Month 2018
Sophoridine Derivatives Bearing an Acyclic Aryloxy Phosphoramidate Mustard
Functionality
Synthetic procedure and characterization data of 8a–e.
Synthetic procedure and characterization data of 7a–e
were seen in the Supporting Information.
Compound 3 (3.80 g, 12 mmol) and triethylamine
(1.21 g, 12 mmol) were mixed in anhydrous CH3CN
(80 mL), stirred at room temperature, and treated with
7a–e (10 mmol). After addition, it was stirred overnight
until thin-layer chromatography indicated that the reaction
was complete. The reaction mixture was concentrated
and then purified through silica gel chromatography to
2H, NCH2CH), 3.17 (s, 1H, NCH), 2.89 (d, J = 47.1 Hz,
4H, NCH2CH2Cl), 2.41 (ddd, J = 109.5, 43.2, 9.1 Hz,
6H, NCH2CH2, CH2CO), 1.85–1.03 (m, 15H, CH2,
NCHCH). 13C NMR (400 MHz, CDCl3) δ 173.61
(C¼O), 150.47 (Ar–C), 132.65 (Ar–C), 132.62 (Ar–C),
122.06 (Ar–C), 121.80 (Ar–C), 117.34 (Ar–C), 58.80,
58.68, 58.48, 54.51, 51.57 (OCH3), 50.28, 49.89, 46.18,
45.29, 45.00, 44.38, 42.39 (CH2Cl), 42.24 (CH2Cl),
38.69, 37.84, 33.73, 33.59, 30.84, 29.29, 26.90, 25.91,
25.01, 24.94, 22.50, 22.34, 18.99. ESI-MS for
C26H39BrCl2N3O4P: [M+H]+, calcd, m/z 637.12; found,
638.33. Elemental analysis C 48.84, H 6.15, N 6.57;
generate target products 8a–e.
Methyl-4-((1R,3aR,3a1S,10aS)-2-((bis(2-chloroethyl)amino)
(4-fluorophenoxy)phosphoryl)decahydro-1H,4H-pyrido[3,2,1-
ij][1,6]naphthyridin-1-yl)butanoate (8a). Yellow oil; yield
found C 48.98, H 6.30, N 6.75.
Methyl-4-((1R,3aR,3a1S,10aS)-2-((bis(2-chloroethyl)amino)
(naphthalen-1-yloxy)phosphoryl)decahydro-1H,4H-
1
72%; H NMR (400 MHz, CDCl3) δ 7.11 (s, 2H, Ar–H),
pyrido[3,2,1-ij][1,6]naphthyridin-1-yl)butanoate
(8d).
7.01–6.90 (m, 2H, Ar–H), 3.59 (d, J = 2.8 Hz, 3H,
OCH3), 3.54–3.44 (m, 4H, CH2Cl), 3.41–3.30 (m, 2H,
NCH2CH), 3.17–3.09 (m, 1H, NCH), 3.03–2.62 (m, 6H,
NCH2CH2Cl, NCH2CH2), 2.47 (dd, J = 31.7, 11.1 Hz,
2H, NCH2CH2), 2.33–2.10 (m, 2H, CH2CO), 1.66 (dd,
J = 33.9, 19.3 Hz, 8H, CH2, NCHCH), 1.37–1.11 (m,
7H, CH2). 13C NMR (400 MHz, CDCl3) δ 173.67
(C¼O), 156.99 (Ar–C), 153.98 (Ar–C), 121.67 (Ar–C),
119.65 (Ar–C), 117.97 (Ar–C), 116.34 (Ar–C), 84.02,
59.04, 54.30, 51.60 (OCH3), 50.27, 49.88, 46.03,
45.32, 42.40 (CH2Cl), 42.27 (CH2Cl), 33.54, 30.81,
28.92, 27.02, 24.56, 22.51, 18.88. ESI-MS for
C26H39Cl2FN3O4P: [M+H]+, calcd, m/z 577.20; found,
578.40. Elemental analysis C 53.98, H 6.80, N 7.26;
1
Yellow oil; yield 60%; H NMR (400 MHz, CDCl3) δ
7.89 (d, J = 7.6 Hz, 1H, Ar–H), 7.74–7.55 (m, 2H, Ar–
H), 7.48 (t, J = 7.3 Hz, 1H, Ar–H), 7.38 (dd, J = 15.4,
8.1 Hz, 2H, Ar–H), 7.24 (t, J = 7.9 Hz, 1H, Ar–H), 3.47
(s, 3H, OCH3), 3.43–3.29 (m, 6H, CH2Cl, NCH2CH),
3.10 (dt, J = 19.1, 9.7 Hz, 1H, NCH), 2.94–2.49 (m, 4H,
NCH2CH2Cl), 2.47–1.89 (m, 6H, NCH2CH2, CH2CO),
1.88–0.89 (m, 15H, CH2, NCHCH). 13C NMR
(400 MHz, CDCl3) δ 173.63 (C¼O), 147.05 (Ar–C),
134.76 (Ar–C), 126.53 (Ar–C), 126.36 (Ar–C), 126.23
(Ar–C), 125.82 (Ar–C), 125.70 (Ar–C), 124.32 (Ar–C),
121.03 (Ar–C), 115.31 (Ar–C), 58.89, 58.74, 58.56,
58.38, 54.58, 54.45, 51.55 (OCH3), 50.07, 49.76, 49.71,
46.20, 45.41, 45.06, 44.85, 42.18 (CH2Cl), 38.20, 37.70,
33.78, 31.00, 29.38, 29.07, 26.96, 26.80, 25.89, 25.03,
24.88, 22.64, 22.53, 19.03, 18.79. ESI-MS for
C30H42Cl2N3O4P: [M+H]+, calcd, m/z 609.23; found,
610.47. Elemental analysis C 59.02, H 6.93, N 6.88;
found C 54.50, H 6.92, N 7.55.
Methyl-4-((1R,3aR,3a1S,10aS)-2-((bis(2-chloroethyl)amino)
(3-chlorophenoxy)phosphoryl)decahydro-1H,4H-pyrido[3,2,1-
ij][1,6]naphthyridin-1-yl)butanoate (8b). Yellow oil; yield
1
75%; H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 9.0 Hz,
1H, Ar–H), 7.20–7.10 (m, 2H, Ar–H), 7.05 (d,
J = 7.2 Hz, 1H, Ar–H), 3.56 (s, 3H, OCH3), 3.53–3.43
(m, 4H, CH2Cl), 3.38–3.27 (m, 2H, NCH2CH), 3.08 (d,
J = 10.1 Hz, 1H, NCH), 2.84 (d, J = 11.2 Hz, 2H,
NCH2CH2Cl), 2.70 (t, J = 11.2 Hz, 2H, NCH2CH2Cl),
2.40 (ddd, J = 62.0, 32.1, 22.6 Hz, 6H, NCH2CH2,
CH2CO), 1.77–1.14 (m, 15H, CH2, NCHCH). 13C NMR
(400 MHz, CDCl3) δ 173.58 (C¼O), 151.84 (Ar–C),
134.89 (Ar–C), 130.40 (Ar–C), 124.78 (Ar–C), 120.69
(Ar–C), 118.44 (Ar–C), 58.44, 54.50, 51.53 (OCH3),
49.83, 46.16, 45.26, 45.09, 42.18 (CH2Cl), 37.88, 33.71,
30.84, 29.23, 26.89, 25.93, 24.95, 22.48, 18.96. ESI-MS
for C26H39Cl3N3O4P: [M+H]+, calcd, m/z 593.17; found,
594.47. Elemental analysis C 52.49, H 6.61, N 7.06;
found C 59.21, H 7.22, N 6.95.
Methyl-4-((1R,3aR,3a1S,10aS)-2-((bis(2-chloroethyl)amino)
(naphthalen-2-yloxy)phosphoryl)decahydro-1H,4H-
pyrido[3,2,1-ij][1,6]naphthyridin-1-yl)butanoate
(8e).
1
Yellow oil; yield 69%; H NMR (400 MHz, CDCl3) δ
7.75 (dd, J = 28.7, 21.4 Hz, 4H, Ar–H), 7.49–7.22 (m,
3H, Ar–H), 3.64 (d, J = 13.6 Hz, 3H, OCH3), 3.60–3.35
(m, 7H CH2Cl, NCH2CH, NCH2CH2Cl), 3.19 (d,
J = 9.1 Hz, 1H, NCH), 3.02–2.75 (m, 3H, NCH2CH2Cl),
2.62–2.45 (m, 2H, NCH2CH2), 2.36–2.02 (m, 4H,
NCH2CH2, CH2CO), 1.87–0.94 (m, 15H, CH2,
NCHCH). 13C NMR (400 MHz, CDCl3) δ 173.67
(C¼O), 148.89 (Ar–C), 133.94 (Ar–C), 130.66 (Ar–C),
129.77 (Ar–C), 127.66 (Ar–C), 127.41 (Ar–C), 126.80
(Ar–C), 125.38 (Ar–C), 120.20 (Ar–C), 116.48 (Ar–C),
58.55, 54.48, 51.55 (OCH3), 50.04, 45.19, 42.43
(CH2Cl), 42.30 (CH2Cl), 37.92, 33.79, 30.89, 29.25,
26.99, 25.83, 24.92, 22.55, 18.96. ESI-MS for
C30H42Cl2N3O4P: [M+H]+, calcd, m/z 609.23; found,
610.33. Elemental analysis C 59.02, H 6.93, N 6.88;
found C 59.21, H 7.22, N 6.95.
found C 52.65, H 6.88, N 7.21.
Methyl-4-((1R,3aR,3a1S,10aS)-2-((bis(2-chloroethyl)amino)
(4-bromophenoxy)phosphoryl)decahydro-1H,4H-pyrido[3,2,1-
ij][1,6]naphthyridin-1-yl)butanoate (8c). Yellow oil; yield
1
65%; H NMR (400 MHz, CDCl3) δ 7.44 (s, 2H, Ar–H),
7.16 (dd, J = 23.5, 8.2 Hz, 2H, Ar–H), 3.66 (s, 3H,
OCH3), 3.62–3.51 (m, 4H, CH2Cl), 3.43 (d, J = 5.9 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet