This application claims priority to Indian patent application no 3896/CHE/2010 filed on Dec 20, 2010 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to novel impurities of Piperaquine and process for the preparation thereof.

BACK GROUND OF THE INVENTION:

Piperaquine is an antimalarial drug that belongs to the bisquinoline class of chemical compounds. It is chemically known as 1, 3-bis [1-(7-chloro-4-quinolyl)-4'-piperazinyl] propane and is represented by:

US Pat. No. 3173918 discloses process for the preparation of Piperaquine and its non-toxic acid addition salts, wherein 4,7-dichloroquinoline is reacted with 1,3-bis-l'-piperazinylpropane in phenol at 115-120°C and the resultant mixture is poured into an aqueous base solution to obtain crude Piperaquine. The crude product is recrystallized from the mixture of dimethylformamide and water to get pure product as shown in scheme-l.

Indian Journal of Heterocyclic Chemistry Vol. 19, 2010, pp 215-220 discloses six impurities are formed during the process development of Piperaquine phosphate.
Since the impurity profile study of pharmaceutical substances is a crucial part of process development, because presence of trace impurities arising either during synthesis or storage may lead to markedly different toxicity than would be expected and make the drug inactive. Therefore it becomes necessary to identify impurities which are present or developed during the process development of Piperaquine.

There is a general rule that chemical purity of the active pharmaceutical ingredient (API) produced in the industrial scale is one of the critical parameters for its commercialization.

The American Food and Drug Administration (FDA) as well as European medicament control offices require, according to the Q7A ICH (International Conference on Harmonization) instruction, that API is free from impurities to the maximum possible extent. The reason is achieving maximum safety of using the drug in the clinical practice. National inspection and control offices usually require that the content of an individual impurity in an API should not

exceed the limit of 0.1%. All the substances (generally referred to as impurities) contained in an API over the limit of 0.1% should be isolated and characterized in accordance with the ICH recommendations.

The present invention discloses identification and synthesis of novel impurities formed during the process development of Piperaquine phosphate.

SUMMARY OF THE INVENTION:

One aspect of the present invention provides, piperaquine impurity 5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl} piperazin-1-yl) quinoline of formula-1.

Another aspect of the present invention provides, piperaquine impurity 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-quinolin-4-one of formula-2.
Yet another aspect of the present invention provides, a process for the preparation of compounds of formula 1 & 2 which comprising the steps of: a) reacting 5-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl] quinoline in the presence of a base and a catalyst in a solvent at reflux temperature, b) removing the solvent, and c) separating compounds of formula 1 & 2.

Yet another aspect of the present invention provides, piperaquine impurity 5-chloro-4-piperazin-1 -yl-quinoline of formula-3.

Yet another aspect of the present invention provides, a process for the preparation of compound of formula-3 which comprising the steps of: a) reacting 4,5-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature, b) removing the solvent, and c) isolating compound of formula-3.

Yet another aspect of the present invention provides, piperaquine impurity {1,3-bis[1-5-chloro-4-quinolyl]-4-piperazinyl} propane of formula-4.

Yet another aspect of the present invention provides, a process for the preparation of ^ compound of formula-4 which comprising the steps of: a) reacting 5-chloro-4-piperazin-1-yl

quinoline with 1,3-dibromopropane in the presence of a base in a solvent at reflux temperature, b) removing the solvent, and c) isolating compound of formula-4.

Yet another aspect of the present invention provides, piperaquine impurity 5-chloro-4-[4(3-chloro-propyl)-piperazin-1-yl]-quinoline of formula-5.

Yet another aspect of the present invention provides, a process for the preparation of compound of formula-5 which comprising the steps of: a) reacting 5-chloro-4-piperazin-1-yl quinoline with bromochloropropane in the presence of a base in a solvent, b) removing the solvent, and c) isolating compound of formula-5.

Yet another aspect of the present invention provides, piperaquine impurity 5-chloro-4-[4-(5-chloroquinolin-4-yl)piperazin-1 -yl]quinoline of formula-6.

Yet another aspect of the present invention provides, a process for the preparation of compound of formula-6 which comprising the steps of: a) reacting 4,7-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature, b) removing the solvent, and c) isolating compound of formula-6.

Yet another aspect of the present invention provides, piperaquine impurity 5-chloro-4-[4-(3-piperazin-1-yl-propyl)-piperazin-1-yl]-quinoline of formula-7.

Yet another aspect of the present invention provides, a process for the preparation of compound of formula-7 which comprising the steps of: a) reacting 1-chloro-3-(5-chloro-4-quinolyl-4-piperazinyl)propane with piperazine in a solvent at reflux temperature, b) removing the solvent, and c) isolating compound of formula-7.

Yet another aspect of the present invention provides, piperaquine impurity tris-piperazinyl quinoline of formula-8.

Further aspect of the present invention provides, a process for the preparation of compound of formula-8 which comprising the steps of: a) reacting 5-chloro-4-[4-(3-piperazin-1-yl)-propyl)-piperazin-1 -yl)-quinoline with 5-chloro-4-[4-(3-chloro-propyl)-piperzin-1 -yl]quinoline in the presence of a catalyst in a solvent at reflux temperature, b) removing the solvent, and c) isolating compound of formula-8.

According to the present invention compounds of formula-1 to 8 are characterized by 1H NMR.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention is related to eight novel impurities of piperaquine phosphate and process for the preparation thereof.

One embodiment of the present invention provides, piperaquine impurity 5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl} piperazin-1-yl) quinoline of formula-1.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-quinolin-4-one of formula-2.

Formula-2 Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula 1& 2 which comprising the steps of:

a) reacting 5-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl] quinoline in the presence of a base and a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) separating compounds of formula 1 & 2.
According to the present invention 5-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl] quinoline is refluxed in a ketone solvent in presence of a base and catalyst for about 12-16 hrs. Product is extracted into a chlorinated organic solvent and evaporated the solvent to get crude compounds of formula 1 & 2. This mixture is separated using known

methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-piperazin-1-yt-quinoline of formula-3.

Formula-3 Yet another embodiment of the present invention provides, a process for the

preparation of compound of formula-3 which comprising the steps of:

a) reacting 4,5-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-3.
According to the present invention 4, 5-dichloro quinoline is reacted with piperazine in an alcoholic solvent in presence of a catalyst at reflux temperature for about 8-12 hrs. Reaction mass is cooled to room temperature and inorganic salts are filtered. The filtrate is concentrated under reduced pressure to get compound of formula-3.

Yet another embodiment of the present invention provides, piperaquine impurity 1,3-bis[1-(5-chloro-4-quinolyl)-4-piperazinyl) propane of formula-4.
Formula-4 Yet another embodiment of the present invention provides, a process for the

preparation of compound of formula-4 which comprising the steps of:

a) reacting 5-chloro-4-piperazin-1-yl quinoline with 1,3-dibromo propane in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-4.

According to the present invention 5-chloro-4-piperazin-1-yl quinoline is reacted with 1, 3-

dibromopropane in the presence of a base in alcoholic solvent at reflux temperature for 38-

42 hrs. Reaction mass cooled to room temperature and filtered to get compound of formula-
4.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-

[4(3-chloro-propyl)-piperazin-1-yl]-quinoline of formula-5.
rormuia-o Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-5 which comprising the steps of:

a) reacting 5-chloro-4-piperazin-1-yl quinoline with bromochloropropane in the presence of a base in a solvent,

b) removing the solvent, and

c) isolating compound of formula-5.
According to the present invention 5-chloro-4-piperazin-1-yl quinoline is reacted with bromochloropropane in the presence of a base in dimethylformamide solvent at 55-60°C for 4-6hrs. Reaction mass cooled to room temperature and inorganic salts are filtered. Filtrated is diluted with water and product is extracted into chlorinated organic solvent, evaporated to get compound of formula-5.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-[4-(5-chloroquinolin-4-yl)piperazin-1-yl]quinolineof formula-6.
Formula-6 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-6 which comprising the steps of:

a) reacting 4,7-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-6.

According to the present invention 4,7-dichloro quinoline is reacted with piperazine in presence of catalyst in alcoholic solvent at reflux temperature for about 8-12 hrs. Reaction mass is cooled to room temperature, filtered the inorganic salts. Filtrate is diluted with water and product is extracted into chlorinated organic solvent and evaporated to get residue. The residue is dissolved in ether solvent and purified by preparative HPLC to get compound of formula-6.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-[4-(3-piperazin-1 -yl-propyl)-piperazin-1 -yll-quinoline of formula-7.
Formula-7 Yet another embodiment of the present invention provides, a process for the
preparation of compound of formula-7 which comprising the steps of:

a) reacting 1-chloro-3-(5-chloro-4-quinolyl-4-piperazinyl)propane with piperazine in

a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-7.

According to the present invention 1-chloro-3-(5-chloro-4-quinolyl-4-piperazinyl)propane is reacted with piperazine in alcoholic solvent at reflux temperature for about 3-7hrs and evaporated the solvent to get residue. The obtained residue is diluted with water and extracted into chlorinated solvent and evaporated to get crude compound of formula-7. The crude compound is purified using known methods like preparative

HPLC, column chromatography or recrystallisation, preferably preparative HPLC.
Yet another embodiment of the present invention provides, piperaquine impurity tris-piperazinyl quinoline impurity of formula-8.

Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-8 which comprising the steps of:

a) reacting 5-chloro-4-[4-(3-piperazin-1-yl)-propyl)-piperazin-1-yl)-quinoline with 5-chloro-4-[4-(3-chloro-propyl)-piperzin-1-yl]quinoline in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-8.

According to the present invention 5-chloro-4-[4-(3-piperazin-1-yl)-propyl)-piperazin-1-yl)-quinoline is reacted with 5-chloro-4-[4-(3-chloro-propyl)-piperzin-1-yl]quinoline in presence of a base and catalyst in alcoholic solvent at reflux temperature for about 3-7hrs, after the completion of the reaction solvent is evaporated to get residue. The residue is dissolved in ether solvent and purified by column chromatography to get compound of formula-8.

Yet another embodiment of the present invention provides, piperaquine impurity 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1, 4-dihydro-quinolin-4-ol of formula-9.

Yet another embodiment of the present invention provides, piperaquine impurity 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1 -yl]-propyl}-1 H-quinolin-4-one of fomnula-10.

Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula-9 & 10 which comprising the steps of:

a) reacting 7-chloro quinolin-4-ol with 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline in the presence of a base and a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) separating compounds of formula-9 & 10.

According to the present invention 7-chloro quinolin-4-ol with 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline is refluxed in a ketone solvent in presence of a base and catalyst for about 12-16 hrs. Product is extracted into a chlorinated organic solvent and evaporated the solvent to get crude compounds of formula 9 & 10. This mixture is separated using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1, 4-dihydro-quinolin-4-ol of formula-11.

Formula-11 Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-of formula-12.

Formula-12 Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1 -yl]-propyl}-1 H-quinolin-4-one of formula-13.

Formula-13 Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula-12 & 13 which comprising the steps of:

a) reacting 5-chloro quinolin-4-ol with 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline in the presence of a base and a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) separating compounds of formula-12 & 13.

According to the present invention 5-chloro quinolin-4-ol with 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline is refluxed in a ketone solvent in presence of a base and catalyst for about 12-16 hrs. Product is extracted into a chlorinated organic solvent and evaporated the solvent to get crude compounds of formula 12 & 13. This mixture is separated using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 7-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol of formula-14.

Formula-14 Yet another embodiment of the present invention provides, piperaquine impurity 7-Chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}1 H-quinolin-4-one of formula-15.

Formula-15

Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula-14 & 15 which comprising the steps of:

a) reacting 7-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline in the presence of a base and a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) separating compounds of formula-14 & 15.

According to the present invention 7-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline is refluxed in a ketone solvent in presence of a base and catalyst for about 12-16 hrs. Product is extracted into a chlorinated organic solvent and evaporated the solvent to get crude compounds of formula 14 & 15. This mixture is separated using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 7-chloro-4-piperazin-1-yl-quinoline 1-oxide of formula-16.

Yet another embodiment of the present invention provides, piperaquine impurity 4-(7-Chloro-quinolin-4-yl)-piperazin-1 -ol-anion of formula-17.

Yet another embodiment of the present invention provides, piperaquine impurity 4-(7-Chloro-1 -oxy-quinolin-4-yl)-piperazin-1 -ol-anion of formula-18.

Formula-18 Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula-16, 17 & 18 which comprises the steps of:

a) oxidizing 7-chloro-4-piperazin-1-yl-quinoline in a solvent in the presence of an oxidizing agent, and

b) separating the compounds of formula-16, 17 & 18.
According to present invention 5-chloro-4-piperazin-1-yl-quinoline is reacted in a mixture of chlorinated and alcoholic solvent with oxidizing agent for about 1-5 hrs. After the completion of reaction the reaction mixture was filtered. And the filtrate was washed with alcoholic solvent to get crude compound of formula-16, 17 & 18. The crude is separated using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.
Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-piperazin-1-yl-quinoline 1-oxide of formula-19.

Formula-19

Yet another embodiment of the present invention provides, piperaquine impurity 4-(5-chloro-quinolin-4-yl)-piperazin-1-ol-anion of formula-20.
Yet another embodiment of the present invention provides, piperaquine impurity 4-(5-Chloro-1 -oxy-quinolin-4-yl)-piperazin-1 -ol-anion of formula-21.

Formula-21 Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula-19, 20 and 21 which comprises the steps of:

a) oxidizing 5-chloro-4-piperazin-1-yl-quinoline in a solvent in the presence of an oxidizing agent, and,

b) separating the compounds of formula-19, 20 & 21.

According to present invention 5-chloro-4-piperazin-1-yl-quinoline is reacted in a mixture of chlorinated and alcoholic solvent with oxidizing agent for about 1-5 hrs. After the completion of reaction the reaction mixture was filtered. And the filtrate was washed with alcoholic solvent to get crude compound of formula-19, 2 0 & 21. The crude is separated using known

methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 3-[4-(5-chloroquinolin-4-yl)piperazin-1-yl]propan-1-ol of formula-22.

Formula-22 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-22 which comprises the steps of:

a) reacting 5-chloro-4-piperazin-1-yl quinoline with 1-bromo-3-propanol in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-22.

According to the present invention 5-chloro-4-piperazin-1-yl quinoline is reacted with 1-bromo-3-propanol in the presence of a base in ketone solvent at reflux temperature for about 4-8 hrs. Reaction mass cooled to room temperature and filtered to get compound of formula-22.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-[4-(3-ethoxy-propyl)-piperazin-1 -yl]-quinoline of formula-23.

Formula-23 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-23 which comprises the steps of:

a) reacting 5-chloro-4-[4-(3-chloropropyl) piperazin-1-yl]quinoline in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-23.

According to the present invention 5-chloro-4-[4-(3-chloropropyl) piperazin-1-yl] quinoline is refluxed in the presence of a base in alcoholic solvent at temperature for about 2-6 hrs. Reaction mass cooled to room temperature and distill off the solvent to get residue. And the

compound was extracted into chlorinated organic solvent, evaporated to get compound of
formula-23.

Yet another embodiment of the present invention provides, piperaquine impurity 4-(3-
bromopropoxy)-5-chloro-quinoline of formula-24.

Formula-24 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-24 which comprises the steps of:

a) reacting 5-chloro-quinolin-4-ol with 1, 3 dibromopropane in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-24.

According to the present invention 5-chloro-quinolin-4-ol is reacted with 1,3-dibromopropane is refluxed in the presence of a base in alcoholic solvent for about 38-42hrs.. Reaction mass cooled to room temperature and filtered to get compound of formula-24.

Yet another embodiment of the present invention provides, piperaquine impurity 4-(3-chloropropoxy)-5-chloro-quinoline of formula-25.

Formula-25 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-25 which comprises the steps of:

a) reacting 5-chloro-quinolin-4-ol with Bromochloropropane in the presence of a
base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-25.

According to the present invention 5-chloro-quinolin-4-ol is reacted with Bromochloropropane is refluxed in the presence of a base in alcoholic solvent for about 38-42hrs. Reaction mass cooled to room temperature and filtered to get the crude compound of

formula-25. The crude compound is purified using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-{[5-chloroquinolin-4-yl-oxy]propoxyl) auinoline of formula-26

Formula-26 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-26 which comprises the steps of:

a) reacting 5-chloro-quinolin-4-ol with 1, 3 di bromo propane in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-26.

According to the present invention 5-chloro-quinolin-4-ol is reacted with 1,3 di bromo propane is refluxed in the presence of a base in alcoholic solvent for about 38-42hrs.

Reaction mass cooled to room temperature and filtered to get the crude compound of formula-26. The crude compound is purified using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

According to the present invention alcoholic solvent is selected from the group comprising methanol, ethanol, isopropanol, butanol or isobutanol. Chlorinated organic solvent is selected from the group comprising dichloromethane, dichloroethane, chloroform, carbantetrachloride or chlorobenzene. Ether solvent is selected from the group comprising diethylether, diisopropylether or tetrahydrofuron. Ketone solvent is selected form the group comprising acetone, methylethylketone or methylisobutylketone.

According to the present invention the base employed in the reaction is organic base or inorganic base. The inorganic base is selected from the group comprising sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium oxide or magnesium hydroxide. The organic base selected from the group comprising triethylamine, diisopropylamine or pyridine.

According to the present invention the catalyst employed for the reaction is potassium iodide or sodium iodide.

According to the present invention the oxidizing agent used in the reaction is selected from the group comprising hydrogen peroxide, chromium trioxide, potassium permanganate, osmium tetroxide or silver oxide.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXPERIMENTAL SECTION:

Example-1: Preparation of (5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl}
piperazin-1-yl) quinoline (formula-1), 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-

piperazin-1-yl]-propyl}-1 H-quinolin-4-one (formula-2) and 5-chloro-1-{3-[4-(5-chloro-
quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-11).

To a mixture of 5-chloro quinolin-4-ol (5g, 0.027 mol), potassium carbonate (10g, 0.07 mol),
and potassium iodide (2.3g, 0.014mol) in acetone was added 5-chloro-4-[4-(3-chloro-propyl)-

piperazin-1-yl]quinoline (9g, 0.027mol) and heated the reaction mixture to reflux temperature
for about 14 hours. The reaction mixture was distilled under reduced pressure; the residue
obtained was diluted with water (100 ml) and extracted with dichloromethane (2X 50 ml).

The combined organic layer was washed with brine and dried over sodium sulphate The
combined organic layer was concentrated under reduced pressure to yield the oily crude.

The crude contains (5-chloro-4(4-{3-[5-chloroquioline-4-yl) oxy] propyl} piperazin-1-yl)
quinoline (formula-1), 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-
quinolin-4-one (formula-2) and 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-

propyl}-1,4-dihydro-quinolin-4-ol (formula-11) and this were purified by preparative

HPLC/column chromatography/recrystallisation.
1H-NMR(DMSO-d6. 300 MHz, ppm) values of formula-1:- 5 8-8.05 (CH, 1H), 8.03-8.05 CH,
1H), 7.41-7.48 (2CH, 2H), 8.16 (CH, 1H), 7.96 CH.1H), 6.85 (CH, 1H), 6.77 (CH, 1H), 8.73
(CH, 1H), 8.75 (CH, 1H), 3.27-3.38 (2CH2, 4H), 2.74-2.81 (2CH2, 4H), 2.74-2.81 (2CH2, 2H),
2.17-2.26 (CH2-2H), 4.32 (CH2-2H).
1H-NMR(DMSO-d6. 300 MHz, ppm) values of formula-2:- 5 8.05 (CH, 1H), 7.59 (CH, 1H),
7.41-7.44 (CH, 1H), 7.32-7.35 (CH.1H), 7.94 (CH.1H), 7.62 (CH, 1H), 6.87 (CH, 1H), 6.27

(CH, 1H), 8.74 (CH, 1H), 8.40 (CH, 1H), 3.30 (2CH2, 4H), 2.74 (2CH2, 4H), 2.48 (CH2, 2H), 2.05-2.10 (CH2, 2H), 4.24 (CH, 2H).

Example-2: Preparation of 5-chloro-4-piperazin-1-yl-quinoline (formula-3)
Mixture of 4,5-dichloroquinoline (15g, 0.075mol), potassium iodide (3.15g 0.018mol) and piperazine (18.92g, 0.22 mol) in isopropyl alcohol was refluxed for about 10 hours. The reaction mass was filtered, washed with isopropyl alcohol and distilled off the filtrate under vacuum below 45°C. The residue was diluted with dichloromethane and washed with brine. The combined organic layer was dried over sodium sulphate. The solvent was removed under reduced pressure to get the compound of formuJa-3.
1H-NMR(DMSO-d6. 300 MHz, ppm) :- 5 8.65(CH, 1H), 7.90 (CH, 1H), 7.58 (2CH, 2H), 7.05(CH, 1H), 3.31 (CH2, 2H), 3.06 (2CH2, 4H), 2.72 (CH2, 2H).
Example-3: Preparation of 1, 3-Bis [1-(5-chloro-4-quinolyl)-4'piperazinyl) propane

(formula-4)
Mixture of 5-chloro-4-piperazin-1-yl quinoline (15g, 0.06 mol), 1, 3 Dibromo propane (12.2g 0.06 mol) and triethyl amine (18.3g, 0.18 mol) in methanol was refluxed for 40 hours. The reaction mixture was cooled to room temperature and filtered. The solid obtained was washed with methanol and water to get the compound of formula-4. The 1H-NMR data complies with proposed structure of formula-4.
1H-NMR(DMSO-d6. 300 MHz, ppm) :- 5 8.81 (2CH, 2H), 8.19 (2CH, 2H), 7.88 (2CH, 2H), 7.77(2CH, 2H), 7.49 (2CH, 2H), 4.17(2CH2, 4H), 4.0 (2CH2, 4H), 3.83 (4CH2, 8H), 3.48 (2CH2, 4H), 2.54 (CH2, 4H).

Example-4: Preparation of 5-chloro-4-[4(3-chloro-propyl)-piperazin-1-yl]-quinoline (formula-5)

To a stirred mixture of 5-chloro-4-piperazin-1-yl-quinoline (20g, 0.08 mol), bromo chloro propane (32g, 0.2 mol) in dimethylformamide was added triethyl amine (3.3g, 0.032 mol), heated the reaction mixture to 60°C and stirred at the same temperature for about 5 hours The reaction mixture was cooled to room temperature and filtered the precipitated solid. The filtrate was concentrated under reduced pressure, the residue obtained was diluted with DM water (200 ml) and extracted with methylene dichloride (2X50 ml). The combined organic layers were dried over sodium sulphate. The solvent was removed under reduced pressure

to yield the oily compound of formula-5. Yield 22 g, 84.61 %. The 1H-NMR data complies

with proposed structure of formula-5.
1H-NMR(DMSO-d6. 300 MHz, ppm) :- 6 8.04 (CH, 1H), 7.40-7.44 (CH, 1H), 7.94 (CH, 1H),
6.83 (CH, 1H), 8.72 (CH, 1H), 3.24 (2CH2, 4H), 2.74 (2CH2, 4H), 3.65 (CH2, 2H), 1.97-2.14
(CH2, 2H), 2.63 (CH2, 2H).

Example-5: Preparation of 5-chloro-4-[4-(5-chloroquinolin-4-yl)piperazin-1-yl]quinoline (formula-6)

To a mixture of 4,7-dichloro quinoline (15g, 0.075mol), potassium iodide (3.15g, 0.018mol) and piperazine (18.92 g 0.22 mol) in isopropyl alcohol was refluxed for about 10 hours. The reaction mass was filtered, washed with isopropyl alcohol and distilled off the filtrate under vacuum below 45°C. The residue was diluted with dichloromethane and washed with brine. The combined organic layers were dried over sodium sulphate. The solvent was removed under reduced pressure, the residue was stirred with isopropyl ether and filtered. The filtrate was collected and concentrated under vacuum. The filtrate crude was purified by preparative HPLC/column chromatography to get the compound of formula-6. The 1H-NMR data complies with proposed structure of formula-6.
1H-NMR(DMSO-d6. 300 MHz, ppm):- 5 8.11 (2CH, 1H), 7.65 (2CH, 2H), 8.34 (2CH, 2H), 7.13 (2CH, 2H), 8.63 (2CH, 2H), 4.43 (4CH2, 8H).

Example-6: Preparation of 5-chloro-4-[4-(3-piperazin-1-yl-propyl)-piperazin-1-yl]-quinoline (formula-7)
Mixture of 1-chloro-3-(5-chloro-4-quinolyl-4-piperazinyl) propane (10g, 0.03mol), piperazine (8g, 0.042mol) in isopropyl alcohol was refluxed for about 5 hours. The reaction mixture was cooled to room temperature and distilled off isopropyl alcohol. The residue was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulphate. The solvent was removed under reduced pressure to get the title compound of formula-7. The crude was purified by preparative HPLC/column chromatography/recrystallisation. The 1H-NMR data complies with proposed structure of formula-7. 1H-NMR(DMSO-d6. 300 MHz. PPm):- 5 8.04 (CH, 1H), 7.40-7.44 (CH.1H), 7.95 (CH, 1H),
6.84 (CH, 1H), 8.71 (CH, 1H), 3.24-3.25 (2CH2, 4H), 2.74 (2CH2, 4H), 2.39-2.53 (2CH2, 4H),
2.39-2.53 (2CH2, 4H), 2.90-2.96 (CH2, 2H), 1.74-1.82 (CH2, 2H), 2.90-2.96 (CH2, 2H).

Example-7: Preparation of Tris -piperazinyl quinoline impurity (formula-8)
To the mixture of 5-chloro-4-[4-(3-piperazin-1-yl)-propyl)-piperazin-1-yl)-quinoline (8g, 0.021 mol), potassium iodide (1.8g, 0.01 mol) in isopropyl alcohol was added 5-chloro-4-[4-(3-chloro-propyl)-piperzin-1-yl]quinoline, the resulted reaction mixture was refluxed for about 5 hours. The reaction mixture was cooled to room temperature and distilled off isopropyl alcohol. The residue was diluted with isopropyl ether (80ml) and filtered to get the compound of formula-8. The crude was purified by column chromatography. The 1H-NMR data complies with proposed structure of formula-8.
1H-NMR(DMSO-dg. 300 MHz, ppm):- 5 8.04 (2CH, 2H), 7.40-7.44 (2CH, 2H), 7.93 (2CH, 2H), 6.84 (2CH, 2H), 8.72 (2CH, 2H), 3.27 (4CH2, 8H), 2.78 (2CH2, 4H), 2.78 (2CH2, 4H), 2.57 (2CH2, 4H), 1.95 (2CH2,4H), 3.01 (4CH2, 8H).

Example-8: Preparation of 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-9) and 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1H-quinolin-4-one (formula-10).
To a mixture of 7-chloro quinolin-4-ol (5g, 0.027 mol), potassium carbonate (10g, 0.07 mol), and potassium iodide (2.3g, 0.014 mol) in acetone was added 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl] quinoline (9g, 0.027 mol) and heated the reaction mixture to reflux temperature for about 14 hours. The reaction mixture was distilled under reduced pressure, the residue obtained was diluted with water (100 ml) and extracted with dichloromethane (2X 50 ml). The combined organic layer was washed with brine and dried over sodium sulphate. The combined organic layer was concentrated under reduced pressure to yield the oily crude. The crude contains 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-9) and 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1H-quinolin-4-one (formula-10) and this were purified by preparative HPLC/column chromatography/recrystallisation.

Example-9: Preparation of 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-12) and 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-quinolin-4-one (formula-13).

To a mixture of 5-chloro quinolin-4-ol (5 g,0.027 mol), potassium carbonate(10 g,0.07 mol), and potassium iodide(2.3g ,0.014 mol) in acetone was added 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline (9g, 0.027 mol) and heated the reaction mixture to reflux temperature for about 14 hours. The reaction mixture was distilled under reduced pressure,

the residue obtained was diluted with water (100 ml) and extracted with dichloromethane (2X 50 ml). The combined organic layer was washed with brine and dried over sodium sulphate The combined organic layer was concentrated under reduced pressure to yield the oily crude. The crude contains 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-12) and 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1H-quinolin-4-one (formula-13) and this were purified by preparative HPLC/column chromatography/recrystallisation.

Example-10: Preparation of 7-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-14) and 7-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-quinolin-4-one (formula-15)
To a mixture of 7-chloro quinolin-4-ol (5g, 0.027 mol), potassium carbonate (10g, 0.07 mol), and potassium iodide (2.3g, 0.014mol) in acetone was added 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline (9g, 0.027mol) and heated the reaction mixture to reflux temperature for about 14 hours. The reaction mixture was distilled under reduced pressure, the residue obtained was diluted with water (100 ml) and extracted with dichloromethane (2X 50 ml). The combined organic layer was washed with brine and dried over sodium sulphate. The combined organic layer was concentrated under reduced pressure to yield the oily crude. The crude contains 7-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1, 4-dihydro-quinolin-4-ol (formula-14) and 7-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-quinolin-4-one (formula-15) and this were purified by preparative HPLC/column chromatography/recrystallisation.

Example-11: Preparation of 7-chloro-4-piperazin-1-yl-quinoline-1-oxide (formula-16), 4-(7-chloro-quinolin-4-yl)-piperazin-1-ol-anion (formula-17) and 4-(7-Chloro-1-oxy-quinolin-4-yl)-piperazin-1-ol-anion (formula-18)
Mixture of 7-chloro-4-piperazin-1-yl-quinoline (10g, 0.04 mol), methylene dichloride and methanol was cooled to 5°C and hydrogen peroxide (2.53g, 0.0746 mol) was added to the solution and stirred for about 3 hours. The solid formed was filtered and washed with methanol.

The crude contains 7-chloro-4-piperazin-1-yl-quinoline 1-oxide (formula-16), 4-(7-Chloro-quinolin-4-yl)-piperazin-1-ol-anion (formula-17) and 4-(7-Chloro-1-oxy-quinolin-4-yl)-piperazin-1-ol-anion (formula-18) and this were purified by preparative HPLC/column chromatography/recrystallisation.

Example-12: 5-chloro-4-piperazin-1-yl-quinoline 1-oxide (formula-19), 4-(5-chloro-quinolin-4-yl)-piperazin-1-ol-anion (formula-20) and 4-(5-chloro-1-oxy-quinolin-4-yl)-piperazin-1 -ol-anion (formula-21)
Mixture of 5-chloro-4-piperazin-1-yl-quinoline (10g, 0.04mol) in methylene dichloride and methanol was cooled to 5°C and hydrogen peroxide (2.53g, 0.0746mol) was added to the solution and stirred for about 3 hours. The solid formed was filtered and washed with methanol. The crude contains 5-chloro-4-piperazin-1-yl-quinoline 1-oxide (formula-19), 4-(5-Chloro-quinolin-4-yl)-piperazin-1-ol-anion (formula-20) and 4-(5-Chloro-1-oxy-quinolin-4-yl)-piperazin-1-ol-anion (formula-21) and this were purified by preparative HPLC/column chromatography/recrystallisation.

Example-13: Preparation of 3-[4-(5-chloroquinolin-4-yl)piperazin-1-yl]propane-1-ol (formula-22)
Mixture of 5-chloro-4-piperazin-1-yl quinoline (10g, 0.04 mol), triethyl amine (4.9g, 0.04 mol), 1-bromo-3-propanol (5.6g, 0.04 mol) in acetonitrile was refluxed for about 6 hours. The reaction mixture was cooled to room temperature and then filtered. The solid thus obtained was washed with aqueous sodium bicarbonate and brine solution and dried to get the compound of formula-22. Yield 10.6 g 85.62 %.

Example-14: Preparation of 5-chloro-4-[4-(3-ethoxypropyl)piperazin-1-yl]quinoline (formula-23)

Mixture of 5-chloro-4-[4-(3-chloropropyl)piperazin-1-yl]quinoline (2g, 0.006mol) sodium hydroxide (0.36g, 0.009 mol) in ethanol was refluxed for about 4 hours. The reaction mixture was cooled to room temperature and distilled off ethanol. The residue was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulphate. The solvent was removed under reduced pressure to get compound of formula-23.

Example-15: Preparation of 4-(3-bromopropoxy)-5-chloroquinoline (formula-24)
Mixture of 5-chloro-quinolin-4-ol (15g, 0.08mol), 1,3 dibromo propane (16.2g, 0.05mol) and triethylamine (15.1g, 0.15 mol) in methanol was refluxed for about 40 hours. The reaction mixture was cooled to room temperature and filtered. The solid obtained was washed with methanol and water to get compound of formula-24.

Example-16: Preparation of 4-(3-chloropropoxy)-5-chloroquinoline (formula-25)
Mixture of 5-chloro-quinolin-4-ol (10g, 0.05 mol), bromo chloro propane (7.9g, 0.05 mol) and triethyl amine (15.1g, 0.15 mol) in methanol was refluxed for about 40 hours.

The reaction mixture was cooled to room temperature and filtered. The solid obtained was washed with methanol and water to get compound of formula-25. The crude was purified by preparative HPLC/column chromatography/recrystallisation.

Example-17: Preparation of 5-chloro-4-{[5-chloroquinolin-4-yl) oxy] propoxyl} quinoline (formula-26)
Mixture of 5-chloro-quinolin-4-ol (10g, 0.06mol), 1,3 Dibromo propane (12.2g, 0.06mol) and triethyl amine (18.3g, 0.18mol) in methanol was refluxed for about 40 hours. The reaction mixture was cooled to room temperature and filtered. The solid obtained was washed with methanol and water. The crude was purified by preparative HPLC/column chromatography/recrystallisation to get the compound of formula-26.

We Claim:

1. Piperaquine impurity

a. 5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl} piperazin-1-yl) quinoline
of formula-1,

Formula-1

b. 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl) -piperazin-1-yl]- propyl}-1H-quinolin-
4-one of formula-2,

Formula-2

c. 5-chloro-4-piperazin-1-yl-quinoline of formula-3,

Formula-3

d. {1, 3-bis [1-5-chloro-4-quinolyl]-4-piperazinyl} propane of formula-4,
formula--4

e. 5-chloro-4-[4(3-chloro-propyl)-piperazin-1-yl]-quinoline of formula-5,


Formula-5

f. 5-chloro-4-[4-(5-chloroquinolin-4-yl) piperazin-1- yl] quinoline of formula-6,

Formula-6

g. 5-chloro-4-[4-(3-piperazin-1-yl-propyl)-piperazin-1-yl]-quinoline of formula-7,
furmula-7
h. tris-piperazinyl quinoline of formula-8.

Formula-8

2. A process for the preparation of 5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl}
piperazin-1-yl) quinoline of formula-1 which comprising the steps of:

a) reacting 5-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl] quinoline in the presence of a base and a catalyst in a solvent,

b) removing the solvent, and

c) isolating 5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl} piperazin-1-yl) quinoline.

3. A process for the preparation of 5-chloro-1 -{3-[4-(5-chloro-quinolin-4-yl) -piperazin-1 -
yl]- propyl}-1 H-quinolin-4-one of formula-2 which comprising the steps of:

a) reacting 5-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-

piperazin-1-yl] quinoline in the presence of a base and a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl) -piperazin-1-yl]- propyl}-1H-quinolin-4-one.

4. A process for the preparation of 5-chloro-4-piperazin-1-yl-quinoline of formula-3
which comprising the steps of:

a) reacting 4,5-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating 5-chloro-4-piperazin-1-yl-quinoline.

5. A process for the preparation of {1,3-bis [1-5-chloro-4-quinolyl]-4-piperazinyl}
propane of formula-4 which comprising the steps of:

a) reacting 5-chloro-4-piperazin-1-yl quinoline with 1,3-dibromo propane in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating {1, 3-bis [1-5-chloro-4-quinolyl]-4-piperazinyl} propane.

6. A process for the preparation of 5-chloro-4-[4(3-chloro-propyl)-piperazin-1-yl]-
quinoline of formula-5 which comprising the steps of:

a) reacting 5-chloro-4-piperazin-1-yl quinoline with bromo chloro propane in the presence of a base in a solvent,

b) removing the solvent, and

c) isolating 5-chloro-4-[4(3-chloro-propyl)-piperazin-1-yl]-quinoline.

7. A process for the preparation of 5-chloro-4-[4-(5-chloroquinolin-4-yl) piperazin-1- yl]
quinoline of formual-6 which comprising the steps of:

a) reacting 4,7-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating 5-chloro-4-[4-(5-chloroquinolin-4-yl) piperazin-1- yl] quinoline.

8. A process for the preparation of 5-chloro-4-[4-(3-piperazin-1-yl-propyl)-piperazin-1-
yl]-quinoline of formula-7 which comprising the steps of:

a) reacting 1-chloro-3-(5-chloro-4-quinolyl-4-piperazinyl)propane with piperazine in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating 5-chloro-4-[4-(3-piperazin-1 -yl-propyl)-piperazin-1 -yl]-quinoline.

9. A process for the preparation of tris-piperazinyl quinoline of formuala-8 which
comprising the steps of:

a) reacting 5-chloro-4-[4-(3-piperazin-1 -yl)-propyl)-piperazin-1 -yl)-quinoline with 5-chloro-4-[4-(3-chloro-propyl)-piperzin-1-yl]quinoline in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating tris-piperazinyl quinoline.

10. The process according to claims 2-9, wherein the base employed for the reaction is
is selected from the group comprising sodium carbonate, potassium carbonate,
sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium oxide,
magnesium hydroxide, triethylamine, diisopropylamine or pyridine, the catalyst
employed for the reaction is potassium iodide and solvent is selected from the group
comprising methanol, ethanol, isopropanol, butanol, isobutanol, dichloromethane,
dichloroethane, chloroform, carbantetrachloride, chlorobenzene, diethylether,
diisopropylether, tetrahydrofuron or acetone.

This application claims priority to Indian patent application no 3896/CHE/2010 filed on Dec 20, 2010 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to novel impurities of Piperaquine and process for the preparation thereof.

BACK GROUND OF THE INVENTION:
Piperaquine is an antimalarial drug that belongs to the bisquinoline class of chemical compounds. It is chemically known as 1, 3-bis [1-(7-chloro-4-quinolyl)-4'-piperazinyl] propane and is represented by:

US Pat. No. 3173918 discloses process for the preparation of Piperaquine and its non-toxic acid addition salts, wherein 4,7-dichloroquinoline is reacted with 1,3-bis-l'-piperazinylpropane in phenol at 115-120°C and the resultant mixture is poured into an aqueous base solution to obtain crude Piperaquine. The crude product is recrystallized from the mixture of dimethylformamide and water to get pure product as shown in scheme-l.

Indian Journal of Heterocyclic Chemistry Vol. 19, 2010, pp 215-220 discloses six impurities are formed during the process development of Piperaquine phosphate.

Since the impurity profile study of pharmaceutical substances is a crucial part of process development, because presence of trace impurities arising either during synthesis or storage may lead to markedly different toxicity than would be expected and make the drug inactive. Therefore it becomes necessary to identify impurities which are present or developed during the process development of Piperaquine.

There is a general rule that chemical purity of the active pharmaceutical ingredient (API) produced in the industrial scale is one of the critical parameters for its commercialization.

The American Food and Drug Administration (FDA) as well as European medicament control offices require, according to the Q7A ICH (International Conference on Harmonization) instruction, that API is free from impurities to the maximum possible extent. The reason is achieving maximum safety of using the drug in the clinical practice. National inspection and control offices usually require that the content of an individual impurity in an API should not

exceed the limit of 0.1%. All the substances (generally referred to as impurities) contained in an API over the limit of 0.1% should be isolated and characterized in accordance with the ICH recommendations.

The present invention discloses identification and synthesis of novel impurities formed during the process development of Piperaquine phosphate.

SUMMARY OF THE INVENTION:

One aspect of the present invention provides, piperaquine impurity 5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl} piperazin-1-yl) quinoline of formula-1.
Another aspect of the present invention provides, piperaquine impurity 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-quinolin-4-one of formula-2.
Yet another aspect of the present invention provides, a process for the preparation of compounds of formula 1 & 2 which comprising the steps of: a) reacting 5-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl] quinoline in the presence of a base and a catalyst in a solvent at reflux temperature, b) removing the solvent, and c) separating compounds of formula 1 & 2.

Yet another aspect of the present invention provides, piperaquine impurity 5-chloro-4-piperazin-1 -yl-quinoline of formula-3.

Yet another aspect of the present invention provides, a process for the preparation of compound of formula-3 which comprising the steps of: a) reacting 4,5-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature, b) removing the solvent, and c) isolating compound of formula-3.

Yet another aspect of the present invention provides, piperaquine impurity {1,3-bis[1-5-chloro-4-quinolyl]-4-piperazinyl} propane of formula-4.

Yet another aspect of the present invention provides, a process for the preparation of ^ compound of formula-4 which comprising the steps of: a) reacting 5-chloro-4-piperazin-1-yl

quinoline with 1,3-dibromopropane in the presence of a base in a solvent at reflux temperature, b) removing the solvent, and c) isolating compound of formula-4.

Yet another aspect of the present invention provides, piperaquine impurity 5-chloro-4-[4(3-chloro-propyl)-piperazin-1-yl]-quinoline of formula-5.

Yet another aspect of the present invention provides, a process for the preparation of compound of formula-5 which comprising the steps of: a) reacting 5-chloro-4-piperazin-1-yl quinoline with bromochloropropane in the presence of a base in a solvent, b) removing the solvent, and c) isolating compound of formula-5.

Yet another aspect of the present invention provides, piperaquine impurity 5-chloro-4-[4-(5-chloroquinolin-4-yl)piperazin-1 -yl]quinoline of formula-6.

Yet another aspect of the present invention provides, a process for the preparation of compound of formula-6 which comprising the steps of: a) reacting 4,7-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature, b) removing the solvent, and c) isolating compound of formula-6.

Yet another aspect of the present invention provides, piperaquine impurity 5-chloro-4-[4-(3-piperazin-1-yl-propyl)-piperazin-1-yl]-quinoline of formula-7.

Yet another aspect of the present invention provides, a process for the preparation of compound of formula-7 which comprising the steps of: a) reacting 1-chloro-3-(5-chloro-4-quinolyl-4-piperazinyl)propane with piperazine in a solvent at reflux temperature, b) removing the solvent, and c) isolating compound of formula-7.

Yet another aspect of the present invention provides, piperaquine impurity tris-piperazinyl quinoline of formula-8.
Further aspect of the present invention provides, a process for the preparation of compound of formula-8 which comprising the steps of: a) reacting 5-chloro-4-[4-(3-piperazin-1-yl)-propyl)-piperazin-1 -yl)-quinoline with 5-chloro-4-[4-(3-chloro-propyl)-piperzin-1 -yl]quinoline in the presence of a catalyst in a solvent at reflux temperature, b) removing the solvent, and c) isolating compound of formula-8.

According to the present invention compounds of formula-1 to 8 are characterized by 1H NMR.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention is related to eight novel impurities of piperaquine phosphate and process for the preparation thereof.

One embodiment of the present invention provides, piperaquine impurity 5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl} piperazin-1-yl) quinoline of formula-1.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-quinolin-4-one of formula-2.

Formula-2 Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula 1& 2 which comprising the steps of:

a) reacting 5-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl] quinoline in the presence of a base and a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) separating compounds of formula 1 & 2.

According to the present invention 5-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl] quinoline is refluxed in a ketone solvent in presence of a base and catalyst for about 12-16 hrs. Product is extracted into a chlorinated organic solvent and evaporated the solvent to get crude compounds of formula 1 & 2. This mixture is separated using known

methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-piperazin-1-yt-quinoline of formula-3.

Formula-3 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-3 which comprising the steps of:

a) reacting 4,5-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-3.

According to the present invention 4, 5-dichloro quinoline is reacted with piperazine in an alcoholic solvent in presence of a catalyst at reflux temperature for about 8-12 hrs. Reaction mass is cooled to room temperature and inorganic salts are filtered. The filtrate is concentrated under reduced pressure to get compound of formula-3.

Yet another embodiment of the present invention provides, piperaquine impurity 1,3-bis[1-(5-chloro-4-quinolyl)-4-piperazinyl) propane of formula-4.
Formula-4 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-4 which comprising the steps of:

a) reacting 5-chloro-4-piperazin-1-yl quinoline with 1,3-dibromo propane in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-4.

According to the present invention 5-chloro-4-piperazin-1-yl quinoline is reacted with 1, 3-
dibromopropane in the presence of a base in alcoholic solvent at reflux temperature for 38-
42 hrs. Reaction mass cooled to room temperature and filtered to get compound of formula-

4.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-
[4(3-chloro-propyl)-piperazin-1-yl]-quinoline of formula-5.
rormuia-o Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-5 which comprising the steps of:

a) reacting 5-chloro-4-piperazin-1-yl quinoline with bromochloropropane in the presence of a base in a solvent,

b) removing the solvent, and

c) isolating compound of formula-5.

According to the present invention 5-chloro-4-piperazin-1-yl quinoline is reacted with bromochloropropane in the presence of a base in dimethylformamide solvent at 55-60°C for 4-6hrs. Reaction mass cooled to room temperature and inorganic salts are filtered. Filtrated is diluted with water and product is extracted into chlorinated organic solvent, evaporated to get compound of formula-5.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-[4-(5-chloroquinolin-4-yl)piperazin-1-yl]quinolineof formula-6.
Formula-6 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-6 which comprising the steps of:

a) reacting 4,7-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-6.

According to the present invention 4,7-dichloro quinoline is reacted with piperazine in presence of catalyst in alcoholic solvent at reflux temperature for about 8-12 hrs. Reaction mass is cooled to room temperature, filtered the inorganic salts. Filtrate is diluted with water and product is extracted into chlorinated organic solvent and evaporated to get residue. The residue is dissolved in ether solvent and purified by preparative HPLC to get compound of formula-6.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-[4-(3-piperazin-1 -yl-propyl)-piperazin-1 -yll-quinoline of formula-7.
Formula-7 Yet another embodiment of the present invention provides, a process for the

preparation of compound of formula-7 which comprising the steps of:

a) reacting 1-chloro-3-(5-chloro-4-quinolyl-4-piperazinyl)propane with piperazine in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-7.

According to the present invention 1-chloro-3-(5-chloro-4-quinolyl-4-piperazinyl)propane is reacted with piperazine in alcoholic solvent at reflux temperature for about 3-7hrs and evaporated the solvent to get residue. The obtained residue is diluted with water and extracted into chlorinated solvent and evaporated to get crude compound of formula-7. The crude compound is purified using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.
Yet another embodiment of the present invention provides, piperaquine impurity tris-piperazinyl quinoline impurity of formula-8.

Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-8 which comprising the steps of:

a) reacting 5-chloro-4-[4-(3-piperazin-1-yl)-propyl)-piperazin-1-yl)-quinoline with 5-chloro-4-[4-(3-chloro-propyl)-piperzin-1-yl]quinoline in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-8.

According to the present invention 5-chloro-4-[4-(3-piperazin-1-yl)-propyl)-piperazin-1-yl)-quinoline is reacted with 5-chloro-4-[4-(3-chloro-propyl)-piperzin-1-yl]quinoline in presence of a base and catalyst in alcoholic solvent at reflux temperature for about 3-7hrs, after the completion of the reaction solvent is evaporated to get residue. The residue is dissolved in ether solvent and purified by column chromatography to get compound of formula-8.

Yet another embodiment of the present invention provides, piperaquine impurity 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1, 4-dihydro-quinolin-4-ol of formula-9.

Yet another embodiment of the present invention provides, piperaquine impurity 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1 -yl]-propyl}-1 H-quinolin-4-one of fomnula-10.

Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula-9 & 10 which comprising the steps of:
a) reacting 7-chloro quinolin-4-ol with 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline in the presence of a base and a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) separating compounds of formula-9 & 10.

According to the present invention 7-chloro quinolin-4-ol with 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline is refluxed in a ketone solvent in presence of a base and catalyst for about 12-16 hrs. Product is extracted into a chlorinated organic solvent and evaporated the solvent to get crude compounds of formula 9 & 10. This mixture is separated using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1, 4-dihydro-quinolin-4-ol of formula-11.

Formula-11 Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-of formula-12.

Formula-12 Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1 -yl]-propyl}-1 H-quinolin-4-one of formula-13.

Formula-13 Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula-12 & 13 which comprising the steps of:

a) reacting 5-chloro quinolin-4-ol with 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline in the presence of a base and a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) separating compounds of formula-12 & 13.

According to the present invention 5-chloro quinolin-4-ol with 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline is refluxed in a ketone solvent in presence of a base and catalyst for about 12-16 hrs. Product is extracted into a chlorinated organic solvent and evaporated the solvent to get crude compounds of formula 12 & 13. This mixture is separated using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 7-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol of formula-14.

Formula-14 Yet another embodiment of the present invention provides, piperaquine impurity 7-Chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}1 H-quinolin-4-one of formula-15.

Formula-15

Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula-14 & 15 which comprising the steps of:

a) reacting 7-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline in the presence of a base and a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) separating compounds of formula-14 & 15.

According to the present invention 7-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline is refluxed in a ketone solvent in presence of a base and catalyst for about 12-16 hrs. Product is extracted into a chlorinated organic solvent and evaporated the solvent to get crude compounds of formula 14 & 15. This mixture is separated using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 7-chloro-4-piperazin-1-yl-quinoline 1-oxide of formula-16.

Yet another embodiment of the present invention provides, piperaquine impurity 4-(7-Chloro-quinolin-4-yl)-piperazin-1 -ol-anion of formula-17.

Yet another embodiment of the present invention provides, piperaquine impurity 4-(7-Chloro-1 -oxy-quinolin-4-yl)-piperazin-1 -ol-anion of formula-18.

Formula-18 Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula-16, 17 & 18 which comprises the steps of:

a) oxidizing 7-chloro-4-piperazin-1-yl-quinoline in a solvent in the presence of an oxidizing agent, and

b) separating the compounds of formula-16, 17 & 18.
According to present invention 5-chloro-4-piperazin-1-yl-quinoline is reacted in a mixture of chlorinated and alcoholic solvent with oxidizing agent for about 1-5 hrs. After the completion of reaction the reaction mixture was filtered. And the filtrate was washed with alcoholic solvent to get crude compound of formula-16, 17 & 18. The crude is separated using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-piperazin-1-yl-quinoline 1-oxide of formula-19.

Formula-19

Yet another embodiment of the present invention provides, piperaquine impurity 4-(5-chloro-quinolin-4-yl)-piperazin-1-ol-anion of formula-20.
Yet another embodiment of the present invention provides, piperaquine impurity 4-(5-Chloro-1 -oxy-quinolin-4-yl)-piperazin-1 -ol-anion of formula-21.

Formula-21 Yet another embodiment of the present invention provides, a process for the preparation of compounds of formula-19, 20 and 21 which comprises the steps of:

a) oxidizing 5-chloro-4-piperazin-1-yl-quinoline in a solvent in the presence of an oxidizing agent, and,

b) separating the compounds of formula-19, 20 & 21.

According to present invention 5-chloro-4-piperazin-1-yl-quinoline is reacted in a mixture of chlorinated and alcoholic solvent with oxidizing agent for about 1-5 hrs. After the completion of reaction the reaction mixture was filtered. And the filtrate was washed with alcoholic solvent to get crude compound of formula-19, 2 0 & 21. The crude is separated using known

methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 3-[4-(5-chloroquinolin-4-yl)piperazin-1-yl]propan-1-ol of formula-22.

Formula-22 Yet another embodiment of the present invention provides, a process for the

preparation of compound of formula-22 which comprises the steps of:

a) reacting 5-chloro-4-piperazin-1-yl quinoline with 1-bromo-3-propanol in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-22.

According to the present invention 5-chloro-4-piperazin-1-yl quinoline is reacted with 1-bromo-3-propanol in the presence of a base in ketone solvent at reflux temperature for about 4-8 hrs. Reaction mass cooled to room temperature and filtered to get compound of formula-22.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-[4-(3-ethoxy-propyl)-piperazin-1 -yl]-quinoline of formula-23.

Formula-23 Yet another embodiment of the present invention provides, a process for the

preparation of compound of formula-23 which comprises the steps of:

a) reacting 5-chloro-4-[4-(3-chloropropyl) piperazin-1-yl]quinoline in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-23.

According to the present invention 5-chloro-4-[4-(3-chloropropyl) piperazin-1-yl] quinoline is refluxed in the presence of a base in alcoholic solvent at temperature for about 2-6 hrs. Reaction mass cooled to room temperature and distill off the solvent to get residue. And the

compound was extracted into chlorinated organic solvent, evaporated to get compound of
formula-23.

Yet another embodiment of the present invention provides, piperaquine impurity 4-(3-
bromopropoxy)-5-chloro-quinoline of formula-24.

Formula-24 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-24 which comprises the steps of:

a) reacting 5-chloro-quinolin-4-ol with 1, 3 dibromopropane in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-24.

According to the present invention 5-chloro-quinolin-4-ol is reacted with 1,3-dibromopropane is refluxed in the presence of a base in alcoholic solvent for about 38-42hrs.. Reaction mass cooled to room temperature and filtered to get compound of formula-24.

Yet another embodiment of the present invention provides, piperaquine impurity 4-(3-chloropropoxy)-5-chloro-quinoline of formula-25.

Formula-25 Yet another embodiment of the present invention provides, a process for the

preparation of compound of formula-25 which comprises the steps of:

a) reacting 5-chloro-quinolin-4-ol with Bromochloropropane in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-25.

According to the present invention 5-chloro-quinolin-4-ol is reacted with Bromochloropropane is refluxed in the presence of a base in alcoholic solvent for about 38-42hrs. Reaction mass cooled to room temperature and filtered to get the crude compound of

formula-25. The crude compound is purified using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

Yet another embodiment of the present invention provides, piperaquine impurity 5-chloro-4-{[5-chloroquinolin-4-yl-oxy]propoxyl) auinoline of formula-26
Formula-26 Yet another embodiment of the present invention provides, a process for the preparation of compound of formula-26 which comprises the steps of:

a) reacting 5-chloro-quinolin-4-ol with 1, 3 di bromo propane in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating compound of formula-26.

According to the present invention 5-chloro-quinolin-4-ol is reacted with 1,3 di bromo propane is refluxed in the presence of a base in alcoholic solvent for about 38-42hrs. Reaction mass cooled to room temperature and filtered to get the crude compound of formula-26. The crude compound is purified using known methods like preparative HPLC, column chromatography or recrystallisation, preferably preparative HPLC.

According to the present invention alcoholic solvent is selected from the group comprising methanol, ethanol, isopropanol, butanol or isobutanol. Chlorinated organic solvent is selected from the group comprising dichloromethane, dichloroethane, chloroform, carbantetrachloride or chlorobenzene. Ether solvent is selected from the group comprising diethylether, diisopropylether or tetrahydrofuron. Ketone solvent is selected form the group comprising acetone, methylethylketone or methylisobutylketone.

According to the present invention the base employed in the reaction is organic base or inorganic base. The inorganic base is selected from the group comprising sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium oxide or magnesium hydroxide. The organic base selected from the group comprising triethylamine, diisopropylamine or pyridine.

According to the present invention the catalyst employed for the reaction is potassium iodide or sodium iodide.

According to the present invention the oxidizing agent used in the reaction is selected from the group comprising hydrogen peroxide, chromium trioxide, potassium permanganate, osmium tetroxide or silver oxide.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXPERIMENTAL SECTION:

Example-1: Preparation of (5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl}
piperazin-1-yl) quinoline (formula-1), 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-
piperazin-1-yl]-propyl}-1 H-quinolin-4-one (formula-2) and 5-chloro-1-{3-[4-(5-chloro-
quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-11).

To a mixture of 5-chloro quinolin-4-ol (5g, 0.027 mol), potassium carbonate (10g, 0.07 mol),
and potassium iodide (2.3g, 0.014mol) in acetone was added 5-chloro-4-[4-(3-chloro-propyl)-

piperazin-1-yl]quinoline (9g, 0.027mol) and heated the reaction mixture to reflux temperature
for about 14 hours. The reaction mixture was distilled under reduced pressure; the residue
obtained was diluted with water (100 ml) and extracted with dichloromethane (2X 50 ml).

The combined organic layer was washed with brine and dried over sodium sulphate The
combined organic layer was concentrated under reduced pressure to yield the oily crude.
The crude contains (5-chloro-4(4-{3-[5-chloroquioline-4-yl) oxy] propyl} piperazin-1-yl)

quinoline (formula-1), 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-
quinolin-4-one (formula-2) and 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-
propyl}-1,4-dihydro-quinolin-4-ol (formula-11) and this were purified by preparative

HPLC/column chromatography/recrystallisation.
1H-NMR(DMSO-d6. 300 MHz, ppm) values of formula-1:- 5 8-8.05 (CH, 1H), 8.03-8.05 CH,
1H), 7.41-7.48 (2CH, 2H), 8.16 (CH, 1H), 7.96 CH.1H), 6.85 (CH, 1H), 6.77 (CH, 1H), 8.73
(CH, 1H), 8.75 (CH, 1H), 3.27-3.38 (2CH2, 4H), 2.74-2.81 (2CH2, 4H), 2.74-2.81 (2CH2, 2H),
2.17-2.26 (CH2-2H), 4.32 (CH2-2H).
1H-NMR(DMSO-d6. 300 MHz, ppm) values of formula-2:- 5 8.05 (CH, 1H), 7.59 (CH, 1H),
7.41-7.44 (CH, 1H), 7.32-7.35 (CH.1H), 7.94 (CH.1H), 7.62 (CH, 1H), 6.87 (CH, 1H), 6.27

(CH, 1H), 8.74 (CH, 1H), 8.40 (CH, 1H), 3.30 (2CH2, 4H), 2.74 (2CH2, 4H), 2.48 (CH2, 2H), 2.05-2.10 (CH2, 2H), 4.24 (CH, 2H).

Example-2: Preparation of 5-chloro-4-piperazin-1-yl-quinoline (formula-3)
Mixture of 4,5-dichloroquinoline (15g, 0.075mol), potassium iodide (3.15g 0.018mol) and piperazine (18.92g, 0.22 mol) in isopropyl alcohol was refluxed for about 10 hours.
The reaction mass was filtered, washed with isopropyl alcohol and distilled off the filtrate under vacuum below 45°C. The residue was diluted with dichloromethane and washed with brine. The combined organic layer was dried over sodium sulphate. The solvent was removed under reduced pressure to get the compound of formuJa-3.
1H-NMR(DMSO-d6. 300 MHz, ppm) :- 5 8.65(CH, 1H), 7.90 (CH, 1H), 7.58 (2CH, 2H), 7.05(CH, 1H), 3.31 (CH2, 2H), 3.06 (2CH2, 4H), 2.72 (CH2, 2H).

Example-3: Preparation of 1, 3-Bis [1-(5-chloro-4-quinolyl)-4'piperazinyl) propane (formula-4)
Mixture of 5-chloro-4-piperazin-1-yl quinoline (15g, 0.06 mol), 1, 3 Dibromo propane (12.2g 0.06 mol) and triethyl amine (18.3g, 0.18 mol) in methanol was refluxed for 40 hours. The reaction mixture was cooled to room temperature and filtered. The solid obtained was washed with methanol and water to get the compound of formula-4. The 1H-NMR data complies with proposed structure of formula-4.
1H-NMR(DMSO-d6. 300 MHz, ppm) :- 5 8.81 (2CH, 2H), 8.19 (2CH, 2H), 7.88 (2CH, 2H), 7.77(2CH, 2H), 7.49 (2CH, 2H), 4.17(2CH2, 4H), 4.0 (2CH2, 4H), 3.83 (4CH2, 8H), 3.48 (2CH2, 4H), 2.54 (CH2, 4H).
Example-4: Preparation of 5-chloro-4-[4(3-chloro-propyl)-piperazin-1-yl]-quinoline (formula-5)

To a stirred mixture of 5-chloro-4-piperazin-1-yl-quinoline (20g, 0.08 mol), bromo chloro propane (32g, 0.2 mol) in dimethylformamide was added triethyl amine (3.3g, 0.032 mol), heated the reaction mixture to 60°C and stirred at the same temperature for about 5 hours The reaction mixture was cooled to room temperature and filtered the precipitated solid. The filtrate was concentrated under reduced pressure, the residue obtained was diluted with DM water (200 ml) and extracted with methylene dichloride (2X50 ml). The combined organic layers were dried over sodium sulphate. The solvent was removed under reduced pressure

to yield the oily compound of formula-5. Yield 22 g, 84.61 %. The 1H-NMR data complies
with proposed structure of formula-5.
1H-NMR(DMSO-d6. 300 MHz, ppm) :- 6 8.04 (CH, 1H), 7.40-7.44 (CH, 1H), 7.94 (CH, 1H),
6.83 (CH, 1H), 8.72 (CH, 1H), 3.24 (2CH2, 4H), 2.74 (2CH2, 4H), 3.65 (CH2, 2H), 1.97-2.14
(CH2, 2H), 2.63 (CH2, 2H).

Example-5: Preparation of 5-chloro-4-[4-(5-chloroquinolin-4-yl)piperazin-1-yl]quinoline (formula-6)

To a mixture of 4,7-dichloro quinoline (15g, 0.075mol), potassium iodide (3.15g, 0.018mol) and piperazine (18.92 g 0.22 mol) in isopropyl alcohol was refluxed for about 10 hours. The reaction mass was filtered, washed with isopropyl alcohol and distilled off the filtrate under vacuum below 45°C. The residue was diluted with dichloromethane and washed with brine. The combined organic layers were dried over sodium sulphate. The solvent was removed under reduced pressure, the residue was stirred with isopropyl ether and filtered. The filtrate was collected and concentrated under vacuum. The filtrate crude was purified by preparative HPLC/column chromatography to get the compound of formula-6. The 1H-NMR data complies with proposed structure of formula-6.
1H-NMR(DMSO-d6. 300 MHz, ppm):- 5 8.11 (2CH, 1H), 7.65 (2CH, 2H), 8.34 (2CH, 2H), 7.13 (2CH, 2H), 8.63 (2CH, 2H), 4.43 (4CH2, 8H).

Example-6: Preparation of 5-chloro-4-[4-(3-piperazin-1-yl-propyl)-piperazin-1-yl]-quinoline (formula-7)
Mixture of 1-chloro-3-(5-chloro-4-quinolyl-4-piperazinyl) propane (10g, 0.03mol), piperazine (8g, 0.042mol) in isopropyl alcohol was refluxed for about 5 hours. The reaction mixture was cooled to room temperature and distilled off isopropyl alcohol. The residue was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulphate. The solvent was removed under reduced pressure to get the title compound of formula-7. The crude was purified by preparative HPLC/column chromatography/recrystallisation. The 1H-NMR data complies with proposed structure of formula-7. 1H-NMR(DMSO-d6. 300 MHz. PPm):- 5 8.04 (CH, 1H), 7.40-7.44 (CH.1H), 7.95 (CH, 1H),
6.84 (CH, 1H), 8.71 (CH, 1H), 3.24-3.25 (2CH2, 4H), 2.74 (2CH2, 4H), 2.39-2.53 (2CH2, 4H),
2.39-2.53 (2CH2, 4H), 2.90-2.96 (CH2, 2H), 1.74-1.82 (CH2, 2H), 2.90-2.96 (CH2, 2H).

Example-7: Preparation of Tris -piperazinyl quinoline impurity (formula-8)
To the mixture of 5-chloro-4-[4-(3-piperazin-1-yl)-propyl)-piperazin-1-yl)-quinoline (8g, 0.021 mol), potassium iodide (1.8g, 0.01 mol) in isopropyl alcohol was added 5-chloro-4-[4-(3-chloro-propyl)-piperzin-1-yl]quinoline, the resulted reaction mixture was refluxed for about 5 hours. The reaction mixture was cooled to room temperature and distilled off isopropyl alcohol. The residue was diluted with isopropyl ether (80ml) and filtered to get the compound of formula-8. The crude was purified by column chromatography. The 1H-
NMR data complies with proposed structure of formula-8.

1H-NMR(DMSO-dg. 300 MHz, ppm):- 5 8.04 (2CH, 2H), 7.40-7.44 (2CH, 2H), 7.93 (2CH, 2H), 6.84 (2CH, 2H), 8.72 (2CH, 2H), 3.27 (4CH2, 8H), 2.78 (2CH2, 4H), 2.78 (2CH2, 4H), 2.57 (2CH2, 4H), 1.95 (2CH2,4H), 3.01 (4CH2, 8H).
Example-8: Preparation of 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-9) and 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1H-quinolin-4-one (formula-10).

To a mixture of 7-chloro quinolin-4-ol (5g, 0.027 mol), potassium carbonate (10g, 0.07 mol), and potassium iodide (2.3g, 0.014 mol) in acetone was added 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl] quinoline (9g, 0.027 mol) and heated the reaction mixture to reflux temperature for about 14 hours. The reaction mixture was distilled under reduced pressure, the residue obtained was diluted with water (100 ml) and extracted with dichloromethane (2X 50 ml). The combined organic layer was washed with brine and dried over sodium sulphate. The combined organic layer was concentrated under reduced pressure to yield the oily crude. The crude contains 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-9) and 7-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1H-quinolin-4-one (formula-10) and this were purified by preparative HPLC/column chromatography/recrystallisation.

Example-9: Preparation of 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-12) and 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-quinolin-4-one (formula-13).

To a mixture of 5-chloro quinolin-4-ol (5 g,0.027 mol), potassium carbonate(10 g,0.07 mol), and potassium iodide(2.3g ,0.014 mol) in acetone was added 7-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline (9g, 0.027 mol) and heated the reaction mixture to reflux temperature for about 14 hours. The reaction mixture was distilled under reduced pressure,

the residue obtained was diluted with water (100 ml) and extracted with dichloromethane (2X 50 ml). The combined organic layer was washed with brine and dried over sodium sulphate The combined organic layer was concentrated under reduced pressure to yield the oily crude. The crude contains 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-12) and 5-chloro-1-{3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1H-quinolin-4-one (formula-13) and this were purified by preparative HPLC/column chromatography/recrystallisation.

Example-10: Preparation of 7-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1,4-dihydro-quinolin-4-ol (formula-14) and 7-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-quinolin-4-one (formula-15)
To a mixture of 7-chloro quinolin-4-ol (5g, 0.027 mol), potassium carbonate (10g, 0.07 mol), and potassium iodide (2.3g, 0.014mol) in acetone was added 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl]quinoline (9g, 0.027mol) and heated the reaction mixture to reflux temperature for about 14 hours. The reaction mixture was distilled under reduced pressure, the residue obtained was diluted with water (100 ml) and extracted with dichloromethane (2X 50 ml). The combined organic layer was washed with brine and dried over sodium sulphate. The combined organic layer was concentrated under reduced pressure to yield the oily crude. The crude contains 7-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1, 4-dihydro-quinolin-4-ol (formula-14) and 7-chloro-1-{3-[4-(5-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-1 H-quinolin-4-one (formula-15) and this were purified by preparative HPLC/column chromatography/recrystallisation.

Example-11: Preparation of 7-chloro-4-piperazin-1-yl-quinoline-1-oxide (formula-16), 4-(7-chloro-quinolin-4-yl)-piperazin-1-ol-anion (formula-17) and 4-(7-Chloro-1-oxy-quinolin-4-yl)-piperazin-1-ol-anion (formula-18)

Mixture of 7-chloro-4-piperazin-1-yl-quinoline (10g, 0.04 mol), methylene dichloride and methanol was cooled to 5°C and hydrogen peroxide (2.53g, 0.0746 mol) was added to the solution and stirred for about 3 hours. The solid formed was filtered and washed with methanol.

The crude contains 7-chloro-4-piperazin-1-yl-quinoline 1-oxide (formula-16), 4-(7-Chloro-quinolin-4-yl)-piperazin-1-ol-anion (formula-17) and 4-(7-Chloro-1-oxy-quinolin-4-yl)-piperazin-1-ol-anion (formula-18) and this were purified by preparative HPLC/column chromatography/recrystallisation.

Example-12: 5-chloro-4-piperazin-1-yl-quinoline 1-oxide (formula-19), 4-(5-chloro-quinolin-4-yl)-piperazin-1-ol-anion (formula-20) and 4-(5-chloro-1-oxy-quinolin-4-yl)-piperazin-1 -ol-anion (formula-21)
Mixture of 5-chloro-4-piperazin-1-yl-quinoline (10g, 0.04mol) in methylene dichloride and methanol was cooled to 5°C and hydrogen peroxide (2.53g, 0.0746mol) was added to the solution and stirred for about 3 hours. The solid formed was filtered and washed with methanol. The crude contains 5-chloro-4-piperazin-1-yl-quinoline 1-oxide (formula-19), 4-(5-Chloro-quinolin-4-yl)-piperazin-1-ol-anion (formula-20) and 4-(5-Chloro-1-oxy-quinolin-4-yl)-piperazin-1-ol-anion (formula-21) and this were purified by preparative HPLC/column chromatography/recrystallisation.

Example-13: Preparation of 3-[4-(5-chloroquinolin-4-yl)piperazin-1-yl]propane-1-ol (formula-22)

Mixture of 5-chloro-4-piperazin-1-yl quinoline (10g, 0.04 mol), triethyl amine (4.9g, 0.04 mol), 1-bromo-3-propanol (5.6g, 0.04 mol) in acetonitrile was refluxed for about 6 hours. The reaction mixture was cooled to room temperature and then filtered. The solid thus obtained was washed with aqueous sodium bicarbonate and brine solution and dried to get the compound of formula-22. Yield 10.6 g 85.62 %.

Example-14: Preparation of 5-chloro-4-[4-(3-ethoxypropyl)piperazin-1-yl]quinoline (formula-23)
Mixture of 5-chloro-4-[4-(3-chloropropyl)piperazin-1-yl]quinoline (2g, 0.006mol) sodium hydroxide (0.36g, 0.009 mol) in ethanol was refluxed for about 4 hours. The reaction mixture was cooled to room temperature and distilled off ethanol. The residue was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulphate. The solvent was removed under reduced pressure to get compound of formula-23.

Example-15: Preparation of 4-(3-bromopropoxy)-5-chloroquinoline (formula-24)
Mixture of 5-chloro-quinolin-4-ol (15g, 0.08mol), 1,3 dibromo propane (16.2g, 0.05mol) and triethylamine (15.1g, 0.15 mol) in methanol was refluxed for about 40 hours. The reaction mixture was cooled to room temperature and filtered. The solid obtained was washed with methanol and water to get compound of formula-24.

Example-16: Preparation of 4-(3-chloropropoxy)-5-chloroquinoline (formula-25)
Mixture of 5-chloro-quinolin-4-ol (10g, 0.05 mol), bromo chloro propane (7.9g, 0.05 mol) and triethyl amine (15.1g, 0.15 mol) in methanol was refluxed for about 40 hours.

The reaction mixture was cooled to room temperature and filtered. The solid obtained was washed with methanol and water to get compound of formula-25. The crude was purified by preparative HPLC/column chromatography/recrystallisation.

Example-17: Preparation of 5-chloro-4-{[5-chloroquinolin-4-yl) oxy] propoxyl} quinoline (formula-26)
Mixture of 5-chloro-quinolin-4-ol (10g, 0.06mol), 1,3 Dibromo propane (12.2g, 0.06mol) and triethyl amine (18.3g, 0.18mol) in methanol was refluxed for about 40 hours. The reaction mixture was cooled to room temperature and filtered. The solid obtained was washed with methanol and water. The crude was purified by preparative HPLC/column chromatography/recrystallisation to get the compound of formula-26.

We Claim:

1. Piperaquine impurity
a. 5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl} piperazin-1-yl) quinoline
of formula-1,

Formula-1

b. 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl) -piperazin-1-yl]- propyl}-1H-quinolin-
4-one of formula-2,

Formula-2

c. 5-chloro-4-piperazin-1-yl-quinoline of formula-3,

Formula-3

d. {1, 3-bis [1-5-chloro-4-quinolyl]-4-piperazinyl} propane of formula-4,
formula--4

e. 5-chloro-4-[4(3-chloro-propyl)-piperazin-1-yl]-quinoline of formula-5,


Formula-5

f. 5-chloro-4-[4-(5-chloroquinolin-4-yl) piperazin-1- yl] quinoline of formula-6,

Formula-6

g. 5-chloro-4-[4-(3-piperazin-1-yl-propyl)-piperazin-1-yl]-quinoline of formula-7,
furmula-7

h. tris-piperazinyl quinoline of formula-8.

Formula-8

2. A process for the preparation of 5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl}
piperazin-1-yl) quinoline of formula-1 which comprising the steps of:

a) reacting 5-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-piperazin-1-yl] quinoline in the presence of a base and a catalyst in a solvent,

b) removing the solvent, and

c) isolating 5-chloro-4(4-{3-[5-chloroquioline -4-yl) oxy] propyl} piperazin-1-yl) quinoline.

3. A process for the preparation of 5-chloro-1 -{3-[4-(5-chloro-quinolin-4-yl) -piperazin-1 -
yl]- propyl}-1 H-quinolin-4-one of formula-2 which comprising the steps of:

a) reacting 5-chloro quinolin-4-ol with 5-chloro-4-[4-(3-chloro-propyl)-

piperazin-1-yl] quinoline in the presence of a base and a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating 5-chloro-1-{3-[4-(5-chloro-quinolin-4-yl) -piperazin-1-yl]- propyl}-1H-quinolin-4-one.

4. A process for the preparation of 5-chloro-4-piperazin-1-yl-quinoline of formula-3
which comprising the steps of:

a) reacting 4,5-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating 5-chloro-4-piperazin-1-yl-quinoline.

5. A process for the preparation of {1,3-bis [1-5-chloro-4-quinolyl]-4-piperazinyl}
propane of formula-4 which comprising the steps of:

a) reacting 5-chloro-4-piperazin-1-yl quinoline with 1,3-dibromo propane in the presence of a base in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating {1, 3-bis [1-5-chloro-4-quinolyl]-4-piperazinyl} propane.

6. A process for the preparation of 5-chloro-4-[4(3-chloro-propyl)-piperazin-1-yl]-
quinoline of formula-5 which comprising the steps of:

a) reacting 5-chloro-4-piperazin-1-yl quinoline with bromo chloro propane in the presence of a base in a solvent,

b) removing the solvent, and

c) isolating 5-chloro-4-[4(3-chloro-propyl)-piperazin-1-yl]-quinoline.

7. A process for the preparation of 5-chloro-4-[4-(5-chloroquinolin-4-yl) piperazin-1- yl]
quinoline of formual-6 which comprising the steps of:

a) reacting 4,7-dichloro quinoline with piperazine in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating 5-chloro-4-[4-(5-chloroquinolin-4-yl) piperazin-1- yl] quinoline.

8. A process for the preparation of 5-chloro-4-[4-(3-piperazin-1-yl-propyl)-piperazin-1-
yl]-quinoline of formula-7 which comprising the steps of:

a) reacting 1-chloro-3-(5-chloro-4-quinolyl-4-piperazinyl)propane with piperazine in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating 5-chloro-4-[4-(3-piperazin-1 -yl-propyl)-piperazin-1 -yl]-quinoline.

9. A process for the preparation of tris-piperazinyl quinoline of formuala-8 which
comprising the steps of:

a) reacting 5-chloro-4-[4-(3-piperazin-1 -yl)-propyl)-piperazin-1 -yl)-quinoline with 5-chloro-4-[4-(3-chloro-propyl)-piperzin-1-yl]quinoline in the presence of a catalyst in a solvent at reflux temperature,

b) removing the solvent, and

c) isolating tris-piperazinyl quinoline.

10. The process according to claims 2-9, wherein the base employed for the reaction is
is selected from the group comprising sodium carbonate, potassium carbonate,
sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium oxide,
magnesium hydroxide, triethylamine, diisopropylamine or pyridine, the catalyst
employed for the reaction is potassium iodide and solvent is selected from the group
comprising methanol, ethanol, isopropanol, butanol, isobutanol, dichloromethane,
dichloroethane, chloroform, carbantetrachloride, chlorobenzene, diethylether,
diisopropylether, tetrahydrofuron or acetone.