Manufacturing process for antibacterial macrocyclic peptides

Abstract

The present invention relates to 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-pentazatricyclo[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 present invention relates to a novel process for preparing TIFF2025526023000023.tif5462. The present invention further relates to certain synthetic intermediates useful in the novel process according to the invention. The process according to the invention is particularly suitable for large-scale production of compounds of formula (I) under GMP conditions.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to 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-pentazatricyclo[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. [ka] The present invention relates to a novel process for producing

[0002] The present invention further relates to certain synthetic intermediates useful in the novel processes according to the invention.

[0003] The process according to the invention is particularly suitable for large scale production of compounds of formula (I) under GMP conditions. [Background technology]

[0004] Background of the Invention The compound of formula (I) is a potent antibiotic with selective activity against Acinetobacter baumannii, as discussed in International Publication No. 2019206853. The compound of formula (I) is also known as INN zoslavulpin (WHO Drug Information, Vol. 36, No. 2, 2022).

[0005] WO 2019206853 discloses a laboratory-scale synthesis of the compound of Formula (I), which relies on a Suzuki coupling reaction characterized by high catalyst loading (approximately 20 mol%) and a relatively large amount of boronic acid component (approximately 1.5 equivalents). In addition to incurring high costs, high catalyst loading results in palladium impurities in the final product that are difficult to remove. Similarly, the use of large amounts of boronic acid results in the formation of organic impurities. Furthermore, the process disclosed in WO 2019206853 involves the use of the toxic solvent dioxane and relies on chromatography to purify certain intermediates as well as the final product.

[0006] In summary, the process for producing the compound of formula (I) described in WO 2019206853 is not well suited for industrial-scale synthesis of the compound of formula (I). Thus, there is a high unmet need for new processes for producing the compound of formula (I) to offer patients this new treatment option for Acinetobacter baumannii infections and resulting diseases. Summary of the Invention

[0007] Summary of the Invention The present invention provides an improved process for preparing compounds of formula (I) that overcomes the problems outlined above. The present invention also provides certain synthetic intermediates useful in the new process. DETAILED DESCRIPTION OF THE INVENTION

[0008] Detailed Description of the Invention definition It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where inconsistent therewith. All features disclosed herein (including any accompanying claims, and abstract), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel or any novel combination of features disclosed herein (including any accompanying claims, and abstract), or any novel or any novel combination of steps of any method or process so disclosed.

[0009] The term "palladium catalyst" as used herein refers to any palladium catalyst capable of reacting aryl bromide 1 with (4-carbomethoxyphenyl)boronic acid 2 as described herein to yield compound 3 as defined herein on an industrial scale. Palladium-catalyzed reactions according to the present invention require a zero-valent palladium species (Pd(0)). Exemplary catalytically active Pd(0) species may be applied directly or may be formed in situ from a palladium source in combination 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, where L is selected from PBu3, AmPhos, CPhos, RuPhos, and SPhos. Further 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] trifluoromethanesulfonate (L = ligand as defined above, X = ligand as defined above), [Pd(L)(2-(2'-amino-1,1'-biphenyl)Cl] (L = as defined above), [Pd(L)(2-(2'-amino-1,1'-biphenyl)]methyl). Examples of suitable PdI(L) methanesulfonate include [Pd(L)(2-(2'-methylamino-1,1'-biphenyl)]methanesulfonate (L = as defined above), [Pd(L)(2-(2-aminoethyl)phenyl)Cl] (L = as defined above), PdLCl, PdLCl (L = PtBu, AmPhos, PtBuBu, PtBuPh, PtBu-p-CHCF), dppf, dcypf, dippf, dtbpf. [PdI(L)] (L = PtBu, AmPhos).Examples of palladium sources that, in combination with an appropriate ligand, form a palladium catalyst in situ include palladium bis(dibenzylideneacetone) (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 bisacetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienylallylpalladium, allylpalladium(II) ) chloride dimer (Pd(allyl)Cl)2), (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl) chloride dimer, (p-tert-butylindenyl)palladium(II) chloride dimer, di-μ-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2'-(methylamino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), and di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II). Examples of ligands that, in combination with the above-described palladium sources, form palladium catalysts in situ include mono- or diphosphines such as PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf.

[0010] The term "salt" as used herein refers to any type of salt formed by reacting a compound disclosed herein with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., especially hydrochloric acid, and an organic acid, 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. When a compound disclosed herein contains a free acidic moiety, a salt can also be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. 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.

[0011] Manufacturing Process In a first aspect, the present invention provides compound 3, or a salt thereof. [ka] a process for producing The process comprises: (a) In the presence of a palladium catalyst and a base, aryl bromide 1 [ka] (4-Carbomethoxyphenyl)boronic acid (2) [ka] to obtain compound 3.

[0012] In a further aspect, the present invention provides compound 3, or a salt thereof. [ka] a process for producing The process comprises: (a) In an aromatic solvent, aryl bromide 1 is reacted with aryl bromide 1 in the presence of a palladium catalyst and a base. [ka] (4-Carbomethoxyphenyl)boronic acid (2) [ka] to obtain compound 3, wherein the palladium catalyst is i) 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 a preformed catalyst selected from the group consisting of: 2-butenyl, 2-methylallyl, 1-phenylallyl, and p-tert-butylindenyl; 1 is selected from PBu3, AmPhos, CPhos, RuPhos, and SPhos, and L 2 is selected from PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3), dppf, dcypf, dippf, and dtbpf, and L 3is selected from PtBu3, AmPhos, and ii) iia) Palladium bis(dibenzylideneacetone) (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 bisacetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2) a palladium source selected from (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl)chloride dimer, (p-tert-butylindenyl)palladium(II) chloride dimer, di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2′-(methylamino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), and di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II); iib) ligands selected from mono- and diphosphines, in particular PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf and dtbpf, a catalyst formed in situ selected from The base is selected from inorganic bases and alcoholates, preferably the base is selected from Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F, and NaOH, more preferably the base is K3PO4 or K2CO3.

[0013] As described in WO2019206853, Suzuki coupling of aryl bromide 1 with (4-carbomethoxyphenyl)boronic acid (2) rather than (4-(tert-butoxycarbonyl)phenyl)boronic acid affords new intermediate 3, which can be partially deprotected under basic conditions to afford new intermediate 4 (see below). This contrasts with the gobal deprotection under acidic conditions (trifluoroacetic acid) described in WO2019206853. Importantly, new intermediate 4 is crystalline and can therefore be conveniently purified by crystallization, replacing the need for chromatography as described in WO2019206853.

[0014] In one embodiment of step (a) of the process according to the invention, the palladium catalyst is i) 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 3a preformed catalyst selected from the group consisting of: 2-butenyl, 2-methylallyl, 1-phenylallyl, and p-tert-butylindenyl; 1 is selected from PBu3, AmPhos, CPhos, RuPhos, and SPhos, and L 2 is selected from PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3), dppf, dcypf, dippf, and dtbpf, and L 3 is selected from PtBu3, AmPhos, and ii) iia) Palladium bis(dibenzylideneacetone) (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 bisacetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2) a palladium source selected from (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl)chloride dimer, (p-tert-butylindenyl)palladium(II) chloride dimer, di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2′-(methylamino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), and di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II); iib) ligands selected from mono- and diphosphines, in particular PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf and dtbpf, Catalyst formed in situ from is selected from.

[0015] In one embodiment of step (a) of the process according to the invention, the palladium catalyst is 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, and L 1 is selected from PBu3, AmPhos, CPhos, RuPhos, and SPhos, and L 2 is selected from PtBu3, AmPhos, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3), dppf, dcypf, dippf, and dtbpf, and L 3 is selected from PtBu3, AmPhos.

[0016] In one embodiment of step (a) of the process according to the invention, the palladium catalyst is i) Palladium bis(dibenzylideneacetone) (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 bisacetylacetonate (Pd(acac)2), (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl)2), a palladium source selected from (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium (1-phenylallyl) chloride dimer, (p-tert-butylindenyl)palladium(II) chloride dimer, di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2′-(methylamino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), and di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II); ii) a ligand selected from mono- and diphosphines; It is formed in situ from

[0017] In preferred embodiments, the mono- and diphosphine ligands are selected from PtBu3, PAd3, AmPhos, cataCXiumA, PtBu2Bu, PtBu2Ph, PtBu2-p-C6H4CF3, cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf.

[0018] In a preferred embodiment of step (a) of the process according to the invention, the palladium catalyst is selected from Pd(PPh3)4, CPhosPdG3, Pd2(dba)3+CPhos, and PdCl2(dtbpf).

[0019] The palladium catalyst PdCl(dtbpf) has been found to work particularly well in the Suzuki coupling according to the present invention. Thus, Suzuki coupling with PdCl(dtbpf) requires very low catalyst loading (2 mol % or less) and only a slight excess of boronic acid 2, resulting in reduced contamination of the final product with palladium and organic impurities, reduced costs, and reduced waste. These are all important aspects when producing chemicals on an industrial scale, especially when producing pharmaceuticals.

[0020] Thus, in a particularly preferred embodiment of step (a) of the process according to the invention, the palladium catalyst is PdCl2(dtbpf).

[0021] In one embodiment of step (a) of the process according to the invention, the palladium catalyst is present in an amount of 1 mol % to 10 mol % relative to the aryl bromide 1.

[0022] In one embodiment of step (a) of the process according to the invention, the palladium catalyst is present in an amount of 1 mol % to 5 mol % relative to the aryl bromide 1.

[0023] In a preferred embodiment of step (a) of the process according to the invention, the palladium catalyst is present in an amount of 1 mol % to 3 mol % relative to the aryl bromide 1.

[0024] 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.

[0025] In a 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 1 mol % to 10 mol % relative to the aryl bromide 1.

[0026] In a further 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 1 mol % to 5 mol % relative to the aryl bromide 1.

[0027] In a further 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 1 mol % to 3 mol % relative to the aryl bromide 1.

[0028] 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.

[0029] In one embodiment of step (a) of the process according to the invention, the base is selected from inorganic bases and alcoholates.

[0030] In a preferred embodiment of step (a) of the process according to the invention, the base is selected from Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, TlOH, KF, CsF, Bu4F, and NaOH.

[0031] In a preferred embodiment of step (a) of the process according to the invention, the base is selected from K3PO4 and K2CO3.

[0032] In a particularly preferred embodiment of step (a) of the process according to the invention, the base is K3PO4.

[0033] In a particularly preferred embodiment of step (a) of the process according to the invention, the base is K2CO3.

[0034] In one embodiment of step (a) of the process according to the invention, 1 to 4 equivalents of the base relative to the aryl bromide 1 are used.

[0035] In a preferred embodiment of step (a) of the process according to the invention, 1 to 3 equivalents of said base relative to aryl bromide 1 are used.

[0036] In a further preferred embodiment of step (a) of the process according to the invention, 1 to 2 equivalents of said base relative to aryl bromide 1 are used.

[0037] 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.

[0038] One advantage of the Suzuki coupling in step (a) of the process according to the invention is that it works very well in toluene, as opposed to the toxic dioxane described in WO 2019206853. This is particularly important when the reaction is carried out on an industrial scale, given the fact that the final antibiotic product of formula (I) is intended for mammalian administration and traces of toxic solvents cannot be tolerated.

[0039] Thus, in one embodiment of step (a) of the process according to the invention, step (a) is carried out in an aromatic solvent.

[0040] In one embodiment, the aromatic solvent is selected from toluene, xylene (o-xylene, p-xylene, m-xylene or mixtures thereof), ethylbenzene, anisole, cumene and cymene.

[0041] In a preferred embodiment, the aromatic solvent is toluene.

[0042] The methyl ester moiety of boronic acid building block 2 was found to be prone to hydrolysis under the reaction conditions used, however, it was unexpectedly discovered that the addition of water to the reaction mixture prevented this hydrolysis, allowing fewer equivalents of this building block to be used.

[0043] Thus, in one embodiment of step (a) of the process according to the invention, the process is carried out in the presence of additional water.

[0044] In one embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of 1 to 30 equivalents of water relative to the aryl bromide 1.

[0045] In one embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of 1 to 20 equivalents of water relative to the aryl bromide 1.

[0046] In one embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of 5 to 25 equivalents of water relative to the aryl bromide 1.

[0047] In a preferred embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of 10 to 25 equivalents of water relative to the aryl bromide 1.

[0048] In a further preferred embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of 12.5 to 25 equivalents of water relative to the aryl bromide 1.

[0049] In a particularly preferred embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of 25 equivalents of water relative to the aryl bromide 1.

[0050] In one embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of 5 to 15 equivalents of water relative to the aryl bromide 1.

[0051] In one embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of 10 to 15 equivalents of water relative to the aryl bromide 1.

[0052] In a particularly preferred embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of 12.5 equivalents of water relative to the aryl bromide 1.

[0053] In one embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of water, which 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.

[0054] In one embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of water, which 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 7 hours.

[0055] In a preferred embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of water, which is added continuously over a period of 3 to 6 hours to the reaction mixture comprising the aryl bromide 1, the boronic acid 2, the palladium catalyst and the base.

[0056] In one embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of water, which is added continuously over a period of 2 to 5 hours to a reaction mixture comprising aryl bromide 1, boronic acid 2, palladium catalyst and base.

[0057] In a preferred embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of water, which is added continuously over a period of 2 to 4 hours to the reaction mixture comprising the aryl bromide 1, the boronic acid 2, the palladium catalyst and the base.

[0058] In a particularly preferred embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of water, which 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 6 hours.

[0059] In a particularly preferred embodiment of step (a) of the process according to the invention, the process is carried out in the additional presence of water, which is added continuously over a period of 3 hours to the reaction mixture comprising the aryl bromide 1, the boronic acid 2, the palladium catalyst and the base.

[0060] As mentioned above, the new Suzuki coupling according to the present invention allows the use of fewer equivalents of boronic acid 2 compared to the amount of boronic acid used in the process described in WO2019206853.

[0061] Thus, in one embodiment of step (a) of the process according to the invention, 1 to less than 1.5 equivalents of boronic acid 2 relative to aryl bromide 1 are used.

[0062] In a preferred embodiment of step (a) of the process according to the invention, 1 to 1.4 equivalents of boronic acid 2 relative to aryl bromide 1 are used.

[0063] In a further preferred embodiment of step (a) of the process according to the invention, 1 to 1.3 equivalents of boronic acid 2 relative to aryl bromide 1 are used.

[0064] In a further preferred embodiment of step (a) of the process according to the invention, 1.05 to 1.2 equivalents of boronic acid 2 relative to aryl bromide 1 are used.

[0065] In a further preferred embodiment of step (a) of the process according to the invention, 1 to 1.2 equivalents of boronic acid 2 relative to aryl bromide 1 are used.

[0066] In a further preferred embodiment of step (a) of the process according to the invention, 1 to 1.1 equivalents of boronic acid 2 relative to aryl bromide 1 are used.

[0067] In a particularly preferred embodiment of step (a) of the process according to the invention, 1.2 equivalents of boronic acid 2 relative to aryl bromide 1 are used.

[0068] In a particularly preferred embodiment of step (a) of the process according to the invention, 1.05 equivalents of boronic acid 2 relative to aryl bromide 1 are used.

[0069] If desired, the level of palladium contamination of compound 3 can be reduced, typically to levels of <10 ppm, by treating compound 3 in situ with N-acetylcysteine or ammonium pyrrolidinedithiocarbamate.

[0070] Thus, in one embodiment, the process for producing compound 3 or a salt thereof according to the present invention optionally further comprises: (b) adding an aqueous solution of ammonium pyrrolidinedithiocarbamate or N-acetylcysteine to the reaction mixture obtained from step (a).

[0071] In one embodiment, the process for producing compound 3 or a salt thereof according to the present invention optionally further comprises: (b) adding an aqueous solution of N-acetylcysteine to the reaction mixture obtained from step (a).

[0072] In one embodiment, the process for producing compound 3 or a salt thereof according to the present invention optionally further comprises: (b) adding ammonium pyrrolidinedithiocarbamate to the reaction mixture resulting from step (a).

[0073] In a further aspect, the present invention provides compound 4, or a salt thereof. [ka] The present invention provides a process for producing comprising steps (a) and (b) as described herein, and further comprising: (c) reacting compound 3 described herein with sodium hydroxide to obtain compound 4.

[0074] In one embodiment, step (c) is carried out in a solvent which is an alcohol, preferably methanol.

[0075] In a further aspect, the present invention provides a process for preparing compound 4 or a salt thereof, the process comprising steps (a) and (b) described herein, and further comprising: (c) reacting compound 3 according to claim 1 with 2 to 10 equivalents, preferably 3 to 8 equivalents, more preferably 4 to 7 equivalents, in particular 7 equivalents, of sodium hydroxide to obtain 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, in particular 16% w / w aqueous solution to a solution of compound 3 in an alcoholic solvent or a mixture of water and an alcoholic solvent.

[0076] In one embodiment, the alcohol solvent is methanol.

[0077] The main advantage of the novel compound 4 according to the present invention is its crystalline nature, which allows for purification by crystallization, which is a convenient means of purifying chemicals, especially on an industrial scale, as opposed to other purification techniques such as chromatography.

[0078] Thus, in one embodiment, the process for producing compound 4 according to the present invention optionally further comprises: (d) crystallizing said compound 4.

[0079] In a preferred embodiment of step (d) of the process according to the invention, said crystallization of compound 4 is crystallization of compound 4 from a mixture of alcohol and acetone.

[0080] In a preferred embodiment, the alcohol is selected from 2-propanol and 1-propanol.

[0081] In a particularly preferred embodiment, the alcohol is 1-propanol.

[0082] In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] The present invention provides a process for producing A process comprising steps (a) to (d) of the process described herein, and further comprising: (e) reacting compound 4 described herein with an acid to obtain the compound of formula (I).

[0083] In a preferred embodiment of step (e) of the process according to the invention, the acid is hydrochloric acid.

[0084] In one embodiment, step (e) is carried out in a solvent mixture selected from acetone / water, THF / water and acetonitrile / water.

[0085] In one embodiment, 2 to 6 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.

[0086] 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 invention.

[0087] In a further preferred embodiment, 4 to 5 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.

[0088] In a further 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 invention.

[0089] 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.

[0090] In a further particularly preferred embodiment, 4 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.

[0091] In a further particularly preferred embodiment, 4.1 equivalents of acid relative to compound 4 are used in step (e) of the process according to the invention.

[0092] In one embodiment, step (e) of the process according to the invention is carried out between room temperature and reflux.

[0093] In a preferred embodiment, step (e) of the process according to the invention is carried out at a temperature between 30° C. and reflux.

[0094] In a further preferred embodiment, step (e) of the process according to the invention is carried out at a temperature of from 35°C to 65°C.

[0095] In a particularly preferred embodiment, step (e) of the process according to the invention is carried out at a temperature of from 35°C to 60°C.

[0096] In a further aspect, the present invention provides the use of the process for preparing compound 3 described herein in the preparation of a compound of formula (I).

[0097] In a further aspect, the present invention provides the use of the process for preparing compound 4 described herein in the preparation of a compound of formula (I).

[0098] Compounds of the Invention The present invention relates to certain synthetic intermediates useful in the preparation of the novel antibiotics of formula (I) described herein.

[0099] The present invention also relates to certain compounds when made according to the novel chemical processes described herein.

[0100] More particularly, in one aspect, the present invention provides a compound that 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-pentazatricyclo[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. [ka] to provide.

[0101] In a further 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-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4), or a salt thereof. [ka] to provide.

[0102] In a further aspect, the invention relates to compound 3 when prepared according to the process for preparing compound 3 described herein.

[0103] In a further aspect, the invention relates to compound 3 when prepared according to the process for preparing compound 3 described herein.

[0104] In a further aspect, the present invention relates to a compound of formula (I) when prepared according to the process for preparing a compound of formula (I) described herein.

[0105] In a further aspect, the present invention relates to the use of compound 3 as described herein in the preparation of a compound of formula (I).

[0106] In a further aspect, the present invention relates to the use of compound 4 as described herein in the preparation of a compound of formula (I). [Example]

[0107] The present invention will be more fully understood by reference to the following examples, which, however, should not be construed as limiting the scope of the claims to the examples.

[0108] The following abbreviations are used herein:

[0109] 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-t-butyl(n-butyl)phosphine; PtBu2Ph = Di-t-butyl(phenyl)phosphine; PtBu2-p-C6H4CF3 = Di-t-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'-ferrocenediyl-bis(diphenylphosphine); dcypf = 1,1'-ferrocenediyl-bis(dicyclohexylphosphine); dippf = 1,1'-ferrocenediyl-bis(diisopropylphosphine); dtbpf = 1,1'-bis(di-tert-butylphosphino)ferrocene; Pd(PPh3)4 = tetrakis(triphenyl-phosphino)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).

[0110] Example 1 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-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid [ka] A dry, Ar-flushed flask was charged with 3-[[(11S,14S,17S)-22-bromo-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-12,15,18-triketo-16-methyl-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-1-carboxylic acid tert-butyl ester (1) (30.0 g, 28.57 mmol, 1.0 equiv), potassium phosphate tripotassium (9.10 g, 42.85 mmol, 1.5 equiv), and toluene (300 ml, 10 vol). The mixture was degassed and heated to 90°C. To the hot mixture was added (4-carbomethoxyphenyl)boronic acid (2) (5.4 g, 30.00 mmol, 1.05 equiv.) and PdCl(dtbpf) (372 mg, 0.571 mmol, 0.02 equiv.). To the resulting suspension was added water (6.43 g, 357.1 mmol, 12.5 equiv.) over 3 hours via syringe pump. The mixture was stirred for 4 hours. The mixture was cooled to 60°C, and 9% w / w aqueous 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 charcoal at room temperature.

[0111] The mixture was distilled under reduced pressure, the solvent exchanged 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 aqueous sodium hydroxide (25.0 g, 200.0 mmol, 7.0 equiv.) was added. The mixture was stirred for 5 hours, 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 charged 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 with water (150 ml). The organic phase was concentrated under reduced pressure to 3 volumes. The solvent was switched to 1-propanol to a final volume of approximately 3.3 volumes. The residue was heated to 60°C. Acetone (198 g, 250 ml, 8.33 vol) is added over 1.5 hours. The resulting suspension is cooled to 20° C. over 5 hours. The solid is collected by suction filtration, 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-triketo-16-methyl-2-thia-4,10,13,16,19-pentazatricyclo[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.

[0112] Example 1a 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-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid [ka] A dry, Ar-flushed flask was charged with 3-[[(11S,14S,17S)-22-bromo-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-12,15,18-triketo-16-methyl-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-17-yl]methyl]indole-1-carboxylic acid tert-butyl ester (1) (5.0 g, 4.76 mmol, 1.0 equiv), potassium carbonate (0.987 g, 7.14 mmol, 1.5 equiv), and toluene (50 ml, 10 vol). The mixture was degassed and heated to 90 °C. To the hot mixture was added (4-carbomethoxyphenyl)boronic acid (2) (1.0 g, 5.56 mmol, 1.2 equiv.) 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 equiv.) was added, and the mixture was stirred at 85–90 °C for approximately 30 min. Water (2.14 g, 119.03 mmol, 25.0 equiv.) was added via syringe pump over 6 h. The mixture was stirred for at least 2 h.

[0113] Ammonium pyrrolidinedithiocarbamate (237 mg, 1.43 mmol, 0.3 equiv.) was added. The mixture was stirred at 85-90°C for at least 1 hour, and then the phases were separated. The organic phase was extracted with water.

[0114] The organic layer was distilled under reduced pressure, and methanol (12.5 ml, 2.5 volumes) was added. The mixture was cooled to 40°C. 16% w / w aqueous sodium hydroxide solution (8.33 g, 33.33 mmol, 7.0 equiv.) was added. The mixture was stirred for at least 5 hours, then cooled to 20°C. 35% w / w aqueous citric acid solution (13.07 g, 23.81 mmol, 5.0 equiv.) was charged 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 approximately 1 hour. The resulting suspension was cooled to 0°C over 12 hours and stirred for at least 2 hours. The solid was collected 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-pentazatricyclo[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.

[0115] Example 2 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-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid [ka] 4-[(11S,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-11-[3-(tert-butoxycarbonylamino)propyl]-17-(1H-indol-3-ylmethyl)-12,15,18-triketo-16-methyl-2-thia-4,10,13,16,19-pentazatricyclo[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 equiv.), tetrahydrofuran (455 mL), and water (320 mL) were charged into a 2000 mL four-neck reaction vessel and stirred at 35 °C. A solution of HCl 25% (99.8 mL, 821 mmol, 4.1 equiv) and water (200 mL) was added within 10 min at 35 to 50° C. The dropping funnel was rinsed with water (50 mL) and the reaction mixture was stirred at 60° C. for 4 h. After basic workup and crystallization at pH 10, the title compound was obtained as a white powder (158.3 g, 98.5%).

Claims

1. 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-pentazatricyclo[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 【Chemical 1】 。

2. 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-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3,5,7,21,23-hexaen-22-yl]benzoic acid (4), or a salt thereof 【Chemistry 2】 。

3. 10. A method for producing compound 3 or a salt thereof according to claim 1, comprising: (a) in an aromatic solvent in the presence of a palladium catalyst and a base, Aryl bromide 1 【Chemistry 3】 (4-carbomethoxyphenyl)boronic acid (2) 【Chemistry 4】 to obtain compound 3, wherein the palladium catalyst is i) Pd(PPh ３ ) 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 ) Cl ２ , Pd(L ２ ) ２ Cl ２ , and [PdI(L ３ )] ２ wherein X is selected from allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, p-tert-butylindenyl; １ is PBu ３ , AmPhos, CPhos, RuPhos, and SPhos; ２ is PtBu ３ , AmPhos, PtBu ２ Bu, PtBu ２ Ph, PtBu ２ -p-C ６ H ４ CF ３ ) ２ , dppf, dcypf, dippf, and dtbpf, and L ３ is PtBu ３ , AmPhos), and ii) iia) Palladium bis(dibenzylideneacetone) (Pd(dba) ２ ), (Pd ２ (dba) ３ ), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh ３ ) ２ Cl ２ ), palladium acetate (Pd(OAc) ２ , palladium trifluoroacetate (Pd(TFA) ２ ), palladium chloride (PdCl ２ ), palladium bromide (PdBr ２ ), palladium iodide (PdI ２ ), palladium bisacetylacetonate (Pd(acac) ２ ), (Pd(PPh ３ ) ４ ), bis(acetonitrile)-palladium(II) dichloride (PdCl ２ (CH ３ CN) ２ ), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer (Pd(allyl)Cl) ２ a palladium source selected from (2-butenyl)chloropalladium dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl)chloride dimer, (p-tert-butylindenyl)palladium(II) chloride dimer, di-μ-chlorobis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2′-(amino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), di-μ-mesylbis[2′-(methylamino-N)[1,1′-biphenyl]-2-yl-C]dipalladium(II), and di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II); iib) Ligands selected from mono- and diphosphines, in particular PtBu ３ , PAd ３ , AmPhos, cataCXiumA, PtBu ２ Bu, PtBu ２ Ph, PtBu ２ -p-C ６ H ４ CF ３ , cataCXium POMeCy, CPhos, RuPhos, SPhos, dppf, dcypf, dippf, and dtbpf; and Catalyst formed in situ from is selected from The base is selected from inorganic bases and alcoholates, preferably Na ２ CO ３ , Ba(OH) ２ , K. ３ P.O. ４ , Cs ２ CO ３ , K. ２ CO ３ , TlOH, KF, CsF, Bu ４ F, and NaOH, more preferably said base is selected from K ３ P.O. ４ or K ２ CO ３ That's the method.

4. 4. The method of 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 %, and most preferably 2 mol %, relative to the aryl bromide 1.

5. 5. The method 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. 6. The process 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 mixtures thereof), ethylbenzene, anisole, cumene and cymene.

7. 7. The method of claim 6, wherein the aromatic solvent is toluene.

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

9. 9. The method of claim 8, wherein the water is added continuously to a 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, and most preferably over a period of 3 to 6 hours.

10. 10. The method according to claim 3, wherein 1 to less than 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. Optionally, further:

11. The method of claim 3, further comprising the step of: (b) adding an aqueous solution of ammonium pyrrolidinedithiocarbamate or N-acetylcysteine to the reaction mixture obtained from step (a).

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

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

14. Optionally, further:

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

15. A compound of formula (I) or a pharmaceutically acceptable salt thereof 【Chemistry 5】 1. A method for producing The method according to any one of claims 12 to 14, and further (e) reacting compound 4 of claim 2 with an acid, preferably hydrochloric acid, to obtain said compound of formula (I).

16. 16. The method of claim 15, wherein step (e) is carried out in a solvent mixture selected from acetone / water, THF / water, and acetonitrile / water.

17. 17. The method according to claim 15 or 16, wherein 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 relative to compound 4 are used in step (e).

18. 18. The process according to any one of claims 15 to 17, wherein the process is carried out at a temperature 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. 12. Compound 3 according to claim 1, or a salt thereof, when prepared according to the process of any one of claims 3 to 11.

20. 15. Compound 4 according to claim 2, or a salt thereof, when prepared according to the process of any one of claims 12 to 14.

21. A compound of formula (I), or a pharmaceutically acceptable salt thereof, when prepared according to the process of any one of claims 15 to 18. 【Chemistry 6】 。

22. A compound of formula (I), 【Chemistry 7】 15. Use of the method of any one of claims 3 to 14 in the manufacture of benzodiazepine or a pharmaceutically acceptable salt thereof.

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

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

25. 10. The invention as hereinbefore described.

Images