Synthetic Approaches to New Drugs Approved During 2016 - Journal

Perspective Cite This: J. Med. Chem. 2018, 61, 7004−7031

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Synthetic Approaches to New Drugs Approved During 2016 Andrew C. Flick,† Hong X. Ding,‡ Carolyn A. Leverett,† Sarah J. Fink,§ and Christopher J. O’Donnell*,† †

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Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, Connecticut 06340, United States ‡ Pharmacodia (Beijing) Co., Ltd., Beijing, 100085, China § BioDuro, 11011 Torreyana Road, San Diego, California 92121, United States ABSTRACT: New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely processscale synthetic approaches to 19 new chemical entities that were approved for the first time in 2016.

1. INTRODUCTION

2. ANTI-INFECTIVE DRUGS 2.1. Beclabuvir (Ximency). Beclabuvir is a non-nucleoside, nonstructural protein 5B (NS5B) polymerase inhibitor approved in Japan as part of a fixed-dose combination product for the treatment of hepatitis C virus (HCV). Upon administration and after intracellular uptake, the drug binds to the allosteric, noncatalytic “Thumb 1” site of NS5B resulting in a decreased rate of viral RNA synthesis and replication.4 Beclabuvir is combined with asunaprevir and declatasvir (both approved in 2014) and was discovered and developed by Bristol-Myers Squibb.4 The syntheses of asunaprevir and declatasvir were described in an earlier review article.2m The synthesis to produce 10−100 g of beclabuvir is described in Scheme 1.5 Condensation of indole-6-carboxylic acid (1) with cyclohexanone under basic conditions gave acid 2 in quantitative yield. Hydrogenation of the double bond in 2 using Pearlman’s catalyst was followed by esterification to give ester 3 in high yield.6 Bromination of the indole at the 2-position was accomplished with pyridinium tribromide, and this was followed by saponification to provide acid 4. Treatment of 4 with carbonyldiimidazole (CDI) followed by N,N-dimethylsulfamide and 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) gave compound 5 in 74% yield. Suzuki coupling of 5 with commercial boronic acid 6 provided intermediate 7, which converted to hemiaminal 8 upon continued heating in 61% yield. Compound 8 was then treated with methyl 2-(dimethoxyphosphoryl)acrylate (9) to affect a tandem conjugate addition and Horner−Wadsworth− Emmons (HWE) olefination to give ester 10. Alternatively, the Suzuki coupling reaction of 5 with 6 could be stopped at intermediate 7, which could be treated with 9 to promote the

“The most f ruitf ul 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 Inaugurated 15 years ago,2 this annual review presents synthetic methods for molecular entities that were approved for the first time by governing bodies within various countries during 2016. Because drugs can have structural homology across similar biological targets, it is widely believed that the knowledge of new chemical entities and approaches to their construction will enhance the ability to discover new drugs more efficiently. This review describes the most likely processscale synthetic approaches to the 19 small molecule new chemical entities (NCEs) that were approved for the first time in 2016 by a governing body anywhere in the world (Figure 1), and each section will only contain a limited introduction to the pharmacology of the drug as more detailed reviews on this topic are readily available.3 New indications for previously launched medications, new combinations or formulations of existing drugs, and drugs synthesized purely via bioprocesses or peptide synthesizers have been excluded from this review. Drugs presented in this review are divided into the following seven therapeutic categories: anti-infective, neuroscience, dermatologic, gastrointestinal, metabolic, oncology, and ophthalmology. Within each of these therapeutic areas, drug coverage follows alphabetical order by generic name. It is important to note that a drug’s process-scale synthetic approach is often not explicitly disclosed at the time of this review’s publication. However, the synthetic sequences presented in this review have all been published in the public domain and represent scalable routes that originate from commercially available starting materials (determined by explicit statement in the description or by experimental detail). © 2018 American Chemical Society

Received: February 15, 2018 Published: April 5, 2018 7004

DOI: 10.1021/acs.jmedchem.8b00260 J. Med. Chem. 2018, 61, 7004−7031

Journal of Medicinal Chemistry

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Figure 1. Structures of 19 NCEs approved in 2016.

medication. In clinical trials, the two drugs were coadministered as separate tablets and administered as a fixed-dose combination tablet with the primary end point being the sustained virological response rate 12 weeks post-treatment (SVR12); patients exhibited a 95% SVR12 rate overall.7 Elbasvir inhibits HCV NS5A, which is necessary for viral RNA replication and virion assembly.7 Grazoprevir inhibits HCV NS3/4A protease, which is essential for the proteolytic cleavage of the HCV encoded polyprotein and viral replication.7 For the purpose of this review, the synthesis of elbasvir and grazoprevir for HCV treatment will be discussed separately. Elbasvir possesses a particularly interesting molecular architecture consisting of two identical N-Moc-valine-linked

tandem conjugate addition/HWE to give 10. Corey− Chaykovsky cyclopropanation of 10 using sodium hydride and trimethylsulfoxonium iodide followed by chiral separation provided cyclopropane 11 in good yield and >99% enantiomeric excess (ee). Saponification of the methyl ester of 11 followed by coupling with 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (12) gave beclabuvir (I) in high yield. 2.2. Elbasvir/Grazoprevir (Zepatier). Discovered and developed by Merck, the combination of elbasvir and grazoprevir was approved by the United States Food and Drug Administration (USFDA) for the treatment of adults with chronic hepatitis C virus (HCV) genotype 1 or 4 infection.7 Interestingly, neither of these drugs is approved as a separate 7005



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Scheme 1. Synthesis of Beclabuvir (I)

steric hindrance to favor ketone formation at the position para to the bromide substituent. Ketone 16 was subsequently converted to the corresponding imine 17 upon condensation with ammonia in methanol. At this point, the stage was set for a critical stereochemical relay strategy for the construction of the hemiaminal geometry within elbasvir. This chirality-establishing sequence ultimately began with an asymmetric reduction of imine 17 in which ruthenium-catalyzed transfer hydrogenation conditions utilizing a metal−ligand complex, originally described by Wills,9 delivered branched amine 18 in excellent yield and enantioselectivity. This was followed by an intramolecular copper-mediated amination reaction to furnish indoline 19. This indoline, which possessed a stereogenic center unlikely to epimerize under strongly acidic conditions, was treated with benzaldehyde in warm TFA and acetonitrile to

pyrrolidinoimidazole subunits appended to a 2-arylindolyl hemiaminal spacer. A clever process-scale synthesis of elbasvir, as described by researchers at Merck in both a 2014 publication and a patent application, relies upon a stereochemical relay approach to set the challenging hemiaminal stereogenic center.8 The synthetic route began with esterification of commercially available 2,5-dibromoacetic acid (13) with 3-bromophenol (14), a reaction that proceeded through the corresponding acyl halide of 13 en route to ester 15 (Scheme 2). Next, a Fries rearrangement was employed to effect ester-to-ketone transposition. Exposure of 15 to a mixture of methanesulfonic acid and methanesulfonic anhydride at elevated temperatures gave rise to acetophenone 16. Although the authors do not explicitly comment about the regiochemical considerations of this reaction, presumably the meta-aryl bromide provides sufficient 7006



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Scheme 2. Synthesis of Dibromoarene Fragment 20 for Elbasvir

Scheme 3. Synthesis of Elbasvir (II)

Scheme 4. Synthesis of Pyrrolidino Bromoimidazole Fragment 21 for Elbasvir

borane (Scheme 3), and this reaction was followed by a crosscoupling with pyrrolidino bromoimidazole 21 (whose preparation is described in Scheme 4). Salt formation with pnitrobenzoic acid furnished azacycle 22 in 82% overall yield

facilitate smooth conversion to tetrahydrooxazinoindole 20 in excellent yield and a remarkable 99:1 diastereomeric ratio (dr). From dibromoarene 20, Miyaura conditions were employed to convert both aryl bromides to the corresponding bis-pinacol 7007



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Scheme 5. Synthesis of Chloroquinoxaline Fragment 29 for Grazoprevir

Scheme 6. Synthesis of Chiral Cyclopropanol Fragment ent-32 for Grazoprevir

from 20. Coincidentally, this two-step sequence also resulted in oxidation of the indoline ring, establishing the 2,3-indolyl πbond within 22. Next, exposure to potassium carbonate followed by reaction with methanolic HCl removed both Boc groups, converted 22 to diamine 23, which was immediately coupled with commercially available methyl carbamate (Moc)substituted valine (24) under standard amide bond-forming conditions. Recrystallization in warm ethanol completed the assembly of elbasvir (II) in 80% yield from 23.8 Pyrrolidino bromoimidazole 21 was derived from oxidation of commercially available S-Boc-prolinol (25, Scheme 4) followed by exposure to ammonia and glyoxal to secure the imidazole ring to give 26. Perbromination of 26 and subsequent reduction completed the construction of key bromide coupling partner 21.8 Grazoprevir hydrate is one of several structurally related macrocycles developed for the treatment of patients with HCV. The structure of the drug presents considerable complexity given the numerous stereocenters both within and external to the macrocyclic array. Several different approaches to the construction of grazoprevir have been reported.10 Interestingly, the original synthetic approach used by the discovery team proceeded through the use of a ring-closing olefin metathesis to produce the macrocyclic ring.10a,b However, this route suffered from low yield in the key macrocycle forming step, necessitating development of an alternative strategy on scale, which hinges upon a macrolactamization disconnection. Toward this end, grazoprevir was retrosynthetically subdivided into three key fragments: chloroquinoxaline 29, cyclopropanol ent-32, and amine 38. The synthesis and union of these three fragments represents the most likely process-scale entry to this structurally complex drug given that the patent application exemplified the synthetic sequence on kilogram scale, which is described in Schemes 5−8.11

The synthesis of chloroquinoxaline 29 started with the acidmediated condensation of 4-methoxy-1,2-benzenediamine dihydrochloride salt (27) with oxalic acid followed by bischlorination to provide the corresponding dichloroquinoxaline (Scheme 5).11a Upon exposure to SNAr conditions (DBU, DMA) in the presence of commercially available hydroxyproline 28, chloroquinoxaline 29 was isolated in 68% yield. This three-step reaction sequence delivered the product with 95:5 selectivity for the desired regioisomer, which could be further purified by recrystallizing from MTBE/heptanes. The cyclopropanol ent-32 was prepared using a strategy that relied on enzymatic resolution (Scheme 6).11b A diastereoselective cyclopropanation of a vinyl boronate resembling 30 was attempted, but low yields and difficult purification prompted the authors to consider a racemic cyclopropanation. On 34.3 kg scale, commercially available vinyl boronate 30 was subjected to trifluoroacetic acid-modified cyclopropanation conditions developed by Shi and co-workers (ICH2ZnO2CCF3), which gave higher conversion and a cleaner impurity profile than those of classic Simmons−Smith conditions (Zn(CH2I)2).12 The product was isolated as a solution in heptane (96% yield) and treated directly with 10 M sodium hydroxide and aqueous hydrogen peroxide to provide racemic cyclopropanol rac-31, which was carried forward crude as a solution in MTBE. Direct displacement of the chloride with lithium acetylide-ethylene diamine complex was optimized to generate terminal alkyne rac-32. Safety considerations surrounding the use of lithium acetylide-ethylene diamine on scale were closely examined due to the risk of uncontrolled release of acetylene gas. To minimize acetylene gas evolution, pretreatment of rac-31 with 1.2 equiv of n-hexyllithium (HexLi) formed the alkoxide prior to addition of 1.1 equiv of lithium acetylide-ethylene diamine at 50 °C. This procedure was used successfully to synthesize rac32 on 16.1 kg scale from the bulk stream of rac-31. Next, acylation of crude rac-32 in MTBE gave rise to ester rac-33, the 7008



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Scheme 7. Synthesis of Grazoprevir Hydrate (III)

used without further purification. After extensive optimization, the Sonogashira cross-coupling product of alkyne 35 and chloroquinoxaline 29 was isolated in 98% HPLC purity following aqueous workup and carried forward without purification. The resulting alkyne was subjected to catalytic hydrogenation conditions to furnish the macrocyclization precursor 36, which was also not isolated. Phenylsulfonic acid-mediated Boc removal followed by direct addition of excess DIPEA and slow addition of the mixture to a solution of HATU in acetonitrile resulted in intramolecular lactam formation with minimal dimerization byproducts (1 kg of narlaprevir and required no chromatographic separation steps.16,17,19 Amine salt 48 was prepared by first subjecting commercially available pentanal (49) to Knoevenagel condensation conditions using malonic acid followed by conversion of the resulting acid to the corresponding t-butyl ester 50 by reaction with H2SO4 and isobutylene (Scheme 10).19a The key transformation for establishing the requisite stereocenter in intermediate 48 relied on an asymmetric conjugate addition of a bis-protected lithiated amine followed by enolate trap with an electrophilic source of oxygen. In practice, treatment of αmethyl-N-(phenylmethyl)-(αS)-benzenemethanamine (51) with n-hexyllithium resulted in stereoselective 1,4-addition to enone 50. Subjection of lithium enolate intermediate 52 to (1S)-(+)-(10-camphorsulfonyl)oxaziridine (53) then furnished the α-hydroxyl group and delivered the syn-amino alcohol derivative 54 in 81% yield for the two-step protocol.20 tert-Butyl ester removal was realized by exposure of 54 to TFA in warm toluene. Subsequent coupling of the resulting acid with cyclopropylamine (55) utilizing EDC and HOBt conditions provided cyclopropyl amide 56 in 71% yield from 54. Finally, hydrogenolytic removal of the benzyl groups from the β-amine followed by subjection of the product to refluxing HCl provided amine salt 48 in 83% yield.19a 2.4. Nemonoxacin (Taigexyn). Nemonoxacin is a novel nonfluorinated quinolone and broad-spectrum antibiotic for the treatment of drug-resistant bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA) and quinolone-resistant MRSA as well as quinolone-resistant Streptococcus pneumonia.21 The drug was originally discovered by Procter & Gamble Pharmaceuticals (P&GP).22 It was codeveloped by 7011



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Scheme 11. Synthesis of Nemonoxacin (V)

Scheme 12. Synthesis of Aminopiperidine Fragment 65 for Nemonoxacin

to the corresponding ester 68 in 52% yield prior to treatment with Bredereck’s reagent to give enamine 69 (Scheme 12). Next, catalytic hydrogenation of 69 using a Pfaudler reactor and 5% Pd/C converted the vinylogous amide to the corresponding methyl group, delivering 70 in nearly quantitative yield and 93:7 diastereomeric excess in favor of the desired geometry. Further reduction of 70 using NaBH4 followed by treatment with calcium chloride dihydrate gave the corresponding diol 71

synthesis. Exposure of 64 to aminopiperidine 65 (whose synthesis is described in Scheme 12) under SNAr conditions provided aniline derivative 66. This was followed by basemediated borate removal, acidic quench with concomitant Boc deprotection, and basification to furnish nemonoxacin (V) in 79% yield from 64.24d For the preparation of aminopiperidine fragment 65 of nemonoxacin, commercial proline derivative 67 was converted 7012



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Scheme 13. Synthesis of Tenofovir Alafenamide Fumarate (VI)

isolated. Hydrolysis of the phosphonate esters with trimethylsilyl bromide followed by recrystallization from water gave phosphonic acid 77 in 50% yield. Interestingly, replacing Mg(Ot-Bu)2 with PhMgCl/t-BuOH led to improved yields for the alkylation step (74 → 76) on a 100 g scale.27 Additionally, the authors note that conditions for hydrolyzing the phosphonate ester can be modified using HCl or HBr for improved yields on smaller scale.28 Dicyclohexylcarbodiimide (DCC) coupling of 77 with phenol produced phosphonate 78 in 51% yield. This step was also reported to proceed in higher yield on smaller scale by changing the solvent to cyclopentylmethyl ether.28 Monophosphonate ester 78 was treated with thionyl chloride followed by L-alanine isopropyl ester (79) and triethylamine to give tenofovir alafenamide rac-80 as a mixture of phosphonate diastereomers in 47% yield. The diastereomers were separated using simulated moving bed chromatography29 to give the desired diastereomer ent-80 in 47% yield and 99% diastereomeric purity. The diastereomers could also be separated using a crystallization-induced dynamic resolution of rac-80.30 Tenofovir alafenamide fumarate (VI) was prepared from ent-80 and fumaric acid in 83% yield. 5.6. Velpatasvir/Sofosbuvir (Epclusa). In 2016, velpatasvir was approved in the US, Europe, and Canada as a once-

in 66% yield. Mesylation of diol 71 followed by cyclization with benzylamine and hydrogenation to remove the N-benzyl group provided aminopiperidine 65.24c The yields of the last three steps were not reported. 2.5. Tenofovir Alafenamide Fumarate (Vemlidy). Tenofovir alafenamide fumarate is an oral phosphonoamidate prodrug of the reverse transcriptase inhibitor tenofovir. It was approved by the USFDA for the treatment of chronic hepatitis B virus infection with compensated liver disease. Tenofovir alafenamide fumarate was discovered and developed by Gilead as a potentially safer form of the previously approved tenofovir disoproxil fumarate (Viread).25 A multikilogram synthesis of tenofovir alafenamide fumarate was described in a Gilead patent.26 Additional process improvements on specific steps of the Gilead process have been reported on 100 g scale, and these will be noted throughout the description of the synthesis. The synthesis was initiated with the alkylation of adenine (72) with (R)-propylene carbonate (73) to give hydroxypropyl adenine 74 in 75% yield (Scheme 13). It should be noted that sodium hydroxide can be replaced by potassium bases with increased yields on 100 g scale.27 Alkylation of 74 with diethyl p-toluenesulfonyloxymethylphosphonate (75) gave intermediate 76, which was not 7013



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Scheme 14. Synthesis of Tetralone Fragment 86 for Velpatasvir

Scheme 15. Preparation of Velpatasvir Ethereal Pyrrolidine 91

authored by scientists at Gilead; this patent also describes several alternative routes to the drug’s key building blocks.36 It is important to note that no yields are reported throughout the patent, and only the route to pyrrolidine 91 was exemplified on multikilogram scale.36,37 Synthesis of the central tetracyclic intermediate in the velpatasvir synthesis, tetralone 86, began with commercial 2-bromo-5-iodo-benzenemethanol (81), which underwent iodide-metal exchange and subsequent quenching with acetamide 82 (Scheme 14).36 Mesylation of the resulting alcohol followed by treatment with LiBr furnished benzyl bromide 83, which was then subjected to nucleophilic attack by commercial 7-hydroxytetralone (84) in the presence of K2CO3/MeCN to provide ether 85. An innovative use of an intramolecular Pd-mediated C−H activation reaction catalyzed by Pd(OAc)2/PPh3 secured the central tetracyclic core, which then underwent bis-α-keto-bromination with pyridinium tribromide in MeOH/DCM at room temperature to furnish tetralone 86.36 The preparation of the ethereal pyrrolidine subunit 91 began with formylation of commercial glutamate 87 followed by an intramolecular cyclocondensation reaction facilitated by TFA to secure dihydropyrrole 88 (Scheme 15).36 It should be noted that although TFA was used to affect the formation of enamine 88, the reported route indicates no loss of Boc or t-Bu ester

daily oral treatment for chronic HCV genotypes 1−6 when used as a combination therapy with the recently approved HCV inhibitor sofosbuvir (SOVALDI).2l Whereas velpatasvir functions as an HCV NS5A protein inhibitor, sofosbuvir serves as an inhibitor of HCV NS5B RNA polymerase, both of which play key roles in inhibiting HCV replication. 31 The combination, developed by Gilead, has been shown to provide very high rates of sustained virological responses (SVRs) in a variety of clinical trials31a,32 and exhibits full antiviral activity against resistance-associated variants developed by other HCV inhibitors with varying mechanisms of action. 31 The velpatasvir/sofosbuvir combination has been classified as pangenotypic,32a demonstrating antiviral activity for all known HCV genotypes, and joins a class of direct-acting antivirals (DAAs) that can also be used for patients suffering from severe liver failure who were previously contraindicated for treatment with standard interferon- and ribavirin-based regimens.32a,33 The synthetic strategy for the preparation of velpatasvir involves a series of bidirectional functionalizations that require the preparation and union of several structural subunits. Although several routes to velpatasvir intermediates have been recently published,34 including a potential alternate process route,35 the most likely process-scale route to the drug target has been described in a 2015 patent application 7014



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Scheme 16. Synthesis of Methyl Pyrrolidine Fragment 96 for Velpatasvir

Scheme 17. Synthesis of Velpatasvir (VII)

protecting groups in this transformation, and no further discussion was provided by the authors.36,37 Reduction of the enamine (H2, Pd/C, HOAc) and ester (NaBH4, H2O/THF) moieties present in 88 yielded pyrrolidine 89 as a mixture of

diastereomers. Global deprotection of this mixture using room temperature HCl in methanol generated the free amino acid, which was immediately subjected to mono reprotection with Boc anhydride to allow isolation of the Boc-protected amino 7015



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Scheme 18. Synthesis of Zabofloxacin D-Aspartate (VIII)

triphosphate salt. A second neutralizing step (aq NH4OH) and CDMT/NMM-mediated coupling of the free amine with commercially available phenylacetic acid derivative 99 provided velpatasvir (VII).36 2.7. Zabofloxacin D-Aspartate (Zabolante). Zabofloxacin is a quinolone antibiotic originally developed by Dong Wha Pharmaceuticals and licensed to Pacific Beach Biosciences in 2007.38 In March 2015, Korea’s Ministry of Food and Drug Safety (MFDS) approved zabofloxacin for the treatment of acute bacterial exacerbation of chronic obstructive pulmonary disease (ABE-COPD).39 In 2016, zabofloxacin gained approval from the USFDA for the treatment of community-acquired pneumonia. ABE-COPD is caused by respiratory tract and pulmonary parenchyma that cause chronic pulmonary inflammation and obstruction in the respiratory tract, which leads to irreversible damage. In the nonclinical evaluation process, zabofloxacin showed strong antibiotic activity on respiratory germs (e.g., Streptococcus pneumonia, S. Haemophilus, S. moraxella) and was the most potent antibacterial agent against penicillin-resistant S. pneumoniae (PRSP) in the murine systemic infection model.40 The synthesis of zabofloxacin leverages the wide commercial availability of chloronaphthyridinone acid 106 to essentially reduce the task to the construction of functionalized diazaspirocyclic pyrrolidine 105 (Scheme 18).41 As described in a series of patents from researchers at Dong Wha who have

acid intermediate 90. Final steps of the synthesis of 91 included alkylation with methyl iodide and dicyclohexylamine salt formation, enabling isolation of the desired cis isomer after crystallization. Finally, subjection to NaOH in MTBE/H2O provided the desired ethereal pyrrolidine 91.36 Construction of the final building block, methylpyrrolidine 96, began with a ring-opening reaction to convert N-Bocpyrrolidinone 92 to ketone 93 followed by a one-pot Bocdeprotection/ring-closing reductive amination sequence (Scheme 16).36 This step resulted in stereoselective hydride addition from the face opposite the ethyl ester,37 leading to the desired syn product, which was isolated as tosylate salt 94 after heating with p-toluenesulfonic acid monohydrate. Subsequent coupling with commercially available valine derivative 95 under standard peptide coupling conditions (HATU, DIPEA) and ester saponification with LiOH/MeOH furnished methyl pyrrolidine 96.36 The final approach to the velpatasvir synthesis proceeded linearly, starting with the central tetralone core and building outward (Scheme 17).36 Alkylation of dibromide 86 first with acid 91 and second with acid 96 resulted in the transient bisketoester intermediate 97, which was converted to bis-imidazole 98 using ammonium acetate followed by DDQ oxidation. Finally, introduction of fragment 99 relied upon Bocdeprotection with HCl/MeOH and subsequent neutralization of the resulting HCl salt to enable crystallization as the 7016



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Scheme 19. Synthesis of Brivaracetam (IX)

penetration, and faster onset of action against seizures than levetiracetam.43,44 Regarding the large-scale synthetic approach to brivaracetam, stereocontrolled installation of the 4-n-propyl group stands as the central challenge in the assembly of the molecule. Several routes have been published that require chiral separation.44,45 Two enantioselective routes have been reported, one employing an enzymatic resolution46 and the other utilizing (R)(−)-epichlorohydrin as a chiral starting material.47 The route detailed in Scheme 19, which involves an enzymatic resolution, is the only kilogram-scale route disclosed in the literature to date and reportedly permits the production of brivaracetam within the required commercial quality specifications. However, the authors note that the development of this route for commercial purposes has been stopped.46 Commercial dimethyl n-propylmalonate 108 was first alkylated with tertbutyl-2-bromoacetate. The resulting product underwent Krapcho decarboxylation to afford racemic succinate derivative 109 in 94% yield over the two steps.46 Optimized conditions for the key enzymatic resolution employed protease C from Bacillus subtilis type 2 at 30 °C for 18 h to resolve ester 109 and provide the acid enantiomer 110. This biocatalytic process allowed for residual unreacted diester 109 to be washed away with cyclohexane at pH 9 (adjusted with 0.5 M NaOH), and the desired acid 110 could be isolated upon lowering the pH (∼1) and extracting with isopropyl acetate (42% yield, 97% ee). The transformation of acid 110 into propyllactone 111 proceeded in nearly quantitative yield by a three-step sequence: activation of the acid with ethyl chloroformate, reduction to the alcohol with sodium borohydride, and cyclization upon acidic workup with TFA. Exposure of 111 to HBr in acetic acid followed by esterification of the resulting acid-generated bromoester 112. Finally, TBAI-catalyzed alkylation of 112 with commercial (S)-2-aminobutanamide (113) in refluxing isopropyl acetate introduced the n-butylamide moiety while facilitating lactamization. Addition of MTBE followed by

exemplified the synthesis on multikilogram scale, the route began with first converting the commercially available ketone 100 to the corresponding oxime followed by formylation to give oximyl alcohol 101. Next, mesylation of the alcohol was followed by conversion of the nitrile to the corresponding amine 103. An intramolecular ring closing step then occurred to secure the azetidine using aqueous sodium hydroxide. Salt formation with phthalic acid furnished 104 in good yield. Next, Boc-protection of the azetidine followed by hydrogenative Cbz removal and treatment with succinic acid resulted in the formation of amine salt 105, and this was followed by a substitution reaction with 106 to deliver the Boc-protected zabofloxacin structure 107. Lastly, removal of Boc via TFA followed by basification and subjection to D-aspartate in warm ethanol furnished zabofloxacin D-aspartate (VIII) in 56% yield for the three-step sequence.

3. CNS DRUGS 3.1. Brivaracetam (Briviact). Brivaracetam, a novel oral antiepileptic drug with a high affinity for synaptic vesicle protein 2A (SV2A), was approved in Europe and the US as an adjunctive therapy for the treatment of partial onset seizures with or without secondary generalization in patients aged 16 or older.42 Brivaracetam is very closely related to levetiracetam, an antiepileptic treatment whose immediate release formulation has been available in the United States as a generic drug since 2008, but whose extended release formulation is under patent protection until 2028. The two drugs, which were both developed by UCB Pharma, are structurally similar with brivaracetam having an n-propyl group at the C-4 position of the pyrrolidinone ring and levetiracetam having a hydrogen at this same position. A systematic investigation of the various substitutions of levetiracetam resulted in the identification of more potent and selective SV2A ligands and ultimately culminated in the discovery of brivaracetam, which has greater affinity for SV2A, improved selectivity, more rapid brain 7017



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Scheme 20. Synthesis of Opicapone (X)

Scheme 21. Synthesis of Acid Chloride Fragment 119 for Opicapone

filtration and recrystallization from isopropyl acetate afforded brivaracetam (IX) in 32% yield and 96% ee. 3.2. Opicapone (Ongentys). Opicapone is a selective and reversible catechol O-methyltransferase (COMT) inhibitor that was developed by the Portuguese pharmaceutical firm Bial and sold to Neurocrine Biosciences.48 The drug was approved by the USFDA as adjunctive treatment to levodopa (L-Dopa)/ dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson’s disease (PD) and end-of-dose motor fluctuations that cannot be stabilized on those combinations.49 In 14- to 15week double-blind multinational trials and in one-year openlabel extension studies in this patient population, opicapone was an effective and generally well-tolerated adjunctive therapy to L-Dopa plus a DDCI and other PD therapies.49 During the double-blind phase, adjunctive opicapone (50 mg once daily) provided significantly greater improvements in motor fluctuations than placebo, and no new unexpected safety concerns were identified after treatment with opicapone over a 1.4 year period.49 Furthermore, no serious cases of hepatotoxicity were reported in clinical trials, which represents a significant safety profile improvement over existing standard-of-care COMT inhibitors enticapone, tolcapone, and nebicapone.48,49 Although several synthetic approaches to opicapone or opicapone subunits have been disclosed,50 a synthetic approach described by Bial was exemplified on a scale capable of producing 14.4 kg of the active pharmaceutical ingredient (API).50e Commercial 2,4-pentanedione (114) was condensed with cyanoacetamide in warm methanol to give rise to

cyanopyridone 115 in excellent yield (Scheme 20). Chlorination with sulfuryl chloride in chilled acetonitrile followed by treatment with phosphorus oxychloride resulted in dichloropyridine 117. Next, treatment with hydroxylamine in aqueous methanol converted nitrile 117 to the corresponding Nhydroxyamidine 118, and this was followed by exposure to pyridine and acid chloride 119 (whose preparation is described in Scheme 21). These operations facilitated a cyclization reaction, which furnished the key oxadiazole 120 in good yield. Subjection of 120 to urea hydrogen peroxide (UHP) in dichloromethane to establish the pyridine N-oxide functionality within opicapone preceded methyl ether cleavage through the use of aluminum trichloride in warm pyridine to furnish opicapone (X) in 53% yield for the two-step sequence. The preparation of acid chloride 119 involved the nitration of commercially available benzoic acid 121 followed by thionyl chloride-mediated conversion of the resulting nitrobenzoic acid 122 to acid chloride 119 (Scheme 21). Interestingly, although the nitration step is low-yielding and involves nitric acid, the authors report an operationally simple isolation method that has been exemplified on multiple kilogram scale. No yield was reported for the conversion of 122 to 119. 3.3. Pimavanserin Tartrate (Nuplazid). Pimavanserin, developed by San Diego-based Acadia Pharmaceuticals, is a selective and potent serotonin 2A (5-HT2A) receptor inverse agonist.51 The USFDA approved this once-daily drug to treat the delusions and hallucinations associated with psychosis as a function of Parkinson’s disease.52 Pimavanserin has a unique 7018



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Scheme 22. Synthesis of Pimavanserin Tartrate (XI)

in 50% yield over the two-step protocol and a 10.6% overall yield from 123.54c 3.4. Pitolisant Hydrochloride (Wakix). Pitolisant hydrochloride, a first-in-class inverse agonist of the histamine H3 receptor, was approved in the EU for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy with or without cataplexy.55 The drug, which was developed by Bioprojet and has orphan drug designation in the EU and US, enhances wakefulness by increasing histaminergic neuron activity. With once daily oral administration in the morning, patients taking pitolisant exhibited significantly reduced EDS versus placebo but not versus modafinil.56 Plasma levels of the drug are reduced at the end of the day such that its waking effect is minimized at night (plasma t1/2 10−12 h). Several articles have been published detailing the discovery of pitolisant.57 The most likely scale preparation of pitolisant hydrochloride consists of only four synthetic steps starting with the mesylation of commercial 3-(4-chlorophenyl)propan-1-ol (132, Scheme 24).58 Displacement of the mesylate with the sodium salt of commercial 3-(piperidin-1-yl)propan-1-ol (133) in warm DMA assembled the parent drug in 97% yield over two steps.59 Salt formation was affected by pH adjustment to 3−4 using HCl gas in EtOAc. Recrystallization from ethyl acetate and isopropanol provided pitolisant hydrochloride (XII) on kilogram scale in 78% overall yield across the short four-step protocol.60

mechanism of action relative to other antipsychotics, behaving as a selective inverse agonist of the serotonin 5-HT2A receptor while exhibiting 40-fold selectivity over the 5-HT2C receptor and having no significant affinity or activity with the 5-HT2B or dopamine receptors.53 Three patent applications filed by Acadia described the process-scale synthetic approach to pimavanserin.54 The kilogram-scale synthesis (Scheme 22) began with the alkylation of commercially available 4-hydroxybenzaldehyde (123) with isobutyl bromide (124) under basic conditions. Condensation of the resultant benzaldehyde 125 with hydroxylamine furnished the corresponding oxime 126 in 63% yield from 123. Hydrogenation of 126 catalyzed by Pd/C under acidic conditions produced benzylamine 127, which was isolated as the acetate salt in 41% yield. This compound underwent sodium hydroxide workup followed by reaction with HCl gas and phosgene to deliver isocyanate 128. Nucleophilic attack of this isocyanate by benzylamine 129 (prepared from reductive amination of commercially available N-methylpiperid-4-one 130 with 4-fluorobenzylamine 131, Scheme 23) followed by salt formation using tartaric acid in aqueous isopropyl acetate, and THF completed the synthesis of pimavanserin tartrate (XI) Scheme 23. Synthesis of Benzylamine Fragment 129 for Pimavanserin

4. DERMATOLOGIC DRUGS 4.1. Crisaborole (Eucrisa). Crisaborole is a phosphodiesterase-4 (PDE4) inhibitor that was approved by the USFDA for the treatment of mild to moderate atopic dermatitis (AD) in patients aged two years and older.61 The drug, which was developed by Anacor Pharmaceuticals and later acquired and marketed by Pfizer, is delivered as a 2% ointment, which is 7019



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Scheme 24. Synthesis of Pitolisant Hydrochloride (XII)

Scheme 25. Synthesis of Crisaborole (XIII)

Scheme 26. Synthesis of Obeticholic Acid (XIV)

applied topically.61 The unique employment of boron within the chemical structure of the drug is designed to enable selective engagement of PDE4 (an enzyme involved in the conversion of cAMP into AMP, which signals for downstream inflammatory events), effective penetration of the drug through human skin, and rapid clearance to limit systemic circulation.62

During in vitro experiments, the drug demonstrated significantly reduced cytokine production from peripheral blood mononuclear cells in a pattern similar to other PDE4 inhibitors and distinct from corticosteroids.62 In phase 1 and 2 clinical studies, crisaborole ointment was generally well tolerated and 7020



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Scheme 27. Synthesis of Migalastat Hydrochloride (XV)

provided methyl ester 139, which was treated with trimethylsilyl chloride and triethylamine to protect the secondary alcohol. Reaction of the protected alcohol with lithium diisopropylamine and trimethylsilyl chloride gave silyl enol ether 140. Aldol condensation with acetaldehyde and boron trifluoride etherate followed by saponification of the methyl ester produced enone 141. Hydrogenation of the olefin followed by heating to reflux to epimerize the resulting ethyl group produced the α-ethyl ketone 142 in 62% yield from compound 138. Reduction of the ketone in 142 with sodium borohydride and subsequent crystallization from phosphoric acid and water gave obeticholic acid (XIV) in 90% yield.

improved AD disease severity scores, pruritus, and all other AD signs and symptoms.62 Several disclosures describing synthetic approaches to ethereal boron-containing anti-inflammatory compounds have been published by Anacor.63 A scalable synthetic route to crisaborole is described in Scheme 25 and closely follows an approach to the drug reported in the public literature by researchers at Anacor.63e Commercially available bromobenzaldehyde 134 was protected as the corresponding acetal upon subjection to warm ethylene glycol in the presence of catalytic p-toluenesulfonic acid. This was followed by nucleophilic aromatic substitution involving 4-fluorobenzonitrile and subsequent acetal deprotection to furnish diaryl ether 136. Although multiple approaches to crisaborole have been reported from this intermediate diaryl ether 136,63 the published literature approach involves the following sequence: reduction of the aldehyde with sodium borohydride followed by THP protection to furnish bromobenzene 137, which then underwent lithium-halogen exchange prior to quenching with triisopropyl borate and acidification to arrive at crisaborole (XIII).63e Alternatively, patents from Anacor describe a general approach employing a Miyaura coupling of 136, enabling the installation of the corresponding pincacol borane, which could then be exposed to reduction conditions using sodium borohydride followed by boric acid wash, aqueous workup, and lyophilization to furnish XIII.63e

6. METABOLIC DRUGS 6.1. Migalastat Hydrochloride (Galafold). Migalastat, which is marketed by Amicus Therapeutics, received approval in the EU for the treatment of Fabry disease in adults and adolescents aged 16 or older.67 Fabry disease is caused by mutations of the enzyme α-galactosidase A (α-GAL A) that cause protein misfolding and prevents efficient metabolism of the glycosphingolipid globotriaosylceramide (GL3).68 Accumulation of GL3 in lysosomes, blood vessels, and various tissues ultimately leads to significant heart, kidney, and dermatological problems.68 Migalastat functions as a molecular chaperone to αGAL A, engaging the enzyme and enabling it to adopt the proper conformation allowing for efficient breakdown of GL3.67 Because the standard of care prior to 2016 for treating Fabry disease was enzyme replacement therapy (ERT), migalastat’s approval in the EU represents an important advance for patients suffering from this disorder.67 Several unique synthetic approaches to migalastat, which is also known as D-1-deoxygalactonojirimycin (DGJ), have been reported in the literature.69 Although the most likely commercial-scale preparation of this drug proceeds through a microbial fermentation process disclosed in a 2015 patent,70 a kilogram-scale synthesis of the drug outlined in Scheme 27 has been described in a 2008 patent application filed by Amicus. This route closely resembles a procedure disclosed in 1999 by Uriel and Santoyo-Gonzalez69i,71 that presented handling and safety concerns.69i Commercial D-galactose (143) was treated with five equivalents of pivaloyl imidazole (144),69i followed by triflation, treatment with Hünig’s base, and exposure to sodium nitrite to furnish the tetrapivaloyl altofuranose triflate 145 after recrystallization from heptane. Next, stereospecific azide displacement of the triflate successfully delivered azidofuranose

5. GASTROINTESTINAL DRUGS 5.1. Obeticholic Acid (Caliva). Obeticholic acid is a potent and selective farnesoid X receptor agonist that promotes the flow of bile in the liver.64 The drug was approved by the USFDA for the treatment of the rare chronic liver disease primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with inadequate response to UDCA or as a single agent therapy in adults unable to tolerate UDCA.65 Obeticholic acid was discovered at the Università de Perugia and developed by Intercept Pharmaceuticals. Obeticholic acid has also been granted orphan drug designation for the treatment of primary sclerosing cholangitis and primary biliary cirrhosis and has received breakthrough therapy designation for the treatment of patients with nonalcohol steatohepatitis (NASH) with liver fibrosis. The synthesis of obeticholic acid was initiated from commercial 3α-hydroxy-7-keto-5β-cholan-24-oic acid (138) and is described in Scheme 26.66 Fischer esterification of 138 7021



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7.2. Rucaparib Camsylate (Rubraca). Rucaparib was approved in the US as an oral treatment for advanced ovarian cancer.77 Development of rucaparib began with collaborations between Cancer Research UK and Agouron Pharmaceuticals (later acquired by Pfizer). Global development rights for rucaparib were ultimately granted to Clovis Oncology via a licensing agreement from Pfizer.77 To qualify for treatment with rucaparib monotherapy, patients must demonstrate deleterious breast cancer (BRCA) mutation (germline and/or somatic)associated advanced ovarian cancer and also must have previously been treated with two or more chemotherapy regimens.78 Rucaparib functions as a small molecule poly(ADPribose) polymerase (PARP) inhibitor, which plays an important role in DNA repair.78,79 This newly approved drug displays nanomolar potency against PARP-1, -2, and -3 enzymes,80 which translates into improved efficacy over alternative therapies such as olaparib or niraparib.81 Furthermore, rucaparib is also known to cause vasodilation, which is thought to induce tumor perfusion and increased accumulation of the drug in cancer cells.82 Although rucaparib shows higher cytotoxicity in cancer cells with mutation of BRCA1/2 genes and other DNA repair genes,77,83 reduced tumor growth was observed in mouse xenograft models of human cancers with and without BRCA mutations.77 Rucaparib is also being pursued as a treatment for breast cancer84 and has displayed promising initial results in trials for pancreatic cancer.85 Synthesis of rucaparib camsylate begins from commercially available phthalimide acetal 151 (Scheme 29).86 Unveiling of the aldehyde via treatment with aqueous HCl and precipitation from toluene provided aldehyde 152 in 62% yield. To avoid polymerization, 152 was immediately subjected to 6-fluoro-1Hindole-4-carboxylic acid methyl ester (153) under reductive conditions in the presence of acid to give rise to tryptamine derivative 154. After considerable research, optimal conditions for this transformation (triethylsilane in DCM/TFA)87 were found that were successful on up to 15.7 kg scale, enabling clean separation of the aldehyde reduction byproduct following crystallization.86 Conversion of the phthalimide within 154 to the corresponding amine using aqueous methylamine at room temperature was accompanied by an intramolecular cyclization reaction to secure the intermediate lactam as a solid in 89% isolated yield. This was followed by a high-yielding bromination reaction (83%) at the indole C-2 position employing pyridinium tribromide, providing access to indoloazepinone 155. After screening various catalysts for the coupling of bromide 155 and commercial boronic acid 156, Pd(dppf)Cl2· DCM was found to reliably deliver the desired coupling product with reasonable rates of reaction. Thus, after development of an extensively optimized reaction protocol,86 Suzuki coupling of 155 and 4-formylphenylboronic acid (156) with Pd(dppf)Cl2·DCM and Na2CO3 in DMA at 90 °C generated the desired 2-arylated indole 157 in high yield (92%) after trituration and reslurry with methanol. Conversion of aldehyde 157 to amine 158 necessitated a two-pot procedure designed to limit the formation of dimerization and aldehyde reduction products that generally arise under conventional onepot reductive amination conditions and have traditionally been problematic on scale. Toward this end, subjection of aldehyde 157 to a methylamine solution in EtOH/MeOH/THF and wash of the resulting reaction solids with methanol led to efficient isolation of pure imine intermediate, which could be immediately reduced with NaBH4 in THF/MeOH, providing hydrochloride salt 158 upon acidic workup in 76% over two

146 in 65−70% yield. This reaction generated over 3 kg of the desired alkyl azide after recrystallization from ethanol and water. Lastly, palladium-catalyzed hydrogenolysis in the presence of sodium methoxide, a methanolic acidification step, and then a subsequent acidification step using HCl in THF furnished migalastat hydrochloride (XV) in 70−75% yield over the three-step sequence from 146.

7. ONCOLOGY DRUGS 7.1. Olmutinib (Olita). Olmutinib, codeveloped by Boehringer Ingelheim and Hanmi Pharmaceutical Co., was approved by the Korean Ministry of Food and Drug Safety (MFDS) for treatment of locally advanced or metastatic EGFR T790 M mutation-positive non-small cell lung cancer (NSCLC).72 Olmutinib serves as a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), which is being used as an oral therapy for patients who have previously been treated with an alternate EGFR TKI.72a Firstand second-generation EGFR TKIs, which bind reversibly and irreversibly to the TK domain, respectively, are both generally effective at onset of treatment but result in development of resistance within the first year of treatment.72b,73 Thirdgeneration EGFR TKIs such as olmutinib have demonstrated the ability to covalently bind to the kinase domain of EGFR while sparing wild-type EGFR, leading to irreversible inhibition of both EGFR mutations and the T790 M mutation, which is linked to EGFR TKI resistance.72b,74 Synthetically, olmutinib can be accessed in two steps beginning with 2,4-dichloro-thieno[3,2-d]pyrimidine (147, Scheme 28), which is commercially available and can be Scheme 28. Synthesis of Olmutinib (XVI)

prepared in two steps from urea and 3-aminothiophene 2carboxylate.75 Nucleophilic addition of N-(3-hydroxyphenyl)-2propenamide (148) to 147 proceeded with complete regioselectivity via treatment with K2CO3 in warm DMSO, smoothly providing the desired diaryl ether 149 in 87% yield after crystallization from isopropanol and water.75b,76 From 149, substitution with commercially available piperazinyl aniline 150 under acidic heating conditions (DMA, IPA, TFA, 90 °C) provided olmutinib in 82% yield. After recrystallization, olmutinib (XVI) was obtained in 60% overall yield and 99.1% purity.76 7022



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Scheme 29. Synthesis of Rucaparib Camsylate (XVII)

Scheme 30. Synthesis of Azaindole Fragment 162 for Venetoclax

and halted due to undesired inhibition of BCL-XL, leading to significant thrombocytopenia and demonstrating the need for more selective inhibitors.89b Venetoclax is also currently being considered for approval in Europe and Canada for similar indications and is in various stages of development for the treatment of non-Hodgkin lymphomas (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), and several other disorders, either as a combination therapy or a stand-alone treatment.89a The manufacturing route to venetoclax takes place by coupling of three key structural subunits: azaindole 162, sulfonamide 165, and piperazine 172.91 The first of these subunits was generated in two steps from commercially available 4-bromo-2-fluoro-1-iodo-benzene (159, Scheme 30). Grignard formation of iodide 159 (i-PrMgCl) followed by quenching with Boc2O provided the desired tert-butyl ester 160 without the need for chromatographic purification. Aromatic substitution of crude 160 with azaindole 161 provided access to 162 in 86% yield after recrystallization from EtOAc/heptane.

steps. The two remaining steps for conversion to the drug involve a salt-swap, first breaking the HCl salt with NaOH in MeOH, then treatment with (S)-camphorsulfonic acid/IPA/ H2O at 70 °C. Filtration and washing of the cake with water generated rucaparib camsylate (XVII) in 95% yield.86 7.3. Venetoclax (Venclexta). Venetoclax, codeveloped by AbbVie (previously Abbott Laboratories) and Genentech/ Roche, was approved in the US for treatment of patients with chronic lymphocytic leukemia (CLL). To meet qualifications for venetoclax treatment, patients must have received prior therapy and possess the 17p deletion genetic mutation, as determined by USFDA testing.88 Venetoclax functions as a selective inhibitor of B cell lymphoma subtype 2 (BCL-2), which is often overexpressed on malignant cells and thus leads to impairment of the apoptotic pathway.89 Along these lines, the orally dosed small molecule drug restores the ability of malignant cells to undergo apoptosis as its mechanism of action.90 Although other BCL-2 inhibitors are known, development of similar agents such as navitoclox have been pursued 7023



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Separately, as shown in Scheme 31, sulfonamide 165 was formed in 91% yield and 99.9% purity via aromatic substitution of commercially available 163 with amine 164 at 80 °C (DIPEA, MeCN).91a

yielding venetoclax (XVIII) in free base form91,92 in 71% over the two final steps.90,91 This synthetic route was capable of fashioning the drug target in 52% overall yield based on the longest linear sequence (7 steps).91b

Scheme 31. Synthesis of Sulfonamide Fragment 165 for Venetoclax

8. OPHTHALMOLOGIC DRUGS 8.1. Lifitegrast (Xiidra). Lifitegrast, initially designed and developed by SARcode Bioscience (which was acquired by Shire in 2013),93a is a novel tetrahydroisoquinoline derivative that is marketed as a 5% ophthalmic solution.93 The drug was approved by the USFDA for the treatment of dry eye disease.93a As a small molecule integrin antagonist, lifitegrast reduces inflammation through binding inhibition of the proteins lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), influencing T-cell activation and cytokine (protein) release. Lifitegrast represents the first LFA-1/ICAM-1 interaction inhibitor approved globally, making it a first-in-class therapy for the treatment of dry eye disease by this mechanism.93−95 The most likely synthetic approach capable of delivering lifitegrast on scale is described in Scheme 34 beginning with commercial 3-bromo-L-phenylalanine (174) as the starting material.96 After Boc protection, reaction with sodium methanesulfinate in the presence of copper iodide, K2CO3, and L-proline gave rise to sulfonate 176. Esterification of 176 with benzyl alcohol followed by removal of the Boc group within 177 yielded the corresponding HCl salt of the aminoester 178. Amide bond coupling with acid 179 (prepared as shown in Scheme 35) furnished amide 180, which was then subjected to 4 N HCl in dioxane resulting in trityl removal and arrival at HCl salt 181 in 88% yield over two steps. Tetrahydroisoquinoline 181 was then coupled with commercial benzofuranyl acid 182 to give rise to lifitegrast benzyl ester in 90% yield. Finally, saponification delivered lifitegrast (XIX) in 88% yield.96c Tetrahydroisoquinoline-6-carboxylic acid 179 was prepared starting from commercial 3,5-dichlorobenzaldehyde 183 (Scheme 35). Reductive amination with 1-chloro-2-aminoethane 184 gave chloroethyl amine 185, which underwent an efficient intramolecular Friedel−Crafts reaction using AlCl3 to generate the corresponding tetrahydroisoquinoline 186 in 91% yield. N-Tritylation of 186 proceeded in 89% yield, and this was

Synthesis of the third venetoclax subunit, piperazine amine hydrochloride salt 172, began with commercial cyclohexanone 166 (Scheme 32).91a Vilsmeier−Haack formylation of the sterically more accessible enol tautomer of 166 delivered vinyl chloride 167 in quantitative yield. Coupling of this chloride with commercial aryl boronate 168 gave rise to transient enal 169 in 87% assay yield, which was not isolated. Crude 169 was then carried into a reductive amination reaction with commercial N-Boc piperazine (170). Precipitation and recrystallization from acetonitrile ultimately furnished piperazinyl alkene 171 in 74% yield from 167. Finally, subunit 172 was obtained via Boc removal with concentrated HCl in IPA at 65 °C and subsequent filtration, conditions that provided a 95% yield of high purity intermediate 172 (>99.5%).91a The final approach to venetoclax involved a palladiumcatalyzed coupling of amine 172 with aryl bromide 162, ester hydrolysis, and coupling of the resulting carboxylic acid with sulfonamide 165 (Scheme 33).91 In practice, Buchwald− Hartwig amination of 162 with 172 proceeded smoothly and relied upon workup with cysteine to enable cleansing of residual palladium from the reaction mixture. This reaction gave rise to advanced intermediate 173 in 89% yield after crystallization from cyclohexane. Treatment of 173 with tBuOK/H2O/2-MeTHF at 55 °C provided the corresponding free acid, which was immediately activated with EDC/DMAP/ Et3N to promote coupling with sulfonamide 165 at room temperature. The final drug target could be accessed by crystallization from EtOAc and washing with 1:1 DCM/EtOAc,

Scheme 32. Synthesis of Piperazine Hydrochloride Amine Fragment 172 for Venetoclax

7024



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Scheme 33. Synthesis of Venetoclax (XVIII)

Scheme 34. Synthesis of Lifitegrast (XIX)

7025



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Scheme 35. Synthesis of Tetrahydroisoquinoline-6-carboxylic Acid Fragment 179 for Lifitegrast

and information service in the pharmaceutical R&D field. In 2010− 2013, Hongxia joined Shenogen Pharma Group, a China-based Biotech company. As senior director of the R&D department, Hongxia is responsible for the CMC development of a novel ERα36 targeted phase II candidates drug named Icaritin (SNG162) and the discovery and development of second-generation small molecules based on the structure optimization of SNG162. Before Shenogen, Hongxia worked at BioDuro since 2006 as senior group leader and senior research scientist.

followed by a directed o-metalation reaction and carbon dioxide quench to furnish the requisite acid 179 in 75% yield.

9. CONCLUSIONS In summary, the pharmaceutical industry collectively enjoyed a productive 2016, a year that saw the introduction of these 19 new and important small molecule medicines to the marketplace. Innovative synthetic chemistry, particularly new methods for bond construction and the assembly of complex molecular architectures that can be effectively applied not only in the discovery setting but on process scale as well, will continue to permit access to challenging and/or novel chemical space. As the discipline continues to advance, the discovery of new synthetic methodologies and expansion of the limits of known bond-making technologies to new substrates through deeper mechanistic understanding will play an increasingly important role in the discovery and development of new medicines. This review continues to highlight the application of such technology and innovation toward the production of important treatments for disease and will hopefully provide inspiration to researchers worldwide in the continued discovery of new drugs.

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Carolyn Leverett began her career at Pfizer in 2012, focusing on the development of microtubule inhibitor-based payloads for use as antibody−drug conjugates. She currently works in the Applied Synthesis Technologies group, where she is involved in the discovery of biocatalytic routes to support various chemistry therapeutic areas. Carolyn is a native of North Carolina and obtained her B.S. in chemistry from North Carolina State University. She completed her doctoral studies with Professor Albert Padwa at Emory University in Atlanta, GA working on total synthesis of several piperidine-based natural products and the alkaloid minfiensine. Prior to joining Pfizer, she was a postdoctoral fellow working with Professor Daniel Romo at Texas A&M University exploring new applications of nucleophilecatalyzed aldol lactonization reactions.

AUTHOR INFORMATION

Sarah Fink is a Senior Manager for Integrated Programs at BioDuro and is based in the Boston area. She obtained a B.A. in Chemistry and English literature from Williams College followed by a Ph.D. in Organic Chemistry from the University of Cambridge with Professor Ian Paterson. Her thesis work focused on the total synthesis of aplyronine C. After a fellowship for young international scientists at Shanghai Institute of Materia Medica, Sarah joined BioDuro in Shanghai in 2014, where she was a scientist and chemistry group leader for integrated drug discovery projects in multiple therapeutic areas. She relocated to Boston in early 2017; in her current role, she provides medicinal chemistry and scientific project management support for collaborations with pharma and biotech.

Corresponding Author

*Phone: 860-303-1138. E-mail: [email protected]. ORCID

Christopher J. O’Donnell: 0000-0003-1004-7139 Notes

The authors declare no competing financial interest. Biographies Andrew C. Flick earned a B.A. in Chemistry from Lake Forest College and then joined Abbott Laboratories’ Diagnostics Group in Abbott Park, Illinois. He then moved to Array BioPharma in Longmont as a Research Associate in their Process Chemistry Group. In 2003, he joined Professor Albert Padwa’s laboratory at Emory University where he successfully demonstrated a Michael addition-nitrone dipolar cycloaddition approach for the total synthesis of the marine natural alkaloid cylindricine C. After obtaining his Ph.D. in 2008, he joined the Medicine Design group at Pfizer in Groton, CT where he has been involved in numerous discovery projects within the Neurosciences, Rare Diseases, and Inflammation & Immunology therapeutic areas. Andy has authored over 30 peer-reviewed publications and patents.

Christopher J. O’Donnell obtained a B.S. in Chemistry from the University of Illinois in Urbana/Champaign and a Ph.D. in Organic Chemistry from the University of Wisconsin, Madison. After postdoctoral research at the University of California-Irvine, he joined the Neuroscience Medicinal Chemistry group at Pfizer. As a scientist, project leader, and manager, he has led teams to the nomination of over 10 clinical candidates and he is the inventor of the Phase 2 AMPA PAM PF-04958242 for schizophrenia. Chris moved to the Oncology Medicinal Chemistry group to build the Antibody Drug Conjugate chemistry group, and his team nominated 14 conjugates for clinical development. In 2017, Chris built the Applied Synthesis Technology group at Pfizer. Chris is an author/inventor of 70 peer-reviewed journal articles and patents.

Hongxia (Sheryl) Ding obtained a B.S. in Pharmaceutics in 2001 and a Ph.D. in Medicinal Chemistry in 2006 from Zhejiang University in Hangzhou, China. Hongxia is the cofounder and Chief Executive Officer of PHARMACODIA, a company founded in 2013, which is an online platform (http://www.pharmacodia.com) providing big data 7026



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ACKNOWLEDGMENTS The authors thank Dr. Matthew Perry for helpful and insightful discussions regarding crisaborole. The authors also thank Dr. Emma McIntuff and Dr. John Ragan for helpful discussions and suggestions.

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ABBREVIATIONS USED Ac, acetyl; Ad, adamantyl; aq, aqueous; Bn, benzyl; Boc, N-tertbutoxycarbonyl; Bu, n-Bu, butyl, n-butyl; cat, catalytic; Cbz, benzyloxycarbonyl; CDI, N,N′-carbonyldiimidazole; CDMT, 2chloro-4,6-dimethoxy-1,3,5-triazine; CPME, cyclopentyl methyl ether; CSA, camphorsulfonic Acid; Cy, cyclohexyl; dba, dibenzylideneacetone; DBU, 1,8-diazabicyclo[5.4.0]undec-7ene; DCC, 1,3-dicyclohexylcarbodiimide; DCE, dichloroethane; DCM, dichloromethane; DDQ, 2,3-dichloro-5,6dicyano-1,4-benzoquinone; DIPEA, diisopropylethylamine; DMA, dimethylacetamide; DMAP, 4-dimethylaminopyridine; DME, 1,2-dimethoxyethane; DMF, N,N-dimethylformamide; DMF-DMA, dimethylformamide−dimethylacetal; DMPU, 1,3dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; DMSO, dimethyl sulfoxide; DPPA, diphenyl phosphoryl azide; dppf, 1,1′-ferrocenediyl-bis(diphenylphosphine); dr, diastereomeric ratio; EDC, N-(3-dimethylaminopropal)-N-ethylcarbodiimide; EDTA, ethylenediaminetetraacetic acid; ee, enantiomeric excess; Et, ethyl; EtOAc, ethyl acetate; HATU, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-Nmethyl methanaminium hexafluorophosphate N-oxide; Hex, nHex, hexyl; HMDS, hexamethyldisilazane; HOBt, 1-hydroxybenzotriazole hydrate; HWE, Horner−Wadsworth−Emmons; i-Pr, isopropyl; IPA, isopropyl alcohol; IPAc, isopropyl acetate; LAH, lithium aluminum hydride; LDA, lithium diisopropylamide; Me, methyl; MeCN, acetonitrile; MEK, methyl ethyl ketone; Moc, methoxycarbonyl; Ms, methylsulfonyl, mesyl; MTBE, methyl tert-butyl ether; NBS, N-bromosuccinimide; NMM, N-methyl morpholine; NMP, N-methyl-2-pyrrolidone; Ph, phenyl; Pin, pinacolato; Piv, pivaloyl; p-TsOH, ptoluenesulfonic acid; Py, pyridine; rac, racemic; rt, room temperature; TBAB, tert-butyl ammonium bromide; TBAF, tetrabutylammonium fluoride; TBAH, tetrabutylammonium hydroxide; TBAI, tetrabutylammonium iodide; TBTU, O(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate; t-Bu, tert-butyl; TEA, triethylamine; TES, triethylsilane; TEMPO, 2,2,6,6-tetramethylpiperidine 1-oxyl; Tf, triflic, trifluoromethanesulfonyl; TFA, trifluoroacetic acid; TFAA, trifluoroacetic acid anhydride; THF, tetrahydrofuran; THP, tetrahydropyranyl; TMEDA, N,N,N′,N′-tetramethylethylenediamine; TMS, trimethylsilyl; tol, toluene; Tr, trityl, triphenylmethyl; Ts, p-toluenesulfonyl; UHP, urea hydrogen peroxide

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