4085-31-8

Basic information

• Product Name: Piperaquine phosphate
• Synonyms: 1,3-bis[1-(7-chloro-4-quinolyl)-4'-piperazinyl]propane tetraphosphate tetrahydrate;Piperaquine phosphate CP2000;PIRERAQUINE PHOSPHATE;4,4'-(1,3-Propanediydi-4,1-piper-azinediyl)bis[7-chloroquinoline];4,4'-(trimethylenedi-4,1-piperazinediyl)bis(7-chloro-quinoline);piperaquinoline;4,4'-[1,3-Propanediylbis(4,1-piperazinediyl)]bis(7-chloroquinoline);Piperaquine phosphate
• CAS NO: 4085-31-8
• Molecular Formula: C₂₉H₃₂Cl₂N₆
• Molecular Weight: 633.51
• EINECS: 202-303-5
• Product Categories: APIS
• Mol File: 4085-31-8.mol
• Article Data: 2

Chemical Properties

• Melting Point: 198-200 °C
• Boiling Point: 721.1 °C at 760 mmHg
• Flash Point: 389.9 °C
• Appearance: /
• Density: 1.292 g/cm³
• Solubility: ≤0.2mg/ml in DMSO
• PKA: 8.92±0.50(Predicted)
• CAS DataBase Reference: Piperaquine phosphate(CAS DataBase Reference)
• NIST Chemistry Reference: Piperaquine phosphate(4085-31-8)
• EPA Substance Registry System: Piperaquine phosphate(4085-31-8)

Safety Data

• Hazardous Substances Data: 4085-31-8(Hazardous Substances Data)

Usage

Chemical Properties

To class white crystalline powder

Definition

ChEBI: An aminoquinoline that is 1,3-di(piperazin-1-yl)propane in which the nitrogen at position 4 of each of the piperazine moieties is replaced by a 7-chloroquinolin-4-yl group.

Biological Activity

piperaquine, an antimalarial drug, is first synthesised in the 1960s and extensively used as prophylaxis and treatment during the next 20 years.

in vitro

in 280 p. falciparum isolates, the ic50 for piperaquine ranged from 9.8 nm to 217.3 nm and a significant but low correlation was observed between the ic50 values for piperaquine and chloroquine. however, the coefficient of determination indicated that only 2.1% of the variation in the response to piperaquine was explained by the variation in the response to chloroquine. moreover, the mean value for piperaquine was 74.0 nm in the pfcrt k76 wild-type group and 87.7 nm in the 76t mutant group and such difference was not significant [1].

in vivo

male sd rats were orally administered piperaquine or as a short-term i.v. infusion. results showed that piperaquine disposition was best described by a 3-compartment model with a rapid initial distribution phase after i.v. administration. the pk of piperaquine was characterized by a low clearance, a large volume of distribution and a long terminal half-life [2].

IC 50

9.8 to 217.3 nm for p. falciparum isolates

references

[1] pascual a et al. in vitro piperaquine susceptibility is not associated with the plasmodium falciparum chloroquine resistance transporter gene. malar j. 2013 nov 25;12:431. [2] tarning j, lindegardh n, sandberg s, day nj, white nj, ashton m. pharmacokinetics and metabolism of the antimalarial piperaquine after intravenous and oral single doses to the rat. j pharm sci. 2008 aug;97(8):3400-10.[3] denis mb, davis tm, hewitt s, incardona s, nimol k, fandeur t, poravuth y, lim c, socheat d. efficacy and safety of dihydroartemisinin-piperaquine (artekin) in cambodian children and adults with uncomplicated falciparum malaria. clin infect dis. 2002 dec 15;35(12):1469-76.

Synthetic route

1,3-dibromo-propane (109-64-8) + 7-chloro-4-piperazinylquinoline (837-52-5) → 1,3-bis[1-(7-chloroquinolin-4-yl)piperazin-4-yl]propane (4085-31-8)

Conditions	Yield
With sodium carbonate In water at 100℃; for 15h;
With triethylamine In methanol Product distribution / selectivity; Heating; Reflux;

4,7-dichloroquinoline (86-98-6) → 1,3-bis[1-(7-chloroquinolin-4-yl)piperazin-4-yl]propane (4085-31-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium iodide / isopropyl alcohol / 10 h / Reflux; Heating 2: triethylamine / methanol / Heating; Reflux View Scheme

1,3-bis[1-(7-chloroquinolin-4-yl)piperazin-4-yl]propane (4085-31-8) → Piperaquine tetraphosphate

Conditions	Yield
With phosphoric acid; water In methanol; dichloromethane for 1 - 2h; Product distribution / selectivity;	99.9%

1,3-bis[1-(7-chloroquinolin-4-yl)piperazin-4-yl]propane (4085-31-8) → 1,3-bis[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propanephosphate

Conditions	Yield
With phosphoric acid; water at 5 - 15℃; for 4 - 5h;

Upstream product

• 109-64-8 1,3-dibromo-propane 
• 837-52-5 7-chloro-4-piperazinylquinoline 
• 86-98-6 4,7-dichloroquinoline 

Downstream Products

• 85547-56-4 Piperaquine tetraphosphate 
• 915967-82-7 1,3-bis[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propanephosphate 

Relevant articles and documents

AN IMPROVED PROCESS FOR THE PREPARATION OF PIPERAQUINE

The present invention relates to an improved process for the preparation of 7-chloro- 4-piperazin-1-yl-quinoline of formula (I), a key intermediate for the synthesis of Piperaquine or its pharmaceutically acceptable salts.