Bioorganic & Medicinal Chemistry 22 (2014) 2005–2032

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry

journal homepage: www.elsevier.com/locate/bmc

Review

Synthetic approaches to the 2012 new drugs

Hong X. Ding a, , Carolyn A. Leverett b,à, Robert E. Kyne Jr. b,§, Kevin K.-C. Liu c,–, Subas M. Sakya d,k,
Andrew C. Flick b,  , Christopher J. O’Donnell b,⇑
a
PharmaPhase Co., Ltd, Beijing 100193, China
b
Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, CT 06340, United States
c
Lilly China Research and Development Center, Shanghai 201203, China
d
BioDuro Co., Ltd, Shanghai 200131, China

a r t i c l e i n f o a b s t r a c t

Article history: New drugs introduced to the market every year represent a privileged structure for a particular biological
Received 27 December 2013 target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as
Revised 11 February 2014 leads for designing future new drugs. This review covers the synthesis of twenty-six NCEs that were
Accepted 13 February 2014
launched or approved worldwide in 2012 and two additional drugs which were launched at the end of
Available online 25 February 2014
2011.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
New drug molecules
New chemical entities
Medicine
Therapeutic agents

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2006
2. Aclidinium bromide (Tudorza PressairÒ, Eklira GenuairÒ, Bretaris GenuaiÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2006
3. Allisartan isoproxil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2006
4. Anagliptin (BeskoaÒ, SuinyÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2006
5. Axitinib (InlytaÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2009
6. Azilsartan (AzilvaÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2010
7. Bedaquiline fumarate (SirturoÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2012

Abbreviations: 1,2-DAP, 1,2-diaminopropane; 1,2-DCE, 1,2-dichloroethane; Ac, acetyl; aq, aqueous; B2(pin)2, bis(pinacolato)diboron; BINAP, 2,20 -bis(diphenylphosphino)-
1,10 -binaphthyl; BOP, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophospate; CDI, N,N0 -carbonyldiimidazole; DAP, diaminopropane; DBU, 1,5-diazabi-
cycolo[4.3.0]non-5-ene; DCC, 1,3-dicyclohexylcarbodiimide; DCM, dichloromethane; DIC, 1,3-diisopropylcarbodiimide; DIEA/DIPEA, diisopropylethylamine; DMA, dimeth-
ylacetamide; DMAP, 4-dimethylaminopyridine; DME, dimethoxyethane; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; DPPA, diphenylphosphoryl azide; EDC,
N-(3-dimethylaminopropal)-N0 -ethylcarbodiimide; Fmoc, 9-fluorenylmethoxycarbonyl; HBTU, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate;
HOBT, 1-hydroxybenzotriazole hydrate; IPAc, isopropyl acetate; LAH, lithium aluminum hydride; LHMDS, lithium bis(trimethylsilyl)amide; LDA, lithium diisopropylamide;
MEK, methyl ethyl ketone; MIBK, 4-methyl-2-pentanone; NBS, N-bromosuccinimide; NMM, N-methylmorpholine; NMP, N-methyl-2-pyrrolidone; Pd2(dba)3, tris(dibenzyl-
ideneacetone)dipalladium(0); Pd(dppf)Cl2, [1,10 -bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4, tetrakis(triphenylphosphine)palladium(0); pin, pinacol;
Py, pyridine; RT, room temperature; STAB-H, sodium triacetoxyborohydride; TBAF, t-butyl ammonium fluoride; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TMSCl,
trimethylsilyl chloride; XantPhos, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
⇑ Corresponding author. Tel.: +1 860 715 4118.
E-mail addresses: Hongxia.ding@gmail.com (H.X. Ding), carolyn.a.leverett@pfizer.com (C.A. Leverett), robert.kynejr@pfizer.com (R.E. Kyne), Liu_kang_zhi_kevin@lilly.com
(K.K.-C. Liu), subas.sakya@bioduro.com (S.M. Sakya), andrew.flick@pfizer.com (A.C. Flick), christopher.j.odonnell@pfizer.com (C.J. O’Donnell).
 
Tel.: +86 10 8484 8357.
à
Tel.: +1 860 441 3936.
§
Tel.: +1 860 441 1510.
–
Tel.: +86 21 2080 5590.
k
Tel.: +86 38139788x3904.
  
Tel.: +1 860 715 0228.

http://dx.doi.org/10.1016/j.bmc.2014.02.017
0968-0896/Ó 2014 Elsevier Ltd. All rights reserved.
2006 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

8. Bosutinib hydrate (BosulifÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2013

9. Cabozantinib (S)-malate (CometriqÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2015
10. Carfilzomib (KyprolisÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2015
11. Dapagliflozin propanediol hydrate (ForxigaÒ, EmplicitiÒ, EdistrideÒ, AppebbÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2016
12. Enzalutamide (XtandiÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2016
13. Iguratimod (CareramÒ, IremodÒ). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2017
14. Imrecoxib (HengyangÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2019
15. Ingenol mebutate (PicatoÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2020
16. Ivacaftor (KalydecoÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2021
17. Lorcaserin hydrochloride hydrate (BelviqÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2021
18. Omacetaxine mepesuccinate (SynriboÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2022
19. Pasireotide (SigniforÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2022
20. Perampanel hydrate (FycompaÒ). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2024
21. Pixantrone dimaleate (PixuvriÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2024
22. Ponatinib hydrochloride (IclusigÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2025
23. Radotinib hydrochloride (SupectÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2026
24. Regorafenib hydrate (StivargaÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2026
25. Tafamidis meglumine (VyndaqelÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2027
26. Teneligliptin hydrobromide hydrate (TeneliaÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2028
27. Teriflunomide (AubagioÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2028
28. Tofacitinib citrate (XeljanzÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2029
29. Vismodegib (ErivedgeÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2029
References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2029

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 No-
bel Prize in medicine.1
This annual review was inaugurated eleven years ago2–11 and
presents synthetic methods for molecular entities that were
launched in various countries during the past year. Given that
drugs tend to have structural homology across similar biological
targets, it is widely believed that the knowledge of new chemical
entities and their syntheses will greatly enhance the ability to de-
sign new drugs in shorter periods of time. The pharmaceutical
industry enjoyed a banner year in 2012, with a total of 36 new
products, including new chemical entities, biological drugs and
diagnostic agents having reached the worldwide market for the
first time. Although an additional 22 new products were approved
for the first time in 2012, these were not launched before year
end,12 and therefore this review focuses on the syntheses of 26
drugs that were launched or approved in 2012 and two additional
drugs that was launched at the end of 2011 (Fig. 1). New indica-
tions for previously launched medications, new combinations,
new formulations of existing drugs, and drugs synthesized purely
via bio-processes or peptide synthesizers have been excluded from
this review. Although the scale of the synthetic routes were not
explicitly disclosed in most cases, this review covers, perceptibly,
the most scalable routes based on published or patent literature.
Drugs are covered in alphabetical order by the drug’s generic name.
2. Aclidinium bromide (Tudorza PressairÒ, Eklira GenuairÒ,
Bretaris GenuaiÒ)
Aclidinium bromide was approved by the U.S. Food and Drug
Administration (FDA) in July 2012 for the treatment of chronic
obstructive pulmonary disease (COPD).13 Marketed by Forest Phar-
maceuticals, aclidinium bromide selectively binds to five human
muscarinic receptors (M1–M5), and posesses a subnanomolar bind-
ing affinity for these particular targets. Administered by inhalation,
this medicine has demonstrated favorable onset and duration of
action, and its safety profile is an improvement over competitor
therapies.14 While no manufacturing route has been disclosed to
date,15 the most scalable published synthesis is described in
Scheme 1.16 Dimethyl oxalate (1) was initially treated with two
equivalents of Grignard 2 to give bis-thiophenoate 3 in 36% yield.
Subsequent transesterification with (R)-quinuclidinol (4) gave rise
to the quinuclidine-containing ester 5 in 50% yield. Aclidinium bro-
mide (I) could be accessed by two different methods involving bro-
moalkyl phenyl ether 6: an excess of bromide in the presence of an
acetonitrile/chloroform mixture gave the drug in 89% isolated
yield, or with fewer equivalents of electrophile (1.25 equiv) during
exposure to refluxing acetophenone, has reportedly delivered (I)
quantitatively on multi-gram scale.17 From commercial 2,18 the
multi-gram synthesis of Aclidinium bromide (I) was completed
in 17.8% over three steps.
3. Allisartan isoproxil
Allisartan isoproxil, a member of a new class of selective angio-
tensin II-1 receptor antagonists, was approved by the Chinese Food
and Drug Administration (CFDA) for the treatment of hypertension
in July 2012.19 At time of publication, there is no trade name asso-
ciated with this drug. Allisartan was discovered and developed by
the Chinese biomedical company Allist Pharmaceuticals. Allisartan
isoproxil is a prodrug which is readily hydrolyzed to active
metabolite EXP3174, which is also the active metabolite of losartan
(des-triphenylmethyl-9, Scheme 2).20 Although several synthetic
routes have been reported within two patents,21,22 the most likely
scalable process route is described in Scheme 2. Commercial
2-butyl-4-chloro-5-(hydroxymethyl)-imidazole (7) was alkylated
with N-triphenylmethyl-5-(40 -bromomethylbiphenyl-2-yl)tetra-
zole (8) under basic conditions in warm DMF, providing alcohol 9
in 90% yield. This alcohol was then oxidized to the corresponding
carboxylic acid 10 with KMnO4 in 88% yield. Etherification of
acid 10 with isopropyl chloromethyl carbonate (11) followed by
de-tritylation of the tetrazole group under acidic conditions gave
allisartan isoproxil (II) in 69% yield.22
4. Anagliptin (BeskoaÒ, SuinyÒ)
Anagliptin, which is marketed as Beskoa or Suiny, is a dipeptidyl
peptidase-IV (DPP-4) inhibitor which was approved in September
2012 and launched in November 2012 in Japan for the treatment
of Type II diabetes. The drug was co-developed by three Japanese
 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2007

Cl
N O
O
O
S N O O O CN
H
OH O N
O N N N
S H
N+
O N
O N N
Br -
N
N NH
I Aclidinium bromide II Allisartan isoproxil III Anagliptin

N
O NH
N CO2 H
H O
S N H OH
N O O Ph
N HO2 C
HO N NH
O O
H3 C
N
N
Br

IV Axitinib V Azilsartan VI Bedaquiline fumarate

Cl Cl H H
N N

HN O O O
O F
O CN
O O
N O N HO
OH
O N
N O OH
H 2O

VII Bosutinib hydrate VIII Cabozantinib (S)-malate

Cl
O O O O
H H HO
N N OH
N N N
H H HO OH OH
O O O O
OH H 2O
O

IX Carfilzomib X Dapagliflozin propanediol hydrate

F O O
H
N O S
F3C N S O
S O
H O O
N
NC N O N H
N H
O
O
O

XI Enzalutamide XII Iguratimod XIII Imrecoxib

OH
O
O O
H Cl
N NH HCl
O H
O HO 1/2 H 2O
N
HO H
HO

XIV Ingenol mebutate XV Ivacaftor XVI Lorcaserin hydrochloride hydrate

Figure 1. Structures of 28 NCEs marketed/approved in 2012.

2008 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

OBn

Ph
O H
N H2 N N
( )3 HN
O
H O
O O N
O O
HN O O O
O O
O O HN
OH NH
N
O H
Ph H2 N
H N

HO

XVII Omacetaxine mepesuccinate XVIII Pasireotide

NH2
O HN
N N
COOH
O
3/4 H2O N 2
CN COOH
O HN
NH2

XIX Perampanel hydrate XX Pixantrone dimaleate

N
N
N
HCl N N
H
N N N N
H N N
N H
N O
N
O 2 HCl CF3
CF3

XXI Ponatinib hydrochloride XXII Radotinib dihydrochloride

CF3 O Cl O
Cl O O
O N OH
H
N
N N N OH OH
H H Cl H
F H 2O N
HO
OH OH

XXIII Regorafenib hydrate XXIV Tafamidis meglumine

NH O

N N
N CF3
OH O
S
N N 2.5 HBr N
x H 2O H
CN

XXV Teneligliptin hydrobromide hydrate XXVI Teriflunomide

N
N
N CN Cl
O Cl
O OH
N
HOOC COOH N
N N H
H HOOC SO 2Me
XXVII Tofacitinib citrate XXVIII Vismodegib

Fig. 1 (continued)
 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2009

S
OH
O MgBr S
2 N 4
MeO OH
OMe MeO S
Et2 O, −30 °C NaH, toluene, ↑↓
O
36% O 50%

1 3

S
S
Br OPh 6 OH
OH O
O S CH3 CN : CHCl3 (2:3), RT N+
O S
N O 89%
O Br -

5 I Aclidinium bromide

Br OPh , Acetophenone, ↑↓
99%

Scheme 1. Synthesis of aclidinium bromide (I).

Cl
Br N OH

Cl N
N OH K2 CO3 , DMF, 90 °C
+
N N 90%
H N
N
N N
CPh3 N N
N CPh3
7 8 9

Cl O
OH Cl O
N
N O O
N O 1. K2 CO 3, DME, RT
1% KMnO 4 2. 11, 50 °C N O
0 °C to 50 °C, 88% 3. 4 N HCl, dioxane, RT
69%
N
N N
N Cl O O
N CPh3 N
NH
N
O

10 11 II Allisartan isoproxil

Scheme 2. Synthesis of allisartan isoproxil (II).

companies; Kowa, Sanwa Kagaku and JW pharmaceutical. Anaglip- 5. Axitinib (InlytaÒ)

tin, which is more selective against several recombinant human
proteases by comparison to sitagliptin and vildagliptin,23 has more
than 10,000-fold selectivity over the structurally homologous DPP-
8 and DPP-9 enzymes.
The most likely process-scale synthesis is depicted in Scheme 3.24
Commercially available (S)-1-(2-chloroacetyl)-pyrrolidine-2-carboni-
trile (12) was alkylated with t-butyl (2-amino-2-methyl-1-propyl)
carbamate (13), giving rise to (S)-t-butyl (2-((2-(2-cyanopyrrolidin-1-
yl)-2-oxoethyl)amino)-2-methylpropyl)carbamate (14). This Boc-pro-
tected system was subsequently treated with strong acid to give the
ethylene diamine derivative 15 in 96% yield. Activation of 15 with
CDI followed by coupling with commercially available 2-methylpy-
razolo[1,5-a] pyrimidine-6-carboxylic acid (16) gave anagliptin (III)
in 90% yield.
Sold under the brand name InlytaÒ by Pfizer, Inc., axitinib was
approved by the FDA in January 2012 for the treatment of ad-
vanced renal cell carcinoma (RCC), specifically after the failure of
other systemic treatments.25 Axitinib slows cancer cell prolifera-
tion by inhibition of the vascular endothelial growth factor
(VEGF)/VEGF receptor tyrosine (RTK) signaling pathway. In partic-
ular, axitinib is a potent inhibitor of VEGF/RTK 1–3, which selec-
tively slows angiogenesis, vascular permeability, and blood flow
in solid tumors.26,27 While numerous patents and papers have been
disclosed on the synthesis of axitinib,28–37 a recently published
manuscript details the development of the manufacturing route,
and this route is depicted in Scheme 4.38 The synthesis began with
Migita coupling of commercial iodide 17 with thiophenol 18.
2010 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

O CN O O CN
13, NaI, K2CO3 , acetone H 4 N HCl/Dioxane
Cl N
N O N N
0 °C to RT, 91% H 0 °C to RT, 96%

12 14

O O CN
H
O CN N
H 1. 16, CDI, THF N N N
N H
H 2N N
2. Et 3N, THF, 0 °C to RT N
90% N
15 III Anagliptin

O
O N OH
NH 2
O N N
H
N

13 16

Scheme 3. Synthesis of anagliptin (III).

H O NH O NH
I N Pd 2(dba)3 , XantPhos
H
N SH S N
NaHCO3, NMP, 50 °C
N

17 18 19

O NH
1. Ac 2O, DIPEA, NMP, 60 °C
H
O NH 2. Pd(OAc)2 , 2-vinylpyridine S N
I2, NMP, aq. KOH H XantPhos, 90 °C N
S N
85-90% f or 2 steps N 3. 1,2-DAP, THF, polishing filter
4. NMP, THF, 62% for 4 steps
I N

20 IV Axitinib

Scheme 4. Synthesis of axitinib (IV).

Interestingly, this transformation’s efficiency relied upon attention
to the number of equivalents of base and an inert atmosphere in
the reaction vessel, conditions which minimized catalyst poisoning
during the reaction. Without isolation, indazole 19 was iodinated
to afford diarylthioether 20 in 85–90% yield over the two steps.
Protection of the indazole within 20 as its acetamide preceeded a
Heck reaction with 2-vinylpyridine, and then subsequent removal
of the indazole protection followed by a series of recrystallizations
yielded axitinib (IV) in a combined 62% yield over the final 4 steps.
6. Azilsartan (AzilvaÒ)
Azilsartan is an orally active angiotensin II blocker which was
approved and launched in Japan for the treatment of arterial
hypertension in May 2012.39 Azilsartan, which is marketed under
the trade name AzilvaÒ, was discovered and developed by Take-
da—the same firm which had developed and launched a prodrug
of azilsartan (azilsartan kamedoxomil, EdarbiÒ) in 2010. Azilsartan
exhibits higher potency and slower off-rate kinetics for type 1
angiotensin II receptors, which contributes to azilsartan’s compar-
atively improved blood pressure lowering effect.40
The most likely process-scale synthetic route mimics that
which is disclosed in Takeda’s patents, and this is described in
Scheme 541,42. Commercially available benzoic acid 21 was acti-
vated as the corresponding acyl azide and underwent a Curtius
rearrangement to give carbamate 22 in 57% yield (three steps from
compound 21). The resulting aniline 22 was alkylated with com-
mercial 4-(bromomethyl)-2’-cyanobiphenyl (23) to give benzyl-
amine 24 in 85% yield. Nitroamine 24 was then exposed to
mildly acidic conditions to affect Boc-removal prior to reduction
via ferric chloride hydrate in the presence of hydrazine hydrate.
The resulting diamine 25 arose in 64% yield across the two-step se-
quence. Interestingly, it was found that metal catalysts under con-
ventional hydrogenation conditions caused partial debenzylation,
which led the authors to arrive at the hydrazine/ferric chloride
conditions. Next, benzimidazole formation was achieved upon
treatment of diamine 25 with ethyl orthocarbonate in acetic acid.
The resulting ethoxylbenzimidazole 26 was procured in 86% yield,
and this benzonitrile was further reacted with hydroxylamine
hydrochloride and sodium methoxide to provide amidoxime 27
in 90% as a white powder. Next, activation with ethyl chlorocar-
bonate gave 28 followed by heating in refluxing xylene to give
 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2011

NO 2 NO2
1. SOCl2, DMF, toluene, ↑↓
CO 2H 2. NaN 3, H2 O, 0 °C NHBoc

O O 3. t-BuOH, ↑↓, 57% for 3 steps O O

21 22

Br CN NO2 NH2

Boc 1. 1 N HCl
N NH
23 EtOAc, RT, 77%
K2 CO3, CH 3 CN, ↑↓, 85% O O CN 2. FeCl3•6 H2 O O O CN
0 °C, THF/MeOH
↑↓; NH 2NH2 •H2 O
↑↓, 64%
24 25

N N

N O N O OH
(EtO)4 C, AcOH O NHOH•HCl, NaOMe/MeOH O
O N NH2
CN O
80 °C, 86% DMSO, 90 °C, 90%

26 27

N O

N O O OEt
ClCO2 Et, CH 2Cl2, THF O N NH2
O
Et3N, RT

28

N N
O O
N O O N O O
xylenes, ↑↓ O 2 N LiOH, MeOH, ↑↓ HO
N NH N NH
O O
23% for 2 steps 84%

29 V Azilsartan

Scheme 5. Synthesis of azilsartan (V).

N N
O O
N O OH N O O
O NaOMe, O O O
N NH2 N NH
O O
DMSO, RT, 85-90%

30 29

N
O
N O O
aq. NaOH HO N NH
O
50 °C, 88-90%

V Azilsartan

Scheme 6. Improved synthesis of azilsartan (V).

2012 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

oxadiazolone 29 in 23% yield from hydroxyamidine 27. Finally,
ester 29 was saponified with 2 N LiOH in methanol to give
azilsartan (V) in 84% yield.
An improved scalable route (Scheme 6) to azilsartan was re-
ported and features reproducibly better yields.43 Hydroxyamidine
30 was treated with dimethyl carbonate and sodium methoxide,
which triggered they key cyclization along with concomitant
transesterification to deliver 29. Milder aqueous sodium hydroxide
hydrolysis converted this methyl ester 29 to azilsartan (V) in
88–90% yield.
7. Bedaquiline fumarate (SirturoÒ)
Bedaquiline fumarate is a diarylquinone drug developed by
Janssen Pharmaceutical which is marketed under the trade name
SirturoÒ.44 The drug, which was approved in 2012 for the

• HCl
O N O N O
aq. NaOH, 60 °C OH
P
98% O
O

31 32
34

N N
CO2 H
Ph OH H OH
Ph • Ph
Br HO2 C
O O
CH3 1. LDA, THF, -70 °C H3 C H 3C
N O 2. 32, THF, -70 °C fumaric acid, i-PrOH
N N
3. AcOH, THF, -10 °C 50-80 °C
4. 34, DMSO, ↑↓ Br 82% Br
5. 10% aq. K2CO3
33 35 VI Bedaquiline fumarate
toluene, 85 °C
39% for five steps

Scheme 7. Synthesis of bedaquiline fumarate (VI).

H 3CO Cl Br 37 H3 CO N NH
39
i-PrOH, 1 N NaOH
HO NO2 70 °C, 82% Cl O NO2 NaI, DME, ↑↓, 77%

36 38

N N
H2 , Pd/C 42, HC(OEt) 3, i-PrOH
O O
N N
i-PrOH, RT ↑↓, 93% for 2 steps
O NO2 O NH 2

40 41
Cl Cl Cl Cl

O NH HN O
O NC O CN
O POCl3, sulfolane

N O N 70 °C to 105 °C N O N
H
N 75-82%, >99% purity N
H 2O
43 VII Bosutinib monohydrate

O
45 Cl Cl
Cl Cl NC O
OH
NC
DIC, THF, ↑↓, 88% N O
H2 N O H

44 42

Scheme 8. Synthesis of bosutinib hydrate (VII).

 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2013

treatment of multidrug-resistant tuberculosis (MDR-TB), was
developed in partnership with Johnson & Johnson and represents
the first new tuberculosis therapy approved in over four decades.44
Bedaquiline is the first member of a new class of diarylquinoline
compounds whose mechanism of action inhibits Mycobaterium
tuberculosis ATP synthase which deprives bacterium of energy.44
Of the relatively few synthetic approaches to bedaquiline (or its
fumarate salt) that have been reported,45–47 the most likely pro-
cess-scale route is that described by Porstmann and co-workers
from Janssen Pharmaceutical, and this route is outlined in
Scheme 7.48 The synthesis was initiated by first treating commer-
cially available dimethylaminoketone 31 with sodium hydroxide
to provide naphthylone 32 in nearly quantitative yield. Treatment
of commercially available quinoline 33 with LDA and subsequent
trapping with naphthylone 32 provided a mixture of diastereo-
mers, whereby the major diastereomer obtained from this reaction
corresponded to the bedaquiline geometry. The minor diastereo-
mer was resolved through multiple recrystallizations and seeding
techniques.48 This racemate of the major diastereomer subse-
quently underwent a chiral resolution upon treatment with BINAP
derivative 34 in refluxing DMSO. Cooling and subjection to
aqueous base in warm toluene furnished bedaquiline 35, bearing
the requisite (R,S)-configuration of the two vicinal chiral centers
corresponding to that of the drug. The overall yield of the
conversion of 33 to enantiopure 35 was 39%. Aminoquinolinol 35
was then prepared as the corresponding fumarate salt upon
treatment with fumaric acid in the presence of isopropanol, and
this salt formation delivered bedaquiline fumarate (VI) in 82%
yield.49
8. Bosutinib hydrate (BosulifÒ)
BosulifÒ (Bosutinib hydrate), also known as (SKI-606), is a novel
4-phenylamino-3-quinolinecarbonitrile kinase inhibitor approved
for treatment of adults with chronic, accelerated, or blast phase
Philadelphia chromosome-positive chronic myeloid leukemia
(Ph+CML).50 Bosutinib is an orally-dosed, dual Src/Abl kinase inhib-
itor51,52 which provides an alternative treatment to patients exhib-
iting immunity to imatinib and other kinase inhibitors utilized for
this treatment.53,54 In contrast to competitor tyrosine inhibitors,
bosutinib inhibits autophosphorylation of both Srs and Abl kinases,
leading to decreased cell growth and apoptosis.51 Bosutinib was
originally developed by Wyeth and continues to be marketed by
Pfizer after the merger of Wyeth and Pfizer in 2009.55
Several synthetic routes to bosutinib have been reported,
including synthetic work for scale up and processing to obtain pure
salt forms of bosutinib for pharmaceutical applications.56–59 The
current manufacturing route begins with reaction of 2-methoxy-
5-nitrophenol (36) and 1-bromo-3-chloropropane (37) to provide
aryl chloroether 38 in 82% yield.58 Reaction of 38 with N-methylpi-
perazine (39) and NaI in refluxing DME provided the functionalized
aryl-nitro-piperazine 40 (77% yield), which was converted directly

NH 2
OH Cl H 2N OH
O POCl3 , CH 3 CN O O
77 °C, 70% t-BuONa, DMA, 105 °C O
O N O N 72%
O N
46 47 48

H H
N N

51, K2CO3 , THF, H 2O, RT O O

O F
96% O

O N
52

H H
N N

(S)-malic acid O O
O F
MEK, H 2O, 55 °C to RT O O
HO
75% OH
O N O OH

VIII Cabozantinib (S)-malate

O O F F
1. SOCl2, Et 3 N, THF, 5 °C O O oxalyl chloride O O
HO OH HO N DMF, THF, RT Cl N
F H H
2. , THF, 10 °C
49 H 2N 50 51
70% for two steps

Scheme 9. Synthesis of cabozantinib (S)-malate (VIII).

2014 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

to aniline 41 under hydrogenolysis conditions. Aniline 41 was then
reacted with triethyl orthoformate and aryl cyanoamide 42, which
was generated in one step from 2,4-dichloro-5-methoxy-aniline
(44), 1,3-diisopropylcabodiimide (DIC), and cyanoacetic acid (45)
under refluxing conditions, to yield advanced intermediate 43
(93% over 2 steps).58,59 Finally, conversion of 43 to bosutinib was
facilitated by a POCl3-promoted cyclization in the presence of sul-
folane. As shown in Scheme 8, employment of carefully optimized
conditions for the isolation of bosutinib hydrate (VII) provided
material in 75–82% yields and >99% purity.59

BOP, HOBT, DMF H

N CO2 Me
BocHN
DIPEA, 0 °C, 93%
BocHN CO2H O
H2 N CO2 Me

53 54 55

O
H
BocHN N CO2 Me
1. TFA, DCM, 0 °C N
H
2. Boc-Homophe-OH, BOP O
HOBT, DMF, DIPEA, 0 °C
85% for 2 steps

56

Cl O O
H H 1. KI, THF H H
N N CO2 Me N N CO2 H
1. TFA, DCM N morpholine N N
H H
O O O O O
2. ClCH2C(O)Cl 2. LiOH, MeOH
DMF, DIPEA, 0 °C 0 °C to 5 °C
67% for 2 steps 87% for 2 steps

57 58

O O O
H H
N N
1. 59, HBTU, HOBT, DMF, DIPEA, 0 °C N N N
H H
O O O O
2. Recrystallization from MeOH/H 2 O
75% for 2 steps

O
IX Carfilzomib
TFA H2 N
O
59

Scheme 10. Synthesis of carfilzomib (IX).

i-BuOC(O)Cl, DCM OMe MgBr 61

N
MeONHMe•HCl, NMM BocHN THF, 5 °C, 81% BocHN
BocHN CO2H
Et3N, −20 °C, 94% O O

54 60 62

1. Ca(OCl)2 , NMP, H2 O
−10 °C to −5 °C, 41% O
2. TFA, CH 2 Cl2 , 0 °C, 92% TFA H 2 N
O
59

Scheme 11. Synthesis of fragment 59 of carfilzomib (IX).

 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2015

9. Cabozantinib (S)-malate (CometriqÒ) 10. Carfilzomib (KyprolisÒ)

Cabozantinib (S)-malate (CometriqÒ), which was discovered
and developed by Exelixis, gained approval by the U.S. FDA in
November 2012. The drug’s indication is for the treatment of med-
ullary thyroid cancer (MTC), and is the second drug for this disease
after AstraZeneca’s vandetanib (CaprelsaÒ). The drug was success-
fully launched on January 24, 2013.60,61 Cabozantinib inhibits mul-
tiple receptor tyrosine kinases including RET, MET, VEGFR-1, -2
and -3, KIT, TRKB, FLT-3, AXL, and TIE-2.62 It is currently also
undergoing clinical trials for the treatment of prostate, ovarian,
brain, melanoma, breast, non-small cell lung, pancreatic, hepato-
cellular and kidney cancers. Of the three syntheses of cabozantinib
reported,63–66 the kilo-gram scale process route65,66 is described in
Scheme 9.
The preparation began with 6,7-dimethoxy-quinoline-4-ol (46)
which upon treatment with POCl3 provided chloride 47 in 70%
yield. Exposure of 47 to 4-aminophenol under basic conditions
using t-BuONa furnished diaryl ether 48 in 72% yield. This aniline
was then coupled with amidoacid chloride 51 (which arose from
the activation of commercial diacid 49 to the corresponding mono-
chloride, coupling with p-fluoroaniline, and subsequent exposure
to oxalyl chloride to furnish the transient acid chloride) to con-
struct cabozantinib as the free base 52 in 95% yield. Salt formation
of cabozantinib 52 was carried out with (S)-malic acid, which ulti-
mately delivered the final product of cabozantinib (S)-malate (VIII)
in 75% yield.65,66
Carfilzomib is an irreversible inhibitor of the chymotrypsin-like
protease in the proteasome and was approved in the U.S. for the
treatment of multiple myeloma.67,68 Carfilzomib was discovered
by Proteolix, which was later acquired by Onyx Therapeutics,
who completed the development of this drug. Carfilzomib is also
undergoing clinical evaluation for additional oncology indications
such as relapsed solid tumors, lymphoma, prolymphocytic leuke-
mia, acute myeloid leukemia and acute lymphocytic leukemia. Car-
filzomib is an analog of the natural product epoxomicin which was
first synthesized in the laboratories of Professor Crews at Yale Uni-
versity.69 Subsequent development of the SAR led to the discovery
of YU-101 in which 3 of the amino acids of this pentapeptide were
modified to improve the potency of the molecule.70 After licensing
the molecule to Proteolix, the introduction of the morpholino
group was found to improve the solubility of the drug while main-
taining efficient interaction with the target. The most scalable
route to carfilzomib closely resembles the original route developed
toward epoximicin and is described herein.71,72
The synthesis was initiated with the amide coupling of phenyl
alanine methyl ester (53) and N-Boc leucine (54) using standard
coupling reagents to afford dipeptide 55 in high yield (Scheme 10).
Acidic removal of the amine protecting group, followed by a second
amide coupling reaction with N-Boc homophenyl alanine, provided
tripeptide 56 in 85% yield for the two steps. Acidic removal of the
amine protecting group and subsequent acylation with chloroace-

O O O O
HO TMSO
TMSCl, NMM, THF
HO OH 0 °C to 35 °C, then -20 °C, 99% TMSO OTMS
OH OTMS

63 64

Cl Cl

Cl 1. (COCl) 2, DCM, DMF O

Br Br
20 °C, 100% Et3 SiH, BF3 •OEt2
O
Br 2. phenetole, AlCl3 , DCM CH 3CN, 10 °C, 75%
OH 0 °C to 5 °C, 91%
O O

65 66 67

Cl

O
HO
1. n-BuLi, 64, THF, toluene, -78 °C OMe
2. MeOH, CH3 SO3 H, 85% HO OH
OH

68

1. aq. LiOH
Cl Cl
1. Et3 SiH, BF3 •OEt2 THF, H2 O
DCM, CH3 CN O MeOH O OH
AcO HO
-10 °C RT, 100% OH
2. Ac 2O, pyridine AcO OAc 2. propanediol HO OH
H 2O
DMAP, DCM OAc H 2O OH
55% f or 2 steps O O
69
X Dapagliflozin propanediol hydrate

Scheme 12. Synthesis of dapagliflozin propanediol hydrate (X).

2016 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

tyl chloride yielded b-chloro amide 57 in 67% yield. Reaction of 57
with morpholine in the presence of catalytic amounts of potassium
iodide followed by saponification of the methyl ester with lithium
hydroxide led to acid 58 in 87% yield for the two steps. Finally,
amide coupling between acid 58 and keto-epoxyamine 59 (whose
preparation is described in Scheme 11) using HOBT as the coupling
reagent and recrystallization of the resulting product ultimately
gave carfilzomib (IX) in 75% yield.
Keto-epoxyamine 59 was prepared from N-Boc leucine (54) as
described in Scheme 11. Reaction of 54 with isobutyl chlorofor-
mate followed by N,O-dimethylhydroxylamine provided Weinreb
amide 60 in 94% yield. Grignard addition of isopropenylmagnesium
bromide (60) provided enone 62 in 81% yield. Epoxidation of 62
with calcium hypochlorite provided a mixture of epoxides giving
41% yield of the desired isomer (presumably isolated by chroma-
tography), and subsequent treatment with TFA liberated the
amine, providing the TFA salt of ketoepoxy amine 59 in 92% yield.
11. Dapagliflozin propanediol hydrate (ForxigaÒ, EmplicitiÒ,
EdistrideÒ, AppebbÒ)
Dapagliflozin propanediol hydrate, an orally active sodium glu-
cose cotransporter type 2 (SGLT-2) inhibitor, was developed by
Bristol–Myers Squibb (BMS) and AstraZeneca for the once-daily
treatment of type 2 diabetes. As opposed to competitor SGLT-2
inhibitors, dapagliflozin was not associated with renal toxicity or
long-term deterioration of renal function in phase III clinical tri-
als.73 The drug exhibits excellent SGLT-2 potency with more than
1200-fold selectivity over the SGLT-1 enzyme.74
The most likely process-scale synthesis has been described in a
literature publication and patent, and this is summarized in
Scheme 12 below.74,75 The synthesis began with global silylation
glucolactone 63 to form tetrasiloxide 64. In parallel, commercial
5-bromo-2-chlorobenzoyl acid (65) was converted to the corre-
sponding acid chloride with oxalyl chloride. Subsequently, this
acid chloride was subjected to Friedel–Crafts acylation with ethyl
phenyl ether (‘phenetole’) in the presence of aluminum trichloride
at low temperature to give benzophenone 66 in 91% yield. Next,
the carbonyl functionality within 66 was removed upon treatment
with triethylsilane and boron trifluoride-etherate, producing
5-bromo-2-chloro-40 -ethoxydiphenylmethane (67) in 75% yield as
the aglycon partner. Aryl bromide 67 was subjected to lithium hal-
ogen exchange conditions and subsequent exposure to lactone 64,
provided a mixture of lactols which were then immediately sub-
jected to methanesulfonic acid, leading to glucol 68 in 85% yield.
The anomeric methoxy group of 68 was reduced with triethylsilane
and boron trifluoride-etherate followed by peracetylation to deli-
ver a-C-glycoside tetraacetate 69 in 55% (two steps) after recrys-
talliaztion in ethanol. Hydrolysis of polyacetate 69 with lithium
hydroxide gave dapagliflozin in quantitative yield, and upon treat-
ment with propanediol in water, dapagliflozin propanediol hydrate
(X) was produced.
12. Enzalutamide (XtandiÒ)
In August 2012, the FDA approved enzalutamide, marketed by
Medivation and Astellas Pharma U.S. for the treatment of meta-
static castration-resistant prostate cancer (CRPC), specifically for
those patients who had previously received docetaxel.76 Enzaluta-
mide is an inhibitor of androgen receptors (AR)—whose increased
expression has been closely linked with castration-resistant pros-
tate cancer (CRPC), thus, AR inhibitors have seen increased recent
attention from the medicinal chemistry community. Phase I/II
trials were particularly promising for enzalutamide, as 43% of
patients showed >50% sustained suppression of a key serum
biomarker.77 Of the several patents and papers describing

O O
CO 2H
SOCl2, IPAc Cl CH3 NH2 , IPAc, 2 °C to 35 °C NHMe
Br F DMF, 60 °C to 72 °C 90% for 2 steps
Br F Br F

70 71 72

O
H2 N CO2 H 73 NHMe K2 CO3 , DMF, H 2 O
HO MeI, 30 °C to 40 °C
CuCl, K2 CO3, DMF, H 2O, 30 °C N F
H 95%
then 2-acetylcyclohexanone, 105 °C O
76%
74

CF3
O
NC
NHMe 76, DMSO S
O
MeO IPAc, 84 °C N
N F N
H 78% NHMe
O O F
75 XI Enzalutamide

S
CF3 CF3
NC Cl Cl NC
Heptane, H 2O, 5 °C to 40 °C
NH2 NCS
84%
77 76

Scheme 13. Synthesis of enzalutamide (XI).

 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2017

synthetic approaches,78–81 a 2011 patent represents the most likely
scale production route to enzalutamide, and this is described in
Scheme 13.82
Commercially available carboxylic acid 70 was first converted
to the corresponding acid chloride 71, followed by amide forma-
tion with methylamine to furnish benzamide 72 in 90% yield over
two steps. Bromide 72 was then coupled with amine 73 using cop-
per(I) catalysis to afford trisubstituted benzene 74 in 76% isolated
yield. Esterification of 74 to 75 with iodomethane furnished one
fragment for the key ring-forming event. Isothiocyanate 76, avail-
able in one step from the corresponding aniline 77, was then ex-
posed to aminoester 75 in the presence of warm isopropyl
acetate, resulting in construction of the lynchpin thiohydantoin
and delivering enzalutamide (XI) in an impressive 78% yield. This
5-step process has successfully generated multi-gram quantities
of the drug in 50.7% overall yield.
13. Iguratimod (CareramÒ, IremodÒ)
Iguratimod, which was discovered by Toyama Pharmaceuticals
and jointly co-developed with Eisai in Japan, was approved by the
PMDA (Pharmaceuticals and Medical Devices Agency) of Japan on
June 29, 2012 for the treatment of rheumatoid arthritis.83 This drug
was also independently developed by Simcere Pharmaceutical
Group and is marketed as IremodÒ in China. The drug exhibited
inhibitory effects on granuloma inflammation, and was shown to
be efficacious for the prevention of joint destruction in adjuvant
arthritis.84,85 While several synthesis of iguratimod have been pub-
lished,86 the most likely scale synthesis, which does not require
chromatographic purification, is described in Scheme 14.87
The synthesis began with commercially available 3-nitro-4-
chloro anisole (78) which was reacted with potassium phenoxide
(generated from phenol and potassium t-butoxide at 110 °C) to
provide the corresponding nitrophenyl ether which was subse-
quently reduced and sulfonylated to furnish sulfonamide 79. Next,
this diphenyl ether was submitted to a Friedel–Crafts reaction with
aminoacetonitrile hydrochloride which gave rise to aminomethy-
lacetophenone 80 in 90% yield. This aminoketone was then formy-
lated with formic trimethylacetic anhydride 81 at room
temperature to afford formamide 82 in 91% yield, and this material
was immediately subjected to O-demethylation conditions with
aluminum trichloride and sodium iodide in acetonitrile to give
the phenol 83 in 95% yield. Finally, treatment of the aminomethyl
acetophenone phenol 83 with N,N-dimethylformamide dimethyl-
acetal in DMF at low temperatures furnished iguratimod (XII) in
87% yield.

H
N O
1. PhOH, t-BuOK, DMF, 110 °C, 84% S
O 2N O O O
2. Fe/4 N HCl, EtOH, 65 °C to 70 °C, 72%
O
Cl 3. MeSO 2Cl•Py, 0 °C to RT, 82%

78 79

H O O H
N O N O
1. NCCH2 NH2 •HCl, AlCl3 , 40 °C S S O
O O O H O O
2. dry HCl, 25-30 °C, PhNO2 81
O NH 2 O N H
90% for 2 steps HCl acetone, RT, 91% H
O O

80
82

H H
N OH O N O
S O N S O
AlCl3 , NaI O O O O O
O N H O N H
CH3 CN, RT, 95% H DMF, 15 °C, 87% H
O O

83 XII Iguratimod

Scheme 14. Synthesis of iguratimod (XII).

COOH

85 O O
O O S S
S O NH 2 O
1. 85, Et 3N, CH 3CN, RT O , HOAc N

Br 2. Et 3N, CH3 CN, 75 °C 50 °C to 120 °C, 85%

O O
O 72% for two steps

84 86 XIII Imrecoxib

Scheme 15. Synthesis of imrecoxib (XIII).

2018 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

O O
H H
acetone, cat. p-TsOH, RT

HO HO 69% HO HO
HO O
HO O

87; ingenol 88

O O
O O
O
89 H H3 PO4, RT H

LHMDS, THF, RT, 73% O 71% O

O HO O HO
O HO
O HO

90 XIV Ingenol mebutate

Scheme 16. Synthesis of ingenol mebutate (XIV).

O O
OH O O O
EtO O H2 SO4 , HNO 3 EtO O
EtO Cl DCM, 0 °C to RT Cl
Et3N, EtOAc 57%
N
0 °C to RT, 99% O2 N H
94

91 92 93

O
OH
EtO O
O O
1. Pd/C, H 2, MeOH O O KOH, MeOH
2. 94, Et3N, DCM, RT 96% N
N H
53% f or 2 steps H N
N H
H
95 XV Ivacaftor

Scheme 17. Synthesis of ivacaftor (XV).

OH PBr 3, 0 °C to 85 °C Br 1. 1-amino-2-propanol, 85 °C to 100 °C

95% 2. SOCl2 , DMA, PhCH3 , 65 °C
Cl Cl
71% for 2 steps
96 97

1. AlCl3, 1,2-dichlorobenzene, 128 °C O OH

NH • HCl 2. aq. NaOH, cyclohexane NH • OH
Cl Cl HO
3. L-(+)-tartaric acid, acetone /H2 O
4. Recrystallization from acetone/H 2O OH O
Cl
27% for 4 steps 2
98 99

1. K2 CO3, H2O, RT
2. EtOAc NH • HCl
Cl • 1/2 H 2O
3. HCl (gas), 0 °C to 5 °C
90% for 3 steps
XVI Lorcaserin hydrochloride hydrate

Scheme 18. Synthesis of lorcaserin hydrochloride hydrate (XVI).

 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2019

Br 1. i. Mg, THF HO CO2 Et 1. p-TsOH, toluene, 65 °C, 69%

ii. diethyl oxalate, ↑↓, 70% 2. KOH, EtOH, ↑↓, 98%
CH 2CO2 Me
2. 101 , LHMDS, THF 3. BF3, MeOH, RT, 69%
100 -78 °C, 72% 102

O O R* O R*
1. 104 , Et3N, DMAP, toluene, RT
CO2 H +
2. 105 , RT, 84% O O
MeO2 C (2 diastereomers, 1:1) MeO 2C MeO2 C

103 106a (desired) 106b (undesired)

OMe OMe
Cl O
N N
O Cl R* =
OH O
O Cl Cl N N

101 104 105 quinine

Scheme 19. Synthesis of fragment 106a of omacetaxine mepesuccinate (XVII).

O
N
O
O OH 1. 104 , Et N, toluene , 30 °C H
H2 , Pd/C 3
106a O
EtOAc, RT, 50% O 2. 108 , RT, 43% O OMe
MeO2C O

CO2Me
107 109

O
N
O
H O
N
O
1. HBr/HOAc, DCM, -10 °C, 87% OMe O
O H
O
2. 5% aq. NaHCO3 , acetone, RT, 47%
O OH HO
OMe
108 cephalotaxine
HO

XVII Omacetaxine mepesuccinate

Scheme 20. Synthesis of omacetaxine mepesuccinate (XVII).

O 1. Fmoc-OSu, aq. Na2CO3 , THF, RT Fmoc

H
N 2. triphosgene, N-Boc-diaminoethane N
O OH
O THF, RT
BocHN
3. 0.1 N HCl in THF N O O
HO H
49% f or 3 steps

110 111

Scheme 21. Synthesis of fragment 111 of pasireotide (XVIII).

14. Imrecoxib (HengyangÒ)
Imrecoxib, a new non-steroid anti-inflammtory drug (NSAID),
was launched in China with the trade name of HengyangÒ for the
treatment of osteoarthritis in 2012. It was originally designed
and synthesized by Guo and co-workers at the Institute of Materia
Medica (IMM) of the Chinese Academy of Medical Sciences in col-
laboration with Hengrui Pharmaceuticals.88 Imrecoxib, which is a
moderately selective COX-2 inhibitor (with IC50 values against
COX-1 and COX-2 being 115 ± 28 and 18 ± 4 nM, respectively),89
is the subject of two synthetic routes reported across several
publications.90–93
2020 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

OBn O 1. 20% piperidine in

DMF, 0 ºC to RT, 0.25 h
OBn O O
Fmoc-Lys(Boc)-OH 2. Fmoc-DTrp(Boc)-OH
O DIC/HOBt, DMF, RT, 16 h DIC/HOBt, DMF, RT, 16 h
O
O
O
O O NH
HN
R NH
( )4
BocHN Fmoc
20% piperidine,
112; R = Fmoc
DMF, 0 ºC to rt, 114
113; R = H
0.25 h

OBn O
O OBn O
1. 20% piperidine in
DMF, 0 ºC to RT, 0.25 h O
O 2. Fmoc-PhG-OH
DIC/HOBt, DMF, RT, 16 h O
O
O NH O
O O NH
NHFmoc O Ph
( )4 N H
H N
BocHN ( )4 N NHFmoc
H
Boc N BocHN O
Boc N

115
116

Scheme 22. Synthesis of pasireotide intermediate 116. (XVIII).

The most likely process-scale route to this drug is described in
Scheme 15,93 which began with 2-bromo-40 -(methylsulfonyl)-ace-
tophenone (84) and p-tolylacetic acid (85) as starting materials. In
the presence of base, a-bromoketone 84 was treated with acid 85
which resulted in lactone 86 in 72% yield across the two-step se-
quence. Exposure of lactone 86 with propylamine triggered a
ring-opening-ring closing reaction, which resulted in imrecoxib
(XIII) directly in 85% yield.93
15. Ingenol mebutate (PicatoÒ)
Ingenol mebutate is a diterpene ester which was approved in
the U.S., EU, Australia, and Brazil for the treatment of actinic kera-
tosis, a disease stage associated with sun exposure which can
potentially develop into cancer.94 The drug, which is marketed by
LEO Pharma A/S as PicatoÒ, is administered as a topical gel
(0.015%, 0.05%) which has been proven effective in treating face-,
scalp-, and trunk-localized actinic keratosis in four randomized,
double-blind, vehicle-controlled, multicenter studies.94 The drug
exhibits mild side effects limited to application-site conditions
(e.g. irritation, pain, pruritus), and no detectable concentrations
of ingenol mebutate or two of its metabolites were found in blood
samples.94 Traditionally used as a home remedy for various skin
conditions, the ingenol mebutate, also referred to as ingenol
3-angelate, is the main active constituent of sap from the plant
Euphorbia pelpus.95 From natural extractions, 17 kg of fresh E. pel-
pus afforded 7 g of ingenol 3-angelate as an oil, which upon further
purification was deemed insufficient for process-scale produc-
tion.96 Although several synthetic approaches to the ingenol family
of terpenes have been reported,97–113 Liang and coworkers at LEO
Pharma have reported a semisynthesis of the API from naturally-
occurring ingenol. This natural product’s accessibility from the
seeds of E. lathyris renders it widely commercial on scale. The con-
version of ingenol to ingenol mebutate involves a protection, ester-
ification, and deprotection strategy to procure scale quantities of
the drug (Scheme 16).114 Conversion of ingenol (87) to the corre-
sponding 5, 20-acetonide 88 proceeded in good yield using a pro-
tocol modified from the original conditions described by Hecker.115
A considerable amount of study was conducted by Liang to affect
efficient angeloylation with minimal isomerization of the double-
bond to the corresponding Z-isomer (tiglate). It was found that an-
gelic anhydride 89 (which is a commercially available reagent, but
for process scale was prepared immediately prior to usage from the
self-condensation of 99.5% pure angelic acid with 0.5 equivalents
of DCC) in the presence of LHMDS gave acetonide 90 in over 95%
conversion and was practically free of the undesired tiglate bi-
product after recrystallization (73% yield).96 Deprotection of the
acetonide 90 was affected using phosphoric acid and after three
recrystallizations, ingenol mebutate (XIV) was produced on multi-
gram scale in a combined yield of 37% starting from ingenol 87.96
 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2021

16. Ivacaftor (KalydecoÒ) 17. Lorcaserin hydrochloride hydrate (BelviqÒ)

Vertex’s ivacaftor was granted breakthrough therapy desig-
nation by the FDA in January 2012 for cystic fibrosis (CF)
patients who bear the G551D mutation in the Cystic Fibrosis
Transmembrane Regulator (CFTR) gene. This CFTR mutation
occurs in roughly 4% of the 30,000 people living with CF in
the United States. While the compound has been identified
as a potentiator in cell-based assays, its mechanism of action
is currently unknown.116–118 While several patents describe a
synthesis of ivacaftor,119–133 only one demonstrates the synthe-
sis on scale and includes yields, which is depicted in
Scheme 17.134
Beginning with treatment of commercial di-tert-butylphenol
derivative 91 with ethyl chloroformate, the synthesis of carbon-
ate 92 was achieved in quantitative yield. Nitration of 92 pro-
vided the desired nitroarene regioisomer 93 in 57% yield which
was isolated by recrystallization. Reduction of the newly-in-
stalled nitro group and subsequent amide bond formation via
reaction with commercially available acid chloride 94 produced
amide 95 in 53% yield over the two step sequence. Finally, cleav-
age of the carbonate unmasked the phenol to furnish ivacaftor
(XV) in 96% yield.
Lorcaserin hydrochloride is a selective serotonin 5HT2C agonist
approved in the U.S. for the treatment of obesity. Lorcaserin hydro-
chloride was discovered and developed by Arena Pharmaceuticals,
Inc. and licensed to Eisai. Lorcaserin hydrochloride is reported to be
approximately 100 fold more active at the 5HT2C receptor than the
5HT2B receptor.135 The significance of this selectivity is that 5HT2B
activation is hypothesized to be associated with the cardiac valvul-
opathy side effect of the infamous ‘fen–phen’ (fenfluramine + dex-
fenfluramine) combination treatment for obesity.136 Numerous
syntheses of lorcaserin hydrochloride have been reported135,137,138
and the process scale route is highlighted in Scheme 18.139
Commercial 2-(40 -chlorophenyl)ethanol (96) was treated with
phosphorus tribromide to give 2-(40 -chlorophenyl)ethyl bromide
(97) in 95% yield. Alkylation of 1-amino-2-propanol with 97 fol-
lowed by treatment of the corresponding alcohol with thionyl
chloride gave chloroamine 98 in 71% yield. Friedel–Crafts acylation
of 98 with aluminum trichloride followed by a classical resolution
with L-(+)-tartaric acid gave the desired (R)-enantiomer tartrate
salt of lorcaserin 99 in 27% overall yield from 98. The free base of
99 was liberated upon treatment with aqueous potassium carbon-
ate and this material was then immediately extracted into ethyl

OBn O 1. 20% piperidine in

O DMF, 0 ºC to RT, 0.25 h
2. Fmoc-Phe-OH,
O DIC/HOBt, DMF, RT, 16 h
1. 20% piperidine in 3. 20% piperidine in
DMF, 0 ºC to RT, 0.25 h O DMF, 0 ºC to RT, 0.25 h
2. 111, DIC/HOBt O NH
O Ph O Fmoc 4. 2% TFA in CH2 Cl2
DMF, RT, 16 h H
N N RT, 1 h
116 ( )4 N N (S)
H H
BocHN O (R)
Boc N
O
HN
O
BocHN
117

OBn

OBn
O
Ph
OH NH 2 H
1. DPPA, DIEA, H2 N N
O NH O DMF, 0 ºC, 16 h ( ) 3 HN
O Ph O Ph
H 2. aq. TFA, RT, 40 O
N N mins O O N
( )4 N N O
H H HN O O
BocHN O O O
Boc N 20% from 112 HN
O NH
HN N
H H2 N
O Ph
BocHN H N

119 XVIII Pasireotide

Scheme 23. Conversion of pasireotide intermediate 116 to pasireotide (XVIII).

2022 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

acetate and treated with HCl gas to give lorcaserin hydrochloride
hydrate (XVI) in 90% yield.
18. Omacetaxine mepesuccinate (SynriboÒ)
SynriboÒ (Omacetaxine mepesuccinate) was approved by the
FDA for the treatment of adult patients with chronic or accelerated
phase chronic myeloid leukemia (CML) exhibiting resistance or
intolerance to tyrosine kinase inhibitors (TKI’s). Omacetaxine
mepesuccinate inhibits protein synthesis and prevents amino-
acyl-tRNA binding during the elongation phase and targets myelo-
ma-promoting molecules Mcl-1, XIAP, and b-catenin,140–142 which
are particularly important in the survival of myeloma cells.143
Omacetaxine mepesuccinate is also known as homoharringtonine,
an alkaloid originally discovered144 and structurally identified145–147
from Cephalotaxus harringtonia, which occurs naturally in Japan
and eastern Asia. Because of its leukemic activity and interesting
chemical structure, the core and ester side chains of the cephalo-
taxine alkaloids have been the focus of numerous synthetic stud-
ies.148 However, large-scale production often utilizes a
semisynthetic route which relies upon cephalotaxine (CET) derived
from natural sources149 coupled with a synthetically obtained ester
side chain.150,151 The challenges associated with direct esterifica-
tion of cephalotaxine with the homoharringtonine and other re-
lated ester side chains are the basis of ongoing research aimed at
identification of improved side-chain coupling methods.148,152
The most likely process-scale synthetic route features the coupling
of the homoharringtonine side chain with the cephalotaxine core,
and a subsequent conversion of the a-hydroxy moiety to a bridged
heterocyclic species. Following this coupling, ring opening
provided the active homoharringtonine product, which is de-
scribed in Scheme 19.152,153
The method for large scale synthesis of homoharringtonine be-
gins with derivatization of commercial 5-bromo-2-methyl-pent-2-
ene (100) with diethyl oxalate and the pre-formed enolate of
methyl acetate (101), generating diester 102 in 50% overall yield
(Scheme 19).153 Acid-promoted pyran formation, followed by uni-
versal ester saponification and selective re-esterification provided
the desired racemic pyran acid 103. Activation of acid 103 with
2,4,6-trichlorobenzoyl chloride (104) and subsequent addition of
quinine (105) led to a mixture of diastereomers 106a/106b (1:1)
in 84% yield, which were separable by chromatographic methods.
Diastereomer 106a was then carried on to the synthesis of homo-
harringtonine (Omacetaxine mepesuccinate) as described in
Scheme 20.153
From isomer 106a, hydrogenolysis with Pd/C and H2 provided
acid 107 in 50% yield. Activation of 107 with 2,4,6-trichlorobenzoyl
chloride (104) followed by addition of cephalotaxine (CET) (108)
provided the desired cephalotaxine-coupled product 109 in 43%
yield. Sequential treatment with HBr/HOAc and 5% aqueous
NaHCO3 completed the synthesis, providing omacetaxine mepe-
succinate (XVII) in 41% yield (over two steps).153
19. Pasireotide (SigniforÒ)
Pasireotide, also known as SOM230, is a cyclic, hexameric
peptide developed by Novartis which exhibits somatostatin-like
activity as an antisecretory agent used in the treatment of
Cushing’s disease.154 Pasireotide activates a broad range of
somatostatin receptors, and in particular displays a significantly

N
Br 1. n-BuLi, hexanes
Br2 , NaOAc, EtOAc N THF, –76 °C N N
OMe 10 °C to 50 °C, 86% OMe 2. 122
OMe
120 121 123

HCl, H 2O 125, Cu(OAc)2 , H2 O NBS, DMF

N NH N N
↑↓, 60% pyridine, DMF 30 °C
O 28 °C to 40 °C, 91% O

124 126

1. 128, Pd(OAc) 2, PPh 3, CuI N N

N N K2CO3 , DME, ↑↓
O 3/4 H2 O
2. Recrystallization from acetone /H2 O
O CN
86% for 3 steps
Br

127 XIX Perampanel hydrate

O N
B B
O
N S O O
B O
O B
O

122 125 128

Scheme 24. Synthesis of perampanel hydrate (XIX).

 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2023

higher binding affinity for somatostatin receptors 1, 3, and 5 than
its competitor somatostatin-mimic octreotide in vitro, as well as a
comparable binding affinity for somatostatin receptor 2.154
Pasireotide is more potent than somatostatin in inhibiting the
secretion of human growth hormone (HGH), glucagon, and
insulin.155
The synthesis of pasireotide is relatively straightforward, given
that the chemical entity is a cyclic peptide. The most likely scalable
route closely mimics that described by the discovery authors
involving a series of conventional couplings and deprotection steps
to arrive at a linear peptide which then underwent sequential re-
lease from solid support, macrocyclization, and a global deprotec-
tion step.156
Beginning from (2S,4R)-4-hydroxyproline methyl ester (110) in
Scheme 21 above, this pyrrolidine nitrogen was first Fmoc-pro-
tected in 85% yield, followed by treatment with triphosgene and
N-Boc diaminoethane to provide the prolino carbamate. 111 in
49% yield over the two step sequence after a recrystallization with
ethyl acetate.156
Next, commercially available Fmoc-Tyr(Bzl)-O-CH2-Ph(3-
OCH3)-O-CH2-SASRIN157 resin (112) was used as starting material
in a manually operated reactor and carried through a standard
protocol consisting of repetitive cycles of Na deprotection (piper-
idine/DMF, 2:8), repeated washings with DMF, and coupling using
DIC/HOBT in DMF (Schemes 22 and 23). The following amino acid
derivatives were sequentially coupled: Fmoc-Lys(Boc)-OH,

O O O F O F
F F
OH Ac 2O 131 + N
O
N OH ↑↓, 76% N AlCl3, ↑↓, 84% N
CO2 H CO2 H
O O F F
129 130 132a 133b

NH2
O F NH2 O HN O
1.
H2N 134
20% H 2SO4 THF, 55 °C OH
•2
N N OH
140 °C, 81% 2. AcOH, H 2O
O F 3. 3 M aq. maleic acid O HN O
40 °C to 50 °C NH 2
92% for 3 steps
133 XX Pixantrone dimaleate

Scheme 25. Synthesis of pixantrone dimaleate (XX).

N
Si(CH 3) 3 136 TBAF, THF N
N N
N N
N Pd(PPh3) 4, CuI, DIPEA RT, 94% N
N
Br CH 3 CN RT, 71%
Si(CH 3) 3
135 137 138

N
N
N
HCl
1. 139, Pd(PPh3 )4 , CuI N
EtOAc, Et3 N, RT H
N N
2. EtOH, HCl, RT
53% for 2 steps O
CF3

XXI Ponatinib hydrochloride

I I

1. SOCl2, DCM, RT O
CF 3
OH 2. H 2N
N HN
O N
N
140 141 CF3 139
N
DCM, DIPEA, DMAP, RT, 65%

Scheme 26. Synthesis of ponatinib hydrochloride (XXI).

2024 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

Fmoc-D-Trp(Boc)-OH, Fmoc-PhG-OH, proline derivative 111
above, and finally Fmoc-Phe-OH. Couplings were continued or
repeated until complete disappearance of residual amino groups
as monitored with a ninhydrin stain test. Before cleavage of the
protected linear peptide from its resin support, the Fmoc group
was removed. After washings with dichloromethane, the peptide
resin was transferred into a column and the peptide fragment
was cleaved from solid support upon subjection to 2% TFA in
dichloromethane. The eluant was immediately neutralized with
a saturated NaHCO3 solution which resulted in the side
chain protected fragment 119 (Scheme 23). This material was
obtained in 93% homogeneity and cyclized without further
purification. For cyclization, the linear fragment was dissolved
in DMF and subsequently treated with DIPEA and 1.5 equiv of
diphenylphosphoryl azide, resulting in the protected cyclized
product in good yield. For complete deprotection, the residue
was dissolved at 0 °C in aqueous TFA, and the mixture was
stirred at this temperature for 30 min. The product was then
precipitated with ether containing ca. 10 equiv of HCl, then
filtered and washed with ether, and finally dried. The entire
sequence produced pasireotide (XVIII) in 20% yield from
resin-bound 112.156
20. Perampanel hydrate (FycompaÒ)
Perampanel is a selective, non-competitive a-amino-3-hydro-
xy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antago-
nist approved for partial-onset seizures in patients with
epilepsy.158,159 Perampanel was discovered and developed by Eisai.
A number of synthetic routes to perampanel have been reported160
and the process scale route is described herein.161,162
Bromination of commercial 2-methoxypyridine (120) gave
5-bromo-2-methoxypridine 121 in 86% yield (Scheme 24). Lithium
halogen exchange was then accomplished by treating 121 with n-
butyllithium, followed by reaction with 2-benzenesulfonylpyridine
(122) to provide bi-aryl 123. Hydrolysis of 123 under acidic condi-
tions gave pyridinone 124 in 60% overall yield. N-Arylation with
triphenylboroxine (125) in the presence of copper acetate afforded
N-aryl pyridinone 126 in 91% yield. Pyridone 126 was reacted with
N-bromosuccinimide to give bromopyridine 127, which was
coupled with 2-(1,3,2-dioxaborinan-2-yl)benzonitrile (128) under
palladium-catalyzed conditions to give perampanel hydrate (XIX)
in 86% yield after recrystallization from acetone/H2O.
21. Pixantrone dimaleate (PixuvriÒ)
Pixuvri (Pixantrone dimaleate) is a novel aza-anthracenedione
derivative approved in Europe for the treatment of adult patients
with non-Hodgkin B-cell lymphoma.163 It is also being pursued
as a treatment for various cancers, and specifically as an alternative
to other structurally-related drugs like mitoxantrone, employed for
treatment of breast cancer, acute myeloid leukemia (AML), and
non-Hodgkins lymphoma.164 Pixantrone dimaleate has been de-
signed to maintain antitumor efficacy while decreasing highly car-
diotoxic side effects observed during treatment with other related
anti-tumor anthracenedione derivatives.164–166 Like many anthra-
cenedione drugs, the mechanism of action for pixantrone dimal-
eate likely includes a number of pathways and processes, with
studies suggesting intercalation into DNA and/or interference with
DNA—Topoisomerase II activity, leading to subsequent protein
associated-DNA strand breaks and eventually to cell death.167,168
Pixantrone dimaleate, also known as BBR 2778, was originally

O
O N O
O
N N 144, NaOH, i-PrOH, ↑↓
N

N Et 3 N, 110 °C, 81% N

142 143

N N
N H
N N N
N O 146, t -BuOK, THF N N
N N H
H -25 °C to RT, 85% O
O N
N
CF3
145 147

N N
H
N N N
35% aq. HCl, acetone N N
H
O
0°C to RT N
2 HCl CF3
XXII Radotinib dihydrochloride

N
NH H2N N
O
H 2N N
H
O
HNO 3 CF3
144 146

Scheme 27. Synthesis of radotinib dihydrochloride (XXII).

 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2025

synthesized by Professors Krapcho and Hacker at the University of
Vermont,169 and determination of in vitro tumor cell cytotoxicity
was co-identified by the Boehringer Mannheim Italia research
center and the University of Vermont.170 After the merger of
Boehringer Mannheim with La-Roche, Novuspharm, and Cell
Therapeautics, Inc., pixantrone dimaleate has been developed and
marketed by Cell Therapeutics, Inc.
The manufacturing scale synthesis of pixantrone dimaleate re-
lies on several process modifications171,172 from the original syn-
thesis reported by Krapcho in 1994.169 This modified procedure
has provided active pharmaceutical ingredient (API) in high purity
(>99%) and is acceptable for use in pharmaceutical applications
(Scheme 25).171 Beginning with pyridine 3,4-dicarboxylic acid
(129), generation of the corresponding anhydride 130 proceeded
in 76% yield upon treatment with refluxing Ac2O. Next, an
AlCl3-promoted Friedel–Crafts reaction of 1,4-difluorobenzene
(131) with 130 under reflux conditions provided a mixture of
nicotinic acid isomers 132a/132b in 84% yield, which were carried
directly to the next step. Cyclization with fuming H2SO4 yielded
the desired difluorobenzo-isoquinoline-dione core 133, which
was further functionalized with ethylenediamine (134) to provide
the free base of pixantrone. Subjection of the pixantrone free base
to aqueous acetic anhydride and maleic acid provided pixantrone
dimaleate (XX) in 92% yield over 3 steps.171
22. Ponatinib hydrochloride (IclusigÒ)
Ponatinib hydrochloride (IclusigÒ), previously known as
AP24534, is a multi-targeted tyrosine kinase inhibitor approved
in the U.S. as an oral treatment for resistant or intolerant chronic

O 1. SOCl2, DMF, chlorobenzene O

70 °C to 90 °C Cl 1. toluene, NaOH
OH N
2. methylamine H 2. 150, t-BuOK, NMP
N N
toluene, H 2O, 20 °C 100 °C, 84%
3. acetyl chloride HCl
EtOH, toluene, RT, quant.
148 149

CF3
Cl 152
O CF3 O
O Cl O
N N C O O N
H H
N N
H 2N THF, RT, 83% N N
H H
F F H2 O

151 XXIII Regorafenib hydrate

H 2N OH
N OH
cyclohexane, ↑↓
F
F
153 150

Scheme 28. Synthesis of regorafenib hydrate (XXIII).

Cl
Cl
O
H2 N CO2Me O
pyridine, DCM
HN CO2Me
HO Cl
Cl
Cl
HO
154 155 156

Cl
O CO2 Me 1. LiOH, THF, H2 O, 40 °C
p-TsOH, toluene , ↑↓

N 2. N-methyl-D-glucamine
Cl i-PrOH, H2 O, 82%
157

Cl O
O OH
N OH OH
Cl H
N
HO
OH OH

XXIV Tafamidis meglumine

Scheme 29. Synthesis of tafamidis meglumine (XXIV).

2026 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

myeloid leukemia (CML) and Philadelphia chromosome-positive
(Ph+) acute lymphoblastic leukemia (ALL).173 Ponatinib hydrochlo-
ride was designed for treatment of tumors containing the T351I
mutation which are present in some forms of CML and resistant
to traditional therapies such as imatinib.173–175 Ponatinib hydro-
chloride was developed by Ariad Pharmaceauticals, and operates
by a similar mechanism of action as other tyrosine kinase inhibi-
tors, inhibiting the enzymatic activity of BCR-ABL, an abnormal
tyrosine kinase responsible for unregulated and excess white blood
cell production by bone marrow.176 However, the ability of ponati-
nib hydrochloride to target isoforms of the BCR-ABL gene typically
leading to resistance in other known tyrosine kinase inhibitors pro-
vides an alternate form of therapy not previously available.175
A significant amount of research has been devoted towards
identification of a manufacturing synthesis of ponatinib hydrochlo-
ride.177–180 A majority of methods rely on two key Sonagashira
couplings to generate the imidazo[1,2-b]pyridazin-3-ylethynyl
framework. The most likely process-scale method begins with 3-
bromo-imidazo[1,2-b]pyridazine (135) (Scheme 26).177,180 Direct
Sonogashira coupling of (135) with ethynyltrimethylsilane (136)
in the presence of Pd(PPh3)4 and CuI, followed by treatment with
TBAF/THF led to the desired alkynyl imidazo[1,2-b]pyridazine
138 in 71% and 94% yields, respectively. Alkyne 138 was then cou-
pled under similar Sonogashira conditions with functionalized aryl
iodide 139 (generated in two steps from 3-iodo-4-methylbenzoic
acid (140) and commercially available piperazinyl aniline 141)
providing ponatinib free base, which was then immediately treated
with EtOH/HCl at room temperature to ultimately furnish ponati-
nib hydrochloride (XXI).177,180
23. Radotinib hydrochloride (SupectÒ)
In January 2012, radotinib hydrochloride (marketed as SupectÒ)
obtained its approval from the KFDA (Korea Food and Drug Admin-
istration) for the treatment of patients with Philadelphia chromo-
some-positive chronic myeloid leukemia (CML) who have
become resistant to existing drugs such as Gleevec, Tasigna and
Sprycel.181 Originally developed by IL-YANG pharmaceuticals of
South Korea as an oral second-generation tyrosine kinase inhibitor,
the drug inhibits both Bcr-Abl fusion protein and the platelet-de-
rived growth factor receptor (PDGFR).182 Because of the structural
similarity of radotinib to that of nilotinib (TasignaÒ), the process-
scale synthetic route (which is depicted in Scheme 27) is capable
of furnishing both drugs.183–185
Claisen condensation of commerical 2-acetylpyrazine (142)
with N,N-dimethylformamide dimethylacetal gave rise to the ena-
mino ketone 143 in 81% yield.186 Under basic conditions, vinylo-
gous amide 143 was coupled with commercial guanidine nitrate
144187 to produce aminopyridine 145.184 Subsequent condensation
with commercial aniline (146) by means of potassium t-butoxide
in THF constructed radotinib 147 in 85% yield as the free base,
and this material could be converted to the radotinib dihydrochlo-
ride (XXII) upon exposure to concentrated hydrochloric acid in
chilled acetone.185
24. Regorafenib hydrate (StivargaÒ)
Regorafenib was approved by the U.S. Food and Drug Adminis-
tration (FDA) in September 2012 for the treatment of metastatic

O
O O NHNH 2
159 1. MsOH, RT
Boc N NH Boc N N O
DMF, RT, 86% 2. pyridine, POCl3 , RT, 12%

158 160

N N Boc N NH
N N TFA, DCM N N

88%

NaBH(OAc)3 , AcOH
161 162 1,2-DCE, RT, 50%
Boc O
H O H
N Boc N
HN 1. HOBt, EDC, DMF, RT, 62% N
OH + S
S 2. DMSO, SO3 Py, RT, 55%
HO
O
163 164 165

Boc
N O NH O

N N N N
N N
S 1. TFA, DCM, RT, 93% S
N N 2. 48% HBr, ↑↓, EtOH, 90% N N 2.5 HBr
x H 2O

166 XXV Teneligliptin hydrobromide hydrate

Scheme 30. Synthesis of teneligliptin hydrobromide hydrate (XXV).

 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032 2027

colorectal cancer in patients who have previously undergone flu-
oropyrimidine-, oxaliplatin-, and irinotecan-based therapies.188
The FDA expanded the approved use of the drug to include patients
with advanced gastrointestinal stromal tumors (GIST) that cannot
be surgically removed and no longer respond to imatinib and sun-
itinib, two other drugs approved for treatment of GIST. Regorafe-
nib, marketed under the trade name StivargaÒ, was discovered
and developed by Bayer Pharmaceuticals and marketed jointly
with Onyx Pharmaceuticals.189 The active metabolites of the drug
inhibit multiple targets within a variety of kinase families includ-
ing those in the RET, VEGF, FGFR, PTK, and Abl pathways.190,191
Among several published synthesis,192,193 the most likely pro-
cess scale synthesis will be highlighted from the two published
syntheses, and this is described in Scheme 28.194 Commercially
available picolinic acid (148) was heated with thionyl chloride to
provide the crude intermediate 4-chloro-2-pyridyl acid chloride
which was subsequently reacted with aqueous methylamine in tol-
uene to give 4-chloro-2-methylcarboxamide as its hydrochloride
salt 149 in quantitative yield after treatment with acetyl chloride
in toluene and ethanol. Conversion of 149 to its free base form
was performed with sodium hydroxide, and this intermediate
was immediately reacted with imine 150 (formed upon exposure
to 4-amino-3-fluorophenol (153) in refluxing 3-methyl-2-buta-
none) in base to provide diaryl ether 151 in 85% yield. Reaction
of amine 151 with the commercially available isocyanate 152 ulti-
mately delivered regorafenib hydrate (XXIII) in 83% yield.
25. Tafamidis meglumine (VyndaqelÒ)
Tafamidis meglumine is a transthyretin amyloid inhibitor that
was approved for the treatment of transthyretin amyloid polyneu-
ropathy (ATTR-PN) and transthyretin familial amyloid polyneropa-

CF3 CF3
O O O O
xylene KBr, H 2O 2, toluene
+ O N
H 2N ↑↓, 51% H
HCl (conc.), RT, 67%

167 168 169

CF3 CF3
O O OH O
NaCN, DMSO, RT
N 85% N
H H
Br CN

170 XXVI Teriflunomide

Scheme 31. Synthesis of teriflunomide (XXVI).

1. H2 , 5% Rh/C (JM C101023-5)

KOt -Bu, (MeO 2C)2 O O AcOH O
N N NBn
H 2N 2-MeTHF, toluene O N 2. PhCHO, NaHB(OAc) 3 O N
20 °C to 35 °C, 87% H toluene, 73% H

171 172 173

1. LAH, THF, RT 1. 2 N NaOH, i-PrOH, MeOH HO2 C O

NBn
2. HCl, i-PrOH, 87% N 2. di-p-toluoyl-L-tartaric acid NBn
H N
2HCl 42% for 2 steps H HO2 C O
2
174 175 98.6% ee O

Cl

N 176
NBn 1. H2 , Pd(OH)2 /C N OH
Cl N N N H 2 O, 70 °C to 75 °C N CN
H HOOC COOH
O
K2 CO 3, H 2 O, 95 °C to 105 °C N 2. DBU, MeOCCH 2CN N
quant. 1-butanol, 40 °C HOOC
Cl N N 3. citric acid, 90% N N
H H
177 XXVII Tofacitinib citrate

OH Cl

N POCl3, DIPEA N
N toluene, 106 °C N
HO N 52% Cl N
H H

178 176

Scheme 32. Synthesis of tofacitinib citrate (XXVII).

2028 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032

thy (TTR-FAP).195–197 These diseases represent a rare autosomal
neurodegenerative disorder characterized by autonomic, sensory
and motor impairment which are typically fatal. Tafamidis was dis-
covered at The Scripps Research Institute and developed by Pfizer.
Numerous synthetic routes have been reported including the use of
direct CH activation to form the key biaryl bond.198,199 Although
only reported on small scale, the most likely production route is
detailed in Scheme 29.200–202
Condensation of methyl 4-amino-3-hydroxybenzoic acid (154)
with 3,5-dichlorobenzoyl chloride (155) in refluxing pyridine gave
intermediate amide 156, which underwent cyclization upon treat-
ment with p-TsOH in refluxing toluene, producing benzoxazole
157. Saponification of the methyl ester with LiOH (aq) afforded
tafamidis. The free acid was treated with N-methyl-D-glutamine
to provide tafamidis meglumine (XXIV) in 82% yield.
26. Teneligliptin hydrobromide hydrate (TeneliaÒ)
Teneligliptin is a DPP-4 inhibitor which was approved in Japan
in 2012 for the treatment of type II diabetes.203 It was discovered
and developed by Mitsubishi Tanabe Pharma under the trade name
TeneliaÒ. Similar to other marketed DPP-4 inhibitors, teneligliptin
was well tolerated in all studies and QD dosing produced a long-
lasting inhibitory action against DPP-4 and an increase in active
GLP-1 levels, with very low rates of renal excretion.204
The only reported synthesis of teneligliptin is described in
Scheme 30.203 Reaction of commercially available N-Boc-pipera-
zine (158) with diketene (159) in DMF at room temperature gave
acetoacetamide 160 in 86% yield, and this material was immedi-
ately condensed with phenylhydrazine in methanesulfonic acid
followed by a cyclodehydration with phosphorus oxychloride to
give pyrazole 161 in 12% yield. The t-butyl carbamate was then re-
moved with TFA in dichloromethane to give amine 162 in 88%
yield. This amine was then subjected to butyrolactam 165 (which
was prepared from N-Boc-trans-4-hydroxy-L-proline (163) coupled
with thiazolidine (164) under conventional amide-forming condi-
tions using EDC) in the presence of sodium triacetoxy borohydride
(STAB-H) in acetic acid.205 This reductive amination reaction affor-
ded the cis-aminopyrrolidine 166 exclusively in 50% yield. Removal
of the t-butyl carbamate group with TFA afforded the teneligliptin
free amine in 93% yield, which was then subsequently treated with
48% hydrobromic acid in refluxing ethanol to give teleligliptin
hydrobromide hydrate (XXV) in 90% yield.
27. Teriflunomide (AubagioÒ)
Teriflunomide (AubagioÒ), also known as A77 1726, is an imm-
unosupressant marketed by Sanofi for the teatment of multiple
sclerosis (MS).206 Teriflunomide is the active metabolite of lefluno-
mide, used for treatment of patients diagnosed with rheumatoid
arthritis, and therefore simultaneously can be used as a treatment
for rheumatoid arthritis.207 Teriflunomide acts as an inhibitor of
the mitochondrial enzyme dihydrorotate dehydrogenase,208–210
inhibiting pyrimidine formation,211 and resulting in reduced B
and T cell proliferation.210
Numerous syntheses of teriflunomide have been developed to
date,212–217 most relying on the use of 4-trifluoromethyl aniline
(167).212 The current optimized method for scale-up synthesis of
teriflunomide, developed by Keshav and coworkers, begins with
reaction of commercial 4-trifluoromethyl aniline 167 and ethylace-
toacetate (168) in refluxing xylenes, providing acetoamidate 169 in
51% yield (Scheme 31).215 The resulting acetoamidate 169 was

I I
Cl
H2 SO4 (conc.), NaIO4 , KI, RT Cl t-BuOH, DPPA Cl
O
73% Et 3 N, ↓↑, 84%
CO2 H N Ot-Bu
CO2 H
H
179 180 181

O O N
B2(pin) 2 , Pd(dppf)Cl 2 B 2-bromopyridine, Pd(PPh 3 )4
Cl Cl
KOAc, DMSO, 110 °C, 91% O NaHCO3 , H 2O, DME O
↑↓, quant.
N Ot-Bu N Ot-Bu
H H
182 183

N
N
TFA, DCM, 0 °C 185 , Et 3N, DCM Cl
Cl O Cl
98% 0°C to 5 °C, 99%
N
NH2 H
SO 2Me
184 XXVIII Vismodegib

Cl O Cl
HO 2C 10% NaOH, toluene, Et3 N
Cl
DMF, SOCl2 , 0 °C to 50 °C
SO2 Me SO2 Me
186 185

Scheme 33. Synthesis of vismodegib (XXVIII).

 H. X. Ding et al. / Bioorg. Med. Chem. 22 (2014) 2005–2032
then treated with H2O2, KBr, and concentrated HCl at room tem-
perature, providing bromide 170 in 67% yield. Bromide 170 was re-
acted with NaCN in DMSO, generating teriflunomide (XXVI) in 85%
yield.215
28. Tofacitinib citrate (XeljanzÒ)
Tofacitinib, a pan-Janus Kinase (JAK) inhibitor, was approved by
the FDA for the treatment of moderate to serious cases of rheuma-
toid arthritis (RA) in patients that have not responded to mono
therapy with methotrexate therapy.188 Tofacitinib, which was dis-
covered and developed by Pfizer Inc.,218 is a potent and selective
inhibitor of the JAK family of kinases and has shown potential for
treating psoriasis and organ transplant in addition to RA.219 Both
the initial discovery synthetic route220,221 and the process scale
synthetic route have been disclosed in the chemical literature,
and the process approach is described in Scheme 32 below.222,223
Commercially available aminopyridine 171 was reacted with
dimethyl dicarbonate in the presence of potassium t-butoxide to
give the methyl carbamate 172 in 87% yield. Hydrogenation of this
carbamate 172 in the presence of 20 wt % of 5% Rh/C (JM type
C101023-5) in acetic acid followed by reductive amination with
benzaldehyde and sodium triacetoxy borohydride furnished the
cis-benzyl protected piperidine 173 in 73% yield. Reduction of the
methyl carbamate within 173 with lithium aluminum hydride
(LAH) in THF gave the corresponding methyl amino piperidine
which was isolated as the dihydrochloride salt 174 in 87% yield.
Enantiomeric resolution of the methyl amino piperidine was
achieved by preparation of the free base of 174 with sodium
hydroxide, conversion to the di-toluol-L-tartaric acid salt, and sub-
sequent crystallization to give 175 in 42% yield and 98.6% ee. The
enantioenriched tartrate salt 175 was then directly reacted with
dichloride 176 (obtained from reaction of commercial 7H-pyrrol-
o[2,3-d]pyrimidine-2,4-diol (178) with phosphorous oxychloride)
in the presence of potassium carbonate in water to give the cou-
pled product 177 in essentially quantitative yield. Hydrogenation
of intermediate 177 with DeGussa’s catalyst triggered concomitant
debenzylation and chloride removal, and this was followed by
installation of the cyanoacetate group and subsequent treatment
with citric acid to provide tofacitinib citrate (XXVII) in 90%
yield.224
29. Vismodegib (ErivedgeÒ)
Until the approval of Genentech’s visomodegib, the only treat-
ment options for patients with advanced or metastatic basal-cell
carcinoma (BCC) were surgery or radiation therapy. Because it rep-
resented a first-in-class treatment, vismodegib received priority
review from the FDA as the drug progressed through clinical trials.
The drug, which is marketed as ErivedgeÒ, derives its efficacy
through inhibition of the hedgehog signaling pathway which exists
in most BCC’s.225,226 While there are several patents that cover the
synthesis of vismodegib,227–229 the scale route has been published,
and this route is depicted in Scheme 33.230
The synthesis began with selective iodination of commercial
carboxylic acid 179, affording trisubstituted arene 180 in 73% yield.
A Curtius reaction then converted 180 to carbamate 181 in 84%
yield, and this was followed by a palladium(0)-catalyzed boryla-
tion of 181 which furnished Suzuki coupling partner 182 in 91%
yield. Pinacol borane 182 was exposed to commercial 2-bromopyr-
idine under conventional cross-coupling conditions to furnish biar-
yl 183, which underwent Boc-deprotection in quantitative
conversion to generate 184. Amide bond formation with acid chlo-
ride 185 (readily available from the corresponding commercial
acid)231 produced vismodegib (XXVIII) in 99% yield.
2029
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