L. Al-Ghanim et al.
Bioorganic & Medicinal Chemistry xxx (xxxx) xxx–xxx
7
.94–7.99 (1H, m), 7.34 (2H, t, J = 9.0 Hz), 7.25 (1H, brs), 6.91–6.95
1H, m), 4.20–4.26 (1H, m), 4.00–4.10 (1H, m), 3.62–3.75 (2H, m),
.53–3.61 (2H, m), 3.09–3.29 (6H, m), 2.50–2.56 (2H, m), 2.14–2.20
1H, m), 1.96–2.02 (2H, m).
(2 × 300 mL), the organic layer was separated, dried over Na
2
SO , and
4
(
filtered. The filtrate was concentrated in vacuo to dryness, followed by
column chromatography on silica gel to afford 1-(5-chloropyridin-2-yl)-
4-(3-((4-fluorophenyl)thio)propyl)-1,4-diazepane 7. The product was
converted into the salt by the addition of ethereal HCl and the salt was
3
(
1
3
C NMR (75 MHz, DMSO‑d
6
): δ 197.8, 165.5 (d, J = 250.7 Hz),
1
52.5, 143.8, 137.7, 133.5 (d, J = 2.3 Hz), 131.3 (d, J = 9.1 Hz), 116.2
purified by recrystallization from MeOH-Et
2
O to afford the HCl salt, in a
.
(
d, J = 21.8 Hz), 113.0, 112.6, 56.2, 53.3, 52.8, 48.1, 43.3, 35.7, 23.0,
yield of 42%, Mp 191–193 °C. Calcd for C19
H
25Cl
3
FN
3
S 0.5 H
2
O: C
1
8.5.
49.41, H 5.67, N 9.10; Found: C 49.41, H 5.65, N 9.08.
1
H NMR (300 MHz, DMSO‑d ): δ 10.91 (1H, brs), 8.08 (1H, d,
6
5
.3.3. 1-(4-fluorophenyl)-4-(4-(pyrimidin-2-yl)-1,4-diazepan-1-yl)butan-
-one (4·2HBr)
J = 2.4 Hz), 7.63 (1H, dd, J = 3.0, 9.0 Hz), 7.38–7.45 (2H, m),
7.14–7.21 (2H, m), 6.75 (1H, d, J = 9.0 Hz), 4.20–4.27 (1H, m),
3.67–3.75 (1H, m), 3.41–3.53 (4H, m), 3.11–3.17 (2H, m), 3.03–3.07
(2H, m), 2.95–3.00 (2H, m), 2.31–2.41 (1H, m), 2.04–2.16 (1H, m),
1.90–2.00 (2H, m).
1
The free base was treated with ethereal HBr to form a salt.
Recrystallization from MeOH:Et O, afforded 1-(4-fluorophenyl)-4-(4-
2
(
pyrimidin-2-yl)-1,4-diazepan-1-yl)butan-1-one 4, dihydrobromide, in
1
3
a yield of 33%, Mp 225–230 °C. Calculated for C19
H
25Br
FN
2 4
O: C 45.26,
C NMR (75 MHz, DMSO‑d ): δ 161.4 (d, J = 241.7 Hz), 154.5,
6
H 5, N 11.11; Found: C 45.47, H 5.07, N 11.02.
141.4, 140.1, 131.9 (d, J = 7.6 Hz), 131.1 (d, J = 2.8 Hz), 118.7, 116.7
1
H NMR (600 MHz, DMSO‑d ): δ 9.80 (1H, s), 8.51 (2H, d,
6
(d, J = 21.4 Hz), 110.6, 52.3, 54.0, 53.5, 47.0, 42.2, 30.9, 23.6, 23.3.
J = 4.9 Hz), 8.21–7.92 (2H, m), 7.52–7.25 (2H, m), 6.81 (1H, t,
J = 4.9 Hz), 4.49–4.21 (1H, m), 3.93–3.81 (2H, m), 3.78–3.74 (1H, m),
5.5. Synthesis of oximes 22–24
3
.72–3.65 (1H, m), 3.62–3.52 (1H, m), 3.34–3.23 (2H, m), 3.23–3.14
(
4H, m), 2.37–2.3 (1H, m), 2.25–2.13 (1H, m), 2.08–1.99 (2H, m).
General Procedure II: A mixture of 4-(4-(5-chloropyridin-2-yl)-1,4-
diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one 2 (0.65 g, 1.73 mmol) ,
hydroxylamine hydrochloride (0.25 g, 3.46 mmol), KOH (0.19 g,
3.46 mmol) in EtOH (10 mL) was heated to reflux at 90˚C for 5 h. After
1
3
C NMR (151 MHz, DMSO‑d ): δ 197.7, 165.1 (d, J = 250.0 Hz),
6
1
1
61.5, 157.6, 133.6, 131.4 (d, J = 9.4 Hz), 116.2 (d, J = 21.7 Hz),
10.7, 56.8, 55.4, 54.78, 4.36, 45.9, 36.0, 27.4, 22.2.
cooling to room temperature, H O was added to the reaction mixture to
2
5
.3.4. 4-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-1-(4-fluorophenyl)butan-
-one (8·HCl)
precipitate the compound. The residue was washed with water and
1
EtOAc and the aqueous layer was extracted twice with EtOAc. The
The free base was converted into the salt by addition of ethereal HCl
combined organic layer was dried over anhydrous Na
2
SO and filtered.
4
and the salt was purified by recrystallization from MeOH-Et
2
O to afford
The filtrate was evaporated and the residue purified by flash chroma-
tography using (90:10% EtOAc: Hexane).
the pure salt in
a
yield of 25%, Mp 183–185 °C. Calcd for
.
C
19
H
22Cl
2
FN
3
O 1.0 H
2
O: C 54.81, H 5.81, N 10.09; Found: C 54.89, H
5
.47, N 10.09.
5.5.1. (4-(4-(5-chloropyridin-2-yl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)
butan-1-one oxime (22)
1
H NMR (300 MHz, DMSO‑d ): δ 10.47 (1H, brs), 8.15 (1H, d,
6
J = 2.7 Hz), 8.06 (1H, d, J = 5.7 Hz), 8.03 (1H, d, J = 5.7 Hz), 7.68
1H, dd, J = 2.7, 9.0 Hz), 7.36 (2H, t, J = 9.0 Hz), 6.98 (1H, d,
The product was recrystallized using EtOAc/Hexane to afford (4-(4-
(5-chloropyridin-2-yl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)butan-1-
one oxime 22 in a yield of 37%, Mp 148–150 °C. Calculated for
(
J = 9.3 Hz), 4.33 (2H, d, J = 14.1 Hz), 3.56 (2H, d, J = 14.1 Hz),
3
1
.21–3.32 (2H, m), 3.00–3.21 (6H, m), 1.91–2.06 (2H, m).
C
20
14.33.
H
24ClFN O: C 61.46, H 6.19, N 14.33; Found: C 61.68, H 6.28, N
4
1
3
C NMR (75 MHz, DMSO‑d
6
): δ 197.7, 165.5 (d, J = 250.1 Hz),
1
57.0, 145.8, 138.1, 133.6, 131.3 (d, J = 9.3 Hz), 120.5, 116.2 (d,
H NMR (600 MHz, DMSO‑d ); δ 11.16 (1H, s), 8.03 (1H, d,
6
J = 21.4 Hz), 109.8, 55.5, 50.6, 42.3, 35.7, 18.1.
J = 2.7 Hz), 7.83–7.58 (2H, m), 7.51 (1H, dd, J = 2.7, 9.1 Hz),
7
.42–6.94 (2H, m), 6.63 (1H, d, J = 9.2 Hz), 3.71–3.59 (2H, m), 3.56
5
.3.5. 1-(5-chloropyridin-2-yl)-4-(4-(4-fluorophenyl)butyl)piperazine
10·HCl)
The free base was converted into the salt by addition of ethereal HCl
and the residue was purified by recrystallization from MeOH-Et O to
(2H, t, J = 6.1 Hz), 2.72–2.65 (2H, m), 2.65–2.60 (2H, m), 2.49–2.44
(2H, m), 2.43 (2H, dd, J = 8.7, 15.6 Hz), 1.92–1.69 (2H, m), 1.69–1.49
(2H, m).
(
1
3
2
C NMR (151 MHz, DMSO‑d ): δ 162.8 (d, J = 244.3 Hz), 156.9,
6
afford the pure salt in a yield of 31%, Mp 195–196 °C. Calcd for
156.4, 146.0, 137.3, 133.2, 128.3 (d, J = 8.3 Hz), 117.4, 115.7 (d,
J = 21.6 Hz), 107.2, 57.0, 55.0, 54.5, 47.3, 46.6, 27.3, 24.4, 23.4.
C
19
0.90.
H
24Cl
2
FN
3
: C 59.38, H 6.29, N 10.93; Found: C 59.22, H 6.04, N
): δ 10.30 (1H, brs), 8.15 (1H, d,
1
1
H NMR (300 MHz, DMSO‑d
6
5.5.2. 1-(4-fluorophenyl)-4-(4-(pyridin-2-yl)-1,4-diazepan-1-yl)butan-1-
one oxime (23)
J = 1.8 Hz), 7.68 (1H, dd, J = 2.7, 9.0 Hz), 7.21–7.26 (2H, m), 7.09
2H, t, J = 9.0 Hz), 6.97 (1H, d, J = 8.4 Hz), 4.32 (2H, d, J = 14.2 Hz),
.47–3.51 (2H, m), 3.17–3.26 (2H, m), 2.93–3.12 (4H, m), 2.56–2.61
2H, m), 1.62–1.71 (2H, m), 1.52–1.60 (2H, m).
(
Using the general method II, 1-(4-fluorophenyl)-4-(4-(pyridin-2-yl)-1,4-
diazepan-1-yl)butan-1-one, 3 was treated with hydroxylamine hydro-
chloride to form the product which was recrystallized from EtOAc/Hexane
to afford 1-(4-fluorophenyl)-4-(4-(pyridin-2-yl)-1,4-diazepan-1-yl)butan-1-
one oxime 23 in a yield of 48%, Mp 108–112 °C. Calculated for
3
(
1
3
C NMR (75 MHz, DMSO‑d
6
): δ 161.1 (d, J = 239.5 Hz), 157.0,
1
46.1, 138.2, 138.0, 130.5 (d, J = 7.7 Hz), 120.5, 115.4 (d,
J = 20.3 Hz), 109.6, 55.6, 50.6, 42.2, 34.1, 28.6, 23.0.
C
20
H
25FN O: C 67.39, H 7.07, N 15.72; Found: C 67.43, H 6.90, N 15.66.
4
1
H NMR (600 MHz, DMSO‑d ): δ 11.16 (1H, s), 8.43–7.87 (1H, m),
6
5
.4. Synthesis of 1-(5-chloropyridin-2-yl)-4-(3-((4-fluorophenyl)thio)
7.89–7.54 (2H, m), 7.46–7.43 (1H, m), 7.36–7.08 (2H, m), 6.57 (1H, d,
J = 8.7 Hz), 6.54–6.46 (1H, m), 3.78–3.63 (2H, m), 3.57 (2H, t,
J = 6.2 Hz), 2.76–2.66 (2H, m), 2.68–2.59 (2H, m), 2.48–2.44 (2H, m),
2.43 (2H, t, J = 7.0 Hz), 1.80 (2H, dt, J = 6.0, 11.7 Hz), 1.69–1.49 (2H,
m).
propyl)-1,4-diazepane hydrochloride (7· HCl)
The method previously reported in Sampson et al.3 was used. A
4
mixture of 3-((4-fluorophenyl)-thio)propyl methanesulfonate (0.86 g,
1
3
3
.5 mmol), 1-(5-chloropyridin-2-yl)-1,4-diazepane (0.85 g, 4.0 mmol)
C NMR (151 MHz, DMSO‑d ): δ 162.8 (d, J = 244.3 Hz), 158.3,
6
i
2
6a, KI (150 mg), NaHCO
3
(1.0 g, 11.9 mmol) in PrOH (10 mL) was
156.4, 148.1, 137.7, 133.2 (d, J = 2.4 Hz), 128.3 (d, J = 8.3 Hz), 115.7
(d, J = 21.4 Hz), 111.5, 105.8, 57.0, 55.3, 54.6, 46.9, 46.2, 27.5, 24.4,
23.4.
heated to reflux under N
2
for 12 h. After cooling to rt, the mixture was
diluted with EtOAc (500 mL), followed by washing with water
5