J. Guo et al.
Bioorganic Chemistry 113 (2021) 105013
= 2.2 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.13 (s, 1H), 6.56 (s, 1H), 5.18 (s,
2H), 3.65 (s, 2H), 3.54 (s, 3H), 3.49 (s, 2H), 3.23 (d, J = 2.4 Hz, 2H),
2.33 (s, 3H), 2.33 (t, J = 2.4 Hz, 2H).
4.9.4. 2-(((4-Chlorobenzyl)(prop-2-yn-1-yl)amino)methyl)-5-hydroxy-1-
methylpyridin ꢀ 4(1H)-one (14d)
1
◦
Yield: 86%, white solid, m.p. 188.1–189.8 C, H NMR (400 MHz,
DMSO‑d6) δ 11.10 (br, 1H), 8.30–8.23 (m, 1H), 7.45–7.33 (m, 6H), 4.03
(s, 3H), 3.84 (s, 2H), 3.68 (s, 2H), 3.38 (t, J = 2.4 Hz, 1H), 3.26 (d, J =
2.4 Hz, 2H).13C NMR (100 MHz, DMSO‑d6) δ 160.3, 146.2, 144.7, 136.6,
133.9, 132.6, 131.4, 128.8, 114.7, 78.0, 77.9, 56.6, 53.9, 43.6, 41.8.
HRMS (ESI): m/z calcd for C17H18ClN2O2 [M + H]+: 317.1051 found
317.1054. HPLC purity: 100%.
4.8.12. 5-(Benzyloxy)-1-methyl-2-(((4-methylbenzyl)(prop-2-yn-1-yl)
amino)methyl) pyridin-4(1H)-one (13l)
Yield: 75%, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.43–7.38 (m,
2H), 7.36–7.32 (m, 2H), 7.32–7.27 (m, 1H), 7.19–7.08 (m, 5H), 6.93 (s,
1H), 6.55 (s, 1H), 5.17 (s, 2H), 3.61 (s, 2H), 3.54 (s, 3H), 3.49 (s, 2H),
3.23 (d, J = 2.5 Hz, 2H), 2.33 (s, 3H), 2.31 (t, J = 2.5 Hz, 2H).
4.9.5. 2-(((2-Fluorobenzyl)(prop-2-yn-1-yl)amino)methyl)-5-hydroxy-1-
4.8.13. 5-(Benzyloxy)-1-methyl-2-((prop-2-yn-1-yl(4-(trifluoromethyl)
benzyl)amino) methyl)pyridin-4(1H)-one (13m)
methylpyridin ꢀ 4(1H)-one (14e)
1
◦
Yield: 80%, white solid, m.p. 176.5–178.2 C, H NMR (400 MHz,
DMSO‑d6) δ 11.17 (br, 1H), 8.29 (s, 1H), 7.45–7.30 (m, 3H), 7.21–7.12
(m, 2H), 4.02 (s, 3H), 3.88 (s, 2H), 3.73 (s, 2H), 3.40 (t, J = 2.4 Hz, 1H),
Yield: 76%, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.0
Hz, 2H), 7.45–7.39 (m, 4H), 7.39–7.30 (m, 3H), 6.99 (s, 1H), 6.60 (s,
1H), 5.19 (s, 2H), 3.74 (s, 2H), 3.63 (s, 3H), 3.57 (s, 2H), 3.26 (d, J = 2.4
Hz, 2H), 2.37 (t, J = 2.4 Hz, 1H).
3.29 (d, J = 2.4 Hz, 2H). 13C NMR (100 MHz, DMSO) δ 161.3 (d, 1JC-F
=
244.1 HZ), 160.2, 146.2, 144.7, 134.0, 132.0 (d, 3JC-F = 4.1 HZ), 130.2
(d, 3JC-F = 8.2 HZ), 124.9 (d, 4JC-F = 3.2 HZ), 124.5 (d, 2JC-F = 14.0 HZ),
2
4.8.14. 5-(Benzyloxy)-2-(((3,5-difluorobenzyl)(prop-2-yn-1-yl)amino)
methyl)-1-methylpyridin-4(1H)-one (13n)
115.9 (d, JC-F = 21.4 HZ), 114.8, 78.0, 77.9, 54.0, 50.4, 43.3, 41.8.
HRMS (ESI): m/z calcd for C17H18FN2O2 [M + H]+: 301.1347 found
Yield: 77%, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.44–7.39 (m,
2H), 7.33 (dt, J = 13.4, 6.8 Hz, 3H), 6.93 (s, 1H), 6.83–6.78 (m, 2H),
6.76–6.66 (m, 1H), 6.53 (s, 1H), 5.17 (s, 2H), 3.64 (s, 2H), 3.62 (s, 3H),
3.54 (s, 2H), 3.24 (d, J = 2.4 Hz, 2H), 2.34 (t, J = 2.4 Hz, 1H).
301.1346. HPLC purity: 99.38%.
4.9.6. 2-(((3-Fluorobenzyl)(prop-2-yn-1-yl)amino)methyl)-5-hydroxy-1-
methylpyridin ꢀ 4(1H)-one (14f)
1
◦
Yield: 82%, white solid, m.p. 185.3–187.2 C, H NMR (400 MHz,
DMSO‑d6) δ 11.15 (br, 1H), 8.28 (s, 1H), 7.43–7.34 (m, 2H), 7.21–7.06
(m, 3H), 4.04 (s, 3H), 3.86 (s, 2H), 3.71 (s, 2H), 3.40 (t, J = 2.4 Hz, 1H),
3.28 (d, J = 2.4 Hz, 2H).13C NMR (100 MHz, DMSO‑d6) δ 162.7 (d, 1JC-F
= 263.4 HZ), 160.3, 146.4, 144.6, 140.8 (d, 3JC-F = 7.3 Hz), 134.0, 130.8
4.9. Preparation method of compounds 14a-n
Intermediate 13a-o (1 mmol) were completely dissolved in anhy-
drous DCM (10 mL), then 3 mL of BCl3 solution (1 mmol/L DCM) was
added to the solution at ꢀ 20 ◦C, and the reaction was carried out under
nitrogen protection. After the addition, the reaction system was
continuously stirred for 2 h, quenched with methanol (15 mL), warmed
to room temperature and stirred for 12 h. The solvent was concentrated
and the obtained crude material was purified by recrystallization
(methanol/ether) to obtain 14a-n as white solids.
4
(d, 3JC-F = 8.3 Hz), 125.4 (d, JC-H = 2.4 Hz), 115.9 (d, 2JC-F = 21.1),
114.8 (d, 2JC-F = 20.9), 114.6, 80.2, 77.9, 56.9, 54.0, 43.5, 41.9. HRMS
(ESI): m/z calcd for C17H18FN2O2 [M + H]+: 301.1347 found 301.1349.
HPLC purity: 99.94%.
4.9.7. 2-(((4-Fluorobenzyl)(prop-2-yn-1-yl)amino)methyl)-5-hydroxy-1-
methylpyridin ꢀ 4(1H)-one (14g)
1
◦
Yield: 85%, white solid, m.p. 188.6–190.1 C, H NMR (400 MHz,
DMSO‑d6) δ 11.16 (br, 1H), 8.29 (s, 1H), 7.42 (s, 1H), 7.41–7.35 (m,
2H), 7.18–7.12 (m, 2H), 4.03 (s, 3H), 3.85 (s, 2H), 3.68 (s, 2H), 3.39 (t, J
= 2.4 Hz, 1H), 3.26 (d, J = 2.4 Hz, 2H). 13C NMR (100 MHz, DMSO‑d6) δ
162.0 (d, 1JC-F = 242 Hz), 160.3, 146.3, 144.7, 134.0, 133.0, 131.5 (d,
3JC-F = 8.2 Hz), 115.6 (d, 2JC-F = 21.1 Hz) 114.7, 80.1, 77.9, 56.6, 53.9,
43.5, 41.8. HRMS (ESI): m/z calcd for C17H18FN2O2 [M + H]+: 301.1347
found 301.1345. HPLC purity: 99.19%.
4.9.1. 2-((Benzyl(prop-2-yn-1-yl)amino)methyl)-5-hydroxy-1-
methylpyridin-4(1H)-one (14a)
1
◦
Yield: 80%, white solid, m.p. 173.6–175.2 C, H NMR (400 MHz,
DMSO‑d6) δ 11.12 (br, 1H), 8.28 (s, 1H), 7.42 (s, 1H), 7.33 (d, J = 4.4
Hz, 3H), 7.31–7.24 (m, 1H), 4.04 (s, 3H), 3.86 (s, 2H), 3.70 (s, 2H), 3.38
(t, J = 2.4 Hz, 1H), 3.27 (d, J = 2.4 Hz, 2H).13C NMR (100 MHz,
DMSO‑d6) δ 160.3, 146.3, 144.7, 137.5, 134.0, 129.5, 128.9, 128.0,
114.7, 77.9, 65.4, 57.5, 53.9, 43.5, 41.8. HRMS (ESI): m/z calcd for
C17H19N2O2 [M + H]+: 283.1441 found 283.1438. HPLC purity:
99.60%.
4.9.8. 5-Hydroxy-2-(((2-methoxybenzyl)(prop-2-yn-1-yl)amino)methyl)-
1-methylpyr idin-4(1H)-one (14h)
1
◦
Yield: 86%, white solid, m.p. 136.3–138.2 C, H NMR (400 MHz,
DMSO‑d6) δ 11.20 (br, 1H), 8.31 (s, 1H), 7.40 (s, 1H), 7.26 (t, J = 7.3 Hz,
2H), 7.02–6.85 (m, 2H), 4.03 (s, 3H), 3.87 (s, 2H), 3.73 (s, 3H), 3.65 (s,
2H), 3.39 (s, 1H), 3.30 (d, J = 2.4 Hz, 2H). 13C NMR (100 MHz,
DMSO‑d6) δ 160.2, 158.0, 146.1, 144.8, 134.0, 131.0, 129.6, 124.9,
120.6, 115.1, 111.4, 78.1, 77.8, 55.8, 54.1, 51.6, 43.4, 42.0. HRMS
(ESI): m/z calcd for C18H21N2O3 [M + H]+: 313.1547 found 313.1550
HPLC purity: 100%.
4.9.2. 2-(((2-Chlorobenzyl)(prop-2-yn-1-yl)amino)methyl)-5-hydroxy-1-
methylpyridin ꢀ 4(1H)-one (14b)
1
◦
Yield: 81%, white solid, m.p. 190.1–191.6 C, H NMR (400 MHz,
DMSO‑d6) δ 11.17 (br, 1H), 8.29 (s, 1H), 7.49–7.40 (m, 2H), 7.36–7.28
(m, 2H), 4.02 (s, 3H), 3.89 (s, 2H), 3.77 (s, 2H), 3.42 (t, J = 2.4 Hz, 1H),
3.31 (d, J = 2.4 Hz, 2H).13C NMR (100 MHz, DMSO‑d6) δ 160.2, 146.2,
144.7, 135.1, 134.1, 134.0, 131.9, 130.0, 129.9, 127.7, 115.0, 78.0,
78.0, 54.3, 54.1, 43.4, 42.0. HRMS (ESI): m/z calcd for C17H18ClN2O2
[M + H]+: 317.1051 found 317.1056. HPLC purity: 99.50%.
4.9.9. 5-Hydroxy-2-(((3-methoxybenzyl)(prop-2-yn-1-yl)amino)methyl)-
1-methylpyr idin-4(1H)-one (14i)
4.9.3. 2-(((3-Chlorobenzyl)(prop-2-yn-1-yl)amino)methyl)-5-hydroxy-1-
1
◦
Yield: 88%, white solid, m.p. 159.2–161.2 C, H NMR (400 MHz,
DMSO‑d6) δ 11.13 (br, 1H), 8.27 (s, 1H), 7.39 (s, 1H), 7.24 (t, J = 7.8 Hz,
1H), 6.90 (dt, J = 7.5, 1.2 Hz, 1H), 6.88–6.80 (m, 2H), 4.04 (s, 3H), 3.84
(s, 2H), 3.74 (s, 3H), 3.67 (s, 2H), 3.8 (t, J = 2.4 Hz, 1H), 3.29 (d, J = 2.4
Hz, 2H). 13C NMR (100 MHz, DMSO‑d6) δ 160.2, 159.8, 146.3, 144.7,
139.2, 133.9, 130.0, 121.6, 114.9, 114.7, 113.4, 78.0, 77.9, 57.6, 55.5,
53.9, 43.5, 42.0. HRMS (ESI): m/z calcd for C18H21N2O3 [M + H]+:
313.1547 found 313.1544 HPLC purity: 99.55%.
methylpyridin ꢀ 4(1H)-one (14c)
1
◦
Yield: 85%, white solid, m.p. 177.5–179.2 C, H NMR (400 MHz,
DMSO‑d6) δ 11.16 (br, 1H), 8.29 (s, 1H), 7.40 (s, 1H), 7.38–7.28 (m,
3H), 4.05 (s, 3H), 3.86 (s, 2H), 3.71 (s, 2H), 3.41 (t, J = 2.4 Hz, 1H), 3.29
(d, J = 2.4 Hz, 2H).13C NMR (100 MHz, DMSO‑d6) δ 160.2, 146.2, 144.7,
140.4, 134.0, 133.5, 130.8, 129.1, 128.1, 128.0, 114.7, 80.2, 78.0, 56.9,
54.0, 43.5, 41.9. HRMS (ESI): m/z calcd for C17H18ClN2O2 [M + H]+:
317.1051 found 317.1050. HPLC purity: 99.78%.
12