Scalable synthesis of a tetrasubstituted 7-azabenzofuran as a key intermediate for a class of potent HCV NS5B inhibitors

Article abstract of DOI:10.1016/j.tet.2020.131642

A series of tetrasubstituted 7-azabenzofurans displays remarkable pan-genotype inhibition of HCV NS5B polymerase. One of them has been identified as a potential clinical candidate. Completely different from the original synthesis of a common and key intermediate for this class of compounds, two novel and improved synthetic approaches are developed. Almost every step of the synthesis has been optimized, including several important but not fully explored transformations, such as radical bromination with methyl pyridine and cyanide substitution with TMSCN. The 7-azabenzofuran core is prepared by an acylation-heterocyclization reaction, using acyl chloride as both the reactant and the activation reagent for the N-oxide substrate. Compared with the BMS synthesis, the overall yield has been tripled, and those harmful or cost-effective synthetic steps have been reduced. Furthermore, a transition-metal-free synthetic method for the construction of 3-cyano substituted 7-azabenzofurans is presented.

Full text of DOI:10.1016/j.tet.2020.131642

Journal Pre-proof
Scalable Synthesis of a Tetrasubstituted 7-Azabenzofuran as a Key Intermediate for a
Class of Potent HCV NS5B Inhibitors
Dong Wang, Mindong Huang, Gaoyu Li, Shixin Zheng, Peng Yu
PII:
S0040-4020(20)30849-8
https://doi.org/10.1016/j.tet.2020.131642
TET 131642
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 August 2020
Revised Date: 25 September 2020
Accepted Date: 26 September 2020
Please cite this article as: Wang D, Huang M, Li G, Zheng S, Yu P, Scalable Synthesis of a
Tetrasubstituted 7-Azabenzofuran as a Key Intermediate for a Class of Potent HCV NS5B Inhibitors,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131642.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
©
2020 Elsevier Ltd. All rights reserved.

Graphical Abstract

Graphical Abstract
Scalable Synthesis of a Tetrasubstituted 7-
Azabenzofuran as a Key Intermediate for a
Class of Potent HCV NS5B Inhibitors
Leave this area blank for abstract info.
Dong Wang*, Mindong Huang, Gaoyu Li, Shixin Zheng and Peng Yu
College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China

3
Tetrahedron
journal homepage: www.elsevier.com
Scalable Synthesis of a Tetrasubstituted 7-Azabenzofuran as a Key Intermediate
for a Class of Potent HCV NS5B Inhibitors
Dong Wang*, Mindong Huang, Gaoyu Li, Shixin Zheng and Peng Yu
College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of tetrasubstituted 7-azabenzofurans displays remarkable pan-genotype inhibition of
HCV NS5B polymerase. One of them has been identified as a potential clinical candidate.
Completely different from the original synthesis of a common and key intermediate for this
class of compounds, two novel and improved synthetic approaches are developed. Almost
every step of the synthesis has been optimized, including several important but not fully
explored transformations, such as radical bromination with methyl pyridine and cyanide
substitution with TMSCN. The 7-azabenzofuran core is prepared by an acylation-
heterocyclization reaction, using acyl chloride as both the reactant and the activation reagent
for the N-oxide substrate. Compared with the BMS synthesis, the overall yield has been
tripled, and those harmful or cost-effective synthetic steps have been reduced. Furthermore, a
transition-metal-free synthetic method for the construction of 3-cyano substituted 7-
azabenzofurans is presented.
Available online
Keywords:
Nitrogen heterocycles
Nitrogen oxides
Synthesis design
7
-Azabenzofuran
2
009 Elsevier Ltd. All rights reserved.
inhibitors i. e., BMT-052 as a potential clinical candidate,
which is able to overcome the poor metabolic stability of
the previous analogues and has escalating inhibition.
1. Introduction
[5]
Hepatitis C virus (HCV) is a serious disease endangering
human health with high mortality and morbidity. It initi-
ates critical liver malfunction like cirrhosis, hepatocellular
carcinoma or liver HCV cancer. Though the vaccine therapy
for prototypes of Hepatitis A and B is available, vaccination
program to combat Hepatitis C is still in progress. The
treatment has been progressed rapidly,[1] but morbidity
and mortality rates are still predicted to rise, efficacious
and tolerable therapies are urgently needed. It has become
the bottleneck problem in treating this disease that the
appropriate treatment regimen and duration can vary
Scheme 1. Compound 1 as the Common and Key Interme-
diate for Bioactive 7-Azabenzofurans.
[2]
depending on the patient’s viral genotype. Therefore, the
development of pan-genotypic NS5B polymerase inhibitors
is the ideal regimen in treating HCV.
In 2014, BMS scientists reported a series of novel
tetrasubstituted 7-azabenzofurans (I, Scheme 1) exhibiting
[3]
pan-genotype inhibition of HCV NS5B polymerase. After
extensive SAR studies, BMS-986139 was selected as a
preclinical candidate.[ Unfortunately, it becomes ineffec-
tive in phase I due to microcrystallization problems in
toxicological studies. Further studies led to the identifica-
tion of the second generation of pan HCV NS5B polymerase
4]

4
Compound 1,
a
5-bromo-6-chloro substituted 7-
alcohols, thiols, et al. through S Ar, or both the C5-bromo
N
azabenzofuran, attracts our attention. It is not only the
common and key intermediate for this class of HCV NS5B
polymerase inhibitors, but also can be converted to various
bioactive 7-azabenzofurans. As shown in Scheme 1, BMT-
and C6-chloro atoms can be substituted by aryl and alkyl
groups via metal catalyzed cross coupling reactions to
afford those biologically active 7-azabenzofuran III. One of
[6]
the good examples can be found with CB1R modulators.
0
52 is prepared from 1 in 4 steps by simply replacing the
Therefore, the efficient and facile synthesis of 1 not only
offers large scale production of this series of compounds,
but also provides access to various tetrasubstituted 7-
azabenzofurans.
[5]
bromo and chloro atoms. Similarly, BMS-986139 is pre-
pared in 3 steps.[ Besides, a more general form II can be
accessed by a similar synthetic approach to 1. The C6-
chloro atom can be easily substituted by various amines,
4]
Scheme 2. Route 1-BMS Synthesis of Compound 1.
Although 1 is relatively small in size, the construction of
-azabenzofuran core and the presence of four substitu-
We were initially focused on the synthesis of pyridine-3-
acetate 10 (Scheme 3), which is the appropriate substrate
for Emery’s synthesis of 3-ester substituted 7-
7
ents, especially the two reactive halogen atoms make it a
quite challenging synthetic problem. BMS scientists devel-
oped two approaches to 1 (Scheme 2). The optimized syn-
[10]
azabenzofuran.
We explored several routes and we
finally envisioned attachment of an ester group to inex-
pensive and readily available 3-bromo-2-chloro-5-
[4]
thesis requires 6 steps with an overall yield of 16%, and
the original one is longer (9 steps in total, 6 steps from 2)
and tedious.[ The low total yield renders this synthetic
route not practical in the large scale production of the final
target. Besides, there are many drawbacks in this synthesis
from green chemistry standpoint. First, too many halogen-
ating reagents were used in the synthesis. The synthesis
commenced with 2-chloro-6-methoxypyridine, and halo-
[11]
methylpyridine (6, Sigma Aldrich price: $56.10/25g ).
Attempt conversion of the dihalide 6 to 10 by benzylic
3b]
[12]
deprotonation
with various bases and alkylation with
dimethyl carbonate or methyl chloroformate resulted in
vain. Bromination of metalated 7 via Li-Zn transmeta-
[13]
lation
Scheme 3. Route 2-Synthesis of the Advanced Intermedi-
ate 10.
genating reagents, such as NBS, BBr and NIS were used in
3
every step of the first five steps. The use of these halogen-
ating reagents is not only harmful to the environment, but
also is wasted as the three halogen atoms in 3 are all sub-
stituted by carbon or nitrogen atoms finally. Second, one
third of the reactions were catalyzed by Pd catalysts. This
not only increases the cost, but also causes environmental
problems. Finally, the highly toxic CO gas was used in the
last step, and high-pressure operation (300 psi) was re-
quired.
Our group is particularly interested in the preparation of
biologically active complex pyridine derivatives based on
pyridine N-oxides chemistry,[ which has been demon-
strated to be a powerful and versatile strategy for direct
did not yield 10 either. Then, a three-step synthesis of 10
7]
was developed. Although CCl
4
is a common solvent for
radical bromination, the yield is not satisfactory for those
[8]
incorporation of new functionalities at the C-2 position.
[14]
N-heterocyclic compounds.
The optimization of this
We recently reported the efficient synthesis of a compound
reaction is carried out. Initial attempts to effect benzylic
bromination of 6 with NBS in acetonitrile under the cataly-
sis of benzoyl peroxide afforded 8 in only 32% yield (entry
with structure I,[ but this route cannot be applied to BMT-
9]
0
52. In order to solve the aforementioned problems asso-
ciated with this class of compounds, we reported herein a
practical, scalable and greener synthesis of compound 1.
1
, Table 1). The dibrominated byproduct 8-bis was detect-
ed, and lots of 6 remained unreactive. Stronger conditions
were applied, including higher reaction temperature in a
sealed tube, more benzoyl peroxide and more concentrat-
2. Results and Discussion

5
ed reaction media, but did not afford essential difference
entries 2-4). In order to reduce the formation of 8-bis,
TMSCN is relatively underexplored. Following a known
procedure under basic conditions and the catalysis of KI,
[
15]
(
less NBS was employed. Although the reaction was still
incomplete, the yield improved to 73% (entry 5). However,
further reducing the quantity of NBS was harmful to the
reaction (entry 6). Next, screening of the solvent led to the
identification of DCE as the best one (entries 7-10). Alt-
lots of starting material remained without detecting the
desired product 9. Obtained instead was the iodide substi-
tuted 9-bis (entry 1, Table 2). Switching the reaction sol-
vent to acetone or DMF, or increasing reaction tempera-
ture did not afford 9 either (entries 2-4). Failure to per-
form this reaction may be rationalized by the weaker nu-
cleophilicity of TMSCN. Strategies that could enhance the
nucleophilicity of TMSCN was then tested. TBAF or LiOH
was selected as both of them could initiate silicon-carbon
cleavage, generating cyanide ion to promote the reaction.
Gratifyingly, both reagents produced 9 (entries 5 & 6), and
LiOH afforded excellent yield (entry 6). Moreover, this
condition was also successfully applied to 5.4 g scale reac-
tion (entry 7). Hydrolysis of 9 in methanol afforded 10 in
hough the yield is similar to CH CN, DCE is preferred due
3
to the less toxicity. Incomplete reaction resulting in lower
yield was detected utilizing less NBS (entry 11). This reac-
tion is scalable. The yield of 5.0 g scale is slightly higher
than that of 0.2 g scale (entry 12).
Table 1. Optimization of the radical bromination.*
9
4% yield (Scheme 3). Fortunately, the C2-chloro atom
survived and not substituted by methoxy or hydroxy
group.
T (℃ )
yield
%)
entry
solvent
eq. of NBS
We envisioned that cyanide 9 as a possible precursor for
the construction of 7-azabenzofuran core, which would
lead to a more concise synthesis of 1 than starting from 10.
9 was oxidized by peroxytrifluoroacetic acid, generated in
situ by reaction of urea hydrogen peroxide with TFAA, to
give pyridine N-oxide 11 cleanly and quantitatively
(
1
2
CH
CH
3
CN
CN
CN
CN
CN
CN
3.0
3.0
3.0
3.0
1.5
1.1
1.5
1.5
1.5
1.5
1.1
1.5
reflux
100
32
54
45
40
73
70
50
0
3
a
3
4
CH
CH
CH
CH
CCl
3
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
b
3
5
3
6
7
8
9
3
(
Scheme 4). Due to the similar electron withdrawing char-
4
acter of cyano group and ester group, it was expected that
the cyano substituted 7-azabenzofuran 12 would be pro-
duced in high efficiency by subjecting 11 to the acylation-
THF
dioxane
DCE
DCE
DCE
0
0c
1
1
1
75
71
79
d
e
[10]
heterocyclization conditions developed by Emery. How-
12
ever, lots of 11 remained and 12 was obtained in only 18%
yield (entry 1, Table 3). Switching DCM to chloroform and
heating the reaction to reflux gave similar result (entry 2).
The acylation reaction is the rate determining step, there-
fore faster deprotonation by a stronger base may offer
better result. After careful screening of bases and solvents,
LiHMDS was identified as the best choice (21% yield, entry
*
Unless otherwise noted, all reactions were conducted with 6 (200
a
mg, 1.0 equiv), Bz
equiv of Bz
2
O
2
(0.1 equiv) and NBS in solvent (0.34 M). 0.2
2
O
2
was used.b More concentrated solution (0.68 M) was
c
d
applied. The reaction is complete in 6 hours. About 20% of com-
pound 6 remained unreactive after 10 hours of reaction. 5.0 g of 6
e
was used.
8
). Doubling the amount of THF and increasing the quanti-
Table 2. Optimization of the benzylic cyanation.*
ty of acyl chloride afforded better result (entry 9). To our
delight, the yield was almost doubled by doubling the
quantity of LiHMDS (entry 10), but further increase of
LiHMDS was harmful to the reaction (entry 11). Finally, we
found that the yield could be increased to 63% by adding
1
.0 equiv of DMAP to the reaction mixture, which also
en-
try
1
2
3
eq. of
TMSCN
2.0
2.0
2.0
2.0
1.5
1.2
1.2
yield
(%)
0
0
0
resulted in easier isolation of the product from the large
excess of 4-fluorobenzoyl chloride. Moreover, similar re-
sult was achieved for larger scale reaction (59% yield for
additive/eq.
solvent
CH CN
acetone
DMF
T°C
25
25
25
reflux
25
25
KI/0.2 + K
KI/0.2 + K
KI/0.2 + K
KI/0.2 + K
2
2
2
2
CO
3
CO
3
CO
3
CO
3
/2.0
/2.0
/2.0
/2.0
3
4
.40 g scale, see Experimental Section). Switching the base
to LDA led to worse result (entry 13).
4
5
acetone
0
TBAF/1.5
LiOH/1.2
LiOH/1.2
CH
3
CH
3
CH
3
CN
CN
CN
39
93
95
6
Scheme 4. Attempt Synthesis of 1 and 4 from Cyanide
Precursor.
a
7
25
*
Unless otherwise noted, all reactions were conducted with 8 (100
a
mg, 1.0 equiv), additive and TMSCN in solvent (0.25 M). 5.41 g of 8
was used.
Compound 8 was then proceeded to the next step. Alt-
hough substitution of benzyl bromide with cyanide by KCN
or NaCN is well documented, the use of much less toxic

6
Finally, the advanced intermediate 10 was selected
and elaborated to 1 successfully by two efficient routes
Scheme 5). 10 was oxidized to afford 13 in quantitative
(
yield without the need of any column purification. Com-
pound 13 was then subjected to the acylation-
heterocyclization conditions, and the tetrasubstituted 7-
azabenzofuran 4 was obtained in 85% yield after extensive
studies (Table 4). Completion of the synthesis was accom-
plished by an ester hydrolysis and HBTU-mediated cou-
pling between 5 and tert-butylamine with above 90% yield
for both steps. Intermediate 4 was also proceeded to the
ester aminolysis step to explore a more concise synthesis
of 1. Original attempts to perform this reaction using
2
Table 3. Optimization of the acylation-heterocyclization
with cyanide substrate.*
CN
MeNH under various basic conditions did not yield any
Br
Cl
CN
base, additive
solvent, T °C
Br
Cl
[
17]
[18]
desired product, neither did AlMe
which have been reported very effective for amidation of
esters. Running the reaction with BBr , another effective
ester aminolysis reagent, afforded the desired product 1
in 68% yield (Scheme 5). Further optimization did not give
any satisfactory result.
3
nor Mg(OMe)
2
,
F
N+
O- 11
+
F
COCl
N
O
AC
12
3
[19]
en-
try
eq. of
DMAP
6 equiv
6 equiv
none
none
none
none
none
none
none
none
none
1 equiv
1 equiv
yield
(%)
18
15
0
0
0
5
0
21
30
56
45
63
42
base
eq. of AC
solvent
DCM
a
1
2
DBU
DBU
NaH
NaH
NaH
6.0
6.0
2.0
2.0
2.0
2.0
4.0
2.0
6.0
6.0
6.0
6.0
6.0
Table 4. Optimization of the acylation-heterocyclization
with ester substrate.*
a,b
CHCl
3
c
3
THF
toluene
DMF
THF
THF
THF
THF
THF
THF
THF
c
4
c
5
c
6
NaNH
2
c
t
7
BuOK
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LDA
c
8
9
d
1
1
1
0
1
2
eq. of
LiHMDS
eq. of
DMAP
yield
(%)
e
entry
eq. of AC
d
1
2
3
4
2.2
1.1
1.1
1.1
1.1
1.1
1.0
1.0
none
1.0
1.0
1.0
6.0
6.0
6.0
4.0
6.0
6.0
65
86
78
79
68
85
13
THF
*
Unless otherwise noted, all reactions were conducted with N-oxide
(
100 mg, 1.0 equiv), base: DBU (1.2 equiv) / LiHMDS (1.1 equiv) /
a
5
6
t
NaH (1.2 equiv) / NaNH
2
(1.2 equiv)/ BuOK (1.2 equiv)/ LDA (2.2
b
a
equiv), additive, and AC in solvent (0.125 M) at r.t. 0.17 M concentra-
tion was applied. The reaction was heated to reflux. c 0.25 M concen-
tration was applied. d 2.2 equiv of LiHMDS was used. 4.0 equiv of
LiHMDS was used.
b
*
(
Unless otherwise noted, all reactions were conducted with N-oxide
e
200 mg, 1.0 equiv), LiHMDS (1.1 equiv), DMAP, and AC in THF (0.25
M) at r.t. KHMDS was used to replace LiHMDS. b 4.74 g of 13 was
a
used.
With the advanced intermediate 12 in hand, it seems
that the following transformation to 1 is straight forward
3
. Conclusions
(Scheme 4). Unfortunately, this synthetic route is not fea-
sible. Attempts to convert 12 directly to primary amide 1
Table 5. Comparison of the key information of synthetic
[16]
by modified Ritter reaction procedure were unsuccess-
ful. Alongside the Ritter reaction, we simultaneously pur-
sued the hydrolysis of 12 to 4. However, following the
procedure of the transformation from 9 to 10 did not pro-
duce the desired product.
routes
Key information
Total yield
Total steps
Route 1
16%
Route 2
a
51% (41%)
a
6
7 (6)
Production scales
1: 0.567 g
Y
1: 4.66 g
Commercial availability of SM
No. of steps using precious metals
No. of steps using highly toxic rea-
gents
No. of steps using halogenating rea-
gents
Y
0
0
2 (4, 6)b
1 (CO）
Scheme 5. Route 2-Completion of the Synthesis.
5 (1-5)b
0
2 (1, 3)b
0
No. of high temperature reactions (≥
1
00℃)
No. of low temperature reactions (< 0
0
1(5)b
0
℃
)
No. of high-pressure reactions
1 (6)b

7
a
Those numbers in the parentheses represent the total yield or total
steps using ester aminolysis approach. b Those numbers in the paren-
theses represent the step number of the synthesis
harmful and cost-effective synthetic steps of BMS have
been decreased, including reactions requiring the use of
halogenating reagents, precious metals, high temperature
or high-pressure operation (Table 5). Furthermore, a new
.
In conclusion, two novel synthetic approaches to a
common and key intermediate for a series of potent HCV
NS5B polymerase inhibitors, have been accomplished in 7
or 6 linear steps with an overall yield of 51% or 41%
synthetic
method
for
3-cyano
substituted
7-
azabenzofurans utilizing easily accessible pyridine N-
oxides as substrates has been developed. The high efficien-
cy and scalability of the synthesis reported herein not only
offers the practical large-scale production of this series of
HCV NS5B polymerase inhibitors that may be proceeded to
on market drugs in future, but also provides a new strategy
for the divergent synthesis of various tetrasubstituted 7-
azabenzofuran derivatives.
(
Scheme 6). Almost every step of the synthesis has been
optimized, including several important but not fully ex-
plored transformations. Although the synthetic steps are
not reduced in comparison with the BMS synthesis, the
overall yield has been tripled (Table 5). In addition, those
Scheme 6. The whole synthetic route of compound 1.
ml) and extracted twice with ethyl acetate. The combined
organic extracts were washed with brine, dried over Na SO ,
2 4
4. Experimental section
filtered and concentrated in vacuo. The resulting residue was
chromatographed gradiently on silica gel with PE/EA
The preparation experiments were performed under air
or an argon atmosphere in oven dried glassware. Solvents
used as reaction media were distilled immediately before
use: THF was distilled from Na/benzophenone ketyl, DCM
and DCE were distilled from calcium hydride, DMF was
obtained from vacuum distillation. All reagents were pur-
chased at the highest commercial quality and used without
further purification. Oil bath was used as the heat source
for those reactions that require heating. Reactions were
monitored by thin layer chromatography (TLC) using ultra
violet light (UV) as the visualizing agent. Nuclear magnetic
resonance spectra (NMR) were recorded on Bruker AV-
(
100:1~50:1) to give the product (5.41 g, 79% yield) as a
white solid. The synthesis of 8 has been reported in literature
[
14]
utilizing CCl
4
as solvent but resulted in much lower yield.
1
H NMR (400 MHz, CDCl ) δ 8.34 (s, 1H), 7.98 (d, J = 1.2
3
1
3
Hz, 1H), 4.40 (s, 2H). C NMR (100 MHz, CDCl
3
) δ 150.7,
1
47.8, 142.7, 134.2, 120.4, 27.3.
2-(5-Bromo-6-chloropyridin-3-yl)acetonitrile (9). To sus-
pension of compound 8 (5.41 g, 19.13 mmol) and LiOH•H O
2
(
3
963 mg, 22.96 mmol) in anhydrous CH CN (76 mL) at 0 °C
was added TMSCN (2.28 g, 22.96 mmol) dropwise under
argon atmosphere. The reaction mixture was then warmed to
r.t. and stirred for 4 h. The reaction was complete as indicated
by TLC. Water and ethyl acetate were added to the mixture.
After separation of the organic phase, water phase was ex-
tracted by ethyl acetate for two more times. The combined
organic phases were washed with water, brine, dried over
Na SO , filtered and concentrated in vacuo. The resulting
4
00 instruments and were calibrated using residual un-
1
deuterated solvent as an internal reference ( H NMR:
CHC1
3
7.26 ppm, 13C NMR: CHCl
77.16 ppm). High resolu-
3
tion mass spectra (HRMS) were recorded on a hybrid IT-
TOF mass spectrometer (Shimadzu LCMS-IT-TOF, Kyoto,
Japan). The following abbreviations were used to indicate
multiplicities: s = singlet, d = doublet, t = triplet, q = quar-
tet, quin = quintet, sex = sextet, sep = septet, dd = doublet
of doublets, dt = doublet of triplets, ddd = doublet of dou-
blet of doublets, ddt = doublet of doublet of triplets, m =
multiplet).
2
4
residue was chromatographed gradiently on silica gel with
PE/EA (20:1~5:1) to give the product (4.18 g, 95% yield) as a
1
white solid. H NMR (400 MHz, CDCl
) δ 8.30 (d, J = 2.0 Hz,
3
1
3
1H), 7.97 (d, J = 2.0 Hz, 1H), 3.77 (s, 2H). C NMR (100
MHz, CDCl ) δ 151.0, 147.0, 141.7, 126.4, 120.9, 116.0, 20.2.
3
3
-Bromo-5-(bromomethyl)-2-chloropyridine (8). To a
solution of compound 6 (5.0 g, 24.22 mmol) in DCE (70 mL)
-
HRMS (-ESI-TOF) m/z: [M-H] Calcd for C
7
H
3
BrClN
2
2
28.9174; Found 228.9167.
was added NBS (4.3 g, 36.32 mmol) and Bz O (587 mg, 2.42
2
2
mmol). The resulting solution was heated to reflux and stirred
for 6 h. The reaction was complete as indicated by TLC. After
cooled down to r.t., the reaction was quenched with water (140
Methyl 2-(5-bromo-6-chloropyridin-3-yl)acetate (10). To a
solution of compound 9 (4.18 g, 18.18 mmol) in MeOH (15

8
mL) was added SOCl (3.3 ml, 45.45 mmol) dropwise at 0℃ .
= 4 ~ 5. Subsequently, the suspension was filtered and the
2
The reaction mixture was increased to r.t. and stirred overnight
until the reaction was complete as indicated by TLC. The
reaction mixture was concentrated in vacuo. Saturated aqueous
solid was washed with cold water and dried in vacuo to give
the product (5.09 g, 95% yield) as a white solid. H NMR (400
1
MHz, d6-DMSO) δ 13.71 (s, 1H), 8.59 (s, 1H), 8.16 (dd, J =
1
3
NaHCO and DCM were added to the residue. After separa-
5.6, 8.8 Hz, 2H), 7.43 (t, J = 8.8 Hz, 2H). C NMR (100
MHz, d6-DMSO) δ 163.7 (d, J = 168 Hz), 163.2, 159.4, 157.1,
143.9, 136.9, 132.3 (d, J = 9 Hz), 124.2, 120.9, 115.7 (d, J =
3
tion of the organic phase, water phase was extracted by DCM
for two more times. The combined organic extracts were
washed with brine, dried over Na SO , filtered and concentrat-
-
22 Hz), 115.1, 108.3. HRMS (-ESI-TOF) m/z: [M-H] Calcd
2
4
ed in vacuo. The resulting residue was chromatographed gra-
diently on silica gel with PE/EA (30:1~10:1) to give the prod-
uct (4.47 g, 94% yield) as a white solid. H NMR (400 MHz,
5 3
for C14H BrClFNO 367.9131; Found 367.9133.
1
5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-
b]pyridine-3-carboxamide (1). HBTU (7.61 g, 20.01 mmol)
was added to a stirring solution of compound 5 (5.09 g, 13.74
mmol), methylamine hydrochloride (4.57 g, 67.75 mmol) and
DIEA (8.76 g, 67.75 mmol) in THF (90 mL). The resulting
solution was stirred at r.t. overnight. TLC indicated complete
conversion. The solution was then diluted with EtOAc and 1
M HCl. The layers were separated and water layer was ex-
tracted with EtOAc. The combined organic extracts were
washed with water, brine, dried over Na SO , filtered and
CDCl ) δ 8.23 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H),
3
13
3
1
.73 (s, 3H), 3.61 (s, 2H). C NMR (100 MHz, CDCl ) δ
3
70.3, 149.8, 148.5, 143.2, 130.1, 120.2, 52.7, 37.0. HRMS
+
(
+ESI-TOF) m/z: [M+H] Calcd for C H NO ClBr 263.9421;
8
8
2
Found 263.9411.
3
-bromo-2-chloro-5-(2-methoxy-2-oxoethyl)pyridine
oxide (13). To a stirred solution of compound 10 (4.47 g,
7.00 mmol) and urea hydrogen peroxide (7.53 g, 80.09
1-
1
2
4
mmol) in DCM (78 mL) was added TFAA (15.29 g, 72.70
mmol) dropwise at 0 °C. The reaction mixture was warmed to
r.t and stirred for 1 h. The reaction was complete as indicated
by TLC. The excess peroxide was destroyed by saturated
aqueous Na S O and water. The resulting mixture was ex-
concentrated in vacuo. The resulting residue was chromato-
graphed gradiently on silica gel with PE/EA (50:1~10:1) to
afford the desired product (4.66 g, 90% yield) as a white solid.
The spectroscopic data are consistent with data previously
[4] 1
reported. H NMR (400 MHz, CDCl ) δ 8.47 (s, 1H), 7.85 -
2
2
3
3
tracted with EA for two times. The combined organic phases
were washed with brine, dried over Na SO , filtered and con-
7.89 (m, 2H), 7.21 (t, J = 8.8 Hz, 2H), 5.89 (s, 1H), 2.98 (d, J
13
= 4.8 Hz, 3H). C NMR (100 MHz, CDCl ) δ 164.4 (d, J =
2
4
3
centrated under reduced pressure to afford the product (4.74 g,
252 Hz), 162.8, 157.9, 154.8, 145.7 135.9, 130.9 (d, J = 9 Hz),
124.2 (d, J = 3 Hz), 120.8, 116.7 (d, J = 22 Hz), 115.8, 111.2,
26.7.
1
1
8
00% yield) as a white solid. H NMR (400 MHz, CDCl ) δ
3
13
.25 (s, 1H), 7.45 (s, 1H), 3.72 (s, 3H), 3.54 (s, 2H). C NMR
(
5
C
100 MHz, CDCl ) δ 169.3, 142.4, 139.8, 130.9, 130.5, 121.2,
3
+
2.8, 37.1. HRMS (+ESI-TOF) m/z: [M+Na] Calcd for
Synthesis of compound 1 from compound 4. To a solution
of compound 4 (200 mg, 0.52 mmol) in DCE (6.3 mL) was
8
H
7
NO
3
ClBrNa 301.9190; Found 301.9177.
added a solution of BBr (1.15 ml, 1.57 mmol) in DCM (1.57
3
Methyl
5-bromo-6-chloro-2-(4-fluorophenyl)furo[2,3-
ml) at 0℃ under argon atmosphere. The reaction mixture was
b]pyridine-3-carboxylate (4). To a solution of compound
increased to r.t. and kept stirring for 4 h. The reaction was then
1
3 (4.74 g, 17.00 mmol) in anhydrous THF (68 mL) under
quenched with MeNH (10.5 ml, 2 M in THF, 20.88 mmol)
2
argon was added dropwise a solution of LiHMDS (18.7 mL, 1
M in THF, 18.7 mmol) at -78°C. After the addition, the result-
ing solution was stirred for 2 h at -78℃ . 4-Fluorobenzoyl
chloride (16.17 g, 101.98 mmol) and DMAP (2.08 g, 16.99
mmol) were then added. The resulting solution was slowly
increased to r.t. and stirred overnight. The reaction was
quenched with saturated potassium carbonate solution and
extracted twice with ethyl acetate. The combined organic
extracts were washed with water, brine, dried over Na SO ,
and diluted with EtOAc and water. After separation of the two
phases, the organic layer was washed with brine, dried over
Na SO , filtered and concentrated to give the crude product,
2 4
which was chromatographed gradiently on silica gel with
PE/EA (50:1~10:1) to afford the desired product (135 mg,
68% yield) as a white solid.
3-bromo-2-chloro-5-(cyanomethyl)pyridine 1-oxide (11).
To a stirred solution of compound 9 (4.12 g, 17.80 mmol) and
urea hydrogen peroxide (6.94 g, 73.79 mmol) in DCM (72
mL) was added TFAA (14.07 g, 66.98 mmol) dropwise at 0
°C. The reaction mixture was warmed to r.t and stirred for 1 h.
The reaction was complete as indicated by TLC. The excess
2
4
filtered and concentrated in vacuo. The resulting residue was
chromatographed gradiently on silica gel with PE/EA
(
100:1~50:1) to give the product (5.53 g, 85% yield) as a
1
white solid. H NMR (400 MHz, CDCl
3
) δ 8.53 (s, 1H), 8.16
(
dd, J = 5.2, 8.8 Hz, 2H), 7.20 (t, J = 8.8 Hz, 2H), 3.97 (s, 3H).
peroxide was destroyed by saturated aqueous Na S O and
water. The resulting mixture was extracted with EA for two
times. The combined organic phases were washed with brine,
2 2 3
13
C NMR (100 MHz, CDCl
60.8, 157.6, 145.8, 137.2, 132.2 (d, J = 9 Hz), 124.1 (d, J = 3
Hz), 120.2, 116.1, 115.9 (d, J = 22 Hz), 107.2, 52.4. HRMS
3
) δ 164.7 (d, J = 253 Hz), 163.0,
1
dried over Na SO , filtered and concentrated under reduced
2 4
+
(
3
+ESI-TOF) m/z: [M+H] Calcd for C H NO FClBr
pressure to afford the product (4.40 g, 100% yield) as a white
15
9
3
1
83.9433; Found 383.9434.
solid. H NMR (400 MHz, d6-DMSO) δ 8.53 (t, J = 0.8 Hz,
1
3
1
H), 7.80 (d, J = 1.6 Hz, 1H), 4.05 (s, 2H). C NMR (100
5
-bromo-6-chloro-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-
MHz, d6-DMSO) δ 141.2, 139.1, 129.4, 129.2, 120.7, 117.6,
19.3. HRMS (+ESI-TOF) m/z: [M+Na] Calcd for
+
carboxylic acid (5). To a solution of compound 4 (5.53 g,
4.43 mmol) in MeOH (72 mL) was added aqueous NaOH
14.4 ml, 3 N, 43.29 mmol). The resulting mixture was stirred
at 70℃ for 2 h, cooled to r.t. and acidified with 6 N HCl to pH
1
(
C H N OClBrNa 268.9088; Found 268.9076.
7
4
2

9
5
-bromo-6-chloro-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-
carbonitrile (12). To a solution of compound 11 (4.40 g,
7.91 mmol) in anhydrous THF (143 mL) under argon was
added dropwise a solution of LiHMDS (39.4 mL, 1 M in THF,
9.4 mmol) at -78°C. After the addition, the resulting solution
was stirred for 2 h at -78℃ . 4-Fluorobenzoyl chloride (17.04 g,
07.45 mmol) and DMAP (2.19 g, 17.91 mmol) were then
[5] K. Parcella, K. Eastman, K.-S. Yeung, K. A. Grant-Young,
J. Zhu, T. Wang, Z. Zhang, Z. Yin, D. Parker, K. Mosure, H. Fang, Y.-K.
Wang, J. Lemm, X. Zhuo, U. Hanumegowda, M. Liu, K. Rigat, M.
Donoso, M. Tuttle, T. Zvyaga, Z. Haarhoff, N. A. Meanwell, M. G.
Soars, S. B. Roberts, J. F. Kadow, ACS Med. Chem. Lett. 2017, 8,
71-774.
6] S. N. Sirakanyan, A. A. Hovakimyan, A. S. Noravyan, Russ.
Chem. Rev. 2015, 84, 441-454.
7] a) D. Wang, Y. Wang, J. Zhao, M. Shen, J. Hu, Z. Liu, L. Li,
F. Xue, P. Yu, Org. Lett. 2017, 19, 984-987; b) D. Wang, H. Feng, L.
Li, Z. Liu, Z. Yan, P. Yu, J. Org. Chem. 2017, 82, 11275-11287; c) D.
Wang, J. Hu, J. Zhao, M. Shen, Y. Wang, P. Yu, Tetrahedron 2018,
74, 4100-4110; d) D. Wang, M. Shen, Y. Wang, J. Hu, J. Zhao, P. Yu,
Asian J. Org. Chem. 2018, 7, 879-882; e) D. Wang, Z. Liu, Z. Wang,
X. Ma, P. Yu, Green Chem. 2019, 21, 157-163.
1
3
7
[
1
added. The resulting solution was slowly increased to r.t. and
stirred overnight. The reaction was quenched with saturated
potassium carbonate solution and extracted twice with ethyl
acetate. The combined organic extracts were washed with
water, brine, dried over Na SO , filtered and concentrated in
[
2
4
vacuo. The resulting residue was chromatographed gradiently
on silica gel with PE/EA (100:1~50:1) to give the product
1
[8] a) J. Wu, X. Cui, L. Chen, G. Jiang, Y. Wu, J. Am. Chem. Soc.
009, 131, 13888-13889; b) A. T. Londregan, S. Jennings, L. Wei,
(
3.70 g, 59% yield) as a white solid. H NMR (400 MHz,
2
CDCl
2
1
3
) δ 8.21 (s, 1H), 8.12-8.16 (m, 2H), 7.20 (t, J = 8.8 Hz,
1
3
Org. Lett. 2011, 13, 1840-1843; c) A. T. Londregan, K. Burford, E.
L. Conn, K. D. Hesp, Org. Lett. 2014, 16, 3336-3339; d) X. Chen, X.
Cui, F. Yang, Y. Wu, Org. Lett. 2015, 17, 1445-1448; e) D. I.
Bugaenko, M. A. Yurovskaya, A. V. Karchava, J. Org. Chem. 2017,
82, 2136-2149; f) D. H. Jones, S. T. Kay, J. A. McLellan, A. R. Kenne-
dy, N. C. O. Tomkinson, Org. Lett. 2017, 19, 3512-3515; g) L.-Y.
Xie, S. Peng, F. Liu, J.-Y. Yi, M. Wang, Z. Tang, X. Xu, W.-M. He, Adv.
Synth. Catal. 2018, 360, 4259-4264; h) L.-Y. Xie, T.-G. Fang, J.-X.
Tan, B. Zhang, Z. Cao, L.-H. Yang, W.-M. He, Green Chem. 2019, 21,
3858-3863.
H). C NMR (100 MHz, CDCl ) δ 165.2 (d, J = 255 Hz),
3
62.0, 157.3, 147.2, 134.2, 129.6 (d, J = 9 Hz), 122.9 (d, J = 3
Hz), 120.1, 117.3, 117.0 (d, J = 8 Hz), 112.6, 86.1. HRMS
+
(
+ESI-TOF) m/z: [M+H] Calcd for C H N OFClBr
14 6 2
3
50.9331; Found 350.9341.
Supplenmentary Data
[
9] C. Fu, G. Li, M. Shen, L. Zhang, P. Yu, D. Wang, Asian J.
Supplementary data (Supplementary data associated with this
article, including NMR spectra) associated with this article can
Org. Chem. 2020, 9, 749-752.
[10] F. Fumagalli, F. da Silva Emery, J. Org. Chem. 2016, 81,
10339-10347.
be
found
in
the
online
version
at
[
11] The price of the material from Sigma–Aldrich website
http://dx.doi.org/10.1016/xxx.
th
on March 5 2020.
[
12] M. L. Davis, B. J. Wakefield, J. A. Wardell, Tetrahedron
992, 48, 939-952.
13] K. Menzel, E. L. Fisher, L. DiMichele, D. E. Frantz, T. D.
Nelson, M. H. Kress, J. Org. Chem. 2006, 71, 2188-2191.
14] U. E. Hille, C. Zimmer, J. Haupenthal, R. W. Hartmann,
ACS Med. Chem. Lett. 2011, 2, 559-564.
15] Z. Xu, J. Li, Y. Wu, Z. Sun, L. Luo, Z. Hu, S. He, J. Zheng, H.
Zhang, X. Zhang, Eur. J. Med. Chem. 2016, 108, 154-165.
16] a) A. Garcia Martinez, R. Martinez Alvarez, E. Teso Vilar,
A. Garcia Fraile, M. Hanack, L. R. Subramanian, Tetrahedron Lett.
989, 30, 581-582; b) M. Y. Lebedev, M. B. Erman, Tetrahedron
Lett. 2002, 43, 1397-1399.
17] A. Basha, M. Lipton, S. M. Weinreb, Tetrahedron Lett.
1977, 48, 4171-4174.
18] M. W. Bundesmann, S. B. Coffey, S. W. Wright, Tetrahe-
dron Lett. 2010, 51, 3879-3882.
19] H. Yazawa, K. Tanaka, K. Kariyone, Tetrahedron Lett.
974, 46, 3995-3996.
1
Corresponding Author
[
*E-mail: wangdong@tust.edu.cn
[
[
■
Acknowledgements
[
Financial support by the National Key R&D Program of China
2018YFA0901700) is greatly acknowledged.
(
1
[
■
References and notes
[
[1] N. M. Ganta, G. Gedda, B. Rathnakar, M. Satyanarayana,
B. Yamajala, M. J. Ahsan, S. S. Jadav, T. Balaraju, Eur. J. Med. Chem.
[
2
2
019, 164, 576-601.
2] J. Zhang, K.-Q. Hu, D. Nguyen, N Am J Med Sci (Boston)
016, 9, 47-54.
3] a) K. J. Eastman, K. E. Parcella, J. F. Kadow,
1
[
[
US20140275154A1, 2014; b) K.-S. Yeung, K. J. Eastman, K. E.
Parcella, WO2014159559A1, 2014.
[4] K. J. Eastman, K. Parcella, K.-S. Yeung, K. A. Grant-Young,
J. Zhu, T. Wang, Z. Zhang, Z. Yin, B. R. Beno, S. Sheriff, K. Kish, J.
Tredup, A. G. Jardel, V. Halan, K. Ghosh, D. Parker, K. Mosure, H.
Fang, Y.-K. Wang, J. Lemm, X. Zhuo, U. Hanumegowda, K. Rigat, M.
Donoso, M. Tuttle, T. Zvyaga, Z. Haarhoff, N. A. Meanwell, M. G.
Soars, S. B. Roberts, J. F. Kadow, MedChemComm 2017, 8, 796-806.

1
0
1
0

Highlights
ò Two practical synthetic approaches to a common and key intermediate for
BMT-052.
ò 7 steps, total yield: 51%; average yield: 91% per step.
ò Harmful or cost-effective synthetic steps have been reduced.

Declaration of interests
☐
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☒
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
All authors are inventors on patent application CN202010012690.8, submitted by Tianjin University of
Science and Technology, that covers part of the synthetic procedure for the key intermediate of BMT-052.
All authors declare no other competing financial interests.