FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Method for industrial production of piperaquine, salt and hydrate thereof
2. APPLICANT
(a) NAME: IPCA LABORATORIES LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner
in which it is to be performed
Granted
19-2-2008

Field of invention
The present invention relates to a cost effective industrial method for production of piperaquine tetraphosphate tetrahydrate, an anti-malarial drug molecule, in higher purity.
Background of the invention
Piperaquine (Formula I) is a bisquinoline anti-malarial drug that was first synthesized in the 1960s (refer: GB 991838 patent), and used extensively in China and Indochina as prophylaxis treatment during the next 20 years. A number of reports documented that it was at least as effective as, and better tolerated than, chloroquine against falciparum and vivax malaria. However with the emergence/development of piperaquine-resistant strains of Plasmodium falciparum and the development of the artemisinin derivatives, its use declined during the 1980s.

However, during the last decade, piperaquine has been rediscovered by Chinese scientists as one of the most suitable compound for the treatment of malaria in combination with artemisinin derivatives. The rationale for such artemisinin combination therapies (ACTs) was to provide an inexpensive, short-course treatment regimen with a high cure rate and good tolerability that would reduce transmission and protect against the development of parasite resistance.
Recent studies have confirmed the excellent clinical efficacy of piperaquine-DHA (Dihydro artemisinin) combinations (28-day cure rates >95%), and have demonstrated that the currently recommended regimens are not associated with significant cardio-toxicity or other adverse

effects, which otherwise a major drawback associated with most of the available antimalarial
treatments.
The pharmaco-kinetic properties of piperaquine have also been characterized recently, 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 an ACT.
GB 991838 patent discloses a number of synthetic strategies of which most of the intermediates are difficult to prepare and involves reduction methods using lithium aluminium hydride, which are not industrial friendly. The method, which appears to be most suitable, according to the '838 patent, is depicted below:

However this method on reproduction gave a major impurity {dimer- l,4-Bis[7-chloroquinoline-4-] -piperazine (Formula IV)} results from the reaction of 4,7-dichloroquinoline and piperazine. The dimer which is active yet toxic (refer Journal of Medicinal Chemistry, 1971, Vol. 14, 283-286) is formed in about 5 to 14 % depending upon the solvent and mole ratio of piperazine used in the reaction. An exact reproduction by following the method in the patent, the dimer impurity was carried forward to the piperaquine phosphate and contaminated the product in about 4 to 5%

invariably. A further problem of the process is that it uses an expensive reactant dibromopropane, in the second step, which escalates the cost of production.

Subsequent disclosures (Journal of Medicinal Chemistry, 1971, Vol. 14, 283-286; and Journal of Medicinal Chemistry, 1992, vol.35, No. 11, 2129-2134) have shown that the reaction of 4,7-dichloroquinoline and piperazine when carried out in 10 fold excess of piperazine in ethoxyethanol as solvent was able to reduce the dimer formation. In our hands, even with a use of 10 fold excess piperazine, the toxic dimer impurity is formed to an extent of 1 to 2% which again contaminates the final piperaquine. Additionally the process necessitates recovery and recycling of excess piperazine.
Yet another report in Indian Journal of Chemistry, Vol. 34B, 1995, 164-166 has shown that the intermediate of Formula II {7-chloro-4-piperazinyl quinoline} was prepared in 60 % yield which was an oil. In fact the intermediate of Formula II is solid and has a definite melting point in the range of 113-115 °C.
Thus there is a need for piperaquine phosphate free of the dimer impurity and an efficient process to provide piperaquine of high purity by using more cost effective reagents. Again, to the best of our knowledge no prior art discloses a method for preparation of piperquine tetraphosphate in its tetrahydrate form.

Objective of the invention
It is an objective of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art or to provide a useful alternative.
It is an objective of the present invention, in its preferred form, to provide piperaquine phosphate
free of toxic bis impurity (dimer) of Formula IV and an efficient process for preparing pure
piperaquine.
A further objective is to use cost-effective reagents in the preparation of piperquine and a process
specifically for obtaining piperaquine tetraphosphate in tetrahydrate form.
Summary of the invention
Accordingly, a cost effective production method for piperaquine is provided which comprises in a first step a) creating a first reaction mixture by mixing 4,7-dichloroquinoline with about 2.5 to 3.5 moles of piperazine in solvents selected from C1 to C4 alcohol at 45 °C to reflux temperature, to form an intermediate compound (II), which upon completion of reaction cooled to a temperature of 7 to 18 °C, and filtered to get compound of Formula II in a purity of at least 98.0% with a dimer content of 1 to 1.5%; and in a second step
b) creating a second reaction mixture by mixing the compound of Formula II with bromochloropropane in an aprotic solvent like dimethyl formamide in presence of a base substance, organic or inorganic base to form piperaquine of Formula I{ l,3-bis[l-(7-chloro-4-quinolyl)-4-piperazinyl]propane} in the reaction and isolating by cooling the reaction mass to a temperature of-10 to 30 °C, and filtering to get piperaquine free of dimer impurity as well as mono-substituted impurity of Formula V (3-chloro-l-[4-(7-chloroquinoline-4-)-pieparazine-l-] propane}.
In another aspect, the present invention provides a process for preparing piperaquine tetraphosphate tetrahydrate comprises treating piperaquine with phosphoric acid in water at ambient temperature to 60 °C and cooling the suspension to about 0 to 5 °C to isolate piperaquine tetraphophate in tetrahydrate crystalline form.

The present invention also provides an efficient purification method for removal of bis-impurity of Formula IV from the intermediate of Formula II comprises treating said intermediate in Ct to C4 alcohol solvents at ambient to reflux temperature, cooling the obtained suspension or solution to a temperature of 7 to 15 °C, filtering the suspension to remove the bis-impurity and isolating intermediate of Formula II from the alcohol solvent by evaporation or addition of an anti-solvent. Anti-solvent herein means a solvent wherein the compound is insoluble or sparingly soluble and upon addition to the solution allows the compound to precipitate from the solution. In yet another aspect the present invention relates to piperaquine and its tetraphosphate salt free of toxic dimer impurity of Formula IV.
Detailed description of the invention
Thus the present invention relates to piperaquine and its tetraphosphate salt free of toxic dimer impurity and also to provide a cost effective synthetic process for production of piperquine substantially free of impurities by suitable reaction conditions & effective purification methods. The process with the specific and preferred embodiments is detailed herein.
In the first step of the process, according to the present invention, 4,7-dichloroquinoline is reacted with piperazine in solvents selected from Q to C4 alcohols at about 45 °C to reflux temperature. In a preferred embodiment of the invention, on completion of reaction, the mass containing the intermediate of Formula II along with about 4 to 6 % dimer of Formula IV is cooled to a temperature of about 7 to 18 °C to allow selective precipitation of dimer as well as by-product piperazine hydrochloride and are removed by filtration to yield an intermediate (II) of purity at least 98.0% after evaporation of the alcohol solvent. The dimer content, if required, is further reduced to less than 0.5%, preferably less than 0.2% by further re-crystallization from C1 to C4 alcohols, preferably methanol.
In the above process step, the piperazine is preferably used in a molar amount ranging from about 2.5 to 3.5 moles relative to the starting 4,7-dichloroquinoline. The most preferable amount of piperazine is 3 moles relative to the starting 4,7-dichloroquinoline. The C1 to C4 alcohols are

preferably methanol, ethanol, n-propyl alcohol, isopropyl alcohol, butyl alcohol etc., but preferably methanol or ethanol is used in the process of the present invention. The volume of the solvent is critical for the success of effective purification of intermediate II, and is in the range of about 2 to 5 volumes relative to the starting 4,7-dichloroquinoline. Although higher volumes can be used in the reaction, but in such cases an additional purification from the above-mentioned solvents may be required.
The reaction is preferably carried out at reflux temperature of the solvent. The preferable cooling temperature for the selective precipitation of the dimer impurity is in the range of about 7 to 15 °C and the most preferable temperature is about 8 to 12 °C.
After filtration the mother liquor (filtrate) is preferably evaporated to remove the alcoholic solvent and extracted from water using a chlorinated solvent like dichloromethane. The compound II is isolated from extraction solvent by evaporation of solvent. It is performed to remove traces of piperazine, if present.
The present invention also provides a purification process for intermediate of Formula II, prepared by following any process, wherein the content of dimer is at least 2 %, preferably 5 % or more by suspending or dissolving the dimer contaminated compound II in C1 to C4 alcohols, preferably methanol or ethanol, at reflux temperature. The dimer is being removed by cooling the suspension to about 7 to 15 °C to effect selective precipitation of dimer impurity and is removed by filtration. The compound II is then isolated from the mother liquor (filtrate) by evaporating the purification solvent. The purification solvent, i.e., alcohol, is preferably used in about 2 to 5 volumes relative to the crude intermediate (II) and is preferably cooled to about 8 to 12 °C.
In the second step of the process, according to the present invention, Intermediate II is reacted with bromochloropropane in presence of a base substance in solvents selected from aprotic polar solvents like N,N-dimethylformamide. The problem associated with use of much cheaper reactant, bromochloropropane, in place of dibromopropane was the incomplete reaction of it with

intermediate II and gives a mono-substituted impurity (V) in the final product. The present invention provides an excellent process condition for achieving complete reaction of bromochloropropane with intermediate II. The base substance used in the present invention is selected from organic bases like tfiethyl amine or diisopropyl amine and the organic base is preferably used in excess relative to intermediate II used in the reaction. Preferably the organic base used is in molar amount ranging from about 1.6 to 3.5 moles relative to intermediate II.
The reaction of intermediate II with bromochlorpropane is carried out at a temperature of about 75 to 100 °C, preferably at 85 to 90 °C for a period of about 30 to 50 hours. The solvent used is preferably dimethyl formamide and preferably used in 2 to 4 volume/weight of starting intermediate II.
On completion of reaction the piperaquine formed in the reaction is isolated by cooling the reaction mass to about -10 to 30 °C to precipitate piperaquine and the product obtained after filtration is free of dimer impurity of Formula IV and monosubstituted impurity of Formula V, which may be further purified to get piperaquine of at least 99.5 to 99.9% with an isolated yield of 72 to 69% yield.
The present invention provides a process for preparation of piperaquine tetraphosphate in tetrahydrate form that comprises combining piperaquine with orthophosphoric acid in an aqueous medium. The aqueous suspension formed is maintained under stirring for a period of 2 to 3 hours and then cooled to isolate piperaquine tetraphosphate in tetrahydrate form. The aqueous solvents are water or its mixture with mater miscible polar solvents like methanol, ethanol, isopropyl alcohol, acetonitrile, tetrahydrofuran, dimethylformamide etc. The preferable solvent for salt formation and crystallization is water. The salt formation is preferably carried out at ambient temperature.
The piperquine tetraphosphate tetrahydrate shows water content of 6 to 8 % and purity of about 99.5% or more by HPLC analysis using a standard. The yield of piperaquine tetraphosphate from

piperaquine base is nearly 95 % and the overall yield starting from 4.7-dichloroquine is in the range of 56 to 62%.
The following non-limiting specific examples presented to illustrate the best mode of carrying out the process of the present invention.
Example 1.: 7-chloro-4-piperazinyl quinoline
In a reaction vessel, 4,7-dichloroquinoline (250 gm, 1.2626 moles), piperazine (326 gm, 3.79 moles) and methanol (1250 ml) were taken and the mixture is heated to reflux with agitation. The mass was maintained at reflux for about 8 hours and cooled to 10 °C. The precipitate was filtered off and the filtrate was evaporated to remove methanol completely. The residue was taken in water and extracted with dichloromethane. The extract is then evaporated to remove dichloromethane, the residue slurried in hexane and filtered to yield 7-chloro-4-piperazinyl quinoline 290 gms (dry) (yield 92%, Purity 98%). Melting point: 112-114 °C. Example 2: l,3-bis[l-(7-chloro-4-quinolyl)-4-piperazinyl]propane - (Piperaquine) In a reaction vessel, PPQ1 (250 gm, 1.0093 moles), bromochloropropane (87.4 gm, 0.55 moles), triethyl amine (204.3 gm, 2.0188 moles) and dimethylformamide (625 ml) were taken and the mixture is heated to about 90 °C with agitation. The mass was maintained at a temperature of 85 to 90 °C for about 40 hours and then cooled to 10 °C. The precipitate was filtered under suction and the residue was taken in chloroform and washed with water. The chloroform solution was evaporated to remove solvent and the residue obtained was further slurry washed with ethanol to yield 189 gms l,3-bis[l-(7-chloro-4-quinolyl)-4-piperazinyl]propane (yield 92%, purity 99.0%). Melting point: 198 -200 °C.
Example 3: Piperquine tetraphosphate tetrahydrate
In a reaction vessel, piperaquine (10 kg, 0.0187 kg moles), and water (100 L) were taken and 9.53 Kg orthophosphoric acid (35%) was added slowly with agitation. The mass was maintained under stirring for 3 hours and filtered. The crystals of piperquine tetraphosphate tetrahydrate was dried to give 17.2 kg (yield 92%, purity: 99.8%). Melting point: 198 -200 °C.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

We claim,
1. A process for preparation of piperaquine or its salts of formula I comprising the steps of:

a) providing intermediate of formula II by reacting 4,7-dichloroquinoline with piperazine characterized in that the reaction is carried out in one or more alcohol solvent(s);
b) isolating 7-chloro-4-piperazinyl quinoline (Formula II) from said alcohol by cooling to about 7 to 15°C and filtering out selectively the dimer impurity to obtain a purity of at least 98% for 7-chloro-4-piperazinyl quinoline;
c) reacting said 7-chloro-4-piperazinyl quinoline with l-bromo-3-chloropropane in presence of a base substance in an aprotic solvent to form piperaquine; and
d) precipitating said piperaquine substantially free of both dimer impurity of Formula IV and monochloro substituted impurity of Formula V by cooling said step c) reaction mass to about -10 to 30 °C.

2. The process as claimed in 1, wherein the amount of piperazine is 2.0 to 3.5 moles relative to 4,7- dichloroquinoline.
3. The process as claimed in 1, wherein the step a) is carried out at a temperature ranging from 45 °C to reflux temperature of said alcohol(s) to form 7-chloro-4-piperazinyl quinoline
4. The process as claimed in 1 to 3, wherein the alcohol is methanol, ethanol or isopropyl alcohol.
5. The process as claimed in claim 1 , wherein step c) is carried out at a temperature ranging from 50 to 100°C to form piperaquine.
6. The process as claimed in claim 1 or 5, wherein said base substance is selected from triethylamine or diisopropylamine.
7. The process as claimed in claim 1 or 6, wherein said base is used in molar amounts ranging from 1.6 to 3.5 relative to the 7-chloro-4-piperazinyl quinoline.
8. The process as claimed in any one of the preceding claim, wherein said aprotic solvent in step (b) is N, N-dimethylformamide.
9. The process as claimed in claim 1 further comprising the step of converting piperaquine into piperaquine tetraphosphate tetrahydrate by combining piperaquine with orthophosphoric acid in aqueous solvent medium to obtain the piperaquine tetraphosphate in tetrahydrate form.
10. The process as claimed in claim 9, wherein said aqueous solvent(s) is selected from water or its mixture with water miscible solvents.

11. The process for preparation of piperaquine and its tetraphosphate tetrahydrate as substantially described herein with reference to the examples 1 to 3.
Dated this 19th day of September 2005
Dr. P. Aruna Sree Agent for the Applicant