Preparation method of intermediate of sartan active compound

Abstract

Provided herein is a process for the preparation of a compound of formula (II) wherein R is selected from the group consisting of formulae (1), (2), (3), (4) and (5) wherein R "is selected from the group consisting of a hydrogen atom and a (C1-C3) alkyl group, comprising reacting a compound of formula (III) with a compound RH or one of the salts thereof under metal-catalyzed dehydroamidation conditions wherein R is as defined above.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical science, and specifically relates to a method for preparing a synthetic intermediate for synthesizing an active sartan compound having a tetrazolium ring. Background Technology

[0002] Irbesartan, losartan, valsartan, and candesartan are all prescription angiotensin receptor blockers (ARBs), also known as "sartans." Sartans are a class of drugs used to treat patients with hypertension to help prevent heart attacks and strokes. Specifically, irbesartan is an antihypertensive drug, specifically an angiotensin II type I (AII1) receptor antagonist used to treat hypertension. It was also the first approved primary antihypertensive drug for treating patients with hypertension, type 2 diabetes, and kidney disease.

[0003] The prior art describes a method for preparing an intermediate (hereinafter referred to as a compound of formula (II)) involved in the synthesis of an active sartan compound, and the method comprises three steps, starting with o-tolylbenzonitrile (hereinafter referred to as a compound of formula (III)), as disclosed in Scheme 1 below:

[0004] Option 1

[0005]

[0006] R is selected from equations (1), (2), (3), (4) and (5) as defined below.

[0007] In existing technologies, such as those described in WO 2023052309 and Manian Rajesh Kumar et al. Adv. Synth. Catal. 2010, 352, 3255-3266, the R group of the active sartan compound is introduced in a second step by nucleophilic substitution with one of the compounds RH or its salts, starting from a monobrominated compound. This has several drawbacks.

[0008] In fact, the bromination step, the first step in the above scheme, produces a large amount of bromide-containing salts, which must then be treated as an aqueous effluent. For example, one kilogram of bromide is used to synthesize one kilogram of irbesartan. Furthermore, the bromination step is often not highly selective because it also produces a dibromide product. Therefore, this step requires another treatment step before nucleophilic substitution, corresponding to the reduction of the dibromide product to a monobromide product using phosphine. In addition, the bromination step is carried out in dichloromethane as a solvent, which is a hazardous volatile organic compound. Finally, the brominated product can cause allergies and thus health problems.

[0009] Other existing technical literature, such as David J Carini et al. J. Med. Chem. 1991, 34, 2525-2547, also deals with monobrominated intermediates obtained by a bromination step, which has the aforementioned disadvantages.

[0010] Other existing technical literature, such as Lukas J. Goossen et al. J. org. Chem. 2007, 72, 7473-7476, discloses the synthesis of sartan precursors using compounds containing aldehyde groups.

[0011] Furthermore, the monobromination product has been identified as a precursor to the well-known and dangerous benzyl azide impurities formed during the synthesis of active sartan compounds, as defined in more detail below.

[0012] Based on the drawbacks detailed above and in view of industrial and environmental requirements, there is still a need to provide new routes for the synthesis of active sartan compounds. Summary of the Invention

[0013] This article discloses a novel method for preparing compounds of formula (II):

[0014] (II)

[0015] Where R is selected from equations (1), (2), (3), (4), and (5):

[0016] (1); (2); (3);

[0017] (4); and (5),

[0018] Where R" is selected from hydrogen atoms and (C1-C3) alkyl groups,

[0019] It includes compounds of formula (III).

[0020] (III) Reaction with compound RH or one of its salts under metal-catalyzed dehydroamidation conditions, wherein R is as defined above.

[0021] Compared to the prior art synthetic route described in Scheme 1 above, which involves three reaction steps, this method allows for a synthetic route that forms a compound of formula (II) as defined above using only one reaction step. Therefore, a simpler route is obtained due to the fewer steps, thus achieving atom economy. Compared to known methods, this means fewer separation, solvent, and purification steps are implemented, thereby reducing waste generated in the process.

[0022] Typically, this process bypasses the monobrominated product synthesis route described in Scheme 1, thereby avoiding hazardous intermediates (especially allergenic brominated products), hazardous solvents (e.g., dichloromethane), and some effluent treatments (e.g., aqueous effluents containing bromide salts).

[0023] Furthermore, this method avoids dangerous intermediates, particularly allergenic bromides, by bypassing the monobromination product synthesis route. These are also sources of dangerous benzyl azide impurities, such as azidonitrile and azidotetrazole, as described in the "Tetrazole Step" section below.

[0024] Furthermore, this method provides high-yield synthesis of compounds of formula (II) as defined above, as well as robust and scalable conditions that meet current industrial requirements.

[0025] Furthermore, this method is cost-effective by reducing the number of steps and by using, for example, inexpensive catalysts (as is evident in the “Catalyst Source” paragraph described below).

[0026] Finally, given the advantages mentioned above, this method meets the requirements of green chemistry.

[0027] This article also discloses a novel method for preparing an active sartan compound of formula (I) or one of its pharmaceutically acceptable salts:

[0028] (I), where R is defined above.

[0029] The process includes a tetrazolization step that reacts a compound of formula (II) as defined above, prepared by the above method, particularly a tetrazolization step with at least one azide derivative in a reaction medium, wherein benzyl azide impurities formed during the tetrazolization process are converted into aldehyde derivatives.

[0030] In other words, this paper also discloses a novel method for preparing an active sartan compound of formula (I) or one of its pharmaceutically acceptable salts:

[0031] (I), where R is defined above.

[0032] The process includes a tetrazolization step that reacts a compound of formula (II) as defined above, prepared by the above method, particularly a tetrazolization step with at least one azide derivative in a reaction medium, wherein benzyl azide impurities formed during the tetrazolization process are converted into aldehyde derivatives.

[0033] In other words, this article discloses a method for preparing an active sartan compound of formula (I) or one of its pharmaceutically acceptable salts:

[0034] (I), where R is defined above.

[0035] The method includes a tetrazolization step that reacts a compound of formula (II) as defined above, and wherein the method includes a step involving metal-catalyzed dehydroamidation under conditions for the preparation of a compound of formula (II).

[0036] In particular, the tetrazolization step in the reaction medium using at least one azide derivative, wherein the benzyl azide impurities formed during the tetrazolization are converted into aldehyde derivatives.

[0037] This article also discloses an active sartan compound of formula (I) or one of its pharmaceutically acceptable salts:

[0038] (I), wherein R is as defined above, which is obtained by the novel method described above and a subsequent tetrazolization step as defined above, and comprises at least one of the compounds of formulas (V) and (VI):

[0039] (V), (VI).

[0040] This document further discloses a composition comprising:

[0041] - One of the sartan active compounds of formula (I) or a pharmaceutically acceptable salt thereof:

[0042] (I), where R is as defined above, and can be obtained by the method described above and the subsequent tetrazolization step described above, and

[0043] - At least one of the compounds of formulas (V) and (VI):

[0044] (V), (VI). Detailed Implementation

[0045] definition

[0046] As used herein, unless otherwise stated throughout this specification, certain terms have the following definitions:

[0047] As used in this article, the term "base" refers to a substance that can donate electrons, accept protons, or release one or more hydroxyl (OH) ions. - ) chemical substances containing ions.

[0048] As used in this article, the term "acid" refers to an acid that has formed a covalent bond with an electron pair by accepting electrons or is able to release one or more protons (H+). +or H3O + Organic acids are chemical substances. In particular, organic acids are capable of releasing one or more protons (H+). + or H3O + ).

[0049] As used herein, the term "salt" refers to an inorganic or organic chemical substance. For example, organic salts are formed by a chemical substance containing nitrogen atoms in the form of ammonium with a chloride ion as a counterion, and are also known as chloride hydrates or hydrochlorides.

[0050] As used herein, the term “starting material” means one or more chemical substances that participate in a reaction, particularly those that undergo transformation, conversion, and / or participate in a catalytic cycle.

[0051] As used herein, the term “ambient temperature” or “room temperature” (also known as RT) refers to a temperature ranging from 15°C to 35°C, more specifically from 25°C to 35°C.

[0052] As disclosed herein, 2-n-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopentan-2-imidazolin-5-one and 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one are the same products. These products can be key intermediates in the synthesis of irbesartan and are referred hereinafter as compounds of formula (II)(1) as defined above.

[0053] In the context of this disclosure, unless otherwise stated throughout this specification, the following terms shall have the following definitions:

[0054] - Alkyl group: a straight-chain or branched saturated hydrocarbon aliphatic group. More specifically, -(C x -C y Alkyl groups, where x and y are integers, x < y, are straight-chain or branched saturated hydrocarbon aliphatic groups containing x to y carbon atoms (e.g., 1 to 4 carbon atoms). Examples, but not limited to, include: methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0055] - Hydroxyl group: Straight-chain or branched saturated divalent alkyl group. More specifically, (C x -C y (C1-C6) alkylene groups, where x and y are integers and x < y, are straight-chain or branched saturated divalent alkyl groups containing x to y carbon atoms. For example, (C1-C6) alkylene groups represent straight-chain or branched divalent carbon chains having 1 to 6 carbon atoms. Examples include, but are not limited to, methylene, ethylene, 1-methylethylene, propylene, butylene, pentylene, hexylene, etc.

[0056] - Alkoxy: -O-alkyl, wherein the alkyl group is as previously defined. More specifically, -(C x -C y )alkoxy, where x and y are integers, x < y, and it is an -O-(Cx-Cy)alkyl, where (C x -C y Alkyl groups are as previously defined. For example, an alkoxy group is -(C1-C3)alkoxy or -(C1-C4)alkoxy. Examples, but not limited to, may include: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.

[0057] - Cycloalkyl: Cyclic alkyl group. More specifically, (C3-C2)cycloalkyl, where z is an integer greater than or equal to 4, is a cycloalkyl group containing 3 to z carbon atoms and is saturated or partially unsaturated and unsubstituted or substituted, unless otherwise specified. For example, cycloalkyl is a (C3-C6)cycloalkyl-group. Examples, but not limited to, include: cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexyl, etc.

[0058] - "Optional substitution" means "not substituted" or "substituted by".

[0059] - "Aryl": A cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent categories. Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthyl, etc. For example, aryl is phenyl.

[0060] Metal-catalyzed dehydroamidation reaction

[0061] This disclosure relates to a method for preparing compounds of formula (II):

[0062] (II)

[0063] Where R is selected from equations (1), (2), (3), (4), and (5):

[0064] (1); (2); (3); (4); and (5),

[0065] Where R" is selected from hydrogen atoms and (C1-C3) alkyl groups,

[0066] It includes compounds of formula (III).

[0067] (III) Reaction with compound RH or one of its salts under metal-catalyzed dehydroamidation conditions, wherein R is as defined above.

[0068] As used herein, the term "metal-catalyzed dehydroamidation" refers to a reaction carried out in the presence of at least one metal catalyst.

[0069] As disclosed herein, the compound of formula (III) is also known as OTBN, which is an abbreviation for o-tolylbenzyl nitrile.

[0070] In an implementation, this document further provides a method in which R is selected from equations (1), (2), (3) and (5) as defined above.

[0071] Catalyst source

[0072] In an embodiment, this document further provides a method in which the reaction is carried out in the presence of a metal catalyst selected from copper catalysts, iron catalysts, manganese catalysts, cobalt catalysts and nickel catalysts and mixtures thereof, particularly in the presence of an iron catalyst or a copper catalyst.

[0073] As used herein, the term "metal catalyst" refers to an active metal catalyst that participates in the dehydrogenation amidation step of metal catalysis. "Metal catalyst" can also refer to "metal complex".

[0074] As used herein, the term "metal complex" refers to a compound with a metal atom or ion at its center and other molecules or ions surrounding it. These surrounding molecules or ions are typically attached to the central metal via coordinate bonds and are typically referred to as ligands. A "metal complex" can be a metal catalyst or a metal catalyst source as described above.

[0075] In the implementation scheme, the metal catalyst is generated from a substance referred to as a "metal catalyst source," "metal source," or "precatalyst," which in particular takes different forms, such as metal salts or metal complexes.

[0076] In the implementation scheme, the metal catalyst may be generated from a commercially available metal catalyst source in the form of a salt or complex.

[0077] In the implementation scheme, the metal catalyst is generated directly in the reaction mixture, in other words, generated in situ from a metal source, as shown in Examples 1 to 4.

[0078] In another embodiment, the metal catalyst is generated from a synthetic metal catalyst source in the form of a salt or metal complex. For example, a synthetic metal catalyst source in the form of a complex is obtained by premixing a metal in the form of a salt or complex with a ligand and then adding it to a reaction mixture. For example, a synthetic metal catalyst source can be obtained by premixing copper iodide or copper bromide (I) with 1,10-o-phenanthroline as a ligand.

[0079] In the specific implementation plan, the reaction is carried out in the presence of a copper catalyst.

[0080] In the embodiments, this document further provides a method wherein the copper catalyst is generated from copper (I) or copper (II) (also referred to as copper (I) source or copper (II) source, respectively, in the form of a salt or complex or a mixture thereof), particularly selected from CuCl, CuBr, CuI, copper thiophene-2-carboxylate (I), CuBr•SMe2, CuBr(Phen), CuI(Phen), CuCl(Phen), copper acetate (I), Cu2S, copper thiophenol (I), (4-bromophenyl)-thiocopper (I), mesitylene copper (I), CuCN, CuS CN, (1,10-o-phenanthroline)(trifluoromethyl)copper(I), CuBr2, anhydrous or hydrated copper acetate(II), CuF2, anhydrous or hydrated CuCl2, CuS, anhydrous or hydrated CuSO4, CuO, anhydrous or hydrated Cu(NO3)2, copper trifluoromethanesulfonate(II), anhydrous or hydrated copper ethyl acetoacetate(II), copper 2-ethylhexanoate(II), anhydrous or hydrated copper trifluoroacetate(II), copper trifluoroacetylacetonate(II), tert-butylacetoacetate(II), copper isobutyrate(II), copper 2-pyrazine carboxylate(II), anhydrous or hydrated hexafluoroacetate Copper pyruvate (II), anhydrous or hydrated copper trifluoromethanesulfonyl imide (II), copper dichloro(1,10-o-phenanthroline) (II), copper cyclohexanebutyrate (II), tetra(pyridine) copper trifluoromethanesulfonate (II), anhydrous or hydrated copper 3,5-diisopropylsalicylate (II), anhydrous or hydrated copper tetrafluoroborate (II), copper phthalate (II), copper di(2-naphthoic acid) (II), anhydrous or hydrated copper benzoate (II), copper methyl acetoacetate (II), copper ethyl benzoylacetate (II), copper ethyl 2-fluorobenzoylacetate (II), copper ethyl 2-chlorobenzoylacetate (I) I), Copper 3-(fluorosulfonyl)benzoate (II), Copper ethyl 3-(fluorosulfonyl)benzoylacetate (II), Copper 8-hydroxyquinoline (II), Copper dichloro(N-(2-pyridylmethylene)aniline-N,N') (II), Copper ethyl 2-(4-(pentoxy)benzoyl)acetate (II), Copper ethyl α-acetyl-3-(fluorosulfonyl)benzoylacetate (II), Copper ethyl α-acetyl-4-(fluorosulfonyl)benzoylacetate (II), Copper ethyl α-acetyl-3-(methoxycarbonyl)benzoylacetate (II), 2,3-diazaspiro[bicyclic[2.2].1] Heptene-7,1'-cyclopropane copper(II), α-(3,5-dichloro-2-pyridylimino)-o-cresol copper(II), α-(6-methyl-2-pyridylimino)-o-cresol copper(II), α-(3-methyl-2-pyridylimino)-o-cresol copper(II), α-(5-chloro-2-pyridylimino)-o-cresol copper(II), α-(4-methyl-2-pyridylimino)-o-cresol copper(II), bis(2,2,6,6-tetramethyl-3,5-heptadecanoic acid) copper(II) and bis(6,6,7,7 Copper(II) ,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedione, more particularly selected from CuCl, CuBr, CuI, copper thiophene-2-carboxylate (I), CuBr•SMe2, CuBr(Phen), CuI(Phen), CuCl(Phen), copper acetate (I), CuBr2 and anhydrous copper acetate (II), even more particularly selected from CuBr, CuI, CuBr(Phen), CuI(Phen), CuBr•SMe2 and CuBr2, for example CuBr•SMe2.

[0081] As used in this article, the term "copper(I)" is also referred to as cuprous ion (Cu). + In other terms, "copper(I)" refers to copper in its +1 oxidation state.

[0082] As used in this article, the term "copper(II)" is also referred to as copper ion (Cu). 2+ In other terms, "copper(II)" refers to copper in its +2 oxidation state.

[0083] In specific implementations, the copper (I) source is in the form of a salt, referred to as "copper (I) salt", or in the form of a complex, referred to as "copper (I) complex".

[0084] In specific implementations, the copper(II) source is in the form of a salt, referred to as "copper(II) salt", or in the form of a complex, referred to as "copper(II) complex".

[0085] In a specific implementation, the copper catalyst is generated from CuCl, CuBr, CuI, copper thiophene-2-carboxylate (I), CuBr•SMe2, CuBr(Phen), CuI(Phen), CuCl(Phen), copper acetate (I), CuBr2, and anhydrous copper acetate (II), or a mixture thereof.

[0086] In a specific implementation, the copper catalyst is generated from the group consisting of CuBr, CuI, CuBr(Phen), CuI(Phen), CuBr•SMe2 or CuBr2, or mixtures thereof.

[0087] In a specific implementation, the copper catalyst is generated from CuBr•SMe2. This implementation can be as shown in Examples 1 and 3.

[0088] In another embodiment, this document further provides a method in which the iron catalyst is generated from iron (II) or iron (III) (also referred to as iron (II) source or iron (III) source, respectively, in the form of salts or complexes or mixtures thereof), particularly selected from FeCl2, FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3, Fe(OH)3, FeCl3•6H2O, FeF3•3H2O, Fe4(P2O7)3, Fe4(Fe(CN)6)3 and Fe(H2PO2)3, particularly selected from FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3 and Fe(OH)3, more particularly selected from FeBr3, FeCl2, FeCl3 and FeCl3•6H2O, such as FeBr3.

[0089] In a specific implementation, the iron catalyst is produced from iron (II) or iron (III) in the form of a salt or complex, or a mixture thereof.

[0090] As used in this article, the term "iron(II)" is also referred to as ferrous ion (Fe). 2+ In other terms, "iron(II)" refers to iron in its +2 oxidation state.

[0091] As used in this article, the term "iron (III)" is also referred to as iron ion (Fe). 3+ In other terms, "iron(III)" refers to iron in the +3 oxidation state.

[0092] In specific implementations, the iron(II) source is in the form of a salt, referred to as an "iron(II) salt", or in the form of a complex, referred to as an "iron(II) complex".

[0093] In specific implementations, the iron (III) source is in the form of a salt, referred to as "iron (III) salt", or in the form of a complex, referred to as "iron (III) complex".

[0094] In a specific implementation, the iron catalyst is generated from a group consisting of FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3 and Fe(OH)3.

[0095] In a specific implementation, the iron catalyst is generated from a group consisting of FeBr3, FeCl2, FeCl3, and FeCl3•6H2O.

[0096] In a specific implementation, the iron catalyst is generated from FeBr3. This implementation can be as shown in Examples 2 and 4.

[0097] In a specific embodiment, the reaction can be carried out in the presence of a metal catalyst, which is a mixture of a copper catalyst and an iron catalyst, specifically generated from at least one of the previously mentioned copper (I) and / or copper (II) sources and at least one of the previously mentioned iron (II) and / or iron (III) sources.

[0098] In another embodiment, this document further provides a method wherein the manganese catalyst, cobalt catalyst, and nickel catalyst are generated from the following:

[0099] - (i) Manganese source, also known as manganese(II) source, which is in the form of salt or complex, or mixture thereof, particularly selected from MnBr2 and MnCl2,

[0100] -(ii) Cobalt source, also known as cobalt(II) source, which is in the form of a salt or complex, or a mixture thereof, particularly selected from CoCl2 and CoBr2, and

[0101] - (iii) Nickel source, also known as nickel (II) source, which is in the form of a salt or complex, or a mixture thereof, particularly selected from NiBr2 and NiCl2.

[0102] In a specific implementation, the manganese catalyst is generated from a manganese source, also known as a manganese (II) source, which is in the form of a salt or complex, or a mixture thereof.

[0103] As used in this article, the term “manganese(II)” refers to manganese in the +2 oxidation state.

[0104] In specific implementations, the manganese(II) source is in the form of a salt, referred to as "manganese(II) salt", or in the form of a complex, referred to as "manganese(II) complex".

[0105] In a specific implementation, the manganese catalyst is generated from a group consisting of MnBr2 and MnCl2.

[0106] In a specific implementation, the cobalt catalyst is generated from a cobalt source, also known as a cobalt(II) source, which is in the form of a salt or complex, or a mixture thereof.

[0107] As used in this article, the term "cobalt(II)" refers to cobalt in the +2 oxidation state.

[0108] In specific implementations, the cobalt(II) source is in the form of a salt, referred to as a "cobalt(II) salt", or in the form of a complex, referred to as a "cobalt(II) complex".

[0109] In a specific implementation, the cobalt catalyst is generated from a group consisting of CoCl2 and CoBr2.

[0110] In a specific implementation, the nickel catalyst is generated from a nickel source, also known as a nickel (II) source, which is in the form of a salt or complex, or a mixture thereof.

[0111] As used in this article, the term “nickel(II)” refers to the element nickel in the +2 oxidation state.

[0112] In specific implementations, the nickel(II) source is in the form of a salt, referred to as a "nickel(II) salt", or in the form of a complex, referred to as a "nickel(II) complex".

[0113] In a specific implementation, the nickel catalyst is generated from a group consisting of NiBr2 and NiCl2.

[0114] In the implementation, this document further provides a method wherein a metal source, particularly a copper (I) source, a copper (II) source, an iron (II) source and / or an iron (III) source, is present in a molar percentage ranging from 0.1% to 20% relative to the amount of the compound RH as defined above.

[0115] In a specific implementation, the metal source, particularly copper (I), copper (II), iron (II) and / or iron (III) sources, is present in a molar percentage ranging from 0.5% to 15% relative to the amount of compound RH as defined above.

[0116] In a specific implementation, the metal source, particularly copper (I), copper (II), iron (II) and / or iron (III) sources, is present in a molar percentage ranging from 1% to 10% relative to the amount of compound RH as defined above.

[0117] ligands

[0118] In the embodiments, this document further provides a method in which the metal catalyst is in the form of a metal complex comprising a ligand, the ligand being particularly selected from bidentate ligands, monodentate ligands, and mixtures thereof, and more particularly selected from:

[0119] - Bidentate or monodentate nitrogen ligands, particularly bidentate nitrogen ligands, more particularly optionally substituted bipyridine ligands, and even more particularly o-phenanthroline ligands, such as 1,10-o-phenanthroline, 4,4′-di-tert-butyl-2,2′-bipyridine, dimethylglycine, N,N,N',N'-tetramethylethylenediamine, trans-N,N′-dimethylcyclohexane-1,2-diamine, N-(2-pyridylmethylene)aniline, 1,1'-binaphthyl-2,2'-diamine, or 1-methylimidazole;

[0120] - Bidentate or monodentate phosphine ligands, particularly monodentate phosphine ligands, and more particularly phosphine ligands optionally substituted with at least one aryl group, such as triphenylphosphine; or

[0121] - Bidentate diketone ligands, particularly 1,3-diketone ligands, such as ethyl 2-oxocyclohexanecarboxylate.

[0122] As used in this article, the term "ligand" refers to a chemical substance that can coordinate with metal atoms or ions.

[0123] In specific implementation schemes, the ligands are selected from bidentate ligands, monodentate ligands, and mixtures thereof.

[0124] As used herein, the term "monodentate ligand" refers to a ligand that can coordinate with a metal atom or ion by means of one atom, particularly one heteroatom (such as a nitrogen atom or a phosphine atom).

[0125] As used herein, the term “bident ligand” refers to a ligand that is capable of coordinating with a metal atom or ion by two atoms, particularly heteroatoms (e.g., one or more nitrogen atoms, one or more oxygen atoms, and / or one or more phosphine atoms, etc.).

[0126] In specific implementation schemes, the ligands are selected from bidentate ligands, monodentate nitrogen ligands, and mixtures thereof.

[0127] As used herein, the term "monodentate nitrogen ligand" refers to a ligand that can coordinate with a metal atom or ion with a single nitrogen atom, particularly to form a metal complex.

[0128] As used herein, the term "bident nitrogen ligand" refers to a ligand capable of coordinating with a metal atom or ion, particularly forming a metal complex, using at least one nitrogen atom and another heteroatom (such as another nitrogen atom or another oxygen atom).

[0129] In a specific implementation scheme, the ligand is selected from bidentate nitrogen ligands and mixtures thereof.

[0130] In a specific implementation, the ligand is selected from optionally substituted bipyridine ligands and mixtures thereof.

[0131] In a specific implementation scheme, the ligand is selected from o-phenanthroline ligands and mixtures thereof.

[0132] In a specific implementation, the ligand is 1,10-o-phenanthroline. This implementation is shown in Example 1.

[0133] In a specific embodiment, the ligand is selected from 1,10-o-phenanthroline, 4,4′-di-tert-butyl-2,2′-bipyridine, dimethylglycine, N,N,N',N'-tetramethylethylenediamine, trans-N,N′-dimethylcyclohexane-1,2-diamine, N-(2-pyridylmethylene)aniline, 1,1'-binaphthyl-2,2'-diamine or 1-methylimidazole and mixtures thereof.

[0134] In specific implementation schemes, the ligands are selected from bidentate ligands, monodentate phosphine ligands, and mixtures thereof.

[0135] As used herein, the term "monodentate phosphine ligand" refers to a ligand that can coordinate with a metal atom or ion with a single phosphine atom, particularly to form a metal complex.

[0136] As used herein, the term "bident phosphine ligand" refers to a ligand capable of coordinating with a metal atom or ion using two phosphine atoms, particularly to form a metal complex.

[0137] In a specific embodiment, the ligand is selected from monodentate phosphine ligands optionally substituted with at least one aryl group and mixtures thereof.

[0138] In a specific implementation scheme, the ligand is selected from triphenylphosphine, triphenylphosphine derivatives, and mixtures thereof.

[0139] In a specific implementation, the ligand is selected from bidentate diketone ligands and mixtures thereof.

[0140] As used herein, the term "bident diketone ligand" refers to a ligand that can coordinate with a metal atom or ion, particularly to form a metal complex, using the two oxygen atoms of a diketone.

[0141] In a specific implementation, the ligand is selected from 1,3-dione ligands and mixtures thereof.

[0142] In a specific implementation, the ligand may be ethyl 2-oxocyclohexanecarboxylate.

[0143] In specific implementations, the reaction is carried out in the absence of ligands, as shown in Examples 2 and 4.

[0144] Oxidizing agent

[0145] In the embodiments, this document further provides a method wherein the reaction is carried out in the presence of an oxidant, particularly selected from peroxides of formula R1-OO-R2 or R'1-OO-R'-OO-R'2, oxalates of formula R3-OC(O)-C(O)-O-R4, and mixtures thereof.

[0146] R1, R'1, R2, and R'2 independently represent a hydrogen atom, an alkyl group optionally substituted with an aryl group, a cycloalkyl group, an aryl group, or an oxo group optionally substituted with an alkyl group, an alkoxy group, or an aryl group.

[0147] R' represents a (C1-C6) alkylene group, and

[0148] R3 and R4 independently represent a hydrogen atom, an aryl group, or an alkyl group optionally substituted with an aryl group.

[0149] In a specific embodiment, the oxidant is selected from peroxides of the formula R1-OO-R2 and mixtures thereof, where R1 and R2 independently represent a hydrogen atom, an alkyl group optionally substituted with an aryl group, a cycloalkyl group, an aryl group, or an oxo group optionally substituted with an alkyl group, an alkoxy group, or an aryl group.

[0150] In a specific implementation scheme, the oxidant is selected from di-tert-butyl peroxide, tert-butyl hydrogen peroxide, benzoyl peroxide, diisopropylphenyl peroxide, hydrogen peroxide, and mixtures thereof.

[0151] In a specific implementation scheme, the oxidant is selected from di-tert-butyl peroxide, tert-butyl hydrogen peroxide, and diisopropylphenyl peroxide.

[0152] In a specific implementation scheme, the oxidant is di-tert-butyl peroxide, as shown in Examples 1 to 4.

[0153] In a specific embodiment, the oxidant is selected from peroxides of the formula R'1-OO-R'-OO-R'2 and mixtures thereof, where R'1 and R'2 independently represent a hydrogen atom, an alkyl group optionally substituted with an aryl group, a cycloalkyl group, an aryl group, or an oxo group optionally substituted with an alkyl group, an alkoxy group, or an aryl group, and R' represents a (C1-C6) hydrocarbon group.

[0154] In a specific implementation scheme, the oxidant is selected from 2,5-di(tert-butylperoxy)-2,5-dimethyl-3-hexyne, 2,5-di(tert-butylperoxy)-2,5-dimethyl-3-hexane, 1,1-bis(tert-butylperoxy)cyclohexane and mixtures thereof.

[0155] In a specific embodiment, the oxidant is selected from oxalate esters of the formula R3-OC(O)-C(O)-O-R4 and mixtures thereof, where R3 and R4 independently represent a hydrogen atom, an alkyl group optionally substituted with an aryl group, or an aryl group.

[0156] In the specific implementation plan, the oxidant is di-tert-butyl oxalate.

[0157] In an embodiment, this document further provides a method wherein the oxidant is present in an amount corresponding to 1 equivalent ranging from 0.1 to 10, particularly relative to the amount corresponding to 1 equivalent ranging from 0.5 to 8, and more particularly relative to the amount corresponding to 1 equivalent ranging from 1 to 5.

[0158] In a specific embodiment, the oxidant is present in an amount relative to the compound RH as defined above and in an amount corresponding to 1 equivalent ranging from 0.5 to 8 equivalents.

[0159] In a specific embodiment, the oxidant is present in an amount relative to the compound RH as defined above and in an amount corresponding to an equivalent ranging from 1 to 5.

[0160] solvent

[0161] In the implementation scheme, this document further provides a method wherein the reaction is carried out in the presence of a solvent, particularly an organic solvent, and more particularly a solvent selected from the group consisting of:

[0162] - Aromatic solvents, and more specifically selected from benzyl nitrile, o-tolylbenzyl nitrile, chlorobenzene, dichlorobenzene, and anisole, such as o-tolylbenzyl nitrile.

[0163] - Alcohol solvents, and more specifically selected from hexafluoroprop-2-ol, isobutanol, tert-butanol, and n-butanol, such as tert-butanol and n-butanol.

[0164] - Ketone solvents, such as methyl isobutyl ketone.

[0165] - Ether solvents, such as cyclopentane methyl ether,

[0166] - Hydrocarbon solvents, such as heptane,

[0167] - Ester solvents, such as isobutyl acetate,

[0168] - Polar solvents, and more specifically selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, diethyl carbonate, and n-methylpyrrolidine (NMP),

[0169] - water,

[0170] - Acidic solvents, such as acetic acid.

[0171] and its mixtures.

[0172] As used herein, the term "solvent" also refers to "co-solvent." The term "co-solvent" may also refer to a mixture of at least two solvents.

[0173] In a specific embodiment, the solvent is selected from aromatic solvents and mixtures thereof. Hereinafter, the term "aromatic solvent" refers to a solvent containing at least an aromatic hydrocarbon derivative, such as optionally substituted benzene or toluene.

[0174] In a specific embodiment, the metal-catalyzed dehydroamidation reaction is carried out in the presence of a solvent, which is a compound of formula (III) corresponding to o-tolylbenzonitrile. In particular, o-tolylbenzonitrile (OTBN) is used as both the solvent and the starting material.

[0175] In a specific implementation scheme, the solvent is selected from benzonitrile, o-tolylbenzonitrile, chlorobenzene, dichlorobenzene, anisole, and mixtures thereof.

[0176] In a specific embodiment, the solvent is selected from alcohol solvents and mixtures thereof. Hereinafter, the term "alcohol solvent" refers to a solvent containing at least an optionally substituted organic alcohol, such as methanol, ethanol, propanol, butanol, pentanol, and their isomers.

[0177] In a specific implementation scheme, the solvent is selected from hexafluoroprop-2-ol, isobutanol, tert-butanol, n-butanol, and mixtures thereof.

[0178] In a specific embodiment, the solvent is tert-butanol alone or a mixture of it with at least one of the solvents described above and below.

[0179] In a specific implementation, the solvent is selected from ketone solvents and mixtures thereof.

[0180] As used herein, the term "ketone solvent" means a solvent containing at least one ketone functional group, particularly present on an optionally substituted straight-chain, branched, or cyclic hydrocarbon chain (such as an aliphatic or aromatic chain).

[0181] In a specific embodiment, the solvent is methyl isobutyl ketone alone or a mixture of methyl isobutyl ketone and at least one of the solvents described above and below.

[0182] In a specific implementation, the solvent is selected from ether solvents and mixtures thereof.

[0183] As used herein, the term "ether solvent" means a solvent containing at least one oxygen atom, said oxygen atom being an interrupted, particularly optionally substituted, straight-chain, branched, or cyclic hydrocarbon chain.

[0184] In a specific embodiment, the solvent is cyclopentane methyl ether alone or a mixture of it with at least one of the solvents described above and below.

[0185] In a specific implementation scheme, the solvent is selected from hydrocarbon solvents and mixtures thereof.

[0186] As used herein, the term "hydrocarbon solvent" refers to a solvent that primarily contains carbon and hydrogen atoms, particularly (C1-C2) hydrocarbons. 10 Straight chain, (C1-C)10 Branched or (C3-C8) cyclic hydrocarbon chains, such as aliphatic chains or aromatic rings, for example, pentane, hexane, heptane or octane.

[0187] In a specific embodiment, the solvent is heptane alone or a mixture of heptane and at least one of the solvents described above and below.

[0188] In a specific implementation, the solvent is selected from ester solvents and mixtures thereof.

[0189] As used herein, the term "ester solvent" means a solvent containing at least one ester functional group, particularly present on an optionally substituted straight-chain, branched, or cyclic hydrocarbon chain (such as an aliphatic chain or an aromatic group).

[0190] In a specific embodiment, the solvent is isobutyl acetate alone or a mixture of it with at least one of the solvents described above and below.

[0191] In a specific implementation, the solvent is selected from polar solvents and mixtures thereof.

[0192] As used herein, the term "polar solvent" refers to a solvent with a strong dielectric constant.

[0193] In a specific implementation scheme, the solvent is selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, diethyl carbonate, n-methylpyrrolidine (NMP), and mixtures thereof.

[0194] In a specific embodiment, the solvent is water alone or a mixture of water and at least one of the solvents described above and below.

[0195] In a specific embodiment, the solvent is acetic acid alone or a mixture with at least one of the above solvents.

[0196] RH and alkali in salt form

[0197] In the implementation scheme, this document further provides a method in which the reaction is carried out in the presence of a base, particularly when the RH as defined above is in the form of a salt, wherein the base is optionally selected from:

[0198] - Inorganic base,

[0199] - Alkoxide base,

[0200] - An organic base containing at least one nitrogen atom, such as triethylamine or N,N-diisopropylethylamine.

[0201] and its mixtures.

[0202] In a specific implementation plan, the alkali is selected from inorganic alkalis and mixtures thereof.

[0203] As used herein, the term "inorganic base" or "mineral base" refers to a base in salt form that contains at least hydroxide ions, carbonate ions, or bicarbonate ions (also known as bicarbonate ions).

[0204] In a specific implementation plan, the alkali is selected from Na2CO3, Cs2CO3, K2CO3, NaHCO3, NaOH, KOH and mixtures thereof.

[0205] In a specific embodiment, the solvent is K2CO3 alone or a mixture with at least one of the above or below bases.

[0206] In a specific implementation plan, the alkali is selected from alkali salts and mixtures thereof.

[0207] As used herein, the term "alkoxide base" refers to the conjugate base of an alcohol. In other words, an alkoxide contains an organic group bonded to a negatively charged oxygen atom. As is known to those skilled in the art, alkoxide bases contain counterions, such as, but not limited to, sodium, lithium, or potassium ions.

[0208] In a specific embodiment, the solvent is tBuOK alone or a mixture with at least one of the above or below bases.

[0209] In a specific implementation, the base is selected from organic bases containing at least one nitrogen atom.

[0210] In a specific implementation scheme, the base is selected from triethylamine, N,N-diisopropylethylamine, and mixtures thereof.

[0211] In the implementation scheme, this document further provides a method in which the reaction is carried out in the presence of a base when RH as defined above is in the form of a salt, particularly in the form of RH hydrochloride (e.g., RH•HCl salt).

[0212] reaction time

[0213] In the implementation scheme, this document further provides a method in which the reaction is carried out for 1 hour to 20 hours.

[0214] In the specific implementation plan, the reaction takes 8 to 18 hours.

[0215] In the specific implementation plan, the reaction takes place for 10 to 16 hours.

[0216] In specific implementation plans, the reaction can be carried out for 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12.5 hours, 14 hours, 15 hours, 16 hours, 18 hours, 20 hours, or 24 hours.

[0217] In specific implementation plans, the reaction is carried out for 8 hours, 15 hours, or 20 hours.

[0218] In the specific implementation plan, the reaction takes place for 8 or 15 hours.

[0219] In the specific implementation plan, the reaction takes 15 hours.

[0220] Temperature and / or photoactivation conditions

[0221] In an embodiment, this document further provides a method wherein the reaction is carried out at a temperature ranging from 20°C to 200°C, particularly from 90°C to 180°C, more particularly from 100°C to 150°C and / or under photoactivated conditions with wavelengths ranging from 200 nm to 900 nm, particularly from 200 nm to 800 nm, more particularly from 250 nm to 400 nm or combinations thereof, and optionally in the presence of a photosensitizer.

[0222] In a specific implementation, the reaction is carried out at temperatures ranging from 20°C to 200°C.

[0223] In a specific implementation, the reaction is carried out at a temperature ranging from 90°C to 180°C.

[0224] In a specific implementation, the reaction is carried out at a temperature ranging from 100°C to 150°C.

[0225] In the specific implementation plan, the reaction is carried out under photoactivated conditions.

[0226] In a specific implementation, the reaction is carried out under photoactivation conditions with wavelengths ranging from 200 nm to 900 nm or combinations thereof.

[0227] In a specific implementation, the reaction is carried out under photoactivation conditions with wavelengths ranging from 200 nm to 800 nm or combinations thereof.

[0228] In a specific implementation, the reaction is carried out under photoactivation conditions with wavelengths ranging from 250 nm to 400 nm or combinations thereof.

[0229] In a specific implementation, the reaction is carried out under photoactivated conditions at temperatures ranging from 20°C to 80°C.

[0230] In a specific implementation, the reaction is carried out under photoactivated conditions at temperatures ranging from 40°C to 60°C.

[0231] As used herein, the term "photoinduced reaction" refers to a "photochemical reaction" carried out under photoactivated conditions, corresponding to a reaction activated using incident photons. The light refers to wavelengths belonging to the UV, visible, or IR spectrum.

[0232] In a specific embodiment, the reaction is carried out at a temperature ranging from 20°C to 80°C under photoactivated conditions with wavelengths ranging from 200 nm to 900 nm, particularly from 200 nm to 800 nm, more particularly from 250 nm to 400 nm, or combinations thereof.

[0233] In a specific implementation, the reaction is carried out at a temperature ranging from 40°C to 60°C under photoactivated conditions with a wavelength range of 200 nm to 900 nm or a combination of wavelengths.

[0234] In a specific implementation, the reaction is carried out at a temperature ranging from 40°C to 60°C under photoactivated conditions with a wavelength range of 200 nm to 800 nm or a combination of wavelengths.

[0235] In a specific implementation, the reaction is carried out at a temperature ranging from 40°C to 60°C under photoactivated conditions with wavelengths ranging from 250 nm to 400 nm or a combination of wavelengths.

[0236] In a specific implementation scheme, when photoactivation conditions are used, the reaction takes place in the presence of a photosensitizer.

[0237] As used herein, the term "photosensitizer" refers to a chemical substance that absorbs light of a specific wavelength and converts it into energy that can be used to activate a reaction. In particular, a photosensitizer is a photocatalyst used in photocatalytic conditions, and more specifically, a donor-acceptor photocatalyst.

[0238] In a specific implementation scheme, the photosensitizer is selected from cyano aromatic hydrocarbon derivatives, diketone derivatives, and conjugated ketones or aldehydes, such as aromatic ketones or aldehydes.

[0239] In a specific implementation scheme, the photosensitizer is selected from 1,2,3,5-tetra(carbazole-9-yl)-4,6-dicyanobenzene; 2,4,5,6-tetra(9H-carbazole-9-yl)isophthalonitrile, also known as 4CzIPN; 2,3-butane-dione; fluorenone and mixtures thereof.

[0240] In a specific embodiment, the reaction is carried out in the presence of a photosensitizer at a temperature ranging from 40°C to 60°C and at a wavelength combination ranging from 200 nm to 800 nm. The photosensitizer is 2,3,5-tetra(carbazole-9-yl)-4,6-dicyanophenylene; 2,4,5,6-tetra(9H-carbazole-9-yl)isophthalonitrile, also known as 4CzIPN.

[0241] Other conditions

[0242] In the embodiments, this document further provides a method in which a metal-catalyzed dehydroamidation reaction is carried out in the presence of a promoter.

[0243] As used in this article, the term "accelerator" refers to a chemical substance that can increase the rate of a reaction.

[0244] In a specific implementation, the accelerator is a base, more particularly an alkali base, such as tBuOK.

[0245] In the implementation scheme, this document further provides a method in which the reaction is carried out under an inert atmosphere.

[0246] As used herein, "inert atmosphere" means an atmosphere containing an inert gas (such as argon or nitrogen). This means that the atmosphere does not contain oxygen. For example, an inert atmosphere can be nitrogen or argon.

[0247] In the implementation scheme, this document further provides a method in which the reaction is carried out in an ambient air atmosphere.

[0248] Characterization methods based on the presence of dimer byproducts

[0249] In the implementation scheme, this document further provides a method in which a dimeric byproduct compound of formula (IV) o-tolylbenzyl nitrile is formed.

[0250] (IV), as shown in Example 3.

[0251] As used herein, the compound of formula (IV) is also referred to as OTBN dimer, 4',4''-(ethane-1,2-diyl)bis([1,1'-biphenyl]-2-carboxynitrile), o-tolylbenzylnitrile dimer byproduct, OTBN dimer byproduct, or OTBN dimer.

[0252] In a specific implementation, the method includes a further purification step of the catalytic dehydroamidation reaction to remove most of the compound of formula (IV), particularly at least 99% of the compound of formula (IV).

[0253] In the embodiments, this document further provides a method in which a metal-catalyzed dehydroamidation reaction is carried out, particularly at a temperature ranging from 100°C to 150°C and under an inert atmosphere, in the presence of the following substances:

[0254] - Copper catalysts, particularly those produced from CuBr•SMe2, are specifically in the form of metal complexes containing ligands, particularly 1,10-o-phenanthroline.

[0255] -Oxidizing agents, particularly di-tert-butyl peroxide, and

[0256] -OTBN is both a reactant and a solvent.

[0257] In a specific implementation, the above method can provide a compound of formula (II) as defined above, wherein R has formula (1) as defined above, as shown in Example 1.

[0258] In the embodiments, this document further provides a method in which a metal-catalyzed dehydroamidation reaction is carried out, particularly at a temperature ranging from 100°C to 150°C and under an inert atmosphere, in the presence of the following substances:

[0259] - Iron catalysts, specifically produced from FeBr3,

[0260] -Oxidizing agents, particularly di-tert-butyl peroxide, and

[0261] -OTBN is both a reactant and a solvent.

[0262] In a specific implementation, the above method can provide a compound of formula (II) as defined above, wherein R has formulas (1), (2), (3) and (5) as defined above, as shown in Examples 2 and 4.

[0263] In a specific implementation, the method includes a step of further purifying the catalytic dehydroamidation reaction.

[0264] In the implementation plan, this document further provides a method, which includes, in sequence:

[0265] - Catalytic dehydroamidation reactions, such as those described above,

[0266] -At least the purification steps, and

[0267] - Tetrazolization step.

[0268] Tetrazolate step

[0269] In the implementation scheme, this document further provides a method for preparing one of the sartan active compounds of formula (I) or a pharmaceutically acceptable salt thereof:

[0270] (I), where R is defined above.

[0271] It includes a tetrazolization step: reacting a compound of formula (II) as defined above, prepared by a method for preparing a compound of formula (II) as defined above.

[0272] Tetrazolylation refers to the conversion of nitrile into tetrazolium.

[0273] The literature describes tetrazolization via reaction with azide derivatives (e.g., tributyltin azide or alkali metal azides such as sodium azide) and a base (e.g., triethylamine hydrochloride). Thus, for example, it is known to prepare 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (also known as spiromethylbiphenylnitrile) from 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (also known as irbesartan) by heating under reflux in the presence of tributyltin azide.

[0274] Among the sartan active compounds of formula (I) as defined above, irbesartan, losartan, valsartan, candesartan, or olmesartan may be mentioned. In particular, among the sartan active compounds of formula (I) as defined above, irbesartan, losartan, valsartan, or olmesartan may be mentioned.

[0275] In the implementation scheme, this document further provides a method wherein the sartan active compound of formula (I) is irbesartan, also known as 2-n-butyl-4-spirocyclopentane-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-2-imidazolin-5-one or 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one.

[0276] In the implementation scheme, the tetrazolization step is performed under normal conditions known to those skilled in the art.

[0277] In a specific embodiment, the tetrazolization step is carried out in the presence of an azide derivative selected from the group consisting of: azidoic acid (HN3), azide salts such as metal azides (e.g., sodium azide (NaN3), potassium azide (KN3), or calcium azide (Ca(N3)2), SnBu3N3, SnMe3N3), trialkylammonium azides (e.g., triethylammonium azide), particularly metal azides or azide salts (e.g., sodium azide or triethylammonium azide).

[0278] In this embodiment, the tetrazolization step is carried out in the presence of an azide derivative and a base. Specifically, the base is selected from the group consisting of triethylamine (Et3N), N,N-dicyclohexylmethylamine, and Hunig bases such as N,N-diisopropylethylamine. The base can particularly be triethylamine, and more particularly, triethylamine hydrochloride (also known as TEA, HCl).

[0279] In the implementation scheme, the tetrazolization step is carried out at a temperature below the reflux temperature and under an inert atmosphere, using an azide derivative and a base in an inert polar aprotic solvent.

[0280] As used herein, the term "polar aprotic solvent" means a polar solvent that cannot release one or more protons. Conversely, as used herein, the term "polar protic solvent" means a polar solvent that can release one or more protons.

[0281] In a specific embodiment, the tetrazolization step is carried out in the presence of a polar aprotic solvent having reducing properties and more particularly selected from the group consisting of: N-methylformamide (MFo), N,N-dimethylformamide (DMF), N-methyl,N-tert-butylformamide, acetamide (Ac), N-methylacetamide (MAc), N,N-dimethylacetamide (DMAc), urea, tetramethylurea (TMU), dimethylpropylene urea (DMPU), dimethyl ethyl urea (DMEU), triethylamine (TEA), hexamethylphosphoramide (HMPA), hexamethylphosphoric triamine (HMPT), 2-pyrrolidone (2-Py), N-methyl-2-pyrrolidone (NMP), N-phenyl-2-pyrrolidone (NPP), N-vinylpyrrolidone (NVP), and 5-methyl-2-pyrrolidone (MPy). Other polar aprotic solvents with reducing properties may also be used, particularly those selected from N-methylformamide (MFo), N,N-dimethylformamide (DMF), N-methyl,N-tert-butylformamide, acetamide (Ac), N-methylacetamide (MAc), N,N-dimethylacetamide (DMAc), urea, tetramethylurea (TMU), dimethylpropylene urea (DMPU), dimethyl ethyl urea (DMEU), triethylamine (TEA), hexamethylphosphoramide (HMPA), hexamethylphosphoric triamine (HMPT), 2-pyrrolidone (2-Py), N-methyl-2-pyrrolidone (NMP), N-phenyl-2-pyrrolidone (NPP), N-vinylpyrrolidone (NVP), and 5-methyl-2-pyrrolidone (MPy).

[0282] In the embodiments, the tetrazolization step is carried out with an equimolar alkali metal azide and triethylamine hydrochloride in a ratio of 1 to 5 mol / mol of the compound of formula (II) as defined above, advantageously about 1.2 to about 2 mol / mol of the compound of formula (II) as defined above.

[0283] In the embodiments, the tetrazolization step is carried out at a temperature ranging from room temperature to 150°C, particularly from 100°C to 135°C, and for example, 150°C.

[0284] In the embodiment, after heating for 6-20 hours, tetrazolization is completed and the reaction mixture is post-treated according to conventional techniques. Specifically, the aqueous phase containing salts, particularly chlorides and azides, is discarded by neutralizing the mixture with the addition of a base (e.g., an alkali metal hydroxide) in an aqueous solution. The organic phase is then treated with water and various organic solvents (aromatic compounds, halogenated compounds, esters, ketones, etc.) such as toluene, ethyl acetate, dichloromethane (DCM), methyl ethyl ketone, optionally sequentially with two different solvents, to remove byproducts of the tetrazolization reaction. These washing steps are conventional and well known to those skilled in the art. The final product is then crystallized, for example, by a crystallization step well known to those skilled in the art. Further conventional filtration and washing steps may then be performed, if necessary.

[0285] In a specific embodiment, the tetrazolization step is carried out in a reaction medium using at least one azide derivative, wherein benzyl azide impurities formed during the tetrazolization are converted into aldehyde derivatives. The tetrazolization step can be performed according to patent application WO 2023 / 052309, wherein benzyl azide impurities formed during the tetrazolization are converted into aldehyde derivatives.

[0286] As used herein, the terms "benzyl azide impurity" or "azido-based impurity class" encompass all byproducts or impurities that may arise from compounds containing at least one activated carbon atom in their structure via nucleophilic substitution with an alkali metal azide. In the context of this disclosure, "activated carbon atom" means a carbon atom carrying a detachable group such as a halogen atom (chlorine, bromine, or iodine), an alcohol group, a toluenesulfonate group, a methanesulfonate group, an alkyl phosphate group, an ester group, or an amide group. More particularly, such "activated carbon atom" is a carbon atom attached to a phenyl ring, thereby forming an activated benzyl structure. Therefore, the "benzyl azide impurity" can be present during a tetrazolization step, which begins with an intermediate compound having a cyanophenyl moiety (such as compounds of formula (II) as defined above) and carries out an alkali metal azide.

[0287] In conventional methods for synthesizing sartan-active compounds involving cyano derivative intermediates used in the tetrazolization step, two well-known mutagenic benzyl azidoides are formed: an azidonitrile of formula (A), also known as 5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-nitrile or 4'-(azidomethyl)-[1,1'-biphenyl]-2-carboxynitrile; and an azidotetrazole of formula (B), also known as (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole or 5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-1,2,3,4-tetrazole, as follows:

[0288] (A); and (B)

[0289] These two benzyl azide impurities (A) and (B) can be formed from several different potential precursors during the tetrazolization of compounds of formula (II) as defined above, including monobrominated derivatives used in the prior art for synthesizing compounds of formula (II) as previously mentioned.

[0290] Typically, the conversion of benzyl azide impurities formed during the tetrazolization process to aldehyde derivatives allows for the provision of an amount of the benzyl azide impurities of less than 1 ppm relative to the total amount of irbesartan after the final purification step, as illustrated in patent application WO 2023 / 052309. In particular, the benzyl azide impurities are converted to aldehyde derivatives in the presence of FeCl3.

[0291] The method was characterized by the presence of a dimer byproduct containing at least one tetrazolium group.

[0292] In specific embodiments, the tetrazolization step as defined above can result in the formation of at least one byproduct of formula (V) and (VI) as defined below. Specifically, the tetrazolization step can be carried out by reacting a mixture comprising a compound of formula (II) as defined above and an o-tolylbenzyl nitrile dimer byproduct compound of formula (IV), said mixture being prepared by a method for preparing a compound of formula (II) as defined above, the method comprising metal-catalyzed dehydroamidation. As shown in Example 5, the tetrazolization step can be initiated from the o-tolylbenzyl nitrile dimer byproduct compound of formula (IV) to obtain byproducts of formula (V) and (VI) as defined below.

[0293] In a specific embodiment, the sartan active compound of formula (I) as described above comprises at least one of the compounds of formulas (V) and (VI):

[0294] (V), (VI).

[0295] In a specific embodiment, this document further provides a composition comprising:

[0296] - The sartan active compound of formula (I) as described above, and

[0297] - At least one of the compounds of formulas (V) and (VI):

[0298] (V), (VI).

[0299] In a specific implementation, the active sartan compound is obtained after a purification step following the tetrazolization step.

[0300] In a specific embodiment, the sartan active compound of formula (I) as described above comprises at least one of the compounds of formulas (V) and (VI) as described above, particularly comprising trace amounts of at least one of the compounds of formulas (V) and (VI) as described above, and more particularly comprising less than 0.1% by weight of each of formulas (V) and (VI) relative to the total weight of the sartan active compound, for example less than 0.05% by weight of each of formulas (V) and (VI) relative to the total weight of the sartan active compound.

[0301] In specific embodiments, a composition comprising at least one of the sartan active compound of formula (I) as described above and the compounds of formulas (V) and (VI) as described above may particularly comprise trace amounts of at least one of the compounds of formulas (V) and (VI) as described above, and more particularly comprises less than 0.1% by weight of each of formulas (V) and (VI) relative to the total weight of the sartan active compound, for example less than 0.05% by weight of each of formulas (V) and (VI) relative to the total weight of the sartan active compound.

[0302] In the implementation scheme, this document further provides a mixture, an active sartan compound of formula (I), or one of its pharmaceutically acceptable salts:

[0303] (I), wherein R is as defined above, and can be obtained by a method for preparing a compound of formula (II) as defined above, followed by a tetrazolization step as defined above, comprising at least one of compounds of formulas (V) and (VI):

[0304] (V), (VI).

[0305] In an embodiment, this document further provides a composition, particularly a mixture, comprising:

[0306] - One of the sartan active compounds of formula (I) or a pharmaceutically acceptable salt thereof:

[0307] (I), where R is as defined above, and can be obtained by a method for preparing a compound of formula (II) as defined above, followed by a tetrazolization step as defined above, and

[0308] - At least one of the compounds of formulas (V) and (VI):

[0309] (V), (VI).

[0310] In a specific embodiment, the active sartan compound is irbesartan, also known as 2-n-butyl-4-spirocyclopentane-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-2-imidazolin-5-one or 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one, and comprises at least one of the compounds of formulas (V) and (VI):

[0311] (V), (VI).

[0312] In specific embodiments, the composition may comprise a sartan active compound, namely irbesartan, also known as 2-n-butyl-4-spirocyclopentane-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-2-imidazolin-5-one or 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one, and at least one of the compounds of formulas (V) and (VI):

[0313] (V), (VI).

[0314] In a specific embodiment, the sartan active compound is selected from losartan, valsartan and its esters (such as methyl or ethyl ester), candesartan and its esters (such as methyl or ethyl ester), olmesartan and its esters (such as methyl or ethyl ester), and includes at least one compound of formulas (V) and (VI):

[0315] (V), (VI).

[0316] In a specific embodiment, the composition may comprise a sartan active compound selected from losartan, valsartan and its esters (such as methyl or ethyl ester), candesartan and its esters (such as methyl or ethyl ester), olmesartan and its esters (such as methyl or ethyl ester), and comprising at least one compound of formulas (V) and (VI):

[0317] (V), (VI).

[0318] Example

[0319] Examples of schemes for preparing compounds of formula (II) as defined above according to the novel methods provided herein are described below. These examples are non-limiting and are for illustrative purposes only. In the examples below, when their preparation is not described, the starting compounds and reactants are commercially available or described in the literature, or can be prepared by methods known to those skilled in the art.

[0320] In the following embodiments, the following abbreviations and empirical formulas are used:

[0321]

[0322]

[0323] Thin-layer chromatography was performed using F-254 indicator on silica gel aluminum plates and observed by UV light (254 nm) and / or by chemical staining with KMnO4 solution.

[0324] Rapid column chromatography purification was performed using 0.040 - 0.063 nm silica gel.

[0325] Recorded at 300.1 MHz on a Bruker DXP 300 MHz spectrometer. 1 H NMR spectra, recorded at 75.5 MHz 13 C10 NMR spectrum. Chemical shift (δ) relative to TMS ( 1 δH is in ppm. Coupling constant (J) is in Hz. Residual solvent signals are used as references (CDCl3: δH = 7.26 ppm, δC = 77.16 ppm; (CD3)2SO: δH = 2.50 ppm, δC = 39.52 ppm). The following abbreviations are used to represent multiplicity: s: singlet, d: doublet, t: triplet, q: quartet, dd: doublet, m: multiplicity.

[0326] High-resolution mass spectrometry (HRMS) was performed on an electro-ionization mass spectrometer equipped with a miniature TOF analyzer.

[0327] Infrared spectra were recorded on a Perkin Elmer Paragon 100 FT-IR spectrometer (ATR). The wavenumber (ν) of the recorded IR signal (ATR) is expressed in cm⁻¹. -1 Units.

[0328] LC-MS: System: Thermo Vanquish LC system and Thermo ISQ EM MS detector. Column: AcquityWaters HSS T3 (1.7 µm) 2.1 mm x 50 mm. Phase A: Purified water + 0.1% formic acid. Phase B: Acetonitrile + 0.1% formic acid.

[0329] qNMR: Using 1,3,5-trimethoxybenzene as an internal standard and as recorded above. 1 The quantitative method using H NMR spectroscopy is known and commonly used by those skilled in the art.

[0330] In Examples 1 and 2, the conditions are details of the metal-catalyzed dehydroamidation used to prepare compounds of formula (II) as defined above, wherein R has formula (1) as defined above, corresponding to 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one of formula (II)(1):

[0331] (II)(1)

[0332] Example 1: Preparation of a compound of formula (II) in the presence of a copper catalyst produced by CuBr•SMe2, wherein R has the properties of formula (1).

[0333] 2-Butyl-1,3-diazaspiro[4.4]non-1-en-4-one (48.6 mg, 0.25 mmol), CuBr•SMe2 (2.5 mg, 0.0125 mmol), and o-phenanthroline (4.6 mg, 0.025 mmol) [from the glove box] were placed in a flame-dried 8 mL microwave-safe vial, followed by the addition of OTBN (2.73 g, 14 mmol). The vial was sealed with a PTFE diaphragm. The vial was placed under vacuum and then flushed with argon, and this process was repeated 3 times. It was then placed in an oil bath preheated to 135°C. The reaction mixture was then allowed to reach 135°C after 30 min, with DTBP (20 μL) added hourly for 4 h, to allow a total of (91 μL, 1 mmol) of DTBP to react. The reaction mixture was then stirred at this temperature for another 11 h. It was then allowed to cool. The crude product was subjected to silica gel chromatography (10 cm SiO2 column; 3.5 cm diameter) with 400 mL of cyclohexane and EtOAc as eluent (80 / 20), followed by purification with cyclohexane / EtOAc (70 / 30) as eluent to obtain 77.5 mg (81% yield) of the desired product as a yellow, viscous, oily substance. Rf = 0.13 (in cHex / EtOAc 7 / 3).

[0334] 1 H NMR (300.1 MHz, CDCl3) δ 7.77 (d, J = 7.7, 1H), 7.65 (t, J = 7.7Hz, 1H), 7.61 - 7.39 (m, 4H), 7.28 (d, J = 8.5 Hz, 2H), 4.75 (s, 2H), 2.40 -2.30 (m, 2H), 2.01 (dp, J = 15.7, 5.6 Hz, 6H), 1.89 - 1.81 (m, 1H), 1.33 (dt,J = 14.4, 7.2 Hz, 2H), 0.87 (t, J = 7.3 Hz, 4H).

[0335] 13 C NMR (75.5 MHz, CDCl3) δ 186.9, 161.7, 144.9, 137.8, 137.3, 134.0,133.0, 130.2, 129.5, 127.9, 127.2, 118.7, 111.3, 53.6, 43.4, 37.6, 29.0,27.9, 26.3, 22.5, 13.9.

[0336] HRMS: For C 25 H 28 N3 [M+H] + The calculated m / z is 365.2232, and the measured value is 386.2241.

[0337] Example 2: Preparation of a compound of formula (II) in the presence of an iron catalyst produced by FeBr3, wherein R has the properties of formula (1).

[0338] 2-Butyl-1,3-diazaspiro[4.4]non-1-en-4-one (97.2 mg, 0.5 mmol), FeBr3 (7.4 mg, 0.03 mmol), and then OTBN (2.51 g, 13 mmol) were added to a flame-dried 8 mL microwave-safe vial. The vial was sealed with a PTFE diaphragm. The vial was placed under vacuum and then flushed with argon, and this process was repeated three times. The vial was then placed in an oil bath preheated to 80°C and stirred at that temperature for 30 min. The reaction mixture was heated to 135°C and DTBP (184 μL, 1 mmol) was added, and the reaction mixture was stirred at that temperature for 4 h. The mixture was then cooled to room temperature. The crude product was purified by silica gel chromatography using n-heptane and EtOAc as eluents (from 90 / 10 to 70 / 30) to give 160.0 mg (83% yield) of the desired product as a yellow, viscous, oily substance.

[0339] 1 H NMR (300.1 MHz, CDCl3) δ 7.77 (d, J = 7.7, 1H), 7.65 (t, J = 7.7Hz, 1H), 7.61 - 7.39 (m, 4H), 7.28 (d, J = 8.5 Hz, 2H), 4.75 (s, 2H), 2.40 -2.30 (m, 2H), 2.01 (dp, J = 15.7, 5.6 Hz, 6H), 1.89 - 1.81 (m, 1H), 1.33 (dt,J = 14.4, 7.2 Hz, 2H), 0.87 (t, J = 7.3 Hz, 4H).

[0340] 13 C NMR (75.5 MHz, CDCl3) δ 186.9, 161.7, 144.9, 137.8, 137.3, 134.0,133.0, 130.2, 129.5, 127.9, 127.2, 118.7, 111.3, 53.6, 43.4, 37.6, 29.0,27.9, 26.3, 22.5, 13.9.

[0341] HRMS: For C 25 H 28 N3 [M+H] + The calculated m / z is 365.2232, and the measured value is 386.2241.

[0342] Example 3: Formation of OTBN dimer byproduct under metal-catalyzed dehydrogenation conditions

[0343] Under certain conditions, as described below, metal-catalyzed dehydrogenation can lead to the formation of OTBN dimer byproducts of formula (IV).

[0344] (IV)

[0345] 2-Butyl-1,3-diazaspiro[4.4]non-1-en-4-one (48.6 mg, 0.25 mmol), CuBr•SMe2 (2.5 mg, 0.0125 mmol), and OTBN (2.73 g, 14 mmol) were added to a flame-dried 8 mL microwave-safe vial. The vial was sealed with a PTFE diaphragm. The vial was placed under vacuum and then flushed with argon, and this process was repeated 3 times. The reaction mixture was then allowed to reach 135°C after 30 min, and DTBP (91 μL) was added. The reaction mixture was stirred at this temperature for 15 h. Then it was allowed to cool. The crude product was purified by silica gel chromatography (h = 10 cm, d = 3 cm) using cyclohexane / EtOAc (7 / 3) as the eluent. The first fraction (Rf = 0.7, cHex / EtOAc 7 / 3) was separated. The fraction was concentrated and found to contain a mixture of OTBN dimer byproduct of formula (IV) and 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one dimer. The fraction was then subjected to preparative thin-layer chromatography (eluting with cyclohexane / EtOAc (9 / 1)) to give 28.5 mg of OTBN dimer byproduct of formula (IV) (Rf = 0.52; in cyclohexane / EtOAc).

[0346] Chemical analysis of the OTBN dimer byproduct of formula (IV) is described below:

[0347] 1 H NMR (300.1 MHz, CDCl3) δ 7.78 - 7.73 (m, 2H), 7.70 - 7.58 (m, 2H), 7.58 - 7.47 (m, 8H), 7.43 (m, 2H), 7.39 - 7.28 (d, J = 8.3 Hz, 4H), 3.04(s,4H).

[0348] 13 C NMR (75.5 MHz, CDCl3) δ 145.6, 133.9, 132.9, 130.2, 130.2, 129.0, 128.9, 127.5, 111.4, 37.6.

[0349] IR: ν (cm) -1) 2923, 2223, 1704, 1478, 762.

[0350] HRMS: For C 28 H 20 N2H [M+H] + The calculated m / z is 385.1705, and the measured value is 385.1709.

[0351] Example 4: Preparation of compounds of formula (II) in the presence of an iron catalyst produced by FeBr3, wherein R has the following formulas (2), (3) and (5).

[0352] One of the compounds RH, where R has the formula (2), (3), or (5) as defined above (see Table 1 below for the amount of RH starting material used), FeBr3 (7.4 mg, 0.03 mmol), was placed in a flame-dried 8 mL microwave-safe vial, followed by OTBN (2.51 g, 13 mmol). The vial was sealed with a PTFE diaphragm. The vial was placed under vacuum and then flushed with argon, and this process was repeated 3 times. It was then placed in an oil bath preheated at 80°C. The reaction mixture was then allowed to reach 135°C after 30 min, with the addition of DTBP (184 μL, 1 mmol). The reaction mixture was stirred at this temperature for 4 h. The reaction mixture was then cooled and subjected to LC-MS and qNMR as described above. 1 Quantitative analysis using 1H NMR. Specifically, using... 1 The yield of compounds of formula (II) was determined quantitatively by ¹H NMR, where R has formulas (2), (3), and (5), as described in Table 1. Typically, the yield was determined by using 1,3,5-trimethoxybenzene as an internal standard. 1 Quantitative analysis using 1H NMR, in other words, adding a known amount of 1,3,5-trimethoxybenzene as an internal standard to a mixture in which metal-catalyzed dehydroamidation is carried out.

[0353] Table 1

[0354]

[0355] As shown in the examples above, the method for preparing compounds of formula (II) as described above implements metal-catalyzed dehydroamidation conditions and allows for the preparation of various sartan intermediates with only one reaction step compared to classical synthetic routes, and in particular uses inexpensive metal catalysts, such as copper or iron catalysts, which are more specifically derived from copper (II) or iron (III) sources.

[0356] Example 5: Tetrazolization of OTBN dimer byproducts

[0357] Under certain conditions, as described below, the tetrazolization step results in the formation of OTBN dimer mono- and / or di-tetrazolium byproducts having formulas (V) and (VI), respectively:

[0358] (V), (VI).

[0359] OTBN dimer of formula (IV) (358.2 mg, 1 mmol), NaN3 (143.0 mg, 2.2 mmol), and triethylamine hydrochloride (344.3 mg, 2.5 mmol) as starting materials were added to a flame-dried 8 mL microwave-safe vial, followed by the addition of NMP (2 mL), and the reaction mixture was heated at 130°C for 18 h. The reaction mixture was then cooled to room temperature, and a precipitate formed, which was filtered. The solid was washed with water (3 * 5 mL) and EtOAc (3 * 5 mL) to obtain the di-tetraazole byproduct of OTBN dimer of formula (VI).

[0360] The filtrate was purified by silica gel chromatography using DCM / MeOH (9 / 1) as the eluent. The fraction containing neither the starting material nor the OTBN dimer di-tetraazole byproduct of formula (VI) was concentrated to obtain the OTBN dimer mono-tetraazole byproduct of formula (V).

[0361] Chemical analysis of the OTBN dimer mono-tetraazole byproduct of formula (V) is described below:

[0362] 1 H NMR (300.1 MHz, d-DMSO) δ 7.96-7.92 (m, 1H), 7.81 - 7.76 (m, 1H), 7.74-7.61 (m, 4H), 7.59-7.53 (m, 2H) 7.51 (d, J = 8.0 Hz, 2H), 7.41 (d, J =8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 2.21-2.14(m, 4H).

[0363] LC / MS: For C 28 H 21 N5H [M+H] + The calculated m / z is 428.2, and the measured value is 428.4.

[0364] Chemical analysis of the OTBN dimer di-tetraazole byproduct of formula (VI) is described below:

[0365] 1 H NMR (300.1 MHz, d-DMSO) δ 7.69 - 7.61 (m, 4H), 7.58 - 7.51 (m,4H), 7.18 (d, J = 8.2 Hz, 4H) 7.01 (d, J = 8.2 Hz, 4H), 2.85 (s, 4H).

[0366] LC / MS: For C 28 H 22 N8H [M+H] + The calculated m / z is 471.2, and the measured value is 471.4.

[0367] Although preferred embodiments of this disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and alternatives will now occur to those skilled in the art without departing from this disclosure. It should be understood that various alternatives to the embodiments of this disclosure described herein may be employed in the practice of this disclosure. It is contemplated that the following claims define the scope of this disclosure and thereby cover the methods and structures within the scope of these claims and their equivalents. All patent and scientific literature disclosures cited herein are incorporated herein by reference in their entirety. In the event of any inconsistency between any incorporated material and the express content of this disclosure, the express content shall prevail.

Claims

1. A method for preparing compounds of formula (II): (II) Where R is selected from equations (1), (2), (3), (4), and (5): (1); (2); (3); (4); and (5), Where R" is selected from hydrogen atoms and (C1-C3) alkyl groups, It includes compounds of formula (III). (III) Reaction with compound RH or one of its salts under metal-catalyzed dehydroamidation conditions, wherein R is as defined above.

2. The method according to claim 1, wherein, The reaction is carried out in the presence of a metal catalyst selected from copper catalysts, iron catalysts, manganese catalysts, cobalt catalysts and nickel catalysts and mixtures thereof, particularly in the presence of iron catalysts or copper catalysts.

3. The method according to the preceding claim, wherein, The copper catalyst is generated from copper (I) or copper (II) in the form of salts or complexes or mixtures thereof, also referred to as copper (I) source or copper (II) source, respectively, and is particularly selected from CuCl, CuBr, CuI, copper thiophene-2-carboxylate (I), CuBr•SMe2, CuBr(Phen), CuI(Phen), CuCl(Phen), copper acetate (I), Cu2S, copper thiophenol (I), (4-bromophenyl)-thiocopper (I), mesitylene copper (I), CuCN, CuSCN, (1,10-o-phenanthroline) (trimethylammonium chloride) Copper(I) fluoromethyl ester (FME), CuBr2, anhydrous or hydrated copper acetate (II), CuF2, anhydrous or hydrated CuCl2, CuS, anhydrous or hydrated CuSO4, CuO, anhydrous or hydrated Cu(NO3)2, copper trifluoromethanesulfonate (II), anhydrous or hydrated copper ethyl acetoacetate (II), copper 2-ethylhexanoate (II), anhydrous or hydrated copper trifluoroacetate (II), copper trifluoroacetylacetonate (II), tert-butylacetylacetonate (II), copper isobutyrate (II), copper 2-pyrazine carboxylate (II), anhydrous or hydrated copper hexafluoroacetylacetonate (II), anhydrous Or hydrated copper trifluoromethanesulfonyl imide (II), copper dichloro(1,10-o-phenanthroline) dichloro(II), copper cyclohexanebutyrate (II), copper tetra(pyridine) trifluoromethanesulfonate (II), anhydrous or hydrated copper 3,5-diisopropylsalicylate (II), anhydrous or hydrated copper tetrafluoroborate (II), copper phthalate (II), copper di(2-naphthoic acid) dichloro(II), copper anhydrous or hydrated copper benzoate (II), copper methyl acetoacetate (II), copper ethyl benzoylacetate (II), copper ethyl 2-fluorobenzoylacetate (II), copper ethyl 2-chlorobenzoylacetate (II), 3-( Copper(II) fluorosulfonyl)benzoate, copper(II) ethyl 3-(fluorosulfonyl)benzoylacetate, copper(II) 8-hydroxyquinoline copper(II), copper(II) dichloro(N-(2-pyridylmethylene)aniline-N,N')copper(II), copper(II) ethyl 2-(4-(pentoxy)benzoyl)acetate, copper(II) ethyl α-acetyl-3-(fluorosulfonyl)benzoylacetate, copper(II) ethyl α-acetyl-4-(fluorosulfonyl)benzoylacetate, copper(II) ethyl α-acetyl-3-(methoxycarbonyl)benzoylacetate, copper(II), 2,3-diazaspiro[bicyclo[2.2].1] Heptene-7,1'-cyclopropane copper(II), α-(3,5-dichloro-2-pyridylimino)-o-cresol copper(II), α-(6-methyl-2-pyridylimino)-o-cresol copper(II), α-(3-methyl-2-pyridylimino)-o-cresol copper(II), α-(5-chloro-2-pyridylimino)-o-cresol copper(II), α-(4-methyl-2-pyridylimino)-o-cresol copper(II), bis(2,2,6,6-tetramethyl-3,5-heptadecanoic acid) copper(II) and bis(6,6,7,7 Copper(II) ,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedione, more particularly selected from CuCl, CuBr, CuI, copper thiophene-2-carboxylate (I), CuBr•SMe2, CuBr(Phen), CuI(Phen), CuCl(Phen), copper acetate (I), CuBr2 and anhydrous copper acetate (II), even more particularly selected from CuBr, CuI, CuBr(Phen), CuI(Phen), CuBr•SMe2 and CuBr2, for example CuBr•SMe2.

4. The method according to claim 2, wherein, The iron catalyst is generated from iron (II) or iron (III) in the form of salts or complexes or mixtures thereof, also referred to as iron (II) source or iron (III) source, particularly selected from FeCl2, FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3, Fe(OH)3, FeCl3•6H2O, FeF3•3H2O, Fe4(P2O7)3, Fe4(Fe(CN)6)3 and Fe(H2PO2)3, particularly selected from FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3 and Fe(OH)3, more particularly selected from FeBr3, FeCl2, FeCl3 and FeCl3•6H2O, for example FeBr3.

5. The method according to claim 2, wherein, The manganese catalyst, cobalt catalyst, and nickel catalyst are respectively generated from the following: - (i) Manganese source, also known as manganese(II) source, which is in the form of salt or complex, or mixture thereof, particularly selected from MnBr2 and MnCl2, -(II) cobalt sources, also known as cobalt(II) sources, which are in the form of salts or complexes, or mixtures thereof, are particularly selected from CoCl2 and CoBr2, and - (iii) Nickel source, also known as nickel (II) source, which is in the form of a salt or complex, or a mixture thereof, particularly selected from NiBr2 and NiCl2.

6. The method according to any one of claims 1 to 5, wherein, The metal catalyst is in the form of a metal complex containing a ligand, the ligand being particularly selected from bidentate ligands, monodentate ligands, and mixtures thereof, and more particularly selected from: - Bidentate or monodentate nitrogen ligands, particularly bidentate nitrogen ligands, more particularly optionally substituted bipyridine ligands, and even more particularly o-phenanthroline ligands, such as 1,10-o-phenanthroline, 4,4′-di-tert-butyl-2,2′-bipyridine, dimethylglycine, N,N,N',N'-tetramethylethylenediamine, trans-N,N′-dimethylcyclohexane-1,2-diamine, N-(2-pyridylmethylene)aniline, 1,1'-binaphthyl-2,2'-diamine, or 1-methylimidazole; - Bidentate or monodentate phosphine ligands, particularly monodentate phosphine ligands, and more particularly phosphine ligands optionally substituted with at least one aryl group, such as triphenylphosphine; or - Bidentate diketone ligands, particularly 1,3-diketone ligands, such as ethyl 2-oxocyclohexanecarboxylate.

7. The method according to any one of claims 2 to 5, wherein, The metal source, particularly the copper (I) source, the copper (II) source, the iron (II) source and / or the iron (III) source, is present in a molar percentage relative to the amount of the compound RH as defined in claim 1, ranging from 0.1% to 20%, particularly from 0.5% to 15% and more particularly from 1% to 10%.

8. The method according to any one of claims 1 to 7, wherein, The reaction is carried out in the presence of an oxidizing agent, specifically selected from peroxides of formula R1-OO-R2 or R'1-OO-R'-OO-R'2 and oxalates of formula R3-OC(O)-C(O)-O-R4 and mixtures thereof. R1, R'1, R2, and R'2 independently represent a hydrogen atom, an alkyl group optionally substituted with an aryl group, a cycloalkyl group, an aryl group, or an oxo group optionally substituted with an alkyl group, an alkoxy group, or an aryl group. In particular, the peroxides of the formula R1-OO-R2 are selected from di-tert-butyl peroxide, tert-butyl hydroperoxide, benzoyl peroxide, diisopropylphenyl peroxide, and hydroperoxide, and even more particularly from di-tert-butyl peroxide, tert-butyl hydroperoxide, and diisopropylphenyl peroxide, such as di-tert-butyl peroxide. R' represents a (C1-C6) alkylene group, and in particular, the peroxide of the formula R'1-OO-R'-OO-R'2 is selected from 2,5-di(tert-butylperoxy)-2,5-dimethyl-3-hexyne, 2,5-di(tert-butylperoxy)-2,5-dimethyl-3-hexane, and 1,1-bis(tert-butylperoxy)cyclohexane; and R3 and R4 independently represent a hydrogen atom, an aryl group, or an alkyl group optionally substituted with an aryl group, such as di-tert-butyl oxalate.

9. The method according to the preceding claim, wherein, The oxidant is present in an amount corresponding to the amount of the compound RH as defined in claim 1 and corresponding to an equivalent range from 0.1 to 10, particularly corresponding to the amount of the compound RH as defined in claim 1 and corresponding to an equivalent range from 0.5 to 8, and more particularly corresponding to the amount of the compound RH as defined in claim 1 and corresponding to an equivalent range from 1 to 5.

10. The method according to any one of claims 1 to 9, wherein, The reaction is carried out in the presence of a solvent, particularly an organic solvent, and more particularly a solvent selected from the following: - Aromatic solvents, and more specifically selected from benzyl nitrile, o-tolylbenzyl nitrile, chlorobenzene, dichlorobenzene, and anisole, such as o-tolylbenzyl nitrile. - Alcohol solvents, and more specifically selected from hexafluoroprop-2-ol, isobutanol, tert-butanol, and n-butanol, such as tert-butanol and n-butanol. - Ketone solvents, such as methyl isobutyl ketone. - Ether solvents, such as cyclopentane methyl ether, - Hydrocarbon solvents, such as heptane, - Ester solvents, such as isobutyl acetate, - Polar solvents, and more specifically selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, diethyl carbonate, and n-methylpyrrolidine (NMP), - water, - Acidic solvents, such as acetic acid. and its mixtures.

11. The method according to any one of claims 1 to 10, wherein, The reaction is carried out in the presence of a base, particularly when the RH as defined in claim 1 is in the form of a salt, wherein the base is optionally selected from: - Inorganic bases, such as Na₂CO₃, Cs₂CO₃, K₂CO₃, NaHCO₃, NaOH, or KOH. - Alkoxide bases, such as tBuOK, - An organic base containing at least one nitrogen atom, such as triethylamine or N,N-diisopropylethylamine. and its mixtures.

12. The method according to any one of claims 1 to 11, wherein, The reaction is carried out at a temperature ranging from 20°C to 200°C, particularly from 90°C to 180°C, more particularly from 100°C to 150°C and / or under photoactivated conditions in the wavelength range of 200 nm to 900 nm, particularly from 200 nm to 800 nm, more particularly from 250 nm to 400 nm or combinations thereof, and optionally in the presence of a photosensitizer.

13. The method according to any one of claims 1 to 12, wherein, Formation of (IV) o-tolylbenzyl nitrile dimer byproduct compounds (IV)。 14. A method for preparing one of the sartan active compounds of formula (I) or a pharmaceutically acceptable salt thereof: (I), wherein R is as defined in claim 1, It includes a tetrazolization step of reacting a compound of formula (II) as defined in claim 1, prepared by any one of claims 1 to 13, with a reaction in a reaction medium with at least one azide derivative, wherein benzyl azide impurities formed during the tetrazolization are converted into aldehyde derivatives.

15. The method according to the preceding claim, wherein, The active sartan compound of formula (I) is irbesartan, also known as 2-n-butyl-4-spirocyclopentane-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-2-imidazolin-5-one or 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one.

16. The method according to any one of claims 14 or 15, wherein, The sartan active compound of formula (I) comprises at least one of the compounds of formulas (V) and (VI): (V), (VI).

17. A composition comprising: - One of the sartan active compounds of formula (I) or a pharmaceutically acceptable salt thereof: (I), wherein R is as defined in claim 1, and can be obtained by the method according to any one of claims 1 to 13 followed by a tetrazolization step as defined in claim 14, and - At least one of the compounds of formulas (V) and (VI): (V), (VI).

18. The composition according to the preceding claims, wherein, The active sartan compound of formula (I) is irbesartan, also known as 2-n-butyl-4-spirocyclopentane-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-2-imidazolin-5-one or 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one, and comprises at least one of the compounds of formulas (V) and (VI): (V), (VI).

19. The composition according to claim 17, wherein, The active sartan compound of formula (I) is selected from losartan, valsartan and its esters, candesartan and its esters, olmesartan and its esters, and includes at least one compound of formulas (V) and (VI): (V), (VI).

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