Chloroquine

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:

·           https://pubchem.ncbi.nlm.nih.gov/compound/ chlorokuin # section = Top

·           Sharma, R. Tiwari, A. & Parate, Anupama. 2015. Synthesis Of New Chloroquine Derivates As Antimalarial Agents. Pharmaceutical Chemistry Journal , 49 (8), 537 - 542