Process for preparing sartan active compounds having a tetrazole ring - Patents.com

Abstract

The present disclosure relates to a process for the preparation of at least one sartan active compound of formula (I), wherein R is selected from the group of formulas (1), (2), (3), (4) and (5), which comprises the tetrazolylation of a compound of formula (II) in a reaction medium with at least one azide derivative, wherein R is as defined above, and the benzyl azide impurity formed during said tetrazolylation is converted to an aldehyde derivative. [Case 1] TIFF2024536219000036.tif9788

Description

[Technical field]

[0001] The present invention belongs to the field of pharmacology, and in particular relates to a method for synthesizing high purity sartan active 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. "Sartans" are a class of drugs used to treat patients with high blood pressure, helping to 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 high blood pressure. This drug is also the first major antihypertensive drug approved for the treatment of patients with high blood pressure, type 2 diabetes, and kidney disease.

[0003] Various methods for preparing irbesartan and related compounds are disclosed in the literature. One of these methods performs the tetrazolylation step generally described in US Pat. No. 5,399,992 for irbesartan.

[0004] As far as irbesartan is concerned, the tetrazolylation step can be carried out from the following intermediate compounds: 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 is tetrazolylated with an alkali metal azide (also referred to herein as alkaline azide or alkaline azide) and a base to form irbesartan. However, said synthetic route presents a major weakness consisting in the formation of azide impurities such as (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2yl)-1H-nitrile (also named in the present text as 4'-(azidomethyl)-[1,1'-biphenyl]-2-carbonitrile or azidonitrile) and (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2-yl)-1H-tetrazole (also named in the present text as 5-(4'-(azidomethyl)-[1,1'-biphenyl]-2yl)-1H-1,2,3,4-tetrazole or azidotetrazole) during this tetrazolylation. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] EP0 708 103 Summary of the Invention [Problem to be solved by the invention]

[0006] The azide impurity, (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2yl)-1H-tetrazole, has recently been found to have mutagenic properties. Mutagens are chemicals that can cause changes in the DNA of cells. These mutations can increase the risk of cancer, but the exact risk of this azide impurity causing cancer in humans is unknown. Health authorities are therefore now seeking to ensure that the levels of the azide impurity remain below the Threshold of Toxicological Concern (TTC). As the azide impurity must not be detectable in the finished drug product, there is a demand to improve the existing manufacturing process for producing sartans with a tetrazole ring, thus implementing a tetrazolylation step. [Means for solving the problem]

[0007] The present invention achieves this need by providing a manufacturing process that allows the resolution of azide impurities, more particularly benzyl azide impurities. The present invention more particularly provides an impurity profile of the obtained sartans that complies with these required low levels of benzyl azide impurities, which can typically be 10 ppm or less, or even 5 ppm or less, relative to the total amount of sartan compound. Thus, said sartans bearing a tetrazole ring can be manufactured in high quality within the framework of the present invention.

[0008] The present invention provides an advantageous process useful for preparing sartan active compounds having a tetrazole ring, in particular irbesartan, having a significantly low amount of azide impurities such as (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2yl)-1H-nitrile and (5-(4'-(azidomethyl)-[1,1'-biphenyl]-2yl)-1H-tetrazole), starting from commonly used cyano derivative intermediates suitable for tetrazolylation.

[0009] As used herein, the formula (I) [ka] [In the formula, R is a group represented by formulas (1), (2), (3), (4), and (5): [ka] is selected from the group [ka] is the binding site] 2. A process for producing at least one sartan active compound of

[0010] Formula (II) [ka] wherein R is as defined above. in a reaction medium with at least one azide derivative, A process is described in which the benzyl azide impurity formed during the tetrazolylation is converted to an aldehyde derivative.

[0011] The present process further exhibits the advantage of implementing the classical N-1 intermediates normally used for tetrazolylation, i.e. intermediates bearing a cyanophenyl moiety, in particular compounds of formula (II) as defined hereinafter, in the sense that the process adjustments required are very mild with respect to existing processes, while providing the required very high level of purity of the sartan compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present disclosure relates to a compound of formula (I) [ka] [In the formula, R is a compound represented by formula (1), (2), (3), (4) or (5). [ka] is selected from the group [ka] is the binding site] 2. A process for producing at least one sartan active compound of

[0013] Formula (II) [ka] wherein R is as defined above. in a reaction medium with at least one azide derivative, The benzyl azide impurity formed during the tetrazolylation is converted to an aldehyde derivative.

[0014] As used herein, the term "ambient temperature" or "room temperature" (also referred to as RT) refers to a temperature in the range of 15°C to 35°C, more particularly, 25°C to 35°C.

[0015] As used herein, "inert atmosphere" refers to an atmosphere that is not favorable for oxidation. This means that there is no oxygen in the atmosphere. For example, the inert atmosphere can be nitrogen gas or argon gas.

[0016] In the sense of the present disclosure, the term "benzyl azide impurity" encompasses all by-products or impurities that may be generated by the nucleophilic substitution of a compound containing at least one activated carbon atom in its structure with an alkali metal azide. By "activated carbon atom" in the context of the present disclosure is meant a carbon atom bearing 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 an "activated carbon atom" is more particularly a carbon atom attached to a phenyl ring, thus forming an activated benzyl structure. Thus, said "benzyl azide impurity" may be present during the tetrazolylation step starting from an intermediate compound bearing a cyanophenyl moiety and carrying out an alkali metal azide.

[0017] There is further provided herein a process according to the present disclosure, wherein said benzyl azide impurity is converted to an aldehyde derivative by performing an oxidation step followed by a hydrolysis step.

[0018] Methods according to the present disclosure are described in further detail later in the specification.

[0019] Transformation of benzyl azide impurities: Oxidation followed by hydrolysis As mentioned above, in conventional processes using cyano derivative intermediates for tetrazolylation, two well-known mutagenic benzyl azide impurities are generated, namely, azidonitriles of formula (A) and azidotetrazoles of formula (B) as shown below: [ka] is formed.

[0020] Hence, there is further provided herein a method according to the present disclosure, wherein said benzyl azide impurities at least comprise compounds of formulae (A) and (B) as defined above.

[0021] In fact, these two benzyl azide impurities can form during the tetrazolylation of the compounds of formula (II) defined in this disclosure from several different potential precursors.

[0022] The method according to the present disclosure allows the degradation of these benzyl azide impurities and, more specifically, their conversion to the corresponding aldehyde derivatives, which are assessed as class 5 impurities, i.e., considered as non-mutagenic compounds.

[0023] More specifically, this transformation consists of an oxidation step followed by a hydrolysis step. Starting from a benzyl azide impurity, the oxidation step makes it possible to obtain the corresponding chemically unstable benzylimine in situ.

[0024] These unstable benzylimines are then converted by hydrolysis to the corresponding aldehyde derivatives upon contact with water.

[0025] More specifically, the aldehyde derivatives may be of formula (A1) (also referred to in this disclosure as nitrile aldehyde impurity) and (B1) (also referred to in this disclosure as tetrazole aldehyde impurity), which are represented by formulas (A) and (B), respectively: [ka] This is due to the benzyl azide impurity.

[0026] As used herein, the aldehyde derivative thus obtained is at least one represented by the formula (B1): [ka] Further provided is a method according to the disclosure, comprising the compound of

[0027] It is herein understood that the resulting sartan active compound of formula (I) as defined in the present disclosure is of formula (B1): [ka] There is further provided a method according to the present disclosure, wherein the composition contains less than 10 ppm, in particular less than 5 ppm, and more particularly less than 1 ppm of the compound.

[0028] The conversion in the method according to the present disclosure converts the benzyl azide impurity into at least divalent iron ions (Fe 2+ ) can be contacted with the

[0029] Thus, there is further provided herein a method according to the present disclosure, wherein said benzyl azide impurity is converted to an aldehyde derivative by contacting said benzyl azide impurity with at least divalent iron ions.

[0030] The supply of the divalent iron ions can be carried out according to two variants.

[0031] According to a first variant, the said ferrous ions are converted into ferric ions (Fe 3+ ) can be formed in situ by reduction of

[0032] Therefore, there is further provided herein a method according to the present disclosure, wherein said ferrous ions are formed in situ by reduction of ferric ions, in particular in the presence of a polar aprotic solvent having reducing properties.

[0033] Among the compounds capable of generating ferric ions, 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, in particular FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3 or Fe(OH)3, for example FeCl3. Advantageously, said compound capable of generating ferric ions is anhydrous, in particular anhydrous FeCl3.

[0034] Thus, there is further provided herein a method according to the present disclosure, wherein said 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 from Fe(H2PO2)3, in particular FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3, or Fe(OH)3, e.g. FeCl3.

[0035] During this conversion, the temperature used may be between 80°C and 150°C, in particular between 100°C and 135°C, and may be under an inert atmosphere when a ferric ion 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, in particular FeCl3, FePO4, FeI3, FeF3, FeBr3, Fe2(SO4)3, Fe2(C2O4)3, or Fe(OH)3, e.g. FeCl3, is used.

[0036] According to a second variant, the ferrous ions can be incorporated directly into the reaction medium.

[0037] Among the compounds capable of generating the divalent iron ion, for example, FeCl2, FeBr2, FeI 2、 FeF 2、 FeCO 3、 One may cite 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, in particular FeCl2, FeBr2, FeI2, FeF2, FeCO3, FeSO4, Fe3(PO4)2, Fe2SiO4, Fe(OH)2, or FeCl2, such as Fe(C2H3O2).

[0038] Furthermore, the conversion of the benzyl azide impurity can be carried out simultaneously with said tetrazolylation or after said tetrazolylation in two embodiments.

[0039] According to one embodiment, the conversion can be carried out simultaneously with said tetrazolylation.

[0040] According to said embodiment, the total amount of ferrous ions present in the reaction medium can be controlled. More particularly, the total amount of ferrous ions can be introduced in catalytic amounts, which can reduce, avoid or prevent the thermal instability of the azide derivative.

[0041] More particularly, the divalent iron ions may be present in a catalytic amount in the basic medium containing the azide derivative, in particular in a molar percentage ranging from 0.005% to 0.1%, in particular from 0.01% to 0.05%, relative to the amount of the compound of formula (II) as defined in the present disclosure.

[0042] Further according to said embodiment, when the sartan active compound of formula (I) is irbesartan, the ferrous ions may be present in a molar percentage ranging from 0.005% to 0.1%, in particular 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.

[0043] According to another embodiment, the conversion can be carried out after said tetrazolylation.

[0044] According to said embodiment, the total amount of divalent iron ions present in the reaction medium may not be of great importance if, in the first embodiment, the tetrazolylation step is completed.

[0045] Thus, the divalent iron ion can be present in any amount in the reaction medium, for example, a catalytic amount or a stoichiometric amount.

[0046] For example, the divalent iron ion can be present in a molar percentage ranging from 0.005% to 10%.

[0047] Tetrazolylation Tetrazolylation refers to the conversion of a nitrile to a tetrazole.

[0048] Tetrazolylation by reaction with azide derivatives, for example alkali metal azides such as tributyltin azide or sodium azide, and a base such as triethylamine hydrochloride, has been described in the literature.

[0049] Thus, 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 named irbesartan) from 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (also named spiromethylbiphenylnitrile in the present disclosure) by heating at reflux in the presence of tributyltin azide is known.

[0050] In WO 02 / 04331, the use of 1-methylpyrrolidin-2-one as a solvent at a temperature of about 150° C., ie the temperature at which reflux is observed, is shown to be particularly advantageous for overcoming the drawbacks.

[0051] Thus, the privileged route to carry out this tetrazolylation is by reaction of a compound of formula (II) as defined in the present disclosure with an azide derivative and a base in an inert polar aprotic solvent at a temperature below reflux and under an inert atmosphere.

[0052] The following scheme 1 shows the reaction of a compound of formula (II) to obtain a compound of formula (I). [ka] wherein R is as defined above. The tetrazolylation from the compound of formula (I) is shown briefly.

[0053] Among the azide derivatives, mention may be made especially of hydrazoic acid (HN3), salt azides, for example metal azides such as sodium azide (NaN3), potassium azide (KN3), or calcium azide (Ca(N3)2), SnBu3N3, SnMe3N3, trialkylammonium azides such as triethylammonium azide, in particular sodium azide or triethylammonium azide, or metal or salt azides such as sodium azide or triethylammonium azide.

[0054] Among the polar aprotic solvents with reducing properties, there may be mentioned, inter alia, 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), hexamethylphosphoramide (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).

[0055] Thus, there is further provided herein a method according to the present disclosure, wherein said 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), dimethylpropyleneurea (DMPU), dimethylethyleneurea (DMEU), triethylamine (TEA), hexamethylphosphoramide (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).

[0056] The base may be selected from Hunig's bases such as triethylamine (EtN), N,N-dicyclohexylmethylamine, and N,N-diisopropylethylamine, etc. The base may in particular be triethylamine, more particularly triethylamine hydrochloride (TEA, also named HCl).

[0057] Preferably, equimolecular amounts of alkali metal azide and triethylamine hydrochloride are used in a ratio of 1 to 5 moles per mole of starting nitrile, advantageously from about 1.2 to about 2 moles per mole of nitrile.

[0058] During the tetrazolylation, the reaction medium can be heated at a temperature ranging from room temperature to 150°C, in particular from 100°C to 135°C, for example at 150°C.

[0059] After 6-20 hours of heating, the tetrazolylation is complete and the reaction mixture is worked up according to conventional techniques. In particular, the mixture is neutralized by adding a base, e.g., an alkali metal hydroxide, in aqueous solution, and the aqueous phase containing salts, particularly chlorides and azides, is discarded.

[0060] The organic phase can then be treated with water and various organic solvents (aromatic, halogenated, esters, ketones...) such as toluene, ethyl acetate, dichloromethane (DCM), methyl ethyl ketone, and optionally with two different solvents in sequence to remove reaction by-products.

[0061] These washing steps are conventional and well known to those skilled in the art.

[0062] The final product is then crystallized via crystallization steps well known to those skilled in the art, followed by additional conventional filtration and washing steps, if necessary.

[0063] Among the sartan active compounds of formula (I) as defined above, mention may be made especially of irbesartan, losartan, valsartan, candesartan or olmesartan, in particular irbesartan.

[0064] According to a particular embodiment, the sartan active compound of formula (I) as defined above is irbesartan, also called 2-n-butyl-4-spirocyclopentan-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.

[0065] In this specification, - having a reaction mixture containing at least iron ions, in particular ferrous ions, more particularly ferric ions, obtained in situ via an alkali metal azide and a base in a polar aprotic solvent having reducing properties, below reflux temperature and under an inert atmosphere, - adding to the reaction mixture 2-n-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopentan-2-imidazolin-5-one; - promoting said tetrazolylation; - recovering the irbesartan thus obtained in the form of one of its alkali metal salts in an aqueous solution.

[0066] Thus, in the present specification, the polar aprotic solvent having reducing properties is 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 (TME), Further provided is a method according to the present disclosure in which the reactant is selected from N-methyl-2-pyrrolidone (NMP), N-phenyl-2-pyrrolidone (NPP), N-vinylpyrrolidone (NVP), 5-methyl-2-pyrrolidone (MPy), and in particular 1-methylpyrrolidin-2-one, and at a temperature of 80° C. to 150° C., in particular 100° C. to 135° C.

[0067] When the sartan active compound of formula (I) is irbesartan, 1-methylpyrrolidin-2-one can in particular be used as a polar aprotic solvent having reducing properties at temperatures between 80°C and 150°C, in particular between 100°C and 135°C.

[0068] As used herein, the irbesartan thus obtained is represented by the formula (B): [ka] There is further provided a method according to the present disclosure, comprising the steps of:

[0069] As used herein, the irbesartan thus obtained is represented by the formula (B1): [ka] There is further provided a method according to the present disclosure, wherein the composition contains less than 10 ppm, in particular less than 5 ppm, and more particularly less than 1 ppm of the compound.

[0070] The compound of formula (B1) can then be removed to yield the sartan compound, after conventional filtration and washing, as is commonly performed in syntheses involving tetrazolylation.

[0071] During tetrazolylation, the nitrile group contained in the compound of formula (II) defined in the present disclosure can be converted to tetrazole group to form irbesartan.The same reaction can be carried out to convert the compound of formula (A) to the compound of formula (B).At the end of conventional tetrazolylation, the compound of formula (A) is less than 1 ppm (detection limit), and only the compound of formula (B) remains.

[0072] The present inventors compared the amount of the compound of formula (B1) obtained without converting the benzyl azide impurity into an aldehyde derivative for the synthesis of irbesartan with the amount of the compound of formula (B1) obtained by converting the benzyl azide impurity into an aldehyde derivative.

[0073] It has been found that in the prior art process not carrying out the conversion of the benzyl azide impurity formed during said tetrazolylation, the irbesartan obtained after the tetrazolylation step may exhibit an amount (at the end of the tetrazolylation reaction) of about 130 ppm relative to the total amount of irbesartan, whereas the process according to the present invention carrying out the conversion of the benzyl azide impurity formed during said tetrazolylation gives an amount of less than 10 ppm, in particular less than 5 ppm, relative to the total amount of irbesartan, before the final purification step.

[0074] Even if subsequent conventional steps of purification are carried out, in the prior art manufacturing processes, i.e. manufacturing processes not carrying out the conversion of the benzyl azide impurity formed during said tetrazolylation, the irbesartan thus obtained may exhibit an amount of 30±10 ppm relative to the total amount of irbesartan, which is still far beyond the requirements of the health authorities.

[0075] The process according to the invention, i.e. carrying out the conversion of the benzyl azide impurity formed during said tetrazolylation, makes it possible to provide an amount of said benzyl azide impurity of less than 1 ppm relative to the total amount of irbesartan after the final purification step.

[0076] Further impurities Furthermore, the inventors note that, particularly due to the presence of the solvent in its oxidized form, further impurities other than the aldehydic impurities may also potentially be formed.

[0077] More specifically, when the sartan active compound (I) was irbesartan and the inert aprotic polar solvent used was N-methyl-2-pyrrolidone, in addition to the tetrazole aldehyde impurities, four NMP irbesartan adduct impurities were detected. Their presence is due to the reaction of oxidized NMP with irbesartan. These four adducts have the following formulae (C1), (D1), (E1) and (F1), as shown below: [ka] has.

[0078] However, with regard to the tetrazole aldehyde impurities of formula (B1) defined above, these four irbesartan adducts were assessed as class 5 impurities, which means that the four irbesartan adducts were considered as non-mutagenic compounds, and therefore their co-presence in the final product is not harmful in view of the requirements of the health authorities.

[0079] The present invention will now be described in more detail with reference to the following examples, which are provided to illustrate the present invention and should not be construed as limiting the scope and spirit of the present invention. EXAMPLES

[0080] 1H NMR spectra were recorded on a Bruker AC200 spectrometer operating at 200 MHz and were obtained from a 2% (m / V) solution of irbesartan in hexadeuterated dimethylsulfoxide (DMSO-d6) containing tetramethylsilane as an internal standard. 1 H RMN spectra were referenced at 2.5 ppm at a temperature of 300 K. Chemical shifts were calibrated relative to the TMS signal (the signal at 0 ppm is due to the internal standard tetramethylsilane).

[0081] or 1 H NMR spectra were recorded on a Bruker Avance III spectrometer operating at 400 MHz, and chemical shifts (δ (ppm)) were referenced to 7.26 ppm using the solvent CDCl3 at a temperature of 300 K. Chemical shifts were calibrated with respect to the TMS signal (the signal at 0 ppm is based on the internal standard tetramethylsilane).

[0082] [Example 1] Preparation of crude irbesartan and quantification of impurities (compounds of formula (A), (B) and (B1)) by the method according to the present disclosure

[0083] [Example 1-1] Preparation of crude irbesartan In a suitable reactor inerted with nitrogen gas, a mixture of 35.2 g triethylamine hydrochloride, 31.5 mg FeCl, 82 g N-methylpyrrolidone, 16.8 g sodium azide, and 80 g 2-N-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one was gradually heated to a temperature of approximately 130-135°C.

[0084] The mixture was then maintained at a temperature of approximately 130-135° C. for at least 14 hours.

[0085] The mixture was then cooled to 20-30° C., and 12 g of N-methylpyrrolidone, 127 g of toluene, and 11 g of water were added thereto. The mixture was then repeatedly washed with a 30 w / w % aqueous sodium hydroxide solution.

[0086] Water was then added and the reaction medium was acidified with concentrated hydrochloric acid to a pH of approximately 4 at 10-15° C. The organic phase was then discarded and the remaining solid material was washed with water.

[0087] Next, the organic layer was poured into an 8 w / w % aqueous sodium hydroxide solution at about 5 to 10° C. After stirring for 15 minutes, the organic phase was discarded, and the aqueous layer was washed with about 80 ml of toluene.

[0088] 122 ml of methyl ethyl ketone and 12 ml of water were added, the pH adjusted to 8 with concentrated HCl at about 15° C., filtered through a charcoal cartridge, heated to 50° C., and the pH adjusted to 7 with HCl.

[0089] After seeding and acidification to pH 4, the slurry was cooled to 25° C., held for 1 h and filtered.

[0090] The cake was washed repeatedly with isopropanol and dried to deliver pure irbesartan.

[0091] Irbesartan 1 The H RMN characterization is as follows: 1 H RMN (200 MHz, δ in ppm, DMSO): 0.8 (T, 3H); 1.3 (sextuplet, 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)

[0092] [Example 1-2] Quantitation of compounds of formula (A), (B) and (B1) For compounds of formula (A), (B) and (B1) 1 The characterization of the H RMN is as follows:

[0093] For compounds of formula (A): 1H RMN (400 MHz, δ in ppm, CDCl3): 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)

[0094] For compounds of formula (B): 1 H RMN (400 MHz, δ in ppm, CDCl3): 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)

[0095] 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)

[0096] The impurity amounts in equations (A), (B) and (B1) are calculated using two moments: First, at the end of the tetrazolylation reaction carried out in Example 1-1 above, and - Secondly, pure isolated irbesartan was measured as obtained according to Example 1-1 above.

[0097] The analytical methods used to determine the amounts of compounds of formula (A) and (B) were as follows:

[0098] Analysis was performed by UPLC.

[0099] For the liquid chromatography portion (UPLC Vanquish ThermoScientific): Chromatography was performed using a column with the following characteristics:

[0100] [Table 1] - Column temperature: 50°C - Sample changer temperature: 25°C - Injection volume: 2μL - Spectrophotometer detector set to 254 nm (optional) - mobile phase containing mixture: A: HO + 0.1% formic acid (v / v) and B: methanol, The gradient is:

[0101] [Table 2]

[0102] Chromatography was performed by using the following switching valves:

[0103] [Table 3]

[0104] The analysis time was 16 minutes.

[0105] For mass spectrometry (Q Exactive Thermo Fischer Scientific): Quantification was performed using the following: - Ionization mode: HESI - Spray voltage: 3500V - Capillary temperature: 300℃ - Sheet gas: 70 arbitrary units - Auxiliary gas: 20 arbitrary units - Sweep gas: 0 arbitrary units - Auxiliary gas temperature: 300℃ - RF level of S-lens: 50 arbitrary units

[0106] The mode of detection of the compounds of formula (A) and (B) is as follows: PRM (Parallel Reaction Monitoring) in positive mode with extraction of fragment m / z (resolution 17500) by inclusion list:

[0107] [Table 4]

[0108] Search for ions of compounds of formula (A) and (B):

[0109] [Table 5]

[0110] The analytical method used to measure the content of the compound of formula (B1) is as follows: The analysis was carried out in LC-MS on a LC-MS SRDA-UC09-FUSION (column content HSS C18-50*2.1mm-1.8μm, mobile phase A=H2O and mobile phase B=methanol, debit=0.8mL / min, column temperature=50°C, gradient=5%B to 90%B in 5 min, mass detection: positive ESI - SIM at m / z=251 and m / z=267).

[0111] These results are summarized in Table 1 below.

[0112] [Table 6]

[0113] These results demonstrate that the method according to the present disclosure makes it possible to decompose the azide impurity, and more particularly to convert the compound of formula (B) to the compound of formula (B1).

[0114] Furthermore, it has been shown that the filtration and purification steps carried out after tetrazolylation to obtain pure isolated irbesartan make it possible to reduce both the content of compound of formula (B) (from 5 ppm to 1 ppm) and the content of compound of formula (B1) (from 50 ppm to less than 5 ppm).

[0115] [Example 2] (Comparison): Preparation of crude irbesartan by a method outside the present disclosure (i.e., no presence of divalent iron ions in the medium) and quantification of impurities (compounds of formula (A) and (B))

[0116] [Example 2-1] Preparation of crude irbesartan by a method outside the present disclosure (FeCl3 not included) A similar method to that described in Example 1 above was carried out, except that FeCl3 was not used. Details are as follows.

[0117] In a suitable reactor inerted with nitrogen gas, a mixture of 35.2 g triethylamine hydrochloride, 82 g N-methylpyrrolidone, 16.8 g sodium azide, and 80 g 2-N-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one was gradually heated to a temperature of approximately 130-135°C.

[0118] The mixture was then maintained at a temperature of approximately 130-135° C. for at least 14 hours.

[0119] The mixture was then cooled to 20-30° C., and 12 g of N-methylpyrrolidone, 127 g of toluene, and 11 g of water were added thereto. The mixture was then repeatedly washed with a 30 w / w % aqueous sodium hydroxide solution.

[0120] Water was then added and the reaction medium was acidified with concentrated hydrochloric acid to a pH of approximately 4 at 10-15° C. The organic phase was then discarded and the remaining solid material was washed with water.

[0121] Next, the organic layer was poured into an 8 w / w % aqueous sodium hydroxide solution at about 5 to 10° C. After stirring for 15 minutes, the organic phase was discarded, and the aqueous layer was washed with about 80 ml of toluene.

[0122] 122 ml of methyl ethyl ketone and 12 ml of water were added, the pH adjusted to 8 with concentrated HCl at about 15° C., filtered through a charcoal cartridge, heated to 50° C., and the pH adjusted to 7 with HCl.

[0123] After seeding and acidification to pH 4, the slurry was cooled to 25° C., held for 1 h and filtered.

[0124] The cake was washed repeatedly with isopropanol and dried to deliver pure irbesartan.

[0125] Irbesartan 1 The H RMN characterization is as follows: 1 H RMN (200 MHz, δ in ppm, DMSO): 0.8 (T, 3H); 1.3 (sextuplet, 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)

[0126] [Example 2-2] Quantitation of compounds of formula (A) and (B) Compounds of formula (A) and (B) 1 The H RMN properties are as follows:

[0127] For compounds of formula (A): 1H RMN (400 MHz, δ in ppm, CDCl3): 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)

[0128] For compounds of formula (B): 1 H RMN (400 MHz, δ in ppm, CDCl3): 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)

[0129] The contents of impurities of formula (A) and (B) were determined at two moments: First, at the end of the tetrazolylation reaction carried out in Example 2-1 above, and - Secondly, pure isolated irbesartan was measured as obtained according to Example 2-1 above.

[0130] The analytical methods used to determine the content of compounds of formula (A) and (B) were similar to those used and described in Example 1-2 above.

[0131] These results are summarized in Table 2 below.

[0132] [Table 7]

[0133] By comparing the results of Examples 1-2 and 2-2, the following is evident: The presence of divalent iron ions in the process according to the present disclosure makes it possible to significantly reduce the content of compound of formula (B) both at the end of the tetrazolylation reaction (5 ppm vs. 130±20 ppm) and when pure isolated irbesartan is obtained (1 ppm vs. 30±10 ppm). - the weak amount of the compound of formula (A) is similar in both methods, the compound of formula (B1) is obtainable only by carrying out the method according to the present disclosure, showing that the presence of divalent iron ions in the medium results in the conversion of the compound of formula (B) into the compound of formula (B1).

[0134] [Example 3] Decomposition of the compound of formula (B) in the presence of FeCl3 to the compound of formula (B1)

[0135] [Example 3-1] To 0.11 g of the compound of formula (B), 4.11 g of NMP and 0.013 g of FeCl3 were added. 、 These were heated at 135° C. for 2 hours with magnetic stirring.

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

[0137] At 6.6 min, the majority of the peak corresponding to the compound of formula (B1) was observed (UV 250 nm), and at 8.33 min, the compound of formula (B) was no longer detectable.

[0138] [Example 3-2] Two solutions were prepared as follows: 1) Solution 1: 11.1 mg of compound (B) was added to 6 ml of NMP and then solubilized (1850 ppm). 2) Solution 2: 8.8 mg of FeCl3 was added to 1 mL of NMP and then solubilized.

[0139] A blank and two samples were then prepared and filled into three different vials as follows: - Blank: Solution 1 (vial 1) 2 mL - Sample 1: 2 mL of solution 1 (vial 2) containing 50 μL of solution 2 (i.e. 0.2 equivalents) - Sample 2: 50 μL (ie 0.2 equivalents) of solution 2 and 2 mL of solution 1 containing argon were bubbled in before the vial was closed and heated (vial 3).

[0140] The three reaction media were heated for 15 minutes, then colored and heated at 135° C. for 3 hours.

[0141] These results are summarized in Table 3 as follows:

[0142] [Table 8]

[0143] From these results, it is clear that the profiles are the same for Sample 1 and Sample 2, meaning that the presence or absence of oxygen has no effect and compound (B) disappears in the presence of FeCl3.

[0144] Thus, Example 3 demonstrates the decomposition of the azidotetrazole impurity of formula (B) to the tetrazole aldehyde impurity of formula (B1) caused by the presence of FeCl3.

[0145] This example also demonstrates that the conversion of a compound of formula (B) to a compound of formula (B1) can be carried out simultaneously with or subsequent to the tetrazolylation reaction.

[0146] [Example 4] Decomposition of the compound of formula (B) in the presence of FeCl2 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 at 100° C. for 3 hours.

[0147] The reaction mixture was cooled to room temperature and analyzed by HPLC, providing degradation of the compound of formula (B) by observing the disappearance of the corresponding peak.

[0148] The results are as follows: Compound (B) before reaction: 100% area at RT 3.2 min Compound (B) after 3 h at 100 °C: the main decomposition product at RT 3.2 min is 5.1 area %, in addition to the main decomposition product at 1.3 min representing 54 area %.

[0149] Operating conditions column: Phase: X-Bridge C 18 Length: 100mm Diameter: 4.6mm Particle size distribution: 3.5μm Supplier: Waters Reference Number 186003033 Column temperature: 35℃ Injector temperature: Room temperature Mobile phase: A = 10 mM solution of ammonium acetate (e.g., 770 mg in 1 L of H2O) adjusted to pH = 4.5 with dilute aqueous acetic acid. B=acetonitrile.

[0150] gradient: [Table 9] Debit: 1.2ml / min Injection volume: 5 μl Detection: 250nm Analysis duration: 12 min Equilibration time: 5 min

Claims

1. Formula (I) 【Chemical 1】 wherein R is a group represented by formula (1), (2), (3), (4) and (5). 【Chemistry 2】 is selected from the group 【Chemistry 3】 is the binding site] 1. A method for producing at least one sartan active compound of the formula: Formula (II) 【Chemistry 4】 wherein R is as defined above. in a reaction medium with at least one azide derivative, The benzyl azide impurity formed during the tetrazolylation is converted to an aldehyde derivative.

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

3. The benzyl azide impurity is reacted with at least a divalent iron ion. The method of claim 1, wherein the compound is converted to an aldehyde derivative by contacting the compound with the compound.

4. 4. The method according to claim 3, wherein the ferrous ions are formed in situ by reduction of ferric ions, in particular in the presence of a polar aprotic solvent having reducing properties.

5. The iron(III) ion is 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 or Fe(H ２ P.O. ２ ) ３ , especially 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 , for example, FeCl ３ The method of claim 4, wherein the compound is produced from

6. 5. The method of claim 4, 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), dimethylpropyleneurea (DMPU), dimethylethyleneurea (DMEU), triethylamine (TEA), hexamethylphosphoramide (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).

7. 10. The method of claim 1, wherein the benzyl azide impurity is converted to an aldehyde derivative simultaneously with the tetrazolylation.

8. 2. The method according to claim 1, wherein the divalent iron ions are present in a catalytic amount in the basic medium containing the azide derivative, in particular in a molar percentage ranging from 0.005% to 0.1%, in particular from 0.01% to 0.05%, relative to the amount of compound of formula (II) as defined in claim 1.

9. 10. The method of claim 1, wherein the benzyl azide impurity is converted to an aldehyde derivative after tetrazolylation.

10. The benzyl azide impurity is represented by the formula (A) and (B): 【Chemistry 5】 10. The method of claim 1, comprising at least two of the following compounds:

11. The aldehyde derivative thus obtained has at least the formula (B1) 【Chemistry 6】 10. The method of claim 1, comprising the compound of formula:

12. The resulting sartan active compound of formula (I) as defined in claim 1 has the formula (B1) 【Chemistry 7】 2. The method according to claim 1, wherein the water contains less than 10 ppm, in particular less than 5 ppm, more particularly less than 1 ppm of compounds of formula (I).

13. 2. The method of claim 1, wherein the sartan active compound of formula (I) as defined in claim 1 is irbesartan, also known as 2-n-butyl-4-spirocyclopentan-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.

14. having a reaction mixture obtained in situ in a polar aprotic solvent having reducing properties below reflux temperature and under an inert atmosphere, comprising at least iron ions, in particular ferrous ions, more particularly ferric ions, an alkali metal azide and a base; adding 2-n-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one to the reaction mixture; promoting the tetrazolylation; and recovering the irbesartan thus obtained in the form of one of its alkali metal salts in an aqueous solution.

15. The polar aprotic solvents having reducing properties include N-methylformamide (MFo), N,N-dimethylformamide (DMF), N-methyl, N-tert-butylformamide, acetamide (Ac), N-methylacetamide (MAc), N,N-dimethylacetamide (MAc), N,N-dimethylacetamide (N-dimethylformamide), N-methylformamide (MFo), N-tert-butylformamide (DMF), N-methylacetamide (MAc), N-tert-butylformamide (Tetramide ...tert-butylformamide (Tetramide), N-tert-butylformamide (Tetramide), N-tert-butylformamide (Tetramide), N-tert-butylformamide (Tetramide), N- 15. The method of claim 14, wherein the hydroxybenzoate is selected from cetoamide (DMAc), urea, tetramethylurea (TMU), dimethylpropyleneurea (DMPU), dimethylethyleneurea (DMEU), triethylamine (TEA), hexamethylphosphoramide (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), in particular 1-methylpyrrolidin-2-one, at a temperature of from 80°C to 150°C, in particular from 100°C to 135°C.

16. The irbesartan thus obtained has the formula (B): 【Chemistry 8】 16. The method according to claim 14 or 15, wherein the composition contains less than 10 ppm, in particular less than 5 ppm, of compounds of the formula:

17. The irbesartan thus obtained has the formula (B1) 【Chemistry 9】 16. The method according to claim 14 or 15, wherein the composition contains less than 10 ppm, in particular less than 5 ppm, more particularly less than 1 ppm of compounds of the formula:

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