University of Groningen

Innovative multicomponent reactions and their use in medicinal chemistry Zarganes Tzitzikas, Tryfon

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Download date: 24-09-2021 CHAPTER 6 INDUSTRIAL APPLICATIONS OF MULTICOMPONENT REACTIONS (MCRS)

Chapter contained in the Rodriguez-Bonne book Stereoselectve Multple Bond-Forming Transformatons in Organic Synthesis

2015 by John Wiley & Sons, Inc.

Tryfon Zarganes – Tzitzikas, Ahmad Yazbak, Alexander Dömling Chapter 6

INTRODUCTION

Multcomponent reactons (MCRs) can be defned as processes in which three or more reactants introduced simultaneously are combined through covalent bonds to form a single product, regardless of the mechanisms and protocols involved.[1]

Many basic MCRs are name reactons, for example, Ugi,[2] Passerini,[3] van Leusen,[4] Strecker,[5] Hantzsch,[6] Biginelli,[7] or one of their many variatons. Several descriptve tags are regularly atached to MCRs they are atom economic, for example, the majority if not all of the atoms of the startng materials are incorporated in the product; they are efcient, for example, they efciently yield the product since the product is formed in one-step instead of multple sequental steps; they are convergent, for example, several startng materials are combined in one reacton to form the product; they exhibit a very high bond-forming-index (BFI), for example, several non-hydrogen atom bonds are formed in one synthetc transformaton.

Since MCRs are ofen highly compatble with a range of unprotected orthogonal functonal groups, on a second level, the scafold diversity of MCR can be greatly enhanced by the introducton of orthogonal functonal groups into the primary MCR product and react them in subsequent transformatons, e.g. ring forming reactons. This two layered strategy has been extremely fruitul in the past leading to a great manifold of scafolds now routnely used in combinatorial and medicinal chemistry for drug discovery purposes.[8]

A versatle example of this strategy are the Ugi-Deprotecton-Cyclizaton procedures (UDC) leading to a great scafold diversity, e.g. benzimidazoles, benzodiazepinedione, tetrazolodiazepinone, quinoxalinones, γ-lactams, and piperazines.[9] Similarly multple bond-forming transformatons (MBFTs) require the involvement of substrates exhibitng multple potental reacton sites and the selectve control of their reactvity in each individual bond-forming event. Some classes of densely functonalized small molecules have been shown to be partcularly suited for use in these transformatons, and in this context, 1,2- and 1,3-dicarbonyl compounds are exceptonal synthetc platorms.[10] The rapid and easy access to biologically relevant compounds by MCRs and their scafold diversity has recognized them by the synthetc community in industry and academia as a preferred method to design and discover biologically actve compounds. Although the list of MCR applicatons towards the synthesis of marketed drugs or drugs under development is much longer we will focus and discuss in the following chapters eight recent examples.

140 Industrial applicatons of multcomponent reactons (MCRs)

APPLICATIONS OF MCRS

Xylocaine The reacton of isocyanides, oxo components, and primary or secondary amines yields α-amino carbonamides, as disclosed by Ugi in 1959. The reacton has been employed by Ugi early on to synthesize the local anesthetc Xylocaine (Scheme 1).[11] It clearly shows the genius of Ivar Ugi who recognized the important applicatons of MCR chemistry several decades before the area of combinatorial chemistry was born. Xylocaine alters depolarizaton in neurons, by blocking the fast voltage gated sodium (Na+) channels in the cell membrane. While there are many synthetc approaches towards Xylocaine such as the one in (Scheme 1) Ugi’s approach is amongst the shortest and without doubts the most convergent and diverse one. e.g. many newer derivatves of the same class of anesthetcs can be synthesized by the same route by simple variaton of the three startng material classes, amine, oxo and isocyanide components (Scheme 2).

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Scheme 1. Synthesis of Xylocaine

Almorexant Almorexant is a frst-in-class orexin receptor antagonist that was undergoing phase III clinical development for insomnia untl 2011. The tetrahydroisoquinoline derivatve was originally discovered from a series of Ugi/Pictet−Spengler reacton products. Originally developed by Actelion, from 2007 Almorexant was being reported as a potental blockbuster drug, as its novel mechanism of acton (orexin receptor antagonism) was thought to produce beter quality sleep and fewer side efects than the traditonal benzodiazepine and z-drugs, that dominate the mult- billion dollar insomnia medicaton market. [12]

141 Chapter 6

Scheme 2. Derivatves of Xylocaine

Figure 1 . Structure of Almorexant

The discovery synthesis of Almorexant starts with an Ugi three-component reacton (Ugi-3CR) between benzaldehyde (4), 2-(3,4-dimethoxyphenyl)ethanamine (5) and methyl isocyanide (6) afording product 7, which in a post Pictet−Spengler reacton with 3-(4-(trifuoromethyl)phenyl) propanal (8) in the presence of strongly acidic conditons gives the end product Almorexant (9). Clearly, the synthesis is not stereoselectve and yields four diferent stereoisomers of which only one is biologically highly actve (Scheme 3).

142 Industrial applicatons of multcomponent reactons (MCRs)

Scheme 3. Discovery synthesis of Almorexant involving a one pot Ugi-3CR and Pictet-Spengler-2CR reacton

Lefort et al. reported on two new efcient catalytc systems for the enantoselectve synthesis of intermediate 10 needed for the synthesis of Almorexant (Scheme 4).[13] The frst one relies on an asymmetric hydrogenaton of 11 using an iridium complex with a ferrocene-based ligand while the second one relies on an asymmetric transfer hydrogenaton of 11 using a ruthenium catalyst with a diamine ligand. Both catalysts were studied further and appeared to be suited for large- scale manufacturing (Scheme 5). In case Almorexant had not been stopped from phase III clinical development in 2011, a fnal choice would have been guided mainly by the cost of goods for the two routes, considering the availability of the producton units and the delivery tme of the raw materials.

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Scheme 4. Almorexant and its key intermediate

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Scheme 5 . Asymmetric hydrogenaton of 11 with Ir/TaniaPhos and asymmetric transfer hydrogenaton with Noyori catalyst towards 10

Interestngly TaniaPhos catalysts used in the asymmetric hydrogenatons can be synthesized from the (R)-Ugi amine 15 in two steps.[14] The (R)-Ugi amine can be synthesized via a Mannich reacton between ferrocene 12, dimethyl amine (13) and acetaldehyde (14) (Scheme 6).[15]

Scheme 6. Synthesis of (R)-Ugi amine

144 Industrial applicatons of multcomponent reactons (MCRs)

(−)-Oseltamivir (Tamilfu®) New infectous diseases appear regularly in diverse parts of the globe, most recently swine fu, creatng new global health threats. The upcoming of new multple drug resistance seasonal fu and infectous and deadly infuenza pandemics in regular intervals of 20-40 years is of great concern. Current weaponry to fght infuenza can only build on a handful of chemotherapeutc optons besides immunizaton. While immunizaton is suitable to control seasonal fu it is not believed to work with new fu pandemics. The antinfuenza neuraminidase inhibitor (−)-oseltamivir is one of the few remaining chemotherapy optons and has been recently synthesized by the Hayashi group by a remarkably short and high yielding asymmetric synthesis (Scheme 7).[16] The synthesis consists of a one-pot MCR involving the Michael reacton of α-alkoxyaldehyde (16) and cis- nitroalkene 17, catalyzed by (S)-diphenylprolinol silyl ether (18), proceeded in the presence of

HCO2H in chlorobenzene to aford the Michael product 19 in good yield with excellent diastereo and enantoselectvity. Ethyl acryl derivatve 20 and Cs2CO3 were added to the same pot generatng the desired product 21 and two diferent intermediates which were later converted into 21 by the additon of EtOH. In the next step the Michael reacton of toluenethiol (22), followed by epimerizaton at the α-positon of the nitro group, aforded the thiol Michael adduct 23a with the desired stereochemical confguraton. By additon of Zn and TMSCl to the same vessel, reducton of the nitro group gave the amine 23b, from which a retro-Michael reacton of the thiol group proceeded by treatment with base to aford Oseltamivir (Tamilfu®) in a single pot and without the need to exchange or evaporate solvents. The gram-scale synthesis was demonstrated in 28% total yield, to aford 1.02 g of product from nitroalkene 17 (1.5 g) in a one-pot procedure (Scheme 7).

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Scheme 7 . One-pot synthesis of (−)-Oseltamivir

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Telaprevir (Incivek®) Hepatts C is a viral infectous disease afectng more than 200 million people worldwide and is currently treated by a combinaton of PEGylated interferon and ribavirin. However, a signifcant number of patents do not respond to this therapy due to adverse efects or viral rebound due to resistant strains. Recently, the hepatts C virus (HCV) NS3 protease has emerged as a clinically validated target for the treatment of hepatts C infecton. Two peptdic HCV NS3 protease inhibitors Telaprevir and Boceprevir (Figure 2) have recently been approved for the treatment of HCV infecton. The reported technical synthesis of Telaprevir involves a lengthy, highly linear strategy relying on standard peptde chemistry and involving more than 20 steps.[17] For example, the central bicyclic proline derivatve is synthesized in racemic form via a nine-step sequence. The desired enantomer is only obtained afer chiral HPLC separaton. Optmizaton of the synthesis of Telaprevir could signifcantly lower the cost of goods, thereby making this promising drug available to an increased proporton of the world populaton in the future.

Figure 2 . HCV NS3 protease inhibitors

Recently Orru and co-workers composed a highly efcient and stereoselectve synthesis of Telaprevir (Incivek®) based on biocatalysts and multicomponent reactions (MCRs).[18] The synthesis is comprised of only eleven steps in total compared to twenty-four in the originally reported procedure.

Scheme 8. Retrosynthetc analysis of Telaprevir (Incivek®)

146 Industrial applicatons of multcomponent reactons (MCRs)

A retrosynthetc analysis of 24 using an MCR sequence is presented in (Scheme 8). The required startng materials for the key Ugi-type 3CR were the carboxylic acid 25, cyclic imine 26, and isocyanide 28. The acid 25 could be accessed by standard peptde chemistry, while imine 26 was generated in situ from commercially available (27) by catalytc oxidaton with enzyme MAO-N (monoamine oxidase N) from Aspergillus niger. The isocyanide 28 was accessed via a Passerini three-component reacton (P-3CR) of 29, 30, and acetc acid.

Coupling of pyrazinecarboxylic acid (33) and L-Cyclohexylglycine methyl ester (34) with a subsequent saponifcaton aforded 35 in excellent yield (Scheme 9). Subsequent coupling with L-tert-Leucine methyl ester 36 and saponifcaton furnished the required optcally pure acid 37. The Orru group was able to signifcantly increase both the atom and step economy and the overall yield (74% vs. 11% over four steps) of acid 37 compared to the already known synthesis.

Scheme 9. Synthesis of chiral carboxylic acid 37

The constructon of the isocyanide fragment 28 was done in three steps in which a Passerini three-component reacton (P-3CR) played a key role. Commercial (S)-2-amino-1-pentanol (32) was transformed to formamide 33 by N-formylaton. Following the work of Ngouansavanh and Zhu,[19] 6 the group was able to combine both the oxidaton of alcohol 33 and a P-3CR which gave access to 34 in a one-pot process. Both the alcohol oxidaton and the Passerini reacton were performed in CH2Cl2, with the acetc acid, a by-product in the Dess–Martn oxidaton, used as the carboxylic acid input in the P-3CR. Thus, one-pot Dess–Martn oxidaton/Passerini reacton of 38 furnished 39 in 60% yield. Dehydraton then aforded the required isocyanide 28 in very good yield (87%). No racemizaton of the C3 stereocenter was observed. This crucial fragment was thus accessible in only three steps from commercial startng materials (Scheme 10).

Scheme 10. Synthesis of chiral isocyanide 28

The last step towards the three-component Ugi-type coupling envisaged in the retrosynthesis is described below. The, commercial amine 27 was oxidized to imine 26 (94% ee) by MAO-N

147 Chapter 6

(monoamine oxidase N) as it was previously described,[20] then combined with 25 and 28 give the advanced intermediate 40. Finally, cleavage of the acetate followed by Dess–Martn oxidaton gave Telaprevir (24) as a 83 : 13 : 4 mixture of diastereomers, with one minor diastereomer derived from the incomplete stereoinducton of the Ugi-type 3CR, and the other from the minor enantomer of imine 26. Flash chromatography allowed straightorward separaton of the diastereomers to aford pure Telaprevir (24) in 80% yield over the last two steps (Scheme 11).

Scheme 11. Endgame of the MCR synthesis of Telaprevir (Incivek®)

Ezetmibe (Zeta®)

Figure 3. Ezetmibe (Zeta®)

Another recently approved compound is the cholesterol absorpton inhibitor Ezetmibe (Zeta©) (Figure 3) discovered and initally produced by Schering-Plough, with a linear synthesis of 7 steps.[21-23] The commercial process towards the synthesis of Ezetmibe (Zeta®) starts with a CBS reducton (5% catalyst load) of ketone 41, afording chiral alcohol 42 in 95% yield. Judicious choice of the trimethylsilyl protectng group allowed clean in situ protecton of both the benzylic and phenolic hydroxyl groups with TMS-Cl. Alcohol 42 was treated with two equivalents of TMS-Cl, followed by ttanium enolate formaton (TiCl4), and then additon of phenolic imine. Excess TMS-Cl present in the reacton reacted with the C4-phenol to aford crystalline 43. Cyclizaton mediated by BSA and TBAF proceeded smoothly, but two equivalents of TBAF were required to get complete deprotecton of the benzylic and phenolic hydroxyl groups. Minor modifcatons of this process have been used to produce Ezetmibe (Zeta®) on a commercial scale (Scheme 12). [24-25]

148 Industrial applicatons of multcomponent reactons (MCRs)

Scheme 12. Schering-Plough commercial process to Ezetmibe (Zeta®)

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Scheme 13. Staudinger-3CR process to Ezetmibe (Zeta®)

Alternatvely the multcomponent Staudinger-3CR can also be used in order to access to Ezetmibe (Zeta®).[26] In fact the frst synthesis of ezetmibe was based on a Staudinger type reacton.

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Treatment of acyl chloride 44 with imine 45 in the presence of a base aforded trans-β-lactam 46 containing adequate substtuton at the nitrogen and C4 carbon atoms (Scheme 13). Pure enantomers were isolated by means of chiral chromatography. Ester hydrolysis, formaton of the corresponding acyl chloride, and subsequent Negishi-type coupling gave ketone 47, which was reduced with borane-methyl sulfde complex afording a mixture of diastereoisomers that were again separated by chiral chromatography. Final debenzylaton led to the desired product Ezetmibe (Zeta®).

Crixivan (Indinavir®) HIV-1 protease (HIV) is known to play a critcal role in the reproducton of human immunodefciency virus, the causatve agent for AIDS. Site directed mutagenesis of this virally encoded protease resulted in the producton of noninfectous virions. Therefore, HIV-1 protease has been considered as one of the most atractve targets for AIDS chemotherapy. Much efort has been concentrated on the development of efectve inhibitors of HIV and a number of inhibitors featuring various structural motfs have been reported.[27]

Of the currently available HIV medicatons seven of them are HIV protease inhibitors. Similar to the above mentoned HCV NS3 protease inhibitors the described inhibitors are quite large and have a peptde-like appearance. Ofen they have to be synthesized by sequental up to 20 steps synthesis. Therefore it is worthwhile to consider alternatve synthetc approaches involving MCRs. E.g. the key intermediate piperazine 49 of Crixivan (Indinavir®) produced by Merck was advantageously and stereoselectvely synthesized using a key and quanttatve U-4CR followed by an enantoselectve hydrogenaton.[28]

A key step in the assembly of the HIV protease inhibitor Crixivan (Indinavir®) is the coupling of the enantomerically pure epoxide 48 with the enantomerically pure piperazine 49 to aford the backbone of the drug (Scheme 14).

Scheme 14. Synthesis of Crixivan

The synthesis of the epoxide 48 is described in (Scheme 15) in three steps startng with a diastereoselectve allylaton of the lithium (Z)-enolate of 50 followed by a diastereoselectve conversion of 51 to iodohydrin 52 via NIS-mediated cyclic iodoimidate formaton and hydrolysis. Finally a base-mediated conversion of 52 to the epoxide 48 was accomplished with all three steps having excellent yields.[29]

150 Industrial applicatons of multcomponent reactons (MCRs)

Scheme 15. Synthesis of epoxide 48

In contrast the second main building block for the synthesis of the drug, piperazine 49 was not that easily prepared due to the large number of steps (fve) needed to get access to the hydrogenaton intermediate 53. So although the chiral hydrogenaton occurs in high yield and high ee using the Rh-BINAP catalyst (Scheme 16), the synthesis of 49 was abandoned and a new methodology involving an Ugi- 4CR was introduced.

Scheme 16. Synthesis of piperazine 49

Piperazine 49 was ingeniously assembled from readily available startng materials such as N-Boc- ethylenediamine (54), dichloroacetaldehyde (55), tert-butyl isocyanide (56) and formic acid. The resultng Ugi adduct 57 could be isolated; however, the desired vinylchloride 58 was obtained 6 more conveniently in essentally quanttatve overall yield by the Et3N induced HCl eliminaton from 57. Interestngly, 58 exists as a single diastereomer which is the Z-isomer (Scheme 17). [28]

Scheme 17. Synthesis of 58, precursor of piperazine 49

The subsequent cyclizaton of 58 to 59 proved difcult. The most promising results were obtained with alkoxide bases such as LiOtBu, NaOtBu and KOtBu with KOtBu being the best choice. An acceptable yield (60%) in the cyclizaton was realized by careful control of the amount of base, concentraton and solvent of the reacton. With a short synthesis of the tetrahydropyrazine

151 Chapter 6

59 in hand, Merck also examined the chiral hydrogenaton of this substrate (Scheme 18). Tetrahydropyrazine 59 difered from the frequently examined N-acyl dehydroaminoacid hydrogenaton substrates not only by the positon of the double bond in the ring between two nitrogen atoms, but also by the scarcely precedented use of the formyl group for the protecton of N-1. A screen of various Rh and Ru based catalysts under a standard set of conditons (3.5 atm

H2, 18 h, MeOH, 2 mol% catalyst) was undertaken. The best actvity and enantoselectvity was obtained using the Rh-BINAP catalyst and complete conversion of 59 to 60 could be achieved at

100 atm H2 pressure at 40 °C in MeOH with 7 mol% catalyst giving the product 60 with 97% ee.

Scheme 18. Final steps for the synthesis of 49

In the last step of the synthesis the formyl group in 60 had to be removed without the racemizaton of the newly formed chiral center. Since the N-1 protectng group is derived from the acid used in the Ugi condensaton, the use of a carbamate protectng group, such as Cbz, was precluded. The scientsts envisioned that only easily deprotected amides, such as formamide, might allow for the required mild deprotecton. Indeed, treatment of 60 with dilute aqueous NaOH cleanly removed the formyl group, but with concomitant racemizaton: the ee of 49 was reduced to 80% from the 99% of the startng material even when the deprotecton was performed at 0 °C. Remarkably, heatng 60 with 35% aqueous hydrazine led to a clean deprotecton to give 49 in 91% yield while leaving the enantomeric purity essentally unchanged at 98% (Scheme 18).

Oxytocine Antagonists: Retosiban and Epelsiban Preterm labor is the major reason for neonatal morbidity and occurs in 10% of all birth worldwide. Currently, antagonistc derivatves of the neurohypophyseal nonapeptde hormone oxytocin are used to control preterm labors, however they are associated with the typical disadvantages of peptde drugs, such as lacking oral bioavailability, short half life tme and potental immunogenicity. The diketopiperazine scafold 61 has been discovered in a HTS campaign which afer further medicinal chemistry optmizaton developed to the frst clinical class of small molecular weight oxytocin antagonists Epelsiban and Retosiban. The later is also the frst oxytocin antagonist drug developed for the treatment of premature ejaculaton in men (Scheme 19).[30,31]

Because of the convergent and efcient nature of the MCR chemistry detailed SAR of the scafolds substtuents could be performed giving rapid access to all eight stereoisomers of this Ugi DKP backbone in a landmark paper involving Ugi chemistry.[32]

152 Industrial applicatons of multcomponent reactons (MCRs)

Scheme 19. Oxytocin antagonists Epelsiban and Retosiban

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Scheme 20. SAR of 2,5-DKP

E.g. reacton of the chiral N- and C-protected amino acid derivatves 62 and 63, respectvely with tert-butyl isocyanide 64 and benzaldehyde 65 yields the Ugi product 66. N-deprotecton and cyclizaton under basic conditons yields the two stereoisomers 67 (R,R,R) and 68 (R,R,S) difering in the benzaldehyde-derived stereocenter. The two diastereomers can be conveniently separated using silica chromatography (Scheme 21).

The (R,R,R) stereoisomer (67) can be prepared alternatvely using an inital U-5C-4CR employing unprotected L-Leu HCl salt (69), benzaldehyde (65) and tert-butyl isocyanide (64), yielding the iminodicarboxylic acid mono amide derivatve 70 in very good yields and diastereoselectvity. Saponifcaton, acylaton, N-deprotecton and subsequent cyclizaton yields the expected stereoisomer 67 on a mult mg scale. The other stereoisomers were synthesized using similar strategies and enantomerically pure amino acids as startng materials. It is important to note that two diferent variatons of the Ugi chemistry have been employed in this exercise, the U-5C-4CR

153 Chapter 6

and the Ugi-4CR (Scheme 22). Interestngly both the discovery synthesis and the later technical syntheses of the two clinical compounds are performed by Ugi chemistry.

Scheme 21. Synthesis of the (R,R,R)-67 and (R,R,S)-68 stereoisomers of Oxytocin Antagonist Derivatves

Scheme 22. Alternatve MCR Synthesis of the (R,R,R) stereoisomer 67 of oxytocin antagonist derivatves.

General procedure for the preparaton of compounds 67 and 68 by Sollis et al.:[32] To a soluton of (R)-leucine methyl ester hydrochloride (63) (600 mg) in methanol (8 mL) was added triethylamine (0.46 mL) and benzaldehyde (65) (0.22 mL). The mixture was strred for 2.5 h before (2R)-[(t-butoxycarbonyl)amino](2,3- dihydro-1H-inden-2-yl)ethanoic acid (62) (962 mg) and t-butylisonitrile (65) (0.56 mL) were sequentally added. Afer being strred for 18 h, the solvent was removed in vacuo, and the residue was dissolved in dichloromethane (4 mL) and trifuoroacetc acid (10 mL) and strred for 3 h at ambient temperature. Afer this tme, the solvent was removed in vacuo. The residue was treated with triethylamine in dioxane (2% soluton, 20 mL)

154 Industrial applicatons of multcomponent reactons (MCRs)

and was lef to str overnight. Afer this tme, the dioxane was removed in vacuo, and the residue was dissolved in dichloromethane. The soluton was washed with 0.1 M hydrochloric acid soluton, and the organic phase was separated using a hydrophobic frit and evaporated in vacuo. This crude material was purifed by fash chromatography elutng with ethyl acetate/cyclohexane (50-100% ethyl acetate) to give the less polar diastereomer, (2R)-N-(t-butyl)-2-[(3R,6R)- 3-(2,3-dihydro-1H- inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1- yl]-2-phenylethanamide (67) as a white solid (120 mg, 19%). This also gave the more polar diastereomer 68 as a white solid (622 mg, 40%).

Praziquantel (Biltricide®) Neglected tropical diseases (NTDs) such as schistosomiasis, ascariasis, trichuriasis, hookworm infecton, and onchocerciasis are a group of infectous conditons, that mainly afict the world’s poorest people leading to chronic or long-term illness, impaired childhood development, disfgurement, and decreased productve capacity. They are thus the primary reason for the poverty of the majority of people in developing countries. Three drugs are currently used to fght the most devastatng and common NTDs with Praziquantel (PZQ or Biltricide®) (76) being the most efectve to treat Schistosomiasis.[33] While the other two drugs are fully donated by the producing pharmaceutcal companies to treat the sufering populaton, unfortunately, Praziquantel is currently not donated in sufcient quanttes. So the need for a cheap and environmental friendly route to it synthesis have interested the scientfc and industrial community for a long tme. In the next paragraphs we discuss some examples of these eforts and ultmately present and discuss an MCR approach that proves to be the fastest and easiest access to Praziquantel while compettve by cost-of-good measures.

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Figure 4. Praziquantel (PZQ or Biltricide®)

The classical Merck synthesis frst proposed in 1977 is stll widely used to produce Praziquantel (Biltricide®) on a large scale.[34] It consists of a fve-step sequental synthesis using inexpensive and readily available startng materials. The frst step is a Reissert reacton of isoquinoline 71 with potassium cyanide and benzyl chloride to give 72 in 95% yield. The resultng product 72 is catalytcally hydrogenated under pressure to yield 73. Further acylaton with chloroacetyl chloride 74 yields 75. Base-catalyzed ring closure and fnal hydrogenaton of the benzoyl group yields PZQ-(76).[35] The frst step of this sequence (71 to 72) is can be environmentally unfriendly due to the use of highly toxic cyanide which is used in great excess along with large quanttes of toxic aqueous waste. In fact deadly accidents have been reported repeatedly in China (Scheme 23).

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Scheme 23. First synthesis of PZQ-(76) by Seubert at Merck

In early 1983 the Korean company Shin Poong pursued a low-cost strategy to produce PZQ-(76) in bulk and to circumvent extensive patent protecton, and thus became by 1993 the largest global producer of PZQ-(76). Their strategy involves treatment of chloroacetyl chloride (74) with phenylethylamine (77) to give (78), which then undergoes an amino alkylaton reacton with amino acetaldehyde dimethyl acetal to produce 79. Cyclizaton to 80 was achieved by treatment with concentrated sulfuric acid. Compound 80 was then converted by acylaton with cyclohexane carbonyl chloride to PZQ-(76) (Scheme 24).[36]

Scheme 24. The Shin Poong process to PZQ

Currently one other company also produces PZQ-(76) at producton scale using a method similar to that of Shin Poong. In their process, phenylethylamine (77) is treated with glycyl chloride hydrochloride (81) to produce (82). This then undergoes an amino alkylaton reacton with 2-chloro-1,1-dimethoxyethane to produce 83, which is then cyclized via polytungstc acid in dichloromethane. Compound 80 is then converted by acylaton with cyclohexane carbonyl chloride to PZQ-(76) (Scheme 25).[37]

156 Industrial applicatons of multcomponent reactons (MCRs)

Scheme 25. The Yixing Xinyu Chemical factory process to PZQ-(76)

The latest and most convergent additon to the manifold PZQ-(76) syntheses was described by Cao and Dömling (Scheme 26).[38] This efcient synthesis employs, as a key step, an Ugi four-component reacton (U-4CR) between the readily available cheap startng materials phenylethyl isocyanide (84), formaldehyde (86), amino acetaldehyde dimethyl acetal (85), and cyclohexane carboxylic acid (87). The Ugi reacton gives the advanced intermediate 88 in quanttatve yield under mild conditons. Compound 88 can be converted into PZQ-(76) by a Pictet–Spengler reacton under strongly acidic conditons. Overall, this short two-step process afords PZQ-(76) from inexpensive and readily available startng materials in 70% yield.

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Scheme 26. Ugi MCR PZQ-(76) synthesis by Dömling et al.

General procedure for the preparaton of compound 76 by Dömling et al.:[38] Synthesis of 88 (Ugi reacton): To a mixture of paraformaldehyde (86) (3.33 g, 0.11 mol), 2,2-dimethoxyethylamine (85) (11.67 g, 0.11 mol), and cyclohexyl carboxylic acid (87) (14.22 g, 0.11 mol) in methanol (110 mL) (2-isocyanoethyl)benzene (84) (15.0 g, 0.11 mol) was added dropwise at 8 °C. Afer strred at room temperature for 48 h, the mixture was concentrated. The residue was dissolved in diethyl ether (150 mL) and washed with water (100 mL) and brine (100 mL), and dried over anhydrous magnesium sulfate. The drying agent was removed by fltraton. Afer concentraton, pale yellowish oil was obtained, which upon standing crystallizes to yield 88 (40.9 g, 98%).

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Synthesis of Praziquantel (76); (Pictet–Spengler reacton): N-(2,2- Dimethoxyethyl)-N-(2-oxo-2-(2 phenethylamino)ethyl)cyclohexanecarboxamide (70) (30.0 g, 79.8 mmol) was added porton wise to methanesulfonic acid (104.0 mL, 1.6 mol) at 8 °C. Afer heatng to 70 °C for 6 h, the reacton mixture was poured into an ice-water mixture and adjusted to pH 8 with an aqueous soluton of NaOH (20%). The soluton was extracted with diethyl ether (4×100 mL). The combined organic layers were washed with brine (100 mL), dried and concentrated to aford 75 (19.0 g, 76%) as yellowish solid. The residue was recrystallized from ethyl acetate/hexane (1:1) to aford 76 (16.2 g, 65%) as a white solid.

SUMMARY AND OUTLOOK

Diferent large scale technical syntheses of six marked drugs along with two drugs that are currently in clinical trials are presented in this book chapter. The authors try to describe the power and efciency of multcomponent reactons (MCRs) through detailed schemes on how this approach towards the synthesis of a drug or even an intermediate is always more atractve, useful and intellectually stmulatng. Each sub-chapter gives a short introducton about the original/ commercial synthetc approach with which a drug is produced. Clearly, each applicaton of MCR in the synthesis of drugs has its domain of applicaton. Sometmes MCR might be specifcally useful in the discovery chemistry for the fast and tme saving evaluaton of structure actvity relatonship of a compound class. However the discovery route might not be pursued during the GMP upscaling of large quanttes for clinical trials. Instead another chemistry route might be used, e.g. due to issues of stereochemistry. In other cases, however, modifed MCR chemistries also used in the preclinical discovery routes might be suitable for upscaling of material. Clearly, the growing number of compounds on the market and in development discovered and synthesized by MCR technologies manifests their growing importance for the scientfc and industrial community.

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