Optimized and convergent synthesis of potent anti-malarial aminoquinoline compounds: Easy access to analogs

Article abstract of DOI:10.1515/HC.2010.011

Amodiaquine is one of the most active antimalarial 4-aminoquinoline. Previously we have described new analogs of amodiaquine and amopyroquine, in which the hydroxyl group was replaced by various amino groups and identified highly potent compounds. Here we

Full text of DOI:10.1515/HC.2010.011

Heterocycl. Commun., Vol. 16(4-6), pp. 235–239, 2010 • Copyright © by Walter de Gruyter • Berlin • New York. DOI 10.1515/HC.2010.011
Optimized and convergent synthesis of potent anti-malarial
aminoquinoline compounds: easy access to analogs
Nicolas Le Fur1–3, Paul-Emmanuel Larchanché1–3
were reported associated with AQ prophylaxis and its use was
halted (Hatton et al., 1986; Thomas et al., 2004). AQ toxicity
and Patricia Melnyk1–3,
*
has been explained by the presence of its 4-hydroxyanilino
moiety, which is believed to undergo extensive metaboliza-
tion by cytochrome P450 to its quinoneimine variant (Maggs
et al., 1988; Harrison et al., 1992). Nevertheless AQ is com-
mercialized in combination with an artemisinin derivatives as
Arsucam® speciality.
1 Université Lille Nord de France, F-59000 Lille, France
2 UDSL, EA 4481, UFR Pharmacie, F-59000 Lille, France
3 UMR CNRS 8161, F-59000 Lille, France
*Corresponding author
e-mail: patricia.melnyk@univ-lille2.fr
We recently evaluated the effects of the 4′-hydroxyl group
substitution (Delarue-Cochin et al., 2008a,b) and demon-
strated that derivatives substituted in 4′-position with an
alkyl, aryl or heteroaryl group 1 (Paunescu et al., 2009) or 5′-
position with an amido 2 (Delarue et al., 2001) or an amino
3 (Delarue-Cochin et al., 2008a,b) functionality presented
good in vitro nanomolar antimalarial activities (Figure 2).
More excitingly, we developed a series of analogs where
4′-hydroxy group was replaced by various amino substitu-
ents 4 (Paunescu et al., 2008). Furthermore, as AQ-analogs
obtained by the replacement of the N-diethylamino function
of the side chain, with a pyrrolidine cycle (amopyroquine,
ApQ) or a N-tert-butyl group were proved to be as active
and metabolically less labile (Hawley et al., 1996; Verdier et
al., 1989), we completed our study with the development of
parallel ApQ-analogs series. The substitution of 4′-hydroxy
by N-methylpiperazine (compound 5) or morpholine (com-
pound 6) provided low nanomolar activity upon K1 chloro-
quino-resistant strain and low cytotoxicity (Paunescu et al.,
2008).
Abstract
Amodiaquine is one of the most active antimalarial 4-amin-
oquinoline. Previously we have described new analogs of
amodiaquine and amopyroquine, in which the hydroxyl group
was replaced by various amino groups and identified highly
potent compounds. Here we describe a more efficient syn-
thesis of this family of compounds allowing the rapid and
convergent access of new analogs bearing a piperazine or a
morpholine ring at the 4′-position and diverse heterocyclic
amino side chains.
Keywords: antimalarials; 4-aminoquinolines; morpholine;
piperazine.
Introduction
In spite of the recent decline of the pathology, malaria remains
a major health problem. In 2008, there were an estimated 243
million cases of malaria worldwide and about 860 000 deaths
in more than 100 countries (Vangapandu et al., 2007; 2009
WHO report), but 85–90% of cases and deaths were in the
African Region. Malaria is one of the main obstacles to so-
cio-economic development in sub-Saharian Africa and other
tropical regions in the world. The need for new therapy is
still relevant.
Chloroquine (CQ, Figure 1) was a mainstream drug in
the fight against Plasmodium falciparum, but its efficacy is
eroded by the emergence of resistant parasites. Quinoline
antimalarials are concentrated in the parasite food vacuole
and are thought to exert their activity by preventing effective
formation of hemozoin by interacting to heme through π-π
stacking of their planar aromatic structures, resulting in heme-
mediated toxicity to the parasite (Vippagunta et al., 1999).
The lack of an enzyme drug target for quinoline antimalari-
als is probably a chief reason why resistance development to
these drugs is relatively slow. Amodiaquine (AQ, Figure 1),
another 4-aminoquinoline proved to be effective against CQ-
resistant strains (Rieckmann, 1971; Ridley, 2002). But in the
1980s, cases of agranulocytosis, neutropenia and hepatisis
In this study, we optimized the synthetic process and syn-
thesized a family of analogs (Figure 3).
Results and discussion
A first synthesis of 4′-amino analogs was described as a six-
step procedure and global yields were about 30% (Paunescu
et al., 2008). Moreover, the introduction of the amino func-
tions was the third and fourth step, avoiding convergent and
rapid access to analogs. We developed a process in which the
diverse amino function NR3R4 was introduced in the last syn-
thetic step.
Starting from commercially available 2-fluoro-5-nitroben-
zaldehyde, the target compounds could be obtained in a 5
step-synthesis with high yields (Scheme 1). As previously
described by our laboratory, benzyl alcohol 7 could easily
be obtained with a quantitative yield (Paunescu et al., 2008).
Aromatic nucleophilic substitution of fluorine atom with N-
methylpiperazine or morpholine provided intermediates 8
and 14 with high yield of 94% and 99% respectively. Next
several conditions for the reduction of the nitro group were
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236 N. Le Fur et al.
OH
NR2
NHtBu
NR1R2
NR3R4
N
N
N
N
N
HN
HN
HN
NR1R2, NR3R4
=
O
Cl
Cl
N
N
Cl
N
Chloroquine (CQ)
Amodiaquine (AQ): NR2=NEt2
Amopyroquine (ApQ): NR2=pyrrolidino
Figure 1 Structure of some aminoquinoline anti-malarial
Figure 3 Target compounds.
compounds.
of intermediate compounds were checked by LCMS, using a Waters
Alliance 2695 system (X-Terra column, ionization mass spectrome-
ter). The following eluent systems were used: a (H2O/TFA, 100:0.01)
and B (CH3CN/H2O/TFA, 80:20:0.01). Retention times (tR) were ob-
tained, at flow rate of 0.3 ml/min, using the following conditions: a
gradient run from 100% eluent A to 100% eluent B over 8 min, then
100% eluent B for 90 s. The purity of final compounds was verified by
two types of high pressure liquid chromatography (HPLC) columns:
C18 Deltapak (C18N) and C4 Interchrom UP5WC4-25QS (C4) on a
Shimadzu system equipped with a UV detector set at 254 nm, same
eluents as for LCMS method, at flow rate of 1 ml/min, with a 40 min
method: a gradient run from 100% eluent A during 1 min, then to
100% eluent B over the next 30 min. For some compounds mass
spectra were recorded on a MALDI-TOF Voyager-DE-STR (Applied
Biosystems) apparatus.
tested: tin chloride, iron chloride. Optimized conditions were
obtained using hydrogen transfert with ammonium formate
and Pd/C in ethanol. Compounds 9 and 15 were obtained in
quantitative yield without need of purification. Nucleophilic
aromatic substitution of the chlorine atom in position 4 of the
4,7-dichloroquinoline allowed the synthesis of derivatives 10
and 16. In this case, the use of acidic conditions to enhance
the electrophilic character of quinoline C-4 was not neces-
sary. In the last step, benzyl alcohol was activated with thio-
nyl chloride and substituted in one pot by various amines in
NMP (N-methylpyrrolidone) with yields over 80%. With this
synthetic route compounds 5 and 6 were obtained with global
yield of 65% and 75% respectively, compared with only 23%
and 37% in the last procedure.
Reagents were obtained from Acros, Aldrich, Lancaster,
Novabiochem and Avocado.
The following abbreviations were used: AcOEt (ethyl acetate),
DCM (dichloromethane), rt (room temperature), Quino (quinoline).
Conclusion
Despite recent progress, malaria still remains a major health
problem. Aminoquinoline derivatives are historically inter-
esting compounds to treat his pathology. We have described
a new synthesis of a potent amodiaquine analogs devoided
of potential metabolic instability and the convergent access
to analogs. Further work will evaluate the metabolic stability
and the anti malarial activity of these new analogs.
Aromatic nucleophilic substitution
2-Fluoro-5-nitrobenzyl alcohol 7 (Paunescu et al., 2008) (1 g,
5.84 mmol) and amine (2 eq) were heated at 130°C for 1 h. The reac-
tion mixture was then diluted with 25 ml of THF and washed with
a saturated aqueous solution of Na2CO3 and then with brine. The
organic layer was dried over Na2SO4, filtered and evaporated. The
residue was thoroughly washed with pentane and filtered off to yield
expected compound.
Experimental section
[2-(4-Methylpiperazino)-5-nitrophenyl]methanol (8) Orange
powder (94% yield). LC/MS tR=5.0 min; PHPLC >99%; m/z (ESI)
252.1 [M+H]+. 1H NMR (300 MHz, MeOH-d4) δ 8.46 (d, J=2.8 Hz,
1H, H-6), 8.18 (dd, J=8.9 and 2.9 Hz, 1H, H-4), 7.26 (d, J=8.90 Hz,
1H, H-3), 4.75 (s, 2H, O-CH2), 3.20-3.10 (m, 4H, N-CH2), 2.75-2.65
(m, 4H, N-CH2), 2.44 (s, 3H, CH3); 13C NMR (75 MHz, MeOH-d4)
All reactions were monitored by thin-layer chromatography carried
out on 0.2 mm E. Merck silica gel plates (60F-254) using UV light as
a visualizing agent. 1H and 13C NMR spectra were obtained using a
Bruker 300 MHz spectrometer, chemical shifts (δ) were expressed in
ppm relative to TMS used as an internal standard. Purity and identity
O
N
HN
NHR
R
NR1R2
NEt2
Cl
NR2
NEt2
NR3R4
HN
HN
HN
N
HN
N
Cl
N
1
N
Cl
Cl
2
3
4
5 NR1R2=N-methylpiperazino; NR3R4=pyrrolidino
6 NR1R2=morpholino; NR3R4=pyrrolidino
R=alkyl, aryl
Figure 2 Structure of some potent amodiaquine analogs.
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Convergent synthesis of 4’-amino analogs of amodiaquine 237
N
N
N
N
f
d
d
e
N
N
N
N
O2N
H2N
HN
N
HN
N
OH
OH
9
OH
NR3R4
5, 11-13
b
10
8
Cl
Cl
f
F
F
a
O2N
CHO
O2N
c
OH
O
O
O
O
7
e
N
N
N
N
HN
HN
O2N
H2N
OH
OH
OH
NR3R4
15
14
16
6, 17-19
Cl
N
Cl
N
Scheme 1 Reagents: (a) Paunescu et al., 2008; (b) N-methylpiperazine, 130°C; (c) morpholine, 115°C; (d) HCOONH4, Pd/C (10%), EtOH,
r.t.; (e) 4,7-dichloroquinoline, n-pentanol, reflux; (f) SOCl2, NMP, r.t., then amine, NMP, 0°C to r.t.
δ 156.5 (C), 143.4 (C), 136.6 (C), 124.1 (C-6), 123.6 (C-4), 119.0
(C-3), 59.5 (O-CH2), 55.2 (N-CH2), 51.7 (N-CH2), 45.2 (CH3).
reaction mixture was then evaporated and purified by flash chro-
matography (DCM/MeOH/NH4OH//8/2/0.1) to yield expected
compound.
[2-Morpholino-5-nitrophenyl]methanol (14) Yellow oil (99%
1
yield). MALDI-TOF m/z 206.1 [M-O2+H]+, 223.1 [M-O+H]+; H
{5-[(7-Chloroquinolin-4-yl)amino]-2-(4-methylpiperazino)
phenyl}methanol (10) Pale brown solid (143 mg, 83% yield).
LC/MS tR=5.8 min; PHPLC>99%; m/z (ESI) 383.1-385.1 [M+H]+. 1H
NMR (300 MHz, MeOH-d4) δ 8.38 (d, J=5.4 Hz, 1H, Quino-2), 8.36
(d, J=2.5 Hz, 1H, Quino-5), 7.89 (d, J=2.0 Hz, 1H, Quino-8), 7.58
(dd, J=9.1 and 2.1 Hz, 1H, Quino-6), 7.55-7.53 (m, 1H, H-6), 7.35-
7.28 (m, 2H, H-3, H-4), 6.89 (d, J=6.1 Hz, 1H, Quino-3), 4.78 (s, 2H,
O-CH2), 3.20-3.02 (m, 8H, N-CH2), 2.69 (s, 3H, N-CH2); 13C NMR
(75 MHz, MeOH-d4) δ 152.1 (C), 149.3 (Quino-5), 148.0 (C), 146.7
(C), 138.3 (C), 137.0 (C), 135.7 (C), 126.4 (Quino-6), 124.9-124.8
(Quino-8, C-6), 124.2-124.1 (Quino-2, C-4), 121.1 (C-3), 117.9 (C),
117.5 (C), 101.2 (Quino-3), 59.9 (O-CH2), 55.0 (2 N-CH2), 51.4
(2 N-CH2), 44.0 (N-CH3).
NMR (300 MHz, MeOH-d4) δ 8.44 (d, J=2.7 Hz, 1H, H-6), 8.16 (dd,
J=9.0 and 2.8 Hz, 1H, H-4), 7.23 (d, J=8.7 Hz, 1H, H-3), 4.75 (s, 2H,
O-CH2), 3.89 (m, 4H, O-CH2), 3.09 (m, 4H, N-CH2); 13C NMR (75
MHz, MeOH-d4) δ 156.5 (C), 143.4 (C), 136.6 (C), 124.1 (C-6), 123.5
(C-4), 118.8 (C-3), 67.0 (O-CH2), 59.4 (O-CH2), 52.6 (N-CH2).
Reduction of nitro function
Nitro compound 8 or 14 (3.98 mmol) was hydrogenated using am-
monium formate (2.51 g, 10 eq) and Pd/C (10% Pd, 0.43 mg, 0.1
eq) in 50 ml of EtOH. The mixture was stirred overnight at room
temperature and then filtered through a celite pad. The filtrate was
evaporated and the residue was dissolved in DCM and washed with
a saturated aqueous solution of Na2CO3. The aqueous layer was ex-
tracted with DCM. The combined organic layers were dried over
Na2SO4, filtered and evaporated to yield expected compound.
{5-[(7-Chloroquinolin-4-yl)amino]-2-morpholinophenyl}
methanol hydrochloride (16) Yellow powder (1.90 g, 80%
yield). LC/MS tR=6.3 min; PHPLC >99%; m/z (ESI) 370.3 [M+H]+.
1H NMR (300 MHz, MeOH-d4) δ 8.55 (d, J=9.0 Hz, 1H, Quino-5),
8.33 (d, J=6.0 Hz, 1H, Quino-2), 7.93 (d, J=1.8 Hz, 1H, Quino-8);
7.77 (dd, J=9.0 and 2.1 Hz, 1H, Quino-6), 7.58-7.56 (m, 1H), 7.57 (d,
J=2.2 Hz, 1H, H-6); 7.40-7.28 (m, 2H, H-3, H-4), 6.86 (d, J=6.2 Hz,
1H, Quino-3), 4.78 (s, 2H, O-CH2), 3.85 (m, 4H, O-CH2), 2.97 (m,
4H, N-CH2); 13C NMR (75 MHz, DMSO-d6) δ 154.9 (C), 149.0 (C),
143.2 (Quino-2), 139.0 (C), 138.3 (C), 138.2 (C), 131.8 (C), 127.2
(Quino-6), 126.2 (C-6), 124.8-124.3 (C-3, Quino-5), 119.8 (C-4),
119.1 (Quino-8), 115.9 (C), 100.1 (Quino-3), 66.5 (2 O-CH2), 58.2
(O-CH2), 52.4 (2 N-CH2).
[5-Amino-2-(4-methylpiperazino)phenyl]methanol (9) Pale
1
yellow oil (0.85 g, 97% yield). H NMR (300 MHz, MeOH-d4) δ
7.00 (d, J=8.4 Hz, 1H, H-3), 6.78 (d, J=2.7 Hz, 1H, H-6), 6.64 (dd,
J=8.7 and 2.7 Hz, 1H, H-4), 4.65 (s, 2H, O-CH2), 2.95-2.85 (m, 4H,
N-CH2), 2.70-2.50 (m, 4H, N-CH2), 2.34 (s, 3H, N-CH3); 13C NMR
(75 MHz, MeOH-d4) δ 144.5 (C), 142.2 (C), 137.1 (C), 121.2 (C-3),
115.7 (C-6), 115.2 (C-4), 61.2 (O-CH2), 55.8 (2 N-CH2), 52.7 (2
N-CH2), 45.2 (N-CH3).
(5-Amino-2-morpholinophenyl)methanol (15) Brown powder
(1.21 g, 99% yield). LC/MS tR=2.8 min; PHPLC=95%; m/z (ESI)
209.2 [M+H]+. 1H NMR (300 MHz, MeOH-d4) δ 7.02 (d, J=9.0 Hz,
1H, H-3), 6.83 (d, J=3.0 Hz, 1H, H-6), 6.68 (dd, J=9.0 and 3.0 Hz,
1H, H-4), 4.71 (s, 2H, CH2), 3.82 (m, 4H, O-CH2), 2.87 (m, 4H,
N-CH2); 13C NMR (75 MHz, MeOH-d4) δ 121.1 (C-3), 115.7 (C-6),
115.2 (C-4), 67.6 (O-CH2), 60.9 (2 O-CH2), 53.7 (2 N-CH2).
Synthesis of target compounds
To benzyl alcohol 10 or 16 (0.78 mmol) in 6 ml of NMP at 0°C
was added thionyl chloride (0.28 ml, 5 eq). The reaction mixture was
warmed up to room temperature and stirred for 2 h. The solvent was
evaporated. The residue was suspended in 6 ml of NMP and amine
(20 eq) was added at 0°C. The solution was stirred overnight at room
temperature, evaporated and the residue was purified by flash chro-
matography to yield expected compound.
Aromatic substitution of the chlorine atom
Aniline derivatives 9 or 15 (0.45 mmol) and 4,7-dichloroquinoline
(94 mg, 1.1 eq) were refluxed in 1 ml of n-pentanol overnight. The
7-Chloro-N-[4-(4-methylpiperazino)-3-(pyrrolidinomethyl)
phenyl]quinolin-4-amine (5) (Paunescu et al., 2008). Yellow
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238 N. Le Fur et al.
solid (97 mg, 86% yield). LC/MS t R=5.2 min; PHPLC=98%; m/z (ESI)
436.4-438.4 [M+H]+. HPLC (C4) tR=7.1 min; PHPLC=99%; HPLC
(C18) tR=12.3 min; PHPLC >99%.
NMR (300 MHz, MeOH-d4) δ 8.36 (d, J=5.6 Hz, 1H, Quino-2), 8.29
(d, J=9.0 Hz, 1H, Quino-5), 7.85 (d, J=2.1 Hz, 1H, Quino-8), 7.49 (dd,
J=9.1and2.4Hz, 1H, Quino-6), 7.43(d, J=1.7Hz, 1H, H-6), 7.4-7.3(m,
2H, H-3, H-4); 6.91 (d, J=5.6 Hz, 1H, Quino-3), 3.96 (s, 2H, N-CH2),
3.9-3.8 (m, 4 H, O-CH2), 3.0-2.9 (m, 4H, N-CH2), 1.30 (s, 9H, CH3);
13C NMR (75 MHz, MeOH-d4) δ 152.5 (Quino-2), 151.2 (C), 150.2
(C), 150.1 (C), 138.0 (C), 136.8 (C), 136.0 (C), 127.8 (Quino-8), 127.1
(C-6), 126.7 (Quino-6), 125.3 (C-3 or C-4), 124.7 (Quino-5), 123.5
(C-3 or C-4), 119.5 (C), 102.6 (Quino-3), 68.5 (O-CH2), 54.7 (N-CH2),
50.8 (C), 43.7 (2 N-CH2), 28.1 (3 CH3). HPLC (C4) tR=7.3 min; PHPLC
>99%; HPLC (C18) tR=15.1 min; PHPLC=97%.
N-{3-[(tert-Butylamino)methyl]-4-(4-methylpiperazino)
phenyl}-7-chloroquinolin-4-amine (11) Yellow solid (101 mg,
74% yield). LC/MS tR=5.4 min; PHPLC=99%; m/z (ESI) 438.4-
440.4 [M+H]+. HPLC (C4) tR=6.3 min; PHPLC >99%; HPLC (C18)
1
tR=15.4 min; PHPLC=99%; H NMR (300 MHz, MeOH-d4) δ 8.36
(d, J=5.6 Hz, 1H, Quino-2), 8.27 (d, J=9.1 Hz, 1H, Quino-5),
7.85 (d, J=2.1 Hz, 1H, Quino-8), 7.49 (dd, J=9.1 and 2.1 Hz, 1H,
Quino-6), 7.39-7.24 (m, 3H, H-3, H-4, H-6), 6.90 (d, J=5.6 Hz, 1H,
Quino-3), 3.82 (s, 2H, N-CH2), 3.02 (m, 4H, N-CH2), 2.67 (m, 4H,
N-CH2), 2.39 (s, 3H, N-CH3), 1.24 (s, 9H, 3 CH3); 13C NMR (75
MHz, MeOH-d4) δ 151.5 (Quino-2), 150.4 (C), 149.2 (C), 148.9 (C),
137.2 (C), 136.7 (C), 135.7 (C), 126.8 (Quino-5), 126.1 (Quino-6),
125.6-123.8-123.7-122.2 (Quino-8, C-3, C-4, C-6), 118.4 (C), 101.5
(Quino-3), 55.8 (N-CH2), 52.7 (2 N-CH2), 51.1 (C), 45.3 (N-CH3),
43.4 (2 N-CH2), 27.9 (3 CH3).
7-Chloro-N-[4-morpholino-3-(morpholinomethyl)phenyl]
quinolin-4-amine (18) Yellow solid (83 mg, 77% yield). LC/
MS tR=5.9 min; PHPLC=99%; m/z (ESI) 439.1-441.1 [M+H]+. 1H
NMR (300 MHz, CDCl3) δ 8.49 (d, J=5.6 Hz, 1H, Quino-2), 8.02
(d, J=2.0 Hz, 1H, Quino-8), 7.88 (d, J=9.1 Hz, 1H, Quino-5), 7.5-
7.4 (m, 2H, Quino-6, H-6), 7.22 (dd, J=8.5 and 1.8 Hz, 1H, H-4);
7.15 (d, J=8.6 Hz, 1H, H-3); 6.83 (d, J=5.8 Hz, 1H, Quino-3), 3.87
(m, 4H, O-CH2), 3.69 (m, 4H, O-CH2), 3.59 (s, 2H, N-CH2), 2.9-
2.8 (m, 4H, N-CH2), 2.5-2.4 (m, 4H, N-CH2); 13C NMR (75 MHz,
CDCl3) δ 151.5 (Quino-2), 149.7 (C), 148.6 (C), 135.7 (C), 134.9
(C), 134.7 (C), 128.7 (Quino-8), 126.6-125.8 (Quino-6, C-6), 123.0
(C-3 or C-4), 121.4-121.2 (Quino-5, C-3 or C-4), 117.9 (C), 102.0
(Quino-3), 67.6 (2 O-CH2), 67.2 (2 O-CH2), 57.9 (N-CH2), 53.9
(2 N-CH2), 53.5 (2 N-CH2). HPLC (C4) tR=9.4 min; PHPLC=99%;
HPLC (C18) tR=14.3 min; PHPLC=99%.
7-Chloro-N-[4-(4-methylpiperazino)-3-(morpholinomethyl)
phenyl]quinolin-4-amine (12) Yellow solid (97 mg, 86% yield).
LC/MS tR=5.3 min; PHPLC >99%; m/z (ESI) 452.2-454.3 [M+H]+. 1H
NMR (300 MHz, MeOH-d4) δ 8.51 (d, J=5.3 Hz, 1H, Quino-2), 8.00
(d, J=2.0 Hz, 1H, Quino-8), 7.89 (d, J=9.0 Hz, 1H, Quino-5), 7.5-7.4
(m, 2H, Quino-6, H-6), 7.2-7.1 (m, 2H, H-3, H-4), 6.9-6.8 (m, 2H,
Quino-3, NH), 3.7-3.6 (m, 4H, O-CH2), 3.57 (s, 2H, N-CH2), 3.0-
2.9 (m, 4H, N-CH2), 2.7-2.4 (m, 8H, N-CH2), 2.36 (s, 3H, N-CH3);
13C NMR (75 MHz, MeOH-d4) δ 154.5 (C), 150.1 (C), 144.9
(Quino-2), 141.5 (C), 139.1 (C), 134.8 (C), 132.8 (C), 128.0-127.4
(Quino-6, C-6), 125.6 (Quino-5), 124.8 (C-3 or C-4), 122.3 (C-3 or
C-4), 121.0 (Quino-8), 116.6 (C), 100.7 (Quino-3), 63.6 (2 O-CH2),
57.1 (N-CH2), 54.1 (2 N-CH2), 53.1 (2 N-CH2), 43.4 (2 N-CH2),
42.6 (N-CH3). HPLC (C4) tR=6.0 min; PHPLC=99%; HPLC (C18)
tR=14.6 min; PHPLC >99%.
7-Chloro-N-{3-[(4-methylpiperazino)methyl]-4-morpho-
linophenyl}quinolin-4-amine (19) Yellow solid (120 mg, 99%
yield). LC/MS tR=5.7 min; PHPLC=99%; m/z (ESI) 452.2-454.2
[M+H]+; 1H NMR (300 MHz, MeOH-d4) δ 8.33 (d, J=5.7 Hz,
1H, Quino-2), 8.27 (d, J=9.0 Hz, 1H, Quino-5), 7.85 (d, J=2.1 Hz,
1H, Quino-8), 7.49 (dd, J=9.0 and 2.1 Hz, 1H, Quino-6), 7.45 (d,
J=2.2 Hz, 1H, H-6), 7.3-7.2 (m, 2H, H-3, H-4); 6.81 (d, J=5.7 Hz,
1H, Quino-3), 3.9-3.8 (m, 4H, O-CH2), 3.68 (s, 2H, N-CH2); 3.0-2.9
7-Chloro-N-[4-(4-methylpiperazino)-3-[(4-methylpiperazino)
methyl]phenyl] quinolin-4-amine (13) Yellow solid (94 mg,
78% yield). LC/MS tR=5.3 min; PHPLC=98%; m/z (ESI) 465.1-467.2
(m, 4H, N-CH2), 2.7-2.5 (m, 8H, N-CH2), 2.37 (s, 3H, N-CH3); 13
C
NMR (75 MHz, MeOH-d4) δ 152.0 (Quino-2), 151.8 (C), 151.0 (C),
149.8 (C), 136.9 (C), 136.7 (C), 135.3 (C), 127.4-127.3 (Quino-8,
C-6), 126.7 (Quino-6), 124.9-124.8 (Quino-5, C-3 or C-4), 122.3
(C-3 or C-4), 119.3 (C), 103.3 (Quino-3), 68.5 (2 O-CH2), 57.9
(N-CH2), 55.7 (2 N-CH2), 54.6 (2 N-CH2), 53.1 (2 N-CH2); 28.1
(N-CH3) .
1
[M+H]+. H NMR (300 MHz, MeOH-d4) δ 8.56 (d, J=9.1 Hz, 1H,
Quino-5), 8.42 (d, J=6.7 Hz, 1H, Quino-2), 7.97 (d, J=2.0 Hz, 1H,
Quino-8), 7.76 (dd, J=9.1 and 2.1 Hz, 1H, Quino-6), 7.59 (s, 1H,
H-6), 7.5-7.4 (m, 2H, H-3, H-4), 6.90 (d, J=6.7 Hz, 1H, Quino-3),
3.81 (s, 2H, N-CH2), 3.5-3.4 (m, 4H, N-CH2), 3.3-3.1 (m, 8H,
N-CH2), 2.99 (s, 3H, N-CH3), 2.9-2.8 (m, 4H, N-CH2), 2.87 (s, 3H,
N-CH3); 13C NMR (75 MHz, MeOH-d4) δ 154.1 (C), 149.8 (C),
145.8 (Quino-2), 142.5 (C), 138.8 (C), 134.5 (C), 134.5 (C), 127.6-
127.3 (Quino-6, C-6), 125.1-125.0 (Quino-5, C-3 or C-4), 122.2 (C-3
or C-4), 121.7 (Quino-8), 116.9 (C), 100.8 (Quino-3), 56.5 (N-CH2),
54.6 (2 N-CH2), 53.9 (2 N-CH2), 50.4 (2 N-CH2), 50.0 (2 N-CH2),
42.8 (N-CH3), 42.6 (N-CH3). HPLC (C4) tR=5.7 min; PHPLC >99%;
HPLC (C18) tR=11.9 min; PHPLC >99%.
Acknowledgements
We express our thanks to G. Montagne and E. Boll for NMR ex-
periments and H. Drobecq and G. Hochart for MS spectra. This work
was supported by Université de Lille II.
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