FIELD OF THE INVENTION:

The present invention primarily discloses the process for the preparation of Rupatadine Fumarate Form A.

BACKGROUND OF THE INVENTION:

Rupatadine is a second generation antihistamine and PAF antagonist used to treat allergies. It was discovered and developed by J. Uriach y Cia and is marketed as Rupafin and under several other trade names.
Rupatadine Fumarate has been approved for the treatment of allergic rhinitis and chronic urticaria in adults and children over 12 years. It is available as round, light salmon coloured tablets containing 10 mg of Rupatadine (as fumarate) to be administered orally, once a day
The efficacy of Rupatadine as treatment for allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) has been investigated in adults and adolescents (aged over 12 years) in several controlled studies, showing a rapid onset of action and a good safety profile even in prolonged treatment periods of a year.
Rupatadine is a second generation, non-sedating, long-acting histamine antagonist with selective peripheral H1 receptor antagonist activity. It further blocks the receptors of the platelet-activating factor (PAF) according to in vitro and in vivo studies.
Rupatadine possesses anti-allergic properties such as the inhibition of degranulation of mast cells induced by immunological and non-immunological stimuli, and inhibition of the release of cytokines, particularly of the tumor necrosis factors (TNF) in human mast cells and monocytes.
Rupatadine has several active metabolites such as Desloratadine, 3-hydroxydesloratadine, 6-hydroxydesloratadine and 5-hydroxydesloratadine. Rupatadine discovery, pre-clinical and clinical development was performed by J. Uriach y Cia, a Spanish pharmaceutical company. It was launched in 2003 in Spain under the brand name of Rupafin. The registration of the product is approved in 23 countries from EU, Canada, 8 Central American countries, Brazil, Argentina, Chile, Turkey and 14 African countries.
Rupatadine Fumarate of structural Formula-I chemically named as Fumarate salt of 8-Chloro-11-[1-(5-methylpyridin-3-ylmethyl)-piperidin-4-ylidene]-6,11-dihydro-5H-benzo[5,6]-cyclohepta [1,2-b]pyridine is a potent orally active dual antagonist of platelet-activating factor (PAF) and effect through its interaction with histamine (H1) receptor.
Formula – I.
Various synthetic procedures for the preparation of Rupatadine Fumarate are disclosed in prior art.
EP0577957B1 discloses three different processes for the preparation of Rupatadine and its fumarate salt. One of the processes discloses hydrolytic removal of N-ethoxycarbonyl group of Loratadine to give Desloratadine which is N-acylated with 5-methylnicotinic acid using 1,3-dicyclohexylcabodiimide (DCC) and 1-hydroxybenzotriazole hydrate (HOBT) to give amide derivative, which further reacts with Phosphorus oxychloride (POCl3) and Sodium borohydride (NaBH4) to give Rupatadine Base.
Several approaches were reported for the synthesis of Rupatadine (Formula I). Carceller et al. synthesized Rupatadine by the reaction of Desloratadine with 3-(Bromomethyl)-5-methyl pyridine, which was prepared by the bromination of 3,5-Lutidine. This synthesis furnished Rupatadine in 40% overall yield. A repetition of this reported procedure in our hands revealed that bromination of 3,5-Lutidine yielded mono- and dibromo- compounds along with unreacted 3,5-Lutidine. The poor yield of the mono-bromo compound contributed to the poor overall yield of this synthesis.
In another reported procedure, 5-Methyl nicotinic acid was condensed with Desloratadine to yield amide, which on further treatment with Phosphorous oxychloride/Sodium borohydride furnished Rupatadine. The condensation of 5-methyl nicotinic acid with Desloratadine has been carried out in the presence of 1,3-Dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate. The dicyclohexyl urea generated during this reaction cannot be easily removed during workup and the purification of the impure N-(5-Methyl nicotinyl)-4-hydroxypiperidine leads to loss of overall yield (46.8%). The reaction of 8-Chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine-11-one with 3-[(4-M-piperidin-1-yl)methyl]-5-methylpyridine (where M is -Mg X or -Li; X being a halogen atom) furnished 4-[8-Chloro-6,11-dihydro-11-hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]piperidin-11-yl]-1[(5-methyl-3-pyridinyl) methyl piperidine, which on dehydration yielded Rupatadine in overall yield of 42%.
ES2042421 (which is equivalent to US 5476856, US5407941,ES2076817T3) discloses preparation of Rupatadine which involves bromination of 3,5 Lutidine in Carbon tertachloride using NBS followed by reaction of the product formed with Desloratadine using 4-(dimethylamino)pyridine at room temperature for 18 hours followed by extractive workup using dichloromethane solvent and chromatographic purification to give Rupatadine in 40% yield.
Rupatadine is further converted to different salts like Trihydrochloride, Hemipentafumarate, dioxalate and Hemicitrate using Ethyl acetate and salts formed using corresponding acid in solvent; for hemipentafumarate and citrate salts, the corresponding acids are taken in methanol and for dioxalate salt, oxalic acid is taken in ethyl acetate, while for making trihydrochloride salt, diethyl ether saturated with HCl gas is used. The main drawbacks of this process in the step of preparing Rupatadine are (i) long reaction times of the order of 18 hours; (ii) chromatographic purification used for isolating Rupatadine; (iii) the yield of 40% makes the process commercially unviable.
A process for the preparation of Rupatadine is described in ES2120899 which comprises reacting [8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridine-11-one with 3-[(4-M-substituted piperidin-l-yl)methyl]-5-methylpyridine (where M is MgX or Li; being X, a halogen atom ) to give 4-[8-Chloro 6,11-dihydro-l 1-hydroxy-5H-benzo[5,6]ciclohepta[l,2-b]piperidin-11-yl]-l-[(5-methyl-3- pyridinyl)methyl]piperidine which on dehydration gives Rupatadine. Rupatadine is then transformed into a pharmaceutically acceptable salt. The main drawbacks of the process are:
(i) Long reaction times of 18 hours.
(ii) The reaction product needs to be chromatographed on silica gel to get pure compound.
(iii) The overall yield of 42% (50% for Grignard addition and 84% for dehydration) makes the process commercially unviable.
U.S. Patent No. 6803468 describes a process for the preparation of N-(5- Methylnicotinoyl)-4 hydroxypiperidine - a key intermediate of Rupatadine wherein reaction of 5-methylnicotinic acid with alkyl chloroformate or pivaloyl chloride in a suitable solvent in the presence of an organic base gives corresponding mixed anhydride which reacts with 4-hydroxypiperidine to give N-(5-Methylnicotinoyl)-4 hydroxypiperidine.
The shortcoming of this process is that it involves multi step extractive work-up making it commercially unattractive.
ES 2087818 Al discloses preparation of Rupatadine which involves bromination of 3,5 Lutidine in Carbon tetrachloride using NBS followed by reaction of the product formed with Desloratadine using 4-(Dimethylamino)pyridine at room temperature for 18 hours followed by extractive workup using dichloromethane solvent and chromatographic purification to give Rupatadine in 40% yield. Further, Rupatadine is converted to Rupatadine Fumarate using ethanol solvent in 70 % yield.
The main drawbacks of this process are:
(i) Long reaction times of the order of 18 hours.
(ii) Chromatographic purification used for isolating Rupatadine.
(iii) The yield of 40% makes the process commercially unviable.
It is desirable to minimize the number of reaction steps including chromatographic separations to make the process commercially suitable. The present invention provides a process for preparation of Rupatadine Fumarate without intermediate purification / isolation steps.
Cadila in WO2016114676A2 discloses a process where Rupatadine is synthesized by phase transfer catalyzed N-alkylation of Desloratadine in biphasic solvent system using aqueous alkali by reaction of a compound of formula (A), X= leaving group as -OH -OTs, OMs -OAc -OAr -Br -Cl, -l with Desloratadine at temperature up to 50°C, wherein solvent selected is water immiscible organic solvent. Rupatadine is further converted to Rupatadine fumarate by reaction of Rupatadine in ketonic solvent with an alcoholic solution of fumaric acid.
U.S. Pat. No. 5,407,941 described that Rupatadine obtained (in example 4) is purified using column chromatography and the Rupatadine free base obtained in the process has melting point of 58°-61° C.
Journal of Medicinal Chemistry 1994, 37(17), 2697-2703 described that Rupatadine obtained (page No. 2701) is purified using column chromatography and the Rupatadine free base obtained in the process has melting point of 58°-61 °C.
It has now been found that Rupatadine free base can be obtained in another crystalline form designated as crystalline Form-B. For the sake of convenience, Rupatadine crystalline form obtained in, for example, U.S. Pat. No. 5,407,941, is designated as crystalline Form-A.
It has also been found that no chromatographic purification is required if Rupatadine free base can be isolated as crystalline Form-B from reaction mass comprising Rupatadine.
It has also been found that isolation method of Rupatadine free base as crystalline Form-B can be used for purification of impure Rupatadine free base or a salt thereof.
SUMMARY OF THE INVENTION:
The present invention primarily involves the dissolution of any polymorphic form of 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-enzo[5,6]cyclohepta [1,2-b]pyridine fumarate or Rupatadine Fumarate in a suitable solvent such as Acetone, Isopropyl alcohol, Ethyl acetate or Tetrahydrofuran and other solvents, at elevated temperature followed by cooling to ambient temperature so as to recrystallize the material to give desired polymorphic form A of Rupatadine Fumarate.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a novel process for preparation 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6] cyclohepta [1,2-b]pyridine fumarate or Rupatadine Fumarate Form A is disclosed which comprises (Example 1):
i. stirring any polymorphic form of 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate or Rupatadine Fumarate in an aliphatic ketone which may be selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof;
ii. heating the reaction mass to 50-60 °C and stirring for 1-2 hours to ensure dissolution;
iii. cooling of reaction mass to 20-30 °C;
iv. stirring for 2-4 hours at this temperature to ensure proper crystallization;
v. isolating the product by filtration and providing running washing with aliphatic ketone as used in step i) above; and
vi. drying the wet cake at 50-60 °C for 10-15 hours to get pure 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate polymorphic Form A.
According to the second embodiment of the present invention, a novel process for preparation 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6] cyclohepta [1,2-b]pyridine fumarate or Rupatadine Fumarate Form A is disclosed which comprises (Example 2):
i. stirring any polymorphic form of 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta [1,2-b]pyridine fumarate or Rupatadine Fumarate in a cyclic or acyclic ethers like tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl ether or a mixture thereof;
ii. heating the reaction mass to 60-70 °C and stirring for 1-2 hours to ensure dissolution;
iii. cooling of reaction mass to 20-30 °C;
iv. stirring for 2-4 hours at this temperature to ensure proper crystallization;
v. isolating the product by filtration and providing running washing with cyclic or acyclic ether as used in step i) above; and
vi. drying the wet cake at 50-60 °C for 10-15 hours to get pure 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate polymorphic Form A.

According to the third embodiment of the present invention, a novel process for preparation 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6] cyclohepta [1,2-b]pyridine fumarate or Rupatadine Fumarate Form A is disclosed which comprises (Example 3):
i. stirring any polymorphic form of 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridinefumarate or Rupatadine Fumarate in a C1-C3 aliphatic ester, e.g. ethyl acetate, propyl acetate, butyl acetate or a mixture thereof;
ii. heating the reaction mass to 70-80 °C and stirring for 2-3 hours to ensure dissolution;
iii. cooling of reaction mass to 20-30 °C;
iv. stirring for 2-4 hours at this temperature to ensure proper crystallization;
v. isolating the product by filtration and providing running washing in a C1-C3 aliphatic ester as used in step i) above; and
vi. drying the wet cake at 50-60 °C for 10-15 hours to get pure 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate polymorphic Form A.
According to the fourth embodiment of the present invention, a novel process for the preparation 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6] cyclohepta [1,2-b]pyridine fumarate or Rupatadine Fumarate Form A is disclosed which comprises (Example 4):
i. stirring any polymorphic form of 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridinefumarate or Rupatadine Fumarate in an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof;
ii. heating the reaction mass to 70-80 °C and stirring for 2-3 hours to ensure dissolution;
iii. cooling of reaction mass to 20-30 °C;
iv. stirring for 2-4 hours at this temperature to ensure proper crystallization;
v. isolating the product by filtration and providing running washing in an aliphatic alcohol as used in step i) above; and
vi. drying the wet cake at 50-60 °C for 10-15 hours to get pure 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate polymorphic Form A.
According to the fifth embodiment of the present invention, a novel process for preparation 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6] cyclohepta[1,2-b]pyridine fumarate or Rupatadine Fumarate Form A is disclosed which comprises (Example 5):
i. stirring any polymorphic form of 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridinefumarate or Rupatadine Fumarate in a mixture of aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol and aliphatic amide like N,N-Dimethylformamide & N,N-Dimethylacetamide or a mixture thereof;
ii. heating the reaction mass to 70-80 °C and stirring for 2-3 hours to ensure dissolution;
iii. cooling of reaction mass to 20-30 °C;
iv. stirring for 2-4 hours at this temperature to ensure proper crystallization;
v. isolating the product by filtration and providing running washing with an aliphatic alcohol as used in step i) above; and
vi. drying the wet cake at 50-60 °C for 10-15 hours to get pure 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate polymorphic Form A.
The above-mentioned invention is supported by the following non-limiting examples.
EXAMPLES:
Example 1: 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate (100 g) is taken in Acetone (300 ml) and the reaction mass is heated to 50-60 °C. The reaction mass is then stirred for 1-2 hours to ensure proper dissolution. It is then cooled to 20-30 °C and stirred for 2-4 hours. The resulting solid is isolated by filtration and given running washing with acetone (50 ml). The wet cake is dried at 50-60 °C for 10-15 hours to get 80 g of the product 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate Polymorphic Form A (HPLC purity= 99.84%) having XRD as per figure 1.
Example 2: 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate (100 g) is taken in Tetrahydrofuran (300 ml) and the reaction mass is heated to 60-70 °C. The reaction mass is thereafter stirred for 1-2 hours to ensure proper dissolution. It is then cooled to 20-30 °C and stirred for 2-4 hours. The resulting solid is isolated by filtration and given running washing with tetrahydrofuran (50 ml). The wet cake is dried at 50-60 °C for 10-15 hours to get 81 g of the product 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclo hepta[1,2-b] pyridine fumarate or Rupatadine Fumarate Polymorphic Form A (HPLC purity= 99.90%) having XRD as per figure 1.
Example 3: 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate (100 g) is taken in Ethyl acetate (300 ml) and the reaction mass is heated to 70-80 °C. The reaction mass is then stirred for 2-3 hours to ensure proper dissolution. It is then cooled to 20-30 °C and stirred for 2-4 hours. The resulting solid is isolated by filtration and given running washing with Ethyl acetate (50 ml). The wet cake is dried at 50-60 °C for 10-15 hours to get 88 g of the product 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta [1,2-b]pyridine fumarate or Rupatadine Fumarate Polymorphic Form A (HPLC purity= 99.87%) having XRD as per figure 1.
Example 4: 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate (100 g) is taken in Isopropylalcohol or 2-propanol (500 ml) and the reaction mass is heated to 70-80 °C. The reaction mass is then stirred for 2-3 hours to ensure proper dissolution. It is then cooled to 20-30 °C and stirred for 2-4 hours. The resulting solid is isolated by filtration and given running washing with Isopropylalcohol or 2-propanol (50 ml). The wet cake is dried at 50-60 °C for 10-15 hours to get 80 g of the product 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclo hepta[1,2-b] pyridine fumarate or Rupatadine Fumarate Polymorphic Form A (HPLC purity= 99.83%) having XRD as per figure 1.
Example 5: 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate (100 g) is taken in Methanol (500 ml) and the reaction mass is heated to 70-80 °C. The reaction mass is then stirred for 2-3 hours to ensure proper dissolution. It is thereafter cooled to 20-30 °C and stirred for 2-4 hours. The resulting solid is isolated by filtration and given running washing with Methanol (50 ml). The wet cake is dried at 50-60 °C for 10-15 hours to get 80 g of the product 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclo hepta[1,2-b] pyridine fumarate or Rupatadine Fumarate Polymorphic Form A (HPLC purity > 99.50%) having XRD as per figure 1.

Example 6: 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate (100 g) is taken in a mixture of Methanol (600 ml) and N,N-Dimethylformamide (200 ml); and the reaction mass is heated to 70-80 °C. The reaction mass is stirred for 2-3 hours to ensure proper dissolution. It is then cooled to 20-30°C and stirred for 2-4 hours. The resulting solid is isolated by filtration and given running washing with Methanol (50 ml). The wet cake is dried at 50-60 °C for 10-15 hours to get 80 g of the product 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate Polymorphic Form A (HPLC purity > 99.50%) having XRD as per figure 1.

We Claim:

1. A novel process for preparation of 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6] cyclohepta [1,2-b]pyridine fumarate or Rupatadine Fumarate Polymorphic Form A which comprises:
a) dissolving any polymorphic form of 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate or Rupatadine Fumarate in a solvent;
b) stirring and heating the reaction mass at a particular temperature for 1-2 hours to ensure complete dissolution;
c) cooling of reaction mass to 20-30 °C;
d) further stirring the reaction mass for 2-4 hours to ensure complete crystallization;
e) isolating the desired product as wet cake by filtration;
f) washing the wet cake with running solvent as used in step a); and
g) drying of wet cake under vacuum at 50-60 °C for 10-15 hours to get pure 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6] cyclohepta[1,2-b] pyridine fumarate or Rupatadine Fumarate polymorphic Form A as product.

2. The process as claimed in claim 1 wherein the solvent used in step a) and f) is an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof and the temperature of dissolution in step b) is 50-60°C.

3. The process as claimed in claim 1 wherein the solvent used in step a) and f) is a cyclic or acyclic ether selected from tetrahydrofuran, dioxane, diisopropyl ether, tert-butyl methyl ether or a mixture thereof and the temperature of dissolution in step b) is 60-70°C.

4. The process as claimed in claim 1 wherein the solvent used in step a) and f) is a C1-C3 aliphatic ester selected from ethyl acetate, propyl acetate, butyl acetate or a mixture thereof and the temperature of dissolution in step b) is 70-80°C.

5. The process as claimed in claim 1 wherein the solvent used in step a) and f) is an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof and the temperature of dissolution in step b) is 70-80°C.

6. The process as claimed in claim 1 wherein the solvent used in step a) and f) is a mixture of aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol and a aliphatic amide selected from N,N-Dimethylformamide and N,N-Dimethylacetamide and the temperature of dissolution in step b) is 70-80°C.