CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALS(Review)
Fluorine is a key element in drug design due to its ability to enhance metabolic stability, binding affinity, and bioavailability. Fluorine’s properties lead to more stable drugs with longer half-lives, reducing dosing frequency and improving patient compliance. Its small size and high electronegati...
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| Дата: | 2025 |
|---|---|
| Автори: | , , , , , , , , |
| Формат: | Стаття |
| Мова: | Англійська |
| Опубліковано: |
V.I.Vernadsky Institute of General and Inorganic Chemistry
2025
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| Назва журналу: | Ukrainian Chemistry Journal |
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Ukrainian Chemistry Journal| _version_ | 1871466115636396032 |
|---|---|
| author | Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander Baecker, Daniel Ono, Taizo Klika, Karel Soloshonok, Vadim |
| author_facet | Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander Baecker, Daniel 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": "Gagan Dhawan",
"institution": "School of Allied Medical Sciences, Delhi Skill and Entrepreneurship University, Dwarka, New Delhi-110077, India"
},
{
"author": "Wei Zhang",
"institution": "Department of Chemistry, University of Massachusetts Boston, Boston MA 02125, Unites States;"
},
{
"author": "Alexander Sorochinsky",
"institution": "Department of Fine Organic Synthesis, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, The National Academy of Sciences of Ukraine, 1 Murmanska str., Kyiv 02094, Ukraine"
},
{
"author": "Daniel Baecker",
"institution": "Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany"
},
{
"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 | 2026-07-22T08:23:55Z |
| description | Fluorine is a key element in drug design due to its ability to enhance metabolic stability, binding affinity, and bioavailability. Fluorine’s properties lead to more stable drugs with longer half-lives, reducing dosing frequency and improving patient compliance. Its small size and high electronegativity also improve binding affinity, resulting in more effective treatments with lower doses. For example, fluorine increases a compound’s ability to cross cell membranes. This article highlights advancements in chiral, fluorine-containing pharmaceuticals introduced over the past five years, focusing on their synthesis, therapeutic benefits, mechanisms of action, and the impact of fluorine on efficacy and safety. Chiral molecules, essential in drug development, exist in two enantiomeric forms with distinct biological activities. Synthesizing chiral, fluorine-containing drugs involves techniques like asymmetric synthesis to produce pure enantiomers, resulting in drugs with increased potency, selectivity, and reduced side effects. Understanding their mechanisms of action provides valuable insights into efficacy and safety. Reviewing recently FDA-approved chiral drugs offers insights into fluorine chemistry in drug development and future therapeutic innovations. Recent FDA approvals highlight the significance of chiral, fluorine-containing drugs in various therapeutic areas, enabling targeted and effective treatments. Analyzing these approvals reveals trends shaping drug development’s future. The article also addresses the need for more research into self-disproportionation of enantiomers (SDE) in chiral, fluorinated compounds and concerns about excessive fluorine levels. SDE can affect pharmaceutical product purity. Research into SDE in fluorinated compounds ensures drug quality. Additionally, fluorine’s widespread use raises environmental and health concerns, necessitating studies on long-term effects and mitigation strategies. |
| doi_str_mv | 10.33609/2708-129X.91.2.2025.55-90 |
| first_indexed | 2025-09-24T17:44:00Z |
| format | Article |
| fulltext |
55
UDC 546.26-162: 541.13:549.21 doi: 10.33609/2708-129X.91.2.2025.55-90
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALS
Jianlin Han1*, Alicja Wzorek,2 Gagan Dhawan3,4,*, Wei Zhang5,*, Alexander E. Sorochinsky6,*,
Daniel Baecker7*, Taizo Ono8, Karel D. Klika9, Vadim A. Soloshonok10,11*
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
3School of Allied Medical Sciences, Delhi Skill and Entrepreneurship University,
Dwarka, New Delhi-110077, India;
4 Department of Biomedical Science, Acharya Narendra Dev College, University of Delhi,
Kalkaji, New Delhi-110019, India;
5 Department of Chemistry, University of Massachusetts Boston,
Boston MA 02125, Unites States;
6 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry,
The National Academy of Sciences of Ukraine, Kyiv 02094, Ukraine;
7 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin,
Königin-Luise-Straße 2+4, 14195 Berlin, Germany;
8 National Institute of Advanced Industrial Science and Technology (AIST),
2266-98, Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463-8560, Japan;
9 Research and Development Center, Archer Daniels Midland,
1001 N Brush College Rd., Decatur, IL 62521, USA;
10 Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU,
Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain;
11 IKERBASQUE, Basque Foundation for Science,
María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain
email: vadimsoloshonok@gmail.com
Fluorine is a key element in drug design due to its ability to enhance metabolic stabili-
ty, binding affinity, and bioavailability. Fluorine’s properties lead to more stable drugs with
longer half-lives, reducing dosing frequency and improving patient compliance. Its small size
and high electronegativity also improve binding affinity, resulting in more effective treatments
with lower doses. For example, fluorine increases a compound’s ability to cross cell memb
ranes. This article highlights advancements in chiral, fluorine-containing pharmaceuticals
introduced over the past five years, focusing on their synthesis, therapeutic benefits, mecha-
nisms of action, and the impact of fluorine on efficacy and safety. Chiral molecules, essential
in drug development, exist in two enantiomeric forms with distinct biological activities. Syn-
thesizing chiral, fluorine-containing drugs involves techniques like asymmetric synthesis to
produce pure enantiomers, resulting in drugs with increased potency, selectivity, and reduced
side effects. Understanding their mechanisms of action provides valuable insights into effi-
cacy and safety. Reviewing recently FDA-approved chiral drugs offers insights into fluorine
56 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
chemistry in drug development and future therapeutic innovations. Recent FDA approvals
highlight the significance of chiral, fluorine-containing drugs in various therapeutic areas,
enabling targeted and effective treatments. Analyzing these approvals reveals trends shaping
drug development’s future. The article also addresses the need for more research into self-dis-
proportionation of enantiomers (SDE) in chiral, fluorinated compounds and concerns about
excessive fluorine levels. SDE can affect pharmaceutical product purity. Research into SDE in
fluorinated compounds ensures drug quality. Additionally, fluorine’s widespread use raises
environmental and health concerns, necessitating studies on long-term effects and mitigation
strategies.
Keywords: Fluorine, chirality, drug design, pharmaceuticals, self-disproportionation of
enantiomers, bioactivity.
INTRODUCTION. Pharmaceuticals play a
crucial role in modern medicine, significant-
ly enhancing the quality of life for millions of
people worldwide. They are essential for treat-
ing a wide range of diseases and conditions,
from chronic illnesses to acute infections, and
have revolutionized healthcare by providing
effective and targeted therapies [1–5].
One of the key factors in drug design and
development is chirality. The importance of
chirality cannot be overstated as the spatial
arrangement of atoms in a molecule can dras-
tically affect a drug’s efficacy and safety. Enan-
tiomers can have different biological activities,
often with one being therapeutically active
while the other may be inactive or even harm-
ful. Therefore, understanding and controlling
chirality is vital for developing safe and effec-
tive pharmaceuticals. It comes as no surprise
that over 70% of small-molecule drugs on the
market today are chiral [6–11].
Fluorine has emerged as a critical element
in drug design and development [12–14]. Its
unique chemical properties, such as high elec-
tronegativity and small size, allow it to form
strong bonds with carbon, enhancing the me
tabolic stability and binding affinity of drugs.
Fluorine can also improve the bioavailability
and pharmacokinetic profiles of pharmaceu-
ticals rendering them more effective [15–19].
However, the synthesis of fluorine-contain-
ing compounds presents significant challenges,
particularly in asymmetric synthesis. Achieving
the desired chirality in fluorine-containing mo
lecules requires sophisticated techniques and
precise control over reaction conditions. The
difficulties associated with these syntheses can
complicate the drug development process and
result in increased production costs [20–31].
Fluorine is also one of the most promi-
nent self-disproportionation of enantiomers
(SDE)-phoric groups [32–34] i.e., the abili-
ty to express strongly the SDE phenomenon
[35–37]. The SDE phenomenon leads to the
enrichment of one enantiomer over the oth-
er during synthesis when fractionation is in-
volved, which is crucial for producing enan-
tiomerically pure drugs [38–40]. Thus, SDE
tests are essential during the production of
chiral, fluorine-containing drugs to ensure the
desired enantiomeric purity and consequent
therapeutic efficacy [41, 42].
57https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Daniel Baecker, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 2 / Vol. 91
Despite its benefits, fluorine-containing
drugs have a dark side. Fluoride, a common
form of fluorine, is a poison that can accumu-
late in the body over time. Chronic exposure
to high levels of fluoride can lead to adverse
health effects, including dental and skele-
tal fluorosis. Therefore, the use of fluorine in
pharmaceuticals must be carefully managed to
balance its therapeutic advantages against po-
tential risks [43–49].
According to surveys published up to 2020
[12, 13, 50, 51], around 400 fluorine-contain-
ing pharmaceuticals have been approved by
the FDA. Reviews from 2020–2024 profiled 50
new fluorine-containing, small-molecule phar-
maceuticals [52–56]. Unsurprisingly, most of
these drugs (~75%) are chiral and have been
approved as specific enantiomers. For examp
le, highly grossing drugs such as Asciminib
(Scemblix™) 1 [57], Melflufen (Pepaxto™) 2 [58],
and Krazati™ (Adagrasib) 3 [59] are all chiral
(Fig. 1).
Figure 1. Examples of chiral, fluorine-containing compounds displaying stereogenic centers on residues of
tailor-made amino acids or related amino alcohols and diamines.
However, the fluorine atom in these molecules is situated quite far from the stereogenic
centers, consequently having minimal effects on their synthesis and chiral properties. Since most
approved chiral compounds are based on amino acids or related amino alcohols and diamines,
modern pharmaceuticals derived from tailor-made amino acids [60–65] and featuring fluorine
constitute a unique and rapidly growing segment of the small-molecule pharmaceutical market [56,
66–68].
In this review, we profile compounds approved by the FDA during the period 2020–2024
that display fluorine or fluoroalkyl groups directly bonded to stereogenic centers. These structural
features highlight the great impact fluorine can have on the asymmetric synthesis, chiro-optic,
physical, and biological properties of these molecules. This group of compounds (Fig. 2) include:
Fluoroestradiol F-18 (Cerianna™) 4, a radioactive diagnostic agent used in positron emission
tomography (PET) imaging to detect estrogen receptor-positive lesions in patients with recurrent or
metastatic breast cancer; Inqovi™ 5, a combination of a nucleoside metabolic inhibitor and a
cytidine deaminase inhibitor approved to treat adults with myelodysplastic syndromes including
chronic myelomonocytic leukemia; Belzutifan (Welireg™) 6, used to treat adults with von
Hippel–Lindau (VHL) disease who require therapy for associated renal cell carcinoma, central
nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not need
immediate surgery; Voranigo® (Vorasidenib) 7, an isocitrate dehydrogenase-1 and isocitrate
dehydrogenase-2 inhibitor prescribed to treat adults and pediatric patients aged 12 years or older
with Grade 2 astrocytoma or oligodendroglioma following surgery that have a susceptible isocitrate
dehydrogenase-1 or isocitrate dehydrogenase-2 mutation; Vivjoa™ (Oteseconazole) 8, an antifungal
medication used to reduce the risk of recurrent vulvovaginal candidiasis (RVVC) in females with a
history of RVVC who are not potentially reproductive; Sunlenca™ (Lenacapavir) 9, developed and
administered in combination with other antiretroviral medicines to treat adults with HIV-1 infection
who have received multiple HIV-1 medicines in the past and have the HIV-1 virus that is resistant to
many HIV-1 medicines; Voydeya® (Danicopan) 10, which inhibits complement Factor D that plays
a key role in the immune system’s alternative pathway and approved as an add-on therapy for adults
with paroxysmal nocturnal hemoglobinuria who experience ongoing anemia due to extravascular
hemolysis despite treatment with Ravulizumab (Ultomiris) or Eculizumab (Soliris); Jaypirca®
(Pirtobrutinib) 11, used to treat adults with relapsed or refractory mantle cell lymphoma, chronic
lymphocytic leukemia, and small lymphocytic lymphoma who have received at least two prior lines
of therapy, including a Bruton’s tyrosine kinase inhibitor and a BCL-2 inhibitor; and finally,
Figure 1. Examples of chiral, fluorine-containing compounds displaying stereogenic centers on resi-
dues of tailor-made amino acids or related amino alcohols and diamines.
However, the fluorine atom in these mole-
cules is situated quite far from the stereogenic
centers, consequently having minimal effects
on their synthesis and chiral properties. Since
most approved chiral compounds are based
on amino acids or related amino alcohols and
diamines, modern pharmaceuticals derived
from tailor-made amino acids [60–65] and fea-
turing fluorine constitute a unique and rapidly
growing segment of the small-molecule phar-
maceutical market [56, 66–68].
In this review, we profile compounds ap-
proved by the FDA during the period 2020–
2024 that display fluorine or fluoroalkyl groups
directly bonded to stereogenic centers. These
structural features highlight the great impact
fluorine can have on the asymmetric synthe-
sis, chiro-optic, physical, and biological pro
perties of these molecules. This group of com-
pounds (Fig. 2) include: Fluoroestradiol F-18
(Cerianna™) 4, a radioactive diagnostic agent
used in positron emission tomography (PET)
imaging to detect estrogen receptor-positive
lesions in patients with recurrent or metastatic
58 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
breast cancer; Inqovi™ 5, a combination of a
nucleoside metabolic inhibitor and a cytidine
deaminase inhibitor approved to treat adults
with myelodysplastic syndromes including
chronic myelomonocytic leukemia; Belzuti-
fan (Welireg™) 6, used to treat adults with von
Hippel–Lindau (VHL) disease who require
therapy for associated renal cell carcinoma,
central nervous system hemangioblastomas,
or pancreatic neuroendocrine tumors that
do not need immediate surgery; Voranigo®
(Vorasidenib) 7, an isocitrate dehydrogenase-1
and isocitrate dehydrogenase-2 inhibitor pre-
scribed to treat adults and pediatric patients
aged 12 years or older with Grade 2 astrocy-
toma or oligodendroglioma following surgery
that have a susceptible isocitrate dehydroge-
nase-1 or isocitrate dehydrogenase-2 muta-
tion; Vivjoa™ (Oteseconazole) 8, an antifungal
medication used to reduce the risk of recurrent
vulvovaginal candidiasis (RVVC) in females
with a history of RVVC who are not potential-
ly reproductive; Sunlenca™ (Lenacapavir) 9,
developed and administered in combination
with other antiretroviral medicines to treat
adults with HIV-1 infection who have received
multiple HIV-1 medicines in the past and have
the HIV-1 virus that is resistant to many HIV-1
medicines; Voydeya® (Danicopan) 10, which
inhibits complement Factor D that plays a
key role in the immune system’s alternative
pathway and approved as an add-on therapy
for adults with paroxysmal nocturnal hemo-
globinuria who experience ongoing anemia
due to extravascular hemolysis despite treat-
ment with Ravulizumab (Ultomiris) or Eculi-
zumab (Soliris); Jaypirca® (Pirtobrutinib) 11,
used to treat adults with relapsed or refractory
mantle cell lymphoma, chronic lymphocytic
leukemia, and small lymphocytic lymphoma
who have received at least two prior lines of
therapy, including a Bruton’s tyrosine kinase
inhibitor and a BCL-2 inhibitor; and finally,
Itovebi® (Inavolisib) 12 prescribed in com-
bination with Palbociclib and Fulvestrant to
treat adults with hormone receptor-positive,
human epidermal growth factor receptor
2-negative breast cancer that has an abnor-
mal phosphatidylinositol-3-kinase catalytic
subunit alpha gene, and has spread to near-
by tissue or lymph nodes (locally advanced),
or to other parts of the body (metastatic),
and has returned after hormone (endocrine)
therapy.
Fluoroestradiol F-18 (Cerianna™) 4.
Estrogen receptors serve as crucial prog-
nostic biomarkers enabling the visualization
of tumor progression/regression or facilitating
targeted hormone therapy. Molecules labeled
with radioactive 18F can accumulate in can-
cerous tissues expressing estrogen receptors,
providing powerful contrast agents for diagno-
sis. These agents also allow for the assessment
of estrogen receptor expression heterogeneity
without the need for biopsy [69, 70]. Nume
rous 18F-labeled radiopharmaceuticals have
been documented in the literature for PET
imaging [71–74]. Incorporating a small, high-
ly electronegative fluorine atom as a hydro-
gen mimic can enhance pharmacokinetic and
physicochemical properties, including binding
affinity, metabolic stability, and bioavailabili-
ty. The goal of developing high-affinity, estro-
gen receptor-targeted diagnostic agents capa-
ble of crossing the blood–brain barrier led to
the synthesis of radioactive fluoroestradiols.
These molecules exhibit high binding affinity
for estrogen receptors and exceptional tissue
permeability, including the blood–brain barri-
er [75, 76].
59https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Daniel Baecker, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 2 / Vol. 91
Figure 2. The structures of pharmaceuticals featuring fluorine or fluoroalkyl groups directly bonded
to stereogenic centers.
Fluoroestradiol F-18 4 (also known as
[18F]16α-fluoroestradiol) was developed by
Zionexa USA and brought to market by Pet-
net Solutions, Zionexa USA’s manufacturing
arm and exclusive distributor in the USA.
On May 20th, 2020, the FDA approved Fluo-
roestradiol F-18 4 as a radioactive diagnostic
agent for the non-invasive monitoring of es-
trogen receptor-positive lesions during PET
scans in patients with recurrent or metastatic
breast cancer. Fluoroestradiol F-18 4 enables
the detection of multiple tumor sites without
causing patient discomfort. FDA’s approval
was primarily based on data from two pub-
lished clinical trials [77, 78]. In these trials, all
patients with recurrent or metastatic estrogen
60 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
receptor-positive breast cancer received Fluo-
roestradiol F-18 4 prior to their PET scans and
the results compared to tissue biopsy data.
Kiesewetter et al. pioneered synthetic pro-
cedures for preparing 18F-labeled estrogens
[78] and subsequently other research groups
[79, 80] successfully synthesized fluoroestra-
diols. The 18F radioisotope used in these syn-
theses is generated from 18O-H2O [79]. The
synthesis of Fluoroestradiol F-18 4 begins with
compound 13 (Scheme 1), activated for nu-
cleophilic substitution, which is reacted with
K18F in anhydrous acetonitrile at 110 °C for 15
minutes to yield intermediate 14. Following 18F
fluorination, the solution is then treated with
2 N HCl followed by neutralization with aque-
ous NaHCO3. The crude product 4 is purified
by semi-preparative HPLC using 50% aqueous
ethanol as eluent [81]. The radiochemical yield
can be as high as 43%.
high binding affinity for estrogen receptors and exceptional tissue permeability, including the
blood–brain barrier [75, 76].
Fluoroestradiol F-18 4 (also known as [18F]16α-fluoroestradiol) was developed by Zionexa
USA and brought to market by Petnet Solutions, Zionexa USA’s manufacturing arm and exclusive
distributor in the USA. On May 20th, 2020, the FDA approved Fluoroestradiol F-18 4 as a
radioactive diagnostic agent for the non-invasive monitoring of estrogen receptor-positive lesions
during PET scans in patients with recurrent or metastatic breast cancer. Fluoroestradiol F-18 4
enables the detection of multiple tumor sites without causing patient discomfort. FDA’s approval
was primarily based on data from two published clinical trials [77, 78]. In these trials, all patients
with recurrent or metastatic estrogen receptor-positive breast cancer received Fluoroestradiol F-18 4
prior to their PET scans and the results compared to tissue biopsy data.
Kiesewetter et al. pioneered synthetic procedures for preparing 18F-labeled estrogens [78]
and subsequently other research groups [79, 80] successfully synthesized fluoroestradiols. The 18F
radioisotope used in these syntheses is generated from 18O-H2O [79]. The synthesis of
Fluoroestradiol F-18 4 begins with compound 13 (Scheme 1), activated for nucleophilic substitution,
which is reacted with K18F in anhydrous acetonitrile at 110 °C for 15 minutes to yield intermediate
14. Following 18F fluorination, the solution is then treated with 2 N HCl followed by neutralization
with aqueous NaHCO3. The crude product 4 is purified by semi-preparative HPLC using 50%
aqueous ethanol as eluent [81]. The radiochemical yield can be as high as 43%.
Scheme 1. The synthesis of Fluoroestradiol F-18 4.
Decitabine/Cedazuridine (Inqovi™) 5.
Inqovi 5, a fixed-dose combination of Decitabine 15 and Cedazuridine 17, was developed by Astex
Pharmaceuticals Inc., a subsidiary of Otsuka Pharmaceuticals. The FDA approved it on July 7th,
2020 for treating myelodysplastic syndromes and chronic myelomonocytic leukemia. Decitabine 15
(Fig. 3), a hypomethylating nucleoside metabolic inhibitor also known as a cytidine antimetabolite,
incorporates itself into DNA after metabolism, inhibiting DNA methyltransferase in proliferating
cancer cells. This leads to the reactivation of silenced tumor suppressor genes and apoptosis of
cancerous cells, restoring normal cellular differentiation and proliferation [82–84].
Figure 3. The structures of Decitabine 15, tetrahydrouridine (16), and Cedazuridine 17.
high binding affinity for estrogen receptors and exceptional tissue permeability, including the
blood–brain barrier [75, 76].
Fluoroestradiol F-18 4 (also known as [18F]16α-fluoroestradiol) was developed by Zionexa
USA and brought to market by Petnet Solutions, Zionexa USA’s manufacturing arm and exclusive
distributor in the USA. On May 20th, 2020, the FDA approved Fluoroestradiol F-18 4 as a
radioactive diagnostic agent for the non-invasive monitoring of estrogen receptor-positive lesions
during PET scans in patients with recurrent or metastatic breast cancer. Fluoroestradiol F-18 4
enables the detection of multiple tumor sites without causing patient discomfort. FDA’s approval
was primarily based on data from two published clinical trials [77, 78]. In these trials, all patients
with recurrent or metastatic estrogen receptor-positive breast cancer received Fluoroestradiol F-18 4
prior to their PET scans and the results compared to tissue biopsy data.
Kiesewetter et al. pioneered synthetic procedures for preparing 18F-labeled estrogens [78]
and subsequently other research groups [79, 80] successfully synthesized fluoroestradiols. The 18F
radioisotope used in these syntheses is generated from 18O-H2O [79]. The synthesis of
Fluoroestradiol F-18 4 begins with compound 13 (Scheme 1), activated for nucleophilic substitution,
which is reacted with K18F in anhydrous acetonitrile at 110 °C for 15 minutes to yield intermediate
14. Following 18F fluorination, the solution is then treated with 2 N HCl followed by neutralization
with aqueous NaHCO3. The crude product 4 is purified by semi-preparative HPLC using 50%
aqueous ethanol as eluent [81]. The radiochemical yield can be as high as 43%.
Scheme 1. The synthesis of Fluoroestradiol F-18 4.
Decitabine/Cedazuridine (Inqovi™) 5.
Inqovi 5, a fixed-dose combination of Decitabine 15 and Cedazuridine 17, was developed by Astex
Pharmaceuticals Inc., a subsidiary of Otsuka Pharmaceuticals. The FDA approved it on July 7th,
2020 for treating myelodysplastic syndromes and chronic myelomonocytic leukemia. Decitabine 15
(Fig. 3), a hypomethylating nucleoside metabolic inhibitor also known as a cytidine antimetabolite,
incorporates itself into DNA after metabolism, inhibiting DNA methyltransferase in proliferating
cancer cells. This leads to the reactivation of silenced tumor suppressor genes and apoptosis of
cancerous cells, restoring normal cellular differentiation and proliferation [82–84].
Figure 3. The structures of Decitabine 15, tetrahydrouridine (16), and Cedazuridine 17.
Scheme 1. The synthesis of Fluoroestradiol F-18 4.
Decitabine/Cedazuridine (Inqovi™) 5.
Inqovi 5, a fixed-dose combination of Deci
tabine 15 and Cedazuridine 17, was developed
by Astex Pharmaceuticals Inc., a subsidiary of
Otsuka Pharmaceuticals. The FDA approved it
on July 7th, 2020 for treating myelodysplastic
syndromes and chronic myelomonocytic leu-
kemia. Decitabine 15 (Fig. 3), a hypomethylat-
ing nucleoside metabolic inhibitor also known
as a cytidine antimetabolite, incorporates itself
into DNA after metabolism, inhibiting DNA
methyltransferase in proliferating cancer cells.
This leads to the reactivation of silenced tumor
suppressor genes and apoptosis of cancerous
cells, restoring normal cellular differentiation
and proliferation [82–84].
Figure 3. The structures of Decitabine 15, tetrahydrouridine (16), and Cedazuridine 17.
However, its oral bioavailability is limit-
ed due to first-pass metabolism by cytidine
deaminase in the gut, kidney, and liver. To en-
hance oral bioavailability and reduce gastro-
61https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Daniel Baecker, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 2 / Vol. 91
intestinal toxicity associated with high-dose
Decitabine 15, the cytidine deaminase inhibi-
tor tetrahydrouridine (16) is co-administered.
This approach was patented by Otsuka Phar-
maceutical Co. Ltd [85].
Cytidine and deoxycytidine are both sub-
strates for CDA, demonstrating that the
2’-hydroxy group of cytidine does not play a
specific role in binding [86, 87]. This was fur-
ther confirmed by the co-crystal structure
of mouse CDA with tetrahydrouridine (16),
which revealed that only the 3’-OH and 5’-
OH groups of the sugar form critical hydro-
gen bonds with specific amino acid residues
in the active site [88]. Later studies showed
that 2’-deoxytetrahydrouridine is more potent
than tetrahydrouridine (16) [89]. To enhance
acid stability and systemic exposure, Ferraris
et al. developed 2’-fluorinated tetrahydrouri-
dine derivatives, such as Cedazuridine 17, as
next-generation CDA inhibitors that prevent
the breakdown and enhance the efficacy of
Decitabine 15 in primates [90]. The acid-stable
CDA inhibitor Cedazuridine 17 demonstrated
improved stability in acidic environments and
better oral bioavailability in rhesus monkeys
compared to tetrahydrouridine (16) and its
analogs. Co-administration with the CDA sub-
strate Decitabine 15 resulted in increased plas-
ma levels of Decitabine 15 in primates [90–93].
The orientation of the 4-hydroxyl group in 16
is crucial for CDA inhibition, explaining the
difference in potency between its isomers.
A similar binding mode and interaction with
the active-site zinc atom were observed for
fluorinated analogs. The FDA approved Ce-
dazuridine 17 for combination with Deci
tabine 15, marketed by Astex Pharmaceuticals
Inc. under the name Inqovi™ 5. This approval
was based on phase III studies evaluating sys-
temic exposure to Decitabine 15 from Inqovi™
5 as well as its safety and efficacy [94].
The fluorinated analog of 16, Cedazuridine
17, is prepared using the procedures reported
by the Sturla group [90] for the synthesis of
2′-deoxytetrahydrouridine. As illustrated in
Scheme 2, gemcitabine 18 served as starting
material. The first step is rhodium-catalyzed
hydrogenation of 18 to form 2′-deoxy-2′,2′-di-
fluorodihydrouridine (19). This is followed by
reduction of 19 with NaBH4 to give a mixture
of difluorinated tetrahydrouridine 17 along
with diastereomer 21 as well as the 4-deoxy
byproduct 20. Preparative HPLC is used to iso-
late enantiomerically pure Cedazuridine 17 in
less than 30% yield.
However, its oral bioavailability is limited due to first-pass metabolism by cytidine
deaminase in the gut, kidney, and liver. To enhance oral bioavailability and reduce gastrointestinal
toxicity associated with high-dose Decitabine 15, the cytidine deaminase inhibitor tetrahydrouridine
(16) is co-administered. This approach was patented by Otsuka Pharmaceutical Co. Ltd [85].
Cytidine and deoxycytidine are both substrates for CDA, demonstrating that the 2'-hydroxy group
of cytidine does not play a specific role in binding [86, 87]. This was further confirmed by the
co-crystal structure of mouse CDA with tetrahydrouridine (16), which revealed that only the 3'-OH
and 5'-OH groups of the sugar form critical hydrogen bonds with specific amino acid residues in the
active site [88]. Later studies showed that 2'-deoxytetrahydrouridine is more potent than
tetrahydrouridine (16) [89]. To enhance acid stability and systemic exposure, Ferraris et al.
developed 2'-fluorinated tetrahydrouridine derivatives, such as Cedazuridine 17, as next-generation
CDA inhibitors that prevent the breakdown and enhance the efficacy of Decitabine 15 in primates
[90]. The acid-stable CDA inhibitor Cedazuridine 17 demonstrated improved stability in acidic
environments and better oral bioavailability in rhesus monkeys compared to tetrahydrouridine (16)
and its analogs. Co-administration with the CDA substrate Decitabine 15 resulted in increased
plasma levels of Decitabine 15 in primates [90–93]. The orientation of the 4-hydroxyl group in 16 is
crucial for CDA inhibition, explaining the difference in potency between its isomers. A similar
binding mode and interaction with the active-site zinc atom were observed for fluorinated analogs.
The FDA approved Cedazuridine 17 for combination with Decitabine 15, marketed by Astex
Pharmaceuticals Inc. under the name Inqovi™ 5. This approval was based on phase III studies
evaluating systemic exposure to Decitabine 15 from Inqovi™ 5 as well as its safety and efficacy
[94].
The fluorinated analog of 16, Cedazuridine 17, is prepared using the procedures reported by
the Sturla group [90] for the synthesis of 2′-deoxytetrahydrouridine. As illustrated in Scheme 2,
gemcitabine 18 served as starting material. The first step is rhodium-catalyzed hydrogenation of 18
to form 2′-deoxy-2′,2′-difluorodihydrouridine (19). This is followed by reduction of 19 with NaBH4
to give a mixture of difluorinated tetrahydrouridine 17 along with diastereomer 21 as well as the
4-deoxy byproduct 20. Preparative HPLC is used to isolate enantiomerically pure Cedazuridine 17
in less than 30% yield.
Scheme 2. The synthesis of Cedazuridine 17.
Belzutifan (Welireg™) 6.
VHL disease is a rare genetic disorder that significantly increases the risk of developing multiple
organ cancers [96, 97]. Renal cell carcinoma is often linked to the inactivation of the VHL protein, a
crucial component of an E3 ubiquitin ligase complex responsible for protein degradation. The VHL
protein primarily regulates hypoxia-inducible factors (HIF). HIF-2α, in particular, plays a vital role
Scheme 2. The synthesis of Cedazuridine 17.
62 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
Belzutifan (Welireg™) 6.
VHL disease is a rare genetic disorder that
significantly increases the risk of developing
multiple organ cancers [96, 97]. Renal cell car-
cinoma is often linked to the inactivation of
the VHL protein, a crucial component of an
E3 ubiquitin ligase complex responsible for
protein degradation. The VHL protein prima
rily regulates hypoxia-inducible factors (HIF).
HIF-2α, in particular, plays a vital role in renal
cell carcinoma. Oxygen-dependent HIF pro-
lyl-hydroxylase enzymes control the activity of
HIF-2α by hydroxylating specific proline resi-
dues, creating a recognition site for VHL pro-
tein and targeting it for rapid proteasomal deg-
radation. In patients with renal cell carcinoma,
defective or absent VHL protein leads to the
accumulation and transcriptional activation of
HIF-2α [98, 99].
Several research groups have demonstrated
that small molecules can allosterically inhibit
the inner pocket of HIF-2α, reducing its pro-
tein–protein interaction with ARNT and there-
by inhibiting transcriptional activity [100–
103]. The first-generation HIF-2α inhibitor 22
(Fig. 4) developed through structure-guided
studies showed clinical activity in advanced re-
nal cell carcinoma patients [104]. However, its
use was limited due to extensive phase 2 meta
bolism via glucuronide conjugation [105–107].
in renal cell carcinoma. Oxygen-dependent HIF prolyl-hydroxylase enzymes control the activity of
HIF-2α by hydroxylating specific proline residues, creating a recognition site for VHL protein and
targeting it for rapid proteasomal degradation. In patients with renal cell carcinoma, defective or
absent VHL protein leads to the accumulation and transcriptional activation of HIF-2α [98, 99].
Several research groups have demonstrated that small molecules can allosterically inhibit the inner
pocket of HIF-2α, reducing its protein–protein interaction with ARNT and thereby inhibiting
transcriptional activity [100–103]. The first-generation HIF-2α inhibitor 22 (Fig. 4) developed
through structure-guided studies showed clinical activity in advanced renal cell carcinoma patients
[104]. However, its use was limited due to extensive phase 2 metabolism via glucuronide
conjugation [105–107].
Figure 4. The structures of Belzutifan 6 and its structural precursor 22.
Structural modification of compound 22 to Belzutifan 6, achieved by altering its geminal
difluoro group to a vicinal difluoro moiety, resulted in enhanced potency, reduced lipophilicity, and
an improved ADME profile with decreased glucuronide conjugate formation. The FDA has
approved Belzutifan (Welireg™) 6, a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor developed
by Merck, for treating cancers associated with VHL disease that do not require immediate surgery.
As shown in Figure 4, Belzutifan 6 is a chiral compound with three adjacent stereogenic carbon
atoms and three fluorine substitutions consisting of two C(sp3)–F bonds and one C(sp2)–F bond.
The synthesis of Belzutifan 6 (Scheme 3) begins with enantiomerically pure fluorinated
alcohol 22 as starting material [108–110]. Compound 22 is converted into ester 23 in 87% yield by
reaction with acetic anhydride in the presence of 4-(dimethylamino)pyridine and triethylamine.
Ester 23 is then brominated by a radical reaction initiated by azodiisobutyronitrile with the use of
N-bromosuccinimide at 80 °C for 3 hours giving rise to compound 24 in 65% yield. The treatment
of 24 with AgClO4 at 70 °C for 2 hours allows for the substitution of bromine by a hydroxy group
furnishing alcohol 25 in low 23% yield but with the required configuration of the stereogenic
centers. Subsequently, stereoselective fluorination reaction of 25 with (diethylamino)sulfur
trifluoride at −78 °C provides the vicinal difluoro compound 26 in 74% yield. Finally, the ester
group in compound 26 is hydrolyzed by 0.5 N LiOH solution at 0 °C to afford Belzutifan 6.
Figure 4. The structures of Belzutifan 6 and its structural precursor 22.
Structural modification of compound 22
to Belzutifan 6, achieved by altering its gemi-
nal difluoro group to a vicinal difluoro moiety,
resulted in enhanced potency, reduced lipo-
philicity, and an improved ADME profile with
decreased glucuronide conjugate formation.
The FDA has approved Belzutifan (Welireg™) 6,
a hypoxia-inducible factor-2 alpha (HIF-2α)
inhibitor developed by Merck, for treating can-
cers associated with VHL disease that do not
require immediate surgery. As shown in Fi
gure 4, Belzutifan 6 is a chiral compound with
three adjacent stereogenic carbon atoms and
three fluorine substitutions consisting of two
C(sp3)–F bonds and one C(sp2)–F bond.
The synthesis of Belzutifan 6 (Scheme 3)
begins with enantiomerically pure fluorinat-
ed alcohol 22 as starting material [108–110].
Compound 22 is converted into ester 23 in
87% yield by reaction with acetic anhydride
in the presence of 4-(dimethylamino)pyridine
and triethylamine. Ester 23 is then brominated
by a radical reaction initiated by azodiisobuty-
ronitrile with the use of N-bromosuccinimide
at 80 °C for 3 hours giving rise to compound
24 in 65% yield. The treatment of 24 with
AgClO4 at 70 °C for 2 hours allows for the sub-
stitution of bromine by a hydroxy group fur-
nishing alcohol 25 in low 23% yield but with
the required configuration of the stereogenic
63https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Daniel Baecker, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 2 / Vol. 91
centers. Subsequently, stereoselective fluorina-
tion reaction of 25 with (diethylamino)sulfur
trifluoride at −78 °C provides the vicinal difluo
ro compound 26 in 74% yield. Finally, the ester
group in compound 26 is hydrolyzed by 0.5 N
LiOH solution at 0 °C to afford Belzutifan 6.
Scheme 3. The synthesis of Belzutifan 6. Legend: AIBN, azodiisobutyronitrile; DAST, (diethylami-
no)sulfur trifluoride; DMAP, 4-(dimethylamino)pyridine; NBS, N-bromosuccinimide; THF, tetrahydro
furan.
Scheme 3. The synthesis of Belzutifan 6. Legend: AIBN, azodiisobutyronitrile; DAST, (diethylamino)sulfur
trifluoride; DMAP, 4-(dimethylamino)pyridine; NBS, N-bromosuccinimide; THF, tetrahydrofuran.
Voranigo® (Vorasidenib) 7.
Gliomas are the most common malignant brain tumors in adults [111, 112]. A subset of these tumors
harbor mutations in the genes encoding the metabolic enzymes IDH1 or IDH2 [112–118]. Gliomas
with IDH1 or IDH2 mutations and an unbalanced translocation (1p/19q codeletion) are classified as
oligodendrogliomas, while IDH-mutant gliomas without 1p/19q codeletion are defined as
astrocytomas [119, 120]. These tumors are notorious for infiltrating normal brain tissue and, over
time, progressing into more aggressive forms characterized by features such as neovascularization
[121, 122]. Vorasidenib 7, an orally administered, brain-penetrant drug with potential antineoplastic
activity, acts as a dual inhibitor of the enzymes IDH1 and IDH2. By inhibiting the activity of mutant
IDH1 and IDH2 enzymes in cancer cells, Vorasidenib 7 effectively slows the progression of brain
tumors. In August 2024, Vorasidenib 7 received FDA approval for the treatment of Grade 2
astrocytoma or oligodendroglioma with susceptible IDH1 or IDH2 mutations [123].
Vorasidenib 7 demonstrates superior brain penetration and higher drug exposure compared
to Enasidenib 28 (Fig. 5), a known trifluoromethyl-containing achiral drug [124–126]. In contrast to
28, Vorasidenib 7 is a chiral triazine derivative with two chiral centers both of R configuration.
Structure–activity relationship studies revealed that introducing two trifluoromethyl groups led to
excellent inhibition in the neurosphere TS603 cell assay using IDH1-R132H/IDH1-wild type cells
with an IC50 of 0.6 nmol/L [124]. Replacing the trifluoromethyl groups with cyclopropyl groups
(i.e., compound 27) resulted in a loss of inhibitory potency. While the racemate, 29, displayed
nanomolar potency, Vorasidenib 7 with R,R absolute configuration exhibited approximately ten-fold
greater potency in cell assays [124]. Treatment with Vorasidenib 7 reduced the concentration of the
oncometabolite 2-hydroxyglutarate which is linked to the reversal of gene expression and epigenetic
alterations commonly observed in gliomas with IDH mutations [127–129].
Voranigo® (Vorasidenib) 7.
Gliomas are the most common malignant
brain tumors in adults [111, 112]. A subset of
these tumors harbor mutations in the genes
encoding the metabolic enzymes IDH1 or
IDH2 [112–118]. Gliomas with IDH1 or IDH2
mutations and an unbalanced translocation
(1p/19q codeletion) are classified as oligoden-
drogliomas, while IDH-mutant gliomas with-
out 1p/19q codeletion are defined as astrocy-
tomas [119, 120]. These tumors are notorious
for infiltrating normal brain tissue and, over
time, progressing into more aggressive forms
characterized by features such as neovascu-
larization [121, 122]. Vorasidenib 7, an orally
administered, brain-penetrant drug with po-
tential antineoplastic activity, acts as a dual in-
hibitor of the enzymes IDH1 and IDH2. By in-
hibiting the activity of mutant IDH1 and IDH2
enzymes in cancer cells, Vorasidenib 7 effec-
tively slows the progression of brain tumors.
In August 2024, Vorasidenib 7 received FDA
approval for the treatment of Grade 2 astrocy-
toma or oligodendroglioma with susceptible
IDH1 or IDH2 mutations [123].
Vorasidenib 7 demonstrates superior brain
penetration and higher drug exposure com-
pared to Enasidenib 28 (Fig. 5), a known tri
fluoromethyl-containing achiral drug [124–
126]. In contrast to 28, Vorasidenib 7 is a chiral
64 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
triazine derivative with two chiral centers both
of R configuration. Structure–activity rela-
tionship studies revealed that introducing two
trifluoromethyl groups led to excellent inhibi-
tion in the neurosphere TS603 cell assay using
IDH1-R132H/IDH1-wild type cells with an IC50
of 0.6 nmol/L [124]. Replacing the trifluorome-
thyl groups with cyclopropyl groups (i.e., com-
pound 27) resulted in a loss of inhibitory po-
tency. While the racemate, 29, displayed nano-
molar potency, Vorasidenib 7 with R,R absolute
configuration exhibited approximately ten-fold
greater potency in cell assays [124]. Treatment
with Vorasidenib 7 reduced the concentration
of the oncometabolite 2-hydroxyglutarate which
is linked to the reversal of gene expression and
epigenetic alterations commonly observed in
gliomas with IDH mutations [127–129].
Figure 5. The structures of Vorasidenib 7 and its structural 27 and 28 and optical 29 analogs.
Figure 5. The structures of Vorasidenib 7 and its structural 27 and 28 and optical 29 analogs.
Vorasidenib 7 works by reducing the production of 2-hydroxyglutarate, which inhibits
2-hydroxyglutarate-mediated signaling. This action restores cellular differentiation and inhibits
cellular proliferation in mIDH-mutant tumor cells. As a result, Vorasidenib 7 effectively treats
certain forms of glioma by slowing tumor growth and delaying relapse [130–132].
The synthesis of Vorasidenib 7 (Scheme 4) [133] begins with the cyclization of bi-urea with
methyl 6-chloropicolinate 30 using NaOEt as a base to furnish the 1,3,5-triazine intermediate 31.
Compound 31 is then treated with POCl3 and PCl5 to yield the 2,4-dichloro-1,3,5-triazine
compound 32. The reaction of 32 with (R)-1,1,1-trifluoropropan-2-amine HCl salt (33) in the
presence of diisopropylethylamine [134] at 95–100 ºC for 20 hours resulted in the formation of
Vorasidenib 7 as an off-white solid after purification by crystallization. It should be noted that the
key chiral, fluorinated compound in this synthesis, (R)-1,1,1-trifluoropropan-2-amine [135–137]
and related compounds featuring a trifluoromethyl group in the α position relative to the amino
group, are readily available via biomimetic transamination of the corresponding keto compounds
[138–141].
Vorasidenib 7 works by reducing the pro-
duction of 2-hydroxyglutarate, which inhibits
2-hydroxyglutarate-mediated signaling. This
action restores cellular differentiation and in-
hibits cellular proliferation in mIDH-mutant
tumor cells. As a result, Vorasidenib 7 effec-
tively treats certain forms of glioma by slowing
tumor growth and delaying relapse [130–132].
The synthesis of Vorasidenib 7 (Scheme 4)
[133] begins with the cyclization of bi-urea with
methyl 6-chloropicolinate 30 using NaOEt as a
base to furnish the 1,3,5-triazine intermediate
31. Compound 31 is then treated with POCl3
and PCl5 to yield the 2,4-dichloro-1,3,5-tria
zine compound 32. The reaction of 32 with
(R)-1,1,1-trifluoropropan-2-amine HCl salt
(33) in the presence of diisopropylethylamine
[134] at 95–100 ºC for 20 hours resulted in
the formation of Vorasidenib 7 as an off-white
solid after purification by crystallization. It
65https://ucj.org.ua
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should be noted that the key chiral, fluorinat-
ed compound in this synthesis, (R)-1,1,1-trif-
luoropropan-2-amine [135–137] and related
compounds featuring a trifluoromethyl group
in the α position relative to the amino group,
are readily available via biomimetic transami
nation of the corresponding keto compounds
[138–141].
Figure 5. The structures of Vorasidenib 7 and its structural 27 and 28 and optical 29 analogs.
Vorasidenib 7 works by reducing the production of 2-hydroxyglutarate, which inhibits
2-hydroxyglutarate-mediated signaling. This action restores cellular differentiation and inhibits
cellular proliferation in mIDH-mutant tumor cells. As a result, Vorasidenib 7 effectively treats
certain forms of glioma by slowing tumor growth and delaying relapse [130–132].
The synthesis of Vorasidenib 7 (Scheme 4) [133] begins with the cyclization of bi-urea with
methyl 6-chloropicolinate 30 using NaOEt as a base to furnish the 1,3,5-triazine intermediate 31.
Compound 31 is then treated with POCl3 and PCl5 to yield the 2,4-dichloro-1,3,5-triazine
compound 32. The reaction of 32 with (R)-1,1,1-trifluoropropan-2-amine HCl salt (33) in the
presence of diisopropylethylamine [134] at 95–100 ºC for 20 hours resulted in the formation of
Vorasidenib 7 as an off-white solid after purification by crystallization. It should be noted that the
key chiral, fluorinated compound in this synthesis, (R)-1,1,1-trifluoropropan-2-amine [135–137]
and related compounds featuring a trifluoromethyl group in the α position relative to the amino
group, are readily available via biomimetic transamination of the corresponding keto compounds
[138–141].
Scheme 4. The synthesis of Vorasidenib 7. Legend: DIPEA, diisopropylethylamine.
VivjoaTM (Oteseconazole) 8.
Oteseconazole 8, a potent oral antifungal
agent developed by Mycovia Pharmaceuticals,
belongs to the class of tetrazole antifungal agents
[142]. It inhibits cytochrome P450 (CYP51) by
disrupting the formation and integrity of the
fungal cell membrane. In studies on Candida
albicans cells, 8’s binding strength to CYP51
was found to be similar to other azole antifun-
gal agents, including Fluconazole, demonstrat-
ing tight binding inhibition. However, unlike
other azole antibacterial agents, Otesecona-
zole 8 does not bind to human CYP51 or inhi
bit its activity [143, 144]. Research confirmed
8’s effectiveness in treating initial episodes of
VVC and highlighted its superior efficacy and
safety in treating RVVC compared to the cur-
rent standard care drug, Fluconazole, for VVC
[145]. Oteseconazole 8 is a chiral compound
featuring a difluoromethyl pyridine unit bond-
ed to the stereogenic carbon, a tetrazole hete
rocyclic moiety, a difluorophenyl group at the
chiral carbinol center, and a trifluoroethoxy
group representing the third case of fluorina-
tion in this molecule. Structure–activity rela-
tionship studies by Viamet Pharmaceuticals
Inc. revealed that replacing the trifluoroethyl
ether with a chloro group in compound 34
(Fig. 6) led to a decrease in inhibitory activity
against Trichophyton rubrum with the MIC in-
creasing from < 0.001 to 0.004 µM. Addition-
ally, Oteseconazole 8 demonstrated high selec-
tivity for CYP3A4 vs. T. rubrum [146].
66 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
Figure 6. The structures of Oteseconazole 8 and its non-fluorinated analog 34.
Scheme 4. The synthesis of Vorasidenib 7. Legend: DIPEA, diisopropylethylamine.
VivjoaTM (Oteseconazole) 8.
Oteseconazole 8, a potent oral antifungal agent developed by Mycovia Pharmaceuticals, belongs to
the class of tetrazole antifungal agents [142]. It inhibits cytochrome P450 (CYP51) by disrupting
the formation and integrity of the fungal cell membrane. In studies on Candida albicans cells, 8’s
binding strength to CYP51 was found to be similar to other azole antifungal agents, including
Fluconazole, demonstrating tight binding inhibition. However, unlike other azole antibacterial
agents, Oteseconazole 8 does not bind to human CYP51 or inhibit its activity [143, 144]. Research
confirmed 8’s effectiveness in treating initial episodes of VVC and highlighted its superior efficacy
and safety in treating RVVC compared to the current standard care drug, Fluconazole, for VVC
[145]. Oteseconazole 8 is a chiral compound featuring a difluoromethyl pyridine unit bonded to the
stereogenic carbon, a tetrazole heterocyclic moiety, a difluorophenyl group at the chiral carbinol
center, and a trifluoroethoxy group representing the third case of fluorination in this molecule.
Structure–activity relationship studies by Viamet Pharmaceuticals Inc. revealed that replacing the
trifluoroethyl ether with a chloro group in compound 34 (Fig. 6) led to a decrease in inhibitory
activity against Trichophyton rubrum with the MIC increasing from < 0.001 to 0.004 M.
Additionally, Oteseconazole 8 demonstrated high selectivity for CYP3A4 vs. T. rubrum [146].
Figure 6. The structures of Oteseconazole 8 and its non-fluorinated analog 34.
On April 26th, 2022 the FDA approved Vivjoa™ (Oteseconazole) 8 as an oral antifungal
drug to reduce the incidence of recurrent RVVC in women with a history of RVVC who are not
potentially reproductive. This makes it the first and only drug approved by the FDA specifically for
RVVC [142].
The synthesis of Oteseconazole 8 is presented in Scheme 5. 2,5-Dibromopyridine is reacted
with difluorobromoethyl acetate in the presence of Cu to yield the coupling product 35. Compound
35 is next reacted with tetrazol-1-ethyl acetate to furnish the Claisen reaction product keto ester 36.
The next step involves the hydrolysis of the ester function followed by the decarboxylation of the
carboxylic group to give ketone 37. The p-ethoxy phenyl group is incorporated by Suzuki coupling
of 37 with dioxaborolane 38. Finally, compound 39 is reacted with the Grignard reagent derived
from 2,4-difluorobromobenzene in the presence of chiral ligand (R)-BINOL to yield Oteseconazole
8 [147].
On April 26th, 2022 the FDA approved
Vivjoa™ (Oteseconazole) 8 as an oral antifun-
gal drug to reduce the incidence of recurrent
RVVC in women with a history of RVVC who
are not potentially reproductive. This makes it
the first and only drug approved by the FDA
specifically for RVVC [142].
The synthesis of Oteseconazole 8 is present-
ed in Scheme 5. 2,5-Dibromopyridine is reacted
with difluorobromoethyl acetate in the presence
of Cu to yield the coupling product 35. Com-
pound 35 is next reacted with tetrazol-1-ethyl
acetate to furnish the Claisen reaction product
keto ester 36. The next step involves the hydro
lysis of the ester function followed by the decar-
boxylation of the carboxylic group to give ke-
tone 37. The p-ethoxy phenyl group is incorpo-
rated by Suzuki coupling of 37 with dioxaboro-
lane 38. Finally, compound 39 is reacted with
the Grignard reagent derived from 2,4-difluoro-
bromobenzene in the presence of chiral ligand
(R)-BINOL to yield Oteseconazole 8 [147].
Scheme 5. The synthesis of Oteseconazole 8 starting from 2,5-dibromopyridine.
Compound 39 can also be prepared starting from 5-bromo-2-pyridinecaldehyde (Scheme 6).
Suzuki coupling reaction of 5-bromo-2-pyridinecaldehyde with dioxaborolane 38 yields
trifluoroethoxy aldehyde 40. Subsequently, intermediate 40 is converted to difluoromethyl
derivative 41 by reaction with (diethylamino)sulfur trifluoride. Finally, 41, in the presence of strong
base, is reacted with reagent 42 to yield 39 [147].
Scheme 6. The synthesis of the key difluoro ketone 39. Legend: DAST, (diethylamino)sulfur trifluoride;
NHMDS, sodium bis(trimethylsilyl)amide.
Oteseconazole 8 can be obtained enantiomerically pure by chiral HPLC [148]. In this regard,
it is interesting to note a very recent breakthrough development in chiral purifications, viz. achiral
simulated moving bed chromatography [149] leveraging the SDE phenomenon [150–152].
SunlencaTM (Lenacapavir) 9.
HIV/AIDS continues to be a major concern due to the rise of multidrug resistance and the
challenges patients face in sticking to their treatment regimens [153]. There is currently no cure for
HIV or AIDS. The HIV-1 capsid protein plays a crucial role in the viral replication cycle by
protecting the virus’s genetic material and other enzymes [154, 155]. Unlike earlier antiretroviral
drugs that target protease, reverse transcriptase, and integrase, the capsid protein functions through
protein–protein interactions making it a key target for novel drug design [156]. The capsid protein,
Scheme 5. The synthesis of Oteseconazole 8 starting from 2,5-dibromopyridine.
67https://ucj.org.ua
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Compound 39 can also be prepared start-
ing from 5-bromo-2-pyridinecaldehyde (Sche
me 6). Suzuki coupling reaction of 5-bromo-
2-pyridinecaldehyde with dioxaborolane 38
yields trifluoroethoxy aldehyde 40. Subse-
quently, intermediate 40 is converted to difluo
romethyl derivative 41 by reaction with (di
ethylamino)sulfur trifluoride. Finally, 41, in
the presence of strong base, is reacted with re-
agent 42 to yield 39 [147].
Scheme 5. The synthesis of Oteseconazole 8 starting from 2,5-dibromopyridine.
Compound 39 can also be prepared starting from 5-bromo-2-pyridinecaldehyde (Scheme 6).
Suzuki coupling reaction of 5-bromo-2-pyridinecaldehyde with dioxaborolane 38 yields
trifluoroethoxy aldehyde 40. Subsequently, intermediate 40 is converted to difluoromethyl
derivative 41 by reaction with (diethylamino)sulfur trifluoride. Finally, 41, in the presence of strong
base, is reacted with reagent 42 to yield 39 [147].
Scheme 6. The synthesis of the key difluoro ketone 39. Legend: DAST, (diethylamino)sulfur trifluoride;
NHMDS, sodium bis(trimethylsilyl)amide.
Oteseconazole 8 can be obtained enantiomerically pure by chiral HPLC [148]. In this regard,
it is interesting to note a very recent breakthrough development in chiral purifications, viz. achiral
simulated moving bed chromatography [149] leveraging the SDE phenomenon [150–152].
SunlencaTM (Lenacapavir) 9.
HIV/AIDS continues to be a major concern due to the rise of multidrug resistance and the
challenges patients face in sticking to their treatment regimens [153]. There is currently no cure for
HIV or AIDS. The HIV-1 capsid protein plays a crucial role in the viral replication cycle by
protecting the virus’s genetic material and other enzymes [154, 155]. Unlike earlier antiretroviral
drugs that target protease, reverse transcriptase, and integrase, the capsid protein functions through
protein–protein interactions making it a key target for novel drug design [156]. The capsid protein,
Scheme 6. The synthesis of the key difluoro ketone 39. Legend: DAST, (diethylamino)sulfur trifluo-
ride; NHMDS, sodium bis(trimethylsilyl)amide.
Oteseconazole 8 can be obtained enantio-
merically pure by chiral HPLC [148]. In this
regard, it is interesting to note a very recent
breakthrough development in chiral purifica-
tions, viz. achiral simulated moving bed chro-
matography [149] leveraging the SDE phe-
nomenon [150–152].
SunlencaTM (Lenacapavir) 9.
HIV/AIDS continues to be a major con-
cern due to the rise of multidrug resistance
and the challenges patients face in sticking to
their treatment regimens [153]. There is cur-
rently no cure for HIV or AIDS. The HIV-1
capsid protein plays a crucial role in the viral
replication cycle by protecting the virus’s ge-
netic material and other enzymes [154, 155].
Unlike earlier antiretroviral drugs that target
protease, reverse transcriptase, and integrase,
the capsid protein functions through protein–
protein interactions making it a key target for
novel drug design [156]. The capsid protein,
along with Gag and Gag-Pol polyproteins, fa-
cilitates crucial interactions required for virion
assembly [157]. The self-assembly of the capsid
protein in the virion, which is responsible for
the virus’s infectivity, is initiated by cleavage
mediated by HIV-1 protease [157, 158]. Ad-
ditionally, the infection of a new cell is regu-
lated by interactions with various host factors
that support reverse transcription and proviral
DNA integration [159–161]. Lenacapavir 9 is a
groundbreaking HIV medication known as a
capsid inhibitor. Developed by Gilead Scienc-
es, Lenacapavir 9 can be used in conjunction
with other antiretroviral drugs as a biannu-
al treatment regimen. In December 2022,
the FDA approved Lenacapavir 9 for HIV-1
68 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
treatment in adults with multidrug-resistant
HIV infection. It works by preventing the virus
from replicating and consequently reducing
the levels of viral particles in the body [162].
This compound features a difluorobenzyl ring
that fits into the same phenylalanine–glycine
binding pocket as polyadenylation specificity
factor subunit 6 (CPSF6) and nucleoporin 153
(Nup153). This binding establishes strong hy-
drophobic and hydrogen bonding interactions,
thereby disrupting the interactions of capsid
protein with Nup153 and CPSF6 [163–167].
By any measure, Lenacapavir 9 is a structurally
unique pharmaceutical as it contains 10 fluo-
rine atoms, representing four types of fluori-
nation, and features three stereogenic centers.
The synthesis of the key intermediate 47 for
the preparation of Lenacapavir 9 is presented
in Scheme 7 [168]. The bicyclic ketone 43 is
treated with lithium bis(trimethylsilyl)amide
and ethyl trifluoroacetate to generate enolate
44. The reaction of 44 with N-aminoglycine
under Knorr pyrazole synthesis conditions af-
fords 45. The heterocyclic compound 45 is oxi-
dized with N-hydroxyphthalimide and NaClO2
to yield ketone 46. Compound 46 is subjected
to deoxyfluorination to afford the target 47.
Enantiomerically pure 47 is then obtained by
chiral supercritical fluid chromatography.
Scheme 7. The synthesis of key compound 47. Legend: LHMDS, lithium bis(trimethylsilyl)amide;
MTHF, 2-methyl tetrahydrofuran; SFC, supercritical fluid chromatography .
along with Gag and Gag-Pol polyproteins, facilitates crucial interactions required for virion
assembly [157]. The self-assembly of the capsid protein in the virion, which is responsible for the
virus’s infectivity, is initiated by cleavage mediated by HIV-1 protease [157, 158]. Additionally, the
infection of a new cell is regulated by interactions with various host factors that support reverse
transcription and proviral DNA integration [159–161]. Lenacapavir 9 is a groundbreaking HIV
medication known as a capsid inhibitor. Developed by Gilead Sciences, Lenacapavir 9 can be used
in conjunction with other antiretroviral drugs as a biannual treatment regimen. In December 2022,
the FDA approved Lenacapavir 9 for HIV-1 treatment in adults with multidrug-resistant HIV
infection. It works by preventing the virus from replicating and consequently reducing the levels of
viral particles in the body [162]. This compound features a difluorobenzyl ring that fits into the
same phenylalanine–glycine binding pocket as polyadenylation specificity factor subunit 6 (CPSF6)
and nucleoporin 153 (Nup153). This binding establishes strong hydrophobic and hydrogen bonding
interactions, thereby disrupting the interactions of capsid protein with Nup153 and CPSF6
[163–167]. By any measure, Lenacapavir 9 is a structurally unique pharmaceutical as it contains 10
fluorine atoms, representing four types of fluorination, and features three stereogenic centers.
The synthesis of the key intermediate 47 for the preparation of Lenacapavir 9 is presented in
Scheme 7 [168]. The bicyclic ketone 43 is treated with lithium bis(trimethylsilyl)amide and ethyl
trifluoroacetate to generate enolate 44. The reaction of 44 with N-aminoglycine under Knorr
pyrazole synthesis conditions affords 45. The heterocyclic compound 45 is oxidized with
N-hydroxyphthalimide and NaClO2 to yield ketone 46. Compound 46 is subjected to
deoxyfluorination to afford the target 47. Enantiomerically pure 47 is then obtained by chiral
supercritical fluid chromatography.
Scheme 7. The synthesis of key compound 47. Legend: LHMDS, lithium bis(trimethylsilyl)amide; MTHF,
2-methyl tetrahydrofuran; SFC, supercritical fluid chromatography .
The synthesis of Lenacapavir 9 is illustrated in Scheme 8. Enantiomerically pure imine 48,
bearing an Ellman chiral auxiliary [169–172], undergoes reaction with the corresponding
difluorobenzyl zinc reagent to provide amine 49. Compound 49 is then subjected to Sonogashira
coupling to afford product 50. Next, Suzuki coupling is used to transform 50 to 52 using reagent 51.
The key intermediate, compound 47, bearing a free carboxylic group, and amino compound 52 are
reacted under peptide bond forming conditions to produce Lenacapavir 9.
The synthesis of Lenacapavir 9 is illustrated
in Scheme 8. Enantiomerically pure imine 48,
bearing an Ellman chiral auxiliary [169–172],
undergoes reaction with the corresponding di-
fluorobenzyl zinc reagent to provide amine 49.
Compound 49 is then subjected to Sonogashi-
ra coupling to afford product 50. Next, Suzuki
coupling is used to transform 50 to 52 using
reagent 51. The key intermediate, compound
47, bearing a free carboxylic group, and amino
compound 52 are reacted under peptide bond
forming conditions to produce Lenacapavir 9.
69https://ucj.org.ua
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Scheme 8. The synthesis of Lenacapavir 9. Legend: DIPEA, diisopropylethylamine; DTBC, di-tert-bu-
tyl decarbonate; HATU, hexafluorophosphate azabenzotriazole tetramethyl uranium.
Scheme 8. The synthesis of Lenacapavir 9. Legend: DIPEA, diisopropylethylamine; DTBC, di-tert-butyl
decarbonate; HATU, hexafluorophosphate azabenzotriazole tetramethyl uranium.
Voydeya® (Danicopan) 10.
Voydeya® 10, marketed under the name Danicopan, is structurally derived from
γ-fluorine-substituted proline with the fluorine atom directly bonded to the stereogenic carbon.
Approved by the FDA on March 29th, 2024 it was developed by Alexion Pharmaceuticals, a
subsidiary of AstraZeneca. Voydeya® 10 is specifically designed to address rare diseases, aligning
with Alexion’s specialization in orphan drug development [173]. Cyclic amino acids, such as
proline and its derivatives used in the design of Voydeya® 10, play a crucial role in drug
development due to their increased steric constraints compared to linear analogs [174, 175].
Incorporating a fluorine atom or –CF3 groups into five-membered rings [176–178] further limits
conformational flexibility, allowing precise modulation of biological properties. Specifically,
introducing a fluorine atom into the pyrrolidine-2-carboxamide framework, in contrast to
non-fluorinated analogs like compounds 53 and 54 (Fig. 7), significantly enhances activity, e.g.
achieving an impressive IC50 of 0.027 μM. This modification highlights exceptional potency and
positions the compound as a leading candidate within its class [179, 180].
Voydeya® (Danicopan) 10.
Voydeya® 10, marketed under the name Da
nicopan, is structurally derived from γ-fluo
rine-substituted proline with the fluorine atom
directly bonded to the stereogenic carbon. Ap-
proved by the FDA on March 29th, 2024 it was
developed by Alexion Pharmaceuticals, a sub-
sidiary of AstraZeneca. Voydeya® 10 is specifi-
cally designed to address rare diseases, aligning
with Alexion’s specialization in orphan drug
development [173]. Cyclic amino acids, such
as proline and its derivatives used in the de-
sign of Voydeya® 10, play a crucial role in drug
development due to their increased steric con-
straints compared to linear analogs [174, 175].
Incorporating a fluorine atom or –CF3 groups
into five-membered rings [176–178] further
limits conformational flexibility, allowing pre-
cise modulation of biological properties. Spe-
cifically, introducing a fluorine atom into the
pyrrolidine-2-carboxamide framework, in
contrast to non-fluorinated analogs like com-
pounds 53 and 54 (Fig. 7), significantly en-
hances activity, e.g. achieving an impressive
IC50 of 0.027 μM. This modification highlights
exceptional potency and positions the com-
pound as a leading candidate within its class
[179, 180].
70 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
Figure 7. The structures of Voydeya® 10 and its fluorine-free analogs.
Scheme 8. The synthesis of Lenacapavir 9. Legend: DIPEA, diisopropylethylamine; DTBC, di-tert-butyl
decarbonate; HATU, hexafluorophosphate azabenzotriazole tetramethyl uranium.
Voydeya® (Danicopan) 10.
Voydeya® 10, marketed under the name Danicopan, is structurally derived from
γ-fluorine-substituted proline with the fluorine atom directly bonded to the stereogenic carbon.
Approved by the FDA on March 29th, 2024 it was developed by Alexion Pharmaceuticals, a
subsidiary of AstraZeneca. Voydeya® 10 is specifically designed to address rare diseases, aligning
with Alexion’s specialization in orphan drug development [173]. Cyclic amino acids, such as
proline and its derivatives used in the design of Voydeya® 10, play a crucial role in drug
development due to their increased steric constraints compared to linear analogs [174, 175].
Incorporating a fluorine atom or –CF3 groups into five-membered rings [176–178] further limits
conformational flexibility, allowing precise modulation of biological properties. Specifically,
introducing a fluorine atom into the pyrrolidine-2-carboxamide framework, in contrast to
non-fluorinated analogs like compounds 53 and 54 (Fig. 7), significantly enhances activity, e.g.
achieving an impressive IC50 of 0.027 μM. This modification highlights exceptional potency and
positions the compound as a leading candidate within its class [179, 180].
Voydeya® 10, an oral complement Factor D
inhibitor, is used as an add-on therapy to the
complementary C5 inhibitors Ravulizumab
and Eculizumab for treating extravascular
hemolysis in adults with paroxysmal noctur-
nal hemoglobinuria (PNH) [181, 182]. PNH is
a rare disorder in which the immune system’s
complement pathway attacks red and white
blood cells as well as platelets, causing intra-
vascular hemolysis and increasing the risk of
thrombosis and organ damage. While C5 in-
hibitors are the standard treatment, some pa-
tients continue to experience residual extravas-
cular hemolysis and anemia [183]. Voydeya®
10 was first approved in Japan on January 18th,
2024 for use in combination with C5 inhibitors
to treat adults with PNH [184]. On February
23rd, 2024 the European Medicines Agency
also recommended its use for patients with re-
sidual hemolytic anemia despite undergoing
C5 inhibition therapy [185].
The synthesis of Voydeya® 10 [186–188]
begins with the formation of several key in-
termediates. As depicted in Scheme 9, 5-bro-
mo-1H-indazole-3-carbonitrile 53 undergoes
reaction with methylmagnesium bromide ge
nerating an imine magnesium salt interme
diate. Subsequent acid treatment at pH 5 hyd
rolyzes this intermediate yielding ketone 54.
The process continues with a Michael addition,
resulting in ester 55 in 81% yield.
Figure 7. The structures of Voydeya® 10 and its fluorine-free analogs.
Voydeya® 10, an oral complement Factor D inhibitor, is used as an add-on therapy to the
complementary C5 inhibitors Ravulizumab and Eculizumab for treating extravascular hemolysis in
adults with paroxysmal nocturnal hemoglobinuria (PNH) [181, 182]. PNH is a rare disorder in
which the immune system’s complement pathway attacks red and white blood cells as well as
platelets, causing intravascular hemolysis and increasing the risk of thrombosis and organ damage.
While C5 inhibitors are the standard treatment, some patients continue to experience residual
extravascular hemolysis and anemia [183]. Voydeya® 10 was first approved in Japan on January
18th, 2024 for use in combination with C5 inhibitors to treat adults with PNH [184]. On February
23rd, 2024 the European Medicines Agency also recommended its use for patients with residual
hemolytic anemia despite undergoing C5 inhibition therapy [185].
The synthesis of Voydeya® 10 [186–188] begins with the formation of several key
intermediates. As depicted in Scheme 9, 5-bromo-1H-indazole-3-carbonitrile 53 undergoes reaction
with methylmagnesium bromide generating an imine magnesium salt intermediate. Subsequent acid
treatment at pH 5 hydrolyzes this intermediate yielding ketone 54. The process continues with a
Michael addition, resulting in ester 55 in 81% yield.
Scheme 9. The synthesis of intermediate 55. Legend: THF, tetrahydrofuran.
The synthesis of another key intermediate, compound 58, is depicted in Scheme 10.
Boc-protected fluoropyrrolidine 56 undergoes amide alkylation using the Ghosez reagent and
diisopropylethylamine [134] followed by deprotection of the amino group in 57 to afford precursor
58.
Scheme 10. The synthesis of intermediate 58. Legend: Boc, tert-butyloxycarbonyl; DIPEA,
diisopropylethylamine.
The final assembly of Voydeya® using the key intermediates 55 and 58 is illustrated in
Scheme 11. Bromide 55 is reacted with boronate 59 to yield diester 60. The second step involves
palladium-catalyzed Suzuki–Miyaura coupling resulting in bis-aryl derivative 62. Hydrolysis of the
ester function using trifluoroacetic acid yields the free carboxylic acid 63. The closing peptide
coupling reaction using previously prepared fluoro proline derivative 58 affords Voydeya® 10.
Scheme 9. The synthesis of intermediate 55. Legend: THF, tetrahydrofuran.
71https://ucj.org.ua
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The synthesis of another key intermedi-
ate, compound 58, is depicted in Scheme 10.
Boc-protected fluoropyrrolidine 56 undergoes
amide alkylation using the Ghosez reagent and
diisopropylethylamine [134] followed by de-
protection of the amino group in 57 to afford
precursor 58.
Figure 7. The structures of Voydeya® 10 and its fluorine-free analogs.
Voydeya® 10, an oral complement Factor D inhibitor, is used as an add-on therapy to the
complementary C5 inhibitors Ravulizumab and Eculizumab for treating extravascular hemolysis in
adults with paroxysmal nocturnal hemoglobinuria (PNH) [181, 182]. PNH is a rare disorder in
which the immune system’s complement pathway attacks red and white blood cells as well as
platelets, causing intravascular hemolysis and increasing the risk of thrombosis and organ damage.
While C5 inhibitors are the standard treatment, some patients continue to experience residual
extravascular hemolysis and anemia [183]. Voydeya® 10 was first approved in Japan on January
18th, 2024 for use in combination with C5 inhibitors to treat adults with PNH [184]. On February
23rd, 2024 the European Medicines Agency also recommended its use for patients with residual
hemolytic anemia despite undergoing C5 inhibition therapy [185].
The synthesis of Voydeya® 10 [186–188] begins with the formation of several key
intermediates. As depicted in Scheme 9, 5-bromo-1H-indazole-3-carbonitrile 53 undergoes reaction
with methylmagnesium bromide generating an imine magnesium salt intermediate. Subsequent acid
treatment at pH 5 hydrolyzes this intermediate yielding ketone 54. The process continues with a
Michael addition, resulting in ester 55 in 81% yield.
Scheme 9. The synthesis of intermediate 55. Legend: THF, tetrahydrofuran.
The synthesis of another key intermediate, compound 58, is depicted in Scheme 10.
Boc-protected fluoropyrrolidine 56 undergoes amide alkylation using the Ghosez reagent and
diisopropylethylamine [134] followed by deprotection of the amino group in 57 to afford precursor
58.
Scheme 10. The synthesis of intermediate 58. Legend: Boc, tert-butyloxycarbonyl; DIPEA,
diisopropylethylamine.
The final assembly of Voydeya® using the key intermediates 55 and 58 is illustrated in
Scheme 11. Bromide 55 is reacted with boronate 59 to yield diester 60. The second step involves
palladium-catalyzed Suzuki–Miyaura coupling resulting in bis-aryl derivative 62. Hydrolysis of the
ester function using trifluoroacetic acid yields the free carboxylic acid 63. The closing peptide
coupling reaction using previously prepared fluoro proline derivative 58 affords Voydeya® 10.
Scheme 10. The synthesis of intermediate 58. Legend: Boc, tert-butyloxycarbonyl; DIPEA, diisopro-
pylethylamine.
The final assembly of Voydeya® using the
key intermediates 55 and 58 is illustrated in
Scheme 11. Bromide 55 is reacted with boro
nate 59 to yield diester 60. The second step
involves palladium-catalyzed Suzuki–Miyau-
ra coupling resulting in bis-aryl derivative 62.
Hydrolysis of the ester function using trifluo-
roacetic acid yields the free carboxylic acid 63.
The closing peptide coupling reaction using
previously prepared fluoro proline derivative
58 affords Voydeya® 10.
Scheme 11. The synthesis of Voydeya® 10. Legend: DIPEA, diisopropylethylamine; DMF, dimethylfor-
mamide; HATU, hexafluorophosphate azabenzotriazole tetramethyl uranium.
Scheme 11. The synthesis of Voydeya® 10. Legend: DIPEA, diisopropylethylamine; DMF,
dimethylformamide; HATU, hexafluorophosphate azabenzotriazole tetramethyl uranium.
Jaypirca® (Pirtobrutinib) 11.
Eli Lilly’s Pirtobrutinib 11 is a highly selective and reversible Bruton’s tyrosine kinase (BTK)
inhibitor that can be administered orally [189]. BTK is crucial for the growth, activation, and
survival of B cells, a type of white blood cell responsible for antibody production. However,
uncontrolled B cell growth can lead to cancer [189]. Unlike the previously approved BTK inhibitor
Ibrutinib 64 (Fig. 8), which binds irreversibly to the C481 residue in the kinase domain of BTK,
Pirtobrutinib 11 offers a non-covalent, reversible inhibition method [190]. This unique mechanism
makes Pirtobrutinib 11 effective in treating ibrutinib-resistant chronic lymphocytic leukemia that
arises due to mutations in the C481 kinase domain [191].
Figure 8. The structures of the clinically approved BTK inhibitors Pirtobrutinib 11 and Ibrutinib 64.
Pirtobrutinib 11 features an aminopyrazole carboxamide ring, replacing the
4-aminopyrazolopyrimidine core of Ibrutinib 64. The pyrazole ring acts as an ATP analog, binding
competitively to the ATP binding site of BTK and ensuring the proper conformation for effective
inhibition. Additionally, the covalent binding region of Ibrutinib 64 has been modified to a
non-covalently bonded CF3-substituted ethyl group.
In January 2023, the FDA approved Pirtobrutinib 11 for treating adult patients with relapsed
or refractory mantle cell lymphoma following at least two lines of systemic therapy, including a
BTK inhibitor [192, 193].
Eli Lilly’s approach to synthesize Pirtobrutinib 11, guided by Loxo Oncology, involves the
preparation of two key intermediates: aminopyrazole derivative 65 (Scheme 12) and potassium
trifluoroborate salt 66 (Scheme 13) [194, 195]. The meticulous process requires the synthesis of
aminopyrazole derivative 65 and begins with the reaction between acid chloride 67 and
malononitrile catalyzed by diisopropylethylamine. This is followed by O-methylation of the
72 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
Jaypirca® (Pirtobrutinib) 11.
Eli Lilly’s Pirtobrutinib 11 is a highly se-
lective and reversible Bruton’s tyrosine kinase
(BTK) inhibitor that can be administered
orally [189]. BTK is crucial for the growth,
activation, and survival of B cells, a type of
white blood cell responsible for antibody pro-
duction. However, uncontrolled B cell growth
can lead to cancer [189]. Unlike the previously
approved BTK inhibitor Ibrutinib 64 (Fig. 8),
which binds irreversibly to the C481 residue
in the kinase domain of BTK, Pirtobrutinib
11 offers a non-covalent, reversible inhibition
method [190]. This unique mechanism makes
Pirtobrutinib 11 effective in treating ibrutinib-
resistant chronic lymphocytic leukemia that
arises due to mutations in the C481 kinase do-
main [191].
Scheme 11. The synthesis of Voydeya® 10. Legend: DIPEA, diisopropylethylamine; DMF,
dimethylformamide; HATU, hexafluorophosphate azabenzotriazole tetramethyl uranium.
Jaypirca® (Pirtobrutinib) 11.
Eli Lilly’s Pirtobrutinib 11 is a highly selective and reversible Bruton’s tyrosine kinase (BTK)
inhibitor that can be administered orally [189]. BTK is crucial for the growth, activation, and
survival of B cells, a type of white blood cell responsible for antibody production. However,
uncontrolled B cell growth can lead to cancer [189]. Unlike the previously approved BTK inhibitor
Ibrutinib 64 (Fig. 8), which binds irreversibly to the C481 residue in the kinase domain of BTK,
Pirtobrutinib 11 offers a non-covalent, reversible inhibition method [190]. This unique mechanism
makes Pirtobrutinib 11 effective in treating ibrutinib-resistant chronic lymphocytic leukemia that
arises due to mutations in the C481 kinase domain [191].
Figure 8. The structures of the clinically approved BTK inhibitors Pirtobrutinib 11 and Ibrutinib 64.
Pirtobrutinib 11 features an aminopyrazole carboxamide ring, replacing the
4-aminopyrazolopyrimidine core of Ibrutinib 64. The pyrazole ring acts as an ATP analog, binding
competitively to the ATP binding site of BTK and ensuring the proper conformation for effective
inhibition. Additionally, the covalent binding region of Ibrutinib 64 has been modified to a
non-covalently bonded CF3-substituted ethyl group.
In January 2023, the FDA approved Pirtobrutinib 11 for treating adult patients with relapsed
or refractory mantle cell lymphoma following at least two lines of systemic therapy, including a
BTK inhibitor [192, 193].
Eli Lilly’s approach to synthesize Pirtobrutinib 11, guided by Loxo Oncology, involves the
preparation of two key intermediates: aminopyrazole derivative 65 (Scheme 12) and potassium
trifluoroborate salt 66 (Scheme 13) [194, 195]. The meticulous process requires the synthesis of
aminopyrazole derivative 65 and begins with the reaction between acid chloride 67 and
malononitrile catalyzed by diisopropylethylamine. This is followed by O-methylation of the
Figure 8. The structures of the clinically approved BTK inhibitors Pirtobrutinib 11 and Ibrutinib 64.
Pirtobrutinib 11 features an aminopyrazole
carboxamide ring, replacing the 4-aminopyra-
zolopyrimidine core of Ibrutinib 64. The pyra-
zole ring acts as an ATP analog, binding com-
petitively to the ATP binding site of BTK and
ensuring the proper conformation for effective
inhibition. Additionally, the covalent binding
region of Ibrutinib 64 has been modified to a
non-covalently bonded CF3-substituted ethyl
group.
In January 2023, the FDA approved Pir-
tobrutinib 11 for treating adult patients with
relapsed or refractory mantle cell lymphoma
following at least two lines of systemic therapy,
including a BTK inhibitor [192, 193].
Eli Lilly’s approach to synthesize Pirtobru-
tinib 11, guided by Loxo Oncology, involves
the preparation of two key intermediates:
aminopyrazole derivative 65 (Scheme 12) and
potassium trifluoroborate salt 66 (Scheme 13)
[194, 195]. The meticulous process requires the
synthesis of aminopyrazole derivative 65 and
begins with the reaction between acid chloride
67 and malononitrile catalyzed by diisopropyl-
ethylamine. This is followed by O-methylation
of the resulting 2-(hydroxymethylene)malo
nonitrile derivative 68 using dimethyl sulfate,
forming the 2-(methoxymethylene)malononi-
trile derivative 69. Subsequent cyclization with
(S)-(2,2,2-trifluoro-1-methyl)ethylhydrazine
hydrochloride in the presence of triethylamine
in ethanol at 80 °C yields aminopyrazole deri
vative 65 in an impressive 91% yield.
The synthesis of potassium trifluorobo-
rate salt 66 (Scheme 13) starts with the reac-
tion of pinacol bromomethyl boronic ester 70
with the sterically hindered potassium bis(tri-
methylsilyl)amide, resulting in silylated amino
boronic ester 71. This compound is then desi-
lylated under mild conditions using methanol,
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followed by acylation with acid chloride 72 to
yield the amido boronic ester 73. The cleavage
of this pinacol boronic ester 73 using potassi-
um bifluoride in a methanol/H2O mixture at
room temperature yields the desired potassi-
um trifluoroborate salt 66.
Scheme 12. The synthesis of compound 65. Legend: DIPEA, diisopropylethylamine; THF, tetrahydro-
furan.
resulting 2-(hydroxymethylene)malononitrile derivative 68 using dimethyl sulfate, forming the
2-(methoxymethylene)malononitrile derivative 69. Subsequent cyclization with
(S)-(2,2,2-trifluoro-1-methyl)ethylhydrazine hydrochloride in the presence of triethylamine in
ethanol at 80 °C yields aminopyrazole derivative 65 in an impressive 91% yield.
Scheme 12. The synthesis of compound 65. Legend: DIPEA, diisopropylethylamine; THF, tetrahydrofuran.
The synthesis of potassium trifluoroborate salt 66 (Scheme 13) starts with the reaction of pinacol
bromomethyl boronic ester 70 with the sterically hindered potassium bis(trimethylsilyl)amide,
resulting in silylated amino boronic ester 71. This compound is then desilylated under mild
conditions using methanol, followed by acylation with acid chloride 72 to yield the amido boronic
ester 73. The cleavage of this pinacol boronic ester 73 using potassium bifluoride in a
methanol/H2O mixture at room temperature yields the desired potassium trifluoroborate salt 66.
Scheme 13. The synthesis of compound 66. Legend: KHMDS, potassium bis(trimethylsilyl)amide; TMS,
trimethylsilyl.
The culmination of these efforts is the palladium-catalyzed cross-coupling reaction of aryl bromide
65 with potassium trifluoroborate salt 66 (Scheme 14). This reaction, facilitated by Pd(OAc)2 as the
precatalyst, Xphos as the ligand, and Cs2CO3 as the base in a tetrahydrofuran/H2O mixture at 85 °C,
yields the target 5-aminopyrazole-4-carbonitrile 74 in 87% yield after flash column chromatography
over silica gel. The final step involves the hydrolysis of 74 using a solution of sulfuric acid and
trifluoroacetic acid at 55 °C followed by flash column chromatography over silica gel, yielding
Pirtobrutinib 11 as a white solid in 51% yield.
resulting 2-(hydroxymethylene)malononitrile derivative 68 using dimethyl sulfate, forming the
2-(methoxymethylene)malononitrile derivative 69. Subsequent cyclization with
(S)-(2,2,2-trifluoro-1-methyl)ethylhydrazine hydrochloride in the presence of triethylamine in
ethanol at 80 °C yields aminopyrazole derivative 65 in an impressive 91% yield.
Scheme 12. The synthesis of compound 65. Legend: DIPEA, diisopropylethylamine; THF, tetrahydrofuran.
The synthesis of potassium trifluoroborate salt 66 (Scheme 13) starts with the reaction of pinacol
bromomethyl boronic ester 70 with the sterically hindered potassium bis(trimethylsilyl)amide,
resulting in silylated amino boronic ester 71. This compound is then desilylated under mild
conditions using methanol, followed by acylation with acid chloride 72 to yield the amido boronic
ester 73. The cleavage of this pinacol boronic ester 73 using potassium bifluoride in a
methanol/H2O mixture at room temperature yields the desired potassium trifluoroborate salt 66.
Scheme 13. The synthesis of compound 66. Legend: KHMDS, potassium bis(trimethylsilyl)amide; TMS,
trimethylsilyl.
The culmination of these efforts is the palladium-catalyzed cross-coupling reaction of aryl bromide
65 with potassium trifluoroborate salt 66 (Scheme 14). This reaction, facilitated by Pd(OAc)2 as the
precatalyst, Xphos as the ligand, and Cs2CO3 as the base in a tetrahydrofuran/H2O mixture at 85 °C,
yields the target 5-aminopyrazole-4-carbonitrile 74 in 87% yield after flash column chromatography
over silica gel. The final step involves the hydrolysis of 74 using a solution of sulfuric acid and
trifluoroacetic acid at 55 °C followed by flash column chromatography over silica gel, yielding
Pirtobrutinib 11 as a white solid in 51% yield.
Scheme 13. The synthesis of compound 66. Legend: KHMDS, potassium bis(trimethylsilyl)amide;
TMS, trimethylsilyl.
The culmination of these efforts is the palla-
dium-catalyzed cross-coupling reaction of aryl
bromide 65 with potassium trifluoroborate
salt 66 (Scheme 14). This reaction, facilitated
by Pd(OAc)2 as the precatalyst, Xphos as the
ligand, and Cs2CO3 as the base in a tetrahyd
rofuran/H2O mixture at 85 °C, yields the tar-
get 5-aminopyrazole-4-carbonitrile 74 in 87%
yield after flash column chromatography over
silica gel. The final step involves the hydrolysis
of 74 using a solution of sulfuric acid and trif-
luoroacetic acid at 55 °C followed by flash co
lumn chromatography over silica gel, yielding
Pirtobrutinib 11 as a white solid in 51% yield.
74 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
Scheme 14. The synthesis of Pirtobrutinib 11 by combining intermediates 65 and 66. Legend: DIPEA,
diisopropylethylamine; THF, tetrahydrofuran.
Scheme 14. The synthesis of Pirtobrutinib 11 by combining intermediates 65 and 66. Legend: DIPEA,
diisopropylethylamine; THF, tetrahydrofuran.
Itovebi® (Inavolisib) 12.
Inavolisib 12, known commercially as Itovebi®, has received FDA approval for the treatment of
locally advanced or metastatic breast cancer [196]. This innovative drug acts as an inhibitor of the
phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, marking a new era of cancer
therapeutics. It boasts an enhanced toxicity profile, surpassing that of its predecessor, alpelisib [197,
198].
PI3K enzymes are vital players in the orchestration of cell growth and differentiation,
comprising both regulatory and catalytic subunits [199]. These enzymes come in four distinct
isoforms: PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. Of these, PI3Kα stands out as the most closely tied to
cancer development thanks to mutations in the PIK3CA gene that encodes the p110α unit [200, 201].
Remarkably, nearly one third of breast cancer cases display such pathway anomalies [202], often
marking a bleak prognosis [203].
The pursuit of selective PI3Kα inhibitors which circumvent the side effects associated with
blocking other PI3K isoforms is a top priority [201–203]. Inavolisib 12 is a true virtuoso in this
regard with an IC50 of only 0.034 nM for PI3Kα in comparison to 100 nM for PI3Kβ, 18 nM for
PI3Kγ, and 12 nM for PI3Kδ. Inavolisib 12 thus exhibits an impressive 350-fold selectivity for
PI3Kα [204]. Moreover, Inavolisib 12 also promotes the degradation of the mutated p110α subunit
[205]. 12’s precise targeting and high selectivity underscore a significant leap forward in the fight
against breast cancer, offering hope and potential for more effective treatments.
It is intriguing to note that introducing a trifluoromethyl group in compound 75 (Fig. 9)
leads to a PI3Kα IC50 of 0.095 nM and a PI3Kδ/PI3Kα ratio of 171, showing reduced selectivity for
the α isoform. By contrast, with a difluoromethyl group, Inavolisib 12 exhibits a PI3Kα IC50 of
0.034 nM and a PI3Kδ/PI3Kα ratio of 361, highlighting a much higher selectivity for PI3Kα [206].
Itovebi® (Inavolisib) 12.
Inavolisib 12, known commercially as Itove-
bi®, has received FDA approval for the treat-
ment of locally advanced or metastatic breast
cancer [196]. This innovative drug acts as an
inhibitor of the phosphatidylinositol-4,5-bis-
phosphate 3-kinase (PI3K) pathway, marking
a new era of cancer therapeutics. It boasts an
enhanced toxicity profile, surpassing that of its
predecessor, alpelisib [197, 198].
PI3K enzymes are vital players in the or-
chestration of cell growth and differentiation,
comprising both regulatory and catalytic subu-
nits [199]. These enzymes come in four distinct
isoforms: PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. Of
these, PI3Kα stands out as the most closely tied
to cancer development thanks to mutations
in the PIK3CA gene that encodes the p110α
unit [200, 201]. Remarkably, nearly one third
of breast cancer cases display such pathway
anomalies [202], often marking a bleak prog-
nosis [203].
The pursuit of selective PI3Kα inhibitors
which circumvent the side effects associated
with blocking other PI3K isoforms is a top
priority [201–203]. Inavolisib 12 is a true vir-
tuoso in this regard with an IC50 of only 0.034
nM for PI3Kα in comparison to 100 nM for
PI3Kβ, 18 nM for PI3Kγ, and 12 nM for PI3Kδ.
Inavolisib 12 thus exhibits an impressive 350-
fold selectivity for PI3Kα [204]. Moreover, Ina
volisib 12 also promotes the degradation of
the mutated p110α subunit [205]. 12’s precise
targeting and high selectivity underscore a sig-
nificant leap forward in the fight against breast
cancer, offering hope and potential for more
effective treatments.
It is intriguing to note that introducing a
trifluoromethyl group in compound 75 (Fig. 9)
leads to a PI3Kα IC50 of 0.095 nM and a PI3Kδ/
PI3Kα ratio of 171, showing reduced selectivi-
ty for the α isoform. By contrast, with a difluo-
romethyl group, Inavolisib 12 exhibits a PI3Kα
IC50 of 0.034 nM and a PI3Kδ/PI3Kα ratio of
361, highlighting a much higher selectivity for
PI3Kα [206].
75https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Daniel Baecker, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 2 / Vol. 91
Figure 9. The structures of Inavolisib 12 and its CF3-containing analog 75.
Figure 9. The structures of Inavolisib 12 and its CF3-containing analog 75.
From a chemical perspective, Inavolisib 12 is comprised of a benzoxazepine oxazolidinone
core adorned with an alanine amide moiety and an amino alcohol derived from difluoroalanine.
This particular difluoroalanine derivative is highly attractive to PI3Kα, significantly boosting the
drug’s selectivity for this isoform. The efficacy of 12’s interactions with its target is enhanced by
hydrogen bonds formed between the amide and amino groups of the alanine fragment. Furthermore,
the difluoromethyl group of Inavolisib 12 engages with the hydroxyl group of Ser774 within the
p110α pocket [204]. Hence, strategic fluorination is the key to the high potency of this PI3Kα
inhibitor.
The synthesis of Inavolisib 12 (Scheme 15) begins with
1,2:5,6-bis-O-(1-methylethylidene)-D-mannitol (76) to provide the desired stereochemical
configuration [206]. The process begins with sodium periodate in hot water which is added to silica
to form a powder that is combined with compound 30 dissolved in dichloromethane. After stirring
at room temperature for an hour, carbaldehyde 77 is produced. As the reaction cools,
diethylaminosulfur trifluoride is gradually added to the carbaldehyde 77 solution in
dichloromethane, which is then stirred at room temperature for three hours to produce
(R)-4-difluoromethyl-2,2-dimethyl[1,3]dioxolane (78). Intermediate 78 is dissolved in methanol and
hydrochloric acid in dioxane is added followed by stirring at room temperature for 30 minutes. The
acetal is cleaved to form the respective diol. Following work up, the residue is dissolved in
dichloromethane followed by the addition of tert-butyldimethylsilyl chloride, triethylamine, and a
catalytic amount of 4-dimethylaminopyridine. After stirring for an hour at room temperature,
compound 79 is obtained. The next step involves adding trifluoromethanesulfonic anhydride
dropwise to a solution of 79 and pyridine in dichloromethane. The temperature is maintained at
−20 °C for 20 minutes then brought to 0 °C for an hour while stirring. After extraction and work up,
the residue is dissolved in dimethyl formamide and sodium azide is added followed by stirring for
two hours at room temperature to produce intermediate 80. Azide 80 is then reduced using
palladium hydroxide on carbon under hydrogen by stirring for 16 hours in ethyl acetate and
methanol, yielding primary amine 81. This product is dissolved in methanol and stirred in a solution
of HCl in dioxane for two hours at room temperature to remove the protecting group. After work up,
the crude product is dissolved in toluene and aqueous potassium hydroxide at 0 °C. Phosgene is
added gradually, followed by stirring for an hour to obtain (S)-4-difluoromethyloxazolidin-2-one
(82). This is then combined with
9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]-oxazepane (83), copper acetate
From a chemical perspective, Inavolisib
12 is comprised of a benzoxazepine oxazo-
lidinone core adorned with an alanine amide
moiety and an amino alcohol derived from
difluoroalanine. This particular difluoroala-
nine derivative is highly attractive to PI3Kα,
significantly boosting the drug’s selectivity for
this isoform. The efficacy of 12’s interactions
with its target is enhanced by hydrogen bonds
formed between the amide and amino groups
of the alanine fragment. Furthermore, the di-
fluoromethyl group of Inavolisib 12 engages
with the hydroxyl group of Ser774 within the
p110α pocket [204]. Hence, strategic fluori
nation is the key to the high potency of this
PI3Kα inhibitor.
The synthesis of Inavolisib 12 (Scheme 15)
begins with 1,2:5,6-bis-O-(1-methylethylide
ne)-d-mannitol (76) to provide the desired
stereochemical configuration [206]. The pro-
cess begins with sodium periodate in hot water
which is added to silica to form a powder that
is combined with compound 30 dissolved in
dichloromethane. After stirring at room tem-
perature for an hour, carbaldehyde 77 is pro-
duced. As the reaction cools, diethylaminosul-
fur trifluoride is gradually added to the carbal-
dehyde 77 solution in dichloromethane, which
is then stirred at room temperature for three
hours to produce (R)-4-difluoromethyl-2,2-di-
methyl[1,3]dioxolane (78). Intermediate 78 is
dissolved in methanol and hydrochloric acid in
dioxane is added followed by stirring at room
temperature for 30 minutes. The acetal is cleaved
to form the respective diol. Following work up,
the residue is dissolved in dichloromethane fol-
lowed by the addition of tert-butyldimethylsilyl
chloride, triethylamine, and a catalytic amount
of 4-dimethylaminopyridine. After stirring for
an hour at room temperature, compound 79
is obtained. The next step involves adding tri-
fluoromethanesulfonic anhydride dropwise to
a solution of 79 and pyridine in dichlorometh-
ane. The temperature is maintained at −20 °C
for 20 minutes then brought to 0 °C for an hour
while stirring. After extraction and work up, the
residue is dissolved in dimethyl formamide and
sodium azide is added followed by stirring for
two hours at room temperature to produce in-
termediate 80. Azide 80 is then reduced using
76 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
palladium hydroxide on carbon under hydro
gen by stirring for 16 hours in ethyl acetate and
methanol, yielding primary amine 81. This
product is dissolved in methanol and stirred in a
solution of HCl in dioxane for two hours at room
temperature to remove the protecting group. Af-
ter work up, the crude product is dissolved in to
luene and aqueous potassium hydroxide at 0 °C.
Phosgene is added gradually, followed by stir-
ring for an hour to obtain (S)-4-difluoromethy-
loxazolidin-2-one (82). This is then combined
with 9-bromo-2-iodo-5,6-dihydrobenzo[f]imi-
dazo[1,2-d][1,4]-oxazepane (83), copper acetate
monohydrate, 3,4,7,8-tetramethyl-1,10-phenan
throline, and cesium carbonate in dioxane. The
mixture is heated to 100 °C for 18 hours under
an argon atmosphere resulting in compound 84
[206].
Compound 84 is then suspended in dime-
thyl sulfoxide with l-alanine, cuprous iodide,
and potassium phosphate tribasic with heating
at 100 °C for two hours. Once cooled to am-
bient temperature, dimethyl sulfoxide, ammo-
nium chloride, and triethylamine are added.
To this suspension, hexafluorophosphate aza
benzotriazole tetramethyl uranium is added
dropwise and stirred at room temperature for
an hour to finally obtain Inavolisib 12 [206].
monohydrate, 3,4,7,8-tetramethyl-1,10-phenanthroline, and cesium carbonate in dioxane. The
mixture is heated to 100 °C for 18 hours under an argon atmosphere resulting in compound 84
[206].
Compound 84 is then suspended in dimethyl sulfoxide with L-alanine, cuprous iodide, and
potassium phosphate tribasic with heating at 100 °C for two hours. Once cooled to ambient
temperature, dimethyl sulfoxide, ammonium chloride, and triethylamine are added. To this
suspension, hexafluorophosphate azabenzotriazole tetramethyl uranium is added dropwise and
stirred at room temperature for an hour to finally obtain Inavolisib 12 [206].
Scheme 15. The synthesis of Inavolisib 12. Legend: DAST, (diethylamino)sulfur trifluoride; DMAP,
4-(dimethylamino)pyridine; DMF, dimethylformamide; HATU, hexafluorophosphate azabenzotriazole
tetramethyl uranium; TBDMSCl, tert-butyl dimethyl silyl chloride; Tf2O, trifluoromethanesulfonic anhydride;
THF, tetrahydrofuran; TMPhen, 3,4,7,8-tetramethyl-1,10-phenanthroline.
Conclusions. Each of the nine compounds profiled in this review features a unique structural
arrangement of fluorine with respect to the chirality of the molecule. Fluoroestradiol F-18
(Cerianna™) 4 has a single fluorine atom on the stereogenic carbon β to a hydroxy group. This unit
is part of a five-membered ring, which is itself part of a polycyclic system possessing five
consecutive stereogenic centers. Cedazuridine 17 features a difluoromethylene group as part of a
tetrahydrofuran heterocyclic moiety bearing three additional amino, hydroxy, and hydroxymethyl
substitutions on three stereogenic carbons. The molecule contains four centers of chirality overall.
Belzutifan (Welireg™) 6 possesses a 1,2-difluoroethylene group as part of a dihydroindene system
with a hydroxy group and a stereogenic center vicinal to one of the fluorine atoms. Each fluorine
atom is directly bonded to a stereogenic carbon thus there are three consecutive chiral centers
within the five-membered ring. Voranigo® (Vorasidenib) 7 has two trifluoromethyl groups as
fragments of chiral trifluoro-isopropylamine moieties, which sterically and electronically influence
the properties of the amino groups. Vivjoa™ (Oteseconazole) 8 features an acyclic
difluoromethylene group bonded directly to a quaternary stereogenic carbon. Additionally, the
molecule includes two aromatic fluorine substitutions and a trifluoroethoxy group. In Sunlenca™
(Lenacapavir) 9, the difluoromethylene group is bonded to a stereogenic center as part of a highly
sterically constrained tricyclic system composed of one three-membered and two five-membered
rings. The molecule possesses two aromatic fluorines, one aromatic trifluoromethyl, and one
Scheme 15. The synthesis of Inavolisib 12. Legend: DAST, (diethylamino)sulfur trifluoride; DMAP,
4-(dimethylamino)pyridine; DMF, dimethylformamide; HATU, hexafluorophosphate azabenzotriazole
tetramethyl uranium; TBDMSCl, tert-butyl dimethyl silyl chloride; Tf2O, trifluoromethanesulfonic anhy-
dride; THF, tetrahydrofuran; TMPhen, 3,4,7,8-tetramethyl-1,10-phenanthroline.
77https://ucj.org.ua
Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander E. Sorochinsky, Daniel Baecker, Taizo Ono, Karel D. Klika, Vadim A. Soloshonok UCJ № 2 / Vol. 91
Conclusions. Each of the nine compounds
profiled in this review features a unique struc-
tural arrangement of fluorine with respect to the
chirality of the molecule. Fluoroestradiol F-18
(Cerianna™) 4 has a single fluorine atom on the
stereogenic carbon β to a hydroxy group. This
unit is part of a five-membered ring, which is
itself part of a polycyclic system possessing five
consecutive stereogenic centers. Cedazuridine
17 features a difluoromethylene group as part
of a tetrahydrofuran heterocyclic moiety bear-
ing three additional amino, hydroxy, and hyd
roxymethyl substitutions on three stereogenic
carbons. The molecule contains four centers of
chirality overall. Belzutifan (Welireg™) 6 pos-
sesses a 1,2-difluoroethylene group as part of
a dihydroindene system with a hydroxy group
and a stereogenic center vicinal to one of the
fluorine atoms. Each fluorine atom is direct-
ly bonded to a stereogenic carbon thus there
are three consecutive chiral centers within the
five-membered ring. Voranigo® (Vorasidenib) 7
has two trifluoromethyl groups as fragments of
chiral trifluoro-isopropylamine moieties, which
sterically and electronically influence the pro
perties of the amino groups. Vivjoa™ (Otese
conazole) 8 features an acyclic difluoromethyl-
ene group bonded directly to a quaternary ste-
reogenic carbon. Additionally, the molecule in-
cludes two aromatic fluorine substitutions and a
trifluoroethoxy group. In Sunlenca™ (Lenacapa-
vir) 9, the difluoromethylene group is bonded to
a stereogenic center as part of a highly sterically
constrained tricyclic system composed of one
three-membered and two five-membered rings.
The molecule possesses two aromatic fluorines,
one aromatic trifluoromethyl, and one trifluo-
roethyl substitution and has three centers of chi-
rality overall. Voydeya® (Danicopan) 10 features
a monofluoroproline residue as a centerpiece
of its structure and is the fluorinated analog
of natural occurring hydroxyproline, a com-
pound which is essential for collagen structure
and function. The molecule has two stereogenic
centers within the glycine-fluoroproline dipep-
tide unit. Jaypirca® (Pirtobrutinib) 11 includes a
trifluoromethyl group bonded to the stereogenic
center of a trifluoropropanylhydrazine struc-
tural fragment. Finally, Itovebi® (Inavolisib) 12
possesses a chiral oxazolidinone ring with a di-
fluoromethyl group bonded to the stereogenic
carbon. The second stereogenic center in the
molecule is associated with an alanine residue.
This diverse array of chiral, fluorine sub-
stitutions shows that there is currently no es-
tablished structurally favored pattern in the
design of modern drugs. Consequently, there
remains a need for the synthesis of a variety of
chiral, fluorine molecules for data collection,
analysis, and theoretical predictions. It is well
established that incorporating elements of chi-
rality, particularly a stereogenic center, in com-
pounds under development enhances their
success rate as they progress from discovery
to marketing approval. For example, approxi-
mately 65% of approved drugs have at least one
element of chirality, compared to about 50% of
candidates in the discovery phase [207]. There-
fore, it is anticipated that chiral, fluorine-con-
taining compounds will continue to play an
indispensable role in modern medicinal che
mistry, becoming even more prominent in the
drug candidates being designed, developed,
and submitted for approval.
We gratefully acknowledge the finan
cial support from the National Na
tural Science Foundation of China
(No. 21761132021), the Qing-Lan Pro
ject of Jiangsu Province (for Han), and
IKERBASQUE, Basque Foundation for
Science (for Soloshonok).
78 ISSN 2708-129X. Укр. хім. журн., 2025
CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALSORGANIC CHEMISTRY
ХІРАЛЬНІ ФАРМАЦЕВТИЧНІ ПРЕПАРАТИ,
ЩО МІСТЯТЬ ФТОР
Ц. Хань,1 А. Взорек,2 Г. Дхаван,3,4 В. Зханг,5
О. Є. Сорочинський,6 Д. Бекер,7 Т. Оно,8
К. Д. Клика,9 В. A. Солошонок10,11*
1Спільний інноваційний центр Цзянсу з
ефективного оброблення та використання
лісових ресурсів, Коледж хімічної інженерії,
Нанкінський лісотехнічний університет,
Нанкін 210037, Китай;
2Інститут хімії, Університет імені Яна
Кохановського в Кельцях, Кельці, Польща;
3Школа медичних наук, Університет під-
приємництва Делі, Нью-Делі-110077, Індія;
4Коледж Ачаріа Нарендра Дев, Університет
Делі, Нью-Делі 110019, Індія;
5Департамент хімії, Массачусетський уні-
верситет, Бостон, Массачусетс 02125,
США;
6Інститут біоорганічної хімії та нафтохі-
мії ім. В.П. Кухаря НАН України,
Київ, Україна;
Адреса!
7Департамент фармацевтичної та медич-
ної хімії, Інститут фармації, Вільний уні-
верситет Берліна, 14195 Берлін, Німеччина;
8Національний інститут передових про-
мислових наук і технологій, 463–8560, На-
гоя, Японія;
9 Центр досліджень і розробок,
Archer Daniels Midland, 1001 N Brush College
Rd., Декейтер, Іллінойс 62521, США;
10Хімічний факультет, Університет Краї-
ни Басків, 20018 Сан-Себастьян, Іспанія;
11 ІКЕРБАСК, Баскський фонд науки, 48013
Більбао, Іспанія
*email: vadimsoloshonok@gmail.com
Фтор, відомий своїми унікальними хі-
мічними властивостями, став ключовим
елементом у розробленні лікарських за-
собів завдяки його здатності підвищувати
метаболічну стабільність, покращувати
спорідненість зв’язування та збільшувати
біодоступність. Ця стаття досліджує ос-
танні досягнення у сфері хіральних фар-
мацевтичних препаратів, що містять фтор,
які було введено на ринок за останні п’ять
років, зосереджуючись на їхньому синтезі,
терапевтичних перевагах, механізмах дії
та впливу фтору на їхню ефективність та
профіль безпеки. Через огляд хіральних
препаратів, нещодавно схвалених FDA, ми
прагнемо надати уявлення про розвиток хі-
мії фтору у розробленні лікарських засобів
та її значення для майбутніх терапевтич-
них інновацій. Наголошено на необхідно-
сті більшого дослідження явища самоди-
спропорціонування енантіомерів (SDE) у
хіральних фторвмісних сполуках. Зазначе-
но надмірний рівень фтору як у навколиш-
ньому середовищі, так і у життєдіяльності
людей.
Ключові слова: фтор, хіральність, фар-
мацевтичні препарати, розроблення лікар-
ських засобів, синтез, SDE, біоактивність.
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Cтаття надійшла 27.01.2025.
|
| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-710 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:12:48Z |
| publishDate | 2025 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
| record_format | ojs |
| resource_txt_mv | ucjorgua/8a/43b21a1fd1fce6d582693c560114898a.pdf |
| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-7102026-07-22T08:23:55Z CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALS(Review) Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander Baecker, Daniel Ono, Taizo Klika, Karel Soloshonok, Vadim Fluorine, chirality, drug design, pharmaceuticals, self-disproportionation of enantiomers, bioactivity. Fluorine is a key element in drug design due to its ability to enhance metabolic stability, binding affinity, and bioavailability. Fluorine’s properties lead to more stable drugs with longer half-lives, reducing dosing frequency and improving patient compliance. Its small size and high electronegativity also improve binding affinity, resulting in more effective treatments with lower doses. For example, fluorine increases a compound’s ability to cross cell membranes. This article highlights advancements in chiral, fluorine-containing pharmaceuticals introduced over the past five years, focusing on their synthesis, therapeutic benefits, mechanisms of action, and the impact of fluorine on efficacy and safety. Chiral molecules, essential in drug development, exist in two enantiomeric forms with distinct biological activities. Synthesizing chiral, fluorine-containing drugs involves techniques like asymmetric synthesis to produce pure enantiomers, resulting in drugs with increased potency, selectivity, and reduced side effects. Understanding their mechanisms of action provides valuable insights into efficacy and safety. Reviewing recently FDA-approved chiral drugs offers insights into fluorine chemistry in drug development and future therapeutic innovations. Recent FDA approvals highlight the significance of chiral, fluorine-containing drugs in various therapeutic areas, enabling targeted and effective treatments. Analyzing these approvals reveals trends shaping drug development’s future. The article also addresses the need for more research into self-disproportionation of enantiomers (SDE) in chiral, fluorinated compounds and concerns about excessive fluorine levels. SDE can affect pharmaceutical product purity. Research into SDE in fluorinated compounds ensures drug quality. Additionally, fluorine’s widespread use raises environmental and health concerns, necessitating studies on long-term effects and mitigation strategies. V.I.Vernadsky Institute of General and Inorganic Chemistry 2025-03-25 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/710 10.33609/2708-129X.91.2.2025.55-90 Ukrainian Chemistry Journal; Vol. 91 No. 2 (2025): Ukrainian Chemistry Journal; 55-90 Украинский химический журнал; ##issue.vol## 91 ##issue.no## 2 (2025): Ukrainian Chemistry Journal; 55-90 Український хімічний журнал; Том 91 № 2 (2025): Ukrainian Chemistry Journal; 55-90 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/710/359 Copyright (c) 2025 Jianlin Han, Alicja Wzorek, Gagan Dhawan, Wei Zhang, Alexander Sorochinsky, Daniel Baecker, Taizo Ono, Karel Klika, Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Han, Jianlin Wzorek, Alicja Dhawan, Gagan Zhang, Wei Sorochinsky, Alexander Baecker, Daniel Ono, Taizo Klika, Karel Soloshonok, Vadim CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALS(Review) |
| title | CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALS(Review) |
| title_full | CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALS(Review) |
| title_fullStr | CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALS(Review) |
| title_full_unstemmed | CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALS(Review) |
| title_short | CHIRAL, FLUORINE-CONTAINING PHARMACEUTICALS(Review) |
| title_sort | chiral, fluorine-containing pharmaceuticals(review) |
| topic_facet | Fluorine chirality drug design pharmaceuticals self-disproportionation of enantiomers bioactivity. |
| url | https://ucj.org.ua/index.php/journal/article/view/710 |
| work_keys_str_mv | AT hanjianlin chiralfluorinecontainingpharmaceuticalsreview AT wzorekalicja chiralfluorinecontainingpharmaceuticalsreview AT dhawangagan chiralfluorinecontainingpharmaceuticalsreview AT zhangwei chiralfluorinecontainingpharmaceuticalsreview AT sorochinskyalexander chiralfluorinecontainingpharmaceuticalsreview AT baeckerdaniel chiralfluorinecontainingpharmaceuticalsreview AT onotaizo chiralfluorinecontainingpharmaceuticalsreview AT klikakarel chiralfluorinecontainingpharmaceuticalsreview AT soloshonokvadim chiralfluorinecontainingpharmaceuticalsreview |