WO2009050734A2 - An industrially feasible process for the manufacture of bisquinoline derivatives by using substantially pure n-monosubstituted piperazines - Google Patents

An industrially feasible process for the manufacture of bisquinoline derivatives by using substantially pure n-monosubstituted piperazines Download PDF

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WO2009050734A2
WO2009050734A2 PCT/IN2008/000643 IN2008000643W WO2009050734A2 WO 2009050734 A2 WO2009050734 A2 WO 2009050734A2 IN 2008000643 W IN2008000643 W IN 2008000643W WO 2009050734 A2 WO2009050734 A2 WO 2009050734A2
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chloro
quinoline
piperazin
acid salt
formula
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PCT/IN2008/000643
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French (fr)
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WO2009050734A9 (en
WO2009050734A3 (en
Inventor
Rajiv Sakhardande
Manmohan Nimbalkar
Subarao Patil
Santosh Bhalekar
Rajendra Patil
Rohidas Mhaske
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Elder Pharmaceuticals Ltd.
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Priority to EP08839611A priority Critical patent/EP2212310A4/en
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Publication of WO2009050734A3 publication Critical patent/WO2009050734A3/en
Publication of WO2009050734A9 publication Critical patent/WO2009050734A9/en

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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

Definitions

  • the present invention relates to the preparation of substantially pure intermediate N-monosubstituted piperazines free from dimer impurity of Bisquinoline derivatives, particularly it relates to the preparation of substantially pure piperaquine and its salt.
  • Piperaquine is an antimalarial drug that was first synthesized in the 1960s (US Pat. No. 3173918).
  • Piperaquine is available as a free base and also as its water insoluble tetraphosphate and mono phosphate salt.
  • Piperaquine base is a pale white to yellow crystalline solid with a melting point of 212 — 213 0 C
  • Piperaquine phosphate is a white to pale yellow crystalline solid, insoluble in water, slightly bitter, sensitive to light and has a melting point 246-252°C (B. Med. Sci. Thesis, Crawley (WA), University of Western Australia, 2002).
  • US Pat. No. 3173918 discloses the piperaquine and its non-toxic acid addition salt.
  • Various processes for the preparation of piperaquine are exemplified in the example I, VIII and XVII in US. Pat. No 3173918.
  • Example I describes condensation of 4,7-dichloroquinoline and 1,3-bis-l'- piperazinylpropane in phenol at 115-120°C.
  • Example VIII describes condensation of 7-chloro-4-(piperazin-l-yl) quinoline (Formula II) and 1,3-dibromopropane in Methyl ethyl ketone. It is mentioned in the same example that compound of Formula II is prepared by the condensation of 4,7-dichloroquinoline with piperazine.
  • Example XVII describes condensation of l-(l-7'-chloro-4'-quinolyl-4- piperazinyl)-3-l'-piperazinyl propane with 4,7-dichloroquinoline in phenol.
  • 7-chloro-4-(piperazin-l-yl) quinoline is one of the key intermediate during the. preparation of piperaquine and 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.
  • a further object of the invention is to provide a process to prepare 7-chloro-4- (piperazin-1-yl) quinoline and its organic acid salt free from dimer impurity.
  • a further object of the invention is to provide one pot process to prepare piperaquine and its acid salt without isolating 7-chloro-4-(piperazin-l-yl) quinoline or its salt.
  • the present invention describes the process to prepare 7-chloro-4-(piperazin-l-yl) quinoline of formula II and its organic acid salt, such as acetate, formate, oxalate, succinate, fumarate, tartarate, mesylate, particularly its acetate and succinate salt substantially free from dimer impurity of formula III, includes a) reacting 4,7 - dichloroquinoline with 1 to 3 mole of piperazine in presence of conventional base particularly potassium carbonate in solvents selected from polar protic, polar aprotic or non polar solvents such as methanol, ethanol, Isopropyl alcohol, N 5 N- dimethylformamide, dichloromethane, toluene; b) working up the reaction by filtering and optionally distilling out the solvent and treating the mass with water and water immiscible solvents such as dichloromethane, toluene, and extracting 7- chloro-4-(piperazm-l-yl) quinoline base in
  • a further aspect of the invention includes one pot process for the preparation of piperaquine and its salt by reacting substantially pure.7-chloro-4-(piperazin-l-yl) quinoline or its organic salt formed in the reaction without isolation, with 1,3- dibromopropane or l-bromo-3-chloropropane in presence of conventional base.
  • a further aspect of the invention includes process for the preparation of pure piperaquine and its acid salt, by using pure 7-chloro-4-(piperazin-l-yl) quinoline free from dimer impurity.
  • the present invention also provides method of preparation and isolation of pure 7- chloro-4-(piperazin-l-yl) quinoline acetate and 7-chloro-4-(piperazin-l-yl) quinoline succinate.
  • the present invention describes 7-chloro-4-(piperazin-l-yl) quinoline of formula II and its organic acid salts, such as acetate, formate, oxalate, succinate, fumarate, tartarate, mesylate, particularly its acetate and succinate salt substantially free from dimer impurity and hence describes the preparation of substantially pure piperaquine and its acid salt. It also describes one pot process for the preparation of piperaquine and its salt by reacting substantially pure 7-chloro-4-(piperazin-l- yl) quinoline and its salt without isolation, with 1,3-dibromopropane or 1-bromo- 3-chloropropane in presence of conventional base.
  • a process for preparation of 7-chloro-4-(piperazin-l-yl) quinoline and its acetate and succinate salt thereof is provided by reacting 4,7— dichloroquinoline with 1 to 3 mole of piperazine in presence of conventional base in solvents selected from polar protic, polar aprotic or non polar solvent such as methanol, ethanol, isopropyl alcohol, N, N-dimethylformamide, dichloromethane, toluene at 35°C to reflux temperature of solvents for about 20 -30 hrs.
  • Conventional bases can be potassium carbonate, sodium carbonate, sodium bicarbonate, triethyl amine, diisopropyl amine and used in the mole ratio of 1 to 2 with respect to 4,7-dichloroquinoline.
  • base used is potassium carbonate and molar proportion used is 1 mole with respect to 4,7-dichloroquinoline. After completion of reaction, which was monitored by HPLC, reaction was cooled to room temperature and filtered.
  • solvent is distilled off or is treated with water and mass is converted to two immiscible layers and respective layers are separated or reaction mass in water is treated with water immiscible solvent such as dichloromethane, toluene, ether, hexane, and organic and aqueous layer is separated. Separated organic layer is washed with water. pH of organic layer is adjusted by using acid solution. Acid used to adjust pH can be acetic acid, succinic acid, formic acid, oxalic acid, tartaric acid, methane sulfonic acid, fumaric acid. pH adjustment results in respective water soluble salt formation of 7-chloro-4-(piperazin-l-yl) quinoline.
  • acetic acid and succinic acid is used to adjust pH.
  • Acidic reaction mass is treated with water and hence results in immiscible reaction mass.
  • Immiscible reaction mass is separated and water insoluble dimer impurity formed in the reaction mass gets extracted in organic layer.
  • Water soluble salt of 7-chloro-4- (piperazin-1-yl) quinoline is optionally isolated as its organic acid salt or insitu can be converted to its free base by reacting it with conventional base.
  • isolated 7-chloro-4-(piperazin-l-yl) quinoline acetate or 7-chloro-4-(piperazin-l-yl) quinoline succinate is used to prepare substantially pure piperaquine and its acid salt, free from dimer impurity.
  • 7-chloro-4-(piperazin-l-yl) quinoline acetate formed is insitu converted to its free base and used to prepare pure piperaquine and its acid salt, free from dimer impurity.
  • Free base formation of 7-chloro-4- (piperazin-1-yl) quinoline is carried out by using any .conventional base.
  • bases used in the reaction are sodium hydroxide, sodium carbonate, liquid ammonia.
  • 7-chloro-4-(piperazin-l-yl) quinoline acetate and 7-chloro-4-(piperazin-l-yl) quinoline succinate is isolated as formed in the reaction. Isolation is carried out by distilling out solution of 7-chloro-4- (piperazin-1-yl) quinoline acetate and 7-chloro-4-(piperazin-l-yl) quinoline succinate in suitable, solvent, preferably water and crystallizing salt from suitable solvent such as acetonitrile, hexane, cyclohexane, toluene. Most preferably acetonitrile is used as a suitable crystallizing solvent.
  • Substantially pure 7-chloro-4-(piperazin-l-yl) quinoline formed in the invention is converted to its pure piperaquine and its acid salt, free from dimer impurity by using any conventional process or by the invented process. Most preferably conversion is carried out by reacting substantially pure 7-chloro-4-(piperazin-l- yl) quinoline with 1,3-dibromopropane in polar or non-polar solvent or mixture thereof, in presence of suitable base.
  • Reaction can be carried out in solvents such as water, N, N-dimethylformamide, methyl ethyl ketone, toluene or mixture of solvents in presence of base such as triethyl amine, diisopropyl amine, sodium carbonate, potassium carbonate.
  • solvent used in the reaction is water, N, N-dimethylformamide
  • base used is potassium carbonate, triethyl amine. Reaction is carried out at 30-100 0 C, most preferably at 80-85 0 C.
  • Piperaquine formed in the reaction is free from dimer ' impurity of formula III and is converted to its acid salt by reacting piperaquine base with respective acid such as acetic acid, phosphoric acid, hydrochloric acid, preferably phosphoric acid.
  • Piperaquine is converted to its piperaquine letraphosphate salt by reacting piperaquine with ortho phosphoric acid in suitable solvent.
  • piperaquine and its salt is isolated in one pot process which involves reacting 4,7-dichloroquinoline with 1 to 3 mole of piperazine in presence of conventional base in solvents selected from polar protic, polar aprotic or non polar solvent such as methanol, ethanol, isopropyl alcohol, N,N-dimethylformamide, dichloromethane, toluene at 35°C to reflux temperature of solvents for about 20 -30 hrs.
  • Conventional bases can be, potassium carbonate, sodium carbonate, sodium bicarbonate, triethyl amine, diisopropyl amine and used in the mole ratio of 1 to 2 with respect to 4,7— dichloroquinoline.
  • base used is potassium carbonate and molar proportion used is 1 mole with respect to 4,7-dichloroquinoline.
  • solvent is distilled off or is treated with water and mass is converted to two immiscible layers and respective layers are separated or reaction mass in water is treated with water immiscible solvent such as dichloromethane, toluene, ether, hexane, and organic and aqueous layer is separated. Separated organic layer is washed with water. pH of organic layer is adjusted by using acid solution. Acid used to adjust pH can be acetic acid, succinic acid, formic acid, oxalic acid, tartaric acid, methane sulfonic acid, fumaric acid. pH adjustment results in respective water soluble salt formation of 7-chloro-4-(piperazin-l-yl) quinoline.
  • acetic acid and succinic acid is used to adjust pH.
  • Acidic reaction mass is treated with water and hence results in immiscible reaction mass.
  • Immiscible reaction mass is separated and water insoluble dimer impurity formed in the reaction mass gets extracted in organic layer.
  • Water soluble salt of 7-chloro-4- (piperazin-1-yl) quinoline is optionally converted to its free base form or as its acid salt without isolation, is reacted with 1,3-dibromopropane or l-bromo-3- chloropropane in presence of conventional base as such or in suitable solvent such as N, N-dimethylformamide and piperaquine formed in the reaction is insitu converted to its acid salt.
  • reaction vessel charged 140 ml isopropyl alcohol, 25.8 gm piperazine, 13.8 gm potassium carbonate, 19.8 gm of 4,7-dichloroquinoline, and reaction mixture was heated to reflux.
  • the reaction mass was cooled to 15 — 20°C and filtered and distilled the isopropyl alcohol.
  • Water and dichloromethane was charged to the residue and mass was stirred.
  • Dichloromethane layer separated out and mixed with distilled water and the pH was adjusted to 2.5 - 3.0 with 20% hydrochloric acid. Reaction mass was stirred and separated out organic layer and aqueous layer.
  • reaction mass was stirred and layer separated.
  • reaction vessel charged 140 ml isopropyl alcohol, 25.8 gm piperazine, 13.8 gm potassium carbonate, 19.8 gm of 4,7-dichloroquinoline, and reaction mixture was heated to reflux. Distilled out isopropyl alcohol under vacuum. Water and dichloromethane was charged to the residue and mass was stirred and layer separated. Charged distilled water to dichloromethane layer and the pH was adjusted to 1.5 - 2.0 with 85% orthophosphoric acid. Reaction mass was stirred, and separated out organic layer and aqueous layer. Distilled out aqueous layer under vacuum and white solid obtained was isolated and dried under vacuum at 65 - 70°C for 7 hrs.
  • Solid (17 gm) obtained was characterized as 7-chloro-4- (piperazin-1-yl) quinoline phosphate, m.p. 231-236°C and HPLC purity 93.27 % with dimer impurity 2.67%.
  • reaction vessel charged 140 ml isopropyl alcohol, 25.8 gm piperazine, 13.8 gm potassium carbonate, 19.8 gm of 4,7-dichloroquinoline and reaction mixture was heated to reflux. The reaction mass was distilled out. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer separated out and mixed with distilled water and the pH was adjusted to 4 - 4.5 with 50% Aq. acetic acid. Reaction mass was stirred and separated out organic layer and aqueous layer. Distilled out organic layer and solid obtained was characterized as dimer impurity. Distilled out aqueous layer under vacuum and solid obtained was stirred and isolated with acetonitrile for 30 min.
  • reaction vessel charged 140 ml isopropyl alcohol, 25.8 gm piperazine, 13.8 gm potassium carbonate, 19.8 gm of 4,7-dichloroquinoline and reaction mixture was heated to reflux and distilled isopropyl alcohol under vacuum. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer was separated. Methanol was charged to the reaction mass, heated to reflux & methanolic succinic acid solution was charged to reaction mass at reflux temperature. Reaction mass was cooled to 30°C and water was charged. Stirred the reaction mass and separated out aqueous and organic layer. Distilled out organic layer and solid obtained was characterized as dimer impurity.
  • reaction vessel charged 1400 ml isopropyl alcohol, 258 gm piperazine, 138 gm potassium carbonate, 198 gm of 4,7-dichloroquinoline and reaction mixture was heated to reflux.
  • the reaction mass was cooled to room temperature and filtered and distilled the isopropyl alcohol.
  • Water and dichloromethane was charged to the residue and mass was stirred.
  • Dichloromethane layer separated out and mixed with distilled water and the pH was adjusted to 4-4.5 with 50% Aq. acetic acid.
  • Reaction mass was stirred and separated out organic layer and aqueous layer. Distilled out organic layer and solid obtained was characterized as dimer impurity.
  • reaction vessel charged 200 gm 7-chloro-4-(piperazin-l-yl) quinoline isolated by following EXAMPLE 3. Charged 1000 ml N,N-dimethylformamide, 97.75 gm triethyl amine, 93.46 gm 1,3-dibromopropane and the reaction was heated. Reaction was cooled to room temperature and filtered the mass and wet solid was purified & dried to obtain 125 - 135 gm of solid as piperaquine base. Purity : 98.92%
  • Piperaquine base (235 gm) formed as per EXAMPLE 4 was treated with 85% ortho phosphoric acid (187.5 gm) in aqueous medium at 5 -10 0 C. Stirred for 2 hrs at 10°C, filtered and dried to obtain piperaquine tetraphosphate tetrahydrate. Purity : 99.59%
  • reaction vessel charged 1400 ml isopropyl alcohol, 258 gm piperazine, 138 gm potassium carbonate, 198 gm of 4,7-dichloroquinoline and reaction mixture was heated to reflux; The reaction mass was cooled to 15 - 20 0 C and filtered and distilled the isopropyl alcohol. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer was separated out and mixed with distilled water and the pH was adjusted to 4-4.5 with 50% Aq. acetic acid. Reaction mass was stirred and separated out organic layer and aqueous layer. Distilled out organic layer and solid obtained was characterized as dimer impurity.

Abstract

A process for the preparation of substantially pure 7-chloro-4-(ρiρerazin-1-yl) quinoline of formula II free from dimer impurity of formula III and process for the preparation of substantially pure piperaquine and its acid salt by using pure 7- chloro-4-(piperazin-1-yl) quinoline.

Description

TITLE:
An industrially feasible process for the manufacture of Bisquinoline derivatives by using substantially pure N-monosubstituted piperazines
FIELD OF THE INVENTION:
The present invention relates to the preparation of substantially pure intermediate N-monosubstituted piperazines free from dimer impurity of Bisquinoline derivatives, particularly it relates to the preparation of substantially pure piperaquine and its salt.
BACKGROUND OF THE INVENTION:
Malaria has been one of the most significant public health problems for centuries. It affects many tropical and subtropical regions of the world. It is established that 120 million cases occur worldwide each year, causing over one "million deaths. The problem has been compounded by the emergence of strains of P. falciparum resistant to virtually all anti-malarial agents. Resistance to chloroquine has now spread to almost all areas where malaria is endemic. Chloroquine resistant strains are typically cross-resistant to all drugs of relative chemical structure, and therefore the need for finding new molecules with novel modes of action is urgent. In an effort to discover active compounds against the chloroquine resistant malaria, several bisquinolyl piperazines such as piperaquine, Quinoline, 4, 4'-(l,3- propanediyldi-4,1 -piper azinediyl) bis [7-chloro- of Formula I have been reported. Piperaquine is an antimalarial drug that was first synthesized in the 1960s (US Pat. No. 3173918).
However Piperaquine and piperaquine phosphate was extensively used in China and Indonesia as prophylaxis and treatment during the next 20 years.
Figure imgf000003_0001
(I)
Figure imgf000003_0002
( H ) ( Ml )
A number of Chinese research groups documented that it was at least as effective as, and better tolerated than, chloroquine against P. falciparum and vivax malaria, but no pharmacokinetic characterization was undertaken. With the development of piperaquine resistant strains of P. falciparum and emergence of the artemisinin derivatives, its used declined during the 1980s, Drugs, (2005), 65, 1, pp. 75-87. However, during the next decades, piperaquine was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with artemisinin derivatives. The rationale for artemisinin combination therapy was to provide an inexpensive, short course treatment regime with a high cure rate and good tolerability that would reduce transmission and protect against the development of parasite resistance. The pharmacokinetic properties of piperaquine have been characterized (Drugs, (2005), 65, I5 pp. 75-87), revealing that it is a highly lipid-soluble drug with a large volume of distribution at steady state / bioavailability, long elimination half- life and a clearance that is markedly higher in children than in adults. The tolerability, efficacy, pharmaco-kinetic profile and low cost of piperaquine make it a promising partner drug for use as part of artemisinin combination therapy. Piperaquine is available as a free base and also as its water insoluble tetraphosphate and mono phosphate salt. Piperaquine base is a pale white to yellow crystalline solid with a melting point of 212 — 2130C [J. Chromatography B. Analyt. Technol. Biomed. Life Sci. (2003), 791, 93-101] Piperaquine phosphate is a white to pale yellow crystalline solid, insoluble in water, slightly bitter, sensitive to light and has a melting point 246-252°C (B. Med. Sci. Thesis, Crawley (WA), University of Western Australia, 2002). US Pat. No. 3173918 discloses the piperaquine and its non-toxic acid addition salt. Various processes for the preparation of piperaquine are exemplified in the example I, VIII and XVII in US. Pat. No 3173918.
Example I describes condensation of 4,7-dichloroquinoline and 1,3-bis-l'- piperazinylpropane in phenol at 115-120°C. Example VIII describes condensation of 7-chloro-4-(piperazin-l-yl) quinoline (Formula II) and 1,3-dibromopropane in Methyl ethyl ketone. It is mentioned in the same example that compound of Formula II is prepared by the condensation of 4,7-dichloroquinoline with piperazine. Example XVII describes condensation of l-(l-7'-chloro-4'-quinolyl-4- piperazinyl)-3-l'-piperazinyl propane with 4,7-dichloroquinoline in phenol. After condensation, the reaction is worked up as described and isolated by chromatographic separation. However by following the process as described in Example VIII at our end it was found that piperaquine was contaminated with toxic dimer impurity of (Formula III). (J. of Medicinal chemistry; 1971, 14, 283- 286). Dimer impurity, which is carry forwarded in piperaquine, was formed during the preparation of 7-chloro-4-(piperazin-l-yl) quinoline as one of the impurity. Intermediate compound of Formula II, 7-chloro-4-(piperazin-l-yl) quinoline, which is used to prepare piperaquine is described in US Pat. No. 3331843. It is prepared by the condensation of 4,7-dichloroquinoline with anhydrous piperazine in the presence of phenol. 7-Chloro-4-(piperazin-l-yl) quinoline obtained by the above process is recrystallized from cyclohexane. Also dihydrobromide, dihydrochloride hydrate and monomaleic acid salts of the compound of Formula II are disclosed and the patent is silent about dimer impurity of Formula III formed in the reaction.
(J. of Medicinal chemistry; 1971, 14, 283-286) describes preparation of 7-chloro- 4-(piperazin-l-yl) quinoline by carrying out the reaction by condensing 4,7- dichloroquinoline with piperazine in ethoxyethanol. The reaction uses 1 OM of piperazine. It also describes preparation of compound of Formula III, which is active but toxic in nature.
(J. Med Chem 1998, 41, 4360-4364) prepared 7-chloro-4-(piperazin-l-yl) quinoline by carrying out the reaction by condensing 4,7-dichloroquinoline with piperazine in ethoxyethanol and the reaction is worked up in aqueous alkaline solution and the mass is extracted in mixture of ethyl acetate, diethyl ether and dichloromethane and no method is disclosed to remove the dimer impurity formed in the reaction.
US 7220856 describes preparation of 7-chloro-4-(piperazin-l-yi) quinoline in ethanol and excess of piperazine and there is no teaching about the formation and removal of dimer impurity formed in the reaction.
Indian Application 639/MUM/2005 describes synthesis of 7-chloro-4-(piperazin- 1-yl) quinoline by condensing 4,7-dichloroquinoline with piperazine in one or more alcohol and isolating 7-chloro-4-(piperazin-l-yl) quinoline by cooling to about 7 to 150C, means selective precipitation and filtering the mass to obtain 7- chloro-4-(piperazin-l-yl) quinoline of at least 98% purity with a dimer impurity content of 1 to 1.5% and if needed reducing the dimer impurity to less than 0.5% by further recrystallisation from C1 to C4 alcohols. At our end when we reproduced the process, it was necessary to carry out the recrystallisation to remove dimer impurity as selective single crystallization was not feasible for larger scale batches.
7-chloro-4-(piperazin-l-yl) quinoline is one of the key intermediate during the. preparation of piperaquine and 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.
Hence there is a need to develop a process for the preparation of piperaquine and its acid salt and hence further to prepare substantially pure 7-chloro-4~(piperazin-
1-yl) quinoline of Formula II either in free base or in its organic acid salt form.
OBJECTIVE OF THE INVENTION
It is an object of the present invention to prepare pure piperaquine and its acid salt, free from dimer impurity.
A further object of the invention is to provide a process to prepare 7-chloro-4- (piperazin-1-yl) quinoline and its organic acid salt free from dimer impurity. A further object of the invention is to provide one pot process to prepare piperaquine and its acid salt without isolating 7-chloro-4-(piperazin-l-yl) quinoline or its salt.
SUMMARY OF THE INVENTION
The present invention describes the process to prepare 7-chloro-4-(piperazin-l-yl) quinoline of formula II and its organic acid salt, such as acetate, formate, oxalate, succinate, fumarate, tartarate, mesylate, particularly its acetate and succinate salt substantially free from dimer impurity of formula III, includes a) reacting 4,7 - dichloroquinoline with 1 to 3 mole of piperazine in presence of conventional base particularly potassium carbonate in solvents selected from polar protic, polar aprotic or non polar solvents such as methanol, ethanol, Isopropyl alcohol, N5N- dimethylformamide, dichloromethane, toluene; b) working up the reaction by filtering and optionally distilling out the solvent and treating the mass with water and water immiscible solvents such as dichloromethane, toluene, and extracting 7- chloro-4-(piperazm-l-yl) quinoline base in water immiscible solvent; c) converting 7-chloro-4-(piperazin-l-yl) quinoline to its organic acid salt, particularly acetate and succinate salt by adjusting pH and treating the mass with water followed by separating solvent and aqueous layer and isolating dimer impurity from the reaction mass in water immiscible solvent; and d) 7-chloro-4- (piperazin-1-yl) quinoline salt thus formed is optionally isolated as acid salt such as 7-chloro-4-(piperazin-l-yl) quinoline acetate or 7-chloro-4-(piperazin-l-yl) quinoline succinate and converted to its free base by treating it with conventional base.
A further aspect of the invention includes one pot process for the preparation of piperaquine and its salt by reacting substantially pure.7-chloro-4-(piperazin-l-yl) quinoline or its organic salt formed in the reaction without isolation, with 1,3- dibromopropane or l-bromo-3-chloropropane in presence of conventional base.
A further aspect of the invention includes process for the preparation of pure piperaquine and its acid salt, by using pure 7-chloro-4-(piperazin-l-yl) quinoline free from dimer impurity.
The present invention also provides method of preparation and isolation of pure 7- chloro-4-(piperazin-l-yl) quinoline acetate and 7-chloro-4-(piperazin-l-yl) quinoline succinate.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention describes 7-chloro-4-(piperazin-l-yl) quinoline of formula II and its organic acid salts, such as acetate, formate, oxalate, succinate, fumarate, tartarate, mesylate, particularly its acetate and succinate salt substantially free from dimer impurity and hence describes the preparation of substantially pure piperaquine and its acid salt. It also describes one pot process for the preparation of piperaquine and its salt by reacting substantially pure 7-chloro-4-(piperazin-l- yl) quinoline and its salt without isolation, with 1,3-dibromopropane or 1-bromo- 3-chloropropane in presence of conventional base.
In one aspect a process for preparation of 7-chloro-4-(piperazin-l-yl) quinoline and its acetate and succinate salt thereof is provided by reacting 4,7— dichloroquinoline with 1 to 3 mole of piperazine in presence of conventional base in solvents selected from polar protic, polar aprotic or non polar solvent such as methanol, ethanol, isopropyl alcohol, N, N-dimethylformamide, dichloromethane, toluene at 35°C to reflux temperature of solvents for about 20 -30 hrs. Conventional bases can be potassium carbonate, sodium carbonate, sodium bicarbonate, triethyl amine, diisopropyl amine and used in the mole ratio of 1 to 2 with respect to 4,7-dichloroquinoline.
In a preferred embodiment of the invention base used is potassium carbonate and molar proportion used is 1 mole with respect to 4,7-dichloroquinoline. After completion of reaction, which was monitored by HPLC, reaction was cooled to room temperature and filtered.
Optionally solvent is distilled off or is treated with water and mass is converted to two immiscible layers and respective layers are separated or reaction mass in water is treated with water immiscible solvent such as dichloromethane, toluene, ether, hexane, and organic and aqueous layer is separated. Separated organic layer is washed with water. pH of organic layer is adjusted by using acid solution. Acid used to adjust pH can be acetic acid, succinic acid, formic acid, oxalic acid, tartaric acid, methane sulfonic acid, fumaric acid. pH adjustment results in respective water soluble salt formation of 7-chloro-4-(piperazin-l-yl) quinoline. Preferably acetic acid and succinic acid is used to adjust pH. Acidic reaction mass is treated with water and hence results in immiscible reaction mass. Immiscible reaction mass is separated and water insoluble dimer impurity formed in the reaction mass gets extracted in organic layer. Water soluble salt of 7-chloro-4- (piperazin-1-yl) quinoline is optionally isolated as its organic acid salt or insitu can be converted to its free base by reacting it with conventional base. In a preferred embodiment isolated 7-chloro-4-(piperazin-l-yl) quinoline acetate or 7-chloro-4-(piperazin-l-yl) quinoline succinate is used to prepare substantially pure piperaquine and its acid salt, free from dimer impurity. In another preferred embodiment 7-chloro-4-(piperazin-l-yl) quinoline acetate formed is insitu converted to its free base and used to prepare pure piperaquine and its acid salt, free from dimer impurity. Free base formation of 7-chloro-4- (piperazin-1-yl) quinoline is carried out by using any .conventional base. Preferably bases used in the reaction are sodium hydroxide, sodium carbonate, liquid ammonia.
In another preferred embodiment 7-chloro-4-(piperazin-l-yl) quinoline acetate and 7-chloro-4-(piperazin-l-yl) quinoline succinate is isolated as formed in the reaction. Isolation is carried out by distilling out solution of 7-chloro-4- (piperazin-1-yl) quinoline acetate and 7-chloro-4-(piperazin-l-yl) quinoline succinate in suitable, solvent, preferably water and crystallizing salt from suitable solvent such as acetonitrile, hexane, cyclohexane, toluene. Most preferably acetonitrile is used as a suitable crystallizing solvent.
Substantially pure 7-chloro-4-(piperazin-l-yl) quinoline formed in the invention is converted to its pure piperaquine and its acid salt, free from dimer impurity by using any conventional process or by the invented process. Most preferably conversion is carried out by reacting substantially pure 7-chloro-4-(piperazin-l- yl) quinoline with 1,3-dibromopropane in polar or non-polar solvent or mixture thereof, in presence of suitable base. Reaction can be carried out in solvents such as water, N, N-dimethylformamide, methyl ethyl ketone, toluene or mixture of solvents in presence of base such as triethyl amine, diisopropyl amine, sodium carbonate, potassium carbonate. Preferably solvent used in the reaction is water, N, N-dimethylformamide, and base used is potassium carbonate, triethyl amine. Reaction is carried out at 30-1000C, most preferably at 80-850C. Piperaquine formed in the reaction is free from dimer' impurity of formula III and is converted to its acid salt by reacting piperaquine base with respective acid such as acetic acid, phosphoric acid, hydrochloric acid, preferably phosphoric acid. Piperaquine is converted to its piperaquine letraphosphate salt by reacting piperaquine with ortho phosphoric acid in suitable solvent.
In another aspect of the invention piperaquine and its salt is isolated in one pot process which involves reacting 4,7-dichloroquinoline with 1 to 3 mole of piperazine in presence of conventional base in solvents selected from polar protic, polar aprotic or non polar solvent such as methanol, ethanol, isopropyl alcohol, N,N-dimethylformamide, dichloromethane, toluene at 35°C to reflux temperature of solvents for about 20 -30 hrs. Conventional bases can be, potassium carbonate, sodium carbonate, sodium bicarbonate, triethyl amine, diisopropyl amine and used in the mole ratio of 1 to 2 with respect to 4,7— dichloroquinoline. In a preferred embodiment of the invention base used is potassium carbonate and molar proportion used is 1 mole with respect to 4,7-dichloroquinoline. After completion of reaction, which was monitored by HPLC, reaction was , cooled to room temperature and filtered.
Optionally solvent is distilled off or is treated with water and mass is converted to two immiscible layers and respective layers are separated or reaction mass in water is treated with water immiscible solvent such as dichloromethane, toluene, ether, hexane, and organic and aqueous layer is separated. Separated organic layer is washed with water. pH of organic layer is adjusted by using acid solution. Acid used to adjust pH can be acetic acid, succinic acid, formic acid, oxalic acid, tartaric acid, methane sulfonic acid, fumaric acid. pH adjustment results in respective water soluble salt formation of 7-chloro-4-(piperazin-l-yl) quinoline. Preferably acetic acid and succinic acid is used to adjust pH. Acidic reaction mass is treated with water and hence results in immiscible reaction mass. Immiscible reaction mass is separated and water insoluble dimer impurity formed in the reaction mass gets extracted in organic layer. Water soluble salt of 7-chloro-4- (piperazin-1-yl) quinoline is optionally converted to its free base form or as its acid salt without isolation, is reacted with 1,3-dibromopropane or l-bromo-3- chloropropane in presence of conventional base as such or in suitable solvent such as N, N-dimethylformamide and piperaquine formed in the reaction is insitu converted to its acid salt.
The following examples illustrate the particular aspects of the invention. However this illustration does not limit the scope of the invention.
REFERENCE EXAMPLE 1:
In a reaction vessel charged 140 ml isopropyl alcohol, 25.8 gm piperazine, 13.8 gm potassium carbonate, 19.8 gm of 4,7-dichloroquinoline, and reaction mixture was heated to reflux. The reaction mass was cooled to 15 — 20°C and filtered and distilled the isopropyl alcohol. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer separated out and mixed with distilled water and the pH was adjusted to 2.5 - 3.0 with 20% hydrochloric acid. Reaction mass was stirred and separated out organic layer and aqueous layer. Distilled out aqueous layer under vacuum and solid obtained was stirred with acetonitrile and white solid obtained was isolated and dried under vacuum at 40 - 45°C for 1.5 hrs. Solid (15.8 gm) obtained was characterized as 7-chloro-4- (piperazin-1-yl) quinoline hydrochloride, m.p. 280-2820C (decomposition) and HPLC purity 95.66% with dimer impurity 3.85%.
REFERENCE EXAMPLE 2:
In a reaction vessel charged 140 ml isopropyl alcohol, 25.8 gm piperazine, 13.8 gm potassium carbonate, 19.8 gm of 4,7-dichloroquinoline and reaction mixture was heated to reflux. The reaction mass was cooled to 15 - 20°C and filtered and distilled isopropyl alcohol under vacuum. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer separated. Water was charged to the dichloromethane layer and mass was stirred and the pH was adjusted to 2.0 - 2.5 with 50% Aq. Sulfuric acid. Reaction mass was stirred and layer separated. Distilled out aqueous layer under vacuum & stripped out it with acetonitrile and charged isopropyl alcohol, stirred & filtered. White solid obtained was isolated and dried under vacuum at 40 — 45°C for 3 hrs. Solid obtained (33.89 gm) was characterized as 7-chloro-4-(piperazin-l-yl) quinoline sulfate, m.p. 195-2110C (decomposition) and HPLC purity 95.47 % with dimer impurity 3.14 %.
REFERENCE EXAMPLE 3:
In a reaction vessel charged 140 ml isopropyl alcohol, 25.8 gm piperazine, 13.8 gm potassium carbonate, 19.8 gm of 4,7-dichloroquinoline, and reaction mixture was heated to reflux. Distilled out isopropyl alcohol under vacuum. Water and dichloromethane was charged to the residue and mass was stirred and layer separated. Charged distilled water to dichloromethane layer and the pH was adjusted to 1.5 - 2.0 with 85% orthophosphoric acid. Reaction mass was stirred, and separated out organic layer and aqueous layer. Distilled out aqueous layer under vacuum and white solid obtained was isolated and dried under vacuum at 65 - 70°C for 7 hrs. Solid (17 gm) obtained was characterized as 7-chloro-4- (piperazin-1-yl) quinoline phosphate, m.p. 231-236°C and HPLC purity 93.27 % with dimer impurity 2.67%.
EXAMPLE 1:
In a reaction vessel charged 140 ml isopropyl alcohol, 25.8 gm piperazine, 13.8 gm potassium carbonate, 19.8 gm of 4,7-dichloroquinoline and reaction mixture was heated to reflux. The reaction mass was distilled out. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer separated out and mixed with distilled water and the pH was adjusted to 4 - 4.5 with 50% Aq. acetic acid. Reaction mass was stirred and separated out organic layer and aqueous layer. Distilled out organic layer and solid obtained was characterized as dimer impurity. Distilled out aqueous layer under vacuum and solid obtained was stirred and isolated with acetonitrile for 30 min. and white solid obtained was isolated and dried under vacuum at room temperature for 3 hrs. Solid obtained was characterized as 7-chloro-4-(piperazin- 1-yl) quinoline acetate, m.p. 233-237°C (decomposition) and HPLC purity 96 % with dimer impurity nil. Yield : 62.2 - 66.5 % EXAMPLE 2:
In a reaction vessel charged 140 ml isopropyl alcohol, 25.8 gm piperazine, 13.8 gm potassium carbonate, 19.8 gm of 4,7-dichloroquinoline and reaction mixture was heated to reflux and distilled isopropyl alcohol under vacuum. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer was separated. Methanol was charged to the reaction mass, heated to reflux & methanolic succinic acid solution was charged to reaction mass at reflux temperature. Reaction mass was cooled to 30°C and water was charged. Stirred the reaction mass and separated out aqueous and organic layer. Distilled out organic layer and solid obtained was characterized as dimer impurity. Distilled out aqueous layer and white solid obtained was isolated and dried under vacuum at 50 - 60°C for 4 hrs. Solid obtained (19.3 gm) was characterized as 7-chloro-4-(piperazin-l-yl) quinoline succinate, m.p. 127-131°C and HPLC purity 99.56 % with dimer impurity nil.
EXAMPLE 3:
In a reaction vessel charged 1400 ml isopropyl alcohol, 258 gm piperazine, 138 gm potassium carbonate, 198 gm of 4,7-dichloroquinoline and reaction mixture was heated to reflux. The reaction mass was cooled to room temperature and filtered and distilled the isopropyl alcohol. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer separated out and mixed with distilled water and the pH was adjusted to 4-4.5 with 50% Aq. acetic acid. Reaction mass was stirred and separated out organic layer and aqueous layer. Distilled out organic layer and solid obtained was characterized as dimer impurity. Aqueous layer was basified with liquor ammonia, and stirred, and product was extracted in dichloromethane as 7-chloro-4-(piperazin-l-yl) quinoline free from dimer impurity. Distilled out dichloromethane and isolated in hexane and the solid obtained was characterized as 7-chloro-4-(piperazin-l-yl) quinoline, m.p.114-117 °C and HPLC purity 98.56 % with dimer impurity nil. Yield : 82.2 - 86.3 % EXAMPLE 4:
In a reaction vessel charged 200 gm 7-chloro-4-(piperazin-l-yl) quinoline isolated by following EXAMPLE 3. Charged 1000 ml N,N-dimethylformamide, 97.75 gm triethyl amine, 93.46 gm 1,3-dibromopropane and the reaction was heated. Reaction was cooled to room temperature and filtered the mass and wet solid was purified & dried to obtain 125 - 135 gm of solid as piperaquine base. Purity : 98.92%
EXAMPLE 5:
Piperaquine base (235 gm) formed as per EXAMPLE 4 was treated with 85% ortho phosphoric acid (187.5 gm) in aqueous medium at 5 -100C. Stirred for 2 hrs at 10°C, filtered and dried to obtain piperaquine tetraphosphate tetrahydrate. Purity : 99.59%
EXAMPLE 6:
Piperaquine base (235 gm) formed as per EXAMPLE 4 was treated with 85% ortho phosphoric acid (187.5 gm) in toluene at 5 -100C. Stirred for 2 hrs at 100C, filtered and dried to obtain piperaquine tetraphosphate. Purity: 99.07%; Yield = 366.6 gm
EXAMPLE 7:
In a reaction vessel, charged 1400 ml isopropyl alcohol, 258 gm piperazine, 138 gm potassium carbonate, 198 gm of 4,7-dichloroquinoline and reaction mixture was heated to reflux; The reaction mass was cooled to 15 - 200C and filtered and distilled the isopropyl alcohol. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer was separated out and mixed with distilled water and the pH was adjusted to 4-4.5 with 50% Aq. acetic acid. Reaction mass was stirred and separated out organic layer and aqueous layer. Distilled out organic layer and solid obtained was characterized as dimer impurity. Aqueous layer was basified with liquor ammonia, and stirred, and product was extracted in dichloromethane as 7-chloro-4-(piperazin-l-yl) quinoline free from dimer impurity. Distilled out dichloromethane, charged 1000 ml N,N-dimethylformamide, 111 gm triethyl amine, 94.72 gm 1,3- dibromopropane and the reaction was heated. Reaction was cooled to room temperature and filtered the mass and wet solid was purified & dried to obtain 180 gm of solid piperaquine base. HPLC Purity : 99.21 %

Claims

We claim:
L. A process for the preparation of substantially pure 7-chloro-4-(piperazin- 1 -yl) quinoline of formula II comprising: (a) reacting 4,7-dichloroquinoline with piperazine in presence of suitable base in polar protic, polar aprotic or non polar solvent or mixture thereof; (b) converting impure 7-chloro-4-(piperazin- 1-yl) quinoline of formula II to its organic acid salt in suitable solvent; (c) removing dimer impurity of formula III from organic acid salt of 7-chloro-4- (piperazin-1-yl) quinoline of formula II; and (d) isolating substantially pure 7- chloro-4-(piperazin-l-yl) quinoline or 7-chloro-4-(piperazin-l-yl) quinoline organic acid salt.
Figure imgf000016_0001
( II ) ( HI )
2. A process for the preparation of Piperaquine and its acid salt of formula I comprising: reacting substantially pure 7-chloro-4-(piperazin-l-yl) quinoline as claimed in claim 1 in polar or non polar solvent or mixture thereof, with 1,3-dibromopropane or l-bromo-3-chloropropane in presence of suitable base and converting Piperaquine base as formed in the reaction to its acid salt.
Figure imgf000017_0001
(I)
3. Substantially pure 7-chloro-4-(piperazin-l-yl) quinoline of formula II, free from dimer impurity of formula III and its organic acid salt.
4. 7-chloro-4-(piperazin-l-yl) quinoline as claimed in any one of the preceding claim is its acetate and succinate salt.
5. The process as claimed in claim 1, wherein base is potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, or diisopropyl amine.
6. The process as claimed in claim 1, wherein polar protic solvents are methanol, ethanol, Isopropyl alcohol and polar aprotic solvents are "N ,N- dimethylformamide, dimethylsulfoxide and non polar solvents are dichloromethane, toluene.
7. The process as claimed in claim 2, polar solvents are methanol, ethanol, Isopropyl alcohol, methyl ethyl ketone, acetone, N,N-dimethylformamide, dimethylsulfoxide and non polar solvents are dichloromethane, toluene.
8. The process as claimed in claim 2, wherein base is potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, or diisopropyl amine.
9. A process for the preparation of Piperaquine and its acid salt of formula I comprising: (a) reacting 4,7-dichloroquinoline with piperazine in presence of suitable base in polar protic, polar aprotic or non polar solvent or mixture thereof; (b) converting impure 7-chloro-4-(piperazin-l-yl) quinoline of formula II to its organic acid salt in suitable solvent; (c) removing dimer impurity of formula III, from organic acid salt of 7-chloro-4-(piperazin-l-yl) quinoline of formula II; and (d) reacting substantially pure 7-chloro-4- (piperazin-1-yl) quinoline or 7-chloro-4-(piperazin-l-yl) quinoline organic acid salt with 1,3-dibromopropane or l-bromo-3-chloropropane in presence of conventional base.
10. The process as described herein with examples.
PCT/IN2008/000643 2007-10-15 2008-10-06 An industrially feasible process for the manufacture of bisquinoline derivatives by using substantially pure n-monosubstituted piperazines WO2009050734A2 (en)

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WO2011095885A1 (en) * 2010-02-08 2011-08-11 Matrix Laboratories Ltd. An improved process for the preparation of piperaquine
WO2012048894A1 (en) * 2010-10-14 2012-04-19 Julius-Maximilians-Universität Würzburg Hybrid compounds of 4- and 8-aminoquinolines for the prophylactic and therapeutic treatment of malaria and other parasitic diseases
WO2012168213A2 (en) 2011-06-06 2012-12-13 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Novel process for the synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline
CN103058926A (en) * 2012-12-14 2013-04-24 重庆康乐制药有限公司 Preparation method of 7-chlorine-4-(piperazineyl-1-yl) quinoline
CN105330601A (en) * 2015-11-03 2016-02-17 重庆康乐制药有限公司 Preparation method of piperaquine derivative
CN110606830A (en) * 2018-06-14 2019-12-24 珠海润都制药股份有限公司 Method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by applying piperazine

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Cited By (13)

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Publication number Priority date Publication date Assignee Title
WO2011095885A1 (en) * 2010-02-08 2011-08-11 Matrix Laboratories Ltd. An improved process for the preparation of piperaquine
WO2012048894A1 (en) * 2010-10-14 2012-04-19 Julius-Maximilians-Universität Würzburg Hybrid compounds of 4- and 8-aminoquinolines for the prophylactic and therapeutic treatment of malaria and other parasitic diseases
JP2014516065A (en) * 2011-06-06 2014-07-07 シグマ−タウ・インドゥストリエ・ファルマチェウチケ・リウニテ・ソシエタ・ペル・アチオニ Novel synthesis method of 7-chloro-4- (piperazin-1-yl) -quinoline
WO2012168213A3 (en) * 2011-06-06 2013-03-07 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Novel process for the synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline
CN103596927A (en) * 2011-06-06 2014-02-19 希格马托制药工业公司 Novel process for the synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline
WO2012168213A2 (en) 2011-06-06 2012-12-13 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Novel process for the synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline
US9206133B2 (en) 2011-06-06 2015-12-08 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Process for the synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline
EA024202B1 (en) * 2011-06-06 2016-08-31 Сигма-Тау Индустрие Фармасьютике Риуните С.П.А. Crystalline polymorphs b, c and d of 7-chloro-4-(piperazin-1-yl)quinoline and processes for preparation thereof
CN103058926A (en) * 2012-12-14 2013-04-24 重庆康乐制药有限公司 Preparation method of 7-chlorine-4-(piperazineyl-1-yl) quinoline
CN103058926B (en) * 2012-12-14 2014-12-10 重庆康乐制药有限公司 Preparation method of 7-chlorine-4-(piperazineyl-1-yl) quinoline
CN105330601A (en) * 2015-11-03 2016-02-17 重庆康乐制药有限公司 Preparation method of piperaquine derivative
CN110606830A (en) * 2018-06-14 2019-12-24 珠海润都制药股份有限公司 Method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by applying piperazine
CN110606830B (en) * 2018-06-14 2022-03-18 珠海润都制药股份有限公司 Method for producing piperaquine phosphate intermediate quinoline piperazine hydrochloride by applying piperazine

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