Нові ліки, які з’явилися на ринку в 2023 році: молекули, що містять флуор та модифіковані амінокислотні фрагменти
Dedication: As we celebrate Professor Iwao Ojima's 80th birthday on June 5th, 2025, we express gratitude for his dedication to chemistry, mentoring, and friendship. His teaching style, blending expertise and enthusiasm, has inspired countless students and colleagues. His kindness, guidance, and...
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2024
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Ukrainica Bioorganica Acta| _version_ | 1871193606437470208 |
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| author | Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander E. Ono, Taizo Soloshonok, Vadim A. |
| author_facet | Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander E. Ono, Taizo Soloshonok, Vadim A. |
| author_institution_txt_mv | [
{
"author": "Jianlin Han",
"institution": "Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, China"
},
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Kielce, Poland"
},
{
"author": "Gagan Dhawan",
"institution": "DAcharya Narendra Dev College, University of Delhi, New Delhi, India "
},
{
"author": "Wei Zhang",
"institution": "University of Massachusetts Boston, Boston, MA, USA"
},
{
"author": "Alexander E. Sorochinsky",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology (AIST), Anagahora, Shimoshidami, Moriyama-ku, Nagoya, Japan"
},
{
"author": "Vadim A. Soloshonok",
"institution": "University of the Basque Country, San Sebastián, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain"
}
] |
| author_sort | Han, Jianlin |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:54Z |
| description | Dedication: As we celebrate Professor Iwao Ojima's 80th birthday on June 5th, 2025, we express gratitude for his dedication to chemistry, mentoring, and friendship. His teaching style, blending expertise and enthusiasm, has inspired countless students and colleagues. His kindness, guidance, and encouragement have nurtured lasting bonds. We honor his remarkable achievements and the lives he's touched
This article profiles eight new FDA-approved drugs containing fluorine along with the fragments of amino acids or their derivatives. These pharmaceuticals include Eflornithine, Lotilaner, Leniolisib, Fezolinetant, Nirmatrelvir, Repotrectinib, Nirogacestat, and Pirtobrutinib, representing such therapeutic areas as cancer, neuromuscular disorder, immunodeficiency, virology, and infectious diseases. Importance of fluorination, amino acid residues as well as chirality in the design of new pharmaceuticals is highlighted |
| doi_str_mv | 10.15407/bioorganica2024.01.003 |
| first_indexed | 2025-07-17T12:19:58Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
UDC 547.466 + 615.31
DOI: https://doi.org/10.15407/bioorganica2024.01.003
3
REVIEW
New drugs appearing on the market in 2023: molecules containing
fluorine and fragments of tailor-made amino acids
Jianlin Han1, Alicja Wzorek2, Gagan Dhawan3, Wei Zhang4, Alexander E. Sorochinsky5,
Taizo Ono6, Vadim A. Soloshonok7,8*
1 Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering,
Nanjing Forestry University, Nanjing, China
2 Institute of Chemistry, Jan Kochanowski University in Kielce, Kielce, Poland
3 DAcharya Narendra Dev College, University of Delhi, New Delhi, India
4 University of Massachusetts Boston, Boston, MA, USA
5 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
6 National Institute of Advanced Industrial Science and Technology (AIST), Anagahora, Shimoshidami, Moriyama-ku, Nagoya, Japan
7 University of the Basque Country, San Sebastián, Spain
8 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
Dedication: As we celebrate Professor Iwao Ojima's 80th birthday on June 5th, 2025, we express gratitude for his dedication to chemistry,
mentoring, and friendship. His teaching style, blending expertise and enthusiasm, has inspired countless students and colleagues. His
kindness, guidance, and encouragement have nurtured lasting bonds. We honor his remarkable achievements and the lives he's touched.
Abstract: This article profiles eight new FDA-approved drugs containing fluorine along with the fragments of amino acids or their
derivatives. These pharmaceuticals include Eflornithine, Lotilaner, Leniolisib, Fezolinetant, Nirmatrelvir, Repotrectinib, Nirogacestat, and
Pirtobrutinib, representing such therapeutic areas as cancer, neuromuscular disorder, immunodeficiency, virology, and infectious diseases.
Importance of fluorination, amino acid residues as well as chirality in the design of new pharmaceuticals is highlighted.
Keywords: pharmaceuticals; amino acids; fluorine-containing compounds; drug design and development.
Introduction
Amino acids (AAs), often referred to as the fundamental
building blocks of life, play a crucial role in the origin and
evolution of all known life forms. Since their isolation from
numerous natural sources and structural characterization in
the early 1800s [1], AAs and their derivatives continue to
be the most studied compounds in multidisciplinary areas of
health sciences and technology [2]. In addition to basic
scientific exploration, the major goal of medicinal
Received:
Revised:
Accepted:
Published online:
10.04.2024
13.05.2024
20.05.2024
30.06.2024
Corresponding author. Tel.: +34-94-301-5177;
e-mail: vadym.solosholok@ehu.es (V.A. Soloshonok)
ORCID: 0000-0003-0681-4526
chemistry research in the area of tailor-made AAs [3] is the
development of more selective and potent pharmaceuticals
[4]. From a structural standpoint, AAs represent an example
of molecular dichotomy allowing for a step-wise synthesis
of polymers with never-repeating sequences of monomers.
Such polymers, peptides serve numerous key roles in living
organisms including catalytic (enzymes), signaling
(hormones) mechano-structural functions [5]. Thus, in the
modern paradigms of drug discovery, tailor-made AAs
serve as indispensable components and their derivatives are
increasingly found in newly marketed pharmaceuticals [6].
In fact, over 30% of small-molecule drugs contain residues
of tailor-made AAs or derived from them amino-alcohols
and di-amines [7]. Another quite established trend in the
design of modern medicines is the selective introduction of
fluorine-containing substituents into the structure of a drug
candidate [8]. Usually, this strategy is used to protect the
most oxidatively vulnerable positions thus increasing the
metabolic stability of the designed
© Han J. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Ukrainica Bioorganica Acta
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https://orcid.org/0000-0003-0681-4526
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
4
H
N
NN
NH2
Me
CF3
H2N
O
O
OMe
F
JaypricaTM (Pirtobrutinib)
JoenjaTM (Leniolisib)
N
N
N
HN
NMeO
F3C
N
O
VeozahTM (Fezolinetant)
N
N
N
N
O
F
S
N
N
Me
Me
N
Me Me
O
NH
CF3
O
O
HN
CN
NH
O
5 PaxlovidTM (Nirmatrelvir, Ritonavir)
O
N
S
N
H
H
N
O
O
CF3
Me
CF3
Cl
Cl
Cl
XdemvyTM (Lotilaner)
HN
HN
O
Me
O
N
N
N
Me
F
AugtyroTM (Repotrectinib)
NH
O
H
NF
F
N
N
NH
Me
Me
OgsiveoTM (Nirogacestat)
8
4
3
Nirmatrelvir (5A)
2
6 7
IwilfinTM (Eflornithine)
H2N OH
O
F2HC NH2
1
H
N
N
H
H
N O
O
OHO
O
N
Me
N
S N
S
Ritonavir (5B)
Figure 1. Structures of new drugs 1-8 containing fluorine as well as a residue of AA or its derivative.
molecule. Furthermore, selective fluorination allows for
fine-tuning of the desired bioactivity and pharmacokinetics.
Over the last 20 years, fluorine scanning and editing have
become rather standard steps in the design of modern drugs
[9].
In this review article, we profile the eight
pharmaceuticals approved by the FDA in 2023 (Figure 1),
which contain fluorine as well as a residue of AA or its
derivative. These include: IwilfinTM (Eflornithine) 1,
XdemvyTM (Lotilaner) 2, JoenjaTM (Leniolisib) 3,
VeozahTM (Fezolinetant) 4, PaxlovidTM (Nirmatrelvir,
Ritonavir) 5, AugtyroTM (Repotrectinib) 6, OgsiveoTM
(Nirogacestat) 7 and JaypricaTM (Pirtobrutinib) 8. The
discussion includes therapeutic areas of application and
detailed chemical synthesis.
General Aspects of Asymmetric Synthesis of
Tailor-Made AAs
Asymmetric synthesis of AAs is a mature science that
offers a plethora of diverse approaches [10]. However, the
issues of cost, operational convenience, and environment-
tal/climate concerns are constantly raising the bar of
synthetic efficiency, requiring continuous advances and
improvement of the synthetic methodology. Analysis of the
literature may suggest that preparation of both general type
and tailor-made AAs via Ni(II) complex intermediates
(Scheme 1) is currently the most frequently used approach
[11]. As shown in Scheme 1, abstractly presented chiral
ligands 9 possess three adaptable modules, A, B, and C,
which can be rationally designed to attain desired chemical
(steric strain, chirality, reactivity) and physicochemical
(solubility, crystallinity) properties [12]. Tridentate chiral
ligands 9 can be directly used for the complexation of
unprotected AAs to form the corresponding Ni(II)
complexes 11 to perform dynamic kinetic resolution of the
racemic α- and β-AAs [13]. This approach can also be used
for interconversion of readily available L-AAs to the
corresponding D enantiomers.
A more synthetically multipurpose application of this
methodology involves the preparation of a glycine Schiff
base Ni(II) complexes 10 which serve as chiral nucleophilic
glycine equivalents in reactions with electrophilic reagents.
For example, alkylation of glycine derivative 10 affords
tailor-made AAs of types 12-15 via alkylation with general
alkyl halides [14], chiral secondary alkyl halides [15] or a
bis-alkylation procedure [16]. Alkylation approach can also
be used for the asymmetric synthesis of phosphorus analogs
of dicarboxylic AAs [17]. Michael addition reactions of
Ni(II) complex of glycine Schiff base 10 serve as a general
approach for preparation of various poly-substituted
derivatives of glutamic acid 16 [18], glutamine [19],
pyroglutamic acid 17 [20] and proline 18 [21]. Aldol and
J. Han, A. Wzorek, et al.
5
ONHO
N
A B
C
NNO
NA
B
C
OO
Ni
NNO
NA
B
C
OO
Ni
9
10
11
Gly, Ni(II)
base
Alkylations,
additions, etc.
Acidic
disassembly
Recovery and reuse of
chiral ligands 9 and Ni(II)
for continuous
asymmetric synthesis
of tailor-made AAs
12
COOH
NH2
R
COOH
NH2
R
R'
13 14 15
22
N
Alkylation:
COOH
NH2
R
Me
COOH
NH2
X
H2N
COOH
Michael
additions: COOH
NH2
HOOC
R
R' O COOH
H
RR'
N COOH
H
RR'
16 17 18
Aldol,
Mannich: COOH
NH2
R
OH
19
COOH
NH2
R
NH2
20
DKR:
12
COOH
NH2
R
21
COOH
R
NH2
Miscella-
neous:
COOHH2N
23
COOH
R
NH2
OH
24
COOH
NH2
R
N
O
O
O
O R
H
25
R
Scheme 1. Preparation of tailor-made AAs in enantiomerically pure form via Ni(II) complexes.
Mannich addition reactions provide a convenient method
for the asymmetric synthesis of β-hydroxy and β-amino
tailor-made AAs 19 [22] and 20 [23], correspondingly. This
Ni(II) complex methodology can be expanded for the
preparation of more structurally complex tailor-made AAs
and their derivatives, such as (1R,2S)-1-amino-2-
vinylcyclo-propanecarboxylic acid 22 [24], α-hydroxy-β-
amino acids 23 [25], 3-methyleneglutamic acids 24 [26] and
configurationally stable thalidomides 25 [27]. Products 11
can be conveniently disassembled under mild acidic
conditions giving rise to the target tailor-made AAs of types
12-25, along with recovery and reuse of the tridentate chiral
ligands 9 and Ni(II) ions. Recycling of the ligands 9 is
economically attractive, rendering this methodology on par
with catalytic approaches. Over the last decade, noticeable
progress has been made in the design of new tridentate
ligands 9, attaining synthetically useful levels of
stereocontrol and overall practicality. Several structurally
new and synthetically versatile glycine Schiff base Ni(II)
complexes are presented in Figure 2.
For example, it was found that Ni(II) complex 26,
containing three chlorine atoms in certain positions, adopts
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
6
NNO
N OO
Ni
Cl
Cl
Cl
(S)-26
NNO
N OO
Ni
Cl
(S)(S)-27
Cl
NNO
N OO
Ni
Cl
(SC)(SN)-28
Cl
CH3
H
NNO
N OO
Ni
Cl
(S)-29
Figure 2. Structural types of chiral Ni(II) complexes 26-29.
parallel displaced-type p-interactions between the aromatic
rings [28], resulting in virtually complete (>98% de)
thermodynamic stereocontrol in the reactions of complex 26
with electrophilic reagents [29]. The design of Ni(II)
complex 27 is based on the matching stereocontrolling
effect of the central and axial elements of chirality,
providing for effectively complete diastereoselectivity
(>99%) of its alkylations and addition reactions [30]. Ni(II)
Complex 28, featuring stereogenic nitrogen and an
extremely lipophilic adamantyl group, was designed for
KDR of racemic AAs via a quite rare process of second-
order asymmetric transformation control, i.e. precipitation
of one diastereo- and enantiomerically pure product form a
solution [31]. Glycine Schiff base complex 29 possesses
unracemizeable, under normal reaction conditions, axial
chirality, and, therefore, can be recycled and reused without
limitation [32]. These complexes can be prepared on a large
scale [33] and the whole methodology holds a significant
promise for the practical synthesis of virtually any type of
tailor-made AAs of pharmaceutical importance.
New FDA approved drugs featuring amino acid
residues and fluorination
Iwilfin™ (Eflornithine)
Ornithine decarboxylase inhibitor Eflornithine (α-difluo-
romethylornithine, DFMO, MDL-71728, Iwilfin™) 1 was
developed by US WorldMeds [34]. It is designed to be used
specifically to reduce the risk of relapse in adults and
pediatric patients with a high-risk of neuroblastoma
(HRNB). Structurally, Eflornithine 1 contains the amino
acid frag-ment and the key difluoromethyl moiety at the α-
position (Figure 1). The drug has one chiral carbon center;
however, it is filed to be used as a racemic mixture. It
should be mentioned that enantiomerically pure 1 has been
described by Ashton et al. who reported a chiral
chromatographic method for the isolation of pure
enantiomers on a semi-preparative milligram scale [35].
Biological studies on catalytic irreversible inhibition of
mammalian ornithine decarboxylase (ODC) showed that the
difluoromethyl group is absolutely essential for the
inhibition process [36]. In general, AA derivatives that
position fluorine atoms β-to the amino group take advantage
of fluorine as a leaving group and have found application in
the design of suicide substrates mechanism-based inhibitors
of enzymes, in particular, bacterial racemases and
mammalian and non-mammalian decarboxylases [37].
Synthetic route for the preparation of drug 1 is presented
in Scheme 2 [38]. The sequence starts with the alkylation of
N-(diphenylmethylene)glycine ethyl ester 30 with 3-chloro-
propionitrile using potassium carbonate as a base in
acetonitrile at 80 ºC to afford α-cyanoalkyl glycine ester 31.
Next, compound 31 undergoes difluoromethylation with
OH
O
NH2
NC
OEt
O
NH2F
F
F
F
OEt
O
NH2F
F 2HCl
Pt/C, EtOH,
H2 (95 psi),
1 h
con. HCl
HCl,
110 oC
NC OEt
O
NF
F Ph
Ph
HCl (aq.),
MTBE
1.5 h, 20 oC
33 34
N
O
OEt
Ph
Ph
NC Cl
K2CO3, MeCN
10 h, 80 oC
OEt
O
N
Ph
Ph
CHF2Cl,
NaOtBu
THF, -25 oC,
10 min
31 3230
Eflornithine 1
H2N H2N
CN
Scheme 2. Synthesis of Eflornithine 1.
J. Han, A. Wzorek, et al.
7
Freon-22 in the presence of NaOtBu resulting in a
formation of product 32 in 70% yield (two steps).
Treatment of compound 32 with aqueous HCl in methyl
tert-butyl ether (MTBE) gives rise to amino ester 33 (93%
yield). The next step is a Pt/C-catalyzed reduction of the
cyano group in 33 to afford diamino ester 34. The final step,
hydrolysis of the ester group in 34 under acidic conditions,
provided the target Eflornithine 1 in 88% yield.
Xdemvy™ (Lotilaner)
Isoxazoline moiety is frequently found in compounds
possessing antiparasitic activity, among which some notable
examples include Fluralaner 35 (Figure 3), Afoxolaner, and
O
N
S
N
H
H
N
O
O
CF3
Me
CF3
Cl
Cl
Cl
XdemvyTM (Lotilaner)
2
O N
CF3
Cl
Cl
35
CH3
HN
O
O
H
N CF3
Fluralaner
Figure 3. Structures of Lotilaner 2 and Fluralaner 35.
Sarolaner [39]. It is also has been reported that
isoxazolines-containing molecules can act as specific
blockers of GABACls and GluCls channels in insects [40].
Furthermore, some isooxazoline derivatives, including the
title compound Lotilaner 2, have been widely used as
veterinary medicines for the treatment of flea and tick
infestations in animals. Lotilaner 2, developed by Tarsus
Pharmaceuticals, received FDA approval in July 2023 as an
antiparasitic agent for the treatment of Demodex blepharitis.
Blepharitis is an inflammatory disease of the eyelid that
causes redness and eye irritation. In addition to Demodex
blepharitis, Lotilaner 2 can be applied to control flea allergy
dermatitis [41].
Drug 2 was shown to act as a non-competitive antagonist
of γ-aminobutyric acid (GABA), highly selectively
targeting mites without inhibiting mammalian GABA-
mediated chloride channels (GABA-Cl) [40]. Similar to
Fluralaner 35, Lotilaner 2 has a stereogenic carbon as a part
of the isoxazoline ring (Figure 3). Interestingly, only the
(S)-enantiomer shows the desired bioactivity, while the
(R)-enantiomer is almost inactive. Inhibition of GABA-Cl
by 2 causes paralysis of the target microorganism, with
eventual death to follow. This mode of biological action is
effective for treating several conditions such as Blepharitis,
Meibomian Gland Dysfunction, and Lyme Disease [42].
Synthesis of Lotilaner 2 is based on 2,2,2-trifluoro-1-
(3,4,5-trichlorophenyl)ethan-1-one 36 as the starting
material (Scheme 3). Keton 36 reacted with 1-(5-bromo-4-
methylthiophen-2-yl)ethan-1-one 37 in the presence of Et3N
(TEA) to give the unsaturated intermediate 38 [43].
Compound 38 was subjected to a cyclization reaction with
OF3C
Cl
ClCl
O
N
S
N
H
H
N
O
O
CF3
Me
CF3
Cl
Cl
Cl
XdemvyTM (Lotilaner)2
S
O
CH3Br
H3C
36
37
1) TEA, TBME, 57 oC, 2 hrs
2) SOCl2, 40 oC, 3 hrs
CF3 O
S
Cl
Cl
Cl
Br
CH3
38
NH2OH HCl,
EtOH, 5 oC
NaOH H2O, 5 hrs
Cl
Cl
Cl
NO
CF3
S Br
CH3
39
EtMgBr,
THF, CO2
Cl
Cl
Cl
NO
CF3
S COOH
CH3
40
Optical resolution with (R)-41
H3C
NH2
CH3
Cl
Cl
Cl
NO
CF3
S COOH
CH3
(S)-40
H2N
O
N
H
CF3
1) SOCl2, 110 oC
2) TEA, 5 oC
42
(R)-41
Scheme 3. Synthesis of Lotilaner 2.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
8
NH2OH in the presence of NaOH leads to the formation of
isoxazole product 39. Introduction of the carboxylic group
was achieved via the reaction of isoxazole 39 with EtMgCl
in THF under a carbon dioxide atmosphere. Taking
advantage of the carboxylic group, racemic compound 40
was successfully resolved using (R)-41. Enantiomerically
pure (S)-40 was converted into acyl chloride and then
directly reacted with 2-amino-N-(2,2,2-trifluoroethyl)-
acetamide 42, in the presence TEA affording the target
Lotilaner 2.
It should be mentioned that key fluorinated amine 50
(Scheme 4), needed for the preparation of 42 (Scheme 3),
can be obtained from trifluoroacetic acid via double
biomimetic amination [44]. As precented in Scheme 4, in
this unusual process, the treatment of starting acid 43 with a
mixture of BnNH2/Ph3P/CCl4, and TEA initiates a cascade
of five consecutive reactions, via intermediates 44-48,
resulting in the formation of 48 as a final product.
Compound 48, without isolation, can be further transformed
into the target amine 50 using two simple hydrolysis steps.
The overall process is a unique example of a double
biomimetic amination making use of both benzylic
hydrogens of benzylamine for the reduction of the carbonyl
group [45].
F3C O
OH
F3C O
N
H
Ph
F3C Cl
N Ph
F3C Cl
N Ph
F3C
N Ph
Cl
F3C
N Ph
Cl
F3C
N
H
Ph
O
F3C NH2
HCl
A: BnNH2 (1 equiv.), Ph3P (4 equiv.)/CCl4 (4 equiv.),
TEA (1.5 equiv.), CHCl3 reflux, 40 min,
A
HCl HCl
43 44 45
46 47 48
49 50
Scheme 4. Preparation of trifluoroethylamine 50 from
trifluoroacetic acid via double biomimetic amination.
Joenja™ (Leniolisib)
Leniolisib 3, was discovered by Novartis and developed
into a marketed product by Pharming Group. Drug 3 is a
selective phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor
that was designed for the treatment of immunodeficiency
disease [46]. As presented in Figure 4, Leniolisib 3 is a
chiral compound, which features a key 5,6,7,8-tetrahydro-
pyrido[4,3-d]-pyrimidine bicyclic fragment, a (S)-3-ami-
nopyrrolidine and a trifluoromethylated pyridine ring.
Leniolisib 3 possesses high inhibitory activity against PI3K
with the cellular IC50 of 1.67 μM, 2.25 μM and 0.056 μM
for PI3Kα, PI3Kβ and PI3Kδ respectively [47]. The
structure-activity relationship study conducted by Novartis
revealed that the trifluoromethyl group played an
imperative role in the observed for 3 bioactivity. It is
interesting to note that not-fluorinated analog 51 (Figure 4)
shows a similar spectrum of biological activity, however
with significantly reduced magnitude. Thus, the
introduction of a trifluoro-methyl group on the
methoxypyridine moiety led to a four-fold increased PI3Kδ
potency (31, IC50 = 0.246 μM) [46a]. Moreover, drug 3
features adequate hydrophility, good solubility, and
metabolic stability, as well as favorable membrane
permeability. Based on the findings from the Phase II/III
clinical trial, Leniolisib 3 received its first FDA approval
under the name Joenja™ for the treatment of activated
phosphoinositide 3-kinase delta syndrome (APDS) [48].
IC50 = 0.056 M
N
N
N
HN
NMeO
H3C
N
O
N
N
N
HN
NMeO
F3C
N
O
IC50 = 0.246 M
3
51
Figure 4. Structures of Leniolisib 3 and its non-fluorinated analog
51.
Synthesis of Leniolisib 3 presented in Scheme 5 was
developed by Novartis. The process is based on tetrahydro-
pyrido[4,3-d]pyrimidine heterocyclic compound 54 as the
key intermediate [46ab, 49]. Assembly of fused pyrimidine
cycle in 53 was accomplished via a cyclization reaction of
methyl 1-benzyl-4-oxopiperidine-3-carboxylate (52) with
acetic acid methanimidamide in the presence of sodium
methoxide. Thus generated compound 53 was treated
with phosphorus oxychloride (POCl3) and triethylamine as
a base in toluene at 100 ºC to afford the chlorinated
tetrahydropyrido[4,3-d]pyrimidine intermediate 54 in 58%
yield. Substitution reaction of the compound 54 by
(S)-3-aminopyrrolidine 55 in an autoclave at 120 ºC gave
rise to compound 56, which was subjected to a Pd-catalyzed
benzyl deprotection reaction in the presence of ammonium
formate to give the free fused heterocycle 57. Pd-catalyzed
coupling reaction of 57 with 5-bromo-2-methoxy-3-
(trifluoromethyl)pyridine 58 led to compound 59 in 74%
isolated yield. Final steps in this synthesis included the
removal of the Boc-protecting group, from 59 to 60, and
acylation of the cyclic NH function in 60 with propionyl
chloride to afford the target Leniolisib 3 in 76% yield [46].
J. Han, A. Wzorek, et al.
9
58
N
N
N
HN
NMeO
F3C
N
O
N
N
N
HN
NMeO
F3C
NBoc
N
N
N
HN
NMeO
F3C
NH
Cl
O
Br
NMeO
F3C
HN
N
N
HN
NBoc
N
N
N
HN
NBoc
PhH2N
NBoc
N
N
NPh
Cl
N
N
NPh
OH POCl3,
Et3N
toluene,
100 oC, 2 h
54, 58% yield
TFA, CH2Cl2
20 oC, 1 h NaHCO3 (aq.),
CH2Cl2
rt, 1 h
Et3N, 120 oC, 42 h
56, 93% yield
Pd/C,
MeOH
ammonium
formate
reflux, 1 h
57, 66% yield
Pd2(dba)3, tBuDavePhos
tBuONa, tBuOH
59, 74% yield
100 oC, 5 h, Ar
Leniolisib 3, 76% yield
60
N
O
OMe
O
Ph
NHH2N
MeOH, NaOMe
CH3CO2H
52 53, 83% yield
90 oC, 3 h
55
Scheme 5. Synthesis of Leniolisib 3.
Veozah™ (Fezolinetant)
Fezolinetant 4 was discovered by Euroscreen S.A. as an
oral, neurokinin 3 receptor (NK3R) antagonist for the
treatment of sexual hormone disorders [50]. Drug 4 is a
chiral compound featuring a triazolopiperazine core, a
1,2,4-thiadiazole unit, and a 4-fluorobenzoyl group. The
bioactivity data for 4 and its close analogs 61-63 clearly
indicate the advantageous significance of fluorination on
the biological properties (Figure 5). In this series of
structurally analogous compounds, fezolinetant 4 is the best
in terms of overall hERG (human ether-a-go-gorelated
gene) and CYP (cytochrome P450) safety profile [50].
Fezolinetant 4 was developed by Astellas Pharma Inc. and
in May of 2023, it received approval by the FDA as a first-
in-class nonhormonal treatment for severe vasomotor
symptoms (VMS) or menopausal hot flashes [51].
Synthetic strategy for the preparation of fezolinetant 4,
developed by Euroscreen S.A., is presented in Scheme 6.
The formation of the fused triazolopiperazine via
cyclodehydration of piperazinoimidate and 1,2,4-thia-
diazole-5-carbohydrazide, from 67 to 69, is a key step in
this approach [50]. The intermediate 1,2,4-thiadiazole-5-
carbohydrazide 64 was obtained in 64% yield via the
reaction between ethyl 3-methyl-1,2,4-thiadiazole-5-
carboxylate and hydrazine in ethanol at ambient
temperature. 2,4-Dimethoxybenzyl protected compound 66
was prepared via reductive amination of (R)-3-methyl-
piperazin-2-one (65) and 2,4-dimethoxybenzaldehyde with
sodium triacetoxyborohydride as a reductive reagent in the
presence of acetic acid under nitrogen atmosphere [52].
Meerwein reagent (Et3OBF4) and Na2CO3 as a base, were
used to transform piperazin-2-one 66 to piperazinoimidate
67 in 68% yield and 98.8% ee, indicating some racemi-
zation of the carbon stereogenic center. It was found that the
use of Meerwein reagent under buffered conditions allows
to minimize racemization during this step [50]. Next, the
piperazinoimidate 67 underwent a cyclodehydration reacti-
on with the 1,2,4-thiadiazole-5-carbohydrazide 68 at 70 ºC
for 8 h affording the fused triazolopiperazine 69 in 80%
yield. Deprotection of 2,4-dimethoxybenzyl group in 69 via
the treatment with TFA at 0 ºC gave rise to free
logD7.4 =
hERG IC50 =
S
3.0
8 M
Cl F
1.3
50 M
2.0
66 M
1.5
>100 M
61 62 63 4
R =
NN
N
NMe
R
O
S
N
N
Me
Figure 5. Biological activity of fezolinetant 4 and its close structu-
ral analogs 61-63. .
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
10
N
N
N
N
O
F
S
N
N
Me
Me
Et3OBF4, Na2CO3
N
N
Me
O
MeO OMe
SN
N
O
N
H
NH2
Me
SN
N
O
OEtMe
hydrazine
S
N
N
Me
N
N
N
N
Me
MeO OMe
TFA, 2 h, 0 oC
NH
HN
O
Me
MeO OMe
O
CH3CN, 20 oC, N2
66 98%
NaB(OAc)3H, HOAc
+
CH2Cl2, 45 min
67
68% yield
ethanol, rt
64 64%
SN
N
O
N
H
NH2
Me
MeOH, 70 oC, 8 h
69
80% yield
S
N
N
Me
N
HN
N
N
Me
70
>99% yield
Cl
O
F
NaHCO3, rt, 15 min
65
68
NH
N
O
Me
OMeMeO
Fezolinetant (4)
97% yield
Scheme 6. Synthesis of Fezolinetan 4.
amine 70 in quantitative yield. Finally, acylation of the
amine group in 70 with 4-fluorobenzoyl chloride at ambient
temperature afforded the target fezolinetan 4 in 97% yield.
Since the piperazin-2-one 66 is structurally quite like
amid derived from AA alanine, its partial racemization
under basic reaction conditions to yield piperazinoimidate
67 was rather expected and therefore timely detected and
consequently mitigated. In this regard, it should be
emphasized that the acquaintance of practitioners working
in this field with self-disproportionation of enantiomers
would be quite beneficial for increasing the veracity of the
reported data [53].
Paxlovid™ (Nirmatrelvir, Ritonavir)
Paxlovid 5 is an oral antiviral pharmaceutical containing
nirmatrelvir 5A and ritonavir 5B. Developed by Pfizer, it
received the FDA approval on May 25th, 2023 for the
treatment of mild-to-moderate cases of coronavirus in
patients who are at high risk for progression to severe
COVID-19 [54]. Nirmatrelvir 5A acts as a protease
inhibitor. It disrupts the viral life cycle by targeting the
SARS-CoV-2 protease. This inhibition is critical for
preventing the virus from replicating. Notably, the low off-
target activity of nirmatrelvir 5A is valuable for reducing
undesired side effects associated with potential interaction
with human proteins [55]. Ritonavir 5B, in this combination
treatment, serves a two-fold purpose. First, as a human HIV
protease inhibitor, it contributes to the antiviral effect.
Second, ritonavir 5B works as a pharmacokinetic enhancer
by inhibiting CYP3A4, an enzyme involved in drug
metabolism. By slowing down the metabolism of
nirmatrelvir, ritonavir 5B aids to increase its bioavailability
and extend its presence in the body. This mechanism allows
for higher concentrations of nirmatrelvir, enhancing its
efficacy in fighting the SARS-CoV-2 virus [56]. The
combination of nirmatrelvir (5A) and ritonavir (5B), as
pointed out above, illustrates a targeted and synergistic
approach to inhibiting viral replication and treating early
COVID-19 infections, with the potential to prevent the
development to more severe symptoms.
Structurally, drugs 5A and 5B have a significant
proportion of tailor-made AAs and underscore the
importance of AAs in the modern drug design. Thus,
nirmatrelvir 5A is a protein mimetic tripeptide, and its
design was inspired by the detailed biological studies
conducted on Lufotrelvir 71 and a dipeptide Boceprevir 72
(Figure 6) [57]. In particular, it was demonstrated that the
incorporation of the gem-dimethyl cyclopropyl proline
fragment increased the biological potency of the drug. This
finding was rather influential in the design of Nirmatrelvir
5A. The strategy of incorporating a bicyclic amino acid was
employed to identify potent molecules for treating SARS-
CoV-2. This underscores a rational design approach based
on known structural features that enhance antiviral activity.
Also, nirmatrelvir 5A features a trifluoromethyl group,
which is important for the bioactivity disclosed by the SAR
studies. The enzymatic IC50, cellular EC50, and antiviral
EC50 values of the protease inhibitory activity for
J. Han, A. Wzorek, et al.
11
N
Me Me
O
NH
CF3
O
O
HN
CN
NH
O
5A
N
Me Me
O
NHO
O
HN
CN
NH
O
73
H
N
N
O
O
H
N
71
N
H O
H
N
OMe
O
O
O
P
O
OH
OH
H
NO
72
H H
Me Me
O
H
N
O
O NH2
Lufotrelvir
Boceprevir
Nirmatrelvir
Figure 6. Structures of drugs Lufotrelvir 71, Boceprevir 72,
Nirmatrelvir 5A and its analog 73.
nirmatrelvir 5A were reported as 66 nM, 3.4 μM, and 1.3
μM, respectively. Interestingly, substitution of the
trifluoromethyl by tert-butyl in compound 73 resulted in an
eleven-fold decrease of the inhibitory activity (enzymatic
IC50 = 720 nM) [58].
The synthesis of Nirmatrelvir 5A developed by
researchers from Pfizer is presented in Scheme 7 [59]. The
process begins with the transformation of Boc-protected
trans-4-hydroxy L-proline benzylester 74 to methane-
sulfonate 75. Thus prepared compound 75 is treated with
PhSeSePh to generate the 4-(phenylselanyl)pyrrolidine 76.
Oxidation pyrrolidine 76 followed by elimination reaction
afforded unsaturated proline 77 which was subjected to a
cyclopropanation reaction with 2,2-dichloropropane cataly-
zed by (2-t-BuPDI)CoBr2 in the presence of ZnBr2 and Zn
giving rise to a bicyclic compound 78. Removal of the Boc-
protecting group in 78 under acidic conditions was followed
by a conversion of 79 to dipeptide 80 under usual amid
bond-forming conditions. The final step in this synthesis
consists of two-reaction sequence including deprotection of
the OBn group followed by the second peptide bond forma-
tion with 81 to give the target product 5A in about 17%
total yield. [60].
One may agree that the key compound in this synthetic
method is the preparation of proline derivative 78. In this
regard, one might be interested in exploring other approa-
ches for the preparation of β,γ-disubstituted prolines [61].
Augtyro
TM
(Repotrectinib)
Repotrectinib 6 (Figure 1) is a tyrosine kinase inhibitor
(TRKI). It possesses appreciable inhibitory activity and
N
OBn
O
HO
Boc
N
OBn
O
MsO
Boc
N
OBn
O
PhSe
Boc
DMAP, Et3N
MsCl, CH2Cl2
0-25 oC, 3.5 h
PhSeSePh, NaBH4
tBuOH, reflux
N
OBn
O
Boc
H2O2, pyridine
CH2Cl2, 25 oC, 1 h
ClCl
(2-t-BuPDI)CoBr2, ZnBr2 N
OBn
O
Boc
Me
Me 4 N HCl,
dioxane
HN
OH
CF3
O
O
t-Bu
NMM, DMAP, HATU
DMF, rt, 12 h
NH
O
NC
H2N
1) 10% Pd/C, H2, MeOH, rt, 12 h
2) NMM, HATU, DMAP, DMF, rt, 12 h
74
77
0 oC, 3 h
N
Me Me
O
NH
CF3
O
O
HN
CN
NH
O
5A
Zn, THF, 25 oC, 60 h N
H
OBn
O
Me
Me
HCl
N
Me Me
O
NH
CF3
O
O
OBn
75 76
78 79
80
81
Nirmatrelvir
Scheme 7. Synthesis of Nirmatrelvir 5A.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
12
HN
N
O
OH2N
O
O
O
Cs2CO3, DMF,
110 oC, 6 h
N
H
N
N
O
COOEt
80
POCl3
MeCN,
100 oC
N
N
N
Cl
COOEt
81
F
OH O
H
S
O
NH2 S
O
N
HO
F
MeMgBr
S
O
N
H
HO
F
Me
82 83
H2N
HO
F
Me
84
N
N
N
Cl
COOEt
81
DIPEA, BuOH, 120 oC N
N
N
HN
COOEt
Me
OH
F
85
HO
H
N
Boc
Me
86
N
N
N
HN
CO2Et
Me
O
F
Me
H
N
Boc
LiOH, THF, MeOH
N
N
N
HN
COOH
Me
O
F
Me
H
N
Boc
HCl, dioxane, CH2Cl2
N
N
N
HN
COOH
Me
O
F
Me
NH2
FDPP, DIPEA
87
88 89
H2O, 70 oC, 2 h
HN
HN
O
Me
O
N
N
N
Me
F
6
DMF, CH2Cl2
3HCl
Repotrectinib
Scheme 8. Synthesis of Repotrectinib 6.
high selectivity for proto-oncogene tyrosine-protein kinase
ROS1 (ROS1) and of the tropomyosin receptor tyrosine
kinases (TRKs) TRKA, TRKB, and TRKC. Drug 6, is
being prescribed under the brand name Augtyro, as an
orally available anti-cancer medication used for the
treatment of non-small cell lung cancer. Repotrectinib 6
was approved by the FDA in November 2023 [62].
Structurally, compound 6 is a macrocyclic lactam featuring
fused heteroaromatic and benzene rings connected via
amino and 1,2-hydroxyamino fragments bearing two
stereogenic carbon centers. Fluorination in molecule 6 is
represented by a single aromatic fluorine, located in p-
position to the ether oxygen atom. This pattern of
fluorination is frequently used in the drug design to prevent
oxidative metabolic degradation of aromatic moieties [7c].
As presented in Scheme 8, one of the important
intermediates in the synthesis of repotrectinib 6 is
chloropyrazolo[1,5-a]pyrimidine 81. The process starts with
the reaction of ethyl 5-amino-1H-pyrazole-4-carboxylate
with (E)-ethyl 3-ethoxyacrylate to produce ethyl 4,5-
dihydro-5-oxopyrazolo[1,5-a]pyrimidine-3-carboxylate 80.
Its transformation to 81 via chlorinative aromatization was
performed using POCl2 in MeOH [63]. The second
important intermediate in the preparation of repotrectinib 6
is 2-((R)-1-aminoethyl)-4-fluorophenol 84. Synthesis of
compound 84 involves the use of tert-butanesulfinamide as
a chiral auxiliary [64]. Sulfineimine 82, obtained from 5-
fluoro-2-hydroxybenzaldehyde and tert-butanesulfinamide,
reacted with MeMgBr to yield addition product 83 with
virtually complete diastereoselectivity (>95% de).
Purification and deprotection of compound 83 under usual
acidic conditions [65] afforded free amine 84 in optically
pure form. Thus prepared compounds 81 and 84 were
combined in the aromatic nucleophilic substitution of the
chlorine atom in 81 by the amino group in 84 under
relatively harsh reaction conditions at 129 ºC using DIPEA
[66] as a base [63]. The resulting product 85 was further
reacted with chiral amino alcohol 86 to form the
corresponding ester 87. Deprotection of the ester group in
87 and N-Boc group in 88, under the correspondingly basic
and acidic conditions, afforded compound 89, obtained as a
J. Han, A. Wzorek, et al.
13
triple hydrochloric salt. Lastly, the cyclization of salt 89 via
a peptide bond-forming reaction using pentafluorophenyl
diphenylphosphinate (FDPP) as a coupling agent gave rise
to the target repotrectinib 6 [67].
There is yet another literature approach to the
intermediate 84 via a catalytic enantioselective reductive
amination [68]. As presented in Scheme 9, product (R)-84
was obtained from 1-(5-fluoro-2-hydroxyphenyl)ethan-1-
one with the application of a Ru-chelated phosphine ligand
90 as a catalyst and NH4OAc a source of nitrogen and H2 as
a reducing reagent. The process was reproduced on a 20 g
scale with a respectable stereochemical outcome. Quite
unfortunately, the reported enantioselectivity was not
indisputably confirmed by the necessary in such cases SDE
study [69]. It is known that low-to-moderate chemical yield,
like 65% in this work, and high-to-excellent
enantioselectivity (94% ee) are usually indicative of an
erroneous recording of the stereochemical outcome due to
the SDE. Furthermore, it is well established that fluorine-
containing chiral amines [70], and α-phenylethylamines
[71] as a rule show rather exceptional magnitude of SDE
under the routine conditions of achiral column
chromatography usually used by practitioners for isolation
and/or purification of the reaction products.
F
OH O
Me H2N
HO
F
Me
84
PPh2
PPh2
O
O
O
O
(1 mol%)
H2, NH4OAc, MeOH
80 oC, 24 h
65% yield, 94% ee
90
Scheme 9. Catalytic enantioselective synthesis of amine 84.
Ogsiveo™ (Nirogacestat)
Nirogacestat 7 was developed by Pfizer in 2011 [72].
Biological action of this drug consists in γ-secretase
inhibition that blocks proteolytic activation of the Notch
receptor [73]. As presented in Figure 7, nirogacestat 7 has
two stereogenic carbons and should be administered in the
enantiomerically pure form of (S),(S)-configuration.
Furthermore, it features three key structural units,
difluorinated tetralin, tailor-made AA L-Norvaline, and
amino imidazole ring. Detailed SAR studies revealed that
the fluorination plays a pivotal role in the bioactivity. In
particular, starting with non-fluorinated analog 91 (CFA
IC50 = 85.7 nM), the introduction of just one fluorine atom
at the tetralin ring led to about five-fold potency
improvement in the cell-free assay (mono-fluoro analog 92,
CFA IC50 = 19.3 nM). Still, the addition of one more
fluorine atom on the tetralin unit, difluorinated compound
93, showed further improved bioactivity with a WCA IC50
value of 5.4 nM and CFA IC50 value of 4.1 nM [72].
Variation of other functional groups on candidate 93 led to
the replacement of the pyrolidine ring by 2,2-
dimethylpropan-1-amine fragment allowing to obtain even
better activity (WCA IC50 = 1.2 nM), prompting compound
7 for clinical development. Nirogacestat 7 received the
approval by the FDA in November under the trade name
OgsiveoTM for the treatment of desmoid tumors.
R2
HN
O
H
N
N
NR1
Me
Me
91-93 and 7
91
92
93
7
H
H
F
H
F
F
F
F
N
N
N
N
H
R1
R2 WCA IC50
53.9 nM
19.5 nM
5.4 nM
1.2 nM
Figure 8. Structures of Nirogacestat 7 and its analogs 91-93.
Pfizer also developed a synthetic method for the
preparation of nirogacestat 7. As presented in Scheme 10,
this approach is based on enantiomerically pure fluorinated
tetralin-containing amino acid 96 of the required S-confi-
guration and amino imidazole 101 as the two key
intermediates [72, 74]. Friedel-Crafts reaction of 2,4-di-
fluorophenyl acetyl chloride with ethylene in the presence
of AlCl3 in dichloromethane gave the 6,8-difluoro-3,4-
dihydronaphthalen-2(1H)-one 94. Reduction amination of
the ketone 94 with L-Norvaline t-butyl ester by using
Na(OAc)3BH as a reductive reagent generated product 95
with almost no stereocontrol of newly created stereogenic
carbon. Therefore, it was necessary to use column
chromatography to separate the corresponding dia-
stereomers. Diastereomerically and enantiomerically pure
(S),(S)-95 was treated with hydrochloric acid to remove the
t-butyl ester and afford compound 96. Second key
intermediate 101 was prepared starting with nitroimidazole
97. Reduction of the ester function in nitroimidazole 97 by
DIBAL at -30 ºC provided the aldehyde 98, which was
subjected to a condensation reaction with 2,2-dimethyl-
propan-1-amine in the presence of 4Å MS to yield imine
99. Compound 99 was reduced using Na(OAc)3BH giving
rise to nitroimidazole featuring the target secondary amino
group 100. Next, hydrogenation of the nitroimidazole 100
with 10% Pd/C as a catalyst in methanol at 20 ºC provided
the key compound 101. The last step in this synthesis is a
condensation reaction between amino acid 96 and
aminoimidazole 101 in the presence of O-(1,2-dihydro-2-
oxo-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
14
NO2
N
NMeO
Me
Me
O
NO2
N
N
Me
Me
O
H
NH2 NO2
N
NN
Me
Me
NO2
N
NHN
Me
Me NH2
N
NHN
Me
Me
HN
O
F
F
HO
CH2Cl2, -30 oC
DIBAL
CH2Cl2, 4Å MS
Na(OAc)3BH
CH2Cl2
10% Pd/C, H2
MeOH, 20 oC
TPTU, DIPEA, DMF
Cl
F
F
O
H
H H
H
AlCl3, CH2Cl2
F
F
O
NH2
O
O
HN
O
F
F
O
1) Na(OAc)3BH, CH2Cl2
HCl, H2O
HN
O
F
F
HO
94 95
96
97 98 99
100 101
96
2) chiral separation
HN
O
H
N F
F
N
NHN
Me
Me
Nirogacestat
7
Scheme 10. Synthesis of Nirogacestat 7.
(TPTU), DIPEA to deliver the desired molecule 7.
Jaypirca™ (Pirtobrutinib)
Pirtobrutinib 8 is an orally bioavailable, highly selective,
reversible inhibitor of Bruton's tyrosine kinase (BTK)
(Figure 8) [75] developed by Eli Lilly. BTK plays a central
role in the development, activation, and survival of B cells
[75]. B cells belong to the lymphocyte subtype of white
cells and are responsible for producing vitally important
antibodies. On the other hand, uncontrolled growth of B
cells can lead to cancer. Pirtobrutinib 8 inhibits BTK via a
different mechanism, as compared to the previously
approved BTK inhibitor ibrutinib 102 (Figure 8), involving
a reversible binding to the C481 residue in the kinase
domain of BTK [76]. Therefore, newly introduced drug 8 is
effective for the treatment of ibrutinib-resistant chronic
lymphocytic leukemia that develops due to C481 kinase
domain mutations [77]. Structurally, pirtobrutinib 8 is based
on the aminopyrazole carboxamide ring designed to replace
the 4-aminopyrazolopyrimidine core of ibrutinib 102. The
pyrazole ring acts as an ATP analogue competitively
N
NN
NH2
Me
CF3
H2N
O
O
O
F
Pirtobrutinibnn
Ibrutinib
O
N
N
N
N
N
O
H2N
Me
H
102
8
Figure 8. Structures of clinically approved BTK inhibitors
Ibrutinib 102 and Pirtobrutinib 8.
binding to the ATP binding site of the BTK and enabling
the appropriate conformation for effective inhibition. The
covalent binding region of ibrutinib 102 is changed to a
non-covalently bonded CF3-containing ethyl group.
Pirtobrutinib 8 was approved by the FDA in January 2023
J. Han, A. Wzorek, et al.
15
for the treatment of adult patients with relapsed or
refractory mantle cell lymphoma (MCL) [78].
Synthesis of pirtobrutinib 8 is presented in Scheme 11
[79]. Chlorination of 5-fluoro-2-methoxybenzoic acid using
thionyl chloride yielded acid chloride 103, followed by its
reaction with 4-(aminomethyl)benzoic acid to give amid
104. Chlorination of compound 104 with thionyl chloride
followed by condensation of resulting acid chloride 105
without isolation with malononitrile in the presence of TEA
in acetonitrile at -10 ºC gave rise to 2-(hydroxymethylene)-
malononitrile derivative 106. Subsequent O-methylation of
106 using trimethyl orthoformate led to 2-(methoxy-
methylene)malononitrile derivative 107 in 64% yield. Next,
cycloaddition reaction of 107 with (S)-(2,2,2-trifluoro-1-
methyl)ethylhydrazine hydrochloride 108 in the presence of
Et3N in EtOH afforded 5-aminopyrazole-4-carbonitrile 109
in 83% yield. Finally, hydrolysis of the nitrile group in 109,
by treatment with MsOH in H2O at 55 ºC, provided the
target drug molecule pirtobrutinib 8 in 84% yield.
An alternative synthesis of pirtobrutinib 8, presented in
Scheme 12, requires the preparation of two key
intermediates: aminopyrazole derivative 115 and potassium
trifluoroborate salt 112 [80]. The synthesis of salt 112 starts
with a reaction of amino boronic ester 110 with methanol
under mild conditions and acylation with acid chloride 103
to produce amido boronic ester 111. Removal of pinacol
boronic ester 111 with potassium bifluoride in MeOH/H2O
at ambient temperature gave trifluoroborate salt 112.
Synthesis of aminopyrazole 115 starts off with reaction
between 4-bromobenzoyl chloride and malononitrile in the
presence of N,N-diisopropylethylamine (DIPEA) followed
by O-methylation of 2-(hydroxymethylene)malononitrile
113 with dimethyl sulfonate to form the 2-
(methoxymethylene)malononitrile 114. Cyclization with
(S)-(2,2,2-trifluoro-1-methyl)ethylhydrazine 108 using Et3N
in EtOH at 80 °C gave aminopyrazole 115 in 91% yield.
Palladium-catalyzed cross-coupling of aryl bromide 115
with potassium trifluoroborate salt 112 proceeded smoothly
in the presence of Pd(OAc)2 as precatalyst, the air-stable
and bulky Xphos as a ligand, Cs2CO3 as a base in THF/H2O
at 85 °C. Prepared under these conditions compound 109
required purification by flash column chromatography on
silica gel. Like in the previous method, the final step in this
procedure is a controlled hydrolysis of the CN to CONH2
conducted in a solution of sulfuric acid and trifluoroacetic
acid at 55 °C. After purification by flash column
chromatography on silica gel pirtobrutinib 8 was obtained
with a 51% yield.
It should be noted that (S)-(2,2,2-trifluoro-1-
methyl)ethylhydrazine 108 used in both methods can be
prepared via asymmetric biomimetic reductive amination
from trifluoroacetone [81].
F
MeO
N
H
O
HO
106
CNNC
trimethyl
orthoformate
95 oC, 15 h
F
MeO
N
H
O
MeO
107, 64% yield
CNNC
F3C N
H
NH2
Me
HCl
TEA, EtOH, 25 oC, 18 h
109, 83%, 99.7% ee
CO2H
F
MeO
HO
O F
MeO
N
H
O
HO
O
F
MeO
N
H
O
Cl
O
SOCl2
MeCN
2 h, 25 oC
TEA, -10 oC, 15 h
104
105
NC CN
SOCl2
F
MeO
Cl
O
103
N
NN
NH2
Me
CF3
H2N
O
O
O
F
Pirtobrutinib
H
N
NN
CN
NH2
Me
CF3
O
OMe
F
MsOH, H2O
H2N
Me
H
108
85 oC, 6 h
8, 84% yield
Scheme 11. Synthesis of Pirtobrutinib 8.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 1
16
CsCO3, Pd(OAc)2, XPhos
O
B
O N(TMS)2 N
H
O
B
O
O
1) MeOH, 0 oC, 1 h
Cl
O
0 oC to rt, 2 h
KHF2
DIPEA
THF, toluene
NC CN
CN
HO
Br
NC
Me2SO4
115, 91% yield
N
N
H2N
CNF3C
Me
113
110
MeO
F
MeO
F
111 112
109, 87%
H2SO4,
CF3CO2H
Cl
O
CN
MeO
Br
NC
114
F3C N
H
NH2
Me
HCl
TEA, THF, 80 oC, 14 h
2)
N
H
O
KF3B
MeO
F
THF, H2O, 85 oC, 16 h
H
N
NN
CN
NH2
Me
CF3
O
OMe112
N
H
KF3B
MeO
F
55 oC, 5 h
H
N
NN
NH2
Me
CF3
H2N
O
O
OMe
F
Pirtobrutinib
103
MeOH, H2O, rt
108
Br
F
Br
8, 51% yield
O
Scheme 12. Alternative synthesis of Pirtobrutinib 8.
Conclusions
In this year, the FDA approved 55 new drugs, among
which there were 32 small-molecule drugs. Moreover,
twelve small molecules featured various types of
fluorinations. These include Iwilfin™ (Eflornithine) 1,
Xdemvy™ (Lotilaner) 2, Joenja™ (Leniolisib) 3, Veozah™
(Fezolinetant) 4, Paxlovid™ (Nirmatrelvir and Ritonavir) 5,
Augtyro™ (Repotrectinib) 6, Ogsiveo™ (Nirogacestat) 7,
and Jayprica™ (Pirtobrutinib) 8. These drugs represent such
therapeutic areas as cancer (1, 6, 7, 8), infectious diseases
(2), immunodeficiency (3), neuromuscular disorder (4), and
virology (5). Tailor-made AAs are represented by 2,5-di-
aminopentanoic acid (1), (S)-2-amino-3,3-dimethylbuta-
noic acid (5), β,γ-disubstituted proline (5), (S)-2-aminopen-
tanoic acid (7), (Z)-3-aminoacrylic acid (8), (S)-2-amino-3-
[(S)-2-oxopyrrolidin-3-yl]propanoic acid (5), derivatives of
linear aliphatic (2, 5, 6) and cyclic aliphatic derivatives (3,
4). Types of fluorination are represented by difluoromethyl
(1) quaternary trifluoromethyl (2), aliphatic trifluoromethyl
(2, 8), aromatic trifluoromethyl (3), aromatic monofluorina-
tion (4, 6, 8) and aromatic difluorination (7). Furthermore,
compounds 2 and 8 display two types of fluorine residues
on the same molecule. Additional important trend in the
series of these newly approved drugs is that all compounds
are chiral possessing up to seven, as in nirmatrelvir 5,
stereogenic carbons. Considering the FDA requirements for
the application of chiral drugs, continuous advances in
asymmetric synthesis and characterization of chiral
fluorine-containing compounds are of great importance. In
this regard, particular attention should be given to the
phenomenon of the self-disproportionation of enantiomers
(SDE), the non-linear behavior of enantiomerically enriched
compounds [82]. The SDE properties of chiral drugs,
especially those containing fluorine and/or AA residues, are
a critical public safety issue, requiring an additional level of
scrutiny in the evaluation of their enantiomeric purity [83].
Notes
Acknowledgments and finances. We gratefully
acknowledge the financial support from the National
Natural Science Foundation of China (No. 21761132021),
the Qing-Lan Project of Jiangsu Province (for Han), and
IKERBASQUE, Basque Foundation for Science (for
Soloshonok).
The authors declare no conflict of interest.
Author contributions. The manuscript was written
through contributions of all authors. All authors have given
approval to the final version of the manuscript.
J. Han, A. Wzorek, et al.
17
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(SDE) to Ensure Accurate Reporting of the Stereochemical Outcome
of Enantioselective Reactions. Molecules 2021, 26, 2757. (b) Han, J.;
Dembinski, R.; Soloshonok, V.A.; Klika, K.D. A Call for a Change
in Policy Regarding the Necessity for SDE Tests to Validate the
Veracity of the Outcome of Enantioselective Syntheses, the Inherent
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Нові ліки, які з’явилися на ринку в 2023 році: молекули, що містять флуор та
модифіковані амінокислотні фрагменти
Ц. Хань1, А. Взорек2, Г. Дхаван3*, В. Чжан4, О.Є. Сорочинський5, Т. Оно6, В.A. Солошонок7,8*
1 Нанкінський лісотехнічний університет, Нанкін, КНР
2 Інститут Хімії, Університет імені Яна Кохановського в Кельцях, Кельці, Польща
3 Коледж Ачаріа Нарендра Дев, Університет Делі, Нью-Делі, Індія
4 Массачусетській Університет, Бостон, Массачусетс, США
5 Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
6 Національний інститут передових промислових наук і технологій (AIST), Анагахора, Шімосідамі, Моріяма-ку, Нагоя, Японія
7 Університет Країни Басків, Сан-Себастьян, Іспанія
8 ІКЕРБАСК, Баскський фонд науки, Більбао, Іспанія
Присвята: Відзначаючи 80-річчя професора Івао Одзіми 5 червня 2025 року, ми висловлюємо вдячність за його відданість хімії, наставництво та
дружбу. Його стиль викладання, який поєднує досвід і ентузіазм, надихнув незліченну кількість студентів і колег. Його доброта, керівництво та
підтримка завжди сприяли зміцненню зв'язків між хіміками всього світу. Цей огляд присвячений вшануванню видатних наукових досягнень,
яким професор Одзіма присвятив своє життя.
Резюме: У статті описано 8 нових схвалених FDA препаратів, що містять флуор разом із фрагментами амінокислот або їх похідними. Ці
фармацевтичні препарати включають: ефлорнітин, лотіланер, леніолісіб, фезолінетант, нірматрелвір, репотректиніб, нірогацестат і піртобрутиніб,
які представляють такі терапевтичні сфери, як рак, нервово-м’язові розлади, імунодефіцити, вірусологія та інфекційні захворювання.
Підкреслено важливість флуорування, амінокислотних залишків, а також хіральності в дизайні нових фармацевтичних препаратів.
Ключові слова: фармацевтичні препарати; амінокислоти; флуоровмісні сполуки; дизайн і розробка ліків.
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0032-1316812
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0032-1316812
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0032-1316812
https://www.sciencedirect.com/science/article/pii/S004040201200395X
https://www.sciencedirect.com/science/article/pii/S004040201200395X
https://www.sciencedirect.com/science/article/pii/S004040201200395X
https://www.sciencedirect.com/science/article/pii/S0960894X10018822
https://www.sciencedirect.com/science/article/pii/S0960894X10018822
https://www.sciencedirect.com/science/article/pii/S0960894X10018822
https://www.sciencedirect.com/science/article/pii/S0006497123004044
https://www.sciencedirect.com/science/article/pii/S0006497123004044
https://www.sciencedirect.com/science/article/pii/S0006497123004044
https://aacrjournals.org/clincancerres/article/30/1/17/732065/FDA-Approval-Summary-Pirtobrutinib-for-Relapsed-or
https://aacrjournals.org/clincancerres/article/30/1/17/732065/FDA-Approval-Summary-Pirtobrutinib-for-Relapsed-or
https://aacrjournals.org/clincancerres/article/30/1/17/732065/FDA-Approval-Summary-Pirtobrutinib-for-Relapsed-or
https://www.sciencedirect.com/science/article/pii/S0040402003001388
https://www.sciencedirect.com/science/article/pii/S0040402003001388
https://www.sciencedirect.com/science/article/pii/S0040402003001388
https://www.sciencedirect.com/science/article/pii/S0040402003001388
https://www.sciencedirect.com/science/article/pii/S0957416610002880
https://www.sciencedirect.com/science/article/pii/S0957416610002880
https://www.sciencedirect.com/science/article/pii/S0957416610002880
|
| id | oai:ojs2.bioorganica.com.ua:article-79 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:23Z |
| publishDate | 2024 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/22/ed09b80bce9171d41552527538e8f722.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-792026-07-19T14:56:54Z New drugs appearing on the market in 2023: molecules containing fluorine and fragments of tailor-made amino acids Нові ліки, які з’явилися на ринку в 2023 році: молекули, що містять флуор та модифіковані амінокислотні фрагменти Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander E. Ono, Taizo Soloshonok, Vadim A. pharmaceuticals amino acids fluorine-containing compounds drug design and development фармацевтичні препарати амінокислоти флуоровмісні сполуки дизайн і розробка ліків Dedication: As we celebrate Professor Iwao Ojima's 80th birthday on June 5th, 2025, we express gratitude for his dedication to chemistry, mentoring, and friendship. His teaching style, blending expertise and enthusiasm, has inspired countless students and colleagues. His kindness, guidance, and encouragement have nurtured lasting bonds. We honor his remarkable achievements and the lives he's touched This article profiles eight new FDA-approved drugs containing fluorine along with the fragments of amino acids or their derivatives. These pharmaceuticals include Eflornithine, Lotilaner, Leniolisib, Fezolinetant, Nirmatrelvir, Repotrectinib, Nirogacestat, and Pirtobrutinib, representing such therapeutic areas as cancer, neuromuscular disorder, immunodeficiency, virology, and infectious diseases. Importance of fluorination, amino acid residues as well as chirality in the design of new pharmaceuticals is highlighted Присвята: Відзначаючи 80-річчя професора Івао Одзіми 5 червня 2025 року, ми висловлюємо вдячність за його відданість хімії, наставництво та дружбу. Його стиль викладання, який поєднує досвід і ентузіазм, надихнув незліченну кількість студентів і колег. Його доброта, керівництво та підтримка завжди сприяли зміцненню зв'язків між хіміками всього світу. Цей огляд присвячений вшануванню видатних наукових досягнень, яким професор Одзіма присвятив своє життя У статті описано 8 нових схвалених FDA препаратів, що містять флуор разом із фрагментами амінокислот або їх похідними. Ці фармацевтичні препарати включають: ефлорнітин, лотіланер, леніолісіб, фезолінетант, нірматрелвір, репотректиніб, нірогацестат і піртобрутиніб, які представляють такі терапевтичні сфери, як рак, нервово-м’язові розлади, імунодефіцити, вірусологія та інфекційні захворювання. Підкреслено важливість флуорування, амінокислотних залишків, а також хіральності в дизайні нових фармацевтичних препаратів V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2024-06-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/79 10.15407/bioorganica2024.01.003 Ukrainica Bioorganica Acta; Vol. 19 No. 1 (2024): Ukrainica Bioorganica Acta; 3-20 Ukrainica Bioorganica Acta; Том 19 № 1 (2024): Ukrainica Bioorganica Acta; 3-20 1814-9766 1814-9758 10.15407/bioorganica2024.01 en https://bioorganica.com.ua/index.php/journal/article/view/79/78 Copyright (c) 2024 Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Taizo Ono, Vadim A. Soloshonok https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | фармацевтичні препарати амінокислоти флуоровмісні сполуки дизайн і розробка ліків Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander E. Ono, Taizo Soloshonok, Vadim A. Нові ліки, які з’явилися на ринку в 2023 році: молекули, що містять флуор та модифіковані амінокислотні фрагменти |
| title | Нові ліки, які з’явилися на ринку в 2023 році: молекули, що містять флуор та модифіковані амінокислотні фрагменти |
| title_alt | New drugs appearing on the market in 2023: molecules containing fluorine and fragments of tailor-made amino acids |
| title_full | Нові ліки, які з’явилися на ринку в 2023 році: молекули, що містять флуор та модифіковані амінокислотні фрагменти |
| title_fullStr | Нові ліки, які з’явилися на ринку в 2023 році: молекули, що містять флуор та модифіковані амінокислотні фрагменти |
| title_full_unstemmed | Нові ліки, які з’явилися на ринку в 2023 році: молекули, що містять флуор та модифіковані амінокислотні фрагменти |
| title_short | Нові ліки, які з’явилися на ринку в 2023 році: молекули, що містять флуор та модифіковані амінокислотні фрагменти |
| title_sort | нові ліки, які з’явилися на ринку в 2023 році: молекули, що містять флуор та модифіковані амінокислотні фрагменти |
| topic | фармацевтичні препарати амінокислоти флуоровмісні сполуки дизайн і розробка ліків |
| topic_facet | pharmaceuticals amino acids fluorine-containing compounds drug design and development фармацевтичні препарати амінокислоти флуоровмісні сполуки дизайн і розробка ліків |
| url | https://bioorganica.com.ua/index.php/journal/article/view/79 |
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