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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*

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

1. INTRODUCTION
The most fruitful basis for the discovery of a new drug is to
start with an old drug.

only a discovery-scale or a general synthetic approach capable

of delivering the active pharmaceutical ingredient (API) has
been made available. Nonetheless, the synthetic sequences
described in this review have all been previously reported in
either patent or public chemical literature and, to the best of
our assessment, represent scalable routes originating from
commercially available starting materials (as determined by
explicit statement or inferred by experimental detail).

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 the first time by a governing body anywhere in
the world during the 2018 calendar year (Figure 1).3 Each drug
is prefaced by a brief introduction summarizing the relevant
pharmacology or differentiating features of the medicine.4 New
indications for previously launched medications, new combinations or formulations of existing drugs, and drugs
synthesized entirely by biological processes or peptide
synthesizers have been excluded from coverage. For organizational 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, ophthalmologic, 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,
© XXXX American Chemical Society

2. ANTIBIOTIC AND ANTIFUNGAL DRUGS
2.1. Eravacycline (Xerava). Eravacycline belongs to the
tetracycline class of antibiotics and was approved by the
United States Food and Drug Administration (USFDA) for
the treatment of complicated intra-abdominal infections in
patients aged 18 years and older. Eravacycline is a fully
synthetic broad-spectrum antibiotic that exhibits potent
activity against both Gram-positive and Gram-negative
bacterial strains, including many that have acquired tetracycline-specific resistant mechanisms.5 Eravacycline was discovered and developed by Tetraphase Pharmaceuticals and was
Received: February 26, 2020
Published: April 27, 2020

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Figure 1. continued

B


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Figure 1. continued

C

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Figure 1. Structures of 39 NCEs approved in 2018.

licensed to Everest Medicines for commercialization in many
eastern Asian countries.
Two other tetracycline antibiotics, sarecycline and omadacycline, were also approved this year, but both molecules were

prepared from previously approved tetracyclines that were
ultimately obtained via fermentation. Eravacycline is a fully

synthetic tetracycline, and a highly convergent route for its
preparation was first described by the laboratory of Professor
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Figure 2. Retrosynthetic approach to eravacycline.

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

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 1.8c Dimethyl maleate (5) was treated with bromine in
the presence of azo-bis(isobutyronitrile) (AIBN) and ultraviolet light to give dibromide 6 in 92% yield. Condensation of
6 with 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 tertbutylsulfinyl group was removed under acidic conditions. The
resulting primary amine was treated with formaldehyde in the
presence of sodium acetate and then reduced using a picoline−
borane complex to give the dimethylamine coupling partner 4
in 88% yield for the two-step sequence (96.0% ee). The ee was
enhanced to 99.0% by tartrate salt formation, giving 4·tartrate
in 91% yield.
The preparation of the tricyclic Michael acceptor enone 2 is
described in Scheme 2.8b Treating 4·tartrate with sodium
hydroxide provided the free base 4, which was reacted with
tetramethylpiperidine (TMP) magnesium chloride−lithium
chloride complex to effect the direct magnesiation of 4 on
the oxazole ring, with no competing allylic metalation. This
intermediate was reacted with aldehyde 3 to give alcohols 11a/
11b in 95% yield (3.57:1 dr). Heating the mixture of 11a/11b
in DMSO, DIPEA, butylated hydroxytoluene, and isopropyl
acetate effected the intramolecular Diels−Alder reaction to
give 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 sulfur
trioxide pyridine complex to give ketones 13a/13b in 99.1:0.9
dr and 74% overall yield from 11a/b. Treating 13a/13b with
boron trichloride efficiently effected demethylation of the
methyl enol ether, which spontaneously underwent ring
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Scheme 2. Construction of Eravacycline Tricyclic Michael Acceptor Enone 2

Scheme 3. Preparation of Dibenzyl Amine Protected Coupling Partner 1

ether gave nitroarene 18. Reduction of the nitro group with
sodium bisulfite provided aniline 19 in 83% from compound
15. Amine 19 was reacted with benzyl bromide to produce the
dibenzylamine-protected coupling partner 1 in 80% yield.
The completion of the synthesis of eravacycline (I) is
described in Scheme 4.8a Compound 1 was treated with LDA
followed by compound 2 to promote the desired intermolecular Michael addition. The resulting Michael adduct was
then treated with lithium bis(trimethylsilyl)amide (LHMDS)
to induce an intramolecular Dieckmann cyclization, which gave

compound 20 in 94% yield. The silyl protecting group was

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
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Scheme 4. Final Assembly of Eravacycline (I)

Scheme 5. Synthesis of Ravuconazole (35)

removed using hydrofluoric acid, and the resulting intermediate was treated with hydrogen and palladium on carbon.


These conditions resulted in the removal of the dibenzylamine
and benzyl ether protecting groups, which further gave rise to
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Scheme 6. Synthesis of Fosravuconazole L-Lysine Ethanolate (II)

Scheme 7. Synthesis of Omadacycline III

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 2018.9 F-RVCZ is
a prodrug of ravuconazole with improved solubility and oral
bioavailability.10 Originally discovered by Eisai,11 ravuconazole
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 improved
safety-profile (lower hepatic functional disorders), and
improved dosing regimen (once daily for 12 weeks) over
existing standards of care such as terbinafine and itraconazole.12
In addition to several disclosures describing the gram-scale
synthesis of ravuconazole and related precursors,13 a robust
plant-scale preparation has been described by researchers at
BMS (Scheme 5).14 This route utilized lactate 23 as a starting
material for the preparation of arylpropanone 26. First, methyl
ester 23 was converted to a morpholine amide in the presence
of catalytic sodium methoxide. The alcohol was subsequently
protected to generate tetrahydropyranyl ether 24. Use of realtime infrared reaction monitoring allowed for safe formation of
Grignard reagent 25 from the corresponding bromide, which
was then reacted with amide 24 to furnish aryl ketone 26 after
aqueous acetic acid quench. Corey−Chaykovsky epoxidation
and subsequent epoxide opening were performed in a singlestep, telescoped process. Once epoxidation was complete,
heating the reaction mixture to 90 °C triggered a triazolemediated epoxide-opening sequence to form alcohol 28. The
stereochemical outcome of the epoxide-forming step is
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Scheme 8. Synthesis of Plazomicin (IV)

Paratek Pharmaceuticals, omadacycline was licensed to Bayer,
Merck, and Novartis over the course of its clinical development. Ultimately the rights were returned to Paratek, who
collaborated with Zai Lab (Shanghai) Co., Ltd. to commercialize the drug in China.17
A number of syntheses of omadacycline have been
published, and the largest scale route is described in Scheme
7. This route advantageously began with minocycline (38,
Scheme 7) which is a tetracyclic antibiotic drug first patented
in 1961. 1 8 Minocycline was condensed with N(hydroxymethyl)phthalimide (39) in the presence of triflic
acid to give a mixture of the 9-phthalimidomethyl analogs 40
and 41 in approximately a 60:40 ratio. This mixture was
treated with methylamine, which resulted in hydrolysis of the
phthalimide to give an unreported distribution of methylamine
analogs 42 and 43. This mixture was then treated with
pivaldehyde under catalytic hydrogenation conditions to affect
the reductive amination at position N-9, followed by
concomitant removal of the hemiaminal group on the amide,
furnishing omadacycline (III) in 15−18% yield for the overall
process after conversion to the tosylate salt.
2.4. Plazomicin (Zemdri). Originally discovered by

California-based Ionis Pharmaceuticals and later developed
by Achaogen, plazomicin was approved by the USFDA in 2018
for the treatment of patients 18 years of age or older with
complicated urinary tract infections (cUTI), including
pyelonephritis. The drug, a next-generation aminoglycoside

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 dithiophosphate 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 chloromethylphosphate 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 fosravuconazole L-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 communityacquired bacterial pneumonia.16 Discovered and developed by

I

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Scheme 9. Synthesis of Sarecycline Hydrochloride (V)

Scheme 10. Assembly of Baloxavir Piperazine Heterocyclic Core 59

completed the development and launch of the drug before
rights 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 in Scheme
9.23 Iodination of commercially available sancycline 51 with Niodosuccinimide followed by HPLC purification provided
iodosancycline 52 as the trifluoroacetate salt (no yield
reported). Carbonylation of 52 in the presence of palladium
acetate and Xantphos followed by treatment with triethylsilane
provided the corresponding aldehyde, which was treated with
trifluoracetic acid to provide formylsancycline trifluoroacetate
53.24 Condensation of 53 with N,O-dimethylhydroxylamine
hydrochloride, reduction with sodium cyanoborohydride, and
treatment with hydrochloric acid provided sarecycline hydrochloride (V) in 23% yield for the three-step sequence.


that is delivered by injection, was acquired by Cipla as part of
an auction of Achaogen assets after the American firm filed for
chapter 11 bankruptcy.19 As a structural derivative of the antiinfective aminoglycoside sisomycin, plazomicin is a neoglycoside 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 carbapenemresistant 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 ionexchange 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

3. ANTI-INFECTIVE DRUGS
3.1. Baloxavir Marboxil (Xofluza). In 2018, baloxavir
marboxil received its first approval by the Pharmaceuticals and
Medical Devices Agency of Japan (PMDA) for the treatment

of influenza A or B virus infections.25 Later the same year, the
drug was also approved by the USFDA for the treatment of
acute uncomplicated influenza (flu) in patients 12 years of age
and older who have been symptomatic for no more than 48
h.26 Baloxavir marboxil was discovered by Shionogi, who
licensed their rights to Roche in February 2016 for
development and commercialization except in Taiwan and
Japan (Shionogi maintained its rights in these two
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Scheme 11. Construction of Baloxavir Benzothiepine 62

Scheme 12. Final Assembly of Baloxavir Marboxil (VI)

countries).25 Baloxavir 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.28 The route expected to be most scalable is depicted
in Schemes 10, 11, and 12. This approach strategically hinges
upon union of a piperazine tricyclic core and a tricyclic diaryl
mercaptan.28b Acid 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 by
acidification and reduction furnished benzothiepine alcohol
62 in 73% yield.
The final steps in the assembly of baloxavir marboxil are
described in Scheme 12. Enantiomeric resolution of 59 was
performed by reacting 59 with commercial chiral acid 63
followed by recrystallization from warm ethyl acetate. The
diastereomer corresponding to the desired geometry was then
collected and treated with DBU which provided enantiomerically enriched free base 64. Although this reaction was
exemplified on kilogram-scale, the chiral purity was not
reported. The benzyl ether within 64 was then converted to
the corresponding n-hexyl ether using n-hexanol and
isopropylmagnesium chloride, making way for isolation of
tosylate salt 65 after treatment with p-TsOH. Next, 62 was
subjected to propylphosphonic anhydride (T3P) under acidic
conditions and coupled with fragment 65 to form the core
structure of baloxavir marboxil. Subsequent treatment with

base and methanesulfonic acid led to the formation of mesylate
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Scheme 13. Synthesis of Bictegravir (VII)

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.29 This 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
72 and TFA ultimately furnished β-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-aminopentanol 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 bromidemediated demethylation furnished bictegravir (VII).
The preparation of syn-aminopentanol 78 has been
described on gram scale by the Chinese firm Anhui Twisun
Hi-Tech Pharmaceutical Co., Ltd. in Scheme 14.33 CommerScheme 14. Preparation of Bictegravir syn-Aminopentanol
78

cial cyclopentanoic acid 80 was converted to the corresponding Weinreb amide 81 which was then exposed to
methylmagnesium bromide, giving rise to ketone 82.
Subjection of 82 to Baeyer−Villiger oxidation conditions
resulted in a rearrangement product whereby the more
substituted carbon of the ketone underwent rearrangement,
presumably with retention of stereochemical configuration.34

Subsequent treatment with base and finally acidic removal of
the Boc group provided aminopentanol 78. Although yields
were reported for this sequence, stereoselectivity was not.
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Scheme 15. Preparation of Danoprevir Cyclopropyl Aminoester 87

Scheme 16. Synthesis of Danoprevir (VIII)

highly stable complex displaying unusually slow dissociation.37
With a calculated complex half-life of roughly 5 h, the observed
binding kinetics distinguish danoprevir from other related
macrocyclic inhibitors of NS3. Danoprevir is also a substrate of
cytochrome 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 initially
reported in a series of three patents disclosed in 2005.38 A
slightly different route derived from the same starting
cyclopropyl aminoester was published in 2014.39 To date no

explicit scale synthesis has been reported. However, scientists
at Boehringer-Ingelheim have reported a concise approach to

3.3. Danoprevir (Ganovo). Danoprevir is an orally
available hepatitis C virus nonstructural protein 3 (NS3)
protease inhibitor approved in 2018 in China for treatmentnaive patients with noncirrhotic genotype 1b chronic hepatitis
C.35 Discovered 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.35 Hepatitis 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.36 Protease 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
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Scheme 17. Synthesis of Doravirine (IX)

found in treatment-naive patients while exhibiting an improved

safety-profile over existing standard-of-care regimens such as
ritonavir, darunavir, and efavirenz.
A considerable number of accounts related to the
preparation of doravirine and related analogs have been
published,43 and a robust, kilogram-scale synthesis of the drug
has been described by researchers at Merck (Scheme 17).44
Strategically, this scale route was designed to proceed through
substrates that would minimize the evolution of doravirine
byproducts that arose from polymethylation and polycyanation, which were challenging to remove by methods other than
chromatography. Toward this end, an iridium-catalyzed metaborylation−oxidation protocol converted iodochlorobenzene
98 to phenol 99, which then participated in an SNAr reaction
with 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 using
copper cyanide in NMP was achieved under relatively mild
conditions. The authors note that keeping the temperature
under 110 °C was critical for suppressing undesired biscyanation products and that the iodide was chosen over the
analogous bromide to further help ensure selectivity for the
desired mononitrile product 103. Alkylation of 103 with 5(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (104) was
possible under mild conditions to give 2-pyridone 105 in 81%
yield after recrystallization. Although 104 is commercially
available, reports of its preparation have also been previously
published.45 Lastly, after screening a variety of methylation
conditions, 105 was treated with iodomethane and potassium
carbonate in cool NMP, furnishing doravirine (IX) in 68%
yield, with minimal overmethylation products observed.44
3.5. Moxidectin (Moxidectin). Moxidectin was developed
by the nonprofit firm Medicines Development for Global
Health (MDGH) and was approved by the USFDA in 2018 for
the treatment of river blindness, also called onchocerciasis, in

patients aged 12 years and older.46 River blindness is caused by

the building block cyclopropyl aminoester 87 (a substructural
component of several macrocyclic antiviral drugs) on multikilogram scale, and this approach is described in Scheme 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. HATUmediated 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.41 The
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
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Scheme 18. Synthesis of Moxidectin (X)

Scheme 19. Preparation of Tafenoquine Nitroquinoline Intermediate 115

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-aminobutyric acid (GABA) receptors, and/or ATP-binding cassette
(ABC) transporters.48 This induces increased permeability that

leads to an influx of chloride ions and results into flaccid
paralysis of the parasite. Moxidectin is active against microfilariae 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 macrolactone
nemadectin (106), a fermentation product of Streptomyces
cyanogriseus ssp. noncyanogenus.51 Although several Chinese
patents have been filed describing the conversion of
nemadectin to moxidectin,52 the route described in the most
detail is presented in Scheme 18.52d Selective protection of the
nemadectin C-25 allylic hydroxyl group with 4-chlorophenoxy
acetyl chloride 107 furnished 108. The choice of this
protecting group was driven by improved stability and simpler
purification (recrystallization) of the intermediates. The
remaining C-10 secondary alcohol in 108 was oxidized using
modified Pfitzner−Moffat conditions using phenyl phosphorodichloridate (109) to yield ketone 110.53 Oxime formation
and selective saponification of the ester protecting group
furnished moxidectin (X). It should be noted that the oxime
retains the (E)-configuration throughout the final two steps of
the synthesis of the molecule.54
3.6. Tafenoquine (Krintafel). Tafenoquine is an orally
active antimalarial therapy targeting Plasmodium vivax in
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Scheme 20. Synthesis of Tafenoquine (XI)

Scheme 21. Synthesis of Tecovirimat (XII)

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 polymerization57 and induce apoptosis in select strains.58 Tafenoquine
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 pAnisidine 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 subsequent
nitration converted 114 to nitroquinoline 115.
This highly activated quinoline was subjected to a
substitution reaction with phenol 116 under basic conditions.
Next, treatment with Darco KB and hydrazine-promoted
nitroreduction gave amine 117 in a 73% yield for the three step
sequence (Scheme 20). Alkylation of 117 with commercial
iodide 118 was performed in a mixture of warm NMP and
diisopropylamine followed by hydrazine-mediated conversion
of the phthalimide to the corresponding primary amine.
Sequential exposure to potassium hydroxide and succinic acid
completed the synthesis of tafenoquine (XI) in 63% from 119.
3.7. Tecovirimat (Tpoxx). Tecovirimat, which was
developed by SIGA Technologies and the United States
Department of Health and Human Services Biomedical
Advances Research and Development Authority, is the first
oral treatment for smallpox. Although smallpox was eradicated
due to effective vaccination practices, many people worldwide
are now unvaccinated. Because health authorities believe that a
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Scheme 22. Synthesis of Avatrombopag Maleate (XIII)

treatment of thrombocytopenia in adult patients with chronic
liver disease who are scheduled to undergo a procedure. It was
first approved by the USFDA in May 2018 and subsequently
approved by the European Medicine Agency (EMA) in June
2019.67,68 Originally developed by Astellas, avatrombopag’s
development rights have been transferred between a number of
firms, most recently Dova Pharmaceuticals (an affiliate of PBM
Capital). In March 2018, Dova entered into an agreement
(through AkaRx) to grant Shanghai Fosun Pharma the
exclusive development and distribution rights of the drug in
mainland China and Hong Kong.69
A large scale synthetic route to avatrombopag, as well as
crystalline form protocols, have been reported in a series of
patents from Astellas.70 As described in Scheme 22,
bromination of 1-(4-chlorothiophen-2-yl)ethenone (124)
gave bromide 125. Condensation with thiourea produced
thiazolamine 126 in 46% yield over two steps. Thiazolamine
126 was brominated with N-bromosuccinimide (NBS) in
DMF, making way for nucleophilic aromatic substitution with
1-cyclohexylpiperazine (127) to provide 128 in 34% overall
yield. Amide bond formation with 5,6-dichloronicotinic acid
(129) was accomplished by activation with phosphorus
oxychloride to give nicotinamide 130 in 83% yield. A second
nucleophilic aromatic substitution with ethyl isonipecotate

131, followed by hydrolysis, provided avatrombopag (132).70a
Salt formation was demonstrated on 20 kg scale using maleic
acid in a mixture of DMSO/acetone/water (2:2:1) to obtain
avatrombopag maleate (XIII) in 85% yield.70b,c
4.2. Revefenacin (Yupelri). Developed by Theravance
Biopharma and Mylan, revefenacin is a long-acting muscarinic
antagonist approved by the USFDA in 2018 for the treatment
of chronic obstructive pulmonary disease (COPD).71 Administered as an inhaled solution, the drug was first licensed to
GSK from Theravance in 2004. However, the developing rights

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 Tecovirimat was approved under the USFDA’s Animal Rule, as clinical
studies in humans were not ethical or feasible.62 This 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. Government’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.65 Recrystallization 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
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Scheme 23. Synthesis of Revefenacin (XIV)

allowing erythropoiesis to occur.75 The drug also increases iron
bioavailability by suppressing peptide hormone hepcidin levels,
thus ameliorating anemia by boosting the body’s natural
oxygen-sensing and response system without the need of
intravenous iron supplementation. Roxadustat can also be
prescribed to patients who use hemodialysis or peritoneal

dialysis.
A surge of patents published in 2017 and 2018 described
several unique synthetic routes to roxadustat.76 FibroGen
reported the first small scale synthesis of roxadustat in 2004,77
and in 2014 this same organization devised a robust kilogramscale route which is depicted in Scheme 24.78 The nine-step
synthetic sequence commenced with 5-bromophthalide 141,
which was converted to 5-phenoxyphthalide 142 via a modified
Ullman-type coupling.78 The reaction was performed on 85 kg
scale. The γ-lactone 142 was opened to furnish an acid
chloride intermediate which delivered methyl ester 143 upon
treatment with MeOH. Substitution of benzyl chloride 143
with p-toluenesulfonylglycine methyl ester (144) was carried
out under Finkelstein conditions to produce intermediate 145,
which then underwent base-mediated cyclization and subsequent aromatization to produce isoquinoline 146 in 58%
yield from 142. Regiospecific Mannich aminomethylation of
isoquinoline 146 was achieved with bis(dimethylamino)methane 147 in acetic acid to furnish dimethylaminomethyl
intermediate 148, which was subsequently activated with acetic
anhydride to replace the dimethylamino group with an acetoxy
moiety. The reaction yielded the intended isoquinolinol 150.
The undesired bis-acetoxy adduct 149 could be recycled to
generate additional 150 upon treatment with morpholine.
Reduction of the acetoxy group under hydrogenation
conditions yielded 151, and this intermediate was converted

were returned to Theravance in 2009 due to incompatibility
with GSK’s proprietary inhaler device.71 Revefenacin binds
competitively and reversibly to the muscarinic M3 receptors 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 dialysisdependent 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 enzymes
regulate 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,
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Scheme 24. Synthesis of Roxadustat (XV)

Scheme 25. General Route to Elobixibat Sulfone 160

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

5. GASTROINTESTINAL DRUGS

methoxide.

5.1. Elobixibat Hydrate (Goofice). Elobixibat is a highly
potent, first-in-class inhibitor of ileal bile acid transport and
approved for the treatment of chronic idiopathic constipation,
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Scheme 26. Synthesis of Elobixibat Hydrate (XVI)

a tandem alkylation/lactam formation with α,α-disubstitutedβ-halopropanoic acid 155 to form benzothiazepine 156.
Copper-catalyzed installation of the N-phenyl group with an
unspecified halobenzene (halogen represented by “X” within
structure 157) preceded reduction of the carbonyl group
which resulted in amine 159. This amine was oxidized to
sulfone 160 using either hydrogen peroxide or trifluoroacetic
acid (TFAA).82a
A milligram- to gram-scale conversion of phenol 160 to
elobixibat is described in the patent literature. This takes place
via sequential aminoester installations, as is depicted in Scheme
26.82c Phenol 160 was alkylated using ethyl bromoacetate
(161) to provide ester 162, which was saponified with sodium
hydroxide to yield acid 163. Aromatic substitution involving
sodium methanethiolate prior to amide coupling with (R)-2phenylglycine methyl ester hydrochloride mediated by 2-(1Hbenzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (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 subsequent
TFA-mediated tert-butyl cleavage to furnish elobixibat hydrate
(XVI) in 85% yield.

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 in Scheme
25.
Aminobenzothiazole 153 was hydrolyzed using potassium
hydroxide to give mercaptophenol 154, which then underwent
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Scheme 27. Synthesis of Tegoprazan (XVII)

Scheme 28. Preparation of Tegoprazan Chromanol 174


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.83 In 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 2018.84 Tegoprazan 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 Obenzylation. 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 a
precursor to the methyl benzimidazole, which was then
subjected 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 concomitant
condensation with the proximal N-acetyl functionality secured
benzimidazole 171. Hydrolysis of the nitrile required forcing

conditions, most likely due to the benzimidazole N−H
functionality. Coupling of the resulting carboxylic acid with
dimethylamine hydrochloride afforded amide 172. To make
way for chromanol side chain addition, benzimidazole 172 was
first protected as the tosylate prior to benzyl group removal via
hydrogenolysis to give tosyl benzimidazole 173. Treatment of
173 and enantiomerically pure alcohol 174 (Scheme 28) in trin-butylphosphine with 1,1′-(azodicarbonyl)dipiperidine
(ADDP) followed by silica gel purification and recrystallization
afforded ether 175 in high enantiomeric excess and good yield.
Removal of the tosyl group under basic conditions provided
tegoprazan (XVII) in 87% yield (>99% ee).
Chromanol 174 was prepared by the condensation of 3,5difluorophenol (176) with methyl propiolate using tetrabutylammonium fluoride (TBAF) as a base, affording 177 as a 1:1
mixture of E and Z enol ethers. Reduction of the double bond
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Scheme 29. Synthesis of Elagolix Sodium (XVIII)

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 in Scheme 28.86

Neurocrine Biosciences, Inc. has published multiple
synthetic routes to elagolix, with both a milligram and
multikilogram scale demonstration.90 The synthetic route
shown in Scheme 29 represents the most likely process scale
route, beginning with the condensation of urea 180 and tertbutyl acetoacetate (181) under acidic conditions to generate
uracil 182. Iodination of the uracil using iodine monochloride
provided 183 in 90% yield, followed by a Suzuki coupling with
arylboronic acid 184. These conditions provided 185 in high
yield and were demonstrated on a multikilogram scale.
Alkylation of uracil 185 with mesylate 187 (formed by
reaction of (−)-N-Boc-D-α-phenylglycinol with methanesulfonyl chloride (186)) followed by an acidic workup gave rise
to the polysubstituted uracil core 188. Alkylation of the
primary amine with ethyl 4-bromobutyrate enabled access to
ester 189, which required filtration through a plug of silica gel
for purification. Treatment of the ethyl ester with ethanolic
sodium hydroxide followed by heptane recrystallization
provided the target compound elagolix sodium (XVIII) in
78% yield.90
6.2. Fostamatinib (Tavalisse). Fostamatinib was approved by the USFDA in 2018 for the treatment of
thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have not demonstrated sufficient response
to prior treatment.91 Although fostamatinib is marketed by

Rigel Pharmaceuticals, the company has been involved in
licensing agreements with AstraZeneca for development of the
drug for other indications, including rheumatoid arthritis.92
Fostamatinib functions as an inhibitor of spleen tyrosine kinase

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 menstruation, intercourse, urination, and defecation.87 Elagolix is a
gonadotropin-releasing hormone (GnRH) antagonist, which is
active by suppression of luteinizing hormone and folliclestimulating 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.88 On the basis of the outcome of phase III clinic
trial, women who were treated with elagolix showed improvements in productivity at work and less absenteeism, as well as a
significant decrease in reported levels of fatigue.89
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Scheme 30. Synthesis of Fostamatinib (XIX)


(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.95 Due 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.95,96 In 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 At
present, 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 in Scheme
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.98 Installation of the phosphate
side chain was demonstrated by alkylation of 195 with tertbutyl phosphate 196 under basic conditions. Phosphate 196

was prepared in a single step from chloromethyl sulfurochloridate (199) and potassium di-tert-butyl phosphate (200)
as shown in Scheme 31.97 Extraction with i-PrOAc led to a

Scheme 31. Preparation of Fostamatinib tert-Butyl
Phosphate 196

solution of intermediate 197, which was not isolated but
instead heated with aqueous acetic acid which facilitated tertbutyl cleavage and precipitation of phosphonic acid intermediate 198 as an acetic acid solvate. Conversion to the DMF
solvate enabled isolation of clean product in 88% yield after
washing with MTBE. The final step of the synthesis was
performed on 1 kg scale and was accomplished by reaction of
the DMF solvate of 198 with triethylamine in i-PrOH at room
temperature, filtration, and subjection of the filtrate solution to
sodium 2-ethylhexanoate in water and i-PrOH. Fostamatinib
hexahydrate (XIX) was isolated in 92% yield following
precipitation from the reaction mixture.97
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Scheme 32. Synthesis of Evocalcet Aminopyrrolidines 204 and 205

Scheme 33. Synthesis of Evocalcet (XX)

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 hyperparathyroidism in patients on maintenance dialysis. Secondary hyperparathyroidism 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.100 When 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, a
global deprotection was performed with HCl in dioxane. The
crude hydrochloride salts were then recrystallized from an
EtOH and Et2O mixture, obtaining diamine 206 as a bishydrochloride salt and ethanol solvate in 94% yield over two
steps. A subsequent palladium catalyzed Buchwald−Hartwig
amination with pyrrolidine 206 and aryl bromide 207

furnished aniline 208 in 63% yield. Lastly, treatment of ester
208 with aqueous sodium hydroxide facilitated conversion to
the carboxylic acid. A final recrystallization from EtOH
afforded evocalcet (XX) in 73% yield over two steps, with a
longest linear sequence of eight steps (Scheme 33).

8. ONCOLOGY DRUGS
8.1. Anlotinib Dihydrochloride (Fu Ke Wei). Anlotinib
dihydrochloride, co-developed by Jiangsu Chia-Tai Tianqing
Pharmaceutical and Advenchen Laboratories, was approved in
China in 2018 for use as a single-therapy treatment of
metastatic or locally advanced non-small-cell lung cancer
(NSCLC) in patients who have experienced disease progression or recurrence after at least two lines of systemic
chemotherapy treatments.103 The drug serves as a multitargeting tyrosine kinase inhibitor, leading to inhibition of
many vascular endothelial growth factor (VEGFR) tyrosine
kinases, platelet-derived growth factor receptors (PDGFRs),
fibroblast growth factor receptors (FGFRs), and tyrosine
kinase receptor c-kit,104 which are known for their critical role
in regulating tumor angiogenesis and tumor cell proliferation.104,105 Because the availability of effective first- and
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Scheme 34. Synthesis of Anlotinib (XXI)

Scheme 35. Synthesis of Apalutamide (XXII)

route, a scalable synthesis likely involves the commercial
fragments (or related derivatives) shown in Scheme 34:
quinoline 209, indole 210, and cyclopropyl carbamate 213.
Substitution of the chloride within 209 with phenol 210 was
facilitated by DMAP in refluxing dioxane, and this was
followed by removal of the benzyl protecting group by transfer
hydrogenation. Alkylation with mesylate 213 (arising from
alcohol 212) furnished the anlotinib core. Removal of the CBz
protecting group followed by acidification and recrystallization
of the salt in cold ethanol provided anlotinib dihydrochloride
(XXI) in a variety of crystal polymorphs.110a

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.107,108 The 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
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