FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
Improved Process for the Preparation of Piperaquine, its salt and its
intermediate
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is to be performed:

TITLE
Improved Process for the Preparation of Piperaquine, its salt and its intermediate.
FIELD OF THE INVENTION
The present invention relates to a novel process for the synthesis of piperaquine base of formula IV and its intermediate 7-chloro-4-(piperazin-l-yl)quinoline. The present invention also relates to an improved process for the synthesis of piperaquine tetraphosphate tetrahydrate of formula I.

The present invention further relates to a novel process for the synthesis of piperaquine base from its intermediate 7-chloro-4-(piperazin-l-yl)quinoline in the presence of catalyst.
BACKGROUND OF THE INVENTION
7-chloro-4-(4-(3-(4-(7-chloroquinolin-4-yl) piperazin-1-yl) propyl) piperazin-1-yl) quinoline of formula IV, commonly known as Piperaquine, belongs to the class of antimalarial agents.


Piperaquine is a bisquinoline antimalarial drug that was first synthesized in the 1960s, and used extensively in China and Indochina as prophylactic and for treatment of malaria. A number of Chinese research groups documented that it was at least as effective as, and better tolerated than, chloroquine against falciparum and vivax malaria. With the development of piperaquine-resistant strains of Plasmodium falciparum and the emergence of the artemisinin derivatives, its use declined during the 1980s.
During the last decade, piperaquine was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with an artemisinin derivative. 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. This approach has now been endorsed by WHO.
Piperaquine is generally prepared by the process as shown in scheme I below.


It has been observed that formation of intermediate of formula III is always associated with an impurity in the form of dimer of formula V. If the dimer impurity is not removed before the step II process, it affects the purity and yield of piperaquine and its salt piperaquine tetraphosphate tetrahydrate.

The basic patent GB991838 filed in 1962 discloses the product and the process for preparation of piperaquine. The said patent describes step I preparation by reacting 4,7-dichloroquinoIine with piperazine. The patent also describes the process for step II, by reacting formula III with dibromopropane and triethylamine in methyl ethyl ketone. The patent however, does not disclose any process for the removal of the dimer impurity,

IN218633 discloses the process for the synthesis of piperquine tetraphosphate tetrahydrate as shown in Scheme I. The dimer impurity of formula V is removed by recrystallization. However, the patent uses solvents like methanol in first step and dimethyl formamide in step II. Another drawback of the patent is the long reaction time of 40 hours.
WO2009050734 provides the process for the synthesis of piperaquine tetraphosphate tetrahydrate (Scheme I), The process uses 2-propanol and dimethyl formamide as solvents in step I and II respectively. The dimer impurity is removed by tedious work-up procedure, which involves acid-base treatment. Also, the process describes the use of 1,3-dibromopropane as reactant which is very expensive.
US20060270852 discloses the synthesis of piperaquine phosphate wherein step II uses 1,3-dibromopropane as reactant. The said patent application however, does not disclose any process for the removal of the dimer impurity.
The prior art mentioned above suffer from several drawbacks like involving longer reaction time, tedious workup procedures, and use of expensive reagent like 1,3-dibromopropane and use of aprotic solvent like dimethyl formaide.
The inventors of present invention have surprisingly found out improved, efficient, eco-friendly and cost-effective process for the synthesis of piperaquine and its salt piperaquine tetraphosphate tetrahydrate and its intermediate 7-chloro-4-(piperazin-l-yl)quinoline by using water as solvent in step I. The process of the present invention removes the dimer impurity in a simple and efficient way to get the intermediate of formula III with less than 0.5% dimer content. All the other processes used in prior art require organic solvents which are not eco-friendly-
In presence of water, 7-chloro-4-(piperazin-l-yl)quinoline may undergo hydrolysis during work up to give its corresponding quinoline derivative. But the present invention does not allow the 7-chIoro-4-(piperazin-l-yl)quinoline to hydrolyse by

maintaining certain pH range during work up. At a specfic pH range, only the toxic dimer impurity gets removed followed by easy isolation of substantially pure 7-chloro-4-(piperazin-l-yl)quinoline. Toxicity of the dimer impurity is well mentioned in IN2186ss of the present invention also eliminates the use of expensive reactant 1,3-d33.
The proceibromopropane and solvent such as dimethyl formamide.
Thus, the process of present invention overcomes the several drawbacks of prior art processes, which makes the process more cost-effective, simpler and achieves high yield with good purity. The process of the present invention also takes care of the toxic dimer impurity of compound of formula V by applying a simpler method.
OBJECT OF THE INVENTION
The object of the present invention is to provide a novel, simple and cost-effective process for the synthesis of pure piperquine and its salt almost free from dimer impurity.
Further the object of the present invention is to provide an improved process for the synthesis of acid salts of piperaquine such as tetraphosphate salt of piperquine in tetrahydrate form using simpler method.
Further the object of the present invention is to provide an improved process for the synthesis of acid salts of piperaquine such as tetraphosphate salt of piperquine in tetrahydrate form without using water as a solvent.
Another object of the present invention is to provide a novel process for the synthesis of 7-chloro-4-(piperazin-l-yl)quinoline, an intermediate of piperaquine, almost free from dimer impurity, using water as a solvent.

Another object of the present invention is to provide a novel process for the synthesis of piperaquine from an intermediate 7-chloro-4-(piperazin-l-yl)quinoline, almost free from dimmer impurity, using catalyst such as alkali metal halide optionally in presence of second catalyst such as phase transfer catalyst.
Yet another object of the present invention is to use cost-effective reagents in the synthesis of piperaquine and a cost-effective process specifically for obtaining piperquine tetraphosphate tetrahydrate.
SUMMARY OF THE INVENTION
The present invention provides a novel, simple and cost-effective process for the synthesis of piperaquine (Scheme II), comprising the steps of,
a. reacting 4,7-dichloroquinoline of formula II with piperazine in water
in presence of aqueous acid to form an intermediate 7-chloro-4-
(piperazin-l-yl)quinoline of formula III at 80-85°C for about 2-4
hours.
b. cooling the reaction mixture of step 'a' to room temperature and
adjusting the pH with a base for precipitation of dimmer impurity of
formula V. Isolating the dimer impurity of formula V.
c. isolating intermediate 7-chloro-4-(piperazin-l-yl)quinoline of
formula III having dimer content of less than 0.5% from the aqueous
layer by adjusting the pH to 10-12 with a base followed by
extracting with organic solvent and purifying the crude product by
treatment with acetone.
d. reacting 7-chloro-4-(piperazin-l-yl)quinoline of formula III with 1-
bromo-3-chloropropane in the presence of a base and catalysts such
as alkali metal halide alone or optionally in the presence of phase
transfer catalyst in an organic solvent and isolating the product

piperaquine of formula IV, by treatment with an acid followed by neutralization with a base and purifying it.
The present invention also relates to an improved process for the synthesis of piperaquine tetraphosphate tetrahydrate of formula I, salt of piperaquine

comprising reacting piperaquine base of formula IV, with $5-90 % pure orthophosphoric acid in presence of organic solvent alone or in combination with an alcoholic solvent at 25-40°C for 2-4hr. followed by cooling and filtering the reaction mixture to obtain piperaquine tetraphosphate salt in tetrahydrate form of formula I.


The present invention also provides a novel process for the synthesis of an intermediate 7-chloro-4-(piperazin-l-yl)quinoline of formula III almost free from dimer impurity by reacting 4,7-dichloroquinoline of formula II with piperazine in water in presence of an aqueous acid at 80-85°C.
The present invention further provides a novel process for the synthesis of piperaquine base from its intermediate 7-chloro-4-(piperazin-l-yl)quinoline of formula III, almost free from dimer impurity, by reacting it with l-bromo-3-chloropropane in the presence of catalysts such as alkali metal halide alone or optionally in the presence of phase transfer catalyst.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel, simple and cost-effective process for the synthesis of 7-chloro-4-(4-(3-(4-(7-chloroquinolin-4-yl) piperazin-1-yl) propyl) piperazin-1-yl) quinoline of compound of formula IV, commonly known as piperquine and is intermediate 7-chloro-4-(piperazin-l-yl)quinoline.

The present invention also relates to an improved process for the synthesis of acid salts of piperaquine such as piperaquine tetraphosphate tetrahydrate of compound of formula I


In an aspect of the present invention there is provided a novel process for the synthesis of piperaquine of formula IV (Scheme II) comprising the steps of,
a reacting 4,7-dichloroquinoline of formula II with piperazine in water in presence of aqueous acid to form an intermediate 7-chloro-4-(piperazin-l-yl)quinoline of formula III at 80-85°C for about 2-4 hours.
b. cooling the reaction mixture of step 'a' to room temperature and
adjusting the pH with a base for precipitation of dimer impurity of
formula V. Isolating the dimer impurity of formula V.
c. isolating intermediate 7-chloro-4-(piperazin-l-yl)quinoline of formula
III having dimer content of less than 0.5% from the aqueous layer by
adjusting the pH to 10-12 with a base followed by extracting with
organic solvent and purifying the crude product by treatment with
acetone.
d. reacting 7-chloro-4-(piperazin-l-yl)quinoline of formula III with 1-
bromo-3-chloropropane in the presence of a base and catalysts such
as alkali metal halide alone or optionally in the presence of phase
transfer catalyst in an organic solvent and isolating the product
piperaquine of formula IV, by treatment with an acid followed by
neutralization with a base and purifying it.

The process of the present invention for the synthesis of piperaquine, its salt and its intermediate is as shown in the Scheme II below

In another aspect of the present invention, there is provided an improved process for the synthesis of piperaquine tetraphosphate tetrahydrate of compound of formula I comprising, reacting piperaquine base of formula IV with 85-90 % pure orthophosphoric acid in presence of an organic solvent alone or in combination with an alcoholic solvent at 25-40X for 2-4hr. followed by cooling and filtering the reaction mixture to obtain piperaquine tetraphosphate salt in tetrahydrate form of formula I.
In another aspect of the present invention there is provided a novel process for the synthesis of an intermediate 7-chloro-4-(piperazin-l-yl)quinoline of formula III by reacting 4,7-dichloroquinoline of formula II with piperazine in water in presence of an aqueous acid at 80-85°C for about 2-4 hours,
After completion of reaction, the product of formula III is isolated by removing the dimmer impurity of formula V by following the above mentioned process step b and

step c. Thus, an intermediate of formula III obtained by process of present invention is almost free from dimmer impurity of formula V.
In yet another aspect of the present invention there is provided a novel process for the synthesis of piperaquine of formula IV from an intermediate of formula III by reacting an intermediate of formula III with l-bromo-3-chloropropane in the presence of a base and catalysts such as alkali metal halide alone or optionally in the presence of phase transfer catalyst in an organic solvent at a temperature of 80-100°C.
The product piperaquine of formula IV is then isolated by treatment with an acid followed by neutralization with a base and purifying it.
In an embodiment of the present invention, the amount of piperazine used with respect to 4,7-dichloroquinoline is 1.0 to 3.5 mole equivalents, preferably it is 2 to 3 mole, more preferably it is 3 moles.
In another embodiment of the present invention, the reaction of step 'a' is carried out for about 2-4 hr., preferably for 2-3 hr.
In another embodiment of the present invention, the amount of water used in the reaction of step 'a' ranges from 8 to 11 volumes, preferably 10 volumes.
The aqueous acid used in the step 'a' reaction is selected from inorganic acid, preferably hydrochloric acid.
In an embodiment of the present invention, pH of the reaction mixture in step 'b' is adjusted to about 3-7, preferably it is 4.5-6.5.

In another embodiment of the present invention, the amount of acetone used in step 'c' ranges from 3 to 4 volume with respect to 4,7-dichloroquinoIine, preferably from 3.3 to 3.6 volumes.
The base used to adjust the pH in step 'b' and step V is selected from alkali metal hydroxide, preferably sodium hydroxide.
In an embodiment of the present invention, the amount of l-bromo-3-chlorpropane used in step £d' ranges from 0.2 to 1 equivalent with respect to compound of formula III, preferably it is 0.4 to 0.6 equivalents.
In another embodiment of the present invention, the base used in step 'd' is selected from alkali metal carbonates such as potassium carbonate, sodium carbonate, magnesium carbonate or calcium carbonate, preferably it is sodium carbonate.
The amount of base used with respect to compound of formula III ranges from 1 to 1.5 equivalents, preferably 1.2 equivalents.
In an embodiment of the present invention, the catalyst alkali metal halide used in step 'd' is preferably sodium iodide.
In another embodiment of the present invention the amount of alkali metal halide used in step 'd' ranges from 1 to 3 wt% with respect to compound of formula III, preferably it is 1%.
In yet another embodiment of the present invention, optionally the reaction of step 'd' is carried out using second catalyst selected from phase transfer catalysts such as quaternary ammonium or phosphonium salts like tetraethylammonium bromide, tetrabutylammonium bromide, benzyl,triphenyl phosphonium chloride, hexadecyl tributyl phosphonium bromide, preferably tetrabutylammonium bromide.

In yet another embodiment of the present invention the organic solvent used in the reaction of step 'd' is selected from alcohols such as methanol, ethanol, n-butanol, 1-propanol, 2-propanol, tert. butanol, preferably 2-propanoJ.
The amount of organic solvent used in the reaction of step 'd' with respect to compound of formula III ranges from 8 to 12 volumes, preferably 9 to 10 volumes.
The reaction of step 'd5 is carried out at a temperature of 80-100°C, preferably at 80-85°C for 20-30 hr, preferably for 25-30 hr.
The product piperaquine of formula IV is purified using organic solvent alone or in combination with another solvent. Organic solvents used for purification in stepcdJ may be selected from halogenated solvents or alcohols. Halogenated solvents may be selected from dichloromethane, dichloroethane, dichloropropane or chloroform, preferably dichloromethane. Alcohols may be selected from methanol, ethanol, n-butanol, 1-propanol, 2-propanol or tert. butanol, preferably methanol or tert. butanol.
Preferably the product piperaquine of formula IV is purified using mixture of organic solvent such as dichloromethane and methanol or dichloromethane and tert. butanol.
The amount of mixed solvent ratio used for purification is in the ratio of 1:1, preferably 1:0.85 to 1:0,95 in relation to the amount of product piperaquine of formula IV.
The mixed solvent used ranges from 5 to 10 volumes in relation to the amount of product piperaquine of formula IV, preferably ranges from 8 to 9 volumes.
In yet another embodiment of the present invention, in the preparation of piperaquine tetraphosphate tetrahydrate of compound of formula I, the amount of

orthophosphoric acid used with respect to pure piperaquine of compound of formula IV, ranging from 4.0 to 5.0 equivalents, preferably 4.0 to 4.5 equivalents.
Organic solvent used in the preparation of piperaquine tetraphosphate tetrahydrate salt is selected from dichloromethane, dichloro ethane, chloroform or dichloropropane, preferably dichloromethane. The said organic solvent used alone or in combination with an alcoholic solvent. Alcoholic solvent is selected from methanol, ethanol, n-butanol, 1-propanol or 2-propanol, preferably methanol.
The reaction of salt formation of piperaquine is carried out at a temperature of 25-40°C, most preferably at 30-35°C for 2-6 hr, preferably for 2-4 hr.
The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.
Example I:
Preparation of 7-chloro-4-(piperazin-l-yI)quinoline
To the stirred solution of piperazine (130gm, l,5091moles) in water (1.0 lit.) was added dilute hydrochloric acid (50%, 500ml) at room temperature. 4,7-dichloroquinoline (l00gm, 0.5049moles) was added to it with stirring and the resulting mixture was heated to 80-85°C. The reaction was maintained at the same temperature for about 2hr. After which time, the reaction mixture was cooled to room temperature and the pH was adjusted to about 5 using dilute NaOH.. The off-white precipitate of dimer impurity of compound of formula V precipitated out. The reaction mixture was filtered to remove the dimer impurity which precipitated out. The precipitates were washed with water (50ml). The aqueous layer was extracted with dichloromethane (300ml). The pH of the aqueous layer was adjusted to 11.5 to 12 with dilute NaOH solution and extracted with dichloromethane (2 X 500ml). The

combined organic layer was washed with water (500ml) and then dried over sodium sulphate. Solvent was distilled out to give crude product 7-chloro-4-(piperazin-l-yl)quinoline. To the product was added acetone (300ml) and the solution was refluxed for about 15-20 minutes. 1 part (100ml) of acetone was distilled out atmospherically and the resulting slurry was cooied to 0-5°C. After about 30 minutes the slurry was filtered and washed with cold acetone (50ml) to obtain pure 7-chloro-4-(piperazin-1 -yl)quinoline. Yield: 100 gm (79.95%) HPLC Purity: 99.88%
Example II:
Preparation of 7-chloro-4-(4-(3-(4-(7-chloroquinolin-4-yl)piperazin-l-
yl)propyl)piperazin-l-yl)quinoline (piperaquine base)
To the stirred slurry of 7-chloro-4-(piperazin-l-yl)quinoline (lOOgm, 0.4036moles) in 2-propanol (500ml) was added sodium carbonate (51.34gm), sodium iodide (lgm), TBAB (2gm) and bromochloropropane (31.78gm, 0.2017moles) at room temperature. The resulting mixture was refluxed for 28hr. After which time,.the reaction mixture was cooled to 0-5°C and stirred for 30-35 minutes. The slurry was filtered and washed with water (100ml). To the wet cake was added water (400ml) and the pH was adjusted to 2 to 3 with dilute HC1 (50%) at room temperature. The slurry was stirred for about 40 minutes. Dilute NaOH solution was added to bring the pH of reaction mixture to about 7.5 to 8.5 and stirred for 40 minutes. After which time, the slurry was filtered and washed with water (400ml) to obtain 7-chloro-4-(4-(3-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)propy l)piperazin-1-y Oquinol ine, piperaquine base of compound of formula IV. Yield: 90.0gm

Purification:
The above crude (90gm) was taken in a mixture of dichloromethane (360ml) and methanol (63ml). Charcoal (lgm) was added to the clear solution and stirred at room temperature for about 30 minutes. The solution was filtered through celite and was washed with mixture of dichloromethane (45 ml) and methanol (8ml). Dichloromethane was distilled out atmospherically at 40-45°C. Methanol (270ml) was added to it and the solution was stirred for 15minutes. One volume of methanol was distilled out at 65°C. The resulting slurry was cooled to 15-20°C and stirred for about 30 minutes and then filtered. The solid obtained was washed with cold methanol (45ml) to obtain pure piperaquine base of compound of formula IV. Yield:84.5gm(78.18%) HPLC Purity: 98.92%
Example HI:
Preparation of piperaquine tetraphosphate tetrahydrate
To the stirred solution of piperaquine base (5gm, 0.0092moles), dichloromethane (20ml, 4.0vol.) was added solution of orthophosphoric acid (88%, 4.1gmJon 100% basis; dissolved in 3ml methanol) at 30-35°C over the period of 30min. Dichloromethane was added in excess to remove the stickiness formed during stirring. After complete addition the reaction mixture was stirred for 2hr at same temperature. After which time, the reaction mass was cooled to 15-20°C for 30 minutes. The resulting slurry was then filtered and washed with dichloromethane (10ml). The material was dried at 55-65°C till the moisture content was 6-8% to get pure piperaquine tetraphosphate tetrahydrate. Yield: 8.5gm (91.35%)

Example IV:
Preparation of piperaquine tetraphosphate tetrahydrate
To the mixture of dichloromethane (20;0ml, 4.0vol.) and methanol (3.0ml, 0.6vol.) was added piperaquine base (5gm, 0.0092moles). Orthophosphoric acid solution (88%, 4.1gm on 100% basis) was added at 30-35°C over the period of 30min. After complete addition, dichloromethane was added in excess and maintained the reaction for 2hr at same temperature. After which time, the reaction mass was cooled to 15-20°C for about 30 minutes. The resulting slurry was filtered and washed with dichloromethane (10ml). The material was dried at 55-65X till the moisture content becomes 6-8% to get pure piperaquine tetraphosphate tetrahydrate. Yield: 8.8gm (94.6%)
Example V:
Preparation of piperaquine tetraphosphate tetrahydrate
To the mixture of dichloromethane (20.0ml, 4.0vol.) and methanol (3.0ml, 0.6vol.) and Orthophosphoric acid (4.1gm, on 100% basis) was added piperaquine base (5gm, 0.0092moles) over a period of 30min. at 30-35°C. After which time was added dichloromethane (20.0ml) and further maintained for 30mia After which time, the reaction mass was cooled to 15-20°C for about 30 minutes. The resulting slurry was filtered and washed with dichloromethane (10ml). The material was dried at 55-65°C till the moisture content becomes 6-8% to get pure piperaquine tetraphosphate tetrahydrate. Yield: 9. lgm (97.8%)

Example VI:
Preparation of piperaquine tetraphosphate tetrahydrate
To the stirred solution of piperaquine base (5gm, 0.0092moles) and dichloromethane (20.0ml, 4.0vol.) was added orthophosphoric acid (4.1gm, on 100% basis) over a period of 30min. at 30-35°C. After which time was added dichloromethane (20.0ml) and further maintained for 2hr. at same temperature. After which time, the reaction mass was cooled to 15-20°C for about 30 minutes. The resulting slurry was filtered and washed with dichloromethane (10ml). The material was dried at 55-65°C till the moisture content becomes 6-8% to get pure piperaquine tetraphosphate tetrahydrate. Yield:7.5gm(80.6%)
Example VII:
Preparation of piperaquine tetraphosphate tetrahydrate
To the stirred solution of orthophosphoric acid (4.1gm, on 100% basis) and dichloromethane (20.0ml, 4.0vol.) was added piperaquine base (5gm, 0.0092moles) over a period of 30min. at 30-35°C. After which time was added dichloromethane (20.0ml) and further maintained for 2hr. at same temperature. The reaction mass was cooled to 15-20°C for about 30 minutes. The resulting slurry was filtered and washed with dichloromethane (10ml). The material was dried at 55-65°C till the moisture content becomes 6-8% to get pure piperaquine tetraphosphate tetrahydrate. Yield:7.6gm(81.7%)

We Claim
1. A novel process for the synthesis of piperaquine of formula IV and its intermediate 7-chloro-4-(piperazin-1 -yl)quinoline of formula III

comprising the steps of,
a. reacting 4,7-dichloroquinoline of formula II

with piperazine in water in presence of aqueous acid to form an intermediate 7-chloro-4-(piperazin-l-yl)quinoIine of formula III at 80-85°C for about 2-4 hours
b. cooling the reaction mixture of step 'a' to the room temperature and
adjusting the pH with a base for precipitation of dimer impurity of formula V. Isolating the dimer impurity of formula V


c. isolating intermediate 7-chloro-4-(piperazin-l-yl)quinoline of formula
III having dimer content of less than 0.5% from the aqueous layer by adjusting the pH to 10-12 with a base followed by extracting with organic solvent and purifying the crude product by treatment with acetone
d. reacting 7-chloro-4-(piperazin-l-yl)quinoline of formula III with 1-
bromo-3-chloropropane in the presence of a base and catalysts such as
alkali metal halide alone or optionally in the presence of phase transfer
catalyst in an organic solvent and isolating the product piperaquine of
formula IV, by treatment with an acid followed by neutralization with
a base and purifying it
2. An improved process for the synthesis of piperaquine tetraphosphate tetrahydrate of formula I

Formula I
comprising reacting piperaquine base of formula IV,


with 85-90 % pure orthophosphoric acid in presence of organic solvent alone or in combination with an alcoholic solvent at 25-40°C for 2-4hr. followed by cooling and filtering the reaction mixture to obtain piperaquine tetraphosphate salt in tetrahydrate form of formula I
3. The process as claimed in claim 1 , wherein the amount of piperazine used with respect to 4,7-dichloroquinoline is 1.0 to 3.5 mole equivalents, preferably 2 to 3 mole, more preferably 3 moles
4. The process as claimed in claim 1, wherein pH of reaction mixture in step 'b' is adjusted to about 3-7, preferably 4.5-6.5
5. The process as claimed in claim 1, wherein a catalyst alkyl halide used in the step'd' is preferably sodium iodide
6. The process as claimed in claim 5, wherein the amount of alkyl halide used with respect to compound of formula III ranges from 1-3 %, preferably 1%
7. The process as claimed in claim 1, wherein phase transfer catalyst used
optionally in step 'd' is selected from quaternary ammonium salt, preferably
tetrabutylammonium bromide

8. The process as claimed in claim 1, wherein the base used in step 'd' is selected from alkali metal carbonates such as potassium carbonate, sodium carbonate, magnesium carbonate or calcium carbonate, preferably is sodium carbonate
9. The process as claimed in claim 1, wherein the organic solvent used in the reaction of step 'd' is selected from alcohols such as methanol, ethanol, n-butanol, 1-propanol, 2-propanol or tert. butanol, preferably 2-propanol
10. The process as claimed in claim 2, wherein the organic solvent used alone or in combination with an alcoholic solvent such as methanol, is selected from dichloromethane, dichloroethane, dichloropropane or chloroform, preferably dichloromethane.