Synthetic Approaches To The New Drugs 2013

Bioorganic & Medicinal Chemistry 23 (2015) 1895–1922 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc Review Synthetic approaches to the 2013 new drugs Hong X Ding a, , Carolyn A Leverett d,à, Robert E Kyne Jr d,§, Kevin K.-C Liu b,–, Sarah J Fink c,k, Andrew C Flick d,  , Christopher J O’Donnell d,⇑ a Pharmacodia (Beijing) Co., Ltd, Beijing 100085, China Lilly China Research and Development Center, Shanghai 201203, China c BioDuro Co., Ltd, Shanghai 200131, China d Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, CT 06340, United States b a r t i c l e i n f o Article history: Received January 2015 Revised 20 February 2015 Accepted 26 February 2015 Available online March 2015 Keywords: Synthesis New drug molecules New chemical entities Medicine Therapeutic agents a b s t r a c t New drugs introduced to the market every year represent privileged structures for particular biological targets These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs This annual review covers the synthesis of twenty-four NCEs that were approved for the first time in 2013 and two 2012 drugs which were not covered during the previous edition of this review Ó 2015 Elsevier Ltd All rights reserved Contents Introduction Acotiamide hydrochloride hydrate (AcofideÒ) Afatinib dimaleate (GiotrifÒ, GilotrifÒ) Canagliflozin hydrate (InvokanaÒ) Cetilistat (ObleanÒ) 1896 1896 1896 1897 1898 Abbreviations: 1,2-DAP, 1,2-diaminopropane; 1,2-DCE, 1,2-dichloroethane; Ac, acetyl; aq, aqueous; Bn, benzyl; Bz, benzoyl; Boc, t-butoxycarbonyl; B2(pin)2, bis(pinacolato)diboron; BINAP, 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl; BSA, N,O-bistrimethylsilyl acetamide; CDI, N,N0 -carbonyldiimidazole; CDMT, 2-chloro-4, 6-dimethoxy-1,3,5-triazine; DAP, diaminopropane; Dba, dibenzylideneacetone; DBU, 1,5-diazabicycolo[4.3.0]non-5-ene; DCC, 1,3-dicyclohexylcarbodiimide; DCE, dichloroethane; DCM, dichloromethane; DIAD, diisopropyl azodicarboxylate; DIC, 1,3-diisopropylcarbodiimide; DIEA/DIPEA, diisopropylethylamine; (À)-DIP-chloride, (À)-diisopinocampheyl chloroborane; DMA, dimethylacetamide; DMAP, 4-dimethylaminopyridine; DME, dimethoxyethane; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; DPPA, diphenylphosphoryl azide; EDCI, N-(3-dimethylaminopropyl)-N0 -ethylcarbodiimide; EDTA, ethylenediaminetrteaacetic acid; EEDQ, N-ethoxycarbonyl-2ethoxy-1,2-dihydroquinoline; HBTU, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HMDS, bis(trimethylsilyl)amide; HOBT, 1-hydroxybenzotriazole hydrate; IPA, isopropyl alcohol; IPAc, isopropyl acetate; LAH, lithium aluminum hydride; LHMDS, lithium bis(trimethylsilyl)amide; MIBK, methyl isobutyl ketone; MsOH, methansulfonic acid; MsCl, methanesulfonic chloride; MTBE, methyl tert-butyl ether; NaHMDS, sodium bis(trimethylsilyl)amide; NBS, N-bromosuccinimide; NMM, N-methylmorpholine; NMP, N-methyl-2-pyrrolidone; pin, pinacol; Py, pyridine; rt, room temperature; TBAB, tetrabutylammonium bromide; TBAF, t-butyl ammonium fluoride; TFA, trifluoroacetic acid; TFAA, trifluoroacetic anhydride; THF, tetrahydrofuran; TMEDA, tetramethylethylenediamine; TMP, 2,2,6,6-tetramethylpiperidine; TMSCl, trimethylsilyl chloride; TMSI, trimethylsilyl iodide; TBDPS, tert-butyl diisopropylsilyl; Ts, tosyl(p-toluenesulfonyl) ⇑ Corresponding author Tel.: +1 860 715 4118 E-mail addresses: Sheryl.ding@pharmacodia.com (H.X Ding), carolyn.a.leverett@pfizer.com (C.A Leverett), robert.kynejr@pfizer.com (R.E Kyne), Liu_kang_zhi_kevin@lilly com (K.K.-C Liu), Sarah.fink@bioduro.com (S.J Fink), andrew.flick@pfizer.com (A.C Flick), christopher.j.odonnell@pfizer.com (C.J O’Donnell)   Tel.: +86 10 8282 6195 Tel.: +1 860 441 3936 § Tel.: +1 860 441 1510 – Tel.: +86 21 2080 5590 k Tel.: +86 21 3175 2858    Tel.: +1 860 715 0228 http://dx.doi.org/10.1016/j.bmc.2015.02.056 0968-0896/Ó 2015 Elsevier Ltd All rights reserved 1896 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 Cobicistat (TybostÒ) Dabrafenib mesylate (TafinlarÒ) Dolutegravir sodium (TivicayÒ) Efinaconazole (JubliaÒ) Elvitegravir (VitekaÒ) Gemigliptin L-tartrate hydrate (ZemigloÒ) Ibrutinib (ImbruvicaÒ) Istradefylline (NouriastÒ) Levomilnacipran hydrochloride (FetzimaÒ) Lomitapide mesylate (JuxtapidÒ) Macitentan (OpsumitÒ) Olodaterol hydrochloride (Striverdi RespimatÒ) Ospemifene (OsphenaÒ) Pomalidomide (PomalystÒ) Riociguat (AdempasÒ) Saroglitazar (Lipaglyn Ò) Simeprevir (OlysioÒ; SovriadÒ) Sofosbuvir (SovaldiÒ) Topiroxostat (UriadecÒ; TopiloricÒ) Trametinib dimethyl sulfoxide (MekinistÒ) Trastuzumab emtansine (KadcylaÒ) Vortioxetine (BrintellixÒ) Conclusion 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 twelve years ago2–12 and presents synthetic methods for molecular entities that were approved for the first time in various countries during the past year Given that drugs tend to have structural homology across similar biological targets, it is widely believed that the knowledge of new chemical entities and their syntheses will greatly enhance the ability to design new drugs more efficiently The pharmaceutical industry enjoyed a banner year in 2013, with a total of 56 new products including new chemical entities, biological drugs, and diagnostic agents having reached the worldwide market for the first time Although an additional 19 new products were approved for the first time in 2013, some were not launched before the end of the year,13 and therefore this review focuses on the syntheses of twenty-four NCEs that were approved and launched for the first time in 2013 It also includes two additional drugs that although were initially approved in 2012, were not included in our prior review (Fig 1).12 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 were not explicitly disclosed in most cases, this review covers, perceptibly, the most scalable routes that have been disclosed within published or patent literature beginning from commercially available starting materials Drugs presented in this review are ordered alphabetically by generic name Acotiamide hydrochloride hydrate (AcofideÒ) Acotiamide hydrochloride trihydrate is the first drug to be approved in Japan for the treatment of functional dyspepsia (FD) The drug was discovered by Zeria Pharmaceuticals and jointly developed with Astellas Pharmaceuticals.14 The drug blocks muscarinic receptors and inhibits peripheral acetylcholine esterases, thereby increasing the concentration of acetylcholine,14 ultimately improving the impaired gastric motility and delayed gastric 1898 1900 1901 1902 1904 1906 1908 1909 1910 1912 1912 1914 1914 1914 1914 1916 1917 1917 1917 1918 1918 1919 1919 1920 emptying along with the additional symptoms associated with FD, such as post prandial fullness, upper abdominal bloating and early satiation.14–16 Although multiple synthetic approaches to the drug have been reported,17,18 the synthesis highlighted in Scheme and described below represents the largest scale reported to date in a patent application.18 Commercial 3,4,5-trimethoxybenzoic acid (1) was first converted to the corresponding acid chloride 2, which was isolated by co-distillation with hexane In refluxing dichloroethane (DCE), the acid chloride was coupled with the commercially available thiazole amine (3) to give the desired amidothiazole in 89% yield From this intermediate, amide linkage, selective demethylation of the 2-methoxy group, salt formation, and recrystallization were accomplished in the following sequence: the thiazole ester was reacted with N,N-diisopropyl ethylenediamine (5) in DMA at elevated temperatures Upon cooling, the mixture was dissolved in n-butanol and washed with aqueous sodium hydroxide Subsequent treatment with HCl gas in isopropanol gave the corresponding HCl salt as crystals that could be collected by filtration The product obtained was further crystallized from 4:1 isopropanol and water to give the desired product acotimide (I) as the hydrochloride trihydrate in 71% yield Afatinib dimaleate (GiotrifÒ, GilotrifÒ) Afatinib dimaleate was approved by the U.S Food and Drug Administration (FDA) in 2013 for the treatment of non-small cell lung cancer (NSCLC).19 Specifically, it was approved for patients presenting with metastatic NSCLC tumors which contain epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 mutations.19 Afatinib dimaleate is a covalent inhibitor of ErbB tyrosine kinases (tyk), which downregulates ErbB signaling by irreversible binding of EGFR tyk binding sites.19 While no manufacturing route has been disclosed to date,20–24 the most scalable published route likely derives from two Boehringer Ingelheim patents (Scheme 2).25,26 Nitroquinazolinone (6), which is commercially available, was first chlorinated with phosphorous oxychloride (POCl3) followed by treatment with commercial 3-chloro-4-fluoroaniline (7) to afford SNAr adduct in 90% yield over two steps Sulfonylation to 1897 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 F O N N N H OH O Cl O S O NH H N N HN N O N O COOH COOH H 2O HCl O I Acotiamide hydrochloride hydrate II Afatinib dimaleate O O O HO F S HO OH N O 1/2 H 2O OH III Canagliflozin hydrate IV Cetilistat O N O N N N H N H O S F O H N O S F O H N S O S CH SO H V Cobicistat F O O H N CH3 N NH2 HO H N N N F N N O VI Dabrafenib mesylate N F N F N Na+ O- N O VII Dolutegravir sodium F VIII Efinaconazole Figure Structures of 26 NCEs covered in this review afford (86%) and subsequent displacement with (S)-tetrahydrofuran-3-ol gave 10 in 90% yield.25 Raney–Nickel reduction of the nitro group delivered 11 in 97% yield, which set the stage for the final side-chain functionalization 2-(Diethoxyphosphoryl) acetic acid and N,N0 -carbonyldiimidazole (CDI) were pre-mixed and added to aniline 11 to afford 12 in 70% isolated yield Next, a Horner–Wadsworth–Emmons homologation gave the (E)-olefin 13 in quantitative yield, followed by maleate salt formation (92%) to deliver the final API The final five steps of this synthesis have been successfully demonstrated on multi-kilogram scale.24,25 Canagliflozin hydrate (InvokanaÒ) Canagliflozin, an orally active and selective sodium–glucose cotransporter (SGLT2) inhibitor, was co-developed by Mitsubishi Tanabe Pharma and Johnson & Johnson (J&J) for the treatment of type diabetes mellitus (T2DM) and obesity The drug was approved in March by the U.S FDA and launched in April 2013 in the U.S SGLT2 is involved in the glucose re-absorption pathway in the kidney, and its inhibition increases urinary glucose excretion, and reduces plasma glucose and HbA1c levels.27 In addition, canagliflozin is safe in combination with other commonly used antidiabetic agents and has a significant effect on body weight reduction.28 A recently published process patent from ScinoPharm Taiwan describes the synthesis of canagliflozin The preparation of the drug involves a convergent strategy whereby the union of the aglycone and glycoside components of the molecule ultimately secure the atomic framework of the API—the synthesis of each region and their union are described in Scheme 3.29 Synthesis of the aglycone region of canagliflozin was described in a separate patent by first condensing commercially available 5bromo-2-methylbenzoyl chloride (14) and 2-(4-fluorophenyl)thiophene (15) under Friedel–Crafts acylation conditions to give ketone 16 in 69% yield as a crystalline solid.29 Ketone 16 was then reduced with triethylsilyl hydride in the presence of BF3ÁEt2O at low temperature to give aglycone bromide 17 in 70% yield The precursor for the glycoside moiety, commercially available glycoside triol 18, was selectively treated with t-butyldiphenylsilyl chloride (TBDPSCl) in THF in the presence of imidazole to give the bis-silyl ether 19 in 81% yield Next, a unique, stereospecific b-C-arylglucosidation was developed to secure the union of the aglyone- and glycoside-containing portions of canagliflozin Bromide 17 was subjected to magnesium powder under standard Grignard conditions prior to treatment with AlCl3 in THF in situ This resulting mixture was then exposed to a solution of compound 19 in PhOMe which had been pre-treated with n-BuLi, and 1898 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 CF3 OH N O N F3C N O N OH Cl O F O OH O HO N NH2 O OH OH O 1.5 H2O F F X Gemigliptin L-tartrate hydrate IX Elvitegravir OPh O NH2 N N O N N N O N N N N NH2 O O HCl N O XI Ibrutinib XII Istradefylline XIII Levomilnacipran hydrochloride Br CF3 HN F 3C O N O H N S N O N H O N H CH3SO3H XIV Lomitapide mesylate HO H N Br N O O N N XV Macitentan O O H N O O Cl N OH O O NH OH NH2 O O • HCl XVI Olodaterol hydrochloride XVII Ospemifene XVIII Pomalidomide Fig (continued) the entire mixture was then warmed to 150 °C for h to ultimately give the b-anomer 20 in 56% yield Finally, removal of the silyl groups within 20 with tetrabutyl ammonium fluoride (TBAF) in THF delivered canagliflozin hydrate (III) in 73% yield (Scheme 3) methyl chloroformate at room temperature resulted in the formation of cetilistat (IV), which was produced in 31% overall yield from hexadecanol.31 Cobicistat (TybostÒ) Ò Cetilistat (Oblean ) Cetilistat is a selective pancreatic lipase inhibitor which was approved in Japan in September 2013 for the treatment of obesity The drug was discovered by Alizyme PLC and later co-developed with Takeda Cetilistat demonstrated a lower incidence of adverse gastrointestinal events during a 12 week clinical trial, and the degree of weight loss associated with cetilistat is comparable to that of other approved antiobesity therapies.30 The most likely process-scale preparation of cetilistat is described below in Scheme 4.31 Commercially available hexadecanol (21) was treated with phosgene in THF/toluene to give the corresponding chloroformate (22), which was immediately subjected to commercial 2-amino-5methylbenzoic acid (23) in pyridine Subsequent slow addition of Cobicistat, a selective, mechanism-based CYP3A inhibitor, was discovered and developed by Gilead Sciences, Inc In 2013, European Medicines Agency (EMA) approved cobicistat (TybostÒ) for the treatment of HIV-1 infection in combination with protease inhibitors (PIs) atazanavir or darunavir Interestingly, cobicistat does not interact with HIV directly, but instead serves as a pharmacokinetic enhancer to boost the anti-HIV effect of atazanavir or darunavir through blockade of CYP3A.32 Cobicistat slows CYP-mediated metabolism of atazanavir and darunavir, resulting in prolonged systemic exposure of the drug(s).32 Cobicistat is also available as part of a fixed-dose combination tablet (StribildÒ) of four additional drugs with CYP3A liabilities (elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate), which was approved in U.S in 2012, and subsequently approved in Europe 1899 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 F N MeO S N N S N N O N N H2 N O N NH2 O OH O N O Me O HN P O PhO O HO F Me NH O N H N N H N N N H O S XXI Simeprevir N N O O O O XX Saroglitazar XIX Riociguat O N O O H N O N N O F H N N O N I O O XXII Sofosbuvir XXIII Topiroxostat XXIV Trametinib O N O O O trastuzumab O O O Cl O H N O S N H N 3.5 H N N H O N H O OH HBr S O XXV Trastuzumab emtansine hydrobromide XXVI Vortioxetine Fig (continued) O OH O O SOCl2, DMF toluene, 85 °C, 85% O H 2N N OEt DCE, ↑↓, 89% O O O S O O Cl O O S O O N H O N H 2N N O OEt DMA, 135 °C HCl, i-PrOH, rt i-PrOH/H2 O (4/1) crystallization 71% for steps O O N H OH O S N N HCl HN H 2O I Acotiamide hydrochloride hydrate Scheme Synthesis of acotiamide hydrochloride hydrate (I) and Japan in 2013 Although several synthetic routes have been reported,33–37 the improved process route by Gilead Sciences is described in Schemes and 6.37 Commercial L-methionine (24) was treated with bromoacetic acid at elevated temperatures to afford aminolactone salt 25 in 70% yield This material was then reacted with methyl aminomethylthiazole (26) in the presence of CDI and diisopropylethylamine to arrive at urea 27 in 91% yield Next, lactone 27 underwent a ring-opening sequence upon exposure to trimethylsilyl iodide (TMSI) giving intermediate 28 The iodide was then displaced by morpholine, followed by treatment with oxalic acid to deliver the L-thiazole morpholine ethyl ester as the oxalate salt 1900 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 F O NO2 HN Cl N POCl3, Et3N CH3CN, 80 °C F Cl NH NH NO2 N DMF, rt to 90 °C 86% Cl N NH2 Cl PhSO 2Na NO2 N Cl F SO2Ph N 90% for steps F F HO Cl Cl NH O NO2 N t-BuOH, DMF, THF KOt-Bu, 20 °C to 45 °C 90% N NH N Raney-Ni, DMF O N NH4Cl, 40 °C 97% O HO NH2 O OEt P OEt O CDI, THF, 40 °C to 20 °C 70% O O 10 11 F F Cl NH N H N O N O i LiCl, THF, -7 °C ii KOH/H2O, -5 °C OEt P OEt O Cl NH N HCl (aq), then OEt NMe2 EtO -5 °C to 30 °C O O N N O O 100% for steps 12 H N 13 F Cl maleic acid EtOH, 70 °C, 92% NH N N H N O N O O COOH COOH II Afatinib dimaleate Scheme Synthesis of afatinib dimaleate (II) 29 in 71% yield for the sequence Base-mediated hydrolysis of ethyl ester 29, followed by treatment of carboxylate 30 with mono-carbonate hydrochloride 31 in the presence of EDCI and HOBT, provided cobicistat (V) in 76% yield for two steps Of note, the preparation of mono-carbonate hydrochloride 31 arose from commercially available (S)-2-benzylaziridine (32) which was first condensed with N,N-dimethylsulfamoyl chloride to obtain N-tosyl-protected aziridine 33 in 77% yield (Scheme 6) Next, a unique base-induced dimerization reaction was employed to convert aziridine 33 to alkene 34 Presumably this proceeded through initial deprotonation at the methylene carbon within aziridine 33 upon exposure to lithium 2,2,6,6-tetramethylpiperidine (LiTMP) resulting in an unstable trans-R-lithiated terminal aziridine This lithiate then underwent nucleophilic attack onto another molecule of 33 followed by elimination to give the 2-ene-1,4-diamine 34 in 72% yield.37–39 Removal of the sulfonyl groups with 1,3-diaminopropane followed by hydrogenation of the alkene provided diamine 36 in quantitative yield Conversion to the diamine– dihydrogen chloride 37 through the use of HCl in dioxane was followed by a treatment with a single equivalent of base and 5-thiazolylmethyl carbonate 38 (prepared from bis-(4-nitrophenyl)-carbonate (39) with 5-hydroxymethylthiazole) This sequence furnished amino carbamate 31, which then participated in the coupling with carboxylate fragment 30 to prepare cobicistat as described above Dabrafenib mesylate (TafinlarÒ) Dabrafenib mesylate, sold by GlaxoSmithKline under the trade name TafinlarÒ, was approved by the U.S FDA in May 2013 for the treatment of metastatic BRAF-mutant melanoma Dabrafenib reversibly inhibits the BRAF(V600E) mutant kinase as a selective ATP-competitive inhibitor which results in tumor regression.40 While the process-scale route has not yet been disclosed,41–43 the largest scale route to date is represented in Scheme 7.44 Commercially available fluoroaniline 4042 was first converted to sulfonamide 42 in 91% yield by treatment with 2,5-difluorobenzenesulfonyl chloride (41) in the presence of pyridine Next, deprotonation of 2-chloro-4-methylpyrimidine (43) with lithium bis(trimethylsilyl)amide (LHMDS) followed by addition to ester 42 afforded chloropyrimidine 44 in 72% yield Bromination followed by thiazole formation through the use of 2,2-dimethylpropanethioamide gave the penultimate target 45 in 80% over two steps Chloropyrimidine 45 was subjected to SNAr conditions 1901 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 Cl Br AlCl3 , CH 2Cl2, °C to rt S + F O Br S 69% 16 15 14 F O i Et3 SiH, BF3.Et2O, CH3 CN/CH2 Cl2 (1/1) °C to rt Br ii NaHCO3 (aq) , °C S F 70% 17 O O HO O TBDPSCl, imidazole OH TBDPSO °C, THF, 81% OH OTBDPS OH 18 HO O 17, Mg, BrCH 2CH2 Br, THF AlCl3 , THF, rt n-BuLi, rt PhOMe, 150 °C 56% for steps 19 O S TBDPSO F TBAF, THF, rt 73% OTBDPS HO O S HO OH OH 1/2 H2 O OH 20 F III Canagliflozin hydrate Scheme Synthesis of canagliflozin hydrate (III) O OH O COCl2, THF/toluene, rt 21 Cl 22 O 22, pyridine, rt HO2 C O MeOCOCl, rt H2 N O N 31% for steps 23 IV Cetilistat Scheme Synthesis of cetilistat (IV) with ammonium hydroxide to furnish the aminopyrimidine in 88% yield, and this was followed by exposure to methanesulfonic acid to afford dabrafenib mesylate (VI) in 85% yield.44 Dolutegravir sodium (TivicayÒ) Dolutegravir sodium (TivicayÒ), developed and marketed by GlaxoSmithKline,45 was approved by the FDA in August 2013 as a novel integrase inhibitor for the treatment of HIV infection.46 Dolutegravir was fast-tracked by the FDA in February 2012,47 and joins an important class of drugs known as Integrase Strand Transfer inhibitors (INSTi’s).48 INSTi’s are characterized by their two-metal-chelating scaffolds, which are known to chelate Mg2+ cofactors in the enzyme active site,49,50 l interrupting function of HIV-1 integrase, which is essential for replication of viral DNA into host chromatin.49–52 Other drugs in this class, raltegravir and elvitegravir, are known to require either high dosages53 or PK boosting agents,54 respectively, with raltegravir also exhibiting substantial loss of potency in several major HIV-1 integrase mutation pathways.55 Dolutegravir was pursued with the goal of developing a novel INSTi with a once-daily, low-dosage treatment with improved resistance profile and without the need for the use of a PK boosting agent.51,56 Dolutegravir sodium has been approved for treating a broad population of HIV-infected patients, including adults undergoing their first treatment as well as those who have been treated with other integrase transfer strand inhibiting agents.46 The most likely process-scale synthesis of dolutegravir sodium, as described in Scheme 8, began with benzyl protection and alkylation of pyrone 46 with benzaldehyde, yielding alcohol 47 in 74% 1902 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 O S BrCH2COOH, H 2O i-PrOH, AcOH, ↑↓ OH H2N HCl in dioxane, 60 °C O DIPEA, CH2Cl2 CDI, 10 °C to 25 °C O O H2N N 70% S 24 25 N N H S N H 26 HCl O N O 27 91% O N I O TMSI, EtOH, CH2Cl2 N N 10 °C to 22 °C NH O N 10 °C to 22 °C OEt N H S O oxalic acid, acetone O N S N H OEt O O OH HO 71% for two steps O 28 29 O N 31, EDC•HCl, HOBT, CH2Cl2 O KHCO3 (aq), CH2Cl2 N 45% KOH (aq), 10 °C to 20 °C N N H S O O K -18 °C to -20 °C 76% for steps 30 O N O N S N N H H N O O N H O S N V Cobicistat Scheme Synthesis of cobicistat (V) over steps (Scheme 8).57,58 Alcohol mesylation and in situ elimination provided the styrenyl olefin 48 in 94% yield, which further underwent an oxidative cleavage of the olefin to generate 49 by sequential addition of RuCl3/NaIO4 and NaClO2 (56% overall yield) Treatment of pyranone 49 with 3-amino-propane-2-diol (50) in ethanol at elevated temperatures delivered the corresponding pyridinone in 83% yield, and this was followed by esterification and sodium periodate-mediated diol cleavage to furnish intermediate 51 in 71% overall yield across the two-step sequence.57,58 l Next, the key ring-forming step in the synthesis of dolutegravir sodium consisted of cyclization of 51 with (R)-3amino-butan-1-ol, a process which relies on substrate control to provide the desired tricyclic carbamoylpyridone system 52 in high stereoselectivity (20/1 in favor of the desired isomer).51 Previously, cyclization of systems such as 51 with unsubstituted amino alcohols were found to yield a mixture of diastereomeric products, therefore indicating the pivotal role of the chiral amino alcohol in influencing stereochemical bias during the overall cyclization step.51,56 In practice, reaction of 51 with (R)-3-amino-butan-1-ol at 90 °C led to isolation of a single cyclization product 52, after recrystallization from EtOAc.57,58 From 52, N-bromosuccinimide (NBS) bromination and subsequent treatment with amine 53 under palladium-catalyzed amidocarbonylative conditions led to amide 54 in 75% yield over steps Finally, removal of the benzyl group and subsequent crystallization using sodium hydroxide in water and ethanol provided dolutegravir sodium (VII) in 99% yield.57,58 Efinaconazole (JubliaÒ) Efinaconazole, marketed and developed by Valeant Pharmaceuticals International, was first approved for use in Canada in October 2013 under the brand name JubliaÒ for the treatment of onychomycosis, a fungal infection of the nail Efinaconazole is believed to work by 14a-demethylase inhibition, which is a key pathway in ergosterol synthesis.59 Inhibition of ergosterol prevents secondary degenerative changes in the nail bed, plate, and surrounding tissue.59 Although several syntheses of efinaconazole have been reported, none have reported on kilogram-scale.60–64 However, as preparation of the penultimate epoxide (60) has been described on hundred-kilogram scale in the synthesis of ravuconazole,65 and final production of efinaconazole has been disclosed on a 24 g scale route, the presumed scale route is described in Scheme 9.66 Commercially available (R)-methyl lactate (55) was first converted to THP protected alcohol 57 in steps and 78% yield via morpholino amide 56 Grignard displacement of the morpholine afforded ketone 58 in 81% yield Next, ketone 58 was epoxidized by means of the Corey ylide followed by ring-opening of the epoxide by triazole which had been activated by exposure to sodium tbutoxide Finally, subjection to methanesulfonic acid furnished diol 59 in 51% yield as the corresponding mesylate salt Diol 59 was then converted to epoxide 60 through the use of mesyl chloride and triethylamine in 78% yield and >99% ee Finally, treatment 1903 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 O N Cl S O N S N O O NH TMP, n-BuLi THF/heptane (1/3), -10 °C DIPEA, CH2 Cl2 , -10 °C 77% 72% 32 33 H 2N H 2N O N S N H O O H N S N O 34 H 2N NH NH2 NH H2 , Pd/C, MeOH 110 o C, 100% 22 °C, 100% 35 36 O HCl H 2N N HCl in dioxane CH 2Cl2, °C to 22 °C 94% H 2N K2 CO3 , H 2O, CH2 Cl2 , 20 °C 38, DIPEA, CH2 Cl2 NH HCl N H HCl O N N HCl in dioxane 83% for three steps 31 37 O2 N NO2 O O O2 N S HO O N Et3 N, CH2 Cl2 , 78% 39 S O O N O 38 Scheme Synthesis of intermediate 31 of cobicistat (V) F SO 2Cl F H2 N F CO2 Me F F H N O N CO2Me S O 41 pyridine, CH2Cl2 15 °C to 25 °C 91% 40 O H N S O N 43 Cl 42 F F Me LHMDS, THF, °C 72% F F O N N S S N F t-Bu , DMA 20 °C to 75 °C N H2 N F 44 45 80% for steps NH 4OH, 98 °C to 103 °C, 88% MsOH, MeCN, 20 °C to 60 °C, 85% F N S O NBS, CH2Cl2 , 10 to 20 °C Cl F H N O O H N S O F N S CH SO H N F N NH2 VI Dabrafenib mesylate Scheme Synthesis of dabrafenib mesylate (VI) S Cl 1904 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 O O OH i LHMDS, THF ii PhCHO, −60 °C O 46 O OBn MsCl, Et3N, THF, rt DBU, NMP Ph O 47 O RuCl3, NaIO4, CH3CN EtOAc, H2O, rt OH O 48 OH H2N O 50 OBn OH EtOH, 65 °C to 80 °C, 83% OBn HO O OH 51 49 OBn O OBn O OH O N H F NBS, NMP, rt, 89% N CH3OH, toluene AcOH, 90 °C, 83% O O N H N 53, Pd(PPh3)4, CO(g), DIPEA DMSO, 90 °C, 84% F N H O O 54 52 Na O O F H2, Pd/C, CH3OH, rt, 92% OMe N CH3I, NaHCO 3, NMP, rt NaIO4, CH3CN, H2O, AcOH, rt 71% for steps O 56% for steps H2N Ph 94% for steps 74% for steps NaClO2, rt O OBn OH BnBr, K2CO3, CH3CN, 80 °C O N H N NaOH, H2O, EtOH 80 °C to rt, 99% F F NH2 N O H O F 53 VII Dolutegravir sodium Scheme Synthesis of dolutegravir sodium (VII) O MTBE, 60 °C morpholine, 10 °C to 20 °C MeO C OH O O N NaOMe, MeOH °C to 20 °C N OH MsOH, THF, °C O 78% for steps 55 56 F MgBr N F F 57 N NH N Me3 SOI, NaOt-Bu, THF OTHP THF, 25 °C to 35 °C 81%, 98% ee F O N HO N OH F N DMF, 99% ee F HN HBr F HO N N N N F LiOH, CH3 CN 100 °C 87% 60 CH SO H 58 MsCl, Et3 N, THF, MTBE, -10 °C OTHP O F VIII Efinaconazole Scheme Synthesis of efinaconazole (VIII) of epoxide 60 with 4-methylene piperidine–HBr in the presence of lithium hydroxide afforded efinaconazole (VIII) in 87% yield 10 Elvitegravir (VitekaÒ) Elvitegravir is a quinolone-containing HIV integrase inhibitor discovered by Japan Tobacco and licensed to Gilead Pharmaceuticals for worldwide development with the exception of Japan.67 It was approved in Europe in 2013 for the treatment of HIV infection in adults having no known mutations associated with resistance to the drug.67 The drug interferes with HIV replication by preventing the virus from integrating into the DNA of human cells.67,68 In addition to several patent applications that have been filed for the synthesis of elvitegravir, the discovery 1908 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 O CN + 100 Cl O O NaNH2, toluene °C to 10 °C N toluene, rt NaOH (aq), 95 °C HCl (aq), 60 °C 101 OH O AlCl3, NHEt2 102 75% 103 O SOCl2, toluene rt to 50 °C N ethanolamine toluene, 83 °C O HCl, i-PrOH, i-PrAc 30 °C to 10 °C N O potassium phthalimide 45 °C 80% for steps N NH2 O • HCl 74% for steps XIII Levomilnacipran hydrochloride 104 Scheme 16 Synthesis of levomilnacipranÁHCl (XIII) Br(CH2)4Br, n-BuLi, THF O HO COCl2, DMF (cat)/CH2Cl2 HO °C to rt, 85% O Br 105 Et3N, CF3CH2NH2, °C 71% for steps 106 HN NHBoc K2CO3, DMF, 50 °C 109, COCl2, CH2Cl2 HN HN 4N HCl in dioxane, rt F3C O F3C O N 86% for steps Br 108 107 108, Et3N, DMAP CH2Cl2 CH3SO3H 65% for steps NH2 CF HN F3C O N • O N H CH3SO3H XIV Lomitapide mesylate CF3 CF3 O + I HO O rt to 75 °C, 92% HO B(OH)2 110 Pd(OAc)2, H2O 111 109 Scheme 17 Synthesis of lomitapide mesylate (XIV) provided butyl amine 84 Alkylation of 84 with activated alcohol 80 in triethylamine followed by cyclization in acetic acid afforded difluoropyridone 85 Acidic hydrolysis of the ester proceeded with concomitant removal of the Boc protecting group, and was followed by reprotection of the amine with di-tert-butyl dicarbonate to give acid 86 in 84% overall yield for the three-step procedure in >97% ee Coupling of 86 with fragment 75 in the presence of 1-hydroxybenzotriazole (HOBT) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) gave amide 87 in 51% yield Removal of the Boc group with thionyl chloride in ethanol followed by neutralization with aqueous sodium hydroxide and salt formation with L-tartaric acid provided gemigliptin L-tartrate hydrate (X) in 97.5% yield.83 12 Ibrutinib (ImbruvicaÒ) Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) which was granted breakthrough status by the U.S Food and Drug Administration in 2013 for the treatment of mantle cell lymphoma (MCL) and in 2014 for chronic lymphocytic leukemia (CLL).86 In preclinical studies involving CLL cells, the drug effectively promoted apoptosis, inhibited proliferation, and also 1909 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 O O O O O NaH, THF, 40 °C to rt 70% O O Br Br O NHK S N 117 H O DMSO, rt, 83% O H N S N H O N Cl N POCl3 , N,N-dimethylaniline 130 °C, 66% O 114 112 Cl 115 H NH NaOMe, MeOH, °C to rt 113 Br NH • HCl Br O ethylene glycol, KOt-Bu DME, rt to 100 °C, 86% N O OH N 118 116 Br N Cl 119 N THF, NaH, 60 to 75 °C, 88% Br N O H N S N H O N Br O O N N XV Macitentan O Cl S N O 120 C t-BuOH, CH 2Cl2 °C to rt O propylamine, Et3 N CH 2Cl2, °C to rt H N O O S N O O H N HCl/dioxane, rt MeOH, KOt-Bu, rt O NHK S O N H 117 121 Scheme 18 Synthesis of macitentan (XV) prevented CLL cells from responding to survival stimuli provided by the microenvironment.87 Ibrutinib demonstrated superiority over an anti-CD20 antibody (atumumab) in terms of disease progression measurements and overall survival of the patient.87 The drug, which was discovered by Celera Pharmaceuticals and acquired by Pharmacyclics, was developed in partnership with Johnson & Johnson’s Janssen Pharmaceutical division Although several different synthetic approaches to ibrutinib have been described in the patent literature,88–91 the most likely scale route is described in Scheme 14.92–95 Condensation of commercially available 4-phenoxybenzoyl chloride (88) with malononitrile followed by acidic quench and O-methylation with dimethyl sulfate furnished vinyl dinitrile 89 in 84% yield over the three-step sequence Next, treatment with hydrazine hydrate in refluxing ethanol secured aminopyrazole 90 and this was followed by treatment with neat formamide at elevated temperature to furnish pyrimidopyrazole 91 in excellent conversion Selective alkylation of the pyrazole nitrogen with commercially-available (S)-piperidinyl tosylate (92) proceeded in 32% yield.95 Finally, liberation of the amide followed by pH adjustment and amide bond formation with acrolyl chloride furnished ibrutinib (XI) in 50% over the three-step sequence 13 Istradefylline (NouriastÒ) Istradefylline (NouriastÒ ), a selective adenosine A2A inhibitor developed by Kyowa Pharmaceuticals, was approved in Japan in 2013 as an adjunctive therapy for the treatment of Parkinson’s disease (PD).96,97 A majority of therapies for PD, including the primary treatment, Levodopa,98 function via dopamine replacement.99 These treatments are very effective in the early stages of PD but they often exhibit dyskinesias symptoms in long-term treatment, leading to the inability to control motor fluctuations and therefore resulting in involuntary movements in patients.100–102 In contrast, istradefylline has been shown to reverse motor disability in monkeys and provide anti-Parkinsonian effects without exhibiting traditional symptoms of dyskinesias.103 While the ability to completely reproduce these results in human PD patients with istradefylline therapy exclusively are still inconclusive,104 this once-daily oral treatment has shown great potential for improving the quality of life for PD patients because of its effectiveness when used with other dopamine replacement treatments.102,105 Numerous synthetic approaches to istradefylline have been developed, with a large majority of these methods employing 5,6-amino-1,3-diethyluracil 97 as a key intermediate.106–109 Despite the commercial availability of 96, most reported routes to istradefylline rely on sourcing of this intermediate via a wellestablished four-step synthesis from N,N-diethylurea (94) and cyanoacetic acid (95).106,110,111 Specifically, 6-amino-1,3-diethyluracil (96) can be formed by sequential treatment of 94 and 95 with Ac2O and NaOH Nitrosation of 96 with NaNO2/AcOH/H2O, followed by Na2S2O4/NH3-mediated nitroso reduction provided 5,6-amino1,3-diethyluracil (97).110,111 Even though other groups have recently reported modified scale routes to istradefylline,106 the route described herein will focus on the sequence outlined by Kyowa Hakko Kogyo research laboratories during their initial development of istradefylline.109,112–114 EDC-mediated amine coupling involving 97 and 3,4-dimethoxycinnamic acid (98) led to the corresponding amide intermediate After aqueous workup, this crude amide intermediate underwent 1910 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 BnO BnBr, K2CO3 MIBK, 60 °C, 76% HO NO2 H (3 bar), PtO , 2-Me-THF, rt 2 OH OH O H N BnO HNO3, AcOH, 15 to 20 °C, 87% O O O 65 °C, 81% O Cl Cl 122 123 H N BnO 124 O (-)-DIP chloride, THF -30 °C nBu 4NBr3 O dioxane:MeOH (4:1) 20 °C, 74% Br O H N BnO O NaOH, H2O, to 20 °C O O 85%, 98.3% ee O 126 125 H N BnO 127, dioxane, 97 °C HCl, EtOH:dioxane (5:1) crystallization O H N 84-90%, 89.5-99.5% ee O H2 (3 bar), Pd/charcoal MeOH, 40 °C i-PrOH:MeOH crystallization 63-70% OH O HCl 128 H N HO O O H N OH O HCl XVI Olodaterol hydrochloride MeMgCl, toluene, 16-22 °C AcOH, MeCN, H2SO4, 50 °C; H 2O, NH4OH KOH, ethoxyethanol, ethylene glycol, 150 °C O H2N 34-42% for steps OMe O 129 127 Scheme 19 Synthesis of olodaterol hydrochloride (XVI) 132, Zn, TiCl4, 2-Me-THF 15 °C to 70 °C MeOH/H2O (4:1), crystallization ethylene carbonate NaI, toluene, ↑↓ O 94% O OH O OH 46%, 99.9% Z-isomer Cl 130 O 131 Cl O OH XVII Ospemifene 132 Scheme 20 Synthesis of ospemifene (XVII) cyclization with aqueous sodium hydroxide to yield the desired purine dione 99 in 47% yield over steps Methylation of 99 with MeI/K2CO3 provided istradefylline (XII) in 68% yield (Scheme 15).109 14 Levomilnacipran hydrochloride (FetzimaÒ) Levomilnacipran (FetzimaÒ) is a dual serotonin–norepinephrine reuptake inhibitor (SNRI) approved by the FDA in 2013 for the treatment of major depressive disorders (MDD).115–118 Levomilnacipran is the most active enantiomer of the racemate Milnacipran,119 which is currently used to treat pain associated with fibromyalgia.120,121 The drug was developed by Forest Laboratories and the Pierre Fabre group.116,122 Although initial enantiopure samples of levomilnacipran could be obtained by chromatographic separation of Milnacipran, this method was unable to provide sufficient quantities of material for pharmaceutical applications.123–125 Enantioselective routes have also been pursued,119,126–128 but most rely on the use of sodium azide, which suffers from toxicity and stability issues on 1911 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 H2N O O L-glutamine, DMF O O H2, Pd/C, MeOH N O 80 °C to 90 °C, 73% O NO2 H2N O O N O rt, 99% O HO NO 133 NH2 O HO 135 134 O N CDI, CH3CN O NH ↑↓, 88% O NH O XVIII Pomalidomide Scheme 21 Synthesis of pomalidomide (XVIII) O NHNH2 139 O N N O ONa H 2N N TFA, dioxane, ↑↓ F F F 137 N N N N TFA, dioxane, ↑↓ O 50% for steps O 136 138 140 F N NH 3(g), MeOH, rt F (CF3 CO)2 O, pyridine N N 100% N NaOMe/MeOH, rt N N THF, rt, 100% NH O O O NH4 Cl, AcOH, ↑↓, 76% CN 141 142 F F CN N N N N CN N N N N 144 N N N NaOMe, DMF, 110 °C, 73% HN F NH2 92% H2 N N O N N N N NH H 2N N N NaHMDS, THF, -6 °C to -4 °C MeI, °C O i-PrOH, 20 °C to 25 °C 95% HN NH2 NH F N O N 146 F O N 145 O N H 2, Pd/C, DMF, 62 °C N N H2 N 143 NH2 N O DMSO, 100 °C, recrystallization EtOAc, ↑↓ 64% O N N NH2 H2 N N O O XIX Riociguat 147 Scheme 22 Synthesis of riociguat (XIX) large scale.129 However, development of a scalable route to levomilnacipran has now been accomplished via optically active intermediate 102.119,126,128 This synthetic approach is described in Scheme 16.129 Reaction of phenylacetonitrile (100) and commercially available (R)-epichlorohydrin (101) with NaNH2 led to chloride displacement and intramolecular cyclopropanation, yielding lactone 102 after a one-pot nitrile hydrolysis and acid-promoted lactonization 1912 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 S OH O O OH , O S H2 N MsCl n-heptane/THF/toluene (4/1/1) 110 °C to120 °C N 148 OH Et 3N, CH2Cl2 °C to rt 149 S S HO O O O 151 O N N OMs O K2 CO3, toluene, ↑↓, 80% O O 150 152 S NaOH, MeOH, rt HCl, H 2O, 98% N O O OH O XX Saroglitazar Scheme 23 Synthesis of saroglitazar (XX) (75% yield over steps) Lactone ring-opening with Et2NH–AlCl3 complex provided amido-alcohol 103, which was converted to its phthalimido derivative 104 by sequential treatment with thionyl chloride and potassium phthalimide in 80% over three steps Finally, levomilnacipran hydrochloride (XIII) was obtained in >95% optical purity after phthalimide cleavage, HCl salt formation, and crystallization from HCl/i-PrOH/i-PrAc This sequence represents a highly efficient route to levomilnacipran, requiring no isolation of intermediates, resulting in >40% overall yield, and allowing use of the same solvent solution (toluene) for all steps 15 Lomitapide mesylate (JuxtapidÒ) Lomitapide is an orally active microsomal triglyceride transfer protein (MTP) inhibitor for the treatment of hypercholesterolemia.130 The drug was developed by Aegerion Pharmaceuticals Inc and licensed to Bristol–Myers Squibb Co and the University of Pennsylvania.130 Lomitapide effectively lowered LDL–cholesterol, both as a single agent and in combination with commonly prescribed lipid-lowering therapies.130 Sold under the trade name JuxtapidÒ, the drug offers a new treatment option to patients who cannot tolerate statin therapy or who experience insufficient LDL–cholesterol reduction with the currently available therapies, such as patients with homozygous familial hypercholesterolemia caused by mutations in the LDLR gene.130 The most likely scale synthetic route to lomitapide mesylate is described in Scheme 17.131 Commercial 9H-fluorene-9-carboxylic acid (105) was alkylated with 1,4-dibromobutane in the presence of n-butyl lithium in THF to give 9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid (106) in 85% yield Next, activation of the acid as the acid chloride followed by coupling with (2,2,2-trifluoroethylamine) provided amide 107 in 71% yield for the two-step sequence Displacement of the terminal bromide with the appropriate 4-carbamoyl piperidine followed by removal of the Boc group furnished piperidinyl fluorine 108 in high yield Amine 108 was then reacted with the acid chloride derived from acid 109 (derived from the Suzuki coupling of boronic acid 110 and o-iodobenzoic acid 111)132 to give lomitapide, and this was followed by salt formation with methanesulfonic acid to afford lomitapide mesylate (XIV).131 16 Macitentan (OpsumitÒ) Macitentan (OpsumitÒ) is an endothelin receptor antagonist marketed by Actelion,133 and was first approved in the U.S in October 2013 for the treatment of Pulmonary Arterial Hypertension (PAH).134,135 Soon after, the drug obtained approval in Canada, and is currently under regulatory review in other countries.136 Macitentan exhibits greater inhibitory action of ETA versus ETB receptor agonists,137–139 with higher potency than bosentan,138 allowing for once-daily dosing at significantly lower levels.140 The most likely scale worthy route of macitentan is described in Scheme 18.139,141 The preparation of the drug began with reaction of commercial 4-bromophenylacetate (112) with dimethylcarbonate (113) under basic conditions to yield the malonate ester 114.139,141 Treatment of this diester with sodium methoxide and formamidine hydrochloride 115 provided the desired intermediate 4,6dihydroxypyrimidine as a tautomeric mixture; from this system, dichloride 116 was generated in 60–80% yield upon treatment with warm phosphorus oxychloride in N,N-dimethylaniline Reaction of 116 with excess sulfonyl urea potassium salt 117139 provided chloropyrimidine 118 in high yield (83–93%) This was reacted with bromochloropyrimidine 119 in an SNAr reaction to provide macitentan (XV) in 88% yield.141 Synthesis of sulfamide potassium salt 117 was accomplished via sequential reaction of chlorosulfonyl isocyanate (120) with tBuOH and propylamine/Et3N to provide ester sulfamide 121, 1913 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 DPPA, Et 3N, toluene, CO2 H 100 °C; t-BuOH MeO MeO NHBoc NH2 CH3CN, AlCl3, CH2Cl2 , to 70 °C, 40% toluene, ↑↓, quant 153 O TFA, CH2 Cl2 , 20 °C, 88% MeO BCl3, xylenes, °C; O 154 155 N N O MeO N S 156 S Cl NH MeO t-BuOK, t-BuOH dioxane, rt, 90% N S 100 °C, 88% O OH 157 158 Scheme 24 Synthesis of fragment 158 of simeprevir (XXI) H2, Ra-Ni, H2O, Et3N, 20 bar CDMT, NMM, H2O acetone, 25 °C CO 2H O CO 2H HO O cinchonidine, 40 °C to rt 26% over steps, 97% ee N CO2H O N 159 160 N MeO N N-Me hexenylamine, EEDQ, THF, ↑↓ MeOH, MeSO3H, ↑↓ S LiOH, H2O, THF, 25 °C; 162, EEDQ, 50 °C O 158, PPh 3, DIAD, PhCH 3, °C 65% for steps N Boc2O, DMAP, THF, 20 °C 95% yield over steps OMe O O 161 N N MeO N MeO N S S M2 cat , 0.05M, toluene, ↑↓, 82% O Boc N N O O H2SO4, toluene, EtOH, ↑↓, 85% O H N O OEt N O 163 O OEt O 164 H 2N N MeO N CO2Et •0.5 H2SO4 S 162 NaOH, EtOH, H2O, ↑↓, 90% EDCI, CH2Cl2, 20 °C; cyclopropylsulfonamide DBU, CH2Cl2, 20 °C, 89% O H N O N O O O N H O S MesN NMes Ph Cl Ru Cl PCy3 XXI Simeprevir Scheme 25 Synthesis of simeprevir (XXI) M2 cat 1914 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 followed by Boc removal and treatment with potassium t-butoxide to yield 117 This material could be isolated by trituration with diethyl ether 17 Olodaterol hydrochloride (Striverdi RespimatÒ) Olodaterol hydrochloride was approved for long-term, oncedaily maintenance treatment of chronic obstructive pulmonary disease (COPD) in 2013 in the following countries: Canada, Russia, United Kingdom, Denmark, and Iceland.142,143 The drug has been recommended by a federal advisory panel for approval by the FDA.142,143 Developed and marketed by Boehringer Ingelheim, olodaterol is a long-acting b2-adrenergic receptor agonist with high selectivity over the b1- and b3-receptors (219- and 1622-fold, respectively).144 Upon binding to and activating the b2-adrenergic receptor in the airway, olodaterol stimulates adenyl cyclase to synthesize cAMP, leading to the relaxation of smooth muscle cells in the airway Administered by inhalation using the RespimatÒ Soft Mist inhaler, it delivers significant bronchodilator effects within five minutes of the first dose and provides sustained improvement in forced expiratory volume (FEV1) for over 24 h.143 While several routes have been reported in the patent and published literature,144–146 the manufacturing route for olodaterol hydrochloride disclosed in 2011 is summarized in Scheme 19 below.147 Commercial 20 ,50 -dihydroxyacetophenone (122) was treated with one equivalent of benzyl bromide and potassium carbonate in methylisobutylketone (MIBK) to give the 50 -monobenzylated product in 76% yield Subsequent nitration occurred at the 40 -position to provide nitrophenol 123 in 87% yield Reduction of the nitro group followed by subjection to chloroacetyl chloride resulted in the construction of benzoxazine 124 in 82% yield Next, monobromination through the use of tetrabutylammonium tribromide occurred at the acetophenone carbon to provide bromoketone 125, and this was followed by asymmetric reduction of the ketone employing (À)-DIP chloride to afford an intermediate bromohydrin, which underwent conversion to the corresponding epoxide 126 in situ upon treatment with aqueous NaOH This epoxide was efficiently formed in 85% yield and 98.3% enantiomeric excess Epoxide 126 underwent ring-opening upon subjection to amine 127 to provide amino-alcohol 128 in in 84–90% yield and 89.5–99.5% enantiomeric purity following salt formation with HCl Tertiary amine 127 was itself prepared in three steps by reaction of ketone 129 with methylmagnesium chloride, Ritter reaction of the tertiary alcohol with acetonitrile, and hydrolysis of the resultant acetamide with ethanolic potassium hydroxide Hydrogenative removal of the benzyl ether within 128 followed by recrystallization with methanolic isopropanol furnished olodaterol hydrochloride (XVI) in 63–70% yield Overall, the synthesis of olodaterol hydrochloride required 10 total steps (7 linear) from commercially available acetophenone 122 an estrogen-like effect on vaginal epithelium.149 Although several synthetic routes have been reported,150–154 no manufacturing route for ospemifene has been disclosed to date The shortest and largest scale route disclosed in the patent literature is summarized in Scheme 20.155 The drug can be synthesized succinctly in two steps First, alkylation of commercially available 4-hydroxybenzophenone (130) with ethylene carbonate and catalytic sodium iodide in refluxing toluene provided benzophenone 131 in 94% yield This was followed by a McMurry coupling involving benzophenone 131 with chloropropiophenone 132 in the presence of zinc powder and titanium tetrachloride in 2-methyltetrahydrofuran This reaction gave rise to a mixture of triphenylethylenes directly as a 5.5:1 ratio of Z to E isomers which could be separated by crystallization in aqueous methanol to give a mixture of olefins, 98% of which was comprised of the desired Z-isomer corresponding to ospemifene (XVII) The product purity was further improved by recrystallization to give 99.9% of the Z-isomer in 46% yield from 131 Thus, ospemifene was synthesized in two steps and 43% overall yield 19 Pomalidomide (PomalystÒ) Pomalidomide, an anti-angiogenic derivative of thalidomide marketed by Celgene as PomalystÒ, was originally discovered in the early 1990s by D’Amato and co-workers at Boston Children’s Hospital.156 The drug was approved in February 2013 by the U.S Food and Drug Administration (FDA) for the treatment of relapsed and refractory multiple myeloma, and received similar approval from the European Commission in August 2013 (the drug will be marketed in Europe under the name ImnovidÒ).157 Interestingly, the structural optimization of thalidomide and the related therapeutic agent lenalidomide led to the discovery of pomalidomide (XVIII), which is 10-fold more potent than lenalidomide as a TNF-a inhibitor and IL-2 stimulator, and has been shown to be effective in overcoming resistance to lenalidomide and thalidomide as well as the proteosome inhibitor bortezomib.158 A scalable preparation of pomalidomide (which has been developed as a racemate due to rapid interconversion of the R- and S- enantiomers in vivo)159,160 involves the sequence described in Scheme 21.161 First, condensation of commercially available 3-nitrophthalic anhydride (133) and L-glutamine in warm DMF gave nitrophthalimide 134.161 Although the authors from Celgene not explicitly describe the racemization of the stereocenter derived from L-glutamine, scrambling of the stereocenter has been reported during this step under neutral conditions at elevated temperatures.161 Next, hydrogenative reduction of the nitro group furnished the anilinophthalimide 135, and this was followed by treatment with CDI in refluxing acetonitrile to secure the piperidone dione and ultimately furnish pomalidomide (XVIII) as the racemate in 87% overall yield from 134 20 Riociguat (AdempasÒ) Ò 18 Ospemifene (Osphena ) Ospemifene was approved by the U.S FDA in February 2013 for treatment of moderate to severe dyspareunia (painful intercourse), a symptom of menopause-related vulvovaginal atrophy (VVA); it is the first non-hormonal treatment approved for this indication.148 Ospemifene was developed by QuatRx Pharmaceuticals, which acquired the drug as part of a merger with Hormos Medical in 2005, and was licensed to Shionogi for regulatory filing and worldwide commercialization.148 It is a selective estrogen receptor modulator (SERM), and although it possesses a similar structure to tamoxifen and toremifene, ospemifene displays a unique set of tissue-specific estrogenic agonist/antagonist effects which includes Riociguat is a potent, oral stimulator of soluble guanylate cyclase (sGC).162 Riociguat can sensitize sGC to endogenous nitric oxide (NO) by stabilizing NO–sGC binding, and also directly stimulate sGC in a NO-independent manner to increase generation of cGMP to affect subsequent vasodilation.162,163 Discovered by Bayer Healthcare, riociguat obtained approval in Canada for the treatment of adults with persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH), and was later approved by the U.S FDA in 2013 for the treatments of both CTEPH and Pulmonary Arterial Hypertension (PAH).164 Several strategies for the assembly of the drug have been reported,165–171 and the process route is described below in Scheme 22.171 1915 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 Me Me O Me O Me ethylene glycol NaHCO3, acetone, -15 °C Me O Me Ph 3PC(Me)CO2Et O Me 56% NaMnO4 (aq), -10 °C 60% for steps CH2Cl2, -40 °C O O CO2Et Me CO2Et O HO 166 165 Me i-PrOAc, CH3CN, Et3N SOCl2, °C to 10 °C 167 O NaOCl, < 25 °C Et3N, Et3N•HF3, 85 °C - BzCl, DMAP Et3N, CH3CN O HO Me O CO2Et Me F O HO Me 170 NHBz N H Cl BzO Me BzO 172 O O O BzO LHMDS, (NH4)2SO4, PhCl, 135 °C SnCl2, 70 °C F Me F 169 N ii DCM, TBAB SO2Cl2, 40 °C O BzO 71% for steps O BzO O BzO < 40 °C F O3SO HNEt3+ 168 i Red-Al®, CF3CH2OH toluene, -15 °C OH N F Me 171 N NHBz 173 57% for steps O HO O AcOH, 110 °C NH3, MeOH, °C to 15 °C 78% for steps N F Me O 175, t-BuMgCl, THF O HO Me O HN P O PhO -5 °C to °C, 68% NH O O HO O F Me N NH O 174 XXII Sofosbuvir O O P(O)Cl2OPh, Et3N, CH2Cl2, -70 °C Me O O F5-PhOH, °C NH2 Me F O HN P O PhO 34% for steps 176 F F F F 175 Scheme 26 Synthesis of sofosbuvir (XXII) N O N N N NaOMe, MeOH, 40 °C + CN 177 O N H NH 2 HCl (aq), EtOH, ↑↓ N H N 89% 178 179 NaCN, Me NCOCl, DMF, 40 °C H3 PO4 (aq), n-BuOH, 80 °C NaHCO3 (aq), rt N O N N N N N H N 66% XXIII Topiroxostat Scheme 27 Synthesis of topiroxostat (XXIII) The sequence began with condensation of commercial 2-fluorobenzylhydrazine (136) with sodium ethyl cyanopyruvate (137), which derives from diethyl oxalate to generate aminopyrazole 138 This was followed by the cyclocondensation with 3-dimethylaminoacrolein (139) to access pyrazolopyridine 140 in 50% yield for the two-step operation Next, ester 140 was transformed to the corresponding primary amide 141, which was subsequently dehydrated upon treatment with trifluoroacetic acid anhydride (TFAA) to construct nitrile 142 in quantitative yield from 140 Subjection of cyanopyrazole 142 to Pinner conditions using methoxide and ammonium chloride in refluxing acetic acid generated amidine 143, and this was followed by condensation with the malononitrile derivative 144 in base to provide pyrimidine 145 in 73% yield Hydrogenative cleavage of the phenyldiazine converted 1916 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 F F NH2 NH O NH CDI, Et3N, DMF, °C NH2, °C to rt I O HO O F CN N NH I 96% 182 181 O N NaOH, H2O, 80 °C O F N 88% 92% I 183 F O EtOH, rt N O O O HO 186 F OH O N N O N OH N I O 58% for steps 187 185 F O CH3CN, °C to rt, 91% N O O N TsCl, Et3N, Me 3N HCl 189 H2N OTs F N H 93% O O N I H N N H N O O 188 190 O F N H N MeONa/MeOH, THF, rt, 89% DMSO, 80 °C, 92% O N 2,6-lutidine, DMA, 130 °C N I O N Ac2O, 100 °C NH I N 184 N NaBH4, t-BuOH O N DMF•DMA, rt NH2 I CN MsCl, DMF, rt, 96% I 180 F O O N H N N I O O DMSO XXIV Trametinib DMSO Scheme 28 Synthesis of trametinib dimethyl sulfoxide (XXIV) quench with methyl iodide Sequential recrystallization from warm DMSO and refluxing ethyl acetate produced riociguat (XIX) in 64% yield from 147 O HO N HO2 CCH2 CH2 SH CH3 SSO2 CH3 EtOH, H 2O, rt, 90% HO2 CCH2CH 2SSMe 191 192 HO O O N 21 Saroglitazar (Lipaglyn Ò) O EDCI, CH2 Cl2, rt O O SSMe O 193 N H 194 O HO2 C N SSMe DME, H2 O, Et3 N 60% for steps 195 Scheme 29 Synthesis of fragment 195 of trastuzumab emtansine (XXV) 145 to the pyrimidyl triamine 146, which underwent carbamoylation at the 40 position to produce the penultimate carbamate 147 This carbamate was then selectively methylated through deprotonation of the carbamate N–H proton followed by Saroglitazar is an orally active PPAR-a and -c dual agonist in a class of drugs referred to as glitazars Saroglitazar was the first glitazar to be approved by the Drug Controller General of India, and was approved for the treatment of type II diabetes.172,173 The drug was developed by Zydua Cadila, an India-based pharmaceutical firm Saroglitazar has been found to regulate lipid levels and exhibits improved glycemic HbA1c control in comparison to pioglitazone.172,173 In addition, saroglitazar has been found to display no adverse effects associated with cardiac safety.172,173 A scalable synthesis of this drug is described in Scheme 23.174 The sequence began with a Paal–Knorr pyrrole synthesis starting from commercial 1-[4-(methylthio)phenyl]pentane-1,4-dione (148) Subjection of this diketone to ethanolamine in warm pivalic acid furnished pyrrole 149, which was taken forward as the crude product Next, the alcohol was mesylated to afford 150, which was H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 used without further purification Williamson ether conditions were employed to convert mesylate 150 to the corresponding aryl ether 152 through the use of commercial phenol 151 and anhydrous potassium carbonate This reaction proceeded in 80% yield Saponification of the terminal ethyl ester using sodium hydroxide followed by acidic pH adjustment ultimately delivered the carboxylic acid drug saroglitazar (XX) in 98% yield from 152 22 Simeprevir (OlysioÒ; SovriadÒ) Simeprevir is a hepatitis C viral (HCV) NS3/4A protease inhibitor approved in Japan, Canada and the U.S for the treatment of chronic HCV infection in combination with ribavirin and pegylated interferon-a.175,176 Simeprevir was discovered and developed at Medivir,177,178 which was later acquired by Janssen and co-developed by Tibotec, a subsidiary of Johnson & Johnson and Pharmasset (now Gilead) Simeprevir contains a 14-membered ring macrocycle and its process-scale synthesis was nicely described in a recent full paper on its discovery and development,179 with individual process improvements reported throughout the patent literature.180–184 The synthesis of the quinolinol fragment 158 is described in Scheme 24.177,179 Commercial 2-methyl-3-methoxybenzoic acid (153) was treated with diphenylphosphorylazide (DPPA) and triethylamine to affect a Curtius rearrangement and the resulting isocyanate was trapped with t-butanol to produce the Boc-protected aniline 154 in quantitative yield Upon removal of the Boc protecting group with TFA, the resulting aniline was reacted with boron trichloride followed by the addition of acetonitrile and aluminum trichloride to affect Friedel–Crafts acylation to give aminoacetophenone 155 in 40% yield Acylation of the amino group with 4-isopropylthiazole-2-carbonyl chloride (156) gave ketoamide 157 in 90% yield, which was treated with potassium tert-butoxide in t-butanol at 100 °C to furnish quinolinol 158 in 88% yield Use of a ring closing metathesis approach, enabling the synthesis of the macrocyclic portion of the drug and ultimately simeprevir, is described in Scheme 25.179–184 Hydrogenation of commercial trans-cyclopentanone-3,4-dicarboxylic acid (159) over Raney Ni in the presence of triethylamine followed by cyclization to the lactone using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM), and subsequent cinchonidine salt formation gave lactone acid 160 in 26% yield over the steps in 97% ee Next, amide coupling with N-methylhexenylamine using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), Fischer esterification, and subsequent introduction of the quinolinol fragment 158 under Mitsunobu conditions using triphenylphosphine (PPh3) and diisopropyl azodicarboxylate (DIAD) provided methyl ester 161 in 65% overall yield for the three steps Saponification of the ester with lithium hydroxide followed by EEDQ-promoted coupling to (1R,2S)-1-amino-2-vinyl-cyclopropane ethyl ester (162)185 and Boc protection of the resulting amide gave the RCM substrate, diene 163 in 95% yield for the two steps Macrocyclization of 163 using the second generation M2 catalyst186,187 under dilute concentration in refluxing toluene followed by acidic removal of the amide protecting group gave cycloalkene ester 164 in high yield Saponification of the ester, activation of the resulting acid with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and coupling with cyclopropylsulfonamide led to simeprevir (XXI) in high overall yield 23 Sofosbuvir (SovaldiÒ) Sofosbuvir is a NS5B polymerase inhibitor approved for the treatment of the hepatitis C virus (HCV) across several genotypes, 1917 demonstrating the ability to prevent virus replication within the body.188 Sofosbuvir was discovered at Pharmasset and developed by Gilead Sciences, and was approved by the FDA in 2013 Although the preparation of this unique nucleotide monotherapy presents a variety of synthetic challenges,189–201 the penultimate target has been demonstrated on kilogram-scale according to reports in the published literature.202,203 Interestingly, the final step has only been disclosed on a gram-scale, and this overall sequence is described in Scheme 26.204 The enantiopure unsaturated ester 166, which readily arises from olefination of the commercially-available aldehyde 165, was subjected to ethylene glycol-promoted permanganate dihydroxylation conditions to afford diol 167 in 60% yield over the two steps.205 A three-step sequence was then employed to generate lactone 169 Diol 167 was converted to the cyclic sulfite and then oxidized with bleach to give the corresponding cyclic sulfate Treatment with nucleophilic fluorine gave intermediate ammonium sulfonate 168, which, upon acidic hydrolysis of both the acetonide and sulfonate, underwent cyclization to give lactone 169 Next, bis-protection of diol 169 furnished 170 in 71% yield for the four-step sequence Reduction and chlorination through the use of Red-AlÒ and sulfuryl chloride, respectively, constructed chlorotetrahydrofuran 171, which was subsequently reacted with commercial N-(2-oxo-1,2-dihydropyrimidin-4-yl)benzamide 172 in the presence of base and Lewis acid to afford 173 in 57% yield over the two steps Treatment of 173 with AcOH and then ammonia in MeOH removed all benzoyl protection to give rise to diol 174 in 78% yield Finally, treatment of 174 with pentafluorophenolic phosphonate ester 175 and tert-butylmagnesium chloride generated sofosbuvir (XXII) in 68% yield The final step proceeds with excellent chirality transfer from 175 (99.7% ee) Notably, the preparation of the key phosphonate fragment was achieved in a simple two-step sequence beginning with alanine isopropyl ester 176 Phosphorylation in the presence of base at cryogenic temperatures, followed by treatment with pentafluorophenol, delivered scale quantities of 176 in 34% isolated yield and high enantiopurity (>98% ee) after recrystallization 24 Topiroxostat (UriadecÒ; TopiloricÒ) Topiroxostat is an orally-administered, non-purine, selective xanthine oxidase (XO) inhibitor developed for the treatment of hyperuricemia specifically for patients with gout in Japan.206 The drug was discovered and developed by Fuji Yakuhin.207 In contrast to conventional XO inhibitors such as febuxostat, topiroxostat interacts with key amino acid residues of the solvent channel.207 Of the few disclosed preparative approaches to the drug, the most likely scale assembly of topiroxostat is represented in Scheme 27.208,209 The synthesis commenced with the reaction of two commercially available components, nitrile oxide 177 and isonicotinohydrazide (178) Condensation of these two subunits in the presence of sodium methoxide followed by acidic quench gave rise to 1,2,4-triazole 179 in 89% yield Next, utilization of the N-oxide for installation of the nitrile functionality was required to furnish the drug, but it is interesting to note that this step has been the subject of study by Yamamoto and co-workers at Tohoku University in Japan.208 Although the process preparation describes the formation of the drug using sodium cyanide and dimethylcarbamoyl chloride followed by isolation through a salt formation/ freebasing process to deliver topiroxostat (XXIII) in 66% yield,209 Yamamoto has described this same sequence using zinc cyanide and tosylate salt formation (freebasing of the drug was not attempted).208 1918 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 O O O O O O Cl OH O Cl H N LiAlH(OMe)3 H O O 195, DCC, 1M ZnCl2 H O THF, -40 °C, 85% O N H O OH H N O N H O OH 196 Et2O, CH2Cl2, rt, 32% 197 O O O O O Cl O O O SSMe N O dithiothreitol, EtOAc MeOH, 0.05 M potassium H O N H O OH O Cl H N O SH N O H N H O phosphate buffer, pH 7.5 EDTA, rt, 76% O 198 N H O OH O 199 Scheme 30 Synthesis of fragment 199 of trastuzumab emtansine (XXV) 25 Trametinib dimethyl sulfoxide (MekinistÒ) Trametinib, approved by the U.S FDA in May 2013 under the brand name MekinistÒ, is a drug discovered by Japan Tobacco and developed by GlaxoSmithKline for the treatment of metastatic BRAF-mutant melanoma.210 Trametinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK), kinase MEK1 and MEK2, which are downstream from BRAF in the MAPK pathway, resulting in an inhibition of growth factor-mediated cell signaling and cellular proliferation in various cancers.211 In January 2014, the U.S FDA also granted an accelerated approval for the combination of trametinib and darafenib for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma.210 Two synthetic strategies have been reported for trametinib;212,213 and the scalable route is shown in Scheme 28.213 Commercial 2-fluoro-4-iodoaniline (180) was sequentially subjected to CDI and cyclopropylamine to generate urea 181 in 96% yield This was followed by coupling with cyanoacetic acid in the presence of mesyl chloride and DMF to furnish imide 182 in 96% yield Under basic conditions, imide 182 underwent an intramolecular cyclization reaction to produce pyrimidine-2,4dione 183 in 88% yield Next, condensation with DMF–DMA generated formamidine 184 in 92% yield, and this was followed by NaBH4-mediated reduction and subsequent annulation with 2methyl-malonic acid (186) to arrive at trione 187 in 58% from 184 Trione 187 was then treated with p-toluenesulfonyl chloride in Et3N, and the resulting tosylate was exposed to 30 -aminoacetanilide (189) in the presence of 2,6-lutidine and DMA, inducing an addition-elimination reaction to give pyrido[2,3-d]pyrimidine 190 in 93% yield The rearrangement of pyrido[2,3-d]pyrimidine 190 with sodium methoxide in THF/MeOH gave pyrido[4,3d]pyrimidine (trametinib) in 89% yield This was then complexed with a single equivalent of DMSO to produce trametinib DMSO (XXIV) in 92% yield 26 Trastuzumab emtansine (KadcylaÒ) Trastuzumab emtansine is an antibody drug conjugate that is comprised of an anti-human epidermal growth factor receptor (HER2) antibody, trastuzumab, and the potent tubulin based inhibitor, maytansine DM1.214,215 These two entities are connected together via a linker that attaches the cytotoxin through surface exposed lysine side chains on the antibody The linker is stable and does not contain a cleavage element that has been present in other ADCs such as AcetrisÒ or MylotargÒ Instead, after the ADC is internalized it is catabolized within the tumor cell and releases the maytansine-based linker payload with the lysine from the antibody still attached; this molecule is ultimately responsible for destruction of the tumor cell Trastuzumab emtansine was discovered and developed through a collaboration between Immunogen214,216 and Genentech, and it has been approved for the treatment of patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and a taxane The synthesis of trastuzumab emtansine has only been described on small scale, so it is unclear if these methods have translated to a production scale The synthesis of the N-acyl-N-methyl-L-alanine precursor that will be connected to maytansinol is described in Scheme 29.216,217 First, commercial 3-mercaptopropionic acid (191) was treated with methanethiolsufonate to give the corresponding methyldithio analog 192 in 90% yield Activation of the acid with N-hydroxysuccinimide in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) provided the activated ester 193, which was reacted with N-methyl-L-alanine (194) to give acid 195 in 60% yield from compound 192 Preparation of the DM1 linker-payload is described in Scheme 30 The starting material used for the production of DM1 is ansamitocin P-3 (196), which is produced via fermentation of the microorganism Actinosynnema pretiosum The ester group of 196 was removed using a reductive process in the presence of lithium trimethoxyaluminum hydride to give maytansinol 197 in 85% yield.216,218 The use of reductive conditions was required to avoid subsequent elimination to the a,b-unsaturated amide Esterification with 195 in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and zinc chloride provided DM1–SMe 198 in 32% yield.216,217 Reductive removal of the dithiane using dithiothreitol (DTT) in aqueous buffer at pH 7.5 gave DM1 thiol 199 in 76% yield, which was utilized in the conjugation to trastuzumab (200) Completion of the synthesis of trastuzumab emtansine is described in Scheme 31 The surface accessible lysine residues of 1919 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 O N O O 201 O N O N O O H N O 0.1 M Potassium phosphate buffer, pH 7.0, EDTA, 88% O ~4 202 200 199 , 0.1 M Potassium phosphate buffer, pH 7.0 EDTA, DMA O N O O O Cl O N H N O S O O O 3.5 H N H O N H O OH O XXV Trastuzumab emtansine Scheme 31 Synthesis of trastuzumab emtansine (XXV) trastuzumab (200) were treated with succinimidyl-4-(N-maleimidomethyl)-cyclohexane-carboxylate (SMCC, 201) in pH 7.0 buffer to give amide 202 with approximately four SMCC molecules added per antibody in 88% yield.216,219,220 Next, the free thiol group of DM1 (199) was conjugated to the maleimide groups present on 202 to give trastuzumab emtansine (XXV) with an average 3.5 drug molecules loaded per antibody I SH Br Br NaOt-Bu, Pd(dba) + 213 S rac-BINAP, toluene, ↑↓ 215 214 H N 27 Vortioxetine (BrintellixÒ) Vortioxetine is an antidepressant developed by Lundbeck and Takeda and approved in 2013 by the FDA for the treatment of major depressive disorder (MDD) in adult patients This multimodal acting drug, which is marketed in North America under the trade name BrintellixÒ, exhibits a high affinity for a range of serotonergic targets.221 The anti-depressant effects of vortioxetine are thought to be mediated through three serotonergic targets: inhibition of the 5-HT re-uptake which leads to an increase in extracellular 5-HT levels in the brain (in analogy to previous antidepressants), agonism of 5-HT1AR (which is believed to shorten the time to onset of clinical effects), and antagonism of 5-HT3R.222 Preclinical studies have shown that antagonism of 5-HT3R could have positive effects on mood and cognitive dysfunction in patients with depression.223 Although several approaches to the synthesis of vortioxetine have been reported,224–229 BangAndersen and co-workers at Lundbeck describe three approaches to producing vortioxetine on scale.221 The most practical approach according to the authors, which has been executed on multigram scale, is depicted in Scheme 32.224 The sequence involves iterative palladium-catalyzed carbon– heteroatom bond formations, the first establishing the thioethereal bond between commercially available thiol (213) and o-iodobromobenzene (214) employing conditions described by Schopfer and Schlapbach.230 Next, Buchwald–Hartwig conditions were employed to establish the piperazine linkage,231,232 and this was followed by subjection to warm hydrobromic acid to furnish NaOt-Bu, piperazine Pd(dba) 2, rac-BINAP toluene, ↑↓ N S HBr 48 wt % HBr, 70 °C 75% for steps XXVI Vortioxetine hydrobromide Scheme 32 Synthesis of vortioxetine hydrobromide (XXVI) vortioxetine hydrobromide (XXVI) in 75% yield across the entire three-step sequence.224 28 Conclusion In summary, the examples cited in this brief account illustrate the ever-increasing power and potential of synthetic innovation as a major driver in providing access to the 26 drugs approved in late 2012 and 2013 The structures and synthetic routes described herein may be extended to the preparation of additional collections of unique compounds aimed at providing novel therapies or treatments, or as improvements upon current ones The presumed scalable synthesis discussed within not only serves to provide the larger community with a means to access these chemical architectures, but to raise the awareness of modern process-scale synthetic capability Furthermore, the work presented herein and in subsequent editions of this review will serve as a catalyst for future inspiration in the synthesis of medicinally-relevant tool 1920 H X Ding et al / Bioorg Med Chem 23 (2015) 1895–1922 compounds, natural 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trastuzumab, and the potent tubulin based inhibitor, maytansine DM1.214,215 These two entities are connected together via a linker that attaches the cytotoxin