FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
An industrially feasible process for the manufacture of Bisquinoline derivatives by using
substantially pure N-monosubstituted piperazines
2. APPLICANT (S)
(a) NAME : ELDER PHARMACEUTICALS LTD.
(b) NATIONALITY : INDIAN
(c) ADDRESS : Elder House, Plot No. C/9, Dalia Indl. Estate,
Off. New Link Road, Andheri (W),
Mumbai-400 058, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it is to be performed
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DESCRIPTION:
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 piperaquine and hence 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, l,3-Bis-[4-(7'-chloro-quinoline-4') piperazine-1]propane of Formula I have been reported. Piperaquine is an anti malarial drug that was first synthesized in the 1960s (US Pat. No. 3,173,918).
(I)
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However Piperaquine and piperaquine phosphate was extensively used in China and Indonesia as prophylaxis and treatment during the next 20 years.

(II)

(III)

A no. 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, 1, pp. 75-87), revealing that it is a highly lipid - soluble drug with a large volume of distribution at steady state / bioavailibility, 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 - 213°C [J. Chromatography B. Analyt. Technol. Biomed. Life Sci. (2003), 791, 93-101] Piperaquine phosphate is a white to pale yellow crystalline solid, soluble 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. 3,173,918 discloses the piperaquine and its non-toxic acid addition salt. Various processes for the preparation of piperaquine is exemplified in the example I, VIII and XVII in US. Pat. No 3,173,918. 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-l'-piperazinyl-quinoline (Formula II) and 1,3-dibromopropane in
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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-l'-piperazinyl-quinoline as one of the impurity.
Intermediate compound of Formula II, 7-chloro-4-l'-piperazinyl-quinoline, which is used to prepare piperaquine is described in US Pat. No. 3,331,843. It is prepared by the condensation of 4,7-dichloroquinoline with anhydrous piperazine in the presence of phenol. The condensed product is worked up by giving aqueous acid and aqueous alkaline treatment and extracting the reaction mass by using solvents such as ether and benzene to isolate the compound of formula II. 7-chloro-4-l'-piperazinyl-quinoline obtained by the above process is recrystallised from cyclohexane. Also dihydrobromide, dihydrochloride hydrate and monomaleic acid salts of the compound of Formula II are disclosed and the patent is silence about dimer impurity of Formula III formed in the reaction. (J. of Medicinal chemistry; 1971, 14, 283-286) describes preparation of 7-chloro-4-1 '-piperazinyl-quinoline by carrying out the reaction by condensing 4,7-dichloroquinoline with piperazine in ethoxyethanol. The reaction uses 10M of piperazine. It also describes preparation of compound of Formula III by reacting 4,7-dichloroquinoline with amine in phenol. The compound is active but toxic in nature.
(J. Med Chem 1998, 41, 4360-4364) prepared 7-chloro-4-l'-piperazinyl-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-l '-piperazinyl-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-l'-piperazinyl-quinoline by condensing 4,7-dichloroquinoline with piperazine in one or more alcohol and isolating 7-chloro-4-l'-piperazinyl-quinoline by cooling to about 7 to 15°C, means selective precipitation and filtering the mass to obtain 7-chloro-4-l'-piperazinyl-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 Ci 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 crystallization was not feasible for larger scale batches.
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7-chloro-4-l'-piperazinyl-quinoline is one of the key intermediate and dimer impurity is one of the major impurity formed during the preparation of 7-chloro-4-1'-piperazinyl-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-l'-piperazinyl-quinoline of Formula II either in free base or in its 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-l'-
piperazinyl-quinoline and its 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-l'-piperazinyl-quinoline
or its salt.
SUMMARY OF THE INVENTION
The present invention describes the process to prepare 7-chloro-4-l '-piperazinyl-quinoline of formula II and its acid salt, particularly its acetate and phosphate 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, 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-4-1 '-piperazinyl-quinoline base in water immiscible solvent; c) converting 7-chloro-4-l '-piperazinyl-quinoline to its acid salt particularly acetate and phosphate 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-l '-piperazinyl-quinoline salt thus formed is optionally isolated as acid salt such as 7-chloro-4-l'-piperazinyl-quinoline acetate or 7-chloro-4-l '-piperazinyl-quinoline phosphate 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-l '-piperazinyl-quinoline or its 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-l '-piperazinyl-quinoline free from dimer impurity.
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The present invention also provides method of preparation and isolation of 7-chloro-4-l'-piperazinyl-quinoline acetate and 7-chloro-4-l'-piperazinyl-quinoline phosphate.
DETAILED DESCRIPTION OF THE INVENTION:
Thus the present invention describes 7-chloro-4-l'-piperazinyl-quinoline of formula II and its acid salt, particularly its acetate and phosphate 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-l'-piperazinyl-quinoline and its salt without isolation, with 1,3-dibromopropane or l-bromo-3 - chloropropane in presence of conventional base. In one aspect a process for preparation of 7-chloro-4-l'-piperazinyl-quinoline and its acetate and phosphate 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, phosphoric acid. pH adjustment results in respective water soluble salt formation of 7-chloro-4-l'-piperazinyl-quinoline. Preferably acetic acid and phosphoric 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-l'-piperazinyl-quinoline is optionally isolated as its 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-l '-piperazinyl-quinoline acetate is used to prepare substantially pure piperaquine and its acid salt, free from dimer impurity.
In another preferred embodiment 7-chloro-4-l '-piperazinyl-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-l'-piperazinyl-quinoline is carried out by using any conventional base. Preferably
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bases used in the reaction are sodium hydroxide, sodium carbonate, liquid ammonia.
In another preferred embodiment 7-chloro-4-l '-piperazinyl-quinoline acetate and 7-chloro-4-l '-piperazinyl-quinoline phosphate is isolated as formed in the reaction. Isolation is carried out by distilling out solution of 7-chloro-4-l'-piperazinyl-quinoline acetate and 7-chloro-4-l'-piperazinyl-quinoline phosphate 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-l '-piperazinyl-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-l '-piperazinyl-quinoline with 1,3- dibromopropane in polar or non-polar solvent or mixture there of, with 1,3- dibromopropane 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 solvent 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 30-100°C, most preferably at 80-85°C.
Piperaquine formed in the reaction is free from dimer impurity of formula III 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 tetraphosphate 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 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, phosphoric acid. pH adjustment results in respective water soluble salt formation of 7-chloro-4-l'-piperazinyl-quinoline.
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Preferably acetic acid and phosphoric 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-4-1 '-piperazinyl-quinoline is optionally converted to its free base form or as its acid salt without isolation, is reacted with 1,3-dibromopropane or 1-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.
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 room temperature and filtered. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer separated out and mixed with distilled water and 4-4.5 pHwas adjusted 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 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-l '-piperazinyl-quinoline acetate, m.p. 249-252°C (decomposition) and HPLC purity 99% 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, 9.8 gm of 4,7-dichloroquinoline, and reaction mixture was heated to reflux. The reaction mass was cooled to room temperature and filtered. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer separated out and mixed with distilled water and 2-2.5 pH was adjusted 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 room temperature for 6 hrs. Solid (15.8 gm) obtained was characterized as 7-chloro-4-l'-piperazinyl-quinoline hydrochloride, m.p.280-282°C (decomposition) and HPLC purity 95.66%) with dimer impurity 3.85%).
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EXAMPLE 3:
In a reaction vessel charged 140 ml isopropyl alcohol, 25.8gm 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 room temperature and filtered. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer separated out and mixed with distilled water and 1.5 - 2.0 pH was adjusted with 85% orthophosphoric 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 with acetonitrile and white solid obtained was isolated and dried under vacuum at room temperature for 3 hrs. Solid (17 gm) obtained was characterized as 7-chloro-4-l'-piperazinyl-quinoline phosphate.
EXAMPLE 4:
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. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer separated out and mixed with distilled water and 4-4.5 pH was adjusted 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-l'-piperazinyl-quinoline free from dimer impurity. Distilled out dichloromethane and 7-chloro-4-l'-piperazinyl-quinoline solid obtained. Solid obtained was characterized as 7-chloro-4-l '-piperazinyl-quinoline, m.p.l 14-117 °C and HPLC purity 98.56 % with dimer impurity nil. Yield : 82.2 - 86.3 %
EXAMPLE 5:
In a reaction vessel charged 200 gm 7-chloro-4-l'-piperazinyl-quinoline isolated by following EXAMPLE 4. Charged 1000 ml N,N-dimethylformamide, 97.75 gm triethyl amine, 80.74 gm 1,3-dibromopropane and the reaction was heated. Cool reaction to room temperature and filter the mass and wet solid is purified & dried. 125 - 135 gm solid obtained.
EXAMPLE 6 :
Piperaquine base (235 gm) formed in the reaction was treated with 85% ortho phosphoric acid (187.5 gm) in aqueous medium at 5 -10°C. Stirred for (2 hrs) at 10°C and filtered and dried to obtain piperaquine tetraphosphate.
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EXAMPLE 7 :
Piperaquine base (235 gm) formed in the reaction was treated with 85% ortho
phosphoric acid (187.5 gm) in toluene at 5 -10°C. Stirred for
(2 hrs) at 10°C and filtered and dried to obtain piperaquine tetraphosphate.
EXAMPLE 8 :
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. Water and dichloromethane was charged to the residue and mass was stirred. Dichloromethane layer separated out and mixed with distilled water and 4-4.5 pH was adjusted 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-l'-piperazinyl-quinoline free from dimer impurity. Distilled out dichloromethane ,charged 1000 ml N,N-dimethylformamide, 112 gm triethyl amine, 91.8 gm 1,3-dibromopropane and the reaction was heated. Cool reaction to room temperature and filter the mass and wet solid is purified & dried. 180gm solid obtained HPLC Purity :99 %
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7. ABSTRACT OF THE INVENTION:
A process for the preparation of substantially pure 7-chloro-4-r-piperazinyl-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-4-1' -piperazinyl-quinoline.