Process for manufacture of antibiotic macrocyclic peptides

Abstract

The present invention relates to a novel process for the manufacture of 4-[(11S, 14S, 17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12, 15, 18-trioxo-2-thia-4, 10, 13, 16, 19-pentaazatricyclo [19.4.0.03, 8] pentacosa-1 (25), 3 (8), 4, 6, 21, 23-hexaen-22-yl] benzoic acid (I) or a pharmaceutically acceptable salt thereof. The invention further relates to certain synthetic intermediates for use in the novel process according to the invention. The method according to the invention is particularly suitable for the large-scale production of compounds of formula (I) under GMP conditions. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel method for preparing 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (I) or a pharmaceutically acceptable salt thereof.

[0002]

[0003] The present invention further relates to certain synthetic intermediates useful in the novel processes according to the invention.

[0004] The process according to the invention is particularly suitable for large-scale production of compounds of formula (I) under GMP conditions. Background Art

[0005] The compound of formula (I) is a potent antibiotic selective for Acinetobacter baumannii, as discussed in WO2019206853. The compound of formula (I) is also known by the international nonproprietary name (INN) zosurabalpin (WHO Drug Information, Vol. 36, No. 2, 2022).

[0006] WO2019206853 discloses a laboratory-scale synthesis of a compound of formula (I), which relies on a Suzuki coupling reaction, characterized by a high catalyst loading (about 20 mol%) and a relatively high amount of an organic boronic acid structural unit (about 1.5 equivalents). In addition to high costs, high catalyst loading also leads to palladium impurities that are difficult to remove in the final product. Similarly, the use of a high amount of organic boronic acid can lead to the formation of organic impurities. In addition, the method disclosed in WO2019206853 involves the use of a toxic solvent dioxane, and relies on chromatography to purify certain intermediates and final products.

[0007] In summary, the method for preparing the compound of formula (I) as described in WO2019206853 is not suitable for the industrial-scale synthesis of the compound of formula (I). Therefore, there is a high unmet demand for novel methods for manufacturing compounds of formula (I) to provide patients with this new treatment option for Acinetobacter baumannii infection and the diseases caused therefrom. Summary of the invention

[0008] The present invention provides an improved process for preparing compounds of formula (I) which overcomes the above-mentioned problems. The present invention also provides certain synthetic intermediates which can be used in the novel process. DETAILED DESCRIPTION

[0009] definition

[0010] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims and abstract) and / or all steps of any method or process disclosed thereby may be combined in any combination, except for combinations in which at least some of these features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any accompanying claims and abstract), or to any novel step or any novel combination of steps of any method or process disclosed thereby.

[0011] The term "palladium catalyst" as used herein refers to any palladium catalyst capable of reacting an aryl bromide 1 as described herein with (4-carbomethoxyphenyl)boronic acid (2) on an industrial scale to obtain compound 3 as defined herein. The palladium catalyzed reaction according to the present invention requires a zero-valent palladium species (Pd(0)). Exemplary catalytically active Pd(0) species can be applied directly or can be formed in situ by combining a palladium source with a phosphine ligand. In some embodiments, the palladium catalyst is a preformed palladium catalyst. Examples of preformed catalytically active Pd(0) reagents include: Pd(PPh3)4 and Pd(L)2, wherein L is selected from PBu3, AmPhos, CPhos, RuPhos and SPhos. Other examples of preformed palladium catalysts include: [Pd(L)XCl] (L = ligand as defined above, X = allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, p-tert-butylindenyl); [Pd(L)X] triflate (L = ligand as defined above, X = as defined above), [Pd(L)(2-(2'-amino-1,1'-biphenyl)Cl] (L = as defined above); [Pd(L)(2-(2'-amino-1,1'-biphenyl)] methanesulfonate (L = as defined above), [Pd(L)(2-(2'-methylamino-1,1'-biphenyl)] methanesulfonate (L = as defined above), [Pd(L)(2-(2-aminoethyl)phenyl)Cl] (L = as defined above), PdLCl2, PdL2Cl2 (L = PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3)2, dppf, dcypf, dippf, dtbpf, [PdI(L)]2 (L = PtBu3, AmPhos).Examples of palladium sources that form palladium catalysts in situ in combination with suitable ligands include: bis(dibenzylideneacetone)palladium (Pd(dba)2), (Pd2(dba)3), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2, palladium trifluoroacetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2), palladium iodide (PdI2), bis(acetylacetonate)palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienyl allylpalladium, allylpalladium(II) chloride dimer (Pd( Dichlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), bis-μ-methylsulfonylbis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), bis-μ-methylsulfonylbis[2'-(methylamino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), and bis-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II). Examples of ligands that form a palladium catalyst in situ in combination with the above-mentioned palladium source include: monophosphines or diphosphines, such as PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf and dtbpf.

[0012] As used herein, the term "salt" refers to any type of salt formed by reacting the compounds disclosed herein with the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., especially hydrochloric acid; and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. In the case where the compounds disclosed herein contain a free acid moiety, salts can also be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, and the like.

[0013] Manufacturing method

[0014] In a first aspect, the present invention provides a method for producing compound 3 or a salt thereof,

[0015]

[0016] The method includes:

[0017] (a) Making aryl bromide 1

[0018]

[0019] With (4-methoxycarbonylphenyl)boronic acid (2)

[0020]

[0021] The reaction is carried out in the presence of a palladium catalyst and a base to obtain the compound of formula 3. In another aspect, the present invention provides a method for preparing compound 3 or a salt thereof,

[0022]

[0023] The method includes:

[0024] (a) Making aryl bromide 1

[0025]

[0026] With (4-methoxycarbonylphenyl)boronic acid (2)

[0027]

[0028] The reaction is carried out in an aromatic solvent in the presence of a palladium catalyst and a base to obtain the compound 3; wherein the palladium catalyst is selected from:

[0029] i) a preformed catalyst selected from Pd(PPh3)4, Pd(L 1 )2、[Pd(L 1 )XCl]、

[0030] [Pd(L 1 )X] trifluoromethanesulfonate, [Pd(L 1 )(2-(2'-amino-1,1'-biphenyl)Cl];

[0031] [Pd(L 1 )(2-(2'-amino-1,1'-biphenyl)] methanesulfonate, [Pd(L 1)(2-(2'-methylamino-1,1'-biphenyl)] methanesulfonate, [Pd(L 1 )(2-(2-aminoethyl)phenyl)Cl], Pd(L 2 )Cl2、Pd(L 2 )2Cl2 and [PdI(L 3 )] 2; wherein X is selected from allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, p-tert-butylindenyl; L 1 Selected from PBu3, AmPhos, CPhos, RuPhos and SPhos; L 2 Selected from PtBu3, AmPhos, PtBu2Bu, PtBu2Ph,

[0032] PtBu2-p-C6H4CF3)2, dppf, dcypf, dippf and dtbpf; and L 3 Selected from PtBu3,

[0033] AmPhos; and

[0034] ii) Catalysts formed in situ from:

[0035] iia) a palladium source selected from the group consisting of bis(dibenzylideneacetone)palladium (Pd(dba)2), (Pd2(dba)3),

[0036] Bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2,

[0037] Palladium trifluoroacetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2), palladium iodide (PdI2), palladium diacetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-

[0038] Palladium(II) chloride (PdCl2(CH3CN)2), cyclopentadienyl allyl palladium, allyl palladium(II) chloride dimer (Pd(allyl)Cl)2), (2-butenyl) chloropalladium dimer, (2-

[0039] (Methallyl)palladium(II) chloride dimer, (1-phenylallyl)palladium chloride dimer,

[0040] (p-tert-butylindenyl)palladium(II) chloride dimer, di-μ-chlorobis[2'-(amino-N)[1,1'-

[0041] Biphenyl]-2-yl-C]dipalladium(II), bis-μ-methanesulfonylbis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), bis-μ-methanesulfonylbis[2'-(methylamino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II) and bis-μ-chlorobis[2-[(dimethylamino)methyl]phenyl

[0042] -C,N]dipalladium(II); and

[0043] iib) a ligand selected from the group consisting of monophosphines and diphosphines, in particular a ligand selected from the group consisting of: PtBu3,

[0044] PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph,

[0045] PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos,

[0046] dppf, dcypf, dippf, and dtbpf; and

[0047] The base is selected from inorganic bases and alcoholates, preferably wherein the base is selected from Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F and NaOH,

[0048] More preferably wherein the base is K3PO4 or K2CO3.

[0049] As described in WO2019206853, aryl bromide 1 is Suzuki coupled with (4-methoxyformylphenyl)boronic acid (2) rather than (4-(tert-butoxycarbonyl)phenyl)boronic acid to give new intermediate 3, which can be partially deprotected under alkaline conditions to give new intermediate 4 (see below). This is in contrast to the comprehensive deprotection under acidic conditions (trifluoroacetic acid) described in WO2019206853. Importantly, the new intermediate 4 is crystalline and can therefore be easily purified by crystallization, replacing the need for chromatography as described in WO2019206853.

[0050] In one embodiment of step (a) of the method according to the present invention, the palladium catalyst is selected from:

[0051] i) a preformed catalyst selected from Pd(PPh3)4, Pd(L 1 )2、[Pd(L 1 )XCl]、[Pd(L 1 )X]

[0052] trifluoromethanesulfonate, [Pd(L 1 )(2-(2'-amino-1,1'-biphenyl)Cl]; [Pd(L 1 )(2-(2'-amino

[0053] -1,1'-biphenyl)] methanesulfonate, [Pd(L 1 )(2-(2'-methylamino-1,1'-biphenyl)] methanesulfonate,

[0054] [Pd(L 1 )(2-(2-aminoethyl)phenyl)Cl], Pd(L 2 )Cl2、Pd(L 2 )2Cl2 and [PdI(L 3 )]2;

[0055] wherein X is selected from the group consisting of allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, and p-tert-butylindenyl; L 1 Selected from PBu3, AmPhos, CPhos, RuPhos and SPhos;

[0056] L 2 is selected from the group consisting of PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3)2, dppf, dcypf, dippf and dtbpf; and L 3 selected from PtBu3, AmPhos; and ii) a catalyst formed in situ from:

[0057] iia) a palladium source selected from the group consisting of bis(dibenzylideneacetone)palladium (Pd(dba)2), (Pd2(dba)3),

[0058] Bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2, palladium trifluoroacetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2), palladium iodide (PdI2), bis(acetylacetonate)-palladium(II) dichloride (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienyl allylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2), (2-butenyl) chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, (1-phenylallyl)palladium chloride dimer, (p-tert-butylindenyl)palladium(II) chloride dimer, di-μ-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-

[0059] 1,1'-biphenyl-2-yl-C]dipalladium(II), di-μ-methanesulfonylbis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]

[0060] Dipalladium(II), bis-μ-methanesulfonylbis[2'-(methylamino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), and bis-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II); and

[0061] iib) a ligand selected from the group consisting of monophosphines and diphosphines, in particular a ligand selected from the group consisting of: PtBu3,

[0062] PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph,

[0063] PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos,

[0064] dppf, dcypf, dippf and dtbpf.

[0065] In one embodiment of step (a) of the method according to the present invention, the palladium catalyst is selected from Pd(PPh3)4, Pd(L 1 )2、[Pd(L 1 )XCl]、[Pd(L 1 )X] trifluoromethanesulfonate, [Pd(L 1 )(2-(2'-amino-1,1'-biphenyl)Cl]; [Pd(L 1 )(2-(2'-amino-1,1'-biphenyl)] methanesulfonate, [Pd(L 1 )(2-(2'-methylamino-1,1'-biphenyl)] methanesulfonate, [Pd(L 1 )(2-(2-aminoethyl)phenyl)Cl], Pd(L 2 )Cl2、Pd(L 2 )2Cl2 and [PdI(L 3 )] 2; wherein X is selected from allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, p-tert-butylindenyl; L 1 Selected from PBu3, AmPhos, CPhos, RuPhos and SPhos; L 2 is selected from the group consisting of PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3)2, dppf, dcypf, dippf and dtbpf; and L 3 Selected from PtBu3, AmPhos.

[0066] In one embodiment of step (a) of the process according to the invention, the palladium catalyst is formed in situ from:

[0067] i) a palladium source selected from the group consisting of bis(dibenzylideneacetone)palladium (Pd(dba)2), (Pd2(dba)3), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2, palladium trifluoroacetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2), palladium iodide (PdI2), palladium diacetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride

[0068] (PdCl2(CH3CN)2), cyclopentadienyl allyl palladium, allyl palladium chloride (II) dimer (Pd(allyl)Cl)2), (2-butenyl) chloropalladium dimer, (2-methylallyl) palladium chloride (II)

[0069] dimer, (1-phenylallyl)palladium chloride dimer, (p-tert-butylindenyl)palladium(II) chloride dimer, bis-μ-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), bis-μ-methanesulfonylbis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), bis-μ-methanesulfonylbis[2'-(methylamino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), and bis-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II); and

[0070] ii) a ligand selected from the group consisting of monophosphines and diphosphines.

[0071] In a preferred embodiment, the monophosphine ligand and diphosphine ligand are selected from PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf and dtbpf.

[0072] In a preferred embodiment of step (a) of the process according to the present invention, the palladium catalyst is selected from Pd(PPh3)4, CPhosPdG3, Pd2(dba)3+CPhos and PdCl2(dtbpf).

[0073] It has been found that the palladium catalyst PdCl2(dtbpf) works particularly well in the Suzuki coupling according to the present invention. Therefore, the Suzuki coupling with PdCl2(dtbpf) requires only very low catalyst loadings (2 mol% or less) and a small excess of boric acid 2, which results in less contamination with palladium and organic impurities in the final product, lower costs and less waste. These are important aspects when manufacturing chemicals on an industrial scale, especially when manufacturing pharmaceutical products.

[0074] Therefore, in a particularly preferred embodiment of step (a) of the process according to the invention, the palladium catalyst is PdCl2(dtbpf).

[0075] In one embodiment of step (a) of the process according to the present invention, the palladium catalyst is present in an amount of 1 mol % to 10 mol % relative to the aryl bromide 1 .

[0076] In one embodiment of step (a) of the process according to the present invention, the palladium catalyst is present in an amount of 1 mol % to 5 mol % relative to the aryl bromide 1 .

[0077] In a preferred embodiment of step (a) of the process according to the present invention, the palladium catalyst is present in an amount of 1 mol % to 3 mol % relative to the aryl bromide 1 .

[0078] In a particularly preferred embodiment of step (a) of the process according to the invention, the palladium catalyst is present in an amount of 2 mol % relative to the aryl bromide 1 .

[0079] In a preferred embodiment of step (a) of the process according to the present invention, the palladium catalyst is PdCl2(dtbpf) and is present in an amount of 1 mol% to 10 mol% relative to the aryl bromide 1.

[0080] In another preferred embodiment of step (a) of the process according to the present invention, the palladium catalyst is PdCl2(dtbpf) and is present in an amount of 1 mol% to 5 mol% relative to the aryl bromide 1.

[0081] In another preferred embodiment of step (a) of the process according to the present invention, the palladium catalyst is PdCl2(dtbpf) and is present in an amount of 1 mol% to 3 mol% relative to the aryl bromide 1.

[0082] In a particularly preferred embodiment of step (a) of the process according to the invention, the palladium catalyst is PdCl2(dtbpf) and is present in an amount of 2 mol% relative to the aryl bromide 1.

[0083] In one embodiment of step (a) of the process according to the invention, the base is selected from inorganic bases and alcoholates.

[0084] In a preferred embodiment of step (a) of the process according to the present invention, the base is selected from the group consisting of Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F and NaOH.

[0085] In a preferred embodiment of step (a) of the process according to the present invention, the base is selected from K3PO4 and K2CO3.

[0086] In a particularly preferred embodiment of step (a) of the process according to the invention, the base is K3PO4.

[0087] In a particularly preferred embodiment of step (a) of the process according to the invention, the base is K2CO3.

[0088] In one embodiment of step (a) of the process according to the invention, 1 to 4 equivalents of said base relative to the aryl bromide 1 are used.

[0089] In a preferred embodiment of step (a) of the process according to the invention, 1 to 3 equivalents of said base relative to the aryl bromide 1 are used.

[0090] In another preferred embodiment of step (a) of the process according to the invention, 1 to 2 equivalents of said base relative to the aryl bromide 1 are used.

[0091] In a particularly preferred embodiment of step (a) of the process according to the invention, 1.5 equivalents of said base relative to the aryl bromide 1 are used.

[0092] One advantage of the Suzuki coupling of step (a) of the process according to the invention is that it performs very well in toluene, in contrast to toxic dioxanes as described in WO2019206853. This is particularly important when the reaction is carried out on an industrial scale and in view of the fact that the final antibiotic product of formula (I) is intended for administration to mammals, where trace amounts of toxic solvents are unacceptable.

[0093] Therefore, in one embodiment of step (a) of the method of the present invention, step (a) is carried out in an aromatic solvent.

[0094] In one embodiment, the aromatic solvent is selected from toluene, xylene (o-xylene, p-xylene, m-xylene, or a mixture thereof), ethylbenzene, anisole, cumene and isopropyltoluene.

[0095] In a preferred embodiment, the aromatic solvent is toluene.

[0096] It was found that the methyl ester portion of the boronic acid building block 2 was susceptible to hydrolysis under the reaction conditions used. However, it was surprisingly found that the addition of water to the reaction mixture prevented the hydrolysis, thereby allowing the use of fewer equivalents of this building block.

[0097] Therefore, in one embodiment of step (a) of the process according to the present invention, the process is carried out in the further presence of water.

[0098] In one embodiment of step (a) of the process according to the present invention, the process is carried out in the further presence of 1 to 30 equivalents of water relative to the aryl bromide 1 .

[0099] In one embodiment of step (a) of the process according to the present invention, the process is carried out in the further presence of 1 to 20 equivalents of water relative to the aryl bromide 1 .

[0100] In one embodiment of step (a) of the process according to the invention, the process is carried out in the further presence of 5 to 25 equivalents of water relative to the aryl bromide 1 .

[0101] In a preferred embodiment of step (a) of the process according to the invention, the process is carried out in the further presence of 10 to 25 equivalents of water relative to the aryl bromide 1 .

[0102] In another preferred embodiment of step (a) of the process according to the invention, the process is carried out in the further presence of 12.5 to 25 equivalents of water relative to the aryl bromide 1 .

[0103] In a particularly preferred embodiment of step (a) of the process according to the invention, the process is carried out in the further presence of 25 equivalents of water relative to the aryl bromide 1 .

[0104] In one embodiment of step (a) of the process according to the invention, the process is carried out in the further presence of 5 to 15 equivalents of water relative to the aryl bromide 1 .

[0105] In one embodiment of step (a) of the process according to the invention, the process is carried out in the further presence of 10 to 15 equivalents of water relative to the aryl bromide 1 .

[0106] In a particularly preferred embodiment of step (a) of the process according to the invention, the process is carried out in the further presence of 12.5 equivalents of water relative to the aryl bromide 1 .

[0107] In one embodiment of step (a) of the process according to the present invention, the process is carried out in the further presence of water, wherein water is added continuously over a period of 2 to 8 hours to the reaction mixture comprising the aryl bromide 1, the organoboronic acid 2, the palladium catalyst and the base.

[0108] In one embodiment of step (a) of the process according to the present invention, the process is carried out in the further presence of water, wherein water is added continuously to the reaction mixture comprising aryl bromide 1, organoboronic acid 2, palladium catalyst and base over a period of 2 to 7 hours.

[0109] In a preferred embodiment of step (a) of the process according to the present invention, the process is carried out in the further presence of water, wherein water is added continuously over a period of 3 to 6 hours to the reaction mixture comprising the aryl bromide 1, the organoboronic acid 2, the palladium catalyst and the base.

[0110] In one embodiment of step (a) of the process according to the present invention, the process is carried out in the further presence of water, wherein water is added continuously over a period of 2 to 5 hours to the reaction mixture comprising aryl bromide 1, organoboronic acid 2, palladium catalyst and base.

[0111] In a preferred embodiment of step (a) of the process according to the present invention, the process is carried out in the further presence of water, wherein water is added continuously over a period of 2 to 4 hours to the reaction mixture comprising the aryl bromide 1, the organoboronic acid 2, the palladium catalyst and the base.

[0112] In a particularly preferred embodiment of step (a) of the process according to the invention, the process is carried out in the further presence of water, wherein water is added continuously over a period of 6 hours to the reaction mixture comprising aryl bromide 1, organoboronic acid 2, palladium catalyst and base.

[0113] In a particularly preferred embodiment of step (a) of the process according to the invention, the process is carried out in the further presence of water, wherein water is added continuously over a period of 3 hours to the reaction mixture comprising aryl bromide 1, organoboronic acid 2, palladium catalyst and base.

[0114] As mentioned above, the novel Suzuki coupling according to the present invention allows the use of fewer equivalents of the organoboronic acid 2 compared to the amount of boronic acid used in the method described in WO2019206853.

[0115] Therefore, in one embodiment of step (a) of the process according to the invention, 1 to <1.5 equivalents of the organoboronic acid 2 relative to the aryl bromide 1 are used.

[0116] In a preferred embodiment of step (a) of the process according to the present invention, 1 to 1.4 equivalents of the organoboric acid 2 relative to the aryl bromide 1 are used.

[0117] In another preferred embodiment of step (a) of the process according to the invention, 1 to 1.3 equivalents of the organoboric acid 2 relative to the aryl bromide 1 are used.

[0118] In another preferred embodiment of step (a) of the process according to the invention, 1.05 to 1.2 equivalents of the organoboric acid 2 relative to the aryl bromide 1 are used.

[0119] In another preferred embodiment of step (a) of the process according to the invention, 1 to 1.2 equivalents of the organoboric acid 2 relative to the aryl bromide 1 are used.

[0120] In another preferred embodiment of step (a) of the process according to the invention, 1 to 1.1 equivalents of the organoboric acid 2 relative to the aryl bromide 1 are used.

[0121] In a particularly preferred embodiment of step (a) of the process according to the invention, 1.2 equivalents of the organoboric acid 2 relative to the aryl bromide 1 are used.

[0122] In a particularly preferred embodiment of step (a) of the process according to the invention, 1.05 equivalents of the organoboronic acid 2 relative to the aryl bromide 1 are used.

[0123] If desired, palladium contamination levels of compound 3 can be reduced to levels typically <10 ppm by in situ treatment of compound 3 with N-acetylcysteine ​​or ammonium pyrrolidinedithiocarbamate.

[0124] Therefore, in one embodiment, the method for producing compound 3 or a salt thereof according to the present invention optionally further comprises:

[0125] (b) adding an aqueous solution of ammonium pyrrolidinedithiocarbamate or N-acetylcysteine ​​to the reaction mixture obtained from step (a).

[0126] In one embodiment, the method for producing compound 3 or a salt thereof according to the present invention optionally further comprises:

[0127] (b) adding an aqueous solution of N-acetylcysteine ​​to the reaction mixture obtained from step (a).

[0128] In one embodiment, the method for producing compound 3 or a salt thereof according to the present invention optionally further comprises:

[0129] (b) adding ammonium pyrrolidinedithiocarbamate to the reaction mixture obtained from step (a).

[0130] In another aspect, the present invention provides a method for producing compound 4 or a salt thereof,

[0131]

[0132] The method comprises steps (a) and (b) as described herein, and further comprises:

[0133] (c) reacting compound 3 described herein with sodium hydroxide to obtain compound 4 described herein.

[0134] In one embodiment, step (c) is carried out in a solvent which is an alcohol, preferably methanol.

[0135] In another aspect, the present invention provides a method for producing compound 4 or a salt thereof, the method comprising steps (a) and (b) as described herein, and further comprising:

[0136] (c) reacting the compound 3 according to claim 1 with 2 to 10 equivalents, preferably 3 to 8 equivalents, more preferably 4 to 7 equivalents, especially 7 equivalents of sodium hydroxide to obtain the compound 4, wherein the sodium hydroxide is added as a 5% w / w to 30% w / w, preferably 10% w / w to 20% w / w, especially 16% w / w aqueous solution to a solution of the compound 3 in an alcohol solvent or a mixture of water and an alcohol solvent.

[0137] In one embodiment, the alcohol solvent is methanol.

[0138] The main advantage of the novel compound 4 according to the present invention is its crystallinity, which allows its purification by crystallization. Especially on an industrial scale, crystallization is a convenient method for the purification of chemicals, in contrast to other purification techniques such as chromatography.

[0139] Therefore, in one embodiment, the method for producing compound 4 according to the present invention optionally further comprises:

[0140] (d) Crystallizing the compound 4.

[0141] In a preferred embodiment of step (d) of the process according to the present invention, said crystallization of said compound 4 is crystallization of said compound 4 from a mixture of alcohol and acetone.

[0142] In a preferred embodiment, the alcohol is selected from 2-propanol and 1-propanol.

[0143] In a particularly preferred embodiment, the alcohol is 1-propanol.

[0144] In another aspect, the present invention provides a method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0145]

[0146] The method comprises steps (a) to (d) of the method described herein, and further comprises:

[0147] (e) reacting compound 4 described herein with an acid to obtain the compound of formula (I).

[0148] In a preferred embodiment of step (e) of the process according to the present invention, the acid is hydrochloric acid.

[0149] In one embodiment, step (e) is carried out in a solvent mixture selected from acetone / water, THF / water and acetonitrile / water.

[0150] In one embodiment, 2 to 6 equivalents of acid relative to compound 4 are used in step (e) of the process according to the present invention.

[0151] In a preferred embodiment, 3 to 5 equivalents of acid relative to compound 4 are used in step (e) of the process according to the present invention.

[0152] In another preferred embodiment, 4 to 5 equivalents of acid relative to compound 4 are used in step (e) of the process according to the present invention.

[0153] In another preferred embodiment, 3.5 to 4.5 equivalents of acid relative to compound 4 are used in step (e) of the process according to the present invention.

[0154] In a particularly preferred embodiment, 4 to 4.1 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.

[0155] In another particularly preferred embodiment, 4 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.

[0156] In another particularly preferred embodiment, 4.1 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.

[0157] In one embodiment, step (e) of the process according to the present invention is carried out between room temperature and reflux.

[0158] In a preferred embodiment, step (e) of the process according to the invention is carried out between 30° C. and reflux.

[0159] In another preferred embodiment, step (e) of the process according to the invention is carried out between 35°C and 65°C.

[0160] In a particularly preferred embodiment, step (e) of the process according to the invention is carried out between 35°C and 60°C.

[0161] In another aspect, the present invention provides the use of the method for making compound 3 described herein in making a compound of formula (I).

[0162] In another aspect, the present invention provides the use of the method for making compound 4 described herein in making a compound of formula (I).

[0163] Compounds of the present invention

[0164] The present invention relates to certain synthetic intermediates useful in making the novel antibiotics of formula (I) described herein.

[0165] The present invention also relates to certain compounds made according to the novel chemical methods described herein.

[0166] In more detail, in one aspect, the present invention provides a compound, which is tert-butyl 3-[[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-22-(4-methoxycarbonylphenyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-1-carboxylate (3), or a salt thereof

[0167]

[0168] In another aspect, the present invention provides a compound, which is 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4), or a salt thereof

[0169]

[0170] In another aspect, the invention relates to Compound 3 produced according to the method for producing Compound 3 described herein.

[0171] In another aspect, the invention relates to Compound 3 produced according to the method for producing Compound 3 described herein.

[0172] In another aspect, the invention relates to a compound of formula (I) manufactured according to a process for manufacturing a compound of formula (I) as described herein.

[0173] In another aspect, the present invention relates to the use of compound 3 as described herein in the manufacture of a compound of formula (I).

[0174] In another aspect, the present invention relates to the use of compound 4 as described herein in the manufacture of a compound of formula (I).

[0175] Examples

[0176] The present invention will be more fully understood by reference to the following examples. However, the claims should not be interpreted as being limited to the scope of the examples.

[0177] The following abbreviations are used in this article:

[0178] PdCl2(dtbpf)=[1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (CAS 95408-45-0); HCl=hydrochloric acid; PPh3=triphenylphosphine; PtBu3=tri-tert-butylphosphine; PAd3=tri(1-adamantyl)phosphine; AmPhos=(4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine; cataCXiumA=di(1-adamantyl)-n-butylphosphine; PtBu2Bu=di-tert-butyl(n-butyl)phosphine; PtBu2Ph=di-tert-butyl(phenyl)phosphine; PtBu2-p-C6H4CF3=di-tert-butyl(4-trifluoromethylphenyl)phosphine; cataCXium POMeCy = 1-(2-methoxyphenyl)-2-(dicyclohexylphosphino)pyrrole; CPhos = 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; SPhos = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; dppf = 1,1'-ferrocenyldiyl-bis(diphenylphosphine); dcypf = 1,1'-ferrocenyldiyl-bis(dicyclohexylphosphine) ); dippf = 1,1'-diylferrocenyl-bis(diisopropylphosphine); dtbpf = 1,1'-bis(di-tert-butylphosphino)ferrocene; Pd(PPh3)4 = tetrakis(triphenylphosphino)palladium; CPhosPdG3 = [(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0).

[0179] Example 1

[0180] Preparation of 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid

[0181]

[0182] To a dry Ar flushed flask was added tert-butyl 3-[[(11S,14S,17S)-22-bromo-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-12,15,18-trione-16-methyl-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-1-carboxylate (1) (30.0 g, 28.57 mmol, 1.0 eq), tripotassium phosphate (9.10 g, 42.85 mmol, 1.5 eq) and toluene (300 ml, 10 vol). The mixture was degassed and heated to 90°C. To the hot mixture was added (4-methoxyformylphenyl)organoboronic acid (2) (5.4 g, 30.00 mmol, 1.05 eq) and PdCl2(dtbpf) (372 mg, 0.571 mmol, 0.02 eq). Water (6.43 g, 357.1 mmol, 12.5 eq) was added to the resulting suspension via a syringe pump over 3 hours. The mixture was stirred for 4 hours. The mixture was cooled to 60°C and a 9% w / w aqueous solution of N-acetylcysteine ​​was added. The mixture was stirred at 60°C for 1 hour and then the phases were separated. The organic phase was extracted with water. The organic layer was treated with activated carbon at room temperature.

[0183] The mixture was distilled under reduced pressure, the solvent was replaced with methanol and concentrated to a final volume of 80 ml. Methanol (221 ml, 7.4 vol) and water (70 ml, 2.3 vol) were added. The mixture was heated to 50 ° C and 32% w / w sodium hydroxide aqueous solution (25.0 g, 200.0 mmol, 7.0 eq) was added. The mixture was stirred for 5 hours and then cooled to 20 ° C. Methanol was distilled off under reduced pressure. A solution of ethyl acetate (250 ml, 8.3 vol) and citric acid (27.8 g) in water (60 ml, 2 vol) was added to the residue at room temperature. The organic phase was extracted with a solution of sodium bicarbonate (4.88 g) in water (150 ml), and then extracted with water (150 ml). The organic phase was concentrated to 3 vol under reduced pressure. The solvent was replaced with 1-propanol to a final volume of about 3.3 vol. The residue was heated to 60 ° C. Acetone (198 g, 250 ml, 8.33 vol) was added within 1.5 hours. The resulting suspension was cooled to 20° C. over 5 hours. The solid was recovered by suction filtration and rinsed with a solution of 1-propanol (20 g) and acetone (60 g), and dried under reduced pressure. 23.1 g (81.4% yield) of crude 4-[(11S, 14S, 17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-12,15,18-trione-16-methyl-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4) was obtained as an off-white solid.

[0184] Example 1a

[0185] Preparation of 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid

[0186]

[0187] To a dry Ar flushed flask was added tert-butyl 3-[[(11S,14S,17S)-22-bromo-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-12,15,18-trione-16-methyl-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-1-carboxylate (1) (5.0 g, 4.76 mmol, 1.0 eq), potassium carbonate (0.987 g, 7.14 mmol, 1.5 eq) and toluene (50 ml, 10 vol). The mixture was degassed and heated to 90°C. To the hot mixture was added (4-methoxyformylphenyl)boronic acid (2) (1.0 g, 5.56 mmol, 1.2 eq) and toluene (25 ml, 5 vol). The mixture was distilled under reduced pressure until 25 ml of distillate was collected. PdCl2(dtbpf) (62 mg, 0.095 mmol, 0.02 eq) was added and the mixture was stirred at 85 to 90°C for about 30 minutes. Water (2.14 g, 119.03 mmol, 25.0 eq) was added via a syringe pump over 6 hours. The mixture was stirred for at least 2 hours.

[0188] Ammonium pyrrolidinedithiocarbamate (237 mg, 1.43 mmol, 0.3 eq) was added. The mixture was stirred at 85 to 90° C. for at least 1 hour and then the phases were separated. The organic phase was extracted with water.

[0189] The organic layer was distilled under reduced pressure and methanol (12.5 ml, 2.5 vol) was added. The mixture was cooled to 40 ° C. A 16% w / w aqueous solution of sodium hydroxide (8.33 g, 33.33 mmol, 7.0 eq) was added. The mixture was stirred for at least 5 hours and then cooled to 20 ° C. A 35% w / w aqueous solution of citric acid (13.07 g, 23.81 mmol, 5.0 eq) was added to the residue at 20 ° C, and the mixture was distilled under reduced pressure. The residue was extracted with ethyl acetate. The organic phase was extracted with water, dried over sodium sulfate and diluted with ethyl acetate (15 ml). The solution was heated to 60 ° C and stirred for about 1 hour. The resulting suspension was cooled to 0 ° C in 12 hours and stirred for at least 2 hours. The solid was recovered by suction filtration and rinsed with cold ethyl acetate. 3.2 g (80.4% yield) of 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4) were obtained as an off-white solid.

[0190] Example 2

[0191] Preparation of 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosan-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid

[0192]

[0193] 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-12,15,18-trione-16-methyl-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4) (200 g, 201.78 mmol, 1 eq), tetrahydrofuran (455 ml) and water (320 mL) were added to a 2000 mL four-necked reaction vessel at 35°C and stirred. A solution of HCl 25% (99.8 mL, 821 mmol, 4.1 eq) and water (200 mL) was added at 35 to 50° C. over 10 minutes. The addition funnel was rinsed with water (50 mL) and the reaction mixture was stirred at 60° C. for 4 hours. After basic workup and crystallization at pH 10, the title compound (158.3 g, 98.5%) was obtained as a white powder.

Claims

1. A compound, the compound being tert-butyl 3-[[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-22-(4-methoxycarbonylphenyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-1-carboxylate (3), or a salt thereof 2. A compound, the compound being 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentaazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4), or a salt thereof 3. A method for producing compound 3 or a salt thereof according to claim 1, the method comprising: (a) Making aryl bromide 1 With (4-methoxycarbonylphenyl)boronic acid (2) The reaction is carried out in an aromatic solvent in the presence of a palladium catalyst and a base to obtain the compound 3; wherein the palladium catalyst is selected from: i) a preformed catalyst selected from Pd(PPh3)4, Pd(L 1 )2、[Pd(L 1 )XCl]、[Pd(L 1 )X] trifluoromethanesulfonate, [Pd(L 1 )(2-(2'-amino-1,1'-biphenyl)Cl]; [Pd(L 1 )(2-(2'-amino-1,1'-biphenyl)] methanesulfonate, [Pd(L 1 )(2-(2'-methylamino-1,1'-biphenyl)] methanesulfonate, [Pd(L 1 )(2-(2-aminoethyl)phenyl)Cl], Pd(L 2 )Cl2、Pd(L 2 )2Cl2 and [PdI(L 3 )]2; wherein X is selected from the group consisting of allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, and p-tert-butylindenyl; L 1 Selected from PBu3, AmPhos, CPhos, RuPhos and SPhos; L 2 is selected from the group consisting of PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3)2, dppf, dcypf, dippf and dtbpf; and L 3 Selected from PtBu3, AmPhos; and ii) Catalysts formed in situ from: iia) a palladium source selected from the group consisting of bis(dibenzylideneacetone)palladium (Pd(dba)2), (Pd2(dba)3), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium acetate (Pd(OAc)2, palladium trifluoroacetate (Pd(TFA)2), palladium chloride (PdCl2), palladium bromide (PdBr2), palladium iodide (PdI2), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienyl allylpalladium, allylpalladium chloride (II) dimer (Pd(allyl)Cl)2), (2-butenyl)palladium chloride dimer, ( 2-methylallyl)palladium(II) chloride dimer, (1-phenylallyl)palladium(II) chloride dimer, (p-tert-butylindenyl)palladium(II) chloride dimer, bis-μ-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), bis-μ-methanesulfonylbis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), bis-μ-methanesulfonylbis[2'-(methylamino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), and bis-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II); and iib) a ligand selected from the group consisting of monophosphines and diphosphines, in particular a ligand selected from the group consisting of PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf; and The base is selected from inorganic bases and alcoholates, preferably wherein the base is selected from Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F and NaOH, more preferably wherein the base is K3PO4 or K2CO3.

4. The process according to claim 3, wherein the palladium catalyst is present in an amount of 1 mol% to 10 mol%, preferably 1 mol% to 5 mol%, more preferably 1 mol% to 3 mol%, most preferably 2 mol% relative to the aryl bromide 1.

5. The process according to claim 3 or 4, wherein 1 to 4 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2 equivalents, most preferably 1.5 equivalents of the base are used relative to the aryl bromide 1.

6. The method according to any one of claims 3 to 5, wherein the aromatic solvent is selected from toluene, xylene (o-xylene, p-xylene, m-xylene, or a mixture thereof), ethylbenzene, anisole, cumene and isopropyltoluene. The method according to claim 6 , wherein the aromatic solvent is toluene.

8. The process according to any one of claims 3 to 7, wherein the process is carried out in the further presence of water, preferably 1 to 30 equivalents, more preferably 5 to 25 equivalents, most preferably 10 to 25 equivalents, in particular 12.5 to 25 equivalents of water relative to the aryl bromide 1.

9. The process according to claim 8, wherein the water is added continuously to the reaction mixture comprising the aryl bromide 1, the boronic acid 2, the palladium catalyst and the base over a period of 2 to 8 hours, preferably over a period of 2 to 7 hours, most preferably over a period of 3 to 6 hours.

10. The process according to any one of claims 3 to 9, wherein 1 to <1.5 equivalents, preferably 1 to 1.3 equivalents, more preferably 1 to 1.2 equivalents, more preferably 1.05 to 1.2 equivalents of boronic acid 2 are used relative to aryl bromide 1.

11. The method according to any one of claims 3 to 10, optionally further comprising: (b) adding an aqueous solution of ammonium pyrrolidinedithiocarbamate or N-acetylcysteine ​​to the reaction mixture obtained from step (a).

12. A method for producing the compound 4 or a salt thereof according to claim 2, the method comprising the method according to any one of claims 3 to 11, and further comprising: (c) reacting the compound 3 according to claim 1 with 2 to 10 equivalents, preferably 3 to 8 equivalents, more preferably 4 to 7 equivalents, especially 7 equivalents of sodium hydroxide to obtain the compound 4, wherein the sodium hydroxide is added as a 5% w / w to 30% w / w, preferably 10% w / w to 20% w / w, especially 16% w / w aqueous solution to a solution of the compound 3 in an alcohol solvent or a mixture of water and an alcohol solvent.

13. The method according to claim 12, wherein the alcohol solvent in step (c) is methanol.

14. The method according to claim 12 or 13, optionally further comprising: (d) crystallizing said compound 4, preferably from a mixture of 1-propanol and acetone.

15. A method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof, The method comprises the method according to any one of claims 12 to 14, and further comprises: (e) reacting the compound 4 according to claim 2 with an acid, preferably hydrochloric acid, to obtain the compound of formula (I).

16. The process according to claim 15, wherein step (e) is carried out in a solvent mixture selected from the group consisting of acetone / water, THF / water, and acetonitrile / water.

17. The method according to any one of claims 15 or 16, wherein in step (e), 2 to 6 equivalents, preferably 3 to 5 equivalents, more preferably 4 to 5 equivalents, more preferably 3.5 to 4.5 equivalents, in particular 4.1 equivalents of acid are used relative to compound 4.

18. The process according to any one of claims 15 to 17, wherein the process is carried out between room temperature and reflux, preferably between 30°C and reflux, more preferably between 35°C and 65°C, most preferably between 35°C and 60°C.

19. Compound 3 or a salt thereof according to claim 1, which is produced by the method according to any one of claims 3 to 11.

20. Compound 4 or a salt thereof according to claim 2, which is produced according to the method according to any one of claims 12 to 14.

21. A compound of formula (I) or a pharmaceutically acceptable salt thereof, It is produced according to the method according to any one of claims 15 to 18.

22. A process according to any one of claims 3 to 14 for producing a compound of formula (I) or its pharmaceutically acceptable salts.

23. Use of compound 3 according to claim 1 in the manufacture of a compound of formula (I).

24. Use of compound 4 according to claim 2 in the manufacture of a compound of formula (I).

25. The invention as hereinbefore described.

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