Chloroquine
Chloroquine is a prototypical
antimalarial agent with a mechanism that is not well understood. Chloroquine is
4-aminoquinolin with antimalarial and anti-inflammatory. Chloroquine is
aminoquinolin used for prevention and treatment of malaria.
The mechanism of action of
chloroquine plasmodis is not entirely certain. Chloroquine binds to heme (or
FP) to form what is known as the FP-Chloroquine complex; this complex is very
toxic to cells and disrupts membrane function. The mechanism of action of the
Antiprotozoal-Malaria may be based on the ability of chloroquine to bind and
change the properties of DNA. Chloroquine is also carried into acidic vacuoles
from parasites in erythrocytes thereby increasing the pH of acidic vesicles,
disrupting vesicle function and possibly inhibiting phospholipid metabolism.
Chloroquine Structure
Studies in pregnant rats show that
chloroquine is ready to cross the placenta, accumulates selectively in the
structure of the fetal eye's melanin, and is held in ocular tissue for 5 months
after the drug is removed from other body parts. The toxicity of antimalarial
drugs varies due to differences in the chemical structure of this compound. Extraordinary
cardiac complications in long-term chloroquine therapy; Congestive heart
failure and restrictive cardiomyopathy can occur, but conduction disorders are
more common.
All chemicals and reagents used in
synthesis are from synthetic levels obtained from Acros Organic, Merck and
Rankem. The primary intermediary in the reaction with methane sulfonyl chloride
produces the formation of sulfonate esters as a secondary transition.
Scheme I
from the synthesis of "reverse chloroquine"
Scheme II
from the synthesis of "reverse chloroquine"
Primary intermediate synthesis 1. A mixture
of 4,7-dichloroquinolin (4.95 g, 0.025 mol) and ethanolamine (15.27 g, 15.0 mL,
0.25 mol) was heated by stirring at 130-140°C for 24 hours. Completion of the
reaction was confirmed by TLC. After cooling, the mixture is poured into water
(150 mL) and filtered. After drying the air, the solid is boiled in methanol
(100 mL), then cooled to room temperature and then cooled in ice. The solid is
filtered and then washed with a small amount of cold methanol to produce
primary intermediate substance 1 as white solid; yield, 60%; mp 208 - 210°C; Rf
, 0.66 (DCM - metanol, 7: 3); IR (ν, cm-1): 3058 (C-H, sp2
stretch), 850 (C-H, bend sp 2 ), 2918 (C-H, sp3 stretch),
1433 (C=C, stretch ring), 1612 (C=C, bending ring), 3136 (O-H, stretch), 1137
(C-O, stretch), 1334 (C-N, stretch), 3301 (N-H, stretch), 802 (C-Cl, stretch).
Primary intermediate synthesis 2. A mixture
of 4,7-dichloroquinolin (25,35 g, 0,128 mol) and 3-aminopropanol (120 mL, 1.57
mol) was heated by stirring at 130-140°C for 24 hours. Completion of the
reaction was confirmed by TLC. After cooling, the reaction is poured into water
(500 mL), filtered, and washed with water. The solid residue is dried with air
and then boiled in ethyl acetate (250 mL) to produce primary intermediate 2 as
white solid; yield, 80%; mp 100-105°C; Rf , 0.70 (DCM - metanol, 7: 3); IR (ν,
cm-1): 3205 (C-H, sp2 stretch), 854 (C-H, bend sp2),
2893 (C-H, stretch sp3), 1585 (C=C, ring stretch), 3240 (O-H, stretch),
1139 (C-O, stretch), 1280 (C-N, stretch), 3371 (N-H, stretch), 800 (C-Cl, stretch).
Secondary intermediate synthesis 1. For
intermediate 1 primary suspension (1.5 g, 6.7 mmol) in anhydrous DCM (25 mL)
under atmospheric nitrogen triethylamine (2 mL, 14.3 mmol) is added. The
mixture is cooled below 0°C. Metanesulfonylchloride (0.57 mL, 7.41 mmol) is
added slowly, keeping the temperature below 5°C, and the mixture stirred in a
cold bath for 2 hours and then added to the saturated NaHCO3
solution (100 mL). The organic layer is separated and washed with a saturated
NaHCO3 solution (25 mL). The combined aqueous layer is extracted
with DCM (2 x 20 mL). The combined organic extract is evaporated to leave
secondary intermediates 1 as white solids; yield, 30%; mp 135 - 140°C; Rf, 0.63
(DCM - methanol, 7: 3); IR (ν, cm-1): 3056 (C-H, sp2 stretch),
842 (C-H, bend sp2), 2929 (C-H, sp3 stretch), 1433 (C=C,
ring stretch), 1612 (C=C, bend ring), 1334 (C-N, stretch), 3280 (N-H, stretch),
763 (C-Cl, stretch), 1170 (S=O, symmetrical stretch), 1344 (S=O, asymmetric stretch).
Secondary intermediate synthesis 2. For
intermediate primary suspension 2 (0.5 g, 2.1 mmol) in anhydrous THF (10 mL)
under an atmosphere of nitrogen triethylamine (0.66 mL, 4.2 mmol) is added. The
mixture is cooled below 0°C. Metansulfonylchloride (0.17 mL, 2.2 mmol) is added
slowly, keeping the temperature below 5°C and the reaction stirred in a cold
bath for 45 minutes. After dilution with a saturated NaHCO3 solution
(20 mL), the reaction is extracted with ether (20 mL then 2 x 10 mL). The
organic extract was dried over MgSO4, filtered and evaporated to
leave intermediates 2 as white solids; yield, 35%; mp 145-150°C; Rf, 0.66 (DCM
- methanol, 7: 3); IR (ν, cm-1): 3058 (C-H, sp2 stretch
), 842 (C-H, bend sp2), 2929 (C-H, sp3 stretch), 1433 (C=C,
stretch ring), 1612 (C=C, bend ring), 1334 (C-N, stretch), 3280 (N-H, stretch),
768 (C-Cl, stretch), 1175 (S=O, symmetrical stretch), 1362 (S=O, asymmetric stretch).
Synthesis intermediate tertiary
1. 4,4'- dimethylbenzophenone (0,019 mol, 4 g) dissolved in toluene
(100 mL). 4-Aminopiperidine (0.019 mol, 1.9 g, 2 mL) was added and followed by p-polyuenesulfonic
acid (0.3 g). The mixture is heated until reflux for 3 days with Dean-Stark
Trap to remove water. After cooling the mixture to room temperature,
toluene is removed at a low pressure to leave the coarse white powder used
without further purification.
Intermediate synthesis tertiary
2. 4,4'- dichlorobenzophenone (0.0319 mol, 8 g) dissolved in toluene
(200 mL). 4-Aminopiperidine (0.0319 mol, 3.2 g, 3.5 mL) was added and followed
by p-polyuenesulfonic acid (0.3 g). The mixture is heated until reflux
for 3 days with Dean-Stark Trap to remove water. After cooling the
mixture to room temperature, toluene is removed at low pressure to remove the
white coarse crystals used without further purification.
Synthesis of 7-chloro-N-(2-(4-(di-p-tolylmetileneamino)
piperidine-1-yl) ethyl) quinolin-4-amine (compound 1) . Tertiary
intermediate 2 (0.01 mol, 2.92 g) is dissolved in acetonitrile (40 mL) and then
intermediates 1 (0.008 mol, 2.4 g) and potassium carbonate (3 g) are added. The
mixture is stirred at 70°C for 2 days. After cooling the mixture to room
temperature, add water (100 mL) and mix the mixture for 30 minutes. The
deposited solid is filtered, washed with water and recrystallized from hexane
to produce white powder; yield, 25%; mp 82-87°C; Rf, 0.53 (DCM - methanol, 7:
3); IR (ν, cm-1): 3033 (C-H, sp2 stretch), 842 (C-H, bend
sp2 ), 2918 (C-H, sp 3 stretch ), 1485 (C=C, ring stretch),
1604 (C=C, bend ring), 1294 (C-N, stretch), 3272 (N-H, stretch), 678 (N-H,
wagging), 1554 (N-H, bend), 1641 (N=C, stretch), 750 (C-Cl, stretch ); 1H
NMR (CHCl3-d; δ, ppm): 2,437 (12H, CH), 1,584 (2H, CH), 1,255
(2H, CH), 7.285-7.258 (8H, Ar), 7,715-7,688 (5H, Q); mass spectrum (M/z):
497.28 (M+); C13NMR (CHCl3-d; δ, ppm):
24.3, 31.6, 41.9, 47.7, 49.7, 53.4, 113, 119.7,122.5, 127.3, 129.4, 134.9, 136,
140.7, 148.2, 151.4, 154.5, 169.2; elemental analysis : C, 74.89; H, 6.67; Cl,
7.17; N, 11.19.
The synthesis of 7-chloro-N-(3-(4-(di-p-tolylmetileneamino)
piperidine-1-yl) propyl) quinolin-4-amine (compound 2) . Tertiary
Intermediate 2 (0.0013 mol, 0.39 g) is dissolved in acetonitrile (20 mL) and
then secondary intermediates 2 (0.0013 mol, 0.42 g) and potassium carbonate
(0.6 g) are added. The mixture is stirred at 70 ° C for 2 days. After cooling
the mixture to room temperature, add water (100 mL) and mix the mixture for 30
minutes. The deposited solid is filtered, washed with water and recrystallized
from hexane to produce white powder; yield, 30%; mp 78-83°C; Rf, 0.50 (DCM -
methanol, 7: 3); IR (ν, cm-1): 3028 (C-H, sp2 stretch),
842 (C-H, bend sp2), 2920 (C-H, stretch, sp3), 1485 (C=C,
ring stretch), 1604 (C=C, bend ring), 1257 (C-N, stretch), 3276 (N-H, stretch),
678 (N-H, wagging), 1554 (N-H, bend), 1643 (N=C, stretch), 750 (C-Cl, stretch);
1H NMR (CHCl3-d; δ, ppm): 2,438-2,366 (12H, CH),
1.38 5(2H, CH), 1,221 (2H, CH), 7,286-7,259 (8H, Ar), 7,715-7,688 (5H, Q); C13NMR
(δ, ppm): 24.3, 27.2, 31.6, 43.2, 47.9, 50, 50, 51.8, 113, 119.7, 122.5, 127.3,
129.1, 129.4, 134.9, 136, 140.7, 148.2, 151.4, 54.5, 169.2 ; mass spectrum (M/z):
511.30 (M+); elemental analysis: C, 74.87; H, 6.56; Cl, 7.11; N,
11.23.
a.
Synthesis of 7-chloro-N-(2-(4-(di-p-tolylmethylamino)
piperidine-1-yl) ethyl) quinolin-4-amine (compound 3) . Compound 3A (0.0060 mol, 0.3 g) is dissolved
in methanol (20 mL) and cooled in ice. Sodium borohydride (0.002 mol, 0.08 g)
is added and the mixture is stirred overnight at room temperature. After
evaporation of methanol, the residue is stirred with water (50 mL) for 30
minutes and then extracted with DCM (3 x 20 mL). The extract is washed with
water, dried with magnesium sulfate and evaporated to produce colorless
crystals; yield, 80%; mp 62-67°C; Rf, 0.51 (DCM - methanol, 7: 3); IR (ν, cm-1):
3020 (C-H, sp2 stretch), 854 (C-H, bend sp2), 2862 (C-H,
sp3 stretch), 1242 (C-N, strecth), 3299 (N-H, stretch), 678 (N-H,
wagging), 756 (C-Cl, stretch); 1H NMR (CHCl3-d; δ,
ppm): 2,322, 2,123, 2,112 (12H, CH), 1,555 (2H, CH), 1,256 (2H, CH), 7,145-7,118
(8H, Ar), 7,265-7,251 (5H, Q), 5,781 (1H, NH), C13NMR (δ, ppm):
24.3, 31.1, 47.7, 49.5, 49.5, 52.5, 53.4, 58.9, 113, 119.7, 122.5, 127.3,
128.2, 129.6 , 134.9, 135.9, 139.8, 148.2, 151.4, 154.5; mass spectrum (M/z):
498.24 (M+); analysis of elements: C, 74.56; H, 7.01; Cl, 7.05; N,
11.19.
b.
Synthesis of N-(2-(4-(bis-(4-chlorophenyl)
methyleneamino) piperidine-1-yl) ethyl) 7-chloroquinolin-4-amine (compound 5). Tertiary intermediate 3 (0.009 mol, 3 g) was
dissolved in acetonitrile (50 mL) and then added substance secondary
intermediate 1 (0.009 mol, 2.78 g) and potassium carbonate (2.5 g). The mixture
is stirred at 70 ° C for 2 days. After cooling the mixture to room temperature,
add water (100 mL) and mix the mixture for 30 minutes. The deposited solid is
filtered, washed with water and recrystallized from hexane to produce white
powder; yield, 20%; mp 115-120°C; Rf, 0.73 (DCM - methanol, 7: 3); IR (ν, cm-1):
3055 (C-H, sp2 stretch), 848 (C-H, bend sp2), 2923 (C-H,
sp3 stretch), 1485 (C=C, ring stretch), 1581 (C=C, bend ring), 1247
(C-N, stretch), 3278 (N-H, stretch), 732 (N-H, wagging), 1554 (N-H, bend), 754
(C-Cl, stretch), 806, 827 (p-C-Cl, stretch); 1H NMR (CHCl3-d;
δ, ppm): 2,380 (4H, CH), 1,584 (2H, CH), 1,255 (2H, CH), 7,285 - 7,258 (8H,
Ar), 7,715 - 7,688 (5H, Q); C13NMR (δ, ppm) 31.6, 41.9, 47.7, 49.7,
53.4, 113, 119.7, 122.5, 127.3 , 129.4, 130.6, 134.9, 136.6, 137.1 148.2,
151.4, 154.5, 169.2; mass spectrum (M/z): 537.18 (M+); elemental
analysis: C, 64.69; H, 5.02; Cl, 19.75; N, 10.38.
c.
Synthesis of N-(3-(4-(bis-(4-chlorophenyl)methyleneamino)
piperidine-1-yl) propyl) 7-chloroquine-4-amine (compound 6). Tertiary Intermediate 2 (0.0012 mol, 4 g) is
dissolved in acetonitrile (40 mL) and then secondary intermediates 2 (0.012
mol, 3.78 g) and potassium carbonate (5 g) are added. The mixture is stirred at
70 ° C for 2 days. After cooling the mixture to room temperature, add water
(100 mL) and mix the mixture for 30 minutes. The precipitated solid is
filtered, washed with water and recrystallized from hexane to produce white
powder; yield, 35%; mp 100-105°C; Rf, 0.66 (DCM - methanol, 7:3); IR (ν, cm-1):
3018 (C-H, sp2 stretch), 850 (C-H, bend sp2), 2920 (C-H,
sp3 stretch), 1485 (C=C, ring stretch), 1585 (C=C, bend ring), 1245
(C-N, stretch), 3280 (N-H, stretch), 715 (N-H, wagging), 1554 (N-H, bend), 752
(C-Cl, stretch), 804, 831 (p-C-Cl, stretch); 1H NMR (CHCl3-d;
δ, ppm): 2,350 (12H, CH), 1,559 (2H, CH), 1,255 (2H, CH), 7,487 - 7,459 (8H,
Ar), 7,742 - 7,714 (5H, Q); C13NMR (δ, ppm): 31.6, 43.2, 47.9, 50,
51.8, 113, 119.7, 122.5, 127.3, 129, 130.6, 134.9, 136.6, 148.2, 151.4, 154.5,
169.2; mass spectrum (M/z): 551.21 (M+); elemental analysis:
C, 65.23; H, 5.28; Cl, 19.23; N, 10.09.
Source:
·
Sharma, R. Tiwari, A. & Parate, Anupama. 2015.
Synthesis Of New Chloroquine Derivates As Antimalarial Agents. Pharmaceutical
Chemistry Journal , 49 (8), 537 - 542
