Process for preparing intermediates of sultan-active compounds

Abstract

A process for preparing a compound of formula (II) (wherein R is selected from formulas (1), (2), (3), (4), and (5), and R'' is selected from a hydrogen atom and a (C1-C3) alkyl group) is provided herein, the process comprising reacting a compound of formula (III) with one of the compounds RH or a salt thereof (wherein R is as defined above) under metal-catalyzed dehydrogenation amidation conditions. [Formula 1] TIFF2026524701000044.tif106170

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical preparation and, in particular, relates to a process for preparing intermediates used in the synthesis of sultaneous compounds having a tetrazole ring. [Background technology]

[0002] Irbesartan, losartan, valsartan, and candesartan are all prescription angiotensin receptor blockers (ARBs), also known as "sartan" active compounds. "Sartan" is a class of drugs used to treat hypertensive patients to help prevent heart attacks and strokes. In particular, irbesartan is an antihypertensive drug that is an angiotensin II type I (AII1) receptor antagonist for the treatment of hypertension. This drug was also the first major antihypertensive drug approved for the treatment of patients with hypertension, type 2 diabetes, and kidney disease.

[0003] The process for preparing intermediates involved in the synthesis of sultan-active compounds (hereinafter referred to as compounds of formula (II)) is described in the prior art and includes three steps starting from o-tolylbenzonitrile (hereinafter referred to as compounds of formula (III)), as disclosed in Scheme 1 below. Scheme 1 [ka] R is selected from the following formulas (1), (2), (3), (4), and (5).

[0004] In the prior art, for example, in International Publication No. 2023052309 and Manian Rajesh Kumar et al. Adv.Synth.Catal.2010,352,3255-3266, the R group of a sultan-active compound is introduced by starting with a monobrominated compound and using a single nucleophilic substitution of the compound RH or a salt thereof in a second step, but this presents several drawbacks.

[0005] In fact, the bromination step, i.e., the first step of the above scheme, generates a significant amount of bromide-containing salts, which then must be treated as aqueous wastewater. For example, 1 kilogram of bromide is used for the synthesis of 1 kilogram of irbesartan. Furthermore, the bromination step also generates dibrominated products and is thus not very selective. Therefore, such a step requires another treatment step corresponding to the phosphine reduction of the dibrominated product to the monobrominated product before nucleophilic substitution. Additionally, the bromination step is carried out in dichloromethane as a solvent, which is a harmful volatile organic compound. Finally, the brominated product is allergenic and thus may cause health problems.

[0006] Other prior art documents, for example, David J Carini et al. J. Med. Chem. 1991, 34, 2525 - 2547 also involved the monobrominated intermediate obtained by the bromination step showing the above-mentioned drawbacks.

[0007] Other prior art documents, for example, Lukas J. Goossen et al. J. org. Chem. 2007, 72, 7473 - 7476 disclose the synthesis of a sartan precursor using a compound containing an aldehyde group.

[0008] Furthermore, the monobrominated product was identified as a precursor of the well-known harmful benzyl azide impurity formed during the process of synthesizing the sartan active compound.

Summary of the Invention

Problems to be Solved by the Invention

[0009] According to the above detailed drawbacks, considering industrial and environmental requirements, it is necessary to provide a new route for the synthesis of the sartan active compound.

Means for Solving the Problems

[0010] Formula (II):

Chemical Formula

[0011] Such a process makes it possible to provide a synthetic route that forms the compound of formula (II) as defined above in only one reaction step, compared to the conventional synthetic route described in Scheme 1 above, which involves three reaction steps. Thus, thanks to fewer steps, a simpler route is obtained that enables atomic economy. This means that fewer isolation, solvent, and purification steps are performed compared to known processes, thereby reducing the waste generated by the process.

[0012] Typically, such processes avoid the monobrominated product synthesis pathway described in Scheme 1, which avoids harmful intermediates, particularly allergenic brominated products, harmful solvents, such as dichloromethane, and some wastewater treatments, such as aqueous wastewater treatments containing bromides.

[0013] Furthermore, this process avoids harmful intermediates by avoiding the monobromination product synthesis pathway, particularly allergy-inducing bromination products that are sources of harmful benzyl azide impurities, such as azidonitrile and azidotetrazole, as described in the "Tetrazolylation Step" section below.

[0014] In addition, this process provides high-yield synthesis of the compound of formula (II) defined above, as well as robust and scalable conditions that meet current industrial requirements.

[0015] Furthermore, such processes are cost-effective not only by reducing the number of steps, but also by implementing inexpensive catalysts, such as those evident in the “Catalyst Source” paragraph described herein.

[0016] Finally, considering the advantages of this specification, such processes comply with green chemical requirements.

[0017] Sartan-active compounds of formula (I) or pharmaceutically acceptable salts thereof: [ka] A novel process for preparing (wherein R is as defined above), Novel processes are also disclosed herein that include a tetrazolylation step in which a compound of formula (II) as defined above, prepared by the above process, reacts with at least one azide derivative in a reaction medium, wherein a benzyl azide impurity formed during the tetrazolylation is converted to an aldehyde derivative.

[0018] In other words, the sartan-active compound of formula (I) or its pharmaceutically acceptable salt: [ka] Novel processes for preparing (wherein R is as defined above) are also disclosed herein, comprising a tetrazolylation step of reacting the compound of formula (II) as defined above, prepared by the above process, in particular a tetrazolylation step carried out with at least one azide derivative in a reaction medium, wherein the benzyl azide impurity formed during the tetrazolylation is converted to an aldehyde derivative.

[0019] In other words, the sartan-active compound of formula (I) or its pharmaceutically acceptable salt: [ka] A process for preparing (wherein R is as defined above), Disclosed herein is a process comprising a tetrazolylation step of reacting a compound of formula (II) as defined above, wherein the process comprises a step comprising metal-catalyzed dehydrogenation amidation conditions for preparing a compound of formula (II), and in particular a tetrazolylation step carried out with at least one azide derivative in a reaction medium, wherein a benzyl azide impurity formed during the tetrazolylation is converted to an aldehyde derivative.

[0020] Equation (I): [ka] A sultan-active compound of (wherein R is as defined above), or a pharmaceutically acceptable salt thereof, obtained by the novel process described above and the subsequent tetrazolylation step as defined above, of formulas (V) and (VI): [ka] Also disclosed herein are sartan-active compounds of formula (I), or pharmaceutically acceptable salts thereof, comprising at least one of the compounds of formula (I).

[0021] moreover, - Equation (I): [ka] A sultaneous compound of formula (I), or one of its pharmaceutically acceptable salts, obtained by the above process and the subsequent tetrazolylation step, - Equations (V) and (VI): [ka] A composition comprising at least one of the compounds is disclosed herein. [Modes for carrying out the invention]

[0022] definition As used herein, certain terms have the following definitions unless otherwise noted throughout this specification.

[0023] As used herein, the term “base” means the ability to donate electrons, accept protons, or form one or more hydroxides (OH) - This refers to a chemical species that can release ions.

[0024] As used herein, the term “acid” means an acid that forms a covalent bond with an electron pair by accepting an electron, or one or more protons (H + or H3O + This refers to a chemical species that can release one or more protons (H). In particular, organic acids are chemical species that can release one or more protons (H). + or H3O + It can release )

[0025] As used herein, the term "salt" means an inorganic or organic chemical species. For example, organic salts are formed by chemical species (also known as salt hydrates or hydrochlorides) that contain a nitrogen atom in the form of ammonium with a chloride ion as a counterion.

[0026] As used herein, the term “starting material” means one or more chemical species that are involved in the reaction, and in particular are converted, transformed, and / or involved in the catalytic cycle.

[0027] As used herein, the terms “ambient temperature” or “room temperature” (also known as RT) refer to temperatures in the range of 15°C to 35°C, and more particularly 25°C to 35°C.

[0028] As disclosed in this specification, 2-n-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopentane-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 product. The said product may be an important intermediate in the synthesis of irbesartan and is referred to herein as the compound of formula (II)(1) as defined above.

[0029] In the context of this disclosure, the following terms have the following definitions throughout this specification unless otherwise specifically referred to.

[0030] - Alkyl group: A straight-chain or branched-chain saturated hydrocarbon-based aliphatic group. More specifically, x and y are integers, x < y, and it is a straight-chain or branched-chain saturated hydrocarbon-based aliphatic group containing x to y carbon atoms, for example, 1 to 4 carbon atoms, of the form -(C x ~C y )alkyl group. Examples, without limitation, may include methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl groups, etc.

[0031] - Alkylene group: A straight-chain or branched-chain saturated divalent alkyl group. More specifically, x and y are integers, x < y, and it is a straight-chain or branched-chain saturated divalent alkyl group containing x to y carbon atoms, of the form (C x ~C y )alkylene group. For example, a (C1~C6) alkylene group represents a straight-chain or branched-chain divalent carbon-based chain of 1 to 6 carbon atoms. Examples, without limitation, may include methylene group, ethylene group, 1-methylethylene group, propylene group, butylene group, pentylene group, hexylene group, etc.

[0032] - Alkoxy group: -O-alkyl group (where the alkyl group is as previously defined). More specifically, x and y are integers, x < y, and it is of the form (C x ~Cy )The alkyl group is as previously defined, -O-(C x ~C y ) is an alkyl group, -(C x ~C y ) Alkoxy group. For example, an alkoxy group is a -(C1-C3) alkoxy group or a -(C1-C4) alkoxy group. Examples, though not limited to them, include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, and tert-butyloxy groups.

[0033] - Cycloalkyl group: A cyclic alkyl group. More specifically, z is an integer greater than or equal to 4, and unless otherwise specified, it is a cyclic alkyl group containing 3 to z carbon atoms, saturated or partially saturated, unsubstituted or substituted, (C3 to C z ) Cycloalkyl group. For example, a cycloalkyl group is a (C3-C6) cycloalkyl- group. Examples, though not limited to them, include cyclopropyl, cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexyl.

[0034] - "Optionally substituted" means either "not substituted" or "substituted with".

[0035] - "Aryl group": A cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent forms. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. For example, phenyl is an aryl group.

[0036] Metal-catalyzed dehydrogenation amidation reaction This disclosure is based on formula (II): [ka] (wherein R is given by equations (1), (2), (3), (4) and (5): [ka] A process for preparing a compound in which R'' is selected from a hydrogen atom and an alkyl group (C1-C3) Formula (III) [ka] The present invention relates to a process comprising reacting a compound with one of the compounds RH or its salts (wherein R is as defined above) under metal-catalyzed dehydrogenation amidation conditions.

[0037] As used herein, the term "metal-catalyzed dehydrogenation amidation" refers to a reaction carried out in the presence of at least a metal catalyst.

[0038] As disclosed herein, the compound of formula (III) is also known as OTBN, an abbreviation for o-tolylbenzonitrile.

[0039] In one embodiment, R is a process selected from formulas (1), (2), (3), and (5) defined above, which are further provided herein.

[0040] catalyst source In one embodiment, a process is further provided herein in which the reaction is carried out in the presence of a metal catalyst selected from copper catalysts, iron catalysts, manganese catalysts, cobalt catalysts, nickel catalysts, and mixtures thereof, particularly in the presence of an iron catalyst or a copper catalyst.

[0041] As used herein, the term “metal catalyst” means an active metal catalyst species involved in a metal-catalyzed dehydrogenation amidation process. “Metal catalyst” may also mean “metal complex.”

[0042] As used herein, the term “metal complex” means a compound having a metal atom or ion at its center, surrounded by other molecules or ions. Such surrounding molecules or ions are typically bonded to the central metal by coordinate bonds and are typically called ligands. A “metal complex” can be the metal catalyst or metal catalyst source described above.

[0043] In one embodiment, the metal catalyst is produced from a species named "metal catalyst source," "metal source," or "pre-catalyst," the source or pre-catalyst being in a particularly different form, such as a metal salt or a metal complex.

[0044] In one embodiment, the metal catalyst can be produced from a commercially available metal catalyst source in the form of a salt or complex.

[0045] In one embodiment, the metal catalyst is generated directly in the reaction mixture, in other words, generated in situ from a metal source, as shown in Examples 1-4.

[0046] In another embodiment, the metal catalyst is produced from a metal catalyst source synthesized in the form of a salt or metal complex. For example, a metal catalyst source synthesized in the form of a complex is obtained by a premixture of the metal in the form of a salt or complex and a ligand before being added to the reaction mixture. For example, the synthesized metal catalyst source may be obtained by premixing copper(I) iodine or bromine with 1,10-phenanthroline as a ligand.

[0047] In certain embodiments, the reaction is carried out in the presence of a copper catalyst.

[0048] In one embodiment, the copper catalyst is derived from copper(I) or copper(II), respectively, referred to as a copper(I) source or a copper(II) source, and is particularly derived from CuCl, CuBr, CuI, copper(I)thiophene-2-carboxylate, CuBr·SMe2, CuBr(Phen), CuI(Phen), CuCl(Phen), copper(I) acetate, Cu2S, copper(I)thiophenolate, (4-bromophenyl)-thio)-copper(I), mesityl copper(I), CuCN, CuSCN, (1,10-phenanthroline)(T (Lifluoromethyl) Copper(I), CuBr2, copper(II) acetate anhydrous or hydrate, CuF2, CuCl2 anhydrous or hydrate, CuS, CuSO4 anhydrous or hydrate, CuO, Cu(NO3)2 anhydrous or hydrate, copper(II) trifluoromethanesulfonate, copper(II) ethyl acetate anhydrous or hydrate, copper(II) 2-ethylhexanoate, copper(II) trifluoroacetate anhydrous or hydrate, copper(II) trifluoroacetylacetonate, copper(II) tert-butylacetate Tate, copper(II) i-butyrate, copper(II) 2-pyrazine carboxylate, copper(II) hexafluoroacetylacetonate anhydride or hydrate, copper(II) trifluoromethanesulfonimide anhydride or hydrate, dichloro(1,10-phenanthroline) copper(II), copper(II) cyclohexane butyrate, tetrakis(pyridine) copper(II) triflate, copper(II) 3,5-diisopropyl salicylate anhydride or hydrate, copper(II) tetrafluoroborate anhydride or hydrate, phthalic acid Copper(II), copper(II) di(2-naphthoate), copper(II) benzoate anhydrous or hydrate, copper(II) methylacetate, copper(II) ethylbenzoyl acetate, copper(II) ethyl 2-fluorobenzoyl acetate, copper(II) ethyl 2-chlorobenzoyl acetate, copper(II) 3-(fluorosulfonyl)benzoate, copper(II) ethyl 3-(fluorosulfonyl)benzoyl acetate, copper(II) 8-hydroxyquinoline, dichloro(N-(2-pyridylmethylene)aniline-N,N') Copper(II), Ethyl 2-(4-(pentyloxy)benzoyl) acetate copper(II), Ethyl alpha-acetyl-3-(fluorosulfonyl)benzoyl acetate copper(II), Ethyl alpha-acetyl-4-(fluorosulfonyl)benzoyl acetate copper(II), Ethyl alpha-acetyl-3-(methoxycarbonyl)benzoyl acetate copper(II), 2,3-diazaspiro[bicyclo[2.2.1]hept[2]ene-7,1'-cyclopropane copper(II), Alpha-(3,5-dichloro-2-pyridylimino)-o-cresol copper(II), Alpha-(6-methyl-2-pyridylimino)-o-cresol copper(II), Alpha-(3-methyl-2-pyridylimino)-o-cresol copper(II), Alpha-(5-chloro-2-pyridylimino)-o-cresol copper(II), A From rufa-(4-methyl-2-pyridylimino)-o-cresol copper(II), copper(II) bis(2,2,6,6-tetramethyl-3,5-heptanedionate) and copper(II) bis(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate), more particularly CuCl, CuBr, CuI, copper(I) thiophene-2-carboxylate, CuBr·SMe2, CuB Processes for producing salts, complexes, or mixtures thereof from r(Phen), CuI(Phen), CuCl(Phen), copper(I) acetate, CuBr2, and copper(II) acetate anhydrous, and more particularly selected from CuBr, CuI, CuBr(Phen), CuI(Phen), CuBr·SMe2, and CuBr2, for example, CuBr·SMe2, are further provided herein.

[0049] As used herein, the term "copper(I)" refers to the cuprous ion (Cu + Also known as copper(I), in other terminology, "copper(I)" refers to the element copper in its +1 oxidation state.

[0050] As used herein, the term "copper(II)" refers to the cupric ion (Cu 2+ Also known as copper(II), in other terminology, "copper(II)" refers to the element copper in its +2 oxidation state.

[0051] In certain embodiments, the copper(I) source is in the form of a salt called a "copper(I) salt" or a complex called a "copper(I) complex."

[0052] In certain embodiments, the copper(II) source is in the form of a salt called a "copper(II) salt" or a complex called a "copper(II) complex."

[0053] In certain embodiments, the copper catalyst is produced from CuCl, CuBr, CuI, copper(I) thiophene-2-carboxylate, CuBr·SMe2, CuBr(Phen), CuI(Phen), CuCl(Phen), copper(I) acetate, CuBr2, and copper(II) acetate anhydride, or mixtures thereof.

[0054] In certain embodiments, the copper catalyst is CuBr, CuI, CuBr(Phen), CuI(Phen), CuBr·SMe2, or CuBr 2、 Or it is produced from a group consisting of mixtures thereof.

[0055] In certain embodiments, the copper catalyst is produced from CuBr·SMe2. Such embodiments may be as shown in Examples 1 and 3.

[0056] In another embodiment, the iron catalyst is supplied from an iron(II) or iron(III) source, respectively, called an iron(II) source or an iron(III) source, specifically FeCl2, FeCl3, FePO2, etc. 4、Processes are further provided herein for producing salts, complexes, or mixtures thereof selected from 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, and more particularly from FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3 and Fe(OH)3, and more particularly from FeBr3, FeCl2, FeCl3 and FeCl3·6H2O, for example, FeBr3.

[0057] In certain embodiments, the iron catalyst is produced from iron(II) or iron(III) in the form of a salt, a complex, or a mixture thereof.

[0058] As used herein, the term "iron(II)" refers to the ferrous ion (Fe 2+ Also known as iron(II), in other terminology, "iron(II)" refers to the elemental iron in its +2 oxidation state.

[0059] As used herein, the term "iron(III)" refers to the ferric ion (Fe 3+ Also known as iron(III), in other terminology, "iron(III)" refers to the elemental iron in its +3 oxidation state.

[0060] In certain embodiments, the iron(II) source is in the form of a salt called an "iron(II) salt" or a complex called an "iron(II) complex."

[0061] In certain embodiments, the iron(III) source is in the form of a salt called an "iron(III) salt" or a complex called an "iron(III) complex."

[0062] In certain embodiments, the iron catalyst is produced from the group consisting of FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3, and Fe(OH)3.

[0063] In certain embodiments, the iron catalyst is produced from the group consisting of FeBr3, FeCl2, FeCl3, and FeCl3·6H2O.

[0064] In certain embodiments, the iron catalyst is produced from FeBr3. Such embodiments may be as shown in Examples 2 and 4.

[0065] In certain embodiments, the reaction may be carried out in the presence of a metal catalyst, which is a mixture of the copper catalyst and the iron catalyst, produced in particular from at least one of the aforementioned copper(I) and / or copper(II) sources and at least one of the aforementioned iron(II) and / or iron(III) sources.

[0066] In another embodiment, the manganese catalyst, cobalt catalyst, and nickel catalyst are, respectively, -(i) Manganese sources, also called manganese(II) sources, in particular, selected from MnBr2 and MnCl2, in the form of salts, complexes, or mixtures thereof. -(ii) In particular, a cobalt source, also called a cobalt(II) source, in the form of a salt, complex or mixture thereof, selected from CoCl2 and CoBr2. -(iii) Nickel sources, also called nickel(II) sources, in the form of salts, complexes, or mixtures thereof, particularly selected from NiBr2 and NiCl2. Processes for generating from are further provided herein.

[0067] In certain embodiments, the manganese catalyst is produced from a manganese source, also called a manganese(II) source, in the form of a salt, a complex, or a mixture thereof.

[0068] As used herein, the term "manganese(II)" refers to the element manganese in its +2 oxidation state.

[0069] In certain embodiments, the manganese(II) source is in the form of a salt called a “manganese(II) salt” or a complex called a “manganese(II) complex.”

[0070] In certain embodiments, the manganese catalyst is produced from the group consisting of MnBr2 and MnCl2.

[0071] In certain embodiments, the cobalt catalyst is produced from a cobalt source, also called a cobalt(II) source, in the form of a salt, a complex, or a mixture thereof.

[0072] As used herein, the term "cobalt(II)" refers to elemental cobalt in its +2 oxidation state.

[0073] In certain embodiments, the cobalt(II) source is in the form of a salt called a "cobalt(II) salt" or a complex called a "cobalt(II) complex."

[0074] In certain embodiments, the cobalt catalyst is produced from the group consisting of COCl2 and CoBr2.

[0075] In certain embodiments, the nickel catalyst is produced from a nickel source, also called a nickel(II) source, in the form of a salt, a complex, or a mixture thereof.

[0076] As used herein, the term "nickel(II)" refers to elemental nickel in its +2 oxidation state.

[0077] In certain embodiments, the nickel(II) source is in the form of a salt called a "nickel(II) salt" or a complex called a "nickel(II) complex".

[0078] In certain embodiments, the nickel catalyst is produced from the group consisting of NiBr2 and NiCl2.

[0079] In one embodiment, the specification further provides a process in which a metal source, in particular 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 compound RH as defined above.

[0080] In certain embodiments, 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 0.5% to 15% relative to the amount of compound RH as defined above.

[0081] In certain embodiments, 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 1% to 10% relative to the amount of compound RH as defined above.

[0082] Ligand In one embodiment, the metal catalyst is selected from bidentate ligands, monodentate ligands and mixtures thereof, and more particularly, - Bidentate or monodentate nitrogen ligands, especially bidentate nitrogen ligands, more particularly optionally substituted bipyridine ligands, and even more particularly phenanthroline ligands, e.g., 1,10-phenanthroline, 4,4'-di-tert-butyl-2,2'-dipyridyl, dimethylglycine, N,N',N',N'-tetramethylethylethylenediamine, trans-N,N'-dimethylcyclohexane-1,2-diamine, N-(2-pyridinylmethylene)benzeneamine, 1,1'-binaphthyl-2,2'-diamine, or 1-methylimidazole; - Bidentate or monodentate phosphine ligands, especially monodentate phosphine ligands, more particularly phosphine ligands optionally substituted with at least one aryl, e.g., triphenylphosphine; or - Bidentate diketone ligands, especially 1,3-diketone ligands, such as ethyl 2-oxocyclohexanecarboxylate Processes in the form of metal complexes containing ligands selected from are further provided herein.

[0083] As used herein, the term “ligand” refers to a chemical species that can coordinate to a metal atom or ion.

[0084] In certain embodiments, the ligand is selected from bidentate ligands, monodentate ligands, and mixtures thereof.

[0085] As used herein, the term "monovalent ligand" refers to a ligand that can coordinate to a metal atom or ion with one atom, in particular one heteroatom, such as a nitrogen atom or a phosphine atom.

[0086] As used herein, the term “bidentate ligand” refers to a ligand that can coordinate to a metal atom or ion with two atoms, particularly heteroatoms, such as a nitrogen atom, an oxygen atom and / or a phosphine atom.

[0087] In certain embodiments, the ligand is selected from bidentate ligands, monodentate nitrogen ligands, and mixtures thereof.

[0088] As used herein, the term "monodentate nitrogen ligand" refers to a ligand that can coordinate to a metal atom or ion by a single nitrogen atom, in particular for the purpose of forming a metal complex.

[0089] As used herein, the term “bidentate nitrogen ligand” refers in particular to a ligand that can coordinate to a metal atom or ion with at least one nitrogen atom and another heteroatom, such as another nitrogen atom or another oxygen atom, in order to form a metal complex.

[0090] In certain embodiments, the ligand is selected from bidentate nitrogen ligands and mixtures thereof.

[0091] In certain embodiments, the ligand is selected from optionally substituted bipyridine ligands and mixtures thereof.

[0092] In certain embodiments, the ligand is selected from phenanthroline ligands and mixtures thereof.

[0093] In certain embodiments, the ligand is 1,10-phenanthroline. Such embodiments are shown in Example 1.

[0094] In certain embodiments, the ligand is selected from 1,10-phenanthroline, 4,4'-di-tert-butyl-2,2'-dipyridyl, dimethylglycine, N,N,N',N'-tetramethylethylenediamine, trans-N,N'-dimethylcyclohexane-1,2-diamine, N-(2-pyridinylmethylene)benzeneamine, 1,1'-binaphthyl-2,2'-diamine, or 1-methylimidazole and mixtures thereof.

[0095] In certain embodiments, the ligand is selected from bidentate ligands, monodentate phosphine ligands, and mixtures thereof.

[0096] As used herein, the term "monodentate phosphine ligand" refers to a ligand that can coordinate to a metal atom or ion by a single phosphine atom, in particular for the purpose of forming a metal complex.

[0097] As used herein, the term “bidentate phosphine ligand” refers to a ligand that can coordinate to a metal atom or ion by two phosphine atoms, in particular, to form a metal complex.

[0098] In certain embodiments, the ligand is selected from monodentate phosphine ligands, and mixtures thereof, that are optionally substituted with at least one aryl group.

[0099] In certain embodiments, the ligand is selected from triphenylphosphine, triphenylphosphine derivatives, and mixtures thereof.

[0100] In certain embodiments, the ligand is selected from bidentate diketone ligands and mixtures thereof.

[0101] As used herein, the term “bidentate diketone ligand” refers to a ligand that can coordinate to a metal atom or ion by two oxygen atoms of a diketone, in particular for the purpose of forming a metal complex.

[0102] In certain embodiments, the ligand is selected from 1,3-diketone ligands and mixtures thereof.

[0103] In certain embodiments, the ligand may be ethyl 2-oxocyclohexane carboxylate.

[0104] In certain embodiments, the reaction is carried out in the absence of ligands, as shown in Examples 2 and 4.

[0105] Oxidizing agent In one embodiment, the oxidizing agent, particularly the peroxide of formula R1-OO-R2 or formula R'1-OO-R'-OO-R'2, and the formula R3-OC(O)-C(O)-O-R4 (wherein 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), R' represents an (C1-C6) alkylene group, and Further provided herein are processes in which the reaction is carried out in the presence of an oxidizing agent selected from oxalates of (R3 and R4 independently represent a hydrogen atom, an aryl group, or an alkyl group optionally substituted with an aryl group) and mixtures thereof.

[0106] In certain embodiments, the oxidizing agent is selected from peroxides of 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.

[0107] In certain embodiments, the oxidizing agent is selected from di-tert-butyl peroxide, tert-butyl hydroperoxide, benzoyl peroxide, dicumyl peroxide, hydrogen peroxide, and mixtures thereof.

[0108] In certain embodiments, the oxidizing agent is selected from di-tert-butyl peroxide, tert-butyl hydroperoxide, and dicumyl peroxide.

[0109] In certain embodiments, the oxidizing agent is di-tert-butyl peroxide, as shown in Examples 1-4.

[0110] In certain embodiments, the oxidizing agent is selected from peroxides of 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) alkylene group.

[0111] In certain embodiments, the oxidizing agent is selected from 2,5-di(tert-butylperoxy)-2,5-dimethyl-3-hexyne, 2,5-di(tert-butylperoxy)-2,5-dimethylhexane, 1,1-bis(tert-butylperoxy)cyclohexane, and mixtures thereof.

[0112] In certain embodiments, the oxidizing agent is selected from oxalates 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.

[0113] In certain embodiments, the oxidizing agent is ditert-butyl oxalate.

[0114] In one embodiment, a process is further provided herein in which the oxidizing agent is present in an equivalent amount of 0.1 to 10 relative to the amount of compound RH as defined above and corresponding to 1 equivalent, particularly in an equivalent amount of 0.5 to 8 relative to the amount of compound RH as defined above and corresponding to 1 equivalent, and more particularly in an equivalent amount of 1 to 5 relative to the amount of compound RH as defined above and corresponding to 1 equivalent.

[0115] In certain embodiments, the oxidizing agent is present in an equivalent amount ranging from 0.5 to 8 with respect to the amount of compound RH corresponding to one equivalent, as defined above.

[0116] In certain embodiments, the oxidizing agent is present in an equivalent amount ranging from 1 to 5 with respect to the amount of compound RH, as defined above and corresponding to 1 equivalent.

[0117] solvent In one embodiment, the solvent, in particular organic solvents, more particularly: - Benzonitrile, o-tolylbenzonitrile, chlorobenzene, dichlorobenzene and anisole, for example, an aromatic solvent further selected from o-tolylbenzonitrile, - Hexafluoropropan-2-ol, isobutanol, tert-butanol and n-butanol, for example, an alcohol solvent further particularly selected from tert-butanol and n-butanol. - Ketone solvents, for example, methyl isobutyl ketone, - Ether solvents, e.g., cyclopentanemethyl ether, - Hydrocarbon solvents, e.g., heptane, - Ester solvents, for example, isobutyl acetate, - A polar solvent further particularly selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, diethyl carbonate, and n-methylpyrrolidine (NMP), - water - Acidic solvents, for example, acetic acid, Furthermore, a process in which the reaction is carried out in an organic solvent selected from mixtures thereof is also provided herein.

[0118] As used herein, the term “solvent” also means “cosolvent.” The term “cosolvent” may also be used for a mixture of at least two solvents.

[0119] In certain embodiments, the solvent is selected from aromatic solvents and mixtures thereof.

[0120] As used herein, the term “aromatic solvent” means a solvent containing at least one aromatic hydrocarbon derivative, such as benzene or toluene, which is optionally substituted.

[0121] In certain embodiments, the metal-catalyzed dehydrogenation amidation 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 both the solvent and the starting material.

[0122] In certain embodiments, the solvent is selected from benzonitrile, o-tolylbenzonitrile, chlorobenzene, dichlorobenzene, anisole, and mixtures thereof.

[0123] In certain embodiments, the solvent is selected from alcoholic solvents and mixtures thereof.

[0124] As used herein, the term "alcohol solvent" means a solvent containing at least optionally substituted organic alcohols such as methanol, ethanol, propanol, butanol, or pentanol, and their isomers.

[0125] In certain embodiments, the solvent is selected from hexafluoropropan-2-ol, isobutanol, tert-butanol, n-butanol, and mixtures thereof.

[0126] In certain embodiments, the solvent is either tert-butanol alone or a mixture with at least one of the solvents described above and below.

[0127] In certain embodiments, the solvent is selected from ketone solvents and mixtures thereof.

[0128] As used herein, the term “ketone solvent” means a solvent containing at least one ketone functionality, which is present in particular on a linear, branched, or cyclic hydrocarbon chain, such as an optionally substituted aliphatic or aromatic chain.

[0129] In certain embodiments, the solvent is either methyl isobutyl ketone alone or a mixture with at least one of the solvents described above and below.

[0130] In certain embodiments, the solvent is selected from ether solvents and mixtures thereof.

[0131] As used herein, the term "ether solvent" means a solvent containing at least one oxygen atom that selectively suspends linear, branched, or cyclic hydrocarbon chains.

[0132] In certain embodiments, the solvent is either cyclopentane methyl ether alone or a mixture with at least one of the solvents described above and below.

[0133] In certain embodiments, the solvent is selected from hydrocarbon solvents and mixtures thereof.

[0134] As used herein, the term "hydrocarbon solvent" means a solvent that essentially contains carbon and hydrogen atoms, in particular (C1-C1). 10 ) Linear chain, (C1~C 10 ) This means branched chains or (C3-C8) cyclic hydrocarbon chains, including, for example, pentane, hexane, heptane, or octane.

[0135] In certain embodiments, the solvent is heptane alone or a mixture of heptane and at least one of the solvents described above and below.

[0136] In certain embodiments, the solvent is selected from ester solvents and mixtures thereof.

[0137] As used herein, the term "ester solvent" means a solvent containing at least one ester functionality, which is located in particular on a linear, branched, or cyclic hydrocarbon chain, such as an aliphatic or aromatic group that is selectively substituted.

[0138] In certain embodiments, the solvent is isobutyl acetate alone or a mixture with at least one of the solvents described above and below.

[0139] In certain embodiments, the solvent is selected from polar solvents and mixtures thereof.

[0140] As used herein, the term “polar solvent” means a solvent that exhibits a strong dielectric constant.

[0141] In certain embodiments, the solvent is selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, diethyl carbonate, n-methylpyrrolidine (NMP), and mixtures thereof.

[0142] In certain embodiments, the solvent is water alone or a mixture of water with at least one of the solvents described above and below.

[0143] In certain embodiments, the solvent is either acetic acid alone or a mixture with at least one of the above-mentioned solvents.

[0144] Salt form and RH under base In one embodiment, particularly when RH as defined above is in the form of a salt, the process is carried out in the presence of a base, wherein the base is - Inorganic bases, - Alkoxide bases, - An organic base containing at least one nitrogen atom, for example, triethylamine or N,N-diisopropylethylamine, Processes optionally selected from mixtures thereof are further provided herein.

[0145] In certain embodiments, the base is selected from inorganic bases and mixtures thereof.

[0146] As used herein, the terms "inorganic base" or "mineral base" refer to a base in salt form that contains at least a hydroxide ion, a carbonate ion, or a hydride carbonate ion, also known as a bicarbonate ion.

[0147] In certain embodiments, the base is selected from Na2CO3, Cs2CO3, K2CO3, NaHCO3, NaOH, KOH, and mixtures thereof.

[0148] In certain embodiments, the base is either K2CO3 alone or a mixture of K2CO3 with at least one of the bases described above and below.

[0149] In certain embodiments, the base is selected from alkoxide bases and mixtures thereof.

[0150] 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 include, but are not limited to, counterions such as sodium, lithium, or potassium ions.

[0151] In certain embodiments, the base is either tBuOK alone or a mixture of tBuOK with at least one of the bases described above and below.

[0152] In certain embodiments, the base is selected from organic bases containing at least one nitrogen atom.

[0153] In certain embodiments, the base is selected from triethylamine, N,N-diisopropylethylamine, and mixtures thereof.

[0154] In one embodiment, a process is further provided herein in which the reaction is carried out in the presence of a base, in which case the RH defined above is in the form of a salt, particularly in the form of an RH hydrochloride, for example, an RH·HCl salt.

[0155] Reaction time In one embodiment, a process in which the reaction is carried out for 1 to 20 hours is further provided herein.

[0156] In certain embodiments, the reaction is carried out for 8 to 18 hours.

[0157] In certain embodiments, the reaction is carried out for 10 to 16 hours.

[0158] In certain embodiments, the reaction is 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.

[0159] In certain embodiments, the reaction is carried out for 8 hours, 15 hours, or 20 hours.

[0160] In certain embodiments, the reaction is carried out for 8 hours or 15 hours.

[0161] In certain embodiments, the reaction is carried out for 15 hours.

[0162] Temperature and / or photoactivation conditions In one embodiment, a process is further provided herein in which the reaction is carried out at a temperature in the range of 20°C to 200°C, particularly 90°C to 180°C, more particularly 100°C to 150°C, and / or under photoactivation conditions of a wavelength in the range of 200 nm to 900 nm, particularly 200 nm to 800 nm, more particularly 250 nm to 400 nm, or a combination of wavelengths, in the presence of a photosensitizer, which is optionally used.

[0163] In certain embodiments, the reaction is carried out at a temperature in the range of 20°C to 200°C.

[0164] In certain embodiments, the reaction is carried out at a temperature in the range of 90°C to 180°C.

[0165] In certain embodiments, the reaction is carried out at a temperature in the range of 100°C to 150°C.

[0166] In certain embodiments, the reaction is carried out under photoactivation conditions.

[0167] In certain embodiments, the reaction is carried out under photoactivation conditions with wavelengths or combinations of wavelengths in the range of 200 nm to 900 nm.

[0168] In certain embodiments, the reaction is carried out under photoactivation conditions with wavelengths or combinations of wavelengths in the range of 200 nm to 800 nm.

[0169] In certain embodiments, the reaction is carried out under photoactivation conditions with wavelengths or combinations of wavelengths in the range of 250 nm to 400 nm.

[0170] In certain embodiments, the reaction is carried out under photoactivation conditions at a temperature in the range of 20°C to 80°C.

[0171] In certain embodiments, the reaction is carried out at a temperature in the range of 40°C to 60°C under photoactivation conditions.

[0172] As used herein, the term “photo-induced reaction” refers to a “photochemical reaction” carried out under photoactivation conditions corresponding to the activation of a reaction using incident photons. The light corresponds to wavelengths belonging to the UV, visible, or IR spectrum.

[0173] In certain embodiments, the reaction is carried out at a temperature in the range of 20°C to 80°C under photoactivation conditions of wavelengths or combinations of wavelengths in the range of 200 nm to 900 nm, particularly 200 nm to 800 nm, and more particularly 250 nm to 400 nm.

[0174] In certain embodiments, the reaction is carried out at a temperature in the range of 40°C to 60°C under photoactivation conditions with wavelengths or combinations of wavelengths in the range of 200 nm to 900 nm.

[0175] In certain embodiments, the reaction is carried out at a temperature in the range of 40°C to 60°C under photoactivation conditions with wavelengths or combinations of wavelengths in the range of 200 nm to 800 nm.

[0176] In certain embodiments, the reaction is carried out at a temperature in the range of 40°C to 60°C under photoactivation conditions with wavelengths or combinations of wavelengths in the range of 250 nm to 400 nm.

[0177] In certain embodiments, when photoactivation conditions are used, the reaction is carried out in the presence of a photosensitizer.

[0178] As used herein, the term “photosensitizer” refers to a chemical species that absorbs light of a specific wavelength and converts it into energy useful for activating a reaction. In particular, photosensitizers are photocatalysts, more specifically donor-acceptor photocatalysts, used in photocatalytic conditions.

[0179] In certain embodiments, the photosensitizer is selected from cyanoalene derivatives, diketone derivatives, and conjugated ketones or aldehydes, such as aromatic ketones or aldehydes.

[0180] In certain embodiments, the photosensitizer is selected from 1,2,3,5-tetrakis(carbazole-9-yl)-4,6-dicyanobenzene; 2,4,5,6-tetrakis(9H-carbazole-9-yl)isophthalonitrile, also known as 4CzIPN; 2,3-butane-dione; fluorenone; and mixtures thereof.

[0181] In certain embodiments, the reaction is carried out at a temperature in the range of 40°C to 60°C under photoactivation conditions of a combination of wavelengths in the range of 200 nm to 800 nm, in the presence of a photosensitizer, which is 1,2,3,5-tetrakis(carbazole-9-yl)-4,6-dicyanobenzene; 2,4,5,6-tetrakis(9H-carbazole-9-yl) isophthalonitrile, also known as 4CzIPN.

[0182] Other conditions In one embodiment, a process is further provided herein in which a metal-catalyzed dehydrogenation amidation reaction is carried out in the presence of a promoter.

[0183] As used herein, the term "promoter" means a chemical species that can improve the reaction rate.

[0184] In certain embodiments, the promoter is a base, more particularly an alkoxide base, such as tBuOK.

[0185] In one embodiment, a process in which the reaction is carried out under an inert atmosphere is further provided herein.

[0186] As used herein, “inert atmosphere” means an atmosphere containing an inert gas, such as argon or nitrogen. This means that there is no oxygen in the atmosphere. For example, an inert atmosphere may be a nitrogen gas or an argon gas.

[0187] In one embodiment, a process in which the reaction is carried out in an ambient air atmosphere is further provided herein.

[0188] Characterization of the process based on the presence of dimeric by-products In one embodiment, formula (IV) [ka] A process for forming the o-tolylbenzonitrile dimer by-compound, as shown in Example 3, is further provided herein.

[0189] As used herein, the compound of formula (IV) is also called the OTBN dimer, 4',4''-(ethane-1,2-diyl)di([1,1'-biphenyl]-2-carbonitrile), o-tolylbenzonitrile dimer byproduct, OTBN dimer byproduct, or OTBN dimer.

[0190] In certain embodiments, the process includes a step of further purification to a catalytic dehydrogenation amidation reaction to remove the majority of the compound of formula (IV), particularly at least 99% of the compound of formula (IV).

[0191] In one embodiment, the metal-catalyzed dehydrogenation amidation reaction is carried out particularly at a temperature in the range of 100°C to 150°C and under an inert atmosphere. - Copper catalysts, especially copper catalysts produced from CuBr·SMe2, particularly copper catalysts in the form of metal complexes containing a ligand such as 1,10-phenanthroline, - In particular, di-tert-butylperoxide is an oxidizing agent, and - OTBN, which is both a reactant and a solvent. Processes carried out in the presence of are further provided herein.

[0192] In certain embodiments, the above process may provide a compound of formula (II) defined above, where R is formula (1) defined above, as shown in Example 1.

[0193] In one embodiment, the metal-catalyzed dehydrogenation amidation reaction is carried out particularly at a temperature in the range of 100°C to 150°C and under an inert atmosphere. - In particular, iron catalysts produced from FeBr3, - In particular, di-tert-butylperoxide is an oxidizing agent, and - OTBN, which is both a reactant and a solvent. Processes carried out in the presence of are further provided herein.

[0194] In certain embodiments, the above process may provide a compound of formula (II) as defined above, where R is one of the formulas (1), (2), (3), and (5) defined above, as shown in Examples 2 and 4.

[0195] In certain embodiments, the process includes a step of further purification in a catalytic dehydrogenation amidation reaction.

[0196] In one embodiment, - For example, catalytic dehydrogenation amidation reactions such as the one described above, - At least the refining process, - Tetrazolylation process Processes comprising the following steps in sequence are further provided herein.

[0197] Tetrazolylation process In one embodiment, formula (I): [ka] A process for preparing one of the sultan-active compounds of (wherein R is as defined above) or one of its pharmaceutically acceptable salts, Further provided herein are processes comprising a tetrazolylation step of reacting a compound of formula (II) as defined above, which has been prepared by a process for preparing a compound of formula (II) as defined above.

[0198] Tetrazolylation refers to the conversion of nitriles to tetrazoles.

[0199] Azide derivatives, such as alkali metal azides like tributyltin azide or sodium azide, and bases such as triethylamine hydrochloride are described in the literature. For example, the preparation of 2-n-butyl-3-[[2'-(tetrazole-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (also known as irbesartan) from 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (also known as spiromethylbiphenylnitrile) by heating under reflux in the presence of tributyltin azide is known.

[0200] Among the sartan-active compounds of formula (I) defined above, irbesartan, losartan, valsartan, candesartan, or olmesartan may be mentioned. In particular, among the sartan-active compounds of formula (I) defined above, irbesartan, losartan, valsartan, or olmesartan may be mentioned.

[0201] In one embodiment, a process is further provided herein in which the sartan-active compound of formula (I) is irbesartan, also known as 2-n-butyl-4-spirocyclopentan-1-[[2'-(tetrazole-5-yl)biphenyl-4-yl]methyl]-2-imidazolin-5-one or 2-n-butyl-3-[[2'-(tetrazole-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one.

[0202] In one embodiment, the tetrazolylation step is carried out under normal conditions known to those skilled in the art.

[0203] In certain embodiments, the tetrazolylation step is carried out in the presence of a hydrazoic acid (HN3), a salt azide, such as a metal azide such as sodium azide (NaN3), potassium azide (KN3), or calcium azide (Ca(N3)2), SnBu3N3, SnMe3N3, a trialkylammonium azide, such as triethylammonium azide, and in particular a metal or salt azide, such as sodium azide or triethylammonium azide, selected from the group.

[0204] In one embodiment, the tetrazolylation step is carried out in the presence of an azide derivative and a single base. In particular, the base is selected from the group of Hugneg bases, such as triethylamine (Et3N), N,N-dicyclohexylmethylamine, and N,N-diisopropylethylamine. The base may be triethylamine in particular, and more particularly triethylamine hydrochloride (TEA, also called HCl).

[0205] In one embodiment, the tetrazolylation step is carried out using an azide derivative and a single base in an inert polar aprotic solvent at a temperature below the reflux temperature and under an inert atmosphere.

[0206] As used herein, the term “polar aprotic solvent” means a polar solvent that cannot release one or more protons. In contrast, as used herein, the term “polar protic solvent” means a polar solvent that can release one or more protons.

[0207] In certain embodiments, the tetrazolylation step is carried out in the presence of a polar 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), dimethylpropyleneurea (DMPU), dimethylethyleneurea (DMEU), triethylamine (TEA), hexamethylphosphorotriamide (HMPA), hexamethylphosphorotriamide (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 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), dimethylpropyleneurea (DMPU), dimethylethyleneurea (DMEU), triethylamine (TEA), hexamethylphosphorotriamide (HMPA), hexamethylphosphorotriamide (HMPT), 2-pyrrolidone (2-Py), N-methyl-2-pyrrolidone (NMP), N-phenyl-2-pyrrolidone (NPP), N-vinylpyrrolidone (NVP), and 5-methyl-2-pyrrolidone (MPy).

[0208] In one embodiment, the tetrazolylation step is carried out using an alkali metal azide and triethylamine hydrochloride of equimolecular weight in a ratio of 1 to 5 moles per mole of the compound of formula (II) defined above, preferably in a ratio of about 1.2 to about 2 moles per mole of the compound of formula (II) defined above.

[0209] In one embodiment, the tetrazolylation step is carried out at a temperature in the range of room temperature to 150°C, particularly 100°C to 135°C, for example, 150°C.

[0210] In one embodiment, after heating for 6 to 20 hours, the tetrazolylation is completed, and the reaction mixture is prepared according to the conventional technique. In particular, the mixture is neutralized by adding a base, such as an alkali metal hydroxide, to an aqueous solution, and the aqueous phase containing salts, especially chlorides and azides, is discarded. The organic phase is then treated sequentially with water and various organic solvents (aromatic, halogenated, ester, ketone, etc.) such as toluene, ethyl acetate, dichloromethane (DCM), and methyl ethyl ketone, using two different solvents as optional, to remove byproducts of the tetrazolylation reaction. These washing steps are conventional and well known to those skilled in the art. The final product is then crystallized, for example, via a crystallization step well known to those skilled in the art. Subsequently, additional conventional filtration and washing steps may be carried out as needed.

[0211] In certain embodiments, the tetrazolylation step is carried out in a reaction medium having at least one azide derivative, and the benzyl azide impurity formed during the tetrazolylation is converted to an aldehyde derivative. The tetrazolylation step may be carried out in accordance with International Publication No. 2023 / 052309, and the benzyl azide impurity formed during the tetrazolylation is converted to an aldehyde derivative.

[0212] As used herein, the terms “benzyl azide impurities” or “azide impurities, etc.” include all by-products or impurities that may be produced by nucleophilic substitution of compounds containing at least one active carbon atom in their structure with an alkali metal azide. “Active carbon atom” means, as used herein, a carbon atom having a leaving group such as a halogen atom (chlorine, bromine, or iodine atom), an alcohol group, a tosylate group, a mesylate group, an alkyl phosphate group, an ester group, or an amide group. Such “active carbon atoms” are more particularly carbon atoms linked to a phenyl ring, and thus forming an active benzyl structure. Thus, “benzyl azide impurities” may be present during a tetrazolylation step in which an alkali metal azide is implemented, starting from an intermediate compound having a cyanophenyl moiety, such as the compound of formula (II) as defined above.

[0213] In a conventional process for synthesizing sultan-active compounds, including a cyano derivative intermediate for the tetrazolylation step, two well-known mutagenic benzyl azide impurities are formed as follows: an azidonitrile represented by formula (A), also known as 5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-nitrile or 4'-(azidomethyl)-[1,1'-biphenyl]-2-carbonitrile, 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. [ka]

[0214] These two benzyl azide impurities (A) and (B) can be formed during the tetrazolylation of the compound of formula (II) defined above from several different potential precursors, including monobrominated derivatives used in the prior art for the synthesis of the compound of formula (II) described above.

[0215] Typically, by converting the benzyl azide impurity formed during the tetrazolylation to an aldehyde derivative, it becomes possible to provide less than 1 ppm of the benzyl azide impurity relative to the total amount of irbesartan after the final purification step, as shown in the brochure for International Patent Publication No. 2023 / 052309. In particular, the benzyl azide impurity is converted to an aldehyde derivative in the presence of FeCl3.

[0216] Characterization of the process by the presence of a dimeric byproduct containing at least one tetrazole group. In certain embodiments, the tetrazolylation step defined above may result in the formation of at least one byproduct of formulas (V) and (VI) as defined below. In particular, the tetrazolylation step may be carried out by reacting a mixture comprising the compound of formula (II) as defined above and an o-tolylbenzonitrile dimer byproduct of formula (IV), the mixture being prepared by a process for preparing the compound of formula (II) as defined above, which includes metal-catalyzed dehydrogenation amidation. The tetrazolylation step resulting in the byproducts of formulas (V) and (VI) as defined below may be carried out starting with the o-tolylbenzonitrile dimer byproduct of formula (IV), as shown in Example 5.

[0217] In certain embodiments, the sultaneous compound of formula (I) above is formula (V) and (VI): [ka] It contains at least one of the compounds.

[0218] In a particular embodiment, - The sultaneous compound of formula (I) above, and - Equations (V) and (VI): [ka] A composition comprising at least one of the compounds is further provided herein.

[0219] In certain embodiments, the sartan active compound is obtained after a purification step following the tetrazolylation step.

[0220] In certain embodiments, the sartan active compound of formula (I) above comprises at least one of the compounds of formula (V) and (VI) above, particularly, comprises at least one trace of the compounds of formula (V) and (VI) above, and more particularly, each compound of formula (V) and (VI) is less than 0.1% by weight, for example, each compound of formula (V) and (VI) is less than 0.05% by weight, based on the total weight of the sartan active compound.

[0221] In certain embodiments, a composition comprising the sartan active compound of formula (I) above and at least one of the compounds of formula (V) and (VI) above may particularly comprise at least one trace of the compounds of formula (V) and (VI) above, and more particularly, each compound of formula (V) and (VI) is less than 0.1% by weight, for example, each compound of formula (V) and (VI) is less than 0.05% by weight, based on the total weight of the sartan active compound.

[0222] In one embodiment, a mixture, a process for preparing the compound of formula (II) as defined above, and subsequently, a sartan active compound of formula (I):

Chemical formula

Chemical formula

[0223] In one embodiment, - A process for preparing the compound of formula (II) as defined above, and subsequently, a sartan active compound of formula (I) obtainable by the tetrazolylation step as defined above: [Chemical formula] (wherein, R is as defined above) a sartan active compound, or one of their pharmaceutically acceptable salts, and - formulas (V) and (VI): [Chemical formula] The present specification further provides a composition, particularly a mixture, comprising at least one compound of

[0224] In a particular embodiment, the sartan active 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 formulas (V) and (VI): [Chemical formula] comprises at least one of the compounds of

[0225] In a particular embodiment, the composition is a sartan active compound that 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 formulas (V) and (VI): [Chemical formula] may comprise at least one of the compounds of

[0226] In certain embodiments, the sartan-active compound is selected from losartan, valsartan and its esters, e.g., methyl ester or ethyl ester, candesartan and its esters, e.g., methyl ester or ethyl ester, olmesartan and its esters, e.g., methyl ester or ethyl ester, and formulas (V) and (VI): [ka] It contains at least one of the compounds.

[0227] In certain embodiments, the composition may contain a sartan-active compound selected from losartan, valsartan and its esters, e.g., methyl ester or ethyl ester, candesartan and its esters, e.g., methyl ester or ethyl ester, olmesartan and its esters, e.g., methyl ester or ethyl ester, formulas (V) and (VI): [ka] It contains at least one of the compounds. [Examples]

[0228] Examples of protocols for preparing the compound of formula (II) as defined above, using the novel processes provided herein, are described below. These examples are non-limiting and serve merely to illustrate the novel processes. In the following examples, the starting compounds and reactants may be prepared, unless otherwise described, by commercially available or described in the literature, or by methods otherwise known to those skilled in the art.

[0229] In the following embodiments, the following abbreviations and empirical formulas are used.

[0230] [Table 1]

[0231] Analytical thin-layer chromatography was performed on a silica gel aluminum plate with an F-254 indicator and visualized by UV light (254 nm) and / or chemical staining with a KMnO4 solution.

[0232] Flash column chromatography for purification was carried out using 0.040 - 0.063 nm silica gel.

[0233] On a Bruker DXP 300 MHz spectrometer, at 300.1 MHz 1 1H NMR spectra were recorded, and at 75.5 MHz 13 13C NMR spectra were recorded. Chemical shifts (δ) are reported in ppm relative to TMS ( 1 1H). Coupling constants (J) are reported in Hz. Residual solvent signals were 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 were used to indicate multiplicity: s: singlet, d: doublet, t: triplet, q: quartet, dd: doublet of doublets, m: multiplet.

[0234] High-resolution mass spectrometry (HRMS) was performed on an electrospray ionization mass spectrometer equipped with a micro-TOF analyzer.

[0235] Infrared spectra were recorded on a Perkin Elmer FT-IR spectrometer Paragon 100 (ATR), and the wave numbers (ν) of the recorded IR signals (ATR) were cited in cm -1 -1.

[0236] LC-MS: System: LC system Thermo Vanquish and MS detector Thermo ISQ EM. Column: Acquity Waters HSS T3 (1.7 μm) 2.1 mm × 50 mm. Phase A: Purified water + 0.1% formic acid. Phase B: Acetonitrile + 0.1% formic acid.

[0237] qNMR: A quantitative method using 1,3,5-trimethoxybenzene as an internal standard, recorded as described above. 1 This is carried out by 1H NMR spectroscopy. Such quantitative methods are known to those skilled in the art and are commonly used.

[0238] In Examples 1 and 2, the conditions are given by the following equation (II)(1): [ka] Details are provided regarding metal-catalyzed dehydrogenation amidation for the preparation of the compound of formula (II) defined above, where R is formula (1) defined above, corresponding to 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one, where R is formula (1) defined above.

[0239] Example 1: Preparation of compound (II) where R is formula (1) in the presence of a copper catalyst produced from CuBr·SMe2 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 phenanthroline (4.6 mg, 0.025 mmol) were added [from a glove box] to a flame-dried 8 mL microwave vial, followed by the addition of OTBN (2.73 g, 14 mmol). The tube was sealed with a PTFE septum. The tube was placed under vacuum and then flushed with argon, and the procedure was repeated three times. The tube was then placed in an oil bath preheated to 135°C. The reaction mixture was then allowed to reach 135°C after 30 minutes, at which point DTBP (20 μL) was added every hour for 4 hours, reacting with a total of (91 μL, 1 mmol) of DTBP. The reaction mixture was stirred at this temperature for at least 11 hours. It was then allowed to cool. The crude product was purified by silica gel chromatography (10 cm SiO2 column; 3.5 cm diameter) using cyclohexane and Â(80 / 20) as eluents (400 mL), followed by cyclohexane / Â(70 / 30), yielding 77.5 mg (81% yield) of the desired product as a yellow viscous oil. Rf = 0.13 (in cHex / Â(7 / 3)). 1 H NMR(300.1MHz,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=8.5Hz,2H),4.75(s,2H),2.40-2.30 (m,2H),2.01(dp,J=15.7,5.6Hz,6H),1.89-1.81(m,1H),1.33(dt,J=14.4,7.2Hz,2H),0.87(t,J=7.3Hz,4H). 13 C NMR(75.5MHz,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. HRMS:C 25 H 28 N3[M+H] +The calculated m / z value for this is 365.2232; the measured value is 386.2241.

[0240] Example 2: Preparation of compound (II) where R is formula (1) in the presence of an iron catalyst produced from FeBr3 97.2 mg, 0.5 mmol of 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one and 7.4 mg, 0.03 mmol of FeBr3 were added to a flame-dried 8 mL microwave vial, followed by the addition of OTBN (2.51 g, 13 mmol). The tube was sealed with a PTFE septum. The tube was placed under vacuum and then flushed with argon, and the procedure was repeated three times. The mixture was then placed in an oil bath preheated to 80°C and stirred at this temperature for 30 minutes. The reaction mixture was heated to 135°C, 184 μL, 1 mmol of DTBP was added, and the reaction mixture was stirred at this temperature for 4 hours. The mixture was then allowed to cool to room temperature. The crude product was purified by silica gel chromatography using n-heptane and siRNA (90 / 10~70 / 30) as eluents to obtain 160.0 mg (83% yield) of the desired product as a yellow viscous oil. 1 H NMR(300.1MHz,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=8.5Hz,2H),4.75(s,2H),2.40-2.30 (m,2H),2.01(dp,J=15.7,5.6Hz,6H),1.89-1.81(m,1H),1.33(dt,J=14.4,7.2Hz,2H),0.87(t,J=7.3Hz,4H). 13 C NMR(75.5MHz,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. HRMS:C 25 H 28 N3[M+H] +The calculated m / z value for this is 365.2232; the measured value is 386.2241.

[0241] Example 3: Formation of OTBN dimer byproducts under metal-catalyzed dehydrogenation conditions Under certain conditions, metal-catalyzed dehydrogenation of formula (IV) can be performed as described herein. [ka] This can lead to the formation of an OTBN dimer byproduct.

[0242] 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (48.6 mg, 0.25 mmol) and CuBr·SMe2 (2.5 mg, 0.0125 mmol) were added to a flame-dried 8 mL microwave vial, followed by the addition of OTBN (2.73 g, 14 mmol). The tube was sealed with a PTFE septum. The tube was placed under vacuum and then flushed with argon, and the procedure was repeated three times. The reaction mixture was then brought to 135°C after 30 minutes, and DTBP (91 μL) was added. The reaction mixture was stirred at this temperature for 15 hours. It was then cooled. The crude product was purified by silica gel chromatography (h=10 cm, d=3 cm) using cyclohexane / siRNA (7 / 3) as the eluent. The first fraction was isolated (Rf=0.7, cHex / siRNA7 / 3). This fraction was concentrated and found to contain a mixture of the OTBN dimer byproduct of formula (IV) and the 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one dimer. This fraction was then subjected to preparative thin-layer chromatography using cyclohexane / siRNA(9 / 1) as the eluent to obtain 28.5 mg of the OTBN dimer byproduct of formula (IV) (Rf=0.52; in cyclohexane / siRNA).

[0243] The chemical analysis of the OTBN dimer byproduct of formula (IV) is described below: 1H NMR (300.1MHz, 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=8.3Hz,4H),3.04(s,4H). 13 C NMR(75.5MHz,CDCl3)δ 145.6,133.9,132.9,130.2,130.2,129.0,128.9,127.5,111.4,37.6. IR:ν(cm -1 )2923, 2223, 1704, 1478, 762. HRMS:C 28 H 20 N2H[M+H] + The calculated m / z value for this is 385.1705; the measured value is 385.1709.

[0244] Example 4: Preparation of compounds of formula (II) where R is formula (2), (3), and (5) in the presence of an iron catalyst generated from FeBr3. In a flame-dried 8 mL microwave vial, one of the RH compounds (R) defined above as formula (2), (3), or (5) (see Table 1 below for the amount of RH starting material used), FeBr3 (7.4 mg, 0.03 mmol), and then OTBN (2.51 g, 13 mmol) were added. The tube was sealed with a PTFE septum. The tube was placed under vacuum and then flushed with argon, and the procedure was repeated three times. The tube was then placed in an oil bath preheated to 80°C. The reaction mixture was then brought to 135°C after 30 minutes, at which point DTBP (184 μL, 1 mmol) was added. The reaction mixture was stirred at this temperature for 4 hours. The reaction mixture was then cooled and subjected to LC-MS and qNMR as described above. 1 Analysis was performed by 1H NMR quantification. In particular, 1 Using 1H NMR quantification, the yields of compounds of formula (II) where R is formula (2), (3), and (5) were determined, as shown in Table 1. Typically, 1¹H NMR quantification was performed using 1,3,5-trimethoxybenzene as an internal standard; in other words, a known amount of 1,3,5-trimethoxybenzene as an internal standard was added to the mixture that underwent metal-catalyzed dehydrogenation amidation.

[0245] [Table 2]

[0246] As shown in the above examples, the process for preparing the compound of formula (II) involves carrying out metal-catalyzed dehydrogenation amidation conditions and, compared to classical synthetic routes, allows for the preparation of various sultane intermediates in only one reaction step, particularly using inexpensive metal catalysts such as copper or iron catalysts produced from copper(II) or iron(III) sources.

[0247] Example 5: Tetrazoylation of OTBN dimer byproducts Under certain conditions, as described herein, the tetrazoylation process yields formulas (V) and (VI), respectively: [ka] This leads to the formation of OTBN dimer mono and / or ditetrazole byproducts.

[0248] In a flame-dried 8 mL microwave vial, the starting materials were 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). Subsequently, NMP (2 mL) was added, and the reaction mixture was heated at 130 °C for 18 hours. After this time, the reaction mixture was cooled to room temperature, and a precipitate formed was filtered. The solid was washed with water (3 × 5 mL) and RINKAN (3 × 5 mL) to obtain the OTBN dimer ditetrazole byproduct of formula (VI).

[0249] The filtrate was purified by silica gel chromatography using DCM / MeOH(9 / 1) as the eluent. The fraction that did not contain the starting material or the OTBN dimer ditetrazole byproduct of formula (VI) was concentrated to obtain the OTBN dimer monotetrazole byproduct of formula (V).

[0250] The chemical analysis of the OTBN dimer monotetrazole byproduct of formula (V) is described below: 1 H NMR(300.1MHz,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=8.0Hz ,2H),7.41(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),7.02(d,J=8.0Hz,2H),2.21-2.14(m,4H). LC / MS:C 28 H 21 N5H[M+H] + The calculated m / z value for this is 428.2, and the measured value is 428.4.

[0251] The chemical analysis of the OTBN dimer ditetrazole byproduct of formula (VI) is described below: 1 H NMR(300.1MHz,d-DMSO)δ 7.69-7.61(m,4H),7.58-7.51(m,4H),7.18(d,J=8.2Hz,4H)7.01(d,J=8.2Hz,4H),2.85(s,4H). LC / MS:C 28 H 22 N8H[M+H] + The calculated m / z value for this is 471.2, and the measured value is 471.4.

[0252] While preferred embodiments of the Disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Numerous variations, modifications, and substitutions will be conceivable to those skilled in the art without departing from the Disclosure. It should be understood that various alternative forms to the embodiments of the Disclosure described herein may be used when carrying out the Disclosure. The following claims define the scope of the Disclosure, and the methods and structures within these claims, as well as their equivalents, are intended to be encompassed thereby. All patent and scientific literature disclosures cited herein are expressly incorporated herein by reference in their entirety. To the extent that the incorporated material conflicts with the express content of the Disclosure, the express content of the Disclosure shall prevail.

Claims

1. Formula (II): 【Chemistry 1】 (wherein R is found in equations (1), (2), (3), (4), and (5): 【Chemistry 2】 Selected from, R'' is a hydrogen atom and (C １ ~C ３ A method for preparing a compound (selected from alkyl groups), Formula (III) 【Transformation 3】 A method comprising reacting a compound with one of the compounds RH or its salts (wherein R is as defined above) under metal-catalyzed dehydrogenation amidation conditions.

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, nickel catalysts, and mixtures thereof, particularly in the presence of an iron catalyst or a copper catalyst.

3. The copper catalyst is made from copper (I) or copper (II), which are respectively called copper (I) supply source or copper (II) supply source, in particular, CuCl, CuBr, CuI, copper (I) thiophene-2-carboxylate, CuBr·SMe ２ , CuBr(Phen), CuI(Phen), CuCl(Phen), copper (I) acetate, Cu ２ S, copper (I) thiophenolate, (4-bromophenyl)-(thio)-copper (I), mesityl copper (I), CuCN, CuSCN, (1,10-phenanthroline)(trifluoromethyl)copper (I), CuBr ２ , copper (II) acetate anhydride or hydrate, CuF ２ , CuCl ２ anhydride or hydrate, CuS, CuSO ４ anhydride or hydrate, CuO, Cu(NO ３ ) ２ Anhydrous or hydrate, copper(II) trifluoromethanesulfonate, copper(II) ethyl acetate anhydrous or hydrate, copper(II) 2-ethylhexanoate, copper(II) trifluoroacetate anhydrous or hydrate, copper(II) trifluoroacetylacetonate, copper(II) tert-butylacetate, copper(II) i-butyrate, copper(II) 2-pyrazine carboxylate, copper(II) hexafluoroacetylacetonate anhydrous or hydrate, copper(II) trifluoromethanesulfonimide anhydrous or hydrate, dichloro(1,10-phenant) Copper(II), copper(II) cyclohexane butyrate, tetrakis(pyridine)copper(II) triflate, copper(II) 3,5-diisopropyl salicylate anhydride or hydrate, copper(II) tetrafluoroborate anhydride or hydrate, copper(II) phthalate, copper(II) di(2-naphthoate), copper(II) benzoate anhydride or hydrate, copper(II) methylacetate, copper(II) ethylbenzoyl acetate, copper(II) ethyl 2-fluorobenzoyl acetate, copper(II) ethyl 2-chlorobenzoyl acetate, 3-(fluorosulfonyl) Copper(II) benzoate, ethyl 3-(fluorosulfonyl)benzoyl acetate copper(II), 8-hydroxyquinoline copper(II), dichloro(N-(2-pyridylmethylene)aniline-N,N')copper(II), ethyl 2-(4-(pentyloxy)benzoyl) acetate copper(II), ethyl alpha-acetyl-3-(fluorosulfonyl)benzoyl acetate copper(II), ethyl alpha-acetyl-4-(fluorosulfonyl)benzoyl acetate copper(II), ethyl alpha-acetyl-3-(methoxycarbonyl)benzoyl acetate copper(II) II), 2,3-diazaspiro[bicyclo[2.2.1]hept[2]ene-7,1'-cyclopropanecopper(II), alpha-(3,5-dichloro-2-pyridylimino)-o-cresolcopper(II), alpha-(6-methyl-2-pyridylimino)-o-cresolcopper(II), alpha-(3-methyl-2-pyridylimino)-o-cresolcopper(II), alpha-(5-chloro-2-pyridylimino)-o-cresolcopper(II), alpha-(4-methyl-2-pyridylimino)-o-cresolcopper(II), copper(II)bis(2,2,6,From 6-tetramethyl-3,5-heptanedione) and copper(II) bis(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate), more particularly CuCl, CuBr, CuI, copper(I) thiophene-2-carboxylate, CuBr・SMe, ２ , CuBr (Phen), CuI (Phen), CuCl (Phen), copper (I) acetate, CuBr ２ And from anhydrous copper(II) acetate, more particularly CuBr, CuI, CuBr(Phen), CuI(Phen), CuBr·SMe ２ and CuBr ２ For example, CuBr・SMe ２ The method according to claim 1 or 2, produced in the form of a salt, a complex, or a mixture thereof, selected from the above.

4. The iron catalyst is supplied from an iron(II) source or an iron(III) source, respectively, and particularly from an iron(II) source or an iron(III) source, respectively, and FeCl ２ FeCl ３ FePO ４、 FeI ３ FeF ３ , FeBr ３ Fe ２ (SO ４ ) ３ Fe ２ (C ２ O ４ ) ３ Fe(OH) ３ FeCl ３ 6H ２ O, FeF ３ 3H ２ O, Fe ４ (P ２ O ７ ) ３ Fe ４ (Fe(CN) ６ ) ３ and Fe(H ２ PO ２ ) ３ Therefore, in particular, FeCl ３ FePO ４ FeI ３ FeF ３ , FeBr ３ Fe ２ (SO ４ ) ３ Fe ２ (C ２ O ４ ) ３ and Fe(OH) ３ Therefore, especially, FeBr ３ FeCl ２ FeCl ３ and FeCl ３ 6H ２ O, for example, FeBr ３ The method according to claim 2, which is produced in the form of a salt, a complex, or a mixture thereof, selected from the above.

5. The manganese catalyst, cobalt catalyst, and nickel catalyst are, respectively, - (i) In particular, MnBr ２ and MnCl ２ A manganese source, also called a manganese(II) source, is selected from the following, in the form of a salt, a complex, or a mixture thereof. - (ii) In particular, CoCl ２ and CoBr ２ A cobalt source, also called a cobalt(II) source, in the form of a salt, complex, or mixture thereof, selected from the above. - (iii) especially NiBr ２ and NiCl ２ Nickel sources, also called nickel(II) sources, are selected from the following, in the form of salts, complexes, or mixtures thereof. The method according to claim 2, which is generated from.

6. The aforementioned metal catalyst is selected from bidentate ligands, monodentate ligands, and mixtures thereof, and more particularly, - Bidentate or monodentate nitrogen ligands, especially bidentate nitrogen ligands, more particularly optionally substituted bipyridine ligands, and even more particularly phenanthroline ligands, e.g., 1,10-phenanthroline, 4,4'-di-tert-butyl-2,2'-dipyridyl, dimethylglycine, N,N',N',N'-tetramethylethylethylenediamine, trans-N,N'-dimethylcyclohexane-1,2-diamine, N-(2-pyridinylmethylene)benzeneamine, 1,1'-binaphthyl-2,2'-diamine, or 1-methylimidazole; - Bidentate or monodentate phosphine ligands, especially monodentate phosphine ligands, more particularly phosphine ligands optionally substituted with at least one aryl, e.g., triphenylphosphine; or - Bidentate diketone ligands, especially 1,3-diketone ligands, such as ethyl 2-oxocyclohexanecarboxylate The method according to any one of claims 1 to 5, wherein the method is in the form of a metal complex comprising a ligand selected from

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

8. The above reaction is carried out in the presence of an oxidizing agent, particularly one selected from peroxides of formula R1-O-O-R2 or R'1-O-O-R'-O-O-R'2 and oxalates of formula R3-O-C(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, and in particular the peroxide of formula R1-O-O-R2 is selected from di-tert-butyl peroxide, tert-butyl hydroperoxide, benzoyl peroxide, dicumyl peroxide, and hydrogen peroxide, and more particularly selected from di-tert-butyl peroxide, tert-butyl hydroperoxide, and dicumyl peroxide, for example, di-tert-butyl peroxide; R' is (C １ ~C ６ ) represents an alkylene group, and in particular the peroxide of the above formula R'1-O-O-R'-O-O-R'2 is selected from 2,5-di(tert-butylperoxy)-2,5-dimethyl-3-hexyne, 2,5-di(tert-butylperoxy)-2,5-dimethylhexane, and 1,1-bis(tert-butylperoxy)cycloloxane; The method according to any one of claims 1 to 7, wherein R3 and R4 represent a hydrogen atom, an aryl group, or an alkyl group optionally substituted with an aryl group, for example, ditert-butyl oxalate.

9. The method according to any one of claims 1 to 8, wherein the oxidizing agent is defined in claim 1 and is present in an equivalent amount in the range of 0.1 to 10 with respect to the amount of compound RH corresponding to 1 equivalent, particularly as defined in claim 1 and in an equivalent amount in the range of 0.5 to 8 with respect to the amount of compound RH corresponding to 1 equivalent, and more particularly as defined in claim 1 and in an equivalent amount in the range of 1 to 5 with respect to the amount of compound RH corresponding to 1 equivalent.

10. Solvents, especially organic solvents, and more specifically: - Aromatic solvents further selected from, for example, o-tolylbenzonitrile, chlorobenzene, dichlorobenzene, and anisole, for example, o-tolylbenzonitrile. - Hexafluoropropan-2-ol, isobutanol, tert-butanol and n-butanol, for example, an alcohol solvent further particularly selected from tert-butanol and n-butanol, - Ketone solvents, for example, methyl isobutyl ketone, - Ether solvent, for example, cyclopentanemethyl ether, - Hydrocarbon solvents, for example, heptane, - Ester solvents, for example, isobutyl acetate, - A polar solvent further particularly selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, diethyl carbonate, and n-methylpyrrolidine (NMP), - water - Acidic solvents, for example, acetic acid, The method according to any one of claims 1 to 9, wherein the reaction is carried out in an organic solvent selected from a mixture thereof.

11. In particular, when the RH defined in claim 1 is in the form of a salt, the reaction is carried out in the presence of a base, and the base is - Inorganic bases, for example, Na ２ CO ３ , Cs ２ CO ３ _K ２ CO ３ NaHCO ３ NaOH, or KOH, - Alkoxide bases, e.g., tBuOK, - An organic base containing at least one nitrogen atom, for example, triethylamine or N,N-diisopropylethylamine, The method according to any one of claims 1 to 10, wherein a mixture thereof is optionally selected.

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

13. Formula (IV) 【Chemistry 4】 The method according to any one of claims 1 to 12, wherein an o-tolylbenzonitrile dimer by-compound is formed.

14. Equation (I): 【Transformation 5】 A method for preparing a sultan-active compound of formula (II) as defined in claim 1 (wherein R is as defined in claim 1) or a pharmaceutically acceptable salt thereof, comprising a tetrazolylation step of reacting a compound of formula (II) as defined in claim 1, prepared by the method of any one of claims 1 to 13, more particularly a tetrazolylation step carried out with at least one azide derivative in a reaction medium, wherein a benzyl azide impurity formed during the tetrazolylation is converted to an aldehyde derivative.

15. The method according to any one of claims 1 to 14, wherein the sartan-active compound of formula (I) is irbesartan, also known as 2-n-butyl-4-spirocyclopentan-1-[[2'-(tetrazole-5-yl)biphenyl-4-yl]methyl]-2-imidazolin-5-one or 2-n-butyl-3-[[2'-(tetrazole-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one.

16. The sartan-active compound of formula (I) is formula (V) and (VI): 【Transformation 6】 The method according to claim 14 or 15, comprising at least one compound of the following.

17. A composition, - A compound of formula (I) is available by the method according to any one of claims 1 to 13, followed by a tetrazolylation step as defined in claim 14: 【Transformation 7】 A sartan-active compound (wherein R is as defined in claim 1), or one of the pharmaceutically acceptable salts thereof, - Equations (V) and (VI): 【Transformation 8】 A composition comprising at least one compound of the following.

18. The sartan-active compound of formula (I) is irbesartan, also known as 2-n-butyl-4-spirocyclopentan-1-[[2'-(tetrazole-5-yl)biphenyl-4-yl]methyl]-2-imidazolin-5-one or 2-n-butyl-3-[2'-(tetrazole-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (VI) and at least 4-(VI)-1-(VI)-1-(4-yl)-imidazolin-one, and formulas (V) and (VI): 【Chemistry 9】 A composition according to any one of claims 1 to 17, comprising at least one of the compounds.

19. The sartan-active compound of formula (I) is selected from losartan, valsartan and its esters, candesartan and its esters, olmesartan and its esters, and formulas (V) and (VI): 【Chemistry 10】 The composition according to claim 17, comprising at least one of the compounds.

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