Synthetic Approaches To The New Drugs 2016

Uponadministration 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 replicati

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 *, †

†Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, Connecticut 06340, UnitedStates

‡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

process-scale synthetic approaches to 19 new chemical entities that

were approved for thefirst time in 2016

1 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

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

process-scale synthetic approaches to the 19 small molecule new

chemical entities (NCEs) that were approved for thefirst 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

oph-thalmology 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)

2 ANTI-INFECTIVE DRUGS2.1 Beclabuvir (Ximency) Beclabuvir is a non-nucleoside,nonstructural protein 5B (NS5B) polymerase inhibitorapproved in Japan as part of afixed-dose combination productfor the treatment of hepatitis C virus (HCV) Uponadministration 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.4Beclabuvir is combined with asunaprevir and declatasvir (bothapproved in 2014) and was discovered and developed byBristol-Myers Squibb.4

The syntheses of asunaprevir and declatasvir were described

in an earlier review article.2mThe synthesis to produce 10−100

g of beclabuvir is described in Scheme 1.5 Condensation ofindole-6-carboxylic acid (1) with cyclohexanone under basicconditions gave acid 2 in quantitative yield Hydrogenation ofthe double bond in 2 using Pearlman’s catalyst was followed byesterification to give ester 3 in high yield.6

Bromination of theindole at the 2-position was accomplished with pyridiniumtribromide, and this was followed by saponification to provideacid 4 Treatment of 4 with carbonyldiimidazole (CDI)

f o l l o w e d b y N , N d i m e t h y l s u l f a m i d e a n d 1 , 8 diazabicyclo[5.4.0]undec-7-ene (DBU) gave compound 5 in74% yield Suzuki coupling of 5 with commercial boronic acid 6provided intermediate 7, which converted to hemiaminal 8upon continued heating in 61% yield Compound 8 was thentreated with methyl 2-(dimethoxyphosphoryl)acrylate (9) to

-affect a tandem conjugate addition and Horner−Wadsworth−Emmons (HWE) olefination to give ester 10 Alternatively, theSuzuki coupling reaction of 5 with 6 could be stopped atintermediate 7, which could be treated with 9 to promote the

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%

enantio-meric 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

medication In clinical trials, the two drugs were coadministered

as separate tablets and administered as a fixed-dosecombination tablet with the primary end point being thesustained virological response rate 12 weeks post-treatment(SVR12); patients exhibited a 95% SVR12rate overall.7Elbasvirinhibits HCV NS5A, which is necessary for viral RNAreplication and virion assembly.7 Grazoprevir inhibits HCVNS3/4A protease, which is essential for the proteolytic cleavage

of the HCV encoded polyprotein and viral replication.7For thepurpose of this review, the synthesis of elbasvir and grazoprevirfor HCV treatment will be discussed separately

Elbasvir possesses a particularly interesting moleculararchitecture consisting of two identical N-Moc-valine-linked

Figure 1 Structures of 19 NCEs approved in 2016.

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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

trans-position 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

steric hindrance to favor ketone formation at the position para

to the bromide substituent Ketone 16 was subsequentlyconverted to the corresponding imine 17 upon condensationwith ammonia in methanol At this point, the stage was set for acritical stereochemical relay strategy for the construction of thehemiaminal geometry within elbasvir This chirality-establishingsequence ultimately began with an asymmetric reduction ofimine 17 in which ruthenium-catalyzed transfer hydrogenationconditions utilizing a metal−ligand complex, originallydescribed by Wills,9 delivered branched amine 18 in excellentyield and enantioselectivity This was followed by an intra-molecular copper-mediated amination reaction to furnishindoline 19 This indoline, which possessed a stereogeniccenter unlikely to epimerize under strongly acidic conditions,was treated with benzaldehyde in warm TFA and acetonitrile toScheme 1 Synthesis of Beclabuvir (I)

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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

borane (Scheme 3), and this reaction was followed by a coupling with pyrrolidino bromoimidazole 21 (whose prepara-tion is described in Scheme 4) Salt formation with p-nitrobenzoic acid furnished azacycle 22 in 82% overall yield

cross-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

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from 20 Coincidentally, this two-step sequence also resulted in

oxidation of the indoline ring, establishing the 2,3-indolyl

π-bond 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.10Interestingly,

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,bHowever, 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 inSchemes 5−8.11

The synthesis of chloroquinoxaline 29 started with the mediated condensation of 4-methoxy-1,2-benzenediaminedihydrochloride salt (27) with oxalic acid followed by bis-chlorination to provide the corresponding dichloroquinoxaline

DMA) in the presence of commercially available line 28, chloroquinoxaline 29 was isolated in 68% yield Thisthree-step reaction sequence delivered the product with 95:5selectivity for the desired regioisomer, which could be furtherpurified by recrystallizing from MTBE/heptanes

hydroxypro-The cyclopropanol ent-32 was prepared using a strategy thatrelied on enzymatic resolution (Scheme 6).11b A diastereose-lective cyclopropanation of a vinyl boronate resembling 30 wasattempted, but low yields and difficult purification promptedthe authors to consider a racemic cyclopropanation On 34.3 kgscale, commercially available vinyl boronate 30 was subjected totrifluoroacetic acid-modified cyclopropanation conditions de-veloped by Shi and co-workers (ICH2ZnO2CCF3), which gavehigher conversion and a cleaner impurity profile than those ofclassic Simmons−Smith conditions (Zn(CH2I)2).12 Theproduct was isolated as a solution in heptane (96% yield)and treated directly with 10 M sodium hydroxide and aqueoushydrogen peroxide to provide racemic cyclopropanol rac-31,which was carried forward crude as a solution in MTBE Directdisplacement of the chloride with lithium acetylide-ethylenediamine complex was optimized to generate terminal alkynerac-32 Safety considerations surrounding the use of lithiumacetylide-ethylene diamine on scale were closely examined due

to the risk of uncontrolled release of acetylene gas Tominimize acetylene gas evolution, pretreatment of rac-31 with1.2 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

rac-32 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

Scheme 5 Synthesis of Chloroquinoxaline Fragment 29 for Grazoprevir

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

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key substrate for the enzymatic hydrolysis step Optimized

conditions employed Novozyme 435 in MTBE with 0.1 M

aqueous potassium phosphate dibasic Whereas all previous

steps could be carried through without isolation or purification,

chromatography was required to isolate ent-32 (desired) from

ent-33and all other impurities generated through thefive-step

process At 40% conversion, ent-32 could be isolated in 96% ee

and 19% overall yield from 30 An alternate gram-scale

synthesis of this fragment has recently been reported by

researchers at Merck using a route that avoids the use of lithium

acetylide and enzymatic resolution.11c

With chloroquinaxoline 29 and cyclopropanol ent-32 in

hand, assembly of the macrocycle commenced (Scheme 7).11a,d

Ent-32 was reacted with CDI and DIPEA followed by slow

addition ofL-tert-leucine (34) to give carbamate 35, which was

isolated as a solution in cyclopentyl methyl ether (CPME) and

used without further purification After extensive optimization,the Sonogashira cross-coupling product of alkyne 35 andchloroquinoxaline 29 was isolated in 98% HPLC purityfollowing aqueous workup and carried forward withoutpurification The resulting alkyne was subjected to catalytichydrogenation conditions to furnish the macrocyclizationprecursor 36, which was also not isolated Phenylsulfonicacid-mediated Boc removal followed by direct addition ofexcess DIPEA and slow addition of the mixture to a solution ofHATU in acetonitrile resulted in intramolecular lactamformation with minimal dimerization byproducts (<2%).Macrocycle 37 was the first crystalline intermediate to beisolated in this sequence and was obtained in 65% yield inanalytically pure form Careful saponification utilizing LiOHwas followed by amidation with amine 38 (the synthesis ofwhich is described inScheme 8) under conditions designed tominimize proline carboxylate epimerization (EDC, pyridine,MeCN) to give grazoprevir Grazoprevir hydrate (III) was thengenerated by recrystallization from acetone and water at 50°C,and the last three steps were completed in 44% overall yield.Aminovinylcyclopropane 38 was generated in one step fromthe commercially available Boc-protected derivative (39,

same stereogenic vinyl cyclopropane subunit has beenincorporated into a number of other recently approved antiviraldrugs A description of its synthesis, originally developed by

Scheme 7 Synthesis of Grazoprevir Hydrate (III)

Scheme 8 Synthesis of Aminovinylcyclopropane Fragment

38 for Grazoprevir

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researchers at Bristol-Myers Squibb (BMS), has been

summarized in our previous review for the synthesis of

asunaprevir.2m

2.3 Narlaprevir (Arlansa) Narlaprevir was approved as a

treatment for genotype 1 HCV and serves as a class 2 HCV

NS3 serine protease inhibitor In clinical trials, it showed a

rapid and steady decline in HCV-RNA levels in both previously

treated and treatment-naı̈ve patients when used in combination

with ritonavir and PEG-IFN-α.14

This combination ultimatelyled to ≥50% of patients with undetectable HCV-RNA levels

after a second period of treatment.14 Narlaprevir also has

demonstrated activity against HCV mutations resistant to other

treatments such as boceprevir and telaprevir.15 The unique

activity of this drug can be attributed to a critical electrophilic

α-keto-amide “warhead”, which covalently reacts with an HCV

NS3 protease active-site serine residue involved in the HCV

viral replication process.15,16Because of their essential roles in

viral replication, HCV NS3 and NS5B proteases have recently

become key targets for HCV drug development.16Strategically,

the development of narlaprevir stems specifically from the

pursuit of a single-diastereomer, second generation HCV

protease inhibitor, which would provide in vitro potency and

pharmacokinetic profile improvements over the structurally

related antiviral drug boceprevir,2jwhich exists as a mixture of

diastereomers.16,17 After the R-Pharm pharmaceutical group

obtained the license to manufacture narlaprevir from Merck in

2012, further development of the drug was realized through

collaborations with Schering-Plough and Texas Liver

Insti-tute.18

A kilogram-scale synthetic route to narlaprevir has beenreported and proceeds strategically through the union of urea

45, bicyclic amine intermediate 46, and amine salt 48 (Schemes

9 and 10).19 Preparation of urea 45 begins with commercialcyclohexanecarboxylic acid methyl ester (40), which wastreated with freshly prepared LDA and TMSCl in THF toprovide silyl enol ether 41 (Scheme 9) This intermediate wasimmediately reacted with commercial 2-[(chloromethyl)thio]-2-methylpropane (42) under Lewis acid conditions (ZnBr2) toprovide ester 43 in 58% yield over the two-step process.17,19Asolution of crude 43 was subjected to saponification conditions(NaOH, H2O, MeOH) and sulfide oxidation with oxone inDCM/MeOH, leading to the target sulfone 44 in 65% yield.From 44, a Curtius rearrangement delivered an isocyanateintermediate that could be trapped withL-tert-leucine, formingthe desired urea 45 in 53% over the two-step sequence.17,19Coupling 45 with commercially available bicyclic amine 46under peptide coupling conditions (EDC, HOBt, NMM) led tothe desired amide in 79% yield, which was then saponified withaqueous NaOH in 2-methyltetrahydrofuran (2-MeTHF) toprovide acid intermediate 47 (84% yield) This intermediatewas coupled with amine salt 48 (synthesis of 48 is described in

intermediate to narlaprevir Completion of the synthesis reliedupon installation of the essential α-keto-amide functionality,which was accomplished by α-hydroxy amide oxidation usingTEMPO-catalyzed conditions A final recrystallization fromacetone/water completed synthesis of narlaprevir (IV) in 83%yield.19aIt is worth noting that this overall route was used toScheme 9 Synthesis of Narlaprevir (IV)

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generate >1 kg of narlaprevir and required no chromatographic

separation steps.16,17,19

Amine salt 48 was prepared byfirst subjecting commercially

available pentanal (49) to Knoevenagel condensation

con-ditions 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

α-methyl-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.20tert-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 theβ-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

quino-lone-resistant MRSA as well as quinoquino-lone-resistant Streptococcus

pneumonia.21The drug was originally discovered by Procter &

Gamble Pharmaceuticals (P&GP).22 It was codeveloped by

TaiGen Biotechnology for development in Asia and by WarnerChilcott for development in the United States and Europe andwasfirst approved by the China Food and Drug Administration(CFDA).22,23

Although several synthetic approaches to marketed lone antibiotics similar in structure to nemonoxacin have beenreported,23 two dedicated synthetic routes to nemonoxacinhave been reported.24The route depicted inScheme 11, whichhas been disclosed by workers at Warner Chilcott, not onlydescribes a process route to the pharmaceutically activeingredient but also describes the preparation and examination

quino-of several salt forms under consideration for intravenous and/ororal dosing approaches.24d Condensation of commercial 2,4-difluoroacetophenone (57) with ethylene glycol furnished ketal

58 in 86% yield This was followed by fluorine-directed lithiation with n-butyllithium and trimethylborate quench.Acidification followed by oxidation of the boron speciesrendered hydroxyketone 59 in 79% yield from 58 Next,phenol methylation with dimethyl sulfate followed bydeprotonation and reaction with diethyl carbonate (60) gaverise to the keto-ester intermediate, which underwent con-densation with dimethylformamide-dimethylacetal (DMF-DMA) in refluxing toluene to provide the correspondingvinylogous amide 61 An addition−elimination reaction withcyclopropylamine (55) and subjection of this intermediate toacetimidate 62 in refluxing toluene presumably facilitatedalkene isomerization with concomitant cyclization to producethe quinolinone derivative 63 in 82% yield over five steps.Acidic hydrolysis followed by treatment with diboron trioxideand acetic anhydride generated triacetoxyborate 64, whichserved as a unique protecting group for the next step of theScheme 10 Synthesis of Cyclohexane Amino Fragment 48 for Narlaprevir

o-7011

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

base-mediated 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

to the corresponding ester 68 in 52% yield prior to treatmentwith Bredereck’s reagent to give enamine 69 (Scheme 12).Next, catalytic hydrogenation of 69 using a Pfaudler reactor and5% Pd/C converted the vinylogous amide to the correspondingmethyl group, delivering 70 in nearly quantitative yield and93:7 diastereomeric excess in favor of the desired geometry.Further reduction of 70 using NaBH4 followed by treatmentwith calcium chloride dihydrate gave the corresponding diol 71

Scheme 11 Synthesis of Nemonoxacin (V)

Scheme 12 Synthesis of Aminopiperidine Fragment 65 for Nemonoxacin

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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

replaced by potassium bases with increased yields on 100 g

scale.27 Alkylation of 74 with diethyl

p-toluenesulfonyloxyme-thylphosphonate (75) gave intermediate 76, which was not

isolated Hydrolysis of the phosphonate esters with silyl bromide followed by recrystallization from water gavephosphonic acid 77 in 50% yield Interestingly, replacingMg(Ot-Bu)2with PhMgCl/t-BuOH led to improved yields forthe alkylation step (74→ 76) on a 100 g scale.27

trimethyl-Additionally,the authors note that conditions for hydrolyzing thephosphonate ester can be modified using HCl or HBr forimproved 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 higheryield on smaller scale by changing the solvent to cyclo-pentylmethyl ether.28Monophosphonate ester 78 was treatedwith thionyl chloride followed byL-alanine isopropyl ester (79)and triethylamine to give tenofovir alafenamide rac-80 as amixture of phosphonate diastereomers in 47% yield Thediastereomers were separated using simulated moving bedchromatography29to give the desired diastereomer ent-80 in47% yield and 99% diastereomeric purity The diastereomerscould also be separated using a crystallization-induced dynamicresolution 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, velpa-tasvir was approved in the US, Europe, and Canada as a once-Scheme 13 Synthesis of Tenofovir Alafenamide Fumarate (VI)

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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

func-tions 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,32ademonstrating 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

authored by scientists at Gilead; this patent also describesseveral alternative routes to the drug’s key building blocks.36

It

is important to note that no yields are reported throughout thepatent, and only the route to pyrrolidine 91 was exemplified onmultikilogram scale.36,37 Synthesis of the central tetracyclicintermediate in the velpatasvir synthesis, tetralone 86, beganwith commercial 2-bromo-5-iodo-benzenemethanol (81),which underwent iodide-metal exchange and subsequentquenching with acetamide 82 (Scheme 14).36 Mesylation ofthe resulting alcohol followed by treatment with LiBr furnishedbenzyl bromide 83, which was then subjected to nucleophilicattack by commercial 7-hydroxytetralone (84) in the presence

of K2CO3/MeCN to provide ether 85 An innovative use of anintramolecular Pd-mediated C−H activation reaction catalyzed

by Pd(OAc)2/PPh3secured the central tetracyclic core, whichthen underwent bis-α-keto-bromination with pyridiniumtribromide in MeOH/DCM at room temperature to furnishtetralone 86.36

The preparation of the ethereal pyrrolidine subunit 91 beganwith formylation of commercial glutamate 87 followed by anintramolecular cyclocondensation reaction facilitated by TFA tosecure dihydropyrrole 88 (Scheme 15).36It should be notedthat although TFA was used to affect the formation of enamine

88, the reported route indicates no loss of Boc or t-Bu ester

Scheme 14 Synthesis of Tetralone Fragment 86 for Velpatasvir

Scheme 15 Preparation of Velpatasvir Ethereal Pyrrolidine 91

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protecting groups in this transformation, and no further

discussion was provided by the authors.36,37Reduction 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 roomtemperature HCl in methanol generated the free amino acid,which was immediately subjected to mono reprotection withBoc anhydride to allow isolation of the Boc-protected amino

Scheme 16 Synthesis of Methyl Pyrrolidine Fragment 96 for Velpatasvir

Scheme 17 Synthesis of Velpatasvir (VII)

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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-pyrrolidinone 92 to ketone 93 followed by a one-pot

Boc-deprotection/ring-closing reductive amination sequence

addition from the face opposite the ethyl ester,37leading 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).36Alkylation of dibromide 86first with

acid 91 and second with acid 96 resulted in the transient

bis-ketoester intermediate 97, which was converted to bis-imidazole

98 using ammonium acetate followed by DDQ oxidation

Finally, introduction of fragment 99 relied upon

Boc-deprotection with HCl/MeOH and subsequent neutralization

of the resulting HCl salt to enable crystallization as the

triphosphate salt A second neutralizing step (aq NH4OH) andCDMT/NMM-mediated coupling of the free amine withcommercially available phenylacetic acid derivative 99 providedvelpatasvir (VII).36

2.7 Zabofloxacin D-Aspartate (Zabolante) acin is a quinolone antibiotic originally developed by DongWha Pharmaceuticals and licensed to Pacific Beach Biosciences

Zaboflox-in 2007.38In March 2015, Korea’s Ministry of Food and DrugSafety (MFDS) approved zabofloxacin for the treatment ofacute bacterial exacerbation of chronic obstructive pulmonarydisease (ABE-COPD).39In 2016, zabofloxacin gained approvalfrom the USFDA for the treatment of community-acquiredpneumonia ABE-COPD is caused by respiratory tract andpulmonary parenchyma that cause chronic pulmonary inflam-mation and obstruction in the respiratory tract, which leads toirreversible damage In the nonclinical evaluation process,zabofloxacin showed strong antibiotic activity on respiratorygerms (e.g., Streptococcus pneumonia, S Haemophilus, S.moraxella) and was the most potent antibacterial agent againstpenicillin-resistant S pneumoniae (PRSP) in the murinesystemic infection model.40

The synthesis of zabofloxacin leverages the wide commercialavailability of chloronaphthyridinone acid 106 to essentiallyreduce the task to the construction of functionalizeddiazaspirocyclic pyrrolidine 105 (Scheme 18).41 As described

in a series of patents from researchers at Dong Wha who haveScheme 18 Synthesis of ZabofloxacinD-Aspartate (VIII)

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exemplified the synthesis on multikilogram scale, the route

began withfirst 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 toD-aspartate in warm

ethanol furnished zabofloxacinD-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.42Brivaracetam 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

penetration, and faster onset of action against seizures thanlevetiracetam.43,44

Regarding the large-scale synthetic approach to brivaracetam,stereocontrolled installation of the 4-n-propyl group stands asthe central challenge in the assembly of the molecule Severalroutes have been published that require chiral separation.44,45Two enantioselective routes have been reported, one employ-ing an enzymatic resolution46 and the other utilizing (R)-(−)-epichlorohydrin as a chiral starting material.47

The routedetailed inScheme 19, which involves an enzymatic resolution,

is the only kilogram-scale route disclosed in the literature todate and reportedly permits the production of brivaracetamwithin the required commercial quality specifications However,the authors note that the development of this route forcommercial purposes has been stopped.46 Commercialdimethyl n-propylmalonate 108 was first alkylated with tert-butyl-2-bromoacetate The resulting product underwentKrapcho decarboxylation to afford racemic succinate derivative

109in 94% yield over the two steps.46Optimized conditionsfor the key enzymatic resolution employed protease C fromBacillus subtilis type 2 at 30°C for 18 h to resolve ester 109 andprovide the acid enantiomer 110 This biocatalytic processallowed for residual unreacted diester 109 to be washed awaywith cyclohexane at pH 9 (adjusted with 0.5 M NaOH), andthe 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 111proceeded in nearly quantitative yield by a three-step sequence:activation of the acid with ethyl chloroformate, reduction to thealcohol with sodium borohydride, and cyclization upon acidicworkup with TFA Exposure of 111 to HBr in acetic acidfollowed by esterification of the resulting acid-generatedbromoester 112 Finally, TBAI-catalyzed alkylation of 112with commercial (S)-2-aminobutanamide (113) in refluxingisopropyl acetate introduced the n-butylamide moiety whilefacilitating lactamization Addition of MTBE followed byScheme 19 Synthesis of Brivaracetam (IX)

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