The Journal of Organic Chemistry
(1-(3-([1,1'-biphenyl]-2-yloxy)-2-hydroxy (64.0 mg, 0.463, 1 eq) to afford final compound 5a as white
Page 6 of 9
Tert-butyl
1
propyl)pyrrolidin-3-yl)carbamate (3d)
powder (200.1 mg, yield 86%).
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C26H29ClN2O4S, MW 501.04, Monoisotopic Mass 500.15.
UPLC/MS tR = 5.89 min, purity = 98%, [M+H]+ 501.2.
1H NMR (500 MHz, CDCl3) δ 7.89 (t, J = 1.9 Hz, 1H), 7.77 (dt,
J = 7.7, 0.9 Hz, 1H), 7.53 (dq, J = 8.0, 0.9 Hz, 1H), 7.50 (dt,
J = 8.3, 1.4 Hz, 2H), 7.43 (t, J = 8.0 Hz, 1H), 7.36–7.39 (m,
2H), 7.26–7.33 (m, 3H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 6.96 (dd,
J = 8.2, 0.7 Hz, 1H), 5.27 (s, 1H), 3.84–4.00 (m, 3H), 3.16 (spt,
J = 4.3 Hz, 1H), 2.72–2.78 (m, 1H), 2.56–2.62 (m, 1H), 2.34–
2.40 (m, 1H), 2.30 (dd, J = 15.0, 3.8 Hz, 1H), 2.16–2.23 (m,
1H), 1.91–1.99 (m, 1H), 1.68–1.76 (m, 2H), 1.39–1.52 (m, 2H).
13C{1H} NMR (126 MHz, CDCl3) δ 155.6, 143.2, 138.5, 135.3,
132.8, 131.3, 130.9, 130.6, 129.7, 128.8, 127.9, 127.1, 127.0,
126.1, 121.6, 113.2, 70.9, 66.0, 60.5, 53.2, 51.3, 50.8, 33.0,
32.9, 29.7. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C26H30ClN2O4S 501.1615; found: 501.1620. Data in agreement
with lit.29
General procedure C was followed with compound 1a (181.0
mg, 0.800 mmol, 1 eq), 3-Boc-amino-pyrrolidine (149.0 mg,
0.800 mmol, 1 eq) and EtOH (33 µL, η = 0.1 µL·mg-1) to afford
intermediate 3d as white powder (268.7 mg, yield 83%). In this
case, crystallization in EtOH was required to obtain the pure
compound.
C24H32N2O4, MW 412.52, Monoisotopic Mass 412.24.
UPLC/MS tR = 5.52 min, purity = 95%, [M+H]+ 413.2.
1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.6 Hz, 2H), 7.35–
7.40 (m, 2H), 7.32 (dd, J = 7.4, 1.7 Hz, 1H), 7.26–7.30 (m, 2H),
7.03 (td, J = 7.4, 1.1 Hz, 1H), 6.94–7.00 (m, 1H), 5.05–5.13 (m,
1H), 4.09–4.17 (m, 1H), 3.13–3.42 (m, 1H), 2.80–2.89 (m, 1H),
2.67–2.75 (m, 1H), 2.55–2.64 (m, 2H), 2.42–2.52 (m, 1H),
2.34–2.40 (m, 1H), 2.28–2.34 (m, 1H), 2.11–2.23 (m, 2H),
1.48–1.60 (m, 1H), 1.43 (s, 9H). 13C{1H} NMR (126 MHz,
CDCl3) δ 155.6, 155.5, 138.5, 131.3, 130.9, 129.7, 128.8, 128.0,
127.0, 121.6, 113.3, 79.3, 71.2, 71.2, 67.7, 61.7, 61.1, 58.8,
52.8, 49.8, 32.6, 28.5. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C24H33N2O4 413.2440; found: 413.2446.
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3-Chloro-N-(1-(3-([1,1'-biphenyl]-2-yloxy)-2-hydroxy
propyl)piperidin-4-yl)-benzenesulfonamide PZ-1361 (5a)
[CAS 2095849-69-5] (Synthesis on a mmol scale)
Deprotection of Boc function in solid state (general
procedure D)
Intermediate
4
(407.7 mg, 1.12 mmol,
1
eq), 3-
chlorobenzenesulfonyl chloride (158.2 µl, 1.12 mmol, 1 eq),
and previously grinded K2CO3 (155.3 mg, 1.12 mmol, 1 eq)
were introduced in a 35 mL PTFE jar (milling load 25 mg/mL)
with one stainless steel ball (ᴓball = 1.5 cm). The reaction was
carried out for 1 min at rt. Then, the crude mixture was
solubilized in ethyl acetate (25 mL) and the organic phase was
washed with KHSO4 aqueous solution at pH = 3.5 (3 x 10 mL),
saturated NaCl solution (1 x 10 mL), dried over Na2SO4 and
finally filtered and concentrated under vacuum yielding
compound 5a as white powder (472.2 mg, yield 84%).
Intermediate 3a (0.5 g, 1.16 mmol) was submitted to HClgas for
2 h at r.t. to afford the primary amine 4 as white hydrochloride
salt (0.41 g, yield 98%).
1-([1,1'-Biphenyl]-2-yloxy)-3-(4-aminopiperidin-1-yl)
propan-2-ol (4)
White powder (0.41 g, yield 98%). C20H26N2O2·HCl, MW
362.90, Monoisotopic Mass 326.43. UPLC/MS tR = 3.62 min,
purity = 100%, [M+H]+ 327.2. 1H NMR (500 MHz, CD3OD) δ
7.46–7.51 (m, 2H), 7.38–7.44 (m, 2H), 7.29–7.33 (m, 2H),
7.25–7.28 (m, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.01–7.05 (m, 1H),
4.30–4.36 (m, 1H), 4.04 (dd, J = 9.9, 4.4 Hz, 1H), 3.97 (dd,
J = 9.7, 5.6 Hz, 1H), 3.58 (q, J = 7.0 Hz, 2H), 3.44–3.53 (m,
1H), 3.09–3.19 (m, 3H), 2.18–2.28 (m, 2H), 1.96–2.12 (m, 2H),
1.12–1.18 (m, 4H). 13C{1H} NMR (126 MHz, CD3OD) δ 155.4,
138.6, 131.3, 130.5, 129.5, 128.7, 127.9, 126.9, 121.7, 113.4,
70.6, 64.2, 57.0, 50.4, 45.3, 17.2. HRMS (ESI-TOF) m/z
[M+H]+ calcd for C20H27N2O2 327.2073; found: 327.2079.
N-(1-(3-([1,1'-Biphenyl]-2-yloxy)-2-hydroxypropyl)
piperidin-4-yl)benzenesulfonamide (5b)
General procedure E was followed with primary amine 4 (176.7
mg, 0.487 mmol, 1 eq), benzenesulfonyl chloride (62.14 µl,
0.487 mmol, 1 eq), and previously grinded K2CO3 (67.3 mg,
0.487 mmol, 1 eq) to afford final compound 5b as colorless oil
(197.4 mg yield 87%).
C26H30N2O4S, MW 466.59, Monoisotopic Mass 466.19.
UPLC/MS tR = 5.23 min, purity = 98%, [M+H]+ 467.2.
1H NMR (500 MHz, CDCl3) δ 7.87–7.90 (m, 2H), 7.56 (tt,
J = 6.3, 1.4 Hz, 1H), 7.47–7.52 (m, 4H), 7.33–7.39 (m, 2H),
7.26–7.32 (m, 3H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 6.96 (dd,
J = 8.3, 0.9 Hz, 1H), 5.28 (s, 1H), 5.04 (br. s, 1H), 3.86–3.94
(m, 3H), 3.15 (spt, J = 4.3 Hz, 1H), 2.74 (d, J = 11.5 Hz, 1H),
2.58 (d, J = 11.2 Hz, 1H), 2.36 (dd, J = 12.3, 8.6 Hz, 1H), 2.29
(dd, J = 12.6, 4.0 Hz, 1H), 2.19 (t, J = 10.2 Hz, 1H), 1.95 (t,
J = 10.6 Hz, 1H), 1.67–1.75 (m, 2H), 1.36–1.50 (m, 2H).
13C{1H} NMR (126 MHz, CDCl3) δ 155.6, 141.3, 138.5, 132.7,
131.3, 130.9, 129.7, 129.2, 128.8, 128.0, 126.9, 121.6, 113.2,
70.9, 66.0, 60.5, 51.3, 50.6, 33.0, 32.9. HRMS (ESI-TOF) m/z
[M+H]+ calcd for C26H31N2O4S 467.2005; found: 467.2007.
Sulfonylation of primary amine (general procedure E)
Intermediate 4 (1 eq), selected benzenesulfonyl chloride (1 eq),
and previously grinded K2CO3 (1.0 eq) were introduced in a 35
mL PTFE jar (milling load 10 mg/mL) with one stainless steel
ball (ᴓball = 1.5 cm). The reaction was carried out for 1-5 min at
rt. Then, the crude mixture was solubilized in ethyl acetate (20
mL) and the organic phase was washed with KHSO4 aqueous
solution at pH = 3.5 (3 x 7 mL), saturated NaCl solution (1 x 7
mL), dried over Na2SO4 and finally filtered and concentrated
under vacuum.
3-Chloro-N-(1-(3-([1,1'-biphenyl]-2-yloxy)-2-hydroxy
propyl)piperidin-4-yl)-benzenesulfonamide PZ-1361 (5a)
[CAS 2095849-69-5]
2-Fluoro-N-(1-(3-([1,1'-biphenyl]-2-yloxy)-2-hydroxy
propyl)piperidin-4-yl)-benzenesulfonamide (5c)
General procedure E was followed with primary amine 4 (168.2
mg, 0.463 mmol, 1 eq), 3-chloro-benzenesulfonyl chloride
(65.24 µl, 0.463 mmol, 1 eq), and previously grinded K2CO3
General procedure E was followed with primary amine 4 (172.1
mg, 0.474 mmol, 1 eq), 2-fluoro-benzenesulfonyl chloride
(62.80 µl, 0.474 mmol, 1 eq), and previously grinded K2CO3
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