Synthetic Approaches To The New Drugs 2011

Bioorganic & Medicinal Chemistry 21 (2013) 2795–2825 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc Review Synthetic approaches to the 2011 new drugs Hong X Ding a, , Kevin K.-C Liu b,à, Subas M Sakya c,§, Andrew C Flick c,–, Christopher J O’Donnell c,⇑ a b c Shenogen Pharma Group, Beijing, China Pfizer Inc., San Diego, CA 92121, USA Pfizer Inc., Groton, CT 06340, USA a r t i c l e i n f o Article history: Received January 2013 Revised 12 February 2013 Accepted 19 February 2013 Available online April 2013 a b s t r a c t New drugs are introduced to the market every year and each represents a privileged structure for its biological target These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs This review covers the synthesis of 26 NCEs that were launched in the world in 2011 Ó 2013 Elsevier Ltd All rights reserved Keywords: Synthesis New drug molecules New chemical entities Medicine Therapeutic agents Contents 10 11 12 13 14 15 16 17 18 19 20 21 22 Introduction Abiraterone acetate (ZytigaÒ) Alcaftadine (LastacaftÒ) Apixaban (EliquisÒ) Avanafil (ZepeedÒ, StendraÒ) Azilsartan kamedoxomil (EdarbiÒ) Bilastine (BilaxtenÒ) Boceprevir (VictrelisÒ) Brentuximab vedotin (AdcetrisÒ) Ceftaroline fosamil acetate (TeflaroÒ) Crizotinib (XalkoriÒ) Edoxaban tosilate (LixianaÒ) Eldecalcitol (EdirolÒ) Gabapentin enacarbil (HorizantÒ) Icotinib hydrochloride (ConmanaÒ) Linagliptin (TrajentaÒ) Lurasidone hydrochloride (LatudaÒ) Mirabegron (BetainsÒ) Retigabine/Ezogabine (TrobaltÒ/PotigaÒ) Rilpivirine hydrochloride (EdurantÒ) Ruxolitinib phosphate (JakafiÒ) Telaprevir (IncivekÒ) 2796 2796 2796 2796 2796 2797 2799 2801 2803 2806 2807 2808 2810 2811 2811 2813 2813 2813 2813 2815 2816 2817 ⇑ Corresponding author Tel.: +1 860 715 4118 E-mail addresses: Hongxia.ding@shenogen.com (H.X Ding), Liu_kang_zhi_kevin@lilly.com (K.K.-C Liu), subas.m.sakya@pfizer.com (S.M Sakya), andrew.flick@pfizer.com (A.C Flick), christopher.j.odonnell@pfizer.com (C.J O’Donnell)   Tel.: +86 10 8277 4069 Current address: Lilly China Research and Development Center, Shanghai, China Tel.: +86 21 2080 5590 § Tel.: +1 860 715 0425 – Tel.: +1 860 715 0228 0968-0896/$ - see front matter Ó 2013 Elsevier Ltd All rights reserved http://dx.doi.org/10.1016/j.bmc.2013.02.061 2796 23 24 25 26 27 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 Ticagrelor (BriliqueÒ) Vandetanib (CaprelsaÒ, ZactimaÒ, ZictifaÒ) Vemurafenib (ZelborafÒ) Vilazodone hydrochloride (ViibrydÒ) Zucapsaicin (ZuactaÒ) Acknowledgment References and notes Introduction ‘‘The most fruitful basis for the discovery of a new drug is to start with an old drug.’’—Sir James Whyte Black, winner of the 1988 Nobel Prize in medicine.1 This annual review was inaugurated 10 years ago2–10 and presents synthetic methods for molecular entities that were launched in various countries during 2011 It was a productive year for the pharmaceutical industry in 2011, a total of 38 NCEs and biologics for therapeutic use reached the market for the first time.11–13 This review focuses on the syntheses of 26 small molecule NCEs that were launched in 2011 (Fig 1), including the first novel antibody drug conjugate that utilizes a linker/payload prepared by total synthesis New indications for previously launched medications, new combinations, new formulations of existing drugs, and drugs synthesized purely via bio-processes or peptide synthesizers have been excluded from this review Although the scale of the synthetic routes was not disclosed in most cases, this review attempts to highlight the most scalable routes based on published or patent literature, and is arranged in alphabetical order by the drug’s generic name The synthesis of new products that were approved for the first time in 2011 but were not launched before the year’s end will be covered in our next review Abiraterone acetate (ZytigaÒ) Abiraterone acetate was approved by the U.S Food and Drug Administration (FDA) in April 2011 for the treatment of castrationresistant prostate cancer.14 The drug, marketed under the trade name ZytigaÒ, was originally discovered by researchers at the Cancer Research UK Centre for Cancer Therapeutics in 1990, developed by Cougar Biotechnology, and ultimately commercialized by Johnson & Johnson after its acquisition of Cougar in 2009 Abiraterone acetate inhibits CYP17A1—an enzyme expressed in testicular, adrenal, and prostatic tumor tissues—which has been implied in the production of testosterone and the proliferation of such tumor cell lines.15 The most convenient synthesis for scale-up will be highlighted from two published syntheses (Scheme 1).16–22 Commercially available androstenolone was acylated with acetic anhydride in the presence of boron trifluoride-diethyl etherate to give a near quantitative yield of acetate 2.19 The conversion of ketone to vinyl triflate involved careful selection of base to prevent elimination of the acetate group.19 To this extent, subjection of to triflic anhydride in dichloromethane at ambient temperature followed by slow addition of triethylamine minimized undesired side products and delivered triflate in 60% isolated yield Subsequent Suzuki coupling with diethylborane under standard conditions ultimately furnished abiraterone acetate (I) in 75% yield Alcaftadine (LastacaftÒ) Alcaftadine, an ophthalmic histamine H1 receptor antagonist, was approved by the FDA for the prevention of itching associated with allergic conjunctivitis and was launched under the trade name LastacaftÒ in early 2011.11,23 Alcaftadine was discovered by Janssen Pharmaceuticals and marketed by Vistakon Pharmaceuticals, both subsidiaries of Johnson & Johnson However, unlike other 2818 2821 2821 2822 2823 2823 2823 marketed drugs, the synthesis of alcaftadine was only mentioned in the patents filed by Janssen’s scientists approximately twenty years ago The synthetic route described in Scheme is based on the discovery route disclosed in those patents.24,25 1-(2-Phenylethyl)-1H-imidazole is now commercially available, otherwise it could be prepared by reacting imidazole (5) with 2-phenylethyl bromide (6).24–26 With pyridine and triethylamine as base, imidazole was reacted with acyl chloride to provide piperidinecarboxylate in 34% yield, followed by acid hydrolysis with 48% HBr aqueous solution to obtain piperidine dihydrobromide 10 in 98% yield The N-methylation of 10 was acheived by Leuckart reaction with formaldehyde and formic acid to give 4-methylpiperidine 11 in 82% yield Treatment of 11 with trifluoromethanesulfonic acid followed by subsequent basification triggered an intramolecular alkylation–dehydration reaction to generate benzazepine 12 Next, alcohol 13 was obtained by prolonged exposure (7 days) of 12 to hydroxymethylation conditions using 40% aqueous formaldehyde Oxidation of 13 with manganese (IV) oxide provided alcaftadine (II).24,25 The yields of last three steps from compound 11 to alcaftadine (II) were not provided in the patent Apixaban (EliquisÒ) Apixaban is an oral anticoagulant with highly selective inhibition of factor Xa It was approved by the European Medicines Agency (EMA) for the treatment of venous thromboembolic events and first marketed in Germany under the brand name EliquisÒ in June 2011.11 Apixaban was co-developed by Bristol-Myers Squibb and Pfizer and represents the first approved drug for this indication since warfarin over 50 years ago Although several convenient preparations of apixaban (BMS-562247) have been reported,27–30 the most likely process-scale route is described in Scheme The starting material 4-iodoaniline (14) was acylated with 5-bromovaleryl chloride (15) and triethylamine followed by cyclization under basic conditions to give lactam 16 in 49% yield Intermediate 16 was then reacted with phosphorus pentachloride to provide the a,a-dichlorinated lactam 17 in 87% yield.30 This dichloride was reacted with excess morpholine to affect an alkylation–elimination sequence to afford enaminolactam 18 in 86% yield N-Arylation of this iodide with valerolactam 19 using a copper (I) catalyst resulted in a 77% yield of the desired p-bispiperidone 20 Interestingly, sequential exposure of 20 to a nitrile imine generated from the treatment of ethyl 2-chloro-2-(2,4-methoxyphenyl)-hydrazono)acetate 21 with base resulted in a [3+2] dipolarcycloadditon reaction Upon acidification with N HCl, pyrazole 22 was furnished in 67% over two steps Conversion of the ester within 22 to the corresponding amide was achieved via a mixture of formamide and sodium methoxide to give apixaban (III) in 71% yield.29 It is important to note that intermediate 21 was prepared from commercially available 4-methoxyaniline (23) by sequential diazotization and condensation with ethyl 2-chloroacetoacetate (24).27 Avanafil (ZepeedÒ, StendraÒ) Avanafil was originally discovered at Tanabe Seiyaku (now Mitsubishi Tanabe) JW Pharmaceutical (previously Choongwae 2797 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 O O NH H N N N H O H N N O N O N H N O O I Abiraterone acetate II Alcaftadine III Apixaban O N Cl O HN H N N N N N O O O O N O N O N - • K+ O N OH O IV Avanafil V Azilsartan kamedoxomil N N O OH N N H O N H VI Bilastine O N N H O O NH2 O O VII Boceprevir O O S Brentuximab O H N N O O H N O N H O N H H N O O H N N N O O O OH O ~4 NH NH O VIII Brentuximab vedotin NH H N HO N P HO O S N N N O H N O N N S N N O O- S S O Cl O • CH 3COOH • H2 O Cl N NH2 F IX Ceftaroline fosamil acetate X Crizotinib Figure Structures of 26 new drugs marketed in 2011 Pharma) and VIVUS have since developed and launched avanafil, which is an oral PDE5 inhibitor for the treatment of erectile dysfunction (ED) Although many marketed PDE5 inhibitors (e.g sildenafil, vardenafil and tadalafil) are available for the treatment of ED, many patients are still unable to achieve the desired results and experience undesired side-effects with these existing medications As such, second-generation PDE5 inhibitors with enhanced PDE5 selectivity, shorter systemic half-lives, and improved tolerability are desired Developed to meet these criteria, Avanafil exhibited good oral bioavailability and PDE5 selectivity in both preclinical studies and clinical trials Avanafil had a short onset of action ($35 min) and short half-life (1.5 h).31,32 The synthesis presented is based on the published patent procedure and is outlined in Scheme 4.33 Commercially available 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (25) was treated with 3chloro-4-methoxybenzylamine (26) and triethylamine at room temperature to give 4-benzylaminopyrimidine derivative 27 in 96% yield Sulfide 27 was then oxidized with m-chloroperbenzoic acid (m-CPBA), followed bytreatment with L-prolinol and triethylamine to afford ethyl pyrimidinate 28 in 83% yield This ester was then saponified with 10% sodium hydroxide to give pyrimidine-5-carboxylic acid 29 in 80% yield, which then underwent conventional amide bond formation using 2-(aminomethyl) pyrimidine (29a), N-(3-dimethylaminopropal)-N0 -ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole hydrate (HOBt) to give avanafil (IV) in 83% yield Azilsartan kamedoxomil (EdarbiÒ) Azilsartan kamedoxomil, developed by Takeda Pharmaceuticals, was approved for the treatment of hypertension and launched in the U.S under the brand name EdarbiÒ.11 Edarbi is a prodrug that undergoes rapid hydrolysis to liberate azilsartan, the active ingredient (TAK-536, 39, Scheme 5) As the 8th angiotensin receptor blocker (ARB) to enter the world market, azilsartan kamedoxomil 2798 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 O H N N O Cl N H HN OH H N O H O • O S O S OH N CH2 • H2O HO OH N O XI Edoxaban tosilate O XII Eldecalcitol O O O XIII Gabapentin enacarbil O N OH H H N H N XVII Mirabegron H N OEt O N H NH N N H XVI Lurasidone hydrochloride NH S O H O N N XV Linagliptin N • HCl N O N XIV Icotinib hydrochloride O NH2 N N N N O O N N HN OH N H S N O • HCl O O OH • H3PO4 N NC CN N N H N N CN • HCl N F N H N XVIII Retigabine XIX Rilpivirine hydrochloride XX Ruxolitinib phosphate H N H N N O O F HN N N H O H O N N NH O S F N N N OH NH O OH HO XXI Telaprevir O XXII Ticagrelor Br F Cl HN O N O O F F N N H N N XXIII Vandetanib O O N S H XXIV Vemurafenib O O NC O NH2 N O N • HCl N H HO N H XXVI Zucapsaicin XXV Vilazodone hydrochloride Fig (continued) can function as monotherapy or in combination with other antihypertensive agents In several clinical studies, monotherapeutic azilsartan kamedoxomil showed superior antihypertensive activity and a favorable safety/tolerability profile in patients compared with other established therapeutics, including valsartan, olmesartan medoxomil, candesartan, and telmisartan.34–36 In late 2011, 2799 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 N BEt OTf O N H H RT, h, 60% RO O H H THF, 80 °C, h, 75% AcO Ac 2O, BF3•OEt2 , CH2 Cl2 , 25 °C, h 99% 1; R = H 2; R = Ac H Pd(PPh3 )2 Cl2 , M Na2 CO3 Tf2 O, Et3 N, CH 2Cl2 H H H H O I Abiraterone acetate Scheme Synthesis of abiraterone acetate (I) O O N Br H N O N NaOMe, MeOH N N O Cl 6, DMF, 30 °C, 18 h, 32% 48% HBr (aq) 8, Py, Et 3N, MeCN N N RT to ↑↓, h, 34% N N O N N HCHO, HCOOH ↑↓, h, O N N N CF3 SO3H, 110 °C, 72 h NaOH, 82% N H 80 °C, h, 98% O O NaOH N N HBr 10 11 12 O H OH N N 40% HCHO (aq) N MnO2, CHCl3 N ↑↓, h ↑↓, days N N II Alcaftadine 13 Scheme Synthesis of alcaftadine (II) Takeda announced that FDA also approved the fixed-dose combination tablet of azilsartan kamedoxomil with chlorthalidone under the trade name of EdarbyclorÒ.11 Based on the synthesis of azilsartan,37–40 the process-scale approach to azilsartan kamedoxomil is described in Scheme The synthesis started with commercially available methyl 2-[(tert-butoxycarbonyl)amino]-3-nitrobenzoate (30), which can also be prepared by several different routes.41,42 Alkylation of 30 with diaryl bromide 31 gave benzylamine 32 in 78% yield, which was followed by deprotection with 30% ethanolic HCl and alkalinization to produce amine 33 in 77% yield The nitro group within 33 was reduced with hydrazine hydrate and a catalytic amount of ferric chloride to afford 2,3-diaminobenzoate 34 in 64% yield Ring formation was achieved by treatment of 34 with tetraethoxymethane and acetic acid to produce benzimidazole 35 in 91% yield.37 The addition of hydroxylamine to the cyano group of 35 provided amidoxime 36 in 55% yield, which underwent immediate cyclization upon treatment with 2-ethylhexyl chloroformate 37 in refluxing xylenes to give oxadiazolone 38 in 52% yield Hydrolysis of 38 gave azilsartan (39, TAK-536) in 94% yield.38,39 In the presence of perchlorobenzoyl chloride 40 and triethylamine, carboxylic acid 39 was converted to the mixed acid anhydride intermediate, which when condensed with alcohol 41 furnished benzoate 42 in 50% yield Salt preparation of 42 was accomplished with potassium 2-ethylhexyl carboxylate 43 affording azilsartan kamedoxomil (V) in 63% yield.43 Bilastine (BilaxtenÒ) Bilastine is a selective histamine H1 antagonist approved for the treatment of allergic rhinoconjunctivitis and urticaria (hives).44,45 This drug, which has proven to be well tolerated in toxicology profiling,46 was discovered by the Spainsh firm FAES Farma and was approved by the European Union in 2010 In 2011, Collier and co-workers published a communication describing both the original synthesis of bilastine47,48 and an improved route which was amenable to gram-scale production.49 Collier’s second generation route, shown below (Scheme 6), relies upon a convergent approach involving the union of piperidinyl benzimidazole 49 with fully functionalized phenethyl electrophile 48.49 Coupling the commercially available bromophenyl acetate 44 with cyclic trioxatriborinane 45 under conventional Suzuki conditions furnished styrene 46 in good yield Alternatively, this vinylation reaction was also performed under Stille conditions with tributyl vinyl stannane in 83% yield Hydroboration–oxidation of 46 delivered phenethyl alcohol 47 which was then immediately mesylated under basic conditions in toluene to produce adduct 48 This sulfonate was then reacted with piperidine 49 (whose preparation is described in Scheme 7) followed by saponification of the resulting ester 50 to arrive at bilastene (VI) in 26% overall yield from 44.49 For the preparation of bilastine piperidine 49 (Scheme 7), commercially available piperidine 51 was first protected as the 2800 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 O Br Cl 15 NH2 N 15, Et 3N, THF, RT, 16 h I t-BuOK, RT, 18 h, 49% O I Cl ↑↓, 3.5 h, 87% O I 17 16 14 Cl N PCl5, CHCl3 O NH HN O 19 N (excess) 130 °C, h, 86% O I Cu(PPh3 )3 Br, Cs 2CO3 toluene, ↑↓, h, 77% O N O N O O N HCl, 5-20 °C, h 67% (2 steps) N N O N DMF, °C to RT h, 71% N N O HCONH2 , MeONa O N O O III Apixaban 22 O O O NaNO2 , HCl, -5 °C, 20 NH O O N N H 24, NaOAc, EtOH, H O, RT, h 60% (2 steps) Cl O 23 O Cl 21 24 Scheme Synthesis of apixaban (III) O O 26 Cl Cl N Cl SMe HN NH N O SMe m-CPBA, CHCl3 , RT N O DMF, Et 3N, RT, 96% O N L-prolinol, THF Et3 N, RT, 83% O 25 27 O O Cl HN N Cl N HN 10% NaOH (aq) O N OH O 28 29 N O NH2 N 29a , EDCI Cl N HOBt, DMF, RT, 83% N HN H N N N N N N N HO DMSO, RT, 80% O NH O N N O O 20 18 21, TEA, EtOAc, ↑↓, h N O N OH O IV Avanafil Scheme Synthesis of avanafil (IV) OH 2801 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 CN NO2 31 NO2 N H O N Br O Boc NO2 Boc NH O 30% HCl/EtOH, RT, h CN O CN NaHCO3 (aq), 77% K2CO3 , DMF, RT 15 h, 78% O O 32 30 33 NH N FeCl3 /C, MeOH, THF, ↑↓, 0.5 h; O O N NH O CN O (EtO) 4C, AcOH O CN 80-90 °C, 40 min, 91% NH2 NH H2 O, ↑↓, 14 h, 64% 34 35 O Cl O N N O NH2 OH HCl, DMSO, Et3 N N 37 O OH N O N NH2 O 37, Py, DMF, °C, 30 O O O O N NH xylenes, ↑↓, h, 52% 75 °C, 15 h, 55% 36 38 Cl O O O Cl N N NaOH (aq), 70 °C, 1.5 h HO O O Cl O O N NH Cl OH O 40 41 40, Et3 N, THF, RT, 12 h 41, CH2 Cl2 , DMAP, RT, h, 50% 2 N HCl (aq), 94% 39 (Azilsartan) O N N O O O O O O O N NH N O- 43 K+ N O O O O O O O O O N N- + • K acetone, °C, standing, 18 h, 63% V Azilsartan kamedoxomil 42 Scheme Synthesis of azilsartan kamedoxomil (V) Boc-carbamate 52 prior to alkylation of the benzimidazole nitrogen atom with 1-chloro-2-ethoxyethane 53, providing compound 54 The Boc group of 54 was removed under acidic conditions to give fragment 49 This sequence produced the desired piperidine component in 86% overall yield from 51.49 Boceprevir (VictrelisÒ) Boceprevir is an oral inhibitor of HCV NS3/4A protease for the treatment of the chronic hepatitis C genotype infection It is approved as combination therapy with Peg-IFN-alpha and ribavarin to treat adult patients with compensated liver disease who are either treatment naive or who have experienced prior failed therapy with interferon and ribavarin Boceprevir was initially discovered by Schering-Plough and developed and marketed by Merck & Co since its acquisition of Schering-Plough in 2009 Several publications have highlighted the discovery of this drug, which evolved from a potent initial undecapeptide lead structure to boceprevir (VII) as a drug candidate with potent activity and desirable PK properties.50–53 Several publications50–53 and patents,54,55 including process patents describing the preparation of key fragments56–61 and a full synthesis of boceprevir,62–64 have been published Retrosynthetically, the drug can be broken down into or key fragments and assembled in a convergent synthesis as depicted in Scheme Synthesis of t-butyl urea fragment 55 began with esterification of t-butyl amino acid 58 with TMSCl and triethylamine to give silyl ester 59 Silyl ester 59 was then reacted with t-butyl isocyanate 60 to provide urea 55 in 74–89% (2-steps, Scheme 9).56 Although several routes for the preparation of the azbicyclo[3.1.0]hexane ester 56 have been disclosed,57–59 the most recent process-scale synthesis of this heterocyclic core was accomplished using enzymatic desymmetrization of readily available azabicyclo[3.1.0]hexane 61 (Scheme 10).59 This was accomplished through the enzymatic oxidation of 61 followed by trapping of the resulting imine 62 with bisulfate to give the corresponding sulfonate 63 Sulfonate 63 was attained under manufacturing conditions in 95% and 99% ee Without isolation, the sulfonate salt was reacted with sodium cyanide in cyclopentyl methyl ether providing trans nitrile 64 in 90% yield from 61, presumably through an elimination of the sulfonate to regenerate imine 62, followed by addition of the nitrile group from the opposite face of the dimethylcyclopropyl group Nitrile 64 was reacted under Pinner conditions (HCl, MeOH) 2802 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 O B Br B O O B 45 BH 3•Me 2S, THF, °C 45, Pd(PPh3 )4 , K2CO3 MeO2 C 40:1 DME/H 2O, 130 °C, h, 80% MeO2C NaOH, H O2, °C, 83% 44 46 N 49 OEt MsCl, Et3N MeO2 C NH N OMs OH toluene, RT, h, 91% MeO2C , DIPEA DMF, 80 °C, 16 h, 83% 48 47 N N OMe N O LiOH, MeOH, THF N H 2O, 70 °C, 64% N N OEt OH O OEt 50 VI Bilastine Scheme Synthesis of bilastine (VI) OEt Cl 53 N NH N H Boc 2O, M NaOH N 1,4-dioxane, °C, 88% N H NaH, DMF, RT, h N Boc 51 99% 52 N N N Boc NH N N HCl, THF, 80 °C, h N 99% OEt OEt 54 49 Scheme Synthesis of fragment 49 for bilastine (VI) O O H N N N H N H O O O O NH2 O VII Boceprevir N H H 2N N H 55 OH O + NH2 + HN O OMe O 56 58 Scheme Retrosynthetic analysis of the synthesis of boceprevir (VII) to give ester salt 56 in 56% overall yield with greater than 99% ee after recrystallization from MTBE Although several preparations of cyclobutyl amides 57 have been disclosed,50–53,60,61 the process scale preparation is described in Scheme 11.61 Benzophenone-derived imine 65 was alkylated with bromomethylcyclobutane in the presence of base to give the alkylated intermediate, which was immediately treated in situ with HCl to furnish aminoester 66 This aminoester was then protected as the Boc-carbamate 67 prior to reduction of the ester to provide the corresponding alcohol 68 after crystallization from heptane in 43% overall yield This alcohol was then oxidized with TEMPO, sodium bromide and sodium hypochlorite in DCM at À5 to °C to give aldehyde 69 in 91% yield After exchanging solvents, aldehyde 69 was treated with acetone cyanohydrin at room temperature to provide intermediate 70 which, after treatment with potassium carbonate to wash off excess cyanohydrin, was hydrolyzed with hydrogen peroxide at 40 °C to give 90% of amide 71 Hydroxyl amide 71 was deprotected under acidic conditions to give the hydrochloride salt 73.64 Alcohol 71 was also oxidized using EDCI, DMSO and dichloroacetic acid in ethyl acetate to afford the keto amide 72 in 70% yield Subsequent treatment with HCl in isopropyl alcohol provided salt 57 in 91% yield.63 With all four key fragments in hand, the final target was rapidly assembled in a convergent manner as described in Scheme 12.63,64 Carboxylic acid fragment 55 was first coupled to azbicyclo[3.2.1]cyclohexane amine ester salt 56 using EDCI as the coupling reagent under basic conditions to give amide 74 Hydrolysis of the methyl ester with lithium hydroxide followed by salt formation gave rise to carboxylate salt 75 in 90% overall yield Under acidic conditions, salt 75 was coupled directly with cyclobutyl keto 2803 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 OH H2 N N TMSCl, Et N C O 60 OTMS H 2N 58 N H 74-89% (2-steps) O O O OH N H 59 O 55 Scheme Synthesis of fragment 55 for boceprevir (VII) Monoamine oxidase O2 NaCN N H HCl 90% SO2 Na N H N CN N H HOOH 62 61 64 63 CO2 Me N H MeOH 56% from 61 HCl 56 Scheme 10 Synthesis of fragment 56 for boceprevir (VII) O Ph N OEt Ph O (a) KOt -Bu, THF, -30 °C to °C (b) bromomethylcyclobutane, RT H2N OEt LiBH 4, THF, 35 °C crystallization Boc H N 66 OH 43% from 65 NaBr/NaHCO3 /H2 O TEMPO, NaOCl H N O OEt 67 Boc H N O H Acetone cyanohydrin, DMSO, RT K2CO3 CH2Cl2, -5°C to 0°C 91% 68 Boc Boc H N MTBE, RT HCl, H2 O KHCO 65 Boc 2O 69 OH CN H O2 , 40 °C Boc H O, 90% (from 69) H N OH NH2 O EDCI, DMSO Cl2 CHCOOH Boc H N O NH EtOAc, -5 °C, 70% O 72 71 70 HCl 91% HCl O OH H2N H2N NH NH HCl HCl O O 57 73 Scheme 11 Synthesis of fragment 57 for boceprevir (VII) amide salt 57 in the presence of EDCI, HOBt and N-methylmorpholine in acetonitrile to give, after acidic and basic work-ups, boceprevir (VII) in 85–90% yield.63 Alternatively, salt 75 could be coupled with the cyclobutyl alcohol amide salt 73 using EDCI, HOBt and diisopropylethyamine (DIPEA) to give alcohol 76 in 90% yield after acid and base work-ups and crystallization Oxidation of alcohol intermediate 76 with TEMPO and NaOCl in the presence of KBr also furnished boceprevir (VII) in 93% yield.62 Brentuximab vedotin (AdcetrisÒ) Brentuximab vedotin is an antibody drug conjugate that is comprised of an anti-CD30 antibody and the potent tubulin based inhibitor monomethyl auristatin E (MMAE).65–67 These two entities are connected together via a linker consisting of a maleimide conjugation handle that includes an enzyme-cleavable valine-citrulline-para-aminobenzylcarbamate group This conjugation handle releases MMAE after internalization of the conjugate by the cancer cell that recognizes the antibody Brentuximab vedotin was discovered by Seattle Genetics who co-developed the conjugate with Millenium Pharmaceuticals Brentuximab vendotin has been approved for the treatment of relapsed or refractory systemic anaplastic large cell lymphoma (ALCL)68 and relapsed or refractory Hodgkin’s lymphoma.69 Brentuximab vedotin is also undergoing clinical trials for the treatment of CD30-expressing cutaneous T-cell lymphoma and CD30-positive hematologic malignancies.70 Although brentuximab vedotin is classified as a biologic, an exception has been made to include it in this year’s review because the small molecule portion of the conjugate was prepared by total synthesis The synthesis of brentuximab vedotin and monomethyl auristatin E (MMAE) has only been described on small scale.71,72 However, large-scale preparation follows the same strategy described for the total synthesis of dolastatin 10 which was originally described by the Pettit research group at the University of Arizona.73–75 MMAE is a pentapeptide that includes two unusual gamma amino acids, dolaproine (Dap) and dolaisoleuine (Dil) 2804 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 EDCI, 2,6-lutidine O N H O LiOH, MeCN, H 2O N OH N H + HN O HCl 55 N H MeCN OMe 20 °C to 30 °C N H OMe DMCA, isopropylacetate 30 °C to 40 °C O 90% (3 steps) O O 56 74 O O N N H N H O- NH(CH 3) 2+ O HCl, MTBE, RT 57, EDCI, HOBt, NMM, MeCN 85-90% O N H 75 O H N N N H O NH O O VII Boceprevir 73, EDCI, HOBt DIPEA, DMF, EtOAc °C to 30 °C, 90% TEMPO, NaOCl, KBr 10 °C to 20 °C, 93% O N H O OH H N N N H NH2 O O 76 Scheme 12 Synthesis of boceprevir (VII) BH3 •THF, THF, 90% Cbz N Cbz CO 2H SO3 •Py, DMSO, Et N, 87% O N Cbz t-BuOAc, -78°C, 34% H 77 n-BuLi, i-Pr2NH, THF Ot-Bu N OH 79 78 Cbz HCl H2 , Pd/C, MeOH Me3 OBF4 , proton Cbz sponge, 87% Ot-Bu N O Ot-Bu HN EtOAc, HCl, 63% O O 80 Fmoc Ot-Bu H2N EtOH O H N N OH N O 85 Ot-Bu N DEPC, Et3N, CH 2Cl2, 50% O O 83 Fmoc O 82 PyBrop, i-Pr 2NEt CH2 Cl2 , 55% O O H , 10% Pd/C N OH N H 81 O CbzHN O O 84 O Ot -Bu N O O O 86 (val-val-dil) Scheme 13 Synthesis of fragment 86 for brentuximab vedotin (VIII) The synthetic strategy to enable the preparation of brentuximab vedotin is highly convergent and requires the preparation of a Val-Val-Dil tripeptide, a Dap-norephederine dipeptide and the MalC-Val-Cit-PABA linker The synthesis of Val-Val-Dil was initiated from Cbz-protected N-methyl-isoleucine 77 by reduction to the corresponding alcohol with borane and subsequent oxidation to Cbz-protected isoleucinal 78 using dimethyl sulfoxide and sulfur trioxide–pyridine complex This was accomplished in high overall yield for the two steps without epimerization (Scheme 13) Aldol condensation of aldehyde 78 with tert-butyl acetate using LDA provided a 4:3 mixture of diastereomers, from which the desired alco- hol diastereomer 79 was isolated in 34% yield Methylation of 79 with trimethyloxonium tetrafluoroborate afforded methyl ether 80 in 87% yield Hydrogenolysis using 5% palladium on carbon in ethyl acetate/methanol in the presence of hydrogen chloride provided the Dil coupling partner (81) in 63% yield with minimal lactam by-product formation.76 Peptide coupling with Cbz-protected valine 82 using PyBrop provided 83 in 55% yield After Cbz deprotection under hydrogenolysis to give 84, an additional peptide coupling was performed with Fmoc-protected methyl Val 85 employing diethyl cyanophosphonate (DEPC) as the coupling reagent provided the protected Val-Val-Dil tripeptide 86 in 50% yield 2811 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 vitamin D3 analog synthesis that was recently disclosed, based on an earlier reported route for the commercial synthesis of alfacalcidol, will be discussed here (Scheme 24).119,120 An Oppenauer oxidation converted commercially available cholesterol 141 to enone 142 in 80% yield A second oxidation event with DDQ provided dienone 143 in 75% yield Treatment of 143 with sodium ethoxide in ethanol triggered migration of the enone double bond into the B-ring, giving olefin 144 in 53% yield Stereospecific reduction of ketone 144 with sodium borohydride gave alcohol 145 in 53% yield, which was then immediately protected as the corresponding acetate with acetic anhydride to furnish 146 Next, further dehydrogenation of the B-ring was accomplished using radical bromination of the olefin within 146 through the use of NBS and catalytic AIBN, followed by elimination with collidine A subsequent saponification step ultimately gave rise to the key diene 147 Next, in order to selectively epoxidize the A-ring olefin, a unique ‘protection’ strategy was employed using phenyl1,2,4-triazole-3,5-dione (PTAD) Diels–Alder reaction between diene 147 and PTAD produced cycloadduct 148 in 80% overall yield from acetate 146.121 Protection of the alcohol as the corresponding TBS ether preceeded a regio- and stereospecific epoxidation with m-CPBA to afford 1,2a-epoxide 150 in 78% yield Diels–Alder adduct 150 was then subjected to thermal conditions to affect a retro-[4+2] reaction to give diene 151.121 Fluoride-mediated removal of the TBS group prepared 3b-alcohol 152 in 95% yield Subsequent ring-opening reaction with 1,3-propane diol in the presence of potassium t-butoxide, provided 3-hydroxy propoxy ether 153 in 29% yield Microbial oxidation of intermediate 153 was accomplished using an Amycolata autotrophica ATCC 33796 culture to obtain eldecalcitol derivative 154 in 64% yield Subjection of 154 to 400 watt light followed by thermolysis provided eldecalcitol (XII) in 29% yield 14 Gabapentin enacarbil (HorizantÒ) Gabapentin enacarbil is a prodrug of gabapentin (NeurontinÒ, Pfizer) which binds to the a2-d subunit of L-type voltage-regulated calcium channels, reducing the release of several neurotransmitters.122,123 Gabapentin enacarbil was discovered at XenoPort, codeveloped with GlaxoSmithKline, is marketed under the brand name HorizantÒ, and is approved for the treatment of moderate to severe restless leg syndrome.124 Gabapentin enacarbil was designed to increase the absorption of gabapentin through the inter- action with sodium-dependent multivitamin transporter (SMVT) and monocarboxylate transporter type (MCT-1) As a result, the drug demonstrated much better oral bioavailability and more consistent exposure compared to the parent.125 Several related syntheses of gabapentin enacarbil have been reported and two will be described (Scheme 25).124,126,127 Gabapentin 155 was treated with chlorotrimethylsilane and triethylamine followed by acylation with 1-chloroethyl chloroformate 156 to give acid 157 after hydrolysis of the intermediate silyl ester This acid was then used without purification and reacted with isobutyric acid (158) and triethylamine to afford gabapentin enacarbil (XIII) in 9.1% overall yield after crystallization.126 Alternatively, gabapentin 155 was reacted directly with the fully elaborated p-nitrophenyl activated side chain 161 in the presence of potassium carbonate The resulting mixture of products and p-nitrophenol was treated with 10% Pd/C and potassium formate followed by acidic workup to remove the resulting aniline, providing gabaentin enacarbil (XIII) in 36% overall yield from p-nitrophenol 159 after crystallization The required activated side chain 161 was prepared from p-nitrophenol 159 via a two-step, one-pot process involving acylation of the phenol with 1-chloroethyl chloroformate 156 in triethylamine This provided intermediate 160 which was alkylated with isobutyric acid (158) in the presence of zinc oxide and potassium iodide, ultimately furnishing the mixed carbonate 161.127 15 Icotinib hydrochloride (ConmanaÒ) Icotinib hydrochloride, developed by the Chinese pharmaceutical company Zhejiang Bata Pharma Inc., is a potent small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for the treatment of non-small cell lung cancer (NSCLC) It was first approved by the SFDA of China, and launched under the brand name ConmanaÒ in the middle of 2011, representing an important milestone for Chinese pharmaceutical research and development As the third EGFR-TKI drug targeting NSCLS therapy, icotinib hydrochloride possesses a similar structure to gefitinib (IressaÒ, AstraZeneca) and erlotinib (TarcevaÒ, OST & Roche).128,129 Interestingly, a randomized, double-blind phase III clinical study of icotinib versus gefitinib in 399 patients with advanced NSCLC demonstrated that icotinib provides similar efficacy to gefitinib, but with better tolerability in NSCLC patients previously treated with one or two chemotherapy agents.130 O O Cl O TMSCl, Et 3N CH2 Cl2 , 15 °C N H OH CO2 H 158 Et3N, CH2 Cl2, 30 °C; crystallization from Et 2O/CH2 Cl2 9% overall yield 157 O O Cl Cl 156 H2 N CO2 H O 161, K2 CO 3, H2O, toluene, 40 °C; 10% Pd/C, KHCO3 O O O OH N H O crystallization from heptane/EtOAC, 36% over all yield XIII Gabapentin enacarbil 155 Gabapentin O O O O O OH Cl Cl O Cl O O 156 Et3N, toluene, °C O O O ZnO, KI, 80 °C NO2 159 OH 158 NO 160 Scheme 25 Synthesis of gabapentin enacarbil (XIII) NO2 161 2812 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 HO TsCl, NaOH, THF O O OH TsO O O °C, h, 91% 162 163 O O HO 163 , K2CO3 , DMF OEt 90 °C, h, 96% HO O O O O 164 HNO3 , H2SO4 OEt HOAc, °C to °C h, 65% 165 O O O O OTs O OEt Pd/C, H , AcCl, MeOH RT to ↑↓, 85% NO2 O O O O O OEt NH2 • HCl 167 166 Cl O HCONH2, HCOONH4 165 °C, h, 80% O O O O POCl3 , CHCl3 NH DMF, ↑↓, h, 77% N O O O O N N 169 168 H2N 170 HN EtOH, DMF, ↑↓, h O O O O N HCl, 94% for two steps • HCl N XIV Icotinib hydrochloride Scheme 26 Synthesis of icotinib hydrochloride (XIV) N O H N HN O O Br DMF, DIPEA, RT, 83% N N O O NHBoc HN N N N K 2CO3 , DMF, RT, 85% 172 O N Br N N 171 173 N HN Br Br N N O N 175 N N N 176 O CF3COOH, CH 2Cl2 O NHBoc N N N DMSO, 75 °C, 88% 174 RT, 91% Cl N N N O NH N N N N N XV Linagliptin Scheme 27 Synthesis of linagliptin (XV) Icotinib was prepared by a similar process approach to that of erlotinib (Scheme 26).131 Beginning from commercially available 2,20 -(ethylenedioxy)diethanol (162), bis-tosylation to 163, followed by bis-alkylation with commercially available catechol derivative 164 provided crown-4-ether 165 in 96% yield Nitration of polyether 165 using concentrated nitric acid and concentrated sulfuric acid provided nitroarene 166 in 65% yield Reduction of the nitroarene under catalytic hydrogenation conditions gave amine 167 in 85% yield Condensation of the amine 167 with formamide in the presence of ammonium formate afforded quinazolinone 168 in 80% yield The chlorination of 168 using POCl3 furnished quinazolyl chloride 169 in 77% yield The treatment of chloride 169 with amine 170 followed by the HCl salt formation produced icotinib hydrochloride (XIV) in good yield.132,133 2813 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 16 Linagliptin (TrajentaÒ) Linagliptin was originally discovered at Boehringer Ingelheim as an orally active dipeptidyl peptidase-IV (DPP-4) inhibitor Eli Lilly and Boehringer Ingelheim co-developed and launched linagliptin for type II diabetes as an adjunct to diet and exercise for the improvement of adult glycemic control Linagliptin has a superior DPP-4 IC50 value of nM, compared with 19 nM for sitagliptinÒ, 24 nM for alogliptinÒ, 50 nM for saxagliptinÒ and 62 nM for vildagliptinÒ.134 In addition, linagliptin exhibited prolonged pharmacodynamic activity with long-lasting DPP-4 inhibition in several preclinical species Linagliptin showed good efficacy in phase II clinical trials with doses as low as mg and no signs of hypoglycemia with doses as high as 600 mg.135 The prolonged pharmacological effect of DPP-4 activity and the good safety/tolerability profile provided the basis for linagliptin’s approval.136 The synthesis of linagliptin began from commercially available 8-bromo-3-methylxanthine (171) (Scheme 27).137 Sequential alkylations of guanine derivative 171 at N-7 with butyn-2-yl bromide in the presence of N,N-diisopropylethylamine and N-1 with 2(chloromethyl)-4-methylquinazoline (173) in the presence of potassium carbonate, yielded N1,N7-dialkylated xanthine 174 in 85% yield This material was further condensed with (R)-3-Bocaminopiperidine (175) in the presence of potassium carbonate to give aminopurine dione 176 in 88% yield Finally, the primary amine of 176 was liberated with trifluoroacetic acid in methylene chloride to produce linagliptin (XV) in 91% yield 17 Lurasidone hydrochloride (LatudaÒ) Lurasidone hydrochloride is an antipsychotic developed by the Japanese firm Dainippon Sumitomo and approved by the U.S FDA for the treatment of schizophrenia The compound exhibits significant antagonist effects at the D2, 5-HT2A, and 5-HT7 receptors which are linked to learning and cognition.138 In contrast to available antipsychotics, lurasidone lacks anticholinergic side effects, giving it an improved safety profile against existing treatments.139 The drug is manufactured under the trade name LatudaÒ and possesses a linear molecular topology which can be subdivided into three regions: a piperazine benzothiazole, a [2.2.1]-bicycloheptane fused succinimide, and a trans-1,2 disubstituted cyclohexane The large scale preparation of lurasidone involves an interesting ring-opening alkylation reaction of a spirocyclic tetralkyl ammonium salt to produce the 1,2-trans-substituted cyclohexane subunit (Scheme 28) The synthesis commenced with the bismesylation of commercially available diol 177, which proceeded in high yield to give disulfone 178.140 This bis-electrophile underwent dialkylation with commercially available piperazine 179 under basic conditions, giving rise to ammonium species 180, isolated in 80% yield as the mono-mesylate salt This compound was immediately subjected to alkylative conditions in the presence of commercially available succinimide 181 to provide lurasidone in 94% yield from 180141, and lurasidone hydrochloride (XVI) was achieved by subsequent salt formation procedure.142 18 Mirabegron (BetainsÒ) Mirabegron is an orally active b3-adrenoceptor agonist currently in development by Astellas Pharma for the treatment of overactive bladder (OAB) The drug is a nanomolar EC50 antagonist against human b3-AR biochemical assays with good selectivity over b1- and b2-ARs Mirabegron demonstrates a novel mechanism by targeting the b3-AR for bladder relaxation to help manage OAB symptoms such as increased urinary urgency and frequency and urgency incontinence However, mirabegron is a cytochrome P450 2D6 inhibitor, and it raises a concern for drug–drug interaction with concomitant administration of other cytochrome P450 2D6 substrates.143 The synthesis of mirabegron144 began with a condensation reaction between (R)-styrene oxide (182) and 4-nitrophenylethylamine (183) in refluxing isopropanol to yield corresponding aminoalcohol 184 in 22% yield (Scheme 29) Aminoalcohol 184 was protected as its N-Boc derivative with t-butyl dicarbonate in THF in 96% yield, and this was followed by nitro group hydrogenative reduction with 10% Pd/C to give free amine 185 in 96% yield Aniline 185 was coupled with 2-amino-4-thiazolyl acetic acid 186 in the presence of EDCI and HOBt to give amide 187 in 85% yield Removal of the Boc group was affected with N HCl solution in a 2:1 volume ratio in ethyl acetate to obtain mirabegron HCl in 52% yield The HCl salt was neutralized with N NaOH to deliver mirabegron (XVII) 19 Retigabine/Ezogabine (TrobaltÒ/PotigaÒ) Retigabine/ezogabine is an antiepileptic that acts through opening neuronal voltage-gated potassium channels of the KCNQ family and also augments brain currents mediated by c-aminobutyric acid (GABA).145 Retigabine was discovered and initially developed by Asta Medica, licensed to Xcel, and later acquired by Valeant Valeant completed the development in partnership with GlaxoSmithKline and the drug is approved for the adjunctive treatment of partial-onset seizures in adults with epilepsy.146,147 The drug is S N 179 N NH MsCl, Et3N, EtOAc HO OH RT, h, 95% OMs MsO 177 K 2CO3, MeCN, 82 °C 20 h, 80% 178 O H HN O H S N N N H MsO - 180 H 181 K2 CO3 , Bu4N +HSO4 - 181, toulene, H 2O, 110 °C, h, 94% O S N N HCl, acetone, H2 O, 60 °C, h no yield reported N H N • HCl O H XVI Lurasidone hydrochloride Scheme 28 Synthesis of lurasidone hydrochloride (XVI) 2814 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 H2 N OH O H N NO2 183 t-butyl dicarbonate RT, 96% 2-propanol, ↑↓, 22% 184 182 OH ethanol, H2 (1 atm) 10% Pd/C, RT, 96% NO2 S O Boc N NH N HO Boc N OH 186 NH S O EDCI, HOBt, THF, 85% NH N N H 187 185 OH H N MeOH/4 N HCl, 2:1 EtOAc, RT, 52% S O M NaOH NH N N H XVII Mirabegron Scheme 29 Synthesis of mirabegron (XVII) NO2 O H2 N EtO i-PrOH, 75 °C H N H NaBH 4, 79-85% NH2 F O O 191 NH2 NO2 O OEt NaOEt, 80-88% F 188 189 NO2 190 NH2 H N OEt H2 , 1% Pt + 2% Pd/C O N H EtOH, 70 °C, 70-90% H N O N H F OEt F 192 XVIII Retigabine/Ezogabine Scheme 30 Synthesis of retigabine/ezogabine (XVIII) H2N 194 O SMe N NH O CN H N N NH 180-190 °C, h, 77% Cl POCl3 CN N ↑↓, 0.5 h, 77% H N 200, MeCN, K2 CO3 , ↑↓, 24 h, 89% H N N N NC HCl/EtOH CN 196 195 193 H N N • CN HCl XIX Rilpivirine hydrochloride NH 10% Pd/C, NaOAc DMA, 140 °C, 16 h I 197 NH N HCl, 2-propanol EtOH, 60 °C, h CN 198 NC crystallization 64% (2 steps) NH NC 199 (E / Z=80:20) HCl 200 (E/ Z=98:2) Scheme 31 Synthesis of rilpivirine hydrochloride (XIX) known as ezogabine in the U.S and retigabine in the remainder of the world A number of methods have been disclosed for its preparation and two will be described below Commercially available 4-fluorobenzaldehyde (188) was condensed with 4-amino-2-nitroaniline (189) and the resulting imine was reduced with sodium borohydride to give aniline 190 in 79–85% yield (Scheme 30).148,149 Aniline 190 was acylated with diethylcarbonate (191) to give nitrobenzene 192 in 80–88% yield Reduction of the nitro group via catalytic hydrogenation provided retigabine/ezogabine (XVIII) in 70–90% yield An alternative method (not shown) involved initial reduction of nitrobenzene 190 with Zn/NH4Cl followed by acylation with diethylcarbonate (191) or 2815 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 N NH Cl NaH, SEMCl DMAC, 0-5 °C N N 205 B O 203 N 89% N H O HN N Cl N 201 CN N N chiral column separation CN N N LiBF4 , CH3 CN, H O, ↑↓ 94%, 99% ee NH OH (aq), 84% N N N SEM N N SEM N DBU, CH3 CN 70-80 °C, 98% 204 CN N N SEM N 202 H N N CN N Pd(PPh 3) 4, K2 CO N dioxane, H2 O, ↑↓, 64% SEM 206 207 208 CN N N H3 PO4 , i-PrOH, CH Cl2 , 84% N H N • H3 PO4 Recrystallization from MeOH/i-PrOH/n-heptane 90%, 99.8% ee N N N H XX Ruxolitinib phosphate O i-PrO B NIS, H 2O, 89% HN N TMSCl, Et3N THF, 96% 209 211 O TMSN N O HN N I i-PrMgCl, THF; °C to RT, 55% 210 B O 203 Scheme 32 Synthesis of ruxolitinib phosphate (XX) H N H N N O H N O N H N O H NH O H N N O N O O H + H 2N O OH 213 212 OH H N NH O + Cbz H N O OH N 214 OH N H O O XXI Telaprevir N O 215 + Cbz N H OH + O 216 H H Ot-Bu N H O 217 Scheme 33 Retrosynthetic analysis of telaprevir (XXI) ethyl chloroformate/Hunig’s base, providing retigabine/ezogabine (XVIII) in 46–81% overall yield.150,151 20 Rilpivirine hydrochloride (EdurantÒ) Rilpivirine hydrochloride (EdurantÒ), a non-nucleoside reverse transcriptase inhibitor (NNRTI), received its approval both from the U.S FDA and E.U EMA in 2011 for the treatment of HIV-1 infec- tion in treatment-naïve adult patients It was discovered and developed by Janssen Pharmaceuticals and its subsidiary Tibotec Pharmaceuticals As a second generation NNRTI, rilpivirine hydrochloride displayed higher potency and longer half-life with a 25 mg once a day dose, compared to existing NNRTIs, such as the 200 mg BID of efavirenze (SustivaÒ).152–155 In late 2011, the fixed-dose combination products of rilpivirine hydrochloride with two nucleoside reverse transcriptase inhibitor (RTIs) emtricitabine 2816 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 Cbz O H N N+ CH 219 Cbz OH H N OH H N H2 (1 atm), 20% Pd/C O 2,6-dimethylpyridine TFA, CH 2Cl2, RT, 85% O MeOH, 95% 213 220 218 H N H 2N Scheme 34 Discovery synthesis of fragment 213 of telaprevir (XXI) O H N Cbz OH 222 H N HCl O CDI, DIPEA, RT Cbz H N O OH H H 2N NaCN, NaHSO3, MeOH O N HCl, dioxane, ↑↓ 72% (2 steps) LAH, Et 2O 73% (2 steps) OH HCl 218 221 Cbz-OSu, DIPEA Cbz H N OH OH NHS, EDCI, DMF, -5 °C O H2 N Cbz OH H2 N OH H N H N O , DMF -5 °C to RT 56% (3 steps) 224 H (30 psi), 20% Pd/C 223 220 H N O MeOH, 40 °C, 73% 213 Scheme 35 Large scale synthesis of fragment 213 of telaprevir (XXI) H Boc2O, K2CO3 H TBME/H2 O (1:1) 16 °C, 90% N H HCl 225 H H N Boc sec-BuLi, -75 °C NaHSO4 , MTBE H 2O O- O NH3 + H OH CO2(gas) NaHSO4 80% N Boc O rac-227 H Boc2O, DMAP t-BuOH, MTBE, RT 229 MeSO3H THF, RT H Ot Bu N Boc 230 O 228 NH2 H 226 H N Boc H oxalic acid i-PrOAc, RT EtOAc, 25 °C EtOAc, i-PrOH 75 °C to -10 °C slow cooling ~ h 83%, > 99.5% ee H H N H COOH COOH Ot Bu O 81% (4 steps) 231 (217 = free base) Scheme 36 Synthesis of oxalic acid salt of fragment 217 of telaprevir (XXI) and tenofovir disoproxil fumarate, co-developed by Gilead Science and Tibotec, were also approved both by the FDA and EMA under brand names CompleraÒ and EvipleraÒ, respectively.156,157 Similar to efavirenze, rilpivirine hydrochloride is a diarylpyrimidine (DAPY) compound, and the large-scale process synthesis begins with commercially available 2-methylthio-4-pyrimidinone (193) shown in Scheme 31.158–161 Thioether 193 was condensed with neat 4-cyanoaniline (194) at elevated temperature to afford diarylamine 195 in 77% yield Subsequent treatment of pyrimidone 195 with refluxing POCl3 provided the corresponding chloride 196 in 77% yield.160,161 In the presence of K2CO3, chloride 196 was treated with the (E)-cinnamonitrile aniline 200 to give rilpivirine hydrochloride (XIX) in good yield.158 Aniline 200 was prepared via a Heck reaction of commercially available 4-iodo-2,6-dimethyl-benzeneamine (197) and acrylonitrile (198) affording compound 199 as a 4:1 mixture of E/ Z isomers The distribution of E/Z olefins was increased to 98:2 by salt formation and recrystallization to ultimately provide pure (E)-200 in 64% yield for two steps.162 21 Ruxolitinib phosphate (JakafiÒ) Ruxolitinib phosphate is a potent, selective, ATP competitive inhibitor of tyrosine-protein kinases JAK1 and JAK2 which acts by attenuating cytokine signaling and promotes apoptosis Ruxolitinib was discovered and developed by Incyte, is marketed under the brand name Jakafi,Ò and is approved for the treatment of patients with myelofibrosis (MF), including primary MF, post-polycythemia vera MP, and post-essential thrombocythemia MF.163,164 Ruxolitinib is also undergoing clinical evaluation against a wide variety of cancer indications including metastatic prostate cancer, pancreatic cancer, multiple myeloma, leukemia, non-Hodgkin lymphoma, 2817 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 22 Telaprevir (IncivekÒ) and breast cancer Additionally, ruxolitinib is being evaluated for the treatment of psoriasis and thrombocytopenia Ruxolitinib contains one chiral center, and three general strategies for its preparation have been reported.165–167 These include a racemic synthesis followed by chiral separation or resolution, introduction of the side chain via an aza-Michael addition of the pyrazole fragment to 3cyclopentylpropiolonitrile and asymmetric hydrogenation of the resulting alkene, and through introduction of the side chain via an organocatalytic, asymmetric aza-Michael addition The route described herein (Scheme 32) utilizes the first strategy as this appears to be the largest scale reported.165 The synthesis was initiated by SEM protection of commercially available chloropyrrolopyrimidine 201 to provide the protected chloropyrrolopyrimidine 202 in 89% yield Suzuki coupling of 202 with the pyrazole pinacolatoboronate 203 gave pyrazole 204 in 64% yield aza-Michael reaction of pyrazole 204 with 3-cyclopentylacrylonitrile 205 was accomplished in the presence of DBU to furnish SEM-protected ruxolitinib 206 in 98% yield as the racemate The desired enantiomer 207 was isolated via chiral column separation in 93.5% yield and 99.4% ee, on 100 kg scale Removal of the SEM group was accomplished through a two step process via treatment with lithium tetrafluoroborate and aqueous ammonium hydroxide, ultimately giving rise to ruxolitinib 208 in 84% yield The phosphate salt was then prepared by treatment with phosphoric acid Crystallization from MeOH/i-PrOH/n-heptane gave ruxolitinib phosphate (XX) in good overall yield in 99.8% ee Pyrazole pinacolatoboronate 203 was prepared from pyrazole 209 via iodination with N-iodosuccinimide followed by reaction with trimethyl silyl chloride to give protected iodopyrazaole 210 in high yield Reaction of 210 with i-PrMgCl to form the corresponding Grignard reagent followed by reaction with isopropylpinacolborane 211 provided Suzuki boronate synthon 203 in 55% yield Telaprevir is a potent peptide mimetic inhibitor of Hepatitis C virus (HCV) and works via covalent reversible binding to the NSV-3A protease enzyme.168 Telaprevir was discovered and developed by Vertex pharmaceuticals.169 The drug is marketed as an oral treatment for HCV infection in combination with Peg interferon and ribavarin for patients who are refractory to the initial standard therapy The initial SAR studies and the discovery of teleprevir have been published.170–173 In addition, a full review of the discovery process that led to the development of telaprevir, including several iterations of the syntheses of teleprevir leading to the process route, has been reported.170–176 A short and concise synthesis incorporating an enzymatic de-symmetrization and a multicomponent reaction (MCR) on small scale was recently reported.176,177 In this review, we will focus on the process scale synthesis used to make the telaprevir.170,175 For preparation of bulk API, a convergent synthetic strategy was utilized as described in Scheme 33 Retrosynthetically the penultimate intermediate 212, which was coupled with amine 213 for the final step, was prepared by coupling bicyclic amine 217 with amino acids 216 and 215 and then with pyrazine acid 214 In the early stages of development, the cyclopropyl amide fragment 213 was made using a MCR coupling sequence by reacting aldehyde 218 with cyclopropyl isocyanide (219) and triflouroacetic acid to give amide alcohol 220 in 85% yield (Scheme 34) Removal of the Cbz group was accomplished via hydrogenolysis to provide key cyclopropyl amide alcohol 213 in 95% yield While this route was shorter in terms of steps, it was not amenable to large-scale preparation due to difficulties associated with the handling of isocyanide 219 H H EDCI, HOBt H Ot-Bu N H + Cbz O 217 Cbz OH N H DMF, RT, 87% N N H O O 216 H Ot -Bu O 232 H H2 , 20% Pd(OH) 2, EtOH Cbz O H N 215, EDCI, HOBt, DMF, RT H2 , 20% Pd(OH) 2, EtOH N N H O 89% (2 steps) H 214, CDI, DMF, RT Ot-Bu O HCl (conc.), CH 2Cl2, °C 68% (3 steps) 233 H N H N N N H O N O 213, EDCI, HOBt DMF, NMM, RT H OH O H N O H N N O N H O 95% (2 steps) N O O H NH O 212 234 H N H N N DMP, t -BuOH O O N H N O CH2Cl2, RT, 85% O H NH O O NH XXI Telaprevir Scheme 37 Synthesis of telaprevir (XXI) OH NH 2818 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 F HN N N S F N O HO N N NH NH2 Cl + OH O O Cl N F H 2N + N F S OH HO O 235 XXII Ticagrelor 237 236 Scheme 38 Retrosynthetic analysis of ticagrelor (XXII) HO OAc NaN(Boc)2 , cat Pd(PPh3 )4 Boc N Boc HO THF, H 2O, 100% THF, 40 - 45 °C, h, 92% 238 Boc N Boc HO cat OsO4 , NMO NH HO N HCl, MeOH, H 2O dimethoxypropane, acetone HCl (conc.), ↑↓, 92% O O CbzCl, K2 CO 240 H N HO Cbz 4-methyl-2-pentanone RT, 99% HCl OH HO 239 O 241 O 242 O EtO Br 243 KOt-Bu, THF, °C LiBH4 , < °C H N O O Cbz HO O O H2 (1.2 bar), 5% Pd/C NH2 HO EtOH, RT, 83% O O 86% (2 steps) 244 235 Scheme 39 Synthesis of fragment 235 of ticagrelor (XXII) Thus, for large-scale synthesis, the route depicted in Scheme 35 was utilized Commercially available Cbz-protected amino acid 221 was converted to the corresponding Weinreb amide 222 using CDI as the activating agent This was followed by LAH reduction to give aldehyde 218 in 73% yield from 221 Aldehyde 218 was reacted with sodium cyanide under neutral to mildly basic conditions allowing for easy workup of the cyanohydrin, which was immediately hydrolyzed by refluxing in N hydrochloric acid in dioxane to deliver hydroxy acid HCl salt 223 Since the formation of the acyloin resulted in removal of the Cbz protecting group, reinstallation of this protecting group preceded conventional amide bond formation through the intermediacy of the succinate ester of 224 This provided the desired amide alcohol 220 in 56% yield from 223 Hydrogenolysis of Cbz carbamate 220 then furnished the requisite intermediate amine (213) in 73% yield The large-scale synthesis of bicyclic pyrrolidine 231 was accomplished as described in Scheme 36 Commercially available 3-azabicyclo[3.3.0]nonane hydrochloride (225) was first protected as the corresponding Boc carbamate 226 in 90% yield Deprotonation of the bicyclic pyrrolidine carbamate 226 with sec-BuLi and sequential quench with bubbling carbon dioxide gas followed by sodium hydrogensulfate resulted in racemic acid 227 in 80% yield Racemate 227 was resolved using (S)-tetrahydronapthalamine (228) in ethyl acetate and isopropanol at 70–75 °C This mixture was allowed to cool down slowly to effect the crystallization of the optically enriched chiral salt 229 in 83% yield with greater than 99.5% ee This enatioenriched salt was free based with sodium hydrogen sulfate and converted to t-butyl ester 230 using Boc anhydride and DMAP The secondary amine of 230 was liberated using methane sulfonic acid at room temperature followed by salt formation with oxalic acid in isopropyl acetate to give oxalic acid salt 231 in 81% yield over steps With the synthesis of the key intermediates complete, sequential coupling events were then executed to complete the synthesis of teleprevir (Scheme 37) Fragment 217 was coupled with the Cbz-protected valine (216) using EDCI and HOBt to give intermediate 232 in 87% yield Similarly, after removal of the Cbz group of 232 via catalytic hydrogenolysis, the resulting amine was coupled with cyclohexyl amino acid 215 to give dipeptide intermediate 233 in 89% yield over steps Sequential cleavage of the Cbz group in 233 followed by CDI-mediated coupling with commercially available pyrazine acid 214 gave rise to the expected pyrazine amide intermediate Subsequent hydrolysis of the t-butyl ester through the use of concentrated acid in DCM provided the key intermediate tripeptidic acid (212) in 68% over steps The tripeptide 212 was then coupled with cyclopropyl amide amine 213 using EDCI, HOBt and N-methyl morpholine (NMM) to provide penultimate intermediate alcohol 234 in 95% yield Subjection of 234 to Dess–Martin periodinane (DMP) oxidation in t-butanol and DCM furnished telaprevir (XXI) in 85% yield 23 Ticagrelor (BriliqueÒ) Ticagrelor, discovered and developed by AstraZeneca, is a platelet adenosine diphosphate (ADP) P2Y12 (P2T) reversible receptor antagonist approved in the E.U in 2010 and launched in Germany and the UK in 2011 for the treatment of patients with acute coronary syndromes (ACS) It was approved in the U.S and Canada in 2011 following successful clinical trial results in patients with ACS which showed it to be superior to preexisting drugs for reduc- 2819 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 ing death due to vascular causes.11,178 Ticagrelor is an oral drug indicated for use in combination with acetylsalicylic acid (aspirin) for the prevention of atherothrombotic events in adult patients with ACS (unstable angina, non-ST elevation myocardial infarction (NSTEMI), or ST elevation myocardial infarction (STEMI)) Unlike its competitors prasugrelÒ and clopidogrelÒ, which require bioactivation, ticagrelor is not a prodrug and does not require in vivo activation It has a rapid onset of action, relatively rapid reversibility, greater potency, and exhibits consistency in platelet inhibition Following dosing, ticagrelor reaches Cmax in about 1.5 h, with formation of a major metabolite with equipotent intrinsic activity to the parent compound.11,178–180 The initial discovery of the drug and SAR studies were published in 2007, including the initial discovery patent applications.181–185 Since then, a number of patents have been published with various improvements made for largescale synthesis of the drug.186–196 While the molecule has been synthesized using various modifications of the common intermediates, the large-scale preparation proceeds via a convergent strategy involving the coupling of three key intermediates as shown in Scheme 38.186,187 Several routes to the synthesis of cyclopentyl amino alcohol 235 have been reported Most of these routes are based on reaction of cyclopentene acetate 238 with the appropriate amine, which is commercially available.184–189 Interestingly, one route targeting deuterated ticagrelor used a nitroxide Diels–Alder reaction with cyclopentadiene to incorporate the amine into the ring system.190 The most likely process-scale preparation of the key cyclopentyl amine required for ticagrelor is highlighted in Scheme 39.185,186 Commercially available enantiopure acetate 238 was reacted with sodium di-tert-butyloxy diimide under catalytic palladiummediated amination conditions to give bis-Boc amide 239 in 92% yield Dihydroxylation of cyclopentene 239 using catalytic osmium tetraoxide and N-methyl morpholine N-oxide (NMO) in THF/water quantatively resulted in the cis-diol 240 The free amine was liberated with N HCl followed by in situ ketalizaion of the cis-diol hydrochloride salt 241 in 92% yield Cbz carbamate 242 was quantitatively synthesized from 241 under standard conditions Alcohol 242 was treated with potassium t-butoxide and bromoethyl acetate (243), the ester intermediate of which was reduced in situ with lithium borohydride to alcohol 244 in 86% overall yield O S O O H 2N NH O O NaOMe, MeOH + O (two steps) Hydrogenolysis at 1.2 bar of hydrogen pressure with 5% Pd/C gave amino alcohol intermediate 235 in 83% yield This amine (235) was mixed with oxalic acid to provide the oxalate salt in 82% yield, which was subsequently used for the final synthesis of ticagrelor.187 The large-scale preparation of ticagrelor necessitated the synthesis of dichloroamino pyrimidine thioether 236, for which there are several reported routes.181–187 The synthesis is initiated with the construction of thiol barbituric acid 247 (Scheme 40).191 This intermediate was formed from the reaction of dimethyl malonate (245) with thiourea (246) in the presence of sodium methoxide These conditions provided the sodium salt of the pyrimidone thiol 247 in 83% yield, which was isolated via filtration from the reaction mixture Salt 247 was then reacted with propyliodide in aqueous methanolic sodium hydroxide followed by HCl quench to provide the desired thioether 248 in 76% yield Nitration of pyrimidinol thioether 248 was achieved by treatment with fuming nitric acid in acetic acid, furnishing the nitro pyrimidinol 249 in 75% yield Subsequent bis-chlorination with POCl3 converted 249 to dichloropyrimidine thioether 250 in near quantitative yield In an earlier publication, a selective reduction of the nitro dichloropyrimide thioether 250 was demonstrated by hydrogenation at bar hydrogen pressure using 3%Pt/0.6%V/C catalyst to provide the amino dichloropyrimidine thioether 236 in $95% yield.192 It is also of note that for the larger kilo-scale reaction, selective hydrogenation was accomplished with Pt/V/C (2% Pt; 1% V on carbon) catalyst with bar of hydrogen pressure to give the crude amino dichloropyrimidine thioether 236.187 While a number of routes have been described for the preparation of cyclopropyl amine intermediate 237,184–187,193–196 the large scale route used is described (Scheme 41).195 Condensation of malonic acid and 3,4-difluorobenzaldehyde (251) with piperidine in pyridine gave acid 252 in 88% yield after acidic work-up Acid chloride 253 was prepared using thionyl chloride, which was followed by esterification with L-menthol and pyridine to give Lmenthol ester 254 in 93% over steps Cyclopropanation with dimethylsulfoxonium methylide in DMSO gave desired trans cyclopropane 255 in $40% yield and 92% ee after recrystallization Hydrolysis of the ester followed by reaction with thionyl chloride gave acid chloride 257 in 61% overall yield in two steps Acid ↑↓, h to RT, h, 83% N HN I , NaOH H2 O, MeOH, RT, 22 h HCl, 76% (2 steps) S+Na245 246 247 NO2 NO2 HO OH N N HO HNO3 , AcOH Cl OH N N RT to 30 °C, 75% S S 248 POCl3, DIEA toluene, ↑↓, h, 100% 249 NH Cl H (3 bar), 3%Pt/0.6%V/C TBME, 30 °C, h, 95% Cl N N S 236 Scheme 40 Synthesis of fragment 236 of ticagrelor (XXII) Cl N N S 250 2820 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 O O O O HO F H OH F HO F toluene, 65 °C, 100% Cl piperidine, pyridine 90 °C, 88% F O SOCl2, pyridine F 251 F 252 253 O I O L-menthol, pyridine S+ F O toluene, 65 °C, then at RT, 93% F 46 °C, 61% F (R) (R) O SOCl2, pyridine F (R) toluene, 65 °C, 100% OH Cl F 256 F 257 (S) NaN 3, Na 2CO3 ,TBAB H 2O, toluene, °C (S) H 2N toluene, 100 °C F 255 (R) O F (R) O 254 NaOH, EtOH (R) O NaOH, DMSO, RT 41%, 92% ee R-(−)-mandelic acid F (R) H 2N F (R) EtOAc, RT F F 88%, 92% ee O Ph OH OH 237 258 Scheme 41 Synthesis of fragment 237 of ticagrelor (XXII) Cl NH2 N 235 Et 3N, ethylene glycol 236 + S N NaNO2, AcOH NH O 100 °C, h, 88% HO toluene, < 30 °C 30 O O 259 ( S) Cl N N S HN N N O K2CO3 , toluene:H2O < 30 °C O HO S F N N N O O O HO 260 O 261 ( S) HN S F N N HO F (R) N N HCl (conc.), MeOH toluene, 15 °C 90% (3 steps) N N 237 or 258 N F (R) N OH OH O XXII Ticagrelor Scheme 42 Synthesis of ticagrelor (XXII) chloride 257 was then reacted with sodium azide in the presence of sodium carbonate and tetrabutyl ammonium bromide in a biphasic mixture of toluene and water to give the acyl azide intermediate, which was immediately subjected to warm toluene to furnish, after acidic workup, the key intermediate cyclopropyl amine 237 in 88% yield and 92% ee This enantioenriched interme- diate was then mixed with R-(À)-mandelic acid to provide the mandelic acid salt of amine 237 (258) With all three intermediates available from the above mentioned routes, the final assembly of ticagrelor was accomplished as outlined in Scheme 42.187 First, oxalate salt of cyclopentyl amine 235 was coupled with dichloroaminopyrimidine thioether 236 in 2821 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 O O O O BnBr, DIPEA, Et 3N OH MeCN, ↑↓, 93% CH Cl2 , H 2O, CH COOH O H2 SO3 (conc.), < 25 °C HNO3 (conc.), < 20 °C 86% O HO 262 263 O O O O O O Na 2S2 O4 , MeCN O O H2 O, RT to 65 °C 92% NO2 264 NH2 265 O O H2N NH NH HOAc O N toulene, DIPEA, POCl3 , 73 °C Br i-BuOH, 97 °C, 98% , toluene, 73 °C 267 F TFA, 60 °C, 90% (3 steps) H 2N 266 O Br O HN O HO Boc N Br O S HN N O 269 F ® NaOH, Adogen 464, H 2O, 70 °C 77% N O Boc N F N N 268 270 Br HN O HCO2 H, HCHO (aq 37% w/w) 80 °C, 91% O N F N N XXIII Vandetanib Scheme 43 Synthesis of vandetanib (XXIII) the presence of triethylamine and at elevated temperature to give diamine intermediate 259 in 88% yield after crystallization Diamine 259 was then subjected to diazotization with sodium nitrite in acetic acid and toluene at $30 °C, leading to the formation of triazole 260 This intermediate was immediately reacted with 258 (madelic acid salt of cyclopropyl amine 237) to give intermediate 261, which was subsequently taken forward to the final deprotection step Reaction of ketal 261 with concentrated HCl in methanol and toluene at 15 °C provided ticagrelor (XXII) in 82–90% yield over the steps 24 Vandetanib (CaprelsaÒ, ZactimaÒ, ZictifaÒ) Vandetanib, an oral VEGF, EGF, and RET receptor tyrosine kinase inhibitor, was developed by AstraZeneca for the treatment of symptomatic or aggressive medullary thyroid cancer (MTC) in patients with advanced or metastatic disease.197 This is the first drug approved for the treatment of MTC Trials for other cancer indications such as small-cell lung cancer (SCLC), breast cancer, head and neck cancer, colorectal cancer, hormone-resistant prostate cancer, and papillary thyroid cancer are currently being explored While AstraZeneca had previously developed ZD-4190 which displays similar efficacy and pharmacokinetic profile to vandetanib, vandetanib exhibited significantly improved solubility Vandetanib contains a 4-anilinoquinazoline scaffold similar to other EGFR inhibitors, and the synthesis described below is based on a recent patent (Scheme 43).198 Commercially available vanillic acid (262) was treated with benzyl bromide, DIPEA and Et3N to give ethereal ester 263 in 93% yield Arene 263 was then subjected to nitration conditions to provide nitroarene 264 in 86% yield, which underwent immediate reduction with sodium dithionite in acetonitrile and water to give aniline 265 in 92% yield Aniline 265 was then treated with foramidine acetate in isobutanol which affected an intramolecular cyclization reaction, giving rise to dihydroquinazolin-4-one 266 in 98% yield Heterocycle 266 was treated with phosphorous oxychloride and the resulting quinazoline chloride was subsequently reacted with 4-bromo-2-fluoroaniline 267 and trifluoroacetic acid to give hydroxyaniline 268 in 90% for the three-step sequence Phenolic azacycle 268 was then alkylated with sulfonate 269 to furnish piperidine 270 in 77% yield Subsequent treatment with formic acid and aqueous formaldehyde under elevated temperatures gave vandetanib (XXIII) in 91% yield 25 Vemurafenib (ZelborafÒ) Vemurafenib was originally discovered at Plexxikon and has been co-developed by Roche and Plexxikon as an oral BRAF inhibitor for the treatment of patients with BRAFV600E mutation-positive metastatic melanoma.199 The drug displays good potency and selectivity for the V600E mutation (IC50 = 3.2–14 nM), an oncoprotein, over the wild-type BRAF (IC50 = 21–370 nM).200 The compound is less potent in in vitro kinase assays than other Plexxikon BRAF inhibitors, but it was selected for clinical development 2822 H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 Cl Cl Cl (HO)2 B Br N 272 NIS/TFA I DMF, 80 °C, 98% 1% Pd(OAc) 2, 1% PdCl2(dppf) CH 2Cl2 dioxane/H 2O, Na2 CO 90 °C, 83% NH N 271 N NH2 273 274 OEt O B NH2 F 275 O Cl Cl PdCl2(dppf) CH 2Cl2 LiOH, DMF, 70 °C O 278, AlCl3 HCl, 50 °C, 92% N H N O O N S H F CH2 Cl2 , RT, 83% N 276 N H XXIV Vemurafenib F F O HO O N H F S O (COCl)2 , DMF O Cl CH Cl2 O N H F 277 S O 278 Scheme 44 Synthesis of vemurafenib (XXIV) O O O piperazine, NaOt-Bu NH Br NH2 N DavePhos, Pd(dba)2 toluene, ↑↓, 16 h, 70% O HN 279 280 OH Cl O NC 4-chlorobutanoyl chloride N H Al(i-Bu)Cl2 , 15 °C, 1.5 h, 82% NaBH4 , i-PrOH NC NC 83 °C, h, 74% N H N H 281 282 283 OTs O O NC 280, DIPEA, MeCN, 82 °C, h TsCl, Et3N °C, h, 84% NC N H 10-37% HCl in THF, 30 °C, h 79% (2 steps) 284 NH2 N N N H • HCl XXV Vilazodone hydrochloride Scheme 45 Synthesis of vilazodone hydrochloride (XXV) based on its enhanced potency against the BARFV600E-containing A374 melanoma cell line.199 The synthesis described below is based on a recent process patent (Scheme 44).201 Commercially available 2-amino-5-bromopyridine (271) was treated with 4-chlorophenylboronic acid (272) in the presence of Na2CO3 and a catalytic amount of Pd(OAc)2/PdCl2(dppf)ÁCH2Cl2 to give Suzuki product 273 in 83% yield Arene 273 was subjected to iodination conditions using NIS and TFA to provide iodide 274 in 98% yield Iodide 274 and pinacol vinylboronate 275 were coupled under Suzuki conditions followed by treatment with acid to affect a tandem coupling–cyclization sequence which resulted in pyrimidyl pyrrole 276 in good yield This material was treated with aluminum trichloride and then subjected to the the acyl chloride of commercially available sulfonamide acid 277, triggering a FriedelCrafts reaction providing vemurafenib (XXIV) in 85% yield 26 Vilazodone hydrochloride (ViibrydÒ) Vilazodone hydrochloride is a combined serotonin reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist marketed under the trade name ViibrydÒ.202 Viibryd was developed by Merck KGaA (Germany) and approved for the treatment of depression by the U.S FDA on January 21st, 2011 Vilazodone has been shown to be well-tolerated at higher dosage levels, specifically by not causing significant weight gain or decreased sexual desire or function, which are improvements over existing antidepressant treatments.203 Although several synthetic approaches have been reported,204–207 a process-scale synthesis of vilazodone consists of the union of an indole-containing butyl tosylate 284 with a benzofuranyl piperazine 280,208 whose synthesis is described below (Scheme 45) Piperazine H X Ding et al / Bioorg Med Chem 21 (2013) 2795–2825 O Br HO isobutylaldehyde, KOt-Bu DMF, °C, 15 h 71% (2 steps) 285 Acknowledgment O PPh 3, neat, 145 °C, h 2823 HO The authors thank Dr Carolyn Leverett and Dr Robert Kyne Jr for their extremely helpful suggestions in preparing this review (Z)-286 (E/ Z= 11:1) References and notes O SOCl2 , 100 °C, 0.5 h 287, Et 2O, RT, h 66% (2 steps) O N H HO O NH HO 287 XXVI Zucapsaicin Scheme 46 Synthesis of zucapsaicin (XXVI) 280 arises from a Buchwald coupling of commercially available benzofuranyl bromide 279 with piperazine through the use of a unique catalyst system employing the DavePhos ligand.209 This single coupling step, which has been executed on multigram scale in 70% yield,210 circumvented the need for any protecting group chemistry for either the primary amide within 279 or the piperazine amine functionality.211 For the preparation of the key indole subunit, Friedel-Crafts acylation of commercially available 5-cyanoindole (281) proceeded in good yield at the 3-position of the indole with 4-chlorobutanoyl chloride in 82% yield.208 Treatment of the resulting chloroketone with sodium borohydride in refluxing isopropanol converted 282 to the corresponding terminal alcohol 283 Tosylation of this alcohol was followed by displacement with piperazine 280 to give vilazodone hydrochloride (XXV) after acidification.208 27 Zucapsaicin (ZuactaÒ) Zucapsaicin, the cis-isomer of the natural product capsaicin, is a topical analgesic that was initially developed by Winston Pharmaceuticals and approved in Canada in July 2010 for the treatment of severe pain in adults with osteoarthritis of the knee.212 The advantages of zucapsaicin compared with naturally-occurring capsaicin are reported to be a lesser degree of local irritation (stinging, burning, erythema) in patients and a greater degree of efficacy in preclinical animal models of pain.213,214 The analgesic action of both zucapsaicin and capsaicin is mediated through the transient receptor potential vanilloid type (TRPV1) channel, a ligand-gated ion channel expressed in the spinal cord, brain, and localized on neurons in sensory projections to the skin, muscles, joints, and gut.215 The scale preparation of zucapsaicin likely parallels the original approach described by Gannett and co-workers involving the coupling of vanillylamine with (Z)-8-methylnon-6-enoyl chloride.216 Orito and co-workers elaborated this original approach in an effort to prepare both capsaicin and zucapsaicin on gram-scale, and this route is described in Scheme 46.217 Commercial 6-bromohexanoic acid (285) was activated as the Wittig salt prior to condensation with isobutylaldehyde in the presence of strong base to generate an 11:1 ratio of E/Z-olefinic acids favoring Z-isomer 286.218 Removal of the minor isomer was easily achieved by short-path distillation.217 Interestingly, the authors reported that facile olefin isomerization of 286 occurred upon exposure to nitric acid at elevated temperatures, converting 286 to the corresponding E-isomer Recrystallization provided the product on multi-gram scale in 77% yield, representing a possible scale production method for capsaicin.217 For the preparation of zucapsaicin, acid 286 was converted the acid chloride via thionyl chloride followed by immediate condensation with commercially available vanillylamine (287) Two recrystallization steps were subsequently employed to produce gram-scale amounts of zucapsaicin (XXVI) in 66% yield overall for the two-step process.217 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 Raju, T N K Lancet 2000, 355, 1022 Li, J.; Liu, 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formulations of existing drugs, and drugs synthesized purely via bio-processes or peptide synthesizers... refractory to the initial standard therapy The initial SAR studies and the discovery of teleprevir have been published.170–173 In addition, a full review of the discovery process that led to the. .. focus on the process scale synthesis used to make the telaprevir.170,175 For preparation of bulk API, a convergent synthetic strategy was utilized as described in Scheme 33 Retrosynthetically the