50-63-5

Basic information

• Product Name: Chloroquine diphosphate
• Synonyms: 7-chlor-4-(4-(diaethylamino)-1-methylbutylamino)-chinolindiphosphat;7-chloro-4-((4’-diethylamino-1-methylbutyl)amino)quinolinediphosphate;7-chloro-4-(4-diethylamino-1-methyl-butylamino)-quinolindiphosphate;alermine;aralendiphosphate;chingaminphosphate;chloroquindiphosphate;chloroquinebis(phosphate)
• CAS NO: 50-63-5
• Molecular Formula: C₁₈H₂₈ClN₃*2H₂O₄P
• Molecular Weight: 515.86
• EINECS: 200-055-2
• Product Categories: Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Miscellaneous Enzyme;ARALEN;Inhibitors
• Mol File: 50-63-5.mol

Chemical Properties

• Melting Point: 200 °C (dec.)(lit.)
• Boiling Point: 460.6 °C at 760 mmHg
• Flash Point: 232.3 °C
• Appearance: /solid
• Density: ==
• Vapor Pressure: 1.15E-08mmHg at 25°C
• Storage Temp.: Desiccate at RT
• Solubility: H2O: 50 mg/mL, clear
• PKA: pKa 8.10(H2O t = 20 c = 0.0025) (Uncertain)
• Water Solubility: Soluble in water
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in distilled water may be stored at -20° for up to 3 months.
• Merck: 14,2163
• BRN: 4223142
• CAS DataBase Reference: Chloroquine diphosphate(CAS DataBase Reference)
• NIST Chemistry Reference: Chloroquine diphosphate(50-63-5)
• EPA Substance Registry System: Chloroquine diphosphate(50-63-5)

Safety Data

• Hazard Codes: Xn
• Statements: 22-40-20/21/22
• Safety Statements: 22-24/25-36
• RIDADR: 1544
• WGK Germany: 3
• RTECS: VB2450000
• F: 10
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 50-63-5(Hazardous Substances Data)

Usage

Uses

Used in Antimalarial Applications:
Chloroquine diphosphate is used as an antimalarial drug, effective against chloroquine-sensitive strains of Plasmodium falciparum. It is utilized in the prevention and treatment of malaria, particularly in regions where the disease is prevalent.
Used in Antiamebic Applications:
Chloroquine diphosphate is used as an antiamebic agent, targeting the parasitic protozoa that cause amebiasis. It is particularly effective in treating infections caused by Entamoeba histolytica.
Used in Antirheumatic Applications:
Chloroquine diphosphate is used as an antirheumatic drug, helping to manage the symptoms of rheumatoid arthritis and systemic lupus erythematosus (SLE). It exhibits anti-inflammatory properties that can alleviate pain and reduce inflammation in these conditions.
Used in Anticancer Applications:
Chloroquine diphosphate is used as an anticancer agent, demonstrating inhibitory effects on the growth of various cancer cell lines, including oral squamous cell carcinoma and renal cancer cells. It has also shown potential in reducing tumor growth in mouse models.
Used in Cellular Research:
Chloroquine diphosphate is used as a DNA intercalator and to dissociate antigen-antibody complexes without denaturing red blood cell antigens. It is also used to study the role of endosomal acidification in cellular processes, such as the signaling of intracellular Toll-like receptors (TLRs).
Used in Antiviral Applications:
Chloroquine diphosphate has shown high antiviral activity against Nipah virus (NiV) at concentrations lower than 20 μM. It also prevents infection by severe acute respiratory coronavirus 2 (SARS-CoV-2) in Vero cells.
Used in Drug Resistance Studies:
Chloroquine diphosphate is used as a substrate for multidrug resistance-associated protein (MRP) in multidrug-resistant cell lines. It inhibits photoaffinity labeling of MRP by quinoline-based photoactive drug IAAQ, aiding in the study of drug resistance mechanisms.
Chemical Properties:
Chloroquine diphosphate is a white solid with various applications in the medical and research fields. Its diverse properties make it a valuable compound for treating and studying various diseases and conditions.

Originator

Nivaquine,Specia,France,1949

Manufacturing Process

105 g of 4,7-dichloroquinoline (MP 93 to 94°C) are heated with 200 g of 1- diethylamino-4-aminopentane for 7 hours in an oil bath to 180°C while stirring, until a test portion dissolved in diluted nitric acid does not show a precipitation with sodium acetate solution. The mixture is dissolved in diluted acetic acid and made alkaline by adding sodium lye. The base is extracted with ether, dried with potassium carbonate, the ether removed by distillation and the residue fractionated. The 4-(5'- diethylaminopentyl-2'-amino)-7-chloroquinoline (BP 212 to 214C/0.2 mm) is obtained. On cooling the compound solidifies crystalline. It melts, recrystallized from benzene, at 88°C. The base combines with phosphoric acid to yield a diphosphate salt.

Therapeutic Function

Antimalarial

Biochem/physiol Actions

Standard anti-malarial drug. Substrate for MRP in multidrug resistant cell line and inhibits photoaffinity labeling of MRP by quinoline-based photoactive drug IAAQ (N-[4-[1-hydroxy-2-(dibutylamino)ethyl]quinolin-8-yl]-4-azidosalicylamide).

References

1) Frieboes et al. (2014), Chloroquine-mediated cell death in metastatic pancreatic adenocarcinoma through inhibition of autophagy; JOP, 15 189 2) Jiang et al. (2010), Antitumor and antimetastatic activities of chloroquine diphosphate in a murine model of breast cancer; Biomed. Pharmacother., 64 609 3) Choi et al. (2014), Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1; Stem Cells, 32 2309 4) Mulcahy Levy et al. (2014), Autophagy inhibition improves chemosensitivity in BRAFV600E brain tumors; Cancer Discov., 4 773

InChI:InChI=1/C18H26ClN3.2H3O4P/c1-4-22(5-2)12-6-7-14(3)21-17-10-11-20-18-13-15(19)8-9-16(17)18;2*1-5(2,3)4/h8-11,13-14H,4-7,12H2,1-3H3,(H,20,21);2*(H3,1,2,3,4)

Synthetic route

Chloroquine (54-05-7) → chloroquine phosphate (50-63-5)

Conditions	Yield
With phosphoric acid In ethanol	80.32%
With phosphoric acid In ethanol at 60 - 65℃;	66.11%

chloroquine phosphate (50-63-5) → Chloroquine (54-05-7)

Conditions	Yield
With sodium hydroxide In water; ethyl acetate at 0℃; for 1h;	94%
With sodium hydroxide In water at 0℃; for 0.5h;	94%
With sodium hydroxide In water
With sodium hydroxide In dichloromethane; water

potassium tetrachloroplatinate(II) (10025-99-7) + chloroquine phosphate (50-63-5) → trans-Pt(chloroquine diphosphate)2(Cl)2

Conditions	Yield
In water at 20℃; for 18h;	87.8%

silver tetrafluoroborate (14104-20-2) + [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 (52462-29-0) + water (7732-18-5) + chloroquine phosphate (50-63-5) → [Ru(II)(η6-p-cymene)(η6-chloroquineH2)](BF4)2(H2PO4)2*2H2O

Conditions	Yield
In water under N2; Ru complex dissolved in water at 55°C, addn. of silver salt and chloroquine diphosphate, mixt. stirred at 55°C for 20 h; filtration throught Celite, filtrate evapd., residue dried under vac. for 20 h; elem. anal.;	78%

potassium pentacyanonitrosylchromate(III) monohydrate + chloroquine phosphate (50-63-5) → {Cr(NO)(CN)2(chloroquine)(H2O)}

Conditions	Yield
In acetic acid byproducts: CH3COOK, HCN, H2O; aq. acetic acid; heated at 80°C for 20-30 min.; added with shaking; CO2 passed for 2 h; filtered by suction; washed (diluted acetic acid, water); dried over silica gel in a vac. at room temp.; elem. anal.; TGA;	46%

chloroquine phosphate (50-63-5) + β‐cyclodextrin (7585-39-9) → C42H70O35*C18H26ClN3

Conditions	Yield
In water at 40 - 45℃; for 96h; Thermodynamic data;

chloroquine phosphate (50-63-5) + alpha cyclodextrin (10016-20-3) → C36H60O30*C18H26ClN3

Conditions	Yield
In water at 40 - 45℃; for 96h; Thermodynamic data;

chloroquine phosphate (50-63-5) → (+)-Chloroquine

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water; ethyl acetate / 1 h / 0 °C 2: diethylamine / hexane; isopropyl alcohol / 35 °C / Resolution of racemate View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 0.5 h / 0 °C 2: diethylamine / isopropyl alcohol; hexane / 35 °C / Resolution of racemate View Scheme

chloroquine phosphate (50-63-5) → (R)-(-)-chloroquine (54-05-7, 56598-66-4, 58175-86-3, 58175-87-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water; ethyl acetate / 1 h / 0 °C 2: diethylamine / hexane; isopropyl alcohol / 35 °C / Resolution of racemate View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 0.5 h / 0 °C 2: diethylamine / isopropyl alcohol; hexane / 35 °C / Resolution of racemate View Scheme

chloroquine phosphate (50-63-5) → 7-chloro-4-[4-diethylamino-L-methylbutylamino]quinoline diphosphate

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / water; ethyl acetate / 1 h / 0 °C 2: diethylamine / hexane; isopropyl alcohol / 35 °C / Resolution of racemate 3: phosphoric acid / ethanol / 2 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide / water / 0.5 h / 0 °C 2: diethylamine / isopropyl alcohol; hexane / 35 °C / Resolution of racemate 3: phosphoric acid / ethanol / 2 h / Reflux View Scheme

chloroquine phosphate (50-63-5) → (R)-(-)-chloroquine diphosphate

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / water; ethyl acetate / 1 h / 0 °C 2: diethylamine / hexane; isopropyl alcohol / 35 °C / Resolution of racemate 3: phosphoric acid / ethanol / 2 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide / water / 0.5 h / 0 °C 2: diethylamine / isopropyl alcohol; hexane / 35 °C / Resolution of racemate 3: phosphoric acid / ethanol / 2 h / Reflux View Scheme

Upstream product

• 54-05-7 Chloroquine 

Downstream Products

• 54-05-7 Chloroquine 
• 54-05-7 (R)-(-)-chloroquine 
• 69698-56-2 (S)-(+)-chloroquine phosphate 
• 69698-56-2 (R)-chloroquine phosphate 

Relevant articles and documents

Synthesis method of high-purity chloroquine phosphate

The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of chloroquine phosphate, and particularly provides a synthesis method of high-purity chloroquine phosphate. The synthesis method comprises the following steps: (1) condensation: reacting 4, 7-dichloroquinoline with 2-amido-5-diethylamine pentane to obtain a chloroquine crude product; and (2) refining: recrystallizing to obtain chloroquine with higher purity. (3) salifying: stirring and crystallizing the refined chloroquine and phosphoric acid for 2-3 hours, and filtering to obtain a chloroquine phosphate crude product; and (4) purification: recrystallizing the chloroquine phosphate crude product to obtain high-purity chloroquine phosphate. The method is high in atom utilization rate, high in yield, high in product purity, less in solid waste, beneficial to environmental protection and convenient for industrial application, and has a relatively good industrial prospect.

Preparation process of chloroquine phosphate (by machine translation)

The invention discloses a preparation process of chloroquine phosphate. The preparation process of the chloroquine phosphate comprises the following steps: (1) condensation reaction with 4,7 -amino 2 - diethylamino-pentane, and basifying and extracting to obtain chloroquine; (-5 -) synthesizing chloroquine and phosphoric acid obtained in the step (2 1) to obtain chloroquine phosphate. To the preparation process of chloroquine phosphate provided by the invention, the use of other catalysts such as benzene and other catalysts is avoided in the preparation process, the product purity is high, the single impurity is less than 0.1%, the operation is simple, the procedures are simplified, the production efficiency is improved, and the method is suitable for industrial production. (by machine translation)