol) was added to a cold (0-5°C) mixture of ethanol (127 g; 2.76 mol) and tert-butyl methyl ether (940 mL) between 3°C and 12°C over 35 minutes. The solution was stirred for 30 minutes and then added to the free base solution between 20°C and 25°C over 60 minutes. The white suspension was stirred at 20-25°C for 60 minutes, the solid was collected by filtration through a Buchner filter, and the filter cake was washed twice with tert-butyl methyl ether. The filter cake was added back to the flask and ground in tert-butyl methyl ether for 60 minutes. The suspension was filtered through a Buchner filter and the filter cake was washed twice with tert-butyl methyl ether. The solid was dried under vacuum at 70-75°C until constant weight was observed to give the title product as an off-white solid (761 g, yield: 93.2%) with a purity of 97.1% as determined by GC-FID.

[0196] 1 H NMR (400MHz, DMSO-d6): δppm 11.10 (brs, 1H); 7.54 (d, J = 8.8Hz, 1H); 7.01 (d, J = 9.1Hz, 1H); 4.27 (brs, 2H); 3.39 (brs, 10H); 2.72 (brs, 3H); 2.44 (s, 3H)

[0197] Example 7 : Preparation of 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine dihydrochloride

[0198] A 22 L round bottom flask apparatus in distillation mode was charged with 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine hydrochloride (1490 g; 3.88 mol) obtained as described above in Example 6 and water (14.9 L). The water (2.98 L) was partially distilled to remove residual anisole by azeotropy at 50-55° C. and 40-45 Torr. The solution was cooled to 45° C. and then 12N hydrochloric acid (646 mL; 7.76 mol) was added over 5 minutes. The solution was slowly cooled to 20-25° C. over the weekend. The suspension was then cooled to 0-5° C., filtered through a Buchner filter, and the flask was washed with cold water (0-5° C.) (250 mL). The filter cake was washed twice with acetone. The solid was returned to the flask and triturated in acetone for 90 minutes. The suspension was filtered through a Buchner filter and the filter cake was washed twice with acetone. The solid was dried under vacuum at 75-80 °C for 24 h to afford the title product as a white solid (1471 g, yield: 90.2%) with a purity of 99.9% as determined by GC-FID.

[0199] 1 H NMR (400MHz, DMSO-d6): δppm 10.91-13.60(m,2H);7.56(d,J=8.8Hz,1H);7.03(d,J=9.1Hz,1H);4.45(brs,2H);3.58(brs,10H);2.79(brs,3H);2.44(s,3H) 13 C NMR (101MHz, CD3OD, D2O): δppm 153.7,137.9,132.0,124.6,118.0,113.7, 65.3,56.9,51.2,50.8,43.7,20.8

[0200] Example 8 : Preparation of 1-{2-[2-chloro-3-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl}-4-methylpiperazine (boration reaction)

[0201] 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine (800.0 g; 2.30 mol) obtained as described in Example 5 (or converted to the free base from Example 6 or 7) and 2-methyltetrahydrofuran (5.6 L) were added to a 12 L three-necked round bottom flask under nitrogen. The solution was cooled to between -72°C and -76°C using an acetone dry ice bath. A 2.5 M solution of n-butyllithium in hexanes (1196 mL; 2.99 mol) was added over 1.5 hours while maintaining the temperature between -62°C and -74°C. The resulting yellow solution was stirred between -72°C and -76°C for 1 hour. 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (556 g; 2.99 mol) was then added over 45 minutes, while keeping the reaction mixture between -65°C and -76°C. The reaction mixture was stirred for 1 hour at a temperature between -65°C and -76°C. Completion of the reaction was observed by HPLC. The reaction mixture was then warmed to -25°C. Methanol (200 mL) was then added over 15 minutes. The solution was poured into a solution of ammonium chloride (369 g; 6.90 mol) in water (4 L). The phases were separated. The organic phase was washed with water and then evaporated directly to dryness to give a colorless oil. Heptane (2.80 L) was added at 35-40°C to dilute the oil, and crystallization occurred quickly. The suspension was stirred at 35-40°C for 1 hour and then cooled to 5°C for 1 hour. The solid was collected by filtration and then washed with heptane. The wet cake was dried at 40-50°C under high vacuum to constant weight to give the title product as a white solid (2.200 Kg, 85% total yield for 3 batches).

[0202] 1 H NMR (400MHz, CDCl3): δppm 7.61 (d, J=8.3Hz, 1H); 6.72 (d, J=8.3Hz, 1H); 4.14 (t, J=5.9Hz, 2H); 2.85 (t, J=5.9Hz, 2H); 2.64 (brs, 3H); 2,58 (s, 4H); 2.38-2.50(m,4H); 2.25(s,3H); 1.30(s,12H)

[0203] Example 9 : Preparation of 1-{2-[2-chloro-3-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl}-4-methylpiperazine (Miyaura-type borylation reaction)

[0204] A solution of 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine (20.1 g; 58 mmol), obtained as described in Example 5 (or converted to the free base by Example 6 or 7), in 1,4-dioxane (200 mL) was degassed with nitrogen during 20 minutes. Potassium acetate (19.3 g; 197 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborolane (17.8 g; 70 mmol) were added and the suspension was degassed again for 20 minutes. Pd(PPh3)2Cl2 (814 mg; 1.16 mmol) was added and the suspension was heated to 100°C for 2 hours. The reaction was determined to be complete by HPLC. The suspension was cooled to 20-25°C and toluene (100 mL) was added. The suspension was filtered through diatomaceous earth (15 g) and the filter cake was rinsed with toluene (40 mL). Activated carbon (4.0 g) was added to the solution and stirred for 1 hour. The suspension was filtered through diatomaceous earth (15 g) and silica gel (15 g), and the filter cake was then rinsed with toluene (40 mL). The solution was concentrated to dryness, heptane (100 mL) was added, concentrated to dryness, and the operation was repeated once more. The residue was dissolved in heptane (150 mL) and treated with activated carbon (4.0 g) for 60 minutes. The suspension was filtered through diatomaceous earth (15 g) and the filter cake was rinsed twice with heptane (2x20 mL). The solution was concentrated to dryness, heptane (40 mL) was added to the residue, and the product was crystallized at 20-25 ° C for 4 hours. The suspension was cooled to 0-5 ° C for 1 hour and the product was collected by filtration. The filter cake was washed with cold (0-5°C) heptane (20 mL) and the solid was dried at 35-40°C to constant weight to give 10.1 g of product as a white solid. The mother liquor was concentrated to dryness, then heptane (20 mL) was added to the residue and the product was crystallized at 20-25°C over 4 hours. The suspension was cooled to 0-5°C over 1 hour and the product was collected by filtration. The filter cake was washed with cold (0-5°C) heptane (10 mL) and the solid was dried at 35-40°C until constant weight to give 5.6 g of product as a white solid. Two batches were combined to give a total of 15.7 g (69% yield). 1 H NMR (400MHz, CDCl3): δppm 7.64 (d, J = 8.3 Hz, 1H); 6.76 (d, J = 8.3 Hz, 1H); 4.18(t,J=5.8Hz,2H); 2.88(t,J=5.9Hz,2H); 2.25-2.83(m,14H); 1.34(s,12H)

[0205] Example 10: Preparation of 1-{2-[2-chloro-3-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl}-4-methylpiperazine (Miyaura-type borylation reaction)

[0206] 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborolane (784 g; 1.3 eq.), potassium acetate (1284 g; 5.5 eq.) and Pd(PPh3)2Cl2 (50 g; 0.03 eq.) were added to a solution of 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine dihydrochloride (1000 g; 1 eq.; obtained as described in Example 7) in ethyl acetate (10 vol.) under nitrogen. The suspension was heated to reflux for 16 hours under stirring. Then, after cooling to 20° C., the reaction mixture was filtered and the filter cake was washed with ethyl acetate (1.5 vol.). The organic layer was then washed with a 5% aqueous solution of L-acetyl-cysteine, buffered at pH 7 with AcOK (10 vol.). After separation of the layers, the organic layer was concentrated to 2 volumes and then solvent exchanged to acetonitrile was performed under vacuum at 30° C. The temperature was then lowered to −10° C. and crystallization occurred. After filtration, the solid was dried at 40° C. to give the title product as a white solid (48% yield).

[0207] 1 H NMR (400MHz, CDCl3): δppm 7.64(d,J=8.3Hz,1H); 6.76(d,J=8.3Hz,1H); 4.18(t,J=5.8Hz,2H); 2.88(t,J=5.9Hz,2H); 2.25-2.83(m,14H); 1.34(s,12H)

[0208] Embodiment 11 :Large-Scale Preparation of 4-Bromo-2-Chloro-3-Methylphenol (One-Pot Hydroxylation and Regioselective Monobromination)

[0209] Water (390 L, 6.0 vol.) and potassium hydroxide (52.2 Kg, 790.8 mol) were added to the reactor and dissolved. When the heat of dissolution subsided, 1,4-dioxane (130 L, 2 vol.) and 3-bromo-2-chlorotoluene (65 Kg, 316.3 mol) were added, and the solution was degassed with nitrogen for 30 minutes under stirring. t-BuXphos (5.38 Kg, 12.65 mol) and Pd2(dba)3 (2.90 Kg, 3.16 mol) were added, and the suspension was heated to reflux for 90 minutes. The reaction was determined to be complete by GC, and the reaction mixture was then cooled to 20-25°C. Tert-butyl methyl ether (146 L) was added, and the two-phase mixture was stirred for 20 minutes. The reaction mixture was filtered through a Celite pad, the filter cake was washed with tert-butyl methyl ether (39 L, 0.6 vol.) and 1N potassium hydroxide solution (78 L, 1.2 vol.), and then the phases were separated. The aqueous phase was washed three times with tert-butyl methyl ether (3 x 110.5 L, 3 x 1.7 vol.), and then acidified with 12N hydrochloric acid at 25-30°C to pH 1-2. The solution was extracted three times with dichloromethane (1 x 110.5 L, 1.7 vol. and 2 x 42.3 L, 2 x 0.65 vol.). The combined organic layers were transferred to a reactor.

[0210] Acetic acid (107.3 L, 1.65 vol.) was added to the 2-chloro-3-methylphenol solution. The solution was cooled to -10 to -5°C under nitrogen and a solution of bromine (51.1 Kg, 319.5 mol) in dichloromethane (88 L, 1.35 vol.) was added between -10°C and -2°C for 1.5 hours. Water (260 L, 4.0 vol.) was added and the mixture was warmed to 20 to 25°C. Sodium bisulfite (9.9 Kg, 94.9 mol) was added and the solution was stirred for 20 minutes. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed twice with water, twice with 10% potassium bicarbonate solution and twice with 20% sodium chloride solution. The solution was dried over magnesium sulfate and then filtered and the filter cake was washed with dichloromethane. The solvent was removed by vacuum distillation. The residual 1,4-dioxane was azeotroped with heptane to obtain 70.1 Kg of the title product (crude yield: 100.1%).

[0211] 1 H NMR(600MHz, CDCl3):2.50(s,3H),5.57(s,1H),6.78(d,1H),7.35(d,1H)

[0212] Example 12 : Large-scale preparation of 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine monohydrochloride (Ring opening of 1-alkyl-1-azoniabicyclo[2.2.2]octanes)

[0213] Anisole (701 L, 10.0 vol.) and 1,4-diazabicyclo[2.2.2]octane (42.6 Kg, 379.6 mol) were added to the reactor and stirred under nitrogen. Methyl p-toluenesulfonate (64.8 Kg, 348.0 mol) was added in portions. The reaction mixture was heated to 70°C for 1 hour. Cesium carbonate (123.7 Kg, 379.6 mol) was added in one portion, followed by a solution of 4-bromo-2-chloro-3-methylphenol (70.1 Kg, 316.33 mol; obtained as described in Example 11) in anisole (50 Kg) at 70°C. The brown solution was heated to 140°C for 6 hours and the reaction was determined to be complete by GC. After the reaction mixture was cooled to room temperature, water, tert-butyl methyl ether and ethyl acetate were added and the biphasic solution was stirred for 10 minutes. The layers were separated and the organic phase was washed with 20% aqueous sodium chloride solution and then dried over magnesium sulfate. The suspension was filtered through a Buchner filter and the filter cake was washed with tert-butyl methyl ether. The free base solution was added to the reactor and set aside for use.

[0214] Add tert-butyl methyl ether (140.2 L, 2.0 vol.) and ethanol (19.0 Kg, 412.4 mol) to the reactor and cool to 0-5°C. Add acetyl chloride (29.8 Kg, 379.6 mol) below 10-15°C. Stir the solution for 30 minutes and then add it to the solution of the free base between 15°C and 25°C. Stir the white suspension at 20-25°C for 60 minutes and then filter it with a Buchner filter and wash the filter cake with tert-butyl methyl ether. Reload the filter cake and tert-butyl methyl ether into the reactor and stir for 60 minutes. Filter the suspension through a Buchner filter and wash the filter cake with tert-butyl methyl ether. Dry the solid under vacuum at 70-75°C for 16 hours to obtain the title product as a white solid (101 Kg, yield: 83.1%).

[0215] 1 H NMR(600MHz,DMSO-d6):2.42(s,3H),2.70(s,3H),2.8-3.8(br,10H),4.25(br,2H),6.95(d,1H),7.52(d,1H)

[0216] Embodiment 13 : Large-scale preparation of 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine dihydrochloride

[0217] The reactor was charged with water (1010 L, 10 vol.) and 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine monohydrochloride (101 Kg, 262.9 mol; obtained as described in Example 12). The water was partially distilled to remove residual anisole by azeotropy at 45-50°C and 55-60 Torr. 12N hydrochloric acid (43.8 L, 525.8 mol) was added to the aqueous solution at 45°C. The solution was slowly cooled to 15-20°C over 3 hours and stirred for another 12 hours. The suspension was filtered through a Buchner filter and the filter cake was washed with cold water (17 L, 0.17 vol.) and acetone (200 L, 2 vol.). The solid was added back to the reactor, and then acetone was added. The suspension was stirred for 60 minutes and filtered through a Buchner filter. The filter cake was washed with acetone and dried under vacuum at 75-80° C. for 24 hours to obtain the title product (99.5 Kg, 90.0%) as a white solid with a purity of 99.4% as determined by GC-FID.

[0218] 1 H NMR (600MHz, DMSO-d6): 2.43 (s, 3H), 2.78 (s, 3H), 3.2-3.9 (br, 10H), 4.47 (br, 2H), 7.02 (d, 1H), 7.56 (d, 1H).

Claims

1. A method for preparing a compound of formula (I), in: ◆R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group, ◆R3 represents a straight chain or branched (C1-C6) alkyl group, The method comprises the following steps: making a compound of formula (IV) wherein R1 and R2 are as defined above, reacting with a compound of formula (V) in anisole at a temperature above 135° C. in the presence of cesium carbonate, wherein R3 is as defined above, and X - represents a monovalent anionic counter ion.

2. The process according to claim 1, wherein the compound of formula (I) is isolated as a monohydrohalide salt or a dihydrohalide salt.

3. The process according to claim 1, wherein the compound of formula (V) is obtained from 1,4-diazabicyclo[2.2.2]octane.

4. The method according to any one of claims 1 to 3, wherein the compound of formula (IV): wherein R1 and R2 independently represent a halogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C1-C6) alkoxy group, a linear or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group, obtained by regioselective monobromination of a compound of formula (VI) in a solvent in the presence of a brominating agent selected from bromine, sodium bromide / trichloroisocyanuric acid, or bromine / sodium acetate, wherein R1 and R2 are as defined above.

5. The process according to claim 4, wherein the reaction is carried out in the presence of 1 equivalent of a brominating agent.

6. The process according to claim 4, wherein the brominating agent is bromine.

7. The process according to claim 4, wherein the solvent is selected from the group consisting of acetic acid, dichloromethane, a mixture of methanol and sulfuric acid, and a mixture of acetic acid and dichloromethane.

8. The process according to claim 4, wherein the reaction is carried out by diluting the compound of formula (VI) with 10 to 20 volumes of an organic solvent or a mixture of organic solvents.

9. The method according to claim 4, wherein the compound of formula (VI): wherein R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group, Obtained by hydroxylation of a compound of formula (VII) in a solvent in the presence of a transition metal complex and a base, wherein R1 and R2 are as defined above.

10. The method according to any one of claims 5 to 8, wherein the compound of formula (VI): wherein R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group, obtained by hydroxylation of a compound of formula (VII) in a solvent in the presence of a transition metal complex and a base, wherein R1 and R2 are as defined above.

11. The method according to claim 9, wherein the transition metal complex is a palladium complex.

12. The process according to claim 11, wherein the reaction is carried out in the presence of at least 0.01 equivalent of a palladium catalyst.

13. The method according to claim 11, wherein the reaction is carried out in the presence of at least 0.03 equivalents of ligand.

14. The process according to claim 9, wherein the base is a hydroxide.

15. The method according to claim 9, wherein the solvent is 1,4-dioxane or a mixture of water and 1,4-dioxane.

16. The method according to claim 10, wherein the transition metal complex is a palladium complex.

17. The process according to claim 16, wherein the reaction is carried out in the presence of at least 0.01 equivalent of a palladium catalyst.

18. The method according to claim 16, wherein the reaction is carried out in the presence of at least 0.03 equivalents of ligand.

19. The process according to claim 10, wherein the base is a hydroxide.

20. The method according to claim 10, wherein the solvent is 1,4-dioxane or a mixture of water and 1,4-dioxane.

21. The process according to any one of claims 9 and 11 to 20, wherein the conversion of the compound of formula (VII) into the compound of formula (IV) is carried out directly without isolating the compound of formula (VI).

22. The process according to claim 10, wherein the conversion of the compound of formula (VII) into the compound of formula (IV) is carried out directly without isolating the compound of formula (VI).

23. The method according to any one of claims 1 to 3, wherein R1 represents a linear or branched (C1-C6) alkyl group, R2 represents a halogen atom and R3 represents a methyl group.

24. A process according to claim 23, wherein R1 and R3 represent methyl groups and R2 represents a chlorine atom.

25. A process for preparing a compound of formula (II), in: ◆R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group, ◆R3 represents a straight chain or branched (C1-C6) alkyl group, ◆ R4 and R5 represent hydrogen, a linear or branched (C1-C6) alkyl group, or R4 and R5 together with the oxygen atom carrying them form a ring which may be substituted by one to four linear or branched (C1-C6) alkyl groups, The method comprises the following steps: obtaining a compound of formula (I) by the method of claim 1: wherein R1, R2 and R3 are as defined above, The compound of formula (I) is reacted with a boric acid ester of formula (VIII) in an organic solvent or an organic solvent mixture in the presence of a base and a palladium complex: wherein R4 and R5 are as defined above, and R represents a (C0-C6)alkyl-B(OR4)(OR5) group.

26. The method according to claim 25, wherein R1 represents a linear or branched (C1-C6) alkyl group, R2 represents a halogen atom and R3 represents a methyl group.

27. A process according to claim 26, wherein R1 and R3 represent methyl groups and R2 represents a chlorine atom.

28. A method for preparing a compound of formula (II): in: ◆R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group, ◆R3 represents a straight chain or branched (C1-C6) alkyl group, ◆ R4 and R5 represent hydrogen, a linear or branched (C1-C6) alkyl group, or R4 and R5 together with the oxygen atom carrying them form a ring which may be substituted by one to four linear or branched (C1-C6) alkyl groups, Characterized in that the compound of formula (VII) wherein R1 and R2 are as defined above: A hydroxylation reaction is carried out in a solvent in the presence of a transition metal complex and a base. A compound of formula (VI) is obtained wherein R1 and R2 are as defined above: The compound of formula (VI) undergoes a regioselective monobromination reaction in the presence of a brominating agent in a solvent, A compound of formula (IV) is obtained wherein R1 and R2 are as defined above: The compound of formula (IV) is reacted in anisole at a temperature above 135° C. in the presence of cesium carbonate and a compound of formula (V), Wherein R3 is as defined above, and X - represents a monovalent anionic counterion, A compound of formula (I) is obtained wherein R1, R2 and R3 are as defined above: The compound of formula (I) undergoes a borylation reaction in the presence of a boric acid ester of formula (VIII), wherein R4 and R5 are as defined in formula (II), and R represents a hydrogen atom, a hydroxyl group, a straight or branched (C1-C6) alkoxy group, or a (C0-C6) alkyl-B(OR4)(OR5) group, to obtain a compound of formula (II).

29. The method according to claim 28, wherein R1 represents a linear or branched (C1-C6) alkyl group, R2 represents a halogen atom and R3 represents a methyl group.

30. The method according to claim 29, wherein R1 and R3 represent methyl groups and R2 represents a chlorine atom.

31. Use of a compound of formula (VII) for synthesizing a compound of formula (I) or a compound of formula (II), wherein the formula (VII), formula (I) and formula (II) are respectively as follows: in: ◆R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group, ◆R3 represents a straight chain or branched (C1-C6) alkyl group, ◆R4 and R5 represent hydrogen, a linear or branched (C1-C6) alkyl group, or R4 and R5 together with the oxygen atom carrying them form a ring which may be substituted by one to four linear or branched (C1-C6) alkyl groups; Wherein the compound of formula (I) is obtained by the method of claim 9, and the compound of formula (II) is obtained by the method of claim 28.

32. Use of a compound of formula (VII) for synthesizing 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]methoxy}phenyl)propanoic acid or 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid, wherein the formula (VII) is as follows: wherein R1 represents a methyl group and R2 represents a chlorine atom; The compound of formula (VII) is subjected to the process of claim 9 to obtain the compound of formula (I), or the compound of formula (VII) is subjected to the process of claim 28 to obtain the compound of formula (II).

33. Use of a compound of formula (V) for synthesizing a compound of formula (I) or a compound of formula (II), wherein the formula (V) is as follows wherein R3 represents a straight chain or branched (C1-C6) alkyl group, and X - represents a monovalent anionic counterion, The formula (I) and formula (II) are respectively as follows: in: ◆R1 and R2 independently represent a halogen atom, a straight-chain or branched (C1-C6) alkyl group, a straight-chain or branched (C1-C6) alkoxy group, a straight-chain or branched (C1-C6) alkoxy (C1-C6) alkoxy group, a hydroxyl group or a cyano group, ◆R3 represents a straight chain or branched (C1-C6) alkyl group, ◆R4 and R5 represent hydrogen, a linear or branched (C1-C6) alkyl group, or R4 and R5 together with the oxygen atom carrying them form a ring which may be substituted by one to four linear or branched (C1-C6) alkyl groups; Wherein the compound of formula (I) is obtained by the method of claim 1, and the compound of formula (II) is obtained by the method of claim 25.

34. Use of a compound of formula (V) for synthesizing 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]methoxy}phenyl)propanoic acid or 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid, wherein the formula (V) is as follows: Wherein R3 represents a methyl group, and X - represents a monovalent anionic counterion, The compound of formula (V) is subjected to the method of claim 1 to obtain the compound of formula (I), or the compound of formula (V) is subjected to the method of claim 25 to obtain the compound of formula (II).

35. A method for synthesizing 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]methoxy}phenyl)propanoic acid or 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid by using a compound of formula (II), characterized in that The compound of formula (II) is obtained by the process of claim 25 or 28.

36. Synthesis of 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]methoxy}phenyl)propanoic acid or 2-{[5-{3-chloro-2-methyl-4-[ 2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid, by using 1,4-diazabicyclo[2.2.2]octane during the process for preparing the compound of formula (II) according to claim 25 or 28.

Images