WO2023046836A1

WO2023046836A1 - Process for preparing sartans

Info

Publication number: WO2023046836A1
Application number: PCT/EP2022/076381
Authority: WO
Inventors: Silvo Zupancic; Tanja SENICAR; Boštjan PERŠE; Sergeja Bombek; Andrej Klobcar; Dušan KRAŠOVEC
Original assignee: KRKA dd
Current assignee: KRKA dd
Priority date: 2021-09-24
Filing date: 2022-09-22
Publication date: 2023-03-30
Anticipated expiration: 2024-03-24
Also published as: EP4405339A1

Abstract

The present application relates to a process for purifying a tetrazole-containing-sartan or a tetrazole-containing-sartan intermediate, the process comprising the steps of (a) providing a composition comprising an azide-impurity together with a tetrazole-containing-sartan or with an intermediate of a tetrazole-containing-sartan; (b) treating the composition provided in step (a) with a reducing agent; preferably reacting the azide-impurity with a reducing agent thereby obtaining an amine-impurity; and (c) optionally, isolating the tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan from the composition. The application further relates to a process for the synthesis of tetrazole-containing-sartans which ensures azide-impurities free final active pharmaceutical ingredients as well as azide-impurities free intermediates of tetrazole-containing-sartans that are suitable for the subsequent synthesis of tetrazole-containing-sartans.

Description

PROCESS FOR PREPARING SARTANS

[0001] Priorities are claimed of European patent application no. 21198941.3 filed on September 24, 2021, of European patent application no. 21199325.8 filed on September 28, 2021, and of European patent application no. 22150963. 1 filed on January 11, 2022.

[0002] The invention relates to a process for purifying a tetrazole-containing-sartan or a tetrazole-contain- ing-sartan intermediate, the process comprising the steps of

(a) providing a composition comprising an azide-impurity together with a tetrazole-containing-sartan or with an intermediate of a tetrazole-containing-sartan;

(b) treating the composition provided in step (a) with a reducing agent; preferably reacting the azide-impurity with a reducing agent thereby obtaining an amine-impurity; and

(c) optionally, isolating the tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan from the composition.

[0003] The invention further relates to an improved process for the synthesis of tetrazole-containing-sartans which ensures azide-impurities free final active pharmaceutical ingredients (APIs) as well as azide-impuri- ties free intermediates of tetrazole-containing-sartans that are suitable for the subsequent synthesis of tetrazole-containing-sartans.

[0004] Sartans are non-peptide, orally active, specific angiotensin II antagonists useful in the treatment of hypertension.

[0005] N. Georgiou et al., Molecules 2021, 26, 2927, page 1 to 18 review rational design and synthesis of AT1R antagonists.

[0006] Recently, in sartans some genotoxic impurities were detected including nitrosamine impurities (N- nitrosodimethylamine (NDMA), or N-nitrosodiethylamine (NDEA)) and related compounds with azide structural element (for example 5-(4'-(azidomethyl)-[l,l'-biphenyl]-2-yl)-lH-tetrazole).

[0007] J. Tatarkiewicz et al., Folia Cardiologica 2019, vol. 14, no. 6, pages 564-571 report about contamination of antihypertensive drugs with carcinogenic nitrosamines. [0008] In particular, CN 104 045 602 reports the use of sodium azide in the preparation of tetrazole moiety- comprising sartans such as valsartan. As an excess of sodium azide is used, the unreacted excess is later removed by adding sodium nitrite (NaNCh). The drawback of sodium nitrite (NaNCh) as reducing agent is though, that by its application only inorganic azide(s) may be reduced, and that it does not reduce organic azides. Another drawback of sodium nitrite (NaNCh) is that it readily generates N-nitrosamines, particularly in the presence of secondary amines. Thus there is a need in the art for a method for preparing pharmaceutically active compounds which are free of N-nitrosoamines, as well as free of the azide moiety comprising impurities.

[0009] IN 2021 1103 4277 A relates to a process for the preparation of angiotensin receptor blockers or its pharmaceutically acceptable salts thereof. The process comprises the step of providing a solution of losartan or its pharmaceutically acceptable salts thereof in solvent with aqueous alkali. Potassium iodide, sodium iodide and the like can be used along with aqueous sodium hydroxide solution for depletion of azido impurities. Alternatively, reducing agents such as sodium borohydride, lithium borohydride and the like can also be used along with aqueous base solution for depletion of azido impurities.

[0010] P. Yinsheng et al., Chin J Pharm, 2014, 45(8), 714-716 relates to a scalable process to the key intermediate of sartans.

[0011] WO 2009/086753 relates to preparation methods of aminomethyl biphenyl tefrazole compounds of formula I or their salts and salts of formula II comprising that intermediates of formula III, which are reduced by reducing agents in an inert organic solvent to obtain aminomethyl biphenyl tefrazole compounds or their salts (formula I), followed by acidification to obtain their salts (formula II); alternatively, intermediates of formula III are reduced in acidic condition to obtain their salts directly (formula II), in which M is hydrogen or alkali metals or C3-C18 tertiary amine salts, X is Cl, Br, HSO4 or CH3COO.

[0012] The azide group can be introduced in the structure of sartan in a cycloaddition step where related compounds of a precursor react with azide in substitution reactions. The cycloaddition step is an essential reaction step for all tetrazole-containing-sartans such as valsartan, losartan, olmesartan, olmesartan medox- omil, candesartan, candesartan cilexetil, and irbesartan:

candesartan candesartan cilexetil losartan

irbesartan

[0013] For example, the impurity 5-(4'-(azidomethyl)-[l,l'-biphenyl]-2-yl)-lH-tetrazole is formed on following way:

[0014] The 4'-(bromomethyl)-[l,r-biphenyl]-2-carbonitrile present in precursor for cycloaddition reacts with azide in cycloaddition reaction to form the impurity 5-(4'-(azidomethyl)-[l,l'-biphenyl]-2-yl)-lH-te- trazole. Any other azide impurity in any sartan or its intermediate can be formed in a similar way. The azide group can be bonded on any possible position of sartan molecule or its intermediates, starting materials or impurities, preferably the impurities where azide group is bonded on aliphatic carbon of intermediates, starting materials, final sartans or impurities of these sartans.

[0015] Other sartans such as telmisartan, eprosartan, and azilsartan do not have such a tetrazole moiety. [0016] It is an object of the invention to provide tetrazole-containing-sartans or intermediates of tetrazole- containing-sartans which have advantages compared to the prior art. The tetrazole-containing-sartans or intermediates of tetrazole-containing-sartans should have a very low content of azide-impurities, preferably should not contain any detectable azide-impurities.

[0017] This object has been achieved by the subject-matter of the patent claims.

[0018] It has been surprisingly found that azide-impurities can be removed from tetrazole-containing-sartans or intermediates of tetrazole-containing-sartans when they are reduced to the corresponding amines by means of suitable reducing agents.

[0019] Further, it has been surprisingly found that with the amount of reduction agents and reaction conditions the reduction is highly selective to azide moiety.

[0020] A first aspect of the invention relates to a process for purifying a tetrazole-containing-sartan or a tetrazole-containing-sartan intermediate, the process comprising the steps of

(b) treating the composition provided in step (a) with a reducing agent; preferably reacting the azide- impurity with a reducing agent thereby obtaining an amine-impurity; and

(c) optionally, isolating the tetrazole-containing-sartan or the intermediate of the tetrazole-containing- sartan from the composition; preferably without detectable amounts of azide impurities.

[0021] The process of invention includes reduction of one or more azide-impurities to corresponding amine-impurities which are nor genotoxic and can be easily removed by crystallization, extractions or any other method known in the art.

[0022] Step (a) of the process according to the invention involves the provision of a composition comprising an azide-impurity together with a tetrazole-containing-sartan or with an intermediate of a tetrazole- containing-sartan.

[0023] The composition provided in step (a) can be a solid material, preferably a crystalline material, an amorphous material, a glassy material, or a partially crystalline material. [0024] Alternatively, the composition provided in step (a) can be a liquid material, preferably a viscous liquid (oil-like).

[0025] The composition provided in step (a) may be any intermediate reaction product that is obtained in the course of a chemical synthesis providing a tetrazole-containing-sartan. Thus, it is also contemplated that the composition provided in step (a) is a solution or dispersion.

[0026] The composition provided in step (a) of the process according to the invention comprises an azide- impurity.

[0027] For the purpose of the description, an azide-impurity is any compound bearing an azide functional group that differs from the tetrazole-containing-sartan and the intermediate of the a tetrazole-containing- sartan, respectively.

[0028] The presence of azide-impurities can be verified by analytical methods that are known to the skilled person, e.g. by IR spectroscopy or Raman spectroscopy detecting the signals that are characteristic for azide functional groups, as well as by methods such as HPLC, LCMS or GC.

[0029] According to the invention, azide-impurities are related compounds of tetrazole-containing-sartans, which azide-impurities contain azide group. The azide group can be bonded on any possible position of a tetrazole-containing-sartan or of an intermediate of a tetrazole-containing-sartan, a starting material or an impurity. Preferably, the azide-impurity is a compound where an azide group is bonded on an aliphatic carbon of an intermediate of a tetrazole-containing-sartan, a starting material, final sartan or an impurity of a tetrazole-containing-sartan.

[0030] Preferably, the azide-impurity is

- 5-(4'-(azidomethyl)-[l,l'-biphenyl]-2-yl)-lH-tetrazole (AZBT);

- (2S,3R)-2-(N-((2'-(l H-tetrazol-5 -yl)-[ 1 , 1 '-biphenyl]-4-yl)methyl)pentanamido)-4-azido-3 -methylbutanoic acid;

- N-((2'-( lH-tetrazol-5-yl)-[ 1 , 1 '-biphenyl]-4-yl)(azido)methyl)-N -pentanoy 1-L-valine;

- 2-(N-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)pentanamido)-2-azido-3-methylbutanoic acid;

- (S)-2-(N-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)pentanamido)-3-azido-3-methylbutanoic acid;

- N-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)-N-(5-azidopentanoyl)-L-valine (Impl);

- N-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)-N-(4-azidopentanoyl)-L-valine (Imp2); - N-((2'-( lH-tetrazol-5-yl)-[ 1 , 1 '-biphenyl]-4-yl)methyl)-N-(3 -azidopentanoyl)-L-valine;

- N-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)-N-(2-azidopentanoyl)-L-valine;

- 3-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)-2-(2-azidobutyl)-l,3-diazaspiro[4.4]non-l-en-4- one;

- 3-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)-2-(4-azidobutyl)-l,3-diazaspiro[4.4]non-l-en-4- one;

- 3-((2'-( lH-tetrazol-5 -yl)-[ 1 , 1 '-biphenyl] -4-yl)methyl)-7 -azido-2-butyl- 1 ,3 -diazaspiro[4.4]non- 1 -en-4- one;

- 3-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)-2-(3-azidobutyl)-l,3-diazaspiro[4.4]non-l-en-4- one;

- 3-((2'-( lH-tetrazol-5 -yl)-[ 1 , 1 '-biphenyl]-4-yl)methyl)-6-azido-2-butyl- 1 ,3 -diazaspiro[4.4]non- 1 -en-4- one;

- 3-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)-2-(l-azidobutyl)-l,3-diazaspiro[4.4]non-l-en-4- one;

- 3-((2'-( lH-tetrazol-5 -yl)-[ 1 , 1 '-biphenyl]-4-yl)methyl)-2-azido-2-butyl- 1 ,3 -diazaspiro[4.4]nonan-4-one;

3-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)(azido)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4- one; or any combination of any of the foregoing.

[0031] Preferably, the azide-impurity is selected from the group consisting of azidomethyl-biphenyl-te- frazole (AZBT), 4'-(azidomethyl)-[l,l'-biphenyl]-2-carbonitrile (AZBC), 4'-(azidomethyl)-[l,l'-biphenyl]- 2 -formamide (AZBX), and 4'-(azidomethyl)-[l,l'-biphenyl]-2-metanoic acid (AZBA).

[0032] Other azide-impurities include but are not limited to compounds of formula (II-A) to (II-C) :

[0033] The content of the azide-impurity in the composition provided in step (a) is not particularly limited. Preferably, the weight content of the azide-impurity in the composition is at most 1.0 wt.-%, preferably at most 0.1 wt.-%, more preferably at most 500 ppm, most preferably at most 100 ppm, relative to the total weight of the composition.

[0034] The composition may contain two or more different azide-impurities. Preferably, the preferred content defined above independently applies to each azide-impurity separately.

[0035] The composition provided in step (a) of the process according to the invention comprises a tetrazole- containing-sartan or an intermediate of a tetrazole-containing-sartan.

[0036] When the composition comprises a tetrazole-containing-sartan, said tetrazole-containing-sartan is preferably selected from the group consisting of valsartan, losartan, irbesartan, candesartan, candesartan cilexetil, olmesartan, olmesartan medoxomil, and any other tetrazole-containing-sartan, i.e. any other sartan containing a tetrazole group.

[0037] For the purpose of the specification, unless expressly stated otherwise, reference to tetrazole-con- taining-sartans such as valsartan, losartan, irbesartan, candesartan, candesartan cilexetil, olmesartan, olmesartan medoxomil, and any other tetrazole-containing-sartan includes the free base of said tetrazole- containing-sartans as well as their physiologically acceptable salts such as the hydrochlorides.

[0038] For the purpose of the specification, unless expressly stated otherwise, all percentages are weight percent. For the purpose of the specification, unless expressly stated otherwise, all amounts in ppm are expressed on weight basis, i.e. ppmw.

[0039] The content of the tetrazole-containing-sartan in the composition provided in step (a) is not particularly limited. Preferably, the weight content of the tetrazole-containing-sartan in the composition is at least 1.0 wt.-%, preferably at least 5.0 wt.-%, more preferably at least 10 wt.-%, still more preferably at least 25 wt. -%, yet more preferably at least 50 wt.-%, even more preferably at least 75 wt-%, most preferably at least 90 wt.-%, and in particular at least 95 wt.-%, relative to the total weight of the composition.

[0040] When the composition comprises an intermediate of a tetrazole-containing-sartan, said intermediate of a tetrazole-containing-sartan is preferably a compound of general formula (I):

wherein LG is a leaving group; preferably selected from -F, -Cl, -Br, -I, -OS(=O)2CH3, - OS(=O)2CeH4CH3; more preferably -Br.

[0041] Other intermediates of a tetrazole-containing-sartan include but are not limited to compounds of formula (LA) to (LM):

BOC = tert-butyloxycarbonyl; Tr = trityl (i.e. triphenylmethyl)

[0042] The content of the intermediate of the tetrazole-containing-sartan in the composition provided in step (a) is not particularly limited. Preferably, the weight content of the intermediate of the tetrazole-containing-sartan in the composition is at least 1.0 wt.-%, preferably at least 5.0 wt.-%, more preferably at least 10 wt.-%, still more preferably at least 25 wt.-%, yet more preferably at least 50 wt.-%, even more preferably at least 75 wt.-%, most preferably at least 90 wt.-%, and in particular at least 95 wt.-%, relative to the total weight of the composition.

[0043] Step (b) of the process according to the invention involves treating the composition provided in step (a) with a reducing agent; preferably reacting the azide-impurity with a reducing agent thereby obtaining an amine-impurity. The reducing agent is allowed to react with the azide-impurity thereby obtaining an amine- impurity (reduced azide-impurity).

[0044] Preferably, the reducing agent is selected from

- triarylphosphine, preferably triphenylphosphine (PPh₂);

- trialkylphosphine, preferably trimethylphosphine;

- HTcat. H2 without catalyst, NaH;

- Zn, SnCl₂;

- Na₂S, Na₂S₂O₆, Na₂S₂O₄, NaHSCh; and

- NaBH₄, LiAlH₄.

[0045] Preferably, the reducing agent is selected from triphenylphosphine, trimethylphosphine and H₂/cat; more preferably triphenylphosphine.

[0046] The reducing agent is preferably employed in small quantities. Preferably, the molar content of the reducing agent is at most 10 mole.-%, preferably at most 7.5 mole.-%, more preferably at most 5.0 mole.- %, still more preferably at most 2.5 mole.-%, yet more preferably at most 1.0 mole.-%, most preferably at most 0. 1 mole.-% relative to the molar content of the tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan. [0047] Preferably, the reducing agent is allowed to react with the azide-impurity at a temperature within the range from room temperature to temperature of the reflux of the solvent, preferably within the range of from 0 to 80 °C. Suitable reaction temperatures can be determined by routine tests.

[0048] Preferably, the reducing agent is allowed to react with the azide-impurity for up to 1 day, preferably for up to 5 hours. Suitable reaction times can be determined by routine tests.

[0049] Preferably, step (b) of the process according to the invention is performed in a solvent.

[0050] In preferred embodiments of the process according to the invention, step (b) comprises adding the composition provided in step (a) to a solution or suspension of the reducing agent in a solvent.

[0051] In other preferred embodiments of the process according to the invention, step (b) comprises the substeps of

(bl) dissolving the composition provided in step (a) in a solvent; preferably in an organic solvent or in a combination of an organic solvent with water; and

(b2) adding the reducing agent to the solution obtained in substep (bl); preferably in small quantities.

[0052] Preferably, the solvent is an organic solvent or comprises an organic solvent and water, preferably

- an ester (e.g. ethyl acetate, isopropyl acetate, or butyl acetate);

- an alcohol (e.g. methanol, ethanol, or isopropanol);

- a ketone (e.g. acetone or methyl ethyl ketone (MEK));

- an ether (e.g. diethyl ether, tert-butyl methyl ether, or tetrahydrofuran);

- a halogenated alkane (e.g. dichloromethane, chloroform or tetrachloromethan);

- dimethyl sulfoxide (DMSO);

- acetonitrile;

- dimethyl formamide (DMF);

- dimethyl acetamide (DMA);

- toluene, xylene

- alkanes, such as heptane, hexane, cyclohexane - water; or

- any mixture of any of the foregoing.

[0053] In preferred embodiments, particularly when the reducing agent is a triarylphosphine, preferably triphenylphosphine, or a trialkylphosphine, preferably trimethylphosphine, the solvent contains no water.

[0054] In other preferred embodiments, particularly when the reducing agent is H2/cat, the solvent is aqueous.

[0055] In preferred embodiments, the solvent is an ester; preferably an ester selected from ethyl acetate, isopropyl acetate, and butyl acetate; more preferably ethyl acetate.

[0056] In other preferred embodiments, the solvent is a ketone; preferably acetone or methyl ethyl ketone; more preferably methyl ethyl ketone.

[0057] In further preferred embodiments, the solvent is an alcohol; preferably methanol, ethanol, or isopropanol; more preferably ethanol.

[0058] In preferred embodiments, the reducing agent is H2 cat. and the solvent is ethyl acetate or aqueous ethyl acetate.

[0059] In other preferred embodiments, the reducing agent is H2 without catalyst and the solvent is ethyl acetate or aqueous ethyl acetate.

[0060] In further preferred embodiments, the reducing agent is triphenylphosphine and the solvent is ethyl acetate or aqueous ethyl acetate.

[0061] In still further preferred embodiments, the reducing agent is triphenylphosphine and the solvent is aqueous sodium hydroxide.

[0062] In yet further preferred embodiments, the reducing agent is triphenylphosphine and the solvent is methyl ethyl ketone or aqueous methyl ethyl ketone.

[0063] In other preferred embodiments, the reducing agent is triphenylphosphine and the solvent is ethanol or aqueous ethanol. [0064] Preferably, step (b) is performed in the absence of a base. Preferably, the entire process according to the invention is performed in the absence of a base. In this regard, bases that are preferably absent include but are not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide.

[0065] Preferably, the amine -impurity that is obtained by the reduction reaction of the azide-impurity selected from the group consisting of

- 5 -(4'-(aminomethyl)- [ 1 , 1 '-biphenyl] -2-yl)- 1 H-tetrazole;

- (2S,3R)-2-(N-((2'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl)pentanamido)-4-amino-3-methylbuta- noic acid;

- N-((2'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)(amino)methyl)-N-pentanoyl-L-valine;

- 2-(N-((2'-( 1 H-tetrazol-5 -yl)- [1,1 '-biphenyl]-4-yl)methyl)pentanamido)-2-amino-3 -methylbutanoic acid;

- (S)-2-(N-((2'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl)pentanamido)-3-amino-3-methylbutanoic acid;

- N-((2'-( lH-tetrazol-5-yl)-[ 1 , 1 '-biphenyl]-4-yl)methyl)-N-(5 -aminopentanoyl)-L-valine;

- N-((2'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl)-N-(4-aminopentanoyl)-L-valine;

- N-((2'-( lH-tetrazol-5-yl)-[ 1 , 1 '-biphenyl]-4-yl)methyl)-N-(3 -aminopentanoyl)-L-valine;

- N-((2'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl)-N-(2-aminopentanoyl)-L-valine;

- 3 -((2'-( 1 H-tetrazol-5 -yl) - [ 1 , 1 '-biphenyl]-4-yl)methyl)-2-(2-aminobutyl)- 1 ,3 -diazaspiro[4.4]non- 1 -en-4- one;

- 3-((2'-( lH-tetrazol-5 -yl) - [ 1 , 1 '-biphenyl]-4-yl)methyl)-2-(4-aminobutyl)- 1 ,3 -diazaspiro[4.4]non- 1 -en-4- one;

- 3-((2'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl)-7-amino-2-butyl-l,3-diazaspiro[4.4]non-l-en-4- one;

- 3-((2'-( lH-tetrazol-5 -yl) - [ 1 , 1 '-biphenyl]-4-yl)methyl)-2-(3-aminobutyl)- 1 ,3 -diazaspiro[4.4]non- 1 -en-4- one;

- 3-((2'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl)-6-amino-2-butyl-l,3-diazaspiro[4.4]non-l-en-4- one;

- 3-((2'-( lH-tetrazol-5 -yl) - [ 1 , 1 '-biphenyl]-4-yl)methyl)-2-( 1 -aminobutyl)- 1 ,3 -diazaspiro[4.4]non- 1 -en-4- one;

- 3-((2'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl)-6-amino-2-butyl-l,3-diazaspiro[4.4]non-l-en-4- one; - 3-((2'-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl)-2-amino-2-butyl-l,3-diazaspiro[4.4]nonan-4- one; and

- 3-((2'-( lH-tetrazol-5 -yl)-[ 1 , 1 '-biphenyl]-4-yl)(amino)methyl)-2 -butyl- 1 ,3 -diazaspiro[4.4]non- 1 -en-4- one; more preferably 5 -(4'-(aminomethyl)- [ 1 , 1 '-biphenyl] -2-yl)- 1 H-tetrazole.

[0066] Optional step (c) of the process according to the invention involves isolating the tetrazole-contain- ing-sartan or the intermediate of the tetrazole-containing-sartan from the composition.

[0067] Preferably, the tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan is crystallized from the reaction mixture obtained at the end of step (b), which reaction mixture preferably contains a solvent as defined above.

[0068] Isolation preferably also include work-up procedures such as extraction, washing of organic phase with aqueous phases, distillation process, and the like or any combination of any of the foregoing.

[0069] One of the preferred methods, the reaction product obtained at the end of step (b) is acidified, preferably to a pH value of below 2, preferably with aqueous HC1. Preferably, the reaction product obtained at the end of step (b) either comprises an organic phase and an aqueous phase, or it is converted into a composition comprising an organic phase and an aqueous phase, wherein in each case the organic phase is preferably separated from the aqueous phase and evaporated, preferably under reduced pressure.

[0070] For the analysis of azide-impurities suitable analytical methods can be used. Since the content of azide impurities in tetrazole-containing-sartans or intermediates of tefrazole-containing-sartans is typically at the ppm level, the detection limit of the analytical methods should be correspondingly low.

[0071] A preferred method involves HPLC and UV detection, LCMS, HPLC, GC. In this regard, reference is also made to M. Gricar et al., J Pharm Biomed Anal. 2016, 125:27-32.

[0072] Preferably, in step (c) of the process according to the invention the tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan is isolated from the composition, wherein the residual content of azide impurities is below 30% Threshold of Toxicological Concern (TTC), preferably at most 1.0 ppm, preferably at most 0.5 ppm, more preferably at most 0.1 ppm; most preferably wherein amounts of azide impurities are not detectable. [0073] Another aspect of the invention relates to a purified tetrazole-containing-sartan or a purified te- trazole-containing-sartan intermediate that is obtainable by the process for purifying a tetrazole-containing- sartan or a tetrazole-containing-sartan intermediate according to the invention as described above.

[0074] Another aspect of the invention relates to a process for the synthesis of a tetrazole-containing-sartan comprising the process for purifying a tetrazole-containing-sartan or a tetrazole-containing-sartan intermediate according to the invention as described above.

[0075] Preferably, the tetrazole-containing-sartan is selected from the group consisting of valsartan, losar- tan, irbesartan, candesartan, candesartan cilexetil, olmesartan, and olmesartan medoxomil.

[0076] Another aspect of the invention relates to a tetrazole-containing-sartan or a tetrazole-containing- sartan intermediate having a content of azide-impurity of at most 1.0 ppm, preferably not containing any detectable azide-impurity.

[0077] The following examples further illustrate the invention but are not to be construed as limiting its scope.

[0078] Examples 1 to 5 demonstrate the reduction of valsartan azide impurities:

Example 1 - Hydrogenation of valsartan azide impurities in ethyl acetate

[0079] 5.0 g of Valsartan (VS0) were dissolved in 75 ml of ethyl acetate and 0.8 ml of distilled water. Half of the solution was transferred into a hydrogenation reactor. 0.07 g Pd/C was added and inertization with nitrogen was applied. The mixture was then hydrogenated at 30 °C, 5 bar H2 for around 20 hours. The catalyst was filtered off and filtrate was evaporated at reduced pressure to give solid distillation residue (2.5 g; vsi).

Example 2 - Hydrogenation of valsartan azide impurities in alkaline water

[0080] 5.0 g of Valsartan (VS0) were dissolved in 40 ml IM NaOH. The solution was transferred into a hydrogenation reactor and 0.04 g Pd/C were added. Inertization with nitrogen was applied and hydrogenation was performed at 30 °C, 5 bar H2 for around 20 hours. The catalyst was filtered off. The pH of the filtrate was adjusted below 2 with 1 M HC1. 20 ml of ethyl acetate were added, the phases were separated and the aqueous phase was washed with 20 ml of ethyl acetate. The combined organic phases were evaporated under reduced pressure to give an oily, partially crystalline product (4.5 g; VS2).

Example 3 - Hydrogenation of valsartan azide impurities in alkaline water with no catalyst

[0081] 5.0 g of Valsartan (VS0) were dissolved in 40 ml IM NaOH. The solution was transferred into a hydrogenation reactor. Inertization with nitrogen was applied and hydrogenation was performed at 30 °C, 5 bar H2 for around 20 hours (VS1). The pH of the reaction mixture was adjusted below 2 with 1 M HC1. 20 ml of ethyl acetate were added, the phases were separated and the aqueous phase was washed with 20 ml of ethyl acetate (VS2). The combined organic phases were evaporated under reduced pressure to give an oily, partially crystalline product (4.7 g; VS3).

[0082] The content of azide-impurities was determined. The results are compiled in the table here below:

¹ Azide impurities of commercial valsartan (starting material)

* below detection limit, i.e. < 0.1 ppm

Example 4 - Reduction of valsartan azide impurities with triphenylphosphine

[0083] For evaluation of reduction efficiency, two parallel experiments were performed, a first experiment without the addition of triphenylphosphine, the second experiment with the addition of triphenylphosphine. 250 g of valsartan were dissolved in a mixture of 2.3 L ethyl acetate and 1.2 L distilled water. The pH value was adjusted with concentrated HC1 under 1.

[0084] The thus obtained mixture was then divided into 2 identical parts.

[0085] 1. Part (without PPI13): The phases were separated from one another and the organic phase was washed 4 times with diluted HC1 (5.5 ml HC1 cone. + 0.9 L distilled water). The organic phase was concentrated under reduced pressure (130 g; VS4.0).

[0086] 2. Part (with PPh;,): Inertization with nitrogen was applied. 0.7 g triphenylphosphine were added to the solution. The reaction mixture was stirred for around 15 hours at room temperature. The phases were then separated and the organic phase was washed 4 times with diluted HC1 (5.5 ml HC1 cone. + 0.9 L distilled water). The organic phase was concentrated under reduced pressure (150 g; VS4.1).

[0087] The distillation residue was suspended in 600 ml ethyl acetate and stirred until dissolved at around 35 °C. 2.7 g distilled water were added into the solution. A small amount of seed was added and the mixture was stirred for around 3 h at 30 °C. Then the suspension was gradually cooled below 10 °C and the crude product was isolated and dried (94 g; VS4.2).

[0088] The content of azide-impurities was determined. The results are compiled in the table here below:

¹ Azide impurities of commercial valsartan (starting material)

* below detection limit, i.e. < 0.1 ppm

Example 5 - Reduction of valsartan azide impurities with triphenylphosphine during distillation step

[0089] 220 g of valsartan (VS5.0) were dissolved in 2 L ethyl acetate. Inertization with nitrogen was applied. 1.4 g triphenylphosphine were added to the solution. The solution was then concentrated under vacuum at 40-45 °C for around 16 hours (VS5. 1). The distillation residue was dissolved in 1.2 L ethyl acetate at 40-45 °C. Water was partially removed with azeotropic distillation. Then the final solution (1.5 L) was gradually cooled below 10 °C (seed was added at 35 °C) and the crude product was isolated and dried (176 g; VS5.2):

¹ Azide impurities of commercial valsartan (starting material)

[0090] Examples 6 and 7 demonstrate the reduction of losartan azide impurities:

Example 6 - Reduction of losartan azide impurities with triphenylphosphine during purification step

[0091] 10.0 g of losartan (AG6.0) was dissolved in 50 ml of aqueous solution of sodium hydroxide with pH adjusting to 11.5 and spiked with 20 mg of azido impurity AZBT (AG6. 1). To this solution 124 mg of triphenylphosphine was added and heating at 100°C for 6 hours. Final purification with 0.6 g of activated charcoal, suspended in 6 ml of water was doing for 4 hours at the same temperature. [0092] The solution of losartan with activated charcoal was filtered through 300 mg randalite filter to obtain clear solution.

[0093] The purified solution was cooled to below 5 °C and diluted with 10 ml of ethyl acetate. The product was precipitated by adjusting pH to 6 with 6M hydrochloric acid at a temperature below 10°C. After adjusting pH, the stirring was continued for about two hours at 0-5°C.

[0094] The precipitated solid was collected by filtration, washed with water and dried to obtain purified losartan (6.2 g; AG6.2):

¹ Azide impurities of commercial losartan

² Azide impurities of spiked losartan with AZBT

³ Azide impurities of purified losartan

* below detection limit

Example 7 - Reduction of losartan azide impurities with triphenylphosphine during purification step

[0095] 2.0 g of losartan was dissolved in 10 ml of aqueous solution of sodium hydroxide with pH adjusting to 12 (AG7.0). To this solution 25 mg of triphenylphosphine was added and heating at 100°C for 2 hours (AG7.1):

¹ Azide impurities of commercial losartan

² Azide impurities of purified losartan

* below detection limit

[0096] Examples 8 to 10 demonstrate the reduction of irbesartan azide impurities:

Example 8 - Reduction of irbesartan azide impurities with triphenylphosphine (0,01/0,02 equivalents) during recrystallization of irbesartan hydrochloride

[0097] Triphenylphosphine was added in 2 different quantities. [0098] 6 mg of triphenylphosphine was suspended in 3 ml of methyl ethyl ketone, 0. 1 ml of concentrated hydrochloric acid and 0.3 ml of water. 1.0 g of irbesartan hydrochloride (SI8.0) was added to this mixture and stirred at reflux temperature until solution was formed. The mixture was cooled dawn to room temperature and stirred for 2 hours. Than the mixture was cooled below 0 °C. After 15 hours at this temperature, the product was isolated with filtration (0.8 g; SI8.1).

[0099] 12 mg of triphenylphosphine was suspended in 3 ml of methyl ethyl ketone, 0. 1 ml of concentrated hydrochloric acid and 0.3 ml of water. 1.0 g of irbesartan hydrochloride (SI8.0) was added to this mixture and stirred at reflux temperature until solution was formed. The mixture was cooled dawn to room temperature and stirred for 2 hours. Than the mixture was cooled below 0 °C. After 15 hours at this temperature, the product was isolated with filtration (0.8 g; SI8.2):

¹ Azide impurity of commercial irbesartan (starting material)

* below reporting level, i.e. below 30% of TTC

Example 9 - Reduction of irbesartan azide impurities with triphenylphosphine during recrystallization of irbesartan hydrochloride

[0100] For evaluation of reduction efficiency, two parallel experiments were performed, a first experiment with the addition of triphenylphosphine, the second experiment without the addition of triphenylphosphine.

[0101] For both experiments, irbesartan hydrochloride with enriched impurity AZBT was prepared:

[0102] 2.5 g of irbesartan hydrochloride and 1.4 mg of AZBT were suspended in 10 ml of methyl ethyl ketone. The mixture was stirred until homogeneous and concentrated under vacuum (SI9.0).

[0103] 11 mg of triphenylphosphine was suspended in 3 ml of methyl ethyl ketone, 0. 1 ml of concentrated hydrochloric acid and 0.3 ml of water. 1.0 g of irbesartan hydrochloride (SI9.0) was added to this mixture and stirred at reflux temperature for 30 minutes. The mixture was cooled dawn to room temperature and stirred for 2 hours. Than the mixture was cooled below 0 °C. After 15 hours at this temperature, the product was isolated with filtration (1.0 g; SI9.1). [0104] 1.0 g of irbesartan hydrochloride (SI9.0) was suspended in 3 ml of methyl ethyl ketone, 0. 1 ml of concentrated hydrochloric acid and 0.3 ml of water. This mixture was stirred at reflux temperature for 30 minutes. The mixture was cooled dawn to room temperature and stirred for 2 hours. Than the mixture was cooled below 0 °C. After 15 hours at this temperature, the product was isolated with filtration (1.0 g; SI9.2):

¹ Azide impurity of commercial irbesartan (starting material)

* below reporting level, i.e. below 30% of TTC

Example 10 - Reduction of irbesartan azide impurities with triphenylphosphine during recrystallization of irbesartan

[0105] For evaluation of reduction efficiency, two parallel experiments were performed, a first experiment with the addition of triphenylphosphine, the second experiment without the addition of triphenylphosphine.

[0106] To both experiments to the suspension of irbesartan (free base) AZBT impurity was spiked. First AZBT solution was prepared:

[0107] 5.5 mg of AZBT was put into 100 ml volumetric flask. Ethanol was added to give a final solution with a volume of 100 ml.

[0108] 5.0 g of irbesartan was suspended in the mixture of 36 ml of ethanol, 10 ml of water and 4.5 ml of AZBT solution. The mixture was heated to the reflux temperature. When solution was formed, first, a sample was taken (S10.0) and then 136 mg of triphenylphosphine was added. After 10 minutes at reflux temperature, the mixture was cooled to 15 °C and stirred for 40 minutes at this temperature. The precipitated solid was collected by filtration, washed with mixture of ethanol and water (vol. ration 1/4) and dried to obtain purified irbesartan (4.5 g; SI 10.1).

[0109] 5.0 g of irbesartan was suspended in the mixture of 36 ml of ethanol, 10 ml of water and 4.5 ml of AZBT solution. The mixture was heated to the reflux temperature. When solution was formed, a sample was taken (S10.2) and after 10 minutes at reflux temperature, the mixture was cooled to 15 °C and stirred for 40 minutes at this temperature. The precipitated solid was collected by filtration, washed with mixture of ethanol and water (vol. ration 1/4) and dried (4.5 g; SI10.3):

¹ Azide impurity of commercial irbesartan (starting material)

* below reporting level, i.e. below 30% of TTC

[0110] The experimental conditions are results of Examples 1 to 10 are additionally compiled in the table here below:

24 KRKOOIO-WO

SM starting material; REF reference experiment (no reduction step); RED with reduction step; bdl below detection limit; brl below reporting level, i.e. < 30% TTC

Claims

25 Patent claims:

1. A process for purifying a tetrazole-containing-sartan or a tetrazole-containing-sartan intermediate, the process comprising the steps of

(a) providing a composition comprising an azide-impurity together with a tetrazole-containing- sartan or with an intermediate of a tetrazole-containing-sartan;

(b) treating the composition provided in step (a) with a reducing agent; and

2. The process according to claim 1, wherein the composition provided in step (a) comprises a tetrazole- containing-sartan.

3. The process according to claim 1 or 2, wherein the composition provided in step (a) comprises a tetrazole-containing-sartan selected from the group consisting of valsartan, losartan, irbesartan, can- desartan, candesartan cilexetil, olmesartan, and olmesartan medoxomil.

4. The process according to any of the preceding claims, wherein the composition provided in step (a) comprises valsartan.

5. The process according to any of claims 1 to 3, wherein the composition provided in step (a) comprises losartan.

6. The process according to any of claims 1 to 3, wherein the composition provided in step (a) comprises irbesartan.

7. The process according to any of claims 1 to 3, wherein the composition provided in step (a) comprises candesartan or candesartan cilexetil.

8. The process according to any of claims 1 to 3 , wherein the composition provided in step (a) comprises olmesartan or olmesartan medoxomil.

9. The process according to claim 1 or 2, wherein the composition provided in step (a) comprises an intermediate of a tetrazole-containing-sartan. The process according to claims 1, 2 or 9, wherein the composition provided in step (a) comprises a compound of general formula (I):

wherein LG is a leaving group; preferably selected from -F, -Cl, -Br, -I, -OS(=O)2CH3, and -OS(=O)2CeH4CH3; more preferably -Br. The process according to any of the preceding claims, wherein the azide-impurity that is comprised in the composition provided in step (a) is selected from the group consisting of

- 5 -(4'-(azidomethyl)- [ 1 , 1 '-biphenyl] -2-yl)- 1 H-tetrazole (AZBT);

- (2S,3R)-2-(N-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)pentanamido)-4-azido-3- methylbutanoic acid;

- N -((2'-( 1 H-tefrazol-5 -yl)- [1,1 '-biphenyl] -4-yl)(azido)methyl)-N -pentanoyl-L-valine;

- 2-(N-((2'-(l H-tetrazol-5 -yl)- [ 1 , 1 '-biphenyl]-4-yl)methyl)pentanamido)-2-azido-3 -methylbutanoic acid;

- (S)-2-(N-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)pentanamido)-3-azido-3-methyl- butanoic acid;

- N -((2'-( 1 H-tefrazol-5 -yl)- [1,1 '-biphenyl] -4-yl)methyl)-N-(5 -azidopentanoy l)-L-valine;

- N-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)-N-(4-azidopentanoyl)-L-valine;

- N -((2'-( 1 H-tefrazol-5 -yl)- [1,1 '-biphenyl] -4-yl)methyl)-N-(3 -azidopentanoy l)-L-valine;

- 3-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)-2-(2-azidobutyl)-l,3-diazaspiro[4.4]non-l- en-4-one; - 3 -((2'-( lH-tetrazol-5-yl)-[ 1 , 1 '-biphenyl] -4-yl)methyl)-2-(4-azidobutyl)- 1 ,3 -diazaspiro [4.4]non- 1 - en-4-one;

- 3-((2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl)methyl)-7-azido-2-butyl-l,3-diazaspiro[4.4]non-l- en-4-one;

- 3 -((2'-( lH-tetrazol-5 -yl)-[ 1 , 1 '-biphenyl] -4-yl)methyl)-2-(3 -azidobutyl)- 1 ,3 -diazaspiro [4.4]non- 1 - en-4-one;

- 3 -((2'-( lH-tetrazol-5 -yl)-[ 1 , 1 '-biphenyl] -4-yl)methyl)-6-azido-2-butyl- 1 ,3 -diazaspiro[4.4]non- 1 - en-4-one;

- 3 -((2'-( lH-tetrazol-5-yl)-[ 1 , 1 '-biphenyl] -4-yl)methyl)-2-( 1 -azidobutyl)- 1 ,3 -diazaspiro [4.4]non- 1 - en-4-one;

- 3 -((2'-( lH-tetrazol-5-yl)-[ 1 , 1 '-biphenyl] -4-yl)methyl)-6-azido-2-butyl- 1 ,3-diazaspiro[4.4]non-l - en-4-one;

- 3 -((2'-( lH-tetrazol-5-yl)-[ 1 , 1 '-biphenyl] -4-yl)methyl)-2-azido-2-butyl- 1 ,3-diazaspiro[4.4]nonan- 4 -one; and

- 3 -((2'-( lH-tetrazol-5-yl)-[ 1 , 1 '-biphenyl] -4-yl)(azido)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 - en-4-one. The process according to any of the preceding claims, wherein the azide-impurity that is comprised in the composition provided in step (a) is 5-(4'-(azidomethyl)-[l,T-biphenyl]-2-yl)-lH-tetrazole. The process according to any of the preceding claims, wherein the reducing agent is selected from the group consisting of trialkylphosphine, triarylphosphine, F /cat. Zn, SnCb. Na2S, Na2S20e, Na₂S₂O₄, NaHSCh, NaBH₄, LiAlH₄, and NaH. The process according to any of the preceding claims, wherein the reducing agent is selected from the group consisting of triphenylphosphine, trimethylphosphine and H2/cat. The process according to any of the preceding claims, wherein the reducing agent is tri- phenylphosphine . 28 The process according to any of the preceding claims, wherein step (b) involves reacting the azide- impurity with a reducing agent thereby obtaining an amine-impurity. The process according to claim 16, wherein the amine-impurity that is obtained by the reduction reaction of the azide-impurity is 5-(4'-(aminomethyl)-[l,T-biphenyl]-2-yl)-lH-tetrazole:

The process according to any of the preceding claims, wherein the molar content of the reducing agent is at most 10 mole.-%, relative to the molar content of the tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan. The process according to any ofthe preceding claims, wherein the molar content of the reducing agent is at most 7.5 mole.-%, relative to the molar content ofthe tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan. The process according to any ofthe preceding claims, wherein the molar content of the reducing agent is at most 5.0 mole.-%, relative to the molar content ofthe tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan. The process according to any ofthe preceding claims, wherein the molar content of the reducing agent is at most 2.5 mole.-%, relative to the molar content ofthe tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan. The process according to any ofthe preceding claims, wherein the molar content of the reducing agent is at most 1.0 mole.-%, relative to the molar content ofthe tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan. 29 The process according to any of the preceding claims, wherein the molar content of the reducing agent is at most 0.1 mole.-%, relative to the molar content of the tetrazole-containing-sartan or the intermediate of the tetrazole-containing-sartan. The process according to any of the preceding claims, wherein step (b) is performed in a solvent. The process according to any of the preceding claims, wherein step (b) comprises adding the composition provided in step (a) to a solution or suspension of the reducing agent in a solvent. The process according to any of claims 1 to 24, wherein step (b) comprises the substeps of

(bl) dissolving the composition provided in step (a) in a solvent; and

(b2) adding the reducing agent to the solution obtained in substep (bl). The process according to claim 26, wherein in substep (b2) the reducing agent is added to the solution obtained in substep (bl) in quantities of at most 10 mole.-%, preferably at most 7.5 mole.-%, more preferably at most 5.0 mole.-%, still more preferably at most 2.5 mole.-%, yet more preferably at most 1.0 mole.-%, most preferably at most 0. 1 mole.-%, relative to the molar content of the tetrazole- containing-sartan or the intermediate of the tetrazole-containing-sartan. The process according to any of claims 24 to 27, wherein the solvent is an organic solvent or comprises an organic solvent and water. The process according to any of claims 24 to 28, wherein the solvent is selected from the group consisting of esters, alcohols, ketones, ethers, halogenated alkanes, dimethyl sulfoxide, acetonitrile, dimethyl formamide, dimethyl acetamide, water and any mixtures of any of the foregoing. The process according to any of claims 24 to 29, wherein the solvent is an ester; preferably an ester selected from ethyl acetate, isopropyl acetate, and butyl acetate; more preferably ethyl acetate. The process according to any of claims 24 to 29, wherein the solvent is a ketone; preferably acetone or methyl ethyl ketone; more preferably methyl ethyl ketone. The process according to any of claims 24 to 29, wherein the solvent is an alcohol; preferably methanol, ethanol, or isopropanol; more preferably ethanol. 30 The process according to any of claims 24 to 32, wherein the solvent contains no water. The process according to any of claims 24 to 32, wherein the solvent is aqueous. The process according to any of claims 24 to 34, wherein in step (b) the reducing agent is allowed to react with the azide-impurity at a temperature within the range from room temperature to temperature of the reflux of the solvent. The process according to any of the preceding claims, wherein step (b) is performed in the absence of a base; preferably wherein the entire process is performed in the absence of a base. The process according to any of the preceding claims, wherein in step (c) the tetrazole-containing- sartan or the intermediate of the tetrazole-containing-sartan is crystallized from the reaction mixture obtained at the end of step (b). The process according to any of the preceding claims, wherein step (c) includes a work-up procedure selected from the group consisting of extraction, washing of organic phase with aqueous phase, distillation, or any combination of any of the foregoing. The process according to any of the preceding claims, wherein in step (c) the reaction product obtained at the end of step (b) is acidified, preferably to a pH value of below 2, preferably with aqueous HC1. The process according to any of the preceding claims, wherein in step (c) the reaction product obtained at the end of step (b) either comprises an organic phase and an aqueous phase, or is converted into a composition comprising an organic phase and an aqueous phase, wherein in each case the organic phase is separated from the aqueous phase and evaporated, preferably under reduced pressure. The process according to any of the preceding claims, wherein in step (c) the tetrazole-containing- sartan or the intermediate of the tetrazole-containing-sartan is isolated from the composition, wherein the residual content of azide impurities is at most 1.0 ppm, preferably at most 0.5 ppm, more preferably at most 0. 1 ppm; most preferably wherein amounts of azide impurities are not detectable. 31 A purified tetrazole-containing-sartan or a purified tetrazole-containing-sartan intermediate that is obtainable by the process for purifying a tetrazole-containing-sartan or a tetrazole-containing-sartan intermediate according to any of the preceding claims. A process for the synthesis of a tetrazole-containing-sartan comprising the process for purifying a tetrazole-containing-sartan or a tetrazole-containing-sartan intermediate according to any of claims 1 to 40. The process according to claim 43, wherein the tetrazole-containing-sartan is selected from the group consisting of valsartan, losartan, irbesartan, candesartan, candesartan cilexetil, olmesartan, and olmesartan medoxomil. The process according to claim 43 or 44, wherein the tetrazole-containing-sartan is valsartan. The process according to claim 43 or 44, wherein the tetrazole-containing-sartan is losartan. The process according to claim 43 or 44, wherein the tetrazole-containing-sartan is irbesartan. The process according to claim 43 or 44, wherein the tetrazole-containing-sartan is candesartan or candesartan cilexetil. The process according to claim 43 or 44, wherein the tetrazole-containing-sartan is olmesartan or olmesartan medoxomil.