Grignard reagent utilization enables a practical and scalable construction of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives

Article abstract of DOI:10.3390/molecules25235667

A robust, practical, and scalable approach for the construction of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 via the addition of Grignard reagents to 4-amino-2-chloronicotinonitrile (15) was developed. Starting with various Grignard reagents, a wide range of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 were conveniently synthesized in moderate-to-good yields through addition–acidolysis–cyclocondensation. In addition, the robustness and applicability of this synthetic route was proven on a 100 g scale, which would enable convenient sample preparation in the preclinical development of 1,6-naphthyridin-4-one-based MET-targeting antitumor drug candidates.

Full text of DOI:10.3390/molecules25235667

molecules
Article
Grignard Reagent Utilization Enables a Practical and
Scalable Construction of 3-Substituted
5-Chloro-1,6-naphthyridin-4-one Derivatives
Ming-Shu Wang †, Yi Gong †, Zhi-Cheng Yu, Yan-Guang Tian, Lin-Sheng Zhuo *
Wei Huang * and Neng-Fang She *
,
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center
for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University,
Wuhan 430079, China; wms@mails.ccnu.edu.cn (M.-S.W.); gy@mails.ccnu.edu.cn (Y.G.);
yzc@mails.ccnu.edu.cn (Z.-C.Y.); tyguang1996@mails.ccnu.edu.cn (Y.-G.T.)
* Correspondence: zhuolinsheng199010@126.com (L.-S.Z.); weihuangwuhan@126.com (W.H.);
nfshe@mail.ccnu.edu.cn (N.-F.S.); Tel.: +86-27-67867706 (L.-S.Z. & W.H.); +86-27-67867958 (N.-F.S.)
† These authors contributed equally to this work.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Received: 3 November 2020; Accepted: 27 November 2020; Published: 1 December 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: A robust, practical, and scalable approach for the construction of 3-substituted 5-chloro-1,6-
naphthyridin-4-one derivatives 13 via the addition of Grignard reagents to 4-amino-2-chloronicotinonitrile
(15) was developed. Starting with various Grignard reagents, a wide range of 3-substituted
5-chloro-1,6-naphthyridin-4-one derivatives 13 were conveniently synthesized in moderate-to-good yields
through addition–acidolysis–cyclocondensation. In addition, the robustness and applicability of this
synthetic route was proven on a 100 g scale, which would enable convenient sample preparation in the
preclinical development of 1,6-naphthyridin-4-one-based MET-targeting antitumor drug candidates.
Keywords: 1,6-naphthyridine; Grignard reagent; kinase inhibitor; antitumor drug candidate
1. Introduction
Naphthyridine scaffolds represent attractive building blocks widely used in pharmaceuticals [
agrochemicals [ ], and fluorescent probes [ ]. Recently, it has been reported that numerous
naphthyridine-containing molecules have promising medicinal properties for the prevention and
treatment of angiogenic disorders [ ], viral infections [ ], bacterial infections [10 12], parasitic
24]. Therefore,
1,2],
3
4–6
7
8,
9
–
infections [13], heart failure [14], Alzheimer’s disease (AD) [15], and cancers [16
the construction of naphthyridines has received increasing attention recently [25].
–
There are six naphthyridine isomers (1,5-, 1,6-, 1,7-, 1,8- 2,6-, and 2,7-pyridopyridines) [2].
Nowadays, the synthesis of 1,6-naphthyridine, especially for 1,6-naphthyridin-4-one derivatives,
has attracted continuous interest in the pharmaceutical industry for its wide-ranging pharmacological
activity [26,27], and it has been used as a multi-kinase inhibitor (I) [28], an anti-HCMV inhibitor
(II) [29], an antidiabetic agent (III) [30], and antibacterial [31] and antiviral agents (IV) [1] (Figure 1).
In our previous report, 3-phenyl-1,6-naphthyridin-4-one was developed as a potent privileged
skeleton for the discovery of a MET kinase inhibitor [20
–23] from the key building block of
5-chloro-3-phenyl-1,6-naphthyridin-4-one ( ). Extensive structure–activity relationship (SAR) studies
V
and biological evaluations resulted in the discovery of two MET-targeting antitumor drug candidates,
namely, VIa [20] and VIb [23], which are near the clinical stage (Figure 2). In addition to being used as
MET kinase inhibitors, 3-phenyl-1,6-naphthyridin-4-one derivatives have also been reported as
nAChR allosteric modulators VII by ANVYL, LLC and its copartner (Figure 2) [32 33]. Thus, we propose
that diversity-oriented synthesis (DOS), starting from 5-chloro-3-phenyl-1,6-naphthyridin-4-one ( ),
α7
,
V
Molecules 2020, 25, 5667; doi:10.3390/molecules25235667
www.mdpi.com/journal/molecules

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would resulted in more new drug lead compounds VIII based on the highly reactive 5-halo group and
the functionalizable NH group.
Figure 1. Representative 1,6-naphthyride- or 1,6-naphthyridin-4-one-based pharmacologically
active compounds.
Figure 2. Discovery of bioactive 5-amino-3-phenyl-1,6-naphthyridin-4-one derivatives VI, VII and
proposed future work.
However, the construction of the key 3-phenyl-1,6-naphthyridin-4-one skeleton has proven to be
difficult. Currently, the reported procedures for its synthesis can be mainly divided into two types
(Scheme 1a,b). The first method involves the preparation of an ethyl-2-(4,6-dichloro-nicotinoyl)-3-
(dimethylamino)acrylate intermediate (
the desired naphthyridine scaffold . Then, the halodecarboxylation of intermediate
Suzuki–Miyaura coupling with an arylboronic acid results in a 7-functionalized 1,6-naphthyridin-4-one
(Scheme 1a) [34]. Obviously, the synthetic route described above has inherent issues, including:
4
), followed by strong base-catalyzed cyclization to generate
5
5
followed by
7
(i) it is a labor-intensive process (five-step sequence); (ii) non-applicability on a large scale (due to the
physical limitation of microwave heating, the penetration depth of only a few centimeters, and the
limited dimensions of standing wave cavities) [35]; (iii) overfunctionalization of the N-position restricts
its application in the drug discovery process for which N-substituents need to be finely regulated
(the synthesis of the 1,6-naphthyridin-4-one scaffold, keeping a free NH, using this synthetic route
has not been reported and the introduction of N-substituents in the initial step of the synthetic route
makes the substituent regulation process very cumbersome) [36]. The second method was reported
by ANVYL,LLC in their
α7 nAChR allosteric modulators study [33], as well as our team in our
MET kinase inhibitor study (Scheme 1b) [22]; knowledge of the mechanism of Conrad–Limpach
cyclizations led to the introduction of a thermal cyclization to generate the desired naphthyridine
scaffold. However, thermal cyclization is typically carried out in diphenyl ether at 230 ◦C, and the
lost control of chemoselectivity results in the generation of 13a and 14 in almost the same proportions.
The high reaction temperature and the lack of chemoselectivity have resulted in the complex synthesis

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of product compositions and low yields (8.2% for three steps), consequently leading to a labor-intensive
enrichment and purification process.
Scheme 1. Common construction strategies of the 3-phenyl-1,6-naphthyridin-4-one scaffold:
(
(
a
b
)
Suzuki–Miyaura coupling-based construction of 7-functionalized 1,6-naphthyridin-4-one
) Conrad–Limpach cyclizations-based construction of 5-chloro-3- substituted-1,6-naphthyridin-4-one
) Grignard reagent-based strategy for the construction of diversified 5-chloro-3-
7;
derivatives 13a; (
c
substituted-1,6-naphthyridin-4-one derivatives 13.
Altogether, the construction of 3-phenyl-1,6-naphthyridin-4-one derivatives is still a challenging
subject. With our ongoing research interests in the discovery and development of 1,6-naphthyridin-4-one
derivatives as drug candidates, we propose a facile Grignard reagent-based strategy through
addition–acidolysis–cyclocondensation to provide diversified 5-chloro-3-substituted-1,6-naphthyridin-4-one
derivatives 13 (Scheme 1c).
2. Results and Discussion
First, 5-chloro-3-(4-fluorophenyl)-1,6-naphthyridin-4-one (13a), which is the key common
intermediate of our reported MET-targeting drug candidates, was chosen as a target molecule for the
preliminary exploration of new synthetic routes. By retrosynthetic analysis, we reasoned that the
cyclocondensation of 1-(4-amino-2-chloropyridin-3-yl)-2-(4-fluorophenyl)ethan-1-one (17a) and triethyl
orthoformate would provide the desired molecule 13a (Scheme 2). Moreover, our way to intermediate
(17a) is based on the inclusion of a nitrile substituent at the 3-position of 4-amino-2-chloronicotinonitrile
to enable the generation of an α-keto group via Grignard chemistry.

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Scheme 2. Retrosynthetic analysis of 5-chloro-3-(4-fluorophenyl)-1,6-naphthyridin-4-one.
The overall synthetic route of 5-chloro-3-(4-fluorophenyl)-1,6-naphthyridin-4-one (13a) is shown in
Scheme 3. The formation of 1-(4-amino-2-chloropyridin-3-yl)-2- (4-fluorophenyl)ethan-1-one (17a) was
investigated first using 4-amino-2-chloronicotinonitrile (15) and 4-fluorobenzylmagnesium chloride
(16a) (Scheme 4 and Table 1).
Scheme 3. An overall synthetic route of 5-chloro-3-(4-fluorophenyl)-1,6-naphthyridin-4-one.
Scheme 4. Our planned route to key intermediate 17a.
Table 1. Optimization of the reaction conditions a,b for the synthesis of 1-(4-amino-2-chloropyridin-3-yl)-
2-(4-fluorophenyl)ethan-1-one (17a).
Entry
2–5 Equiv.
Solvent
Temp. (◦C)
Reaction Time (h)
Yield c (%)
1
2
3
2
2
2
THF
Et2O
Et2O
25
25
30
16
16
12
5
20
35
Methyl
4
2
30
12
10
tert-butyl ether
Isopropyl ether
Toluene
Et2O
5
6
7
8
9
2
2
3
4
5
30
30
30
30
30
12
12
12
12
12
7
Trace
60
74
73
Et2O
Et2O
a
Reactions were performed using 0.5 mmol of 4-amino-2-chloronicotinonitrile (15) in 1.0 mL solvent under N2
b
c
atmosphere. 2 mL HCl/H2O/EtOH (1:1:2) solvent was added for acidolysis. Isolated yield.
We initially subjected the two reactants to reaction at 25 ◦C for 16 h in two different solvents
commonly used in Grignard chemistry, and it is obvious that diethyl ether exhibited a better effect
on the reaction to provide product 17a than THF (Table 1, entries 1 and 2). It is also worth noting
that the incomplete consumption of 4-amino-2-chloronicotinonitrile (15) was observed. Taking into
consideration that lower temperatures can result in incomplete consumption and require longer
reaction times, the reaction was warmed to 30 ◦C. After 12 h of reaction, the consumption of
4-amino-2-chloronicotinonitrile (15) was no longer detected by HPLC dynamic detection, and the
desired product 17a was obtained at a 35% yield (Table 1, entry 3). Due to the low boiling point of ether,
the temperature could not be increased further. Thus, different inert solvents with higher boiling points

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were evaluated as latent solvents in view of their versatility demonstrated in the Grignard reaction.
Regrettably, lower yields were obtained if methyl tert-butyl ether (MTBE) and isopropyl ether (IPE)
were utilized (Table 1, entries 4 and 5), and toluene did not favor the transformation either (Table 1,
entry 6). Finally, we optimized the reaction by changing the concentration of the Grignard reagent.
As highlighted in Table 1 (entries 7–9), increasing the amount of Grignard reagent to 4.0 eqs afforded
total consumption of 4-amino-2-chloronicotinonitrile (15) and resulted in a 74% yield of the desired
product (Table 1, entries 7 and 8). However, a further increase did not result in a further increase
in yield (Table 1, entry 9), suggesting that 4.0 equiv. is the best amount. In summary, 1.0 equiv. of
4-amino-2-chloronicotinonitrile (15) and 4.0 equiv. of 4-fluorobenzylmagnesium chloride (16a) in ether
at 30 ◦C for 12 h were determined to be the optimum reaction conditions.
With the optimized conditions established, the substrate scope with respect to the Grignard
reagent was then evaluated (Scheme 5). It was found that the various Grignard reagents exposed to
the optimized conditions smoothly provided the corresponding products 17a–n in moderate to good
yields (43–82%). Typically, electron-withdrawing halogens on the benzyl Grignard reagent were well
tolerated to provide the corresponding products in moderate-to-good yields (17a, 17c, 17e, and 17f;
58–74%); only the fluorine atom at the C-2 position of the benzyl group had a negative impact on
the yield of the final products, which resulted in a relative lower yield of 17b and 17d with yields of
43% and 39%, respectively. Notably, an electron-donating group (EDG) might be slightly better than
an electron-withdrawing group (EWG), as exemplified by some typical EDGs, the alkyl-substituted
benzyl Grignard reagents 17h–j (75–80%), including the bulky isopropyl group (17k; 71%). Moreover,
a naphthyl Grignard reagent and chain-growing alkyl Grignard reagents, such as phenethyl and ethyl
Grignard reagents, could also provide good yields (17ln; 67–82%).
Scheme 5. Grignard reagent scope for the construction of 1, 6-naphthyridin-4-one scaffold. (a) 1.5
mmol of 4-amino-2-chloronicotinonitrile (15) and 6.0 mmol of Grignard reagent (16) in 3.0 mL of ether
at 30 ◦C for 12 h under an N2 atmosphere; (
b) 6 mL of the HCl/H2O/EtOH (1:1:2) solvent was added
for acidolysis; (c) Isolated yield.
With these positive results in hand, the optimal reaction conditions of the cyclocondensation of
1-(4-amino-2-chloropyridin-3-yl)-2-(4-fluorophenyl)ethan-1-one (17a) were investigated next (Scheme 6
and Table 2). Initially, we investigated cyclocondensation by employing K2CO3 as a base and DMF
as a solvent at a temperature of 110 ◦C. However, only a trace amount of the desired product was

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formed (Table 2, entry 1). Moreover, the combination of NaH and THF did not work (Table 2, entry 2).
This was improved when we switched the inorganic base to an organic base. A 15% yield of the desired
product was observed when Et3N was used (Table 2, entry 3), and a consistent improvement in the
yield was observed by replacing Et3N with DIPEA or DMAP (Table 2, entries 4 and 5), suggesting that
DMAP is the best base. Then, by utilizing DMAP as the base, the solvent effects were also investigated.
When triethoxymethane was used as both the reactant and solvent, the yield of the desired product
was slightly increased (Table 2, entry 6). Finally, we turned our attention to base loading. By gradually
reducing the amount of base, we found that only a catalytic amount of the base was needed (Table 2,
entries 6–9).
Scheme 6. Our planned route to target molecule 13a.
Table 2. Optimization of the reaction conditions a for the cyclocondensation.
Yield b (%)
Entry
Base (equiv.)
Solvent
Temp. (◦C)
Reaction Time (h)
1
2
3
4
5
6
7
8
9
K2CO3 (2eq)
NaH (2eq)
Et3N (2eq)
DIPEA (2eq)
DMAP (2eq)
DMAP (2eq)
DMAP (1eq)
DMAP (0.1 eq)
No catalyst
DMF
THF
DMF
DMF
DMF
HC(OEt)3
HC(OEt)3
HC(OEt)3
HC(OEt)3
110
60
24
24
24
24
24
24
24
24
24
<1
<1
15
30
65
70
70
72
0
110
110
110
110
110
110
110
a
Reactions were performed using 0.5 mmol of 1-(4-amino-2-chloropyridin-3-yl)-2-(4-fluorophenyl)ethan-1-one (13a
)
b
in 1.0 mL of solvent under an air atmosphere. Isolated yields.
Next, all of the intermediates synthesized above were subjected to the optimized reaction
conditions. To our delight, the reaction demonstrated good compatibility, and a series of 3-substituted
1,6-naphthyridin-4-one derivatives were obtained smoothly with moderate-to-good yields (Scheme 7,
13a–o; 40–82%). Generally, both 3-aryl-1,6-naphthyridin-4-one derivatives (13al; 40–82%) and
3-alkyl-1,6-naphthyridin-4-one derivatives (13m and 13n; 74% and 55%) could be readily constructed,
and the substituents on the benzene ring had less influence on the yields, except for an ortho-fluorine
(13b and 13d; 46% and 40%). Moreover, through changing the reactant triethyl orthoformate into
triethyl orthoacetate, a methyl could be smoothly introduced to the C-2 position of the scaffold (13o
,
69%), which is of great benefit to the study of SARs in drug discovery. Taken together, this approach is
a general method for building various 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives.
More importantly, the synthesis of compound 13a was performed on a 100 g scale to demonstrate
the robustness and applicability of this synthetic route (Scheme 8). By starting from 153.0 g (1.0 mol) of
4-amino-2-chloronicotinonitrile (15), we obtained the desired product at a yield of 53.3% (total yield
for two steps). After completing the enrichment of compound 13a, a kilogram- scale protocol for the
creation of our 1,6-naphthyridin-4-one-based MET-targeting antitumor drug candidate VI was applied
through acid-catalyzed nucleophilic substitution of 5-Cl atoms with high yields (90%) and simple
operation (insensitive to moisture and oxygen; filtration to obtain desired pure product). This would
enable convenient sample preparation in the preclinical development of this drug candidate.

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Scheme 7. Synthesis of 1,6-naphthyridin-4-one derivatives. (a) 0.5 mmol of 1-(4-amino-2-chloropyridin-
3-yl)-2-substituted-ethan-1-one (17) and 0.05 mmol of DMAP in 1.0 mL triethyl orthoformate (13a
–n) or
triethyl orthoacetate (13o) at 110 ◦C for 24 h; (b) Isolated yield.
Scheme 8. The 100 g scale synthesis of 5-chloro-3-(4-fluorophenyl)-1,6-naphthyridin-4-one and its
application in preclinical drug candidate enrichment.
3. Conclusions
In conclusion, we have developed a robust, practical, and scalable approach for the construction
of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 via the addition of Grignard
reagents to 4-amino-2-chloronicotinonitrile (15). Starting with various Grignard reagents through
addition–acidolysis–cyclocondensation, a wide range of 5-chloro-3-substituted-1,6-naphthyridin-4-one
derivatives 13 were synthesized in moderate-to-good yields. In addition, the robustness and
applicability of this synthetic route was proven on a 100 g scale, which would enable convenient
sample preparation in the preclinical development of 1,6-naphthyridin-4-one-based drug candidates.
Further extensions of these naphthyridine derivatives in drug discovery are currently underway in
our laboratories.
4. Materials and Methods
4.1. General Information
Unless otherwise noted, all chemical reagents were commercially available and treated with
standard methods. Silica gel column chromatography (CC). silica gel (200–400 Mesh; Qingdao Makall
Group Co., Ltd; Qingdao; China). Solvents were dried in a routine way and redistilled. All reactions

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involving air- or moisture-sensitive reagents were performed under a nitrogen or argon atmosphere.
Melting points of compounds were measured on a Melt-Temp II apparatus (BUCHI Labortechnik AG,
1
Uster, Switzerland) and are uncorrected. H-NMR spectra (400 MHz) and 13C-NMR (100 MHz) spectra
were recorded on an Ultrashield Plus AV 400 spectrometer (Bruker BioSpin AG, Fällanden, Switzerland)
as dimethyl sulfoxide-d6 (DMSO-d6) solutions using tetramethylsilane (TMS) as an internal standard
1
(δ
= 0) unless noted otherwise. H-NMR spectra (600 MHz) and 13C-NMR (150 MHz) spectra were
recorded on a Varian Mercury-Plus 600 spectrometer (Varian Inc., Palo Alto, CA, USA) as dimethyl
sulfoxide-d6 (DMSO-d6) solutions using tetramethylsilane (TMS) as an internal standard ( = 0) unless
δ
noted otherwise, and all the 1H and 13C NMR Spectra are summarized in the Supplementary Materials.
MS spectra were obtained on a 6120 quadrupole LC/MS (ESI, Agilent Technologies, Santa Clara, CA,
USA). All reactions were monitored using thin-layer chromatography (TLC, Yantai Jiangyou Silica gel
Development Co., Ltd.; Yantai; China) on silica gel plates. Yields were of purified compounds and
were not optimized.
4.2. General Procedure I for the Synthesis of 2-Substituted 1-(4-amino-2-chloropyridin-3-yl)-ethan-1-ones 17a–n
The appropriate Grignard reagent 16 (6.0 mmol, 4.0 equivs.) in ether (3.3 mL) was added at room
temperature to 4-amino-2-chloronicotinonitrile (15, 230.0 mg, 1.5 mmol) in ether (3.0 mL). The reaction
mixture was warmed to 30 ◦C and stirred for 12 h under ether atmosphere. Then the reaction mixture
was cooled to 0 ◦C and 6.0 mL of mixed solvent (HCl/H2O/EtOH = 1:1:2) was added dropwise,
the reaction mixture was refluxed for a further 2 h. After the completion of the reaction, the mixture
was neutralized with sodium carbonate solution and extracted with EtOAc (3
×
15 mL). The organic
layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified
by chromatography (hexane/EA = 5:1) to yield the corresponding compound 17 in good yield.
1-(4-Amino-2-chloropyridin-3-yl)-2-(4-fluorophenyl)ethan-1-one (17a) was prepared from 15 and
(4-fluorobenzyl)magnesium chloride (16a) by general procedure I as a white solid (294 mg, 74%), M.p.
130–133 ◦C, 1H-NMR (400 MHz, DMSO-d6)
2H), 6.61 (d, J = 6.0 Hz, 1H), 6.59 (s, 2H), 4.18 (s, 2H). 13C-NMR (100 MHz, DMSO-d6)
C–F = 241.0 Hz), 153.7, 149.2, 146.7, 132.3(d, JC–F = 8.0 Hz), 130.5(d, JC–F = 3.0 Hz), 118.8, 115.3(d, JC–F
= 24.0 Hz), 110.5, 49.1. MS (ESI): 265.05 [M + H]+.
δ
7.81 (d, J = 6.0 Hz, 1H), 7.3 3–7.30 (m, 2H), 7.17–7.12 (m,
201.5, 161.5 (d,
δ
J
1-(4-Amino-2-chloropyridin-3-yl)-2-(2-fluorophenyl)ethan-1-one (17b) was prepared from 15 and
(2-fluorobenzyl)magnesium chloride (16b) by general procedure I as a white solid (171 mg, 43%), M.p.
127–131 ◦C, 1H-NMR (400 MHz, DMSO-d6)
δ
7.82 (d, J = 6.0 Hz, 1H), 7.47–7.25 (m, 2H), 7.24–7.07
(m, 2H), 6.62 (s, 2H), 6.60 (d, J = 6.0 Hz, 1H), 4.26 (s, 2H). 13C-NMR (100 MHz, DMSO-d6)
δ
200.2,
162.2 (d, JC–F = 243.0 Hz), 154.1, 149.3, 147.1, 133.1 (d, JC–F = 5.0 Hz), 129.6 (d, JC–F = 8.0 Hz), 124.6
(d, JC–F = 3.0 Hz), 121.7 (d, JC–F = 16.0 Hz), 118.3, 115.5 (d, JC–F = 21.0 Hz), 110.7, 43.8. MS (ESI):
265.05 [M + H]+.
1-(4-Amino-2-chloropyridin-3-yl)-2-(3-fluorophenyl)ethan-1-one (17c) was prepared from 15 and
(3-fluorobenzyl)magnesium chloride (16c) by general procedure I as a white solid (246.3 mg, 62%), M.p.
128–132 ◦C, 1H-NMR (400 MHz, DMSO-d6)
δ
7.81 (d, J = 6.0 Hz, 1H), 7.43–7.29 (m, 1H), 7.18–7.02
(m, 3H), 6.62 (s, 2H), 6.60 (d, J = 6.0 Hz, 1H), 4.23 (s, 2H). 13C-NMR (100 MHz, DMSO-d6)
δ
201.0,
162.4 (d, JC–F = 241.0 Hz), 153.8, 149.2, 146.7, 137.1 (d, JC–F = 8.0 Hz), 130.4 (d, JC–F = 8.0 Hz), 126.6
(d, JC–F = 2.0 Hz), 118.8, 117.2 (d, JC–F = 21.0 Hz), 114.1 (d, JC–F = 21.0 Hz), 110.6, 49.5. MS (ESI):
265.05 [M + H]+.
1-(4-Amino-2-chloropyridin-3-yl)-2-(2,4-difluorophenyl)ethan-1-one (17d) was prepared from 15 and
(2,4-difluorobenzyl)magnesium chloride (16d) by general procedure I as a white solid (165.3 mg, 39%),
M.p. 180–183 ◦C, 1H-NMR (400 MHz, DMSO-d6)
δ
7.83 (d, J = 6.0 Hz, 1H), 7.50–7.38 (m, 1H), 7.26–7.15
(m, 1H), 7.11–7.01 (m, 1H), 6.62 (s, 2H), 6.60 (d, J = 6.0 Hz, 1H), 4.25 (s, 2H). 13C-NMR (100 MHz,
DMSO-d6) 200.1, 161.9 (dd, JC–F = 241.0 Hz, 12.0 Hz), 161.2 (dd, JC–F = 241.0 Hz, 12.0 Hz), 154.1,
δ
149.3, 147.1, 134.0 (dd, JC–F = 9.0 Hz, 6.0 Hz), 118.2, 118.1 (dd, JC–F = 15.0 Hz, 3.0 Hz), 111.6 (dd, JC–F
= 21.0 Hz, 5.0Hz), 110.7, 103.9 (t, JC–F = 26.0 Hz), 43.2. MS (ESI): 283.16 [M + H]+.

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1-(4-Amino-2-chloropyridin-3-yl)-2-(4-chlorophenyl)ethan-1-one (17e) was prepared from 15 and
(4-chlorobenzyl)magnesium chloride (16e) by general procedure I as a white solid (273 mg, 65%),
M.p.147–150 ◦C, 1H-NMR (400 MHz, DMSO-d6)
δ 7.82 (d, J = 6.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.31
(d, J = 8.4 Hz, 2H), 6.62 (s, 2H), 6.60 (d, J = 6.0 Hz, 1H), 4.19 (s, 2H). 13C-NMR (100 MHz, DMSO-d6)
201.2, 153.7, 149.2, 146.7, 133.3, 132.2, 132.0, 128.5, 118.7, 110.5, 49.2. MS (ESI): 282.01 [M + H]+.
δ
1-(4-Amino-2-chloropyridin-3-yl)-2-(4-bromophenyl)ethan-1-one (17f) was prepared from 15 and
(4-bromobenzyl)magnesium chloride (16f) by general procedure I as a white solid (283.2 mg, 58%), M.p.
132–133 ◦C, 1H-NMR (400 MHz, DMSO-d6)
δ 7.82 (d, J = 6.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.25 (d,
J = 8.4 Hz, 2H), 6.62 (s, 2H), 6.60 (d, J = 6.0 Hz, 1H), 4.18 (s, 2H). 13C-NMR (100 MHz, DMSO-d6)
201.1, 153.7, 149.2, 146.7, 133.8, 132.6, 131.4, 120.5, 118.7, 110.5, 49.3. MS (ESI): 326.96 [M + H]+.
δ
1-(4-Amino-2-chloropyridin-3-yl)-2-phenylethan-1-one (17g) was prepared from 15 and benzyl-
magnesium chloride (16g) by general procedure I as a white solid (258.9 mg, 70%), M.p.85–87 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ 7.81 (d, J = 6.0 Hz, 1H), 7.33–7.26 (m, 5H), 6.62–6.59 (m, 3H), 4.20 (s,
2H). 13C-NMR (100 MHz, DMSO-d6)
50.0. MS (ESI): 247.06 [M + H]+.
δ 201.6, 153.8, 149.1, 146.7, 134.3, 130.3, 128.6, 127.2, 118.8, 110.5,
1-(4-Amino-2-chloropyridin-3-yl)-2-(p-tolyl)ethan-1-one (17h) was prepared from 15 and (4-methyl-
benzyl)magnesium chloride (16h) by general procedure I as a white solid (312 mg, 80%), M.p.
100–103 ◦C, 1H-NMR (400 MHz, DMSO-d6)
δ 7.80 (d, J = 6.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.11 (d,
J = 8.0 Hz, 2H), 6.60 (d, J = 6.0 Hz, 3H), 4.13 (s, 2H), 2.28 (s, 3H). 13C-NMR (100 MHz, DMSO-d6)
201.7, 153.8, 148.9, 146.6, 136.2, 131.2, 129.2, 118.8, 110.5, 49.7, 21.1. MS (ESI): 261.32 [M + H]+.
δ
1-(4-Amino-2-chloropyridin-3-yl)-2-(m-tolyl)ethan-1-one (17i) was prepared from 15 and (3-methyl-
benzyl)magnesium chloride (16i) by general procedure I as a white solid (297 mg, 76%), M.p. 91–95 ◦C,
1H-NMR (600 MHz, DMSO-d6)
δ
7.80 (d, J = 6.0 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.12–7.01 (m, 3H),
201.7,153.8, 149.3, 146.8,
6.65–6.52 (m, 3H), 4.14 (s, 2H), 2.28 (s, 3H). 13C-NMR (150 MHz, DMSO-d6)
δ
137.7, 134.3, 131.1, 128.6, 127.9, 127.5, 119.0, 110.6, 50.1, 21.5. MS (ESI): 261.08 [M + H]+.
1-(4-Amino-2-chloropyridin-3-yl)-2-(4-ethylphenyl)ethan-1-one (17j) was prepared from 15 and
(4-ethylbenzyl)magnesium chloride (16J) by general procedure I as a white solid (309 mg, 75%), M.p.
89–102 ◦C, 1H-NMR (600 MHz, DMSO-d6)
δ7.80 (d, J = 6.0 Hz, 1H), 7.20–7.11 (m, 4H), 6.60 (d, J = 6.0 Hz,
3H), 4.14 (s, 2H), 2.57 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H). 13C-NMR (150 MHz, DMSO-d6)
153.88, 149.1, 146.7, 142.7, 131.6, 130.3, 128.1, 119.0, 110.6, 49.7, 28.4, 16.2. MS (ESI): 275.09 [M + H]+.
δ201.8,
1-(4-Amino-2-chloropyridin-3-yl)-2-(4-isopropylphenyl)ethan-1-one (17k) was prepared from 15 and
(4-isopropylbenzyl)magnesium chloride (16k) by general procedure I as a white solid (307.5 mg, 71%),
M.p. 71–75 ◦C, 1H-NMR (600 MHz, DMSO-d6)
δ
7.81 (t, J = 5.2 Hz, 1H), 7.22–7.15 (m, 4H), 6.62
(t, J = 4.4 Hz, 3H), 4.14 (s, 1H), 2.85 (p, J = 6.0 Hz, 1H), 1.27–1.14 (m, 6H). 13C-NMR (150 MHz,
DMSO-d6)
δ 201.8, 153.9, 149.1, 147.3, 146.7, 131.7, 130.4, 126.6, 119.1, 110.6, 49.7, 33.6, 24.5. MS
(ESI): 289.11 [M + H]+.
1-(4-Amino-2-chloropyridin-3-yl)-2-(naphthalen-1-yl)ethan-1-one (17l) was prepared from 15 and
(naphthalen-1-ylmethyl)magnesium chloride (16l) by general procedure I as a white solid (297.6 mg,
67%), M.p. 78–80 ◦C, 1H-NMR (400 MHz, DMSO-d6)
δ
7.87–7.86 (m, 1H), 7.85–7.84 (m, 1H), 7.83–7.81
(m, 2H), 7.53–7.50 (m, 2H), 7.48–7.46 (m, 2H), 6.66 (s, 2H), 6.65 (d, J = 6.0 Hz, 1H), 4.70 (s, 2H). 13C-NMR
(100 MHz, DMSO-d6)
δ 201.3, 154.2, 149.0, 147.1, 133.7, 132.6, 131.1, 129.1, 128.8, 128.0, 126.5, 126.1,
125.9, 124.8, 118.6, 110.8, 47.7. MS (ESI): 297.07 [M + H]+.
1-(4-Amino-2-chloropyridin-3-yl)-3-phenylpropan-1-one (17m) was prepared from 15 and phenethyl-
magnesium chloride (16m) by general procedure I as a white solid (320.7 mg, 82%), M.p. 81–83 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ 7.80 (d, J = 6.0 Hz, 1H), 7.41–7.08 (m, 5H), 6.61 (d, J = 6.0 Hz, 1H),
6.58 (s, 2H), 3.15 (t, J = 7.6 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6)
153.8, 149.1, 146.8, 141.1, 128.8, 128.7, 126.4, 118.8, 110.5, 45.3, 29.8.MS (ESI): 261.91 [M + H]+.
δ 203.2,
1-(4-Amino-2-chloropyridin-3-yl)propan-1-one (17n) was prepared from 15 and ethylmagnesium
1
chloride (16n) by general procedure I as a white solid (210 mg, 75%), M.p. 97–100 ◦C, H-NMR
(400 MHz, DMSO-d6)
δ 7.80 (d, J = 6.0 Hz, 1H), 6.61 (d, J = 6.0 Hz, 1H), 6.50 (s, 2H), 2.82 (q, J =

Molecules 2020, 25, 5667
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7.2 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6)
110.4, 37.1, 8.3. MS (ESI): 185.04 [M + H]+.
δ
204.7, 153.5, 149.0, 146.5, 119.3,
4.3. General Procedure II for the Synthesis of 3-Substituted 1,6-naphthyridin-4-ones 13a–o
A solution of 2-substituted 1-(4-amino-2-chloropyridin-3-yl)-ethan-1-one 17 (0.5 mmol) and DMAP
(0.5 mmol) in triethyl orthoformate (18a, for 13a–n) or triethyl orthoacetate (18b, for 13o) (1.0 mL) was
heated to 110 ◦C and stirred for 24 h, then cooled to room temperature, the resulted solid was filtered
and the filter residue was added to a 5 mL round-bottomed flask charged with 2.0 mL isopropanol,
refluxed for 2 h and filtered immediately to afford the corresponding compound 13 in good yield.
5-Chloro-3-(4-fluorophenyl)-1,6-naphthyridin-4-one (13a) was prepared from 17a and triethyl
orthoformate (18a) by general procedure II as a light yellow solid (98 mg, 72%), M.p. 296–299 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ
12.3 (s, 1H), 8.31 (d, J = 5.6 Hz, 1H), 8.15 (s, 1H), 7.69–7.65 (m, 2H),
173.8, 161.8 (d, JC–F
7.45 (d, J = 5.6 Hz, 1H), 7.25–7.20 (m, 2H). 13C-NMR (100 MHz, DMSO-d6)
δ
=
243.0 Hz), 150.6, 148.2, 147.7, 138.2, 131.8 (d, JC–F = 3.0 Hz), 131.1 (d, JC–F = 7.0 Hz), 124.5, 118.0, 115.1
(d, JC–F = 21.0 Hz), 113.1. MS (ESI): 275.21 [M + H]+.
5-Chloro-3-(2-fluorophenyl)-1,6-naphthyridin-4(1H)-one (13b) was prepared from 17b and triethyl
orthoformate (18a) by general procedure II as a light yellow solid (63 mg, 46%), M.p. 264–268 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ
12.38 (s, 1H), 8.33 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.54–7.34 (m, 3H),
173.2, 160.7 (d, JC–F = 244.5 Hz), 150.4, 148.4,
7.32–7.14 (m, 2H). 13C-NMR (150 MHz, DMSO-d6)
δ
147.9, 139.2, 132.6, 129.9 (d, JC–F = 7.5 Hz), 124.4, 123.3 (d, JC–F = 13.5 Hz), 121.3, 117.6, 115.7 (d, JC–F
=
22.5 Hz), 113.1. MS (ESI): 275.23 [M + H]+.
5-Chloro-3-(3-fluorophenyl)-1,6-naphthyridin-4(1H)-one (13c) was prepared from 17c and triethyl
orthoformate (18a) by general procedure II as a light yellow solid (87.9 mg, 64%), M.p. 273–275 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ
12.41 (s, 1H), 8.33 (d, J = 6.0 Hz, 1H), 8.25 (s, 1H), 7.59–7.38 (m, 4H),
173.7, 162.3 (d, JC–F = 244.5 Hz), 150.7, 148.4,
7.20–7.10 (m, 1H). 13C-NMR (150 MHz, DMSO-d6)
δ
147.7 (d, JC–F = 4.5 Hz), 138.9, 137.9, 130.2, 125.0, 123.9 (d, JC–F = 4.5 Hz), 118.1 (d, JC–F = 4.5 Hz),
115.8 (d, JC–F = 22.5 Hz), 114.2 (d, JC–F = 13.5 Hz), 113.15, MS (ESI): 275.03 [M + H]+.
5-Chloro-3-(2,4-difluorophenyl)-1,6-naphthyridin-4(1H)-one (13d) was prepared from 17d and triethyl
orthoformate (18a) by general procedure II as a light yellow solid (58.5 mg, 40%), M.p. 238–241 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ
12.58 (s, 1H), 8.89 (s, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.68–7.62 (m, 1H),
7.46 (td, J1 = 9.6 Hz, J2 = 2.4 Hz, 1H), 7.28 (td, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.05 (d, J = 6.0 Hz,
1H). 13C-NMR (100 MHz, DMSO-d6)
298.0 Hz, 12.0 Hz), 160.6, 149.3, 148.2, 139.0, 133.8 (dd, JC–F = 10.0 Hz, 4.0 Hz), 116.5, 116.1 (dd, JC–F
δ
171.6, 165.9 (dd, JC–F = 298.0 Hz, 12.0 Hz), 163.0 (dd, JC–F
=
=
15.0 Hz, 4.0 Hz), 112.4, (dd, JC–F = 21.0 Hz, 4.0 Hz), 109.1, 104.9 (t, JC–F = 21.0 Hz), 101.7. MS (ESI):
293.42 [M + H]+.
5-Chloro-3-(4-chlorophenyl)-1,6-naphthyridin-4(1H)-one (13e) was prepared from 17e and triethyl
orthoformate (18a) by general procedure II as a light yellow solid (88.5 mg, 61%), M.p. 196–200 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ
12.60 (s, 1H), 8.32 (d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 7.68 (d, J = 8.4 Hz,
2H), 7.49 (d, J = 6.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6)
173.7, 150.6,
148.2, 147.6, 138.4, 134.3, 132.0, 130.8, 128.3, 124.0, 118.0, 113.1. MS (ESI): 292.11 [M + H]+.
δ
3-(4-Bromophenyl)-5-chloro-1,6-naphthyridin-4(1H)-one (13f) was prepared from 17f and triethyl
ortho- formate (18a) by general procedure II as a light yellow solid (85.6 mg, 51%), M.p. 239–241 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ
12.36 (s, 1H), 8.32 (d, J = 6.0 Hz, 1H), 8.18 (s, 1H), 7.64–7.58 (m, 4H),
7.45 (d, J = 6.0 Hz, 1H). 13C-NMR (100 M, DMSO-d6)
173.6, 150.6, 148.2, 147.6, 138.3, 134.7, 131.2,
131.1, 124.1, 120.6, 118.0, 113.0. MS (ESI): 336.95 [M + H]+.
δ
5-Chloro-3-phenyl-1,6-naphthyridin-4(1H)-one (13g) was prepared from 17g and triethyl orthoformate
1
(
18a) by general procedure II as a light yellow solid (89.8 mg, 69%), M.p. 198–200 ◦C, H-NMR
(400 MHz, DMSO-d6)
1.6 Hz, 1H), 7.52 (s, 1H), 7.38–7.18 (m, 4H). 13C-NMR (100 MHz, DMSO-d6)
138.1, 135.5, 129.2, 128.3, 127.5, 125.6, 118.0, 113.0. MS (ESI): 292.11 [M + H]+.
δ
12.22 (s, 1H), 8.21 (d, J = 6.0 Hz, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.53 (d, J =
δ
173.9, 150.7, 148.1, 147.7,

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5-Chloro-3-(p-tolyl)-1,6-naphthyridin-4(1H)-one (13h) was prepared from 17h and tr◦iethyl ortho-
formate (18a) by general procedure II as a light yellow solid (110.9 mg, 82%), M.p. 222–225 C, 1H-NMR
(400 MHz, DMSO-d6)
δ
12.28 (s, 1H), 8.30 (d, J = 6.0 Hz, 1H), 8.09 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.46
173.9, 150.6,
(d, J = 6.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 2.33 (s, 3H). 13C-NMR (100 MHz, DMSO-d6)
δ
148.0, 147.5, 137.7, 136.6, 132.5, 128.9, 128.8, 125.4, 117.9, 113.0, 21.2. MS (ESI): 271.85[M + H]+.
5-Chloro-3-(m-tolyl)-1,6-naphthyridin-4(1H)-one (13i) was prepared from 17i and triethyl
orthoformate (18a) by general procedure II as a light yellow solid (83.9 mg, 62%), M.p. 257–261 ◦C,
1H-NMR (600 MHz, DMSO-d6)
δ
12.32 (s, 1H), 8.31 (d, J = 6.0 Hz, 1H), 8.12 (s, 1H), 7.46 –7.44 (m,
2H), 7.40 (d, J = 6.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 2.35 (s, 3H). 13C-NMR
(150 MHz, DMSO-d6)
δ 173.9, 150.7, 148.2, 147.7, 138.1, 137.3, 135.5, 129.8, 128.3, 128.2, 126.3, 125.7,
118.0, 113.1, 21.7. MS (ESI): 271.85[M + H]+.
5-Chloro-3-(4-ethylphenyl)-1,6-naphthyridin-4(1H)-one (13j) was prepared from 17J and triethyl
ortho- formate (18a) by general procedure II as a light yellow solid (85.4 mg, 60%), M.p. 270–273 ◦C,
1H-NMR (600 MHz, DMSO-d6)
δ
12.30 (s, 1H), 8.30 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.57–7.49 (m, 2H),
7.45 (d, J = 6.0 Hz, 1H), 7.23 (d, J = 7.2 Hz, 2H), 2.62 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H).
13C-NMR (150 MHz, DMSO-d6)
δ 174.0, 150.7, 148.2, 147.7, 143.2, 137.9, 132.9, 129.2, 127.9, 125.6, 118.0,
113.1, 28.5, 16.3. MS (ESI): 285.65[M + H]+.
5-Chloro-3-(4-isopropylphenyl)-1,6-naphthyridin-4(1H)-one (13k) was prepared from 17k and triethyl
orthoformate (18a) by general procedure II as a light yellow solid (91.1 mg, 61%), M.p. 303–304 ◦C,
1H-NMR (600 MHz, DMSO-d6) 12.39 (s, 1H), 8.42 (d, J = 6.0 Hz, 1H), 8.24 (s, 1H), 7.60 (d, J = 6.0 Hz,
1H), 7.55 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 2.99–2.86 (m, 1H), 1.23 (d, J = 7.2 Hz, 6H).
13C-NMR (150 MHz, DMSO-d6)
δ 174.0, 150.7, 148.1, 147.8, 147.7, 137.9, 133.1, 129.2, 126.3, 125.7, 118.0,
113.1, 33.8, 24.5. MS (ESI): 299.63[M + H]+.
5-Chloro-3-(naphthalen-1-yl)-1,6-naphthyridin-4(1H)-one (13l) was prepared from 17l and triethyl
orthoformate (18a) by general procedure II as a light yellow solid (96.6 mg, 63%), M.p. 281–283 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ
12.36 (s, 1H), 8.37 (d, J = 5.6 Hz, 1H), 8.12–8.07 (m, 1H), 8.01–7.91 (m,
2H), 7.71–7.63 (m, 1H), 7.62–7.49 (m, 3H), 7.49–7.37 (m, 2H). 13C-NMR (100 MHz, DMSO-d6)
δ
174.3,
150.6, 148.3, 148.2, 139.2, 134.2, 133.6, 132.5, 128.5, 128.4, 128.3, 126.6, 126.3, 126.2, 125.9, 117.8, 113.2.
MS (ESI): 307.91[M + H]+.
3-Benzyl-5-chloro-1,6-naphthyridin-4(1H)-one (13m) was prepared from 17m and triethyl
orthoformate (18a) by general procedure II as a light yellow solid (100 mg, 74%), M.p. 212–215 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ
12.00 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.89 (s, 1H), 7.39 (d, J = 6.0 Hz,
1H), 7.34–7.21 (m, 4H), 7.21–7.09 (m, 1H), 3.73 (s, 2H). 13C-NMR (100 MHz, DMSO-d6)
174.7, 150.3,
147.8, 140.9, 137.3, 129.0, 128.6, 126.3, 126.2, 116.9, 113.4, 33.5. MS (ESI): 271.77 [M + H]+.
δ
5-Chloro-3-methyl-1,6-naphthyridin-4(1H)-one (13n) was prepared from 17n and triethyl
orthoformate (18a) by general procedure II as a light yellow solid (53.3 mg, 55%), M.p. 181–185 ◦C,
1H-NMR (400 MHz, DMSO-d6)
δ 11.94 (s, 1H), 8.23 (d, J = 6.0 Hz, 1H), 7.89 (s, 1H), 7.36 (d, J = 6.0 Hz,
1H), 1.93 (s, 3H). 13C-NMR (100 MHz, DMSO-d6)
14.1. MS (ESI): 285.69 [M + H]+.
δ 175.6, 150.2, 147.8, 147.5, 136.4, 122.7, 116.3, 112.9,
5-Chloro-3-(4-fluorophenyl)-2-methyl-1,6-naphthyridin-4(1H)-one (13o) was prepared from 17o and
triethyl orthoacetate (18b) by general procedure II as a light yellow solid (99.4 mg, 69%), M.p.
309–311 ◦C, 1H-NMR (600 MHz, DMSO-d6)
δ
12.02 (s, 1H), 8.28 (d, J = 6.0 Hz, 1H), 7.40 (d, J = 6.0 Hz,
1H), 7.30–6.98 (m, 4H), 2.16(s, 3H). 13C-NMR (150 MHz, DMSO-d6)
δ
173.9, 161.8 (d, JC–F = 241.0 Hz),
150.5, 148.3, 147.6, 147.1, 133.2 (d, JC–F = 7.5 Hz), 131.8 (d, JC–F = 1.5 Hz), 124.9, 116.7, 115.3 (d, JC–F
21.0 Hz), 112.6, 19.1. MS (ESI): 289.51 [M + H]+.
=

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4.4. Scale-Up Experiment
4.4.1. Mass Preparation of 1-(4-Amino-2-chloropyridin-3-yl)-2-(4-fluorophenyl)ethan-1-one (17a)
To a 5 L four-neck flask 4-amino-2-chloronicotinonitrile 15 (125.0 g, 0.81 mol) and ether (1500 mL)
were added, followed by (4-fluorobenzyl)magnesium chloride in ether (16a) (1.8 M, 3.24 mol, 1800 mL,
4.0 equivs.) at room temperature. The mixture was warmed to 30 ◦C and stirred for 12 h under
ether atmosphere. Then the reaction was cooled in an ice-water bath with the reaction flask equipped
with a distillation unit, and 3000 mL of mixed solvent (HCl/H2O/EtOH = 1:1:2) was added dropwise,
the volatilized ether was recovered with a distillation unit, and the reaction mixture was refluxed
for a further 2 h. After the completion of the reaction, ethanol was removed under vacuum, and the
residue was stirred for 12 h and filtered to afford 199 g of crude hydrochloride of 17a as a yellow solid.
Next, the yellow solid was added to a 2.0 L flask charged with ethanol (720 mL) and warmed up to
reflux followed by addition of trimethylamine (0.66 mol, 66.86 g) dropwise. The resulted mixture was
refluxed for further 1 h, then cooled to room temperature and stirred overnight. Finally, filtered and
the filter cake was washed with 50% ethanol in water to afford 17a as a light yellow solid, (160 g, 75%).
4.4.2. Mass Preparation of 5-Chloro-3-(4-fluorophenyl)-1,6-naphthyridin-4-one (13a)
To a 2.0 L of four-neck flask equipped with a distillation unit was added 1-(4-amino-2-
chloropyridin-3-yl)-2-(4-fluorophenyl)ethan-1-one (17a, 0.604 mol, 160.0 g) and triethyl orthoformate
(
18a, 1600 mL), the reaction mixture was warmed up to 100 ◦C and stirred for 1.5 h, then DMAP (0.1 eq,
0.6 mol, 7.3 g) was added and the stirring was continued for 24 h at 100 ◦C with the produced ethanol
collected by distillation unit. After the completion of the reaction, the mixture was cooled to room
temperature and filtered, the filter cake was added to a 2.0 L of four-neck flask charged with 1500 mL
isopropanol, refluxed for 5 h and filtered immediately to afford 13a as light yellow solid (123.5 g, 74).
Supplementary Materials: The supplementary materials are available online.
Author Contributions: W.H. and N.-F.S. conceived and designed the experiments; M.W., Y.G., Y.-G.T. and L.-S.Z.
performed synthesis; M.-S.W. and L.-S.Z. analyzed the data; M.-S.W., Z.-C.Y. and W.H. wrote the paper. W.H. was
responsible for the correspondence of the manuscript. All authors have read and agreed to the published version
of the manuscript.
Funding: This work was supported by the National Key Research and Development Program of China
(No. 2017YFA0505200), the Key Research and Development Program of Hubei Province, China (2020BCB042),
the Science and Technology Program of Wuhan (No. 2019020701011460). Dedicated to the 100th anniversary of
Chemistry at Nankai University.
Conflicts of Interest: The authors declare no conflict of interest.
References
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Tabarrini, O.; Massari, S.; Sancineto, L.; Daelemans, D.; Sabatini, S.; Manfroni, G.; Cecchetti, V.; Pannecouque, C.
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