Synthetic Approaches To The New Drugs 2018

Formation of the acid chloride of 16 followed by reaction with phenol provided the corresponding ester, making way for methyl ether cleavage with boron tribromide to provide phenol 17..

Synthetic Approaches to New Drugs Approved during 2018

Andrew C Flick, Carolyn A Leverett, Hong X Ding, Emma McInturff, Sarah J Fink,

Christopher J Helal, Jacob C DeForest, Peter D Morse, Subham Mahapatra,

and Christopher J O’Donnell *

Cite This: https://dx.doi.org/10.1021/acs.jmedchem.0c00345 Read Online

ABSTRACT: New drugs introduced to the market every year represent privileged structures for particular biological targets Thesenew chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs Thisannual review describes the most likely process-scale synthetic approaches to 39 new chemical entities approved for thefirst timeglobally in 2018

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

Medicine1

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

annual review, which is now in its 17th installment,2 presents

synthetic routes for 39 new molecular entities that were

approved for thefirst time by a governing body anywhere in

the world during the 2018 calendar year (Figure 1).3Each drug

is prefaced by a brief introduction summarizing the relevant

pharmacology or differentiating features of the medicine.4

Newindications for previously launched medications, new combi-

nations or formulations of existing drugs, and drugs

synthesized entirely by biological processes or peptide

synthesizers have been excluded from coverage For

organiza-tional purposes, drugs presented in this review are categorized

into the following therapeutic areas: antibiotic and antifungal,

anti-infective, cardiovascular and hematologic, gastrointestinal,

inflammation and immunology, metabolic, oncology,

oph-thalmologic, rare disease, reproductive, and urinary tract

Within each of these therapeutic areas, drugs are ordered

alphabetically 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 In some cases,

only a discovery-scale or a general synthetic approach capable

of delivering the active pharmaceutical ingredient (API) hasbeen made available Nonetheless, the synthetic sequencesdescribed in this review have all been previously reported ineither patent or public chemical literature and, to the best ofour assessment, represent scalable routes originating fromcommercially available starting materials (as determined byexplicit statement or inferred by experimental detail)

2 ANTIBIOTIC AND ANTIFUNGAL DRUGS2.1 Eravacycline (Xerava) Eravacycline belongs to thetetracycline class of antibiotics and was approved by theUnited States Food and Drug Administration (USFDA) forthe treatment of complicated intra-abdominal infections inpatients aged 18 years and older Eravacycline is a fullysynthetic broad-spectrum antibiotic that exhibits potentactivity against both Gram-positive and Gram-negativebacterial strains, including many that have acquired tetracy-cline-specific resistant mechanisms.5

Eravacycline was ered and developed by Tetraphase Pharmaceuticals and was

discov-Received: February 26, 2020 Published: April 27, 2020

© XXXX American Chemical Society https://dx.doi.org/10.1021/acs.jmedchem.0c00345

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Figure 1 continued

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licensed to Everest Medicines for commercialization in many

eastern Asian countries

Two other tetracycline antibiotics, sarecycline and

omadacy-cline, were also approved this year, but both molecules were

prepared from previously approved tetracyclines that wereultimately obtained via fermentation Eravacycline is a fullysynthetic tetracycline, and a highly convergent route for itspreparation wasfirst described by the laboratory of Professor

Figure 1 Structures of 39 NCEs approved in 2018.

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Andrew Myers at Harvard University.6 This route was later

refined at Tetraphase Pharmaceuticals, leading to the discovery

and development of eravacycline.7 The route described has

been published in the primary and patent literature on

multikilogram scale.8 Retrosynthetically, eravacycline (I) was

envisioned to be derived via a Michael addition−Dieckmann

cyclization reaction between the anion of compound 1 and

Michael acceptor 2 (Figure 2) Tricyclic intermediate 2 was

envisioned to come from addition of the anion of isoxazole 4

to the aldehyde 3, followed by an intramolecular Diels−Alder

reaction to set the carbon framework of 2 Isoxazole 4 was

envisioned to come from dimethyl maleate, and the chiral vinyl

amine stereocenter was set via an Ellman sulfinamide auxiliary

The preparation of the chiral isoxazole 4 is described in

Scheme 1.8cDimethyl maleate (5) was treated with bromine in

the presence of azo-bis(isobutyronitrile) (AIBN) and

ultra-violet light to give dibromide 6 in 92% yield Condensation of

6with hydroxyurea in the presence of potassium tert-butoxide

provided isoxazole 7 in 66% yield Benzylation of the hydroxy

group of 7 followed by DIBAL reduction of the ester gave

aldehyde 8 in high yield over the two steps Condensation of 8

with (S)-tert-butylsulfinylamide (Ellman’s auxiliary) in the

presence of copper(II) sulfate provided chiral sulfinimine 9 in

85% yield After reaction optimization, 9 was treated with

vinylmagnesium chloride in the presence of methyllithium and

zinc chloride to give 10 in 95% yield (99.3:0.7 dr) The butylsulfinyl group was removed under acidic conditions Theresulting primary amine was treated with formaldehyde in thepresence of sodium acetate and then reduced using a picoline−borane complex to give the dimethylamine coupling partner 4

tert-in 88% yield for the two-step sequence (96.0% ee) The ee wasenhanced to 99.0% by tartrate salt formation, giving 4·tartrate

in 91% yield

The preparation of the tricyclic Michael acceptor enone 2 isdescribed in Scheme 2.8b Treating 4·tartrate with sodiumhydroxide provided the free base 4, which was reacted withtetramethylpiperidine (TMP) magnesium chloride−lithiumchloride complex to effect the direct magnesiation of 4 onthe oxazole ring, with no competing allylic metalation Thisintermediate was reacted with aldehyde 3 to give alcohols 11a/11bin 95% yield (3.57:1 dr) Heating the mixture of 11a/11b

in DMSO, DIPEA, butylated hydroxytoluene, and isopropylacetate effected the intramolecular Diels−Alder reaction togive a mixture of endo products (12a/12b), arising from 11a,and a mixture of exo products (12c/12d), arising from 11b.This mixture of alcohols 12a−d was oxidized with sulfurtrioxide pyridine complex to give ketones 13a/13b in 99.1:0.9

dr and 74% overall yield from 11a/b Treating 13a/13b withboron trichloride efficiently effected demethylation of themethyl enol ether, which spontaneously underwent ring

Figure 2 Retrosynthetic approach to eravacycline.

Scheme 1 Preparation of Eravacycline Isoxazole 4 (4·Tartrate)

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opening to provide enone 14 in high yield Protection of the

resulting alcohol as its tributylsilyl ether followed by

recrystallization from isopropyl alcohol provided the tricyclic

Michael acceptor coupling partner 2 in 88% yield

The preparation of intermediate 1 is described in Scheme

3.6c Compound 15 was treated initially with LDA and then

quenched with methyl iodide to give arene 16 Formation of

the acid chloride of 16 followed by reaction with phenol

provided the corresponding ester, making way for methyl ether

cleavage with boron tribromide to provide phenol 17

Nitration of 17 and protection of the phenol as a benzyl

ether gave nitroarene 18 Reduction of the nitro group withsodium bisulfite provided aniline 19 in 83% from compound

15 Amine 19 was reacted with benzyl bromide to produce thedibenzylamine-protected coupling partner 1 in 80% yield.The completion of the synthesis of eravacycline (I) isdescribed inScheme 4.8aCompound 1 was treated with LDAfollowed by compound 2 to promote the desired intermo-lecular Michael addition The resulting Michael adduct wasthen treated with lithium bis(trimethylsilyl)amide (LHMDS)

to induce an intramolecular Dieckmann cyclization, which gavecompound 20 in 94% yield The silyl protecting group was

Scheme 2 Construction of Eravacycline Tricyclic Michael Acceptor Enone 2

Scheme 3 Preparation of Dibenzyl Amine Protected Coupling Partner 1

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removed using hydrofluoric acid, and the resulting

inter-mediate was treated with hydrogen and palladium on carbon

These conditions resulted in the removal of the dibenzylamineand benzyl ether protecting groups, which further gave rise to

Scheme 4 Final Assembly of Eravacycline (I)

Scheme 5 Synthesis of Ravuconazole (35)

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the opening of the oxazole ring to ultimately arrive at

compound 21 in 89% yield for the two step sequence

Compound 21 was then reacted with acid chloride 22 to

furnish eravacycline I in 89% yield

2.2 Fosravuconazole L-Lysine Ethanolate (Nailin)

Fosravuconazole L-lysine ethanolate (F-RVCZ) is an orally

administered, broad-spectrum antifungal drug approved in

Japan for the treatment of onychomycosis in 2018.9F-RVCZ is

a prodrug of ravuconazole with improved solubility and oral

bioavailability.10Originally discovered by Eisai,11ravuconazole

was licensed to Bristol-Myers Squibb (BMS) for worldwide

development, excluding Japan, in 1996 However, BMS

terminated development of the drug in 2004, and Eisai

reacquired the worldwide development, manufacturing, and

marketing rights The antifungal activities of ravuconazole, like

other azole drugs, derive from the inhibition of ergosterol

biosynthesis and block the 14α-demethylation pathway present

in many strains of yeasts and molds.10 The lowering of

ergosterol levels leads to accumulation of 14α-methyl sterols,

which impairs normal structure and functions of cell

membranes, ultimately resulting in growth inhibition or

death of fungal cells F-RCVZ exhibited higher efficacy (higher

initial cure rates and lower recurrence rates), an improvedsafety-profile (lower hepatic functional disorders), andimproved dosing regimen (once daily for 12 weeks) overexisting standards of care such as terbinafine and itracona-zole.12

In addition to several disclosures describing the gram-scalesynthesis of ravuconazole and related precursors,13 a robustplant-scale preparation has been described by researchers atBMS (Scheme 5).14This route utilized lactate 23 as a startingmaterial for the preparation of arylpropanone 26 First, methylester 23 was converted to a morpholine amide in the presence

of catalytic sodium methoxide The alcohol was subsequentlyprotected to generate tetrahydropyranyl ether 24 Use of real-time infrared reaction monitoring allowed for safe formation ofGrignard reagent 25 from the corresponding bromide, whichwas then reacted with amide 24 to furnish aryl ketone 26 afteraqueous acetic acid quench Corey−Chaykovsky epoxidationand subsequent epoxide opening were performed in a single-step, telescoped process Once epoxidation was complete,heating the reaction mixture to 90 °C triggered a triazole-mediated epoxide-opening sequence to form alcohol 28 Thestereochemical outcome of the epoxide-forming step is

Scheme 6 Synthesis of FosravuconazoleL-Lysine Ethanolate (II)

Scheme 7 Synthesis of Omadacycline III

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dictated by the adjacent chiral center, providing 27 in 8.6:1 dr.

Removal of the tetrahydropyranyl protecting group within 28

generated an intermediate diol which was converted to

trisubstituted epoxide 29 via selective mesylation of the

secondary alcohol Generation of lithium cyanide in situ from

acetone cyanohydrin 30 and LHMDS followed by subsequent

addition to epoxide 29 delivered the α-cyano alcohol 31 in

90% yield, which was subsequently converted to thioamide

monohydrate salt 33 by treatment with diethyl

dithiophos-phate 32 and sulfuric acid Condensation of the thioamide 33

with 2-bromo-4′-cyanoacetophenone 34 in hot ethanol

resulted in thiazole formation which completed the preparation

of ravuconazole (35)

Conversion of ravuconazole to the highly water-soluble

prodrug fosravuconazole L-lysine ethanolate (II) has been

described by the scientists at Eisai (Scheme 6).15 First,

ravuconazole (35) was O-alkylated with di-tert-butyl

chlor-omethylphosphate 36 to furnish phosphate ester 37

Subjection of ester 37 to trifluoroacetic acid (TFA) and

aqueous sodium hydroxide provided the free acid, which was

subsequently converted to fosravuconazoleL-lysine ethanolate

(II)

2.3 Omadacycline (Nuzyra) Omadacycline belongs to

the aminomethylcycline class of tetracycline antibiotics and

was approved by the USFDA for the treatment of acute

bacterial skin and skin structure infections and

community-acquired bacterial pneumonia.16Discovered and developed by

Paratek Pharmaceuticals, omadacycline was licensed to Bayer,Merck, and Novartis over the course of its clinical develop-ment Ultimately the rights were returned to Paratek, whocollaborated with Zai Lab (Shanghai) Co., Ltd to commerci-alize the drug in China.17

A number of syntheses of omadacycline have beenpublished, and the largest scale route is described inScheme

7 This route advantageously began with minocycline (38,Scheme 7) which is a tetracyclic antibiotic drugfirst patented

in 1961.1 8 Minocycline was condensed with (hydroxymethyl)phthalimide (39) in the presence of triflicacid to give a mixture of the 9-phthalimidomethyl analogs 40and 41 in approximately a 60:40 ratio This mixture wastreated with methylamine, which resulted in hydrolysis of thephthalimide to give an unreported distribution of methylamineanalogs 42 and 43 This mixture was then treated withpivaldehyde under catalytic hydrogenation conditions to affectthe reductive amination at position N-9, followed byconcomitant removal of the hemiaminal group on the amide,furnishing omadacycline (III) in 15−18% yield for the overallprocess after conversion to the tosylate salt

N-2.4 Plazomicin (Zemdri) Originally discovered byCalifornia-based Ionis Pharmaceuticals and later developed

by Achaogen, plazomicin was approved by the USFDA in 2018for the treatment of patients 18 years of age or older withcomplicated urinary tract infections (cUTI), includingpyelonephritis The drug, a next-generation aminoglycosideScheme 8 Synthesis of Plazomicin (IV)

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that is delivered by injection, was acquired by Cipla as part of

an auction of Achaogen assets after the Americanfirm filed for

chapter 11 bankruptcy.19As a structural derivative of the

anti-infective aminoglycoside sisomycin, plazomicin is a

neoglyco-side that is highly active against a variety of bacterial

pathogens, including many of the Gram-negative rods that

are implicated in cUTIs Plazomicin is not affected by most

aminoglycoside-modifying enzymes and retains activity against

multidrug-resistant (MDR) isolates known as

carbapenem-resistant enterobacteriaceae (CRE).20

Two synthetic routes to plazomicin have been reported,

both of which originate from commercial sisomicin (44,

Scheme 8) and vary only by differential protection of the

sisomicin amines.21 Sisomicin was treated with an

ion-exchange resin which furnished trifluoroacetamide 45 after

reaction with ethyl trifluorothioacetate Zinc acetate and

benzyloxycarbonyl succinimide provided the corresponding

Cbz-protected intermediate 46 in a 35% yield from 44 Amide

coupling and removal of the trifluoroacetate group yielded

glycoside 48, which then underwent reductive amination,

benzoyl ester cleavage, and global Cbz removal under

hydrogenative conditions to give rise to plazomicin (IV).21c,d

2.5 Sarecycline Hydrochloride (Seysara) Sarecycline

belongs to the tetracycline class of antibiotics and was

approved by the USFDA for the oral treatment of

inflammatory lesions of non-nodular, moderate-to-severe

acne vulgaris in patients at least 9 years old Sarecycline was

discovered at Paratek Pharmaceuticals and licensed to Warner

Chilcott, which was later acquired by Allergan Allergan

completed the development and launch of the drug beforerights were acquired by Almarall S.A in 2018.22

To date, there are no publications describing the discovery

of sarecycline The only reported synthetic route to the drug,performed on small scale by Paratek, is described inScheme

9.23Iodination of commercially available sancycline 51 with iodosuccinimide followed by HPLC purification providediodosancycline 52 as the trifluoroacetate salt (no yieldreported) Carbonylation of 52 in the presence of palladiumacetate and Xantphos followed by treatment with triethylsilaneprovided the corresponding aldehyde, which was treated withtrifluoracetic acid to provide formylsancycline trifluoroacetate

N-53.24 Condensation of 53 with N,O-dimethylhydroxylaminehydrochloride, reduction with sodium cyanoborohydride, andtreatment with hydrochloric acid provided sarecycline hydro-chloride (V) in 23% yield for the three-step sequence

3 ANTI-INFECTIVE DRUGS3.1 Baloxavir Marboxil (Xofluza) In 2018, baloxavirmarboxil received itsfirst approval by the Pharmaceuticals andMedical Devices Agency of Japan (PMDA) for the treatment

of influenza A or B virus infections.25

Later the same year, thedrug was also approved by the USFDA for the treatment ofacute uncomplicated influenza (flu) in patients 12 years of ageand older who have been symptomatic for no more than 48

h.26 Baloxavir marboxil was discovered by Shionogi, wholicensed their rights to Roche in February 2016 fordevelopment and commercialization except in Taiwan andJapan (Shionogi maintained its rights in these two

Scheme 9 Synthesis of Sarecycline Hydrochloride (V)

Scheme 10 Assembly of Baloxavir Piperazine Heterocyclic Core 59

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countries).25Baloxavir is a novel cap-dependent endonuclease

inhibitor that blocks influenza virus proliferation by inhibiting

the initiation of mRNA synthesis This is in contrast to

neuraminidase inhibitors, which impair viral release from

infected host cells.27

Shionogi has reported two unique synthetic approaches to

baloxavir, each of which originate from different starting

materials.28The route expected to be most scalable is depicted

inSchemes 10,11, and12 This approach strategically hinges

upon union of a piperazine tricyclic core and a tricyclic diaryl

mercaptan.28bAcid 54 was methylated and then subjected to

Boc-hydrazine under weakly acidic conditions to furnish ester

55 which was reacted with amine 58 to afford racemic

hemihydrate 59 Amine 58 can be prepared by the alkylation of

phthalimidyl alcohol 56 with bromide 57, followed by

hydrazine-mediated phthalimide cleavage

Separately, benzothiepine 62 was constructed as outlined in

Scheme 11 Benzoic acid 60 was o-lithiated prior to quench

with DMF The lactone in 61 was formed upon acidification

with D-CSA Intramolecular Friedel−Crafts followed byacidification and reduction furnished benzothiepine alcohol

62in 73% yield

The final steps in the assembly of baloxavir marboxil aredescribed in Scheme 12 Enantiomeric resolution of 59 wasperformed by reacting 59 with commercial chiral acid 63followed by recrystallization from warm ethyl acetate Thediastereomer corresponding to the desired geometry was thencollected and treated with DBU which provided enantiomeri-cally enriched free base 64 Although this reaction wasexemplified on kilogram-scale, the chiral purity was notreported The benzyl ether within 64 was then converted tothe corresponding n-hexyl ether using n-hexanol andisopropylmagnesium chloride, making way for isolation oftosylate salt 65 after treatment with p-TsOH Next, 62 wassubjected to propylphosphonic anhydride (T3P) under acidicconditions and coupled with fragment 65 to form the corestructure of baloxavir marboxil Subsequent treatment withbase and methanesulfonic acid led to the formation of mesylate

Scheme 11 Construction of Baloxavir Benzothiepine 62

Scheme 12 Final Assembly of Baloxavir Marboxil (VI)

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salt 66 Removal of the n-hexyl ether was facilitated by lithium

chloride in warm NMP, followed by isolation of phenol 67

upon precipitation from a warm acetonitrile/water mixture

Subsequent alkylation with alkyl chloride 68 preceded careful

treatment with acid to furnish baloxavir marboxil (VI)

3.2 Bictegravir (Bictarvy) Bictegravir, discovered by

Gilead, was approved in 2018 as part of a combination therapy

involving bictegravir, emtricitabine, and tenofovir alafenamide

for the treatment of HIV-1 infections.29This was based on a

phase 3 clinical trial where the combination of bictegravir,

emtricitabine, and tenofovir alafenamide was shown to be

better tolerated than previous single-tablet regimens.30

Bictegravir belongs to a class of antiretroviral drugs known

as integrase strand transfer inhibitors (INSTIs) Compounds

of this class inhibit HIV-1 integrase (IN), which plays a central

role in viral replication by catalyzing the insertion of viral

cDNA into the genome of the host.31

Process chemists at Gilead have disclosed a seven-step route

to bictegravir.32 Although yields were not reported for this

sequence, the approach allowed for the late-state installation of

chiral aminocyclopentanol 78 (Scheme 13) The synthesis

began with condensation of Meldrum’s acid (69) and

methoxyacetic acid 70 in the presence of pivaloyl chloride,

giving rise to intermediate 71 Subjection of 71 to benzylamine

72and TFA ultimately furnishedβ-ketoamide 73 Treatment

with DMF−DMA followed by condensation with dimethyl

acetal 74 furnished vinylogous amide 75, making way for a

cyclization reaction to generate pyridone 77 by treatment with

dimethyl oxalate (76) and sodium methoxide Acetal

deprotection was followed by treatment with

syn-amino-pentanol 78 under basic conditions This annulation arose

from amide bond formation between primary amine 78 and

the methyl ester within 77, followed by condensation with the

pendant acetal, allowing for arrival at aminal 79, establishing

the polycyclic core of bictegravir Magnesium mediated demethylation furnished bictegravir (VII)

bromide-The preparation of syn-aminopentanol 78 has beendescribed on gram scale by the Chinese firm Anhui TwisunHi-Tech Pharmaceutical Co., Ltd inScheme 14.33Commer-

cial cyclopentanoic acid 80 was converted to the ing Weinreb amide 81 which was then exposed tomethylmagnesium bromide, giving rise to ketone 82.Subjection of 82 to Baeyer−Villiger oxidation conditionsresulted in a rearrangement product whereby the moresubstituted carbon of the ketone underwent rearrangement,presumably with retention of stereochemical configuration.34Subsequent treatment with base andfinally acidic removal ofthe Boc group provided aminopentanol 78 Although yieldswere reported for this sequence, stereoselectivity was not

correspond-Scheme 13 Synthesis of Bictegravir (VII)

Scheme 14 Preparation of Bictegravirsyn-Aminopentanol78

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3.3 Danoprevir (Ganovo) Danoprevir is an orally

available hepatitis C virus nonstructural protein 3 (NS3)

protease inhibitor approved in 2018 in China for

treatment-naive patients with noncirrhotic genotype 1b chronic hepatitis

C.35Discovered by InterMune Inc and Array Biopharma Inc.,

the rights to license danoprevir were acquired by Roche in

2006, who later partnered with Aslectis for the co-development

and commercialization of the drug in China.35Hepatitis C is

reported to affect roughly 1.6% of the population globally and

4.4% of the population in China, with the genotype 1b

predominating in China.36Protease activity of hepatitis C NS3

is crucial for viral replication Danoprevir inhibits the NS3

protease active site through a two-step binding mechanism that

involves an initial collision complex that rapidly isomerizes to a

highly stable complex displaying unusually slow dissociation.37With a calculated complex half-life of roughly 5 h, the observedbinding kinetics distinguish danoprevir from other relatedmacrocyclic inhibitors of NS3 Danoprevir is also a substrate ofcytochrome P4503A To maximize its effectiveness, danoprevir

is coadministered with the CYP3A inhibitor/inducer ritonavir,

as well as the antiviral drugs peginterferon alfa-2a and ribavirin,both of which are also currently used to treat hepatitis C

A synthetic approach to danoprevir sodium was initiallyreported in a series of three patents disclosed in 2005.38 Aslightly different route derived from the same startingcyclopropyl aminoester was published in 2014.39To date noexplicit scale synthesis has been reported However, scientists

at Boehringer-Ingelheim have reported a concise approach to

Scheme 15 Preparation of Danoprevir Cyclopropyl Aminoester 87

Scheme 16 Synthesis of Danoprevir (VIII)

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the building block cyclopropyl aminoester 87 (a substructural

component of several macrocyclic antiviral drugs) on

multi-kilogram scale, and this approach is described inScheme 15.40

The hydrochloride salt of ethyl glycine 83 was condensed with

benzaldehyde to form imine 84, making way for a cyclative

dialkylation with 2-butene-1,4-dibromide 85 through a

sequential SN2−SN2′ reaction Acidic hydrolysis of the imine

and N-Boc protection yielded racemic vinylcylopropane 86 in

65−70% yield over three steps Enzymatic resolution using

Alcalase 2.4L allowed for selective saponification of the

undesired (1S,2R)-carboxylate, providing the desired (1R,2S)

enantiomer 87 in quantitative conversion (including mass

recovery of the acid)

The synthesis of danoprevir continued with deprotection of

the amine within 87 to give 88 and amide formation mediated

by hexafluorophosphate azabenzotriazole tetramethyluronium

(HATU) with carboxylic acid 89 (Scheme 16) This was

followed by a second Boc-deprotection step to afford amino

alcohol 90 in 80% yield over the three-step sequence

HATU-mediated amide coupling with commercial carboxylic acid 91

provided alkene 92, which, when treated with Hoveyda first

generation metathesis catalyst 93, afforded macrocycle 94 in

52% yield Carbonyldiimidazole (CDI)-mediated coupling of

94 and isoindoline 95 followed by basic hydrolysis yielded

carboxylic acid 96 This acid was then reacted with CDI and

cyclopropylsulfonamide 97, furnishing danoprevir (VIII).39

3.4 Doravirine (Pifelto) Doravirine, also referred to as

MK-1439 or“DOR”, is a non-nucleoside reverse transcriptase

inhibitor (NNRTI) discovered and developed by Merck.41The

drug was approved in 2018 by the USFDA for the treatment of

HIV-1 in appropriate patients.41 The once-daily dosed drug,

like all NNRTIs, inhibits viral DNA synthesis by binding to an

allosteric site located about 10 Å from the polymerase active

site of the HIV-1 reverse transcriptase.42 Doravirine has

demonstrated significant antiviral activity against a broad range

of NNRTI-resistance associated mutations that are increasingly

found in treatment-naive patients while exhibiting an improvedsafety-profile over existing standard-of-care regimens such asritonavir, darunavir, and efavirenz

A considerable number of accounts related to thepreparation of doravirine and related analogs have beenpublished,43and a robust, kilogram-scale synthesis of the drughas been described by researchers at Merck (Scheme 17).44Strategically, this scale route was designed to proceed throughsubstrates that would minimize the evolution of doravirinebyproducts that arose from polymethylation and polycyana-tion, which were challenging to remove by methods other thanchromatography Toward this end, an iridium-catalyzed meta-borylation−oxidation protocol converted iodochlorobenzene

98to phenol 99, which then participated in an SNAr reactionwith pyridine 100 to arrive at diaryl ether 101 Basic hydrolysis

of 101 followed by recrystallization gave rise to 2-pyridinol 102

in 87% yield from 98 Next, introduction of the nitrile usingcopper cyanide in NMP was achieved under relatively mildconditions The authors note that keeping the temperatureunder 110 °C was critical for suppressing undesired bis-cyanation products and that the iodide was chosen over theanalogous bromide to further help ensure selectivity for thedesired mononitrile product 103 Alkylation of 103 with 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (104) waspossible under mild conditions to give 2-pyridone 105 in 81%yield after recrystallization Although 104 is commerciallyavailable, reports of its preparation have also been previouslypublished.45 Lastly, after screening a variety of methylationconditions, 105 was treated with iodomethane and potassiumcarbonate in cool NMP, furnishing doravirine (IX) in 68%yield, with minimal overmethylation products observed.443.5 Moxidectin (Moxidectin) Moxidectin was developed

by the nonprofit firm Medicines Development for GlobalHealth (MDGH) and was approved by the USFDA in 2018 forthe treatment of river blindness, also called onchocerciasis, inpatients aged 12 years and older.46River blindness is caused byScheme 17 Synthesis of Doravirine (IX)

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the larvae (microfilariae) of a parasitic worm Onchocerca

volvulus which manifests as severe itching, disfiguring skin

conditions, and visual impairment, including permanent

blindness.47 Nearly 200 million people are at risk of river

blindness, with 99% of patients living in sub-Saharan Africa

Although the actual mechanism of action is unknown, studies

with other nematodes suggest that moxidectin binds to a

parasite’s glutamate-gated ion channels (GluCl),

γ-amino-butyric acid (GABA) receptors, and/or ATP-binding cassette

(ABC) transporters.48This induces increased permeability that

leads to an influx of chloride ions and results into flaccid

paralysis of the parasite Moxidectin is active against

micro-filariae of Onchocerca volvulus but does not kill the adult

worms The drug has a longer half-life than ivermectin, the

current standard of care, and offers an alternative for managing

antiparasitic drug resistance.49

Moxidectin is a 16-membered macrocyclic lactone of the

milbemycin class, which presents significant synthetic

challenges structurally.50 However, the starting material for

the synthesis of the drug is highly functionalized macrolactonenemadectin (106), a fermentation product of Streptomycescyanogriseus ssp noncyanogenus.51 Although several Chinesepatents have been filed describing the conversion ofnemadectin to moxidectin,52the route described in the mostdetail is presented inScheme 18.52dSelective protection of thenemadectin C-25 allylic hydroxyl group with 4-chlorophenoxyacetyl chloride 107 furnished 108 The choice of thisprotecting group was driven by improved stability and simplerpurification (recrystallization) of the intermediates Theremaining C-10 secondary alcohol in 108 was oxidized usingmodified Pfitzner−Moffat conditions using phenyl phosphor-odichloridate (109) to yield ketone 110.53 Oxime formationand selective saponification of the ester protecting groupfurnished moxidectin (X) It should be noted that the oximeretains the (E)-configuration throughout the final two steps ofthe synthesis of the molecule.54

3.6 Tafenoquine (Krintafel) Tafenoquine is an orallyactive antimalarial therapy targeting Plasmodium vivax in

Scheme 18 Synthesis of Moxidectin (X)

Scheme 19 Preparation of Tafenoquine Nitroquinoline Intermediate 115

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patients 16 years of age and older It is available in both

preventative dose-loading regimens and radical cure dosages.55

Developed by the Walter Reed Army Institute of Research in

the 1980s, tafenoquine (also known as WR 238605) was

described as possessing both tissue and blood schizonticidal

activity.56 The exact mechanism of action of tafenoquine,

which is a racemate, is unknown However, current evidence

suggests that tafenoquine may inhibit hematin

polymer-ization57and induce apoptosis in select strains.58Tafenoquine

is currently being developed by GlaxoSmithKline (GSK) in

collaboration with Medicines for Malaria Venture, 60°

Pharmaceutical, Knight Therapeutics, and the United States

Army

Multiple synthetic routes to tafenoquine have been reported

in patents, which have been reviewed.59 A 2003 patent

describes the process chemistry route to access tafenoquine,

and this approach is described in Schemes 19 and 20.60

p-Anisidine 111 was heated in xylenes and ethyl acetoacetate to

give aniline 112 in 87% yield, which was converted to

quinoline 113 via a sulfuric acid-mediated dehydrative

condensation reaction Quinoline 113 was subsequently

chlorinated with phosphorus oxychloride and sulfuryl chloride

to arrive at dichloroquinoline 114 Methoxide addition,treatment with triethylphosphine in base, and subsequentnitration converted 114 to nitroquinoline 115

This highly activated quinoline was subjected to asubstitution reaction with phenol 116 under basic conditions.Next, treatment with Darco KB and hydrazine-promotednitroreduction gave amine 117 in a 73% yield for the three stepsequence (Scheme 20) Alkylation of 117 with commercialiodide 118 was performed in a mixture of warm NMP anddiisopropylamine followed by hydrazine-mediated conversion

of the phthalimide to the corresponding primary amine.Sequential exposure to potassium hydroxide and succinic acidcompleted the synthesis of tafenoquine (XI) in 63% from 119.3.7 Tecovirimat (Tpoxx) Tecovirimat, which wasdeveloped by SIGA Technologies and the United StatesDepartment of Health and Human Services BiomedicalAdvances Research and Development Authority, is the firstoral treatment for smallpox Although smallpox was eradicateddue to effective vaccination practices, many people worldwideare now unvaccinated Because health authorities believe that a

Scheme 20 Synthesis of Tafenoquine (XI)

Scheme 21 Synthesis of Tecovirimat (XII)

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single case of the disease could trigger a global health

emergency, the identification of this small molecule therapy

was intended to serve as a countermeasure Initiated by a

biodefense effort from the National Institute of Allergy and

Infectious Disease, tecovirimat was identified by screening

libraries of over 300,000 known compounds for their ability to

interfere with replication of vaccinia or cowpox The

mechanism of action of tecovirimat likely involves the F13L

gene of the vaccinia virus, which encodes a membrane protein

that is required for extracelullar virus production.61

Tecovir-imat was approved under the USFDA’s Animal Rule, as clinical

studies in humans were not ethical or feasible.62This led to

several challenges, as the variola virus that causes smallpox has

only been observed in humans As a result, it was necessary to

use three animal models: rabbitpox virus in rabbits, ectromelia

virus (mousepox), and monkeypox in non-human primates.63

Upon approval, tecovirimat became part of the U.S

Govern-ment’s Strategic National Stockpile

An efficient, three-step synthetic route to tecovirimat, shown

in Scheme 21, was demonstrated on a small scale.64 Diels−

Alder cycloaddition of cycloheptatriene 120 and maleic

anhydride 121 in refluxing xylenes formed the fused tricyclic

core in a single step and a 4:1 product ratio, favoring the

expected 122-endo isomer, which could be isolated by

recrystallization from MTBE Reaction of this fused anhydride

with 4-(trifluoromethyl)benzohydrazide 123 in a mixture of

alcohols proceeded without inversion or epimerization of the

stereocenters.65Recrystallization from EtOAc/water facilitated

isolation of tecovirimat (XII) as the hydrate.66

4 CARDIOVASCULAR AND HEMATOLOGIC DRUGS

4.1 Avatrombopag Maleate (Doptelet) Avatrombopag

is a thrombopoietin receptor agonist indicated for the

treatment of thrombocytopenia in adult patients with chronicliver disease who are scheduled to undergo a procedure It wasfirst approved by the USFDA in May 2018 and subsequentlyapproved by the European Medicine Agency (EMA) in June

2019.67,68 Originally developed by Astellas, avatrombopag’sdevelopment rights have been transferred between a number offirms, most recently Dova Pharmaceuticals (an affiliate of PBMCapital) In March 2018, Dova entered into an agreement(through AkaRx) to grant Shanghai Fosun Pharma theexclusive development and distribution rights of the drug inmainland China and Hong Kong.69

A large scale synthetic route to avatrombopag, as well ascrystalline form protocols, have been reported in a series ofpatents from Astellas.70 As described in Scheme 22,bromination of 1-(4-chlorothiophen-2-yl)ethenone (124)gave bromide 125 Condensation with thiourea producedthiazolamine 126 in 46% yield over two steps Thiazolamine

126 was brominated with N-bromosuccinimide (NBS) inDMF, making way for nucleophilic aromatic substitution with1-cyclohexylpiperazine (127) to provide 128 in 34% overallyield Amide bond formation with 5,6-dichloronicotinic acid(129) was accomplished by activation with phosphorusoxychloride to give nicotinamide 130 in 83% yield A secondnucleophilic aromatic substitution with ethyl isonipecotate

131, followed by hydrolysis, provided avatrombopag (132).70aSalt formation was demonstrated on 20 kg scale using maleicacid in a mixture of DMSO/acetone/water (2:2:1) to obtainavatrombopag maleate (XIII) in 85% yield.70b,c

4.2 Revefenacin (Yupelri) Developed by TheravanceBiopharma and Mylan, revefenacin is a long-acting muscarinicantagonist approved by the USFDA in 2018 for the treatment

of chronic obstructive pulmonary disease (COPD).71 ministered as an inhaled solution, the drug wasfirst licensed toGSK from Theravance in 2004 However, the developing rightsScheme 22 Synthesis of Avatrombopag Maleate (XIII)

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were returned to Theravance in 2009 due to incompatibility

with GSK’s proprietary inhaler device.71

Revefenacin bindscompetitively and reversibly to the muscarinic M3receptors in

the airway smooth muscle which inhibits bronchoconstriction

and increases bronchodilation.72

Three patent applications have been filed by Theravance

describing the synthesis and solid form considerations with

respect to revefenacin.73 The approach to the drug’s

construction essentially involves a linear sequence which

began with heating piperidine 133 and isocyanate 134 together

(neat) to 70°C (Scheme 23) Subsequent treatment with acid,

transfer hydrogenation, and pH adjustment (pH ∼12)

ultimately furnished carbamate 135 in 99% yield over the

four-step sequence Next, reductive amination with glycine

derivative 136 followed by hydrogenolytic removal of the Cbz

group and recrystallization in isopropyl alcohol produced 137

in 96% yield over the three steps Amide bond formation with

acid 138, pH adjustment, and a reductive amination reaction

with isonipecotamide 140 completed the assembly of the

molecule Aqueous base workup and subjection to isopropyl

alcohol gave rise to revefenacin (XIV) in 88% yield from

aldehyde 139.73b

4.3 Roxadustat (Ai Rui Zhuo) Roxadustat is an orally

active hypoxia-inducible factor prolyl hydroxylase (HIF-PHD)

inhibitor for the treatment of anemia in patients with

dialysis-dependent chronic kidney disease (CKD).74 The drug was

developed by FibroGen, in collaboration with Astellas and

AstraZeneca, and was approved in China in December 2018 as

first-in-class potent HIF-PHD inhibitor.74

HIF-PHD enzymesregulate the degradation of transcription factors in the HIF

family under normal oxygen conditions Inhibition of these

enzymes stabilizes HIF and enhances its activity, leading to an

increase in endogenous erythropoietin (EPO) production,

allowing erythropoiesis to occur.75The drug also increases ironbioavailability by suppressing peptide hormone hepcidin levels,thus ameliorating anemia by boosting the body’s naturaloxygen-sensing and response system without the need ofintravenous iron supplementation Roxadustat can also beprescribed to patients who use hemodialysis or peritonealdialysis

A surge of patents published in 2017 and 2018 describedseveral unique synthetic routes to roxadustat.76 FibroGenreported thefirst small scale synthesis of roxadustat in 2004,77and in 2014 this same organization devised a robust kilogram-scale route which is depicted inScheme 24.78The nine-stepsynthetic sequence commenced with 5-bromophthalide 141,which was converted to 5-phenoxyphthalide 142 via a modifiedUllman-type coupling.78The reaction was performed on 85 kgscale The γ-lactone 142 was opened to furnish an acidchloride intermediate which delivered methyl ester 143 upontreatment with MeOH Substitution of benzyl chloride 143with p-toluenesulfonylglycine methyl ester (144) was carriedout under Finkelstein conditions to produce intermediate 145,which then underwent base-mediated cyclization and sub-sequent aromatization to produce isoquinoline 146 in 58%yield from 142 Regiospecific Mannich aminomethylation ofisoquinoline 146 was achieved with bis(dimethylamino)-methane 147 in acetic acid to furnish dimethylaminomethylintermediate 148, which was subsequently activated with aceticanhydride to replace the dimethylamino group with an acetoxymoiety The reaction yielded the intended isoquinolinol 150.The undesired bis-acetoxy adduct 149 could be recycled togenerate additional 150 upon treatment with morpholine.Reduction of the acetoxy group under hydrogenationconditions yielded 151, and this intermediate was convertedScheme 23 Synthesis of Revefenacin (XIV)

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to roxadustat (XV) via treatment with glycine 152 and sodium

methoxide

5 GASTROINTESTINAL DRUGS5.1 Elobixibat Hydrate (Goofice) Elobixibat is a highlypotent, first-in-class inhibitor of ileal bile acid transport andapproved for the treatment of chronic idiopathic constipation,

Scheme 24 Synthesis of Roxadustat (XV)

Scheme 25 General Route to Elobixibat Sulfone 160

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a disorder that affects approximately 14% of adults Elobixibat

was developed by EA Pharma (a subsidiary of Eisai Co.) and

Mochida and was approved by the Japanese PMDA in 2018.79

The drug interrupts enterohepatic circulation of bile while

increasing the delivery of bile acids to the colon These

circumstances improve colonic motility and mucosal fluid

secretion, resulting in an overall reduction of completely

spontaneous bowel movements.79 Interestingly, multiple

biochemical pathways are reported to impact this disease

state (e.g., 5-HT4, guanylate cyclase C receptor), necessitating

additional studies prior to the drug’s approval in the United

States.80,81

A complete synthetic route to elobixibat is not explicitly

disclosed in peer-reviewed or patent literature However, a

series of patents from AstraZeneca describe the conversion of

an advanced intermediate to the API through a general

synthetic route.82 To date, however, no yields or specific

reaction details are associated with the preparation of the early

stage intermediate sulfone 160, but a general approach

described by authors from AstraZeneca is depicted inScheme

25

Aminobenzothiazole 153 was hydrolyzed using potassium

hydroxide to give mercaptophenol 154, which then underwent

a tandem alkylation/lactam formation with β-halopropanoic acid 155 to form benzothiazepine 156.Copper-catalyzed installation of the N-phenyl group with anunspecified halobenzene (halogen represented by “X” withinstructure 157) preceded reduction of the carbonyl groupwhich resulted in amine 159 This amine was oxidized tosulfone 160 using either hydrogen peroxide or trifluoroaceticacid (TFAA).82a

α,α-disubstituted-A milligram- to gram-scale conversion of phenol 160 toelobixibat is described in the patent literature This takes placevia sequential aminoester installations, as is depicted inScheme

26.82c Phenol 160 was alkylated using ethyl bromoacetate(161) to provide ester 162, which was saponified with sodiumhydroxide to yield acid 163 Aromatic substitution involvingsodium methanethiolate prior to amide coupling with (R)-2-phenylglycine methyl ester hydrochloride mediated by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluorobo-rate (TBTU) delivered aminoester 165 in high yield.Saponification of the ester gave acid 166 which was followed

by coupling with tert-butyl glycinate with 166 and subsequentTFA-mediated tert-butyl cleavage to furnish elobixibat hydrate(XVI) in 85% yield

Scheme 26 Synthesis of Elobixibat Hydrate (XVI)

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5.2 Tegoprazan Tegoprazan (XVII), discovered by Pfizer

and developed by RaQualia Pharma and CJ Healthcare, has an

orthogonal mechanism of action to first-line treatments for

gastroesophageal reflux disease (GERD) such that it is a

reversible and potassium-competitive acid blocker of the H+/

K+ ATPase.83In phase III clinical trials, once-daily dosing of

the drug (50 mg or 100 mg) to patients with erosive

esophagitis demonstrated noninferiority to esomeprazole (40

mg per day) in both healing and tolerability, supporting its

approval in Korea in 2018.84Tegoprazan therefore represents

an alternative treatment approach to proton pump inhibitors

(PPIs) such as esomeprazole, lansoprazole, omeprazole, and

rabeprazole

The most likely scalable synthesis of tegoprazan has been

described in an original patent filed by RaQualia (Scheme

27).85 Key challenges in the preparation of the drug are the

construction of the tetrasubstituted aryl core and efficient

introduction of the enantiomerically pure chromanol side

chain Starting with phenol 168, deprotonation of the phenol

led to enhanced nucleophilicity, enabling selective

O-benzylation Bromination with NBS para to the aniline

functionality afforded 169, an intermediate that contained

four appropriately placed functional groups present in the

heterocyclic core Acetylation of aniline 169 generated aprecursor to the methyl benzimidazole, which was thensubjected to palladium-catalyzed cyanation of the aryl bromide

at high temperature under microwave irradiation to yield 170.Iron-catalyzed reduction of the nitro group and concomitantcondensation with the proximal N-acetyl functionality securedbenzimidazole 171 Hydrolysis of the nitrile required forcingconditions, most likely due to the benzimidazole N−Hfunctionality Coupling of the resulting carboxylic acid withdimethylamine hydrochloride afforded amide 172 To makeway for chromanol side chain addition, benzimidazole 172 wasfirst protected as the tosylate prior to benzyl group removal viahydrogenolysis to give tosyl benzimidazole 173 Treatment of

173and enantiomerically pure alcohol 174 (Scheme 28) in n-butylphosphine with 1,1′-(azodicarbonyl)dipiperidine(ADDP) followed by silica gel purification and recrystallizationafforded ether 175 in high enantiomeric excess and good yield.Removal of the tosyl group under basic conditions providedtegoprazan (XVII) in 87% yield (>99% ee)

tri-Chromanol 174 was prepared by the condensation of

3,5-difluorophenol (176) with methyl propiolate using lammoniumfluoride (TBAF) as a base, affording 177 as a 1:1mixture of E and Z enol ethers Reduction of the double bond

tetrabuty-Scheme 27 Synthesis of Tegoprazan (XVII)

Scheme 28 Preparation of Tegoprazan Chromanol 174

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using catalytic hydrogenation and treatment with triflic acid

facilitated an intramolecular Friedel−Crafts acylation to yield

chromanone 178 in good yield for each step Asymmetric

reduction of ketone 178 with oxazaborolidine catalyst 179

using borane−dimethyl sulfide as the stoichiometric reductant

provided alcohol 174 in 88% yield and 86% ee, which could be

further resolved to >99% ee upon recrystallization A variant of

this route has been developed to provide 174 in increased yield

via conversion of 178 to the chromenone, asymmetric

reduction, and hydrogenation of the double bond, although

the value of the two additional steps is not clear relative to the

one-step process exemplified inScheme 28.86

6 INFLAMMATION AND IMMUNOLOGY DRUGS

6.1 Elagolix Sodium (Orlissa) Elagolix was developed by

AbbVie and Neurocrine Biosciences and approved by the

USFDA in July 2018 for the treatment of women with

endometriosis, a chronic disease resulting in intermenstrual

bleeding, nonmenstrual pelvic pain, and pain during

menstru-ation, intercourse, urinmenstru-ation, and defecation.87 Elagolix is a

gonadotropin-releasing hormone (GnRH) antagonist, which is

active by suppression of luteinizing hormone and

follicle-stimulating hormone Because GnRH-antagonists reduce

estrogen release, these drugs are less prone to side effects

related to complete estrogen suppression, such as bone mineral

density loss.88On the basis of the outcome of phase III clinic

trial, women who were treated with elagolix showed

improve-ments in productivity at work and less absenteeism, as well as a

significant decrease in reported levels of fatigue.89

Neurocrine Biosciences, Inc has published multiplesynthetic routes to elagolix, with both a milligram andmultikilogram scale demonstration.90 The synthetic routeshown inScheme 29 represents the most likely process scaleroute, beginning with the condensation of urea 180 and tert-butyl acetoacetate (181) under acidic conditions to generateuracil 182 Iodination of the uracil using iodine monochlorideprovided 183 in 90% yield, followed by a Suzuki coupling witharylboronic acid 184 These conditions provided 185 in highyield and were demonstrated on a multikilogram scale.Alkylation of uracil 185 with mesylate 187 (formed byreaction of (−)-N-Boc-D-α-phenylglycinol with methanesul-fonyl chloride (186)) followed by an acidic workup gave rise

to the polysubstituted uracil core 188 Alkylation of theprimary amine with ethyl 4-bromobutyrate enabled access toester 189, which requiredfiltration through a plug of silica gelfor purification Treatment of the ethyl ester with ethanolicsodium hydroxide followed by heptane recrystallizationprovided the target compound elagolix sodium (XVIII) in78% yield.90

6.2 Fostamatinib (Tavalisse) Fostamatinib was proved by the USFDA in 2018 for the treatment ofthrombocytopenia in adults with chronic immune thrombocy-topenia (ITP) who have not demonstrated sufficient response

ap-to prior treatment.91 Although fostamatinib is marketed byRigel Pharmaceuticals, the company has been involved inlicensing agreements with AstraZeneca for development of thedrug for other indications, including rheumatoid arthritis.92Fostamatinib functions as an inhibitor of spleen tyrosine kinaseScheme 29 Synthesis of Elagolix Sodium (XVIII)

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(SYK),91b,93 a key regulator of signal transduction pathways

that are involved in various autoimmune diseases.94

Fostamatinb inhibits Fcγ receptor (FcγR)-mediated signal

transduction, preventing cytoskeletal rearrangement which

results in decreased platelet destruction.95Due to low aqueous

solubility of the drug’s active form (R406), fostamatinib is

marketed as a methylene phosphonate prodrug which

undergoes conversion to the active metabolite of the drug in

the gut.95,96In clinical trials, ITP patients (even those who did

not previously respond to splenectomy, rituximab, and/or

thrombopoietic agent treatments) demonstrated statistically

significant responses when treated with fostamatinib.93

Atpresent, studies involving the drug as a treatment for other

indications such as IgA nephropathy and hemolytic anemia are

ongoing.91b

A large scale synthetic route to fostamatinib has been

reported by Rigel Pharmaceuticals and is outlined inScheme

30.97 Chlorination of pyrimidione 190 with POCl3 required

high temperature Upon cooling, monosubstitution with

aminopyridine 192 occurred regioselectively to provide

pyrimidine 193 in 77% yield Substituting chloropyrimidine

193 with amine 194 required heating in aqueous NMP to

furnish intermediate 195 in 91% yield Impressively, studies by

AstraZeneca showed that conditions could provide 195 at over

500 kg in single batch reactions.98Installation of the phosphate

side chain was demonstrated by alkylation of 195 with

tert-butyl phosphate 196 under basic conditions Phosphate 196

was prepared in a single step from chloromethyl chloridate (199) and potassium di-tert-butyl phosphate (200)

sulfuro-as shown in Scheme 31.97 Extraction with i-PrOAc led to a

solution of intermediate 197, which was not isolated butinstead heated with aqueous acetic acid which facilitated tert-butyl cleavage and precipitation of phosphonic acid inter-mediate 198 as an acetic acid solvate Conversion to the DMFsolvate enabled isolation of clean product in 88% yield afterwashing with MTBE The final step of the synthesis wasperformed on 1 kg scale and was accomplished by reaction ofthe DMF solvate of 198 with triethylamine in i-PrOH at roomtemperature,filtration, and subjection of the filtrate solution tosodium 2-ethylhexanoate in water and i-PrOH Fostamatinibhexahydrate (XIX) was isolated in 92% yield followingprecipitation from the reaction mixture.97

Scheme 30 Synthesis of Fostamatinib (XIX)

Scheme 31 Preparation of Fostamatinibtert-ButylPhosphate 196

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7 METABOLIC DRUGS

7.1 Evocalcet (Orkedia) Evocalcet is an oral allosteric

calcium-sensing receptor (CaSR) agonist discovered by

Mitsubishi Tanabe Pharma Corporation and developed by

Kyowa Kirin for the treatment of secondary

hyperparathyroid-ism in patients on maintenance dialysis Secondary

hyper-parathyroidism is a common mineral and bone disorder in

patients with chronic kidney disease.99 Evocalcet acts on

calcium receptors in parathyroid glands, effectively suppressing

parathyroid hormone secretion through a similar mechanism of

action as cinalcacet, a high volume calcimimetic produced by

Amgen.100When compared in a head-to-head phase III clinical

trial, evocalcet demonstrated superior safety and efficacy while

minimizing the upper gastrointestinal symptoms commonly

associated with cinalcacet.101 Evocalcet was granted approval

for manufacturing and market by Japan’s Ministry of Health,

Labor and Welfare (MHLW) in March 2018

The discovery synthesis of evocalcet was reported in a 2018

publication and patent disclosed by Kyowa Kirin and

Mitsubishi Tanabe Pharma Corporation.99,102 The synthesis

began with the activation of N-Boc pyrrolidinol 201 with triflic

anhydride, followed by a nucleophilic displacement with

(R)-(+)-1-(1-naphthyl)ethylamine (202), affording pyrrolidine

203 as a mixture of diastereomers Treatment of the

diastereomeric mixture with triphosgene and t-BuOH under

forcing conditions formed the corresponding Boc-protected

syn- and anti-diastereomers 204 and 205, respectively, which

were separable by column chromatography (Scheme 32)

After the desired syn-aminopyrrolidine 204 was isolated, aglobal deprotection was performed with HCl in dioxane Thecrude hydrochloride salts were then recrystallized from anEtOH and Et2O mixture, obtaining diamine 206 as a bis-hydrochloride salt and ethanol solvate in 94% yield over twosteps A subsequent palladium catalyzed Buchwald−Hartwigamination with pyrrolidine 206 and aryl bromide 207furnished aniline 208 in 63% yield Lastly, treatment of ester

208with aqueous sodium hydroxide facilitated conversion tothe carboxylic acid A final recrystallization from EtOHafforded evocalcet (XX) in 73% yield over two steps, with alongest linear sequence of eight steps (Scheme 33)

8 ONCOLOGY DRUGS8.1 Anlotinib Dihydrochloride (Fu Ke Wei) Anlotinibdihydrochloride, co-developed by Jiangsu Chia-Tai TianqingPharmaceutical and Advenchen Laboratories, was approved inChina in 2018 for use as a single-therapy treatment ofmetastatic or locally advanced non-small-cell lung cancer(NSCLC) in patients who have experienced disease pro-gression or recurrence after at least two lines of systemicchemotherapy treatments.103 The drug serves as a multi-targeting tyrosine kinase inhibitor, leading to inhibition ofmany vascular endothelial growth factor (VEGFR) tyrosinekinases, platelet-derived growth factor receptors (PDGFRs),fibroblast growth factor receptors (FGFRs), and tyrosinekinase receptor c-kit,104which are known for their critical role

in regulating tumor angiogenesis and tumor cell ation.104,105 Because the availability of effective first- and

prolifer-Scheme 32 Synthesis of Evocalcet Aminopyrrolidines 204 and 205

Scheme 33 Synthesis of Evocalcet (XX)

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second-line therapies for NSCLC is often limited, an increasing

need for new third-line therapies currently exists.106 Toward

this end, anlotinib has now shown improved progression-free

survival (PFS) and overall response rate (ORR) compared to

drugs having a similar mechanism of action.107,108The drug is

also currently undergoing clinical trials involving treatment of

metastatic renal cancer, soft tissue sarcomas, and a variety of

carcinomas.103

Although reagents, conditions, and yields for the published

synthetic route to anlotinib dihydrochloride described by

Advenchen Laboratories109 and Jiangsu Chia-Tai Tianqing

Pharmaceutical Co.110 possibly correspond to a discovery

route, a scalable synthesis likely involves the commercialfragments (or related derivatives) shown in Scheme 34:quinoline 209, indole 210, and cyclopropyl carbamate 213.Substitution of the chloride within 209 with phenol 210 wasfacilitated by DMAP in refluxing dioxane, and this wasfollowed by removal of the benzyl protecting group by transferhydrogenation Alkylation with mesylate 213 (arising fromalcohol 212) furnished the anlotinib core Removal of the CBzprotecting group followed by acidification and recrystallization

of the salt in cold ethanol provided anlotinib dihydrochloride(XXI) in a variety of crystal polymorphs.110a

Scheme 34 Synthesis of Anlotinib (XXI)

Scheme 35 Synthesis of Apalutamide (XXII)

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8.2 Apalutamide (Erleada) Apalutamide was approved

by the USFDA in 2018 for the treatment of nonmetastatic

castration-resistant prostate cancer (nmCRPC)111 and

repre-sents thefirst drug approved by the USFDA for nmCRPC.112

Initially discovered by the University of California,113the drug

was licensed to Aragon Pharmaceuticals and later Johnson &

Johnson (Janssen) after the company’s acquisition of Aragon in

2013.114 Apalutamide is a next-generation, nonsteroidal

androgen receptor (AR) antagonist, known to function by

binding to the ligand-binding domain of the AR, ultimately

inhibiting nuclear translocation, DNA binding, and

AR-mediated transcription Traditional treatment for metastatic

prostate cancer has relied on androgen deprivation therapy

(ADT), but resistance to the therapy is common, generally

resulting in progression to castration-resistant forms of the

disease.115 This resistance has spurred efforts for identifying

novel and improved AR-based therapies,116 and apalutamide

was discovered as part of these efforts As such, apalutamide

has shown substantially improved AR binding affinity over

bicalutamide.115 In clinical trials, nmCRPC patients treated

with apalutamide exhibited substantially longer metastasis- and

progression-free survival compared to placebo.117 Several

clinical trials remain ongoing with apalutamide relating to

scales of 50 g or larger.119A plausible scale route outlined by

Aragon is described in Scheme 35.119b

5-Nitro-3-(trifluoromethyl)pyridin-2-ol (215) underwent POBr3

-medi-ated conversion to the 2-bromopyridine intermediate, followed

by cyanation using sodium cyanide and copper(I) iodide in

butyronitrile to provide cyanopyridyl intermediate 216.119b

Chemoselective reduction of the nitro group within 216

involved a catalyst slurry (H3PO2, Pt/C, NH4VO3) in xylenes

and butyronitrile under a hydrogen atmosphere.120 The

resulting aminopyridine 217 was telescoped into a

CDI-mediated coupling reaction with Boc-protected amino acid

218to yield amide 219, which was then purified by distillation

No yields were reported for the three-step telescopedconversion of 215 to 219.119bBoc cleavage using HCl in i-PrOH preceded an Ullman-type coupling with aryl bromide

231giving rise to thiohydantoin precursor 232 in 84% yield.Lastly, exposure of 232 to 1,1′-thiocarbonylbis(pyridin-2(1H)-one) (233) and DMAP in warm DMA provided apalutamide(XXII) in 80% yield.119b

8.3 Binimetinib (Mektovi) Binimetinib is a non-ATPcompetitive mitogen-activated protein kinase 1/2 (MEK1/2)inhibitor discovered by Array BioPharma and approved for use

in combination with the BRAF inhibitor encorafenib (Braftovi)for the treatment of BRAF V600E/K mutant melanomas.121While use of BRAF inhibitors alone provides efficacy in BRAFmutant malignancies including 40−50% of metastaticmelanomas, re-emergence of disease is common.122 Amechanistic understanding of this finding has emerged: inpatients treated with BRAF inhibitors, concomitant inhibition

of wild-type BRAF paradoxically leads to activation of themitogen-activated protein kinase (MAPK) pathway, resulting

in resistance and the development of keratoacanthomas andsquamous cell carcinomas Supplementing Braftovi therapywith binimetinib blocks MAPK-induced MEK1/2 signalingresulting in increased progression-free survival (PFS) andoverall survival (OS) compared to encorafenib or vemurafenib(another BRAF inhibitor).123 Binimetinib is currently mar-keted in the U.S by Pfizer after its acquisition of ArrayBioPharma in 2019

The most recent and largest demonstrated scale (0.1 mol)route to binimetinib avoids the use of silica gel chromatog-raphy and is described inScheme 36.124A noteworthy aspect

of this sequence is the effective introduction and tion of multiple reactive nitrogen atoms in building thepentasubstituted benzoyl core Coupling of 2,3,4-trifluoro-5-nitrobenzoic acid (234) with O-alkylhydroxylamine 235 usingCDI and diisopropylethylamine afforded alkoxyamide 236 inScheme 36 Synthesis of Binimetinib (XXIII)

functionaliza-https://dx.doi.org/10.1021/acs.jmedchem.0c00345

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