Synthetic Approaches To The New Drugs 2014

Bioorganic & Medicinal Chemistry 24 (2016) 1937–1980 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc Review article Synthetic approaches to the 2014 new drugs Andrew C Flick a,y, Hong X Ding b,à, Carolyn A Leverett a,§, Robert E Kyne Jr c,–, Kevin K.-C Liu d,k, Sarah J Fink e,yy, Christopher J O’Donnell a,⇑ a Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, CT 06340, United States Pharmacodia (Beijing) Co., Ltd, Beijing 100085, China c Celgene Avilomics Research, 200 Cambridge Park Drive, Cambridge, MA 02140, United States d China Novartis Institutes for BioMedical Research Co., Ltd, Shanghai 200131, China e BioDuro Co., Ltd, Shanghai 200131, China b a r t i c l e i n f o Article history: Received 14 January 2016 Revised 29 February 2016 Accepted March 2016 Available online March 2016 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 thirty-seven NCEs that were approved for the first time in 2014 and one drug which was approved in 2013 and was not covered in a previous edition of this review Ó 2016 Elsevier Ltd All rights reserved Abbreviations: ABCB1, ATP-binding cassette sub-family B member 1; ABCG2, ATP-binding cassette sub-family G member 2; Ac, Acetyl; ALK, anaplastic lymphoma kinase; BMS, Bristol–Myers Squibb; Bn, benzyl; Boc, N-tert-butoxycarbonyl; CbzCl, benzyl chloroformate; CDI, N,N0 -carbonyldiimidazole; CFDA, Chinese Food and Drug Administration; CNS, central nervous system; COD, 1,5-cyclooctadiene; Cy, cyclohexyl; Dba, dibenzylideneacetone; DBU, 1,8-diazabicycolo[5.4.0]undec-7-ene; DCC, 1,3dicyclohexylcarbodiimide; DCHA, dicyclohexylamine; DCE, 1,2-dichloroethane; DCM, dichloromethane; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 3,4-DHP, 3,4dihydropyran; (DHQ)2PHAL, hydroquinine 1,4-phthalazinediyl diether; DIAD, diisopropyl azodicarboxylate; DIBAL, diisobutylaluminium hydride; DIPEA, N,N-diisopropylethylamine; DMA, dimethylacetamide; DMAC, dimethylacetamide; DMAP, 4-dimethylaminopyridine; DMD, Duchenne’s muscular dystrophy; DME, dimethoxyethane; DMF, N,N-dimethylformamide; DMM, maleic acid dimethyl ester; DMPU, 1,3-dimethyl tetrahydropyrimidin-2(1H)-one; DMSO, dimethyl sulfoxide; DPPA, diphenylphosphoryl azide; EDAC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDC, N-(3-dimethylaminopropyl)-N0 -ethylcarbodiimide; ee, enantiomeric excess; EMA, European Medicine Agency; Et, ethyl; EU, European Union; EtOAc, ethyl acetate; GD1, Gaucher disease 1; GT1, genotype 1; HATU, o-(7-azabenzotriazol-1-yl)-N,N,N0 ,N0 -tetramethyluronium hexafluorophosphate; HBTU, N,N,N0 ,N0 -tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate; HCV, hepatitis C virus; HDAC, histone deacetylase; HOAc, acetic acid; HOBt, 1-hydroxybenzotriazole hydrate; HONB, N-hydroxy-5-norbornene-2,3-dicarboximide; HPLC, High performance liquid chromatography; i-PAc, isopropyl acetate; IPF, idiophathic pulmonary fibrosis; i-Pr, isopropyl; LiHMDS, lithium hexamethyldisilazide; LDA, lithium diisopropylamide; mCPBA, 3-chloroperoxybenzoic acid; Me, methyl; MeCN, acetonitrile; MEK, methyl ethyl ketone; MEMCl, 2-methoxyethoxymethyl chloride; 2-MeTHF, 2-methyltetrahydrofuran; MIBK, methyl isobutyl ketone; Moc, methoxycarbonyl; MsCl, methanesulfonyl chloride; MsOH, methanesulfonic acid; MSRA, methicillin-resistant Staphylococcus aureus; MTBE, methyl tert-butyl ether; MVK, methyl vinyl ketone; MW, microwave; N-Ac-Leu, N-acetyl leucine; n-BuLi, n-butyllithium; NBS, N-bromosuccinimide; NFSI, N-fluorobenzenesulfonimide; NHS, Nhydroxysuccinimide; NK1, Neurokinin-1; NMP, N-methyl-2-pyrrolidone; NMM, N-methyl morpholine; NMMO, 4-methylmorpholine N-oxide; NS5A/B, nonstructural 5A/B; NsCl, 2-nitrobenezenesulfonyl chloride; NSCLC, non-small cell lung cancer; (o-tol)3P, tris(2-methylphenyl)phosphine; Pd2(dba)3, tris(dibenzylideneacetone)dipalladium; Pd (dppf)2Cl2ÁCH2Cl2, [1,10 -bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; PDE-4, phosphodiesterase IV; Pd(OAc)2, palladium acetate; Ph, phenyl; PhMe, toluene; PI3K, phosphatidylinositol 3-kinase; PMDA, Pharmaceuticals and Medical Devices Agency; PPAR, peroxisome proliferator-activated receptor; PPTS, pyridinium p-toluenesulfonate; PSA, psoriatic arthritis; PTCL, peripheral T-cell lymphoma; p-TsOH, p-toluenesulfonic acid; PTSA, p-toluenesulfonamide; Py, pyridine; Red-Al, sodium bis(2-methoxyethoxy)aluminum dihydride; [Rh(COD)2]OTf, bis (1,5-cyclooctadiene)rhodium(I)trifluoromethanesulfonate; rt, room temperature; SGLT2, sodium-glucose co-transporter 2; TB, tuberculosis; TBAF, tetrabutylammonium fluoride; TBAHS, tetrabutylammonium hydrogen sulfide; TBME, tert-butylmethyl ether; t-Bu, tert-butyl; TEA, triethylamine; TEPA, triethylphosphonoacetate; TIPS, triisopropylsilyl; TFA, trifluoroacetic acid; TFE, trifluoroethanol; TfOH, trifluoromethanesulfonic acid; THF, tetrahydrofuran; TMDS, 1,1,3,3-tetramethyldisiloxane; TMS, trimethylsilyl; TNF, tumor necrosis factors; THP, tetrahydropyranyl; THF, tetrahydrofuran; TMSCl, trimethylsilyl chloride; TNF-a, tumor necrosis factor alpha; T3P, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; TPAP, tetrapropylammonium perruthenate; Ts, 4-toluenesulfonyl; USA, United States of America; US FDA, United States Food and Drug Administration; VEGFR2, vascular endothelial growth factor 2; Xantphos, 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene; XPhos, 2-dicyclohexylphosphino-20 ,40 ,60 -triisopropylbiphenyl ⇑ Corresponding author Tel.: +1 860 715 4118 E-mail addresses: andrew.flick@pfizer.com (A.C Flick), Sheryl.ding@pharmacodia.com (H.X Ding), carolyn.a.leverett@pfizer.com (C.A Leverett), rkyne@celgene.com (R.E Kyne), kevin.liu@novartis.com (K.K.-C Liu), sarah.fink@bioduro.com (S.J Fink), christopher.j.odonnell@pfizer.com (C.J O’Donnell) y Tel.: +1 860 715 0228 Tel.: +86 10 8282 6195 § Tel.: +1 860 441 3936 – Tel.: +1 781 541 3749 k Tel.: +86 185 0172 5207 yy Tel.: +86 21 3175 2858 http://dx.doi.org/10.1016/j.bmc.2016.03.004 0968-0896/Ó 2016 Elsevier Ltd All rights reserved 1938 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 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 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 Introduction Alectinib hydrochloride (AlecensaÒ) Apatinib mesylate Apremilast (OtezlaÒ) Asunaprevir (SunvepraÒ) Ataluren (TranslarnaÒ) Belinostat (BeleodaqÒ) Ceritinib (ZykadiaÒ) Chidamide (EpidazaÒ) Daclatasvir dihydrochloride (DaklinzaÒ) Dasabuvir sodium (ExvieraÒ) Delamanid (DeltybaÒ) Eliglustat tartrate (CerdelgaÒ) Empagliflozin (JardianceÒ) Finafloxacin (XtoroÒ) Idelalisib (ZydeligÒ) Ipragliflozin L-proline (SuglatÒ) Ledipasvir (HarvoniÒ) Lobeglitazone sulfate (DuvieÒ) Luseogliflozin hydrate (LusefiÒ) Morinidazole (迈灵达Ò) Naloxegol oxalate (MovantikTM, MoventigÒ) Netupitant (AkynzeoÒ) Nintedanib esylate (OfevÒ) Olaparib (LynparzaÒ) Ombitasvir (Viekira PakTM) (TechnivieÒ) Oritavancin diphosphate (OrbactivÒ) Paritaprevir (TechnivieÒ) Phenothrin (SumithrinÒ) Ripasudil hydrochloride hydrate (GlanatecÒ) Suvorexant (BelsomraÒ) Tasimelteon (HetliozÒ) Tavaborole (KerydinÒ) Tedizolid phosphate (SivextroÒ) Tofogliflozin hydrate (DeberzaÒ) Umeclidinium bromide (ElliptaÒ) Vonoprazan fumarate (TakecabÒ) Vorapaxar sulfate (ZontivityÒ) Vaniprevir (VanihepÒ) 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 thirteen years ago2–13 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 1938 1939 1940 1941 1942 1947 1947 1948 1949 1949 1950 1951 1952 1956 1956 1956 1956 1957 1957 1957 1958 1958 1958 1960 1960 1962 1963 1963 1965 1965 1966 1967 1969 1971 1972 1972 1974 1976 1976 1976 ability to design new drugs more efficiently The pharmaceutical industry enjoyed a banner year for productivity during 2014, having new chemical entities, biological drugs, and diagnostic agents totaling 55 new products which were introduced to the worldwide market for the first time.14 Anti-infectives were particularly active in terms of drugs introduced within a therapeutic area—11 new drugs and biologics of this class reached the market—and this was followed by oncology medications and hematologic therapies brought to the market in 2014 An additional 16 new products were in the process of approval from various governing bodies during 2014, but were not launched before the end of the year.14 1939 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 O O CN CN N H N N N H NH N O HCl I Alectinib Hydrochloride II Apatinib Mesylate O O O N Cl O O O S O O N NH HN O H O S O N O NH CH3 SO3 H N O O NH O III Apremilast IV Asunaprevir O F O N O N H N OH O NH O S O N H N H N H OH O O N N O VI Belinostat V Ataluren Cl H N S H N N O O · HCl VII Ceritinib Hydrochloride NH2 F VIII Chidamide Figure Structures of 38 NCEs approved in 2014 In this review, we focus on the syntheses of thirty-eight NCEs that were approved for the first time in 2014 around the world, including five novel compounds which were approved as active ingredients of fixed-dose combinations (Fig 1) 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 Alectinib hydrochloride (AlecensaÒ) Alectinib hydrochloride, developed by Chugai Pharmaceutical/ Hoffman-La Roche under the trade name AlecensaÒ, was approved in Japan in April 2014 for the treatment of anaplastic lymphoma kinase (ALK) fusion-gene positive, unresectable, advanced, or recurrent non-small cell lung cancer (NSCLC).15 The compound is a highly selective second-generation ALK inhibitor,16,17 and while alectinib currently remains a focus of further development in Europe and the U.S., the compound has been granted orphan drug designation in Japan after showing a 93.5% objective response rate in phase II clinical trials.15,18,19 In addition to providing rapid treatment response time in a majority of patients, trials showed a 76% 2-year progression-free survival rate.19,20 Since the initial approval of crizotinib—the first ALK inhibitor indicated for treatment of ALKrearranged NSCLC —patients treated with crizotinib have shown remarkable improvement as compared to treatment with other chemotherapeutic methods,21 although drug resistance has shown to be a major side effect of this therapy.22 Preliminary preclinical and clinical studies of alectinib have shown significant promise for overcoming drug resistance developed with other ALK inhibitors.16,23,24 The synthetic route to alectinib as reported by Chugai25–29 begins with 7-methoxy-2-tetralone (1, Scheme 1) Bis-methylation with tetrabutylammonium hydrogen sulfide (TBAHS)/aq KOH/MeI followed by bromination with N-bromosuccinimide (NBS) provided the bromo-tetralone in 67% yield over the two steps Further reaction of with 3-hydrazinobenzonitrile/trifluoroacetic 1940 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 O O H N N N H N NH H O O H H N HN N H O HCl O IX Daclatasvir Dihydrochloride O NN Na+ O O H2 O N F F O N S N H O XI Delamanid X Dasabuvir Sodium Hydrate N O O O 2N O O F N OH Cl O O O HO NH O O HO HO OH O OH OH OH 1/2 XIII Empagliflozin XII Eliglustat Tartrate F O H O N O F F HN O OH O OH N N HN N HO N N CN N O H XIV Finafloxacin NH XV Idelalisib O HO S OH OH · H N CO2H H XVI Ipragliflozin L-Proline Fig (continued) acid (TFA) led to formation of the desired Fischer indole product, albeit as a 1:1 mixture of regioisomers (3/4), which were carried forward as a mixture to oxidation with 2,3-dichloro-5,6-dicyano1,4-benzoquinone (DDQ) It is important to note that although representative procedures are published describing the conversion of to alectinib (I), no yields were provided for these transformations Following oxidation, the desired product could be isolated as a single isomer via precipitation from the crude reaction mixture Installation of the 4-morpholino-piperidine moiety took place in three transformations from 5, beginning with 1-dodecanethiol/ N-methyl-2-pyrrolidone (NMP)/NaOMe-facilitated methyl cleavage The corresponding phenol was then readily converted to the triflate intermediate and displaced with 4-(piperidin-4-yl)morpholine (6) at elevated temperature, providing intermediate Crosscoupling of the bromide with ethynyl triisopropylsilane under Pd-catalyzed cross-coupling conditions (Pd(CH3CN)2Cl2/2-dicyclo- hexylphosphino-20 ,40 ,60 -triisopropylbiphenyl (XPhos), reflux) followed by cleavage of the resulting alkylsilane with tetrabutylammonium fluoride (TBAF) yielded the ethynyl precursor to alectinib Hydrogenation of this unsaturated system under standard conditions (H2, Pd/C) followed by HCl salt formation furnished the final drug target alectinib hydrochloride (I) Apatinib mesylate Apatinib mesylate, discovered by Advenchen Laboratories (United States of America, USA) and co-developed by Jiangsu Hengrui Medicine Co Ltd (China), was approved by the Chinese Food and Drug Administration (CFDA) in October 2014 for the treatment of metastatic gastric carcinoma.30,31 Apatinib mesylate is an oral tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor (VEGFR2), which prevents 1941 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 O O HN O F F N H H N H N N N N H N O O O XVII Ledipasvir N O O S O N N O S HO HN O O O OH HO H 2SO xH 2O OH XVIII Lobeglitazone Sulfate XIX Luseogliflozin Hydrate O N OH HO OH O 2N O N N CF3 N OH N O O HO XX Morinidazole O O N O N N XXI Naloxegol Oxalate CF3 XXII Netupitant O N N N O F N N NH O O N H O N NH O S OH O O O XXIII Nintedanib Esylate XXIV Olaparib Fig (continued) new blood vessel formation selectively in tumor tissue.32 Apatinib has shown inhibition of the VEGF signaling pathway with an IC50 value of nM for VEGFR-2 in in vitro enzyme experiments.33 A multicenter phase II study of apatinib is underway with patients in non-triple-negative metastatic breast cancer trials.34 Non-clinical studies concluded that apatinib may reverse the ATP-binding cassette subfamily B member and subfamily G member (ABCB1- and ABCG2, respectively)-mediated multidrug resistance which allows cancer cells to circumvent certain conventional antineoplastic drugs, suggesting that apatinib could be effective as a combination therapy.35 The synthetic route of apatinib mesylate (II) described in Scheme is based on a patent disclosure.36,37 The synthesis started with commercially available 1-phenyl cyclopentane carbonitrile (8), which was nitrated to provide nitrobenzene Subsequent reduction of gave aniline 10, which was coupled with 2-chloronicotinoyl chloride (11) to afford aryl amide 12 Subjection of the 2-pyridyl chloride within 12 to pyridin-4-ylmethanamine (13) in hot pentanol gave 14 The preparation of apatinib 14 from starting material were reported on gram or milligram reaction scale with no yield.36 170 g of 14 was mixed with methylsulfonic acid in 95% isopropanol–H2O solution to give 161.5 g of apatinib mesylate (II) in 77% yield.37 Apremilast (OtezlaÒ) Apremilast is the first and only oral phosphodiesterase IV (PDE4) inhibitor and anti-tumor necrosis factor alpha (TNFa) agent launched in the USA by Celgene for the treatment of active psoriatic arthritis (PsA).38 Apremilast was also approved for the treatment of moderate to severe plaque psoriasis in the USA.39 Later, this drug was also approved in the European Union (EU) for both indications Although multiple approaches to the synthesis of apremilast have been described,40,41 the most likely process scale 1942 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 H N O H N N O O O H N N N O H N O O O 4.5 H 2O XXV Ombitasvir Hydrate Cl H N OH O OH O O OH Cl O O O OH O Cl OH O O HO H 2N O H N HN HO O N H O H2 N O O O OH OH HO O H N N H H N H 3PO XXVI Oritavancin Diphosphate O H 2O N O N O N H O O O XXVIII Phenothrin H N N O O O S N H O N HN N N S O F O HCl H 2O XXVII Paritaprevir Hydrate XXIX Ripasudil Hydrochloride Hydrate Fig (continued) approach involves the construction of the challenging stereogenic benzylic carbon center by catalytic asymmetric hydrogenation, and this is described in Scheme Dimethyl sulfone was first subjected to n-butyllithium in tetrahydrofuran (THF) prior to exposure to commercially available 3-ethoxy-4-methoxybenzonitrile (15) at low temperature to afford enamine 16 in 83% yield, presumably as a single isomer enamine possessing the E-configuration After considerable studies conducted by researchers at Celgene regarding the reduction of this enamine and alternative substrates,41 enamine 16 was reduced under asymmetric hydrogenation conditions consisting of [Rh (COD)2]OTf and (S,R)-t-Bu Josiphos in trifluoroethanol (TFE) at 50 °C under 90 psi of hydrogen pressure Immediate exposure of the product to N-acetyl-L-leucine in methanol afforded the corresponding benzylamine salt 18 in 80% yield and more than 99% enantiomeric excess (ee) Finally, compound 18 was condensed with commercially available N-(phthalimid-3-yl)acetamide (19) in refluxing acetic acid to provide apremilast (III) in 83% yield and 99.4% ee Asunaprevir (SunvepraÒ) Sold under the trade name SunvepraÒ, asunaprevir received approval in Japan as part of a combination treatment for the hepatitis C virus (HCV) Working in concert with daclatasvir (IX) (vide infra), asunaprevir is a unique treatment for HCV, as it is free from 1943 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 O O O Cl N N N N H N N N OH B O F O XXX Suvorexant O N N N N XXXII Tavaborole XXXI Tasimelteon N O O O HO N HO F O HO P OH O XXXIII Tedizolid Phosphate OH H2 O OH XXXIV Tofogliflozin Hydrate N N+ OH O O S O N O OH HO Br - O F XXXV Umeclidinium Bromide O H H O H N NH XXXVI Vonoprazan Fumarate O O HH H O O N N O N N H O H O N S O O H2 SO4 HN O O F XXXVII Vorapaxar Sulfate XXXVIII Vaniprevir Fig (continued) both interferon and ribavirin and is administered orally This direct-acting anti-viral, which was developed by Bristol–Myers Squibb (BMS), works as an NS3/4A protease inhibitor, representing a valuable treatment option for patient populations who are unable to receive, or not respond to, the standard course of treatment—peginterferon/ribavirin.42 While a manufacturing route has not been disclosed to date, several synthetic approaches are reported in the literature.43–45 The most likely scale route is presented in Schemes 4–6, closely following patent literature describing the scale preparation of the active pharmaceutical ingredient as disclosed by BMS.46,47 In the retrosynthetic sense, asunaprevir (IV) can be subdivided into three main fragments: chloroisoquinolinoxy proline derivative 27,46 vinylcyclopropane amino acid 35,47 and commercially available N-Boc-3-methyl-L-valine (37) The preparation of subunits 27 and 35 are described in Schemes and 5, respectively The preparation of chloroquinoline 27 began with bromination of commercially available acetophenone 20, which was carefully carried out on over kg scale in a reactor equipped with an HBr scrubbing mechanism (bubbler outfitted) to furnish a-bromoketone 21 (Scheme 4).46 Next, nucleophilic displacement of the bromide using sodium diformamide (22) under phase transfer conditions led to the putative intermediate 23 This system underwent in situ deprotection of the diformamide functionality followed by cyclization under mildly acidic conditions to arrive at isoquinolone 24 in 78% yield across the two-step, one-pot sequence Next, methylation of the hydroxyl group at C-4 was carried out using methanolic methanesulfonic acid at elevated temperatures followed by treatment with aqueous ammonium hydroxide to quench any excess acid Subsequent treatment with phosphorous oxychloride furnished dichloroisoquinoline 26 in good yield A nucleophilic aromatic substitution reaction 1944 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 1) TBAHS, MeI, THF aq KOH, ↑↓, 73% O O Br 3-hydrazinobenzonitrile O O 2) NBS, MeCN, rt, 92% TFA, 100 °C R2 O Br R1 DDQ, THF H2 O, rt N H O CN Br 2) pyridine, Tf O DCM, rt 3) NMP, 120 °C N H O 3: R1 = CN, R2 = H 4: R1 = H, R = CN 1) NaOMe, NMP 1-dodecanethiol 160 °C, 65% HN N O O CN Br N H N 1) TIPS , MeCN XPhos, Pd(CH CN)2 Cl2 Cs2CO 3, ↑↓ O CN N O N H N 2) TBAF, THF 3) H 2, Pd/C, THF, MeOH, rt 4) MEK, H2 O, HOAc, 60 °C O then HCl, EtOH N • HCl I Alectinib Hydrochloride Scheme Synthesis of alectinib hydrochloride (I) KNO3, H 2SO4 CN HOAc, °C to rt no yield reported Pd/C, H CN EtOH, rt CN H 2N O 2N 10 O Cl N N Cl 11 K2CO3 , DCM, rt CN NH2 CN pentanol, 120 °C N H N O 13 O N N H NH no yield reported Cl N 12 14 O CH3 SO3 H, 95% i-PrOH, ↑↓ 77% N CN N H NH CH 3SO3 H N II Apatinib Mesylate Scheme Synthesis of apatinib mesylate (II) employing potassium t-butoxide was used to establish an arylpyrrolidino ether linkage and, upon workup with mildly acidic conditions, the proline derivative 27 emerged in 59% yield.46 Although the synthesis of asunaprevir vinyl cyclopropane subunit 35 has been described by researchers at BMS,47 it is interesting to note that this subunit, or structural derivatives of 35, have been 1945 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 1) Rh(cod) OTf, H2 , TFE (S, R)-t-Bu Josiphos, 50 °C (t-Bu) 2P Fe NH2 O CN 17 O n-BuLi, Me2 SO2 THF, °C, 83% O PPh2 SO2 Me O 2) N-Ac-Leu, MeOH 80% for steps, 99% ee 15 16 O O O O O O 19 NHAc O H2 N N HOAc, ↑↓ 83%, 99% ee SO 2Me O O H O S O O NH N-Ac-Leu 18 III Apremilast Scheme Synthesis of apremilast (III) H Br CH3 O Cl O Br 2, PhMe, °C O OCH NH Cl 23 OCH3 1) MsOH, MeOH, 60 °C 2) aq NH4OH, MeOH, °C 90% for steps H OCH3 21 HOAc MeOH, 25 °C O O Cl MeCN, °C OH 78% for steps O OCH3 20 O N N O Na 22 (n-Bu) 4Br, THF O Cl 60% O H H NH Cl O OCH POCl3 MeCN, 30 °C 87% N Cl O 24 Cl 25 26 O 1) N-Boc-3-(R)-hydroxy- L-proline t-BuOK, DMSO, 10 °C 2) aq HCl to pH = ~ 5, EtOAc, rt N Cl O OH 59% for steps NBoc O 27 Scheme Synthesis of asunaprevir chloroisoquinolinoxy proline subunit 27 found within a number of other antiviral drugs, particularly those which target inhibition of NS3 protease as its mechanism of action For example, researchers at Boehringer-Ingelheim have described a scale synthesis of (1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid (des-N-tert-butoxycarbonyl (Boc) 32, Scheme 5; also referred to as ‘vinyl-ACCA’) as a means to incorporate this subunit into that company’s antiviral agent BILN 2061.48 A macrocyclic version of this same cyclopropane-containing system is found in the antiviral agents paritaprevir hydrate (XXVII) developed by Enanta and Abbvie, and a saturated version in vaniprevir (XXXVII) developed by Merck and described later in this review (vide infra) The preparation of 32 described by Beaulieu and co-workers was performed on pilot-plant scale and the details surrounding the conversion of 32 to 35 are described by the BMS patent.47 Beginning with commercially available methyl glycine HCl (28), condensation with benzaldehyde in the presence of a dehydrating reagent (trimethyl orthoformate) and base led to the transient imine 29 This underwent a highly diastereoselective alkylation reaction whereby treatment with lithium t-butoxide followed by subjection to 1,4dibromo-2-butene facilitated an SN2–SN20 reaction Subsequent acidification and Boc protection resulted in 30-rac as a racemate that existed as a single diastereomer having the vinyl and the ester groups in a cis configuration The authors postulate that the lithium enolate intermediate which forms upon the initial alkylation binds 1946 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 H 2N CO2 Me HCl PhCHO, CH(OMe) Et 3N, PhMe N CO2Me NMP, °C, 96% 28 1) 1,4-dibromo-2-butene t-BuOLi, NMP, TBME PhMe, rt MeO 2C BocHN 2) 3.75% HCl 3) Boc O, NaOH, acetone °C 29 30 -rac single diastereomer 53% for steps Acalase 2.4 L Na3PO 4, 50% aq MeO C NaOH, 39 °C, DMSO 49%, 100% ee BocHN HO2 C LiOH, MeOH HOOC BocHN THF, 87% BocHN 31a (desired) O O S H 2N 31b O O O S N H BocHN 33 CDI, DBU, THF 65 °C, 92% 32 O O O S N H H 2N 1) TFA, DCM 2) HCl, Et2O HCl 92% for steps 34 35 Scheme Synthesis of asunaprevir vinyl cyclopropyl subunit 35 O 27 + 35 EDAC, HOBt O N Cl DIPEA, DCM 89% HN O O O S NH 1) HCl, i-PrOH, 85% 2) t-Bu Boc NBoc O 36 O N H OH (S) O 37 HATU, DCM, DIPEA, 94% O S NH O O N Cl HN O O N O O NH O IV Asunaprevir Scheme Endgame synthesis of asunaprevir (IV) the proximal bromine atom which accounts for the stereoselectivity of the reaction Next, selective saponification of the undesired enantiomer 31b took place via treatment with acalase 2.4 L, which is a remarkably versatile and relatively inexpensive enzyme capable of resolving a wide variety of racemic esters,49 under basic conditions This enzymatic resolution returned a 49% yield of the desired ester 31a (theoretical 50%), and a simple aqueous workup removed the undesired acid 31b Methyl ester 31a was then saponified using methanolic lithium hydroxide to give 32, which was subsequently coupled with cyclopropanesulfonamide 33 to deliver 34 in excellent yield Next, removal of the Boc group using TFA followed by salt formation with ethereal HCl delivered the key cyclopropane subunit 35.46,47 The endgame coupling and protecting group manipulation is described in Scheme Cyclopropyl amine 35 was subjected to proline derivative 27 under conventional amide bond-forming conditions This was followed by removal of the pyrrolidine nitrogen Boc group with acid and subsequent coupling with N-Boc-3-methyl valine (37) to deliver asunaprevir (IV) in good yield for each of these steps 1966 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 O NO2 Br ZnCl2, t-BuOH, PhH + O2 N Et2 NH, rt, 61% O 208 209 210 NO2 OH 1) (CH SO2 )2 O, i-Pr NEt 2-MeTHF, -25 °C to rt OH 211 B(OMe) , PhNEt2 BH3 MeOH, THF, 16 °C 2) 4-t-Bu-aniline, 65 °C OH O2 N 51% for steps 212 61%, 99.3% ee O 2N O O 2N NH Ph Ph NO2 N H 2, Raney-Ni H 2N NH N THF, rt 213 1) 215, T3 P, DIPEA EtOAc, °C to rt NO2 O 214 H N O 2) Recrystallization from EtOH/heptane H N N O O H N N N O O 4.5 H 2O O H N O O XXV Ombitasvir hydrate Scheme 34 Synthesis of ombitasvir hydrate (XXV) O H2 N OH 1) ClCO2Me, aq NaOH Na2 CO3, 15 °C, 90% 2) EDC, HOBt, DMF, L-proline benzyl ester, TEA, rt, 90% 3) H 2, 5% Pd/Alumina, THF, rt OH H N O N O O O 216 215 Scheme 35 Synthesis of ombitasvir dipeptide acid 215 31 Suvorexant (BelsomraÒ) Suvorexant, a dual orexin receptor antagonist marketed under the trade name BelsomraÒ, discovered and developed by Merck for the treatment of insomnia, was approved by the US FDA in August 2014 and became available in Japan in November of the same year.232 The drug’s mechanism of action operates through the competitive blockade of wake-promoting neuropeptides orexin A and orexin B toward receptors orexin receptor type and orexin receptor type 2, which are believed to modulate sleep-wake cycles.233 Researchers at Merck have disclosed the process-scale synthetic route to the drug in a recent article authored by Baxter and Cleator,232 and this approach is summarized in Schemes 42 and 43 below.232 Commercially available acid 240 (Scheme 42) was first subjected to a copper-assisted substitution reaction involving 1,2,3-triazole in DMF at elevated temperatures Although these conditions resulted in an excellent yield of a triazole-substituted product, an approximate 4:1 ratio of the desired 2-arylated triazole 241 and the undesired 1-arylated triazole byproduct were recovered from the reaction The mixture was then treated with N,Ndimethylethylenediamine in acid to sequester copper Next, the mixture of arylated triazoles was carefully subjected to sodium tbutoxide in DMF and ethyl acetate to form the corresponding sodium salts, and interestingly it was found that the desired sodium salt of 241 could be isolated based on its solubility profile under these conditions Acidification of the desired carboxylate salt using dilute HCl gave rise to acid 241 in 60% yield across the fourstep sequence Next, subjection of this acid to oxalyl chloride in chilled DMF generated the acid chloride 242 in excellent yield This crude acid chloride was used immediately in the next step of the synthetic sequence, as shown in Scheme 43.232 For the preparation of the diazepine-containing portion of suvorexant, the synthesis commenced with the condensation of commercial 2-amino-4-chlorophenol (243) with thiophosgene (244) to furnish benzoxazole 245 (Scheme 43) Next, thiol 245 was converted to the corresponding chloride prior to exposure to Boc-protected ethylenediamine 246 under basic conditions This was followed by a Michael addition of the resulting aminobenzoxazole and methyl vinyl ketone (MVK) The result of this sequence of reactions delivered aminobenzoxazole ketone 247 in 75% yield over the three steps Next, subjection of the carbamate to 1967 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 OH H2 N O OH O OH O Cl OH O Cl Cl H O O 218 O O HO H 2N O O H N HN O HO O H N N H H2 N N H O NaBH 3CN, MeOH, ↑↓ 69% crude yield; H N 16-18% yield after HPLC purification; (salt formation) O O HO O OH O OH OH 217 Cl H N OH O OH O O OH Cl O O O OH O Cl OH O O HO H 2N O H N HN HO O N H O H2 N O O O OH OH HO O H N N H H N H 3PO XXVI Oritavancin Diphosphate Scheme 36 Synthesis of oritavancin diphosphate (XXVI) methanesulfonic acid removed the Boc functionality and this was followed by an intramolecular reductive amination sequence to construct the diazaepine ring Acid–base workup ultimately provided the racemic diazepine 248 in 92% yield from 247 Next, salt formation with a benzoyl tartaric acid and subsequent recrystallization upgrade using isopropyl acetate and methanol at ambient temperature was used to resolve racemic 248 into the tartrate salt 249 in 27% yield and excellent enantiomeric excess Finally, salt 249 was freebased using sodium hydroxide prior to exposure to the crude acid chloride 242 under basic conditions to ultimately deliver suvorexant (XXX) in 95% yield and 99% ee across the twostep sequence.232 32 Tasimelteon (HetliozÒ) Tasimelteon, which is marketed by Vanda Pharmaceuticals as HetliozÒ and developed in partnership with Bristol-Myers Squibb, is a drug that was approved by the US FDA in January 2014 for the treatment of non-24-hour sleep–wake disorder (also called Non-24, N24 and N24HSWD).234 Tasimelteon is a melatonin MT1 and MT2 receptor agonist; because it exhibits a greater affinity to the MT2 receptor than MT1, is also known as Dual Melatonin Receptor Agonist.234 Two randomized controlled trials (phases II and III) demonstrated that tasimelteon improved sleep latency and maintenance of sleep with a shift in circadian rhythms, and therefore has the potential to treat patients with transient insomnia associated with circadian rhythm sleep disorders.235 Preclinical studies showed that the drug has similar phase-shifting properties to melatonin, but with less vasoconstrictive effects.236 The most likely scale preparation of the drug, much of which has been published in the chemical literature, is described below in Scheme 44 Activation of commercial bis-ethanol 250 with 2.5 equivalents of the Vilsmeier salt 251 followed by treatment with base resulted an intramolecular cyclization reaction with the proximal phenol and concomitant elimination of the remaining imidate to deliver the vinylated dihydrobenzofuran 252 in 76% yield.237 Interestingly, this reaction could be performed on multi-kilogram scale, required no chromatographic purification, and generated environmentallyfriendly DMF and HCl as byproducts.237 Sharpless asymmetric dihydroxylation of olefin 252 delivered diol 253 in 86% yield and impressive enantioselectivity (>99% ee) This diol was then activated with trimethylsilyl chloride and then treated with base to 1968 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 1) DIPEA, HATU, DMF, PhMe O OH H 2N N 1) t-BuONa, NMP BocN TsOH 222 OEt O + OH N Cl 2) HCl, MTBE 2) HCl, i-PrOH 3) NaOH BocN O OH O 219 220 221 N N N O O H N OH N O O O H N HN 224 OEt O EDC, HONB, DMF O N O OEt O N H N,N-dimethylethylene diamine O H N N N 223 225 MesN NMes Cl Ru Cl O O S O NMe2 226 N 1) Boc 2O, DMAP 2) 226, PhMe, imidazole O O N 3) HCl, dioxane, MeCN O H N N O 1) LiOH, THF, H2 O 2) Et2 NH, MeCN OEt 3) aq H3 PO4 , THF 2-MeTHF O N H N 227 N O N 1) CDI, DBU, NMP O O H N N O N H O S H 2N O OH O N 33 O 2) i-PrOAc, EtOH, H O N N O N H O O H N N O S N H O H 2O N 228 O XXVII Paritaprevir Hydrate Scheme 37 Synthesis of paritaprevir hydrate (XXVII) O BocHN OH 1) HCl, i-PrOAc 2) 230 , N,N'-disuccinimidyl carbonate, TEA, DMAP, NMP 3) HCl, H 2O N H N N O O N OH OH O N 230 229 224 Scheme 38 Synthesis of paritaprevir acid 224 1969 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 HO (COCl) 2, cat DMF OH Cl pyridine, DCM, rt, 96% DCM, rt, 99% O O 233 O 231 232 O O O XXVIII Phenothrin Scheme 39 Synthesis of phenothrin (XXVIII) NH HO CH3 H N 1) NsCl, aq NaHCO3 MsO THF, rt, 82% 1) 3-aminopropanol K2CO3 , MeCN, 70 °C Ns CH3 2) MsCl, NMM °C to rt, 91% OH N S Ns Ns = Boc CH3 2) (Boc) O, rt O NO2 O 95% for steps 234 235 1) PPh3 , DIAD, THF °C to rt, 75% 2) thiophenol, K2 CO3, 20 °C 86%, 99.9% ee H N Boc NH N 236 1) 238, TEA, MeCN °C, quant 2) M HCl in EtOAc, °C 93%, 99.9% ee 3) M HCl in EtOH 4) H 2O, acetone 80 °C to rt, 83% N HN N S O F O HCl H2 O XXIX Ripasudil Hydrochloride Hydrate 237 Scheme 40 Synthesis of ripasudil hydrochloride hydrate (XXIX) N F N 1) H 2SO4 , SO 2) SOCl2, 25 to 70 °C 3) M HCl in EtOAc Cl S O F O 238 239 Scheme 41 Synthesis of ripasudil isoquinoline sulfonyl chloride 238 generate epoxide 254.238 Next, a modified Horner–Wadsworth– Emmons reaction involving triethylphosphonoacetate (TEPA, 255) was employed to convert epoxide 254 to cyclopropane 256.239 The reaction presumably proceeds through removal of the acidic TEPA proton followed by nucleophilic attack at the terminal epoxide carbon The resulting alkoxide undergoes an intramolecular phosphoryl transfer reaction resulting in an enolate, which then O I HO CH3 240 1) 1,2,3-triazole, K2 CO3, CuI, THF DMF, 65 ºC 2) N,N-dimethylethylenediamine 3.6 M HCl, 25 ºC 3) t-BuONa, THF, EtOAc, 25 ºC 4) 0.22 M HCl, EtOAc, 25 ºC 60% attacked the newly formed phosphonate ester in an SN2 fashion resulting in the trans-cyclopropane ester, which was ultimately saponified and re-acidified to furnish cyclopropane acid 256.239 Conversion of this acid to the corresponding primary amide preceded carbonyl reduction with sodium borohydride The resulting amine was acylated with propionyl chloride to furnish tasimelteon (XXXI) as the final product in 86% yield across the four-step sequence 33 Tavaborole (KerydinÒ) Tavaborole (KerydinÒ), discovered and developed by Anacor, was approved by the US FDA in July 2014.240 Tavaborole, topical solution, 5% is an oxaborole antifungal indicated for the treatment of onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes.241,242 The mechanism of action of O N N N HO O (COCl)2 , DMF N N N Cl 10 ºC, 98% CH3 241 Scheme 42 Synthesis of suvorexant triazole 242 CH3 242 1970 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 Cl NH2 S + Cl OH 243 Cl N SH ºC 245 75% for steps 1) MsOH, THF, 60 ºC 2) NaOAc, AcOH, NaBH(OAc)3 DCM, 20 ºC N Boc N N Cl N O NH N 3) M HCl, then M NaOH, 10 ºC 92% for steps O 247 1) (COCl) 2, DCM, DMF, 20 ºC 2) 246 ,TEA, DCM, 10 ºC 3) MVK, DBU, MeCN, 20 ºC O 244 H Cl Cl aq MeOH O H 3C 248 1) Di-benzoyl- D-tartaric acid THF, DCM, 20 ºC Cl O N OH O O 2) IPAc, MeOH, 20 ºC OBz NH N OBz O 27%, 96% ee 249 O 1) M NaOH, DCM, 20 ºC 2) 242, TEA, DMF, DCM, 20 ºC Cl N N N H N H2 N N N 95%, 99% ee N Boc 246 O XXX Suvorexant Scheme 43 Synthesis of suvorexant (XXX) OH Cl+ Cl OH 250 K3Fe(CN) 6, (DHQ)2 PHAL K2OsO 2(OH) , aq K2 CO3 1) MeCN, -15 ºC 2) TEA, MeCN, 50 ºC N+ OH H 3) aq NaOH, n-Bu4NOH KI, t-BuOMe, 50 ºC 251 76% for steps t-BuOH, 25 ºC O 86%, 99% ee 252 1) t-BuONa, DME, 70 ºC O OH OH 1) (MeO) CMe, TMSCl THF, to ºC 2) t-BuOK, THF, to ºC (EtO) (O)P O 255 3) 85% H 3PO4 , ºC O 89%, 98% ee 253 HO 2) aq NaOH, 60 ºC 3) 0.5 M HCl pH = 7.5-8.5 O CO2 Et O 88% for steps 254 256 O 1) SOCl2 , DCM, reflux 2) aq NH3, THF, rt 3) NaBH 4, AcOH, THF, rt N H 4) propionyl chloride, TEA rt; aq HCl O 86% for steps XXXI Tasimelteon Scheme 44 Synthesis of tasimelteon (XXXI) tavaborole is inhibition of fungal protein synthesis, which inhibits an aminoacyl-transfer ribonucleic acid synthetase.243–246 Three syntheses of tavaborole (XXXII) have been reported.241,246–250 The 26.9 g scale approach (Scheme 45) started with 2-bromo-5-fluorophenyl methanol (257), which was treated with ethyl vinyl ether (258) to produce o-bromobenzyl alcohol derivative 259 in 82% yield 259 was then converted into the corresponding phenylboronic acid, followed by the one-pot 1971 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 Br OH F PPTS, DCM, 82% O F O 2) M HCl F 43% for steps 259 257 OH B O 1) n-BuLi, B(O-iPr) THF, -78 °C to rt Br 258 O XXXII Tavaborole Scheme 45 Synthesis of tavaborole (XXXII) NC NaN3 , NH4 Cl N Br 1) MeI, NaOH THF/DMF (3:1) 40 to 48 °C N N HN N DMF, 90 °C, 80% N 260 Br 261 N N N N N 2) M HCl, DCM 3) 50% NaOH to pH = 10.6 4) IPAc, 50 °C to rt Br 262 33% for steps O 1) Pd2 (dba) , PCy3 K2 CO3 , 263 dioxane, H2 O, 70 °C N N N N 2) EtOAc, 75 °C O 265 NHCbz N LiHMDS, THF, rt then DMPU °C to rt, 89% F 74% for steps 264 O O N N N N N O 1) POCl3 , TEA, THF, °C N F O 2) M NaOH, H2 O then EtOH M HCl to pH = 1.34 76% for steps HO 266 N N N N N O N F XXXIII Tedizolid Phosphate O HO P OH O Scheme 46 Synthesis of tedizolid phosphate (XXXIII) NH2 Br F NHCbz 1) CbzCl, NaHCO3 , THF, 20 °C 2) B(Oi-Pr ), n-BuLi, THF -72 to -65 °C HO B OH F 61% over steps 267 263 Scheme 47 Synthesis of tedizolid boronic acid 263 deprotection and spontaneous cyclization upon treatment with M hydrochloric acid, delivering tavaborole (XXXII) in 43% yield.246 34 Tedizolid phosphate (SivextroÒ) Tedizolid phosphate was approved by the US FDA in June 2014 for treatment of acute bacterial skin and skin structure infections caused by susceptible gram-positive pathogens, including MRSA.251,252 Tedizolid phosphate was discovered by Dong-A Pharmaceuticals in South Korea and developed in the USA by Cubist Pharmaceuticals (acquired from Trius Therapeutics in 2013,253 became a wholly owned subsidiary of Merck in 2015).254–256 The worldwide commercialization rights for tedizolid phosphate are divided between Cubist in the USA, Canada, and EU, and Bayer in Asia–Pacific, Latin America, and Africa.255 This second-generation oxazolidinone prodrug is rapidly converted to the active form tedizolid in the presence of endogenous phosphatases.257 It inhibits bacterial protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit of the ribosome, preventing formation of the 70S ribosomal initiation complex, and is 4-fold to 16-fold more potent against staphylococci and enterococci compared to linezolid.251 With high oral bioavailability (approximately 90%) and long half-life (approximately 12 hours), tedizolid phosphate is the first oxazolidinone antibiotic which can be dosed once daily either orally or intravenously.258 The process route reported by Trius Therapeutics is highlighted in Scheme 46259,260 and a description of the medicinal chemistry development of tedizolid phosphate has also been published.261,262 Commercial 5-bromo-2-cyanopyridine (260, Scheme 46) was treated with sodium azide and ammonium chloride in DMF to produce tetrazole 261, which was isolated by precipitation of the tetrazole ammonium salt Subsequent methylation with methyl iodide in THF/DMF (3:1) afforded a 3.85:1 mixture of 262 and the corresponding N1-regioisomer Acidification with M HCl followed by treatment with 50% aqueous NaOH (to pH 10.6) enabled isolation of 262 in 96% isomeric purity; crude 262 was further purified by recrystallization from isopropyl acetate and obtained in 33% yield from 261 A Suzuki reaction of 262 with boronic acid 263 (which was prepared from commercial 4-bromo-3-fluoroaniline (267) as described in Scheme 47, via carboxybenzyl (Cbz) protection and lithiation/borylation) followed by recrystallization from ethyl acetate produced triaryl system 264 Deprotonation of the carbamate within 264 using lithium hexamethyldisilazide (LiHMDS) followed by reaction with R-(À)-glycidyl butyrate (265) in the presence of 1,3-dimethyl tetrahydropyrimidin-2 (1H)-one (DMPU) generated tedizolide 266 in 85% yield Reaction with POCl3 in THF at 1–2 °C followed by subjection to sodium hydroxide and subsequent acidification furnished tedizolid phosphate (XXXIII) in 76% yield across the three steps 1972 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 O B(OMe) , BH in THF OH HO 270 Py-p- TsOH, -15 °C 30% Br 268 269 O O HO 25 to 30 °C, 89% Br O O OH O O 1) n-BuLi, PhMe, -10 to °C 2) MgBr2 , THF, 25 °C O HO 3) 272, -15 °C 4) p-TsOH, MeOH, 20 to °C Br 271 O HO OH OH 273 50% for steps OH B OH O ClCOOMe, DMAP MeCN 12 to 20 °C, 56% O MeOOCO MeOOCO OH OCOOMe 275 PdCl2(dppf), K2CO3 , DME 2-methyl-2-butanol, 80 °C 77% OCOOMe OCOOMe 274 MeOOCO MeOOCO O O NaOH, H 2O, DME OCOOMe OCOOMe 20 °C, 75% HO O O HO OH OH H 2O XXXIV Tofogliflozin Hydrate 276 Scheme 48 Synthesis of tofogliflozin hydrate (XXXIV) HO O O HO OH OH TMSCl, NMP, THF 30 to 40 °C 19% TMSO O TMSO 277 O OTMS OTMS 272 Scheme 49 Synthesis of tofogliflozin lactone 272 35 Tofogliflozin hydrate (DeberzaÒ) Tofogliflozin hydrate, which is a sodium-glucose co-transporter inhibitor, was approved in Japan for the treatment of type diabetes at the same time as luseogliflozin hydrate (XIX) The drug was discovered by Chugai Pharmaceutical and jointly developed with Sanofi-Aventis and Kowa.263 Tofogliflozin hydrate reduces glucose levels by inhibiting the reuptake of glucose by selectively inhibiting SGLT2, and plays a key role in the reuptake of glucose in the proximal tubule of the kidneys.264–266 The synthetic approach described in Scheme 48 represents the largest scale reported to date in a patent application.263,266–268 Reduction of commercially available 2-bromoterephtalic acid (268, Scheme 48) through the use of trimethoxyborane and borane-THF proceeded in 89% yield to afford diol 269 Subjection of this compound to 2-methoxypropene (270) under acidic conditions generated bis-acetonide 271 This bromide then underwent lithium–halogen exchange followed by exposure to magnesium bromide and treatment with lactone 272 (which was prepared by persilylation of commercially available (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H- pyran-2-one (277, Scheme 49) This mixture was worked up with aqueous ammonium chloride and upon treatment with p-TsOH in methanol resulted in spiroacetal 273 Next, global protection of all alcohol functionalities within 273 was affected by reaction with methylchloroformate and DMAP in acetonitrile The benzyl carbonate within 274 was selectively exchanged via Suzuki coupling with 4-ethylphenylboronic acid (275) to afford methylene dibenzyl system 276 Subsequent treatment with aqueous sodium hydroxide in methanol followed by crystallization from 1:6 acetone and water furnished the desired product tofogliflozin hydrate (XXXIV) in 75% yield 36 Umeclidinium bromide (ElliptaÒ) Umeclidinium bromide is a long-acting muscarinic acetylcholine antagonist developed by GlaxoSmithKline and approved by the US FDA at the end of 2013 for use in combination with vilanterol, a b2 agonist, for the treatment of chronic obstructive pulmonary disease.269 Due to umeclidinium’s poor oral bioavailability, the drug is administrated by inhalation as dry powder.269 The most likely scale preparation of the drug is described in Scheme 50.270 Commercially available ethyl isonipecotate (278) was alkylated with 1-bromo-2-chloroethane in the presence of K2CO3 in acetone to give ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (279) This material was then treated with lithium diisopropylamine (LDA) in THF to affect a transannular substitution reaction resulting in the cyclized quinuclidine 280 in 96% yield.270 Excess of phenyllithium was added to ester 280 in THF starting at low temperature then gradually warming to room temperature to give tertiary alcohol 1973 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 O NH ClCH2 CH2 Br, K2 CO3 O acetone, 38% EtO EtO LDA, THF N -50 °C to rt, 96% Cl 278 279 Br O O 282 N PhLi, THF N EtO OH -30 °C to rt, 61% MeCN, CHCl3 , 60 °C, 69% 281 280 N+ OH O Br - XXXV Umeclidinium Bromide Scheme 50 Synthesis of umeclidinium bromide (XXXV) O NC CuBr2 , EtOAc Br ↑↓ F O F 283 O 285 O O K2CO3 , acetone, 45 °C O F quant for steps O 284 286 H N M HCl/EtOAc H N 10% Pd/C, H Cl F rt, 53% CN rt, 18% 1.5 N DIBAL/PhMe F THF, -78 °C O O O O 287 288 N N HCl H N F OH MeCN, rt 60% for steps F CHO 289 O S O N NaH, 15-Crown-5 THF, rt, 82% F 290 N 292 O S O N O OH 294 O S O N OH O F NH NH 293 O HO MeOH, EtOAc, rt 74% for steps F CHO N O HO 1) MeNH MeOH, rt 2) NaBH MeOH, rt O S O 291 Cl H N TPAP, NMMO XXXVI Vonoprazan Fumarate Scheme 51 Synthesis of vonoprazan fumarate (XXXVI) 1974 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 OH 5% TsOH + 295 OH O OBn 296 O H O H H , Pd/C O HH H BnO O 299 OBn 298 O O 2) xylenes, ↑↓ 3) DBU, THF 38% for steps H2 , THF, 93% O 71% for steps 297 1) 300 , DCC, DCM °C to rt Lindlar's cat 2) BnOC(O)Cl 3) Dowex, rt >98% O OH (R) OTHP 1) n-BuLi, THF -78 °C O O O EtOAc, rt, >98% HH HO H O 301 O H 1) M HCl, acetone 50 to 60 °C, 76% NH2 ClCO2 Et, aq NaOH EtOH, 40 to 20 °C O 2) 10% Pd/C, HCO2 NH4 EtOH:H2 O (5:1) °C to rt HH HO 302 O H O then recrystallization H 50% for steps O HH HO H O 304 O H 1) (COCl) 2, DMF, rt 2) 5% Pd/C, THF H2 , lutidine 66% for steps H H N O O O HH H O O 303a/303b O H H N H H O 1) LDA, 306 , THF -20 °C, 90% H N H O O HH 2) H 2SO 4, MeCN 50 °C, 85% O H N H2 SO4 305 F XXXVII Vorapaxar sulfate Scheme 52 Synthesis of vorapaxar sulfate (XXXVII) O O Br O O 5% PdCl2(PPh 3) DMF, 75 °C, 71% O O 308 O O 307 O O THF, MeOH OH O M NaOH >98% 309 300 Scheme 53 Synthesis of vorapaxar dienyl acid 300 O Me N P(OEt) LDA, -80 to -50 °C N then ClP(O)(OEt) 2, 85% F F 310 306 Scheme 54 Synthesis of vorapaxar phosphonate ester 306 281 in 61% yield Amine 281 was finally alkylated with benzyl 2bromoethyl ether (282) in MeCN/CHCl3 at elevated temperatures to afford umeclidinium bromide (XXXV) in 69% yield 37 Vonoprazan fumarate (TakecabÒ) Vonoprazan fumarate (TakecabÒ), discovered and developed by Takeda and Otsuka, was approved by the PMDA of Japan in December 2014, and is indicated for the treatment of gastric ulcer, duodenal ulcer and reflux esophagitis.271 Vonoprazan fumarate has a novel mechanism of action called potassium-competitive acid blockers, which competitively inhibit the binding of potassium ions to H+, K+-ATPase (also known as the proton pump) in the final step of gastric acid secretion in gastric parietal cells.272 Vonoprazan does not inhibit Na+, K+-ATPase activity even at concentrations 500 times higher than that of their IC50 values against gastric H+, K+-ATPase activity.273 Furthermore, the drug is unaffected by the gastric secretory state, unlike PPIs.274 1975 A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 BnNH2 , NaHCO3 PhCl, PhMe 90 to 95 °C Br Br then TsOH H O PhMe, PhCl Br 311 Br NBn 1) NaOH 2) AcCl, PhCl 90 °C TsOH 3) MeOH, ↑↓ then HCl HCl Br 88% for steps 312 90% for steps NH 313 1) Pd(t-Bu 3P) 2, NMP, 93 to 98 °C HO O O CO2Me N Cbz N 314 O O Br CDI, DIPEA, DMF 60 °C, 91% O N Cbz 315 (S) CO2 H 2) Pd/C, H2 , i-PAc, rt, 96% O O O N N O O O H N O 316 N H N H O CO2 H 1) DIPEA, DMAP, DMF HATU, rt, 97% OH N 2) LiOH, MeOH, THF 98% H N O O O O O 317 318 O N TsOH O H N H 2N O S O O 319 H N HN N S O O O H N O EDC, HOBt, DIPEA 15 to 20 °C, 87% O O O XXXVIII Vaniprevir Scheme 55 Synthesis of vaniprevir (XXXVIII) CO2Et 320 1) LDA, DMPU, THF -20 to -10 °C CO2 Et 2) 4-bromo-1-butene -20 °C, 88% (used crude) 321 1) CDI, DMF, rt 2) L-t-leucine, Et3 N, 90 °C 3) DCHA, MeCN, 45 °C DIBAL, THF OH -20 to -10 °C >98% (used crude) 322 O O N H CO2 H HN 316 Scheme 56 Synthesis of vaniprevir hexenyl fragment 316 Researchers at Takeda have reported a preparation of vonoprazan fumarate that likely resembles the process synthetic approach and is shown in Scheme 51.275,276 Commercially available 2-fluoroacetophenone (283) was brominated to yield a-bromo-acetophenone derivative 284 This compound was treated with ethyl 2-cyanoacetate (285) under basic conditions to provide ketoester 286 in essentially quantitative yield Next, intramolecular condensation of 286 upon treatment of M HCl furnished the tri-substituted pyrrole 287 in 53% yield Reduction of the chloride under hydrogenolytic conditions facilitated arrival at pyrrole 288, albeit in just 18% yield Subsequent diisobutylaluminium hydride (DIBAL) reduction, followed by the oxidation with tetrapropylammonium perruthenate (TPAP) and 4-methylmorpholine N-oxide (NMMO) afforded the corresponding aldehyde 290 in 1976 Boc A C Flick et al / Bioorg Med Chem 24 (2016) 1937–1980 N H H N O S O O followed by quench with diethyl chlorophosphonate resulted in phosponate ester 306 1) 5% Ru/C, H , rt MeOH, 90%, 99% ee 2) TsOH, n-PrOH, 60 °C, 74% H N H 2N O S O O TsOH 34 319 Scheme 57 Synthesis of vaniprevir cyclopropylamine fragment 319 60% yield across the steps Next, N-pyrrole substitution with pyridine-3-sulfonyl chloride 291 gave rise to N-sulfonylpyrrole 292 in 82% yield Reductive amination of 292 afforded amine 293, which was treated with fumaric acid (294) via co-crystallization to provide vonoprazan fumarate (XXXVI) in 74% for the two steps 38 Vorapaxar sulfate (ZontivityÒ) Merck Sharp & Dohme successfully obtained approval in the EU in 2014 for vorapaxar sulfate, marketed as ZontivityÒ The drug is a first-in-class thrombin receptor (also referred to as a protease-activated or PAR-1) antagonist which, when used in conjunction with antiplatelet therapy, has been shown to reduce the chance of myocardial infarction and stroke, particularly in patients with a history of cardiac events.277 Antagonism of PAR-1 allows for thrombin-mediated fibrin deposition while blocking thrombinmediated platelet activation.277 Although a variety of papers and patents describe the synthesis of vorapaxar sulfate (XXXVII),278–282 a combination of two patents describe the largest-scale synthesis reported in the literature, and this is depicted in Scheme 52 Retrosynthetically, the drug can be divided into olefination partners 306 and 305.283,284 Lactone 305 is further derived from synthons 300 and 299, which are readily prepared from commercially available starting materials Dienyl acid 300 was constructed in two steps starting from commercial vinyl bromide 307, which first undergoes a Heck reaction with methacrylate (308) followed by saponification of the ester to afford the desired acid 300 in 71% over two steps (Scheme 53) The synthesis of alcohol 299 begins with tetrahydropyranyl (THP) protection of enantioenriched alcohol 295 to afford butyne 297 (Scheme 52) Lithiation of this system followed by trapping with (benzyloxy)chloroformate and Dowex work-up to remove the protective functionality provided acetyl ester 298 Hydrogenation of the alkyne with Lindlar’s catalyst delivered cis-allylic alcohol 299 in 93% yield Acid 300 was then esterified with alcohol 299 by way of a 1,3-dicyclohexylcarbodiimide (DCC) coupling and, upon heating in refluxing xylenes, an intramolecular Diels– Alder reaction occurred Subsequent subjection to DBU secured the tricyclic system 301 in 38% over three steps as a single enantiomer Diastereoselective hydrogenation reduced the olefin with concomitant benzyl removal to give key fragment 302 Next, acidic revelation of the ketone followed by reductive amination with ammonium formate delivered primary amines 303a/303b as a mixture of diastereomers These amines were then converted to the corresponding carbamates, and resolution by means of recrystallization yielded 50% of 304 as the desired diastereomer Acid 304 was treated with oxalyl chloride and the resulting acid chloride was reduced to aldehyde 305 in 66% overall yield Finally, deprotonation of phosphonate ester 306 (whose synthesis is described in Scheme 54) followed by careful addition of 305 and acidic quench delivered vorapaxar sulfate (XXXVII) in excellent yield over the two-step protocol The preparation of vorapaxar phosponate ester 306 (Scheme 54) commenced from commercial sources of 5-(3-fluorophenyl)-2methylpyridine (310) Removal of the methyl proton with LDA 39 Vaniprevir (VanihepÒ) Vaniprevir, which was approved in Japan in 2014 and sold under the trade name VanihepÒ, is one of several structurallyrelated macrocycles developed for the treatment of patients afflicted with the hepatitis C virus.285 Specifically, the drug is indicated for patients with untreated, interferon-unresponsive, or relapsed genotype chronic hepatitis C Similar to asunaprevir (IV), vaniprevir is a NS3/4A protease inhibitor, and thus has a comparable mechanism of action.285 While several publications describe creative routes to vaniprevir,286–291 Merck has disclosed a route on kilogram scale, and this is described below in Schemes 55–57.292 Beginning with commercial bis-benzylbromide 311 (Scheme 55), subjection to benzylamine under basic conditions followed by acidification afford the isoindoline as the toluene sulfonic acid salt 312 This salt was then freebased and acylative removal of the benzyl protecting group took place through the use of acetyl chloride Hydrochloric acid in refluxing methanol removed the acetamide to liberate indoline 313, which was isolated as the HCl salt Next, exposure of 313 to alcohol 314 in the presence of CDI and warm DMF gave rise to carbamate 315 This was followed by Heck installation of n-hexenyl fragment 316 (Scheme 56) and subsequent hydrogenation of the olefin with concomitant removal of the benzoyl carbamate protecting group delivered macrocycle precursor 317 Next, an intramolecular lactamization reaction furnished the macrocyclic system and this was followed by saponification of the prolinate ester to give 318 This acid was then coupled with cyclopropylamine 319 (Scheme 57) under standard coupling conditions to furnish vaniprevir in 87% yield The preparation of hexenyl fragment 316 (Scheme 56) started with the lithiation of commercially available ethyl isobutyrate (320) and alkylative quench with 1-bromo-4-butene to provide hexenyl ester 321 Next, DIBAL reduction followed by CDI-mediated carbamate formation with L-t-leucine and subsequent treatment with dicyclohexylamine (DCHA) furnished the key hexenyl fragment 316 The assembly of cyclopropylamine 319 (Scheme 57) stems from cyclopropyl fragment 34, whose synthesis was described in Scheme Hydrogenation of this system to saturate the 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B toward receptors orexin receptor type and orexin receptor type 2, which are believed to modulate sleep-wake cycles.233 Researchers at Merck have disclosed the process-scale synthetic route to