MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS(Review)
This review profiles ten marketed pharmaceuticals approved by the US Food and Drug Agency within the last five years that feature aliphatic fluorination – a key structural feature pivotal to their biological activity. These include ivosidenib, developed for the treatment of acute myeloid leukemia an...
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| Дата: | 2025 |
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| Автори: | , , , , |
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| Мова: | Англійська |
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V.I.Vernadsky Institute of General and Inorganic Chemistry
2025
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Ukrainian Chemistry Journal| _version_ | 1871466139670806528 |
|---|---|
| author | Han, Jianlin Wzorek, Alicja Ono, Taizo Klika, Karel Soloshonok, Vadim |
| author_facet | Han, Jianlin Wzorek, Alicja Ono, Taizo Klika, Karel Soloshonok, Vadim |
| 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 210037, China"
},
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25-406 Kielce, Poland"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology, 463-8560, Nagoya, Japan"
},
{
"author": "Karel Klika",
"institution": "Molecular Structure Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 280, 69120 Heidelberg, Germany"
},
{
"author": "Vadim Soloshonok",
"institution": "University of Basque Country"
}
] |
| author_sort | Han, Jianlin |
| baseUrl_str | https://ucj.org.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-22T08:23:56Z |
| description | This review profiles ten marketed pharmaceuticals approved by the US Food and Drug Agency within the last five years that feature aliphatic fluorination – a key structural feature pivotal to their biological activity. These include ivosidenib, developed for the treatment of acute myeloid leukemia and cholangiocarcinoma (bile duct cancer); ubrogepant, approved for the acute treatment of migraines; asciminib, prescribed for the treatment of chronic myeloid leukemia in the chronic phase; omaveloxolone, used in the treatment of Friedreich’s ataxia, a rare genetic disorder causing progressive damage to the spinal cord, peripheral nerves, and brain; flurpiridaz (18F), a radioactive diagnostic agent for myocardial perfusion imaging by positron emission tomography; upadacitinib, designed to address several inflammatory and autoimmune conditions, including rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spondyloarthritis; tezacaftor, approved for the treatment of cystic fibrosis as an effective remedy; alpelisib, prescribed for the treatment of breast cancer, effectively inhibiting tumor growth and abnormal cell proliferation; pretomanid, used in combination therapies for the treatment of extensively drug-resistant and multi-drug-resistant tuberculosis; and atogepant, approved for the preventive treatment of migraines in adults, targeting both episodic and chronic  migraines. Molecules featuring aliphatic fluorination present challenges due to higher production costs and the complexity of predicting their biological profiles. However, the undeniable medicinal benefits of aliphatic fluorination invigorate this area of research, paving the way for the development of more innovative drugs to enter the pharmaceutical market. Beyond the incorporation of aliphatic fluorine atoms, six of the pharmaceuticals discussed in this review feature residues of amino acids or their derivatives as pivotal structural design elements. Another characteristic shared by all these drugs is their chirality, with each molecule possessing between one and six stereogenic carbons. Special attention should be directed toward the phenomenon of self-disproportionation of enantiomers (SDE), a behavior observed in enantiomerically enriched compounds. The SDE properties of chiral drugs, particularly those containing fluorine and/or amino acid residues, represent a vital public safety concern, necessitating rigorous evaluation of enantiomeric purity. Additionally, caution should be exercised in light of growing public concerns over the potential harmful effects of fluorine on human health. Since fluoride is recognized as the final metabolite of organic fluorinated compounds, patients prescribed fluorine-containing drugs should consult their physicians about non-fluorinated alternatives where available or take steps to limit fluoride exposure from other sources, such as fluoridated water and industrially produced foods treated with fluorinated agrochemicals. Despite these concerns, it remains an undeniable fact that fluorine-containing drugs are indispensable in modern medicine. They provide life-saving treatments, improve quality of life, and drive medical innovation addressing urgent health challenges and laying the foundation for future advancements in healthcare. |
| doi_str_mv | 10.33609/2708-129X.91.6.2025.15-54 |
| first_indexed | 2025-10-23T01:32:48Z |
| format | Article |
| fulltext |
15
UDC 546.26-162: 541.13:549.21 doi: 10.33609/2708-129X.91.6.2025.15-54
MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC
FLUORINE-CONTAINING GROUPS.
Jianlin Han1, Alicja Wzorek2, Taizo Ono3, Karel D. Klika4, Vadim A. Soloshonok5,6*
1 Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources,
College of Chemical Engineering, Nanjing Forestry University,
Nanjing 210037, China;
2 Institute of Chemistry, Jan Kochanowski University in Kielce,
Uniwersytecka 7, 25-406 Kielce, Poland;
3 National Institute of Advanced Industrial Science and Technology (AIST),
2266-98, Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463-8560, Japan;
4 Research & Development Center, Archer Daniels Midland,
1001 N Brush College Rd., Decatur, IL 62521, USA;
5 Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country
UPV/EHU,
Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain;
6 IKERBASQUE, Basque Foundation for Science,
María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain.
e-mail: vadimsoloshonok@gmail.com
This review profiles ten marketed pharmaceuticals approved by the US Food and Drug
Agency within the last five years that feature aliphatic fluorination – a key structural feature
pivotal to their biological activity. These include ivosidenib, developed for the treatment of
acute myeloid leukemia and cholangiocarcinoma (bile duct cancer); ubrogepant, approved for
the acute treatment of migraines; asciminib, prescribed for the treatment of chronic myeloid
leukemia in the chronic phase; omaveloxolone, used in the treatment of Friedreich’s ataxia, a
rare genetic disorder causing progressive damage to the spinal cord, peripheral nerves, and
brain; flurpiridaz (18F), a radioactive diagnostic agent for myocardial perfusion imaging by
positron emission tomography; upadacitinib, designed to address several inflammatory and
autoimmune conditions, including rheumatoid arthritis, psoriatic arthritis, atopic dermatitis,
ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spon-
dyloarthritis; tezacaftor, approved for the treatment of cystic fibrosis as an effective remedy;
alpelisib, prescribed for the treatment of breast cancer, effectively inhibiting tumor growth
and abnormal cell proliferation; pretomanid, used in combination therapies for the treatment
of extensively drug-resistant and multi-drug-resistant tuberculosis; and atogepant, approved
for the preventive treatment of migraines in adults, targeting both episodic and chronic
16 ISSN 2708-129X. Укр. хім. журн., 2025
MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
migraines. Molecules featuring aliphatic fluorination present challenges due to higher pro-
duction costs and the complexity of predicting their biological profiles. However, the un-
deniable medicinal benefits of aliphatic fluorination invigorate this area of research, paving
the way for the development of more innovative drugs to enter the pharmaceutical market.
Beyond the incorporation of aliphatic fluorine atoms, six of the pharmaceuticals discussed in
this review feature residues of amino acids or their derivatives as pivotal structural design ele
ments. Another characteristic shared by all these drugs is their chirality, with each molecule
possessing between one and six stereogenic carbons. Special attention should be directed to-
ward the phenomenon of self-disproportionation of enantiomers (SDE), a behavior observed
in enantiomerically enriched compounds. The SDE properties of chiral drugs, particularly
those containing fluorine and/or amino acid residues, represent a vital public safety concern,
necessitating rigorous evaluation of enantiomeric purity. Additionally, caution should be
exercised in light of growing public concerns over the potential harmful effects of fluorine on
human health. Since fluoride is recognized as the final metabolite of organic fluorinated com-
pounds, patients prescribed fluorine-containing drugs should consult their physicians about
non-fluorinated alternatives where available or take steps to limit fluoride exposure from
other sources, such as fluoridated water and industrially produced foods treated with fluori-
nated agrochemicals. Despite these concerns, it remains an undeniable fact that fluorine-con-
taining drugs are indispensable in modern medicine. They provide life-saving treatments,
improve quality of life, and drive medical innovation addressing urgent health challenges and
laying the foundation for future advancements in healthcare.
Key words: Fluorine, Aliphatic Fluorination, Pharmaceutical Drugs, Drug Design, Syn-
thesis, Chirality, Bioactivity, Self-Disproportionation of Enantiomers (SDE), Public Health
Concerns, Human and Environmental Overload with Fluorine.
INTRODUCTION. Pharmaceutical drugs
are indispensable components of modern civ-
ilization, significantly shaping public health
and quality of life. Their impact is multifaceted,
beginning with their fundamental role in treat-
ing and managing a vast spectrum of diseases,
both acute and chronic [1, 2]. Antibiotics, for
instance, have revolutionized the management
of bacterial infections, saving countless lives,
while medications for chronic conditions like
diabetes, hypertension, and cardiovascular di
seases enable individuals to maintain producti
vity and longevity [3]. Similarly, advancements
in cancer therapies, including chemotherapy
and targeted treatments, have drastically im-
proved survival rates [4]. The widespread
availability of pharmaceuticals has also con-
tributed to a substantial increase in life expec-
tancy with vaccines eradicating or significantly
reducing the incidence of formerly devastating
infectious diseases. Beyond disease manage-
ment, pharmaceuticals enhance quality of life
by alleviating pain, controlling symptoms, and
improving overall well-being. Medications for
mental health disorders, such as depression
and anxiety, allow individuals to function ef-
17https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 6 / Vol. 91
fectively within society, and pain management
drugs enable participation in daily activities
[5]. Furthermore, pharmaceuticals are essen-
tial for modern medical procedures, including
surgery, organ transplantation, and intensive
care where anesthesia, immunosuppressants,
and other drugs are critical. They are also vital
for public health initiatives, such as vaccina-
tion campaigns and disease control programs,
playing a crucial role in preventing the spread
of infectious diseases [6]. The pharmaceutical
industry’s continuous investment in research
and development drives the discovery of new
drugs and therapies ensuring ongoing progress
in addressing emerging health challenges.
Fluorine plays a pivotal role in the design
of modern pharmaceuticals, revolutionizing
drug development and enhancing therapeu-
tic efficacy. Its unique properties make it an
invaluable element in medicinal chemistry
[7–11]. Fluorine atoms can block metabolic
oxidation sites, preventing drugs from being
broken down too quickly in the body, which
increases the drug’s half-life and ensures sus-
tained therapeutic effects [7, 10, 11]. Its high
electronegativity can modulate the electronic
properties of a molecule, improving its inte
raction with biological targets like enzymes or
receptors, leading to greater potency and se-
lectivity. Incorporating fluorine can improve a
drug’s solubility, membrane permeability, and
bioavailability ensuring it reaches its intended
site of action more effectively. By fine-tuning a
molecule’s properties, fluorine can help mini
mize off-target interactions and reduce the
likelihood of adverse effects [7–11]. Fluorine
isotopes, such as fluorine-18, are widely used
in positron emission tomography (PET) imag-
ing aiding in early disease detection and moni
toring [12–17]. Fluorine’s versatility has made
it a cornerstone in the development of life-
saving drugs, from cholesterol-lowering agents
to cancer therapies, and its continued explora-
tion in pharmaceutical research promises even
greater advancements in medicine [18, 19].
The pharmaceutical industry favors aro-
matic fluorination over aliphatic fluorination
due to several key factors that impact drug de-
sign and development. Aromatic fluorinated
compounds often exhibit enhanced metabolic
stability, increased lipophilicity, and improved
binding affinity to target proteins, all critical
properties for drug candidates. The aromatic
ring provides a rigid scaffold that allows for
predictable structure–activity relationships,
facilitating the optimization of drug properties
[20–22]. In contrast, aliphatic fluorination can
introduce significant conformational flexibili-
ty, making it challenging to predict and con-
trol drug–target interactions. Furthermore,
the direct introduction of fluorine into alipha
tic chains can lead to unpredictable metabolic
pathways and potential toxicity issues [23, 24].
The relative ease of synthesizing diverse aro-
matic fluorinated compounds, coupled with
the well-established understanding of their
impact on drug properties, makes them more
attractive for pharmaceutical applications. Ad-
ditionally, the ability to fine-tune the electronic
and steric properties of aromatic rings through
strategic fluorination allows for the optimiza-
tion of drug–receptor interactions. Finally, the
relative stability of aromatic fluorinated com-
pounds compared to their aliphatic counter-
parts contributes to their suitability for phar-
maceutical development where long shelf life
and consistent performance are essential.
According to comprehensive surveys span-
ning the last 25 years [7, 25–32], over 450 fluo-
rine-containing pharmaceuticals have received
18 ISSN 2708-129X. Укр. хім. журн., 2025
MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
US Food and Drug Agency (FDA) approval.
This comprehensive data analysis demon-
strates that the structural and functional cha
racteristics of fluorinated drugs align closely
with those of non-fluorinated pharmaceuti-
cals. Heterocyclic compounds, integral to me-
dicinal chemistry, are present in over 85% of
approved drugs. Their diverse biological activi-
ties and structural versatility make them indis-
pensable as backbones in drug design [33–40].
Similarly, amino acid-derived compounds play
a crucial role in drug development. Data reveal
that over 30% of small-molecule drugs incor-
porate amino acid residues or their derivatives
such as amino-alcohols and diamines. Amino
acid residues enhance structural diversity and,
by introducing chirality, facilitate three-di-
mensional designs that optimize biological ac-
tivity [41–54]. Chirality is a critical aspect of
drug design with more than 70% of pharma-
ceutical drugs on the market being chiral [55–
60]. One metric unique to fluorinated drugs
is the relative proportion of aromatic versus
aliphatic fluorination. Surveys indicate a ratio
of approximately one aliphatic to five aroma
tic substitutions in such drugs. As previously
mentioned, the incorporation of aliphatic fluo-
rine poses significant synthetic challenges and
introduces complexities related to reactivity,
chirality, electrostatic effects, steric hindrance,
and the chemical properties of the resultant
structural modifications [61–65]. Neverthe-
less, the biological advantages conferred by
aliphatic fluorination frequently outstrip these
obstacles, solidifying its importance as a strate-
gic and valuable method in drug development.
In this review, we profile ten recently ap-
proved pharmaceutical drugs featuring ali-
phatic fluorination. These include ivosidenib 1
(Fig. 1), marketed under the brand name
Tibsovo, which is primarily used for the treat-
ment of acute myeloid leukemia (AML) and
cholangiocarcinoma (bile duct cancer). It is
specifically effective for patients with a sus-
ceptible mutation in the IDH1 gene which is
involved in cancer cell growth. Ubrogepant 2,
marketed under the brand name UbrelvyTM,
is used for the acute treatment of migraines
in adults, with or without aura. It belongs to
the class of calcitonin gene-related peptide
(CGRP) receptor antagonists which work by
blocking CGRP, a protein involved in migraine
pain. Asciminib 3, marketed under the brand
name Scemblix®, is used for the treatment of
chronic myeloid leukemia (CML) in the chro
nic phase. It is particularly effective for patients
who have resistance or intolerance to at least
two prior tyrosine kinase inhibitors or those
with the T315I mutation. Asciminib 3 is a first-
in-class allosteric inhibitor that specifically
targets the myristoyl pocket of the BCR-ABL1
protein offering a novel mechanism of action
in CML therapy. Omaveloxolone 4, marketed
under the brand name SkyclarysTM, is used for
the treatment of Friedreich’s ataxia. This rare
genetic disorder causes progressive damage to
the spinal cord, peripheral nerves, and brain,
leading to uncoordinated muscle movement,
difficulty walking, and other complications.
Omaveloxolone 4 works by activating the Nrf2
pathway, which helps mitigate oxidative stress
and improve mitochondrial function thereby
addressing key aspects of the disease. Flurpiri-
daz (18F) 5, marketed under the brand name
Flyrcado®, is a radioactive diagnostic agent used
for PET myocardial perfusion imaging. It is
indicated for adults with known or suspected
coronary artery disease to evaluate myocardial
ischemia and infarction. This imaging process
helps assess blood flow through the heart mus-
19https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 6 / Vol. 91
cle under rest or stress conditions (pharmaco-
logic or exercise). Upadacitinib 6, marketed
under the brand name RinvoqTM, is used to
treat several inflammatory and autoimmune
conditions, including rheumatoid arthritis,
psoriatic arthritis, atopic dermatitis, ulcerative
colitis, Crohn’s disease, ankylosing spondylitis,
and non-radiographic axial spondyloarthritis.
Tezacaftor 7 is used in the treatment of cys
tic fibrosis CF. It is often combined with other
drugs, such as ivacaftor (brand name Symde-
koTM) or elexacaftor and ivacaftor (brand name
Trikafta), to improve the function of the cystic
fibrosis transmembrane conductance regulator
(CFTR) protein in patients with specific gene
mutations such as the F508del mutation. Teza-
caftor 7 acts as a corrector helping the CFTR
protein fold properly and reach the cell sur-
face thereby enhancing its activity. Alpelisib 8,
marketed under the brand names PiqrayTM
and Vijoice, is used in the treatment of breast
cancer and PIK3CA-Related Overgrowth
Spectrum (PROS). Alpelisib 8 is a PI3K-alpha
inhibitor targeting the PIK3CA mutation to
inhibit tumor growth or abnormal cell proli
feration. Pretomanid 9 is used in combination
with other medications, such as bedaquiline
and linezolid, for the treatment of extensively
Fig. 1. The structures of marketed pharmaceutical drugs highlighted in this review
with aliphatic fluorination as a key structural feature.
20 ISSN 2708-129X. Укр. хім. журн., 2025
MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
drug-resistant tuberculosis (XDR-TB) or multi-
drug-resistant tuberculosis (MDR-TB) of the
lungs. It is specifically indicated for patients
who cannot tolerate or do not respond to other
TB treatments. Pretomanid 9 works by inhi
biting the growth of the tuberculosis bacteria.
Atogepant 10, marketed under the brand name
QuliptaTM, is used for the preventive treatment
of migraines in adults, including both episodic
and chronic migraines. It belongs to the class
of CGRP receptor antagonists, which work by
blocking CGRP, a protein involved in migraine
pain and inflammation. For each drug, we dis-
cuss its discovery, mode of biological activity,
and detailed synthesis. Whenever possible, we
examine the impact of fluorination on the bio-
logical profile of the drug.
Ivosidenib (Tibsovo) 1.
Ivosidenib was approved as an inhibitor of
mutated cytosolic isocitrate dehydrogenase
(IDH1) for the treatment of patients with re-
lapsed or refractory AML. Following FDA ap-
proval, ivosidenib received orphan drug status
for glioma in the United States. The drug was
developed and licensed by Agios Pharmaceu-
ticals in collaboration with Celgene Corpora-
tion and CStone Pharmaceuticals. Ivosidenib
1 has also shown promising potential for the
treatment cholangiocarcinoma with an IDH1
mutation [66].
Fluorine plays a fundamental role in the
bioactivity of ivosidenib as substitution of
fluorine at the 5-position of the pyridine ring
imparts nanomolar potency in enzyme and
cell-based assays while also enhancing meta
bolic stability. The introduction of a difluoro
cyclobutyl moiety contributes to metabolic
stability, albeit causing a slight reduction in
potency [67].
A multihundred gram-scale synthesis [67,
68] of 1 starts with the preparation of isocy-
anide 13 from commercially available 3,3-di-
fluorocyclobutan-1-amine hydrochloride (11)
(Scheme 1). This two-step process starts with
the reaction of 11, trimethylamine, and an ex-
cess of ethyl formate at 85 °C. After extraction
with ethyl acetate and trituration with hexane,
N-(3,3-difluorocyclobutyl)formamide (12) is
isolated in 86% yield. In the second step, for-
mamide 12 is treated with triphenylphosphine
and triethylamine under nitrogen at 45 °C.
Subsequent purification by chromatography
over silica gel provides isocyanide 13 in 76%
yield. Alternatively, a synthesis developed by
Agios Pharmaceuticals uses the same strategy
but derives amine 11 from 3-oxocyclobutane
carboxylic acid. Here, the amino group re-
places the carboxylic acid through a Curtius
rearrangement of the corresponding acyl azide
while fluorine is introduced via the reaction of
the keto group with diethylaminosulfur trifluo
ride. Two protocols were employed differing in
the sequence of functionalization [69].
A four-component Ugi coupling reaction
[70] involving isocyanide 13, benzaldehyde 14,
5-fluoropyridin-amine 15, and (S)-pyroglu-
tamic acid 16 yielded a diastereomeric mixture
of the phenyl glycine intermediate 17 in 46%
yield after purification by chromatography
over silica gel. The final step involved a Buch-
wald–Hartwig Pd-mediated coupling reaction
[71, 72] of compound 17 with 2-bromoisonico
tinonitrile resulting in a diastereomeric mix-
ture of compound 1. Chiral resolution through
crystallization provided ivosidenib 1 in 22%
isolated yield. While chromatographic purifi-
cation facilitates isolated yield, it significantly
increases the overall cost. In this regard it is
worth highlighting the recently developed in-
21https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 6 / Vol. 91
tegrated simulated moving bed and self-dis-
proportionation of enantiomers (SDE) tech-
niques as a potentially highly efficient method
for enantiomer purification [73, 74].
Scheme 1. Synthesis of ivosidenib 1.
Ubrogepant (UbrelvyTM) 2.
Ubrogepant 2 (Fig. 2), developed by Aller-
gan and licensed from Merck, has received FDA
approval for the acute treatment of migraines.
Employing a similar structural design of cyclic
α,δ-diamino acid and a chiral spirotetracyclic
moiety, Merck successfully synthesized seve
ral non-fluorinated compounds, e.g. 18, 19, as
piperidinone carboxamide azaindane CGRP
receptor antagonists [75]. The treatment of mi-
graines and CGRP receptor antagonists target
the CGRP pathway which plays a crucial role
in migraine pathophysiology. CGRP is a neu-
ropeptide involved in vasodilation and pain
transmission and its overactivity is associated
with migraine attacks. CGRP receptor antago-
nists, such as piperidinone carboxamide azain-
dane derivatives, work by blocking the CGRP
receptor thereby preventing the peptide’s ef-
fects and alleviating migraine symptoms. This
mechanism aligns with the bioactivity of other
migraine treatments that target the CGRP
pathway, including monoclonal antibodies and
small-molecule antagonists like ubrogepant 2
and atogepant 10 [76–78].
Fig. 2. The structures of ubrogepant 2 and its non-fluorinated analogs 18 and 19.
22 ISSN 2708-129X. Укр. хім. журн., 2025
MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
The structure and preparation of ubroge-
pant 2 and its related molecules were initially
detailed in a patent filed by Merck [79]. The
synthesis involved separately preparing the two
key components of ubrogepant–a spirocyc
lic carboxylic acid and an aminopiperidinone
molecule–before utilizing a coupling agent to
form the amide bond between them. Subse-
quent Merck patents [80, 81] introduced slight
modifications to the original synthesis.
A comprehensive description of these syn-
thetic advancements, including yields, was
later published in an academic article [82]. In
the improved synthesis, the N-protected race-
mic serine ester 20 (Scheme 2) underwent de-
hydration to yield compound 21 which was
then subjected to a Michael addition to pro-
duce keto amino ester 22. Compound 22 was
cyclized into product 23, comprising a mix-
ture of C-3 epimers, through dynamic kinetic
transamination with an enzyme tailored spe-
cifically for this reaction. Under basic condi-
tions, the C-3 stereogenic center inverts favor-
ing the desired configuration. N-alkylation of
the diastereomeric mixture 23 was then per-
formed requiring the highly reactive reagent
CF3CH2OTf. Careful optimization was crucial
to minimize alkylation on both nitrogen atoms.
The crude products 24 and 25 were subjected
to selective Boc deprotection whereby unre-
acted compound 23 was initially deprotected
and removed followed by the deprotection
and separation of 24 from the double alkyla
ted byproduct 25. The mixture of diastereome
ric amines 26 was treated with p-toluic acid
to form a crystalline salt and a 3,5-dichloro-
salicylaldehyde catalyst for C-3 epimerization
via reversible imine formation inducing a dia
stereoselective transformation.
Scheme 2. Preparation of fluorinated aminopiperidinone 27.
The preparation of spirocyclic carboxylic
acid 35 began with 2,3-dibromo-5-chloropyri-
dine 28 (Scheme 3). Selective halogen–lithium
exchange was followed by the introduction of
a formyl group at the C-3 position and its im-
mediate reduction using NaBH4. The resulting
23https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 6 / Vol. 91
compound 29 was O-protected with 3,4-di-
hydro-2H-pyran (DHP). A second selective
halogen–lithium exchange facilitated the ad-
dition of a formyl group at the C-2 position.
Condensation of aldehyde 30 with N-(tert-bu-
tyl)-azaindolone yielded alkene 31 with a Z
configuration for the double bond. Subse-
quent reduction of the newly formed C=C
double bond and O-deprotection produced
racemic alcohol 32. The hydroxyl group was
replaced with chlorine by reaction with SOCl2
yielding 33. Enantioselective spirocyclization
of compound 33 was achieved using a cin-
chona-derived chiral phase-transfer catalyst
forming product 34. The final steps included
carbonylation and removal of the N-tert-bu-
tyl group to yield spirocyclic carboxylic acid
35. This compound was then coupled with
aminopiperidinone salt 27 in the presence of
1-ethyl-3-(3-dimethylaminopropyl)carbodii
mide (EDC) ultimately leading to the formation
of ubrogepant 2.
Scheme 3. Synthesis of ubrogepant 2.
Asciminib (Scemblix®) 3.
Asciminib 3 is a potent, small-molecule,
orally bioavailable, and selective allosteric in-
hibitor developed by Novartis for the treat-
ment of hematologic malignancies, including
Philadelphia chromosome-positive (Ph+)
CML [83, 84]. It received FDA approval for
two distinct indications in CML [83]. In vit-
ro anticancer activity tests against leukemia
cell lines MV411 (ATCC) and K562 (ATCC)
demonstrated that asciminib 3 exhibits signifi-
cant inhibitory activity with cellular IC50 values
24 ISSN 2708-129X. Укр. хім. журн., 2025
MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
of 8.65 μmol/L and 0.32 μmol/L for K562 and
MV411, respectively. In contrast, its structu
rally similar analog 36 (Fig. 3) displayed only
moderate activity against these cell lines (K562,
IC50 > 30 μmol/L and MV411, IC50 > 30 μmol/L).
These findings highlight the importance of the
chlorodifluoro group in asciminib 3 which
plays a crucial role in inducing inactive tar-
get conformations. Additionally, the pyrazole
ring in asciminib 3’s structure helps mitigate
human ether-a-go-go-related gene (hERG)
toxicity [84, 85]. As an allosteric inhibitor, as-
ciminib 3 targets ABL1 by binding to its myris-
toyl pocket, thereby inhibiting BCR-ABL1 ac-
tivity. This mechanism distinguishes it from
competitive inhibitors like imatinib, dasatinib,
and nilotinib which act at the ATP binding site
[86–89]. Due to its unique allosteric regulato-
ry mechanism, asciminib 3 not only inhibits
wild-type ABL1 kinase but also demonstrates
potent activity against the T315I-mutated
ABL1 significantly minimizing the off-target
effects associated with ATP-binding site inhi
bitors. The FDA granted accelerated approval
to asciminib 3 for the treatment of newly di-
agnosed adult patients with Philadelphia chro-
mosome-positive CML in the chronic phase
(Ph+ CML-CP) [83].
Fig. 3. The structures and bioactivity data for asciminib 3 and its fluorine-free analog 36.
Several research groups [84, 90, 91] have de-
tailed the synthesis of asciminib 3. One stream-
lined approach (Scheme 4) utilizes 5-bro-
mo-6-chloronicotinic acid (37) as the starting
material [84] which is reacted with SOCl2 in
the presence of dimethyl formamide (DMF) to
yield the acyl chloride intermediate. The acid
chloride is then treated with 4-(chlorodifluo-
romethoxy)aniline and diisopropylethylamine
(DIPEA) as the base in tetrahydrofuran (THF)
at room temperature producing amide 38 in
77% yield. Next, amide 38 undergoes substi-
tution by (R)-pyrrolidin-3-ol (39) under basic
conditions [92] at elevated temperatures form-
ing intermediate 40. A Suzuki–Miyaura coup
ling reaction in which compound 40 reacts
with (1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-
zol-5-yl)boronic acid pinacol ester (41) creates
intermediate 42. The final step involves trea
ting intermediate 42 with trifluoroacetic acid
(TFA) in dichloromethane (DCM) providing
asciminib 3 in an impressive 77% yield. This
method showcases efficient synthetic strategies
with significant yields highlighting the preci-
sion required for the development of such a
complex molecule.
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Scheme 4. Synthesis of asciminib 3.
Omaveloxolone (Skyclarys™) 4.
Omaveloxolone 4, an orally active small
molecule developed by Reata Pharmaceu-
ticals Inc., stands out as a powerful activator
of the transcription factor Nrf2 (Fig. 4) [93].
Nrf2 serves as the primary regulator of phase
II cellular antioxidant responses playing a cri
tical role in neuroprotection and detoxification
[94]. Under normal conditions, Nrf2 remains
bound to the protein KEAP1 in the cytosol
where it is ubiquitinated and degraded [95].
However, during oxidative stress, ubiquitina-
tion is inhibited allowing Nrf2 to translocate
to the nucleus and activate genes that contain
antioxidant response elements (ARE).
Omaveloxolone 4, along with related triter
penoids bardoxolone methyl 44 and 2-cyano-
3,12-dioxoolean-1,9-dien-28-oic acid (CDDO)
43, features a cyanoenone moiety that enables
covalent and reversible binding to KEAP1.
This binding blocks ubiquitination and protea-
somal degradation of Nrf2 thereby stimulating
the intracellular antioxidative pathway [95,
96]. Among these triterpenoids, omaveloxo
lone 4, modified with a 1,1-difluoroethylamide
moiety, has been identified as one of the most
potent activators of ARE activity exhibiting
over a 16-fold increase at 62.5 nM in an Nrf2-
GST-ARE luciferase reporter assay [97].
Omaveloxolone 4 has also earned FDA ap-
proval as the first therapeutic for Friedreich’s
ataxia, a rare inherited degenerative disorder
that impacts the nervous system. This con-
dition manifests through symptoms such as
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MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
impaired muscle coordination, difficulty walk-
ing, poor balance, and changes in speech and
swallowing [98]. The unique mechanism and
therapeutic efficacy of omaveloxolone high-
light its significant contribution to modern
medicine.
Fig. 4. The structures of compounds 43, 44, and omaveloxolone 4.
The synthesis of omaveloxolone 4, deve
loped by Reata Pharmaceuticals Inc., begins
with compound 46 as the starting material
(Scheme 5) [99]. The precursor, diketo acid
CDDO 46, is derived in 11 steps from the natu
rally occurring oleanolic acid 45 in an overall
yield of 29% [100]. To transform compound 46
into azide derivative 47, diphenylphosphoryl
azide is used in the presence of triethylamine
with toluene as the solvent at room tempera-
ture. After purification by chromatography
over silica gel, acyl azide 47 is obtained in an
impressive 94% yield.
Scheme 5. Synthesis of omaveloxolone 4.
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Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 6 / Vol. 91
The acyl azide 47 then undergoes a Curtius
rearrangement through heating in anhydrous
benzene forming isocyanate 48. Without re-
quiring isolation, isocyanate 48 is hydrolyzed
by treatment with HCl in acetonitrile at room
temperature yielding amine 49 with preserva-
tion of its configuration. Omaveloxolone 4 is
finally obtained through peptide-like coup
ling reactions between amine 49 and 2,2-di
fluoropropanoic acid. The carboxylic group
of 2,2-difluoropropanoic acid is pre-activated
using dicyclohexylcarbodiimide (DCC), enab
ling the formation of the desired product. After
purification by chromatography over silica gel,
omaveloxolone 4 is obtained in a commenda-
ble 73% yield from compound 46 over 4 steps.
This synthesis reflects the precision and effi-
ciency required to produce such a complex
molecule demonstrating innovative approa
ches in modern medicinal chemistry.
Flurpiridaz (18F) (Flyrcado®) 5.
Flurpiridaz (18F) 5 has received FDA ap-
proval as a radioactive drug for myocardial
perfusion imaging, a critical tool in diagnos-
ing coronary artery disease [101]. Labeled
with the radioisotope fluorine-18 (β+ decay),
this diagnostic agent serves as a tracer for PET.
PET-MPI using flurpiridaz (18F) 5 has demons
trated superiority over the more widely used
single photon emission computed tomogra-
phy (SPECT) which typically employs techne-
tium-99m [102, 103].
The efficacy of flurpiridaz (18F) 5 in PET
imaging is made possible by radiofluoroalkyla
tion, leveraging the unique properties of fluo-
rine-18. This isotope offers distinct advantages,
including a clinically practical half-life of 109.8
minutes compared to other PET radiotracers
such as nitrogen-13 (∼10 minutes), oxygen-15
(∼2 minutes), and rubidium-82 (∼76 seconds),
or the SPECT radiotracer technetium-99m
(6 hours) [104]. The extended half-life of fluo
rine-18 eliminates the need for on-site cyclotron
facilities as transportation from an off-site fa-
cility becomes feasible [105]. Moreover, radio-
fluorination provides additional benefits, such
as reduced positron energy, which enhanc-
es image resolution [106]. This improvement
translates into superior diagnostic and prog-
nostic capabilities enabling the detection of
even subtle circulatory abnormalities [107].
Flurpiridaz (18F) 5 exemplifies how cutting-edge
radiotracer technology can revolutionize medi-
cal imaging and disease detection.
Flurpiridaz (18F) 5 exhibits rapid uptake and
slow excretion by myocardial cells ensuring
effective imaging while being well tolerated
and demonstrating a high myocardial extrac-
tion fraction [104, 108]. Pharmacologically, its
mechanism of action involves binding to and
inhibiting mitochondrial complex 1 (MC1) in
the heart [104]. Structure–activity studies have
revealed that introducing fluorine into the
alkyl side chain significantly enhances MC1
binding affinity compared to its incorporation
into the pyridazinone core [109].
From a chemical perspective, flurpiridaz
(18F) 5 is a derivative of the pesticide pyrida-
ben due to its tert-butyl-substituted pyridazi-
none moiety [108]. Its molecular architecture
is composed of two main components: a li-
pophilic heterocyclic headpiece (the tert-bu-
tyl-substituted pyridazinone) and an alkylated
phenyl sidechain. These two units are bridged
by a linker containing an ether group which
contributes to the molecule’s unique properties
[109].
The synthesis of flurpiridaz (18F) 5 be-
gins with 4-hydroxymethyl benzoate as the
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MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
starting material (Scheme 6) [109]. The first
step is the ring-opening of ethylene oxide by
4-hydroxymethyl benzoate in DCM facilitated
by BF3·OEt2 to provide methyl-4-(2-hydroxy
ethoxymethyl)benzoate (50) in 17% yield.
Subsequently, the alcohol functionality is
protected at room temperature using tert-bu-
tyldimethylsilyl chloride (TBDMSCl) yielding
4-[2-(tert-butyldimethylsilanyloxy)ethoxyme-
thyl]benzoic acid methyl ester (51). Reduction
of 51 with LiAlH4 provides alcohol 52 in an
impressive 91% yield.
Scheme 6. Synthesis of flurpiridaz (18F) 5.
The next critical step employs a Mitsunobu-
like reaction in which alcohol 52 reacts with
4-chloro-5-hydroxy-2-tert-butyl-(2H)-pyri-
dazin-3-one (53) using PPh3 and DIAD as re-
agents to produce intermediate 54 [110]. The
synthesis of pyridazinone derivative 53 has
been well-documented in the literature [111].
Removal of the TBDMS protecting group from
ether 54 is achieved with tetra-n-butylammo-
nium fluoride (TBAF) in THF yielding alco-
hol 55 [112]. This intermediate is then con-
verted into the sulfonate ester 56. Finally, the
sulfonate ester 56 undergoes substitution by
potassium fluoride (K18F) in the presence of
Kryptofix222 [113] (4,7,13,16,21,24-hexaoxa-
1,10-diazabicyclo[8.8.8]hexacosan) at 90 °C
for 10 minutes, culminating in the formation
of the desired flurpiridaz (18F) 5. This method
elegantly showcases the precision and optimi-
zation required to create such a sophisticated
molecule.
The aforementioned synthesis faced signifi-
cant challenges, primarily due to its inefficiency
and reliance on hazardous reagents. The ove
rall yield falls below 10% with the first step—
forming ether 50—achieving a meager yield of
just 17%. Compounding the issue, this step in-
volved the use of ethylene oxide, a volatile and
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Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 6 / Vol. 91
carcinogenic gas known to cause respiratory
irritation [114, 115]. Handling this reagent
proved problematic, not only due to its toxici-
ty, but also because of its high volatility posing
risks in both safety and practicality. To address
these limitations, Ahmed and co-workers de-
vised an alternative synthesis pathway that
entirely circumvented the risky alkylation pro-
cess. Instead, they employed a silver oxide-pro-
moted reaction between methyl 4-(bromome-
thyl)benzoate and 2-((tert-butyldimethylsilyl)
oxy)ethanol to produce intermediate 50. This
innovative approach not only enhanced safe-
ty but also significantly improved efficiency,
boosting the overall yield approximately five-
fold [107]. Their work stands as a testament to
the potential of optimized synthesis routes in
overcoming challenges while achieving supe-
rior results.
Upadacitinib (RinvoqTM) 6.
Upadacitinib 6, a remarkable innovation
first discovered by Abbott Laboratories and
further refined by its spin-off AbbVie Inc.,
achieved a major breakthrough with FDA
approval. This approval was granted for the
treatment of adults with moderate to severe
rheumatoid arthritis who had an inadequate
response or were intolerant to methotrexate
(Fig. 5). The journey to upadacitinib’s creation
involved a thorough and meticulous structu
ral investigation centered on its critical tri
cyclic core. By systematically varying the hete
rocyclic cores, the side chain, and the amido
moiety, researchers fine-tuned the molecule’s
design. This effort ultimately led to the deve
lopment of upadacitinib 6, distinguished by a
2,2,2-trifluoroethyl substitution on the nitro-
gen atom—an essential feature that enhances
its therapeutic effectiveness [116, 117].
Fig. 5. Structure of upadacitinib 6 and its non-fluorinated analog 57.
Rheumatoid arthritis is a complex syste
mic autoimmune disorder marked by chronic
inflammatory synovitis and the relentless de-
struction of joints. At its core, these patholo
gical processes are driven by inflammatory cy-
tokines and autoreactive T cells. A critical play-
er in this cascade is the family of Janus kinases
(JAKs), which serve as pivotal mediators in cy-
tokine-activated cell signaling pathways. Their
phosphorylation triggers a chain of events that
exacerbate rheumatoid arthritis and other auto
immune diseases. The JAK family comprises
four members–JAK1, JAK2, JAK3, and TYK2–
each with unique and highly specialized roles
in regulating immune responses. Recognizing
this, researchers have developed a spectrum of
JAK inhibitors with varying selectivities, many
of which have progressed to clinical trials
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MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
including upadacitinib 6 [116]. Upadaciti
nib 6, a selective JAK1 inhibitor, boasts impres-
sive specificity with an IC50 of 0.043 mmol/L
for JAK1 compared to 0.2 mmol/L for JAK2,
2.3 mmol/L for JAK3, and 4.7 mmol/L for
TYK2. This targeted selectivity has translated
into demonstrated efficacy, safety, and tolera-
bility during clinical trials in patients with va
rious autoimmune conditions showcasing its
potential as a transformative treatment option.
For rheumatoid arthritis, following the suc-
cess of Phase II trials, multiple Phase III trials
were conducted on patients who had either an
inadequate response to conventional synthe
tic disease-modifying antirheumatic drugs or
were refractory to biologic disease-modifying
antirheumatic drugs [118–120]. Across all tri-
als, upadacitinib 6 demonstrated both safety
and efficacy, though higher doses were associ-
ated with a slight increase in infection risk. No-
tably, an additional Phase III trial revealed that
upadacitinib 6 outperformed adalimumab in
terms of efficacy [121]. In patients with mode
rate to severely active Crohn’s disease who had
not responded well to or could not tolerate im-
munomodulators or anti-TNF therapy, a Phase
II trial demonstrated both symptomatic and
endoscopic remission [122]. The safety profile
observed was consistent with other studies of
upadacitinib 6 and Phase III trials are current-
ly underway [123]. Similarly, a Phase II study
evaluating upadacitinib 6 in patients with ul-
cerative colitis revealed a clear dose-response
relationship [124]. For individuals with active
ankylosing spondylitis who failed to respond
adequately to or could not tolerate non-steroi-
dal anti-inflammatory drugs, the Phase II/III
SELECT-AXIS 1 trial established that a 15 mg
dose of upadacitinib 6 was both effective and
welltolerated. Notably, no cases of serious in-
fections, herpes zoster, malignancy, venous
thromboembolic events, or deaths were re-
ported. Recruitment for a Phase III study is
currently ongoing. In the case of moderate
to severe atopic dermatitis, upadacitinib 6
demonstrated strong efficacy and maintained a
favorable benefit–risk profile. While infections
were more common among upadacitinib-
treated patients compared to those receiving
a placebo, serious infections were rare [125].
Additionally, Phase III trials are advancing for
psoriatic arthritis and giant cell arteritis fur-
ther expanding the therapeutic potential of
upadacitinib 6.
Synthetic pathways leading to upadacitinib
6 are documented exclusively within patents.
The initial patent from Abbott Laboratories,
which first disclosed the structure of upada
citinib 6, includes details of its synthesis. How-
ever, the fragmented presentation of substeps
scattered throughout the document renders
the reconstruction of the complete synthetic
pathway particularly challenging [126]. A sub-
sequent patent filed by AbbVie is comparative-
ly more accessible, but its vague procedural
descriptions introduce ambiguity complicat-
ing the reproducibility of the synthesis [127].
In contrast, a 2017 AbbVie patent provides a
detailed and coherent synthetic pathway of-
fering greater clarity and precision in the step-
by-step process. The synthesis begins with the
construction of the pyrrolidine-containing
segment derived from a Cbz-protected gly-
cine ester 58 (Scheme 7). This compound un-
dergoes a reaction with ethyl acrylate through
conjugate addition followed by an intramole
cular Claisen condensation leading to the for-
mation of ester intermediate 59. Subsequently,
intermediate 59 undergoes O-sulfonylation to
prepare 60 for use in the next step where an
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ethyl group is introduced via a Suzuki cross-
coupling reaction producing compound 61.
The ester functionality in 61 is then hydroly
zed to afford acid 62 followed by enantioselec-
tive hydrogenation to give cyclic β-amino acid
[128] isolated as a salt with dicyclohexylamine
63. While it has been reported that [(S)-seg-
phos]Ru(OAc)2-catalyzed enantioselective hy-
drogenation proceeded with >99% enantiose-
lectivity, this claim is not supported by ruling
out enantiomeric enrichment via SDE [129,
130] during the isolation procedure.
Scheme 7. Asymmetric synthesis of cyclic amino acid 63 from glycine 58.
Following purification, salt 63 was conver
ted into (R)-1-(naphthalen-1-yl)ethanamine
salt 64 (Scheme 8) which was subsequently
transformed into pyrrolidine carboxylic acid
65. The carboxylic acid group of 65 was mod-
ified into a COCH2Br group, compound 67,
using sulfoxonium ylide 66. This reactive in-
termediate, compound 67, was then employed
in the N-alkylation of the carbamate moiety
within heterocyclic compound 68.
The resulting intermediate, compound 69,
underwent cyclization with trifluoroacetic an-
hydride to form compound 70. This was fol-
lowed by hydrogenolytic deprotection of the
Cbz group yielding compound 71. In the final
step, carbonyldiimidazole (CDI) and 2,2,2-tri-
fluoroethylamine were utilized to establish the
carbamide functionality to complete the syn-
thesis of the target molecule upadacitinib 6
[131, 132].
2,2,2-Trifluoroethylamine, along with other
trifluoromethyl amines and amino acids, can
be synthesized through biomimetic transami-
nation of corresponding carbonyl compounds
using benzylamine or its derivatives [133–136].
Particularly noteworthy, as shown in Scheme 9,
is the preparation of 2,2,2-trifluoroethylamine
from TFA (72) through a ‘double’ biomimetic
transamination involving a single molecule of
benzylamine. This innovative approach begins
with the in situ formation of amide 73 which
is subsequently transformed into imidoyl chlo-
ride 74. Following this, the first biomimetic
1,3-proton transfer generates imine 75. A chlo-
rotropic shift then converts imine 75 into imi
ne 76 which undergoes a second biomimetic
1,3-proton transfer yielding imidoyl chloride
77. This intermediate 77 can be isolated and,
through two hydrolytic steps, transformed into
the desired 2,2,2-trifluoroethylamine. Remar
kably, despite involving a seven-step process,
this method achieves an exceptional isolated
yield of over 90% underscoring its efficiency
and practicality [137].
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MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
Scheme 8. Synthesis of upadacitinib 6.
Scheme 9. Synthesis of 2,2,2-trifluoroethylamine via ‘double’ biomimetic transamination.
Tezacaftor (SymdekoTM) 7.
SymdekoTM, a coformulation of tezacaftor 7
and ivacaftor (Fig. 1) developed by Vertex
Pharmaceuticals, represents a significant ad-
vancement in the treatment of cystic fibrosis.
Approved by the FDA, it addresses this de-
bilitating condition marked by the buildup
of thick, sticky mucus in the lungs, pancreas,
gastrointestinal tract, and reproductive system
[138]. The root cause lies in mutations of the
CFTR gene with the F508del mutation being
one of the most prevalent [139]. Tezacaftor 7
and ivacaftor function in a complementary
manner to combat the effects of this mutation.
Tezacaftor 7 acts as a corrector, enhancing the
transport of functional CFTR protein to the
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cell membrane. Meanwhile, ivacaftor serves
as a potentiator helping to open the chloride
channel within the CFTR protein. This dual
mechanism promotes water movement out of
the cells effectively reducing mucus viscosity
and alleviating symptoms associated with cys
tic fibrosis.
The synthesis of tezacaftor 7, developed by
Auspex Pharmaceuticals, is a sophisticated
process involving the preparation of two key
intermediates [140]. The process begins with
the carbonylation of aryl bromide 78 (Scheme
10) where palladium catalysts and an atmos-
phere of carbon monoxide in methanol are
employed to produce methyl ester 79. This
intermediate is then reduced using LiAlH4 to
yield primary alcohol 80. To further functio
nalize the molecule, the alcohol group in com-
pound 80 is replaced with a chloride forming
compound 81. A nucleophilic substitution
with sodium cyanide transforms 81 into nit
rile derivative 82. The cyclopropane ring is
then introduced via phase-transfer catalysis
utilizing 1-bromo-2-chloroethane, to produce
cyclopropane derivative 83. In the next step,
compound 83 undergoes nitrile hydrolysis
with aqueous hydroxide yielding free acid 84.
Finally, the carboxylic acid group of 84 is con-
verted into the reactive chloroanhydride 85
through treatment with thionyl chloride. This
meticulously designed, high yielding synthetic
pathway highlights the precision and strategic
optimization integral to the development of
tezacaftor 7.
Scheme 10. Synthesis of key compound 85.
The synthesis of the second key interme-
diate began with the preparation of terminal
alkyne 89 (Scheme 11). This process involved
a precise four-step sequence. First, ethynyl-
trimethylsilane was added to acetone in the
presence of butyllithium resulting in the for-
mation of alcohol 86. Next, alcohol 86 was
transformed into alkyl chloride 87. In the third
step, the corresponding Grignard reagent was
generated and reacted with compound 87
yielding benzyl ether 88. Finally, the trimethyl-
silane protecting group was removed through
a potassium hydroxide-mediated methanolysis
producing the target alkyne ether 89.
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Scheme 11. Synthesis of intermediate 89.
The synthesis of the second key intermedi-
ate and the assembly of tezacaftor 7 began with
the bromination of 3-fluoro-4-nitroaniline
(90) (Scheme 12) yielding aryl bromide 91.
This was followed by alkylation of the amino
group using optically pure epoxide 92 produc-
ing amino alcohol 93. The nitro group in 93
was then reduced using a combination of zinc
and ammonium chloride in ethanol resulting
in aniline derivative 94. Aniline 94 was sub-
sequently subjected to a palladium-catalyzed
coupling reaction with acetylene derivative 89
(Scheme 11) forming product 95. The next step
involved a palladium-catalyzed intramolecular
cyclization of 95 which generated the second
key intermediate indole 96.
The synthesis of tezacaftor 7 was accom-
plished by coupling indole derivative 96 with
acyl chloride 85 (Scheme 10) by straightforward
amide bond formation where the amino group
of 96 reacts with the acyl chloride group of 85 in
the presence of triethylamine. A hydrogenation
step completes the process yielding tezacaftor 7
in moderate yield. This synthesis showcases a
logical and efficient sequence of transforma-
tions to achieve the desired molecule.
Scheme 12. Synthesis of tezacaftor 7.
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Alpelisib (PiqrayTM) 8.
Alpelisib 8, a highly potent phosphatidy-
linositol-3 kinase α (PI3Kα) inhibitor, was
developed by Novartis for the treatment of
breast cancer [141–143]. The 2-aminothiazole
scaffold has proven to be an exceptional tem-
plate for designing selective PI3K inhibitors,
particularly when paired with a urea-linked,
sterically constrained (S)-pyrrolidine carbox-
amide unit (an amide of pyroglutamic acid)
attached to the 2-amino group of 97 (Fig. 6)
[144].
Alpelisib 8 stands out as a chiral 2-amino
thiazole derivative, optimized with an (S)-py
rrolidine carboxamide moiety linked via a urea
bond, making it the most effective candidate
within this PI3K inhibitor class. The inclu-
sion of a trifluoromethyl group significantly
enhanced its potency delivering robust dou-
ble-digit nanomolar inhibition of PI3Kα-de-
pendent Akt activation. In comparison, com-
pound 98 (Fig. 6), which featured a tert-butyl
group instead of a trifluoromethyl group, dis-
played noticeably reduced activity.
Fig. 6. The structures of alpelisib 8 and its fluorine-free analogs 97 and 98.
In an assay for the inhibition of p110α,
p110β, p110δ, and p110γ activity, alpelisib 8
achieved impressive IC50 values of 0.005, 1.2,
0.29, and 0.25 mmol/L, respectively, while
fluorine-free 98 exhibited weaker IC50 values of
0.014, 4.4, 0.33, and 0.43 mmol/L, respectively.
Additionally, metabolic stability assessments
using rat liver microsomes showed that alpeli
sib 8, with a –CF3 group, demonstrated dra-
matically reduced in vitro clearance compared
to 98. Despite its excellent activity against
wild-type PI3Kα, alpelisib 8 displayed rela-
tively lower efficacy against PI3Kβ, PI3Kδ, and
PI3Kγ [141, 142]. Approved by the FDA under
the trade name Piqray™ for the treatment of
HR+, HER2-negative, and PIK3CA-mutated
advanced or metastatic breast cancer, alpelisib
8 is administered in combination with fulves-
trant, offering new hope for patients battling
this challenging disease [145].
The synthesis of alpelisib 8 (Scheme 13)
[141] hinges on a pivotal Pd-catalyzed cou-
pling between 4-methyl-2-acetaminothiazole
(104) and 4-bromopyridine intermediate 103.
The process begins with chloride 100 prepared
from 3,3,3-trifluoro-2,2-dimethylpropanoic
acid and oxalyl chloride. Chloride 100 is then
reacted with 4-methoxybut-3-en-2-one 99
in the presence of lithium bis(trimethylsilyl)
amide (LiHMDS) at −78 °C. The reaction pro-
gresses through enolization of 99, substitution
of the chlorine in 100, a secondary enolization
of the resulting 1,3-diketone, and a TFA-me-
diated cyclization which substitutes the meth-
oxy group to yield 4H-pyran-4-one interme-
diate 101. The next step involves amination of
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MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
4H-pyran-4-one intermediate 101 with ammo-
nia at 65 °C, producing pyridin-4(1H)-one 102.
Treatment of 102 with POBr3 affords bromide
intermediate 103, albeit in only 51% yield. The
Pd-catalyzed coupling between intermediate
103 and 4-methyl-2-acetaminothiazole (104)
produces compound 105 which is then hydro-
lyzed in the presence of 6 M HCl. The result-
ing amine 106 undergoes condensation with
1H-imidazole-1-carboxylic acid to form imi-
dazole intermediate 107. Finally, intermediate
107 is reacted with (S)-pyroglutamic acid at
room temperature culminating in the forma-
tion of the target compound alpelisib 8.
Scheme 13. Synthesis of alpelisib 8.
Pretomanid 9.
Pretomanid 9, developed by the Global Alli
ance for TB Drug Development (TB Alliance),
has emerged as one of the most promising
antituberculosis drug candidates [146–149].
This compound possesses two key structural
features: a bicyclic nitroimidazole scaffold and
a trifluoromethoxy-substituted benzyl ether
with S absolute configuration at the stereogenic
carbon. Related compounds, such as metroni-
dazole 109 (Fig. 7) and OPC-67683, have also
been identified as potential nitroimidazole-
based drugs for tuberculosis. Pretomanid 9
demonstrated significant anti-TB activity, with
IC50 values ranging from 0.015–0.25 mmol/L
[148]. The in vitro evaluation of pretomanid 9
against H37Rv Mycobacterium tuberculosis in
GAST and 7H12 media yielded IC50 values of
0.12 mmol/L and 0.09 mmol/L, respectively
[149]. Notably, pretomanid 9 exhibited strong
antibacterial efficacy against M. tuberculosis
in vitro and underwent clinical trials for tu-
berculosis treatment. In sharp contrast, its R
enantiomer, compound 108, showed no acti
vity against M. tuberculosis [147]. Pretomanid
9 received FDA approval under the trade name
Pretomanid for the treatment of adults with
drug-resistant tuberculosis. Its approval marks
a significant step forward in combating this
challenging disease [150].
37https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 6 / Vol. 91
Fig. 7. The structures of pretomanid 9, its R enantiomer 108,
and the related compound metronidazole 109.
A four-step synthesis of pretomanid 9 [148]
(Scheme 14) begins with the esterification
of (R)-3-chloro-1,2-propanediol (110) with
p-methoxybenzoyl chloride in DCM using
imidazole as the base to provide ester 111 in
78% yield and >99% enantiomeric excess (ee).
Next, 4-(trifluoromethoxy)benzyl trichloro-
acetimidate (112), derived from 4-(trifluo-
romethoxy)benzyl alcohol, reacts with ester
111 in the presence of a stoichiometric amount
of p-toluenesulfonic acid (TsOH) providing
glycidol-derived alkyl chloride 113 in 80%
yield. Intermediate 113 next undergoes substi-
tution with 2-chloro-4-nitroimidazole in the
presence of sodium iodide and potassium car-
bonate in DMF at 120 °C to form intermediate
114. The final step involves deprotection of the
p-methoxybenzoyl group and an intramolecu-
lar cyclization under basic conditions to afford
pretomanid 9 in 62% yield. Recrystallization
from isopropanol–hexane provides pretoma-
nid 9 with 99.9% ee.
Scheme 14. Synthesis of pretomanid 9.
38 ISSN 2708-129X. Укр. хім. журн., 2025
MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
This method represents a significant im-
provement over the original synthesis which
utilized 2,4-dinitroimidazole as the star
ting material [151] and it is also suitable for
large-scale production. Notably, the synthesis
of (S)-configured pretomanid 9 begins with
(R)-3-chloro-1,2-propanediol (110). The ap-
parent change in absolute configuration from
R to S following the substitution step from 113
to 114 is not due to inversion of the stereoge
nic carbon but is a consequence of CIP priority
rules [152, 153].
Atogepant (QuliptaTM) 10.
CGRP is a powerful, naturally occurring
37-amino acid neuromodulatory peptide
found in the central and peripheral nervous
systems. It plays a crucial role in various bio-
logical processes, including vasodilation. Re-
search shows that CGRP receptors are promi
nently expressed in brain regions linked to
migraine pathophysiology and CGRP levels
are elevated during migraine episodes. This
peptide exerts its biological effects by binding
to specific cell surface receptors which activate
the adenylyl cyclase enzyme [154–156].
Clinical trials have demonstrated the ef-
fectiveness of CGRP antagonists in treating
acute migraine attacks as well as neurogenic
inflammation and inflammatory pain [157,
158]. Furthermore, multiple studies have re-
ported that the vascular effects of CGRP can
be diminished or reversed with CGRP antago-
nists [159–164]. Among these breakthroughs,
Merck conducted a structure–activity rela-
tionship study, leading to the development
of atogepant 10, a potent and selective CGRP
antagonist. This compound is noteworthy as
the first orally administered CGRP antago
nist to receive FDA approval for the pre-
vention of episodic migraines and cluster
headaches.
As illustrated in Fig. 1, atogepant 10 bears a
close structural resemblance to ubrogepant 2.
Both feature a chiral spirotetracyclic moiety, a
cyclic α,δ-diamino acid core [165–167], and a
trifluoroethylamine residue. However, the key
distinction lies in atogepant’s incorporation
of three additional aromatic fluorine atoms as
part of the cyclic amino acid fragment. While
seemingly minor, this structural variation re-
sults in differences in bioactivity and chemi-
cal synthesis. Ubrogepant 2 and atogepant 10,
though both CGRP receptor antagonists, differ
in their clinical applications. Ubrogepant 2 is
designed for the acute treatment of migraines;
it is taken as needed during a migraine episode
to provide rapid relief by blocking CGRP activ-
ity which contributes to migraine symptoms.
In contrast, atogepant 10 was developed for the
preventive treatment of episodic migraines.
Administered regularly, it reduces the frequen-
cy of migraine attacks over time. While both
drugs share the mechanism of blocking CGRP
activity, their bioactivity is tailored to align
with their specific purposes–ubrogepant 2 for
immediate relief and atogepant 10 for long-
term management. In summary, both medica-
tions have proven effective in their respective
roles offering valuable options for individuals
affected by migraines.
Scheme 15 outlines the synthesis of atoge
pant 10. Starting with fluorinated 2-pheny-
lacetic acid 115 [168, 169], the substrate was
converted to its acid chloride by reacting with
POCl3 in DMF and isopropyl acetate (iPAc)
at 0 °C for 30 minutes. The resulting mix-
ture was added to a solution of K2CO3 and
NHMe(OMe)·HCl in water below 8 °C provid-
ing compound 116 in an excellent 99% yield.
39https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 6 / Vol. 91
The synthesis continued with a CeCl3-pro-
moted reaction between intermediate 116 and
MeMgCl in THF. This was followed by treat-
ment with 2 N hydrochloric acid and methyl
tert-butyl ether (MTBE) at 5–10 °C to produce
l-(2,3,6-trifluorophenyl)propan-2-one (117)
in 95% yield. Intermediate 117 then undergoes
substitution with isopropyl N-(tert-butoxycar-
bonyl)-O-(methylsulfonyl)serinate (118) in
the presence of ZnBr2 and tBuOLi, affording
intermediate 119 in 67% yield after 24 hours.
The asymmetric cyclization of intermediate
119 was achieved by treating it with sodium
tetraborate decahydrate, isopropylamine, pyri
doxal-5-phosphate (PLP), and SEQ ID NO: 1
in borate buffer at 55 °C for 24 hours. This step
resulted in the carbamate intermediate 120
as a mixture of cis- and trans-isomers in 71%
yield. The crude mixture of 120 in Me-THF
was treated with tBuOK at room temperature
for 2 hours and subsequently crystallized from
iPAc/heptane at 60 °C providing crystalline cis-
121 in 85% yield. This transformation involved
α epimerization of the cyclic α,δ-diamino acid,
a mechanism akin to dynamic kinetic resolu-
tions commonly employed for preparing enan-
tiomerically pure α-amino acids [170–172]. To
introduce a trifluoroethyl group, trifluoroethyl
trifluoromethanesulfonate was utilized fol-
lowed by removal of the Boc group generating
the free amine 122 in 92% yield. Finally, com-
pound 122 was coupled with carboxylic acid
123 in the presence of hydroxybenzotriazole
(HOBt) monohydrate and 1-ethyl-3-(3-di-
methylaminopropyl)carbodiimide (EDC) hy-
drochloride at room temperature for 4 hours
resulting in atogepant 10 as a monohydrate in
95% yield. This optimized synthesis demons
trates efficient and high yielding steps suitable
for the large-scale preparation of atogepant 10.
Scheme 15. Synthesis of atogepant 10.
40 ISSN 2708-129X. Укр. хім. журн., 2025
MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
CONCLUSIONS. In this review we have
profiled ten marketed pharmaceuticals ap-
proved by the FDA within the last five years
that feature aliphatic fluorination—a key struc-
tural feature pivotal to their biological activity.
These include ivosidenib 1, developed for the
treatment of AML and cholangiocarcinoma
(bile duct cancer); ubrogepant 2, approved
for the acute treatment of migraines; ascimi
nib 3, prescribed for the treatment of CML in
the chronic phase; omaveloxolone 4, used in
the treatment of Friedreich’s ataxia, a rare ge-
netic disorder causing progressive damage to
the spinal cord, peripheral nerves, and brain,
leading to uncoordinated movement, difficulty
walking, and other complications; flurpiridaz
(18F) 5, a radioactive diagnostic agent for PET
myocardial perfusion imaging; upadacitinib 6,
designed to address several inflammatory and
autoimmune conditions, including rheuma-
toid arthritis, psoriatic arthritis, atopic derma-
titis, ulcerative colitis, Crohn’s disease, anky-
losing spondylitis, and non-radiographic axial
spondyloarthritis; tezacaftor 7, approved for
the treatment of cystic fibrosis as an effective
remedy; alpelisib 8, prescribed for the treat-
ment of breast cancer, effectively inhibiting
tumor growth and abnormal cell proliferation;
pretomanid 9, used in combination therapies
for the treatment of extensively drug-resis
tant and multi-drug-resistant tuberculosis;
and atogepant 10, approved for the preven-
tive treatment of migraines in adults, targeting
both episodic and chronic migraines. As high-
lighted in the discussion, molecules featuring
aliphatic fluorination present challenges due to
higher production costs and the complexity of
predicting their biological profiles. However,
the undeniable medicinal benefits of aliphatic
fluorination are likely to invigorate this area of
research paving the way for the development
of more innovative drugs to enter the pharma-
ceutical market.
Beyond the incorporation of aliphatic fluo
rine atoms, six of the pharmaceuticals dis-
cussed in this review feature residues of amino
acids or their derivatives as pivotal structural
design elements. As noted in the discussion,
the significance of asymmetric synthesis in
producing tailor-made amino acids [173–175]
and its profound impact on the modern phar-
maceutical industry cannot be overstated. An-
other noteworthy characteristic shared by all
these drugs is their chirality with each mole-
cule possessing between one and six stereo
genic carbons. In light of the FDA require-
ments for chiral drugs [176–178], continuous
advancements in the asymmetric synthesis
and characterization of chiral fluorine-con-
taining compounds are critically important.
Special attention should be directed towards
the SDE phenomenon, a behavior observed in
enantiomerically enriched compounds [179–
181]. The SDE properties of chiral drugs, par-
ticularly those containing fluorine [182–184]
and/or amino acid residues [185–187], repre-
sent a vital public safety concern necessitating
rigorous evaluation of enantiomeric purity
[188–191]. Monitoring the enantiomeric in-
tegrity of pharmaceutical drugs throughout
synthesis [192, 193], production, and even
storage is essential as SDE via sublimation
poses a specific challenge for fluorine-con-
taining drugs [194–196].
Additionally, caution should be exercised in
light of growing public concerns over the po-
tential harmful effects of fluorine on human
health [197–199]. Since fluoride is recognized
as the final metabolite of organic fluorinated
compounds [197–201], patients prescribed
41https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 6 / Vol. 91
fluorine-containing drugs should consult their
physicians about non-fluorinated alternatives
where available or take steps to limit fluoride
exposure from other sources such as fluori-
dated water and industrially produced foods
treated with fluorinated agrochemicals [202].
Sadly, fluoride and the recent rise of perfluo
rinated “forever chemicals” (PFAS) [203]
are notorious contributors to the persistent
commercial-driven degradation of both the
environment and human health [197] in ad-
dition to other contributions such as micro
plastics [204].
Despite these concerns, it remains an un-
deniable truth that pharmaceutical drugs
are indispensable in modern medicine. They
provide life-saving treatments, improve qua
lity of life, and drive medical innovation ad-
dressing urgent health challenges and laying
the foundation for future advancements in
healthcare.
ACKNOWLEDGMENTS:
We gratefully acknowledge the finan
cial support from the National Na
tural Science Foundation of China
(No. 21761132021) and the Qing-Lan
Project of Jiangsu Province (for Han)
and IKERBASQUE, Basque Founda
tion for Science (for Soloshonok). The
authors acknowledge the assistance
of Microsoft Copilot and Google Ge
mini for their support with Ukrainian
translation.
СУЧАСНІ ФАРМАЦЕВТИЧНІ ПРЕПАРАТИ, ЩО
МІСТЯТЬ АЛІФАТИЧНІ ФТОРВМІСНІ ГРУПИ
Дзяньлінь Хань,¹ Аліція Взорек,²
Карел Д. Кліка,³ Таїзо Оно,⁴
Вадим А. Солошонок5,6*
1 Цзянсу, Центр співінновацій ефективного
оброблення та використання лісових
ресурсів, Хімічний факультет,
Лісотехнічний університет Нанкіна,
Нанкін 210037, Китай;
2 Хімічний інститут, Університет Яна
Кохановського в Кельці,
вул. Університетська 7, 25–406 Кельце,
Польща;
3 Центр досліджень і розробок, Archer
Daniels Midland, 1001 N Brush College Rd.,
Декатур, IL 62521, США;
4 Національний інститут передової науки
та технологій (AIST),
2266–98, Анагахора, Шімошідамі,
район Моріяма, Нагоя, 463–8560, Японія;
5 Відділ органічної хімії I, Хімічний
факультет, Університет Країни Басків
UPV/EHU, Paseo Manuel Lardizábal 3,
20018 Сан-Себастьян, Іспанія;
6 ІКЕРБАСКЕ, Баскська наукова фундація,
вул. Марія Діас де Харо 3, Площа Бізкая,
48013 Більбао, Іспанія,
e-mail: vadimsoloshonok@gmail.com
У статті представлено десять лікар-
ських засобів, що надійшли в продаж та
були схвалені Управлінням з контролю за
якістю харчових продуктів і медикаментів
США (US FDA) протягом останніх п’яти
років, які містять аліфатичне фторуван-
ня – ключову структурну характеристику,
42 ISSN 2708-129X. Укр. хім. журн., 2025
MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS.ORGANIC CHEMISTRY
що має вирішальне значення для їхньої
біологічної активності. Серед них: івоси-
деніб, розроблений для лікування гостро-
го мієлоїдного лейкозу та холангіокарци-
номи (раку жовчних проток); уброгепант,
схвалений для гострого лікування мігрені;
аскімініб, що призначається для лікування
хронічного мієлоїдного лейкозу в хроніч-
ній фазі; омавелоксолон, який використо-
вують для лікування атаксії Фрідрайха,
рідкісного генетичного розладу, що спри-
чиняє прогресуюче ураження спинного
мозку, периферичних нервів та головного
мозку; флурпіридаз – радіоактивний діа-
гностичний засіб для позитронно-емісій-
ної томографії перфузії міокарда; yпадаци-
тиніб, розроблений для лікування кількох
запальних та аутоімунних станів, включа-
ючи ревматоїдний артрит, псоріатичний
артрит, атопічний дерматит, виразковий
коліт, хворобу Крона, анкілозуючий спон-
диліт та нерентгенографічний аксіальний
спондилоартрит; тезакафтор, схвалений
для лікування муковісцидозу як ефектив-
ний засіб; алпелісіб, що призначається для
лікування раку молочної залози, ефектив-
но інгібуючи ріст пухлини та аномальну
проліферацію клітин; претоманід, який ви-
користовують у комбінованих терапіях для
лікування туберкульозу з широкою та мно-
жинною лікарською стійкістю; атогоепант,
схвалений для профілактичного лікування
мігрені у дорослих, спрямований як на епі-
зодичну, так і на хронічну мігрень. Моле-
кули, що містять аліфатичне фторування,
становлять труднощі через вищі виробничі
витрати та складність прогнозування їхніх
біологічних профілів. Однак незаперечні
медичні переваги аліфатичного фторуван-
ня, ймовірно, активізують цю галузь дослі-
джень, відкриваючи шлях для розроблення
більш інноваційних лікарських засобів, що
вийдуть на фармацевтичний ринок. Ок-
рім включення аліфатичних атомів фтору,
шість із лікарських засобів, розглянутих у
цій статті, містять залишки амінокислот або
їхні похідні як ключові елементи структур-
ного дизайну. Ще однією характеристикою,
спільною для всіх цих препаратів, є їхня хі-
ральність, причому кожна молекула має від
одного до шести стереогенних атомів вуг-
лецю. Особливу увагу слід приділити яви-
щу самодиспропорціонування енантіоме-
рів (SDE), нелінійній поведінці, що спосте-
рігається в енантіомерно збагачених сполу-
ках. SDE-властивості хіральних лікарських
засобів, особливо тих, що містять фтор та/
або залишки амінокислот, є важливою про-
блемою громадської безпеки, що вимагає
ретельної оцінки енантіомерної чистоти.
Крім цього, слід проявляти обережність у
світлі зростаючої громадської стурбова-
ності щодо потенційно шкідливого впливу
фтору на здоров’я людини. Оскільки фто-
рид визнано кінцевим метаболітом орга-
нічних фторованих сполук, то пацієнтам,
яким призначено фторвмісні препарати,
слід проконсультуватися зі своїми лікаря-
ми щодо нефторованих альтернатив, якщо
такі є, або вжити заходів для обмеження
впливу фториду з інших джерел, таких як
фторована вода та промислово вироблені
продукти харчування, оброблені фторо-
ваними агрохімікатами. Незважаючи на ці
занепокоєння, залишається незаперечною
істиною те, що фармацевтичні препарати
є незамінними в сучасній медицині. Вони
забезпечують життєво важливе лікуван-
ня, покращують якість життя та стимулю-
ють медичні інновації, вирішуючи нагальні
43https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 6 / Vol. 91
проблеми зі здоров’ям та закладаючи осно-
ву для майбутніх досягнень у сфері охоро-
ни здоров’я.
Ключові слова: фтор, аліфатичне фто-
рування, фармацевтичні препарати, дизайн
лікарських засобів, синтез, хіральність, біо-
логічна активність, самодиспропорціону-
вання енантіомерів (SDE), проблеми гро-
мадського здоров’я, перевантаження фто-
ром організму людини та навколишнього
середовища.
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Стаття надійшла 25.05.2025.
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| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-733 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:13:11Z |
| publishDate | 2025 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
| record_format | ojs |
| resource_txt_mv | ucjorgua/9b/b20f2084b6e7fc49ee7c6d20a1443c9b.pdf |
| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-7332026-07-22T08:23:56Z MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS(Review) Han, Jianlin Wzorek, Alicja Ono, Taizo Klika, Karel Soloshonok, Vadim Fluorine, Aliphatic Fluorination, Pharmaceutical Drugs, Drug Design, Synthesis, Chirality, Bioactivity, Self-Disproportionation of Enantiomers (SDE), Public Health Concerns, Human and Environmental Overload with Fluorine. This review profiles ten marketed pharmaceuticals approved by the US Food and Drug Agency within the last five years that feature aliphatic fluorination – a key structural feature pivotal to their biological activity. These include ivosidenib, developed for the treatment of acute myeloid leukemia and cholangiocarcinoma (bile duct cancer); ubrogepant, approved for the acute treatment of migraines; asciminib, prescribed for the treatment of chronic myeloid leukemia in the chronic phase; omaveloxolone, used in the treatment of Friedreich’s ataxia, a rare genetic disorder causing progressive damage to the spinal cord, peripheral nerves, and brain; flurpiridaz (18F), a radioactive diagnostic agent for myocardial perfusion imaging by positron emission tomography; upadacitinib, designed to address several inflammatory and autoimmune conditions, including rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spondyloarthritis; tezacaftor, approved for the treatment of cystic fibrosis as an effective remedy; alpelisib, prescribed for the treatment of breast cancer, effectively inhibiting tumor growth and abnormal cell proliferation; pretomanid, used in combination therapies for the treatment of extensively drug-resistant and multi-drug-resistant tuberculosis; and atogepant, approved for the preventive treatment of migraines in adults, targeting both episodic and chronic  migraines. Molecules featuring aliphatic fluorination present challenges due to higher production costs and the complexity of predicting their biological profiles. However, the undeniable medicinal benefits of aliphatic fluorination invigorate this area of research, paving the way for the development of more innovative drugs to enter the pharmaceutical market. Beyond the incorporation of aliphatic fluorine atoms, six of the pharmaceuticals discussed in this review feature residues of amino acids or their derivatives as pivotal structural design elements. Another characteristic shared by all these drugs is their chirality, with each molecule possessing between one and six stereogenic carbons. Special attention should be directed toward the phenomenon of self-disproportionation of enantiomers (SDE), a behavior observed in enantiomerically enriched compounds. The SDE properties of chiral drugs, particularly those containing fluorine and/or amino acid residues, represent a vital public safety concern, necessitating rigorous evaluation of enantiomeric purity. Additionally, caution should be exercised in light of growing public concerns over the potential harmful effects of fluorine on human health. Since fluoride is recognized as the final metabolite of organic fluorinated compounds, patients prescribed fluorine-containing drugs should consult their physicians about non-fluorinated alternatives where available or take steps to limit fluoride exposure from other sources, such as fluoridated water and industrially produced foods treated with fluorinated agrochemicals. Despite these concerns, it remains an undeniable fact that fluorine-containing drugs are indispensable in modern medicine. They provide life-saving treatments, improve quality of life, and drive medical innovation addressing urgent health challenges and laying the foundation for future advancements in healthcare. V.I.Vernadsky Institute of General and Inorganic Chemistry 2025-07-25 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/733 10.33609/2708-129X.91.6.2025.15-54 Ukrainian Chemistry Journal; Vol. 91 No. 6 (2025): Ukrainian Chemistry Journal; 15-54 Украинский химический журнал; ##issue.vol## 91 ##issue.no## 6 (2025): Ukrainian Chemistry Journal; 15-54 Український хімічний журнал; Том 91 № 6 (2025): Ukrainian Chemistry Journal; 15-54 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/733/371 Copyright (c) 2025 Jianlin Han, Alicja Wzorek, Taizo Ono, Karel Klika, Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Han, Jianlin Wzorek, Alicja Ono, Taizo Klika, Karel Soloshonok, Vadim MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS(Review) |
| title | MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS(Review) |
| title_full | MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS(Review) |
| title_fullStr | MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS(Review) |
| title_full_unstemmed | MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS(Review) |
| title_short | MODERN PHARMACEUTICAL DRUGS FEATURING ALIPHATIC FLUORINE-CONTAINING GROUPS(Review) |
| title_sort | modern pharmaceutical drugs featuring aliphatic fluorine-containing groups(review) |
| topic_facet | Fluorine Aliphatic Fluorination Pharmaceutical Drugs Drug Design Synthesis Chirality Bioactivity Self-Disproportionation of Enantiomers (SDE) Public Health Concerns Human and Environmental Overload with Fluorine. |
| url | https://ucj.org.ua/index.php/journal/article/view/733 |
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