Process for preparing sartan active compounds having a tetrazole ring

Abstract

This disclosure relates to a method for producing at least one sartan active compound of formula (I), wherein R is selected from formulas (1), (2), (3), (4), and (5), the method comprising tetrazolizing a compound of formula (II) in a reaction medium having at least one azide derivative, wherein R is as previously defined, wherein benzyl azide impurities formed during the tetrazolization are converted into aldehyde derivatives.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, and specifically relates to a method for synthesizing high-purity sartan active compounds with a tetrazolium ring. Prior 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 that acts as 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] Various methods for preparing irbesartan and related compounds have been disclosed in the literature. One of these methods involves a tetrazolization step, as typically described for irbesartan in EP 0 708 103.

[0004] In the case of irbesartan, the tetrazolization step can be carried out from the following intermediate compound: 2-n-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopentan-2-imidazolin-5-one or 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one, wherein the intermediate is tetrazolized with an alkali metal azide (also referred to in this text as a basic azide or base azide) and a base to form irbesartan. However, the synthetic route has a major drawback in that it forms azide impurities during this tetrazolization, such as (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-nitrile (also referred to in this text as 4'-(azidomethyl)-[1,1'-biphenyl]-2-carboxynitrile or azide nitrile) and (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole (also referred to in this text as 5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-1,2,3,4-tetrazole or azide tetrazazole).

[0005] The azido group impurity (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole) has recently been found to possess mutagenic properties. Mutagens are chemicals that can induce changes in cellular DNA. These mutations can increase the risk of cancer, but the specific risk of this azido group impurity causing cancer in humans is unclear. Therefore, health authorities now require that the levels of azido group impurities be kept below the Toxicological Concern (TTC). Since azido group impurities can no longer be detected in the final pharmaceutical products, there is a need to improve existing manufacturing methods for sartans with a tetrazolium ring by implementing a tetrazolization step.

[0006] This invention achieves this requirement by providing a method for manufacturing sartans that allows for the degradation of azide-based impurities, and more particularly benzyl azide impurities. More specifically, this invention provides an impurity profile of the obtained sartans that meets these required low levels of benzyl azide impurities, typically less than or equal to 10 ppm, and even less than or equal to 5 ppm, relative to the total amount of sartan compounds. Therefore, the sartans with a tetrazolium ring can be manufactured with high quality within the framework of this invention. Summary of the Invention

[0007] Starting with common cyano derivative intermediates suitable for tetrazolization, this invention provides an advantageous method for preparing tetrazolium-containing sartan active compounds (especially irbesartan) with significantly lower amounts of azido group impurities (such as (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-nitriles and (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole).

[0008] This article describes a method for manufacturing at least one sartan active compound of formula (I). (I) Where R is selected from equations (1), (2), (3), (4), and (5): (1); (2); (3); (4); and (5), It is an attachment site. The method comprises tetrazolizing a compound of formula (II) in a reaction medium having at least one azide derivative. (II) Where R is as previously defined, The benzyl azide impurities formed during the tetrazolization process are converted into aldehyde derivatives.

[0009] The manufacturing method of the present invention further exhibits the advantage of implementing classic N-1 intermediates (i.e., intermediates having a cyanophenyl moiety, and particularly compounds of formula (II) as defined below) commonly used for tetrazolization. This means that the required method adjustments are relatively small compared to existing methods, while providing the desired extremely high level of purity of the sartan compound. Simple Explanation of the Diagram

[0010] none Implementation

[0011] This disclosure relates to a method for manufacturing at least one sartan active compound of formula (I). (I) Where R is selected from equations (1), (2), (3), (4), and (5): (1); (2); (3); (4); and (5), It is an attachment site. The method comprises tetrazolizing a compound of formula (II) in a reaction medium having at least one azide derivative. (II) Where R is as previously defined, The benzyl azide impurities formed during the tetrazolization process are converted into aldehyde derivatives.

[0012] As used in this article, the term "ambient temperature" or "room temperature" (also known as RT) refers to a temperature ranging from 15ºC to 35ºC, and more particularly from 25ºC to 35ºC.

[0013] As used in this article, "inert atmosphere" refers to an atmosphere unsuitable for oxidation. This means that the atmosphere does not contain oxygen. For example, an inert atmosphere can be nitrogen or argon.

[0014] In the context of this disclosure, "benzyl azide impurities" encompasses all byproducts or impurities that may arise from nucleophilic substitution of a compound with an alkali metal azide, the compound containing at least one activated carbon atom in its structure. In the context of this disclosure, "activated carbon atom" refers to a carbon atom with a leaving group (such as a halogen atom (chlorine, bromine, or iodine atom), an alcohol group, a toluenesulfonate group, a methanesulfonate group, an alkyl phosphate group, an ester group, or a amide group, etc.). More specifically, such "activated carbon atom" is a carbon atom attached to a benzene ring to form an activated benzyl structure. Therefore, the "benzyl azide impurities" can be present starting from an intermediate compound having a cyanophenyl moiety and during the tetrazolization step of the alkali metal azide.

[0015] This document further provides a method according to this disclosure, wherein the benzyl azide impurity is converted into an aldehyde derivative by an oxidation step followed by a hydrolysis step.

[0016] The method according to this disclosure is described in more detail below.

[0017] [, Transformation of benzyl azide impurities: oxidation followed by hydrolysis , ] [, , ]

[0018] As described above, in conventional methods involving cyano derivative intermediates for tetrazolization, two well-known mutagenic benzyl azide impurities are formed, namely, an azide nitrile of formula (A) and an azide tetrazolium of formula (B), as shown below: (A); and (B)

[0019] Therefore, this document further provides a method according to this disclosure, wherein the benzyl azide impurity comprises at least compounds of formulas (A) and (B) as defined above.

[0020] In fact, these two benzyl azide impurities can be formed from several different potential precursors during the tetrazolization of compounds of formula (II) as defined in this disclosure.

[0021] The method according to this disclosure allows for the degradation of these benzyl azide impurities, and more specifically, they are converted into the corresponding aldehyde derivatives that are assessed as Class 5 impurities, that is, they are considered non-mutagenic compounds.

[0022] More specifically, this transformation involves an oxidation step followed by a hydrolysis step. The oxidation step, starting from the benzyl azide impurity, allows for the in-situ yield of the corresponding chemically unstable benzyl imine.

[0023] Then, when these unstable benzylimines come into contact with water, they are converted into the corresponding aldehyde derivatives via hydrolysis.

[0024] More specifically, the aforementioned aldehyde derivatives can be those of formula (A1) (also referred to herein as nitrile aldehyde impurities) and (B1) (also referred to herein as tetrazolium aldehyde impurities), respectively derived from benzyl azide impurities of formulas (A) and (B): (A1); and (B1).

[0025] This document further provides a method according to this disclosure, wherein the aldehyde derivative thus obtained comprises at least a compound of formula (B1). (B1).

[0026] This document further provides a method according to this disclosure, wherein the obtained sartan active compound of formula (I) as defined in this disclosure contains less than 10 ppm, particularly less than 5 ppm and more particularly less than 1 ppm of a compound of formula (B1). (B1).

[0027] The conversion in the method according to this disclosure can be carried out by contacting the benzyl azide impurity with at least ferrous ions (Fe2+).

[0028] Therefore, this document further provides a method according to this disclosure, wherein the benzyl azide impurity is converted into an aldehyde derivative by contacting the benzyl azide impurity with at least ferrous ions.

[0029] The ferrous ions can be supplied according to two variations.

[0030] According to the first variant, the ferrous ion is formed in situ by reduction of ferric ions (Fe3+), particularly in the presence of a polar aprotic solvent with reducing properties as defined below.

[0031] Therefore, this document further provides a method according to the present disclosure, wherein the ferrous ion is formed in situ by reduction of ferric ions, particularly in the presence of a polar aprotic solvent with reducing properties.

[0032] Among the compounds capable of generating ferric ions are, for example, 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, or Fe(H₂PO₂)₃, especially FeCl₃, FePO₄, FeI₃, FeF₃, FeBr₃, Fe₂(SO₄)₃, Fe₂(C₂O₄)₃, or Fe(OH)₃, such as FeCl₃. Advantageously, the compounds capable of generating said ferric ions are anhydrous, and especially anhydrous FeCl₃.

[0033] Therefore, this document further provides a method according to this disclosure, wherein the ferric ions are generated from 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, or Fe(H2PO2)3, particularly from FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3, or Fe(OH)3, such as FeCl3.

[0034] During this conversion, when using ferric ions such as 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, or Fe(H2PO2)3, especially FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3, or Fe(OH)3, such as FeCl3, the temperature used can be from 80ºC to 150ºC, especially from 100ºC to 135ºC, and under an inert atmosphere.

[0035] According to the second variation, the ferrous ions can be directly incorporated into the reaction medium.

[0036] Among the compounds that can generate the ferrous ions, those mentioned include, for example, FeCl₂, FeBr₂, FeI₂, FeF₂, FeCO₃, FeSO₄, Fe₃(PO₄)₂, Fe₂SiO₄, Fe(OH)₂, Fe(C₂H₃O₂)₂, FeSO₄·H₂O, FeSO₄·7H₂O, FeSO₄·4H₂O, FeS, FeI₂·4H₂O, FeF₂·4H₂O, FeCl₂·4H₂O, FeCl₂·2H₂O, FeBr₂·6H₂O, Fe(NO₃)₂·6H₂O, Fe(NO₃)₂, or Fe(AlO₂)₂, especially FeCl₂, FeBr₂, FeI₂, FeF₂, FeCO₃, FeSO₄, Fe₃(PO₄)₂, and Fe₃(PO₄)₂. 4) 2. Fe 2SiO 4. Fe(OH) 2 or Fe(C 2H 3O 2) 2, such as FeCl 2.

[0037] Furthermore, the conversion of the benzyl azide impurity can be carried out simultaneously with or after the tetrazolization, as illustrated in two embodiments.

[0038] According to one embodiment, the conversion can be performed simultaneously with the tetrazolization.

[0039] According to the embodiments described, the total amount of ferrous ions present in the reaction medium can be controlled. More specifically, the total amount of ferrous ions can be introduced in a catalytic amount. This catalytic amount allows for the reduction, avoidance, or prevention of the thermal instability of the azide derivatives.

[0040] More specifically, the ferrous ions may be present in an alkaline medium containing the azide derivative at a catalytic amount, particularly in molar percentages ranging from 0.005% to 0.1%, particularly from 0.01% to 0.05%, relative to the amount of the compound of formula (II) according to this disclosure.

[0041] Still according to the embodiments described, when the active sartan compound of formula (I) is irbesartan, ferrous ions may be present in molar percentages ranging from 0.005% to 0.1%, particularly from 0.01% to 0.05%, relative to the amount of 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one.

[0042] According to another embodiment, the conversion can be performed after the tetrazolization.

[0043] According to the embodiments described, the total amount of ferrous ions present in the reaction medium may not be as critical as in the first embodiment (where the tetrazolization step is completed).

[0044] Therefore, the ferrous ions can be present in the reaction medium in any amount (e.g., in catalytic or stoichiometric amounts).

[0045] For example, ferrous ions can be present in mole percentages ranging from 0.005% to 10%.

[0046] [, Tetrazolate , ] [, , ]

[0047] Tetrazolylation refers to the conversion of nitrile into tetrazolium.

[0048] The literature describes tetrazolization by reacting with azide derivatives (e.g., tributyltin azide or alkali metal azides (e.g., sodium azide)) and bases (e.g., triethylamine hydrochloride).

[0049] Therefore, for example, the preparation of 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (also referred to as spiromethylbiphenyl nitrile in this disclosure) from 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (also referred to as irbesartan) by heating under reflux in the presence of tributyltin azide is known.

[0050] EP 0 708 103 shows that using 1-methylpyrrolidone as a solvent at a temperature of about 150ºC (i.e., at the temperature at which reflux is observed) is particularly advantageous for overcoming the disadvantages.

[0051] Therefore, a superior approach to carrying out such tetrazolization is to react the compound of formula (II) as defined in this disclosure with an azide derivative and a base in an inert polar aprotic solvent at a temperature below the reflux temperature and under an inert atmosphere.

[0052] Scheme 1 below briefly illustrates the tetrazolization of the compound of formula (II) to obtain the compound of formula (I).

[0053] Option 1 R is defined as above.

[0054] Among azide derivatives, azidoic acid (HN3) and azide salts such as metal azides (e.g., sodium azide (NaN3), potassium azide (KN3) or calcium azide (Ca(N3)2)), SnBu3N3, SnMe3N3, and trialkylammonium azide (e.g., triethylammonium azide), especially metal azides or salt azides such as sodium azide or triethylammonium azide.

[0055] Among the polar aprotic solvents with reducing properties, those that can be mentioned include N-methylformamide (MFo), N,N-dimethylformamide (DMF), N-methyl,N-tert-butylformamide, acetamide (Ac), N-methylacetamide (MAc), N,N-dimethylacetamide (DMAc), urea, tetramethylurea (TMU), dimethylacrylurea (DMPU), dimethylvinylurea (DMEU), triethylamine (TEA), hexamethylphosphonic acid (HMPA), hexamethylphosphonic triacetamide (HMPT), 2-pyrrolidone (2-Py), N-methyl-2-pyrrolidone (NMP), N-phenyl-2-pyrrolidone (NPP), N-vinylpyrrolidone (NVP), and 5-methyl-2-pyrrolidone (MPy).

[0056] Therefore, this document further provides a method according to this disclosure, wherein the polar aprotic solvent having reducing properties is 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), dimethylacrylurea (DMPU), dimethylvinylurea (DMEU), triethylamine (TEA), hexamethylphosphonamide (HMPA), hexamethylphosphonitrile (HMPT), 2-pyrrolidone (2-Py), N-methyl-2-pyrrolidone (NMP), N-phenyl-2-pyrrolidone (NPP), N-vinylpyrrolidone (NVP), and 5-methyl-2-pyrrolidone (MPy).

[0057] The base may be selected from triethylamine (Et 3N), N,N-dicyclohexylmethylamine, and Hunig bases (such as N,N-diisopropylethylamine). Specifically, the base may be triethylamine, and more specifically, triethylamine hydrochloride (also known as TEA HCl).

[0058] Preferably, alkali metal azides and triethylamine hydrochloride of equal molecular weight are used, in a ratio of 1 to 5 moles / moles of starting nitrile, advantageously about 1.2 to about 2 moles / moles of starting nitrile.

[0059] During tetrazolization, the reaction medium can be heated in the range of room temperature to 150ºC, particularly between 100ºC and 135ºC, and at temperatures such as 150ºC.

[0060] After heating for 6–20 hours, tetrazolization is complete, and the reaction mixture is post-treated according to conventional techniques. In particular, the mixture is neutralized by adding a base (e.g., an alkali metal hydroxide) to the aqueous solution, and the aqueous phase containing salts (especially chlorides and azides) is discarded.

[0061] Then, the organic phase is treated with water and various organic solvents (aromatics, halogens, esters, ketones, etc.) (such as toluene, ethyl acetate, dichloromethane (DCM), methyl ethyl ketone, optionally two different solvents in sequence) to remove reaction byproducts.

[0062] These washing steps are routine and well-known to technicians.

[0063] The final product is then crystallized using crystallization steps well known to those skilled in the art. Further conventional filtration and washing steps may then be performed, if necessary.

[0064] Among the sartan active compounds of formula (I) as defined above, irbesartan, losartan, valsartan, candesartan or olmesartan may be mentioned, especially irbesartan.

[0065] According to specific embodiments, the active sartan compound of formula (I) as defined above 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.

[0066] This document further provides a method, which includes at least the following steps: - A reaction mixture comprising at least iron ions, an alkali metal azide, and a base in a polar aprotic solvent with reducing properties at a temperature below reflux and under an inert atmosphere, wherein the iron ions are particularly ferrous ions and more particularly obtained in situ via ferric ions. - Add 2-n-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopent-2-imidazolin-5-one to the reaction mixture. - Promotes the tetrazolization, and - Recover irbesartan obtained in aqueous solution as one of its alkali metal salts.

[0067] This document further provides a method according to this disclosure, wherein the polar aprotic solvent with reducing properties is 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), dimethylacrylurea (DMPU), dimethylvinylurea (DMEU), triethylamine (TEA), hexamethylphosphonic acid (HMPA), hexamethylphosphonic triacetamide (HMPT), 2-pyrrolidone (2-Py), and N-methyl-2-pyrrolidone (NMP). N-phenyl-2-pyrrolidone (NPP), N-vinylpyrrolidone (NVP) and 5-methyl-2-pyrrolidone (MPy), especially 1-methylpyrrolidone at temperatures from 80ºC to 150ºC, particularly from 100ºC to 135ºC.

[0068] When the active sartan compound of formula (I) is irbesartan, 1-methylpyrrolidone-2-one at temperatures of 80ºC to 150ºC, especially 100ºC to 135ºC, can be used as a polar aprotic solvent with reducing properties.

[0069] This document further provides a method according to this disclosure, wherein the irbesartan thus obtained contains less than 10 ppm, particularly less than 5 ppm, of the compound of formula (B). (B)

[0070] This document further provides a method according to this disclosure, wherein the irbesartan thus obtained contains less than 10 ppm, particularly less than 5 ppm and more particularly less than 1 ppm of a compound of formula (B1). (B1).

[0071] The compound of formula (B1) can then be eliminated after routine filtration and washing, which is typically carried out in the synthesis involving tetrazolization, to obtain the sartan compound.

[0072] During tetrazolization, the nitrile group contained in a compound of formula (II) as defined in this disclosure can be converted to a tetrazolium group to form irbesartan. The same reaction can be carried out to convert a compound of formula (A) to a compound of formula (B). At the end of conventional tetrazolization, the compound of formula (A) is less than 1 ppm (limit of detection), and only the compound of formula (B) is retained.

[0073] Regarding the synthesis of irbesartan, the inventors compared the amounts of compound of formula (B1) obtained without converting the benzyl azide impurity to an aldehyde derivative and with converting the benzyl azide impurity to an aldehyde derivative.

[0074] The results show that, according to the prior art, in a manufacturing method that does not involve the conversion of benzyl azide impurities formed during the tetrazolization, irbesartan obtained after the tetrazolization step can present an amount of approximately 130 ppm relative to the total amount of irbesartan (at the end of the tetrazolization reaction), while the manufacturing method according to the present invention, which involves the conversion of benzyl azide impurities formed during the tetrazolization, gives an amount of less than 10 ppm, particularly less than 5 ppm, relative to the total amount of irbesartan (before the final purification step).

[0075] Even with subsequent routine purification steps, according to existing manufacturing methods (i.e., without implementing the conversion of benzyl azide impurities formed during the tetrazolization), the resulting irbesartan can present an amount of 30 ± 10 ppm relative to the total amount of irbesartan, which far exceeds the requirements of health authorities.

[0076] The manufacturing method according to the invention (i.e., the conversion of benzyl azide impurities formed during the tetrazolization) 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.

[0077] [, Other impurities , ] [, , ]

[0078] Furthermore, the inventors have noted that other impurities, distinct from aldehyde impurities, may also be formed, particularly those formed due to the presence of solvents in oxidized form.

[0079] More specifically, when the active sartan compound (I) is irbesartan and the inert aprotic polar solvent used is N-methyl-2-pyrrolidone, four NMP irbesartan adduct impurities were detected in addition to tetrazolium aldehyde impurities. Their presence is due to the reaction of oxidized NMP with irbesartan. These four adducts have the following formulas (C1), (D1), (E1), and (F1), as shown below: (C1); (D1); (E1); and (F1)

[0080] However, for tetrazolium impurities as defined in formula (B1) above, these four irbesartan adducts were assessed as Class 5 impurities, meaning they are considered non-mutagenic compounds. Therefore, given the requirements of health authorities, their co-occurrence in the final product is harmless.

[0081] The invention will be described in more detail below with reference to the following examples. These examples are provided to illustrate the invention and should not be construed as limiting the scope and spirit of the invention. [, Example , ] [, , ]

[0082] 1H NMR spectra of irbesartan were recorded on a Bruker AC200 spectrometer running at 200 MHz in a 2% (m / V) solution of hexadeuterated dimethyl silane (DMSO-d6) containing tetramethylsilane as an internal standard (referenced at 2.5 ppm at 300 K). The chemical shift was calibrated relative to the TMS signal (the signal at 0 ppm is due to the tetramethylsilane internal standard).

[0083] Alternatively, 1H NMR spectra were recorded on a Bruker Avance III spectrometer operating at 400 MHz, with chemical shifts (δ in ppm) using the solvent CDCl3 (7.26 ppm as a reference at 300 K). The chemical shifts were calibrated relative to the TMS signal (the signal at 0 ppm is due to the internal standard tetramethylsilane).

[0084] [, Example , ] [, 1 , ] [, : Preparation of crude irbesartan and quantification of impurities (formula) according to the method of this disclosure , ] [, (A) , ] [, 、 , ] [, (B) , ] [, and , ] [, (B1) , ] [, (compounds) , ] [, , ]

[0085] [, Example , ] [, 1-1 , ] [, Preparation of crude irbesartan , ]

[0086] In a suitable reactor inertized with nitrogen, a mixture of 35.2 g triethylamine hydrochloride, 1.5 mg FeCl3, 82 g N-methylpyrrolidone, 16.8 g sodium azide and 80 g 2-n-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopentan-2-imidazolin-5-one was gradually heated to a temperature of approximately 130ºC-135ºC.

[0087] Then, maintain the mixture at a temperature of approximately 130ºC–135ºC for at least 14 hours.

[0088] The mixture was then cooled to 20°C–30°C, and 12 g of N-methylpyrrolidone, 127 g of toluene, and 11 g of water were added. The mixture was then repeatedly washed with a 30 w / w% aqueous sodium hydroxide solution.

[0089] Water was then added and the reaction medium was acidified to a pH of approximately 4 with concentrated hydrochloric acid at 10°C to 15°C. The organic phase was then discarded and the remaining solid material was washed with water.

[0090] The organic layer was then poured onto an 8 w / w% sodium hydroxide aqueous solution at 5ºC to 10ºC. After stirring for 15 min, the organic phase was discarded and the aqueous layer was washed with approximately 80 ml of toluene.

[0091] Add 122 ml of methyl ethyl ketone and 12 ml of water and adjust the pH to 8 with concentrated HCl at about 15ºC. Filter through an activated carbon column, heat to 50ºC and adjust the pH to 7 with HCl.

[0092] After seeding and acidifying to pH 4, the slurry is cooled to 25ºC, maintained for 1 h, and then filtered.

[0093] The cake was repeatedly washed with isopropanol and dried to obtain pure irbesartan.

[0094] The 1H RMN characterization of irbesartan is as follows: [, 1 , ] [H RMN](200 MHz, δ in ppm, DMSO): 0.8 (T, 3H); 1.3 (sutt, J=8.0 Hz, 2H); 1.5 (q, 2H); 1.6 to 2.0 (m, 8H); 2.3 (t, 2H); 4.7 (s, 2H); 7.1 (s 4H); 7.4 to 7.8 (m, 4H)

[0095] [, Example , ] [, 1-2 , ] [, :Mode , ] [, (A) , ] [, 、 , ] [, (B) , ] [, and , ] [, (B1) , ] [, Quantification of compounds , ] [, , ]

[0096] The 1H RMN characterization of compounds of formulas (A), (B), and (B1) is as follows:

[0097] For compounds of formula (A): [, 1 , ] [HRMN](400 MHz, δ in ppm, CDCl 3): 4.34 (s, 2H); 7.12 (d, J=8.0 Hz, 2H); 7.25 (d, J=8.0Hz, 2H); 7.43 (d, J=7.5Hz, 1H); 7.50 (t, J=7.5Hz, 1H); 7.60 (t, J=7.5Hz, 1H); 7.91 (d, J=7.5Hz, 1H)

[0098] For compounds of formula (B): [, 1 , ] [HRMN](400 MHz, δ in ppm, CDCl 3): 4.42 (s, 2H); 7.44 (d, J=8.0 Hz, 2H); 7.46 (m, 1H); 7.51 (d, J=8.0Hz, 1H); 7.58 (d, J=8.0Hz, 2H); 7.65 (td, J=7.5Hz, J=1.5Hz, 1H) ; 7.77 (d, J=7.5Hz, 1H)

[0099] For compounds of formula (B1): [, 1 , ] [H RMN](400 MHz, δ in ppm, DMSO): 7.32 (d, J=8.0 Hz, 2H); 7.55 (d, J=7.5Hz, 1H); 7.59 (t, J=7.5 Hz, 1H); 7.66 (t, J=7.5Hz, 1H); 7.73 (d, J=7.5Hz, 2H); 7.83 (d, J=8.0Hz, 2H); 10.00 (s, 1H)

[0100] The amount of impurities in equations (A), (B), and (B1) is measured at two time points: - First, at the end of the tetrazolization reaction as described in Example 1-1 above, and - Secondly, when pure isolated irbesartan is obtained according to Example 1-1 above.

[0101] The analytical method for measuring the amount of compounds of formulas (A) and (B) is as follows: Analysis was performed using UPLC.

[0102] For the liquid chromatography portion (UPLC Vanquish ThermoScientific): Chromatography was performed using columns with the following characteristics. [project] [feature] Mutually Acquity HSS T3 length 100 mm diameter 2.1 mm Fineness measurement 1.8 µm supplier Waters-Reference:186003539 - Column temperature: 50ºC - Sample changer temperature: 25ºC - Injection volume: 2 µL - Spectrophotometer detector set to 254 nm (optional) - A mobile phase containing the following mixture: A: H₂O + 0.1% formic acid (v / v) and B: Methanol Its gradient is as follows: [time(] [min] [)] [A] [(] [%] [)] [B] [(] [%] [)] [Flow rate ()] [mL / min] [)] 0 50 50 0.5 5 50 50 0.5 10 40 60 0.5 11 40 60 0.5 11.1 5 95 0.5 13 5 95 0.5 13.1 50 50 0.5 16 50 50 0.5

[0103] Chromatography is performed using the following switching valve: [Analysis Time] [Valve Position] 0 1-2 Oriented towards MS (mass spectrometry) 5 min 1-6 Oriented Waste Liquid Tank 7.25 min 1-2 Oriented towards MS (mass spectrometry) The analysis time was 16 minutes.

[0104] For the mass spectrometry section (Q Exactive Thermo Fischer Scientific): Quantification is performed using the following methods: - Ionization mode: HESI - Voltage spray: 3500 V - Capillary temperature: 300ºC - Sheath gas: 70 arbitrary units - Auxiliary gas: 20 units of any amount - Purging gas: 0 arbitrary units - Assist gas temperature: 300ºC - S-lens RF level: 50 arbitrary units

[0105] The detection modes for compounds of formulas (A) and (B) are as follows: PRM (parallel reaction monitoring) in positive ion mode, with the following fragment m / z extraction (resolution 17,500) including the following list: [Mode] [(A)] [of compounds] [Mode] [(B)] [of compounds] Mass (m / z) 207.09167 278.11487 Mode C14H10N4 C14H11N7 model +H +H polarity Positive Positive Start (min) 7.25 0 End (min) 16 5 Collision energy 35 35 Resolution 17,500 17,500 Separation window of quadrupole 2 2

[0106] Find the ions of compounds with formulas (A) and (B): [Compound] [Filter] [quality(] [m / z] [)] Formula (A) FTMS+p ESI Full ms2 207.09@hcd35.00 [50.00-230.00] 207.09167 Formula (B) FTMS+p ESI Full ms2 278.11@hcd35.00 [50.00-300.00] 207.09167

[0107] The analytical method for measuring the amount of compound (B1) is as follows: Analysis was performed using an LC-MS SRDA-UC09-FUSION (column consistency HSS C18-50*2.1mm-1.8µm, mobile phase A = H₂O and mobile phase B = methanol, flow rate = 0.8 mL / min, column temperature = 50ºC, gradient = from 5% B to 90% B in five minutes, mass assay: positive ESI-SIM at m / z = 251 and m / z = 267).

[0108] The results are collected in Table 1 below.

[0109] [, surface , ] [, 1 , ] [End of tetrazolization reaction] [Obtained pure isolated irbesartan] The amount of compound of formula (A) < 1 ppm Compared to Irbesartan < 1 ppm Compared to Irbesartan The amount of compound of formula (B) 5 ppm Compared to Irbesartan 1 ppm Compared to Irbesartan The amount of compound of formula (B1) 50 ppm Compared to Irbesartan < 5 ppm Compared to Irbesartan

[0110] These results show that the method according to this disclosure allows for the degradation of azide-based impurities, and more specifically allows for the conversion of compounds of formula (B) into compounds of formula (B1).

[0111] Furthermore, the results showed that, in order to obtain pure isolated irbesartan, the filtration and purification steps performed after tetrazolization allowed for a reduction in the amount of both the compound of formula (B) (from 5 ppm to 1 ppm) and the compound of formula (B1) (from 50 ppm to less than 5 ppm).

[0112] [, Example , ] [, 2 , ] [, (Comparison): Crude irbesartan and quantified impurities (formula) were prepared by methods other than those disclosed herein (i.e., in the absence of ferrous ions in the medium). , ] [, (A) , ] [, and , ] [, (B) , ] [, (compounds) , ] [, , ]

[0113] [, Example , ] [, 2-1 , ] [, : Through methods other than those disclosed herein (no) , ] [, FeCl3 , ] [, Preparation of crude irbesartan , ]

[0114] Perform a method similar to that described in Example 1 above, except that FeCl3 is not used. Details are explained below.

[0115] In a suitable reactor inertized with nitrogen, 35.2 g of triethylamine hydrochloride, 82 g of N-methylpyrrolidone, 16.8 g of sodium azide and 80 g of 2-n-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopentan-2-imidazolin-5-one were gradually heated to a temperature of approximately 130ºC-135ºC.

[0116] Then, maintain the mixture at a temperature of approximately 130ºC–135ºC for at least 14 hours.

[0117] The mixture was then cooled to 20°C–30°C, and 12 g of N-methylpyrrolidone, 127 g of toluene, and 11 g of water were added. The mixture was then repeatedly washed with a 30 w / w% aqueous sodium hydroxide solution.

[0118] Water was then added and the reaction medium was acidified to a pH of approximately 4 with concentrated hydrochloric acid at 10°C to 15°C. The organic phase was then discarded and the remaining solid material was washed with water.

[0119] The organic layer was then poured onto an 8 w / w% sodium hydroxide aqueous solution at 5ºC to 10ºC. After stirring for 15 min, the organic phase was discarded and the aqueous layer was washed with approximately 80 ml of toluene.

[0120] Add 122 ml of methyl ethyl ketone and 12 ml of water and adjust the pH to 8 with concentrated HCl at about 15ºC. Filter through an activated carbon column, heat to 50ºC and adjust the pH to 7 with HCl.

[0121] After seeding and acidifying to pH 4, the slurry is cooled to 25ºC, maintained for 1 h, and then filtered.

[0122] The cake was repeatedly washed with isopropanol and dried to obtain pure irbesartan.

[0123] The 1H RMN characterization of irbesartan is as follows: [, 1 , ] [H RMN](200 MHz, δ in ppm, DMSO): 0.8 (T, 3H); 1.3 (sutt, J=8.0 Hz, 2H); 1.5 (q, 2H); 1.6 to 2.0 (m, 8H); 2.3 (t, 2H); 4.7 (s, 2H); 7.1 (s 4H); 7.4 to 7.8 (m, 4H)

[0124] [, Example , ] [, 2-2 , ] [, :Mode , ] [, (A) , ] [, and , ] [, (B) , ] [, Quantification of compounds , ] [, , ]

[0125] The 1H RMN characterization of the compounds of formulas (A) and (B) is as follows:

[0126] For compounds of formula (A): [, 1 , ] [HRMN](400 MHz, δ in ppm, CDCl 3): 4.34 (s, 2H); 7.12 (d, J=8.0 Hz, 2H); 7.25 (d, J=8.0Hz, 2H); 7.43 (d, J=7.5Hz, 1H); 7.50 (t, J=7.5Hz, 1H); 7.60 (t, J=7.5Hz, 1H); 7.91 (d, J=7.5Hz, 1H)

[0127] For compounds of formula (B): [, 1 , ] [HRMN](400 MHz, δ in ppm, CDCl 3): 4.42 (s, 2H); 7.44 (d, J=8.0 Hz, 2H); 7.46 (m, 1H); 7.51 (d, J=8.0Hz, 1H); 7.58 (d, J=8.0Hz, 2H); 7.65 (td, J=7.5Hz, J=1.5Hz, 1H) ; 7.77 (d, J=7.5Hz, 1H)

[0128] The amount of impurities in equations (A) and (B) is measured at two time points: - First, at the end of the tetrazolization reaction as described in Example 2-1 above, and - Secondly, when pure isolated irbesartan is obtained according to Example 2-1 above.

[0129] The analytical methods used to measure the amount of compounds of formulas (A) and (B) are similar to those used and described in Examples 1-2 above.

[0130] The results are collected in Table 2 below.

[0131] [, surface , ] [, 2 , ] [End of tetrazolization reaction] [Obtained pure isolated irbesartan] The amount of compound of formula (A) < 1 ppm Compared to Irbesartan < 1 ppm Compared to Irbesartan The amount of compound of formula (B) 130 ± 20 ppm Compared to Irbesartan 30 ± 10 ppm Compared to Irbesartan

[0132] By comparing the results of Examples 1-2 and 2-2, we can conclude that: - The presence of ferrous ions in the method according to this disclosure allows for a significant reduction in the amount of compound of formula (B) at the end of the tetrazolization reaction (5 ppm compared to 130 ± 20 ppm) and when pure isolated irbesartan is obtained (1 ppm compared to 30 ± 10 ppm). - The trace amounts of the compound of formula (A) are similar in both methods. - Only by performing the method according to this disclosure can the compound of formula (B1) be obtained, which indicates that the compound of formula (B) is transformed into the compound of formula (B1) due to the presence of ferrous ions in the medium.

[0133] [, Example , ] [, 3 , ] [, :exist , ] [, FeCl3 , ] [, The existence of the following formula , ] [, (B) , ] [, The compound degrades into the formula , ] [, (B1) , ] [, compounds , ] [, , ]

[0134] [, Example , ] [, 3-1 , ]

[0135] Add 4.11 g NMP and 0.013 g FeCl3 to 0.11 g of the compound of formula (B), and heat at 135ºC for 2 hours with stirring using a magnetic stirrer.

[0136] The presence of compounds of formula (B) and (B1) was detected by LC-MS using an XBridge C18 column (100*4.6 mm - 3.5 µm) and a gradient of 10 mM ammonium acetate at pH 4.5 / acetonitrile on an SRDA-UC09-FUSION instrument.

[0137] At 6.6 min, a main peak (UV 250 nm) was observed, which corresponds to the compound of formula (B1), and at 8.33 min, the compound of formula (B) was no longer detected.

[0138] [, Example , ] [, 3-2 , ]

[0139] Two solutions are prepared as follows: 1) Solution 1: Add 11.1 mg of compound (B) to 6 ml of NMP and dissolve (1850 ppm). 2) Solution 2: Add 8.8 mg FeCl3 to 1 mL NMP and dissolve.

[0140] Then, a blank and two samples were prepared and placed in three different vials, as shown below: - Blank: 2 mL solution 1 (vial 1) - Sample 1: 2 mL of Solution 1 and 50 µL of Solution 2 (i.e., 0.2 equivalents) (vial 2) - Sample 2: 2 mL of solution 1 and 50 µL of solution 2 (that is, 0.2 equivalents), and argon gas is bubbled in, then the vial is sealed and heated (via vial 3).

[0141] The three reaction media changed color after heating for 15 minutes and were heated at 135ºC for 3 hours.

[0142] The results are collected in Table 3 below:

[0143] [, surface , ] [, 3 , ] [, sample , ] [, / , ] [, small bottle , ] [, , ] [, compound , ] [, (B) , ] [, content( , ] [, ppm , ] [, ) , ] [, , ] Blank - Small Bottle 1 119 Sample 1 - Bottle 2 <1 Sample 2 - Bottle 3 <1

[0144] The results showed that Sample 1 and Sample 2 had the same characteristics, which means that the presence or absence of oxygen had no effect, and compound (B) disappeared in the presence of FeCl3.

[0145] Therefore, Example 3 demonstrates that the azide-tetrazole impurity of formula (B) degrades into the tetrazolium aldehyde impurity of formula (B1) due to the presence of FeCl3.

[0146] This example also demonstrates that the conversion of the compound of formula (B) to the compound of formula (B1) can occur simultaneously with or after the tetrazolization reaction.

[0147] [, Example , ] [, 4 , ] [, :Mode , ] [, (B) , ] [, The compounds in , ] [, FeCl2 , ] [, Degradation in the presence of [something]. , ] [, , ]

[0148] In a suitable vessel, 1.47 g of the compound of formula (B), 34 mg of FeCl2 and 800 ml of N-methylpyrrolidone were heated to 100ºC and held for 3 hours.

[0149] The reaction mixture was cooled to room temperature and analyzed by HPLC. The disappearance of the corresponding peaks indicated the degradation of the compound of formula (B).

[0150] The results are as follows: • Compound B before reaction: 100% area at retention time 3.2 min • Compound (B) after 3 hours at 100ºC: 5.1% area at retention time of 3.2 min, and 54% area represented by major degradation products at 1.3 min.

[0151] Operating conditions Tube column: [, , ] Phase: X-Bridge C 18 Length: 100 mm Diameter: 4.6 mm Fineness measurement: 3.5 µm Supplier: Waters (Ref. 186003033) Column temperature: 35ºC Syringe temperature: room temperature Moving phase: A 10 mM ammonium acetate aqueous solution (e.g., 770 mg in 1 L H₂O) is adjusted to pH 4.5 with diluted acetic acid aqueous solution. B = Acetonitrile. gradient: [, , ] [, time , ] [, , ] [, A , ] [, B , ] [, T = 0 min , ] 67% 33% [, T = 1.6 min , ] 67% 33% [, T = 6.9 min , ] 41% 59% [, T = 12.0 min , ] 41% 59% [, T = 13.0 min, ] 67% 33% [, T = 18.0 min , ] 67% 33% Flow rate: 1.2 ml / min Injection volume: 5 µl Detection: 250 nm Analysis duration: 12 min; Equilibrium time: 5 min

[0152] none

[0153] none

Claims

1. A method for producing at least one sartan active compound of formula (I), (I) wherein R is selected from formulas (1), (2), (3), (4) and (5): (1); (2); (3); (4); and (5), is an attachment site, the method comprising tetrazolizing a compound of formula (II) in a reaction medium having at least one azide derivative, (II) wherein R is as defined above, wherein a benzyl azide impurity formed during the tetrazolization is converted into an aldehyde derivative by contacting the benzyl azide impurity with at least a ferrous ion, wherein the ferrous ion is present in an alkaline medium containing the azide derivative in a catalytic amount in a molar percentage ranging from 0.005% to 0.1% relative to the compound of formula (II); The azide derivative is selected from azido acid, salt azide, metal azide, sodium azide, potassium azide, calcium azide, tributyltin azide, trimethyltin azide, trialkylammonium azide and triethylammonium azide; and the aldehyde derivative comprises at least a compound of formula (B1).

2. The method of claim 1, wherein the benzyl azide impurity is converted into an aldehyde derivative by an oxidation step followed by a hydrolysis step.

3. The method of claim 1, wherein the ferrous ion is formed in situ by reduction of ferric ions in the presence of a polar aprotic solvent with reducing properties.

4. The method of claim 3, wherein the ferric ions are generated from 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, or Fe(H2PO2)3.

5. The method of claim 3, wherein the polar aprotic solvent having reducing properties is 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), dimethylacrylurea (DMPU), dimethylvinylurea (DMEU), triethylamine (TEA), hexamethylphosphonic acid (HMPA), hexamethylphosphonic triacetamide (HMPT), 2-pyrrolidone (2-Py), N-methyl-2-pyrrolidone (NMP), N-phenyl-2-pyrrolidone (NPP), N-vinylpyrrolidone (NVP), and 5-methyl-2-pyrrolidone (MPy).

6. The method as claimed in claim 1 or 2, wherein the benzyl azide impurity is converted into an aldehyde derivative during the tetrazolization.

7. The method of claim 1 or 2, wherein the ferrous ion system is present in a molar percentage ranging from 0.01% to 0.05% relative to the amount of the compound of formula (II) as defined in claim 1.

8. The method as claimed in claim 1 or 2, wherein the benzyl azide impurity is converted into an aldehyde derivative after the tetrazolization.

9. The method of claim 1 or 2, wherein the benzyl azide impurity comprises at least two compounds of formula (A) and (B).

10. The method of claim 1 or 2, wherein the sartan active compound of formula (I) obtained as defined in claim 1 contains less than 10 ppm of compound (B1) of formula (B1).

11. The method as claimed in claim 1 or 2, wherein the active sartan compound of formula (I) as defined in claim 1 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.

12. The method of claim 1 or 2, comprising at least the following steps: - a reaction mixture having at least iron ions, an alkali metal azide, and a base in a polar aprotic solvent having reducing properties at a temperature below reflux and under an inert atmosphere; - adding 2-n-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopent-2-imidazolin-5-one to the reaction mixture; - promoting the tetrazolization; and - recovering irbesartan obtained in aqueous solution as one of its alkali metal salts.

13. The method of claim 12, wherein the polar aprotic solvent having reducing properties is 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), dimethylacrylurea (DMPU), dimethylvinylurea (DMEU), triethylamine (TEA), hexamethylphosphonamide (HMPA), hexamethylphosphonitrile (HMPT), 2-pyrrolidone (2-Py), N-methyl-2-pyrrolidone (NMP), N-phenyl-2-pyrrolidone (NPP), N-vinylpyrrolidone (NVP), and 5-methyl-2-pyrrolidone (MPy) at a temperature of 80ºC to 150ºC.

14. The method of claim 12, wherein the irbesartan thus obtained contains less than 10 ppm of compound (B) of formula (B).

15. The method of claim 12, wherein the irbesartan thus obtained contains less than 10 ppm of a compound of formula (B1).