Recent Advances in the Synthesis of Ibuprofen and Naproxen

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Review Recent Advances in the Synthesis of Ibuprofen and Naproxen

Min-Woo Ha 1,2 and Seung-Mann Paek 3,*

1 Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University, 102 Jejudaehak-ro, Jeju 63243, Jeju-do, Korea; [email protected] 2 Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, 102 Jejudaehak-ro, Jeju 63243, Jeju-do, Korea 3 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju 52828, Gyeongnam-do, Korea * Correspondence: [email protected]; Tel.: +82-55-772-2424

Abstract: Herein, we review the recent progress in the synthesis of representative nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen and naproxen. Although these drugs were discovered over 50 years ago, novel practical and asymmetric approaches are still being developed for their synthesis. In addition, this endeavor has enabled access to more potent and selective derivatives from the key frameworks of ibuprofen and naproxen. The development of a synthetic route to ibuprofen and naproxen over the last 10 years is summarized, including developing methodologies, finding novel synthetic routes, and applying continuous-flow chemistry.

Keywords: NSAIDs; ibuprofen; naproxen; synthesis

1. Introduction Inflammation is a natural defense response of the immune system to non-self-recognition Citation: Ha, M.-W.; Paek, S.-M. or unusual self-abnormality [1]. Although this crucial process protects our body from Recent Advances in the Synthesis of unusual disorders, it sometimes causes unwanted physical symptoms such as pain and Ibuprofen and Naproxen. Molecules heat. In this regard, a therapeutic method for blocking uncontrolled inflammation has 2021, 26, 4792. https://doi.org/ been studied [2]. Steroids are the most powerful anti-inflammatory medicines used for 10.3390/molecules26164792 this purpose [3]. However, steroidal therapy for anti-inflammation causes additional side effects such as anabolism, sexual dysfunction, and problematic mineral absorption [4,5]. Academic Editor: Michael John Plater Since steroids are sensitive to hormones in various organs, non-steroidal therapy has also been pursued. Acetylsalicylic acid (ASA), known as aspirin, has been used for this purpose, Received: 11 July 2021 although its exact mechanism was only uncovered almost 70 years after its first discovery Accepted: 4 August 2021 Published: 7 August 2021 in 1897 [6]. ASA exerts its effects through the formation of a covalent bond between an acetyl

Publisher’s Note: MDPI stays neutral group in ASA and a serine residue in the active site of the cyclooxygenase enzyme with regard to jurisdictional claims in (COX). This irreversible bond formation inhibits the activity of COX in the production of published maps and institutional affil- prostaglandin, which is pivotal in inflammation processes [7]. However, this irreversible in- iations. hibition of target proteins causes severe side effects such as gastrointestinal ulceration [8,9] and bleeding [10]. Since COX2 was reported in 1991 [11], numerous studies have been performed to realize more selective and potent medicines. Currently, many medicines are available in this class. These are nonsteroidal anti-inflammatory drugs (NSAIDs) as shown in Figure1[12,13]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. As NSAIDs prevail as pain relievers, they have become highly popular drugs in the This article is an open access article pharmaceutical market. Their large market has forced the pharmaceutical community distributed under the terms and to discover advanced synthesis routes for NSAID skeletons [14–16]. From a structural conditions of the Creative Commons viewpoint, NSAIDs skeletons are usually classified as being an aromatic acetic acid or Attribution (CC BY) license (https:// propionic acid skeleton that contains an additional chiral center. Among the aromatic creativecommons.org/licenses/by/ propionic acid skeletons, ibuprofen and naproxen are the most widely used. Ibuprofen was 4.0/). developed in the 1960s [17] and was valued at around 300 million US dollars in 2020 [18].

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In addition, it was prescribed more than 2.4 million times in the USA in 2018 [19] and was the most prescribed NSAID in that year. The second most prescribed NSAID was naproxen, Molecules 2021, 26, x FOR PEER REVIEWwhich was developed in the 1970s. Considering that both ibuprofen and naproxen can 2 of 22 be purchased without a prescription, it is believed that their medicinal beneﬁts have signiﬁcantly improved patients’ lives.

FigureFigure 1. 1.Structure Structure of representative of representative NSAIDs. NSAIDs. Ibuprofen and naproxen have an aryl-propanoic acid skeleton, possessing stereogenic center.As (Figure NSAIDs1) Although prevail it features as pain a relatively relievers, small they structure, have become its synthesis highly has been popular drugs in the studiedpharmaceutical to reduce synthetic market. steps, Their improve large reaction market conditions, has forced increase the reaction pharmaceutical scales, and community to acquirediscover facial advanced selectivity. synthesis It is also interesting routes for that NSAID they were skeletons sometimes [14 prepared–16]. forFrom the a structural view- purpose of demonstration of synthetic methodologies, which were recently developed. point,In this NSAIDs review, weskeletons present novel are usually endeavors classified to improve as the being synthesis an ofaromatic ibuprofen acetic or acid or propi- naproxenonic acid over skeleton the last 10 that years. contains Although an synthetic additional procedures chiral have center. been wellAmong established, the aromatic propionic moreacid advancedskeletons, synthesis ibuprofen routes areand still naproxen required to findare efficientthe most preparation widely methods used. Ibuprofen and was devel- potentoped derivativesin the 1960s of ibuprofen [17] and and was naproxen valued [20]. at around 300 million US dollars in 2020 [18]. In 2.addition, Classical Synthesisit was prescribed of Ibuprofen more than 2.4 million times in the USA in 2018 [19] and was the The most classical prescribed synthesis of NS ibuprofenAID in is shown that inyear. Scheme The1. When second the Boots most Pure prescribed Drug NSAID was Companynaproxen, developed which ibuprofen was developed in 1961, it was in preparedthe 1970s. in six steps,Considering including the that use both of ibuprofen and toxic aluminum chloride in the early stage [21]. However, in 1992, the Hoechst Company protocolnaproxen improved can be this purchased procedure by without using recyclable a prescription, hydrogen fluorideit is believed as an alternative that their medicinal ben- toefits aluminum have significantly chloride. Moreover, improve the synthesisd patients’ was accomplished lives. using a simple carbon monoxideIbuprofen (CO) insertion and method naproxen without have additional an aryl hydrolysis-propanoic or dehydration acid skeleton, [22]. With possessing stereo- agenic three-step center. procedure, (Figure ibuprofen 1) Although can be supplied it features worldwide. a relatively However, small there structure, is still an its synthesis has unmet need for a simpler, more efficient, and stereospecific route. been studied to reduce synthetic steps, improve reaction conditions, increase reaction scales, and acquire facial selectivity. It is also interesting that they were sometimes prepared for the purpose of demonstration of synthetic methodologies, which were recently developed. In this review, we present novel endeavors to improve the synthesis of ibuprofen or naproxen over the last 10 years. Although synthetic procedures have been well established, more advanced synthesis routes are still required to find efficient preparation methods and potent derivatives of ibuprofen and naproxen [20].

2. Classical Synthesis of Ibuprofen The classical synthesis of ibuprofen is shown in Scheme 1. When the Boots Pure Drug Company developed ibuprofen in 1961, it was prepared in six steps, including the use of toxic aluminum chloride in the early stage [21]. However, in 1992, the Hoechst Company protocol improved this procedure by using recyclable hydrogen fluoride as an alternative to aluminum chloride. Moreover, the synthesis was accomplished using a simple carbon monoxide (CO) insertion method without additional hydrolysis or dehydration [22]. With a three-step procedure, ibuprofen can be supplied worldwide. However, there is still an unmet need for a simpler, more efficient, and stereospecific route.

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Scheme 1. Classical synthesis of ibuprofen.

SchemeScheme3. Recent 1. 1.Classical ClassicalSynthetic synthesis synthesis Advances ofibuprofen. of ibuprofen. in Ibuprofen 3. RecentThe Synthetic application Advances of continuous in Ibuprofen-flow synthesis for ibuprofen is shown in Scheme 2 3. Recent Synthetic Advances in Ibuprofen [23].The This application synthetic of continuous-flow route adapts synthesisthe iodine for ibuprofen-mediated is shown 1,2-aryl in Scheme migration2[ 23 ]. reaction. ThisMcQuade syntheticThe application group route used adapts of trifluorosulfonic continuous the iodine-mediated-flow acid synthesis as 1,2-aryl a reaction for migration ibuprofen catalyst reaction. isinstead shown McQuade of inthe Scheme conven- 2 group[23]tional. used Thisreagent, trifluorosulfonic synthetic aluminum route acidchloride, adapts as a reaction to the achieve catalyst iodine continuous- insteadmediated of- the flow 1,2 conventional- arylsynthesis. migration reagent,Aluminum reaction. by- aluminumMcQuadeproducts are chloride,group incompatible used to achieve trifluorosulfonic in continuous-flowfurther steps. acid The as synthesis. anext reaction step Aluminum was catalyst the 1,2 byproductsinstead-aryl migrationof the are conven- reac- incompatibletionaltion. After reagent, the in furthermodelaluminum study steps. chloride, and The nextcareful to step achieve survey was thecontinuous of 1,2-aryl reaction migration-flow conditions, synthesis. reaction. substrate Aluminum After ketone by- 9 the model study and careful survey of reaction conditions, substrate ketone 9 could be productscould be quantitativelyare incompatible converted in further into steps. methyl The ester next 10step. Finally, was the saponification 1,2-aryl migration of the reac- me- quantitativelytion. After the converted model study into methyl and careful ester 10 survey. Finally, of saponificationreaction conditions, of the methyl substrate ester ketone 9 functionalitythyl ester functionality afforded ibuprofen afforded as aibuprofen light orange as solid.a light It orange is noteworthy solid. It that is noteworthy the reaction that the could be quantitatively converted into methyl ester 10. Finally, saponification of the me- couldreaction be completedcould be completed in 10 min usingin 10 amin flow using reactor a flow with reactor a 68% overallwith a yield68% overall (51% after yield (51% recrystallization).thylafter ester recrystallization). functionality Moreover, affordedMoreover, the simplicity ibuprofen the andsimplicity efficiencyas a light and of orange thisefficiency synthetic solid. of It process isthis noteworthy synthetic makes it thatprocess the likelyreactionmakes to it satisfy couldlikely the beto unmetcompletedsatisfy need the unmet forin 10 improved min need using for ibuprofen improveda flow synthesis reactor ibuprofen with [24]. a synthesis 68% overall [24] yield. (51% after recrystallization). Moreover, the simplicity and efficiency of this synthetic process makes it likely to satisfy the unmet need for improved ibuprofen synthesis [24].

SchemeScheme 2. 2.Synthetic Synthetic strategy strategy for for continuous-ﬂow continuous-flow synthesis synthesis of ibuprofen. of ibuprofen.

SchemeAnotherAnother 2. Synthetic approach approach strategy employing employing for continuous continuous-ﬂow continuous-flow synthesissynthesis,flow synthesis, of ibuprofen. reported reported in 2019, in is shown2019, is shown in Scheme3[ 25]. This synthesis involves direct alkylation of the benzylic anion via in Scheme 3 [25]. This synthesis involves direct alkylation of the benzylic anion via ‘su- ‘superbase’-mediated deprotonation. Starting from p-xylene, in situ generated ‘superbase’ perbase’Another-mediated approach deprotonation. employing continuousStarting from-flow p-xylene, synthesis, in situreported generated in 2019, ‘superbase’ is shown infrom Scheme KOtBu 3 and[25] .t BuLiThis synthesisafforded theinvolves desired direct benzylic alkylation anion toof meetthe benzylic with ad equateanion viaelectro- ‘superbase’philes sequentially.-mediated deprotonation. After 10 min, theStarting process, from which p-xylene, employed in situ the generated use of MeOTf, ‘superbase’ iPrI, fromand CO KO2,t Buproduced and tBuLi 2.3 afforded g ibuprofen the desired (50% in benzylic three steps). anion toThe meet readily with availableadequate startingelectro- philes sequentially. After 10 min, the process, which employed the use of MeOTf, iPrI, and CO2, produced 2.3 g ibuprofen (50% in three steps). The readily available starting

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Molecules 2021, 26, x FOR PEER REVIEW 4 of 22 from KOtBu and tBuLi afforded the desired benzylic anion to meet with adequate elec- trophiles sequentially. After 10 min, the process, which employed the use of MeOTf, iPrI, and CO2, produced 2.3 g ibuprofen (50% in three steps). The readily available starting materialmaterial and repeated repeated usage usage of of the the mixed mixed base base increases increases the the cost cost-effectiveness-effectiveness of this of this ap- approach.proach. However However,, the the strong strong basicity basicity of ofthis this procedure procedure still still requires requires improvement improvement for forin- industrialdustrial purposes. purposes.

SchemeScheme 3.3. Continuous-ﬂowContinuous-flow synthesissynthesis ofof ibuprofenibuprofenusing using C-H C-H metalation. metalation. THF; THF; tetrahydrofuran. tetrahydrofuran. Tf; triﬂuoromethansulfonyl.Tf; trifluoromethansulfonyl.

TheThe construction construction of of a a 2-arylpropionic 2-arylpropionic acid acid skeleton skeleton inspired inspired hydrocarboxylation, hydrocarboxylation, whichwhich isis crucialcrucial forfor ibuprofen or naproxen synthesis [[26]26].. Iron-catalyzedIron-catalyzed hydrocarboxylation,tion, asas reportedreported by by Thomas Thomas et et al., al. is, is shown shown in in Scheme Scheme4[ 274 [].27] Although. Although hydrocarboxylation hydrocarboxyla- oftion styrene of styrene was was expected expected to introduceto introduce the the ibuprofen ibuprofen skeleton, skeleton, the theregioselectivity regioselectivity ham- peredpered itit [[28]28].. However,However, thethe highlyhighly selectiveselective additionaddition ofof COCO22 waswas possiblepossible byby employingemploying anan iron catalyst and and pyridine pyridine ligand ligand 15.15 The. The follow followinging mechanistic mechanistic study study showed showed that that the thetransmetallation transmetallation and and hydrometallation hydrometallation of iron of iron and and styrene styrene moieties moieties are areimportant important for forre- regioselectivegioselective addition. addition.

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Scheme 4. Iron-catalyzed hydrocarboxylation for ibuprofen synthesis. Scheme 4.4.Iron-catalyzed Iron-catalyzed hydrocarboxylation hydrocarboxylation for for ibuprofen ibuprofen synthesis. synthesis.

HydrocarboxylationHydrocarboxylation of of styrene styrene using using Cp CpTiCl2TiClcatalyst,2 catalyst, reported reported by theby Xithe group Xi group in in Hydrocarboxylation of styrene using Cp2 2TiCl2 2 catalyst, reported by the Xi group in 2016,2016, isis shown in Scheme5 5[ [29]29].. For For this this approach, approach, the the regioselectivity regioselectivity of of the the styrene styrene moi- 2016, is shown in Scheme 5 [29]. For this approach, the regioselectivity of the styrene moi- moietyety was was screened screened using using various various Grignard Grignard reagents reagents and and additives. additives. When When this this reaction was ety was screened using various Grignard reagents and additives. When this reaction was wasapplied applied to alkyl to alkyl-substituted-substituted alkenes, alkenes, reversed reversed regioselectivity regioselectivity was observed toto have have re- applied to alkyl-substituted alkenes, reversed regioselectivity was observed to have re- resultedsulted in in a alinear linear product product,, nonanoic acidacid18 18. . sulted in a linear product, nonanoic acid 18.

SchemeScheme 5. 5.Titanium-mediated Titanium-mediated hydrocarboxylation hydrocarboxylation for for ibuprofen ibuprofen synthesis. synthesis. Cp; cyclopentadienyl.Cp; cyclopentadienyl. Scheme 5. Titanium-mediated hydrocarboxylation for ibuprofen synthesis. Cp; cyclopentadienyl. AA similarsimilar approach approach reported reported by by Wang Wang and and Li’s Li groups’s groups in 2018 in 2018 is shown is shown in Scheme in Scheme6 . 6. TheyTheyA attemptedattempted similar approach to to insert insert carbonreported carbon monoxide monoxideby Wang (CO) and (CO) intoLi into’s styrenegroups styrene 14in [20181430 ].[30] Foris .shown For a high a highin regiose- Scheme regiose- 6. lectivityThey attempted of styrene, to manyinsert cocatalysts,carbon monoxide including (CO) metals into orstyrene acids, were14 [30] tested.. For a When high ironregiose- lectivity of styrene, many cocatalysts, including metals or acids, were tested. When iron chloridelectivity (FeClof styrene,3) was many used ascocatalysts the cocatalyst,, including a highly metals selective or acids, addition were of tested CO was. When per- iron chloride (FeCl3) was used as the cocatalyst, a highly selective addition of CO was per- formedchloride with (FeCl approximately3) was used 90% as the yield. cocatalyst, Arylethanol a highly19 was selective also used addition in the reaction of CO system. was performed with approximately 90% yield. Arylethanol 19 was also used in the reaction sys- Interestingly,formed with theapproximately regioselectivity 90% was yield. fully Arylethanol reversed when 19 thewas iron also cocatalyst used in wasthe reaction changed sys- Molecules 2021, 26, x FOR PEER REVIEWtem. Interestingly, the regioselectivity was fully reversed when the iron cocatalyst5 ofwas 22 from iron bromide to iron triﬂate. Although mechanistic studies are still required, versatile tem.changed Interestingly from iron, the bromide regioselectivity to iron triflate. was fully Although reversed mechanistic when the ironstudies cocatalyst are still was re- applicationchanged from of this iron strategy bromide could tobe iron used triflate. as a valuable Although lead mechanistic compound in studies drug discovery. are still required, versatile application of this strategy could be used as a valuable lead compound quired, versatile application of this strategy could be used as a valuable lead compound in drug discovery. in drug discovery.

Scheme 6.4.Iron-catalyzed Iron-catalyzed regioselective hydrocarboxylation carboxylation for ibuprofen for ibuprofen synthesis. synthesis. Ts; p-toluenesulfonyl.

RegioselectiveHydrocarboxylation hydrocarboxylation of styrene using was alsoCp2TiCl performed2 catalyst, using reported a nickel by catalyst the Xi in group the in presence2016, is shown of visible in light,Scheme such 5 [29] as a.blue For LEDthis approach, [31], and is the shown regioselectivity in Scheme7. Hantzschof the styrene ester, moiety was screened using various Grignard reagents and additives. When this reaction was applied to alkyl-substituted alkenes, reversed regioselectivity was observed to have re- sulted in a linear product, nonanoic acid 18.

Scheme 5. Titanium-mediated hydrocarboxylation for ibuprofen synthesis. Cp; cyclopentadienyl.

A similar approach reported by Wang and Li’s groups in 2018 is shown in Scheme 6. They attempted to insert carbon monoxide (CO) into styrene 14 [30]. For a high regioselectivity of styrene, many cocatalysts, including metals or acids, were tested. When iron chloride (FeCl3) was used as the cocatalyst, a highly selective addition of CO was performed with approximately 90% yield. Arylethanol 19 was also used in the reaction system. Interestingly, the regioselectivity was fully reversed when the iron cocatalyst was changed from iron bromide to iron triflate. Although mechanistic studies are still required, versatile application of this strategy could be used as a valuable lead compound in drug discovery.

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Scheme 6. Iron-catalyzed regioselective carboxylation for ibuprofen synthesis. Ts; p-toluenesulfonyl. Molecules 2021, 26, 4792 6 of 22 Regioselective hydrocarboxylation was also performed using a nickel catalyst in the presence of visible light, such as a blue LED [31], and is shown in Scheme 7. Hantzsch molecularester, molecular sieves, andsieves, nickel and catalyst nickel werecatalyst added were with added the aid with of visiblethe aid light. of visible Conversely, light. Con- Königversely, group König used group a neocuproine used a neocuproine ligand to amplifyligand to the amplify regioselectivity the regioselectivity of this reaction. of this re- Whenaction. other When phosphine other phosphine ligands such ligands as 1,4-bis(diphenylphosphino)butane such as 1,4-bis(diphenylphosphino (dppb))butane were (dppb) usedwere instead used instead of neocuproine, of neocuproine, a linear additiona linear productaddition was product obtained was exclusively.obtained exclusively. Addi- tionally,Additionally, they also they performed also performed mechanistic mechanistic studies studies to elucidate to elucidate the in situ the generationin situ generation of nickel-hydrideof nickel-hydride complexes complexes that are that responsible are responsible for irreversible for irreversible addition toaddition styrene. to Although styrene. Alt- thishough reaction this reaction system usessystem various uses ligandsvarious forligands ibuprofen for ibuprofen synthesis, synthesis, visible-light-assisted visible-light-as- room-temperaturesisted room-temperature reactions reactions may be valuable may be for valuable environmentally for environmentally friendly industrial friendly syn- indus- thesistrial synthesis [32–34]. [32–34].

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Scheme 6. Iron-catalyzed regioselective carboxylation for ibuprofen synthesis. Ts; p-toluenesulfonyl.

Regioselective hydrocarboxylation was also performed using a nickel catalyst in the SchemepresenceScheme 7. 7. Visible ofVisible visible light light light combining combining, such regioselectiveas regioselective a blue LED carboxylation carboxylation [31], and foris for shown ibuprofen ibuprofen in synthesis.Scheme synthesis 7. 4CzIPN;. 4CzIPN;Hantzsch 2,4,5,6-Tetrakis(9H-carbazol-9-yl) isophthalonitrile, N,N-dimethylformamide. 2,4,5,6-Tetrakis(9H-carbazol-9-yl)ester, molecular sieves, and nickel isophthalonitrile, catalyst wereN,N-dimethylformamide. added with the aid of visible light. Con- versely, König group used a neocuproine ligand to amplify the regioselectivity of this re- AA similarsimilar result result was was published published in in 2018; 2018; however, however, its its approach approach differed differed in in that that no no ex- action. When other phosphine ligands such as 1,4-bis(diphenylphosphino)butane (dppb) externalternal reductant, reductant, such as HantzschHantzsch ester, ester, was was necessary necessary [35 [35]]. The. The replacement replacement of benzylic of benzylic were used instead of neocuproine, a linear addition product was obtained exclusively. quaternaryquaternary ammonium ammonium salt salt by by carboxylic carboxylic acid acid functionality functionality through through an iridium-catalyzed an iridium-catalyzed Additionally, they also performed mechanistic studies to elucidate the in situ generation carbonylationcarbonylation process process is is shown shown in in Scheme Scheme8[ 368 –[3638–].38 Upon]. Upon using using a blue a blue LED, LED, a smooth a smooth conversionof nickel-hydride to the desiredcomplexes product that wasare responsible observed. Notably, for irreversible the reaction addition was completedto styrene. Alt- conversion to the desired product was observed. Notably, the reaction was completed withouthough this the needreaction for ansystem additional uses various reducing ligands agent, similarfor ibuprofen to the previous synthesis, conversion. visible-light It -as- without the need for an additional reducing agent, similar to the previous conversion. It wassisted designed room-temperature such that the reactions released amine-leaving may be valuable group for might environmentally act as an electron friendly donor. indus- was designed such that the released amine-leaving group might act as an electron donor. Additionally,trial synthesis naproxen [32–34].2 was successfully obtained by employing this reaction condition. Additionally, naproxen 2 was successfully obtained by employing this reaction condition.

Scheme 8. Reductant-free coupling for ibuprofen or naproxen synthesis. SchemeScheme 8. 7.Reductant-free Visible light combining coupling for regioselective ibuprofen or carboxylation naproxen synthesis. for ibuprofen synthesis. 4CzIPN; 2,4,5,6The-Tetrakis(9H carboxylation-carbazol of- 9quaternary-yl) isophthalonitrile ammonium, N,N salt,-dimethylformamide achieved by a .direct electrochemi- The carboxylation of quaternary ammonium salt, achieved by a direct electrochemical cal reaction with CO2, is shown in Scheme 9 [39]. Although this conversion shows a similar reaction with CO , is shown in Scheme9[ 39]. Although this conversion shows a similar reactionA similar pathway, result2 it featureswas published electrochemical in 2018; however, coupling itsof quaternaryapproach differed ammonium in that bromide no ex- reaction pathway, it features electrochemical coupling of quaternary ammonium bromide ternal reductant, such as Hantzsch ester, was necessary [35]. The replacement of benzylic 2323 fromfrom benzylicbenzylic bromidebromide22 22[ 40[40]] with with COCO2 withoutwithout furtherfurther metalmetal catalysts,catalysts, complexcomplex lig- quaternary ammonium salt by carboxylic acid2 functionality through an iridium-catalyzed ligands,ands, or or external external reducing reducing agents. agents. As the voltagevoltage apparatusapparatus is is renewable renewable [41 [41]], this, this type type of carbonylation process is shown in Scheme 8 [36–38]. Upon using a blue LED, a smooth ofconversion conversion could could provide provide a a solution solution for thethe greengreen synthesis synthesis of of NSAIDs NSAIDs [42 [42]]. . conversion to the desired product was observed. Notably, the reaction was completed without the need for an additional reducing agent, similar to the previous conversion. It was designed such that the released amine-leaving group might act as an electron donor. Additionally, naproxen 2 was successfully obtained by employing this reaction condition.

Scheme 8. Reductant-free coupling for ibuprofen or naproxen synthesis.

The carboxylation of quaternary ammonium salt, achieved by a direct electrochemical reaction with CO2, is shown in Scheme 9 [39]. Although this conversion shows a similar reaction pathway, it features electrochemical coupling of quaternary ammonium bromide 23 from benzylic bromide 22 [40] with CO2 without further metal catalysts, complex ligands, or external reducing agents. As the voltage apparatus is renewable [41], this type of conversion could provide a solution for the green synthesis of NSAIDs [42].

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Scheme 9. Electrochemical carboxylation for ibuprofen synthesis. Scheme 9. 9.Electrochemical Electrochemical carboxylation carboxylation for ibuprofen for ibuprofen synthesis. synthesis. A more direct CO2 addition from benzylic C-H activation through photo-activation was Aperformed more direct in CO 2019.addition After fromKönig benzylic et al. reported C-H activation blue LED through-mediated photo-activation photocarboxyla- A more direct CO2 2 addition from benzylic C-H activation through photo-activation wastion performed (as shown in in 2019. Scheme After König7), they et al. also reported attempted blue LED-mediated to add CO2 photocarboxylationto the alkyl benzene sub- was performed in 2019. After König et al. reported blue LED-mediated photocarboxyla- (asstrate, shown which in Scheme is readily7), they available also attempted from commercial to add CO sources2 to the alkyl[43–45 benzene]. Scheme substrate, 10 shows the tion (as shown in Scheme 7), they also attempted to add CO2 to the alkyl benzene sub- whichresults is of readily this endeavor available from[46]. commercialTriisopropylsilyl sources thiol [43–45 was]. Scheme used to10 facshowsilitate the hydrogen results atom strate, which is readily available from commercial sources [43–45]. Scheme 10 shows the oftransfer this endeavor for practical [46]. Triisopropylsilyl conversion of the thiol sp was3-hybridized used to facilitate C-H bond hydrogen to the atom carbanion transfer interme- results of this endeavor [46]. Triisopropylsilyl3 thiol was used to facilitate hydrogen atom fordiate practical. The resulting conversion benzylic of the sp radical-hybridized was then C-H bondreduced to the to carbaniona carbanion intermediate. intermediate via Thetransfer resulting for practical benzylic radicalconversion was thenof the reduced sp3-hybridized to a carbanion C-H intermediatebond to the viacarbanion electron interme- electron transfer from 4CzIPN. Finally, the resultant benzylic anion intermediate reacted transferdiate. The from resulting 4CzIPN. benzylic Finally, theradical resultant was benzylicthen reduced anion intermediateto a carbanion reacted intermediate with via with CO2 to produce the desired 2-arylpropionic acid skeleton. Visible light was necessary COelectron2 to produce transfer the from desired 4CzIPN. 2-arylpropionic Finally, the acid resultant skeleton. benz Visibleylic light anion was intermediate necessary to reacted completeto complete the reactionthe reaction [47]. [47]. with CO2 to produce the desired 2-arylpropionic acid skeleton. Visible light was necessary to complete the reaction [47].

SchemeScheme 10. 10.Photo-chemical Photo-chemical carboxylation carboxylation of alkyl of benzene alkyl benzene substrate forsubstrate ibuprofen for or ibuprofen naproxen synthesis. or naproxen synthesis. SchemeHowever, 10. Photo the-chemical relatively carboxylation low chemical of yield alkyl hampers benzene further substrate application, for ibuprofen along or with naproxen unwantedsynthesis.However, isomers the from relatively ibuprofen low synthesis, chemical whichyield ishampers a problem further that hasapplication, not yet been along with solved. Nevertheless, this conversion method still presents a major opportunity because unwanted isomers from ibuprofen synthesis, which is a problem that has not yet been it canHowever, be achieved the without relatively a metal low catalystchemical or yield bulky hampers ligand under further convenient application, reaction along with solved. Nevertheless, this conversion method still presents a major opportunity because conditions.unwanted isomers In addition, from the ibuprofen naproxen synthesis skeleton can, which be accessed is a problem selectively that usinghas not this yet been it can be achieved without a metal catalyst or bulky ligand under convenient reaction con- reactionsolved. asNevertheless, it has only one this benzylic conversion carbon. method still presents a major opportunity because ditions. In addition, the naproxen skeleton can be accessed selectively using this reaction it canAnother be achieved synthetic without protocol a metal for ibuprofen catalyst synthesis or bulky is summarizedligand under in convenient Scheme 11[ 48 reaction]. It con- wasas it attempted has only toone substitute benzylic allylic carbon. alcohol 28 by the allylic oxidation of terminal methylene ditions. In addition, the naproxen skeleton can be accessed selectively using this reaction 27 usingAno ather simple synthetic Appel reaction protocol [49 for]. However, ibuprofen they synthesis found that, is summarized unexpectedly, in isomeric Scheme 11 [48]. as it has only one benzylic carbon. aldehydeIt was attempted29 was obtained to substitute as the major allylic product. alcohol After 28 by the the mechanistic allylic oxidation study and of optimiza- terminal meth- Another synthetic protocol for ibuprofen synthesis is summarized in Scheme 11 [48]. tionylene of 27 the using reaction a simple conditions, Appel aldehyde reaction29 was[49]. produced However, with they 92% found yield, that, suggesting unexpectedly, that iso- uneventfulIt was attempted oxidation to ofsubstitute the aldehyde allylic afforded alcohol ibuprofen 28 by the in allylic good oxidation yield. Although of terminal this meth- meric aldehyde 29 was obtained as the major product. After the mechanistic study and ylene 27 using a simple Appel reaction [49]. However, they found that, unexpectedly, iso- optimization of the reaction conditions, aldehyde 29 was produced with 92% yield, sug- meric aldehyde 29 was obtained as the major product. After the mechanistic study and optimization of the reaction conditions, aldehyde 29 was produced with 92% yield, sug-

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Molecules 2021, 26, 4792 gesting that uneventful oxidation of the aldehyde afforded ibuprofen8 in of 22good yield. Alt- hough this reaction protocol requires more steps than the conventional BHC protocol, the scientificgesting that importance uneventful of variousoxidation synthetic of the aldehyde routes still afforded exists. ibuprofen in good yield. Alt- reactionhough this protocol reaction requires protocol more steps requires than the more conventional steps than BHC the protocol, conventional the scientiﬁc BHC protocol, the importancescientific importance of various synthetic of various routes synthetic still exists. routes still exists.

Scheme 11. CBr4/PPh3-mediated isomeric oxidation protocol for ibuprofen synthesis.

Scheme 11. CBr /PPh -mediated isomeric oxidation protocol for ibuprofen synthesis. SchemeA chemoselective 11. CBr4 4/PPh3 3-mediated aromatic isomeric coupling oxidat approachion protocol has foralso ibuprofen been studied synthesis and. is shown in SchemeA chemoselective 12 [50]. In aromatic2014, Zhang coupling group approach published has also sequential been studied coupling and is shown with an aromatic inhalide SchemeA withchemoselective 12[ 50zinc]. In enolate, 2014, Zhangaromatic followed group coupling published by an alkylapproach sequential zinc hasreagent. coupling also withbeenAlthough an studied aromatic this and procedure is shown re- in halidequiresScheme with complex 12 zinc [50] enolate, .ligands In 2014, followed and Zhang metals, by angroup alkylthe publishedrequired zinc reagent. reaction sequential Although sequence thiscoupling procedure is simple with an. Moreover, aromatic requires complex ligands and metals, the required reaction sequence is simple. Moreover, thehalide simplicity with zinc of theenolate, starting followed material by is an also alkyl impressive. zinc reagent. However, Although its iterative this procedure use of met- re- thequires simplicity complex of the ligands starting material and metals, is also impressive. the required However, reaction its iterative sequence use of is metals simple. Moreover, mayals may hamper hamper further further development. development. the simplicity of the starting material is also impressive. However, its iterative use of metals may hamper further development.

Scheme 12. 12.Reformatsky–Negishi Reformatsky–Negishi approach approach for ibuprofen for ibuprofen synthesis. synthesis Dba; dibenzylideneacetone,. Dba; dibenzylideneacetone,

TFA; triﬂuoroacetic trifluoroacetic acid. acid. Scheme 12. Reformatsky–Negishi approach for ibuprofen synthesis. Dba; dibenzylideneacetone, A Pd-catalyzed allylic oxidation procedure was also developed and is shown in TFA; trifluoroacetic acid. SchemeA 13Pd[ 51-catalyzed]. Although allylic this conversion oxidation can procedure be performed was using also SeO developed2/t-BuOOH and as is shown in describedScheme 13 earlier, [51] Jiang. Although group used this oxygen conversion gas and can catalytic be performed PdCl2. The resultingusing SeO allylic2/t-BuOOH as de- A Pd-catalyzed allylic oxidation procedure was also developed and is shown in alcoholscribed28 earlier,could beJiang transformed group used into ibuprofenoxygen gas by employingand catalytic a reduction/oxidation PdCl2. The resulting allylic al- sequence.coholScheme 28 13 Acould novel [51] . synthetic beAlthough transformed route this for conversion ibuprofen into ibuprofen is thus can possible. be by performed employing using a reduction/oxidation SeO2/t-BuOOH as de- se- quence.scribed earlier,A novel Jiang synthetic group route used for oxygen ibuprofen gas and is thus catalytic possible. PdCl 2. The resulting allylic alcohol 28 could be transformed into ibuprofen by employing a reduction/oxidation sequence. A novel synthetic route for ibuprofen is thus possible.

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SchemeScheme 13.13. AerobicAerobic oxidationoxidation approachapproach for ibuprofen synthesis synthesis.. DMSO; DMSO; dimethylsulfoxide, dimethylsulfoxide, PDC; PDC; pyridinium dichlorochromate. pyridiniumpyridinium dichlorochromate.dichlorochromate.

AnotherAnother impressive impressive strategy strategy was was developed developed by by adding adding cyanide cyanide to aromatic to aromatic alkynes alkynes [52] as[52] shown as shown in Scheme in Scheme 14. For 14 Markovnikov’s. For Markovnikov’s addition addition of cyanide, of cyanide, 4-cyanopyridine 4-cyanopyridineN-oxide N- 34oxidewas 34 adapted was adapted for cyanide for cyanide supply. supply. After After the the addition addition of of cyanide cyanide to to afford affordterminal terminal 4 methylene,methylene, it underwent underwent one one-pot-pot reduction reduction with with NaBH NaBH4. Therefore,4. Therefore, it was it was possible possible to pro- to produceduce substituted substituted benzyl benzyl cyanide cyanide 3535 usingusing this this strategy, strategy, which which could could be transformed intointo ibuprofenibuprofen via via simple simple acidic acidic hydrolysis. hydrolysis. However, However, this this protocol protocol employs employs excess excess reagents, reagents in-, cludingincluding zinc. zinc. In thisIn this regard, regard, further further research research is still is still required. required However,. However, its unique its unique synthetic syn- approachthetic approach and moderate and moderate chemical chemical yield are yield highly are highly valuable. valuable.

SchemeScheme 14.14. Alkyne-cyanationAlkyne-cyanation approach for ibuprofen synthesis synthesis.. TFAA; TFAA; trifluoroacetic triﬂuoroacetic anhydride, anhydride, DMA;DMA; NN,,NN-dimethylacetamide.-dimethylacetamide.

AlthoughAlthough ibuprofenibuprofen hashas beenbeen commercializedcommercialized asas aa racemicracemic mixture,mixture, enantiomericallyenantiomerically purepure ((SS)-ibuprofen)-ibuprofen has better better efficacy efﬁcacy and and potency. potency. In In line line with with this this merit, merit, synthesis synthesis of (S of)- (ibuprofenS)-ibuprofen has has been been studied studied extensively. extensively. Scheme Scheme 15 15 is is a agood good example example of of this this endeavor. IncorporationIncorporation ofof COCO andand anilineaniline intointo thethe styrenestyrene 2727was was accomplished accomplished enantiomericallyenantiomerically purepure mannermanner. [[53]53]. It It features features asymmetric asymmetric Markovnikov Markovnikov-type-type hydroaminocarbonylation hydroaminocarbonylation of ofstyrene styrene with with catalysis catalysis of Pd of Pdand and phosphoramidite phosphoramidite ligand ligand 36. Although36. Although this type this of type addi- of additiontion reaction reaction has been has been reported, reported, it is impressive it is impressive that this that reaction this reaction can be can achieved be achieved at room at roomtemperature, temperature, with high with regioselectivity high regioselectivity (branched:linear (branched:linear = 99:1) = 99:1)and stere andoselectivity stereoselectivity (90% (90% ee). ee).

SchemeScheme 15.15. AsymmetricAsymmetric synthesissynthesis ofof ((SS)-ibuprofen.)-ibuprofen.

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Molecules 2021, 26, 4792 10 of 22 4. Classical Synthesis of Naproxen

4. ClassicalThe classical Synthesis synthesis of Naproxen of naproxen is shown in Scheme 16. Whilst ibuprofen is utilized as a racemic mixture, the utilization of naproxen is optically active. Therefore, chiral 4. ClassicalThe classical Synthesis synthesis of Naproxen of naproxen is shown in Scheme 16. Whilst ibuprofen is uti- resolution [54] or asymmetric synthesis [55–58] is necessary in early development. When lizedThe as a classical racemic synthesis mixture, of the naproxen utilization is shown of naproxen in Scheme is optically 16. Whilst active. ibuprofen Therefore, is chiral Syntex introduced naproxen in 1976, a synthetic procedure was adopted based on the tra- utilizedresolution asa [54] racemic or asymmetric mixture, the synthesis utilization [55 of– naproxen58] is necessary is optically in early active. development. Therefore, When chiralditional resolution Friedel [–54Crafts] or asymmetric alkylation synthesis [59] and [ 55Willgerodt–58] is necessary–Kindler in earlyrearrangement development. [60] to af- Syntex introduced naproxen in 1976, a synthetic procedure was adopted based on the tra- Whenford arylacetic Syntex introduced acid 40. naproxenEsterification in 1976, and a synthetic simple methylation procedure was directly adopted produced based on racemic ditional Friedel–Crafts alkylation [59] and Willgerodt–Kindler rearrangement [60] to af- thearylpropionic traditional Friedel–Crafts ester 41. Finally, alkylation saponification [59] and Willgerodt–Kindler and chiral resolution rearrangement using cinchonidine [60] to re- ford arylacetic acid 40. Esterification and simple methylation directly produced racemic affordsulted arylacetic in (S)-naproxen acid 40. Esteriﬁcationin an enantiomerically and simple methylationpure form [61] directly. produced racemic arylpropionicarylpropionic ester ester41 41. Finally,. Finally, saponiﬁcation saponification and and chiral chiral resolution resolution using using cinchonidine cinchonidine re- resultedsulted in in ( (SS))-naproxen-naproxen inin an an enantiomerically enantiomerically pure pure form form [61]. [61].

Scheme 16. Classical synthesis of (S)-naproxen. Scheme5.Scheme Recent 16. 16. ClassicalSynthetic Classical synthesis synthesis Advances of ( Sof)-naproxen. (inS)- naproxenNaproxen. 5. Recent Synthetic Advances in Naproxen 5. RecentIn studies Synthetic of naproxen Advances synthesis, in Naproxen the asymmetric induction of chiral centers and con- structionIn studies of an of arylpropionic naproxen synthesis, acid skeleton the asymmetric are important. induction Zakarian of chiral et centers al. reported and direct In studies of naproxen synthesis, the asymmetric induction of chiral centers and con- constructionmethylation of of an ( arylpropionicS)-naproxen acidusing skeleton a chiral are enolate, important. as Zakarianshown in et Scheme al. reported 17. directIn contrast to struction of an arylpropionic acid skeleton are important. Zakarian et al. reported direct methylationconventional of ( chiralS)-naproxen alkylatio usingn a requiring chiral enolate, chiral as shown auxiliary in Scheme attachment 17. In contrast and detachment to methylation of (S)-naproxen using a chiral enolate, as shown in Scheme 17. In contrast to conventional[62,63], this chiralchiral alkylation enolate (reagent) requiring gives chiral auxiliarythe desired attachment product and directly detachment in a highly [62,63], stereose- thisconventional chiral enolate chiral (reagent) alkylatio givesn the requiring desired product chiral directly auxiliary in a attachment highly stereoselective and detachment lective manner. Although the author reported that the recovery of chiral amines was pos- manner.[62,63], Althoughthis chiral the enolate author (reagent) reported thatgives the the recovery desired of product chiral amines directly was in possible a highly and stereose- sible and readily available [64], excess use of base and electrophile needs to be improved readilylective availablemanner. [ 64Although], excess usethe ofauthor base and reported electrophile that the needs recovery to be improved of chiral for amines further was pos- for further application and industrial-scale synthesis. applicationsible and readily and industrial-scale available [64] synthesis., excess use of base and electrophile needs to be improved for further application and industrial-scale synthesis.

Scheme 17. S Scheme 17.Chiral Chiral enolate enolate strategy strategy for (for)-naproxen (S)-naproxen synthesis. synthesis. SchemeDiaryliodoniumDiaryliodonium 17. Chiral enolate salt salt wasstrategy was also also for used ( Suse) for-naproxend thefor synthesisthe synthesis synthesis of.( S)-naproxen, of (S)-naproxen, as shown as inshown in Scheme 18[ 65]. For enantioselective α-arylation of the carbonyl group [66–68], silyl ketene Scheme 18 [65]. For enantioselective α-arylation of the carbonyl group [66–68], silyl ketene N,O-aminalDiaryliodonium43 was chosen salt as thewas nucleophile, also used whilefor the reactive synthesis aryliodonium of (S)-naproxen, salt 44 was usedas shown in N,O-aminal 43 was chosen as the nucleophile, while reactive aryliodonium salt 44 was asScheme the electrophile 18 [65]. For [69, 70enantioselective]. When the nucleophile α-arylation and electrophileof the carbonyl were group mixed with[66–68 a chiral], silyl ketene used as the electrophile [69,70]. When the nucleophile and electrophile were mixed with copperN,O-aminal catalyst, 43 thewas desired chosen (S )-arylpropionicas the nucleophile, acid skeleton while reactive was enantiomerically aryliodonium pure. salt 44 was Whilea chiral this copper reaction catalyst, can be performed the desired in a(S one)-arylpropionic pot reaction efﬁciently, acid skeleton the resource was enantiomerically require- used as the electrophile [69,70]. When the nucleophile and electrophile were mixed with mentspure. ofWhile diaryliodonium this reaction electrophile can be performed44 [71,72] and in a non-atom one pot economicalreaction efficiently, nucleophile the43 resource a chiral copper catalyst, the desired (S)-arylpropionic acid skeleton was enantiomerically stillrequirement need furthers of improvement. diaryliodonium electrophile 44 [71,72] and non-atom economical nucleo- pure. While this reaction can be performed in a one pot reaction efficiently, the resource phile 43 still need further improvement. requirements of diaryliodonium electrophile 44 [71,72] and non-atom economical nucleophile 43 still need further improvement.

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Scheme 18. Asymmetric alkylation strategy using iodonium salt for (S)-naproxen synthesis. TBS; t- butyldimethylsilyl. Scheme 18. 18.Asymmetric Asymmetric alkylation alkylation strategy strategy using iodonium using iodonium salt for (S)-naproxen salt for (S synthesis.)-naproxen TBS; synthesis. TBS; t- tbutyldimet-butyldimethylsilyl.A similarhylsilyl. approach was studied using Pd-mediated alkylation of silyl ketene acetal, as shownA similar in approach Scheme was 19 studied[73]. For using this Pd-mediated conversion, alkylation aryl triflate of silyl ketenewas used acetal, as the coupling asreagent shownA similar with in Scheme a approachsimple 19[ 73 ketene]. Forwas this studiedacetal conversion, 48 using in the aryl Pd presence triﬂate-mediated was of used aalkylation Pd as catalyst. the coupling of Msilylore ketene importantly, acetal, reagentasa chiralshown with ligand in a simple Scheme 49 ketenedominantly 19 acetal[73]. 48For directsin thethis presence conversion,facial ofselectivity a Pd catalyst.aryl triflateto More produce importantly,was usedthe ( S aas)- arylpropionicthe coupling chiralreagentacid ligand framework with49 dominantlya simple 50 [74] ketene directs. This acetal facial strategy selectivity 48 in the also to presence produce showed the ofthat ( Sa)-arylpropionic Pd other catalyst. NSAIDs, acidMore importantly, such as (S)- framework 50 [74]. This strategy also showed that other NSAIDs, such as (S)-fenoprofen, afenoprofen, chiral ligand (S) -49flurbiprofen dominantly, and directs (S)-ketoprofen, facial selectivity could be to obtained produce in the good (S) -chemicalarylpropionic yield (S)-ﬂurbiprofen, and (S)-ketoprofen, could be obtained in good chemical yield and stereos- electivityacidand stereoselectivity framework (>90% yield, 50 >88% [74](>90% ee).. This yield, strategy >88% ee) also. showed that other NSAIDs, such as (S)- fenoprofen, (S)-flurbiprofen, and (S)-ketoprofen, could be obtained in good chemical yield and stereoselectivity (>90% yield, >88% ee).

SchemeScheme 19. 19.Asymmetric Asymmetric Pd-coupling Pd-coupling strategy strategy for (S)-naproxen for (S)-naproxen synthesis. synthesis TMS; trimethylsilyl,. TMS; trimethylsilyl, TMEDA;TMEDA; tetramethylethylenediamine, tetramethylethylenediamine Cy; cyclohexyl., Cy; cyclohexyl. SchemePd-catalyzed 19. Asymmetric coupling Pd of-coupling aromatic halidesstrategy with for carboxylic(S)-naproxen acids synthesis has played. TMS; an im-trimethylsilyl, portantTMEDA;Pd role- catalyzetetramethylethylenediamine in organicd coupling synthesis of [75 aromatic–77,]. Cy; Employing cyclohexyl. halides Pd-coupling with carboxylic technology acids in has this played an im- regard,portant Hartwig role in group organic showed synthesis that aryl bromide[75–77].51 Employingcould react with Pd- propioniccoupling acid technology via a in this re- TMS-enolategard,Pd Hartwig-catalyze intermediate groupd coupling showed [78] to obtainof thataromatic an aryl arylpropionic bromidehalides acidwith51 could skeleton carboxylic react with with anacids excellent propionic has played acid an via im- a yieldportantTMS [-79enolate] role (Scheme in int organic20ermediate). This conversionsynthesis [78] to does [75obtain– not77 ] requirean. Employing arylpropionic a highly Pd complex- couplingacid ligand skeleton technology or reac- with an in excellent this re- tion system. It was possible to synthesize racemic naproxen in gram scale or ibuprofen in overgard,yield 95% [79]Hartwig yield (Scheme using group a 20). simple showed This procedure. conversion that aryl Although bromidedoesthis not procedure 51require could a still reacthighly requires with complex further propionic ligand acid or viareac- a advancesTMStion system.-enolate in asymmetric Itint wasermediate possible synthesis, [78] to its synthesizeto ability obtain to an construct racemic arylpropionic anaproxen carbonframework acid in gramskeleton with scale anwith or ibuprofenan excellent in efﬁcientyieldover 95%[79] methodology (Schemeyield using is20). noteworthy. a This simple conversion procedure. does Although not require this a procedurehighly complex still requires ligand or further reac- tionadvances system. in Itasymmetric was possible synthesis, to synthesize its ability racemic to constructnaproxen ain carbon gram scale framework or ibuprofen with anin overefficient 95% methodology yield using a is simple noteworthy. procedure. Although this procedure still requires further advances in asymmetric synthesis, its ability to construct a carbon framework with an efficient methodology is noteworthy.

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Scheme 20. Pd-coupling for racemic naproxen or ibuprofen synthesis. LHMDS; lithium bis(trimethylsilyl)amide.

SchemeSchemeα- 20.Haloester 20.Pd-coupling Pd-coupling was for racemicalso for utilized racemic naproxen innaproxen or the ibuprofen coupling or synthesis. ibuprofen reaction LHMDS; synthesis to lithiumafford. LHMDS; bis(trimethy- (S)-naproxen lithium [80,81] bis(trime-. lsilyl)amide.Nakamurathylsilyl)amide et al.. reported that an arylmagnesium reagent could react with α-chloroester 54 withα-Haloester the assistance was also of utilized an iron in thecatalyst coupling [82 reaction–84] and to chiral afford (phosphineS)-naproxen ligand [80,81]. 55 to afford Nakamuraenantiomericallyα-Haloester et al. reported enrichedwas thatalso an esterutilized arylmagnesium 56. in For the increased coupling reagent could selectivity, reaction react with to an affordα -chloroester uncommon (S)-naproxen ester was[80,81] . 54used,Nakamurawith as the it assistancecould et al. be reported ofconverted an iron that catalyst to (anS) [-82arylmagnesiumnaproxen–84] and chiralunder phosphine acidicreagent cond ligandcoulditions55 reactto [85] afford with(Scheme α-chloroester 21). A 56 enantiomericallymechanistic54 with the investigationassistance enriched of ester anwas iron .also For catalyst increasedperformed [82 selectivity,– 84to ]elucidate and an chiral uncommon the phosphine radical ester intermediate wasligand 55 to and afford used,divalent as it couldiron species be converted important to (S)-naproxen for the undercatalytic acidic cycle. conditions The paper [85] (Scheme also includes21). A that this mechanisticenantiomerically investigation enriched was also ester performed 56. For to elucidate increased the selectivity, radical intermediate an uncommon and ester was reaction can be applied to (S)-ibuprofen synthesis in 65% yield with over 99% enantiopu- divalentused, as iron it could species be important converted for theto ( catalyticS)-naproxen cycle. Theunder paper acidic also includesconditions that [85] this (Scheme 21). A rity. reactionmechanistic can be appliedinvestigation to (S)-ibuprofen was also synthesis performed in 65% yield to elucidate with over 99% the enantiopurity. radical intermediate and divalent iron species important for the catalytic cycle. The paper also includes that this reaction can be applied to (S)-ibuprofen synthesis in 65% yield with over 99% enantiopurity.

SchemeScheme 21. 21.Iron-catalyzed Iron-catalyzed chiral chiral coupling coupling to α-haloester to α-haloester strategy forstrategy (S)-naproxen for (S) synthesis.-naproxen Acac; synthesis. Acac; acetylacetonate.acetylacetonate. Nakamura et al. further modified the iron-catalyzed coupling reaction to enantios- electiveNakamura Suzuki–Miyaura et al. further coupling modified with α-bromoester the iron-catalyzed58, as shown coupling in Scheme reaction 22[ 86 ].to enantiose- ConsideringlectiveScheme Suzuki 21. theIron– efficiencyMiyaura-catalyzed of coupling arylchiral borates coupling with for α metal-catalyzed-tobromoester α-haloester 58 strategy coupling,, as shown for this (inS type) -Schemenaproxen of chi- 22 synthesis [86]. Con-. Acac; ralsideringacetylacetonate coupling the can efficiency be. utilized of foraryl practical borates synthesis. for metal Chiral-catalyzed coupling coupling, followed this by simpletype of chiral cou- acidicpling hydrolysiscan be utilized assessed for both practical enantiomerically synthesis. enriched Chiral (S)-naproxen coupling and followed (S)-ibuprofen. by simple acidic However,hydrolysis readily assessed available both chiral enantiomerically ligands and high selectivity enriched are (S still)-naproxen required. and (S)-ibuprofen. TheNakamura asymmetric et addition al. further of thiophenol modified was alsothe attempted,iron-catalyzed as shown coupling in Scheme reaction 23 [87]. to enantiose- However, readily available chiral ligands and high selectivity are still required. Thelectiveα,β-unsaturated Suzuki–Miyaura terminal coupling alkene 62 was with treated α-bromoester with thiophenol 58, toas produceshown ain Michael Scheme 22 [86]. Con- adductsidering64. the This efficiency conversion of proceeded aryl borates asymmetrically for metal- withcatalyzed the influence coupling, of cinchona- this type of chiral cou- derivedpling can catalyst be 63utilized. Raney-Ni for and practical NaPH2O 2synthesis.were treated Chiral to cleave cou thepling carbon-sulfur followed bond by simple acidic in the next step. Finally, hydrolysis and recrystallization afforded enantiomerically pure (Shydrolysis)-naproxen in assessed good yields. both Employing enantiomerically this strategy, (S )-ibuprofen enriched could (S)-naproxen also be obtained and (S)-ibuprofen. withHowever, a similar readily yield and available enantiomeric chiral purity. ligands Thus, and the authorhigh selectivity proposed that are thiourea still required. as a chiral catalyst could interact with the dicarbonyl groups in the substrate via hydrogen bonding, serving as a chiral platform for the asymmetric Michael addition of thiophenol.

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SchemeScheme 22. 22.Iron-catalyzed Iron-catalyzed Suzuki–Miyaura Suzuki–Miyaura coupling coupling for (S)-naproxen for (S or)-naproxen (S)-ibuprofen or synthesis. (S)-ibuprofen synthesis.

The asymmetric addition of thiophenol was also attempted, as shown in Scheme 23 [87]. The α,β-unsaturated terminal alkene 62 was treated with thiophenol to produce a Michael adduct 64. This conversion proceeded asymmetrically with the influence of cinchona-derived catalyst 63. Raney-Ni and NaPH2O2 were treated to cleave the carbon-sulfur bond in the next step. Finally, hydrolysis and recrystallization afforded enantiomerically pure (S)-naproxen in good yields. Employing this strategy, (S)-ibuprofen could also be obtained with a similar yield and enantiomeric purity. Thus, the author proposed that thiourea as a chiral catalyst could interact with the dicarbonyl groups in the substrate via hydrogen bonding, serving as a chiral platform for the asymmetric Michael addition of thiophenol.

SchemeScheme 23.23. AsymmetricAsymmetric additionaddition ofof thiolthiol forfor ((SS)-naproxen)-naproxen synthesis.synthesis. Ra-Ni;Ra-Ni; Raney-nickel.Raney-nickel.

TheThe synthesissynthesis of of alkenyl alkenyl boron boron via via hydroboration hydroboration of1,1-disubstituted of 1,1-disubstituted allenes allenes was alsowas pursued,also pursued, as shown as shown in Scheme in Scheme 24[ 88 24–90 [88].– Hoveyda90]. Hoveyda et al. et reported al. reported that that asymmetric asymmetric hydroborationhydroboration of alleneof allene65 could 65 could be achieved be achieved by employing by employing a copper a copper catalyst, catalyst,N-heterocyclic N-heterocyclic carbene (NHC) ligand 66, and pinacolborane. When the reaction was performed at room temperature for 2 d, the desired alkenyl pinacolatoboron 67 could be produced with excellent enantio-and regioselectivity. Finally, the oxidation of alkenes using OsO4 followed by NaIO4 afforded (S)-naproxen directly. Mechanistic investigations and further applications are currently in progress [91].

Scheme 24. Hydroboration of allene strategy for (S)-naproxen synthesis. Pin; pinacol.

Another asymmetric hydroboration route to (S)-naproxen was developed in 2014 [92]. The terminal alkene 68 was chosen for pivotal hydroboration to use a more versatile substrate. Remarkably, cobalt catalyst 69 was prepared for this conversion after an exten- sive screening of the catalyst and reaction conditions. After the desired pinacolatoboron 70 was obtained exclusively, it was oxidized to (S)-naproxen via a three-step sequence without any epimerization. The overall yield was 66% from the starting alkene 68, as shown in Scheme 25. Hence, considering the easy preparation of chiral catalysts and their low loading, this reaction could be considered for the large-scale synthesis of other NSAIDs if cobalt can be treated in an environmentally friendly manner.

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Scheme 23. Asymmetric addition of thiol for (S)-naproxen synthesis. Ra-Ni; Raney-nickel. Molecules 2021, 26, 4792 14 of 22 The synthesis of alkenyl boron via hydroboration of 1,1-disubstituted allenes was also pursued, as shown in Scheme 24 [88–90]. Hoveyda et al. reported that asymmetric hydroboration of allene 65 could be achieved by employing a copper catalyst, N-hetero- carbenecyclic carbene (NHC) (NHC) ligand ligand66, and 66 pinacolborane., and pinacolborane. When When the reaction the reaction was performed was performed at room at temperatureroom temperature for 2 d, for the 2 d, desired the desired alkenyl alkenyl pinacolatoboron pinacolatoboron67 could 67 becould produced be produced with excel- with lentexcellent enantio-and enantio regioselectivity.-and regioselectivity. Finally, Fi thenally, oxidation the oxidation of alkenes of usingalkenes OsO using4 followed OsO4 fol- by NaIOlowed4 affordedby NaIO (4 Safforded)-naproxen (S) directly.-naproxen Mechanistic directly. Mechanistic investigations investigations and further applicationsand further areapplications currently are in progresscurrently [91 in]. progress [91].

Scheme 24. Hydroboration of allene strategy forfor ((SS)-naproxen)-naproxen synthesis.synthesis. Pin;Pin; pinacol.pinacol.

Another asymmetric asymmetric hydroboration hydroboration route route to to(S )-naproxen (S)-naproxen was was developed developed in 2014 in 2014 [92]. The[92]. terminalThe terminal alkene alkene68 was 68 was chosen chosen for for pivotal pivotal hydroboration hydroboration to to use use a a more more versatileversatile substrate.substrate. Remarkably,Remarkably, cobalt cobalt catalyst catalyst69 69was was prepared prepared for for this this conversion conversion after after an extensivean exten- screeningsive screening of the of catalyst the catalyst and reaction and reaction conditions. conditions. After theAfter desired the desired pinacolatoboron pinacolatoboron70 was obtained70 was obtained exclusively, exclusively, it was oxidized it was oxidized to (S)-naproxen to (S)-naproxen via a three-step via a three sequence-step sequence without anywithout epimerization. any epimerization. The overall The yieldoverall was yield 66% was from 66% the from starting the starting alkene 68 alkene, as shown 68, as inshownScheme in Scheme 25. Hence, 25. Hence, considering considering the easy the preparation easy preparation of chiral of chiral catalysts catalysts and theirand their low Molecules 2021, 26, x FOR PEER REVIEW 15 of 22 loading,low loading, this reaction this reaction could be could considered be considered for the large-scale for the large synthesis-scale of synthesis other NSAIDs of other if cobaltNSAIDs can if becobalt treated can inbe an treated environmentally in an environmentally friendly manner. friendly manner.

SchemeScheme 25.25. HydroborationHydroboration ofof terminalterminal alkenealkene strategystrategy forfor ((SS)-naproxen)-naproxen synthesis.synthesis.

HydroformylationHydroformylation in in flow flow reactions reactions has has also also been been studied studied for forindustrial industrial purposes purposes[93–95 []93. Resear–95]. Researcherschers at the atUniversity the University of Wisconsin of Wisconsin-Madison-Madison and Eli and Lilly Eli LillyCorporate Corporate Cen- Centerter published published a paper a paper on the on asymmetric the asymmetric synthesis synthesis of (S of)-naproxen (S)-naproxen using using rhodium rhodium--cata- catalyzedlyzed hydroformylation, hydroformylation, as shown as shown in Scheme in Scheme 26 [96] 26. In[ 96this]. paper, In this gas paper, and gasliquid and reagents liquid were mixed in a flow reactor. After a systematic survey of the reactor design and chiral ligands, (S)-naproxen was produced in two steps in over 80% yield and 92% enantiomeric excess from the simple vinyl substrate 72. As this reaction is designed to work in a continuous-flow reactor system, its use for the industrial synthesis of (S)-naproxen is also possible [97].

Scheme 26. Asymmetric hydroformylation strategy for (S)-naproxen synthesis. BDP; (R,R,R)- Bisdiazaphos-SPE.

Asymmetric hydrogenation is a valuable methodology for chiral medicine synthesis [98–100]. For NSAID synthesis, the chiral ferrocene-ruthenium complex was reported to be promising, as shown in Scheme 27 in 2016 [101]. This reduction process was developed for NSAID synthesis and other chiral propionic acid skeletons, such as artemisinin. In some examples, catalyst loading could be reduced to 0.02 mol%; therefore, further development and wide applications are promising. Moreover, (S)-naproxen and (S)-ibuprofen were obtained in over 97% chemical yield and over 97% enantiomeric purity.

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Scheme 25. Hydroboration of terminal alkene strategy for (S)-naproxen synthesis.

Hydroformylation in flow reactions has also been studied for industrial purposes Molecules 2021, 26, 4792 [93–95]. Researchers at the University of Wisconsin-Madison and Eli Lilly Corporate15 of 22 Cen- ter published a paper on the asymmetric synthesis of (S)-naproxen using rhodium-catalyzed hydroformylation, as shown in Scheme 26 [96]. In this paper, gas and liquid reagents reagentswere mixed were in mixed a flow in areactor. ﬂow reactor. After Aftera systematic a systematic survey survey of the of thereactor reactor design design and chiral andligands, chiral (S ligands,)-naproxen (S)-naproxen was produced was produced in two steps in two in steps over in 80% over yield 80% and yield 92% and enantiomeric 92% enantiomericexcess from excessthe simple from thevinyl simple substrate vinyl substrate 72. As this72. Asreaction this reaction is designed is designed to work to work in a contin- inuous a continuous-ﬂow-flow reactor system, reactor system,its use for its use the for industrial the industrial synthesis synthesis of (S of)-naproxen (S)-naproxen is also is possi- alsoble [97] possible. [97].

SchemeScheme 26. 26.Asymmetric Asymmetric hydroformylation hydroformylation strategy strategy for ( Sfor)-naproxen (S)-naproxen synthesis. synthesis BDP;. ( RBDP;,R,R )-Bis-(R,R,R)- diazaphos-SPE.Bisdiazaphos-SPE.

AsymmetricAsymmetric hydrogenation hydrogenation isa is valuable a valuable methodology methodology for chiral for chiral medicine medicine synthe- synthesis sis [98–100]. For NSAID synthesis, the chiral ferrocene-ruthenium complex was reported to [98–100]. For NSAID synthesis, the chiral ferrocene-ruthenium complex was reported to be promising, as shown in Scheme 27 in 2016 [101]. This reduction process was developed forbe NSAIDpromising, synthesis as shown and other in Scheme chiral propionic 27 in 2016 acid [101] skeletons,. Thissuch reduction as artemisinin. process In was some developed examples,for NSAID catalyst synthesis loading and could other be reducedchiral propionic to 0.02 mol%; acid therefore, skeletons, further such development as artemisinin. In Molecules 2021, 26, x FOR PEER REVIEW 16 of 22 andsome wide examples, applications catalyst are promising.loading could Moreover, be reduced (S)-naproxen to 0.02 mol% and (S; )-ibuprofentherefore, further were devel- obtainedopment inand over wide 97% applications chemical yield are and promising. over 97% enantiomericMoreover, ( purity.S)-naproxen and (S)-ibuprofen were obtained in over 97% chemical yield and over 97% enantiomeric purity.

Scheme 27. 27.Asymmetric Asymmetric hydrogenation hydrogenation strategy strategy for (S for)-naproxen (S)-naproxen or (S)-ibuprofen or (S)-ibuprofen synthesis. synthesis.

Other chiral ligands for asymmetric hydrogenation have been reported simultane- Other chiral ligands for asymmetric hydrogenation have been reported simultane- ously [102]. Pursuing high enantioselectivity and low catalyst loading, a new class of ously [102]. Pursuing high enantioselectivity and low catalyst loading, a new class of biphosphorus ligand with a ferrocene moiety was developed and screened. Wudaphos wasbiphosphorus chosen after ligand a survey with of thea ferrocene chiral ligands moiety with was a rhodium developed catalyst and for screened. asymmetric Wudaphos was chosen after a survey of the chiral ligands with a rhodium catalyst for asymmetric reduction (Scheme 28) [103]. Mechanistically, this ligand was designed to interact via hydrogen bonding of the ammonium ion of the ligand and carboxylate ion of the substrate. It is noteworthy that the turnover number (TON) reaches 20,000. Moreover, its high efficiency has received increased industrial attention for chiral NSAIDs or other active pharmaceutical ingredients (APIs).

Scheme 28. Rhodium-catalyzed asymmetric hydrogenation for (S)-naproxen synthesis.

Cobalt-catalyzed asymmetric hydrogenation was also studied, as shown in Scheme 29. During his continuous research on cobalt-catalyzed asymmetric reduction [104], Chi- rik et al. reported that the addition of hydrogen could be enantioselective via cobalt-mediated catalysis [105]. A mechanistic study was also conducted. Carboxylic acid was added to the cobalt complex as a ligand, and the face was selectively reduced. It was validated by X-ray crystallography to elucidate the intermediate structure of the catalyst. This highly effective methodology is compatible with various substrate functionalities.

Molecules 2021, 26, x FOR PEER REVIEW 16 of 22

Scheme 27. Asymmetric hydrogenation strategy for (S)-naproxen or (S)-ibuprofen synthesis.

Other chiral ligands for asymmetric hydrogenation have been reported simultane- ously [102]. Pursuing high enantioselectivity and low catalyst loading, a new class of Molecules 2021, 26, 4792 biphosphorus ligand with a ferrocene moiety was developed and screened.16 of 22 Wudaphos was chosen after a survey of the chiral ligands with a rhodium catalyst for asymmetric reduction (Scheme 28) [103]. Mechanistically, this ligand was designed to interact via hy- reductiondrogen bonding (Scheme 28of)[ the103 ammonium]. Mechanistically, ion of this the ligand ligand was and designed carboxylate to interact ion of via the substrate. hydrogenIt is noteworthy bonding ofthat the the ammonium turnover ion number of the ligand(TON) and reaches carboxylate 20,000. ion Moreover, of the sub- its high effi- strate. It is noteworthy that the turnover number (TON) reaches 20,000. Moreover, its high efﬁciencyciency has has received received increased industrial industrial attention attention for chiralfor chiral NSAIDs NSAIDs or other or activeother active phar- pharmaceuticalmaceutical ingredients ingredients (APIs).

SchemeScheme 28. 28.Rhodium-catalyzed Rhodium-catalyzed asymmetric asym hydrogenationmetric hydrogenation for (S)-naproxen for (S) synthesis.-naproxen synthesis.

Cobalt-catalyzed asymmetric hydrogenation was also studied, as shown in Scheme 29. Cobalt-catalyzed asymmetric hydrogenation was also studied, as shown in Scheme During his continuous research on cobalt-catalyzed asymmetric reduction [104], Chirik et29. al. During reported his that continuous the addition ofresearch hydrogen on could cobalt be- enantioselectivecatalyzed asymmetric via cobalt-mediated reduction [104], Chi- catalysisrik et al. [105 reported]. A mechanistic that the study addition was also of conducted.hydrogen Carboxylic could be acidenantioselective was added to the via cobalt-me- Molecules 2021, 26, x FOR PEER REVIEWcobaltdiated complex catalysis as a ligand,[105]. andA mechanistic the face was selectively study was reduced. also It conducted. was validated Carboxylic by X-ray acid17 ofwas 22

crystallographyadded to the tocobalt elucidate complex the intermediate as a ligand, structure and the of the face catalyst. was selectively This highly effectivereduced. It was val- methodologyidated by X is-ra compatibley crystallography with various to substrate elucidate functionalities. the intermediate structure of the catalyst. This highly effective methodology is compatible with various substrate functionalities.

SchemeScheme 29. 29.Cobalt-catalyzed Cobalt-catalyzed asymmetric asymmetric hydrogenation hydrogenation for (S)-naproxen for (S)- synthesis.naproxen synthesis.

For the asymmetric synthesis of NSAIDs, a different approach was realized by List et al. inFor 2019. the As asymmetric shown in Scheme synthesis 30[ 106 of], chiralNSAIDs, protonation a different of bis-TMS approach ketene was acetal realized75 by List waset al. attempted in 2019. to As afford shown a new in stereogenicScheme 30 center [106] [,107 chiral–110 ].protonation The face-selective of bis protonation-TMS ketene acetal 75 couldwas attempted be accomplished to afford in a a high new ratio stereogenic by using center chiral disulfonimide [107–110]. The76 faceproton-selective donors. protonation Similarly,could be isobutyl accomplished analog 77 inwas a successfullyhigh ratio by transformed using chiral into (disulfonimideS)-ibuprofen. However, 76 proton donors. thisSimilarly, deracemization isobutyl route analog has the77 was drawback successfully that it still transformed requires complete into (S construction)-ibuprofen. However, ofthis a ﬁnal deracemization racemic compound. route Inhas addition, the drawback they must that compete it still with requires traditional complete and well- construction of established chiral resolution routes. Nevertheless, the low catalyst loading and simple procedurea final racemic of this asymmetriccompound. protonation In addition, process they still must indicates compete its potential with traditional for further and well-es- applicationtablished andchiral development. resolution routes. Nevertheless, the low catalyst loading and simple procedure of this asymmetric protonation process still indicates its potential for further application and development.

Scheme 30. Asymmetric protonation strategy for enantiomerically enriched (S)-naproxen or (S)- ibuprofen synthesis. DSI; disulfonimide.

Another synthetic procedure for racemic naproxen was reported in 2018, as shown in Scheme 31 [111]. This procedure features nickel-catalyzed cyanation of benzyl pivalate 79 through methylation and esterification of the resulting secondary alcohol starting from an aromatic aldehyde 78. Zinc cyanide was used as a 0.55 equivalent for low cyanide loading. It is also interesting that the use of zinc ligands suppresses the competing elimination process. Therefore, racemic naproxen was efficiently produced with this four-step synthesis.

Molecules 2021, 26, x FOR PEER REVIEW 17 of 22

Scheme 29. Cobalt-catalyzed asymmetric hydrogenation for (S)-naproxen synthesis.

For the asymmetric synthesis of NSAIDs, a different approach was realized by List et al. in 2019. As shown in Scheme 30 [106], chiral protonation of bis-TMS ketene acetal 75 was attempted to afford a new stereogenic center [107–110]. The face-selective protonation could be accomplished in a high ratio by using chiral disulfonimide 76 proton donors. Similarly, isobutyl analog 77 was successfully transformed into (S)-ibuprofen. However, this deracemization route has the drawback that it still requires complete construction of a final racemic compound. In addition, they must compete with traditional and well-es- Molecules 2021, 26, 4792 tablished chiral resolution routes. Nevertheless, the low catalyst loading and simple17 ofpro- 22 cedure of this asymmetric protonation process still indicates its potential for further application and development.

SchemeScheme 30.30. Asymmetric protonation protonation strategy strategy for for enantiomerically enantiomerically enriched enriched (S ()S-naproxen)-naproxen or or(S) (-S)- ibuprofenibuprofen synthesis. synthesis. DSI; DSI; disulfonimide. disulfonimide.

AnotherAnother syntheticsynthetic procedure procedure for for racemic racemic naproxen naproxen was was reported reported in 2018,in 2018, as shownas shown in Schemein Scheme 31[ 31111 [111]]. This. This procedure procedure features features nickel-catalyzed nickel-catalyzed cyanation cyanation of benzyl of benzyl pivalate pivalate79 through79 through methylation methylation and and esteriﬁcation esterification of the of the resulting resulting secondary secondary alcohol alcohol starting starting from from an aromatican aromatic aldehyde aldehyde78. Zinc78. Zinc cyanide cyanide was was used used as a as 0.55 a 0.55 equivalent equivalent for for low low cyanide cyanide loading. load- Molecules 2021, 26, x FOR PEER REVIEW 18 of 22 Iting is. alsoIt is also interesting interesting that that the the use use of zincof zinc ligands ligands suppresses suppresses the the competing competing elimination elimination process.process. Therefore, Therefore, racemic racemic naproxen naproxen was was efﬁciently efficiently produced produced with with this this four-step four-ste synthesis.p synthesis.

SchemeScheme 31.31. Ni-catalyzedNi-catalyzedcyanation cyanation strategy strategy for for naproxen naproxen synthesis. synthesis Piv;. Piv; pivaloyl, pivaloyl, DMAP; DMAP; 4-dimethyl- 4-dime- aminopyridine,thylaminopyridine, dppf; dppf; 1,10- 1, bis(diphenylphosphino)ferrocene.1′- bis(diphenylphosphino)ferrocene.

BasedBased on the the synthetic synthetic advance advance described described above, above, more more promising promising derivatives derivatives of ibu- of ibuprofenprofen and and naproxen naproxen are are still still studied. studied. Scheme Scheme 32 32 presents presents an an interesting showcase. GrabowskyGrabowsky and Beckmann Beckmann’s’s group group reported reported substitution substitution of of silicon silicon instead instead of ofcarbon carbon at atalkyl alkyl side side chain chain in in ibuprofen ibuprofen structure. structure. This This simple simple sisilicon-substitutedlicon-substituted ibuprofen 8282 showedshowed improvedimproved physicalphysical propertyproperty suchsuch asas solubilitysolubility inin bodybody [[112].112]. Although selectivity onon COX1/COX2 is is still still demanding, demanding, this this simple simple and and direct direct change change of structure of structure can canbe an- be anotherother solution solution for for further further development. development.

SchemeScheme 32.32. IntroductionIntroduction ofof siliconsilicon inin ibuprofenibuprofen structure.structure.

6. Conclusions Since the discovery of aspirin on 10 August 1897, anti-inflammatory medicines have attracted tremendous attention from pharmacologists and medicinal chemists. After the elucidation and differentiation of COX into COX1 and COX2, mechanistic studies were deeply investigated. However, a breakthrough in chemical synthesis was essential for more selective and potent medicines, as the Kolbe–Schmidt reaction occurred in 1859. The reaction suggested that salicylic acid is not supplied from salicin, a natural source, but from a chemical compound, phenol, NaOH, and CO2. It is more impressive that the structural modification of salicylic acid was extensively pursued using the confirmed structure of salicylic acid and its easy availability. Thus, this synthetic breakthrough paved the way for the discovery of aspirin. However, there is still a need for further innovation in NSAID drug development, as the Kolbe–Schmidt reaction did. Gratifyingly, enormous chemical studies on asymmetric synthesis, large-scale preparation, and new methodology development are still ongoing. Based on the achievement, NSAIDs such as ibuprofen or naproxen could be purchased without a price issue nowadays. However, novel demonstrations of a newly developed methodology for ibuprofen or naproxen skeleton are still a good showcase of organic/medicinal chemistry research. In addition, medicinal chemists have tried to find advanced NSAIDs with regard to safety and efficacy. To find selective COX2 inhibitor without undesired side effects, tremendous research is underway. This endeavor includes a simple exchange of atom as well as a modification of mother skeleton in NSAIDs. Thus, it is anticipated that there will be a promising breakthrough in the near future.

Molecules 2021, 26, 4792 18 of 22

6. Conclusions Since the discovery of aspirin on 10 August 1897, anti-inflammatory medicines have attracted tremendous attention from pharmacologists and medicinal chemists. After the elucidation and differentiation of COX into COX1 and COX2, mechanistic studies were deeply investigated. However, a breakthrough in chemical synthesis was essential for more selective and potent medicines, as the Kolbe–Schmidt reaction occurred in 1859. The reaction suggested that salicylic acid is not supplied from salicin, a natural source, but from a chemical compound, phenol, NaOH, and CO2. It is more impressive that the structural modification of salicylic acid was extensively pursued using the confirmed structure of salicylic acid and its easy availability. Thus, this synthetic breakthrough paved the way for the discovery of aspirin. However, there is still a need for further innovation in NSAID drug development, as the Kolbe–Schmidt reaction did. Gratifyingly, enormous chemical studies on asymmetric synthesis, large-scale preparation, and new methodology development are still ongoing. Based on the achievement, NSAIDs such as ibuprofen or naproxen could be purchased without a price issue nowadays. However, novel demonstrations of a newly developed methodology for ibuprofen or naproxen skeleton are still a good showcase of organic/medicinal chemistry research. In addition, medicinal chemists have tried to find advanced NSAIDs with regard to safety and efficacy. To find selective COX2 inhibitor without undesired side effects, tremendous research is underway. This endeavor includes a simple exchange of atom as well as a modification of mother skeleton in NSAIDs. Thus, it is anticipated that there will be a promising breakthrough in the near future.

Author Contributions: M.-W.H. and S.-M.P. planned the paper and wrote the manuscript together. Both authors have read and agreed to the published version of the manuscript. Funding: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (NRF-2020R1F1A1050481). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conﬂicts of Interest: The authors declare no conﬂict of interest. Sample Availability: Samples of the compounds are available from the authors.

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