Improved laboratory synthesis of YC-071, a potent azole antifungal agent

Article abstract of DOI:10.3184/174751917X14902201357419

An improved laboratory synthesis of YC-071, a potent azole antifungal agent, has been developed. Compared with the original route, the new route is operationally simple, requiring only limited purification of all the intermediates. The new route is an imp

Full text of DOI:10.3184/174751917X14902201357419

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 APRIL, 241–245
RESEARCH PAPER 241
Improved laboratory synthesis of YC-071, a potent azole antifungal agent
Yazhou Zhenga, Anran Qianb,c, Chenyu Lingb,c, Xufeng Caob,c, YongMei Cuia and Yushe Yangb,c*
aDepartment of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, P.R. China
bShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
cUniversity of Chinese Academy of Sciences, Beijing 100049, P.R. China
An improved laboratory synthesis of YC-071, a potent azole antifungal agent, has been developed. Compared with the original route,
the new route is operationally simple, requiring only limited purification of all the intermediates. The new route is an important scalable
synthesis, which meets the need for YC-071 for use in preclinical studies.
Keywords: triazole, reductive amination, intramolecular cyclisation, antifungal agent
Results and discussion
Invasive fungal infections are an increasing threat to
human health. For people who have AIDS/HIV and other
immunodeficiency diseases, fungal infections are almost
always a fatal problem.1,2 Among the drugs that are used to
treat fungal infections, triazole agents such as fluconazole
(1, Fig. 1), voriconazole (2, Fig. 1)3 and itraconazole (3, Fig.
1)4 are commonly used as antifungal agents. However, there
are some drawbacks with these drugs, such as emerging drug
resistance,5 poor water-solubility and drug–drug interactions.6
This situation has led to an ongoing search for new azole agents
with a broad spectrum of activity, high aqueous solubility and
low toxicity.
Previously, we have reported the design, synthesis and
evaluation of novel fused heterocyclic-linked triazoles, leading
to the discovery of YC-071 (4, Fig. 1), which has a potent
antifungal activity against common pathogenic fungi as well
as fluconazole-resistant strains.7 Furthermore, YC-071 has
a favourable pharmacokinetic profile and exhibits no hERG
inhibition or hepatocyte toxicity. As it has been selected for
preclinical study, multigram quantities of the material are
needed. With this background in mind, we have developed a
novel and scalable synthesis of the potent azole antifungal agent
YC-071.
The original medicinal chemistry route to YC-071 is based
on a ring-opening reaction of epoxide 5 (Scheme 1)8 by an
amino fragment. This is the common synthetic method used
for structurally similar triazole agents such as 6,9 7,10 and 811
(Fig. 2). However, this route possessed two major problems
that hampered its scale-up (Scheme 1): (1) the preparation of
amino fragment 13 required a Sandmeyer reaction to install the
bromo atom, which produced several cupric salts and required
a tedious work-up; (2) the LiClO4-catalysed ring-opening
reaction of the epoxide 5 gave a complex reaction mixture under
microwave conditions, which resulted in a low yield and could
not be scaled up. These problems prompted us to seek a better
laboratory synthesis of YC-071, which in turn meant that an
efficient synthesis of its precursor 14 was needed.
As shown in Scheme 2, retrosynthetic analysis suggests that
compound 14 can be disconnected to a two-carbon linker and
the amino compound 15. This can be obtained by reductive
amination reaction of amine 16 and aldehyde 17. Amine 16 is
a known compound that can be easily prepared from epoxide
5 in good yield.12 The preparation of aldehyde 17 started from
commercially available 3,5-dibromo-1H-1,2,4-triazole by
formylation at the C3 position after protection of the nitrogen
O
N
N
N
N
O
OH
N
N
N
O
N
N
F
N
N
N
O
N
N
Cl
F
Cl
Fluconazole (1)
Itraconazole (2)
F
N
OH
N
OH
N
N
F
N
N
N
N
N
N
F
N
CN
N
N
F
F
YC-071 (4)
Voriconazole (3)
Fig. 1 Chemical structures of triazole antifungal agents.
* Correspondent. E-mail: ysyang@simm.ac.cn

242 JOURNAL OF CHEMICAL RESEARCH 2017
N
OH
O
N
N
OH
N
F
N
N
N
N
S
N
F
N
N
N
CN
N
N
F
N
O
tail group
F
N
F
N
YC-071 (4)
7
HN
F
5
N
OH
N
OH
N
F
N
N
N
F
N
N
N
F
N
F
F
Efinaconazole (6)
8
Fig. 2 Epoxy ring-opening reaction used in the synthesis of YC-071, efinaconazole, 7 and 8.
O
NH2
a
S
N
N
N
N
N
b
c
N
N
N
N
C
HN
+
NH2
Br
EtO
N
N
Br
N
N
N
9
10
11
12
13
N
OH
N
OH
N
O
N
N
d
N
HN
N
N
N
N
e
N
N
N
N
N
+
F
Br
F
Br
F
N
N
N
CN
N
N
N
F
F
F
YC-071
13
14
5
Reagents and conditions: (a) (i) 1,4-dioxane, r.t., 12 h, (ii) triethylamine, hydroxylamine hydrochloride, MeOH/EtOH, r.t., 2 h, then reflux, 4 h. (b) NaNO ,
CuBr, HBr, acetic acid/H2O, 0 °C, 2 h, then reflux overnight; (c) LiBH4, EtOH, 50 °C, 6 h; (d) LiClO4, CH3CN, microwave; (e) 2-cyanopyridine-5-boroni2c
acid pinacol ester, Pd(PPh3)4, Cs2CO3, 1,4-dioxane-H2O, 80 °C.
Scheme 1 Initial medicinal chemistry route to YC-071.
N
OH
N
OH
Br
Br
N
F
N
F
N
N
N
N
N
N
H
Br
Br
HN
N
N
N
F
F
14
15
N
O
F
N
OH
H
Br
N
F
OHC
THP
N
N
F
N
N
NH2
N
+
Br
Br
N
N
N
N
F
17
16
5
Scheme 2 Initial retrosynthetic analysis of compound 14.

JOURNAL OF CHEMICAL RESEARCH 2017 243
atom. However, when we attempted this synthetic strategy, no
reaction occurred between the late-stage intermediate 15 and
1,2-dibromoethane, even when catalytic NaI and an elevated
temperature were used. When chloroacetyl chloride was used
as the two-carbon linker instead of 1,2-dibromoethane, no
product was formed under various conditions. Steric hindrance
is thought to be the reason for the low reactivity of compound
15. A minor modification was then made to this synthetic route,
and the aldehyde 17 was replaced by the aldehyde 18, which
bears a 2-bromoethyl substituent on the nitrogen atom, so that
an intramolecular cyclisation can be performed after a reductive
amination reaction between the aldehyde 18 and the amine 16
(Scheme 3).
The final synthetic route to YC-071 is illustrated in Scheme
4. After a nucleophilic ring-opening reaction of the epoxide 5
with sodium azide, catalytic hydrogenation under a hydrogen
atmosphere gave the amino fragment 16. The synthesis of
aldehyde 18 started from commercially available 3,5-dibromo-
1H-1,2,4-triazole. Alkylation of 3,5-dibromo-1H-1,2,4-
triazole with 1,2-dibromoethane afforded compound 20 in
68% yield. Regioselective Br/Mg exchange of compound
20 using isopropylmagnesium bromide at −78 °C followed
by addition of methyl formate gave the aldehyde 18 in 66%
yield.13 With the amine 16 and aldehyde 18 in hand, a reductive
amination reaction was performed with an AcOH/NaBH4
system to yield compound 19. NaI-catalysed intramolecular
cyclisation of compound 19 under a two-phase reaction
system afforded compound 14 in 70% yield. Suzuki coupling
of compound 14 with 2-cyanopyridine-5-boronic acid pinacol
ester finally furnished YC-071 in 57% yield.
Conclusion
In summary, we have developed a novel and scalable synthesis
of the potent azole antifungal agent YC-071. The key steps
involved a reductive amination reaction of the amine 16 and
aldehyde 18 followed by an intramolecular cyclisation to give
the key intermediate 14. The new route is operationally simple,
requiring only limited purification of all the intermediates,
and with the exception of a Sandmeyer reaction and the ring-
opening reaction between epoxide 5 and the amine 13, it can
readily be scaled up. Using this new process, we were able to
produce YC-071 in multigram quantities in an overall yield of
23% from the epoxide 5.
Experimental
All reagents were purchased from commercial suppliers and used
without further purification. Silica gel thin-layer chromatography was
performed on pre-coated plates GF254 (Qindao Haiyang Chemical,
N
OH
N
OH
H
N
OHC
N
F
Br
N
F
N
N
N
N
N
NH2
N
+
Br
Br
Br
N
N
N
N
N
Br
F
14
F
16
18
Scheme 3 Second retrosynthetic analysis of compound 14.
Br
N
N
Br
N
H
N
Br
b
Br
a
CHO
N
Br
N
N
N
N
Br
Br
20
18
N
OH
N
N
F
NH
Br
N
d
Br
N
O
F
N
N
OH
N
N
F
N
F
c
NH2
N
N
F
F
19
5
16
N
OH
N
OH
N
F
N
F
N
N
N
N
N
N
f
e
Br
N
N
N
CN
N
N
F
14
F
YC-071
Reagents and conditions: (a) BrCH CH2Br, NaHCO3, 55 °C, DMF, 68.3%; (b) HCO2CH3, i-PrMgBr, −80 °C, THF, 65.9%; (c) (i) NaN3, NH Cl, 105 °C, DMF,
(ii) H , Pd/C, 1 atm, r.t., EtOH, 80% (22 steps); (d) AcOH, NaBH CN, MS, 25 °C, THF, 72%; (e) NaI, benzyltrimethylylammonium chloride4, NaHCO3, 60 °C,
THF/2H2O, 70%; (f) 2-cyanopyridine-5-boronic acid pinacol es3ter, Pd(PPh3)4, Cs2CO3, 80 °C, 1,4-dioxane/H2O, 57%.
Scheme 4 Final synthetic route to YC-071.

244 JOURNAL OF CHEMICAL RESEARCH 2017
China). Column chromatography was performed on silica gel H (200–300
mesh). The solvent proportions were expressed on a volume:volume basis.
1H NMR and 13C NMR spectra were obtained with Bruker ARX-400 or
ARX-500 spectrometers using TMS as an internal standard; chemical
shifts are given in parts per million (δ) values and coupling constants (J) in
Hertz. ESI-MS spectra were obtained on a Kratos MS 80 mass
spectrometer and EI-MS spectra were obtained on a Finnigan MAT95
spectrometer. Melting points (uncorrected) were determined on an X-4
melting point apparatus. Optical rotations were determined with a Perkin-
Elmer 241 polarimeter at 22 °C and 589 nm using a sodium lamp and a 1
mL cell. Data are reported as follows: [α]2ꢀ2 (concentration in g 100 mL−1,
solvent).
NaBH3CN (2.6 g, 0.041 mol) was added and the reaction was stirred
for another 30 min at r.t. The reaction was quenched with water (15 mL)
and extracted with EtOAc (80 mL × 3). The combined organic layers
were washed with brine (80 mL × 2) and saturated NaHCO3 solution
(80 mL × 2), dried over Na2SO4 and concentrated in vacuo. The residue
was purified by silica gel column chromatography to provide compound
1
19 as: White jelly; yield 6.6 g (72%); H NMR (400 MHz, CDCl3): δ
7.84 (s, 1H), 7.80 (s, 1H), 7.44–7.36 (m, 1H), 6.81–6.71 (m, 2H), 4.94
(d, J = 14.2 Hz, 2H), 4.78 (d, J = 14.2 Hz, 1H), 4.71–4.56 (m, 2H), 4.25
(d, J = 14.3 Hz, 1H), 3.97 (d, J = 14.3 Hz, 1H), 3.82 (t, J = 6.1 Hz, 2H),
3.25 (q, J = 6.5 Hz, 1H), 0.99 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3): δ 162.65, 158.19, 156.68, 151.80, 144.07, 139.34, 130.42, 123.76,
111.68, 104.04, 78.63, 57.24, 55.72, 50.11, 42.25, 29.29, 14.28; MS (ESI)
m/z: 536.1 ([M + H]+). HRMS (ESI) m/z calcd for C17H20Br2F2N7O ([M +
H]+): 534.0059; found: 534.005.
(2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-
2-ol (16)
A solution of 5 (10.00 g, 39.80 mmol) and NH4Cl (3.51 g, 65.67 mmol) in
DMF (100 mL) was treated with NaN3 (7.76 g, 119.40 mmol) and then the
reaction mixture was stirred for 4 h at 105 °C. After cooling, the mixture
was partitioned between water (80 mL) and EtOAc (200 mL × 2). The
organic layer was then washed with brine (60 mL × 2), dried over Na2SO4
and concentrated in vacuo to afford a dark brown oil, which was used for
the following reaction without further purification. The crude solid was
dissolved in EtOH (100 mL) and 10% palladium on carbon (1.2 g) was
added. The reaction mixture was stirred under a hydrogen atmosphere for
6 h at r.t. Then, the mixture was filtered and the filtrate was concentrated
in vacuo. The residue was purified by silica gel column chromatography to
provide compound 16 as: White solid; m.p. 154–155 °C (lit.14 146–148 °C);
yield 8.5 g (80% for two steps);1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H),
7.81 (s, 1H), 7.57–7.44 (m, 1H), 6.88–6.72 (m, 2H), 4.78–4.62 (m, 2H), 3.64
(qd, J = 6.5, 2.8 Hz, 1H), 1.30 (br, 2H), 0.87 (d, J = 6.5 Hz, 3H);13C NMR
(125 MHz, CDCl3): δ 163.74, 161.26, 159.83, 157.42, 130.08, 111.45, 103.88,
56.65, 50.39, 19.38; MS (ESI) m/z: 269.1 ([M + H]+). HRMS (ESI) m/z
calcd for C12H15F2N4O ([M + H]+): 269.1208; found: 269.1205.
(2R,3R)-3-(2-bromo-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-
7(8H)-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
(14)
A solution of 17 (2.4 g, 0.0045mol) in THF (80 mL) was treated
with NaHCO3 (2.7 g, 0.0326 mol), NaI (0.51 g, 0.0012 mol),
benzyltrimethylammonium chloride (0.6 g, 0.0032 mol) and water
(20 mL). The mixture was stirred for 24 h at 60 °C. After cooling to
r.t., the mixture was extracted with EtOAc (50 mL × 3). The combined
organic layers were washed with brine (60 mL × 2), dried over Na2SO4
and concentrated in vacuo. The residue was purified by silica gel column
chromatography and recrystallised from dichloromethane to provide
compound 14 as: White solid; m.p. 198–199 °C (lit.7 195–197 °C); yield
1.43g (70%); 1H NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 7.79 (s, 1H),
7.43 (td, J = 9.0, 6.5 Hz, 1H), 6.87–6.60 (m, 2H), 5.08 (d, J = 1.3 Hz, 1H),
4.93 (dd, J = 14.5, 1.3 Hz, 1H), 4.86 (d, J = 14.5 Hz, 1H), 4.30–4.14 (m,
3H), 3.95 (d, J = 15.9 Hz, 1H), 3.82 (br, 1H), 3.33 (q, J = 6.9 Hz, 1H), 2.94
(dt, J = 12.9, 6.8 Hz, 1H), 0.98 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3): δ 163.21, 161.22, 158.24, 156.29, 152.54, 151.56, 143.43, 139.17,
130.10, 123.76, 111.31, 103.66, 79.38, 62.38, 55.41, 46.81, 6.28; MS (ESI)
m/z: 454.1 ([M + H]+). HRMS (ESI) m/z calcd for C17H17BrF2N7O ([M −
H]–): 452.0652; found: 452.0649.
3,5-dibromo-1-(2-bromoethyl)-1H-1,2,4-triazole (20)
A mixture of 3,5-dibromo-1H-1,2,4-triazole (15.5 g, 0.068 mol) and
NaHCO3 (6.8 g, 0.082 mol) in DMF (150 mL) was slowly treated
with 1,2-dibromoethane (26.0 g, 0.137 mol). The mixture was stirred
for overnight at 55 °C. Then, the reaction was quenched with water
(20 mL) and extracted by EtOAc (60 mL × 2). The organic layer was
washed with brine (40 mL × 2), dried over Na2SO4 and concentrated in
vacuo. The residue was purified by silica gel column chromatography
to provide compound 20 as: White solid; m.p. 47–48 °C; yield 15.5 g
5-(7-((2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-
1-yl)butan-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)
picolinonitrile (YC-071) (4)
A mixture of 14 (2 g, 0.0044 mol), CsCO3 (2.87 g, 0.0088 mol),
2-cyanopyridine-5-boronic acid pinacolester (1.32 g, 0.0057 mol) in
dioxane (30 mL) and H2O (10 mL) under an argon atmosphere was treated
with Pd(PPh3)4 (0.76 g, 0.0007 mol). The mixture was heated at 80 °C for
8 h. The solvent was evaporated under reduced pressure. The residue was
diluted with water (80 mL) and extracted with EtOAc (50 mL × 3). The
combined organic layers were washed with water (80 mL × 2) and brine
(80 mL × 2), dried over anhydrous Na2SO4, and filtrated, then
concentrated in vacuo. The residue was purified by silica gel column
chromatography to give YC-071 as: White solid; m.p. 204–205 °C (lit.15
199–201 °C); yield 1.2 g (57.1%); [α]2ꢀ2 = −55.6° (c = 0.125 g 100 mL−1,
CHCl3); 1HNMR (400 MHz, DMSO-d6): δ 9.30 (dd, J = 2.1, 0.8 Hz, 1H),
8.52 (dd, J = 8.1, 2.1 Hz, 1H), 8.26 (s, 1H), 8.15 (dd, J = 8.1, 0.8 Hz, 1H),
7.66 (s, 1H), 7.33 (td, J = 9.0, 7.0 Hz, 1H), 7.16 (ddd, J = 11.9, 9.0, 2.6 Hz,
1H), 6.95 (td, J = 8.5, 2.6 Hz, 1H), 5.74 (s, 1H), 4.85 (s, 2H), 4.43–4.27 (m,
2H), 4.22 (d, J = 15.1 Hz, 1H), 4.08 (d, J = 15.1 Hz, 1H), 3.58–3.51 (m, 1H),
3.48 (q, J = 6.9 Hz, 1H), 3.07–2.97 (m, 1H), 0.87 (d, J = 6.9 Hz, 3H);
13CNMR (125 MHz, DMSO-d6): δ 162.98, 161.36, 159.67, 158.13, 157.11,
153.65, 150.91, 148.33, 145.11, 134.72, 132.77, 130.53, 129.75, 117.81,
111.19, 104.35, 79.41, 62.74, 55.87, 47.57 (3C, overlap), 8.06; MS (ESI) m/z:
478.2 ([M + H]+). HRMS (ESI) m/z calcd for C23H21F2N9ONa ([M + Na]+):
500.1735; found: 500.1732.
1
(68%); H NMR (400 MHz, CDCl3): δ 4.52 (t, J = 6.3 Hz, 2H), 3.72
(t, J = 6.3 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 142.03, 131.66,
51.96, 29.10; MS (EI) m/z: 331 (M+). HRMS (EI) m/z calcd for
C4H4Br3N3(M+): 330.7955; found: 330.7960.
3-bromo-1-(2-bromoethyl)-1H-1,2,4-triazole-5-carbaldehyde (18)
A solution of 20 (5 g, 0.015 mol) in THF (80 mL) was treated with
i-PrMgBr (1 M, 18.0 mL, 0.018 mmol) at −78 °C under an argon
atmosphere. After the mixture had been stirred at this temperature for
1 h, HCO2CH3 (1.16 g, 0.0158 mol) was added. Then, the reaction was
stirred for another 1 h at −40 °C. The reaction was quenched with aqueous
NH4Cl (15 mL) and extracted with EtOAc (3 mL × 50). The combined
organic layer was washed with brine (80 mL × 2), dried over Na2SO4
and concentrated in vacuo. The residue was purified by silica gel column
chromatography to provide compound 18 as: White solid; m.p. 69–70 °C;
yield 2.8 g (65.9%); 1H NMR (400 MHz, CDCl3): δ 9.95 (s, 1H), 4.99 (t,
J = 6.3 Hz, 2H), 3.76 (t, J = 6.3 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ
180.10, 150.23, 140.57, 51.42, 28.33; MS (EI) m/z: 281 (M+). HRMS (EI)
m/z calcd for C5H5Br2N3O(M+): 280.8799; found: 280.8800.
(2R,3R)-3-(((3-bromo-1-(2-bromoethyl)-1H-1,2,4-triazol-5-yl)
methyl)amino)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)
butan-2-ol (19)
Acknowledgements
A solution of 18 (4.6 g, 0.0163 mol) and 16 (4.58 g, 0.017 mmol)
in 100 mL THF was treated with AcOH (0.3 mL, 0.005 mmol)
and molecular sieve (4Å, 10g), and stirred for 30 min at r.t. Then,
This work was supported by the National Natural Science
Foundation of China (No. 21402223).

JOURNAL OF CHEMICAL RESEARCH 2017 245
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Electronic Supplementary Information
The ESI is available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
Received 15 January 2017; accepted 4 March 2017
Paper 1704537
https://doi.org/10.3184/174751917X14902201357419
Published online: 3 April 2017
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