Rational Design and Synthesis of AT1R Antagonists

molecules

Review Rational Design and Synthesis of AT1R Antagonists

Nikitas Georgiou 1,†, Vasileios K. Gkalpinos 2,†, Spyridon D. Katsakos 2,†, Stamatia Vassiliou 1,*, Andreas G. Tzakos 2,3,* and Thomas Mavromoustakos 1,*

1 Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece; [email protected] 2 Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, 45110 Ioannina, Greece; [email protected] (V.K.G.); [email protected] (S.D.K.) 3 University Research Center of Ioannina (URCI), Institute of Materials Science and Computing, 45110 Ioannina, Greece * Correspondence: [email protected] (S.V.); [email protected] (A.G.T.); [email protected] (T.M.) † These authors contributed equally to this work.

Abstract: Hypertension is one of the most common diseases nowadays and is still the major cause of premature death despite of the continuous discovery of novel therapeutics. The discovery of the Renin Angiotensin System (RAS) unveiled a path to develop efﬁcient drugs to fruitfully combat hypertension. Several compounds that prevent the Angiotensin II hormone from binding and activating the AT1R, named sartans, have been developed. Herein, we report a comprehensive review of the synthetic paths followed for the development of different sartans since the discovery of the ﬁrst sartan, Losartan. Keywords: sartans; hypertension; AT1R; Angiotensin II; rational design

Citation: Georgiou, N.; Gkalpinos, V.K.; Katsakos, S.D.; Vassiliou, S.; Tzakos, A.G.; Mavromoustakos, T. Rational Design and Synthesis of 1. Introduction AT1R Antagonists. Molecules 2021, 26, Hypertension is a medical condition where the blood pressure in the arteries is ele- 2927. https://doi.org/10.3390/ vated. However, even if one does not exhibit symptoms, long-term high blood pressure is molecules26102927 the major risk factor for numerous pathologies, such as stroke or heart failure. Angiotensin II (AII) receptor blockers are a class of molecules that act in the Renin Angiotensin System Academic Editors: Brullo Chiara (RAS) through binding to the AT1 receptor (Angiotensin II receptor type 1, AT1R) and and Gyorgy M. Keseru preventing its activity. AT1R is a G-protein-coupled receptor that is responsible for AII pathophysiological actions [1]. Received: 24 March 2021 Sartans are a class of therapeutics that act in RAS through AII binding to the AT1R. Accepted: 10 May 2021 The first of this class of molecules was losartan, which was approved by the FDA in 1995, Published: 14 May 2021 and it was released to the market in April 1995. Specifically, Duncia et al. published the discovery of DuP753 (losartan), a potent, orally active nonpeptide Angiotensin II (AII) Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in receptor antagonist (see Figure1) and other derivatives. Their aim was to develop a peptide- published maps and institutional affil- mimetic molecule based on structural features of the AII peptide, which are responsible for iations. its biological activity. This is a similar approach to that followed by Cushman and Ondetti that led to the discovery of captopril [2,3]. The first, important, evidence that triggered the discovery of losartan was the fact that the C-terminal amino acids of AII are responsible for binding to the AT1R. The C-terminal tetrapeptide (AII 5–8) has a very low binding affinity to the AT1R, but at high concentration Copyright: © 2021 by the authors. displaces [125I]-AII from the receptor. The first hypothesis was that both AII and the Licensee MDPI, Basel, Switzerland. This article is an open access article lead molecules of the Takeda Pharmaceutical Company Limited (imidazole-5-acetic acid distributed under the terms and derivatives) [4], bind to the same receptor site. They hypothesized that the poor binding conditions of the Creative Commons affinity of the Takeda’s molecules was due to their small size and partial resemblance to Attribution (CC BY) license (https:// the AII. They overlapped compound 3 (Figure1) with a conformer of AII in the following creativecommons.org/licenses/by/ way: (a) the carboxylic acid group of 3 was aligned with the C-terminal carboxylic acid of 4.0/). AII; (b) the imidazole of 3 was aligned with the imidazole His6 of AII; (c) the lipophilic

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Molecules 2021, 26, 2927 2 of 18 following way: (a) the carboxylic acid group of 3 was aligned with the C-terminal carboxylic acid of AII; (b) the imidazole of 3 was aligned with the imidazole His6 of AII; (c) the n-butyllipophilic side n-butyl chainof side3 was chain pointed of 3 was into pointed an area into where an thearea Ile5 where residue’s the Ile5 aliphatic residue’s side ali- chain resides;phatic side (d) the chain benzyl resides; group (d) the was benzyl pointing grou towardp was pointing the N terminus toward the of AII. N terminus The para of position AII. ofThe the para benzyl position group of seemedthe benzyl to begroup the seemed ideal place to be to the attach ideal aplace functional to attach group a functional to enlarge thesegroup compounds to enlarge these and allow compounds them to and better allow mimic them AII.to better As AII mimic contains AII. As two AII acidic contains groups, thetwoβ -COOHacidic groups, of Asp the and β-COOH the OH of of Asp Tyr and they the introduced OH of Tyr they a second introduced acidic a functional second acidic group, namely,functional a carboxylic group, namely, acidinto a carboxylic the para acid position into the of para the phenyl position ring of the of 3phenyl. Losartans’ ring of active 3. metaboliteLosartans’ isactive EXP metabolite 3174 that isis responsibleEXP 3174 that for is the responsible mapped for antihypertensive the mapped antihyperten- activity [5,6]. siveLosartan activity [5,6]. is commercially available and it was the first orally active drug, approved by theLosartan FDA for is the commercially treatment ofavailable hypertension. and it was The the production first orally ofactive losartan drug, was approved followed by the FDA for the treatment of hypertension. The production of losartan was followed by seven other commercially available derivatives that were classified as sartans. It is of by seven other commercially available derivatives that were classified as sartans. It is of interest to note that losartan was designed and developed based solely on the solution interest to note that losartan was designed and developed based solely on the solution conformation of the peptide hormone AII which was further modified by rational design conformation of the peptide hormone AII which was further modified by rational design steps. At the time there were no crystallographic data about its structure, which had yet steps. At the time there were no crystallographic data about its structure, which had yet toto be be crystallized crystallized [[7]7] asas alsoalso of the AT1R. AT1R. Although Although numerous numerous conformations conformations have have been been publishedpublished inin differentdifferent environments environments for for AII AII [5–18] [5–18 the] theputative putative bioactive bioactive conformation conformation of ofAII AII has has been been recently recently unveiled unveiled through through its bindin its bindingg to the AT1R to the [7,10,19,20]. AT1R [7,10 In,19 this,20 article]. In this articlewe will we focus will on focus the onmajor the synthetic major synthetic routes followed routes followedto commercially to commercially available sartans available sartans(Figure (Figure 2). 2).

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FigureFigure 1. 1.Design Design effortsefforts thatthat led to the the development development of of losartan. losartan.

Figure 2. 2. StructuresStructures of of commercially commercially available available sartans. sartans.

2. Synthetic Routes of Different Sartans 2.1. Synthetic Routes of Losartan One common structural characteristic of the commercially AT1R antagonists is that they contain an acidic group such as carboxylate or tetrazole or 5-oxo-1,2,4-oxadiazole ring. Tetrazole and 5-oxo-1,2,4-oxadiazole ring groups are prepared from nitrile group and are bioisosteric. They also retain a more favorable pharmacological effect, pharmacokinetic profile and they are metabolically more stable compared to carboxylate group. The replacement of a functional group by another that modifies beneficially the pharmaceutical profile of a compound is a fundamental medicinal chemistry strategy known as isosteric or bioisosteric replacement [21–25]. It has been claimed that the substitution of the tetrazole ring in candesartan by the structurally identical 5-oxo-1,2,4-oxadiazole ring on azilsartan has led to unique pharmacological properties [26]. In an efficient and green synthetic route to losartan, Shangxia et al. [27] in the last step converted the nitrile derivative to tetrazole ring. Their synthetic methodology is devoid of hazardous chemicals like hydrogen chloride and ammonia, making the process convenient and eco-friendly (Scheme 1, [27]).

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2. Synthetic Routes of Different Sartans 2.1. Synthetic Routes of Losartan One common structural characteristic of the commercially AT1R antagonists is that they contain an acidic group such as carboxylate or tetrazole or 5-oxo-1,2,4-oxadiazole ring. Tetrazole and 5-oxo-1,2,4-oxadiazole ring groups are prepared from nitrile group and are bioisosteric. They also retain a more favorable pharmacological effect, pharmacokinetic profile and they are metabolically more stable compared to carboxylate group. The replacement of a functional group by another that modifies beneficially the pharmaceutical profile of a compound is a fundamental medicinal chemistry strategy known as isosteric or bioisosteric replacement [21–25]. It has been claimed that the substitution of the tetrazole ring in candesartan by the structurally identical 5-oxo-1,2,4-oxadiazole ring on azilsartan has led to unique pharmacological properties [26]. In an efficient and green synthetic route to losartan, Shangxia et al. [27] in the last step converted the nitrile derivative to tetrazole ring. Their synthetic methodology is devoid of MoleculesMolecules 20212021,, 2626,, xx FORFOR PEERPEER REVIEWREVIEW 44 ofof 2020 hazardous chemicals like hydrogen chloride and ammonia, making the process convenient and eco-friendly (Scheme1,[27]).

SchemeScheme 1.1. AnAnAn efficientefficient efﬁcient synthesissynthesis synthesis ofof losartan.losartan. of losartan. TheThe lastlast The ststep lastep resultedresulted step resulted inin thethe formationformation in the formation ofof thethe tetrazoletetrazole of the ringtetrazolering [27].[27]. ring [27].

InIn a a USUS US patent,patent, patent, ReddyReddy Reddy A.V.A.V. A.V. providedprovided provided thethe the samesame same conversionconversion conversion usingusing using aa similarsimilar a similar reactionreaction reac- (Schemetion(Scheme (Scheme 2,2, [28]).[28]).2,[ TheThe28]). three-stepthree-step The three-step synthesynthetic synthetictic processprocess process usesuses commerciallycommercially uses commercially availableavailable available 44′′-(bromo--(bromo- 40- methyl)-2-cyanobiphenyl(bromomethyl)-2-cyanobiphenylmethyl)-2-cyanobiphenyl ((11)) asas aa starting (starting1) as a startingmaterial.material. material. TheThe mamainin The drawbackdrawback main drawback ofof thisthis synthesissynthesis of this issynthesisis thethe useuse of isof the excessiveexcessive use of hazardousexcessivehazardous hazardous organotinorganotin organotin reagentreagent inin reagent thethe lastlast in step.step. the last step.

SchemeScheme 2.2. AA patentedpatented syntheticsynthetic routeroute ofof losartanlosartan inin whichwhich inin thethe lastlast stepstep takingtaking placeplace thethe conversionconversion ofof nitrilenitrile toto tetrazoletetrazole ringring [[28].[28].28].

2.2.2.2. SyntheticSynthetic RoutesRoutes forfor ValsartanValsartan ValsartanValsartan waswas approvedapproved fromfrom thethe FDAFDA andand releasedreleased toto thethe USUS marketmarket atat 19961996 underunder thethe namename ofof Diovan.Diovan. SimilarSimilar sysyntheticnthetic reagentsreagents areare describeddescribed byby GhoshGhosh etet al.al. whowho synthe-synthe- sizedsized valsartanvalsartan thatthat alsoalso bearsbears aa tetrazoletetrazole ringring (Scheme(Scheme 3,3, [29]).[29]). InIn hishis work,work, authorauthor de-de- scribedscribed threethree previousprevious syntheticsynthetic pathwayspathways A–A–C,C, whichwhich allall havehave thethe samesame drawback;drawback; thethe useuse ofof expensiveexpensive boronicboronic acidacid substratessubstrates andand palladiumpalladium catalystcatalyst inin thethe cross-couplingcross-coupling step.step. InIn aa refinedrefined approach,approach, inexpensiveinexpensive andand commerciallycommercially availableavailable o-anisico-anisic acidacid 1010 hashas beenbeen usedused asas thethe startingstarting material.material.

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2.2. Synthetic Routes for Valsartan Valsartan was approved from the FDA and released to the US market at 1996 under the name of Diovan. Similar synthetic reagents are described by Ghosh et al. who synthesized valsartan that also bears a tetrazole ring (Scheme3,[ 29]). In his work, author described three previous synthetic pathways A–C, which all have the same drawback; the use of expensive boronic acid substrates and palladium catalyst in the cross-coupling step. In a Molecules 2021, 26reﬁned, x FOR PEER approach, REVIEW inexpensive and commercially available o-anisic acid 10 has been used 5 of 20

as the starting material.

SchemeScheme 3. Synthesis 3. Synthesis of valsartan of valsartan through thro cyclisationugh cyclisation of nitrile of nitrile derivatives derivatives 5 and 5 17 and [29 17]. [29].

Zhang et al. (SchemeZhang4,[ et30 al.]), (Scheme Harel et 4, al. [30]), (Scheme Harel5,[ et31 al.]) (Scheme and Kankan 5, [31]) et al. and (Scheme Kankan6 , et al. (Scheme [32]) used nitrile6, derivatives [32]) used nitrile for cyclization derivatives in valsartan.for cyclization in valsartan. Zhang emphasizedZhang in emphasized the ortho-metalation in the ortho-metalation of p-bromotoluene of p-bromotoluene4 that produces 4 that aproduces a bo- boronic acid intermediateronic acid 10intermediatewhich was 10 subjected which was to palladium-catalyzed subjected to palladium-catalyzed Suzuki coupling. Suzuki coupling. ImplementationImplementation of valsartan synthesis of valsartan using synthesis Suzuki reaction using Suzu is theki mainreaction advantage is the main of this advantage of this methodology. Themethodology. saponiﬁcation The ofsaponifica the methyltion ester of the11 methyl, was realized ester 11 in, was a convenient realized in and a convenient and economical mannereconomical and it ismanner more suitable and it is for more industrial suitable production. for industrial Overall, production the synthe-. Overall, the synthesis is characterizedsis is by characterized minimum use by ofminimum expensive use and of ex hazardouspensive and metals hazardous and increased metals and increased efﬁciency (Schemeefficiency4). (Scheme 4).

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SchemeScheme 4. 4.Synthesis Synthesis of of valsartan valsartan throughthrough nitrilenitrile derivativederivative 1 [[30].30].

InIn a a patent patent byby HarelHarel andand Rukhman,Rukhman, aa syntheticsynthetic process for valsartan valsartan is is incorporated incorporated Molecules 2021, 26, x FOR PEER REVIEWwhichwhich isis substantially substantially freefree ofof itsits isoleucineisoleucine analogue.analogue. Impurities is is a a major major issue issue in in6 drugof drug 20

synthesis;synthesis; therefore, therefore, their their elimination elimination is is the the focus focus of of this this synthetic synthetic methodology methodology (Scheme (Scheme5 ). 5).

Scheme 5. Synthesis of valsartan through nitrile derivative 7 [31].

In a later patent by Kankan et al., an alternative synthesis was described (Scheme 6). The main disadvantages of this synthesis are: the use of toxic tributyl azide, the formation of explosive hydrogen azide, the oily nature of the intermediates which require repeated step of crystallization making the process laborious and time consuming for industrial scale.

SchemeScheme 5. 4.Synthesis Synthesis ofof valsartanvalsartan throughthrough nitrile derivative 1 7 [30]. [31].

In a patent by Harel and Rukhman, a synthetic process for valsartan is incorporated which is substantially free of its isoleucine analogue. Impurities is a major issue in drug synthesis; therefore, their elimination is the focus of this synthetic methodology (Scheme 5).

Scheme 5. Synthesis of valsartan through nitrile derivative 7 [31].

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In a later patent by Kankan et al., an alternative synthesis was described (Scheme6). The main disadvantages of this synthesis are: the use of toxic tributyl azide, the formation of Molecules 2021, 26, x FOR PEER REVIEWexplosive hydrogen azide, the oily nature of the intermediates which require repeated7 stepof 20 Molecules 2021, 26, x FOR PEER REVIEW 7 of 20 of crystallization making the process laborious and time consuming for industrial scale.

Scheme 6. Synthesis of valsartan through nitrile derivative 3 [32]. SchemeScheme 6. 6.Synthesis Synthesis of of valsartan valsartan through through nitrile nitrile derivative derivative 3 3 [ 32[32].].

2.3.2.3. SyntheticSynthetic RoutesRoutes ofof IrbesartanIrbesartan IrbesartanIrbesartan waswaswas approvedapprovedapproved from fromfrom the thethe FDA FDAFDA and andand released releasedreleased to toto the thethe US USUS market marketmarket at atat 1996 19961996 under underunder thethe name namename of ofof Avapro. Avapro.Avapro. A AA similar similarsimilar strategy strategystrategy was waswas used ususeded for forfor the thethe synthesis synthesissynthesis of ofof irbesartan irbesartanirbesartan (Schemes (Schemes(Schemes7 and77 andand8,[ 8,8,33 [33–35]).–[33–35]).35]). In particular,InIn particular,particular, irbesartan irbesartanirbesartan was was synthesizedwas synthesizedsynthesized through throughthrough dehydration dehydrationdehydration and tetrazole andand te-te- formationtrazoletrazole formation formation in one step in in one one from step step a substituted from from a a substituted substituted cyclopentane cyclopentane cyclopentane derivative derivative derivative6 with tributyltin 6 6 with with tributyltin tributyltin chloride andchloridechloride sodium andand azide. sodiumsodium The azide. purityazide. The ofThe the puritypurity compound ofof thethe was compoundcompound 99.85% as waswas conﬁrmed 99.85%99.85% by asas HPLC confirmedconfirmed analysis. byby MinimizationHPLCHPLC analysis.analysis. of MinimizationtheMinimization impurities ofwasof thethe the impuritiesimpurities mail focus waswas of this thethe synthetic mailmail focusfocus methodology ofof thisthis syntheticsynthetic (Scheme meth-meth-7 , [odologyodology33,34]). (Scheme(Scheme 7,7, [33,34]).[33,34]).

Scheme 7. Synthesis of irbesartan by Prasada Rao et al. through nitrile derivative 6, tributyltin SchemeScheme 7.7. Synthesis of of irbesartan irbesartan by by Prasada Prasada Ra Raoo et etal. al. through through nitrile nitrile derivative derivative 6, tributyltin6, tributyltin chloride and sodium azide in the presence of DMF [33,34]. chloridechloride andand sodium sodium azide azide in in the the presence presence of of DMF DMF [ 33[33,34].,34]. In an elegant approach, irbesartan was synthesized through a new catalytic system InIn anan elegantelegant approach, approach, irbesartan irbesartan waswas synthesized synthesized throughthrough aa new new catalytic catalytic system system basedbased on onon palladium-amido- palladium-amido-palladium-amido-NN-heterocyclicN-heterocyclic-heterocyclic carbenes carbenescarbenes for forfor Suzuki–Miyaura SuSuzuki–Miyaurazuki–Miyaura coupling couplingcoupling reactions reac-reac- oftionstions heteroaryl ofof heteroarylheteroaryl bromides. bromides.bromides. In this InIn synthetic thisthis synthesynthe method,tictic method,method, the biaryl thethe biaryl structurebiaryl structurestructure was formed waswas formedformed using ausingusing very aa low veryvery catalytic lowlow catalyticcatalytic load making loadload makingmaking the procedure thethe procedureprocedure industrial industrialindustrial friendly. friendly.friendly. Thus, Thus,Thus, the use thethe ofuseuse the ofof industry-advantageousthethe industry-advantageousindustry-advantageous Suzuki SuzukiSuzuki reaction reactionreaction is theisis thethe hallmark hallmarkhallmark of ofof this thisthis synthetic syntheticsynthetic methodology methodologymethodology (Scheme(Scheme(Scheme8 8,,[8, 35 [35]).[35]).]).

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SchemeScheme 8.8.8. SynthesisSynthesis ofof irbesartanirbesartan throughthrough nitrilenitrilenitrile derivativederivativederivative 6 66 by byby Kumar, Kumar,Kumar, A.S A.SA.S et etet al. al.al. [ [35].35[35].].

2.4.2.4. SyntheticSynthetic RoutesRoutes ofof AzilsartanAzilsartan AzilsartanAzilsartan waswas approvedapproved fromfromfrom thethethe FDAFDAFDA andandand releasedrereleasedleased to toto the thethe US USUS market marketmarket at atat 2011 20112011 under underunder thethethe namenamename ofofof Edarbi.Edarbi.Edarbi. Nitriles Nitriles areare alsoalso usefulusefuluseful forforfor thethethe synthesissynthesissynthesis ofofof 1,2,4-oxadiazol1,2,4-oxadiazol1,2,4-oxadiazol ringringring ofofof azilsartanazilsartan (Schemes (Schemes(Schemes9 9 9and andand 10 10,10,,[ [36,37]).[36,37]).36,37]). TheThe methodmethod describeddescribed ininin SchemeSchemeScheme 10 10,10,,[ [36][36]36] isisis superiorsuperior tototo previouspreviousprevious publishedpublishedpublished (Scheme(Scheme(Scheme9 9,,[9, [37])[37])37]) becausebecausebecause ititit isisis veryveryvery efﬁcientefficientefficient (90%(90%(90% yield)yield)yield) andandand doesdoesdoes controlcontrol thethethe impuritiesimpuritiesimpurities (99.93%(9(99.93%9.93% HPLCHPLCHPLC purity). purity).purity). ItItIt mustmustmust bebebe pointedpointedpointed outout thatthat impuritiesimpurities inin thethe synthesissynthesis of of AT1R AT1R antagonistsantagonists isis anan im-im- portantportantportant issue. issue.issue. It ItIt is isis sufﬁce sufficesuffice to toto say saysay that thatthat recently recentlyrecently Princeton PrincetonPrinceton Pharmaceuticals PharmaceuticalsPharmaceuticals recalled recalledrecalled numerous numer-numer- irbesartanousous irbesartanirbesartan tablets tabletstablets and sevenandand sevenseven lots of lotslots irbesartan ofof irirbesartanbesartan hydrochlorothiazide hydrochlorothihydrochlorothiazideazide (HCTZ) (HCTZ)(HCTZ) because becausebecause after testingafterafter testingtesting revealed revealedrevealed the drugs thethe drugsdrugs contained containedcontained trace amountstracetrace amountsamounts of a carcinogen ofof aa carcinogencarcinogen [38,39 [38,39].].[38,39].

SchemeScheme 9. 9. SynthesisSynthesisSynthesis ofof azilsartan.azilsartan. of azilsartan. TheThe nitrilenitrile The derivative nitrilederivative derivative 11 isis cyclizedcyclized1 is toto cyclized finalfinal productproduct to ﬁnal 55 (azilsartan)(azilsartan) product 5 [37]. (azilsartan)[37]. [37].

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SchemeScheme 10.10.Synthesis Synthesis ofof azilsartan.azilsartan.Improved Improved synthesis synthesis of of the the nitrile nitrile derivative derivative1 1is is cyclized cyclized to to ﬁnal Scheme 10. Synthesis of azilsartan. Improved synthesis of the nitrile derivative 1 is cyclized to final product 5 (azilsartan) [36]. product 5 (azilsartan)final [product36]. 5 (azilsartan) [36]. 2.5. Synthetic Routes of Telmisartan 2.5. Synthetic Routes2.5. Synthetic of Telmisartan Routes of Telmisartan Telmisartan was approved from the FDA at 1998 and released to the US market at Telmisartan wasTelmisartan approved was from approved the FDA from at 1998 the and FDA released at 1998 to and the released US market to the at US market at 2000 under the name of Micardis. Telmisartan is assembled by two benzimidazole subu- 2000 under the name2000 under of Micardis. the name Telmisartan of Micardis. is assembled Telmisartan by twois assembled benzimidazole by two subunits benzimidazole subunits and a biphenyl-2-carboxylic acid segment. A nitrile group can also be used to produce and a biphenyl-2-carboxylicnits and a biphenyl-2-carboxylic acid segment. A nitrile acid groupsegment. can A also nitrile be usedgroup to can produce also be the used to produce the carboxylate group of telmisartan through hydrolysis. The benzimidazole moiety can carboxylate groupthe carboxylate of telmisartan group through of telmisartan hydrolysis. throug Theh benzimidazole hydrolysis. The moiety benzimidazole can be moiety can be created through an improved, copper-catalyzed, cyclisation of o-haloarylamidines ob- created throughbe an created improved, through copper-catalyzed, an improved, cyclisation copper-catalyzed, of o-haloarylamidines cyclisation of obtainedo-haloarylamidines obtained from o-haloarylamines. The total synthesis started from the commercially available from o-haloarylamines.tained from The o-haloarylamines. total synthesis startedThe total from synthesis the commercially started from the available commercially 4- available Nitro-4-Nitro-m-toluicm-toluic acid4-Nitro- acid and andm it-toluic wasit was achieved acid achieved and init inwas seven seven achieved steps steps with inwith seven an an overall overallsteps with yield yield an of of overall 54%. 54%. The Theyield of 54%. The advantageadvantage of of this thisadvantage synthesis, synthesis, of relatively thisrelatively synthesis, to to the th relatively previouse previous reported,to reported, the previous is theis the absencereported, absence of is theof the the use absence use of of the use of possibly harmful HNO3/H2SO4 for nitration and polyphosphoric acid (PPA) for cyclisa- possibly harmfulof HNO possibly3/H harmful2SO4 for HNO nitration3/H2 andSO4 polyphosphoricfor nitration and acid polyphosph (PPA) fororic cyclisation acid (PPA) for cyclisa- (Schemetion (Scheme 11,[40 11,]).tion [40]). (Scheme 11, [40]).

Scheme 11. SynthesisScheme of telmisartan11.Scheme Synthesis 11. by of SynthesisZhang, telmisartan J et of al. telmisartanby The Zhang, nitrile J by etderivative al. Zhang, The nitrile J7 et in al. thederivative The last nitrile step 7 isin derivative convertedthe last step7 toin iscarboxylate theconverted last step to iscarboxylate analog 8 [40]. analog 8 [40].converted to carboxylate analog 8 [40].

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TelmisartanTelmisartan has has also also been been prepared prepared through through different different methodologies methodologies where where the the dimer di- benzimidazolemer benzimidazole rings rings are incorporated are incorporated (Schemes (Schemes 12–16 12–16,,[14,41 [14,41–44]).–44]). TheThe originaloriginal synthesissynthesis ofof telmisartantelmisartan was was developeddeveloped by by Ries Ries et et al. al. inin 19931993 ((SchemeScheme 1212,, [[14]),14]), beginningbeginning with the stepwise stepwise construction construction of of the the central central benzimidazole benzimidazole ring ring from from 4- 4-amino-amino-mm-toluic-toluic acid acid methyl methyl ester ester 1. Saponification1. Saponiﬁcation of the of theresu resultinglting substituted substituted benzimid- benz- imidazoleazole 2 was2 wasfollowed followed by condensation by condensation with withN-methyl-1,2-phenylenediamineN-methyl-1,2-phenylenediamine using using poly- polyphosphoricphosphoric acid acid at elevated at elevated temperature temperature (150 (150 °C) ◦toC) afford to afford the thefunctionalized functionalized dibenzim- diben- zimidazoleidazole 3. Alkylation3. Alkylation of the of thelatter latter with with 4′-(bromomethyl)-2-biphenylcarboxylic 40-(bromomethyl)-2-biphenylcarboxylic acid acidtert- tert-butylbutyl ester ester 4 followed4 followed by byhydrolysis hydrolysis of of the the resulting resulting ester ester provided provided telmisartan inin 21%21% overalloverall yieldyield overover eighteight linearlinear steps.steps. AlbeitAlbeit thethe relativelyrelatively lowlow overalloverall yield,yield, thethe syntheticsynthetic methodologymethodology isis attractiveattractive becausebecause ofof thethe reactions’reactions’ simplicitysimplicity andand thethe availabilityavailability ofof thethe cheapcheap reagents.reagents.

SchemeScheme 12.12. FirstFirst reportedreported synthesissynthesis ofof telmisartantelmisartan byby UweUwe J.J. RiesRies etet al.al. [ 14[14].].

GoossenGoossen etet al.al. (Scheme(Scheme 1313,,[ [4411])]) introducedintroduced thethe biarylbiaryl moietymoiety ofof telmisartantelmisartan usingusing aa Pd/CuPd/Cu decarboxylative catalyst catalyst system. system. Construc Constructiontion of of the the biaryl biaryl moiety moiety with with the the aid aid of ofa powerful a powerful tool tool like like decarboxylative decarboxylative coupling coupling instead instead of using of using appropriate appropriate reagents reagents con- containingtaining it is it the isthe characteristic characteristic of this of this synthetic synthetic pathway. pathway.

SchemeScheme 13. 13. SynthesisSynthesis of telmisartan of telmisartan by Lukas by J. Lukas Goossen J. et Goossen al. via decarboxylative et al. via decarboxylative cross-coupling cross-coupling[41]. [41].

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InInIn thethethe methodmethodmethod reportedreportedreported bybyby KumarKumarKumar etetet al.al.al. (Scheme(Scheme 1414,14,,[ [44]),[44]),44]), thethethe biarylbiarylbiaryl moietymoietymoiety ofofof telmisartantelmisartantelmisartan was waswas elaborated elaboratedelaborated by byby the thethe directed directeddirected metalation memetalationtalation of ofof an anan appropriate appropriateappropriate carboxy carboxycarboxy protecting protect-protect- group followed by transmetalation with zinc chloride and then transition metal catalyzed inging groupgroup followedfollowed byby transmetalationtransmetalation withwith zinczinc chloridechloride andand thenthen transitiontransition metalmetal cata-cata- cross coupling with aryl bromides. Construction of the biaryl moiety is again the hallmark lyzedlyzed crosscross couplingcoupling withwith arylaryl bromides.bromides. ConstrConstructionuction ofof thethe biarylbiaryl moietymoiety isis againagain thethe of this synthesis. hallmarkhallmark ofof thisthis synthesis.synthesis.

SchemeScheme 14.14.14. AA modiﬁedmodifiedmodified synthesissynthesis ofofof telmisartantelmisartantelmisartan bybyby A. A.A. Sanjeev SanjeevSanjeev Kumar KumarKumar et etet al. al.al. [ [44].[44].44]. The key strategy in the synthesis reported by Wang et al. (Scheme 15,[42]) was the TheThe keykey strategystrategy inin thethe synthesissynthesis reportedreported byby WangWang etet al.al. (Sch(Schemeeme 15,15, [42])[42]) waswas thethe construction of bis-benzimidazole 7 by reductive cyclization of o-nitroaniline 6 with butyl constructionconstruction ofof bis-benzimidazolebis-benzimidazole 77 byby reductivereductive cyclizationcyclization ofof oo-nitroaniline-nitroaniline 66 withwith butylbutyl aldehyde. The overall process is operational simple, with low production cost. aldehyde.aldehyde. TheThe overalloverall processprocess isis operatiooperationalnal simple,simple, withwith lowlow productionproduction cost.cost.

Scheme 15. A highly practical and cost-effective synthesis of telmisartan by Ping Wang et al. [42]. Scheme 15.15. A highly practical and cost-effective synthesissynthesis ofof telmisartantelmisartan byby PingPing WangWang etet al.al. [[42].42].

InInIn thethethe synthesissynthesissynthesis reportedreportedreported bybyby MartinMartinMartin etetet al.al.al. (Scheme(Scheme 1616,16,,[ [43]),[43]),43]), twotwo differentiallydifferentially substi-substi- tutedtutedtuted benzimidazolebenzimidazolebenzimidazole derivatives derivativesderivatives and andand a biphenyl-2-carboxylicaa biphenyl-2-carboxylicbiphenyl-2-carboxylic acid acidacid synthon synthonsynthon were werewere assembled assem-assem- viabledbled a via Suzukivia aa SuzukiSuzuki cross-coupling cross-couplingcross-coupling reaction, reaction,reaction, providing providingproviding telmisartan telmisartantelmisartan in 72% inin overall 72%72% overalloverall yield. Highyield.yield. overallHighHigh overalloverall yielding yieldingyielding synthetic syntheticsynthetic methodology methodmethodology makesology makesmakes this procedure thisthis procedureprocedure attractive. attractive.attractive.

2.6. Synthetic Routes of Eprosartan Eprosartan was approved from the FDA at 2001 and released to the US market at 2003 under the name of Teveten. Eprosartan is one of the AT1R antagonists that does not contain a biphenyl tetrazole ring. It contains two heterocycles, the imidazole and the unique thiophene. Below are reported synthetic routes used to develop it (Schemes 17–20,[45–49]). The process described by Ramakrishnan et al. (Scheme 18,[46]) comprises condensation of valerimidine methyl ester with dihydroxyacetone to give a diacetate which was treated with α-carboxymethylbenzyl alcohol in the presence of triﬂic acid to give 2-n-butyl- 5-acetoxymethyll-(4-carboxyphenyl)-methyl-lH-imidazole. Thus obtained compound on further oxidization with manganese dioxide and thereafter condensation with methyl-3-(3-

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(2-theinyl)-propionate in the presence of n-butyl lithium at −78 ◦C gives an ester which is hydrolyzed to give eprosartan. Eprosartan is further converted to its desired salt form. Eprosartan synthesis was reported by Matsuoka et al. to proceed in three stages (Scheme 19,[45]). These stages are: the regioselective protection of 2-n-butyl-4- formylimidazole 1, followed by reaction with (2-thienyimethyl)-propanedioic acid, mono- alkyl ester and 4-(bromomethyl)benzoate. The efﬁciency of this synthetic sequence and the quality and yield of eprosartan are particularly important. The synthesis reported by Weinstock et al. starts with alkylation of 4-chloro-5-formyl- Molecules 2021, 26, x FOR PEER REVIEW2-butylimidazole 1 with p-carbomethoxybenzylbromide 2 to give eprosartan in three12 stepsof 20 (Scheme 20,[47,48]).

2.7. Synthetic Routes of Olmesartan Medoxomil & Candesartan Cilexetil Olmesartan and candesartan are given as pro-drugs olmesartan medoxomil and candesartan cilexetil. Olmesartan was approved from the FDA and released to the US market at 2002 under the name of Benicar while candesartan was approved at 1998 and Molecules 2021, 26, x FOR PEER REVIEWreleased to the US market at 1999 under the name of Atacand. Synthetic routes are provided12 of 20

in the following schemes (Schemes 21–24,[50–53]).

Scheme 16. Total synthesis of telmisartan by Alex D. Martin et al. via a Suzuki cross-coupling reaction between two functionalized benzimidazoles [43].

contain a biphenyl tetrazole ring. It contains two heterocycles, the imidazole and the SchemeuniqueScheme thiophene. 16.16. Total synthesis synthesis Below ofare of telmisartan telmisartanreported syntheticby by Alex Alex D. D.routes Martin Martin used et etal. al.tovia develop viaa Suzuki a Suzuki it cross-coupling (Schemes cross-coupling 17–20, re- reaction[45–49]).action between between two two functional functionalizedized benzimidazoles benzimidazoles [43]. [43].

Scheme 17. Synthesis of eprosartan by Finkelstein et al. [[49].49].

The process described by Ramakrishnan et al. (Scheme 18, [46]) comprises condensation of valerimidine methyl ester with dihydroxyacetone to give a diacetate which was treated with α-carboxymethylbenzyl alcohol in the presence of triflic acid to give 2-n-butyl-5-acetoxymethyll-(4-carboxyphenyl)-methyl-lH-imidazole. Thus obtained compound on further oxidization with manganese dioxide and thereafter condensation with methyl- 3-(3-(2-theinyl)-propionateScheme 17. Synthesis of eprosartan in the by presence Finkelstein of et n-butyl al. [49]. lithium at −78 °C gives an ester which is hydrolyzed to give eprosartan. Eprosartan is further converted to its desired salt form.The process described by Ramakrishnan et al. (Scheme 18, [46]) comprises condensation of valerimidine methyl ester with dihydroxyacetone to give a diacetate which was treated with α-carboxymethylbenzyl alcohol in the presence of triflic acid to give 2-n-butyl-5-acetoxymethyll-(4-carboxyphenyl)-methyl-lH-imidazole. Thus obtained compound on further oxidization with manganese dioxide and thereafter condensation with methyl- 3-(3-(2-theinyl)-propionate in the presence of n-butyl lithium at −78 °C gives an ester which is hydrolyzed to give eprosartan. Eprosartan is further converted to its desired salt form.

Molecules 2021, 26, x FOR PEER REVIEW 13 of 20

OH N O O N n-Bu H2N n-Bu 1) NH3 O O HO + 2) Ac O + OH NH 2 O O Molecules 2021, 26, x FOR PEER REVIEW 1 2 3 4 13 of 20 Molecules 2021, 26, 2927 12 of 18 TEA, (CF3CO2)2O, CH2Cl2, DIPEA, Trifluoroacetic anhydride OH N N O F C N O O H 3 O N n-Bu H2N N n-Bun-Bu1) NH3 O n-BuO O HO O N + O 2) Ac O + S OH NH 2 O O 1) NaOH, CH3OH, 1 4 1) ,LDA,THF 2 O H2O 3 O 2) Ac O, DMAP 2) MnO , toluene, 2 OH 2 O CH2Cl2 TEA, (CF3CO2)2O, CH Cl , DIPEA, 6 2 2 Trifluoroacetic5 anhydride

N F C N S O H S 3 O n-Bu O O N N HO N N n-Bu O O S n-Bu n-Bu O N 1)O NaOH, CH NOH, O 1) DBU 3 1) ,LDA,THFO O H2O O 2) NaOH 2) Ac O, DMAP 2) MnO , toluene, 2 O OH 2 O O CH2Cl2 OH 6 OH 5 7 8 eprosartan S S SchemeO 18.N Synthesis of eprosartanHO byN Ramakrishnan et al. [46]. n-Bu n-Bu O N O N O 1) DBU O Eprosartan synthesis2) NaOH was reported by Matsuoka et al. to proceed in three stages O O

(Scheme 19, [45]).OH These stages are: theOH regioselective protection of 2-n-butyl-4-formylimidazole 17 , followed by reaction with8 (2-thienyimethyl)-propanedioiceprosartan acid, mono-alkyl ester and 4-(bromomethyl)benzoate. The efficiency of this synthetic sequence and the qual- SchemeScheme 18. 18.Synthesis Synthesis of of eprosartan eprosartan by by Ramakrishnan Ramakrishnan et al. et [46al.]. [46]. ity and yield of eprosartan are particularly important. Eprosartan synthesis was reported by Matsuoka et al. to proceed in three stages (Scheme 19, [45]). These stages are: the regioselective protection of 2-n-butyl-4-formylimidazole 1, followed by reaction with (2-thienyimethyl)-propanedioic acid, mono-alkyl ester and 4-(bromomethyl)benzoate. The efficiency of this synthetic sequence and the quality and yield of eprosartan are particularly important.

SchemeScheme 19. 19.Synthesis Synthesis of eprosartan of eprosartan by Matsuoka by Matsuoka et al. [ 45et]. al. [45].

CandesartanThe synthesis was reported synthesized by Weinstock using an efficient et al. starts protocol with alkylation for C–H arylation of 4-chloro-5-formyl- by a catalytic system involving [RuCl (p-cymene)] and triphenylphosphine (Scheme 21,[50]). 2-butylimidazole 1 with p-carbomethoxybenzylbromide2 2 2 to give eprosartan in three steps By careful monitoring of the reaction conditions, Babu et al., described an olmesartan medoxomilScheme(Scheme 19. 20, synthesis,Synthesis [47,48]) of where eprosartan impurities by Matsuoka were minimized et al. [45]. (Scheme 22,[51]). Venkanna et al. identified the impurities resulting from the olmesartan medoxomil syntheticThe processsynthesis (Scheme reported 23,[ by52 ]).Weinstock et al. starts with alkylation of 4-chloro-5-formyl- 2-butylimidazoleIn a patent filled 1 with by Toplak p-carbomethoxybenzylbromide Casar [53], two variations of 2 anto give one-pot eprosartan trityl olmesartan in three steps medoxomil(Scheme 20, synthesis [47,48]) have been described (Schemes 24 and 25). In this methodology, the intermediates are not isolated in each step and by using the same solvent and the same base, no material is removed or exchanged. This feature renders this methodology particularly attractive.

Molecules 2021, 26, x FOR PEER REVIEW 14 of 20 Molecules 2021, 26, 2927 13 of 18

Molecules 2021, 26, x FOR PEER REVIEW 15 of 20

SchemeScheme 20. 20.Synthesis Synthesis of eprosartanof eprosartan by Weinstock by Weinstock et al. [ 47et ,48al.]. [47,48].

2.7. Synthetic Routes of Olmesartan Medoxomil & Candesartan Cilexetil Olmesartan and candesartan are given as pro-drugs olmesartan medoxomil and candesartan cilexetil. Olmesartan was approved from the FDA and released to the US market at 2002 under the name of Benicar while candesartan was approved at 1998 and released to the US market at 1999 under the name of Atacand. Synthetic routes are provided in the following schemes (Schemes 21–24, [50–53]). Candesartan was synthesized using an efficient protocol for C–H arylation by a catalytic system involving [RuCl2(p-cymene)]2 and triphenylphosphine (Scheme 21, [50]).

SchemeScheme 21. 21.A A practical practical synthesis synthesis of of prodrug prodrug candesartan candesartan cilexitil cilexitil by Masahiko by Masahiko Seki etSeki al. et [50 al.]. [50].

By careful monitoring of the reaction conditions, Babu et al., described an olmesartan medoxomil synthesis, where impurities were minimized (Scheme 22, [51]).

Molecules 2021, 26, x FOR PEER REVIEW 16 of 20

Molecules 2021, 26, x FOR PEER REVIEW 16 of 20 Molecules 2021, 26, 2927 14 of 18

Scheme 22. Synthesis of the prodrug olmesartan medoxomil by Babu et al. [51].

SchemeSchemeVenkanna 22. 22.Synthesis Synthesis et al. of of identified the the prodrug prodrug the olmesartan olmesartan impurities medoxomil medoxomil resulting by by from Babu Babu the et et al. al.olmesartan [51 [51].]. medoxomil synthetic process (Scheme 23, [52]). Venkanna et al. identified the impurities resulting from the olmesartan medoxomil HO HO synthetic process (Scheme 23, [52]). N N O HO Br N N OHO OHO HO N N O HO N Br N K2CO3 N KOH N O N N + N O O N Acetone N IPA, H2O N OHO H N N Tr N N N N Tr Tr 12N 3 O N K2CO3 KOH 4 + N N N Acetone IPA, H O N N 2 O N O H N N Tr N N N N Tr Tr OO K2CO3 12 3 4Acetone Cl O

K CO HO OOHO 2 3 O O Acetone O O N Cl N O O O O N N HO HO O O O O O Formic acid O N N O O O O N N O N O N N Formic acid N N NH N N Tr 6 olmesartan medoxomil 5 N N N N N NH N N SchemeScheme 23.23. SynthesisSynthesis ofof thethe prodrugprodrug olmesartanolmesartan medoxomilmedoxomil byby VenkannaVenkanna et et al. al.Tr [ 52[52].]. 6 olmesartan medoxomil 5 SchemeIn a 23. patent Synthesis filled of by the Toplak prodrug Casar olmesartan [53], two medoxomil variations by Venkannaof an one-pot et al. trityl[52]. olmesartan medoxomil synthesis have been described (Schemes 24 and 25). In this methodology, the intermediatesIn a patent are filled not isolatedby Toplak in Casareach step[53], andtwo byvariations using the of samean one-pot solvent trityl and olmesartan the same medoxomil synthesis have been described (Schemes 24 and 25). In this methodology, the intermediates are not isolated in each step and by using the same solvent and the same

Molecules 2021, 26, x FOR PEER REVIEW 17 of 20 Molecules 2021, 26, x FOR PEER REVIEW 17 of 20

Molecules 2021, 26, 2927 base, no material is removed or exchanged. This feature renders this methodology 15partic- of 18 ularlybase, no attractive. material is removed or exchanged. This feature renders this methodology particularly attractive. HO HO HO HO N N O Na+ -O Br N N O N Na+ -O N O O Br N N HO O O HO N O N K2CO3 N NaOH N N + N O N N MeCN N DMA N O H N N K2CO3 N N NaOH N N + N CPh N N N 3 MeCN N CPh3 DMA N CPh3 O H N N N N CPh N N 1 2 3 3 CPh3 4 CPh3 3 4 1 2 O O OO K2CO3,DMA, EtOAc, NaCl(aq) OO K2CO3,DMA, Cl EtOAc, NaCl(aq) Cl HO HO O O O HO O HO O N O N O O O O O O N N O O N O O N O O N N O O

N 1) NaOH(aq) N N 2) HCl, EtOAc N N 1) NaOH(aq) N N NH N N N 2) HCl, EtOAc N CPh3 NH N 6 olmesartan medoxomilN N CPh3 5 6 olmesartan medoxomil 5 SchemeScheme 24.24. FirstFirst variationvariation ofof one-potone-pot synthesissynthesis ofof thethe prodrugprodrug olmesartanolmesartan medoxomilmedoxomil [[53].53]. Scheme 24. First variation of one-pot synthesis of the prodrug olmesartan medoxomil [53].

Scheme 25. Second variation of one-pot synthesis of the prodrug olmesartan medoxomil [53]. SchemeScheme 25.25.Second Second variationvariation ofof one-potone-pot synthesissynthesis ofofthe the prodrug prodrug olmesartan olmesartan medoxomil medoxomil [ 53[53].]. 3. Conclusions 3. Conclusions 3. ConclusionsThe development of sartan AT1R antagonists have shaped the basis to compact hypertension.TheThe developmentdevelopment Intriguingly, of their sartan sartan rational AT1R AT1R design antagonists antagonists has been have have ba shapedsed shaped on pharmacophore the the basis basis to compact to compact mimicry hy- hypertension.topertension. the C-terminus Intriguingly, Intriguingly, of a low their their energy rational rational conforme design design hasr has of been beenthe natural ba basedsed on hormone pharmacophore AII. Structurally mimicrymimicry totheseto the the C-terminusmolecules C-terminus contain of of a lowa lowa energyheterocycle, energy conformer conforme an alkyl ofr the chain,of naturalthe and natural hormonethe majorityhormone AII. of Structurally AII. them Structurally constitute these moleculesathese biphenyl molecules containtetrazole contain a segment heterocycle, a heterocycle, or an an acidic alkyl an group.alkyl chain, chain, Heterocycles and and the majoritythe majoritysuch as of tetrazole themof them constitute andconstitute 1,2,4- a biphenyloxadiazola biphenyl tetrazole ring tetrazole are derived segment segment from or or an nitrilean acidic acidic derivati group. group.ves. Heterocycles Heterocycles The reagents such such for as theiras tetrazole tetrazole preparations andand 1,2,4-1,2,4- are oxadiazoldescribedoxadiazol ringinring the are total derived synthesis from from ofnitrile nitrile sartans derivati derivatives. containingves. The The these reagents reagents rings. for The for their theircarboxylate preparations preparations group are areofdescribed telmisartan described in the in is thetotal also total synthesis derived synthesis offrom sartans of a sartans nitrile containing containingderivative. these these rings.Moreover, rings. The carboxylatecandesartan The carboxylate group and groupolmesartanof telmisartan of telmisartan are isprovided also is derived also as derivedprodrugs, from froma nitrilethus a nitrile in derivative. the derivative. form ofMoreover, candesartan Moreover, candesartan candesartancilexitil andand andolmesartanolmesartan olmesartan medoxomilare areprovided provided and as their asprodrugs, prodrugs,synthetic thus routes thus in in arethe the provided.form form of candesartancandesartan cilexitilcilexitil andand olmesartanolmesartan medoxomilmedoxomil andand theirtheir synthetic synthetic routes routes are are provided. provided. Another issue described in the total synthesis of sartans is the elimination of impurities. Novel strategies have been invented to eliminate the impurity content that can be

Molecules 2021, 26, 2927 16 of 18

detrimental to the human health. Purer, safer and efﬁcient synthesis with lesser steps will be continuing to be a constant challenge for synthetic chemists. This will suppress the recall of danger lots by the pharmaceutical companies to protect human health. The synthetic strategy of sartans basically involves two critical synthetic steps: (a) coupling of aromatic derivatives with heterocyclic segments and (b) conversion of nitrile group to an acidic bioisosteric one. The synthetic effort as it is already pointed out is targeting towards the reduction of the original synthetic steps to restrain impurities and enhance reaction yields. There is no doubt that synthetic strategies described herein and involved in the synthesis of sartans could be adapted and re-purposed for other drug molecules possessing common heterocycles.

Funding: This research received no external funding. Data Availability Statement: All data, belongs to this work, is given and presented herein. Acknowledgments: The research work was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 991 to AGT). Conﬂicts of Interest: The authors declare no conﬂict of interest.

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