WO2011095885A1 - An improved process for the preparation of piperaquine - Google Patents
An improved process for the preparation of piperaquine Download PDFInfo
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- WO2011095885A1 WO2011095885A1 PCT/IB2011/000218 IB2011000218W WO2011095885A1 WO 2011095885 A1 WO2011095885 A1 WO 2011095885A1 IB 2011000218 W IB2011000218 W IB 2011000218W WO 2011095885 A1 WO2011095885 A1 WO 2011095885A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
Definitions
- the present invention relates to an improved process for the preparation of 7-chloro- 4-piperazin-l-yl-quinoline of formula I, which is a key intermediate for the synthesis of Piperaquine or its pharmaceutically acceptable salts.
- Piperaquine is an antimalarial drug that belongs to the bisquinoline class of chemical compounds. It is chemically known as l ,3-Bis[l-(7-chloro-4-quinolyl)-4'- piperazinyl] propane and is represented by the compound of formula II.
- US Pat No. 3331843 discloses 7-chloro-4-(piperazin-l-yl) quinoline of formula I, which is prepared by the condensation of 4,7-dichloroquinoline with anhydrous Piperazine in presence of phenol to get crude, it is subjected to crystallization in cyclohexane to give pure 7-chloro-4-(piperazin-l-yl) quinoline. It is further converted into acid addition salts such as dihydrobromide, dihydrochloride hydrate and monomaleic acid.
- the present invention relates to an improved and efficient process for the preparation of 7-chloro-4-(piperazin-l-yl) quinoline of formula I, which is a key intermediate for the synthesis of Piperaquine of formula II.
- One aspect of the present invention provides an improved process for the preparation of 7-chloro-4-(piperazin-l-yl)-quinoline of Formula I comprises, a) reacting 4,7-dichloroquinoline with piperazine in the presence of catalyst in a solvent, b) removing the solvent, c) adding mixture of water and water immiscible organic solvent, d) giving acid base treatment, and d) isolating give 7-chloro-4- (piperazin- 1 -yl)-quinoline of Formula I.
- Another aspect of the present invention provides process for the preparation of Piperaquine comprises, a) reacting pure 7-chloro-4-(piperazin-l-yl) quinoline of formula I with 1,3-dibromopropane in the presence of a base, and isolating Piperaquine of formula II or its pharmaceutically acceptable salt.
- the present invention relates to an improved process for the preparation of 7-chloro- 4-(piperazin-l-yl) quinoline of formula I, which is a key intermediate for the synthesis of Piperaquine of formula I.
- One embodiment of the present invention is to provide an improved process for preparing 7-chloro-4-(piperazin-l-yl) quinoline of formula I, which comprises the steps of:
- reaction mass temperature is heated to 60-80°C and maintained for about 18-24 hrs, preferably 20hrs.
- solvent is removed by known techniques such as distillation, evaporation to get residue, which is diluted with water and water immiscible solvents.
- the resulting solution pH is adjusted to 2-5, preferably 3-3.5, with an acid.
- Aqueous layer is separated and washed with organic solvent.
- the resulting aqueous layer pH is adjusted to 9-12, preferably pH 10-11, obtained solid is filtered to get compound of formula I, which is free of dimer impurity.
- solvent used in condensation reaction is selected from methanol, ethanol or isopropanol or ethyl acetate.
- Catalyst used herein is a metal halide selected from potassium iodide, sodium iodide or imidazole.
- water immiscible solvent used herein is selected from chlorinated solvents such as dichloromethane or aromatic hydrocarbons such as toluene.
- the acid used for the pH adjustment is selected from hydrochloride or sulfuric acid and the base is ammonia.
- Another embodiment of the present invention provides a process for preparing Piperaquine of formula II or its pharmaceutically acceptable salt, which comprises; a) reacting pure 7-chloro-4-(piperazin-l-yl) quinoline of formula I with 1 ,3- dibromopropane in the presence of a base,
- 7-chloro-4-(piperazin-l-yl) quinoline of formula I is reacted with 1,3 -dibromopropane in the presence of a base selected from triethylamine or aqueous ammonia; optionally in a solvent selected from methanol, ethanol or isopropanol.
- a base selected from triethylamine or aqueous ammonia
- a solvent selected from methanol, ethanol or isopropanol.
- the crude compound thus obtained is stirred in a solvent mixture and filtered the pure Piperaquine free base.
- the pure Piperaquine free base further converted to its pharmaceutically acceptable salt by conventional method.
- the solvent used for the purification of Piperaquine is selected from, dichloromethane, chloroform, methanol, ethanol, isopropanol or mixture thereof.
- pharmaceutically acceptable salt is selected from hydrochloric acid, sulphate, phosphate, malate, maleate, mesylate, tosylate or its hydrates thereof.
- Another embodiment of the present invention provides isopiperaquine impurity of formula IV.
- Example-1 7-Chloro-4-(piperazin-l-yl) quinoline.
- the pH of aqueous layer was adjusted to 10-1 1 with ammonia solution.
- the reaction mass was filtered and washed the precipitate with water till pH of mother liquor become neutral.
- the solid obtained was suck dried, unloaded the wet mass and dried at 50°C under vacuum to yield 44g of the title compound.
- aqueous layer was adjusted to 10 with liquid ammonium hydroxide and methylene chloride (100 ml) was added and stirred for about 30 minutes. Methylene chloride layer was separated and aqueous layer was extracted with (2x100 ml) methylene chloride. All the methylene chloride layers were combined, distilled under vacuum and dried over diisopropyl ether (100ml). The reaction mass was stirred overnight and cooled to 0-5°C. The reaction mass then filtered, washed with diisopropyl ether (2x10 ml), suck dried, unloaded the wet mass and dried at 50°C under vacuum to yield 8g of the title compound.
- Example-3 7-Chloro-4-(piperazin-l-yl) quinoline (I).
- Example-4 7-Chloro-4-(piperazin-l-yI) quinoline.
- Example-5 Piperaquine free base.
- Example-7 Piperaquine free base.
- the filtered crude was washed with (400 ml) of water and dried under vacuum to get the Piperaquine tetra phosphate tetra hydrate ( 180 g 99.9 % with all impurities & ROI less than 0.1) .
- product is protected from light &
- the material shall be packed in LDPE bag, twisted and tied with plastic fastener. It then inserted in triple laminated aluminum bag inside black cover along with two silica gel sachets, one molecular sieve and one O-buster pack, and heat sealed under vacuumed nitrogen. Both these bags are then put into the outer bag of triple laminated aluminum bag inside black cover and heat-sealed.
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
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.
Description
An improved process for the preparation of piperaquine
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of 7-chloro- 4-piperazin-l-yl-quinoline of formula I, which is a key intermediate for the synthesis of Piperaquine or its pharmaceutically acceptable salts.
Formula I
BACK GROUND OF THE INVENTION:
Piperaquine is an antimalarial drug that belongs to the bisquinoline class of chemical compounds. It is chemically known as l ,3-Bis[l-(7-chloro-4-quinolyl)-4'- piperazinyl] propane and is represented by the compound of formula II.
US Pat No. 3331843 discloses 7-chloro-4-(piperazin-l-yl) quinoline of formula I, which is prepared by the condensation of 4,7-dichloroquinoline with anhydrous Piperazine in presence of phenol to get crude, it is subjected to crystallization in cyclohexane to give pure 7-chloro-4-(piperazin-l-yl) quinoline. It is further converted into acid addition salts such as dihydrobromide, dihydrochloride hydrate and monomaleic acid.
4,7-dichloroquinoline Piperazine Formula I
US '843 process involves the use of phenol as a reaction medium and requires the crystallization of crude product in a cyclohexane solvent.
Journal of medicinal chemistry, 1971, 14, 283-286 describes preparation of 7-chloro- 4-(piperazin-l-yl) quinoline by condensation of 4,7- dichloroquinoline with excess amount of Piperazine in ethoxyethanol.
Journal of medicinal chemistry, 1998, 41 , 4360-4364 describes preparation of 7- chloro-4-(piperazin-l-yl) quinoline by condensing 4,7-dichloroquinoline with piperazine in ethoxyethanol after completion of the reaction, reaction mass is diluted with the aqueous alkaline solution, the resulting solution is extracted in mixture of
ethyl acetate, diethyl ether and dichloromethane followed by concentration to give 7- chloro-4-(piperazin-l-yl) quinoline. This process involves the different low boiling solvents in workup and isolation. US Pat No. 7220856 describes preparation of 7-chloro-4-(piperazin-l-yl) quinoline in ethanol and excess amount of piperazine.
US Pat. No. 3173918 discloses process for the preparation of Piperaquine and its non-toxic acid addition salts, wherein 4,7-dichloroquinoline is reacted with 1,3-bis-l'- piperazinylpropane in phenol at 115-120°C and the resultant mixture is poured into an aqueous base solution to obtain crude Piperaquine. It is recrystallized in mixture of dimethylformamide and water to get pure product as shown in scheme-I.
US '918 patent also describes condensation of 7-chloro-4-(piperazin-l-yl) quinoline (formula I) and 1,3-dibromopropane in methyl ethyl ketone followed by crystallization in ethanol to get Piperaquine.
Pure Piperaquine
7-chloro-4-(piperazin-l-yl) quinoline (formula I) is one of the key intermediate during the preparation of Piperaquine. Dimer impurity is one of the major impurity formed during the preparation of 7-chloro-4-(piperazin-l-yl) quinoline. It is observed in the range of 6-14% by HPLC, depending upon the solvent and mole ratio of Piperazine used in the reaction.
The above prior art processes are not disclosed how to control the dimmer impurity neither intermediate stage nor final product, which needs number of purification steps in different solvents to get desire quality of the 7-chloro-4-(piperazin-l-yl) quinoline.
Thus there is a need to develop substantially pure 7-chloro-4-(piperazin-l-yl) quinoline of formula I by controlled reaction by using catalyst, simple acid base treatment to remove dimer impurity without recrystallization. SUMMARY OF THE INVENTION
The present invention relates to an improved and efficient process for the preparation of 7-chloro-4-(piperazin-l-yl) quinoline of formula I, which is a key intermediate for the synthesis of Piperaquine of formula II. One aspect of the present invention, provides an improved process for the preparation of 7-chloro-4-(piperazin-l-yl)-quinoline of Formula I comprises, a) reacting 4,7-dichloroquinoline with piperazine in the presence of catalyst in a solvent, b) removing the solvent, c) adding mixture of water and water immiscible organic solvent, d) giving acid base treatment, and d) isolating give 7-chloro-4- (piperazin- 1 -yl)-quinoline of Formula I.
Another aspect of the present invention, provides process for the preparation of Piperaquine comprises, a) reacting pure 7-chloro-4-(piperazin-l-yl) quinoline of formula I with 1,3-dibromopropane in the presence of a base, and isolating Piperaquine of formula II or its pharmaceutically acceptable salt.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of 7-chloro- 4-(piperazin-l-yl) quinoline of formula I, which is a key intermediate for the synthesis of Piperaquine of formula I.
One embodiment of the present invention is to provide an improved process for preparing 7-chloro-4-(piperazin-l-yl) quinoline of formula I, which comprises the steps of:
a) reacting 4,7-dichloro-quinoline with piperazine in the presence of catalyst in a solvent,
b) optionally removing the solvent, adding mixture of water and water immiscible organic solvent,
c) treating with an acid,
d) separating aqueous and organic layers,
e) treating with aqueous base, and
f) isolating 7-chloro-4-piperazin-l-yl-quinoline of formula (I).
According to the present invention 4,7-dichloroquinoline and piperazine are dissolved in an solvent, added a catalyst at room temperature. Reaction mass temperature is heated to 60-80°C and maintained for about 18-24 hrs, preferably 20hrs. After completion of the reaction, solvent is removed by known techniques such as distillation, evaporation to get residue, which is diluted with water and water immiscible solvents. The resulting solution pH is adjusted to 2-5, preferably 3-3.5, with an acid. Aqueous layer is separated and washed with organic solvent. The resulting aqueous layer pH is adjusted to 9-12, preferably pH 10-11, obtained solid is filtered to get compound of formula I, which is free of dimer impurity.
According to the present invention, solvent used in condensation reaction is selected from methanol, ethanol or isopropanol or ethyl acetate. Catalyst used herein is a
metal halide selected from potassium iodide, sodium iodide or imidazole. After completion of the reaction, reaction mass is diluted with water immiscible solvent used herein is selected from chlorinated solvents such as dichloromethane or aromatic hydrocarbons such as toluene. The acid used for the pH adjustment is selected from hydrochloride or sulfuric acid and the base is ammonia.
The use of potassium iodide or sodium iodide in the present invention is not only as a catalyst but also to speed up the reaction. According to the present invention, reaction is completed in lesser time as compared to the prior art processes. Thus, the formation of dimmer impurity is less as compared to the known processes.
Another embodiment of the present invention provides a process for preparing Piperaquine of formula II or its pharmaceutically acceptable salt, which comprises; a) reacting pure 7-chloro-4-(piperazin-l-yl) quinoline of formula I with 1 ,3- dibromopropane in the presence of a base,
b) isolating pure Piperaquine of formula II, and
c) Optionally converting to pharmaceutically acceptable salt.
According to the present invention 7-chloro-4-(piperazin-l-yl) quinoline of formula I is reacted with 1,3 -dibromopropane in the presence of a base selected from triethylamine or aqueous ammonia; optionally in a solvent selected from methanol, ethanol or isopropanol. After completion of the reaction the obtained solid is filtered to get crude product. The crude compound thus obtained is stirred in a solvent mixture and filtered the pure Piperaquine free base. The pure Piperaquine free base further converted to its pharmaceutically acceptable salt by conventional method.
According to the present invention the solvent used for the purification of Piperaquine is selected from, dichloromethane, chloroform, methanol, ethanol, isopropanol or mixture thereof.
According to the present invention pharmaceutically acceptable salt is selected from hydrochloric acid, sulphate, phosphate, malate, maleate, mesylate, tosylate or its hydrates thereof. Another embodiment of the present invention provides isopiperaquine impurity of formula IV.
Formula IV
The schematic description of the improved process for the preparation of compound of formula II is as shown in scheme-II given below:
Piperaquine (Formula II)
The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.
Example-1: 7-Chloro-4-(piperazin-l-yl) quinoline.
To a mixture of 4,7-dichloroquinoline (50g), isopropylalcohol (350ml) and piperazine (65g) was added potassium iodide (21g) at 25-35°C and stirred for about 10 min at the same temperature. The reaction mixture was heated to reflux temperature and maintained for about 20 hr. Isoproylalcohol was distilled completely under vacuum. Water (1 150ml) and methylenechloride was added to the residue thus obtained and stirred for about 10 min at room temperature. The pH of the reaction mass was adjusted to 3-3.5 with dil.HCl (1 150ml), separated aqueous layer and washed with methylene chloride. The pH of aqueous layer was adjusted to 10-1 1 with ammonia solution. The reaction mass was filtered and washed the precipitate with water till pH of mother liquor become neutral. The solid obtained was suck
dried, unloaded the wet mass and dried at 50°C under vacuum to yield 44g of the title compound.
ExampIe-2 : 7-Chloro-4-(piperazin-l-yl)quinoline.
To a mixture of 4,7-dichloroquinoline (lOg) and ethyl acetate (100ml) was added piperazine (lg) and imidazole (3.4g) at 25-35°C and stirred for about 10 min at the same temperature. The reaction mass was heated to reflux temperature and maintained for about 10 hr. Ethyl acetate was distilled out completely under vacuum. Water (150ml) and methylene chloride (50ml) was added to the residue thus obtained and stirred for about 10 min at room temperature. The pH of the reaction mass was adjusted to 4-5 with dil.HCl, separated aqueous layer and washed with methylene chloride (3 x 50 ml). The pH of aqueous layer was adjusted to 10 with liquid ammonium hydroxide and methylene chloride (100 ml) was added and stirred for about 30 minutes. Methylene chloride layer was separated and aqueous layer was extracted with (2x100 ml) methylene chloride. All the methylene chloride layers were combined, distilled under vacuum and dried over diisopropyl ether (100ml). The reaction mass was stirred overnight and cooled to 0-5°C. The reaction mass then filtered, washed with diisopropyl ether (2x10 ml), suck dried, unloaded the wet mass and dried at 50°C under vacuum to yield 8g of the title compound.
Example-3: 7-Chloro-4-(piperazin-l-yl) quinoline (I).
To a mixture of 4,7-dichloroquinoline(100g), isopropylalcohol(700ml) and piperazine (130g) was added potassium iodide (21g) at 25-35 °C and stirred for about 10 min at the same temperature. The reaction mass was heated to reflux temperature and maintained for about 10 hr. The reaction mass was then cooled to room temperature, filtered the precipitated solids and washed with isopropyl alcohol. Isopropylalcohol was evaporated from filtered mother liquor under reduced pressure. The crude obtained was diluted with dichloromethane (400 ml) and washed with water at pH 8-13(2X500 ml) for two times. Water (300ml) was added to dichloromethane layer and adjusted the pH of aqueous layer to 2-5 using (~60-100
ml) conc.HCl. Aqueous layer was washed with dichloromethane (2X400 ml) for two times. 10% NaOH was added to the aqueous layer to readjust the pH of the aqueous layer to 9-13. And extracted again with dichloromethane evaporated the organic layer and isolated the 7-chloro-4-piperazine-l-ylquinoline from isopropylether(500 ml) to get 1 10 g pure 7-chloro-4-piperazine-l-ylquinoline (purity above; 99% free from piperazine).
Example-4: 7-Chloro-4-(piperazin-l-yI) quinoline.
A stirred mixture of 4, 7-Dichloroquinoline (100 g, 0.505 mol), Piperazine (130 g, 1.5 mol), and Potassium Iodide (21 g, 0.12 mol) in isopropyl alcohol (700 ml), was refluxed for 10 hours, Cooled the reaction mass to room temperature . The precipitated solids were filtered and washed with IPA. Isopropyl alcohol was evaporated from filtered mother liquor under reduced pressure. The crude obtained was diluted with dichloromethane (400 ml) and washed with water at pH 8 - 13 (2 x 500 ml) at for two times. To the dichloromethane layer there was added water (300 ml). , and adjust pH of aqueous layer 2-5 using (~ 60 -100 ml) cone. HC1. The clear layer separation obtained, then aqueous layer was washed dichloromethane (2 x 400 ml) for two times. The water layer taken again there was added 10 % NaOH solution to readjust pH of the aqueous layer between 9-13. And extracted again with dichloromethane .evaporated the organic layer and isolated the 7-chloro-4- piperazine-l-ylquinoline from (500 ml) Isopropyl ether to get 1 10 g pure 7-chloro-4- piperazine-l-ylquinoline (purity above; 99% free from piperazine)
Example-5: Piperaquine free base.
To a mixture of 7-chloro-4-(piperazin-l-yl)quinoline(10g) and isopropylalcohol (100ml) was added 1,3-dibromopropane (4.6g) and raised the temperature of the reaction mixture to reflux. The reaction mass was cooled to room temperature, filtered the solid and suck dried. The wet material was unloaded and dried to get 8.5 g of the title compound
Example-6: Piperaquine free base.
To a mixture of 7-chloro-4-(piperazin-l-yl)quinoline (lOg) and 1,3-dibromopropane (5.7g) was added liquor ammonia (17g). The reaction mass was cooled to 5-10°C, stirred for about 24-36 hours and maintained at the same temperature for about 3 days. The solid obtained was filtered and suck dried. The wet material was unloaded and dried at 50°C for 24 hrs to yield 8.2g of the title compound.
Example-7: Piperaquine free base.
To a mixture of 7-chloro-4-piperazine-l-yl quinoline (100g) in methanol (1000ml) and 1,3-dibromopropane (80g) was added triethyl amine (150g) at 25-30°C. The reaction mass was heated to reflux temperature and stirred for about 24-60 hours. The reaction mixture was cooled to room temperature and filtered the solid. Water (500ml), methanol (500ml) were added to the solid obtained and adjusted the pH to
0- 2 with cone. HC1 (300ml). The reaction mass was stirred for about 15 minutes and 10% NaOH solution was added to clear solution to readjust pH of the reaction mixture to 8-13. The precipitated solids were stirred at ambient temperature for about
1- 2 hours, and filtered the reaction mass. The crude obtained was stirred in MDC Methanol (1200 ml each) mixture for 15 minutes at ambient temperature. Filtered & evaporated the clear solution obtained up to the formation of product and the solids were precipitated out which was filtered and suction dried to get Piperaquine (85 g, Purity: 99.9 % with all impurities & ROI less than 0.1%) packed in LDPE bag, twisted and tied with plastic fastener. It then inserted in HDPE bag along with one silica gel sachet and one O-buster pack, twisted, and tied with plastic fastener. Both these bags are then put into the outer bag of triple laminated aluminum bag inside black cover and heat-sealed/ twisted and tied with plastic fastener.
Example-8: Piperaquine Tetraphosphate
To a stirred clear solution of Piperaquine (100 g 0.19) in methanol and dichloromethane (1000 ml each) there was added activated carbon and stirred for 30 minutes. Carbon was removed from the solution by filtration. The clear solution of 1
Piperaquine in methanol and dichloromethane was cooled to -10 to 30° C and there was added (4-4.5 moles) of Ortho phosphoric acid in water in 60 to 120 minutes. The thick slurry obtained was stirred and then filtered. The filtered crude was washed with (400 ml) of water and dried under vacuum to get the Piperaquine tetra phosphate tetra hydrate ( 180 g 99.9 % with all impurities & ROI less than 0.1) . product is protected from light & The material shall be packed in LDPE bag, twisted and tied with plastic fastener. It then inserted in triple laminated aluminum bag inside black cover along with two silica gel sachets, one molecular sieve and one O-buster pack, and heat sealed under vacuumed nitrogen. Both these bags are then put into the outer bag of triple laminated aluminum bag inside black cover and heat-sealed.
These bags are further packed in HDPE drum.
Example-8: Piperaquine Tetraphosphate Tetrahydrate
To a stirred clear solution of 1, 3-Bis {4(7-chloro-quinoline-4)-piperazine-l } propane (100 g 0.186) in Methanol and Dichloromethane (500 ml each) there was added activated carbon and stirred for 30 minutes. Carbon was removed from the solution by filtration. The clear solution of 1 , 3-Bis {4(7-chloro-quinoline-4)- piperazine-1 } propane in Methanol and Dichloromethane was cooled to 6 to 20° C and there was added (84 to 90 %) of Ortho phosphoric acid (91.5 g 1500 ml of water) in 60 to 120 minutes, the thick slurry obtained was stirred for 3 hours and then followed by the distillation of Dichloromethane atmospherically below 55° C. Then cooled to room temperature and filtered .The solids obtained were washed with (400 ml) of water and suction dried. Dried under vacuum to get the Piperaquine Tetra Phosphate Tetra Hydrate.(Yield-170 g ).
Claims
Claims
An improved process for preparation of 7-chloro-4-(piperazin-l-yl) quinoline of formula I,
Formula I which comprises the steps of:
a) reacting 4,7-dichloro-quinoline with piperazine in the presence of catalyst in a solvent,
b) optionally removing the solvent, adding mixture of water and water immiscible organic solvent,
c) treating with an acid,
d) separating aqueous and organic layers,
e) treating with aqueous base, and
f) isolating 7-chloro-4-piperazin-l-yl-quinoline of formula (I).
2. The process according to claim 1 , the said solvent in step a) is selected from methanol, ethanol, isopropanol, butanol, ethyl acetate or mixture thereof and immiscible solvent in step b) is selected from dichloromethane or chloroform. 3. The process according to claim 1 , the said catalyst in step a) is selected from potassium idodide, sodium iodide or imidazole.
The process according to claim 1, the said acid in step c) is selected from aqueous hydrochloric acid, aqueous sulfuric acid or acetic acid.
5. The process according to claim 1, the solution pH in step c) is adjusted to 2-5.
6. The process according to claim 1, said base in step e) is selected from ammonia, sodium hydroxide or sodium carbonate, potassium hydroxide. 7. The process according to claim 1, the solution pH in step c) is adjusted to 9-
13.
Process for the preparation of Piperaquine or its pharmaceutically acceptable salt, which comprises the steps of:
a) reacting pure 7-chloro-4-(piperazin-l-yl) quinoline of formula I with 1,3- dibromopropane in the presence of a base,
b) isolating Piperaquine, and
c) optionally converting to pharmaceutically acceptable salt.
The process according to claim 8, the said base is selected from ammonia, triethyl amine.
10. The process according to claim 8, pharmaceutically acceptable salt in step c) is selected from phosphate, hydrochloride or sulfate salt.
Applications Claiming Priority (2)
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| IN305/CHE/2010 | 2010-02-08 | ||
| IN305CH2010 | 2010-02-08 |
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| WO2011095885A1 true WO2011095885A1 (en) | 2011-08-11 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402815A (en) * | 2014-09-15 | 2015-03-11 | 桂林南药股份有限公司 | Control method of piperaquine phosphate impurity |
| CN109970639A (en) * | 2018-11-23 | 2019-07-05 | 重庆康乐制药有限公司 | The method of piperaquine intermediate is synthesized in a kind of continuous current micro-reactor |
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|---|---|---|---|---|
| US3331843A (en) * | 1963-04-04 | 1967-07-18 | American Cyanamid Co | 1-substituted-4-substituted aminoalkylene piperazines |
| WO2009050734A2 (en) * | 2007-10-15 | 2009-04-23 | Elder Pharmaceuticals Ltd. | An industrially feasible process for the manufacture of bisquinoline derivatives by using substantially pure n-monosubstituted piperazines |
| CN101440063A (en) * | 2008-12-19 | 2009-05-27 | 重庆康乐制药有限公司 | Preparation of piperaquini phosphatis |
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2011
- 2011-02-08 WO PCT/IB2011/000218 patent/WO2011095885A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3331843A (en) * | 1963-04-04 | 1967-07-18 | American Cyanamid Co | 1-substituted-4-substituted aminoalkylene piperazines |
| WO2009050734A2 (en) * | 2007-10-15 | 2009-04-23 | Elder Pharmaceuticals Ltd. | An industrially feasible process for the manufacture of bisquinoline derivatives by using substantially pure n-monosubstituted piperazines |
| CN101440063A (en) * | 2008-12-19 | 2009-05-27 | 重庆康乐制药有限公司 | Preparation of piperaquini phosphatis |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402815A (en) * | 2014-09-15 | 2015-03-11 | 桂林南药股份有限公司 | Control method of piperaquine phosphate impurity |
| CN104402815B (en) * | 2014-09-15 | 2017-04-19 | 桂林南药股份有限公司 | Control method of piperaquine phosphate impurity |
| CN109970639A (en) * | 2018-11-23 | 2019-07-05 | 重庆康乐制药有限公司 | The method of piperaquine intermediate is synthesized in a kind of continuous current micro-reactor |
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