S. Consalvi, G. Venditti, J. Zhu et al.
European Journal of Medicinal Chemistry 226 (2021) 113843
2-Amino-6-fluorophenyl(pyrrolidin-1-yl)methanone
(11).
115.62, 113.12, 106.58, 100.78. LRMS (M þ H)þ(ESIþ) 246.11 [M þ
H]þ(calcd for C13H13FN3O þ 246.10).
White solid (30% yield). 1H NMR (400 MHz, CDCl3),
d
ppm ¼ 7.10e7.05 (m, 1H), 6.49e6.40 (m, 2H), 3.66 (t, 2H,
2-Amino-6-fluoro-N'-(4-fluorophenyl) benzohydrazide (21).
J ¼ 6.9 Hz), 3.41e3.37 (m, 2H), 2.02e1.84 (m, 4H). 13C NMR
White solid (17% yield). 1H NMR (400 MHz, CDCl3),
d
ppm ¼ 8.36 (d,
1H), 7.18e7.13 (m, 1H), 6.89e6.81 (m, 4H), 6.48e6.38 (m, 2H), 5.92
(s broad, 2H). 13C NMR (100 MHz, CDCl3),
ppm ¼ 165.05, 150.25,
150.18, 146.22, 132.15, 132.04, 115.76, 115.54, 114.01, 111.93, 102.71,
102.38. LRMS (M
H)þ(ESIþ) 264.06 [M H]þ(calcd for
13H12F2N3Oþ 264.09).
2-Amino-6-fluoro-N'-(3-fluorophenyl) benzohydrazide (22).
White solid (17% yield). 1H NMR (400 MHz, DMSO‑d6),
ppm ¼ 10.10 (s broad, 1H), 8.23 (s broad, 1H), 7.21e7.12 (m, 2H),
6.64e6.61 (m, 1H), 6.57e6.48 (m, 3H), 6.43e6.38 (m, 1H), 5.80 (s
broad, 2H). 13C NMR (100 MHz, CDCl3),
(100 MHz, CDCl3),
d
ppm ¼ 168.30, 163.88, 161.48, 152.23, 152.17,
132.85, 132.72, 113.12, 113.10, 102.92, 102.66, 100, 50.30, 22.79.
LRMS (M þ H)þ(ESIþ) 209.12 [M þ H]þ(calcd for C11H14FN2Oþ
209.11).
d
þ
þ
2-Amino-6-fluorophenyl(4-methylpiperazin-1-yl)meth-
C
anone (12). White solid (53% yield). 1H NMR (400 MHz, CDCl3),
d
ppm ¼ 7.11e7.06 (m, 1H), 6.50e6.39 (m, 2H), 4.29 (s broad, 2H),
3.87e3.73 (m, 2H), 3.46e3.34 (m, 2H), 2.57e2.32 (m, 7 H). 13C NMR
(100 MHz, DMSO‑d6),
d
d
ppm ¼ 164.89, 161.78, 159.46, 148.92,
148.83, 131.26, 131.15, 111.44, 108.86, 108.67, 102.58, 102.29, 54.91,
d
ppm ¼ 166.91, 161.86,
50.13, 44.96. LRMS (M þ H)þ(ESIþ) 238.13 [M þ H]þ(calcd for
161.73, 161.15, 152.12, 148.34, 148.28, 147.94, 147.99, 133.44, 133.31,
133.11, 130.75, 115.28, 113.35, 113.33, 113.22, 107.10, 106.94, 103.14,
102.88, 101.34, 101.18. LRMS (M þ H)þ(ESIþ) 264.10 [M þ H]þ(calcd
for C13H12F2N3Oþ 264.09).
C
12H17FN3Oþ 238.14).
2-Amino-N-cyclohexyl-6-fluorobenzamide (13). White solid
(70% yield). 1H NMR (400 MHz, DMSO‑d6),
1H), 7.08e7.03 (m, 1H), 6.50 (d, 1H, J ¼ 8.1 Hz), 6.33e6.29 (m, 1H),
5.73 (s broad, 2H), 3.75 (s broad, 1H), 1.82e1.70 (m, 4H), 1.59e1.56
(m, 1H), 1.34e1.11 (m, 5H). 13C NMR (100 MHz, DMSO‑d6),
d
ppm ¼ 8.04e8.02 (m,
2-Amino-N'-(2-chlorophenyl)-6-fluorobenzohydrazide (23).
Brownish solid (yield 18%). 1H NMR (400 MHz, CDCl3),
(d, 1H), 7.31 (dd, 1H, J ¼ 8.1 Hz, 1.7 Hz), 7.19e7.14 (m, 2H), 7.01 (dd,
1H, J ¼ 8.1 Hz, 1.7 Hz), 6.85 (td, 1H, J ¼ 8.1 Hz, 1.7 Hz), 6.49e6.39 (m,
d
ppm ¼ 8.36
d
ppm ¼ 163.59,161.92,159.35,149.90,149.78,131.26,131.03,111.76,
108.86, 108.67, 102.38, 102.23, 48.38, 32.67, 25.68, 25.12. LRMS
2H). 13C NMR (100 MHz, CDCl3),
d
ppm ¼ 166.56, 161.19, 152.13,
(M þ H)þ(ESIþ) 237.13 [M þ H]þ(calcd for C13H18FN2O þ 237.14).
152.06, 144.08, 133.33, 133.12, 129.48, 127.76, 121.48, 119.62, 113.80,
113.26, 113.24, 103.07, 102.81. LRMS (M þ H)þ(ESIþ) 280.08 [M þ
H]þ(calcd for C13H12ClFN3O þ 280.06).
2-Amino-6-fluorophenyl(piperidin-1-yl)methanone
(14).
Grey solid (42% yield). 1H NMR (400 MHz, CDCl3),
ppm ¼ 7.12e7.04 (m, 1H), 6.50e6.39 (m, 2H), 3.84e3.65 (m, 3H),
3.40e3.27 (m, 3H), 1.63e1.46 (m, 4H). 13C NMR (100 MHz,
DMSO‑d6),
d
2-Amino-N'-(3-chlorophenyl)-6-fluorobenzohydrazide (24).
White solid (yield 35%). 1H NMR (400 MHz, CDCl3),
d
ppm ¼ 8.35 (d,
d
ppm ¼ 164.11, 161.39, 159.10, 149.94, 148.87, 131.22,
1H), 7.19e7.14 (m, 2H), 6.92 (t, 1H, J ¼ 1.5 Hz), 6.89e6.88 (m, 1H),
131.05, 112.25, 104.47, 103.23, 102.67, 48.50, 24.94, 23.42. LRMS
6.82 (dd, 1 H, J ¼ 8.1 Hz, 1.5 Hz), 6.48 (d, 1 H, J ¼ 8.1 Hz), 6.44e6.39
(M þ H)þ(ESIþ) 222.13 [M þ H]þ(calcd for C12H15FN2Oþ 222.12).
(m, 2H). 13C NMR (100 MHz, CDCl3),
d
ppm ¼ 166.56, 161.19, 149.47,
2-Amino-6-fluorophenyl(morpholino)methanone
(15).
149.40, 144.08, 134.11, 134.05, 133.28, 129.48, 127.76, 121.48, 113.80,
113.26, 112.26, 112.23, 103.07, 102.81. LRMS (M þ H)þ(ESIþ) 280.07
[M þ H]þ(calcd for C13H12ClFN3O þ 280.06).
White solid (42% yield). 1H NMR (400 MHz, CDCl3),
ppm ¼ 7.12e7.07 (m 1H), 6.51e6.40 (m, 2H), 3.90e3.69 (m, 5H),
3.64e3.57 (m, 1H), 3.51e3.44 (m, 1H), 3.36e3.33 (m, 1H). 13C NMR
(100 MHz, CDCl3),
ppm ¼ 168.30, 163.88, 161.43, 152.23, 152.17,
132.85, 132.72, 113.12, 113.10, 102.92, 102.66, 100, 66.62, 45.56.
LRMS (M
H)þ(ESIþ) 225.09 [M H]þ(calcd for
11H14FN2O2 þ 225.10).
2-Amino- 6-fluoro-N-(4-fluorophenyl) benzamide (16). White
solid (12% yield). 1H NMR (400 MHz, CDCl3),
d
2-Amino-N'-(4-chlorophenyl)-6-fluorobenzohydrazide (25).
d
Yellowish solid (yield 70%). 1H NMR (400 MHz, CDCl3),
d
ppm ¼ 8.35
(d, 1H), 7.20e7.13 (m, 3H), 6.88 (d, 2H, J ¼ 8.8 Hz), 6.46e6.38 (m,
þ
þ
2H), 6.26 (s broad, 1H), 5.95 (s broad, 2H). 13C NMR (100 MHz,
C
CDCl3),
133.26, 133.13, 129.21, 126.10, 114.92, 113.26, 113.24, 103.12, 102.86.
LRMS (M
H)þ(ESIþ) 280.04 [M H]þ(calcd for
13H12ClFN3O þ 280.06).
2-Amino-N'-(2,3-dichlorophenyl)-6-fluorobenzohydrazide
(26). Yellowish solid (yield 13%). 1H NMR (400 MHz, CDCl3),
d
ppm ¼ 166.84, 163.59, 161.16, 152.06, 151.99, 146.92,
d
ppm ¼ 8.33e8.29 (d,
þ
þ
1H), 7.55e7.53 (m, 2H), 7.19e7.15 (m, 1H), 7.13e7.04 (m, 2H),
6.55e6.53 (d, 1H, J ¼ 8.1 Hz), 6.47e6.41 (m, 1H). 13C NMR (100 MHz,
C
CDCl3),
d
ppm ¼ 168.30, 150.24, 150.18, 146.22, 132.15, 132.04,
115.76, 115.54, 114.01, 111.93, 102.71. LRMS (M þ H)þ(ESIþ) 248.09
d
ppm ¼ 8.38 (d, 1H), 7.20e7.14 (m, 1H), 7.11 (t, 1H, J ¼ 8.1 Hz), 7.01
[M þ H]þ(calcd for C13H11F2N2O þ 248.08).
(dd, 1H, J ¼ 8.1 Hz, 1.4 Hz), 6.91 (dd, 1H, J ¼ 8.1 Hz, 1.4 Hz), 6.72 (s
tert-butyl
2-(2-amino-6-fluorobenzoyl)hydrazine-1-
broad, 1H), 6.50e6.40 (m, 2H). 13C NMR (100 MHz, CDCl3),
carboxylate (18). White solid (60% yield). 1H NMR (400 MHz,
d
ppm ¼ 166.91, 161.15,150.14, 149.91, 146.28, 133.44, 133.31, 130.75,
CDCl3),
d
ppm ¼ 8.32 (d, 1H), 7.16e7.11 (m, 1H), 6.66 (s braod, 1H),
127.47, 119.29, 116.08, 112.57, 11.75, 103.14, 102.88. LRMS
(M þ H)þ(ESIþ) 314.05 [M þ H]þ(calcd for C13H11Cl2FN3Oþ 314.03).
2-Amino-N'-(2,4-dichlorophenyl)-6-fluorobenzohydrazide
(27). Grey solid (yield 28%); 1H NMR (400 MHz, CDCl3),
6.48 (d, 1H, J ¼ 8.1 Hz), 6.38e6.35 (m, 1H), 1.50 (s, 9H). 13C NMR
(100 MHz, DMSO‑d6),
d
ppm ¼ 164.69, 159.61, 155.89, 149.41, 131.88,
131.77, 111.43, 102.08, 101.86, 80.03, 28.56. LRMS (M þ H)þ(ESIþ)
270.10 [M þ H]þ(calcd for C12H17FN3Oþ3 270.12).
d
ppm ¼ 8.36 (d, 1 H), 7.33 (d, 1H, J ¼ 2.2 Hz), 7.15e7.12 (m, 2H), 6.92
2-Amino-N0-cyclohexyl-6-fluorobenzohydrazide (19). White
(d, 1H, J ¼ 8.3 Hz), 6.59 (s broad, 1H), 6.49e6.39 (m, 2H). 13C NMR
solid (33% yield). 1H NMR (400 MHz, CDCl3),
d
ppm ¼ 7.12e7.08 (m,
1H), 6.45 (d, 1H, J ¼ 8.1 Hz), 6.38e6.33 (m, 1H), 2.90e2.85 (m, 1H),
1.94e1.18 (m, 11H). 13C NMR (100 MHz, DMSO‑d6),
(100 MHz, CDCl3),
d
ppm ¼ 166.91, 161.15, 150.14, 149.91, 142.85,
133.44, 133.31, 128.60, 127.74, 126.97, 119.29, 116.08, 112.57, 111.75,
d
ppm ¼ 168.30,
103.14, 102.88. LRMS (M þ H)þ(ESIþ) 314.06 [M þ H]þ(calcd for
161.92, 159.35, 149.90, 149.78, 131.26, 131.03, 111.76, 108.86, 108.67,
102.38, 102.23, 48.38, 32.67, 25.68, 25.12. LRMS (M þ H)þ(ESIþ)
252.17 [M þ H]þ(calcd for C13H19FN3Oþ 252.15).
C
13H11Cl2FN3Oþ 314.03).
2-Amino-N'-(2,5-dichlorophenyl)-6-fluorobenzohydrazide
(28). Yellowish solid (yield 29%). 1H NMR (400 MHz, DMSO‑d6)
2-Amino-6-fluoro-N0-phenylbenzohydrazide (20). White solid
d
ppm ¼ 10.26 (s broad, 1H), 7.90 (s broad, 1H),7.35 (d, 1H,
(yield 25%). 1H NMR (400 MHz, CDCl3),
d
ppm ¼ 8.36 (d, 1H),
J ¼ 8.2 Hz), 7.17e7.11 (m,1H), 6.82e6.79 (m, 2H), 6.55e6.53 (m, 1H),
7.28e7.24 (m, 2H), 7.18e7.12 (m, 1H), 6.95e6.91 (m, 3H), 6.48e6.38
6.42e6.38 (m, 1H), 5.80 (s broad, 2H). 13C NMR (100 MHz,
(m, 2H), 6.07 (s broad, 2H). 13C NMR (100 MHz, CDCl3),
DMSO‑d6),
d
ppm ¼ 181.84, 164.99, 150.14, 149.91, 146.28, 133.03,
d
ppm ¼ 170.02, 159.82, 153.02, 148.78, 133.21, 128.85, 119.39,
132.11, 132.07, 131.03, 119.29, 116.08, 112.57, 111.75, 102.22, 102.07.
10